Robust machine-learning based prognostic index using cytotoxic T lymphocyte evasion genes highlights potential therapeutic targets in colorectal cancer.

BACKGROUND: A minute fraction of patients stands to derive substantial benefits from immunotherapy, primarily attributable to immune evasion. Our objective was to formulate a predictive signature rooted in genes associated with cytotoxic T lymphocyte evasion (CERGs), with the aim of predicting outcomes and discerning immunotherapeutic response in colorectal cancer (CRC). METHODS: 101 machine learning algorithm combinations were applied to calculate the CERGs prognostic index (CERPI) under the cross-validation framework, and patients with CRC were separated into high- and low-CERPI groups. Relationship between immune cell infiltration levels, immune-related scores, malignant phenotypes and CERPI were further analyzed. Various machine learning methods were used to identify key genes related to both patient survival and immunotherapy benefits. Expression of HOXC6, G0S2, and MX2 was evaluated and the effects of HOXC6 and G0S2 on the viability and migration of a CRC cell line were in-vitro verified. RESULTS: The CERPI demonstrated robust prognostic efficacy in predicting the overall survival of CRC patients, establishing itself as an independent predictor of patient outcomes. The low-CERPI group exhibited elevated levels of immune cell infiltration and lower scores for tumor immune dysfunction and exclusion, indicative of a greater potential benefit from immunotherapy. Moreover, there was a positive correlation between CERPI levels and malignant tumor phenotypes, suggesting that heightened CERPI expression contributes to both the occurrence and progression of tumors. Thirteen key genes were identified, and their expression patterns were scrutinized through the analysis of single-cell datasets. Notably, HOXC6, G0S2, and MX2 exhibited upregulation in both CRC cell lines and tissues. Subsequent knockdown experiments targeting G0S2 and HOXC6 resulted in a significant suppression of CRC cell viability and migration. CONCLUSION: We developed the CERPI for effectively predicting survival and response to immunotherapy in patients, and these results may provide guidance for CRC diagnosis and precise treatment.

Impact of a dual glucose-dependent insulinotropic peptide/glucagon-like peptide-1 receptor agonist tirzepatide on heart rate among patients with type 2 diabetes: A systematic review and pairwise and network meta-analysis.

AIMS: To evaluate the impact of a dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide (TZP), and its potential dose-response effect, on heart rate. METHODS: Articles were searched from PubMed, Web of Science, Embase, Cochrane Library, and clinical trials registries (ClinicalTrials.gov) databases. Randomized controlled trials (RCTs) comparing TZP at doses of 5, 10 and 15 mg in adults with type 2 diabetes were included. Six study arms were summarized from original research (TZP 5, 10 and 15 mg, GLP-1 receptor agonists [GLP-1RAs], insulin, placebo). The GLP-1RA and non-GLP-1RA groups were combined to form a control group. Two reviewers independently extracted data and assessed the quality of each study. Mean differences (MDs) were calculated as effect estimates for continuous outcomes. Pairwise meta-analyses and network meta-analyses were conducted. The study protocol was prospectively registered (PROSPERO ID: CRD42023418551). RESULTS: Eight articles were included in this systematic review and meta-analysis. The mean baseline heart rate ranged from 65.2 to 75.7 beats per minute. Pairwise meta-analysis showed that, compared with combined the control group, there were significantly greater increases in heart rates in the TZP group (MD 1.82, 95% confidence interval [CI] 0.75, 2.89). Similar significant rises were identified when comparing TZP with GLP-1RAs and non-GLP-1RAs (GLP-1 RAs: MD 2.29, 95% CI 1.00, 3.59; non-GLP-1RAs: MD 1.58, 95% CI 0.26, 2.91). TZP 5 mg was associated with smaller increases in heart rates compared to TZP 10 mg and TZP 15 mg (TZP 10 mg: MD -0.97, 95% CI -1.79, -0.14; TZP 15 mg: MD -2.57, 95% CI -3.79, -1.35). TZP 10 mg increased heart rate less than TZP 15 mg (MD -1.5, 95% CI -2.38, -0.82). Network meta-analysis indicated that TZP 15 mg was associated with significant increases in heart rate compared with TZP 5 mg (MD 2.53, 95% CI 1.43, 3.62), TZP 10 mg (MD 1.44, 95% CI 0.35, 2.53), GLP-1RAs (MD 3.46, 95% CI 1.67, 5.25), insulin (MD 2.86, 95% CI 1.32, 4.41) and placebo (MD 2.96, 95% CI 1.36, 4.57). CONCLUSIONS: Our study showed not only that there was a greater increase in heart rate in the TZP group than in the control, GLP-1RA and non-GLP-1RA groups, but also that the 15-mg dose of TZP had the strongest impact on increasing heart rates compared with the other five inventions, with a TZP dose-response impact on heart rate. Further research on the effects of TZP treatment-related increases in heart rate is required.

Leukocyte telomere length independently predicts hyperuricemia risk in a longitudinal study of the Chinese population.

BACKGROUND AND AIMS: Leukocyte telomere length (LTL) has been correlated with uric acid levels, although results are inconsistent, and prospective studies are lacking. In this longitudinal, prospective cohort study, we aimed to assess whether a shorter LTL predicts the risk of hyperuricemia. METHODS AND RESULTS: We conducted a longitudinal study in a Chinese cohort of 599 participants. Of these, 266 participants completed a 5.9-year follow-up from June 2014 to December 2021. LTL was assessed at baseline using real-time polymerase chain reaction. Hyperuricemia was defined as serum uric acid ≥420 mmol/L according to Chinese guidelines for diagnosis and treatment of hyperuricemia and gout. Participants who had developed hyperuricemia during follow-up (n = 17) had shorter LTL at baseline. Baseline LTL was independently associated with the development of hyperuricemia at follow-up after adjusting for conventional hyperuricemia risk factors (odds ratio [OR] 2.347 [95% confidence interval [CI] 1.123, 4.906]; P = 0.023). After grouping according to LTL tertiles, the incidence of hyperuricemia was 18.334-fold higher for the first than for the third tertile (OR 18.334 [95%CI 1.786, 191.272]; P = 0.014, P for trend = 0.050). CONCLUSION: Our findings in a prospective cohort suggest that LTL could predict hyperuricemia risk, which might inform the timely prevention and treatment of hyperuricemia.

Bavachin protects against diet-induced hepatic steatosis and obesity in mice.

Non-alcoholic fatty liver disease (NAFLD) is a major health concern worldwide, and the incidence of metabolic disorders associated with NAFLD is rapidly increasing because of the obesity epidemic. There are currently no approved drugs that prevent or treat NAFLD. Recent evidence shows that bavachin, a flavonoid isolated from the seeds and fruits of Psoralea corylifolia L., increases the transcriptional activity of PPARγ and insulin sensitivity during preadipocyte differentiation, but the effect of bavachin on glucose and lipid metabolism remains unclear. In the current study we investigated the effects of bavachin on obesity-associated NAFLD in vivo and in vitro. In mouse primary hepatocytes and Huh7 cells, treatment with bavachin (20 µM) significantly suppressed PA/OA or high glucose/high insulin-induced increases in the expression of fatty acid synthesis-related genes and the number and size of lipid droplets. Furthermore, bavachin treatment markedly elevated the phosphorylation levels of AKT and GSK-3ß, improving the insulin signaling activity in the cells. In HFD-induced obese mice, administration of bavachin (30 mg/kg, i.p. every other day for 8 weeks) efficiently attenuated the increases in body weight, liver weight, blood glucose, and liver and serum triglyceride contents. Moreover, bavachin administration significantly alleviated hepatic inflammation and ameliorated HFD-induced glucose intolerance and insulin resistance. We demonstrated that bavachin protected against HFD-induced obesity by inducing fat thermogenesis and browning subcutaneous white adipose tissue (subWAT). We revealed that bavachin repressed the expression of lipid synthesis genes in the liver of obese mice, while promoting the expression of thermogenesis, browning, and mitochondrial respiration-related genes in subWAT and brown adipose tissue (BAT) in the mice. In conclusion, bavachin attenuates hepatic steatosis and obesity by repressing de novo lipogenesis, inducing fat thermogenesis and browning subWAT, suggesting that bavachin is a potential drug for NAFLD therapy.

Tumor necrosis factor-alpha mediates the negative association between telomere length and kidney dysfunction.

Aim/hypothesis: The relationship between peripheral blood leukocyte telomere length (LTL) and kidney dysfunction, especially in people with hypertension, remains unclear. No clinical study has explored the role of inflammation and oxidative stress in the relationship between LTL and kidney dysfunction. Therefore, we examined the relationship between baseline LTL and albuminuria progression and/or rapid renal function decline in Chinese patients with or without hypertension and investigated whether inflammation and oxidative stress played a mediating role in this relationship. Methods: We conducted a prospective study including 262 patients in a 7-year follow-up period from 2014 to 2021. Data on LTL, inflammation, oxidative markers, renal function, and urine protein levels were assessed. Kidney dysfunction was defined as either albuminuria progression, rapid decline in renal function, or the composite endpoint (albuminuria progression and rapid decline in renal function). Logistic regression and simple mediation models were used for the analysis. Results: In this cohort (mean age, 54.3±9.7 years; follow-up period, 5.9±1.1 years), 42(16.0%), 21(8.0%), and 59(22.5%) patients developed albuminuria progression, rapid eGFR decline, and the composite endpoint of kidney dysfunction, respectively. Logistic regression analysis showed that each standard deviation decrease of baseline LTL and the lower quartile (Q) of baseline LTL were significantly correlated with an increased risk of rapid decline in renal function (OR=1.83 [95% CI 1.07, 3.27] per 1SD, P=0.03; OR=7.57 [95% CI 1.25, 145.88] for Q1 vs. Q4, P for trend=0.031); and the composite endpoint of kidney dysfunction (OR=1.37 [95% CI 0.97, 1.96] per 1SD, borderline positive P=0.072; OR=2.96[95% CI 1.15, 8.2] for Q1 vs. Q4, P for trend=0.036). The mediating analysis showed that tumor necrosis factor (TNF)-a partly mediated the relationship between LTL and rapid decline in renal function (direct effect: ß=0.046 95%CI [0.006, 0.090],P=0.02; indirect effect: ß=0.013 95%CI [0.003, 0.020]), and the mediating proportion was 22.4%.In subgroup analyses, LTL was inversely associated with rapid decline in renal function or the composite endpoint of kidney dysfunction only in patients with hypertension (OR=49.07[3.72,211.12] vs.1.32[0.69,2.58] per 1SD, P for interaction=0.045;OR=3.10 [1.48, 7.52] vs.1.08[0.92,1.63] per 1SD, P for interaction=0.036). Conclusion: Baseline LTL could independently predict kidney dysfunction at follow-up, especially in participants with hypertension. TNF-a partially mediated the negative association between LTL and kidney dysfunction.

Analysis of related factors affecting hemoporfin-mediated photodynamic therapy for port-wine stain: A retrospective study.

BACKGROUND: Hemoporfin-mediated photodynamic therapy (HMME-PDT) is currently considered one of the most promising therapies for port-wine stain (PWS). However, the efficacy of this is very variable and needs further studies. METHODS: A total of 101 patients with PWS in the face, neck, or extremities who received at least 2 HMME-PDT sessions were included in the study, and correlations of efficacy with age, gender, locations, treatment sessions, and PDL treatment history were analyzed. RESULTS: The efficacy of HMME-PDT in patients with different ages, locations, and different numbers of prior PDL treatment showed constantly significant differences after 1/2/last session (p < .05). The number of treatments was associated with efficacy, and patients who received more than two sessions had a better response than those who underwent two sessions only (p < .001). Ordinal logistic regression analysis confirmed the above-mentioned associations. Nevertheless, patients of different sex, subtype, and lesion size showed no significant differences. CONCLUSIONS: Our studies demonstrated that HMME-PDT is effective in the treatment of PWS. The more prior PDL treatments, older age, lips involvement, PWS on limbs were adverse factors for Hemoporfin-PDT, while multiple HMME-PDT sessions can improve effective and response rate. Besides, ambient temperature and lesions temperature should be concerned, local cooling provides some relief from pain but may influence effect.

Liraglutide Attenuates Hepatic Oxidative Stress, Inflammation, and Apoptosis in Streptozotocin-Induced Diabetic Mice by Modulating the Wnt/ß-Catenin Signaling Pathway.

Liraglutide has been extensively applied in the treatment of type 2 diabetes mellitus and also has hepatoprotective effects. However, the role of liraglutide treatment on liver injury in a mouse model of type 1 diabetes mellitus (T1DM) induced by streptozotocin (STZ) and its underlying mechanisms remain to be elucidated. In the present study, diabetes was initiated in experimental animals by single-dose intraperitoneal inoculation of STZ. Forty female C57BL/6J mice were equally assigned into five groups: diabetic group, insulin+diabetic group, liraglutide+diabetic group, insulin+liraglutide+diabetic group, and control group for eight weeks. Diabetic mice exhibited a significantly elevated blood glucose level and decreased body weight, and morphological changes of increased steatosis and apoptosis were observed in the liver compared with the control. Furthermore, a significant increase in the levels of malondialdehyde and inflammatory markers such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin 1ß (IL-1ß) and the proapoptotic proteins caspase-3 and Bax were observed in the livers of diabetic mice, together with marked increases in antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GPX) as well as antiapoptotic protein Bcl-2, all of which were significantly mitigated by treatment with liraglutide, insulin, and their combinations. Interestingly, liraglutide monotherapy showed better efficacy in ameliorating liver injury in T1DM mice than insulin monotherapy, similar to the combined drug therapy. Furthermore, the expression of Wnt/ß-catenin signaling pathway-associated molecules was upregulated in the liver of mice treated with liraglutide or insulin. The results of the present study suggested that liraglutide improves T1DM-induced liver injury and may have important implications for the treatment of nonalcoholic fatty liver disease (NAFLD) in patients with T1DM.

Conductive bimetal organic framework nanorods decorated with highly dispersed Co3O4nanoparticles as bi-functional electrocatalyst.

The poor electronic conductivity and low intrinsic electrocatalytic activity of metal organic frameworks (MOFs) greatly limit their direct application in electrocatalytic reactions. Herein, we report a conductive two-dimensionalπ-dconjugated Ni and Co bimetal organic framework (MOF)-NiCo-(2,3,6,7,10,11-hexaiminotriphenylene) (NiCo-HITP) nanorods decorated with highly dispersed Co3O4nanoparticles (NPs) as a promising bi-functional electrocatalyst towards oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) through an effective and facile strategy by modifying the rod-shaped -Ni3HITP2crystals using cobalt ions. The triggered electrocatalytic activity of the resulting MOF-based materials was achieved by increasing the electrical conductivity (7.23 S cm-1) originated from Ni3HITP2substrate and also by creating the cooperative catalysis sites of Co-Nxand Co3O4NPs. Optimized syntheses show a promising ORR activity with a high half-wave potential (0.77 V) and also a significantly improved OER activity compared with pure Ni3HITP2in alkaline electrolyte. Furthermore, a rechargeable Zn-air battery using the as-prepared material as air-cathode also shows a high power density (143.1 mW cm-2)-even comparable to a commercial Pt/C-RuO2-based battery. This methodology offers a new prospect in the design and synthesis of non-carbonized MOF bi-functional electrocatalysts for efficient catalysis towards ORR and OER.

Diagnosis, treatment and genetic analysis of two cases of congenital hyperinsulinemic hypoglycemia caused by GCK gene mutation.

Congenital hyperinsulinemia (CHI) is a heterogeneous disorder characterized by persistent hypoglycemia due to inappropriate insulin secretion. A total of 15 gene mutations have already been reported to be associated with CHI. Among them, CHI caused by the GCK mutation is named GCK-CHI, which is considered to be a rare form of CHI. Here, we reported two cases of GCK-CHI diagnosed by genetic testing and summarized the clinical characteristics. In patients with recurrent or persistent hypoglycemia, CHI should be taken into consideration. Genetic testing should be perfomed in these patients to avoid misdiagnosis and provide accurate intervention, thus to improve prognosis.

Fecal microbiota as a noninvasive biomarker to predict the tissue iron accumulation in intestine epithelial cells and liver.

Iron is an essential trace mineral required for growth, metabolism, and immune response. Dysregulation of iron homeostasis is linked with the development and progression of various diseases. Iron accumulation is associated with inflammatory diseases and cancer, while iron deficiency leads to the growth retardation. Several studies have suggested that iron imbalance results in alteration of gut microbiota, leading to the disruption of microbial diversity, the increase of pathogen abundance, and the induction of intestinal inflammation. However, in screening studies done in the past decades, the association between the iron availability and gut microbiota has not been systemically explored. Furthermore, a noninvasive and convenient approach to determine the iron levels in tissues is lacking. In the present study, a murine model for iron dysregulation was established. 16S rRNA amplicon sequencing and bioinformatic algorithms were used to identify the key taxa. Using the key taxa identified and machine learning models, we established an easily accessible prediction model, which could accurately distinguish between iron-deprived or iron-fortified condition. This prediction model could precisely predict the iron level of the intestinal epithelial cells and the liver and could be used for early diagnosis of iron dysbiosis-related diseases, in a noninvasive manner, in the future.

Synchronous distance education vs traditional education for health science students: A systematic review and meta-analysis.

CONTEXT: Synchronous distance education (SDE) has been widely used for health science students in recent years. This study examined the effectiveness and acceptance of SDE compared with traditional education for health science students and explored the potential moderators that could impact the pooled results. METHODS: A systematic review and meta-analysis was conducted of randomised controlled trials (RCTs) from January 2000 to March 2020 searched on nine electronic databases, including Web of Science, PubMed, Cochrane Library, Scopus, EMBASE, CINAHL, ERIC, PsycINFO, and ProQuest Dissertations and Theses. The outcomes measured were knowledge, skills with objective assessments and overall satisfaction with subjective evaluations. The pooled results were calculated using random-model effects, and moderators were explored through meta-regression. RESULTS: A total of seven RCTs with 594 participants were included. At the post-test level, the pooled effect size of knowledge acquisitions (SMD 0.12, 95% CI -0.07-0.32) showed insignificant difference between the SDE and traditional education groups (P = .207), with low heterogeneity (I2  = 17.6%). Subgroup analyses observed no factors that significantly impacted the pooled results of knowledge acquisition at the post-test levels (P for interaction > 0.05). Knowledge gains from pretest to post-test in SDE groups also did not differ significantly between groups (SMD 0.15, 95% CI -0.22-0.53; P = .428). The pooled effect size of skills (SMD 0.02, 95% CI -0.24-0.28; P = .735) was similarly insignificant. The pooled effect size of overall satisfaction (SMD 0.60, 95% CI 0.38-0.83; P < .001) significantly favoured SDE over traditional education. Incorporating two-group studies without randomisations did not significantly change the overall results of knowledge acquisition at the post-test level (SMD -0.002, 95% CI -0.11-0.10; P = .994), with moderate heterogeneity (I2  = 61.9%). CONCLUSIONS: Synchronous distance education was not significantly different from traditional education in effectiveness and had higher satisfaction ratings. Our findings might provide indications for adoptions of online remote education in health science education centres.

Negative Association between Caloric Intake and Estimated Glomerular Filtration Rate in a Chinese Population: Mediation Models Involving Mitochondrial Function.

BACKGROUND: With the shortening of leukocyte telomere length (LTL) and decrease in the copy number of mitochondrial DNA, mitochondrial dysfunction and oxidative stress are considered important drivers of the aging process. Although previous experimental studies report that caloric intake is associated with age-related renal dysfunction through the changes in mitochondrial function, there are insufficient epidemiological data to establish this association. OBJECTIVE: We aimed to explore the association between caloric intake and renal function and to investigate whether mitochondrial DNA copy number (mtDNAcn) mediated this association by cross-sectional analysis. METHODS: A total of 403 individuals from a Chinese rural cohort (women = 66.50%; mean age = 53.94 ± 10.27 years) with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and with differences in the glucose tolerance status (diabetes, n = 106; prediabetes, n = 125; normal glucose tolerance, n = 172) were included. Dietary data were obtained by a 24-h food recall, and caloric intake was normalized by ideal body weight. The mtDNAcn and LTL were detected using real-time PCR assay. The associations between caloric intake, aging markers, and renal function were analyzed by partial correlation analysis and multiple linear regression analysis. Mediation analysis was applied to examine the role of mtDNAcn in the association between caloric intake and eGFR. RESULTS: Caloric intake was higher while age-adjusted mtDNAcn was lower in individuals with eGFR <90 mL/min/1.73 m2 (n = 140) than in those with eGFR ≥90 mL/min/1.73 m2 (n = 263). After adjusting for multiple factors, linear regression analysis revealed that caloric intake was negatively associated with eGFR and mtDNAcn, while mtDNAcn was positively associated with eGFR. Moreover, mediation analysis indicated that the indirect effect of caloric intake on eGFR through mtDNAcn was significant (ß = -0.0505, 95% confidence interval -0.0931 to -0.0190). CONCLUSIONS: Caloric intake was negatively associated with eGFR in a Chinese population, and the association was partly mediated by decreased mtDNAcn.

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.

BAMBI shuttling between cytosol and membrane is required for skeletal muscle development and regeneration.

Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) gene encodes a transmembrane protein and is involved in multiple physiological and pathological processes, such as inflammatory response, tumor development and progression, cell proliferation and differentiation. A previous study suggested that BAMBI may interact with the Wnt/ß-catenin signaling pathway via promoting ß-catenin nuclear translocation associated with C2C12 myogenic myoblast differentiation. However, its biological function in skeletal muscle still remains unknown and requires further characterization. The present work sought to investigate its biological function in skeletal muscle, especially the physiological roles of BAMBI during skeletal muscle growth and regeneration. Our current work suggests that BAMBI protein is highly expressed in skeletal muscle and is only detected in cytosolic fraction in the resting muscle. Moreover, BAMBI protein is co-localized in fast-twitch (glycolytic) fibers, but not in slow-twitch (oxidative) fibers. Comparing with the cytosolic trapping in resting muscle, BAMBI protein is enriched on cellular membrane during the muscle growth and regeneration, suggesting that BAMBI-mediated a significant signaling pathway may be an essential part of muscle growth and regeneration.

Multifunctional Nanosystem Based on Graphene Oxide for Synergistic Multistage Tumor-Targeting and Combined Chemo-Photothermal Therapy.

Locating nanomedicines at the active sites plays a pivotal role in the nanoparticle-based cancer therapy field. Herein, a multifunctional nanotherapeutic is designed by using graphene oxide (GO) nanosheets with rich carboxyl groups as the supporter for hyaluronic acid (HA)-methotrexate (MTX) prodrug modification via an adipicdihydrazide cross-linker, achieving synergistic multistage tumor-targeting and combined chemo-photothermal therapy. As a tumor-targeting biomaterial, HA can increase affinity of the nanocarrier toward CD44 receptor for enhanced cellular uptake. MTX, a chemotherapeutic agent, can also serve as a tumor-targeting enhancer toward folate receptor based on its similar structure with folic acid. The prepared nanosystems possess a sheet shape with a dynamic size of approximately 200 nm and pH-responsive drug release. Unexpectedly, the physiological stability of HA-MTX prodrug-decorated GO nanosystems in PBS, serum, and even plasma is more excellent than that of HA-decorated GO nanosystems, while both of them exhibit an enhanced photothermal effect than GO nanosheets. More importantly, because of good blood compatibility as well as reduced undesired interactions with blood components, HA-MTX prodrug-decorated GO nanosystems exhibited remarkably superior accumulation at the tumor sites by passive and active targeting mechanisms, achieving highly effective synergistic chemo-photothermal therapeutic effect upon near-infrared laser irradiation, efficient ablation of tumors, and negligible systemic toxicity. Hence, the HA-MTX prodrug-decorated hybrid nanosystems have a promising potential for synergistic multistage tumor-targeting therapy.

The shape of the glucose response curve during an oral glucose tolerance test heralds ß-cell function in a large Chinese population.

BACKGROUND: The shape of the glucose response curve during an oral glucose tolerance test (OGTT) can predict ß-cell function and insulin resistance. However, there have been few studies conducted on Chinese people. Thus, we aimed to verify the usefulness of the glucose response curve in a large Chinese population. METHODS: A total of 9059 OGTT (3-h tests) were categorized into either a monophasic or a multiphasic group based on the shape of the glucose response. Homeostasis model assessments of fasting insulin resistance, the Matsuda Index, the insulinogenic index, and the disposition index were assessed by plasma glucose and serum insulin concentration obtained at fasting or during an OGTT. RESULTS: The shape of the OGTT glucose response curve was monophasic in 87.3% and multiphasic in 12.7% of participants. Individuals in the multiphasic group were younger compared to those in the monophasic group (38.6 ± 13.6 vs. 35.4 ± 13.5, P < 0.001). Individuals in the monophasic group had significantly higher fasting plasma glucose (FPG 5.6 ± 13.5 vs. 5.2 ± 0.6, P < 0.001), fasting insulin (FINS 14.8 ± 8.7 vs. 13.5 ± 7.9, P < 0.01), and homeostasis model assessment of insulin resistance (HOMA-IR 3.8 ± 2.6 vs. 3.1 ± 2.0, P < 0.001) and impaired ß-cell function (disposition index 12.7 ± 14.1 vs. 16.6 ± 17.8, P < 0.001) compared to those in the multiphasic group. CONCLUSION: The monophasic OGTT glucose response curve could reflect impaired ß-cell function in a large Chinese population.

Metformin impairs systemic bile acid homeostasis through regulating SIRT1 protein levels.

Metformin is widely used to treat hyperglycemia. However, metformin treatment may induce intrahepatic cholestasis and liver injury in a few patients with type II diabetes through an unknown mechanism. Here we show that metformin decreases SIRT1 protein levels in primary hepatocytes and liver. Both metformin-treated wild-type C57 mice and hepatic SIRT1-mutant mice had increased hepatic and serum bile acid levels. However, metformin failed to change systemic bile acid levels in hepatic SIRT1-mutant mice. Molecular mechanism study indicates that SIRT1 directly interacts with and deacetylates Foxa2 to inhibit its transcriptional activity on expression of genes involved in bile acids synthesis and transport. Hepatic SIRT1 mutation elevates Foxa2 acetylation levels, which promotes Foxa2 binding to and activating genes involved in bile acids metabolism, impairing hepatic and systemic bile acid homeostasis. Our data clearly suggest that hepatic SIRT1 mediates metformin effects on systemic bile acid metabolism and modulation of SIRT1 activity in liver may be an attractive approach for treatment of bile acid-related diseases such as cholestasis.