A network pharmacology approach and experimental validation to investigate the anticancer mechanism of Qi-Qin-Hu-Chang formula against colitis-associated colorectal cancer through induction of apoptosis via JNK/p38 MAPK signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The Qi-Qin-Hu-Chang Formula (QQHCF) is a traditional Chinese medicine prescription that is clinically used at the Affiliated Hospital of Nanjing University of Chinese Medicine for the treatment of colitis-associated colorectal cancer (CAC). AIM OF THE STUDY: To evaluate the potential therapeutic effects of QQHCF on a CAC mouse model and investigate its underlying mechanisms using network pharmacology and experimental validation. MATERIALS AND METHODS: The active components and potential targets of QQHCF were obtained from Traditional Chinese Medicine Systems Pharmacology (TCMSP) and herb-ingredient-targets gene network were constructed by Cytoscape 3.9.2. Target genes of CAC were obtained from GeneCards, Online Mendelian Inheritance in Man, and DrugBank database. The drug disease target protein-protein interaction (PPI) network was constructed and the core targets were visualized and identified using Cytoscape. The Metascape database was used for GO and KEGG enrichment analysis. UHPLC-MS/MS was used to further identify the active compounds in QQHCF. Subsequently, the therapeutic effects and potential mechanism of QQHCF against CAC were investigated in AOM/DSS-induced CAC mouse in vivo, and HT-29 and HCT116 cells in vitro. Finally, interactions between JNK, p38, and active ingredients were assessed by molecular docking. RESULTS: A total of 176 active compounds, 273 potential therapeutic targets, and 2460 CAC-related target genes were obtained. The number of common targets between QQHCF and CAC were 165. KEGG pathway analysis indicated that the MAPK signaling pathway was closely associated with CAC, which may be the potential mechanism of QQHCF against CAC. Network pharmacology and UHPLC-MS/MS analyses showed that the active compounds of QQHCF included quercetin, kaempferol, luteolin, wogonin, oxymatrine, lupanine, and baicalin. Animal experiments demonstrated that QQHCF reduced tumor load, number, and size in AOM/DSS-treated mice, and induced apoptosis in colon tissue. In vitro experiments further showed that QQHCF induced apoptosis and inhibited cell viability, migration, and invasion in HCT116 and HT-29 cells. Notably, QQHCF activated the JNK/p38 MAPK signaling pathway both in vivo and in vitro. Molecular docking analysis revealed an ability for the main components of QQHCF and JNK/p38 to bind. CONCLUSION: The present study demonstrated that QQHCF could ameliorate AOM/DSS-induced CAC in mice by activating the JNK/p38 MAPK signaling pathway. These results have important implications for the development of effective treatment strategies for CAC.

Integrated Network Pharmacology, Molecular Docking and Animal Experiment to Explore the Efficacy and Potential Mechanism of Baiyu Decoction Against Ulcerative Colitis by Enema.

Background: Baiyu Decoction (BYD), a clinical prescription of traditional Chinese medicine, has been proven to be valuable for treating ulcerative colitis (UC) by enema. However, the mechanism of BYD against UC remains unclear. Purpose: A combination of bioinformatics methods including network pharmacology and molecular docking and animal experiments were utilized to investigate the potential mechanism of BYD in the treatment of UC. Materials and Methods: Firstly, the representative compounds of each herb in BYD were detected by liquid chromatography-mass spectrometry. Subsequently, we predicted the core targets and potential pathways of BYD for treating UC through network pharmacology. And rat colitis model was established with dextran sodium sulfate. UC rats were subjected to BYD enema administration, during which we recorded body weight changes, disease activity index, and colon length to assess the effectiveness of BYD. Besides, quantitative real-time PCR, western blotting, ELISA and immunofluorescence were used to detect intestinal inflammatory factors, intestinal barrier biomarkers and TOLL-like receptor pathway in rats. Finally, the core components and targets of BYD were subjected to molecular docking so as to further validate the results of network pharmacology. Results: A total of 41 active compositions and 203 targets related to BYD-UC were subjected to screening. The results of bioinformatics analysis showed that quercetin and kaempferol may be the main compounds. Additionally, AKT1, IL-6, TP53, TNF and IL-1ß were regarded as potential therapeutic targets. KEGG results explained that TOLL-like receptor pathway might play a pivotal role in BYD protecting against UC. In addition, animal experiments and molecular docking validated the network pharmacology results. BYD enema treatment can reduce body weight loss, lower disease activity index score, reverse colon shortening, relieve intestinal inflammation, protect intestinal barrier, and inhibit TOLL-like receptor pathway in UC rats. Besides, molecular docking suggested that quercetin and kaempferol docked well with TLR4, AKT1, IL-6, TP53. Conclusion: Utilizing network pharmacology, animal studies, and molecular docking, enema therapy with BYD was confirmed to have anti-UC efficacy by alleviating intestinal inflammation, protecting the intestinal barrier, and inhibiting the TOLL-like receptor pathway. Researchers should focus not only on oral medications but also on the rectal administration of medications in furtherance of the cure of ulcerative colitis.

Effect of comprehensive nursing intervention on the outcomes of in vitro fertilization in patients with polycystic ovary syndrome: A randomized controlled study.

OBJECTIVE: To explore the effects of comprehensive nursing intervention on in vitro fertilization (IVF) and pregnancy outcomes in patients with polycystic ovary syndrome (PCOS). METHOD: A total of 130 patients with PCOS admitted to our hospital from April 2021 to March 2023 were selected as the research subjects. They were evenly divided according to a random number table method. The control group received routine care for the patients, while the study group received comprehensive care for the patients. The IVF, pregnancy outcomes, negative emotional changes, serum and follicular fluid (FF) amyloid-related protein and C-reactive protein (CRP) levels of the 2 groups of patients were compared. RESULT: The data on IVF rate and pregnancy rate in the study group were significantly better than those in the control group (P < .05). The SAS and SDS scores of the study group patients after intervention were significantly lower than those of the control group (P < .05). After intervention, the levels of serum and FF amyloid associated protein and CRP in the study group were significantly lower than those in the control group (P < .05). CONCLUSION: Patients with PCOS who receive comprehensive care can increase their probability of IVF, improve their pregnancy outcomes, and have a positive significance in reducing negative emotions.

Therapeutic role of curcumin in adult neurogenesis for management of psychiatric and neurological disorders: a scientometric study to an in-depth review.

Aberrant neurogenesis is a major factor in psychiatric and neurological disorders that have significantly attracted the attention of neuroscientists. Curcumin is a primary constituent of curcuminoid that exerts several positive pharmacological effects on aberrant neurogenesis. First, it is important to understand the different processes of neurogenesis, and whether their dysfunction promotes etiology as well as the development of many psychiatric and neurological disorders; then investigate mechanisms by which curcumin affects neurogenesis as an active participant in pathophysiological events. Based on scientometric studies and additional extensive research, we explore the mechanisms by which curcumin regulates adult neurogenesis and in turn affects psychiatric diseases, i.e., depression and neurological disorders among them traumatic brain injury (TBI), stroke, Alzheimer's disease (AD), Gulf War Illness (GWI) and Fragile X syndrome (FXS). This review aims to elucidate the therapeutic effects and mechanisms of curcumin on adult neurogenesis in various psychiatric and neurological disorders. Specifically, we discuss the regulatory role of curcumin in different activities of neural stem cells (NSCs), including proliferation, differentiation, and migration of NSCs. This is geared toward providing novel application prospects of curcumin in treating psychiatric and neurological disorders by regulating adult neurogenesis.

Dan-Lou tablets reduces inflammatory response via suppression of the MyD88/p38 MAPK/NF-κB signaling pathway in RAW 264.7 macrophages induced by ox-LDL.

ETHNOPHARMACOLOGICAL EVIDENCE: The anti-inflammatory effect of Dan-Lou tablets (DLT) have been reported; however, the signaling pathways involved and their role in foam cell formation remains unclear. AIM OF THE STUDY: The purpose of this study was to determine the molecular target and mechanism of DLT in the treatment of coronary heart disease (CHD), and investigate the role of DLT in inhibiting foam cell formation and the anti-inflammatory effects of RAW 264.7 macrophages. MATERIALS AND METHODS: This study explored and elucidated the main active components, therapeutic targets, and pharmacological mechanisms of DLT treatment for CHD using network pharmacology. Secondly, the accuracy of the interaction of key active compounds with key proteins was verified by molecular docking analysis. Eight chemical compositions were determined from the ethanol extract of DLT (EEDL) by high-performance liquid chromatography. Finally, this study used EEDL intervention with oxidized low-density lipoprotein (ox-LDL) to induce RAW264.7 macrophages to verify the results of network pharmacology. RESULTS: According to network pharmacological analysis, 269 common targets of DLT and CHD were obtained from an online database, and 24 key targets were obtained from further analysis. GO enrichment and KEGG analyses were performed, mainly involving the cAMP, cGMP-PKG, MAPK, and NF-κB signaling pathways, and vascular smooth muscle contraction. Molecular docking showed that the active components in DLT docked well with MyD88, NF-κB, and p38 MAPK. The eight compounds from the EEDL have been identified as gallic acid, salvianolic acid, puerarin, daidzein, paeoniflorin, salvianolic acid B, cryptotanshinone, and tanshinone IIA with concentrations of 4.62, 4.76, 23.73, 34.24, 14.59, 21.69, 0.34, and 0.47 µg/mg, respectively. Further in vitro experiments showed that the levels of MyD88 and p-p38 MAPK in RAW 264.7 macrophages induced by ox-LDL increased noticeably. Stimulating the NF-κB signaling pathway increased the release of pro-flammatory factors (TNF-α and IL-1ß) and strengthened the inflammatory response (P < 0.05 or P < 0.01), while the levels of MyD88, p38 MAPK, NF-κB, TNF-α, and IL-1ß decreased after EEDL treatment (P < 0.05 or P < 0.01). CONCLUSION: The study demonstrated that the anti-inflammatory activity of the DLT intervention of ox-LDL-induced RAW 264.7 macrophages may involve the MyD88/p38 MAPK/NF-κB signaling pathway.

Manganese, iron, copper, and selenium co-exposure and osteoporosis risk in Chinese adults.

BACKGROUND & AIMS: Previous experimental studies demonstrated that either deficient or excessive trace elements, such as manganese (Mn), iron (Fe), copper (Cu) and selenium (Se), are detrimental to bone health. Epidemiologic evidence for the effect of the four trace elements on osteoporosis (OP) risk remains inadequate. This cross-sectional study aimed to examine their associations with the OP risk among Chinese adults. METHODS: Concentrations of Mn, Fe, Cu, and Se were measured in plasma using an inductively coupled plasma mass spectrometer among 627 Chinese adults aged ≥ 50 years. Individual effect of the four elements on OP risk was analyzed by logistic regression and Bayesian Kernel Machine Regression (BKMR) models. The latter model was also adopted to examine the exposure-response relationships and joint effects of the four elements on OP risk. RESULTS: The median Mn, Fe, Cu, and Se levels were 4.78, 1026.63, 904.55, and 105.39 µg/L, respectively, in all participants. Inverse associations of Fe and Se levels with OP risk were observed in the logistic regression model. BKMR analysis revealed a U-shape pattern for the Fe-OP association, and a reduced OP risk in response to co-exposure of the four elements above the 50th percentiles but an elevated one in response to that below the 50th percentiles. Sex discrepancy existed in the findings. No interactions were found for the four elements affecting OP risk. CONCLUSIONS: Co-exposure to Mn, Fe, Cu, and Se was associated with improved bone density, where Fe contributed most to the beneficial effect. Further studies are needed to verify these findings and explore the underlying biological mechanism.

Systematic identification of the interventional mechanism of Qingfei Xiaoyan Wan (QFXYW) in treatment of the cytokine storm in acute lung injury using transcriptomics-based system pharmacological analyses.

CONTEXT: Acute lung injury (ALI) is a complex, severe inflammation disease with high mortality, and there is no specific and effective treatment for ALI. Qingfei Xiaoyan Wan (QFXYW) has been widely used to treat lung-related diseases for centuries. OBJECTIVE: This study evaluates the potential effects and elucidates the therapeutic mechanism of QFXYW against LPS induced ALI in mice. MATERIALS AND METHODS: BALB/c Mice in each group were first orally administered medicines (0.9% saline solution for the control group, 0.5 mg/kg Dexamethasone, or 1.3, 2.6, 5.2 g/kg QFXYW), after 4 h, the groups were injected LPS (1.0 mg/kg) to induce ALI, then the same medicines were administered repeatedly. The transcriptomics-based system pharmacological analyses were applied to screen the hub genes, RT-PCR, ELISA, and protein array assay was applied to verify the predicted hub genes and key pathways. RESULTS: QFXYW significantly decreased the number of leukocytes from (6.34 ± 0.51) × 105/mL to (4.01 ± 0.11) × 105/mL, accompanied by the neutrophil from (1.41 ± 0.19) × 105/mL to (0.77 ± 0.10) × 105/mL in bronchoalveolar lavage fluid (BALF). Based on Degree of node connection (Degree) and BottleNeck (BN), important parameters of network topology, the protein-protein interaction (PPI) network screened hub genes, including IL-6, TNF-α, CCL2, TLR2, CXCL1, and MMP-9. The results of RT-PCR, ELISA, and protein chip assay revealed that QFXYW could effectively inhibit ALI via multiple key targets and the cytokine-cytokine signalling pathway. CONCLUSIONS: This study showed that QFXYW decreased the number of leukocytes and neutrophils by attenuating inflammatory response, which provides an important basis for the use of QFXYW in the treatment of ALI.

Apple Polyphenols Extracts Ameliorate High Carbohydrate Diet-Induced Body Weight Gain by Regulating the Gut Microbiota and Appetite.

To investigate the potential contribution of appetite regulation and modulation of gut microbiota to the ameliorated effects of apple polyphenols extracts (APE) on high carbohydrate diet (HCD)-induced body weight (BW) gain, we conducted this study. One hundred C57BL/6 male mice were randomly divided into seven groups and fed with the following diets for 12 weeks: chow diet (CON), HCD (HCD), high fructose and sucrose diet (HSCD), and HCD and HSCD with 125 or 500 mg/kg·day APE gavage. Compared to the CON group, the BW of mice in the HCD and HSCD groups increased significantly. HSCD induced a more significant weight gain in the white adipose tissue (WAT) and liver than HCD, accompanied by severe impairment of glucose tolerance and a larger diameter of adipocytes. On the other hand, by decreasing food intake, APE significantly reduced BW via mechanisms, including decreased weights of the WAT and liver, amelioration of glucose tolerance, and amplification of WAT browning by upregulating the mRNA levels of Ucp-1 and Cidea. Moreover, APE promoted transcription and secretion of GLP-1, with the increased expression of gut anorexigenic hormone peptides Ffar 2/3 in the colon and anorectic neuropeptide gene expression of Pomc, Cart, and Mc4r in the hypothalamus, causing increased satiety. Additionally, APE significantly increased Verrucomicrobia colonization and the relative abundance of Akkermansia. APE potentially ameliorates high simple carbohydrate diet-induced body weight gain by mechanisms related to gut microbiota regulation and appetite inhibition.

Targeting hippocampal phospholipid and tryptophan metabolism for antidepressant-like effects of albiflorin.

BACKGROUND: Current antidepressant therapy remains unsatisfactory due to its delayed clinical onset of action and the heterogeneity of depression. Targeting disturbed neurometabolic pathways could provide a novel therapeutic approach for the treatment of depression. Albiflorin is a phytomedicine isolated from the root of Peony (Paeonia albiflora Pall) with excellent clinical tolerance. Until now, the antidepressant-like activities of albiflorin in different subtypes of depression and its effects on neurometabolism are unknown. PURPOSE: The objective of this study was to investigate the rapid antidepressant-like effects of albiflorin in three common animal models of depression and elucidate the pharmaco-metabolic mechanisms of its action using a multi-omics approach. RESULTS: We found that albiflorin produces rapid antidepressant-like effects in chronic unpredictable mild stress (CUMS), olfactory bulbectomy (OBX), and lipopolysaccharide (LPS)-induced murine models of depression. Using a system-wide approach combining metabolomics, lipidomics, and transcriptomics, we showed that the therapeutic effects of albiflorin are highly associated with the rapid restoration of a set of common metabolic abnormities in the hippocampus across all three depression models, including phospholipid and tryptophan metabolism. Further mechanistic analysis revealed that albiflorin normalized the metabolic dysregulation in phospholipid metabolism by suppressing hippocampal cytosolic phospholipases A2 (cPLA2). Additionally, inhibition of cPLA2 overexpression by albiflorin corrects abnormal kynurenine pathway of tryptophan metabolism via the cPLA2-protein kinase B (Akt1)-indoleamine 2,3-dioxygenase 1(IDO1) regulatory loop and directs tryptophan catabolism towards more hippocampal serotonin biosynthesis. CONCLUSION: Our study contributed to a better understanding of the homogeneity in the metabolic mechanisms of depression and established a proof-of-concept for rapid treatment of depression through targeting dysregulated neurometabolic pathways.

Quantitative Proteomics Reveal That Metabolic Improvement Contributes to the Cardioprotective Effect of T89 on Isoproterenol-Induced Cardiac Injury.

BACKGROUND: T89, a traditional Chinese medicine, has passed phase II, and is undergoing phase III clinical trials for treatment of ischemic cardiovascular disease by the US FDA. However, the role of T89 on isoproterenol (ISO)-induced cardiac injury is unknown. The present study aimed to explore the effect and underlying mechanism of T89 on ISO-induced cardiac injury. METHODS: Male Sprague-Dawley rats received subcutaneous injection of ISO saline solution at 24 h intervals for the first 3 days and then at 48 h intervals for the next 12 days. T89 at dose of 111.6 and 167.4 mg/kg was administrated by gavage for 15 consecutive days. Rat survival rate, cardiac function evaluation, morphological observation, quantitative proteomics, and Western blotting analysis were performed. RESULTS: T89 obviously improved ISO-induced low survival rate, attenuated ISO-evoked cardiac injury, as evidenced by myocardial blood flow, heart function, and morphology. Quantitative proteomics revealed that the cardioprotective effect of T89 relied on the regulation of metabolic pathways, including glycolipid metabolism and energy metabolism. T89 inhibited the enhancement of glycolysis, promoted fatty acid oxidation, and restored mitochondrial oxidative phosphorylation by regulating Eno1, Mcee, Bdh1, Ces1c, Apoc2, Decr1, Acaa2, Cbr4, ND2, Cox 6a, Cox17, ATP5g, and ATP5j, thus alleviated oxidative stress and energy metabolism disorder and ameliorated cardiac injury after ISO. The present study also verified that T89 significantly restrained ISO-induced increase of HSP70/HSP40 and suppressed the phosphorylation of ERK, further restored the expression of CX43, confirming the protective role of T89 in cardiac hypertrophy. Proteomics data are available via ProteomeXchange with identifier PXD024641. CONCLUSION: T89 reduced mortality and improves outcome in the model of ISO-induced cardiac injury and the cardioprotective role of T89 is correlated with the regulation of glycolipid metabolism, recovery of mitochondrial function, and improvement of myocardial energy.

Selenomethionine alleviates LPS-induced JNK/NLRP3 inflammasome-dependent necroptosis by modulating miR-15a and oxidative stress in chicken lungs.

Selenium (Se) was involved in many physiological processes in humans and animals. microRNAs (miRNAs) also played important roles in lung diseases. However, the regulatory mechanism of miRNA in chicken lungs and the mechanism of lipopolysaccharide (LPS)-induced pneumonia remained unclear. To further study these mechanisms, we established a supplement of selenomethionine (SeMet) and/or LPS-treated chicken model and a cell model of LPS and/or high and low expression of miR-15a in chicken hepatocellular carcinoma (LMH) cells. We detected the expression of some selenoproteins, p-c-Jun N-terminal kinase (JNK), nod-like receptor protein 3 (NLRP3), caspase1, receptor-interacting serine-threonine kinase 1 (RIPK1), receptor-interacting serine-threonine kinase 3 (RIPK3), mixed lineage kinase domain-like pseudokinase (MLKL), miR-15a, and oxidative stress kits. Additionally, we observed the morphology of lungs by H.E. staining in vitro. The results indicated that necroptosis occurred in LPS-treated chicken and LMH cells. Moreover, LPS stimulation inhibited miR-15a, and increased the expression of JNK, NLRP3, caspase1, RIPK1, RIPK3, and MLKL. We also found that LPS treatment not only increased the content of H2O2 and MDA in the lungs but also increased the activities of iNOS and CAT and the content of GSH decreased. Conclusion: SeMet could reduce the oxidative damage and activate NLRP3 inflammasome reaction by stimulating miR-15a/JNK, thus reduced the pulmonary necroptosis induced by LPS.

Integration of transcriptomics and system pharmacology to reveal the therapeutic mechanism underlying Qingfei Xiaoyan Wan to treat allergic asthma.

ETHNOPHARMACOLOGICAL RELEVANCE: Asthma is a chronic inflammatory disease, characterized by airway inflammation, hyperresponsiveness, and bronchial smooth muscle contraction. Qingfei Xiaoyan Wan (QFXYW), a traditional Chinese formula, has been shown to exert anti-asthma effects and immune response in multiple diseases. AIM OF THIS STUDY: In this study, we evaluated the therapeutic mechanism of QFXYW in the suppression of allergic asthma by integrating of transcriptomics and system pharmacology. MATERIALS AND METHODS: BALB/c mice were sensitized with ovalbumin (OVA) to establish the allergic asthma model, and its success was confirmed with behavioral observations. Lung histopathological analysis, inflammatory pathology scores, transcription factors were used to evaluate the effects of QFXYW on allergic asthma. The therapeutic mechanism of QFXYW in treating allergic asthma through integrated transcriptomics and system pharmacology was then determined: hub genes were screened out by topological analysis and functional enrichment analysis were performed to identify key signaling pathway. Subsequently, quantitative RP-PCR and protein array were performed to detect the mRNA of hub genes and to predict the key pathway in OVA-induced allergic asthma, respectively. RESULTS: Our results demonstrated that QFXYW could significantly attenuate inflammatory cell infiltration, mucus secretion, and epithelial damage. The transcriptomics analysis found the six hub genes with the highest values- CXCL10, CXCL2, CXCL1, IL-6, CCL-5, and CCL-4 were screened out. Functional enrichment analysis showed that the differentially expressed genes (DEGs) were mainly enriched in the inflammatory response and cytokine signaling pathway. Moreover, the quantitative RT-PCR verification experiment found the CXCL2 and CXCL1 were significantly suppressed after treatment with QFXYW. The results of protein array showed that QFXYW inhibited the multi-cytokines of OVA-induced allergic asthma via cytokine signaling pathway. CONCLUSIONS: QFXYW may have mediated OVA-induced allergic asthma mainly through the hub genes CXCL2, CXCL1, and the cytokine signaling pathway. This finding will offer a novel strategy to explore effective and safe mechanism of Traditional Chinese Medicine (TCM) formula to treat allergic asthma.

Selenomethionine ameliorates LPS-induced intestinal immune dysfunction in chicken jejunum.

Selenomethionine (SeMet) is a widely used food supplement. However, the research on the effect of SeMet on intestinal immune function is not enough. Therefore, in this experiment, SeMet was added to the diet of chickens, and lipopolysaccharide (LPS) was used as harmful stimulation to study the effect of SeMet on intestinal immune function in chickens. We chose chicken jejunum as the research object. The results showed that LPS treatment decreased the expressions of selenoproteins and induced inflammatory reaction, cytokine disorder, decreases of immunoglobulin levels, heat shock protein expression disorder, and decreases of defensin expression levels in jejunum. However, dietary SeMet can effectively alleviate the above injury caused by LPS. Our results showed that SeMet could improve the intestinal immunity in chickens, and feeding SeMet could alleviate the intestinal immune dysfunction caused by LPS. The application range of SeMet in feed can be roughly given through our experiment; i.e. 0.35-0.5 mg/kg SeMet was effective. We speculated that dietary SeMet could effectively alleviate the intestinal immune dysfunction caused by harmful stimulation and help to resist the further damage caused by harmful stimulation.

Puerarin from Pueraria lobata alleviates the symptoms of irritable bowel syndrome-diarrhea.

As a functional bowel disorder, irritable bowel syndrome (IBS), especially IBS-diarrhea (IBS-D), affects approximately 9-20% of the population worldwide. Classical treatments for IBS usually result in some side effects and intestinal microbial disorders, which inhibit the clinical effects. Natural edible medicines with beneficial effects and few side effects have received more attention in recent years. Puerarin is the main active ingredient in pueraria and has been used in China to treat splenasthenic diarrhea and as a natural food in folk medicine for hundreds of years. However, there have been no reports of using puerarin in the treatment of IBS-D, and the underlying mechanism is also still unclear. In this study, a comprehensive model that could reflect the symptoms of IBS-D was established by combining neonatal maternal separation (NMS) and adult colonic acetic acid stimulation (ACAAS) in rats. The results showed that puerarin could reverse the abdominal pain and diarrhea in IBS-D rats. The therapeutic effect was realized by regulating the richness of the gut microbiota to maintain the stabilization of the intestinal micro-ecology. Furthermore, the possible mechanism might be related to the activity of the hypothalamic-pituitary-adrenal (HPA) axis by the suppressed expression of corticotropin-releasing hormone receptor (CRF) 1. At the same time, intestinal function was improved by enhancing the proliferation of colonic epithelial cells by upregulating the expression of p-ERK/ERK and by repairing the colonic mucus barrier by upregulating occludin expression. All these results suggest that puerarin could exert excellent therapeutic effects on IBS-D.

Albicanol antagonizes Cd-induced apoptosis through a NO/iNOS-regulated mitochondrial pathway in chicken liver cells.

Cadmium (Cd) induces hepatocyte injury by oxidative stress. Albicanol is a sesquiterpenoid extracted from the medicinal plant Dryopteris fragrans that has previously been shown to exhibit anti-aging and antioxidant activity. In this study, we explored the mechanism of albicanol inhibition of the Cd-induced apoptosis of chicken hepatoma cells (LMH) by treating these cells with CdCl2 (25 µM) and/or albicanol (2.5 × 10-5 µg mL-1) for 24 h. Under Cd treatment, the research results showed that the apoptosis rate markedly increased in LMH cells. In addition, the iNOS activity and NO content increased significantly, which promoted the expressions of genes associated with the mitochondrial apoptosis pathway (Bax, CytC, Caspase-3 and Caspase-9) and inhibited the expression of Bcl-2 in this pathway. However, Cd + albicanol co-treatment significantly reduced the apoptosis rate and the expressions of iNOS and genes associated with the mitochondrial apoptosis pathway (Bax, CytC, Caspase-3 and Caspase-9), and promoted the expression of Bcl-2 in this pathway. In addition, molecular docking supported a link between the albicanol ligand and the iNOS receptor. These results indicated that albicanol can inhibit Cd-induced apoptosis by regulating the NO/iNOS-mediated mitochondrial pathway.

Apple polyphenol extract alleviates lipid accumulation in free-fatty-acid-exposed HepG2 cells via activating autophagy mediated by SIRT1/AMPK signaling.

Defective degradation of intracellular lipids induced by autophagy is causally linked to the development of non-alcoholic fatty liver disease (NAFLD). Natural agents that can restore autophagy could therefore have the potentials for clinical applications for this public health issue. Herein, we investigated the effects of apple polyphenol extract (APE) on fatty acid-induced lipids depositions in HepG2 cells. APE treatment alleviated palmitic acid and oleic acid-induced intracellular lipid accumulation, concomitant with the increased autophagy, restored lysosomal acidification, inhibited lipid synthesis and slight promotion of fatty acid oxidation. Mechanistically, APE up-regulated the expression of SIRT1, activated LKB1/AMPK pathway and inhibited mTOR signaling. Over-expressed or knock-down SIRT1 positively regulated AMPK and ATG7 expressions. SIRT1 and ATG7 knock-down impaired APE induction of improved lipid accumulation, increased intracellular TG content. Thus, APE induction of autophagy to ameliorate fatty acid-induced lipid deposition is SIRT1 dependent, APE conserved preventive potentials for clinical hepatosteatosis.

Apple polyphenols extract alleviated dextran sulfate sodium-induced ulcerative colitis in C57BL/6 male mice by restoring bile acid metabolism disorder and gut microbiota dysbiosis.

To investigate and compare the preventive effects of apple polyphenols extract (APE) with phloretin on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC), 60 male mice were treated with 125 or 500 mg/(kg bw d) APE or 100 mg/(kg bw d) phloretin, the single-ingredient of APE, for continuous 3 weeks by intragastric administration, meanwhile, mice were provided with 3% DSS dissolved in drinking water to induce UC during the third week. Both APE and phloretin significantly ameliorated DSS-induced UC by inhibiting body weight loss, preventing colon shortening and mucosa damage. Except the same mechanisms of the inhibited activation of NF-κB signaling, decreased hyodeoxycholic acid level and increased abundance of Verrucomicrobia at phylum and Bacteroides and Akkermansia at genus, APE increased ß-muricholic acid level and decreased Bacterodetes abundance, while phloretin decreased Firmicutes abundance. Furthermore, APE treatment showed much lower disease activity index score, less body weight loss and lighter spleen than phloretin. Thus, our study supported the potentiality of APE as a promising dietary intervention for the prevention of experimental UC.

Intranasal delivery of berberine via in situ thermoresponsive hydrogels with non-invasive therapy exhibits better antidepressant-like effects.

The efficacy of antidepressant therapy is frequently limited by challenges related to the potential to reach the brain. The development of new strategies to deliver more antidepressants to the brain so as to bypass the blood-brain barrier (BBB) is beneficial for the treatment of nervous system diseases, especially depression. Here, we have reported an unconventional strategy by the intranasal delivery of berberine with an in situ thermoresponsive hydrogel as the holder in the nasal cavity to improve its antidepressant-like activity. A berberine/hydroxylpropyl-ß-cyclodextrin (HP-ß-CD) inclusion complex was first prepared to improve the solubility of berberine and loaded into a thermoresponsive hydrogel system of poloxamers. A radioactive tracer of 125I-labeled berberine was used to investigate brain targeting. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was performed to study the pharmacokinetic change in the hippocampus. Monoamine neurotransmitters were analyzed in a reserpine-induced depression model, and metabolomic analysis of the hippocampus was performed in a chronic unpredictable mild stress (CUMS)-induced depression model. The radioactive tracer analysis manifested that the thermoresponsive hydrogel administered intranasally could maintain a high concentration gradient of berberine to the brain, and the relative bioavailability of berberine was enhanced approximately by 110 times that of the oral berberine/HP-ß-CD inclusion complex in the hippocampus. The thermoresponsive hydrogel system resulted in similar or better antidepressant-like efficacy even with a lower dosage in reserpine and CUMS-induced depression in rats. The pharmacometabolomics analysis revealed that in addition to increasing the hippocampal monoamine levels, berberine via intranasal administration exhibited a unique mechanism by restoring the mitochondrial dysfunction as well as phospholipid and sphingolipid abnormalities as compared to intragastric (IG) administration. We consider this a safer and more effective strategy with a lower dosage than traditional oral drugs for the treatment of depression.

Dietary citrus and/or its extracts intake contributed to weight control: Evidence from a systematic review and meta-analysis of 13 randomized clinical trials.

Randomized controlled trials, being published in English and investigating the associations of at least 4 weeks intervention of citrus and/or its extracts on weight loss among adults, were searched from PubMed, Web of Science, Scopus, and Cochrane by June 2019 to conduct a meta-analysis. Thirteen articles, including 921 participants, were selected and evaluated by modified Jadad scale. Pooled results by the random-effects model showed that citrus and/or its extracts administration significantly reduced 1.280 kg body weight (95% CI: -1.818 to -0.741, p = 0.000, I2 = 81.4%), 0.322 kg/m2 BMI (95% CI: -0.599 to -0.046, p = 0.022, I2 = 87.0%), 2.185 cm WC (95% CI: -3.804 to -0.566, p = 0.008, I2 = 98.3%), and 2.137 cm HC (95% CI: -3.775 to -0.500, p = 0.011, I2 = 96.2%), respectively, but no significantly decreased effects on WHR and body fat were observed. Subgroup analysis deduced the different effects of study location, intervention duration on body weight associated indices. No publication bias was observed. Our meta-analysis supported the beneficial effects of citrus and/or its extracts supplement on body weight control, and future well-designed studies are required to firmly establish the clinical efficacy of citrus and/or its extracts intervention on body weight.

Antagonistic effect of selenium on lead-induced neutrophil apoptosis in chickens via miR-16-5p targeting of PiK3R1 and IGF1R.

Environmental contamination by heavy metals, such as lead (Pb), can lead to severe immune dysfunction. MicroRNAs (miRNAs) are involved in regulating immunity. Whether Pb can regulate neutrophil apoptosis through miRNA, and whether selenium (Se) can antagonize this response are still unknown. We treated neutrophils with 12.5 µM (CH3OO)2Pb and 1 µM Na2SeO3 for 3 h, after which apoptosis was evaluated using acrideine orange/ethidium bromide (AO/EB) dual fluorescent staining and flow cytometry. The results showed that neutrophil apoptosis was significantly increased following Pb exposure, and that this response was prevented upon Se addition. Pb up-regulates miR-16-5p and leads to the subsequent down-regulation of the target genes phosphoinositide-3-kinase regulatory subunit 1 (PiK3R1), insulin-like growth factor 1 receptor (IGF1R), and phosphatidylinositol 3 kinase (Pi3K)-protein kinase B (AKT), followed by activation of the tumor protein P53 (P53)-B-cell lymphoma-2 (Bcl-2)/Bcl-2-Associated X protein (Bax)-cytochrome c (Cytc)-Caspase 9 (mitochondrial apoptotic pathway) and the tumor necrosis factor receptor superfamily member 6 (Fas)-Fas-associated death domain protein (Fadd)-Caspase 8 (death receptor pathway). Pb also triggered oxidative stress and indirectly activated the mitochondrial apoptotic pathway. We conclude that miR-16-5p plays a key role in the apoptosis of neutrophils exposed to Pb by down-regulating the expression of PiK3R1 and IGFR1, thereby activating the mitochondrial apoptotic pathway and death receptor pathway. Se can prevent Pb-induced apoptosis.