Phytotherapy Research最新文献

Acute liver injury (ALI) is characterized by excessive inflammation and macrophage polarization, with the M1-to-M2 phenotypic shift emerging as a critical regulatory node. Punicalagin (PUN), a polyphenolic compound derived from pomegranate, has demonstrated hepatoprotective effects in preclinical models; however, its molecular mechanisms underlying macrophage polarization and inflammatory signaling remain unclear. This study aims to investigate the role of PUN in modulating macrophage polarization and inflammatory pathways in chemical- and drug-induced ALI. CCL₄- and APAP-induced ALI mouse models were employed to assess the hepatoprotective effects of PUN through liver enzyme analysis, histology, and immune phenotyping. In vitro, LPS-stimulated RAW264.7 macrophages were treated with PUN, and mechanisms were examined through western blotting, qRT-PCR, flow cytometry, and ELISA. PUN (12.5 mg kg^-1) significantly reduced serum levels of ALT and AST, as well as the necrotic area in both ALI models. It reduced hepatic infiltration of monocyte-derived macrophages (MDMs) and lowered the expression of M1 markers (CD86, iNOS), while simultaneously increasing the expression of M2 markers (CD206, Arg-1). Mechanistically, PUN inhibited the phosphorylation of NF-κB and STAT1, while promoting the activation of STAT3, which resulted in a reduction of TNF-α and IL-6 levels (approximately 62%-71%), alongside an increase in IL-10 and TGF-β, both in vivo and in vitro. Similar reprogramming from M1 to M2 and cytokine shifts were observed in LPS-challenged RAW264.7 cells. PUN alleviates ALI by promoting M1-to-M2 macrophage polarization through the dual inhibition of NF-κB/STAT1 and the activation of STAT3. These findings underscore PUN as a potential therapeutic agent for ALI by reprogramming the hepatic immune microenvironment.

Oxyberberine (OBB), a key metabolite of berberine (BBR), has exhibited enhanced pharmacological efficacy compared to BBR. Nonetheless, the potential of OBB in the treatment of hyperuricemic nephropathy (HN) warrants further investigation. Therefore, this investigation focused on elucidating the therapeutic efficacy and underlying mechanism of OBB in counteracting HN. An HN mouse model was established for in vivo study, while uric acid (UA)-stimulated human renal tubular epithelial cells (HK-2) were used for in vitro evaluation. Bioinformatics and molecular docking analyses were also employed. Bioinformatics analysis and molecular docking results underscored the critical involvement of the NLRP3 axis in mediating the protective effects of OBB against HN. In vivo, OBB treatment significantly reduced kidney weight and index, improved renal function, and mitigated abnormal histopathological alterations. Moreover, OBB lowered MDA, ROS, IL-1β, IL-18, and TNF-α levels, along with enhanced SOD and CAT activities, both in vitro and in vivo. Mechanistically, OBB markedly lowered serum UA levels by increasing the expression of organic cation transporter 1/2 (OCT1/2) and organic cation/carnitine transporter 1/2 (OCTN1/2) at both transcriptional and translational levels. Additionally, OBB markedly reduced the expression of Keap1, TXNIP, NLRP3, ASC, Caspase-1, and GSDMD-N, while promoting Nrf2 nuclear translocation and enhancing the protein expression of HO-1, NQO1, CAT, SOD1, GCLC, and GPX4. Our results for the first time indicated that OBB treatment exerted a significant anti-HN effect. It reduced serum UA level by modulating the OCTs and OCTNs, a mechanism distinct from that of current first-line agents. Additionally, OBB alleviated renal damage through the modulation of the Keap1/Nrf2-NLRP3 axis.

In recent years, small molecules derived from traditional Chinese medicine (TCM) have garnered increasing attention in anticancer research due to their well-defined structures, multi-target regulatory capabilities, and low toxicity. Mitophagy, a critical process for selectively clearing damaged mitochondria and maintaining cellular homeostasis, plays a significant role in tumor development. This review explores the types and molecular mechanisms of mitophagy, its dual role in tumor progression, and its functions across various cancers. We also summarize 21 representative TCM-derived small molecules, such as ginsenosides, oridonin, and sanguinarine, which directly or indirectly regulate key mitophagy-related signaling pathways, including PINK1/Parkin and BNIP3/NIX. These TCM small molecules modulate mitophagy and mitochondrial function, induce tumor cell apoptosis, overcome drug resistance, and improve the tumor microenvironment. This review systematically integrates the molecular mechanisms of mitophagy and its dynamic regulation in cancer, highlighting how TCM small molecules maintain mitochondrial homeostasis, remodel the tumor microenvironment, and reverse therapeutic resistance. It aims to provide a theoretical foundation for future research on anticancer TCM and to inspire the clinical development of effective, low-toxicity, mitochondria-targeted therapies.

Lung cancers are among the most widespread and deadly cancers worldwide. Although platinum-based chemotherapies such as cisplatin are standard treatments for non-small cell lung cancer (NSCLC), their efficacy is often hindered by the development of drug resistance. The present study aimed to investigate the therapeutic potential and molecular mechanisms of quercetin in monotherapy and in combination treatment with cisplatin in NSCLC. In vitro and in vivo models of cisplatin-resistant NSCLC were employed to evaluate the therapeutic efficacy of quercetin-cisplatin combination therapy. Comprehensive mechanistic investigations included lncRNA sequencing, Western blotting, immunofluorescence, malondialdehyde (MDA) quantification, reactive oxygen species (ROS) detection, microscale thermophoresis (MST), real-time quantitative PCR, and dual-luciferase reporter assays. This study examines the potential of combining quercetin with cisplatin to overcome chemoresistance in NSCLC models, focusing on the molecular pathways involved. We determined that ferroptosis is the primary cause of cell death induced by quercetin in NSCLC and associated animal models. As a master transcriptional factor, p53 orchestrates a diverse network of downstream effector genes. Research shows that constant expression of wild-type p53 in cancer cells induces ferroptosis, which is caused by inhibiting the xCT/GPX4 axis and managing iron homeostasis and lipid peroxidation pathways. We found that p53 knockdown inhibits quercetin's anticancer effects. Transcriptomics revealed significant alterations in the long non-coding DDB2-AS1, a new lncRNA sequence associated with damage-specific DNA binding protein 2 (DDB2), after quercetin treatment of cisplatin-resistant NSCLC. A further study showed that quercetin upregulates the expression of p53 by regulating the lncRNA DDB2-AS1/miR-4728-5p pathway, thereby inducing ferroptosis in cisplatin-resistant NSCLC cells, thus overcoming cisplatin resistance. These findings demonstrate that quercetin induces ferroptosis through the DDB2-AS1/miR-4728-5p/p53 axis, thereby reversing cisplatin resistance in NSCLC, and highlighting its potential as an effective adjuvant in NSCLC chemotherapy.

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.