Nano-curcumin versus curcumin in amelioration of deltamethrin-induced hippocampal damage.

We aimed to prove that oxidative stress is the main mechanism responsible for hippocampal neurotoxicity induced by deltamethrin (DLM). The protective role of curcumin (CMN) and nano-curcumin (NCMN) over this toxicity was studied. The rats were categorized into four groups: control, DLM, CMN and NCMN. The study continued for 30 days. Hippocampus was processed for histological, biochemical and immunohistochemical studies. Caspase-3, glial fibrillar acidic protein (GFAP), acetylcholinesterase (AChE), malondialdehyde (MDA), glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) were measured for DLM-induced oxidative stress (increased MDA by 354%/decreased GSH by 61%, SOD by 61%, CAT 57%). Oxidative stress induced apoptosis of hippocampal neurons through increasing Nrf2, gamma-glutamyl cysteine synthetase heavy subunit (GCS-HS) and light subunit (GCS-LS) and decreasing AChE. It increases the activity of astrocytes through increasing GFAP. Finally, oxidative stress has a bad impaction on cognitive function. Improvement of oxidative stress was observed with use of CMN and NCMN (decrease of MDA/increase of GSH, SOD, CAT). The level of Nrf2, GCS-HS and GCS-LS decreased, while AChE, GFAP increased. Improvement of cognitive function was observed in both groups. In conclusion, oxidative stress is the common mechanism responsible for DLM-induced hippocampal neurotoxicity. It exerts apoptosis of hippocampal neurons through increasing Nrf2, HS-GCS, LS-GCS and decreasing AChE. In addition, it activates astrocytes through increasing expression of GFAP. The protective role of CMN and CMMN is related to their potent antioxidant effect. Much improvement has been detected with NCMN as compared to CMN.

Wellness programme at the workplace promotes dietary change and improves health indicators in a longitudinal retrospective study.

OBJECTIVE: To determine the effectiveness of a workplace wellness programme intervention in improving participants' behaviour towards choosing a healthy diet and the correlation with health indicators. DESIGN: A retrospective cohort study. SETTING: Wellness programme in the Midwest, USA. SUBJECTS: Employees (n 12 636) who participated in a wellness programme for three consecutive years during years 2004 to 2013 and who completed web-based health risk questionnaires. The wellness programme included annual health screening, laboratory measures, health risk questionnaire and personalized health-care programme. Participants' food group intakes, BMI and health indicators were compared between the first and last year of participation. McNemar's non-parametric test was used for paired nominal data. Pearson correlations were computed for paired food and health indicator measurements. Correlations between dietary intake and BMI, cholesterol and TAG were computed using Pearson correlations and McNemar's test. RESULTS: There were negative correlations between intakes of fruits, vegetables, grains, dairy, healthy eating pattern and health outcome indicators such as BMI and TAG levels. Additionally, the percentage of employees who increased their consumption of fruits (16·88 v. 12·08 %, P<0·001), vegetables (15·20 v. 11·44 %, P<0·001) and dark green leafy vegetables (12·03 v. 7·27 %, P 0·001) was significantly higher than the percentage of participants who decreased their intake of these food groups during the third-year follow-up. CONCLUSIONS: The wellness programme improved some health indicator parameters and had a positive impact on increasing participants' intakes of fruits, vegetables and whole grains at the third year of follow-up.

Neighbourhood exposure to point-of-sale price promotions for cigarettes is associated with financial stress among smokers: results from a population-based study.

AIM: To examine the association between neighbourhood exposure to point-of-sale (POS) cigarette price promotions and financial stress among smokers in a Midwestern metropolitan area in the USA. METHODS: Survey data from 888 smokers provided information on sociodemographic and smoking related variables. Financial stress was measured with the question: 'In the last six months, because of lack of money, was there a time when you were unable to buy food or pay any important bills on time, such as electricity, telephone, credit card, rent or your mortgage? (Yes/No).' Using audit data from 504 tobacco retailers, we estimated a score of POS price promotions for each respondent by summing the different types of promotion in each store in their neighbourhood, as defined by a 1-km roadway buffer. RESULTS: Adjusted results provided strong support for an association between higher scores of neighbourhood POS cigarette price promotions and a higher probability of financial stress (p=0.007). CONCLUSION: Exposure to POS cigarette price promotions is associated with financial stress. This finding, coupled with previous reports that smokers with financial stress are less likely to attempt to quit or succeed in quitting smoking, suggests that POS cigarette price promotions may act as an impediment to smoking cessation.

The influence of BMI on the association between serum lycopene and the metabolic syndrome.

Overweight and obese individuals have an increased risk of developing the metabolic syndrome because of subsequent chronic inflammation and oxidative stress, which the antioxidant nutrient lycopene can reduce. However, studies indicate that different BMI statuses can alter the positive effects of lycopene. Therefore, the purpose of this study was to examine how BMI influences the association between serum lycopene and the metabolic syndrome. The tertile rank method was used to divide 13 196 participants, aged 20 years and older, into three groups according to serum concentrations of lycopene. The associations between serum lycopene and the metabolic syndrome were analysed separately for normal-weight, overweight and obese participants. Overall, the prevalence of the metabolic syndrome was significantly higher in the first tertile group (OR 38·6%; 95% CI 36·9, 40·3) compared with the second tertile group (OR 29·3%; 95% CI 27·5, 31·1) and the third tertile group (OR 26·6%; 95% CI 24·9, 28·3). However, the associations between lycopene and the metabolic syndrome were only significant for normal-weight and overweight participants (P0·05), even after adjusting for possible confounding variables. In conclusion, BMI appears to strongly influence the association between serum lycopene and the metabolic syndrome.

Point-of-sale cigarette marketing and smoking-induced deprivation in smokers: results from a population-based survey.

BACKGROUND: Strict restrictions on outdoor cigarette marketing have resulted in increasing concentration of cigarette marketing at the point-of-sale (POS). The association between POS cigarette marketing and smoking-induced deprivation (SID) has never been studied. The aim of this study was to examine this association and how it is mediated by cravings to smoke, urges to buy cigarettes, and unplanned purchases of cigarettes. METHODS: Data from a telephone survey of 939 smokers were collected in Omaha, Nebraska. POS cigarette marketing was measured by asking respondents three questions about noticing pack displays, advertisements, and promotions such as cigarette price discounts within their respective neighborhoods. SID was measured with the following question: "In the last six months, has there been a time when the money you spent on cigarettes resulted in not having enough money for household essentials such as food? [yes/no]" We used structural equation modeling to examine the study aim. RESULTS: There was overwhelming evidence for an association between higher levels of POS cigarette marketing and a higher probability of SID (p < 0.001). This association was partly mediated by cravings to smoke, urges to buy cigarettes, and unplanned purchases of cigarettes during a visit to a neighborhood store (p < 0.001). CONCLUSION: Given that POS cigarette marketing is associated with a higher probability of experiencing SID, policies that ban POS cigarette marketing might help some smokers afford essentials household items such as food more easily and thus have better standards of living.

A Sex-Specific Analysis of Nutrition Label Use and Health, Douglas County, Nebraska, 2013.

INTRODUCTION: In 2014 the US Food and Drug Administration proposed a series of changes to its 1992 guidelines on nutrition facts labeling to help consumers make informed food choices. To date, few studies have examined the association between consumers' use of the nutrition label and health. The objective of this study was to assess the association between nutrition label use and health and to determine whether the association differs by sex. METHODS: Using data from a population-based, random sample survey of 1,503 participants conducted in Nebraska in 2013, we performed χ(2) tests to examine bivariate associations between selected health variables and nutrition label use, followed by logistic regression analysis to estimate these associations in a multivariate framework. RESULTS: A U-shaped relationship between self-rated health (SRH) and nutrition label use was observed. Both excellent and poor SRH were associated with a higher likelihood of nutrition label use than the 3 SRH categories in between. Being obese or having 1 of 4 chronic conditions (hypertension, diabetes, heart disease, high cholesterol) were both associated with higher odds of nutrition label use (odds ratio [OR] = 2.63, P < .001; OR = 1.71, P < .05, respectively) among men. These associations, however, were not significant among women. CONCLUSION: A close association existed between health and nutritional label use. This association was more pronounced among men than among women. Nutrition education may benefit from factoring in the association between health and use of nutrition labels and the differences in these associations by sex.

The potential effect of ambrisentan as monotherapy and combined with tadalafil on diabetic erectile dysfunction in rats.

INTRODUCTION: This study investigated the role of ambrisentan; the selective endothelin type-A receptor (ETAR) blocker on experimental diabetic erectile dysfunction in rats. MATERIALS AND METHODS: Eighty-four adult male Sprague Albino rats were divided randomly into 7 groups. Three control groups received 1 mL saline, 0.2 mg/kg/d ambrisentan and 1.5 mg/kg/d tadalafil, respectively orally for 4 weeks. The remaining four groups were fed high fat diet for 14 days. Diabetes was induced by a single intra-peritoneal injection of 40 mg/kg streptozotocin. After 72 h, diabetes was confirmed by plasma glucose level ⩾250 mg/dL. Diabetic rats were divided randomly into four groups, numbered from 4 to 7. The fourth group was the diabetic-control group, while the fifth and sixth groups received ambrisentan and tadalafil respectively. The seventh group received a combination of both drugs. Treatment continued for 4 weeks then, copulatory, intracavernous pressure measurement, and laboratory tests were conducted. RESULTS: In diabetic rats, ambrisentan and tadalafil improved fasting glucose, insulin, insulin resistance, testosterone, nitric oxide, and rho kinase (ROCK) values compared to diabetic group with the maximum improvement achieved in ambrisentan/tadalafil group (p < 0.05). Ambrisentan also enhanced ICP and improved latency to erection and number of mounts with a tolerable SBP. Yet, ambrisentan/tadalafil combined therapy resulted in deterioration in SBP with consecutive worsening in ICP and mating indices. CONCLUSION: Ambrisentan showed significant therapeutic potential to prevent and improve diabetic ED in rats comparable to tadalafil.

Oral Vitamin D Treatment in Patients with Telogen Effluvium: Clinical and Dermoscopic Evaluation.

Background: Telogen effluvium (TE) is the most common hair loss. Vitamin D is related to hair and skin diseases due to its immunomodulatory and anti-inflammatory effects. Objective: To investigate Vitamin D serum level role in TE pathogenesis. Patients and Methods: Forty females with TE were collected and twenty age- and sex-matched healthy individuals as controls. Serum 25(OH) Vitamin D level was estimated prior and 3 months after oral Vitamin D. Results: The mean serum 25(OH) Vitamin D levels were significantly lower in TE patients than controls (13.31 ± 5.8 ng/ml vs. 33.61 ± 8.16 ng/ml) respectively, P < 0.001. The mean serum 25(OH) Vitamin D levels before treatment in acute TE was 12.31 ± 6.88 ng/ml, compared to 10.6 ± 3.9 ng/ml in chronic TE without a significant difference, (P = 0.544). The mean serum 25(OH) Vitamin D levels in TE group after 3 months oral Vitamin D therapy were 38.4 ± 15.22 ng/ml with significant increase compared to pretreatment level, (P < 0.001). However, without a significant difference between acute TE (45.4 ± 9.22 ng/ml) and chronic TE (42.1 ± 10.6 ng/ml), (P = 0.711). Conclusion: Oral Vitamin D has a promising effect in TE treatment, but the results need to be verified on a larger scale with evidence-based recommendation regarding the exact dose and treatment duration.

The Exposome and Nutritional Pharmacology and Toxicology: A New Application for Metabolomics.

The exposome refers to all of the internal and external life-long exposures that an individual experiences. These exposures, either acute or chronic, are associated with changes in metabolism that will positively or negatively influence the health and well-being of individuals. Nutrients and other dietary compounds modulate similar biochemical processes and have the potential in some cases to counteract the negative effects of exposures or enhance their beneficial effects. We present herein the concept of Nutritional Pharmacology/Toxicology which uses high-information metabolomics workflows to identify metabolic targets associated with exposures. Using this information, nutritional interventions can be designed toward those targets to mitigate adverse effects or enhance positive effects. We also discuss the potential for this approach in precision nutrition where nutrients/diet can be used to target gene-environment interactions and other subpopulation characteristics. Deriving these "nutrient cocktails" presents an opportunity to modify the effects of exposures for more beneficial outcomes in public health.

Telmisartan versus metformin in downregulating myostatin gene expression and enhancing insulin sensitivity in the skeletal muscles of type 2 diabetic rat model.

Objective: Telmisartan is an angiotensin receptor blocker (ARB) that specifically blocks angiotensin II type-1 receptors (AT1R). Telmisartan has been proven to have antidiabetic effects via a variety of mechanisms, and it can be utilized in some diabetic patients due to its dual benefit for hypertensive patients with type 2 DM (T2DM) and when the other oral antidiabetic medications are intolerable or contraindicated. However, its precise underlying hypoglycemic mechanism is still obscure. Aim of work: We sought to establish a link between telmisartan administration and myostatin expression in skeletal muscles of T2DM rat model as a potential hypoglycemic mechanism of telmisartan. Materials and Methods: 32 male albino rats were included in the study; 8 rats served as controls (group I). T2DM was inducted in the other 24 rats, which were then randomly subdivided into 3 groups (8 in each): (group II) the Diabetic group and (groups III and IV) which were treated with either telmisartan (8 mg/kg/day) or metformin (250 mg/kg/day) respectively via oral gavage for a 4-week period. Results: Telmisartan administration resulted in a significant improvement in OGTT, HOMA-IR, glucose uptake, and muscle mass/body ratios in Telmisartan group as compared to Diabetic group (p < 0.05). Additionally, telmisartan induced a significant boost in adiponectin and IL-10 serum levels with a substantial drop in TNF-α and IL-6 levels in Telmisartan group compared to diabetic rats (p < 0.05). Moreover, telmisartan significantly boosted SOD and GSH, and decreased MDA levels in the skeletal muscles of telmisartan group. Furthermore, a significant downregulation of myostatin and upregulation of insulin receptor, IRS-1, and IRS-3 genes in the skeletal muscles of Telmisartan group were also detected. Histologically, telmisartan attenuated the morphological damage in the skeletal muscle fibers compared to diabetic rats, as evidenced by a considerable decrease in the collagen deposition area percentage and a reduction in NF-kB expression in the muscle tissues of group III. Conclusion: Telmisartan administration dramatically reduced myostatin and NF-kB expressions in skeletal muscles, which improved insulin resistance and glucose uptake in these muscles, highlighting a novel antidiabetic mechanism of telmisartan in treating T2DM.

Intermittent fasting and time-restricted eating role in dietary interventions and precision nutrition.

Intermittent fasting (IF), time-restricted eating (TRE) and fasting-mimicking diets (FMD) are gaining popularity as weight loss programs. As such, the timing and frequency of meals have been recognized as essential contributors to improving cardiometabolic health and a role as adjuvant therapy in cancer. Randomized controlled trials suggested that the weight loss associated with IF is due to a reduced energy intake due to time restriction. Although the supervised TRE clinical trials documented the dietary caloric intake, many free-living studies focused on the timing of meals without a complete characterization of the dietary intake, caloric density, or macronutrient composition. It is possible that both caloric-restriction diets and time-restriction protocols could work synergistically or additively to improve metabolic health outcomes. Like personalized medicine, achieving precision nutrition mandates the provision of the right nutrients to the right patient at the right time. To accomplish this goal, future studies need to evaluate the benefits of IF and TRE. Randomized controlled trials were conducted in different populations, ethnic groups, ages, geographic distribution, physical activity levels, body composition and in patients with obesity, diabetes, and cardiovascular diseases. Also, it is crucial to analyze the dietary composition and caloric density as related to circadian rhythm and timing of meals. It is conceivable that IF and TRE may contribute to precision nutrition strategies to achieve optimal health. However, more research is needed to evaluate IF and TRE effects on health outcomes and any side effects.

mTORC1 and mTORC2 Complexes Regulate the Untargeted Metabolomics and Amino Acid Metabolites Profile through Mitochondrial Bioenergetic Functions in Pancreatic Beta Cells.

Background: Pancreatic beta cells regulate bioenergetics efficiency and secret insulin in response to glucose and nutrient availability. The mechanistic Target of Rapamycin (mTOR) network orchestrates pancreatic progenitor cell growth and metabolism by nucleating two complexes, mTORC1 and mTORC2. Objective: To determine the impact of mTORC1/mTORC2 inhibition on amino acid metabolism in mouse pancreatic beta cells (Beta-TC-6 cells, ATCC-CRL-11506) using high-resolution metabolomics (HRM) and live-mitochondrial functions. Methods: Pancreatic beta TC-6 cells were incubated for 24 h with either: RapaLink-1 (RL); Torin-2 (T); rapamycin (R); metformin (M); a combination of RapaLink-1 and metformin (RLM); Torin-2 and metformin (TM); compared to the control. We applied high-resolution mass spectrometry (HRMS) LC-MS/MS untargeted metabolomics to compare the twenty natural amino acid profiles to the control. In addition, we quantified the bioenergetics dynamics and cellular metabolism by live-cell imaging and the MitoStress Test XF24 (Agilent, Seahorse). The real-time, live-cell approach simultaneously measures the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) to determine cellular respiration and metabolism. Statistical significance was assessed using ANOVA on Ranks and post-hoc Welch t-Tests. Results: RapaLink-1, Torin-2, and rapamycin decreased L-aspartate levels compared to the control (p = 0.006). Metformin alone did not affect L-aspartate levels. However, L-asparagine levels decreased with all treatment groups compared to the control (p = 0.03). On the contrary, L-glutamate and glycine levels were reduced only by mTORC1/mTORC2 inhibitors RapaLink-1 and Torin-2, but not by rapamycin or metformin. The metabolic activity network model predicted that L-aspartate and AMP interact within the same activity network. Live-cell bioenergetics revealed that ATP production was significantly reduced in RapaLink-1 (122.23 ± 33.19), Torin-2 (72.37 ± 17.33) treated cells, compared to rapamycin (250.45 ± 9.41) and the vehicle control (274.23 ± 38.17), p < 0.01. However, non-mitochondrial oxygen consumption was not statistically different between RapaLink-1 (67.17 ± 3.52), Torin-2 (55.93 ± 8.76), or rapamycin (80.01 ± 4.36, p = 0.006). Conclusions: Dual mTORC1/mTORC2 inhibition by RapaLink-1 and Torin-2 differentially altered the amino acid profile and decreased mitochondrial respiration compared to rapamycin treatment which only blocks the FRB domain on mTOR. Third-generation mTOR inhibitors may alter the mitochondrial dynamics and reveal a bioenergetics profile that could be targeted to reduce mitochondrial stress.

Insulin Receptor Genetic Variants Causal Association with Type 2 Diabetes: A Mendelian Randomization Study.

Background: Type 2 diabetes (T2D) is a prevalent chronic disease associated with several comorbidities. Objectives: This study investigated whether the risk of T2D varied with genetically predicted insulin (INS), insulin receptor (INS-R), or insulin-like growth factor 1 receptor (IGF-1R) using genetic variants in a Mendelian randomization (MR) study. Methods: A 2-sample MR study was conducted using summary statistics from 2 genome-wide association studies (GWASs). Genetic predictors of the exposures (INS, INS-R, and IGF-1R) were obtained from a publicly available proteomics GWAS of the INTERVAL randomized controlled trial of blood donation in the United Kingdom. For T2D, the study leveraged the DIAbetes Meta-ANalysis of Trans-Ethnic association studies (DIAMANTE) consortium. The estimated associations of INS, INS-R, and IGF-1R proteins with T2D were based on independent single nucleotide polymorphisms (SNPs) strongly (P < 5 × 10-6) predicting each exposure. These SNPs were applied to publicly available genetic associations with T2D from the DIAMANTE case (n = 74,124) and control (n = 824,006) study of people of European descent. SNP-specific Wald estimates were meta-analyzed using inverse variance weighting with multiplicative random effects. Sensitivity analysis was conducted using the weighted median (WM) and MR-Egger. Results: INS-R (based on 13 SNPs) was associated with a lower risk of T2D (OR: 0.95 per effect size; 95% CI: 0.92, 0.98; P = 0.001), with similar estimates from the WM and MR-Egger. Insulin (8 SNPs) and IGF-1R (10 SNPs) were not associated with T2D. However, 1 of the SNPs for INS-R was from the ABO blood group gene. Conclusions: This study is consistent with a causally protective association of the INS-R with T2D. INS-R in RBCs regulates glycolysis and thus may affect their functionality and integrity. However, a pleiotropic effect via the blood group ABO gene cannot be excluded. The INS-R may be a target for intervention by repurposing existing therapeutics or otherwise to reduce the risk of T2D.

Prevalence of Chronic Kidney Disease in Nonalcoholic Fatty Liver Disease Patients.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide. It is not only associated with liver-related mortality and morbidity but is a multisystem disease that affects multiple extra-hepatic organ systems, such as the kidneys and cardiovascular system. Our study was conducted to evaluate the possible relationship between NAFLD and the risk of chronic kidney disease (CKD) development. This is a comparative cross-sectional study. The study was conducted on 100 patients who were diagnosed with NAFLD by abdominal ultrasound, CKD was diagnosed either by estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m2 or by the presence of albuminuria (albumin creatinine ratio >30 mg/g).These patients were classified into two groups, the CKD group and the non-CKD group, and the two groups were compared according to different parameters. The data were collected, presented, and statistically analyzed with the computer program IBM SPSS Statistics version 23. Among 100 NAFLD patients, there were 19 patients developed CKD diagnosed either by eGFR or by the presence of albuminuria. These CKD patients were older, have abdominal obesity, higher body mass index, higher cholesterol level, higher low-density lipoprotein level, higher triglycerides levels, higher systolic and diastolic blood pressure, and higher fatty liver index and a higher degree of fatty liver by ultrasound. Our current study suggests that NAFLD may be associated with a high risk of CKD.

Distance to Health Care Facilities, Lifestyle Risk Factors, and Stage at Diagnosis in relation to Geographic Pattern of Esophageal Cancer in Tanzania, 2006-2016.

Esophageal cancer is an aggressive, often deadly disease globally that represents a significant health problem in Tanzania. The WHO reported 604,100 new esophageal cancer cases worldwide during 2020 and 544,076 deaths (Sung, 2021; World Health Organization, 2020). In Eastern Africa, 16,137 cases and 15,188 deaths were related to this disease in 2020. Esophageal cancer is associated with various etiologic risk factors, and access to the disease treatment is a major barrier to survival. This study examined associations between the prevalence of four geographically stratified, population-level, etiologic risk factors (tobacco use, unprotected water use, solid fuel source use, and poverty), as well as two access-to-care predictors (persons per hospital and distance from residence to where esophageal cancer treatment occurs). Regional- and coarser-scale zonal incidence rates were calculated for 2006 through 2016 and evaluated for geographic differences in relation to risk factors and access to care predictors using Poisson regression. Differences in the geographic distribution of esophageal cancer were observed. Distance from the region of residence to the treatment center (Ocean Road Cancer Institute) was statistically associated with the geographic pattern of esophageal cancer incidence. Further research into etiologic risk factors, dietary practices, and nutrition is needed to better understand the associations with esophageal cancer in Tanzania and other parts of Eastern Africa.

Queueing theory model of mTOR complexes' impact on Akt-mediated adipocytes response to insulin.

A queueing theory based model of mTOR complexes impact on Akt-mediated cell response to insulin is presented in this paper. The model includes several aspects including the effect of insulin on the transport of glucose from the blood into the adipocytes with the participation of GLUT4, and the role of the GAPDH enzyme as a regulator of mTORC1 activity. A genetic algorithm was used to optimize the model parameters. It can be observed that mTORC1 activity is related to the amount of GLUT4 involved in glucose transport. The results show the relationship between the amount of GAPDH in the cell and mTORC1 activity. Moreover, obtained results suggest that mTORC1 inhibitors may be an effective agent in the fight against type 2 diabetes. However, these results are based on theoretical knowledge and appropriate experimental tests should be performed before making firm conclusions.

Effect of nebivolol on altered skeletal and cardiac muscles induced by dyslipidemia in rats: impact on oxidative and inflammatory machineries.

AIM: High cholesterol diet is greatly linked to deleterious health consequences. In this work we tried to explore direct effects of high cholesterol diet on striated (skeletal and cardiac) muscle tissues and the mechanisms by which nebivolol could improve such harmful effects. METHODS: The study included 24 healthy adult male albino rats weighing 200-220 grams that were assigned into four groups: control group, control drug group, high cholesterol diet fed groups; one untreated the other was treated with nebivolol. RESULTS: In the cholesterol fed group, we found decreased blood HDL and NO with elevated total cholesterol, triglycerides, myoglobin, CK, LDH, ALP, in addition to elevated muscle tissue levels of HIF-1, NF-kB, MDA, and decreased expression of both eNOS, reduced GSH. Wire hanging test time was shorter in the high cholesterol group than control group rats, which was confirmed histologically by increased striated muscle fibre thickness and cytochrome area %. Nebivolol treatment ameliorated the effects of high cholesterol diet. CONCLUSION: High cholesterol diet caused myopathic changes in rat striated muscle tissues mostly due to oxidative stress associated with enhanced NF-kB and HIF-1 expression. Nebivolol appears beneficial in the management of hypercholesterolaemia-induced striated muscle injury.

Long Non-Coding RNAs ASB16-AS1 and AFAP1-AS1: Diagnostic, Prognostic Impact and Survival Analysis in Colorectal Cancer.

Background: We aimed to evaluate the diagnostic roles of AFAP1-AS1 and ASB16-AS1 in colorectal cancer and highlight their roles in predicting colorectal cancer patients' prognosis. Methods: In this case-control study, 146 participants were involved. Group I included 47 patients with CRC. Group II composed of 49 patients with benign lesions in the colon, and Group III included 50 apparently normal subjects of coincided age and gender as controls. All participants were subjected to clinical and endoscopic evaluations, CA19-9, CEA, and quantification of relative expression of lncRNAs ASB16-AS1 and AFAP1-AS1. Results: CRC patients had significantly elevated expression levels of both lncRNAs in tissue and plasma samples versus benign and control groups (p < 0.001). Despite the higher sensitivity of tissue samples results, the relative expression of both lncRNAs in plasma samples was very encouraging in the discrimination between patients with CRC versus control and benign groups. Furthermore, both lncRNAs could discriminate patients with early-stage CRC (stage I&II) from being colonic lesion and control groups with better sensitivity and specificity presented by ASB16-AS1 in tissue and plasma than results detailed by AFAP1-AS1. High expression levels of ASB16-AS1 in tissue and plasma and tissue lncRNA AFAP1-AS1 are significantly correlated with decreased overall survival (p < 0.001) and reduced progression-free (p < 0.001) compared to low expression in CRC patients. Conclusion: We propose the utilization of lncRNA ASB16-AS1 and lncRNA AFAP1-AS1 as biomarkers in diagnosis and prognosis estimation for CRC patients. Moreover, their value in early CRC patients may affect the assortment of target therapy and treatment protocols.

mTOR Ser-2481 autophosphorylation monitors mTORC-specific catalytic activity and clarifies rapamycin mechanism of action.

The mammalian target of rapamycin (mTOR) Ser/Thr kinase signals in at least two multiprotein complexes distinguished by their different partners and sensitivities to rapamycin. Acute rapamycin inhibits signaling by mTOR complex 1 (mTORC1) but not mTOR complex 2 (mTORC2), which both promote cell growth, proliferation, and survival. Although mTORC2 regulation remains poorly defined, diverse cellular mitogens activate mTORC1 signaling in a manner that requires sufficient levels of amino acids and cellular energy. Before the identification of distinct mTOR complexes, mTOR was reported to autophosphorylate on Ser-2481 in vivo in a rapamycin- and amino acid-insensitive manner. These results suggested that modulation of mTOR intrinsic catalytic activity does not universally underlie mTOR regulation. Here we re-examine the regulation of mTOR Ser-2481 autophosphorylation (Ser(P)-2481) in vivo by studying mTORC-specific Ser(P)-2481 in mTORC1 and mTORC2, with a primary focus on mTORC1. In contrast to previous work, we find that acute rapamycin and amino acid withdrawal markedly attenuate mTORC1-associated mTOR Ser(P)-2481 in cycling cells. Although insulin stimulates both mTORC1- and mTORC2-associated mTOR Ser(P)-2481 in a phosphatidylinositol 3-kinase-dependent manner, rapamycin acutely inhibits insulin-stimulated mTOR Ser(P)-2481 in mTORC1 but not mTORC2. By interrogating diverse mTORC1 regulatory input, we find that without exception mTORC1-activating signals promote, whereas mTORC1-inhibitory signals decrease mTORC1-associated mTOR Ser(P)-2481. These data suggest that mTORC1- and likely mTORC2-associated mTOR Ser-2481 autophosphorylation directly monitors intrinsic mTORC-specific catalytic activity and reveal that rapamycin inhibits mTORC1 signaling in vivo by reducing mTORC1 catalytic activity.