Secondary metabolites from the Actinomadura sp. and their cytotoxic activity.

Actinomadura sp., which is usually found in muddy habitats, produces various secondary metabolites with biological activities. In this study, five new compounds named formosensin A (1), formosensin B (2), oxanthroquinone-3-O-α-d-mannose (8), oxanthromicin A (9), and oxanthromicin B (10) were isolated from the culture of Actinomadura sp. together with five known compounds (3-7). Their structures were elucidated by extensive spectroscopic methods including NMR and MS. In particular, the absolute configurations of compounds 1 and 2 were determined using computational methods. Moreover, compounds 1-2 and 8-10 were screened for cytotoxic activity using a panel of human tumor cell lines. Compound 9 induced significant cytotoxicity in five human tumor cell lines (HL-60, A-549, SMMC-7721, MCF-7, and SW480) with IC50 values of 8.7, 17.5, 15.0, 17.8, and 14.6 µM, respectively. These findings suggested that compound 9 could provide therapeutic benefits in the treatment of tumor-related diseases.

Olfactomedin-4 deletion exacerbates DSS-induced colitis through a matrix metalloproteinase-9-dependent mechanism.

Background and Aims: Olfactomedin-4 is a glycoprotein that is upregulated in inflamed gastrointestinal tissues. This study aimed to investigate the role and underlying mechanisms of olfactomedin-4 in ulcerative colitis. Methods: C57BL/6 mice and olfactomedin-4 knockout mice were fed dextran sulfate sodium in drinking water to establish a colitis model. An in vitro inflammation model was constructed in HCT116 and NCM460 cells stimulated with lipopolysaccharide. The expression of olfactomedin-4 was detected by Western blotting, immunohistochemistry staining, and qRT‒PCR. The differences in the severity of colitis between olfactomedin-4 knockout mice and wild-type mice were compared, and the underlying mechanisms were explored. Results: Olfactomedin-4 expression was significantly upregulated in colonic tissues of active ulcerative colitis patients and in cellular and mouse models of colitis. Compared with wild-type littermates, olfactomedin-4 knockout mice were more susceptible to dextran sulfate sodium-induced colitis and produced higher levels of proinflammatory cytokines and chemokines. In addition, olfactomedin-4 deficiency significantly promoted intestinal epithelial cell apoptosis and increased intestinal permeability, which was mediated by the p53 pathway. Moreover, olfactomedin-4 directly interacted with and negatively regulated matrix metalloproteinase-9. Inhibiting matrix metalloproteinase-9 significantly decreased colonic p53 expression and ameliorated experimental colitis in olfactomedin-4 knockout mice, while overexpression of matrix metalloproteinase-9 aggravated colitis. Further experiments showed that matrix metalloproteinase-9 regulated p53 through the Notch1 signaling pathway to promote ulcerative colitis progression. Conclusions: Olfactomedin-4 is significantly upregulated in ulcerative colitis and may protect against colitis by directly inhibiting matrix metalloproteinase-9 and further decreasing p53-mediated apoptosis via Notch1 signaling.

Polyethylene glycol combined with lactulose has better efficacy than polyethylene glycol alone in bowel preparation before colonoscopy: A meta-analysis.

BACKGROUND: The accuracy of diagnosis and the safety of treatment in colonoscopy depends largely on the quality of bowel cleansing. This study aimed to compare the efficacy and adverse reactions of Polyethylene Glycol (PEG) combined with lactulose with that of PEG alone in bowel preparation before colonoscopy. METHODS: The authors searched a number of databases including EMBASE, MEDLINE, Cochrane Library, and China Academic Journals Full-text Database. The authors screened according to literature inclusion and exclusion criteria, assessed the quality of the included literature, and extracted the data. The meta-analysis of included literature used RevMan 5.3 and Stata 14.0 software. RESULTS: A total of 18 studies, including 2274 patients, were enrolled. The meta-analysis showed that PEG combined with lactulose had a better efficacy (OR = 3.87, 95% CI 3.07‒4.87, p = 0.000, and I2 = 36.2% in the efficiency group; WMD = 0.86, 95% CI 0.69‒1.03, p = 0.032 and I2 = 0% in the BBPS score group) in bowel preparation for patients with or without constipation. Moreover, PEG combined with lactulose had fewer adverse reactions, including abdominal pain (OR = 1.42, 95% CI 0.94‒2.14, p = 0.094), nausea (OR = 1.60, 95% CI 1.13‒2.28, p = 0.009) and vomiting (OR = 1.77, 95% CI 1.14‒2.74, p = 0.011), than PEG alone. No significant reduction in the incidence of abdominal distention was observed. CONCLUSION: PEG combined with lactulose may be a better choice for bowel preparation before colonoscopy compared with PEG alone.

Polyethylene glycol combined with lactulose has better efficacy than polyethylene glycol alone in bowel preparation before colonoscopy: A meta-analysis

Abstract Background: The accuracy of diagnosis and the safety of treatment in colonoscopy depends largely on the quality of bowel cleansing. This study aimed to compare the efficacy and adverse reactions of Polyethylene Glycol (PEG) combined with lactulose with that of PEG alone in bowel preparation before colonoscopy. Methods: The authors searched a number of databases including EMBASE, MEDLINE, Cochrane Library, and China Academic Journals Full-text Database. The authors screened according to literature inclusion and exclusion criteria, assessed the quality of the included literature, and extracted the data. The meta-analysis of included literature used RevMan 5.3 and Stata 14.0 software. Results: A total of 18 studies, including 2274 patients, were enrolled. The meta-analysis showed that PEG combined with lactulose had a better efficacy (OR = 3.87, 95% CI 3.07‒4.87, p = 0.000, and I2 = 36.2% in the efficiency group; WMD = 0.86, 95% CI 0.69‒1.03, p = 0.032 and I2 = 0% in the BBPS score group) in bowel preparation for patients with or without constipation. Moreover, PEG combined with lactulose had fewer adverse reactions, including abdominal pain (OR = 1.42, 95% CI 0.94‒2.14, p = 0.094), nausea (OR = 1.60, 95% CI 1.13‒2.28, p = 0.009) and vomiting (OR = 1.77, 95% CI 1.14‒2.74, p = 0.011), than PEG alone. No significant reduction in the incidence of abdominal distention was observed. Conclusion: PEG combined with lactulose may be a better choice for bowel preparation before colonoscopy compared with PEG alone.

Iron Status and NAFLD among European Populations: A Bidirectional Two-Sample Mendelian Randomization Study.

Background and aim: Previous observational studies have suggested a paradoxical relationship between iron status and the risk of non-alcoholic fatty liver disease (NAFLD). Observed associations in these epidemiological studies fail to show sequential temporality and suffer from problems of confounding. Therefore, we performed a bidirectional two-sample Mendelian randomization (MR) to evaluate the relationship between serum iron status and NAFLD. Methods: The inverse weighted method (IVW) meta-analysis with the fixed-effect model was the main method to estimate the relationship between iron status, including serum ferritin, iron, transferrin saturation (TSAT) and total iron-binding capacity (TIBC), and NAFLD. Weighted median, penalized weighted median, and MR Robust Adjusted Profile Score (MR RAPS) methods were used as additional analyses. Sensitivity analyses were performed with Cochran's Q test, MR-Egger regression, Steiger filtering, and the MR PRESSO test. Results: Iron status, including serum ferritin, iron, and TSAT, was associated with an increased risk of NAFLD (odds ratio (OR) (95% confidence interval (CI)): 1.25 (1.06, 1.48); 1.24 (1.05, 1.46), 1.16 (1.02, 1.31), respectively). In contrast, minimal effects of NAFLD on serum ferritin, iron, TSAT, and TIBC were observed (OR (95% CI): 1.01 (1.00, 1.02), 1.01 (1.00, 1.02), 1.03 (1.01, 1.05), 1.03 (1.01, 1.05), respectively). Conclusions: Our findings corroborated the causal associations between serum ferritin, iron, TSAT, and NAFLD, which might suggest the potential benefits of iron-related therapy. In addition, NAFLD might, in turn, slightly affect iron homeostasis indicated as serum ferritin, iron, TSAT, and TIBC, but this needs to be further confirmed.

MPST deficiency promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via AKT.

BACKGROUND & AIMS: Excessive inflammatory responses and oxidative stress are considered the main characteristics of inflammatory bowel disease (IBD). Endogenous hydrogen sulfide (H2S) has been reported to show anti-inflammatory activity in IBD. The main aim of this study was to explore the role of 3-mercaptopyruvate sulfurtransferase (MPST), a key enzyme that regulates endogenous H2S biosynthesis, in IBD. METHODS: Colonic MPST expression was evaluated in mice and patients with IBD. Various approaches were used to explore the concrete mechanism underlying MPST regulation of the progression of colitis through in vivo and in vitro models. RESULTS: MPST expression was markedly decreased in colonic samples from patients with ulcerative colitis (UC) or Crohn's disease (CD) and from mice treated with DSS. MPST deficiency significantly aggravated the symptoms of murine colitis, exacerbated inflammatory responses and apoptosis, and inhibited epithelium stem cell-derived organoid formation in an H2S-independent manner. Consistently, when HT29 cells were treated with TNF-α, inhibition of MPST significantly increased the expression of proinflammatory cytokines, the amount of ROS and the prevalence of apoptosis, whereas overexpression of MPST markedly improved these effects. RNA-seq analysis showed that MPST might play a role in regulating apoptosis through AKT signaling. Mechanistically, MPST directly interacted with AKT and reduced the phosphorylation of AKT. Additionally, MPST expression was positively correlated with AKT expression in human IBD samples. In addition, overexpression of AKT rescued IEC apoptosis caused by MPST deficiency, while inhibition of AKT significantly aggravated it. CONCLUSIONS: MPST protects the intestines from inflammation most likely by regulating the AKT/apoptosis axis in IECs. Our results may provide a novel therapeutic strategy for the treatment of colitis.

Remnant Cholesterol Predicts Long-term Mortality of Patients With Metabolic Dysfunction-associated Fatty Liver Disease.

CONTEXT: Elevated serum remnant cholesterol independently predicts risks of cardiovascular diseases. However, the association between remnant cholesterol and metabolic dysfunction-associated fatty liver disease (MAFLD) remains unclear. OBJECTIVE: This study aimed to explore the association of remnant cholesterol with MAFLD and its long-term mortality. METHODS: We extracted data from the NHANES III, 1988 to1994 and the linked mortality data until December 31, 2015. The association between remnant cholesterol and MAFLD was analyzed by multivariable logistic regression. Cox proportional hazards regression was performed to assess whether elevated remnant cholesterol increased all-cause and cause-specific mortalities in MAFLD patients. RESULTS: At baseline, 28.6% (1474/5156) of participants had MAFLD. In multivariable logistic regression, the fourth quartile of remnant cholesterol was associated with an increased risk of MAFLD compared with the first quartile (odds ratio [OR]: 1.714; 95% CI, 1.586-1.971; P < .001). In participants with normal levels of triglycerides, low-density lipoprotein and high-density lipoprotein cholesterol, the relationship between remnant cholesterol and MAFLD risk remained significant (OR: 1.346; 95% CI, 1.248-1.761; P < .001). During a median follow-up of 307 months, MAFLD patients with serum remnant cholesterol in the fourth quartile were associated with a higher risk of all-cause mortality (hazard ratio [HR]: 2.183; 95% CI, 1.825-2.407; P < .001), as well as a higher risk of cardiovascular mortality (HR: 2.346; 95% CI, 2.046-2.885; P < .001) and cancer-related mortality (HR: 2.366; 95% CI, 1.864-2.932; P < .001) compared with MAFLD patients in the first quartile. CONCLUSION: Remnant cholesterol was independently associated with the risk of MAFLD and predicted all-cause, cardiovascular, and cancer-related mortalities in MAFLD patients.

The DEAD-box helicase DDX3x ameliorates non-alcoholic fatty liver disease via mTORC1 signalling pathway.

BACKGROUND & AIMS: The DEAD (Asp-Glu-Ala-Asp)-box helicase family member DDX3x has been proven to involve in hepatic lipid disruption during HCV infection. However, the role of DDX3x in non-alcoholic fatty liver disease (NAFLD), in which lipid homeostasis is severely disrupted, remains unclear. Here, we aimed to illustrate the potential role of DDX3x in NAFLD. METHODS: DDX3x protein levels were evaluated in NAFLD patients and NAFLD models via immunohistochemistry or western blotting. In vivo ubiquitin assay was performed to identify the ubiquitination levels of DDX3x in the progression of steatosis. DDX3x protein levels in mice livers were manipulated by adeno-associated virus-containing DDX3x short hairpin RNA or DDX3x overexpression plasmid. Hepatic or serum triglyceride and total cholesterol were evaluated and hepatic steatosis was confirmed by haematoxylin and eosin staining and oil red o staining. Western blotting was performed to identify the underlying mechanisms of DDX3x involving in the progression of NAFLD. RESULTS: DDX3x protein levels were significantly decreased in NAFLD patients and NAFLD models. DDX3x protein might be degraded via ubiquitin-proteasome system in the progression of steatosis. Knockdown of hepatic DDX3x exacerbated HFD-induced hepatic steatosis in mice, while overexpression of hepatic DDX3x alleviated HFD-induced hepatic steatosis in mice. Further explorative experiments revealed that knockdown of DDX3x could lead to the overactivation of mTORC1 signalling pathway which exacerbates NAFLD. CONCLUSIONS: DDX3x involved in the progression of NAFLD via affecting the mTORC1 signalling pathway. DDX3x might be a potential target for NAFLD treatment.

3-Mercaptopyruvate sulfurtransferase represses tumour progression and predicts prognosis in hepatocellular carcinoma.

BACKGROUND AND: AIMS: The prognosis of hepatocellular carcinoma (HCC) remains dismal, and its molecular pathogenesis has not been completely defined. The enzyme 3-mercaptopyruvate sulfurtransferase (MPST) regulates endogenous hydrogen sulfide (H2 S) biosynthesis. However, the role of MPST in HCC has never been intensively investigated. METHODS: MPST protein expression was analysed in HCC tumour tissues and matched adjacent tissues. The effect of MPST on HCC progression was studied in vitro and in vivo. RESULTS: The mRNA and protein expression of MPST was significantly downregulated in HCC samples compared with their paired nontumour counterparts. A low MPST expression was associated with larger tumour size and a worse overall survival. Overexpression of MPST in HCC cells inhibited cell proliferation and induced apoptosis. MPST overexpression also significantly suppressed the growth of tumour xenografts in nude mice, whereas silencing MPST by intratumour delivery of siRNA substantially promoted tumour growth. Moreover, diethylnitrosamine-induced mouse HCC was aggravated by MPST gene knockout. Mechanistically, MPST suppressed the cell cycle associated with H2 S production and inhibition of the AKT/FOXO3a/Rb signalling pathway in HCC development. In addition, MPST expression negatively correlated with that of pRb in HCC specimens and the combination of these two parameters is a more powerful predictor of poor prognosis. CONCLUSIONS: MPST may function as a tumour suppressor gene that plays an essential role in HCC proliferation and liver tumorigenesis. It is a candidate predictor of clinical outcome in patients with HCC and may be used as a biomarker and intervention target for new therapeutic strategies.

Association between circulating cystatin C and hyperuricemia: a cross-sectional study.

INTRODUCTION/OBJECTIVES: Circulating cystatin C has reportedly been related to cardiovascular disease, diabetes, and metabolic syndrome, apart from its traditional role in estimating the glomerular filtration rate. However, whether circulating cystatin C is related to hyperuricemia remains unclear. METHOD: We included 2406 men and 1273 women who attended their annual health checkups in this study. Anthropometric and biochemical parameters were measured. Hyperuricemia was diagnosed as fasting serum uric acid > 420 µmol/L in men and women. RESULTS: A total of 695 (18.9%) participants were diagnosed with hyperuricemia. Hyperuricemic patients had significantly higher serum cystatin C levels than healthy controls (0.91 (0.83-1.02) versus 0.82 (0.72-0.92) mg/L, P < 0.001). Serum cystatin C levels were positively related to the prevalence of hyperuricemia, which was 5.18%, 14.76%, 22.66%, and 31.24% in participants with serum cystatin C levels in the first, second, third, and fourth quartiles, respectively (P < 0.001 for trend). In stepwise multivariate logistic regression analysis, participants with serum cystatin C in the fourth quartile had a more than twofold increased risk of hyperuricemia (OR 2.262, 95% CI 1.495-3.422; P < 0.001) compared with those with serum cystatin C in the first quartile. In subgroup analyses, the fourth quartile of cystatin C was related to increased risks of hyperuricemia in both non-obese and obese participants (OR 4.405, 95% CI 1.472-13.184, P = 0.008; OR 1.891, 95% CI 1.228-2.911, P = 0.004, respectively), in non-metabolic syndrome participants (OR 3.043, 95% CI 1.692-5.473; P < 0.001) but not in metabolic syndrome participants (OR 1.689, 95% CI 0.937-3.045; P = 0.081), and in non-non-alcoholic fatty liver disease (non-NAFLD) (OR 2.128, 95% CI 1.424-3.180; P < 0.001, respectively) and young and middle-aged participants (OR 2.235, 95% CI 1.492-3.348, P < 0.001) but not in NAFLD and elderly participants. CONCLUSIONS: This study revealed a positive association of circulating cystatin C with hyperuricemia. Key Points • Serum cystatin C is associated with an increased risk of hyperuricemia. • Serum cystatin C is a useful biomarker in distinguishing patients at high risk of having hyperuricemia.

Prevalence and risk factors of hyperuricaemia in non-obese Chinese: a single-centre cross-sectional study.

OBJECTIVES: Hyperuricaemia is closely related to metabolic diseases and is receiving increasing attention from all over the world. This study aimed to investigate the prevalence and factors associated with hyperuricaemia in non-obese Chinese population. DESIGN: Retrospective cross-sectional study. SETTING: A large general hospital that can provide health check-ups in Hangzhou, China. PARTICIPANTS: A total of 5731 apparently healthy Chinese adults (2349 men and 3382 women) who took their health check-ups during the year of 2019. EXCLUSION CRITERIA: (1) those with body mass index ≥24 kg/m2; (2) those with incomplete anthropometric and biochemical data; (3) those with a history of malignancy and (4) those under urate-lowering treatment. PRIMARY AND SECONDARY OUTCOME MEASURES: The prevalence and factors associated with hyperuricaemia in non-obese Chinese adults. RESULTS: Of the 5731 non-obese subjects enrolled, 538 (9.4%) were identified as having hyperuricaemia, specifically 16.3% in men and 4.6% in women. The prevalence of hyperuricaemia markedly increased in women aged above 50 years. The prevalence of hyperuricaemia was significantly higher in metabolically unhealthy participants with normal weight than in metabolically healthy participants with normal weight. Participants with hyperuricaemia showed a higher prevalence of metabolic syndrome and fatty liver disease than participants with normouraemia. Age, waist circumference, estimated glomerular filtration rate, blood urea nitrogen, excessive drinking and fatty liver were associated with hyperuricaemia in both genders. CONCLUSION: The prevalence of hyperuricaemia was 9.4% in non-obese Chinese adults. Non-obese participants with hyperuricaemia also showed multiple metabolic disorders. We suggest that clinicians pay attention to serum uric acid level in non-obese patients.

Vitamin D receptor inhibits EMT via regulation of the epithelial mitochondrial function in intestinal fibrosis.

We previously showed that the vitamin D receptor (VDR) plays a crucial role in acute inflammatory bowel disease and that intestinal fibrosis is a common complication of Crohn's disease (CD). Epithelial-mesenchymal transition (EMT) is an important hallmark of fibrogenesis through which epithelial cells lose their epithelial phenotype and transform into mesenchymal cells. It is known that the VDR plays an essential role in epithelial integrity and mitochondrial function, but its role in intestinal fibrosis remains unknown. Here, we investigated whether the VDR is involved in epithelial mitochondrial dysfunction that results in EMT in intestinal fibrosis. Using human CD samples, intestine-specific VDR-KO mice, and fibroblast cellular models, we showed that the expression of the VDR was significantly lower in intestinal stenotic areas than in nonstenotic areas in patients with chronic CD. Genetic deletion of the VDR in the intestinal epithelium exacerbated intestinal fibrosis in mice administered with dextran sulfate sodium or 2,4,6-trinitrobenzene sulfonic acid, two experimental colitis inducers. In addition, we found that vitamin D dietary intervention regulated intestinal fibrosis by modulating the intestinal expression of the VDR. Mechanistically, knocking down the VDR in both CCD-18Co cells and human primary colonic fibroblasts promoted fibroblast activation, whereas VDR overexpression or VDR agonist administration inhibited fibroblast activation. Further analysis illustrated that the VDR inhibited EMT in the HT29 cell model and that mitochondrial dysfunction mediated epithelial integrity and barrier function in VDR-deficient epithelial cells. Together, our data for the first time demonstrate that VDR activation alleviates intestinal fibrosis by inhibiting fibroblast activation and epithelial mitochondria-mediated EMT.

Leukocyte cell-derived chemotaxin 2 promotes the development of nonalcoholic fatty liver disease through STAT-1 pathway in mice.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), whose pathogenesis remains unelucidated, has become an increasingly prevalent disease globally requiring novel treatment strategies. This study aims to explore the role of leukocyte cell-derived chemotaxin 2 (LECT2), one of the known hepatokines, in the development of NAFLD. METHODS: The serum LECT2 level was evaluated in patients with NAFLD and male C57BL/6 mice fed a high-fat diet (HFD) for 8 weeks. Tail intravenous injection of adeno-associated virus that contained Lect2 short hairpin RNA or Lect2 overexpression plasmid was administered to mice to inhibit or increase hepatic Lect2 expression. Hepatic steatosis was evaluated by histological staining with haematoxylin and eosin and Oil Red O, and also by quantitative hepatic triglyceride measurements. RNA-seq was performed to discover the specific targets of LECT2 on NAFLD. RESULTS: Serum and hepatic LECT2 levels were elevated in NAFLD patients and HFD-fed mice. Inhibition of hepatic Lect2 expression alleviated HFD-induced hepatic steatosis and inflammation, whereas hepatic overexpression of Lect2 aggravated HFD-induced hepatic steatosis and inflammation. RNA-seq and bioinformatical analysis suggested that the signal transducers and activators of transcription-1 (STAT-1) pathway might play an indispensable role in the interaction between LECT2 and NAFLD. A STAT-1 inhibitor could reverse the accumulation of hepatic lipids caused by Lect2 overexpression. CONCLUSION: LECT2 expression is significantly elevated in NAFLD. LECT2 induces the occurrence and development of NAFLD through the STAT-1 pathway. LECT2 may be a potential therapeutic target for NAFLD.

GCSF deficiency attenuates nonalcoholic fatty liver disease through regulating GCSFR-SOCS3-JAK-STAT3 pathway and immune cells infiltration.

Granulocyte colony stimulating factor (GCSF) is a cytokine with immunomodulation effects. However, little is known about its role in metabolic diseases. In the current study, we aimed to explore the role of GCSF in nonalcoholic fatty liver disease (NAFLD). Male GCSF-/- mice were used to investigate the function of GCSF in vivo after high-fat diet (HFD). Primary hepatocytes were used for evaluating the function of GCSF in vitro. Liver immune cells were isolated and analyzed by flow cytometry. Our results showed that GCSF administration significantly increased serum triglyceride (TG) levels in patients. Circulating GCSF was markedly elevated in HFD-fed mice. GCSF-/- mice exhibited alleviated HFD-induced obesity, insulin resistance, and hepatic steatosis. Extra administration of GCSF significantly aggravated palmitic acid (PA)-induced lipid accumulation in primary hepatocytes. Mechanically, GCSF could bind to granulocyte colony stimulating factor receptor (GCSFR) and regulate suppressors of cytokine signaling 3, Janus kinase, signal transducer and activator of transcription 3 (SOCS3-JAK-STAT3) pathway. GCSF also enhanced hepatic neutrophils and macrophages infiltration, thereby modulating NAFLD. These findings suggest that GCSF plays an important regulatory role in NAFLD and may be a potential therapeutic target for NAFLD.NEW & NOTEWORTHY We found GCSF was involved in lipid metabolism and NAFLD development. GCSF administration increased serum triglyceride levels in patients. GCSF deficiency alleviated HFD-induced insulin resistance and hepatic steatosis in mice. GCSF could directly act on hepatocytes through GCSFR-SOCS3-JAK-STAT3 pathway, and regulate the infiltration of immune cells into the liver to indirectly modulate NAFLD. Our finding indicates that GCSF may provide new strategies for the treatment of NAFLD.

Tufting Enteropathy: A Review of Clinical and Histological Presentation, Etiology, Management, and Outcome.

Congenital tufting enteropathy (CTE), also named intestinal epithelial dysplasia, is a rare, autosomal recessive enteropathy with persistent and life-threatening intractable diarrhea early in life. Intractable diarrhea is present independent of breast or formula feeding. Most CTE patients require total parenteral nutrition (TPN), and in severe cases, small bowel transplantation is needed. In the last decade, we have seen remarkable progress in certain aspects, such as the pathogenesis and diagnostic methods of the disease. Rapidly developing molecular analysis techniques have improved the diagnostic methods for CTE and reduced invasive and expensive procedures. Mutations in the gene encoding human epithelial cell adhesion molecule (EpCAM) were identified in the typical form of CTE, which usually exhibits isolated refractory diarrhea. Moreover, the syndromic form of CTE features anal and choanal atresias as well as ophthalmologic signs, which are associated with mutations in the gene encoding Serine Peptidase Inhibitor Kunitz Type 2 (SPINT2). This article reviews CTE disease based on its clinical and histological presentation, etiology and pathogenesis, and management and outcome.

Deficiency in the anti-apoptotic protein DJ-1 promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via p53.

Parkinson disease autosomal recessive, early onset 7 (PARK7 or DJ-1) is involved in multiple physiological processes and exerts anti-apoptotic effects on multiple cell types. Increased intestinal epithelial cell (IEC) apoptosis and excessive activation of the p53 signaling pathway is a hallmark of inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD). However, whether DJ-1 plays a role in colitis is unclear. To determine whether DJ-1 deficiency is involved in the p53 activation that results in IEC apoptosis in colitis, here we performed immunostaining, real-time PCR, and immunoblotting analyses to assess DJ-1 expression in human UC and CD samples. In the inflamed intestines of individuals with IBD, DJ-1 expression was decreased and negatively correlated with p53 expression. DJ-1 deficiency significantly aggravated colitis, evidenced by increased intestinal inflammation and exacerbated IEC apoptosis. Moreover, DJ-1 directly interacted with p53, and reduced DJ-1 levels increased p53 levels both in vivo and in vitro and were associated with decreased p53 degradation via the lysosomal pathway. We also induced experimental colitis with dextran sulfate sodium in mice and found that compared with DJ-1-/- mice, DJ-1-/-p53-/- mice have reduced apoptosis and inflammation and increased epithelial barrier integrity. Furthermore, pharmacological inhibition of p53 relieved inflammation in the DJ-1-/- mice. In conclusion, reduced DJ-1 expression promotes inflammation and IEC apoptosis via p53 in colitis, suggesting that the modulation of DJ-1 expression may be a potential therapeutic strategy for managing colitis.

Convolutional neural network for the diagnosis of early gastric cancer based on magnifying narrow band imaging.

BACKGROUND: Magnifying endoscopy with narrow band imaging (M-NBI) has been applied to examine early gastric cancer by observing microvascular architecture and microsurface structure of gastric mucosal lesions. However, the diagnostic efficacy of non-experts in differentiating early gastric cancer from non-cancerous lesions by M-NBI remained far from satisfactory. In this study, we developed a new system based on convolutional neural network (CNN) to analyze gastric mucosal lesions observed by M-NBI. METHODS: A total of 386 images of non-cancerous lesions and 1702 images of early gastric cancer were collected to train and establish a CNN model (Inception-v3). Then a total of 341 endoscopic images (171 non-cancerous lesions and 170 early gastric cancer) were selected to evaluate the diagnostic capabilities of CNN and endoscopists. Primary outcome measures included diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: The sensitivity, specificity, and accuracy of CNN system in the diagnosis of early gastric cancer were 91.18%, 90.64%, and 90.91%, respectively. No significant difference was spotted in the specificity and accuracy of diagnosis between CNN and experts. However, the diagnostic sensitivity of CNN was significantly higher than that of the experts. Furthermore, the diagnostic sensitivity, specificity and accuracy of CNN were significantly higher than those of the non-experts. CONCLUSIONS: Our CNN system showed high accuracy, sensitivity and specificity in the diagnosis of early gastric cancer. It is anticipated that more progress will be made in optimization of the CNN diagnostic system and further development of artificial intelligence in the medical field.

Preparation of Immunotherapy Liposomal-Loaded Thermal-Responsive Hydrogel Carrier in the Local Treatment of Breast Cancer.

To reduce the side effects of immune drugs and the sustainable release of immune drugs on local parts, we have designed an injectable thermal-sensitive hydrogel containing an imiquimod-loaded liposome system. In the extracellular environment of tumor tissues (pH 6.4), 50% of the drug was released from the carrier, which could be a result of the morphological changes of the liposomal microstructure in the acidic environment. According to the results in animals, the drug-containing liposomes combined with hydrogel can be effectively applied in breast cancer therapy to delay the growth of tumors as well as to dramatically reduce the death rate of mice.