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Schisandrin B (Sch B) is well-known for its antitumor effect; however, its underlying mechanism remains confusing. Our study aimed to investigate the role of selenoproteins in Sch B-induced autophagy and Th1/Th2 imbalance in Hepa1-6 cells. Hepa1-6 cells were chosen to explore the antitumor mechanism and were treated with 0, 25, 50, and 100 μM of Sch B for 24 h, respectively. We detected the inhibition rate of proliferation, transmission electron microscopy (TEM), monodansylcadaverine (MDC) staining, reactive oxygen species (ROS) level and oxidative stress-related indicators, autophagy-related genes, related Th1/Th2 cytokines, and selenoprotein mRNA expression. Moreover, the heat map, principal component analysis (PCA), and correlation analysis were used for further bioinformatics analysis. The results revealed that Sch B exhibited well-inhibited effects on Hepa1-6 cells. Subsequently, under Sch B treatment, typical autophagy characteristics were increasingly apparent, and the level of punctate MDC staining enhanced and regulated the autophagy-related genes. Overall, Sch B induced autophagy in Hepa1-6 cells. In addition, Sch B-promoted ROS accumulation eventually triggered autophagy initiation. Results of Th1 and Th2 cytokine mRNA expression indicated that Th1/Th2 immune imbalance was observed by Sch B treatment in Hepa1-6 cells. Intriguingly, Sch B downregulated the majority of selenoprotein expression. Also, the heat map results observed significant variation of autophagy-related genes, related Th1/Th2 cytokines, and selenoprotein expression in response to Sch B treatment. PCA outcome suggested the key role of Txnrd1, Txnrd3, Selp, GPX2, Dio3, and Selr with its potential interactions in ROS-mediated autophagy and Th1/Th2 imbalance of Hepa1-6 cells. In conclusion, Sch B induced ROS-mediated autophagy and Th1/Th2 imbalance in Hepa1-6 cells. More importantly, the majority of selenoproteins were intimately involved in the process of autophagy and Th1/Th2 imbalance, Txnrd3, Selp, GPX2, Dio3, and Selr had considerable impacts on the process.

The aim of this study was to investigate the improving effect of Schisandrin B (Sch B) on metabolic associated fatty liver disease (MAFLD) by regulating the PPARγ signaling pathway and gut microbiota, and its mechanism in mice. Male C57BL/6 mice were fed with a high-fat diet (HFD) continuously for 16 weeks to establish a MAFLD model. The levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), and lipopolysaccharide (LPS) in serum, as well as the level of malondialdehyde (MDA), and the activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in the liver tissue were measured. Changes in the gut microbiota of mice was analyzed by 16S rRNA sequencing technology. The expression levels of PPARγ, Plin2, Pck1, Acsl4, and Fads1 proteins, as well as those of zonula occludins 1 (ZO-1) and Occludin proteins in the colon tissue were detected by Western Blot. The results showed that Sch B could alleviate the structure disorder, ballooning degeneration, inflammatory cell infiltration, liver lipid droplets, and fibrosis in liver tissue, lower the levels of AST, ALT, TG, TC, LDL-C, and LPS, increase the level of HDL-C and lower the levels of TNF-α and IL-6 in serum, increase the level of IL-10, and lower the level of MDA and increase the activities of SOD and GSH-Px in liver tissue in MAFLD mice. Sch B could increase the expression levels of PPARγ, Pck1, and Fads1 proteins, but decrease Plin2 and Acsl4 proteins in liver tissue. Sch B could improve the diversity and abundance of the gut microbiota, restore the normal composition of the gut microbiota at the phylum and genus levels, alleviate the disruption of the gut barrier caused by HFD, and enhance the expression of ZO-1 and Occludin proteins in colon tissue in MAFLD mice. This study showed Sch B can improve HFD-induced MAFLD, and the mechanism may be through regulating the PPARγ, Plin2, PCk1, Acsl4 and Fads1 signaling pathway, restoring the diversity of gut microbiota, and improving the gut barrier to delay the progression of MAFLD.

National levels of personal health-care access and quality can be approximated by measuring mortality rates from causes that should not be fatal in the presence of effective medical care (ie, amenable mortality). Previous analyses of mortality amenable to health care only focused on high-income countries and faced several methodological challenges. In the present analysis, we use the highly standardised cause of death and risk factor estimates generated through the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to improve and expand the quantification of personal health-care access and quality for 195 countries and territories from 1990 to 2015. We mapped the most widely used list of causes amenable to personal health care developed by Nolte and McKee to 32 GBD causes. We accounted for variations in cause of death certification and misclassifications through the extensive data standardisation processes and redistribution algorithms developed for GBD. To isolate the effects of personal health-care access and quality, we risk-standardised cause-specific mortality rates for each geography-year by removing the joint effects of local environmental and behavioural risks, and adding back the global levels of risk exposure as estimated for GBD 2015. We employed principal component analysis to create a single, interpretable summary measure–the Healthcare Quality and Access (HAQ) Index–on a scale of 0 to 100. The HAQ Index showed strong convergence validity as compared with other health-system indicators, including health expenditure per capita (r=0·88), an index of 11 universal health coverage interventions (r=0·83), and human resources for health per 1000 (r=0·77). We used free disposal hull analysis with bootstrapping to produce a frontier based on the relationship between the HAQ Index and the Socio-demographic Index (SDI), a measure of overall development consisting of income per capita, average years of education, and total fertility rates. This frontier allowed us to better quantify the maximum levels of personal health-care access and quality achieved across the development spectrum, and pinpoint geographies where gaps between observed and potential levels have narrowed or widened over time. Between 1990 and 2015, nearly all countries and territories saw their HAQ Index values improve; nonetheless, the difference between the highest and lowest observed HAQ Index was larger in 2015 than in 1990, ranging from 28·6 to 94·6. Of 195 geographies, 167 had statistically significant increases in HAQ Index levels since 1990, with South Korea, Turkey, Peru, China, and the Maldives recording among the largest gains by 2015. Performance on the HAQ Index and individual causes showed distinct patterns by region and level of development, yet substantial heterogeneities emerged for several causes, including cancers in highest-SDI countries; chronic kidney disease, diabetes, diarrhoeal diseases, and lower respiratory infections among middle-SDI countries; and measles and tetanus among lowest-SDI countries. While the global HAQ Index average rose from 40·7 (95% uncertainty interval, 39·0–42·8) in 1990 to 53·7 (52·2–55·4) in 2015, far less progress occurred in narrowing the gap between observed HAQ Index values and maximum levels achieved; at the global level, the difference between the observed and frontier HAQ Index only decreased from 21·2 in 1990 to 20·1 in 2015. If every country and territory had achieved the highest observed HAQ Index by their corresponding level of SDI, the global average would have been 73·8 in 2015. Several countries, particularly in eastern and western sub-Saharan Africa, reached HAQ Index values similar to or beyond their development levels, whereas others, namely in southern sub-Saharan Africa, the Middle East, and south Asia, lagged behind what geographies of similar development attained between 1990 and 2015. This novel extension of the GBD Study shows the untapped potential for personal health-care access and quality improvement across the development spectrum. Amid substantive advances in personal health care at the national level, heterogeneous patterns for individual causes in given countries or territories suggest that few places have consistently achieved optimal health-care access and quality across health-system functions and therapeutic areas. This is especially evident in middle-SDI countries, many of which have recently undergone or are currently experiencing epidemiological transitions. The HAQ Index, if paired with other measures of health-system characteristics such as intervention coverage, could provide a robust avenue for tracking progress on universal health coverage and identifying local priorities for strengthening personal health-care quality and access throughout the world. Bill & Melinda Gates Foundation.

Pancreatic cancer (PC) is a lethal malignant tumor of the digestive system with a low survival rate. Current therapies provide only modest benefits for patients and new therapeutic options are urgently needed. Schisandrin B (Sch B) has demonstrated novel antitumor activity in several preclinical models; however, its effects on PC remain unclear. In the present study, the anti-proliferative effects of Sch B in vitro were evaluated in PC cell lines. The underlying molecular mechanisms were explored using RNA sequencing, drug affinity responsive target stability (DARTS), molecular docking and small interfering RNA transfection. The antitumor effects of Sch B in vivo were evaluated using both a subcutaneous xenograft mouse model and an orthotopic genetically engineered mouse model. The in vitro studies showed that Sch B significantly inhibited the proliferation of PC cells and induced cell death in a dose-dependent manner. Mechanistically, transcriptome Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that differentially expressed genes were significantly enriched in the 'ferroptosis' signaling pathway. Sch B triggered ferroptosis by promoting iron overload, lipid peroxidation and glutathione (GSH) depletion, as well as regulating the expression of ferroptosis-related proteins [including GSH peroxidase 4, solute carrier family 3 member 2, acyl-CoA synthetase long-chain family member 4 (ACSL4), γ-glutamyl-cysteine ligase catalytic subunit and GSH synthetase]. Furthermore, pre-treatment with the ferroptosis inhibitor ferrostatin-1 partially reversed the anti-proliferative effects and ferroptosis-related events induced by Sch B. DARTS assays and molecular docking analyses confirmed the direct interaction between Sch B and ACSL4. Notably, silencing ACSL4 expression also partially reversed the anti-proliferative effects and ferroptosis-related events induced by Sch B. The in vivo studies demonstrated that Sch B suppressed tumor growth in subcutaneous xenograft models with good biosafety, and inhibited metastasis in orthotopic genetically engineered mice. In conclusion, Sch B may exert anti-proliferative effects at least partially by inducing ACSL4-dependent ferroptosis in PC.

Temozolomide (TMZ) is a standard chemotherapeutic agent for glioma, but prolonged use frequently leads to drug resistance, reducing its therapeutic efficacy. Schisandrin B (Sch B), a lignan isolated from Schisandra chinensis, demonstrates promising anti-neoplastic activity. This study investigated the synergistic effects of Sch B and TMZ on U87 glioma cells to explore their combined influence on cell viability, apoptosis, and mitochondrial function. U87 glioma cells were treated with Sch B, TMZ, or their combination. Cell viability was assessed using MTT assays. Apoptosis was evaluated by Hoechst staining and flow cytometry, while JC-1 staining and Western blotting were used to assess mitochondrial membrane potential, oxidative stress markers, and apoptosis-related proteins. Cell cycle analysis and pre-treatment with Z-VAD-FMK were performed to confirm pathway involvement. Combination treatment significantly reduced cell viability (54.14%) compared to TMZ (72.47%) or Sch B (70.4%) alone. Flow cytometry indicated elevated apoptosis (22.3%) in the combination group. JC-1 staining and protein expression analyses revealed mitochondrial depolarization, cytochrome c release, activation of caspase-3 and -9, and a decreased Bcl-2/Bax ratio. The combined treatment induced G2/M cell cycle arrest via p53/p21 activation and increased oxidative stress. Pre-treatment with Z-VAD-FMK partially reversed these effects, confirming caspase-dependent mitochondrial apoptosis. Sch B enhances TMZ-induced cytotoxicity in U87 glioma cells by promoting mitochondrial dysfunction, oxidative stress, and caspase-mediated apoptosis. These findings suggest that Sch B may serve as a promising adjuvant to improve the efficacy of TMZ-based glioma therapy, warranting further validation in resistant and models.

Neutrophils serve as critical players in the pathogenesis of liver diseases. Chemokine receptors CXCR1 and CXCR2 are required for neutrophil chemotaxis to the site of inflammation/injury and are crucial in hepatic inflammatory response. However, key mechanism of neutrophil-mediated liver injury in acute-on-chronic liver failure (ACLF) remains highly elusive; which could be targeted for the development of new therapeutic interventions. To demonstrate the role of CXCR1/CXCR2-expressing neutrophils in hepatic injury, we investigated CXCR1/CXCR2 receptor expression in 17 hepatitis B virus-related ACLF patients in comparison to 42 chronic hepatitis B and 18 healthy controls. Mechanism of neutrophil-mediated cell death was analyzed by coculture assays and correlated with the patient data. In addition, to find out any etiological-based variations in ACLF, 19 alcohol-related ACLF patients were also included. In ACLF, neutrophils have high expression of CXCR1/CXCR2 receptors, which potentially participate in hepatocyte death through early apoptosis and necrosis in contact-dependent and -independent mechanisms. Importantly, blockade of CXCR1/CXCR2 with SCH 527123 antagonist significantly reduced cell death by targeting both the mechanisms. No etiology-based differences were seen between ACLF groups. Importantly, absolute neutrophil count was particularly higher in clinically severe ACLF patients and non-survivors (  < 0.0001). Multivariate analysis demonstrated ANC and CXCL8/IL-8 as a predictor of mortality. Further, receiver operating characteristics curve confirmed the cutoff of ANC >73.5% (sensitivity: 76.5% and specificity: 76.5%) and CXCL8/IL-8 >27% (sensitivity: 70% and specificity: 73%) in prediction of mortality. Blockade of CXCR1/CXCR2 diminished the production of inflammatory mediators and reduced cell death; therefore, pharmacological neutralization of CXCR1/CXCR2 could provide novel therapeutic target in the management of ACLF.

Background: Cyclooxygenase 2 (COX-2) and matrix metalloproteinases (MMPs) have been implicated in tissue injury and fibrogenesis in animal models but little is known regarding their role in hepatitis C virus (HCV) related liver disease in humans. Aims: To characterise the intrahepatic expression pattern of COX-2 and MMPs in chronic HCV infection and determine whether HCV core and NS5A proteins could promote their expression in cultured hepatocyte derived cell lines. Patients: Thirty two anti-HCV+ and 10 anti-HCV− patients were studied. Methods: Western blot, reverse transcription-polymerase chain reaction (RT-PCR), enzyme immunoassay, and immunohistochemistry were used to assess the expression pattern of COX-2 and MMPs in liver biopsy samples from all patients. COX-2 gene expression and MMP-9 protein levels were also determined by immunoblot, RT-PCR, and luciferase assays in core and NS5A transfected hepatocyte derived cells. Results: The intrahepatic expression level of COX-2, MMP-2, and MMP-9 was significantly higher in HCV+ than in HCV− patients, increasing with the fibrotic stage of liver disease. We further demonstrated that COX-2 mRNA, protein, and activity were induced in resting and activated core and NS5A transfectants. Both viral proteins induced transcriptional activity of the COX-2 gene promoter whereas core, but not NS5A, exerted an inducer effect on MMP-9 protein levels in cultured hepatocyte derived cells. Conclusions: Intrahepatic COX-2, MMP-2, and MMP-9 overexpression is associated with progressive hepatic fibrosis in chronic HCV infection, suggesting their pathogenic role in fibrogenesis. HCV core and NS5A proteins were able to upregulate COX-2 and MMP-9 gene expression in hepatocyte derived cells, providing a potential mechanism for hepatic fibrosis during chronic HCV infection.

To investigate whether Saussurea tridactyla Sch. Bip.-derived polysaccharides and flavones exert apoptosis-inhibiting effects in ultraviolet B (UVB)-irradiated HaCaT cells. We divided HaCaT cells into low radiation UVB and high radiation UVB groups. Low radiation UVB and high radiation UVB groups were further divided into a control group, UVB radiation group (UVB group), S. tridactyla Sch. Bip.-derived polysaccharides and flavones low-dose group, and S. tridactyla Sch. Bip.-derived polysaccharides and flavones high-dose group. Cell viability and morphology were assayed by MTT and trypan blue staining. Superoxide dismutase activity, glutathione content, malondialdehyde content, and catalase activity test kits were used to detect superoxide dismutase activity, glutathione content, malondialdehyde content, and catalase activity, respectively. Cell apoptosis, intracellular Ca(2+) levels, and mitochondrial membrane potential (Δψ) were detected by flow cytometry. Protein levels were analyzed by Western blotting and immunofluorescence. S. tridactyla Sch. Bip.-derived polysaccharides and flavones were found to increase the absorbance of MTT, decrease cell death, alleviate the degree of cell edema, restore the cell morphology, reduce cell death fragments and chip phenomenon, increase superoxide dismutase activity, glutathione content, and catalase activity while decreasing the content of malondialdehyde, lowering the population of apoptotic cells, reducing the intracellular Ca(2+) fluorescence, increasing the mitochondrial membrane potential (Δψ), increasing the expressions of p-38, p-53, Bcl-2, and decreasing the expressions of Bax and active-caspase-3. S. tridactyla Sch. Bip.-derived polysaccharides and flavones can reduce cell apoptosis to protect HaCaT cells from oxidative damage after UVB irradiation; however, this effect does not occur via the p38MAPK pathway.

Obesity has escalated into a pandemic over the past few decades. In turn, research efforts have sought to elucidate the molecular mechanisms underlying the regulation of energy balance. A host of endogenous mediators regulate appetite and metabolism, and thereby control both short- and long-term energy balance. These mediators, which include gut, pancreatic and adipose neuropeptides, have been targeted in the development of anti-obesity pharmacotherapy, with the goal of amplifying anorexigenic and lipolytic signaling or blocking orexigenic and lipogenic signaling. This article presents the efficacy and safety of these anti-obesity drugs.

d-Amphetamine is known to have effects on heart rate, body temperature and locomotor activity. However, it is not known if GABAB receptor stimulation modifies these actions of d-amphetamine. Using telemetry recordings, this study examined the interactions between the GABAB receptor agonist baclofen and d-amphetamine, on heart rate responses, body temperature and locomotor activity, and whether these effects could be blocked by the GABAB receptor antagonist SCH 50911. Rats were prepared with telemetry implants, which allowed continuous monitoring of heart rate, core temperature and spontaneous locomotor activity. Drugs were subsequently administered subcutaneously to the animals for simultaneous recording over a period of 180 min. d-Amphetamine alone (0.3, 1.0 and 3.0 mg/kg) produced a dose-related increase in heart rate, but was without any effect on body temperature, whilst at 1.0 mg/kg, it significantly increased locomotor activity. Baclofen increased heart rate without affecting locomotor activity, and, at the highest dose of 10.0 mg/kg, it induced a significant reduction in body temperature. Graded doses of baclofen (3.0-10.0 mg/kg), when co-administered with d-amphetamine (1.0 mg/kg), did not modify the d-amphetamine-induced increase in heart rate, but the combination produced significant reductions of body temperature. The latter was only partially reversed by the GABAB receptor antagonist SCH 50911 (10.0 mg/kg). By contrast, the increase in locomotor activity by d-amphetamine was markedly blocked by baclofen in a dose-related manner, and this effect was abolished by SCH 50911 (10.0 mg/kg). SCH 50911 alone at doses of 3.0, 6.0 and 10.0 mg/kg had no effect on temperature or locomotor activity. Heart rate was increased significantly, but the magnitude of change was small. The results of the present study suggest that stimulation of GABAB receptors by baclofen completely blocks the locomotor stimulatory effects of d-amphetamine. Baclofen did not significantly modify the increase in heart rate produced by d-amphetamine and decreased body temperature, both alone and in combination with d-amphetamine. GABAB receptor ligands may well have potential as pharmacotherapies in the treatment of amphetamine abuse and dependence.