Assessment of the Relationship Between Genetic Determinants of Obesity, Unhealthy Eating Habits and Chronic Obstructive Pulmonary Disease: A Mendelian Randomisation Study.

Background: Clinical studies have shown that the onset and exacerbation of chronic obstructive pulmonary disease (COPD) are related to obesity and dietary behaviours, but the genetic relationship between them is not clear.Aims: To investigate the relationship between the genetic determinants of obesity, dietary habits (alcohol consumption, intake of sweets, salt intake) and COPD.Methods: Exposure and outcome datasets were obtained from the IEU Open GWAS project. The exposure dataset includes dietary habits (Salt added to food, Sweets intake, Alcohol consumption), obesity level (represented by body mass index (BMI) and body fat percentage (BFP) data sets.). The outcome dataset includes COPD and acute COPD admissions. The collected data were imported into the RStudio software and conducted Mendelian randomisation analysis. Additionally, heterogeneity and horizontal pleiotropy tests were conducted on the data to ensure the veracity of the results.Results: The results showed that BMI was positively correlated with the risk of acute COPD admission (OR = 1.74, 95% CI 1.39-2.18) and COPD (OR = 1.81, 95%CI 1.41-2.33). In addition, BFP was also a risk factor for COPD (OR = 1.98, 95% CI 1.42-2.77) and acute exacerbation of COPD admission (OR = 1.99, 95%CI 1.43-2.77). The increase of salt, sugar and alcohol consumption will not increase the risk of COPD and the risk of hospitalisation due to COPD.Conclusion: Therefore, we should strengthen the guidance of diet and living habits of obese patients. For patients with heavier weight and higher body fat rate, they should be instructed to lose weight and fat to prevent the occurrence of COPD. For obese patients with COPD, more attention should be paid to prevent the occurrence of acute exacerbation of COPD in advance.

LncRNA SNHG8 regulates the migration and angiogenesis of pHUVECs induced by high glucose via the TRPM7/ERK1/2 signaling axis.

This study aimed to evaluate the regulatory effect and molecular mechanism of long noncoding RNA small nucleolus RNA host gene 8 (LncRNA SNHG8) in the migration and angiogenesis of primary human umbilical vein endothelial cells (pHUVECs) under high-glucose (HG) conditions. The HG-induced endothelial injury model was established in vitro.The cell model of silencing SNHG8, overexpressing SNHG8, and silencing TRPM7 was established by transfecting SNHG8-siRNA, SNHG8 plasmid and TRPM7-siRNA into cells with liposomes.The SNHG8 level was determined through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression levels of transient receptor potential melastatin 7 (TRPM7), endothelial nitric oxide synthase (eNOS), p-eNOS, extracellular signal-regulated kinase 1/2(ERK1/2), and p-ERK1/2 were assessed through western blot. Nitric oxide (NO) levels were measured with DAF-FM. pHUVEC migration was examined through wound healing and Transwell assay, and pHUVEC angiogenesis was observed through a tube formation assay. Results showed that HG promoted the expression of lncRNA SNHG8 and TRPM7 and decreased the ratio of p-eNOS/eNOS and p-ERK1/2/ERK1/2 in pHUVECs . NO production, migration , and angiogenesis were inhibited in pHUVECs under HG conditions. Silencing lncRNA SNHG8 and TRPM7 could significantly reverse the HG-induced decrease in eNOS activation, NO production , migration, and angiogenesis . SNHG8 and U0126 (ERK pathway inhibitor) overexpression enhanced the HG effects, whereas using U0126 did not affect the TRPM7 expression. In conclusion, lncRNA SNHG8 participates in HG-induced endothelial cell injury and likely regulates NO production, migration, and angiogenesis of pHUVECs via the TRPM7/ERK1/2 signaling axis.

Prognostic value of long-term antidiabetic and antihypertensive therapy in postoperative gastric cancer patients: the FIESTA study.

BACKGROUND: Gastric cancer is often comorbid with hypertension and diabetes mellitus and increases the mortality risk. MATERIALS AND METHODS: We conducted this prospective cohort study to investigate antidiabetics and antihypertensives' impact on gastric cancer survival. 3012 patients with gastric carcinoma undergoing radical gastrectomy were enrolled since January 2000 and followed up until July 2020. RESULTS: Hypertension and diabetes patients had worse survival than patients without hypertension and diabetes [median survival time (MST): 48 versus 112.5 months, p < 0.001 for hypertension, MST: 32.7 versus 183+ months, p < 0.001 for diabetes]. Compared to untreated patients, treated patients had better survival (MST: 109.7 months versus 39.1 months, p < 0.001 for antihypertensives, MST: 120.9 months versus 22.3 months, p < 0.001 for antidiabetics). Antihypertensives and antidiabetics were related to 42% (HR 0.58, 95% CI 0.47-0.73, p < 0.001) and 70% (HR 0.30, 95% CI 0.24-0.38, p < 0.001) reduced mortality risk relative to those without medications. metformin and Calcium channel blockers can better-improved prognosis compared to others (p = 0.00029 and p = 0.015). CONCLUSION: Post-surgical gastric cancer patients could benefit substantially from anti-diabetes and antihypertensive therapy. Metformin and Calcium channel blockers may be superior to other medications.

Hyperglycemia induces gastric carcinoma proliferation and migration via the Pin1/BRD4 pathway.

Diabetes is a potential risk factor for gastric cancer (GC). Pin1, a peptidyl-prolyl cis/trans isomerase, promotes GC cell proliferation and migration. The role and underlying mechanism of the Pin1/BRD4 axis in hyperglycemia-induced proliferation and migration of GC cells were analyzed in vivo and in vitro. Proliferation and migration of GC cells were measured; Pin1 and BRD4 expression of the cell cycle were determined. Pin1 and BRD4 were downregulated by transfecting Pin1 shRNA lentivirus into GC cells and JQ1-intervention GC cells. Tumor formation and lung metastasis were assessed in vivo. Inhibition of Pin1 and BRD4 significantly suppressed high-glucose (HG)-induced GC cell proliferation and migration. HG enhanced G1/S cell-cycle transition, associated with increased Pin1 and BRD4 expression. Silencing Pin1 significantly downregulated the expression of BRD4 and NAP1L1 and upregulated that of P21 in GC cells. In vivo studies indicated that hyperglycemia promotes tumor growth and lung metastasis by inducing Pin1 and BRD4 expression. Thus, Pin1/BRD4 plays an important role in hyperglycemia-promoted tumor growth. The significance of these findings toward improved prognosis of diabetic patients with GC cannot be underestimated.

Ketamine for Monitored Anesthesia Care During Transcatheter Aortic Valve Replacement.

PURPOSE: To study the feasibility and outcomes of ketamine as an anesthetic adjunct during monitored anesthesia care (MAC) in transcatheter aortic valve replacement (TAVR). DESIGN: This was a retrospective study. METHODS: Data from 155 consecutive TAVR patients at a tertiary care high-volume TAVR medical center were reviewed and analyzed. FINDINGS: Among the 155 TAVR cases under MAC, intravenous ketamine was administered as an adjunct in 126 patients. The most common ketamine dose was 20 mg. There was no significant difference for postoperative stroke, intraoperative conversion to general anesthesia, postoperative delirium, need for permanent pacemaker implantation, perivalvular leak and length of stay between the ketamine and non-ketamine groups. The ketamine group demonstrated a statistically significant lower 30-day mortality (P = .0381) and intraoperative cardiac arrest (P = .0025) rate when compared to the nonketamine group. CONCLUSIONS: Our results demonstrated that employing ketamine as an adjunct during MAC for TAVR is a feasible option.

The Impact of Bariatric Surgery Versus Non-Surgical Treatment on Blood Pressure: Systematic Review and Meta-Analysis.

The purpose of this study was to compare bariatric surgery versus non-surgical treatment on blood pressure for patients with obesity. Nineteen RCTs (1353 total patients) were included. In the pooled analyses, bariatric surgery reduces more systolic blood pressure (WMD: - 3.937 mmHg, CI95%: - 6.000 to - 1.875, p < 0.001, I2 = 0%), diastolic blood pressure (WMD: - 2.690 mmHg, CI95%: - 3.994 to - 1.385, P < 0.001, I2 = 0%) and more antihypertensives. In subgroup analyses, patients after Roux-en-Y gastric bypass, with poor control of hypertension (BP > 130/80 mmHg) and diabetes mellitus (HbA1C > 7.0%, FPG > 7.0 mmol/L), elder patients (> 45 years), non-severe obesity (BMI < 40 kg/cm2, body weight < 120 kg), less waist circumference (< 115 cm) tend to decrease more blood pressure. Besides, patients after surgery also lost more weight (p < 0.001), decreased more waist circumference (p < 0.001), fasting plasma glucose (p < 0.001), glycosylated hemoglobin (p < 0.001), triglycerides (p < 0.001), hsCRP (p = 0.001), increased more high-density lipoprotein cholesterol (p < 0.001), and had better remission of metabolic syndrome (p < 0.001). Changes in total cholesterol, low-density lipoprotein cholesterol, renal function, resting heart rate, and 6-min walking test were not significantly different. Therefore, bariatric surgery is more effective than non-surgical treatment in controlling patients' blood pressure.

Differential gene expression pattern in hypothalamus of chickens during fasting-induced metabolic reprogramming: functions of glucose and lipid metabolism in the feed intake of chickens.

Fasting-induced hypothalamic metabolic reprogramming is involved in regulating energy homeostasis and appetite in mammals, but this phenomenon remains unclear in poultry. In this study, the expression patterns of a panel of genes related to neuropeptides, glucose, and lipid metabolism enzymes in the hypothalamus of chickens during fasting and refeeding were characterized by microarray analysis and quantitative PCR. Results showed that 48 h of fasting upregulated (P < 0.05) the mRNA expressions of orexigenic neuropeptide Y and agouti-related protein but downregulated (P < 0.05) that of anorexigenic neuropeptide pro-opiomelanocortin; growth hormone-releasing hormone; islet amyloid polypeptide; thyroid-stimulating hormone, ß; and glycoprotein hormones, α polypeptide. After 48 h of fasting, the mRNA expression of fatty acid ß-oxidation [peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase 1A, and forkhead box O1], energy sensor protein [sirtuin 1 (SIRT1) and forkhead box O1], and glycolysis inhibitor (pyruvate dehydrogenase kinase, isozyme 4) were enhanced, but that of fatty acid synthesis and transport associated genes (acetyl-CoA carboxylase α, fatty acid synthase, apolipoprotein A-I, endothelial lipase, and fatty acid binding protein 7) were suppressed. Liver and muscle also demonstrated similar expression patterns of genes related to glucose and lipid metabolism with hypothalamus, except for that of acetyl-CoA carboxylase α, acyl-CoA synthetase long-chain family member 4, and apolipoprotein A-I. The results of intracerebroventricular (ICV) injection experiments confirmed that α-lipoic acid (ALA, pyruvate dehydrogenase kinase, isozyme 4 inhibitor, 0.10 µmol) and NADH (SIRT1 inhibitor, 0.80 µmol) significantly suppressed the appetite of chickens, whereas 2-deoxy-d-glucose (glycolytic inhibitor, 0.12 to 1.20 µmol) and NAD(+) (SIRT1 activator, 0.08 to 0.80 µmol) increased feed intake in chickens. The orexigenic effect of NAD(+) was also blocked by cotreatment with NADH. However, ICV injection of either GW7647 (PPARα agonist) or GW6471 (PPARα antagonist) showed no effects on feed intake. Results suggested that hypothalamic glycolysis (inhibited by ALA and promoted by 2-deoxy-d-glucose) and SIRT1 (inhibited by NADH and promoted by NAD(+)), not PPARα, were probably involved in feed intake regulation in chickens.

The anorexigenic effect of serotonin is mediated by the generation of NADPH oxidase-dependent ROS.

Serotonin (5-HT) is a central inhibitor of food intake in mammals. Thus far, the intracellular mechanisms for the effect of serotonin on appetite regulation remain unclear. It has been recently demonstrated that reactive oxygen species (ROS) in the hypothalamus are a crucial integrative target for the regulation of food intake. To investigate the role of ROS in the serotonin-induced anorexigenic effects, conscious mice were treated with 5-HT alone or combination with Trolox (a ROS scavenger) or Apocynin (an NADPH oxidase inhibitor) by acute intracerebroventricular injection. Both Trolox and Apocynin reversed the anorexigenic action of 5-HT and the 5-HT-induced hypothalamic ROS elevation. The mRNA and protein expression levels of pro-opiomelanocortin (POMC) were dramatically increased after ICV injection with 5-HT. The anorexigenic action of 5-HT was accompanied by markedly elevated hypothalamic MDA levels and GSH-Px activity, while the SOD activity was decreased. Moreover, 5-HT significantly increased the mRNA expression of UCP-2 but reduced the levels of UCP-3. Both Trolox and Apocynin could block the 5-HT-induced changes in UCP-2 and UCP-3 gene expression. Our study demonstrates for the first time that the anorexigenic effect of 5-HT is mediated by the generation of ROS in the hypothalamus through an NADPH oxidase-dependent pathway.

Berberine protects human renal proximal tubular cells from hypoxia/reoxygenation injury via inhibiting endoplasmic reticulum and mitochondrial stress pathways.

BACKGROUND: Ischemia/reperfusion injury plays a crucial role in renal transplantation, and represents a significant risk factor for acute renal failure and delayed graft function. The pathophysiological contribution of endoplasmic reticulum and mitochondria stress to ischemia/reperfusion injury has also been highlighted. Berberine (BBR) has been showed to attenuate ischemia/reperfusion injury by inhibiting oxidative stress. The study was carried out to investigate whether the pretreatment of BBR could reduce hypoxia/reoxygenation (H/R)-induced injury by inhibiting mitochondria stress and endoplasmic reticulum stress pathways. METHODS: The cultured human renal proximal tubular cell line HK-2 cells were exposed to 24 h hypoxia (5% CO2, 1% O2, 94% N2) followed by 3 h reoxygenation (5% CO2, 21% O2, 74% N2). And BBR was added to the culture medium 2h prior to the treatment. Then the cell viability, oxidative stress level, morphological change of apoptosis and apoptotic rate were determined. In addition, Western blot analysis was performed to identify the expression of apoptotic pathway parameters, including Bcl-2, Bax and cytochrome C involved in mitochondrial-dependent pathway and ER stress hallmarks such as glucose-regulated protein 78 and CCAAT/enhancer binding protein homologous protein. RESULTS: H/R produced dramatic injuries in HK-2 cells. The cell viability and the oxidative stress level in group H/R was significantly decreased. The classical morphological change of apoptosis was found, while the apoptotic rate and the expression of proteins involved in mitochondrial stress and endoplasmic reticulum stress pathways increased (p<0.05). Administration of BBR significantly inhibited these H/R induced changes (p<0.05). CONCLUSION: This study revealed that BBR pretreatment serves a protective role against H/R induced apoptosis of human renal proximal tubular cells, and the mechanism is related to suppression of mitochondrial stress and endoplasmic reticulum stress pathways.

Effects of "Bioactive" amino acids leucine, glutamate, arginine and tryptophan on feed intake and mRNA expression of relative neuropeptides in broiler chicks.

Feed intake control is vital to ensuring optimal nutrition and achieving full potential for growth and development in poultry. The aim of the present study was to investigate the effects of L-leucine, L-glutamate, L-tryptophan and L-arginine on feed intake and the mRNA expression levels of hypothalamic Neuropeptide involved in feed intake regulation in broiler chicks. Leucine, glutamate, tryptophan or arginine was intra-cerebroventricularly (ICV) administrated to 4d-old broiler chicks respectively and the feed intake were recorded at various time points. Quantitative PCR was performed to determine the hypothalamic mRNA expression levels of Neuropeptide Y (NPY), agouti related protein (AgRP), pro-opiomelanocortin (POMC), melanocortin receptor 4 (MC4R) and corticotrophin releasing factor (CRF). Our results showed that ICV administration of L-leucine (0.15 or 1.5 µmol) significantly (P < 0.05) increased feed intake up to 2 h post-administration period and elevated both hypothalamic NPY and AgRP mRNA expression levels. In contrast, ICV administration of L-glutamate (1.6 µmol) significantly (P < 0.05) decreased feed intake 0.25, 0.5 and 2 h post-injection, and increased hypothalamic CRF and MC4R mRNA expression levels. Meanwhile, both L-tryptophan (10 or 100 µg) and L-arginine (20 or 200 µg) had no significant effect on feed intake. These findings suggested that L-leucine and L-glutamate could act within the hypothalamus to influence food intake, and that both orexigenic and anorexigenic Neuropeptide genes might contribute directly to these effects.