Smooth Muscle Research Articles

Reproducibility of smooth muscle mechanical properties in consecutive stretch and activation protocols.

Mechanical organ models are crucial for understanding organ function and clinical applications. These models rely on input data regarding smooth muscle properties, typically gathered from experiments involving stimulations at different muscle lengths. However, reproducibility of these experimental results is a major challenge due to rapid changes in active and passive smooth muscle properties during the measurement period. Usually, preconditioning of the tissue is employed to ensure reproducible behavior in subsequent experiments, but this process itself alters the tissue's mechanical properties. To address this issue, three protocols (P1, P2, P3) without preconditioning were developed and compared to preserve the initial mechanical properties of smooth muscle tissue. Each protocol included five repetitive experimental cycles with stimulations at a long muscle length, varying in the number of stimulations at a short muscle length (P1: 0, P2: 1, P3: 2 stimulations). Results showed that P2 and P3 successfully reproduced the initial active force at a long length over five cycles, but failed to maintain the initial passive forces. Conversely, P1 was most effective in maintaining constant passive forces over the cycles. These findings are supported by existing adaptation models. Active force changes are primarily due to the addition or removal of contractile units in the contractile apparatus, while passive force changes mainly result from actin polymerization induced by contractions, leading to cytoskeletal stiffening. This study introduces a new method for obtaining reproducible smooth muscle parameters, offering a foundation for future research to replicate the mechanical properties of smooth muscle tissue without preconditioning.

Age-associated increase in AT1R expression in human testis and its intervention effects on Leydig cell senescence in aged rodents.

The active peptide hormone Ang II (angiotensin II) mediates the vast majority of the RAS (renin-angiotensin system) action, mainly through activation of AT1R (Angiotensin II type-1 receptor). AT1R expression peaks in newborn males and decreases toward the adult age, and it is shown to exhibit an inhibitory effect on hCG (human chorionic gonadotropin)-stimulated steroidogenesis in LCs (Leydig cells), as well as an promoting effect on smooth muscle and endothelial cell senescence. However, whether hyperactivation of the AT1R signaling exerts any effects on Leydig cell senescence, which could provide insights into hypogonadism mechanisms for aging males, remains unexplored. We herein reported that AT1R expression was significantly upregulated in aged human and rat testes. Transgenic overexpression of AT1R in LCs mimicked multiple late-onset hypogonadism phenotypes, including acceleration of Leydig cell senescence, defective steroidogenesis and spermatogenesis, and increased inflammation and oxidative stress. One of the core biochemical events underpinning AT1R action was the AT1R-induced enhancement of the interaction between MDM2 (murine double minute 2) and the p65 subunit of NF-κB (nuclear factor-kappaB), consequently augmenting polyubiquitination and activation of p65, in a p38-dependent manner. Conversely, repression of AT1R activity ameliorated Leydig cell senescence and rescued testicular steroidogenesis in old rats. Together, forced expression of AT1R within the testicular interstitium potentiates aging-related traits in LCs, thereby leading to fertility impairment with defective steroidogenesis and spermatogenesis in male rodents. Our systematic analysis also indicates that blocking the Ang II/AT1R signal might be beneficial in intervening disorders of late-onset hypogonadism in old males.

More severe vascular remodeling in deep brain regions caused by hemodynamic differences is a potential mechanism of hypertensive cerebral small vessel disease.

In hypertension-associated arteriolosclerosis cerebral small vessel disease (CSVD), various studies have shown that MRI-detected lesions-such as lacunes, white matter hyperintensities, enlarged perivascular spaces, and cerebral microbleeds-are more prevalent in deep brain regions (DBR) than in the cortex. However, the underlying mechanisms remain poorly understood. We propose that differential vascular remodeling between DBR small vessels and superficial cortical branches contributes to this heterogeneity. Using a stroke-prone renovascular hypertensive rat (RHRsp) model, we observed pronounced changes in vessel density, diameter, extracellular matrix deposition, and smooth muscle cell alterations in DBR small arteries compared to that of the cortex. These findings were further confirmed in human brain tissue of our study. Additionally, our mathematical modeling indicated greater hemodynamic alterations in DBR vessels, with increased shear and circumferential stress under hypertension conditions. Overall, our study highlights more severe vascular remodeling and hemodynamic changes in the deep brain regions, where CSVD-associated MRI lesions are frequently detected.

Posttransplant EBV-positive Smooth Muscle Tumors in Children, Adolescents, and Young Adults: A Multi-Institution Experience.

Epstein-Barr virus (EBV)-positive smooth muscle tumors (SMTs) are rare tumors seen in immunocompromised patients. There is no clear standard of care for the management and treatment of EBV-SMTs. Patients are often treated with chemotherapy, surgery, and/or radiation. Additional options include antiretroviral treatment, reduction in immunosuppression, and EBV-directed virus-specific T cells (VSTs). This report describes the treatment regimens and outcomes of eight patients with EBV-associated SMTs. Although no consensus treatment for EBV-SMTs has been identified, VSTs show promise in providing a period of stable disease or partial response and surgical removal may offer long-term benefits in cases of localized disease.

NLRP3 deficiency abrogates silica-induced neutrophil infiltration, pulmonary damage and fibrosis

BackgroundSilicosis is a progressive and often fatal occupational lung disease. The NLRP3 inflammasome is an innate immune sensor that is activated by silica. Accumulating evidence has implicated a role for NLRP3 in silicosis pathogenesis. In this study, we mechanistically elucidated the contribution of NLRP3 to silica-induced pulmonary disease.MethodsThe in vivo role of NLRP3 was investigated following intranasal delivery of 2 mg of silica or diluent alone to wildtype, NLRP3 reporter, and NLRP3-deficient mice. Protein expression, inflammation, and histopathology were analyzed in the lung.ResultsIntranasal administration of silica recapitulated the key pathological features of human silicosis, including nonresolving inflammation, the formation of silicotic nodules, and diffuse lung fibrosis. A reporter mouse placed under the native NLRP3 promoter revealed silica rapidly upregulated NLRP3 expression throughout the lung. NLRP3-deficient mice displayed marked early reductions in silica-induced IL-1β and IL-18 levels in the airways. Additionally, NLRP3 deficiency impaired the rapid infiltration of conventional Siglec-F− and fibrotic Siglec-F+ neutrophils, which correlated with reduced levels of neutrophil elastase. Deficiency in acute NLRP3-mediated inflammation correlated with significantly reduced pulmonary transforming growth factor beta and alpha smooth muscle actin expression, tissue damage, and fibrosis in the chronic phase of disease progression. Importantly, this included reduced silicotic nodule size and cellularity.ConclusionsThese findings highlight a major detrimental role for the NLRP3 inflammasome in driving silica-induced pulmonary neutrophil infiltration, TGFβ-mediated myofibroblast activation, tissue damage, and fibrosis.

HIF1A facilitates hypoxia-induced changes in H3K27ac modification to promote myometrial contractility

Prior studies have established that myometrial hypoxia during labor is pivotal in intensifying contractions, the alterations in gene expression and histone modifications in myometrial cells under hypoxia have yet to be documented. Here, hypoxia’s enhancement of cellular contractility was confirmed, and RNA-seq identified 2,262 differentially expressed genes in human myometrial smooth muscle cells (hMSMCs) under hypoxia. Chromatin immunoprecipitation (ChIP), high-throughput chromosome conformation capture followed by ChIP (Hi-ChIP) were employed to investigate the epigenetic changes, specifically histone modifications (H3K27ac, H3K4me1, H3K27me3, and H3K4me3), in hMSMCs under hypoxia. We identified the enhancer and super-enhancer regions in hMSMCs and found HIF1A as the key mediator of these H3K27ac changes under hypoxia. Labor-associated genes regulated by HIF1A have been identified. Validation experiments on these genes such as CXCL8, RUNX1, IL-6, and PTGES3 demonstrated that HIF1A knockdown reduces their expression and associated H3K27ac modifications in peak regions of their promoters or enhancers. These findings indicate that HIF1A probably mediate changes in histone H3K27ac modifications to regulate myometrial cell contractions under hypoxia, providing potential therapeutic and intervention targets for disorders related to parturition.

Blockade of YAP Mechanoactivation Prevents Neointima Formation and Adverse Remodeling in Arterialized Vein Grafts.

Bypass surgery using saphenous vein (SV) grafts is commonly performed to revascularize the ischemic heart and lower limbs. These interventions have limited success due to adverse remodeling caused by overproliferation of smooth muscle cells in the intima layer, leading to progressive bypass stenosis. We previously showed that cyclic strain deriving from exposure to coronary flow induces the expression of the matricellular protein thrombospondin-1 in the human SV, promoting activation of progenitor cells normally residing in the adventitia. We analyzed the data of an RNA-sequencing profiling of human SV progenitors subjected to uniaxial strain we previously performed by. Experiments in cell culture, exvivo, and invivo vein arterialization models were performed to substantiate findings with particular reference to the role of mechanically activated transcription factors. Validation was performed invitro and in exvivo/in vivo models of vein graft disease. Results of bioinformatic assessment of the RNA-sequencing data indicated Yes-associated protein (YAP) as a possible mechanically regulated effector in pathologic evolution of SV progenitors. Inhibition of YAP by verteprofin-a drug that abolishes the interaction of YAP with Tea Domain DNA-binding proteins-reduced the expression of pathologic markers invitro and reduced intima hyperplasia invivo. Our results reveal that desensitizing the SV-resident cells to mechanoactivation of YAP is feasible to reduce the graft disease progression.

Immunohistochemical analysis of smooth muscle actin and CD31 in feline post-injection site fibrosarcomas: association with tumour grade, vascular density, and multinucleated giant cells

BackgroundMultinucleated giant cells are commonly observed in various malignancies; however their clinical and biological significance remains largely unexplored and it has been hypothesised that the cells may play a role in vascular mimicry, tumour progression and tumour survival. This study aimed to investigate the expression of smooth muscle actin and CD31 in feline post-injection site fibrosarcomas, focusing on relationships between multinucleated giant cells presence, tumour grade, and vascular density to elucidate their potential role in tumour progression.ResultsA total of 61 feline post-injection site fibrosarcomas, histologically graded into grades I, II, and III, were examined immunohistochemically. Smooth muscle actin immunoreactivity was detected in 57/61 (93.4%) cases. Multinucleated giant cells expressing CD31 were identified in 39/61 (63.9%) cases, predominantly in high-grade tumours, with a correlation observed between multinucleated giant cell presence, tumour grade, and mitotic index. Vascular density differed across tumour grades. A negative correlation between vascular density, tumour grade and necrosis score was identified. Additionally, a negative correlation was observed between multinucleated giant cells presence and vascular density.ConclusionsThe findings suggest a complex tumour microenvironment in which multinucleated giant cells and vascular mimicry may facilitate tumour survival under hypoxic conditions, potentially contributing to an aggressive tumour phenotype.

Low-intensity pulsed ultrasound elevates blood pressure for shock.

Fluid replacement is the primary treatment for life-threatening shock but is challenging in harsh environments. This study explores low-intensity pulsed ultrasound (LIPUS) as a resuscitation strategy. Cervical LIPUS stimulation effectively elevated blood pressure in shocked rats. It also improved cerebral and multiorgan perfusion. Mechanistically, LIPUS activated pathways related to sympathetic nerve excitation and vascular smooth muscle contraction, increasing plasma catecholamines and stimulating blood pressure-regulating neural nuclei. Partial sympathetic nerve transection reduced LIPUS efficacy, while complete inhibition of these nuclei abolished the response. Preliminary clinical trials demonstrated LIPUS's ability to raise blood pressure in shock patients. The findings suggest that LIPUS enhances sympathetic nerve activity and activates blood pressure-regulating nuclei, offering a noninvasive, neuromodulation-based approach to shock treatment. This method holds potential for improving blood pressure and organ perfusion in shock patients, especially in resource-limited environments.

Chemokine (C-C Motif) Ligand 2 Expressing Adventitial Fibroblast Expansion During Loeys-Dietz Syndrome Aortic Aneurysm Formation.

Loeys-Dietz syndrome (LDS), caused by mutations in the TGF-β (transforming growth factor-β) signaling cascade, leads to aggressive thoracic aneurysms. While vascular smooth muscle cell (SMC) phenotype modulation has been implicated in thoracic aneurysm formation, we sought to characterize the role of cell state transitions in LDS aneurysm pathogenesis. We performed single-cell transcriptomic characterization of aortic root/ascending aorta from a murine LDS model (Tgfbr2G357W/+ versus littermate WT [wild-type] control) at 8 weeks, 24 weeks, and aortic root/ascending aortic samples from human LDS surgical specimens (n=5 LDS [TGFBR1/2] and n=2 donor control) to understand cell state transitions and transcriptomic alterations in LDS. Select cell markers were spatially localized with RNA in situ hybridization, immunofluorescence, and immunohistochemistry. Single-cell RNA sequencing of murine and human LDS samples (>30 000 cells) revealed unique SMC, fibroblast, and macrophage transcriptomic profiles in LDS. Instead of SMC phenotypic modulation seen in Marfan syndrome, transcriptomic alterations observed in LDS are most prominent in the adventitial fibroblast in the Tgfbr2G357W/+ mouse model. While a distinct modulated SMC cluster does not appear in Tgfbr2G357W/+, SMCs transcriptomically differ from WT counterparts. Adventitial fibroblasts were activated into a proinflammatory state associated with increased macrophage recruitment (Ccl2, Il6, Ccl7, and Cxcl2) and fibrotic response genes (Col1a1, Col1a2, and Col3a1), with a 6-fold increase in aortic wall macrophage content in Tgfbr2G357W/+ compared with WT. Similar findings were also observed in human LDS aortic samples with increased proinflammatory adventitial fibroblast transcriptomic program in parallel with heightened macrophage recruitment. Despite phenotypic similarities in aneurysm formation, the dominant cellular and molecular mechanism of Marfan syndrome and LDS aneurysms are distinct. LDS mouse and human adventitial fibroblasts transcriptomically modulate into a proinflammatory state. Adventitial fibroblasts, in addition to SMCs, are another important pathological cell population during LDS aneurysm formation to consider for targeted therapy to potentially impede LDS aneurysm formation.

Enhanced Drug Effect With Cutting Balloon Followed by Drug Coated Balloon in a Rabbit Model.

Drug-coated balloon (DCB) are effective treatment options for patients with coronary artery disease and using of scoring or cutting balloon before the DCB usage were recommended. However, the effectiveness of lesion preparation with cutting balloons (CB) followed by DCB (CB + DCB) has not been evaluated before. The aim of the current study was to compare the biological effect of various types of balloon angioplasty in a healthy rabbit iliac artery model. Each of the four kinds of treatments as balloon angioplasty (BA), CB alone, DCB alone, and CB + DCB were performed in the healthy iliac arteries of 12 rabbits, which were euthanized after 14 days. The treated iliac arteries were sequentially cut, stained with hematoxylin and eosin and Movat Pentachrome, and histopathologically evaluated. The depth of medial smooth muscle cell (SMC) loss score, an indicator of drug effect, was highest with CB + DCB, followed by DCB, CB, and BA (CB + DCB vs. DCB vs. CB vs. BA: 3.83 (3.67-4.00) vs. 3.17 (2.67-3.67), 1.67 (1.67-2.08) vs. 1.50 (1.00-1.67), p < 0.0001). The angle with severe SMC loss was also the highest with CB + DCB group, followed by DCB group, CB group, and BA group (123.7 (104.5-132.2) vs. 52.1 (34.7-100.6), 0.0 (0.0-14.2) vs. 0.0 (0.0-0.0), respectively, p < 0.0001), suggesting a higher drug effect in CB + DCB compared with DCB alone. The drug effect of DCB was enhanced when CB was used before DCB treatment, suggesting the effectiveness of the combination therapy of CB and DCB.

Utilising Human Myometrial and Uterine Fibroid Stem Cell-Derived Three Dimentional Organoids as a Robust Model System for Understanding the Pathophysiology of Uterine Fibroids.

Uterine fibroids (UFs) are the most common benign gynecologic tumours affecting women of reproductive age. This study aims to deepen the understanding of UFs complex aetiology through harnessing the power of 3D organoid models derived from human myometrial stem cells to emulate the invivo behaviour of these tumours. Isolated SCs were cultured over 7 days under a defined culture system. Immunohistochemistry, Immunofluorescence, organoid stiffness, RNA Sequencing was conducted, and differential gene expression was assessed using RT-PCR. The derived organoids exhibited diverse populations of cells, including stem cells, smooth muscle, and fibroblasts. Excessive ECM deposition was shown via Collagen and Fibronectin expression. We confirmed that our organoids expressed oestrogen receptor in a pattern similar to that in their corresponding tissue, as well as responded to steroid hormone. Interestingly, we revealed significant racial disparities in ECM accumulation within organoids derived from different racial groups. This augmented ECM deposition is theorised to enhance tissue stiffness, as assessed using Young's modulus. Additionally, our research demonstrated significant decreases in fibrotic markers upon treatment with Vitamin D3 and Doxercalciferol. Furthermore, the pro-fibroid effects of environmental phthalates further elucidate the potential factors contributing to UF pathology. The 3D organoid model can serve as a robust platform to study the underlying molecular mechanisms of UFs, besides offering invaluable insights for potential therapeutic interventions.

Investigation of the mechanistic impact of CBL0137 on airway remodeling in asthma

BackgroundBronchial asthma, a chronic inflammatory airway disease, is characterized by airway remodeling, including thickening of the airway smooth muscle layer, primarily due to abnormal proliferation of airway smooth muscle cells (ASMCs). CBL0137 (Curaxin-137 hydrochloride), a histone chaperone facilitate chromatin transcription (FACT) inhibitor, has demonstrated anti-tumor properties, including inhibition of proliferation, promotion of apoptosis, and increased autophagy. However, its effects on ASMCs and airway remodeling remain unexplored.MethodsAsthma models were established using ovalbumin (OVA) in female C57BL/6 J mice, with therapeutic interventions using CBL0137 and budesonide. Lung tissues were analyzed using Hematoxylin and eosin (H&E), PAS, Masson’s trichrome, and α-SMA immunofluorescence staining. ASMCs extracted from Sprague–Dawley rats were cultured in vitro experiments, with phenotypic changes assessed via flow cytometry. Gene and protein expressions were analyzed using RT-PCR and Western blotting.ResultsCBL0137 significantly reduced airway resistance, goblet cell proliferation, alveolar collagen deposition, and airway smooth muscle layer thickening in asthmatic mice. In vitro, CBL0137 inhibited ASMC proliferation and induced apoptosis, downregulating cyclin-B1, Cdc2, and Bcl-2 while upregulating caspase-3.ConclusionsCBL0137 mitigates airway remodeling of asthmatic mice by modulating ASMC proliferation and apoptosis, presenting a potential therapeutic strategy for asthma treatment.

Increased Endothelin-1 Is Associated WithMorbidity in Single Ventricle HeartDisease in Children Undergoing Fontan Palliation.

Increased Endothelin-1 Is Associated WithMorbidity in Single Ventricle HeartDisease in Children Undergoing Fontan Palliation.

Overexpression of ABCA1 in Carotid Endothelium of Hyperlipidemic Rabbits Modulates Vascular Inflammation.

Endothelial activation and dysfunction are key early steps in atherogenesis. Vascular gene therapy targeting endothelial inflammation and cholesterol accumulation could decrease atherosclerosis progression. ATP-binding cassette subfamily A member 1 (ABCA1) exhibits anti-inflammatory properties and promotes cholesterol efflux. A mouse model showed that systemic endothelial overexpression of ABCA1 decreased diet-induced atherosclerosis. To test if local ABCA1 endothelial overexpression protects against atherosclerosis, we used helper-dependent adenoviral vectors (HDAd) to express ABCA1 or a "Null" control in the carotid endothelium of hyperlipidemic rabbits. Both ABCA1 mRNA and endothelial protein were increased 3 days after vector infusion. After 24 weeks on a high-fat diet, laser-microdissected endothelium showed increased ABCA1 mRNA expression, but whole-vessel ABCA1 mRNA was decreased with HDAdABCA1. Endothelial ABCA1 protein could not be measured at 24 weeks, so its overexpression may be transient. CD68 expression was decreased (-23%, p < 0.001), but ITGAM (-15%, p = 0.3) was unchanged. Macrophage markers for both M1-like macrophages (IL1B: -44% [p = 0.02]; IL6: -40% [p = 0.02]; CCL2: -25% [p = 0.02]) and M2-like macrophages (ARG1: -27% [p = 0.03]; IL10: -23% [p = 0.09]; TGFB1: -13% [p < 0.001]) were also decreased. The inflammatory cytokines IL6 (-100%; p < 0.001) and TNF (p < 0.05) were significantly decreased in the laser-microdissected endothelium, but VCAM1 (+5%, p = 1.0) was unchanged and ICAM1 (+101%; p = 0.03) increased. Lesion size, intimal lipid, and intimal macrophage content were all unchanged (p > 0.5 for all), and vascular cholesterol measured by mass spectrometry (-11%; p = 0.9) also showed no difference. There was a small decrease in the intimal/medial ratio. scRNAseq revealed that vector transcripts were not restricted to endothelial cells after 24+ weeks but were detected in most cell types. The exception was modulated smooth muscle cells, which were found in substantial numbers in larger lesions. Overall, transient overexpression of ABCA1 in the vascular endothelium subtly alters the expression of inflammatory markers, providing only a modest atheroprotection.

Activin a regulates vascular formation and stabilization indirect coculture of dental pulp stem cells and endothelialcells.

Establishing functional circulation on time is crucial to dental pulp tissue regeneration. Mesenchymal stem cells (MSCs) could act as mural cells to stabilize newly formed blood vessels, accelerating anastomosis. Our preliminary study found that direct coculture of dental pulp stem cells (DPSCs) and human umbilical vein endothelial cells (HUVECs) significantly enhanced Activin A secretion. This study aimed to disclose the dynamic patterns of Activin A expression and its regulation on vascular formation and stabilization. DPSCs and HUVECs were cocultured directly at a ratio of 1:1 for 3 and 6 days. Activin A and Follistatin expression were evaluated by qRT-PCR and ELISA. HUVECs were exposed to 100 ng/mL Activin A or the conditioned medium (CM) generated from DPSC monoculture and DPSC-HUVEC coculture, respectively. HUVEC proliferation, migration, tube formation and angiogenic sprouting were assessed. In parallel, membrane-bound vascular endothelial growth factor receptors (mVEGFR1 and mVEGFR2) and soluble VEGFR1 (sVEGFR1) were analysed at days 3 and 6. Activin A expression and secretion were elevated time-dependently during DPSC-HUVEC coculture. Follistatin expression decreased in DPSC-HUVEC coculture while the ratio of Activin A/Follinstain increased significantly. Activin A treatment did not promote DPSC towards smooth muscle cell (SMC)-specific differentiation, while Activin A and DPSC+HUVEC-CM suppressed HUVEC proliferation, migration, tube formation and sprouting. Activin A and DPSC+HUVEC-CM treatment markedly increased mVEGFR1 expression and sVEGFR1 secretion, suppressing HUVEC vascular formation. Activin A IgG partially reversed the effects of DPSC+HUVEC-CM on HUVECs by decreasing VEGFR1 expression and increasing vessel formation. Activin A pretreatment downregulated VEGF-triggered VEGFR2 phosphorylation of HUVECs. INHBA knockdown DPSCs disrupted the stabilization of the preformed HUVEC vascular tube network. DPSC-HUVEC direct coculture upregulates Activin A secretion, interrupting VEGF receptors' balance in HUVECs to suppress HUVEC angiogenic sprouting and enhance vascular stabilization. These findings provide novel insights into the paracrine interactions on vascular stabilization of DPSC-HUVEC direct coculture.

Identification and Experimental Validation of NETosis-Mediated Abdominal Aortic Aneurysm Gene Signature Using Multi-omics, Machine Learning, and Mendelian Randomization.

Abdominal aortic aneurysm (AAA) is a life-threatening disorder with limited therapeutic options. Neutrophil extracellular traps (NETs) are formed by a process known as "NETosis" that has been implicated in AAA pathogenesis, yet the roles and prognostic significance of NET-related genes in AAA remain poorly understood. This study aimed to identify key AAA- and NET-related genes (AAA-NETs-RGs), elucidate their potential mechanisms in contributing to AAA, and explore potential therapeutic compounds for AAA therapy. Through bioinformatics analysis of multiomics and machine learning, we identified six AAA-NETs-RGs: DUSP26, FCN1, MTHFD2, GPRC5C, SEMA4A, and CCR7, which exhibited strong diagnostic potential for predicting AAA progression, were significantly enriched in pathways related to cytokine-cytokine receptor interaction and chemokine signaling. Immune infiltration analysis revealed a causal association between AAA-NETs-RGs and immune cell infiltration. Cell-cell communication analysis indicated that AAA-NETs-RGs predominantly function in smooth muscle cells, B cells, T cells, and NK cells, primarily through cytokine and chemokine signaling. Gene profiling revealed that CCR7 and MTHFD2 exhibited the most significant upregulation in AAA patients compared to non-AAA controls, as well as in in vitro AAA models. Notably, genetic depletion of CCR7 and MTHFD2 strongly inhibited Ang II-induced phenotypic switching, functional impairment, and senescence in vascular smooth muscle cells (VSMCs). Based on AAA-NETs-RGs, molecular docking analysis combined with the Connectivity Map (CMap) database identified mirdametinib as a potential therapeutic agent for AAA. Mirdametinib effectively alleviated Ang II-induced phenotypic switching, biological dysfunction, and senescence. These findings provide valuable insights into understanding the pathophysiology of AAA and highlight promising therapeutic strategies targeting AAA-NETs-RGs.

Multifaceted role of transgelin isoforms in cancer hallmarks.

Transgelins (TAGLNs) are actin-binding proteins within the calponin family, playing a crucial role in modulating actin-myosin interactions and maintaining actin filament stability. These proteins are expressed in both smooth and non-smooth muscle cells, contributing to the regulation of muscle contractility and cell migration. TAGLNs family has three isoforms that differ in their isoelectric point, namely: TAGLN1, TAGLN2, and TAGLN3. TAGLNs regulation is involved in the development of many diseases, such as pulmonary arterial hypertension, asthma, atherosclerosis, obstructive nephropathy, diabetes, and cancer. Recent research indicates TAGLNs involvement in carcinogenesis and chemoresistance. This review investigates TAGLNs as potential cancer biomarkers, exploring their versatile tissue-specific impact on patient outcomes. We also highlight their roles as, tumor suppressor agents and tumor progression oncogenes depending on the tumor type, tumor genetic variations and TAGLNs expression profiles. Furthermore, emerging evidence suggests that the interplay between TAGLN2 and chemoresistance to anticancer drugs is mediated by its interaction with the chemoresistance double agent MT-2, with possible bidirectional implications. TAGLNs present a promising avenue for novel therapeutic strategies against cancer, owing to their tissue-specific duality in promoting/suppressing tumor growth and cell migration in cancer cells. Thus, they can serve as a potential prognostic/diagnostic biomarker. The focus should be on leveraging, in future therapeutics, the interplay between TAGLNs and MTs to reverse tumor progression and chemoresistance, transforming them into tumor suppression.

Trimethylamine N-oxide Aggravates Thoracic Aortic Aneurysm by Inhibiting Axl to Promote Vascular Smooth Muscle Cell Dysfunction.

Thoracic aortic aneurysm (TAA) is a life-threatening condition that currently lacks an effective therapeutic strategy. Phenotypic switching in vascular smooth muscle cells (VSMCs) and extracellular matrix (ECM) degradation are considered to be among the causes of TAA development. Trimethylamine N-oxide (TMAO) is a gut microbial metabolite that has been associated with the increased risk of cardiovascular diseases. However, its general association with TAA remains unclear. Therefore, the present study aimed to assess the possible role of TMAO in TAA development. In the mouse TAA model, TMAO exacerbates aortic dilation and degeneration, promoting the development of thoracic aortic aneurysm. Furthermore, TMAO was observed to impair murine cardiac function. In vitro, it was demonstrated that TMAO inhibited proliferation whilst promoting migration and apoptosis in VSMCs. RNA-sequence analysis of TMAO targets subsequently identified Axl and a cohort of genes associated with extracellular matrix signaling. Mechanistically, it was found that TMAO inducing a shift from a contractile to a synthetic phenotype by inhibiting Axl. Overexpressing Axl suppresses this transition. In summary, TMAO worsens TAA progression by impairing vascular smooth muscle cell function, and restoring Axl expression can counteract the phenotypic shift caused by high TMAO levels. Thus, targeting the TMAO-Axl regulatory axis could be a therapeutic strategy for TAA patients with elevated TMAO expression.

Multiplex immunohistochemistry reveals histological features of three different intestinal polyp subtypes in pediatric patients

BackgroundHistologically, our understanding of intestinal polyps remains limited in scope, particularly regarding the diverse subtypes observed in pediatric patients. To enhance our comprehension, three different polyp subtypes including solitary juvenile polyps (SJPs), juvenile polyposis syndrome (JPS)-related polyps, and Peutz‒Jeghers syndrome (PJS)-related polyps were investigated.MethodsThis study used advanced multiplex immunohistochemistry (mIHC) technology to analyze polyps comprising 4 SJP, 4 JPS and 4 PJS polyps from 12 individual patients who underwent colonoscopies or radical surgical procedures. subtypes.ResultsThese mIHC analyses revealed some differences among these polyp subtypes. PJS-related polyps, specifically, displayed epithelial dysplasia with dendritic gland hyperplasia and distinct villous structures adorned with finger-like projections on their surfaces. In contrast, SJP and JPS polyps exhibited cystic glandular dilation, with their surfaces lined with continuous but eroded epithelia. Furthermore, PJS polyps had an abundance of microvessels and thick smooth muscle fibers, whereas SJP and JPS polyps were characterized by lymphoid follicle-like structures.ConclusionsThese findings not only deepen our structural understanding of various intestinal polyp subtypes but also offer valuable insights that may inform the diagnosis of patients with these conditions.