Phytomedicine最新文献

Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a often heterogeneous condition in urology. Accumulating evidence suggests that the autoimmune response against prostate antigens is related to CP/CPPS. The gut microbiota may be a possible cause of a number of autoimmune diseases. Eriocalyxin B (EriB) is used as an anti-inflammatory treatment for autoimmune disorders. The underlying mechanism of fecal metabolome involved in CP/CPPS treatment by EriB remains unclear.

Methods: The experimental autoimmune prostatitis (EAP) mouse model was generated by subcutaneous immunization. Macrophages, inflammatory cytokines, intestinal microbiota, and fecal metabolome of the mice were analyzed. The alteration of the fecal metabolome was investigated in detail in EriB-treated EAP mice and confirmed by in vitro experiments.

Results: EriB ameliorated significantly decreased prostate inflammation in EAP mice and promoted macrophage phenotype polarizing from M1 to M2. The gut microbiome was altered, and intestinal barrier damage was improved by EriB treatment. Furthermore, the enrichment of vitamin digestion and absorption pathways in the fecal metabolome revealed that vitamin D₃ was altered by EriB. In vitro experiments confirmed that macrophage polarization from M1 to M2 was promoted by vitamin D₃. Finally, fecal transplantation from EriB-treated mice markedly reduced inflammatory indicators and the macrophage M1/M2 ratio in pseudogerm-free EAP mice. In our study, the immune state of macrophage regulated by gut microbiota-mediated vitamin D3 alteration was first time revealed in EAP treatment.

Conclusions: EriB ameliorated in mice with EAP, the gut microbiota mediates vitamin D₃ alterations to modulate macrophage phenotype polarizing from M1 to M2.

Background: Hypoxic pulmonary vasoconstriction (HPV) is a reflex constriction of vascular smooth muscle. This study aims to investigate the role of Salidroside (Sal) in pulmonary arterial dilatation and the potential mechanism of Sal regulating hypoxic pulmonary hypertension in vitro and in vivo.

Methods: A rat model of hypoxic pulmonary hypertension (HPH) was constructed using hypoxic chamber. The effect of Sal on HPH were evaluated using vascular ring, whole cell patch-clamp, WGA staining, HE staining, and Sirius Scarlet staining assays.

Results: Sal treatment alleviated the injury of acute hypoxia on pulmonary circulation in SD rats. Meanwhile, Sal treatment reduced the pulmonary vascular tone of acute hypoxia in a concentration-dependent manner, which was involved in the TWIK-related acid-sensitive potassium channel 1 (TASK-1) mediating diastolic effect. We found that Sal treatment significantly increased the TASK-1 current of pulmonary artery smooth muscle cells (PASMCs) in a concentration-dependent manner, as well as reversed the inhibitory effect of acute hypoxia on the TASK-1 current. Moreover, Sal treatment improved the TASK-1 current density, suppressed the proliferation, and enhanced the apoptosis of PASMCs in SD rats under continuous hypoxic condition. In addition, we found that the electrophysiological remodeling and pulmonary vascular remodeling of PASMCs were improved by the treatment of Sal through the regulation of TASK-1 channel.

Conclusions: Sal could alleviate HPH by restoring the function of TASK-1 channel, which may provide a novel method for the treatment of HPH.

Background and purpose: Swertiamarin (STM), a secoiridoid glycoside from Swertia chirayita (Roxb.) H. Karst, has been shown to decrease body weight, blood glucose, and blood lipids by inhibiting adipose tissue hypertrophy. However, the underlying mechanisms remain unclear. In particular, adipose thermogenesis is a novel avenue for exploring the pharmacological effects of STM. We aim to investigate the efficacy of STM on type 2 diabetes mellitus (T2DM), with a focus on underlying mechanisms, particularly the activation of ADRB3/UCP1 thermogenic signaling pathways.

Methods: T2DM model was established by a high-fat diet (HFD) and streptozotocin (STZ) in C57BL/6 J male mice. Mice were given to either 100 or 200 mg kg^-1/day of STM, or 200 mg kg^-1/day of metformin (Glucophage) via intragastric administration for 7 weeks. In vitro, 3T3-L1 cells were differentiated into adipocytes. Molecular markers related to ADRB3-UCP1 signals, lipolysis, and mitochondrial function were detected.

Results: STM-treated diabetic mice showed a reduction of body weight, fat mass, and blood glucose/lipids and an improvement in insulin sensitivity. Bioinformatics analysis indicated STM promoted lipid metabolism and mitochondrial function, features by closely associated with adipose thermogenesis. STM upregulated the lipolysis-related genes and p-HSL protein in inguinal subcutaneous white adipose tissue (igSWAT) and brown adipose tissue (BAT). STM-treated mice processed a more active energy metabolism. Additionally, the ADRB3-UCP1 signals, mitochondrial-related genes, and oxidative phosphorylation were improved in igSWAT and BAT. In vitro, we found STM interacted with ADRB3, increasing glucose uptake, glycerol release, ADRB3-UCP1 signals, p-HSL expression, mitochondrial content, oxidative phosphorylation complex expression with improved mitochondrial Δψm, as well as reduced lipid accumulation in adipocytes. All these effects were reversed upon ADRB3 inhibition.

Conclusion: This study identifies a previously unknown role of STM activating ADRB3/UCP1 signals in adipose tissue, suggesting a potential strategy for treating T2DM.

Background: Rheumatoid arthritis (RA) is partially affected by the integrity of the intestinal barrier. Licorice (GC), a medicinal and food-related herb, exhibits potent anti-inflammatory activity; however, studies on its mechanisms of action in RA are limited.

Method: Using a bovine type-II collagen-induced arthritis rat model, this study examined how GC influences the gut-joint axis to decrease RA. The Th17/Treg cell ratios in the blood, colon, and joints were also measured. Metabolomics and 16S rRNA sequencing were applied to explore the effects of variations in gut flora and metabolites.

Results: The arthropathological slices, inflammation markers, and joint inflammation index scores in the GC treatment group significantly differed from those in the CIA group. Studies on the effect of GC on the gut-joint axis showed changes in the levels of lipopolysaccharide and diamine oxidase, both directly associated with intestinal permeability. ZO-1, occludin, and claudin-1, three intestinal tight-junction proteins, may express themselves more when exposed to GC. By maintaining an appropriate Th17/Treg cell ratio in the blood, colon, and joints, GC may reduce impaired to the intestinal barrier. An imbalance in the intestinal microenvironment, caused by modifications in gut flora and endogenous substances, can damage the intestinal barrier. GC may modify the relative abundances of Papillibacter, Clostridium, Eubacterium, Helicobacter, Provotella, and Barnesiella during RA treatment by repairing the intestinal barrier. The metabolic differences were mainly related to primary bile acid biosynthesis, pyrimidine metabolism, steroid biosynthesis, biotin metabolism, and sphingolipid metabolism. A fecal microbiota transplantation experiment confirmed the involvement of the gut microbiota and its metabolites in GC-mediated RA therapy.

Conclusion: The results demonstrated that GC repairs the intestinal barrier and adjusts the gut-joint axis to manage immunological imbalance in RA.

Background: Yi-Fei-San-Jie Formula (YFSJF), a proprietary medicine of the First Affiliated Hospital of Guangzhou University of Chinese Medicine, has been widely used in clinical practice for several years and is currently being tested in randomized controlled trials for early-stage lung cancer in China. However, the mechanisms by which YFSJF affects lung cancer biology, particularly the immune microenvironment and metabolic processes, remain poorly understood.

Purpose: This study aims to explore how YFSJF modulates the immune microenvironment and metabolism in lung cancer, specifically its unique role in inhibiting immune evasion by targeting the TGR5/STAT3/PD-L1 pathway, which has not previously been reported.

Methods: Computed Tomography (CT) scan was used to assess YFSJF efficacy in patients with lung cancer and a mouse model of urethane-induced lung cancer. Histopathological evaluation, flow cytometry, and metabolomic analysis were used to assess lung tissue structure, immune cell subset changes, and metabolism modulation, respectively. Western blotting and immunohistochemistry were used to detect Ki67, TTF-1, TGR5, STAT3, p-STAT3, and PD-L1 protein expression. Serum cytokines were detected by ELISA.

Results: YFSJF effectively reduced the size of human lung cancer lesions and decreased the tumor burden and improved survival rates in mice. Lung tissue structure was also improved after YFSJF treatment. YFSJF regulated T-cell subsets, particularly by downregulating cells with PD-1-positive expression of CD3⁺, CD4⁺, and CD8⁺, and elevated serum TNF-α, IFN-γ, and GzmB levels. In addition, YFSJF modulated bile acid metabolism, particularly by inhibiting deoxycholic acid metabolism, which participates in immune regulation in lung cancer by acting on the G protein-coupled bile acid receptor TGR5.

Conclusion: Finally, YFSJF inhibited immune evasion by blocking the TGR5-mediated STAT3/PD-L1 pathway, weakening PD-L1 and PD-1 binding and reviving T-cell immune activity, thereby countering lung cancer immune evasion and exerting anti-tumor effects.

Background: Colorectal cancer (CRC) is the second primary malignancy in China with tough treatment challenge. Although Oleanolic acid (OA) protects against various cancers, its mechanisms in CRC are not well defined. Our previously study showed that Nur77 has CRC promoting effect. Thus, we investigated the roles of OA as Nur77 ligand and the regulatory effects on Nur77 degradation in CRC progression.

Methods: The proliferative and metastatic phenotypes of OA was examined by CCK-8, EdU, organoid culture, would healing and transwell assays, respectively. Epithelial-mesenchymal transition (EMT) properties were assessed by Western blotting (WB). The interaction between OA and Nur77 was monitored by molecular docking and Molecular Dynamics stimulation (MD). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene set enrichment analysis (GSEA) were employed to screen the downstream regulatory pathways. The half-time and proteasome degradation of Nur77 were treated with cycloheximide (CHX) and MG132. Co-immunoprecipitation (Co-IP) and ubiquitination assays were employed to detect direct association between Nur77 and PPARγ. Rescued experiments were performed by Nur77 agonist Cytosporone B (Csn-B) treatment. The findings were verified in xenograft and in situ models.

Results: For the first time, we found the effect of OA on ubiquitination degradation. OA inhibited CRC cell survival and EMT phenotypes by suppressing Nur77. Mechanistically, OA directly bind to Nur77 and facilitated the ubiquitin degradation of Nur77. During this process, PPARγ acted as the ubiquitination activator via interacting with Nur77. Rescued experiments revealed that OA-induced inhibition was recovered by replenishing Nur77. In both subcutaneous and orthotopic CRC models, OA exhibited significant anti-tumor effect together with Nur77 inhibition.

Conclusion: We revealed a new regulatory effect of OA in CRC tumorigenesis via PPARγ-mediated Nur77 ubiquitin degradation.

Background: Chronic inflammation is closely related to the occurrence and progression of many cancers, especially colorectal cancer (CRC), which can be triggered by repeated and sustained induction of colitis in mice. CRC is a typical type of cancer that can be caused by inflammation and NLRP3 inflammasome dysregulation plays a certain role in the pathogenesis of CRC.

Purpose: As an edible Chinese medicine, Abrus cantoniensis Hance (ACH) has both anti-inflammatory and anti-tumor activities. However, most research has focused on inflammation-related diseases, and less research has been done on its active ingredients and targets and its application in CRC. Here, this study deeply explored the target of 2',4'-DHC and its pharmacological mechanism in anti-colon cancer, and provided a new strategy for its drug development and treatment of colon cancer.

Methods: The cytotoxicity of ACH's active ingredient in HT29 and CT26 cells was measured by CCK-8, clone formation, apoptosis, and cell cycle assay. The metastasis inhibition of CRC cells was determined by wound-healing assay. Western blotting was used to detect the NLRP3 inflammasome activation, pyroptosis, and apoptosis activation. Finally, the in vivo efficacy of 2',4'-DHC was verified by establishing CT26 and HT29 tumor transplant models in mice.

Results: Here, our study firstly demonstrated that 2',4'-DHC inhibited the growth of CRC cells mainly by increasing CRC cell death and ameliorating tumor immunosuppressive environment, which is verified by inducing apoptosis and pyroptosis by regulating caspase-3/4/11, arresting cell cycle in G2/M phase, suppressing the migration of CRC cells, and inhibiting NLRP3 inflammasome activation through inhibiting the NF-κB pathway, enhancing the anticancer immune response by increasing the infiltration of T cells and function of CD8⁺ cytotoxic T cells but decreasing the infiltration of CD11b⁺ CD206⁺ macrophages and function. Importantly, the administration of 2',4'-DHC decreased liver and spleen indexs to mice's normal levels and reduced the burden of CT26 and HT29 tumor-bearing in mice without pathological changes in the major organs.

Conclusion: 2',4'-DHC inhibited CRC growth through various mechanisms, mainly by regulating NLRP3 inflammasome and caspase-3/4/11 activation. Considering the anti-tumor and immunomodulation roles of 2',4'-DHC, it might be a new direction for the development of new strategies to treat colorectal cancer.