Phytotherapy Research最新文献

Trauma-induced osteonecrosis of the femoral head (TIONFH) is a complex, enigmatic, and rapidly deteriorating orthopedic disease. Many scholars are striving to find noninvasive treatments to stop or reverse TIONFH. Blood vessels in bone tissues, especially the type-H vessels, play an important role in bone remodeling. Panax notoginseng saponins (PNS), also known as the Xuesaitong capsule, are a traditional Chinese medicine widely used in the treatment of ischemia-related diseases. This trial is to explore the effect of PNS on angiogenesis-mediated bone formation in TIONFH. The main components of PNS were identified using UPLC-Q-Orbitrap mass spectrometry. The TIONFH model was surgically established in SD rats, which were subsequently treated with PNS. Four weeks after treatment, the vascularization within the femoral head and the repair of osteonecrosis were evaluated. Rat endothelial progenitor cells (EPCs) were cultured in vitro to examine the effects of PNS on EPCs' proliferation, migration, angiogenesis, and the PDGF-BB/PDGFR pathway. Additionally, EPCs and osteoblasts were co-cultured to analyze the impact of EPC-derived angiogenic-osteogenic factors on osteoblasts' function. Eleven components were identified in PNS through UPLC-Q-Orbitrap mass spectrometry, with saponin being the most predominant among them. In vivo, we observed the presence of type-H vessels within the femoral heads of rats and discovered that PNS could dose-dependently increase the bone mass, type-H vessels' number, PDGF-BB/PDGFR pathway-related factors of rats with the TIONFH. In vitro, PNS-containing serum intervention significantly increased cell viability, migration, angiogenesis, and phosphorylation level of PDGF-BB/PDGFR pathway-related proteins in EPCs. Meanwhile, PNS-containing serum could also reverse the inhibitory effect of PDGFR inhibitor (AG1296) on the EPCs' function. Furthermore, the coculture results of EPCs-osteoblasts confirmed that VEGF derived from EPCs under PNS treatment significantly stimulated the proliferation and mineralization of osteoblasts. In conclusion, PNS could promote angiogenesis-mediated osteogenesis repair in rats with the TIONFH in a dose-dependent manner, which was partly related to the activation and phosphorylation of the PDGF-BB/PDGFR signaling pathway in EPCs.

Liver fibrosis is an increasingly serious global health issue, and an effective treatment strategy is to inhibit the activation of hepatic stellate cells (HSCs). The role of daphnetin (Daph), which is a natural coumarin derivative isolated from plants of the genus Daphne, in the treatment of hepatic fibrosis is still unclear. Mice were treated with carbon tetrachloride (CCl₄), and the inhibitory effect of Daph on hepatic fibrosis was evaluated. In vitro, the effect of Daph on the activated human HSCs line LX-2 was studied. In vivo, Daph alleviated collagen accumulation and reduced the expression of fibrotic genes. However, these changes were reversed with ferrostatin-1 (Fer-1). In vitro, Daph induced ferroptosis in LX-2 cells, which was characterized by increased lipid peroxidation and iron accumulation. However, deferoxamine (DFO) and Fer-1 partially abrogated the antifibrotic effect of Daph. Mechanically, Daph exerted an antifibrotic effect by ubiquitinating glutathione peroxidase 4 (GPX4) and stimulating ferritinophagy-mediated ferroptosis in HSCs. These results indicated that Daph promoted the ubiquitination of GPX4 and ferritinophagy-mediated ferroptosis in HSCs, which could provide new clues for further pharmacological research on the antifibrotic effect of Daph.

Harringtonine (HT) is an alkaloid extracted from the botanical cephalotaxus fortunei Hook.f., which has potent anti-tumor activity. Nevertheless, the target and mechanism of HT in cancer have not been reported. The present work aims to explore the crucial target of HT in triggering ferroptosis and elucidate its mechanism. Lewis lung cancer cells and tumor-bearing mice models prepared thereof were used in this study. Network pharmacology and RNA sequencing were utilized to screen the pivotal target and information. Flow cytometry, Western blots, qRT-PCR, and immunoprecipitation were exploited to elucidate the mechanism. The affinity experiments were employed to analyze the interaction of HT and FASN. Reduced cell viability and increased apoptosis were observed in HT-treated lung cancer cells and the 3-D cell model. Consistently, HT exhibited pronounced anti-cancer effects in in vivo experiments. The interaction molecules of HT and lung cancer were enriched in ferroptosis, which was validated by the accumulation of ferrous ions etc. Blockage of ferroptosis mitigated HT-mediated efficacy. Further investigation showed alternations in fatty acid metabolism when adding HT, especially fatty acid synthase (FASN). HT was demonstrated to bind to FASN, thereby dampening SYVN1-mediated ubiquitination. Finally, the silence of FASN dampened the ferroptosis and anti-cancer efficacy introduced by HT. Collectively, HT could bind to FASN and thereby enhance the activity by reducing ubiquitination, resulting in increased fatty acid synthesis and infiltrating into the membrane, which leads to ferroptosis. The present work identifies the critical target for phytomedicine HT-driven ferroptosis and provides a foundation for cancer therapy.

Viral diseases, whether pandemic, endemic, or epidemic, are a leading cause of global mortality and disability. Consequently, developing effective viral inhibitors is a critical public health priority. Beyond antiviral drugs, a promising therapeutic strategy involves using immunomodulators, which are antiviral agents that enhance the host's immune system against infection. Phytochemicals (PCHs) derived from plants exhibit diverse bioactive properties, including significant antioxidant and immunomodulatory effects. Notably, PCHs have attracted considerable attention due to their broad-spectrum inhibitory actions against numerous viruses, including SARS-CoV-2, dengue virus, hepatitis viruses, and herpes viruses. Recent research has shown how PCHs may target specific signaling pathways implicated in a cytokine storm, a potentially fatal clinical syndrome characterized by an excessive production of pro-inflammatory cytokines and immune cell activation. Numerous studies have investigated the immunomodulatory effects of PCHs on immune function, specifically their ability to regulate key cellular and molecular interactions within the immune system. Additionally, by modulating host immunity, PCHs can enhance the antiviral response. Furthermore, these substances interfere with complex cellular signaling networks, emphasizing their efficacy in preventing viral infections. This review examines the significant and advanced mechanisms PCHs influence immune function during viral illnesses. We subsequently evaluate the potential applications of PCHs as immunomodulatory agents for treating viral infections and discuss their current clinical limitations.

Calycosin, a natural flavonoid small-molecule compound derived from traditional Chinese medicine, has demonstrated remarkable pharmacological activity in the field of cancer therapy. This study systematically elucidates the molecular mechanisms of Calycosin in colorectal cancer (CRC) treatment through integrated in vivo and in vitro experiments. In vivo experiments revealed that Calycosin effectively inhibits subcutaneous tumor growth in CRC-bearing mice. In vitro assays and transcriptome sequencing confirmed that Calycosin effectively suppresses migration, invasion, epithelial-mesenchymal transition (EMT), and induces ferroptosis in human CRC cells, thereby inhibiting malignant tumor behaviors. Cellular Thermal Shift Assay (CETSA) and site-directed mutagenesis experiments first identified cytochrome P450 1B1 (CYP1B1) and Gly-329 as critical binding targets and sites for Calycosin. Functional studies showed that CYP1B1 knockdown in vitro and in vivo suppresses GPX4 expression and enhances ferroptosis in CRC cells. Mechanistically, CYP1B1 activates the AKT/SP-1 signaling pathway to upregulate GPX4 expression, thereby modulating colorectal carcinogenesis and progression. In summary, this study first unveils the crucial role of Calycosin and the CYP1B1-AKT/SP1-GPX4 regulatory axis in CRC ferroptosis, providing novel theoretical foundations for targeted therapy using traditional Chinese medicine-derived small molecules against colorectal cancer.

In recent years, the incidence of complications and mortality related to various lung diseases has escalated significantly. These ailments have become a major public health burden worldwide. The lung endothelium plays a crucial role in the pathogenesis and development of lung diseases. In these conditions, the immune response of the pulmonary endothelium can be activated through various mechanisms. It is capable of identifying pathogens or damaged cells by means of specific receptors, subsequently initiating a cascade of immune responses, including the recruitment of immune cells and the secretion of cytokines. Traditional Chinese medicine (TCM) contains a wealth of active components, such as terpenes, flavonoids, alkaloids, and others. These active components may act on the pulmonary endothelium in different ways. TCM compound, which is a combination of multiple herbs in TCM, may have a synergistic effect when acting on the pulmonary endothelium. It can enhance the overall effect through multiple targets and multiple pathways, thus better promoting the repair and normalization of pulmonary endothelium function. Keywords including 'lung disease', 'lung endothelium and immunity', and 'traditional Chinese medicine' were utilized. The databases employed encompass Pubmed, Google Scholar, Web of Science, among others, and relevant literatures published within the past 10 years have been searched. This review mainly involves two parts: first, we reviewed the immune and anti-inflammatory mechanisms of pulmonary endothelium in lung diseases; second, we in - depth discussed the active components of TCM and the mechanism of TCM compound acting on pulmonary endothelium. This will help researchers better understand how to use TCM to intervene in lung diseases from the perspective of pulmonary endothelium - related mechanisms, and also provide theoretical support for clinical practice in the future.

Exosomes critically regulate pre-metastatic niche formation and tumor metastasis in colorectal cancer (CRC). Our prior research revealed that RALY, an RNA-binding protein, regulates exosome biogenesis during CRC metastasis. Furthermore, we recently demonstrated that Astragaloside IV (ASIV) inhibits CRC metastasis by suppressing tumor exosome release in a dose-dependent manner. However, its pharmacological targets and mechanisms remain unclear. Exosomes derived from MC38 cells with/without ASIV treated were characterized and quantified using NanoSight analysis, transmission electron microscopy (TEM), and Western blot (WB). The regulatory roles of ASIV and RALY in exosome biogenesis were assessed by immunofluorescence (IF) staining. RNA immunoprecipitation (RIP) and co-immunoprecipitation (co-IP) assays identified RALY-interacting partners, while methylated RIP measured m6A levels on PLD2 transcripts. Liver metastasis model in mice was established by injecting MC38 or shRALY single cell suspension into the spleen of mice to observe the effect of ASIV on CRC liver metastasis. Limited Proteolysis-Small Molecule Mapping (LiP-SMap) screened ASIV-binding proteins, followed by molecular docking and cellular thermal shift assays (CETSA) to confirm direct target interactions. ASIV reduced RALY levels in CRC cells, inhibiting exosome release. Mechanistically, ASIV disrupted the RALY-PLD2 interaction, regulating exosome biogenesis. TERT was identified as a direct ASIV target, blocking RALY transcription due to its nuclear translocation function. In vivo experiments showed that ASIV attenuated liver metastasis by down-regulating RALY and inhibiting exosome release through disrupting RBM15b-driven m6A modification of PLD2. Our findings revealed that ASIV mitigated CRC liver metastasis by downregulating the RALY/PLD2 axis, which was instrumental in exosome biogenesis. This discovery furnished compelling experimental evidence supporting the clinical utility of ASIV in combating CRC metastasis. Significantly, our research underscored the substantial advantages of targeting exosome-mediated metastasis, thereby highlighting the necessity for subsequent clinical validation.

Lung adenocarcinoma (LUAD) poses a leading cause of cancer-related mortality, necessitating the need for effective and less toxic therapies. Chlorogenic Acid (CGA), a naturally occurring polyphenol, has attracted attention for its potential anti-tumor properties, but its efficacy and mechanisms in LUAD require thorough investigation. To evaluate CGA's potential, we conducted a comprehensive study in a LUAD mouse model. We performed CT scanning and histopathological analysis to confirm its dose-dependent inhibition of tumor growth. Body weight monitoring assessed its lower systemic toxicity compared to cisplatin. Flow cytometry revealed CGA's unique ability to reprogram tumor-associated macrophages by reducing immunosuppressive M2 polarization and promoting anti-tumor M1 phenotypes. Metabolomic profiling identified a significant reduction in the pro-tumor metabolite taurodeoxycholic acid (TDCA) upon CGA treatment. Subsequent in vitro co-culture studies and western blot analysis demonstrated that CGA disrupts the TDCA-activated TGR5/STAT3 signaling axis, which is crucial for M2 macrophage polarization. Our findings unveil a novel immunometabolic mechanism through which CGA suppresses LUAD by remodeling the tumor microenvironment, highlighting its promise as a therapeutic agent or adjunct with both efficacy and a favorable safety profile.

Previous studies anticipated that supplementation with Luteolin could potentially serve as a strategy to improve diabetic kidney disease. However, there remains a lack of evidence. The present study aimed to test the effect of Luteolin supplementation on kidney damage and long-term prognosis in diabetic patients. Data for the study participants were obtained from the NHANES database. Information regarding mortality was extracted from the 2019 public-use linked mortality files provided by the NCHS. Flavonoid intake data were extracted from the FNDDS Flavonoid database. A total of 2591 participants were included in this study. Logistic regression analysis was performed to preliminarily analyze the relationship between flavonoid intake dosage and kidney damage prevalence. Kaplan-Meier survival curve was used to illustrate the associations between Luteolin supplementation and survival probability in diabetic patients, with Cox regression analysis employed to investigate whether Luteolin supplementation positively affected survival probability. Covariates including gender, age, ethnicity, education level, marital status, BMI, SBP, HbA1c, smoking status, alcohol intake, and hypertension prevalence were adjusted in multivariate analysis. Preliminary analysis revealed that the intake dosage of Luteolin was an independent influencing factor for the kidney damage prevalence in diabetes. Diabetic patients in the Luteolin-high intake group had a lower prevalence of kidney damage compared to those in the Luteolin-low intake group. The urinary microalbumin to urinary creatinine ratio (UACR) of diabetic patients in the high Luteolin intake group was significantly lower than that of diabetic patients in the low Luteolin intake group. Furthermore, at a median follow-up time of 121 months, there was a decrease in mortality by 14.2% [HR = 0.858, 95% CI: 0.744-0.990, p = 0.036] for every 1 mg/d increase in Luteolin intake. The findings suggested that high Luteolin intake is associated with low kidney damage prevalence and high survival probability among diabetic patients.

With the growing challenge of antibiotic resistance (AR), there is an urgent need for effective alternatives in clinical practice. Traditional Chinese medicine (TCM) has been a major treatment method in China for several thousand years and has treated many diseases. In recent years, the global influence of TCM has been on the rise, with an increasing number of countries and regions paying attention to, researching, and exploring the value of TCM. This review summarizes recent findings on how TCM combats bacterial infections by enhancing host defense mechanisms, mechanical, chemical, biological, and immunological barriers, and inhibiting bacterial growth with various approaches. In contrast to previous reviews that mainly emphasize the phytochemical composition or antibacterial activities of individual TCM compounds, this work bridges the interaction concepts of host defense regulation, pathogen suppression, and TCM active ingredients, providing a novel and holistic perspective that links traditional pharmacological principles with modern immunological and microbiological understanding. These insights highlight TCM's potential as a complementary or alternative strategy to address AR through dual mechanisms: host defense regulation and pathogen suppression.