LAL deficiency

Lysosomal acid lipase (LAL) is a key enzyme in the metabolic pathway of neutral lipids, whose deficiency (LAL-D) induces the differentiation of myeloid lineage cells into myeloid-derived suppressor cells (MDSCs), which promotes tumor growth and metastasis. This protocol provides detailed procedures for assessment of various LAL biochemical and physiological activities in Ly6G+ and CD11c+ MDSCs, including isolation of Ly6G+ and CD11c+ cells from the bone marrow and blood of mice, assays of LAL-D-induced cellular metabolic and mitochondrial activities, assessment of LAL-D-induced pathogenic immunosuppressive activity and tumor stimulatory activity...

In the last sixty years, there has been an alarming decline in food quality and a decrease in a wide variety of nutritionally essential minerals and nutraceutical compounds in imperative fruits, vegetables, and food crops. The potential causes behind the decline in the nutritional quality of foods have been identified worldwide as chaotic mineral nutrient application, the preference for less nutritious cultivars/crops, the use of high-yielding varieties, and agronomic issues associated with a shift from natural farming to chemical farming...

OBJECTIVES: The study aimed to describe the clinical course, outcomes, and analyze genotype-phenotype correlation in patients with tight junction protein 2 (TJP2) deficiency. METHODS: Data from all children with chronic cholestasis and either homozygous or compound heterozygous mutations in TJP2 were extracted and analyzed. The patients were categorized into three genotypes: TJP2-A (missense mutations on both alleles), TJP2-B (missense mutation on one allele and a predicted protein-truncating mutation (PPTM) on the other), and TJP2-C (PPTMs on both alleles)...

The metabolic contribution of the small intestine (SI) is still unclear despite recent studies investigating the involvement of single cells in regional differences. Using untargeted proteomics, we identified regional characteristics of the three intestinal tracts of C57BL/6J mice and found that proteins abundant in the mouse ileum correlated with the high ileal expression of the corresponding genes in humans. In the SI of C57BL/6J mice, we also detected an increasing abundance of lysosomal acid lipase (LAL), which is responsible for degrading triacylglycerols and cholesteryl esters within the lysosome...

BACKGROUND: efficacy of therapeutic cholecalciferol supplementation for severe COVID-19 is sparingly studied. OBJECTIVE: effect of single high-dose cholecalciferol supplementation on sequential organ failure assessment (SOFA) score in moderate-to-severe COVID-19. METHODS: participants with moderate to severe COVID-19 with PaO2/FiO2 ratio < 200 were randomized to 0.6 million IU cholecalciferol oral (intervention) or placebo. OUTCOMES: primary outcome was change in Day 7 SOFA score and pre-specified secondary outcomes were SOFA and 28-day all-cause mortality...

Myelin antigen-reactive Th1 and Th17 cells are critical drivers of central nervous system (CNS) autoimmune inflammation. Transcription factors T-bet and RORγt play a crucial role in the differentiation and function of Th1 and Th17 cells, and impart them a pathogenic role in CNS autoimmune inflammation. Mice deficient in these two factors do not develop experimental autoimmune encephalomyelitis (EAE). While T-bet and RORγt are known to regulate the expression of several cell adhesion and migratory molecules in T cells, their role in supporting Th1 and Th17 trafficking to the CNS is not completely understood...

OBJECTIVE: Lysosomal acid lipase (LAL) is the only enzyme known to hydrolyze cholesteryl esters (CE) and triacylglycerols in lysosomes at an acidic pH. Despite the importance of lysosomal hydrolysis in skeletal muscle (SM), research in this area is limited. We hypothesized that LAL may play an important role in SM development, function, and metabolism as a result of lipid and/or carbohydrate metabolism disruptions. RESULTS: Mice with systemic LAL deficiency (Lal-/-) had markedly lower SM mass, cross-sectional area, and Feret diameter despite unchanged proteolysis or protein synthesis markers in all SM examined...

Sugar beet, a zinc-loving crop, is increasingly limited by zinc deficiency worldwide. Foliar zinc application is an effective and convenient way to supplement zinc fertilizer. However, the regulatory mechanism of foliar zinc spraying on sugar beet leaf photosynthetic characteristics remains unclear. Therefore, we investigated the effects of foliar ZnSO4 ·7H2 O application (0, 0.1%, 0.2%, and 0.4%) on the photosynthetic performance of sugar beet leaves under controlled hydroponic conditions. The results indicated that a foliar spray of 0...

Focal cortical dysplasia type II (FCDII) is the most common cause of drug-resistant focal epilepsy in children. Herein, we performed a deep histopathology-based genotype-phenotype analysis to further elucidate the clinico-pathological and genetic presentation of FCDIIa compared to FCDIIb. Seventeen individuals with histopathologically confirmed diagnosis of FCD ILAE Type II and a pathogenic variant detected in brain derived DNA whole-exome sequencing or mTOR gene panel sequencing were included in this study...

Background: The LIPA gene encodes for lysosomal acid lipase (LAL), which catalyzes the hydrolysis of cholesterol esters and triglycerides. Variations in the LIPA gene impair LAL activity, predisposing patients to a rare metabolic disorder called LAL deficiency (LAL-D). The lack of functioning LAL promotes lipid accumulation and subsequent dyslipidemia, which can increase the likelihood of complications in both infants and adults. Although the worldwide prevalence is 1:500,000 births, the frequency in Mizrahi Jewish populations is projected to be as high as 1 in every 4200 births (Valles-Ayoub et al...

Lysosomal acid lipase deficiency (LAL-D) is underrecognized because it manifests clinically with lipid and lipoprotein values similar to those observed in heterozygous familial hypercholesterolemia (FH). Although LAL-D is uncommon, understanding the differences between the 2 diseases has significant management implications. We present a case of LAL-D that masqueraded as FH. ( Level of Difficulty: Advanced. ).

Herein, we report the accomplishment of Rh2 (II)-catalyzed intramolecular amination of aryl azide-tethered 1,3-dicarbonyls to access privileged heterocyclic scaffolds with exclusive diastereoselectivity under simple reaction conditions. This method also allows an unconventional direct α-amination at electron-deficient C(sp3 )-H bonds of aryl azide-tethered 1,3-diketones to afford fused 2-azatricyclo[4.4.0.02,8 ]decanones and 2,2-disubstituted indolines, which are present in several biologically active alkaloids...

UNLABELLED: DNA-dependent protein kinase (DNA-PK), a driver of the non-homologous end-joining (NHEJ) DNA damage response pathway, plays an instrumental role in repairing double-strand breaks (DSB) induced by DNA-damaging poisons. We evaluate ZL-2201, an orally bioavailable, highly potent, and selective pharmacologic inhibitor of DNA-PK activity, for the treatment of human cancerous malignancies. ZL-2201 demonstrated greater selectivity for DNA-PK and effectively inhibited DNA-PK autophosphorylation in a concentration- and time-dependent manner...

Benign Paroxysmal Positional Vertigo is a peripheral labyrinthine disease and is one of the most common causes of dizziness in the general population. The proposed study was conducted in the Department of Otorhinolaryngology - Head and Neck Surgery at Indira Gandhi Medical College and Hospital, Shimla, Himachal Pradesh for a period of one year. About 44 patients aged between 14 and 60 years who came out positive on Dix Hallpike test and were willing for study were included in case group, whereas 44 patients aged 14-60 years who came out negative on Dix Hallpike test and with no complaint of vertiginous feeling were included in control group...

Lysosomal acid lipase (LAL) is the sole lysosomal enzyme responsible for the degradation of cholesteryl esters and triacylglycerols at acidic pH. Impaired LAL activity leads to LAL deficiency (LAL-D), a severe and fatal disease characterized by ectopic lysosomal lipid accumulation. Reduced LAL activity also contributes to the development and progression of non-alcoholic fatty liver disease (NAFLD). To advance our understanding of LAL-related liver pathologies, we performed comprehensive proteomic profiling of livers from mice with systemic genetic loss of LAL (Lal-/-) and from mice with hepatocyte-specific LAL-D (hepLal-/-)...

BACKGROUND: The LIPA gene on chromosome 10q23.31 contains 10 exons and encodes lipase A, the lysosomal acid lipase (LAL) containing 399 amino acids. Pathogenic variants in the LIPA result in autosomal recessive Wolman disease and cholesteryl ester storage disease (CESD). Here, we report a novel missense variant (NM_001127605.3:c.928T>A, p.Trp310Arg) of LIPA in an Iranian family with fatty liver disease identified by whole-exome sequencing and confirmed by Sanger sequencing. METHODS: A 28-year-old woman referred with lean NASH cirrhosis and extremely high cholesterol levels...

PURPOSE: Glioblastoma (GBM), is the most common brain malignancy with median survival <2 yrs. Standard-of-care temozolomide (TMZ) has marginal efficacy in ~70% of patients due to MGMT expression. LP-184 is an acylfulvene-derived prodrug activated by the oxidoreductase PTGR1 that alkylates at N3-adenine, not repaired by MGMT. This paper examines LP-184 efficacy against preclinical GBM models and identifies molecular predictors of efficacy in clinical GBM. EXPERIMENTAL DESIGN: LP-184 effects on GBM cell viability and DNA damage were determined using cell lines, primary patient-derived cells and neurospheres...

Lysosomal acid lipase (LAL) is a necessary enzyme for the hydrolysis of both triglycerides (TGs) and cholesteryl esters (CEs) in the lysosome. Deficiency of this enzyme encoded by the lipase A (LIPA) gene leads to LAL deficiency (LAL-D). A severe disease subtype of LAL-D is known as Wolman disease (WD), present with diarrhea, hepatosplenomegaly, and adrenal calcification. Untreated patients do not survive more than a year. The aim of this study was to assess the clinical and molecular characterizations of WD patients in Egypt...

UNLABELLED: Peanut is mostly grown in calcareous soils with high pH which are deficient in available iron (Fe2+ ) for plant uptake causing iron deficiency chlorosis (IDC). The most pertinent solution is to identify efficient genotypes showing tolerance to limited Fe availability in the soil. A field screening of 40 advanced breeding lines of peanut using NRCG 7472 and ICGV 86031 as IDC susceptible and tolerant checks, respectively, was envisaged for four years. PBS 22040 and 29,192 exhibited maximum tolerance while PBS 12215 and 12,185 were most susceptible...

BACKGROUND: Parenteral nutrition (PN) deficient in mitochondrial substrates and thiamine may lead to acidosis. This, combined with fatigue seen in patients with intestinal failure (IF), may suggest suboptimal oxidative metabolism. We therefore studied oxygen utilisation in otherwise apparently well-nourished individuals with intestinal failure receiving long term PN. METHODS: This was a retrospective analysis conducted in a tertiary IF institution, from 2010 to 2019, comparing treadmill/bicycle cardiopulmonary exercise test (CPET) derived variables including peak oxygen consumption (VO2 peak ), anaerobic threshold (AT) and ventilatory efficiency (minute ventilation (VE)/CO2 output (VCO2 ) of patients with IF (cases) to those without (controls), matched in a 1:2 ratio for age ( ± 3 years), gender, use of beta-blockers and physiology parameters of p-POSSUM score ( ± 5)...