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Cholesteryl ester transfer protein (CETP) deficiency and lipoprotein phenotypes with CETP inhibitors were compared. The effects on atherosclerotic cardiovascular disease (ASCVD) and the recently suggested retinal disease of age-related macular degeneration (ARMD) were summarized and discussed in relation to CETP deficiency and extremely increased high-density lipoprotein (HDL) cholesterol levels (＞100 mg/dL). In CETP truncated variants leading to reduced low-density lipoprotein cholesterol levels, ASCVD risk was decreased in heterozygotes. ASCVD prevalence did not increase in homozygotes with CETP deficiency. However, the association between ASCVD and ARMD risks in cases of very high HDL cholesterol level found in multifactorial hyperalphalipoproteinemia needs to be clarified on an etiological basis. The hurdles facing the development of CETP inhibitors are summarized, including a new result for obicetrapib. Show less

Evidence of the benefits of cordycepin (Cpn) for treating obesity is accumulating, but detailed knowledge of its therapeutic targets and mechanisms remains limited. This study aimed to systematically identify Cpn's therapeutic targets and pathways in Western diet (WD)-induced obesity using integrated network pharmacology, transcriptomics, and experimental validation. A Western diet (WD)-induced mice model was used to evaluate the effectiveness of Cpn in ameliorating obesity. A network pharmacology analysis was then employed to identify the potential anti-obesity targets of Cpn. GO functional enrichment and KEGG pathway analysis were performed to elucidate the potential functions of the identified targets, followed by constructing a protein-protein interaction network to screen the core targets. Meanwhile, quantitative transcriptomics was conducted to validate and broaden the network pharmacology findings. Finally, molecular docking and quantitative real-time PCR assay were used for the core target validation. Cpn treatment effectively alleviated obesity-related symptoms in WD-induced mice. The metabolic pathway, insulin signaling pathway, HIF-1 signaling pathway, FoxO signaling pathway, lipid and atherosclerosis pathway, and core targets including CPS1, HRAS, MAPK14, PAH, ALDOB, AKT1, GSK3B, HSP90AA1, BHMT2, EGFR, CASP3, MAT1A, APOM, APOA2, APOC3, and APOA1 are involved in regulating the therapeutic effect of Cpn. This study comprehensively uncovers the potential mechanism of Cpn against obesity based on network pharmacology and quantitative transcriptomics, which provides evidence for revealing the pathogenesis of obesity, suggesting that Cpn is a possible lead compound for anti-obesity treatment. Show less

RNA interference (RNAi) therapy represents an evolving advancement in the management of dyslipidemia. One prominent form of RNAi therapy is small interfering RNA (siRNA), which has emerged as a promising therapeutic strategy. This study aims to critically analyze the efficacy and safety of siRNA in the treatment of dyslipidemia. PubMed, Scopus, and Web of Science servers were used to conduct a systematic search in compliance with the PRISMA guidelines. A total of 20 studies with 6651 participants were included in the analysis. The drugs used in the studies were. Inclisiran led to a notable 44.09% reduction in LDL and 37.5% in apolipoprotein levels among individuals with hypercholesterolemia. In hyperlipoproteinemia(a), therapies like Lepodisiran and Olpasiran achieved a 75.69% drop in apolipoproteins and 16.25% in LDL. For hypertriglyceridemia, agents such as ARO-APOC3 and Plozasiran showed over 50% reductions in both VLDL and triglycerides. In mixed hyperlipidemia and chylomicronemia, Plozasiran significantly reduced triglycerides by up to 79% and apolipoproteins by 87.5%. The 5 most common adverse effects reported were nasopharyngitis, diabetes mellitus (including new-onset diabetes mellitus and worsening diabetes mellitus), injection site adverse effects, back pain, and hypertension. In conclusion, the benefits of siRNA therapy in dyslipidemia management appear to outweigh its potential drawbacks, demonstrating promising efficacy and safety profiles. However, further research is necessary to fully understand its long-term effects and optimize its therapeutic potential. Show less

Earthworms are valued as a dietary protein source in many regions. Earthworm protein can yield bioactive peptides, but enzymatic hydrolysis is inefficient by commercial proteases, and bioactivity development is still inadequate. This study developed a novel efficient method for degrading earthworm protein and investigated the lipid-lowering activity and mechanism of earthworm peptides. It was found that combining autolysis and alcalase exhibited a higher hydrolysis degree of earthworm protein of 43.64 ± 0.78% compared to using autolysis or alcalase only. The hydrolysate significantly reduced lipid accumulation in steatotic hepatocytes. LC-MS/MS results showed that the primary lipid-lowering peptides (EWPs) in the hydrolysate were small molecule peptides with molecular weights of 500-1000 Da and chain lengths of 4-7 amino acid residues. Western blot results demonstrated that EWP regulated the expression of lipid metabolism-related proteins, including APOC3, HMGCR, PCSK9, SREBP1, C/EBP-α, NPC1L1, PPAR-γ, and CYP7A1. Transcriptomic analysis and validation experiments indicated that the lipid-lowering activity of EWP was associated with its suppression of inflammatory factors, such as IL-6. This study presents an efficient enzymatic hydrolysis strategy for earthworm protein utilization, laying the foundation for its application in functional foods such as protein supplements, nutraceutical capsules, hypoallergenic infant formulas, and sports nutrition products. Show less

Hypertriglyceridemia has been proposed as a risk factor for atherosclerotic cardiovascular disease (ASCVD). Triglycerides (TG) are viewed as a marker for remnant cholesterol in triglyceride-rich lipoproteins, as this remnant cholesterol has been identified as a causal risk factor for ASCVD. The limited number of effective treatments for elevated TG has fueled the search for novel pharmacotherapy options, and multiple medication classes are being explored. Apolipoprotein C3 (APOC3) and angiopoietin-like protein 3 (ANGPTL3) are among the most promising targets. Several novel agents utilizing these pathways, including olezarsen, plozasiran, and zodasiran, are currently under development for the management of elevated TG, with olezarsen approved in 2024 for the management of familial chylomicronemia syndrome. This comprehensive review provides updated insights into the development of novel hypertriglyceridemia treatments. Show less

Breast cancer (BC) is among the cancers with the highest incidence rates. Although multiple therapies are available, there is an unmet need for prediction of prognoses and treatment responses. Increasing evidence has shown that lipid metabolism is important for the development of BC. The tumor-promoting role of lipid metabolism in BC has inspired us to build a model to predict prognosis and stratify patients using lipid metabolism-related genes (LMRGs) that may reflect the underlying biological mechanisms of BC. We identified a list of genes involved in lipid metabolism that were associated with the overall survival of BC. The above genes were selected by the least absolute shrinkage and selection operator (LASSO) method to avoid overfitting, and the stepwise Cox proportional hazards regression model was applied. The BC cohort of the Cancer Genome Atlas was divided into a training cohort and a test cohort at a ratio of 1:1. A six-gene signature, comprising APOC3, CEL, CPT1A, JAK2, NFKBIA, and PLA2G1B, was developed using the training cohort. There was a clear distinction in overall survival between low- and high-risk patients in the training cohort, the test cohort, various validation cohorts, and different clinical subgroups. Then, immune cell infiltration analysis, GO and KEGG analyses were performed. Enrichment analyses were applied to explore the possible underlying mechanisms. We also analyzed the susceptibility of patients to predefined drugs in different risk groups in an attempt to identify potential therapeutic drugs. Carnitine palmitoyl transferase 1A (CPT1A), one of the signature genes, is a key enzyme in lipid metabolism that has been related to cancer progression. Therefore, we analyzed the prognostic values of CPT1A in public cohorts and our independent BC cohort by performing immunohistochemistry. CPT1A was significantly related to overall survival in patients with BC in the cohorts. In general, the LMRG signature can predict overall survival and potential immunotherapy response in patients with BC, including triple-negative BC. The findings have highlighted the role of lipid metabolism and CPT1A in BC, showing the implications for further research, and the signature is a potential tool for prognosis prediction and may help clinicians with clinical decisions. Show less

Patients with dyslipidemia are at higher risk for inflammatory bowel disease (IBD), yet the impact of lipid-lowering medications on IBD remains unclear. This study investigates the causal relationship between lipid-lowering drug target and IBD, with a focus on the roles of gut microbiota and inflammatory cytokines. Genetic variants associated with lipid-lowering drug targets were extracted from the Global Lipids Genetics Consortium, whereas summary statistics for IBD, Crohn's disease (CD), and ulcerative colitis were sourced from the International Inflammatory Bowel Disease Genetics Consortium. Drug-target Mendelian randomization analysis revealed that inhibiting angiopoietin-like protein 3 increased the risk of IBD and CD, whereas inhibition of apolipoprotein C-III (APOC3) heightened the risk of CD. Conversely, enhancement of LPL and LDL receptor reduced the risk of IBD and CD. Mediation analysis demonstrated that gut microbiota and inflammatory cytokines partially mediated these effects, with specific pathways such as Lachnospiraceae FCS020 (17.26%) for APOC3 and Clostridium sensu stricto 1 (20.12%) for LPL accounting for significant portions of the effects. These findings suggest that lipid-lowering drugs targeting angiopoietin-like protein 3 and APOC3 may increase the risk of IBD, whereas those targeting LPL and LDL receptor may reduce the risk. The results highlight potential for repurposing lipid-lowering drugs for IBD prevention and warrant future clinical trials to explore these targets further. Show less

Ischemia-reperfusion (IR) and adriamycin (also named doxorubicin, DOX)-induced acute myocardial injuries have a significant impact on health, causing serious economic and medical burdens. Therefore, we need to explore and identify drugs with potential therapeutic value for treating I/R- and DOX-induced myocardial injury. In the present study, we explored the therapeutic potential of FGF4 for I/R and DOX-induced myocardial injury. We found that FGF4 showed good improvement in acute cardiac injury. However, due to the short half-life of FGF4, we further prepared a myocardial-targeted FGF4-sustained release nanoliposome (named FGF4-NANO-IMTP). We investigated the effect of FGF4-NANO-IMTP on myocardial injury caused by I/R and DOX. Show less

Recent evidence suggests that elevated lipoprotein(a) [Lp(a)] contributes to atherosclerotic cardiovascular disease (ASCVD). The predictive value of specific Lp(a) cutoff points of 30 mg/dL remains to be established. This study investigated the relationship between Lp(a) concentrations and cardiovascular outcomes in Taiwanese individuals, stratified by pre-existing ASCVD status. We conducted a retrospective analysis of 51,934 subjects from the Chang Gung Research Database (January 2004 to June 2019), comprising 49,363 individuals without ASCVD and 2,571 with established ASCVD. The primary outcome was major adverse cardiovascular events (MACEs), encompassing acute myocardial infarction, ischemic stroke, revascularization procedures, peripheral arterial interventions, and cardiovascular mortality. Individuals were followed until their last visit to our institutions or December 31, 2019. During a mean follow-up of 6.6 years (standard deviation: 5.0 years), the study population demonstrated a median Lp(a) of 9.6 mg/dL (interquartile range: 4.6-18.5). In ASCVD-free individuals, Lp(a) concentrations ≥30 mg/dL were associated with increased MACE risk (adjusted subdistribution hazard ratio [aSHR]: 1.24; 95% confidence interval [CI]: 1.07-1.43). Similarly, in the ASCVD cohort, elevated Lp(a) predicted higher MACE occurrence (aSHR: 1.36; 95% CI: 1.07-1.74). Restricted cubic spline analysis confirmed a progressive risk elevation beyond the 30 mg/dL threshold in both groups. Lp(a) levels ≥30 mg/dL independently predicted adverse cardiovascular outcomes, regardless of baseline ASCVD status. This threshold appears suitable for cardiovascular risk stratification in both primary and secondary prevention settings. Show less

Twenty types of GABAergic interneurons form intricate networks to fine-tune neural circuits in the brain. Parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons, which are the two largest populations of neocortical interneurons, innervate the soma and/or proximal dendrites, and distal dendrites of pyramidal neurons, respectively. Using PV- and SST-specific knockout mouse models, we show that PV+ interneurons require FGFR2, which responds to FGF7, to drive PV+ inhibitory presynaptic maturation on perisomatic regions of Layer V pyramidal neurons. In contrast, SST+ interneurons rely on both FGFR1 and FGFR2, which respond to FGF10 or FGF22, to promote SST+ inhibitory presynaptic maturation on distal dendrites of pyramidal neurons in cortical Layer I. Mechanistically, FGF-FGFR signaling sustains VGAT protein levels in interneurons through PP2A and Akt pathways. Together, these findings demonstrate that distinct FGF ligand-receptor combinations regulate inhibitory presynaptic differentiation by PV+ and SST+ interneurons, contributing to the formation of compartment-specific synaptic patterns. Show less

This study aims to investigate the molecular differences and commonalities between systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) by analyzing RNA-sequencing (RNA-seq) data. By focusing on differentially expressed genes and enriched pathways, the investigation seeks to identify unique biomarkers, shared pathways, and potential therapeutic targets for these autoimmune diseases. This study involved 10 patients with SSc and 24 with SLE who did not receive immunosuppressants. RNA-seq data from patients with SSc and SLE were analyzed using DESeq2 to identify differentially expressed genes. Functional and pathway enrichment analyses were conducted and comparative analyses were performed. We identified 2055 differentially expressed genes (DEGs) between patients with SSc and controls. Notably, the expression of the shared gene RGS5 was significantly downregulated in both SLE and SSc, with a more pronounced downregulation in SSc. Additionally, the expression of the key transcription factor EGR1 was upregulated in SSc, whereas that of BLK, ITGAM, and IFNG was upregulated in SLE. Network analysis identified hub genes-AP3D1, FTX, USP47, CUX1, ZC3H4, CAND1, INTS1, TRNT1, MTERF1, and SETD1B-that may play critical roles in the progression of both SLE and SSc. These findings suggest that RGS5 could serve as a shared biomarker for vascular dysfunction, while EGR1 and BLK may represent therapeutic targets in SSc and SLE. Overall, this analysis enhances understanding of distinct and overlapping gene expression signatures in SSc and SLE, providing a foundation for future targeted treatment strategies and requiring further validation in larger cohorts. Show less

Studies have found that there is tertiary lymphoid structure (TLS) in IgA nephropathy (IgAN), and the existence of TLS has an impact on renal function, creatinine, and proteinuria in patients. We aim to explore the potential molecular mechanisms and therapeutic targets of TLS in IgA nephropathy by bioinformatics methods, hoping to provide treatment methods. The datasets GSE226840, GSE237120, and GSE116626 from the Gene Expression Omnibus (GEO) database were employed to investigate the potential therapeutic targets of TLS in IgAN. The R was used to obtain the differentially expressed genes (DEGs) of three datasets, and the Venny was used to intersect the above three parts of the DEGs to obtain the common DEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on obtained genes using Metascape. Protein-Protein interaction (PPI) network was constructed. The intersection of the above common differential genes and IgAN differential genes was obtained by Venny tool. The Nephroseq platform was used to screen core genes and explore their relationship with clinical features. Meanwhile, CIBERSORT was utilized to further delve into the correlation between core genes and immune cells. 92 TLS-related genes and 486 IgAN related genes were obtained, and 6 common genes were obtained after crossing the two genes. The intersection genes were verified by Nephroseq, and CDKN1A, CD83, DUSP6, and CD48 were identified as core genes. At the same time, there were differences in the composition of immune cells between the disease group and the control group when the immune infiltration analysis was performed. And by further analyzing the correlation between core genes and immune cells, the study found that the four genes were positively correlated with T cells, B cells, plasma cells, and other immune cells. By exploring the relationship between core genes and clinical features, CDKN1A and DUSP6 were negatively correlated with Glomerular Filtration Rate (GFR) and positively correlated with proteinuria in IgAN patients. CD48 was negatively correlated with GFR and positively correlated with Blood Urea Nitrogen (BUN). The four genes highly associated with TLS and IgAN were screened using GEO database in study. And CDKN1A, CD83, DUSP6 and CD48 may provide potential therapeutic targets for the treatment of TLS in IgAN. At the same time, studies have found that T cells, B cells, and macrophages may be involved in the formation of TLS in IgAN. Show less

Multiple cancers are driven by aberrant fibroblast growth factor receptor (FGFR) signaling and vascular endothelial growth factor receptor (VEGFR)-linked angiogenesis. Several therapeutic agents targeting FGFR and VEGFR have been developed and approved for use in solid cancers; however, there is still a high unmet medical need for new agents that have a more powerful antitumor activity and a broader antitumor spectrum. Here, we report the discovery of FH-2001, a novel and potent FGFR/VEGFR dual inhibitor, with additional activity of modulating programmed cell death ligand 1 (PD-L1) gene expression. In biochemical assays, FH-2001 showed potent inhibition of FGFR1, 2, 3, and 4, with half-maximal inhibitory concentration (IC 50 ) of 0.2, 0.2, 0.4, and 2.0 nM, respectively, and VEGFR1, 2, and 3, with IC 50 values of 2.0, 0.3, and 0.5 nM, respectively. FH-2001 significantly suppressed the cell growth of FGFR- or VEGFR-driven cancer cell lines. In representative cell line- and patient-derived tumor xenografts with aberrant FGFR or VEGFR signaling, FH-2001 substantially inhibited tumor growth. Furthermore, FH-2001 demonstrated marked antitumor activities when treated alone or combined with PD-L1 or PD-1 antibody in syngeneic mouse models. Flow cytometric analysis revealed that FH-2001 alone or in combination with anti-PD-L1 increased T and natural killer cells and decreased myeloid cells in the tumor microenvironment. Mechanistically, FH-2001 treatment dramatically reduced c-Myc and PD-L1 mRNA and protein levels in a dose-dependent manner in vitro . Taken together, FH-2001 is a promising dual-target inhibitor of FGFR and VEGFR and also modulates cancer immunity, while its robust antitumor activity positions it as a potentially class-leading anticancer agent. Show less

To investigate the genetic etiology of six adult patients with Dilated cardiomyopathy (DCM), and analyze the structure of the identified variants, for providing reference for the diagnosis of DCM. Six adult patients with DCM (patients 1-6) admitted to the Department of Cardiology of Zhumadian Central Hospital from January 2023 to December 2023 were recruited. Clinical data of the patients were retrospectively collected. And 5 mL of peripheral blood was collected from each patient. Pathogenic variants of the patients were detected by whole exome sequencing (WES), and candidate variants were verified by Sanger sequencing. The possible functional significance of the identified missense variants was evaluated using software including SIFT, PolyPhen-2 and Mutation Taster. Specific regions of the MYBPC protein encoded by the MYBPC3 gene from different species were aligned using Mutation Taster. The wild-type and mutant MYBPC proteins were constructed using homologous modeling software MODELLER v10.4 and three-dimensional structures were visualized using PyMOL software. The molecular interaction between MYBPC-C5 domain and myosin with or without the mutation was further analyzed using ZDOCK module in Discovery Studio 2019 software. Pathogenicity ratings for the detected variant sites were performed in accordance with the Standards and Guidelines for the Interpretation of Sequence variants by the American College of Medical Genetics and Genomics (ACMG) (hereafter referred to as the ACMG Guidelines). This study was reviewed and approved by the Ethics Committee of Zhumadian Central Hospital (Approval No. 2022092007). The six DCM patients had typical symptoms of heart failure, and echocardiography showed whole-heart dilation and decreased ventricular wall motion, left ventricular end-diastolic dimension (LVEDD) was 59-74 mm, left ventricular ejection fraction (LVEF) was 35%-43%, and left ventricular fractional shortening (LVFS) was 17%-28%. Variations of the DCM related genes, including a c.98473A>T (p.Lys32825*) variation of the TTN gene and a c.1976T>C (p.Ile659Thr) variation of the MYBPC3 gene, were identified in two patients. Multiple software predicted that both mutations were deleterious. MYBPC3-Ile659Thr mutation affected the highly conserved residue within the C5 domain of MYBPC. Three-dimensional structural analysis of homologous modeling revealed the alterations in amino acid properties and interactions with surrounding amino acids caused by the MYBPC3-Ile659Thr mutation. Further molecular docking analysis showed that the Ile659Thr mutation altered both the hydrogen bond and salt-bridge interactions between the MYBPC-C5 domain and the ligand myosin. Two mutations associated with DCM were identified in this study. The abnormal conformation of the mutant protein further affected its interaction with the ligand myosin, resulting in the phenotype of DCM. Show less

Several protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) levels in statin-intolerant patients, but none have been verified in Chinese patients. This study aimed to evaluate the efficacy and safety of ongericimab, a novel PCSK9 monoclonal antibody, in Chinese statin-intolerant patients with primary hypercholesterolemia or mixed dyslipidemia. This was a randomized, multicenter, double-blind, placebo-controlled phase 3 study designed to enroll 120 statin-intolerant adult patients. Eligible patients were randomly assigned in a 2:1 ratio to receive ongericimab 150 mg or placebo subcutaneously every 2 weeks for 12 weeks in the double-blind treatment period, followed by 40 weeks of ongericimab treatment during the open-label period. The primary endpoint was a percentage change in LDL-C from baseline to week 12. The key secondary endpoints included percentage change from baseline to week 12 in non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol (TC), and lipoprotein(a) [Lp(a)]. From February 6, 2023, to September 23, 2024, a total of 139 patients were enrolled. The least-squares (LS) mean difference between ongericimab and placebo groups in LDL-C from baseline to week 12 was -66.2 % (95 % CI: 74.2 %, -58.2 %; p < 0.0001), with reductions sustained up to week 52. Ongericimab also significantly reduced levels of non-HDL-C, ApoB, TC, and Lp(a). The overall incidence of treatment-emergent adverse events was comparable between the ongericimab and placebo groups. Ongericimab significantly reduced LDL-C as well as other atherogenic lipid levels and was well tolerated in Chinese statin-intolerant patients with primary hypercholesterolemia or mixed dyslipidemia. http://www. gov; Unique Identifier: NCT05621070. Show less

Chemically modified small interfering RNAs (siRNAs) are a promising drug class that silences disease-causing genes via mRNA degradation. Both siRNA-specific features (e.g. sequence, modification pattern, and structure) and target mRNA-specific factors contribute to observed efficacy. Systematically defining the relative contributions of siRNA sequence, structure, and modification pattern versus the native context of the target mRNA is necessary to inform design considerations and facilitate the widespread application of this therapeutic platform. To address this, we synthesized a panel of ∼1260 differentially modified siRNAs and evaluated their silencing efficiency against therapeutically relevant mRNAs (APP, BACE1, MAPT, and SNCA) using both reporter-based and native expression assays. Our results demonstrate that the siRNA modification pattern (e.g. level of 2'-O-methyl content) significantly impacts efficacy, while structural features (e.g. symmetric versus asymmetric configurations) do not. Furthermore, we observed substantial differences in the number of effective siRNAs identified per target. These target-specific differences in hit rates are largely mitigated when efficacy is tested in the context of a reporter assay, confirming that native mRNA-specific features influence siRNA performance. Key target-specific factors, including exon usage, polyadenylation site selection, and ribosomal occupancy, partially explained efficacy variability. These insights led to a proposed framework of parameters for optimizing therapeutic siRNA design. Show less

Glucagon-like peptide-1 receptor (GLP-1R)/glucose-dependent insulinotropic peptide receptor (GIPR) agonistic analogs have yielded superior results in enhancing glycemic control and weight management compared to GLP-1R agonism alone. Intriguingly, GIPR agonism appears to induce antiemetic effects, potentially alleviating part of the nausea and vomiting side effects common to GLP-1R agonists like semaglutide. Here, we show in rats and shrews that GIPR agonism blocks emesis and attenuates other malaise behaviors elicited by GLP-1R activation while maintaining reduced food intake and body weight loss and improved glucose tolerance. The GLP-1R/GIPR agonist tirzepatide induced significantly fewer side effects than equipotent doses of semaglutide. These findings underscore the therapeutic potential of combined pharmaceutical strategies activating both incretin systems, leading to enhanced therapeutic index and reduced occurrence of nausea and vomiting for obesity and diabetes treatments. Show less

Obesity is a global health challenge characterized by significant heterogeneity in causes and treatment responses, complicating sustainable management. This narrative review explores the genomic architecture of obesity and its implications for personalized interventions, focusing on how genetic variations influence key biological pathways and treatment outcomes. A comprehensive literature search, guided by the authors' expertise, was conducted to identify key publications on the genomics of obesity and personalized approaches. The selection of articles prioritized those that provided direct insights into the genomic basis of obesity and its potential for informing tailored strategies. Genomic studies reveal both monogenic and polygenic influences on obesity, identifying numerous susceptibility loci. Genome-wide association studies (GWASs) have linked common variants in genes like Show less

The development of novel sophisticated medications that induce weight loss has revolutionized the management of people living with obesity (PwO). However, when body weight is reduced, muscle and bone are lost along with fat. In the present review, we quote and discuss existing evidence on the effects of the major anti-obesity medications on bone metabolism. Glucagon-like peptide-1 receptor (GLP-1R) agonists have shown a positive impact in preclinical studies but a neutral or negative, albeit not clinically significant, effect on bone turnover markers and bone mineral density in clinical studies. Nevertheless, fracture risk does not seem to increase with GLP-1R agonists use, at least in clinically relevant doses. Limited, mostly preclinical, data suggest that other incretin analogues, including dual GLP-1R and glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) agonists, dual GLP-1R and glucagon receptor (GCGR) agonists, and triple GLP-1R, GIPR and GCGR agonists, may have a positive effect on bone. Preclinical data with amylin analogues imply the same. Activin type II receptor (ActRII) antagonists may combine anti-obesity effects with simultaneous muscle and bone mass preservation and could be used either as monotherapy or in combination with incretin analogues. The bone effects of opioid receptor antagonists and setmelanotide are largely unknown, while the impact of the combination of phentermine with topiramate is assumed to be negative. Finally, very limited clinical evidence suggests that orlistat may have a neutral effect on bone metabolism. Show less

Type 2 diabetic patients exhibited an increased secretion of triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol levels with a greater amount of small dense low-density lipoprotein (LDL). Given that apolipoprotein B (apoB), a proatherogenic lipoprotein, exists at both triglyceride-rich lipoproteins and LDL particles, circulating apoB may associate with diabetic coronary atherosclerosis. The OPTIMAL study was a prospective randomized-controlled study which employed serial near-infrared spectroscopy (NIRS)/intravascular ultrasound (IVUS) imaging to evaluate the efficacy of glycemic control on coronary atherosclerosis in 94 statin-treated type 2 diabetic patients with coronary artery disease (CAD) (UMIN000036721). Of these, 78 patients with both serial apoB levels and NIRS/IVUS images at baseline and week 48 were analyzed. NIRS/IVUS-derived plaque measures were compared in those with and without any reduction of apoB levels. All of the study subjects received a statin, and 60.6% of the study subjects exhibited any reduction of apoB levels. There was no significant difference in the atheroma progression rate between the 2 groups (-0.27 ± 0.15% vs -0.33 ± 0.51%, P = .44). However, patients with any reduction of apoB levels exhibited a greater frequency of change in maximal lipid-core burden index at 4-mm segment (maxLCBI In statin-treated type 2 diabetic patients with CAD, a greater delipidation of coronary atherosclerosis was observed in association with a reduction of apoB levels. The current findings indicate a potential anti-atherosclerotic effect of lowering apoB levels, which may ultimately mitigate future coronary events risk in statin-treated type 2 diabetic patients with CAD. Show less

Behavioral Tagging (BT) is a well-established phenomenon under in vivo conditions to understand molecular framework of long-term memory (LTM) consolidation. BT has been extensively explored using different learning tasks and novelties at the behavioral level, while at the molecular level, handful of plasticity related proteins (PRPs) such as PKMζ, CREB, BDNF have been explored in various manners thereof. Hence, the quest for novel PRPs in BT becomes a necessity, since repeated studies of known PRPs results in scientific stagnation and cessation of further exploration. Emerging literature suggests potential role of BACE1 and endogenous Aβ in maintenance of synaptic plasticity and long-term potentiation. The present study aims to characterize the effects of BACE1 inhibition using minocycline on novel object recognition (NOR) LTM through environment enrichment (EE) mediated BT. BACE1 is responsible for endogenous Aβ generation, hence its inhibition also subdues the Aβ synthesis. Our results significantly demonstrate the active involvement of BACE1 and endogenous Aβ in facilitating NOR-LTM consolidation through EE mediated BT for the first time under in vivo conditions. Interestingly, EE exposure was found to induce the synthesis of BACE1 and endogenous Aβ in BT paradigm along with their potential interplay with PKMζ signaling to facilitate NOR-LTM consolidation. Taken together, our results provide first hand evidence of the role of BACE1 and endogenous Aβ as novel PRP complex in EE mediated BT phenomenon. The results provide significant advance in our understanding of LTM consolidation process and paves the way for exploration of novel molecular pathways involved in the process. Show less

This study aimed to investigate the role of the Midline1 gene in secondary palate development by analyzing its expression and function in palatal shelf fusion and morphology. Initially, twenty mouse embryos were collected for each of the embryonic stages E13.5, E13.75, and E14.5. Whole-mount in situ hybridization was performed approximately ten times to optimize the experimental protocol and to analyze the expression pattern of Midline1 (MID1) in the palatal tissues at these developmental stages. Subsequently, palatal tissues from E13.5 embryos were treated with varying concentrations of Midline1 small interfering RNA (MID1 siRNA), and the knockdown efficiency was evaluated using Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR), with each concentration tested in triplicate. Based on the results, the most effective concentration, 100 nM MID1 siRNA, was selected for further experiments. Subsequently, twelve E13.5 palatal explants were allocated into two groups: six explants were treated with 100 nM MID1 siRNA (experimental group), and six with scrambled small interfering RNA(Scramble siRNA; control group). After 48 h of in vitro culture, hematoxylin and eosin (HE) staining was performed to evaluate the morphology of palatal shelf fusion. To evaluate apoptotic activity, Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) staining was performed on both experimental and control groups. Finally, immunohistochemistry and Western blot analyses were conducted to examine the expression levels of Matrix Metalloproteinase 8 (MMP8) and Snail Family Transcription Factors (Snail) proteins in three biological replicates from each group. Midline1 deficiency resulted in incomplete palatal shelf fusion and significantly reduced apoptosis. Additionally, the knockdown of Midline1 led to the upregulation of Snail and MMP8 gene expression, indicating that Midline1 plays a critical role in regulating epithelial-to-mesenchymal transition and maintaining cytoskeletal stability during palate development. Midline1 is essential for normal secondary palate development. Its dysregulation disrupts palatal shelf fusion and morphology, potentially contributing to craniofacial abnormalities such as cleft palate. These findings provide new insights into the molecular mechanisms underlying palate development and suggest that Midline1 could be a therapeutic target for addressing cleft palate and related defects. Show less

Sustained activation of hepatic stellate cells (HSCs) drives liver fibrosis in response to chronic liver injury and inflammation. It is reported that profibrogenic signals released from stressed/injured hepatocytes evoke fibrogenic responses in HSCs. However, intrahepatocyte players that modulate such cell-to-cell communications remain poorly defined. In this study, hepatic ChREBPα is found to be reduced in mouse models of chemical-induced liver fibrosis as well as in three groups of human patients with liver fibrosis. Chrebpα-LKO mice are highly sensitive to both chemical (CCL4 and TAA) and bile duct ligation (BDL)-induced liver injury and developed more advanced liver fibrosis without affecting liver lipid content. Hepatocyte ChREBPα overexpression suppressed the activation of HSCs in an in vitro medium transfer experiment in part via inhibiting the expression of profibrogenic factors THBS1 and CTGF. RNA-Seq analysis revealed that E2F1, a novel effector of TGFβ-mediated fibrogenic pathway, is highly induced in the liver of Chrebpα-LKO mice. Hepatic knockdown of E2F1 ameliorated the increased liver fibrosis in mice with hepatic Chrebpα deficiency while reducing the expression of hepatic THBS1 and CTGF. Show less

Macrophages are essential immune cells in all tissues and are vital for maintaining tissue homeostasis, immune surveillance, and immune responses. Considerable efforts have identified shared and tissue-specific gene programs for macrophages across organs during homeostasis. This information has dramatically enhanced the understanding of tissue-restricted macrophage programming and function. However, few studies have addressed the overlapping and tissue-specific responses of macrophage subsets following inflammation. One subset of macrophages observed across several studies, lipid-associated macrophages (LAMs), have gained interest due to their unique role in lipid metabolism and potential as a therapeutic target. LAMs are associated with regulating disease outcomes in metabolically related disorders including atherosclerosis, obesity, and metabolic dysfunction-associated steatotic liver disease. We utilized single-cell RNA sequencing datasets to profile LAM diversity across multiple tissues and inflammatory conditions in mice and humans, to define a shared LAM transcriptional profile, including Trem2 and Lpl, and sets of tissue-specific gene programs. Importantly, LAM markers were highly conserved with human LAM populations that emerge in inflammation. Overall, this analysis provides a detailed transcriptional landscape of tissue-restricted and shared LAM gene programs, data that may help instruct appropriate molecular targets for broad or tissue-restricted therapeutic interventions to modulate LAM populations in disease. Show less

During obesity, the excessive accumulation of fat in tissue promotes dysregulated hormonal and cytokine homeostasis that triggers chronic inflammation, which is, in part, associated with an increased incidence of some cancers. This protumoral inflammatory environment is further exacerbated through the secretome of mature adipocytes, which promotes tumor angiogenesis. Emerging studies suggest that human adipocyte-derived mesenchymal stromal/stem cells (ADMSCs) may contribute to a complementary process supporting local angiogenesis termed vasculogenic mimicry (VM). The molecular mechanisms linking ADMSCs to VM and inflammation remain poorly understood. ADMSC 3D capillary-like structures were generated upon seeding on Cultrex. Structure analysis was performed using WIMASIS. Total RNA was extracted using TRIzol and RT-qPCR was performed to assess gene expression or screen RT Our findings revealed that in vitro priming of ADMSCs with Cultrex led to the formation of 3D capillary-like structures and the acquisition of an inflammatory molecular signature. VM-derived ADMSCs share a common proinflammatory molecular signature similar to that induced in 2D ADMSC monolayers by tumor necrosis factor (TNF)-alpha and are characterized by upregulated expression of COX2, CCL2, CCL5, CXCL5, CXCL8, IL-6, SNAI1, and MMP9. Interestingly, pharmacological inhibition or gene silencing of the JAK2/STAT3 signaling pathway reduced chemotactic cell migration, in vitro VM and the expression of proinflammatory and invasive biomarkers. Overall, we provide novel evidence that inhibiting JAK2/STAT3-regulated VM can also alter the acquisition of a proinflammatory signature and prevent the contribution of ADMSCs to alternative tumor neovascularization processes. Show less

An acute increase of lipids in the upper small intestine (USI) of rodents and humans triggers lipid-sensing pathways to reduce food intake. However, USI lipid sensing does not reduce feeding in high-fat (HF) fed conditions, and the underlying mechanism remains elusive. Here, we report that HF feeding in male rats impaired USI lipid infusion to stimulate glucose-dependent insulinotropic polypeptide (GIP) secretion and decrease refeeding, and the defects of USI lipid sensing were restored by metformin. Next, we found that infusion of GIP receptor (GIPR) agonist in the nucleus of the solitary tract (NTS), but not mediobasal hypothalamus or area postrema, resulted in decreased refeeding in chow-fed rats. The anorectic effect of NTS GIPR agonist remained intact in HF rats and was inhibited by a genetic knockdown of GIPR. Finally, an inhibition of NTS GIPR also negated the ability of USI lipid sensing with metformin to decrease refeeding despite an increase in plasma GIP levels in HF rats. Thus, USI lipid sensing in HF rats is enhanced by metformin to trigger an endocrine GIP to NTS GIPR axis to reduce food intake, thereby unveiling small intestinal lipid-sensing pathways as potential targets to enhance GIP action and reduce weight in obesity. High-fat (HF) feeding in rats impairs upper small intestine (USI) lipid sensing to increase plasma glucose-dependent insulinotropic polypeptide (GIP) levels and reduce feeding. Metformin enhances USI lipids to increase GIP and reduce feeding in HF-fed rats. GIP activates the GIP receptor (GIPR) in the nucleus of the solitary tract (NTS), which reduces food intake in HF-fed rats. GIPR in the NTS is required for small intestinal lipids with metformin to reduce feeding. Show less

In this study, a comprehensive bioinformatics workflow is employed to investigate the impact of APOE gene variants on Alzheimer's disease (AD) and to explore their relevance for improving therapeutic strategies. Multiple databases were screened to identify key non-synonymous single nucleotide polymorphisms (nsSNPs) in APOE. Six variants: rs769452 (L46P), rs429358 (C130R), rs267606664 (G145D), rs121918393 (R154S), rs7412 (R176C), and rs267606661 (R269G) were selected, of which five were predicted to be deleterious. Given its high interaction score (0.789), the FDA-approved AD drug Donepezil was chosen as the ligand to assess binding with both wild-type and mutant APOE proteins. Structural modeling using AlphaFold3 generated high-quality APOE structures, and in silico mutagenesis revealed mutation-dependent destabilization. AutoDock4 molecular docking was performed to evaluate binding affinities of Donepezil with the predicted active-site residues of wild-type and mutant APOE. Furthermore, 100 ns molecular dynamics simulations using AMBER20 were conducted for all APOE-Donepezil complexes. Analyses of RMSD, RMSF, and radius of gyration indicated overall structural stability, residue-level flexibility, and protein compactness throughout the simulations. Interaction profiling revealed stable hydrophobic contacts and hydrogen bonds in both wild-type and mutant complexes. Our findings suggest that structural variations arising from APOE genotypes may modulate Donepezil binding and potentially influence therapeutic response in AD patients. However, these computational predictions require validation through biophysical assays, cellular experiments, and genotype-stratified clinical studies. Integrating molecular modeling with experimental research will be essential for advancing APOE-guided precision medicine and optimizing Donepezil therapy for Alzheimer's disease. Show less