Search Results (3,770)

Hypertriglyceridemia is a well-recognized contributor to residual atherosclerotic cardiovascular disease risk and a predisposing factor for acute pancreatitis. Despite the availability of currently available pharmacologic agents and lifestyle interventions, patients with severe and refractory hypertriglyceridemia often fail to achieve adequate control. Recent advances in the molecular understanding of triglyceride metabolism have driven the development of targeted therapies that selectively modulate key regulatory pathways. This study sought to provide an overview of triglyceride regulation, the atherogenic role of remnant lipoproteins, and clinical evidence of emerging triglyceride-lowering therapies. Lipoprotein metabolism is regulated by a complex network of regulatory proteins that include lipoprotein lipase (LPL), apolipoproteins such as apolipoprotein C-III (ApoC-III), and angiopoietin-like proteins (ANGPTLs). Targeting these proteins in the metabolic cascade has shown promising results in reducing triglyceride levels. Emerging therapies such as antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) directed against ApoC-III (volanesorsen, olezarsen, and plozasiran), inhibitors of ANGPTL3 (evinacumab and zodasiran), and fibroblast growth factor 21 (FGF-21) analogs (pegozafermin) have demonstrated substantial triglyceride-lowering efficacy. These agents have achieved reductions in triglyceride levels of up to 80 percent in clinical trials. Additionally, preliminary evidence suggests that these agents may also reduce the incidence of acute pancreatitis and improve cardiometabolic risk profiles, although dedicated trials are still needed to confirm these outcomes. The therapeutic landscape for hypertriglyceridemia is rapidly evolving. Integrating these novel agents into clinical practice will require individualized treatment plans, sustained lifestyle modification, and careful safety monitoring. Full article

CRISPR interference (CRISPRi), a programmable transcriptional repression technology derived from nuclease-deficient CRISPR-Cas systems, has emerged as a powerful method for selectively inhibiting oncogene expression without altering the genomic DNA. This feature offers a major advantage over other oncogene targeting technologies such as CRISPR-mediated gene knockout, mRNA inhibition by siRNA or miRNA, or small-molecule inhibitors of the proteins encoded by the oncogenes, especially in cancers driven by transcriptional dysregulation or otherwise undruggable oncogenes. Here, I present a comprehensive review of CRISPRi mechanisms, delivery strategies, and preclinical applications in oncology (including advances in targeting core oncogenic drivers like MYC and KRAS). The advantages of CRISPRi as well as in vivo validation of CRISPRi-mediated tumor suppression are discussed. Finally, I outline translational challenges and future directions for incorporating CRISPRi into precision cancer therapies. The accumulated evidence suggests that CRISPRi could become a cornerstone for next-generation gene-regulatory therapeutics. Full article

Attention-Deficit/Hyperactivity Disorder (ADHD), affecting 5–10% of children globally, faces treatment limitations due to adverse effects and uncertain long-term risks of current pharmacotherapies. This study investigated the therapeutic potential of sepia ink (SI), a marine-derived natural complex from cuttlefish, in a scopolamine-induced ADHD-like mouse model. The chemical constituents of SI were characterized via Ultra-Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS). The behavioral assessments, histopathological examinations, flow cytometry, and complete blood counts were utilized to evaluate its effects on ADHD-like phenotypes, neuroinflammation, and immune function. Integrated transcriptomic, plasma metabolomic, and 16S rRNA sequencing were used to explore the underlying mechanisms. SI significantly alleviated hyperactivity and improved spatial learning and memory deficits. It reduced hippocampal neuronal damage, attenuated neuroinflammation, and reversed scopolamine-induced immunosuppression in spleen and thymus. SI also restored the balance of immune cell subsets in both mesenteric lymph nodes and spleen, and the peripheral blood cell counts. Multi-omics analyses suggested that the beneficial effects of SI were associated with reduced neuroinflammation, rebalanced systemic immune responses, partial correction of lipid metabolic disturbances, and restoration of gut microbiota homeostasis. Collectively, our findings indicate that SI effectively mitigates the in vivo ADHD-like impairments by coordinating immune, metabolic, and gut microbiota-related processes, thereby supporting its potential as a marine-derived therapeutic candidate for further ADHD treatment. Full article

Objectives: The mechanism of action of genes related to lactate metabolism in papillary thyroid carcinoma (PTC) is still unclear. In this study, key genes that play a role in PTC were selected from the known genes related to lactate metabolism, and their roles in promoting lactate metabolism in PTC cells were investigated. Methods: Through bioinformatics analysis and cell experiments, the roles of the relevant genes in lactate metabolism and their roles in the occurrence and development of PTC were verified. Results: Through bioinformatics analysis, 12 candidate genes were obtained. Through qRT-PCR experiments, it was confirmed that the expressions of TIMP1 and DPP4 were higher in thyroid papillary carcinoma than in normal PTC cells. By inhibiting the expression of TIMP1 and DPP4 using siRNA, the invasion and proliferation abilities of PTC could be reduced. Compared with normal thyroid cells, the contents of lactic acid and LDHA in PTC cells were higher. Knocking down the expression of TIMP1 and DPP4 would reduce the lactate production ability of PTC cells, and TIMP1 and DPP4 promoted the accumulation of lactate in PTC cells.Conclusions: In this study, by screening the differentially expressed lactate metabolism genes in PTC, different prognostic subtypes were constructed based on the molecular expression patterns. Multi-group student’s t-tests were conducted on the differential signaling pathways and tumor immune regulation of the prognostic subtypes, and a PTC prognosis prediction model was constructed. It was further confirmed that the lactate metabolism genes TIMP1 and DPP4 are highly expressed in PTC and can regulate the proliferation, invasion, metastasis and lactate metabolism of PTC cells. Full article

Background/Objectives: Influenza A virus (IAV) infection triggers robust inflammation and acute lung injury. Andrographolide, a primary active compound from Andrographis paniculata, can mitigate IAV-induced inflammation; however, its precise mechanisms remain poorly elucidated. This study aimed to define its host-directed protective effects and molecular mechanisms. Methods: We used a lethal IAV (H1N1, PR8) model in BALB/c mice and infected A549 cells. Survival, lung pathology, cytokines, and viral titers were measured. Lung RNA sequencing identified dysregulated signaling pathways. PI3K/AKT and pyroptosis pro-teins were analyzed by Western blot. The PI3K/AKT axis was functionally validated with the AKT inhibitor in vivo and AKT1 siRNA in vitro. Results: Andrographolide improved survival, attenuated body weight loss, and reduced lung pathology and inflammatory cytokine levels in IAV-infected mice, without exhibiting direct antiviral activity. Consistent with the in vivo findings, andrographolide enhanced cell viability and suppressed cytokine secretion in infected cells. RNA sequencing revealed marked upregulation of the PI3K/AKT signaling pathway in the lungs of treated mice, as confirmed by increased PI3K and AKT phosphorylation. Furthermore, andrographolide downregulated the expression of key pyroptosis-executing proteins, including cleaved caspase-3 and the gasdermin E (GSDME) N-terminal fragment. These protective effects were substantially abrogated by an AKT inhibitor and AKT1 siRNA. Conclusions: These findings reveal a novel host-directed mechanism by which andrographolide alleviates IAV-induced immunopathology by activating the PI3K/AKT pathway, thereby suppressing caspase-3/GSDME-dependent pyroptosis. Thus, this axis represents a promising target for controlling excessive inflammation in severe influenza. Full article

Background: Chronic kidney disease (CKD) associated vascular calcification (VC) is a leading cause of cardiovascular mortality, partially driven by osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation cellular process. However, the precise role and mechanism of CMA in CKD-associated vascular calcification remain unknown. Methods: We studied calcified arteries from CKD patients and rats fed on a high-phosphate diet using histological and ultrastructural methods. VSMCs' calcification was induced by a calcification medium containing high phosphate and calcium. CMA activity was measured by a KFERQ reporter and lysosomal staining. The expression of LAMP2a and HSP90AA1 was knocked down by siRNA, overexpressed by plasmid, and activated by QX77.1. Bioinformatic analysis, protein interaction studies, immunofluorescence and co-immunoprecipitation were performed to investigate the potential mechanism of CMA in VC. Results: The expression of LAMP2a was increased in human calcified radial artery tissues (n = 3, p < 0.05) and rats' calcified aortic tissues (n = 3, p < 0.01), accompanied by lysosomal abnormalities. The activity of CMA was increased during the osteogenic transdifferentiation of VSMCs, as indicated by increased expression of RUNX2 and reduced expression of SM22α (p < 0.05). LAMP2a knockdown attenuated VSMCs’ calcification (p < 0.05), whereas pharmacological activation of CMA aggravated calcification in VSMCs (p < 0.01). Bioinformatic screening identified HSP90AA1 as a candidate involved in CMA in vascular calcification. Elevated HSP90AA1 expression was observed in human calcified radial artery tissues (n = 3, p < 0.01) and rat calcified aortic tissues (n = 3, p < 0.01), which promoted osteogenic transdifferentiation of VSMCs (p < 0.05). HSP90AA1 interacted with LAMP2a and positively regulated its expression (p < 0.01). Conclusions: These findings support an association between CMA activation and CKD vascular calcification. It suggests that HSP90AA1 facilitates vascular calcification in chronic kidney disease involving chaperone-mediated autophagy. Full article

This study aims to evaluate the therapeutic efficacy of emodin (EMO) in rheumatoid arthritis (RA) and to verify whether its underlying mechanism involves the blockade of pathological angiogenesis via the inhibition of the nuclear factor-kappa B (NF-κB)/hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) signaling axis. Bovine type II collagen-induced arthritis (CIA) mouse models and lipopolysaccharide (LPS)-stimulated EA.hy926 endothelial cells were utilized in this study. The effects of EMO on joint pathological alterations, the expression of NF-κB/HIF-1α/VEGF axis proteins, inflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β)), and angiogenic capacity were assessed using histopathological analysis, Western blotting, immunohistochemistry (IHC), immunofluorescence, and tube formation assays. Furthermore, small interfering RNA (siRNA) interference targeting key molecules was employed to validate the molecular mechanisms underlying the therapeutic effects of EMO. In the CIA model group, the ankle joints of mice exhibited pronounced inflammatory infiltration, synovial hyperplasia, and bone destruction. Compared with the model group, both the EMO and methotrexate (MTX) treatment groups demonstrated attenuated synovial hyperplasia and cartilage destruction, along with significantly downregulated expression levels of key NF-κB pathway proteins, HIF-1α, and VEGF in joint tissues (p < 0.001). In vitro experiments revealed that EMO treatment significantly reduced the LPS-induced secretion of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) (p < 0.001), and decreased both the number and total length of tubular structures formed by endothelial cells compared to the control (p < 0.001). Notably, siRNA-mediated knockdown of p65 resulted in decreased intracellular protein levels of HIF-1α and VEGF, accompanied by a significant reduction in tube formation (p < 0.001). This study demonstrates that EMO alleviates pathological damage in RA by inhibiting the activation of the NF-κB signaling pathway, which subsequently downregulates pathological angiogenesis and inflammatory responses mediated by the HIF-1α/VEGF axis. These findings provide a robust experimental basis for the potential application of EMO as a therapeutic agent for RA. Full article

Gallbladder cancer (GBC) is an aggressive malignancy with limited treatment options and poor clinical outcomes. Identifying novel molecular targets is critical for improving therapeutic strategies. Sorcin (SRI), a calcium-binding protein implicated in tumor progression, has not been comprehensively investigated in GBC. SRI expression was analyzed by immunohistochemistry (IHC) in a large cohort of gallstone disease (GSD) controls (n = 85) and GBC tissues (n = 85). Functional assays, including cell proliferation, wound healing, transwell invasion, and Western blot analyses of epithelial–mesenchymal transition (EMT) markers, were performed in the NOZ GBC cell line following siRNA-mediated SRI knockdown. IHC revealed that 67% of GBC cases exhibited positive staining whereas all the GSD cases exhibited negative staining of SRI, demonstrating a significant upregulation of SRI in GBC (p < 0.001). SRI knockdown resulted in reduced proliferative capacity and markedly impaired migration and invasion. Further, SRI knockdown decreased vimentin levels, indicating suppression of EMT. SRI is significantly overexpressed in GBC and promotes key oncogenic traits, including proliferation, migration, invasion, and EMT. These findings highlight SRI as a potential therapeutic target in GBC. Further validation in animal models may facilitate translation into clinical applications. Full article

Background: Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. Changes in the ubiquitination system in GBM cells can promote uncontrolled tumor growth and reduce the effectiveness of treatments. However, the exact targets and regulatory elements of the ubiquitin–proteasome system involved in GBM are still not well understood. Methods: All data were obtained by using in silico analysis, immunohistochemistry, Western blot, RT-qPCR, gene silencing and proliferation assay. Results: Computational and protein analyses show that aggressive gliomas have higher expression of the RING ligase RNF182, with significantly greater levels in glioblastoma (GBM) than in low-grade gliomas. Elevated RNF182 is strongly associated with GBM growth. Experiments using siRNA to inhibit RNF182 in the human glioblastoma cell line U87MG significantly reduced cell proliferation, suggesting that RNF182 promotes tumor growth and may be a potential therapeutic target. Conclusions: These findings create a connection between the ubiquitin–proteasome system and the unchecked growth observed in GBM, identifying RNF182 as a new marker associated with GBM proliferation and an additional target for GBM treatment. Full article

Background: Aralia echinocaulis has therapeutic effects on rheumatoid arthritis (RA), with total polysaccharide and glycoside (TPGs) as main active components. RA pathogenesis involves gut microbiota dysbiosis and immune–metabolic crosstalk, but the role of microbiota-derived succinate in RA remains unclear. Objective: This study explored the role of succinate-GPR91 signaling in intestinal dendritic cells (DCs) in the context of RA and the therapeutic mechanism of A. echinocaulis TPGs. Methods: Collagen-induced arthritis (CIA) mice were treated with TPGs or exogenous succinate. Paw edema, inflammation, gut succinate levels, the Th17/regulatory T (Treg) balance, and DC activation via succinate-GPR91 were detected, and GPR91-targeting siRNA and CD4+ T-cell coculture assays for verification. Results: TPGs alleviated symptoms in CIA mice and restored the Th17/Treg balance by reducing intestinal succinate levels. Succinate activated DCs via GPR91 to promote Th17 differentiation, while TPGs suppressed DC maturation and Th17-driven inflammation, supporting the involvement of a gut-centric immunometabolic axis in RA. Conclusions: TPGs ameliorate RA by targeting the succinate-GPR91-Th17 pathway, identifying succinate as a novel RA target and TPGs as a potential microbiota-modulating agent. Full article

Sarcocystis, a diverse and species-rich protist genus infecting reptiles, birds, and mammals, remains poorly understood in terms of true diversity and their lifecycles. Typically, sarcocysts are found in the muscle tissue of the intermediate host (IH), while oocysts undergo sporulation in the intestines of the definitive host (DH). Rodent-associated Sarcocystis species often form cryptic species complexes with strong specificity to their DHs; however, their presence in the intestines of wild carnivores, whose IHs are rodents, is understudied. The aim of this study was to investigate the distribution of rodent-associated Sarcocystis species in the intestines of wild Mustelidae and Canidae from Lithuania using light microscopy (LM) and nested PCR targeting 28S rRNA. LM analysis of intestinal scraping revealed Sarcocystis spp. in 56.3% of canids and mustelids, while DNA sequence analysis identified 41.0% of mustelids and 11.6% of canids as positive. Three Sarcocystis species, S. arvalis, S. myodes, and S. ratti, and the genetic lineage Sarcocystis sp. Rod8, which belong to the same cryptic species complex, were identified in mustelids, while S. arvalis and S. myodes were detected in canids. Thus, mustelids contribute more than canids to the natural transmission of Sarcocystis spp. from rodents in Lithuania. Full article

The role of fatty acid transporter 4 (FATP4) in regulating lipid metabolism has been well studied. However, how it affects IMF deposition, especially in goats, remains poorly understood. Here, we cloned the whole coding sequence of the goat FATP4 gene and revealed its closest affinity to sheep by amino acid sequence blast analysis. In addition, we found that the FATP4 reached its highest expression level at day 6 of goat preadipocyte differentiation in vitro. Functionally, in cultured goat intramuscular preadipocytes, siRNA-induced FATP4 knockdown dramatically raised the mRNA expression of lipogenesis-related genes and encouraged lipid deposition. At the same time, FATP4 deficiency inhibited cell proliferation and significantly decreased apoptosis. Unexpectedly, although the overexpression of FATP4 promoted cell proliferation and suppressed apoptosis, it only slightly decreased cellular lipid deposition in goat intramuscular preadipocytes. For RNA-seq (performed on pooled cell samples with three technical replicates), a total of 467 differential genes (DEGs) were identified after silencing of FATP4 in goat preadipocytes, including 47 upregulated genes and 420 downregulated genes. These DEGs were mainly enriched in the signaling pathways of Focal adhesion, HIF-1, and PI3K-Akt by KEGG analysis. To validate these findings, knockdown of FATP4 increased the expression of phosphatidylinositol 3-kinase (PI3k) and vice versa. Convincingly, we rescued the phenotype observed in FATP4 knockout goat preadipocytes by blocking the PI3k-Akt signaling pathway with an AKT inhibitor (LY294002). In summary, in our in vitro model, FATP4 plays a crucial role in directing fatty acids toward cell proliferation (prioritized over cellular lipid deposition) via the PI3K-Akt signaling pathway in goat intramuscular preadipocytes. These findings provide preliminary mechanistic insights into the regulatory network of IMF formation at the cellular level, and offer theoretical clues for future research aimed at enhancing meat quality from the standpoint of IMF deposition. Full article

Extensive evidence now confirms Lipoprotein(a) [Lp(a)] as a causal, independent risk factor for atherosclerotic cardiovascular disease. Elevated Lp(a) levels are detected in approximately 20% of the global population, positioning it as a major contributor to residual cardiovascular risk. Circulating Lp(a) levels are determined predominantly by genetic factors, so they are largely unresponsive to lifestyle modifications or conventional lipid-lowering therapies. Therefore, multiple international guidelines now endorse a one-time, lifetime measurement of Lp(a), as lowering Lp(a) concentrations is expected to have a positive impact on the reduction of cardiovascular risk. Currently, the therapeutic landscape of Lp(a) lowering drugs is rapidly evolving. Some RNA-based therapies (antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs)) have been demonstrated to reduce plasma Lp(a) concentrations by up to 98% in early-phase clinical trials. The efficacy and safety of these compounds are currently being evaluated in large-scale cardiovascular outcome trials. The results of these studies will be critical in validating the “Lp(a) hypothesis”: specific reduction of Lp(a) levels can lead to a measurable decrease in cardiovascular events. The purpose of this narrative review is to examine and discuss the available evidence on the role of Lp(a) as a risk factor and pharmacological target to provide a practical tool for decision-making in clinical practice. Full article

Regulated cardiomyocyte death is a central contributor to myocardial infarction (MI)-associated injury. Mixed lineage kinase domain-like protein (MLKL), a key effector of necroptosis, has been implicated in cardiovascular disease; however, its role in MI remains incompletely defined. MLKL expression was evaluated in hypoxia-treated cardiomyocytes, infarcted murine hearts, and human cardiac tissue. MLKL function was investigated using siRNA-mediated knockdown in neonatal mouse cardiomyocytes and genetic deletion in mice subjected to left anterior descending (LAD) coronary artery ligation. Apoptosis- and pyroptosis-related signaling were assessed by immunoblotting and immunostaining. RIP3 expression and regulation were examined at both protein and mRNA levels, and the RIP3 inhibitor GSK’872 was used to assess pathway dependence. MLKL expression was increased in hypoxic cardiomyocytes, infarcted mouse hearts, and human failing cardiac tissue. Unexpectedly, MLKL deficiency was associated with aggravated myocardial injury, impaired cardiac function, and increased fibrosis following MI. Mechanistically, MLKL deficiency was associated with increased RIP3 protein abundance without a corresponding increase in RIP3 mRNA, consistent with post-transcriptional regulation. Further analyses indicated that MLKL deficiency reduced RIP3 ubiquitination and impaired proteasome-mediated degradation, resulting in RIP3 stabilization. Elevated RIP3 levels were accompanied by increased expression of apoptosis- and pyroptosis-related proteins, particularly at early time points after MI. Pharmacological inhibition of RIP3 with GSK’872 was associated with reduced apoptosis- and pyroptosis-related signaling and improved cardiac function. MLKL deficiency is associated with stabilization of RIP3 and enhanced activation of apoptosis- and pyroptosis-related signaling following MI, contributing to aggravated myocardial injury. These findings support a regulatory role for the MLKL–RIP3 axis in cardiomyocyte death and suggest that targeting RIP3 may represent a potential therapeutic strategy in myocardial infarction. Full article

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease. The Shen-Kang Recipe (SKR) is a traditional Chinese medicine formula used clinically to slow DKD progression, but its bioactive constituents and molecular targets remain unclear. Solute carrier family 15 member 2 (SLC15A2/PEPT2), a high-affinity peptide transporter expressed in renal proximal tubules, has been implicated in kidney pathophysiology, yet its potential role in mediating the therapeutic effects of the SKR has not been explored. Here, we evaluated the effects of the SKR in db/db mice and found that SKR treatment significantly improved renal function, attenuated glomerulosclerosis, and reduced interstitial collagen deposition. Wide-target metabolomics and quantitative proteomics revealed that the SKR broadly reversed DKD-associated metabolic and proteomic disturbances, particularly in pathways related to energy and amino acid metabolism. Proteomic analysis identified SLC15A2 as a key proximal tubule protein downregulated in DKD and selectively restored by the SKR. UPLC-Q-TOF/MS-based serum pharmacochemistry and network pharmacology highlighted quercetin as a principal bioactive component of the SKR. Molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) confirmed direct, high-affinity binding between quercetin and SLC15A2 (KD = 7.5 µM). In TGF-β1-stimulated HK-2 cells, quercetin suppressed epithelial-mesenchymal transition (EMT), as evidenced by restored E-cadherin and reduced N-cadherin, vimentin, and α-SMA expression; this effect was abrogated by siRNA-mediated SLC15A2 knockdown, demonstrating the functional necessity of this axis. Collectively, these findings identify a quercetin-SLC15A2 axis through which the SKR inhibits EMT and alleviates renal fibrosis in DKD, providing a mechanistic basis for its clinical application and nominating SLC15A2 as a potential therapeutic target. Full article