Exploring the causal association between serum metabolites and erectile dysfunction: a bidirectional Mendelian randomisation study.

Erectile dysfunction is a common sexual disorder in men. Some studies have found a strong association between some serum metabolites and erectile dysfunction. To investigate this association further, we used bidirectional Mendelian randomisation to investigate causality and possible biological mechanisms.Firstly, this study screened the statistics of genome-wide association studies of serum metabolites and erectile dysfunction to obtain instrumental variables. Inverse variance weighting was used as the primary method for causal effect analysis of instrumental variables in forward or reverse Mendelian randomisation, and the results obtained by MR-Egger regression and the weighted median method were used as references. Subsequently, the metabolites causally associated with erectile dysfunction were subjected to replication analyses and meta-analyses, and the results of the meta-analyses were analysed by pathway analyses to find influential pathways. In this process, Mendelian randomisation results need to be assessed for stability and reliability using sensitivity analysis.It was found that a total of six serum metabolites were causally associated with erectile dysfunction in a forward Mendelian randomisation study. 1,3,7-trimethyluraten (0.85 (0.73-0.99), P = 0.0368), ergothioneine (0.65 (0.45-0.94), P = 0.0226) and gamma-glutamylglutamate (0.63 (0.46-0.88), P = 0.0059) were protective against the development of erectile dysfunction, whereas 2-hydroxyhippurate (1.10 (1.02-1.19), P = 0.0152), N2,N2-dimethylguanosine (1.57 (1.02-2.40), P = 0.0395) and octanoylcarnitine (1.38 (1.06-1.82), P = 0.0183) were able to induce the development of erectile dysfunction. In addition, metabolic pathway analysis showed that 1,3,7-trimethylurate was able to influence the development of erectile dysfunction via the caffeine metabolism pathway (P = 0.0454). On the other hand, reverse Mendelian randomisation analysis showed that erectile dysfunction reduced serum homocitrulline levels (0.99 (0.97-1.00), P = 0.0360). Sensitivity analyses, including heterogeneity tests and pleiotropy tests, confirmed the reliability of the results.In conclusion, this study demonstrated a bidirectional causal relationship between serum metabolites and erectile dysfunction using bidirectional Mendelian randomisation analysis and replication meta-analysis. On this basis, this study provides a new direction of thinking and strong evidence for the therapeutic application and adjunctive diagnosis of serum metabolites in erectile dysfunction, and provides a certain reference value for subsequent related studies.

Targeting macrophagic RasGRP1 with catechin hydrate ameliorates sepsis-induced multiorgan dysfunction.

BACKGROUND: The proinflammatory response induced by macrophages plays a crucial role in the development of sepsis and the resulting multiorgan dysfunction. Identifying new regulatory targets for macrophage homeostasis and devising effective treatment strategies remains a significant challenge in contemporary research. PURPOSE: This study aims to identify new regulatory targets for macrophage homeostasis and develop effective strategies for treating sepsis. STUDY DESIGN AND METHODS: Macrophage infiltration in septic patients and in lungs, kidneys, and brains of caecum ligation and puncture (CLP)-induced septic mice was observed using CIBERSORT and immunofluorescence (IF). Upon integrating the MSigDB database and GSE65682 dataset, differently expressed macrophage-associated genes (DEMAGs) were identified. Critical DEMAGs were confirmed through machine learning. The protein level of the critical DEMAG was detected in PBMCs of septic patients, RAW264.7 cells, and mice lungs, kidneys, and brains using ELISA, western blot, immunohistochemistry, and IF. siRNA was applied to investigate the effect of the critical DEMAG in RAW264.7 cells. A natural product library was screened to find a compound targeting the critical DEMAG protein. The binding of compounds and proteins was analyzed through molecular docking, molecular dynamics simulations, CETSA, and MST analysis. The therapeutic efficacy of the compounds against sepsis was then evaluated through in vitro and in vivo experiments. RESULTS: Macrophage infiltration was inversely correlated with survival in septic patients. The critical differentially expressed molecule RasGRP1 was frequently observed in the PBMCs of septic patients, LPS-induced RAW264.7 cells, and the lungs, kidneys, and brains of septic mice. Silencing RasGRP1 alleviated proinflammatory response and oxidative stress in LPS-treated RAW264.7 cells. Catechin Hydrate (CH) was identified as an inhibitor of RasGRP1, capable of maintaining macrophage homeostasis and mitigating lung, kidney, and brain damage during sepsis. CONCLUSION: This study demonstrates that RasGRP1, a novel activator of macrophage proinflammatory responses, plays a crucial role in the excessive inflammation and oxidative stress associated with sepsis. CH shows potential for treating sepsis by inhibiting RasGRP1.

Danlou tablet alleviates sepsis-induced acute lung and kidney injury by inhibiting the PARP1/HMGB1 pathway.

Background: Sepsis-associated acute lung injury (ALI) and acute kidney injury (AKI) are common complications that significantly impact patient prognosis. Danlou tablet (DLT) is a traditional herbal preparation with anti-inflammatory and antioxidant properties. However, its therapeutic potential in sepsis remains unknown. Methods: The impact of DLT on ALI and AKI was evaluated using the cecal ligation and puncture (CLP) experimental sepsis animal model. The effects of DLT on macrophages were observed through LPS-stimulated RAW264.7 cell line. Inflammatory cytokines, oxidative stress indicators, HE, PAS, and DHE staining, lung wet-to-dry weight ratio, and serum creatinine and urea nitrogen levels were used to assess tissue injury. Network pharmacology, molecular docking, and molecular dynamics simulations were used to explore the potential regulatory mechanisms of DLT in sepsis. Western blot and immunohistochemical staining were used to validate the expression of mechanism-related proteins. Results: DLT inhibited the inflammatory response and oxidative stress, improved structural and functional abnormalities in lung and kidney tissues in CLP mice, and alleviated pro-inflammatory responses of LPS-stimulated macrophages. PARP1 and HMGB1 were identified as key regulatory targets. The results of in vitro and in vivo experiments suggest that DLT can effectively inhibit PARP1/HMGB1 and improve sepsis-associated ALI and AKI. Conclusion: The present study demonstrated that DLT suppressed pro-inflammatory responses of macrophage and alleviated ALI and AKI in the CLP mice by inhibiting the transition activation of PARP1/HMGB1. These findings partially elucidate the mechanism of DLT in sepsis-associated ALI and AKI and further clarify the active components of DLT, thereby providing a scientific theoretical basis for treating sepsis with DLT.

Signal enhancement ratio of multi-phase contrast-enhanced MRI: an imaging biomarker for survival in pancreatic adenocarcinoma.

OBJECTIVES: To evaluate signal enhancement ratio (SER) for tissue characterization and prognosis stratification in pancreatic adenocarcinoma (PDAC), with quantitative histopathological analysis (QHA) as the reference standard. METHODS: This retrospective study included 277 PDAC patients who underwent multi-phase contrast-enhanced (CE) MRI and whole-slide imaging (WSI) from three centers (2015-2021). SER is defined as (SIlt - SIpre)/(SIea - SIpre), where SIpre, SIea, and SIlt represent the signal intensity of the tumor in pre-contrast, early-, and late post-contrast images, respectively. Deep-learning algorithms were implemented to quantify the stroma, epithelium, and lumen of PDAC on WSIs. Correlation, regression, and Bland-Altman analyses were utilized to investigate the associations between SER and QHA. The prognostic significance of SER on overall survival (OS) was evaluated using Cox regression analysis and Kaplan-Meier curves. RESULTS: The internal dataset comprised 159 patients, which was further divided into training, validation, and internal test datasets (n = 60, 41, and 58, respectively). Sixty-five and 53 patients were included in two external test datasets. Excluding lumen, SER demonstrated significant correlations with stroma (r = 0.29-0.74, all p < 0.001) and epithelium (r = -0.23 to -0.71, all p < 0.001) across a wide post-injection time window (range, 25-300 s). Bland-Altman analysis revealed a small bias between SER and QHA for quantifying stroma/epithelium in individual training, validation (all within ± 2%), and three test datasets (all within ± 4%). Moreover, SER-predicted low stromal proportion was independently associated with worse OS (HR = 1.84 (1.17-2.91), p = 0.009) in training and validation datasets, which remained significant across three combined test datasets (HR = 1.73 (1.25-2.41), p = 0.001). CONCLUSION: SER of multi-phase CE-MRI allows for tissue characterization and prognosis stratification in PDAC. CLINICAL RELEVANCE STATEMENT: The signal enhancement ratio of multi-phase CE-MRI can serve as a novel imaging biomarker for characterizing tissue composition and holds the potential for improving patient stratification and therapy in PDAC. KEY POINTS: Imaging biomarkers are needed to better characterize tumor tissue in pancreatic adenocarcinoma. Signal enhancement ratio (SER)-predicted stromal/epithelial proportion showed good agreement with histopathology measurements across three distinct centers. Signal enhancement ratio (SER)-predicted stromal proportion was demonstrated to be an independent prognostic factor for OS in PDAC.

Mutation and clinical analysis of the CLCC1 gene in amyotrophic lateral sclerosis patients from Central South China.

INTRODUCTION: Recently, chloride channel CLIC-like 1 (CLCC1) was reported to be a novel ALS-related gene. We aimed to screen CLCC1 variants in our ALS cohort and further explore the genotype-phenotype correlation of CLCC1-related ALS. METHODS: We screened rare damaging variants in CLCC1 from our cohorts of 1005 ALS patients and 1224 healthy controls with whole-exome sequencing in Central South China. Fisher's exact test was conducted for association analysis at the entire gene level and single variant level. RESULTS: In total, four heterozygous missense variants in CLCC1 were identified from four unrelated sporadic ALS patients and predicted to be putative pathogenic by in silico tools and protein model prediction, accounting for 0.40% of all patients (4/1005). The four variants were c.A275C (p.Q92P), c.G1139A (p.R380K), c.C1244T (p.T415M), and c.G1328A (p.R443Q), respectively, which had not been reported in ALS patients previously. Three of four variants were located in exon 10. Patients harboring CLCC1 variants seemed to share a group of similar clinical features, including earlier age at onset, rapid progression, spinal onset, and vulnerable cognitive status. Statistically, we did not find CLCC1 to be associated with the risk of ALS at the entire gene level or single variant level. CONCLUSION: Our findings further expanded the genetic and clinical spectrum of CLCC1-related ALS and provided more genetic evidence for anion channel involvement in the pathogenesis of ALS, but further investigations are needed to verify our findings.

QiShenYiQi pills preserve endothelial barrier integrity to mitigate sepsis-induced acute lung injury by inhibiting ferroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: The QiShengYiQi pill (QSYQ) is a traditional Chinese medicinal formulation. The effectiveness and safety of QSYQ in treating respiratory system disorders have been confirmed. Its pharmacological actions include anti-inflammation, antioxidative stress, and improving energy metabolism. However, the mechanism of QSYQ in treating sepsis-induced acute lung injury (si-ALI) remains unclear. AIM OF THE STUDY: Si-ALI presents a clinical challenge with high incidence and mortality rates. This study aims to confirm the efficacy of QSYQ in si-ALI and to explore the potential mechanisms, providing a scientific foundation for its application and insights for optimizing treatment strategies and identifying potential active components. MATERIALS AND METHODS: The impact of QSYQ on si-ALI was evaluated using the cecal ligation and puncture (CLP) experimental sepsis animal model. The effects of QSYQ on endothelial cells were observed through coculturing with LPS-stimulated macrophage-conditioned medium. Inflammatory cytokine levels, HE staining, Evans blue staining, lung wet/dry ratio, and cell count and protein content in bronchoalveolar lavage fluid were used to assess the degree of lung injury. Network pharmacology was utilized to investigate the potential mechanisms of QSYQ in treating si-ALI. Western blot and immunofluorescence analyses were used to evaluate barrier integrity and validate mechanistically relevant proteins. RESULTS: QSYQ reduced the inflammation and alleviated pulmonary vascular barrier damage in CLP mice (all P < 0.05). A total of 127 potential targets through which QSYQ regulates si-ALI were identified, predominantly enriched in the RAGE pathway. The results of protein-protein interaction analysis suggest that COX2, a well-established critical marker of ferroptosis, is among the key targets. In vitro and in vivo studies demonstrated that QSYQ mitigated ferroptosis and vascular barrier damage in sepsis (all P < 0.05), accompanied by a reduction in oxidative stress and the inhibition of the COX2 and RAGE (all P < 0.05). CONCLUSIONS: This study demonstrated that QSYQ maintains pulmonary vascular barrier integrity by inhibiting ferroptosis in CLP mice. These findings partially elucidate the mechanism of QSYQ in si-ALI and further clarify the active components of QSYQ, thereby providing a scientific theoretical basis for treating si-ALI with QSYQ.

Design and Screening of Fluorescent Probes Based upon Hemicyanine Dyes to Sensitively Respond to HSO3- in Living Cells.

SO2, a gas signaling molecule, can be produced endogenously in mitochondria. Its hydrolysate, HSO3-, plays a key role in food preservation, cardiovascular relaxation, and other fields, suggesting that it is important to achieve its detection. Here, based on the Michael addition mechanism, four hemicyanine dye fluorescent probes (ETN, ETB, STB, and EIB) were designed and synthesized for responding to HSO3-. We evaluated the reaction ability of different probes with HSO3- and tried to explain the reasons for the significantly different response effects between probes and HSO3- according to the structure-activity relationship. The influence of different substituents of probes on the properties of mitochondria-targeting was also discussed. Finally, we screened out ETN as the optimal HSO3- probe due to its high sensitivity, rapid reactivity, and good mitochondria-targeting, and it could sensitively respond to HSO3- in living cells. The LODs of ETN for HSO3- were calculated by both absorption and fluorescence methods, respectively, which were 2.727 and 0.823 µM. Our work provided valuable references for designing strategies and potential tools for response to SO2 derivatives in biosystems.

Genetic and clinical analysis of TP73 gene in amyotrophic lateral sclerosis patients from Chinese mainland.

Introduction: TP73 was recently identified as a novel causative gene for amyotrophic lateral sclerosis (ALS). We aimed to determine the contribution of variations in TP73 in the Chinese ALS population and to further explore the genotype-phenotype correlations. Methods: We screened rare, putative pathogenic TP73 mutations in a large Chinese ALS cohort and performed association analysis of both rare and common TP73 variations between cases and controls. Results: Of the 985 ALS patients studied, six rare, heterozygous putative pathogenic variants in TP73 were identified among six unrelated sALS patients. Exon 14 of TP73 might be a mutant hotspot in our cohort. Patients with ALS with only rare, putative pathogenic TP73 mutations exhibited a characteristic clinical profile. Patients harboring multiple mutations in TP73 and other ALS-related genes displayed a significantly earlier onset of ALS. Association analysis revealed that rare TP73 variants in the untranslated regions (UTRs) were enriched among ALS patients; meanwhile, two common variants in the exon-intron boundary were discovered to be associated with ALS. Discussion: We demonstrate that TP73 variations also have contributed to ALS in the Asian population and broaden the genotypic and phenotypic spectrum of TP73 variants in the ALS-frontotemporal dementia (FTD) spectrum. Furthermore, our findings first suggest that TP73 is not only a causative gene, but also exerts a disease-modifying effect. These results may contribute to a better understanding of the molecular mechanism of ALS.

Advances in the Functional Nucleic Acid Biosensors for Detection of Lead Ions.

Lead ions (Pb2+) are destructive to the natural environment and public health, so the efficient detection of Pb2+ is particularly important. Although the instrumental analysis methods have high accuracy, they require high cost and precise operation, which limits their wide application. Therefore, many strategies have been extensively studied for detecting Pb2+ by biosensors. Functional nucleic acids have become an efficient tool in this field. This review focuses on the recent biosensors of detecting Pb2+ based on functional nucleic acids from 2010 to 2020, in which DNAzyme, DNA G-quadruplex and aptamer will be introduced. The biosensors are divided into three categories that colorimetric, fluorometric and electrochemical biosensors according to the different reported signals. The action mechanism and detection effect of each biosensor are explained. Finally, the present situation of nucleic acid biosensor for the detection of Pb2+ is summarized and the future research direction is prospected.

Asparagine synthetase regulates lung-cancer metastasis by stabilizing the ß-catenin complex and modulating mitochondrial response.

The availability of asparagine is the limitation of cell growth and metastasis. Asparagine synthetase (ASNS) was an essential enzyme for endogenous asparagine products. In our study, ASNS-induced asparagine products were essential to maintain tumor growth and colony formations in vitro. But mutated ASNS which defected endogenous asparagine products still upregulated cell invasiveness, which indicated that ASNS promoted invasiveness by alternative pathways. Mechanically, ASNS modulated Wnt signal transduction by promoting GSK3ß phosphorylation on ser9 and stabilizing the ß-catenin complex, as result, ASNS could promote more ß-catenin translocation into nucleus independent of endogenous asparagine. At the same time, ASNS modulated mitochondrial response to Wnt stimuli with increased mitochondrial potential and membrane fusion. In summary, ASNS promoted metastasis depending on Wnt pathway and mitochondrial functions even without endogenous asparagine products.

A cysteine and Hg2+ detection method based on transformation supramolecular assembly of cyanine dye by AGRO100.

ETC (3,3'-di(3-sulfopropyl)-4,5,4',5'-dibenzo-9-ethylthiacarbocyanine triethylammonium salt), as a derivative of thiazole, is capable of forming various aggregates by the short-range noncovalent interaction forces under specific conditions, accompanying with significant absorbance and fluorescence characteristics. In this work, a label-free probe (ETC) for the detection of Cys (Cysteine) and Hg2+ was developed based on transformation between monomers and J-aggregations by AGRO100. AGRO100 can transform between single-stranded DNA and G-quadruplex to realize recognition of Cys and Hg2+ in dual-channel mode. These recognitional signals can be captured by UV-visible absorption spectra and fluorescence spectroscopy. ETC exhibits high sensitivity and selectivity with the detection limit of 0.197 nM in a wide range of 0-15 µM, which can apply of Cys and Hg2+ detection in human serum.

Identification of distinct clinical phenotypes of acute respiratory distress syndrome with differential responses to treatment.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome, and the identification of homogeneous subgroups and phenotypes is the first step toward precision critical care. We aimed to explore whether ARDS phenotypes can be identified using clinical data, are reproducible and are associated with clinical outcomes and treatment response. METHODS: This study is based on a retrospective analysis of data from the telehealth intensive care unit (eICU) collaborative research database and three ARDS randomized controlled trials (RCTs) (ALVEOLI, FACTT and SAILS trials). We derived phenotypes in the eICU by cluster analysis based on clinical data and compared the clinical characteristics and outcomes of each phenotype. The reproducibility of the derived phenotypes was tested using the data from three RCTs, and treatment effects were evaluated. RESULTS: Three clinical phenotypes were identified in the training cohort of 3875 ARDS patients. Of the three phenotypes identified, phenotype I (n = 1565; 40%) was associated with fewer laboratory abnormalities, less organ dysfunction and the lowest in-hospital mortality rate (8%). Phenotype II (n = 1232; 32%) was correlated with more inflammation and shock and had a higher mortality rate (18%). Phenotype III (n = 1078; 28%) was strongly correlated with renal dysfunction and acidosis and had the highest mortality rate (22%). These results were validated using the data from the validation cohort (n = 3670) and three RCTs (n = 2289) and had reproducibility. Patients with these ARDS phenotypes had different treatment responses to randomized interventions. Specifically, in the ALVEOLI cohort, the effects of ventilation strategy (high PEEP vs low PEEP) on ventilator-free days differed by phenotype (p = 0.001); in the FACTT cohort, there was a significant interaction between phenotype and fluid-management strategy for 60-day mortality (p = 0.01). The fluid-conservative strategy was associated with improved mortality in phenotype II but had the opposite effect in phenotype III. CONCLUSION: Three clinical phenotypes of ARDS were identified and had different clinical characteristics and outcomes. The analysis shows evidence of a phenotype-specific treatment benefit in the ALVEOLI and FACTT trials. These findings may improve the identification of distinct subsets of ARDS patients for exploration in future RCTs.

Synergistical Performance Modification of Epoxy Resin by Nanofillers and Carboxyl-Terminated Liquid Nitrile-Butadiene Rubber.

Epoxy composite materials are widely used in power equipment. As the voltage level increases, the requirement of material properties, including electrical, thermal, and mechanical, has also increased. Introducing thermally conductive nanofiller to the epoxy/liquid rubber composites system is an effective approach to improve heat performance, but the effects of thermally conductive nanofillers on relaxation characteristics remain unclarified. In this paper, nano-alumina (nano-Al2O3) and nano-boron nitride (nano-BN) have been employed to modify the epoxy/carboxyl-terminated liquid nitrile-butadiene rubber (epoxy/CTBN) composites system. The thermal conductivity and glass transition temperature of different formula systems have been measured. The effect of the nanofillers on the relaxation behaviors of the resin matrix has been investigated. Results show that the different kinds of nanofillers will introduce different relaxation processes into the matrix and increase the conductivity at the same time. This study can provide a theoretical basis for the synergistic improvement of multiple properties of epoxy resin composites.

Intestinal microbiota and antibiotic-associated acute gastrointestinal injury in sepsis mice.

BACKGROUND: To investigate the changes of intestinal microbiota and metabolites in sepsis mice with acute gastrointestinal injury before and after the use of antibiotics, and to explore the possible effects of these changes on the body. METHODS: Twenty-four 6-8-w-old SPF-grade C57BL/6J male mice were selected, and the mice were randomly divided into three groups. The mice were treated by tail vein injection for 3 days. The intestinal motility of mice after administration was detected. The mice feces were collected for 16S rRNA and Untargeted metabonomics detection. RESULTS: The use of antibiotics in sepsis mice can change the composition of intestinal microbiota and metabolites. LD3, AD3 and LAD3 samples had significant differences in bacterial species. Desulfovibrio was the species with a significant difference in LAD3. In addition, we found that the composition of those intestinal microbiota were correlated with changes in intestinal motility. The untargeted metabolomics analysis showed that the fecal metabolites of LD3 and LAD3 samples were significantly different. In addition to the basic metabolites, Benzoic acid and 4-Hydroxybenzoic acid were also found, and Desulfovibrio was associated with them. CONCLUSIONS: The use of antibiotics in sepsis mice can lead to changes in the intestinal microbiota and metabolite levels, which may be related to the severity of acute gastrointestinal injury in sepsis mice. Inhibiting Desulfovibrio in the intestine and using Benzoic acid and 4-Hydroxybenzoic acid as a marker for the production of Desulfovibrio may reduce the inflammatory degree of acute gastrointestinal injury in sepsis.

Erratum to "An Inhibitor of DRP1 (Mdivi-1) Alleviates LPS-Induced Septic AKI by Inhibiting NLRP3 Inflammasome Activation".

[This corrects the article DOI: 10.1155/2020/2398420.].

Dielectric Relaxation Characteristics of Epoxy Resin Modified with Hydroxyl-Terminated Nitrile Rubber.

Utilizing liquid rubber to toughen epoxy resin is one of the most mature and promising methods. However, the dielectric relaxation characteristics of the epoxy/liquid rubber composites have not been studied systematically, while the relaxation behaviours are a critical factor for both micro and macro properties. In this paper, hydroxyl-terminated liquid nitrile rubber (HTBN) is employed to reinforce a kind of room-temperature-cured epoxy resin. The dielectric spectrum is measured and analysed. Results show that two relaxation processes are introduced in the binary composites. The α relaxation of HTBN shows a similar temperature dependence with the ß relaxation of epoxy resin. The interfacial polarization leads to an increase of complex permittivity, which reaches its maximum at 70 °C. In addition, affected by interfacial polarization, the thermionic polarization is inhibited, and the samples with filler ratios of 15% and 25% show lower DC-conductivity below 150 °C. In addition, the α relaxation and thermionic polarization of epoxy resin obey the Vogel‒Fulcher‒Tammann law, while the interfacial polarization and DC-conductivity satisfy with the Arrhenius law. Furthermore, the fitting results of the Vogel temperature of α relaxation, glass transition temperature, apparent activation energy of interfacial polarization and DC-conductivity all decline with HTBN content. These results can provide a reference and theoretical guidance for the assessment of dielectric properties and the improvement of the formulation of liquid-rubber-toughened epoxy resin.

An Inhibitor of DRP1 (Mdivi-1) Alleviates LPS-Induced Septic AKI by Inhibiting NLRP3 Inflammasome Activation.

Mitochondria play an essential role in energy metabolism. Oxygen deprivation can poison cells and generate a chain reaction due to the free radical release. In patients with sepsis, the kidneys tend to be the organ primarily affected and the proximal renal tubules are highly susceptible to energy metabolism imbalances. Dynamin-related protein 1 (DRP1) is an essential regulator of mitochondrial fission. Few studies have confirmed the role and mechanism of DRP1 in acute kidney injury (AKI) caused by sepsis. We established animal and cell sepsis-induced AKI (S-AKI) models to keep DRP1 expression high. We found that Mdivi-1, a DRP1 inhibitor, can reduce the activation of the NOD-like receptor pyrin domain-3 (NLRP3) inflammasome-mediated pyroptosis pathway and improve mitochondrial function. Both S-AKI models showed that Mdivi-1 was able to prevent the mitochondrial content release and decrease the expression of NLRP3 inflammasome-related proteins. In addition, silencing NLRP3 gene expression further emphasized the pyroptosis importance in S-AKI occurrence. Our results indicate that the possible mechanism of action of Mdivi-1 is to inhibit mitochondrial fission and protect mitochondrial function, thereby reducing pyroptosis. These data can provide a potential theoretical basis for Mdivi-1 potential use in the S-AKI prevention.

Curcumin reduces LPS-induced septic acute kidney injury through suppression of lncRNA PVT1 in mice.

OBJECTIVE: To investigate the protective effects of curcumin on LPS-induced septic acute kidney injury and to explore its underlying molecular mechanisms. METHODS: A mouse model of septic acute kidney injury (AKI) was given an intraperitoneal injection of lipopolysaccharide (LPS), followed by administration of variable levels of curcumin (intragastric). And NRK cells were used as the kidney cell model for all in vitro studies. RESULTS: Curcumin significantly decreased the levels of serum Scr, BUN, and Cyc c and reduced kidney injury in LPS-induced AKI mice. Kidney tissues of LPS-induced AKI mice showed an increase in PVT1, ED-1, TNF-α, IL-1ß, IL-6, p-IkBα/IkBα, p-p65/p65, p-JNK/JNK, and p-c-JUN/c-JUN expression levels; however, treatment with curcumin significantly reduced this effect. Curcumin increased the survival rate NRK cells exposed to LPS-induced inflammation in vitro. Moreover, NRK cells that overexpressed PVT1 had lower survival rates than WT NRK cells obtained from mice that received curcumin treatment after treating with LPS. Additionally, curcumin reduced the LPS-induced increase in Bax, cleaved-caspase3/caspase 3, p-IkBα/IkBα, p-p65/p65, p-JNK/JNK, and p-c-JUN/c-JUN protein expression, and increased Bcl2 protein expression in NRK cells. However, the extent of these changes was low in NRK cells that overexpressed PVT1. CONCLUSION: Curcumin decreased PVT1 expression in LPS-induced septic acute kidney tissues and reduced LPS-induced septic acute kidney injury in mice. This might be related to the inhibition of the JNK/NF-κB pathway by curcumin through suppression of lncRNA PVT1.

Immunonutrition vs Standard Nutrition for Cancer Patients: A Systematic Review and Meta-Analysis (Part 1).

The aim of this study was to determine the efficacy of immunonutrition vs standard nutrition in cancer patients treated with surgery. Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, EBSCOhost, and Web of Science were searched. Sixty-one randomized controlled trials were included. Immunonutrition was associated with a significantly reduced risk of postoperative infectious complications (risk ratio [RR] 0.71 [95% CI, 0.64-0.79]), including a reduced risk of wound infection (RR 0.72 [95% CI, 0.60-0.87]), respiratory tract infection (RR 0.70 [95% CI, 0.59-0.84]), and urinary tract infection (RR 0.69 [95% CI, 0.51-0.94]) as well as a decreased risk of anastomotic leakage (RR 0.70 [95% CI, 0.53-0.91]) and a reduced hospital stay (MD -2.12 days [95% CI -2.72 to -1.52]). No differences were found between the 2 groups with regard to sepsis or all-cause mortality. Subgroup analyses revealed that receiving arginine + nucleotides + ω-3 fatty acids and receiving enteral immunonutrition reduced the rates of wound infection and respiratory tract infection. The application of immunonutrition at 25-30 kcal/kg/d for 5-7 days reduced the rate of respiratory tract infection. Perioperative immunonutrition reduced the rate of wound infection. For malnourished patients, immunonutrition shortened the hospitalization time. Therefore, immunonutrition reduces postoperative infection complications and shortens hospital stays but does not reduce all-cause mortality. Patients who are malnourished before surgery who receive arginine + nucleotides + ω-3 fatty acids (25-30 kcal/kg/d) via the gastrointestinal tract during the perioperative period (5-7 days) may show better clinical efficacy.

Effects of Immunonutrition on Chemoradiotherapy Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: We conducted a systematic review to assess the effects of immunonutrition on chemoradiotherapy patients. METHODS: We searched the Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, CINAHL, and the Web of Science. We assessed the risk of bias using the Cochrane Risk of Bias tool. Our primary outcomes were the incidence of oral mucositis and diarrhea. The secondary outcomes were the incidence of esophagitis, grade ≥3 oral mucositis, grade ≥3 diarrhea, grade ≥3 esophagitis, and body weight loss. RESULTS: A total of 1478 patients and 27 studies were included. There were no significant differences in the incidence of oral mucositis (relative risk [RR] = 0.91; 95% confidence interval [CI], 0.79-1.05), diarrhea (RR = 0.89; 95% CI, 0.76-1.05), or esophagitis (RR = 0.55; 95% CI, 0.11-2.86) between the immunonutrition group and standard nutrition/placebo group. Nevertheless, immunonutrition significantly reduced the incidence of grade ≥3 oral mucositis (RR = 0.45; 95% CI, 0.22-0.92), grade ≥3 diarrhea (RR = 0.56; 95% CI, 0.35-0.88), grade ≥3 esophagitis (RR = 0.15; 95% CI, 0.04-0.54), and losing >5% body weight (RR = 0.34; 95% CI, 0.18-0.64). CONCLUSIONS: In this study, immunonutrition failed to reduce the incidence rates of oral mucositis, diarrhea, or esophagitis but was conducive to significantly improving the severity of oral mucositis and diarrhea esophagitis and reducing the rate of body weight loss.