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Polychlorinated biphenyls (PCBs) are environmental pollutants associated with various health issues, including breast cancer. This study investigates potential molecular mechanisms by which PCBs may influence breast cancer progression using computational and preliminary experimental approaches. We conducted a differential expression analysis using the TCGA-BRCA dataset. PCBs-related toxicological targets were collected from the Comparative Toxicogenomics Database (CTD). Enrichment and pathway analyses identified candidate biological processes and pathways. Protein-protein interaction (PPI) networks were constructed to identify hub genes. Single-cell expression levels of key targets were analyzed (GSE114727 dataset). Molecular docking predicted binding affinities of PCBs congeners with key targets. Cell experiments assessed gene expression changes upon PCBs exposure. We identified 52 upregulated and 24 downregulated PCBs-related toxicological targets in breast cancer. Enrichment analysis highlighted potential associations with pathways such as PI3K-Akt, MAPK, and HIF-1, including genes like BRCA1, FGFR1, IGF1, AKT1, and EGF. PPI network analysis identified key hub genes like EZH2, EGF, BRCA1, AKT1, IL6, and TNF. Single-cell analysis suggested variable expression of key targets across immune cell types. Molecular docking predicted strong binding affinities of PCB 105 with EZH2 and EGF Our integrated analysis proposes that PCBs exposure may perturb key molecular pathways in breast cancer. Computational findings implicate targets like EZH2 and EGF, while preliminary cell experiments support further investigation. These results highlight a need for mechanistic studies to confirm PCB-induced effects and their therapeutic relevance, underscoring environmental pollutants as potential risk factors in cancer. Show less

Conflicting results have been reported regarding the effect of word predictability when reading with eccentric vision. The present study aims to shed light on these discrepancies by investigating how in-context word predictability influences reading performance with a simulated scotoma, while considering the visual and lexical features of words. Thirty-five healthy young people read aloud sentences presented using the self-paced reading paradigm. A group of 22 participants practiced reading with a 10° diameter, gaze-contingent simulated central scotoma, with the other group serving as controls. Each participant underwent two in-lab sessions, reading 304 sentences (2-4 hours, depending on their group). Reading time, fixation number, and duration were analyzed for each target word using mixed-effect models. When reading with a simulated scotoma, in-context predictability shows a significant effect on performance, with a 35% decrease in reading time for highly predictable words compared with unpredictable ones (2.5 seconds vs. 1.6 seconds). This effect is modulated by practice, with the decrease dropping to 22% (1.3 seconds vs. 1.0 seconds) after only few hours of scotoma exposure. This effect seems to be driven by the total number of fixations required to identify words and is absent in the control group. These results support the hypothesis that reading with eccentric vision, which limits visual access to text, results in a stronger in-context predictability advantage. Moreover, this effect has a greater impact early in eccentric reading practice. This suggests greater reliance on linguistic inferences to compensate for impaired visual input, compared with central reading, at least until functional adaptation occurs. Show less

To investigate the gene detection results of 2 patients with familial hypercholesterolemia (FH) caused by complex heterozygous variation, and to clarify the relationship between clinical manifestations and gene variation. Two patients (patient 1 and 2) with FH who visited Beijing Anzhen Hospital Affiliated to Capital Medical University in 2018 were selected as research subjects. A retrospective study method was used to collect clinical and family history data of the two patients. And 2 mL of peripheral venous blood from each of the two patients was collected, and genomic DNA extraction was performed on the blood samples. Sanger sequencing was used to validate the variant sites of the two patients detected by whole-exome sequencing (WES). Pathogenicity of variants was classified based on the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Classification of Genetic Variants (hereinafter referred to as the "ACMG Guidelines"), and the impact of variant was analyzed using multiple bioinformatics tools including SIFT, PolyPhen-2, and SWISS-MODEL. This study has been approved by Beijing Anzhen Hospital Affiliated to Capital Medical University (Ethics No. 2024215X). Patient 1 initially presented with early-onset coronary heart disease, with initial lipid levels of serum total cholesterol (TC) 9.86 mmol/L (normal reference value: 3.10~5.20 mmol/L) and serum low-density lipoprotein cholesterol (LDL-C) 8.37 mmol/L (normal reference value: 1.27~3.12 mmol/L) on admission. Patient 1 initially underwent treatment with rosuvastatin combined with ezetimibe for one month, but the lipid-lowering effect was not significant. The lipid-lowering therapy was then adjusted to atorvastatin combined with ezetimibe and probucol. After one year of treatment, the patient developed paroxysmal chest pain symptoms. A follow-up lipid profile showed a serum TC level of 4.50 mmol/L and a LDL-C level of 3.55 mmol/L. The lipid-lowering regimen was continued, and the serum LDL-C levels were maintained between 2.65 and 3.66 mmol/L. Patient 2 was found to have an abnormally high blood lipid level and carotid artery hardening during physical examination, with an initial blood lipid level of serum TC 11.82 mmol/L and serum LDL-C 9.63 mmol/L. After receiving rosuvastatain therapy, the lipid-lowering effect was significant. WES revealed that patient 1 carried the heterozygous variants c.1871₁₈₇₃del(p.Ile624del) and c.1747C>T (p.His583Tyr) in the LDLR gene (NM₀₀₀₅₂₇.4), while patient 2 carried the heterozygous variants c.1747C>T (p.His583Tyr) in the LDLR gene and c.6936₆₉₃₇inv (p.Ile2313Val) in the APOB gene (NM₀₀₀₃₈₄₎. According to the ACMG Guidelines, the LDLR gene c.1747C>T (p.His583Tyr) was classified as a pathogenic variant (PS3+PM1+PM2_supporting+PM5+PP2+PP3), and c.1871₁₈₇₃del (p.Ile624del) was classified as a pathogenic variant (PS3+PS4+PM2_supporting+PM1+PM4); the APOB gene c.6936₆₉₃₇inv (p.Ile2313Val) was classified as a variant of uncertain clinical significance (PM2_supporting BP4). Patients 1 and 2 in this study were patients with complex heterozygous variant FH, and their genotypic differences may be related to the differences in clinical serum LDL-C levels and the efficacy of hypolipidemic agents. Show less

The importance of any enhanced atherogenicity of triglyceride (TG)-rich lipoproteins (TRLs) will depend on the relative abundance of these particles compared with low-density lipoprotein (LDL) or total apolipoprotein (apo)B. Accordingly, we determined the contribution that TRLs make to total apoB as TG or apoB concentrations increase. We also describe compositional changes in TRLs as TG or apoB increases to assess whether very low-density lipoprotein (VLDL-[C]) is a valid proxy for VLDL-apoB. We used sequential ultracentrifugation to separate lipoprotein fractions in plasma samples from 1940 dyslipidemic patients not on lipid-lowering medication, and measured apoB, cholesterol and TG in the plasma and in each subfraction. We analyzed these data in quartiles of TG or apoB. There was wide variance in all parameters in all quartiles of both TG and apoB. Although VLDL-apoB accounted for almost all the increase in total apoB across TG quartiles, LDL-apoB still accounted for 80% of the total in TG quartile 4. In contrast, LDL-apoB accounted for 90% of the increase in apoB across apoB quartiles. As TG increases, the increase in VLDL-C is explained more by increased VLDL-C/apoB when TG is moderately elevated, and more by increased VLDL-apoB when TG is very high. In conclusion, VLDL-apoB only becomes a substantial component of total apoB with extreme hypertriglyceridemia and VLDL-C is not an appropriate proxy for VLDL-apoB. Show less

Preventing the progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a considerable clinical challenge. In this study, we elucidate the role of WNT5A in accelerating the AKI-to-CKD transition and its underlying mechanisms. Renal biopsies from patients with AKI showed marked upregulation of WNT5A and its receptor, CD146, in proximal tubules, with higher expression in patients with CKD progression. In murine AKI models, Wnt5a knockdown attenuated CKD progression. Conversely, proximal tubular overexpression of Wnt5a exacerbated renal fibrosis in ischemia-reperfusion injury (IRI) mice, which was alleviated by Box5, a specific WNT5A antagonist. In vitro, WNT5A overexpression in transforming growth factor β (TGF-β)-stimulated HK-2 cells promoted CD146 upregulation, activated JNK phosphorylation, and enhanced SNAI1 expression. The genetic silencing of WNT5A/CD146 and JNK inhibition suppresses SNAI1 expression and attenuates fibrotic responses. Mechanistically, JNK-mediated c-JUN phosphorylation promoted its interaction with KLF5 at the SNAI1 promoter, driving renal fibrosis. Elevated serum levels of soluble CD146 correlated with renal function in patients with AKI and were higher in patients exhibiting CKD progression. Inhibition of WNT5A could serve as a therapeutic target for delaying renal fibrosis in AKI progression. Show less

Familial hypercholesterolaemia (FH) is a severely underdiagnosed, inherited disease, causing dyslipidaemia and premature atherosclerotic cardiovascular disease. In order to facilitate screening in a broad clinical spectrum, we aimed to analyse the current yield of routine genetic diagnostics for FH and to evaluate the performance of the Dutch Lipid Clinic Network Score (DLCNS) compared to a single value, the off-treatment LDL-cholesterol exceeding 190 mg/dL. We investigated all patients that underwent molecular genotyping routinely performed for FH over a 4-year period in two Austrian specialist lipid clinics. Variants reported in FH-causing genes including LDLR, APOB, PCSK9, LDLRAP, and APOE were collected and classified. For clinical classification, the DLCNS was calculated retrospectively and compared to the original scores documented in patient charts. Additionally, a literature review on comparisons of DLCNS to LDL-C was performed. Of 469 patients tested, 21.3% had a disease-causing variant. A median of 3 out of 8 (excluding genotyping results and LDL-C) DLCNS criteria were unavailable. DLCNS was documented in 48% of cases, with significant discrepancies compared to retrospective scoring (P < 0.001). DLCNS did not outperform off-treatment LDL-C alone (Δ = 0.006; P = 0.660), analogously to several reports identified in the literature. A single cut-off of 190 mg/dL LDL-C compared to DLCNS ≥ 6 showed excellent sensitivity (84.9% vs. 53.8%) and acceptable specificity (39.0% vs. 84.1%). Missing criteria and severe discrepancies observed between retrospective and on-site scoring by treating physicians were highly prevalent, confirming limited utility of DLCNS in clinical routine and warranting a single off-treatment LDL-C cut-off of 190 mg/dL for enhanced index-case identification. Show less

Melanocortin receptor-4 (MC4R) belongs to the G protein-coupled receptor family, characterized by a classical structure of seven transmembrane domains (7TMD). They play an important role in food intake and weight regulation. In the present study, we identified melanocortin-4-receptor-like (caMC4RL) mutants of goldfish from the Qian River in the Qin Ling region and characterized their functional properties, including the constitutive activities of the mutants, ligand-induced cAMP and ERK1/2 accumulation, and AMPK activation. The results show that six caMC4RL mutants were identified in goldfish from the Qian River in the Qin Ling region, and are located in the conserved position of the Cyprinidae MC4Rs. The mutations (E57K, P296S, and R302T/K) result in the loss of Gs signaling function. The mutations (P296 and R302T/K) exhibited biased signaling in response to ACTH stimulation in the MAPK/ERK pathway. In addition, the E57K mutant may play a role in weight regulation and could serve as molecular markers for molecular breeding. These data will provide fundamental information for functional studies of teleost GPCR mutants and MC4R isoforms. Show less

Factors influencing the macrophage surfaceome define macrophage identity and behavior. Here, we use genome-wide phenotypic screens to identify genes affecting the accessibility and surface expression of macrophage signal regulatory protein alpha (SIRPA). Our data are consistent with previous evidence but also implicate glutaminyl-peptide cyclotransferase-like (QPCTL) in cis CD47-SIRPA interactions. We also identify endolysosomal factors encoded by Ras-associated binding protein 21 (RAB21) and members of the CCC (COMMD/CCDC22/CCDC93) and Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complexes as modulators of SIRPA expression. Surface immunophenotyping and surfaceome profiling show that inactivation of either Sirpa or Rab21 remodels cell surface protein expression. In contrast to Sirpa, Rab21 appears to be a general regulator of established macrophage cell surface markers. Perturbation of RAB21/Rab21 reduced Fc gamma receptor (FcγR) expression, leading to decreased uptake of antibody-nanoparticle conjugates and impaired phagocytosis of opsonized cells. To summarize, our study describes circuitry controlling SIRPA expression on macrophages and reveals a conserved RAB21-dependent trafficking pathway that has a role in modeling the cell surface of macrophages. Show less

Elevated circulating lactate serves as a critical biomarker in sepsis, yet the epigenetic mechanisms by which lactate influences disease progression remain unclear. This study aims to identify lactate-associated genes in sepsis, decode their regulatory roles, and assess their potential as therapeutic targets. We performed transcriptome-wide bioinformatic analyses to identify lactylation-related differentially expressed genes (DEGs) between sepsis patients and healthy controls. Pathway enrichment highlighted immune signaling circuits. Five DEGs (ZC3H4, RBM10, PCBP2, RBM25, HNRNPM) were prioritized via ROC analysis, and their combined expression formed a prognostic signature with strong predictive power (AUC > 0.85). Validation in murine sepsis-induced acute lung injury (ALI) models (cecal ligation-puncture and LPS challenge) confirmed significant upregulation of these five genes by qRT-PCR. RBM25 was selected for deeper functional study. Mechanistic assays implicate an RBM25-Acly axis that couples altered metabolism to histone lactylation and transcriptional reprogramming. Notably, we propose the RBM25-Acly axis that couples altered metabolism to histone lactylation and transcriptional reprogramming. Our work uncovers a novel metabolic-epigenetic circuit in sepsis driven by lactylation, with RBM25 and its regulation of ACLY as a key node. The lactylation-based gene signature offers a high-fidelity prognostic tool, and targeting the RBM25-Acly pathway may open new therapeutic avenues. These findings lay a foundation for precision interventions that integrate metabolic and epigenetic strategies in sepsis care. Show less

Facial wrinkling is a prominent sign of aging, yet individuals exhibit unique trajectories of biological aging, contributing to the variability in facial appearance. Here, we present a pioneering study exploring the association between lifestyle choices, DNA methylation, and SNP genotypes with a range of facial skin aging phenotypes. The study demonstrated that age-related facial skin phenotypes are influenced by multiple environmental stressors. Epigenome-wide association analyses identified differentially methylated cytosines mapped to 151 loci, including novel genes associated with facial wrinkles, such as EDAR (cg02925966, p = 4.96 × 10 Show less

High-risk human papillomaviruses (HPV), particularly HPV16, are major causes of anogenital and oropharyngeal cancers. The HPV late promoter, P670 in the case of HPV16, is activated upon host cell differentiation and drives the expression of viral capsid proteins. While differentiation-specific host transcription factors have been implicated in regulating this promoter, the mechanism remains incompletely understood. HPV E2 proteins activate transcription by interacting with the host protein BRD4 (Bromodomain-containing protein 4). A biotin proximity ligation screen identified several novel E2 interactors, of which many overlap with the BRD4 interactome, suggesting BRD4 mediates a large fraction of these interactions. One such interactor, ZC3H4 (Zinc finger CCCH domain-containing protein 4), is known to restrict the expression of long non-coding RNAs, including enhancer and promoter upstream antisense RNAs (uaRNAs). E2 recruits ZC3H4 in a BRD4-dependent manner to specifically activate the P670 promoter in reporter assays. Supporting this, E2 and ZC3H4 co-localize in cells with high P670 activity. ZC3H4 is upregulated during differentiation, and its knockdown in differentiated HPV16- or HPV31-positive cells reduces late viral transcripts in an E2-BRD4-dependent manner. Interestingly, knockdown of ZC3H4 does not increase viral uaRNAs, suggesting that ZC3H4 does not enhance HPV late transcription by regulating viral antisense transcription. High-risk human papillomaviruses (HPVs), particularly HPV16, can cause anogenital and oropharyngeal cancers. HPV16 relies on the differentiation-dependent activation of its late promoter, P670, to produce capsid proteins. While host transcription factors contribute to this regulation, the mechanisms remain incompletely defined. Our findings reveal that the viral E2 protein collaborates with the host protein BRD4-a critical transcriptional regulator-to recruit other cellular partners, such as ZC3H4. Normally, ZC3H4 suppresses non-coding RNAs in cells, but HPV16 repurposes it via BRD4 to activate P670. This interaction intensifies in differentiated cells, where ZC3H4 levels rise, and disrupting ZC3H4 specifically blocks late viral gene expression without affecting antisense viral transcription. This highlights a unique, differentiation-dependent strategy HPV16 uses to hijack host machinery for its replication. Show less

Obesity increases the risk of respiratory diseases that reduce respiratory chemosensitivity, such as Obesity Hypoventilation Syndrome and sleep apnea. Recent evidence suggests that obesity-related changes in the brain, including alterations in melanocortin signaling via the melanocortin-4 receptor (MC4R), may underly altered chemosensitivity. Setmelanotide, an MC4R agonist, causes weight loss in both humans and animal models. However, it is unknown the extent to which setmelanotide affects respiratory chemosensitivity independent of body weight loss. The present study uses diet-induced obese, male C57bl/6 J mice to determine the extent to which acute setmelanotide treatment affects the hypercapnic ventilatory response (HCVR). We find that ten days of daily setmelanotide treatment at 1 mg/kg, but not 0.2 mg/kg, is sufficient to cause weight loss and increase HCVR. In a separate group of animals, we find that we can emulate setmelanotide's effect on weight loss by restricting daily calories to match the hypophagia triggered by setmelanotide. These pair-fed animals exhibit improvements in HCVR similar to those who receive setmelanotide. We conclude that acute treatment with setmelanotide is as effective as weight loss at improving respiratory hypercapnic chemosensitivity. Show less

In view of the favorable effect of hormone replacement therapy (HRT) on the lipid profile in postmenopausal women, and the discrepancies that exist on the effect of medroxyprogesterone acetate (MPA) on lipoprotein concentrations and cardiovascular disease (CVD) risk, we conducted this meta-analysis of randomized controlled trials (RCT) to assess the efficacy of MPA on apolipoprotein and lipoprotein(a) concentrations in healthy postmenopausal women. A systematic search was conducted across multiple databases, including for English-language papers published up to September 2023 comparing the effect of MPA on ApoA-I, Apo-AII, and Lp(a) levels with those of a control group. A meta-analysis was conducted using a random-effects model, reporting the results as the weighted mean difference (WMD) with a 95 % confidence interval (CI). The current meta-analysis included 11 publications. the comprehensive findings indicated a noteworthy reduction in ApoA-I (WMD:-8.70 mg/dL,95 %CI: -12.80, -4.59,P<0.001), a significant increase in Lp(a) concentrations (WMD: 1.36 mg/dL, 95 % CI: 0.10, 2.63, P=0.033), and a non-significant increase in ApoB concentrations (WMD: 0.57 mg/dL, 95 %CI: -1.25, 2.40, P=0.539) after the administration of MPA in postmenopausal women. In addition, a significant reduction in ApoB levels was identified in studies with a mean participant BMI ≥25 kg/m2 (WMD: -4.94 mg/dL, 95 %CI: -5.71 to -4.18,P< 0.001) and a greater impact on ApoA-1 and Lp(a) levels was observed in trials with doses of 5 mg/day compared with 2.5 mg/day. MPA administration resulted in a significant increase in Lp(a) and decrease in ApoA-I levels and a non-significant increase in ApoB levels in healthy postmenopausal women. Show less

Numerous studies have shown that exposure to cadmium [Cd(II)] contributes to the development of cancers in the lung and other organs. Cd(II) compounds are classified as confirmed human carcinogens; however, the mechanisms underlying Cd(II)-induced carcinogenesis remain poorly understood. Small nucleolar RNA host gene 1 (SNHG1), a long non-coding RNA (lncRNA), has been identified as an oncogene. In this study, we investigated the role of SNHG1 in the invasion and migration of Cd(II)-transformed cells. Our findings revealed that SNHG1 expression was significantly elevated in Cd(II)-transformed cells compared to their passage-matched normal BEAS-2B counterparts. Silencing SNHG1 reduced the invasive and migratory capacities of Cd(II)-transformed cells and inhibited malignant transformation induced by long-term Cd exposure. Notably, ectopic expression of SNHG1 alone in BEAS-2B cells was sufficient to drive malignant transformation and enhance invasion and migration, underscoring its oncogenic potential. SRY-box 2 (Sox2), a transcription factor implicated in cancer cell proliferation, invasion, and migration, was found to be upregulated in Cd(II)-transformed cells, while SNHG1 knockdown led to decreased Sox2 protein levels. Similarly, ras-related C3 botulinum toxin substrate 1 (Rac1), a key regulator of cytoskeletal dynamics linked to tumor growth, invasion, and metastasis, was also elevated in Cd(II)-transformed cells. Knockdown of SNHG1 reduced Rac1 protein levels, and Rac1 knockout significantly suppressed invasion and migration. Additionally, we observed increased expression of Slug, a key transcription factor invovlved in epithelial-mesenchymal transition (EMT), and decreased expression of its downstream target E-cadherin in Cd(II)-transformed cells. Collectively, these results demonstrate that elevated SNHG1 promotes the expression of Sox2, Rac1, and Slug, thereby driving the invasive and migratory behavior of Cd(II)-transformed cells. Show less

Pancreatic islets undergo coordinated cellular remodeling during obesity-induced insulin resistance (IR). However, the associated molecular changes across endocrine and non-endocrine compartments remain largely unexplored. Here, using longitudinal single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) on islets from C57BL/6 mice subjected to high-fat diet (HFD) feeding for 8, 16, and 24 weeks, along with age-matched controls on regular chow, we mapped dynamic changes in islet cell composition and transcriptional states. Beta cells demonstrated pronounced stress-induced reprogramming, with the emergence of proliferative and dysfunctional subsets. Alpha and delta cell fractions declined under HFD, despite increased polyhormonal biosynthesis, suggesting functional rather than numerical adaptation. Immune profiling showed robust expansion of proinflammatory M1 macrophages and upregulation of NF-κB and chemotaxis pathways, particularly at 16 weeks. Notably, cell-cell communication analyses revealed diet-specific disruption in signaling networks. Under HFD conditions, intercellular communication among beta cells, macrophages, and delta cells was markedly altered, leading to the disruption of key signaling pathways such as the gastric inhibitory polypeptide receptor (GIPR) and major histocompatibility complex-I (MHC-I). Notably, C-C motif chemokine ligand 27A ( Show less

Sneddon-Wilkinson (SW) disease is rare condition which typically occurs in the context of a monoclonal immunoglobulin and treatment options have not been well studied. Here we present a case of a 65-year-old female with SW with underlying, otherwise indolent, lymphoplasmacytic lymphoma (LPL) with an IgA paraprotein, who achieved a complete skin remission with the administration of the Bruton Tyrosine Kinase inhibitor (BTKi), acalabrutinib. Show less

Monogenic obesity caused by mutations in the melanocortin-4 receptor (MC4R) gene remains a significant health challenge, despite numerous efforts to discover effective treatments. The MC4R has emerged as a promising target for drug development due to its role in energy homeostasis and adipose tissue formation. Show less

Gentidelasides A-G (1-7) seven unreported loganin derivatives and fourteen known compounds (8-21) were isolated from the flowers of Gentiana delavayi Franch. Their structures including absolute configurations were unambiguously elucidated by analysis of extensive NMR spectroscopy, ECD, and HRESIMS, as well as enzymatic hydrolysis. In vitro bioassay, compound 7 showed obvious inhibitory effects on the production of Aβ40 and Aβ42, with IC Show less

Bladder cancer (BLCA) is a prevalent urological malignancy. We aim to identify novel biomarkers for BLCA and elucidate the specific regulatory mechanisms of polo-like kinase 1 (PLK1). Using differentially expressed genes (DEGs) screened from GSE38264 and GSE130598 datasets, we constructed protein-protein interaction networks to identify hub genes, whose expression was validated using reverse transcription-quantitative polymerase chain reaction. The malignant phenotype of BLCA cells was assessed by Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, Transwell, and wound-healing assays. Hematoxylin-eosin and immunohistochemical staining were employed to evaluate BLCA development in mouse xenograft models. The protein expression was detected by Western blot. PLK1, AURKA, AURKB, CDK1, ERBB2, ERBB3, FGFR1, FYN, ABL1, and PRKDC were hub genes with predictive value for BLCA. Among them, PLK1 was selected as a key target of BLCA. PLK1 knockdown inhibited the viability, proliferation, migration, and invasion of BLCA cells. In vivo, PLK1 knockdown inhibited tumor growth. Silencing PLK1 activated the Hippo pathway in BLCA cells and tumor tissues. The Hippo pathway inhibitor reversed the inhibitory effects of PLK1 silencing on malignant phenotype of BLCA cells. PLK1 knockdown exerts an inhibitory effect on BLCA via activating the Hippo pathway, which presents promising therapeutic strategies for BLCA. Show less

Low-density lipoprotein (LDL) aggregation is nowadays considered a therapeutic target in atherosclerosis. DP3, the retro-enantio version of the sequence Gly Tg mice were fed an HFD for 21 days to induce atherosclerosis and then randomized into three groups that received a daily subcutaneous administration (10 mg/kg) of i) vehicle, ii) DP3 peptide, or iii) a non-active peptide (IP321). The in vivo biodistribution of a fluorescent-labeled peptide version (TAMRA-DP3), and its colocalization with ApoB100 in the arterial intima, was analyzed by imaging system (IVIS) and confocal microscopy. Heart aortic roots were used for atherosclerosis detection and quantification. LDL functionality was analyzed by biochemical, biophysical, molecular, and cellular studies. Intimal neutral lipid accumulation in the aortic root was reduced in the DP3-treated group as compared to control groups. ApoB100 in LDLs from the DP3 group exhibited an increased percentage of α-helix secondary structures and decreased immunoreactivity to anti-ApoB100 antibodies. LDL from DP3-treated mice were protected against passive and sphingomyelinase (SMase)-induced aggregation, although they still experienced SMase-induced sphingomyelin phospholysis. In patients with familial hypercholesterolemia (FH), DP3 efficiently inhibited both SMase-induced phospholysis and aggregation. DP3 peptide administration inhibits atherosclerosis by preserving the α-helix secondary structures of ApoB100 in a humanized ApoB100 murine model that mimicks the hallmark of human hypercholesterolemia. Show less

Infiltration of adipocytes into the pancreatic parenchyma has been linked to impaired insulin secretion in individuals with increased genetic risk of T2D and prediabetic conditions. However, the study of this ectopic fat depot has been limited by the lack of suitable in vitro models. Here, we developed a novel 3D model of functionally mature human pancreatic adipose tissue organoids by aggregating human pancreatic adipose tissue-derived stromal vascular fraction (SVF) cells into organoids and differentiating them over 19 days. These organoids carry biological properties of the in situ pancreatic fat, presenting levels of adipogenic markers comparable to native pancreatic adipocytes and improved lipolytic and anti-lipolytic response compared to conventional 2D cultures. The organoids harbour a small population of immune cells, mimicking in vivo adipose environment. Furthermore, they express GIPR, allowing investigation of incretin effects in pancreatic fat. In accordance, GIP and the dual GLP1R/GIPR agonist tirzepatide stimulate lipolysis but had distinct effects on the expression of proinflammatory cytokines. This novel adipose organoid model is a valuable tool to study the metabolic impact of incretin signalling in pancreatic adipose tissue, revealing potential therapeutic targets of incretins beyond islets. The donor-specific metabolic memory of these organoids enables examination of the pancreatic fat-islet crosstalk in a donor-related metabolic context. Show less

Alzheimer's disease (AD) is the leading cause of dementia, characterized by the buildup of amyloid plaques and neurofibrillary tangles, which lead to neuronal damage and trigger inflammatory responses in glial cells. The fibroblast growth factor receptor 1 (FGFR1)-mediated signaling pathways support the function of damaged neurons and modulate the inflammatory response. The FGFR1 agonists, including Fibroblast growth factor 1 (FGF1) and FG loop peptide (FGL), have been implicated in multiple disease therapies. However, whether FGFR1 agonists can improve pathology and cognitive function in AD remains unknown. This study showed that administration of FGF1 and FGL to the AD mouse model reversed spatial memory impairment, enhanced neurogenesis, suppressed reactive astrogliosis, and restricted dystrophic neurites. However, only FGF1 treatment reduced the deposition of senile plaque. In microglial culture studies, FGF1 improves the phagocytosis ability of microglia, but this effect is blocked by the FGFR1-specific inhibitor. Together, our findings suggested that FGFR1 agonists alleviate pathological and cognitive impairments in the AD mouse model. Show less

This study investigated the effects of periodontitis (P) and non-surgical periodontal therapy (NSPT) on behavior, neurodegeneration, and neuroinflammation in rats with Alzheimer's disease (AD)-like pathology. AD-like pathology was induced in rats (n = 28) using STZ neurodegeneration model. Periodontitis was experimentally induced (n = 32), and half of which received NSPT with Chlorhexidine (CHX) gel. Behavioral assessment included the passive avoidance task (PA) and Morris water maze (MWM). Levels of NLRP3, phosphorylated tau (p-tau), and tau in the hippocampus, cerebrospinal fluid (CSF), and serum were measured by ELISA, while BACE1, IL1β, iNOS, and NF-κβ proteins were assessed by Western blotting. Rats in the AD and AD + P groups performed worse in behavioral tests compared to controls (p < 0.05), whereas the NSPT group showed similar performance to controls (p > 0.05). CSF p-tau levels were comparable between AD and AD + P groups, but the hippocampal p-tau/tau ratio was significantly higher in the AD + P group (p < 0.05). BACE1 levels were similar in P and AD groups. NLRP3 and iNOS levels did not show significant differences across groups. Notably, the NSPT group exhibited reduced NF-κβ levels (p < 0.05). Periodontitis may exacerbate AD-like molecular pathology, particularly by promoting tau hyperphosphorylation, while NSPT appears to mitigate disease progression and improve behavioral outcomes. Show less

This study aimed to explore active ingredients in Scrophularia ningpoensis Hemsl (SNH) with potential effects on ameloblastoma (AM) using network pharmacological approach, bioinformatic gene analysis and in vitro cell experiments. The active ingredients and their corresponding targets of SNH were identified from the Traditional Chinese Medicine Systems Pharmacology (TCMSP), as well as SwissTargetPrediction. Disease targets of AM were selected from GeneCards and DisGeNET databases. Differentially expressed genes (DEGs) of AM were identified, and Gene Ontology enrichment analysis were performed using the Gene Expression Omnibus (GEO) dataset GSE38494 through bioinformatic analysis. The STRING database platform was utilized to generate a protein-protein interaction network diagram, followed by hub gene analysis using Cytoscape software. AutoDock Vina software was used to perform molecular docking verification of the effects of the active ingredients on potential core targets. Additionally, in vitro experiments including quantitative reverse transcription polymerase chain reaction (RT-qPCR), EdU assay and CCK-8 cell proliferation assay were conducted using AM cell line AM-1 after SNH extract treatment. The study revealed that SNH contains eight active ingredients and a total of 388 drug targets, including 10 potential core targets in AM. Hub genes identified in the analysis were CCNA2, HRAS, PTGS2, PIK3CB, FGFR1, CASP3, MMP1, SLC2A1, MMP14, and MME. Molecular docking analysis demonstrated strong binding activity between key active ingredients (β-sitosterol, scropolioside A_qt, scropolioside D, scropolioside D_qt, and sugiol) and target genes (CASP3, FGFR1, HRAS, PTGS2, and SLC2A1). Gene Ontology enrichment analysis indicated that SNH exerts its effects on AM through pathways related to cellular response to abiotic stimulus, cellular response to hypoxia, and exopeptidase activity. Immunohistochemical analysis using tissue microarray showed higher expression of MMP14 and PTGS2 in AM compared to dentigerous cyst. Using AM-1 cell line, RT-qPCR results confirmed that SNH suppressed the expression of MMP14 and PTGS2 at mRNA level. Additionally, the EdUassay and CCK-8 assay indicated the inhibitory effect of SNH on the proliferation of AM-1 cells. These findings showed that SNH could suppress expression of MMP14 and PTGS2 and restrain the proliferation of AM. Our study highlights the potential of SNH as a promising therapeutic candidate for AM, which may provide more options for clinical treatment. Show less

Introduction: Pathogenic heterozygous melanocortin-4 receptor (MC4R) variants are the most common cause of monogenic obesity, affecting central satiety and appetite regulatory areas of the brain. Case Presentations: We report a pedigree with a pathogenic MC4R variant (c.380C>T, p.Ser127Leu). In the proband with obesity (BMI 35 kg/m2) and severe insulin resistance, use of combination of semaglutide and naltrexone-bupropion was successful in reducing insulin requirements and weight. His adult monozygotic twin daughters both had childhood-onset obesity; however, weight trajectories differed. Twin 1 had a peak BMI of 29.1 kg/m2, which decreased to 19.7 kg/m2 with intensive exercise and diet control without weight-lowering medication. Twin 2 had a sedentary lifestyle and epilepsy and had a peak BMI of 30.1 kg/m2; she responded well to naltrexone-bupropion and BMI decreased to 26 kg/m2. Conclusion: The manifestation of obesity, even in cases of monogenic obesity, can vary significantly due to the influence of environmental and lifestyle factors.

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Hyperphagia is a hallmark of both congenital and acquired rare melanocortin-4 receptor (MC4R) pathway diseases. Currently, the medical community has no standard treatment guidelines or approach to establishing treatment benefit. This narrative review discusses current understandings of the pathophysiology, burden, and treatment of hyperphagia and summarizes findings from a systematic literature review of validated instruments for assessing the response to hyperphagia treatment. Hyperphagia can result from dysfunction within, or damage impacting, hypothalamic pathways including the MC4R pathway, a key regulator of energy balance. The burden of hyperphagia is substantial, with negative effects experienced across physiologic, emotional, and social domains. Approaches for hyperphagia management include environmental control, lifestyle intervention, pharmacotherapy, neurocognitive approaches, and neurostimulation. There are varied approaches to determine treatment response; however, standard methodology has not been determined and largely relies on questionnaires. Studies of rare MC4R pathway diseases have improved understanding of the etiology of hyperphagia and established the need for indication-specific treatment. Targeted treatments are limited, and methods for determining treatment efficacy are varied. There is a need for consensus guidelines to establish a standard approach for the management of hyperphagia and related assessment of treatment response to improve patient morbidity. 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 balance between proliferation and persistence of pseudorabies virus (PRV) in the host is crucial for its long-term survival. Understanding the mechanisms that regulate viral survival may offer new strategies for disease prevention and control. The immediate-early gene 180 (IE180) is essential for PRV replication, and we previously identified a G-quadruplex (PQS18-1) located in the 3' untranslated region (3'UTR) of IE180 that enhances its expression and promotes viral replication. However, the mechanisms by which this G-quadruplex is unwound and contributes to immune evasion remain unclear. In this study, we identified the host helicase DHX36 as a binding partner of PQS18-1 through RNA pull-down assays. Both in vitro and cellular experiments demonstrated that DHX36 destabilizes the G-quadruplex, thereby suppressing gene expression and regulating PRV replication. Our findings reveal a novel host-virus interaction mechanism involving G-quadruplex structures and helicase activity, which may offer new targets for therapeutic intervention. Show less