Hypoxia-inducible factor prolyl hydroxylase inhibitor alleviates heatstroke-induced acute kidney injury by activating BNIP3-mediated mitophagy.

Hypoxia-induced inflammation and apoptosis are important pathophysiological features of heat stroke-induced acute kidney injury (HS-AKI). Hypoxia-inducible factor (HIF) is a key protein that regulates cell adaptation to hypoxia. HIF-prolyl hydroxylase inhibitor (HIF-PHI) stabilizes HIF to increase cell adaptation to hypoxia. Herein, we reported that HIF-PHI pretreatment significantly improved renal function, enhanced thermotolerance, and increased the survival rate of mice in the context of HS. Moreover, HIF-PHI could alleviate HS-induced mitochondrial damage, inflammation, and apoptosis in renal tubular epithelial cells (RTECs) by enhancing mitophagy in vitro and in vivo. By contrast, mitophagy inhibitors Mdivi-1, 3-MA, and Baf-A1 reversed the renoprotective effects of HIF-PHI. Mechanistically, HIF-PHI protects RTECs from inflammation and apoptosis by enhancing Bcl-2 adenovirus E18 19-kDa-interacting protein 3 (BNIP3)-mediated mitophagy, while genetic ablation of BNIP3 attenuated HIF-PHI-induced mitophagy and abolished HIF-PHI-mediated renal protection. Thus, our results indicated that HIF-PHI protects renal function by upregulating BNIP3-mediated mitophagy to improve HS-induced inflammation and apoptosis of RTECs, suggesting HIF-PHI as a promising therapeutic agent to treat HS-AKI.

Beclin1 is essential for the pancreas development.

Beclin1 (Becn1) is a multifunctional protein involved in autophagy regulation, membrane trafficking, and tumor suppression. In this study, we examined the roles of Becn1 in the pancreas development by generating mice with conditional deletion of Becn1 in the pancreas using pancreatic transcriptional factor 1a (Ptf1a)-Cre mice (Becn1f/f; Ptf1aCre/+). Surprisingly, loss of Becn1 in the pancreas resulted in severe pancreatic developmental defects, leading to insufficient exocrine and endocrine pancreatic function. Approximately half of Becn1f/f; Ptf1aCre/+ mice died immediately after birth. However, duodenum and neural tissue development were almost normal, indicating that pancreatic insufficiency was the cause of death. These findings demonstrated a novel role for Becn1 in pancreas morphogenesis, differentiation, and growth, and suggested that loss of this factor leaded to pancreatic agenesis at birth.

Modulating Electrochemical Energy Storage and Multi-Spectra Defense of MXenes by Interfacial Dual-Filler Engineering.

MXenes have attracted growing interest in electrochemical energy storage owing to their high electronic conductivity and editable surface chemistry. Besides, rendering MXenes with spectrum defense properties further broadens their versatile applications. However, the development of MXenes suffers from weak van der Waal interaction-driven self-restacking that leads to random alignment and inferior interface microenvironments. Herein, a nacre-inspired MXene film is tailored by dual-filling of 2-ureido-4[1H]-pyrimidinone (UPy)-modified polyvinyl alcohol (PVA-UPy) and carbon nanotubes (CNTs). The dual-nanofillers engineering endows the nanocomposite film with a highly ordered structure (a Herman's order value of 0.838), a high mechanical strength (139.5 MPa), and continuous conductive pathways of both the ab plane and c-axis. As a proof-of-concept, the tailored nanocomposite film achieves a considerable capacitance of 508.2 F cm-3 and long-term cycling stability without performance degradation for 10 000 cycles. It is efficient for spectra defense in radar and infrared bands, displaying a high electromagnetic shielding capacity (19186 dB cm2 g-1) and a super-low infrared (IR) emissivity (0.16), with negligible performance decay after saving in the air for 1 year, responsible for the applications in specific and complex conditions. This interfacial dual-filler engineering concept showcases effective nanotechnology toward sustainable energy applications with a long lifetime and safety.

A Multi-Enzyme Nanocascade to Target Disease-Relevant Metabolites.

Metabolic processes in living organisms depend on the synergistic actions of enzymes working in proximity and in concert, catalyzing reactions effectively while regulating the formation of metabolites. This enzyme synergy offers promising therapeutic application for diseases such as alcohol intoxication, cancer, and hyperinflammation. Despite their potential, the clinical translation of enzyme cascades is restricted by challenges including poor enzyme stability, short half-life, and a lack of delivery strategies that maintain enzyme proximity. In this study, multi-enzyme nanocascades synthesized are developed through in situ atom transfer radical polymerization using a zwitterionic monomer. This method markedly enhances enzyme stability and proximity, thereby prolonging their circulation half-life after systemic administration. It is demonstrated that the nanocascades of uricase and catalase effectively reduce uric acid levels without excessive hydrogen peroxide production, providing a potential antidote for hyperuricemia. Moreover, in a murine breast cancer model, the nanocascades of glucose oxidase and catalase inhibited tumor progression and enhanced the therapeutic efficacy of doxorubicin. The prolonged circulation and promoted reaction efficacy of these nanocascades underscore their substantial potential in enzyme replacement therapy and the treatment of various diseases.

Imipenem reduces the efficacy of vancomycin against Elizabethkingia species.

BACKGROUND: Elizabethkingia spp. are emerging as nosocomial pathogens causing various infections. These pathogens express resistance to a broad range of antibiotics, thus requiring antimicrobial combinations for coverage. However, possible antagonistic interactions between antibiotics have not been thoroughly explored. This study aimed to evaluate the effectiveness of antimicrobial combinations against Elizabethkingia infections, focusing on their impact on pathogenicity, including biofilm production and cell adhesion. METHODS: Double-disc diffusion, time-kill, and chequerboard assays were used for evaluating the combination effects of antibiotics against Elizabethkingia spp. We further examined the antagonistic effects of antibiotic combinations on biofilm formation and adherence to A549 human respiratory epithelial cells. Further validation of the antibiotic interactions and their implications was performed using ex vivo hamster precision-cut lung sections (PCLSs) to mimic in vivo conditions. RESULTS: Antagonistic effects were observed between cefoxitin, imipenem and amoxicillin/clavulanic acid in combination with vancomycin. The antagonism of imipenem toward vancomycin was specific to its effects on the genus Elizabethkingia. Imipenem further hampered the bactericidal effect of vancomycin and impaired its inhibition of biofilm formation and the adhesion of Elizabethkingia meningoseptica ATCC 13253 to human cells. In the ex vivo PCLS model, vancomycin exhibited dose-dependent bactericidal effects; however, the addition of imipenem also reduced the effect of vancomycin. CONCLUSIONS: Imipenem reduced the bactericidal efficacy of vancomycin against Elizabethkingia spp. and compromised its capacity to inhibit biofilm formation, thereby enhancing bacterial adhesion. Clinicians should be aware of the potential issues with the use of these antibiotic combinations when treating Elizabethkingia infections.

The effect of hetrombopag combined with conventional treatment on immune function and quality of life in patients with severe aplastic anemia.

This study aimed to investigate the effect of hetrombopag combined with conventional treatment on immune function in patients with severe aplastic anemia (SAA). Patients were categorized into the control group (n = 50, receiving conventional treatment only) and experimental group (n = 50, receiving hetrombopag combined with conventional treatment). Before treatment and at weeks 18, 24, and 52 after treatment, the two groups were compared in routine blood test indicators, natural killer (NK) cell activity, and peripheral blood inflammatory factor levels. The overall remission rate and incidence of adverse events were also compared between the two groups. Outpatient or telephone follow-up was performed before treatment and at weeks 18, 24, and 52 after treatment to observe patients' immune function, treatment outcome, quality of life, and adverse events. Hemoglobin (Hb), and platelet count (PLT) (P < 0.05), and a rise in NK cell activity (P < 0.05). Interleukin (IL-10) levels were significantly higher, while IL-6 levels were significantly lower in the experimental group compared to the control group (P < 0.05). After receiving the treatment, all scores of SF-36 domains in both groups were higher than before treatment, particularly with higher scores in the experimental group (P < 0.05). Hetrombopag combined with conventional treatment improved the immune function and hematopoiesis of patients with SAA.

Editorial Perspective: Extending IPDMA methodology to drive treatment personalisation in child mental health.

To improve outcomes for youth who do not respond optimally to existing treatments, we need to identify robust predictors, moderators, and mediators that are ideal targets for personalisation in mental health care. We propose a solution to leverage the Individual Patient Data Meta-analysis (IPDMA) approach to allow broader access to individual-level data while maintaining methodological rigour. Such a resource has the potential to answer questions that are unable to be addressed by single studies, reduce researcher burden, and enable the application of newer statistical techniques, all to provide data-driven strategies for clinical decision-making. Using childhood anxiety as the worked example, the editorial perspective outlines the rationale for leveraging IPDMA methodology to build a data repository, the Platform for Anxiety Disorder Data in Youth. We also include recommendations to address the methods and challenges inherent in this endeavour.

Repositioning baloxavir marboxil as VISTA agonist that ameliorates experimental asthma.

V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA), a novel negative checkpoint regulator, plays an essential role in allergic pulmonary inflammation in mice. Treatment with a VISTA agonistic antibody could significantly improve asthma symptoms. Thus, for allergic asthma treatment, VISTA targeting may be a compelling approach. In this study, we examined the functional mechanism of VISTA in allergic pulmonary inflammation and screened the FDA-approved drugs for VISTA agonists. By using mass cytometry (CyTOF), we found that VISTA deficiency primarily increased lung macrophage infiltration in the OVA-induced asthma model, accompanied by an increased proportion of M1 macrophages (CD11b+F4/80+CD86+) and a decreased proportion of M2 macrophages (CD11b+F4/80+CD206+). Further in vitro studies showed that VISTA deficiency promoted M1 polarization and inhibited M2 polarization of bone marrow-derived macrophages (BMDMs). Importantly, we discovered baloxavir marboxil (BXM) as a VISTA agonist by virtual screening of FDA-approved drugs. The surface plasmon resonance (SPR) assays revealed that BXM (KD = 1.07 µM) as well as its active form, baloxavir acid (BXA) (KD = 0.21 µM), could directly bind to VISTA with high affinity. Notably, treatment with BXM significantly ameliorated asthma symptoms, including less lung inflammation, mucus secretion, and the generation of Th2 cytokines (IL-5, IL-13, and IL-4), which were dramatically attenuated by anti-VISTA monoclonal antibody treatment. BXM administration also reduced the pulmonary infiltration of M1 macrophages and raised M2 macrophages. Collectively, our study indicates that VISTA regulates pulmonary inflammation in allergic asthma by regulating macrophage polarization and baloxavir marboxil, and an old drug might be a new treatment for allergic asthma through targeting VISTA.

Tumor acidification and GSH depletion by bimetallic composite nanoparticles for enhanced chemodynamic therapy of TNBC.

Chemodynamic therapy (CDT) based on intracellular Fenton reaction to produce highly cytotoxic reactive oxygen species (ROS) has played an essential role in tumor therapy. However, this therapy still needs to be improved by weakly acidic pH and over-expression of glutathione (GSH) in tumor microenvironment (TEM), which hinders its future application. Herein, we reported a multifunctional bimetallic composite nanoparticle MnO2@GA-Fe@CAI based on a metal polyphenol network (MPN) structure, which could reduce intracellular pH and endogenous GSH by remodeling tumor microenvironment to improve Fenton activity. MnO2 nanoparticles were prepared first and MnO2@GA-Fe nanoparticles with Fe3+ as central ion and gallic acid (GA) as surface ligands were prepared by the chelation reaction. Then, carbonic anhydrase inhibitor (CAI) was coupled with GA to form MnO2@GA-Fe@CAI. The properties of the bimetallic composite nanoparticles were studied, and the results showed that CAI could reduce intracellular pH. At the same time, MnO2 could deplete intracellular GSH and produce Mn2+ via redox reactions, which re-established the TME with low pH and GSH. In addition, GA reduced Fe3+ to Fe2+. Mn2+ and Fe2+ catalyzed the endogenous H2O2 to produce high-lever ROS to kill tumor cells. Compared with MnO2, MnO2@GA-Fe@CAI could reduce the tumor weight and volume for the xenograft MDA-MB-231 tumor-bearing mice and the final tumor inhibition rate of 58.09 ± 5.77%, showing the improved therapeutic effect as well as the biological safety. Therefore, this study achieved the high-efficiency CDT effect catalyzed by bimetallic through reshaping the tumor microenvironment.

An Overview of Bioactive Compounds' Role in Modulating the Nrf2/Keap1/NF-κB Pathway to Alleviate Lipopolysaccharide-Induced Endometritis.

Endometritis is a common inflammatory condition of the uterine endometrial lining that primarily affects perinatal dairy animals and causes significant economic losses in agriculture. It is usually triggered by pathogenic bacteria and is associated with chronic postpartum reproductive tract infections. Bacterial lipopolysaccharides (LPSs) are known to increase levels of reactive oxygen species (ROS), leading to oxidative stress and inflammation through the activation of the NF-κB signaling pathway and the inhibition of Nrf2 nuclear translocation, which regulates antioxidant response elements (AREs). The effectiveness of the conventional management strategy involving antibiotics is decreasing due to resistance and residual concerns. This review explores the potential therapeutic benefits of targeting the Nrf2/Kelch-like ECH-associated protein 1 (Keap1)/NF-κB signaling pathway to alleviate LPS-induced endometritis. We discuss recent advancements in veterinary medicine that utilize exogenous antioxidants to modulate these pathways, thereby reducing oxidative stress and inflammatory responses in endometrial cells. This review highlights the efficacy of several bioactive compounds that enhance Nrf2 signaling and suppress NF-κB activation, offering protective effects against oxidative damage and inflammation. By examining various in vitro studies, this review emphasizes the emerging role of these signaling pathways in developing new therapeutic strategies that could potentially replace or supplement traditional treatments and mitigate the economic impacts of endometritis in livestock.

Infection may play an important role in the pathogenesis of alveolar osteonecrosis following facial herpes zoster: a case report and literature review.

BACKGROUND: Herpes zoster (HZ) is one of the most common skin diseases caused by viruses. Facial HZ develops when the varicella-zoster virus affects the trigeminal nerve, and alveolar osteonecrosis is a rare complication. However, the exact pathogenesis of postherpetic alveolar osteonecrosis remains unclear. CASE DESCRIPTION: We encountered a patient who presented to the dermatology clinic with facial HZ and tooth exfoliation in the upper right jaw, and panoramic radiography revealed decreased bone density and poor alveolar socket healing in his right maxilla. Biopsy of the alveolar process revealed fragments of nonvital lamellar bone, which were devoid of osteoblasts and osteocytes and were surrounded by numerous neutrophils and bacterial aggregates. Thus, the diagnosis of alveolar osteonecrosis following facial HZ was confirmed. He then underwent resection of the osteonecrotic tissue. The pathological findings of postoperative tissue were similar to those of previous biopsies. Varicella-zoster virus and multiple types of bacteria were detected through next-generation sequencing, and the species of bacteria were consistent with the results of bacterial culture. Antibiotics and valaciclovir were administered during the perioperative period. The patient showed good recovery at the 9-month follow-up. CONCLUSIONS: The coexistence of bacterial and viral infection may play an important role in the pathogenesis of alveolar osteonecrosis following HZ. To our knowledge, we are the first to directly explore microbial pathogens in a case of postherpetic alveolar osteonecrosis through next-generation sequencing and bacterial culture. We recommend that oral examinations be carefully conducted for patients who are diagnosed with facial HZ, even if their facial rashes have faded away. We suggest that a prolonged and full-dose antiviral therapy course may be beneficial for the treatment of facial HZ with intraoral lesions. The implementation of dental preventive measures should be considered for patients with facial HZ. The application of antibiotics and excision of necrotic bone may reduce the abundance of bacteria in lesions and improve wound healing.

Risk factors for complications in patients undergoing gastrointestinal endoscopy under acupuncture anesthesia.

Objective: To identify risk factors for complications in patients undergoing gastrointestinal endoscopy under acupuncture anesthesia and to construct a nomogram predictive model. Methods: This retrospective study included 292 patients who underwent gastrointestinal endoscopy under acupuncture anesthesia at the Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from June 2020 to May 2023. Logistic regression analysis was used to identify risk factors for complications in patients undergoing gastrointestinal endoscopy under acupuncture anesthesia. A nomogram prediction model was constructed using the RMS package of R4.1.2 software based on the independent risk factors identified. The predictive performance of the model was assessed using consistency index (C-index), calibration curve, and receiver operating characteristic (ROC) curve. Results: Seventy-five patients (25.68%) had complications. Body mass index (BMI), history of cardiovascular diseases, fasting time, history of respiratory diseases, and Sedation-Agitation Scale (SAS) score were identified as risk factors for complications. Based on this risk, a nomogram predictive model was constructed. The C-index of the nomogram model was 0.927. Calibration curve showed a good consistency between actual observations and nomogram predictions. The ROC curve area under curve (AUC) was 0.927 (95% CI: 0.895-0.959), indicating a certain predictive value for the occurrence of complications. When the optimal cut-off value was selected, the sensitivity and specificity of the model were 77.0% and 92.0%, respectively, indicating that the predictive model was effective. Conclusions: BMI, history of cardiovascular disease, fasting time, history of respiratory disease, and SAS score are independent risk factors for complications in patients undergoing gastrointestinal endoscopy under acupuncture anesthesia. The constructed nomogram predictive model has a good performance in predicting the occurrence of complications in patients undergoing gastrointestinal endoscopy with under acupuncture anesthesia.

Spatioselective Occlusion of Copolymer Nanoparticles within Calcite Crystals Generates Organic-Inorganic Hybrid Materials with Controlled Internal Structures.

Efficient occlusion of particulate additives into a single crystal has garnered an ever-increasing attention in materials science because it offers a counter-intuitive yet powerful platform to make crystalline nanocomposite materials with emerging properties. However, precisely controlling the spatial distribution of the guest additives within a host crystal remains highly challenging. We herein demonstrate a unique, straightforward method to engineer the spatial distribution of copolymer nanoparticles within calcite (CaCO3) single crystals by judiciously adjusting initial [Ca2+] concentration used for the calcite precipitation. More specifically, polymerization-induced self-assembly is employed to synthesize well-defined and highly anionic poly(3-sulfopropyl methacrylate potassium)41-block-poly(benzyl methacrylate)500 [PSPMA41-PBzMA500] diblock copolymer nanoparticles, which are subsequently used as model additives during the growth of calcite crystals. Impressively, such guest nanoparticles are preferentially occluded into specific regions of calcite depending on the initial [Ca2+] concentration. These unprecedented phenomena are most probably caused by dynamic change in electrostatic interaction between Ca2+ ions and PSPMA41 chains based on systematic investigations. This study not only showcases a significant advancement in controlling the spatial distribution of guest nanoparticles within host crystals, enabling the internal structure of composite crystals to be rationally tailored via a spatioselective occlusion strategy, but also provides new insights into biomineralization.

Interfacial Supra-Assembly of Copolymer Nanoparticles Enables the Formation of Nanocomposite Crystals with a Tunable Internal Structure.

It is highly desirable but technically challenging to precisely control the spatial composition and internal structure of crystalline nanocomposite materials, especially in a one-pot synthetic route. Herein, we demonstrate a versatile pathway to tune the spatial distribution of guest species within a host inorganic crystal via an incorporation strategy. Specifically, well-defined block copolymer nanoparticles, poly(methacrylic acid)x-block-poly(styrene-alt-N-phenylmaleimide)y [PMAAx-P(St-alt-NMI)y], are synthesized by polymerization-induced self-assembly. Such anionic nanoparticles can supra-assemble onto the surface of larger cationic nanoparticles via an electrostatic interaction, forming colloidal nanocomposite particles (CNPs). Remarkably, such CNPs can be incorporated into calcite single crystals in a spatially controlled manner: the depth of CNPs incorporation into calcite is tunable. Systematic investigation indicates that this interesting phenomenon is governed by the colloidal stability of CNPs, which in turn is dictated by the PMAAx-P(St-alt-NMI)y adsorption density and calcium ion concentration. This study opens up a general and efficient route for the preparation of a wide range of crystalline nanocomposite materials with a controlled internal composition and structure.

Electrochemical Enhancement of Lithium-Ion Diffusion in Polypyrrole-Modified Sulfurized Polyacrylonitrile Nanotubes for Solid-to-Solid Free-Standing Lithium-Sulfur Cathodes.

The energy density of lithium-sulfurized polyacrylonitrile (Li-SPAN) batteries has chronically suffered from low sulfur content. Although a free-standing electrode can significantly reduce noncapacity mass contribution, the slow bulk reaction kinetics still constrain the electrochemical performance. In this regard, a novel electrochemically active additive, polypyrrole (PPy), is introduced to construct PAN nanotubes as a sulfur carrier. This hollow channel greatly facilitates charge transport within the electrode and increases the sulfur content. Both electrochemical tests and simulations show that the SPANPPy-1% cathode possesses a larger lithium-ion diffusion coefficient and a more homogeneous phase interface than the SPAN cathode. Consequently, significantly improved capabilities and rate properties are achieved, as well as decent exportations under high-sulfur-loading or lean-electrolyte conditions. In-situ and semi-situ characterizations are further performed to demonstrate the nucleation growth of lithium sulfide and the evolution of the electrode surface structure. This type of electrochemically active additive provides a well-supported implementation of high-energy-density Li-S batteries.

Transcriptomic data recover a new superfamily-level phylogeny of Cucujiformia (Coleoptera, Polyphaga).

Cucujiformia, the largest taxon in the order Coleoptera, exhibits extraordinary morphological, ecological, and behavioral diversity. This infraorder is currently divided into seven superfamilies, but considerably incongruent relationships among superfamilies have been reported by recent phylogenomic studies. Here, we combined the 21 newly sequenced transcriptomes representing six superfamilies with nine previously published cucujiform genomes/transcriptomes to elucidate the phylogeny and evolution of Cucujiformia. The monophyly of each of five superfamilies were consistently supported by all phylogenetic analyses based on the twelve datasets (matrix occupancy, amino acid and nucleotide data) and the two analytical methods (maximum likelihood method and Bayesian inference). Both the amino acid datasets and the RY recoded nucleotide datasets recovered the monophyly of Cucujoidea. Topology test results statistically supported the following robust superfamily-level phylogeny in Cucujiformia: (Coccinelloidea, (Cleroidea, (Tenebrionoidea, (Cucujoidea, (Chrysomeloidea, Curculionoidea))))). Our divergence time analyses recovered a Permian origin of Cucujiformia and a Jurassic-Cretaceous origin of most superfamilies. The diversification of phytophagous beetles that occurred in the Cretaceous can be attributed to its co-evolution with angiosperms, supporting the hypothesis of a Cretaceous Terrestrial Revolution.

Role of exosome-derived miRNAs in diabetic wound angiogenesis.

Chronic wounds with high disability are among the most common and serious complications of diabetes. Angiogenesis dysfunction impair wound healing in patients with diabetes. Compared with traditional therapies that can only provide symptomatic treatment, stem cells-owing to their powerful paracrine properties, can alleviate the pathogenesis of chronic diabetic wounds and even cure them. Exosome-derived microRNAs (miRNAs), important components of stem cell paracrine signaling, have been reported for therapeutic use in various disease models, including diabetic wounds. Exosome-derived miRNAs have been widely reported to be involved in regulating vascular function and have promising applications in the repair and regeneration of skin wounds. Therefore, this article aims to review the current status of the pathophysiology of exosome-derived miRNAs in the diabetes-induced impairment of wound healing, along with current knowledge of the underlying mechanisms, emphasizing the regulatory mechanism of angiogenesis, we hope to document the emerging theoretical basis for improving wound repair by restoring angiogenesis in diabetes.

Imatinib and M351-0056 enhance the function of VISTA and ameliorate the development of SLE via IFN-I and noncanonical NF-κB pathway.

V-domain immunoglobulin suppressor of T-cell activation (VISTA), an important negative checkpoint protein, participates in immunoregulation. Systemic lupus erythematosus (SLE) is an autoimmune disease in which patients exhibit high levels of autoantibodies and multi-organ tissue injury, primarily involving the kidney and skin. In wild-type (WT) mice and Vsir-/- mice with pristane-induced lupus-like disease, we found that VISTA deficiency exacerbated the lupus-like disease in mice, possibly through aberrant activation of type I interferon (IFN-I) signaling, CD4+ T cell, and noncanonical nuclear factor-κB (NF-κB) pathway. Surface plasmon resonance results showed that imatinib, an FDA-approved tyrosine kinase inhibitor, may have a high affinity for human VISTA-ECD with a KD value of 0.2009 µM. The biological activities of imatinib and VISTA agonist M351-0056 were studied in monocytes and T cells and in lupus-like disease murine model of chronic graft-versus-host disease (cGVHD) and lupus-prone MRL/lpr mice. VISTA small-molecule agonist reduced the cytokine production of peripheral blood mononuclear cells (PBMCs) and Jurkat cells and inhibited PBMCs proliferation. Moreover, they attenuated the levels of autoantibodies, renal injury, inflammatory cytokines, chemokines, and immune cell expansion in the cGVHD mouse model and MRL/lpr mice. Our findings also demonstrated that VISTA small-molecule agonist ameliorated the development of SLE through improving aberrantly activated IFN-I signaling and noncanonical NF-κB pathway. In conclusion, VISTA has a protective effect on the development and progression of SLE. VISTA agonist M351-0056 and imatinib have been firstly demonstrated to attenuate SLE, suggesting interventions to enhance VISTA function may be effective in treating SLE. VISTA deficiency exacerbates pristane-induced lupus-like disease in mice by promoting activation of the IFN-I and noncanonical NF-κB pathway. Imatinib was screened as a small-molecule VISTA agonist by molecular docking, SPR, and cellular level experiments. VISTA agonists (M351-0056 and imatinib) alleviated lupus-like disease progression in the cGVHD mouse model and MRL/lpr mice by inhibiting activation of IFN-I and noncanonical NF-κB pathway.

Increased circulating FGF21 level predicts the burden of metabolic demands and risk of vascular diseases in adults with type 2 diabetes.

OBJECTIVES: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by chronic hyperglycemia and metabolic stress, involved in the stepwise development of cardiovascular complications. Fibroblast growth factor 21 (FGF21) is a novel hepatokine involved in regulating glucose and lipid metabolism, and has been linked to the prediction, treatment, and improvement of prognosis in multiple cardiovascular diseases (CVDs). The aim of this study is to explore the relationship between FGF21 levels and vascular diseases (VDs) including carotid atherosclerosis (CAS) and hypertension (HP) in patients with T2DM. METHODS: Baseline serum FGF21 was determined in a cross-sectional study of 701 patients with T2DM and 258 healthy control. RESULTS: The morbidity of CAS was increased in T2DM patients with HP as compared with those without (p < 0.001). The average serum FGF21 level of healthy was [123.9 (67.2-219.3)]. Baseline FGF21 was significantly higher in those who developed CAS or HP than in those who did not [305.9 (177.2-508.4) vs. 197.2 (129.7-308.3) pg/mL, p < 0.001]. In addition, an elevated serum FGF21 was observed in T2DM patients with HP and CAS than that of T2DM patients with CAS or HP [550.5 (312.6-711.3) vs. 305.9 pg/mL, p < 0.001]. Serum FGF21 levels were positively correlated with body mass index and carotid intima media thicknes (p < 0.05), the association remained significant after adjusting for age and T2DM duration. Furthermore, the multinomial logistic regression showed that serum FGF21 was independently associated with CAS and HP in patients with T2DM after adjustment for demographic and traditional VDs risk factors (p < 0.001). CONCLUSIONS: Baseline FGF21 is elevated in VDs during diabetes, changes of serum FGF21 levels were appropriately matched to metabolic stress. FGF21can be used as an independent predictor for diagnosing VDs and predicting prognosis.

Safety of prone emergence from general endotracheal anesthesia in patients undergoing ERCP: a randomized controlled trial.

BACKGROUND: Conventional supine emergence and prone extubation from general endotracheal anesthesia (GEA) are associated with extubation-related adverse events (ERAEs). Given the minimally invasive nature of endoscopic retrograde cholangiopancreatography (ERCP) as well as the improved ventilation/perfusion matching and easier airway opening in the prone position, we aimed to assess the safety of prone emergence and extubation in patients undergoing ERCP under GEA. METHODS: Totally, 242 eligible patients were recruited and randomized into the supine extubation group (n = 121; supine group) and the prone extubation group (n = 121; prone group). The primary endpoint was the incidence of ERAEs during emergence, including hemodynamic fluctuations, coughing, stridor, and hypoxemia requiring airway maneuvers. The secondary endpoints included the incidence of monitoring disconnections, extubation time, recovery time, room exit time, and post-procedure sore throat. RESULTS: The incidence of ERAEs was significantly lower in the prone group compared with the supine group (8.3% vs 34.7%, OR = 0.17, 95% CI 0.18-0.56; P < 0.001). Moreover, the prone group demonstrated no monitoring disconnections, shorter extubation time and room exit time, faster recovery, and, lower frequency and milder sore throat after the procedure. CONCLUSIONS: For patients undergoing ERCP under GEA, compared with supine, prone emergence, and extubation had remarkably lower rates of EAREs and better recovery, and can maintain continuous monitoring and improve efficiency.