Histone Deacetylase Inhibitor (SAHA) Reduces Mortality in an Endotoxemia Mouse Model by Suppressing Glycolysis.

Sepsis is a life-threatening medical emergency triggered by excessive inflammation in response to an infection. High mortality rates and limited therapeutic options pose significant challenges in sepsis treatment. Histone deacetylase inhibitors (HDACi), such as suberoylanilide hydroxamic acid (SAHA), have been proposed as potent anti-inflammatory agents for treating inflammatory diseases. However, the underlying mechanisms of sepsis treatment remain poorly understood. In this study, we investigated the effects of SAHA treatment in the lipopolysaccharide (LPS)-induced endotoxemia mouse model as it closely mimics the early stages of the systemic inflammation of sepsis. Our results demonstrate a reduced inflammatory mediator secretion and improved survival rates in mice. Using quantitative acetylomics, we found that SAHA administration increases the acetylation of lactate dehydrogenase (LDHA), and consequently inhibits LDHA activity. Notably, the reduced enzyme activity of LDHA results in a reduced rate of glycolysis. Furthermore, our experiments with bone marrow-derived macrophages (BMDMs) show that SAHA administration reduced oxidative stress and extracellular ATP concentrations, ultimately blunting inflammasome activation. Overall, our study provides insights into the mechanism underlying SAHA's therapeutic effects in sepsis treatment and highlights LDHA as a potential target for developing novel sepsis treatment.

Preparation of Biomass Biochar with Components of Similar Proportions and Its Methylene Blue Adsorption.

Rapeseed straw, bagasse, and walnut peel have a large amount of resource reserves, but there are few technologies for high value-added utilization. In the research of biochar, walnut green husk is rarely used as raw material. In addition, the three main components of biomass (lignin, cellulose, and hemicellulose) are present in similar proportions, and the differences between the physical and chemical properties of biochar prepared with similar amounts of biomass raw materials are not clear. Using three kinds of biomass of the same quality as raw materials, biochar was prepared via pyrolysis at 400 °C, and activated carbon was prepared via CO2 activation at 800 °C. The results showed that the pore numbers of the three kinds of biochar increased after activation, resulting in the increase of the specific surface area. The resulting numbers were 352.99 m2/g for sugarcane bagasse biochar (SBB)-CO2, 215.04 m2/g for rapeseed straw biochar (RSB)-CO2, and 15.53 m2/g for walnut green husk biochar (WGB)-CO2. Ash increased the amount of carbon formation, but a large amount of ash caused biochar to form a perforated structure and decreased the specific surface area (e.g., WGB), which affected adsorption ability. When the three main components were present in similar proportions, a high content of cellulose and lignin was beneficial to the preparation of biochar. The adsorption value of MB by biochar decreased with the increase of biomass ash content. After activation, the maximum adsorption value of MB for bagasse biochar was 178.17 mg/g, rapeseed straw biochar was 119.25 mg/g, and walnut peel biochar was 85.92 mg/g when the concentration of methene blue solution was 300 mg/L and the biochar input was 0.1 g/100 mL at room temperature. The adsorption of MB by biochar in solution occurs simultaneously with physical adsorption and chemical adsorption, with chemical adsorption being dominant. The optimal MB adsorption by SBB-CO2 was dominated by multimolecular-layer adsorption. This experiment provides a theoretical basis for the preparation of biochar and research on its applications in the future.

Single-cell RNA sequencing reveals the dynamics and heterogeneity of lymph node immune cells during acute and chronic viral infections.

Introduction: The host immune response determines the differential outcome of acute or chronic viral infections. The comprehensive comparison of lymphoid tissue immune cells at the single-cell level between acute and chronic viral infections is largely insufficient. Methods: To explore the landscape of immune responses to acute and chronic viral infections, single-cell RNA sequencing(scRNA-seq), scTCR-seq and scBCR-seq were utilized to evaluate the longitudinal dynamics and heterogeneity of lymph node CD45+ immune cells in mouse models of acute (LCMV Armstrong) and chronic (LCMV clone 13) viral infections. Results: In contrast with acute viral infection, chronic viral infection distinctly induced more robust NK cells and plasma cells at the early stage (Day 4 post-infection) and acute stage (Day 8 post-infection), respectively. Moreover, chronic viral infection exerted decreased but aberrantly activated plasmacytoid dendritic cells (pDCs) at the acute phase. Simultaneously, there were significantly increased IgA+ plasma cells (MALT B cells) but differential usage of B-cell receptors in chronic infection. In terms of T-cell responses, Gzma-high effector-like CD8+ T cells were significantly induced at the early stage in chronic infection, which showed temporally reversed gene expression throughout viral infection and the differential usage of the most dominant TCR clonotype. Chronic infection also induced more robust CD4+ T cell responses, including follicular helper T cells (Tfh) and regulatory T cells (Treg). In addition, chronic infection compromised the TCR diversity in both CD8+ and CD4+ T cells. Discussion: In conclusion, gene expression and TCR/BCR immune repertoire profiling at the single-cell level in this study provide new insights into the dynamic and differential immune responses to acute and chronic viral infections.

Effects of Long-Term Dietary Zinc Oxide Nanoparticle on Liver Function, Deposition, and Absorption of Trace Minerals in Intrauterine Growth Retardation Pigs.

To investigate the long-term effects of dietary zinc oxide nanoparticle (Nano-ZnO, 20-40 nm) on the relative organ weight, liver function, deposition, and absorption of trace minerals in intrauterine growth retardation (IUGR) pigs, piglets were allocated to NBW (6 normal birth weight piglets fed basal diets), IUGR (6 IUGR piglets fed basal diets) and IUGR+NZ (6 IUGR piglets fed basal diets + 600 mg Zn/kg from Nano-ZnO) groups at weaning (21 days of age), which were sampled at 163 days of age. There were no noteworthy changes in the relative weight of organs, hepatic histomorphology, serum alkaline phosphatase, glutamic pyruvic transaminase and glutamic oxalacetic transaminase activities, and Mn, Cu, and Fe concentrations in leg muscle, the liver, the tibia, and feces among the IUGR, NBW, and IUGR+NZ groups (P>0.05), and no intact Nano-ZnO in the jejunum, liver, and muscle was observed, while dietary Nano-ZnO increased the Zn concentrations in the tibia, the liver, serum, and feces (P<0.05) and mRNA expression of metallothionein (MT) 1A, MT2A, solute carrier family 39 member (ZIP) 4, ZIP14, ZIP8, divalent metal transporter 1, solute carrier family 30 member (ZnT) 1, ZnT4 and metal regulatory transcription factor 1, and ZIP8 protein expression in jejunal mucosa (P<0.05). Immunohistochemistry showed that dietary Nano-ZnO increased the relative optical density of ZIP8 (mainly expressed in cells of brush border) and MT2A (mainly expressed in villus lamina propria and gland/crypt) (P<0.05). In conclusion, long-term dietary Nano-ZnO showed no obvious side effects on the development of the major organs, liver function, and metabolism of Cu, Fe, and Mn in IUGR pigs, while it increased the Zn absorption and deposition via enhancing the expression of transporters (MT, ZIP, and ZnT families) in the jejunum, rather than via endocytosis as the form of intact nanoparticles.

The Inflamm-Aging Model Identifies Key Risk Factors in Atherosclerosis.

Background: Atherosclerosis, one of the main threats to human life and health, is driven by abnormal inflammation (i.e., chronic inflammation or oxidative stress) during accelerated aging. Many studies have shown that inflamm-aging exerts a significant impact on the occurrence of atherosclerosis, particularly by inducing an immune homeostasis imbalance. However, the potential mechanism by which inflamm-aging induces atherosclerosis needs to be studied more thoroughly, and there is currently a lack of powerful prediction models. Methods: First, an improved inflamm-aging prediction model was constructed by integrating aging, inflammation, and disease markers with the help of machine learning methods; then, inflamm-aging scores were calculated. In addition, the causal relationship between aging and disease was identified using Mendelian randomization. A series of risk factors were also identified by causal analysis, sensitivity analysis, and network analysis. Results: Our results revealed an accelerated inflamm-aging pattern in atherosclerosis and suggested a causal relationship between inflamm-aging and atherosclerosis. Mechanisms involving inflammation, nutritional balance, vascular homeostasis, and oxidative stress were found to be driving factors of atherosclerosis in the context of inflamm-aging. Conclusion: In summary, we developed a model integrating crucial risk factors in inflamm-aging and atherosclerosis. Our computation pipeline could be used to explore potential mechanisms of related diseases.

Comparative Analysis of Multiple Neurodegenerative Diseases Based on Advanced Epigenetic Aging Brain.

Background: Neurodegenerative Diseases (NDs) are age-dependent and include Alzheimer's disease (AD), Parkinson's disease (PD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), and so on. There have been numerous studies showing that accelerated aging is closely related (even the driver of) ND, thus promoting imbalances in cellular homeostasis. However, the mechanisms of how different ND types are related/triggered by advanced aging are still unclear. Therefore, there is an urgent need to explore the potential markers/mechanisms of different ND types based on aging acceleration at a system level. Methods: AD, PD, PSP, FTD, and aging markers were identified by supervised machine learning methods. The aging acceleration differential networks were constructed based on the aging score. Both the enrichment analysis and sensitivity analysis were carried out to investigate both common and specific mechanisms among different ND types in the context of aging acceleration. Results: The extracellular fluid, cellular metabolisms, and inflammatory response were identified as the common driving factors of cellular homeostasis imbalances during the accelerated aging process. In addition, Ca ion imbalance, abnormal protein depositions, DNA damage, and cytoplasmic DNA in macrophages were also revealed to be special mechanisms that further promote AD, PD, PSP, and FTD, respectively. Conclusion: The accelerated epigenetic aging mechanisms of different ND types were integrated and compared through our computational pipeline.

Effects of Supranutritional Selenium Nanoparticles on Immune and Antioxidant Capacity in Sprague-Dawley Rats.

The present study was conducted to investigate the effects of supranutritional selenium nanoparticles (SeNPs) on immune and antioxidant capacity in rats. Forty male Sprague-Dawley (SD) rats were randomly divided into four groups and given intragastric administration of SeNPs at doses of 0, 0.2, 0.4, and 0.8 mg Se/kg BW, respectively, for 2 weeks. Serum immune parameters, serum and organic tissues (liver, heart, kidney) antioxidant indices, and liver mRNA expression of glutathione peroxidase 1 (GPx1) and glutathione peroxidase 4 (GPx4) were examined. The results showed that supranutritional doses of 0.4 and 0.8 mg Se/kg BW SeNPs promoted the immune responses in serum. SeNPs administration improved antioxidant capacity in the liver and kidney, and the best improvement on antioxidant capacity was found in the kidney. Furthermore, intragastric administration of SeNPs upregulated mRNA expression of GPx1 and GPx4 in the liver. The results obtained indicated that SeNPs administration at supranutritional levels had beneficial effects on immune and antioxidant capacity and supplemental SeNPs at dose of 0.4 mg Se/kg BW exhibited the best response in SD rats.

Prooxidation and Cytotoxicity of Selenium Nanoparticles at Nonlethal Level in Sprague-Dawley Rats and Buffalo Rat Liver Cells.

The effects of selenium nanoparticles (SeNPs) on the antioxidant capacity in Sprague-Dawley (SD) rats were investigated. The rats were given intragastric administration of an SeNP suspension at doses of 0, 2, 4, and 8 mg Se/kg BW for two weeks. The antioxidant capacity in serum and organic tissues (liver, heart, and kidney) and the gene expression levels of glutathione peroxidase 1 (GPX1) and glutathione peroxidase 4 (GPX4) in the liver were measured. Buffalo rat liver (BRL) cell lines were further constructed to explore the cytotoxicity mechanism induced by SeNPs through the determination of antioxidant capacity; cell activity; apoptosis; and Caspase-3, Caspase-8, and Caspase-9 family activities. The results showed that SeNP administration over 4.0 mg Se/kg BW decreased the antioxidant capacities in the serum, liver, and heart and downregulated mRNA expression of GPX1 and GPX4 in the liver. The BRL cell line experiments showed that treatment with over 24 µM SeNPs decreased the viability of the cells and damaged the antioxidant capacity. Flow cytometry analysis showed that decreased cell viability induced by SeNPs is mainly due to apoptosis, rather than cell necrosis. Caspase-3 and Caspase-8 activities were also increased when BRL cells were treated with 24 µM and 48 µM SeNPs. Taken together, a nonlethal level of SeNPs could impair the antioxidant capacity in serum and organic tissues of rats, and the liver is the most sensitive to the toxicity of SeNPs. A pharmacological dose of SeNPs could lead to cytotoxicity and induce cell death through apoptosis and extrinsic pathways contributing to SeNP-induced apoptosis in BRL cells.

Effects of Chromium-Loaded Chitosan Nanoparticles on Glucose Transporter 4, Relevant mRNA, and Proteins of Phosphatidylinositol 3-Kinase, Akt2-Kinase, and AMP-Activated Protein Kinase of Skeletal Muscles in Finishing Pigs.

The study was conducted to evaluate the effects of chromium-loaded chitosan nanoparticles (Cr-CNP) on glucose transporter 4 (GLUT4), relevant messenger RNA (mRNA), and proteins involved in phosphatidylinositol 3-kinase (PI3K), Akt2-kinase, and AMP-activated protein kinase (AMPK) of skeletal muscles in finishing pigs. A total of 120 crossbred barrows (BW 65.00 ± 1.26 kg) were randomly allotted to four dietary treatments, with three pens per treatment and 10 pigs per pen. Pigs were fed the basal diet supplemented with 0, 100, 200, or 400 µg/kg of Cr from Cr-CNP for 35 days. After the feeding trials, 24 pigs were slaughtered to collect longissimus muscle samples for analysis. Cr-CNP supplementation increased GLUT4 messenger RNA (mRNA) (quadratically, P < 0.01) and total and plasma membrane GLUT4 protein contents (linearly and quadratically, P < 0.001) in skeletal muscles. Glycogen synthase kinase 3ß (GSK-3ß) mRNA was decreased linearly (P < 0.001) and quadratically (P < 0.001). Supplemental Cr-CNP increased insulin receptor (InsR) mRNA quadratically (P < 0.01), Akt2 total protein level linearly (P < 0.01) and quadratically (P < 0.001), and PI3K total protein was increased significantly (P < 0.05) in 200 µg/kg treatment group. The mRNA of AMPK subunit gamma-3 (PRKAG3) and protein of AMPKα1 was significantly increased (P < 0.001) with the addition of Cr-CNP. The results indicate that dietary supplementation of Cr-CNP may promote glucose uptake by leading to recruitment of GLUT4 to the plasma membrane in skeletal muscles, and these actions may be associated with the insulin signal transduction and AMPK.

Effects of Selenium Nanoparticles on Reproductive Performance of Male Sprague-Dawley Rats at Supranutritional and Nonlethal Levels.

This research investigated the influence of selenium nanoparticles (SeNPs) on the reproductive performance of male Sprague-Dawley (SD) rats. A suspension of SeNPs was consecutively administered by oral gavage for 2 weeks at supranutritional (0.2, 0.4, or 0.8 mg Se/kg bw) and nonlethal (2.0, 4.0, or 8.0 mg Se/kg bw) levels to male SD rats. The normal control (NC) rats were exposed to physiological saline alone. Biochemical parameters, sperm motility, gene expression of GPx1 and GPx4, and histopathological evaluation of male spermary were measured in this work. The supranutritional doses could promote the sperm motility (P < 0.001) and movement parameters (P < 0.05). The nonlethal levels of 4.0 and 8.0 mg Se/kg bw reduced the testis weight (P < 0.001), sperm concentration, and motility (P < 0.05), and also caused histopathological injury of testis and epididymis tissues to various degrees. The content of testosterone in serum was increased in the 0.8 group (P < 0.05) and decreased in the 4.0 (P < 0.01) and 8.0 mg Se/kg bw groups (P < 0.001), respectively. No significant effects were observed on antioxidant enzyme activities and mRNA concentration of GPx in the supranutritional dose group, and nonlethal levels were also not observed. In conclusion, SeNPs in the supranutritional dose has a positive effect on the reproductive function of male SD rats and has damaging effect higher than 4.0 mg Se/kg bw.

Toxicity of selenium nanoparticles in male Sprague-Dawley rats at supranutritional and nonlethal levels.

AIMS: We synthesized selenium nanoparticles (SeNPs) and examined their toxicity in male rats at supranutritional and nonlethal doses. MAIN METHODS: The SeNPs were administered daily by gavage at doses of 0.0, 0.2, 0.4, 0.8, 2.0, 4.0, or 8.0 mg Se/kg-body weight (bw) in 2 mL of 0.9% saline for 14 consecutive days. Body weight, viscera index and blood biochemical parameters were measured. Histopathological examination was performed on selected tissues, and liver tissue was examined for apoptotic cells. KEY FINDINGS: Body weight decreased considerably in the groups given doses of 2.0, 4.0, and 8.0 mg Se/kg-bw, but increased in the groups given doses of 0.2 and 0.4 mg Se/kg-bw. The viscera index and some biochemical parameters in the 8.0 mg Se/kg-bw group differed from the control group. Lesions in the liver, kidneys, lungs, and thymus, and apoptotic liver cells were observed in the 4.0 and 8.0 mg Se/kg-bw groups. SIGNIFICANCE: From this study, we conclude that supranutritional levels of SeNPs had no obvious toxic effects in rats, and could be used as potential candidates for cancer chemoprevention, although doses greater than 2.0 mg Se/kg-bw induced chronic toxicity.

Efficacy of dietary chromium (III) supplementation on tissue chromium deposition in finishing pigs.

The study was conducted to evaluate the efficacy of different forms of trivalent chromium (Cr) supplementation on tissue chromium deposition in finishing pigs. A total of 96 pigs with an initial average body mass 65.57±1.05 kg were blocked by body mass and randomly assigned to four treatments with three replicates. Pigs were offered one of four diets including a control diet or the control diet supplemented with 200 µg/kg chromium from either chromium chloride (CrCl(3)), chromium picolinate (CrPic) or chromium nanocomposite (CrNano) for 40 days. During the trial, all pigs were given free access to feed and water. After feeding trial, eight pigs from each treatment were slaughtered for samples collection. The results showed that supplemental CrNano increased Cr content in blood, longissimus muscle, heart, liver, kidney, jejunum, and ileum (P<0.05). Supplemental Cr from three sources increased Cr excretion from all feces (P<0.05). Urinary Cr excretion was increased by CrNano or CrPic supplementation significantly. These results suggested that chromium nanocomposite exhibited more effective on tissue Cr deposition in pigs, which indicated higher absorption compared with CrCl(3) and CrPic.

Effects of copper-loaded chitosan nanoparticles on intestinal microflora and morphology in weaned piglets.

The objective of the present study was to investigate the effects of dietary supplementation with copper-loaded chitosan nanoparticles (CNP-Cu) on growth performance, intestinal microflora, and morphology in weaned piglets. A number of 90 weaned piglets (Duroc × Landrace × Yorkshire), weaned at 21 days with body weight of 7.2 ± 0.81 kg, were randomly divided into three groups by weight and sex, each treatment including three replicates of ten pigs. The piglets were fed the same basal diet supplemented with 0 (the control group), 100 mg/kg CNP-Cu, and 100 mg/kg chlortetracycline (the positive group). The results showed that 100 mg/kg CNP-Cu significantly increased average daily gain and feed intake and decreased feed/gain ratio and diarrhea rate (P < 0.05). Compared with the control group, the amount of Escherichia coli in duodenum, jejunal, and caecum were significantly decreased by 100 mg/kg CNP-Cu; the number of lactobacillus in jejunal and caecum were increased (P < 0.05), and the amount of bifidobacterium in duodenum and caecum were also increased (P < 0.05). Moreover, the villous height of duodenum, jejunum, and ileum mucosa was significantly increased (P < 0.05), and the crypt depth was significantly decreased (P < 0.05). The results indicated that CNP-Cu is beneficial to growth and intestinal microflora and morphology and could be a potential substitution of chlortetracycline in diets of weaned piglets.

Effects of chromium-loaded chitosan nanoparticles on growth, blood metabolites, immune traits and tissue chromium in finishing pigs.

Effects of chromium-loaded chitosan nanoparticles (Cr-CNP) on growth performance, blood metabolites, immune traits, and tissue chromium in finishing pigs were investigated. A total of 160 crossbred barrows (66.06 ± 1.01 kg initial weight) were randomly divided into four groups, each group with four pens, ten pigs per pen. Pigs were fed on the same basal diet supplemented with 0 (the control), 100, 200, and 400 µg/kg Cr from Cr-CNP. All pigs were given free access to feed and water. Eight pigs from each treatment were selected to collect blood and tissue samples after 35 days on trial for analysis of blood metabolites and immune traits and tissue chromium. The results of feeding trial showed that there were no significant difference in growth performance between control and Cr-CNP-treated groups. The supplementation of Cr-CNP decreased serum glucose (P < 0.001) in a linear and quadratic manner. Serum immunoglobulins A and M were linearly increased in Cr-CNP-treated groups (P < 0.001), and serum complement 4 in Cr-CNP-treated groups was also linearly increased (P < 0.05). Cr-CNP supplementation linearly increased the chromium content in the blood, longissimus muscle, heart, liver, kidney, and pancreas (P < 0.001). These results suggested that dietary supplementation of Cr as Cr-CNP affects serum glucose, influences immune status, and increases the tissue chromium content of blood, muscle, and selected organs in finishing pigs.