GSDMD KNOCKOUT ALLEVIATES SEPSIS-ASSOCIATED SKELETAL MUSCLE ATROPHY BY INHIBITING IL18/AMPK SIGNALING.

ABSTRACT: Background: Sepsis commonly leads to skeletal muscle atrophy, characterized by substantial muscle weakness and degeneration, ultimately contributing to an adverse prognosis. Studies have shown that programmed cell death is an important factor in the progression of muscle loss in sepsis. However, the precise role and mechanism of pyroptosis in skeletal muscle atrophy are not yet fully comprehended. Therefore, we aimed to examine the role and mechanism of action of the pyroptosis effector protein GSDMD in recognized cellular and mouse models of sepsis. Methods: The levels of GSDMD and N-GSDMD in skeletal muscle were evaluated 2, 4, and 8 days after cecal ligation and puncture. Sepsis was produced in mice that lacked the Gsdmd gene (Gsdmd knockout) and in mice with the normal Gsdmd gene (wild-type) using a procedure called cecal ligation and puncture. The degree of muscular atrophy in the gastrocnemius and tibialis anterior muscles was assessed 72 h after surgery in the septic mouse model. In addition, the architecture of skeletal muscles, protein expression, and markers associated with pathways leading to muscle atrophy were examined in mice from various groups 72 h after surgery. The in vitro investigations entailed the use of siRNA to suppress Gsdmd expression in C2C12 cells, followed by stimulation of these cells with lipopolysaccharide to evaluate the impact of Gsdmd downregulation on muscle atrophy and the related signaling cascades. Results: This study has demonstrated that the GSDMD protein, known as the "executive" protein of pyroptosis, plays a crucial role in the advancement of skeletal muscle atrophy in septic mice. The expression of N-GSDMD in the skeletal muscle of septic mice was markedly higher compared with the control group. The Gsdmd knockout mice exhibited notable enhancements in survival, muscle strength, and body weight compared with the septic mice. Deletion of the Gsdmd gene reduced muscular wasting in the gastrocnemius and tibialis anterior muscles caused by sepsis. Studies conducted in living organisms ( in vivo ) and in laboratory conditions ( in vitro ) have shown that the absence of the Gsdmd gene decreases indicators of muscle loss associated with sepsis by blocking the IL18/AMPK signaling pathway. Conclusion: The results of this study demonstrate that the lack of Gsdmd has a beneficial effect on septic skeletal muscle atrophy by reducing the activation of IL18/AMPK and inhibiting the ubiquitin-proteasome system and autophagy pathways. Therefore, our research provides vital insights into the role of pyroptosis in sepsis-related skeletal muscle wasting, which could potentially lead to the development of therapeutic and interventional approaches for preventing septic skeletal muscle atrophy.

Programmable Persistent Room Temperature Phosphorescence Switches through Wavelength-Selective Photoactivation.

Controlling multicolor persistent room-temperature phosphorescence (RTP) through photoirradiation holds fundamental significance but remains a significant challenge. In this study, we engineered a wavelength-selective photoresponsive system utilizing the Förster resonance energy transfer strategy. This system integrates a photoactivated long-lived luminescent material as the energy donor with a fluorescent photoswitch as the energy acceptor, facilitating programmable persistent luminescence switches. Distinct afterglow color states, such as initial nonemissive, green, yellow, and orange, were achieved through irradiation at 400 nm, 365 nm, and 254 nm, respectively. Based on this capability, we established an interacting network for multistate afterglow color switching among these four emissive states. In addition, we demonstrate the potential of this wavelength-selective photoresponsive system in the photo-controlled rewritable printing of multicolor afterglow images on a single thin film. This work represents a substantial step towards the fabrication of sophisticated wavelength-selective photoresponsive systems, potentially revolutionizing applications in optical data storage, security labeling, and smart displays by enabling precise control over photoresponsive behaviors under various photoirradiation wavelengths.

Role of mesenchymal stem cells in sepsis and their therapeutic potential in sepsis­associated myopathy (Review).

Sepsis­induced myopathy (SIM) is one of the leading causes of death in critically ill patients. SIM mainly involves the respiratory and skeletal muscles of patients, resulting in an increased risk of lung infection, aggravated respiratory failure, and prolonged mechanical ventilation and hospital stay. SIM is also an independent risk factor associated with increased mortality in critically ill patients. At present, no effective treatment for SIM has yet been established. However, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach and have been utilized in the treatment of various clinical conditions. A significant body of basic and clinical research supports the efficacy of MSCs in managing sepsis and muscle­related diseases. This literature review aims to explore the relationship between MSCs and sepsis, as well as their impact on skeletal muscle­associated diseases. Additionally, the present review discusses the potential mechanisms and therapeutic benefits of MSCs in the context of SIM.

Cerebral microbleeds in patients with COVID-19: is there an inevitable connection?

The COVID-19 pandemic has underscored the critical interplay between systemic infections and neurological complications, notably cerebral microbleeds. This comprehensive review meticulously aggregates and analyses current evidence on cerebral microbleeds' prevalence, pathophysiological underpinnings and clinical implications within COVID-19 cohorts. Our findings reveal a pronounced correlation between cerebral microbleeds and increased severity of COVID-19, emphasizing the role of direct viral effects, inflammatory responses and coagulation disturbances. The documented association between cerebral microbleeds and elevated risks of morbidity and mortality necessitates enhanced neurological surveillance in managing COVID-19 patients. Although variability in study methodologies presents challenges, the cumulative evidence substantiates cerebral microbleeds as a critical illness manifestation rather than mere coincidence. This review calls for harmonization in research methodologies to refine our understanding and guide targeted interventions. Prioritizing the detection and study of neurological outcomes, such as cerebral microbleeds, is imperative for bolstering pandemic response strategies and mitigating the long-term neurological impact on survivors.

Facile synthesis of a novel CeCO3OH@(H/C-CdS) catalyst with synergistic effect of heterophase junction and heterojunction for enhanced visible-light photocatalytic degradation efficiency at room temperature.

A new CeCO3OH@(hexagonal/cubic phases-CdS) (CeCO3OH@(H/C-CdS)) composite catalyst was facilely synthesized by a simple microinjection titration-stirring method, in which CdS nanoparticles were dispersed on the surface of CeCO3OH nanolines. The optimal conditions for the preparation of composite catalysts with high photocatalytic performance were determined by single-factor experiments and response surface experiments. Under these conditions, the degradation rate of 30 mL 2.000 g/L rhodamine B (Rh B) by CeCO3OH@(H/C-CdS) in a photocatalytic reaction for 1 h at 25 °C was up to 86.81 % and its degradation rate in a photocatalytic reaction for 150 min was up to 99.62 %. The degradation rate could be maintained above 80 % even after six times recycling. Especially, the photocatalytic degradation efficiency of 2.000 g/L Rh B on the composite catalyst under sunlight and at room temperature for 30 min reached 97.66 %. Meanwhile, the large size of CeCO3OH considerably alleviated the agglomeration of CdS, providing more adsorption and active sites for visible light-mediated degradation of Rh B. Importantly, the Z-scheme charge transfer realized by CdS and CeCO3OH enhanced the efficient separation of photogenerated electrons and holes, and successfully inhibited the recombination of photogenerated electrons with holes. At the same time, owing to the low energy band difference between the two phases of CdS, charge was transferred between the hexagonal and cubic phases, leaving more effective photogenerated charge to participate in the degradation of Rh B. The synergism of the heterophase junction and heterojunction and the presence of oxygen and sulfur vacancies considerably enhanced the degradation performance of the catalyst. Thus, this study provides a new strategy for the modification and enhanced visible-light catalysis performance of CdS-based catalysts.

Identification of ferroptosis-associated genes and potential pharmacological targets in sepsis-induced myopathy.

Background: The role of Ferroptosis in the course of sepsis-induced myopathy is yet unclear. The objective of our work is to identify key genes connected with Ferroptosis in sepsis-induced myopathy and investigate possible pharmaceutical targets related to this process. This research aims to provide new insights into the management of sepsis-induced myopathy. Methods: We got the GSE13205 dataset from the Gene Expression Omnibus (GEO) and extracted Ferroptosis-associated genes from the FerrDb database. After conducting a functional annotation analysis of these genes, we created a protein-protein interaction network using Cytoscape software to identify important genes. Subsequently, we employed CMap to investigate prospective pharmaceuticals that could target these crucial genes. Results: A total of 61 genes that are expressed differently (DEGs) have been found concerning Ferroptosis. These genes are involved in a wide range of biological functions, including reacting to signals from outside the cell and the availability of nutrients, programmed cell death, controlling apoptosis, and responding to peptides, chemical stressors, and hormones. The KEGG pathway study revealed that these pathways are involved in Ferroptosis, autophagy, P53 signaling, PI3K-Akt signaling, mTOR signaling, HIF-1 signaling, endocrine resistance, and different tumorigenic processes. In addition, we created a network that shows the simultaneous expression of important genes and determined the top 10 medications that have the potential to treat sepsis-induced myopathy. Conclusion: The bioinformatics research undertaken sheds insight into the probable role of Ferroptosis-associated genes in sepsis-induced myopathy. The identified critical genes show potential as therapeutic targets for treating sepsis-induced myopathy, offering opportunities for the development of tailored medicines.

Simultaneously enhancing organic phosphorescence quantum yields and lifetimes for triphenylphosphine salt doped polymer films.

Simultaneously enhancing the quantum yields and luminescence lifetimes of organic persistent room temperature phosphorescence (RTP) molecules is a priority in the organic photonic area, but it remains a formidable challenge. Here, an effective strategy was proposed to improve both quantum efficiencies and emission decay times for phosphorescent triphenylphosphine salts. This approach involves integrating an electron donor unit into a triphenylphosphine salt via an alkyl chain. This structure facilitates an intermediate through-space charge transfer excited state, which enhances the intersystem crossing process to boost RTP performance. Moreover, the electron donor moiety contributes additional triplet excitons to the triphenylphosphine salts through triplet-to-triplet energy transfer, substantially increasing the population of triplet excitons. Specifically, compared to butyl(naphthalen-1-yl) diphenylphosphonium bromide (Φphos. = 4.9% and τ = 255.79 ms), (2-(9H-carbazol-9-yl)ethyl)(naphthalen-1-yl)diphenylphosphonium bromide demonstrates a higher phosphorescence quantum yield of 19.6% and an extended emission lifetime of 800.59 ms. This advancement lays the groundwork for developing high-performance organic RTP materials, unlocking new possibilities for advanced photonic applications.

Chromosome Doubling Enhances Biomass and Carotenoid Content in Lycium chinense.

Lycium chinense, a type of medicinal and edible plant, is rich in bioactive compounds beneficial to human health. In order to meet the market requirements for the yield and quality of L. chinense, polyploid induction is usually an effective way to increase plant biomass and improve the content of bioactive components. This study established the most effective tetraploid induction protocol by assessing various preculture durations, colchicine concentrations, and exposure times. The peak tetraploid induction efficacy, 18.2%, was achieved with a 12-day preculture and 24-h exposure to 50 mg L-1 colchicine. Compared to diploids, tetraploids exhibited potentially advantageous characteristics such as larger leaves, more robust stems, and faster growth rates. Physiologically, tetraploids demonstrated increased stomatal size and chloroplast count in stomata but reduced stomatal density. Nutrient analysis revealed a substantial increase in polysaccharides, calcium, iron, and zinc in tetraploid leaves. In addition, seventeen carotenoids were identified in the leaves of L. chinense. Compared to the diploid, lutein, ß-carotene, neoxanthin, violaxanthin, and (E/Z)-phytoene exhibited higher levels in tetraploid strains T39 and T1, with T39 demonstrating a greater accumulation than T1. The findings suggest that the generated tetraploids harbor potential for further exploitation and lay the foundation for the selection and breeding of novel genetic resources of Lycium.

Synthesis, structure, theoretical calculation and antibacterial property of two novel Zn(II)/Ni(II) compounds based on 3, 5-dichlorosalicylaldehyde thiocarbamide ligand.

Two new compounds namely [Zn(L1)phen]31 and Ni(L1)phen(MeOH) 2 (L1 = 3, 5-dichlorosalicylaldehyde thiosemicarbazone) were synthesized by the slow evaporation method at room temperature. The structure of ligand L1 was determined using 1H NMR and 13C NMR spectra. X-ray single crystal diffraction analysis revealed that compounds 1-2 can form 3D supramolecular network structures through π···π stacking and hydrogen bonding interactions. The DFT calculation shows that the coordination of ligand and metal is in good agreement with the experimental results. Hirshfeld surface analysis revealed that H…H and Cl…H interactions were the predominant interactions in compounds 1-2. Energy framework analysis indicated that dispersion energy played a dominant role in the energy composition of compounds 1-2. The inhibitory effects of compounds 1-2 against Escherichia coli (E. coli) and Methicillin-resistant Staphylococcus aureus (MRSA) were tested using the paper disk diffusion method (1: E. coli: 18 mm, MRSA: 17 mm, 2: E. coli: 15 mm, MRSA: 16 mm). Ion releasing experiments were conducted to assess the ion release capacity of compounds 1-2 (Zn2+, 4 days, 38.33 µg/mL; Ni2+, 4 days, 29.12 µg/mL). Molecular docking demonstrated the interaction modes of compounds 1-2 with UDP-N-acetylenolpyruvoylglucosamine reductase (MurB) and dihydrofolate reductase (DHFR) in bacteria, involving hydrophobic, stacking, hydrogen bonding and halogen bonding interactions. The generation of reactive oxygen species (ROS) in bacteria under the presence of compounds 1-2 were evaluated using a fluorescent dye known as dichlorodihydrofluorescein diacetate (DCFH-DA). Potential antibacterial mechanisms of compounds 1-2 were proposed.

FTO Deficiency Alleviates LPS-induced Acute Lung Injury by TXNIP/NLRP3-mediated Alveolar Epithelial Cell Pyroptosis.

N6-methyladenosine (m6A) plays a role in various diseases, but it has rarely been reported in acute lung injury (ALI). The FTO (fat mass and obesity-associated) protein can regulate mRNA metabolism by removing m6A residues. The aim of this study was to examine the role and mechanism of the m6A demethylase FTO in LPS-induced ALI. Lung epithelial FTO-knockout mice and FTO-knockdown/overexpression human alveolar epithelial (A549) cell lines were constructed to evaluate the effects of FTO on ALI. Bioinformatics analysis and a series of in vivo and in vitro assays were used to examine the mechanism of FTO regulation. Rescue assays were conducted to examine whether the impact of FTO on ALI depended on the TXNIP/NLRP3 pathway. In LPS-induced ALI, RNA m6A modification amounts were upregulated, and FTO expression was downregulated. In vivo, lung epithelial FTO knockout alleviated alveolar structure disorder, tissue edema, and pulmonary inflammation and improved the survival of ALI mice. In vitro, FTO knockdown reduced A549 cell damage and death induced by LPS, whereas FTO overexpression exacerbated cell damage and death. Mechanistically, bioinformatics analysis revealed that TXNIP was a downstream target of FTO. FTO deficiency mitigated pyroptosis in LPS-induced ALI via the TXNIP/NLRP3 pathway. Rescue assays confirmed that the impact of FTO on the TXNIP/NLRP3 pathway was significantly reversed by the TXNIP inhibitor SRI-37330. Deficiency of FTO alleviates LPS-induced ALI via TXNIP/NLRP3 pathway-mediated alveolar epithelial cell pyroptosis, which might be a novel therapeutic strategy for combating ALI.

Targeting SIRT4/TET2 Signaling Alleviates Human Keratinocyte Senescence by Reducing 5-hydroxymethylcytosine Loss.

Skin aging is characterized by wrinkle formation and increased frailty and laxity, leading to the risk of age-related skin diseases. Keratinocyte is an important component of the epidermis in skin structure, and keratinocyte senescence has been identified as a pivotal factor in skin aging development. Because epigenetic pathways play a vital role in the regulation of skin aging, we evaluated human skin samples for DNA hydroxymethylation (5-hydroxymethylcytosine; 5-hmC) and SIRT4 expressions. Results found that both 5-hmC and SIRT4 showed a significant decrease in aged human skin samples. To test the results in vitro, human keratinocytes were cultured in H2O2, which modulates skin aging in vivo. However, H2O2-induced keratinocytes showed senescence-associated protein expression and significant downregulation of 5-hmC and SIRT4 expressions. Moreover, 5-hmC-converting enzymes ten eleven translocation 2 (TET2) showed a decrease and enhanced TET2 acetylation level in H2O2-induced keratinocytes. However, the overexpression of SIRT4 in keratinocytes alleviates the senescence phenotype, such as senescence-associated protein expression, decreases the TET2 acetylation, but increases TET2 and 5-hmC expressions. Our results provide a novel relevant mechanism whereby the epigenetic regulation of keratinocytes in skin aging may be correlated with SIRT4 expression and TET2 acetylation in 5-hmC alteration. Our study may provide a potential strategy for antiskin aging, which targets the SIRT4/TET2 axis involving epigenetic modification in keratinocyte senescence.

Development and validation of a nomogram for predicting persistent inflammation, immunosuppression, and catabolism syndrome in trauma patients.

Background: Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PIICS) is a significant contributor to adverse long-term outcomes in severe trauma patients. Objective: The objective of this study was to establish and validate a PIICS predictive model in severe trauma patients, providing a practical tool for early clinical prediction. Patients and methods: Adult severe trauma patients with an Injury Severity Score (ISS) of ≥16, admitted between October 2020 and December 2022, were randomly divided into a training set and a validation set in a 7:3 ratio. Patients were classified into PIICS and non-PIICS groups based on diagnostic criteria. LASSO regression was used to select appropriate variables for constructing the prognostic model. A logistic regression model was developed and presented in the form of a nomogram. The performance of the model was evaluated using calibration and ROC curves. Results: A total of 215 patients were included, consisting of 155 males (72.1%) and 60 females (27.9%), with a median age of 51 years (range: 38-59). NRS2002, ISS, APACHE II, and SOFA scores were selected using LASSO regression to construct the prognostic model. The AUC of the ROC analysis for the predictive model in the validation set was 0.84 (95% CI 0.72-0.95). The Hosmer-Lemeshow test in the validation set yielded a χ2 value of 14.74, with a value of p of 0.098. Conclusion: An accurate and easily implementable PIICS risk prediction model was established. It can enhance risk stratification during hospitalization for severe trauma patients, providing a novel approach for prognostic prediction.

Targeting NAT10 protects against sepsis-induced skeletal muscle atrophy by inhibiting ROS/NLRP3.

AIMS: To identify N-acetyltransferase 10 (NAT10) and its downstream signaling pathways in myocytes and skeletal muscle, and to investigate its role in inflammation-induced muscle atrophy. MATERIALS AND METHODS: Cecal ligation and puncture models were used to induce sepsis in C57BL/6 mice, which were treated with either a NAT10 inhibitor or a control agent. The therapeutic effect of NAT10 inhibitor was investigated by evaluating the mass, morphology, and molecular characteristics of mouse skeletal muscle. C2C12 cells were stimulated with LPS, and the expression of the NAT10 gene, downstream protein content, and atrophy phenotype were analyzed using a NAT10 inhibitor, to further explore the atrophic effect of NAT10 on C2C12 differentiated myotubes. RESULTS: Gene set enrichment analysis revealed that NAT10 expression was elevated in the Lateral femoris muscle of patients with ICUAW. In vitro and in vivo experiments showed that sepsis or LPS induced the upregulation of NAT10 expression in skeletal muscles and C2C12 myotubes. Skeletal muscle mass, tissue morphology, gene expression, and protein content were associated with atrophic response in sepsis models. Remodelin ameliorated the LPS-induced skeletal muscle weight loss, as well as muscular atrophy, and improved survival. Remodelin reversed the atrophy program that was induced by inflammation through the downregulation of the ROS/NLRP3 pathway, along with the inhibition of the expression of MuRF1 and Atrogin-1. CONCLUSION: NAT10 is closely related to skeletal muscle atrophy during sepsis. Remodelin improves the survival rate of mice by improving the systemic inflammatory response and skeletal muscle atrophy by downregulating the ROS/NLRP3 signaling pathway.

Membrane vesicle delivery of a streptococcal M protein disrupts the blood-brain barrier by inducing autophagic endothelial cell death.

M family proteins are critical virulence determinants of Streptococci. Streptococcus equi subsp. zooepidemicus (SEZ) are Group C streptococci that cause meningitis in animals and humans. SzM, the M protein of SEZ, has been linked to SEZ brain invasion. Here, we demonstrate that SzM is important in SEZ disruption of the blood-brain barrier (BBB). SEZ release SzM-bound membrane vesicles (MVs), and endocytosis of these vesicles by human brain endothelial microvascular cells (hBMECs) results in SzM-dependent cytotoxicity. Furthermore, administration of SzM-bound MVs disrupted the murine BBB. A CRISPR screen revealed that SzM cytotoxicity in hBMECs depends on PTEN-related activation of autophagic cell death. Pharmacologic inhibition of PTEN activity prevented SEZ disruption of the murine BBB and delayed mortality. Our data show that MV delivery of SzM to host cells plays a key role in SEZ pathogenicity and suggests that MV delivery of streptococcal M family proteins is likely a common streptococcal virulence mechanism.

Gut-muscle axis and sepsis-induced myopathy: The potential role of gut microbiota.

Sepsis is described as an immune response disorder of the host to infection in which microorganisms play a non-negligible role. Most survivors of sepsis experience ICU-acquired weakness, also known as septic myopathy, characterized by skeletal muscle atrophy, weakness, and irreparable damage/regenerated or dysfunctional. The mechanism of sepsis-induced myopathy is currently unclear. It has been believed that this state is triggered by circulating pathogens and their related harmful factors, leading to impaired muscle metabolism. Sepsis and its resulting alterations in the intestinal microbiota are associated with sepsis-related organ dysfunction, including skeletal muscle wasting. There are also some studies on interventions targeting the flora, including fecal microbiota transplants, the addition of dietary fiber and probiotics in enteral feeding products, etc., aiming to improve sepsis-related myopathy. In this review, we critically assess the potential mechanisms and therapeutic prospects of intestinal flora in the development of septic myopathy.

Melatonin: A potential adjuvant therapy for septic myopathy.

Septic myopathy, also known as ICU acquired weakness (ICU-AW), is a characteristic clinical symptom of patients with sepsis, mainly manifested as skeletal muscle weakness and muscular atrophy, which affects the respiratory and motor systems of patients, reduces the quality of life, and even threatens the survival of patients. Melatonin is one of the hormones secreted by the pineal gland. Previous studies have found that melatonin has anti-inflammatory, free radical scavenging, antioxidant stress, autophagic lysosome regulation, mitochondrial protection, and other multiple biological functions and plays a protective role in sepsis-related multiple organ dysfunction. Given the results of previous studies, we believe that melatonin may play an excellent regulatory role in the repair and regeneration of skeletal muscle atrophy in septic myopathy. Melatonin, as an over-the-counter drug, has the potential to be an early, complementary treatment for clinical trials. Based on previous research results, this article aims to critically discuss and review the effects of melatonin on sepsis and skeletal muscle depletion.

Multifunctional Nanocrystalline-Assembled Porous Hierarchical Material and Device for Integrating Microwave Absorption, Electromagnetic Interference Shielding, and Energy Storage.

Multifunctional applications including efficient microwave absorption and electromagnetic interference (EMI) shielding as well as excellent Li-ion storage are rarely achieved in a single material. Herein, a multifunctional nanocrystalline-assembled porous hierarchical NiO@NiFe2 O4 /reduced graphene oxide (rGO) heterostructure integrating microwave absorption, EMI shielding, and Li-ion storage functions is fabricated and tailored to develop high-performance energy conversion and storage devices. Owing to its structural and compositional advantages, the optimized NiO@NiFe2 O4 /15rGO achieves a minimum reflection loss of -55 dB with a matching thickness of 2.3 mm, and the effective absorption bandwidth is up to 6.4 GHz. The EMI shielding effectiveness reaches 8.69 dB. NiO@NiFe2 O4 /15rGO exhibits a high initial discharge specific capacity of 1813.92 mAh g-1 , which reaches 1218.6 mAh g-1 after 289 cycles and remains at 784.32 mAh g-1 after 500 cycles at 0.1 A g-1 . In addition, NiO@NiFe2 O4 /15rGO demonstrates a long cycling stability at high current densities. This study provides an insight into the design of advanced multifunctional materials and devices and provides an innovative method of solving current environmental and energy problems.

Effects of moldy corn on the performance, antioxidant capacity, immune function, metabolism and residues of mycotoxins in eggs, muscle, and edible viscera of laying hens.

Mycotoxins, including aflatoxin B1 (AFB1), zearalenone (ZEN) and deoxynivalenol (DON), are common contaminants of moldy feeds. Mycotoxins can cause deleterious effects on the health of chickens and can be carried over in poultry food products. This study was conducted to investigate the effects of moldy corn (containing AFB1, ZEN, and DON) on the performance, health, and mycotoxin residues of laying hens. One hundred and eighty 400-day-old laying hens were divided into 4 treatments: basal diet (Control), basal diet containing 20% moldy corn (MC20), 40% moldy corn (MC40) and 60% moldy corn (MC60). At d 20, 40, and 60, the performance, oxidative stress, immune function, metabolism, and mycotoxin residues in eggs were determined. At d 60, mycotoxin residues in muscle and edible viscera were measured. Results showed the average daily feed intake (ADFI) and laying performance of laying hens were decreased with moldy corn treatments. All the moldy corn treatments also induced significant oxidative stress and immunosuppression, reflected by decreased antioxidase activities, contents of cytokines, immunoglobulins, and increased malonaldehyde level. Moreover, the activities of aspartate aminotransferase and alanine transaminase were increased by moldy corn treatments. The lipid metabolism was influenced in laying hens receiving moldy corn, reflected by lowered levels of total protein, high density lipoprotein cholesterol, low density lipoprotein cholesterol, total cholesterol, and increased total triglyceride as well as uric acid. The above impairments were aggravated with the increase of mycotoxin levels. Furthermore, AFB1 and ZEN residues were found in eggs, muscle, and edible viscera with moldy corn treatments, but the residues were below the maximum residue limits. In conclusion, moldy corn impaired the performance, antioxidant capacity, immune function, liver function, and metabolism of laying hens at d 20, 40, and 60. Moldy corn also led to AFB1 residue in eggs at d 20, 40, and 60, and led to both AFB1 and ZEN residues in eggs at days 40 and 60, and in muscle and edible viscera at d 60. The toxic effects and mycotoxin residues were elevated with the increase of moldy corn levels in feed.

Inhibition of DDX3X alleviates persistent inflammation, immune suppression and catabolism syndrome in a septic mice model.

OBJECTIVE: DDX3X is involved in various pathological processes such as infection, immunity and cell death. This study aimed to investigate the effect of RK-33, a specific inhibitor of DDX3X, on the progression of sepsis to persistent inflammation, immune suppression and catabolism syndrome(PICS). METHODS: The septic mice model was established using caecal ligation and perforation (CLP). The mice were randomly divided into four groups: sham group, sham + RK-33 group (20 mg/kg, intraperitoneal injection, once a day), CLP group and CLP + RK-33 group (20 mg/kg, intraperitoneal injection, once a day). The number of inflammatory cells in the peripheral blood, spleen and bone marrow was calculated, and inflammatory cytokines were detected using an enzyme-linked immunosorbent assay. The septic mice's body weight and skeletal muscle mass were measured, and skeletal muscle tissues were examined using eosin staining. Western blotting was performed to detect the expression levels of MuRF1, atrogin1 and NLRP3 in the skeletal muscle of septic mice. Additionally, reactive oxidative species, superoxide dismutase and malondialdehyde were measured using commercial kits. RESULTS: RK-33 reduced inflammatory cell counts and cytokine levels in CLP mice, ameliorated the decline in CD4 and CD8 T cells and prevented the loss of body weight and skeletal muscle mass in septic mice. Additionally, RX-33 reduced oxidative stress in the skeletal muscle of septic mice. CONCLUSION: In the established sepsis mouse model, RK-33 alleviated inflammation and oxidative stress, ameliorated CLP-induced immunosuppression and skeletal muscle atrophy and improved survival. These findings suggest that RK-33 could be a novel potential therapeutic agent for preventing the progression of sepsis to PICS.

Inhibition of DDX3X ameliorated CD4+ T cells pyroptosis and improves survival in septic mice.

Over-expression of DDX3X mRNA is associated with T cell loss in septic patients. This study aimed to investigate the molecular mechanism of DDX3X on T cell reduction in sepsis. The sepsis model was established using lipopolysaccharide stimulation in vitro and cecal ligation and puncture (CLP) surgery in vivo. Results showed that the expression of DDX3X was significantly upregulated in CD4+ T cells in sepsis. RK-33, the inhibitor of DDX3X, was found to dramatically increase CD4+ T cell counts and prolong the survival rate of mice with sepsis. The results also showed that the expression of caspase-1/GSDMD in CD4+ T cells was significantly increased in vitro and in vivo, and RK-33 can substantially reduce CD4+ T cell pyroptosis through inhibiting NLRP3/caspase-1/GSDMD. Globally, our results suggest that DDX3X is involved in the loss of CD4+ T cells partly through activating the pyroptotic pathway during sepsis, which may provide potential targets for therapeutic interventions in this highly lethal disease.