Phytotherapy Research最新文献

Withania somnifera, commonly known as Ashwagandha, is a widely recognized medicinal plant in India, belonging to the family Solanaceae, used in Ayurveda due to its diverse therapeutic properties. The roots of Ashwagandha are considered the most active part of the plant, for its biological and pharmacological effects. However, very little scientific evidence regarding its safety assessment has been published. Thus, the objective of the present study was to assess the safety of the standardized extract of Ashwagandha, known as Shagandha, which is prepared from the roots of Ashwagandha containing 2.5% Withanolides, analysed using a USP method (HPLC). The GLP studies for acute, subacute, subchronic, reproductive, bacterial reverse mutation assay, and mammalian erythrocyte micronucleus test were conducted following the test guidelines established by the Organization for Economic Cooperation and Development (OECD). Treatment with Shagandha (Ashwagandha Root Extract-ARE) did not result in any toxicologically significant changes regarding abnormal clinical signs or behavioral changes, body weight, reproductive and developmental parameters, or gross and histopathological changes. Additionally, the results of genotoxicity as evaluated by the in vitro reverse mutation assay and in vivo micronucleus test in mice demonstrated that ARE did not induce any genotoxic effects. These findings indicate that the oral administration of ARE is safe in rodents, non-mutagenic, with no adverse effects under experimental conditions.

Stigmasterol glucoside (SG), a phytosterol glycoside derived from plants, is widely distributed in numerous natural sources-particularly medicinal and edible plants-and is recognized to possess potential anti-inflammatory properties, although its mechanisms of action remain incompletely understood. Experimental results demonstrated that SG significantly attenuated lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 macrophages. In a murine model of systemic inflammatory response syndrome (SIRS) established by LPS challenge, SG effectively mitigated systemic inflammation and ameliorated LPS-induced hepatic dysfunction. Integrated network pharmacological analysis and transcriptomic sequencing revealed that SG primarily exerts its anti-inflammatory activity through modulation of the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling pathways, thereby conferring protection against liver injury and systemic inflammation. These findings highlight SG as a promising therapeutic candidate for inflammation-related disorders.

Lupus nephritis (LN) is a severe autoimmune disease often complicated by steroid resistance (SR), leading to treatment failure and poor prognosis like atherosclerosis (AS). Our study found that Panax notoginseng saponins (PNS) improve lipid metabolism and prevent AS in steroid-resistant LN by up-regulating PPARγ, though mechanisms are unclear. Recent research highlights the roles of macrophages, with M1 Mø promoting inflammation and M2 Mø providing protection, as PPARγ influences Mø's polarization, linking it to inflammation and M2 polarization, necessitating further investigation. Therefore, we conduct this study to investigate the regulatory effect of PNS on the "Mø M2 polarization-PPARγ" positive regulation, endeavoring to elucidate its therapeutic potential of delaying AS and reversing SR in LN. PPARγ expression in polarized Mø was measured via PCR and WB, while M1/M2 biomarkers and cytokines, influenced by PPARγ modulation, were assessed using flow cytometry and ELISA. In mouse Mø treated with PNS, IL-4, or both, PPARγ and cytokines were measured. ICR and MRL/lpr mice were used to establish an in vivo SR model to confirm PNS's role in M2 polarization of Mø and AS protection by analyzing blood lipid levels, iNOS, Lp(a), and apoptosis rates through WB, immunohistochemistry, HE-staining, and TUNEL. PNS's efficacy in renal protection and SR reversal was evaluated through Scr, BUN, urine protein, renal pathology, and P-gp; MDR1 expression was assessed via biochemical detection, HE-staining, flow cytometry, and WB. This study confirmed that PNS upregulates PPARγ and promotes M2 polarization, improving abdominal aorta pathology and delaying AS. It also enhances renal function and reverses SR by reducing P-gp and MDR1. This study shows that PNS promotes Mø polarization to M2 and enhances PPARγ expression, effectively preventing AS, improving renal function, and reversing SR in LN, offering insights for LN treatment and expanding PNS's therapeutic benefits for future research.

Recently, macrophage senescence has been identified as an important pathological risk factor for atherosclerosis (AS). Oxymatrine (OMT) has demonstrated potential in ameliorating cellular senescence. This study aims to investigate the pharmacological properties and underlying mechanisms of OMT in alleviating AS progression. High-fat diet-fed ApoE^-/- mice and oxLDL-induced macrophage senescence models were used to study OMT's effects in vivo and in vitro. Furthermore, OMT's mechanisms were investigated using network pharmacology, pharmacological intervention, gene silencing, molecular docking, Cellular Thermal Shift Assay (CETSA), and Drug Affinity Responsive Target Stability (DARTS) assays. The results demonstrated that OMT inhibited macrophage senescence, thereby improving AS progression. Network pharmacology analysis and biological experiments suggested that the mechanism of OMT improving AS is involving the regulation of SIRT1. Functional validation assays revealed that the effects of OMT were aborted by EX527 and SIRT1 shRNA. OMT enhanced the interaction between SIRT1 and P53, promoting P53 deacetylation and subsequent ubiquitination. Furthermore, Idasanutlin attenuated the functional effects of OMT, which indicated the pivotal role of P53. Molecular docking, CETSA, and DARTS assays confirmed that OMT directly binds to SIRT1 and stabilizes its protein. Our results highlight the potential anti-atherosclerotic effects of OMT both in vitro and in vivo. Mechanistically, OMT stabilizes SIRT1, enhancing its activity to promote P53 deacetylation, ubiquitination, and degradation. Consequently, this process delays macrophage senescence-induced foam cell formation, ultimately ameliorating AS. Our findings suggest OMT as a promising therapeutic candidate for AS.

Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) frequently coexist due to shared risk factors, yet optimal therapeutic interventions remain elusive. Berberine (BBR), a widely used isoquinoline alkaloid, has demonstrated potential anti-arrhythmic properties. However, its specific effects and regulatory mechanisms in HFpEF-related AF are not fully understood. The present study was designed to clarify the pathological characteristics of HFpEF-associated AF and further evaluate the therapeutic effects of BBR. In this study, we developed a high-fat diet plus Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced murine HFpEF model to investigate the impact of berberine on the pathogenesis of HFpEF-associated AF. Bioinformatics and in vivo analyses revealed a progressive increase in atrial endoplasmic reticulum (ER) stress and lipid metabolic dysregulation. The HFpEF model exhibited significant atrial structural and electrical remodeling, which was dose-dependently reversed by berberine treatment. Further investigation showed that berberine effectively preserved atrial lipid metabolism, reduced ER stress and atrial inflammation, and restored atrial AMP-activated protein kinase (AMPK) activity. These protective effects were abolished by Compound C treatment, yet replicated by metformin or 4-phenylbutyric acid administration. Notably, the beneficial effects of berberine were validated in an isoprenaline/palmitic acid (ISO/PA)-treated HL-1 cell model. Our study highlights the therapeutic potential of berberine in mitigating HFpEF-associated atrial ER stress, lipid accumulation, and inflammatory responses. By targeting and preserving atrial AMPK signaling, berberine offers a promising therapeutic approach to combat HFpEF-associated AF.

Tumors progress within a complex intricate territory consisting of tumorigenic cancer cells with heterogeneous stromal, cellular and non-cellular soluble constituents. The tumor microenvironment (TME) continuously crosstalks with the tumor cells, which helps the tumor cells in achieving different malignant phenotypes and later aids in tumor initiation, progression, and metastasis. Cancer associated fibroblasts (CAFs) constitute a chief component of the TME that is often corroborated with unfavorable disease outcomes, therapy resistance and distant metastasis. CAFs are essential components of TME which facilitate intricate communication between cancer cells, release numerous regulatory factors, thereby aiding tumor growth, synthesize and remodel the extracellular matrix providing drug resistance and regulating immune cell infiltration into TME. Thus, inspecting new therapeutic approaches for targeting CAFs may reverse the current landscape of cancer therapy. Recently, several phytochemicals, such as curcumin, resveratrol, quercetin, silibinin and others, have been studied to demonstrate several regulatory effects on TME. These phytochemicals often target different oncogenic signaling pathways orchestrated within TME components like cancer cells, CAFs, immune cells, cancer stem cells, and endothelial cells crucial for tumor development and progression. Several research findings have demonstrated that different anti-fibrotic phytochemicals in combination with chemotherapeutics have shown better therapeutic efficacy by modulating CAFs in TME. However, despite promising preclinical outcomes, challenges such as poor bioavailability, low solubility, hydrophobicity and obscure target specificity restrict their therapeutic applications in the clinic. There has been acontinually increasing interest to formulate phytonanomedicine, the integration of phytochemicals and nanotechnology using various nanocarriers like liposomes, micelles, and nanoemulsions to improve their bioavailability and target specificity, thereby maximizing the therapeutic potential. In the present review, we have highlighted the mechanistic pathways through which phytonanomedicine interacts with CAFs, addresses current challenges in clinical translation, and suggests future research directions to optimize the use of natural-product-based nanotherapeutics in anti-CAF strategies for cancer treatment.

Gut microbiota dysbiosis is implicated in metformin non-response. This study aimed to investigate whether baicalin, a microbiota-modulating flavonoid derived from Radix Scutellariae, could restore metformin sensitivity and explored the underlying mechanisms. Fecal samples from metformin-treated responders and non-responders were collected and used to establish mouse models via fecal microbiota transplantation (FMT). The hypoglycemic efficacy of baicalin in combination with metformin was then evaluated. Serum levels of imidazole propionate (ImP) and the expression of downstream signaling proteins were assessed. Gut microbiota analysis identified ImP-producing bacteria modulated by baicalin, which was further validated in vitro. The roles of these bacteria and short-chain fatty acids (SCFAs) in metformin responsiveness were also examined. In vitro experiments were conducted to investigate the mechanism of SCFAs affect the production of ImP. Metformin responder and non-responder mouse models were successfully established. Baicalin co-administration significantly ameliorated insulin resistance in non-responder mice, reduced serum ImP levels, suppressed p38γ/Akt/AMPK (S485) signaling, and restored AMPK (T172) phosphorylation. Baicalin markedly suppressed key ImP-producing bacteria-Staphylococcus epidermidis and Streptococcus mutans. Notably, colonization with S. epidermidis induced metformin non-response in previously responsive mice. Furthermore, baicalin increased the abundance of SCFA-producing bacteria and elevated colonic SCFAs levels. SCFAs reduced ImP production by inhibiting the growth of ImP-producing bacteria, thereby enhancing metformin responsiveness. These findings indicate that baicalin restores metformin sensitivity by enriching SCFAs, suppressing ImP-producing bacteria, and lowering serum ImP, thereby reinstating metformin's hypoglycemic action. This study supports the potential of baicalin as an adjunct therapy for overcoming metformin non-response.

The clinical management of ulcerative colitis (UC) remains a significant challenge in modern gastroenterology. Flavonoids have emerged as promising therapeutic candidates due to their broad spectrum of pharmacological activities; however, their precise efficacy in the treatment of UC has yet to be substantiated by systematic clinical evidence. This study conducted a systematic review and meta-analysis to comprehensively evaluate the therapeutic effects of flavonoids in animal models of UC and their potential mechanisms of action. A comprehensive literature search and screening process was conducted across the PubMed, Web of Science, and Embase databases, covering the period from database inception to August 1, 2024. The SYRCLE risk of bias assessment tool was utilized to evaluate the methodological quality of the included studies. Data analysis was performed using STATA 15.1 software, and a time-dose response model was applied to explore the potential dose-response relationship between flavonoid administration and UC outcomes. Ultimately, 33 studies involving a total of 600 experimental animals were included in the analysis. The overall results demonstrated that flavonoids significantly reduced DAI, HS, MPO, MDA, TNF-α, IL-1β, IL-6, iNOS, COX-2, and Spleen Index, while markedly increasing body weight, CL, SOD, GSH, CAT, IL-10, ZO-1, and occludin levels. Time-dose effect analysis revealed that within the dose range of 3.2-400 mg/kg, a significantly enhanced therapeutic outcome can be achieved when combined with an intervention period of 3 to 49 days. Therefore, flavonoids may exert protective effects against UC through anti-inflammatory and antioxidant mechanisms, as well as by modulating intestinal barrier function and gut microbiota. However, the efficacy and safety of flavonoids in treating UC require further validation through extensive clinical trials.

Pathogen-induced pneumonia represents a major global health threat, owing to its high morbidity and mortality. Conventional antibiotic therapies are increasingly constrained by limited efficacy and the growing prevalence of antimicrobial resistance, highlighting the urgent need for innovative therapeutic strategies capable of concurrently targeting multiple pathogenic mechanisms. In this study, we developed a carrier-free nanomedicine that co-delivers two natural compounds with synergistic pharmacological activity. Using a self-assembly approach, Baicalein (BAI) and Resveratrol (RES) were formulated into stable BAI-RES nanoparticles (BR NPs), designed to enhance aqueous solubility and improve therapeutic outcomes. BR NPs demonstrated preferential accumulation in pulmonary macrophages of pathogen-infected mice, and enabled pH-responsive drug release within the inflammatory microenvironment. Mechanistically, BR NPs modulated inflammatory and immune responses by suppressing M1 macrophage polarization, reducing excessive neutrophil infiltration, and mitigating oxidative stress through the regulation of critical signaling pathways, such as Toll-like receptor, TNF, and HIF-1 pathways. These findings indicate that carrier-free BR nanoparticles exhibit synergistic effects, macrophage-targeting and controlled-release properties, as well as multi-target and multi-pathway therapeutic benefits, thus offering a novel and promising strategy for the treatment of pneumonia induced by pathogens.

Febrile seizure is a common pediatric neurological emergency that may potentially increase the risks of epilepsy and neurodevelopmental disorders. Ginsenosides are the primary active component of ginseng, demonstrating notable neuroprotective effects. However, the effects and mechanisms of Ginsenosides in febrile seizures remain poorly understood. This study aims to investigate the effects and potential molecular targets of Ginsenosides in mitigating febrile seizures and further elucidate its underlying mechanism. Seizure behaviors and EEG recordings were conducted in mice to investigate the effect of Ginsenosides on febrile seizures. Direct targets of Ginsenosides were identified through Thermal Proteome Profiling (TPP), subsequently validated by Surface Plasmon Resonance (SPR), Cellular Thermal Shift Assay (CETSA), and molecular docking. The mechanisms of Ginsenosides targeting Dynamin-related protein 1 (Drp1) in inhibiting febrile seizures were elucidated through proteomic analysis, molecular biology techniques, mitochondrial function assessments, and metabolite profiling. These findings demonstrate that Ginsenosides significantly attenuated febrile seizure severity and reduced the incidence of generalized tonic-clonic seizures (GTCS), showing a superior safety and efficacy profile compared to Ilepcimide. Using the TPP method, we identified and validated Drp1 as a promising direct target for therapeutic intervention in febrile seizures. Mechanistically, Ginsenoside-mediated Drp1 inhibition restored mitochondrial calcium homeostasis, promoting ATP production and elevating region-specific cortical levels of the endogenous anti-seizure metabolite adenosine. Moreover, Ginsenosides upregulated adenosine A1 receptor expression and suppressed the cyclic Adenosine Monophosphate (cAMP) signaling pathway, ultimately exerting anti-seizure effects. In summary, this study reveals that Ginsenosides significantly inhibit febrile seizures by directly targeting Drp1, thereby increasing adenosine levels and suppressing cAMP signaling, effectively suppressing seizures. Our findings demonstrate the potential of Ginsenosides in febrile seizures prevention and highlight Drp1 as a promising therapeutic target, thereby providing novel strategies for identifying targets of bioactive compounds.