ZSCAN10 deficiency causes a neurodevelopmental disorder with characteristic oto-facial malformations.

Neurodevelopmental disorders are major indications for genetic referral and have been linked to more than 1500 loci including genes encoding transcriptional regulators. The dysfunction of transcription factors often results in characteristic syndromic presentations; however, at least half of these patients lack a genetic diagnosis. The implementation of machine learning approaches has the potential to aid in the identification of new disease genes and delineate associated phenotypes. Next generation sequencing was performed in seven affected individuals with neurodevelopmental delay and dysmorphic features. Clinical characterization included reanalysis of available neuroimaging datasets and 2D portrait image analysis with GestaltMatcher. The functional consequences of ZSCAN10 loss were modelled in mouse embryonic stem cells (mESCs), including a knockout and a representative ZSCAN10 protein truncating variant. These models were characterized by gene expression and western blot analyses, chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR) and immunofluorescence staining. Zscan10 knockout mouse embryos were generated and phenotyped. We prioritized bi-allelic ZSCAN10 loss-of-function variants in seven affected individuals from five unrelated families as the underlying molecular cause. RNA-sequencing analyses in Zscan10-/- mESCs indicated dysregulation of genes related to stem cell pluripotency. In addition, we established in mESCs the loss-of-function mechanism for a representative human ZSCAN10 protein truncating variant by showing alteration of its expression levels and subcellular localization, interfering with its binding to DNA enhancer targets. Deep phenotyping revealed global developmental delay, facial asymmetry and malformations of the outer ear as consistent clinical features. Cerebral MRI showed dysplasia of the semicircular canals as an anatomical correlate of sensorineural hearing loss. Facial asymmetry was confirmed as a clinical feature by GestaltMatcher and was recapitulated in the Zscan10 mouse model along with inner and outer ear malformations. Our findings provide evidence of a novel syndromic neurodevelopmental disorder caused by bi-allelic loss-of-function variants in ZSCAN10.

Circulating expression levels of CircHIPK3 and CDR1as circular-RNAs in type 2 diabetes patients.

BACKGROUND: Recent investigations suggested that deregulated levels of Circular RNAs (circRNAs) could be associated with type 2 diabetes mellitus (T2DM) pathogenesis. Accordingly, this study aimed to determine the expression levels of circulating CircHIPK3, CDR1as and their correlation with biochemical parameters in patients with T2DM, pre-diabetes and control subjects. METHODS AND RESULTS: The expression of circRNAs in peripheral blood was determined using QRT-PCR in 70 patients with T2DM, 60 pre-diabetes and in 69 age and sex matched healthy controls. Moreover, bioinformatics tools were applied to explore and predict the potential interactions between circRNAs and other non-coding RNAs (ncRNAs). Our analysis revealed that the expression level of CircHIPK3 was significantly elevated in T2DM patients compared to healthy participants (P < 0.001) and pre-diabetes subjects (P = 0.018). In addition, ROC analysis suggested that at the cutoff value of 0.24 and the sensitivity and specificity of 50% and 88.4%, respectively, CircHIPK3 could distinguish between T2DM patients and control subjects. Furthermore, it was observed that the expression level of CDR1as is higher in pre-diabetic individuals than healthy individuals (P = 0.004). Finally, Spearman correlation analysis showed that there was a significant correlation between CircHIPK3 and CDR1as expression levels and clinical and anthropometrical parameters such as BMI, systolic and diastolic blood pressure, HbA1c and fasting blood glucose (P < 0.005). CONCLUSIONS: The data of this study provided evidence that the expression levels of CircHIPK3, CDR1as increased in T2DM and pre-diabetes subjects, respectively.

Circulating mRNA and plasma levels of osteoprotegerin and receptor activator of NF-κB ligand in nonalcoholic fatty liver disease.

Pathogenesis of the beginning and progression of nonalcoholic fatty liver disease (NAFLD) has not been clarified exactly. The osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) axis seems to play an imperative function in the onset and progression of this disease. The goal of the present study was to investigate the peripheral blood mononuclear cell (PBMC) expression and plasma levels of RANKL and OPG cytokines in NAFLD patients and compare them with healthy group. Plasma levels of OPG and RANKL were determined with ELISA kits in 57 men with NAFLD and 25 healthy men as controls. Biochemical and anthropometric parameters tests were also evaluated in the study groups. RANKL and OPG mRNA contents were evaluated by quantitative RT-PCR. OPG contents were markedly decreased in NAFLD patients as compared with healthy patients [1.43 (1.05-5.45)] versus [2.94 (1.76-4.73)] ng/mL; P = 0.007). The levels of RANKL were significantly reduced in NAFLD patients [74.00 (56.26-203.52) ng/mL] than in healthy patients [119.37 (83.71-150.13) ng/mL]; (P = 0.03). Also, OPG and RANKL gene expression were significantly decreased in NAFLD patients in comparison with the control group (P < 0.05). Moreover, receiver operating characteristic curve indicated that OPG may have a good capability to discriminate between NAFLD patients and normal individuals. A positive correlation was observed between OPG and RANKL in plasma sample (r = 0.495) (P = 0.000). Decreased plasma levels and gene expression of RANKL and OPG cytokines in NAFLD patients indicate that there is a relationship between these cytokines and the pathology of NAFLD disease. Confirmation of this association as well as the mechanism and role of these cytokines in NAFLD require further studies.

An updated review of the H19 lncRNA in human cancer: molecular mechanism and diagnostic and therapeutic importance.

Accumulating evidence has reported that H19 long non-coding RNA (lncRNA) expression level is deregulated in human cancer. It has been also demonstrated that de-regulated levels of H19 could affect cancer biology by various mechanisms including microRNA (miRNA) production (like miR-675), miRNA sponging and epigenetic modifications. Furthermore, lncRNA could act as a potential diagnosis and prognosis biomarkers and also a candidate therapeutic approach for different human cancers. In this narrative review, we shed light on the molecular mechanism of H19 in cancer development and pathogenesis. Moreover, we discussed the expression pattern and diagnostic and therapeutic importance of H19 as a potential biomarker in a range of human malignancies from breast to osteosarcoma cancer.

SUCLG1 mutations and mitochondrial encephalomyopathy: a case study and review of the literature.

The mitochondrial encephalomyopathies represent a clinically heterogeneous group of neurodegenerative disorders. The clinical phenotype of patients could be explained by mutations of mitochondria-related genes, notably SUCLG1 and SUCLA2. Here, we presented a 5-year-old boy with clinical features of mitochondrial encephalomyopathy from Iran. Also, a systematic review was performed to explore the involvement of SUCLG1 mutations in published mitochondrial encephalomyopathies cases. Genotyping was performed by implementing whole-exome sequencing. Moreover, quantification of the mtDNA content was performed by real-time qPCR. We identified a novel, homozygote missense variant chr2: 84676796 A > T (hg19) in the SUCLG1 gene. This mutation substitutes Cys with Ser at the 60-position of the SUCLG1 protein. Furthermore, the in-silico analysis revealed that the mutated position in the genome is well conserved in mammalians, that implies mutation in this residue would possibly result in phenotypic consequences. Here, we identified a novel, homozygote missense variant chr2: 84676796 A > T in the SUCLG1 gene. Using a range of experimental and in silico analysis, we found that the mutation might explain the observed phenotype in the family.

Decreased Plasma Level of TRIB3 is Associated with Circulating miR-124a in Patients with Type 2 Diabetes.

BACKGROUND: Recent evidence indicates that TRIB3 and miR-124 levels have been deregulated in type 2 diabetes (T2D); however, the simultaneous evaluation of these markers in diabetic patients has not been investigated to date. METHODS: This case-control study included 50 T2D patients and 40 age-gender matched controls. The circulation level of miR-124a was assessed by real-time PCR. TRIB3 plasma level was measured using the enzyme-linked im-munosorbent assay. RESULTS: Our findings revealed that the TRIB3 plasma level was significantly increased (p = 0.025), while miR-124a plasma levels were significantly reduced (p = 0.028) in diabetic patients compared to healthy subjects. ROC analysis showed that TRIB3 and miR-124a levels could discriminate control subjects and diabetic patients. Interestingly, a significant negative correlation was found between the TRIB3 and miR-124a plasma levels. Furthermore, there was a significant positive correlation between the TRIB3 plasma level with fasting blood glucose and insulin resistance. CONCLUSIONS: In this study, we showed deregulation of TRIB3 level in diabetic patients and its association with miR-124a circulating level and clinical parameters. These findings suggest that miR-124a may affect T2D incidence and progression by modulating the expression of TRIB3 protein level.

Nanofiber-acellular dermal matrix as a bilayer scaffold containing mesenchymal stem cell for healing of full-thickness skin wounds.

Full-thickness skin defect is one of the main clinical problems, which cannot be repaired spontaneously. The aim of this study was to evaluate the feasibility of combining nanofibers with ADM as a bilayer scaffold for treatment of full-thickness skin wounds in a single-step procedure. The nanofibrous polycaprolactone/fibrinogen scaffolds were fabricated by electrospinning. Subsequently, mesenchymal stem cells were isolated from rat adipose tissues and characterized by flow cytometry. Cell adhesion, proliferation, and the epidermal differentiation potential of adipose-derived stem cells (ADSCs) on nanofibrous scaffolds were investigated by scanning electron microscopy (SEM), alamarBlue, and real-time PCR, respectively. In animal studies, full-thickness excisional wounds were created on the back of rats and treated with following groups: ADM, ADM-ADSCs, nanofiber, nanofiber-ADSCs, bilayer, and bilayer-ADSCs. In all groups, wounds were harvested on days 14 and 21 after treatment to evaluate re-epithelialization, blood vessel density, and collagen content. The results indicated that ADSCs seeded on ADM, nanofiber, and bilayer scaffolds can promote re-epithelialization, angiogenesis, and collagen remodeling in comparison with cell-free scaffolds. In conclusion, nanofiber-ADSCs showed the best results for re-epithelialization (according to histological scoring), average blood vessel density (92.7 ± 6.8), and collagen density (87.4 ± 4.9%) when compared to the control and other experimental groups.

Circular RNAs in ß-cell function and type 2 diabetes-related complications: a potential diagnostic and therapeutic approach.

Recent investigations have indicated that altered expression of non-coding RNAs (ncRNAs) could be associated with human diseases such as type 2 diabetes (T2D). Circular RNAs (circRNAs) are a new discovered class of ncRNAs with unique structural characteristics that involved in several molecular and cellular functions. Exploring of the circulating circRNAs as a reliable non-invasive biomarker for monitoring and diagnosing of human diseases has grown significantly. However, the molecular functions and clinical relevance of circRNAs are not yet well clarified in T2D. Accordingly, in this review, the involvement of circRNAs in the ß-cell function and T2D-related complications is highlighted. The study also shed light on the possibility of using circRNAs as a biomarker for T2D diagnosis.

Decreased Serum Level of miR-155 is Associated with Obesity and its Related Metabolic Traits.

BACKGROUND: Type 2 diabetes is the most common metabolic disease, affecting many of the adult population all around the world. In recent years much attention has been paid to the role of circulating miRNAs as novel biomarkers for various diseases. The aim of this study was to investigate the expression level of miR-155 in serum samples of diabetic and healthy subjects. METHODS: 42 healthy and 45 type 2 diabetic subjects participated in the study. Serum miR-155 level of the subjects was measured using real-time PCR. The levels of IL-6 and TNF-α were quantified using ELISA. RESULTS: There was no significant difference in the level of miR-155 between the diabetic and non-diabetic groups. The level of miR-155 in non-diabetic obese group was significantly lower than the non-diabetic lean subjects. Correlation analyses in non-diabetic group revealed a significant negative correlation between the amount of miR155 and body mass index and cholesterol levels after the elimination of the confounding factors. In diabetic group, a negative correlation was found between miR-155 and insulin, HOMA-IR, and waist circumference levels. Furthermore, no significant relationship between miR-155 and inflammatory cytokines (TNF-α and IL-6) was observed in both diabetic and healthy groups. CONCLUSIONS: A reduced level of miR-155 might associate with obesity and its related metabolic traits such as hyperinsulinemia and dyslipidemia.

Association of the rs1870634 Variant in Long Intergenic Non-protein Coding RNA 841 with Coronary Artery Disease: A GWAS-Replication Study in an Iranian Population.

Recent genome-wide association studies (GWAS) identified a list of single-nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD). Replication of GWAS findings in different population corroborated the observed association in the parent GWAS. In this study, we aimed to replicate the association of rs1870634, a GWAS identified SNP, to CAD in an Iranian population. The study population consisted of 267 subjects undergoing coronary angiography coronary angiography including 155 CAD patients and 112 non-CAD age- and gender-matched controls. The genotype determination of rs1870634 SNP performed using high-resolution melting analysis (HRM) technique. Our results revealed that the GG genotype frequency was significantly higher in CAD patients compared with controls (P = 0.03). The results of binary logistic regression suggested that this genotype was significantly associated with CAD risk adjustment for age, BMI, sex, TC, and LDL-C lipid levels (OR of 2.78, 95% CI (1.10-7.01), P = 0.03). Moreover, our results showed that the GG+TG genotypes were 2.52 times more likely to develop CAD (95% CI 1.05-6.03) than TT genotype carriers after adjusting for age, sex, and lipid profiles (P = 0.037). These data showed that the GG genotype could be associated with increased risk of CAD in a sample of Iranian population.

The Circulating Levels of Complement-C1q/TNF-Related Protein 13 (CTRP13) in Patients with Type 2 Diabetes and its Association with Insulin Resistance.

BACKGROUND: Complement-C1q/TNF-related protein 13 (CTRP13) is a novel adipokine involved in the regulation of energy metabolism. Here, we sought to evaluate serum levels of CTRP13 and adiponectin in patients with type 2 diabetes (T2D) (n = 40) and healthy subjects (n = 40) and also to study the association of CTRP13 levels with diabetes-related indices. METHODS: Circulating levels of CTRP13 and adiponectin were measured by enzyme-linked immunosorbent assay (ELISA) in T2D patients (n = 40) and in an age and gender-matched control group (n = 40). The anthropometric assessment and biochemical evaluation were done in all subjects. RESULTS: Circulating levels of CTRP13 and adiponectin were significantly lower in T2D patients in comparison with controls ( = 0.025 and p < 0.001, respectively). CTRP13 was inversely correlated with fasting blood sugar (Spearman's  = -0.420, p < 0.001), HbA1C (Spearman's  = -0.554, p < 0.001), and HOMA-IR (Spearman's  = -0.403, p < 0.001). ROC curve analysis showed that CTRP13 might be used as a biomarker for differentiating T2D patients from healthy individuals (area under the curve with 95% confidence intervals = 0.841, 0.752 - 0.929). A CTRP13 level equal to or lower than 0.885 ng/mL was found to be the optimal cutoff (sensitivity = 92.5%, specificity = 70%, Youden Index = 0.625) for differentiating T2D patients from healthy individuals. CONCLUSIONS: It appears that CTRP13 is a novel adipokine associated with T2D in humans as its serum level was significantly lower in T2D patients and also was inversely correlated with insulin resistance and FBS in humans.

The pre-mir-499 Variant rs3746444 May Contribute to Coronary Artery Disease Susceptibility: a Case-Control and Meta-Analysis Study.

BACKGROUND: Recent reports have suggested that single-nucleotide polymorphisms (SNPs) in microRNA genes may contribute to individual susceptibility to coronary artery disease (CAD). The purpose of this study was to evaluate the association between rs3746444 in pre-miR-499 with CAD. METHODS: We performed a case-control study including 288 CAD patients and 150 control subjects. DNA was extracted from blood samples and genotyped through the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Meta-analysis was performed under fixed effect and random effect models whenever appropriate. RESULTS: We found that the GG genotype is significantly more frequent in CAD patients than controls (adjusted p = 0.010; OR = 1.99, 95%; CI: 1.18 - 3.38). Additionally, through a meta-analysis, we showed that miR-499rs3746444 has a significant association with cardiovascular disease. CONCLUSIONS: Our results suggest that miR-499-rs3746444-GG is associated with CAD susceptibility and development.

Association of miR-146a rs2910164 and miR-149 rs2292832 Variants with Susceptibility to Type 2 Diabetes.

BACKGROUND: The deregulation of miRNAs has been implicated in the pathogenesis of type 2 diabetes (T2D). Single nucleotide polymorphisms (SNPs) located within the miRNA sequence could alter miRNA maturation and expression or change the binding affinity of miRNAs to their target mRNAs. In the present study we aimed to elucidate the possible association between the miR-146a rs2910164 and miR-149 rs2292832 variants with the susceptibility to T2D and its related metabolic traits in an Iranian population. METHODS: The study population consisted of 183 type 2 diabetic and 192 non-diabetic subjects. The genotyping of the variants was performed by a PCR-RFLP method. RESULTS: The frequency of the CC genotype of the miR-146a rs2910164 variant was significantly higher in diabetic patients than in controls (15.85% vs. 7.81%, p = 0.043). The results of binary logistic regression suggested that this genotype was significantly associated with T2D (OR of 2.43 (95% CI 1.17 - 5.02, p = 0.016). Moreover, subjects carrying the CC genotype had significantly higher values for diastolic blood pressure, triglycerides, total cholesterol, fasting blood glucose and HbAlc levels compared to individuals having the GG and GC genotypes. Our bioinformatic analyses also showed that the miR-146a sequence is conserved across primate taxa and substituting G to C causes the structural instability of pre-miR-146a by changing the minimum free energy. For the rs2292832 variant, no statistically significant difference was detected for allele or genotype frequencies between T2D and control groups. CONCLUSIONS: Our findings suggest that miR-146a rs2910164 polymorphism might be associated with T2D and its cardiovascular risk factors in an Iranian population.

A Bioinformatics Approach to the Identification of Variants Associated with Type 1 and Type 2 Diabetes Mellitus that Reside in Functionally Validated miRNAs Binding Sites.

The present work is aimed at finding variants associated with Type 1 and Type 2 diabetes mellitus (DM) that reside in functionally validated miRNAs binding sites and that can have a functional role in determining diabetes and related pathologies. Using bioinformatics analyses we obtained a database of validated polymorphic miRNA binding sites which has been intersected with genes related to DM or to variants associated and/or in linkage disequilibrium (LD) with it and is reported in genome-wide association studies (GWAS). The workflow we followed allowed us to find variants associated with DM that also reside in functional miRNA binding sites. These data have been demonstrated to have a functional role by impairing the functions of genes implicated in biological processes linked to DM. In conclusion, our work emphasized the importance of SNPs located in miRNA binding sites. The results discussed in this work may constitute the basis of further works aimed at finding functional candidates and variants affecting protein structure and function, transcription factor binding sites, and non-coding epigenetic variants, contributing to widen the knowledge about the pathogenesis of this important disease.

Bioinformatics prioritization of SNPs perturbing microRNA regulation of hematological malignancy-implicated genes.

The contribution of microRNAs (miRNAs) to cancer has been extensively investigated and it became obvious that a strict regulation of miRNA-mRNA regulatory network is crucial for safeguarding cell health. Apart from the direct impact of miRNA dysregulation in cancer pathogenesis, genetic variations in miRNAs are likely to disrupt miRNA-target interaction. Indeed, many evidences suggested that SNPs within miRNA regulome are associated with the development of different hematological malignancies. However, a full catalog of SNPs within miRNAs target sites of genes relevant to hematopoiesis and hematological malignancies is still lacking. Accordingly, we aimed to systematically identify and characterize such SNPs and provide a prioritized list of most potentially disrupting SNPs. Although in the present study we did not address the functional significance of these potential disturbing variants, we believe that our compiled results will be valuable for researchers interested in determining the role of target-SNPs in the development of hematological malignancies.

Effect of metformin on the long non-coding RNA expression levels in type 2 diabetes: an in vitro and clinical trial study.

BACKGROUND: It has been suggested that the anti-hyperglycemic effect of metformin could be associated with its impact on long non-coding RNA (lncRNA) expression levels. Accordingly, in the current study, we evaluated the effect of metformin on the expression of H19, MEG3, MALAT1, and GAS5 in in vitro and in vivo situations. METHODS: The effect of hyperglycemia and metformin treatment on the lncRNAs expression level was evaluated in HepG2 cells. A total of 179 age- and sex-matched subjects, including 88 newly diagnosed patients with type 2 diabetes (T2D) and 91 healthy volunteers, were included in the case-control phase of the study. Moreover, 40 newly diagnosed patients participated in the study's open-labeled non-controlled clinical trial phase. The expression levels of lncRNA in HepG2 cells and whole blood samples were determined using QRT-PCR. RESULTS: In vitro results showed that hyperglycemia induced H19 and MALAT1 and decreased GAS5 expression levels. Moreover, metformin decreased H19 and increased GAS5 expression in high glucose-treated cells. Case-control study findings revealed that the circulating levels of H19, MALAT1, and MEG3 were significantly elevated in T2D patients compared to the control subjects. Finally, results showed that the level of circulating H19 levels decreased while GAS5 increased in T2D patients after taking metformin for 2 months. CONCLUSION: The results of the current study provided evidence that metformin could exert its effect in the treatment of T2D by altering the expression levels of H19 and GAS5.

Circulating Levels of HOTAIR- lncRNA Are Associated with Disease Progression and Clinical Parameters in Type 2 Diabetes Patients.

Background: Recent studies have implicated dysregulated long non-coding RNA (lncRNA) levels in the pathogenesis of type 2 diabetes (T2D). This study aimed to assess the expression of circulating HOTAIR and uc.48+, examining their correlation with clinical and biochemical variables in T2D patients, pre-diabetic individuals, and healthy controls. Methods: Peripheral blood levels of lncRNAs were quantified using QRT-PCR in 65 T2D patients, 63 pre-diabetic individuals, and 63 healthy subjects. Pathway enrichment analysis was conducted to explore the functional enrichment of lncRNA-miRNA targets. Results: Analysis revealed a significantly elevated circulating level of HOTAIR in both T2D (P < 0.0001) and pre-diabetic patients (P = 0.04) compared to controls. ROC analysis demonstrated that, at a cutoff value of 9.1, with a sensitivity of 80% and specificity of 62%, HOTAIR could distinguish T2D patients from controls (AUC = 0.723, 95% CI 0.637-0.799, P < 0.0001). Spearman correlation analysis identified a significant positive correlation between HOTAIR expression, HbA1c, and insulin resistance (P < 0.005). MiRNA enrichment analysis indicated significant enrichment of diabetes-related pathways among HOTAIR's miRNA targets. Conversely, no significant difference in uc.48+ circulating levels between groups was observed, but a significant positive correlation emerged between uc.48+ and systolic blood pressure. Conclusions: This study provides evidence that elevated HOTAIR expression levels are associated with T2D progression, suggesting their potential as biomarkers for early diagnosis and prognosis.

Multi-Drug Resistance against Second-Line Medication and MicroRNA Plasma Level in Metastatic Breast Cancer Patients.

Background: Circulating microRNAs (miRNAs) can help to predict the chemotherapy response in breast cancer with promising results. The aim of the present study was to investigate the relationships between the miR-199a, miR-663a, and miR-663b expression and chemotherapy response in metastatic breast cancer patients. Methods: This study is a case-control study performed at Yasuj University of Medical Sciences (2018-2021). The expression levels of miR-663a, miR-663b, and miR-199a in the serum of 25 patients with metastatic breast cancer versus 15 healthy individuals were determined by the real-time polymerase chain reaction method. The response to treatment was followed up in a 24-month period. All patients were treated with second-line medications. Two or more combinations of these drugs were used: gemcitabine, Navelbine®, Diphereline®, Xeloda®, letrozole, Aromasin®, and Zolena®. Statistical analyses were performed in SPSS 21.0 and GraphPad Prism 6 software. The expression levels were presented as mean±SD and analyzed by Student's t test. Results: The results and clinicopathological features of patients were analyzed by t test. The statistical analysis showed that miR-663a expression was related to human epidermal growth factor receptor 2 (HER2) status and was significantly lower in the HER2+ than HER2- group (P=0.027). Moreover, the expression of miR-199a and miR-663b was significantly correlated with the response to treatment, in which the expression of miR-199a was higher in the poor-response group (P=0.049), while the higher expression of miR-663b was seen in the good-response group (P=0.009). Conclusion: These findings state that the high plasma level of miR-199a and the low plasma level of miR-663b may be related to chemoresistance in patients with metastatic breast cancer.

Chlorella vulgaris is an effective supplement in counteracting non-alcoholic fatty liver disease-related complications through modulation of dyslipidemia, insulin resistance, and inflammatory pathways.

This study was aimed to investigate the effect of microalgae Chlorella vulgaris (C. vulgaris) on nonalcoholic fatty liver disease (NAFLD)-related complications induced by high-fat diet (HFD). Fifty adult male rats were divided into six groups. Control group and HFD group treated with or without C. vulgaris 5% and 10%. Biochemical parameters in serum were measured by spectrophotometric and enzyme-linked immunosorbent assay (ELISA) methods. The relative gene expression levels of Tumor Necrosis Factor-alpha (TNF-α), NF-kappa B (NF-ƙB), and p38 Mitogen-Activated Protein Kinases (p38 MAPK) in the liver were assessed by using quantitative real-time PCR, while the protein levels of NF-ƙB and TNF-α in the liver homogenate were determined by ELISA. The effects of HFD significantly were reversed by C. vulgaris, especially at a 10% dose. Therefore, it can be concluded that C. vulgaris therapeutically could be useful to improve NAFLD and its complications. PRACTICAL APPLICATIONS: It is established that NAFLD is associated with the resistance to insulin, dyslipidemia, and inflammation. Accordingly, modulating of these conditions may be useful in the management of NAFLD. Our results showed the effectiveness of C. vulgaris against NAFLD-related complication through the alleviating insulin resistance, dyslipidemia and also down-regulation of inflammatory genes in p38 MAPK/TNF-α/NF-ƙB pathway. The results of our study may be useful for scientist to prepare an effective supplement from C. vulgaris to overcoming NAFLD-related complications.

Genotype-phenotype associations in hereditary spastic paraplegia: a systematic review and meta-analysis on 13,570 patients.

AIMS: The hereditary spastic paraplegias (HSPs) are a heterogeneous group of inherited neurodegenerative disorders. Although, several genotype-phenotype studies have carried out on HSPs, the association between genotypes and clinical phenotypes remain incomplete since most studies are small in size or restricted to a few genes. Accordingly, this study provides the systematic meta-analysis of genotype-phenotype associations in HSP. METHODS AND RESULTS: We retrieved literature on genotype-phenotype associations in patients with HSP and mutated SPAST, REEP1, ATL1, SPG11, SPG15, SPG7, SPG35, SPG54, SPG5. In total, 147 studies with 13,570 HSP patients were included in our meta-analysis. The frequency of mutations in SPAST (25%) was higher than REEP1 (3%), as well as ATL1 (5%) in AD-HSP patients. As for AR-HSP patients, the rates of mutations in SPG11 (18%), SPG15 (7%) and SPG7 (13%) were higher than SPG5 (5%), as well as SPG35 (8%) and SPG54 (7%). The mean age of AD-HSP onset for ATL1 mutation-positive patients was earlier than patients with SPAST, REEP1 mutations. Also, the tendency toward younger age at AR-HSP onset for SPG35 was higher than other mutated genes. It is noteworthy that the mean age at HSP onset ranged from infancy to adulthood. As for the gender distribution, the male proportion in SPG7-HSP (90%) and REEP1-HSP (78%) was markedly high. The frequency of symptoms was varied among patients with different mutated genes. The rates of LL weakness, superficial sensory abnormalities, neuropathy, and deep sensory impairment were noticeably high in REEP1 mutations carriers. Also, in AR-HSP patients with SPG11 mutations, the presentation of symptoms including pes cavus, Neuropathy, and UL spasticity was higher. CONCLUSION: Our comprehensive genotype-phenotype assessment of available data displays that the mean age at disease onset and particular sub-phenotypes are associated with specific mutated genes which might be beneficial for a diagnostic procedure and differentiation of the specific mutated genes phenotype among diverse forms of HSP.