Publications by authors named "Xiaoyu Hu"

218 Publications

Tumor infiltrating lymphocytes associated competitive endogenous RNA networks as predictors of outcome in hepatic carcinoma based on WGCNA analysis.

PLoS One 2021 29;16(7):e0254829. Epub 2021 Jul 29.

Department of Infectious Disease, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.

Background: The important regulatory role of competitive endogenous RNAs (ceRNAs) in hepatocellular carcinoma (HCC) has been confirmed. Tumor infiltrating lymphocytes (TILs) are of great significance to tumor outcome and prognosis. This study will systematically analyze the key factors affecting the prognosis of HCC from the perspective of ceRNA and TILs.

Methods: The Cancer Genome Atlas (TCGA) database was used for transcriptome data acquisition of HCC. Through the analysis of the Weighted Gene Co-expression Network Analysis (WCGNA), the two modules for co-expression of the disease were determined, and a ceRNA network was constructed. We used Cox regression and LASSO regression analysis to screen prognostic factors and constructed a risk score model. The Gene Expression Omnibus (GEO) was used to validate the model. The Kyoto Encyclopedia of Genes and Genomes (KEGG) was used for mRNAs functional analysis. The cell composition of TILs was analyzed by the CIBERSORT algorithm, and Pearson correlation analysis was utilized to explore the correlation between TILs and prognostic factors.

Results: We constructed a ceRNA regulatory network composed of 67 nodes through WGCNA, including 44 DElncRNAs, 19 DEGs, and 4 DEmiRNAs. And based on the expression of 4 DEGs in this network (RRM2, LDLR, TXNIP, and KIF23), a prognostic model of HCC with good specificity and sensitivity was developed. CIBERSORT analyzed the composition of TILs in HCC tumor tissues. Correlation analysis showed that RRM2 is significantly correlated with T cells CD4 memory activated, T cells CD4 memory resting, T cells CD8, and T cells follicular helper, and TXNIP is negatively correlated with B cells memory.

Conclusions: In this study, a ceRNA with prognostic value in HCC was created, and a prognostic risk model for HCC was constructed based on it. This risk score model is closely related to TILs and is expected to become a potential therapeutic target and a new predictive indicator.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254829PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321115PMC
July 2021

Aryl hydrocarbon receptor activation by Lactobacillus reuteri tryptophan metabolism alleviates Escherichia coli-induced mastitis in mice.

PLoS Pathog 2021 Jul 23;17(7):e1009774. Epub 2021 Jul 23.

Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, China.

The intestinal microbiota has been associated with the occurrence and development of mastitis, which is one of the most serious diseases of lactating women and female animals, but the underlying mechanism has not yet been elucidated. Aryl hydrocarbon receptor (AhR) activation by microbiota tryptophan metabolism-derived ligands is involved in maintaining host homeostasis and resisting diseases. We investigated whether AhR activation by microbiota-metabolic ligands could influence mastitis development in mice. In this study, we found that AhR activation using Ficz ameliorated mastitis symptoms, which were related to limiting NF-κB activation and enhancing barrier function. Impaired AhR activation by disturbing the intestinal microbiota initiated mastitis, and processed Escherichia coli (E. coli)-induced mastitis in mice. Supplementation with dietary tryptophan attenuated the mastitis, but attenuation was inhibited by the intestinal microbiota abrogation, while administering tryptophan metabolites including IAld and indole but not IPA, rescued the tryptophan effects in dysbiotic mice. Supplementation with a Lactobacillus reuteri (L. reuteri) strain with the capacity to produce AhR ligands also improved E. coli-induced mastitis in an AhR-dependent manner. These findings provide evidence for novel therapeutic strategies for treating mastitis, and support the role of metabolites derived from the intestinal microbiota in improving distal disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.ppat.1009774DOI Listing
July 2021

Molybdenum disulfide-graphene oxide composites as dispersive solid-phase extraction adsorbents for the enrichment of four paraben preservatives in cosmetics.

Mikrochim Acta 2021 Jul 15;188(8):256. Epub 2021 Jul 15.

Department of Chemistry, Capital Normal University, Beijing, 100048, People's Republic of China.

Molybdenum disulfide-graphene oxide composite (MoS/GO) was synthesized and used as the adsorbent in dispersive solid-phase extraction. Four paraben preservatives, namely, methylparaben, ethylparaben, propylparaben, and butylparaben, were enriched with MoS/GO and determined by ultra-high-performance liquid chromatography. Molybdenum disulfide was intercalated into graphene oxide layers to reduce self-aggregation by using the solvothermal method. The experimental results indicated that the as-prepared MoS/GO composite exhibited great enrichment capability toward those four paraben preservatives, and the adsorption time was 10 min and the elution time was as short as 1 min. The mechanism of MoS/GO composite and parabens is attributed to hydrogen bonding and electrostatic attraction. The relative standard deviation (RSD, n = 9) of this method was below 7.6%. Limits of detection and limits of quantification were in the range 0.4-2.3 ng/mL and 1.4-7.6 ng/mL, respectively. The recoveries obtained from the parabens of cosmetic sample were in the range 91.3-124% with RSDs below 10%. The developed method has great potential for the determination of emerging contaminants with low cost and high sensitivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00604-021-04908-9DOI Listing
July 2021

Kynurenic acid protects against mastitis in mice by ameliorating inflammatory responses and enhancing blood-milk barrier integrity.

Mol Immunol 2021 Jul 8;137:134-144. Epub 2021 Jul 8.

Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province 130062, China. Electronic address:

Mastitis is one of the most serious diseases in humans and animals, especially in the modern dairy industry. Seeking safe and effective mastitis prevention strategies is urgent since food safety and drug residues in milk remain an enormous concern, despite the contribution of antibiotics to control mastitis. Kynurenic acid (KYNA), derived from the kynurenine pathway of tryptophan metabolism, has been shown to exhibit anti-inflammatory and immunomodulatory effects in many diseases. Recently, it was reported that impaired KYNA levels were associated with mastitis. However, the physiological role of KYNA in mastitis has not yet been elucidated. Therefore, the aim of this study was to investigate the protective role of KYNA in pathogen-induced mastitis in mice, as well as the underlying mechanism of this effect. We first evaluated the effects of KYNA on LPS-induced mastitis in mice. Additionally, the underlying anti-inflammatory mechanism of KYNA was investigated in mammary epithelial cells (MMECs). Furthermore, we examined the effects of KYNA on S. aureus and E. coli induced mastitis in mice. Our results demonstrated that KYNA alleviated LPS-induced mastitis by reducing inflammatory responses and enhancing blood-milk barrier integrity. The fundamental mechanisms involved the inhibition of NF-κB and activation of Nrf2/Ho-1, which is probably mediated by G protein-coupled receptor 35 but not aryl hydrocarbon receptor. Notably, KYNA also protected against S. aureus and E. coli induced mastitis in mice. In conclusion, our results highlight the role of KYNA in mastitis and serve as a basis for using endogenous metabolite as a novel preventative or therapeutic strategy for disease intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molimm.2021.06.022DOI Listing
July 2021

The synergy of BET inhibitors with aurora A kinase inhibitors in MYCN-amplified neuroblastoma is heightened with functional TP53.

Neoplasia 2021 Jun 7;23(6):624-633. Epub 2021 Jun 7.

Department of Pediatrics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA. Electronic address:

Amplification of MYCN is a poor prognostic feature in neuroblastoma (NBL) indicating aggressive disease. We and others have shown BET bromodomain inhibitors (BETi) target MYCN indirectly by downregulating its transcription. Here we sought to identify agents that synergize with BETi and to identify biomarkers of resistance. We previously performed a viability screen of ∼1,900 oncology-focused compounds combined with BET bromodomain inhibitors against MYCN-amplified NBL cell lines. Reanalysis of our screening results prominently identified inhibitors of aurora kinase A (AURKAi) to be highly synergistic with BETi. We confirmed the anti-proliferative effects of several BETi+AURKAi combinations in MYCN-amplified NBL cell lines. Compared to single agents, these combinations cooperated to decrease levels of N-myc. We treated both TP53-wild type and mutant, MYCN-amplified cell lines with the BETi JQ1 and the AURKAi Alisertib. The combination had improved efficacy in the TP53-WT context, notably driving apoptosis in both genetic backgrounds. JQ1+Alisertib combination treatment of a MYCN-amplified, TP53-null or TP53-restored genetically engineered mouse model of NBL prolonged survival better than either single agent. This was most profound with TP53 restored, with marked tumor shrinkage and apoptosis induction in response to combination JQ1+Alisertib. BETi+AURKAi in MYCN-amplified NBL, particularly in the context of functional TP53, provided anti-tumor benefits in preclinical models. This combination should be studied more closely in a pediatric clinical trial.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neo.2021.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192452PMC
June 2021

Mitocytosis, a migrasome-mediated mitochondrial quality-control process.

Cell 2021 May;184(11):2896-2910.e13

State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Centre for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address:

Damaged mitochondria need to be cleared to maintain the quality of the mitochondrial pool. Here, we report mitocytosis, a migrasome-mediated mitochondrial quality-control process. We found that, upon exposure to mild mitochondrial stresses, damaged mitochondria are transported into migrasomes and subsequently disposed of from migrating cells. Mechanistically, mitocytosis requires positioning of damaged mitochondria at the cell periphery, which occurs because damaged mitochondria avoid binding to inward motor proteins. Functionally, mitocytosis plays an important role in maintaining mitochondrial quality. Enhanced mitocytosis protects cells from mitochondrial stressor-induced loss of mitochondrial membrane potential (MMP) and mitochondrial respiration; conversely, blocking mitocytosis causes loss of MMP and mitochondrial respiration under normal conditions. Physiologically, we demonstrate that mitocytosis is required for maintaining MMP and viability in neutrophils in vivo. We propose that mitocytosis is an important mitochondrial quality-control process in migrating cells, which couples mitochondrial homeostasis with cell migration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2021.04.027DOI Listing
May 2021

Unreliable Estimation of Fibrosis Regression During Treatment by Liver Stiffness Measurement in Patients With Chronic Hepatitis B.

Am J Gastroenterol 2021 Apr 8. Epub 2021 Apr 8.

Department of Liver Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; Department of Liver Diseases, the 960th Hospital of Chinese PLA Joint Logistics Support Force, Taian, Shandong Province, China; Traditional Chinese Medicine Hospital of Chongqing, Chongqing, China; Liver Disease Department, Fuyang 2nd People's Hospital, Fuyang, Anhui Province, China; Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan Province, China; Department of Infectious and Liver Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Fuzhou Infectious Diseases Hospital, Fuzhou, Fujian Province, China; Department of Infection and Liver Disease, Yichun People's Hospital, Yichun, Jiangxi Province, China; Traditional Chinese Medicine Hospital of Taihe, Taihe, Anhui Province, China; Department of Infectious Diseases, the First Affiliated Hospital (the Southwest Hospital) of the Third Military Medical University, Chongqing, China; Guangzhou 8th People's Hospital, Guangzhou, Guangdong Province, China; Department of Infectious Disease, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Department of Hepatic Diseases, Shanghai Public Health Clinical Center, Shanghai, China; Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China.

Introduction: Little reliable evidence has been reported regarding usefulness of liver stiffness measurement (LSM) for monitoring the hepatic fibrosis changes during treatment. We aimed to assess the association between changes in LSM and histological outcomes in patients with chronic hepatitis B.

Methods: In this prospective multicenter study, 727 treatment-naive patients receiving entecavir-based therapy, who underwent paired biopsies at treatment baseline and week 72, were analyzed. Changes in LSM were defined as ≥30% decrease, minor change, and ≥30% increase. Multivariate logistic regression was used to estimate odds ratios (ORs) of changes in LSM on clinical outcomes accounting for regression to the mean. A new on-treatment LSM threshold was established by receiver operating curve.

Results: Overall regression of fibrosis, improvement of inflammation, significant histological response, virologic response, alanine aminotransferase normalization, and hepatitis B e antigen seroconversion were 51.2%, 74.4%, 22.0%, 86.0%, 83.5%, and 13.3%, respectively. The association between changes in LSM and improvement of inflammation was nonlinear (P = 0.012). LSM decrease ≥30% was associated with regression of fibrosis (OR 1.501, 95% confidence interval [CI] 1.073-2.099, P = 0.018), significant histological response (OR 1.726, 95% CI 1.124-2.652, P = 0.013), and alanine aminotransferase normalization (OR 2.149, 95% CI 1.229-3.757, P = 0.007). After adjusting for regression to the mean, LSM increase ≥30% became negatively associated with the above 3 outcomes. A new on-treatment LSM cutoff value of 5.4 kPa was established for indicating the significant histological response.

Discussion: Changes in LSM are unreliable to estimate regression of fibrosis during treatment; the established cutoff value of on-treatment LSM can optimize monitoring strategy for histological outcomes in patients with chronic hepatitis B.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14309/ajg.0000000000001239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315185PMC
April 2021

Evaluation of exposure risk for healthcare personnel performing the open technique HIPEC procedure using cisplatin.

Gynecol Oncol 2021 Apr 30;161(1):261-263. Epub 2021 Jan 30.

Department of Gastrointestinal Surgery, Beijing Shijitan Hospital, Capital Medical University. No. 10 Tieyi Road, Yangfangdian, Haidian District, Beijing, 100038, China.

Objective: To perform an evaluation of the risk to healthcare personnel of exposure to cisplatin during a Hyperthermic Intraperitoneal Chemotherapy (HIPEC) procedure in an operating room environment.

Methods: Breathing zone air samples were taken from the operating room (OR) before, during and after the procedure of HIPEC filter membrane adsorption and the liquid impact method was applied to collect air samples. The samples of surface wipe from the floor of the OR were taken after the procedure. Inductively coupled plasma mass spectrometry(ICP-MS) was used to detect the content of cisplatin in all the samples.

Results: Thirty-six air samples and three surface wipes were collected from three different locations of healthcare personnel breathing zones. All the breathing zone air samples were negative for cisplatin; however, cisplatin contamination was detected on three surface wipes from the floor, but in a lowconcentration(≤ 2.25 ng).

Conclusion: The results suggest that the risk of inhalation of cisplatin was extremely low for the healthcare personnel during the procedure of HIPEC, but the contamination of the OR floor should be taken into consideration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygyno.2021.01.016DOI Listing
April 2021

High expression of ACE2 and TMPRSS2 and clinical characteristics of COVID-19 in colorectal cancer patients.

NPJ Precis Oncol 2021 Jan 21;5(1). Epub 2021 Jan 21.

Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.

Little is known of the patterns of expression of ACE2 and TMPRSS2 or the clinical characteristics of COVID-19 in patients with COVID-19 and colorectal cancer. We found in both bulk and single-cell RNA-seq profiles that ACE2 and TMPRSS2 were expressed at high levels on tumor and normal colorectal epithelial tissues. Clinically, patients with colorectal cancer and COVID-19 were more likely to have lymphopenia, higher respiratory rate, and high hypersensitive C-reactive protein levels than matched patients with COVID-19 but without cancer. These results suggest that patients with colorectal cancer may be particularly susceptible to SARS-CoV-2 infection. Further mechanistic studies are needed to support our findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41698-020-00139-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820314PMC
January 2021

Changes of microbial and metabolome of the equine hindgut during oligofructose-induced laminitis.

BMC Vet Res 2021 Jan 6;17(1):11. Epub 2021 Jan 6.

Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, 130062, People's Republic of China.

Background: Laminitis is a common and serve disease which caused by inflammation and pathological changes of the laminar junction. However, the pathologic mechanism remains unclear. In this study we aimed to investigate changes of the gut microbiota and metabolomics in oligofructose-induced laminitis of horses.

Results: Animals submitted to treatment with oligofructose had lower fecal pH but higher lactic acid, histamine, and Lipopolysaccharide (LPS) in serum. Meanwhile, oligofructose altered composition of the hindgut bacterial community, demonstrated by increasing relative abundance of Lactobacillus and Megasphaera. In addition, the metabolome analysis revealed that treatment with oligofructose decreased 84 metabolites while 53 metabolites increased, such as dihydrothymine, N3,N4-Dimethyl-L-arginine, 10E,12Z-Octadecadienoic acid, and asparagine. Pathway analysis revealed that aldosterone synthesis and secretion, regulation of lipolysis in adipocytes, steroid hormone biosynthesis, pyrimidine metabolism, biosynthesis of unsaturated fatty acids, and galactose metabolism were significantly different between healthy and laminitis horses. Furthermore, correlation analysis between gut microbiota and metabolites indicated that Lactobacillus and/or Megasphaera were positively associated with the dihydrothymine, N3,N4-Dimethyl-L-arginine, 10E,12Z-Octadecadienoic acid, and asparagine.

Conclusions: These results revealed that disturbance of gut microbiota and changes of metabolites were occurred during the development of equine laminitis, and these results may provide novel insights to detect biomarkers for a better understanding of the potential mechanism and prevention strategies for laminitis in horses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12917-020-02686-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789226PMC
January 2021

Contraception, unintended pregnancy, and induced abortion within 24 months of delivery in China: a retrospective cohort study.

Contraception 2021 Mar 27;103(3):144-150. Epub 2020 Dec 27.

NHC Key Lab. of Reproduction Regulation(Shanghai Institute of Planned Parenthood Research), School of Public Health, Fudan University, Shanghai, China.

Objective: To explore the prevalence of contraceptive use, unintended pregnancy, and induced abortions within 24 months postpartum in eastern, central, and western regions of China and in China overall.

Study Design: We conducted a retrospective cohort study and selected women who delivered a live birth between 12 and 24 months before the survey at 60 hospitals in eastern, central, and western regions of China. We used structured questionnaires for data collection and applied life-table analyses to estimate the prevalence of contraception, unintended pregnancy, and abortions. We used clustered log-rank tests to compare trends and rate differences at each time interval between/among regions.

Results: A total of 19,939 postpartum women were contacted, and 18,045 (90.5%) of them agreed to be interviewed. The 6-, 12-, and 24-month rates for modern contraceptive methods were 62.7% (95% confidence interval [CI] 58.9-66.4), 72.4% (95% CI 68.8-75.7), and 73.2% (95% CI 69.6-76.6), respectively. Condoms accounted for 79% of contraceptive initiators. The 6-, 12-, and 24-month rates were 1.4% (95% CI 1.2-1.7), 5.3% (95% CI 4.5--6.1), and 13.1% (95% CI 11.3-14.8) for unintended pregnancy; and 1.1% (95% CI 0.8-1.3), 4.0% (95% CI 3.4-4.6), and 10.4% (95% CI 8.9-11.8) for induced abortion, respectively. By 24 months postpartum, 3-quarters of unintended pregnancies ended in abortion. The 24-month rates of modern contraceptive methods (75.2% vs73.4%, 71.1%), unintended pregnancy (15.3% vs 11.1%, 12.6%), and induced abortion (11.8% vs 9.9%, 9.4%) were higher in the western region relative to the eastern or central regions.

Conclusion: Postpartum contraception use was relatively high in China but dominated by less-effective methods, and these may contribute to higher risks of unintended pregnancy and induced abortion during the postpartum period. Use of long-acting reversible contraceptives and effective and reliable short-acting methods should thus be fostered in postpartum family planning services in China.

Implications: A national postpartum family planning program is needed in China. Service providers should work on counselling postpartum women and their partners with respect to long-acting reversible contraceptive methods, and to effectively and reliably use short-acting methods during the postpartum period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.contraception.2020.12.014DOI Listing
March 2021

Def6 regulates endogenous type-I interferon responses in osteoblasts and suppresses osteogenesis.

Elife 2020 12 29;9. Epub 2020 Dec 29.

Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, United States.

Bone remodeling involves a balance between bone resorption and formation. The mechanisms underlying bone remodeling are not well understood. DEF6 is recently identified as a novel loci associated with bone mineral density. However, it is unclear how Def6 impacts bone remodeling. We identify Def6 as a novel osteoblastic regulator that suppresses osteoblastogenesis and bone formation. Def6 deficiency enhances both bone resorption and osteogenesis. The enhanced bone resorption in Def6 mice dominates, leading to osteoporosis. Mechanistically, Def6 inhibits the differentiation of both osteoclasts and osteoblasts via a common mechanism through endogenous type-I IFN-mediated feedback inhibition. RNAseq analysis shows expression of a group of IFN stimulated genes (ISGs) during osteoblastogenesis. Furthermore, we found that Def6 is a key upstream regulator of IFNβ and ISG expression in osteoblasts. Collectively, our results identify a novel immunoregulatory function of Def6 in bone remodeling, and shed insights into the interaction between immune system and bone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.59659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771961PMC
December 2020

ASF (a Compound of Traditional Chinese Medicine) in the treatment of patients with alcohol dependence: Study protocol of a randomized, double-blinded, placebo-controlled clinical trial.

Medicine (Baltimore) 2020 Dec;99(52):e23899

Chengdu University of Traditional Chinese Medicine, Chengdu, China.

Background: Alcohol dependence is one of the biggest problems facing public health worldwide. Currently, it is an under-diagnosed and under-treated disease. Even when given treatments for addiction withdrawal, over 2/3 of patients who have undergone abstinence-oriented treatment will relapse in the first year. Therefore, it is necessary to find an efficacious way to prevent and treat alcohol dependence. ASF (a Compound of Traditional Chinese Medicine) has proven to inhibit the formation and expression of ethanol-induced behavioral sensitization and the development of conditioned place preference in mice. As an empirical prescription for abstinence from alcohol, ASF has long been used in clinical patients. However, the effect of ASF in humans has not yet been investigated. The purpose of this study is to evaluate the efficacy of ASF for patients with alcohol dependence.

Methods: The effect of ASF will be studied in a randomized, double-blinded, placebo-controlled clinical trial. 82 outpatients and inpatients will be recruited and randomly assigned to treatment with either ASF or placebo for 6 weeks as a complement to cognitive behavioural therapy. The primary endpoints are the changes in the average daily alcohol consumption of the 2 groups before and after treatment and comparison of the scores of the psychological craving self-rating scale during the courses of treatment of 2 groups. The secondary endpoints include abstinence rates of the 2 groups during the follow-up period, days without consumption, and changes of Short Form Health Survey (SF-36) scores in 2 groups before and after therapy.

Discussion: This study is the first randomized controlled trial to investigate ASF in the treatment of alcohol dependence. ASF is likely to be a new and effective drug for the treatment of alcohol dependence developed from natural products with a low incidence of side effects or toxicity.

Trial Registration: Registry number: ChiCTR2000039397.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000023899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769360PMC
December 2020

DNaseI protects lipopolysaccharide-induced endometritis in mice by inhibiting neutrophil extracellular traps formation.

Microb Pathog 2021 Jan 11;150:104686. Epub 2020 Dec 11.

Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, 130062, PR China. Electronic address:

Endometritis is an inflammatory of the inner lining of the uterus caused by bacterial infections that affect female reproductive health in humans and animals. Neutrophil extracellular traps (NETs) have the ability to resist infections that caused by pathogenic invasions. It has been proved that the formation of NETs is related to certain inflammatory diseases, such as mastitis and chronic obstructive pulmonary disease (COPD). However, there are sparse studies related to NETs and endometritis. In this study, we investigated the role of NETs in lipopolysaccharide (LPS)-induced acute endometritis in mice and evaluated the therapeutic efficiency of DNaseI. We established LPS-induced endometritis model in mice and found that the formation of NETs can be detected in the mice uterine tissues in vivo. In addition, DNaseI treatment can inhibit NETs construction in LPS-induced endometritis in mice. Moreover, myeloperoxidase (MPO) activity assay indicated that DNaseI treatment remarkably alleviated the inflammatory cell infiltrations. ELISA test indicated that the treatment of DNaseI significantly inhibited the expression of the proinflammatory cytokines TNF-α, and IL-1β. Also, DNaseI was found to increase proteins expression of the uterine tissue tight junctions and suppress LPS-induced NF-κB activation. All the results indicated that DNaseI effectively inhibits the formation of NETs by blocking the NF-κB signaling pathway and enhances the expression of tight junction proteins, consequently, alleviates inflammatory reactions in LPS-induced endometritis in mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.micpath.2020.104686DOI Listing
January 2021

CD127 imprints functional heterogeneity to diversify monocyte responses in human inflammatory diseases.

bioRxiv 2020 Nov 10. Epub 2020 Nov 10.

Studies on human monocytes historically focused on characterization of bulk responses, whereas functional heterogeneity is largely unknown. Here, we identified an inducible population of CD127-expressing human monocytes under inflammatory conditions and named the subset M127. M127 is nearly absent in healthy individuals yet abundantly present in patients with infectious and inflammatory conditions such as COVID-19 and rheumatoid arthritis. Multiple genomic and functional approaches revealed unique gene signatures of M127 and unified anti-inflammatory properties imposed by the CD127-STAT5 axis. M127 expansion correlated with mild COVID-19 disease outcomes. Thereby, we phenotypically and molecularly characterized a human monocyte subset marked by CD127 that retained anti-inflammatory properties within the pro-inflammatory environments, uncovering remarkable functional diversity among monocytes and signifying M127 as a potential therapeutic target for human inflammatory disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.11.10.376277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668730PMC
November 2020

Loss of the Conserved Alveolate Kinase MAPK2 Decouples Cell Growth from Cell Division.

mBio 2020 11 10;11(6). Epub 2020 Nov 10.

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

Mitogen-activated protein kinases (MAPKs) are a conserved family of protein kinases that regulate signal transduction, proliferation, and development throughout eukaryotes. The apicomplexan parasite expresses three MAPKs. Two of these, extracellular signal-regulated kinase 7 (ERK7) and MAPKL1, have been implicated in the regulation of conoid biogenesis and centrosome duplication, respectively. The third kinase, MAPK2, is specific to and conserved throughout the Alveolata, although its function is unknown. We used the auxin-inducible degron system to determine phenotypes associated with MAPK2 loss of function in We observed that parasites lacking MAPK2 failed to duplicate their centrosomes and therefore did not initiate daughter cell budding, which ultimately led to parasite death. MAPK2-deficient parasites initiated but did not complete DNA replication and arrested prior to mitosis. Surprisingly, the parasites continued to grow and replicate their Golgi apparatus, mitochondria, and apicoplasts. We found that the failure in centrosome duplication is distinct from the phenotype caused by the depletion of MAPKL1. As we did not observe MAPK2 localization at the centrosome at any point in the cell cycle, our data suggest that MAPK2 regulates a process at a distal site that is required for the completion of centrosome duplication and the initiation of parasite mitosis. is a ubiquitous intracellular protozoan parasite that can cause severe and fatal disease in immunocompromised patients and the developing fetus. Rapid parasite replication is critical for establishing a productive infection. Here, we demonstrate that a protein kinase called MAPK2 is conserved throughout the Alveolata and essential for parasite replication. We found that parasites lacking MAPK2 protein were defective in the initiation of daughter cell budding and were rendered inviable. Specifically, MAPK2 (TgMAPK2) appears to be required for centrosome replication at the basal end of the nucleus, and its loss causes arrest early in parasite division. MAPK2 is unique to the Alveolata and not found in metazoa and likely is a critical component of an essential parasite-specific signaling network.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.02517-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667025PMC
November 2020

MicroRNAs of the miR-17~9 family maintain adipose tissue macrophage homeostasis by sustaining IL-10 expression.

Elife 2020 11 5;9. Epub 2020 Nov 5.

Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

Macrophages are critically involved in not only immune and inflammatory responses but also maintenance of metabolic fitness of organisms. Combined genetic deficiency of three clusters in the miR-17~92 family drastically shifted macrophage phenotypes toward the inflammatory spectrum characterized by heightened production of pro-inflammatory mediator TNF and diminished expression of anti-inflammatory cytokine IL-10. Consequently, macrophages residing in the adipose tissues from myeloid-specific miRNA triple knockout mice spontaneously developed inflammatory phenotypes and displayed alterations of overall physiological conditions as evidenced by obesity and compromised glucose tolerance. Mechanistically, miR-17~92 family miRNAs sustained IL-10 production by promoting transcription of the gene, which is secondary to downregulation of by transcription factor YY1, a direct target of miR-17~92 family miRNAs. Together, these results identified miR-17~92 family miRNAs as crucial regulators of the balance between pro- and anti-inflammatory cytokines and exemplified how macrophage-intrinsic regulatory circuit exerted impactful influence on general physiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.55676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676864PMC
November 2020

A quantitative and qualitative study on the neuropsychiatric sequelae of acutely ill COVID-19 inpatients in isolation facilities.

Transl Psychiatry 2020 10 19;10(1):355. Epub 2020 Oct 19.

Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore.

This study examined the neuropsychiatric sequelae of acutely ill patients with coronavirus disease 2019 (COVID-19) infection who received treatment in hospital isolation wards during the COVID-19 pandemic. Ten COVID-19 patients who received treatment in various hospitals in Chongqing, China; 10 age- and gender-matched psychiatric patients; and 10 healthy control participants residing in the same city were recruited. All participants completed a survey that collected information on demographic data, physical symptoms in the past 14 days and psychological parameters. Face-to-face interviews with COVID-19 patients were also performed using semi-structured questions. Among the COVID-19 patients, 40% had abnormal findings on the chest computed topography scan, 20% had dysosmia, 10% had dysgeusia, and 80% had repeated positivity on COVID-19 reverse-transcription polymerase chain reaction testing. COVID-19 and psychiatric patients were significantly more worried about their health than healthy controls (p = 0.019). A greater proportion of COVID-19 patients experienced impulsivity (p = 0.016) and insomnia (p = 0.039) than psychiatric patients and healthy controls. COVID-19 patients reported a higher psychological impact of the outbreak than psychiatric patients and healthy controls, with half of them having clinically significant symptoms of posttraumatic stress disorder. COVID-19 and psychiatric patients had higher levels of depression, anxiety and stress than healthy controls. Three themes emerged from the interviews with COVID-19 patients: (i) The emotions experienced by patients after COVID-19 infection (i.e., shock, fear, despair, hope, and boredom); (ii) the external factors that affected patients' mood (i.e., discrimination, medical expenses, care by healthcare workers); and (iii) coping and self-help behavior (i.e., distraction, problem-solving and online support). The future direction in COVID-19 management involves the development of a holistic inpatient service to promote immune and psychological resilience.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41398-020-01039-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570419PMC
October 2020

Retention enema with traditional Chinese medicine for hepatic encephalopathy: A protocol for a systematic review and meta-analysis.

Medicine (Baltimore) 2020 Oct;99(40):e22517

Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine.

Background: Hepatic encephalopathy (HE) is one of the common complications of many serious liver diseases. Western medicine treatment is mainly symptomatic treatment such as neutralizing blood ammonia and protecting liver, which has poor curative effect, easy repetition and high mortality. Retention enema with traditional Chinese medicine (TCM) has been used on treatment of HE in China for many years. And it has been clinically proved that retention enema with TCM is effective and safe. But there is absent convincing evidence-based medicine to confirm the efficacy of retention enema with TCM for HE. Thus, we aimed to conduct this meta-analysis to summarize the efficacy of retention enema with TCM in patients with HE.

Methods: The study only selects clinical randomized controlled trials of retention enema with TCM for HE. We will search each database from the built-in until December 31, 2020. The English literature mainly searches Cochrane Library, Pubmed, EMBASE, and Web of Science. While the Chinese literature comes from CNKI, CBM, VIP, and Wanfang database. Meanwhile, we will retrieve clinical trial registries and gray literature. Two researchers worked independently on literature selection, data extraction and quality assessment. The dichotomous data is represented by relative risk (RR), and the continuous is expressed by mean difference (MD) or standard mean difference (SMD), eventually the data is synthesized using a fixed effect model (FEM) or a random effect model (REM) depending on the heterogeneity. The total effective rate, blood ammonia and the total bilirubin were evaluated as the main outcomes. While several secondary outcomes were also evaluated in this study. The statistical analysis of this Meta-analysis was conducted by RevMan software version 5.3.

Results: This study will synthesize and provide high-quality evidence based on the data of the currently published retention enema with TCM for the treatment of HE.

Conclusion: This meta-analysis aims to evaluate the benefits of retention enema with TCM for the treatment of HE reported in randomized controlled trials, and provide more options for clinicians and patients with HE.

Registration Number: INPLASY202080107.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000022517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535768PMC
October 2020

α-Defensins Promote Colonization on Mucosal Reservoir to Prevent Antibiotic-Induced Dysbiosis.

Front Immunol 2020 9;11:2065. Epub 2020 Sep 9.

Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

In addition to their established functions in host defense, accumulating evidence has suggested an emerging role for antimicrobial proteins (AMPs) in shaping commensal microbiota. However, the role of α-defensins, the most abundant AMPs of intestine, in regulating microbial ecology remains inconclusive. Here, we report that α-defensins promote commensal colonization by enhancing bacterial adhesion to the mucosal reservoir. Experiments utilizing mice deficient in matrix metalloproteinase 7 (MMP7), the α-defensin-activating enzyme, with rigorous littermate controls showed that α-defensin deficiency did not significantly influence steady-state intestinal microbiota. In contrast, α-defensins are essential for replenishment of commensal from the mucosal reservoir following antibiotics-induced dysbiosis, shown by markedly compromised recovery of in animals. Mechanistically, α-defensins promote colonization on epithelial surfaces and adhesion to epithelial cells . Moreover, α-defensins unexpectedly does not show any microbicidal activities against . Together, we propose that α-defensins promote commensal bacterial colonization and recovery to maintain microbial diversity upon environmental challenges.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.02065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509133PMC
May 2021

Dimethyl itaconate protects against lipopolysaccharide-induced endometritis by inhibition of TLR4/NF-κB and activation of Nrf2/HO-1 signaling pathway in mice.

Iran J Basic Med Sci 2020 Sep;23(9):1239-1244

Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province 130062, People, Republic of China.

Objectives: Endometritis is the inflammation of the uterine lining that is associated with infertility. It affects milk production and reproductive performance and leads to huge economic losses in dairy cows. Dimethyl itaconate (DI), a promising chemical agent, has recently been proved to have multiple health-promoting effects. However, the effects of DI on endometritis remain to be unknown.

Materials And Methods: In this study, we assessed the anti-inflammatory effects of DI on Lipopolysaccharide (LPS)-induced endometritis in mice. The endometritis was induced by LPS treatment for 24 hr, and DI was given 24 hr before induction of LPS.

Results: As a result, DI administered mice significantly suffered less impairment of uterine tissue and less recruitment of inflammatory cells than LPS administered mice. In addition, DI markedly inhibited uterine myeloperoxidase (MPO) activity and pro-inflammatory cytokines of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) induced by LPS. Moreover, LPS-induced toll-like receptor 4/ nuclear factor-kappa B (TLR4/NF-κB) activation was suppressed by DI. In addition, the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase (HO-1) were upregulated by DI.

Conclusion: These findings suggest that DI has anti-inflammatory functions in the LPS-induced mice and may be a therapeutic agent against endometritis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.22038/ijbms.2020.44151.10346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491490PMC
September 2020

Enhancing KDM5A and TLR activity improves the response to immune checkpoint blockade.

Sci Transl Med 2020 09;12(560)

School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Beijing Advanced Innovation Center for Human Brain Protection, Tsinghua University, Beijing 100084, China.

Immune checkpoint blockade (ICB) therapies are now established as first-line treatments for multiple cancers, but many patients do not derive long-term benefit from ICB. Here, we report that increased amounts of histone 3 lysine 4 demethylase KDM5A in tumors markedly improved response to the treatment with the programmed cell death protein 1 (PD-1) antibody in mouse cancer models. In a screen for molecules that increased KDM5A abundance, we identified one (D18) that increased the efficacy of various ICB agents in three murine cancer models when used as a combination therapy. D18 potentiated ICB efficacy through two orthogonal mechanisms: (i) increasing KDM5A abundance, which suppressed expression of the gene (encoding phosphatase and tensin homolog) and increased programmed cell death ligand 1 abundance through a pathway involving PI3K-AKT-S6K1, and (ii) activating Toll-like receptors 7 and 8 (TLR7/8) signaling pathways. Combination treatment increased T cell activation and expansion, CD103 tumor-infiltrating dendritic cells, and tumor-associated M1 macrophages, ultimately enhancing the overall recruitment of activated CD8 T cells to tumors. In patients with melanoma, a high gene signature correlated with expression and could potentially serve as a marker of response to anti-PD-1 immunotherapy. Furthermore, our results indicated that bifunctional agents that enhance both KDM5A and TLR activity warrant investigation as combination therapies with ICB agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aax2282DOI Listing
September 2020

A graphene oxide-molybdenum disulfide composite used as stationary phase for determination of sulfonamides in open-tubular capillary electrochromatography.

J Chromatogr A 2020 Oct 14;1629:461487. Epub 2020 Aug 14.

Department of Chemistry, Capital Normal University, Beijing, 100048, PR China. Electronic address:

A graphene oxide-molybdenum disulfide (GO-MoS) composite was synthesized and utilized as the highly efficient stationary phase of open-tubular capillary electrochromatography (OT-CEC). The characterization results indicated that GO-MoS composite was successfully synthesized. The GO-MoS-coated capillary column was prepared by covalent immobilization method for the determination of seven sulfonamides. The baseline separation of seven sulfonamides was achieved by GO-MoS-coated capillary column. The linear range was 0.05-100 μg/mL for sulfisomidine, sulfathiazole, sulfamerazine, phthalylsulfathiazole and sulfacetamide, 0.1-100 μg/mL for sulfamonomethoxine and sulfachloropyridazine with a satisfactory correlation coefficients (R) > 0.9994. This developed OT-CEC method was successfully applied to determinate of seven sulfonamides in environmental water and milk samples with good recoveries of 85.77% - 109.10% and 80.03% - 109.97%, respectively. These results indicated that GO-MoS-coated capillary column possessed good stability and repeatability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chroma.2020.461487DOI Listing
October 2020

Association between Sleep Timing and Weight Status among 14- to 19-Year-Old Adolescents in Wuhan, China.

Int J Environ Res Public Health 2020 08 7;17(16). Epub 2020 Aug 7.

School of Health Sciences, Wuhan University, Wuhan 430071, China.

This study examined the cross-sectional and longitudinal association of sleep timing with weight status in 14- to 19-year-old adolescents in Wuhan, China. A prospective school-based study was conducted in Wuhan, China between 28 May and 29 September 2019. Data on sociodemographic information, academic performance, diet, mental health status, physical activity, sleep characteristics, body weight, and height were collected. A linear regression model and binary logistic regression model were performed. A total of 1194 adolescents were included in the analysis. Adolescents who woke up before 05:45 had higher body mass index (BMI) Z-score (odds ratio (OR) with 95% confidence interval (CI) = 1.28 (1.05, 1.57), = 0.02) and higher odds of overweight/obesity (odds ratio (OR) with 95% confidence interval (CI) = 1.74 (1.10, 2.76), = 0.02) at baseline after fully adjustment for covariates, compared with those who woke up after 05:45. Longitudinal data showed a nonsignificant association between waking up time and change in BMI Z-score ( = 0.18). No association of bedtime with weight status was observed in this sample after full adjustment ( > 0.1). Earlier waking up time might contribute to overweight and obesity in adolescents; however, more data are needed to test and elucidate this relationship.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph17165703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460288PMC
August 2020

Probiotics, prebiotics, antibiotic, Chinese herbal medicine, and fecal microbiota transplantation in irritable bowel syndrome: Protocol for a systematic review and network meta-analysis.

Medicine (Baltimore) 2020 Aug;99(32):e21502

Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu city, Sichuan province.

Background: Irritable bowel syndrome (IBS) is a functional gastrointestinal disease, with a high global incidence, which seriously influences the quality of life and work efficiency of patients. Extensive research showed that IBS is related to changes in the intestinal microenvironment. The novel treatment strategy targeting the gut microbiota is being actively implemented. Probiotics, antibiotics, prebiotics, fecal microbiota transplantation, and Chinese Herbal Medicine have been proven to be effective in the treatment of IBS, and all have an impact on the intestinal flora of patients. However, these 5 treatments have their own pros and cons and have not been systematically evaluated and compared. Therefore, this study will indirectly compare the safety and effectiveness of these 5 methods in the treatment of IBS through network meta-analysis.

Methods: The following databases including Embase, Pubmed, Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature Database, WHO International Clinical Trials Registry Platform and ClinicalTrials.gov will be retrieved from inception to June 2020 without language restrictions. Literature selection, data extraction, and bias analysis will be done by 2 researchers. The primary outcome is global symptoms improvement. The secondary outcomes will include individual IBS symptom scores, emotional response, and adverse events. The conventional pair-wise meta-analysis will be performed using Stata V.14.0 and be pooled using a random-effects model. We will use WinBUGS V.1.4.3 (Cambridge, United Kingdom) with a Bayesian hierarchical random-effects model to conduct the network meta-analysis.

Results: This study will provide systematic reviews and indirect network comparison results about treatments of IBS.

Conclusions: This study will systematically evaluate and compare 5 intestinal flora-related therapies for IBS and to provide an evidence-based medical decision-making basis for clinicians.

Trial Registration Number: INPLASY202050047.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000021502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593021PMC
August 2020

Synergistic Effect of Biejia-Ruangan on Fibrosis Regression in Patients with Chronic Hepatitis B Treated with Entecavir: A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial.

J Infect Dis 2020 May 21. Epub 2020 May 21.

Department of Liver Diseases of Chinese PLA General Hospital, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.

Background And Aims: Long-term nucleos(t)ide analogues (NAs) treatment can reverse liver fibrosis in chronic hepatitis B (CHB), but its effect on fibrosis regression remains limited. Biejia-Ruangan (BR) has been approved in China as an anti-fibrotic traditional Chinese medicine drug in patients with chronic liver diseases. A multicenter randomized controlled trial aims to evaluate the effect of BR on fibrosis regression in CHB patients treated with NAs.

Methods: CHB patients with histologically confirmed advanced fibrosis or cirrhosis were randomly assigned to receive entecavir (ETV) (0.5mg per day) plus BR (2g three times a day) or placebo for 72 weeks. Liver fibrosis regression was defined as a reduction of ≥1 point by the Ishak Fibrosis Stage (IFS).

Results: Overall, 500 patients were enrolled in each group as the intention-to-treat population. The rate of fibrosis regression after 72 week treatment was significantly higher in ETV+BR group (40% versus 31.8%, P=0.0069). Among 388 patients with cirrhosis (i.e., IFS ≥5) at baseline, the rate of cirrhosis reversal (i.e., IFS ≤4) was significantly higher in ETV+BR group (41.5% versus 30.7%, P=0.0103).

Conclusions: Addition of BR to the current standard treatment with NAs in CHB patients with advanced fibrosis or cirrhosis can improve liver fibrosis regression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiaa266DOI Listing
May 2020

Ancient MAPK ERK7 is regulated by an unusual inhibitory scaffold required for apical complex biogenesis.

Proc Natl Acad Sci U S A 2020 06 14;117(22):12164-12173. Epub 2020 May 14.

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390;

Apicomplexan parasites use a specialized cilium structure called the apical complex to organize their secretory organelles and invasion machinery. The apical complex is integrally associated with both the parasite plasma membrane and an intermediate filament cytoskeleton called the inner-membrane complex (IMC). While the apical complex is essential to the parasitic lifestyle, little is known about the regulation of apical complex biogenesis. Here, we identify AC9 (apical cap protein 9), a largely intrinsically disordered component of the IMC, as essential for apical complex development, and therefore for host cell invasion and egress. Parasites lacking AC9 fail to successfully assemble the tubulin-rich core of their apical complex, called the conoid. We use proximity biotinylation to identify the AC9 interaction network, which includes the kinase extracellular signal-regulated kinase 7 (ERK7). Like AC9, ERK7 is required for apical complex biogenesis. We demonstrate that AC9 directly binds ERK7 through a conserved C-terminal motif and that this interaction is essential for ERK7 localization and function at the apical cap. The crystal structure of the ERK7-AC9 complex reveals that AC9 is not only a scaffold but also inhibits ERK7 through an unusual set of contacts that displaces nucleotide from the kinase active site. ERK7 is an ancient and autoactivating member of the mitogen-activated kinase (MAPK) family and its regulation is poorly understood in all organisms. We propose that AC9 dually regulates ERK7 by scaffolding and concentrating it at its site of action while maintaining it in an "off" state until the specific binding of a true substrate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1921245117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275706PMC
June 2020

Negative elongation factor complex enables macrophage inflammatory responses by controlling anti-inflammatory gene expression.

Nat Commun 2020 05 8;11(1):2286. Epub 2020 May 8.

Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.

Studies on macrophage gene expression have historically focused on events leading to RNA polymerase II recruitment and transcription initiation, whereas the contribution of post-initiation steps to macrophage activation remains poorly understood. Here, we report that widespread promoter-proximal RNA polymerase II pausing in resting macrophages is marked by co-localization of the negative elongation factor (NELF) complex and facilitated by PU.1. Upon inflammatory stimulation, over 60% of activated transcriptome is regulated by polymerase pause-release and a transient genome-wide NELF dissociation from chromatin, unexpectedly, independent of CDK9, a presumed NELF kinase. Genetic disruption of NELF in macrophages enhanced transcription of AP-1-encoding Fos and Jun and, consequently, AP-1 targets including Il10. Augmented expression of IL-10, a critical anti-inflammatory cytokine, in turn, attenuated production of pro-inflammatory mediators and, ultimately, macrophage-mediated inflammation in vivo. Together, these findings establish a previously unappreciated role of NELF in constraining transcription of inflammation inhibitors thereby enabling inflammatory macrophage activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-16209-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210294PMC
May 2020

The gut microbiota contributes to the development of Staphylococcus aureus-induced mastitis in mice.

ISME J 2020 07 27;14(7):1897-1910. Epub 2020 Apr 27.

Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin, People's Republic of China.

Mastitis is one of the most prevalent diseases in dairy farming worldwide. The gut microbiota plays an important role in the regulation of systemic and local inflammatory diseases, such as mastitis. However, the regulatory mechanism of the gut microbiota on mastitis is still unclear. Thus, the aim of this study was to investigate the function and regulatory mechanisms of the gut microbiota in host defense against mastitis caused by Staphylococcus aureus (S. aureus) infection. Increased blood-milk barrier permeability, and S. aureus-induced mastitis severity were observed gut microbiota-dysbiosis mice compared with those in control mice. Moreover, feces microbiota transplantation (FMT) to microbbiota-dysbiosis mice reversed these effects. Furthermore, established disruption of commensal homeostasis results in significantly increased abundance of pathogenic Enterobacter bacteria, while the relative abundance of short-chain fatty acid (SCFAs)-producing bacterial phyla (Firmicutes and Bacteroidetes) was significantly reduced. However, FMT to gut microbiota-dysbiosis mice reversed these changes. In addition, dysbiosis reduced the levels of SCFAs, and administration of sodium propionate, sodium butyrate, and probiotics (butyrate-producing bacteria) reversed the changes in the blood-milk barrier and reduced the severity of mastitis induced by S. aureus. In conclusion, this new finding demonstrated that the gut microbiota acts as a protective factor in host defense against mastitis and that targeting the gut-mammary gland axis represents a promising therapeutic approach for mastitis treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41396-020-0651-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305118PMC
July 2020

Hydrogel Microfiber Encapsulation Enhances Cryopreservation of Human Red Blood Cells with Low Concentrations of Glycerol.

Biopreserv Biobank 2020 Jun 21;18(3):228-234. Epub 2020 Apr 21.

Department of Electronic Science and Technology, University of Science and Technology of China, Hefei, China.

Cryopreservation of red blood cells (RBCs) has been studied as a typical example of cryobiology methodology. To date, a mature and long-term cryopreservation process for RBCs has been developed, which has the weakness of complicated procedures due to high concentrations of glycerol (Gly). Therefore, it is still a research focus to find a new method for cryopreservation of RBCs to reduce the concentrations of cryoprotectants (CPAs). In this study, alginate hydrogels, which have been widely used in preservation research, were selected because of their advantages such as lower cost, cytocompatibility, and crosslinking occurring under mild conditions. With a variety of CPA solutions, the RBC recovery with the cryopreservation of RBCs and RBC-laden hydrogel microfibers was compared in different situations. It was found that hydrogel microfiber encapsulation enhances cryopreservation of human RBCs with low concentrations of CPAs. And Gly can be removed by washing directly with a 0.9% sodium chloride solution. This study validated the feasibility of cryopreservation of RBC-laden hydrogel microfibers. It may provide a new and evolving direction for reducing the concentrations of CPAs used in the preservation of RBCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/bio.2020.0003DOI Listing
June 2020
-->