OBJECTIVES: Over 25% of the global population is affected by metabolic dysfunction-associated fatty liver disease (MAFLD), yet its pathogenesis remains unclear. Endoplasmic reticulum stress (ERS) may be involved in the onset and progression of MAFLD. Adenosine 5'-monophosphate-activated protein kinase α2 (AMPKα2), a key regulator of hepatic energy metabolism, may influence MAFLD development via ERS modulation. This study aims to investigate the role of AMPKα2 in a high-fat diet-induced MAFLD mouse model and its regulatory effect on the inositol-requiring enzyme 1 alpha (IRE1α)-c-Jun N-terminal kinase (JNK) signaling pathway. METHODS: Liver-specific AMPKα2 knockout mice on a C57BL/6 background were generated and subjected to MAFLD induction. Mice were divided into four groups: wild-type control (WT+Chow, basic diet for 12 weeks), wild-type high-fat diet (WT+HFD, high-fat diet for 12 weeks), AMPKα2 knockout control (AMPKα2 KO+Chow), and AMPKα2 knockout high-fat diet (AMPKα2 KO+HFD). Blood glucose, lipid levels, and liver function were assessed post-treatment. Liver histology was analyzed using Oil Red O, hematoxylin-eosin, Masson, and Sirius Red staining. Western blotting was used to evaluate the expression of AMPKα2, ERS markers, autophagy, apoptosis, and ferroptosis-related proteins. RESULTS: Compared with the WT+Chow group, the WT+HFD group showed significantly elevated blood glucose, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels (all P<0.01); histological analyses revealed hepatic steatosis, vacuolization, and fibrosis, with a significantly increased non-alcoholic steatohepatitis activity score (NAS) (P<0.001). Phosphorylated IRE1α and the autophagy marker microtubule-associated protein light chain (LC) 3II/LC3I were markedly upregulated, while apoptotic proteins (Cleaved-Caspase 3, BAX, Bcl-2) and ferroptosis markers (SLC7A11, GPX4) showed no significant change (P>0.05). In the AMPKα2 KO+HFD group, blood glucose, ALT, and AST levels were significantly reduced compared to the WT+HFD group. Histological improvements were observed with reduced vacuolization and lipid accumulation. Expression of p-IRE1α, JNK, and LC3II/LC3I was significantly decreased (P<0.05). CONCLUSIONS Hepatic AMPKα2 knockout alleviates high-fat induced MAFLD, potentially by inhibiting the IRE1α-JNK pathway and reducing autophagy.
Animals ; AMP-Activated Protein Kinases/physiology* ; Protein Serine-Threonine Kinases/metabolism* ; Mice, Knockout ; Diet, High-Fat/adverse effects* ; Mice, Inbred C57BL ; Mice ; Endoplasmic Reticulum Stress ; Endoribonucleases/metabolism* ; Male ; Liver/pathology* ; Non-alcoholic Fatty Liver Disease/metabolism* ; MAP Kinase Signaling System/physiology* ; Fatty Liver/metabolism* ; Signal Transduction

Influenza viruses are common pathogens causing respiratory infections in humans. Among the four seasonal influenza viruses, influenza A virus H3N2 has become the leading cause of seasonal influenza illness and death, posing a great threat to public health and the economy. Since it first emerged and caused a pandemic in 1968, H3N2 has been circulating repeatedly in human beings and continually evades host immune attack by antigenic drift, resulting in a decrease in vaccine efficacy. In this paper, the antigenic evolution of influenza A virus H3N2, the impact of antigenic evolution on the selection of vaccine strains and some models for predicting the evolution of influenza viruses were analyzed and reviewed, which paved the road for understanding the antigenic evolution of influenza virus and vaccine development.

Influenza has caused high morbidity and mortality worldwide, seriously endangering human health and life. The continuous mutation of influenza virus has brought new challenges to the prevention and treatment of influenza. Animal models provide convenience for a comprehensive understanding of influenza virus pathogenesis, transmission mechanism, vaccine development, and evaluation of therapeutic effects. The construction and use of animal models of influenza virus infection vary in different studies, and the application of different animal models also has its own characteristics. This article reviewed the current status of the construction and use of various animal models, and summarized the advantages and limitations of animal models in evaluating the efficacy of antibodies, drugs and vaccines, with the aim of providing reference for the selection and optimization of animal models in the future.

Influenza viruses are responsible for a large number of infections and deaths annually, posing a serious threat to public health. Vaccination is the most effective measure to prevent influenza virus infection. However, current seasonal influenza vaccines only protect against closely matched circulating strains. Even with extensive surveillance and annual reformulation, yearly updated vaccines are still a step behind the fast-evolving viruses, often resulting in poor matches or less effective vaccines. Due to the relatively complex evolution of influenza A viruses, it is a new idea and a new means to prevent influenza epidemics by using a series of innovative technologies to develop universal influenza vaccines that can provide extensive and long-lasting protection against influenza viruses. This review summarized the latest progress in the development of universal vaccines targeting HA in the past three years, including design methods for universal vaccines targeting HA, HA stem and other conserved epitopes, compared the advantages and disadvantages of different technologies, explored the impact of immunization programs and strategies, and discussed the potential challenges to be overcome, hoping to provide reference for the successful development of universal vaccines.

Sepsis is a critical illness with high morbidity and mortality. Anaerobic glycolysis plays an important role in the pathogenesis of sepsis. Pyruvate dehydrogenase complex (PDHC) serves as a key regulator during sepsis. With PDHC dephosphorylation and deacetylation, PDHC activity is upregulated, allowing pyruvate translocate to mitochondria in aerobic condition, preceding the production of acetyl-CoA to accelerate aerobic oxidation. Activation of PDHC improves the prognosis of sepsis through regulating the balance of lactate, release of inflammatory factors and energy metabolism. A variety of remedies can improve the prognosis of patients with sepsis by up-regulating the activity of PDHC, including dichloroacetate (DCA), vitamin B1, milrinone, tumor necrosis factor binding protein, and ciprofloxacin.This article reviews the role and the regulatory mechanism of PDHC and signal pathway in the sepsis metabolism, in order to innovate treatment for sepsis and multiple organ dysfunction.

Cardiovascular diseases are life-threatening illnesses with high morbidity and mortality. Suppressed vagal (parasympathetic) activity and increased sympathetic activity are involved in these diseases. Currently, pharmacological interventions primarily aim to inhibit over-excitation of sympathetic nerves, while vagal modulation has been largely neglected. Many studies have demonstrated that increased vagal activity reduces cardiovascular risk factors in both animal models and human patients. Therefore, the improvement of vagal activity may be an alternate approach for the treatment of cardiovascular diseases. However, drugs used for vagus nerve activation in cardiovascular diseases are limited in the clinic. In this review, we provide an overview of the potential drug targets for modulating vagal nerve activation, including muscarinic, and β-adrenergic receptors. In addition, vagomimetic drugs (such as choline, acetylcholine, and pyridostigmine) and the mechanism underlying their cardiovascular protective effects are also discussed.
Acetylcholine ; pharmacology ; Animals ; Cardiovascular Diseases ; drug therapy ; Cholinergic Agents ; therapeutic use ; Humans ; Receptors, Muscarinic ; drug effects ; Sympathetic Nervous System ; drug effects ; physiopathology ; Vagus Nerve ; drug effects ; physiopathology

Objective To study the effects of dichloroacetate (DCA) on cell colony-forming,cell invasion and cell migration of the bladder cancer cells and to study the underlying mechanism.Methods The bldder cancer cells T24 were randomly divided into two groups:the observation group and the control group.Cells in the observation groups were treated with 5 mmol/L,10 mmol/L and 20 mmol/L dichloroacetate,and the control group was treated with the same amount of dimethyl sulfoxide.Colony formation assays were detected with Giemsa staining.Cell wound scratch assay and Transwell assay were applied to evaluate the ability of the T24 cell invasion and migration.Realtime PCR and Western blot were applied to detect the expression of the epithelial-mesenchymal transition (EMT)-related marker,including E-cadherin,N-cadherin,vimentin,Snail and Slug.Results Compared with the control group,the colony formation assays of T24 cells constantly decreased along with the increased doses in the observation group(P ＜ 0.01).The cell wound scratch assay showed that the scratch width of the observation groups were significantly higher along with the increased doses and prolonged time than that in the control group (P ＜ 0.01).The transwell assay showed that the invasion ability of the observation groups were significantly discreased along with the increased doses than that in the the control group (P ＜ 0.01).The expression levels of E-cadherin mRNA and protein in combination the control group were higher than those in the the observation groups (P ＜ 0.05).However,the expression levels of N-cadherin,vimentin,Snail and Slug mRNAs and proteins in combination the control group were lower than those in the the observation groups (P ＜ 0.05).Conclusion Dichloroacetate can inhibit the colony-forming,invasion and migration of bladder cancer T24 cells,and its mechanism may inhibit the expression of epithelial mesenchymal transition in T24 cells by down-regulating the expression of nuclear transcription factor Snail and Slug.

Edong Healthcare Group is cited as an example to summarize its practice of centralized purchasing of supplies in the recent two years.In addition to a success in its process and mechanism, the authors analyzed some challenges for the purpose of furthering the group-based reform of public hospitals.

Objective: To investigate the presence of hepatitis E virus (HEV) RNA and HEV antigen (HEV-Ag) and to evaluate the infectivity of HEV in urine through a SPF rabbit model of HEV infection. Methods: Serum, fecal and urine samples collected from SPF rabbits with HEV infection were tested for viral and biochemical markers using real-time RT-PCR and ELISA. Liver and kidney biopsies were performed for observing histopathological changes and immunohistochemical staining. Rabbits were challenged with HEV isolated in urine samples to evaluate the infectivity. Results: Rabbit R1# that was injected with rabbit HEV presented viremia, fecal shedding of HEV, high serum level of HEV-Ag, elevated aspartate transaminase (AST) and alanine transaminase (ALT) and typical symptoms of hepatitis. Urine samples of rabbit R1# continued to be positive for HEV RNA and HEV-Ag. Ratios of HEV-Ag to RNA in urine samples of rabbit R1# were significantly higher than those in serum and feces samples. The parameters quantified in routine urinalysis remained within the normal ranges in rabbit R1#. However, pathological changes and the presence of HEV-Ag were observed in kidney tissues. Furthermore, serum and fecal samples that were collected from one of the two rabbits injected with rabbit R1# urine-derived HEV were HEV positive and the virus strains isolated form feces remained infective to rabbits. Conclusion HEV infection may result in kidney injury and the urine may pose a risk of transmission. HEV-Ag detection in urine may be valuable for the diagnosis of ongoing HEV infection.

Objective To analyze the practicability of using ELISA kit for the detection of hepati-tis E virus antigen ( HEV-Ag) in plasma donations and Biomex HEV seroconversion panels. Methods The HEV-Ag positive samples were screened out from 36 340 donated blood plasma samples. Real-time fluores-cent PCR was performed for the detection of HEV RNA in HEV-Ag positive samples. The open reading frame 2 (ORF2) in HEV RNA was amplified by nested RT-PCR and the amplified products were confirmed by sequencing analysis. Phylogenetic tree was constructed for HEV genotyping. Five Biomex HEV serocon-version panels were used in this study for the detection of HEV-Ag, anti-HEV antibody and HEV RNA as well as the correlation analysis between HEV-Ag and HEV RNA. Results Twenty-six out of 36 340 plasma samples (0. 07%) were positive for HEV-Ag. Of the 26 samples, 25 samples were positive for HEV RNA as indicated by the results of nested RT-PCR and 23 positive samples were confirmed by sequencing analysis. The positive rate of HEV RNA in blood plasma donators was 1 ∶ 1 580 (0. 06%). There were 17 samples of genotype 1 (74%) and 6 samples of genotype 4 (26%) according to the phylogenetic tree analysis. All of the HEV-Ag positive samples were also positive for HEV RNA as indicated by the analysis of Biomex sero-conversion panels. HEV-Ag was consistent with the peak of the HEV RNA concentration. Conclusion A close relationship between HEV-Ag and HEV RNA was observed. HEV-Ag screening could be used as a measure to reduce the risk of HEV transmission by blood transfusion.