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Apigenin (C15H10O5, API) is a natural flavonoid widely found in vegetables, fruits, and plants such as celery, oranges, and chamomile. In recent years, API has attracted considerable attention as a dietary supplement due to its low toxicity, non-mutagenic properties and remarkable therapeutic efficacy in various diseases. In particular, evidence from a large number of preclinical studies suggests that API has promising effects in the prevention and treatment of a variety of liver diseases, including multifactorial liver injury, non-alcoholic fatty liver disease/non-alcoholic steatohepatitis, liver fibrosis and liver cancer. This paper provides a comprehensive review of the progress of research into the therapeutic applications of API in liver diseases as of August 2024, based on literature retrieved from databases such as Web of Science, PubMed, CNKI, Google Scholar and ScienceDirect. The hepatoprotective effects of API involve multiple molecular mechanisms, including inhibition of inflammation, alleviation of hepatic oxidative stress, amelioration of insulin resistance, promotion of fatty acid oxidation, inhibition of liver cancer cell proliferation and differentiation, and induction of tumour cell apoptosis. More importantly, signaling pathways such as Nrf2, NF-κB, PI3K/Akt/mTOR, NLRP3, Wnt/β-catenin, TGF-β1/Smad3, AMPK/SREBP, PPARα/γ, MAPKs, and Caspases are identified as key targets through which API exerts its beneficial effects in various liver diseases. Studies on its toxicity and pharmacokinetics indicate that API has low toxicity, is slowly metabolized and excreted in vivo, and has low oral bioavailability. In addition, the paper summarises and discusses the sources, physicochemical properties, new dosage forms, and current challenges and opportunities of API, with the aim of providing direction and rationale for the further development and clinical application of API in the food, pharmaceutical and nutraceutical fields.

Background and aim: Rivaroxaban is an emerging oral anticoagulant for postoperative anticoagulation after percutaneous left atrial appendage closure (LAAC). Because a once-daily dosing regimen of rivaroxaban causes fluctuations in the drug plasma concentration, we studied the feasibility and safety of twice-daily rivaroxaban as a postoperative anticoagulation regimen for patients with atrial fibrillation (AF) undergoing LAAC.Methods: This study involved patients with AF who underwent LAAC and took rivaroxaban postoperatively. A total of 326 patients who received a standard total dose (15 or 20 mg) of rivaroxaban based on their creatinine clearance rate were divided into the twice-daily (BID) rivaroxaban group (n = 208) and once-daily (QD) rivaroxaban group (n = 118) according to their anticoagulation strategy. Transesophageal echocardiography was recommended at 3–6 months postoperatively to check for device-related thrombosis (DRT). Clinical outcomes were evaluated during postoperative anticoagulation.Results: The median CHA2DS2-VASc score (4 [3, 5] vs. 4 [3, 5], p = 0.28) and HAS-BLED score (2 [2, 3] vs. 2 [2, 3], p = 0.48) were not significantly different between the groups. During the anticoagulation period (4.1 ± 0.7 vs. 4.1 ± 0.9 months, p = 0.58), 148 (71.2%) patients in the BID group and 75 (63.6%) in the QD group underwent follow-up transesophageal echocardiography. There were no statistically significant differences between the two groups in terms of DRT (1.4% vs. 2.7%, p = 0.60), minor bleeding (8.2% vs. 11.0%, p = 0.39), thromboembolic events (1.0% vs. 0.8%, p = 1.00), major bleeding (0.5% vs. 0.8%, p = 1.00), or death.Conclusion: A short course of twice-daily rivaroxaban following LAAC is a feasible alternative regimen with a low rate of major bleeding events, DRT, and thromboembolic events for patients with AF.

Objective: To investigate the efficacy of Integrative medicine (IM), compare with Western medicine (WM), in the treatment of rheumatoid arthritis (RA) in a cohort study.Methods: This is a cohort study with recruitment of RA patients from 10 hospitals in China. The primary outcome was change in disease activity score 28 (DAS28) during 4 follow-up visits. Generalized estimating equation (GEE) models that controlled for variables were used to investigate a time trend and assess group differences in the primary outcome and secondary outcomes after propensity score matching (PSM).Results: A total of 3195 patients with RA received IM (n = 1379, 43.2%) or WM (n = 1816, 56.8%). Following 1:1 propensity score matching, 1,331 eligible patients prescribed IM were compared to 1,331 matched patients prescribed WM. The GEE analysis with PSM showed that the IM was more beneficial to significantly decrease the levels of VAS, PGA and PhGA (VAS: odds ratio (OR), 0.76; 95% CI, 0.63–0.92; p = 0.004; PGA: OR, 0.76; 95% CI, 0.64–0.92; p = 0.007; and PhGA: OR, 0.77; 95% CI, 0.64, 0.93; p = 0.004), and reduce DAS28 (OR, 0.84; 95% CI, 0.73–0.98; p = 0.030) in the per-protocol population.Conclusion: This study suggests that compare to WM, IM has advantages in improving RA-related outcomes. However, the statistical significance might not reveal significant clinical difference. Further studies should be focused on specific treatment strategies and/or disease stages.

Objectives: Osteoarthritis (OA) is a common disease that mainly manifests as inflammation and destruction of cartilage and subchondral bone. Recently, necroptosis has been reported to play an important role in the development of OA. Selumetinib displays a contrasting expression pattern to necroptosis-related proteins. The present study aimed to investigate the potential therapeutic effects of selumetinib in OA process.Methods:In vitro experiments, interleukin-1β (IL-1β) was used to induce necroptosis of chondrocytes. We used high-density cell culture, Western Blot and PT-PCR to observe the effect of different concentrations of selumetinib on the extracellular matrix of cartilage. Afterwards, we visualized the effect of selumetinib on osteoclast formation by TRAP staining and F-actin rings. In vivo experiment, we induced experimental osteoarthritis in mice by surgically destabilizing the medial meniscus (DMM) while administering different concentrations of selumetinib intraperitoneally.Results: Selumetinib promoted cartilage matrix synthesis and inhibited matrix decomposition. We found that selumetinib exerted a protective function by inhibiting the activation of RIP1/RIP3/MLKL signaling pathways in chondrocytes. Selumetinib also inhibited the activation of RANKL-induced NF-κB and MAPK signaling pathways in BMMs, thereby interfering with the expression of osteoclast marker genes. In the DMM-induced OA model, a postsurgical injection of selumetinib inhibited cartilage destruction and lessened the formation of TRAP-positive osteoclasts in subchondral bone.Conclusion: Selumetinib can protect chondrocytes by regulating necroptosis to prevent the progression of OA and reduce osteoclast formation. In summary, our findings suggest that selumetinib has potential as a therapeutic agent for OA.

Platelet-derived growth factor-BB (PDGF-BB) is a cytokine involved in tissue repair and tumor progression. It has been found to have expression differences between normal and degenerative intervertebral discs. However, it is not clear whether PDGF-BB has a protective effect on intervertebral disc degeneration (IDD). In this experiment, we treated nucleus pulposus cells (NPCs) with IL-1β to simulate an inflammatory environment and found that the extracellular matrix (ECM) anabolic function of NPCs in an inflammatory state was inhibited. Moreover, the induction of IL-1β also enhanced the expression of NLRP3 and the cleavage of caspase-1 and IL-1β, which activated the pyroptosis of NPCs. In this study, we studied the effect of PDGF-BB on IL-1β-treated NPCs and found that PDGF-BB not only significantly promotes the ECM anabolism of NPCs, but also inhibits the occurrence of pyroptosis and the production of pyroptosis products of NPCs. Consistent with this, when we used imatinib to block the PDGF-BB receptor, the above-mentioned protective effect disappeared. In addition, we found that PDGF-BB can also promote the ECM anabolism of NPCs by regulating the ERK, JNK, PI3K/AKT signaling pathways, but not the P38 signaling pathway. In vivo studies, mice that blocked PDGF-BB receptors showed more severe histological manifestations of intervertebral disc degeneration. In summary, our results indicate that PDGF-BB participates in inhibiting the occurrence and development of IDD by inhibiting pyroptosis and regulating the MAPK signaling pathway.

Erianin, a natural product derived from Dendrobium chrysotoxum Lindl, has been proved to play antitumor activity in various cancers. However, the effects and molecular mechanisms of erianin in bladder cancer cells remain unexplored. In this study, we found that erianin triggered cell death and cell cycle arrest in bladder cancer cells. Then we demonstrated that erianin could promote the accumulation of lethal lipid-based reactive oxygen species (ROS) and the depletion of glutathione (GSH), suggesting the induction of ferroptosis. In the further study, the ferroptosis inhibitor deferoxamine (DFO), N-Acetylcysteine (NAC) and GSH but not necrostatin-1, CQ or Z-VAD-FMK rescued erianin-caused cell death, showing ferroptosis played a major role in erianin-caused cell death. In vivo, we also showed that erianin suppressed the tumor growth by inducing ferroptosis. Mechanistically, we demonstrated that nuclear factor E2-related factor 2 (NRF2) inactivation was a key determinant of ferroptosis caused by erianin. In bladder cancer cells, the compound tert-butylhydro-quinone (TBHQ), an activator of NRF2, suppressed erianin-induced ferroptosis. Whereas, NRF2 inhibition used shRNA augmented the ferroptosis response induced by erianin treatment. In conclusion, our data provide the first evidence that erianin can initiate ferroptosis-like cell death and lipid peroxidation in bladder cancer, which will hopefully become a promising anticancer compound for the treatment of bladder cancer.

Vemurafenib, a BRAF V600E inhibitor, provides therapeutic benefits for patients with melanoma, but the frequent emergence of drug resistance remains a challenge. An understanding of the mechanisms underlying vemurafenib resistance may generate novel therapeutic strategies for patients with melanoma. Here, we showed that eIF3a, a translational regulatory protein, was an important mediator involved in vemurafenib resistance. eIF3a was expressed at significantly lower levels in vemurafenib-resistant A375 melanoma cells (A375R) than in parental A375 cells. Overexpression of eIF3a enhanced the sensitivity to BRAF inhibitors by reducing p-ERK levels. Furthermore, eIF3a controlled ERK activity by regulating the expression of the phosphatase PPP2R1B via a translation mechanism, thus determining the sensitivity of melanoma cells to vemurafenib. In addition, a positive correlation between eIF3a and PPP2R1B expression was also observed in tumor samples from the Human Protein Atlas and TCGA databases. In conclusion, our studies reveal a previously unknown molecular mechanism of BRAF inhibitor resistance, which may provide a new strategy for predicting vemurafenib responses in clinical treatment.

Siegesbeckia orientalis L. (SO) is a commonly used Chinese medicinal herb. It has long been used as a remedy in traditional Chinese medicine (TCM) for symptoms that resemble inflammatory joint disorders. However, it is slightly toxic. According to the TCM theory, processing can reduce the toxicity of the herbs. Here, we performed metabolomics to determine whether processing with rice wine reduces the toxicity of raw SO, and to explore the mechanisms underlying the raw SO–induced toxicity and the toxicity-reducing effect of processing. Our results showed that raw SO has long-term toxicity in rats. It significantly elevated the serum level of LDH and caused histopathological damages in the lung tissues. It is worth noting that the LDH level in the PSO group was lower than that in the raw SO group, and the damages in lung tissues were relatively mild in PSO-treated rats, suggesting that processing reduces the pulmonary toxicity of the raw. Moreover, a total of 32 significantly changed metabolites were identified. Based on the MetaboAnalyst pathway analysis, we found that two characteristic metabolic pathways including alanine, aspartate and glutamate metabolism and glycerophospholipid metabolism were only changed in the raw SO group, while histidine metabolism was only changed in the PSO group, which suggests that induction of oxidative stress contributes to raw SO–induced pulmonary toxicity, and free radical scavenging might be responsible for the toxicity-reducing effect of processing. Our data shed new light on how raw SO induces pulmonary toxicity and how the toxicity can be reduced by processing. This study not only provides scientific justifications for the traditional processing theory of SO, but also helps to optimize the processing protocol and the clinical drug combination of SO.

Endothelial dysfunction is involved in the pathophysiological processes of contrast media (CM)–induced acute kidney injury (CI-AKI) after vascular angiography or intervention. Previous study found that apolipoprotein A-I (apoA-I) mimetic peptide, D-4F, alleviates endothelial impairments via upregulating heme oxygenase-1 (HO-1) expression and scavenging excessively generated reactive oxygen species (ROS). However, whether D-4F could ameliorate oxidative injuries in endothelial cells through suppressing ROS production remains unclear. In this study, a representative nonionic iodinated CM, iodixanol, was chosen for the in vitro and in vivo studies. Endothelial cell viability was assayed using micrographs, lactate dehydrogenase (LDH) activity, and cell counting kit-8 (CCK-8). Apoptosis was detected using flow cytometry analysis and caspase-3 activation. Endothelial inflammation was tested using monocyte adhesion assay and adhesion molecule expression. ROS production was detected by measuring the formation of lipid peroxidation malondialdehyde (MDA) through the thiobarbituric acid reactive substance (TBARS) assay. Peroxynitrite (ONOO⁻) formation was tested using the 3-nitrotyrosine ELISA kit. Iodixanol impaired cell viability, promoted vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) expression, and induced cell apoptosis in human umbilical vein endothelial cells (HUVECs). However, D-4F mitigated these injuries. Furthermore, iodixanol induced the phosphorylation of protein kinase C (PKC) beta II, p47, Rac1, and endothelial nitric oxide synthase (eNOS) at Thr495, which elicited ROS release and ONOO⁻ generation. D-4F inhibited NADPH oxidase (NOX) activation, ROS production, and ONOO⁻ formation via the AMP-activated protein kinase (AMPK)/PKC pathway. Additionally, after an intravascular injection of iodixanol in Sprague Dawley rats, iodixanol induced a remarkable inflammatory response in arterial endothelial cells, although significant apoptosis and morphological changes were not observed. D-4F alleviated the vessel inflammation resulting from iodixanol in vivo. Collectively, besides scavenging ROS, D-4F could also suppress ROS production and ONOO⁻ formation through the AMPK/PKC pathway, which ameliorated oxidative injuries in endothelial cells. Hence, D-4F might serve as a potential agent in preventing CI-AKI.

Network pharmacology is considered as the next paradigm in drug discovery. In an era when obesity has become global epidemic, network pharmacology becomes an ideal tool to discover novel herbal-based therapeutics with effective anti-obesity effects. Zanthoxylum bungeanum Maxim (ZBM) is a medicinal herb. The mature pericarp of ZBM is used for disease treatments and as spice for cooking. Here, we used the network pharmacology approach to investigate whether ZBM possesses anti-obesity effects and reveal the underlying mechanism of action. We first built up drug–ingredient–gene symbol–disease network and protein–protein interaction network of the ZBM-related obesity targets, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. The results highlight apoptosis as a promising signaling pathway that mediates the anti-obesity effects of ZBM. Molecular docking also reveals quercetin, a compound in ZBM has the highest degree of connections in the compound-target network and has direct bindings with the apoptotic markers. Furthermore, the apoptotic effects of ZBM are further validated in 3T3-L1 adipocytes and in the high-fat diet–induced obesity mouse model. These findings not only suggest ZBM can be developed as potential anti-obesity therapeutics but also demonstrate the application of network pharmacology for the discovery of herbal-based therapeutics for disease treatments.

Accumulating evidence indicated that gut microbiota-targeted therapy is a promising strategy to treat Cardiovascular Disease (CVD). Traditional Chinese Medicine (TCM) has been used in CVD treatments for over 2,000 years which is believed to result from the modulation of gut microbiota, yet the underlying mechanism remains elusive. According to the theoretical system of TCM, we developed an innovative formula of TCM named “TongMai ZhuYu (TMZY)” on top of one classic Chinese herbal formula [“XueFu ZhuYu (XFZY)”], which can more effectively alleviate CVD in the clinical practice. Here, we first systematically assessed the pharmacological effects of TMZY, XFZY, and atorvastatin on atherosclerosis (AS) induced by high-fat diet (HFD) in rats. TMZY typically outperformed others in alleviating AS rats by characterization of pathological morphology, immunohistochemistry, inflammatory cytokines. Remarkably, combining this modified TCM formula (TMZY) with atorvastatin can further help the alleviation of AS in rats by suppressing immune and inflammatory responses. Furthermore, to test whether TMZY alleviated AS symptoms by altering gut microbial compositions (dysbiosis), we employed 16S amplicon sequencing to investigate gut microbiota changes in the AS mice induced by high choline diet (HCD) using both TMZY and XFZY under antibiotic-treated and untreated conditions. TCM formulas induced consistent and remarkable changes in the phenotypes and microbiota in the HCD mice. TMZY modulated more changes in the gut microbiota to improve diseased phenotypes than XFZY. Notably, the TMZY-intervention effect on CVD in mice attenuated after the suppression of gut microbial activity by antibiotics. Collectively, we demonstrated that TCM herbals could effectively modulate the gut microbiota as a mechanism for altering the pathogenesis of cardiovascular disorders in mice/rats.

BackgroundType 2 diabetes (T2D) is a metabolic dysfunction disease that causes several complications. Liver injury is one of these that severely affects patients with diabetes. Fibroblast growth factor 1 (FGF1) has glucose-lowering activity and plays a role in modulation of several liver injuries. Nevertheless, the effects and potential mechanisms of FGF1 against diabetes-induced liver injury are unknown.MethodsTo further investigate the effect of FGF1 on diabetic liver injury, we divided db/db mice into two groups and intraperitoneally (i.p.) injected either with FGF1 at 0.5 mg/kg body weight or saline every other day for 4 weeks. Then body weights were measured. Serum and liver tissues were collected for biochemical and molecular analyses.ResultsFGF1 significantly reduced blood glucose and ameliorated diabetes-induced liver steatosis, fibrosis, and apoptosis. FGF1 also restored defective hepatic autophagy in db/db mice. Mechanistic investigations showed that diabetes markedly induced oxidative stress and endoplasmic reticulum stress and that FGF1 treatment significantly attenuated these effects.ConclusionsFGF1-associated glucose level reduction and amelioration of cellular stress are potential protective effects of FGF1 against diabetes-induced liver injury.

Myocardial ischemia-reperfusion (I/R) injury, characterized by myocardial cell death (e.g., apoptosis) and generation of reactive oxygen species (ROS) such as superoxide (O2·−) and hydrogen peroxide (H2O2), is a serious threat to human health and property. Saponin astragaloside IV (ASIV), extracted from Chinese herbal medicine astragalus, is effective in resolving multiple pathological issues including myocardial I/R injury. Recent studies have shown that autophagy is regulated by ROS and plays an important role in myocardial I/R injury. However, regulation of autophagy by ASIV during myocardial I/R injury and the role of specific ROS involved in the process have been rarely reported. In the present study, we found that SOD2 was downregulated and O2·− was upregulated in H2O2-induced H9C2 cardiac myocyte injury in vitro and myocardial I/R injury in vivo, while such alterations were reversed by ASIV. ASIV possessed the ability to alleviate myocardial I/R injury via attenuating I/R-caused autophagosome accumulation. Upregulate of O2·− by 2-methoxyestradiol (2-ME) reversed the effect of ASIV-mediated autophagy regulation, which suggested that O2·− was vital in this process. In conclusion, our results contribute to understanding the mechanism of ASIV-induced cardioprotective effect.