Diabetic cardiomyopathy is a distinct form of cardiomyopathy that can lead to heart failure, arrhythmias, cardiogenic shock, and sudden death. It has become a major cause of mortality in diabetic patients. The pathogenesis of diabetic cardiomyopathy is complex, involving increased oxidative stress, activation of inflammatory responses, disturbances in glucose and lipid metabolism, accumulation of advanced glycation end products (AGEs), abnormal autophagy and apoptosis, insulin resistance, and impaired intracellular Ca²⁺ homeostasis. Recent studies have shown that adenosine monophosphate-activated protein kinase (AMPK) plays a crucial protective role by lowering blood glucose levels, promoting lipolysis, inhibiting lipid synthesis, and exerting antioxidant, anti-inflammatory, anti-apoptotic, and anti-ferroptotic effects. It also enhances autophagy, thereby alleviating myocardial injury under hyperglycemic conditions. Consequently, AMPK is considered a key protective factor in diabetic cardiomyopathy. As part of diabetes prevention and treatment strategies, both pharmacological and exercise interventions have been shown to mitigate diabetic cardiomyopathy by modulating the AMPK signaling pathway. However, the precise regulatory mechanisms, optimal intervention strategies, and clinical translation require further investigation. This review summarizes the role of AMPK in the prevention and treatment of diabetic cardiomyopathy through drug and/or exercise interventions, aiming to provide a reference for the development and application of AMPK-targeted therapies. First, several classical AMPK activators (e.g., AICAR, A-769662, O-304, and metformin) have been shown to enhance autophagy and glucose uptake while inhibiting oxidative stress and inflammatory responses by increasing the phosphorylation of AMPK and its downstream target, mammalian target of rapamycin (mTOR), and/or by upregulating the gene expression of glucose transporters GLUT1 and GLUT4. Second, many antidiabetic agents (e.g., teneligliptin, liraglutide, exenatide, semaglutide, canagliflozin, dapagliflozin, and empagliflozin) can promote autophagy, reverse excessive apoptosis and autophagy, and alleviate oxidative stress and inflammation by enhancing AMPK phosphorylation and its downstream targets, such as mTOR, or by increasing the expression of silent information regulator 1 (SIRT1) and peroxisome proliferator-activated receptor‑α (PPAR‑α). Third, certain anti-anginal (e.g., trimetazidine, nicorandil), anti-asthmatic (e.g., farrerol), antibacterial (e.g., sodium houttuyfonate), and antibiotic (e.g., minocycline) agents have been shown to promote autophagy/mitophagy, mitochondrial biogenesis, and inhibit oxidative stress and lipid accumulation via AMPK phosphorylation and its downstream targets such as protein kinase B (PKB/AKT) and/or PPAR‑α. Fourth, natural compounds (e.g., dihydromyricetin, quercetin, resveratrol, berberine, platycodin D, asiaticoside, cinnamaldehyde, and icariin) can upregulate AMPK phosphorylation and downstream targets such as AKT, mTOR, and/or the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), thereby exerting anti-inflammatory, anti-apoptotic, anti-pyroptotic, antioxidant, and pro-autophagic effects. Fifth, moderate exercise (e.g., continuous or intermittent aerobic exercise, aerobic combined with resistance training, or high-intensity interval training) can activate AMPK and its downstream targets (e.g., acetyl-CoA carboxylase (ACC), GLUT4, PPARγ coactivator-1α (PGC-1α), PPAR-α, and forkhead box protein O3 (FOXO3)) to promote fatty acid oxidation and glucose uptake, and to inhibit oxidative stress and excessive mitochondrial fission. Finally, the combination of liraglutide and aerobic interval training has been shown to activate the AMPK/FOXO1 pathway, thereby reducing excessive myocardial fatty acid uptake and oxidation. This combination therapy offers superior improvement in cardiac dysfunction, myocardial hypertrophy, and fibrosis in diabetic conditions compared to liraglutide or exercise alone.

This study aims to investigate the ameliorating effect of Corni Fructus(CF) on the myocardial ischemic injury and the pharmacokinetic properties of characteristic components of CF. The mouse model of isoproterenol-induced myocardial ischemia was established and administrated with the aqueous extract of CF. The general efficacy of CF in ameliorating the myocardial ischemic injury was evaluated based on the cardiac histopathology and the levels of myocardial injury markers: creatine kinase isoenzyme(CK-MB) and cardiac troponin I(cTn-I). The metabolomics analysis was carried out for the heart and serum samples of mice to screen the biomarkers of CF in ameliorating the myocardial ischemic injury and then the predicted biomarkers were submitted to metabolic pathway enrichment. The pharmacokinetic analysis was performed for morroniside, loganin, and cornuside Ⅰ in mouse heart and serum samples to obtain the pharmacokinetic parameters of these components. The pharmacokinetic parameters were then integrated on the basis of self-defined weighting coefficients to simulate an integrated pharmacokinetic profile of CF iridoid glycosides in the heart and serum of the mouse model of myocardial ischemia. The results indicated that CF reduced the pathological damage to cardiac cells and tissue(hematoxylin-eosin staining) and lowered the levels of CK-MB and cTn-I in the serum of the mouse model of myocardial ischemia(P<0.01). Metabolomics analysis screed out 31 endogenous metabolites in the heart and 35 in the serum as biomarkers of CF in ameliorating the myocardial ischemic injury. These biomarkers were altered by modeling and restored by CF. Six metabolic pathways in the heart and 5 in the serum were enriched based on these metabolic markers. The main integrated pharmacokinetic parameters of CF iridoid glycosides were T_(max)=1 h, t_(1/2)=(1.52±0.05) h in the heart and T_(max)=1 h, t_(1/2)=(1.56±0.50) h in the serum. Both concentration-time curves showed a double-peak phenomenon. In conclusion, CF demonstrated the cardioprotective effect by regulating metabolic pathways such as taurine and hypotaurine metabolism, and pantothenic acid and coenzyme A biosynthesis. The integrated pharmacokinetics reflect the general pharmacokinetic properties of characteristic components in CF.
Animals ; Cornus/chemistry* ; Mice ; Metabolomics ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Myocardial Ischemia/metabolism* ; Humans ; Troponin I/metabolism* ; Myocardium/pathology* ; Disease Models, Animal ; Biomarkers/metabolism* ; Creatine Kinase, MB Form/metabolism*

BACKGROUND: Hypertension is associated with an increased risk of calcific aortic valve stenosis (CAVS). However, the directionality of causation between blood pressure traits and aortic stenosis is unclear, as is the benefit of antihypertensive drugs for CAVS. METHODS: Using genome-wide association studies (GWAS) summary statistics, we performed bidirectional two-sample univariable mendelian randomization (UVMR) to assess the causal associations of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) with CAVS. Multivariable mendelian randomization (MVMR) was conducted to evaluate the direct effect of hypertension on CAVS, adjusting for confounders. Drug target mendelian randomization (MR) and summary-level MR (SMR) were used to estimate the effects of 12 classes of antihypertensive drugs and their target genes on CAVS risk. Inverse variance weighting was the primary MR method, with sensitivity analyses to validate results. RESULTS: UVMR showed SBP, DBP, and PP have causal effects on CAVS, with no significant reverse causality. MVMR confirmed the causality between hypertension and CAVS after adjusting for confounders. Drug-target MR analyses indicated that calcium channel blockers (CCBs), loop diuretics, and thiazide diuretics via SBP lowering exerted protective effects on CAVS risk. SMR analysis showed that the CCBs target gene CACNA2D2 and ARBs target gene AGTR1 were positively associated with CAVS risk, while diuretics target genes SLC12A5 and SLC12A1 were negatively associated with aortic stenosis risk. CONCLUSIONS Hypertension has a causal relationship with CAVS. Managing SBP in hypertensive patients with CCBs may prevent CAVS. ARBs might exert protective effects on CAVS independent of blood pressure reduction. The relationship between diuretics and CAVS is complex, with opposite effects through different mechanisms.

Ovarian tumor (OT) is the most lethal form of gynecologic malignancy, with minimal improvements in patient outcomes over the past several decades. Metastasis is the leading cause of ovarian cancer-related deaths, yet the underlying mechanisms remain poorly understood. Psychological stress is known to activate the glucocorticoid receptor (NR3C1), a factor associated with poor prognosis in OT patients. However, the precise mechanisms linking NR3C1 signaling and metastasis have yet to be fully elucidated. In this study, we demonstrate that chronic restraint stress accelerates epithelial-mesenchymal transition (EMT) and metastasis in OT through an NR3C1-dependent mechanism involving nuclear protein 1 (NUPR1). Mechanistically, NR3C1 directly regulates the transcription of NUPR1, which in turn increases the expression of snail family transcriptional repressor 2 (SNAI2), a key driver of EMT. Clinically, elevated NR3C1 positively correlates with NUPR1 expression in OT patients, and both are positively associated with poorer prognosis. Overall, our study identified the NR3C1/NUPR1 axis as a critical regulatory pathway in psychological stress-induced OT metastasis, suggesting a potential therapeutic target for intervention in OT metastasis.

Objective To investigate the changing antibiotic resistance profiles of E.coli isolated from patients in the 52 hospitals participating in the CHINET program from 2015 to 2021.Methods Antimicrobial susceptibility was tested for clinical isolates of E.coli according to the unified protocol of CHINET program.WHONET 5.6 and SPSS 20.0 software were used for data analysis.Results Atotal of 289 760 nonduplicate clinical strains ofE.coli were isolated from 2015 to 2021,mainly from urine samples(44.7±3.2)％.The proportion of E.coli strains isolated from urine samples was higher in females than in males(59.0％vs 29.5％).The proportion of E.coli strains isolated from respiratory tract and cerebrospinal fluid samples was significantly higher in children than in adults(16.7％vs 7.8％,0.8％vs 0.1％,both P＜0.05).The isolates from internal medicine department accounted for the largest proportion(28.9±2.8)％with an increasing trend over years.Overall,the prevalence of ESBLs-producing E.coli and carbapenem resistant E.coli(CREco)was 55.9％and 1.8％,respectively during the 7-year period.The prevalence of ESBLs-producing E.coli was the highest in tertiary hospitals each year from 2015 to 2021 compared to secondary hospitals.The prevalence of CREco was higher in children's hospitals compared to secondary and tertiary hospitals each year from 2015 to 2021.The prevalence of ESBLs-producing E.coli in tertiary hospitals and children's hospitals and the prevalence of CREco in children's hospitals showed a decreasing trend over the 7-year period.The prevalence of CREco in secondary and tertiary hospitals increased slowly.Antibiotic resistance rates changed slowly from 2015 to 2021.Carbapenem drugs(imipenem,meropenem)were the most active drugs amongβ-lactams against E.coli(resistance rate≤2.1％).The resistance rates of E.coli to β-lactam/β-lactam inhibitor combinations(piperacillin-tazobactam,cefoperazone-sulbactam),aminoglycosides(amikacin),nitrofurantoin and fosfomycin(for urinary isolates only)were all less than 10％.The resistance rate of E.coli strains to antibiotics varied with the level of hospitals and the departments where the strains were isolated,especially for cefazolin and ciprofloxacin,to which the resistance rate of E.coli strains from children in non-ICU departments was significantly lower than that of the strains isolated from other departments(P＜0.05).The E.coli isolates from ICU showed higher resistance rate to most antimicrobial agents tested(excluding tigecycline)than the strains isolated from other departments.The E.coli strains isolated from tertiary hospitals showed higher resistance rates to the antimicrobial agents tested(excluding tigecycline,polymyxin B,cefepime and carbapenems)than the strains from secondary hospitals and children's hospitals.Conclusions E.coli is an important pathogen causing clinical infection.More than half of the clinical isolates produced ESBL.The prevalence of CREco is increasing in secondary and tertiary hospitals over the 7-year period even though the overall prevalence is still low.This is an issue of concern.

Objective:To assess the precision of various automated antimicrobial susceptibility testing systems for ciprofloxacin, levofloxacin, piperacillin/tazobactam, amikacin, gentamicin and tobramycin before and after the update of the breakpoints by Clinical and Laboratory Standards Institute.Methods:A total of 65 strains of Enterobacterales (34 Escherichia coli and 31 Klebsiella pneumoniae) and 33 strains of Pseudomonas aeruginosa were collected from Peking University People′s Hospital, Sichuan Provincial People′s Hospital, and the First Affiliated Hospital of Sun Yat-sen University in 2023. Broth microdilution (BMD) was employed as the reference method to assess the accuracy of ten antimicrobial susceptibility panels (NMIC-413, GN09, N335, NMIC45, GN4F, NMIC-150, DL-120E, DL-120NE, ONE-96 and NF-96) in seven automated antimicrobial susceptibility testing systems currently utilized in China. Results:Except for the GN-09, N-335, and NMIC-150, there were breakpoints that were not covered for the minimum inhibitory concentrations reported by the other panels in the validation. There was no very major error (VME) in the verification results except for the cases of not covered. Among the 65 strains of Enterobacterales, the essential agreement rate (EA%) of ciprofloxacin and levofloxacin was higher than 92.3% (60/65), and the categorical agreement rate (CA%) of ciprofloxacin using the new breakpoint decreased from 100% (65/65)-98.5% (64/65) to 95.4% (62/65)-86.2% (56/65). The major error rate (ME%) of N-335 card increased from 1.5% (1/65) to 4.6% (3/65); except for GN-09 and N-335 cards, the CA% of other cards under new breakpoint was ≥96.9% (63/65) with no ME; the EA% of piperacillin/tazobactam was ≥93.8% (61/65), and the CA% under new breakpoint was ≥92.3% (60/65), and the ME% of N-335 card increased from 1.5% (1/65) to 4.6% (3/65). The EA% and CA% under new breakpoint of amikacin, gentamicin and tobramycin were all ≥ 96.9% (63/65) with no ME. Among the 33 tested Pseudomonas aeruginosa isolates, the EA% of ciprofloxacin was ≥93.8% (30/32), and after applying the new breakpoints, the CA% of ciprofloxacin decreased from 90.6% (29/32)-100% (33/33) to 84.4% (27/32)-100% (33/33). On the NMIC-413 card, 2 strains showed ME. For levofloxacin, the EA% was ≥90.9% (30/33), and the CA% of the new breakpoint interpretation decreasing from 90.6% (29/32)-100% to 69.7% (23/33)-93.8% (30/32), with no ME. For amikacin and tobramycin, the EA% was ≥93.8% (30/32), and on most panels, the CA% of new breakpoints for amikacin and tobramycin were ≥96.9% (31/32).Conclusions:At present, the breakpoints cannot be covered by the panels in many automated antimicrobial sensitivity testing systems in China. Ciprofloxacin and levofloxacin did not meet the validation requirements for Enterobacterales and Pseudomonas aeruginosa in most antimicrobial susceptibility testing systems. After the breakpoints updated, it is essential to validate the automated antimicrobial susceptibility system for clinical application.

Objective:To explore the predictive value of cervical length(CL)measured at 16-24 weeks of ges-tation for spontaneous preterm birth in twin pregnancies.Methods:A retrospective study was conducted on 1001 twin pregnancy cases,including 569 cases in the spontaneous preterm birth group and 432 cases in the term birth group.Univariate and multivariate Logistic regression analyses were used to identify factors associated with spon-taneous preterm birth.The predictive value of CL for spontaneous preterm birth was analyzed by the receiver op-erating characteristic(ROC)curve.Results:At 16-24 weeks of pregnancy,the CL in the spontaneous preterm birth group(3.460±0.866 cm)was significantly shorter than that in the term birth group(3.711±0.589 cm),and the difference was statistically significant(P=0.005).There were statistically significant differences in the cervical fun-neling and its morphology between the term birth group and the spontaneous preterm birth group(P<0.05).Multivariate Logistic regression analysis showed that monochorionicity(aOR 0.161,95％ CI 0.074-0.351) and CL at 16-24 weeks of pregnancy(aOR 0.655,95％ CI 0.496-0.864) were influencing factors for spontaneous preterm birth(P <0.05).ROC curve analysis indicated that a CL cutoff of 3.045 cm at 16-24 weeks of pregnancy predicted spontaneous preterm birth before 34 weeks,with a sensitivity of 90.2％ ,specificity of 64.9％ ,and an area under the curve of 0.650.Conclusions:Measurement of CL at 16-24 weeks of pregnancy is a potential predictor of spontaneous preterm birth in twin pregnancies.In addition,when establishing a prediction model for spontaneous preterm birth,future research should also consider cervical funnel morphology.

Objective To examine the changing prevalence and antimicrobial resistance profiles of Burkholderia cepacia in 52 hospitals across China from 2015 to 2021.Methods A total of 9 261 strains of B.cepacia were collected from 52 hospitals between January 1,2015 and December 31,2021.Antimicrobial susceptibility of the strains was tested using Kirby-Bauer method or automated antimicrobial susceptibility testing systems according to a unified protocol.The results were interpreted according to the breakpoints released in the Clinical & Laboratory Standards Institute(CLSI)guidelines(2023 edition).Results A total of 9 261 strains of B.cepacia were isolated from all age groups,especially elderly patients.The proportion was 11.1％(1 032 strains)in children,significantly lower than the proportion in adults.About half(46.5％,4 310/9 261)of the strains were isolated from patients at least 60 years old and 42.3％(3 919/9 261)of the strains were isolated from young adults.Most isolates(71.1％)were isolated from sputum and respiratory secretions,followed by urine(10.7％)and blood samples(8.1％).B.cepacia isolates were highly susceptible to the five antimicrobial agents recommended in the CLSI M100 document(33rd edition,2023).B.cepacia isolates showed relatively higher resistance rates to meropenem and levofloxacin.However,the resistance rates to ceftazidime,trimethoprim-sulfamethoxazole,and minocycline remained below 8.1％.The percentage of B.cepacia strains resistant to levofloxacin was the highest compared to other antibiotics in any of the three age groups(from 12.4％in the patients＜18 years old to 20.6％in the patients aged 60 years or older).Conclusions B.cepacia is one of the clinically important non-fermenting gram-negative bacteria.Accurate and timely reporting of antimicrobial susceptibility test results and ongoing antimicrobial resistance surveillance are helpful for rational prescription of antimicrobial agents and proper prevention and control of nosocomial infections.

Wound repair and infection have long posed significant challenges in clinical medicine.Am-phibians,adapting to complex environments through long-term natural selection,have evolved skin sys-tems with remarkable abilities to resist external damage and promote rapid wound healing,making them an important source for discovering candidate molecules for wound healing.In this study,a novel peptide composed of 22 amino acids,with the sequence"VGKAGLETAACKATNSCFNIDW"and a molecular weight of 2299.6 D,was screened from the cDNA library of Odorrana tormota and named PN-VW22.The peptide was synthesized by solid-phase synthesis,and its effects on cell proliferation were evaluated using the CCK-8 assay and scratch wound healing assay in human keratinocytes(HaCaT)and mouse em-bryonic fibroblasts(NIH3T3).Antibacterial activity was assessed by determining the minimum inhibitory concentration(MIC).Results showed that PN-VW22 at various concentrations had no significant effect on the cell viability in NIH3T3 cells(P＞0.05),but significantly enhanced HaCaT cell viability at 0.5μmol/L(P＜0.001).Meanwhile,PN-VW22 induced cell proliferation and promoted wound healing in HaCaT cells,with a healing rate of 64.44％after 24 h incubation at 0.5 μmol/L.Furthermore,PN-VW22 exhibited antibacterial activity against Staphylococcus aureus with an MIC value of 13.92 μmol/L.In sum,this study identified PN-VW22 as a novel bifunctional peptide with both wound repair and anti-infective properties,providing a new toxin peptide template for the development of wound healing drugs.