Glucose metabolic disorders (GMD) can promote insulin resistance (IR) and diabetes, and damage liver and kidney.
Gynostemma pentaphyllum
is commonly used in the clinical treatment of diabetes, but ...the research on its main active constituents and GMD has not been reported yet. This study explores the therapeutic potential of gypenosides of heat-processed
Gynostemma pentaphyllum
(HGyp) on high-fat diet-induced GMD in mice. HGyp was administered at different doses for 12 weeks. The investigation encompassed an array of parameters, including body weight, blood lipids, blood glucose, and liver tissue components. Metabolomic and network analyses were conducted to uncover potential targets and pathways associated with HGyp treatment. The results revealed that HGyp alleviated GMD by reducing body weight, blood glucose, and improving blood lipids levels, while increasing liver glycogen and antioxidant enzyme levels. Additionally, HGyp exhibited protective effects on liver and kidney health by reducing tissue damage. Fourteen blood components were detected by LC-MS. Metabolomic and network analyses indicated the potential engagement of the AGE-RAGE signaling pathway in the therapeutic effects of HGyp.Furthermore, Western blot and ELISA assays confirmed that HGyp upregulated GLO1 and GLUT4 while down-regulating AGEs and RAGE expression in liver tissue. In light of these findings, HGyp demonstrates promise as a potential therapeutic candidate for combating GMD, warranting further exploration in the development of therapeutic strategies or functional products.
Reportedly, nasopharyngeal carcinoma (NPC) patients with MHC I Class aberration are prone to poor survival outcomes, which indicates that the deficiency of tumor neoantigens might represent a ...mechanism of immune surveillance escape in NPC.
To clearly delineate the landscape of neoantigens in NPC, we performed DNA and RNA sequencing on paired primary tumor, regional lymph node metastasis and distant metastasis samples from 26 patients. Neoantigens were predicted using pVACseq pipeline. Subtype prediction model was built using random forest algorithm.
Portraying the landscape of neoantigens in NPC for the first time, we found that the neoantigen load of NPC was above average compared to that of other cancers in The Cancer Genome Atlas program. While the quantity and quality of neoantigens were similar among primary tumor, regional lymph node metastasis and distant metastasis samples, neoantigen depletion was more severe in metastatic sites than in primary tumors. Upon tracking the clonality change of neoantigens, we found that neoantigen reduction occurred during metastasis. Building a subtype prediction model based on reported data, we observed that subtype I lacked T cells and suffered from severe neoantigen depletion, subtype II highly expressed immune checkpoint molecules and suffered from the least neoantigen depletion, and subtype III was heterogenous.
These results indicate that neoantigens are conducive to the guidance of clinical treatment, and personalized therapeutic vaccines for NPC deserve deeper basic and clinical investigations to make them feasible in the future.
Hydrogels have been extensively investigated for their unique mechanical and ionic conductive properties. Currently, conventional hydrogels are not sufficiently durable for use and do not respond ...sensitively to environmental stimuli. Accordingly, the development of a hybrid hydrogel exhibiting self-healing ability and environmental responsiveness is of critical significance in broadening its application in smart wearable devices. For the formation of a color-changing and self-healing hybrid hydrogel, thermochromic dye microcapsules and photochromic dye microcapsules were mixed with a multi-branched polyacrylate and zinc sulphate in this study. This hybrid hydrogel exhibited an excellent sensing property, and can be applied to wearable device for monitoring the actions of human joints or faces. Even though the hybrid hydrogel was damaged during its application, the damaged parts of the hydrogel were self-repaired, which was dependent on the powerful ionic bonds and multi-hydrogen bonds among the polyacrylate, zinc ions, as well as microcapsules. Furthermore, under the synergistic effect of microcapsules and polyacrylate, the rapid change of color and current under thermal or UV stimulus facilitates monitoring human physiological health, as well as achieving adaptive camouflage. This smart hybrid hydrogel exhibiting self-healing, conductive, and color-changing properties has promising applications in human body monitoring, safety warning, adaptive camouflage, and artificial intelligence for wearable electronic devices.
A novel color-changing and self-healing hybrid hydrogel was prepared by mixing the thermochromic dye microcapsules and photochromic dye microcapsules with the multi-branched polyacrylate.
Although great success has been achieved in catalytic asymmetric hydroamination of unactivated alkenes using transition metal catalysis and organocatalysis, the development of catalytic ...desymmetrising hydroamination of such alkenes remains a tough challenge in terms of attaining a high level of stereocontrol over both remote sites and reaction centers at the same time. To address this problem, here we report a highly efficient and practical desymmetrising hydroamination of unactivated alkenes catalysed by chiral Brønsted acids with both high diastereoselectivity and enantioselectivity. This method features a remarkably broad alkene scope, ranging from mono-substituted and gem -/1,2-disubstituted to the challenging tri- and tetra-substituted alkenes, to provide access to a variety of diversely functionalized chiral pyrrolidines bearing two congested tertiary or quaternary stereocenters with excellent efficiency under mild and user-friendly synthetic conditions. The key to success is indirect activation of unactivated alkenes by chiral Brønsted acids via a concerted hydroamination mechanism.
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IJS, KILJ, NUK, UL, UM, UPUK
The density and viscosity ratios on partially liquid-filled sloshing with baffle have been investigated numerically in this study. As the key to success in the present simulation, the Coupled Level ...Set and the Volume of Fluid (CLSVOF) method and the Immersed Boundary (IB) method are used to capture gas/liquid and fluid/structure interfaces, respectively. Within the CLSVOF method, surface normal in weighting factors is calculated by the level set function, resulting in a more accurate solution. Furthermore, the Tangent of Hyperbola for INterface Capturing (THINC) coupled with the Weighted Linear Interface Calculation (WLIC) scheme is used for capturing moving interface. As a standard practice, we first validate the code by comparing it with experimental results of liquid sloshing, which involves large deformation of interface. In addition to the validation study of the present method, the problems of liquid sloshing with baffle are investigated to understand kinematics and dynamics behaviors under different density and viscosity ratios.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
palmitoylation, a reversible post-translational modification, is initiated by the DHHC family of palmitoyltransferases and reversed by several acyl protein thioesterases. However, the role ...and mechanisms for protein palmitoylation in renal fibrosis have not been elucidated. Here we show protein palmitoylation and DHHC9 were downregulated in the fibrotic kidneys of mouse models and chronic kidney disease (CKD) patients. Ablating DHHC9 in tubular cells aggravated, while inducing DHHC9 overexpression with adeno-DHHC9 transfection or iproniazid treatment protected against kidney fibrosis in male mouse models. Mechanistically, DHHC9 palmitoylated β-catenin, thereby promoted its ubiquitination and degradation. Additionally, acyl protein thioesterase 1 (APT1) was induced in the fibrotic kidneys, which depalmitoylated β-catenin, increased its abundance and nuclear translocation. Ablating tubular APT1 or inhibiting APT1 with ML348 markedly protected against unilateral ureter obstruction (UUO) or ischemia/reperfusion injury (IRI)-induced kidney fibrosis in male mice. This study reveals the regulatory mechanism of protein palmitoylation in kidney fibrosis.
Hepatitis B virus affects more than 2 billion people worldwide, 350 million of which have developed chronic hepatitis B (CHB). The genetic factors that confer CHB risk are still largely unknown. We ...sought to identify genetic variants for CHB susceptibility in the Chinese population. We undertook a genome‐wide association study (GWAS) in 2,514 CHB cases and 1,130 normal controls from eastern China. We replicated 33 of the most promising signals and eight previously reported CHB risk loci through a two‐stage validation totaling 6,600 CHB cases and 8,127 controls in four independent populations, of which two populations were recruited from eastern China, one from northern China and one from southern China. The joint analyses of 9,114 CHB cases and 9,257 controls revealed significant association of CHB risk with five novel loci. Four loci are located in the human leukocyte antigen (HLA) region at 6p21.3, including two nonsynonymous variants (rs12614 R32W in complement factor B CFB, Pmeta=1.28 × 10−34; and rs422951 T320A in NOTCH4, Pmeta = 5.33 × 10−16); one synonymous variant (rs378352 in HLA‐DOA corresponding to HLA‐DOA*010101, Pmeta = 1.04 × 10−23); and one noncoding variant (rs2853953 near HLA‐C, Pmeta = 5.06 × 10−20). Another locus is located at 20q13.1 (rs1883832 in the Kozak sequence of CD40, Pmeta = 2.95 × 10−15). Additionally, we validated seven of eight previously reported CHB susceptibility loci (rs3130542 at HLA‐C, rs1419881 at TCF19, rs652888 at EHMT2, rs2856718 at HLA‐DQB1, rs7453920 at HLA‐DQB2, rs3077 at HLA‐DPA1, and rs9277535 at HLA‐DPA2, which are all located in the HLA region, 9.84 × 10−71 ≤ Pmeta ≤ 9.92 × 10−7). Conclusion: Our GWAS identified five novel susceptibility loci for CHB. These findings improve the understanding of CHB etiology and may provide new targets for prevention and treatment of this disease. (Hepatology 2015;62:118‐128)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high morbidity and mortality. Targeting abnormal cholesterol metabolism is a potential therapeutic direction. Therefore, ...more natural drugs targeting cholesterol in HCC need to be developed. Gypenosides (Gyp), the major constituent of Gynostemma pentaphyllum, has been demonstrated to have pharmacological properties on anti-cancer, anti-obesity, and hepatoprotective. We investigated whether Gyp, isolated and purified by our lab, could inhibit HCC progression by inhibiting cholesterol synthesis. The present research showed that Gyp inhibited proliferation and migration, and induced apoptosis in Huh-7 and Hep3B cells. Metabolomics, transcriptomics, and target prediction all suggested that lipid metabolism and cholesterol biosynthesis were the mechanisms of Gyp. Gyp could limit the production of cholesterol and target HMGCS1, the cholesterol synthesis-related protein. Downregulation of HMGCS1 could suppress the progression and abnormal cholesterol metabolism of HCC. In terms of mechanism, Gyp suppressed mevalonate (MVA) pathway mediated cholesterol synthesis by inhibiting HMGCS1 transcription factor SREBP2. And the high expression of HMGCS1 in HCC human specimens was correlated with poor clinical prognosis. The data suggested that Gyp could be a promising cholesterol-lowering drug for the prevention and treatment of HCC. And targeting SREBP2-HMGCS1 axis in MVA pathway might be an effective HCC therapeutic strategy.
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•Gypenosides could suppress HCC by blocking cholesterol biosynthesis.•HMGCS1 downregulation inhibited proliferation and migration in HCC.•Mevalonate pathway was a potential target for HCC therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background & Aims To investigate diagnostic and prognostic values of sulfite oxidase (SUOX) in patients with hepatocellular carcinoma (HCC) who underwent curative resection. Methods We investigated ...immunohistochemically the expression dynamics of SUOX, aldo-ketoreductase family 1 member B10 (AKR1B10) and CD34 at different stages of HCC. The differential diagnostic performance of three markers or their combinations in high-grade dysplastic nodules (HGDNs) and well-differentiated small HCC (WD-sHCC) were investigated by logistic regression models and validated in an independent testing set. Overall survival (OS) and time to recurrence (TTR) were evaluated in 300 patients with HCC as the testing cohort, and validated in 198 patients with HCC. Results SUOX was decreased and AKR1B10 and CD34 were increased with the stepwise progression of hepatocarcinogenesis. For differential diagnosis of WD-sHCC from HGDNs, the sensitivity and specificity of the SUOX + AKR1B10 + CD34 combination for WD-sHCC detection were 93.8% and 95.2%, respectively, and overall accuracy was much higher than any of the three individual markers and two marker combinations. In addition, SUOX, but not AKR1B10 and CD34, was an independent prognostic factor for OS and TTR, and showed better correlation with OS and TTR if combined with serum α-fetoprotein (AFP) for both the testing and validation cohorts. Conclusions SUOX + AKR1B10 + CD34 combination could make a substantial contribution to hepatic immunopathological diagnosis to distinguish WD-sHCC from HGDNs. Meanwhile, SUOX combined with serum AFP may predict postoperative outcome and tumor recurrence risk.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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•Li-rich spring and ancient spring have a vital source significance to Li-rich brine.•Tectonic fissures provide a vital route for movement and influx of Li-rich fluid.•The main ...enrichment mechanisms of lithium in Kushui Lake are evaporation and mixing.•δ7Li is more effective for source tracing in catchments with shorter discharge path.•Lithium behavior is different due to various factors under each hydrological region.
Lithium-rich salt lakes have attracted much attention as important lithium resources. The source and enrichment mechanisms of lithium in salt lakes are fundamental to uncovering the genesis of brine-type lithium deposits. However, the origin of lithium in salt lakes has been controversial, especially for lithium-rich brines associated with hard rock lithium ore has not been concerned by scholars. In this study, for the first time, we investigated the lithium isotope and hydrochemical composition characteristics of a lithium-rich salt lake (Kushui Lake) and a series of surrounding water samples in the lithium pegmatites district of West Kunlun, Xinjiang, China. Hydrochemical composition shows that different samples in the basin are rich in Li, Na, and K and poor in Mg and Ca. The water chemistry of the Kushui River, the largest river within the catchment, changes from carbonate type to sulfate subtype through evaporation. The precipitate of sulfate and chloride minerals is also gradually increasing.
In addition, Li, B, Sr, Rb, Cs, U, Ti, V, Mn, Cu, Zn, Cr, Co, Ni, and REE are abnormally enriched in the rivers and lakes of the basin, especially in the spring water, which is several times higher than in the rivers. Likewise, dissolved Li and δ7Li showed ranges of 0.01–287.86 mg/L and 3.28–16.44 ‰, respectively. These data were used to determine the origin of lithium and its enrichment process in salt lakes. The results show that the source of Li in Kushui Lake is closely related to the surrounding felsic volcanic rocks, pegmatite-type lithium ore and deep fluids, whereas the water–rock interaction in the deep crust and the chemical weathering in the supergene environment play an influential role during the formation of Li-rich fluids. In addition, the spring samples in the northwestern of Kushui Lake have inherited the lithium isotopic signature of lithium-bearing source rocks from the water–rock reaction process in the deep crust, allowing us further to isolate the source of Li in the target waters. With the movement of water, lithium exhibits a trend of continuous enrichment under the influence of evaporation and mixing. At different stages of evaporation, the Li/Na ratio in water in this catchment shows a trend of increasing, decreasing, and increasing due to the adsorption of 6Li by secondary minerals and the crystallization of Na. It suggests that strong evaporation under arid conditions is the main mechanism responsible for the rapid enrichment of Li in salt lakes. Moreover, the positive relationship between Li content and the δ7Li value of rivers along the discharge path indicated that the adsorption of 6Li by secondary minerals still existed even at a minor watershed scale, resulting in the fractionation of lithium isotopes in river waters. This study may contribute to a deeper understanding of lithium sources and their enrichment processes in Li-rich salt lakes. In addition, it is also beneficial to search for new lithium resources based on the source relationships among the various lithium reservoirs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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