Quercetin is a naturally existing plant pigment belonging to the flavonoid group; it is contained in a wide range of vegetables and fruits. The accumulated evidence points to the potential uses of ...quercetin in protection of some disease conditions. Lead is one of the highly toxicant heavy metals that are widely spread in the environment and implicated in a wide spectrum of industries. No previous study has been reported to evaluate the effect of quercetin on lead toxicity. Therefore, the present study was conducted to elucidate some aspects of quercetin bioactivities in regard to its ability to combat the oxidative stress induced by lead toxicity. For this purpose, a total of sixty male Wistar rats were randomly and equally divided into three groups of 20 animals each; untreated control animals (group 1), lead-exposed animals (group 2; exposed to lead daily by oral gavage at the dose of 80 mg/Kg b.w.), and group 3 of animals, which were exposed to lead and daily received quercetin (10 h gap time between lead exposure and the receiving of quercetin) by oral gavage at the dose of 350 mg/Kg b.w. The experiment period was 8 weeks. All the assayed hematological and biochemical parameters of animals exposed to lead were significantly altered compared with the untreated control levels. Animals exposed to lead (group 2) exhibited significant decrements of the erythrocytic and total leucocytic counts, hemoglobin concentration, packed cell volume percent, total proteins, albumin and globulin. These animals also disclosed significantly decreased levels of antioxidant markers including total thiols, catalase and glutathione. On the other hand, these animals demonstrated significant increments in the levels of bilirubin, urea, creatinine, BUN, serum enzymes, H
O
and MDA. Animals exposed to lead and given quercetin (group 3) exhibited improvement of these parameters, which were brought back at varying degrees toward the untreated control levels. Basing on the improvements of the assayed hematological and biochemical parameters, it was concluded that quercetin as a dietary supplement can act efficiently as an antioxidant to counteract the oxidative stress induced by lead toxicity and to maintain the oxidant antioxidant balance.
Ciliopathies are clinically diverse disorders of the primary cilium. Remarkable progress has been made in understanding the molecular basis of these genetically heterogeneous conditions; however, our ...knowledge of their morbid genome, pleiotropy, and variable expressivity remains incomplete.
We applied genomic approaches on a large patient cohort of 371 affected individuals from 265 families, with phenotypes that span the entire ciliopathy spectrum. Likely causal mutations in previously described ciliopathy genes were identified in 85% (225/265) of the families, adding 32 novel alleles. Consistent with a fully penetrant model for these genes, we found no significant difference in their "mutation load" beyond the causal variants between our ciliopathy cohort and a control non-ciliopathy cohort. Genomic analysis of our cohort further identified mutations in a novel morbid gene TXNDC15, encoding a thiol isomerase, based on independent loss of function mutations in individuals with a consistent ciliopathy phenotype (Meckel-Gruber syndrome) and a functional effect of its deficiency on ciliary signaling. Our study also highlighted seven novel candidate genes (TRAPPC3, EXOC3L2, FAM98C, C17orf61, LRRCC1, NEK4, and CELSR2) some of which have established links to ciliogenesis. Finally, we show that the morbid genome of ciliopathies encompasses many founder mutations, the combined carrier frequency of which accounts for a high disease burden in the study population.
Our study increases our understanding of the morbid genome of ciliopathies. We also provide the strongest evidence, to date, in support of the classical Mendelian inheritance of Bardet-Biedl syndrome and other ciliopathies.
Pycnodysostosis is characterized by short stature, osteosclerosis, acro-osteolysis, increased tendency of fractures, and distinctive dysmorphic features. It is a rare autosomal recessive disease ...caused by biallelic CTSK mutations. The clinical details of 18 patients from Saudi Arabia were reviewed. Short stature, osteopetrosis, acro-osteolysis, and distinctive facial dysmorphism were documented in all cases. Our results highlight the significant complications associated with this disease. The large anterior fontanelle is one of the cardinal signs of this disease; however, half of our patients had small fontanelles and a quarter had craniosynostosis, which caused optic nerve compression. Sleep apnea was of the major complications in three patients. Bone fracture can be a presenting symptom, and in our patients it mainly occurred after the age of 3 years. Bone marrow suppression was seen in a single patient of our cohort who was misdiagnosed initially with malignant osteopetrosis. In this study, we also describe two novel (c.5G > A p.Trp2Ter, c.538G > A p.Gly180Ser) and two reported (c.244-29 A > G, c.830C > T p.Ala277Val) CTSK mutations. Our results indicate that the recurrent intronic variant, c.244-29 A > G is likely to be a founder mutation, as it was found in 78% (14/18 patients) of our cohort belonging to the same tribe.
Background: The present study was carried out to test the antioxidant activity of lactoferrin as a dietary supplement to alleviate the effects of oxidative stress induced by mercury toxicity. ...Hematological and biochemical assays were employed to evaluate the ameliorating effects of lactoferrin. Methods: Sixty male Wistar rats were allotted randomly and equally into three groups; animals in Group 1 served as untreated control, animals in Group 2 were administered orally with mercuric chloride (HgCl 2 ) at the dose of 6 mg/kg bw/day, and animals in Group 3 were administered with HgCl 2 at the same dose and orally dosed with lactoferrin (400 mg/kg bw/day). Hematological indices (erythrocytic and total leukocytic counts, hemoglobin concentration%, and packed cell volume, (PCV%), and biochemical parameters (serum and homogenates of liver and kidney tissues) were assessed in all animals. Serum and tissue homogenate levels of total thiols, glutathione (GSH), catalase, and total antioxidant capacity (TAC) represented the antioxidant markers. The oxidation markers were represented by H 2 O 2 and malondialdehyde (MDA). Results: Compared to the untreated control group, animals in Group 2 (administered with HgCl 2 ) exhibited significantly increased levels of serum enzymes (alanine transferase (ALT), aspertate transferase (AST), and alkaline phosphatase), urea, blood urea nitrogen, creatinine, H 2 O 2 , and MDA. These animals showed significantly decreased levels of erythrocytic and total leukocytic counts, hemoglobin concentration, PCV%, total proteins, total thiols, GSH, catalase, and TAC. The hematological and biochemical changes were comparatively reversed toward the control levels in animals of Group 3 (administered with HgCl 2 and orally dosed with lactoferrin). The reversed levels of hematological and biochemical parameters were significantly different compared to Group 2. Conclusions: Based on the encountered amelioration of the assayed hematological and biochemical parameters in animals treated with HgCl 2 and given lactoferrin, it could be concluded that lactoferrin as a dietary supplement might function as an efficient antioxidant to alleviate the oxidative stress induced by mercury toxicity.
The cell-traversal protein for ookinetes and sporozoites (CelTOS), expressed on the surface of ookinetes and sporozoitesin 'Plasmodium species', is a promising malaria vaccine candidate. CelTOS is ...essential for parasite invasion into mosquito midgut and human hepatocytes, thereby contributing to malaria transmission and disease pathogenesis. This study explores the genetic diversity, polymorphisms, haplotypes, natural selection, phylogenetic analysis, and epitope prediction in the full-length 'Plasmodium knowlesi CelTOS' gene in clinical samples from Sarawak, Malaysian Borneo, and long-term laboratory strains from Peninsular Malaysia and the Philippines. Our analysis revealed a high level of genetic variation in the 'PkCelTOS' gene, with a nucleotide diversity of pi ~ 0.021, which was skewed towards the 3' end of the gene. This level of diversity is double that observed in PfCelTOS and 20 times that observed in PvCelTOS from worldwide clinical samples. Tests of natural selection revealed evidence for positive selection within clinical samples. Phylogenetic analysis of the amino acid sequence of 'PkCelTOS' revealed the presence of two distinct groups, although no geographical clustering was observed. Epitope prediction analysis identified two potential epitopes (96AQLKATA102 and 124TIKPPRIKED133) using the IEDB server and one epitope (125IKPPRIKED133) by Bcepred server on the C' terminal region of 'PkCelTOS' protein. Both the servers predicted a common epitope region of nine amino acid length (IKPPRIKED) peptide, which can be studied in the future as a potential candidate for vaccine development. These findings shed light on the genetic diversity, polymorphism, haplotypes, and natural selection within 'PkCelTOS' in clinical samples and provide insights about its future prospects as a potential candidate for 'P. knowlesi' malaria vaccine development.
Autistic Spectrum Disorder (ASD) is a complex neurodevelopmental brain disorder characterized by two core behavioral symptoms, namely impairments in social communication and restricted/repetitive ...behavior. The molecular mechanisms underlying ASD are not well understood. Recent genetic as well as non-genetic animal models contributed significantly in understanding the pathophysiology of ASD, as they establish autism-like behavior in mice and rats. Among the genetic causes, several chromosomal mutations including duplications or deletions could be possible causative factors of ASD. In addition, the biochemical basis suggests that several brain neurotransmitters, e.g., dopamine (DA), serotonin (5-HT), gamma-amino butyric acid (GABA), acetylcholine (ACh), glutamate (Glu) and histamine (HA) participate in the onset and progression of ASD. Despite of convincible understanding, risperidone and aripiprazole are the only two drugs available clinically for improving behavioral symptoms of ASD following approval by Food and Drug Administration (FDA). Till date, up to our knowledge there is no other drug approved for clinical usage specifically for ASD symptoms. However, many novel drug candidates and classes of compounds are underway for ASD at different phases of preclinical and clinical drug development. In this review, the diversity of numerous aetiological factors and the alterations in variety of neurotransmitter generation, release and function linked to ASD are discussed with focus on drugs currently used to manage neuropsychiatric symptoms related to ASD. The review also highlights the clinical development of drugs with emphasis on their pharmacological targets aiming at improving core symptoms in ASD.
Molecular and clinical spectra of FBXL4 deficiency El‐Hattab, Ayman W.; Dai, Hongzheng; Almannai, Mohammed ...
Human mutation,
December 2017, 2017-12-00, 20171201, Letnik:
38, Številka:
12
Journal Article
Recenzirano
Odprti dostop
F‐box and leucine‐rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function is not yet known. However, cellular studies have suggested that it plays significant roles in ...mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics. Biallelic pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect syndrome that is a multisystem disease characterized by lactic acidemia, developmental delay, and hypotonia. Other features are feeding difficulties, growth failure, microcephaly, hyperammonemia, seizures, hypertrophic cardiomyopathy, elevated liver transaminases, recurrent infections, variable distinctive facial features, white matter abnormalities and cerebral atrophy found in neuroimaging, combined deficiencies of multiple electron transport complexes, and mtDNA depletion. Since its initial description in 2013, 36 different pathogenic variants in FBXL4 were reported in 50 affected individuals. In this report, we present 37 additional affected individuals and 11 previously unreported pathogenic variants. We summarize the clinical features of all 87 individuals with FBXL4‐related mtDNA maintenance defect, review FBXL4 structure and function, map the 47 pathogenic variants onto the gene structure to assess the variants distribution, and investigate the genotype–phenotype correlation. Finally, we provide future directions to understand the disease mechanism and identify treatment strategies.
FBXL4 is a mitochondrial protein playing roles in mitochondrial bioenergetics and mtDNA maintenance. Pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect characterized by lactic acidemia, developmental delay, and hypotonia. Since its initial description, 36 different pathogenic variants in FBXL4 were reported in 50 individuals. Herein, we present 37 additional affected individuals and 11 previously unreported pathogenic variants. We summarize the clinical features of all 87 affected individuals and discuss the 47 FBXL4 pathogenic variants.
Ehlers–Danlos syndrome (EDS) describes a group of clinical entities in which the connective tissue, primarily that of the skin, joint and vessels, is abnormal, although the resulting clinical ...manifestations can vary widely between the different historical subtypes. Many cases of hereditary disorders of connective tissue that do not seem to fit these historical subtypes exist. The aim of this study is to describe a large series of patients with inherited connective tissue disorders evaluated by our clinical genetics service and for whom a likely causal variant was identified. In addition to clinical phenotyping, patients underwent various genetic tests including molecular karyotyping, candidate gene analysis, autozygome analysis, and whole-exome and whole-genome sequencing as appropriate. We describe a cohort of 69 individuals representing 40 families, all referred because of suspicion of an inherited connective tissue disorder by their primary physician. Molecular lesions included variants in the previously published disease genes
B3GALT6
,
GORAB
,
ZNF469
,
B3GAT3
,
ALDH18A1
,
FKBP14
,
PYCR1
,
CHST14
and
SPARC
with interesting variations on the published clinical phenotypes. We also describe the first recessive EDS-like condition to be caused by a recessive
COL1A1
variant. In addition, exome capture in a familial case identified a homozygous truncating variant in a novel and compelling candidate gene,
AEBP1
. Finally, we also describe a distinct novel clinical syndrome of cutis laxa and marked facial features and propose
ATP6V1E1
and
ATP6V0D2
(two subunits of vacuolar ATPase) as likely candidate genes based on whole-genome and whole-exome sequencing of the two families with this new clinical entity. Our study expands the clinical spectrum of hereditary disorders of connective tissue and adds three novel candidate genes including two that are associated with a highly distinct syndrome.
The liquid whey is a byproduct produced during cheese making. Cadmium is a highly hazardous heavy metal with cumulative toxic effects. The present research work was done to clarify the possible role ...of whey proteins in alleviating cadmium-induced oxidative stress. The used rats were allotted equally and randomly into three experimental groups; untreated control, cadmium-exposed, and cadmium-exposed and whey protein-administered groups. The biochemical and haematological assays of rats exposed to cadmium (group 2) manifested significant alterations compared to those of untreated control animals. Concerning the biochemical serum profile, group 3 animals showed relatively increased levels of total proteins, significant increments of total thiols, glutathione, total antioxidant capacity (TAC), and catalase, and significant decrements in the levels of blood cadmium, alanine transferase (ALT), aspartate transferase (AST), alkaline phosphatase (ALP), creatinine, urea, bilirubin, hydrogen peroxide (H2O2), and malondialdehyde (MDA) compared to the animals exposed to cadmium (group 2). Homogenates of liver and kidney tissues obtained from group 3 animals demonstrated similar results to that revealed by the serum assay. It was concluded that whey proteins as a dietary supplement can offer potential antioxidant properties that enable these supplementary proteins to alleviate cadmium-induced oxidative stress.
In this study, nitrogen-nitrogen bonds containing compounds such as hydrazine derivatives are examined. There are relatively few hydrazine molecules in nature, but some have been isolated from ...plants, marine organisms and microorganisms. Thus, hydrazine molecules are widely used in the manufacture of synthetic catalysts, agriculture chemicals, pesticides, and also cause irreversible pollution to air, water, and soil. Hydrazine compounds were evaluated via larvicidal profile in a stagnant water system. According to the above observation, new 1H-pyrazolo3,4-bpyridin-3(2H)-one derivatives can be synthesized via catalyst free green chemistry approach.A range of FT-IR spectroscopic measures, 1H and 13C NMR, as well as mass spectra, were used to characterize the compounds (2a-e). The compound 2e was more potent (95,6% mortality, LD50: 20.1 µg/ mL) against Culex quinquefasciatus than natural pyrazolidine derivatives. Therefore, the objective of this study, prospered with a few of the pyrzolopyridine hydrazine models, which are demonstrated to be low toxic environmentally safe and high potential larvicidal profile.
PDF
![Pyrazolo[3,4-b]pyridin-3(2H...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1018-3647/small "Pyrazolo[3,4-b]pyridin-3(2H)-one derivatives: Synthesis and their investigation of mosquito larvicidal activity")