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Background Long non-coding RNAs (lncRNAs) play essential roles in molecular diagnosis and therapeutic response in several diseases. Purpose For the first time, we aimed to evaluate the association of four lncRNAs TUG1 (rs7284767G/A), MIAT (rs1061540T/C), MALAT1 (rs3200401C/T), and SENCR (rs12420823C/T) variants with susceptibility to diabetic retinopathy (DR), disease severity, and early therapeutic response to intravitreous anti-vascular endothelial growth factor aflibercept therapy. Patients and Methods This case-control study enrolled 126 adult patients with type 2 diabetes. TaqMan assays using Real-Time PCR were run for genotyping. Multivariable regression analyses were applied to assess the role of each polymorphism after the adjustment of covariates. Results Carriers of TUG1 A/G and MIAT T/C and C/C genotypes were more likely to develop DR [OR=3.15 (95% CI=1.15–8.64), and OR=4.31 (95% CI=1.78–10.47)], while MALAT1 T/C conferred protection (OR=0.40, 95% CI=0.16–0.99). For TUG1, MALAT1, MIAT, and SENCR genotype combinations, GTCT and GCCC had a higher disease risk (P=0.012). For disease severity, MIAT T/T homozygosity was associated with higher DR grade [33.3% (T/T) vs 10% (C/C) and 4.2% (C/T) carriers, P=0.012]. Otherwise, patients with the SENCR T variant exhibited better pre-treatment best-corrected visual acuity level (p=0.021). Following aflibercept administration, carrying the TUG1 A or MIAT T/C was associated with a poor therapeutic response (OR=5.02, 95% CI=1.60–15.76, and OR=10.23, 95% CI=1.51–69.15, respectively). Conclusion The lncRNAs TUG1 (rs7284767G/A) and MIAT (rs1061540T/C) were associated with increased DR susceptibility and poor response to aflibercept treatment, while MALAT1 (rs3200401C/T) conferred protection to DR. These genetic determinants could be useful in DR risk stratification and pharmacogenetics after validation in large-scale studies., Graphical Abstract

Background: Viral warts are benign growths that result from an infection of epidermal or mucosal cells with the human papillomavirus. Epidemiological studies have demonstrated a link between vitamin D deficiency and increased rates of infectious diseases and their resistance to treatment. Such a link between vitamin D level and wart recalcitrance is yet to be revealed. To the best of our knowledge, there were no previous studies conducted to reveal the possible relationship between vitamin D and recalcitrant warts. Aim: To assess serum vitamin D levels in patients with recalcitrant palmoplantar warts. Subjects and Methods:A cross-sectional study conducted on two groups. The first group included 35 patients with recalcitrant palmoplantar warts, the second group included 35 healthy volunteers matched for age, sex. Serum vitamin D level was measured. Results: A total of 78 participants were enrolled in this study, including 30 males and 48 females, distributed among the 3 groups. There was no statistically significant difference in serum vitamin D levels between the studied groups. Its mean level in the recalcitrant group was 26.03 ng/ml, while in the responsive group it was 29.36 ng/ml and reached 25.15ng/ml in the control group. Conclusion: low serum vitamin D levels do not seem to increase the susceptibility of warts to get resistant to treatment.

Doxorubicin is a drug that belongs to the anthracycline antibiotics. Nephrotoxicity is one of the serious side effects of doxorubicin treatment. Crocin, which is one of the most bioactive components of saffron, has antioxidant, anti-inflammatory, and antitumor effects. The current study was aimed at investigating the possible protective effects of crocin against doxorubicin-induced nephrotoxicity to elucidate the underlying mechanism of this effect. The study included four groups, six rats in each group: normal control, crocin control, doxorubicin, and crocin/doxorubicin. Doxorubicin and crocin/doxorubicin groups received intraperitoneal injections of doxorubicin (3.5 mg/kg twice weekly for 3 weeks). Rats in the crocin control group and the crocin/doxorubicin group were treated with intraperitoneal injections of crocin (100 mg/kg body weight per day) for 3 weeks. Biomarkers of kidney function and oxidative stress as well as the abundance of mRNA for nuclear factor-κβ and inducible nitric oxide synthase were evaluated. In addition, the abundance of cyclooxygenase 2 and tumor necrosis factor α immunoreactivity was evaluated. Crocin treatment had renoprotective effects manifested by significant improvement in kidney function as well as a reduction in the abundance of biomarkers of oxidative stress markers and inflammatory mediators. In conclusion, crocin has a protective effect against doxorubicin-induced nephrotoxicity in rats by serving as an antioxidant and attenuating the expression of NF-κB, iNOS, COX2, and TNFα.

BACKGROUND Chronic spontaneous urticaria (CSU) is a distressing skin disease. Family clustering and heterogeneity in the onset and progression indicate that susceptibility to CSU is a complex trait. In this study, we performed haplotype analysis for one of the key player gene, IL17RA, for CSU to test the association with disease susceptibility and severity. METHODOLOGY The study included 70 CSU patients and 30 healthy controls. The severity of the disease was evaluated by autologous serum skin test (ASST) and urticaria activity score (UAS). ASST test was done and quality of life was assessed using a questionnaire. Allelic discrimination analysis for rs4819554 and rs879577 was performed using real-time polymerase chain reaction technology. RESULTS Carriers of rs4819554*G were more prone to develop CSU than its counterpart (P = .039), while rs4819554*A allele displayed more severe phenotype in the form of more prolonged disease duration (P = .040), concurrent angioedema (P

Background: Chronic spontaneous urticaria (CSU) is a distressing skin disease. Family clustering and heterogeneity in the onset and progression indicate that susceptibility to CSU is a complex trait. In this study, we performed haplotype analysis for one of the key player gene, IL17RA, for CSU to test the association with disease susceptibility and severity.MethodsThe study included 70 CSU patients and 30 healthy controls. The severity of the disease was evaluated by autologous serum skin test (ASST) and urticaria activity score (UAS). ASST test was done and quality of life was assessed using a questionnaire. Allelic discrimination analysis for rs4819554 and rs879577 was performed using Real-Time Polymerase Chain Reaction technology.Results: Carriers of rs4819554*G were more prone to develop CSU than its counterpart (p = 0.039), while rs4819554*A allele displayed more severe phenotype in the form of more prolonged disease duration (p = 0.040), concurrent angioedema (p < 0.001), higher level of treatment (p < 0.001), and higher score of quality of life (p < 0.001). Additionally, homozygote patients with rs879577*CC were associated with angioedema (p < 0.001). Haplotype analysis revealed that cohorts with both rs4819554*A and rs879577*T conferred protection against developing CSU (OR = 0.07, 95%CI = 0.01 - 0.32, p = 0.001).Conclusions: Our results showed that IL17RA gene polymorphisms might contribute to the increased susceptibility to CSU.

Accumulating evidence indicates the implication of microRNAs (miRs) in cutaneous and hair follicle immunobiology. We evaluated, for the first time, the miR-17-92a-1 cluster host gene (MIR17HG) expression in peripheral blood of 248 unrelated alopecia areata (AA) patients compared to 244 matched controls using Real-Time qPCR. We also tested its association with different rs4284505A>G genotypes (based on TaqMan allelic discrimination PCR) and the available clinical data. The adjusted odds ratio (OR) and 95% confidence interval (CI) were calculated for each genetic association model. The upregulation of miR-17 was observed in the serum of patients with alopecia compared to controls (p-value = 0.004). The ROC curve showed high diagnostic performance of miR-17 in differentiating between patients and controls (AUC = 0.85, p-value < 0.001). rs4284505*A/G heterozygotes were more susceptible to the disease (OR = 1.57, 95% CI = 1.01–2.45) under the over-dominant model. Interestingly, patients with the rs4284505*G/G genotype had a higher level of miR-17 than those with the A/A and A/G genotypes. The G/G genotype was associated with the severe phenotype (p-value = 0.038). A/G carriers were the youngest (p-value < 0.001), had more frequent scalp infection (p-value = 0.006), exhibited the worst dermatology life quality index score (p-value = 0.037), and responded less to treatment (p-value = 0.033). In conclusion, MIR17HG expression and the rs4284505 variant were significantly associated with AA and could play a role in pathogenesis and phenotype in the Egyptian population. Further multi-center studies in other ethnicities are warranted to replicate the findings.

Recent advances in genome editing technologies have significantly enhanced making specific changes in the genomes of different types cells. Genetically engineered T cells, or the 'living drugs', is considered a new era in antitumor therapy. Current clinical trials using chimeric antigen receptors (CARs) T cells showed a promising result in patients with some intractable hematological malignancies. In this Review, some of the most recent advances in CAR T cell therapy are mentioned high lightening the use of genome editing in this field.

Introduction Globally, the prevalence of overweight and obesity is increasing, predisposing females to health hazards including compromised reproductive capacity. Our objective was to investigate the effect of ad libitum, isocalorically and hypocalorically restricted high-fat diet (HFD) feeding on reproductive function in diet-induced obese female rats. Material and methods Twenty female albino Sprague Dawley rats were used; 5 rats were kept on a standard pellet animal diet to serve as a control group (A) and 15 rats were fed a HFD for 9 weeks to induce obesity. The HFD fed animals were equally divided into three groups: an ad libitum HFD group (B), an isocalorically restricted HFD group (C), and a hypocalorically restricted HFD group (D). Estrous cyclicity, hormonal levels, ovarian histopathology and caspase-3 immunoreactivity were evaluated. Results The HFD-fed rats in groups B, C and D had significant irregularity in estrous cyclicity Vs group A (p = 0.001, 0.003 and 0.034 respectively). Groups C and D had significant reduction in serum progesterone level (p = 0.006 and 0.018 Vs A). Isocaloric restriction of HFD feeding significantly increased serum LH. Groups B and C had a significant increase in caspase-3 expression in the ovary (p < 0.001). Conclusions Ad libitum HFD interfered with the normal estrous cycle and enhanced apoptosis of luteal cells in obese female rats. The HFD restriction interfered with the normal estrous cycle and caused functional insufficiency of the corpus luteum in obese female rats. These results suggest that HFD feeding determinately affects female reproductive function independently of caloric intake.

Traditionally, asthma, atopic dermatitis and allergic rhinitis, in addition to food allergy, categorized as atopic diseases, the term allergy refer to immediate hypersensitivity which used to describe the combined immediate and late phase reactions. This study aimed to determine serum total IgE level, eosinophil count, and serum level of IFN-γ, in relation to the age of atopic patients and genotyping of the IFN-γ gene at +874 T/A in relation to serum IFN-γ level. As well as comparing of IFN-γ concentrations of atopic patients according to genotypes in atopic patients and apparently healthy control. The studied groups were 25 apparently healthy controls and 75 atopic patients (25 asthma patients, 25 allergic rhinitis patients and 25 atopic dermatitis patients). The obtained results showed that, the prevalence of atopic diseases occurred in the age group between 21 and 40 (second group) are more than the age group less than 21 (first group) and the age group of more than 40, third group (p = .0001). Moreover, total IgE is significantly increased in the three atopic groups compare to control (P

Vitamin D deficiency has been described in SLE and OA. Low vitamin D level is prevalent in Egyptian SLE patients while controversial studies are present regarding its level in OA patients in Egypt. We investigated whether vitamin D receptor (VDR) genes Bsm1 and Fok1 polymorphisms could be used as genetic markers for the susceptibility to SLE and /or OA in a sample of Egyptian population. The study was carried out on 100 SLE patients, 100 osteoarthritic patients and 100 normal controls using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Our results showed a statistically significant difference in Fok1 genotype distribution between SLE and OA patients (p=0.001). In SLE group, the "f" allele was significantly over-represented where 30% had "f" allele compared to 0% in OA (P = 0.03). Fok1 ff genotypes showed a significant association with disease activity in SLE patients. In addition, the fb haplotype frequency was significantly higher in SLE patients than controls (P=0.01). In conclusion Fok1 genotype and f allelic frequencies may be susceptible risk factors for SLE rather than OA in Egyptian patients.

The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is associated with vitiligo in the Indians and Koreans, but not in those of English or Turkish background. We investigated the ACE (I/D) polymorphism in vitiligo patients for the first time in Egypt and compared serum ACE levels between vitiligo patients and controls. The present study was carried out in 100 vitiligo patients (40 males and 60 females) and in 100 healthy controls of an Egyptian population using the polymerase chain reaction genotyping method.The ACE genotype and allele frequency was significantly different between vitiligo patients and controls. Our results revealed a significant increase in the frequency of the ACE I allele (p=0.002; odds ratio: 1.99; 95% confidence intervals: 1.207-3.284) with an overrepresentation of I/D genotype in the vitiligo patient group. Furthermore, there was a significant difference between the segmental, nonsegmental, and focal vitiligo in ACE gene genotype distribution. Serum ACE levels were significantly increased in vitiligo patients compared to controls (p=0.034).This study suggests that, for the first time, ACE gene polymorphism confers susceptibility to vitiligo in the Egyptian population.

The United Arab Emirates (UAE) is a consortium of seven states, located in the region of Middle East and North Africa (MENA); it has the second largest economy in the Arab world. In 2012, it has a gross domestic product (GDP) of $377 billion. Due to the support of the ruler of the government, tremendous advances have been made in the field of oil, gas, tourism, and healthcare since its independence. Health is identified as a prime concern of the country; hence, remarkable advancement and phenomenal growth have been exhibited by the healthcare industry of the UAE. As a result of increase in the immigration population, the UAE healthcare system is striving to meet the expanding healthcare needs. Ministry of Health (MoH), Health Ministers’ Council for Gulf Cooperation (GCC), Health Authority of Abu Dhabi (HAAD), and Dubai Health Authority (DHA) are the major regulatory bodies of the UAE. Various pharmaceutical legislations and policies majorly concerning accessibility, availability, affordability, quality, and pricing of medicines have been devised by these bodies; however, implementation is still a concern. This chapter describes the health system of the UAE, its regulatory structure, and present challenges with prime focus on pharmaceutical policies and medicines regulation in the UAE.

The aims of the study are determine some immunological aspects namely total IgE, specific IgE, eosinophil count, IFN-γ, IL-10 and CCL-17 in serum of atopic patients and apparently healthy control to determine their relationship to atopic diseases. The age group of 21–40 years seems to be the most affect group with atopic diseases (P =0.0001) and asthmatic and allergic rhinitis patients are at this age group also (P =0.005, P =0.001respectively). There is a major differences (P < 0.001) in level of total IgE between allergic subjects and controls and among three atopic patients groups (P < 0.001) but Specific IgE is significantly higher in asthmatics than allergic rhinitis and atopic dermatitis patients (P < 0.05). Inhalation of outdoor allergens is significantly affected asthmatic patients and allergic rhinitis patients (P < 0.01). Controversially, indoor allergens are significantly affecting atopic dermatitis (P < 0.01). The mean of IFN-γ serum level in asthma patients was lower than IFN-γ serum level of the control group and atopic dermatitis patients (P < 0.05). The allergic rhinitis patients mean of serum level of IL-10 was significantly low as compared to the mean of the serum level of IL-10 control group (P= 0.020). All of three groups of atopic patients are significantly have high level of CCL-17 compare to mean of serum level of control group (P < 0.01).

Macrophage colony-stimulating factor (M-CSF) regulates the production, survival and function of macrophages through Fms, the receptor tyrosine kinase. Recently, interleukin-34 (IL-34), which shares no sequence homology with M-CSF, was identified as an alternative Fms ligand. Here, we provide the first evidence that these ligands indeed resemble but are not necessarily identical in biological activity and signal activation. In culture systems tested, IL-34 and M-CSF showed an equivalent ability to support cell growth or survival. However, they were different in the ability to induce the production of chemokines such as MCP-1 and eotaxin-2 in primary macrophages, the morphological change in TF-1-fms cells and the migration of J774A.1 cells. Importantly, IL-34 induced a stronger but transient tyrosine phosphorylation of Fms and downstream molecules, and rapidly downregulated Fms. Even in the comparison of active domains, these ligands showed no sequence homology including the position of cysteines. Interestingly, an anti-Fms monoclonal antibody (Mab) blocked both IL-34-Fms and M-CSF-Fms binding, but another MAb blocked only M-CSF-Fms binding. These results suggested that IL-34 and M-CSF differed in their structure and Fms domains that they bound, which caused different bioactivities and signal activation kinetics/strength. Our findings indicate that macrophage phenotype and function are differentially regulated even at the level of the single receptor, Fms.

HIV-1 Nef accelerates the progression to AIDS by binding with and activating a Src kinase Hck, but underlying molecular basis is not understood. We revealed that Nef disturbed N-glycosylation/trafficking of a cytokine receptor Fms in an Hck-dependent manner, a possible trigger to worsen uncontrolled immune system. Here, we provide direct evidence that dys-regulated activation of Hck pre-localized to the Golgi apparatus causes this Fms maturation arrest. A striking change in Hck induced by Nef other than activation was its skewed localization to the Golgi due to predominant Golgi-localization of Nef. Studies with different Nef alleles and their mutants showed a clear correlation among higher Nef-Hck affinity, stronger Hck activation, severe Golgi-localization of Hck and severe Fms maturation arrest. Studies with a newly discovered Nef-Hck binding blocker 2c more clearly showed that skewed Golgi-localization of active Hck was indeed the cause of Fms maturation arrest. 2c blocked Nef-induced skewed Golgi-localization of an active form of Hck (Hck-P2A) and Fms maturation arrest by Nef/Hck-P2A, but showed no inhibition on Hck-P2A kinase activity. Our finding establishes an intriguing link between the pathogenesis of Nef and a newly emerging concept that the Golgi-localized Src kinases regulate the Golgi function.

Background Currently, natural products have built a well-recognized role in the management of many degenerative diseases, mainly rheumatoid arthritis. Recent studies suggest that Spirulina, a unicellular blue-green alga, may have a variety of health benefits and curative properties and is also competent of acting as an anti-inflammatory, antioxidant and recently anti-angiogenic agent. In the present study, the antioxidant and the immunomodulatory effect of Spirulina platensis as well as its anti-angiogenic effect against complete Freund's adjuvant-induced arthritis (AIA) in rat model were tested. Results We found that the development of arthritis was concealed; moreover it successfully inhibited the development of macroscopic as well as microscopic and histopathological lesions in AIA rats when compared to control. Spirulina treated group showed a higher survival rate and moreover, it reduced the clinical score of RA in a dose dependent manner. Furthermore, Spirulina decreased serum levels of COX-2, TNF-α, IL-6, TBARS, VEGF and increased serum levels of GSH compared to the RA non-treated group. Conclusions The present study concluded that Spirulina is able to restrain the changes produced through adjuvant-induced arthritis. The suppressing effect of Spirulina could be attributed, at least in part, to anti-inflammatory, antioxidant and anti-angiogenic properties.

Background Although HIV can infect several cellular subsets, such as CD4+ T lymphocytes and macrophages, it remains unclear whether an HIV infection in macrophages supports cytotoxic T lymphocyte (CTL) escape. Here, we tested two naturally-arising mutations located in the well-conserved polyproline region of Nef for their effects on CTL recognition, Nef's functionality, and viral replication capacity in macrophages. These mutations were selected because they are known to cause CTL escape in the context of T lymphocytes. Findings Monocyte-derived macrophages (MDMs) infected with the wild-type virus, but not with variant viruses, were efficiently killed by CTL clones targeting Nef epitopes, VY8 (VPLRPMTY) and RY11 (RPQVPLRPMTY). The CTL-escape mutation, Arg75Thr, or Arg75Thr/Tyr85Phe double mutation, reduced the HLA class I down-regulation activity and, interestingly, increased the susceptibility of virus-infected MDMs to recognition by CTLs targeting a different epitope. The same mutations reduced the CCR5, but not CD4, down-regulation activity. Moreover, the Nef variants were impaired for Hck activation and enhancement of viral replication in MDMs. Conclusions These results suggest that HIV-infected MDMs are killed by CTLs targeting Nef epitopes, contributing to selection and adaptation of CTL-escape viral variants.

Nef is a multifunctional pathogenetic protein of HIV-1, the interaction of which with Hck, a Src tyrosine kinase highly expressed in macrophages, has been shown to be responsible for the development of AIDS. However, how the Nef-Hck interaction leads to the functional aberration of macrophages is poorly understood. We recently showed that Nef markedly inhibited the activity of macrophage colony-stimulating factor (M-CSF), a primary cytokine for macrophages. Here, we show that the inhibitory effect of Nef is due to the Hck-dependent down-regulation of the cell surface expression of M-CSF receptor Fms. In the presence of Hck, Nef induced the accumulation of an immature under–N-glycosylated Fms at the Golgi, thereby down-regulating Fms. The activation of Hck by the direct interaction with Nef was indispensable for the down-regulation. Unexpectedly, the accumulation of the active Hck at the Golgi where Nef prelocalized was likely to be another critical determinant of the function of Nef, because the expression of the constitutive-active forms of Hck alone did not fully down-regulate Fms. These results suggest that Nef perturbs the intracellular maturation and the trafficking of nascent Fms, through a unique mechanism that required both the activation of Hck and the aberrant spatial regulation of the active Hck.

The effect of obesity on reproductive function in obese men is much less investigated than in women. In addition, the mechanism of male reproductive outcomes in obesity is unknown. So this study was designed to investigate the effect of prepubertal induction of obesity on the reproductive function in male rats at maturity and to address whether inflammation and testicular oxidative stress are involved at the mechanistical level. Fourteen male albino rats, 4 weeks old were included and divided into control group (n=6) and high fat diet group (n=8). The animal characteristics were assessed, serum biochemical parameters, FSH, LH, testosterone, estradiol, TNFα, IL-6 and IL-10 were measured, sperm count and motility were measured, testicular oxidative stress markers were assayed and histopathological evaluation of spermatogenesis was done. HFD feeding induced significant increase in body weight, BMI, Lee index, serum cholesterol, triglycerides, TNFα and testicular malondialdehyde. HFD feeding induced significant decrease in relative testicular weight, IL-10, sperm count and progressive movement and testicular glutathione peroxidase. HFD group revealed defective spermatogenesis. Prepubertal induction of obesity impaired the reproductive function in mature male rats. Testicular oxidative stress and inflammation may be playing an important role in this effect.