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关键词： HIV   AIDS animal model   nonhuman primate   northern pig-tailed macaque   stHIV-1sv/G53D  

摘要： Simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) infections in nonhuman primates closely approximate human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), but intrinsic viral differences limit translational relevance. A physiologically accurate HIV-1 model remains elusive. Here, we established a progressive HIV-1-like infection model using northern pig-tailed macaques (NPMs) infected with stHIV-1sv/G53D and monitored for 200 days. Results showed persistent viremia, progressive CD4+ T-cell depletion, and influenza-like symptoms, mirroring clinical features of HIV-1 infection. Infected macaques recapitulated T-cell exhaustion, innate immune activation, chronic immunosuppression, multi-organ biomarker alterations, and microbial dysbiosis. Transient and attenuated antiviral immunity may underlie this disease trajectory. In summary, this model serves as a complementary platform for validating direct antiviral strategies targeting HIV-1.

关键词： Tryptophan   diabetes mellitus   GLP-1  

摘要： L-Tryptophan, an essential amino acid, precursor of serotonin, melatonin and niacin, has been implicated in glucose metabolism and gut hormone regulation. However, its role in diabetes remains obscure. This pilot study evaluated the effects of L-Tryptophan (Trp) supplementation on glycemic control, intestinal glucose absorption, biochemical markers and tissue histology in streptozotocin (STZ)-induced diabetic rats. Adult Wistar rats (n = 24) were divided into four groups: normal control, diabetic control, diabetic + Trp (50 mg/kg), and Trp control. Diabetes was induced by STZ (50 mg/kg). Trp was administered orally for 10 days. Blood glucose, serum biochemical parameters, intestinal glucose absorption, and Na+/K+-ATPase activity were assessed. Qualitative histological analysis of pancreatic and hepatic tissues was performed. Trp treatment in diabetic rats significantly reduced blood glucose and intestinal glucose absorption compared to diabetic controls. Pancreatic and intestinal Na+/K+-ATPase(NKA) remained statistically insignificant (p > 0.669 and 0.369). Improvements were observed in serum protein and cholesterol levels, pancreatic and hepatic histology as well as pancreatic GLP-1. L-Tryptophan demonstrated improved glycemia, metabolic benefits and tissue integrity in diabetic rats. These findings are preliminary and are interpreted within the limitations of a short duration. Further Mechanistic studies may elucidate Tryptophan-mediated mechanisms to evaluate its relevance in hyperglycemia.

关键词： Enzymatic inhibitor   microscale thermophoresis   non-competitive inhibition   paraxonase-2   triazolo[4,3-a]quinoline  

摘要： A plethora of studies have demonstrated the pathophysiological roles played by paraxonase 2 (PON2) in oxidative stress control, inhibition of apoptosis, infections, and the progression of various types of malignancies. The continuous interest in PON2 has not gone hand in hand with the development of its inhibitors. Indeed, only one inhibitor for PON2, namely TQ416, is known, although neither its preparation nor a systematic structure-activity relationship analysis has been so far reported. Herein, we outline the first study aimed at the definition of structure-activity relationships of TQ416 by the preparation of a small library of its analogues. Successfully, we identified some [1,2,4]triazolo[4,3-a]quinoline derivatives more potent than TQ416 as PON2 inhibitors, and among them one endowed with an IC50 value in the nanomolar range. We tested the parent TQ416 and its most effective congener 2 in cells showing their effectiveness and complex behaviour.

关键词： Bergamottin   acute kidney injury   ferroptosis   BACE-1   GPX4  

摘要： Bergamottin is a natural furanocoumarin compound that possesses antioxidative and anticancer properties. However, the effect of bergamottin (BGM) on acute kidney injury (AKI) is unknown. Human renal tubular HK-2 cells and mice that received cisplatin were pretreated with BGM, after which their cytotoxicity and renal function were evaluated. BGM pretreatment alleviated cisplatin-induced cytotoxicity in vitro. Moreover, synergistic protection against cisplatin-induced cytotoxicity was observed when BGM and apoptosis, autophagy, or necrosis inhibitors were used together. There was no synergistic effect between BGM and the ferroptosis inhibitor. Furthermore, BGM significantly inhibited ferroptosis induction-induced damage to HK-2 cells. BGM pretreatment alleviated renal dysfunction and pathological damage by reducing renal proinflammatory cytokines and inhibiting inflammatory cell infiltration, lipid peroxidation and ferroptosis. Based on predictions by SwissTarget and molecular docking, BGM strongly interacts with residues of beta-secretase 1 (BACE-1) via hydrogen and hydrophobic interactions. Moreover, BACE-1 expression was significantly upregulated in the kidneys of AKI mice and HK-2 cells treated with cisplatin but markedly reduced following BGM intervention. Interestingly, siRNA-mediated silencing of BACE-1 in vitro substantially abolished the protective effect of BGM on HK-2 cells that received cisplatin. BGM effectively alleviated AKI by targeting BACE-1 to reduce ferroptosis, suggesting that BGM could be developed as a potential agent for managing and pretreating AKI.

关键词： Monkeypox virus   Mpox   Cambodia   lineage C.1   Bayesian phylodynamics  

摘要： Mpox is an infectious disease caused by the Monkeypox virus, which is divided into two main genetic clades: Clade I and Clade II. A large-scale outbreak linked to Clade IIb emerged in 2022 and rapidly spread to more than 100 countries worldwide. Here, we describe the first and only documented Mpox outbreak in Cambodia (2023-2024), the public health outbreak response efforts and analysis, and integrating epidemiological and genomic *** investigate the outbreak, samples from suspect cases were confirmed using qPCR before virus whole genome sequences were obtained for phylogenomic *** investigation revealed transmission primarily through intimate contact within socially connected networks, exclusively among men who have sex with men. None of the confirmed cases reported recent international travel or zoonotic exposure. Phylogenomic analysis showed that all Cambodian Mpox genomes belonged to lineage C.1, nested within Clade IIb. Bayesian analysis of publicly available C.1 genomes indicated that the most closely related sequence was from Thailand. Monophyletic clustering of Cambodian sequences, alongside a high proportion of APOBEC3 mutations, indicates localized human-to-human transmission after ***, these results illustrate the risk of regional lineages like C.1 introducing Mpox into previously unaffected countries, where socially connected human networks can sustain outbreaks despite control efforts.

关键词： Salvianolic acid B   benzoylpaeoniflorin   ischemic stroke   angiogenesis   Nrf2/HO-1/VEGFA signaling axis  

摘要： ContextAngiogenesis is one of the essential protective mechanisms that promote neural repair and regeneration after ischemic stroke (IS). Salvianolic Acid B (SAB) and Benzoyl paeoniflorin (BP) are compounds extracted from the Chinese medicines Salvia miltiorrhiza Bunge and Paeonia suffruticosa Andrews, *** investigated whether SAB combined with BP alleviated IS by promoting micrangium angiogenesis and determined the potential molecular *** and methodsThe impact of SAB-BP on angiogenesis after IS was investigated in middle cerebral artery occlusion (MCAO) rat model, ponatinib-induced ischemic stroke in zebrafish, and human umbilical vein endothelial cells (HUVECs). The neuroprotective effect of SAB-BP in rats was assessed using behavior tests and histopathological staining. The cerebral thrombosis assessment and angiogenesis assay were performed in the zebrafish model. Cell proliferation and angiogenesis in oxygen-glucose deprivation and reperfusion (OGD/R) HUVECs were assessed through cell viability, tube formation, migration, and invasion assays. Western blot analysis and immunofluorescence staining were used to determine the protein expression levels of Nrf2, HO-1, and *** findings indicated that SAB-BP significantly reduced neurological impairment following IS and promoted the formation of functional vessels in the cerebral ischemic penumbra. Furthermore, SAB-BP up-regulated the protein expression of Nrf2, HO-1, HIF-1 alpha, and VEGFA. Intriguingly, the pro-angiogenic effect of SAB-BP markedly restrained by adding the inhibitor of Nrf2 (ML385).Discussion and conclusionOur study demonstrates that SAB-BP enhances angiogenesis following IS by modulating the Nrf2/HO-1/VEGFA signaling axis both in vivo and in vitro. SAB-BP could serve as a promising therapeutic agent for IS recovery.

关键词： Preeclampsia   second trimester   sFlt-1/PlGF ratio   composite adverse neonatal outcome   neonatal risk prediction  

摘要： Objectives To investigate the predictive performance of the second-trimester soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio for composite adverse neonatal outcome (CANO) in preeclampsia (PE). Methods This retrospective cohort study enrolled 253 PE women during June 2022-June 2024. Maternal serum levels of sFlt-1 and PlGF were assessed, and their ratio was determined at 13-27 gestational weeks. Subjects were stratified into CANO (n = 80) and non-CANO (n = 173) groups. Baseline characteristics and the sFlt-1/PlGF ratio were compared. Univariate and multivariate logistic regression analyses were employed to identify independent risk factors for CANO. Predictive value was assessed using ROC curve analysis, and a nomogram prediction model was constructed. Results The sFlt-1/PlGF ratio was markedly higher in the CANO group than the non-CANO group (p < 0.001). Multivariate analysis identified the sFlt-1/PlGF ratio (OR = 1.040, 95% CI: 1.020-1.060, p < 0.001), serum uric acid level (OR = 1.007, 95% CI: 1.000-1.013, p = 0.043), and history of pre-pregnancy hypertension (OR = 13.51, 95% CI: 2.065-88.36, p = 0.007) as independent risk factors for CANO. Conversely, gestational age at delivery (OR = 0.727, 95% CI: 0.621-0.852, p < 0.001) was a protective factor. The sFlt-1/PlGF ratio predicted CANO with an AUC of 0.799 (95% CI: 0.743-0.855). The integrated nomogram model achieved a C-index of 0.880 (95% CI: 0.836-0.923), indicating excellent discrimination. Conclusion The second-trimester sFlt-1/PlGF ratio is an independent predictor for CANO in PE. A model incorporating this biomarker facilitates the early identification of high-risk neonates, informing personalized perinatal management.

关键词： Type 1 diabetes   cardiovascular risk   risk prediction   subclinical atherosclerosis   precision medicine   risk stratification  

摘要： IntroductionCardiovascular disease (CVD) remains the leading cause of premature mortality in type 1 diabetes (T1D). Despite this burden, current prevention guidelines and risk stratification tools are largely extrapolated from type 2 diabetes or general populations, often failing to capture the unique pathophysiological drivers of atherosclerosis in T1D. This narrative review aims to critically evaluate current cardiovascular prevention strategies, identify the limitations of generic risk calculators, and analyse the clinical utility and discriminatory performance of population-specific risk *** clinical practice guidelines provide heterogeneous and inconsistent recommendations for T1D. Generic risk calculators (e.g. SCORE2, ACC/AHA pooled cohort equations) are limited by short-term prediction horizons and a lack of validation in T1D cohorts, frequently leading to poor diagnostic performances in this population. Conversely, T1D-specific equations, such as Steno Type 1 Risk Engine (Steno-Risk) and the emerging LIFE-T1D model, incorporate disease-specific variables such as diabetes duration or albuminuria. Available evidence indicates that T1D equations as Steno-Risk demonstrate superior discriminatory performance compared to generic scores identifying those individuals with higher cardiovascular risk. However, despite improved calibration, specific tools still classify a substantial proportion of patients with established subclinical atherosclerotic disease as 'moderate risk,' creating a grey area that complicates therapeutic *** cardiovascular risk algorithms are inadequate for the T1D population. While specific equations represent a significant advancement toward accurate stratification, mathematical models alone may be insufficient. Moving toward precision medicine requires a combined approach that integrates validated T1D-specific risk calculators with subclinical atherosclerosis screening (e.g. carotid ultras

关键词： Antimicrobial peptide   acinetobacter baumannii   carbapenem-resistance   cell membrane   lipopolysaccharide   oxidative stress  

摘要： The treatment of carbapenem-resistant A. baumannii (CRAB) infections has become a major global medical challenge;therefore, there is an urgent need for new antimicrobial development. Antimicrobial peptides hold great promising potential due to their rapid bactericidal activity and low induction of drug resistance. In this study, we screened and synthesized the antimicrobial peptide lachnospirin-1, which exhibited significant bactericidal activity against CRAB and can also effectively eliminate its biofilms and persister cells. Mechanism studies, including fluorescent probe detection, transmission electron microscopy observations, and molecular dynamics simulations, et al. indicated that lachnospirin-1 exerts its effects through multiple mechanisms, such as disrupting bacterial cell membranes, neutralizing lipopolysaccharide, as well as inducing oxidative stress, which also demonstrates its certain potential. In addition, the favorable safety profile and effective in vivo bactericidal activity of lachnospirin-1 were determined by mouse models. Overall, our study found that lachnospirin-1 has considerable research potential as a lead compound and possesses latent value as a clinical therapy for refractory infections caused by CRAB.