Annonaceous Acetogenins Synergistically Inhibit Hepatocellular Carcinoma with Sorafenib.

Sorafenib was first approved as the standard treatment for advanced hepatocellular carcinoma (HCC). Despite providing an advantage in terms of patient survival, sorafenib has shown poor clinical efficacy and severe side effects after long-term treatment. Thus, combination treatment is a potential way to increase the effectiveness and reduce the dose-limiting toxicity of sorafenib. Extracts of the seeds of Annona montana have shown synergistic antitumor activity with sorafenib, and seven annonaceous acetogenins, including three new acetogenins, muricin P (2), muricin Q (3), and muricin R (4), were isolated from the extracts by bioguided fractionation and showed synergy with sorafenib. The structures of these compounds were determined using spectroscopic and chemical methods. Annonacin (1) and muricin P (2), which reduced intracellular ATP levels and promoted apoptosis, exhibited synergistic cytotoxicity with sorafenib in vitro. In vivo, annonacin (1) displayed synergistic antitumor activity by promoting tumor cell apoptosis. Moreover, the potential mechanism of annonacin (1) was predicted by transcriptomic analysis, which suggested that SLC33A1 is a potential target in HCC. Annonacin (1) might be a novel candidate for combination therapy with sorafenib against advanced HCC.

LN-439A, a novel BAP1 inhibitor, suppresses the growth of basal-like breast cancer by degrading KLF5.

Basal-like breast cancer (BLBC) is the most malignant subtype of breast cancer because of its aggressive clinical behaviour and lack of effective targeted agents. Krüppel-like factor 5 (KLF5) is an oncogenic transcription factor that is highly expressed in BLBC. The deubiquitinase (DUB) BRCA1-associated protein 1 (BAP1) stabilizes KLF5 and promotes BLBC growth and metastasis. Therefore, pharmacological inhibition of the BAP1‒KLF5 axis is an effective therapeutic strategy for BLBC. Here, through screening, we identified a series of tetrahydro-ß-carboline derivatives that effectively reduced the protein expression of KLF5 and exhibited strong antitumour activity. Among the investigated compounds, the lead compound LN-439A presented the strongest antitumour activity and inhibitory effect on KLF5 expression. LN-439A suppressed the proliferation and migration of BLBC cells, induced G2/M arrest, and induced apoptosis. Mechanistically, LN-439A functions as a small molecule catalytic inhibitor of BAP1 by binding to the catalytic pocket of BAP1, leading to the ubiquitination and degradation of KLF5. Consistent with this finding, the overexpression of KLF5 suppressed the antitumour effects of LN-439A. In summary, LN-439A is a promising therapeutic agent for BLBC that functions by targeting the BAP1‒KLF5 axis.

A study to untangle the puzzle of urinary incontinence and frailty co-occurrence among older adults: The roles of depression and activity engagement.

AIMS: To explore the co-occurrence of urinary incontinence and frailty by testing the roles of depression and activity engagement guided by the mechanisms of common cause and interaction pathways. DESIGN: A secondary analysis of a 1-year three-wave panel data collected from older nursing home residents in China. METHODS: Changes in depression and activity engagement were regressed on urinary incontinence and frailty incidence underpinned by the common cause mechanism of chronic conditions co-occurrence, and these changes were also taken as mediators linking from frailty to urinary incontinence incidence supported by the interaction pathways' mechanism. RESULTS: A total of 348 older adults were included in this study, and 55.7% were women. The co-occurrence of urinary incontinence and frailty was found in 16.7% of the participants at baseline. Older adults with sole frailty at baseline had almost twice the rate of incident urinary incontinence (32.7%) compared with those without (16.7%) over a 1-year period. The subsample analyses showed that changes in depression and activity engagement failed to significantly predict the incidence of urinary incontinence and frailty. The mediating roles of these changes linking frailty to urinary incontinence incidence were also not statistically significant. CONCLUSION: The co-occurrence of urinary incontinence and frailty is prevalent in older nursing home residents. Older adults with frailty at baseline are more likely to develop urinary incontinence a year later. The common cause and interaction pathways mechanisms for the co-occurrence of urinary incontinence and frailty were not verified with changes in depression and activity engagement. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The phenomenon of urinary incontinence and frailty co-occurrence should be given extreme emphasis. Although statistically significant findings on the roles of depression and activity engagement were not inferred, this study provides multiple possibilities for future studies to test and depict a clear picture of this co-occurrence. IMPACT: What problem did the study address? This study was designed to test the roles of depression and activity engagement in predicting the incidence of urinary incontinence and frailty, and the mediating roles in linking frailty to urinary incontinence incidence. What were the main findings? Despite the methodological pitfalls in literature have been addressed, neither depression nor activity engagement would significantly predict the incidence of urinary incontinence and frailty in older adults. Their mediating roles in linking frailty to urinary incontinence incidence were also not significant. Where and on whom will the research have an impact? Our findings add important pieces of evidence to promote researchers' understanding and provide an important basis for untangling the puzzle of urinary incontinence and frailty co-occurrence. REPORTING METHOD: The report of this study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement guidelines. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Effects of evidence-based nursing care interventions on wound pain and wound complications following surgery for finger tendon injury.

We conducted this study aimed to examine the impact of evidence-based nursing interventions on postoperative wound pain and complications after surgery for finger tendon injury. A total of 86 patients treated for finger tendon injuries at our hospital from January 2021 to October 2023 were selected and randomly divided into an experimental group and a control group. The control group received conventional nursing care, while the experimental group received evidence-based nursing interventions. The study compared the postoperative wound pain intensity, incidence of complications and patient satisfaction with nursing care between the two groups. The analysis revealed that compared with conventional care, evidence-based nursing interventions significantly reduced the level of wound pain (p = 0.034) and the incidence of complications (4.65% vs. 18.60%, p = 0.043). It also increased patient satisfaction with the nursing care (97.67% vs. 83.72%, p = 0.026). The study indicates that the application of evidence-based nursing interventions for patients with finger tendon injuries can reduce postoperative wound pain, decrease the incidence of complications and enhance patient satisfaction with nursing care.

Prediction of biochemical nonresolution in patients with chronic drug-induced liver injury: A large multicenter study.

BACKGROUND AND AIMS: To clarify high-risk factors and develop a nomogram model to predict biochemical resolution or biochemical nonresolution (BNR) in patients with chronic DILI. APPROACH AND RESULTS: Retrospectively, 3655 of 5326 patients with chronic DILI were enrolled from nine participating hospitals, of whom 2866 underwent liver biopsy. All of these patients were followed up for over 1 year and their clinical characteristics were retrieved from electronic medical records. The endpoint was BNR, defined as alanine aminotransferase or aspartate aminotransferase >1.5× upper limit of normal or alkaline phosphatase >1.1× ULN, at 12 months from chronic DILI diagnosis. The noninvasive high-risk factors for BNR identified by multivariable logistic regression were used to establish a nomogram, which was validated in an independent external cohort. Finally, 19.3% (707 of 3655) patients presented with BNR. Histologically, with the increase in liver inflammation grades and fibrosis stages, the proportion of BNR significantly increased. The risk of BNR was increased by 21.3-fold in patients with significant inflammation compared to none or mild inflammation (p < 0.001). Biochemically, aspartate aminotransferase and total bilirubin, platelets, prothrombin time, sex, and age were associated with BNR and incorporated to construct a nomogram model (BNR-6) with a concordance index of 0.824 (95% CI, 0.798-0.849), which was highly consistent with liver histology. These results were successfully validated both in the internal cohort and external cohort. CONCLUSIONS: Significant liver inflammation is a robust predictor associated with biochemical nonresolution. The established BNR-6 model provides an easy-to-use approach to assess the outcome of chronic DILI.

Cells respond to space microgravity through cytoskeleton reorganization.

Decades of spaceflight studies have provided abundant evidence that individual cells in vitro are capable of sensing space microgravity and responding with cellular changes both structurally and functionally. However, how microgravity is perceived, transmitted, and converted to biochemical signals by single cells remains unrevealed. Here in this review, over 40 cellular biology studies of real space fights were summarized. Studies on cells of the musculoskeletal system, cardiovascular system, and immune system were covered. Among all the reported cellular changes in response to space microgravity, cytoskeleton (CSK) reorganization emerges as a key indicator. Based on the evidence of CSK reorganization from space flight research, a possible mechanism from the standpoint of "cellular mechanical equilibrium" is proposed for the explanation of cellular response to space microgravity. Cytoskeletal equilibrium is broken by the gravitational change from ground to space and is followed by cellular morphological changes, cell mechanical properties changes, extracellular matrix reorganization, as well as signaling pathway activation/inactivation, all of which ultimately lead to the cell functional changes in space microgravity.

MicroRNA-7a-5p ameliorates diabetic peripheral neuropathy by regulating VDAC1/JNK/c-JUN pathway.

AIMS: The pathogenesis of diabetic peripheral neuropathy (DPN) is complex, and its treatment is extremely challenging. MicroRNA-7a-5p (miR-7a-5p) has been widely reported to alleviate apoptosis and oxidative stress in various diseases. This study aimed to investigate the mechanism of miR-7a-5p in DPN. METHODS: DPN cell model was constructed with high-glucose-induced RSC96 cells. Cell apoptosis and viability were detected by flow cytometry analysis and cell counting kit-8 (CCK-8) assay respectively. The apoptosis and Jun N-terminal kinase (JNK)/c-JUN signalling pathway-related proteins expression were detected by Western blotting. The intracellular calcium content and oxidative stress levels were detected by flow cytometry and reagent kits. Mitochondrial membrane potential was evaluated by tetrechloro-tetraethylbenzimidazol carbocyanine iodide (JC-1) staining. The targeting relationship between miR-7a-5p and voltage-dependent anion-selective channel protein 1 (VDAC1) was determined by RNA pull-down assay and dual-luciferase reporter gene assay. The streptozotocin (STZ) rat model was constructed to simulate DPN in vivo. The paw withdrawal mechanical threshold (PTW) was measured by Frey capillary line, and the motor nerve conduction velocity (MNCV) was measured by electromyography. RESULTS: MiR-7a-5p expression was decreased, while VDAC1 expression was increased in HG-induced RSC96 cells and STZ rats. In HG-induced RSC96 cells, miR-7a-5p overexpression promoted cell proliferation, inhibited apoptosis, down-regulated calcium release, improved mitochondrial membrane potential and repressed oxidative stress response. MiR-7a-5p negatively regulated VDAC1 expression. VDAC1 knockdown improved cell proliferation activity, suppressed cell apoptosis and mitochondrial dysfunction by inhibiting JNK/c-JUN pathway activation. MiR-7a-5p overexpression raised PTW, restored MNCV and reduced oxidative stress levels and nerve cell apoptosis in STZ rats. CONCLUSION: MiR-7a-5p overexpression ameliorated mitochondrial dysfunction and inhibited apoptosis in DPN by regulating VDAC1/JNK/c-JUN pathway.

Anxiety, depression, and coping styles among patients with chronic pancreatitis in East China.

BACKGROUND: Anxiety and depression are common psychological comorbidities in patients with chronic pancreatitis (CP). There is still a lack of epidemiological studies on anxiety and depression in Chinese CP patients. This study aimed to identify the incidence and related factor of anxiety and depression among East Chinese CP patients and explore the relationship between anxiety, depression, and coping styles. METHODS: This prospective observational study was conducted from June 1, 2019 to March 31, 2021 in Shanghai, China. Patient diagnosed with CP were interviewed using the sociodemographic and clinical characteristics questionnaire, Self-rating Anxiety Scale (SAS), Self-rating Depression Scale (SDS), and Coping Style Questionnaire (CSQ). Multivariate logistic regression analysis was conducted to identify the related factors of anxiety and depression. Correlation test was preformed to analyze the correlation between anxiety, depression, and coping styles. RESULTS: The incidence of anxiety and depression in East Chinese CP patients was 22.64% and 38.61%, respectively. Patients' previous health status, level of disease coping, frequency of abdominal pain episodes, and pain severity were significantly associated with anxiety and depression. Mature coping styles (Problem solving, Seeking for help) had a positive impact on anxiety and depression, while immature coping styles (Self-blame, Fantasy, Repression, Rationalization) had negative effects on anxiety and depression. CONCLUSION: Anxiety and depression were common in patients with CP in China. The factors identified in this study may provide references for the management of anxiety and depression in CP patients.

[Related factors of endogenous erythropoietin and its association with 10-year risks of cardiovascular disease in a community-based Chinese study].

OBJECTIVE: To investigate the associated factors of endogenous erythropoietin (EPO) and its association with 10-year risks of atherosclerotic cardiovascular disease in a Chinese community-based general population. METHODS: The participants of this study were from an atherosclerosis cohort survey which was established by the Department of Cardiology, Peking University First Hospital in 2011. The cohort survey was performed in the Gucheng and Pingguoyuan communities of Shijingshan district in Beijing, China. The inclusion criteria of this study were: (1) endogenous EPO was measured; (2) health questionnaire data and other clinical data were complete; (3) participatants who had cardiovascular or cerebrovascular diseases (defined as self-reported coronary heart disease, stroke or transient ischemic attack) or anemia or estimated glomerular filtration rate (eGFR) < 60 mL/(min·1.73 m2) at baseline were excluded. Multivariate linear regression model was used to examine the associated factors of endogenous EPO. The participants were grouped into low (< 5%), moderate (5%-10%) and high risk (≥10%) groups, based on predicted 10-year cardiovascular disease risk using the prediction for atherosclerotic cardiovascular disease risk in China (China-PAR) equations. RESULTS: A total of 4 013 participants were included. Mean age of them was (55.9±8.2) years, 62.2% (n=2 496) of them were female, and 46.3% (n=1 859), 70.9% (n=2 845), 21.9% (n=879) had hypertension, dyslipidemia and diabetes, individually. The average body mass index was (26.1±3.3) kg/m2. The median of EPO level was 12.8 (9.3-17.4) IU/L and 25.1% (n=998) were at high 10-years risk of cardiovascular disease. Hemoglobin (ß=-0.05, 95%CI: -0.07 to -0.04) and eGFR ≥90 mL/(min·1.73 m2) (ß=-0.05, 95%CI: -0.07 to -0.04) were associated with lower in transformed EPO levels while hypertension (ß=0.08, 95%CI: 0.05 to 0.12) and obesity (ß=0.14, 95%CI: 0.09 to 0.18) were associated with higher in transformed EPO levels in multivariate linear regression analyses. Ten-year cardiovascular disease risks were positively associated with in transformed EPO levels (ß=0.07, 95%CI: 0.05 to 0.09). The participants at moderate and high cardiovascular disease risks had significant higher EPO levels than the low risk group (all P < 0.05). CONCLUSION: In community-based Beijing populations, endogenous EPO was associated with hemoglobin, renal function, obesity and hypertension. Individuals at high 10-years cardiovascular disease risks have higher endogenous EPO levels. Endogenous EPO may be a potential risk marker of cardiovascular disease.

[Esophageal Angiolipoma:Report of One Case and Literature Review].

Esophageal angiolipoma is a rare disease with unspecific clinical manifestations.This paper reported a case of esophageal angiolipoma confirmed by upper gastrointestinal endoscopy and summarized the clinical manifestations,endoscopic and pathological features,treatment and prognosis of the patients by reviewing the relevant literature,aiming to provide references for clinical diagnosis and treatment of this disease in the future.

Hydrogen sulfide prevents arecoline-induced neurotoxicity via promoting leptin/leptin receptor signaling pathway.

Arecoline, a major alkaloid of the areca nut, has potential toxicity to the nervous system. Our previous study reveals that the neurotoxicity of arecoline involves in inhibited endogenous hydrogen sulfide (H2 S) generation. Therefore, the present study investigated whether exogenous H2 S protects against arecoline-induced neurotoxicity and further explore the underlying mechanisms focusing on leptin/leptin receptor signaling pathway. The cell viability was measured by CCK-8 kit. The apoptosis were detected by Hoechst 33258 and Annexin V/PI (propidium iodide) staining. The protein expressions were determined by Western blot analysis. Our results demonstrated that NaHS, an exogenous H2 S donor, significantly increases the cell viability, decreases apoptosis ratio, and reduces caspase-3 activity as well as Bax/Bcl-2 ratio in PC12 cells exposed to arecoline, indicating the protection of H2 S against arecoline-induced cytotoxicity and apoptosis. Also, NaHS attenuated arecoline-induced endoplasmic reticulum (ER) stress, as evidenced by the decreases in the expressions of glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), and Cleaved caspase-12. Meanwhile, NaHS promoted leptin/leptin receptor signaling pathway in arecoline-exposed PC12 cells, as illustrated by upregulations of leptin and leptin receptor expressions. Furthermore, leptin tA, an antagonist of leptin receptor, obviously abolished the inhibitory effects of NaHS on arecoline-induced cytotoxicity, apoptosis, and ER stress in arecoline-exposed PC12 cells. Taken together, these results suggested that H2 S prevents arecoline-induced neurotoxicity via enhancing the leptin/leptin receptor signaling pathway.

Optimization of endometrial cancer organoids establishment by cancer-associated fibroblasts.

Most endometrial cancers (EC) are diagnosed at an early stage with a favorable prognosis. However, for patients with advanced or recurrent disease, the chemotherapy response rate and overall survival remain poor. A novel in vitro model, tumor organoids, has important value in providing a more individualized treatment plan for tumor patients. However, the slow growth of the established EC organoid seriously hinders the application of EC organoids. Cancer-associated fibroblasts (CAFs), the main component of tumor stroma, have been reported to promote the proliferation of endometrial cancer cell lines and primary endometrial cancer cells in vivo and in vitro. Therefore, we optimized the current endometrial cancer organoid by introducing CAFs isolated from EC lesions. Here we developed long-term expandable organoids from endometrial cancer lesions, which show disease-associated traits and cancer-linked mutations. Based on the co-culture of CAFs and endometrial cancer organoids, we found that CAFs could promote the growth of endometrial cancer organoids, might by secreting factors according to the result that CAFs could also promote the growth. Our research provided a more promising model for the basic and preclinical study of endometrial cancer.

Investigation on Potential Biomarkers and Immune-Related Mechanisms of Ischemic Stroke.

BACKGROUND: This study aimed to reveal the detailed immune-related mechanisms underlying ischemic stroke (IS) and identify new immune-associated biomarkers for clinical management. METHODS: Differentially expressed genes (DEGs) between IS samples and normal controls were identified using the GSE16561 dataset. The feature genes of the immune cells were investigated using the GSE72642 dataset. Weighted correlation network analysis (WGCNA) was performed to reveal module genes, followed by an investigation of common DEGs and a functional enrichment analysis. Potential biomarkers were identified based on hub genes in protein-protein interaction networks and WGCNA. Finally, GSE158312 was used for biomarker verification. RESULTS: In total, 1230 DEGs were identified between the IS samples and normal controls. Seven clinically significant modules were identified using WGCNA. The yellow module genes were positively correlated with polymorphonuclear cells (PMNC), whereas the brown module genes were positively correlated with CD4+ T cells. Eight genes were selected as hub genes. These genes are mainly involved in functions such as the innate immune response. Upregulated TLR2 and ARG1 levels were significantly different between the two groups in the verification dataset. CONCLUSIONS: Our findings suggest ARG1 and TLR2 as novel biomarkers for IS. Upregulated TLR2 might play a role in IS development by participating in the innate immune response function.

MDM2-Mediated Ubiquitination of RXRß Contributes to Mitochondrial Damage and Related Inflammation in Atherosclerosis.

A novel function of retinoid X receptor beta (RXRß) in endothelial cells has been reported by us during the formation of atherosclerosis. Here, we extended the study to explore the cellular mechanisms of RXRß protein stability regulation. In this study, we discovered that murine double minute-2 (MDM2) acts as an E3 ubiquitin ligase to target RXRß for degradation. The result showed that MDM2 directly interacted with and regulated RXRß protein stability. MDM2 promoted RXRß poly-ubiquitination and degradation by proteasomes. Moreover, mutated MDM2 RING domain (C464A) or treatment with an MDM2 inhibitor targeting the RING domain of MDM2 lost the ability of MDM2 to regulate RXRß protein expression and ubiquitination. Furthermore, treatment with MDM2 inhibitor alleviated oxidized low-density lipoprotein-induced mitochondrial damage, activation of TLR9/NF-κB and NLRP3/caspase-1 pathway and production of pro-inflammatory cytokines in endothelial cells. However, all these beneficial effects were reduced by the transfection of RXRß siRNA. Moreover, pharmacological inhibition of MDM2 attenuated the development of atherosclerosis and reversed mitochondrial damage and related inflammation in the atherosclerotic process in LDLr-/- mice, along with the increased RXRß protein expression in the aorta. Therefore, our study uncovers a previously unknown ubiquitination pathway and suggests MDM2-mediated RXRß ubiquitination as a new therapeutic target in atherosclerosis.

[Changes of intestinal flora in children with acute lymphoblastic leukemia before and after chemotherapy]. / å„¿ç«¥æ€¥æ€§æ·‹å·´ç»†èƒžç™½è¡€ç— åŒ–ç–—å‰åŽè‚ é“èŒç¾¤å˜åŒ–ç‰¹ç‚¹.

OBJECTIVES: To examine the changes of intestinal flora in children newly diagnosed with acute lymphoblastic leukemia (ALL) and the influence of chemotherapy on intestinal flora. METHODS: Fecal samples were collected from 40 children newly diagnosed with ALL before chemotherapy and at 2 weeks, 1 month, and 2 months after chemotherapy. Ten healthy children served as the control group. 16S rDNA sequencing and analysis were performed to compare the differences in intestinal flora between the ALL and control groups and children with ALL before and after chemotherapy. RESULTS: The ALL group had a significant reduction in the abundance of intestinal flora at 1 and 2 months after chemotherapy, with a significant reduction compared with the control group (P<0.05). Compared with the control group, the ALL group had a significant reduction in the diversity of intestinal flora before and after chemotherapy (P<0.05). At the phylum level, compared with the control group, the ALL group had a significant reduction in the relative abundance of Actinobacteria at 2 weeks, 1 month, and 2 months after chemotherapy (P<0.05) and a significant increase in the relative abundance of Proteobacteria at 1 and 2 months after chemotherapy (P<0.05). At the genus level, compared with the control group, the ALL group had a significant reduction in the relative abundance of Bifidobacterium at 2 weeks, 1 month, and 2 months after chemotherapy (P<0.05); the relative abundance of Klebsiella in the ALL group was significantly higher than that in the control group at 1 and 2 months after chemotherapy and showed a significant increase at 1 month after chemotherapy (P<0.05); the relative abundance of Faecalibacterium in the ALL group was significantly lower than that in the control group before and after chemotherapy and showed a significant reduction at 2 weeks and 1 month after chemotherapy (P<0.05). The relative abundance of Enterococcus increased significantly at 1 and 2 months after chemotherapy in the ALL group (P<0.05), and was significantly higher than that in the control group (P<0.05). CONCLUSIONS: The diversity of intestinal flora in children with ALL is significantly lower than that in healthy children. Chemotherapy significantly reduces the abundance of intestinal flora and can reduce the abundance of some probiotic bacteria (Bifidobacterium and Faecalibacterium) and increase the abundance of pathogenic bacteria (Klebsiella and Enterococcus) in children with ALL.

SIRT1 Mediates H2S-Ameliorated Diabetes-Associated Cognitive Dysfunction in Rats: Possible Involvement of Inhibiting Hippocampal Endoplasmic Reticulum Stress and Synaptic Dysfunction.

Diabetes-associated cognitive dysfunction (DACD) characterized by hippocampal injury increases the risk of major cerebrovascular events and death. Endoplasmic reticulum (ER) stress and synaptic dysfunction play vital roles in the pathological process. At present, no specific treatment exists for the prevention and/or the therapy of DACD. We have recently reported that hydrogen sulfide (H2S) exhibits therapeutic potential for DACD, but the underlying mechanism has not been fully elucidated. Silent information regulator 1 (SIRT1) has been shown to play a role in regulating the progression of diabetes and is also indispensable for memory formation and cognitive performance. Hence, the present study was performed to explore whether SIRT1 mediates the protective effect of H2S on streptozotocin (STZ)-induced cognitive deficits, an in vivo rat model of DACD, via inhibiting hippocampal ER stress and synaptic dysfunction. The results showed that administration of NaHS (an exogenous H2S donor) increased the expression of SIRT1 in the hippocampus of STZ-induced diabetic rats. Then, results proved that sirtinol, a special blocker of SIRT1, abrogated the inhibition of NaHS on STZ-induced cognitive deficits, as appraised by Morris water maze test, Y-maze test, and Novel object recognition behavioral test. In addition, administration of NaHS eliminated STZ-induced ER stress as evidenced by the decreases in the expressions of ER stress-related proteins including glucose-regulated protein 78, C/EBP homologous protein, and cleaved caspase-12 in the hippocampus, while these effects of NaHS were also reverted by sirtinol. Furthermore, the NaHS-induced up-regulation of hippocampal synapse-related protein (synapsin-1, SYN1) expression in STZ-induced diabetic rats was also abolished by sirtinol. Taken together, these results demonstrated that SIRT1 mediates the protection of H2S against cognitive dysfunction in STZ-diabetic rats partly via inhibiting hippocampal ER stress and synaptic dysfunction.

Switching from entecavir to tenofovir alafenamide for chronic hepatitis B patients with low-level viraemia.

BACKGROUND AND AIMS: About 20% of patients receiving nucleos(t)ide analogues treatment experienced low-level viraemia (LLV), which is associated with progression of liver fibrosis and high risk of hepatocellular carcinoma. We aimed to evaluate the effectiveness and safety of switching from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) in ETV-treated patients with LLV. METHODS: In this prospective study, ETV-treated patients with LLV, presented to our hospital from December 2018 to October 2019, were enrolled. Switching to TAF or continuing ETV was given. The primary effectiveness endpoint was complete virological response (CVR) at 24 weeks, and the safety endpoint was the first occurrence of any clinical adverse event during the treatment. RESULTS: Totally, 211 patients were recruited and propensity score matching (PSM) generated 75 patients in either TAF or ETV group. After PSM, baseline characteristics were balanced in two groups. After 24-week treatment, the CVR and ALT normalization in TAF group were 62.7% and 47.6%, which were higher than 9.3% and 10.5% in ETV group (OR 16.4, 95% CI 6.6-40.0, P < .001) respectively. Subgroup analysis showed that switching to TAF achieved favours CVR regardless of the status of sex, age, CHB family history, HBV DNA, HBeAg and cirrhosis, whereas alcohol consumption and diabetes mellitus might compromise the CVR of switching to TAF. Both therapies were well tolerated and had satisfying renal safety. CONCLUSIONS: For ETV-treated patients with LLV, switching to TAF is safe enough and superior compared with continuing ETV monotherapy regarding both virological and biochemical benefits.

Formaldehyde induces ferritinophagy to damage hippocampal neuronal cells.

Formaldehyde (FA) causes neurotoxicity and contributes to the occurrence of neurodegenerative diseases. However, the mechanism of FA-induced neurotoxicity has not been fully elucidated. Ferritinophagy, an autophagy process of ferritin mediated by the nuclear receptor coactivator 4 (NCOA4), is a potential mechanism of neurotoxicity. In this study, we explored whether ferritinophagy is associated with the neurotoxicity of FA. Our results showed that FA (50, 100, 200 µM; 24 h) exposure upregulated ferritinophagy in the mouse hippocampal neuronal HT22 cells, which was evidenced by the upregulated autophagic flux, the increased colocalizations of NCOA4 with ferritin heavy chain (FTH1) and NCOA4 with microtubule-associated protein 1 light chain-3B (LC3B), the augmented expression of NCOA4, and the reduced content of FTH1. We also found that FA (0.1, 1, and 10 µmol, i.c.v., 7d) administration boosted ferritinophagy in the hippocampus of Sprague-Dawley (SD) rats, which was demonstrated by the accumulated autophagosomes, the increased expressions of LC3II/I and NCOA4, and the decreased contents of p62 and FTH1 in the hippocampus. Further, we confirmed that inhibition of ferritinophagy by silencing the expression of NCOA4 decreased FA-induced toxic damage in HT22 cells. These results indicated that FA induces neurotoxicity by promoting ferritinophagy. Our findings suggest a potential mechanism insight into the FA-induced neurotoxicity, which in turn provides a new thought for the treatment of FA-related neurodegenerative diseases.

Effects of high pressure and thermal combinations on gel properties and water distribution of pork batters.

The effects of high pressure (100-500 MPa) and heated (80 °C, 25 min) combinations on gel properties, rheological characteristic and water distribution of pork batters were investigated. Compared to the only-heat, the cooking yield, a* value, hardness, cohesiveness, and chewiness of cooked pork batters treated less than 300 MPa were significantly increased (P < 0.05), meanwhile, the b* value was significantly decreased (P < 0.05). Opposite, the color and cooking yield were not significant different (P > 0.05) when over 300 MPa, except the L* value. At 300 MPa, the cooking yield, hardness, chewiness, and G' value at 80 °C of pork batter were the highest. The initial relaxation time of T21 was decreased significantly (P < 0.05), and the peak ration of P21 was increased significantly (P < 0.05) when treated at 200 and 300 MPa, that indicated the water was bound tightly and the ratio of immobilized water was increased. Overall, 300 MPa treatment and thermal combinations could improve the gel properties of pork batters.

Dietary inulin decreases circulating ceramides by suppressing neutral sphingomyelinase expression and activity in mice.

Elevated circulating levels of ceramides (Cers) are associated with increased risk of cardiometabolic diseases, and Cers may play a causative role in metabolic dysfunction that precedes cardiac events, such as mortality as a result of coronary artery disease. Although the mechanisms involved are likely complex, these associations suggest that lowering circulating Cer levels could be protective against cardiovascular diseases. Conversely, dietary fibers, such as inulin, have been reported to promote cardiovascular and metabolic health. However, the mechanisms involved in these protective processes also are not well understood. We studied the effects of inulin on lipid metabolism with a model of atherosclerosis in LDL receptor-deficient mice using lipidomics and transcriptomics. Plasma and tissues were collected at 10 days and/or 12 weeks after feeding mice an atherogenic diet supplemented with inulin or cellulose (control). Compared with controls, inulin-fed mice displayed a decreased C16:0/C24:0 plasma Cer ratio and lower levels of circulating Cers associated with VLDL and LDL. Liver transcriptomic analysis revealed that Smpd3, a gene that encodes neutral SMase (NSMase), was downregulated by 2-fold in inulin-fed mice. Hepatic NSMase activity was 3-fold lower in inulin-fed mice than in controls. Furthermore, liver redox status and compositions of phosphatidylserine and FFA species, the major factors that determine NSMase activity, were also modified by inulin. Taken together, these results showed that, in mice, inulin can decrease plasma Cer levels through reductions in NSMase expression and activity, suggesting a mechanism by which fiber could reduce cardiometabolic disease risk.