Long delay in diagnosis of a case with MEN1 due to concomitant presence of AIMAH with insulinoma: a case report and literature review.

BACKGROUND: ACTH-independent macronodular hyperplasia (AIMAH) is an uncommon disorder characterized by massive enlargement of both adrenal glands and hypersecretion of cortisol. Concomitant AIMAH and multiple endocrine neoplasia type1 (MEN1) is rare to our knowledge. CASE PRESENTATION: Herein, we describe a 32 year old woman with long history of prolactinoma and secondary ammonhrea presented with not-severe manifestation of hypoglycemia due to concomitant presence of insulinoma with AIMAH leading to 12 years delay of MEN1 diagnosis. Laboratory tests showed severe hypoglycemia associated with hyper insulinemia (non-fasting blood sugar = 43 mg/dl, insulin = 80.6 µIU /ml, C-peptide = 9.3 ng/ml) hyperparathyroidism (calcium = 10.3 mg/dl, phosphor = 3.1 mg/dl, PTH = 280 pg/ml) and chemical evidence of an ACTH-independent hypercortisolism (serum cortisol value of 3.5, after 1 mg dexamethasone suppression test serum ACTH value of 17 pg/ml, and high urinary cortisol level). Abdominal CT scan demonstrated two enhancing well-defined masses 27*20 mm and 37*30 mm in the tail and body of the pancreas, respectively, and a 36*15 mm mass in left adrenal gland (seven Hounsfield units). Dynamic pituitary MRI revealed a partial empty sella. The physical examination of the patient was unremarkable. Distal pancreatectomy and a left adrenalectomy were performed. After the surgery, we observed clinical and biochemical remission of hyper insulinemia and gradual decrease in urinary cortisol. The histological features of the removed left adrenal gland were consistent with AIMAH. Histological examination of the pancreatic lesions revealed well differentiated neuroendocrine tumors. Genetic abnormalities in the MEN1, heterozygote for pathogenic variant chr11; 645,773,330-64577333AGAC, c.249-252delGTCT, p. (11e85Serfs Ter33) in exon 2 were found. It was recommended the patient undergoes parathyroidectomy as soon as possible. CONCLUSION: Given the history and presentation of our case, we recommend that the clinicians consider the possibility of autonomous cortisol production in MEN1 patients who do not show severe symptoms of hypoglycemia in the presence of insulinoma.

MicroRNA let-7 and viral infections: focus on mechanisms of action.

MicroRNAs (miRNAs) are fundamental post-transcriptional modulators of several critical cellular processes, a number of which are involved in host defense mechanisms. In particular, miRNA let-7 functions as an essential regulator of the function and differentiation of both innate and adaptive immune cells. Let-7 is involved in several human diseases, including cancer and viral infections. Several viral infections have found ways to dysregulate the expression of miRNAs. Extracellular vesicles (EV) are membrane-bound lipid structures released from many types of human cells that can transport proteins, lipids, mRNAs, and miRNAs, including let-7. After their release, EVs are taken up by the recipient cells and their contents released into the cytoplasm. Let-7-loaded EVs have been suggested to affect cellular pathways and biological targets in the recipient cells, and can modulate viral replication, the host antiviral response, and the action of cancer-related viruses. In the present review, we summarize the available knowledge concerning the expression of let-7 family members, functions, target genes, and mechanistic involvement in viral pathogenesis and host defense. This may provide insight into the development of new therapeutic strategies to manage viral infections.

Virus, Exosome, and MicroRNA: New Insights into Autophagy.

Autophagy is known as a conserved self-eating mechanism that contributes to cells to degrade different intracellular components (i.e., macromolecular complexes, aggregated proteins, soluble proteins, organelles, and foreign bodies). Autophagy needs formation of a double-membrane structure, which is composed of the sequestered cytoplasmic contents, called autophagosome. There are a variety of internal and external factors involved in initiation and progression of autophagy process. Viruses as external factors are one of the particles that could be associated with different stages of this process. Viruses exert their functions via activation and/or inhibition of a wide range of cellular and molecular targets, which are involved in autophagy process. Besides viruses, a variety of cellular and molecular pathways that are activated and inhibited by several factors (e.g., genetics, epigenetics, and environment factors) are related to beginning and developing of autophagy mechanism. Exosomes and microRNAs have been emerged as novel and effective players anticipated in various stages of autophagy. More knowledge in these pathways and identification of accurate roles of them could help to provide better therapeutic approaches in several diseases such as cancer. We highlighted the roles of viruses, exosomes, and microRNAs in the autophagy processes.

Sex specific trajectories of central adiposity, lipid indices, and glucose level with incident hypertension: 12 years Follow-up in Tehran lipid and glucose study.

AIMS: To identify sex specific trajectories of waist circumference (WC),triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and fasting plasma glucose (FPG) during adulthood and examine their associations with incident hypertension. METHODS: The cohort consisted of 5030 participants (2051 males) with at least 2 repeated measurement during a median of 12 years follow up. We identified trajectory groups using latent class growth mixture model, their association with hypertension was examined using multivariate Cox-regression analysis. RESULTS: We found 997 cases of hypertension (483 male). For both exposures, three distinct trajectory groups were identified in both genders. For WC, in women: low-increasing, 82.4%; high-stable, 13.4%; high-increasing, 4.2% and in men: stable, 94.6%; low-increasing, 3.6% and for high- increasing, 1.7%. For TG, in women: stable, 91.3%; decreasing, 5.9%; inverse U-shape, 2.8%; in men: stable, 89.7%; inverse U- shape, 6.2% and for decreasing, 4.1%. Regarding WC, high stable and high-increasing trajectories were associated with hypertension in the multivariate model [(hazard ratio (HR) = 1.66 (95% CI 1.26-2.20) and 2.78(1.79-3.60), respectively]. Among men, this association was shown only for the low-increasing trajectory [2.76: 1.49-5.10]. For TG, among women decreasing and inverse U-shape trajectories were significantly associated with hypertension in the multivariate model [1.32:1.01-1.76] and [2.23:1.58-3.23, respectively]. We did not find any impact of increasing trajectories of FPG and HDL-C on incident hypertension. Considering TC, all individuals followed a stable trajectory. CONCLUSION: WC dynamic changes in both gender and TG trajectory among women were significantly associated with incident hypertension.

Therapeutic Gene Editing in Dyslipidemias.

Dyslipidemia, characterized by abnormal lipid levels in the blood, significantly escalates the risk of atherosclerotic cardiovascular disease and requires effective treatment strategies. While existing therapies can be effective, long-term adherence is often challenging. There has been an interest in developing enduring and more efficient solutions. In this context, gene editing, particularly clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology, emerges as a groundbreaking approach, offering potential long-term control of dyslipidemia by directly modifying gene expression. This review delves into the mechanistic insights of various gene-editing tools. We comprehensively analyze various pre-clinical and clinical studies, evaluating the safety, efficacy, and therapeutic implications of gene editing in dyslipidemia management. Key genetic targets, such as low-density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein 3 (ANGPTL3), apolipoprotein C3 (APOC3), and lipoprotein (a) (Lp(a)), known for their pivotal roles in lipid metabolism, are scrutinized. The paper highlights the promising outcomes of gene editing in achieving sustained lipid homeostasis, discusses the challenges and ethical considerations in genome editing, and envisions the future of gene therapy in revolutionizing dyslipidemia treatment and cardiovascular risk reduction.

Coronary artery event-free or resilient familial hypercholesterolemia: what's in a name?

PURPOSE OF REVIEW: Familial hypercholesterolemia (FH) is an autosomal semi-dominant condition, characterized by excessive circulating low-density lipoprotein cholesterol (LDL-C) from birth that substantially accelerates the onset and progression of atherosclerotic cardiovascular disease (ASCVD), classically coronary artery disease (CAD). Elevated plasma LDL-C integrated over time is unequivocally the major determinant of ASCVD in heterozygous FH (HeFH); however, the wide variation in incidence and progression of ASCVD suggests a role for a wide spectrum of risk modifiers. We reviewed recent evidence describing the features of an ASCVD-free entity referred to as resilient FH among patients with HeFH. RECENT FINDINGS: Compared with nonresilient FH patients, resilient patients are more likely to be female, and have a lower prevalence of ASCVD comorbidities, higher levels of HDL-C and larger HDL particles, as well as a lower level of lipoprotein(a). A lower SAFEHEART risk score is also an independent predictor of resilient FH. Gene expression studies also demonstrate that resilient FH patients are associated with a less atherogenic gene expression profile in relation to HDL metabolism and immune responses, as reflected by higher expression of ABCA1 and ABCG1, and lower expression of STAT2 and STAT3, respectively. SUMMARY: A group of HeFH patients, referred as resilient FH, can survive to advance ages without experiencing any ASCVD events. Several key contributors to the event-fee CAD in HeFH patients have been identified. This could not only improve risk stratification and management for FH but also be of major importance for the general population in primary and secondary prevention. However, resilient FH remains an under-investigated area and requires further research.

Kidney function decline is associated with mortality events: over a decade of follow-up from Tehran Lipid and Glucose Study.

BACKGROUND: To investigate the association between estimated glomerular filtration rate (eGFR) change and mortality risk in a cohort from the Middle East and North Africa region with increasing chronic kidney disease burden. METHODS: We included 2210 participants aged ≥ 50 years from the prospective cohort of the Tehran Lipid and Glucose Study. The interval for eGFR measurement was between the examinations in 2002-2005 to 2009-2011, and participants were followed through March 2018. Glomerular filtration rate was estimated from serum creatinine using the CKD-EPI creatinine equation. We assessed the association of rapid kidney function decline, (defined as annual eGFR decline ≥ 3 ml/min/1.73 m2 per year); ≥ 30% eGFR decline over six years; and certain drop in kidney function (≥ 25% eGFR decline plus drop in eGFR category) with mortality outcomes. RESULTS: During a median follow-up of 14.3 years after recruitment, 315 all-cause and 112 cardiovascular disease deaths were recorded. The multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause death for rapid kidney function decline, ≥ 30% decline in eGFR over 6 years, and drop in kidney function were 1.68 (1.24-2.27), 2.01 (1.46-2.78), and 1.49 (1.11-1.98), respectively. The HRs of all-cause death and for rapid kidney function decline in those without and with chronic kidney disease were 1.41 (1.03-1.91) and 3.38 (1.69-6.76), respectively. Similar findings were observed regarding cardiovascular disease-related and non-cardiovascular disease-related mortality. CONCLUSIONS: Estimated GFR decline is associated with an increased mortality risk, indicating its ability to provide additional prognostic information beyond traditional risk predictors in the general population.

Impact of optimal cholesterol levels on subclinical atherosclerosis in the absence of risk factors in young adults.

BACKGROUND AND AIMS: We aimed to assess the association of blood lipids with the prevalence, incidence, and progression of subclinical atherosclerosis among young individuals without dyslipidemia and other traditional cardiovascular risk factors (CVRFs). METHODS: A total of 1270 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study aged 32-46 years free of cardiovascular disease, diabetes, hypertension, current smoking, and dyslipidemia (total cholesterol [TC] ≥ 240 mg/dL, triglycerides [TG] ≥ 150 mg/dL, low-density lipoprotein cholesterol [LDL-C] ≥ 160 mg/dL, high-density lipoprotein cholesterol [HDL-C] < 40 mg/dL, or taking lipid-lowering medications) were included. A subgroup with optimal lipids within the low-CVRF group was defined with TC < 200 mg/dL, LDL-C < 100 mg/dL, non-HDL-C < 130 mg/dL, and women with HDL-C ≥ 50 mg/dL. RESULTS: 1-SD higher TC (25.9 mg/dL), LDL-C (24.7 mg/dL), and non-HDL-C (26.6 mg/dL) were associated with a greater risk of presence (hazard ratios: 1.30-1.36), incidence (1.30-1.32), and progression (1.31-1.35) of coronary artery calcium (CAC) and a 42-44% greater odds of composite mean carotid intima-media thickness (CIMT) ≥ 75th percentile [780 µm] (p < 0.05). Repeating the analyses in a subset of participants with a CAC score of zero did not alter the association of TC, LDL-C, and non-HDL-C with CIMT. In the subgroup with optimal lipids, these lipid indices remained associated with an increased risk of presence and incidence of CAC and greater CIMT measures. CONCLUSIONS: Among adults aged 32-46 years, in the absence of traditional CVRFs, elevated cholesterol levels, even within what is considered optimal, are associated with atherosclerosis and arteriopathy.

Association of Anthropometric Indices With Midlife Cardiovascular Risk in Young Individuals Without Obesity and Traditional Risk Factors.

BACKGROUND: The aim of this study was to assess how early-adulthood body mass index (BMI) and waist circumference (WC) relate to long-term cardiovascular structure, function, and prognosis in individuals without obesity and with low cardiovascular risk factor (CVRF) burden. METHODS AND RESULTS: A total of 2024 participants aged 18 to 30 from the CARDIA (Coronary Artery Risk Development in Young Adults) study, without obesity and with low CVRFs defined as the absence of cardiovascular disease (CVD), diabetes, hypertension, current smoking, and dyslipidemia were included. A CVRF-optimal subgroup was also defined, with blood pressure<120/80 mm Hg, fasting glucose <100 mg/dL, total cholesterol <200, low-density lipoprotein cholesterol <130, and women with high-density lipoprotein cholesterol ≥50 mg/dL. Coronary artery calcification, carotid intima-media thickness, left ventricular mass, left ventricular ejection fraction, longitudinal peak systolic strain, and diastolic function were assessed in midlife. Cox regression was used to calculate hazard ratios of BMI and WC for all-cause death and CVD events. Logistic regression was used to estimate odds ratios for subclinical CVD. Over 33.9 years (median follow-up), 5.2% (n=105) died, and 2.6% (n=52) had CVD events. Each 1-SD BMI increase was associated with 27% (95% CI, 1.10-1.47), 24% (1.08-1.43), 42% (1.20-1.68), 28% (1.05-1.57), 51% (1.20-1.90), and 49% (1.10-2.02) higher odds of coronary artery calcification presence, increased carotid intima-media thickness, left ventricular hypertrophy, reduced left ventricular ejection fraction, low longitudinal peak systolic strain, and diastolic dysfunction, respectively, in the CVRF-low group. Generally, similar associations were found for WC and in the CVRF-optimal subgroup. No significant associations between BMI and WC with CVD and death were found. CONCLUSIONS: Elevations in BMI and WC among young low-risk individuals, even within the nonobesity range, are associated with midlife cardiovascular health.

The prognostic significance of insulin resistance in COVID-19: a review.

Objectives: Emerging publications indicate that diabetes predisposes patients with COVID-19 to more severe complications, which is partly attributed to inflammatory condition. In the current review, we reviewed recent published literature to provide evidence on the role of insulin resistance (IR) in diabetes, the association between diabetes and COVID-19 severity and mortality, the impact of COVID-19 infection on incident new-onset diabetes, mechanisms responsible for IR in COVID-19 patients, and the predictive value of different surrogates of IR in COVID-19. Method: The literature search performs to find out studies that have assessed the association between IR surrogates and morbidity and mortality in patients with COVID-19. Results: We showed that there is a bulk of evidence in support of the fact that diabetes is a potent risk factor for enhanced morbidity and mortality in COVID-19 patients. COVID-19 patients with diabetes are more prone to remarkable dysglycemia compared to those without diabetes, which is associated with an unfavourable prognosis. Furthermore, SARS-COV2 can make patients predispose to IR and diabetes via activating ISR, affecting RAAS signaling pathway, provoking inflammation, and changing the expression of PPARÉ£ and SREBP-1. Additionally, higher IR is associated with increased morbidity and mortality in COVID-19 patients and different surrogates of IR can be utilized as a prognostic biomarker for COVID-19 patients. Conclusion: Different surrogates of IR can be utilized as predictors of COVID-19 complications and death.

Change in blood pressure status defined by 2017 ACC/AHA hypertension guideline and risk of cardiovascular disease: results of over a decade of follow-up of the Iranian population.

Background: Hypertension (HTN) is known to be the leading cause of cardiovascular disease (CVD) and mortality. We aimed to assess the impact of changes in 3 years in different blood pressure (BP) categories on incident CVD. Methods: In this study, 3,685 Tehranians aged ≥30 years (42.2% men) free of prevalent CVD with BP level <140/90 mmHg and not on BP-lowering medications were enrolled. Participants were grouped according to baseline BP category using the 2017 ACC/AHA hypertension guideline definition: normal BP (<120/80 mmHg), elevated BP (120-129/<80), and stage 1 HTN (130-139 and/or 80-89). The hazard ratio of incident CVD by changes in the BP category was estimated after adjustment for traditional risk factors using Cox's proportional hazard model, with stable normotension as a reference. Results: During a median follow-up of 11.7 years, 346 CVD events (men = 208) occurred. Compared to the reference group, among participants with normal BP at baseline, only those with BP rising to stage 1 HTN [1.47 (0.99-2.16)], and among those with stage 1 HTN at baseline, regression to elevated BP [1.80 (1.11-2.91)], remaining at stage 1 [1.80 (1.29-2.52)], and progression to stage 2 HTN [1.81 (1.25-2.61)] had a higher risk for CVD; however, regression to normal BP attenuated this risk [1.36 (0.88-2.12)]. Conversion from elevated BP to any other categories had no significant association with CVD risk. Conclusions: Generally, prevalent stage 1 HTN (regardless of changing category) and incident stage 1 HTN were significantly associated with a higher risk of CVD; even regression to elevated BP did not attenuate the risk. Accordingly, these populations are potential candidates for antihypertensive management.

The impact of long-term exposure to PM10, SO2, O3, NO2, and CO on incident dysglycemia: a population-based cohort study.

To examine the associations between long-term exposure to five major air pollutants including SO2, PM10, O3, NO2, and CO, and incident dysglycemia, impaired fasting glucose (IFG), and diabetes, separately. A total of 4254 (1720 men) normoglycemic individuals aged 20-69 years at baseline were followed from 2001 to 2018 every 3 years. To measure the long-term hazards of air pollutants for incident dysglycemia, the Weibull proportional hazards models for every 10-unit increment adjusted for diabetes risk factors were fitted. The air pollutants were put in the models in the form of averages of 1-, 2-, and 3-year periods. During a median follow-up of 12.2 years, we observed 1780 dysglycemia events. In contrast to NO2, the increase in SO2, O3, and PM10 levels were significantly associated with a higher risk of dysglycemia and IFG in all time spans excluding PM10 at 2 years. The largest hazard ratios for incident dysglycemia and IFG were attributable to PM10 in 3 years (2.20 (95% CI 1.67, 2.89) and 2.08 (1.55, 2.80), respectively). Moreover, exposure to all the pollutants except NO2 in 1 year (0.89 (0.80, 0.98)) had no significant associations with incident diabetes. There was a signal that younger (< 45 years) and never-smoker individuals were more predispose to dysglycemic effects of air pollution (all P for interactions > 0.03). Our findings suggested that long-term exposure to air pollution increased incident dysglycemia risk, the effect which was mainly attributable to IFG status.

Non-coding RNAs and Exosomal Non-coding RNAs in Traumatic Brain Injury: the Small Player with Big Actions.

Nowadays, there is an increasing concern regarding traumatic brain injury (TBI) worldwide since substantial morbidity is observed after it, and the long-term consequences that are not yet fully recognized. A number of cellular pathways related to the secondary injury in brain have been identified, including free radical production (owing to mitochondrial dysfunction), excitotoxicity (regulated by excitatory neurotransmitters), apoptosis, and neuroinflammatory responses (as a result of activation of the immune system and central nervous system). In this context, non-coding RNAs (ncRNAs) maintain a fundamental contribution to post-transcriptional regulation. It has been shown that mammalian brains express high levels of ncRNAs that are involved in several brain physiological processes. Furthermore, altered levels of ncRNA expression have been found in those with traumatic as well non-traumatic brain injuries. The current review highlights the primary molecular mechanisms participated in TBI that describes the latest and novel results about changes and role of ncRNAs in TBI in both clinical and experimental research.

Role of non-coding RNAs in neuroblastoma.

Neuroblastoma is known as the most prevalent extracranial malignancy in childhood with a neural crest origin. It has been widely accepted that non-coding RNAs (ncRNAs) play important roles in many types of cancer, including glioma and gastrointestinal cancers. They may regulate the cancer gene network. According to recent sequencing and profiling studies, ncRNAs genes are deregulated in human cancers via deletion, amplification, abnormal epigenetic, or transcriptional regulation. Disturbances in the expression of ncRNAs may act either as oncogenes or as anti-tumor suppressor genes, and can lead to the induction of cancer hallmarks. ncRNAs can be secreted from tumor cells inside exosomes, where they can be transferred to other cells to affect their function. However, these topics still need more study to clarify their exact roles, so the present review addresses different roles and functions of ncRNAs in neuroblastoma.

The impact of conventional smoking versus electronic cigarette on the expression of VEGF, PEMPA1, and PTEN in rat prostate.

Background: The use of electronic cigarettes (e-cigarettes), the alternative to conventional smoking, is increasing considerably worldwide; however, their safety is a matter of debate. Several studies have demonstrated their toxic effects, but no study assessed their effects on the prostate. Objective: The current study aimed at evaluating e-cigarettes and conventional smoking prostate toxicity and effects on the expression of vascular endothelial growth factor A (VEGFA), phosphatase and tensin (PTEN), and prostate transmembrane protein androgen induced 1 (PMEPA1). Method: 30 young Wistar rats were categorized into three groups (n = 10) as follows: the control group, the conventional smoking group, and the e-cigarette group. The case groups were exposed to cigarettes or e-cigarettes for 40 minutes, 3 times a day for four months. Serum parameters, prostate pathology, and gene expression were measured at the end of the intervention. Data were analyzed by Graph Pad prism 9. Results: Histopathological findings presented that both types of cigarette-induced hyperemia and induced inflammatory cell infiltration and hypertrophy of smooth muscle of the vascular wall in the e-cigarette group. Expression of PMEPA1, and VEGFA genes significantly increased in conventional (2.67-fold; P = 0.0108, 1.80-fold; P = 0.0461 respectively) and e-cigarettes (1.98-fold; P = 0.0127, 1.34-fold; P = 0.938, respectively) groups compared to the control group. Expression of the PTEN gene non-significantly decreased in the case of groups compared to the control group. Conclusion: We found no significant differences between the two groups in terms of PTEN and PMEPA1 expression, whereas VEGFA was significantly more expressed in a conventional smoking group compared to the e-cigarette group. Therefore, it seems that e-cigarettes could not be taken into account as a better option than conventional smoking, and quitting smoking still is the optimal option.

Effects of microRNAs and long non-coding RNAs on chemotherapy response in glioma.

Glioma is the most prevalent invasive primary tumor of the central nervous system. Glioma cells can spread and infiltrate into normal surrounding brain tissues. Despite the standard use of chemotherapy and radiotherapy after surgery in glioma patients, treatment resistance is still a problem, as the underlying mechanisms are still not fully understood. Non-coding RNAs are widely involved in tumor progression and treatment resistance mechanisms. In the present review, we discuss the pathways by which microRNAs and long non-coding RNAs can affect resistance to chemotherapy and radiotherapy, as well as offer potential therapeutic options for future glioma treatment.

Association between Wrist Circumference and Risk of Any Fracture in Adults: Findings from 15 Years of Follow-Up in the Tehran Lipid and Glucose Study.

We evaluated whether wrist circumference (WrC), as a novel anthropometric measure, is associated with incidences of any fractures. The study population included 8288 adults (45.3% men) aged ≥30 years, who were followed for incidences of any fractures from 31 January 1999 to 16 March 2016. We used Cox proportional hazard models adjusted for well-known risk factors to evaluate the association of WrC, both as continuous and categorical variables (bottom tertile as reference), with incidences of any fractures and major osteoporotic fractures (MOF). Over 15 years of follow-ups, 348 fractures occurred (men = 162). For a 1 cm increase in WrC, hazard ratios (HRs) were 1.18 (95% CI: 1.03-1.35) for incident any fractures and 1.22 (1.01-1.49) for incident MOF. In addition to WrC, age, female sex, lower BMI, higher WC, current smoking, and usage of steroidal medications were significantly associated with the incidences of any fractures. Moreover, participants in the middle and top tertiles of WrC had a higher risk of incidence for any fractures [HR = 1.62 (1.19-2.20) and 1.70 (1.14-2.55), respectively, p-value for trend = 0.012]. We presented WrC as a strong and independent risk factor for incidences of any fractures that might be considered in the risk prediction of bone fracture in Iranian adults.

Applications of resveratrol in the treatment of gastrointestinal cancer.

Natural product compounds have lately attracted interest in the scientific community as a possible treatment for gastrointestinal (GI) cancer, due to their anti-inflammatory and anticancer properties. There are many preclinical, clinical, and epidemiological studies, suggesting that the consumption of polyphenol compounds, which are abundant in vegetables, grains, fruits, and pulses, may help to prevent various illnesses and disorders from developing, including several GI cancers. The development of GI malignancies follows a well-known path, in which normal gastrointestinal cells acquire abnormalities in their genetic composition, causing the cells to continuously proliferate, and metastasize to other sites, especially the brain and liver. Natural compounds with the ability to affect oncogenic pathways might be possible treatments for GI malignancies, and could easily be tested in clinical trials. Resveratrol is a non-flavonoid polyphenol and a natural stilbene, acting as a phytoestrogen with anti-cancer, cardioprotective, anti-oxidant, and anti-inflammatory properties. Resveratrol has been shown to overcome resistance mechanisms in cancer cells, and when combined with conventional anticancer drugs, could sensitize cancer cells to chemotherapy. Several new resveratrol analogs and nanostructured delivery vehicles with improved anti-GI cancer efficacy, absorption, and pharmacokinetic profiles have already been developed. This present review focuses on the in vitro and in vivo effects of resveratrol on GI cancers, as well as the underlying molecular mechanisms of action.

Novel combination therapy of prostate cancer cells with arsenic trioxide and flutamide: An in-vitro study.

OBJECTIVE: The study objective was to assess the therapeutic potential of Arsenic Trioxide (ATO) and Flutamide combination for metastatic prostate cancer (PCa) treatment. MATERIAL AND METHOD: LNCaP and PC3 cell lines were treated with different concentrations of ATO and PCa conventional drug Flutamide alone and/or in combination to find effective doses and IC50 values. Percentages of apoptotic cells were evaluated by Annexin/PI staining and the proliferative inhibitory effect was assessed by Micro Culture Tetrazolium Test (MTT). Expression of SNAIL, KLK2, E-cadherin, and angiogenesis genes (VEGFA and VEGFC), and apoptosis genes (Bcl2, and P53) were examined by real-time PCR. RESULTS: The combination of Flutamide and ATO significantly increased the percentage of apoptotic cells and inhibited PCa cells proliferation compared with each drug alone in LNCaP and PC3 cell lines. Generally, both cell lines treated with the combination of Flutamide and ATO showed a decrease in expression of KLK2, angiogenesis genes (VEGFA and VEGFC), and apoptosis gene (Bcl2), and an increase in expression of E-cadherin and P53 genes; however, contradictory findings were found regarding SNAIL expression in LNCaP and PC3 cells. CONCLUSION: The combination therapy with ATO and flutamide has augmented the anti-tumor effect on LNCaP and PC3 cells, which probably originates from their potential to induce apoptosis and inhibit the proliferation of PCa cells simultaneously.