Search Results (1,835)

Background: Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) has been implicated in vascular inflammation beyond its action on LDL-C degradation. We investigated whether PCSK9 may exacerbate proinflammatory signaling of M1 macrophages and if its neutralization with alirocumab could attenuate this effect and plaque progression by LDL-C independent mechanisms. Methods: ApoE⁻/⁻ mice were treated with alirocumab for 13 weeks, and aortic arches were isolated for atherosclerotic plaque characterization based on lesion size and lipid and macrophage infiltration. Plasma and splenic monocytes/macrophages were also assessed by flow cytometry, and PCSK9, the lipid profile, and inflammatory cytokines were measured by qPCR or Western blot. Cultured THP-1-derived M1 macrophages were stimulated with PCSK9 and evaluated for TLR4-NFκB-NLRP3 activation and cytokine production. In addition, soluble PCSK9, LDL-C, and proinflammatory factors were analyzed in 1190 patients with acute coronary syndrome (ACS). Results: Alirocumab reduced plaque lesion (0.42-fold; p < 0.05) and lipid (0.63-fold; p < 0.01) and macrophage (0.61-fold; p < 0.05) infiltration, mainly the M1 subtype (0.37-fold; p < 0.01), as well as TLR4, NLRP3 and caspase-1 expressions (0.49-fold, 0.51-fold and 0.51-fold, respectively; p < 0.05), without altering LDL-C. Also, it decreased proinflammatory cytokines but enhanced anti-inflammatory factors and M2 markers at the descending aorta. Alirocumab enriched circulating Ly6C^low monocytes (1.51-fold; p < 0.05) and splenic M2 macrophages (1.32-fold; p < 0.01), while reducing M1 (0.62-fold; p < 0.05). In cultured M1 macrophages, PCSK9 overexpressed proinflammatory cytokines (i.e., CXCL9, CXCL10, TNF-α, IL-1β, and IL-6), downregulated anti-inflammatory mediators (i.e., CCL17, TGM2, TGF-β1, and IL-10), and promoted NFκB-p65 nuclear translocation and NLRP3 and gasdermin-D activation. However, TLR4 inhibition or silencing blunted these effects. In patients with AC, there was a positive association between PCSK9 and hsCRP and FGF-23 plasma levels, independently of LDL-C. Conclusions: PCSK9 may be released in parallel to proinflammatory factors such as hsCRP and FGF-23 in patients with ACS, independently of LDL-C levels. PCSK9 may directly promote macrophage-driven inflammatory responses through the TLR4-NFκB-NLRP3 signaling, but its neutralization with alirocumab attenuated this inflammatory axis and limited atherosclerotic progression, supporting an anti-inflammatory benefit secondary to PCSK9 inhibition. Full article

Physical exercise is a potent non-pharmacological strategy for the prevention and management of Metabolic dysfunction—associated steatotic liver disease (MASLD), a multifactorial disorder characterized by hepatic lipid accumulation, insulin resistance, oxidative stress, and chronic inflammation. Emerging evidence demonstrates that the benefits of exercise extend beyond caloric expenditure and are largely mediated by coordinated molecular and cellular adaptations within the liver and peripheral tissues. This review synthesizes current knowledge on the mechanisms through which exercise modulates MASLD pathophysiology, emphasizing intracellular signaling pathways, mitochondrial remodeling, antioxidant defenses, and myokine-driven muscle–liver crosstalk. Exercise induces acute and chronic activation of pathways such as AMPK, PGC-1α, Nrf2, and Akt, resulting in enhanced mitochondrial biogenesis, improved fatty acid oxidation, restored insulin signaling, and reduced inflammatory and oxidative stress. Repeated skeletal muscle contraction stimulates the release of myokines—including irisin, IL-6, and FGF21—that act through endocrine and paracrine routes to regulate hepatic lipid metabolism, promote systemic metabolic flexibility, and attenuate disease progression. Epigenetic modifications and exercise-responsive microRNAs further contribute to long-term hepatic metabolic reprogramming. Collectively, these molecular adaptations position exercise as a systemic, disease-modifying stimulus capable of restoring hepatic homeostasis, slowing the transition from steatosis to NASH and fibrosis, and improving long-term metabolic health. Understanding these mechanisms provides a foundation for developing targeted, personalized exercise-based interventions in the clinical management of MASLD. Full article

Optimizing calcium metabolism is crucial for skeletal development and overall productivity in growing ruminants. Twenty-four Sunite lambs were randomly assigned to four groups and fed 0, 0.6, 1.2, or 2.4 g/(d·head) of γ-PGA for 60 days. Growth performance, serum parameters, duodenal morphology and calcium transporter expression, bone microarchitecture, and duodenal microbiota were analyzed. Supplementation with 1.2 g/(d·head) of γ-PGA (the M group) yielded optimal results, significantly improving final body weight and size. It enhanced duodenal health, evidenced by increased villus height, crypt depth, and microvilli density. Crucially, this dose significantly upregulated the expression of key duodenal calcium transporters (TRPV5/6, CaBPD9k, PMCA, VDR, claudin-12) and altered systemic calcium-regulating hormones (elevated calcitriol, PTH, FGF23). Bone micro-CT analysis revealed changes in trabecular architecture indicative of active remodeling. 16S rRNA sequencing and weighted OTU co-expression network analysis (WOCNA) revealed that γ-PGA reshaped the duodenal microbiota and identified core microbial modules strongly associated with host phenotypes. Genera such as [Eubacterium]_ruminantium_group, Fusicatenibacter, and Prevotella emerged as central hubs. In conclusion, dietary γ-PGA at 1.2 g/(d·head) enhances calcium absorption and bone metabolism in lambs through a coordinated modulation of intestinal integrity and calcium transport, systemic endocrine responses, and the duodenal microbial community, with specific microbiota identified as potential key mediators associated with these effects. Full article

Juvenile nasopharyngeal angiofibroma (JNA), a rare vascular tumor in adolescent males, involves dysregulated angiogenesis and hormonal interplay. Key molecular drivers include HIF-1α, VEGF, bFGF, and β-catenin, promoting tumor growth via pathways like Wnt/β-catenin and Ras signaling. Androgens and estrogen modulate progression, though mechanisms remain debated. Targeted therapies reduce tumor proliferation and vascularity in preclinical studies, yet clinical translation is hindered by drug resistance and inconsistent biomarker expression. Hormonal and MMP-targeted approaches also show potential but require validation. This review consolidates JNA’s molecular landscape, emphasizing the need for personalized strategies, biomarker refinement, and combination therapies to improve therapeutic outcomes for this challenging tumor. Full article

Background: Low-level laser irradiation (LLLI) can promote wound healing. However, the biological effects of the erbium-doped yttrium aluminum garnet (Er:YAG) laser on gingival wound healing remain unclear. Objectives: To assess the effects of low-level Er:YAG laser irradiation on endothelial cell activity in vitro and on early phase gingival wound healing in vivo. Methods: In vitro, human umbilical vein endothelial cells were irradiated with a low-level Er:YAG laser (30 mJ/pulse, 10 Hz, 20 and 30 s, defocused, no water spray) and assessed for viability, cytotoxicity, and migration. Standardized bilateral wounds (4 × 1 mm) were created in the palatal gingiva of 14 male mice using a scalpel and curette. The wounds were irradiated for 20 s under the same irradiation settings, using a contact tip (diameter 800 μm) to induce superficial blood surface coagulation, while contralateral sites were assigned to controls in a split-mouth design. Postoperative wound area and mRNA expression of IL-6, TNF-α, VEGF, FGF-2, and TGF-β1 were analyzed after 48 h. Results: In vitro, LLLI significantly enhanced cell proliferation with/without increasing cytotoxicity. In the wound healing assay, the LLLI significantly promoted cell migration compared with the control. In vivo, the reduction in residual wound area in the laser group was comparable to that in the control group. IL-6 and TNF-α expressions were significantly downregulated, whereas VEGF was significantly upregulated in the laser group. Conclusions: Low-level Er:YAG laser irradiation enhances anti-inflammatory and pro-angiogenic effects, suggesting its potential in promoting gingival wound healing. Full article

Background: Periplaneta americana grease (PAG), a lipid-rich fraction with documented wound-repair properties, remains challenging. This study aimed to develop a stable and patient-friendly film-forming agent (PAP) from PAG for topical wound management. Methods: The chemical profile of PAG was characterized with GC-MS. The formulation was optimized via single-factor and orthogonal experimental design. Comprehensive physicochemical characterization was performed. A vehicle control (film without PAG) was used to isolate PAG’s bioactive effects. In vitro, antioxidant (DPPH/ABTS assays) and antibacterial activity were evaluated. In vivo efficacy was assessed using a murine full-thickness wound model (mice, 150 µL applied 3 times daily for 10 days), with bFGF and Kangfuxin solution as positive controls. Histological analysis was conducted on healed tissue. Results: GC-MS revealed PAG’s complex composition, rich in sterols, terpenoids, and heterocyclic compounds. The optimized PAP formed a uniform, flexible film with suitable mechanical strength and shear-thinning rheology. PAP showed significant antioxidant activity and selective antibacterial activity against Staphylococcus aureus. In the wound model, PAP treatment significantly accelerated wound closure, achieving a 98.2% healing rate by day 10, comparable to positive controls and significantly superior to the vehicle control. Histology demonstrated enhanced re-epithelialization, reduced inflammation, and improved collagen organization. Conclusions: PAP was successfully formulated into a multifunctional film-forming agent that addresses key barriers to healing—infection, oxidative stress, and tissue regeneration. The results demonstrate its potential as an innovative therapeutic strategy for wound care. Full article

Fused granular fabrication (FGF) offers high deposition efficiency and low material cost for large-scale mold production, but commonly yields parts with surface defects and dimensional deviations. This study develops a six-axis robotic post-processing workstation that integrates multi-DOF toolpath planning and real-time communication to flexibly machine FGF components with complex geometries. Using short-fiber-reinforced polypropylene (PP-GF), robotic milling experiments were performed, and spindle speed, feed rate, and cutting depth were systematically optimized to enhance surface quality and dimensional accuracy. The NSGA-III algorithm optimizes parameters, thereby increasing machining efficiency by 4.9% and reducing surface roughness by 12.35%. Results show that the proposed platform effectively improves the machining performance of FGF-printed parts, demonstrating its feasibility for high-precision post-processing. The work provides a practical technical route for the hybrid additive–subtractive manufacturing of large 3D-printed structures. Full article

Fipronil (FPN), a widely used insecticide, poses health risks through environmental contamination. Although its toxicity is increasingly recognized, the impact of fipronil on glucose metabolism remains poorly understood. In this study, mice on a normal diet (ND) or high-fat diet (HFD) received a daily oral administration of fipronil (0, 0.25, 1, or 4 mg/kg) for 35 days. Blood glucose and insulin were measured, and glucose/insulin/pyruvate tolerance tests were performed. We found that fipronil compromised glucose tolerance in mice fed an ND. Gut microbiota composition was assessed by 16S rRNA sequencing and the expression of inflammatory factors was detected in the tissues. Serum fibroblast growth factor 15 (FGF15) and bile acid were determined. In HFD-fed mice, fipronil exacerbated glucose metabolic disorders and enhanced insulin resistance. These metabolic disturbances were associated with gut microbiota dysbiosis, particularly a marked reduction in Akkermansia muciniphila (A. muciniphila) abundance, and increased systemic inflammation. Fipronil exposure also decreased serum FGF15 and elevated serum bile acids. Our results suggest that fipronil disrupts glucose metabolism in association with gut microbiota alterations, impairment of the FGF15-bile acid axis, and induction of inflammation, highlighting its potential relevance to diabetes risk. Further studies are warranted to validate our findings. Full article

Cuminum cyminum (cumin) is widely used as a culinary spice and medicinal plant, yet its endothelial effects remain poorly defined, and viability-only toxicity tests may miss relevant changes. We evaluated whether four C. cyminum extracts (aqueous, methanolic, acetonic, hexane) induce sublethal endothelial injury (SEI), defined as preserved viability with functional, molecular, and morphological alterations. Human microvascular endothelial cells (HMEC-1) were exposed to increasing extract concentrations, and endothelial viability, migration, molecular responses, and cytomorphology were evaluated. Organic extracts (methanolic, acetonic, and hexane) induced endothelial stress and injury-related responses. Methanolic and acetonic extracts caused concentration- and time-dependent cytotoxicity, accompanied by reduced migration, stress-related gene modulation, and marked morphological damage, whereas the hexane extract induced pronounced cytomorphological disruption and strong NOS2 induction. In contrast, the aqueous extract exhibited minimal cytotoxicity and significantly enhanced endothelial migration, together with FGF2 upregulation and moderate NOS2 induction, consistent with a sublethal, pro-migratory phenotype. Overall, extract composition strongly influenced endothelial responses, demonstrating that SEI can occur in the absence of overt cytotoxicity and highlighting the need to incorporate functional endothelial endpoints into the safety evaluation of herbal and plant-derived extracts. Full article

Neonicotinoid insecticides and fluoroquinolone antibiotics frequently co-occur in aquatic and terrestrial environments, posing a threat to human health, yet their combined neurotoxic potential remains poorly characterized. This study aimed to assess the cytotoxicity of typical neonicotinoids and fluoroquinolones as well as their mixtures in human neuroblastoma SK-N-SH cells and identify affected pathways. SK-N-SH cells were exposed to clothianidin (CLO), imidacloprid (IMI), enrofloxacin (ENR), and ofloxacin (OFX) individually and in fixed-ratio mixtures (50% of each compound’s IC₅₀) for 24 h and 48 h, and cell viability was quantified using the alamarBlue^® method. Single-compound dose–response testing showed time-dependent cytotoxicity, with higher potency for fluoroquinolones (24 h IC₅₀: ENR 1.446 mM, OFX 2.742 mM; 48 h IC₅₀: ENR 0.826 mM, OFX 2.005 mM) than neonicotinoids (24 h IC₅₀: IMI 4.754 mM, CLO 5.356 mM; 48 h IC₅₀: IMI 3.631 mM, CLO 4.029 mM). Concentration-addition analysis indicated that most mixtures produced synergistic interaction in reduction in cell viability, with ENR+OFX showing the strongest effect at 48 h (Observed viability 7.138% vs. Predicated viability 82.368%). RNA-seq (24 h) revealed that binary mixtures generally induced more differentially expressed genes than single exposures, and ENR-containing mixtures showed the largest transcriptomic shifts, enriching pathways related to cellular stress and injury as well as neuronal signaling and connectivity. RT-qPCR validated the changes in expressions of five key neurobiology-relevant genes (LMO3, NOS1, ADCY8, FGF7 and TNFRSF12A). These findings highlight the importance of assessing insecticide–antibiotic mixtures when evaluating their hazards in environment. Full article

Chronic inflammation is a recognized driver of colorectal cancer (CRC) development, particularly in patients with Crohn’s disease (CD). This study aimed to explore serum inflammatory cytokine profiles in patients with Crohn’s disease and colorectal cancer and to assess their associations with disease activity and tumor-related features. Seventy-eight participants were included: 24 with CD, 31 with CRC, and 23 healthy controls. Serum levels of 27 cytokines were measured using the Bio-Plex Pro Human Cytokine 27-plex Assay. Principal component analysis identified three cytokine clusters (factors). Factor 2, comprising IL-9, MIP-1β, and PDGF-β, was significantly elevated in CD patients compared to controls (p < 0.001), showed intermediate levels in CRC patients, and positively correlated with fecal calprotectin (R = 0.44; p = 0.04), indicating an association with local intestinal inflammation. In CRC patients, Factor 1, comprising key Th1/Th17 cytokines (IL-1β, IL-2, IL-4, IL-5, IL-15, IL-17A, FGF-B, GM-CSF, IFN-γ, TNF-α, and VEGF), reflecting pro-inflammatory and cell-mediated immune signaling, correlated with lymph node metastasis (τ = 0.27; p = 0.03), while Factor 2 showed a trend toward a negative correlation with tumor histological grade (τ = −0.22; p = 0.09). Factor 3, encompassing regulatory and hematopoietic cytokines, did not differ significantly between groups (p = 0.21). These findings suggest that IL-9, MIP-1β, and PDGF-β reflect inflammatory activity and may be involved in inflammation-associated tumorigenic processes in the gut. Serum profiling of selected cytokines may provide biologically relevant information and support further investigation of inflammation-associated immune patterns in CD and CRC. Further studies are warranted to validate their clinical utility and to elucidate their mechanistic role in inflammation-driven colorectal carcinogenesis. Full article

Ischemic heart disease is the main cause of death worldwide. Classic cardiac biomarkers, such as troponin, which are released due to myocyte necrosis, are widely used for diagnosis, but they provide limited information about the initial underlying cellular processes involved in myocardial infarction. Autophagy is now considered fundamental in the pathophysiology of cardiac ischemia and related reperfusion injury. This systematic review aims to identify and highlight candidate autophagy-related biomarkers in cardiac ischemia and infarction with potential benefits for early diagnosis, prognosis, and therapy. A comprehensive literature search was conducted up to 1 June 2025. We included studies that examined biomarkers involved in the autophagy process in cardiac ischemia/infarction, which involved humans and animal models. A total of 14 eligible articles were reviewed. Thirteen autophagy-related biomarkers were identified, including LC3-II/I, Beclin-1, ATG5, ATG7, p62, WIPI1, FGF21, CHRF, Rubicon, IL-1β, IL-18, and adiponectin. These biomarkers have a dynamic pattern, and they exhibited time-dependent changes during the different stages of myocardial infarction. Autophagy biomarkers present a promising understanding of the molecular mechanism of early myocardial ischemia and infarction. Integration of autophagy biomarkers with the classic markers should improve risk stratification, therapeutic decision-making, and prognosis in patients with ischemic heart disease. Full article

Mutations in the fibroblast growth factor 10 (FGF10) gene in humans cause aplasia of the lacrimal and salivary glands (ALSG). In patients with ALSG, heterozygous loss-of-function mutations are found, and FGF10 haploinsufficiency results in the absence of these secretory organs. Lacrimal glands (LGs) are formed through epithelial thickening, budding, and branching morphogenesis. To compare the variable phenotypes of the Fgf10^+/− Harderian glands (HGs) previously reported, we examined the development of LGs in wild-type (WT), Fgf10^+/−, and Fgf10-null mice. Pax6 immunostaining was performed to visualize the LG primordia from embryonic day 15.5 (E15.5) onwards. In situ hybridization of the genes encoding the epithelial receptor of FGF10, FGFR2b, and its other ligands was performed to determine their potential involvement in LG development. LG primordia were not observed in Fgf10^+/− mice bilaterally at E16.5 or later stages. At E15.5, budding from the developing conjunctival epithelium (CE) was observed in a small fraction of the Fgf10^+/− LG primordia. In contrast, the Fgf10-null CE failed to promote budding. Among Fgf1, Fgf3, Fgf7, Fgf10, and Fgf22, Fgf10 was expressed in the mesenchyme surrounding developing LG epithelial cells, whereas Fgf1 was expressed in the LG epithelium of WT mice. Fgf7 was initially expressed in the mesenchyme surrounding the nascent LG epithelium, but its expression subsequently became diffused. Thus, we conclude that among the FGFR2b ligands, initial LG formation is dependent on the mesenchymal factors FGF10 and FGF7, and FGF1 is likely to function as an epithelial factor in the LG primordia. A single allele of Fgf10 was found to be insufficient to support the budding process during LG morphogenesis. Full article

The long hair phenotype of the dog is ascribed to variants in the fibroblast growth factor 5 (FGF5) gene. Currently, there are five variant alleles known, Lh1 through Lh5, with any combination of these alleles resulting in a long-haired phenotype in dogs. Recently, genotyping of several long-haired dogs for the known Lh1–Lh5 variants yielded unexpected results as these dogs contained no or only one variant in the FGF5 gene known to result in the long-hair phenotype. Analysis of the coding region for the FGF5 gene identified four novel variants associated with the long-haired phenotype. One dog of mixed ancestry had an insertion of G very similar to and near to the long-hair variant Lh4, NC_006614.4: g.37352832insCC. A group of 24 Tibetan Mastiffs showed the Lh1 variant NC_006614.4:g.37372096C>A in 11 dogs only, and no other known Lh variant. Within the coding frame of the FGF5 gene, three unknown variants were discovered that were predicted to have a phenotypic effect. These new variants were inherited in a Mendelian fashion and, in combination with one of the known FGF5 alleles, likely predict the long-hair phenotype. Lastly, eight of the 24 Tibetan Mastiff dogs carried three FGF5 variants. Full article

The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is rising worldwide. hFGF1^ΔHBS, a variant of human fibroblast growth factor 1 with three substitutions in its heparin-binding sites, was previously shown by our group to ameliorate fatty liver. However, hFGF1^ΔHBS also significantly modulates systemic metabolism, making it unclear whether its hepatic benefits arise from direct liver-specific actions. Additionally, its poor pharmacokinetic profile underscores the need for alternative delivery strategies. Here, we employed adeno-associated virus serotype 8 under the thyroxine-binding globulin promoter (AAV8-TBG) to achieve sustained, hepatocyte-specific expression of hFGF1^ΔHBS. In high-fat-, high-cholesterol-diet-fed apolipoprotein E knockout mice, liver-directed hFGF1^ΔHBS expression markedly reduced hepatic steatosis, inflammation, and fibrosis, independent of changes in body weight, blood glucose, insulin sensitivity, body composition, or circulating triglyceride and cholesterol levels. Mechanistically, hFGF1^ΔHBS gene transfer normalized fatty acid synthesis and suppressed fatty acid uptake by downregulation of stearoyl-CoA desaturase-1 and cluster of differentiation 36. Importantly, these therapeutic effects were achieved without inducing hepatic hyperproliferation, as evidenced by unchanged expression of proliferating cell nuclear antigen and antigen Kiel 67. Collectively, our findings demonstrate that hFGF1^ΔHBS exerts direct hepatoprotective effects and that AAV8-TBG-mediated liver-directed hFGF1^ΔHBS delivery represents a safe and effective strategy for treating MASH. Full article