Frontiers in Pharmacology最新文献

Background: Postoperative Intestinal Adhesions (PIAs) remain a significant complication of abdominal surgery that can cause pain, infertility, and a potentially lethal bowel obstruction. Kangnian (KN) decoction, a Traditional Chinese Medicine prescription, has been shown to be effective in treating PIAs. Nevertheless, its underlying mechanisms remain unclear.

Objective: This study aims to explore the therapeutic effects of KN decoction in a PIA rat model, as well as its potential mechanisms via metabolomics and proteomics analyses.

Materials and methods: 60 rats were randomly assigned to six groups: Normal Control (NC), PIA model, Dexamethasone, KN-Low, KN-Medium, and KN-High. The PIA model was created by abdominal surgery under anesthesia. Pathological damage was evaluated through H&E staining and adhesion grading of affected tissues. The levels of serum cytokines (IL-1β, IL-6, TNF-α, and TGF-1), Connective Tissue Growth Factor (CTGF), and Motilin (MTL) in adherent intestinal tissues were detected using ELISA kits. Untargeted metabolomics was used to investigate potential metabolic pathways of the KN decoction intervention in intestinal adhesions and to screen for differential biomarkers. The label-free quantitative proteomics technique was employed to detect Differentially Expressed Proteins and for biological function and pathway enrichment analyses.

Results: In PIA rats, KN decoction significantly improved the pathological injury associated with intestinal adhesions and effectively regulated the blood inflammation indicators. Furthermore, KN presented a favorable anti-fibrotic and protective effect against abdominal adhesions, effectively modifying gastrointestinal motility disorders in PIA rats. We identified 58 variables as potential biomarkers and discovered seven main pathological pathways that may be associated with PIAs. Proteomics analysis revealed 75 DEPs that were primarily involved in Valine, leucine, and isoleucine degradation, the MAPK signaling pathway, and retrograde endocannabinoid signaling.

Conclusion: This study proved that KN reduces intestinal mucosal injury, downregulates inflammatory factors, and alleviates intestinal adhesions, thus protecting the intestinal barrier function in PIA rats. The combination of proteomics and metabolomics provided a feasible approach for unraveling the therapeutic mechanism of KN decoction in PIAs.

Introduction: Depression is a common psychological disorder, accompanied by a disturbance of the gut microbiota and its metabolites. Recently, microbiota-derived tryptophan metabolism and AMPK/mTOR pathway were found to be strongly linked to the development of depression. Shugan Hewei Decoction (SHD) is a classical anti-depression traditional Chinese medicine formula. Although, we have shown that SHD exerted antidepressant effects via cecal microbiota and cecum NLRP3 inflammasome, the specific mechanism of SHD on metabolism driven by gut microbiota is unknown. In this study, we focus on the tryptophan metabolism and AMPK/mTOR pathway to elucidate the multifaceted mechanisms of SHD.

Methods: Male rats were established to the chronic unpredictable stress (CUS)/social isolation for 6 weeks, and SHD-L (7.34 g/kg/d), SHD-H (14.68 g/kg/d), Fructooligosaccharide (FOS) (3.15 g/kg/d) were given by intragastric administration once daily during the last 2 weeks. Behavioral experiments were carried out to evaluate the model. The colonic content was taken out for shotgun metagenomic sequencing combined with the untargeted metabolomics, the targeted tryptophan metabolomics. ELISA was used to detect the levels of zonula occludens 1 (ZO-1), Occludin in colon, as well as lipopolysaccharide (LPS), diamine oxidase (DAO), D-lactate (DLA) in serum. The expressions of mRNA and proteins of adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway of autophagy were examined using RT-qPCR and Western blot in colon.

Results: SHD modulated gut microbiota function and biological pathways, which were related to tryptophan metabolism. In addition, SHD could regulate microbiota-derived tryptophan production (such as reduction of 3-HK, 3-HAA etc., increment of ILA, IAA etc.), which metabolites belong to kynurenine (KYN) and indole derivatives. Further, SHD reduced intestinal permeability and enhanced the intestinal barrier function. Moreover, SHD could upregulate the levels of AMPK, microtubule associated protein light chain 3 (LC3), autophagy related protein 5 (ATG5) and Beclin1, downregulate the levels of mTOR, p62, promoted autophagy in colon. Spearman's analysis illustrated the close correlation between tryptophan metabolites and intestinal barrier, AMPK/mTOR pathway.

Conclusion: SHD may exert antidepressant-like effects by regulating microbiota-derived tryptophan metabolism, and triggering the AMPK/mTOR pathway of autophagy, enhancing the intestinal barrier function.

Introduction: Monoiodoacetate (MIA)-induced osteoarthritis (OA) is the most commonly used rodent model for testing anti-OA drug candidates. Herein, we investigated the effects of our patented multitarget drug candidate SZV-1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl) propanal oxime) that is currently under clinical development for neuropathic pain and characterized the mouse model through complex functional, in vivo imaging, and morphological techniques.

Methods: Knee OA was induced by intraarticular MIA injection (0.5 and 0.8 mg). Spontaneous pain was assessed based on weight distribution, referred pain by paw mechanonociception (esthesiometry), edema by caliper, neutrophil myeloperoxidase activity by luminescence, matrix metalloproteinase activity, vascular leakage and bone remodeling by fluorescence imaging, bone morphology by micro-CT, histopathological alterations by semiquantitative scoring, and glia activation by immunohistochemistry. Then, SZV-1287 (20 mg/kg/day) or its vehicle was injected intraperitoneally over a 21-day period.

Results: MIA induced remarkably decreased thresholds of weight bearing and paw withdrawal, alterations in the tibial and femoral structures (reactive sclerosis, increased trabeculation, and cortical erosions), histopathological damage (disorganized cartilage structure, hypocellularity, decreased matrix staining and tidemark integrity, and increased synovial hyperplasia and osteophyte formation), and changes in the astrocyte and microglia density in the lumbar spinal cord. There were no major differences between the two MIA doses in most outcome measures. SZV-1287 inhibited MIA-induced weight bearing reduction, hyperalgesia, edema, myeloperoxidase activity, histopathological damage, and astrocyte and microglia density.

Conclusion: SZV-1287 may have disease-modifying potential through analgesic, anti-inflammatory, and chondroprotective effects. The MIA mouse model is valuable for investigating OA-related mechanisms and testing compounds in mice at an optimal dose of 0.5 mg.