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The neuronal ceroid lipofuscinoses (NCLs) are a group of childhood-onset neurodegenerative lysosomal storage disorders mainly affecting the brain and the retina. In the NCLs, disease-causing mutations in 13 different ceroid lipofuscinoses genes (CLN) have been identified. The clinical symptoms include seizures, progressive neurological decline, deterioration of motor and language skills, and dementia resulting in premature death. In addition, the deterioration and loss of vision caused by progressive retinal degeneration is another major hallmark of NCLs. To date, there is no curative therapy for the treatment of retinal degeneration and vision loss in patients with NCL. In this review, the key findings of different experimental approaches in NCL animal models aimed at attenuating progressive retinal degeneration and the decline in retinal function are discussed. Different approaches, including experimental enzyme replacement therapy, gene therapy, cell-based therapy, and immunomodulation therapy were evaluated and showed encouraging therapeutic benefits. Recent experimental ocular gene therapies in NCL animal models with soluble lysosomal enzyme deficiencies and transmembrane protein deficiencies have shown the strong potential of gene-based approaches to treat retinal dystrophies in NCLs. In CLN3 and CLN6 mouse models, an adeno-associated virus (AAV) vector-mediated delivery of Show less

Sickle cell disease (SCD) is a well-studied monogenetic disease with an established chronic inflammatory component. The paradigm shift towards inflammation has made the pathophysiology of SCD even more complex. Studies have shown that an imbalance between the pro-inflammatory and anti-inflammatory cytokines in SCD exists; however, the reports are skewed toward the pro-inflammatory mediators. We enumerate recent in vitro and in vivo studies on anti-inflammatory cytokines in SCD patients, and discuss the biology of anti-inflammatory cytokines including the already reported IL-2, TGF-β, and IL-10 as well as the recently discovered IL-27, IL-35 and IL-37. This review will improve the understanding of the pathophysiology of SCD and aid in the search of new therapeutic options for patients with SCD. Show less

STAT3 is a transcription factor which is activated via various signaling transduction pathways or Epstein-Barr virus (EBV) infection and plays an oncogenic role in lymphoid malignancies including Hodgkin lymphoma (HL). The tumor cells of HL are derived from germinal center B-cells and transformed by chromosomal rearrangements, aberrant signal transduction, deregulation of developmental transcription factors, and EBV activity. HL cell lines represent useful models to investigate molecular principles and deduced treatment options of this malignancy. Using cell line L-540, we have recently shown that constitutively activated STAT3 drives aberrant expression of hematopoietic NKL homeobox gene HLX. Here, we analyzed HL cell line AM-HLH which is EBV-positive but, nevertheless, HLX-negative. Consistently, AM-HLH expressed decreased levels of STAT3 proteins which were additionally inactivated and located in the cytoplasm. Combined genomic and expression profiling data revealed several amplified and overexpressed gene candidates involved in opposed regulation of STAT3 and EBV. Corresponding knockdown studies demonstrated that IRF4 and NFATC2 inhibited STAT3 expression. MIR155 (activated by STAT3) and SPIB (repressed by HLX) showed reduced and elevated expression levels in AM-HLH, respectively. However, treatment with IL6 or IL27 activated STAT3, elevated expression of HLX and MIR155, and inhibited IRF4. Taken together, this cell line deals with two conflicting oncogenic drivers, namely, JAK2-STAT3 signaling and EBV infection, but is sensitive to switch after cytokine stimulation. Thus, AM-HLH represents a unique cell line model to study the pathogenic roles of STAT3 and EBV and their therapeutic implications in HL. Show less

Hyperlipidemia is one of the key risk factors causing many chronic diseases, and lowering blood lipid levels can prevent many diseases. In this paper, a hyperlipidemic cell model of oleic acid (OA) induced hepatocellular carcinoma cells (HepG2) was established using polyphenols extracted from Shanxi-aged vinegar (SAVEP). The effects of SAVEP on nuclear damage, mitochondrial membrane potential, apoptosis, cellular lipid deposition, and lipid metabolism protein expression in HepG2 hyperlipidemic cells were examined to investigate the lipid-lowering mechanism of SAVEP at the cellular level. The results showed that SAVEP could reduce the content of TC/TG index, repair the nuclear damage, reduce lipid accumulation and finally decrease the rate of apoptosis by up-regulating the expression of key proteins such as PPARα, LXRα, and ABCA1 in the process of lipid metabolism. PRACTICAL APPLICATIONS: In this thesis, the hypolipidemic activity of polyphenol extracts from Shanxi-aged vinegar was analyzed on the level of HepG2 cells. The hypolipidemic mechanism of oxidative stress, lipid metabolism and inflammatory stress was also elucidated. It provided a theoretical basis for the in-depth understanding of the hypolipidemic health effects of Shanxi-aged vinegar. Show less

Adiponectin is a potent vascular protective molecule. Recent findings have suggested adiponectin resistance during early diabetes. However, the molecular mechanisms responsible remain unidentified. Here, we took an unbiased approach to identify whether hyperlipidemic plasma molecules exist that bind and inhibit adiponectin function, contributing to adiponectin resistance and diabetic vascular injury. Adult rats were randomly assigned to receive either a normal or a high-fat diet for 8 weeks. Plasma was co-immunoprecipitated with anti-APN antibody and analyzed by mass spectrometry. The APN binding molecules and their effect upon APN biological activity were determined. As expected, the high-fat-diet increased plasma triglyceride, total cholesterol, and low-density lipoprotein. Importantly, the circulating APN level was significantly increased at this time point. Mass spectrometry identified 18 proteins with increased APN binding in hyperlipidemic plasma, among which four proteins critical in lipid metabolism, including apolipoprotein A1 (APOA1), APOA4, APOC1, and paraoxonase 1, were further investigated. Incubating recombinant APN with APOA1 markedly (P < 0.01), and incubating with APOC1 significantly (P < 0.05), inhibited APN activity as evidenced by the reduced AMPK activation in HUVECs. APOA4 and paraoxonase 1 incubation had no effect upon APN activity. Finally, plasma APOA1 was significantly increased (P < 0.05) in hyperlipidemic plasma compared with the control plasma. It was demonstrated for the first time that increased APOA1 and APOC1 in hyperlipidemic plasma binds and inhibits APN activity. This result not only identifies a novel molecular mechanism responsible for adiponectin resistance during early stage diabetes, but also provides additional new insight into the diverse/controversial (protective and harmful) functions of high-density lipoprotein. Show less

Grey matter (GM) atrophy due to neuronal loss is a striking feature of patients with CLN3 disease. A precise and quantitative description of disease progression is needed in order to establish an evaluation tool for current and future experimental treatments. In order to develop a quantitative marker to measure brain volume outcome, we analysed the longitudinal volumetric development of GM, white matter (WM) and lateral ventricles and correlated those with the clinical course. One hundred twenty-two MRI scans of 35 patients (21 females; 14 males; age 15.3 ± 4.8 years) with genetically confirmed CLN3 disease were performed. A three-dimensional T1-weighted sequence was acquired with whole brain coverage. Volumetric segmentation of the brain was performed with the FreeSurfer image analysis suite. The clinical severity was assessed by the Hamburg jNCL score, a disease-specific scoring system. The volumes of supratentorial cortical GM and supratentorial WM, cerebellar GM, basal ganglia/thalamus and hippocampus significantly (r =  - 0.86 to - 0.69, p < 0.0001) decreased with age, while the lateral ventricle volume increased (r = 0.68, p < 0.0001). Supratentorial WM volume correlated poorer with age (r =  - 0.56, p = 0.0001). Supratentorial cortical GM volume showed the steepest (4.6% (± 0.2%)) and most uniform decrease with strongest correlation with age (r =  - 0.86, p < 0.0001). In addition, a strong correlation with disease specific clinical scoring existed for the supratentorial cortical GM volume (r = 0.85, p =  < 0.0001). Supratentorial cortical GM volume is a sensitive parameter for assessment of disease progression even in early and late disease stages and represents a potential reliable outcome measure for evaluation of experimental therapies. Show less

(1) Background: Existing lipid-lowering therapies have difficulty in achieving lipid target levels in patients with familial hypercholesterolemia (FH), especially in the treatment of patients with homozygous familial hypercholesterolemia. (2) Method: All of the literature data containing "Familial hypercholesterolemia" and "Gene Therapy" in PubMed and Clinical Trials from 2018 to 2022 were selected. (3) Results: The rapid development of gene therapy technology in recent years is expected to change the treatment status of FH patients. As emerging gene therapy vectors, the optimized adeno-associated viruses, exosomes, and lipid nanoparticles have demonstrated an improved safety and higher transfection efficiency. Various RNA-targeted therapies are in phase 1-3 clinical trials, such as small interfering RNA-based drugs inclisiran, ARO-ANG3, ARO-APOC3, olpasiran, SLN360, and antisense oligonucleotide-based drugs AZD8233, vupanorsen, volanesorsen, IONIS-APO(a)Rx, etc., all of which have demonstrated excellent lipid-lowering effects. With gene editing technologies, such as CRISPR-Cas 9 and meganuclease, completing animal experiments in mice or cynomolgus monkeys and demonstrating lasting lipid-lowering effects, patients with FH are expected to reach a permanent cure in the future. (4) Conclusion: Gene therapy is being widely used for the lipid-lowering treatment of FH patients and has shown excellent therapeutic promise, but the current delivery efficiency, economic burden, immunogenicity and the precision of gene therapy can be further optimized. Show less

This study aimed to investigate the effect of using high-quality colostrum in addition to paromomycin on the treatment outcomes and serum proteomes of calves naturally affected by cryptosporidiosis. Thirty Holstein calves infected with only Cryptosporidium spp. were divided into three equal groups. Calves in the PC group received paromomycin orally at a dose of 100 mg/kg once daily for 5 days. Calves in PCOL and PBCOL groups received 250 ml colostrum 3 h after feeding twice a day for 3 days. The PBCOL group was also given 6 g of sodium bicarbonate 15 min before colostrum administration. While the fecal scores of all calves were evaluated daily for 10 days from the initiation of the treatment, fecal oocyst counts were determined on the 0, 1, 2, 3, 5, 7, and 10th days. Brix%, total protein (TP), immunoglobulin G (IgG), gamma-glutamyltransferase (GGT) levels, and proteomic analyses were performed on the 0 and 3rd days' sera. Considering pretreatment values, fecal scores (8th, 2nd, and 2nd day), and fecal oocyst counts (10th, 3rd, and 2nd day) improved in a significantly (p < 0.05) shorter time in the colostrum groups than in the control group. By serum proteomic analysis, 99, 93, and 83 proteomes were detected in PC, PCOL, and PBCOL groups, respectively. Although the significant changes in any protein in Group PC were absent, significant changes were observed in Alpha-1B-glycoprotein (A1BG), Zinc transporterZIP11 (S39AB), Cathelicidin-1 (CTHL1), Actin_ cytoplasmic-1 (ACTB), and Apolipoprotein A-IV (APOA4) proteins in Group PCOL and Alpha-1-antiproteinase (A1AT), Serum amyloid A protein (SAA), Actin-cytoplasmic-2 (ACTG), Protein HP-20 homolog (HP20) proteins in Group PBCOL with colostral treatment, which indicated that the use of colostrum had an effect on calf serum proteomes. The more pronounced healing and shorter clinical improvement time in the colostrum groups especially colostrum with sodium bicarbonate revealed that these proteomes have positive effects in the treatment with their systemic and local effects in the intestines. Show less

Lymph node metastasis is associated with poor prognosis of oral squamous cell carcinoma (OSCC), and few studies have explored the relevance of postoperative lymphatic drainage (PLD) in metastatic OSCC. Alpha-enolase (ENO1) is a metabolic enzyme, which is related to lymphatic metastasis of OSCC. However, the role of ENO1 in PLD in metastatic OSCC has not been elucidated. Herein, we collected lymphatic drainage after lymphadenectomy between metastatic and non-metastatic lymph nodes in OSCC patients to investigate the relationship between ENO1 expression and metastasis, and to identify the proteins which interacted with ENO1 in PLD of patients with metastatic OSCC by MS/GST pulldown assay. Results revealed that the metabolic protein apolipoprotein C-III (ApoC3) was a novel partner of ENO1. The ENO1 bound to ApoC3 in OSCC cells and elicited the production of interleukin (IL)-8, as demonstrated through a cytokine antibody assay. We also studied the function of IL-8 on Jurkat T cells co-cultured with OSCC cells in vitro. Western blot analysis was applied to quantitate STAT3 (signal transducer and activator of transcription 3) and p-STAT3 levels. Mechanistically, OSCC cells activated the STAT3 signaling pathway on Jurkat T cells through IL-8 secretion, promoted apoptosis, and inhibited the proliferation of Jurkat T cells. Collectively, these findings illuminate the molecular mechanisms underlying the function of ENO1 in metastasis OSCC and provide new strategies for targeting ENO1 for OSCC treatment. Show less

Patients suffering from childhood acute lymphoblastic leukemia (ALL) are at risk of late adverse treatment-related effects. The examination of targeted biomarkers could be used to improve the diagnosis and prediction of life-threatening ALL sequelae. The purpose of this cross-sectional study was to search for treatment-related alterations in apolipoprotein (Apo) levels as potential markers of the occurrence of obesity in subjects treated for ALL, and to assess the relationships between weight, gender, anticancer treatment, and Apo concentrations. Fifty-eight ALL survivors were included in the study. The mean time of follow-up after treatment cessation was 5.41 ± 4.29 years. Serum levels of apolipoproteins were measured using a multiplex assay kit. Among ALL survivors, we observed a significant correlation of Apo-C1, Apo-C3, Apo-H, and Apo-J levels, depending on body mass index (BMI). Marked differences were observed in the area under the curve of Apo-A1, Apo-A2, Apo-C1, Apo-D. In our study, patients with a history of childhood ALL developed alterations in their Apo profile. Furthermore, this is the first study revealing that some apolipoproteins may act as valuable biomarkers useful in the prognosis of metabolic imbalance. We believe that this paper, at least partially, will highlight the importance of long-term prognosis of metabolic complications associated with the anticancer chemotherapy used to treat hematological malignancies in children. Show less

The heterogeneity of hepatocellular carcinoma (HCC) highlights the importance of precision therapy. In recent years, single-cell RNA sequencing has been used to reveal the expression of genes at the single-cell level and comprehensively study cell heterogeneity. This study combined big data analytics and single-cell data mining to study the influence of genes on HCC prognosis. The cells and genes closely related to the HCC were screened through single-cell RNA sequencing (71,915 cells, including 34,414 tumor cells) and big data analysis. Comprehensive bioinformatics analysis of the key genes of HCC was conducted for molecular classification and multi-dimensional correlation analyses, and a prognostic model for HCC was established. Finally, the correlation between the prognostic model and clinicopathological features was analyzed. 16,880 specific cells, screened from the single-cell expression profile matrix, were divided into 20 sub-clusters. Cell typing revealed that 97% of these cells corresponded to HCC cell lines, demonstrating the high specificity of cells derived from single-cell sequencing. 2,038 genes with high variability were obtained. The 371 HCC samples were divided into two molecular clusters. Cluster 1 (C1) was associated with tumorigenesis, high immune score, immunotherapy targets (PD-L1 and CYLA-4), high pathological stage, and poor prognosis. Cluster 2 (C2) was related to metabolic and immune function, low immune score, low pathological stage, and good prognosis. Seven differentially expressed genes (CYP3A4, NR1I2, CYP2C9, TTR, APOC3, CYP1A2, and AFP) identified between the two molecular clusters were used to construct a prognostic model. We further validated the correlation between the seven key genes and clinical features, and the established prognostic model could effectively predict HCC prognosis. Our study identified seven key genes related to HCC that were used to construct a prognostic model through single-cell sequencing and big data analytics. This study provides new insights for further research on clinical targets of HCC and new biomarkers for clinical application. Show less

Recently, clinical trials of adeno-associated virus-mediated replacement therapy have suggested long-term therapeutic effects for several genetic diseases of the liver, including hemophilia. However, there remain concerns regarding decreased therapeutic effects when the liver is regenerated or when physiological proliferation occurs. Although genome editing using the clustered regularly interspaced short palindromic repeats/Cas9 system provides an opportunity to solve this problem, low knock-in efficiency may limit its application for therapeutically relevant expression. Here, we identified a novel gene, Show less

CLN3 disease is a lysosomal storage disorder associated with fatal neurodegeneration that is caused by mutations in CLN3, with most affected individuals carrying at least one allele with a 966 bp deletion. Using CRISPR/Cas9, we corrected the 966 bp deletion mutation in human induced pluripotent stem cells (iPSCs) of a compound heterozygous patient (CLN3 Δ 966 bp and E295K). We differentiated these isogenic iPSCs, and iPSCs from an unrelated healthy control donor, to neurons and identified disease-related changes relating to protein synthesis, trafficking and degradation, and in neuronal activity, which were not apparent in CLN3-corrected or healthy control neurons. CLN3 neurons showed numerous membrane-bound vacuoles containing diverse storage material and hyperglycosylation of the lysosomal LAMP1 protein. Proteomic analysis showed increase in lysosomal-related proteins and many ribosomal subunit proteins in CLN3 neurons, accompanied by downregulation of proteins related to axon guidance and endocytosis. CLN3 neurons also had lower electrophysical activity as recorded using microelectrode arrays. These data implicate inter-related pathways in protein homeostasis and neurite arborization as contributing to CLN3 disease, and which could be potential targets for therapy. Show less

BackgroundApolipoprotein C-III (apoC-III) is a regulator of triglyceride (TG) metabolism, and due to its association with risk of cardiovascular disease, is an emergent target for pharmacological intervention. The impact of substantially lowering apoC-III on lipoprotein metabolism is not clear.MethodsWe investigated the kinetics of apolipoproteins B48 and B100 (apoB48 and apoB100) in chylomicrons, VLDL1, VLDL2, IDL, and LDL in patients heterozygous for a loss-of-function (LOF) mutation in the APOC3 gene. Studies were conducted in the postprandial state to provide a more comprehensive view of the influence of this protein on TG transport.ResultsCompared with non-LOF variant participants, a genetically determined decrease in apoC-III resulted in marked acceleration of lipolysis of TG-rich lipoproteins (TRLs), increased removal of VLDL remnants from the bloodstream, and substantial decrease in circulating levels of VLDL1, VLDL2, and IDL particles. Production rates for apoB48-containing chylomicrons and apoB100-containing VLDL1 and VLDL2 were not different between LOF carriers and noncarriers. Likewise, the rate of production of LDL was not affected by the lower apoC-III level, nor were the concentration and clearance rate of LDL-apoB100.ConclusionThese findings indicate that apoC-III lowering will have a marked effect on TRL and remnant metabolism, with possibly significant consequences for cardiovascular disease prevention.Trial registrationClinicalTrials.gov NCT04209816 and NCT01445730.FundingSwedish Heart-Lung Foundation, Swedish Research Council, ALF grant from the Sahlgrenska University Hospital, Novo Nordisk Foundation, Sigrid Juselius Foundation, Helsinki University Hospital Government Research funds, Finnish Heart Foundation, and Finnish Diabetes Research Foundation. Show less

Low plasma levels of High Density Lipoprotein (HDL) cholesterol (HDL-C) are associated with increased risks of atherosclerotic cardiovascular disease (ASCVD). In cell culture and animal models, HDL particles exert multiple potentially anti-atherogenic effects. However, drugs increasing HDL-C have failed to prevent cardiovascular endpoints. Mendelian Randomization studies neither found any genetic causality for the associations of HDL-C levels with differences in cardiovascular risk. Therefore, the causal role and, hence, utility as a therapeutic target of HDL has been questioned. However, the biomarker "HDL-C" as well as the interpretation of previous data has several important limitations: First, the inverse relationship of HDL-C with risk of ASCVD is neither linear nor continuous. Hence, neither the-higher-the-better strategies of previous drug developments nor previous linear cause-effect relationships assuming Mendelian randomization approaches appear appropriate. Second, most of the drugs previously tested do not target HDL metabolism specifically so that the futile trials question the clinical utility of the investigated drugs rather than the causal role of HDL in ASCVD. Third, the cholesterol of HDL measured as HDL-C neither exerts nor reports any HDL function. Comprehensive knowledge of structure-function-disease relationships of HDL particles and associated molecules will be a pre-requisite, to test them for their physiological and pathogenic relevance and exploit them for the diagnostic and therapeutic management of individuals at HDL-associated risk of ASCVD but also other diseases, for example diabetes, chronic kidney disease, infections, autoimmune and neurodegenerative diseases. Show less

Genetic factors play a critical role in the pathogenesis of osteoporosis. The imbalance of WNT/β-catenin will cause the occurrence of osteoporosis. LRP5 and AXIN1 play an important role in the classical Wnt/β-catenin signaling pathway. Our study was aimed to determine the association between five candidate single nucleotide polymorphisms (SNPs) of LRP5 or AXIN1 and osteoporosis susceptibility in Chinese Han population. A total of 599 osteoporosis patients and 599 healthy individuals were recruited for this case-control study. Agena MassARRAY was used to genotype SNPs. The association between SNPs and osteoporosis susceptibility in different genetic models was analyzed by PLINK software. We used false-positive report probability (FPRP) analysis to detect whether the positive results were just chance or noteworthy observations. Multifactor dimension reduction (MDR) was used to analyze the interaction of SNP-SNP in the osteoporosis risk. Finally, haplotype analysis was performed by plink1.07 and Haploview software. We found that LRP5 rs11228240, AXIN1 rs2301522, and rs9921222 were significantly associated with the osteoporosis susceptibility. The results of subgroup analysis showed that LRP5 rs11228240 (protective factor) and AXIN1 rs2301522 (risk factor) were associated with the susceptibility of osteoporosis among participants who were age >60 years, female or BMI ≤ 24; AXIN1 rs9921222 significantly increased the risk of osteoporosis among participants with BMI ≤ 24. The genotype A The LRP5-rs11228240, AXIN1-rs2301522, and AXIN1- rs9921222 were associated with osteoporosis susceptibility in Chinese Han population. Show less

We evaluated whether cholesteryl ester transfer protein (CETP) gene polymorphisms are associated with the presence of coronary artery disease (CAD) and/or restenosis in patients with coronary stent. Two polymorphisms of the CETP gene [-971 A/G (rs4783961), and Taq1B A/G (rs708272)] were genotyped by 5'exonuclease TaqMan assays in 219 patients with CAD (66 patients with restenosis and 153 without restenosis) and 607 control individuals. The distribution of polymorphisms was similar in patients with and without restenosis. However, when the whole group of patients (with and without restenosis) was compared to healthy controls, under dominant model, the G allele of the Taq1B A/G polymorphism was associated with increased risk of CAD (odds ratio [OR] = 1.48, pCDom = 0.032). In the same way, under codominant, dominant, and additive models, the A allele of the -971 A/G polymorphisms was associated with an increased risk of developing CAD (OR = 2.03, pCCo-dom = 0.022, OR = 1.83, pCDom = 0.008, and OR = 1.39, pCAdd = 0.011, respectively). In addition, the linkage disequilibrium showed that the "AG" haplotype was associated with increased risk of developing CAD (OR = 1.28, p = 0.03). This study demonstrates that CETP Taq1B A/G and CETP -971 A/G polymorphisms are associated with an increased risk of developing CAD, but no association with restenosis was observed. Show less

Large, observational genetic studies are commonly used to identify genetic factors associated with diseases and disease-related traits. Such cohorts have not been commonly used to identify genetic predictors of drug dosing or concentrations, perhaps because of the heterogeneity in drug dosing and formulation, and the random timing of blood sampling. We hypothesized that large sample sizes relative to traditional pharmacokinetic studies would compensate for this variability and enable the identification of pharmacogenetic predictors of drug concentrations. We performed a cross-sectional, proof-of-concept association study to replicate the well-established association between metoprolol concentrations and CYP2D6 genotype-inferred metabolizer phenotypes in participants from the Montreal Heart Institute Hospital Cohort undergoing metoprolol therapy. Plasma concentrations of metoprolol and α-hydroxymetoprolol (α-OH-metoprolol) were measured in samples collected randomly regarding the previous metoprolol dose. A total of 999 individuals were included. The metoprolol daily dose ranged from 6.25 to 400 mg (mean 84.3 ± 57.1 mg). CYP2D6-inferred phenotype was significantly associated with both metoprolol and α-OH-metoprolol in unadjusted and adjusted models (all p < 10 Show less

Unlike many animals that reduce activity during fasting, northern elephant seals (NES) undergo prolonged fasting during energy-intensive life-history stages such as reproduction and molting, fueling fasting energy needs by mobilizing fat stores accrued during foraging. NES display several unique metabolic features such as high fasting metabolic rates, elevated blood lipid and high-density lipoprotein (HDL) cholesterol levels, efficient protein sparing and resistance to oxidative stress during fasting. However, the cellular mechanisms that regulate these adaptations are still not fully understood. To examine how metabolic coordination is achieved during prolonged fasting, we profiled changes in blubber, skeletal muscle and plasma proteomes of adult female NES over a 5 week fast associated with molting. We found that while blubber and muscle proteomes were remarkably stable over fasting, over 50 proteins changed in abundance in plasma, including those associated with lipid storage, mobilization, oxidation and transport. Apolipoproteins dominated the blubber, plasma and muscle proteome responses to fasting. APOA4, APOE and APOC3, which are associated with lipogenesis and triglyceride accumulation, decreased, while APOA1, APOA2 and APOM, which are associated with lipid mobilization and HDL function, increased over fasting. Our findings suggest that changes in apolipoprotein composition may underlie the maintenance of high HDL levels and, together with adipokines and hepatokines that facilitate lipid catabolism, may mediate the metabolic transitions between feeding and fasting in NES. Many of these proteins have not been previously studied in this species and provide intriguing hypotheses about metabolic regulation during prolonged fasting in mammals. Show less

Coronary artery disease (CAD) is a multifactorial disorder, which is partly heritable. Herein, we implemented a mapping of CAD-associated candidate genes by using genome-wide enhancer-promoter conformation (H3K27ac-HiChIP) and expression quantitative trait loci (eQTL). Enhancer-promoter anchor loops from human coronary artery smooth muscle cells (HCASMC) explained 22% of the heritability for CAD. 3D enhancer-promoter genome mapping of CAD-genes in HCASMC was enriched in vascular eQTL genes. By using colocalization and Mendelian randomization analyses, we identified 58 causal candidate vascular genes including some druggable targets (MAP3K11, CAMK1D, PDGFD, IPO9 and CETP). A network analysis of causal candidate genes was enriched in TGF beta and MAPK pathways. The pharmacologic inhibition of causal candidate gene MAP3K11 in vascular SMC reduced the expression of athero-relevant genes and lowered cell migration, a cardinal process in CAD. Genes connected to enhancers are enriched in vascular eQTL and druggable genes causally associated with CAD. Show less

CLN8-Batten disease (CLN8 disease) is a rare neurodegenerative disorder characterized phenotypically by progressive deterioration of motor and cognitive abilities, visual symptoms, epileptic seizures, and premature death. Mutations in CLN8 results in characteristic Batten disease symptoms and brain-wide pathology including accumulation of lysosomal storage material, gliosis, and neurodegeneration. Recent investigations of other subforms of Batten disease (CLN1, CLN3, CLN6) have emphasized the influence of biological sex on disease and treatment outcomes; however, little is known about sex differences in the CLN8 subtype. To determine the impact of sex on CLN8 disease burden and progression, we utilized a Cln8 Several notable sex differences were observed in the presentation of brain pathology, including Cln8 Taken together, our results provide further evidence of biologic sex as a modifier of Batten disease progression and outcome, thus warranting consideration when conducting investigations and monitoring therapeutic impact. Show less

The aim of the study was to identify additional factors that contributed to coronary artery disease (CAD). We conducted integrative analysis on publicly available data from genome-wide association studies and quantitative trait locus studies by employing Mendelian randomization methods to examine the associations of gene expression in liver cells and circulating protein levels with LDL-C and CAD. We found that the mRNA expression levels of This study showed that regulatory SNPs in Show less

Capicua transcriptional repressor (CIC)-rearranged sarcoma, belonging to the undifferentiated round cells sarcoma family, is characterized by high metastatic rate and poor chemo response. CIC sarcoma represents a new entity harboring the recurrent chromosomal translocation between Show less

Despite the increasing prevalence of type 2 diabetes mellitus (T2DM), limited pharmacologic options are available for prevention. Cholesteryl ester transfer protein inhibitors (CETPis) have been studied primarily as a therapy to reduce cardiovascular disease, but have also been shown to reduce new-onset diabetes. As new trial data have become available, this meta-analysis examines the effect of CETP inhibitors on new-onset diabetes and related glycaemic measures. We searched MEDLINE, EMBASE, and Cochrane databases (all articles until 4 March, 2021) for randomised controlled trials (RCT) ≥1-year duration, with at least 500 participants, comparing CETPi to placebo, and that reported data on new-onset diabetes or related glycaemic measures [haemoglobin A1C (HbA1C), fasting plasma glucose, insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)]. A fixed effects meta-analysis model was applied to all eligible studies to quantify the effect of CETPi therapy on new-onset diabetes. Four RCTs (n = 75 102) were eligible for quantitative analysis of the effect of CETPi on new-onset diabetes. CETPis were found to significantly decrease the risk of new-onset diabetes by 16% (RR: 0.84; 95% CI: 0.78, 0.91; P < 0.001), with low between-trial heterogeneity (I2 = 4.1%). Glycaemic measures were also significantly improved or trended towards improvement in those with and without diabetes across most trials. Although RCTs have shown mixed results regarding the impact of CETPi on cardiovascular disease, they have shown a consistent reduction in the risk of new-onset diabetes with CETPi therapy. Future trials of CETPis and potentially other HDL-raising agents should therefore specify new-onset diabetes and reversal of existing T2DM as secondary endpoints. Show less

Anorexia nervosa (AN) is a severe eating disorder affecting primarily female adolescents and younger adults. The energy deprivation associated with AN has been shown to alter lipoprotein metabolism, which may affect cardiovascular risk. However, the mechanisms leading to alterations in the composition, structure, and function of lipoproteins in AN patients are not well-understood yet. Here, we investigated the lipid abnormalities associated with AN, particularly changes in the distribution, composition, metabolism, and function of lipoprotein subclasses. In this exploratory study, we analyzed serum samples of 18 women diagnosed with AN (BMI < 17.5 kg/m2) and 24 normal-weight women (BMI from 18.5−24.9 kg/m2). Using the Quantimetrix Lipoprint® system, we determined low-density lipoprotein (LDL) subclass distribution, including quantitative measurements of very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and high-density lipoprotein (HDL) subclass distribution. We quantified the most abundant apolipoproteins of HDL and assessed lecithin-cholesterol acyltransferase (LCAT) and cholesteryl-ester transfer protein (CETP) activities. In addition, anti-oxidative capacity of apoB-depleted serum and functional metrics of HDL, including cholesterol efflux capacity and paraoxonase activity were assessed. The atherogenic lipoprotein subclasses VLDL and small LDL particles were increased in AN. Levels of VLDL correlated significantly with CETP activity (rs = 0.432, p = 0.005). AN was accompanied by changes in the content of HDL-associated apolipoproteins involved in triglyceride catabolism, such as apolipoprotein C-II (+24%) and apoA-II (−27%), whereas HDL-associated cholesterol, phospholipids, and triglycerides were not altered. Moreover, AN did not affect HDL subclass distribution, cholesterol efflux capacity, and paraoxonase activity. We observed a shift to more atherogenic lipoprotein subclasses in AN patients, whereas HDL functionality and subclass distribution were not altered. This finding underpins potential detrimental effects of AN on lipid metabolism and the cardiovascular system by increasing atherosclerotic risk factors. Show less

Pharmacogenomics (PGx), forming the basis of precision medicine, has revolutionized traditional medical practice. Currently, drug responses such as drug efficacy, drug dosage, and drug adverse reactions can be anticipated based on the genetic makeup of the patients. The pharmacogenomic data of Pakistani populations are limited. This study investigates the frequencies of pharmacogenetic variants and their clinical relevance among ethnic groups in Pakistan. The Pharmacogenomics Knowledge Base (PharmGKB) database was used to extract pharmacogenetic variants that are involved in medical conditions with high (1A + 1B) to moderate (2A + 2B) clinical evidence. Subsequently, the allele frequencies of these variants were searched among multiethnic groups of Pakistan (Balochi, Brahui, Burusho, Hazara, Kalash, Pashtun, Punjabi, and Sindhi) using the 1000 Genomes Project (1KGP) and ALlele FREquency Database (ALFRED). Furthermore, the published Pharmacogenomics literature on the Pakistani population was reviewed in PubMed and Google Scholar. Our search retrieved (n = 29) pharmacogenetic genes and their (n = 44) variants with high to moderate evidence of clinical association. These pharmacogenetic variants correspond to drug-metabolizing enzymes (n = 22), drug-metabolizing transporters (n = 8), and PGx gene regulators, etc. (n = 14). We found 5 pharmacogenetic variants present at >50% among 8 ethnic groups of Pakistan. These pharmacogenetic variants include This study highlights the frequency of important clinical pharmacogenetic variants (1A, 1B, 2A, and 2B) among multi-ethnic Pakistani populations. The high prevalence (>50%) of single nucleotide pharmacogenetic variants may contribute to the drug response/diseases outcome. These PGx data could be used as pharmacogenetic markers in the selection of appropriate therapeutic regimens for specific ethnic groups of Pakistan. Show less