Using In Silico Bioinformatics Algorithms for the Accurate Prediction of the Impact of Spike Protein Mutations on the Pathogenicity, Stability, and Functionality of the SARS-CoV-2 Virus and Analysis of Potential Therapeutic Targets.

Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We have used bioinformatics to investigate seventeen mutations in the spike protein of SARS-CoV-2, as this mediates infection of human cells and is the target of most vaccine strategies and antibody-based therapies. Two mutations, H146Y and S221W, were identified as being most pathogenic. Mutations at positions D614G, A829T, and P1263L might also have deleterious effects on protein function. We hypothesized that candidate small molecules may be repurposed to combat viral infection. We investigated changes in binding energies of the ligands and the mutant proteins by assessing molecular docking. For an understanding of cellular function and organization, protein-protein interactions are also critical. Protein-protein docking for naïve and mutated structures of SARS-CoV-2 S protein was evaluated for their binding energy with the angiotensin-converting enzyme 2 (ACE2). These interactions might limit the binding of the SARS-CoV-2 spike protein to the ACE2 receptor or may have a deleterious effect on protein function that may limit infection. These results may have important implications for the transmission of SARS-CoV-2, its pathogenesis, and the potential for drug repurposing and immune therapies.

Effect of Curcumin and Its Derivates on Gastric Cancer: Molecular Mechanisms.

Gastric carcinoma is one of the most prevalent malignancies and is associated with a high mortality. Chemotherapy is the principal therapeutic option in the treatment of gastric cancer, but its success rate is restricted by severe side effects and the prevalence of chemo-resistance. Curcumin is a polyphenolic compound derived from turmeric that has potent antioxidant, anti-inflammatory and anti-tumor effects. There is accumulating evidence that curcumin may prevent gastric cancer through regulation of oncogenic pathways. Furthermore some curcumin analogues and novel formulation of curcumin appear to have anti-tumor activity. The aim of this review was to give an overview of the therapeutic potential of curcumin and its derivatives against gastric cancer in preclinical and clinical studies.

Prevalence of combined and noncombined dyslipidemia in an Iranian population.

BACKGROUND: Combination of dyslipidemic phenotypes, including elevated plasma levels of low-density lipoprotein cholesterol (LDL-C), elevated plasma triglycerides (TG), and decreased low-density lipoprotein cholesterol (HDL-C) concentrations, is important because of the association of individual phenotypes with increased risk of cardiovascular disease (CVD). We investigated the prevalence of combined dyslipidemias and their effects on CVD risk in an Iranian large population. METHOD: A total of 9847 individuals were recruited as part of the Mashhad Stroke and Heart Atherosclerotic Disorders (MASHAD) cohort study. Anthropometric parameters and biochemical indices were measured in all of the subjects. Different types of combined dyslipidemias including high TG + low HDL-C, high TG + low HDL-C + high LDL-C, low HDL-C + high LDL-C, high TG + high LDL-C, and finally high TG + high LDL-C + low HDL-C were considered. Ten-year CVD risk was calculated using the QRISK2 risk algorithm and adjustments were made as suggested by the Joint British Societies' (JBS2). Logistic regression analyses were performed to determine the association between different combined dyslipidemias and categorical QRISK. RESULTS: A total of 3952 males and 5895 females were included in this current study. Among the included subjects, 83.4% had one form of dyslipidemia, and 16.6% subjects were not dyslipidemic. The mean age was 48.88 ± 7.9 and 47.02 ± 8.54 years for dyslipidemic and nondyslipidemic groups, respectively. The results showed that the frequency of dyslipidemia was 98%, 87.1%, and 90% in subjects with metabolic syndrome, CVD, and diabetes, respectively. Our results suggested that around 15.7% of study population were at 10 years CVD risk (high ≥20) and it was higher in men than women (P < .001). Moreover, risk of CVD was higher in TG↑ & HDL↓ & LDL↑ group than other groups. CONCLUSION: Prevalence of dyslipidemia was 83.4% among Iranian adults. The results showed that individuals with increased plasma TG and LDL-C, and low HDL-C levels had the highest 10 years CVD risk compared to other combined dyslipidemic phenotypes.

The role of cancer-associated fibroblasts and exosomal miRNAs-mediated intercellular communication in the tumor microenvironment and the biology of carcinogenesis: a systematic review.

CAFs (cancer-associated fibroblasts) are highly flexible cells of the cancer microenvironment. They produce the extracellular matrix (ECM) constituents that form the structure of the tumor stroma but are also a source of metabolites, growth factors, chemokines, and exosomes that impact every aspect of the tumor, including its response to treatment. It is believed that exosomal miRNAs facilitate intercellular signaling, which is essential for the development of cancer. The role of miRNAs and CAFs in the tumor microenvironment (TME) and carcinogenesis is reviewed in this paper. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) 2020 guidelines were used to perform a systematic review. Several databases, including Web of Science, Medline, Embase, Cochrane Library, and Scopus, were searched using the following keywords: CAFs, CAF, cancer-associated fibroblasts, stromal fibroblasts, miRNA, exosomal miRNAs, exosome and similar terms. We identified studies investigating exosomal miRNAs and CAFs in the TME and their role in carcinogenesis. A total of 12,572 papers were identified. After removing duplicates (n = 3803), 8774 articles were screened by title and abstract. Of these, 421 were excluded from further analysis. It has been reported that if exosomal miRNAs in CAFs are not functioning correctly, this may influence the secretory phenotype of tip cells and contribute to increased tumor invasiveness, tumor spread, decreased treatment efficacy, and a poorer prognosis. Under their influence, normal fibroblasts (NFs) are transformed into CAFs. Furthermore, they participate in metabolic reprogramming, which allows for fast proliferation of the cancer cell population, adaptation to growing energy demands, and the capacity to avoid immune system identification.

Insulinemic potential of lifestyle is associated with depression and anxiety in adults: A large community-based study.

BACKGROUND: We aimed to investigate the association between an empirical lifestyle index for hyperinsulinemia (ELIH), empirical lifestyle index for insulin resistance (ELIR), and depression and anxiety in an adult Iranian population. METHODS: In this cross-sectional study, a total of 6450 participants, aged 35-65 years were recruited as part of the MASHAD cohort study. Dietary intakes were assessed using a validated food frequency questionnaire (FFQ). Depression and anxiety were screened using Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI). ELIH and ELIR were calculated using dietary intake, body mass index, and physical activity information. Multivariable ordinal logistic regression models were applied to determine the association between ELIH, ELIR, and depression and anxiety severity. RESULTS: In a fully adjusted model, participants with the highest ELIH quartile had a higher odds of more severe depression and anxiety compared to those in the lowest category (OR = 1.44; 95 % CI = 1.22-1.71 and OR = 1.62; 95 % CI = 1.37-1.25, respectively). Participants with the highest ELIR had higher odds of more severe depression and anxiety compared to those in the lowest category (OR = 1.22; 95 % CI = 1.04-1.43 and OR = 1.21; 95 % CI = 1.03-1.42, respectively). LIMITATIONS: The assessment of dietary intake and mental health by questionnaires may increases the rate of misclassification. Due to the study's cross-sectional nature, causal relationships cannot be established. CONCLUSION: There was a significant positive association between the hyperinsulinemia and insulin resistance potential of lifestyle and severity of depression and anxiety among Iranian adults.

G-Protein Signaling Modulator 2 as a Potential Biomarker in Colorectal Cancer: Integrative Analysis Using Genetic Profiling and Pan-Cancer Studies.

Colorectal cancer (CRC) imposes a significant healthcare burden globally, prompting the quest for innovative biomarkers to enhance diagnostic and therapeutic strategies. This study investigates the G-protein signaling modulator (GPSM) family across several cancers and presents a comprehensive pan-cancer analysis of the GPSM2 gene across several gastrointestinal (GI) cancers. Leveraging bioinformatics methodologies, we investigated GPSM2 expression patterns, protein interactions, functional enrichments, prognostic implications, genetic alterations, and immune infiltration associations. Furthermore, the expression of the GPSM2 gene was analyzed using real-time analysis. Our findings reveal a consistent upregulation of GPSM2 expression in all GI cancer datasets analyzed, suggesting its potential as a universal biomarker in GI cancers. Functional enrichment analysis underscores the involvement of GPSM2 in vital pathways, indicating its role in tumor progression. The prognostic assessment indicates that elevated GPSM2 expression correlates with adverse overall and disease-free survival outcomes across multiple GI cancer types. Genetic alteration analysis highlights the prevalence of mutations, particularly missense mutations, in GPSM2. Furthermore, significant correlations between GPSM2 expression and immune cell infiltration are observed, suggesting its involvement in tumor immune evasion mechanisms. Collectively, our study underscores the multifaceted role of GPSM2 in GI cancers, particularly in CRC, emphasizing its potential as a promising biomarker for prognosis and therapeutic targeting. Further functional investigations are warranted to elucidate its clinical utility and therapeutic implications in CRC management.

The Emerging Roles of Aldehyde Dehydrogenase in Acute Myeloid Leukemia and Its Therapeutic Potential.

Acute myeloid leukemia (AML) is a malignant disorder characterized by myeloid differentiation arrest and uncontrolled clonal expansion of abnormal myeloid progenitor cells. AML is the most common malignant bone marrow (BM) disease in adults and accounts for approximately 80% of adult leukemia cases. There has been little improvement in the treatment of patients with AML over the past decade. Cytogenetic and morphologic heterogeneity of AML and the difficulty in distinguishing leukemic stem cells (LSCs) from normal hematopoietic stem cells (HSCs) continue to be the major challenges in treating this malignancy. In recent years, intensive efforts have been made to explore novel potential markers for the efficient identification and characterization of leukemic stem cells. Aldehyde dehydrogenase (ALDH) is a potential target molecule that plays crucial roles in leukemic stem cell survival and multidrug resistance, mainly through its involvement in the detoxification of many endogenous and exogenous aldehydes. The selection and isolation of cancer stem cells based on high ALDH activity seem to be a useful approach in many human malignancies, especially leukemia. Moreover, it is worth mentioning that several previous studies have indicated that a high ALDH activity (classified as ALDHbr cells in flow cytometry) can act as an independent prognostic factor in several types of cancer. In the present review, we update and critically discuss the available data regarding the importance of ALDH activity in normal and leukemic stem cells and its potential diagnostic and therapeutic implications.

The Effects of Vitamin D Fortified Products on Bone Biomarkers: A Systematic Review and Meta-Analysis.

Background: Vitamin D plays an essential role in the regulation of bone metabolism. The current meta-analysis aimed to assess the effectiveness of vitamin D fortification on special bone biomarkers. Methods: Five main databases (PubMed/Medline, ISI Web of Knowledge, Science Direct, Scopus, Cochrane Library as well as Science Direct, and Scopus) were considered for this systematic review, until Jan 2020. All randomized controlled trials were included to evaluate the probable relationship between consumption of vitamin D fortification products and bone biomarkers profile in this review. Results: Among serum bone biomarkers (osteocalcin and telopeptides of type-1 collagen) investigated, only the level of telopeptides of type-1 collagen significantly decreased after fortification of vitamin D in the intervention group. A significant increase in vitamin D was seen in those older than 18 yr old, while the increase in younger children was not statistically significant between intervention and control groups. Conclusion: Vitamin D fortification was not associated with a significant improvement in bone mass density (BMD), while it resulted in decreased PTH levels. Vitamin D fortified foods have some benefits on bone health due to increase in the level of vitamin D and IGF-1; and decreasing PTH and CTx levels.

Exosomes: Emerging modulators of signal transduction in colorectal cancer from molecular understanding to clinical application.

Exosomes are small cell derived membrane nano-vesicles that carry various components including lipids, proteins and nucleic acids. There is accumulating evidence that exosomes have a role in tumorigenesis, tumor invasiveness and metastasis. Furthermore, oncogene mutation may influence exosome release from tumor cells. Exosomes may induce colorectal cancer by altering signaling cascades such as the Wnt/ß-catenin and KRAS pathways that are involved in cell proliferation, apoptosis, dissemination, angiogenesis, and drug resistance. The aim of this review was to overview recent findings evaluating the association between tumor cells-derived exosomes and their content in modulating signaling pathways in colorectal cancer.

Association between Cardiometabolic risk factor and responsiveness to vitamin D supplementation: a new approach using artificial neural network analysis.

BACKGROUND: There are increasing data highlighting the effectiveness of vitamin D supplementation in the treatment of vitamin D deficiency. But individuals vary in their responsiveness to vitamin D supplementation. In this study, the association between several cardiometabolic risk factors and the magnitude of response to vitamin D supplementation (change in vitamin D level) was investigated using a novel artificial neural networks (ANNs) approach. METHODS: Six hundred eight participants aged between 12 to 19 years old were recruited to this prospective interventional study. Nine vitamin D capsules containing 50,000 IU vitamin D/weekly were given to all participants over the 9 week period. The change in serum 25(OH) D level was calculated as the difference between post-supplementation and basal levels. Suitable ANNs model were selected between different algorithms in the hidden and output layers and different numbers of neurons in the hidden layer. The major determinants for predicting the response to vitamin D supplementation were identified. RESULTS: The sigmoid in both the hidden and output layers with 4 hidden neurons had acceptable sensitivity, specificity and accuracy, assessed as the area under the ROC curve, was determined in our study. Baseline serum vitamin D (30.4%), waist to hip ratio (10.5%), BMI (10.5%), systolic blood pressure (8%), heart rate (6.4%), and waist circumference (6.1%) were the most important factors in predicting the response to serum vitamin D levels. CONCLUSION: We provide the first attempt to relate anthropometric specific recommendations to attain serum vitamin D targets. With the exception of cardiometabolic risk factors, the relative importance of other factors and the mechanisms by which these factors may affect the response requires further analysis in future studies (Trial registration: IRCT201509047117N7; 2015-11-25; Retrospectively registered).

Association of a genetic variant in the angiopoietin-like protein 4 gene with cervical cancer.

BACKGROUND: Cervical cancer is among the most aggressive gynecological tumors and is a consequence of interactions between genetic and epigenetic factors. Several genetic polymorphisms related to cervical cancer have been reported in previous clinical studies. In this study, we aimed to explore the possible relationship between polymorphisms of the ANGPTL4 gene locus and susceptibility to cervical cancer. METHODS: We investigated the relationship between a single nucleotide polymorphism (SNP) in the ANPGTL4 gene (rs116843064) and risk of cervical cancer in a total of 378 individuals with (n = 151), or without (n = 227) cancer. DNA was extracted, and genotyped using a Taq-Man based real time PCR. RESULTS: The ANPGTL4 polymorphism was found to be associated with an increased risk of developing cervical neoplasia using dominant model (OR = 12.48, CI = 4.9-31.82, p < 0.0001) and additive model (OR = 30.54, CI = 7.35-126.89, p < 0.0001). CONCLUSION: Our results indicate that there is a strong association between ANPGTL4 and the susceptibility for cervical cancer suggesting that it is a potential risk factor for cervical neoplasia.

The effects of curcumin and a modified curcumin formulation on serum Cholesteryl Ester Transfer Protein concentrations in patients with metabolic syndrome: A randomized, placebo-controlled clinical trial.

OBJECTIVE: Cholesteryl Ester Transfer Protein (CETP) mediates the transfer of cholesteryl ester from HDL-C to LDL-C and VLDL-C. The aim of the present trial was to evaluate the effect of curcumin and its modified formulation on serum CETP concentrations in patients with metabolic syndrome. MATERIALS AND METHODS: Participants were randomly allocated to one of three groups of 40 subjects receiving either unmodified curcumin or its phospholipid complex or placebo. Lipid profile and plasma CETP were measured at the start and six weeks after initiation of the treatment. The normality of data distribution was assessed by Kolmogorov-Smirnov test. Wilcoxon test was used for comparing the data before and after the intervention. The percent changes of CETP and biochemical factors among the three groups were compared using Kruskal-Wallis test. RESULTS: Serum CETP levels were not significantly altered among patients receiving curcumin. CONCLUSION: Curcumin and its complex had no significant effect on serum CETP concentrations.

24-Hour survival after cardiopulmonary resuscitation is reduced in patients with diabetes mellitus.

Introduction: Diabetes mellitus is a risk factor for cardiovascular disease. Some recent studies have shown an association between diabetes and out-of-hospital cardiac arrest incidence and survival. We aimed to investigate whether there is an association between the presence of diabetes mellitus and survival after cardiopulmonary resuscitation (CPR) in patients with an in-hospital cardiac arrest. Methods: A cross-sectional study was conducted during the period of January to February 2014, among 80 cases of cardiopulmonary arrest in patients at Qaem hospital of Mashhad, Iran. A code 99 was announced after a cardiac arrest was identified, and CPR was performed by the cardiac arrest team. Twenty four hour survival was compared in diabetic and non-diabetic patients who had a return to spontaneous circulation after CPR. We used SPSS statistics for Windows version 16 for data analysis. Results: The return to spontaneous circulation in the diabetic group was not significantly lower than for the non-diabetic group (42.9% versus 61.0% [P = 0.15]). However, the 24-hour survival in the diabetic group was significantly lower than for the non-diabetic group (19.0% versus 44.1% [P = 0.04]). Conclusion: The presence of diabetes mellitus is associated with a significantly lower rate of survival after CPR.

Saffron supplements modulate serum pro-oxidant-antioxidant balance in patients with metabolic syndrome: A randomized, placebo-controlled clinical trial.

OBJECTIVES: We have investigated the effect of a saffron supplement, given at a dose of 100 mg/kg, on prooxidant-antioxidant balance (PAB) in individuals with metabolic syndrome. MATERIALS AND METHODS: A randomized, placebo-controlled trial design was used in 75 subjects with metabolic syndrome who were randomly allocated to one of two study groups: (1) the case group received 100mg/kg saffron and (2) the placebo control group received placebo for 12 weeks. The serum PAB assay was applied to all subjects before (week 0) and after (weeks 6 and 12) the intervention. RESULTS: There was a significant (p=0.035) reduction in serum PAB between week 0 to week 6 and also from week 0 to week 12. CONCLUSION: Saffron supplements can modulate serum PAB in subjects with metabolic syndrome, implying an improvement in some aspects of oxidative stress or antioxidant protection.