No Association of AS3MT Gene Polymorphisms with Susceptibility to Hepatotoxicity in APL Patients Treated with AS2O3: A Single-Center Study.

Background: Arsenic three oxide (As2O3) is the treatment choice for acute promyelocytic leukemia (APL). Little is known about possible risk factors with predictive value for toxicity caused by As2O3. Biomethylation is considered to be a major pathway of detoxification for inorganic arsenics (iAs). Arsenic Methyltransferase (AS3MT) is one of the key enzymes involved in the transfer of a methyl group from S-adenosyl-L-methionine to trivalent arsenical and plays a critical role in arsenic detoxification. Polymorphisms in hAS3MT lead to a change in the catalytic activity of the enzyme and may increase the risk of arsenic-related toxicity. In this study, we investigated the association of the AS3MT polymorphisms (rs11191439, rs3740390, and rs3740393) genes with hepatotoxicity in APL patients treated with As2O3. Materials and Methods: Genotyping was performed in 140 adult patients with APL treated with As2O3 using PCR-RFLP for rs11191439 and tetra-primer ARMS-PCR for rs3740390 and rs3740393. The results of PCR-RFLP and ARMS-PCR were confirmed by direct sequencing of 10 % of DNA samples. The results were analyzed using SNPStats, SPSS, and FinchTV. Hepatotoxicity was graded according to the National Cancer Institute's Common Toxicity Criteria (CTC). Results : Hepatotoxicity was seen in 52 of the 140 patients (37.1%), with grades I and II hepatotoxicity in 40 (28.6%) and grades III and IV hepatotoxicity in 12 (8.5%) patients. The association between the three polymorphisms and hepatotoxicity was evaluated using five genetic models and none of the three studied polymorphisms were significantly associated with hepatotoxicity. Discussion : The results of our study showed that AS3MT rs11191439, rs3740390, and rs3740393 polymorphisms are not associated with hepatotoxicity in APL patients. Genetic polymorphisms in enzymes which are involved in arsenic metabolism have been shown to have ethnicity and race-related differences. To more precisely characterize the association between AS3MT gene polymorphism and hepatotoxicity, future large-scale studies in non-Asian populations and other ethnicities are needed.

Recent findings on the Coronavirus disease 2019 (COVID-19); immunopathogenesis and immunotherapeutics.

Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) is responsible for recent ongoing public health emergency in the world. Sharing structural and behavioral similarities with its ancestors [SARS and Middle East Respiratory Syndrome (MERS)], SARS-CoV-2 has lower fatality but faster transmission. We have gone through a long path to recognize SARS and MERS, therefore our knowledge regarding SARS-CoV-2 is not raw. Various responses of the immune system account for the wide spectrum of clinical manifestations in Coronavirus disease-2019 (COVID-19). Given the innate immune response as the front line of defense, it is immediately activated after the virus entry. Consequently, adaptive immune response is activated to eradicate the virus. However, this does not occur in every case and immune response is the main culprit causing the pathological manifestations of COVID-19. Lethal forms of the disease are correlated with inefficient and/or insufficient immune responses associated with cytokine storm. Current therapeutic approach for COVID-19 is in favor of suppressing extreme inflammatory responses, while maintaining the immune system alert and responsive against the virus. This could be contributing along with administration of antiviral drugs in such patients. Furthermore, supplementation with different compounds, such as vitamin D, has been tested to modulate the immune system responses. A thorough understanding of chronological events in COVID-19 contributing to the development of a highly efficient treatment has not figured out yet. This review focuses on the virus-immune system interaction as well as currently available and potential therapeutic approaches targeting immune system in the treatment of COVID-19 patients.

The impact of genetic variation on metabolism of heavy metals: Genetic predisposition?

Genetic variations can be considered as internal contributing factors in susceptibility of individuals to heavy metals related toxicities. However, the exact mechanism of such inherent factors in body response to toxic materials, as well as their potentials to be considered as actual susceptibility factors are remaining to be more explored. So far, variations in different genes, which are directly/indirectly involving in the metabolism of heavy metals have been investigated by some experiments. Metallothioneins as one of the well-known groups of enzymes involving in detoxification of heavy metals, were shown to behave differentially among individuals. This phenomenon is due to the presence of some genetic variations in the middle or upper parts of their genomic sequences. The presence of different single nucleotide polymorphisms in metallothionein 2 A gene and the association of these variations with heavy metals body burden have been shown in different populations. Such genetic variations and their potential effects on heavy metal metabolisms and toxicities were shown in other genes, such as divalent metal transporter 1, glutathione related genes and methylenetetrahydrofolate reductase. However, the current data on different populations are challenging because of the presence of various other interference factors like different dietary and life habits, levels of exposure, as well as papulation related factors. Age, sex, smoking, dietary habits, ancestry differences and diverse metal exposure levels are seemed to be other effective variables in this area. In this review, we introduced several potential genes, their studied genetic variations and their impacts on heavy metal body burden, as well as body sensitivity in different populations.

Cardioprotective microRNAs: Lessons from stem cell-derived exosomal microRNAs to treat cardiovascular disease.

The stem cell-based therapy has emerged as a promising therapeutic strategy for treating cardiovascular ischemic diseases (CVIDs), such as myocardial infarction (MI). However, some important functional shortcomings of stem cell transplantation, such as immune rejection, tumorigenicity and infusional toxicity, have overshadowed stem cell therapy in the setting of cardiovascular diseases (CVDs). Accumulating evidence suggests that the therapeutic effects of transplanted stem cells are predominately mediated by secreting paracrine factors, importantly, microRNAs (miRs) present in the secreted exosomes. Therefore, novel cell-free therapy based on the stem cell-secreted exosomal miRs can be considered as a safe and effective alternative tool to stem cell therapy for the treatment of CVDs. Stem cell-derived miRs have recently been found to transfer, via exosomes, from a transplanted stem cell into a recipient cardiac cell, where they regulate various cellular process, such as proliferation, apoptosis, stress responses, as well as differentiation and angiogenesis. The present review aimed to summarize cardioprotective exosomal miRs secreted by transplanted stem cells from various sources, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), and cardiac stem/progenitor cells, which showed beneficial modulatory effects on the myocardial infracted heart. In summary, stem cell-exosomal miRs, including miR-19a, mirR-21, miR-21-5p, miR-21-a5p, miR-22 miR-24, miR-26a, miR-29, miR-125b-5p, miR-126, miR-201, miR-210, and miR-294, have been shown to have cardioprotective effects by enhancing cardiomyocyte survival and function and attenuating cardiac fibrosis. Additionally, MCS-exosomal miRs, including miR-126, miR-210, miR-21, miR-23a-3p and miR-130a-3p, are found to exert cardioprotective effects through induction of angiogenesis in ischemic heart after MI.

In vitro osteogenic differentiation potential of the human induced pluripotent stem cells augments when grown on Graphene oxide-modified nanofibers.

Due to the several limitations that surgeons are faced during bone tissue implantation there are daily increases in introducing new cell-co-polymer composites for use in bone tissue engineering approaches. In this study tried to develop a suitable nanostructured bio-composite for enhancing osteogenic differentiation of the human induced pluripotent stem cells (iPSCs). Polyvinylidene fluoride-Graphene oxide (PVDF-GO) nanofibers was fabricated by electrospinning and then characterized using scanning electron microscope, tensile and viability assays. After that osteogenic differentiation of the iPSCs was investigated in three groups, including PVDF, PVDF-GO and tissue culture plate as a control group. Alkaline phosphatase activity and calcium content of the iPSCs cultured on PVDF-GO were significantly higher than those cultured on other groups. In addition, Runx2, osteocalcin and osteonectin genes were up regulated in iPSCs cultured on PVDF-GO significantly higher than those cells cultured on PVDF and control. Finally, osteocalcin and osteopontin proteins expression evaluated and the results confirmed higher osteoinductivity of the PVDF-GO nanofibers in comparison with the PVDF nanofibers. According to the results, it was demonstrated that PVDF-GO nanofibers have a great osteoinductive potential and taking together iPSCs-PVDF-GO nanofibrous construct can be an appropriate bio-implant to use for bone tissue engineering applications.

Epigenetics and Epi-miRNAs: Potential markers/therapeutics in leukemia.

Epigenetic variations can play remarkable roles in different normal and abnormal situations. Such variations have been shown to have a direct role in the pathogenesis of various diseases either through inhibition of tumor suppressor genes or increasing the expression of oncogenes. Enzymes involving in epigenetic machinery are the main actors in tuning the epigenetic-based controls on gene expressions. Aberrant expression of these enzymes can trigger a big chaos in the cellular gene expression networks and finally lead to cancer progression. This situation has been shown in different types of leukemia, where high or low levels of an epigenetic enzyme are partly or highly responsible for involvement or progression of a disease. DNA hypermethylation, different histone modifications, and aberrant miRNA expressions are three main epigenetic variations, which have been shown to play a role in leukemia progression. Epigenetic based treatments now are considered as novel and effective therapies in order to decrease the abnormal epigenetic modifications in patient cells. Different epigenetic-based approaches have been developed and tested to inhibit or reverse the unusual expression of epigenetic agents in leukemia. The reciprocal behavior of miRNAs in the regulation of epigenetic modifiers, while being regulated by them, unlocks a new opportunity in order to design some epigenetic-based miRNAs able to silence or sensitize these effectors in leukemia.