Silent information regulator sirtuin 1 ameliorates acute liver failure via the p53/glutathione peroxidase 4/gasdermin D axis.

BACKGROUND: Acute liver failure (ALF) has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis. The silent information regulator sirtuin 1 (SIRT1)-mediated deacetylation affects multiple biological processes, including cellular senescence, apoptosis, sugar and lipid metabolism, oxidative stress, and inflammation. AIM: To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms. METHODS: This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) testing. C57BL/6 mice were also intraperitoneally pretreated with SIRT1, p53, or glutathione peroxidase 4 (GPX4) inducers and inhibitors and injected with lipopolysaccharide (LPS)/D-galactosamine (D-GalN) to induce ALF. Gasdermin D (GSDMD)-/- mice were used as an experimental group. Histological changes in liver tissue were monitored by hematoxylin and eosin staining. ALT, AST, glutathione, reactive oxygen species, and iron levels were measured using commercial kits. Ferroptosis- and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction. SIRT1, p53, and GSDMD were assessed by immunofluorescence analysis. RESULTS: Serum AST and ALT levels were elevated in patients with ALF. SIRT1, solute carrier family 7a member 11 (SLC7A11), and GPX4 protein expression was decreased and acetylated p5, p53, GSDMD, and acyl-CoA synthetase long-chain family member 4 (ACSL4) protein levels were elevated in human ALF liver tissue. In the p53 and ferroptosis inhibitor-treated and GSDMD-/- groups, serum interleukin (IL)-1ß, tumour necrosis factor alpha, IL-6, IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated. In mice with GSDMD knockout, p53 was reduced, GPX4 was increased, and ferroptotic events (depletion of SLC7A11, elevation of ACSL4, and iron accumulation) were detected. In vitro, knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels, the cytostatic rate, and GSDMD expression, restoring SLC7A11 depletion. Moreover, SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group, accompanied by reduced p53, GSDMD, and ACSL4, and increased SLC7A11 and GPX4. Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalN-induced in vitro and in vivo models. CONCLUSION: SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.

Autoimmune hepatitis-primary biliary cholangitis overlap syndrome complicated by various autoimmune diseases: A case report.

BACKGROUND: Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are two common clinical autoimmune liver diseases, and some patients have both diseases; this feature is called AIH-PBC overlap syndrome. Autoimmune thyroid disease (AITD) is the most frequently overlapping extrahepatic autoimmune disease. Immunoglobulin (IgG) 4-related disease is an autoimmune disease recognized in recent years, characterized by elevated serum IgG4 levels and infiltration of IgG4-positive plasma cells in tissues. CASE SUMMARY: A 68-year-old female patient was admitted with a history of right upper quadrant pain, anorexia, and jaundice on physical examination. Laboratory examination revealed elevated liver enzymes, multiple positive autoantibodies associated with liver and thyroid disease, and imaging and biopsy suggestive of pancreatitis, hepatitis, and PBC. A diagnosis was made of a rare and complex overlap syndrome of AIH, PBC, AITD, and IgG4-related disease. Laboratory features improved on treatment with ursodeoxycholic acid, methylprednisolone, and azathioprine. CONCLUSION: This case highlights the importance of screening patients with autoimmune diseases for related conditions.

Human placental extract suppresses mast cell activation and induces mast cell apoptosis.

BACKGROUND: Human placental extract (HPE) has been documented to facilitate the healing of certain disorders including allergy. However, the effects of HPE on the functionality of mast cells, a critical cell type in allergic diseases, have not been reported. METHODS: To investigate the effects of HPE on the regulation of allergy with respect to the biological functions of mast cells, the mast cell line C57 or HMC-1 cells were treated with HPE followed by the assessment of cell proliferation, apoptosis, activation, chemotaxis and phagocytosis. Mouse peritoneal mast cells were also investigated for their responses to induction of apoptosis by HPE in vivo. Furthermore, the effect of HPE on mast cell degranulation was confirmed using the passive cutaneous anaphylaxis (PCA) assay, an acute allergy model. RESULTS: HPE was capable of suppressing mast cell proliferation and inducing mast cell apoptosis. Mast cell degranulation in response to compound 48/80- or anti-DNP IgE and DNP-mediated activation was suppressed. In addition, treatment with HPE compromised the production of cytokines by mast cells and cell chemotaxis. These observations were consistent with the dampened passive cutaneous anaphylaxis (PCA) assay following treatment with HPE. CONCLUSION: This study revealed a suppressive effect of HPE on overall mast cell activities, suggesting a potential regulatory role of HPE on the alleviation of allergic diseases through mast cells.

Pacenta polypeptide injection alleviates the fibrosis and inflammation in cigarette smoke extracts-induced BEAS-2B cells by modulating MMP-9/TIMP-1 signaling.

Chronic obstructive pulmonary disease (COPD) has high morbidity and mortality. Here, we aimed to explore the roles and potential correlation of placenta polypeptide injection (PPI) and MMP-9/TIMP-1 signaling pathway in COPD. BEAS-2B cells were treated with cigarette smoke extract (CSE) to establish a COPD cell model in vitro. The cell survival and cytotoxic effect were measured by CCK-8, LDH release and flow cytometry assays. The inflammatory responses were determined by western blot and ELISA assay. Cell fibrosis was assessed by immunofluorescence and western blot assays. PPI treatment had no cytotoxic effect on BEAS-2B cells until the final concentration reached to 10%. In the range of 0%-8% final concentration, PPI treatment weakened CSE-induced the decrease of cell viability and the increase of LDH level in a concentration-dependent manner. Four percent PPI treatment enhanced cell viability and decreased cell apoptosis of CSE-treated cells in a time-dependent manner. Moreover, 4% PPI treatment significantly decreased inflammatory responses and fibrosis induced by CSE, while AMPA (MMPs agonist) had opposite effects. Notably, AMPA reversed the protective roles of PPI on CSE-induced inflammation and fibrosis. Mechanistically, 4% PPI treatment significantly suppressed MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, and MMP-19 levels, but enhanced TIMP-1, TIMP-2, TIMP-3, and TIMP-4 levels. Among them, MMP-9 and TIMP-1 might be the main target of PPI. PPI effectively attenuated CSE-induced inflammation and fibrosis in vitro by regulating MMP-9/TIMP-1 signaling pathway.

Prognosis of male lung cancer patients with urinary cancer: a study from a national population-based analysis.

Lung cancer accounts for the most cancer-related deaths in the world. Our previous study suggested the improved survival of lung cancer patients, mainly female patients, with subsequent metachronous primary breast cancer. However, whether the survival advantages of the two primaries are associated with patients' sex and the specific breast cancer is unclear. Whether male lung cancer patients with another primary may encounter the same survival advantage as female patients is also uncertain. The uncertainty hinders these patients from the potential benefit of lung cancer clinical trial. A total of 343 male lung adenocarcinoma patients with subsequent bladder papillary transitional cell carcinoma (LCBC), 1539 lung adenocarcinoma patients with prior bladder papillary transitional cell carcinoma (BCLC), 1181 lung adenocarcinoma patients with subsequent prostate adenocarcinoma (LCPC), 7426 lung adenocarcinoma patients with prior prostate adenocarcinoma (PCLC), and patients with single bladder/prostate/lung (SLC) cancer were identified from the Surveillance, Epidemiology, and End Results. Patients were classified into simultaneous two primary cancer (sTPC), metachronous two primary cancer 1 (mTPC1), or mTPC2 groups when interval time between two cancers was within 6 months, between 7 and 60 months, or over 60 months, respectively. Propensity matching score program was executed to match the two primary cancers with single primary. Cox regression and competing risk regression were performed to identify confounders associated with all-cause and cancer-specific survival, respectively. The major cancer-related and non-cancer-related death in the two primaries were lung cancer and heart disease, respectively. Median overall survival times since lung primary of LCBC and SLC were 97 and 17 months, respectively, and incidence of all-cause and cancer-specific death in LCBC since lung malignancy was significantly lower (Coef. - 1.24, 95% CI - 1.49 to 0.99; SHR 0.42, 95% CI 0.33-0.53). Among the categorized groups, prognosis values of sTPC and mTPC2 groups were not statically different from that of the matched single lung cancer, whereas increased overall survival time and decreased incidence of all-cause and cancer-specific death relative to the matched patients were observed in mTPC1 group (H.R 0.28, 95% CI 0.19-0.41; SHR 0.33, 95% CI 0.23-0.47). Similar prognosis of LCPC relative to SLC was also observed. Furthermore, a generally improved survival relative to SLC was observed in PCLC (median survival times of PCLC and SLC were 17 and 12 months, respectively; Coef. - 0.32, 95% CI - 0.43 to 0.22; SHR 0.77, 95% CI 0.69-0.85), whereas prognosis of BCLC was similar to the matched ones. These results hinted that survival of lung cancer patients might vary with prior cancer history. Further analysis among groups with the two primaries suggested that advanced bladder cancer was not associated with prognosis of patients with LCBC and BCLC. On the contrary, advanced prostate cancer was associated with all-cause and cancer-specific death in patients with PCLC but not in patients with LCPC. Compared with patients with single lung cancer, male lung cancer patients with subsequent bladder/prostate primary over 6 months experienced generally improved survival. These results were similar to our previous study regarding female lung cancer patients with another breast primary. On the contrary, male lung cancer patients with prior primary malignancy encountered varied prognosis: improved survival relative to single lung primary was observed in lung cancer with prior prostate cancer, whereas prognosis of lung cancer with prior bladder cancer was not different. Therefore, great attention was required to characterize prognosis of lung cancer patients with another primary in advance, which was essential to eliminate the potential bias when these patients were included into the clinical trials.

Effects of short-term waterfall forest aerosol air exposure on rat lung proteomics.

Background: Chronic exposure to airborne microparticles has been shown to increase the incidence of several chronic diseases. Previous studies have found that waterfall forest aerosols contribute to a diminished immune stress response in patients with asthma. However, the specific effects of short-term waterfall forest aerosol exposure on lung proteins have not been fully elucidated. Methods: This study used liquid chromatography-tandem mass spectrometry (LC-MS) to analyze changes in protein expression in the lungs of rats exposed to short-term waterfall forest aerosol environments. Specific protein markers were identified using bioconductivity analysis screening and validated using immunohistochemistry. Results: Waterfall forest aerosol environment exposure on day 5 downregulated the expression of the classical inflammatory pathway nuclear factor κB (NF-κB) signaling pathway. As the waterfall forest aerosol environment increased due to the duration of exposure, it was involved in oxidative phosphorylation and then hormone signaling in lung cells from the very beginning. In contrast, at day 15 of exposure, there is an effect on the regulation of the immune-related high-affinity IgE receptor pathway. In addition, iron-sulfur Rieske protein (Uqcrfs1), mitochondrial Tu translation elongation factor (Tufm) and ribosomal protein L4 (Rpl4) were identified as possible bioindicators for the evaluation of air quality. Conclusions: These results provide a comprehensive proteomic analysis that supports the positive contribution of a good air quality environment to lung health.

Protective effect of endothelial progenitor cell-derived exosomal microRNA-382-3p on sepsis-induced organ damage and immune suppression in mice.

OBJECTIVE: To explore the role of endothelial progenitor cell (EPC)-derived exosomal microRNA-382-3p (miR-382-3p) in septic injury in mice. METHODS: A murine model of sepsis was introduced by cecal ligation and puncture (CLP). The model mice were treated with EPC-derived exosomes (Exos). The lung, kidney and liver tissues of mice were collected and stained with hematoxylin and eosin. The lymphocytes in murine spleen tissues, and the proportion and phenotype of the T helper cells (Ths) were examined by flow cytometry. The exosomal miRNAs were screened using a microarray analysis. The expressions of miR-382-3p and beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) were measured to explore possible mechanism of Exos in septic injury in mice. RESULTS: EPC-derived Exos alleviated CLP-induced tissue damage in the lung, kidney and liver tissues in septic mice. They also restored the number of lymphocytes and the concentration of Ths, and reduced the imbalance in Th1 and Th2 cells in mice. The Exos mainly contained miR-382-3p, and miR-382-3p directly targeted BTRC mRNA. Either downregulation of miR-382-3p or upregulation of BTRC blocked the protective roles of Exos in septic injury and immune suppression. Overexpression of BTRC increased the phosphorylation of nuclear factor kappa B (NF-κB) inhibitor α (IκBα) and NF-κB. CONCLUSION: EPC-derived exosomal miR-382-3p alleviates sepsis-induced organ damage and immune suppression in septic mice through regulating BTRC and the IκBα/NF-κB axis.

Hydrogel-Based, Dynamically Tunable Plasmonic Metasurfaces with Nanoscale Resolution.

Flat metasurfaces with subwavelength meta-atoms can be designed to manipulate the electromagnetic parameters of incident light and enable unusual light-matter interactions. Although hydrogel-based metasurfaces have the potential to control optical properties dynamically in response to environmental conditions, the pattern resolution of these surfaces has been limited to microscale features or larger, limiting capabilities at the nanoscale, and precluding effective use in metamaterials. This paper reports a general approach to developing tunable plasmonic metasurfaces with hydrogel meta-atoms at the subwavelength scale. Periodic arrays of hydrogel nanodots with continuously tunable diameters are fabricated on silver substrates, resulting in humidity-responsive surface plasmon polaritons (SPPs) at the nanostructure-metal interfaces. The peaks of the SPPs are controlled reversibly by absorbing or releasing water within the hydrogel matrix, the matrix-generated plasmonic color rendering in the visible spectrum. This work demonstrates that metasurfaces designed with these spatially patterned nanodots of varying sizes benefit applications in anti-counterfeiting and generate multicolored displays with single-nanodot resolution. Furthermore, this work shows system versatility exhibited by broadband beam-steering on a phase modulator consisting of hydrogel supercell units in which the size variations of constituent hydrogel nanostructures engineer the wavefront of reflected light from the metasurface.

Mechanism of the Huangguoshu waterfall forest environment's promotive effect on human health in Guizhou, China.

Background: The aim of this study was to investigate the specific mechanisms underlying the human health-promoting effects of the forest environment at Huangguoshu Falls, Guizhou, China. Methods: Ninety-five participants were recruited and an eye tracker was used to record fixation and sweep indices. A questionnaire was also used to evaluate the effects of different subject environments on human emotions, perceived recovery and preferences. Thereafter, 24 participants with chronic fatigue syndrome (CFS) were recruited and the participants' fatigue and stress-related scale indices and inflammatory factor levels were examined. Serum metabolites of the participants under different time waterfall forest interventions were detected by ultra performance liquid chromatography-quadrupole-time of flight mass spectrometry (UHPLC-Q/TOF-MS). Results: Eye tracking paradigm analysis showed that the "waterfall" element was the most interesting element for participants and that the "charm" of the waterfall forest environment could be well perceived by participants. Scores on the Fatigue Scale, Anxiety Scale and Depression Scale decreased as the duration of treatment in the waterfall forest environment increased. Levels of inflammatory factors decreased after treatment in the waterfall forest environment. At the same time the level of antioxidants, represented by L-ascorbic acid, increased significantly. Conclusions: The charm of the Huangguoshu waterfall scenery could be perceived by the participants and have a positive modulating effect on mood and cognitive function. In addition, the unique mixture of negative oxygen ions in this environment can increase the content of endogenous antioxidants and balance the metabolism of choline and amino acids.

Transparent and Flexible Electromagnetic Interference Shielding Materials by Constructing Sandwich AgNW@MXene/Wood Composites.

Electromagnetic interference (EMI) shielding materials have attracted intensive attention with the increased electromagnetic pollution, which are required to possess high transparency and flexibility for applications in visualization windows, aerospace equipment, and wearable devices. However, it remains a challenge to achieve high-performance EMI shielding while maintaining excellent light transmittance. Herein, a sandwich composite is constructed by coating the core material of transparent wood (TW) with silver nanowire (AgNW)@MXene, exhibiting a maximum transmittance of 28.8% in the visible range and a longitudinal tensile strength of 47.8 MPa. The average EMI shielding effectiveness can reach up to 44.0 dB under X-band (8-12.4 GHz), ascribed to the increased absorption shielding induced by the multireflection of electromagnetic waves within microchannels of the TW layer and the interfacial polarization between AgNW and MXene. Simultaneously, large-scale EMI shielding films can be conveniently produced by our proposed method, which provides inspiration for the development of advanced EMI shielding materials for wide applications.

The monomer TEC of blueberry improves NASH by augmenting tRF-47-mediated autophagy/pyroptosis signaling pathway.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is one of the most common liver diseases and has no safe and effective drug for treatment. We have previously reported the function of blueberry, but the effective monomer and related molecular mechanism remain unclear. METHODS: The monomer of blueberry was examined by ultra performance liquid chromatography-mass spectrometry (UPLC-MS). The NASH cell model was constructed by exposing HepG2 cells to free fatty acids. The NASH mouse model was induced by a high-fat diet for 12 weeks. NASH cell and mouse models were treated with different concentrations of blueberry monomers. The molecular mechanism was studied by Oil Red O staining, ELISA, enzyme activity, haematoxylin-eosin (H&E) staining, immunohistochemistry, immunofluorescence, western blot, RNA sequencing, and qRT-PCR. RESULTS: We identified one of the main monomer of blueberry as tectorigenin (TEC). Cyanidin-3-O glucoside (C3G) and TEC could significantly inhibit the formation of lipid droplets in steatosis hepatocytes, and the effect of TEC on the formation of lipid droplets was significantly higher than that of C3G. TEC can promote cell proliferation and inhibit the release of inflammatory mediators in NASH cell model. Additionally, TEC administration provided a protective role against high-fat diets induced lipid damage, and suppressed lipid accumulation. In NASH mouse model, TEC can activate autophagy, inhibit pyroptosis and the release of inflammatory mediators. In NASH cell model, TEC inhibited pyroptosis by stimulating autophagy. Then, small RNA sequencing revealed that TEC up-regulated the expression of tRF-47-58ZZJQJYSWRYVMMV5BO (tRF-47). The knockdown of tRF-47 blunted the beneficial effects of TEC on NASH in vitro, including inhibition of autophagy, activation of pyroptosis and release of inflammatory factors. Similarly, suppression of tRF-47 promoted the lipid injury and lipid deposition in vivo. CONCLUSIONS: These results demonstrated that tRF-47-mediated autophagy and pyroptosis plays a vital role in the function of TEC to treat NASH, suggesting that TEC may be a promising drug for the treatment of NASH.

Hepatitis B virus genotype is an independent prognostic factor of telbivudine and tenofovir treatment in hepatitis B surface antigen-positive pregnant women.

To investigate whether HBV genotype influences the effect of tenofovir and telbivudine on HBV DNA and RNA levels in HBsAg-positive pregnant women. This was a retrospective study of 74 HBsAg-positive pregnant women in Guizhou of China. All patients were treated with telbivudine or tenofovir from 12 weeks of pregnancy and HBV infection to the date of delivery. Blood samples were collected at 12-24, 28-32, and 36-40 weeks of pregnancy for the measurement of genotype, HBsAg, hepatitis B e antigen (HBeAg), HBV DNA, HBV RNA, and liver function, including alanine transaminase, aspartate transaminase, total bilirubin, total bile acids, cholinesterase, alkaline phosphatase (ALP), and gamma-glutamyl transferase. All women with HBsAg were followed up. The HBV genotype was B in 64.9% and C in 35.1%. There were 37 patients of telbivudine and tenofovir group respectively. The telbivudine and tenofovir groups showed no differences in demographic and clinical characteristics, including liver function tests, HBsAg, HBeAg, log10(HBV DNA), and log10(HBV RNA). Compared with baseline (12-24 weeks), telbivudine group showed a significant increase in ALP and significant reductions in HBsAg, HBeAg, log10(HBV DNA), and log10(HBV RNA) at 36-40 weeks (p < .05). Tenofovir group exhibited a significant increase in ALP and significant reductions in HBeAg, log10(HBV DNA), and log10(HBV RNA) at 36-40 weeks, compared with baseline (p < .05). HBV genotype (B vs. C) was independently associated with HBV DNA change after therapy (p = .005). In telbivudine group, log10 (HBV DNA) increased from 3.38 (2.00-7.30) to 7.43 (4.68-8.70). In tenofovir group, log10 (HBV DNA) decreased from 7.52 (3.32-8.70) to 2.98 (2.00-5.01). HBV genotype was independently associated with HBV DNA change response to telbivudine or tenofovir in pregnant women with hepatitis B. These findings might be helpful for risk assessment regarding vertical transmission of HBV in HBeAg-positive mothers treated with nucleos(t)ide analogues.

MiR-571 affects the development and progression of liver fibrosis by regulating the Notch3 pathway.

Exploring the expression of miR-571 in patients with liver fibrosis and its role in the progression of liver fibrosis. A total of 74 patients with liver fibrosis in our institution from September to December 2018 were collected for study, and the expression of miR-571, Notch3 and Jagged1 in patients with different progressions of liver fibrosis was determined by RT-PCR and Western blot analysis. Set up Notch3 up group and Notch3 down regulated group, RT-PCR and Western blot were used to determine the effect of Notch signaling on the expression of fibrogenic factors. CCK-8, cell scratch assays, Transwell assays, flow cytometry were used to determine the effect of miR-571 on LX-2 proliferation, migration, apoptosis in human stem stellate cells, and RT-PCR, Western blot assays were performed to determine the effect of miR-571 on the Notch3 signaling pathway and the expression of profibrogenic factors. miR-571, Notch3 and Jagged1 are up-regulated in patients with liver fibrosis and is associated with the progression of liver fibrosis. Notch3 signaling pathway can promote the expression of fibroblast in human hepatic stellate cells; miR-571 can inhibit the apoptosis of human hepatic stellate cells, promote cell proliferation and migration; up regulation of miR-571 can promote the expression of Notch3 and Jagged1, and up-regulation of miR-571 also promoted the expression of related fibroblasts. MiR-571 can promote the activation of human stem cell stellate cells and the expression of fibroblast related factors through Notch3 signaling pathway.

Transforming growth factor beta-1 upregulates glucose transporter 1 and glycolysis through canonical and noncanonical pathways in hepatic stellate cells.

BACKGROUND: Hepatic stellate cells (HSCs) are the key effector cells mediating the occurrence and development of liver fibrosis, while aerobic glycolysis is an important metabolic characteristic of HSC activation. Transforming growth factor-ß1 (TGF-ß1) induces aerobic glycolysis and is a driving factor for metabolic reprogramming. The occurrence of glycolysis depends on a high glucose uptake level. Glucose transporter 1 (GLUT1) is the most widely distributed glucose transporter in the body and mainly participates in the regulation of carbohydrate metabolism, thus affecting cell proliferation and growth. However, little is known about the relationship between TGF-ß1 and GLUT1 in the process of liver fibrosis and the molecular mechanism underlying the promotion of aerobic glycolysis in HSCs. AIM: To investigate the mechanisms of action of GLUT1, TGF-ß1 and aerobic glycolysis in the process of HSC activation during liver fibrosis. METHODS: Immunohistochemical staining and immunofluorescence assays were used to examine GLUT1 expression in fibrotic liver tissue. A Seahorse extracellular flux (XF) analyzer was used to examine changes in aerobic glycolytic flux, lactate production levels and glucose consumption levels in HSCs upon TGF-ß1 stimulation. The mechanism by which TGF-ß1 induces GLUT1 protein expression in HSCs was further explored by inhibiting/promoting the TGF-ß1/mothers-against-decapentaplegic-homolog 2/3 (Smad2/3) signaling pathway and inhibiting the p38 and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. In addition, GLUT1 expression was silenced to observe changes in the growth and proliferation of HSCs. Finally, a GLUT1 inhibitor was used to verify the in vivo effects of GLUT1 on a mouse model of liver fibrosis. RESULTS: GLUT1 protein expression was increased in both mouse and human fibrotic liver tissues. In addition, immunofluorescence staining revealed colocalization of GLUT1 and alpha-smooth muscle actin proteins, indicating that GLUT1 expression was related to the development of liver fibrosis. TGF-ß1 caused an increase in aerobic glycolysis in HSCs and induced GLUT1 expression in HSCs by activating the Smad, p38 MAPK and P13K/AKT signaling pathways. The p38 MAPK and Smad pathways synergistically affected the induction of GLUT1 expression. GLUT1 inhibition eliminated the effect of TGF-ß1 on HSC proliferation and migration. A GLUT1 inhibitor was administered in a mouse model of liver fibrosis, and GLUT1 inhibition reduced the degree of liver inflammation and liver fibrosis. CONCLUSION: TGF-ß1 induces GLUT1 expression in HSCs, a process related to liver fibrosis progression. In vitro experiments revealed that TGF-ß1-induced GLUT1 expression might be one of the mechanisms mediating the metabolic reprogramming of HSCs. In addition, in vivo experiments also indicated that the GLUT1 protein promotes the occurrence and development of liver fibrosis.

Thymosin beta 4 alleviates non-alcoholic fatty liver by inhibiting ferroptosis via up-regulation of GPX4.

Thymosin beta 4 (Tß4) can improve the liver fibrosis and reduce inflammation, while the role of Tß4 in non-alcoholic fatty liver disease (NAFLD) whether mediated by ferroptosis remains unclear. A rat model of NAFLD was established on a high-fat diet (HFD), and rats were assigned ferroptosis inducer erastin and inhibitor Ferrostatin 1 (Fer-1). Subsequently, histopathology of the liver and the expression of ferroptosis-related genes in rat liver were detected. The steatosis of LO2 cells was induced by palmitic acid (PA) to reproduce the results of the rat experiment. The small interfering RNA (siRNA) was used to interfere with GPX4 expression to explore the influence on Tß4 function. Tß4 improved the inflammation, biochemical and lipid metabolism indexes, increased the antioxidant level, and inhibited abnormal accumulation of intracellular reactive oxygen species in HFD-induced NAFLD rats. Also, Tß4 improved PA-induced LO2 damage and inhibited apoptosis of PA-induced LO2 cells. Both in vivo and in vitro, Tß4 regulated expression of genes associated with ferroptosis, and Fer-1 treatment exaggerated the above effects of Tß4, while erastin attenuated the protective effect of Tß4. Moreover, siRNA GPX4 attenuated the protective effect of Tß4 on the rat liver and on the mitochondrial membrane integrity of LO2 cells. Interfered expression of GPX4 with siRNA also regulated the expression of Bcl-2, Bax, Caspase-3 and SOD1, which attenuated therapeutic effect of Tß4 on rat liver and LO2 cells. This study revealed that Tß4 protects hepatocytes by inhibiting the GPX4-mediated ferroptosis pathway, which provides a new strategy and target for the treatment of NAFLD.

Survival analysis of patients with primary breast duct carcinoma and lung adenocarcinoma: a population-based study from SEER.

The appeal to enroll patients with primary breast and lung cancer in clinical trials is increasing, but survival of these two primary cancers remains to be elucidated. This study analyzed the prognosis of primary breast duct carcinoma with subsequent lung adenocarcinoma (BCLA) and primary breast duct carcinoma with prior lung adenocarcinoma (LABC). Cohorts of 3,515 patients with BCLA and 654 patients with LABC were identified from the Surveillance, Epidemiology, and End Results database. Patients were classified into simultaneous two primary cancer (sTPC), metachronous two primary cancer (mTPC1), or mTPC2 groups when the interval times between breast and lung cancer were within 6 months, between 7 and 60 months, or over 60 months, respectively. The propensity score matching program (PSM) was applied to determine the survival of BCLA/LABC relative to single breast/lung cancer. Cox proportional hazard regression model and competing risk modes were performed to identify confounders associated with all-cause and cancer-specific death, respectively. Survival of patients with LABC/BCLA relative to single breast/lung cancer was accessed via median survival time. The survival of patients with BCLA/LABC was generally poor compared with the survival of those with single breast cancer. The PSM-estimated HR in the sTPC group with BCLA and in the mTPC1 and mTPC2 groups with LABC were 0.75 (95% CI 0.62-0.90), 0.52 (95% CI 0.27-0.98), and 0.36 (95% CI 0.20-0.65), respectively, whereas the SHRs were 0.80 (95% CI 0.66-0.97), 0.68 (95% CI 0.34-1.34), and 0.46 (95% CI 0.27-0.80), respectively, compared with those in the single lung cancer group. By contrast, the survival rates of the remaining patients did not differ. The median survival times since secondary malignancy were 42, 23, and 20 months in the sTPC, mTPC1, and mTPC2 groups with BCLA, respectively, and 18, 60, and 180 months in those with LABC, respectively. For patients with BCLA, the adjusted Cox regression suggested incidences of all-cause deaths in mTPC1group were statically higher than those in sTPC group, whereas the incidences of all-cause and cancer-specific death in the mTPC1 and mTPC2 groups were statistically lower than those in the sTPC group. The prognosis of patients with breast cancer and subsequent lung cancer of over 18 months was not significantly different than that of single lung cancer, which supported the profound appeal to increase the involvement of these two primary cancers in potential beneficial clinical trials. For patients with lung cancer and prior breast cancer of within 6 months and subsequent breast cancer of over 18 months, prognosis was improved relative to single lung cancer. Therefore, additional attention is needed to eliminate the potential bias may when these patients are recruited in the clinical trials.

Association of central obesity with hepatocellular carcinoma in patients with chronic hepatitis B receiving antiviral therapy.

BACKGROUND: Obesity is typically associated with metabolic dysfunction, but its impact on hepatocellular carcinoma (HCC) remains unclear in patients with chronic hepatitis B (CHB). AIM: To study the effect of obesity on HCC development in patients with CHB receiving antiviral therapy. METHODS: We included patients from a Chinese multicentre, prospective, observational, treated CHB cohort in this study. General obesity was evaluated by body-mass index (BMI). Central obesity was evaluated by waist circumference, waist-to-hip ratio and waist-to-height ratio. RESULTS: A total of 5754 nucleos(t)ide analogue treated patients were enrolled in the analysis. The 5-year cumulative incidence of HCC was 2.9%. Waist-to-height ratio performed better in predicting HCC development than BMI, waist circumference or waist-to-hip ratio. Patients with central obesity (defined as waist-to-height ratio >0.5) had significantly higher 5-year incidence of HCC than those without central obesity in the overall population (3.9% vs 2.1%, hazard ratio [HR]: 2.06, P = 0.0001) and 745 propensity score matched pairs (4.7% vs 2.3%, HR: 2.04, P = 0.026), respectively. Besides cirrhosis status and aMAP HCC risk score, central obesity was also independently associated with HCC risk (HR: 1.63, P = 0.013). Waist-to-height ratio gain within 1 year was associated with a significantly higher HCC risk with an adjusted HR value of 1.88 (95% confidence interval: 1.12-3.13, P = 0.017). CONCLUSIONS: Central obesity, evaluated by the waist-to-height ratio, was associated with a twofold increase in HCC risk among CHB patients receiving antiviral treatment, highlighting the important role of abnormal metabolic function in the progression of liver disease.

Waterfall Forest Environment Regulates Chronic Stress via the NOX4/ROS/NF-κB Signaling Pathway.

Background: Forest therapy has been proven to have beneficial effects on people with depression and anxiety. However, it remains unknown whether the waterfall forest environment (WF) affects the physical and psychological health of patients with chronic fatigue and how the WF regulates chronic stress. Methods: Twenty-four patients with chronic fatigue were randomly divided into two groups: the WF group and the urban (U) group. Scores on the Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), and Fatigue Scale-14 (FS-14) were evaluated before and after environmental intervention. Detection of physiological indexes and inflammatory factor levels and immunological analysis were also performed. In addition, the chronic stress rat model was constructed, and the effects of the WF on hopelessness and liver damage of rats were investigated. Results: Patients with chronic fatigue in the WF group showed a significant decrease in FS-14, HAMA, and HAMD scores compared with the U group. The expression levels of glutathione peroxidase and superoxide dismutase were remarkably higher in the WF group than in the U group. However, the expression levels of malondialdehyde and inflammatory factors (IL-1ß, TNF-α, IL-6, and IL-10) were remarkably decreased after the intervention of the WF. In addition, animal experiments confirmed that the WF improved hopelessness, liver damage, and excitability of neurons of chronic stress rats. Mechanistically, the WF reduced the liver damage caused by chronic stress in rats by inhibiting the NOX4/ROS/NF-κB signaling pathway. Conclusions: Collectively, the WF had a positive effect on immune enhancement and physical and psychological health in patients with chronic fatigue and might inhibit chronic stress by regulating the NOX4/ROS/NF-κB signaling pathway.

Integrative proteomic and lipidomic analysis of Kaili Sour Soup-mediated attenuation of high-fat diet-induced nonalcoholic fatty liver disease in a rat model.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease and is characterized by excessive fat accumulation. Kaili Sour Soup, a food typical of Guizhou Province, is believed to have significant health benefits. Thus, we aimed to identify and assess the impact of Kaili Sour Soup on NAFLD and its underlying mechanism using integrative proteomic and lipidomic analysis. METHODS: A high-fat diet and male Wistar rats were used to construct a NAFLD rat model. Haematoxylin and eosin (HE) and Oil Red O staining analyses were used to perform the histologic examination. Proteomic analysis was utilized to systematically identify the global protein profile in NAFLD with and without Kaili Sour Soup treatment. Western blot assays were used to verify the expression of proteins screened by proteomic analysis. Lipidomic analysis was performed to screen lipid metabolism in NAFLD with and without Kaili Sour Soup treatment. RESULTS: Kaili Sour Soup alleviated high-fat diet (HFD)-induced fatty liver and had a normalizing effect on physiological and biochemical indicators of NAFLD, including body weight, liver weight, liver index, total cholesterol (TC), triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and insulin resistance level of homeostasis model assessment (HOMA-IR). Kaili Sour Soup decreased the levels of 13 proteins (Tmem44, Rnaseh2b, Gstm6l, LOC100910877, Rufy4, Slc12a2, Pcif1, P4503A1, Sult1e1, Nop53, AABR07065656.4, AABR07065789.3) that were upregulated by HFD and increased the levels of 3 proteins (Sult1c2, Sult1c2a, Snrnp48) that were downregulated by HFD. Kaili Sour Soup attenuated the HFD-induced increase in acyl carnitine (AcCa) and enhanced the HFD-induced decreases in gangliosides (GM3) and lysophosphatidylserine (LPS) in the NAFLD rat model. CONCLUSIONS: Altogether, this study revealed that Kaili Sour Soup attenuated HFD-induced fatty liver and systematically identified abnormal proteins and lipids involved in the role of Kaili Sour Soup in a NAFLD rat model.