Chemical Biology & Drug Design
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2022
·Vol. 101
·期 1
·24-39
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IF 2.873
Donglin Zhang,Aiqin Pan,Jianke Gu,Renfeng Liao,Xueyu Chen,Zhaozhu Xu
MicroRNAs (miRs) are implicated in heart failure (HF). Thereby, we aim to uncover the role of miR-144-3p in HF. Doxorubicin (Dox)-induced HF model was constructed in rats and cardiomyocytes H9C2, and the cardiac function was determined using ultrasound cardiogram. Morphology of cardiac tissue was observed using hematoxylin–eosin (H&E) staining. The viability and apoptosis of Dox-treated and transfected cardiomyocytes were determined using Cell Counting Kit-8 (CCK-8) assay and flow cytometry. Relative expressions of the HF-associated miRs (including miR-144-3p), suppressor of cytokine signaling 2 (SOCS2), apoptosis- and phosphoinositide 3-kinase (PI3K)/AKT pathway-related factors (B-cell lymphoma 2, Bcl-2; Bcl-2 associated X protein, Bax; cleaved [C] capsase-3; phosphoinositide 3-kinase, PI3K; phosphorylated-PI3K, p-PI3K; p-AKT; AKT) were measured with quantitative real-time polymerase chain reaction or Western blot. Target gene of miR-144-3p was predicted by Starbase and TargetScan and confirmed with dual-luciferase reporter assay. Dox caused rat cardiac dysfunction, aggravated cardiac injury, decreased cardiomyocytes viability, and the expression of miR-144-3p, Bcl-2, and phosphorylation of both PI3K and AKT yet the upregulated those of Bax and C caspase-3, which was reversed by upregulating miR-144-3p, whereas downregulating miR-144-3p did oppositely. SOCS2 was the target gene of miR-144-3p, Dox promoted SOCS2 expression, which was reversed by upregulating miR-144-3p, while downregulating miR-144-3p did conversely. In addition, silencing SOCS2 reversed the effects of miR-144-3p downregulation in Dox-treated cardiomyocytes. Upregulating miR-144-3p alleviated Dox-induced cardiac dysfunction and cell apoptosis via targeting SOCS2, providing a novel evidence of miR-144-3p in HF.
研究领域:
心脏病学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Arabian Journal of Chemistry
·
2023
·
IF 6
Peipei Zhou,Ying Kuang,Lihua Zuo,Shuhong Liang,Zhuolun Li,Lei Chen,Jingxue Li,Jun Zhang,Chenhan He,Xiaobao Wang,Yaojuan Chu,Jianying Pei,Zhi Sun,Shuzhang Du
Background Danshen Ligustrazine Injection (DSLI), composed of the extract of Salvia miltiorrhiza Bunge and Conioselinum anthriscoides 'Chuanxiong', is commonly used in the clinical treatment of ischemic stroke, which is the most common type of cerebrovascular disease, affected by multiple factors. The brain-gut axis is a new type of influencing factor for ischemic stroke, however, there is a lack of systematic research on the relationship between microbiota and host metabolic phenotype. This study aimed to investigate the host metabolic phenotype-microbiome interface in ischemic stroke and the immunomodulatory effects of DSLI. Methods In the study, liquid chromatography-mass spectrometry was used to primarily analyze the quality markers (Q-markers) and the polyphenols of DSLI. Based on 16S rRNA gene sequencing and metabolomics, the variations of microbial composition in different groups were characterized. In addition, a network diagram was constructed to reveal the interrelationship between DSLI-regulated gut microbiota changes and DSLI-regulated brain metabolites in MCAO/R rats. The expression of the aryl hydrocarbon receptor (AhR) in the colon and brain by immunofluorescence and suppressors of cytokine signaling 2 (SOCS2) by western blot were further detected. Results Diminished metabolic diversity and alterations in the tryptophan metabolism pathway were a feature of IS in the study. The results revealed that Clostri_UCG-014 was positively correlated with indoleacrylic acid, indole-3-methylacetate, and Ruminococcaceae was strongly related with L-tryptophan, 3-methylindole, and indole. The results of immunofluorescence showed that the expression of AhR in the colon and brain tissues of rats in the model group was greatly reduced compared with that in the sham-operated group, and was heavily activated with the treatment of DSLI. The levels of aryl hydrocarbon nuclear receptor ARNT2 and SOCS2 were down-regulated in the brains of Model rats, whereas increased by DSLI, further confirming that the brain-gut microbiota-Trp metabolism exists in the pathological changes of stroke and the intervention mechanism of DSLI. Conclusions The present study findings suggest Clostri_UCG-014, Ruminococcaceae, and Firmicute_RF39 play an important role in improving the regulation of immune function in stroke through tryptophan metabolites by acting on the AhR-SOCS2 axis.
研究领域:
药理学
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神经科学
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微生物学
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代谢组学
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免疫学
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DOI
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Hong Pan,Shuyi Chen,Shanming Ruan,Jiamin Lu,Kai Zhang
Prostate cancer (PCa) frequently progresses to castration-resistant stages with poor prognosis, in which vasculogenic mimicry (VM) contributes to tumor aggressiveness and therapeutic resistance. Here, we investigated the antitumor effects of the natural quassinoid Ailanthone (AIL) and its impact on VM in PCa. Our study demonstrates that AIL markedly suppresses PCa cell viability, induces apoptosis and G1/S cell-cycle arrest, and inhibits migration, invasion, stemness, and VM formation. Mechanistically, AIL enhances early growth response protein 3 (EGR3) binding to the promoter of suppressor of cytokine signaling 2 (SOCS2), leading to SOCS2 upregulation and subsequent inhibition of JAK/STAT3 signaling. Functional rescue experiments reveal that SOCS2 or EGR3 silencing partially reverses the inhibitory effects of AIL on malignant phenotypes and VM. In vivo , AIL significantly reduces tumor growth, promotes apoptosis, and attenuates VM formation, effects that are weakened upon SOCS2 knockdown. Collectively, these findings indicate that AIL exerts potent anti-tumor and anti-VM activities in PCa by activating the EGR3-SOCS2 axis and suppressing JAK/STAT3 signaling, highlighting its potential as a promising therapeutic strategy for advanced and treatment-resistant PCa.
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DOI
PubMed
高影响因子
JOURNAL OF IMMUNOLOGY
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2026
·Vol. 215
·期 4
·
IF 4
Xu Shujuan,Jiang Yixiang,Wang Shengtao,Chen Beili,Lin Wenyuan,Jiang Fang,Wu Xianyi,Tang Rongfang,Nie Yuwei,Chen Tongtong,Wang Xiaotao
Myelodysplastic syndrome (MDS) is a heterogeneous group of myeloid neoplasms characterized by treatment difficulties and a propensity to progress to acute myeloid leukemia. Impaired natural killer (NK) cell surveillance is a hallmark of MDS, yet the underlying molecular mechanisms remain poorly understood. This study aims to elucidate the mechanism by which HIF-1α regulates NK cell differentiation disorders and its impact on NK cell cytotoxicity in MDS. Flow cytometry was employed to compare HIF-1α expression and NK cell differentiation between wild-type and NUP98/HOXD13 (NHD13) mice. Our results demonstrated a significant increase in HIF-1α expression in the bone marrow and peripheral blood of MDS mice, accompanied by a notable decrease in immature NK cell subsets and activating receptors (NKG2D, NKp44, and DNAM-1). Overexpression of HIF-1α in human NK cells or pharmacological stabilization with CoCl2 inhibits the differentiation into mature NK cells, suppresses the expression of degranulation molecules such as Granzyme B, and impairs NK cell cytotoxicity. Western blot analysis indicated that HIF-1α regulates NK cell differentiation and function via the JAK1/STAT5/SOCS2 signaling pathway. Collectively, these findings suggest that the hypoxic microenvironment in MDS enhances HIF-1α expression, which subsequently impairs NK cell maturation and inhibits their cytotoxicity. Targeting HIF-1α may delay MDS progression by enhancing NK cell function via the JAK1/STAT5/SOCS2 signaling pathway.
✓ 已验证
DOI
PubMed
高影响因子
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