High-dose sinomenine attenuates ischemia/reperfusion-induced hepatic inflammation and oxidative stress in rats with diabetes mellitus.

INTRODUCTION: Ischemia-reperfusion (I/R) injury, resulting from blood flow interruption and its subsequent restoration, is a prevalent complication in liver surgery. The liver, as a crucial organ for carbohydrate and lipid metabolism, exhibits decreased tolerance to hepatic I/R in patients with diabetes mellitus (DM), resulting in a significant increase in hepatic dysfunction following surgery. This may be attributed to elevated oxidative stress and inflammation. Our prior research established sinomenine's (SIN) protective role against hepatic I/R injury. Nevertheless, the impact of SIN on hepatic I/R injury in DM rats remains unexplored. OBJECTIVE AND METHODS: This study aimed to investigate the therapeutic potential of SIN in hepatic I/R injury in DM rats and elucidate its mechanism. Diabetic and hepatic I/R injury models were established in rats through high-fat/sugar diet, streptozotocin injection, and hepatic blood flow occlusion. Liver function, oxidative stress, inflammatory reaction, histopathology, and Nrf-2/HO-1 signaling pathway were evaluated by using UV spectrophotometry, biochemical assays, enzyme-linked immunosorbent assay, hematoxylin-eosin staining, and Western blot analysis. RESULTS: High-dose SIN (300 mg/kg) significantly attenuated hepatic I/R injury in DM rats, reducing serum activities of ALT and AST, decreasing the AST/ALT ratio, enhancing tissue contents of SOD and GSH-Px, suppressing the levels of TNF-α and IL-6, improving the liver histopathology, and activating Nrf-2/HO-1 signaling by promoting Nrf-2 trans-location from cytoplasm to nucleus. Low-dose SIN (100 mg/kg) was ineffective. CONCLUSIONS: This study demonstrates that high-dose sinomenine's mitigates hepatic I/R-induced inflammation and oxidative stress in diabetes mellitus (DM) rats via Nrf-2/HO-1 activation, suggesting its potential as a preventive strategy for hepatic I/R injury in DM patients.

Sinomenine treats rheumatoid arthritis by inhibiting MMP9 and inflammatory cytokines expression: bioinformatics analysis and experimental validation.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease marked by inflammatory cell infiltration and joint damage. The Chinese government has approved the prescription medication sinomenine (SIN), an effective anti-inflammation drug, for treating RA. This study evaluated the possible anti-inflammatory actions of SIN in RA based on bioinformatics analysis and experiments. Six microarray datasets were acquired from the gene expression omnibus (GEO) database. We used R software to identify differentially expressed genes (DEGs) and perform function evaluations. The CIBERSORT was used to calculate the abundance of 22 infiltrating immune cells. The weighted gene co-expression network analysis (WGCNA) was used to discover genes associated with M1 macrophages. Four public datasets were used to predict the genes of SIN. Following that, function enrichment analysis for hub genes was performed. The cytoHubba and least absolute shrinkage and selection operator (LASSO) were employed to select hub genes, and their diagnostic effectiveness was predicted using the receiver operator characteristic (ROC) curve. Molecular docking was undertaken to confirm the affinity between the SIN and hub gene. Furthermore, the therapeutic efficacy of SIN was validated in LPS-induced RAW264.7 cells line using Western blot and Enzyme-linked immunosorbent assay (ELISA). The matrix metalloproteinase 9 (MMP9) was identified as the hub M1 macrophages-related biomarker in RA using bioinformatic analysis and molecular docking. Our study indicated that MMP9 took part in IL-17 and TNF signaling pathways. Furthermore, we found that SIN suppresses the MMP9 protein overexpression and pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the LPS-induced RAW264.7 cell line. In conclusion, our work sheds new light on the pathophysiology of RA and identifies MMP9 as a possible RA key gene. In conclusion, the above findings demonstrate that SIN, from an emerging research perspective, might be a potential cost-effective anti-inflammatory medication for treating RA.

Functional Activity of Enantiomeric Oximes and Diastereomeric Amines and Cyano Substituents at C9 in 3-Hydroxy-N-phenethyl-5-phenylmorphans.

The synthesis of stereochemically pure oximes, amines, saturated and unsaturated cyanomethyl compounds, and methylaminomethyl compounds at the C9 position in 3-hydroxy-N-phenethyl-5-phenylmorphans provided µ-opioid receptor (MOR) agonists with varied efficacy and potency. One of the most interesting compounds, (2-((1S,5R,9R)-5-(3-hydroxyphenyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-9-yl)acetonitrile), was found to be a potent partial MOR agonist (EC50 = 2.5 nM, %Emax = 89.6%), as determined in the forskolin-induced cAMP accumulation assay. Others ranged in potency and efficacy at the MOR, from nanomolar potency with a C9 cyanomethyl compound (EC50 = 0.85 nM) to its totally inactive diastereomer, and three compounds exhibited weak MOR antagonist activity (the primary amine 3, the secondary amine 8, and the cyanomethyl compound 41). Many of the compounds were fully efficacious; their efficacy and potency were affected by both the stereochemistry of the molecule and the specific C9 substituent. Most of the MOR agonists were selective in their receptor interactions, and only a few had δ-opioid receptor (DOR) or κ-opioid receptor (KOR) agonist activity. Only one compound, a C9-methylaminomethyl-substituted phenylmorphan, was moderately potent and fully efficacious as a KOR agonist (KOR EC50 = 18 nM (% Emax = 103%)).

Sinomenine attenuates bleomycin-induced pulmonary fibrosis, inflammation, and oxidative stress by inhibiting TLR4/NLRP3/TGFß signaling.

OBJECTIVE: The present work concentrated on validating whether sinomenine alleviates bleomycin (BLM)-induced pulmonary fibrosis, inflammation, and oxidative stress. METHODS: A rat model of pulmonary fibrosis was constructed through intratracheal injection with 5 mg/kg BLM, and the effects of 30 mg/kg sinomenine on pulmonary inflammation, fibrosis, apoptosis, and 4-hydroxynonenal density were evaluated by hematoxylin and eosin staining, Masson's trichrome staining, TUNEL staining, and immunohistochemistry. Hydroxyproline content and concentrations of inflammatory cytokines and oxidative stress markers were detected using corresponding kits. MRC-5 cells were treated with 10 ng/ml PDGF, and the effects of 1 mM sinomenine on cell proliferation were assessed by EdU assays. The mRNA expression of inflammatory cytokines and the protein levels of collagens, fibrosis markers, and key markers involved in the TLR4/NLRP3/TGFß signaling were tested with RT-qPCR and immunoblotting analysis. RESULTS: Sinomenine attenuated pulmonary fibrosis and inflammation while reducing hydroxyproline content and the protein expression of collagens and fibrosis markers in BLM-induced pulmonary fibrosis rats. Sinomenine reduced apoptosis in lung samples of BLM-challenged rats by increasing Bcl-2 and reducing Bax and cleaved caspase-3 protein expression. In addition, sinomenine alleviated inflammatory response and oxidative stress in rats with pulmonary fibrosis induced by BLM. Moreover, sinomenine inhibited the TLR4/NLRP3/TGFß signaling pathway in lung tissues of BLM-stimulated rats. Furthermore, TLR4 inhibitor, TAK-242, attenuated PDGF-induced fibroblast proliferation and collagen synthesis in MRC-5 cells. CONCLUSION: Sinomenine attenuates BLM-caused pulmonary fibrosis, inflammation, and oxidative stress by inhibiting the TLR4/NLRP3/TGFß signaling, indicating that sinomenine might become a therapeutic candidate to treat pulmonary fibrosis.

[Sinomenine inhibits PDGF/PDGFR signaling pathway to reduce RA-FLS migration induced by NETs].

This study aims to decipher the mechanism of sinomenine in inhibiting platelet-derived growth factor/platelet-derived growth factor receptor(PDGF/PDGFR) signaling pathway in rheumatoid arthritis-fibroblast-like synoviocyte(RA-FLS) migration induced by neutrophil extracellular traps(NETs). RA-FLS was isolated from the synovial tissue of 3 RA patients and cultured. NETs were extracted from the peripheral venous blood of 4 RA patients and 4 healthy control(HC). RA-FLS was classified into control group, HC-NETs group, RA-NETs group, RA-NETs+sinomenine group and RA-NETs+sinomenine+CP-673451 group. RNA-sequencing(RNA-seq) was conducted to identify the differentially expressed genes between HC-NETs and RA-NETs groups. Sangerbox was used to perform the Gene Ontology(GO) function and the Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment. Cytoscape was employed to build the protein-protein interaction(PPI) network. AutoDock Vina and PyMOL were used for molecular docking of sinomenine with PDGFß and PDGFRß. The cell proliferation and migration were determined by the cell counting kit-8(CCK-8) and cell scratch assay, respectively. Western blot was employed to determine the protein level of PDGFRß. Real-time quantitative polymerase chain reaction(RT-qPCR) was carried out to determine the mRNA levels of matrix metalloproteinases(MMPs). The results revealed that neutrophils in RA patients were more likely to produce NETs. Compared with HC-NETs group, RA-NETs group showed up-regulated expression of PDGFß and PDGFRß. Compared with control group, RA-NETs group showed increased cell proliferation and migration and up-regulated protein level of PDGFRß and mRNA levels of PDGFß, PDGFRß, MMP1, MMP3, and MMP9(P<0.05). Compared with RA-NETs group, RA-NETs+sinomenine group presented decreased cell proliferation and migration and down-regulated protein and mRNA level of PDGFRß and mRNA levels of MMP1, MMP3, and MMP9(P<0.05). Compared with RA-NETs+sinomenine group, the proliferation ability of RA-NETs+sinomenine+CP-673451 group decreased(P<0.05). The findings prove that sinomenine reduces the RA-NETs-induced RA-FLS migration by inhibiting PDGF/PDGFR signaling pathway, thus mitigating RA.

Systematic Structure-Activity Relationship Study of Nalfurafine Analogues toward Development of Potentially Nonaddictive Pain Management Treatments.

Despite the availability of numerous pain medications, the current array of Food and Drug Administration-approved options falls short in adequately addressing pain states for numerous patients and consequently worsens the opioid crisis. Thus, it is imperative for basic research to develop novel and nonaddictive pain medications. Toward addressing this clinical goal, nalfurafine (NLF) was chosen as a lead and its structure-activity relationship (SAR) systematically studied through design, syntheses, and in vivo characterization of 24 analogues. Two analogues, 21 and 23, showed longer durations of action than NLF in a warm-water tail immersion assay, produced in vivo effects primarily mediated by KOR and DOR, penetrated the blood-brain barrier, and did not function as reinforcers. Additionally, 21 produced fewer sedative effects than NLF. Taken together, these results aid the understanding of NLF SAR and provide insights for future endeavors in developing novel nonaddictive therapeutics to treat pain.

Sinomenine attenuates pulmonary fibrosis by downregulating TGF-ß1/Smad3, PI3K/Akt and NF-κB signaling pathways.

BACKGROUND: Since COVID-19 became a global epidemic disease in 2019, pulmonary fibrosis (PF) has become more prevalent among persons with severe infections, with IPF being the most prevalent form. In traditional Chinese medicine, various disorders are treated using Sinomenine (SIN). The SIN's strategy for PF defense is unclear. METHODS: Bleomycin (BLM) was used to induce PF, after which inflammatory factors, lung histological alterations, and the TGF-/Smad signaling pathway were assessed. By administering various dosages of SIN and the TGF- receptor inhibitor SB-431,542 to human embryonic lung fibroblasts (HFL-1) and A549 cells, we were able to examine proliferation and migration as well as the signaling molecules implicated in Epithelial-Mesenchymal Transition (EMT) and Extra-Cellular Matrix (ECM). RESULTS: In vivo, SIN reduced the pathological changes in the lung tissue induced by BLM, reduced the abnormal expression of inflammatory cytokines, and improved the weight and survival rate of mice. In vitro, SIN inhibited the migration and proliferation by inhibiting TGF-ß1/Smad3, PI3K/Akt, and NF-κB pathways, prevented the myofibroblasts (FMT) of HFL-1, reversed the EMT of A549 cells, restored the balance of matrix metalloenzymes, and reduced the expression of ECM proteins. CONCLUSION: SIN attenuated PF by down-regulating TGF-ß/Smad3, PI3K/Akt, and NF-κB signaling pathways, being a potential effective drug in the treatment of PF.

Protective effects of sinomenine against dextran sulfate sodium-induced ulcerative colitis in rats via alteration of HO-1/Nrf2 and inflammatory pathway.

BACKGROUND: Dextran Sulfate Sodium (DSS) induces ulcerative colitis (UC), a type of inflammatory bowel disease (IBD) that leads to inflammation, swelling, and ulcers in the large intestine. The aim of this experimental study is to examine how sinomenine, a plant-derived alkaloid, can prevent or reduce the damage caused by DSS in the colon and rectum of rats. MATERIAL AND METHODS: Induction of ulcerative colitis (UC) in rats was achieved by orally administering a 2% Dextran Sulfate Sodium (DSS) solution, while the rats concurrently received oral administrations of sinomenine and sulfasalazine. The food, water intake was estimated. The body weight, disease activity index (DAI), colon length and spleen index estimated. Antioxidant, cytokines, inflammatory parameters and mRNA expression were estimated. The composition of gut microbiota was analyzed at both the phylum and genus levels in the fecal samples obtained from all groups of rats. RESULTS: Sinomenine treatment enhanced the body weight, colon length and reduced the DAI, spleen index. Sinomenine treatment remarkably suppressed the level of NO, MPO, ICAM-1, and VCAM-1 along with alteration of antioxidant parameters such as SOD, CAT, GPx, GR and MDA. Sinomenine treatment also decreased the cytokines like TNF-α, IL-1, IL-1ß, IL-6, IL-10, IL-17, IL-18 in the serum and colon tissue; inflammatory parameters viz., PAF, COX-2, PGE2, iNOS, NF-κB; matrix metalloproteinases level such as MMP-1 and MMP-2. Sinomenine significantly (P < 0.001) enhanced the level of HO-1 and Nrf2. Sinomenine altered the mRNA expression of RIP1, RIP3, DRP3, NLRP3, IL-1ß, caspase-1 and IL-18. Sinomenine remarkably altered the relative abundance of gut microbiota like firmicutes, Bacteroidetes, F/B ratio, Verrucomicrobia, and Actinobacteria. CONCLUSION: The results clearly indicate that sinomenine demonstrated a protective effect against DSS-induced inflammation, potentially through the modulation of inflammatory pathways and gut microbiota.

Sinomenine Hydrochloride Protects IgA Nephropathy Through Regulating Cell Growth and Apoptosis of T and B Lymphocytes.

Purpose: Sinomenine hydrochloride (SH) is used to treat chronic inflammatory diseases such as rheumatoid arthritis and may also be efficacious against Immunoglobulin A nephropathy (IgAN). However, no trial has investigated the molecular mechanism of SH on IgAN. Therefore, this study aims to investigate the effect and mechanism of SH on IgAN. Methods: The pathological changes and IgA and C3 depositions in the kidney of an IgAN rat model were detected by periodic acid-Schiff (PAS) and direct immunofluorescence staining. After extracting T and B cells using immunomagnetic beads, we assessed their purity, cell cycle phase, and apoptosis stage through flow cytometry. Furthermore, we quantified cell cycle-related and apoptosis-associated proteins by Western blotting. Results: SH reduced IgA and C3 depositions in stage 4 IgAN, thereby decreasing inflammatory cellular infiltration and mesangial injury in an IgAN model induced using heteroproteins. Furthermore, SH arrested the cell cycle of lymphocytes T and B from the spleen of IgAN rats. Regarding the mechanism, our results demonstrated that SH regulated the Cyclin D1 and Cyclin E1 protein levels for arresting the cell cycle and it also regulated Bax and Bcl-2 protein levels, thus increasing Cleaved caspase-3 protein levels in Jurkat T and Ramos B cells. Conclusion: SH exerts a dual regulation on the cell cycle and apoptosis of T and B cells by controlling cell cycle-related and apoptosis-associated proteins; it also reduces inflammatory cellular infiltration and mesangial proliferation. These are the major mechanisms of SH in IgAN.

Discovery and validation of anti-arthritic ingredients and mechanisms of Qingfu Juanbi Tang, a Chinese herbal formulation, on rheumatoid arthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Qingfu Juanbi Tang (QFJBT), a novel and improved Chinese herbal formulation, has surged in recent years for its potential in the therapy of rheumatoid arthritis (RA). Anti-arthritic effects and underlying molecular mechanisms of QFJBT have increasingly become a focal point in research. AIM OF THE STUDY: This study utilized network pharmacology, molecular docking, and experimental validation to elucidate effective ingredients and anti-arthritic mechanisms of QFJBT. MATERIALS AND METHODS: Targets associated with QFJBT and RA were identified from relevant databases and standardized using the Uniprot for gene nomenclature. A "QFJBT-ingredient-target network" and a "Venn diagram of QFJBT and RA targets" were created from the data. The overlap in the Venn diagram highlighted potential targets of QFJBT in the treatment of RA. These targets were subjected to PPI network, GO, and KEGG pathway analysis. The findings were subsequently confirmed through molecular docking and pharmacological experiments to propose the mechanism of action of QFJBT. RESULTS: The study identified 236 active ingredients in QFJBT, with 120 predicted to be effective against RA. Molecular docking showed high binding affinity of key targets (JUN, PTGS2, and TNF-α) with bioactive compounds (rhein, sinomenine, calycosin, and paeoniflorin) of QFJBT. Pharmacodynamic evaluation demonstrated the effects of QFJBT at the dose of 4.56 g/kg in ameliorating symptoms of AIA rats and in reducing levels of JUN, PTGS2, and TNF-α in synovial tissues. In vitro studies further exhibited that rhein, paeoniflorin, sinomenine, calycosin, and QFJBT-containing serum significantly inhibited abnormal proliferation of RA fibroblast-like synoviocytes. Interestingly, rhein and paeoniflorin specifically decreased p-JUN/JUN expression and TNF-α release, respectively, while sinomenine and calycosin selectively increased PTGS2 expression. Consistently, QFJBT-containing serum demonstrated similar effects as those active ingredients identified in QFJBT did. CONCLUSIONS: QFJBT, QFJBT-containing serum, and its active ingredients (rhein, paeoniflorin, sinomenine, and calycosin) suppress inflammatory responses in RA. Anti-arthritic effects of QFJBT and its active ingredients are likely linked to their modulatory impact on identified hub targets.

Morphinan Evolution: The Impact of Advances in Biochemistry and Molecular Biology.

Morphinan-based opioids, derived from natural alkaloids like morphine, codeine and thebaine, have long been pivotal in managing severe pain. However, their clinical utility is marred by significant side effects and high addiction potential. This review traces the evolution of the morphinan scaffold in light of advancements in biochemistry and molecular biology, which have expanded our understanding of opioid receptor pharmacology. We explore the development of semi-synthetic and synthetic morphinans, their receptor selectivity and the emergence of biased agonism as a strategy to dissociate analgesic properties from undesirable effects. By examining the molecular intricacies of opioid receptors and their signaling pathways, we highlight how receptor-type selectivity and signaling bias have informed the design of novel analgesics. This synthesis of historical and contemporary perspectives provides an overview of the morphinan landscape, underscoring the ongoing efforts to mitigate the problems facing opioids through smarter drug design. We also highlight that most morphinan derivatives show a preference for the G protein pathway, although detailed experimental comparisons are still necessary. This fact underscores the utility of the morphinan skeleton in future opioid drug discovery.

Bioactivities and Mechanisms of Action of Sinomenine and Its Derivatives: A Comprehensive Review.

Sinomenine, an isoquinoline alkaloid extracted from the roots and stems of Sinomenium acutum, has been extensively studied for its derivatives as bioactive agents. This review concentrates on the research advancements in the biological activities and action mechanisms of sinomenine-related compounds until November 2023. The findings indicate a broad spectrum of pharmacological effects, including antitumor, anti-inflammation, neuroprotection, and immunosuppressive properties. These compounds are notably effective against breast, lung, liver, and prostate cancers, exhibiting IC50 values of approximately 121.4 nM against PC-3 and DU-145 cells, primarily through the PI3K/Akt/mTOR, NF-κB, MAPK, and JAK/STAT signaling pathways. Additionally, they manifest anti-inflammatory and analgesic effects predominantly via the NF-κB, MAPK, and Nrf2 signaling pathways. Utilized in treating rheumatic arthritis, these alkaloids also play a significant role in cardiovascular and cerebrovascular protection, as well as organ protection through the NF-κB, Nrf2, MAPK, and PI3K/Akt/mTOR signaling pathways. This review concludes with perspectives and insights on this topic, highlighting the potential of sinomenine-related compounds in clinical applications and the development of medications derived from natural products.

Recent Advances in the Therapeutic Potential of Sinomenine for Cancer Treatment.

BACKGROUND: Cancer is a major cause of death worldwide. Although modern medicine has made strides in treatment, a complete cure for cancer remains elusive. SUMMARY: Utilization of medicinal plants in traditional medicine for the treatment of multiple diseases, including cancer, is a well-established practice. Sinomenine is an alkaloid extracted from a medicinal plant and has a diverse range of biological properties, including anti-oxidative, anti-inflammatory, and antibacterial effects. Sinomenine exhibits inhibitory effects on various types of tumor cells, including breast, lung, and liver cancers. The anticancer properties of sinomenine are believed to involve stimulation of apoptosis and autophagy as well as suppression of cell proliferation, invasion, and metastasis. KEY MESSAGE: This review summarizes the current research on sinomenine's potential as an anticancer agent, which may contribute to the discovery of more effective cancer treatments.

Proposal for the classification of sinomenine alkaloids.

The chemical structure of sinoacutine is formed by a phenanthrene nucleus and an ethylamine bridge. Because it has a similar parent structure to morphine, it is subdivided into morphinane. At present, all reports have pointed out that the basic skeleton of morphine alkaloids is salutaridine (the isomer of sinoacutine), which is generated by the phenol coupling reaction of (R)-reticuline. This study shows that the biosynthetic precursors of sinoacutine and salutaridine are different. In this paper, the sinoacutine synthetase (SinSyn) gene was cloned from Sinomenium acutum and expressed SinSyn protein. Sinoacutine was produced by SinSyn catalyzed (S)-reticuline, according to the results of enzyme-catalyzed experiments. The optical activity, nuclear magnetic resonance, and mass spectrum of sinoacutine and salutaridine were analyzed. The classification and pharmacological action of isoquinoline alkaloids were discussed. It was suggested that sinoacutine should be separated from morphinane and classified as sinomenine alkaloids.

Discovery of sinomenine/8-Bis(benzylthio)octanoic acid hybrids as potential anti-leukemia drug candidate via mitochondrial pathway.

Traditional Chinese medicine Qingfengteng primarily acquired from the dried canes of Sinomenium acutum (Thunb.) Rehd. et Wils. var. cinereum Rehd. et Wils. and S. acutum (Thunb.) Rehd. et Wils. For the therapeutic treatment of rheumatism, acute arthritis, and rheumatoid arthritis based on Qingfengteng, sinomenine hydrochloride was recently made the principal active ingredient in various dosage forms. 8-Bis(benzylthio)octanoic acid (CPI-613) was an orphan medicine that the FDA and EMA approved orphan for the treatment of certain resistant malignancies. Its unique mode of action and minimal toxicity toward normal tissues made for an apt pharmacophore. In order to expand the field of sinomenine anticancer structures, sinomenine/8-Bis(benzylthio)octanoic acid derivatives were designed and synthesized. Among them, target hybrids e4 stood out for having notable cytotoxic effects against cancer cell lines, especially for K562 cells, with IC50 values of 2.45 µM and high safety. In-depth investigations demonstrated that e4 caused apoptosis by stopping the cell cycle at G1 phase, and doing so by altering the morphology of the nucleus and causing membrane potential of the in mitochondria to collapse. These results indicated e4 exerted an antiproliferative effect through apoptosis induction via mitochondrial pathway.

Pharmacological mechanisms of sinomenine in anti-inflammatory immunity and osteoprotection in rheumatoid arthritis: A systematic review.

BACKGROUND: Sinomenine (SIN) is the main pharmacologically active component of Sinomenii Caulis and protects against rheumatoid arthritis (RA). In recent years, many studies have been conducted to elucidate the pharmacological mechanisms of SIN in the treatment of RA. However, the molecular mechanism of SIN in RA has not been fully elucidated. PURPOSE: To summarize the pharmacological effects and molecular mechanisms of SIN in RA and clarify the most valuable regulatory mechanisms of SIN to provide clues and a basis for basic research and clinical applications. METHODS: We systematically searched SciFinder, Web of Science, PubMed, China National Knowledge Internet (CNKI), the Wanfang Databases, and the Chinese Scientific Journal Database (VIP). We organized our work based on the PRISMA statement and selected studies for review based on predefined selection criteria. OUTCOME: After screening, we identified 201 relevant studies, including 88 clinical trials and 113 in vivo and in vitro studies on molecular mechanisms. Among these studies, we selected key results for reporting and analysis. CONCLUSIONS: We found that most of the known pharmacological mechanisms of SIN are indirect effects on certain signaling pathways or proteins. SIN was manifested to reduce the release of inflammatory cytokines such as Tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), and IL-1ß, thereby reducing the inflammatory response, and apparently blocking the destruction of bone and cartilage. The regulatory effects on inflammation and bone destruction make SIN a promising drug to treat RA. More notably, we believe that the modulation of α7nAChR and the regulation of methylation levels at specific GCG sites in the mPGES-1 promoter by SIN, and its mechanism of directly targeting GBP5, certainly enriches the possibilities and the underlying rationale for SIN in the treatment of inflammatory immune-related diseases.

Protection of pancreatic islets from oxidative cell death by a peripherally-active morphinan with increased drug safety.

OBJECTIVE: Dextromethorphan (DXM) is a commonly used antitussive medication with positive effects in people with type 2 diabetes mellitus, since it increases glucose tolerance and protects pancreatic islets from cell death. However, its use as an antidiabetic medication is limited due to its central nervous side effects and potential use as a recreational drug. Therefore, we recently modified DXM chemically to reduce its blood-brain barrier (BBB) penetration and central side effects. However, our best compound interacted with the cardiac potassium channel hERG (human ether-à-go-go-related gene product) and the µ-opioid receptor (MOR). Thus, the goal of this study was to reduce the interaction of our compound with these targets, while maintaining its beneficial properties. METHODS: Receptor and channel binding assays were conducted to evaluate the drug safety of our DXM derivative. Pancreatic islets were used to investigate the effect of the compound on insulin secretion and islet cell survival. Via liquor collection from the brain and a behavioral assay, we analyzed the BBB permeability. By performing intraperitoneal and oral glucose tolerance tests as well as pharmacokinetic analyses, the antidiabetic potential and elimination half-life were investigated, respectively. To analyze the islet cell-protective effect, we used fluorescence microscopy as well as flow cytometric analyses. RESULTS: Here, we report the design and synthesis of an optimized, orally available BBB-impermeable DXM derivative with lesser binding to hERG and MOR than previous ones. We also show that the new compound substantially enhances glucose-stimulated insulin secretion (GSIS) from mouse and human islets and glucose tolerance in mice as well as protects pancreatic islets from cell death induced by reactive oxygen species and that it amplifies the effects of tirzepatide on GSIS and islet cell viability. CONCLUSIONS: We succeeded to design and synthesize a novel morphinan derivative that is BBB-impermeable, glucose-lowering and islet cell-protective and has good drug safety despite its morphinan and imidazole structures.

Analysis of non-volatile metabolites and quantitation of the anti-arthritic alkaloid sinomenine from blood fruit (Haematocarpus validus (Miers) Bakh.f. ex Forman).

Haematocarpus validus (Miers) Bakh. f. ex Forman, a lesser-known fruit and medicinal plant of high nutraceutical and medicinal value, is used as anti-arthritic, hepatoprotective, and anti-inflammatory agents in ethnomedicine. Metabolome studies in H. validus are a virgin area of research and here we report the spectra of non-volatiles present in the methanolic leaf and fruit extract, using high-resolution liquid chromatography-mass spectrometry. Furthermore, the alkaloid sinomenine was quantified using high-performance thin layer chromatography spectrodensitometric analysis owing to its pharmacological importance as anti-arthritic and anti-inflammatory drug. Electrospray ionization with protonation in positive mode was selected for the analysis and the spectral data was interrogated using MassHunter software. A total of 40 compounds were identified from leaf and fruit samples and the major classes of compounds identified were alkaloids, terpenoids, steroids, tripeptides, vitamins, and related compounds. For separation and quantitation of sinomenine, chloroform:methanol:water (60:30:6.5, v/v) was used as the mobile phase and sinomenine hydrochloride as reference compound. The analysis confirmed the presence of sinomenine in both non-defatted and defatted methanolic leaf extract with quantities 45.73 and 26.02 mg/100 g dry weight, respectively. H. validus is a non-conventional source of sinomenine, the anti-arthritic and anti-inflammatory alkaloid. Sinomenine detected in this study supports the ethnomedicinal uses of H. validus as an anti-arthritic agent. Further study is needed to elucidate the underlying molecular mechanism of its anti-arthritic attributes as well as the corresponding structure-activity relationships.

A review on pharmacokinetics of sinomenine and its anti-inflammatory and immunomodulatory effects.

Autoimmune diseases (ADs), with significant effects on morbidity and mortality, are a broad spectrum of disorders featured by body's immune responses being directed against its own tissues, resulting in chronic inflammation and tissue damage. Sinomenine (SIN) is an alkaloid isolated from the root and stem of Sinomenium acutum which is mainly used to treat pain, inflammation and immune disorders for centuries in China. Its potential anti-inflammatory role for treating immune-related disorders in experimental animal models and in some clinical applications have been reported widely, suggesting an inspiring application prospect of SIN. In this review, the pharmacokinetics, drug delivery systems, pharmacological mechanisms of action underlying the anti-inflammatory and immunomodulatory effects of SIN, and the possibility of SIN as adjuvant to disease-modifying anti-rheumatic drugs (DMARDs) therapy were summarized and evaluated. This paper aims to reveal the potential prospects and limitations of SIN in the treatment of inflammatory and immune diseases, and to provide ideas for compensating its limitations and reducing the side effects, and thus to make SIN better translate to the clinic.

[Development of a Simple and Sensitive Enzyme-linked Immunosorbent Assay for Sinomenine].

Sinomenine (SIN) is a major component contained in extracts of the Chinese medicinal herb Sinomenium acutum. SIN has various pharmacological properties, including cytoprotection, immunosuppression and anti-inflammation effects. Furthermore, recent studies have reported that SIN has anti-tumor and antidepressant effects, which has created a strong need for SIN kinetic studies. This paper reports a simple and sensitive competitive enzyme-linked immunosorbent assay (ELISA) for the pharmacokinetic evaluation of SIN. Anti-SIN serum was obtained by immunizing mice with an antigen conjugated with bovine serum albumin and carboxylic modified SIN using the N-succinimidyl ester method. Enzyme labeling of SIN with horseradish peroxidase was similarly performed using carboxylic modified SIN. Under optimized conditions, this ELISA shows a linear detection range from 40 to 5000 pg/mL, and a limit of detection of 12.1 pg/mL for 50-µL samples. This assay was specific for SIN and showed very slight cross-reactivity with dextromethorphan (0.45%), dimemorfan (0.22%) and codeine (0.01%), but no cross-reactivity with 2-methoxycyclohex-2-enone (<0.001%). Using this ELISA, SIN levels were easily determined in the blood of mice after oral administration of Kampo medicine, Boiogito. The ELISA may be a valuable tool for studies of the biological and pharmacological properties of SIN.