The antioxidant and anti-inflammatory effects of astaxanthin supplementation on the expression of miR-146a and miR-126 in patients with type 2 diabetes mellitus: A randomised, double-blind, placebo-controlled clinical trial.

BACKGROUND: The pathogenesis of type 2 diabetes mellitus (T2DM) is associated with chronic oxidative stress and inflammation. It is well known that the expression of some miRNAs such as miRNA-146a is upregulated in diabetic and hyperglycaemic patients, whereas circulating miRNA-126 is reduced. Therefore, we aimed to determine the effects of astaxanthin (AST) supplementation on the circulating malondialdehyde (MDA) and interleukin 6 (IL-6) levels, and the expression of miR-146a and miR-126 in patients with T2DM. METHODS: This randomised, double-blind, placebo-controlled clinical trial was conducted in 44 patients with T2DM randomly receiving 8 mg/d of oral AST (n = 22) or placebo (n = 22) for 8 weeks. RESULTS: We observed that AST supplementation could decrease plasma levels of MDA and IL-6 (P < .05) and decrease the expression level of miR-146a over time (fold change: -1/388) (P < .05). CONCLUSION: AST supplementation might be beneficial for improving circulating MDA and IL-6 and the down-regulation of miR-146a. However, future investigations are suggested to confirm these results.

The worldwide molecular spectrum and distribution of thalassaemia: a systematic review.

CONTEXT: Thalassaemia is one of the most common inherited autosomal recessive disorders around the world. A considerable amount of literature has been published about the type of mutations and the prevalence of thalassaemia, but findings are often contradictory. OBJECTIVE: This systematic review aimed to provide a comprehensive view of the prevalence of thalassaemia-associated mutations in different countries, their effect on haemoglobin (Hb) levels, as well as reporting thalassaemia-associated rare mutations. METHODS: A systematic search of the literature was carried out through major indexing databases (MEDLINE/PubMed, Scopus, EMBASE, Cochrane central, and ISI web of science) using keywords: "Co-inheritance, αα, ß, thalassaemia" and "α-ß thalassaemia, Mediterranean anemia, mutations" from 1998-September 2019. Hand-searching was also performed. There was no language restriction. RESULTS: The initial searches yielded 1059 studies, of which 92 articles were included following inclusion and exclusion criteria. Of these, 3.3% (3) of articles were cohort studies, and 96.7% (89) of the remaining articles were cross-sectional studies. Our findings showed that 45.6% (42) of researchers investigated ß-thalassaemia, 22.9% (21) αα-ß thalassaemia, and 31.5% (29) α thalassaemia. CONCLUSION: The present study provides valuable information about the spectrum of thalassaemia-associated mutations, which can be useful for preventing thalassaemia, reducing costs of care, reducing the treatment-related side effects, and showing the most defective mutations.HighlightEvaluating the increase or decrease in the birth prevalence of thalassaemiaIdentifying the most common and rare mutations in various parts of the worldComparing researchers' findings from various parts of the world.

Effect of weight-loss diet combined with taurine supplementation on body composition and some biochemical markers in obese women: a randomized clinical trial.

Taurine (Tau), an endogenous non-protein and sulfuric-amino acid, is involved in various biological pathways including anti-inflammatory, anti-oxidation, insulin resistance inhibition, and lipid profile improvement. According to some experimental and clinical studies, insulin resistance and excess body weight are associated with reduced serum level of Tau. Therefore, this study was aimed to evaluate Tau supplementation and a diet-induced weight-loss intervention on body composition and some biochemical indices of obese women. Participants were divided randomly into the intervention (standard weight-loss group + cap Tau 3 g/day for 8 weeks, n = 20) and control (standard weight-loss group + cap placebo for 8 weeks, n = 18) groups. To achieve weight loss, all participants received an individualized diet that included a 30% reduction in their total energy intake. Chi-square test was applied to compare categorical variables between two groups at baseline. Paired t test and independent-sample t test were also used to analyze the parametric continuous data within and between the two groups, respectively. Analysis of covariance was run for controlling the confounding variables. At the post-intervention, the mean changes of total cholesterol (p = 0.03), low-density lipoprotein cholesterol (p = 0.03), leptin (p = 0. 006), total adiponectin (p = 0.04), and high sensitivity C-reactive protein (p = 0.03) decreased significantly in Tau group compared with the control group. No significant results were found in the mean changes of high-density lipoprotein cholesterol, anthropometric measurements, glycemic indices, and liver enzymes between the two groups (p > 0.05). The findings showed that Tau supplementation along with a weight-loss diet may be more effective in improving the lipid profile and metabolic risk factors compared with a weight-loss diet alone.

A novel pathogenic variant in the MARVELD2 gene causes autosomal recessive non-syndromic hearing loss in an Iranian family.

BACKGROUND AND AIMS: Hearing loss (HL) is the most common sensorineural disorder and one of the most common human defects. HL can be classified according to main criteria, including: the site (conductive, sensorineural and mixed), onset (pre-lingual and post-lingual), accompanying signs and symptoms (syndromic and non-syndromic), severity (mild, moderate, severe and profound) and mode of inheritance (Autosomal recessive, autosomal dominant, X-linked and mitochondrial). Autosomal recessive non-syndromic HL (ARNSHL) forms constitute a major share of the HL cases. In the present study, next-generation sequencing (NGS) was applied to investigate the underlying etiology of HL in a multiplex ARNSHL family from Khuzestan province, southwest Iran. METHODS: In this descriptive study, 20 multiplex ARNSHL families from Khuzestan province, southwest of Iran were recruited. After DNA extraction, genetic linkage analysis (GLA) was applied to screen for a panel of more prevalent loci. One family, which was not linked to these loci, was subjected to Otogenetics deafness Next Generation Sequencing (NGS) panel. RESULTS: NGS results showed a novel deletion-insertion variant (c.1555delinsAA) in the MARVELD2 gene. The variant which is a frameshift in the seventh exon of the MARVELD2 gene fulfills the criteria of being categorized as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guideline. CONCLUSION: NGS is very promising to identify the molecular etiology of highly heterogeneous diseases such as HL. MARVELD2 might be important in the etiology of HL in this region of Iran.

A novel infram deletion in MSH6 gene in glioma: Conversation on MSH6 mutations in brain tumors.

OBJECTIVE AND BACKGROUND: Histological and molecular information and biopsy help in the diagnosis of the type and grade of tumors and increase the value of estimation of the biological behavior of tumors. In this study, we focused on a consanguineous Iranian Family with high prevalence of brain tumors in their pedigree and reviewed the literature on MSH6 mutations in brain tumors and the treatment responses focused on Gliomas. METHOD: We chose a family with a high prevalence of brain tumor in their pedigree. We studied the proband's neuroimaging and brain proton magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), biopsy result, and whole-genome sequencing. RESULT: The neuroimaging and brain proton MRS reported a lesion in the right frontoparietal. The MRI revealed a large enhancible heterogenous mass in the right temporo-fronto-parieto-occipital lobes with involvement of corpus callosum which was suggestive of glioma. The patient revealed a homozygous pattern for a novel 9 base-pare deletion at the 912-914 codon on exon 4 of the MSH6 gene. DISCUSSION: We discuss several studies on MSH6 mutations in brain tumors and we discuss treatment responses in MSH6 mutations and the studies conducted to sensitize chemotherapy and radiotherapy resistance brain tumors to face this subject efficiently. CONCLUSION: Patients should be evaluated for MMR mutation before chemo and radiotherapy, and it is valuable to follow-up these mutations during the treatment too. In temozolomide (TMZ)-resitance cases, it is suggested to use complementary strategies such as using HDACis and a combination of a STAT3 Inhibitor and an mTOR inhibitor, BER inhibition mechanism, and PARP-1 inhibitor.

Exome sequencing revealed a p.G299R mutation in the COMP gene in an Iranian family suffering from pseudoachondroplasia.

BACKGROUND: Short-stature (SS) is multifactorial pathologic condition that originates from either genetic or environmental factors. The diagnosis is based on family history, clinical findings, radiological examination and genetic analysis. A variety of genes have been reported for SS, among which FGFR-3 was the main gene in achondroplasia and hypochondroplasia. In other forms of SS, the gene involved varies from one patient to another. Whole exome sequencing (WES) and comparative genomic hybridization (CGH) have recently introduced a growing body of genes annually. The present study performed a WES analysis on an Iranian family suffering from an inherited form of SS aiming to diagnose the causative gene. The father and all of his four sons were diagnosed as SS. METHODS: The blood samples were collected from the proband and his available family members. Genomic DNA was extracted using salting-out method. The DNA of the proband was analyzed using WES and confirmed through polymerase chain reaction (PCR)-sequencing. The WES-extracted variant was evaluated in silico using software aiming to determine whether this nucleotide change is pathogenic. The presence of the variant was traced in other affected family members using PCR-sequencing. RESULTS: Following segregation analysis, variant c.896 G>A of the COMP gene was found in all of the affected individuals in a heterozygous form. This variant resulted in substitution of glycine 299 with arginine and was previously predicted as pathogenic in the Human Gene Mutation Database dataset, although it represents the first report in Iran. CONCLUSIONS: The findings of the present study suggest consideration of the c.896 G>A variant of the COMP gene with respect to the genetic counseling of inherited skeletal dysplasia in Iran.

Identification and Clinical Implications of a Novel MYO15A Variant in a Consanguineous Iranian Family by Targeted Exome Sequencing.

BACKGROUND AND OBJECTIVES: Hereditary hearing loss (HL) is known by a very high genetic heterogeneity, which makes a molecular diagnosis problematic. Next-generation sequencing (NGS) is a new strategy that can overcome this problem. METHOD: A comprehensive family history was obtained, and clinical evaluations and pedigree analysis were performed in the family with 3 affected members. After excluding mutations in the GJB2 and 7 other most common autosomal recessive nonsyndromic HL genes via Sanger sequencing and genetic linkage analysis in the family, we applied the Otogenetics deafness NGS panel in the proband of this family. RESULTS: NGS results showed a novel rare variant (c.7720C>T) in the MYO15A gene. This nonsense variant in the exon 40 of the MYO15A gene fulfills the criteria of being categorized as pathogenic according to the American College of Medical Genetics and Genomics guideline. CONCLUSIONS: New DNA sequencing technologies could lead to identification of the disease causing variants in highly heterogeneous disorders such as HL.

A pathogenic variant in SLC26A4 is associated with Pendred syndrome in a consanguineous Iranian family.

Objective: Hearing loss (HL) is a common sensory deficit with high phenotypic and genotypic heterogeneity. A large Iranian family with HL was genetically assessed in this study. Design: A proband from a consanguineous multiplex HL family from Iran was examined via Targeted Next-Generation Sequencing (TNGS). Sanger sequencing allowed the segregation analysis of the variant of interest and the investigation of its presence in a cohort of 50 ethnicity-matched healthy control individuals. The gene was previously associated with HL. Therefore, to determine whether the variant was specifically associated with Pendred Syndrome (PDS) or DFNB4, biochemical analyses, PTA, thyroid scans by Tc99m, perchlorate discharge test and high-resolution CT scan of the temporal bone were carried out on the affected family members. Study sample: Ten members of a large multiplex Iranian family with HL were recruited in this study. In addition, 50 unrelated healthy controls of the same ethnic group were randomly selected to genotype the variant. Results: A homozygous missense variant (NM_000441.1: c.1211C > T/p.Thr404Ile) in exon 10 was found segregating in the family. Based on the ACMG's guidelines, the variant was classified as pathogenic. Conclusion: This study expands the spectrum of SLC26A4 pathogenic variants in hearing loss.

How is the relationship between TWIST-1 and BCR-ABL1 gene expressions in chronic myeloid leukaemia patients?

BACKGROUND: The activation and increased expression of BCR-ABL1 lead to malignant chronic myelogenous leukaemia (CML) cells, as well as the resistance to antitumour agents and apoptosis inducers. Moreover, TWIST-1 protein is a prognostic factor of leukemogenesis, and its level is raised in CML patients with cytogenetic resistance to imatinib. So, there is a likely relationship between BCR-ABL1 and TWIST-1 genes. OBJECTIVE: The aim of the study was to assess the relationship between TWIST-1 and BCR-ABL1 expressions. METHODS: Peripheral blood samples were obtained from 44 CML patients under treatment and also from ten healthy subjects as normal controls. The expression of TWIST-1 and BCR-ABL1 genes was measured using real-time PCR, and ABL1 was used as the reference gene. The gene expression was evaluated by REST software. RESULTS: The expression levels of TWIST-1 and BCR-ABL1 genes in CML patients was changed 40.23 ± 177.75-fold and 6 ± 18-fold, respectively. DISCUSSION: No significant relationship was observed between the expressions of TWIST-1 and BCR-ABL1 genes. All patients with TWIST-1 expression levels ≥100-fold had failure of response to treatment. CONCLUSION: The probability of the relationship between BCR-ABL1 and TWIST-1 is still debatable, and the average of TWIST-1 expression has been higher in patients without response to treatment. Definitive conclusion needs further investigations.

Identification of a novel mutation in ARSA gene in three patients of an Iranian family with metachromatic leukodystrophy disorder.

Metachromatic leukodystrophy disorder (MLD) is an autosomal recessive and lysosomal storage disease. The disease is caused by the deficiency of the enzyme arylsulfatase A (ARSA) which is encoded by the ARSA gene. Different mutations have been reported in different populations. The present study was aimed to detect the mutation type of the ARSA gene in three relative Iranian patients. We found a novel homozygous missense mutation c.1070 G > T (p.Gly357Val) in exon 6 of these patients. The mutation was found to be reported for the first time in MLD patients. The data can update the mutation profile and contribute toward improved clinical management and counseling of MLD patients.

Retinitis pigmentosa-1 due to an RP1 mutation in a consanguineous Iranian family: Report of a novel mutation.

Key Clinical Message: The identification of a novel RP1 gene mutation highlights the importance of precise variant identification for retinitis pigmentosa prognosis and genetic consultations, emphasizing comprehensive genetic analysis for personalized care. Abstract: Our study unveils a noteworthy association between retinitis pigmentosa-1 and a newly discovered homozygous mutation (c.5326delC; p.Asp1777Ilefs*32) within the RP1 gene. This highlights the crucial role of accurate variant identification in not only informing prognosis but also improving genetic consultations and influencing future diagnostic approaches for individuals affected by retinitis pigmentosa.

A Novel Deleterious MYO15A Gene Mutation Causes Nonsyndromic Hearing Loss.

Introduction: Hearing loss (HL) is the most frequent sensory neurodeficiency, affecting a broad spectrum of individuals globally. Within this context, the role of genetic factors takes center stage, particularly in cases of hereditary HL. Case Report: Here, we present a nonsyndromic HL (NSHL) case report. The patient is a 21-year-old man with progressive HL. The whole-exome sequencing (WES) demonstrated a novel homozygous missense mutation, c.9908A>C; p.Lys3303Thr, in the proband's exon 61 of the MYO15A gene. Further analysis has revealed that the detected mutation is present in a heterozygous state in the parents. Conclusion: WES analysis in this study revealed a novel mutation in the MYO15A gene. Our data indicates that the MYO15A-p.Lys3303Thr mutation is the likely pathogenic variant associated with NSHL. Additionally, this finding enhances genetic counseling for individuals with NSHL patients, highlighting the value of the WES method in detecting rare genetic variants.

Folate gene polymorphisms CBS 844ins68 and RFC1 A80G and risk of Down syndrome offspring in young Iranian women: A cross-sectional study.

Background: Cytogenetics and association studies showed that folate gene polymorphisms can increase the risk of chromosomal nondisjunction and aneuploidies. The folate-metabolizing gene polymorphisms in Down syndrome mothers (DSM) have been assessed in a variety of populations. Reduced folate carrier 1 (RFC1) and cystathionine beta-synthase (CBS) are key enzymes in folate metabolism. Objective: 2 common polymorphisms, CBS 844ins68 and RFC1 A80G, were analyzed to determine their probable risk for having Down syndrome (DS) babies in young mothers of Khuzestan province, Iran. Materials and Methods: This study was conducted on 100 mothers who had trisomy 21 DS children. 100 age- and ethnic-matched mothers with at least 2 healthy children and no history of abnormal pregnancies were considered as control. The samples were collected from all the mothers from June 2019 to April 2021. Genomic DNA was extracted from peripheral blood. The CBS-844ins68 and RFC1-A80G were genotyped using polymerase chain reaction-electrophoresis and restriction fragment length polymorphism, respectively. Results: The frequency of RFC1 AG and GG genotypes in DSM was significantly higher than the control mothers (odds ratio [OR] of 2.38 and 3.07, respectively). The heterozygote genotype of CBS 844ins68 was significantly more prevalent among DSM than the control (OR: 2.419). The OR was significantly increased to 6.667 when the homozygote of both variants was found together. Conclusion: Studying polymorphisms possibly increases the susceptibility of having a DS child. However, ethnicity, nutrition, and epistatic interactions are considerable factors to be evaluated in future studies.

Telomerase activity in human brain tumors: astrocytoma and meningioma.

Somatic cells do not have telomerase activity but immortalized cell lines and more than 85 % of the cancer cells show telomerase activation to prevent the telomere from progressive shortening. The activation of this enzyme has been found in a variety of human tumors and tumor-derived cell lines, but only few studies on telomerase activity in human brain tumors have been reported. Here, we evaluated telomerase activity in different grades of human astrocytoma and meningioma brain tumors. In this study, assay for telomerase activity performed on 50 eligible cases consisted of 26 meningioma, 24 astrocytoma according to the standard protocols. In the brain tissues, telomerase activity was positive in 39 (65 %) of 50 patients. One sample t test showed that the telomerase activity in meningioma and astrocytoma tumors was significantly positive entirely (P < 0.001). Also, grade I of meningioma and low grades of astrocytoma (grades I and II) significantly showed telomerase activity. According to our results, we suggest that activation of telomerase is an event that starts mostly at low grades of brain including meningioma and astrocytoma tumors.

Does prepubertal testicular tissue vitrification influence spermatogonial stem cells (SSCs) viability?

PURPOSE: Testicular cryopreservation prior to chemotherapy or radiotherapy in children with cancer is one of the ways to preserve fertility. However, cryopreservation may cause damage to the testicular parenchyma cells. The objective of this study was to investigate effects of vitrification on the intracellular LDH leakage, cell cycle/apoptotic responses and apoptosis-related gene expression patterns in the spermatogonial stem cells (SSCs) obtained from the vitrified testis. METHODS: The testes of the mice pups (6-day-old, BALB/c) both vitrified and fresh groups were digested with enzymes (collagenase, DNaseΙ, trypsin-EDTA) to disperse the cells. The SSCs, type A, were isolated from the rest of testicular cells by MACS. The amount of damage to the SSCs immediately was evaluated by Cytotoxicity assay, Flow cytometry assay and Real-time PCR. RESULTS: The intracellular LDH leakage in the SSCs,harvested from the vitrified testes, was less reported compared with the fresh ones. Moreover, the percentage of apoptotic and necrotic SSCs obtained from the vitrified testes was lower than that of yielded from the fresh samples. Also, the apoptosis-related genes of the SSCs,collected from the vitrified testes, changed their expression profile as increasing P53 and BCL-2 expression levels and decreasing Bax and Fas expression levels. CONCLUSIONS: The study indicates that vitrification of prepubertal testicular tissue does not increase the expression profile of apoptosis-related genes such as Bax and Fas in the testicular SSCs consistent with diminished cell apoptotic/necrotic responses and no increasing intracellular LDH leakage.

Do NGS-based techniques represent a first-line testing in suspected Duchenne muscular dystrophy?

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene, which mostly affects boys. The subject was an 8-year-old child who had typical symptoms of muscle weakness. The NGS may be used as an efficient and cost-effective molecular diagnostic strategy for identifying patients with DMD.

A machine learning technology to improve the risk of non-invasive prenatal tests.

BACKGROUND: Timely and accurate diagnosis of genetic diseases can lead to proper action and prevention of irreparable events. OBJECTIVE: In this work we propose an integrated genetic-neural network (GNN) to improve the prediction risk of trisomy diseases including Down's syndrome (T21), Edwards' syndrome (T18) and Patau's Syndrome (T13). METHODS: A dataset including 561 pregnant were created. In this integrated model, the structure and input parameters of the proposed multilayer feedforward network (MFN) were optimized. RESULTS: The results of execution of the GNN on the testing dataset showed that the developed model can be accurately classify the anomalies from healthy fetus with 97.58% accuracy rate, and 99.44% and 85.65% sensitivity, and specificity, respectively. In the proposed GNN model, the Levenberg Merquident (LM) algorithm, the Radial Basis (Radbas) function from various types of functions were selected by the proposed GA. Moreover, maternal age, Nuchal Translucency (NT), Crown-rump length (CRL), Pregnancy-associated plasma protein A (PAPP-A) were selected by the proposed GA as the most effective factors for classifying the healthfetuses from the cases with fetal disorders. CONCLUSION: The proposed computerized model increases the diagnostic performance of the physicians especially in the accurate detection of healthy fetus with non - invasive and low - cost treatments.

AHI1 gene mutation in a consanguineous Iranian family affected by Joubert syndrome: A case report.

This point of detected mutation could be considered as a novel mutational hotspot point that carried in patient ancestors. Moreover, the obtained results and family history suggest a precise genetic consulting and molecular prenatal evaluation for suspect individuals with a family history of mental and physical abnormalities.

Identification of a Novel WFS1 Mutation Using the Whole Exome Sequencing in an Iranian Pedigree with Autosomal Dominant Hearing Loss.

INTRODUCTION: Sensorineural hearing loss is the most frequent type of hearing impairment in the human population. Genetic factors account for over 60% of hearing loss in patients. This is a genetically heterogeneous sensorineural disorder. CASE REPORT: We carried out whole exome sequencing (WES) to screen hearing loss candidate genes in a member of an Iranian family with hearing loss. The Sanger process was used to sequencing the variant in the family members. A novel mutation (c. 559C > T) was found in the WFS1 gene (in exon 5) in the patient leading to a heterozygous missense mutation (p.L187F). Furthermore, it co-segregated with HL in the family. All affected individuals in the family had severe-to-profound HL. CONCLUSION: This survey is the first to describe WFS1 related HL in the Iranian population. Our data propose that the WFS1-p.L187F mutation is the pathogenic variant for autosomal dominant nonsyndromic hearing loss. Our results extend the range of the WFS1 gene mutations.

Effect of lipoic acid supplementation on gene expression and activity of glutathione S-transferase enzyme in infertile men.

Oxidative stress has become the focus of interest as a potential cause of male infertility. We evaluate effects of lipoic acid (LA) supplementation on glutathione S-transferase (GST) expression. This randomized, triple-blind, placebo-controlled clinical trial was conducted on 44 infertile males with idiopathic asthenozoospermia. Men were randomized to receive 600 mg LA or placebo once daily for 12 weeks and semen samples and venous blood samples were obtained. GST expression, reactive oxygen species (ROS) levels, GST activity and reproductive hormone profiles were also measured. GST expression in the intervention group were significantly higher than the control group. Also, at the end of the study, GST activity increased, and ROS levels decreased significantly compared to the baseline. Additionally, the intervention group showed an increase in testosterone and decrease in serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin after 12 weeks, but this difference was not significant. We conclude a 12-week treatment with LA leads to improvements in reproductive hormones in serum, and significantly reduces the generation of ROS and increases the gene expression and activity of GST in seminal fluid.