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Query Topic: IL6

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necrosis factor alpha(28)

A 192 bp ERV fragment insertion in the first intron of porcine TLR6 may act as an enhancer associated with the increased expressions of TLR6 and TLR1.
Toll-like receptors (TLRs) play important roles in building innate immune and inducing adaptive immune responses. Associations of the TLR genes polymorphisms with disease susceptibility, which are the basis of molecular breeding for disease resistant animals, have been reported extensively. Retrotransposon insertion polymorphisms (RIPs), as a new type of molecular markers developed recently, have great potential in population genetics and quantitative trait locus mapping. In this study, bioinformatic prediction combined with PCR-based amplification was employed to screen for RIPs in porcine TLR genes. Their population distribution was examined, and for one RIP the impact on gene activity and phenotype was further evaluated. Five RIPs, located at the 3' flank of TLR3, 5' flank of TLR5, intron 1 of TLR6, intron 1 of TLR7, and 3' flank of TLR8 respectively, were identified. These RIPs were detected in different breeds with an uneven distribution among them. By using the dual luciferase activity assay a 192 bp endogenous retrovirus (ERV) in the intron 1 of TLR6 was shown to act as an enhancer increasing the activities of TLR6 putative promoter and two mini-promoters. Furthermore, real-time quantitative polymerase chain reaction (qPCR) analysis revealed significant association (p < 0.05) of the ERV insertion with increased mRNA expression of TLR6, the neighboring gene TLR1, and genes downstream in the TLR signaling pathway such as MyD88 (Myeloid differentiation factor 88), Rac1 (Rac family small GTPase 1), TIRAP (TIR domain containing adaptor protein), Tollip (Toll interacting protein) as well as the inflammatory factors IL6 (Interleukin 6), IL8 (Interleukin 8), and TNFα (Tumor necrosis factor alpha) in tissues of 30 day-old piglet. In addition, serum IL6 and TNFα concentrations were also significantly upregulated by the ERV insertion (p < 0.05). A total of five RIPs were identified in five different TLR loci. The 192 bp ERV insertion in the first intron of TLR6 was associated with higher expression of TLR6, TLR1, and several genes downstream in the signaling cascade. Thus, the ERV insertion may act as an enhancer affecting regulation of the TLR signaling pathways, and can be potentially applied in breeding of disease resistant animals.
Publication Date: 2021-08-20
Journal: Mobile DNA

tumor necrosis factor-α(26)

[Protective effects of Lonicerae Japonicae Flos against acute alcoholic liver injury in rats based on network pharmacology].
This study aims to explore underlying mechanism of Lonicerae Japonicae Flos(LJF) in protecting rats against acute alcoholic liver injury(ALI) based on mitogen-activated protein kinase(MAPK) pathway. First, the targets of LJF in preventing ALI were predicted by network pharmacology and the component-target-pathway network was constructed, so that the key targets of LJF components acting on MAPK pathway were screened. Second, male SD rats were randomized into the control(KB) group, model(MX) group, positive(YX) group, and LJF high-(GJ), medium-(ZJ), and low-(DJ) dose groups. Each administration group was given(ig) corresponding drugs for 7 days and KB group and MX group received(ig) equal volume of distilled water every day. Except for KB group, rats were given Chinese spirit(56%, 3 days) for ALI modeling. The levels of aspartate transaminase(AST), alanine transaminase(ALT), interleukin-6(IL6) and tumor necrosis factor-α(TNF-α) in serum and malondialdehyde(MDA), glutathione(GSH), superoxide dismutase(SOD) and glutathione peroxidase(GSH-Px) in liver tissue of rats in each group were detected. Furthermore, we employed quantitative real-time PCR(qRT-PCR) to probe the effects of LJF on the key targets of MAPK pathway in ALI rats. A total of 28 active components of LJF were screened from TCMSP database, and 317 intersected with ALI-related targets. According to Kyoto encyclopedia of genes and genomes(KEGG) pathway enrichment analysis, the 317 targets involved 226 pathways, which were mainly liver disease, inflammation, immunity, apoptosis and other related pathways. According to the MAPK pathway-target-active component network, the key active components of LJF, such as chlorogenic acid, hederagenol, and hyperoside, acted on 25 key targets of MAPK pathway. The results of in vivo experiments showed decreased levels of AST, ALT, and MDA in DJ, ZJ, and GJ groups(P<0.01 or P<0.05), reduced levels of IL6 in DJ and GJ groups(P<0.01 or P<0.05), and improved levels of SOD and GSH in ZJ and GJ groups(P<0.01 or P<0.05). The results of qRT-PCR demonstrated that the expression levels of mitogen-activated protein kinase kinase 4(MAPK2 K4) and mitogen-activated protein kinase 3(MAPK3) were decreased in DJ, ZJ, and GJ groups(P<0.01). The network pharmacology and experimental verification showed that the active components in LJF can reduce the inflammatory factor level and enhance the activities of SOD and GSH-Px by inhibiting the expression of key targets of MAPK pathway, thus alleviating and preventing liver damage caused by alcohol.
Publication Date: 2021-09-29
Journal: Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica

necrosis factor tnf(21)

Dynamics of local gene regulations in synovial fluid leukocytes from horses with lipopolysaccharide-induced arthritis.
The role of resident cells such a synoviocytes and chondrocytes in intra-articular inflammation is well-characterized, however the in vivo gene expression patterns of cells (predominantly leukocytes) in the synovial fluid (SF) of an inflamed joint have never previously been investigated. The aim of this study was to investigate gene expression in SF leukocytes from the inflamed joint cavity after intra-articular lipopolysaccharide (LPS) injection in horses to improve our understanding of the temporal regulation of the intra-articular inflammatory response. Gene expression was investigated in SF samples available from six horses 2, 4, 8 16 and 24 h after experimental induction of inflammation in the radiocarpal joint by lipopolysaccharide (LPS) injection. Leukocytic expression of 43 inflammation-related genes was studied using microfluidic high throughput qPCR (Fluidigm®). Expression of 26 genes changed significantly over the 24 h study period, including pro- and anti-inflammatory genes such as interleukin (IL)1, IL6, tumor necrosis factor (TNF), cyclooxygenase 2 (COX2), IL1 receptor antagonist (IL1RN), IL10, and superoxide dismutase 2 (SOD2), chemokine genes, apoptosis-related genes, and genes related to cartilage turnover (matrix metalloproteinase 8 and tissue inhibitor of metalloproteinase 1). The inflammatory responses appeared to be regulated, as an early increase (at 2 h) in expression of the pro-inflammatory genes IL1, IL6, TNF and COX2 was rapidly followed by increased expression (at 4 h) of several anti-inflammatory genes (IL10, IL1RN and SOD2). Similarly, both pro- and anti-apoptotic gene expression as well as expression of chondrodegenerative and chondroprotective genes were activated in SF leukocytes. Thus, the inflammatory response in leukocytes infiltrating the joint in the acute stage of arthritis was well orchestrated in this single-hit LPS-induced arthritis model. This study is the first to describe gene expression patterns in SF-derived leukocytes in vivo during severe joint inflammation, and the results thus expand our knowledge of basic inflammatory mechanisms in the early local response in an inflamed joint.
Publication Date: 2021-09-26
Journal: Veterinary immunology and immunopathology

polymerase chain reaction(19)

Serum MMP3 Correlated With IL1β Messenger RNA Expressions of Peripheral Blood Mononuclear Cells in Patients With Relapsing Polychondritis With Respiratory Involvement.
Respiratory involvement was intimately associated with poorer prognosis in patients with relapsing polychondritis (RP). We previously reported that high serum matrix metalloproteinase-3 (MMP3) was frequently observed in patients with RP with respiratory involvement. Elevated MMP3 secreted through local inflammation may be associated with the development of airway lesions. We collected peripheral blood mononuclear cells (PBMCs) and sera from 30 patients with RP and 14 healthy individuals. Interleukin (IL) 1β, IL6, and tumor necrosis factor (TNF) α messenger RNA (mRNA) expressions were analyzed in freshly isolated and cultured PBMCs with phytohemagglutinin and phorbol myristate acetate stimulation by real-time reverse transcription polymerase chain reaction and serum MMP3 by enzyme-linked immunosorbent assay (ELISA). We confirmed our previous finding that patients with respiratory involvements showed higher serum MMP3 compared with patients lacking respiratory involvement. IL1β mRNA expression was significantly higher in patients with RP than in healthy individuals after mitogenic stimulation. TNFα mRNA expression after stimulation was significantly lower in patients with RP compared with in healthy individuals. We performed correlation analyses between MMP3 and cytokine mRNA expressions in patients with RP. In patients with respiratory involvement, MMP3 correlated with IL1β and IL6 after stimulation. In patients without respiratory involvement, no positive correlations between MMP3 and cytokine mRNA expressions were observed regardless of culture condition. We did not find any positive correlations between MMP3 and TNFα mRNA expression in patients with RP. It is possible that IL1β mRNA expression associates by some means with airway inflammation via the secretion of MMP3 in patients with RP. Involvement of proinflammatory cytokines, including IL1β, was suggested for the pathophysiology of airway lesions in patients with RP.
Publication Date: 2021-07-22
Journal: ACR open rheumatology

interleukin 1 beta(12)

Overexpression of the receptor for advanced glycation end-products in the auditory cortex of rats with noise-induced hearing loss.
The receptor for advanced glycation end-products (RAGE) is involved in neuroinflammation. This study investigated the changes in RAGE expression following noise-induced hearing loss. Three-week-old female Sprague-Dawley rats were exposed to 115 dB SPL white noise for 4 h daily for 3 d (noise group, n = 16). In parallel, age and sex-matched control rats were raised under standard conditions without noise exposure (control group, n = 16). After 2 h (noise immediate, n = 8) and 4 wk (noise 4-week, n = 8) of noise exposure, the auditory cortex was harvested and cytoplasmic and nuclear fractions were isolated. The gene expression levels of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL6), interleukin 1 beta (IL1β), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and RAGE were evaluated using real-time reverse transcription polymerase chain reaction. The protein expression levels of nuclear RAGE and cytosolic RAGE were evaluated using western blotting. Additionally, matrix metalloproteinase 9 (MMP9) was pharmacologically inhibited in the noise immediate group, and then nuclear and cytosolic RAGE expression levels were evaluated. The noise immediate and noise 4-week groups exhibited increased auditory thresholds at 4, 8, 16, and 32 kHz frequencies. The genes encoding the pro-inflammatory cytokines TNF-α, IL6, IL1β, and NF- κB were increased 3.74, 1.63, 6.42, and 6.23-fold in the noise immediate group, respectively (P = 0.047, 0.043, 0.044, and 0.041). RAGE mRNA expression was elevated 1.42-fold in the noise 4-week group (P = 0.032). Cytosolic RAGE expression was increased 1.76 and 6.99-fold in the noise immediate and noise 4-week groups, respectively (P = 0.04 and 0.03). Nuclear RAGE expression was comparable between the noise and control groups. matrix metalloproteinase 9 (MMP9) inhibition reduced cytosolic RAGE expression in the noise immediate group (P = 0.004). Noise exposure increased the expression of cytosolic RAGE in the auditory cortex and upregulated pro-inflammatory genes, but this response could be alleviated by MMP9 inhibition.
Publication Date: 2021-05-23
Journal: BMC neuroscience

interleukin-6 il6(90)

Cytochrome P450-2D6: A novel biomarker in liver cancer health disparity.
Liver cancer morbidity and mortality rates differ among ethnic groups. In the United States, the burden of liver cancer in Asian Americans (AS) is higher compared to Caucasian Americans (CA). Research on liver cancer health disparities has mainly focused on environmental and socioeconomic factors yet has ignored the genotypic differences among various racial/ethnic groups. This lack of molecular level understanding has hindered the development of personalized medical approaches for liver cancer treatment. To understand the genetic heterogeneity of liver cancer between AS and CA, we performed a systematic analysis of RNA-seq data of AS and CA patients from The Cancer Genome Atlas (TCGA). We used four differential gene expression analysis packages; DESeq2, limma, edgeR, and Superdelta2, to identify the differentially expressed genes. Our analysis identified cytochrome P450-2D6 enzyme (CYP2D6) as the gene with the greatest differential expression with higher levels in AS compared to CA. To scrutinize the underlying mechanism of CYP2D6, Ingenuity Pathway Analysis (IPA) and Cytoscape were conducted and found hepatocyte nuclear factor-4α (HNF4A) and interleukin-6 (IL6) in direct association with CYP2D6. IL6 is downregulated in AS compared to CA, while HNF4A is not significantly different. Herein, we report that CYP2D6 may serve as a putative biomarker in liver cancer health disparities. Its negative association with IL6 proclaims an intricate relationship between CYP2D6 and inflammation in the ethnic differences seen in AS and CA liver cancer patients. The goal of the present study was to understand how genetic factors may contribute to the interethnic variability of liver cancer prevalence and outcomes in AS and CA patients. Identifying ethnic-specific genes may help ameliorate detection, diagnosis, surveillance, and treatments of liver cancer, as well as reduce disease-related incidence and mortality rates in the vulnerable population.
Publication Date: 2021-10-02
Journal: PloS one

pro-inflammatory cytokines(71)

Mild Traumatic Brain Injury Contributes to the Development of Delayed Neuroinflammation.
In recent years, according to the literature, the problem of mild traumatic brain injury (mTBI) has become more and more urgent. Compared to moderate to severe craniocerebral trauma, mTBI occurs in a far greater number of people. The delayed sequelae caused by a single mTBI or multiple mTBIs are a significant public health problem. A weight-drop model was used for the formation of mTBI. A metal rod weighing 337 g with a blunt tip of 3 mm diameter was uplifted at 8 cm height and held by a lever. The trauma was created by lowering the lever and the rod and free-dropping onto the rat skull. In the cerebral cortex of experimental animals, we analyzed the level of microglial activity (Iba-1-positive system) and the expression of pro-inflammatory markers (IL1β, IL6, and CD86). Also, the expression level of the endocannabinoid system receptor (cannabinoid receptor type 1 [CB1]) was assessed in brain samples. Experiments have shown that mTBI increases (1) the amount of microglia (iba-1) activated by the pro-inflammatory pathway (CD86); (2) the level of pro-inflammatory cytokines IL1β and IL6; and (3) CB1R activity. Overall, the results of this study indicate that mTBI induces a sustained neuroinflammatory response.
Publication Date: 2021-09-29
Journal: Neuroimmunomodulation

il6 il10(62)

Mechanisms of Immunomodulation and Cytoprotection Conferred to Pancreatic Islet by Human Amniotic Epithelial Cells.
Inhibiting pro-inflammatory cytokine activity can reverse inflammation mediated dysfunction of islet grafts. Human amniotic epithelial cells (hAECs) possess regenerative, immunomodulatory and anti-inflammatory properties. We hypothesized that hAECs could protect islets from cellular damage induced by pro-inflammatory cytokines. To verify our hypothesis, hAEC monocultures, rat islets (RI), or RI-hAEC co-cultures where exposed to a pro-inflammatory cytokine cocktail (Interferon γ: IFN-γ, Tumor necrosis factor α: TNF-α and Interleukin-1β: IL-1β). The secretion of anti-inflammatory cytokines and gene expression changes in hAECs and viability and function of RI were evaluated. The expression of non-classical Major Histocompatibility Complex (MHC) class I molecules by hAECs cultured with various IFN-γ concentrations were assessed. Exposure to the pro-inflammatory cocktail significantly increased the secretion of the anti-inflammatory cytokines IL6, IL10 and G-CSF by hAECs, which was confirmed by upregulation of IL6, and IL10 gene expression. HLA-G, HLA-E and PDL-1 gene expression was also increased. This correlated with an upregulation of STAT1, STAT3 and NF-κB1gene expression levels. RI co-cultured with hAECs maintained normal function after cytokine exposure compared to RI cultured alone, and showed significantly lower apoptosis rate. Our results show that exposure to pro-inflammatory cytokines stimulates secretion of anti-inflammatory and immunomodulatory factors by hAECs through the JAK1/2 - STAT1/3 and the NF-κB1 pathways, which in turn protects islets against inflammation-induced damages. Integrating hAECs in islet transplants appears as a valuable strategy to achieve to inhibit inflammation mediated islet damage, prolong islet survival, improve their engraftment and achieve local immune protection allowing reducing systemic immunosuppressive regimens. This study focuses on the cytoprotective effect of isolated hAECs on islets exposed to pro-inflammatory cytokines in vitro. Exposure to pro-inflammatory cytokines stimulated secretion of anti-inflammatory and immunomodulatory factors by hAECs putatively through the JAK1/2 - STAT1/3 and the NF-κB1 pathways. This had protective effect on islets against inflammation-induced damages. Taken together our results indicate that incorporating hAECs in islet transplants could be a valuable strategy to inhibit inflammation mediated islet damage, prolong islet survival, improve their engraftment and achieve local immune protection allowing to reduce systemic immunosuppressive regimens.
Publication Date: 2021-10-07
Journal: Stem cell reviews and reports

growth factor(47)

Integrative analysis of potential biomarkers and immune cell infiltration in Parkinson's disease.
Parkinson's disease (PD) is a common neurodegenerative disease in the elderly population. However, there are no reliable diagnostic biomarkers for PD, and the pathogenesis of PD still needs further study. The aim of the current study was to identify potential biomarkers and explore the pathogenesis of PD. We conducted an integrative analysis of messenger RNA (mRNA), microRNA (miRNA), and long noncoding RNA (lncRNA) expression profiles of PD using data from the Gene Expression Omnibus (GEO). The GSE110720, GSE110719 and GSE133347 data sets were selected and analysed. Gene ontology (GO) enrichment and gene set variation analysis (GSVA) were performed for annotation, visualization, and integrated discovery. Protein-protein interaction (PPI) and competing endogenous RNA (ceRNA) networks were constructed, and hub genes were identified. Meanwhile, the immune infiltration analysis of hub genes was analysed. Moreover, receiver operating characteristic (ROC) curves were generated to verify the diagnostic value of the differentially expressed genes (DEGs). Finally, the genes with high area under the curve (AUC) values were verified by human samples. We identified 464 DEGs closely related to PD, including 154 mRNAs, 134 miRNAs, and 176 lncRNAs. The GO analyses indicated that changes in PD were mainly enriched in receptor ligand activity and cytokine receptor binding. The KEGG enrichment analysis showed that these DEGs were significantly involved in cytokine-cytokine receptor interactions, signalling pathways regulating the pluripotency of stem cells and Th17 cell differentiation. GSVA suggested that growth factor binding, IL2-stat5 signalling, and IL6-jak-stat3 signalling were crucial in the development of PD. A total of five hub genes (NPBWR2, CXCL10, CXCL5, S1PR5, and GALR1) were selected via the PPI network. A ceRNA network of the CXCL5, CXCL10 and S1PR5 genes was constructed, and target genes of the three genes were screened. The immune infiltration analysis showed that there were significant differences in a variety of immune cells between the hub genes. The expression of DEGs was validated in clinical human samples by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The expression levels of hsa-miR6895-5p, hsa-miR6791-5p, hsa-miR518f-5p, hsa-miR455-3p and TEKT4P2 were decreased, while the levels of TPTE2P6 were increased in human samples. These findings are consistent with the bioinformatics analysis results. We found that the immune inflammatory response and immune cell regulation were involved in the pathogenesis of PD. Five hub genes involved in the immune infiltration biological processes of PD based on bioinformatics. We verified the DEGs with significant differences by qRT-PCR. These findings might provide new insight into the pathogenesis of PD and the development of diagnostic and therapeutic strategies for PD.
Publication Date: 2021-09-19
Journal: Brain research bulletin

signaling pathway(46)

The calcium-binding protein S100B reduces IL6 production in malignant melanoma via inhibition of RSK cellular signaling.
S100B is frequently elevated in malignant melanoma. A regulatory mechanism was uncovered here in which elevated S100B lowers mRNA and secreted protein levels of interleukin-6 (IL6) and inhibits an autocrine loop whereby IL6 activates STAT3 signaling. Our results showed that S100B affects IL6 expression transcriptionally. S100B was shown to form a calcium-dependent protein complex with the p90 ribosomal S6 kinase (RSK), which in turn sequesters RSK into the cytoplasm. Consistently, S100B inhibition was found to restore phosphorylation of a nuclear located RSK substrate, CREB, which is a potent transcription factor for IL6 expression. Thus, elevated S100B reduces IL6-STAT3 signaling via RSK signaling pathway in malignant melanoma. Indeed, the elevated S100B levels in malignant melanoma cell lines correspond to low levels of IL6 and p-STAT3.
Publication Date: 2021-08-20
Journal: PloS one

proinflammatory cytokines(42)

Bee Venom Alleviated Edema and Pain in Monosodium Urate Crystals-Induced Gouty Arthritis in Rat by Inhibiting Inflammation.
Bee venom (BV) acupuncture has anti-inflammatory and analgesic effects; therefore, it was used as a traditional Korean medicine for various musculoskeletal disorders, especially arthritis. In this study, we investigated the effect of BV on monosodium urate (MSU) crystal-induced acute gouty rats. An intra-articular injection of MSU crystal suspension (1.25 mg/site) was administered to the tibiotarsal joint of the hind paw of Sprague Dawley rats to induce MSU crystal-induced gouty arthritis. Colchicine (30 mg/kg) was orally administered 1 h before MSU crystal injection as a positive control, and BV (0.5 mg/kg) was injected into the tibiotarsal joint immediately after MSU crystal injection. The ankle thickness, mechanical allodynia, and expression of proinflammatory cytokines (TNF-α, IL-1β, IL6, COX2 and iNOS) and chemokines (MIP-1α, MIP-1β, MCP-1, GRO-α, MIP-2α) were then evaluated. BV reduced the expression of proinflammatory cytokines and chemokines, which are important mediators of MSU crystal-induced inflammatory responses. This anti-inflammatory effect was also confirmed histologically to attenuate synovitis and neutrophil infiltration. We demonstrated that BV markedly ameliorated ankle edema and mechanical allodynia in gouty rats. These results suggest that BV acupuncture is a potential clinical therapy for acute gouty management.
Publication Date: 2021-09-27
Journal: Toxins

il6 levels(37)

Skin-brain axis signaling mediates behavioral changes after skin wounding.
Patients with chronic wounds often have associated cognitive dysfunction and depression with an as yet unknown mechanism for this association. To address the possible causality of skin wounding inducing these changes, behavior and cognitive functions of female C57BL/6 mice with an excisional skin wound were compared to unwounded animals. At six days post wounding, animals exhibited anxiety-like behaviors, impaired recognition memory, and impaired coping behavior. Wounded animals also had concomitant increased hippocampal expression of Tnfa, the pattern recognition receptor (PRR) Nod2, the glucocorticoid receptors GR/Nr3c1 and Nr3c2. Prefrontal cortex serotonin and dopamine turnover were increased on day six post-wounding. In contrast to the central nervous system (CNS) findings, day six post -wounding serum catecholamines did not differ between wounded and unwounded animals, nor did levels of the stress hormone corticosterone, TNFα, or TGFβ. Serum IL6 levels were, however elevated in the wounded animals. These findings provide evidence of skin-to-brain signaling, mediated either by elevated serum IL6 or a direct neuronal signaling from the periphery to the CNS, independent of systemic mediators. Wounding in the periphery is associated with an altered expression of inflammatory mediators and PRR genes in the hippocampus, which may be responsible for the observed behavioral deficits.
Publication Date: 2021-10-01
Journal: Brain, behavior, & immunity - health

significantly increased(36)

Heterogeneity of Melanoma Cell Responses to Sleep Apnea-Derived Plasma Exosomes and to Intermittent Hypoxia.
Obstructive sleep apnea (OSA) is associated with increased cutaneous melanoma incidence and adverse outcomes. Exosomes are secreted by most cells, and play a role in OSA-associated tumor progression and metastasis. We aimed to study the effects of plasma exosomes from OSA patients before and after adherent treatment with continuous positive airway pressure (CPAP) on melanoma cells lines, and also to identify exosomal miRNAs from melanoma cells exposed to intermittent hypoxia (IH) or normoxia. Plasma-derived exosomes were isolated from moderate-to-severe OSA patients before (V1) and after (V2) adherent CPAP treatment for one year. Exosomes were co-incubated with three3 different melanoma cell lines (CRL 1424; CRL 1619; CRL 1675) that are characterized by genotypes involving different mutations in BRAF, STK11, CDKN2A, and PTEN genes to assess the effect of exosomes on cell proliferation and migration, as well as on pAMK activity in the presence or absence of a chemical activator. Subsequently, CRL-1424 and CRL-1675 cells were exposed to intermittent hypoxia (IH) and normoxia, and exosomal miRNAs were identified followed by GO and KEG pathways and gene networks. The exosomes from these IH-exposed melanoma cells were also administered to THP1 macrophages to examine changes in M1 and M2 polarity markers. Plasma exosomes from V1 increased CRL-1424 melanoma cell proliferation and migration compared to V2, but not the other two cell lines. Exposure to CRL-1424 exosomes reduced pAMPK/tAMPK in V1 compared to V2, and treatment with AMPK activator reversed the effects. Unique exosomal miRNAs profiles were identified for CRL-1424 and CRL-1675 in IH compared to normoxia, with six miRNAs being regulated and several KEGG pathways were identified. Two M1 markers (CXCL10 and IL6) were significantly increased in monocytes when treated with exosomes from IH-exposed CRL-1424 and CRL-1625 cells. Our findings suggest that exosomes from untreated OSA patients increase CRL-1424 melanoma malignant properties, an effect that is not observed in two other melanoma cell lines. Exosomal cargo from CRL-1424 cells showed a unique miRNA signature compared to CRL-1675 cells after IH exposures, suggesting that melanoma cells are differentially susceptible to IH, even if they retain similar effects on immune cell polarity. It is postulated that mutations in STK-11 gene encoding for the serine/threonine kinase family that acts as a tumor suppressor may underlie susceptibility to IH-induced metabolic dysfunction, as illustrated by CRL-1424 cells.
Publication Date: 2021-10-14
Journal: Cancers

inflammatory response(32)

Combination therapy of tanshinone IIA and puerarin for pulmonary fibrosis via targeting IL6-JAK2-STAT3/STAT1 signaling pathways.
Efficient therapy of idiopathic pulmonary fibrosis (IPF) is still a major challenge. The current studies with single-target drug therapy are the pessimistic approaches due to the complex characteristics of IPF. Here, a combination therapy of Tanshinone IIA and Puerarin for IPF was proposed to alleviate IPF due to their antiinflammatory and anti-fibrotic effects. In vivo, the combination therapy could significantly attenuate the area of ground glass opacification that was presented by 85% percentile density score of the micro-CT images when compared to single conditions. In addition, the combination therapy enormously improved the survival rate and alleviated pathological changes in bleomycin (BLM)-induced IPF mice. By using a wide spectrum of infiltration biomarkers in immunofluorescence assay in pathological sections, we demonstrate that fewer IL6 related macrophage infiltration and fibrosis area after this combination therapy, and further proved that IL6-JAK2-STAT3/STAT1 is the key mechanism of the combination therapy. In vitro, combination therapy markedly inhibited the fibroblasts activation and migration which was induced by TGF-β1 or/and IL6 through JAK2-STAT3/STAT1 signaling pathway. This study demonstrated that combination therapeutic effect of TanIIA and Pue on IPF may be related to the reduced inflammatory response targeting IL6, which could be an optimistic and effective approach for IPF.
Publication Date: 2021-08-25
Journal: Phytotherapy research : PTR

protein crp(30)

Molecular Biology Networks and Key Gene Regulators for Inflammatory Biomarkers Shared by Breast Cancer Development: Multi-Omics Systems Analysis.
As key inflammatory biomarkers C-reactive protein (CRP) and interleukin-6 (IL6) play an important role in the pathogenesis of non-inflammatory diseases, including specific cancers, such as breast cancer (BC). Previous genome-wide association studies (GWASs) have neither explained the large proportion of genetic heritability nor provided comprehensive understanding of the underlying regulatory mechanisms. We adopted an integrative genomic network approach by incorporating our previous GWAS data for CRP and IL6 with multi-omics datasets, such as whole-blood expression quantitative loci, molecular biologic pathways, and gene regulatory networks to capture the full range of genetic functionalities associated with CRP/IL6 and tissue-specific key drivers (KDs) in gene subnetworks. We applied another systematic genomics approach for BC development to detect shared gene sets in enriched subnetworks across BC and CRP/IL6. We detected the topmost significant common pathways across CRP/IL6 (e.g., immune regulatory; chemokines and their receptors; interferon γ, JAK-STAT, and ERBB4 signaling), several of which overlapped with BC pathways. Further, in gene-gene interaction networks enriched by those topmost pathways, we identified KDs-both well-established (e.g., JAK1/2/3, STAT3) and novel (e.g., CXCR3, CD3D, CD3G, STAT6)-in a tissue-specific manner, for mechanisms shared in regulating CRP/IL6 and BC risk. Our study may provide robust, comprehensive insights into the mechanisms of CRP/IL6 regulation and highlight potential novel genetic targets as preventive and therapeutic strategies for associated disorders, such as BC.
Publication Date: 2021-09-29
Journal: Biomolecules

il8 il10(29)

Correlation of Hair Cortisol and Interleukin 6 with Structural Change in the Active Progression of Keratoconus.
Evaluate interleukin and hair cortisol concentrations (HCC) in progressive keratoconus (KC) and compare them with KC stable eyes and healthy controls. Determine the correlation of these inflammatory mediators and HCC and their relationship with structural damage represented by increased corneal curvature. University of Sao Paulo. Prospective observational comparative study. The study included 135 eyes of 75 patients.The concentrations of tear cytokines: interleukin (IL) 1B, IL6, IL8, IL10, IL12p70 and tumor necrosis factor α (TNFα) were obtained by capillary flow and measured using flow cytometer.HCC were determined from the most proximal hair segment as an index of cumulative secretion and measured by liquid chromatography mass spectrometry. Only IL6 was increased in progressive KC tears compared with stable KC (6.59 ± 3.25 pg/ml vs. 4.72 ± 1.91pg/ml; p<0.0001) with a positive correlation between IL6 and maximum keratometry (Kmax) (p<0.0001).Progressive KC exhibited significantly higher HCC than stable KC (0.624 ± 0.160ng/mg vs. 0.368 ± 0.0647ng/mg; p< 0.0001) and healthy controls (0.624 ± 0.160ng/mg vs. 0.351 ± 0.0896ng/mg; p<0.0001).There was a significant correlation between HCC and Kmax (p<0.0001). Keratoconus eyes that are progressing have a higher concentration of IL-6 and long-term cortisol than patients with stable forms of KC;Second, there is a significant correlation between this increase in IL6 and cortisol with corneal structural damage.Finally, there is a meaningful relationship between this interleukin and the past few months' cortisol levels.
Publication Date: 2021-09-07
Journal: Journal of cataract and refractive surgery

tnfα il6(29)

PDL1 expression on monocytes is associated with plasma cytokines in Tuberculosis and HIV.
PDL1 and its interaction with PD1 is implicated in immune dysfunction in TB and HIV. The expression of PDL1 on multiple subsets of monocytes as well as their associations with cytokines and microbial products have not been well studied. HIV (TB-HIV+), TB (TB+HIV-) and TB/HIV co-infected (TB+HIV+) patients as well as apparently healthy controls (TB-HIV-) were recruited. TB and HIV patients were treatment naïve while TB/HIV patients were both ART naïve and experienced but not yet started TB therapy. Monocyte subsets were evaluated for PDL1 expression by flow cytometry; plasma TNFα, IL6, IP10, IFNγ and IL10 were measured by Luminex; and cytokine mRNA from purified monocytes quantitated by qPCR. The association of PDL1 with cytokines, clinical and microbial indices, including HIV viral load, TB smear microscopy and TB urinary lipoarabinomannan (LAM) were assessed. Monocyte expression of PDL1 was significantly higher in TB, HIV and TB/HIV co-infected patients compared with healthy controls (p = 0.0001), with the highest levels in TB/HIV co-infected patients. The highest expression of PDL1 was on intermediate (CD14+CD16+) monocytes in all participant groups. PDL1 strongly correlated with HIV viral load in TB/HIV while weakly correlated in HIV. PDL1 levels moderately correlated with plasma TNFα, IL6, IP10, IFNγ and IL10 level in TB subjects whereas weakly correlated with TNFα and IP10 in HIV patients. However, cytokine mRNA from purified monocytes showed no association with either plasma cytokines or monocyte PDL1 expression, implying that if cytokines modulate PDL1, they are likely not originating from circulating monocytes themselves. These results underscore the importance of further characterization of multiple monocyte subsets and their phenotypic and functional differences in different disease states.
Publication Date: 2021-10-02
Journal: PloS one

oxidative stress(24)

Sex-dependent acrolein sensitivity in mice is associated with differential lung cell, protein, and transcript changes.
Acrolein is a reactive inhalation hazard. Acrolein's initial interaction, which in itself can be function-altering, is followed by time-dependent cascade of complex cellular and pulmonary responses that dictate the severity of the injury. To investigate the pathophysiological progression of sex-dependent acrolein-induced acute lung injury, C57BL/6J mice were exposed for 30 min to sublethal, but toxic, and lethal acrolein. Male mice were more sensitive than female mice. Acrolein of 50 ppm was sublethal to female but lethal to male mice, and 75 ppm was lethal to female mice. Lethal and sublethal acrolein exposure decreased bronchoalveolar lavage (BAL) total cell number at 3 h after exposure. The cell number decrease was followed by progressive total cell and neutrophil number and protein increases. The BAL total cell number in female mice exposed to a sublethal, but not lethal dose, returned to control levels at 16 h. In contrast, BAL protein content and neutrophil number were higher in mice exposed to lethal compared to sublethal acrolein. RNASeq pathway analysis identified greater increased lung neutrophil, glutathione metabolism, oxidative stress responses, and CCL7 (aka MCP-3), CXCL10 (aka IP-10), and IL6 transcripts in males than females, whereas IL10 increased more in female than male mice. Thus, the IL6:IL10 ratio, an indicator of disease severity, was greater in males than females. Further, H3.3 histone B (H3F3B) and pro-platelet basic protein (PPBP aka CXCL7), transcripts increased in acrolein exposed mouse BAL and plasma at 3 h, while H3F3B protein that is associated with neutrophil extracellular traps formation increased at 12 h. These results suggest that H3F3B and PPBP transcripts increase may contribute to extracellular H3F3B and PPBP proteins increase.
Publication Date: 2021-10-05
Journal: Physiological reports

tnf-α il6(22)

Predictors of Infarction in Tuberculous Meningitis in Indian Patients.
Stroke is a devastating complication of tuberculous meningitis (TBM) and is an important determinant of its outcome. We propose a model which would help to predict development of infarction or cerebrovascular events in patients of TBM. A prospective study with n=129 patients of TBM were evaluated for predictors and outcomes of stroke. A diagnostic grid was formulated with clinical, laboratory and radiology as parameters to predict the vascular outcomes. All patients were followed up for mortality and disability on the basis of modified rankin score (mRS). MRI & CSF cytokines TNF-alpha, IFN- gamma & IL-6,8, 10 were measured at baseline and 3 months. The diagnosis of TBM included definite, probable & possible types and stage I & II with early and late onset of symptoms respectively. The mortality was 16.2% and 19.4% of all patients developed stroke. The mean GCS, barthel index and mRS at admission was 57.03± 9.5,10.2±2.3 & 3.3±0.03 respectively mild to moderate infection and functional limitation. Barthel index (BI) happened to be a strong predictor [F=32.6, p=0.001, t=15.5, βeta coefficient =0.002] followed by biomarker TNF-α [F=18.9, p=0.02, t= -2.07, βeta coefficient=-0.04]. N=25 patients developed stroke with TNF-α, IL-6, IFN -γ showing statistically significant increase in all the stroke affected TBM (95% CI; 4.5 to 1.2; p=0.003). At 3 months, it was observed that mRS was statistically significant between stage I & II (95% CI; 5.4 to 2.1; p=0.04). Our data revealed that 19.4% patients developed vascular events during the hospital stay or follow up. We recruited late onset TBM as compared to early onset. BI, TNF-α, IL6 are most potent predictors of stroke post TBM.
Publication Date: 2021-09-19
Journal: Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association

il4 il6(22)

Cytokine Levels at Birth in Children Who Developed Acute Lymphoblastic Leukemia.
Prenatal immune development may play an important role in the etiology of childhood acute lymphoblastic leukemia (ALL). Seven cytokines, IL1β, IL4, IL6, IL8, GM-CSF, TNFα, and VEGF, were analyzed in blood spots collected at birth from 1,020 ALL cases and 1,003 controls participating in the California Childhood Leukemia Study. ORs and 95% confidence intervals (95% CI) associated with an interquartile range increment in cytokine levels were calculated using logistic regression, adjusting for sociodemographic and birth characteristics. We found that patients with ALL were born with higher levels of a group of correlated cytokines than controls [IL1β: OR of 1.18 (95% confidence interval [CI], 1.03-1.35); IL8: 1.19 (1.03-1.38); TNFα: 1.15 (1.01-1.30); VEGF: 1.16 (1.01-1.33)], especially among children of Latina mothers (ORs from 1.31 to 1.40) and for ALL with high hyperdiploidy (ORs as high as 1.27). We found that neonatal cytokine levels were correlated with neonatal levels of endogenous metabolites which had been previously associated with ALL risk; however, there was no evidence that the cytokines were mediating the relationship between these metabolites and ALL risk. We posit that children born with altered cytokine levels are set on a trajectory towards an increased risk for subsequent aberrant immune reactions that can initiate ALL. This is the first study to evaluate the interplay between levels of immunomodulatory cytokines at birth, prenatal exposures, and the risk of childhood ALL.
Publication Date: 2021-06-04
Journal: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

control group(22)

Markers of Inflammation and Vascular Parameters in Selective Progesterone Receptor Modulator (Ulipristal Acetate)-Treated Uterine Fibroids.
The exact mechanism of selective progesterone receptor modulator action in leiomyoma still challenges researchers. The aim of the study was to assess the effects of ulipristal acetate (UPA) on immunoexpression of inflammatory markers and vascularization in fibroids. UPA-treated patients were divided into three groups: (1) good response (≥25% reduction in volume of fibroid), (2) weak response (insignificant volume reduction), (3) and no response to treatment (no decrease or increase in fibroid volume). The percentage of TGFβ, IL6, IL10, CD117, and CD68-positive cells were significantly lower in the group with a good response to treatment vs. the control group. Moreover, the percentage of IL10 and CD68-positive cells in the group with a good response to treatment were also significantly lower compared to the no response group. Additionally, a significant decrease in the percentage of IL10-positive cells was found in the good response group vs. the weak response group. There were no statistical differences in the percentage of TNFα-positive cells and vessel parameters between all compared groups. The results of the study indicate that a good response to UPA treatment may be associated with a decrease of inflammatory markers, but it does not influence myoma vascularization.
Publication Date: 2021-08-28
Journal: Journal of clinical medicine

95 ci(21)

Genetic Associations Between IL-6 and the Development of Autoimmune Arthritis Are Gender-Specific.
To find out the genetic association between IL6 and autoimmune arthritis. We performed a two-sample Mendelian randomization (MR) study using multiple genome-wide association studies (GWAS) datasets. Furthermore, a sex-stratified MR study was performed to identify sexual dimorphism in the association between IL6 and autoimmune arthritis. Then, LocusZoom plots were displayed based on the IL6R gene region to present evidence of genetic colocalization between diseases. The MR result denoted a genetic association between the increased level of IL-6 signaling and risk of RA (β=0.325, 95%CI 0.088, 0.561, p=7.08E-03) and AS (β=1.240, 95%CI 0.495, 1.980, p=1.1E-03). Accordingly, sIL6R was found to have negatively correlation with the onset of RA (β=-0.020, 95%CI -0.0320, -0.008, p=1.18E-03) and AS (β=-0.125, 95%CI -0.177, -0.073, p=2.29E-06). However, no genetic association between IL6/sIL6R and PsA was detected. The gender-stratified MR analysis showed that IL6 was associated with AS in the male population, with RA in the female population, and with PsA in the male population. Additionally, ADAR, a gene identified by a sensitive test, could be the reason for the nonsignificant association between IL6 and PsA in a pooled population. Our findings showed that the overactive IL6 signal pathway led to autoimmune arthritis, especially in RA and AS. Sexual difference was also observed in IL6-intermediate susceptibility to autoimmune arthritis.
Publication Date: 2021-09-21
Journal: Frontiers in immunology

il1a il1b(19)

Comparison of the uterine inflammatory response to frozen-thawed sperm from high and low fertility bulls.
Some bulls with apparently normal semen quality yield unacceptably low pregnancy rates. We hypothesised that a differential uterine immunological response to sperm from high and low fertility bulls may contribute to these differences. The experimental model used was heifer follicular phase uterine explants incubated with frozen-thawed sperm from high and low fertility bulls (3-5 replicates per experiment). Inflammatory gene expression of IL1A, IL1B, IL6, TNFA and CXCL8 were assessed by qPCR and IL1-β and IL-8 were quantified in explant supernatants by ELISA. Neutrophil binding affinity to sperm from high and low fertility bulls was also assessed. There was a significant up-regulation of IL1A, IL1B and TNFA from frozen-thawed sperm, irrespective of fertility status, compared to the unstimulated control. This response was confirmed at the protein level, with an increase of IL-1β and IL-8 protein concentrations by 5 and 2.7 fold, respectively (P < 0.05). Although no significant differences in the inflammatory response at the gene or protein level were evident between high and low fertility bulls, more sperm from low compared to high fertility bulls bound to neutrophils (P < 0.05). Using bulls of unknown fertility, cauda epididymal sperm (CES) plus seminal plasma (SP) upregulated IL6 (P < 0.05) but there was no upregulation of any inflammatory gene expression for CES alone. Overall, this ex vivo study demonstrated an upregulation of inflammatory gene expression in the uterus in response to frozen-thawed bull sperm. While there was no difference between sperm from high and low fertility bulls, there was a greater binding affinity of low fertility sperm by neutrophils.
Publication Date: 2021-09-27
Journal: Theriogenology

pg ml(18)

Performance of the Roche IL-6 chemiluminescent immunoassay in patients with COVID-like respiratory symptoms.
We evaluated the Roche Elecsys IL6 assay on the Cobas immunoassay analyser. Serum IL6 of 144 controls were compared to 52 samples from patients with COVID-like respiratory symptoms (17 SARS-CoV-2 RT-PCR positive); 25 of these were from the intensive care unit (ICU). We compared the IL6 levels to C-reactive protein (CRP) and procalcitonin (PCT) levels in all cases. The IL6 assay had coefficient-of-variation (CV) of 2.3 % (34.1 pg/mL) and 2.5 % (222.5 pg/mL), a limit of quantitation <1.6 pg/mL, and was linear from 1.6 to 4948 pg/mL. There was a significant difference in IL6 values between patients with COVID-like respiratory symptoms versus controls (p < 0.001). ROC analysis showed that IL6 > 6.4 pg/mL identified symptomatic cases (AUC 0.94, sensitivity 88.2 %, specificity 97.2 %). There was a significant difference between the IL6 of symptomatic ICU/non-ICU cases (median IL6 228 vs 11 pg/mL, p < 0.0001); ROC analysis showed IL6 > 75 pg/mL (sensitivity 76.0 %, specificity 88.9 %) was superior to CRP and PCT in predicting ICU admission (AUC: IL6 0.83, CRP 0.71, PCT 0.82). The performance of Elecsys IL6 assay is in keeping with the manufacturer's claims. IL6 > 6.4 pg/mL differentiates healthy from suspected COVID-19 cases and appears to be raised earlier than the other inflammatory markers in some cases. IL6 > 75 pg/mL was a good predictor of ICU admission.
Publication Date: 2021-07-03
Journal: Journal of virological methods

serum il6(18)

Expression quantitative trait loci for ETV4 and MEOX1 are associated with adult asthma in Japanese populations.
ETS variant transcription factor 4 (ETV4) is a recently identified transcription factor that regulates gene expression-based biomarkers of asthma and IL6 production in an airway epithelial cell line. Given that ETV4 has not yet been implicated in asthma genetics, we performed genetic association studies of adult asthma in the ETV4 region using two independent Japanese cohorts (a total of 1532 controls and 783 cases). SNPs located between ETV4 and mesenchyme homeobox 1 (MEOX1) were significantly associated with adult asthma, including rs4792901 and rs2880540 (P = 5.63E-5 and 2.77E-5, respectively). The CC haplotype of these two SNPs was also significantly associated with adult asthma (P = 8.43E-7). Even when both SNPs were included in a logistic regression model, the association of either rs4792901 or rs2880540 remained significant (P = 0.013 or 0.007, respectively), suggesting that the two SNPs may have independent effects on the development of asthma. Both SNPs were expression quantitative trait loci, and the asthma risk alleles at both SNPs were correlated with increased levels of ETV4 mRNA expression. In addition, the asthma risk allele at rs4792901 was associated with increased serum IL6 levels (P = 0.041) in 651 healthy adults. Our findings imply that ETV4 is involved in the pathogenesis of asthma, possibly through the heightened production of IL6.
Publication Date: 2021-09-24
Journal: Scientific reports

genes il6(16)

Weighted gene co-expression network analysis of hub genes in lung adenocarcinoma.
Lung adenocarcinoma (LUAD) is a tumor with high incidence. This study aimed to identify the central genes of LUAD. LUAD were analyzed by weighted gene co-expression network (WGCNA), and differentially expressed genes (DEGs) were identified. Samples were obtained from The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases and included 515 LUAD samples and 347 normal samples. The WGCNA algorithm generated a total of 10 modules. The top 2 modules (MEturquoise and MEblue) with the highest correlation to LUAD were selected. Ten Hub genes (IL6, CDH1, PECAM1, SPP1, THBS1, HGF, SNCA, CDH5, CAV1, and DLC1) were screened in the intersecting genes of DEGs and WGCNA (MEturquoise and MEblue). Only SPP1 was correlated with LUAD poor survival, indicating that SPP1 may be a key Hub gene for LUAD. The competing endogenous RNA (ceRNA) network was constructed to analyze the regulatory relationship of Hub genes, and SPP1 may be directly regulated by 4 microRNAs (miRNAs) and indirectly regulated by 49 long noncoding RNAs (lncRNAs).
Publication Date: 2021-04-30
Journal: Evolutionary bioinformatics online

il6 rs1800795(16)

The genetic association with injury risk in male academy soccer players depends on maturity status.
It is currently unknown if injury risk is associated with genetic variation in academy soccer players (ASP). We investigated whether nine candidate single nucleotide polymorphisms were associated (individually and in combination) with injury in ASP at different stages of maturation. Saliva samples and one season's injury records were collected from 402 Caucasian male ASP from England, Spain, Uruguay and Brazil, whose maturity status was defined as pre- or post-peak height velocity (PHV). Pre-PHV COL5A1 rs12722 CC homozygotes had relatively higher prevalence of any musculoskeletal soft-tissue (22.4% vs. 3.0%, P=0.018) and ligament (18.8% vs. 11.8%, P=0.029) injury than T-allele carriers, while VEGFA rs2010963 CC homozygotes had greater risk of ligament/tendon injury than G-allele carriers. Post-PHV IL6 rs1800795 CC homozygotes had a relatively higher prevalence of any (67.6% vs. 40.6%, P=0.003) and muscle (38.2% vs. 19.2%, P=0.013) injuries than G-allele carriers. Relatively more post-PHV EMILIN1 rs2289360 CC homozygotes suffered any injury than CT and TT genotypes (56.4% vs. 40.3% and 32.8%, P=0.007), while the 'protective' EMILIN1 TT genotype was more frequent in post- than pre-PHV ASP (22.3 vs. 10.0%, P=0.008). Regardless of maturity status, T-alleles of ACTN3 rs1815739 and EMILIN1 rs2289360 were associated with greater absence following ankle injury, while the MMP3 rs679620 T-allele and MYLK rs28497577 GT genotype were associated with greater absence following knee injury. The combination of injury-associated genotypes was greater in injured vs. non-injured ASP. This study is the first to demonstrate that a genetic association exists with injury prevalence in ASP, which differs according to maturity status.
Publication Date: 2021-10-12
Journal: Scandinavian journal of medicine & science in sports

tnfa il6(15)

The opportunistic intracellular bacterial pathogen Rhodococcus equi elicits type I interferon by engaging cytosolic DNA sensing in macrophages.
Rhodococcus equi is a major cause of foal pneumonia and an opportunistic pathogen in immunocompromised humans. While alveolar macrophages constitute the primary replicative niche for R. equi, little is known about how intracellular R. equi is sensed by macrophages. Here, we discovered that in addition to previously characterized pro-inflammatory cytokines (e.g., Tnfa, Il6, Il1b), macrophages infected with R. equi induce a robust type I IFN response, including Ifnb and interferon-stimulated genes (ISGs), similar to the evolutionarily related pathogen, Mycobacterium tuberculosis. Follow up studies using a combination of mammalian and bacterial genetics demonstrated that induction of this type I IFN expression program is largely dependent on the cGAS/STING/TBK1 axis of the cytosolic DNA sensing pathway, suggesting that R. equi perturbs the phagosomal membrane and causes DNA release into the cytosol following phagocytosis. Consistent with this, we found that a population of ~12% of R. equi phagosomes recruits the galectin-3,-8 and -9 danger receptors. Interestingly, neither phagosomal damage nor induction of type I IFN require the R. equi's virulence-associated plasmid. Importantly, R. equi infection of both mice and foals stimulates ISG expression, in organs (mice) and circulating monocytes (foals). By demonstrating that R. equi activates cytosolic DNA sensing in macrophages and elicits type I IFN responses in animal models, our work provides novel insights into how R. equi engages the innate immune system and furthers our understanding how this zoonotic pathogen causes inflammation and disease.
Publication Date: 2021-09-03
Journal: PLoS pathogens

cytokines il6(15)

SARS-CoV-2 and its beta variant of concern infect human conjunctival epithelial cells and induce differential antiviral innate immune response.
SARS-CoV-2 RNA has been detected in ocular tissues, but their susceptibility to SARS-CoV-2 infection is unclear. Here, we tested whether SARS-CoV-2 can infect human conjunctival epithelial cells (hCECs) and induce innate immune response. Conjunctival tissue from COVID-19 donors was used to detect SARS-CoV-2 spike and envelope proteins. Primary hCECs isolated from cadaver eyes were infected with the parental SARS-CoV-2 and its beta variant of concern (VOC). Viral genome copy number, and expression of viral entry receptors, TLRs, interferons, and innate immune response genes were determined by qPCR. Viral entry receptors were examined in hCECs and tissue sections by immunostaining. Spike protein was detected in the cell culture supernatant by dot blot. Spike and envelope proteins were found in conjunctiva from COVID-19 patients. SARS-CoV-2 infected hCECs showed high viral copy numbers at 24-72h post-infection; spike protein levels were the highest at 24hpi. Viral entry receptors ACE2, TMPRSS2, CD147, Axl, and NRP1 were detected in conjunctival tissue and hCECs. SARS-CoV-2 infection-induced receptor gene expression peaked at early time points post-infection, but gene expression of most TLRs peaked at 48 or 72hpi. SARS-CoV-2 infected hCECs showed higher expression of genes regulating antiviral response, RIG-I, interferons (α, β, & λ), ISG15 & OAS2, cytokines (IL6, IL1β, TNFα), and chemokines (CXCL10, CCL5). Compared to the parental strain, beta VOC induced increased viral copy number and innate response in hCECs. Conjunctival epithelial cells are susceptible to SARS-CoV-2 infection. Beta VOC is more infectious than the parental strain and evokes a higher antiviral and inflammatory response.
Publication Date: 2021-09-29
Journal: The ocular surface

il-1β il6(13)

Microglia NLRP3 Inflammasomes Activation Involving Diabetic Neuroinflammation in Diabetic Mice and BV2 Cells.
Hyperglycemia-induced microglia activation can cause a continuous release of proinflammatory cytokines, which gradually damages neurons and contributes to central diabetic neuroinflammation. This study aimed to illustrate the possible mechanism related to NLRP3 inflammasome and the aggravation of diabetes neuroinflammation. The targeted proteins from BV2 cells and brain tissues were tested by Western blot or immunohistochemistry. Cytokines from cell supernatant and serum were detected by ELISA. Meanwhile, cytoplasm and mitochondria ROS were determined by DCFHDA and Mito sox Red, respectively. In vitro, BV2 cells were stimulated by different glucose concentrations (5.5 to 65 mM/L) above physiological values and maintained for different periods (12 to 48h). The proinflammatory cytokines IL-1β, IL18, IL6, TNFα and cytoplasm ROS were significantly increased in a dose-dependent manner, while mitochondrial ROS was unaffected. NLRP3 inflammasomes, MAPKs, and NF-κB pathways were obviously activated at the concentration of 35 mM/L for 12h. Inhibition assay using specific inhibitors indicated that the treatment of glucose (35 mM/L for 12h) could stimulate NLRP3 inflammasome activation via ROS/JNK MAPKs/NF-κB pathway. In STZ induced diabetes mice models, microglia NLRP3, ASC, and caspase-1 proteins were highly expressed, and serum cytokines IL-1β, IL6, IL18, and TNFα were remarkably increased. Microglia NLRP3 inflammasomes activation involves diabetic neuroinflammation in diabetic mice and BV2 cells via ROS/JNK MAPKs/NF-κB pathways.
Publication Date: 2021-07-20
Journal: Current pharmaceutical design

il2 il4(12)

Viral loads, lymphocyte subsets and cytokines in asymptomatic, mildly and critical symptomatic patients with SARS-CoV-2 infection: a retrospective study.
Tens of million cases of coronavirus disease-2019 (COVID-19) have occurred globally. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) attacks the respiratory system, causing pneumonia and lymphopenia in infected individuals. The aim of the present study is to investigate the laboratory characteristics of the viral load, lymphocyte subset and cytokines in asymptomatic individuals with SARS-CoV-2 infection in comparison with those in symptomatic patients with COVID-19. From January 24, 2020, to April 11, 2020, 48 consecutive subjects were enrolled in this study. Viral loads were detected by RT-PCR from throat-swab, sputum and feces samples. Lymphocyte subset levels of CD3 + , CD4 + , and CD8 + T lymphocytes, B cells and NK cells were determined with biological microscope and flow cytometric analysis. Plasma cytokines (IL2, IL4, IL5, IL6, IL8, IL10, TNF-α, IFN-α and IFN-γ) were detected using flow cytometer. Analysis of variance (ANOVA), Chi-square or Fisher's exact test and Pearson's Correlation assay was used for all data. Asymptomatic (AS), mild symptoms (MS) and severe or critical cases (SCS) with COVID-19 were 11 (11/48, 22.9%), 26 (54.2%, 26/48) and 11 cases (11/48, 22.9%), respectively. The mean age of AS group (47.3 years) was lower than SCS group (63.5 years) (P < 0.05). Diabetes mellitus in AS, MS and SCS patients with COVID-19 were 0, 6 and 5 cases, respectively, and there was a significant difference between AS and SCS (P < 0.05). No statistical differences were found in the viral loads of SARS-CoV-2 between AS, MS and SCS groups on admission to hospital and during hospitalization. The concentration of CD 3 + T cells (P < 0.05), CD3 + CD4 + T cells (P < 0.05), CD3 + CD8 + T cells (P < 0.01), and B cells (P < 0.05) in SCS patients was lower than in AS and MS patients, while the level of IL-5 (P < 0.05), IL-6 (P < 0.05), IL-8 (P < 0.01) and IL-10 (P < 0.01), and TNF-α (P < 0.05) was higher. The age was negatively correlated with CD3 + T cells (P < 0.05), CD3 + CD4 + T cells (P < 0.05), and positively correlated with IL-2 (P < 0.001), IL-5 (P < 0.05), IL-6 (P < 0.05) IL-8 (P < 0.05), and IL-10 (P < 0.05). The viral loads were positively correlated with IL-2 (P < 0.001), IL-5 (P < 0.05), IL-6 (P < 0.05) IL-8 (P < 0.05) and IL-10 (P < 0.05), while negatively correlated with CD 3 + T cells (P < 0.05) and CD3 + CD4 + T cells (P < 0.05). The viral loads are similar between asymptomatic, mild and severe or critical patients with COVID-19. The severity of COVID-19 may be related to underlying diseases such as diabetes mellitus. Lymphocyte subset and plasma cytokine levels may be as the markers to distinguish severely degrees of disease, and asymptomatic patients may be as an important source of infection for the COVID-19.
Publication Date: 2021-06-14
Journal: Virology journal

crp il6(11)

Interleukin 6 (rs1800795) and pentraxin 3 (rs2305619) polymorphisms-association with inflammation and all-cause mortality in end-stage-renal disease patients on dialysis.
Chronic inflammation plays an important role in the progression and outcome of chronic kidney disease (CKD). The circulating levels of the inflammatory biomarkers interleukin 6 (IL6) and pentraxin 3 (PTX3) are enhanced in CKD patients, and are associated with the progression of the disease and with higher risk for cardiovascular events, the major cause of death in CKD patients. Our aim was to study how specific polymorphisms of IL6 and PTX3 encoding genes affect the inflammatory response and outcome of end-stage renal disease (ESRD) patients on dialysis. Methodology included the analysis of two single nucleotide polymorphisms (SNP), namely the IL6 (rs1800795) polymorphism in the promoter region (-174G > C), and the PTX3 (rs2305619) polymorphism in the intron 1 (+ 281A > G), which were analyzed in ESRD patients on dialysis and in a group of heathy individuals. The allelic frequencies, genotype distribution and their association with circulating levels of the inflammatory markers C-reactive protein (CRP), IL6, growth differentiation factor 15 (GDF15) and PTX3, were determined in ESRD patients. Events of death were recorded along one year, to assess the association of the studied SNPs with all-cause mortality and the inflammatory biomarkers, in ESRD patients. Results showed that the allelic frequencies and genotype distribution for IL6 and PTX3 SNPs in the control group and ESRD patients were similar and in agreement with other European reports. For the IL6 polymorphism, we found a trend towards higher levels of high-sensitivity (hs) CRP, IL6 and PTX3 in the homozygous genotypes; the CC genotype also showed the highest levels of GDF15. The mortality rate after the 1-year follow-up was 10.4%. The CC genotype (IL6 SNP) was associated to a higher risk of mortality and deceased patients carrying this genotype also showed the highest levels of hsCRP. Regarding the studied PTX3 SNP, the AA genotype was linked to an enhanced inflammatory response, showing the highest values of hsCRP and IL6. Nevertheless, this genotype had no significant impact on the mortality rate. In conclusion, both studied SNPs seem to modulate the inflammatory response in ESRD and may, therefore, be determinant on disease progression and patients' outcome. Our data also highlights the importance of research on genetic variants that, although less frequent, may have significant biological value.
Publication Date: 2021-07-22
Journal: Scientific reports

il6 vegfa(10)

Molecular mechanism of Epicedium treatment for depression based on network pharmacology and molecular docking technology.
Increasing attention has been paid to the effect of Epimedium on the nervous system, particularly anti-depression function. In the present study, we applied network pharmacology to introduce a testable hypothesis on the multi-target mechanisms of Epicedium against depression. By reconstructing the network of protein-protein interaction and drug-component-target, we predicted the key protein targets of Epicedium for the treatment of depression. Then, through molecular docking, the interaction of the main active components of Epicedium and predicted candidate targets were verified. Nineteen active compounds were selected from Epicedium. There were 200 targets associated with Epicedium and 537 targets related to depression. The key targets of Epicedium for treating depression were IL6, VEGFA, AKT1, and EGF. According to gene ontology functional enrichment analysis, 22 items of biological process (BP), 13 items of cell composition (CC) and 9 items of molecular function (MF) were obtained. A total of 56 signaling pathways (P < 0.05) were identified by Kyoto Encyclopedia of Genes and Genomes analysis, mainly involving depression-related pathways such as dopaminergic synapse, TNF signaling pathway, and prolactin signaling pathway. The results of molecular docking showed that the most important activity components, including luteoklin, quercetin and kaempferol, were well combined with the key targets. Luteoklin, quercetin, kaempferol and other active compounds in Epicedium can regulate multiple signaling pathways and targets such as IL6, AKT1, and EGF, therefore playing therapeutic roles in depression.
Publication Date: 2021-09-05
Journal: BMC complementary medicine and therapies

il6 il17(8)

Interleukins and Interleukin Receptors Evolutionary History and Origin in Relation to CD4+ T Cell Evolution.
Understanding the evolution of interleukins and interleukin receptors is essential to control the function of CD4+ T cells in various pathologies. Numerous aspects of CD4+ T cells' presence are controlled by interleukins including differentiation, proliferation, and plasticity. CD4+ T cells have emerged during the divergence of jawed vertebrates. However, little is known about the evolution of interleukins and their origin. We traced the evolution of interleukins and their receptors from Placozoa to primates. We performed phylogenetic analysis, ancestral reconstruction, HH search, and positive selection analysis. Our results indicated that various interleukins' emergence predated CD4+ T cells divergence. IL14 was the most ancient interleukin with homologs in fungi. Invertebrates also expressed various interleukins such as IL41 and IL16. Several interleukin receptors also appeared before CD4+ T cells divergence. Interestingly IL17RA and IL17RD, which are known to play a fundamental role in Th17 CD4+ T cells first appeared in mollusks. Furthermore, our investigations showed that there is not any single gene family that could be the parent group of interleukins. We postulate that several groups have diverged from older existing cytokines such as IL4 from TGFβ, IL10 from IFN, and IL28 from BCAM. Interleukin receptors were less divergent than interleukins. We found that IL1R, IL7R might have diverged from a common invertebrate protein that contained TIR domains, conversely, IL2R, IL4R and IL6R might have emerged from a common invertebrate ancestor that possessed a fibronectin domain. IL8R seems to be a GPCR that belongs to the rhodopsin-like family and it has diverged from the Somatostatin group. Interestingly, several interleukins that are known to perform a critical function for CD4+ T cells such as IL6, IL17, and IL1B have gained new functions and evolved under positive selection. Overall evolution of interleukin receptors was not under significant positive selection. Interestingly, eight interleukin families appeared in lampreys, however, only two of them (IL17B, IL17E) evolved under positive selection. This observation indicates that although lampreys have a unique adaptive immune system that lacks CD4+ T cells, they could be utilizing interleukins in homologous mode to that of the vertebrates' immune system. Overall our study highlights the evolutionary heterogeneity within the interleukins and their receptor superfamilies and thus does not support the theory that interleukins evolved solely in jawed vertebrates to support T cell function. Conversely, some of the members are likely to play conserved functions in the innate immune system.
Publication Date: 2021-06-03
Journal: Genes

il10 il12(8)

Extracellular vesicles secreted by Giardia duodenalis regulate host cell innate immunity via TLR2 and NLRP3 inflammasome signaling pathways.
Giardia duodenalis, also known as G. intestinalis or G. lamblia, is the major cause of giardiasis leading to diarrheal disease with 280 million people infections annually worldwide. Extracellular vesicles (EVs) have emerged as a ubiquitous mechanism participating in cells communications. The aim of this study is to explore the roles of G. duodenalis EVs (GEVs) in host-pathogen interactions using primary mouse peritoneal macrophages as a model. Multiple methods of electron microscopy, nanoparticle tracking analysis, proteomic assays, flow cytometry, immunofluorescence, qPCR, western blot, ELISA, inhibition assays, were used to characterize GEVs, and explore its effects on the host cell innate immunity as well as the underlying mechanism using primary mouse peritoneal macrophages. Results showed that GEVs displayed typical cup-shaped structure with 150 nm in diameter. GEVs could be captured by macrophages and triggered immune response by increasing the production of inflammatory cytokines Il1β, Il6, Il10, Il12, Il17, Ifng, Tnf, Il18, Ccl20 and Cxcl2. Furthermore, activation of TLR2 and NLRP3 inflammasome signaling pathways involved in this process. In addition, CA-074 methyl ester (an inhibitor of cathepsin B) or zVAD-fmk (an inhibitor of pan-caspase) pretreatment entirely diminished these effects triggered by GEVs exposure. Taken together, these findings demonstrated that GEVs could be internalized into mouse peritoneal macrophages and regulate host cell innate immunity via TLR2 and NLRP3 inflammasome signaling pathways.
Publication Date: 2021-04-03
Journal: PLoS neglected tropical diseases

ifnγ il6(7)

Targeting Haemagglutinin Antigen of Avian Influenza Virus to Chicken Immune Cell Receptors Dec205 and CD11c Induces Differential Immune-Potentiating Responses.
Improving the immunogenicity and protective efficacy of vaccines is critical to reducing disease impacts. One strategy used to enhance the immunogenicity of vaccines is the selective delivery of protective antigens to the antigen presenting cells (APCs). In this study, we have developed a targeted antigen delivery vaccine (TADV) system by recombinantly fusing the ectodomain of hemagglutinin (HA) antigen of H9N2 influenza A virus to single chain fragment variable (scFv) antibodies specific for the receptors expressed on chicken APCs; Dec205 and CD11c. Vaccination of chickens with TADV containing recombinant H9HA Foldon-Dec205 scFv or H9HA Foldon-CD11c scFv proteins elicited faster (as early as day 6 post primary vaccination) and higher anti-H9HA IgM and IgY, haemagglutination inhibition, and virus neutralisation antibodies compared to the untargeted H9HA protein. Comparatively, CD11c scFv conjugated H9HA protein showed higher immunogenic potency compared to Dec205 scFv conjugated H9HA protein. The higher immune potentiating ability of CD11c scFv was also reflected in ex-vivo chicken splenocyte stimulation assay, whereby H9HA Foldon-CD11c scFv induced higher levels of cytokines (IFNγ, IL6, IL1β, and IL4) compared to H9HA Foldon-Dec205 scFv. Overall, the results conclude that TADV could be a better alternative to the currently available inactivated virus vaccines.
Publication Date: 2021-08-07
Journal: Vaccines

il10 tnfα(7)

Objective of the study - to identify the relationship of immunological parameters and their role in termination of pregnancy. 28 women, with a history of 2 or more miscarriages in their medical history, were examined immediately after the termination of pregnancy up to 12 weeks. The control group consisted of 20 healthy non-pregnant women. The content of natural killers of peripheral blood pNK - CD16+, interleukins IL2, IL6, IL10, TNFα; VEGF and γINF were examined by the method of enzyme immunoassay. In women with a history of recurrent miscarriage, immediately after the next termination of pregnancy in the first trimester examinations revealed immune shifts characterized by increased activity pNK - CD16+ compared with the control group - 27.5% (р<0,01); also an increase in the production of interleukins: TNFα to 39.0 pg/ml compared with the control group - 27.5 pg/ml (р<0,05) and IL6 up to 28.5 pg/ml in the control group 13.95 pg/ml (р<0,01). The above changes indicate a dysregulation of the immune system what may be related to the termination of pregnancy in the first trimester.
Publication Date: 2021-06-10
Journal: Georgian medical news

il1b p(4)

Effects of external low intensity focused ultrasound on inflammatory markers in neuropathic pain.
Changes in inflammatory cytokine levels contribute to the induction and maintenance of neuropathic pain. We have shown that external low intensity focused ultrasound (liFUS) reduces allodynia in a common peroneal nerve injury (CPNI). Here, we investigate an underlying mechanism of action for this treatment and measure the effect of liFUS on inflammatory markers. Male rats were divided into four groups: CPNI/liFUS, CPNI/shamliFUS, shamCPNI/liFUS, and shamCPNI/shamliFUS. Mechanical nociceptive thresholds were measured using Von Frey filaments (VFF) to confirm the absence/presence of allodynia at baseline, after CPNI, and after liFUS. Commercial microarray and ELISA assays were used to assess cytokine expression in the treated L5 dorsal root ganglion (DRG) and dorsal horn (DH) tissue 24 and 72 h after liFUS. VFF thresholds were significantly reduced following CPNI in both groups that received the injury (p < 0.001). After liFUS, only the CPNI/liFUS cohort showed a significant increase in mechanical thresholds (p < 0.001). CPNI significantly increased TNFa, IL6, CNTF, IL1b (p < 0.05 for all) levels in the DRG and DH, compared to baseline, consistent with previous work in sciatic nerve injury. LiFUS in CPNI rats resulted in a decrease in these cytokines in DRG 72 h post-therapy (TNFa, IL6, CNTF and IL1b, p < 0.001). In the DH, IL1b, CNTF, and TNFa (p < 0.05 for all) decreased 72 h after liFUS. We have demonstrated that liFUS modifies inflammatory cytokines in both DRG and DH in CPNI rats. These data provide evidence that liFUS, reverses the allodynic phenotype, in part, by altering inflammatory cytokine pathways.
Publication Date: 2021-05-24
Journal: Neuroscience letters


Interleukin 6 trans-signalling and the risk of future cardiovascular events in men and women.
Pro-inflammatory interleukin 6 (IL6) trans-signalling is associated with increased risk of cardiovascular events (CVEs). Whether this association exists for both sexes is, however, uncertain. Hence, we analysed the risk of CVE associated with IL6 trans-signalling in men and women and investigated if potential interaction between IL6 trans-signalling and sex affects the risk. In a prospective cohort of 60-year-old men and women without cardiovascular disease (men=2039, women=2193), subjects were followed for 20 years. To assess the IL6 trans-signalling activity, the proportion between the active binary and inactive ternary IL6 complexes, the binary/ternary ratio (B/T ratio), was estimated. CVE (myocardial infarction, angina pectoris and ischaemic stroke, n=629) risk was analysed with Cox regression, presented as HRs with 95% CIs. B/T ratio was dichotomised, with levels >median representing IL6 trans-signalling. Interaction was analysed on the additive scale and expressed as the synergy index (S). Analyses were adjusted for cardiovascular risk factors. B/T ratio >median was associated with increased CVE risk in men (HR 1.63; 95% CI 1.32 to 2.01), but not in women (HR 1.21; 95% CI 0.93 to 1.57). There was a significant synergistic interaction (S=1.98; 95% CI 1.15 to 3.42) between the B/T ratio and male sex, the combination increasing the risk by 88%. Our results suggest differential susceptibility to inflammation mediated by IL6 trans-signalling and subsequent CVE in men and women. The B/T ratio could be considered as a novel biomarker for cardiovascular risk in men, but not in women.
Publication Date: 2021-10-13
Journal: Open heart


Exploring the mechanism of Jianpi Qushi Huayu Formula in the treatment of chronic glomerulonephritis based on network pharmacology.
This study was to explore the effective components, potential targets, and pathways of Jianpi Qushi Huayu Formula (JQHF) for the treatment of chronic glomerulonephritics (CGN). First, the Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), GeneCards, and OMIM databases were used to collect the major active components of JQHF and potential therapeutic targets of CGN. Then, functional enrichment analysis was performed to clarify the mechanisms of the JQHF on CGN. Subsequently, molecular docking was simulated to assess the binding ability of key targets and major active components. Finally, quantitative real-time PCR and western blot were performed for experimental verification of cells in vitro. A total of 55 active ingredients contained and 220 putative identified targets were screened from JQHF, of which 112 overlapped with the targets of CGN and were considered potential therapeutic targets. Then, we found quercetin and kaempferol are two key ingredients of JQHF, which may act on the top 10 screened targets of PPI, affecting CGN through related signal transduction pathways. Subsequently, molecular docking predicted that quercetin and kaempferol bind firm with the top 10 core targets of PPI. Further experiment verified some results and showed that JQHF has protected glomerular mesangial cells from lipopolysaccharide-induced inflammation by inhibiting expressions of IL6, TNF-α, and AKT1, and activating expressions of VEGFA. Based on network pharmacology, we explored the multi-component, multi-target, and multi-pathway characteristics of JQHF in treating CGN, and found that JQHF could act on IL6, TNF-α, VEGFA, and AKT1 to exert the effect of anti-CGN, which provided new ideas and methods for further research on the mechanism of JQHF in treating CGN.
Publication Date: 2021-10-08
Journal: Naunyn-Schmiedeberg's archives of pharmacology


Novel Insights into Epigenetic Regulation of IL6 Pathway: In Silico Perspective on Inflammation and Cancer Relationship.
IL-6 pathway is abnormally hyperactivated in several cancers triggering tumor cell growth and immune system inhibition. Along with genomic mutation, the IL6 pathway gene expression can be affected by DNA methylation, microRNAs, and post-translational modifications. Computational analysis was performed on the Cancer Genome Atlas (TCGA) datasets to explore the role of IL6, IL6R, IL6ST, and IL6R transmembrane isoform expression and their epigenetic regulation in different cancer types. IL6 was significantly modulated in 70% of tumor types, revealing either up- or down-regulation in an approximately equal number of tumors. Furthermore, IL6R and IL6ST were downregulated in more than 10 tumors. Interestingly, the correlation analysis demonstrated that only the IL6R expression was negatively affected by the DNA methylation within the promoter region in most tumors. Meanwhile, only the IL6ST expression was extensively modulated by miRNAs including miR-182-5p, which also directly targeted all three genes. In addition, IL6 upregulated miR-181a-3p, mirR-214-3p, miR-18a-5p, and miR-938, which in turn inhibited the expression of IL6 receptors. Finally, the patients' survival rate was significantly affected by analyzed targets in some tumors. Our results suggest the relevance of epigenetic regulation of IL6 signaling and pave the way for further studies to validate these findings and to assess the prognostic and therapeutic predictive value of these epigenetic markers on the clinical outcome and survival of cancer patients.
Publication Date: 2021-09-29
Journal: International journal of molecular sciences


Pet ownership in pregnancy and methylation pattern in cord blood.
Having pets in the house during the first years of life has been shown to protect against allergies. However, the result of different studies is heterogeneous. The aim of this study was to evaluate the methylation pattern in cord blood in relation to pet ownership during pregnancy.We investigated the methylation patterns of 96 cord blood samples, participants of the Epigenetic Hallmark of Maternal Atopy and Diet-ELMA project, born to mothers who either owned pets (n = 32) or did not own pets (n = 64) during their pregnancy. DNA from cord blood was analysed using the Infinium methylation EPIC. For statistical analysis, RnBeads software was applied.We found 113 differentially methylated sites (DMs) in the covariate-adjusted analysis (FDR p < 0.05), with small methylation differences. The top DMs were associated with genes: UBA7, THRAP3, GTDC1, PDE8A and SBK2. In the regional analysis, two promoter regions presented with significance: RN7SL621P and RNU6-211P. Cis-regulatory element analysis revealed significant associations with several immune-related pathways, such as regulation of IL18, Toll signalling, IL6 and complement.We conclude that pet exposure during pregnancy causes subtle but significant changes in methylation patterns in cord blood, which are reflected in the biological processes governing both innate and adaptive immune responses.
Publication Date: 2021-10-14
Journal: Genes and immunity


Study on the Mechanism of treating COVID-19 with Shenqi Wan based on Network Pharmacology.
Through the method of network pharmacology, the active components and targets of Shenqi wan (SQW) were excavated, the relationship with COVID-19 was discussed, and the possible mechanism of SQW in the treatment of COVID-19 was revealed from the aspects of multi-components, multi-targets, and multi-pathways. Firstly, the active components of SQW were screened from TCMSP and the 2020 edition of Chinese Pharmacopoeia, and the related targets of the components were obtained. Then the disease targets related to COVID-19 were screened from GeneCards and OMIM. Venny was used to map the relationship between component-target and disease-target, and String was used to analyzing the interaction of common targets. The network was constructed and analyzed by Cytoscape, the function of GO and KEGG genes was enriched by Metascape, and the molecular docking was verified by CB-Dock. Finally, 45 active components of SQW were obtained, and 72 potential targets were related to COVID-19, ACE2, IL6, NOS3, and CRP may be the key targets. GO enrichment of 1715 projects, such as lipopolysaccharide stress response, active oxygen metabolism, positive regulation of cell migration, and other GO enrichment. 136 KEGG pathways were obtained, TNF signaling pathway, IL-17 signaling pathway, HIF-1 signaling pathway. Molecular docking showed that kaempferol, quercetin, luteolin, astragaloside, calyx isoflavone glucoside, matrine, and other COVID-19-related targets such as ACE2, 3CLpro, PLpro, PTGS2 have good binding ability. According to the above results, it is suggested that SQW may play a role in the treatment of COVID-19 by directly or indirectly combining kaempferol, quercetin, and luteolin with ACE2, 3CLpro, PLpro, and PTGS2 to regulate multiple biological functions and signaling pathways.
Publication Date: 2021-10-05
Journal: Drug development and industrial pharmacy


Toxicological analysis of synthetic dye orange red on expression of NFκB-mediated inflammatory markers in Wistar rats.
Orange red is a food and cosmetic coloring agent made by the amalgamation of two azo dyes carmoisine and sunset yellow.The current study demonstrates the effect of different concentrations of orange red on antioxidant status, inflammatory biomarkers (TNFα, IFNγ, IL1β, IL6, COX-2, iNOS, and NFκB/p65), biochemical enzymes, and liver histology. In totality, 25 male Wistar rats were procured and arbitrarily alienated into 5 different groups each with 5 animals. Group I was taken as the control. Groups II-V were designated as treatment groups. Groups II and III were administered with (5 and 25 mg/kg b.wt.) and groups IV and V with (150 and 300 mg/kg b.wt.) of orange red via oral gavage for 30 days. It was observed that both low and high concentrations of orange red (25, 150, and 300 mg/kg) remarkably augmented the levels of serum inflammatory cytokines (TNFα, IFNγ, IL1β, and IL6) and the protein and gene expression of COX-2, iNOS, and NFκB/p65. A significant decrease in glutathione reductase, glutathione peroxidase, glutathione-
Publication Date: 2021-09-25
Journal: Drug and chemical toxicology


Drug repurposing for COVID-19 based on an integrative meta-analysis of SARS-CoV-2 induced gene signature in human airway epithelium.
Drug repurposing has the potential to bring existing de-risked drugs for effective intervention in an ongoing pandemic-COVID-19 that has infected over 131 million, with 2.8 million people succumbing to the illness globally (as of April 04, 2021). We have used a novel `gene signature'-based drug repositioning strategy by applying widely accepted gene ranking algorithms to prioritize the FDA approved or under trial drugs. We mined publically available RNA sequencing (RNA-Seq) data using CLC Genomics Workbench 20 (QIAGEN) and identified 283 differentially expressed genes (FDR<0.05, log2FC>1) after a meta-analysis of three independent studies which were based on severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection in primary human airway epithelial cells. Ingenuity Pathway Analysis (IPA) revealed that SARS-CoV-2 activated key canonical pathways and gene networks that intricately regulate general anti-viral as well as specific inflammatory pathways. Drug database, extracted from the Metacore and IPA, identified 15 drug targets (with information on COVID-19 pathogenesis) with 46 existing drugs as potential-novel candidates for repurposing for COVID-19 treatment. We found 35 novel drugs that inhibit targets (ALPL, CXCL8, and IL6) already in clinical trials for COVID-19. Also, we found 6 existing drugs against 4 potential anti-COVID-19 targets (CCL20, CSF3, CXCL1, CXCL10) that might have novel anti-COVID-19 indications. Finally, these drug targets were computationally prioritized based on gene ranking algorithms, which revealed CXCL10 as the common and strongest candidate with 2 existing drugs. Furthermore, the list of 283 SARS-CoV-2-associated proteins could be valuable not only as anti-COVID-19 targets but also useful for COVID-19 biomarker development.
Publication Date: 2021-09-29
Journal: PloS one


Determination role of some biomarkers tests for severe SARS-COV-2 infections in babylon province / IRAQ.
In a series of 30 SARS-COV-2 infected patients whom clinically proven as severe pulmonary infection form. These were found with male/female ratio of 1:1. The age range of below 50years old account for 60% and those of above 50 years old constitute the remaining 40%. They were the residents of Merjan Teaching Hospital/ Babylon Province/Iraq, to the period of March to April 2021 and primary screen by PCR for Sars-cov-2 RNA genes, in public health central laboratory found to be positive. The over- all laboratory investigation were; D -dimer, Ferritin, LDH, acute phase reactant C, and IL6.LDH was tempted to probe the immune mediated pulmonary tissue injury (367.48 U/L.), ferritin response may indicate hemolytic and acute phase reactant expressed as hyper-inflammation (331.1 ng/L.). |The D-dimer shed a light on the fibrino-lytic responses (6049 ng/L.) post to the immune-thrombotic overreactions, where IL6 levels give a clue to the state of hyper-cytokinemia (171.92 pg/L.). The overall immune status of these patients was as; Hyper-inflammatory and immune overreaction. The inflammatory and immune herd plots were of skewed distribution types.
Publication Date: 2021-09-07
Journal: Materials today. Proceedings


Antimicrobial protein REG3A and signaling networks are predictive of stroke outcomes.
Regenerating Family Member 3 Alpha (REG3A) is a multifunctional protein with antimicrobial activity, and primarily secreted by the intestine and pancreas. Studies have shown an increased expression of REG3A in systemic inflammatory responses to acute injury and infection, but studies investigating REG3A during the pathogenesis of ischemic stroke are limited. The aims of this study were to examine the associations between arterial expression of REG3A and other arterial inflammatory proteins implicated in stroke pathogenesis, as well as associations between REG3A and markers of poor outcome for ischemic stroke. The University of Kentucky Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) protocol ( NCT03153683) utilizes thrombectomy to isolate intracranial arterial blood (i.e. distal to thrombus) and systemic arterial blood (i.e. carotid). Samples were analyzed by Olink Proteomics for N = 42 subjects. Statistical analyses of plasma proteins included 2-sample t-tests, spearman and biserial correlations, and robust regression models to elucidate network signaling and association to clinical outcomes. Results indicated that levels of systemic REG3A were positively correlated with inflammatory proteins interleukin IL6 (R = 0.344, p = 0.030) and IL17C (R = 0.468, p = 0.002). 2-sided t- tests examining differences of systemic REG3A within quartiles of NIHSS admission score depicted significant differences between quartiles. Those with NIHSS scores corresponding to moderate and moderate-severe neurofunctional deficits had significantly higher levels of systemic REG3A compared to those with NIHSS scores corresponding to mild and mild-moderate neurofunctional deficits (p = 0.016). STRING analyses of proteins in each robust regression model demonstrated substantial networking between REG3A and other systemic proteins highly relevant to ischemic stroke. The present study provides novel data on systemic REG3A in the context of ischemic stroke. These results demonstrate the influential role of REG3A regarding surrogate functional and radiographic outcomes of stroke severity. Additionally, they provide novel insight into the role of REG3A and related proteins during the complex neuroinflammatory process of ischemic stroke. These data provide a foundation for future studies to investigate REG3A and related networking proteins as potential biomarkers with prognostic potential, as well as potential therapeutic targets.
Publication Date: 2021-09-25
Journal: Journal of neurochemistry


Genetic profiles of subcutaneous panniculitis-like T-cell lymphoma and clinicopathological impact of HAVCR2 mutations.
Recent studies identified germline mutations in HAVCR2 (encoding T-cell immunoglobulin mucin 3) as a genetic factor that predisposes to subcutaneous panniculitis-like T-cell lymphoma (SPTCL). However, the differences between HAVCR2-mutated (HAVCR2MUT) and HAVCR2 wild-type (HAVCR2WT) SPTCLs remain unclear. A nationwide cohort of 53 patients with SPTCL diagnosed at 8 Korean institutions was established. Whole-exome sequencing and RNA-sequencing were performed on 8 patients in the discovery set. In the validation set, targeted gene sequencing or direct sequencing of HAVCR2 was performed. Of 49 patients with available HAVCR2 status, 25 (51.0%) were HAVCR2Y82C. HAVCR2Y82C was associated with younger age (P = .001), development of hemophagocytic lymphohistiocytosis or hemophagocytic lymphohistiocytosis-like systemic illness (P < .001), and short relapse-free survival (RFS) (P = .023). Most mutated genes in SPTCLs were involved in immune responses, epigenetic modifications, and cell signaling. Mutations in UNC13D, PIAS3, and KMT2D were more frequent in HAVCR2WT SPTCLs. At the gene expression level, HAVCR2Y82C SPTCLs were enriched in genes involved in IL6-JAK-STAT3 signaling and in tumor necrosis factor-α signaling via NF-κB. CCR4 was significantly upregulated in HAVCR2WT SPTCLs both at the messenger RNA level and at the protein level. We established a risk stratification system for SPTCL by integrating clinical and histopathological features, including age and HAVCR2 mutation status. This risk stratification system was strongly associated with RFS (P = .031). In conclusion, the HAVCR2Y82C mutation was common in Korean patients with SPTCL and was associated with unique clinicopathological and genetic features. Combining clinicopathological parameters could aid in predicting prognosis for patients with SPTCL.
Publication Date: 2021-09-18
Journal: Blood advances


Interleukin-6 gene -174G>C promoter polymorphism reduces the risk of periodontitis in Brazilian populations: A meta-analysis.
Periodontitis is a host-mediated oral disease caused by multifactorial microbes. Previous studies suggested that interleukin-6 (IL-6) gene promoter polymorphisms (-174G>C) are associated with the risk of periodontitis, although the results were inconclusive. This study investigated the association between IL-6 -174G>C polymorphism and susceptibility to periodontitis. A comprehensive search was conducted in PubMed, EMBASE, Web of Science, and Google Scholar databases to retrieve relevant studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the association between 174G>C polymorphism and the risk of periodontitis. Cochrane Q and I Our results showed significant differences in the allelic (C vs. G: OR = 0.82, CI = 0.65-1.03), recessive (CC vs. GC+GG: OR = 0.69, CI = 0.42- 1.13), and dominant (GC+CC vs. GG: OR = 0.85, CI = 0.63-1.13) genetic models of the IL6 -174G>C polymorphism and risk of periodontitis. Furthermore, subgroup analysis showed decreased susceptibility to periodontitis associated with IL6 -174 G>C in a Brazilian population (C vs. G: OR = 0.60, CI = 0.41- 0.88; GC+CC vs. GG: OR = 0.57, CI = 0.42- 0.78) but not in Asian or Caucasian populations. The findings of this study revealed that the IL6 -174 "C" allele is protective against periodontitis in the Brazilian population.
Publication Date: 2021-09-04
Journal: Journal of oral biosciences


Identification of ferroptosis-associated genes exhibiting altered expression in response to cardiopulmonary bypass during corrective surgery for pediatric tetralogy of fallot.
Tetralogy of Fallot (ToF) is a life-threatening congenital cardiovascular disorder. Currently, the most effective therapeutic intervention for pediatric ToF remains corrective surgery with cardiopulmonary bypass (CPB). Ferroptosis is an iron-dependent form of regulated cell death, driven by an accumulation of lipid peroxides to levels sufficient to trigger cell death. Ferroptosis was recently linked to cardiac ischemia and reperfusion injury. However, few studies have examined CPB-associated ferroptosis. In the current study, pediatric ToF patient pre- and post-CPB atrial biopsy gene expression profiles were downloaded from a public database, and 117 differentially expressed genes (DEGs) were identified using the Wilcoxon rank-sum test and weighted gene correlation network analysis. These were screened for ferroptosis-associated genes using the FerrDb database, thereby identifying ten genes. Finally, the construction of gene-microRNA (miRNA) and gene-transcription factor (TF) networks, in conjunction with gene ontology and biological pathway enrichment analysis, were used to inform hypotheses regarding the molecular mechanisms underlying CPB-associated ferroptosis. Ten genes involved in CPB-associated ferroptosis(ATF3,TNFAIP3,CDKN1A, ZFP36, JUN,SLC2A3, IL6, CXCL2, PTGS2, and DDIT3). Ferroptosis-associated genes were largely involved in myocardial inflammatory responses and may be regulated by a number of identified miRNAs and TFs, thereby suggesting modulatable pathways potentially involved in CPB-associated ferroptosis. Results suggest that CPB precipitates ferroptosis within cardiac tissue during corrective Surgery for Pediatric Tetralogy of Fallot. These findings may ultimately help improve outcomes of corrective surgery for pediatric ToF.
Publication Date: 2021-10-13
Journal: Science progress


Chimeric antigen receptor T cells self-neutralizing IL6 storm in patients with hematologic malignancy.
IL6 is one of the most elevated cytokines during chimeric antigen receptor (CAR) T cell cytokine release syndrome (CRS), and IL6R blockade by Tocilizumab has successfully relieved the most life-threatening aspects of CRS in patients. In addition, latest studies demonstrated the essential role of IL1 in driving CART induced neurotoxicity in mouse models. Here we present a clinical investigation (ChiCTR2000032124; ChiCTR2000031868) of anti-CD19 and anti-BCMA CART (41BBζ) secreting an anti-IL6 scFv and IL1 receptor antagonist (IL1RA) in treating patients with hematologic malignancy. Our results revealed that IL6 and IL1B were maintained at low levels without significant elevation during CRS, rendering Tocilizumab dispensable. Moreover, treated patients did not show neurotoxicity during CRS and exhibited mild to moderate CRS. Notably, we observed high rate of complete response (CR) and significant CART expansion during treatment. In sum, we conclude that CART-secreting anti-IL6 scFv and IL1RA could self-neutralize IL6 storm and maintain low levels of IL1B during CART therapy to minimize IL6- and IL1-associated cytokine toxicity and neurotoxicity without impairing therapeutic efficacy.
Publication Date: 2021-09-15
Journal: Cell discovery


The association between interleukin-6 promoter polymorphisms and rheumatoid arthritis by ethnicity: A meta-analysis of 33 studies.
We performed a meta-analysis to determine the effect Interleukin-6 (IL-6) promoter polymorphism (-174 G>C, -572 G>C, and -597 G>A) have on the development rheumatoid arthritis (RA) by ethnicity. PubMed, EBSCO, LILACS, and Scopus databases were searched for studies exploring the association between any IL6 polymorphisms and RA until November 2018. Genotype distributions were extracted and, depending on the level heterogeneity, determined by the ψ From 708 identified publications, 33 were used in this analysis. For the -174 polymorphism, Asians (OR Here, the -174 G>C polymorphism increased the risk of developing RA in Asians and Middle East populations. Interestingly, for Latinos, the polymorphism was associated with a benefit. For the -572 polymorphism, only the Asian population showed an increased risk of developing RA for the CC genotype.
Publication Date: 2021-10-10
Journal: Reumatologia clinica


Glycosaminoglycan content of a mineralized collagen scaffold promotes mesenchymal stem cell secretion of factors to modulate angiogenesis and monocyte differentiation.
Effective design of biomaterials to aid regenerative repair of craniomaxillofacial (CMF) bone defects requires approaches that modulate the complex interplay between exogenously added progenitor cells and cells in the wound microenvironment, such as osteoblasts, osteoclasts, endothelial cells, and immune cells. We are exploring the role of the glycosaminoglycan (GAG) content in a class of mineralized collagen scaffolds recently shown to promote osteogenesis and healing of craniofacial bone defects. We previously showed that incorporating chondroitin-6-sulfate or heparin improved mineral deposition by seeded human mesenchymal stem cells (hMSCs). Here, we examine the effect of varying scaffold GAG content on hMSC behavior, and their ability to modulate osteoclastogenesis, vasculogenesis, and the immune response. We report the role of hMSC-conditioned media produced in scaffolds containing chondroitin-6-sulfate (CS6), chondroitin-4-sulfate (CS4), or heparin (Heparin) GAGs on endothelial tube formation and monocyte differentiation. Notably, endogenous production by hMSCs within Heparin scaffolds most significantly inhibits osteoclastogenesis via secreted osteoprotegerin (OPG), while the secretome generated by CS6 scaffolds reduced pro-inflammatory immune response and increased endothelial tube formation. All conditioned media down-regulated many pro- and anti-inflammatory cytokines, such as IL6, IL-1β, and CCL18 and CCL17 respectively. Together, these findings demonstrate that modifying mineralized collagen scaffold GAG content can both directly (hMSC activity) and indirectly (production of secreted factors) influence overall osteogenic potential and mineral biosynthesis as well as angiogenic potential and monocyte differentiation towards osteoclastic and macrophage lineages. Scaffold GAG content is therefore a powerful stimulus to modulate reciprocal signaling between multiple cell populations within the bone healing microenvironment.
Publication Date: 2021-08-10
Journal: Materialia


Integrated transcriptome profiling in THP-1 macrophages infected with bunyavirus SFTSV.
Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne bunyavirus that causes an emerging hemorrhagic fever termed SFTS with high mortality. However, knowledge of SFTSV-host interactions is largely limited. Here, we performed a global transcriptome analysis of mRNAs and lncRNAs in THP-1 macrophages infected with SFTSV for 24 and 48 h. A total of 2,334 differentially expressed mRNAs and 154 differentially expressed lncRNAs were identified with 577 mRNAs and 31 lncRNAs commonly changed at both time points. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that differentially expressed mRNAs were mainly associated with innate immune, cytokine signaling, systemic lupus erythematosus, and alcoholism. Differentially expressed lncRNAs were enriched in systemic lupus erythematosus, alcoholism, and ribosome. Bioinformatic analysis also revealed hub regulatory mRNAs including IL6, TNF, UBA52, SRC, IL10, CXCL10, and CDK1 and core regulatory lncRNAs including XLOC_083027 and XLOC_113317. Transcription factor analysis of the differentially expressed mRNAs revealed that IRF1, SPI1, SPIB, ELF5, and FEV were enriched during SFTSV infection. Taken together, our studies illustrate the complex interaction between THP-1 macrophages and SFTSV.
Publication Date: 2021-10-13
Journal: Virus research


Mechanisms and molecular targets of the Yu-Ping-Feng powder for allergic rhinitis, based on network pharmacology.
In traditional Chinese medicine (TCM), Yu-Ping-Feng powder (YPFP) has been used to treat allergic rhinitis (AR) for centuries. However, the mechanisms underlying its effects or its molecular targets in AR treatment are yet to be elucidated. Therefore, the active compounds of YPFP and their targets were collected and identified from the Traditional Chinese Medicine Systems Pharmacology database. Moreover, AR-associated targets were acquired from the GeneCards and Online Mendelian Inheritance in Man database. Proteins interactions network of YPFP presumed targets and AR-associated targets were examined and merged to reveal the candidate YPFP targets against AR.Cytoscape software and BisoGenet Database were employed to perform the Visualization and Integrated Discovery (Cluster Profiler R package, version: 3.8.1). Kyoto Encyclopedia of Genes and Genomes and genome pathway analyses. To identify the key target genes, a gene-pathway network has been constructed.We identified 44 effective active compounds and 622 YPFP targets. Also 1324 target genes related to AR were identified. Twenty pathways, including those of AGE-RAGE signaling, fluid shear stress, atherosclerosis, PI3K-Akt signaling, and tumor necrosis factor signaling was enriched significantly. MAPK1 was identified as the core gene, while others including RELA, AKT1, NFKBIA, IL6, and JUN, were also important in the gene-pathway network. Clearly, network pharmacology can be applied in revealing the molecular targets and mechanisms of action of complex herbal preparations.These findings suggested that YPFP could treat AR by regulating immunological functions, diminishing inflammation, and improving immunity through different pathways.
Publication Date: 2021-09-04
Journal: Medicine


Crocus sativus (saffron) petals extract and its active ingredient, anthocyanin improves ovarian dysfunction, regulation of inflammatory genes and antioxidant factors in testosterone-induced PCOS mice.
Saffron petal has traditionally been used to treat a variety of diseases, such as gynecological disease such as primary dysmenorrhea and premenstrual tension. Polycystic Ovary Syndrome (PCOS) is a form of gynecological disease that causes amenorrhea, infertility, menopausal and urogenital disorders. This disease may be treated with saffron petals. In this study, the effects of saffron petal extract (SPE) and saffron petal anthocyanins (SPA) on ovarian hormones, steroidogenic enzymes, ovarian dysfunction, regulation of anti-inflammatory genes, and antioxidant factors in female PCOS mice were studied. The PCOS mouse model was induced by testosterone enanthate (TE), and an in vivo evaluation of whether the dietary consumption of SPE and SPA improved the PCOS-like symptoms was conducted. The luteinizing hormone (LH), testosterone, and estrogen levels increased in PCOS mice, but decreased following SPE and SPA treatment. In the PCOS mice, the reduced follicular-stimulating hormone (FSH) progesterone levels were restored to that of normal controls with SPE and SPA treatment in serum. The transcription level(s) of gonadotropin receptors (Fshr and Lhr), steroid receptors (Pgr, and Esr1), inflammatory markers (TNFα, IL1ß, IL6 and IL18), inflammatory-related factors (NF-κB, NF-κB p65, IκB) and antioxidant enzymes (GPx, SOD, CAT, GST, and GSH) changed under the PCOS condition. Moreover, they were regulated by SPE and SPA treatment in PCOS mice ovaries. The reproductive tissues of TE induced PCOS mice were restored into estrogenic conditions from androgen environments. The study of antioxidant activity of SPE and SPA using FRAP and DPPH tests showed high antioxidant activity. These results suggest that SPE and SPA ameliorates symptoms of PCOS by improving dysregulation of ovarian steroids, steroidogenic, antioxidant enzymes and inflammatory markers in PCOS mice.
Publication Date: 2021-09-05
Journal: Journal of ethnopharmacology


Assessment of cytokines, microRNA and patient related outcome measures in conversion disorder/functional neurological disorder (CD/FND): The CANDO clinical feasibility study.
Conversion disorder/functional neurological disorder (CD/FND) occurs often in neurological settings and can lead to long-term distress, disability and demand on health care services. Systemic low-grade inflammation might play a role, however, the pathogenic mechanism is still unknown. 1) To explore the feasibility to establish and assess a cohort of CD/FND with motor symptoms, involving persons with lived experience (PPI). 2) To generate proof of concept regarding a possible role for cytokines, microRNA, cortisol levels and neurocognitive symptoms in patients with motor CD/FND. Feasibility study. The study showed active involvement of patients despite high clinical illness burden and disability, neurocognitive symptoms, childhood adverse experiences (ACE) and current life events. The study provided valuable knowledge regarding the feasibility of conducting a study in these patients that will inform future study phases. In the sample there were elevated levels of IL6, IL12, IL17A, IFNg, TNFa and VEGF-a, suggesting systemic low-grade inflammation. Also, microRNAs involved in inflammation and vascular inflammation were correlated with TNFa and VEGFa respectively, suggesting proof of concept for an epigenetic mechanism. Owing to the COVID-19 outbreak, the patient sample was limited to 15 patients. It is a novelty that this study is conducted in the clinical setting. This innovative, translational study explores stress-related SLI in CD/FND patients and the feasibility of a larger project aiming to develop new treatments for this vulnerable population. Given the positive findings, there is scope to conduct further research into the mechanism of disease in CD/FND.
Publication Date: 2021-10-01
Journal: Brain, behavior, & immunity - health


[Study on potential effective components and mechanism of Zhishe Tongluo Capsules in treatment of ischemic stroke].
To explore the potential effective components and mechanism of Zhishe Tongluo Capsules in the treatment of ischemic stroke via network pharmacology, molecular docking and cellular experiment. The chemical constituents of Zhishe Tongluo Capsules were found by TCMSP, BATMAN-TCM and literatures. The constituents-target network was predicted by BATMAN-TCM database. Key words such as cerebral stroke, ischemic stroke and cerebral ischemic stroke were used to search ischemic stroke related targets, and then Venny Map was constructed based on the targets of traditional Chinese medicine and the targets of ischemic stroke. The overlapping targets were imported into STRING database to establish the interaction network. Furthermore, the core targets were screened out by Cytoscape software. Go and KEGG enrichment analysis were performed through DVIAD database. The results showed a total of 193 potential chemical constituents, 985 drug targets and 6 035 disease targets. There were 631 potential targets, 44 core targets and 55 potential active components for treating ischemic stroke through Venny mapping. GO enrichment analysis mainly involved response to hypoxia and positive regulation of ERK1/ERK2. KEGG pathway enrichment analysis mainly involved cholinergic synapse, cAMP signaling pathway, and calcium signaling pathway. Molecular docking data revealed that TP53, EGFR, IL6, INS, TNF and SRC had a good capability to bind with their corresponding active components. To ensure the protective effect Zhishe Tongluo Capsules on the inflammation reaction, an in vitro model of lipopolysaccharide(LPS)-induced RAW264.7 cells was built. The contents of IL-1α, IL-1β, IL-6 and TNF-α in the supernatant were significantly decreased by enzyme linked immunosorbent assay(ELISA). The findings suggested that Zhishe Tongluo Capsules could prevent the injury of ischemic stroke by inhibiting the inflammation.
Publication Date: 2021-09-02
Journal: Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica


Computational Analysis Illustrates the Mechanism of Qingfei Paidu Decoction in Blocking the Transition of COVID-19 Patients from Mild to Severe Stage
The epidemic of SARS-CoV-2 has made COVID-19 a serious threat to human health around the world. The severe infections of SARS-CoV-2 are usually accompanied by higher mortality. Although the Qingfei Paidu Decoction (QFPDD) has been proved to be effective in blocking the transition of COVID-19 patients from mild to severe stage, its mechanism remains unclear. This study aims to explore the mechanism of QFPDD in blocking the transition of COVID-19 patients from mild to severe stage. In the process of screening active ingredients, oral bioavailability (OB) and drug likeness (DL) are key indicators, which can help to screen out pivotal compounds. Therefore, with the criteria of OB≥30% and DL≥0.18 , we searched active ingredients of QFPDD in the Traditional Chinese Medicine Systems Pharmacology (TCMSP, by using its 21 herbs as keywords. We filtered out 6 pivotal ingredients from QFPDD by using the bioinformatics method, namely quercetin, luteolin, berberine, hederagenin, shionone and kaempferol, which can inhibit the highly expressed genes (i.e. CXCR4, ICAM1, CXCL8, CXCL10, IL6, IL2, CCL2, IL1B, IL4, IFNG) in severe COVID-19 patients. By performing KEGG enrichment analysis, we found seven pathways, namely TNF signaling pathway, IL-17 signaling pathway, Toll-like receptor signaling pathway, NF-kappa B signaling pathway, HIF-1 signaling pathway, JAK-STAT signaling pathway, and Th17 cell differentiation, by which QFPDD could block the transition of COVID-19 patients from mild to severe stage. QFPDD can prevent the deterioration of COVID-19 in the following mechanisms, i.e. inhibiting SARS-CoV-2 invasion and replication, anti-inflammatory and immune regulation, and repairing body damage. These results will be helpful for the prevention and treatment of COVID-19.
Publication Date: 2021-09-09
Journal: Current gene therapy


Exploring the Pharmacological Mechanism of Radix Salvia Miltiorrhizae in the Treatment of Radiation Pneumonia by Using Network Pharmacology.
Radiation pneumonia (RP) is the most common complication of radiotherapy to the thorax and seriously affects the survival rate and quality of life of patients. Radix Salviae Miltiorrhizae (RSM) is an ancient Chinese medicine, whose main pharmacological effect is to promote blood circulation and remove stasis. A growing number of studies have proved that RSM has a good effect on RP. However, the underlying mechanism is still unclear and needs to be fully elucidated. The effective components and predictive targets of RSM were analyzed by Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, and the related targets of RP were predicted by GeneCards database. The common targets of the two targets mentioned above were analyzed by protein-protein interaction on the STRING website, GO and KEGG analysis on the DAVID website, visualization by CytoScape3.7.0, and screening for Hubber gene by cytoHubber plug-in. A search of the TCMSP database revealed that RSM contains 65 chemical constituents and 165 potential protein targets. A total of 2,162 protein targets were found to be associated with RP. The top 10 hub genes were obtained by MCC algorithm for 70 common genes, including TP53, CASP3, MAPK1, JUN, VEGFA, STAT3, PTGS2, IL6, AKT1, and FOS. By analyzing the Gene Ontology, The anti-radiation pneumonia effect of RSM is that it performs molecular functions (protein homodimerization activity) in the nucleus through three biological processes (positive regulation of transcription from RNA polymerase II promoter,Extrinsic apoptotic signaling pathway in absence of ligand and lipopolysaccharide-mediated signaling pathway). Through KEGG analysis, the mechanism of RSM treatment of radiation pneumonia may be through PI3K-Akt, HIF-1, TNF signaling pathways. Through network pharmacology analysis, we found the possible target genes of RSM on RP and revealed the most likely signaling pathway, providing theoretical basis for further elucidating the potential mechanism of RSM on RP.
Publication Date: 2021-08-17
Journal: Frontiers in oncology


Continuous digital hypothermia reduces expression of keratin 17 and 1L-17A inflammatory pathway mediators in equine laminitis induced by hyperinsulinemia.
The euglycemic hyperinsulinemic clamp model (EHC) of equine endocrinopathic laminitis induces rapid loss of lamellar tissue integrity, disrupts keratinocyte functions, and induces inflammation similar to natural disease. Continuous digital hypothermia (CDH) blocks tissue damage in this experimental model, allowing identification of specific genes or molecular pathways contributing to disease initiation or early progression. Archived lamellar tissues (8 horses, 48 h EHC treatment, including CDH-treated front limbs) were used to measure relative expression levels of genes encoding keratin 17 (KRT17), a stress-induced intermediate filament protein, and genes upregulated downstream of keratin 17 and/or interleukin 17A (IL-17A), as mediators of inflammation. Compared to front or hind limbs at ambient temperature, CDH resulted in significantly lower expression of KRT17, CCL2, CxCL8, PTGS2 (encoding COX2), IL6, TNFα, S100A8 and MMP1. By immunofluorescence, COX2 was robustly expressed in lamellar keratinocytes from ambient limbs, but not in CDH-treated limbs. Genes not significantly reduced by CDH were IL17A, DEFB4B, S100A9 and MMP9. Overall, 8 of 12 genes were expressed at lower levels in the CDH-treated limb. These 8 genes are expressed by wounded or stress-activated keratinocytes in human disease or mouse models, highlighting the role of keratinocytes in equine laminitis.
Publication Date: 2021-09-26
Journal: Veterinary immunology and immunopathology