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Individuals with obesity caused by biallelic pathogenic LEPR (leptin receptor) variants can benefit from setmelanotide, the novel MC4R agonist. An ongoing phase 3 clinical trial (NCT05093634) includes individuals with obesity who carry a heterozygous LEPR variant, although the obesogenic impact of these variants remains incompletely evaluated. The aim of this study was to functionally assess heterozygous variants in LEPR and to evaluate their effect on obesity. We sequenced LEPR in ∼10,000 participants from the French RaDiO study. We found 86 rare heterozygous variants. Each identified variant was then investigated in vitro using luciferase and western blot assays. Using the criteria of the American College of Medical Genetics and Genomics (ACMG), including the strong criterion related to functional assays, we found 12 pathogenic LEPR variants. Most heterozygotes did not present with obesity, and we found no association between these pathogenic variants and body mass index (BMI). This lack of association between pathogenic LEPR variants and obesity risk or BMI was confirmed using exome data from 200,000 individuals in the UK Biobank. In the literature, among 55 reported heterozygotes for of a rare pathogenic LEPR variant, only 27% had obesity. In conclusion, monoallelic pathogenic LEPR variants were functionally tested, and they do not elevate the risk of obesity or BMI levels. This raises questions about the use of setmelanotide, a costly drug with potential side effects, based solely on the presence of a heterozygous LEPR variant. Show less

The neuronal ceroid lipofuscinoses (NCLs) comprise a group of inherited neurodegenerative disorders with thirteen NCL-disease causing genes ceroid lipofuscinosis neuronal ( We recruited 14 patients from 13 unrelated families who carried biallelic variants in the We detected 21 variants in three Patients with variants in the three Show less

Xeroderma Pigmentosum C is a dermal hereditary disease caused by a mutation in the DNA damage recognition protein XPC that belongs to the Nucleotide excision repair pathway. XPC patients display heightened sensitivity to light and an inability to mend DNA damage caused by UV radiation, resulting in the accumulation of lesions that can transform into mutations and eventually lead to cancer. To address this issue, we conducted a screening of siRNAs targeting human kinases, given their involvement in various DNA repair pathways, aiming to restore normal cellular behavior. We introduced this siRNA library into both normal and XPC patient-derived fibroblasts, followed by UVB exposure to induce DNA damage. We assessed the reversal of the XPC phenotype by measuring reduced photosensitivity and enhanced DNA repair. Among the 1292 kinase-targeting siRNAs screened, twenty-eight showed significant improvement in cellular survival compared to cells transfected with non-targeting siRNA after UV exposure in XPC cells. From these candidates, PIK3C3 and LATS1 were identified as particularly effective, promoting over 20% repair of 6-4 photoproduct (6-4PP) DNA lesions. Specifically targeting the autophagy-related protein PIK3C3 alone demonstrated remarkable photoprotective effects in XPC-affected cells, which were validated in primary XPC patient fibroblasts and CRISPR-Cas9 engineered XPC knockout keratinocytes. PIK3C3 knock down in XP-C cells ameliorated in UVB dose response analysis, decreased apoptosis with no effect on proliferation. More importantly, PIK3C3 knock down was found to induce an increase in UVRAG expression, a previously reported cDNA conveying lower photosensitivity in XP-C cells. Thus, attempts to improve the XPC photosensitive and deficient repair phenotype using PIK3C3 inhibitors could pave a way for new therapeutic approaches delaying or preventing tumor initiation. Show less

The present study was undertaken to investigate the therapeutic effect and underlying mechanisms of lumbrokinase (LK) on diabetic kidney disease (DKD). Kidney tissue samples from DKD patients and normal controls were collected from hospitals. The type 2 diabetic nephropathy model was induced in db/db mice. The mice were then randomly divided into a model group (DM group) and an LK group. db/m mice were used as the control group (Con group). After 12 weeks of treatment with LK (234 KU/kg/day), biochemical parameters were tested, and pathological changes in the kidney were observed under a light microscope. The epithelial-to-mesenchymal transition (EMT), mRNA m6A methylation proteins, and activated TGF-β1/Smad pathway components were assessed by western blot or immunofluorescence in DKD patients, model mice, and high glucose-stimulated HK-2 cells. We found that the m6A eraser METTL3 was expressed at low levels in DKD patients, model mice, and high glucose-stimulated HK-2 cells. METTL3 overexpression reversed the high glucose-induced activation of the TGF-β1/Smad pathway and EMT through snail in vitro. However, LK can restore the expression of the m6A-modifying enzyme METTL3 in vivo and in vitro, suppressed EMT, and alleviated renal interstitial fibrosis by downregulating snail. Overall, LK ameliorated renal fibrosis through the regulation of Snail via m6A RNA METTL3. Show less

The alarming global increase in lifestyle-related disorders such as obesity and type 2 diabetes mellitus (T2DM) has increased during the last several decades. Poor dietary choices significantly contribute to this increase and prevention measures are urgently needed. Dietary intake of bioactive compounds found in foods are linked to a decrease likelihood of these disorders. For this purpose, a randomized crossover meal study was performed to compare the postprandial metabolic effects of lecithin and oat polar lipids in healthy subjects. Eighteen young healthy subjects ingested test meals enriched with lecithin, oat polar lipids (PLs) or rapeseed oil. There were four test meals (i) 15 g oat polar lipids: OPL, (ii) 18 g sunflower lecithin (of which 15 g were polar lipids): LPL, (iii) 18 g rapeseed oil: RSO, and (iv) reference white wheat bread: WWB. Lipid-enriched test meals contained equivalent amounts of total fat (18 g), and all breakfast meals contained 50 g available carbohydrates. The meals were served as breakfast followed by a standardised lunch (white wheat bread and meat balls) after 3.5 h. Test variables were measured at fasting and repeatedly during 5.5 h after ingestion of the breakfast. Our study demonstrated that both LPL and OPL had beneficial effects on postprandial glucose and insulin responses, and appetite regulating gut hormones, as compared to RSO and WWB. Significant increase in GLP-1, GIP, and PYY concentrations were seen after consuming breakfast meals with LPL and OPL, and ghrelin concentration was reduced compared to meals with RSO and WWB ( Our study revealed that the consumption of both lecithin and oat PLs included in breakfast meal may similarly enhance postprandial glucose tolerance, reduce TG, and enhance the secretion of incretins and appetite regulating hormones in healthy young adults. ClinicalTrials.gov, identifier NCT05139355. Show less

Arylamine To test this, we treated cryopreserved human hepatocytes with agonists towards four different hepatic transcription factors/nuclear hormone receptors, namely FXR (NR1H4), PXR (NR1I2), LXR (NR1H3), and PPARα (PPARA), and measured their effects on the level of While the treatment with a FXR, PXR, or LXR agonist (i.e., GW-4064, SR-12813, or GW-3965) significantly induced their respective target genes, treatment with these agonists did not significantly alter the transcript level of In summary, hepatic nuclear receptors we examined in the present study (FXR, PXR, LXR, and PPARα) did not significantly alter Show less

The central melanocortin system links nutrition to energy expenditure, with melanocortin-4 receptor (MC4R) controlling appetite and food intake, and MC3R regulating timing of sexual maturation, rate of linear growth and lean mass accumulation. Melanocortin-2 receptor accessory protein-2 (MRAP2) is a single transmembrane protein that interacts with MC4R to potentiate it's signalling, and human mutations in MRAP2 cause obesity. Previous studies have been unable to consistently show whether MRAP2 affects MC3R activity. Here we used single-molecule pull-down (SiMPull) to confirm that MC3R and MRAP2 interact in HEK293 cells. Analysis of fluorescent photobleaching steps showed that MC3R and MRAP2 readily form heterodimers most commonly with a 1:1 stoichiometry. Human single-nucleus and spatial transcriptomics show MRAP2 is co-expressed with MC3R in hypothalamic neurons with important roles in energy homeostasis and appetite control. Functional analyses showed MRAP2 enhances MC3R cAMP signalling, impairs β-arrestin recruitment, and reduces internalization in HEK293 cells. Structural homology models revealed putative interactions between the two proteins and alanine mutagenesis of five MRAP2 and three MC3R transmembrane residues significantly reduced MRAP2 effects on MC3R signalling. Finally, we showed genetic variants in MRAP2 that have been identified in individuals that are overweight or obese prevent MRAP2's enhancement of MC3R-driven signalling. Thus, these studies reveal MRAP2 as an important regulator of MC3R function and provide further evidence for the crucial role of MRAP2 in energy homeostasis. Show less

Obesity poses a significant global health challenge, with an alarming rise in prevalence rates. Traditional interventions, including lifestyle modifications, often fall short of achieving sustainable weight loss, ultimately leading to surgical interventions, which carry a significant burden and side effects. This necessitates the exploration of effective and relatively tolerable pharmacological alternatives. Among emerging therapeutic avenues, glucagon-based treatments have garnered attention for their potential to modulate metabolic pathways and regulate appetite. This paper discusses current research on the physiological mechanisms underlying obesity and the role of glucagon in energy homeostasis. Glucagon, traditionally recognized for its glycemic control functions, has emerged as a promising target for obesity management due to its multifaceted effects on metabolism, appetite regulation, and energy expenditure. This review focuses on the pharmacological landscape, encompassing single and dual agonist therapies targeting glucagon receptors (GcgRs), glucagon-like peptide-1 receptors (GLP-1Rs), glucose-dependent insulinotropic polypeptide receptors (GIPRs), amylin, triiodothyronine, fibroblast growth factor 21, and peptide tyrosine tyrosine. Moreover, novel triple-agonist therapies that simultaneously target GLP-1R, GIPR, and GcgR show promise in augmenting further metabolic benefits. This review paper tries to summarize key findings from preclinical and clinical studies, elucidating the mechanisms of action, safety profiles, and therapeutic potential of glucagon-based therapies in combating obesity and its comorbidities. Additionally, it explores ongoing research endeavors, including phase III trials, aimed at further validating the efficacy and safety of these innovative treatment modalities. Show less

Patients with metastatic ovarian cancer (OvCa) have a 5-year survival rate of <30% due to the persisting dissemination of chemoresistant cells in the peritoneal fluid and the immunosuppressive microenvironment in the peritoneal cavity. Here, we report that intraperitoneal administration of β-glucan and IFNγ (BI) induced robust tumor regression in clinically relevant models of metastatic OvCa. BI induced tumor regression by controlling fluid tumor burden and activating localized antitumor immunity. β-glucan alone cleared ascites and eliminated fluid tumor cells by inducing intraperitoneal clotting in the fluid and Dectin-1-Syk-dependent NETosis in the omentum. In omentum tumors, BI expanded a novel subset of immunostimulatory IL27+ macrophages and neutralizing IL27 impaired BI efficacy in vivo. Moreover, BI directly induced IL27 secretion in macrophages where single agent treatment did not. Finally, BI extended mouse survival in a chemoresistant model and significantly improved chemotherapy response in a chemo-sensitive model. In summary, we propose a new therapeutic strategy for the treatment of metastatic OvCa. Show less

Increasing evidence suggests that metabolic disorders such as obesity are implicated in the development of Alzheimer's disease (AD). The pathological buildup of lipids in microglia is regarded as a key indicator in brain aging and the progression of AD, yet the mechanisms behind this process remain uncertain. The adipokine ANGPTL4 is strongly associated with obesity and is thought to play a role in the advancement of neurodegenerative diseases. This study utilized RNA sequencing to identify differential expression in lipid-accumulating BV2 microglia and investigated the potential mechanism through ANGPTL4 overexpression in BV2. Subsequently, animal models and clinical data were employed to further explore alterations in circulating ANGPTL4 levels in AD. RNA sequencing results indicated a correlation between ANGPTL4 and microglial lipid accumulation. The overexpression of ANGPTL4 in microglia resulted in increased secretion of inflammatory factors, elevated oxidative stress levels, and diminished antiviral capacity. Furthermore, when simulating the coexistence of AD and obesity through combined treatment with Amyloid-Beta 1-42 peptide (Aβ) and Free Fatty Acids (FFA) in vitro, we observed a notable upregulation of ANGPTL4 expression, highlighting its potential role in the interplay between AD and obesity. In vivo experiments, we also observed a significant increase in ANGPTL4 expression in the hippocampus and plasma of APP/PS1 mice compared to wild-type controls. This was accompanied by heightened microglial activation and reduced expression of longevity-related genes in the hippocampus. Clinical data from the UK Biobank indicated that plasma ANGPTL4 levels are elevated in patients with AD when compared to healthy controls. Moreover, significantly higher ANGPTL4 levels were observed in obese AD patients relative to their non-obese counterparts. Our findings suggest that ANGPTL4-mediated microglial aging may serve as a crucial link between AD and obesity, proposing ANGPTL4 as a potential biomarker for AD. Show less

Brain-derived neurotrophic factor (BDNF) is known for its potent prosurvival effect. Despite successfully replicating this effect in various clinical and pre-clinical models, the complete characterization of the molecular mechanisms underlying its neuroprotective action remains incomplete. Emerging research suggests a vital role for A-kinase anchoring proteins (AKAPs) as central nodal points orchestrating BDNF-dependent signaling. Among the over 50 identified AKAPs, AKAP6 has recently gained special attention due to its involvement in the neurotrophin-mediated survival of injured retinal ganglion cells (RGCs). However, the mechanisms by which AKAP6 responds to pro-survival BDNF signaling remain unknown. In this study, we shown that AKAP6 plays a crucial role in regulating BDNF-mediated NFAT transcriptional activity in neuronal survival by anchoring protein phosphatase calcineurin (CaN) and nuclear factor of activated T cells (NFATc4). Furthermore, we demonstrate that disrupting the anchoring of CaN diminishes the pro-survival effect of BDNF. Lastly, through experiments with NFATc4-/- mice, we provide evidence that NFATc4 acts downstream to BDNF's neuroprotection in vivo. These findings could offer valuable insights for developing neuroprotective strategies aimed at preserving injured neurons from degeneration and promoting their regeneration. Show less

Clearance of residual Host Cell Proteins (HCPs) is critical for the manufacturing processes of biotherapeutics. HCPs have the potential to impact product efficacy and quality, posing a risk to patient safety. It is therefore essential to be able to both identify and quantitate HCPs throughout drug development, even if the proteins are present in low concentrations. Traditional Enzyme-Linked Immunosorbent Assays (ELISAs) have historically served as the gold standard for monitoring HCPs; however, ELISA methods are labor-intensive and costly. With an increase of HCPs being identified below detectable quantification levels, there is a need for simultaneous detection of selectively targeted HCPs. Here, we develop a Luminex multiplexing method that is able to accurately quantify two "high-risk" lipases Lipoprotein Lipase (LPL) and Phospholipase B-Like 2 (PLBL2) within the same assay. This study outlines the method development for optimizing parameters such as antibody constructs, conjugation ratios, signal enhancement, and more in order to create the most efficient multiplexing method. As a result, a Luminex multiplexing method can provide a similar result to a monoplexing ELISA method but in a faster and more cost-effective manner. This method can be expanded to include other "high-risk" HCPs and used for future HCP applications. Show less

Several new treatments have recently been shown to have heart and kidney protective benefits in people with diabetes. Because these treatments were developed in parallel, it is unclear how the different molecular pathways affected by the therapies may overlap. Here, we examined the effects of the mineralocorticoid receptor antagonist finerenone in mice with comorbid diabetes, focusing on the regulation of expression of the glucagon-like peptide-1 receptor (GLP-1R), gastric inhibitory polypeptide receptor (GIPR) and glucagon receptor (GCGR), which are targets of approved or investigational therapies in diabetes. Male C57BL/6J mice were fed a high fat diet for 26 weeks. Twelve weeks into the high fat diet feeding period, mice received an intraperitoneal injection of streptozotocin before being followed for the remaining 14 weeks (DMHFD mice). After 26 weeks, mice were fed a high fat diet containing finerenone (100 mg/kg diet) or high fat diet alone for a further 2 weeks. Cell culture experiments were performed in primary vascular smooth muscle cells (VSMCs), NRK-49 F fibroblasts, HK-2 cells, and MDCK cells. DMHFD mice developed albuminuria, glomerular mesangial expansion, and diastolic dysfunction (decreased E/A ratio). Glp1r and Gcgr were predominantly expressed in arteriolar VSMCs and distal nephron structures of mouse kidneys respectively, whereas Gipr was the predominant of the three transcripts in mouse hearts. Kidney Glp1r and Gcgr and cardiac Gipr mRNA levels were reduced in DMHFD mice and this reduction was negated or attenuated with finerenone. Mechanistically, finerenone attenuated upregulation of the profibrotic growth factor Ccn2 in DMHFD kidneys, whereas recombinant CCN2 downregulated Glp1r and Gcgr in VSMCs and MDCK cells respectively. Through its anti-fibrotic actions, finerenone reverses Glp1r and Gcgr downregulation in the diabetic kidney. Both finerenone and GLP-1R agonists have proven cardiorenal benefits, whereas receptor co-agonists are approved or under development. The current findings provide preclinical rationale for the combined use of finerenone with the GLP-1R agonist family. They also provide mechanism of action insights into the potential benefit of finerenone in people with diabetes for whom GLP-1R agonists or co-agonists may not be indicated. Show less

Several studies provide evidence for a role of serum cytokines imbalance including IL-10 and IL-27 in immune thrombocytopenia pathogenesis and prognosis. The aim of this study was designed to investigate the role of serum levels of IL-10 and IL-27 in prognosis the efficiency of treatment in thrombocytopenic Iraqi children. This case controls study was carried out at Department of Biochemistry, College of Medicine, University of Baghdad, during the period from October 2023 to March 2024. It included 88 children, 63 children previously diagnosed with immune thrombocytopenia, and 25 apparently healthy children who served as control group. The included immune thrombocytopenic children were sub-grouped according to their treatment into three groups: Romiplostim group (group 1), Prednisolone group (group 2), Prednisolone and intravenous immunoglobulin (IVIG) or Prednisolone and mycophenolate group (group 3). Investigations included serum level measurements of IL-10 and IL-27 by using enzyme linked immunosorbent assay ELISA. Platelet count of each included children was measured by Huma Count 30 TS Human, Germany. The mean (±SEM) values of serum IL-10 and IL-27 levels of immune thrombocytopenic children were insignificantly lower than that of controls. In addition, there was non- significant differences in serum levels of IL-10 and IL-27 among and between the three groups of patient children. The mean value of platelet count of patient children was significantly increased by all types of treatment in whole immune thrombocytopenic children (117.48±18.15*10⁹/L). Measurement of serum IL-10 and IL-27 are helpful biomarker in prognosis of thrombocytopenia irrespective of type of treatment. Show less

This study aimed to investigate the possible mechanisms by which ANGPTL4 is involved in the pathogenesis of choroidal neovascularization (CNV) and subretinal fibrosis. Differentially expressed genes in retinal pigmented epithelium (RPE)-choroid-sclera complex tissues from nAMD patients and control individuals were identified via the GEO database, followed by GO and KEGG analyses. A Venn diagram was used to identify EndMT-related DEGs. A logistic regression model was constructed to screen for prognostic genes. Laser-induced CNV mouse models were established and validated with FFA and OCTA. The expression of ANGPTL4 and EndMT-related markers in the RPE-choroid-sclera complex was measured via RT‒qPCR and Western blotting. TGF-β2-induced HUVECs were used as EndMT cell models, and specific siRNAs targeting ANGPTL4 (si-ANGPTL4) were designed and screened. The effects of ANGPTL4 knockdown on the migration and invasion of HUVECs were also examined. Laser-induced CNV mouse models were constructed, and an intravitreal injection of cholesterol-modified si-ANGPTL4 was used to knock down ANGPTL4. FFA, OCTA and immunofluorescence staining were used to observe CNV formation and subretinal fibrosis, and the expression of ANGPTL4 and EndMT-related markers was determined. ANGPTL4 expression was significantly increased in mice with CNV and colocalized with IB4. In TGF-β2-induced EndMT, ANGPTL4 was also upregulated, and its knockdown led to the inhibition of EndMT and cell migration and invasion, while its overexpression promoted the EndMT process. ANGPTL4 knockdown reduced the formation of CNV and subretinal fibrosis in mice with CNV by suppressing EndMT. ANGPTL4 may promote CNV and subretinal fibrosis through EndMT, suggesting that ANGPTL4 may be a novel potential target for nAMD therapy. Show less

To construct and identify a prognostic and therapeutic signature based on disulfidptosis-related genes in lung adenocarcinoma. Bioinformatic analysis was performed to assess the differential expression of disulfidptosis-related genes between cancerous and control samples from The Cancer Genome Atlas-Lung Adenocarcinoma (TCGA-LUAD) database. Survival analysis, immune cell infiltration assessment, and examination of oncogenic pathways were performed to uncover potential clinical implications of disulfidptosis gene expression. Differential gene expression analysis between subtypes facilitated the development of a prognostic model using a combination of genes associated with survival. A nomogram was further created using independent clinical and molecular factors. We identified the significant upregulation of ten disulfidptosis-related genes and delineated two distinct subtypes, C1 and C2. Subtype C2 was associated with prolonged survival. Then, prognostic modeling utilizing six genes (TXNRD1, CPS1, S100P, SCGB3A1, CYP24A1, NAPSA) demonstrated predictive power in both training and validation datasets. The nomogram, incorporating the risk model with clinical features, provided a reliable tool for predicting one-year (AUC 0.77), three-year (AUC 0.75), and five-year (AUC 0.78) survival rates. Additionally, chemotherapy sensitivity analysis highlighted significant resistance in the high-risk group, primarily associated with subtype C1. Our study reveals distinct LUAD subtypes, offers a robust prognostic model, and underscores clinical implications for personalized therapy based on disulfidptosis-related genes expression profiles. Show less

Sensitive skin (SS) is associated with discomfort, including burning, stinging, and itching. These symptoms are often exacerbated by environmental factors and personal care products. In this genome-wide association study (GWAS), we aimed to identify the genetic variants associated with SS in 1690 Korean female participants; 389 and 1301 participants exhibited sensitive and non-sensitive skin, respectively. Using a combination of self-reported questionnaires, patch tests, and sting tests, we selected 115 sensitive and 181 non-sensitive participants for genetic analysis. A GWAS was performed to identify the loci associated with SS. Although none of the single-nucleotide polymorphisms (SNPs) met the genome-wide significance threshold, we identified several SNPs with suggestive associations. SNP rs11689992 in the 2q11.3 region increased SS risk by approximately 3.67 times. SNP rs7614738 in the Show less

The use of incretin agonists for managing metabolic dysfunction-associated steatohepatitis (MASH) is currently experiencing considerable interest. However, whether these compounds have a direct action on MASH is still under debate. This study aims to investigate whether GLP-1R/GIPR agonists act directly in hepatocytes and hepatic stellate cells (HSCs). For this, human hepatocyte and HSCs lines, as well as primary human hepatocytes and HSCs treated with Liraglutide, Acyl-GIP or the GLP-1/GIP dual agonist (MAR709) were used. We show that the concentrations of each compound, which were effective in insulin release, did not induce discernible alterations in either hepatocytes or HSCs. In hepatocytes displaying elevated fatty acid content after the treatment with oleic acid and palmitic acid, none of the three compounds reduced lipid concentration. Similarly, in HSCs activated with transforming growth factor-β (TGFb), Liraglutide, Acyl-GIP and MAR709 failed to ameliorate the elevated expression of fibrotic markers. The three compounds were also ineffective in phosphorylating CREB, which mediates insulinotropic actions, in both hepatocytes and HSCs. These findings indicate that incretin agonists have no direct actions in human hepatocytes or hepatic stellate cells, suggesting that their beneficial effects in patients with MASH are likely mediated indirectly, potentially through improvements in body weight, insulin resistance and glycemic control. Show less

Infigratinib, an FGFR1-3 selective oral tyrosine kinase inhibitor, has shown clinical activity in cancers with FGFR alterations. The pharmacokinetics (PK) of infigratinib and its major metabolites have been characterized in global populations. This study examined the PK profile of infigratinib and its metabolites in Chinese patients. In this phase II, open-label, single-arm study in China, patients with advanced gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJ) harboring FGFR2 gene amplification received 125 mg infigratinib orally once daily in a "3 weeks on, 1 week off" schedule for 28-day cycles. Plasma PK parameters were calculated with a non-compartmental model. Data were available from 21 patients (19 GC and two GEJ). After a single dose, peak infigratinib plasma concentration was reached at a median time of 3.1 h, with geometric mean C Show less

To analyse the relationships between the expression levels of liver X receptor (LXR), cyclooxygenase-2(COX2) and cholesterol ester transfer protein (CETP) and the severity of obstructive sleep apnoea hypopnoea syndrome (OSAHS) in obese young rats, to obtain information for basic research on OSAHS in obese children. Twenty-four 3-4-week-old young rats were randomly assigned to the normal control group, obesity group, OSAHS group, obesity and OSAHS group. We used polysomnography to measure the obstructive apnoea hypopnoea index (OAHI) to assess the severity of OSAHS and western blotting to test the expression levels of LXRα, COX2, and CETP in the liver, heart, kidney, and brain tissues. LXR, COX2, and CETP expression levels in the remaining groups were considerably higher than those in the control group (P < 0.05). Compared with those in the obesity group, LXRα, COX2, and CETP expression levels in the obesity and OSAHS group were considerably greater in the liver, kidney, and heart tissues (P < 0.05); the brain tissues of the obesity and OSAHS group showed considerably higher expression levels of COX2 and CETP (P < 0.05). Compared with those in the OSAHS group, LXRα, COX2, and CETP expression levels in the obesity and OSAHS group were significantly greater in all tissues (P < 0.05). The expression levels of LXRα, COX2, and CETP and obesity increased with increasing OSAHS severity (r = 0.777, P < 0.01; r = 0.728, P < 0.01; r = 0.793, P < 0.01; r = 0.786, P < 0.01; and r = 0.698, P < 0.01), and the oxygen concentration increased with decreasing OSAHS severity(r=-0.576, P < 0.01). LXR, COX2, and CETP expression levels were significantly increased in the liver, kidney, heart, and brain tissues of young rats with obesity and OSAHS, and were positively correlated with the severity of OSAHS. Show less

The role of leptin in regulating cardiac function is still controversial with conflicting results in clinical and preclinical studies. However, most previous studies have not considered leptin's powerful cardiac effects that are mediated via activation of central nervous system (CNS) leptin receptors (LepRs) which, in turn, elicit major improvements in cardiac metabolism. In this review, we focus mainly on the role of leptin in regulating cardiac function via its CNS LepRs and downstream signaling pathways, such as the brain melanocortin system. Studies from our laboratory showed that CNS LepR activation, without raising plasma leptin levels, has remarkable beneficial effects on cardiac metabolism and function that protect the heart during pathological conditions, including heart failure (HF) induced by myocardial infarction (MI). These cardioprotective effects of leptin appear to be mediated by stimulation of CNS proopiomelanocortin neurons and subsequent activation of melanocortin 4 receptors (MC4R) in the brain. Chronic activation of the brain leptin-melanocortin pathway improves cardiac function and metabolism following myocardial infarction. However, the mechanism underlying this brain-heart crosstalk remains unclear and may have important implications for the development of new therapies for MI and HF. Show less

Dyggve-Melchior-Clausen (DMC) disease is a rare autosomal recessive disorder primarily characterized by spondylo-epimetaphyseal dysplasia, intellectual disability, and distinctive facial features. Patients typically present with severe developmental delays and cognitive impairments, defining features of the syndrome. This case report examines a 13-year-old Moroccan child diagnosed with DMC disease, presenting classical skeletal abnormalities, including spondylo-epimetaphyseal dysplasia, as confirmed through exome sequencing. Notably, the child exhibited a mutation recurrently identified in the Moroccan population. However, the patient showed no signs of developmental delay or intellectual disability, a marked deviation from the traditionally described phenotype. This finding suggests a broader clinical variability associated with DMC disease, emphasizing the importance of individualized assessments. This atypical presentation expands the phenotypic spectrum of DMC disease, challenging its conventional diagnostic criteria. Further research is required to elucidate the factors influencing phenotypic variability in DMC and to explore potential genotype-phenotype correlations. Early identification and documentation of such atypical cases are critical for refining diagnostic and management strategies for rare disorders. Show less

Encephalocraniocutaneous lipomatosis (ECCL), also known as Haberland syndrome, is a sporadic tumor predisposition neurocutaneous disorder, included in the oculoectodermal syndrome group of mosaic RASopathies. ECCL primarily affects the skin, central nervous system and eyes. Key diagnostic features include nevus psiloliparus, a hallmark subcutaneous lipomatous hamartoma associated with alopecia, along with subcutaneous lipomas, focal skin aplasia, and patchy alopecia. Neurologically, intracranial lipomas, particularly in the cerebellopontine angle, are prevalent, along with cortical dysplasia, ventriculomegaly, and vascular malformations. Ocular findings commonly involve choristomas, lipodermoids, and dermoids, which may impair vision. Diagnosis can be made clinically, but further confirmatory genetic testing can in some cases identify a pathogenic variant in the FGFR1 or KRAS genes. Molecular testing aids diagnosis but is not always conclusive. Management is multidisciplinary with focus on symptomatic management, typically involving dermatological, neurological, and ophthalmologic evaluations with consideration of brain and spine neuroimaging and surgical management of tumors. The prognosis varies, with most individuals leading generally normal lives, though there is a risk of developmental delay, seizures, and low-grade gliomas. The severity of CNS involvement does not consistently correlate with cutaneous or ocular abnormalities. Show less

Alzheimer's disease (AD), a progressiveneurodegenerative condition is marked by extensive damage in the brain and dementia. Among the pathological hallmarks of AD is beta-amyloid (Aβ). Production of toxic Aβ oligomers production and accumulation in the brain is among the characteristic features of the disease. The abnormal accumulation Aβ is initiated by the catalytic degradation of Amyloid Precursor Proteins (APP) by Beta Amyloid Cleaving Enzyme 1 (BACE1) to generate insoluble amyloid plaques. The abnormal proteins are mitochondrial poison which disrupt the energy production and liberate excessive free radicals causing neuronal damage and mutations. Consequently, targeting Aβ-associated pathways has become a focus in the pursuit of developing effective AD treatments. An obstacle faced by many medications used to treat neurodegenerative diseases (NDs) is the restricted permeability across the blood-brain barrier (BBB). Unfortunately, no anti-amyloid drug is clinically approved till now. Recent advancements in nanotechnology have provided a possible solution for delivering medications to specific targets. By integrating natural products with nano-medicinal approaches, it is possible to develop novel and highly efficient therapeutic strategies for the treatment of AD. Show less

Angiopoietin-like 4 (ANGPTL4), a key protein involved in lipoprotein metabolism, has diverse effects. There is an association between Angptl4 and diabetic kidney disease; however, this association has not been well investigated. We show that both podocyte- and tubule-specific ANGPTL4 are crucial fibrogenic molecules in diabetes. Diabetes accelerates the fibrogenic phenotype in control mice but not in ANGPTL4 mutant mice. The protective effect observed in ANGPTL4 mutant mice is correlated with a reduction in stimulator of interferon genes pathway activation, expression of pro-inflammatory cytokines, reduced epithelial-to-mesenchymal transition and endothelial-to-mesenchymal transition, lessened mitochondrial damage, and increased fatty acid oxidation. Mechanistically, we demonstrate that podocyte- or tubule-secreted Show less

Chronic lymphocytic leukemia (CLL) can rarely transform into Waldenström macroglobulinemia (WM), posing diagnostic and therapeutic challenges. The diagnosis of WM requires bone marrow infiltration by lymphoplasmacytic cells and the presence of IgM gammopathy. Immunophenotypic markers include FMC7+, CD19+, CD20+, and CD138+. The MYD88 mutation is characteristic. Symptoms arise from tumor infiltration and monoclonal protein production. Here, we present a case of CLL transforming into WM during treatment with ibrutinib. Given the rarity of such a transformation, this case may serve as a valuable reference, and further investigation is needed to understand the pathology underlying this transformation. Show less

Lysosomes and related precursor organelles robustly build up in swollen axons that surround amyloid plaques and disrupted axonal lysosome transport has been implicated in worsening Alzheimer's pathology. Our prior studies have revealed that loss of Adaptor protein-4 (AP-4) complex function, linked primarily to Spastic Paraplegia (HSP), leads to a similar build of lysosomes in structures we term "AP-4 dystrophies". Surprisingly, these AP-4 dystrophies were also characterized by enrichment of components of APP processing machinery, β-site cleaving enzyme 1 (BACE1) and Presenilin 2. Our studies examining whether the abnormal axonal lysosome build up resulting from AP-4 loss could lead to amyloidogenesis revealed that the loss of AP-4 complex function in an Alzheimer's disease model resulted in a strong increase in size and abundance of amyloid plaques in the hippocampus and corpus callosum as well as increased microglial association with the plaques. Interestingly, we found a further increase in enrichment of the secretase, BACE1, in the axonal swellings of the plaques of Alzheimer model mice lacking AP-4 complex compared to those having normal AP-4 complex function, suggestive of increased amyloidogenic processing under this condition. Additionally, the exacerbation of plaque pathology was region-specific as it did not increase in the cortex. The burden of the AP-4 linked axonal dystrophies/AP-4 dystrophies was higher in the corpus callosum and hippocampus compared to the cortex, establishing the critical role of AP-4 -dependent axonal lysosome transport and maturation in regulating amyloidogenic amyloid precursor protein processing. Show less

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder occurring in women of reproductive age. The disease is caused by a complex interplay of genetic and environmental factors including genes encoding components of the hypothalamic-pituitary-adrenal (HPA) axis. We have recently reported the association of melanocortin receptor genes (MC1R, MC2R, MC3R, MC4R, and MC5R) with the risk of type 2 diabetes (T2D) and/or major depressive disorder (MDD). The latter 2 disorders are comorbid with PCOS. In this study, we used microarray to test 12 single nucleotide polymorphisms (SNPs) in the MC1R gene, 10 SNPs in the MC2R gene, 5 SNPs in the MC3R gene, 6 SNPs in the MC4R gene, and 4 SNPs in the MC5R gene in 212 original Italian families with PCOS. We identified 1 SNP in MC1R, 1 SNP in MC2R, 2 SNPs in MC3R, and 2 SNPs in MC5R significantly linked and/or associated to/with the risk of PCOS in Italian families. This is the first study to report the novel implication of melanocortin receptor genes (MC1R, MC2R, and MC5R) in PCOS. MC3R and MC4R were previously reported in PCOS. However, functional studies are needed to validate these results. Show less

The presence of epithelial-mesenchymal transition (EMT) in breast cancer (BC) cells has been linked to worse prognosis and may influence response to systemic treatment. We explored the effect of EMT in tumor samples of patients with metastatic BC on disease-free interval and overall survival in those patients receiving eribulin or cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). Key inclusion criteria included available archived primary BC tissue and, where available, matched metastatic biopsy. Patients received eribulin and/or a CDK4/6i in the metastatic setting. Specimens were assessed for biomarkers by immunohistochemistry (CDH1, AE1/3, VIM, CDH2, ZEB1, pSMAD2, and SMAD4) and gene expression by droplet digital polymerase chain reaction ( Between 2002 and 2020, 127 patients were included (95 early-stage disease at diagnosis with metastatic relapse, 32 de novo metastatic disease). In metastatic samples, presence of ZEB1 overexpression was associated with shorter time to recurrence (48.1 months shorter; We demonstrate in our exploratory study that biomarkers involved in the process of EMT could have a prognostic impact in a cohort of patients with BC uniformly treated and with long-term follow-up. Genes known to be involved in EMT were associated with improved eribulin efficacy, while suggesting a poorer outcome with CDK4/6i. Show less