JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Xin Qiao,Shuang Xu,Zhitao Dai,Ke Zhang,Rui Guo,Aijun Li,Xiaofang Li,Qiong Zhang
p-STAT4 directly binds to the Ak4 promoter to drive its transcription. • STAT4-AK4 signaling engages in the production of mitochondrial DNA (mtDNA). • TAMR inhibits Ak4 transcription and mtDNA synthesis in a STAT4-dependent manner. • TAMR ameliorates UC by suppressing the JAK2-STAT4 signaling pathway. • The JAK2-STAT4-AK4-mtDNA axis represents a novel therapeutic target for UC. Background Ulcerative colitis (UC), a chronic inflammatory bowel disease with increasing global incidence, has inadequate existing treatments, highlighting the urgent need for new therapeutic agents and strategies. The total alkaloids from Menispermi Rhizoma (TAMR) has been clinically used to treat inflammatory diseases in traditional Chinese medicine, but its specific therapeutic effects and mechanisms in UC remain poorly elucidated. Purpose This study aimed to systematically clarify the therapeutic efficacy of TAMR against UC and elucidate its potential molecular mechanisms. Methods A dextran sulfate sodium (DSS)-induced murine colitis model was used to evaluate the efficacy of TAMR, with RNA sequencing providing mechanistic insights. A variety of molecular biology experiments were conducted for subsequent pathway validation in RAW264.7 macrophage cells. STAT4-AK4 interactions were further explored via Stat4 knockdown and chromatin immunoprecipitation (ChIP) assays. Results TAMR treatment effectively ameliorated colonic pathological lesions and reestablished M1/M2 macrophage polarization in DSS-challenged mice. Integrated RNA-seq and Western blot profiling revealed that TAMR specifically suppressed JAK2-STAT4 signaling cascade and AK4 expression, whose inhibition curbed excessive mitochondrial DNA (mtDNA) synthesis in inflammatory macrophages. Notably, STAT4 overexpression entirely negated TAMR-driven AK4 and mtDNA suppression. ChIP experiments confirmed that p-STAT4 directly bound to the Ak4 promoter, and STAT4 silencing abrogated LPS-induced Ak4 transcription and mtDNA synthesis. Conclusions TAMR exerts its anti-colitis effects by inhibiting the JAK2-STAT4 signaling pathway, which in turn suppresses AK4-mediated mtDNA overproduction. This study provides a scientific basis for the clinical application of TAMR in UC treatment and identifies a novel JAK2-STAT4-AK4-mtDNA regulatory axis as a potential therapeutic target for UC. Download: Download high-res image (436KB) Download: Download full-size image
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Xinyu Zhang,Sufang Li,Tingru Lin,Liangying Gan,Li Zhu,Li Zuo
Background Cardiovascular events remain the leading cause of mortality in chronic kidney disease (CKD). Pegmolesatide(P), a novel long-acting EPO receptor modulator, shows cardiovascular benefits in clinical studies. This study aims to demonstrate Pegmolesatide suppressed the formation of EPOR-CD131 heterodimer and to explore its cardioprotective mechanisms against indoxyl sulfate (IS)-induced cardiomyocyte hypertrophy. Methods H9c2 cardiomyocytes were assigned to different treatment groups (vehicle, IS, IS+P, P) and RNA sequencing was performed to identify dysregulated signaling pathways. Mechanistic exploration groups supplemented with CD131 agonist ARA290, STAT3 activator Colivelin, or STAT3 inhibitor Stattic for rescue experiments. Analyses included real-time qPCR/Western blot for cardiac hypertrophy markers and EPOR-CD131/JAK2/STAT3 axis components, phalloidin staining for cell size and co-immunoprecipitation (Co-IP) for EPOR-CD131 heterodimerization. Results Pegmolesatide significantly attenuated IS-induced cardiomyocyte hypertrophy, as evidenced by suppressed expression of cardiac hypertrophy markers (ANP, BNP, and β-MHC), reduced cell surface area, and improved cytoskeletal organization( P < 0.05). Mechanistically, Pegmolesatide upregulated EPOR expression while suppressing CD131 expression and activation of the JAK2/STAT3 signaling. Co-IP analysis demonstrated that Pegmolesatide suppressed the formation of EPOR-CD131 heterodimer. Functional rescue experiments showed that the cardioprotective effects of Pegmolesatide were reversed by CD131 agonist ARA290 or STAT3 activator Colivelin. Notably, combined treatment with ARA290 and STAT3 inhibitor Stattic partially restored its anti-hypertrophic activity. Conclusion Pegmolesatide exerts protective effects against IS-induced cardiomyocyte hypertrophy by inhibiting the EPOR-CD131/JAK2/STAT3 signaling axis. It may be a promising strategy for CKD-related cardiovascular complications.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2021
·
IF 4.432
Guoshu Lin,Qiuxia Yu,Lieqiang Xu,Ziwei Huang,Liting Mai,Linyun Jiang,Ziren Su,Jianhui Xie,Yucui Li,Yuhong Liu,Zhixiu Lin,Jiannan Chen
Phellodendri Chinensis Cortex (PC) is a traditional medicinal material used to treat gout and hyperuricemia (HUA) in China. Berberine (BBR), the main component of PC, possesses anti-hyperuricemic and anti-gout effects. However, BBR exhibits low bioavailability due to its extensive metabolism and limited absorption. Thus, the metabolites of BBR are believed to be the potential active forms responsible for its in vivo biological activities. Berberrubine (BRB), one of the major metabolites of BBR, exhibits appreciable biological activities even superior to BBR. In this work, the anti-hyperuricemic efficacy of BRB was investigated in HUA model mice induced by co-administration with intraperitoneal potassium oxonate (PO) and oral hypoxanthine (HX) for 7 days. Results showed that administration with BRB (6.25, 12.5, and 25.0 mg/kg) significantly decreased the serum levels of uric acid (UA) by 49.70%, 75.35%, and 75.96% respectively, when compared to the HUA group. In addition, BRB sharply decreased the levels of blood urea nitrogen (BUN) (by 19.62%, 28.98%, and 38.72%, respectively) and serum creatinine (CRE) (by 16.19%, 25.07%, and 52.08%, respectively) and reversed the PO/HX-induced renal histopathological damage dose-dependently. Additionally, BRB lowered the hepatic XOD activity, downregulated the expressions of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1), upregulated expressions of organic anion transporter 1/3 (OAT1/3) and ATP-binding cassette transporter subfamily G member 2 (ABCG2) at both protein and mRNA levels, and suppressed the activation of the JAK2/STAT3 signaling pathway. In addition, BRB significantly decreased the levels of inflammatory mediators (IL-1β, IL-6, and TNF-α). In conclusion, our study indicated that BRB exerted anti-hyperuricemic effect, at least in part, via regulating the urate transporter expressions and suppressing the JAK2/STAT3 signaling pathway. BRB was believed to be promising for further development into a potential therapeutic agent for HUA treatment.
研究领域:
药理学
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医学
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生物化学
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2021
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IF 6.291
Liwei Yang,Zikai Song,Yang Pan,Tianyang Zhao,Yanbin Shi,Jiqiang Xing,Aipeng Ju,Liting Zhou,Lin Ye
Background Abnormal lipid accumulation in macrophages may lead to macrophages foaming, which is the most important pathological process of atherosclerosis. Atmospheric PM 2.5 could enter the blood circulation and further affect the lipid metabolism of macrophages. But the underlying mechanism is not unclear. This study was undertaken to clarify the effect of PM 2.5 on lipid metabolism in macrophages, and to explore the role of inflammatory reaction and JAK2/STAT3 signaling pathway in this process. Method Macrophages derived from THP-1 cells were exposed to PM 2.5 (0,100,200,400 μg/mL) for 6 h and 12 h. STAT3 agonist ColivelinTFA is used to specifically excite STAT3. The survival rate of macrophages was detected by CCK-8. The lipid levels in macrophages were detected by colorimetry. The levels of inflammatory factors secreted by macrophages were detected by ELISA. Q-PCR was used to detect the mRNA expression levels, and Western Blot was used to detect the protein expression levels of JAK2/STAT3 pathway genes. Result The survival rate of macrophages was reduced by PM 2.5 , and the levels of TG, T-CHO and LDL-C of macrophages exposed to PM 2.5 were increased. PM 2.5 led to the increasing level of IL-6 and the decreasing level of IL-4, and the JAK2/STAT3 signaling pathway was inhibited by PM 2.5 . Colivelin TFA significantly decreased the increasing levels of TG, T-CHO and LDL-C levels, and increased the decreasing mRNA levels of IL-4, and LPL induced by PM 2.5 ( p < 0.05). Discussion PM 2.5 could cause the lipid accumulation of macrophages by inhibiting the JAK2/STAT3 signaling pathway, and inflammatory responses may be involved in this process.
研究领域:
环境科学
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免疫学
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细胞生物学
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BRITISH JOURNAL OF PHARMACOLOGY
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2019
·Vol. 176
·期 14
·2627-2641
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IF 6.583
Zheng Xu,Chunpeng Zou,Weihui Yu,Sujing Xu,Lan Huang,Zia Khan,Jingying Wang,Guang Liang,Yi Wang
Background and Purpose Hypertension adversely affects the kidney and is the second leading cause of kidney failure. Overproduction of angiotensin II greatly contributes to the progression of hypertensive kidney disease. Angiotensin II has recently been shown to activate STAT3 in cardiovascular cells. However, the underlying mechanisms of STAT3 activation by angiotensin II and downstream functional consequences in the kidneys are not fully understood. Experimental Approach C57BL/6 mice were treated with angiotensin II by subcutaneous infusion for 1 month to develop nephropathy. Mice were treated with either adeno-associated virus expressing STAT3 shRNA or STAT3 inhibitor, S3I-201. Human archival kidney samples from five patients with hypertension and five individuals without hypertension were also examined. In vitro, STAT3 was blocked using siRNA or STAT3 inhibitor S3I-201 in the renal proximal tubular cell line, NRK52E, after exposure to angiotensin II. Key Results Angiotensin II activated STAT3 in kidney epithelial cells through engaging toll-like receptor 4 (TLR4) and JAK2, which was independent of IL-6/gp130 and angiotensin AT 1 receptors. Angiotensin II-mediated STAT3 activation increased fibrotic proteins and resulted in renal dysfunction. Both STAT3 inhibition by the low MW compound S3I-201 and TLR4 deficiency normalized renal fibrosis and dysfunction caused by Ang II in mice, without affecting hypertension. Conclusions and Implications Our study reveals a novel mechanism of STAT3 activation, induced by angiotensin II, in kidney tissues and highlights a translational significance of a STAT3 inhibitor as potential therapeutic agent for hypertensive kidney disease.
研究领域:
肾病学
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药理学
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分子生物学
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心血管疾病
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2026
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IF 5.6
Zheyu Fang,Kun Xiang,Xinhuang Lv,Qiyao Li,Conghui Dai,Yao Yang,Yan Lin,Jiaming Liu,Jing Sun
Post-stroke cognitive impairment (PSCI) is characterized by progressive cognitive decline following ischemic stroke, and recent studies have suggested that natural compounds may offer therapeutic benefits; however, the effects and mechanisms of Betulin in PSCI remain unclear. Male C57BL/6 mice were subjected to ischemic stroke surgery to induce PSCI and treated with Betulin (50 mg/kg/day) for 3 weeks, followed by assessments of cognitive impairment, pathological changes, and the production of pro-inflammatory cytokines. Network pharmacology and RNA sequencing were performed to explore potential mechanisms. In vitro, BV2 microglia were stimulated with lipopolysaccharide to examine the anti-inflammatory effects of Betulin. Betulin improved cognitive performance, reduced microglial activation, and attenuated neuroinflammation, as evidenced by decreased levels of TNF-α, IL-1β, and IL-6. Mechanistically, the epidermal growth factor receptor (EGFR)/JAK2/STAT3 pathway was identified as a key pathway potentially involved in these effects. Further experiments with EGFR point-mutation constructs indicated that disrupting the Betulin-EGFR interaction attenuated the inhibitory effect of Betulin on the EGFR/JAK2/STAT3 pathway. Collectively, these findings suggest that Betulin mitigates microglia-driven neuroinflammation by targeting EGFR and may represent a potential therapeutic candidate for PSCI.
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CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
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2014
·Vol. 33
·期 4
·1130-1138
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IF 3.55
Chen Minggang,Liu Yumei,Yi Dan,Wei Liuping,Li Yumei,Zhang Li
Background: Tanshinone IIA inhibits the proliferation of pulmonary artery smooth muscle cells (PASMCs), but the potential mechanisms of its effects on PASMCs apoptosis remain unclear. Methods: Rat were subjected to hypoxia for 9 days with or without Tanshinone IIA treatment. PASMCs were exposed to the conditions of 2% O2 and 93% N2 for 24 h in vitro. Hematoxylin and eosin (HE) staining was used to evaluate vascular remodeling. The Cell viability was determined using cell fluorescence staining and MTT assays, and apoptosis was assessed using flow cytometry. Protein expression was quantified by Western blotting. Results: Our results showed that Tanshinone IIA treatment reduced pulmonary artery media thickening in hypoxic rats. Tanshinone IIA reduced PASMC viability in a dose-dependent manner. Additionally, Tanshinone IIA promoted PASMC apoptosis, lowered Hsp60 levels, and upregulated caspase-3 expressions under hypoxic conditions. This pro-apoptotic effect of Tanshinone IIA might be due to the reduction of the phosphorylation of JAK2/STAT3 signaling markers and the increase in the levels of the downstream target, Cx43 in PASMCs. Conclusion: These data suggest that Tanshinone IIA promotes PASMC apoptosis during hypoxia and reverses vascular remodeling. This effect is mediated by modulating the expression of Hsp60, caspase-3, and Cx43 via the JAK2/STAT3 signaling pathway. These results might provide a new therapeutic target to explore a novel strategy for hypoxia-induced vessel remodeling
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Cancer Cell International
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2020
·Vol. 20
·期 1
·1-14
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IF 4.175
Yuan Yin,Li Bo,Kuang Yanbin,Ni Shuo,Zhuge Aoxiang,Yang Jing,Lv Longxian,Gu Silan,Yan Ren,Li Yating,Wang Kaicen,Yang Liya,Zhu Xueling,Wu Jingjing,Bian Xiaoyuan,Li Lanjuan
Background Dietary fiber is effective for colorectal cancer (CRC) treatment. Interleukin-6 (IL-6) and its adaptors are potential targets for CRC therapy. Butyrate, a metabolite of dietary fiber, is a new, highly safe type of targeted drug. Methods In this study, Cell Counting Kit-8 cell viability and wound healing assays, western blot analysis, immunofluorescence staining, and xenograft tumor mouse models were used to evaluate the anticancer effect of butyrate and its possible mechanism in vivo and in vitro. Results Dietary fiber and sodium butyrate (NaB) decreased CRC burden by decreasing IL-6 receptor gp130 and blocking IL-6/JAK2/STAT3 axis activation in vitro and in vivo. Furthermore, NaB reduced the gp130 protein level by regulating its degradation rate via targeting TRAF5. Conclusions The fiber metabolite butyrate inhibits CRC development by reducing gp130 via TRAF5.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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Antioxidants
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2025
·Vol. 14
·期 11
·1296
·
IF 6.6
Kang Cheng,Guangbo He,Xiaxia Li,Yuqian Li,Xiaolin Cui,Xuefei Wu,Jau-Shyong Hong,Jie Zhao,Sheng Li,Yanjie Guo
Background: Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder with limited treatment options. Emerging evidence reveals bidirectional crosstalk between gut and brain through inflammatory signaling, leading us to hypothesize that anti-neuroinflammatory agents may concurrently ameliorate intestinal inflammation. The scorpion venom-derived heat-resistant synthetic peptide (SVHRSP), a bioactive peptide initially identified in scorpion venom and subsequently synthesized by our laboratory, possesses neuroprotective, anti-inflammatory, and antioxidative activities. Its properties make SVHRSP a promising candidate for investigating the therapeutic potential of anti-neuroinflammatory strategies in mitigating intestinal inflammation. Methods: Using a chronic dextran sodium sulfate (DSS)-induced colitis model in wild-type and α7 nicotinic acetylcholine receptor (α7nAChR) knockout mice, along with lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages, we assessed SVHRSP’s effects on inflammation, histopathology, gut permeability, oxidative stress markers, and α7nAChR-Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling. Results: SVHRSP treatment significantly ameliorated colitis symptoms in wild-type mice by reducing inflammation, repairing histological damage, restoring gut barrier function, and attenuating oxidative stress, with these effects abolished in α7nAChR knockout mice. Mechanistically, SVHRSP activated JAK2/STAT3 signaling through α7nAChR engagement, suppressing proinflammatory cytokine production in macrophages. Conclusion: These results demonstrated that SVHRSP alleviated intestinal inflammation via α7nAChR-dependent JAK2/STAT3 activation. Combined with its known neuroprotective properties, our findings support the repurposing of this neuroactive peptide, SVHRSP, for treating intestinal inflammatory disorders.
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IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
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2025
·
IF 3
Song Peng,Yang-yang Sun,Qiangqiang Chu,Hua-dong Meng,Ming-wei Hao,Yan-bei Zhang
Background Leonurine (Leo) has antioxidant and anti-inflammatory activities. In this study, we investigated the effect of Leo in a rat model of lipopolysaccharide (LPS)-induced chronic obstructive pulmonary disease (COPD).Methods Rats with COPD were administered Leo, and the pulmonary function parameters, pathological changes, and inflammatory mediators in tissues were evaluated. The expression of IκBa, p65, JAK2, STAT3, p-IκBa, p-p65, p-JAK2 and p-STAT3 was measured using western blotting.Results Leo effectively improved the clinical manifestations of COPD by decreasing the pulmonary function parameters including peak expiratory flow and expiratory flow at 50% tidal volume, and improving pathological changes. Leo reduced lung inflammation and oxidative stress by reducing CD68+ cell infiltration, regulating Treg/Th17 cell differentiation, attenuating the production of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-17, increasing IL-10 secretion, and regulating malondialdehyde and glutathione peroxidase levels. In vitro experiments revealed that Leo exhibits similar inhibitory effects on Th17 cell differentiation and macrophage activation. Furthermore, Leo effectively protected against LPS-induced damage to bronchial airway epithelial cells by reducing reactive oxygen species production. Mechanistic investigations revealed Leo inhibits NF-κB transcriptional activity, downregulates the levels of p-p65, p-JAK2, and p-STAT3 without affecting their total protein levels.Conclusion Our results suggest that Leo exerts therapeutic effect against COPD. Leo inhibited tissue inflammation and oxidative stress in COPD rat models via inhibition of the NF-κB and JAK2/STAT3 signaling pathways.
研究领域:
呼吸医学
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药理学
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分子生物学
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炎症研究
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信号转导
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Frontiers in Bioengineering and Biotechnology
·
2024
·
IF 4.3
Ruijie Wang,Ning Zhou,Jinfang Xue,Yan Li,Yang Wang,Huadong Zhu,Chuanzhu Lv
Background: In sepsis, the lung is one of the worst affected organs, often leading to acute lung injury (ALI). More and more evidence suggests that macrophages are also involved in the pathogenesis of ALI. In our previous study, we successfully synthesized Iron-capsaicin-based nanoparticles (Fe-CAP NPs) and found that it could inhibit the secretion of inflammatory cytokines to alleviate ALI. Here, we further explore the anti-inflammatory mechanism of Fe-CAP NPs.Methods: Bone marrow-derived macrophages (BMDM) and C57 mice were divided into four groups: control group, lipopolysaccharide (LPS) group, CAP + LPS group and Fe-CAP + LPS group. Western blot and Immunofluorescence were used to detect the expression of macrophage phenotypic markers CD86 and CD206 in BMDM and lung tissue. Fluorescence microbeads, Transwell and ROS kit were used to detect the phagocytosis, migration and ROS clearing capability of BMDM. Western blot was used to detect the expression of JAK2/STAT3 pathway and apoptosis proteins in BMDM. TUNEL kit and H&E staining were used to evaluate apoptosis and pathological changes in lung tissue.Results: In vitro, CD86 expression was increased in LPS, but decreased after Fe-CAP pretreatment. CD206 expression was the opposite. Fe-CAP reduced phagocytosis, migration and scavenged ROS in LPS-treated BMDM. Fe-CAP inhibited P-JAK2 and P-STAT3 expression and reduced apoptosis. In vivo, Fe-CAP improved lung histopathology and reduced apoptosis in lung tissue of LPS group. CD86 expression was increased in lung tissue of LPS group, but decreased in Fe-CAP preconditioning, and CD206 expression was reversed.Conclusion: Fe-CAP NPs could alleviate sepsis-induced ALI by regulating the polarization and function of macrophages, reducing ROS level and apoptosis.
研究领域:
免疫学
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药理学
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肺病学
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纳米技术
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2022
·
IF 7.129
Qiong Tang,Chen Xing,Ming Li,Qiang Jia,Cunxiang Bo,Zhenling Zhang
Macrophages play an important role in causing silicosis eventually becoming an irreversible fibrotic disease, and there are no specific drugs for silicosis in the clinic so far. Pirfenidone has consistently been shown to have anti-inflammatory and anti-fibrotic effects, but the specific mechanism by which it ameliorates fibrosis in silicosis is unclear. A rat silicosis model was established in this study, and lung tissues and serum were collected by batch execution at 14, 28, and 56 days. Also, the effects of Pirfenidone on macrophage polarization and pulmonary fibrosis were evaluated in silicosis with early intervention and late treatment by histological examination, Enzyme-linked immunosorbent assay, Hydroxyproline assay, Western blot and Quantitative reverse transcription polymerase chain reaction. The results showed that Pirfenidone significantly reduced pulmonary fibrosis in rats with silicosis, and both early intervention and late treatment effectively inhibited the expression of α-SMA, Col-I, Vimentin, Hydroxyproline, IL-1β, IL-18, and the M2 macrophage marker CD206 and Arg-1, while only early intervention effectively inhibited E-cad, TGF-β1, TNF-α, and the M1 macrophage marker iNOS, CD86. Furthermore, Pirfenidone dramatically reduced the mRNA expression of the JAK2/STAT3. These findings imply that Pirfenidone may reduce pulmonary fibrosis in silicosis rats by inhibiting macrophage polarization via the JAK2/STAT3 signaling pathway.
研究领域:
药理学
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呼吸医学
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免疫学
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分子生物学
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高影响因子
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