Hepatocyte leukotriene B4 receptor 1 promotes NAFLD development in obesity.

BACKGROUND AND AIMS: NAFLD is the most prevalent chronic liver disease worldwide and has emerged as a serious public health issue with no approved treatment. The development of NAFLD is strongly associated with hepatic lipid content, and patients with NAFLD have significantly higher rates of hepatic de novo lipogenesis (DNL) than lean individuals. Leukotriene B4 (LTB4), a metabolite of arachidonic acid, is dramatically increased in obesity and plays important role in proinflammatory cytokine production and insulin resistance. But the role of liver LTB4/LTB4 receptor 1 (Ltb4r1) in lipid metabolism is unclear. APPROACH AND RESULTS: Hepatocyte-specific knockout (HKO) of Ltb4r1 improved hepatic steatosis and systemic insulin resistance in both diet-induced and genetically induced obese mice. The mRNA level of key enzymes involved in DNL and fatty acid esterification decreased in Ltb4r1 HKO obese mice. LTB4/Ltb4r1 directly promoted lipogenesis in HepG2 cells and primary hepatocytes. Mechanically, LTB4/Ltb4r1 promoted lipogenesis by activating the cAMP-protein kinase A (PKA)-inositol-requiring enzyme 1α (IRE1α)-spliced X-box-binding protein 1 (XBP1s) axis in hepatocytes, which in turn promoted the expression of lipogenesis genes regulated by XBP1s. In addition, Ltb4r1 suppression through the Ltb4r1 inhibitor or lentivirus-short hairpin RNA delivery alleviated the fatty liver phenotype in obese mice. CONCLUSIONS: LTB4/Ltb4r1 promotes hepatocyte lipogenesis directly by activating PKA-IRE1α-XBP1s to promote lipogenic gene expression. Inhibition of hepatocyte Ltb4r1 improved hepatic steatosis and insulin resistance. Ltb4r1 is a potential therapeutic target for NAFLD.

The relationship between healthy lifestyles and cognitive function in Chinese older adults: the mediating effect of depressive symptoms.

BACKGROUND: Previous studies have proven the positive relationship between healthy lifestyles and cognitive function in older adults. However, the specific impacts and mechanisms require further investigation. Therefore, this study aimed to investigate whether healthy lifestyles and cognitive function were associated with Chinese older adults and whether depressive symptoms mediated their association. METHODS: 8272 valid samples were included using the latest data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Pearson's test was applied to investigate the relationship between the key variables. Regression models were employed to examine the mediating effects of healthy lifestyles, using Sobel's test and the bootstrap method to confirm path effects. RESULTS: There was a significant correlation between healthy lifestyles, depressive symptoms, and cognitive function (p < 0.01). Healthy lifestyles directly impact cognitive function (ß = 0.162, p < 0.01). Healthy lifestyles had a significant effect on depressive symptoms (ß=-0.301, p < 0.01), while depressive symptoms have a significant impact on cognitive function (ß=-0.108, p < 0.01). Depressive symptoms partially mediated the effect of healthy lifestyles on cognitive function (ß = 0.032, p < 0.01). The Sobel and bootstrap tests confirmed the robustness of the regression analysis results. CONCLUSION: Depressive symptoms mediate the relationship between healthy lifestyles and cognitive function. Our findings suggest that prevention strategies for cognitive impairment in older adults should focus on healthy lifestyles and mental health.

Triglyceride is independently correlated with insulin resistance and islet beta cell function: a study in population with different glucose and lipid metabolism states.

BACKGROUND: Previous studies on the effects of lipotoxicity and oxidative stress on islet beta cell function mainly focused on patients with diabetes, whereas studies on normal glucose tolerance (NGT) are few. The aim of this study was to explore the relationships among triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), oxidative stress indicators, insulin resistance, and beta cell function in populations with different glucose and lipid metabolism states. METHODS: A total of 517 individuals were recruited from a rural community in Beijing, China. Glucose metabolism status was defined according to the results of a 75-g oral glucose tolerance test (OGTT). Dyslipidemia was defined as abnormal TG, HDL-c, or LDL-c levels. The population was divided into four groups: individuals with normal glucose and lipid levels (group A, n = 62); those with dyslipidemia alone (group B, n = 82); those with dysglycemia alone (group C, n = 121); and those with dysglycemia and dyslipidemia (group D, n = 247). Oxidative stress indicators, including superoxide dismutase (SOD), glutathione reductase (GR) and 8-hydroxydeoxyguanosine (8-OHdG), were measured. Homeostasis model assessment of insulin resistance (HOMA-IR) and glucose disposition index (DI30, DI120) were calculated to assess insulin resistance and islet beta cell function, respectively. Stratified multiple linear regression analysis was used to explore relationships between TG, HDL-c, LDL-c, oxidative stress indicators, and insulin resistance (natural log transformation of HOMA-IR, LnHOMA-IR) and beta cell function (natural log transformation of DI30, Ln DI30). RESULTS: Compared with the control group, populations with dyslipidemia and/or dysglycemia showed significantly increased insulin resistance. Dyslipidemia aggravated insulin resistance and beta cell dysfunction in individuals with dysglycemia. Stratified regression analysis showed that TG positively correlated with LnHOMA-IR in individuals with normal glucose levels (beta = 0.321, 0.327, P = 0.011, 0.003 in groups A and B, respectively) and negatively correlated with LnDI30 in participants with dyslipidemia (beta = - 0.225, - 0.122, P = 0.035, 0.048 in groups B and D, respectively). Reduced serum SOD levels in individuals with dysglycemia plus dyslipidemia were observed, and a negative association between TG and SOD levels was found (r = - 0.461, P < 0.001). CONCLUSION: TG correlated with both insulin resistance and beta cell function in individuals with dyslipidemia alone. SOD negatively correlated with TG, indicating a close relationship between oxidative stress and glucose-lipid metabolism. Due to the adverse effect of hypertriglyceridemia on insulin sensitivity and islet beta cell function, more attention should be paid to the detection and management of hypertriglyceridemia.

Corrigendum to "Dietary Magnesium Intake and Leukocyte Telomere Attrition in Adults: The Regulatory Role of Serum Tumor Necrosis Factor α".

[This corrects the article DOI: 10.1155/2020/7610436.].

Dietary Magnesium Intake and Leukocyte Telomere Attrition in Adults: The Regulatory Role of Serum Tumor Necrosis Factor α.

OBJECTIVES: In this study, we assessed the effects of dietary magnesium on leukocyte telomere length (LTL). DESIGNS: The current cross-sectional analysis was based on data collected within a type 2 diabetes project. Settings. Dietary magnesium intake is associated with peripheral blood leukocyte telomere length (LTL). However, few epidemiological studies have evaluated the effects of magnesium on LTL in the clinical setting. Participants. This cross-sectional analysis included 467 participants (34.8% men). Measurements. Serum blood lipid profile, HbA1c, oxidative stress, and proinflammatory mediator levels were measured. Detailed dietary data were obtained using a 24 h food recall. LTL was assessed using a real-time PCR assay. Regression models and simple regulatory models were used for data analysis. RESULTS: There was an inverse relationship between dietary magnesium and LTL (P < 0.001), with a between-extreme-quarter difference of -0.55. Conversely, there was a positive relationship between dietary magnesium and serum tumor necrosis factor (TNF) α, with an interquarter difference of 3.79 pmol/mL (P for trend = 0.006). Multivariate regression analysis revealed that the odds ratios (ORs) for shorter LTL and higher serum TNFα increased with magnesium intake, and the ORs of the differences between extreme quartiles were 2.60 (95% confidence interval (CI): 1.31-5.36; P = 0.003) and 1.98 (95% CI: 1.09-3.59; P = 0.008). There was a direct negative effect of dietary magnesium intake on LTL (B = -0.002; P = 0.001), which appeared to be indirectly influenced by TNFα (-0.002 to -0.0005). CONCLUSIONS: Dietary magnesium intake may be a critical component of the cellular aging process, and its effect could be partly mediated by TNFα.

Breast microcalcifications detection based on fusing features with DTCWT.

BACKGROUND: Breast cancer is a common disease in women. Early detection and early treatment can reduce breast cancer mortality. Studies have shown that breast cancer microcalcifications is one of the important clinical manifestations of early breast cancer, and sometimes even the only manifestation. When the mammography image shows typical malignant microcalcification, it can be diagnosed as breast cancer without any other signs of malignancy. In the aided diagnosis of microcalcifications, it is a crucial step to automatically find and locate regions of interest containing microcalcifications. However, the existing feature extraction method for microcalcifications only extracts features in the time domain or wavelet domain, and does not completely represent all the information of the region of interest. An extraction method based on the combination of Dual-Tree Complex Wavelet Transform (DTCWT) and texture features is proposed in the paper. METHODS: First, the processing operations including denoising, enhancement, and edge detection were performed on mammograms. Sub-image segmentation is then performed. DTCWT features and texture features are extracted for each sub-image.DTCWT features are combined with texture features, and then genetic algorithm is used for feature optimization. The features are classified by the Extreme Learning Machine (ELM) to achieve rapid detection and automatic extraction of ROI with microcalcifications. The experimental results verify that the feature model proposed in this paper has the highest detection rate for ROI regions. The ROI region extracted by the proposed feature model was used as subsequent experimental data. Three different methods were used to detect the microcalcifications, including Top-hat, wavelet transform, and methods combining Top-Hat and wavelet transform. RESULTS: The method was applied to 100 mammograms from the mammograms database of women in Northeast China. In the automatic extraction of ROI, the accuracy, sensitivity, specificity, positive accuracy and negative accuracy of the proposed model combined with DTCWT were 95.92%, 96.71%, 92.20%, 93.65%, 96.33%, respectively. When the Top-hat algorithm was used for microcalcifications detection, the sensitivity reached 89.6%, and the false positive detection rate was 2.6. When the wavelet transform algorithm was used for microcalcifications detection, the sensitivity was 91.1%, and the false positive detection rate was 3.28. When the combined algorithm was used for microcalcifications detection, the sensitivity was 86.7%, and the false positive detection rate decreased to 1.35. CONCLUSIONS: The proposed model combined with DTCWT features achieves better result in the automatic extraction of ROI. Moreover, in the subsequent detection of microcalcifications based on three methods, the three methods achieved better results in sensitivity and false positive detection rate, respectively.

The association between interactive health literacy and dietary behaviors among Chinese college students: a large-scale cross-sectional study.

Background: The association between health literacy and healthy dietary behaviors has been explored in the European population. However, there is currently no evidence available specifically pertaining to Chinese college students particularly for interactive health literacy. Aims: The objective of this study was to investigate the association between interactive health literacy (IHL) and dietary behaviors in Chinese college students. Methods: This study included 11,856 Chinese college students (mean age = 18.8 years, SD = 1.2 years). We defined nine healthy dietary behaviors as consumption of water, egg, milk and milk products, vegetables, fruit, red meat, soy and soy products, seafood, and sugar-sweetened beverages. For each food group, participants who met the criterion for being a regular consumer of the item were assigned a score of 1, and otherwise were assigned a score of 0. Thus, the dietary behaviors score ranged from 0 to 9, with higher scores indicating healthier dietary behaviors. We used the revised 28-item Chinese Adolescent Interactive Health Literacy Questionnaire (CAIHLQ) to evaluate IHL; a higher score on this scale indicates a greater health literacy. Multivariate logistic regression was used to analyze the association between IHL level and frequency of different numbers of dietary behaviors. Results: After adjusting for sex, age, annual family income, place of residence, father's education level, and mother's education level, there was a clear and significant positive association between IHL and the likelihood of exhibiting diverse dietary behaviors. The adjusted odds ratio (95% CI) of exhibiting given nine dietary behaviors with reference to tertile 1 according to categories of IHL was as follows: 1.055 (0.694, 1.603) for tertile 2 and 1.849 (1.269, 2.696) for tertile 3 (p for trend = 0.001). Similarly, there are significant positive associations between IHL and the likelihood of exhibiting 2-8 dietary behaviors, except for exhibiting any one dietary behavior. We further found that, in addition to the health awareness factor, there were significant positive associations between physical activity and nutrition factors, and healthier dietary behaviors. Further, there was a significant negative association between interpersonal relationships and dietary behavior. Conclusion: The findings indicate a positive relationship between IHL and dietary behavior, such that the higher the level of IHL among college students, the healthier the dietary behavior they tend to adopt in their daily lives. These findings suggest the importance of developing stages of change-based educational interventions, which could help individuals with limited IHL to not only acquire necessary health-related knowledge but also to strengthen their motivation to engage in healthy dietary behaviors. Future studies should employ longitudinal prospective designs or randomized controlled trials to establish a causal association between IHL and healthy dietary behaviors.

Multilevel Regulation of NF-κB Signaling by NSD2 Suppresses Kras-Driven Pancreatic Tumorigenesis.

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer with a dismal overall prognosis. NSD2 is an H3K36-specific di-methyltransferase that has been reported to play a crucial role in promoting tumorigenesis. Here, the study demonstrates that NSD2 acts as a putative tumor suppressor in Kras-driven pancreatic tumorigenesis. NSD2 restrains the mice from inflammation and Kras-induced ductal metaplasia, while NSD2 loss facilitates pancreatic tumorigenesis. Mechanistically, NSD2-mediated H3K36me2 promotes the expression of IκBα, which inhibits the phosphorylation of p65 and NF-κB nuclear translocation. More importantly, NSD2 interacts with the DNA binding domain of p65, attenuating NF-κB transcriptional activity. Furthermore, inhibition of NF-κB signaling relieves the symptoms of Nsd2-deficient mice and sensitizes Nsd2-null PDAC to gemcitabine. Clinically, NSD2 expression decreased in PDAC patients and negatively correlated to nuclear p65 expression. Together, the study reveals the important tumor suppressor role of NSD2 and multiple mechanisms by which NSD2 suppresses both p65 phosphorylation and downstream transcriptional activity during pancreatic tumorigenesis. This study opens therapeutic opportunities for PDAC patients with NSD2 low/loss by combined treatment with gemcitabine and NF-κBi.

Experience of multi-disciplinary treatment of multiple cerebellar diffuse large B-cell lymphoma: A case report.

RATIONALE: Primary central nervous system lymphoma (PCNSL) is a rare, highly malignant form of non-Hodgkin lymphoma categorized under the diffuse large B-cell type. It accounts for merely 1% of all non-Hodgkin lymphoma cases and comprises approximately 3% of all brain tumors. The involvement of the cerebellum is observed in only 9% of these cases. Recently, we came across an unusual instance: a young man presenting with multiple lesions located specifically within the cerebellum. PATIENT CONCERNS: A 26-year-old male was admitted to the hospital due to severe headaches. He has a medical history of sporadic headaches, accompanied by dizziness, nausea, and vomiting persisting for a month. Over the last 10 days, his headaches have intensified, coupled with decreased vision and protrusion of the eyeballs. Magnetic resonance imaging (MRI) revealed abnormal signals in both cerebellar hemispheres. DIAGNOSES, INTERVENTIONS, AND OUTCOMES: Diagnostic procedures included cerebellar biopsy, posterior fossa decompression, and lateral ventricle drainage. Histopathological examination identified diffuse large B-cell lymphoma (DLBCL) with high proliferative activity. To minimize neurotoxicity, chemotherapy involved intrathecal methotrexate (MTX) injections combined with the CHOP program. The patient has shown good tolerance to the treatment so far. LESSONS: While the definitive optimal treatment approach remains elusive, current chemotherapy centered on high-dose MTX stands as the standard induction therapy. Integrating surgery with radiotherapy and chemotherapy significantly extends patient survival.

Galectin-3 impairs calcium transients and ß-cell function.

In diabetes, macrophages and inflammation are increased in the islets, along with ß-cell dysfunction. Here, we demonstrate that galectin-3 (Gal3), mainly produced and secreted by macrophages, is elevated in islets from both high-fat diet (HFD)-fed and diabetic db/db mice. Gal3 acutely reduces glucose-stimulated insulin secretion (GSIS) in ß-cell lines and primary islets in mice and humans. Importantly, Gal3 binds to calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1) and inhibits calcium influx via the cytomembrane and subsequent GSIS. ß-Cell CACNG1 deficiency phenocopies Gal3 treatment. Inhibition of Gal3 through either genetic or pharmacologic loss of function improves GSIS and glucose homeostasis in both HFD-fed and db/db mice. All animal findings are applicable to male mice. Here we show a role of Gal3 in pancreatic ß-cell dysfunction, and Gal3 could be a therapeutic target for the treatment of type 2 diabetes.

Trimethylamine N-oxide impairs ß-cell function and glucose tolerance.

ß-Cell dysfunction and ß-cell loss are hallmarks of type 2 diabetes (T2D). Here, we found that trimethylamine N-oxide (TMAO) at a similar concentration to that found in diabetes could directly decrease glucose-stimulated insulin secretion (GSIS) in MIN6 cells and primary islets from mice or humans. Elevation of TMAO levels impairs GSIS, ß-cell proportion, and glucose tolerance in male C57BL/6 J mice. TMAO inhibits calcium transients through NLRP3 inflammasome-related cytokines and induced Serca2 loss, and a Serca2 agonist reversed the effect of TMAO on ß-cell function in vitro and in vivo. Additionally, long-term TMAO exposure promotes ß-cell ER stress, dedifferentiation, and apoptosis and inhibits ß-cell transcriptional identity. Inhibition of TMAO production improves ß-cell GSIS, ß-cell proportion, and glucose tolerance in both male db/db and choline diet-fed mice. These observations identify a role for TMAO in ß-cell dysfunction and maintenance, and inhibition of TMAO could be an approach for the treatment of T2D.

The relationship between internet addiction and risk of suboptimal health status among Chinese college students.

Internet addiction (IA) is a prevalent trend among college students, and the relationship between severe IA and poor health status among college students has been well established. However, whether IA is associated with suboptimal health status (SHS) in college students is unclear. This study aimed to investigate the association between IA and SHS risk in Chinese college students. We conducted a cross-sectional study to assess whether IA was related to SHS risk in 2265 college students in Shenyang, China. SHS was assessed using the Suboptimal Health Status Questionnaire with a cutoff score of ≥35 to document SHS. IA was assessed using the validated 20-item Young's Internet Addiction Test with cutoff scores of 31-49 and 50-100 for mile and moderate-to-severe cases, respectively. The prevalence rate of SHS was 54.0%. After adjusting for potential confounding factors, the IA categories were positively related to a higher risk of SHS. The odds ratios (95% confidence intervals) for SHS across IA categories were 1.00, 7.66 (6.00, 9.78), and 27.93 (20.95, 37.24) (P for trend: <.001) after adjusting for multiple confounding factors. This is the first cross-sectional study to demonstrate that IA is independently associated with SHS. This finding suggests that IA is a negative risk factor for SHS.

Setd2 deficiency promotes gastric tumorigenesis through inhibiting the SIRT1/FOXO pathway.

Gastric cancer (GC) is the fifth most common cancer and the second leading cause of cancer death globally. SETD2 is a histone methyltransferase catalyzing tri-methylation of H3K36 (H3K36me3) and has been shown to participate in diverse biological processes and human tumors. However, the mechanism of SETD2 in GC remains unclear. Here, we reported that Setd2 deficiency predicts poor prognosis of gastric cancer. SETD2 loss facilitated H. felis/MNU and c-Myc-induced gastric tumorigenesis, respectively. The mouse model of stomach-specific Setd2 depletion together with c-MYC overexpression (AMS) developed high-grade epithelial defects, intestinal metaplasia and dysplasia at only 10-12 weeks of age. Mechanistically, Setd2 depletion resulted in impaired epigenetic regulation of Sirt1, thus inhibiting the SIRT1/FOXO pathway. Moreover, the agonists of FOXO signaling or overexpression of SIRT1 significantly rescued the enhanced cell proliferation and migration caused by Setd2 deficiency in SGC7901 cells. Together, our findings highlight an epigenetic mechanism by which SETD2 regulates gastric tumorigenesis through SIRT1/FOXO pathway. It may also pave the way for the development of targeted, patient-tailored therapies for GC patients with Setd2 deficiency.

SETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer.

Patients with polycystic kidney disease (PKD) encounter a high risk of clear cell renal cell carcinoma (ccRCC), a malignant tumor with dysregulated lipid metabolism. SET domain-containing 2 (SETD2) has been identified as an important tumor suppressor and an immunosuppressor in ccRCC. However, the role of SETD2 in ccRCC generation in PKD remains largely unexplored. Herein, we perform metabolomics, lipidomics, transcriptomics and proteomics within SETD2 loss induced PKD-ccRCC transition mouse model. Our analyses show that SETD2 loss causes extensive metabolic reprogramming events that eventually results in enhanced sphingomyelin biosynthesis and tumorigenesis. Clinical ccRCC patient specimens further confirm the abnormal metabolic reprogramming and sphingomyelin accumulation. Tumor symptom caused by Setd2 knockout is relieved by myriocin, a selective inhibitor of serine-palmitoyl-transferase and sphingomyelin biosynthesis. Our results reveal that SETD2 deficiency promotes large-scale metabolic reprogramming and sphingomyelin biosynthesis during PKD-ccRCC transition. This study introduces high-quality multi-omics resources and uncovers a regulatory mechanism of SETD2 on lipid metabolism during tumorigenesis.

Loss of SETD2 aggravates colorectal cancer progression caused by SMAD4 deletion through the RAS/ERK signalling pathway.

BACKGOUND: Colorectal cancer (CRC) is a complex, multistep disease that arises from the interplay genetic mutations and epigenetic alterations. The histone H3K36 trimethyltransferase SET domain-containing 2 (SETD2), as an epigenetic signalling molecule, has a 5% mutation rate in CRC. SETD2 expression is decreased in the development of human CRC and mice treated with Azoxymethane /Dextran sodium sulfate (AOM/DSS). Loss of SETD2 promoted CRC development. SMAD Family member 4 (SMAD4) has a 14% mutation rate in CRC, and SMAD4 ablation leads to CRC. The co-mutation of SETD2 and SMAD4 predicted advanced CRC. However, little is known on the potential synergistic effect of SETD2 and SMAD4. METHODS: CRC tissues from mice and SW620 cells were used as research subjects. Clinical databases of CRC patients were analyzed to investigate the association between SETD2 and SMAD4. SETD2 and SMAD4 double-knockout mice were established to further investigate the role of SETD2 in SMAD4-deficient CRC. The intestinal epithelial cells (IECs) were isolated for RNA sequencing and chromatin immunoprecipitation sequencing (ChIP-seq) to explore the mechanism and the key molecules resulting in CRC. Molecular and cellular experiments were conducted to analyze the role of SETD2 in SMAD4-deficient CRC. Finally, rescue experiments were performed to confirm the molecular mechanism of SETD2 in the development of SMAD4-dificient CRC. RESULTS: The deletion of SETD2 promotes the malignant progression of SMAD4-deficient CRC. Smad4Vil-KO ; Setd2Vil-KO mice developed a more severe CRC phenotype after AOM/DSS induction, with a larger tumour size and a more vigorous epithelial proliferation rate. Further mechanistic findings revealed that the loss of SETD2 resulted in the down-regulation of DUSP7, which is involved in the inhibition of the RAS/ERK signalling pathway. Finally, the ERK1/2 inhibitor SCH772984 significantly attenuated the progression of CRC in Smad4Vil-KO ;Setd2Vil-KO mice, and overexpression of DUSP7 significantly inhibited the proliferation rates of SETD2KO ; SMAD4KO SW620 cells. CONCLUSIONS: Our results demonstrated that SETD2 inhibits the RAS/ERK signaling pathway by facilitating the transcription of DUSP7 in SMAD4-deficient CRC, which could provide a potential therapeutic target for the treatment of advanced CRC.

SETD2 deficiency promotes renal fibrosis through the TGF-ß/Smad signalling pathway in the absence of VHL.

BACKGROUND: Renal fibrosis is the final development pathway and the most common pathological manifestation of chronic kidney disease. Epigenetic alteration is a significant intrinsic factor contributing to the development of renal fibrosis. SET domain-containing 2 (SETD2) is the sole histone H3K36 trimethyltransferase, catalysing H3K36 trimethylation. There is evidence that SETD2-mediated epigenetic alterations are implicated in many diseases. However, it is unclear what role SETD2 plays in the development of renal fibrosis. METHODS: Kidney tissues from mice as well as HK2 cells were used as research subjects. Clinical databases of patients with renal fibrosis were analysed to investigate whether SETD2 expression is reduced in the occurrence of renal fibrosis. SETD2 and Von Hippel-Lindau (VHL) double-knockout mice were used to further investigate the role of SETD2 in renal fibrosis. Renal tubular epithelial cells isolated from mice were used for RNA sequencing and chromatin immunoprecipitation sequencing to search for molecular signalling pathways and key molecules leading to renal fibrosis in mice. Molecular and cell biology experiments were conducted to analyse and validate the role of SETD2 in the development of renal fibrosis. Finally, rescue experiments were performed to determine the molecular mechanism of SETD2 deficiency in the development of renal fibrosis. RESULTS: SETD2 deficiency leads to severe renal fibrosis in VHL-deficient mice. Mechanically, SETD2 maintains the transcriptional level of Smad7, a negative feedback factor of the transforming growth factor-ß (TGF-ß)/Smad signalling pathway, thereby preventing the activation of the TGF-ß/Smad signalling pathway. Deletion of SETD2 leads to reduced Smad7 expression, which results in activation of the TGF-ß/Smad signalling pathway and ultimately renal fibrosis in the absence of VHL. CONCLUSIONS: Our findings reveal the role of SETD2-mediated H3K36me3 of Smad7 in regulating the TGF-ß/Smad signalling pathway in renal fibrogenesis and provide an innovative insight into SETD2 as a potential therapeutic target for the treatment of renal fibrosis.

Insulin induces insulin receptor degradation in the liver through EphB4.

Insulin signaling is essential for glucose metabolism, and insulin decreases insulin receptor (InsR) levels in a dose-dependent and time-dependent manner. However, the regulatory mechanisms of InsR reduction upon insulin stimulation remain poorly understood. Here, we show that Eph receptor B4 (EphB4), a tyrosine kinase receptor that modulates cell adhesion and migration, can bind directly to InsR, and this interaction is markedly enhanced by insulin. Due to the adaptor protein 2 (Ap2) complex binding motif in EphB4, the interaction of EphB4 and InsR facilitates clathrin-mediated InsR endocytosis and degradation in lysosomes. Hepatic overexpression of EphB4 decreases InsR and increases hepatic and systemic insulin resistance in chow-fed mice, whereas genetic or pharmacological inhibition of EphB4 improve insulin resistance and glucose intolerance in obese mice. These observations elucidate a role for EphB4 in insulin signaling, suggesting that EphB4 might represent a therapeutic target for the treatment of insulin resistance and type 2 diabetes.

Association between glucose fluctuation during 2-hour oral glucose tolerance test, inflammation and oxidative stress markers, and ß-cell function in a Chinese population with normal glucose tolerance.

BACKGROUNDS: Glucose fluctuation (GF) may have detrimental effects in individuals with diabetes; however, clinical data on the association between short-term GF, inflammation/oxidative stress markers, and islet ß-cell function based on a population with normal glucose tolerance (NGT) are insufficient. Therefore, we aimed to explore these associations in a Chinese population of 209 individuals with NGT in a cross-sectional analysis. METHODS: Individuals were categorized based on GF tertiles, calculated as the maximum-minimum glucose levels among four time points (0, 30, 60, 120 min) during 2-hour oral glucose tolerance test (OGTT). Plasma inflammation markers tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and oxidative stress markers superoxide dismutase (SOD), and 8-oxo-2'-deoxyguanosine (8-oxo-dG) were measured. Islet ß-cell function was estimated according to the disposition index (DI) at the early (30 min) and total (120 min) phase of the OGTT, adjusted for insulin sensitivity. RESULTS: Individuals in the middle and highest tertile of GF had reduced ß-cell function, and increased plasma SOD and TNF-α levels compared with those in the lowest tertile of GF (P<0.05). Multiple linear regression analysis indicated that GF was positively associated with TNF-α, 8-oxo-dG and SOD levels, but negatively associated with ß-cell function, whereas IL-6, TNF-α, 8-oxo-dG and SOD levels were negatively associated with ß-cell function (P<0.05). CONCLUSIONS: GF may increase inflammation and oxidative stress markers in individuals with NGT, which could contribute to reduced ß-cell function. Thus, maintaining glucose stability after a meal may have beneficial effects on delaying ß-cell dysfunction, suggesting that diet and exercise strategies to decrease diet related GF are warranted.

Development and Validation of Predicting Nomograms for Craniopharyngioma: A Retrospective, Multiple-Center, Cohort Study.

Craniopharyngiomas (CPs) are benign tumors arising from the sellar region. However, little is known about their clinical features and long-term recurrence due to low morbidity and the lack of large cohort studies. Thus, we aimed to develop nomograms to accurately predict the extent of resection and tumor recurrence using clinical parameters. A total of 545 patients diagnosed with CP between 2009 and 2019 were examined: 381 in the development cohort and 164 in the validation cohort. Least absolute shrinkage and selection operator (LASSO) and Cox regression analyses were performed to establish two nomograms. Receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA) and Kaplan-Meier (KM) curves were used to evaluate their predictive performance and discriminative power, respectively, in the two cohorts. In addition, the EORTC QLQ-BN20 questionnaire was used to assess neuropsychological status in the follow-up. In the development cohort, the area under the curve (AUC) and C-index were 0.760 and 0.758, respectively, for predicting the extent of resection and 0.78 and 0.75, respectively, for predicting 3-year progression-free survival (PFS) and 5-year PFS. Additionally, the model had a predictive accuracy of 0.785. Both nomograms showed acceptable discrimination in the two cohorts. Moreover, DCA demonstrated excellent clinical benefits from the two nomograms. Finally, participants were classified into two distinct risk groups according to the risk score, and an online calculator was created for convenient clinical use. During long term follow-up, hypothyroidism (77.61%) and hypocortisolism (76.70%) were the most common endocrine dysfunction after surgery and significant deficits were observed concerning visual disorder, motor dysfunction and seizures in the recurrent groups. In particular, better quality of life was associated with gross total resection (GTR), postoperative radiation, anterior interhemispheric (AI) approach and transsphenoidal approach. To our knowledge, these are the first nomograms based on a very large cohort of patients with CP that show potential benefits for guiding treatment decisions and long-term surveillance. The current study demonstrated the online calculator serve as the practical tool for individual strategies based on the patient's baseline characteristics to achieve a better prognosis.

Erratum to "Sex-Specific Negative Association between Iron Intake and Cellular Aging Markers: Mediation Models Involving TNFα".

[This corrects the article DOI: 10.1155/2019/4935237.].