Objective To investigate the effects of meropenem and amikacin on gut microbiota diversity and composition in a neonatal rat model of necrotizing enterocolitis(NEC).Methods Neonatal SD rats(1～2 d,weighing 5～10 g,both sexes)were subjected to establish a NEC model through artificial formula feeding,hypoxic-cold stress,and lipopolysaccharide(LPS)gavage.The rats were randomly divided into normal control group(Group C,n=12),NEC group(Group N,n=20),meropenem intervention group(Group M,n=20),and amikacin intervention group(Group A,n=20).Following modeling,Group M and Group A received intraperitoneal injections of meropenem(125 mg/kg)or amikacin(468 mg/kg),twice daily for 3 consecutive days.Groups C and N were administered an equal volume of normal saline.At the end of the intervention,colonic contents or fecal samples were collected.The gut microbiota structure was analyzed using 16S rDNA high-throughput sequencing.Bioinformatics analysis was performed using the QIIME2 platform.Alpha diversity was evaluated using Chao1,Shannon,and Simpson indices.Beta diversity was assessed based on Bray-Curtis distance through principal coordinate analysis(PCoA)and non-metric multidimensional scaling(NMDS).Venn and UpSet plots were generated to visualize the composition and overlap of operational taxonomic units(OTUs).Linear discriminant analysis effect size(LEfSe)was applied to identify differentially abundant taxa across groups.Results High-throughput 16S rDNA sequencing showed that the N group had significantly lower 3 indices of α diversity than the C group(P<0.01),that is,a Chao1 index from 230 to 40,a Shannon index from 1.65 to 0.85,and a Simpson index from 0.65 to 0.42.After antibiotic intervention,both the M group and A group obtained obvious increases in the Chao1 index than the N group(P<0.001),with a greater increase observed in the M group than in the A group(P<0.05).However,neither antibiotic group exhibited notable improvements in the Shannon index or Simpson index compared with the N group(P>0.05).Venn and UpSet analyses revealed that the M group had the highest number of unique OTUs(283),while the A group shared the most OTUs(63)with the C group.PCoA and NMDS analyses indicated that the microbial structure of the A group was closer to that of the C group,with better clustering.Taxonomic composition and LEfSe analysis demonstrated that the N group was enriched with potentially pathogenic taxa such as Escherichia coli B2 and Klebsiella under the phylum Proteobacteria,while beneficial bacteria including Lactobacillaceae and Bifidobacteriaceae(phylum Firmicutes)were significantly reduced,indicating severe dysbiosis.In contrast,the A group exhibited a significant increase in beneficial bacteria and a structural tendency toward ecological recovery.The M group,however,was enriched with various conditionally pathogenic and environmentally associated genera,displaying a microbial configuration notably deviating from a healthy state.Conclusion Meropenem and amikacin exhibit differential regulatory effects on the intestinal microbiota in the context of NEC.Amikacin demonstrates superior efficacy in restoring microbial stability and levels of beneficial bacteria,whereas meropenem,although effective for early infection control,warrants caution due to its potential long-term impact on the gut microbiome.

Objective:To investigate the changes in sympathetic nerve activity after lower limb immobilization and the role of sympathetic nerve in regulating disuse atrophy of skeletal muscles.Methods:The experiment was divided into the following 3 parts: ① Twelve 8-week-old male C57 mice were randomly divided into a blank control group and a hind limb fixation group ( n=6). The blank control group received no intervention while the hind limb fixation group received splint fixation of the hind limbs for 2 weeks before the musculoskeletal multi-dimensional characterization was completed at the behavioral, pathological and molecular levels. ② Thirty-six 8-week-old male C57 mice were selected and randomly divided into a control group and 5 hind limb fixation groups (for 1, 3, 5, 7 and 14 days) ( n=6). The control group was fed normally until 14 days without any intervention while the 5 hind limb fixation groups were sampled after fixation for 1, 3, 5, 7 and 14 days, respectively. The level of norepinephrine in the serum and the expression level of tyrosine hydroxylase (TH), a marker of sympathetic nerve activity in the paraventricular nucleus of hypothalamus (PVN), were detected to observe the plasticity of sympathetic nerve activity. ③ Eighteen 8-week-old male C57 mice were selected and randomly divided into a blank control group, a hind limb fixation group and a hind limb fixation plus medication group ( n=6). The blank control group received no intervention while the 2 fixation groups were injected with phosphate buffer (PBS) and propranolol hydrochloride solution for 2 consecutive weeks, respectively. The parameters related to the skeletal muscles were compared between the 3 groups. Results:① Compared with the control group, the mass and function of skeletal muscles in the hind limb fixation group were statistically significantly decreased ( P<0.05). ② The levels of serum norepinephrine [(3.27±1.03) ng/mL, (9.21±1.05) ng/mL, (6.36±0.88) ng/mL, (3.84±1.00) ng/mL, and (3.91±0.75) ng/mL] and the PVN TH levels (42.00%±5.38%, 61.67%±5.57%, 55.82%±3.11%, 50.90%±2.53%, and 39.17%±9.07%) in the 5 hind limb fixation groups (for 1, 3, 5, 7 and 14 days) were significantly higher than those in the control group [(1.81±0.72)] ng/mL and 23.33%±5.50%] ( P<0.05). ③ The wet weight of the gastrocnemius muscle [(93.50±4.32) mg] and the cross-section area of the tibial anterior muscle [(1,180.00±95.09) μm 2] in the hind limb fixation plus medication group were increased significantly compared with those in the hind limb fixation group [(80.83±9.99) mg and (907.80±121.00) μm 2] ( P<0.05). Conclusions:Overactivation of the sympathetic nervous system occurs in the mice model of skeletal muscle disuse atrophy after hind limb fixation. Inhibition of sympathetic nerve activity may reduce the severity of skeletal muscle atrophy at the lower limbs.

The cardioprotective effects of histone deacetylase (HDAC) inhibitors (HDIs) are at odds with the deleterious effects of HDAC depletion. Here, we use HDAC3 as a prototype HDAC to address this contradiction. We show that adult-onset cardiac-specific depletion of HDAC3 in mice causes cardiac hypertrophy and contractile dysfunction on a high-fat diet (HFD), excluding developmental disruption as a major reason for the contradiction. Genetically abolishing HDAC3 enzymatic activity without affecting its protein level does not cause cardiac dysfunction on HFD. HDAC3 depletion causes robust downregulation of lipid oxidation/bioenergetic genes and upregulation of antioxidant/anti-apoptotic genes. In contrast, HDAC3 enzyme activity abolishment causes much milder changes in far fewer genes. The abnormal gene expression is cardiomyocyte-autonomous and can be rescued by an enzyme-dead HDAC3 mutant but not by an HDAC3 mutant (Δ33-70) that lacks interaction with the nuclear-envelope protein lamina-associated polypeptide 2β (LAP2β). Tethering LAP2β to the HDAC3 Δ33-70 mutant restored its ability to rescue gene expression. Finally, HDAC3 depletion, not loss of HDAC3 enzymatic activity, exacerbates cardiac contractile functions upon aortic constriction. These results suggest that the cardiac function of HDAC3 in adults is not attributable to its enzyme activity, which has implications for understanding the cardioprotective effects of HDIs.

OBJECTIVE: To investigate the association between ABO blood types and gestational diabetes mellitus (GDM) risk. METHODS: A prospective birth cohort study was conducted. ABO blood types were determined using the slide method. GDM diagnosis was based on a 75-g, 2-h oral glucose tolerance test (OGTT) according to the criteria of the International Association of Diabetes and Pregnancy Study Groups. Logistic regression was applied to calculate the odds ratios ( ORs) and 95% confidence intervals ( CIs) between ABO blood types and GDM risk. RESULTS: A total of 30,740 pregnant women with a mean age of 31.81 years were enrolled in this study. The ABO blood types distribution was: type O (30.99%), type A (26.58%), type B (32.20%), and type AB (10.23%). GDM was identified in 14.44% of participants. Using blood type O as a reference, GDM risk was not significantly higher for types A ( OR = 1.05) or B ( OR = 1.04). However, women with type AB had a 19% increased risk of GDM ( OR = 1.19, 95% CI = 1.05-1.34; P < 0.05), even after adjusting for various factors. This increased risk for type AB was consistent across subgroup and sensitivity analyses. CONCLUSION The ABO blood types may influence GDM risk, with type AB associated with a higher risk. Incorporating it-either as a single risk factor or in combination with other known factors-could help identify individuals at risk for GDM before or during early pregnancy.
Humans ; Female ; Pregnancy ; Diabetes, Gestational/etiology* ; ABO Blood-Group System ; Adult ; Prospective Studies ; Risk Factors ; Young Adult

BACKGROUND: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS: We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t -test were used to analyze the data. RESULTS: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.
Animals ; MicroRNAs/metabolism* ; Angiotensin II/toxicity* ; Mice ; Renal Insufficiency, Chronic/chemically induced* ; Mice, Knockout ; Disease Models, Animal ; Male ; Signal Transduction/genetics* ; LIM Domain Proteins/genetics* ; Mice, Inbred C57BL ; Cell Line ; Humans

AIM:This study aims to investigate the protective effect of α-lipoic acid(α-LA)against alcohol-induced damage in H9c2 rat cardiomyocytes and to explore the underlying mechanisms.METHODS:An alcohol-induced injury model of H9c2 cells was established,and the cells were divided into 4 groups:control group,alcohol group,α-LA group,and alcohol+α-LA group.Additionally,H9c2 cells overexpressing aldehyde dehydrogenase 2(ALDH2)were cre-ated and further divided into 6 groups:normal control group,normal cells treated with alcohol group,normal cells treated with alcohol+α-LA group,ALDH2 overexpression group,ALDH2-overexpressing cardiomyocytes treated with alcohol group,and ALDH2-overexpressing cardiomyocytes treated with alcohol+α-LA group.Cell proliferation was assessed using 5-ethynyl-2'-deoxyuridine(EdU)staining.Reactive oxygen species(ROS)levels in each group were measured using di-hydroethidium(DHE)staining,while the expression levels of ALDH2,silent information regulator 1(SIRT1),heme oxy-genase 1(HO1)and P53 proteins were detected by Western blot analysis.RESULTS:(1)Alcohol exposure resulted in a decrease in the proliferation of H9c2 cells and an increase in intracellular oxidative stress,evidenced by elevated ROS levels and decreased expression of related proteins(ALDH2,SIRT1 and HO1).However,α-LA treatment significantly mitigated the decline in cell proliferation and the oxidative stress induced by alcohol.(2)Alcohol may induce cellular se-nescence,as demonstrated by the up-regulation of P53 expression,which were reversed by α-LA.(3)The H9c2 cells with high ALDH2 expression markedly improved the cell proliferation in the presence of alcohol,suppressed the ROS pro-duction,prevented the down-regulation of oxidative stress-related proteins(ALDH2,SIRT1 and HO1),and reversed the enhanced expression of the senescence marker P53.CONCLUSION:Treatment with α-LA may counteract oxidative stress and attenuate cellular senescence by activating ALDH2,thereby protecting cardiomyocytes from alcohol-induced damage.

AIM:This study aims to investigate the protective effect of α-lipoic acid(α-LA)against alcohol-induced damage in H9c2 rat cardiomyocytes and to explore the underlying mechanisms.METHODS:An alcohol-induced injury model of H9c2 cells was established,and the cells were divided into 4 groups:control group,alcohol group,α-LA group,and alcohol+α-LA group.Additionally,H9c2 cells overexpressing aldehyde dehydrogenase 2(ALDH2)were cre-ated and further divided into 6 groups:normal control group,normal cells treated with alcohol group,normal cells treated with alcohol+α-LA group,ALDH2 overexpression group,ALDH2-overexpressing cardiomyocytes treated with alcohol group,and ALDH2-overexpressing cardiomyocytes treated with alcohol+α-LA group.Cell proliferation was assessed using 5-ethynyl-2'-deoxyuridine(EdU)staining.Reactive oxygen species(ROS)levels in each group were measured using di-hydroethidium(DHE)staining,while the expression levels of ALDH2,silent information regulator 1(SIRT1),heme oxy-genase 1(HO1)and P53 proteins were detected by Western blot analysis.RESULTS:(1)Alcohol exposure resulted in a decrease in the proliferation of H9c2 cells and an increase in intracellular oxidative stress,evidenced by elevated ROS levels and decreased expression of related proteins(ALDH2,SIRT1 and HO1).However,α-LA treatment significantly mitigated the decline in cell proliferation and the oxidative stress induced by alcohol.(2)Alcohol may induce cellular se-nescence,as demonstrated by the up-regulation of P53 expression,which were reversed by α-LA.(3)The H9c2 cells with high ALDH2 expression markedly improved the cell proliferation in the presence of alcohol,suppressed the ROS pro-duction,prevented the down-regulation of oxidative stress-related proteins(ALDH2,SIRT1 and HO1),and reversed the enhanced expression of the senescence marker P53.CONCLUSION:Treatment with α-LA may counteract oxidative stress and attenuate cellular senescence by activating ALDH2,thereby protecting cardiomyocytes from alcohol-induced damage.

Objective:To investigate the changes in sympathetic nerve activity after lower limb immobilization and the role of sympathetic nerve in regulating disuse atrophy of skeletal muscles.Methods:The experiment was divided into the following 3 parts: ① Twelve 8-week-old male C57 mice were randomly divided into a blank control group and a hind limb fixation group ( n=6). The blank control group received no intervention while the hind limb fixation group received splint fixation of the hind limbs for 2 weeks before the musculoskeletal multi-dimensional characterization was completed at the behavioral, pathological and molecular levels. ② Thirty-six 8-week-old male C57 mice were selected and randomly divided into a control group and 5 hind limb fixation groups (for 1, 3, 5, 7 and 14 days) ( n=6). The control group was fed normally until 14 days without any intervention while the 5 hind limb fixation groups were sampled after fixation for 1, 3, 5, 7 and 14 days, respectively. The level of norepinephrine in the serum and the expression level of tyrosine hydroxylase (TH), a marker of sympathetic nerve activity in the paraventricular nucleus of hypothalamus (PVN), were detected to observe the plasticity of sympathetic nerve activity. ③ Eighteen 8-week-old male C57 mice were selected and randomly divided into a blank control group, a hind limb fixation group and a hind limb fixation plus medication group ( n=6). The blank control group received no intervention while the 2 fixation groups were injected with phosphate buffer (PBS) and propranolol hydrochloride solution for 2 consecutive weeks, respectively. The parameters related to the skeletal muscles were compared between the 3 groups. Results:① Compared with the control group, the mass and function of skeletal muscles in the hind limb fixation group were statistically significantly decreased ( P<0.05). ② The levels of serum norepinephrine [(3.27±1.03) ng/mL, (9.21±1.05) ng/mL, (6.36±0.88) ng/mL, (3.84±1.00) ng/mL, and (3.91±0.75) ng/mL] and the PVN TH levels (42.00%±5.38%, 61.67%±5.57%, 55.82%±3.11%, 50.90%±2.53%, and 39.17%±9.07%) in the 5 hind limb fixation groups (for 1, 3, 5, 7 and 14 days) were significantly higher than those in the control group [(1.81±0.72)] ng/mL and 23.33%±5.50%] ( P<0.05). ③ The wet weight of the gastrocnemius muscle [(93.50±4.32) mg] and the cross-section area of the tibial anterior muscle [(1,180.00±95.09) μm 2] in the hind limb fixation plus medication group were increased significantly compared with those in the hind limb fixation group [(80.83±9.99) mg and (907.80±121.00) μm 2] ( P<0.05). Conclusions:Overactivation of the sympathetic nervous system occurs in the mice model of skeletal muscle disuse atrophy after hind limb fixation. Inhibition of sympathetic nerve activity may reduce the severity of skeletal muscle atrophy at the lower limbs.

Porphyromonas gingivalis is a key pathogenic microorganism that triggers periodontitis.It is closely asso-ciated with oral diseases such as chronic periodontitis and recently found to have a significant correlation with the occurrence,progression,and prognosis of cancer.As the leading malignant tumor in terms of both incidence and mortality worldwide,lung cancer has always been a focus and hotspot of research.The causes of lung cancer are complex and involve multiple factors,in-cluding smoking,occupational factors,air pollution,ionizing radiation,diet and nutrition,genetic factors,etc.Researchers have also begun to pay attention to the relationship between oral microbiota and overall health,especially the link with lung cancer.The article summarizes the latest advancements in research on Porphyromonas gingivalis in lung cancer,primarily encompassing etiology and pathogenic mechanisms,and explores its potential as a therapeutic target for lung cancer,aiming to provide new insights and directions for lung cancer prevention and treatment strategies.

Objective To investigate the current situation of skin tests for β-lactams in 155 hospitals in Beijing.Methods The questionnaires were sent to medical institutions in Beijing to statistically described the current situation of β-lactams skin test,and the relevant influencing factors were analyzed by Fisher exact test,and Chi-square test.Results A total of 3 097 questionnaires were received from 155 medical institutions,of which 3 057 were valid questionnaires(effective rate is 98.71％).In this study,122 hospitals conducted skin test before using intravenous penicillins,accounting for 99.19％of 123 hospitals with intravenous penicillins.Hospitals with infectious disease pharmacists conducted more skin tests before using intravenous penicillins(98.59％vs 88.46％,P＜0.001),and some hospitals didn't conduct skin tests before using oral penicillins.Seventy hospitals(45.16％)had not yet cancelled skin tests for cephalosporins,more hospitals with infectious disease pharmacists cancelled routine skin test(59.74％vs 50.00％,P＜0.05),and more tertiary hospitals cancelled cephalosporin skin test(80.65％vs 51.40％,29.41％,all P＜0.01).After the promulgation of the"Guiding Principle for Skin Test of β-lactams(2021 edition)",more primary hospitals have developed or updated the rules or regulation for skin test of β-lactams according to the Guiding Principle,compared with secondary hospitals(72.22％vs 41.18％,P＜0.05).Hospitals with infectious disease pharmacists developed or updated the rules or regulation for skin test of β-lactams in their hospitals(78.57％vs 60.00％,P＜0.05).Infectious disease pharmacists had promoting effect on the publicity of the rules or regulation of skin test in the hospital(92.65％vs 80.46％,P＜0.05).Conclusion Many hospitals in Beijing have not cancelled cephalosporins skin test,and the current situation of cancelling cephalosporins skin test in tertiary hospitals is better than that in primary and secondary hospitals.