Vine tea total flavonoids activate the AMPK/mTOR pathway to amelioration hepatic steatosis in mice fed a high-fat diet.

Vine tea (Ampelopsis grossedentata), a traditional Chinese tea, is rich in flavonoids with various biological activities. Our study found that Vine tea total flavonoids (TFs) treatment reduced the body mass and blood lipid levels and improved the hepatic tissue morphology in mice fed the high-fat diet (HFD). In vivo, TF treatment activated the hepatic adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, initiated autophagy, and regulated the expression levels of proteins for lipid metabolism in those HFD-fed mice. In vitro, TF treatment dramatically reduced the lipid droplets and triacylglycerol content in HepG2 and L02 cells treated with oleic acid (OA). These were associated with the activation of the AMPK/mTOR pathway and autophagy initiation in OA-treated hepatocytes. This phenotype was abolished in the presence of 3-methyladenine, an autophagy inhibitor. Our results indicated that the TF activation of AMPK/mTOR leads to the stimulation of autophagy and a decrease in the buildup of intracellular lipids in hepatocytes, showing the potential of TF as a therapeutic agent for nonalcoholic fatty liver disease. PRACTICAL APPLICATION: Vine tea, a tea drink, has been consumed by Chinese folk for over a thousand years. The result of this study will provide evidence that vine tea total flavonoids have potential use as a functional material for the prevention and amelioration of nonalcoholic fatty liver disease.

Flavonoid Compounds in Hippophae rhamnoides L. Protect Endothelial Cells from Oxidative Damage Through the PI3K/AKT-eNOS Pathway.

Sea buckthorn, a traditional medicinal plant, has been used for several years in China for the prevention and treatment of various diseases, a practice closely associated with its significant antioxidant activity. The aim of this study was to investigate the protective effects of sea buckthorn flavonoids on vascular endothelial cells in an oxidative stress environment. We isolated and extracted active compounds from sea buckthorn and investigated their impact on endothelial nitric oxide synthase (eNOS) activity through the PI3K/AKT-eNOS signaling pathway through a combination of network pharmacology and cellular experiments, elucidating the regulatory effects of these compounds on endothelial cell functions. Three flavonoids, named Fr.4-2-1, Fr.4-2-2 and Fr.4-2-3, were obtained from sea buckthorn. The results of network pharmacology indicated that they might exert their effects by regulating the PI3K-AKT signaling pathway. In vitro results showed that all three flavonoids were effective in alleviating the degree of oxidative stress in cells, among which Fr.4-2-1 exerted its antioxidant effects by modulating the PI3K/AKT-eNOS pathway. Flavonoids in sea buckthorn can effectively inhibit oxidative stress-induced cellular damage, preserving the integrity and functionality of endothelial cells, which is crucial for maintaining vascular health and function.

Berberine Metabolites Stimulate GLP-1 Secretion by Alleviating Oxidative Stress and Mitochondrial Dysfunction.

Berberine (BBR) is a principal component of Rhizoma coptidis known for its therapeutic potential in treating diseases such as type 2 diabetes mellitus (T2DM) and obesity. Despite the trace levels of BBR in plasma, it's believed that its metabolites play a pivotal role in its biological activities. While BBR is recognized to promote GLP-1 production in intestinal L cells, the cytoprotective effects of its metabolites on these cells are yet to be explored. The present study investigates the effects of BBR metabolites on GLP-1 secretion and the underlying mechanisms. Our results revealed that, out of six BBR metabolites, berberrubine (BBB) and palmatine (PMT) significantly increased the production and glucose-stimulated secretion of GLP-1 in GLUTag cells. Notably, both BBB and PMT could facilitate GLP-1 and insulin secretion and enhance glucose tolerance in standard mice. Moreover, a single dose of PMT could markedly increase plasma GLP-1 and improve glucose tolerance in mice with obesity induced by a high-fat diet. In palmitic acid or TNF[Formula: see text]-treated GLUTag cells, BBB and PMT alleviated cell death, oxidative stress, and mitochondrial dysfunction. Furthermore, they could effectively reverse inflammation-induced inhibition of the Akt signaling pathway. In general, these insights suggest that the beneficial effects of orally administered BBR on GLP-1 secretion are largely attributed to the pharmacological activity of BBB and PMT by their above cytoprotective effects on L cells, which provide important ideas for stimulating GLP-1 secretion and the treatment of T2DM.

Oral supplementation of gut microbial metabolite indole-3-acetate alleviates diet-induced steatosis and inflammation in mice.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. There is growing evidence that dysbiosis of the intestinal microbiota and disruption of microbiota-host interactions contribute to the pathology of NAFLD. We previously demonstrated that gut microbiota-derived tryptophan metabolite indole-3-acetate (I3A) was decreased in both cecum and liver of high-fat diet-fed mice and attenuated the expression of inflammatory cytokines in macrophages and Tnfa and fatty acid-induced inflammatory responses in an aryl-hydrocarbon receptor (AhR)-dependent manner in hepatocytes. In this study, we investigated the effect of orally administered I3A in a mouse model of diet-induced NAFLD. Western diet (WD)-fed mice given sugar water (SW) with I3A showed dramatically decreased serum ALT, hepatic triglycerides (TG), liver steatosis, hepatocyte ballooning, lobular inflammation, and hepatic production of inflammatory cytokines, compared to WD-fed mice given only SW. Metagenomic analysis show that I3A administration did not significantly modify the intestinal microbiome, suggesting that I3A's beneficial effects likely reflect the metabolite's direct actions on the liver. Administration of I3A partially reversed WD-induced alterations of liver metabolome and proteome, notably, decreasing expression of several enzymes in hepatic lipogenesis and ß-oxidation. Mechanistically, we also show that AMP-activated protein kinase (AMPK) mediates the anti-inflammatory effects of I3A in macrophages. The potency of I3A in alleviating liver steatosis and inflammation clearly demonstrates its potential as a therapeutic modality for preventing the progression of steatosis to non-alcoholic steatohepatitis (NASH).

NLRP3 inflammasome-a likely target for the treatment of immunologic conjunctivitis: A protocol for systematic review and meta-analysis.

BACKGROUND: Immune-mediated conjunctivitis is a prevalent ocular ailment characterized by inflammation and immune reactions in the conjunctiva. However, the precise causes and therapeutic approaches for this condition remain the main focus for numerous ophthalmological specialists. Recently, accumulating evidence from human and mouse experiments has demonstrated the critical involvement of the NLRP3 inflammasome, IL-1ß, and IL-18 in the development of allergic diseases. Targeting specific NLRP3 inflammasome and its related inhibitors may hold potential as therapeutic agents for immunologic conjunctivitis. Despite this, there has been no systematic review specifically addressing the treatment of immunologic conjunctivitis related to NLRP3. Therefore, this study aims to conduct a systematic review and meta-analysis of currently published randomized controlled trials (RCTs) on NLRP3-related treatments for immunologic conjunctivitis patients, with the goal of evaluating their efficacy and safety. METHODS: We will conduct a comprehensive search for relevant studies on NLRP3 inflammasome inhibitors or NLRP3-related treatments for immunologic conjunctivitis in various databases including PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP, and Wanfang. The search will encompass studies from their respective inception dates to July 2023. A meta-analysis will be performed using data extracted from eligible randomized controlled trials (RCTs), focusing on the clinical manifestations of immunologic conjunctivitis, levels of NLRP3-related factors in serum or tear samples, quality of life outcomes, and adverse events. Review Manager 5.4.1 software will be employed for the meta-analysis, and the results will be analyzed using either random-effects or fixed-effects models, depending on the presence of heterogeneity. The reliability and quality of evidence will be evaluated using the Grading of Recommendations, Development, and Evaluation (GRADE) system. RESULTS: The findings of this study will yield robust and high-quality evidence regarding the efficacy and safety of NLRP3-related treatments for immunologic conjunctivitis. This evidence will contribute significantly to our understanding of the potential benefits and risks associated with such treatments and will assist healthcare professionals in making informed decisions regarding the management of immunologic conjunctivitis. CONCLUSION: This study represents the first comprehensive meta-analysis aiming to evaluate the efficacy and safety of NLRP3-related treatments for immunologic conjunctivitis. The findings from this study will provide valuable evidence to guide clinical management strategies for this disease. The results are anticipated to significantly contribute to the understanding of the therapeutic potential and safety profile of NLRP3-related treatments, offering valuable insights for healthcare professionals involved in the care of patients with immunologic conjunctivitis. TRIAL REGISTRATION: Systematic review registration: PROSPERO with registration number CRD42023437076.

Magnetic Delivery of Antigen-Loaded Magnetic Liposomes for Active Lymph Node Targeting and Enhanced Anti-Tumor Immunity.

Therapeutic cancer vaccines offer the greatest advantage of enhancing antigen-specific immunity against tumors, particularly for immunogenic tumors, such as melanoma. However, clinical responses remain unsatisfactory, primarily due to inadequate T cell priming and the development of acquired immune tolerance. A major obstacle lies in the inefficient uptake of antigen by peripheral dendritic cells (DCs) and their migration to lymph nodes for antigen presentation. In this context, the magnetic delivery of antigen-loaded magnetic liposomes (Ag-MLs) to actively target lymph node, is proposed. These magnetic responsive liposomes contain soluble mouse melanoma lysate and iron oxide nanoparticles in the core, along with the immunostimulatory adjuvant CpG-1826 incorporated into the lipid bilayer. When applied through magnetic targeting in the mouse melanoma model, Ag-MLs accumulate significantly in the target lymph nodes. This accumulation results in increased population of active DCs in lymph nodes and cytotoxic T lymphocytes (CTLs) within tumors, correlating with effective tumor growth inhibition. Overall, this study demonstrates the potential of magnetic targeting as an effective strategy for delivering cancer vaccines and activating the immune response, offering a novel platform for cancer immunotherapies.

Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study.

BACKGROUND: Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in advanced solid tumours, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. METHODS: This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. Randomisation was done via a centralised interactive response system. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. We report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival. This study is registered with ClinicalTrials.gov (NCT03764293). FINDINGS: Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab-rivoceranib (n=272) or sorafenib (n=271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7·8 months (IQR 4·1-10·6). Median progression-free survival was significantly improved with camrelizumab-rivoceranib versus sorafenib (5·6 months [95% CI 5·5-6·3] vs 3·7 months [2·8-3·7]; hazard ratio [HR] 0·52 [95% CI 0·41-0·65]; one-sided p<0·0001). At the interim analysis for overall survival (Feb 8, 2022), median follow-up was 14·5 months (IQR 9·1-18·7). Median overall survival was significantly extended with camrelizumab-rivoceranib versus sorafenib (22·1 months [95% CI 19·1-27·2] vs 15·2 months [13·0-18·5]; HR 0·62 [95% CI 0·49-0·80]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102 [38%] of 272 patients in the camrelizumab-rivoceranib group vs 40 [15%] of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 [12%] vs 41 [15%]), increased aspartate aminotransferase (45 [17%] vs 14 [5%]), and increased alanine aminotransferase (35 [13%] vs eight [3%]). Treatment-related serious adverse events were reported in 66 (24%) patients in the camrelizumab-rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab-rivoceranib group (ie, multiple organ dysfunction syndrome) and one patient in the sorafenib group (ie, respiratory failure and circulatory collapse). INTERPRETATION: Camrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population. FUNDING: Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.

Magnetic graphitized carbon black based on crystal growth method combined with high-resolution mass spectrometry for screening of 300 pesticide residues in Radix Codonopsis and Angelica sinensis.

In this study, a high-throughput method for analyzing 300 pesticide residues in Radix Codonopsis and Angelica sinensis was established by liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-Q-TOF/MS) using iron tetroxide loaded graphitized carbon black magnetic nanomaterial (GCB/Fe3O4) as the purification material. It was optimized that saturated salt water and 1 % acetate acetonitrile were used as the extraction solution, then the supernatant was purified with 2 g anhydrous CaCl2 and 300 mg GCB/Fe3O4. As a result, 300 pesticides in Radix Codonopsis and 260 in Angelica sinensis achieved satisfactory results. The limits of quantification of 91 % and 84 % of the pesticides in Radix Codonopsis and Angelica sinensis reached 10 µg/kg, respectively. The matrix-matched standard curves ranging from 10 to 200 µg/kg were established with correlation coefficients (R) above 0.99. The pesticides meeting SANTE/12682/2021 accounted for 91.3 %, 98.3 %, 100.0 % and 83.8 %, 97.3, 100.0 % of the total pesticides added in Radix Codonopsis and Angelica sinensis respectively, which were spiked at 10, 20,100 µg/kg. The technique was applied to screen 20 batches of Radix Codonopsis and Angelica sinensis. Five pesticides were detected, three of which were prohibited according to the Chinese Pharmacopoeia (2020 Edition). The experimental results showed that GCB/Fe3O4 coupled with anhydrous CaCl2 exhibited good adsorption performance and could be used for sample pretreatment of various pesticide residues in Radix Codonopsis and Angelica sinensis. Compared with the reported methods for determining pesticides in traditional Chinese medicine (TCM), the proposed method has the advantage of less time-consuming in the clean-up procedure. Furthermore, as a case study on root TCM, this approach may serve as a reference for other TCM.

Clinical effect of Danshen decoction in patients with heart failure: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The incidence of heart failure (HF) is increasing year by year, posing a great threat to human health. Although pharmacotherapy has been able to significantly prolong patient survival, pharmacotherapy for HF still has limitations due to its complex pathogenesis and considerable individual variability, there is a great need to explore complementary and alternative therapies to slow down the progression of HF. Danshen decoction is used to treat several cardiovascular diseases including HF, but the efficacy of stabilization is uncertain. This meta-analysis evaluated the clinical efficacy of Danshen Decoction for the treatment of HF. METHODS: The registration number assigned to this meta-analysis on the PROSPERO platform is CRD42022351918. Four databases were searched, and randomized controlled trials (RCTs) of Danshen decoction combined with conventional treatment (CT) of HF were screened, CT included medical treatments other than Danshen Decoction to which the patient was treated (including but not limited to angiotensin converting enzyme inhibitor, angiotensin receptor blocker, angiotensin receptor neprilysin inhibitors, ß-blockers, diuretics, mineralcorticoid recept antagonist etc.). The clinical efficacy rate (CER), left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic diameter (LVESD), brain natriuretic peptide (BNP), N-terminal pro-B type natriuretic peptide (NT-proBNP) and hypersensitive C-reactive protein (hs-CRP) were included as outcome indicators. The GRADE grading scale was used to grade the above indicators. The Cochrane risk-of-bias tool and the Jadad quality scale were used to assess the methodological quality of RCTs. Finally, RevMan V.4.5 software was used for data synthesis, 95% confidence intervals (CI) for dichotomous data, risk ratios (RR), and mean differences (MD) for continuous variables were calculated, Chi-square and I2 were used for heterogeneity assessment. RESULTS: Nine RCTs with a total of 855 patients were included in this study, and all included RCTs had a low overall quality risk of bias and high quality of reported information. The results of the meta-analysis showed that compared with the use of CT, CER (%) was significantly improved due to Danshen decoction combined with CT (MD = 3.95, 95% CI [2.58, 6.04], P < 0.00001), LVEF (%) was significantly improved (MD = 5.46, 95% CI [5.32, 5.60], P < 0.00001), LVEDD (mm) was significantly reduced (MD = -5.27, 95% CI [-6.21, -4.32], P < 0.00001), LVESD (mm) was significantly reduced (MD = -4.60, 95% CI [-5.87, -3.32], P < 0.00001), BNP (pg/mL) was significantly reduced (MD = -88.61, 95% CI [-121.98, -55.24], P < 0.00001), NT-proBNP (pg/mL) was significantly decreased (SMD = -3.33, 95% CI [-5.92, -0.73], P = 0.01), hs-CRP (mg/L) was significantly decreased (MD = -2.73, 95% CI [-4.11, -1.34], P = 0.0001). The quality of the GRADE evidence for all outcomes was moderate to low and no RCTs reported adverse events. CONCLUSION: Our research demonstrates that Danshen decoction is an effective and safe treatment option for HF. Nevertheless, considering the limitations of methodological and the quality of RCTs, more rigorous, large-scale, multicenter randomized clinical trials are needed to further evaluate the efficacy and safety of Danshen decoction in the treatment of HF patients.

Urinary phytoestrogens and the risk of uterine leiomyomata in US women.

BACKGROUND: Uterine leiomyomata (UL) is a common gynecological disease in women. Studied on the relationship between single metabolites of urinary phytoestrogens and UL, especially for the combined effects of mixed metabolites on UL still are insufficient. METHODS: In this cross-sectional study, we included 1,579 participants from the National Health and Nutrition Examination Survey. Urinary phytoestrogens were assessed by measuring urinary excretion of daidzein, genistein, equol, O-desmethylangolensin, enterodiol and enterolactone. The outcome was defined as UL. Weighted logistic regression was used to analyze the association between single metabolites of urinary phytoestrogens and UL. Notably, we adopted the weighted quantile sum (WQS) regression, Bayesian kernel machine regression (BKMR), and quantile g-computation (qgcomp) models, to investigate the combined effects of six mixed metabolites on UL. RESULTS: The prevalence of UL was approximately 12.92%. After adjusting age, race/ethnicity, marital status, drinking status, body mass index, waist circumference, menopausal status, ovary removed status, use of female hormones, hormones/hormone modifiers, total energy, daidzein, genistein, O-desmethylangolensin, enterodiol, and enterolactone, the association of equol with UL was significant [Odds ratio (OR) = 1.92, 95% confidence interval (CI): 1.09-3.38]. In the WQS model, mixed metabolites of urinary phytoestrogen had a positive association with UL (OR = 1.68, 95%CI: 1.12-2.51), with the highest weighted chemical of equol. In the gpcomp model, equol had the largest positive weight, followed by genistein and enterodiol. In the BKMR model, equol and enterodiol have positive correlation on UL risk, while enterolactone has negative correlation. CONCLUSION: Our results implied a positive association between the mixed metabolites of urinary phytoestrogen and UL. This study provides evidence that urinary phytoestrogen-metabolite mixture was closely related to the risk of female UL.

Gastrodin and Gastrodigenin Improve Energy Metabolism Disorders and Mitochondrial Dysfunction to Antagonize Vascular Dementia.

Vascular dementia (VD) is the second most common dementia syndrome worldwide, and effective treatments are lacking. Gastrodia elata Blume (GEB) has been used in traditional Chinese herbal medicine for centuries to treat cognitive impairment, ischemic stroke, epilepsy, and dizziness. Gastrodin (p-hydroxymethylphenyl-b-D-glucopyranoside, Gas) and Gastrodigenin (p-hydroxybenzyl alcohol, HBA) are the main bioactive components of GEB. This study explored the effects of Gas and HBA on cognitive dysfunction in VD and their possible molecular mechanisms. The VD model was established by bilateral common carotid artery ligation (2-vessel occlusion, 2-VO) combined with an intraperitoneal injection of sodium nitroprusside solution. One week after modeling, Gas (25 and 50 mg/kg, i.g.) and HBA (25 and 50 mg/kg, i.g.) were administered orally for four weeks, and the efficacy was evaluated. A Morris water maze test and passive avoidance test were used to observe their cognitive function, and H&E staining and Nissl staining were used to observe the neuronal morphological changes; the expressions of Aß1-42 and p-tau396 were detected by immunohistochemistry, and the changes in energy metabolism in the brain tissue of VD rats were analyzed by targeted quantitative metabolomics. Finally, a Hippocampus XF analyzer measured mitochondrial respiration in H2O2-treated HT-22 cells. Our study showed that Gas and HBA attenuated learning memory dysfunction and neuronal damage and reduced the accumulation of Aß1-42, P-Tau396, and P-Tau217 proteins in the brain tissue. Furthermore, Gas and HBA improved energy metabolism disorders in rats, involving metabolic pathways such as glycolysis, tricarboxylic acid cycle, and the pentose phosphate pathway, and reducing oxidative damage-induced cellular mitochondrial dysfunction. The above results indicated that Gas and HBA may exert neuroprotective effects on VD by regulating energy metabolism and mitochondrial function.

Curcumol, a major terpenoid from Curcumae Rhizoma, attenuates human uterine leiomyoma cell development via the p38MAPK/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Uterine fibroids (UFs) are the most common benign tumors in women of reproductive age. Curcumae Rhizoma, the main essential oil component of which is curcumol, is widely used for the treatment of phymatosis in China due to its antitumor, anti-inflammatory, antithrombin, anti-tissue fibrosis and anti-oxygen pharmacological activities, but its potential for the treatment of UFs has not been evaluated. AIM OF THE STUDY: This study aimed to investigate the effects and mechanisms of curcumol intervention in human uterine leiomyoma cells (UMCs). MATERIALS AND METHODS: Putative targets of curcumol intervention in UFs were identified using network pharmacology strategies. Molecular docking was performed to assess the binding affinity of curcumol to core targets. A concentration gradient of curcumol (0, 50, 100, 200, 300, 400 and 500 µM) or RU-486 (mifepristone, 0, 10, 20, 40, 50, and 100 µM) was applied to UMCs, and cell viability was detected by the CCK-8 assay. Cell apoptosis and cell cycle were examined by flow cytometry, and cell migration was assessed by a wound-healing assay. Additionally, the mRNA and protein expression levels of critical pathway components were evaluated by RT‒PCR and western blotting. Finally, the actions of curcumol on different tumor cell lines were summarized. RESULTS: Network pharmacology predicted 62 genes with roles in the treatment of UFs with curcumol, and MAPK14 (p38MAPK) displayed a higher interaction degree. GO enrichment and KEGG analyses revealed that the core genes were abundantly enriched in the MAPK signaling pathway. The molecular binding of curcumol to core targets was relatively stable. In UMCs, 200, 300 and 400 µM curcumol treatment for 24 h decreased cell viability compared with that in the control group, and the greatest effect was detected at 48 h and maintained until 72 h. Curcumol arrested cells in the G0/G1 phase and subsequently suppressed mitosis, promoted early apoptosis and reduced the degree of wound healing in a concentration-dependent manner in UMCs. Furthermore, 200 µM curcumol decreased the mRNA and protein expression of p38MAPK, the mRNA expression of NF-κB, and the protein expression of Ki-67 and increased the mRNA and protein expression of Caspase 9. Curcumol (300 and 400 µM) decreased the mRNA and protein expression of p38MAPK, NF-κB, and Ki-67 and increased the protein expression of Caspase 9 in UMCs. Curcumol was demonstrated to treat tumor cell lines, including breast cancer, ovarian cancer, lung cancer, gastric cancer, liver cancer and nasopharyngeal carcinoma, but its effects on benign tumors have not yet been reported. CONCLUSION: Curcumol suppresses cell proliferation and cell migration while arresting the cell cycle in the G0/G1 phase and inducing cell apoptosis in UMCs via a mechanism related to p38MAPK/NF-κB pathway regulation. Curcumol may be a potential therapeutic and preventive agent in the treatment of benign tumors such as UFs.

Proanthocyanins and anthocyanins in chestnut (Castanea mollissima) shell extracts: biotransformation in the simulated gastrointestinal model and interaction with gut microbiota in vitro.

BACKGROUND: Chestnut (Castanea mollissima) shell is rich in flavonoids and our previous studies showed that proanthocyanins and anthocyanins were the two markedly varied flavonoids in chestnut shell extracts (CSE) during digestion. Here, the biotransformation of proanthocyanins and anthocyanins in a simulated gastrointestinal model, and the interactions between non-absorption CSE (NACSE) and gut microbiota in vitro, were investigated by ultra-high-performance liquid chromatography combined with triple-quadrupole mass spectrometry and 16S rRNA sequencing. RESULTS: Chestnut shell was richer in proanthocyanins and anthocyanins, while the loss of proanthocyanins was greater after digestion. Additionally, the content of anthocyanin decreased after gastric digestion but increased after intestinal digestion and remained stable after fermentation. After fermentation, delphinidin-3-O-sambubioside and pelargonidin-3-O-galactoside were newly formed. Furthermore, microbiome profiling indicated that NACSE promoted the proliferation of beneficial bacteria, while inhibiting pathogenic bacteria. CONCLUSION: All these data suggest that CSE may be a promising candidate to protect gut health. © 2023 Society of Chemical Industry.

Angelica oil restores the intestinal barrier function by suppressing S100A8/A9 signalling in mice with ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) progression is driven by the activation of immune cells that release pro-inflammatory mediators to disrupt intestinal epithelial barrier integrity. This study aimed to investigate the potential protective effects of Angelica oil (AO) on the intestinal epithelial barrier in mice with UC and the underlying mechanisms. METHODS: Improvement of the disease state and protective effect of AO on the intestinal epithelial barrier were observed in mice with dextran sulphate sodium salt (DSS)-induced UC. Protein microarrays were used to screen AO-affected cytokine pools and their recruited immune cells for accumulation in the tissues. Furthermore, quantitative proteomics was applied to search for AO-acting molecules and to verify in vitro the functions of key molecules between inflammation and the intestinal mucosal barrier. RESULTS: AO significantly alleviated intestinal inflammation, reduced intestinal permeability, and retained barrier function in mice with UC. Furthermore, cytokines inhibited by AO mainly promoted monocyte and neutrophil activation or chemotaxis. Moreover, proteomic screening revealed that S100A8/A9 was a key molecule significantly regulated by AO, and its mediated TLR4/NF-κB pathway was also inhibited. Finally, we verified that AO inhibited the activation of the S100A8/A9/TLR4 signalling pathway and enhanced the expression of tight junctions (TJs) proteins using a cellular model of intestinal barrier damage induced by S100A8/A9 or macrophage-derived medium. And the enhancement of TJs in intestinal epithelial cells and the inhibition of inflammatory signalling by AO were significantly attenuated due to the application of S100A8/A9 monoclonal antibody. CONCLUSION: These results demonstrated that AO improves intestinal mucosal barrier damage in the inflammatory environment of mice with UC by inhibiting the expression of S100A8/A9 and the activation of its downstream TLR4/NF-κB signalling pathway.

The traditional Chinese medicine Qiangjing tablet prevents blood-testis barrier injury induced by CdCl2 through the PI3K/Akt/Rictor signaling pathway.

OBJECTIVE: Environmental contaminants such as cadmium (Cd) may have a deleterious impact on sperm and reduce male fertility by compromising the blood-testis barrier (BTB). Hence, the effects of the traditional Chinese medicine Qiangjing tablet (QJP) on sperm quality and BTB alterations induced by Cd in mouse testes were examined. METHODS: Adult KM mice challenged with Cd chloride were examined, QJP was administered to mice as an oral drug by gavage, and the experiments lasted 2 weeks. Testicular and epididymal weights, sperm quality, anti-sperm antibodies (AsAb), hormone levels, and histology were evaluated. Changes in the levels of N-cadherin, occludin, ZO-1, claudin-11, F-actin, and ß-tubulin and their mRNAs were evaluated. The effects of QJP on the PI3K/Akt/Rictor pathway were evaluated. RESULTS: CdCl2 decreased reproductive organ weight, sperm quality, and testosterone (T) levels; increased AsAb, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels; induced structural damage in testicles with BTB disruption; increased BTB permeability; and decreased N-cadherin, occludin, ZO-1, claudin-11, F-actin, and ß-tubulin expression. After treatment, QJP blocked the effects of Cd on reproductive organ weight, sperm quality, and T; mitigated germinal epithelium compartment alterations; decreased AsAb, FSH, and LH levels; and preserved BTB ultrastructure and function. In addition, QJP induced increases in N-cadherin, occludin, ZO-1, claudin-11, F-actin, and ß-tubulin levels and the expression of their mRNAs through the PI3K/Akt/Rictor pathway. After the application of JRAB2011, the levels of a specific mTORC2 suppressor, Rictor, and the BTB-protective effect of QJP were greatly reduced. CONCLUSIONS: We demonstrated the effect of QJP against Cd-induced damage to the BTB, and the results indicate that QJP may play a significant role in opposing the effects of Cd through the PI3K/Akt/Rictor pathway.

Assisted biomimetic electrostimulation therapy can improve the clinical pregnancy rate of patients with abnormal endometrial receptivity undergoing frozen-thawed embryo transfer cycles.

This study aimed to explore whether assisted biomimetic electrostimulation (BES) therapy can improve clinical outcomes in patients with abnormal endometrial receptivity undergoing frozen-thawed embryo transfer (FET) cycles. We retrospectively collected data from 132 patients who underwent FET cycles and divided them into the BES (n = 86) and non-BES (NBES) groups (n = 46). The clinical pregnancy rate (55.8 vs. 37.0%), biochemical pregnancy rate (59.3 vs. 41.3%), and live birth rate (44.2 vs. 23.9%) of the BES group were significantly higher than those of the NBES group (p < 0.05). No significant difference between the two groups was observed in endometrial thickness at FET day, embryo implantation rate, and early abortion rate (p > 0.05). The logistic regression analysis indicated that blastocyst transfer (adjusted OR = 3.617; 1.337-9.783; p = 0.011) and BES (adjusted OR = 2.398; 1.094-5.256; p = 0.029) were positively associated with the clinical pregnancy rate. These results suggested that assisted BES therapy can improve clinical outcomes in patients with diseases affecting endometrial receptivity.Impact statementWhat is already known on this subject? Biomimetic electrostimulation (BES) therapy can increase endometrial thickness in patients with thin endometria undergoing embryo transfers and to some extent improve their clinical outcomes.What do the results of this study add? Assisted BES therapy can improve clinical pregnancy rates in patients with abnormal endometrial receptivity undergoing FET cycles (55.8 vs. 37.0%, p = 0.039). After adjusting for covariates, BES was still positively associated with the clinical pregnancy rate (adjusted OR = 2.398; 1.094-5.256; p = 0.029).What are the implications of these findings for clinical practice and/or further research? BES therapy can improve endometrial receptivity. Further studies are needed to understand its specific mechanisms.

"Double-punch" strategy against triple-negative breast cancer via a synergistic therapy of magneto-mechanical force enhancing NIR-II hypothermal ablation.

Triple-negative breast cancer (TNBC) is a form of breast cancer that is more aggressive and harder to treat than others, with a higher probability of relapse. Its nefarious capabilities for migrating and invading other parts of the body together with the current lack of clinically established effective therapies account for a low survival rate. In this work, we demonstrate the in-tandem use of two complementary therapeutic routes to effectively combat TNBC. A versatile magnetic-photothermal converter (MPC) consisting of zinc-doped ferrite nanoparticles and polyethene glycol, is shown to display excellent therapeutic efficiency, being capable to fight TNBC via two distinct routes: magneto-mechanical force (MMF) and near-infrared-II (NIR-II) hypothermal ablation. The combined use of these two complementary and synergistic therapies, which are less aggressive to the human body compared to conventional chemotherapeutic approaches, results in the splendid suppression of TNBC migration and invasion. Remotely controlling the MPCs by an external magnetic field, results in cellular MMF effects that cause direct mechanical destruction to the cancer cell membrane, leading to its necrosis. Furthermore, the MMF disrupts intracellular lysosomes, thereby triggering the release of large amounts of protein hydrolases, which induce intracellular oxidative stress, and accelerate the induction of apoptosis. Complementing the therapeutic approach based on MMF, the excellent photothermal performance of the MPC in the NIR-II region (1064 nm) is exploited to enable effective hypothermal ablation of the tumours, which can be achieved in deep tissue layers. The proposed multifunctional nanocomposites, together with the demonstrated "double-punch" therapeutic approach, hold significant potential to pave the way for future cutting-edge weapons against the dreadful TNBC.

Fine-tuned magnetic nanobubbles for magnetic hyperthermia treatment of glioma cells.

Magnetic nanoparticle (MNP) induced magnetic hyperthermia has been demonstrated as a promising technique for the treatment of brain tumor. However, lower heating efficiency resulting from low intratumoral accumulation of magnetic nanomaterials is still one of the significant limitations for their thermotherapeutic efficacy. In this study, we have designed a nanobubble structure with MNPs decorated on the shell, which leads to the improvement of magnetocaloric performance under an alternating magnetic field. First, the phospholipid coupled with MNPs as the shell to be self-assembled magnetic nanobubbles (MNBs) was fabricated by a temperature-regulated repeated compression self-assembly approach. Then, the optimal magnetic heating concentration, electric current parameters for producing the magnetic field, and the number of magnetic heating times were investigated for tuning the better magnetoenergy conversion. Finally, the well-defined geometrical orientation of MNPs on the nanobubble structure enhanced hypothermia effect was investigated. The results demonstrate that the MNBs could promote the endocytosis of magnetic nanoparticles by glioma cells, resulting in better therapeutic effect. Therefore, the controlled assembly of MNPs into well-defined bubble structures could serve as a new hyperthermia agent for tumor therapy.

Effect of external use of Qingluo San on clinical efficacy in patients with acute gouty arthritis.

OBJECTIVE: The present study aimed to observe the clinical efficacy of the external use of Qingluo San combined with diclofenac sodium double-release enteric capsules in the treatment of acute gouty arthritis (dampness-heat accumulation syndrome). METHODS: A total of 58 acute gouty arthritis patients were divided into two groups using the random number table method. Diclofenac sodium double-release enteric capsules were orally administered in the control group. Based on the treatment in the control group, the external use of Qingluo San was given in the treatment group, with 7-day course of treatment. The changes in visual analog scale (VAS) scores, the tenderness, swelling, and mobility function of the joint, and the traditional Chinese medicine (TCM) syndrome scores before and after the treatment, at day 0, 1, 3, 5 and 7, were observed in both groups, together with the comparison of laboratory indicators (erythrocyte sedimentation rate, ESR; C-reactive protein, CRP; uric acid, UA). RESULTS: The total effective rate was 96.55% in the treatment group and 82.76% in the control group. After treatment, the VAS score, the tenderness, swelling and function scores of the joint, and the TCM syndrome scores decreased in both groups. The treatment group was superior in improving the VAS scores, the tenderness, swelling and mobility function of the joint, and TCM syndrome scores, when compared to the control group (p < 0.05). The laboratory indicators, which included the ESR, CRP and UA, obviously decreased in both groups after treatment (p < 0.05). The ESR significantly decreased in the treatment group, when compared to the control group (p < 0.05). CONCLUSION: The combination of the external use of Qingluo San and oral administration of diclofenac sodium double-release enteric capsules can more rapidly relieve joint pain, and improve the clinical efficacy. This combination therapy also has certain advantages in relieving joint swelling and improving the mobility function of the joint. Hence, this is worthy of clinical promotion and application.

The impacts of vitamin D supplementation in adults with metabolic syndrome: A systematic review and meta-analysis of randomized controlled trials.

Background: Studies have shown the association of vitamin D status with the development of metabolic syndrome (MetS), which has attracted an extensive research interest with inconsistent results. Therefore, we hypothesized that vitamin D supplementation (VDS) will benefit adults with MetS. Aims: To test our hypothesis, we performed a meta-analysis to evaluate the effect of VDS on MetS in adults using relevant biomarkers such as anthropometric parameters, blood pressure, blood lipid profile, glycemia, oxidative stress and vitamin D toxicity (VDT). Methods: Randomized controlled trials published in PubMed, Web of Science, embase and the Cochrane Library between 2012 and 2022 on the effect of VDS on MetS in adults were searched. The language was limited to English. A meta-analysis performed using RevMan 5.4 and Stata 14.0 software, sensitivity analysis, and evaluation of the risk of bias and general quality of the resulting evidence were conducted. Results: Eventually, 13 articles were included in this meta-analysis. Overall, VDS significantly increased the endline serum 25-hydroxyvitamin D levels as compared to the control [MD:17.41, 95% CI (14.09, 20.73), p < 0.00001]. VDS did not affect waist circumference, body mass index, body fat percentage and VDT biomarkers, but decreased waist-to-hip ratio and blood pressure (p < 0.01). VDS significantly decreased fasting plasma glucose (FPG) [MD: 3.78; 95% CI (-6.52, -1.03), p = 0.007], but did not affect the levels of blood high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglyceride (TG). Pooled estimate of nine papers indicated a significant reduction of fasting insulin (FI) (p = 0.006), and homeostasis model assessment of insulin resistance (p = 0.0001). The quantitative insulin check index levels were moderately increased (p = 0.007) without any impact on the glycosylated hemoglobin type A1C (HbA1c). For the oxidative stress parameters, VDS significantly lowered the levels of malondialdehyde and hypersensitive C-reactive protein (p < 0.05). Conclusion: Results of this meta-analysis demonstrate that VDS only reduces insulin resistance and hypertension but not the blood lipid profile and HbA1c. It appears that the evidence for the benefit of VDS in adults with MetS is inconclusive. Further clinical studies are still needed.