Causal associations between severe mental illness and sepsis: a Mendelian randomization study.

Objective: SMI (severe mental illness) has been identified as a risk factor for sepsis in observational studies; however, the causal association between them has yet to be firmly established. We conducted MR (mendelian randomization) to unveil the causal relationship between SMI and sepsis as well as sepsis mortality. Methods: GWAS (Genome-wide association) data for major depression and schizophrenia were selected as exposure. GWAS data for sepsis and sepsis mortality were selected as outcome. Genetic variants significantly associated with the exposure (P value<1x10-6) were selected as instruments. We primarily employed the IVW (inverse-variance weighted) method for analysis. Furthermore, we employed Cochrane's Q test to assess heterogeneity and the MR-Egger intercept test to identify horizontal pleiotropy. Results: We selected 108 SNPs (single nucleotide polymorphism) used to predict major depression and 260 SNPs that predicted schizophrenia. Genetically predicted major depression was suggestively linked to a higher sepsis risk (OR=1.13, 95%CI 1.02-1.26, P=0.023). In contrast, MR analysis did not find an association between schizophrenia and sepsis risk (OR=1.00, 95%CI 0.97-1.04, P=0.811). Furthermore, no significant causal evidence was found for genetically predicted SMI in sepsis mortality. Moreover, no heterogeneity and horizontal pleiotropy were detected. Conclusion: Our research revealed a suggestive association between genetically predicted major depression and an elevated risk of sepsis in individuals of European ancestry. This finding can serve as a reminder for clinicians to consider the possibility of subsequent infection and sepsis in depressive patients, which may help reduce the incidence of sepsis in individuals with depression.

Lung single-cell RNA profiling reveals response of pulmonary capillary to sepsis-induced acute lung injury.

Background: Sepsis-induced acute lung injury (ALI) poses a significant threat to human health. Endothelial cells, especially pulmonary capillaries, are the primary barriers against sepsis in the lungs. Therefore, investigating endothelial cell function is essential to understand the pathophysiological processes of sepsis-induced ALI. Methods: We downloaded single-cell RNA-seq expression data from GEO with accession number GSE207651. The mice underwent cecal ligation and puncture (CLP) surgery, and lung tissue samples were collected at 0, 24, and 48 h. The cells were annotated using the CellMarker database and FindAllMarkers functions. GO enrichment analyses were performed using the Metascape software. Gene set enrichment Analysis (GSEA) and variation Analysis (GSVA) were performed to identify differential signaling pathways. Differential expression genes were collected with the "FindMarkers" function. The R package AUCell was used to score individual cells for pathway activities. The Cellchat package was used to explore intracellular communication. Results: Granulocytes increased significantly as the duration of endotoxemia increased. However, the number of T cells, NK cells, and B cells declined. Pulmonary capillary cells were grouped into three sub-clusters. Capillary-3 cells were enriched in the sham group, but declined sharply in the CLP.24 group. Capillary-1 cells peaked in the CLP.24 group, while Capillary-2 cells were enriched in the CLP.48 group. Furthermore, we found that Cd74+ Capillary-3 cells mainly participated in immune interactions. Plat+ Capillary-1 and Clec1a+ Capillary-2 are involved in various physiological processes. Regarding cell-cell interactions, Plat+ Capillary-1 plays the most critical role in granulocyte adherence to capillaries during ALI. Cd74+ Capillary cells expressing high levels of major histocompatibility complex (MHC) and mainly interacted with Cd8a+ T cells in the sham group. Conclusion: Plat+ capillaries are involved in the innate immune response through their interaction with neutrophils via ICAM-1 adhesion during endotoxemia, while Cd74+ capillaries epxressed high level of MHC proteins play a role in adaptive immune response through their interaction with T cells. However, it remains unclear whether the function of Cd74+ capillaries leans towards immunity or tolerance, and further studies are needed to confirm this.

Spontaneous formation of MoS2 nanoscrolls from flat monolayers with sulfur vacancies: a molecular dynamics investigation.

The unique physical properties exhibited by one-dimensional nanoscrolls assembled from nanosheets have propelled them into the spotlight of two-dimensional materials research. However, the self-scrolling mechanism of transition metal dichalcogenides has not been unveiled with an appropriate theoretical approach. In this paper, we systematically investigate the spontaneous formation of MoS2 nanoscrolls from flat monolayers by molecular dynamics simulations based on a reactive force field. The sulfur vacancies on one side break the atomic symmetry and the reconstruction acts as the driving force for the curling of the flat nanoribbon. If sulfur vacancies are arranged in a line, clear bending angles of the nanoribbon can be obtained and the angle relies on the direction of the line vacancy. With random sulfur vacancies on the top, spontaneous curling and a time-dependent scrolling process of the nanoribbon can be observed. The interplay between dangling bonds and van der Waals (vdW) interactions plays a pivotal role in the formation process of MoS2 nanoscrolls. With an increasing density of sulfur vacancies, the curvature of the nanoscrolls increases. Meanwhile, the scrolling rate accelerates and the time required for the formation of vdW structures decreases. These results provide theoretical insights into the fabrication of nanoscrolls and pave avenues for tailoring nanoscrolls with different morphologies.

Lianhuaqingwen alleviates p53-mediated apoptosis in alveolar epithelial cells to prevent LPS-induced ALI.

BACKGROUND: Our previous study found that Lianhuaqingwen reduces lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice by suppressing p53-mediated apoptosis. To identify the type of lung cells affected by Lianhuaqingwen, we conducted a cell experiment. METHODS: C57/B6 mice and A549 cells were administered Lianhuaqingwen and LPS. A549 cells were transfected with p53 siRNA to inhibit p53. The degree of ALI in mice was validated by haematoxylin and eosin staining as well as measurement of IL-1ß and MCP-1 levels. In A549 cells, Cell Counting Kit-8 (CCK-8), DHE and TUNEL assays were used to assess cell viability, reactive oxygen species (ROS) production and apoptosis, respectively. Western blot analysis was used to evaluate the protein expression of p53, Bcl-2, Bax, caspase-9 and caspase-3. Co-immunofluorescence was used to detect cytochrome C distribution. KEY FINDINGS: Lianhuaqingwen alleviated LPS-induced ALI in vivo. Lianhuaqingwen at 300 µg/ml increased cell viability, lowered ROS production and reduced apoptotic cells in vitro. Lianhuaqingwen enhanced Bcl-2 expression and reduced Bax, caspase-9 and caspase-3 expression as well as blocked cytochrome C release under LPS stimulation. Treatment with a combination of Lianhuaqingwen and p53 siRNA was more effective than treatment with Lianhuaqingwen alone. CONCLUSION: Lianhuaqingwen inhibits p53-mediated apoptosis in alveolar epithelial cells, thereby preventing LPS-induced ALI.

Mechanisms Underlying the Effects of Lianhua Qingwen on Sepsis-Induced Acute Lung Injury: A Network Pharmacology Approach.

Background and Purpose: Sepsis is a life-threatening condition associated with secondary multiple organ injury. Acute lung injury (ALI) caused by sepsis has high morbidity and mortality in critical care units. Lianhua Qingwen (LHQW) is a traditional Chinese medicine composing of 11 herbs and 2 medicinal minerals. LHQW exhibits anti-inflammatory activity and is effective in treating pneumonia. Our study aimed to evaluate the effect of LHQW on sepsis-induced ALI and its underlying mechanism. Materials and Methods: A network pharmacology approach was used to predict the bioactive components and effective targets of LHQW in treating ALI. We established ALI model C57/BL6 mice via an intraperitoneal injection of LPS and inhibited p53 expression by pifithrin-α, in order to validate the mechanism by which LHQW exerted protective role in ALI. Hematoxylin-eosin staining was conducted to assess the severity of lung injury. The severity of inflammation was evaluated based on MPO (myeloperoxidase) activity. TUNEL assay was employed to detect apoptotic cells. The levels of p53 and caspase-3 were tested by immunohistochemical staining and Western blotting. The expression levels of Bcl-2, Bax, cytochrome C and caspase-9 were detected by Western blotting. Results: A total of 80 genes were associated with LHQW in the treatment of ALI. After PPI network construction, four active components (quercetin, luteolin, kaempferol and wogonin) and 10 target genes (AKT1, TP53, IL6, VEGFA, TNF, JUN, STAT3, MAPK8, MAPK1, and EGF) were found to be essential for ALI treatment. GO and KEGG analyses indicated that apoptosis pathway was mainly involved in the LHQW-ALI network. Animal experiments showed that LHQW was able to attenuate LPS-induced ALI, and medium-dose LHQW exhibited the most prominent effect. LHQW could inhibit the overexpression of p53 induced by LPS and suppress p53-mediated intrinsic apoptotic pathways by decreasing the levels of Bax, caspase-3 and caspase-9, increasing the expression of Bcl-2, and attenuating the release of cytochrome C in ALI mice. Conclusion: This study reveals that LHQW may alleviate LPS-induced ALI via inhibiting p53-mediated intrinsic apoptosis pathways.

Comparison and clinical characteristics of COVID-19 between January and February 2020 in Wuhan, China.

BACKGROUND: Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) continues to make a deadly impact on human life all over the world. Therefore, we aimed to analyze the changes in clinical characteristics of coronavirus disease 2019 (COVID-19) patients over time. METHODS: We recruited 896 patients who were admitted to the Renmin Hospital of Wuhan University between 30th January 2020 and 16st March 2020. We conducted a retrospective study collecting clinical characteristics, radiologic and laboratory findings, treatments administered, and clinical outcomes in the patients. The data collected were compared between patients with onset of illness in January 2020 and patients with onset of illness in February 2020, in Wuhan, China. Categorical data and non-normally distributed continuous data were examined by the χ2 test and the Mann-Whitney-Wilcoxon test respectively, and the Kaplan-Meier plot was used to analyze survival data. Univariate and multivariate logistic regression methods were used to explore the risk factors associated with in-hospital death. RESULTS: A total of 896 patients were enrolled; the median age was 60 (range, 47-69) years, 685 (76.5%) were categorized into group A (patients with onset of illness in January 2020), and 211 (23.5%) were categorized into group B (patients with onset of illness in February 2020). Compared with group B, group A had a higher incidence of fever (P<0.001), and a lower rate of asymptomatic individuals (P<0.001). Group A patients had a higher incidence of neutrophilia (P=0.043), an elevated D-dimer (P<0.001), and an increased lactate dehydrogenase (LDH) (P=0.002), but a lower incidence of a normal computed tomography (CT) scan (P=0.001). CD3 cell counts (P=0.015) and CD4 cell counts (P=0.04) were significantly reduced in group A patients. Critically ill patients were less frequent (P=0.005) and patients with milder disease were more common (P=0.001) in group B. The fatality rate was significantly less in group B patients (P=0.028). Multivariate regression indicated that older age (odds ratio 1.086, 95% CI: 1.061-1.111, per year increase; P<0.001) increased the risk of in-hospital death. Female sex (odds ratio 0.523, 95% CI: 0.316-0.865; P=0.012) and being in group B (odds ratio 0.423, 95% CI: 0.212-0.844; P=0.015) significantly decreased the risk of in-hospital death. CONCLUSIONS: The condition of patients with onset of illness in January was more serious than that of patients with onset of illness in February 2020. The time of onset of illness was an independent risk factor for in-hospital death comparing January and February 2020. Changing pathogenicity of SARS-CoV-2 and improved healthcare may have contributed to the results, however, more basic research is required to support this hypothesis.

Genetic or pharmacologic inhibition of EGFR ameliorates sepsis-induced AKI.

Despite recent studies have demonstrated that the EGF receptor (EGFR) activation provided a renoprotective role during ischemic and folic acid-induced AKI, the role and regulation mechanism of EGFR in septic AKI remains unclear. Here, gefitinib, a highly selective EGFR inhibitor, abrogated LPS-induced phosphorylation of EGFR, ERK1/2, and STAT3 as well as expression of COX, eNOS, and proinflammatory cytokines in HK-2 cells. In addition, c-Src is an upstream of EGFR signaling pathway and mediates LPS-induced EGFR transactivation. In vivo, either gefitinib or genetic approaches (Wave-2 mutant mice, which have reduced EGFR tyrosine kinase activity) protected against LPS or cecal ligation and puncture (CLP) induced AKI respectively. Interestingly, the beneficial effects of gefitinib or genetic approaches were accompanied by the dephosphorylation of EGFR, ERK1/2, and STAT3, the down regulation of expression of COX, eNOS, macrophage infiltration, proinflammatory cytokines production and the renal cell apoptosis. Furthermore, mRNA array results indicated that gene families involved in cell death, inflammation, proliferation and signal transduction were down regulated in Wave-2 (Wa-2) mice. Take together, these data suggest that EGFR may mediate renal injury by promoting production of inflammatory factors and cell apoptosis. Inhibition of EGFR may have therapeutic potential for AKI during endotoxemia.

p53 induces miR199a-3p to suppress SOCS7 for STAT3 activation and renal fibrosis in UUO.

The role of p53 in renal fibrosis has recently been suggested, however, its function remains controversial and the underlying mechanism is unclear. Here, we show that pharmacological and genetic blockade of p53 attenuated renal interstitial fibrosis, apoptosis, and inflammation in mice with unilateral urethral obstruction (UUO). Interestingly, p53 blockade was associated with the suppression of miR-215-5p, miR-199a-5p&3p, and STAT3. In cultured human kidney tubular epithelial cells (HK-2), TGF-ß1 treatment induced fibrotic changes, including collagen I and vimentin expression, being associated with p53 accumulation, p53 Ser15 phosphorylation, and miR-199a-3p expression. Inhibition of p53 by pifithrin-α blocked STAT3 activation and the expression of miR-199a-3p, collagen I, and vimentin during TGF-ß1 treatment. Over-expression of miR-199a-3p increased TGFß1-induced collagen I and vimentin expression and restored SOCS7 expression. Furthermore, SOCS7 was identified as a target gene of miR-199a-3p, and silencing of SOCS7 promoted STAT3 activation. ChIp analyses indicated the binding of p53 to the promoter region of miR-199a-3p. Consistently, kidney biopsies from patients with IgA nephropathy and diabetic nephropathy exhibited substantial activation of p53 and STAT3, decreased expression of SOCS7, and increase in profibrotic proteins and miR-199a-3p. Together, these results demonstrate the novel p53/miR-199a-3p/SOCS7/STAT3 pathway in renal interstitial fibrosis.

A study on the transfection of antisense oligonucletide into kidney mediated by lipid microbubbles.

OBJECTIVE: To study the safety and efficiency of the transfection of antisense oligonucletide into kidney mediated by lipid microbubbles, and to evaluate its potential clinical application. METHODS: The potential and conditions regarding the transfection self-made lipid microbubbles (CY5)-labeled-oligonucleotide (ODN) or CY5-labeled-ODN connective tissue growth factor (CTGF) into the rat kidney were evaluated. Th e safety was evaluated by HE staining, liver and renal function tests. The transfection efficiency was evaluated by fluorescence microscopy. Th e expression of CTGF was detected by RT-PCR and Western blot. RESULTS: Self-made lipid microbubble and/or ultrasound significantly enhanced the efficiency of gene transfer and expression in the kidney. Especially, 85%-90% of total glomerular could be transfected. CY5-labeled-ODN expression could be observed in glomerular, tubular and interstitial area. Th ere was no significant change in blood tests aft er gene transfer. Levels of LDH in 7 days were decreased compared with that at the fi rst day aft er the transfection (P<0.05). CTGF expression was successfully suppressed by transfection of CTGF-antisense-ODN into kidney. CONCLUSION: The ultrasound-mediated gene transfer by self-made lipid microbubble could enhance the efficiency of ODN and expression in the rat kidney. Th is self-made lipid microbubbles supplement may be use for transfection of target genes.

Paclitaxel attenuates renal interstitial fibroblast activation and interstitial fibrosis by inhibiting STAT3 signaling.

Recent studies have demonstrated that paclitaxel might inhibit renal fibrosis. However, the underlying molecular mechanism remains unclear. In this study, we hypothesized that low-dose paclitaxel may block the STAT3 (signal transducer and activator of transcription 3) signaling to attenuate fibrosis in a mouse model with unilateral ureteral obstruction. Both NRK-49F cells and mice with unilateral ureteral obstruction were treated with paclitaxel. The results showed that paclitaxel treatment resulted in a dose- and time-dependent decrease in tyrosine-phosphorylated STAT3, and inhibited the expression of fibronectin, alpha-smooth muscle actin (α-SMA), and collagen I in cultured NRK-49F cells. S3I-201, an STAT3 inhibitor, also suppressed the expression of fibronectin, α-SMA, and collagen I in cultured NRK-49F cells. Mechanistically, paclitaxel treatment blocked the STAT3 activity by disrupting the association of STAT3 with tubulin and inhibiting STAT3 nucleus translocation. Furthermore, paclitaxel also ameliorated renal fibrosis by down-regulating the expression of fibronectin, α-SMA, and collagen I, and suppressed the infiltration of macrophages and production of TNF-α, IL-1ß, TGF-ß, and ICAM-1 (intercellular adhesion molecule 1) by inhibition of STAT3 activity in obstructive nephropathy. These results suggest that paclitaxel may block the STAT3 activity by disrupting the association of STAT3 with tubulin and inhibiting STAT3 nucleus translocation, consequently leading to the suppression of renal interstitial fibroblast activation and the development of renal fibrosis, and inhibition of proinflammatory cytokine production.

Paclitaxel: new uses for an old drug.

Paclitaxel (Taxol), one of the most important anticancer drugs, has been used for therapy of different types of cancers. Mechanistically, paclitaxel arrests cell cycle and induces cell death by stabilizing microtubules and interfering with microtubule disassembly in cell division. Recently, it has been found that low-dose paclitaxel seems promising in treating non-cancer diseases, such as skin disorders, renal and hepatic fibrosis, inflammation, axon regeneration, limb salvage, and coronary artery restenosis. Future studies need to understand the mechanisms underlying these effects in order to design therapies with specificity.