Search Results (267)

Background and Objectives: Orbital radiotherapy (OR) has been used for moderate-to-severe active thyroid-associated orbitopathy (TAO) for decades, yet its role is repeatedly questioned. Sham-controlled randomized trials have not demonstrated a benefit of OR on proptosis or soft-tissue change, whereas clinical practice guidelines continue to recommend OR, combined with glucocorticoids, as a second-line option, particularly for diplopia and restricted ocular motility. The insulin-like growth factor 1 receptor (IGF-1R) inhibitor teprotumumab, with marked effects on proptosis and diplopia, has prompted some to regard OR as obsolete. This review aims to reconcile the long-standing discordance between randomized-trial evidence and guideline recommendations and to reposition OR within the contemporary, biologics-inclusive treatment algorithm. Materials and Methods: We performed a semi-systematic narrative review of PubMed and Embase (inception to June 2026), prioritizing randomized controlled trials, comparative and large observational studies, current guideline and consensus documents, and recent systematic reviews and meta-analyses across radiobiology, dose and technique, efficacy, glucocorticoid combination, safety, health economics, and biologics. Results: The randomized endpoints that failed (proptosis and soft-tissue swelling) are not those that OR is mechanistically expected to improve, whereas its benefit for motility and diplopia aligns with the indication guidelines specified; meta-analyses support a motility and combination benefit. Against teprotumumab, OR shows a smaller proptosis effect but established long-term safety, wide accessibility, and far lower cost, while teprotumumab’s real-world durability is limited and its cost and adverse-event burden is substantial. Conclusions: OR is best understood not as a competitor to be replaced but as an accessible, low-cost, motility-directed modality with real limitations of its own (a modest effect on proptosis and a frequent residual need for surgery), whose optimal sequencing alongside glucocorticoids and biologics has yet to be defined by head-to-head and cost-effectiveness studies. Full article

Individuals with Laron syndrome, a rare condition characterized by congenital insulin-like growth factor 1 (IGF-1) deficiency, display a remarkably low incidence of cancer, suggesting the existence of protective mechanisms linking reduced IGF-1 signaling to decreased cancer susceptibility. Consistent with this observation, IGF-1 is a recognized promoter of prostate cancer (PCa) progression, although the underlying mechanisms remain incompletely understood. Methylglyoxal (MG)-derived glycative stress, reflected by the accumulation of MG-derived hydroimidazolone 1 (MG-H1), has been implicated in PCa progression but has never been investigated in Laron syndrome. We found that liver tissues from Laron mice exhibited lower MG-H1 levels, suggesting reduced MG-derived glycative stress associated with low IGF-1 signaling. These findings prompted us to investigate whether MG-derived glycative stress contributes to IGF-1-driven PCa progression. Compared with the less aggressive LNCaP cells, PC3 cells displayed higher basal IGF-1 and MG-H1 levels, consistent with a potential association between IGF-1 and MG-derived glycative stress in PCa progression. Moreover, IGF-1 stimulation of LNCaP cells increased MG-H1 accumulation, proliferation, colony formation, invasiveness, and gene expression of matrix metalloproteinase (MMP)-1, MMP-7, MMP-9, receptor for advanced glycation end-products (RAGE), and Osteopontin (OPN), all of which were markedly attenuated by the MG scavenger aminoguanidine (AG). Collectively, these findings support a potential contribution of MG-derived glycative stress to IGF-1-driven PCa progression. Full article

Identifying physiological changes during the transition period is essential for improving the health and productivity of dairy goats. This study evaluated hematological, biochemical, hormonal, oxidative stress, and molecular alterations in Shami goats during the pre-pregnancy, late pregnancy, and early lactation periods. Eighty clinically healthy goats were examined, and blood samples were analyzed for hematological indices, metabolic and hormonal profiles, oxidative stress biomarkers, and relative expression of genes associated with energy metabolism, antioxidant defense, inflammation, and autophagy. Late pregnancy was characterized by significant (p < 0.05) increases in red blood cell count (RBCs), hemoglobin concentration (Hb), neutrophils, albumin, globulin, urea, insulin-like growth factor-1 (IGF-I), and malondialdehyde (MDA), accompanied by decreased glucose, cholesterol, total protein (TP), antioxidant markers, total leukocyte count, packed cell volume, and monocytes. Early lactation was associated with higher non-esterified fatty acid, triiodothyronine (T3), and thyroxine (T4) levels. Genes involved in lipid mobilization and oxidation, ketogenesis, inflammation, cellular stress, and autophagy; sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor alpha (PPARA), carnitine palmitoyltransferase 1a (CPT1A), 3-hydroxy-3-methylglutaryl-coenzyme a synthase 2 (HMGCS2), cluster of differentiation 36 (CD36), lipase E (LIPE), protein kinase amp-activated catalytic subunit alpha 1 (PRKAA1), solute carrier family 2 member 1 (SLC2A1), haptoglobin (HP), interleukin 6 (IL6), heat shock protein 70 (HSP70), heme oxygenase 1 (HMOX1), beclin 1 (BECN1), and autophagy-related protein 5 (ATG5) were significantly upregulated, whereas antioxidant- and glucose transport-related genes nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 1 (GPX1), catalase (CAT), thioredoxin (TXN), and solute carrier family 2 member 4 (SLC2A4) were downregulated during the transition period. The results indicate well-orchestrated metabolic and molecular adaptations that can be employed as biological indicators to track the physiological status of Shami goats. These findings fulfilled the study objective and identified potential biomarkers of the transition period in Shami goats. Full article

As a traditional element of Chinese medicine, Hippocampus erectus is well known for promoting adolescent growth, yet its active fractions and underlying molecular mechanisms remain unclear. In this study, the aqueous extract of H. erectus was subjected to in vitro simulated gastrointestinal digestion and ultrafiltration to separate three molecular weight fractions (<10 kDa, 10–30 kDa, >30 kDa). Their chemical profiles were characterized, and osteogenic activities were systematically evaluated using cell assays, a juvenile rat model, and integrated transcriptomics and data-independent acquisition (DIA) proteomics. Results revealed that chemical profiling showed the >30 kDa fraction was mainly composed of hemocyanin subunits, and the 10–30 kDa fraction was enriched in growth-related amino acids and steroid derivatives; functionally, the 10–30 kDa fraction promoted preosteoblast proliferation and early differentiation via enhanced alkaline phosphatase (ALP) activity, while the >30 kDa fraction dominated late osteoblast maturation and mineralization. Both fractions significantly increased rat body and bone length by expanding growth plate proliferative zones and elevating serum insulin-like growth factor-1 (IGF-1)/bone morphogenetic protein-2 (BMP-2) levels. Transcriptomic and proteomic analyses identified vascular endothelial growth factor (VEGF), Wingless-related integration site (Wnt), phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt), and extracellular matrix (ECM)–receptor interaction as potential core regulatory pathways. Integrated multi-omics analysis further confirmed Frizzled-related protein B (Frzb) and AKT1 substrate 1 (Akt1s1) as candidate key regulatory targets enriched in the Wnt and adenosine monophosphate-activated protein kinase (AMPK) signaling pathways. These findings elucidate the multi-fraction, multi-pathway mechanism of H. erectus in promoting skeletal development, providing scientific evidence for its traditional use and a theoretical basis for growth-promoting functional food development. Full article

Introduction: Teprotumumab (Tepezza^®), an insulin-like growth factor-1 receptor (IGF-1R) antagonist, is the first FDA-approved targeted therapy for thyroid eye disease (TED). While effective for reducing proptosis and inflammation, increasing post-marketing evidence has linked teprotumumab to auditory adverse events. IGF-1 signaling is essential for cochlear maintenance and neuroprotection; therefore, systemic IGF-1R inhibition presents a biologically plausible mechanism for ototoxicity. Despite growing recognition of these effects, no standardized approach exists for audiologic assessment or monitoring of patients receiving teprotumumab. This review aimed to (1) summarize proposed mechanisms and the reported spectrum of teprotumumab-related auditory effects, (2) evaluate current methods used to assess and monitor these patients, and (3) identify areas of consensus and ongoing uncertainty. Methods: An updated narrative review of the literature was conducting using PubMed, CINAHL, and Google Scholar using Boolean strings targeting teprotumumab exposure and hearing-related outcomes. Studies from 2022 onward were identified using Boolean search strings targeting teprotumumab exposure and hearing-related outcomes. Peer-reviewed English language studies reporting audiometric findings were eligible for inclusion. Results: Ten studies met inclusion criteria. Reported effects most commonly included bilateral high-frequency SNHL, tinnitus, and aural fullness, typically emerging after three to six infusions. Many cases demonstrated persistent deficits despite drug discontinuation. Baseline audiometric assessment was not uniformly reported across studies, and monitoring protocols varied considerably, with inconsistent incorporation of speech testing and immittance measures. Conclusions: Teprotumumab-associated ototoxicity is increasingly recognized and potentially irreversible. Current evidence is insufficient to guide standardized monitoring. Prospective studies are urgently needed to establish evidence-based audiologic surveillance protocols. Full article

Background: Esophageal squamous cell carcinoma (ESCA) represents one of the most common aggressive malignancies worldwide. Insulin-like growth factor binding protein 1 (IGFBP1), a typical member of the IGF superfamily, is closely linked to adverse prognosis in numerous cancers. Up to now, little is known about its functional relevance to cell migration and tumor progression in ESCA. This work focuses on clarifying the relationship between IGFBP1 expression and the progression and migratory characteristics of ESCA. Methods: mRNA expression profiles from ESCA patients were obtained from the TCGA and GEO databases. Differential expression analysis was performed using R software(version 4.2.2), followed by an intersection of DEGs between datasets. The STRING database was applied to establish PPI networks. Cytoscape software(Version 3.7.2) was then used for visual presentation and hub gene identification. IGFBP1 expression was validated in ESCA tissues versus adjacent normal tissues. Prognostic correlation was assessed using GEPIA, while diagnostic and predictive values were evaluated through ROC analysis and Cox regression. Genetic alterations of IGFBP1 were analyzed via cBioPortal. Immune cell infiltration patterns were investigated using TIMER. Functional enrichment analyses (GO, KEGG) were performed on IGFBP1-associated DEGs. In the in vitro experiments, esophageal cancer cell lines (such as Eca109 and TE-1) and normal human esophageal epithelial cell lines (such as HEEC) were selected. The transcriptional level of IGFBP1 was examined using RT-qPCR, while Western blot analysis was conducted to validate its protein expression changes. Changes in the proliferative capacity of cancer cells after IGFBP1 silencing were detected by the CCK-8 assay, and cell migration capacity was determined via wound scratch assays to clarify the related biological effects. Results: Overall, 2870 DEGs were screened from the GEO database, 153 DEGs were screened from the TCGA database, and 34 genes were found to be common to both databases; 10 core genes were screened from the PPI network. IGFBP1 was abnormally expressed in esophageal cancer. Cox regression confirmed that IGFBP1 is an independent risk factor, and prognostic analysis indicated that IGFBP1 is closely associated with poor prognosis. Gene mutation analysis showed that amplification mutations are the most common type of IGFBP1 gene mutation, and genetic alterations in IGFBP1 in ESCA patients are significantly associated with overall survival (OS) (p = 0.0002568). GO analysis indicated that IGFBP1-related differentially expressed genes were enriched in organic anion transport, epidermal development, apical cell components, and metal ion transmembrane transporter activity. Pathway enrichment based on the KEGG database illustrated the main enrichment of target genes in neuroactive ligand–receptor interactions, calcium signaling and cAMP signaling pathways. Additionally, remarkable differences in immune cell infiltration were observed between IGFBP1 high-expression and low-expression subgroups through tumor immune profiling. IGFBP1 expression differed significantly between esophageal cancer cells and normal esophageal epithelial cells, as detected by RT-qPCR (p < 0.05). Moreover, knockdown of IGFBP1 markedly inhibited the proliferation (p < 0.05) and migration abilities (p < 0.05) of TE-1 and Eca109 cells. Conversely, IGFBP1 overexpression facilitated these cellular processes. Conclusions: As a key oncogenic driver for ESCA, IGFBP1 may participate in the oncogenesis of ESCA, possibly influencing clinical outcomes via IGF signaling and the tumor microenvironment. Its dual functions in tumor and immune systems suggest it might be a candidate for ESCA immunotherapy research. Full article

Background: Cancer-associated cachexia (CAC) is a multifactorial syndrome driven by a profound metabolic and inflammatory dysregulation. Due to the central role of the insulin-like growth factor 1 (IGF-1) pathway in regulating muscle mass, energy metabolism, and inflammation, this study evaluated the relevance of five IGF-1 axis-related single-nucleotide polymorphisms (SNPs), namely IGF1 rs6220, insulin-like growth factor 1 receptor (IGF1R) rs2016347 and rs2684788, growth hormone receptor (GHR) rs6873545, and insulin receptor substrate 1 (IRS1) rs1801278. Methods: The impact of these variants on CAC onset and overall survival (OS) was assessed in a cohort of 140 cancer patients. Results: While overall-cohort analyses did not reach statistical significance, exploratory analyses suggested potential associations between the IGF1 rs6220 GG and GHR rs6873545 CC genotypes and increased CAC risk in male patients. A trend for higher CAC prevalence was also noted in younger patients (<63 years) with the rs6873545 CC genotype. For pre-CAC and CAC patients, exploratory subgroup analyses on patients’ OS were conducted following no significant results in the overall cohort. Among older patients and those with high prognostic nutritional index (PNI; >44.2), the IGF1 rs6220 G allele was associated with longer OS. Conversely, the IGF1R rs2016347 G allele and rs2684788 T allele were linked to poorer OS across multiple pre-CAC and CAC subgroups. The effects of GHR rs6873545 varied across subgroups, suggesting context-dependent activity. Conclusions: This study highlights the functional heterogeneity of IGF-1 axis-related genetic variants, indicating potential to serve as predictors of CAC. Given the exploratory nature of these findings, validation in larger cohorts is required to confirm the associations found. Full article

Insulin-like growth factor 1 (IGF-1) signaling plays a complementary role to insulin signaling in glucose metabolism homeostasis. This study characterized the physiological roles of the IGF1 receptor A (Igf1ra) and B (Igf1rb) in zebrafish. The transcripts of igf1ra and igf1rb were detected in multiple zebrafish tissues, including the liver, muscle, and brain. Zebrafish lacking igf1ra or igf1rb were generated using CRISPR/Cas9 technology. Both igf1ra^−/− and igf1rb^−/− zebrafish exhibited stunted growth. Reduced BMI was found in igf1ra^−/− zebrafish, while BMI increased in igf1rb^−/− zebrafish. Hyperglycemia and increased hepatic glycogen were observed in igf1ra^−/− zebrafish, while blood glucose levels in igf1rb^−/− zebrafish were normal. No significant difference in whole-body or hepatic triglyceride content was observed in igf1ra^−/− zebrafish, while the whole-body and hepatic triglyceride content of igf1rb^−/− zebrafish increased compared to their wild-type control siblings. Further analyses of the expression patterns of key genes involved in glucose and lipid metabolism were conducted on igf1r mutants. Decreased levels of genes involved in glucose absorption and glycolysis and increased levels of genes involved in gluconeogenesis and glycogen synthesis were observed in igf1ra^−/− zebrafish, but not in igf1rb^−/− zebrafish. Conversely, significantly decreased levels of transcripts involved in lipolysis and increased levels of transcripts involved in the lipogenesis process were observed in igf1rb^−/− zebrafish, but not in igf1ra^−/− zebrafish. Restricted cell growth and protein synthesis signaling, including AKT and mTOR activation, was also detected in igf1ra^−/− zebrafish, while a moderate elevation in AKT and mTOR activity was seen in igf1rb^−/− zebrafish. Taken together, our results suggest that functional divergence occurred after the duplication of the zebrafish igf1r gene, with igf1ra primarily modulating glucose absorption and utilization, and igf1rb primarily affecting lipid metabolism in the somatotropic axis. Full article

Background: The insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase whose both overexpression and underexpression have been implicated in the initiation and progression of breast tumorigenesis. The mechanism through which underexpression of the receptor contributes to a more aggressive phenotype is currently less understood. Methods: Through the expression of a dominant-negative IGF1R, we studied the phenotypic effects of receptor inhibition on early MMTV-Wnt1 mouse mammary tumors. Utilizing histopathological techniques and single-cell RNA-sequencing, we explored cellular heterogeneity and transcriptional alterations that occur as a result of IGF1R inhibition. Results: Examination of primary tumors failed to reveal obvious differences in tissue architecture or expression of differentiation markers with IGF1R inhibition. Both cohorts of tumors produced metastatic lesions in the lung. Single-cell RNA-sequencing identified previously unknown epithelial subpopulations that were present in both tumor types. In tumors with inhibited IGF1R, a previously undescribed epithelial population marked by expression of both Krt14 and Krt6a was identified, transcriptionally distinct from its MMTV-Wnt1 counterpart, and present in the smallest lung metastases. In human breast cancer patients, expression levels of KRT14 and KRT6A negatively correlated with expression of IGF1R. Conclusions: Inhibition of the IGF1R in a mouse model of basal-like breast cancer produces transcriptionally distinct Krt6a⁺/Krt14⁺ epithelial cells, which are present in the smallest metastatic lesions identified in the lung. Expression of genes associated with this population may potentially be effective biomarkers of metastatic capacity in basal-like breast tumors with low levels of IGF1R expression. Full article

Background: Prostate cancer (PCa) is the most commonly diagnosed malignancy in men and a leading cause of cancer-related mortality worldwide. Growing evidence indicates that metabolic syndrome components, including obesity, insulin resistance, and hyperglycemia, contribute to PCa development, and progression to more aggressive form. At the same time, standard treatments such as androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs) significantly improve oncologic outcomes but are associated with adverse metabolic effects, including increased fat mass, insulin resistance, and sarcopenia, potentially worsening patients’ overall metabolic profile and quality of life. Tumor progression in PCa is strongly driven by androgen receptor (AR) signaling, which is closely linked to cellular metabolic reprogramming, highlighting metabolism as a potential therapeutic target. Aim: The aim of this study was to evaluate and synthesize current evidence on the role of the ketogenic diet (KD) in PCa, with particular emphasis on its interaction with hormonal therapies, underlying metabolic and endocrine mechanisms, and its potential application as an adjunctive strategy in integrated oncologic care. Results: The KD, characterized by high fat and very low carbohydrate intake, induces a metabolic state of ketosis that reduces circulating glucose, insulin, and insulin-like growth factor 1 (IGF-1), potentially counteracting metabolic alterations associated with PCa and its treatments. Preclinical studies consistently demonstrate that carbohydrate restriction and KD can slow tumor growth, modulate key oncogenic pathways such as PI3K/AKT/mTOR, reduce systemic insulin signaling, and enhance survival in prostate cancer models. Additionally, emerging evidence suggests possible synergistic effects when KD is combined with standard therapies, including ADT and immunotherapy. Clinical data, although limited, indicate that low-carbohydrate dietary interventions may improve metabolic parameters and could delay biochemical progression, as suggested by increased prostate-specific antigen (PSA) doubling time. However, results across studies remain heterogeneous, and robust evidence on long-term oncologic outcomes is lacking. Conclusions: Overall, the KD represents a promising but still experimental strategy in PCa management, requiring careful nutritional supervision to avoid adverse effects such as unintended weight loss or sarcopenia. Further well-designed randomized clinical trials are needed to clarify its safety, efficacy, and role in routine clinical practice. Full article

Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, demonstrates robust efficacy in glycemic control and weight reduction. However, substantial interindividual variability in treatment response is observed in clinical practice. In this narrative review, we summarize current evidence on clinical, genetic, and molecular predictors of tirzepatide response and discuss their implications for a precision medicine framework. Data from pivotal clinical trials, post hoc analyses, and relevant preclinical and clinical studies were evaluated to identify determinants of glycemic and weight loss responses, as well as hepatic and renal protective effects. Key clinical predictors include tirzepatide dose, duration of diabetes, β-cell function, baseline glycated hemoglobin, sex, age, race, concomitant therapies, and early treatment response. Genetic factors implicated in treatment variability include variants in GLP-1 receptor, GIP receptor, β-arrestin 1, transcription factor 7-like 2, fat mass and obesity-associated protein, and melanocortin 4 receptor, although tirzepatide-specific validation remains limited. Molecular biomarkers such as branched-chain amino acids, insulin-like growth factor–binding protein-1 and -2, the adiponectin-to-leptin ratio, high-sensitivity C-reactive protein, and interleukin-6 show potential as pharmacodynamic indicators of metabolic response. For organ-specific outcomes, procollagen type III N-terminal peptide and magnetic resonance imaging–proton density fat fraction are supported for assessing hepatoprotective effects, while cystatin C–based estimated glomerular filtration rate and urine albumin-to-creatinine ratio are validated markers of renoprotection. Additional candidates—including tumor necrosis factor receptor 1/2, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin—are promising but require prospective validation. Overall, predicting response to tirzepatide’s multifaceted therapeutic effects necessitates an integrated, multidimensional approach that incorporates clinical characteristics, genetic variation, and molecular profiling. Ongoing validation and harmonization of these predictors may help establish a precision medicine framework for optimizing tirzepatide therapy. Full article

This study investigated the role of microglia-derived insulin-like growth factor 1 (IGF-1) in modulating host defense and disease progression in a viral model of neuroinflammation and demyelination. Intracranial infection of susceptible mice with the glial-tropic JHM strain of mouse hepatitis virus (JHMV) induces acute encephalomyelitis, followed by an immune-mediated demyelinating disease that mimics many clinical and histologic features of multiple sclerosis (MS). Utilizing an inducible fractalkine receptor (Cx3cr1) promoter-driven Cre-loxP recombinant system, we performed timed ablation of Igf1 in microglia to assess its impact on the central nervous system (CNS) response to JHMV. While the loss of microglial IGF-1 did not impair the control of viral replication, it significantly exacerbated spinal cord demyelination. CyTOF and imaging mass cytometry analysis of spinal cords indicated increased myelin damage was associated with increased accumulation of CD8⁺Ly6C⁺ effector T cells and reduced expression of TREM2 that impaired transition into a disease-associated microglia (DAM) phenotype capable of sensing and potentially mitigating myelin damage. Collectively, these findings argue that microglial IGF-1 is a non-redundant coordinator of the CNS immune responses that occur in response to CNS viral infection. Full article

Trastuzumab is the first humanised monoclonal antibody (Mab) developed for breast cancer (BC) therapy. The high affinity of Trastuzumab Fab-domain binding to the human epidermal growth factor receptor 2 (HER2) receptor, with a K_d value of <1 nM, is also accompanied by Fc domain interaction with Fc-receptors in natural killer cells and leukocytes, enabling the killing of tumour cells through antibody-directed cellular cytotoxicity (ADCC). Trastuzumab blocks the over-expressed HER2 receptor-mediated dimerization and consequent intracellular signalling, leading to cancerous growth. However, the trastuzumab resistance (TR) became the major problem within 1 year of treatment. The mutation in phosphatidylinositol 3′-kinase (PI3K) pathway, cross-talk with estrogen receptors, over-expression of Mucin 1 (MUC1) protein, insulin-like growth factor I receptor, etc., are key pathways involved in TR. In this review, we have provided a molecular view of TR and the possible remedies for overcoming TR using BC stem cell (BCSC)-based therapy, PI3K pathway inhibitors, MUC1-based treatment, etc. We have also analysed the patents and clinical trials from the pre-TR and post-TR era to rationalise the possible steps to overcome TR. Our analysis implies that Trastuzumab monotherapy no longer applies to HER2+ BC treatment. Further, combination therapy using other antibodies like pertuzumab and protein kinase inhibitors and targeting pathways like the ubiquitin proteasome pathway will be the future option for BC Treatment. Overall, this review provides a detailed summary of the molecular mechanisms involving TR and its potential ways of evasion, based on updated information from published research articles, clinical trial outcomes, and patent data. Full article

Atherosclerosis is a complex, multifactorial disease that progresses through distinct stages: initiation, progression, and complication, ultimately leading to acute coronary syndromes (ACS). Endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and macrophages are central players in this process, influencing plaque stability and vulnerability. Insulin-Like Growth Factor 1 (IGF-1), soluble-Klotho (S-Klotho), and the Growth Hormone Receptor exon 3 deletion polymorphism (GHRd3) have emerged as key modulators of vascular health, impacting these cellular components through various mechanisms. IGF-1 supports endothelial function, enhances VSMC survival and migration, and mitigates inflammation by inhibiting macrophage recruitment and activation, ultimately reducing the risk of plaque destabilization. S-Klotho, an anti-aging protein with potent anti-inflammatory and antioxidant properties, has been linked to vascular protection, with its deficiency associated with endothelial dysfunction, vascular calcification, and impaired VSMC survival. Evidence suggests that IGF-1 may enhance Klotho shedding, indicating a potential synergistic role in maintaining vascular integrity. This narrative review aims to outline the fundamental stages of atherosclerosis progression, consolidate current evidence on the roles of IGF-1 and S-Klotho in modulating key cellular components of atherosclerosis, and shed light on their potential involvement in plaque healing—an area that remains largely unexplored. By integrating established molecular mechanisms, we explore how these factors may contribute to endothelial integrity, VSMC survival, and macrophage activation and polarization, potentially shaping a more stable plaque phenotype and influencing future therapeutic strategies in cardiovascular disease. Full article

The purpose of our study was to assess if spinacetin (SPC), a flavonoid found in spinach, can alleviate the cyclophosphamide (CYP)-induced changes in cystometric and inflammatory parameters indicative of the development of hemorrhagic cystitis. The animal experiments were conducted in female Wistar rats. The cohort of 60 animals was grouped as follows: I—control, II—CYP group, III—SPC group, and IV—CYP + SPC group. The cystometry and biochemical analyses were performed after a fortnight of SPC administration. SPC was found to restore normal cystometric parameters in CYP-induced cystitis and, similarly, it normalized c-Fos expression changes in the central micturition regions. SPC further prevented a massive increase in the bladder wall thickness/permeability due to exposition to CYP administration. CYP instillation resulted in the elevation of biomarkers found in urine (brain-derived neurotrophic factor, BDNF, and nerve growth factor, NGF), and in the bladder detrusor muscle (Rho kinase and vesicular acetylcholine transporter, VAChT), which were successfully restored after administration of SPC. As for the biomarkers in the bladder urothelium, the CYP-induced increases in TNF-α, IL-1β, IL-6, calcitonin gene-related peptide (CGRP), malondialdehyde, 3-nitrotyrosine, insulin-like growth factor-binding protein 3 (IGFBP-3), occludin, organic cation transporter 3 (OCT-3), orosomucoid-1 (ORM1), pituitary adenylate cyclase receptor 1 (PAC1), synaptosomal-associated protein 23 (SNAP23), SNAP25, and synaptic vesicle glycoprotein (SV2A) levels were attenuated by SPC. Finally, CYP administration resulted in a decrease in the heparin-binding EGF-like growth factor (HB-EGF), hemopexin (HPX), T-H protein, and tight junction protein (Z01), and we noted the successful restoration of all these changes in concentrations after application of SPC. In summary, SPC robustly mitigated cyclophosphamide (CYP)-induced cystometric dysfunction and biochemical alterations characteristic of iatrogenic hemorrhagic cystitis. These findings position SPC as a compelling therapeutic candidate and warrant further translational investigation for the management of CYP-induced bladder injury. Full article