IGF-DES

Abstract

Heparin is a highly sulfated linear glycosaminoglycan with anticoagulant properties, and its excessive use may lead to many diseases. Therefore, developing sensitive detection techniques for precise detection of heparin is of utmost importance. Herein, we reported a novel peptide-based fluorescent probe (TPE-GRGRG) based on tetraphenylethylene (TPE)-labeled pentapeptide (Gly-Arg-Gly-Arg-Gly-NH2) for the highly selective and outstanding sensitive detection of heparin. TPE-GRGRG exhibited a large Stokes shift (132 nm) and typical aggregation-induced emission (AIE) characteristics in DMSO/H2O binary mixtures. TPE-GRGRG demonstrated a significant enhancement of fluorescence intensity in the presence of heparin with a response time of under 30 s and the limit of detection (LOD) as low as 0.30 nM. A series of characterizations revealed that TPE-GRGRG and heparin formed nanoaggregates via electrostatic interactions, including fluorescence spectroscopy, UV-Vis, FTIR, CD, zeta potential, DLS measurements and fluorescence lifetime analyses, which in turn restricted the intramolecular rotation and triggered the fluorescence enhancement. TPE-GRGRG enabled heparin detection over a wide pH range and exhibited good biocompatibility, and was successfully applied to image heparin in living cells and zebrafish larvae. Furthermore, this study established detection platforms based on swab tests for visual qualitative analysis and smartphone RGB analysis, thereby achieving portable and visual heparin monitoring with the LOD of 0.93 μM. Finally, heparin detection was achieved in 0.1% fetal bovine serum with the LOD of 1.46 nM. TPE-GRGRG offers a reliable strategy for point-of-care testing of heparin, holding potential application value in clinical diagnosis and biosensing.

Abstract

Heart failure mortality has risen sharply after years of decline, highlighting the limitations of current risk assessment tools in accuracy, complexity, and cost, and the need for improved predictive models. To address this gap, we developed and validated a deep learning model to improve short-term mortality prediction in heart failure patients.

Abstract

Catalytic radical C(sp3)-N coupling via C-H bond cleavage and nitrene transfer has become a major focus in catalysis over the past few decades. However, asymmetric C(sp3)-N coupling in this context is mostly limited to the intramolecular amination of benzylic or allylic C-H bonds, which is attributed to limited mechanistic pathways. Described herein is copper-catalyzed enantioselective and intermolecular α C-H amidation of α-amino carbonyls with dioxazolones (amidating reagent), affording otherwise hard-to-access chiral aminals. The coupling proceeds under dioxazolone-dependent conditions with possible photoredox assistance and is peptide-compatible. Mechanistic studies of the amidation reaction with methyldioxazolone reveal a radical-polar crossover pathway primed by dual nitrenes as an amidating reagent and a supporting ligand, and the C-N formation occurs via nitrene-primed umpolung rather than through the conventional hydrogen-atom transfer-radical rebound pathway.

Abstract

Glycation cross-links account for more than 40% of all known advanced glycation end products (AGEs) and are correlated with many age-related diseases. Despite much interest, cross-linking AGEs (xl-AGEs) remain poorly understood, as they have been challenging to discover, prepare, and quantify. Here, we describe a peptide platform that is ideally suited for the study of xl-AGEs, which not only facilitates direct comparisons between the prevalence of known xl-AGEs and other AGEs but also enables the discovery of previously unknown xl-AGEs. In this study, we use this platform to discover the first known Arg-Arg xl-AGEs, a pair of methylglyoxal-derived dihydroxyimidazolidine hemiacetal crosslink, or MIDAL, isomers. We show that MIDAL can become the major AGE, exceeding levels of all other AGEs, for substrates in which two Arg glycation sites are optimally positioned. We further demonstrate that MIDAL is readily and reversibly generated in biocompatible conditions, persisting with a half-life of more than 3 days. We also demonstrate that MIDAL can form in living mammalian cells, suggesting that it has the potential to be a dynamic, physiologically relevant and functional xl-AGE. This work therefore offers important insights about MIDAL formation and describes a versatile platform to enable the study of xl-AGEs under a variety of conditions. We expect that it will be highly useful for further discovery of biologically relevant glycation cross-links that are yet to be identified.

Abstract

Artemisia scoparia is a perennial herb belonging to the Asteraceae family. Although research has shown that A. scoparia possesses antioxidant and anti-inflammatory properties, the anti-inflammatory activity and mechanisms of A. scoparia essential oil (ASEO) remain poorly understood.

Abstract

Dendritic cells (DCs) facilitate the maintenance of immunological tolerance in the steady state. We report that transcription factor Etv3 is preferentially expressed in mature DCs, including tissue-derived migratory DCs (migDCs), and facilitates their homeostatic maturation and CCR7-dependent migration. Mice with global or DC-specific deletion of Etv3 manifested the expansion of CD25low regulatory T (Treg) cells, spontaneous activation of conventional T cells, and multiorgan T cell infiltration. Etv3 deficiency exacerbated TLR7-driven systemic lupus erythematosus (SLE)-like disease, supporting the reported genetic association of human ETV3 with SLE. Etv3-deficient migDCs up-regulated multiple costimulatory molecules, including OX40 ligand (OX40L/TNFSF4), whose blockade partially rescued the Treg cell abnormalities. These results identify Etv3 as an essential regulator of the tolerogenic function of DCs and implicate it in the regulation of human autoimmunity.

Abstract

Malaria is a significant health problem in the world and has been increased by the emerging resistance to insecticides and antimalarial drugs. New measures must therefore be implemented as an emergency to break the cycle of Plasmodium parasite transmission by the Anopheles mosquitoes. This systematic review assessed the effectiveness of paratransgenesis, an engineering approach that utilizes symbiotic microbes to deliver antiplasmodial molecules into the midgut of the mosquito as a transmission-blocking agent. PubMed, ScienceDirect, and Web of Science were searched in accordance with the PRISMA guidelines, yielding 1,289 records. Ten eligible studies were then included after screening. The chosen articles studied bacterial and fungal symbionts, such as Asaia, Serratia, Pantoea, Enterobacter, and Aspergillus oryzae, that have been engineered to produce effector proteins, such as Scorpine, EPIP, Defensin, and SM1-2 peptides. The delivery of oral sugar meals was always associated with colonization of the mosquito midguts, and results reported high levels of inhibition of oocysts or sporozoites in the mosquitoes. Scorpine was the strongest and most commonly used effector with a high level of up to 97.8% inhibition of P. falciparum oocysts in various microbial systems. The combination of two or multiple-effector approaches increased the efficacy in some cases, surpassing 89% parasite inhibition. The risk of bias measurement showed moderate variation in the methods, yet it was in favor of the sound findings. All evidence suggests that paratransgenesis is a potentially important malaria control tool, complementing existing approaches to malaria control. Nevertheless, ecological safety, microbial stability, and field validation are the key obstacles before the translation to large-scale use.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss and profound systemic metabolic dysfunction, including hypermetabolism, weight loss, insulin resistance, and altered glucose and lipid homeostasis. Increasing recognition of these metabolic abnormalities has driven interest in repurposing antidiabetic therapies, particularly glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists (GLP-1RAs), for ALS. Beyond their established metabolic actions, GLP-1RAs exert pleiotropic effects relevant to neurodegeneration, including modulation of neuroinflammation, mitochondrial function, oxidative stress, excitotoxicity, and cell-survival signaling, with selected agents demonstrating central nervous system penetration. This narrative review summarizes current knowledge on metabolic impairment in ALS and critically evaluates the mechanistic rationale, preclinical evidence, and emerging clinical data supporting or opposing the use of GLP-1-based therapies in this disease. Preclinical studies suggest that GLP-1 signaling can provide neuroprotective and neurotrophic effects in ALS models, although findings are heterogeneous and highly dependent on compound selection, delivery strategy, and experimental design. In contrast, available clinical evidence is limited and does not demonstrate therapeutic benefit in ALS, while raising important safety concerns, particularly related to weight loss, lean mass reduction, and altered glucose regulation, factors associated with a worse prognosis in ALS. Collectively, current data indicate that although GLP-1-based therapies may have compelling biological plausibility and beneficial effects in other neurodegenerative disorders (NDGs), their role in ALS remains uncertain and potentially harmful. Well-designed, ALS-specific clinical studies are required to clarify safety, efficacy, and patient selection before GLP-1RAs can be considered for therapeutic use in this vulnerable population.

Abstract

Brain meninges contain lymphatic vessels that play roles in clearance of extracellular solute in the central nervous system. But, whether and how the system is involved in acute stroke remains to be fully explored. Here, we show the VEGF-C-Flt4 pathway involvement in brain swelling in acute phase of ischemic stroke in rats. We first confirmed that a prototypical lymphatic mediator VEGF-C was upregulated in brain endothelium and secreted into CSF. Concomitantly, VEGF-C receptor Flt4 was increased in the meninges but not in peri-infarct cortex. Next, we isolated lymphatic endothelial cells from rat meninges using LYVE-1 antibody-conjugated magnetic beads. An in vitro standard matrigel assay confirmed that isolated LYVE1 + cells increased ring-like structures by treatment with VEGF-C or conditioned media from injured brain endothelium subjected to oxygen-glucose deprivation, whereas immunodepletion of VEGF-C from endothelial media decreased the effect. Finally, blocking Flt4 tyrosine kinase in vivo suppressed the acute increase of lymphatic endothelial cells accompanied by reduction of brain swelling. Collectively, the proof-of-concept study suggests that the VEGF-C-Flt4 signaling pathway contributes to brain swelling during the acute phase of ischemic stroke by activating meningeal lymphatic endothelial cells. Targeting this pathway may offer a new approach to mitigate stroke-induced inflammation and edema.

Abstract

Acute kidney injury (AKI) represents a significant complication in patients with COVID-19. Although Remdesivir (RDV) has been shown to reduce viral loads and improve clinical outcomes, concerns persist regarding its safety in individuals with pre-existing kidney impairment. This study investigated the effects of RDV on a rat model of ischemia/reperfusion (I/R)-induced kidney damage. A total of 24 rats were divided randomly into four groups: (1) control, (2) I/R, (3) I/R + RDV by intraperitoneal (ip) injections, and (4) I/R + RDV by subcutaneous (sc) injection groups. Rats in groups 3 and 4 received a single dosage of RDV (25 mg/kg) one hour before I/R induction. The effect of RDV on master genes involved in the mitochondrial biogenesis [Peroxisome proliferator-activated receptor gamma coactivator (PGC-1α)] and dynamics [Dynamin-related protein 1 (Drp-1)], cellular stress [Activating transcription factor 3 (ATF3)], inflammation [Nuclear factor kappa B (NF-κB)], cell death [p53, p21 (a cyclin-dependent kinase inhibitor), and caspase-3], as well as oxidant malondialdehyde (MDA) and antioxidant factors were evaluated. Moreover, renal function, along with histology assessments were studied. Significant reductions in mitochondrial biogenesis marker PGC-1α (P ≤ 0.04) and increases in caspase-3 (P = 0.003) expression levels were observed in the I/R + RDV + sc group compared to the I/R group. Oxidative stress marker was elevated (P = 0.016), while glutathione peroxidase (GPX) activity and total antioxidant capacity (TAC) were significantly decreased in the I/R + RDV + sc group (0.003 and 0.045, respectively). However, no significant changes were observed in p-p53, p-p21, NF-κB, or Drp-1 levels. Subcutaneous injection of RDV could induce more injury to the kidney compared to the intraperitoneal injection. These findings suggest that RDV may exacerbate AKI by hindering mitochondrial biogenesis and promoting renal cell apoptosis, without significantly affecting overall kidney function or histopathology. Clinically, these results highlight the need for caution when using RDV in patients with impaired renal function, especially during COVID-19 treatment.

Abstract

Obesity results from an imbalance between energy intake and energy expenditure (EE). Glucagon-like peptide-1 receptor (GLP-1R) agonists, reduce weight through appetite suppression but exert minimal influence on EE, potentially limiting long-term efficacy due to adaptive declines in metabolic rate. In contrast, glucagon, traditionally regarded as a glucose counter-regulatory hormone, has emerged as a potent catabolic signal with actions on lipid oxidation, substrate mobilization, and EE. These properties position glucagon receptor (GCGR) agonists as complements to GLP-1R agonism, with the potential to close the EE gap in obesity pharmacotherapy.

Abstract

This study elucidates the antiobesity mechanism of the Fu brick tea extract-millet complex (FTE-M). FTE-M exhibited a dense and smooth microstructure, resulting in improved digestive properties compared with millet alone, including a reduced glycemic index and increased slowly digestible starch and resistant starch contents. In a 10-week high-fat diet mouse model, dietary supplementation with FTE-M inhibited small intestinal α-amylase activity, delayed starch digestion, and improved glucose and lipid metabolism while alleviating inflammation. FTE-M also modulated gut microbiota composition, normalized bile acid profiles, and enriched short-chain fatty acids (SCFAs)-producing bacteria, including Akkermansia, leading to a 2.49-fold increase in total SCFAs. Mechanistically, elevated SCFAs were associated with the activation of free fatty acid receptor 2 (Ffar2) and increased expression of glucagon (Gcg) and peptide YY (Pyy), contributing to enhanced satiety. These findings highlight the potential of combining traditional millet with bioactive components to enhance metabolic functionality, providing a theoretical basis for developing starch-based antiobesity foods.

Abstract

Rice-derived anti-inflammatory peptides (AIPs) have attracted growing interest as functional food ingredients. However, their low abundance in enzymatic hydrolysates and high synthesis cost limit practical application. This study presents an integrated strategy for efficient screening and biosynthesis of AIPs. Using receptor-based screening, three peptides (PHP1, GPA1, GPD1) were identified as promising inhibitors of inflammatory targets. To address production challenges, a fusion tag system was employed to express PHP1 recombinantly in E. coli, yielding up to 28.5 ± 3 mg/L. The recombinant peptides significantly reduced pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), nitric oxide, and protected RAW264.7 cells from LPS-induced damage. Mechanistically, PHP1 directly interacted with NF-κB1 (KD = 7.631 μmol/L) and significantly suppressed NF-κB1 phosphorylation. The anti-inflammatory efficacy of PHP1 was further validated in a mouse model of systemic inflammation. These findings demonstrate both the anti-inflammatory potential of PHP1 and the viability of its scalable production, supporting its application in functional food development.

Abstract

Site-specific antibody-drug conjugates (ADCs) represent a promising class of biotherapeutics with enhanced pharmacological profiles. we herein report a novel one-step strategy for preparing homogeneous ADCs with a drug-to-antibody ratio (DAR) of 4. This approach leverages a Fc ligand-directed thioester-based acylating reagent combined with a β-glutamic acid-based branching linker to enable precise conjugation of four MMAE molecules per antibody. Through systematic optimization of buffer composition and pH, we successfully mitigated the hydrophobicity-driven aggregation typically associated with K248-linked DAR4 ADCs, while maintaining exceptional conjugation efficiency. The method demonstrates excellent tolerance to protein concentration and is applicable to multiple IgG subtypes, including those targeting HER2, cMet, ROR1, and FRα. All resulting ADC products exhibited high homogeneity. Notably, ADC-4, functionalized with a VK(SO3H)-modified linker, showed enhanced aggregation stability, potent tumor suppression, and a favorable safety profile, highlighting its promising therapeutic potential.

Abstract

Antibody-drug conjugates (ADCs) that equip multiple cytotoxic drugs on an antibody have been developed, particularly in cancer chemotherapy. In the treatment of viral infectious diseases, there are dominantly fewer examples of ADCs. Recently, we developed double-warhead ADCs targeting the entry of human immunodeficiency virus type 1 (HIV-1) into host cells. One is a small molecule CD4 mimic, which is a competitive inhibitor against the interaction between a viral envelop protein, gp120, and a primary receptor, CD4, and the other is neutralizing antibodies, which recognize the regions of gp120, exposed by its conformational change after the interaction between gp120 and CD4. The conformational changes are also triggered by the binding of gp120 and a CD4 mimic, and therefore, the ADCs show positive effects on anti-HIV-1 activity compared to the combinational use of CD4 mimics with neutralizing antibodies. Herein, we synthesized novel ADCs containing a CD4 mimic and a neutralizing antibody, KD-247, using tCAP chemistry, which is based on a site-specific modification method for IgG antibodies, and evaluated their anti-HIV-1 and antibody-dependent cellular cytotoxicity (ADCC) activities. As a result, the KD-247-adopted ADCs demonstrated enhanced anti-HIV-1 activities, whereas all of the ADCs reduced their ADCC activities.

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are considered safe, effective medications for type 2 diabetes (T2D) and weight loss, used by millions worldwide. While their cardiometabolic benefits are well established, emerging observations suggest a potential association between GLP-1RA use and new-onset nonarteritic anterior ischemic optic neuropathy (NAION).

Abstract

The emergence of multidrug-resistant Klebsiella pneumoniae poses a significant challenge to clinical treatment and public health. Strategies combining antibiotics with FDA-approved non-antibiotic drugs have recently attracted attention as a promising approach to overcome antibiotic resistance. In this study, we systematically evaluated the synergistic effect of the antihistamine loratadine in combination with colistin against K. pneumoniae. Our results demonstrate that loratadine significantly restores the bactericidal activity of colistin against colistin-resistant K. pneumoniae both in vitro and in vivo, without increasing toxicity, while also delaying the development of colistin resistance. Mechanistic investigations using fluorescence-based assays and proteomic analysis revealed that loratadine acts as a potent adjuvant for colistin, effectively restoring its activity against colistin-resistant K. pneumoniae by interfering with lipid A modification. This phenomenon is further supported by the downregulation of lipid A-modifying enzyme-related protein EptB. In addition, the combination of loratadine and colistin disrupts the double-layer membrane barrier, leading to proton motive force (PMF) dysregulation, reduced intracellular ATP levels, and impaired efflux pump activity. Collectively, this study highlights the potential of drug repurposing as an effective strategy to combat antimicrobial resistance and provides a foundation for the development of combination therapies against multidrug-resistant pathogens.

Abstract

Over the past 2 decades, treatment for type 2 diabetes (T2D) has evolved with the introduction of medications that offer greater simplicity. The Simplicity of Diabetes Treatment Questionnaire (Sim-Q™) was developed to assess the simplicity or complexity of treatment for T2D. This study assessed the psychometric properties of the Sim-Q.

Abstract

Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs is an innovative treatment for advanced well-differentiated neuroendocrine tumors (NETs). In Japan, PRRT with Lutetium-177 oxodotreotide (177Lu- oxodotreotide) was recently approved following Phase I and Phase I/II clinical trials, which primarily assessed safety and response rates. However, its long-term efficacy and safety remain unclear. We conducted a record-based analysis of these trials to evaluate progression-free survival (PFS), overall survival (OS), and long-term safety.

Abstract

Inflammatory bowel disease (IBD), including Crohn s disease (CD) and ulcerative colitis (UC), is characterized by chronic intestinal inflammation driven by elevated tumor necrosis factor-alpha (TNF- α ). Infliximab, an anti-TNF- α monoclonal antibody, is widely used in the treatment of inflammatory bowel disease but shows variable effectiveness due to interindividual pharmacokinetic diversity. We develop a low-dimensional mathematical model of ordinary differential equations to describe TNF- α dynamics, its interactions with receptors and infliximab, and the influence of drug clearance on treatment outcomes in CD and UC. This model is combined with a pharmacokinetic framework that enables the estimation of the infliximab clearance coefficient, which can then be used to guide dosage adjustments in the treatment. The model balances biological realism with analytical tractability, enabling rigorous mathematical analysis and numerical simulations. The parameters are adapted for CD and UC. The study investigates how drug clearance influences treatment efficacy, initially using constant clearance values and later incorporating values that vary with the level of inflammation. Simulations are performed across a range of clearance rates and dosing regimens, providing detailed insights into infliximab and TNF- α dynamics, as well as therapeutic drug monitoring parameters. Our results highlight the critical role of clearance and therapeutic drug monitoring in optimizing infliximab therapy. This approach offers valuable insights to support personalized treatment strategies in IBD.

Abstract

Hypothalamic obesity (HO) is a rare, complex disorder characterized by disruption of brain pathways regulating energy intake, expenditure, autonomic function, and hormonal signaling. It occurs in rare monogenic obesity syndromes affecting central leptin-melanocortin pathways or can be acquired (aHO) as a consequence of hypothalamic injury due to a tumor (e.g., craniopharyngioma), its treatment, or trauma. In this narrative review, we focus on aHO. Damage to specific hypothalamic nuclei leads to hyperphagia, central insulin and leptin resistance, decreased sympathetic activity, reduced energy expenditure, and rapid weight gain. Traditional obesity treatments, including lifestyle interventions, often fail to achieve sustained weight loss in patients with aHO. Recent advances in pharmacotherapy show promise by targeting the distinct pathophysiology of aHO. Effective treatment requires personalized approaches due to the heterogeneity of hypothalamic dysfunction and associated comorbidities. Early intervention may improve outcomes, as rapid postoperative weight gain frequently occurs. Emerging therapies target mechanisms of disturbed energy homeostasis pathways. These agents include stimulants, incretin-based therapies (e.g., glucagon-like peptide-1 receptor agonists), insulin modulators, and melanocortin receptor agonists such as setmelanotide. While monotherapies often fail in long-term treatment, combination therapies hold potential to restore energy balance and reduce or eliminate the need for bariatric surgery. Future research should focus on identifying clinical and biomarker profiles of aHO subtypes and evaluating combination therapies. Although challenging, aHO is no longer untreatable. Patients should be referred and managed at specialized centers, with pharmacological treatment preferably conducted within research settings to optimize and personalize care, and to develop evidence-based protocols for this debilitating condition.

Abstract

Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is an intracellular innate immune sensor. Its functions have been extensively studied. Variants in the NOD2 gene are associated with several human diseases. This report provides a comprehensive review of these diseases and biomedical and immunological roles of NOD2.

Abstract

Obesity, type 2 diabetes (T2D), cardiovascular disease (CVD), and chronic kidney disease (CKD) are overlapping conditions that drive premature morbidity and mortality worldwide. Care remains siloed and reactive despite shared risk factors and strong evidence for early intervention. To support integrated disease management, the American Heart Association (AHA) recently introduced the concept of cardiovascular-kidney-metabolic (CKM) syndrome, recognizing the bidirectional links between metabolic, kidney, and cardiovascular health. Kuwait faces one of the highest burdens of CKM-related diseases globally. Three-quarters of adults are overweight or have obesity, and 28% have diabetes, both of which are leading causes of mortality and health system strain. Yet multidisciplinary care remains limited, and innovative pharmacotherapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), are underused. A panel of Kuwaiti endocrinologists, cardiologists, and nephrologists convened to assess barriers to optimal CKM care and define practical recommendations. Discussions focused on current gaps in screening, care coordination, provider education, and access to therapies. Evidence on GLP-1 RAs was reviewed, considering the demonstrated benefits for weight loss, glycemic control, cardiovascular outcomes, and CKD progression. The expert group agreed that multidisciplinary, risk-stratified, and patient-centered approaches are urgently needed. Recommendations include earlier screening and diagnosis, improved integration across specialties, healthcare provider upskilling, public awareness campaigns, and broader access to GLP-1 RAs. Semaglutide was highlighted as a clinically valuable option owing to its broad efficacy and safety profile. Adopting a CKM care model tailored to Kuwait's specific challenges, with appropriate use of GLP-1 RAs, can reduce disease burden, improve outcomes, and increase healthcare system efficiency. The local implementation of evidence-based, cross-specialty strategies is key to altering the trajectory of CKM syndrome in high-risk populations.

Abstract

Sepsis-associated inflammation compromises the blood-brain barrier (BBB), yet the endothelial microRNA circuitry that buffers barrier failure remains poorly defined. Here we identify endothelial miR-7052 as a stress-suppressed regulator of BBB integrity. In human and murine brain microvascular endothelium, lipopolysaccharide (LPS) reduces mature miR-7052 via a VEGFR2-JNK signaling arm. Loss of miR-7052 de-represses ANGPT2 and PDE5A, attenuates Tie2 signaling, and perturbs cGMP homeostasis, yielding disrupted junctional continuity, reduced transendothelial electrical resistance (TEER), and increased macromolecular flux. Restoring miR-7052 increases TEER, lowers 4- and 70-kDa tracer permeability, and preserves ZO-1/claudin-5 organization. Mechanistically, dual-luciferase reporters confirm direct repression of ANGPT2 and PDE5A; prime-editing of endogenous 3'UTR seed sites abolishes miR-7052 control and eliminates miR-dependent changes in transcript half-life. Epistasis tests position both targets downstream: recombinant ANGPT2 partially reverses miR-7052-mediated protection, whereas pharmacological PDE5 inhibition phenocopies barrier stabilization. In vivo, endothelial-specific AAV9 delivery of miR-7052 limits LPS-evoked BBB leakage and reduces microvessel ANGPT2 with concordant reinforcement of BBB transcripts. Together, these data establish miR-7052 as a nodal controller coupling inflammatory receptor input to multi-target suppression of permeability drivers, nominating miR-7052 replacement and combinatorial targeting of the ANGPT2/Tie2 and PDE5A/cGMP axes as therapeutic strategies to preserve the BBB in sepsis.

Abstract

Tuberculosis (TB) remains the leading cause of death globally among infectious bacterial pathogens. As the only licensed vaccine for TB prevention, the BCG vaccine fails to deliver comprehensive protection. To address this limitation, this study selected Rv2031c (HspX)-a key antigen in the latent phase of TB-and Rv2428, an essential antigen in the active phase, for synthesis to construct the fusion antigen AH40. We adopted the pET - 28a vector for the expression of the fusion protein, while the pcDNA3.1(+) vector was utilized to construct the fusion gene DNA vaccine. Subsequently, the immunogenicity of the AH40 subunit vaccine and the corresponding DNA vaccine was evaluated and compared through experiments involving Mycobacterium tuberculosis (M.tb)-infected individuals and animal models.The fusion protein AH40 induced high levels of the cytokines IFN-γ, IL-2, and IL-6 in the peripheral blood of individuals infected with Mycobacterium tuberculosis (M.tb). Notably, the secretion levels of these cytokines stimulated by AH40 were higher than those induced by its individual antigen component. Consistent with this observation, AH40 exhibited enhanced immunogenicity compared to the single antigen. In mouse models, immunization with the protein-adjuvant vaccine AH40/Colloidal Manganese Adjuvant (AH40/MnJ) and the DNA vaccine AH40-DNA (AH40-D) both elicited high titers of IgG subclass antibodies. Further analysis revealed that the induced immune responses were biased toward a Th1-type profile. Collectively, these findings demonstrate that both vaccine formulations possess robust immunogenicity.

Abstract

The mcr gene family, responsible for plasmid-mediated resistance to colistin, poses a growing threat to public health by reducing the efficacy of colistin, a critical last-resort antibiotic for multidrug-resistant Gram-negative bacteria. The mcr-1 gene, discovered in 2015, marked a significant shift in understanding colistin resistance, and subsequent mcr variants (mcr-2 to mcr-10) have emerged globally. These genes alter lipid A in bacterial cell membranes, decreasing colistin's binding and efficacy. The mcr genes are typically located on mobile plasmids, facilitating horizontal gene transfer across bacterial species. Our review examines the evolution, genetic mechanisms, and structural characteristics of the mcr gene family, discussing their spread across human, animal, and environmental contexts. In this review, we highlight the clinical implications of mcr-mediated resistance, noting the co-occurrence of mcr with other antimicrobial resistance determinants, which complicates treatment options. Additionally, it explores detection methods, global epidemiology, and potential strategies to combat mcr resistance, including the development of inhibitors and CRISPR-based gene editing. Our review concludes that combating mcr-mediated colistin resistance requires global surveillance, coordination across sectors, and continued research to stop its spread and impact.

Abstract

This study investigated the basic composition, in vitro digestibility, biological activities, and potential bioactive peptides of Pacific oyster (PO), Mytilus edulis (ME), Argopecten irradians (AIS), and Meretrix meretrix L. (MML) after simulated gastrointestinal digestion (SGD).

Abstract

Triple-negative breast cancer represents a significant therapeutic challenge due to its aggressive behavior and limited treatment options. This study investigates the anticancer potential of microcin H47 (MccH47), a bacteriocin derived from clinical Escherichia coli isolates, against this malignancy. Among 120 screened Enterobacteriaceae isolates, 25 exhibited antimicrobial activity, with isolate 58 confirming MccH47 gene expression through molecular analysis. Cell viability assessment revealed a concentration-dependent reduction in cancer cell survival, while cell death analysis demonstrated approximately 86% apoptosis following 48 h of treatment. Gene expression studies identified significant downregulation of BCL2 and STAT3, indicating involvement of the STAT3/BCL-2 pathway in the observed effects. The extract exhibited biocompatibility toward normal fibroblasts, emphasizing MccH47's dual antimicrobial and antitumor properties with notable therapeutic selectivity. These findings support further development of MccH47 as a novel therapeutic agent for breast cancer treatment.

Abstract

A neoantigen vaccine against 209 frameshift peptides elicited strong, broad, and long-lasting immunity in people with Lynch syndrome in a phase Ib/II study, offering a novel approach for preventing the range of cancers these individuals are at an elevated risk of developing.

Abstract

Starvation elicits profound metabolic adaptations in skeletal muscle, enabling survival during nutrient scarcity. While global proteomic changes underpinning muscle atrophy have been studied, the role of lysine β-hydroxybutyrylation (Kbhb), a novel metabolite-derived post-translational modification linked to ketone metabolism, remains largely unexplored. In this study, we subjected mice to 72 h of food deprivation and performed integrative quantitative proteomics and Kbhb-modified peptide profiling on gastrocnemius muscle. Starvation induced significant body weight and muscle mass loss, accompanied by increased systemic β-hydroxybutyrate levels and widespread Kbhb modification of muscle proteins. Proteomic analysis revealed extensive downregulation of ribosomal and translation-associated proteins, coupled with upregulation of autophagy and lipid catabolism pathways, highlighting a coordinated shift from anabolic processes to catabolic and oxidative metabolism. Deep Kbhb profiling identified over 7500 modified lysine sites across 2000 proteins, with starvation triggering a global increase in Kbhb on key metabolic enzymes involved in glycolysis, TCA cycle, fatty acid β-oxidation, and amino acid metabolism. Notably, starvation-enhanced Kbhb preferentially targeted evolutionarily conserved lysines proximal to catalytic or cofactor-binding domains, implicating a regulatory role in enzymatic activity modulation. Conversely, Kbhb on structural and contractile proteins was downregulated, suggesting functional reprioritization of muscle physiology during fasting. Our findings uncover lysine β-hydroxybutyrylation as a dynamic, metabolically responsive PTM mediating gastrocnemius muscle adaptation to energy deficiency, expanding the paradigm of potentially metabolite-driven epigenetic and non-epigenetic regulatory mechanisms in muscle metabolism.