JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
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2025
·Vol. 39
·期 9
·e70455
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IF 2.8
Lihan Xie,Weinan Li,Shiqi Fan,Jinsong Jin
Diabetic kidney disease (DKD) is a common complication of diabetes, often characterized by podocyte injury, proteinuria, and eventual renal failure. Sinomenine hydrochloride (SH), an active component derived from traditional Chinese medicine, is clinically effective in treating kidney diseases. This study investigates the protective effects of SH on podocytes under high-glucose conditions and its mechanism of action. Mouse podocytes (MPC-5) were treated with SH at concentrations of 50, 200, and 600 μg/mL under high-glucose conditions (30 mmol/L) for 24 h to establish a DKD model. Cell viability was assessed using CCK-8 assays, and apoptosis rates were measured using flow cytometry. Autophagy levels were evaluated by detecting LC3-II, Beclin-1, and P62 proteins via Western blot analysis, while the involvement of the PI3K/AKT/mTOR pathway was analyzed by examining phosphorylated AKT and mTOR. Transmission electron microscopy was employed to observe autophagosomes. SH improved podocyte viability, reduced apoptosis, and enhanced autophagic activity by increasing LC3-II and Beclin-1 expression while decreasing P62 levels. SH also downregulated p-AKT and p-mTOR, indicating inhibition of the PI3K/AKT/mTOR pathway. Electron microscopy confirmed increased autophagosomes in SH-treated groups. SH protects podocytes in a high-glucose environment by enhancing autophagy through inhibition of the PI3K/AKT/mTOR pathway. These findings provide insights into SH as a potential therapeutic agent for DKD management.
研究领域:
药理学
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细胞生物学
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肾病学
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分子生物学
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中医学
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2018
·
IF 3.118
Lang Yi,Yan-jun Lyn,Chong Peng,Rui-li Zhu,Sha-sha Bai,Liang Liu,Pei-xun Wang,Hua Zhou,Yan Dong
Fibroblast like synoviocyte (FLS) is a crucial in the pathogenesis of rheumatoid arthritis (RA), and involved in inflammation and joint destruction. Sinomenine (SIN), an alkaloid derived from the plant Sinomenium acutum , has anti-inflammatory and analgesic effect and been used for RA treatment in China. Alpha 7 nicotinic acetylcholine receptors (α7nAChR), as the key receptor in cholinergic anti-inflammatory pathway (CAP) to inhibit inflammation, has been detected in RA patients synovium , but its role is still unclear. Here we investigated the association between the aggressive proliferation of FLS and α7nAChR expression and the effect of sinomenine. FLS was isolated from synovial tissues of adjuvant-induced-arthritis (AIA) rat. Tumor necrosis factor(TNF)-α was used to induce the aggressive proliferation of FLS. MTT assay was applied to evaluate the proliferation of FLS. The messenger RNA (mRNA) and protein levels of α7nAChR and early growth response gene-1 (Egr-1) were measured. The results showed that TNF-α induced FLS proliferation in vitro (P < .01) and increased the phosphorylation of ERK1/2 and the expression of Egr-1 and α7nAChR (P < .05 or P < .01). U0126 , the inhibitor of ERK1/2 inhibited α7nAChR expression and FLS proliferation significantly (P < .05 or P < .01). Specific short interference RNA(siRNA) of α7nAChR decreased α7nAChR expression and inhibited FLS proliferation as well. SIN inhibited the proliferation of FLS and decreased the phosphorylation of ERK1/2, and the expression of Egr-1 and α7nAChR induced by TNF-α (P < .05). In conclusion, the expression of α7nAChR involved in the aggressive proliferation of FLS induced by TNF-α and was regulated by ERK/Egr-1 signal pathway . SIN inhibited FLS proliferation and α7nAChR expression through inhibiting ERK/Egr-1 signal pathway, this may contribute to the anti-inflammatory and anti-arthritic effect of SIN.
研究领域:
免疫学
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药理学
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风湿病学
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细胞生物学
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PubMed
高影响因子
Scientific Reports
·
2021
·Vol. 11
·期 1
·1-9
·
IF 4.38
Zhou Zhiyong,Qiu Nanqing,Ou Yuntao,Wei Qianqian,Tang Wenting,Zheng Mingcong,Xing Yaluan,Li Jie-Jia,Ling Yong,Li Junxu,Zhu Qing
Chronic pain is a significant public health problem that afflicts nearly 30% of the global population, but current pharmacotherapies are insufficient. Previous report indicated that N -demethylsinomenine, an active metabolite of sinomenine, is efficacious against postoperative pain. The present study investigated whether N -demethylsinomenine is effective for chronic painful conditions or whether repeated treatment alters its effect. Both chronic constriction injury (CCI) surgery and complete Freund’s adjuvant (CFA) intraplantar injection induced significant and reliable mechanical allodynia at least for 7 days. Acute treatment with N -demethylsinomenine (10–40 mg/kg, i.p.) dose-dependently attenuated the mechanical allodynia both in CCI-induced neuropathic pain and CFA-induced inflammatory pain in mice. The potency of N -demethylsinomenine for reducing CFA-induced mechanical allodynia was slightly higher than sinomenine. During the period of repeated treatment, N -demethylsinomenine maintained its anti-allodynic effect against both neuropathic and inflammatory pain without producing carry-over effect. Pretreatment with bicuculline, a selective γ-aminobutyric acid type A (GABA A ) receptor antagonist, almost completely blocked the anti-allodynia of N -demethylsinomenine (40 mg/kg) both in CCI and CFA-treated mice. Our findings indicated that N -demethylsinomenine exhibits GABA A receptor-mediated anti-allodynic effects in mouse models of neuropathic and inflammatory pain, suggesting it may be a useful novel pharmacotherapy for the control of chronic pain.
研究领域:
药理学
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疼痛研究
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神经科学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
·
IF 5.7
Mengting Li,Danyang Chen,Yu Shao,Zimeng Wang,Yanan Peng,Qiu Zhao,Lan Liu
Sinomenine (SIN), a bioactive alkaloid with anti-inflammatory activity, has shown therapeutic potential in ulcerative colitis (UC), but its precise molecular targets remain unclear. This study investigated the key targets and mechanisms underlying SIN-mediated protection in UC. In a dextran sulfate sodium (DSS)-induced colitis mouse model, SIN dose-dependently alleviated colitis symptoms, restored colon length, improved histopathology injury, and enhanced intestinal barrier integrity by increasing ZO-1 and claudin-1 expression. Integrated bioinformatics analyses, including differential expression analysis, WGCNA, network pharmacology, and machine-learning algorithms, identified farnesoid X receptor (FXR) as a core therapeutic target of SIN. Molecular docking predicted stable SIN-FXR binding, and cellular thermal shift assay further supported engagement of SIN with FXR. FXR expression was reduced in UC tissues and DSS-induced colitis mice but was restored after SIN treatment. Functional enrichment and single-cell RNA sequencing analyses linked FXR to lipid metabolism, immune regulation, and the Th17/Treg balance. Mechanistically, SIN suppressed arachidonic acid metabolism, reduced pro-inflammatory cytokines, increased anti-inflammatory cytokines, decreased Th17 cells, and promoted Treg accumulation. Co-administration of SIN with the FXR agonist fexaramine further potentiated its protective effects, whereas the FXR antagonist glycine-β-muricholic acid markedly reversed SIN-mediated improvements in intestinal inflammation, barrier integrity, arachidonic acid metabolism, and Th17/Treg homeostasis. Collectively, these findings demonstrate that SIN ameliorates experimental colitis, at least in part, by targeting FXR to modulate lipid metabolism and restoring Th17/Treg balance. This study provides a mechanistic basis for the therapeutic application of SIN, either alone or in combination with FXR agonists, in UC treatment.
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PHYTOMEDICINE
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2022
·
IF 6.656
Ying-kun Zhi,Jing Li,Lang Yi,Rui-li Zhu,Jin-fang Luo,Qing-ping Shi,Sha-sha Bai,Yan-wu Li,Qun Du,Jia-zhong Cai,Liang Liu,Pei-xun Wang,Hua Zhou,Yan Dong
Background Sinomenine (SIN) is an anti-inflammatory drug that has been used for decades in China to treat arthritis . In a previous study, SIN acted on α7 nicotinic acetylcholine receptor (α7nAChR) to inhibit inflammatory responses in macrophages, which indicates a new anti-inflammatory mechanism of SIN. However, the level of α7nAChR was increased in the inflammatory responses and was downregulated by SIN in vitro, so the underlying mechanisms of SIN acting on α7nAChR remain unclear. Purpose To analyze the role of α7nAChR in inflammation and the effect and mechanism of SIN regulation of α7nAChR. Methods The effects of SIN on α7nAChR in endotoxemic mice and LPS-stimulated macrophages were observed. Nicotine (Nic) was used as a positive control, and berberine (Ber) was used as a negative control targeting α7nAChR. The antagonists of α7nAChR, α-bungarotoxin (BTX) and mecamylamine (Me), were used to block α7nAChR. In RAW264.7 macrophage cells in vitro , α7nAChR short hairpin RNA (shRNA) was used to knock down α7nAChR. Macrophage polarization was analyzed by the detection of TNF-α, IL-6, iNOS, IL-10, Arg-1, and Fizz1. U0126 was used to block ERK phosphorylation. The cytokines α7nAChR, ERK1/2, p-ERK1/2 and Egr-1 were detected. Results SIN decreased the levels of TNF-α, IL-6 and the expression of α7nAChR increased by LPS in endotoxemic mice. The above effects of SIN were attenuated by BTX. In the α7nAChR shRNA transfected RAW264.7 cells, compared with the control, α7nAChR was knocked down, and M1 phenotype markers (including TNF-α, IL-6, and iNOS) were significantly downregulated, whereas M2 phenotype markers (including IL-10, Arg-1, and Fizz1) were significantly upregulated when stimulated by LPS. SIN inhibited the expression of p-ERK1/2 and the transcription factor Egr-1 induced by LPS in RAW264.7 cells, and the above effects of SIN were attenuated by BTX. The expression of α7nAChR was suppressed by U0126, which lessened the expression of p-ERK1/2 and Egr-1. Conclusions SIN acts on α7nAChR to inhibit inflammatory responses and downregulates high expression of α7nAChR in vivo and in vitro . The increase of α7nAChR expression is correlated with inflammatory responses and participates in macrophage M1 polarization. SIN downregulates α7nAChR via a feedback pathway of α7nAChR/ERK/Egr-1, which contributes to inhibiting macrophage M1 polarization and inflammatory responses.
研究领域:
免疫学
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药理学
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细胞生物学
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炎症研究
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PubMed
高影响因子
Journal of Neuroinflammation
·
2018
·Vol. 15
·期 1
·1-12
·
IF 5.193
Gao Bo,Wu Yu,Yang Yuan-Jian,Li Wei-Zu,Dong Kun,Zhou Jun,Yin Yan-Yan,Huang Da-Ke,Wu Wen-Ning
Background Epilepsy is a common neurological disorder and is not well controlled by available antiepileptic drugs (AEDs). Inflammation is considered to be a critical factor in the pathophysiology of epilepsy. Sinomenine (SN), a bioactive alkaloid with anti-inflammatory effect, exerts neuroprotective activity in many nervous system diseases. However, little is known about the effect of SN on epilepsy.Methods The chronic epilepsy model was established by pentylenetetrazole (PTZ) kindling. Morris water maze (MWM) was used to test spatial learning and memory ability. H.E. staining and Hoechst 33258 staining were used to evaluate hippocampal neuronal damage. The expression of nucleotide oligomerization domain (NOD)-like receptor protein 1 (NLRP1) inflammasome complexes and the level of inflammatory cytokines were determined by western blot, quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA) kits.Results SN (20, 40, and 80 mg/kg) dose-dependently disrupts the kindling acquisition process, which decreases the seizure scores and the incidence of fully kindling. SN also increases the latency of seizure and decreases the duration of seizure in fully kindled rats. In addition, different doses of SN block the hippocampal neuronal damage and minimize the impairment of spatial learning and memory in PTZ kindled rats. Finally, PTZ kindling increases the expression of NLRP1 inflammasome complexes and the levels of inflammatory cytokines IL-1β, IL-18, IL-6, and TNF-α, which are all attenuated by SN in a dose- dependent manner.Conclusion sSN exerts anticonvulsant and neuroprotective activity in PTZ kindling model of epilepsy. Disrupting the kindling acquisition, which inhibits NLRP1 inflammasome-mediated inflammatory process, might be involved in its effects.
研究领域:
神经病学
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药理学
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炎症研究
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PubMed
高影响因子
Science Bulletin
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2023
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IF 18.9
Zheng-Meng Jiang,Su-Ling Zeng,Tian-Qing Huang,Yang Lin,Fang-Fang Wang,Xing-Jiao Gao,Jing Li,Ping Li,E-Hu Liu
Gut microbiota dysbiosis is associated with the development of rheumatoid arthritis (RA). Sinomenine (SIN) is an effective immunosuppressive and anti-inflammatory drug used for treating RA, but how SIN regulates gut microbiota to alleviate RA remains underexplored. To identify the critical gut microbial species and microbial metabolites associated with the RA-protective effects of SIN, the microbiota-dependent anti-RA effects of SIN were assessed by 16S rRNA gene sequencing, antibiotic treatment, and fecal microbiota transplantation. Metabolomics analysis, transcriptional analysis, and targeted bacteria/metabolites gavage were conducted to explore how SIN regulates gut microbiota to reduce the severity of RA. SIN could restore intestinal microbial balance by mainly modulating the abundance of Lactobacillus , and significantly relieve collagen-induced arthritis (CIA) symptoms in a gut microbiota-dependent manner. SIN significantly elevated microbial tryptophan metabolites indole-3-acrylic acid (IA), indole-3-propionic acid (IPA), and indole-3-acetic acid (IAA). Tryptophan metabolites supplementation could activate aryl hydrocarbon receptor (AhR) and regulate Th17/Treg balance in CIA rats. Intriguingly, SIN relieved the arthritis symptoms involving the enrichment of two beneficial anti-CIA Lactobacillus species, L. paracasei and L. casei by mono-colonization. The promising therapeutic function of SIN was mostly attributed to the activation of AhR by explicitly targeting the Lactobacillus and microbial tryptophan metabolites. The intestinal bacterium L. paracasei and L. casei may be used to reduce the severity of CIA.
研究领域:
免疫学
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药理学
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微生物学
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代谢组学
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风湿病学
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高影响因子
SHOCK
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2015
·Vol. 44
·期 2
·188
·
IF 3.045
Yi Lang,Luo Jin-fang,Xie Bing-bing,Liu Jian-xin,Wang Jun-yue,Liu Liang,Wang Pei-xun,Zhou Hua,Dong Yan
Sinomenine (SIN), an alkaloid derived from the plant Sinomenium acutum , has anti-inflammatory and analgesic effects and has been used for rheumatoid arthritis treatment in China. This study aims to verify the hypothesis that SIN acts on α7 nicotinic acetylcholine receptor (α7nAChR) to inhibit the activation of macrophages stimulated by lipopolysaccharide. The prototypical α7nAChR antagonist α-bungarotoxin and mecamylamine attenuated the effect of SIN on tumor necrosis factor-α and interleukin-6 in RAW264.7 murine macrophage-like cells and primary peritoneal macrophages of mouse induced by lipopolysaccharide. With the knockdown of α7nAChR expression in RAW264.7 cells by small interfering RNA, the inhibitory effect of SIN on tumor necrosis factor-α and interleukin-6 was reversed. Sinomenine decreased p65 expression in nuclear and increased IκBα expression in cytoplasm, and these effects were reversed by the α7nAChR small interfering RNA as well. These results indicate that the anti-inflammatory effects of SIN on macrophages in vitro depend on α7nAChR.
研究领域:
药理学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2018
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IF 3.04
Yuntao Ou,Man Su,Yong Ling,Qianqian Wei,Fei Pan,Jiejia Li,Jun-Xu Li,Qing Zhu
Sinomenine , a major bioactive ingredient isolated from traditional Chinese medicine Sinomenium acutum , has been reported to have analgesic effects in various pain animal models. N -demethylsinomenine, the N -demethylated product of sinomenine, has been identified to be the major metabolite of sinomenine and is also a natural component extracted from Sinomenium acutum . This study examined the anti-allodynic effects of N -demethylsinomenine in a mouse model of postoperative pain . A significant and sustained mechanical allodynia that lasted for 4 days was induced by making a surgical incision on the right hind paw in mice. Acute treatment with N -demethylsinomenine (10–40 mg/kg, s.c.) relieved the mechanical allodynia in a dose-dependent manner. Although there was no difference in maximal analgesic effect between N -demethylsinomenine (40 mg/kg, s.c.) and sinomenine (40 mg/kg, s.c.), the onset of action of N- demethylsinomenine was quicker than sinomenine. Repeated treatment with N- demethylsinomenine (10–40 mg/kg/day, s.c.) also dose-dependently exerted sustained antinociception against postoperative allodynia and did not produce analgesic tolerance and carry-over effect. The anti-allodynia induced by N -demethylsinomenine (40 mg/kg, s.c.) was attenuated by bicuculline , a selective γ-aminobutyric acid type A (GABA A ) receptor antagonist. In addition, the doses of N -demethylsinomenine used here did not alter the locomotor activity in mice. Our findings demonstrated that N -demethylsinomenine exerts behaviorally-specific anti-allodynia against postoperative allodynia mediated through the GABA A receptors, suggesting it may be a useful novel pharmacotherapy for the control of postoperative pain.
研究领域:
药理学
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疼痛研究
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神经科学
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PubMed
高影响因子
CHINESE JOURNAL OF CHEMICAL ENGINEERING
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2024
·
IF 3.7
Dandan Ren,Jiale Xie,Tianle Chen,Haibin Qu,Xingchu Gong
ABSTRACT The current methods used to industrially produce sinomenine hydrochloride involve several issues, including high solvent toxicity, long process flow, and low atomic utilization efficiency, and the greenness scores of the processes are below 65 points. To solve these problems, a new process using anisole as the extractant was proposed. Anisole exhibits high selectivity for sinomenine and can be connected to the subsequent water-washing steps. After alkalization of the medicinal material, heating extraction, water washing, and acidification crystallization were carried out. The process was modeled and optimized. The design space was constructed. The recommended operating ranges for the critical process parameters were 3.0–4.0 h for alkalization time, 60.0–80.0 °C for extraction temperature, 2.0–3.0 (volume ratio) for washing solution amount, and 2.0–2.4 mol·L −1 for hydrochloric acid concentration. The new process shows good robustness because different batches of medicinal materials did not greatly impact crystal purity or sinomenine transfer rate. The sinomenine transfer rate was about 20% higher than that of industrial processes. The greenness score increased to 90 points since the novel process proposed in this research solves the problems of long process flow, high solvent toxicity, and poor atomic economy, better aligning with the concept of green chemistry.
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JOURNAL OF CHROMATOGRAPHY A
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2025
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IF 4
Jinlai Cheng,Xiaoyu Zhang,Yuyan Xu,Yu Zhao,Guozhuang Zhang,Gejing De,Yuqing Tan,Huajing Wang,Miyi Yang
A thermo-responsive magnetic molecularly imprinted polymer (TMMIP) based on magnetic graphene oxide (MGO) was prepared via surface molecular imprinting technique for selective recognition of sinomenine (SIN) in various complex matrices. The obtained nanoparticles were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), vibrating sample magnetometry (VSM), and thermogravimetric analysis (TGA). The results indicated that the TMMIP exhibited a typical core-shell structure, comprising a molecularly imprinted shell, and demonstrated both magnetic susceptibility and excellent stability. The adsorption performance of TMMIP was also studied via adsorption kinetics, adsorption isotherms and selectivity experiments. The TMMIP exhibited high adsorption capacity, high selectivity for SIN, and mild acidic elution conditions. Under the optimal conditions, an analytical methodology combining TMMIP based dispersive solid-phase microextraction with high-performance liquid chromatography (HPLC) was subsequently established. TMMIP can rapidly adsorb SIN in solution and easily collected with assistance of outer magnetic field. The analysis method exhibited linearity across 0.05-150 μg/mL with a correlation coefficient of 0.9993, while demonstrating detection sensitivity at 0.1 ng/mL (DL) and quantification capability at 0.3 ng/mL (QL). Validation using Caulis sinomenii , oral liquid and blood samples acquired recoveries of 88.8–110.4%. This integrated approach demonstrates high efficiency for SIN extraction and detection in complex matrices and provided an efficient, eco-friendly strategy for SIN analysis.
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ACTA PHARMACOLOGICA SINICA
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2026
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IF 8.4
Li Shuo,Xu Bing,Lu Ming-jun,Wu Qian-wen,Qin Wen-qing,Dai Zi-qi,Li Xiao-jiao-yang,Bai Jin-zhao,Lei Hai-min,Liu Run-ping
The severe inflammation associated with infectious or inflammatory diseases significantly contributes to mortality. Interferon regulatory factor 3 (IRF3) represents a potential anti-inflammatory target, but the development of IRF3 inhibitors has not yielded satisfactory results to date. In this study, we established a phenotype-based high-throughput screening system to conduct activity-guided hierarchical screening of clinical frequently used anti-inflammatory and anti-rheumatic herbal extracts and compounds. Employing a Gaussia-luciferase reporter system driven by the IFNB1 promoter, we identified sinomenine as a potent type I interferon (IFN) inhibitor from a set of 28 anti-inflammatory herbal products. Furthermore, among 24 synthesized sinomenine derivatives modified by various electrophilic groups, Sim-9 (2.5–10 μM) dose-dependently inhibited IFN responses triggered by TLRs, RLRs, and STING activation in mouse RAW264.7 cells and in human THP-1 cells, HT-29 cells and A549 cells. We demonstrated that Sim-9, by covalently binding to Cys222, induced a conformational change in the p LxIS motif-binding surface of IRF3, thus blocking its interaction with upstream adapters, including TRIF, MAVS and STING, and subsequent homodimerization of IRF3 itself, which were all essential for activation of type I IFN responses. In in vivo experiments, we showed that injection of Sim-9 (30, 60 mg/kg, i.p.) effectively protected against devastating inflammation in cecal ligation and puncture (CLP)-induced sepsis in mice, and improved cerulein-induced pancreatitis by inhibiting IRF3. Our study discovers Sim-9 as a novel covalent allosteric inhibitor of IRF3 and reveals that the p LxIS motif binding surface represents a previously uncharacterized druggable target for IRF3 activation, providing a promising therapeutic strategy for the treatment of severe inflammatory injuries.
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高影响因子
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