Background: Influenza A virus (IAV) is a negative-sense RNA virus of the Orthomyxoviridae family and is the etiological agent of a highly contagious acute respiratory disease that can lead to acute lung injury. Objective: To elucidate the molecular mechanisms of IAV infection, an integrative research approach combining gene expression profiling, multinetwork analysis, and in vivo experimental validations was employed. Methods: First, a series of network-based analyses were performed, including protein-protein interaction network construction, weighted gene co-expression network analysis, and subsequent gene set enrichment analysis, to identify the major underlying mechanisms of IAV infection. Following gene expression analysis, core targets, both direct and indirect regulators, were screened. An IAV (H1N1) strain A/PR/8/34-induced acute lung injury mouse model was constructed for in vivo validations. Batch one included two groups to evaluate findings from the multi-network analysis: Mock (n = 10; 5 males and 5 females) and IAV (n = 10; 5 males and 5 females). Batch two included three groups to assess the role of toll-like receptor 3 (TLR3) in IAV infection: Mock (n = 6; 3 males and 3 females), IAV (n = 6; 3 males and 3 females), and TLR3 inhibitor (n = 6; 3 males and 3 females). Body weight was measured on days 0, 3, and 5 after infection. On day 5, lung tissues were collected to assess viral load and histopathological changes. Key targets were examined using enzyme-linked immunosorbent assay, Western blotting, and immunofluorescence staining, both in sera and lung tissues. Results: IAV infection was significantly associated with dysregulation of the immune-inflammation system, such as the LTR, nucle-otide-binding oligomerization domain-(NOD) like receptor, retinoic acid-inducible gene I-like receptor, and nuclear factor kappa-B signaling pathways. Gene set enrichment analysis further indicated that the TLR and necroptosis signaling pathways played crucial roles in the progression of IAV infection (TLR signaling pathway normalized enrichment score = 2.3941, P = 1.00 × 10 ⁻¹⁰; necroptosis normalized enrichment score = 1.9421, P = 6.21 × 10 ⁻⁷). Among the core targets, TLR3 and mixed lineage kinase domain-like protein (MLKL) may regulate gene expression at the transcriptional level (all P < 0.05). In vivo validation using an IAV (PR8) infected acute lung injury mouse model demonstrated increased viral load and lung index, alveolar structural damage, and inflammatory cell infiltration. Immunofluorescence staining exhibited large gaps in Lamin B1 staining and breaches in Emerin signals following IAV-PR8 infection. Expression levels of TLR3, p-receptor-interacting serine/threonine-protein kinase 3 (RIPK3)/RIPK3, and p-mixed lineage kinase domain-like protein (MLKL)/MLKL proteins in lung tissues, as well as proinflammatory factors and mediators in sera, were significantly elevated after IAV infection. Moreover, enhanced neutrophil infiltration (myeloperoxidase) and citrullinated histone H3 (a neutrophil extracellular trap-specific marker), both established indicators of neutrophil extracellular trap formation, were observed. Notably, treatment with a TLR3 inhibitor significantly ameliorated IAV-induced acute lung injury by regulating necroptosis-related targets. Conclusion: Our study provides network-based in vivo evidence that TLR3-receptor-interacting serine/threonine-protein kinase 3-MLKL-mediated necroptosis may underlie IAV-induced acute lung injury and could serve as a potential therapeutic target in severe influenza cases.

As new evidence emerges, treatment strategies toward the functional cure of chronic hepatitis B are evolving. In 2019, a panel of national hepatologists published a Consensus Statement on the functional cure of chronic hepatitis B. Currently, an international group of hepatologists has been assembled to evaluate research since the publication of the original consensus, and to collaboratively develop the updated statements. The 2.0 Consensus was aimed to update the original consensus with the latest available studies, and provide a comprehensive overview of the current relevant scientific literatures regarding functional cure of hepatitis B, with a particular focus on issues that are not yet fully clarified. These cover the definition of functional cure of hepatitis B, its mechanisms and barriers, the effective strategies and treatment roadmap to achieve this endpoint, in particular new surrogate biomarkers used to measure efficacy or to predict response, and the appropriate approach to pursuing a functional cure in special populations, the development of emerging antivirals and immunomodulators with potential for curing hepatitis B. The statements are primarily intended to offer international guidance for clinicians in their practice to enhance the functional cure rate of chronic hepatitis B.

Gastric cancer remains one of the most prevalent and lethal malignancies of the digestive tract worldwide,underscoring the urgent need for more effective targeted therapeutic strategies.Poly(ADP-ri-bose)polymerase(PARP)inhibitors have demonstrated remarkable efficacy in tumors with homologous recombination repair(HRR)deficiency;however,their clinical application in gastric cancer remains limited.Clinical evidence suggests that patients harboring Helicobacter pylori infection in combination with HRR gene mutations exhibit a significantly elevated risk of developing gastric cancer,thereby supporting the potential benefit of PARP inhibition in this setting.In this study,a kinase inhibitor library was screened in combination with the PARP inhibitor olaparib in gastric cancer cells.And we identify the cy-clin-dependent kinase 8/19(CDK8/19)inhibitor Senexin A as a compound that synergistically enhances the cytotoxic effect of PARP inhibition(P<0.05).Phenotypic validation using CCK-8 and colony for-mation assays demonstrated that the combination treatment significantly suppressed cellular proliferation and clonogenic potential compared to either monotherapy(P<0.0001).Mechanistically,alkaline comet assays revealed a significant increase in DNA damage in the combination treatment group relative to either single-agent group(P<0.0001),suggesting that the synergistic effect results from the exacerbation of DNA damage via impaired DNA repair mechanisms.In addition,treatment with CDK8/19 inhibitors a-lone markedly increased the formation of γH2AX and 53BP1 foci in irradiated gastric cancer cells(P<0.0001),indicating inhibition of DNA damage repair pathways.Transcriptome sequencing further re-vealed that CDK8/19 inhibition impacts critical cellular pathways,including DNA repair,cell cycle reg-ulation,and RNA splicing.Co-immunoprecipitation assays confirmed that inhibition of CDK8/19 kinase activity significantly reduces the phosphorylation level of PARP1,suggesting a potential regulatory inter-action.Immunohistochemical analysis of tumor and adjacent non-tumor tissues from gastric cancer pa-tients demonstrated that CDK8 is significantly overexpressed in tumor tissues,supporting its potential as both a prognostic biomarker and a therapeutic target.Collectively,this study elucidates a mechanistic ba-sis by which CDK8/19 inhibition enhances the sensitivity of gastric cancer cells to PARP inhibitors.These findings provide a strong rationale for the combined use of CDK8/19 and PARP inhibitors as a tar-geted therapeutic strategy and offer promising translational implications for advancing personalized medi-cine in gastric cancer treatment.

Magnesium(Mg)-based bone implants have emerged as a promising candidate in bone regeneration due to their elastic modulus matching natural bone,favorable biodegradability,and biocompatibility.The degradation-derived magnesium ions(Mg2+)promote angiogenesis through multifaceted molecular mechanisms,thereby accelerating bone healing.This review systematically elucidates key pathways by which Mg2+regulates vascularization:① Activation of the CGRP-FAK-VEGF signaling axis via dorsal root ganglia-mediated neurovascular coupling;② Stabilization of HIF-1α through inhibiting VHL-mediated ubiquitination degradation and activating MagT1/TRPM7 ion channels,thereby enhancing VEGF transcription;③ Modulation of Notch signaling to drive vascular endothelial differentiation of bone marrow mesenchymal stem cells(BMSCs);④The activation of PI3K/AKT signaling pathway enhances endothelial nitric oxide synthase(eNOS)activity,leading to increased nitric oxide(NO)production which subsequently promotes endothelial cell proliferation and migration;⑤Immunomodulatory effects via macrophage M2 polarization and subsequent secretion of angiogenic factors;⑥stimulation of PDGF-BB secretion from MC3T3-E1 pre-osteoblasts.Notably,Mg2+exhibits concentration-dependent pro-angiogenic effects(optimal range:1-10 mM)and specifically enhances type H vessel formation,which critically couples angiogenesis with osteogenesis to boost bone regeneration efficiency.

Objective To investigate the effect and mechanism of long non-coding RNA(lncRNA)NRON on myocardial fibrosis in mice with myocardial infarction(MI).Methods Thirty-two C57/BL6 mice were randomly assigned to a Sham group,MI group,MI+shNRON group or MI+NC group,with eight mice in each group.The expression level of lncRNA NRON in myocardial tissue of mice was detected by real-time quantitative PCR.Hematoxylin and eosin staining,Masson's trichrome staining,and immunohistochemistry were used to detect the degree of myocardial injury,myocardial fibrosis,and the expression level of collagen Type Ⅰ(col Ⅰ).Western blotting was used to detect the protein expression levels of TGF-β1,p-Smad2,and p-Smad3 in myocardial tissue of the mice.Results Compared with the Sham group,the expression of NRON,col Ⅰ,TGF-β1,p-Smad2,and p-Smad3 proteins were increased in the MI group.Compared with the MI group,the expression of NRON,the degree of myocardial damage and fibrosis,the expression of col Ⅰ,TGF-β1,p-Smad2,and p-Smad3 proteins were decreased in the MI+shNRON group.Conclusion Down-regulation of lncRNA NRON can alleviate myocardial injury and inhibit myocardial fibrosis in mice with MI,and the molecular mechanism may be related to inhibition of the TGF-β/Smad signaling pathway.

Aim To investigate the effects of sodium lactate(NALA)on right heart failure induced by monocrotaline(MCT)-induced pulmonary arterial hy-pertension in rats and to reveal the underlying mecha-nisms.Methods Forty male Sprague-Dawley(SD)rats were randomly allocated into four groups,with ten rats in each group,namely,MCT group,NALA group,and NALA+MCT group;the MCT and NALA+MCT groups were administered a single intraperito-neal injection of MCT at 60 mg·kg-1 to induce pul-monary hypertension,and one week later,the NALA and NALA+MCT groups received intraperitoneal in-jections of NALA at 0.1 g·kg-1(once a day,for 5 weeks),while the CON and MCT groups received e-qual volumes of physiological saline(once a day,for 5 weeks);right heart function was assessed using echo-cardiography,right ventricular and pulmonary artery remodeling were evaluated via histopathological sec-tions,and the expression levels of ANP,BNP,and in-flammatory factors were measured by ELISA,along with assessments of oxidative stress levels,Western blot detection of the expression levels of proteins in the TLR4/NF-κB signaling pathway.Results Compared to the CON group,the MCT group exhibited increased RVSP and RVHI,decreased right heart function,in-creased collagen fiber deposition,and elevated oxida-tive stress and inflammatory factor expression,and the expression levels of proteins in the TLR4/NF-κB signa-ling pathway increased(P＜0.05);compared to the MCT group,the NALA+MCT group showed reduced RVSP and RVHI,improved right heart function,atten-uated pulmonary vascular remodeling,decreased ex-pression of ANP,BNP,inflammatory factors,and H2O2,along with increased antioxidant enzyme expres-sion,and the expression levels of proteins in the TLR4/NF-κB signaling pathway decreased(P＜0.05).Conclusion NALA can inhibit right ventric-ular remodeling in rats with pulmonary hypertension,and the underlying mechanism may involve the allevia-tion of inflammatory responses and oxidative stress through the inhibition of the TLR4/NF-κB signaling pathway.

Objective:To explore the expression of T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3), mitotic arrest deficient 2-like protein 1 (MAD2L1), and microRNA-203a-3p (miR-203a-3p) in colorectal cancer tissues and their relationship with prognosis.Methods:The clinicopathological data of 113 patients with colorectal cancer who underwent radical surgery in Zhengzhou Central Hospital Affiliated to Zhengzhou University from Jan. 2021 to Dec. 2021 were retrospectively analyzed. Both cancer tissues and adjacent tissues were collected postoperatively for the detection of Tim-3, MAD2L1, and miR-203a-3p. Patients were followed up for 3 years, and their prognosis was recorded and divided into a survival group (84 cases) and a death group (29 cases). Univariate and multivariate Cox regression analyses were performed to investigate the factors influencing the prognosis of colorectal cancer patients. Kaplan-Meier survival curves were used to analyze the prognostic significance of Tim-3, MAD2L1, and miR-203a-3p expression.Results:The high expression rates of Tim-3 and MAD2L1 in colorectal cancer group were higher than those in adjacent tissues ( P < 0.05), while the expression of miR-203a-3p was lower than that in adjacent tissues ( P < 0.05). Kaplan-Meier survival curve showed that the 3-year survival rate of patients with high expression of Tim-3 and MAD2L1 was lower than that of patients with low expression ( P < 0.05), while the 3-year survival rate of patients with high expression of miR-203a-3p was higher than that of patients with low expression of miR-203a-3p ( P < 0.05). Cox regression analysis showed that TNM stage III-IV, low differentiation of tissue grade, lymph node metastasis, high expression of Tim-3 and MAD2L1, and low expression of miR-203a-3p were risk factors for poor prognosis in patients with colorectal cancer ( P < 0.05) . Conclusions:Tim-3 and MAD2L1 are highly expressed in colorectal cancer tissues, while miR-203a-3p is lowly expressed. The above indicators are closely related to the poor prognosis of patients, and are expected to become potential biomarkers for prognosis evaluation of colorectal cancer patients.

Objective:To investigate the efficacy and underlying mechanism of modified Wubei powder combined with Banxia Xie Xin decoction in the treatment of reflux esophagitis (RE). Methods:A case-control study was conducted involving 82 patients with RE who received treatment at Department of Spleen and Stomach Diseases, Xi'an Hospital of Traditional Chinese Medicine from June 2022 to June 2023. The patients were randomly assigned to either a control group or an observation group, with 41 patients in each group. The control group received conventional treatment, while the observation group was given Wubei powder combined with modified Banxia Xie Xin decoction orally in addition to the conventional treatment. The traditional Chinese medicine symptom scores, lower esophageal sphincter relaxation rate (LESR), percentage of abnormal esophageal contractions, and levels of substance P (SP), cholecystokinin (CCK), motilin (MTL), gastrin (GAS), serum ghrelin, and vasoactive intestinal peptide (VIP) were compared between the two groups before treatment and at 2 and 4 weeks after treatment. Results:There was no statistically significant difference in traditional Chinese medicine symptom scores between the two groups before treatment ( P > 0.05). However, both groups showed lower symptom scores at 2 and 4 weeks after treatment compared with before treatment ( t = 6.87, 10.87, 9.59, 15.39, all P < 0.05). The observation group demonstrated significantly greater improvement in symptom scores at 2 and 4 weeks compared with the control group [(17.68 ± 2.13) vs. (23.76 ± 2.48); (11.44 ± 1.12) vs. (18.82 ± 1.85), t = 4.18, 4.35, both P < 0.05]. There were no statistically significant differences in LESR or percentage of abnormal contractions between the two groups before treatment (both P > 0.05). However, both LESR and the percentage of abnormal esophageal contractions improved at 2 and 4 weeks after treatment compared with before treatment ( t = 4.25, 5.73, 5.86, 6.49, 3.79, 4.84, 4.48, 5.56, all P < 0.05). Additionally, the observation group had significantly lower LESR at 2 and 4 weeks compared with the control group [(71.62 ± 6.37)% vs. (75.46 ± 6.89)%, (64.92 ± 5.82)% vs. (70.78 ± 6.45)%, t = 5.43, 5.86, both P < 0.05]. The percentage of abnormal esophageal contractions was also significantly lower in the observation group [(45.28 ± 5.18)% vs. (59.56 ± 5.84)%; (33.53 ± 4.24)% vs. (47.74 ± 5.31)%, t = 6.08, 7.24, both P < 0.05]. Before treatment, there were no statistically significant differences in levels of SP, MTL, GAS, or CCK between the two groups (all P > 0.05). The levels of SP, MTL, GAS, and CCK improved in both groups at 2 and 4 weeks compared with before treatment ( t = 4.67, 7.15, 7.24, 9.87, 3.62, 5.85, 4.58, 7.17, 3.55, 5.41, 5.42, 6.89, 3.53, 5.43, 5.39, 6.82, all P < 0.05). Furthermore, the observation group had significantly higher levels of SP, MTL, and GAS at 2 and 4 weeks compared with the control group ( t = 3.65, 4.12, 3.86, 4.25, 4.48, 5.36, all P < 0.05), while CCK levels were significantly lower in the observation group ( t = 4.38, 4.51, both P < 0.05). There were no statistically significant differences in ghrelin or VIP levels between the two groups before treatment (both P > 0.05). However, both ghrelin and VIP levels improved in both groups at 2 and 4 weeks after treatment compared with before treatment ( t = 3.35, 3.72, 3.69, 4.28, 3.76, 4.88, 4.11, 5.69, all P < 0.05). Additionally, the observation group had significantly higher levels of ghrelin compared with the control group ( t = 3.43, 4.11, both P < 0.05), while VIP levels were significantly lower in the observation group ( t = 4.59, 5.71, both P < 0.05). Conclusions:The addition of modified Wubei powder combined with Banxia Xie Xin decoction to conventional treatment can considerably alleviate clinical symptoms in patients with RE and improve esophageal pressure. Furthermore, this combined therapy can effectively regulate serum levels of SP, CCK, MTL, GAS, ghrelin, and VIP, thereby modulating the contraction and relaxation of gastrointestinal smooth muscle, enhancing lower esophageal sphincter pressure, and reducing reflux.

OBJECTIVE To explore the implementation and standardized management of infection control core ele-ments in grass-roots medical institutions within county-level medical communities.METHODS From Mar.2024 to Apr.2024,the current status of implementation of infection control core elements in the grass-roots medical institu-tions within county-level medical communities was investigated by means of questionnaire survey and qualita-tive interview,and the implementation strategies were further explored.RESULTS The infection management or-ganizational system and functions of the two county-level medical institutions within the county medical communi-ties were completed,there is no independent hospital infection management department in the primary medical in-stitutions.The infection management personnel in the 16 grass-roots medical institutions were part-time person-nel,the personnel with the educational background below junior college accounted for 84.21％,the personnel with the professional background of nursing accounted for 100.00％,the personnel with less than 5 years of working experience accounted for 78.95％,none of them had an on-the-job training certificate.The monitoring programs of the county-level medical institutions within the county medical communities were completed,there was no infec-tion management monitoring information platform in the grass-roots medical institutions.The infection cases,hand hygiene,environmental health and occupational exposures were monitored by people.The grass-roots medi-cal institutions had the highest requirements for various professional trainings and increase of training contents of prevention and control of public health infectious diseases(100.00％).The county-level medical institutions had inadequate capabilities of professional examination of medical equipment replacement and construction of medi-cal architecture.CONCLUSION It is necessary for the country and local levels of governments to attach great importance to the implementation of the infection control core elements in the grass-roots medical institutions within the county-lev-el medical communities,establish the county-level regional information platform,formulate the corresponding surveil-lance indexes and homogenized management systems,complete the cultivation of talents,and offer financial support.

OBJECTIVE To observe the isolation rates and drug resistance rates of Acinetobacter baumannii strains isolated from intensive care unit(ICU)patients in 8 consecutive years so as to provide bases for reasonable clinical application of antibiotics and control of infections.METHODS The isolation rates and specimens from which the A.baumannii and carbapenem-resistant A.baumannii(CRAB)strains were isolated from ICU patients of the First People's Hospital of Changzhou between 2017 and 2024 were retrospectively analyzed.The trends of the drug resistance rates were observed.RESULTS Totally 2078(18.03％)strains of A.baumannii were isolated from the ICU patients from 2017 to 2024,and there was no significant difference in the changing trend among the years(x2=-1.573,P=0.116).Among the A.baumannii strains that were isolated from 2017 to 2024,58.08％were isolated from sputum,and 24.25％from lavage fluid specimens;the percentage of sputum specimens showed a downward trend in the 8 years(x2=-8.257,P＜0.001),while the percentage of lavage fluid speci-mens showed an upward trend(x2=12.964,P＜0.001).The isolation rate of the CRAB strains was 91.48％in 2017,92.61％in 2018,92.56％in 2019,82.53％in 2020,52.44％in 2021,showing a down-ward trend,and it began to rise in 2022-2024,there was significant difference(x2=-2.277,P=0.012).The isolation rates of the CRAB strains from both sputum and lavage fluid specimens showed downward trends and then upward trends(all P＜0.05).The drug resistance rates of the A.baumannii strains to piperacillin and minocycline showed slow upward trends,while the drug resistance rates to gentamicin and tigecycline showed downward trends,and there were significant differences(P＜0.05).The drug resistance rates of the A.bau-mannii strains to imipenem and meropenem remained more than 90％.CONCLUSIONS Acinetobacter spp is the major pathogen causing the hospital-acquired infection.The isolation rate of CRAB strains shows a downward trend then a upward trend in recent two years.It is necessary for the hospital to standardize the submission of spu-tum specimens and increase the aseptic submission.The A.baumannii strains show high drug resistance rates to the commonly used antibiotics.Polymyxin B,tigecycline and minocycline are the major antibiotics for treatment of CRAB infection.