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Aberrant G-protein coupled receptor (GPCR) expression is highly prevalent in cortisol-secreting primary bilateral macronodular adrenal hyperplasia (PBMAH) and unilateral adenomas. The aberrant expression of diverse GPCRs and their ligands play an important role in the over-function of various endocrine tumours. Examples include aberrant expression of MC2R, 5-HT4R, AVPR1A, LHCGR, and GnRHR in primary aldosteronism; GCGR, LHCGR, and 5-HT4R in phaeochromocytomas and paragangliomas; TRHR, GnRHR, GIPR, and GRP101 in pituitary somatotroph tumours; AVPR2, D2DR, and SSTR5 in pituitary corticotroph tumours; GLP1R, GIPR, and somatostatin receptors in medullary thyroid carcinoma; and SSTRs, GLP1R, and GIPR in other neuroendocrine tumours. The genetic mechanisms causing the ectopic expression of GIPR in cortisol-secreting PBMAHs and unilateral adenomas have been identified, but distinct mechanisms are implicated in other endocrine tumours. Development of functional imaging targeting aberrant GPCRs should be useful for identification and for specific therapies of this wide spectrum of tumours. The aim of this review is to show that the regulation of endocrine tumours by aberrant GPCR is not restricted to cortisol-secreting adrenal lesions, but also occurs in tumours of several other organs. Show less

N6-methyladenosine (m6A) is the most prevalent post-transcriptional modification of RNAs and plays a key regulatory role in various biological processes. As a member of the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) family, IGF2BP1 has recently demonstrated its ability to specifically bind m6A-modified sites within mRNAs and effectively regulate their mRNA stability. However, the precise roles of IGF2BP1 in mammalian skeletal muscle development, along with its downstream mRNA targets during myogenesis, have yet to be fully elucidated. Here, we observed that IGF2BP1 expression significantly decreased during myogenic differentiation. Knockdown of IGF2BP1 significantly inhibited myoblast proliferation while promoted myogenic differentiation. In contrast, IGF2BP1 overexpression robustly stimulated myoblast proliferation but suppressed their differentiation. Combined analysis of high-throughput sequencing and RNA stability assays revealed that IGF2BP1 can enhance fibroblast growth factor receptor 1 (FGFR1) mRNA stability and promote its translation in an m6A-dependent manner, thereby regulating its expression level and the Extracellular Signal-Regulated Kinase (ERK) pathway. Additionally, knockdown of FGFR1 rescued the phenotypic changes (namely increased cell proliferation and suppressed differentiation) induced by IGF2BP1 overexpression via attenuating ERK signaling. Taken together, our findings suggest that IGF2BP1 maintains the stability and translation of FGFR1 mRNA in an m6A-dependent manner, thereby inhibiting skeletal myogenesis through activation of the ERK signaling pathway. This study further enriches the understanding of the molecular mechanisms by which RNA methylation regulates myogenesis, providing valuable insights into the role of IGF2BP1-mediated post-transcriptional regulation in muscle development. Show less

The leucine-rich repeat-containing (LRRC) superfamily members are known for their significant roles in tumorigenesis and cellular proliferation. However, the specific regulatory role of LRRC45 in lung cancer remains unexplored. This study investigated the impact and underlying mechanisms of LRRC45 on the proliferative, migratory, and invasive capacities of lung adenocarcinoma (LUAD) cells, potentially identifying new targets for therapeutic intervention. The importance of LRRC45 in lung cancer was analyzed using the online databases of UCSC Xena, TCGA, TISIDB, and UALCAN, whereas to detect target gene expression, we used the qRT-PCR, Western blot, and immunofluorescence confocal. The cell growth was monitored by colony formation assay and migration was examined by cell migration assay. Finally, a xenograft mouse tumor model using A549 ​cells was used to explore the in vivo effect of LRRC45 in lung cancer. Inhibition of LRRC45 expression led to a notable decrease in proliferation, migration, and invasion of A549 and H1299 ​cells. LRRC45 silencing significantly reduced the tumor volume and improved the mice's survival. Additionally, inhibition of LRRC45 expression dramatically suppressed c-MYC, Slug, MMP2, and MMP9 expression. Overexpression of c-MYC and/or Slug in the LRRC45-deficient cells can partially or totally restore the LRRC45 deficiency-suppressed growth. Moreover, the overexpression of MMP2 and/or MMP9 could partially or totally restore LRRC45 deficiency-reduced cell metastasis. LRRC45 could promote the proliferative, migrative, and invasive capacities of lung cancer cells by increasing c-MYC, Slug, MMP2, and MMP9 expression, indicating the therapeutic implications and potential significance of these pathways in lung cancer. Show less

Vascular smooth muscle cell (VSMC) phenotype switch and dysfunctions have been reported to participate in aortic dissection (AD) progression. This study was aimed to investigate the role of angiopoietin-like 4 (ANGPTL4) in regulating VSMCs phenotype switch. Key genes were analyzed in AD using public datasets, and it was found that the central differential gene ANGPTL4 was up-regulated in AD. The KEGG signaling pathway annotation was performed to validate the associated pathways, and the expression of ANGPTL4 was verified using multiple datasets and clinical samples. Furthermore, the specific functions of ANGPTL4 on platelet-derived growth factor-BB (PDGF-BB)-treated human aortic smooth muscle cell (HASMC) phenotypes were investigated. The dynamic effects of ANGPTL4 and core signaling antagonists on HASMC phenotypes were examined. Hub gene ANGPTL4 was significantly up-regulated in AD. ANGPTL4 was linked to the PI3K/Akt signaling, angiogenesis, and neovascularization and remodeling. ANGPTL4 overexpression further enhanced PDGF-BB effects on HASMC phenotypes, including promoted cell viability and migration, decreased contractile VSMC markers α-SMA and SM22α, elevated ECM degradation markers MMP-2 and MMP-9, and promoted phosphorylation of PI3K and Akt. ANGPTL4 knockdown partially abolished PDGF-BB-induced contractile/synthetic VSMCs imbalance and HASMC dysfunctions. Furthermore, in ANGPTL4-overexpressing HASMCs pre-treated with PDGF-BB, the PI3K/Akt signaling inhibitor LY294002 also partially eliminated the effects caused by the PDGF-BB treatment and ANGPTL4 overexpression. ANGPTL4 is significantly up-regulated in AD. ANGPTL4 overexpression further enhanced PDGF-BB effects on HASMC phenotype switch and dysfunctions, which might be involved in the PI3K/Akt signaling. Show less

The Fibroblast growth factor (FGFs) family consists of at least 22 members that exert their function by binding and activating fibroblast growth factor receptors (FGFRs). The Fgf8/FgfD subfamily member, Fgf17, is located on human chromosome 8p21.3 and mouse chromosome 14 D2. In humans, FGF17 can be alternatively spliced to produce two isoforms (FGF17a and b) whereas three isoforms are present in mice (Fgf17a, b, and c), however, only Fgf17a and Fgf17b produce functional proteins. Fgf17 is a secreted protein with a cleavable N-terminal signal peptide and contains two binding domains, namely a conserved core region and a heparin binding site. Fgf17 mRNA is expressed in a wide range of different tissues during development, including the rostral patterning centre, midbrain-hindbrain boundary, tailbud mesoderm, olfactory placode, mammary glands, and smooth muscle precursors of major arteries. Given its broad expression pattern during development, it is surprising that adult Fgf17 Show less

Long-chain polyunsaturated fatty acid formation requires fatty acid desaturase (FADS), which is strongly linked to cancer progression. Nevertheless, it's unclear how FADS3 functions in head and neck squamous cell carcinoma (HNSCC). HNSCC cases were retrieved from TCGA and GEO databases, and FADS members with transcriptionally differential expression were identified. Clinical survival, tumor microenvironment (TME), and potential pathogenic mechanism in HNSCC were also investigated. These results were validated using tissue staining, flow cytometry and functional studies in HNSCC cell lines. When comparing HNSCC to normal epithelial tissues, FADS3 expression was much higher in the former. FADS3 upregulation was correlated with poor clinical outcomes. FADS3 was an independent prognostic factor for poor overall survival in HNSCC patients. KEGG, GO, and GSEA revealed that FADS3 expression correlated with several immune-related pathways and the epithelial-mesenchymal transition (EMT). Knocking down FADS3 restrained HNSCC cell proliferation, migration, invasion, and EMT. Single-cell dataset analysis showed an association between FADS3 and TME features. Further investigation revealed that FADS3 FADS3 may represent a target for treatment in HNSCC, which is linked to prognosis, EMT, immune infiltration, and ceRNA regulatory network of HNSCC. Show less

Hertwig's epithelial root sheath (HERS) interacts with dental apical mesenchyme and guides development of the tooth root, which is integral to the function of the whole tooth. However, the key genes in HERS essential for root development are understudied. Here, we show that Axin1, a scaffold protein that negatively regulates canonical Wnt signaling, is strongly expressed in the HERS. Axin1 ablation in the HERS of mice leads to defective root development, but in a manner independent of canonical Wnt signaling. Further studies reveal that Axin1 in the HERS negatively regulates the AKT1-mTORC1 pathway through binding to AKT1, leading to inhibition of ribosomal biogenesis and mRNA translation. Sonic hedgehog (Shh) protein, a morphogen essential for root development, is over-synthesized by upregulated mTORC1 activity upon Axin1 inactivation. Importantly, either haploinsufficiency of the mTORC1 subunit Rptor or pharmacological inhibition of Shh signaling can rescue the root defects in Axin1 mutant mice. Collectively, our data suggest that, independently of canonical Wnt signaling, Axin1 controls ribosomal biogenesis and selective mRNA translation programs via AKT1-mTORC1 signaling during tooth root development. Show less

Obesity is a growing public health concern that affects the longevity and lifestyle of all human populations including children and older individuals. Diverse factors drive obesity, making it challenging to understand and treat. While recent studies highlight the importance of GPCR signaling for metabolism and fat accumulation, we lack a molecular description of how obesogenic signals accumulate and propagate in cells, tissues, and organs. In this issue of the JCI, Jiang et al. utilized germline mutagenesis to generate a missense variant of GRP75, encoded by the Thinner allele, which resulted in mice with a lean phenotype. GPR75 accumulated in the cilia of hypothalamic neurons. However, mice with the Thinner allele showed defective ciliary localization with resistance to fat accumulation. Additionally, GPR75 regulation of fat accumulation appeared independent of leptin and ADCY3 signaling. These findings shed light on the role of GPR75 in fat accumulation and highlight the need to identify relevant ligands. Show less

Preeclampsia is a heterogeneous syndrome of diverse etiologies and molecular pathways leading to distinct clinical subtypes. Herein, we aimed to characterize the extracellular vesicle (EV)-associated and soluble fractions of the maternal plasma proteome in patients with preeclampsia and to assess their value for disease prediction. This case-control study included 24 women with term preeclampsia, 23 women with preterm preeclampsia, and 94 healthy pregnant controls. Blood samples were collected from cases on average 7 weeks before the diagnosis of preeclampsia and were matched to control samples. Soluble and EV fractions were separated from maternal plasma; EVs were confirmed by cryo-EM, NanoSight, and flow cytometry; and 82 proteins were analyzed with bead-based, multiplexed immunoassays. Quantile regression analysis and random forest models were implemented to evaluate protein concentration differences and their predictive accuracy. Preeclampsia subgroups defined by molecular profiles were identified by hierarchical cluster analysis. Significance was set at p < 0.05 or false discovery rate-adjusted q < 0.1. In preterm preeclampsia, PlGF, PTX3, and VEGFR-1 displayed differential abundance in both soluble and EV fractions, whereas angiogenin, CD40L, endoglin, galectin-1, IL-27, CCL19, and TIMP1 were changed only in the soluble fraction (q < 0.1). The direction of changes in the EV fraction was consistent with that in the soluble fraction for nine proteins. In term preeclampsia, CCL3 had increased abundance in both fractions (q < 0.1). The combined EV and soluble fraction proteomic profiles predicted preterm and term preeclampsia with an AUC of 78% (95% CI, 66%-90%) and 68% (95% CI, 56%-80%), respectively. Three clusters of preeclampsia featuring distinct clinical characteristics and placental pathology were identified based on combined protein data. Our findings reveal distinct alterations of the maternal EV-associated and soluble plasma proteome in preterm and term preeclampsia and identify molecular subgroups of patients with distinct clinical and placental histopathologic features. Show less

Intestinal anastomosis is a routine procedure in pediatric surgery, with leakage being a significant complication. Human alpha1-antitrypsin (AAT), whose physiological serum concentrations range from 0.9-2.0 mg/ml, is known to accelerate wound healing and stimulate the expression of cell proliferation-related genes. We hypothesized that AAT might enhance anastomotic healing. In a monolayer of non-tumorigenic HIEC-6 epithelial cells derived from fetal intestine a scratch was created. Standard medium without (control) or with AAT (0.5 and 1 mg/ml) was added. Cells were observed using a Life-Cell Imaging System. Cell proliferation was assessed, and the expression of proliferation-related genes was measured by qRT-PCR. In the presence of AAT, the scratch closed significantly faster. Cells treated with 1 mg/ml AAT showed 53% repopulation after 8 h and 97% after 18 h, while control cells showed 24% and 60% repopulation, respectively (p < 0.02). The treatment with AAT induced HIEC-6-cell proliferation and significantly increased the mRNA-expression of CDKN1A, CDKN2A, ANGPTL4, WNT3 and COL3A1 genes. AAT did not change the mRNA-expression of CXCL8 but decreased levels of IL-8 as compared to controls. At physiological concentrations AAT accelerates the confluence of intestinal cells and increases cell proliferation. The local administration of AAT may bear therapeutic potential to improve anastomotic healing. Show less

SGEF (also known as ARHGEF26), a RhoG specific GEF, can form a ternary complex with the Scribble polarity complex proteins Scribble and Dlg1, which regulates the formation and maintenance of adherens junctions and barrier function of epithelial cells. Notably, silencing SGEF results in a dramatic downregulation of both E-cadherin and ZO-1 (also known as TJP1) protein levels. However, the molecular mechanisms involved in the regulation of this pathway are not known. Here, we describe a novel signaling pathway governed by the Scribble-SGEF-Dlg1 complex. Our results show that the three members of the ternary complex are required to maintain the stability of the apical junctions, ZO-1 protein levels and tight junction (TJ) permeability. In contrast, only SGEF is necessary to regulate E-cadherin levels. The absence of SGEF destabilizes the E-cadherin-catenin complex at the membrane, triggering a positive feedback loop that exacerbates the phenotype through the repression of E-cadherin transcription in a process that involves the internalization of E-cadherin by endocytosis, β-catenin signaling and the transcriptional repressor Slug (also known as SNAI2). Show less

Germ cell tumors (GCTs) constitute diverse neoplasms arising in the gonads or extragonadal locations. Testicular GCTs (TGCTs) are the predominant solid tumors in adolescents and young men. Despite cisplatin serving as the primary therapeutic intervention for TGCTs, 10‑20% of patients with advanced disease demonstrate resistance to cisplatin‑based chemotherapy, and epithelial‑mesenchymal transition (EMT) is a potential contributor to this resistance. EMT is regulated by various factors, including the snail family transcriptional repressor 2 ( Show less

The hippocampus, with its complex subfields, is linked to numerous neuropsychiatric traits. While most research has focused on its global structure or a few specific subfields, a comprehensive analysis of hippocampal substructures and their genetic correlations across a wide range of neuropsychiatric traits remains underexplored. Given the hippocampus's high heritability, considering hippocampal and subfield volumes (HASV) as endophenotypes for neuropsychiatric conditions is essential. We analyzed MRI-derived volumetric data of hippocampal and subfield structures from 41,525 UK Biobank participants. Genome-wide association studies (GWAS) on 24 HASV traits were conducted, followed by genetic correlation, overlap, and Mendelian randomization (MR) analyses with 10 common neuropsychiatric traits. Polygenic risk scores (PRS) based on HASV traits were also evaluated for predicting these traits. Our analysis identified 352 independent genetic variants surpassing a significance threshold of 2.1 × 10 These findings highlight the extensive distribution of pleiotropic genetic determinants between HASVs and neuropsychiatric traits. Moreover, they suggest a significant potential for effectively managing and intervening in these diseases during their early stages. Show less

Alzheimer's disease (AD) is posing an increasing global threat and currently lacks effective treatments. Therefore, this study was aimed at exploring phytochemicals in A total of 27 phytochemicals were evaluated for their inhibitory activity against AChE, BACE1, and TACE with YASARA Structure. ADMET profiles and toxicity were assessed. The top candidate compounds underwent 100 ns MD simulations. All ligands met Lipinski's rule and showed low toxicity. Catechins, compared with the known drug galantamine, showed higher inhibitory activity and interacted with additional active sites on AChE, thus suggesting potentially higher efficacy. Moreover, chlorogenic acid showed stronger inhibitory activity against TACE than the control drug (aryl-sulfonamide), thereby suggesting a different mechanism of action. MD simulation revealed that the formed complexes had good stability. However, further exploration is necessary. Show less

Retinal dystrophies (RDs) are the most common cause of inherited blindness worldwide and are caused by genetic defects in about 300 different genes. While targeted next-generation sequencing (NGS) has been demonstrated to be a reliable and efficient method to identify RD disease-causing variants, it doesn't routinely identify pathogenic structural variant as copy number variations (CNVs). Targeted NGS-based CNV detection has become a crucial step for RDs molecular diagnosis, particularly in cases without identified causative single nucleotide or Indels variants. Herein, we report the exome sequencing (ES) data-based read-depth bioinformatic analysis in a group of 30 unrelated Mexican RD patients with a negative or inconclusive genetic result after ES. CNV detection was performed using ExomeDepth software, an R package designed to detect CNVs using exome data. Bioinformatic validation of identified CNVs was conducted through a commercially available CNV caller. All identified candidate pathogenic CNVs were orthogonally verified through quantitative PCR assays. Pathogenic or likely pathogenic CNVs were identified in 6 out of 30 cases (20%), and of them, a definitive molecular diagnosis was reached in 5 cases, for a final diagnostic rate of ~17%. CNV-carrying genes included CLN3 (2 cases), ABCA4 (novel deletion), EYS, and RPGRIP1. Our results indicate that bioinformatic analysis of ES data is a reliable method for pathogenic CNV detection and that it should be incorporated in cases with a negative or inconclusive molecular result after ES. Show less

MicroRNAs can regulate various biological functions including cell proliferation, differentiation, embryo formation, and implantation. The giant panda exhibits embryonic diapause, with embryo development resuming in late pregnancy. However, the changes in microRNAs during late pregnancy remain poorly understand. After mating, plasma samples were collected on day 40 of early pregnancy (EP; n = 3) and 30 days before delivery of late pregnancy (LP; n = 3). Following microRNAs screening, a total of 120 microRNAs were detected in the plasma exosomes of pregnant pandas. Nine differentially expressed microRNAs (DEmicroRNAs) were identified in LP compared to EP, including three that were upregulated and six that were downregulated. Notably, miR-25b and miR-47 were significantly downregulated in LP group. All DEmicroRNAs were predicted to target a total of 2,675 genes. Pathway enrichment analysis of these target genes revealed significant enrichment in the MAPK and Rap1 signaling pathways, which are closely related to cell proliferation, differentiation, and cell-cell and cell-matrix interactions. Analysis of protein-protein interaction networks showed that most of the hub genes (five out of eight), including Fgfr1, Fgf2, Fgf18, Erbb4, and Kras within the MAPK and Rap1 pathways are associated with the cell proliferation and differentiation. Significantly, Erbb4 was regulated by significantly differentially expressed miRNA-47. We suggest that plasma exosomal microRNAs are involved in cell proliferation and differentiation during embryonic development by regulating key hub genes within MAPK and Rap1 pathways. These findings provided new insights into the development of giant panda embryos. Show less

Due to their low cost, good biocompatibility, and ease of structural modification, organic long-persistent luminescence (LPL) materials have garnered significant attention in organic light-emitting diodes, biological imaging, information encryption, and chemical sensing. Efficient charge separation and carrier migration by the host-guest structure or using polymers and crystal to build rigid environments are effective ways of preparing high-performance materials with long-lasting afterglow. In this study, four types of crystalline materials (MODPA: DDF-O, MODPA: DDF-CHO, MODPA: DDF-Br, and MODPA: DDF-TRC) were prepared by a convenient host-guest doping method at room temperature under ambient conditions, i.e., in the presence of oxygen. The first three types exhibited long-lived charge-separated (CS) states and achieved visible LPL emissions with durations over 7, 4, and 2 s, respectively. More surprisingly, for the DDF-O material prepared with PMMA as the polymer substrate, the afterglow time of DDF-O: PMMA was longer than 10 s. The persistent room-temperature phosphorescence effect caused by different CS state generation efficiencies and rigid environment were the main reason for the difference in LPL duration. The fourth crystalline material was without charge separation and exhibited no LPL because it was not a D-A system. The research results indicate that the CS state generation efficiency and a rigid environment are the key factors affecting the LPL properties. This work provides new understandings in designing organic LPL materials. Show less

Competitive endogenous RNAs (ceRNA) theory has been proved in numerous biological processes. Nevertheless, there is a lack of research applying the ceRNA theory to the study of vascular calcification (VC) in chronic kidney diseases (CKD). In the present study, a ceRNA network was constructed after conducting transcriptome sequencing of differentially expressed genes, followed by experimental validation to identify a new target for the diagnosis and treatment of vascular calcification. Total RNA was extracted from β-glycerophosphate (β-GP) cultured vascular smooth muscle cells (VSMCs) on Day 7. Illumina HiSeq platform was utilized to build sequencing libraries. GO and KEGG analysis was conducted to identify the function of the differentially expressed genes. Protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. A ceRNA network was established based on TargetScan, miRDB, miRWALK, and miRanda database. Western blot and qRT-PCR were used to explore the expression level of protein and RNA, respectively. The direct binding sites were confirmed by dual-luciferase reporter assay. In total, 647 differentially expressed lncRNAs and 289 differentially expressed mRNAs were identified (|log Show less

Digital images have become an important way of transmitting information, and the risk of attacks during transmission is increasing. Image watermarking is an important technical means of protecting image information security and plays an important role in the field of information security. In the field of image watermarking technology, achieving a balance between imperceptibility, robustness, and embedding capacity is a key issue. To address this issue, this paper proposes a high-capacity color image adaptive watermarking scheme based on discrete wavelet transform (DWT), Heisenberg decomposition (HD), and singular value decomposition (SVD). In order to enhance the security of the watermark, Logistic chaotic mapping was used to encrypt the watermark image. By adaptively calculating the embedding factor through the entropy of the cover image, and then combining it with Alpha blending technology, the watermark image is embedded into the Y component of the YCbCr color space to enhance the imperceptibility of the algorithm. In addition, the robustness of the algorithm was further improved through singular value correction methods. The experimental results show that the average PSNR and SSIM of the watermarking scheme are 45.3437dB and 0.9987, respectively. When facing various attacks, the average NCC of the extracted watermark reaches above 0.95, indicating good robustness. The embedding capacity of this scheme is 0.6667bpp, which is higher than other watermarking schemes, and the average running time is 1.1136 seconds, which is better than most schemes. Show less

In recent years, metal-organic framework (MOF) materials with long persistent luminescence (LPL) have inspired extensive attention and presented various applications in security systems, information anticounterfeiting, and biological imaging fields. However, obtaining LPL materials with ultralong lifetime remains challenging. Halogen atoms, as nonmetallic elements existing in the frameworks, can not only induce the heavy-atom effect, effectively enhancing spin-orbit coupling and promoting intersystem crossing (ISC) processes, but also suppress non-radiative transition of the triplet states through the intra- and intermolecular interactions. Specifically, fluorine atoms with the strongest electronegativity may form intermolecular aggregate interlockings through halogen-bonding interactions that restrict molecular motions and vibrations, thereby improving phosphorescent lifetime. With the aforementioned considerations, two distinct types of MOFs with/without fluorine atoms (namely, Ca-MOF and 5FCa-MOF) were synthesized. Notably, by introducing fluorine atoms into MOFs, fluorine-induced intermolecular aggregate interlockings effectively enhanced the phosphorescent lifetime of 5FCa-MOF exceeding 264 ms compared to that of Ca-MOF (103.94 ms). Remarkably, both MOFs displayed bright LPL to the naked eye after removal of the irradiation source, especially 5FCa-MOF which can last for about 2 s. By introducing fluorine atoms, 5FCa-MOF exhibits greatly enhanced ISC with a rate constant up to 4.1 × 10 Show less

Elevated levels of the branched chain α-amino acids valine, leucine, and isoleucine are associated with heart disease and metabolic disorders. The kinase BDK, also known as branched-chain ketoacid dehydrogenase kinase (BCKDK), is a negative regulator of branched-chain α-amino acid metabolism through deactivation of BCKDC, the branched-chain α-ketoacid dehydrogenase complex. Inhibitors of BDK increase the activity of BCKDC and could be useful therapeutic leads for cardiometabolic diseases. We describe a novel bicyclic carboxy amide as an inhibitor of BDK with in vivo activity. Show less

The glucose-dependent insulinotropic polypeptide (GIP) decreases body weight via central GIP receptor (GIPR) signaling, but the underlying mechanisms remain largely unknown. Here, we assessed whether GIP regulates body weight and glucose control via GIPR signaling in cells that express the leptin receptor (Lepr). Hypothalamic, hindbrain, and pancreatic co-expression of Gipr and Lepr was assessed using single cell RNAseq analysis. Mice with deletion of Gipr in Lepr cells were generated and metabolically characterized for alterations in diet-induced obesity (DIO), glucose control and leptin sensitivity. Long-acting single- and dual-agonists at GIPR and GLP-1R were further used to assess drug effects on energy and glucose metabolism in DIO wildtype (WT) and Lepr-Gipr knock-out (KO) mice. Gipr and Lepr show strong co-expression in the pancreas, but not in the hypothalamus and hindbrain. DIO Lepr-Gipr KO mice are indistinguishable from WT controls related to body weight, food intake and diet-induced leptin resistance. Acyl-GIP and the GIPR:GLP-1R co-agonist MAR709 remain fully efficacious to decrease body weight and food intake in DIO Lepr-Gipr KO mice. Consistent with the demonstration that Gipr and Lepr highly co-localize in the endocrine pancreas, including the β-cells, we find the superior glycemic effect of GIPR:GLP-1R co-agonism over single GLP-1R agonism to vanish in Lepr-Gipr KO mice. GIPR signaling in cells/neurons that express the leptin receptor is not implicated in the control of body weight or food intake, but is of crucial importance for the superior glycemic effects of GIPR:GLP-1R co-agonism relative to single GLP-1R agonism. Show less

The role of histone methyltransferase SETDB1 in renal ischemia-reperfusion (I/R) injury has not been explored yet. This study aims to investigate the potential mechanism of SETDB1 in regulating renal I/R injury and its impact on mitochondrial damage and oxidative stress. The in vivo model of renal I/R in mice and the in vitro model of hypoxia/reoxygenation (H/R) in human renal tubular epithelial cells (HK-2) were constructed to detect the expression of SETDB1. Next, the specific inhibitor (R,R)-59 and knockdown viruses were used to inhibit SETDB1 and verify its effects on mitochondrial damage and oxidative stress. Chromatin immunoprecipitation (ChIP) and coimmunoprecipitation (CoIP) were implemented to explore the in-depth mechanism of SETDB1 regulating renal I/R injury. The study found that SETDB1 had a regulatory role in mitochondrial damage and oxidative stress during renal I/R injury. Notably, SESN2 was identified as a target of SETDB1, and its expression was under the influence of SETDB1. Besides, SESN2 mediated the regulation of SETDB1 on renal I/R injury. Through deeper mechanistic studies, we uncovered that SETDB1 collaborates with heterochromatin HP1β, facilitating the labeling of H3K9me3 on the SESN2 promoter and impeding SESN2 expression. The SETDB1/HP1β-SESN2 axis emerges as a potential therapeutic strategy for mitigating renal I/R injury. Show less

Chronic kidney disease confers a high risk of atherosclerotic cardiovascular disease (ASCVD), partly due to hyperlipidemia. Although statins reduce the risk of ASCVD in chronic kidney disease, residual risk persists. We investigated whether higher remnant cholesterol is associated with an increased risk of ASCVD in statin users and nonusers with impaired renal function. We included 107 925 individuals from CGPS (Copenhagen General Population Study) initiated in 2003 to 2015, of whom 10 427 had impaired renal function (estimated glomerular filtration rate, <60 mL/min per 1.73 m In individuals with impaired renal function during up to 15 years of follow-up, 597 were diagnosed with myocardial infarction, 618 with ischemic stroke, and 1182 with ASCVD. In these individuals, a 1-mmol/L (39 mg/dL) higher remnant cholesterol level was associated with multivariable-adjusted hazard ratios of 1.22 (95% CI, 1.05-1.42) for myocardial infarction, 1.16 (95% CI, 0.97-1.38) for ischemic stroke, and 1.21 (95% CI, 1.08-1.36) for ASCVD. Corresponding hazard ratios for ASCVD were 1.40 (95% CI, 1.07-1.83) in statin users and 1.16 (95% CI, 1.01-1.34) in nonusers. Of the 1.36-fold excess risk of ASCVD in impaired versus normal renal function, elevated remnant cholesterol and elevated LDL (low-density lipoprotein) cholesterol explained 25% (95% CI, 2.5%-47%) and 0% in statin users and 8.3% (95% CI, 2.4%-14%) and 14% (95% CI, 6.4%-22%) in nonusers, respectively. Our results suggest that higher remnant cholesterol is a good marker of increased risk of ASCVD in individuals with impaired renal function, while higher LDL cholesterol may not be. Patients with chronic kidney disease who have high levels of remnant cholesterol are identifiable through higher non-HDL (high-density lipoprotein) cholesterol or apoB levels. Show less

This study examined dark microglia-a state linked to central nervous system pathology and neurodegeneration-during postnatal development in the mouse ventral hippocampus, finding that dark microglia interact with blood vessels and synapses and perform trogocytosis of pre-synaptic axon terminals. Furthermore, we found that dark microglia in development notably expressed C-type lectin domain family 7 member A (CLEC7a), lipoprotein lipase (LPL) and triggering receptor expressed on myeloid cells 2 (TREM2) and required TREM2, differently from other microglia, suggesting a link between their role in remodeling during development and central nervous system pathology. Together, these results point towards a previously under-appreciated role for dark microglia in synaptic pruning and plasticity during normal postnatal development. Show less

Since ANGPTL4 was discovered to be involved in lipid metabolism in 2000 for the first time, Angptl4 has attracted the attention of researchers. With the further research, it was found that angptl4 was also involved in many biological activities (glucose metabolism, angiogenesis, wound healing, tumor growth, etc.) in vivo. In this review, we provide an overview of the fundamental role of ANGPTL4 in metabolic regulation and its impact on tumor growth. These insights may provide a way for exploring ANGPTL4 as a potential therapeutic target for future disease treatments. Show less

Bone is a highly dynamic organ that changes with the daily circadian rhythm. During the day, bone resorption is suppressed due to eating, while it increases at night. This circadian rhythm of the skeleton is regulated by gut hormones. Until now, gut hormones that have been found to affect skeletal homeostasis include glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), and peptide YY (PYY), which exerts its effects by binding to its cognate receptors (GLP-1R, GLP-2R, GIPR, and Y1R). Several studies have shown that GLP-1, GLP-2, and GIP all inhibit bone resorption, while GIP also promotes bone formation. Notably, PYY has a strong bone resorption-promoting effect. In addition, gut microbiota (GM) plays an important role in maintaining bone homeostasis. This review outlines the roles of GLP-1, GLP-2, GIP, and PYY in bone metabolism and discusses the roles of gut hormones and the GM in regulating bone homeostasis and their potential mechanisms. Show less

Glucose dependent insulinotropic polypeptide (GIP) is well established as an incretin hormone, boosting glucose-dependent insulin secretion. However, whilst anorectic actions of its sister-incretin glucagon-like peptide-1 (GLP-1) are well established, a physiological role for GIP in appetite regulation is controversial, despite the superior weight loss seen in preclinical models and humans with GLP-1/GIP dual receptor agonists compared with GLP-1R agonism alone. We generated a mouse model in which GIP expressing K-cells can be activated through hM3Dq Designer Receptor Activated by Designer Drugs (DREADD, GIP-Dq) to explore physiological actions of intestinally-released GIP. In lean mice, Dq-stimulation of GIP expressing cells increased plasma GIP to levels similar to those found postprandially. The increase in GIP was associated with improved glucose tolerance, as expected, but also triggered an unexpected robust inhibition of food intake. Validating that this represented a response to intestinally-released GIP, the suppression of food intake was prevented by injecting mice peripherally or centrally with antagonistic GIPR-antibodies, and was reproduced in an intersectional model utilising Gip-Cre/Villin-Flp to limit Dq transgene expression to K-cells in the intestinal epithelium. The effects of GIP cell activation were maintained in diet induced obese mice, in which chronic K-cell activation reduced food intake and attenuated body weight gain. These studies establish a physiological gut-brain GIP-axis regulating food intake in mice, adding to the multi-faceted metabolic effects of GIP which need to be taken into account when developing GIPR-targeted therapies for obesity and diabetes. Show less

Mixed hyperlipidemia represents a substantial public health issue and a considerable burden on healthcare systems. Although the introduction of statins and LDL-cholesterol lowering agents have significantly reduced the incidence of atherosclerotic cardiovascular diseases (ASCVD), a significant portion of the population continues to exhibit ASCVD progression due to elevated triglyceride-rich lipoprotein (TRL) levels. This persistent risk has catalyzed the development of novel pharmacological interventions targeting these lipoproteins. Our special report commenced with a targeted PubMed search using keywords such as 'plozasiran,' 'zodasiran,' and terms related to APOC3 and ANGPTL3. As the review progressed, emergent research questions guided further searches, allowing for the inclusion of additional relevant articles to comprehensively illustrate the linkage between TRLs and cardiovascular disease, discuss the roles of APOC3, ANGPTL3, and the pharmaceutical agents that target these proteins, and provide a comparison on the ARCHES-2 and MUIR trials. The ARCHES-2 and MUIR trials demonstrated effective triglyceride reduction by these therapies, yet it is uncertain if this correlates with significant clinical benefits. Advances in antisense oligonucleotide technology, especially the GalNAc delivery platform, show promise for personalized lipid management, though challenges such as cost and safety concerns remain. Show less