[Exploring efficacy of Chinese medicine injection for promoting blood circulation and removing blood stasis in treatment of acute cerebral infarction based on two complex network analysis methods].
This study aims to explore the efficacy of Chinese medicine injections( CMIs) for promoting blood circulation and removing blood stasis for acute cerebral infarction from the perspectives of clinical medication and mechanism of action based on two complex network analysis methods. Firstly,the current 13 kinds of CMIs for acute cerebral infarction were obtained from 2019 List of medicines for national basic medical insurance,industrial injury insurance and maternity insurance with the method of network Meta-analysis. Secondly,with the use of network pharmacology,the mechanisms of top 2 CMIs with the highest therapeutic effect for acute cerebral infarction were explored from two levels including core target and network function enrichment. The result of network Meta-analysis showed Mailuoning Injection was superior to Danhong Injection in terms of total effectiveness rate for neurological deficit score and NIHSS score. The network pharmacology results showed that Mailuoning Injection had more core targets,interaction networks,enriched biological functions and more signaling pathways than Danhong Injection for cerebral infarction. Both two CMIs can play a role in treating cerebral infarction through core targets such as TP53 and NOS3,biological processes such as fibrinolysis,nitric oxide biosynthesis,nitric oxide-mediated signal transduction,negative regulation of apoptosis in endothelial cells and apoptosis process,as well as the signaling pathways such as PI3 K-Akt signaling pathway,HIF-1 signaling pathway and cell apoptosis signaling pathways. The results of pharmacological studies explained their differences in clinical efficacy to a certain extent. A research strategy based on curative effect should be advocated in efficacy evaluation of traditional Chinese medicine,where comparative research on clinical efficacy can be conducted firstly,and then mechanism research based on outstanding effective drugs to better provide references and basis for selection of similar competitive drugs for one disease in the clinical practice.
Publication Date: 2021-08-18
Journal: Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
Breast adipose regulation of premenopausal breast epithelial phenotype involves interleukin 10.
Epidemiological studies inversely associate body mass index (BMI) with breast cancer risk in premenopausal women, but the pathophysiological linkage remains ill-defined. Despite the documented relevance of the 'local' environment to breast cancer progression and the well-accepted differences in transcriptome and metabolic properties of anatomically distinct fat depots, specific breast adipose contributions to the proliferative potential of non-diseased breast glandular compartment are not fully understood. To address early breast cancer causation in the context of obesity status, we compared the cellular and molecular phenotypes of breast adipose and matched breast glandular tissue from premenopausal non-obese (mean BMI=27 kg/m2) and obese (mean BMI=44 kg/m2) women. Breast adipose from obese women showed higher expression levels of adipogenic, pro-inflammatory and estrogen synthetic genes, than from non-obese women. Obese breast glandular tissue displayed lower proliferation and inflammatory status and higher expression of anti-proliferative/pro-senescence biomarkers TP53 and p21, than from non-obese women. Transcript levels for T-cell receptor and co-receptors CD3 and CD4 were higher in breast adipose of obese cohorts, coincident with elevated adipose Interleukin 10 (IL10) and FOXP3 gene expression. In human breast epithelial cell lines MCF10A and HMEC, recombinant human IL10 reduced cell viability and CCND1 transcript levels, increased those of TP53 and p21, and promoted (MCF10A) apoptosis. Our findings suggest that breast adipose-associated IL10 may mediate paracrine interactions between non-diseased breast adipose and breast glandular compartments and highlight how breast adipose may program the local inflammatory milieu, partly by recruiting FOXP3+ T regulatory cells, to influence premenopausal breast cancer risk.
Publication Date: 2021-08-13
Journal: Journal of molecular endocrinology
TCF19 and p53 regulate transcription of TIGAR and SCO2 in HCC for mitochondrial energy metabolism and stress adaptation.
Alteration in glucose homeostasis during cancer metabolism is an important phenomenon. Though several important transcription factors have been well studied in the context of the regulation of metabolic gene expression, the role of epigenetic readers in this regard remains still elusive. Epigenetic reader protein transcription factor 19 (TCF19) has been recently identified as a novel glucose and insulin-responsive factor that modulates histone posttranslational modifications to regulate glucose homeostasis in hepatocytes. Here we report that TCF19 interacts with a non-histone, well-known tumor suppressor protein 53 (p53) and co-regulates a wide array of metabolic genes. Among these, the p53-responsive carbohydrate metabolic genes Tp53-induced glycolysis and apoptosis regulator (TIGAR) and Cytochrome C Oxidase assembly protein 2 (SCO2), which are the key regulators of glycolysis and oxidative phosphorylation respectively, are under direct regulation of TCF19. Remarkably, TCF19 can form different transcription activation/repression complexes which show substantial overlap with that of p53, depending on glucose-mediated variant stress situations as obtained from IP/MS studies. Interestingly, we observed that TCF19/p53 complexes either have CBP or HDAC1 to epigenetically program the expression of TIGAR and SCO2 genes depending on short-term high glucose or prolonged high glucose conditions. TCF19 or p53 knockdown significantly altered the cellular lactate production and led to increased extracellular acidification rate. Similarly, OCR and cellular ATP production were reduced and mitochondrial membrane potential was compromised upon depletion of TCF19 or p53. Subsequently, through RNA-Seq analysis from patients with hepatocellular carcinoma, we observed that TCF19/p53-mediated metabolic regulation is fundamental for sustenance of cancer cells. Together the study proposes that TCF19/p53 complexes can regulate metabolic gene expression programs responsible for mitochondrial energy homeostasis and stress adaptation.
Publication Date: 2021-08-10
Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) Is Upregulated in Lymphocytes Stimulated with Concanavalin A.
The glycolytic modulator TP53-Inducible Glycolysis and Apoptosis Regulator (TIGAR) is overexpressed in several types of cancer and has a role in metabolic rewiring during tumor development. However, little is known about the role of this enzyme in proliferative tissues under physiological conditions. In the current work, we analysed the role of TIGAR in primary human lymphocytes stimulated with the mitotic agent Concanavalin A (ConA). We found that
Publication Date: 2021-07-25
Journal: International journal of molecular sciences
Genome-wide expression analysis reveal host genes involved in immediate-early infections of different sheeppox virus strains.
This study explored the transcriptome of lamb testis cells infected with sheeppox virus (SPPV) wild strain (WS) and vaccine strain (VS) at an immediate-early time. Most of the differentially expressed genes (DEGs) and differentially expressed highly connected (DEHC) gene network were found to be involved in SPPV-VS infection compared to SPPV-WS. Further, the signaling pathways were mostly involved in SPPV-VS infection than SPPV-WS. SPPV modulates the expression of several important host proteins such as CD40, FAS, ITGβ1, ITGα1, Pak1, Pak2, CD14, ILK leading to viral attachment and entry; immune-related DEGs such as MAPK, JNK, ERK, NFKB, IKB, PI3K, STAT which provide optimal cellular condition for early viral protein expression; and FOXO3, ATF, CDKNA1, TCF, SRF, BDNF which help in inducing apoptosis and MPTP, BAD and Tp53 inhibits apoptosis or cell death at the immediate-early time. The results captured the specific genes and enabled to understand distinct pathogenic mechanisms employed by VS and WS of SPPV.
Publication Date: 2021-07-19
The E3 ubiquitin ligase TRIM31 is involved in cerebral ischemic injury by promoting degradation of TIGAR.
Tripartite motif (TRIM) 31 has been implicated in diverse biological and pathological conditions. However, whether TRIM31 plays a role in ischemic stroke progression is not clarified. Here we demonstrated that TRIM31 was significantly downregulated in the ischemic brain and the deficiency of TRIM31 alleviated brain injury induced by middle cerebral artery occlusion by reducing reactive oxygen species production and maintaining mitochondrial homeostasis. Mechanistically, we found that TRIM31 is an E3 ubiquitin ligase for TP53-induced glycolysis and apoptosis regulator (TIGAR), which confers protection against brain ischemia by increasing the pentose phosphate pathway flux and preserving mitochondria function. TRIM31 interacted with TIGAR and promoted the polyubiquitination of TIGAR, consequently facilitated its degradation in a proteasome-dependent pathway. Furthermore, TIGAR knockdown effectively abolished the protective effect of TRIM31 deficiency after cerebral ischemia. In conclusion, we identified that TRIM31 was a novel E3 ubiquitin ligase for TIGAR, played a critical role in regulating its protein level, and subsequently involved in the ischemic brain injury, suggesting TRIM31 as a potential therapeutic target for ischemic stroke.
Publication Date: 2021-07-05
Journal: Redox biology
Tin Mesoporphyrin Selectively Reduces Non-Small-Cell Lung Cancer Cell Line A549 Proliferation by Interfering with Heme Oxygenase and Glutathione Systems.
In order to maintain redox homeostasis, non-small-cell lung cancer (NSCLC) increases the activation of many antioxidant systems, including the heme-oxygenase (HO) system. The overexpression of HO-1 has been often associated with chemoresistance and tumor aggressiveness. Our results clearly showed an overexpression of the HO-1 protein in A549 NSCLC cell lines compared to that in non-cancerous cells. Thus, we hypothesized that "off-label" use of tin mesoporphyrin, a well-known HO activity inhibitor clinically used for neonatal hyperbilirubinemia, has potential use as an anti-cancer agent. The pharmacological inhibition of HO activity caused a reduction in cell proliferation and migration of A549. SnMP treatment caused an increase in oxidative stress, as demonstrated by the upregulation of reactive oxygen species (ROS) and the depletion of glutathione (GSH) content. To support these data, Western blot analysis was performed to analyze glucose-6-phosphate dehydrogenase (G6PD), TP53-induced glycolysis and the apoptosis regulator (TIGAR), and the glutamate cysteine ligase catalytic (GCLC) subunit, as they represent the main regulators of the pentose phosphate pathway (PPP) and glutathione synthesis, respectively. NCI-H292, a subtype of the NSCLC cell line, did not respond to SnMP treatment, possibly due to low basal levels of HO-1, suggesting a cellular-dependent antitumorigenic effect. Altogether, our results suggest HO activity inhibition may represent a potential target for selective chemotherapy in lung cancer subtypes.
Publication Date: 2021-07-03
Network Pharmacology and Molecular Docking Study on the Potential Mechanism of Yi-Qi-Huo-Xue-Tong-Luo Formula in Treating Diabetic Peripheral Neuropathy.
To investigate the potential mechanism of action of Yi-Qi-Huo-Xue-Tong-Luo formula (YQHXTLF) in the treatment of diabetic peripheral neuropathy (DPN).
Network pharmacology and molecular docking techniques were used in this study. Firstly, the active ingredients and the corresponding targets of YQHXTLF were retrieved using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) platform; subsequently, the targets related to DPN were retrieved using GeneCards, Online Mendelian Inheritance in Man (OMIM), Pharmgkb, Therapeutic Target Database (TTD) and Drugbank databases; the common targets of YQHXTLF and DPN were obtained by Venn diagram; afterwards, the "YQHXTLF Pharmacodynamic Component-DPN Target" regulatory network was visualized using Cytoscape 3.6.1 software, and Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on the potential targets using R 3.6.3 software. Finally, molecular docking of the main chemical components in the PPI network with the core targets was verified by Autodock Vina software.
A total of 86 active ingredients and 229 targets in YQHXTLF were screened, and 81 active ingredients and 110 targets were identified to be closely related to diabetic peripheral neuropathy disease. PPI network mapping identified TP53, MAPK1, JUN, and STAT3 as possible core targets. KEGG pathway analysis showed that these targets are mostly involved in AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, and MAPK signaling pathway. The molecular docking results showed that the main chemical components of YQHXTLF have a stable binding activity to the core pivotal targets.
YQHXTLF may act on TP53, MAPK1, JUN, and STAT3 to regulate inflammatory response, apoptosis, or proliferation as a molecular mechanism for the treatment of diabetic peripheral neuropathy, reflecting its multitarget and multipathway action, and providing new ideas to further uncover its pharmacological basis and mechanism of action.
Publication Date: 2021-06-24
Journal: Journal of diabetes research
Rad21l1 cohesin subunit is dispensable for spermatogenesis but not oogenesis in zebrafish.
During meiosis I, ring-shaped cohesin complexes play important roles in aiding the proper segregation of homologous chromosomes. RAD21L is a meiosis-specific vertebrate cohesin that is required for spermatogenesis in mice but is dispensable for oogenesis in young animals. The role of this cohesin in other vertebrate models has not been explored. Here, we tested if the zebrafish homolog Rad21l1 is required for meiotic chromosome dynamics during spermatogenesis and oogenesis. We found that Rad21l1 localizes to unsynapsed chromosome axes. It is also found between the axes of the mature tripartite synaptonemal complex (SC) in both sexes. We knocked out rad21l1 and found that nearly all rad21l1-/- mutants develop as fertile males, suggesting that the mutation causes a defect in juvenile oogenesis, since insufficient oocyte production triggers female to male sex reversal in zebrafish. Sex reversal was partially suppressed by mutation of the checkpoint gene tp53, suggesting that the rad21l1 mutation activates Tp53-mediated apoptosis or arrest in females. This response, however, is not linked to a defect in repairing Spo11-induced double-strand breaks since deletion of spo11 does not suppress the sex reversal phenotype. Compared to tp53 single mutant controls, rad21l1-/- tp53-/- double mutant females produce poor quality eggs that often die or develop into malformed embryos. Overall, these results indicate that the absence of rad21l1-/- females is due to a checkpoint-mediated response and highlight a role for a meiotic-specific cohesin subunit in oogenesis but not spermatogenesis.
Publication Date: 2021-06-18
Journal: PLoS genetics
The synergy of BET inhibitors with aurora A kinase inhibitors in MYCN-amplified neuroblastoma is heightened with functional TP53.
Amplification of MYCN is a poor prognostic feature in neuroblastoma (NBL) indicating aggressive disease. We and others have shown BET bromodomain inhibitors (BETi) target MYCN indirectly by downregulating its transcription. Here we sought to identify agents that synergize with BETi and to identify biomarkers of resistance. We previously performed a viability screen of ∼1,900 oncology-focused compounds combined with BET bromodomain inhibitors against MYCN-amplified NBL cell lines. Reanalysis of our screening results prominently identified inhibitors of aurora kinase A (AURKAi) to be highly synergistic with BETi. We confirmed the anti-proliferative effects of several BETi+AURKAi combinations in MYCN-amplified NBL cell lines. Compared to single agents, these combinations cooperated to decrease levels of N-myc. We treated both TP53-wild type and mutant, MYCN-amplified cell lines with the BETi JQ1 and the AURKAi Alisertib. The combination had improved efficacy in the TP53-WT context, notably driving apoptosis in both genetic backgrounds. JQ1+Alisertib combination treatment of a MYCN-amplified, TP53-null or TP53-restored genetically engineered mouse model of NBL prolonged survival better than either single agent. This was most profound with TP53 restored, with marked tumor shrinkage and apoptosis induction in response to combination JQ1+Alisertib. BETi+AURKAi in MYCN-amplified NBL, particularly in the context of functional TP53, provided anti-tumor benefits in preclinical models. This combination should be studied more closely in a pediatric clinical trial.
Publication Date: 2021-06-10
Journal: Neoplasia (New York, N.Y.)
Network pharmacology identifies IL6 as an important hub and target of tibolone for drug repurposing in traumatic brain injury.
Traumatic brain injury (TBI) is characterized by a complex network of signals mediating inflammatory, proliferative and apoptotic processes during its acute and chronic phases. Current therapies mitigate damage and are mainly for palliative care and there are currently no effective therapies for secondary damage. This suggests a need to discover a compound with a greater spectrum of action that can control various pathological aspects of TBI. Here we used a network pharmacology approach to explore the benefits of tibolone, an estrogen and androgen receptor agonist with broader actions in cells, as a possible repurposing drug for TBI therapy. Using different databases we retrieved the targets significantly associated to TBI and tibolone, obtaining 2700 and 652, respectively. The top 10 GO enriched terms were mostly related to cell proliferation, apoptosis and inflammation. Following protein-protein functional analysis, the top connected proteins were related to kinase activity (MAPK1/14/3, AKT1 PIK3R1), apoptosis (TP53, CASP3), growth factors (EGFR), estrogen signalling (ESR1) and inflammation (IL6, TNF), with IL6 as an important signalling hub belonging to the top GO categories. Thus, we identified IL6 as a cellular node which we then validated using molecular mechanics-generalized born surface area (MMGBSA) and docking to explore which tibolone metabolite might interact with this protein. Both 3α and 3β-OH tibolone seemed to bind better to IL6 at important sites responsible for its binding to IL6R. In conclusion, our study demonstrates key hubs involved in TBI pathology which indicates IL6 as a target molecule of tibolone as drug repurposing for TBI therapy.
Publication Date: 2021-06-01
Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
TIGAR mitigates atherosclerosis by promoting cholesterol efflux from macrophages.
TP53-induced glycolysis and apoptosis regulator (TIGAR) is now characterized as a fructose-2,6-bisphosphatase to reduce glycolysis and protect against oxidative stress. Recent studies have demonstrated that TIGAR is associated with cardiovascular disease. However, little is known about its role in atherosclerogenesis. In this study, we aimed to investigate the effect of TIGAR on atherosclerosis and explore the underlying molecular mechanism.
The Gene Expression Omnibus (GEO) datasets were used to analyze the differential expression of relative proteins. THP-1-derived macrophages were used as an in vitro model and apolipoprotein E-deficient (Apoe
Our results showed that TIGAR is increased upon the formation of macrophage foam cells and atherosclerosis. TIGAR knockdown markedly promoted lipid accumulation in macrophages. Silencing of TIGAR impaired cholesterol efflux and down-regulated the expression of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 by interfering with liver X receptor α (LXRα) expression and activity, but did not influence cholesterol uptake by macrophages. Additionally, this inhibitory effect of TIGAR deficiency on cholesterol metabolism was mediated through the ROS/CYP27A1 pathway. In vivo experiments revealed that TIGAR deficiency decreased the levels of ABCA1 and ABCG1 in plaques and aorta and impaired the capacity of RCT, thereby leading to the progression of atherosclerosis in Apoe
TIGAR mitigates the development of atherosclerosis by up-regulating ABCA1 and ABCG1 expression via the ROS/CYP27A1/LXRα pathway.
Publication Date: 2021-05-18
Cfdp1 controls the cell cycle and neural differentiation in the zebrafish cerebellum and retina.
Although the cell cycle and cell differentiation should be coordinately regulated to generate a variety of neurons in the brain, the molecules that are involved in this coordination still remain largely unknown. In this study, we analyzed the roles of a nuclear protein Cfdp1, which is thought to be involved in chromatin remodeling, in zebrafish neurogenesis.
Zebrafish cfdp1 mutants maintained the progenitors of granule cells (GCs) in the cerebellum, but showed defects in their differentiation to GCs. cfdp1 mutants showed an increase in phospho-histone 3 (pH 3)-positive cells and apoptotic cells, as well as a delayed cell cycle transition from the G2 to the M phase in the cerebellum. The inhibition of tp53 prevented apoptosis but not GC differentiation in the cfdp1 mutant cerebellum. A similar increase in apoptotic cells and pH 3-positive cells, and defective cell differentiation, were observed in the cfdp1 mutant retina. Although mitotic spindles formed, mitosis was blocked before anaphase in both the cerebellum and retina of cfdp1 mutant larvae. Furthermore, expression of the G2/mitotic-specific cyclin B1 gene increased in the cfdp1 mutant cerebellum.
Our findings suggest that Cfdp1 regulates the cell cycle of neural progenitors, thereby promoting neural differentiation in the brain.
Publication Date: 2021-05-15
Journal: Developmental dynamics : an official publication of the American Association of Anatomists
Circular RNA circPVT1 Contributes to Doxorubicin (DXR) Resistance of Osteosarcoma Cells by Regulating TRIAP1 via miR-137.
Chemoresistance is a major obstacle to the treatment of osteosarcoma patients. Circular RNA (circRNA) circPVT1 has been reported to be related to the doxorubicin (DXR) resistance in osteosarcoma. This study is designed to explore the role and mechanism of circPVT1 in the DXR resistance of osteosarcoma.
circPVT1, microRNA-137 (miR-137), and TP53-regulated inhibitor of apoptosis 1 (TRIAP1) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). The protein levels of ATP-binding cassette, subfamily C, member 1 (ABCC1), multidrug resistance-associated protein 1 (MRP-1), cleaved- (c-) caspase-3, B-cell lymphoma-2 (Bcl-2), and TRIAP1 were examined by a western blot assay. Cell viability, proliferation, and apoptosis were detected by cell counting kit-8 (CCK-8), colony formation, and flow cytometry assays, severally. The binding relationship between miR-137 and circPVT1 or TRIAP1 was predicted by starbase 3.0 and then verified by dual-luciferase reporter and RNA Immunoprecipitation (RIP) assays. The biological role of circPVT1 in osteosarcoma tumor growth and drug resistance was examined by the xenograft tumor model
Publication Date: 2021-05-14
Journal: BioMed research international
TP53-Activated lncRNA GHRLOS Regulates Cell Proliferation, Invasion, and Apoptosis of Non-Small Cell Lung Cancer by Modulating the miR-346/APC Axis.
Non-small cell lung cancer (NSCLC) is the main type of lung cancer with high mortality worldwide. To improve NSCLC therapy, the exploration of molecular mechanisms involved in NSCLC progression and identification of their potential therapy targeting is important. Long noncoding RNAs (lncRNAs) have shown important roles in regulating various tumors progression, including NSCLC. We found lncRNA GHRLOS was decreased in NSCLC cell lines and tissues which correlated with poor prognosis of NSCLC patients. However, the role and underlying mechanisms of lncRNA GHRLOS in NSCLC progression remains elusive. The expression of lncRNA GHRLOS was examined in NSCLC cell lines and biopsy specimens of patients with NSCLC by quantitative real time polymerase chain reaction (qRT-PCR). The effects of GHRLOS on proliferation, invasion and apoptosis of NSCLC cells were determined by both
Publication Date: 2021-05-11
Journal: Frontiers in oncology
Regulatory role of TIGAR on endothelial metabolism and angiogenesis.
Endothelial glycolytic metabolism plays an important role in the process of angiogenesis. TP53-induced glycolysis and apoptosis regulator (TIGAR) is a significant mediator of cellular energy homeostasis. However, the role of TIGAR in endothelial metabolism, angiogenesis, and coronary flow reserve (CFR) has not been studied. The present study investigated whether knockout (KO) of TIGAR improves endothelial glycolytic function and angiogenesis. In vitro, aortic endothelial cells (ECs) from TIGAR KO mice exhibited increased expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform-3 (PFKFB3) and increased glycolytic function. These were accompanied by increased mitochondrial basal/maximal respiration and ATP production. Furthermore, knockout of TIGAR in ECs enhanced endothelial proliferation, migration, and tube formation. Knockout of TIGAR also significantly increased aortic sprouting ex vivo. In vivo, knockout of TIGAR increased the expression of proangiogenic factor, angiopoietin-1 (Ang-1) in mouse hearts. Knockout of TIGAR also significantly increased coronary capillary density with enhanced CFR in these hearts. Furthermore, TIGAR KO mice subjected to pressure overload (PO), a common model to study angiogenesis and cardiac hypertrophy, exhibited elevated expression of Ang-1, VEGF, and PFKFB3 than that of the wild-type (WT) mice. WT mice subjected to PO exhibited a significant reduction of coronary capillary density and impaired CFR, but TIGAR KO mice did not. In addition, knockout of TIGAR blunted TAC-induced cardiac hypertrophy and dysfunction seen in the WT mice. In conclusion, knockout of TIGAR improves endothelial angiogenetic capabilities by enhancing the endothelial glycolytic function, mitochondrial respiration, and proangiogenic signaling, which leads to increased coronary capillary density and vascular function and protects against chronic stress.
Publication Date: 2021-05-01
Journal: Journal of cellular physiology
Anisomycin induces hair cell death and blocks supporting cell proliferation in zebrafish lateral line neuromast.
Ototoxicity of drugs is an important inducement for hearing loss. Anisomycin is a candidate drug for parasite, cancer, immunosuppression, and mental disease. However, the ototoxicity of anisomycin has not been examined. In this study, the ototoxicity of anisomycin was evaluated using zebrafish lateral line. We found the zebrafish treated with anisomycin during lateral line development could inhibit hair cell formation in a time- and dose-dependent manner. After neuromasts are mature with differentiated hair cells by 5 day post-fertilization, anisomycin could induce hair cell loss effectively through chronic exposure rather than acute exposure. TUNEL assay and qPCR of apoptosis related genes tp53, casp8, casp3a, and casp3b indicated that cell apoptotic was induced by chronic anisomycin exposure. Furthermore, knocking down tp53 with antisense morpholino could attenuate the hair cell loss induced by anisomycin. In addition, we found that anisomycin chronic exposure also inhibited the proliferation of supporting cell. Together, these results indicate that chronic anisomycin exposure could induce hair cell death and block supporting cell proliferation, which causes hair cell loss in zebrafish neuromast. This study provides primary ototoxicity evaluation for anisomycin.
Publication Date: 2021-04-23
Journal: Comparative biochemistry and physiology. Toxicology & pharmacology : CBP
Intact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias.
Selective targeting of BCL-2 with the BH3-mimetic venetoclax has been a transformative treatment for patients with various leukemias. TP-53 controls apoptosis upstream of where BCL-2 and its prosurvival relatives, such as MCL-1, act. Therefore, targeting these prosurvival proteins could trigger apoptosis across diverse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL-2 has produced clinically relevant responses in blood cancers with aberrant TP-53. However, in our study, TP53-mutated or -deficient myeloid and lymphoid leukemias outcompeted isogenic controls with intact TP-53, unless sufficient concentrations of BH3-mimetics targeting BCL-2 or MCL-1 were applied. Strikingly, tumor cells with TP-53 dysfunction escaped and thrived over time if inhibition of BCL-2 or MCL-1 was sublethal, in part because of an increased threshold for BAX/BAK activation in these cells. Our study revealed the key role of TP-53 in shaping long-term responses to BH3-mimetic drugs and reconciled the disparate pattern of initial clinical response to venetoclax, followed by subsequent treatment failure among patients with TP53-mutant chronic lymphocytic leukemia or acute myeloid leukemia. In contrast to BH3-mimetics targeting just BCL-2 or MCL-1 at doses that are individually sublethal, a combined BH3-mimetic approach targeting both prosurvival proteins enhanced lethality and durably suppressed the leukemia burden, regardless of TP53 mutation status. Our findings highlight the importance of using sufficiently lethal treatment strategies to maximize outcomes of patients with TP53-mutant disease. In addition, our findings caution against use of sublethal BH3-mimetic drug regimens that may enhance the risk of disease progression driven by emergent TP53-mutant clones.
Publication Date: 2021-04-08
Uncovering the Pharmacology of Xiaochaihu Decoction in the Treatment of Acute Pancreatitis Based on the Network Pharmacology.
Xiaochaihu decoction (XD) has demonstrated the pharmacodynamics on acute pancreatitis. This study was aimed at investigating the material and molecular basis of Xiaochaihu decoction.
Firstly, compounds of seven herbs containing XD were collected from the TCMSP, ETCM, and BATMAN-TCM databases, and the putative targets of pancreatitis were obtained from the OMIM, TTD, and GeneCards databases. Then, the PPI network was constructed according to the matching results between XD potential targets and pancreatic neoplasm targets. Furthermore, enrichment analysis on GO and KEGG by DAVID utilized bioinformatics resources. Finally, molecular docking was performed to simulate the interaction between the active compound of XD and putative targets. In an
A total of 196 active ingredients and 91 putative targets were selected. The PPI network analysis demonstrated that Quercetin was the candidate agent and MAPK3, IL-6, and TP53 were the potential targets for the XD treatment of acute pancreatitis. The KEGG analysis revealed that pathways in cancers, TNF signaling way, and MAPK signaling way might play an important role in pancreatitis therapy. And molecular docking results showed that Quercetin combined well with MAPK3, IL-6, and TP53. An
This study illustrated that XCHD and Quercetin contained in XD played an important role in the treatment of acute pancreatitis by acting on the key genes of MPAK3, IL-6, and TP53 which were associated with inflammation and apoptosis.
Publication Date: 2021-04-08
Journal: BioMed research international
TP53/miR-129/MDM2/4/TP53 feedback loop modulates cell proliferation and apoptosis in retinoblastoma.
Retinoblastoma (RB) is commonly-seen cancer in children. The p53 pathway dysfunction, which can lead to elevated MDM2 or MDM4 (p53 antagonists) protein expression, is frequently observed in almost all human cancers, including RB. The present study attempted to investigate the underlying mechanism from the perspective of non-coding RNA regulation. Here, we demonstrated that p53 and miR-129 were positively correlated with each other in RB. miR-129 directly targeted MDM2/4 to inhibit expression, therefore counteracting MDM2/4-mediated p53 signaling suppression and modulating RB cell proliferation and apoptosis. Moreover, p53 could activate the transcription of miR-129 via binding to the miR-129 promoter region, therefore forming a regulatory loop with MDM2/4 to affect RB progression. Altogether, the p53/miR-129/MDM2/4/p53 regulatory loop can modulate RB cell growth. We provide a solid experimental basis for developing novel therapies for RB.
Publication Date: 2021-03-09
Journal: Cell cycle (Georgetown, Tex.)