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1.
Cell Death Discov ; 10(1): 214, 2024 May 02.
Article En | MEDLINE | ID: mdl-38697992

Neutrophil extracellular traps (NETs) are reticular structures composed of neutrophil elastase (NE), cathepsin G (CG) and DNA-histone enzyme complexes. Accumulating evidence has revealed that NETs play important roles in tumor progression, metastasis, and thrombosis. However, our understanding of its clinical value and mechanism of action in oral squamous cell carcinoma (OSCC) is limited and has not yet been systematically described. Here, we aimed to investigate the clinical significance of NETs in OSCC and the mechanisms by which they affect its invasive and metastatic capacity. Our results demonstrated that high enrichment of NETs is associated with poor prognosis in OSCC, and mechanistic studies have shown that NE in NETs promotes invasion and metastasis via NLRP3-mediated inhibition of pyroptosis in OSCC. These findings may provide a new therapeutic approach for OSCC.

2.
J Cancer Res Clin Oncol ; 150(5): 240, 2024 May 07.
Article En | MEDLINE | ID: mdl-38713284

PURPOSE: Head and neck cancer is the sixth most common type of cancer worldwide, wherein the immune responses are closely associated with disease occurrence, development, and prognosis. Investigation of the role of immunogenic cell death-related genes (ICDGs) in adaptive immune response activation may provide cues into the mechanism underlying the outcome of HNSCC immunotherapy. METHODS: ICDGs expression patterns in HNSCC were analyzed, after which consensus clustering in HNSCC cohort conducted. A 4-gene prognostic model was constructed through LASSO and Cox regression analyses to analyze the prognostic index using the TCGA dataset, followed by validation with two GEO datasets. The distribution of immune cells and the response to immunotherapy were compared between different risk subtypes through multiple algorithms. Moreover, immunohistochemical (IHC) analyses were conducted to validate the prognostic value of HSP90AA1 as a predictor of HNSCC patient prognosis. In vitro assays were performed to further detect the effect of HSP90AA1 in the development of HNSCC. RESULTS: A novel prognostic index based on four ICDGs was constructed and proved to be useful as an independent factor of HNSCC prognosis. The risk score derived from this model grouped patients into high- and low-risk subtypes, wherein the high-risk subtype had worse survival outcomes and poorer immunotherapy response. IHC analysis validated the applicability of HSP90AA1 as a predictor of prognosis of HNSCC patients. HSP90AA1 expression in tumor cells promotes the progression of HNSCC. CONCLUSIONS: Together, these results highlight a novel four-gene prognostic signature as a valuable tool to assess survival status and prognosis of HNSCC patients.


HSP90 Heat-Shock Proteins , Head and Neck Neoplasms , Squamous Cell Carcinoma of Head and Neck , Humans , Squamous Cell Carcinoma of Head and Neck/immunology , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/metabolism , Prognosis , HSP90 Heat-Shock Proteins/genetics , HSP90 Heat-Shock Proteins/metabolism , Head and Neck Neoplasms/immunology , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/metabolism , Female , Male , Immunogenic Cell Death , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Middle Aged , Immunotherapy/methods , Gene Expression Regulation, Neoplastic
3.
JAMA Netw Open ; 7(5): e2410754, 2024 May 01.
Article En | MEDLINE | ID: mdl-38739391

Importance: Newborn screening (NBS) for lysosomal storage disorders (LSDs) is becoming an increasing concern in public health. However, the birth prevalence of these disorders is rarely reported in the Chinese population, and subclinical forms of diseases among patients identified by NBS have not been evaluated. Objective: To evaluate the birth prevalence of the 6 LSDs in the Shanghai population and determine subclinical forms based on clinical, biochemical, and genetic characteristics. Design, Setting, and Participants: This cohort study included 50 108 newborns recruited from 41 hospitals in Shanghai between January and December 2021 who were screened for 6 LSDs using tandem mass spectrometry (MS/MS). Participants with screen-positive results underwent molecular and biochemical tests and clinical assessments. Data were analyzed from January 2021 through October 2022. Exposures: All participants were screened for Gaucher, acid sphingomyelinase deficiency (ASMD), Krabbe, mucopolysaccharidosis type I, Fabry, and Pompe diseases using dried blood spots. Main Outcomes and Measures: Primary outcomes were the birth prevalence and subclinical forms of the 6 LSDs in the Shanghai population. Disease biomarker measurements, genetic testing, and clinical analysis were used to assess clinical forms of LSDs screened. Results: Among 50 108 newborns (26 036 male [52.0%]; mean [SD] gestational age, 38.8 [1.6] weeks), the mean (SD) birth weight was 3257 (487) g. The MS/MS-based NBS identified 353 newborns who were positive. Of these, 27 newborns (7.7%) were diagnosed with 1 of 6 LSDs screened, including 2 newborns with Gaucher, 5 newborns with ASMD, 9 newborns with Krabbe, 8 newborns with Fabry, and 3 newborns with Pompe disease. The combined birth prevalence of LSDs in Shanghai was 1 diagnosis in 1856 live births, with Krabbe disease the most common (1 diagnosis/5568 live births), followed by Fabry disease (1 diagnosis/6264 live births), and ASMD (1 diagnosis/10 022 live births). Biochemical, molecular, and clinical analysis showed that early-onset clinical forms accounted for 3 newborns with positive results (11.1%), while later-onset forms represented nearly 90% of diagnoses (24 newborns [88.9%]). Conclusions and Relevance: In this study, the combined birth prevalence of the 6 LSDs in Shanghai was remarkably high. MS/MS-based newborn screening, combined with biochemical and molecular genetic analysis, successfully identified and characterized newborns who were screen-positive, which may assist with parental counseling and management decisions.


Lysosomal Storage Diseases , Neonatal Screening , Humans , Infant, Newborn , Neonatal Screening/methods , China/epidemiology , Lysosomal Storage Diseases/diagnosis , Lysosomal Storage Diseases/epidemiology , Lysosomal Storage Diseases/genetics , Male , Female , Prevalence , Cohort Studies , Tandem Mass Spectrometry
4.
Orphanet J Rare Dis ; 19(1): 75, 2024 Feb 16.
Article En | MEDLINE | ID: mdl-38365697

BACKGROUND: Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by impaired glucose and galactose utilization as well as proximal renal tubular dysfunction. METHODS: Clinical, biochemical, genetic, treatment, and follow-up data for 11 pediatric patients with FBS were retrospectively analysed. RESULTS: Hepatomegaly (10/11), short stature (10/11) and hypophosphataemic rickets (7/11) were the most common initial symptoms. At diagnosis, all patients had decreased fasting blood glucose (FBG), plasma bicarbonate (HCO3-) and serum phosphorus, as well as elevated liver transaminases, alkaline phosphatase (AKP) and proximal renal tubular dysfunction. Two infant patients were misdiagnosed with transient neonatal diabetes mellitus. After therapy with uncooked cornstarch and conventional rickets treatment, remission of hepatomegaly was observed in all patients, with significant improvements in pre-prandial blood glucose, liver transaminases, triglyceride, plasma HCO3- and AKP (p < 0.05). At the last follow-up, 5/7 patients with elevated AKP had nephrocalcinosis. The mean height standard deviation score (Ht SDS) of eight patients with regular treatment increased from - 4.1 to -3.5 (p = 0.02). Recombinant human growth hormone (rhGH) was administered to 4/9 patients, but their Ht SDS did not improve significantly (p = 0.13). Fourteen variants of the SLC2A2 gene were identified, with six being novel, among which one was recurrent: c.1217T > G (p.L406R) (allele frequency: 4/22, 18%). Patients with biallelic missense variants showed milder metabolic acidosis than those with null variants. Two of five patients from nonconsanguineous families with rare homozygous variations showed 5.3 Mb and 36.6 Mb of homozygosity surrounding the variants, respectively; a region of homozygosity (ROH) involving the entire chromosome 3 covering the SLC2A2 gene, suggesting uniparental disomy 3, was detected in one patient. CONCLUSIONS: Early diagnosis of FBS is difficult due to the heterogeneity of initial symptoms. Although short stature is a major issue of treatment for FBS, rhGH is not recommended in FBS patients who have normal GH stimulation tests. Patients with biallelic null variants may require alkali supplementation since urine bicarbonate loss is genetically related. ROH is a mechanism for rare homozygous variants of FBS in nonconsanguineous families.


Fanconi Syndrome , Infant , Infant, Newborn , Humans , Child , Fanconi Syndrome/drug therapy , Fanconi Syndrome/genetics , Hepatomegaly , Blood Glucose , Bicarbonates , Genetic Profile , Retrospective Studies , China , Transaminases/genetics
5.
Cell Biosci ; 13(1): 186, 2023 Oct 03.
Article En | MEDLINE | ID: mdl-37789469

BACKGROUND: High-fat diet (HFD) is closely associated with the increased prevalence of inflammatory bowel disease (IBD). Excessive gut microbial metabolite deoxycholic acid (DCA) caused by HFD plays significant roles in eliciting intestinal inflammation, however, the mechanism underlining the induction of inflammatory response by DCA has not been fully elucidated. The purpose of this study was to investigate the role of DCA in the triggering of inflammation via affecting CD4+ T cell differentiation. RESULTS: Murine CD4+T cells were cultured under Th1, Th2 or Th17-polarizing conditions treated with or without different dosage of DCA, and flowcytometry was conducted to detect the effect of DCA on CD4+ T cell differentiation. Alteration of gene expression in CD4+ T cells upon DCA treatment was determined by RNA-sequencing and qRT-PCR. Bioinformatic analysis, cholesterol metabolic profiling, ChIP assay and immuno-fluorescent staining were further applied to explore the DCA-regulated pathway that involved in CD4+T cell differentiation. The results showed that DCA could dose-dependently promote the differentiation of CD4+ T cell into Th17 linage with pathogenic signature. Mechanistically, DCA stimulated the expression of cholesterol biosynthetic enzymes CYP51 and led to the increased generation of endogenous RORγt agonists, including zymosterol and desmosterol, therefore facilitating Th17 differentiation. Up-regulation of CYP51 by DCA was largely mediated via targeting transcription factor SREBP2 and at least partially through bile acid receptor TGR5. In addition, DCA-supplemented diet significantly increased intestinal Th17 cell infiltration and exacerbated TNBS-induced colitis. Administration of cholestyramine to eliminate fecal bile acid obviously alleviated colonic inflammation accompanied by decreased Th17 cells in HFD-fed mice. CONCLUSIONS: Our data establish a link between DCA-induced cholesterol biosynthesis in immune cells and gut inflammation. Modulation of bile acid level or targeting cholesterol metabolic pathway may be potential therapeutic measurements for HFD-related colitis.

6.
J Clin Lipidol ; 17(6): 808-817, 2023.
Article En | MEDLINE | ID: mdl-37858495

BACKGROUND: Lipoprotein lipase (LPL) deficiency, the most common familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disease characterized by chylomicronemia and severe hypertriglyceridemia (HTG), with limited clinical and genetic characterization. OBJECTIVE: To describe the manifestations and management of 19 pediatric patients with LPL-FCS. METHODS: LPL-FCS patients from 2014 to 2022 were divided into low-fat (LF), very-low-fat (VLF) and medium-chain-triglyceride (MCT) groups. Their clinical data were evaluated to investigate the effect of different diets. The genotype-phenotype relationship was assessed. Linear regression comparing long-chain triglyceride (LCT) intake and TG levels was analyzed. RESULTS: Nine novel LPL variants were identified in 19 LPL-FCS pediatric patients. At baseline, eruptive xanthomas occurred in 3/19 patients, acute pancreatitis in 2/19, splenomegaly in 6/19 and hepatomegaly in 3/19. The median triglyceride (TG) level (30.3 mmol/L) was markedly increased. The MCT group and VLF group with LCT intakes <20 en% (energy percentage) had considerably lower TG levels than the LF group (both p<0.05). The LF group presented with severe HTG and significantly decreased TG levels after restricting LCT intakes to <20 en% (p<0.05). Six infants decreased TG levels to <10 mmol/L by keeping LCT intake <10 en%. TG levels and LCT intake were positively correlated in both patients under 2 years (r=0.84) and those aged 2-9 years (r=0.89). No genotype-phenotype relationship was observed. CONCLUSIONS: This study broadens the clinical and genetic spectra of LPL-FCS. The primary therapy for LPL-FCS pediatric patients is restricting dietary LCTs to <10 en% or <20 en% depending on different ages. MCTs potentially provide extra energy.


Hyperlipoproteinemia Type I , Hypertriglyceridemia , Pancreatitis , Infant , Humans , Child , Hyperlipoproteinemia Type I/therapy , Hyperlipoproteinemia Type I/drug therapy , Acute Disease , Genetic Profile , Pancreatitis/genetics , Hypertriglyceridemia/genetics , Triglycerides , China , Lipoprotein Lipase/genetics
7.
Nanotechnology ; 34(45)2023 Aug 21.
Article En | MEDLINE | ID: mdl-37524070

The development of low cost efficient catalysts for oxygen evolution reaction (OER) is still a obstacle to realize the commercialization of electrocatalytic water splitting. Herein, interface engineering and heteroatom doping is adopted to synthesize iron and vanadium doped nickel sulfide on nickel foam via hydrothermal method followed by hydrogen treatment to create sulfur defects. The optimized nanoflower-like FeVNi3S2-x/NF is an efficient OER electrocatalyst that outperforms many of the reported transition metals catalysts. Benefiting from abundant sulfur defects and the synergistic effect of heteroatom doping, FeVNi3S2-x/NF exhibits an ultralow overpotential of 230 mV to reach a current density of 100 mA cm-2, a rapid reaction kinetics with a small Tafel slope of 46.6 mV dec-1, and a stable long-term durability in 1 M KOH. Experimental results and characterizations confirm that sulfur vacancies together with the synergistic effect from multiple heteroatom doping can effectively regulate the electronic structure, resulting in increased electrical conductivity and electrochemically active surface area, thus enhancing OER performance. Furthermore,in situRaman spectroscopy reveals that, the reconstitution amorphous nickel oxyhydroxide (NiOOH) on the catalyst surface is responsible for catalyzing the OER reaction. This work represents a promising methodology to synthesize low-cost and highly active OER electrocatalysts.

8.
Orphanet J Rare Dis ; 18(1): 126, 2023 05 26.
Article En | MEDLINE | ID: mdl-37237297

BACKGROUND: X-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency (PAI) and hypogonadotropic hypogonadism (HH), with limited clinical and genetic characterization. METHODS: The clinical, biochemical, genetic, therapeutic, and follow-up data of 42 patients diagnosed with X-linked AHC were retrospectively analysed. RESULTS: Hyperpigmentation (38/42, 90%), vomiting/diarrhoea (20/42, 48%), failure to thrive (13/42, 31%), and convulsions (7/42, 17%) were the most common symptoms of X-linked AHC at onset. Increased adrenocorticotropic hormone (ACTH) (42/42, 100%) and decreased cortisol (37/42, 88%) were the most common laboratory findings, followed by hyponatremia (32/42, 76%) and hyperkalaemia (29/42, 69%). Thirty-one patients presented with PAI within the first year of life, and 11 presented after three years of age. Three of the thirteen patients over the age of 14 exhibited spontaneous pubertal development, and ten of them experienced delayed puberty due to HH. Six patients receiving human chorionic gonadotropin (hCG) therapy exhibited a slight increase in testicular size and had rising testosterone levels (both P < 0.05). The testicular volumes of the three patients with pulsatile gonadotropin-releasing hormone (GnRH) therapy were larger than those of the six patients undergoing hCG therapy (P < 0.05), and they also exhibited some growth in terms of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone. Of the 42 patients, three had an Xp21 deletion, and 39 had an isolated DAX1 defect. Most patients (9/10) with entire DAX1 deletion accounting for 23.8% (10/42) of the total variants had early onset age of less than one year. CONCLUSIONS: This study details the clinical features and genetic spectra of X-linked AHC. Patients with X-linked AHC show a bimodal distribution of the age of onset, with approximately 70% presenting within the first year of life. Pulsatile GnRH may be recommended for HH when hCG therapy is not satisfactory, although it is difficult to achieve normal testicular volume. The combination of clinical features and molecular tests provides information for an accurate diagnosis.


East Asian People , Hypogonadism , Child , Humans , Male , Gonadotropin-Releasing Hormone/therapeutic use , Hypoadrenocorticism, Familial/genetics , Hypoadrenocorticism, Familial/drug therapy , Hypogonadism/drug therapy , Hypogonadism/genetics , Mutation , Retrospective Studies , Testosterone
9.
Nanotechnology ; 34(21)2023 Mar 13.
Article En | MEDLINE | ID: mdl-36753747

The development of high efficiency oxygen evolution electrocatalyst is of great significance for water splitting reaction. Herein, an efficient cone-structured NiFe-LDH/Nicone/Ti catalyst is fabricated by electrodeposition method towards enhanced oxygen evolution reaction (OER). The featured tip curvature of nanocone structure can accelerate the reaction kinetics of OER by offering a field-enhanced aggregation of local hydroxide ion reactant on the catalyst surface, and thus improves the performance of the NiFe catalyst. Accordingly, NiFe-LDH/Nicone/Ti requires only a low overpotential of 292 mV to achieve 50 mA cm-2, and with high stability under continuous high-current operations. In addition, the alkali-electrolyzer using NiFe-LDH/Nicone/Ti electrode exhibits good performance with a voltage of 1.73 V at 50 mA cm-2and displays excellent stability in long-term stability test. This cone-structured catalyst design with field-enhanced local hydroxide ion aggregation effect provides a promising method for the development of highly active OER electrocatalysts.

10.
Biotechnol Prog ; 38(5): e3279, 2022 09.
Article En | MEDLINE | ID: mdl-35661450

As a water-soluble macromolecule polysaccharide, xanthan gum (XG) has several biological activities, such as antitumor, antiviral, and immunomodulatory function. However, the effect of XG on the proliferation and cytotoxicity of cytokines induced killer (CIK) cells is rarely studied. In this study, the effect of XG on CIK cells derived from peripheral blood was investigated by analyzing the expansion fold of total cells, phenotype, cytotoxicity, degranulation, and apoptosis in serum-free medium. The results showed that the expansion fold of total cells with 100 µg/ml XG which molecule weight is 2.95 × 106 Da reached 4534.0 folds, significantly higher than that without XG (1299.0 folds, p < 0.05). The percentage of main effector cells-CD3+ CD56+ cells increased to 25.5% and the cytotoxic activity of CIK cells increased to 45.3%. The cell proportions of expression granzyme B and perforin that related to cytotoxicity in CIK cells reached 53.6% and 48.3%, respectively, significantly higher than 27.5% and 37.5% in the group without XG (p < 0.05). Collectively, XG could stimulate the ex vivo expansion of CIK cells and enhance the cytotoxicity of expanded CIK cells. The above results provide technical support for optimizing the expansion process of CIK cells ex vivo.


Cytokine-Induced Killer Cells , Antiviral Agents/pharmacology , Cells, Cultured , Cytokine-Induced Killer Cells/metabolism , Granzymes/metabolism , Granzymes/pharmacology , Perforin/metabolism , Perforin/pharmacology , Polysaccharides, Bacterial , Tumor Necrosis Factor-alpha , Water/metabolism
11.
Cell Mol Gastroenterol Hepatol ; 13(3): 827-841, 2022.
Article En | MEDLINE | ID: mdl-34902629

BACKGROUND & AIMS: Gut microbiota and microbial factors regulate the pathogenesis of nonalcoholic fatty liver disease (NAFLD) in patients with obesity and metabolic abnormalities, but little is known about their roles in nonobese NAFLD. Expansion of Escherichia is associated with NAFLD pathogenesis. We aimed to investigate the pathogenic role of Escherichia fergusonii and its products in the development of nonobese NAFLD. METHODS: We characterized the intestinal microbiome signature in a cohort of NAFLD patients and healthy controls by 16S ribosomal RNA sequencing. The role of E fergusonii was estimated in rats after 16 weeks of administration, and features of NAFLD were assessed. E fergusonii-derived microRNA-sized, small RNAs (msRNAs) were analyzed by deep sequencing. RESULTS: We detected an expansion of Escherichia_Shigella in NAFLD patients compared with healthy controls, and its increase was associated with disease severity independent of obesity. E fergusonii, a member of the genus Escherichia, induced the development of nonobese NAFLD characterized by hepatic steatosis and hepatocyte ballooning in rats without obesity. It disturbed host lipid metabolism by inhibiting hepatic lipid ß-oxidation and promoting de novo lipogenesis. We also showed that E fergusonii caused the development of hepatic inflammation and fibrosis in a sizable fraction of animals at an advanced stage of NAFLD. Mechanistically, E fergusonii-derived msRNA 23487 down-regulated host hepatic peroxisome proliferator-activated receptor α expression, which could contribute to lipid accumulation in the liver. CONCLUSIONS: These results suggest that E fergusonii promotes the pathogenesis of steatohepatitis and fibrosis in nonobese rats by secreting msRNA 23487, and it might be a potential biomarker for predicting steatohepatitis in nonobese NAFLD.


Non-alcoholic Fatty Liver Disease , Animals , Escherichia , Humans , Lipid Metabolism , Non-alcoholic Fatty Liver Disease/pathology , Rats
12.
J Neuroinflammation ; 18(1): 66, 2021 Mar 06.
Article En | MEDLINE | ID: mdl-33676524

BACKGROUND: Necrotizing enterocolitis (NEC) is an inflammatory gastrointestinal disease in premature neonates with high mortality and morbidity, while the underlining mechanism of intestinal injury and profound neurological dysfunction remains unclear. Here, we aimed to investigate the involvement of NLPR3 inflammasome activation in NEC-related enterocolitis and neuroinflammation, especially long-term cognitive impairment, meanwhile, explore the protective effect of NLRP3 inhibitor MCC950 on NEC in mice. METHODS: NLRP3 inflammasome activation in the intestine and brain was assessed in the NEC mouse model, and NLRP3 inhibitor MCC950 was administrated during the development of NEC. Survival rate, histopathological injury of the intestine and brain, and expression of mature IL-1ß and other pro-inflammatory cytokines were analyzed. Long-term cognitive impairment was evaluated by behavioral test. RESULTS: The expression of NLRP3 and mature IL-1ß in the intestine and brain was greatly upregulated in NEC mice compared to the controls. MCC950 treatment efficiently improved NEC survival rate, reduced intestinal and brain inflammation, and ameliorated the severity of pathological damage in both organs. Additionally, in vivo blockage of NLRP3 inflammasome with MCC950 in early life of NEC pups potently protected against NEC-associated long-term cognitive impairment. CONCLUSIONS: Our findings suggest that NLRP3 inflammasome activation participates in NEC-induced intestinal and brain injury, and early intervention with NLRP3 inhibitor may provide beneficial therapeutic effect on NEC infants.


Cognitive Dysfunction/immunology , Enterocolitis, Necrotizing/immunology , Inflammasomes/immunology , Inflammation/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Animals , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/pathology , Enterocolitis, Necrotizing/metabolism , Enterocolitis, Necrotizing/pathology , Furans/pharmacology , Indenes/pharmacology , Inflammasomes/metabolism , Inflammation/metabolism , Inflammation/pathology , Mice , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Sulfonamides/pharmacology
13.
FASEB J ; 35(2): e21189, 2021 02.
Article En | MEDLINE | ID: mdl-33200449

Disassembly of tight junctions is a major cause of intestinal barrier dysfunction under total parenteral nutrition (TPN), but the precise mechanisms have not been fully understood. Normally, RNA binding protein Lin 28A is highly restricted to embryonic stem cells and dramatically decreases as differentiation progresses; however, in our preliminary study it was found aberrantly increased in the intestinal epithelial cells of TPN rats, and thus its mechanism of action needs to be addressed. Herein, we report a pivotal role of Lin 28A in the regulation of tight junctions, which induces a sustained translational repression of Occludin, leading to disruption of intestinal barrier function under TPN. Using a rat model of TPN, we found time-dependent upregulation of Lin 28A, negatively correlated with Occludin. Using mouse intestinal organoids and human gut-derived Caco-2 cells as in vitro models, we found that expression of Occludin could be significantly suppressed by ectopic overexpression of Lin 28A. The underlying mechanisms may be partially attributed to translational repression, as the abundance of Occludin transcripts in polysomes was dramatically reduced by Lin 28A (polysomal profiling). Furthermore, Lin 28A was found to directly bind to Occludin mRNA 3' untranslated coding region (UTR), thereby repressing the translation of Occludin transcripts through decapping enzyme 1A (DCP1a). Taken together, our findings revealed that Lin 28A/Occludin axis may be a novel mechanism accounting for the development of barrier dysfunction under TPN.


Enterocytes/metabolism , Occludin/metabolism , Parenteral Nutrition/adverse effects , RNA-Binding Proteins/metabolism , Tight Junctions/metabolism , Animals , Caco-2 Cells , Cells, Cultured , Enterocytes/pathology , Humans , Male , Mice , Mice, Inbred C57BL , Rats , Rats, Sprague-Dawley , Signal Transduction , Tight Junctions/pathology
14.
Gut Microbes ; 12(1): 1-20, 2020 11 09.
Article En | MEDLINE | ID: mdl-33006494

High-fat diet (HFD) leads to systemic low-grade inflammation, which has been involved in the pathogenesis of diverse metabolic and inflammatory diseases. Colon is thought to be the first organ suffering from inflammation under HFD conditions due to the pro-inflammatory macrophages infiltration, however, the mechanisms concerning the induction of pro-inflammatory phenotype of colonic macrophages remains unclear. In this study, we show that HFD increased the percentage of gram-positive bacteria, especially genus Clostridium, and resulted in the significant increment of fecal deoxycholic acid (DCA), a gut microbial metabolite produced by bacteria mainly restricted to genus Clostridium. Notably, reducing gram-positive bacteria with vancomycin diminished fecal DCA and profoundly alleviated pro-inflammatory macrophage infiltration in colon, whereas DCA-supplemented feedings to vancomycin-treated mice provoked obvious pro-inflammatory macrophage infiltration and colonic inflammation. Meanwhile, intra-peritoneal administration of DCA also elicited considerable recruitment of macrophages with pro-inflammatory phenotype. Mechanistically, DCA dose-dependently promoted M1 macrophage polarization and pro-inflammatory cytokines production at least partially through toll-like receptor 2 (TLR2) transactivated by M2 muscarinic acetylcholine receptor (M2-mAchR)/Src pathway. In addition, M2-mAchR mediated increase of TLR2 transcription was mainly achieved via targeting AP-1 transcription factor. Moreover, NF-κB/ERK/JNK signalings downstream of TLR2 are involved in the DCA-induced macrophage polarization. In conclusion, our findings revealed that high level DCA induced by HFD may serve as an initiator to activate macrophages and drive colonic inflammation, thus offer a mechanistic basis that modulation of gut microbiota or intervening specific bile acid receptor signaling could be potential therapeutic approaches for HFD-related inflammatory diseases.


Colitis/etiology , Deoxycholic Acid/metabolism , Diet, High-Fat , Gastrointestinal Microbiome , Gram-Positive Bacteria/growth & development , Gram-Positive Bacteria/metabolism , Animals , Anti-Bacterial Agents/pharmacology , Colitis/immunology , Colitis/microbiology , Colon/immunology , Colon/microbiology , Cytokines/metabolism , Deoxycholic Acid/analysis , Deoxycholic Acid/pharmacology , Feces/chemistry , Gastrointestinal Microbiome/drug effects , Gastrointestinal Microbiome/physiology , MAP Kinase Signaling System , Macrophage Activation , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , Phosphorylation , Receptor, Muscarinic M2/metabolism , Toll-Like Receptor 2/genetics , Toll-Like Receptor 2/metabolism , Tyrosine/metabolism , Vancomycin/pharmacology
15.
World J Gastroenterol ; 26(18): 2203-2220, 2020 May 14.
Article En | MEDLINE | ID: mdl-32476787

BACKGROUND: Folic acid has been shown to improve non-alcoholic steatohepatitis (NASH), but its roles in hepatic lipid metabolism, hepatic one-carbon metabolism, and gut microbiota are still unknown. AIM: To demonstrate the role of folic acid in lipid metabolism and gut microbiota in NASH. METHODS: Twenty-four Sprague-Dawley rats were assigned into three groups: Chow diet, high-fat diet (HFD), and HFD with folic acid administration. At the end of 16 wk, the liver histology, the expression of hepatic genes related to lipid metabolism, one-carbon metabolism, and gut microbiota structure analysis of fecal samples based on 16S rRNA sequencing were measured to evaluate the effect of folic acid. Palmitic acid-exposed Huh7 cell line was used to evaluate the role of folic acid in hepatic lipid metabolism. RESULTS: Folic acid treatment attenuated steatosis, lobular inflammation, and hepatocellular ballooning in rats with HFD-induced steatohepatitis. Genes related to lipid de novo lipogenesis, ß-oxidation, and lipid uptake were improved in HFD-fed folic acid-treated rats. Furthermore, peroxisome proliferator-activated receptor alpha (PPARα) and silence information regulation factor 1 (SIRT1) were restored by folic acid in HFD-fed rats and palmitic acid-exposed Huh7 cell line. The restoration of PPARα by folic acid was blocked after transfection with SIRT1 siRNA in the Huh7 cell line. Additionally, folic acid administration ameliorated depleted hepatic one-carbon metabolism and restored the diversity of the gut microbiota in rats with HFD-induced steatohepatitis. CONCLUSION: Folic acid improves hepatic lipid metabolism by upregulating PPARα levels via a SIRT1-dependent mechanism and restores hepatic one-carbon metabolism and diversity of gut microbiota, thereby attenuating HFD-induced NASH in rats.


Folic Acid/pharmacology , Gastrointestinal Microbiome/drug effects , Non-alcoholic Fatty Liver Disease/drug therapy , PPAR alpha/metabolism , Sirtuin 1/metabolism , Animals , Cell Line, Tumor , DNA, Bacterial/isolation & purification , Diet, High-Fat/adverse effects , Disease Models, Animal , Feces/microbiology , Folic Acid/therapeutic use , Gastrointestinal Microbiome/genetics , Humans , Lipid Metabolism/drug effects , Liver/drug effects , Liver/metabolism , Liver/pathology , Male , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/pathology , RNA, Ribosomal, 16S/genetics , RNA, Small Interfering/metabolism , Rats , Sirtuin 1/genetics , Up-Regulation/drug effects
16.
Front Pharmacol ; 11: 593, 2020.
Article En | MEDLINE | ID: mdl-32435194

N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous immunomodulatory peptide that is generated from thymosin ß4 (Tß4) through stepwise hydrolysis, involving meprin-α and prolyl endopeptidase (PREP). It is well acknowledged that AcSDKP exerts beneficial effects on multiple cardiovascular and renal diseases. However, the functional role of AcSDKP in inflammatory bowel disease (IBD) remains poorly understood. Here, we aimed to assess the content of AcSDKP in patients with IBD and investigate the impact of AcSDKP on intestinal inflammation in IBD. We found that in the inflamed mucosal specimens of patients with ulcerative colitis, the expression levels of Tß4 and meprin-α were decreased, while PREP was expressed at similar levels to non-inflamed mucosa. In vitro, AcSDKP inhibited the expression of proinflammatory factors in intestinal epithelial cells partially by reducing the activation of MEK-ERK signaling. In vivo studies showed that transgenic mice, with lower levels of AcSDKP, were more vulnerable to dextran sulfate sodium (DSS)-induced colitis and exhibited more severe intestinal inflammatory responses. On the other hand, exogenous AcSDKP infusion significantly attenuated the clinical symptoms and intestinal mucosal inflammation in DSS-induced mice. In conclusion, results from this study demonstrated the anti-inflammatory function of AcSDKP within the intestine and suggest that AcSDKP has a promising therapeutic potential for IBD treatment.

17.
Mol Immunol ; 104: 11-19, 2018 12.
Article En | MEDLINE | ID: mdl-30396035

BACKGROUND: NLRP3 inflammasome mediates IL-1ß maturation, therefore plays a vital role in the development of IBD. Curcumin is known for possessing strong anti-inflammatory property. OBJECTIVE: The present study was to investigate the protective effects of curcumin on dextran sulfate sodium (DSS)-induced colitis through inhibiting NLRP3 inflammasome activation and IL-1ß production. METHODS: LPS-primed macrophages were treated with curcumin prior to DSS triggering NLRP3 inflammasome activation, IL-1ß secretion and ASC oligomerization were observed. The mechanisms of curcumin in the inhibition of DSS-induced inflammasome activation were explored. Curcumin or caspase-1/NLRP3 inhibitor was administrated respectively in DSS-induced colitis mouse model. The changes of body weight, disease activity index, colon length were measured. Additionally, mature IL-1ß and other inflammatory cytokines, MPO activity and histopathological damage were analyzed for the evaluation of colitis severity. RESULTS: NLRP3 inflammasome activation was dramatically inhibited by curcumin in DSS-stimulated macrophages, as evidenced by decreased IL-1ß secretion, less caspase-1 activation and ASC specks. Mechanistically, curcumin prevented DSS-induced K+ efflux, intracellular ROS formation and cathepsin B release, three major cellular events mediating NLRP3 inflammasome activation. In DSS-induced colitis, curcumin administration significantly ameliorated colitis symptoms by reducing weight loss, DAI and colon length shortening. Meanwhile, curcumin significantly decreased the expression of multiple inflammatory cytokines (including mature IL-1ß, IL-6, MCP-1), MPO activity, caspase-1 activity as well as histopathological damage. Furthermore, blockage of NLRP3 inflammasome activation in vivo with specific NLRP3 inhibitor abrogated the further inhibitory effect of curcumin on DSS-induced colitis. CONCLUSION: Curcumin could strongly suppress DSS-induced NLRP3 inflammsome activation and alleviate DSS-induced colitis in mice, thus it may be a promising candidate drug in clinical application for IBD therapy.


Colitis , Curcumin/pharmacology , Dextran Sulfate/toxicity , Inflammasomes/immunology , Interleukin-1beta/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Animals , Caspase 1/immunology , Colitis/chemically induced , Colitis/immunology , Colitis/pathology , Colitis/prevention & control , Female , Lipopolysaccharides/toxicity , Macrophages, Peritoneal/immunology , Macrophages, Peritoneal/pathology , Mice , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors
18.
J Immunol Res ; 2018: 2481418, 2018.
Article En | MEDLINE | ID: mdl-29854830

We recently have proved that excessive fecal DCA caused by high-fat diet may serve as an endogenous danger-associated molecular pattern to activate NLRP3 inflammasome and thus contributes to the development of inflammatory bowel disease (IBD). Moreover, the effect of DCA on inflammasome activation is mainly mediated through bile acid receptor sphingosine-1-phosphate receptor 2 (S1PR2); however, the intermediate process remains unclear. Here, we sought to explore the detailed molecular mechanism involved and examine the effect of S1PR2 blockage in a colitis mouse model. In this study, we found that DCA could dose dependently upregulate S1PR2 expression. Meanwhile, DCA-induced NLRP3 inflammasome activation is at least partially achieved through stimulating extracellular regulated protein kinases (ERK) signaling pathway downstream of S1PR2 followed by promoting of lysosomal cathepsin B release. DCA enema significantly aggravated DSS-induced colitis in mice and S1PR2 inhibitor as well as inflammasome inhibition by cathepsin B antagonist substantially reducing the mature IL-1ß production and alleviated colonic inflammation superimposed by DCA. Therefore, our findings suggest that S1PR2/ERK1/2/cathepsin B signaling plays a critical role in triggering inflammasome activation by DCA and S1PR2 may represent a new potential therapeutic target for the management of intestinal inflammation in individuals on a high-fat diet.


Colitis/immunology , Deoxycholic Acid/metabolism , Inflammatory Bowel Diseases/immunology , Macrophages/immunology , Alarmins/immunology , Animals , Cathepsin B/metabolism , Cell Line , Colitis/chemically induced , Dextran Sulfate , Disease Models, Animal , Female , Humans , Inflammasomes/metabolism , Mice , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Receptors, Lysosphingolipid , Signal Transduction , Sphingosine-1-Phosphate Receptors
19.
J Cell Mol Med ; 22(3): 1562-1573, 2018 03.
Article En | MEDLINE | ID: mdl-29105957

Enterocyte apoptosis induced by lipid emulsions is a key cause of intestinal atrophy under total parenteral nutrition (TPN) support, and our previous work demonstrated that olive oil lipid emulsion (OOLE) could induce enterocyte apoptosis via CUGBP, Elav-like family member 1 (CELF1)/ apoptosis-inducing factor (AIF) pathway. As TPN-associated complications are partially related to choline deficiency, we aimed to address whether choline supplementation could attenuate OOLE-induced enterocyte apoptosis. Herein we present evidence that supplementary choline exhibits protective effect against OOLE-induced enterocyte apoptosis both in vivo and in vitro. In a rat model of TPN, substantial reduction in apoptotic rate along with decreased expression of CELF1 was observed when supplementary choline was added to OOLE. In cultured Caco-2 cells, supplementary choline attenuated OOLE-induced apoptosis and mitochondria dysfunction by suppressing CELF1/AIF pathway. Compared to OOLE alone, the expression of CELF1 and AIF was significantly decreased by supplementary choline, whereas the expression of Bcl-2 was evidently increased. No obvious alterations were observed in Bax expression and caspase-3 activation. Mechanistically, supplementary choline repressed the expression of CELF1 by increasing the recruitment of CELF1 mRNA to processing bodies, thus resulting in suppression of its protein translation. Taken together, our data suggest that supplementary choline exhibits effective protection against OOLE-induced enterocyte apoptosis, and thus, it has the potential to be used for the prevention and treatment of TPN-induced intestinal atrophy.


Apoptosis Inducing Factor/genetics , Atrophy/prevention & control , CELF1 Protein/genetics , Choline Deficiency/prevention & control , Choline/administration & dosage , Olive Oil/adverse effects , Parenteral Nutrition, Total/adverse effects , Animals , Apoptosis/drug effects , Apoptosis/genetics , Apoptosis Inducing Factor/metabolism , Atrophy/chemically induced , Atrophy/genetics , Atrophy/physiopathology , CELF1 Protein/metabolism , Caco-2 Cells , Caspase 3/genetics , Caspase 3/metabolism , Choline Deficiency/genetics , Choline Deficiency/physiopathology , Disease Models, Animal , Emulsions , Enterocytes/drug effects , Enterocytes/metabolism , Enterocytes/pathology , Gene Expression Regulation , Humans , Intestines/drug effects , Intestines/physiopathology , Male , Mitochondria/drug effects , Mitochondria/metabolism , Olive Oil/administration & dosage , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats , Rats, Sprague-Dawley , Signal Transduction , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolism
20.
Acta Biochim Biophys Sin (Shanghai) ; 49(7): 635-642, 2017 Jul 01.
Article En | MEDLINE | ID: mdl-28510621

Mouse miR-290 cluster miRNAs are expressed specifically in early embryos and embryonic germ cells. These miRNAs play critical roles in the maintenance of pluripotency and self-renewal. Here, we showed that Cyclin D1 is a direct target gene of miR-290 cluster miRNAs. Negative relationships between the expression of Cyclin D1 protein and miR-290 cluster miRNAs in pluripotent and non-pluripotent cells, as well as in differentiating CGR8 cells were observed. Inhibition of miR-290 cluster miRNAs could arrest cells at the G1 phase and slow down the cell proliferation in CGR8 mouse stem cells. Since miR-290 cluster miRNAs are the most dominant stem-cell-specific miRNAs, our results revealed an important cause for the absence of Cyclin D1 in mouse embryonic stem cells.


Cyclin D1/analysis , MicroRNAs/physiology , Mouse Embryonic Stem Cells/chemistry , Animals , Cell Proliferation , Cells, Cultured , Cyclin D1/genetics , Cyclin-Dependent Kinase 4/physiology , Cyclin-Dependent Kinase 6/physiology , G1 Phase , Mice , Mouse Embryonic Stem Cells/cytology
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