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From collapse to comeback: Luteolin rejuvenates nucleus pulposus progenitor cells via SIRT1/ATF5-UPRmt to reverse intervertebral disc degeneration cascade.
Stem Cell Res Ther
Huofeng Wu, Shuangjia Zai, Xuan You +8 more
Intervertebral disc degeneration (IVDD) is a major contributor to low back pain (LBP) and one of the foremost causes of disability worldwide. Oxidative stress-induced senescence of nucleus pulposus progenitor cells (NPPC) and mitochondrial dysfunction are key drivers of IVDD. The mitochondrial unfolded protein response (UPRmt), orchestrated by the Silent Information Regulator 1 (SIRT1)-Activating Transcription Factor 5 (ATF5) axis, plays a pivotal role in maintaining mitochondrial proteostasis. However, its involvement in IVDD remains insufficiently characterized. Luteolin (Lut), a naturally occurring flavonoid with well-documented antioxidant and anti-senescence properties, has emerged as a promising disease-modifying candidate.
Spleen-Targeting Delivery of the Liposomal Antigen via an RBC-Based Platform for Cancer Immunotherapy.
ACS Appl Mater Interfaces
Shengmin Yang, Yanning Bao, Nana Meng +12 more
Efficient delivery of tumor antigens to the spleen remains a challenge for systemic cancer vaccination. Although nanoparticles provide versatile platforms for antigen delivery, intravenous administration often results in preferential sequestration by the reticuloendothelial system, leading to dominant hepatic accumulation and limited spleen-targeting. Here, leveraging the intrinsic splenic clearance property of senescent red blood cells (RBCs), we developed an RBC-based liposomal antigen delivery system by covalently conjugating antigen- and adjuvant-coloaded liposomes onto the RBC surface, thereby inducing senescence-like changes in the carrier RBCs and endowing the modified RBCs with enhanced splenic sequestration. Following intravenous administration, the RBC-liposome vaccine delivery system achieved highly efficient accumulation in the spleen, where the antigen was effectively internalized by splenic immune cells, leading to T cell activation and induction of robust immune responses. This delivery system demonstrated significant therapeutic efficacy in a melanoma-bearing mouse model with a remarkable tumor inhibition rate of 96.5%. Our study might offer a promising strategy for antigen spleen-targeting delivery in cancer immunotherapy.
Intraventricular hemorrhage, suspected EBV reactivation, and TBA-positive epilepsy after deep cervical lymphovenous anastomosis in Alzheimer's disease: a case report.
Front Aging Neurosci
Tiantian Jiang, Fang Yan, Bin Liu +6 more
Lymphovenous anastomosis (LVA) is emerging as a potential surgical intervention to ameliorate cervical lymphatic outflow and enhance glymphatic clearance in Alzheimer's disease (AD). However, the spectrum of neurological sequelae associated with this procedure remains poorly characterized. We report the case of a 67-years-old male with amyloid PET-confirmed AD who underwent bilateral deep cervical LVA. Twenty-three days postoperatively, he presented with high-grade fever and altered consciousness. Head CT revealed acute hemorrhage in the posterior horn of the left lateral ventricle (∼2 mL). Cerebrospinal fluid (CSF) analysis demonstrated lymphocytic pleocytosis and significantly elevated protein levels; the fluid was uniformly bloody, confirming intraventricular hemorrhage. Plasma metagenomic next-generation sequencing (mNGS) identified Epstein-Barr virus (EBV), with serology supporting reactivation. Following antiviral and empirical antibiotic therapy, the patient's condition stabilized, and the hemorrhage resolved. Four months postoperatively, he developed new-onset generalized seizures. Despite negative results from a conventional autoimmune encephalitis antibody panel in both serum and CSF, a tissue-based assay (TBA) proved positive in both samples. Seizures were successfully controlled with levetiracetam. This case suggests a potential association between invasive lymphatic procedures and a hemorrhage-infection-immune cascade in highly vulnerable AD patients with preexisting metabolic and neurodegenerative risk factors.
Spatial coupling of enlarged perivascular spaces and white matter lesions across the Alzheimer's disease continuum.
Front Neurosci
Serena Tang, Pamela Thropp, Isabella Hausle +2 more
Emerging evidence suggests that impaired waste-clearance systems contribute to Alzheimer's disease pathogenesis, yet the etiology of clearance dysfunction markers, such as enlarged perivascular spaces, remains unclear. Because enlarged perivascular spaces and white matter lesions are both consequences of microvascular injury involving neuroinflammation and impaired cerebrovascular function, we hypothesize that these markers may be spatially coupled through local interstitial fluid stagnation, where impaired perivascular clearance associates with white matter injury.
Context‑dependent duality of the apelin/elabela‑APJ system in diabetes and its complications (Review).
Int J Mol Med
Zhenyuan Han, Jiale Zhang, Min Shi +4 more
The apelin/elabela‑apelin receptor (APJ) signaling system is a key regulator of metabolic homeostasis and cardiovascular function in diabetes mellitus. However, its therapeutic application is complicated by its functional divergence: the system exerts protective effects in some tissues while driving pathology in others. The present review examined these distinct roles, focusing on how the biological outcome depends on the specific ligand, disease stage and tissue microenvironment. It discussed the molecular mechanisms underlying this divergence, as well as the varying roles of the same receptor at different stages of the same disease. Finally, it evaluated emerging therapeutic strategies, such as stabilized analogs and biased agonists, proposing that precise targeting of the APJ conformational landscape offers a pathway to move beyond glycemic control toward multi‑organ protection in diabetes.
Targeting the Apelin-APJ Axis: A Promising Strategy to Mitigate Anthracycline-Induced Cardiotoxicity.
Cardiovasc Toxicol
Varsha G Desai
Anthracycline-induced cardiotoxicity remains a major clinical challenge, often progressing to heart failure years after therapy. Conventional cardioprotective agents, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers, are widely used to preserve cardiac function; however, their effectiveness is limited by their inability to comprehensively address the complex, multifactorial pathophysiology of anthracycline-induced cardiotoxicity. This underscores the critical need for more effective and mechanism-based cardioprotective strategies that directly target the underlying molecular mechanisms, particularly oxidative stress and mitochondrial dysfunction. In recent years, the apelin-APJ signalling axis has attracted increasing attention as a potential therapeutic target in cardiovascular diseases owing to its multifaceted biological actions, including positive inotropy, vasodilation, anti-inflammatory, anti-fibrotic, anti-apoptotic, antioxidant, and pro-angiogenic effects. These pleiotropic actions are primarily mediated through the activation of key signalling pathways such as phosphoinositide 3-kinase/protein kinase B, extracellular signal-regulated kinases 1/2, and AMP-activated protein kinase. Given that these signalling cascades are disrupted during anthracycline-induced cardiotoxicity, pharmacological activation of the apelin-APJ axis may represent a promising avenue to mitigate anthracycline-associated cardiac injury with greater efficacy than conventional therapies. While native apelin isoforms (apelin-12, -13, -17, and [Pyr¹]apelin-13) are limited by their short half-lives, chemically modified analogues such as LIT01-196 and apelin-17(A2) exhibit enhanced stability and efficacy, with demonstrated cardioprotective effects in preclinical cardiovascular models and patients with chronic heart failure. However, their therapeutic potential in anthracycline-induced cardiotoxicity remains largely unexplored. This review highlights its promise as a novel cardioprotective strategy for mitigating anthracycline-induced cardiotoxicity.
Glucose-dependent dynamics of glucagon, cortisol and adrenocorticotropic hormone before and after gastric bypass.
J Endocr Soc
Vasileios Chronopoulos, Maria C Kjellsson, Martin H Lundqvist
Roux-en-Y gastric bypass (RYGB) improves glucose homeostasis beyond weight loss, but the underlying mechanisms remain incompletely understood. Counter-regulatory hormones such as glucagon, ACTH, and cortisol are key components of glucose regulation.
Apoptosis induction and migration suppression through regulation of IGF-1R/FoxO signaling pathways in Panc1 pancreatic cancer cells by hAMSCs secretome: An in vitro cell-based therapy.
Cancer Treat Res Commun
Fatemeh Safari, Mohammad Rasouli, Mana Alavi
Pancreatic cancer often referred to as the "king of cancers," is a disease with no symptoms and lacks effective therapy. Current treatment options for pancreatic cancer have not been successful, highlighting the need for new therapeutic avenues with minimal side effects and improved effectiveness. In recent years, new cell-based therapies using stem cells or their derivatives have shown promise in treating various diseases, including cancer. Here, we aimed to explore the impact of the secretome of human amniotic mesenchymal stem cells (hAMSCs) on Panc1 pancreatic cancer cells, focusing on the insulin-like growth factor 1 receptor (IGF-1R)/FoxO signaling pathways. To achieve this, we developed a co-culture system utilizing 6-well plates transwell. After 72 h, cell death and cell invasion in hAMSCs-treated Panc1 cells were assessed using Western blot, Scratch assay, and DAPI staining. Our results showed an increase in the expression levels of AKT, AMPK, FasL, and cleaved caspases 3/9, while there was a decrease in FoxO, IGF-1R, PI3K, 14-3-3, p-FoxO, MMP3, Integrin α3, and Integrin β6 expression. These findings suggest that hAMSCs' secretome promotes cell death and inhibits cell invasion in Panc1 cells, indicating its potential as a novel targeted therapy approach for pancreatic cancer.
Glucagon-Like Peptide-1 Receptor Agonists: Their Therapeutic Potential in Cystic Fibrosis.
Adv Ther
Theodoros Panou, Evanthia Gouveri, Djordje S Popovic +1 more
Cystic fibrosis (CF) is a monogenic disorder leading to pulmonary disease, pancreatic insufficiency and cystic fibrosis-related diabetes (CFRD). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are now being investigated in people with cystic fibrosis (pwCF) and CFRD. To date, their therapeutic potential has been almost exclusively studied in case reports or case series. These agents improved glycated haemoglobin (HbA1c) and continuous glucose monitoring (CGM) parameters. Benefits were also observed in weight reduction, particularly for subjects on cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI). However, discordant results have also been reported. Moreover, GLP-1RAs have improved pulmonary function, even following lung transplantation. Importantly, the dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide has also yielded favourable outcomes. Finally, preliminary evidence suggests potential inhibition of bone resorption, pointing to a therapeutic perspective in cystic fibrosis-related bone disease (CFBD). However, potential adverse events should not be ignored. These include risk of acute pancreatitis, nausea/vomiting, nutritional depletion, bowel dysmotility and distal intestinal obstruction syndrome, as well as others. Adverse events should be addressed with caution, and dose adjustments may be useful. Large prospective multicentre studies are now required to validate these outcomes and to suggest implications for clinical practice.
Effects of tirzepatide, a dual GIP and GLP-1 receptor agonist, on blood pressure, cardiac function, and sympathetic nervous system in stroke-prone spontaneously hypertensive rats.
Hypertens Res
Yoshiyasu Ono, Keisuke Shinohara, Hiroka Nakashima +13 more
Tirzepatide, a dual agonist for glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has shown robust efficacy in treating diabetes and obesity, and in obese patients with heart failure with preserved ejection fraction (HFpEF), it reduced weight, lowered blood pressure, and improved outcomes. However, its cardiovascular effects in non-obese, non-diabetic hypertension remain unclear. We investigated the impact of tirzepatide on blood pressure, cardiac function, and sympathetic nervous system activity in stroke-prone spontaneously hypertensive rats. Starting at 8 weeks of age, rats received tirzepatide (TZP, 25 nmol/kg, every two days), vehicle (VEH), or pair-fed vehicle (VEH-PF) to control for differences in food intake for 4 weeks. Tirzepatide significantly reduced food intake and body weight. Contrary to prior clinical observations, tirzepatide elevated mean blood pressure (197.4 ± 16.6 vs. 153.7 ± 5.4 mmHg at Day 28; TZP vs. VEH-PF, n = 9 vs. 8; p < 0.05) and increased heart rate, accompanied by left ventricular hypertrophy, myocardial fibrosis, and impaired diastolic function. Sympathetic activation was evident, with higher plasma norepinephrine levels and increased ΔFosB expression-a marker of sustained neuronal excitation-in the parvocellular paraventricular nucleus and the rostral ventrolateral medulla. Moreover, ΔFosB expression was increased in anorexigenic proopiomelanocortin neurons within the hypothalamic arcuate nucleus, which reduce feeding and have been implicated in promoting sympathetic excitation. These findings point to a central mechanism underlying increased sympathetic outflow. In conclusion, tirzepatide increased blood pressure and sympathetic activity in hypertensive rats without cardiac protection, highlighting context-dependent cardiovascular actions. Tirzepatide increased blood pressure, impaired LV diastolic function, and induced cardiac hypertrophy and fibrosis, as well as sympathetic overactivation in SHRSP.
Glucagon-Like Peptide-1 Receptor Agonists in Patients with Heart Failure with Reduced Ejection Fraction.
ESC Heart Fail
Joseph Kassab, Mark H Drazner, Jennifer T Thibodeau
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve cardiovascular outcomes in obesity and HFpEF; however, their safety and efficacy in heart failure with reduced ejection fraction (HFrEF) remain uncertain.
Approved weight loss drugs for obesity with a thorough emphasis on GLP-1 agonist medications: A systematic review.
Dis Mon
Praveen Gunasekaran, Pugazhendi Inban, Ashita Agrawal +5 more
Obesity is a worldwide health concern linked to cardiometabolic comorbidities such as type 2 diabetes, hypertension, dyslipidemia, and heart disease. The management of obesity using pharmacotherapy, especially with GLP-1 receptor agonists and dual incretin agents, has proven successful not only for weight loss but also for gaining control of the metabolic components of the disease. Thus, it is pertinent to analyse the GLP-1-based anti-obesity medications to examine cardiometabolic efficacy and safety using weight loss, glycemic control, cardiometabolic, gastro-intestinal tolerability, and serious adverse events as the primary variables.
Cardiometabolic Profiles of Oral and Subcutaneous Glucagon-Like Peptide-1 Receptor Mono-Agonists in Adults With Overweight or Obesity: A Systematic Review and Network Meta-Analysis.
Diabetes Obes Metab
Ying Lu, Jiajie Chen, Yuqing Guo +6 more
To characterize the cardiometabolic profiles of oral and subcutaneous glucagon-like peptide-1 (GLP-1) receptor mono-agonists in adults with overweight or obesity, with or without type 2 diabetes (T2D), using network meta-analysis (NMA).
Overcoming Challenges in Wound Infection: Biofilm and Antimicrobial Resistance.
Adv Wound Care (New Rochelle)
Markus Rothmaier, Matthew J Hardman, Bithi Chatterjee +3 more
Chronic wounds represent a growing clinical and economic burden, affecting 1-2% of the global population, with prevalence expected to rise due to aging and increasing rates of diabetes, obesity, and vascular diseases. Wound persistence is often driven by infection and compounded by antimicrobial resistance (AMR), resulting in poor patient outcomes. High prevalence of microbial biofilms, which shield pathogens from immune clearance and promote AMR, further promotes the chronicity of infected wounds.
Dapagliflozin for cardiorenal protection after intensive care unit discharge: a protocol for a randomised controlled trial evaluating dapagliflozin at ICU discharge for cardiorenal protection (DAPA-ICU).
BMJ Open
François Dépret, Benjamin Chousterman, Claire Roger +20 more
Patients discharged from intensive care units (ICUs) are at high risk of adverse long-term outcomes including cardiovascular and/or renal events and a 1-year mortality of approximately 22%. Plasma biomarkers measured at ICU discharge have demonstrated strong prognostic value, with elevated cardiac or renal biomarkers identifying patients at particularly high risk of poor outcomes. Sodium-glucose cotransporter 2 inhibitors are now widely recognised for their cardioprotective and nephroprotective effects in chronic conditions such as type 2 diabetes, heart failure or chronic kidney disease. These agents improve both morbidity and mortality across a range of high-risk populations. We hypothesise that a therapeutic strategy aimed at preventing the progression of cardiovascular and/or renal injury following ICU discharge may improve long-term outcomes in ICU survivors.
Machine learning-based risk stratification identifies heart failure with preserved ejection fraction as an independent predictor of adverse outcomes in hypertrophic cardiomyopathy.
Sci Rep
Weijie Zhang, Huan Zhao, Zhuchang Tian +16 more
Heart failure with preserved ejection fraction (HFpEF) is increasingly recognized in hypertrophic cardiomyopathy (HCM); however, its prognostic significance, phenotypic heterogeneity, and optimal risk stratification strategies remain incompletely defined. In this multicenter retrospective cohort study, 2802 patients with HCM were enrolled from three tertiary centers. HFpEF was diagnosed using established criteria, and H₂FPEF score-based risk subgrouping was performed to further stratify patients. Propensity score matching was applied to balance baseline characteristics between HFpEF and Non-HFpEF patients. Event-free survival was assessed using Kaplan-Meier and multivariable Cox analyses. Restricted cubic spline modeling evaluated non-linear associations between B-type natriuretic peptide (BNP) levels and outcomes. Four machine learning models were developed for individualized risk prediction, with model interpretability assessed using SHAP analysis. HFpEF was present in 47.8% of patients with HCM and was independently associated with worse event-free survival after propensity score matching (HR = 2.612, 95% CI 2.188-3.118, P < 0.001). Higher H₂FPEF scores conferred graded risk, with HFpEF-High patients exhibiting substantially poorer outcomes (HR 2.925, 95% CI 2.210-3.701; P < 0.001). BNP demonstrated a significant non-linear relationship with adverse events, with risk accelerating at higher concentrations. Among machine learning models, the random forest achieved the best discrimination (AUC = 0.856), with SHAP analysis identifying HFpEF status and BNP as dominant contributors to risk prediction. HFpEF represents a prevalent, heterogeneous, and high-risk phenotype in HCM. Integrating H₂FPEF score-based risk subgrouping, non-linear biomarker modeling, and interpretable machine learning enhances personalized risk stratification and may, pending external validation, inform precision management strategies in HCM.
Sex differences in corticotropin-releasing factor receptor-2α expressing neurons in acutely stressed mice.
Horm Behav
Jennifer J Lafrican, Katherine E Parra, Krystyna A Rybka +12 more
Females are 2-3 times more likely than males to be diagnosed with mood disorders, including depression and anxiety, yet the neurobiological mechanisms contributing to this sex difference are not fully understood. Corticotropin-releasing factor receptor 2 (CRFR2) plays a key role in regulating stress responses, with evidence suggesting it may dampen hypothalamic-pituitary-adrenal (HPA) axis activation and behavioral stress responses. Although CRFR2 has been implicated in stress buffering, little is known about how its expression and activation differs by sex, particularly in the mouse model. To address this gap, we used newly generated CRFR2-Cre-2α-TdTomato mice to investigate sex differences in CRFR2-expressing neurons and their activation across stress-regulating brain regions following an acute restraint. Males exhibited significantly more CRFR2-expressing neurons in the lateral septum, bed nucleus of the stria terminalis, paraventricular nucleus of the hypothalamus, and central amygdala, while females had more CRFR2-expressing neurons in the medial amygdala and ventromedial hypothalamus. Activation of CRFR2 neurons also showed region-specific sex differences, with males generally exhibiting greater CRFR2 colocalization with c-Fos, a marker for neural activation. Corticosterone levels following restraint were correlated with CRFR2 expression or activation in several brain regions, including the paraventricular hypothalamus, medial amygdala, and bed nucleus of the stria terminalis. These findings identify novel sex differences in CRFR2 expression and stress-induced activation of CRFR2 neurons across multiple stress-regulating brain areas. Together, these results suggest that sex differences in CRFR2 signaling may mediate sex differences in HPA axis responsivity as well as behavioral stress responses.
Cushing's Shadow: An Overlooked Diagnosis in Endocrinology.
Horm Metab Res
Lala Soltanova, Serdar Sahin, Yucel Erbilgin +5 more
The purpose of this study was to describe a novel heterozygous missense variant in the nuclear receptor subfamily 3 group C member 1 ligand-binding domain causing primary generalized glucocorticoid resistance and highlight diagnostic pitfalls that can mimic Cushing's disease.A 22-year-old woman was evaluated for suspected Cushing's disease after elevated cortisol levels and pituitary imaging findings. She underwent three transsphenoidal surgeries, but hypercortisolism and clinical symptoms including hirsutism, acne, menstrual irregularities, and weight gain persisted. The absence of classical Cushing's stigmata prompted genetic evaluation, which led to the diagnosis of primary generalized glucocorticoid resistance.Whole-exome sequencing was performed in the index case. The identified variant was validated by Sanger sequencing and segregation analysis was carried out in her sister. A novel heterozygous, likely pathogenic missense variant (NM_000176.3:c.1940T>C, p.(Leu647Pro)) in the nuclear receptor subfamily 3 group C member 1 gene was detected in two siblings. We describe a novel nuclear receptor subfamily 3 group C member 1 variant associated with primary generalized glucocorticoid resistance, expanding the mutational spectrum of glucocorticoid receptor defects. This case underscores the importance of considering primary generalized glucocorticoid resistance in patients with adrenocorticotropic hormone-dependent hypercortisolism lacking typical Cushing's features to prevent unnecessary invasive procedures and guide appropriate genetic counseling.
Carbonless amino acids and a carbonless GHK peptide.
Phys Chem Chem Phys
Piotr Skurski, Iwona Anusiewicz
Carbonless biomolecular design, in which carbon atoms are systematically replaced by boron and nitrogen under an isoelectronicity constraint, offers a route to carbon free analogues that retain the structural logic of familiar biochemistry. The concept is applied to amino acids and peptides, using glycine, histidine, lysine, and the tripeptide Gly-His-Lys (GHK) as a representative system. DFT(ωB97XD)/aug-cc-pVDZ calculations with aqueous PCM solvation, supported by CREST conformer sampling at the GFN2-xTB/ALPB level, identify unique low energy carbonless building blocks, cGly, cHis, and cLys, defined as carbonless analogues of Gly, His, and Lys among all isoelectronic BN constitutional isomers. These residues enable construction of cGHK, defined as the carbonless analogue of GHK, whose conformational landscape is predicted to be broader than that of GHK under physiological aqueous conditions, consistent with enhanced conformational plasticity. Cu(II) complexation is modeled with an experimentally supported 3N1O motif including one explicit water ligand, and an isodesmic ligand exchange thermodynamic cycle based on ensemble Gibbs free energies indicates stronger stabilization of Cu(II) by cGHK than by GHK (ΔGexch = -6.24 kcal mol-1 at 298 K), with only a minor ensemble correction. The results demonstrate the feasibility of carbonless amino acids and peptides and show that BN substitution can tune conformational behavior and metal binding thermodynamics in carbon free bioinspired scaffolds.
miR-449b-5p from adipose-derived mesenchymal stem cell-derived exosomes targets IGF1R to alleviate airway inflammation and improve airway smooth muscle cell dysfunction in children with asthma.
J Immunol
ShuXiang Sui, LiJuan Yang, DongMei Ji +1 more
This study investigated the protective effect of miR-449b-5p from adipose-derived mesenchymal stem cell-derived exosomes (ADSC-Exos) targeting type 1 insulin-like growth factor receptor (IGF1R) on airway smooth muscle cells (ASMCs) and further investigated its mechanism of action. ADSC-Exos were isolated and characterized. Cellular uptake of ADSC-Exos by ASMCs was observed. Differences in serum miR-449b-5p expression levels between healthy children and asthmatic children were detected by RT-qPCR. The possible binding sites of miR-449b-5p and IGF1R were identified and then verified. The proliferation of ASMCs was determined by MTT assay and EdU assay. Cell cycle of ASMCs was measured by flow cytometry. Cell contraction of ASMCs was evaluated by inverted microscopy. IL-4, IL-5, and IFN-γ were measured by ELISA to evaluate the inflammatory response of ASMCs. ADSC-Exos exerted therapeutic effects on ASMCs by effectively inhibiting proliferation, cell contraction, and inflammatory response. miR-449b-5p upregulation in ASMCs effectively inhibited the promoting effect of PDGF-BB on cellular proliferation and contraction, while IGF1R upregulation showed the opposite effect. miR-449b-5p in ADSC-Exos targeted IGF1R to alleviate airway inflammation in asthma and improve ASMC dysfunction. ADSC-Exos carrying miR-449b-5p improve ASMC dysfunction, excessive proliferation, and inflammatory responses by downregulating IGF1R.