Slow gut transit increases the risk of Alzheimer's disease: An integrated study of the bi-national cohort in South Korea and Japan and Alzheimer's disease model mice.

INTRODUCTION: Although the association between Alzheimer's disease (AD) and constipation is controversial, its causality and underlying mechanisms remain unknown. OBJECTIVES: To investigate the potential association between slow gut transit and AD using epidemiological data and a murine model. METHODS: We conducted a bi-national cohort study in South Korea (discovery cohort, N=3,130,193) and Japan (validation cohort, N=4,379,285) during the pre-observation period to determine the previous diagnostic history (2009-2010) and the follow-up period (2011-2021). To evaluate the causality, we induced slow gut transit using loperamide in 5xFAD transgenic mice. Changes in amyloid-beta (Aß) and other markers were examined using ELISA, qRT-PCR, RNA-seq, and behavioral tests. RESULTS: Constipation was associated with an increased risk of AD in the discovery cohort (hazard ratio, 2.04; 95% confidence interval [CI], 2.01-2.07) and the validation cohort (hazard ratio; 2.82; 95% CI, 2.61-3.05). We found that loperamide induced slower gut transit in 5xFAD mice, increased Aß and microglia levels in the brain, increased transcription of genes related to norepinephrine secretion and immune responses, and decreased the transcription of defense against bacteria in the colonic tissue. CONCLUSION: Impaired gut transit may contribute to AD pathogenesis via the gut-brain axis, thus suggesting a cyclical relationship between intestinal barrier disruption and Aß accumulation in the brain. We propose that gut transit or motility may be a modifiable lifestyle factor in the prevention of AD, and further clinical investigations are warranted.

Assessment HOMA as a predictor for new onset diabetes mellitus and diabetic complications in non-diabetic adults: a KoGES prospective cohort study.

BACKGROUND: Homeostasis model assessment for insulin resistance (HOMA-IR) is a biomarker for type 2 diabetes mellitus (T2DM). However, the role of HOMA-IR in the non-diabetic is unclear. This study aimed to determine whether IR measured HOMA-IR value is associated with new onset diabetes as well as vascular disease and can be used as an early predictor for diabetes and vascular diseases in non-diabetic participants. METHODS: From a prospective community-based cohort of 10,030 individuals, 4314 individuals younger than 65 years and without diabetes were enrolled and divided into three groups by baseline HOMA-IR tertiles: low (n = 1454), moderate (n = 1414), and high (n = 1446). The primary outcome was new onset T2DM. Secondary outcomes were chronic kidney disease (CKD) and a composite of coronary artery disease, myocardial infarction, and stroke as macrovascular events. RESULTS: The mean age was 51 years. The prevalence of hypertension and cholesterol and HbA1c were higher in the high HOMA-IR group. New onset T2DM (5.8%) and CKD (12.2%) incidence in the high HOMA-IR group was higher than that in the others. The prevalence of macrovascular events did not differ among groups. High-HOMA-IR was an independent risk factor for new onset T2DM (odds ratio 1.86 [1.17-2.96]; p = 0.01) and CKD (1.49 [1.12-1.98]; p = 0.01). CONCLUSIONS: High HOMA-IR was an early predictor of new onset T2DM and CKD, regardless of HbA1c in non-diabetic individuals. Further research on the specific cut off value will be needed.

LY6D is crucial for lipid accumulation and inflammation in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a serious metabolic disorder characterized by excess fat accumulation in the liver. Over the past decade, NAFLD prevalence and incidence have risen globally. There are currently no effective licensed drugs for its treatment. Thus, further study is required to identify new targets for NAFLD prevention and treatment. In this study, we fed C57BL6/J mice one of three diets, a standard chow diet, high-sucrose diet, or high-fat diet, and then characterized them. The mice fed a high-sucrose diet had more severely compacted macrovesicular and microvesicular lipid droplets than those in the other groups. Mouse liver transcriptome analysis identified lymphocyte antigen 6 family member D (Ly6d) as a key regulator of hepatic steatosis and the inflammatory response. Data from the Genotype-Tissue Expression project database showed that individuals with high liver Ly6d expression had more severe NAFLD histology than those with low liver Ly6d expression. In AML12 mouse hepatocytes, Ly6d overexpression increased lipid accumulation, while Ly6d knockdown decreased lipid accumulation. Inhibition of Ly6d ameliorated hepatic steatosis in a diet-induced NAFLD mouse model. Western blot analysis showed that Ly6d phosphorylated and activated ATP citrate lyase, which is a key enzyme in de novo lipogenesis. In addition, RNA- and ATAC-sequencing analyses revealed that Ly6d drives NAFLD progression by causing genetic and epigenetic changes. In conclusion, Ly6d is responsible for the regulation of lipid metabolism, and inhibiting Ly6d can prevent diet-induced steatosis in the liver. These findings highlight Ly6d as a novel therapeutic target for NAFLD.

Clinical features and molecular genetics associated with brain metastasis in suspected early-stage non-small cell lung cancer.

Introduction: Regarding whether brain magnetic resonance imaging (MRI) should be routine in patients with suspected early-stage lung cancer, guideline recommendations are inconsistent. Therefore, we performed this study to evaluate the incidence of and risk factors for brain metastasis (BM) in patients with suspected early-stage non-small-cell lung cancer (NSCLC). Methods: A review of the medical charts of consecutive NSCLC patients diagnosed between January 2006 and May 2020 was performed. We identified 1,382 NSCLC patients with clinical staging of T1/2aN0M0 (excluding BM), and investigated the incidence, clinical predictors, and prognosis of BM in the cohort. We also performed RNA-sequencing differential expression analysis using transcriptome of 8 patients, using DESeq2 package (version 1.32.0) with R (version 4.1.0). Results: Among 1,382 patients, nine hundred forty-nine patients (68.7%) underwent brain MRI during staging, and 34 patients (3.6%) were shown to have BM. Firth's bias-reduced logistic regression showed that tumor size (OR 1.056; 95% CI 1.009-1.106, p=0.018) was the only predictor of BM, and pathologic type was not a predictor of BM in our cohort (p>0.05). The median overall survival for patients with brain metastasis was 5.5 years, which is better than previously reported in the literature. RNA-sequencing differential expression analysis revealed the top 10 significantly upregulated genes and top 10 significantly downregulated genes. Among the genes involved in BM, Unc-79 homolog, non-selective sodium leak channel (NALCN) channel complex subunit (UNC79) was the most highly expressed gene in the lung adenocarcinoma tissues from the BM group, and an in vitro assay using A549 cells revealed that the NALCN inhibitor suppressed lung cancer cell proliferation and migration. Conclusions: Given the incidence and favorable outcome of BM in patients with suspected early-stage NSCLC, selective screening with brain MRI may be considered, especially in patients with high-risk features.

Pharmacologic Activation of Angiotensin-Converting Enzyme II Alleviates Diabetic Cardiomyopathy in db/db Mice by Reducing Reactive Oxidative Stress.

BACKGRUOUND: Diabetes mellitus is one of the most common chronic diseases worldwide, and cardiovascular disease is the leading cause of morbidity and mortality in diabetic patients. Diabetic cardiomyopathy (DCM) is a phenomenon characterized by a deterioration in cardiac function and structure, independent of vascular complications. Among many possible causes, the renin-angiotensin-aldosterone system and angiotensin II have been proposed as major drivers of DCM development. In the current study, we aimed to investigate the effects of pharmacological activation of angiotensin-converting enzyme 2 (ACE2) on DCM. METHODS: The ACE2 activator diminazene aceturate (DIZE) was administered intraperitoneally to male db/db mice (8 weeks old) for 8 weeks. Transthoracic echocardiography was used to assess cardiac mass and function in mice. Cardiac structure and fibrotic changes were examined using histology and immunohistochemistry. Gene and protein expression levels were examined using quantitative reverse transcription polymerase chain reaction and Western blotting, respectively. Additionally, RNA sequencing was performed to investigate the underlying mechanisms of the effects of DIZE and identify novel potential therapeutic targets for DCM. RESULTS: Echocardiography revealed that in DCM, the administration of DIZE significantly improved cardiac function as well as reduced cardiac hypertrophy and fibrosis. Transcriptome analysis revealed that DIZE treatment suppresses oxidative stress and several pathways related to cardiac hypertrophy. CONCLUSION: DIZE prevented the diabetes mellitus-mediated structural and functional deterioration of mouse hearts. Our findings suggest that the pharmacological activation of ACE2 could be a novel treatment strategy for DCM.

Integrated analysis of the microbiota-gut-brain axis in response to sleep deprivation and diet-induced obesity.

Introduction: Sleep deprivation (SD) and obesity are common in modern societies. SD and obesity frequently coexist, but research on the combined consequences of SD and obesity has been limited. In this study, we investigated the gut microbiota and host responses to SD and high-fat diet (HFD)-induced obesity. In addition, we attempted to identify key mediators of the microbiota-gut-brain axis. Methods: C57BL/6J mice were divided into four groups based on whether they were sleep deprived and whether they were fed a standard chow diet (SCD) or HFD. We then performed fecal microbiome shotgun sequencing, gut transcriptome analysis using RNA sequencing, and brain mRNA expression analysis using the nanoString nCounter Mouse Neuroinflammation Panel. Results: The gut microbiota was significantly altered by the HFD, whereas the gut transcriptome was primarily influenced by SD. Sleep and diet are both important in the inflammatory system of the brain. When SD and the HFD were combined, the inflammatory system of the brain was severely disrupted. In addition, inosine-5' phosphate may be the gut microbial metabolite that mediates microbiota-gut-brain interactions. To identify the major drivers of this interaction, we analyzed the multi-omics data. Integrative analysis revealed two driver factors that were mostly composed of the gut microbiota. We discovered that the gut microbiota may be the primary driver of microbiota-gut-brain interactions. Discussion: These findings imply that healing gut dysbiosis may be a viable therapeutic target for enhancing sleep quality and curing obesity-related dysfunction.

Exploring the Genetic Associations Between the Use of Statins and Alzheimer's Disease.

Objective: Alzheimer's disease (AD) is the most common cause of dementia. The statins have shown beneficial effects on cognitive functions and reduced the risk of dementia development. However, the exact mechanisms of statin effects in AD are not yet fully understood. In this study, we aimed to explore the underlying mechanisms of statin on AD. Methods: We downloaded AD blood dataset (GSE63060) and statin-related blood gene expression dataset (GSE86216). Then we performed gene expression analysis of each dataset and compared blood gene expressions between AD patients and statin-treated patients. Then, we downloaded mouse embryonic neural stem cell dataset (GSE111945) and performed gene expression analysis. Results: From the human blood dataset, we identified upregulated/downregulated genes in AD patients and statin-treated patients. Some of the upregulated genes (AEN, MBTPS1, ABCG1) in the blood of AD patients are downregulated in statin-treated patients. Several downregulated genes (FGL2, HMGCS1, PSME2, SRSF3, and ATG3) are upregulated in statin-treated patients. Gene set enrichment analysis using mouse stem cell dataset revealed a significant relationship of Kyoto Encyclopedia of Genes and Genomes-defined pathway of AD in statin-treated neural stem cells compared to vehicle-treated neural stem cells (normalized enrichment score: -2.24 in male and -1.6 in female). Conclusion: These gene expression analyses from human blood and mouse neural stem cell demonstrate the important clues on the molecular mechanisms of impacts of statin on AD disease. Further studies are needed to investigate the exact role of candidate genes and pathways suggested in our AD pathogenesis study.

Efficacy and Safety of the New Appetite Suppressant, Liraglutide: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Obesity is a chronic disease associated with metabolic diseases such as diabetes and cardiovascular disease. Since the U.S. Food and Drug Administration approved liraglutide as an anti-obesity drug for nondiabetic patients in 2014, it has been widely used for weight control in overweight and obese people. This study aimed to systematically analyze the effects of liraglutide on body weight and other cardiometabolic parameters. METHODS: We investigated articles from PubMed, EMBASE, and the Cochrane Library to search randomized clinical trials that examined body weight changes with liraglutide treatment. RESULTS: We included 31 studies with 8,060 participants for this meta-analysis. The mean difference (MD) between the liraglutide group and the placebo group was -4.19 kg (95% confidence interval [CI], -4.84 to -3.55), with a -4.16% change from the baseline (95% CI, -4.90 to -3.43). Liraglutide treatment correlated with a significantly reduced body mass index (MD: -1.55; 95% CI, -1.76 to -1.34) and waist circumference (MD: -3.11 cm; 95% CI, -3.59 to -2.62) and significantly decreased blood pressure (systolic blood pressure, MD: -2.85 mm Hg; 95% CI, -3.36 to -2.35; diastolic blood pressure, MD: -0.66 mm Hg; 95% CI, -1.02 to -0.30), glycated hemoglobin (MD: -0.40%; 95% CI, -0.49 to -0.31), and low-density lipoprotein cholesterol (MD: -2.91 mg/dL; 95% CI, -5.28 to -0.53; MD: -0.87% change from baseline; 95% CI, -1.17 to -0.56). CONCLUSION: Liraglutide is effective for weight control and can be a promising drug for cardiovascular protection in overweight and obese people.

A Systems Biology Approach to Investigating the Interaction between Serotonin Synthesis by Tryptophan Hydroxylase and the Metabolic Homeostasis.

Obesity has become a global public health and economic problem. Obesity is a major risk factor for a number of complications, such as type 2 diabetes, cardiovascular disease, fatty liver disease, and cancer. Serotonin (5-hydroxytryptamine [5-HT]) is a biogenic monoamine that plays various roles in metabolic homeostasis. It is well known that central 5-HT regulates appetite and mood. Several 5-HT receptor agonists and selective serotonin receptor uptake inhibitors (SSRIs) have shown beneficial effects on appetite and mood control in clinics. Although several genetic polymorphisms related to 5-HT synthesis and its receptors are strongly associated with obesity, there is little evidence of the role of peripheral 5-HT in human metabolism. In this study, we performed a systemic analysis of transcriptome data from the Genotype-Tissue Expression (GTEX) database. We investigated the expression of 5-HT and tryptophan hydroxylase (TPH), the rate-limiting enzyme of 5-HT biosynthesis, in the human brain and peripheral tissues. We also performed differential gene expression analysis and predicted changes in metabolites by comparing gene expressions of tissues with high TPH expression to the gene expressions of tissues with low TPH expression. Our analyses provide strong evidence that serotonin plays an important role in the regulation of metabolic homeostasis in humans.