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Faecalibacterium prausnitzii (F. prausnitzii) has been recognized for its various intestinal and extraintestinal benefits to human. And reduction of F. prausnitzii has been linked to an increased risk of intestinal fibrosis in patients of Crohn's disease (CD). In this study, oral administration of either live F. prausnitzii or its extracellular vesicles (FEVs) can markedly mitigate the severity of fibrosis in mice induced by repetitive administration of DSS. In vitro experiment revealed that FEVs were capable of directing the polarization of peripheral blood mononuclear cells (PBMCs) towards an M2b macrophage phenotype, which has been associated with anti-fibrotic activities. This effect of FEV was found to be stable under various conditions that promote the development of pro-fibrotic M1/M2a/M2c macrophages. Proteomics and RNA sequencing were performed to uncover the molecular modulation of macrophages by FEVs. Notably, we found that FEVs reprogramed every metabolism of macrophages by damaging the mitochondria, and inhibited oxidative phosphorylation and glycolysis. Moreover, FEV-treated macrophages showed a decreased expression of PPARγ and an altered lipid processing phenotype characterized by decreased cholesterol efflux, which may promote energy reprogramming. Taken together, these findings identify FEV as a driver of macrophage reprogramming, suggesting that triggering M2b macrophage polarization by oral admiration of FEV may serve as strategy to alleviate hyperfibrotic intestine conditions in CD.
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Colite , Vesículas Extracelulares , Faecalibacterium prausnitzii , Fibrose , Macrófagos , Camundongos Endogâmicos C57BL , Animais , Macrófagos/metabolismo , Vesículas Extracelulares/metabolismo , Faecalibacterium prausnitzii/metabolismo , Camundongos , Colite/metabolismo , Colite/microbiologia , Colite/patologia , Colite/induzido quimicamente , Masculino , Sulfato de Dextrana , Intestinos/patologia , Doença Crônica , Reprogramação MetabólicaRESUMO
BACKGROUND: Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. METHODS: We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. RESULTS: A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m2, p < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p < 0.0001) in children than in adults. S1 (62% vs. 28%, p < 0.0001) and T1-2 (34% vs. 8%, p < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16-3.02, p = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. CONCLUSIONS: Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children.
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Taxa de Filtração Glomerular , Glomerulonefrite por IGA , Proteinúria , Humanos , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/fisiopatologia , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/patologia , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/terapia , Masculino , Feminino , Criança , Adulto , Proteinúria/etiologia , Proteinúria/diagnóstico , Adolescente , Estudos Prospectivos , Adulto Jovem , Prognóstico , Pessoa de Meia-Idade , Fatores Etários , Hematúria/etiologia , Hematúria/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Hipertensão/diagnóstico , Rim/patologia , Rim/fisiopatologia , Progressão da Doença , Glucocorticoides/uso terapêuticoRESUMO
BACKGROUND: Celiac disease (CeD) is a primary malabsorption syndrome with no specific therapy, which greatly affects the quality of life. Since the pathogenesis of CeD remains riddled, based on multiple transcriptome profiles, this study aimed to establish an immune interaction network and elucidated new mechanisms involved in the pathogenesis of CeD, providing potentially new evidence for the diagnosis and treatment of CeD. METHODS: Three microarray and three RNA sequencing datasets of human duodenal tissue with or without CeD were included in Gene Expression Omnibus and respectively merged into derivation and validation cohorts. Differential expression gene and functional enrichment analysis were developed, then pyroptosis enrichment score (PES) model was established to quantify pyroptosis levels. Immune infiltration and co-expression network were constructed based on Xcell database. Protein-protein interaction and weighted gene co-expression network analysis were determined to identify pyroptosis relative hub genes, whose predictive efficiency were tested using a least absolute shrinkage and selection operator (LASSO) regression model. CeD animal and in vitro cell line models were established to verify the occurrence of pyroptosis and molecules expression employing immunofluorescence, western blotting, cell counting kit-8 assay and enzyme-linked immunosorbent assay. Analysis of single-cell RNAseq (scRNAseq) was performed using "Seurat" R package. RESULTS: Differentially expressed genes (DEGs) (137) were identified in derivation cohort whose function was mainly enriched in interferon response and suppression of metabolism. Since an enrichment of pyroptosis pathway in CeD was unexpectedly discovered, a PES model with high efficiency was constructed and verified with two external databases, which confirmed that pyroptosis was significantly upregulated in CeD epithelia. γδT cells exhibited high expression of IFN-γ were the most relevant cells associated with pyroptosis and occupied a greater weight in the LASSO predictive model of CeD. An accumulation of GSDMD expressed in epithelia was identified using scRNAseq, while animal model and in vitro experiments confirmed that epithelium cells were induced to become "pre-pyroptotic" status via IFN-γ/IRF1/GSDMD axis. Furthermore, gluten intake triggered pyroptosis via caspase-1/GSDMD/IL-1ß pathway. CONCLUSION: Our study demonstrated that pyroptosis was involved in the pathogenesis of CeD, and elucidated the novel role of γδT cells in mediating epithelial cell pyroptosis.
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Doença Celíaca , Piroptose , Animais , Humanos , Transcriptoma , Qualidade de Vida , Células EpiteliaisRESUMO
BACKGROUND: IgA vasculitis nephritis (IgAVN) and IgA nephropathy (IgAN) share several clinical and pathological characteristics, though distinctions also exist. Their interrelation, however, remains undefined. This study investigates the clinicopathological divergences and prognostic disparities in pediatric patients with IgAVN and IgAN. METHODS: Our study encompasses 809 pediatric patients with IgAVN and 236 with IgAN, all of whom underwent kidney biopsy. We utilized the Semiquantitative Classification (SQC) scoring system to juxtapose the pathologies of the two conditions, and performed a COX regression analysis to examine factors influencing their prognoses. RESULTS: Both patient groups demonstrated a predominance of males. A seasonality was observed, with a higher incidence of IgAN in the summer, and IgAVN in the fall (P < 0.0001). Patients with IgAN exhibited more severe tubulointerstitial injury, higher chronicity index, and total biopsy scores compared to those with IgAVN (P < 0.0001). Mesangial deposition intensity of complement C3, and the rate of pure IgA deposition, were found to be greater in patients with IgAVN compared to those with IgAN (P < 0.0001). The intensity of IgA deposition was also significantly higher in IgAVN patients (P = 0.003). IgAVN demonstrated a superior prognosis, with a higher rate of kidney remission (P < 0.0001). COX regression analysis indicated that interstitial fibrosis, as identified in the SQC pathology system, was associated with the prognosis of both conditions. Furthermore, the findings suggest that IgA deposition levels (IgA + + and IgA + + +) could potentially influence the prognosis of IgAVN. CONCLUSIONS: Compared to IgAVN, IgAN manifests more severely with regard to renal impairment, interstitial damage, and prognosis. The disparities in immune complex deposition levels and locations within the kidneys support the hypothesis of IgAVN and IgAN as distinct diseases. Interstitial fibrosis may serve as a key pathological indicator within the SQC system associated with kidney prognosis in children with IgAVN and IgAN. The degree of IgA deposition could also be linked with the prognosis of IgAVN.
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Glomerulonefrite por IGA , Vasculite por IgA , Nefrite , Masculino , Humanos , Criança , Feminino , Glomerulonefrite por IGA/diagnóstico , Vasculite por IgA/complicações , Vasculite por IgA/diagnóstico , Prognóstico , Fibrose , Imunoglobulina ARESUMO
OBJECTIVES: To investigate the clinical characteristics, pathology, and prognosis of children with diffuse endocapillary proliferative Henoch-Schönlein purpura nephritis (DEP-HSPN). METHODS: A retrospective analysis was performed on the clinical, pathological, and prognosis data of 44 children with DEP-HSPN and 765 children without DEP-HSPN. The children with DEP-HSPN were diagnosed by renal biopsy in Jiangxi Provincial Children's Hospital from January 2006 to December 2021. RESULTS: Among the 809 children with purpura nephritis, 44 (5.4%) had DEP-HSPN, with a mean age of (8±3) years, and there were 29 boys (65.9%) and 15 girls (34.1%). Compared with the non-DEP-HSPN group, the DEP-HSPN group had a significantly shorter time from onset to renal biopsy and a significantly higher proportion of children with respiratory infection or gross hematuria, and most children had nephrotic syndrome. The DEP-HSPN group had significantly higher levels of 24-hour urinary protein, urinary protein grading, microscopic hematuria grading, serum creatinine, and blood urea nitrogen and significantly lower levels of serum albumin and complement C3 (P<0.05). The DEP-HSPN group had a higher pathological grading, with predominant deposition of IgA in the mesangial area and capillary loops, and higher activity scores in the modified semi-quantitative scoring system (P<0.05). The Kaplan-Meier survival analysis showed that there was no significant difference in the renal complete remission rate between the two groups (P>0.05). CONCLUSIONS: Children with DEP-HSPN have a rapid onset, severe clinical manifestations and pathological grading, and high activity scores in the modified semi-quantitative scoring system. However, most of the children with DEP-HSPN have a good prognosis, with a comparable renal complete remission rate to the children without DEP-HSPN.
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Vasculite por IgA , Nefrite , Masculino , Feminino , Humanos , Criança , Pré-Escolar , Hematúria , Estudos Retrospectivos , PrognósticoRESUMO
AIM: IgA nephropathy is virtually known as the most common glomerulopathy to end-stage renal failure in the world. Mycophenolate mofetil is a selective immunosuppressant widely used in organ transplantation, yet its tolerance and effectiveness in IgAN is controversial. METHODS: This is a systematic review and random-effects meta-analysis, searching PubMed, Embase, Te Cochrane Library, Science Citation Index, Ovid evidence-based medicine, Chinese Biomedical Literature and Chinese Science and Technology Periodicals. Screen out randomized controlled trials on patients with biopsy-proven IgA nephropathy and analysis mycophenolate mofetil treatment regimens used for therapy of IgA nephropathy. Complete remission and partial remission, doubling of creatinine level, proteinuria, incidence of end-stage kidney disease, infection, Cushing syndrome, diabetes, hepatic dysfunction or gastrointestinal symptoms, neurologic or visual ambiguity, acne, and alopecia were observed. RESULTS: Nine relevant trials were conducted with 587 patients enrolled. In Mycophenolate mofetil or plus medium/low-dose steroid comparing full-dose steroid alone or placebo, there was no significant difference. The risk of Cushing syndrome and diabetes had been significantly lowered with Mycophenolate mofetil-treated patients, while the risk of infection had been increased. CONCLUSIONS: Mycophenolate mofetil therapy did not differ in reducing proteinuria and Scr in patients with IgAN who had persistent proteinuria, while having fewer Cushing syndrome and diabetes risk and more infection risk. However, larger randomized studies are needed to reveal these results.
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Antibióticos Antineoplásicos/uso terapêutico , Glomerulonefrite por IGA/tratamento farmacológico , Ácido Micofenólico/uso terapêutico , Quimioterapia Combinada , Glucocorticoides/uso terapêutico , Humanos , Prednisona/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Camellia japonica is an attractive flowering woody plant with great ornamental and medicinal value in China. However, typical anthracnose lesions on the leaves are usually observed in summer in Zhejiang province. A number of 100 trees have been investigated with over 70% of leaf disease incidence. The symptom initially develops from the tip or edge of the leaf and dark green infected spots appear. The diseased spots expand and become yellow brown. The lesions are covered with abundant, small and black acervuli at the center with yellow edges. The diseased leaves become brittle, cracked, and finally fall off. Sixty leaves with typical anthracnose symptoms were sampled from gardens in Lin'an, Zhejiang province. The diseased tissues were cut into pieces and incubated in moist chambers at 25°C. The spore mass was collected using a sterile needle under dissection microscope and put on 2% malt extract agar (MEA). The cultures were incubated at 25°C in the dark for one week. Thirty single spore cultures were obtained and grown on 2% MEA at 25°C for morphological characterization. White aerial mycelia and black conidiomata with orange masses of conidia developed seven days later. Conidia are cylindrical in shape, 12-19 µm, mean lengths ranging from 15.5 ± 1.0 to 16.0 ± 1.2 µm. The morphological characteristics are consistent with those of Colletotrichum species. DNA was extracted from three selected isolates (HT-71, J-5, J-20) for sequencing. The partial regions of ribosomal internal transcribed spacers (ITS), calmodulin (CAL), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), actin gene (ACT), beta-tubulin (TUB2), Apn2-Mat1-2 intergenic spacer and partial mating type gene (ApMat), and glutamine synthetase (GS) were amplified as described by Liu et al. (2015). Sequences of the above seven loci for the selected isolates were obtained, and deposited in the GenBank database (MZ014901 to MZ014905, MZ514915 to MZ514922, MZ514925 to MZ514930, MZ497332 and MZ497333). BLAST results indicate they represent Colletotricum siamense. Multi-locus phylogenetic analysis including ex-type of C. siamense (ICMP18578=CBS130417) and related species was conducted using Maximum Likelihood method, and C. acutatum (CBS 112996) served as the outgroup. The three obtained isolates clustered with the ex-type isolate of C. siamense. Eight leaves on two Camellia plants were inoculated to confirm the pathogenicity in the field. The leaves were surface sprayed with 75% ethanol and dried with sterilized filter paper. The leaves were inoculated using the wound/drop inoculation method: an aliquot of 10 µL of spore suspension (1.0 × 106 conidia per mL) was dropped on the left side of a leaf after wounding once by pin-pricking with a sterilized needle. The sterile water was dropped on the right side of the same leaf in parallel as control. The initial symptoms were observed seven days later, all inoculated leaves developed lesions similar to those observed in the field, and no symptoms observed in the control. The fungus was successfully re-isolated only from lesions inoculated with spore suspension exhibiting morphological characteristics resembling those in C. siamense, and further confirmed with sequence data. To our knowledge, this represents the first report of anthracnose on C. japonica caused by C. siamense worldwide. Confirmation of this pathogen in the region will be helpful for the disease management on C. japonica, considering previous report of C. camelliae-japonicae on the same host. References Fu, M., et al. 2019. Persoonia. 42: 1. https://doi.org/10.3767/persoonia.2019.42.01 Guarnaccia, V., et al. 2017. Persoonia. 39: 32. https://doi.org/10.3767/persoonia.2017.39.02 Hou, L. W., et al. 2016. Mycosphere. 7: 1111. Doi 10.5943/mycosphere/si/2c/4 Liu, F., et al. 2015. Persoonia. 35: 63. http://dx.doi.org/10.3767/003158515X687597 Vieira, A. D. S., et al. 2019. Mol. Phylogenet. Evol. https://doi.org/10.1016/j.ympev.2019.106694.
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OBJECTIVE: To assess the risk factors associated with acute gastrointestinal failure (AGF) in critically ill patients with traumatic brain injury (TBI). METHODS: Prospective, observational study was conducted in NanFang Hospital, Southern Medical University. All patients admitted to the Department of Critical Care Medicine and Department of Neurosurgery from June 1, 2017 to December 1, 2018 with TBI were enrolled. RESULTS: Overall, 199 patients were enrolled. About 62 episodes (31%) of AGF were diagnosed. In the multivariate analysis, women, severe Glasgow Coma Scale (GCS) classification, frontal lobe injury, abnormal serum sodium, pulmonary infection, and intracranial infection are significantly associated with developing AGF, independent of other prognostic factors. CONCLUSION: The AGF occurs frequently in intensive care unit patients who are suffering from TBI. In critically ill patients with TBI, women, severe GCS classification, frontal lobe injury, abnormal serum sodium, pulmonary infection, and intracranial infection are independent risk factors for AGF.
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Lesões Encefálicas Traumáticas/complicações , Gastroenteropatias/etiologia , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estado Terminal , Feminino , Escala de Coma de Glasgow , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Fatores de Risco , Adulto JovemRESUMO
AIMS: The current study was conducted with the central objective of investigating the expression of microRNA-145 (miR-145) in renal vascular lesions (RVLs) in juvenile lupus nephritis (JLN) and its possible mechanism. METHODS: The clinical data of 49 JLN patients confirmed by renal biopsy were collected and followed by grouping according to the RVLs score after hematoxylin-eosin staining: mild, moderate, and severe groups. In situ hybridization was used to detect the expression of miR-145 in renal vessels which was then being compared among different RVLs groups. Up-LV-miR-145 and LV-miR-NC lentiviral vectors were constructed and transfected into human vascular smooth muscle cells (HVSMCs), respectively. After HVSMCs were treated with 10.0 µg/L platelet-derived growth factor (PDGF)-BB for 24 h, the proliferation, migration, and apoptosis of endothelial cells were detected by MTT, Transwell assay, and flow cytometry, respectively. Western blot was used to detect expression of alpha-smooth muscle actin (α-SM-actin) and osteopontin (OPN). RESULTS: The expression of miR-145 in renal vascular cells was statistically significant. The higher the inner membrane ratio, the lesser the miR-145 expression. After treatment with PDGF-BB, expression of miR-145 in HVSMCs decreased, proliferation and migration ability enhanced, apoptosis decreased, α-SM-actin decreased, and OPN increased. The proliferation and migration ability of HVSMCs in the LV-miR-145 group suppressed, apoptosis enhanced, α-SM-actin increased, and OPN decreased. CONCLUSIONS: Our study revealed that miR-145 expression decreased with the increase of vascular damage. miR-145 can inhibit proliferation, migration, and differentiation phenotypic transformation of HVSMCs induced by PDGF-BB. miR-145 may be involved in the pathogenesis of RVLs and may be a new target for treatment of RVLs in lupus nephritis.
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Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , MicroRNAs/farmacologia , Adolescente , Apoptose/efeitos dos fármacos , Becaplermina/farmacologia , Vasos Sanguíneos/citologia , Vasos Sanguíneos/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Criança , Pré-Escolar , Feminino , Humanos , Rim/irrigação sanguínea , Nefrite Lúpica/etiologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , TransfecçãoRESUMO
Insulin-like growth factor-1 (IGF-1) possesses the ability to attenuate intestinal damage and promote mucosal repair of colitis. ß-Arrestins, as the scaffolding proteins of G protein-coupled receptors or non-G protein-coupled receptors signaling, can be involved in IGF-1-mediated signaling pathways. However, the interaction of IGF-1 and ß-arrestin2 in the mucosal repair of experimental colitis remains unexplored. Ulcerative colitis was induced in ß-arrestin2 wild-type mice and ß-arrestin2 knockout littermates by using 3% dextran sulfate sodium for 5 days, followed by regular water consumption for 1, 2, 3, and 4 weeks to analyze the mucosal repair from experimental colitis. Disease activity index and histologic score analyses were performed. Apoptosis and proliferation were assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and Ki-67 staining, respectively. The expressions of ß-arrestin2, phospho (p)-IGF-1R, and p-extracellular signal-regulated kinase (ERK)1/2 were examined. Furthermore, ß-arrestin2 was overexpressed or altered in HCT116 cells by transfection before IGF-1 treatment in vitro. IGF-1 and ß-arrestin2 expression was up-regulated in the repairing phase of experimental colitis. Targeted deletion of ß-arrestin2 delayed the repair of colitis by inhibiting cell proliferation without affecting the levels of IGF-1 and p-IGF-1R. The ß-arrestin2/ERK signaling pathway was involved in IGF-1-mediated mucosal repair through promoting epithelial cell and goblet cell regeneration from experimental colitis. These results indicate that IGF-1 contributes to the mucosal repair by ß-arrestin2-mediated ERK signaling in experimental colitis.
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Apoptose/fisiologia , Arrestinas/metabolismo , Colite/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Sistema de Sinalização das MAP Quinases , Cicatrização/fisiologia , Animais , Linhagem Celular , Proliferação de Células/fisiologia , Colite/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Camundongos Endogâmicos C57BL , beta-ArrestinasRESUMO
Dapagliflozin (DAPA) confers significant protection against heart and kidney diseases. However, whether DAPA can alleviate type 4 cardiorenal syndrome (CRS-4)-related cardiomyopathy remains unclear. We tested the hypothesis that DAPA attenuates CRS-4-related myocardial damage through pyruvate kinase isozyme M2 (PKM2) induction and FUN14 domain containing 1 (FUNDC1)-related mitophagy. Cardiomyocyte-specific PKM2 knockout (PKM2CKO) and FUNDC1 knockout (FUNDC1CKO) mice were subjected to subtotal (5/6) nephrectomy to establish a CRS-4 model in vivo. DAPA enhanced PKM2 expression and improved myocardial function and structure in vivo, and this effect was abrogated by PKM2 knockdown. A significant improvement in mitochondrial function was observed in HL-1 cells exposed to sera from DAPA-treated mice, as featured by increased ATP production, decreased mtROS production, improved mitochondrial membrane potential, preserved mitochondrial complex activity, and reduced mitochondrial apoptosis. DAPA restored FUNDC1-dependent mitophagy through post-transcriptional dephosphorylation in a manner dependent on PKM2 whereas ablation of FUNDC1 abolished the defensive actions of DAPA on myocardium and mitochondria under CRS-4. Co-IP and molecular docking assays indicated that PKM2 directly interacted with protein phosphatase 1 (PP1) and FUNDC1, leading to PP1-mediated FUNDC1 dephosphorylation. These results suggest that DAPA attenuates CRS-4-related cardiomyopathy through activating the PKM2/PP1/FUNDC1-mitophagy pathway.
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OBJECTIVE: This study aims to elucidate the role of Kruppel-like factor (KLF5) and myxovirus resistance 1 (MX1) in the progression of renal fibrosis in lupus nephritis (LN). METHODS: First, the expression of KLF5 and MX1 was assessed in the peripheral blood of LN patients and healthy participants. Next, the pathological changes in renal tissues were evaluated and compared in BALB/c and MRL/lpr mice, by detecting the expression of fibrosis marker proteins (transforming growth factor-ß [TGF-ß] and CTGF) and α-SMA, the content of urine protein, and the levels of serum creatinine, blood urea nitrogen, and serum double-stranded DNA antibody. In TGF-ß1-induced HK-2 cells, the messenger RNA levels of KLF5 and MX1 were tested by qRT-PCR, and the protein expression of α-SMA, type I collagen (Col I), fibronectin (FN), and matrix metalloproteinase 9 (MMP9) was measured by western blot analysis. Moreover, the relationship between KLF5 and MX1 was predicted and verified. RESULTS: In renal tissues of MRL/lpr mice and the peripheral blood of LN patients, KLF5 and MX1 were highly expressed. Pearson analysis revealed that KLF5 was positively correlated with MX1. Furthermore, KLF5 bound to MX1 promoter and promoted its transcription level. MRL/lpr mice showed substantial renal injury, accompanied by increased expression of α-SMA, TGF-ß, CTGF, Col I, FN, and MMP9. Injection of sh-KLF5 or sh-MX1 alone in MRL/lpr mice reduced renal fibrosis in LN, while simultaneous injection of sh-KLF5 and ad-MX1 exacerbated renal injury and fibrosis. Furthermore, we obtained the same results in TGF-ß1-induced HK-2 cells. CONCLUSION: Knockdown of KLF5 alleviated renal fibrosis in LN through repressing the transcription of MX1.
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Nefrite Lúpica , Metaloproteinase 9 da Matriz , Animais , Camundongos , Fibrose , Nefrite Lúpica/genética , Metaloproteinase 9 da Matriz/genética , Camundongos Endogâmicos MRL lpr , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/genéticaRESUMO
OBJECTIVE: This study aims to construct an artificial intelligence (AI) model capable of effectively discriminating between abdominal Henoch-Schönlein purpura (AHSP) and acute appendicitis (AA) in pediatric patients. METHODS: A total of 6965 participants, comprising 2201 individuals with AHSP and 4764 patients with AA, were enrolled in the study. Additionally, 53 laboratory indicators were taken into consideration. Five distinct artificial intelligence (AI) models were developed employing machine learning algorithms, namely XGBoost, AdaBoost, Gaussian Naïve Bayes (GNB), MLPClassifier (MLP), and support vector machine (SVM). The performance of these prediction models was assessed through receiver operating characteristic (ROC) curve analysis, calibration curve assessment, and decision curve analysis (DCA). RESULTS: We identified 32 discriminative indicators (p < .05) between AHSP and AA. Five indicators, namely the lymphocyte ratio (LYMPH ratio), eosinophil ratio (EO ratio), eosinophil count (EO count), neutrophil ratio (NEUT ratio), and C-reactive protein (CRP), exhibited strong performance in distinguishing AHSP from AA (AUC ≥ 0.80). Among the various prediction models, the XGBoost model displayed superior performance evidenced by the highest AUC (XGBoost = 0.895, other models < 0.89), accuracy (XGBoost = 0.824, other models < 0.81), and Kappa value (XGBoost = 0.621, other models < 0.60) in the validation set. After optimization, the XGBoost model demonstrated remarkable diagnostic performance for AHSP and AA (AUC > 0.95). Both the calibration curve and decision curve analysis suggested the promising clinical utility and net benefits of the XGBoost model. CONCLUSION: The AI-based machine learning model exhibits high prediction accuracy and can differentiate AHSP and AA from a data-driven perspective.
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Apendicite , Vasculite por IgA , Humanos , Criança , Inteligência Artificial , Vasculite por IgA/diagnóstico , Apendicite/diagnóstico , Apendicite/etiologia , Teorema de Bayes , Aprendizado de Máquina , Proteínas Sanguíneas , Chaperonas MolecularesRESUMO
Triple-negative breast cancer (TNBC) is characterized by fast growth, high metastasis, high invasion, and a lack of therapeutic targets. Mitosis and metastasis of TNBC cells are two important biological behaviors in TNBC malignant progression. It is well known that the long noncoding RNA AFAP1-AS1 plays a crucial role in various tumors, but whether AFAP1-AS1 is involved in the mitosis of TNBC cells remains unknown. In this study, we investigated the functional mechanism of AFAP1-AS1 in targeting Polo-like Kinase 1 (PLK1) activation and participating in mitosis of TNBC cells. We detected the expression of AFAP1-AS1 in the TNBC patient cohort and primary cells by in situ hybridization (ISH), northern blot, fluorescent in situ hybridization (FISH) and cell nucleus/cytoplasm RNA fraction isolation. High AFAP1-AS1 expression was negatively correlated with overall survival (OS), disease-free survival (DFS), metastasis-free survival (MFS) and recurrence-free survival (RFS) in TNBC patients. We explored the function of AFAP1-AS1 by transwell, apoptosis, immunofluorescence (IF) and patient-derived xenograft (PDX) models in vitro and in vivo. We found that AFAP1-AS1 promoted TNBC primary cell survival by inhibiting mitotic catastrophe and increased TNBC primary cell growth, migration and invasion. Mechanistically, AFAP1-AS1 activated phosphorylation of the mitosis-associated kinase PLK1 protein. Elevated levels of AFAP1-AS1 in TNBC primary cells increased PLK1 pathway downstream gene expression, such as CDC25C, CDK1, BUB1 and TTK. More importantly, AFAP1-AS1 increased lung metastases in a mouse metastasis model. Taken together, AFAP1-AS1 functions as an oncogene that activates the PLK1 signaling pathway. AFAP1-AS1 could be used as a potential prognostic marker and therapeutic target for TNBC.
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Neoplasias de Mama Triplo Negativas , Animais , Camundongos , Humanos , Neoplasias de Mama Triplo Negativas/genética , Hibridização in Situ Fluorescente , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais , Quinase 1 Polo-LikeRESUMO
OBJECTIVE: To analyze the podocalyxin (PCX) expression in the kidney and the number of urinary podocytes in different pathological grades of Henoch-Schonlein purpura nephritis (HSPN), and to determine whether the number of urinary podocytes reflects the renal damage in HSPN. METHODS: Fifty-six children diagnosed with HSPN in our hospital were enrolled in the study and classified into 4 groups by renal pathology: grade II (IIa+IIb) (n=10), grade III (IIIa+IIIb) (n=21), grade IV (n=16), and grade V (n=9). Four kidney autopsy specimens without histomorphologic lesions and 8 urine samples from healthy children served as controls. With immunofluorescence assay, the PCX expression in 4 normal renal tissues and in the renal tissues of the 56 HSPN children was detected and quantitatively analyzed. Positive rate and the number of urinary podocytes were detected in the 8 healthy children and 56 HSPN children. RESULTS: In the renal tissues of the normal control group and grade II (IIa+IIb) HSPN group, the PCX expression was complete. The percentage of the PCX positive area out of the total glomerular area in the renal tissues of 2 groups had no significant difference (P>0.05). In the renal tissues of grade III (IIIa+IIIb), IV, and V HSPN groups, the PCX expression showed various degrees of loss, decreasing in turn from grade II (IIa+IIb), III (IIIa+IIIb), IV to V, with significant differences between each group (P<0.01). For HSPN with grade III (IIIa+IIIb) or higher, positive PCX expression was found in the urine, suggesting the presence of enough podocytes in the urine. The percentage of fluorescence positive area out of the total glomerular area of PCX in the renal tissues was negatively correlated with the total number of urinary podocytes (r=-0.637, P<0.01). CONCLUSION: Podocyte injury plays a certain role in the pathological progression of HSPN. The urinary detection of podocytes can reflect the degrees of pathological damage in HSPN.
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Vasculite por IgA/complicações , Nefrite/etiologia , Podócitos/metabolismo , Sialoglicoproteínas/metabolismo , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Vasculite por IgA/patologia , Rim/metabolismo , Rim/patologia , Masculino , Nefrite/metabolismo , Nefrite/patologiaRESUMO
This article investigates the consensus problem of multiagent systems (MASs) with time-varying delays subject to switching topologies. For the purpose of obtaining less conservative consensus conditions, first, a delay-product-type Lyapunov-Krasovskii functional (LKF) based on the auxiliary function-based integral inequality (AFBII) is constructed. Then, the generalized reciprocally convex matrix inequality (GRCMI) and a relaxed quadratic function negative-determination lemma are introduced to obtain the maximal-allowable upper bound of time-varying delays. Moreover, a proportional and derivative-like (PD-like) protocol is designed and the result is extended to the leader-following consensus of agents under Lipschitz nonlinear dynamics. Finally, two illustrative examples, including Chua's circuit, are given to demonstrate the advantages of the new consensus criteria.
RESUMO
OBJECTIVE: To analyze the clinical effects of fecal microbiota transplantation (FMT) on the treatment of acute intestinal pseudo obstruction (AIPO) secondary to intracerebral hemorrhage. METHODS: The clinical data of a patient with AIPO secondary to intracerebral hemorrhage who was admitted to Nanfang Hospital of Southern Medical University was analyzed. The flora compositon between donor and patient was compared, finding the changes of intestinal flora before and after FMT (day 0 and day 25). RESULTS: The main clinical findings in the patient were serious bloating, expansion of the intestinal canal and intra-abdominal hypertension. A week of conventional therapy was not effective, and the symptoms became progressively worse, affecting respiratory function.The result of fecal flora suggested the intestinal microbiota dybiosis, so FMT was attempted. After FMT, the patient's gastrointestinal symptoms were significantly relieved, and there were no further episodes within 25 days. The new result of fecal flora showed that the flora colonizing the intestine was dominated by Akkermansia and Bifidobacterium, with a significant decrease in potential pro-inflammatory and gas-producing bacteria and an increased gut microbiota diversity. The results trended to be partly consistent with the donor at 25 days after FMT: at the phylum level, the relative abundance of Bacterioidetes, Vereucomicrobia, Firmicutes and Actinobacteria were increased while Proteobacteria was decreased; at the class level, the relative abundance of Verrucomicrobiae, Bacterioidia, Actinobacteria, Coriobacteriia and Clostridia were increased and Gammaproteobacteria was decreased; at the order level, the relative abundance of Bacterioidales, Verrucomicrobiales, Clostridiale, Coriobacteriales were increased and Betaproteobacteriales, Enterobacteriales were decreased; at the family level, the relative abundance of Bifidobacteriaceae, Akkermansiaceae, Ruminococcaceae were increased and Enterobacteriaceae was decreased; at the genus level, the relative abundance of Akkermansia, Bifidobacterium were increased and Escherichia-Shigella, Klebsiella were decreased. At 1-year follow-up, the patient lived with self-care and scored 5 points in Glasgow outcome scale (GOS). CONCLUSIONS: FMT may provide clinical benefit in treated patients with AIPO secondary to intracerebral hemorrhage, probably by regulating the intestinal microflora, and re-establishing proper intestinal barrier, to maintain intestinal homeostasis.
Assuntos
Transplante de Microbiota Fecal , Pseudo-Obstrução Intestinal , Bactérias , Hemorragia Cerebral/complicações , Hemorragia Cerebral/terapia , Transplante de Microbiota Fecal/métodos , Fezes/microbiologia , Humanos , Resultado do TratamentoRESUMO
Long-term exposure to UVB can trigger acute inflammation of the skin and lead to skin photoaging. To scrutinize the anti-photoaging functions of peptides obtained from milk, the physicochemical including molecular weight and amino acid compositions were first analyzed. Totally 267 peptides were screened out and identified by PEAKS X software, and then evaluated through Peptide Ranker and BIOPEP-UMW. Six peptides with the highest antioxidant ability and relative abundance were selected. This study was then conducted in UVB-damaged human foreskin fibroblasts with proadministration of peptides. The results indicated that at concentrations of 0.08-0.10 mg/mL, milk-derived peptides could realize a damage prevention effect through inhibiting the generation of reactive oxygen species (ROS) and lipid peroxidation malondialdehyde (MDA). Also, these peptides were found to promote the photoaging related enzyme activities of superoxide dismutase (SOD) and catalase (CAT), while to block the production of matrix metalloproteinases-1. Through this study, we found that milk-derived peptide mixture is effective in preventing photoaging damage. Milk-derived peptides found in this study could serve as raw materials for future development of antioxidant functional foods.
Assuntos
Antioxidantes , Prepúcio do Pênis , Aminoácidos/metabolismo , Aminoácidos/farmacologia , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Catalase/metabolismo , Fibroblastos , Prepúcio do Pênis/metabolismo , Humanos , Masculino , Malondialdeído/metabolismo , Metaloproteinases da Matriz/metabolismo , Metaloproteinases da Matriz/farmacologia , Leite/metabolismo , Peptídeos/metabolismo , Peptídeos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Raios Ultravioleta/efeitos adversosRESUMO
Objective: To study and develop a predictive model for the differential diagnosis of acute appendicitis (AA) and Henoch-Schonlein purpura (HSP) in children and to validate the model internally and externally. Methods: The complete data of AA and HSP cases were retrospectively analyzed and divided into internal and external verification groups. SPSS software was used for single-factor analysis and screening of independent variables, and R software was used for the development and verification of the diagnostic model. Lasso regression analysis was used to screen predictors and Lasso-logistic regression model was constructed, and K-fold cross-validation was used for the internal verification. In addition, nonfever patients were selected for model development and validation in the same way. Receiver operating characteristic (ROC) curves and calibration curves were drawn, respectively, to evaluate the 2 models. Results: Internal development and validation of the model showed that fever, neutrophil ratio (NEUT%), albumin (ALB), direct bilirubin (DBIL), C-reactive protein (CRP), and K were predictive factors for the diagnosis of HSP. The model was presented in the form of a nomogram, and the area under ROC curve of the development group and verification group was 0.9462 (95% confidence interval [CI] = 0.9402-0.9522) and 0.8931 (95% CI = 0.8724-0.9139), respectively. In the model of patients without fever, NEUT%, platelets (PLT), ALB, DBIL, alkaline phosphatase (ALP), CRP, and K were predictive factors for the diagnosis of HSP, and the area under ROC curve of the development group and verification group was 0.9186 (95% CI = 0.908-0.9293) and 0.8591 (95% CI = 0.8284-0.8897), respectively. Conclusion: In this study, 2 diagnostic models were constructed for fever or not, both of which had good discrimination and calibration, and were helpful to distinguish AA and HSP in children.
Assuntos
Apendicite , Vasculite por IgA , Apendicite/diagnóstico , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Criança , Diagnóstico Diferencial , Humanos , Vasculite por IgA/diagnóstico , Estudos RetrospectivosRESUMO
OBJECTIVES: Cardiorenal syndrome type-3 (CRS-3) is an abrupt worsening of cardiac function secondary to acute kidney injury. Mitochondrial dysfunction is a key pathological mechanism of CRS-3, and empagliflozin can improve mitochondrial biology by promoting mitophagy. Here, we assessed the effects of empagliflozin on mitochondrial quality surveillance in a mouse model of CRS-3. METHODS: Cardiomyocyte-specific FUNDC1-knockout (FUNDC1CKO) mice were subjected to CRS-3 prior to assessment of mitochondrial homeostasis in the presence or absence of empagliflozin. RESULTS: CRS-3 model mice exhibited lower heart function, increased inflammatory responses and exacerbated myocardial oxidative stress than sham-operated controls; however, empagliflozin attenuated these alterations. Empagliflozin stabilized the mitochondrial membrane potential, suppressed mitochondrial reactive oxygen species production, increased mitochondrial respiratory complex activity and restored the oxygen consumption rate in cardiomyocytes from CRS-3 model mice. Empagliflozin also normalized the mitochondrial morphology, mitochondrial dynamics and mitochondrial permeability transition pore opening rate in cardiomyocytes. Cardiomyocyte-specific ablation of FUN14 domain-containing protein 1 (FUNDC1) in mice abolished the protective effects of empagliflozin on mitochondrial homeostasis and myocardial performance. Empagliflozin activated ß-catenin and promoted its nuclear retention, thus increasing FUNDC1-induced mitophagy in heart tissues; however, a ß-catenin inhibitor reversed these effects. CONCLUSIONS: In summary, empagliflozin activated Wnt/ß-catenin to stimulate FUNDC1-dependent mitochondrial quality surveillance, ultimately improving mitochondrial function and cardiac performance during CRS-3. Thus, empagliflozin could be considered for the clinical management of heart function following acute kidney injury.