Phytomedicine最新文献

Background: Prostate cancer (PCa) is a significant malignancy in men, particularly challenging in the metastatic stage due to poor prognosis and limited treatment efficacy. Traditional Chinese Medicine, particularly Modified Shenqi Dihuang Decoction (MSDD), has demonstrated promise in inhibiting PCa metastasis, although its mechanisms remain unclear.

Methods: The efficacy of MSDD was evaluated using migration assays and a nude mouse model. Metabolomics was employed to identify the biological processes affected by MSDD. Systematic pharmacology, bioinformatics, and molecular dynamics were utilized to determine direct action targets of MSDD. Additionally, luciferase reporter assays, ChIP-qPCR, and gene editing were applied to elucidate the pharmacological mechanisms.

Results: MSDD effectively inhibited prostate metastasis both in vivo and in vitro, without significant adverse events reported. Metabolomics and molecular biology experiments indicated that MSDD transcriptionally represses OGDH, affecting energy metabolism associated with the tricarboxylic acid cycle (TCA) in PCa. The active components of MSDD were found to potentially bind to the transcription factor RELA (NF-kB-p65), and further experiments demonstrated that RELA regulates OGDH transcription. Further experiments revealed that the anti-metastatic effects of MSDD are RELA-dependent, indicating the crucial role of the NF-kB/OGDH axis in this process.

Conclusions: These findings support the clinical use of MSDD in metastatic PCa, emphasizing its potential to address current treatment gaps. The identified NF-kB/OGDH-dependent mechanism not only underpins MSDD's anti-metastatic effects but also reflects OGDH as a potential therapeutic target. Further research into the role of TCA in PCa progression is imperative.

Background: Syringin (SRG) is well-known for its anti-inflammatory effects. However, its pharmacological mechanisms against rheumatoid arthritis (RA) are not fully understood.

Materials and methods: We assessed the anti-RA effects of SRG using a collagen-induced arthritis (CIA) rat model. And, we employed single-cell RNA sequencing (scRNA-seq) to analyze the changes in cell types and gene expression in the synovial tissues. Building on these observations, we investigated the effects of SRG on M1 macrophage polarization and RA-fibroblast-like synoviocytes (FLS) proliferation.

Results: Our findings highlighted the anti-RA effects of SRG on CIA rat. scRNA-seq of rat synovial tissues revealed significant changes in M1 and RA-FLS. Specifically, SRG decreased the levels of inflammatory factors in the supernatants of LPS and IFN-γ induced THP-1 cells and downregulated M1-polarized markers in these cells. Further analysis indicated that SRG's regulation of phosphodiesterase 4 (PDE4) and its associated factors was crucial for its anti-M1 polarization effects. Besides, we found that SRG inhibited the activation of FLS in vivo but showed no direct effects on RA-FLS in vitro. However, in RA-FLS, co-cultured with supernatant from SRG-treated M1-polarized THP-1 cells exhibited lower ability of cell proliferation and activation as compared to co-cultured with supernatant from M1-polarized THP-1 cells.

Conclusion: By integrating scRNA-seq analysis with in vivo and in vitro validations, our study revealed that SRG achieved its anti-RA effects by blocking the interaction between macrophages and RA-FLS, with PDE4 playing a central role. This study may provide a novel research paradigm in studying the multi-cell regulatory mechanisms of natural compounds.

Background: Resistance to senescence in retinal pigment epithelial (RPE) cells can delay the progression of age-related macular degeneration (AMD). However, the mechanisms underlying RPE cell senescence remain inadequately understood, and effective therapeutic strategies are lacking. While astragaloside IV (Ast) has demonstrated anti-aging properties, its specific effects on RPE cell senescence and potential mechanisms are not yet fully clarified.

Purpose: This study aimed to explore the impacts of Ast on RPE cell senescence and to uncover the molecular mechanisms involved.

Methods: The therapeutic efficacy of Ast was assessed using sodium iodate (NaIO₃)-induced adult retinal pigment epithelial cell line 19 (ARPE-19) cell models and an AMD mouse model. To investigate the mechanisms by which Ast mitigated RPE cell senescence, RNA sequencing (RNA-seq), drug affinity responsive target stability-mass spectrometry (DARTS-MS), cellular thermal shift assay (CETSA), reverse transcription quantitative PCR (RT-qPCR), as well as western blotting were conducted.

Results: Ast significantly inhibited NaIO₃-treated ARPE-19 cell senescence and protected against NaIO₃-induced AMD in mice. RNA-seq analysis revealed that Ast significantly attenuated inflammation-related signaling pathways and reduced the mRNA levels of interleukin-1 beta (IL-1β). Specifically, Ast decreased the stability of IL-1β mRNA while enhancing its N6-methyladenosine (m⁶A) methylation. Furthermore, Ast directly interacted with fat mass and obesity-associated protein (FTO). Knockdown or pharmacological inhibition of FTO mitigated the senescence and IL-1β expression in NaIO₃-treated ARPE-19 cells. FTO was essential for Ast to inhibit cellular senescence and IL-1β expression. Additionally, inhibition or knockdown of FTO conferred also provided resistance to AMD in the murine model.

Conclusion: Our results indicated that Ast significantly attenuated RPE cell senescence and showed anti-AMD properties. FTO was demonstrated to be a promising therapeutic target for AMD treatment. These findings may provide a deeper understanding of the molecular mechanisms underlying RPE cell senescence in AMD and offer potential strategies for its prevention and management.

Background: Osteoporosis (OP) is a prevalent global health concern, impacting millions of individuals, especially the elderly. The etiology of senile OP is associated with the imbalance of osteogenic and adipogenic differentiation in the bone marrow mesenchymal stem cells (BMSCs). The imbalance of BMSCs differentiation fate will leading to bone loss and lipids accumulation. β-sitosterol, a naturally occurring phytosterol which is abundant in plants and has a similar structure to cholesterol, demonstrates diverse bioactivities, including lipid-lowering effect and osteogenesis-inducing effects. These effects indicate that β-sitosterol might have anti-OP effects. Nevertheless, the precise mechanism underlying β-sitosterol's anti-osteoporotic efficacy via modulating BMSCs differentiation fate remains obscure.

Purpose: This study endeavors to elucidate whether β-sitosterol has the potential to augment the osteogenic differentiation of BMSCs while mitigating their adipogenic differentiation, thereby exerting an anti-OP effect; and to reveal its molecular mechanisms of action.

Methods: In this study, a dosage form HP-β-cyclodextrin-coated β-sitosterol was developed for intragastric administration in mice to enhancing its bioavailability. Subsequently by using an integrative approach encompassing bioinformatics, computer molecular simulations, high-throughput sequencing, and in vitro/vivo as well as in-tube experiments, we investigated the anti-osteoporotic and bone healing effects of β-sitosterol and delineated its underlying mechanisms.

Results: Our findings demonstrate that β-sitosterol exhibits anti-osteoporotic and bone healing effects both in vitro and in vivo by modulating the osteogenic and adipogenic differentiation of BMSCs. Mechanistically, these effects are mediated through the direct inhibition of mTOR's kinase activity independent of mediating autophagy, leading to the suppression of the mTOR-IMP1-Adipoq axis in BMSCs.

Conclusion: These results unveil β-sitosterol as a promising therapeutic agent for OP, shedding light on its underlying mechanisms. This research contributes potential candidates for diagnostic and therapeutic interventions in the realm of OP.

Background: Psoriasis is a prevalent chronic inflammatory skin condition for which existing treatments often fall short of fully addressing patient needs. Abelmoschi Corolla (AC), a traditional Chinese medicine, and its ethanol extract, huangkui capsule, are well established for the treatment of chronic kidney diseases. The therapeutic mechanisms of AC include anti-inflammatory effects and immune modulation, which align with psoriasis treatment strategies. Nevertheless, the potential of AC as a therapeutic agent for psoriasis remains unexplored.

Purpose: This study aimed to evaluate the efficacy of AC in treating psoriasis and, if effective, to elucidate the underlying mechanisms by which AC exerts its therapeutic effects.

Methods: To assess the therapeutic potential of AC, an imiquimod-induced psoriasis-like mouse model was utilized. Bioinformatics and machine learning approaches were employed to predict the targets and mechanisms of AC in psoriasis. Further validation was performed using targeted metabolite quantification, immunohistochemistry, polymerase chain reaction, and western blotting.

Results: AC treatment significantly improved psoriasis-like skin lesions, as indicated by enhancements in appearance, PASI scores, a reduction in epidermal hyperproliferation, and decreased immune cell infiltration. Bioinformatics and machine learning analyses identified arginase 1 (ARG1) as a key target of AC in psoriasis. Experimental validation demonstrated that AC reduced ARG1 expression, arginine metabolism, and polyamine production by upregulating PP6 expression and inhibiting C/EBP-β activation in psoriatic keratinocytes, resulting in the suppression of dendritic cell infiltration and a reduction in the expression of inflammatory cytokines, including IL-23, IL-6, IL-1β, IL-17A, and TNF-α.

Conclusions: AC disrupted the inflammatory pathways associated with psoriasis and alleviated imiquimod-induced psoriasis-like skin inflammation by inhibiting ARG1 overexpression and arginine metabolism in psoriatic keratinocytes. These findings suggest that AC has significant potential as a therapeutic agent for psoriasis and warrants further research and development.

Background: Sirtuin 6 (SIRT6), a potential therapeutic target for non-alcoholic fatty liver disease (NAFLD), has been shown to regulate fatty acid oxidation (FAO) by interacting with peroxisome proliferator-activated receptor α (PPARα). However, the impact of SIRT6-PPARα pathway on NAFLD phenotype has not yet been reported. Qige decoction (QG), a traditional Chinese medicine (TCM) formula, is widely applied to treat disorders of glycolipid metabolism. Our previous experiments showed that QG reduced hepatic steatosis and provided preliminary evidence that QG may promote FAO. However, a thorough understanding of molecular mechanisms by which QG regulates FAO requires further investigation.

Purpose: To investigate the role of SIRT6-PPARα signalling pathway on NAFLD phenotype and explore the mechanism by which QG improves NAFLD and its relationship with FAO regulated by SIRT6-PPARα signalling pathway.

Methods: In vivo study, NAFLD mice induced by high fat diet (HFD) were divided into two parts. The first part involved four groups: control (CON), model (MOD), PPARα agonist (WY-14,643, WY), and SIRT6 inhibitor (OSS-128,167, OS) groups. The second part involved five groups: CON group, MOD group, positive drug (POS) group, low dose QG (QGL) group, and high dose QG (QGH) group. Widely-targeted lipidomic were performed by UHPLC-QTOF/MS to analyse differential lipids (DELs) in the liver, while differentially expressed genes (DEGs) were analysed by transcriptome analysis on the Illumina sequencing platform. In vitro study, co-immunoprecipitation and dual luciferase assay were employed to further identify the molecular mechanisms of SIRT6-PPARα interaction. The lentiviral vector, TG assay, and acetyl-CoA assay were used to clarify the indispensable role of the SIRT6-PPARα signalling pathway on QG amelioration of lipid accumulation in vitro.

Results: Down-regulation of SIRT6 inhibited PPARα-mediated FAO and aggravated lipid accumulation in hepatocytes both in vivo and in vitro. SIRT6 bound to PPARα in HepG2 cells; however, SIRT6 activation of the PPARα promoter was not detected. Along with QG reduced hepatocyte lipid accumulation, SIRT6-PPARα signalling pathway was upregulated in vivo and in vitro. However, the alleviating effect of QG on lipid accumulation was blocked by SIRT6 silencing in vitro.

Conclusion: This study verified that SIRT6-PPARα signalling pathway inhibition exacerbated NAFLD dyslipidaemia and hepatic steatosis. In addition, this study provided the first in-depth analysis of the molecular mechanisms by which QG ameliorates NFALD, involving promotion of FAO through activation of the SIRT6-PPARα signalling pathway. Our study offers significant insights for the clinical application of QG.

Background: Chronic cerebral hypoperfusion (CCH) contributes significantly to white matter injury (WMI) and cognitive impairment, often leading to vascular dementia (VaD). Inefficient clearance of myelin debris by microglia impedes white matter repair, making microglia-mediated myelin clearance a promising therapeutic strategy for WMI. Puerarin (Pu), an isoflavonoid monomer from Pueraria lobata, is known for its neuroprotective, anti-inflammatory, and immunoregulatory properties. However, its effects and underlying mechanisms in counteracting CCH-induced damage remain unclear. In this study, we aimed to investigate the therapeutic effects and underlying mechanisms of puerarin in a CCH mouse model.

Methods: Right unilateral common carotid artery occlusion (rUCCAO) was used to model CCH in C57BL/6J mice. Puerarin (400 mg/kg/day) was administered intraperitoneally for 10 consecutive days starting immediately post-surgery. Cognitive function was assessed by the Morris Water Maze (MWM) test. WMI, remyelination, neuroinflammation, and microglial phagocytosis were evaluated by western blotting, immunofluorescence staining, RT-PCR, or flow cytometry both in vivo and in vitro.

Results: Puerarin treatment significantly improved cognitive performance and mitigated WMI in rUCCAO mice. These effects were associated with enhanced microglial phagocytosis and remyelination, reduced neuroinflammation, and increased CD36 expression. Additionally, puerarin also increased the levels of IL-10 and phosphorylated STAT3 (p-STAT3) in brain tissues. Notably, IL-10 neutralization reversed these benefits effects by reducing microglial myelin debris uptake, downregulating STAT3 phosphorylation and CD36 expression.

Conclusions: Our findings demonstrate that puerarin has significant therapeutic potential in treating CCH-related cognitive impairments and WMI by modulating CD36-mediated microglial myelin clearance through the IL-10/STAT3 pathway. However, our study was reliant on preclinical animal models, further studies are needed to explore applicability in human subjects.

Background: Huangkui capsule (HKC), a Chinese patent medicine, is clinically used for treating diabetic nephropathy. However, the core disease-specific biomarkers and targets of type 2 diabetic nephropathy (T2DN) and the therapeutic mechanism of HKC are not fully elucidated.

Purpose: This study aimed to investigate the therapeutic effects and underlying molecular mechanisms of HKC for T2DN.

Study design: The db/db mouse model was used to evaluate the efficacy of HKC for T2DN, and the core pathways regulated by HKC were studied to determine its kidney protective mechanism.

Methods: High-throughput UPLC-MS/MS and multivariate analysis were employed to analyze the serum and kidney metabolic profiles of db/db mice, identifying potential core biomarkers of T2DN. Atmospheric pressure matrix-assisted laser desorption/ionization mass spectrometry imaging was used to locate in situ spatial distribution of core biomarkers and drug active ingredients in kidney tissues. Biochemical indicators, histopathology, immunohistochemistry, immunofluorescence, molecular docking, and western blotting were combined to reveal therapeutic effects, pathways, and targets of HKC.

Results: HKC substantially improved pathological characteristics, kidney function, oxidative stress, inflammation, and lipid metabolism indicators of T2DN. Twelve core disease-specific biomarker that significantly influenced clustering were identified and its unique spatial distribution information in the kidneys was revealed. 3-dehydrosphinganine, retinyl ester, and 9-cis-retinoic acid (9cRA) could serve as novel disease-specific biomarkers for T2DN. Based on newly discovered biomarkers, quercetin, myricetin, and isorhamnetin were found to act on key enzymes SPT, ALDH1A1, AOX, LRAT, and DGAT1 in retinol and sphingolipid metabolism pathways. Western blotting showed that HKC ameliorated T2DN by targeting these enzymes, upregulating 9cRA and retinyl ester, downregulating 3-dehydrosphinganine, increasing TGF-β signal transduction, inhibiting the expression of the immune fibrosis proteins OX-8, Col-I and α-SMA, inhibiting Th17 cell development and ceramide synthesis, reducing IL-1β, TNF-α, MDA, TC, LDL-C, and TG levels, and increaseing SOD activity.

Conclusions: HKC exerts significant therapeutic effects on T2DN. HKC corrects the metabolic disorder of sphingolipids and retinol, and improves T2DN by regulating the activities of SPT, ALDH1A1, AOX, LRAT, and DGAT1. This study provides valuable ideas and new mechanistic insights for the treatment of T2DN with HKC.

Background: Atherosclerosis is a major contributor to global cardiovascular morbidity and mortality, driven by the chronic inflammatory proliferation of vascular smooth muscle cells (VSMCs), which destabilizes atherosclerotic plaques. The EphA2/ephrinA1 signaling pathway plays a critical role in modulating VSMC inflammatory responses, making it an attractive therapeutic target. However, the clinical application of EphA2 inhibitors remains limited due to safety concerns. Ruan Mai Jian (RMJ), a traditional Chinese herbal medicine, has demonstrated potential efficacy in treating atherosclerosis, though its precise mechanisms remain insufficiently characterized. To date, no study has investigated a Chinese medicine compound capable of regulating atherosclerotic inflammatory responses via the EphA2/ephrinA1 pathway. This study aims to determine whether RMJ treats atherosclerosis both in vivo and in vitro by modulating the EphA2/ephrinA1 pathway, while evaluating its potential hepatic and renal toxicity.

Study design: A combination of in vivo (ApoE-/- murine model) and in vitro studies was employed to investigate the effects of RMJ on atherosclerotic progression, inflammatory markers, and VSMC function.

Methods: ApoE-/- mice were fed a high-fat diet to induce atherosclerosis and subsequently treated with RMJ at varying doses. Serum lipid levels, inflammatory cytokines (TNF-α, IL-6, IL-1β), and plaque morphology were analyzed. Immunohistochemical and Western blot analyses were performed to assess the modulation of the EphA2/ephrinA1 pathway. VSMC proliferation and migration assays were conducted to evaluate the effects of RMJ on cellular behavior in vitro.

Results: RMJ treatment significantly attenuated serum lipid levels, reduced systemic inflammation, and stabilized atherosclerotic plaques by increasing collagen content and decreasing lipid deposition. RMJ downregulated EphA2 expression and upregulated ephrinA1, effectively inhibiting VSMC proliferation and migration through suppression of the AKT1/ERK1/2 signaling cascade. Importantly, no hepatic or renal toxicity was observed in treated mice, indicating a favorable safety profile.

Conclusion: RMJ demonstrates significant therapeutic potential for the treatment of atherosclerosis, primarily through modulation of the EphA2/ephrinA1 signaling pathway, resulting in reduced inflammation and VSMC proliferation. Its efficacy, combined with the absence of hepatotoxicity or nephrotoxicity, highlights RMJ as a promising candidate for further investigation as a novel therapeutic agent for atherosclerotic cardiovascular disease.