Insulin Resistance and Hypertension: Mechanisms Involved and Modifying Factors for Effective Glucose Control.

Factors such as aging, an unhealthy lifestyle with decreased physical activity, snacking, a standard Western diet, and smoking contribute to raising blood pressure to a dangerous level, increasing the risk of coronary artery disease and heart failure. Atherosclerosis, or aging of the blood vessels, is a physiological process that has accelerated in the last decades by the overconsumption of carbohydrates as the primary sources of caloric intake, resulting in increased triglycerides and VLDL-cholesterol and insulin spikes. Classically, medications ranging from beta blockers to angiotensin II blockers and even calcium channel blockers were used alone or in combination with lifestyle modifications as management tools in modern medicine to control arterial blood pressure. However, it is not easy to control blood pressure or the associated complications. A low-carbohydrate, high-fat (LCHF) diet can reduce glucose and insulin spikes, improve insulin sensitivity, and lessen atherosclerosis risk factors. We reviewed articles describing the etiology of insulin resistance (IR) and its impact on arterial blood pressure from databases including PubMed, PubMed Central, and Google Scholar. We discuss how the LCHF diet is beneficial to maintaining arterial blood pressure at normal levels, slowing down the progression of atherosclerosis, and reducing the use of antihypertensive medications. The mechanisms involved in IR associated with hypertension are also highlighted.

Identification and functional characterization of two rare LDLR stop gain variants (p.C231* and p.R744*) in Saudi familial hypercholesterolemia patients.

BACKGROUND: Familial hypercholesterolemia (FH) is a globally underdiagnosed inherited metabolic disorder. Owing to limited published data from Arab world, this study was conducted with the aim of identifying the genetic and molecular basis of FH in highly consanguineous Saudi population. METHODS: We performed clinical screening, biochemical profiling, whole exome sequencing and variant segregation analysis of two Saudi FH families. Additionally, 500 normolipic individuals were screened to ensure the absence of FH variant in general Saudi population. Functional characterization of FH variants on secondary structure characteristics of RNA and protein molecules was performed using different bioinformatics modelling approaches. RESULTS: WES analysis identified two independent rare LDLR gene stop gain variants (p.C231* and p.R744*) consistent to the clinical presentation of FH patients from two different families. RNAfold analysis has shown that both variants were predicted to disturb the free energy dynamics of LDLR mRNA molecule and destabilize its folding pattern and function. PSIPRED based structural modelling analysis has suggested that both variants bring drastic changes disturbing the secondary structural elements of LDLR molecule. The p.C231* and p.R744* variants are responsible for partial or no protein product, thus they are class 1 variants causing loss of function (LoF) LDLR variants. CONCLUSIONS: This study highlights the effectiveness of the WES, sanger sequencing, and computational analysis in expanding FH variant spectrum in culturally distinct populations like Saudi Arabia. Genetic testing of FH patients is very essential in better clinical diagnosis, screening, treatment, and management and prevention of cardiovascular disease burden in the society.

Low-Carbohydrate Ketogenic Diet for Improvement of Glycemic Control: Mechanism of Action of Ketosis and Beneficial Effects.

The incidence of metabolic syndrome and diabetes mellitus is increasing globally. A diet rich in carbohydrates increases the hyperglycemic state. While considering the lifestyle changes to combat life-threatening diseases, there is an effort to decrease the daily intake of carbohydrates. A low-carbohydrate diet also makes the body rely more on fat for energy, so there is less fat accumulation. A diet is considered to be low-carbohydrate ketogenic if the intake is ≤ 50 g per day. The 'low -carbohydrate ketogenic diet' (LCKD) produces ketosis. LCKD contains high-fat, moderateprotein, and low-carbohydrate components. The main objectives of the present review are to discuss insulin resistance in different viscera of the body, describe the role of adipokines in insulin resistance, understand the mechanism of ketogenesis, and determine the impact of LCKD in overcoming insulin resistance in the body. In the present review, we also highlight the beneficial effects of LCKD in metabolic, neurodegenerative, cardiovascular, and lipid disorders and discuss the effect on longevity and aging. LCKD may help in combating the morbidity and mortality arising from the above-mentioned diseases and also help in leading a better quality of life.

Integrative global co-expression analysis identifies key microRNA-target gene networks as key blood biomarkers for obesity.

BACKGROUND: Obesity is associated with the quantitative changes in miRNAs and their target genes. However, the molecular basis of their dysregulation and expression status correlations is incompletely understood. Therefore, this study aims to examine the shared differentially expressed miRNAs and their target genes between blood and adipose tissues of obese individuals to identify potential blood-based biomarkers. METHODS: In this study, 3 gene expression datasets (two mRNA and one miRNA), generated from blood and adipose tissues of 68 obese and 39 lean individuals, were analyzed by a series of robust computational concepts, like protein interactome mapping, functional enrichment of biological pathways and construction of miRNA-mRNA and transcription factor gene networks. RESULTS: The comparison of blood versus tissue datasets has revealed the shared differential expression of 210 genes (59.5% upregulated) involved in lipid metabolism and inflammatory reactions. The blood miRNA (GSE25470) analysis has identified 79 differentially expressed miRNAs (71% downregulated). The miRNA-target gene scan identified regulation of 30 shared genes by 22miRNAs. The gene network analysis has identified the inverse expression correlation between 8 target genes (TP53, DYSF, GAB2, GFRA2, NACC2, FAM53C, JNK and GAB2) and 3 key miRNAs (hsa-mir-940, hsa-mir-765, hsa-mir-612), which are further regulated by 24 key transcription factors. CONCLUSIONS: This study identifies potential obesity related blood biomarkers from large-scale gene expression data by computational miRNA-target gene interactome and transcription factor network construction methods.

An Overview of the Perspective of Cellular Autophagy: Mechanism, Regulation, and the Role of Autophagy Dysregulation in the Pathogenesis of Diseases.

Autophagy is a cellular process that eliminates unnecessary cytoplasmic materials, such as long-age proteins, destroyed organelles, and foreign microorganisms. Macroautophagy (MaA), chaperone-mediated autophagy, and microautophagy are the three main types of autophagy. It is regulated by the integration of signaling from the AMPK and mTOR-ULK1 pathways. Autophagy plays a physiological role in health, and its dysregulation could be a pathophysiologic mechanism in different disease conditions. In the current study, we reviewed papers of Google Scholar database, PubMed, PubMed Central, Cochrane Database of Systematic Reviews, MEDLINE, and MedlinePlus with no time limitation and a recent World Health Organization report. In the current review, it could be concluded that autophagy plays many physiological functions, including immune system modulation, and regulates different cellular processes such as metabolism, protein synthesis, and cellular transportation. Dysregulation of autophagy is implicated in tumorigenesis, aging, age-related neurodegeneration, and endothelial dysfunctions. Autophagy dysregulation is also implicated in the newly discovered CoV-COVID-19 pathogenesis.

Cellular Senescence and Vitamin D Deficiency Play a Role in the Pathogenesis of Obesity-Associated Subclinical Atherosclerosis: Study of the Potential Protective Role of Vitamin D Supplementation.

The exact link between obesity, vitamin D deficiency, and their relation to cellular senescence in the pathogenesis of subclinical atherosclerosis is still under debate. Therefore, the current study aims to verify the possible role of vitamin D deficiency and cellular senescence in the pathogenesis of obesity-related subclinical atherosclerosis. Moreover, it aims to investigate the possible protective role of vitamin D supplementation. Fifty-seven male albino rats were enrolled in the study and classified into four groups: negative (10) and positive control groups (10), an obese model group (24), and a vitamin-D-supplemented obese group (13). Aortic tissue samples and fasting blood samples were collected. The following biochemical investigations were performed: serum cholesterol, triglycerides, HDL-C, LDL-C, ALT, AST, CPK, CK-MB, and hs-cTnt. HOMA-IR was calculated. Moreover, serum SMP-30, 25 (OH)Vitamin D3, and eNOS were determined by the ELISA technique. Aortic gene expression of eNOS, SMP-30, and P53 was estimated by real-time qRT-PCR. Serum 25(OH) D3 and SMP-30 were lower in the obese group. In addition, the obese group showed higher serum lipid profile, HOMA-IR, eNOS, ALT, AST, CPK, CK-MB, and hs-cTnt than the control groups, while decreased levels were found in the vitamin-D-treated obese group. Gene expression of eNOS and SMP-30 were in accordance with their serum levels. A positive correlation was found between vitamin D level and SMP-30. In conclusion, obesity is associated with vitamin D deficiency and enhanced cellular senescence. They could play a role in the pathogenesis of obesity-associated subclinical atherosclerosis and endothelial dysfunction. Vitamin D supplements could play a protective role against such obesity-related comorbidity.

Study of Cellular Senescence and Vitamin D Deficiency in Nonalcoholic Fatty Liver Disease and The Potential Protective Effect of Vitamin D Supplementation.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a pathological process characterized by excessive hepatic fatty deposition with possible involvement of vitamin D deficiency and cellular senescence. The aim of this study is to investigate the pathophysiologic role of vitamin D deficiency and cellular senescence in NAFLD development. Moreover, it aims to investigate the potential protective role of vitamin D supplementation. METHODS: This is an experimental Case/Control study. Forty-five male albino rats were enrolled in this study. Animals were divided into four groups: negative and positive control groups (10 for each group), a model of NAFLD (11) and vitamin D-treated NAFLD groups (14). At the end of the experiment, all rats were subjected to the following investigation; biochemical estimation of serum 25 hydroxycholecalciferol, senescence marker protein-30 (SMP-30), lipid profile and calculation of homeostatic model of insulin resistance (HOMA-IR). RESULTS: NAFLD group shows a significant increase in glucose, insulin levels, and HOMA- IR compared with both normal controls. This finding indicates the intimate association between insulin resistance and NAFLD pathogenesis. Moreover, it was found that NAFLD group shows a significant decrease in SMP-30 level compared with normal controls. While vitamin D-treated NAFLD group shows significant increased SMP-30 and decrease in HOMA-IR in comparison with nontreated NAFLD group. CONCLUSION: Vitamin D deficiency and increased cellular senescence are key features of NAFLD. Vitamin D supplementation could play a protective role, which needs further investigation including clinical human study.

Changing trends of prosthetic rehabilitation of partially edentulous patients visiting a tertiary care dental hospital.

INTRODUCTION: The choice of prosthetic replacement is largely determined by the patient's choice and economic status, available technology and expertise, as well as the number of missing teeth. The aim of this study was to identify the trend in prosthetic replacement, in partially edentulous patients treated at Riyadh Elm University (REU) hospitals, as well as to investigate the factors that might influence the prosthetic choice. METHODS: The records from Dentoplus digital system of all partially edentulous patients who had a prosthetic replacement at REU 2013, until June 2018, were screened and analyzed using Statistical software SPSS version 25. Chi-square and Fisher exact tests were performed. Alpha level was set at ≤0.05. RESULTS: 6,340 patients received implants, removable or fixed prosthesis. Majority of the patients were females (60%). RPDs were the highest placed restorations (69%). Students (73%) placed most RPDs. Implants significantly increased through the years by almost (30%) (P-value = 0.00). Among FPDs, metal-ceramics were the highest restorations (74%), with a significant increase of all-ceramic restorations through years (P-value = 0.00). Moreover, FPDs were significantly the highest restorations among young-adult and middle-aged patients (P-value = 0.00). CONCLUSION: There was a clear change in prosthetic rehabilitation trends over the past few years. Although removable partial dentures continued to play a major role in prosthetic teeth replacement, the use of dental implants showed a steady increase every year. Students' requirements and level of experience, along with the patient age, had an influence in the prosthetic choice.

Hypobetalipoproteinaemia secondary to chronic hepatitis C virus infection in a patient with familial hypercholesterolaemia.

Familial hypercholesterolaemia (FH) is a common genetic disorder characterized by high plasma low-density lipoprotein (LDL)-cholesterol and premature coronary artery disease. Many factors, such as illness, high-dose statin therapy or a strict vegan diet can cause hypobetalipoproteinaemia (HBL). The more common secondary causes of HBL in the hospital setting include cachexia, intestinal malabsorption, malnutrition, severe liver disease and hyperthyroidism. We report a case of HBL in a 43-year-old man with previously demonstrated marked hypercholesterolaemia who attended a lipid disorders clinic for FH cascade screening. Surprisingly, a lipid profile taken at that time showed low plasma LDL-cholesterol and apolipoprotein B concentrations of 1.6 mmol/L and 0.61 g/L, respectively. He was not on lipid-lowering therapy. DNA sequencing showed that he was heterozygous for the LDLR gene mutation (C677R) present in other affected family members. Of interest, his serum transaminases were increased by approximately 3-fold and hepatitis serology and genotyping confirmed a diagnosis of hepatitis C virus (HCV) infection. In summary, we describe a case of HBL secondary to chronic HCV infection in a patient with FH, confirmed by mutational analysis.

Efficiency of percutaneous testicular sperm aspiration as a mode of sperm collection for intracytoplasmic sperm injection in nonobstructive azoospermia.

PURPOSE: We determined the feasibility of obtaining mature spermatozoa for intracytoplasmic sperm injection (ICSI) by percutaneous testicular sperm aspiration in men with nonobstructive azoospermia. We also compared the results of ICSI using spermatozoa recovered by open excisional biopsy versus percutaneous testicular sperm aspiration. MATERIALS AND METHODS: A total of 84 men with nonobstructive azoospermia underwent percutaneous testicular sperm aspiration to recover testicular spermatozoa for ICSI on the day of ova retrieval from the wife. Percutaneous testicular sperm aspiration was performed with the patient under general anesthesia in the upper and lower poles of each testis. It was followed by immediate microscopic search of the aspirate to confirm the presence of spermatozoa. In the absence of spermatozoa open excisional biopsy was performed in the same setting. RESULTS: Percutaneous testicular sperm aspiration resulted in the recovery of mature spermatozoa in 45 men (53.6%). Of the remaining 39 men (46.4%) requiring open biopsy adequate spermatozoa were recovered in 28 (71.8%). Although the fertilization rate was significantly higher in the sperm aspiration group, the cleavage and pregnancy rates were similar in the 2 groups. CONCLUSIONS: Percutaneous testicular sperm aspiration was a successful initial approach to collect mature spermatozoa in a high proportion of men with nonobstructive azoospermia. It is safe, minimally invasive and well tolerated by all patients.