Tumor Microenvironment Cascade Activated Biodegradable Nano-Enzymes for Glutathione-Depletion and Ultrasound-Enhanced Chemodynamic Therapy.

Chemodynamic therapy (CDT) is emerged as a novel and promising tumor therapy by using the powerful reactive oxygen species (ROS) to kill cancer cells. However, the current CDT is remarkably inhibited due to insufficient H2O2 supply and over-expression of glutathione (GSH) in the tumor microenvironment (TME). Herein, a biodegradable self-supplying H2O2 nano-enzyme of CuO2@CaP with a GSH-consumption effect is designed for cascade enhanced CDT to overcome the problem of H2O2 deficiency and GSH overexpression. In this design, CuO2@CaP is gradually degraded to Ca2+, Cu2+, and H2O2 in acidic TME, resulting in synergistically enhanced CDT owing to the efficient self-supplied H2O2 and GSH-depletion and Ca2+ overload therapy. Interestingly, the faster degradation of CuO2@CaP and promoted production rate of •OH are further achieved after triggering with ultrasound (US). And, the US-enhanced CDT and Ca2+ overload synergistic antitumor therapy is successfully achieved in vivo. These findings provide a promising strategy for designing biodegradable nano-enzymes with self-supplying H2O2 and GSH consumption for US-mediated CDT.

Association between dietary niacin intake and risk of Parkinson's disease in US adults: cross-sectional analysis of survey data from NHANES 2005-2018.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases and involves various pathogenic mechanisms, including oxidative stress and neuroinflammation. Niacin, an important cofactor in mitochondrial energy metabolism, may play a key role in the pathogenesis of PD. An in-depth exploration of the relationship between niacin and mitochondrial energy metabolism may provide new targets for the treatment of PD. The present study was designed to examine the association between dietary niacin intake and the risk of PD in US adults. Data from adults aged 40 years and older collected during cycles of the United States (US) National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018 were used. A multiple logistic regression model was used to analyze the relationship between dietary niacin intake and the risk of PD. Further linear tests using restricted cubic splines (RCS) were performed to explore the shape of the dose-response relationship. Subgroup stratification and interaction analyses were conducted according to years of education, marital status, smoking, and hypertension to evaluate the stability of the association between different subgroups. A total of 20,211 participants were included in this study, of which 192 were diagnosed with PD. In the fully adjusted multiple logistic regression model, dietary niacin intake was negatively associated with the risk of PD (OR: 0.77, 95%CI: 0.6-0.99; p = 0.042). In the RCS linear test, the occurrence of PD was negatively correlated with dietary niacin intake (nonlinearity: p = 0.232). In stratified analyses, dietary niacin intake was more strongly associated with PD and acted as an important protective factor in patients with fewer years of education (OR: 0.35, 95%CI: 0.13-0.93), married or cohabitating (OR: 0.71, 95%CI: 0.5-0.99), taking dietary supplements (OR: 0.6, 95%CI: 0.37 0.97), non-smokers (OR: 0.57, 95%CI: 0.39-0.85), those with hypertension (OR: 0.63, 95%CI: 0.63-0.95), coronary artery disease (OR: 0.77, 95%CI: 0.6-1), and stroke (OR: 0.75, 95%CI: 0.88-0.98), but the interaction was not statistically significant in all subgroups. Dietary niacin intake was inversely associated with PD risk in US adults, with a 23% reduction in risk for each 10 mg increase in niacin intake.

Mutation of Pseudomonas aeruginosa lasI/rhlI diminishes its cytotoxicity, oxidative stress, inflammation, and apoptosis on THP-1 macrophages.

The management of Pseudomonas aeruginosa (P. aeruginosa) infections presents a substantial challenge to clinics and public health, emphasizing the urgent need for innovative strategies to address this issue. Quorum sensing (QS) is an intercellular communication mechanism that coordinates bacterial activities involved in various virulence mechanisms, such as acquiring host nutrients, facilitating biofilm formation, enhancing motility, secreting virulence factors, and evading host immune responses, all of which play a crucial role in the colonization and infection of P. aeruginosa. The LasI/R and RhlI/R sub-systems dominate in the QS system of P. aeruginosa. Macrophages play a pivotal role in the host's innate immune response to P. aeruginosa invasion, particularly through phagocytosis as the initial host defense mechanism. This study investigated the effects of P. aeruginosa's QS system on THP-1 macrophages. Mutants of PAO1 with lasI/rhlI deletion, as well as their corresponding complemented strains, were obtained, and significant downregulation of QS-related genes was observed in the mutants. Furthermore, the ΔlasI and ΔlasIΔrhlI mutants exhibited significantly attenuated virulence in terms of biofilm formation, extracellular polymeric substances synthesis, bacterial adhesion, motility, and virulence factors production. When infected with ΔlasI and ΔlasIΔrhlI mutants, THP-1 macrophages exhibited enhanced scavenging ability against the mutants and demonstrated resistance to cytotoxicity, oxidative stress, inflammatory response, and apoptosis induced by the culture supernatants of these mutant strains. These findings offer novel insights into the mechanisms underlying how the lasI/rhlI mutation attenuates cytotoxicity, oxidative stress, inflammation, and apoptosis in macrophages induced by P. aeruginosa.IMPORTANCEP. aeruginosa is classified as one of the ESKAPE pathogens and poses a global public health concern. The QS system of this versatile pathogen contributes to a broad spectrum of virulence, thereby constraining therapeutic options for serious infections. This study illustrated that the lasI/rhlI mutation of the QS system plays a prominent role in attenuating the virulence of P. aeruginosa by affecting bacterial adhesion, biofilm formation, extracellular polymeric substances synthesis, bacterial motility, and virulence factors' production. Notably, THP-1 macrophages infected with mutant strains exhibited increased phagocytic activity in eliminating intracellular bacteria and enhanced resistance to cytotoxicity, oxidative stress, inflammation, and apoptosis. These findings suggest that targeted intervention toward the QS system is anticipated to diminish the pathogenicity of P. aeruginosa to THP-1 macrophages.

Quercetin promotes the proliferation, migration, and invasion of trophoblast cells by regulating the miR-149-3p/AKT1 axis.

Recurrent spontaneous abortion (RSA) has a complex pathogenesis with an increasing prevalence and is one of the most intractable clinical challenges in the field of reproductive medicine. Quercetin (QCT) is an effective active ingredient extracted from Semen Cuscutae and Herba Taxilli used in traditional Chinese medicine for tonifyng the kidneys and promoting fetal restoration. Although QCT helps improve adverse pregnancy outcomes, the specific mechanism remains unclear. The trophoblast cell line HTR-8/SVneo cultured in vitro was treated with different concentrations of QCT, and the cell counting kit-8 assay, wound healing assay, transwell assay, and western blotting were used to evaluate the effects and mechanisms of QCT on the proliferation, migration, and invasion of HTR-8/SVneo cells, respectively. To assess the expression levels of miR-149-3p and AKT serine/threonine kinase 1 (AKT1), quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting analysis were performed. A dual-luciferase reporter assay was used to investigate the potential regulatory relationship between miR-149-3p and AKT1. Our results showed that QCT promoted the proliferation, migration, and invasion of trophoblast cells, promoted the expression of MMP2, MMP9, and vimentin, and downregulated the expression of E-cadherin. Mechanistically, QCT downregulated the expression of miR-149-3p and upregulated the expression of AKT1, and miR-149-3p directly targets AKT1, negatively regulating its expression. Overexpression of miR-149-3p and silencing of AKT1 counteracted the promotional effects of QCT on trophoblast proliferation, migration, and invasion. Taken together, QCT regulates the migration and invasion abilities of HTR-8/SVneo cells through the miR-149-3p/AKT1 axis, which may provide a promising therapeutic approach for RSA.

The death risk of pediatric patients with cancer-related sepsis requiring continuous renal replacement therapy: a retrospective cohort study.

OBJECTIVE: To assess the outcome of patients with cancer-related sepsis requiring continuous renal replacement therapy (CRRT) in a single-center pediatric intensive care unit (PICU). METHOD: Children with sepsis who necessitate CRRT from January 2017 to December 2021 were enrolled. The patients with leukemia/lymphoma or solid tumors were defined as underlying cancer. Multivariate logistic regression analysis was performed to identify the death risk factors in patients with cancer-related sepsis. RESULTS: A total of 146 patients were qualified for inclusion. Forty-six (31.5%) patients with cancer-related sepsis and 100 (68.5%) non-cancer-related sepsis. The overall PICU mortality was 28.1% (41/146), and mortality was significantly higher in cancer-related sepsis patients compared with non-cancer patients (41.3% vs. 22.0%, p = 0.016). Need mechanical ventilation, p-SOFA, acute liver failure, higher fluid overload at CRRT initiation, hypoalbuminemia, and high inotropic support were associated with PICU mortality in cancer-related sepsis patients. Moreover, levels of IL-6, total bilirubin, creatinine, blood urea nitrogen, and international normalized ratio were significantly higher in non-survivors than survivors. In multivariate logistic regression analysis, pediatric sequential organ failure assessment (p-SOFA) score (OR:1.805 [95%CI: 1.047-3.113]) and serum albumin level (OR: 0.758 [95%CI: 0.581 -0.988]) were death risk factors in cancer-related sepsis receiving CRRT, and the AUC of combined index of p-SOFA and albumin was 0.852 (95% CI: 0.730-0.974). CONCLUSION: The overall PICU mortality is high in cancer-related sepsis necessitating CRRT. Higher p-SOFA and lower albumin were independent risk factors for PICU mortality.

Prenatal High-Sucrose Diet Induced Vascular Dysfunction of Renal Interlobar Arteries in the Offspring via PPARγ-RXRg-ROS/Akt Signaling.

SCOPE: Prenatal nutrition imbalance correlates with developmental origin of cardiovascular diseases; however whether maternal high-sucrose diet (HS) during pregnancy causes vascular damage in renal interlobar arteries (RIA) from offspring still keeps unclear. METHODS AND RESULTS: Pregnant rats are fed with normal drinking water or 20% high-sucrose solution during the whole gestational period. Swollen mitochondria and distributed myofilaments are observed in vascular smooth muscle cells of RIA exposed to prenatal HS. Maternal HS increases phenylephrine (PE)-induced vasoconstriction in the RIA from adult offspring. NG-Nitro-l-arginine (L-Name) causes obvious vascular tension in response to PE in offspring from control group, not in HS. RNA-Seq of RIA is performed to reveal that the gene retinoid X receptor g (RXRg) is significantly decreased in the HS group, which could affect vascular function via interacting with PPARγ pathway. By preincubation of RIA with apocynin (NADPH inhibitor) or capivasertib (Akt inhibitor), the results indicate that ROS and Akt are the vital important factors to affect the vascular function of RIA exposure to prenatal HS. CONCLUSION: Maternal HS during the pregnancy increases PE-mediated vasoconstriction of RIA from adult offspring, which is mainly related to the enhanced Akt and ROS regulated by the weakened PPARγ-RXRg.

Glycyrrhizic acid restores the downregulated hepatic ACE2 signaling in the attenuation of mouse steatohepatitis.

Glycyrrhizic acid (GA), one of the major active components derived from licorice root, exerts liver-protecting activity. Its molecular mechanisms of action, however, remain not completely understood. The angiotensin (Ang) converting enzyme (ACE) 2/Ang-(1-7)/Mas axis, regulated by ACE2 through converting Ang II into Ang-(1-7) to activate Mas receptor, counteracts the pro-inflammatory and pro-steatotic effects of the ACE/Ang II/Ang II receptor type 1 (AT1) axis. Here, it was found that pretreatment with GA suppressed LPS/D-galactosamine-induced serum hyperactivities of alanine aminotransferase and aspartate aminotransferase, hepatomegaly, pathological changes, and over-accumulation of triglycerides and fatty droplets in the liver of mice. GA also diminished LPS/free fatty acid-induced inflammation and steatosis in cultured hepatocytes. Mechanistically, GA restored hepatic protein hypoexpression of ACE2 and Mas receptor, and the decrease in hepatic Ang-(1-7) content. Hepatic overexpression of angiotensin II and AT1 was also suppressed. However, GA did not alter hepatic protein expression of renin and ACE. In addition, GA inhibited hepatic protein over-phosphorylation of the p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and nuclear factor κB at Ser536. Hepatic overexpression of tumor necrosis factor α, interleukin 6, interleukin 1ß, sterol regulatory element-binding protein 1c, and fatty acid synthase was also inhibited. GA-elicited recovery of ACE2 and Mas protein hypoexpression was further confirmed in the hepatocyte. Thus, the present results demonstrate that GA restores the downregulated hepatic ACE2-mediated anti-inflammatory and anti-steatotic signaling in the amelioration of steatohepatitis. We suggest that GA may protect the liver from injury by regulating the hepatic ACE2-mediated signaling.

M2 macrophages independently promote beige adipogenesis via blocking adipocyte Ets1.

Adipose tissue macrophages can promote beige adipose thermogenesis by altering local sympathetic activity. Here, we perform sympathectomy in mice and further eradicate subcutaneous adipose macrophages and discover that these macrophages have a direct beige-promoting function that is independent of sympathetic system. We further identify adipocyte Ets1 as a vital mediator in this process. The anti-inflammatory M2 macrophages suppress Ets1 expression in adipocytes, transcriptionally activate mitochondrial biogenesis, as well as suppress mitochondrial clearance, thereby increasing the mitochondrial numbers and promoting the beiging process. Male adipocyte Ets1 knock-in mice are completely cold intolerant, whereas male mice lacking Ets1 in adipocytes show enhanced energy expenditure and are resistant to metabolic disorders caused by high-fat-diet. Our findings elucidate a direct communication between M2 macrophages and adipocytes, and uncover a function for Ets1 in responding to macrophages and negatively governing mitochondrial content and beige adipocyte formation.

An Activated Structure Transformable Ratiometric Photoacoustic Nanoprobe for Real-Time Dynamic Monitoring of H2S In Vivo.

H2S has emerged as a promising biomarker for many diseases such as colon cancer and metformin-induced hepatotoxicity. Real-time monitoring of H2S levels in vivo is significant for early accurate diagnosis of these diseases. Herein, a new accurate and reliable nanoprobe (Au NRs@Ag) was designed for real-time dynamic ratiometric photoacoustic (PA) imaging of H2S in vivo based on the endogenous H2S-triggered local surface plasmon resonance (LSPR) red-shift. The Au NRs@Ag nanoprobe can be readily converted into Au NRs@Ag2S via the endogenous H2S-activated in situ sulfurative reaction, subsequently leading to a significant red-shift of the LSPR wavelength from 808 to 980 nm and enabling accurate ratiometric PA (PA980/PA808) imaging of H2S. Moreover, dynamic ratiometric PA imaging of metformin-induced hepatotoxicity was also successfully achieved by the designed PA imaging strategy. These findings provide the possibility of designing a new ratiometric PA imaging strategy for dynamic in situ monitoring of H2S-related diseases.

ATF4 knockdown in macrophage impairs glycolysis and mediates immune tolerance by targeting HK2 and HIF-1α ubiquitination in sepsis.

Strengthened glycolysis is crucial for the macrophage pro-inflammatory response during sepsis. Activating transcription factor 4 (ATF4) plays an important role in regulating glucose and lipid metabolic homeostasis in hepatocytes and adipocytes. However, its immunometabolic role in macrophage during sepsis remains largely unknown. In the present study, we found that the expression of ATF4 in peripheral blood mononuclear cells (PBMCs) was increased and associated with glucose metabolism in septic patients. Atf4 knockdown specifically decreased LPS-induced spleen macrophages and serum pro-inflammatory cytokines levels in mice. Moreover, Atf4 knockdown partially blocked LPS-induced pro-inflammatory cytokines, lactate accumulation and glycolytic capacity in RAW264.7. Mechanically, ATF4 binds to the promoter region of hexokinase II (HK2), and interacts with hypoxia inducible factor-1α (HIF-1α) and stabilizes HIF-1α through ubiquitination modification in response to LPS. Furthermore, ATF4-HIF-1α-HK2-glycolysis axis launches pro-inflammatory response in macrophage depending on the activation of mammalian target of rapamycin (mTOR). Importantly, Atf4 overexpression improves the decreased level of pro-inflammatory cytokines and lactate secretion and HK2 expression in LPS-induced tolerant macrophages. In conclusion, we propose a novel function of ATF4 as a crucial glycolytic activator contributing to pro-inflammatory response and improving immune tolerant in macrophage involved in sepsis. So, ATF4 could be a potential new target for immunotherapy of sepsis.

IGFBP­rP1 affects the proliferation, apoptosis and macrophage polarization of endometrial cancer cells by regulating the PI3K/AKT pathway.

Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is a potential tumor suppressor gene in a variety of cancers including colorectal cancer and breast cancer. However, its role and the potential mechanism in endometrial carcinoma (EC) are still unclear. The purpose of this study was to explore the effect of IGFBP-rP1 on EC cell proliferation and apoptosis and its underlying mechanism. Western blot analysis and reverse transcription-quantitative PCR were used to assess protein and gene expression levels of IGFBP-rP1 in EC cells. Overexpression of IGFBP-rP1 and/or AKT serine/threonine kinase was used to analyze their effects on cell proliferation and apoptosis of the EC cells. Co-immunoprecipitation and glutathione S transferase pull-down assays were used to analyze the interaction between IGFBP-rP1 and AKT. The expression of IGFBP-rP1 in EC cells was downregulated. Overexpression of IGFBP-rP1 inhibited the proliferation and induced apoptosis of EC cells, which were abolished by the overexpression of AKT. In addition, IGFBP-rP1 directly interacted with AKT to inhibit PI3K/AKT signaling. Additionally, M0 macrophages were induced by EC cells to differentiate into M2 macrophages, which was reversed by IGFBP-rP1. Overexpression of AKT in EC cells abolished the inhibitory effect of IGFBP-rP1 on M2 polarization. IGFBP-rP1 as an oncogenic factor inhibits M2 polarization of TAMs through PI3K/AKT signaling pathway and may be a potentially valuable target for EC therapy.

Herbal formula Jiawei Xiaochengqi decoction prevents postoperative abdominal adhesion in a rat model through inhibition of CXCL2-CXCR2 pathway.

BACKGROUND: Postoperative abdominal adhesion (PAA) is the most common complication after abdominal surgeries, which can lead to intestinal obstruction, chronic abdominal pain or female infertility. Jiawei Xiaochengqi decoction (JWXCQ) is a hospital preparation widely used for PAA treatment in Nanfang Hospital of Southern Medical University for more than twenty years. PURPOSE: This study aimed to investigate the therapeutic effects and potential mechanism of JWXCQ against PAA and provide beneficial information for its clinical application. METHODS: The main active components of JWXCQ were identified using ultra high performance liquid chromatography (UHPLC) combined with standard substance comparison. The efficacy and underlying mechanism of JWXCQ were evaluated through in vivo experiments with a postsurgical-induced peritoneal adhesion rat model, and in vitro studies with LPS-stimulated Raw 264.7 macrophages and primary fibroblasts. H&E and Masson staining were performed to assess histopathological changes. The levels of cytokines/proteins-associated with inflammation and degradation of extracellular matrix as well as CXCL2-CXCR2 pathway-related proteins were determined by ELISA, qRT-PCR, western blot assays or immunohistochemistry, respectively. Furthermore, siCXCR2 transfection was used to validate the mechanism of action of JWXCQ. RESULTS: JWXCQ treatment significantly reduced the formation of PAA, inhibited the inflammation and collagen deposition, and facilitated the secretion of MMP9, decreased the levels of IL-1ß, IL-6, TIMP1, COL-1, and suppressed the CXCL2-CXCR2 pathway in PAA rats. Furthermore, JWXCQ inhibited its downstream pathways, the JAK2-STAT3 and PI3K-AKT signaling, as indicated by the suppression of the phosphorylation levels of STAT3 and AKT. In vitro cell experiments revealed that JWXCQ reduced IL-1ß and IL-6 secretion in Raw 264.7 macrophages and COL-1 in primary fibroblasts. The CXCL2-CXCR2, JAK2-STAT3 and PI3K-AKT pathways were also inhibited after JWXCQ treatment, which were consistent with the in vivo results. More importantly, silence of CXCR2 eliminated the regulatory effects of JWXCQ. CONCLUSION: JWXCQ could effectively prevent the PAA formation by alleviating inflammation and collagen deposition, which was associated with the inhibition of CXCL2-CXCR2 pathway. This study investigated the relevant pharmacological mechanisms of JWXCQ, providing further evidence for the application of JWXCQ in clinical PAA treatment.

RAGE inhibition alleviates lipopolysaccharides-induced lung injury via directly suppressing autophagic apoptosis of type II alveolar epithelial cells.

BACKGROUND: Advanced glycation end product receptor (RAGE) acts as a receptor of pro-inflammatory ligands and is highly expressed in alveolar epithelial cells (AECs). Autophagy in AECs has received much attention recently. However, the roles of autophagy and RAGE in the pathogenesis of acute lung injury remain unclear. Therefore, this study aimed to explore whether RAGE activation signals take part in the dysfunction of alveolar epithelial barrier through autophagic death. METHODS: Acute lung injury animal models were established using C57BL/6 and Ager gene knockout (Ager -/- mice) mice in this study. A549 cells and primary type II alveolar epithelial (ATII) cells were treated with siRNA to reduce Ager gene expression. Autophagy was inhibited by 3-methyladenine (3-MA). Lung injury was assessed by histopathological examination. Cell viability was estimated by cell counting kit-8 (CCK-8) assay. The serum and bronchoalveolar lavage fluid (BALF) levels of interleukin (IL)-6, IL-8 and soluble RAGE (sRAGE) were evaluated by Enzyme-linked immunosorbent assay (ELISA). The involvement of RAGE signals, autophagy and apoptosis was assessed using western blots, immunohistochemistry, immunofluorescence, transmission electron microscopy and TUNEL test. RESULTS: The expression of RAGE was promoted by lipopolysaccharide (LPS), which was associated with activation of autophagy both in mice lung tissues and A549 cells as well as primary ATII cells. sRAGE in BALF was positively correlated with IL-6 and IL-8 levels. Compared with the wild-type mice, inflammation and apoptosis in lung tissues were alleviated in Ager-/- mice. Persistently activated autophagy contributed to cell apoptosis, whereas the inhibition of autophagy by 3-MA protected lungs from damage. In addition, Ager knockdown inhibited LPS-induced autophagy activation and attenuated lung injury. In vitro, knockdown of RAGE significantly suppressed the activation of LPS-induced autophagy and apoptosis of A549 and primary ATII cells. Furthermore, RAGE activated the downstream STAT3 signaling pathway. CONCLUSION: RAGE plays an essential role in the pathogenesis of ATII cells injury. Our results suggested that RAGE inhibition alleviated LPS-induced lung injury by directly suppressing autophagic apoptosis of alveolar epithelial cells.

Screening and verification of genes related to polycystic ovary syndrome.

OBJECTIVE: To identify key genes involved in occurrence and development of polycystic ovary syndrome (PCOS). METHODS: By downloading the GSE85932 dataset from the GEO database, we used bioinformatical analysis to analyse differentially expressed genes (DEGs) from blood samples of eight women with PCOS and eight matched controls. Following bioinformatic analysis, we performed a cross-sectional study of serum samples taken from 79 women with PCOS and 36 healthy controls. RESULTS: From the 178 DEGs identified by bioinformatical analysis, 15 genes were identified as significant, and of these, ORM1 and ORM2 were selected for further verification as potential biomarkers for PCOS. Serum ORM1 and ORM2 levels were significantly increased in women with PCOS, and had a high diagnostic value. ORM1 and ORM2 were positively correlated with testosterone, cholesterol, and triglycerides. ORM1 levels were negatively correlated with high density lipoprotein (HDL) while ORM2 levels showed no significant correlation. CONCLUSIONS: ORM may be an effective biomarker for the diagnosis of PCOS and its monitoring may be a useful therapeutic strategy.

Activating transcription factor 4 protects mice against sepsis-induced intestinal injury by regulating gut-resident macrophages differentiation.

BACKGROUND: Gut-resident macrophages (gMacs) supplemented by monocytes-to-gMacs differentiation play a critical role in maintaining intestinal homeostasis. Activating transcription factor 4 (ATF4) is involved in immune cell differentiation. We therefore set out to investigate the role of ATF4-regulated monocytes-to-gMacs differentiation in sepsis-induced intestinal injury. METHODS: Sepsis was induced in C57BL/6 wild type (WT) mice and Atf4- knockdown ( Atf4+/ - ) mice by cecal ligation and puncture or administration of lipopolysaccharide (LPS). Colon, peripheral blood mononuclear cells, sera, lung, liver, and mesenteric lymph nodes were collected for flow cytometry, hematoxylin and eosin staining, immunohistochemistry, quantitative reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. RESULTS: CD64, CD11b, Ly6C, major histocompatibility complex-II (MHC-II), CX3CR1, Ly6G, and SSC were identified as optimal primary markers for detecting the process of monocytes-to-gMacs differentiation in the colon of WT mice. Monocytes-to-gMacs differentiation was impaired in the colon during sepsis and was associated with decreased expression of ATF4 in P1 (Ly6C hi monocytes), the precursor cells of gMacs. Atf4 knockdown exacerbated the impairment of monocytes-to-gMacs differentiation in response to LPS, resulting in a significant reduction of gMacs in the colon. Furthermore, compared with WT mice, Atf4+/- mice exhibited higher pathology scores, increased expression of inflammatory factor genes ( TNF-α, IL-1ß ), suppressed expression of CD31 and vascular endothelial-cadherin in the colon, and increased translocation of intestinal bacteria to lymph nodes and lungs following exposure to LPS. However, the aggravation of sepsis-induced intestinal injury resulting from Atf4 knockdown was not caused by the enhanced inflammatory effect of Ly6C hi monocytes and gMacs. CONCLUSION: ATF4, as a novel regulator of monocytes-to-gMacs differentiation, plays a critical role in protecting mice against sepsis-induced intestinal injury, suggesting that ATF4 might be a potential therapeutic target for sepsis treatment.

Continuous renal replacement therapy attenuates polymorphonuclear myeloid-derived suppressor cell expansion in pediatric severe sepsis.

Background: Myeloid-derived suppressor cells (MDSCs) expansion is an important mechanism underlying immunosuppression during sepsis. Though continuous renal replacement therapy (CRRT) may attenuate hyperinflammatory response in sepsis, its role in regulating MDSCs is unknown. The aim of this study was to assess the potential role of CRRT involved in sepsis-induced MDSCs expansion in pediatric sepsis. Method: The proportion of polymorphonuclear MDSCs (PMN-MDSCs) was detected before CRRT (pre-CRRT), at 24 hours after CRRT (CRRT 1st day) and on the 7th day after CRRT (CRRT 7th day). The correlation analyses were performed to elucidate the relationship of MDSCs with clinical indexes in sepsis. Results: Totally 22 pediatric patients with sepsis were enrolled [median age 44 (IQR15, 83) months]. PMN-MDSCs were expanded in pediatric sepsis compared with healthy controls (4.30% vs. 0.37%, P=0.04). The proportion of PMN-MDSCs showed a decreased tendency on the CRRT 7th day compared with that on the CRRT 1st day in survivors (2.29% vs.5.32%, P = 0.088). There was no significant difference in the proportion of PMN-MDSCs between survivors and non-survivors before CRRT (4.51% vs. 3.33%, P=0.745). The levels of interleukin 6 (IL-6) was decreased on the CRRT 7th day compared with CRRT 1st day in survivors. In the subgroups of patients with significantly decreased IL-6 levels after CRRT, the proportion of PMN-MDSCs on the CRRT 7th day were also significantly decreased compared with that on the CRRT 1st day (2.21% vs. 6.67%, P = 0.033). Conclusion: The proportion of PMN-MDSCs was down-regulated on the CRRT 7th day in survivors with sepsis. The reduced PMN-MDSCs expansion may relate to decreased IL-6 level.

Anti-Gouty Arthritis and Anti-Hyperuricemia Properties of Sanghuangporus vaninii and Inonotus hispidus in Rodent Models.

Acute inflammation and hyperuricemia are associated with gouty arthritis. As an edible and therapeutic mushroom, Sanghuangporus vaninii (SV) has an inhibitory effect on tumorigenesis, and Inonotus hispidus (IH) exhibits anti-tumor, anti-inflammatory, and antioxidant properties. In this study, uric acid (UA) and xanthine oxidase (XOD) levels in hyperuricemic mice were examined to determine the regulatory effects of SV and IH. SV and IH reversed the pathogenic state of elevated UA levels in the serum and reduced levels of XOD in the serum and liver of mice with hyperuricemia. SV and IH affected the inflammatory response in rats with acute gouty arthritis. Compared to vehicle-treated rats, monosodium urate crystals (MSU) increased the swelling ratio of the right ankle joints. SV and IH administration significantly reduced swelling and inflammatory cell infiltration. SV reduced the levels of interleukin-8 (IL-8) and chemokine ligand-2 (CCL-2), whereas IH reduced the levels of matrix metalloproteinase-9 (MMP-9), CCL-2, and tumor necrosis factor-α (TNF-α), which were confirmed in articular soft tissues by immunohistochemistry. In summary, our data provide experimental evidence for the applicability of SV and IH in gouty arthritis and hyperuricemia treatment.

TAIGET: A small-molecule target identification and annotation web server.

Background: Accurate target identification of small molecules and downstream target annotation are important in pharmaceutical research and drug development. Methods: We present TAIGET, a friendly and easy to operate graphical web interface, which consists of a docking module based on AutoDock Vina and LeDock, a target screen module based on a Bayesian-Gaussian mixture model (BGMM), and a target annotation module derived from >14,000 cancer-related literature works. Results: TAIGET produces binding poses by selecting ≤5 proteins at a time from the UniProt ID-PDB network and submitting ≤3 ligands at a time with the SMILES format. Once the identification process of binding poses is complete, TAIGET then screens potential targets based on the BGMM. In addition, three medical experts and 10 medical students curated associations among drugs, genes, gene regulation, cancer outcome phenotype, 2,170 cancer cell types, and 73 cancer types from the PubMed literature, with the aim to construct a target annotation module. A target-related PPI network can be visualized by an interactive interface. Conclusion: This online tool significantly lowers the entry barrier of virtual identification of targets for users who are not experts in the technical aspects of virtual drug discovery. The web server is available free of charge at http://www.taiget.cn/.

Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome in children with leukemia/lymphoma: A retrospective case series.

Objective: The cancer patients with severe acute respiratory distress syndrome (ARDS) benefit from extracorporeal membrane oxygenation (ECMO) remains unanswered. We analyzed clinical characteristics and outcomes of pediatric patients with leukemia/lymphoma who developed ARDS and treated with ECMO. Methods: Pediatric leukemia or lymphoma patients with ARDS who underwent ECMO between August 2017 and December 2021 were retrospectively analyzed in a tertiary pediatric intensive care unit (PICU). Results: Seven patients with median age 53 (IQR 42-117) months and 4 males were included. Six cases of leukemia [5 of acute lymphocytic leukemia (ALL) and 1 of acute myelogenous leukemia (AML, M5)] and 1 of non-Hodgkin lymphoma with severe ARDS received ECMO on chemotherapy period. The etiology of ARDS is community or chemotherapy-associated bacterial or/and fungal or viral infection. All the patients received chemotherapy in the 2 weeks prior to ECMO and five were neutropenic at initial ECMO. Six cases underwent veno-arterial ECMO (VA ECMO) and 1 for veno-venous ECMO (VV-ECMO). The median duration of ECMO support was 122 (IQR 56-166) hours. Overall, 42.9% (three of seven) survived to hospital discharge and 6 months survival rate was 28.6% (two of seven). Bleeding was the main ECMO-associated complication occurring in 7 patients, followed by nosocomial infection in 4 cases. All the patients required vasopressor support, and 6 received continuous renal replacement therapy (CRRT). Conclusion: Our experiences suggest that rescue ECMO provides a selective treatment strategy in childhood hematologic malignancies with severe ARDS.