A CASE REPORT ON WILSON’S DISEASE: A RARE CLINICAL CONDITION OF COPPER DEPOSITION IN LIVER

Wilson’s disease is a rare inherited disorder and is characterized by the accumulation of copper in various tissues and also in organs like the liver, brain, kidneys and cornea. Symptoms in paediatrics characteristically appear with hepatic involvement. In this case we have discussed about an eleven-year-old male child, who was presented to the Paediatric department in a tertiary care hospital with chief complaints of yellowish discoloration of eyes, dark coloured urine and high grade fever. Due to the accumulation of copper there were decreased levels of ceruloplasmin and there was an increased 24 hour urinary copper, which confirms the Wilson’s disease in this child. Child was treated with Cephalosporin antibiotics, vitamins, laxative, and bile acid sequestrants. Child showed gradual improvement in clinical symptoms and got discharged without any further event. Quality of evidence was assessed according to the GRADE system. Early diagnosis and management helped to prevent serious complications

Effect of essentiale in diabetic subjects with non-alcoholic fatty liver

Nonalcoholic fatty liver (NAFL) has been reported to be common among subjects with diabetes. However, there are not much therapeutic options for NAFL. In this open labeled clinical trial we studied the effect of Essentiale in diabetic subjects with NAFL. Twenty-eight type 2 diabetic patients attending the out-patient division of M.V. Diabetes Specialities Centre, Chennai and satisfying the inclusion criteria were recruited for the study. High resolution B mode ultrasonography was carried out for diagnosis of NAFL. Liver function markers [Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) and Gamma Glutamyl transferase (GGT)] were measured. 22 out of the 28 patients (78.5%) were available for follow up. The mean age of the study subjects was 41±8 years and 50% were males. A significant reduction in all the liver enzymes were observed after Essentiale treatment (baseline vs. six months after treatment: ALT: 54.5± 29.6 IU/L vs. 37.1±18.7 IU/L, p< 0.05, AST: 38.0±18.0 IU/L vs. 27.6±12.4 IU/L, p< 0.05, GGT: 38.7±27.5 IU/L vs. 29.6±13.8 IU/L, p< 0.05). Ultrasound studies revealed that the hepatic echotexture improved after Essentiale treatment in 12/22 (54.5%) of the study subjects, while there was no change in 9/22 (40.9%), and it worsened in only one patient (4.5%). The study results suggest that Essentiale protects and improves liver function in diabetic subjects with NAFL. Prospective, blinded clinical trials are required to confirm these findings

Nrf2 depletion in the context of loss-of-function Keap1 leads to mitolysosome accumulation

Transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) is the principal determinant of the cellular redox homeostasis, contributing to mitochondrial function, integrity and bioenergetics. The main negative regulator of Nrf2 is Kelch-like ECH associated protein 1 (Keap1), a substrate adaptor for Cul3/Rbx1 ubiquitin ligase, which continuously targets Nrf2 for ubiquitination and proteasomal degradation. Loss-of-function mutations in Keap1 occur frequently in lung cancer, leading to constitutive Nrf2 activation. We used the human lung cancer cell line A549 and its CRISPR/Cas9-generated homozygous Nrf2-knockout (Nrf2-KO) counterpart to assess the role of Nrf2 on mitochondrial health. To confirm that the observed effects of Nrf2 deficiency are not due to clonal selection or long-term adaptation to the absence of Nrf2, we also depleted Nrf2 by siRNA (siNFE2L2), thus creating populations of Nrf2-knockdown (Nrf2-KD) A549 cells. Nrf2 deficiency decreased mitochondrial respiration, but increased the mitochondrial membrane potential, mass, DNA content, and the number of mitolysosomes. The proportion of ATG7 and ATG3 within their respective LC3B conjugates was increased in Nrf2-deficient cells with mutant Keap1, whereas the formation of new autophagosomes was not affected. Thus, in lung cancer cells with loss-of-function Keap1, Nrf2 facilitates mitolysosome degradation thereby ensuring timely clearance of damaged mitochondria

Transcription factors NRF2 and HSF1 have opposing functions in autophagy

Abstract Autophagy plays a critical role in the maintenance of cellular homeostasis by degrading proteins, lipids and organelles. Autophagy is activated in response to stress, but its regulation in the context of other stress response pathways, such as those mediated by heat shock factor 1 (HSF1) and nuclear factor-erythroid 2 p45-related factor 2 (NRF2), is not well understood. We found that the Michael acceptor bis(2-hydoxybenzylidene)acetone (HBB2), a dual activator of NRF2 and HSF1, protects against the development of UV irradiation-mediated cutaneous squamous cell carcinoma in mice. We further show that HBB2 is an inducer of autophagy. In cells, HBB2 increases the levels of the autophagy-cargo protein p62/sequestosome 1, and the lipidated form of microtubule-associated protein light chain 3 isoform B. Activation of autophagy by HBB2 is impaired in NRF2-deficient cells, which have reduced autophagic flux and low basal and induced levels of p62. Conversely, HSF1-deficient cells have increased autophagic flux under both basal as well as HBB2-induced conditions, accompanied by increased p62 levels. Our findings suggest that NRF2 and HSF1 have opposing roles during autophagy, and illustrate the existence of tight mechanistic links between the cellular stress responses

Microevolution of Serial Clinical Isolates of Cryptococcus neoformans var. grubii and C. gattii

We thank the Broad Institute Sequencing Platform for generating the Illumina sequences. We thank Chen-Hsin Yu for helping on the data processing of the phenotypic tests. We acknowledge the South African National Institute for Communicable Diseases’ GERMS-SA surveillance network through which these isolates were originally collected. This project has been funded in whole or in part by the following U.S. Health and Human Services grants from the National Institute of Allergy and Infectious Diseases: U19 AI110818 (Broad Institute), R01 AI93257 (J.R.P.), R01 AI73896 (J.R.P.), and R01 AI025783 (T.G.M.). R.A.F. was supported by the Wellcome Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The content is solely our responsibility and does not necessarily represent the official views of the funders. The use of product names in this manuscript does not imply their endorsement by the U.S. Department of Health and Human Services. The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the CDC.Peer reviewedPublisher PD

KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients

The activity of the transcription factor nuclear factor-erythroid 2 p45-derived factor 2 (NRF2) is orchestrated and amplified through enhanced transcription of antioxidant and antiinflammatory target genes. The present study has characterized a triazole-containing inducer of NRF2 and elucidated the mechanism by which this molecule activates NRF2 signaling. In a highly selective manner, the compound covalently modifies a critical stress-sensor cysteine (C151) of the E3 ligase substrate adaptor protein Kelch-like ECH-associated protein 1 (KEAP1), the primary negative regulator of NRF2. We further used this inducer to probe the functional consequences of selective activation of NRF2 signaling in Huntington's disease (HD) mouse and human model systems. Surprisingly, we discovered a muted NRF2 activation response in human HD neural stem cells, which was restored by genetic correction of the disease-causing mutation. In contrast, selective activation of NRF2 signaling potently repressed the release of the proinflammatory cytokine IL-6 in primary mouse HD and WT microglia and astrocytes. Moreover, in primary monocytes from HD patients and healthy subjects, NRF2 induction repressed expression of the proinflammatory cytokines IL-1, IL-6, IL-8, and TNFα. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology

Evolution of pathogenicity and sexual reproduction in eight Candida genomes

Candida species are the most common cause of opportunistic fungal infection worldwide. Here we report the genome sequences of six Candida species and compare these and related pathogens and non-pathogens. There are significant expansions of cell wall, secreted and transporter gene families in pathogenic species, suggesting adaptations associated with virulence. Large genomic tracts are homozygous in three diploid species, possibly resulting from recent recombination events. Surprisingly, key components of the mating and meiosis pathways are missing from several species. These include major differences at the mating-type loci (MTL); Lodderomyces elongisporus lacks MTL, and components of the a1/2 cell identity determinant were lost in other species, raising questions about how mating and cell types are controlled. Analysis of the CUG leucine-to-serine genetic-code change reveals that 99% of ancestral CUG codons were erased and new ones arose elsewhere. Lastly, we revise the Candida albicans gene catalogue, identifying many new genes.publishe

Tracing Genetic Exchange and Biogeography of Cryptococcus neoformans var. grubii at the Global Population Level

Cryptococcus neoformans var. grubii is the causative agent of cryptococcal meningitis, a significant source of mortality in immunocompromised individuals, typically human immunodeficiency virus/AIDS patients from developing countries. Despite the worldwide emergence of this ubiquitous infection, little is known about the global molecular epidemiology of this fungal pathogen. Here we sequence the genomes of 188 diverse isolates and characterize the major subdivisions, their relative diversity, and the level of genetic exchange between them. While most isolates of C. neoformans var. grubii belong to one of three major lineages (VNI, VNII, and VNB), some haploid isolates show hybrid ancestry including some that appear to have recently interbred, based on the detection of large blocks of each ancestry across each chromosome. Many isolates display evidence of aneuploidy, which was detected for all chromosomes. In diploid isolates of C. neoformans var. grubii (serotype AA) and of hybrids with C. neoformans var. neoformans (serotype AD) such aneuploidies have resulted in loss of heterozygosity, where a chromosomal region is represented by the genotype of only one parental isolate. Phylogenetic and population genomic analyses of isolates from Brazil reveal that the previously “African” VNB lineage occurs naturally in the South American environment. This suggests migration of the VNB lineage between Africa and South America prior to its diversification, supported by finding ancestral recombination events between isolates from different lineages and regions. The results provide evidence of substantial population structure, with all lineages showing multi-continental distributions; demonstrating the highly dispersive nature of this pathogen