De novo KAT6B mutation causes Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome in an Iranian boy: a case report.

BACKGROUND: Say-Barber-Biesecker-Young-Simpson (SBBYS) (OMIM #603736, Ohdo syndrome variant) is a rare type of severe blepharophimosis intellectual disability syndrome, which is generally characterized by a global developmental delay, distinctive facial features, and intellectual disability with multiple congenital anomalies, including skeletal involvement, missing, or underdeveloped kneecaps, and genital anomalies, in affected males. It has been shown that mutations in the KAT6B gene, which is a lysine acetyltransferase-encoding gene, have been associated with SBBYS syndrome. All the known variants are dominant de novo mutations that result in protein truncation. CASE PRESENTATION: A 14-year-old Iranian Azeri boy with an intellectual disability, distinct dysmorphic facial features such as open-mouth expression, sparse medial eyebrows, widely spaced upward-slanted eyes, epicanthal folds, broad nasal bridge, low-set ears, anteverted ears, short philtrum, hypertelorism, microphthalmia is presented in this case study. Cryptorchidism was reported. Neurologically, the patient presented with poor eye contact, hypotonia, and speech difficulties. In the skeletal X-ray, underdeveloped kneecaps with some new features were observed. CONCLUSION: We present the first case of SBBYS syndrome in association with some new anomaly features in the Iranian population. Based on this diagnosis, we could provide the patient with a suitable plan of management as well as appropriate genetic counseling for his family.

Molecular Investigation of the Association Among Common Interleukin-6 Polymorphism and Human Papillomavirus Genotypes with Cervical Cancer Among Iranian Women.

Cervical cancer is the fourth most commonly identified cancer and the third important reason for cancer-related death among women in less developed nations. Aside from the human papillomavirus (HPV), the host genetic factors, especially some polymorphisms in the interleukin 6 (IL-6) gene, might relate to the risk of cervical cancer. This study aims to investigate the molecular investigation of HPV infection and its association with the common polymorphism of IL-6 in cervical carcinoma in Iran. This case-control study collected 62 precancerous and cancerous lesions and 62 healthy samples from cancer-free women, subsequent negative colposcopy, and cervical cytology. The frequency of HPV genotypes and the genotyping of IL-6 rs1800795 and rs1800796 were done by different PCR techniques. Results were analyzed using the Epi Info version 7, 2012, with the χ2 test. Compared with cervical intraepithelial neoplasia grade 1 (CINI), the HPV positivity rate is saliently higher in CINII/III and squamous cell carcinoma (SCC) (56.25%, 66.66%, and 73.63%, respectively, p < 0.001). The HPV positivity rate is also higher in SCC in comparison with CINII/III (p < 0.01). Furthermore, the most detected HPV genotypes were HPV16 and 33 in CINI; HPV16, 31, and 35 in CINII/III; and HPV16 and 18 in SCC groups. HPV16 was the most commonly detected genotype in CINI, CINII/III, and SCC, accounting for 44.44%, 50%, and 71.42%, respectively. In addition, the frequency of GG, CG, and CC genotypes from rs1800795 polymorphism was 0.58, 0.32, and 0.10, respectively (p = 0.033), but in the control group, it was 0.70, 0.27, and 0.03, respectively. The findings suggest that HPV16 plays an important role in the emergence of cervical lesions in Iranian patients. As a result, rs1800795 CC genotype and HPV might increase cervical cancer risk in Iranian women.

Sodium selenite preserves rBM-MSCs' stemness, differentiation potential, and immunophenotype and protects them against oxidative stress via activation of the Nrf2 signaling pathway.

BACKGROUND: The physiological level of reactive oxygen species (ROS) is necessary for many cellular functions. However, during the in-vitro manipulations, cells face a high level of ROS, leading to reduced cell quality. Preventing this abnormal ROS level is a challenging task. Hence, here we evaluated the effect of sodium selenite supplementation on the antioxidant potential, stemness capacity, and differentiation of rat-derived Bone Marrow MSCs (rBM-MSCs) and planned to check our hypothesis on the molecular pathways and networks linked to sodium selenite's antioxidant properties. METHODS: MTT assay was used to assess the rBM-MSCs cells' viability following sodium selenite supplementation (concentrations of: 0.001, 0.01, 0.1, 1, 10 µM). The expression level of OCT-4, NANOG, and SIRT1 was explored using qPCR. The adipocyte differentiation capacity of MSCs was checked after Sodium Selenite treatment. The DCFH-DA assay was used to determine intracellular ROS levels. Sodium selenite-related expression of HIF-1α, GPX, SOD, TrxR, p-AKT, Nrf2, and p38 markers was determined using western blot. Significant findings were investigated by the String tool to picture the probable molecular network. RESULTS: Media supplemented with 0.1 µM sodium selenite helped to preserve rBM-MSCs multipotency and keep their surface markers presentation; this also reduced the ROS level and improved the rBM-MSCs' antioxidant and stemness capacity. We observed enhanced viability and reduced senescence for rBM-MSCs. Moreover, sodium selenite helped in rBM-MSCs cytoprotection by regulating the expression of HIF-1 of AKT, Nrf2, SOD, GPX, and TrxR markers. CONCLUSIONS: We showed that sodium selenite could help protect MSCs during in-vitro manipulations, probably via the Nrf2 pathway.

Molecular investigation of association between common IL-6 polymorphism with cytomegalovirus (CMV) infection and recurrent miscarriage in Iranian women.

BACKGROUND: Recurrent pregnancy loss (RPL) is described as two or more spontaneous abortions. To date, scientists in various fields of knowledge, such as genetics, endocrinology, anatomy, immunology, and microbiology, have identified some important factors that affect abortions; nonetheless, the precise basic etiology is not determined in up to 50% of RPL cases. Human cytomegalovirus (CMV) infection and host genetic background, like IL-6 SNP polymorphisms, play important roles in RPL etiology. OBJECTIVE: This study aimed to evaluate the relationships among single nucleotide polymorphisms (-634C/G and -174 G/C) in the IL-6 gene with CMV infection and the risk of RPL for early detection and treatment. MATERIALS AND METHODS: This case-control study was carried on 80 Iranian females with RPL and 80 healthy females as controls. DNA was extracted from samples and CMV and IL6 SNPs were detected using Tetra ARMS-PCR. Statistics were analyzed by Epi Info TM and SPSS software by X2 test for the roles of CMV detection and two polymorphisms in RPL. RESULTS: The results indicated an increased rate of CMV infection in the RPL group (44%) compared to the control group (25.45%). The prevalence of IL-6-634C/G genotype among RPL patients with CMV infection was 80%, while the frequency of this genotype among RPL patients without CMV infection was 50%. Furthermore, no substantial relation was found between IL-6-174 G/C genotypes and RPL (p = 0.005). CONCLUSION: This study not only indicated a significant role for CMV in RPL, but also showed an association between CMV and allele G in IL6-634 among Iranian women. In addition, the findings suggested the use of CMV and IL-6-634 GG genotypes as diagnostic and prognostic biomarkers for RPL in the Iranian population.

Harnessing rat derived model cells to assess the toxicity of TiO2 nanoparticles.

Until now, a few studies have been conducted on the destructive effects of TiO2 NPs in living organisms, and studies on the toxicity of TiO2 NPs are still in the beginning phases. Because of the widespread use of TiO2 NPs in all areas of human life, it is essential to study their profound and fundamental toxic effects on each organ and body cell. Herein, we evaluate the effect of exposure to TiO2 NPs on in vitro models derived from the rat bone marrow and adipose tissues. Exposure to TiO2 NPs at 100 and 200 µg/ml exhibited cytotoxicity for the rat bone marrow mesenchymal stem cells (rBMSCs) and rat adipose mesenchymal stem cells (rATSC), respectively. Additionally, reduced rBMSCs and rATSCs frequencies in the S phase of the cell cycle. Moreover, TiO2 NPs enhanced the activity of cellular senescence-associated ß-galactosidase in both model cells. Significantly higher relative expression of aging-related genes P53 and NF-kB (p < 0.05) and lower expression levels of anti-aging-related genes Nanog and SIRT1 were found in the treated cells (p < 0.05). Colony-forming and DAPI staining showed the reduction of cell growth and DNA damage in both rBMSCs and rATSCs. Our findings along with other similar findings showed that TiO2 NPs probably have negative effects on the cell growth, prompt the cells for entry into proliferation stop, DNA damage, and trigger the aging process. Graphical abstract.

Keratinocyte growth factor in focus: A comprehensive review from structural and functional aspects to therapeutic applications of palifermin.

Palifermin (Kepivance™) is the first therapeutic approved by the Food and Drug Administration for preventing and managing the oral mucositis provoked by myelotoxic and mucotoxic therapies. Palifermin is a recombinant protein generated from human keratinocyte growth factor (KGF) and imitates the function of endogenous KGF. KGF is an epithelial mitogen involved in various biological processes which belongs to the FGF family. KGF possesses a high level of receptor specificity and plays an important role in tissue repair and maintaining of the mucosal barrier integrity. Based on these unique features, palifermin was developed to enhance the growth of damaged epithelial tissues. Administration of palifermin has shown success in the reduction of toxicities of chemotherapy and radiotherapy, and improvement of the patient's quality of life. Notwithstanding all merits, the clinical application of palifermin is limited owing to its instability and production challenges. Hence, a growing number of ongoing researches are designed to deal with these problems and enhance the physicochemical and pharmaceutical properties of palifermin. In the current review, we discuss KGF structure and function, potential therapeutic applications of palifermin, as well as the latest progress in the production of recombinant human KGF and its challenges ahead.

GJB2 mutations in Iranian Azeri population with autosomal recessive nonsyndromic hearing loss (ARNSHL): First report of c.238 C>A mutation in Iran.

OBJECTIVE: Autosomal-recessive nonsyndromic hearing loss (ARNSHL) is a heterogeneous genetic disorder. Mutations in the gap junction protein beta 2 (GJB2) gene, encoding connexin 26, are a significant cause of ARNSHL in different ethnic groups. This study aimed to identify the frequency and type of GJB2 mutations in the Iranian Azeri population. METHODS: Fifty unrelated families presenting ARNSHL in Ardabil Province, the northwest of Iran, were studied to determine the frequency and type of GJB2 mutations leading to ARNSHL. ARMS-PCR screened all DNA samples to detect c.35delG; p. Gly12Val mutation. In addition, normal samples for c.35delG; p. Gly12Val were analyzed by direct sequencing for other GJB2 mutations. RESULT: Of the fifty families, 13 (26%) showed a GJB2 gene mutation, with c.35delG; p. Gly12Val mutation was the most prevalent one that occurred in eight (61.5%) out of the 13 families. Of the families, two were homozygous for c.358-360delGAC; p. Glu120del mutation, and one was homozygous for c.290dupA; p. Tyr97Ter and c.299-300delAT; p. His100Arg mutations. Also, we detected a novel mutation, c.238C>A; p. Gln80lys, in one of the families. CONCLUSION: Our findings are comparable to previous studies, indicating c.35d3lG; p. Gly12Val mutation in the GJB2 gene is the most common cause of GJB2-related hearing loss in the Iranian Azeri population. Furthermore, our study highlights the significance of ARNSHL screening programs of live births based on local population data in Iran.

The secretome of mesenchymal stem cells and oxidative stress: challenges and opportunities in cell-free regenerative medicine.

Over the last decade, mesenchymal stem cells (MSCs) have been considered a suitable source for cell-based therapy, especially in regenerative medicine. First, the efficacy and functions of MSCs in clinical applications have been attributed to their differentiation ability, called homing and differentiation. However, it has recently been confirmed that MSCs mostly exert their therapeutic effects through soluble paracrine bioactive factors and extracellular vesicles, especially secretome. These secreted components play critical roles in modulating immune responses, improving the survival, and increasing the regeneration of damaged tissues. The secretome content of MSCs is variable under different conditions. Oxidative stress (OS) is one of these conditions that is highly important in MSC therapy and regenerative medicine. High levels of reactive oxygen species (ROS) are produced during isolation, cell culture, and transplantation lead to OS, which induces cell death and apoptosis and limits the efficacy of their regeneration capability. In turn, the preconditioning of MSCs in OS conditions contributes to the secretion of several proteins, cytokines, growth factors, and exosomes, which can improve the antioxidant potential of MSCs against OS. This potential of MSC secretome has turned it into a new promising cell-free tissue regeneration strategy.This review provides a view of MSC secretome under OS conditions, focusing on different secretome contents of MSCs and thier possible therapeutic potential against cell therapy.

An overview of Betacoronaviruses-associated severe respiratory syndromes, focusing on sex-type-specific immune responses.

Emerging beta-coronaviruses (ß-CoVs), including Severe Acute Respiratory Syndrome CoV-1 (SARS-CoV-1), Middle East Respiratory Syndrome-CoV (MERS-CoV), and Severe Acute Respiratory Syndrome CoV-2 (SARS-CoV-2, the cause of COVID19) are responsible for acute respiratory illnesses in human. The epidemiological features of the SARS, MERS, and new COVID-19 have revealed sex-dependent variations in the infection, frequency, treatment, and fatality rates of these syndromes. Females are likely less susceptible to viral infections, perhaps due to their steroid hormone levels, the impact of X-linked genes, and the sex-based immune responses. Although mostly inactive, the X chromosome makes the female's immune system more robust. The extra immune-regulatory genes of the X chromosome are associated with lower levels of viral load and decreased infection rate. Moreover, a higher titer of the antibodies and their longer blood circulation half-life are involved in a more durable immune protection in females. The activation rate of the immune cells and the production of TLR7 and IFN are more prominent in females. Although the bi-allelic expression of the immune regulatory genes can sometimes lead to autoimmune reactions, the higher titer of TLR7 in females is further associated with a stronger anti-viral immune response. Considering these sex-related differences and the similarities between the SARS, MERS, and COVID-19, we will discuss them in immune responses against the ß-CoVs-associated syndromes. We aim to provide information on sex-based disease susceptibility and response. A better understanding of the evasion strategies of pathogens and the host immune responses can provide worthful insights into immunotherapy, and vaccine development approaches.

A combination of herbal compound (SPTC) along with exercise or metformin more efficiently alleviated diabetic complications through down-regulation of stress oxidative pathway upon activating Nrf2-Keap1 axis in AGE rich diet-induced type 2 diabetic mice.

BACKGROUND: SPTC is a mix of four herbal components (Salvia officinalis, Panax ginseng, Trigonella foenum-graeceum, and Cinnamomum zeylanicum) which might be prevented the development of AGE rich diet-induced diabetic complication and liver injury through activated the nuclear factor erythroid-2-related-factor-2 (Nrf2) pathway. Nrf2, as a master regulator of antioxidant response elements by activating cytoprotective genes expression, is decreased oxidative stress that associated with hyperglycemia and increases insulin sensitivity. the aim of this study was to assess whether the combination therapy of SPTC along with exercise or metformin moderate oxidative stress related liver injurie with more favorable effects in the treatment of AGE rich diet-induced type 2 diabetic mice. METHODS: We induced diabetes in C57BL/6 mice by AGE using a diet supplementation and limitation of physical activity. After 16 weeks of intervention, AGE fed mice were compared to control mice. Diabetic mice were assigned into seven experimental groups (each group; n = 5): diabetic mice, diabetic mice treated with SPTC (130 mg/kg), diabetic mice treated with Salvia Officinalis (65 mg/kg), diabetic mice treated with metformin (300 mg/kg), diabetic mice with endurance exercise training, diabetic mice treated with SPTC + metformin (130/300 mg/kg), diabetic mice treated with SPTC + exercise training. RESULTS: SPTC + exercise and SPTC + metformin reduced diabetic complications like gain weight, water and calorie intake, blood glucose, insulin, and GLUT4 content more efficiently than each treatment. These combinations improved oxidative stress hemostasis by activating the Nrf2 signaling pathway and attenuating keap1 protein more significantly. CONCLUSION: Eventually, combined treatment of SPTC with exercise or metformin as a novel approach had more beneficial effects to prevent the development of diabetes and oxidative stress associated with hyperglycemia.

Hybrid of niosomes and bio-synthesized selenium nanoparticles as a novel approach in drug delivery for cancer treatment.

The current study intends to investigate a novel drug delivery system (DDS) based on niosomes structure (NISM) and bovine serum albumin (BSA) which was formulated to BSA coated NISM (NISM-B). Also, selenium nanoparticles (SeNPs) have been prepared by BSA mediated biosynthesis. Finally, the NISM-B was hybridized with SeNPs and was formulated as NISM-B@SeNPs for drug delivery applications. Physicochemical properties of all samples were characterized by UV-Vis spectroscopy, FT-IR, DLS, FESEM, and EDX techniques. The cytotoxicity of all samples against A549 cell line was assessed by cell viability analysis and flow cytometry for apoptotic cells as well as RT-PCR for the expression of MDR-1, Bax, and Bcl-2 genes. Besides, in vivo biocompatibility was performed by LD50 assay to evaluate the acute toxicity. The proposed formulation has a regular spherical shape and approximately narrow size distribution with proper zeta-potential values; the proposed DDS revealed a good biocompatibility. The compound showed a significant cytotoxic effect against A549 cell line. Although the Bax/Bcl-2 expression ratio was significantly in NISM-B@SeNPs- treated cancer cells, the expression of MDR-1 was non-significantly lower in NISM-B@SeNPs-treated cancer cells. The obtained results suggest that the proposed DDS presents a promising approach for drug delivery, co-delivery and multifunctional biomedicine applications.

Cytoprotective effects of antioxidant supplementation on mesenchymal stem cell therapy.

Mesenchymal stem cells (MSCs) are earmarked as perfect candidates for cell therapy and tissue engineering due to their capacity to differentiate into different cell types. However, their potential for application in regenerative medicine declines when the levels of the reactive oxygen and nitrogen species (RONS) increase from the physiological levels, a phenomenon which is at least inevitable in ex vivo cultures and air-exposed damaged tissues. Increased levels of RONS can alter the patterns of osteogenic and adipogenic differentiation and inhibit proliferation, as well. Besides, oxidative stress enhances senescence and cell death, thus lowering the success rates of the MSC engraftment. Hence, in this review, we have selected some representatives of antioxidants and newly emerged nano antioxidants in three main categories, including chemical compounds, biometabolites, and protein precursors/proteins, which are proved to be effective in the treatment of MSCs. We will focus on how antioxidants can be applied to optimize the clinical usage of the MSCs and their associated signaling pathways. We have also reviewed several paralleled properties of some antioxidants and nano antioxidants which can be simultaneously used in real-time imaging, scaffolding techniques, and other applications in addition to their primary antioxidative function.

Lead concentration in the muscles of slaughtered buffalos in northwest regions of Iran.

BACKGROUND: The topic of food safety has become a major public health issue worldwide. Over recent decades, the growing concern for food safety has brought about greater research regarding the risks associated with the consumption of produce that has been contaminated by pesticides, heavy metals and/or toxins. OBJECTIVE: The study was conducted to determine the concentration of Pb in the muscle of buffalos slaughtered in the northwest regions of Iran (Ardabil, Urmia and Tabriz cities). METHODS: The present was a descriptive cross-sectional study in the northwest regions of Iran during 2013 to 2014. A total of 30 muscle samples from individual buffalos were analyzed for Pb concentrations using Atomic Absorption Spectrophotometer (ASS). Statistical analysis was performed using SPSS 17.0. All results were computed as mean standard deviation and subjected to one-way analysis of variance to establish whether the differences in Pb concentrations in meat samples from different cities were significant or not. The Statistical significance was determined at p<0.05. RESULTS: The results showed that the mean concentration of Pb in muscle samples were measured 0.043±0.035 ppm. The highest Pb concentration (0.11 ppm) was detected in the buffalo muscle samples from Urmia city. In total, 25 muscle samples (80.33%) were contaminated with Pb and concentration of Pb in 3.33% of contaminated samples exceeded the permissible limits advised by the European Commission (EC) (0.1 ppm). CONCLUSION: We recommend identifying Pb sources in order to eliminate or control Pb contamination of food, and monitor environmental exposures and hazards to prevent lead poisoning.