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Salmonella enterica serovar Typhimurium (S. Typhimurium) is a major cause of salmonellosis, and the emergence of multidrug-resistant pathovariants has become a growing concern. Here, we investigate a distinct rough colony variant exhibiting a strong biofilm-forming ability isolated in China. Whole-genome sequencing on 2,212 Chinese isolates and 1,739 publicly available genomes reveals the population structure and evolutionary history of the rough colony variants. Characterized by macro, red, dry, and rough (mrdar) colonies, these variants demonstrate enhanced biofilm formation at 28 °C and 37 °C compared to typical rdar colonies. The mrdar variants exhibit extensive multidrug resistance, with significantly higher resistance to at least five classes of antimicrobial agents compared to non-mrdar variants. This resistance is primarily conferred by an IncHI2 plasmid harboring 19 antimicrobial resistance genes. Phylogenomic analysis divides the global collections into six lineages. The majority of mrdar variants belong to sublineage L6.5, which originated from Chinese smooth colony strains and possibly emerged circa 1977. Among the mrdar variants, upregulation of the csgDEFG operons is observed, probably due to a distinct point mutation (-44G > T) in the csgD gene promoter. Pangenome and genome-wide association analyses identify 87 specific accessory genes and 72 distinct single nucleotide polymorphisms associated with the mrdar morphotype.
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Antibacterianos , Biofilmes , Farmacorresistência Bacteriana Múltipla , Genoma Bacteriano , Filogenia , Salmonella typhimurium , Sequenciamento Completo do Genoma , Salmonella typhimurium/genética , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/isolamento & purificação , Farmacorresistência Bacteriana Múltipla/genética , Antibacterianos/farmacologia , Biofilmes/crescimento & desenvolvimento , Biofilmes/efeitos dos fármacos , China , Genoma Bacteriano/genética , Plasmídeos/genética , Testes de Sensibilidade Microbiana , Humanos , Infecções por Salmonella/microbiologiaRESUMO
The gut microbiota and diet-induced changes in microbiome composition have been linked to various liver diseases, although the specific microbes and mechanisms remain understudied. Alcohol-related liver disease (ALD) is one such disease with limited therapeutic options due to its complex pathogenesis. We demonstrate that a diet rich in soluble dietary fiber increases the abundance of Bacteroides acidifaciens (B. acidifaciens) and alleviates alcohol-induced liver injury in mice. B. acidifaciens treatment alone ameliorates liver injury through a bile salt hydrolase that generates unconjugated bile acids to activate intestinal farnesoid X receptor (FXR) and its downstream target, fibroblast growth factor-15 (FGF15). FGF15 promotes hepatocyte expression of ornithine aminotransferase (OAT), which facilitates the metabolism of accumulated ornithine in the liver into glutamate, thereby providing sufficient glutamate for ammonia detoxification via the glutamine synthesis pathway. Collectively, these findings uncover a potential therapeutic strategy for ALD involving dietary fiber supplementation and B. acidifaciens.
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Amônia , Bacteroides , Fibras na Dieta , Fatores de Crescimento de Fibroblastos , Microbioma Gastrointestinal , Camundongos Endogâmicos C57BL , Animais , Bacteroides/metabolismo , Camundongos , Fibras na Dieta/metabolismo , Amônia/metabolismo , Microbioma Gastrointestinal/fisiologia , Fatores de Crescimento de Fibroblastos/metabolismo , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Masculino , Fígado/metabolismo , Hepatócitos/metabolismo , Ácidos e Sais Biliares/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Humanos , Inativação Metabólica , AmidoidrolasesRESUMO
Lysophosphatidic acid (LPA) is a bioactive lipid molecule that regulates a wide array of cellular functions, including proliferation, differentiation, and survival, via activation of cognate receptors. The LPA5 receptor is highly expressed in the intestinal epithelium, but its function in restoring intestinal epithelial integrity following injury has not been examined. Here, we use a radiation-induced injury model to study the role of LPA5 in regulating intestinal epithelial regeneration. Control mice (Lpar5f/f) and mice with an inducible, epithelial cell-specific deletion of Lpar5 in the small intestine (Lpar5IECKO) were subjected to 10 Gy total body X-ray irradiation and analyzed during recovery. Repair of the intestinal mucosa was delayed in Lpar5IECKO mice with reduced epithelial proliferation and increased crypt cell apoptosis. These effects were accompanied by reduced numbers of OLFM4+ intestinal stem cells (ISCs). The effects of LPA5 on ISCs were corroborated by studies using organoids derived from Lgr5-lineage tracking reporter mice with deletion of Lpar5 in Lgr5+-stem cells (Lgr5Cont or Lgr5ΔLpar5). Irradiation of organoids resulted in fewer numbers of Lgr5ΔLpar5 organoids retaining Lgr5+-derived progenitor cells compared with Lgr5Cont organoids. Finally, we observed that impaired regeneration in Lpar5IECKO mice was associated with reduced numbers of Paneth cells and decreased expression of Yes-associated protein (YAP), a critical factor for intestinal epithelial repair. Our study highlights a novel role for LPA5 in regeneration of the intestinal epithelium following irradiation and its effect on the maintenance of Paneth cells that support the stem cell niche.NEW & NOTEWORTHY We used mice lacking expression of the lysophosphatidic acid receptor 5 (LPA5) in intestinal epithelial cells and intestinal organoids to show that the LPA5 receptor protects intestinal stem cells and progenitors from radiation-induced injury. We show that LPA5 induces YAP signaling and regulates Paneth cells.
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Mucosa Intestinal , Receptores de Ácidos Lisofosfatídicos , Regeneração , Transdução de Sinais , Animais , Camundongos , Apoptose/efeitos da radiação , Proliferação de Células/efeitos da radiação , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos da radiação , Intestino Delgado/efeitos da radiação , Intestino Delgado/metabolismo , Lisofosfolipídeos/metabolismo , Camundongos Knockout , Organoides/metabolismo , Organoides/efeitos da radiação , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Receptores de Ácidos Lisofosfatídicos/metabolismo , Receptores de Ácidos Lisofosfatídicos/genética , Regeneração/efeitos da radiação , Células-Tronco/efeitos da radiação , Células-Tronco/metabolismo , Proteínas de Sinalização YAP/metabolismoRESUMO
Electroneutral NaCl transport by Na+/H+ exchanger 3 (NHE3, SLC9A3) is the major Na+ absorptive mechanism in the intestine and decreased NHE3 activity contributes to diarrhea. Patients with diabetes often experience gastrointestinal adverse effects and medications are often a culprit for chronic diarrhea in type 2 diabetes (T2D). We have shown previously that metformin, the most widely prescribed drug for the treatment of T2D, induces diarrhea by inhibition of Na+/H+ exchanger 3 (NHE3) in rodent models of T2D. Metformin was shown to activate AMP-activated protein kinase (AMPK), but AMPK-independent glycemic effects of metformin are also known. The current study is undertaken to determine whether metformin inhibits NHE3 by activation of AMPK and the mechanism by which NHE3 is inhibited by AMPK. Inhibition of NHE3 by metformin was abolished by knockdown of AMPK-α1 or AMPK-α2. AMPK activation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) phosphorylated NHE3 at S555. S555 is the primary site of phosphorylation by protein kinase A (PKA), but AMPK phosphorylated S555 independently of PKA. Using Mass spectrometry, we found S563 as a newly recognized phosphorylation site in NHE3. Altering either S555 or S563 to Ala was sufficient to block the inhibition of NHE3 activity by AMPK. NHE3 inhibition is dependent on ubiquitination by the E3 ubiquitin ligase Nedd4-2 and metformin was shown to induce NHE3 internalization via Nedd4-2-mediated ubiquitination. AICAR did not increase NHE3 ubiquitination when S555 or S563 was mutated. We conclude that AMPK activation inhibits NHE3 activity and NHE3 inhibition is associated with phosphorylation of NHE3 at S555 and S563.NEW & NOTEWORTHY We show that AMP-activated protein kinase (AMPK) phosphorylates NHE3 at S555 and S563 to inhibit NHE3 activity in intestinal epithelial cells. Phosphorylation of NHE3 by AMPK is necessary for ubiquitination of NHE3.
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Diabetes Mellitus Tipo 2 , Metformina , Humanos , Proteínas Quinases Ativadas por AMP/metabolismo , Trocador 3 de Sódio-Hidrogênio/metabolismo , Fosforilação , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metformina/farmacologia , Intestinos , Diarreia , Aminoimidazol Carboxamida/farmacologiaRESUMO
INTRODUCTION: Celastrol is an active pentacyclic triterpenoid extracted from Tripterygium wilfordii and has anti-inflammatory and anti-tumor properties. Whether Celastrol modulates platelet function remains unknown. Our study investigated its role in platelet function and thrombosis. METHODS: Human platelets were isolated and incubated with Celastrol (0, 1, 3 and 5 µM) at 37 °C for 1 h to measure platelet aggregation, granules release, spreading, thrombin-induced clot retraction and intracellular calcium mobilization. Additionally, Celastrol (2 mg/kg) was intraperitoneally administrated into mice to evaluate hemostasis and thrombosis in vivo. RESULTS: Celastrol treatment significantly decreased platelet aggregation and secretion of dense or alpha granules induced by collagen-related peptide (CRP) or thrombin in a dose-dependent manner. Additionally, Celastrol-treated platelets showed a dramatically reduced spreading activity and decreased clot retraction. Moreover, Celastrol administration prolonged tail bleeding time and inhibited formation of arterial/venous thrombosis. Furthermore, Celastrol significantly reduced calcium mobilization. CONCLUSION: Celastrol inhibits platelet function and venous/arterial thrombosis, implying that it might be utilized for treating thrombotic diseases.
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Ativação Plaquetária , Trombose , Humanos , Animais , Camundongos , Cálcio/metabolismo , Trombina/metabolismo , Hemostasia , Agregação Plaquetária , Plaquetas/metabolismo , Triterpenos Pentacíclicos , Trombose/metabolismoRESUMO
OBJECTIVES: To investigate the resistance mechanism of a Salmonella Typhimurium (S. Typhimurium) isolated from a faecal sample of an infant, which exhibited concurrent resistance to ceftriaxone, ciprofloxacin and azithromycin. METHODS: Antimicrobial susceptibility testing was performed by broth microdilution in two kinds of drug-sensitive plates. Antimicrobial resistance (AMR) genes were identified by whole genome sequencing and bioinformatics analysis. Genotyping of the strain was performed by multilocus sequence typing (MLST). Plasmid DNA was sequenced and analysed using plasmid bioinformatics tools. RESULTS: The SH11G993 strain was resistant to 28 antibiotics and carried 54 AMR genes. MLST results showed that the strain belonged to a rare genotype. The plasmid profile and plasmid sequencing showed that the strain carried two resistance plasmids. The pSH11G993-1 carried 14 AMR genes (especially co-harboured blaCMY-2, mphA and ermB) and a variety of insertion sequences, belonging to the IncC. The pSH11G993-2 carried 3 AMR genes and 9 virulence genes, belonging to the IncFIB-FII, forming a novel resistance and virulence co-harbouring plasmid. CONCLUSIONS: Our findings highlight that continuously monitor the changes in antibiotic resistance patterns and research on the resistance mechanisms in potential human pathogens are imperative.
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Azitromicina , Salmonella typhimurium , Humanos , Lactente , Salmonella typhimurium/genética , Azitromicina/farmacologia , Ceftriaxona/farmacologia , Ciprofloxacina/farmacologia , Sorogrupo , Tipagem de Sequências Multilocus , Farmacorresistência Bacteriana Múltipla/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêuticoRESUMO
BACKGROUND AND OBJECTIVES: Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase that plays a crucial role in tumorigenesis. FHND5071, a potent and selective RET kinase inhibitor, could exert antitumor effects by inhibiting RET autophosphorylation. The present work aims to profile the pharmacokinetics of FHND5071 in in vivo and in vitro experiments as a ground work for further clinical research. METHODS: The absorption, distribution, metabolism, and excretion properties of FHND5071 were examined, along with metabolite production and cytochrome P450 (CYP) phenotyping assay. Additionally, plasma protein binding and pharmacokinetics in mice were investigated. RESULTS: Microsomal stability assay corroborated moderate to high clearance of FHND5071, and the use of UPLC-Q-TOF-MS identified a total of six metabolites and suggested a possible metabolic pathway involving oxidation, demethylation, and N-dealkylation. Primary contributors to the CYP-mediated metabolism of FHND5071 were found to be CYP2C8 and CYP3A4, and FHND5071 displayed low permeability and acted as a substrate for the P-glycoprotein (P-gp). FHND5071 had a moderate to high binding in plasma and exhibited a moderate absorption degree (absolute bioavailability > 60%) The distribution of FHND5071 in mouse tissues was rapid (mostly peaking at 1-4 h) and wide (detectable in almost all tissues and organs), with the highest exposure in the spleen. A small fraction of FHND5071 was excreted via the urine and feces, and a presumed metabolic pathway involving 20 metabolites in mice is proposed. CONCLUSION: Pharmacokinetic characteristics of FHND5071 were systemically profiled, which may lay the foundation for further clinical development as a drug candidate.
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Sistema Enzimático do Citocromo P-450 , Inibidores de Proteínas Quinases , Camundongos , Animais , Disponibilidade Biológica , Sistema Enzimático do Citocromo P-450/metabolismo , Administração Oral , Citocromo P-450 CYP3A/metabolismoRESUMO
Gastrointestinal (GI) complications, including diarrhea, constipation, and gastroparesis, are common in patients with diabetes. Dysregulation of the Na+/H+ exchanger NHE3 in the intestine is linked to diarrhea and constipation, and recent studies showed that NHE3 expression is reduced in type 1 diabetes and metformin causes diarrhea in the db/db mouse model of type 2 diabetes (T2D) via inhibition of NHE3. In this study, we investigated whether NHE3 expression is altered in type 2 diabetic intestine and the underlying mechanism that dysregulates NHE3. NHE3 expression in the brush border membrane (BBM) of the intestine of diabetic mice and humans was decreased. Protein kinase C (PKC) activation is associated with pathologies of diabetes, and immunofluorescence (IF) analysis revealed increased BBM PKCα abundance. Inhibition of PKCα increased NHE3 BBM abundance and NHE3-mediated intestinal fluid absorption in db/db mice. Previous studies have shown that Lactobacillus acidophilus (LA) stimulates intestinal ion transporters. LA increased NHE3 BBM expression and mitigated metformin-mediated inhibition of NHE3 in vitro and in vivo. To understand the underlying mechanism of LA-mediated stimulation of NHE3, we used Caco-2bbe cells overexpressing PKCα that mimic the elevated state of PKCα in T2D. LA diminished PKCα BBM expression, increased phosphorylation of ezrin, and the interaction of NHE3 with NHE regulatory factor 2 (NHERF2). In addition, inhibition of PKCι blocked phosphorylation of ezrin and activation of NHE3 by LA. These findings demonstrate that NHE3 is downregulated in T2D, and LA restores NHE3 expression via regulation of PKCα, PKCι, and ezrin.NEW & NOTEWORTHY We used mouse models of type 2 diabetes (T2D) and human patient-derived samples to show that Na+/H+ exchanger 3 (NHE3) expression is decreased in T2D. We show that protein kinase C-α (PKCα) is activated in diabetes and inhibition of PKCα increased NHE3 expression and mitigates diarrhea. We show that Lactobacillus acidophilus (LA) stimulates NHE3 via inhibition of PKCα and phosphorylation of ezrin.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Metformina , Animais , Humanos , Camundongos , Constipação Intestinal , Diarreia/metabolismo , Lactobacillus acidophilus/metabolismo , Metformina/farmacologia , Proteína Quinase C-alfa/metabolismo , Trocador 3 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio/metabolismoRESUMO
DEAD/H-box helicases are an essential protein family with a conserved motif containing unique amino acid sequences (Asp-Glu-Ala-Asp/His). Current evidence indicates that DEAD/H-box helicases regulate RNA metabolism and innate immune responses. In recent years, DEAD/H-box helicases have been reported to participate in the development of a variety of diseases, including hepatitis B virus (HBV) infection, which is a significant risk factor for hepatic fibrosis, cirrhosis, and liver cancer. Furthermore, emerging evidence suggests that different DEAD/H-box helicases play vital roles in the regulation of viral replication, based on the interaction of DEAD/H-box helicases with HBV and the modulation of innate signaling pathways mediated by DEAD/H-box helicases. Besides these, HBV can alter the expression and activity of DEAD/H-box helicases to facilitate its biosynthesis. More importantly, current investigation suggests that targeting DEAD/H-box helicases with appropriate compounds is an attractive treatment strategy for the virus infection. In this review, we delineate recent advances in molecular mechanisms relevant to the interplay of DEAD/H-box helicase and HBV and the potential of targeting DEAD/H-box helicase to eliminate HBV infection.
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Vírus da Hepatite B , Hepatite B , Humanos , DNA Helicases , Cirrose Hepática , Replicação ViralRESUMO
Background: Hereditary hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disease due to biallelic TRPM6 mutations. Although the reports of HSH caused by TRPM6 mutations are not very rare, the age of onset in previously reported HSH cases were <1 year. Methods: We collected and analyzed the clinical data of twin brothers with onset age over 1 year old and performed whole exome sequencing in the patients and their parents. Confirmed by Sanger sequencing, missense mutation was analyzed in silico. We also searched Pubmed, and extracted clinical data from case reports and case series with full text in English, reporting original data of patients with TRPM6 mutations. Results: The twin patients had canonical HSH phenotype with compound novel TRPM6 mutations, p.T87K and c.705dupT, inherited from their father and mother, respectively. T87 is a highly conserved site and T87K is predicted to cause hydrogen bond disruption. We identified 26 articles published between May 28, 2002 to December 31, 2021 which reported a total of 88 patients with TRPM6 mutation. We found that the most common clinical phenotypes were hypomagnesemia, hypocalcemia, and convulsions. However, the age of onset in HSH patients almost always occurred under 12 months old, the twin patients of our study were 18 and 26 months old at onset. Conclusion: We identified two novel TRPM6 mutations in a Chinses family with HSH, and showed that the age of onset with c.704c-c.705(exon7)insT and c.260(exon4)C>A mutation in TRPM6 was much later than other mutations and would be much less serious.
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It was the aim of this study to determine whether abdominal massage reverses high-fat diet-induced insulin resistance compared with RSV treatment. A total of sixty male Sprague-Dawley rats were randomly placed in one of four groups:the non-fat diet (NFD), the high-fat diet (HFD), the HFD with abdominal massage (HFD+ AM), and the HFD plus resveratrol (HFD+ RSV). For eight weeks, rats were fed high-fat diets to create insulin resistance, followed by six weeks of either AM or RSV. Molecular mechanisms of adipogenesis and cytokine production in rats with high-fat diets were investigated. The model rat adipose tissue showed significant improvements in obesity, glucose intolerance, and the accumulation of lipid in the body [the total cholesterol level (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C)], metabolic effects of glucose [The fasting blood glucose (FBG), Fasting insulin levels (FINS)], inflammatory status [interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α, C-reactive protein (CRP)], and macrophage polarization after AM or RSV treatment. Further, AM increased SIRT1/NF-κB signaling in rat adipose tissue. Accordingly, in rat adipose tissue, our results indicate that AM regulates the secretion of proinflammatory cytokines, blood sugar levels, and related signaling pathways, contributing to improvement of IR, which may serves as a new therapeutic approach for the treatment for IR.
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Resistência à Insulina , Insulina , Tecido Adiposo/patologia , Animais , Proteína C-Reativa/metabolismo , Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Massagem , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Sirtuína 1/metabolismo , Sirtuína 1/farmacologia , Sirtuína 1/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Glycemic control is the key to the management of type 2 diabetes. Metformin is an effective, widely used drug for controlling plasma glucose levels in diabetes, but it is often the culprit of gastrointestinal adverse effects such as abdominal pain, nausea, indigestion, vomiting, and diarrhea. Diarrhea is a complex disease and altered intestinal transport of electrolytes and fluid is a common cause of diarrhea. Na+/H+ exchanger 3 (NHE3, SLC9A3) is the major Na+ absorptive mechanism in the intestine and our previous study has demonstrated that decreased NHE3 contributes to diarrhea associated with type 1 diabetes. The goal of this study is to investigate whether metformin regulates NHE3 and inhibition of NHE3 contributes to metformin-induced diarrhea. We first determined whether metformin alters intestinal water loss, the hallmark of diarrhea, in type 2 diabetic db/db mice. We found that metformin decreased intestinal water absorption mediated by NHE3. Metformin increased fecal water content although mice did not develop watery diarrhea. To determine the mechanism of metformin-mediated regulation of NHE3, we used intestinal epithelial cells. Metformin inhibited NHE3 activity and the effect of metformin on NHE3 was mimicked by a 5'-AMP-activated protein kinase (AMPK) activator and blocked by pharmacological inhibition of AMPK. Metformin increased phosphorylation and ubiquitination of NHE3, resulting in retrieval of NHE3 from the plasma membrane. Previous studies have demonstrated the role of neural precursor cell expressed, developmentally down-regulated 4-2 (Nedd4-2) in regulation of human NHE3. Silencing of Nedd4-2 mitigated NHE3 inhibition and ubiquitination by metformin. Our findings suggest that metformin-induced diarrhea in type 2 diabetes is in part caused by reduced Na+ and water absorption that is associated with NHE3 inhibition, probably by AMPK.
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Objective: To make a systematic evaluation of the clinical efficacy of thymopentin combined with antituberculous drugs in treating drug-resistant pulmonary TB (PTB). Methods: Relevant studies were retrieved from PubMed, Embase, Cochrane Library, Chinese Biomedical Literature Database, CNKI, and Wanfang Database. STATA software was used to evaluate the differences in focal absorption rate, the time to cough symptom remission, sputum culture-negative rate, CD3+ T, CD4+ T, and CD8+ T cell levels after treatment. Results: A total of 23 randomized controlled trials literature involving 2031 cases were included. Meta-analysis revealed that compared with conventional therapy, the sputum culture-negative rate was significantly increased after 2-3 months and 6-9 months of treatment and the whole course of combined thymopentin treatment. The risk ratio (RR, 95% CI) was 1.44 (1.26-1.64), 1.47 (1.21-1.78), and 1.27 (1.18-1.36), respectively. In the combined thymopentin treatment group, the focal absorption rate was higher, with RR (95% CI) = 1.36 (1.25-1.47), the time of cough remission was shortened, with WMD (95% CI) =-9.46d (-10.36,-8.57) and the differences were all statistically significant. Combined thymopentin therapy could effectively improve the levels of CD3+ T and CD4+ T lymphocytes in patients with drug-resistant PTB after 2-3 months, 6-9 months of treatment. The WMD (95% CI) were 9.96% (7.84, 12.08), 4.68% (2.90, 6.47) and 10.26% (7.81, 12.71), 7.21% (6.28, 8.15), respectively, and could also reduce the level of CD8+ T lymphocytes after 2-3 months and 6-9 months of treatment. The WMD (95% CI) were -4.06% (-4.96, -3.13), -3.52%, (-4.07,-2.98), respectively, and the differences were all statistically significant. Conclusion: Thymopentin adjuvant treatment for drug-resistant PTB can promote the therapeutic effect and improve the immune indexes in patients with drug-resistant PTB.
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BACKGROUND & AIMS: Regeneration of the epithelium by stem cells in the intestine is supported by intrinsic and extrinsic factors. Lysophosphatidic acid (LPA), a bioactive lipid mediator, regulates many cellular functions, including cell proliferation, survival, and cytokine secretion. Here, we identify LPA5 receptor as a potent regulator of the survival of stem cells and transit-amplifying cells in the intestine. METHODS: We have used genetic mouse models of conditional deletion of Lpar5, Lpar5f/f;Rosa-CreERT (Lpar5KO), and intestinal epithelial cell-specific Lpar5f/f;AhCre (Lpar5IECKO) mice. Mice were treated with tamoxifen or ß-naphthoflavone to delete Lpar5 expression. Enteroids derived from these mice were used to determine the effect of Lpar5 loss on the apoptosis and proliferation of crypt epithelial cells. RESULTS: Conditional loss of Lpar5 induced ablation of the intestinal mucosa, which increased morbidity of Lpar5KO mice. Epithelial regeneration was compromised with increased apoptosis and decreased proliferation of crypt epithelial cells by Lpar5 loss. Interestingly, intestinal epithelial cell-specific Lpar5 loss did not cause similar phenotypic defects in vivo. Lpar5 loss reduced intestinal stem cell marker gene expression and reduced lineage tracing from Lgr5+ ISCs. Lpar5 loss induced CXCL10 expression which exerts cytotoxic effects on intestinal stem cells and progenitors in the intestinal crypts. By co-culturing Lpar5KO enteroids with wild-type or Lpar5KO splenocytes, we demonstrated that lymphocytes protect the intestinal crypts via a LPA5-dependent suppression of CXCL10. CONCLUSIONS: LPA5 is essential for the regeneration of intestinal epithelium. Our findings reveal a new finding that LPA5 regulates survival of stem cells and transit-amplifying cells in the intestine.
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Lisofosfolipídeos , Células-Tronco , Animais , Intestinos , Lisofosfolipídeos/metabolismo , Camundongos , Transdução de Sinais , Células-Tronco/metabolismoRESUMO
Objective: This study aimed to systematically evaluate the factors influencing the restoration of spontaneous circulation (ROSC) after cardiopulmonary arrest (CA). Methods: Relevant papers on the factors influencing the ROSC in patients with CA were retrieved from PubMed, Embase, Cochrane Library, China Biology Medicine disk, China National Knowledge Infrastructure, Wanfang, and VIP databases. After screening, data extraction, and quality evaluation of the papers, a meta-analysis was carried out. Results: A total of 36 papers, involving a total sample size of 2,305 cases, were included. The meta-analysis revealed that the location and time of onset of CA, the type of cardiac rhythm at first monitoring, the start time of cardiopulmonary resuscitation (CPR), the use of electric defibrillation, and the cumulative dose of adrenaline all significantly impacted the ROSC (p < 0.05) and may have affected its success rate. The pH value at CA onset, combined use of adrenaline and vasopressin, CPR duration, mechanical cardiac compression use, and whether CA was caused by heart disease had no significant effect on ROSC. Conclusion: The location and time of onset of CA, the cardiac rhythm at first monitoring, the start time of CPR, the use of electric defibrillation, and the cumulative dose of adrenaline significantly impacted the ROSC.
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[This corrects the article DOI: 10.3389/fmicb.2021.779749.].
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BACKGROUND & AIMS: Diarrhea is one of the most common illnesses and is often caused by bacterial infection. Recently, we have shown that human Na+/H+ exchanger NHE3 (hNHE3), but not non-human NHE3s, interacts with the E3 ubiquitin ligase Nedd4-2. We hypothesize that this property of hNHE3 contributes to the increased severity of diarrhea in humans. METHODS: We used humanized mice expressing hNHE3 in the intestine (hNHE3int) to compare the contribution of hNHE3 and mouse NHE3 to diarrhea induced by cholera toxin (CTX) and enteropathogenic Escherichia coli (EPEC). We measured Na+/H+ exchange activity and fluid absorption. The role of Nedd4-2 on hNHE3 activity and ubiquitination was determined by knockdown in Caco-2bbe cells. The effects of protein kinase A (PKA), the primary mediator of CTX-induced diarrhea, on Nedd4-2 and hNHE3 phosphorylation and their interaction were determined. RESULTS: The effects of CTX and EPEC were greater in hNHE3int mice than in control wild-type (WT) mice, resulting in greater inhibition of NHE3 activity and increased fluid accumulation in the intestine, the hallmark of diarrhea. Activation of PKA increased ubiquitination of hNHE3 and enhanced interaction of Nedd4-2 with hNHE3 via phosphorylation of Nedd4-2 at S342. S342A mutation mitigated the Nedd4-2-hNHE3 interaction and blocked PKA-induced inhibition of hNHE3. Unlike non-human NHE3s, inhibition of hNHE3 by PKA is independent of NHE3 phosphorylation, suggesting a distinct mechanism of hNHE3 regulation. CONCLUSIONS: The effects of CTX and EPEC on hNHE3 are amplified, and the unique properties of hNHE3 may contribute to diarrheal symptoms occurring in humans.
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Escherichia coli Enteropatogênica , Trocador 3 de Sódio-Hidrogênio , Animais , Toxina da Cólera/metabolismo , Toxina da Cólera/farmacologia , Escherichia coli Enteropatogênica/metabolismo , Humanos , Camundongos , Sódio/metabolismo , Trocador 3 de Sódio-Hidrogênio/genética , Trocador 3 de Sódio-Hidrogênio/metabolismo , UbiquitinaçãoRESUMO
BACKGROUND: Obesity is a global epidemic. Since 1975, the global obesity rate has almost tripled. Although many systematic reviews and clinical trials have shown that traditional Chinese medicine (TCM) can effectively treat obesity, the effectiveness and safety of different academic schools of TCM in treating obesity have not been systematically evaluated. METHODS: The retrieval language of this study was Chinese and English. From the date of creation of the following data to June 2023, the data of Medline, PubMed, Embase, Cochrane Science Network, China Biomedical Literature Database, Central Controlled Trial Registration Center, and China Science Journal Database were retrieved, respectively. This study included clinical randomized controlled trials related to the treatment of obesity by different academic schools of TCM. The main outcome measures were body mass index, waist circumference, hip circumference, waist hip ratio, body fat content, fasting blood glucose, glycosylated hemoglobin, and blood lipid level. In addition, we manually searched other resources, including reference lists of identified publications, conference articles, and gray literature. RESULTS: This study will provide a more diverse choice of treatment options. CONCLUSION: The purpose of this study is to summarize and evaluate the effectiveness and safety of different academic schools of TCM in improving and treating obese patients from clinical trials, so as to provide more options for obesity treatment.
Assuntos
Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa , Humanos , Medicina Tradicional Chinesa/métodos , Revisões Sistemáticas como Assunto , Metanálise como Assunto , Instituições Acadêmicas , Projetos de Pesquisa , Obesidade/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: In recent years, the incidence of obesity patients has become younger and younger, and adolescents are gradually becoming one of the groups with a high incidence of obesity. Although several systematic reviews and clinical trials suggest that acupuncture and warm compresses may be effective in the treatment of obesity, the effectiveness and safety of acupuncture combined with warm compresses in the treatment of obesity insulin resistance (IR) in adolescents have not been systematically reviewed. METHODS: The search language of this study is Chinese and English, and the data of Medline, PubMed, Embase, Cochrane Web of Science, China Biomedical Literature Database, Central Controlled Trial Registration Center, and China Scientific Journal Database were searched for this study respectively, from the date of creation of the above data to December 2022. Randomized controlled trials of acupuncture combined with warm compresses in adolescents with obese IR were included in this review. Main outcome measures were body mass index, waist circumference, hip circumference, waist-hip ratio, fasting blood glucose, glycosylated hemoglobin, IR index, body fat content, blood lipid level and blood pressure, etc. In addition, we manually retrieved other resources, including reference lists of identified publications, conference articles and gray literature. RESULTS: This study will provide more clinical treatment ideas and options for adolescent obese IR patients. CONCLUSION: The purpose of this study is to summarize and evaluate the efficacy and safety of acupuncture combined with hot compress in treating obesity IR in adolescents from clinical trials.
Assuntos
Terapia por Acupuntura , Resistência à Insulina , Obesidade Infantil , Adolescente , Humanos , Terapia por Acupuntura/efeitos adversos , Terapia por Acupuntura/métodos , Metanálise como Assunto , Obesidade Infantil/complicações , Obesidade Infantil/terapia , Revisões Sistemáticas como Assunto , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Type 2 diabetes mellitus (T2DM) is a global pandemic with a significant negative impact on health-related quality of life. Worldwide, the prevalence of T2DM has almost doubled since 1980. Although multiple systematic reviews and clinical trials have suggested that electroacupuncture could be effective for T2DM treatment, whether it can improve glucose and lipid metabolism has not been systematically reviewed. METHODS: We searched PubMed, Medline, Embase, Web of Science, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, Chinese Scientific Journal Database, and Wan-Fang Database from the date of creation to December 2022. Language is limited to both Chinese and English languages. Clinical randomized controlled trials related to acupuncture for T2DM were included in this study. Fasting plasma glucose, fasting insulin, lipid profile, and glycated hemoglobin levels were the primary outcomes. In addition, we manually retrieved other resources, including reference lists of identified publications, conference articles, and gray literature. Research selection, data extraction, and research quality assessments were independently completed by 2 researchers. RESULTS: This study provides more options for clinicians and patients to treat obese patients with type 2 diabetes. CONCLUSION: In this study, we aimed to summarize and assess the effectiveness and safety of EA as a supplemental method to treat T2DM patients from clinical trials and provide more options for clinicians and patients to treat T2DM. TRIAL REGISTRATION: This study was registered at INPLASY with registration number INPLASY202180008 (https://inplasy.com/inplasy-2021-8-0008/). SYSTEMATIC REVIEW REGISTRATION: INPLASY202180008.