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Background: To evaluate the prevalence of type 2 diabetes mellitus (T2DM), impaired fasting glucose (IFG), and its cardio-metabolic risk factors in the southern Iranian adult population., Methods: This is a population-based cross-sectional survey on 3944 middle-aged and elderly adults (35-70 years) from Bandare-Kong. The participants were recruited from 2016 to 2018 and the first phase data of the Bandare-Kong Cohort as a part of the PERSIAN Cohort were used for analysis., Results: Among the 3944 included adults, the age-adjusted prevalence of T2DM and IFG was 17.40% and 20.61%, respectively. Mean FPG was higher among those older than 55 years, females, rural residents, current cigarette smokers, hypertriglyceridemia, hypercholesterolemia, unemployed and low educational level in subjects with diabetes and pre-diabetes. T2DM and IFG were more prevalent in women and men, respectively. Also, those with higher waist circumference (WC), higher body mass index (BMI), lower educational levels, rural residents, former cigarette smokers, hypertension (HTN), hypercholesterolemia, hypertriglyceridemia and age older 45 years, had a higher T2DM and IFG prevalence. Multivariable regression analysis showed that older age, higher WC, HTN and hypertriglyceridemia and living in rural regions were statistically significant predictors of T2DM and pre-diabetes while BMI≥25 kg/m 2 was the only significant risk factor for IFG., Conclusion: The current study illustrated that T2DM and IFG have a high prevalence among the middle-aged and elderly adult Iranian population, particularly in rural dwellers. Hence, prevention strategies should be implemented to reduce diabetes and pre-diabetes, especially in rural areas., (© 2022 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Chronic non-communicable diseases (NCDs), are the leading causes of death among adults worldwide. It is projected that half of the NCDs could be avoided by preventing measures. Under the prospective epidemiological research studies in Iran (PERSIAN), we established a prospective population-based cohort study in southern Iran. The present study was designed to observe changing pattern of lifestyle transition over time and investigate the incidence and prevalence of regional modifiable risk factors as well as their associations with major NCDs. At baseline, 4063 participants aged 35-70 years were recruited on Oct, 2016and planned to get re-evaluated every 5 years along with annual follow-up. Data using validated electronic questionnaire comprising 55 questions and 482 items including general, medical and nutrition queries was collected. Blood, hair, nails, urine specimens and anthropometric measurements were taken. The response rate was 99%. In the results; male and female participants were 42.5% and 57.5%, respectively. Of note, 30.4% of women and 16.1% of men were obese. The prevalence of hypertension in men and women was 14.6% and 21%; however, diabetic men and women were 17.4% and 12.4%, respectively. Living in rural areas increased the odds of having hypertension by 1.33 (AOR = 1.33, 95% CI:1-09, 1.61). Noteworthy, logistic regression displayed that aging could predispose individuals to be more overweight, hypertensive and diabetic. The prevalence of multimorbidity of 3 or more NCDs were 8% (No. 326) and 6% (No.240), respectively. Intake of fruits, vegetables and dairy was less than two servings per day in 9.2%, 13% and 58.3% of the participants. Lower cardiovascular diseases and serum level of FBS and higher HDL level in sailors/fishermen compared to other job groups were significant (p-value <0.001). The second annual follow-up was completed and now at the end of the third wave. Findings of the present study signified the high prevalence of behavioral risk factors and their associations with respective NCDs. Subsequently, it is essential to keep track lifestyle variations, the modifiable risk factors and NCDs trends by prospective population-based cohort studies., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Evidence suggests that gestational exposure to Lipopolysaccharide (LPS) results in fetal zinc deficiency and eventually neurodevelopmental abnormalities. In this study, we utilized a rat model of Maternal Immune Activation (MIA) to investigate the possible neuroprotective effects of zinc supplementation during pregnancy on hippocampal astrocytes activation as well as inflammatory cytokines expression in adult offspring., Methods: Pregnant rats received intraperitoneal injections of either LPS (0.5 mg/kg) or saline on Gestational Days (GD) 15 and 16, and orally gavaged with zinc sulfate (30 mg/kg) during pregnancy. Astrocyte density and histological assessment were evaluated in the hippocampus of adult offspring on Postnatal Days (PND) 60 to 62. Also, the mRNA levels of IL-6, TNF-α, IL-1β, NF-κB , and GFAP were measured using qPCR analysis., Results: Prenatal exposure to LPS resulted in upregulated expression levels of IL-6, TNF-α, NF-κB , and GFAP in the hippocampus of adult pups. Moreover, the offspring from the LPS group showed an increased astrocyte density in the CA1 region with no histological alterations in CA1 and CA3 areas. However, maternal zinc supplementation ameliorated the LPS-induced inflammatory alterations., Conclusion: This study supports the premise that zinc supplementation during pregnancy might be an early treatment option to inhibit hippocampal inflammation induced by the maternal immune response to infectious agents., Highlights: Maternal immune activation induced mild hippocampal inflammation in adult offspring.Zinc supplementation suppressed LPS-induced hippocampal inflammation in offspring.Zinc might be an early therapeutic option to inhibit neurodevelopmental impairments., Plain Language Summary: Schizophrenia is a chronic and disabling psychiatric disorder, affecting an estimated one percent of the world's population. To date, the biological mechanisms underlying this mental disorder remain largely elusive, however, research has demonstrated the involvement of both genetic and environmental factors. Of environmental factors, gestational exposure to rubella, influenza, and genital-reproductive infections have gained particular interest among researchers. Based on this evidence, in the present study, we used an animal model of schizophrenia and showed the beneficial effect of zinc supplementation during pregnancy to protect against LPS-induced inflammation in the hippocampus of adult offspring. Collectively, our study provides support for the premise that early treatment might be a suitable option to prevent schizophrenia risk in progeny., Competing Interests: Conflict of interest The authors declared no conflict of interest., (Copyright© 2022 Iranian Neuroscience Society.)

Background: Resistance to cisplatin is a major obstacle to effective treatment of bladder cancer (BC). The present study aimed to determine whether a combination of acriflavine (ACF) with cisplatin could potentiate the antitumor property of cisplatin against the BC cells. Furthermore, the molecular mechanism behind the anticancer action of ACF was considered., Methods and Results: Two human BC cells (5637 and EJ138) contain mutated form of p53 was culture in standard condition. Cotreatment protocol (simultaneous combination of IC 30 value of ACF + various dose of cisplatin for 72 h) and pretreatment protocol (pretreatment with IC 15 value of ACF for 24 h + various dose of cisplatin for 48 h) was used to determine the effect of ACF on the cells' sensitivity to main drug cisplatin. To assess the mechanism of action of ACF, real-time PCR was used to evaluate mRNA levels of hypoxia-inducible factor-1α (HIF-1α), Bax, Bcl-2, topoisomerase1 (TOP1) and topoisomerase 2 (TOP2A). Combination of ACF with cisplatin either as cotreatment or opretreatment protocol could significantly reduce the IC 50 values of cisplatin as compared to the IC 50 of cisplatin when use as a single drug. In addition, ACF could markedly decrease mRNA expression of TOP1 and TOP2A without changing the expression of HIF-1ɑ, Bax and Bcl-2., Conclusions: Our findings indicate that combination of cisplatin with ACF was able to significantly enhance the sensitivity of BC cells to cisplatin. The antitumor activity of ACF is exerted through the downregulation of TOP1 and TOP2A genes expression. ACF may serve as an adjuvant to boost cisplatin-based chemotherapy., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

New investigations suggest a pivotal role of brain-derived neurotrophic factor (BDNF) in cardiovascular homeostasis. However, no data could indicate the association between BDNF methylation status and the risk of coronary artery disease (CAD). The aim of the present study was to assess the association of BDNF methylation status and its serum level with the severity of CAD. According to the angiography report, a total of 84 non-diabetic CAD patients with at least 50% stenosis in one of the major coronary arteries were selected as the CAD group. For comparison, 62 angiographically proven non-CAD participants were selected as control. Additionally, subjects were categorized according to the Gensini Scoring system. Blood sample was used for genomic DNA isolation. Methylation status of the BDNF gene in exonic region was determined using the MS-PCR method and serum BDNF levels were measured with ELISA. BDNF gene methylation was significantly higher in the CAD group than in the non-CAD group. After adjustment for confounding factors, BDNF gene hypermethylation increases the risk of CAD in the total population (OR = 2.769; 95% CI, 1.033-7.423; P  = 0.043). BDNF gene hypermethylation was higher in patients with severe CAD than patients with mild CAD. Additionally, the serum BDNF level was not different from non-diabetic CAD and control groups. Our findings indicate that BDNF hypermethylation was associated with an increased risk of CAD, which may help identify subjects being at the risk of developing CAD. In addition, BDNF hypermethylation shows a significant correlation with the severity of CAD., Competing Interests: Conflict of interestThe authors have no conflicts of interest to declare that are relevant to content of this article., (© Association of Clinical Biochemists of India 2021.)

Experimental and clinical therapies in the field of Alzheimer's disease (AD) have focused on elimination of extracellular amyloid beta aggregates or prevention of cytoplasmic neuronal fibrillary tangles formation, yet these approaches have been generally ineffective. Interruption of nuclear lamina integrity, or laminopathy, is a newly identified concept in AD pathophysiology. Unraveling the molecular players in the induction of nuclear lamina damage may lead to identification of new therapies. Here, using 3xTg and APP/PS1 mouse models of AD, and in vitro model of amyloid beta42 (Aβ42) toxicity in primary neuronal cultures and SH-SY5Y neuroblastoma cells, we have uncovered a key role for cathepsin L in the induction of nuclear lamina damage. The applicability of our findings to AD pathophysiology was validated in brain autopsy samples from patients. We report that upregulation of cathepsin L is an important process in the induction of nuclear lamina damage, shown by lamin B1 cleavage, and is associated with epigenetic modifications in AD pathophysiology. More importantly, pharmacological targeting and genetic knock out of cathepsin L mitigated Aβ42 induced lamin B1 degradation and downstream structural and molecular changes. Affirming these findings, overexpression of cathepsin L alone was sufficient to induce lamin B1 cleavage. The proteolytic activity of cathepsin L on lamin B1 was confirmed using mass spectrometry. Our research identifies cathepsin L as a newly identified lamin B1 protease and mediator of laminopathy observed in AD. These results uncover a new aspect in the pathophysiology of AD that can be pharmacologically prevented, raising hope for potential therapeutic interventions., (© 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background: MicroRNAs (miRNAs) have a pivotal role in Hepatitis B Virus (HBV) infection and its complications by targeting the cellular transcription factors required for gene expression or directly binding to HBV transcripts. Single Nucleotide Polymorphisms (SNPs) in miRNA genes affect their expression and the regulation of target genes, clinical course, diagnosis, and therapeutic interventions of HBV infection., Methods: Computational assessment and cataloging of miRNA gene polymorphisms targeting mRNA transcripts straightly or indirectly through the regulation of hepatitis B infection by annotating the functional impact of SNPs on mRNA-miRNA and miRNA-RBS (miRNA binding sites) interaction were screened by applying various universally available datasets such as the miRNA SNP3.0 software., Results: 2987 SNPs were detected in 139 miRNAs affecting hepatitis B infection. Among them, 313 SNPs were predicted to have a significant role in the progression of hepatitis B infection. The computational analysis also revealed that 45 out of the 313 SNPs were located in the seed region and were more important than others. Has-miR-139-3p had the largest number of SNPs in the seed region (n=6). On the other hand, proteoglycans in cancer, adherens junction, lysine degradation, NFkappa B signaling cascade, ECM-receptor binding, viral carcinogenesis, fatty acid metabolism, TGF-beta signaling pathway, p53 signaling pathway, immune evasion related pathways, and fatty acid biosynthesis were the most important pathways affected by these 139 miRNAs., Conclusion: The results revealed 45 SNPs in the seed region of 25 miRNAs as the catalog in miRNA genes that regulated the hepatitis B infection. The results also showed the most important pathways regulated by these miRNAs that can be targeted for therapeutic purposes., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In COVID-19 patients, cytokine storm due to excessive immune responses can cause severe complications. In this study, we investigated the effect of curcumin nanomicelles on clinical outcome and cellular immune responses subtypes changes in COVID-19 patients. A randomized, triple-blinded, placebo-controlled study was done. Forty COVID-19 patients were included into two groups of nano-curcumin and placebo. The nano-curcumin group received 40 mg of nano-curcumin capsule, four times per day for 2 weeks. Clinical signs and gene expression of TBX21, GATA3, RORC and FOXP3 genes and IFN-γ, IL-4, IL-17 and TGF-β cytokines serum levels were measured at time points of 0, 7 and 14 days. Serum levels of IFN-γ (p = .52) and IL-17 (p = .11) decreased, while IL-4 (p = .12) and TGF-β (p = .14) increased in the nano-curcumin group compared with placebo on day 14. Moreover, gene expressions of TBX21 (p = .02) and FOXP3 (p = .005) genes were significantly decreased and increased between nano-curcumin and placebo groups on day 7, respectively. It can be concluded that administration of nano-curcumin in inflammatory phase of COVID-19 can accelerate recovering of the acute inflammatory phase by modulating inflammatory immune responses. Therefore, it is suggested that this supplement in inflammatory diseases, including COVID-19, can be effective in controlling the inflammatory responses., (© 2021 John Wiley & Sons Ltd.)

To develop a suitable and effective vaccine against Staphylococcus aureus (S. aureus), we selected the Hla-MntC-SACOL0723 (HMS) recombinant protein with two different formulations of alum and Monophosphoryl lipid A (MPL) adjuvants. In this study, we aimed to evaluate the potentials of alum and MPL adjuvants in stimulating the immune response of HMS vaccine candidate against S. aureus. To evaluate the type of induced immune response, anti-HMS total IgG, IgG1, IgG2a, and IFN-γ, IL-2, IL-4, and IL-17 cytokines were determined after vaccination of mice with HMS-alum, HMS-MPL candidates. Mice were challenged with Methicillin-resistant Staphylococcus aureus (MRSA) was isolated from pressure sores and evaluated for bacterial load in the kidney homogenates and survival rate. It was observed that total IgG and isotypes (IgG1 and IgG2a), IL-4, and IL-17 were significantly increased in the group that received HMS-alum vaccine compared with the group that received HMS-MPL formulation. On the other hand, the levels of IFN-γ and IL-2 cytokines in the group that received HMS-MPL were higher than the group that received HMS-alum formulation. Bacterial load in the mice who received HMS protein formulated with alum adjuvant was reduced more than the mice who received HMS protein formulated with MPL adjuvant. Histopathological analysis showed more pathological changes in kidney tissues of the group received of HMS-MPL compared with the HMS-alum formulation. The survival rate was equal in both groups of immunized with HMS-alum and HMS-MPL formulations. Finally, it could be concluded that both adjuvants of alum and MPL are suitable immune response enhancers to HMS vaccine candidate., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder., Methods: A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization., Results: Biallelic variants in the TMEM222 gene were identified in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in the lower extremities, and mild hypotonia. We found relatively high TMEM222 expression levels in the human brain, especially in the parietal and occipital cortex. Additionally, subcellular localization analysis in human neurons derived from induced pluripotent stem cells (iPSCs) revealed that TMEM222 localizes to early endosomes in the synapses of mature iPSC-derived neurons., Conclusion: Our findings support a role for TMEM222 in brain development and function and adds variants in the gene TMEM222 as a novel underlying cause of an autosomal recessive neurodevelopmental disorder.

Ferroptosis is a necrotic form of cell death caused by inactivation of the glutathione system and uncontrolled iron-mediated lipid peroxidation. Increasing evidence implicates ferroptosis in a wide range of diseases from neurotrauma to cancer, highlighting the importance of identifying an executioner system that can be exploited for clinical applications. In this study, using pharmacological and genetic models of ferroptosis, we observed that lysosomal membrane permeabilization and cytoplasmic leakage of cathepsin B unleashes structural and functional changes in mitochondria and promotes a not previously reported cleavage of histone H3. Inhibition of cathepsin-B robustly rescued cellular membrane integrity and chromatin degradation. We show that these protective effects are independent of glutathione peroxidase-4 and are mediated by preventing lysosomal membrane damage. This was further confirmed when cathepsin B knockout primary fibroblasts remained unaffected in response to various ferroptosis inducers. Our work identifies new and yet-unrecognized aspects of ferroptosis and identifies cathepsin B as a mediator of ferroptotic cell death., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The selection of a suitable signal peptide that can direct recombinant proteins from the cytoplasm to the extracellular space is an important criterion affecting the production of recombinant proteins in Escherichia coli, a widely used host. Nanobodies are currently attracting the attention of scientists as antibody alternatives due to their specific properties and feasibility of production in E. coli., Objective: CD44 nanobodies constitute a potent therapeutic agent that can block CD44/HA interaction in cancer and inflammatory diseases. This molecule may also function as a drug against cancer cells and has been produced previously in E. coli without a signal peptide sequence. The goal of this project was to find a suitable signal peptide to direct CD44 nanobody extracellular secretion in E. coli that will potentially lead to optimization of experimental methods and facilitate downstream steps such as purification., Methods: We analyzed 40 E. coli derived signal peptides retrieved from the Signal Peptide database and selected the best candidate signal peptides according to relevant criteria including signal peptide probability, stability, and physicochemical features, which were evaluated using signalP software version 4.1 and the ProtParam tool, respectively., Results: In this in silico study, suitable candidate signal peptide(s) for CD44 nanobody secretory expression were identified. CSGA, TRBC, YTFQ, NIKA, and DGAL were selected as appropriate signal peptides with acceptable D-scores, and appropriate physicochemical and structural properties. Following further analysis, TRBC was selected as the best signal peptide to direct CD44 nanobody expression to the extracellular space of E. coli., Conclusion: The selected signal peptide, TRBC is the most suitable to promote high-level secretory production of CD44 nanobodies in E. coli and potentially will be useful for scaling up CD44 nanobody production in experimental research as well as in other CD44 nanobody applications. However, experimental work is needed to confirm the data., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

5-flurouracil (5-FU)-based chemotherapy is the main pharmacological therapy for advanced colorectal cancer (CRC). Despite significant progress in the treatment of CRC during the last decades, 5-FU drug resistance remains the most important cause of failure in CRC therapy. Resistance to 5-FU is a complex and multistep process. Different mechanisms including microsatellite instability, increased expression level of key enzyme thymidylate synthase and its polymorphism, increased level of 5-FU-activating enzymes and mutation of TP53 are proposed as the main determinants of resistance to 5-FU in CRC cells. Recently, micro-ribonucleic acids (miRNA) and their alterations were found to have a crucial role in 5-FU resistance. In this regard, the miRNA-mediated mechanisms of 5-FU drug resistance reside among the new fields of pharmacogenetics of CRC drug response that has not been completely discovered. Identification of the biological markers that are related to response to 5-FU-based chemotherapy is an emerging field of precision medicine. This approach will have an important role in defining those patients who are most likely to benefit from 5-FU-based chemotherapy in the future. Thereby, the identification of 5-FU drug resistance mechanisms is an essential step to predict and eventually overcome resistance. In the present comprehensive review, we will summarize the latest knowledge regarding the molecular determinants of response to 5-FU-based chemotherapy in CRC by emphasizing the role of miRNAs., Competing Interests: Conflict-of-interest statement: The authors declare no potential financial interests., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Magnesium (Mg) deficiency is known to promote vascular and cardiac dysfunctions such as atherosclerosis. This study investigated the effect of oral MgSO4 therapy to improve lipid profile and serum oxidized LDL level and its receptor (LOX1) in moderate coronary atherosclerotic patients. In this randomized double-blind placebo-controlled clinical trial study, 64 patients with moderate coronary artery disease were selected according to angiography findings. Participants were divided into 2 groups including Mg-treated (n = 32) and placebo (n = 32) The patients received either placebo or MgSO4 supplement capsule, containing 300 mg MgSO4 for 6 months on a daily basis. Lipid profile, HbA1c, 2h postprandial (2hpp) blood glucose, fasting blood sugar, serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), oxidized low-density lipoprotein, and lectin-like ox-LDL receptor 1 (LOX1) concentrations were measured at baseline and every 3 months. HbA1c, serum LOX1, and oxidized low-density lipoprotein concentrations were significantly lower in the Mg-treated group than the placebo group 3 months after MgSO4 administration. 2hpp, serum low-density lipoprotein cholesterol, SGPT, SGOT levels, and HbA1c levels significantly improved in the Mg-treated group compared with the placebo-received group. Overall, the results of this study showed that magnesium treatment improved some of the major risk factors of atherosclerosis. According to the results of liver function tests (SGOT and SGPT), magnesium therapy seems to be safe in patients with moderate atherosclerotic plaque. Therefore, it is suggested that magnesium to be used along with other atherosclerosis control drugs.

Lysosomes are small specialized organelles containing a variety of different hydrolase enzymes that are responsible for degradation of all macromolecules, entering the cells through the endosomal system or originated from the internal sources. This allows for transport and recycling of nutrients and internalization of surface proteins for antigen presentation as well as maintaining cellular homeostasis. Lysosomes are also important storage compartments for metal ions and nutrients. The integrity of lysosomal membrane is central to maintaining their normal function, but like other cellular membranes, lysosomal membrane is subject to damage mediated by reactive oxygen species. This results in spillage of lysosomal enzymes into the cytoplasm, leading to proteolytic damage to cellular systems and organelles. Several forms of lysosomal dependent cell death have been identified in diseases. Examination of these events are important for finding treatment strategies relevant to cancer or neurodegenerative diseases as well as autoimmune deficiencies. In this review, we have examined the current literature on involvement of lysosomes in induction of programed cell death and have provided an extensive list of therapeutic approaches that can modulate cell death. Exploitation of these mechanisms can lead to novel therapies for cancer and neurodegenerative diseases., (Copyright © 2020 Elsevier Inc. All rights reserved.)

There is increased interest in the use of magnetic resonance imaging (MRI) for guiding radiation therapy (RT) in the clinical setting. In this regard, preclinical studies can play an important role in understanding the added value of MRI in RT planning. In the present study, we developed and validated a clinically relevant integrated workflow for MRI-guided volumetric arc therapy (VMAT) in a VX2 rabbit neck tumor model of HNSCC. In addition to demonstrating safety and feasibility, we examined the therapeutic impact of MR-guided VMAT using a single high dose to obtain proof-of-concept and compared the response to conventional 2D-RT. Contrast-enhanced MRI (CE-MRI) provided excellent soft tissue contrast for accurate tumor segmentation for VMAT. Notably, MRI-guided RT enabled improved tumor targeting ability and minimal dose to organs at risk (OAR) compared to 2D-RT, which resulted in notable morbidity within a few weeks of RT. Our results highlight the value of integrating MRI into the workflow for VMAT for improved delineation of tumor anatomy and optimal treatment planning. The model combined with the multimodal imaging approach can serve as a valuable platform for the conduct of preclinical RT trials.

Traumatic spinal cord injury (SCI) elicits a cascade of secondary injury mechanisms that induce profound changes in glia and neurons resulting in their activation, injury or cell death. The resultant imbalanced microenvironment of acute SCI also negatively impacts regenerative processes in the injured spinal cord. Thus, it is imperative to uncover endogenous mechanisms that drive these acute injury events. Here, we demonstrate that the active form of bone morphogenetic protein-4 (BMP4) is robustly and transiently upregulated in acute SCI in rats. BMP4 is a key morphogen in neurodevelopment; however, its role in SCI is not fully defined. Thus, we elucidated the ramification of BMP4 upregulation in a preclinical model of compressive/contusive SCI in the rat by employing noggin, an endogenous antagonist of BMP ligands, and LDN193189, an intracellular inhibitor of BMP signaling. In parallel, we studied cell-specific effects of BMP4 on neural precursor cells (NPCs), oligodendrocyte precursor cells (OPCs), neurons and astrocytes in vitro. We demonstrate that activation of BMP4 inhibits differentiation of spinal cord NPCs and OPCs into mature myelin-expressing oligodendrocytes, and acute blockade of BMPs promotes oligodendrogenesis, oligodendrocyte preservation and remyelination after SCI. Importantly, we report for the first time that BMP4 directly induces caspase-3 mediated apoptosis in neurons and oligodendrocytes in vitro, and noggin and LDN193189 remarkably attenuate caspase-3 activation and lipid peroxidation in acute SCI. BMP4 also enhances the production of inhibitory chondroitin sulfate proteoglycans (CSPGs) in activated astrocytes in vitro and after SCI. Interestingly, our work reveals that despite the beneficial effects of BMP inhibition in acute SCI, neither noggin nor LDN193189 treatment resulted in long-term functional recovery. Collectively, our findings suggest a role for BMP4 in regulating acute secondary injury mechanisms following SCI, and a potential target for combinatorial approaches to improve endogenous cell response and remyelination., Competing Interests: Declaration of Competing Interest Authors declare no competing financial interests., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Temozolomide (TMZ) is a chemotherapy agent used to treat Grade IV astrocytoma, also known as glioblastoma (GBM). TMZ treatment causes DNA damage that results in tumor cell apoptosis and increases the survival rate of GBM patients. However, chemoresistance as a result of TMZ-induced autophagy significantly reduces this anticancer effects over time. Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of the mevalonate (MEV) cascade. Statins are best known for their cholesterol (CH)-lowering effect. Long-term consumption of statins, prior to and in parallel with other cancer therapeutic approaches, has been reported to increase the survival rate of patients with various forms of cancers. In this study, we investigated the potentiation of TMZ-induced apoptosis by simvastatin (Simva) in human GBM cell lines and patient GBM cells, using cell monolayers and three-dimensional cell culture systems. The incubation of cells with a combination of Simva and TMZ resulted in a significant increase in apoptotic cells compared to cells treated with TMZ alone. Incubation of cells with CH or MEV cascade intermediates failed to compensate the decrease in cell viability induced by the combined Simva and TMZ treatment. Simva treatment inhibited the autophagy flux induced by TMZ by blocking autophago-lysosome formation. Our results suggest that Simva sensitizes GBM cells to TMZ-induced cell death in a MEV cascade-independent manner and identifies the inhibition of autophagosome-lysosome fusion as a promising therapeutic strategy in the treatment of GBM., (© 2019 Federation of European Biochemical Societies.)

Background: Socioeconomic-related inequality in oral hygiene behaviors in Iran is poorly understood. This study aims to measure and decompose socioeconomic-related inequalities in oral hygiene behaviors among middle-aged and elderly adults in Iran., Methods: A cross-sectional analysis was performed using data from the Prospective Epidemiological Research Studies in IrAN (PERSIAN), a large national cohort study. A total of 130,016 individuals aged 35 years and above from 17 cohort centers in Iran were included in the study. The normalized concentration index (C n ) was used to measure the magnitude of inequality in oral hygiene behaviors, i.e. brushing at least twice and flossing once daily, among middle-aged and elderly Iranian adults included in the cohort centers. Decomposition analysis was performed to quantify the contribution of each determinant to the observed inequality in oral hygiene behaviors., Results: Totally, 65.5% of middle-aged and elderly adults brushed their teeth twice a day or more, 7.6% flossed at least once a day and 3.48% had both habits. The estimated C n of the two habits combined, i.e. tooth brushing and dental flossing, for all provinces taken part in the PERSIAN cohort study was 0.399 (95% confidence interval [CI]: 0.383 to 0.417), indicating that the prevalence of the two habits combined is more concentrated among individuals with higher socioeconomic status. Inequality in oral hygiene behaviors was pro-rich in all cohort centers. The decomposition results suggested socioeconomic status as the main factor contributing to the overall inequality, followed by the level of education, and the province of residence., Conclusion: A low prevalence of oral hygiene behaviors among middle-aged and elderly Iranian adults was observed. There was also a pro-rich inequality in oral hygiene behaviors among middle-aged and elderly adults in all cohort centers. These results suggest an urgent need for targeted policy interventions to increase the prevalence of preventive oral hygiene behaviors among the poor and less-educated middle-aged and elderly adults in Iran.

Colorectal cancer (CRC) has been designated a major global problem, especially due to its high prevalence in developed countries. CRC mostly occurs sporadically (75%-80%), and only 20%-25% of patients have a family history. Several processes are involved in the development of CRC such as a combination of genetic and epigenetic alterations. Epigenetic changes, including DNA methylation play a vital role in the progression of CRC. Complex interactions between susceptibility genes and environmental factors, such as a diet and sedentary lifestyle, lead to the development of CRC. Clinical and experimental studies have confirmed the beneficial effects of dietary polyunsaturated fatty acids (PUFAs) in preventing CRC. From a mechanistic viewpoint, it has been suggested that PUFAs are pleiotropic agents that alter chromatin remodeling, membrane structure and downstream cell signaling. Moreover, PUFAs can alter the epigenome via modulation of DNA methylation. In this review, we summarize recent investigations linking PUFAs and DNA methylation-associated CRC risk., Competing Interests: Conflict-of-interest statement: Authors declare no conflict of interest related to this article., (©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.)

Oxidative stress is a major complication in diabetes mellitus. The aim of this study was to investigate potential antioxidant activity of coenzyme Q10 (Co Q10) against hyperglycemia-induced oxidative stress in diabetic rat and unraveling its mechanism of action by focusing on silent information regulator 1 (Sirt1) and nuclear factor E2-related factor 2 (Nrf2) mRNA expression level. Furthermore, the activity of two Nrf2-dependent antioxidant enzymes (superoxide dismutase and catalase) in the liver of diabetic rats was studied. After induction of diabetes in rats using streptozotocin (55 mg/kg), rats were divided into five groups of six each. Groups 1 and 2 (healthy control groups) were injected with isotonic saline or sesame oil; group 3 received Co Q10 (10 mg /Kg /day), group 4, as a diabetic control, received sesame oil; and group 5 was diabetic rats treated with Co Q10. Afterwards, serum and liver samples were collected, and oxidative stress markers, lipid profile, as well as the expression of Sirt1 and Nrf2 genes were measured. Diabetes induction significantly reduced expression level of Sirt1 and Nrf2 mRNAs and also declined catalase, superoxide dismutase activities, and total thiol groups levels in diabetic group in comparison to healthy controls, while a significant increase was found in the levels of malondialdehyde and lipid profile. Co Q10 treatment significantly up-regulated Sirt1 and Nrf2 mRNA levels along with an increase in catalase activity in diabetic group as compared with untreated diabetic rats. Furthermore, Co Q10 caused a marked decrease in malondialdehyde levels and significantly improved lipid profile. Our data demonstrated that Co Q10 may exert its antioxidant activity in diabetes through the induction of Sirt1/Nrf2 gene expression., (Copyright: © 2019 Research in Pharmaceutical Sciences.)

We isolated an actinobacterium, Streptomyces sp. strain SP 85 from the marine sponge Dysidea avara. Polyphasic identification of the microorganism showed that the strain SP 85 had high 16S rRNA gene similarity (99%) with Streptomyces olivaceus strain NBRC 12805, while some physiological and biochemical differences were observed. A cytotoxic compound, SP 85 was isolated from the active culture extract of the strain SP 85 by bioassay-guided purification over silica gel column chromatography, preparative TLC, and HPLC. The structure elucidation based on the spectroscopic analysis, including UV, ESI-MS, and 13 C NMR data revealed that SP 85 compound is an analog of anti-tumor drug, "olivomycin A". The SP 85 compound showed high cytotoxic activity against three human cancer cell lines, including SW480, HepG2, and MCF7 with IC 50 values of 16, 93, and 78 nM, respectively. SP 85 exhibited significantly (2-10 times) higher cytotoxicity against the tumor cell lines in comparison with HUVECs as the normal cell line, which also induced apoptosis in the tested cancerous cell line. This is the first report on the production of an "olivomycin A" derivative by a sponge-associated Streptomyces , showing the great potential of sponge-associated actinobacteria in producing cytotoxic natural products., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© King Abdulaziz City for Science and Technology 2019.)

Background: The present study aimed to evaluate the prevalence of intestinal parasitic infection among mentally retarded individuals and the staff of the center in Bandar Abbas, south of Iran., Methods: This cross-sectional study was conducted in central institution for mentally retarded in Bandar Abbas, Hormozgan Province, from 2016 to 2017. A triple fecal specimen was collected from each one of the 163 participants and were evaluated using wet mount and formalin-ethyl acetate methods. Trichrome and Ziehl-Neelsen staining were used to confirm suspected cases of protozoa. As well as Baermann and Harada-Mori techniques and agar plate culture were implemented to diagnosis of Strongyloides stercoralis ., Results: Overall, 163 subjects were examined including 126 mentally retarded individuals and 37 personnel. Ninety (55.2%) cases of participants were infected with at least one of the intestinal parasites, 69 (54.7%) of mentally retarded and 21 (56.7%) of personnel. Twenty-six mentally retarded individuals were infected with S. stercoralis (20.6%), Blastocystis hominis 30.2%, Entamoeba coli 25.4%, Giardia lamblia 5.6%, Enterobius vermicularis 1.6%, Hymenolepis nana 0.8% and Iodamoeba butschlii 1.6% . Twelve staff (32.4%) harbored B. hominis, E. coli 27%, S. stercoralis 2.7%, G. lamblia 10.8%, H. nana 2.7% and Endolimax nana 2.7%., Conclusion: High rate of intestinal parasites particularly, S. stercoralis compared to the most recent studies of general population. Therefore, regular screening and tracking the positive cases, disinfection of the living environment, training and financing of the staff, increasing the number of the workers, recruiting of professionals and trained personnel in these centers are suggested., Competing Interests: Conflict of interest The authors declare that there is no conflict of interests.

Recent reports in pathophysiology of neurodegenerative diseases (ND) have linked nuclear lamina degradation/deficits to neuronal cell death. Lamin-B1 damage is specifically involved in this process leading to nuclear envelope invagination and heterochromatin rearrangement. The underlying mechanisms involved in these events are not yet defined. In this study, while examining the effect of Thioredoxin-1(Trx1) inhibition on cell death in a model of oxidative stress, we noted robust nuclear invagination in SH-SY5Y cells. Evaluation of nuclear lamina proteins revealed lamin-B1 cleavage that was prevented by caspase-6 (CASP6) inhibitor and exacerbated after pharmacologic/genetic inhibition of Trx1 system, but not after glutathione depletion. Activation of CASP6 was upstream of CASP3/7 activation and its inhibition was sufficient to prevent cell death in our system. The effect of Trx1 redox status on CASP6 activation was assessed by administration of reduced/oxidized forms in cell-free nuclei preparation and purified enzymatic assays. Although reduced Trx1 decreased CASP6 enzymatic activity and lamin-B1 cleavage, the fully oxidized Trx1 showed opposite effects. The enhanced CASP6 activation was also associated with lower levels of DJ-1, a neuroprotective and master regulator of cellular antioxidants. The implication of our findings in ND pathophysiology was strengthened with detection of lower Trx1 levels in the hippocampi tissue of a mouse model of Alzheimer's disease. This coincided with higher CASP6 activation resulting in increased lamin-B1 and DJ-1 depletion. This study provides a first mechanistic explanation for the key regulatory role of Trx1 as a gatekeeper in activation of CASP6 and induction of nuclear invagination, an important player in ND pathophysiology., (Copyright © 2019. Published by Elsevier Inc.)

The involvement of glutamate in neuronal cell death in neurodegenerative diseases and neurotrauma is mediated through excitotoxicity or oxytosis. The latter process induces oxidative stress via glutamate-mediated inhibition of cysteine transporter xCT, leading to depletion of the cellular glutathione pool. Mitochondrial damage, loss of mitochondrial membrane potential (MMP), and depletion of energy metabolites have been shown in this process. The Voltage-Dependent Anion Channel-1 (VDAC1) is one of the main components of the mitochondrial outer membrane and plays a gatekeeping role in mitochondria-cytoplasm transport of metabolites. In this study, we explored the possible participation of VDAC-1 in the pathophysiology of oxytosis. Administration of glutamate in HT22 cells that lack the glutamate ionotropic receptors induced an upregulation and oligomerization of VDAC1. This was associated with an increase in ROS and loss of cell survival. Glutamate-mediated oxytosis in this model also decreased MMP and promoted ATP depletion, resulting in translocation of cytochrome c (cyt C) and apoptosis inducing factor (AIF) from mitochondria into the cytosol. This was also accompanied by cleavage of AIF to form truncated AIF. Inhibition of VDAC1 oligomerization using 4,4'-Diisothiocyanatostilbene-2,2'-disulfonate (DIDS), significantly improved the cell survival, decreased the ROS levels, improved mitochondrial functions, and decreased the mitochondrial damage. Notably, DIDS also inhibited the mitochondrial fragmentation caused by glutamate, indicating the active role of VDAC1 oligomerization in the process of mitochondrial fragmentation in oxytosis. These results suggest a critical role for VDAC1 in mitochondrial fragmentation and its potential therapeutic value against glutamate-mediated oxidative neurotoxicity.

Oxidative stress has been hypothesized to play a role in the pathophysiology of Alzheimer's disease (AD). Previously, we found that total nitrosylated protein levels were increased in the brain of amyloid-β protein precursor (AβPP) and presenilin 1 (PS1) double transgenic mice, an animal model for AD, suggesting that cysteine oxidative protein modification may contribute to this disease. Thioredoxin (Trx) is a major oxidoreductase that can reverse cysteine oxidative modifications such as sulfenylation and nitrosylation, and inhibit oxidative stress. Thioredoxin-interacting protein (Txnip) is an endogenous Trx inhibitor. To understand the involvement of Trx and Txnip in AD development, we investigated Trx and Txnip in the brain of AβPP/PS1 mice. Using immunoblotting analysis, we found that although Trx protein levels were not changed, Txnip protein levels were significantly increased in hippocampus and frontal cortex of 9- and 12-month-old AβPP/PS1 mice when compared to wild-type mice. Txnip protein levels were also increased by amyloid-β treatment in primary cultured mouse cerebral cortical neurons and HT22 mouse hippocampal cells. Using biotin switch and dimedone conjugation methods, we found that amyloid-β treatment increased protein nitrosylation and sulfenylation in HT22 cells. We also found that downregulation of Txnip, using CRISPR/Cas9 method in HT22 cells, attenuated amyloid-β-induced protein nitrosylation and sulfenylation. Our findings suggest that amyloid-β may increase Txnip levels, subsequently inhibiting Trx reducing capability and enhancing protein cysteine oxidative modification. Our findings also indicate that Txnip may be a potential target for the treatment of AD.

Autophagy is increasingly identified as a central player in many cellular activities from cell proliferation to cell division, migration, and differentiation. However, it is also considered as a double-edged sword in cancer biology which either promotes oncogenesis/invasion or sensitizes the tumor cells to chemotherapy induced apoptosis. Recent investigations have provided direct evidence for regulation of cellular phenotype via autophagy pathway. One of the most important types of phenotype conversion is Epithelial-Mesenchymal-Transition (EMT), resulting in alteration of epithelial cell properties to a more mesenchymal form. In the current chapter, we provide a method which is established and being used in our laboratory for detection of autophagy and EMT in lung epithelial cells and show the involvement of autophagy in modulation of cellular phenotype.

Considering the crucial importance of hepatitis B and its high prevalence in the society, the present study was conducted to examine the demographic and paraclinical characteristics of patients with chronic hepatitis B. This descriptive cross-sectional study examined 180 patients with hepatitis B presenting to Shahid Mohammadi Hospital and Clinic and other private clinics in Bandar Abbas, Iran, in 2016-17. The patients were divided into three main groups: chronic hepatitis, liver cirrhosis, and healthy carriers. Parametric and nonparametric tests were used to analyze the relationship between the quantitative variables in terms of their normal or nonnormal distribution ( P < 0.05). About 13.5% of the patients had cirrhosis, 35.4% were healthy carriers, and 51.12% had chronic hepatitis. The number of male patients in the cirrhosis group and the number of female participants in the healthy carrier group were higher. The difference in gender distribution between the three groups was statistically significant. According to the results of this study, male and married people constitute a high percentage of the population of patients with chronic hepatitis B. The clinical symptoms of chronic hepatitis B often do not occur until the patient's progress to advanced stages and cirrhosis, and most of the population is asymptomatic. Contact with a person suspected to have hepatitis B is one of the major risk factors of this disease., Competing Interests: There are no conflicts of interest.

Previous studies have shown that chronic stress and chronic stress hormone treatment induce oxidative damage in rodents. Thioredoxin (Trx) is a small redox protein that plays an important role in regulation of oxidative protein cysteine modification. A Trx reduced state is maintained by thioredoxin reductase (TrxR), and the thioredoxin-interacting protein (Txnip) is an endogenous inhibitor of Trx. The purpose of this study was to investigate the effects of chronic treatment with stress hormone corticosterone on Trx, TrxR and Txnip in cultured neuronal cells. Using immunoblotting analysis we found that although chronic corticosterone treatment had no effect on Trx and TrxR protein levels, this treatment significantly increased Txnip protein levels. Using immunocytochemistry we also found that chronic corticosterone treatment increased Txnip in both nucleus and cytosol, while glucocorticoid receptor inhibitor RU486 can block corticosterone-increased Txnip protein levels. Using biotin switch, dimedone conjugation and CRISPR/Cas9 methods we found that chronic corticosterone treatment increased protein nitrosylation and sulfenylation, while knocking out Txnip blocked corticosterone-induced protein nitrosylation and sulfenylation. Since Trx can reduce cysteine oxidative protein modification such as nitrosylation and sulfenylation, our findings suggest that chronic corticosterone treatment may upregulate Txnip by targeting glucocorticoid receptor, subsequently inhibiting Trx activity and enhancing oxidative protein cysteine modification, which contributes to corticosterone-caused oxidative damage., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

In the present research, we aimed to investigate organochlorine toxins accumulated in both Rutilus frisii kutum and Liza aurata captured at the southern Caspian Sea. At six sampling stations, organochlorine toxins were measured in fish tissues by the gas chromatography-electron capture detector (GC-ECD) method. Total organochlorine toxins ranged from 2.102 ppb to 9.033 ppb in L. aurata at the study area. The highest content of total organochlorine toxins was obtained at station 5, whereas the lowest content was achieved at station 4. In L. aurata, lindane showed the highest level among the measured components (1.642 ppb), whereas α-lindane showed the highest mean level of the measured components (0.57 ppb). In this investigation, the total amount of organochlorine compounds in R. frisii kutum was more than that in L. aurata, but these compounds indicated no significant difference between the two types of fishes (p > 0.05). Moreover, the measured components in both types of fishes were lesser than the allowable limit., (Copyright © 2018. Published by Elsevier Ltd.)

5-Fluorouracil (5-FU)-based chemotherapy improves the overall survival rates of patients with colorectal cancer (CRC). However, only a small proportion of patients respond to 5-FU when used as a single agent. The aim of the present study was to investigate whether the anticancer property of 5-FU is potentiated by combination treatment with acriflavine (ACF) in CRC cells. Additionally, the potential underlying molecular mechanisms of the cytotoxic effect of ACF were determined. The cytotoxic effects of ACF, 5-FU and irinotecan on different CRC cell lines with different p53 status were investigated using an MTT assay. SW480 cells that express a mutated form of p53 and two other CRC cell lines were used, HCT116 and LS174T, with wild-type p53. To determine the effect of ACF on the sensitivity of cells to 5-FU, cells were co-treated with the 30% maximal inhibitory concentration (IC 30 ) of ACF and various concentrations of 5-FU, or pretreated with the IC 30 of ACF and various concentrations of 5-FU. To assess the mechanism of action of ACF, cells were treated with IC 30 values of the compound and then the reverse transcription-quantitative polymerase chain reaction was used to evaluate mRNA levels of hypoxia-inducible factor-1α (HIF-1α) and topoisomerase 2. Results indicate that pretreatment with ACF markedly sensitized CRC cells to the cytotoxic effects of 5-FU, whereas simultaneous treatment with ACF and 5-FU were not able to alter the resistance of CRC cells to 5-FU. In comparison with irinotecan, ACF was a more potent agent for enhancing the antitumor activity of 5-FU. ACF did not alter the mRNA levels of either HIF-1α or topoisomerase 2. The results of the present study reveal for the first time that pretreatment of CRC cells with ACF markedly increases the cytotoxic effects of 5-FU, regardless of the p53 status of cells.

Background: The exact mechanisms underlying the protective effect of vitamin D in the pathogenesis of atherosclerosis and coronary heart disease are obscure., Objective: Here, we have addressed the relation between vitamin D status and regulatory T cells (Tregs) inhibitory cytokines in patients suffering from coronary artery disease (CAD)., Materials and Methods: 81 patients were divided into single (n= 20), double (n=20) and triple (n=20) vessel disease groups and compared to no vessel disease (No VD) group (n=21). Interleukin (IL) -35 and TGF- β1 were measured using ELISA. Vitamin D was measured using Electrochemiluminescence assay., Results: Vitamin D, TGF-β1 and IL-35 concentrations in No VD (32.4±15.2, 667.7±427.6, 12.1±11.9 respectively) group were significantly higher than patients with 1 or more vessel disease (18.1±9.8, 360.4±354.1 and 6.8±8.1 respectively, p<0.05). Subgroup analysis revealed that TGF-β1 and IL-35 (but not vitamin D) were significantly higher in double vessel disease patients (591.9±465.7 and 9.2±8.0 respectively) compared to those with triple vessel disease (173.1±163.3 and 3.6±1.4 respectively, p<0.05). Both TGF-β1 and IL-35 were positively correlated to the serum level of vitamin D (r= 0.38, p= 0.001 and r=0.26, p= 0.028 respectively). Vitamin D, TGF-β1 and IL-35 revealed a negative correlation (r= -0.36, r=-0.46 and r-0.024 respectively) with severity of CAD (p< 0.05). Compared to normal serum vitamin D patients (326.6±351.7 pg/mL vs. 754.5±560 pg/mL, p=0.036 respectively) TGF-β1 (but not IL-35), was significantly lower in vitamin D deficient patients., Conclusion: The results suggested that, although decreased TGF-β1 and IL-35 plasma levels correlate positively with decreased vitamin D levels and negatively with severity of CAD, but only TGF-β1 has a significant association with vitamin D deficiency in CAD patients. It seems that the antiatherosclerotic effect of vitamin D is at least partly attributed to the up-regulation of anti-inflammatory cytokines especially TGF- β1., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

5-fluorouracil (5-FU) is one of the major components of many standard regimens for chemotherapy of colorectal cancer (CRC) and some other malignancies. Given the known relationship between thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) activity and 5-FU metabolism, this study investigated the impact of selected functional polymorphisms of the TS and MTHFR genes on chemotherapy resistance in 5 human CRC cell lines. HCT116, SW1116, HT29/219, LS180, and Caco-2 CRC cells were cultured as monolayer and their chemosensitivity to 5-FU, oxaliplatin, and irinotecan was determined by MTT assay. Genomic DNA was extracted from the cultured cells, and a 6-bp insertion or deletion (6-bp ins/del) polymorphism in 3´-UTR of the TS gene was determined by the PCR-RFLP method. Genotyping of MTHFR 677 C/T and 1298A/C single nucleotide polymorphism (SNP) was also performed by MS-PCR and PCR-RFLP, respectively. Caco-2 with the homozygous TS 6-bp ins/ins and MTHFR 677 T/T and 1298 C/C genotype, was the most 5-FU resistant cell line. HCT116 with the homozygous TS 6-bp del/del and MTHFR 1298 A/A and heterozygous MTHFR 677 C/T genotype was the least 5-FU resistant cell. LS180, the second most 5-FU resistant cell line, was heterozygous for all three polymorphic sits. HT29/219 and SW1116 cells with homozygous TS 6-bp ins/ins and heterozygous MTHFR 677 C/T and 1298 A/C genotypes had intermediate 5-FU sensitivity. The results indicate that TS 3´-UTR 6-bp insertion and MTHFR 677T and 1298C alleles increase 5-FU resistance in CRC cells. No relationship was observed between TS and MTHFR genotypes and oxaliplatin or irinotecan sensitivity in these cells.

Hepatitis C infection is one of the main causes of chronic liver disorders worldwide. Nearly three percent (3%) of the world population has an HCV infection. Prevalence of HCV infection was higher in some groups such as injected drug users (IDUs) and HIV positive populations. Acute hepatitis has proven asymptomatic in most cases, and delay of diagnosis might lead to late onset of hepatocellular carcinoma and cirrhosis. Some host characteristics such as age, gender, body mass index, and viral properties are associated with HCV outcome hepatitis. Although disease progression is typically slow, some risk factors such as alcohol abuse and coinfection of patients with HBV and HIV can worsen the disease. On the other hand, viral overload is one of the main causes of prediction of HCV infection outcome. Prevalence of HCV infection will increase if we do not consider means of transmission, virus behaviors, and immunologic responses. Rapid diagnostic tests can help us to create preventive strategies among undeveloped villages and prisoners. Screening and training of the high-risk population such as IV drug users, dialysis patients, and hemophiliacs must be one of main HCV preventive programs. The present review is intended to help health policymakers to design suitable preventive and management programs., Competing Interests: Conflict of Interest: There is no conflict of interest to be declared.

Reactive oxygen species (ROS) are essential for induction of protective autophagy, however unexpected rise in cellular ROS levels overpowers the cellular defense and therefore promotes the programmed apoptotic cell death. We recently reported that inhibition of thioredoxin reductase (TrxR) in starving SH-SY5Y cells interrupted autophagy flux by induction of lysosomal deficiency and promoted apoptosis. (Free Radic Biol Med. 2016: 101:53-70). Here, we aimed to elucidate the underlying mechanisms during autophagy-apoptosis interplay, and focused on regulation of cathepsin B (CTSB) and L (CTSL), the pro-apoptotic and pro-autophagy cathepsins respectively. Inhibition of TrxR by Auranofin, caused lysosomal membrane permeabilization (LMP) that was associated with a significant upregulation of CTSB activity, despite no significant changes in CTSB protein level. Conversely, a significant rise in CTSL protein levels was observed without any apparent change in CTSL activity. Using thiol-trapping techniques to examine the differential sensitivity of cathepsins to oxidative stress, we discovered that Auranofin-mediated oxidative stress interferes with CTSL processing and thereby interrupts its pro-autophagy function. No evidence of CTSB susceptibility to oxidative stress was observed. Our data suggest that cellular fate in these conditions is mediated by two concurrent systems: while oxidative stress prevents the protective autophagy by inhibition of CTSL processing, concomitantly, apoptosis is induced by increasing lysosomal membrane permeability and leakage of CTSB into cytoplasm. Inhibition of CTSB in these conditions inhibited apoptosis and increased cell viability. To our knowledge this is the first report uncovering the impact of redox environment on autophagy-apoptosis interplay in neuronal cells., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The mevalonate (MEV) cascade is responsible for cholesterol biosynthesis and the formation of the intermediate metabolites geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) used in the prenylation of proteins. Here we show that the MEV cascade inhibitor simvastatin induced significant cell death in a wide range of human tumor cell lines, including glioblastoma, astrocytoma, neuroblastoma, lung adenocarcinoma, and breast cancer. Simvastatin induced apoptotic cell death via the intrinsic apoptotic pathway. In all cancer cell types tested, simvastatin-induced cell death was not rescued by cholesterol, but was dependent on GGPP- and FPP-depletion. We confirmed that simvastatin caused the translocation of the small Rho GTPases RhoA, Cdc42, and Rac1/2/3 from cell membranes to the cytosol in U251 (glioblastoma), A549 (lung adenocarcinoma) and MDA-MB-231(breast cancer). Simvastatin-induced Rho-GTP loading significantly increased in U251 cells which were reversed with MEV, FPP, GGPP. In contrast, simvastatin did not change Rho-GTP loading in A549 and MDA-MB-231. Inhibition of geranylgeranyltransferase I by GGTi-298, but not farnesyltransferase by FTi-277, induced significant cell death in U251, A549, and MDA-MB-231. These results indicate that MEV cascade inhibition by simvastatin induced the intrinsic apoptosis pathway via inhibition of Rho family prenylation and depletion of GGPP, in a variety of different human cancer cell lines.

Background & Objective: As the prostate adenocarcinoma is one of the most common malignant tumors in males, looking for a marker to effectively predict aggressiveness and metastatic potential in an apparently localized cancer in initial needle biopsy specimens can help the clinicians to make more appropriate decision for treatment, planning, and choosing appropriate targeted therapy. The present study assessed the value of Endothelin-1 expression to predict prognosis of prostatic cancer., Methods: In a cross sectional study, 83 patients who underwent radical prostatectomy in Hasheminejad Kidney Center in 2008 through 2012 were assigned to two groups including 43 with and 40 without extra-prostatic extension (EPE). Endothelin-1 staining was performed on Paraffin Embedded blocks of preoperative needle biopsies., Results: The expression of Endothelin-1 increased in 72% of patients in the group with EPE (P<0.001). The group with Endothelin-1 positivity showed higher serum level of prostate specific antigen (PSA) (p = 0.039). Endothelin-1 expression was positive in 67% of patients with perineurial invasion (P<0.001). Adjusting the baseline variables of PSA and PN in a multivariable logistic regression model, the Endothelin-1 positivity could effectively predict EPE in patients with prostatic cancer (OR: 5.46, p = 0.010)., Conclusion: Correlation of Endothelin-1 expression in needle biopsy specimens in expected with extra-prostatic extension of tumor in radical prostatectomy specimens, perineurial invasion and serum PSA level at the time of diagnosis., Competing Interests: The authors declare that there was no conflict of interest.

In 1990s, reports of discovery of a small group of cells capable of proliferation and contribution to formation of new neurons in the central nervous system (CNS) reversed a century-old concept on lack of neurogenesis in the adult mammalian brain. These cells are found in all stages of human life and contribute to normal cellular turnover of the CNS. Therefore, the identity of regulating factors that affect their proliferation and differentiation is a highly noteworthy issue for basic scientists and their clinician counterparts for therapeutic purposes. The cues for such control are embedded in developmental and environmental signaling through a highly regulated tempo-spatial expression of specific transcription factors. Novel findings indicate the importance of reactive oxygen species (ROS) in the regulation of this signaling system. The elusive nature of ROS signaling in many vital processes from cell proliferation to cell death creates a complex literature in this field. Here, we discuss the emerging thoughts on the importance of redox regulation of proliferation and maintenance in mammalian neural stem and progenitor cells under physiological and pathological conditions. The current knowledge on ROS-mediated changes in redox-sensitive proteins that govern the molecular mechanisms in proliferation and differentiation of these cells is reviewed.

The mevalonate pathway has been extensively studied for its involvement in cholesterol synthesis. Inhibition of this pathway using statins (3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors; HMGR inhibitors) is the primarily selected method due to its cholesterol-lowering effect, making statins the most commonly used (86-94%) cholesterol-lowering drugs in adults. This pathway has several other by-products that are affected by statins including GTPase molecules (guanine triphosphate-binding kinases), such as Rho/Rho-associated coiled kinase (ROCK) kinases, that are implicated in other diseases, including those of the central nervous system (CNS). These molecules control several aspects of neural cell life including axonal growth, cellular migration, and cell death, and therefore, are of increasing interest in the field of spinal cord injury (SCI). Limited regeneration capacity of nerve fibers in adult CNS has been considered the main obstacle for finding a SCI cure. Over the past two decades, the identity of inhibitory factors for regeneration has been widely investigated. It is well-established that the Rho/ROCK kinase system is specifically activated by the components of damaged spinal cord tissue, including oligodendrocytes and myelin, as well as extracellular matrix. This has led many groups to hypothesize that statin therapy may in fact enhance the current neurorestorative approaches. In this mini-review, a summary of SCI pathophysiology is discussed and the current literature targeting the regeneration obstacles in SCI are reviewed, with special attention to recent publications of the past decade. In addition, we focus on the current literature involving the use of pharmacological and molecular inhibitors of small GTPase molecules for treatment of neurotrauma. Inhibiting these molecules has been shown to increase neuroprotection, enhance axonal regeneration, and facilitate the implementation of cell replacement therapies. Based upon available literature, the need for clinical trials involving targeted inhibition of GTPase molecules remains strong. Some of these drugs are widely used for other diseases, and therefore re-purposing their application for neurotrauma can be fasttracked. These approaches can potentially modify the inhibitory environment of nervous tissue to allow the spontaneous repair capacity of injured tissue., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Oxidative damage and aggregation of cellular proteins is a hallmark of neuronal cell death after neurotrauma and chronic neurodegenerative conditions. Autophagy and ubiquitin protease system are involved in degradation of protein aggregates, and interruption of their function is linked to apoptotic cell death in these diseases. Oxidative modification of cysteine groups in key molecular proteins has been linked to modification of cellular systems and cell death in these conditions. Glutathione and thioredoxin systems provide reducing protons that can effectively reverse protein modifications and promote cell survival. The central role of Thioredoxin in inhibition of apoptosis is well identified. Additionally, its involvement in initiation of autophagy has been suggested recently. We therefore aimed to investigate the involvement of Thioredoxin system in autophagy-apoptosis processes. A model of serum deprivation in SH-SY5Y was used that is associated with autophagy and apoptosis. Using pharmacological and RNA-editing technology we show that Thioredoxin reductase deficiency in this model enhances oxidative stress and interrupts the early protective autophagy and promotes apoptosis. This was associated with decreased protein-degradation in lysosomes due to altered lysosomal acidification and accumulation of autophagosomes as well as impairment in proteasome pathway. We further confirmed that the extent of oxidative stress is a determining factor in autophagy- apoptosis interplay, as upregulation of cellular reducing capacity by N-acetylcysteine prevented impairment in autophagy and proteasome systems thus promoted cell viability. Our study provides evidence that excessive oxidative stress inhibits protein degradation systems and affects the final stages of autophagy by inhibiting autolysosome maturation: a novel mechanistic link between protein aggregation and conversion of autophagy to apoptosis that can be applicable to neurodegenerative diseases., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Ubiquitination is an important cellular mechanism with a pivotal role in the degradation of abnormal or short-lived proteins and the regulation of cell cycle and cell growth. The ubiquitin-proteasome pathway is altered in multiple types of human malignancies, including colorectal cancer (CRC). The alteration in the expression of the novel human gene ubiquitin-conjugating enzyme E2 Q1 (UBE2Q1), as a putative member of the E2 ubiquitin-conjugating enzyme family, has been reported in several malignancies, including carcinoma of the breast, hepatocellular and colorectal cancer, and pediatric acute lymphoblastic leukemia. In the present study, the effect of UBE2Q1 overexpression on cell growth, clonogenicity, motility and cell cycle was investigated in a CRC cell line. The UBE2Q1 gene was cloned in the pCMV6-AN-GFP expression vector. A series of stable transfectants of SW1116 cells overexpressing UBE2Q1 protein were established and confirmed by fluorescence microscopy and western blotting. Using these cells, MTT assay was performed to evaluate cell growth and proliferation, while crystal violet staining was used for clonogenicity assay. Cell cycle analysis was also performed to survey the ratio of cells accumulated in different phases of the cell cycle upon transfection. The motility of these cells was also studied using wound healing assay. UBE2Q1 transfectants exhibited a faster growth in cell culture, increased colony formation capacity and enhanced motility compared with control non-transfected cells and cells transfected with empty vector (mock-transfected cells). UBE2Q1 overexpression also resulted in a significant decrease in the number of cells accumulated in the G0/G1 phase of the cell cycle. The present findings suggest that UBE2Q1 may function as an oncogene that induces proliferation of cancer cells, and could be a novel diagnostic tool and a potential therapeutic target for CRC.

Aim: Verification of dose distributions for gynecological (GYN) brachytherapy implants using EBT Gafchromic film., Background: One major challenge in brachytherapy is to verify the accuracy of dose distributions calculated by a treatment planning system., Materials and Methods: A new phantom was designed and fabricated using 90 slabs of 18 cm × 16 cm × 0.2 cm Perspex to accommodate a tandem and Ovoid assembly, which is normally used for GYN brachytherapy treatment. This phantom design allows the use of EBT Gafchromic films for dosimetric verification of GYN implants with a cobalt-60 HDR system or a LDR Cs-137 system. Gafchromic films were exposed using a plan that was designed to deliver 1.5 Gy of dose to 0.5 cm distance from the lateral surface of ovoids from a pair of ovoid assembly that was used for treatment vaginal cuff. For a quantitative analysis of the results for both LDR and HDR systems, the measured dose values at several points of interests were compared with the calculated data from a commercially available treatment planning system. This planning system was utilizing the TG-43 formalism and parameters for calculation of dose distributions around a brachytherapy implant., Results: The results of these investigations indicated that the differences between the calculated and measured data at different points were ranging from 2.4% to 3.8% for the LDR Cs-137 and HDR Co-60 systems, respectively., Conclusion: The EBT Gafchromic films combined with the newly designed phantom could be utilized for verification of the dose distributions around different GYN implants treated with either LDR or HDR brachytherapy procedures.

Phospholipids in the brain cell membranes contain different polyunsaturated fatty acids (PUFAs), which are critical to nervous system function and structure. In particular, brain function critically depends on the uptake of the so-called "essential" fatty acids such as omega-3 (n-3) and omega-6 (n-6) PUFAs that cannot be readily synthesized by the human body. We extracted natural lecithin rich in various PUFAs from a marine source and transformed it into nanoliposomes. These nanoliposomes increased neurite outgrowth, network complexity and neural activity of cortical rat neurons in vitro. We also observed an upregulation of synapsin I (SYN1), which supports the positive role of lecithin in synaptogenesis, synaptic development and maturation. These findings suggest that lecithin nanoliposomes enhance neuronal development, which may have an impact on devising new lecithin delivery strategies for therapeutic applications.

Understanding the mechanism of tumor resistance is critical for cancer therapy. In this study, we investigated the effect of carcinoembryonic antigen (CEA) overexpression on UV-and 5-fluorouracil (5-FU)-induced apoptosis and autophagy in colorectal cancer cells. We used histone deacetylase (HDAC) inhibitor, NaB and DNA demethylating agent, 5-azacytidine (5-AZA) to induce CEA expression in HT29/219 and SW742 colorectal cancer cell lines. MTT assay was used to measure IC50 value of the cells exposed to graded concentrations of 5- FU with either 0.1 mM NaB or 1 μM 5-AZA for 72 h . Using CHO- and SW742-CEA transfectants, we also investigated the effect of CEA expression on UV- and 5-FU-induced apoptosis and autophagy. Treatment of HT29/219 cell line with NaB and 5-AZA increased CEA expression by 29% and 31%, respectively. Compared with control cells, the IC50 value for 5-FU of NaB and 5-AZA-treated cells increased by 40% and 57%, respectively. Treatment of SW742 cells with NaB or 5-AZA increased neither CEA expression nor the IC50 value for 5-FU. In comparison to parental cells, CEA expression also significantly protected transfected cells against UV-induced apoptosis. Decreased proportions of autophagy and apoptosis were also observed in 5-FU treated SW742- and CHO-CEA transfectants. We conclude that CEA expression can effectively protect colorectal cancer cells against radiation and drug-induced apoptosis and autophagy.

Emerging studies have been shown that the expression of micrRNA-146a (miR-146a, as a regulator of nuclear factor κB (NF-κB)), is changed in diabetic patients and animals. This study was designed to evaluate the possible role of miR-146a in the pathogenesis of diabetes-related microvascular complications. Concurrent with the creation of cellular hyperglycemia (25 mmol/L for 24 h), human umbilical vein endothelial cells (HUVECs) were transfected with 20 nmol/L of hsa-miR-146a antagomir or scramble using HiPerFect reagent (Qiagen). D-mannitol was used as osmotic control. Hyperglycemia increased the NF-κB gene expression and protein activity (as an inflammation index) in cultured HUVECs. Moreover, the gene expression level of miR-146a, and its target proteins, tumor necrosis factor receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1) were increased under hyperglycemic condition. The knockdown of miR-146a by transfection of miR-146a antagomir notably increased the NF-κB activity and decreased the NF-κB mRNA in hyperglycemic HUVECs. Furthermore, miR-146a antagomir significantly increased IRAK1 and TRAF6 mRNA levels under hyperglycemic condition. These results demonstrate that the expression of miR-146a is upregulated in HUVECs during early phase of hyperglycemic condition possibly to regulate the NF-κB activity through inhibition of IRAK1 and TRAF6 (Fig. 4, Ref. 32).

Objectives: This study was conducted to explore whether microRNA-146a and its adapter proteins (TNF-α receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1)) are affected by diabetes in the rat heart., Methods: Twelve male Sprague-Dawley rats were randomized into control and diabetic groups (n = 6). Streptozotocin-nicotinamide experimental model was used to induce type 2 diabetes. The gene expression of MicroRNA-146a, nuclear factor-κB (NF-κB), IRAK1 and TRAF6, as well as NF-κB activity, IRAK1 and TRAF6 protein levels were measured. Moreover, NF-κB activity was measured in response to miR-146a mimic transfection (20 nmol) in human umbilical vein endothelial cells (HUVECs) under hyperglycemic condition (25 mM D-glucose for 24 h)., Results: The expression of MicroRNA-146a was increased in the heart tissue, 2 months after diabetes induction and in HUVECs. Also, the mRNA and protein levels of NF-κB, IRAK1 and TRAF6 were increased in the heart of diabetic rats. Moreover, transfection of miR-146a mimic prevented from a significant increase of NF-κB activity in hyperglycemic HUVECs., Conclusion: Presumably, a defect in the regulation of IRAK1 and TRAF6 can weaken miR-146a regulatory effect and provides a situation for sustained activation of NF-κB and its targets to promote cardiac cells toward abnormalities (Fig. 3, Ref. 28).

A number of bacterial species, both pathogenic and non-pathogenic, use the human CEACAM family members as receptors for internalization into epithelial cells. The GPI-linked CEA and CEACAM6 might play a role in the innate immune defense, protecting the colon from microbial invasion. Previous studies showed that CEA is released from epithelial cells by an endogenous GPI-PLD enzyme. GPI-PLD activity was reported to be inhibited by several synthetic and natural forms of lipid A. We hypothesized that CEA engagement by Gram-negative bacteria might attenuate CEA release from epithelial cells and that this might facilitate bacterial colonization. We tested the hypothesis by examining the effect of Escherichia coli on CEA release from colorectal cancer cells in a co-culture experiment. A subconfluent monolayer culture of colorectal cancer cells (LS-180, Caco-2 and HT29/219) was incubated with E. coli. While there was a significant reduction in CEA secretion from LS-180 and HT29/219 cells, we found only a small reduction of CEA shedding from Caco-2 cells compared to the level from the untreated control cells. Furthermore, lipid A treatment of LS-180 cells inhibited CEA release from the cells in a dosedependent manner. Western blot analysis of total lysates showed that CEA expression levels in cells co-cultured with bacteria did not differ from those in untreated control cells. These results suggest that lipid A of Gram-negative bacteria might play a role in preventing the release of CEA from mucosal surfaces and promote mucosal colonization by bacteria.

Background and aims . In the presence of certain systemic diseases, oral microflora may aggravate the condition of the disease. Microbial population in the oral cavity especially with heart disease can increase the risk of bacterial endocarditis. The aim of this study was to evaluate the rate of oral Streptococcus mutansand the rate of caries in children suffering from heart disease. Materials and methods. In this cross-sectional research, 66 children with congenital or acquired heart disease and 50 healthy children were selected. Children were orally examined and decayed, missing, and filled teeth (DMFT) index was recorded for each subject. Saliva samples were taken from all subjects, and cultured on a special laboratory media and another specific media for S. mutans (sorbitoll +manitol). Bacterial counts were recorded, and for statistical analysis, chi square, Pearson's, and Exact Fisher tests were performed using SPSS 16 software. Results. The rate of S. mutans in children with congenital heart disease was significantly higher than the rates in childrenwith acquired heart disease and healthy control subjects. The mean DMFT in children with acquired heart disease who tookpenicillin as prophylaxis monthly was significantly lower than the other groups. Conclusion . The results revealed lower oral bacteria counts and comparatively lower caries rates in children with heart diseases, probably because of an effect of the regular prophylactic antibiotic regimen.