A single infusion of engineered long-lived and multifunctional T cells confers durable remission of asthma in mice.

Asthma, the most prevalent respiratory disease, affects more than 300 million people and causes more than 250,000 deaths annually. Type 2-high asthma is characterized by interleukin (IL)-5-driven eosinophilia, along with airway inflammation and remodeling caused by IL-4 and IL-13. Here we utilize IL-5 as the targeting domain and deplete BCOR and ZC3H12A to engineer long-lived chimeric antigen receptor (CAR) T cells that can eradicate eosinophils. We call these cells immortal-like and functional IL-5 CAR T cells (5TIF) cells. 5TIF cells were further modified to secrete an IL-4 mutein that blocks IL-4 and IL-13 signaling, designated as 5TIF4 cells. In asthma models, a single infusion of 5TIF4 cells in fully immunocompetent mice, without any conditioning regimen, led to sustained repression of lung inflammation and alleviation of asthmatic symptoms. These data show that asthma, a common chronic disease, can be pushed into long-term remission with a single dose of long-lived CAR T cells.

Ni3C/Ni3S2 Heterojunction Electrocatalyst for Efficient Methanol Oxidation via Dual Anion Co-modulation Strategy.

Enhancing active states on the catalyst surface by modulating the adsorption-desorption properties of reactant species is crucial to optimizing the electrocatalytic activity of transition metal-based nanostructured materials. In this work, an efficient optimization strategy is proposed by co-modulating the dual anions (C and S) in Ni3C/Ni3S2, the heterostructured electrocatalyst, which is prepared via a simple hot-injection method. The presence of Ni3C/Ni3S2 heterojunctions accelerates the charge carrier transfer and promotes the generation of active sites, enabling the heterostructured electrocatalyst to achieve current densities of 10/100 mA cm-2 at 1.37 V/1.53 V. The Faradaic efficiencies for formate production coupled with hydrogen evolution approach 100%, accompanied with a stability record of 350 h. Additionally, operando electrochemical impedance spectroscopy (EIS), in situ Raman spectroscopy, and density functional theory (DFT) calculations further demonstrate that the creation of Ni3C/Ni3S2 heterointerfaces originating from dual anions' (C and S) differentiation is effective in adjusting the d-band center of active Ni atoms, promoting the generation of active sites, as well as optimizing the adsorption and desorption of reaction intermediates. This dual anions co-modulation strategy to stable heterostructure provides a general route for constructing high-performance transition metal-based electrocatalysts.

CircRNA Arf3 suppresses glomerular mesangial cell proliferation and fibrosis in diabetic nephropathy via miR-107-3p/Tmbim6 axis.

Diabetic nephropathy (DN) is one of microvascular complication associated with diabetes. Circular RNAs (circRNAs) have been shown to be involved in DN pathogenesis. Hence, this work aimed to explore the role and mechanism of circ_Arf3 in DN. Mouse mesangial cells (MCs) cultured in high glucose (HG) condition were used for functional analysis. Cell proliferation was determined using 5-ethynyl-2'-deoxyuridine (EdU) and cell counting kit-8 assays. Western blotting was used to measure the levels of proliferation indicator PCNA and fibrosis-related proteins α-smooth muscle actin (α-SMA), collagen I (Col I), fibronectin (FN), and collagen IV (Col IV). The binding interaction between miR-107-3p and circ_Arf3 or Tmbim6 (transmembrane BAX inhibitor motif containing 6) was confirmed using dual-luciferase reporter and pull-down assays. Circ_Arf3 is a stable circRNA, and the expression of circ_Arf3 was decreased after HG treatment in MCs. Functionally, ectopic overexpression of circ_Arf3 protected against HG-induced proliferation and elevation of fibrosis-related proteins in MCs. Mechanistically, circ_Arf3 directly bound to miR-107-3p, and Tmbim6 was a target of miR-107-3p. Further rescue assay showed miR-107-3p reversed the protective action of circ_Arf3 on MCs function under HG condition. Moreover, inhibition of miR-107-3p suppressed HG-induced proliferation and fibrosis, which were attenuated by Tmbim6 knockdown in MCs. CircRNA Arf3 could suppress HG-evoked mesangial cell proliferation and fibrosis via miR-107-3p/Tmbim6 axis, indicating the potential involvement of this axis in DN progression.

The additive effect of the triglyceride-glucose index and estimated glucose disposal rate on long-term mortality among individuals with and without diabetes: a population-based study.

BACKGROUND: The triglyceride-glucose (TyG) index and estimated glucose disposal rate (eGDR), which are calculated using different parameters, are widely used as markers of insulin resistance and are associated with cardiovascular diseases and prognosis. However, whether they have an additive effect on the risk of mortality remains unclear. This study aimed to explore whether the combined assessment of the TyG index and eGDR improved the prediction of long-term mortality in individuals with and without diabetes. METHODS: In this cross-sectional and cohort study, data were derived from the National Health and Nutrition Examination Survey (NHANES) 2001-2018, and death record information was obtained from the National Death Index. The associations of the TyG index and eGDR with all-cause and cardiovascular mortality were determined by multivariate Cox regression analysis and restricted cubic splines. RESULTS: Among the 17,787 individuals included in the analysis, there were 1946 (10.9%) all-cause deaths and 649 (3.6%) cardiovascular deaths during a median follow-up of 8.92 years. In individuals with diabetes, the restricted cubic spline curves for the associations of the TyG index and eGDR with mortality followed a J-shape and an L-shape, respectively. The risk of mortality significantly increased after the TyG index was > 9.04 (all-cause mortality) or > 9.30 (cardiovascular mortality), and after eGDR was < 4 mg/kg/min (both all-cause and cardiovascular mortality). In individuals without diabetes, the association between eGDR and mortality followed a negative linear relationship. However, there was no association between the TyG index and mortality. Compared with individuals in the low TyG and high eGDR group, those in the high TyG and low eGDR group (TyG > 9.04 and eGDR < 4) showed the highest risk for all-cause mortality (hazard ratio [HR] = 1.592, 95% confidence interval [CI] 1.284-1.975) and cardiovascular mortality (HR = 1.683, 95% CI 1.179-2.400) in the overall population. Similar results were observed in individuals with and without diabetes. CONCLUSIONS: There was a potential additive effect of the TyG index and eGDR on the risk of long-term mortality in individuals with and without diabetes, which provided additional information for prognostic prediction and contributed to improving risk stratification.

BNIP3L/NIX-mediated mitophagy alleviates passive stress-coping behaviors induced by tumor necrosis factor-α.

Recent studies based on animal models of various neurological disorders have indicated that mitophagy, a selective autophagy that eliminates damaged and superfluous mitochondria through autophagic degradation, may be involved in various neurological diseases. As an important mechanism of cellular stress response, much less is known about the role of mitophagy in stress-related mood disorders. Here, we found that tumor necrosis factor-α (TNF-α), an inflammation cytokine that plays a particular role in stress responses, impaired the mitophagy in the medial prefrontal cortex (mPFC) via triggering degradation of an outer mitochondrial membrane protein, NIP3-like protein X (NIX). The deficits in the NIX-mediated mitophagy by TNF-α led to the accumulation of damaged mitochondria, which triggered synaptic defects and behavioral abnormalities. Genetic ablation of NIX in the excitatory neurons of mPFC caused passive coping behaviors to stress, and overexpression of NIX in the mPFC improved TNF-α-induced synaptic and behavioral abnormalities. Notably, ketamine, a rapid on-set and long-lasting antidepressant, reversed the TNF-α-induced behavioral abnormalities through activation of NIX-mediated mitophagy. Furthermore, the downregulation of NIX level was also observed in the blood of major depressive disorder patients and the mPFC tissue of animal models. Infliximab, a clinically used TNF-α antagonist, alleviated both chronic stress- and inflammation-induced behavioral abnormalities via restoring NIX level. Taken together, these results suggest that NIX-mediated mitophagy links inflammation signaling to passive coping behaviors to stress, which underlies the pathophysiology of stress-related emotional disorders.

An overview of cyclopropenone derivatives as promising bioactive molecules.

Cyclopropenone is a valuable electrophilic reagent that can react with electrophilic reagents, nucleophilic reagents, free radicals, organic metals, etc. Furthermore, cyclopropenone derivatives have shown significant biological activity in various diseases, such as triple-negative breast cancer (TNBC), melanoma, and alopecia areata (AA). The cyclopropenone analogue diphenylcyclopropenone (DPCP) has been approved for the treatment of AA. Given the potential therapeutic benefits of cyclopropenone derivatives, this review aims to systematically summarize the structures, synthesis routes, and potential pharmacological functions of cyclopropenone analogues in the hope of offering novel insights for further rational design of more drugs based on the cyclopropenone skeleton for the treatment of human diseases.

Targeting DNA methyltransferases for cancer therapy.

DNA methyltransferases (DNMTs) play a crucial role in genomic DNA methylation. In mammals, DNMTs regulate the dynamic patterns of DNA methylation in embryonic and adult cells. Abnormal functions of DNMTs are often indicative of cancers, including overall hypomethylation and partial hypermethylation of tumor suppressor genes (TSG), which accelerate the malignancy of tumors, worsen the condition of patients, and significantly exacerbate the difficulty of cancer treatment. Currently, nucleoside DNMT inhibitors such as Azacytidine and Decitabine have been approved by the FDA and EMA for the treatment of acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), and myelodysplastic syndrome (MDS). Therefore, targeting DNMTs is a very promising anti-tumor strategy. This review mainly summarizes the therapeutic effects of DNMT inhibitors on cancers. It aims to provide more possibilities for the treatment of cancers by discovering more DNMT inhibitors with high activity, high selectivity, and good drug-like properties in the future.

Targeting histone methylation and demethylation for non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide, facing increasing challenges in terms of prevention and treatment. The methylation of lysine and arginine residues on histone proteins is dynamically controlled by histone methyltransferases (HMTs) and histone demethylases (HDMs), regulating chromatin structure and gene transcription. Mutations, genetic translocations, and altered gene expression involving HMTs and HDMs are frequently observed in NAFLD. HMTs and HDMs are receiving increasing attention in regulating NALFD. Targeting specific HMTs and HDMs for drug development is becoming a new strategy for treating NAFLD. This review provides a comprehensive summary of the regulatory mechanism of histone methylation/demethylation in NAFLD. Additionally, we discuss the potential applications of HMTs and HDMs inhibitors in preventing NAFLD, which may provide a scientific basis for the treatment of NAFLD.

Establishment and verification of a method for analyzing nasal blackheads images.

BACKGROUND: As people pay more attention to their skin health and the demand of developing skin care products for facial blackheads grows, the value of objective and efficient image recognition methods for blackheads is becoming more evident. Inspired by this current situation, this study attempted to analyze the number of blackheads of different severity automatically on the nose using an object recognition method on photographs of the nasal blackheads of subjects. METHOD: This study collected 350 subjects' facial photos in the laboratory environment, who aged 18-60, with blackhead symptoms in the nasal region. And expert assessment was used as a reference for machine learning to verify the performance of the nasal blackhead image recognition model through consistency and correlation analysis. RESULTS: The study concluded that the algorithm accuracy reached above 0.9, the model itself was effective, and the consistency between the model and the expert assessor assessment results was good, with the number of nasal blackheads, the count of blackheads of different severity, and the intra-group correlation coefficient ICC of blackhead severity all above 0.9, indicating that the deep learning-based assessment model had high overall performance and the evaluation results were comparable to those of the expert assessor. CONCLUSION: The recognition and analyzing model of nasal blackhead images provides a scientifically objective and accurate method for identifying the number and evaluating the severity of nasal blackheads. By using this model, the efficiency of evaluating nasal blackhead images in the cosmetics clinical trial will be improved. The assessment result of nasal blackheads will be objective and stable, and not only rely on the professional knowledge and clinical experience of assessors. The model can try to be applied in cosmetics efficacy testing and continuously optimized.

Association between living alone and all-cause mortality of young and middle-aged patients with acute myocardial infarction: analysis of the China Acute Myocardial Infarction (CAMI) registry.

BACKGROUND: Lack of social support is a known predictor of the prognosis after acute myocardial infarction (AMI). Although as a common factor associated with social support, there are limited data on long-term prognostic impact of living status in young and middle-aged patients with AMI. METHODS: We analyzed data from the China Acute Myocardial Infarction (CAMI) Registry, consecutive AMI young and middle-aged patients admitted at 108 hospitals in China between January 2013 and September 2014 were included. Eligible patients were assigned to living alone and not living alone groups based on their living status. The primary endpoint was 2-year all-cause mortality. The secondary endpoints included in-hospital mortality and 2-year major adverse cardiac and cerebrovascular events (MACCEs; a composite of all-cause mortality, MI, or stroke). Multilevel logistic and multilevel Cox regression models were used to evaluate the effect of living status on short-term and long-term outcomes. RESULTS: A total of 8307 consecutive AMI young and middle-aged patients were included, 192 (2.3%) patients were living alone. Of the analyzed patients, living alone was associated with 2-year all-cause mortality and MACCEs among all analyzed patients after multivariate adjustment (adjusted hazard ratio [HR] = 2.171 [1.210-3.895], P = 0.009; adjusted HR = 2.169 [1.395-3.370], P = 0.001), but not with poorer in-hospital mortality. CONCLUSIONS: The analysis suggested that living alone was associated with both 2-year all-cause mortality and MACCEs in AMI young and middle-aged patients but did not show an extra effect on the in-hospital mortality after covariate adjustment. TRIAL REGISTRATION: Trial registration number: NCT01874691; Registered 31 October 2012.

A Recursive Non-Uniform Sampling Estimator for Asynchronous Nonlinear Systems.

In this paper, we consider the problem of asynchronous estimation in the presence of packet losses for the randomly sampling nonlinear system. Packet losses occur at the control input and at the measurement side. Firstly, the synchronization of the asynchronous sampling system is realized by weighting the state of the adjacent state update points. Secondly, the projection theorem is used to estimate the system state at the sampling time. Due to modeling errors and unmodeled dynamics, obtaining an accurate dynamic model is challenging. Therefore, observation inference based on interpolation techniques is proposed to solve the asynchronous estimation problem. Furthermore, the algorithm is extended to multi-sensor systems to obtain a distributed fusion estimator. Finally, simulation experiments are conducted to validate the effectiveness of the algorithm.

Enhancing Functional Properties and Protein Structure of Almond Protein Isolate Using High-Power Ultrasound Treatment.

The suitability of a given protein for use in food products depends heavily on characteristics such as foaming capacity, emulsifiability, and solubility, all of which are affected by the protein structure. Notably, protein structure, and thus characteristics related to food applications, can be altered by treatment with high-power ultrasound (HUS). Almonds are a promising source of high-quality vegetable protein for food products, but their physicochemical and functional properties remain largely unexplored, limiting their current applications in foods. Here, we tested the use of HUS on almond protein isolate (API) to determine the effects of this treatment on API functional properties. Aqueous almond protein suspensions were sonicated at varying power levels (200, 400, or 600 W) for two durations (15 or 30 min). The molecular structure, protein microstructure, solubility, and emulsifying and foaming properties of the resulting samples were then measured. The results showed that HUS treatment did not break API covalent bonds, but there were notable changes in the secondary protein structure composition, with the treated proteins showing a decrease in α-helices and ß-turns, and an increase in random coil structures as the result of protein unfolding. HUS treatment also increased the number of surface free sulfhydryl groups and decreased the intrinsic fluorescence intensity, indicating that the treatment also led to alterations in the tertiary protein structures. The particle size in aqueous suspensions was decreased in treated samples, indicating that HUS caused the dissociation of API aggregates. Finally, treated samples showed increased water solubility, emulsifying activity, emulsifying stability, foaming capacity, and foaming stability. This study demonstrated that HUS altered key physicochemical characteristics of API, improving critical functional properties including solubility and foaming and emulsifying capacities. This study also validated HUS as a safe and environmentally responsible tool for enhancing desirable functional characteristics of almond proteins, promoting their use in the food industry as a high-quality plant-based protein.

[Intestinal absorption components and absorption characteristics of Wuwei Qingzhuo San by everted intestinal sac models].

This study investigated the absorption profile of Wuwei Qingzhuo San in different intestinal segments and the absorption characteristics of its alkaloids(piperine, piperanine, piperlonguminine, and dihydropiperlonguminine). The everted gut sac model was established, and the chemical components of Wuwei Qingzhuo San in different intestinal segments were detected by UPLC-Q-TOF-MS. The content of piperine, piperanine, piperlonguminine, and dihydropiperlonguminine in intestinal absorption fluid was determined by UPLC-Q-TRAP-MS and the absorption parameters were calculated. The absorption characteristics in different intestinal segments at different time were analyzed. As a result, 27, 27, 8, and 6 absorbent components from Wuwei Qingzhuo San were detected in the intestinal cyst fluid of jejunum, ileum, duodenum, and colon by UPLC-Q-TOF-MS technology, respectively. It was also found that piperine, piperanine, piperlonguminine, and dihydropiperlonguminine from Wuwei Qingzhuo San showed linear absorption in various intestinal segments, with r values exceeding 0.9. In terms of absorption content, the components were ranked as piperine>piperanine>dihydropiperlonguminine>piperlonguminine in various intestinal segments, but the absorption rate and mechanism of each component varied. The results demonstrate that the absorption of the components of Wuwei Qingzhuo San in different intestinal segments is selective and is not a simple semi-permeable membrane permeation process.

[Urinary protein and renal pathological features in children with immunoglobulin A vasculitis with nephritis and hypercoagulability]. / 儿童IgAè¡€ç®¡ç‚Žè‚¾ç‚Žä¼´é«˜å‡çŠ¶æ€çš„å°¿è›‹ç™½å’Œè‚¾è„ç— ç†ç‰¹å¾åˆ†æž.

OBJECTIVES: To study the association of hypercoagulability with urinary protein and renal pathological damage in children with immunoglobulin A vasculitis with nephritis (IgAVN). METHODS: Based on the results of coagulation function, 349 children with IgAVN were divided into a hypercoagulability group consisting of 52 children and a non-hypercoagulability group consisting of 297 children. Urinary protein and renal pathological features were compared between the two groups, and the factors influencing the formation of hypercoagulability in children with IgAVN were analyzed. RESULTS: Compared with the non-hypercoagulability group, the hypercoagulability group had significantly higher levels of urinary erythrocyte count, 24-hour urinary protein, urinary protein/creatinine, urinary immunoglobulin G/creatinine, and urinary N-acetyl-ß-D-glucosaminidase (P<0.05). The hypercoagulability group also had a significantly higher proportion of children with a renal pathological grade of III-IV, diffuse mesangial proliferation, capillary endothelial cell proliferation, or >25% crescent formation (P<0.05). The multivariate logistic regression analysis showed that capillary endothelial cell proliferation and glomerular crescent formation >25% were associated with the formation of hypercoagulability in children with IgAVN (P<0.05). CONCLUSIONS: The renal injury in IgAVN children with hypercoagulability is more severe, with greater than 25% crescent formation and increased proliferation of glomerular endothelial cells being important contributing factors that exacerbate the hypercoagulable state in IgAVN.

Deep Learning for Fully Automated Prediction of Overall Survival in Patients Undergoing Resection for Pancreatic Cancer: A Retrospective Multicenter Study.

OBJECTIVE: To develop an imaging-derived biomarker for prediction of overall survival (OS) of pancreatic cancer by analyzing preoperative multiphase contrast-enhanced computed topography (CECT) using deep learning. BACKGROUND: Exploiting prognostic biomarkers for guiding neoadjuvant and adjuvant treatment decisions may potentially improve outcomes in patients with resectable pancreatic cancer. METHODS: This multicenter, retrospective study included 1516 patients with resected pancreatic ductal adenocarcinoma (PDAC) from 5 centers located in China. The discovery cohort (n=763), which included preoperative multiphase CECT scans and OS data from 2 centers, was used to construct a fully automated imaging-derived prognostic biomarker-DeepCT-PDAC-by training scalable deep segmentation and prognostic models (via self-learning) to comprehensively model the tumor-anatomy spatial relations and their appearance dynamics in multiphase CECT for OS prediction. The marker was independently tested using internal (n=574) and external validation cohorts (n=179, 3 centers) to evaluate its performance, robustness, and clinical usefulness. RESULTS: Preoperatively, DeepCT-PDAC was the strongest predictor of OS in both internal and external validation cohorts [hazard ratio (HR) for high versus low risk 2.03, 95% confidence interval (CI): 1.50-2.75; HR: 2.47, CI: 1.35-4.53] in a multivariable analysis. Postoperatively, DeepCT-PDAC remained significant in both cohorts (HR: 2.49, CI: 1.89-3.28; HR: 2.15, CI: 1.14-4.05) after adjustment for potential confounders. For margin-negative patients, adjuvant chemoradiotherapy was associated with improved OS in the subgroup with DeepCT-PDAC low risk (HR: 0.35, CI: 0.19-0.64), but did not affect OS in the subgroup with high risk. CONCLUSIONS: Deep learning-based CT imaging-derived biomarker enabled the objective and unbiased OS prediction for patients with resectable PDAC. This marker is applicable across hospitals, imaging protocols, and treatments, and has the potential to tailor neoadjuvant and adjuvant treatments at the individual level.

A neoadjuvant therapy compatible prognostic staging for resected pancreatic ductal adenocarcinoma.

OBJECTIVE: To improve prediction, the AJCC staging system was revised to be consistent with upfront surgery (UFS) and neoadjuvant therapy (NAT) for PDAC. BACKGROUND: The AJCC staging system was designed for patients who have had UFS for PDAC, and it has limited predictive power for patients receiving NAT. METHODS: We examined 146 PDAC patients who had resection after NAT and 1771 who had UFS at Changhai Hospital between 2012 and 2021. The clinicopathological factors were identified using Cox proportional regression analysis, and the Neoadjuvant Therapy Compatible Prognostic (NATCP) staging was developed based on these variables. Validation was carried out in the prospective NAT cohort and the SEER database. The staging approach was compared to the AJCC staging system regarding predictive accuracy. RESULTS: The NAT cohort's multivariate analysis showed that tumor differentiation and the number of positive lymph nodes independently predicted OS. The NATCP staging simplified the AJCC stages, added tumor differentiation, and restaged the disease based on the Kaplan-Meier curve survival differences. The median OS for NATCP stages IA, IB, II, and III was 31.7 months, 25.0 months, and 15.8 months in the NAT cohort and 30.1 months, 22.8 months, 18.3 months, and 14.1 months in the UFS cohort. Compared to the AJCC staging method, the NATCP staging system performed better and was verified in the validation cohort. CONCLUSIONS: Regardless of the use of NAT, NATCP staging demonstrated greater predictive abilities than the existing AJCC staging approach for resected PDAC and may facilitate clinical decision-making based on accurate prediction of patients' OS.

Large-cohort humanized NPI mice reconstituted with CD34+ hematopoietic stem cells are feasible for evaluating preclinical cancer immunotherapy.

Cancer immunotherapy has achieved impressive therapeutic effects in many cancers, while only a small subset of patients benefit from it and some patients even have experienced severe toxicity. It is urgent to develop a feasible large-cohort humanized mouse model to evaluate the pre-clinical efficacy and safety of cancer immunotherapy. Furthermore, developing potentially effective combination therapy between cancer immunotherapy and other therapies also needs humanized mouse model to adequately mimic clinical actual setting. Herein, we established a humanized mouse model engrafted with less human CD34+ HSCs than ever before and then evaluated reconstitution efficiency and the profiles of human immune cells in this humanized mouse model. Also, this humanized mouse model was used to evaluate the preclinical efficacy and safety of cancer immunotherapy. For each batch of CD34+ HSCs humanized mouse model, a relatively-large cohort with over 25% human CD45+ cells in peripheral blood was established. This humanized mouse model could efficiently reconstitute human innate and adaptive immune cells. This humanized mouse model supported patient-derived xenograft tumor growth and tumor infiltration of PD-1+ human T cells. Furthermore, therapeutic efficacy, re-activation of tumor-infiltrated T cells, and side effects of checkpoint blockade therapy could be monitored in this humanized mouse model. Human T cells from this humanized mouse model were successfully engineered with CD19-CAR. CD19 CAR-T cells could effectively deplete B cells and suppress tumor growth of acute lymphoblastic leukemia in vivo in this humanized mouse model. This humanized mouse model also could be used to demonstrate the efficacy of bispecific antibodies, such as anti-CD19/CD3. Overall, our work provides a feasible large-cohort humanized mouse model for evaluating a variety of cancer immunotherapy approaches including checkpoint inhibitors, adoptive cell therapy, and bispecific antibody therapy, and demonstrates that human T cells from this humanized mouse model possess anti-tumor activities in vitro and in vivo.

The dysfunction of hormone-sensitive lipase induces lipid deposition and reprogramming of nutrient metabolism in fish.

Hormone-sensitive lipase (HSL) is one of the rate-determining enzymes in the hydrolysis of TAG, playing a crucial role in lipid metabolism. However, the role of HSL-mediated lipolysis in systemic nutrient homoeostasis has not been intensively understood. Therefore, we used CRISPR/Cas9 technique and Hsl inhibitor (HSL-IN-1) to establish hsla-deficient (hsla-/-) and Hsl-inhibited zebrafish models, respectively. As a result, the hsla-/- zebrafish showed retarded growth and reduced oxygen consumption rate, accompanied with higher mRNA expression of the genes related to inflammation and apoptosis in liver and muscle. Furthermore, hsla-/- and HSL-IN-1-treated zebrafish both exhibited severe fat deposition, whereas their expressions of the genes related to lipolysis and fatty acid oxidation were markedly reduced. The TLC results also showed that the dysfunction of Hsl changed the whole-body lipid profile, including increasing the content of TG and decreasing the proportion of phospholipids. In addition, the systemic metabolic pattern was remodelled in hsla-/- and HSL-IN-1-treated zebrafish. The dysfunction of Hsl lowered the glycogen content in liver and muscle and enhanced the utilisation of glucose plus the expressions of glucose transporter and glycolysis genes. Besides, the whole-body protein content had significantly decreased in the hsla-/- and HSL-IN-1-treated zebrafish, accompanied with the lower activation of the mTOR pathway and enhanced protein and amino acid catabolism. Taken together, Hsl plays an essential role in energy homoeostasis, and its dysfunction would cause the disturbance of lipid catabolism but enhanced breakdown of glycogen and protein for energy compensation.

PDK inhibition promotes glucose utilization, reduces hepatic lipid deposition, and improves oxidative stress in largemouth bass (Micropterus salmoides) by increasing pyruvate oxidative phosphorylation.

In omnivorous fish, the pyruvate dehydrogenase kinases (PDKs)-pyruvate dehydrogenase E1α subunit (PDHE1α) axis is essential in the regulation of carbohydrate oxidative catabolism. Among the existing research, the role of the PDKs-PDHE1α axis in carnivorous fish with poor glucose utilization is unclear. In the present study, we determined the effects of PDK inhibition on the liver glycolipid metabolism of largemouth bass (Micropterus salmoides). DCA is a PDK-specific inhibitor that inhibits PDK by binding the allosteric sites. A total of 160 juvenile largemouth bass were randomly divided into two groups, with four replicates of 20 fish each, fed a control diet and a control diet supplemented with dichloroacetate (DCA) for 8 weeks. The present results showed that DCA supplementation significantly decreased the hepatosomatic index, triglycerides in liver and serum, and total liver lipids of largemouth bass compared with the control group. In addition, compared with the control group, DCA treatment significantly down-regulated gene expression associated with lipogenesis. Furthermore, DCA supplementation significantly decreased the mRNA expression of pdk3a and increased PDHE1α activity. In addition, DCA supplementation improved glucose oxidative catabolism and pyruvate oxidative phosphorylation (OXPHOS) in the liver, as evidenced by low pyruvate content in the liver and up-regulated expressions of glycolysis-related and TCA cycle/OXPHOS-related genes. Moreover, DCA consumption decreased hepatic malondialdehyde (MDA) content, enhanced the activities of superoxide dismutase (SOD), and increased transforming growth factor beta (tgf-ß), glutathione S-transferase (gst), and superoxide dismutase 1 (sod1) gene expression compared with the control diet. This study demonstrated that inhibition of PDKs by DCA promoted glucose utilization, reduced hepatic lipid deposition, and improved oxidative stress in largemouth bass by increasing pyruvate OXPHOS. Our findings contribute to the understanding of the underlying mechanism of the PDKs-PDHE1α axis in glucose metabolism and improve the utilization of dietary carbohydrates in farmed carnivorous fish.

Targeting histone deacetylases for heart diseases.

Histone deacetylases (HDACs) are responsible for the deacetylation of lysine residues in histone or non-histone substrates, leading to the regulation of many biological functions, such as gene transcription, translation and remodeling chromatin. Targeting HDACs for drug development is a promising way for human diseases, including cancers and heart diseases. In particular, numerous HDAC inhibitors have revealed potential clinical value for the treatment of cardiac diseases in recent years. In this review, we systematically summarize the therapeutic roles of HDAC inhibitors with different chemotypes on heart diseases. Additionally, we discuss the opportunities and challenges in developing HDAC inhibitors for the treatment of cardiac diseases.