Latent Transforming Growth Factor Beta Research Articles

Ischemic-Preconditioning Induced Serum Exosomal miR-133a-3p Improved Post-Myocardial Infarction Repair via Targeting LTBP1 and PPP2CA.

Ischemic preconditioning-induced serum exosomes (IPC-exo) protected rat heart against myocardial ischemia/reperfusion injury. However, whether IPC-exo regulate replacement fibrosis after myocardial infarction (MI) and the underlying mechanisms remain unclear. MicroRNAs (miRs) are important cargos of exosomes and play an essential role in cardioprotection. We aim to investigate whether IPC-exo regulate post-MI replacement fibrosis by transferring cardioprotective miRs and its action mechanism. Exosomes obtained from serum of adult rats in control (Con-exo) and IPC groups were identified and analyzed, subsequently intracardially injected into MI rats following ligation. Their miRs profiles were identified using high-throughput miR sequencing to identify target miRs for bioinformatics analysis. Luciferase reporter assays confirmed target genes of selected miRs. IPC-exo transfected with selected miRs antagomir or NC were intracardially administered to MI rats post-ligation. Cardiac function and degree of replacement fibrosis were detected 4 weeks post-MI. IPC-exo exerted cardioprotective effects against excessive replacement fibrosis. MiR sequencing and RT-qPCR identified miR-133a-3p as most significantly different between IPC-exo and Con-exo. MiR-133a-3p directly targeted latent transforming growth factor beta binding protein 1 (LTBP1) and protein phosphatase 2, catalytic subunit, alpha isozyme (PPP2CA). KEGG analysis showed that transforming growth factor-β (TGF-β) was one of the most enriched signaling pathways with miR-133a-3p. Comparing to injection of IPC-exo transfected with miR-133a-3p antagomir NC, injecting IPC-exo transfected with miR-133a-3p antagomir abolished protective effects of IPC-exo on declining excessive replacement fibrosis and cardiac function enhancement, while increasing the messenger RNA and protein expression of LTBP1, PPP2CA, and TGF-β1in MI rats. IPC-exo inhibit excessive replacement fibrosis and improve cardiac function post-MI by transferring miR-133a-3p, the mechanism is associated with directly targeting LTBP1 and PPP2CA, and indirectly regulating TGF-β pathway in rats. Our finding provides potential therapeutic effect of IPC-induced exosomal miR-133a-3p for cardiac repair.

LTBP2 down-regulated FGF2 to repress vascular smooth muscle cell proliferation and vascular remodeling in a rat model of intracranial aneurysm

This work probed into the role of latent transforming growth factor beta binding protein 2 (LTBP2) in intracranial aneurysm (IA). The rats underwent IA modeling and then stereotactic injection of short hairpin RNA against LTBP2 (shLTBP2). Hematoxylin-eosin (HE) staining was employed to assess IA model and vascular remodeling. Rat vascular smooth muscle cells (VSMCs) were transfected with shLTBP2, LTBP2 overexpression plasmid and fibroblast growth factor 2 (FGF2) overexpression plasmid. The mRNA and protein expressions of LTBP2, FGF2 and mitochondrial apoptosis-related factors (Caspase-3, Cyt-c, Mcl-1) were tested through qRT-PCR and Western blot. Cell viability, proliferation and apoptosis were examined by cell counting kit-8, EdU assay and flow cytometry. The up-regulated LTBP2 and down-regulated FGF2 were detected in IA rats. LTBP2 knockdown promoted vascular remodeling and Mcl-1 level, and restrained cell apoptosis and expressions of Caspase-3 and Cyt-c in IA model rats. Moreover, LTBP2 knockdown potentiated cell viability, proliferation and FGF2 level, and repressed apoptosis in rat VSMCs, while overexpressed LTBP2 exerted opposite effects. FGF2 overexpression promoted proliferation and Mcl-1 level, and inhibited apoptosis and expressions of Caspase-3 and Cyt-c in rat VSMCs, which also reversed the effects of overexpressed LTBP2 on these aspects. Collectively, LTBP2 down-regulates FGF2 to repress VSMCs proliferation and vascular remodeling in an IA rat model.

The lung extracellular matrix protein landscape in severe early-onset and moderate chronic obstructive pulmonary disease.

Extracellular matrix (ECM) remodeling has been implicated in the irreversible obstruction of airways and destruction of alveolar tissue in chronic obstructive pulmonary disease (COPD). Studies investigating differences in the lung ECM in COPD have mainly focused on some collagens and elastin, leaving an array of ECM components unexplored. We investigated the differences in the ECM landscape comparing severe-early onset (SEO)-COPD and moderate COPD to control lung tissue for collagen type I α chain 1 (COL1A1), collagen type VI α chain 1 (COL6A1); collagen type VI α chain 2 (COL6A2), collagen type XIV α chain 1 (COL14A1), fibulin 2 and 5 (FBLN2 and FBLN5), latent transforming growth factor β binding protein 4 (LTBP4), lumican (LUM), versican (VCAN), decorin (DCN), and elastin (ELN) using image analysis and statistical modeling. Percentage area and/or mean intensity of expression of LUM in the parenchyma, and COL1A1, FBLN2, LTBP4, DCN, and VCAN in the airway walls, was proportionally lower in COPD compared to controls. Lowered levels of most ECM proteins were associated with decreasing forced expiratory volume in 1 s (FEV1) measurements, indicating a relationship with disease severity. Furthermore, we identified six unique ECM signatures where LUM and COL6A1 in parenchyma and COL1A1, FBLN5, DCN, and VCAN in airway walls appear essential in reflecting the presence and severity of COPD. These signatures emphasize the need to examine groups of proteins to represent an overall difference in the ECM landscape in COPD that are more likely to be related to functional effects than individual proteins. Our study revealed differences in the lung ECM landscape between control and COPD and between SEO and moderate COPD signifying distinct pathological processes in the different subgroups.NEW & NOTEWORTHY Our study identified chronic obstructive pulmonary disease (COPD)-associated differences in the lung extracellular matrix (ECM) composition. We highlight the compartmental differences in the ECM landscape in different subtypes of COPD. The most prominent differences were observed for severe-early onset COPD. Moreover, we identified unique ECM signatures that describe airway walls and parenchyma providing insight into the intertwined nature and complexity of ECM changes in COPD that together drive ECM remodeling and may contribute to disease pathogenesis.

Exploring the Genetic Landscape of Childhood Glaucoma.

Childhood glaucoma, a significant cause of global blindness, represents a heterogeneous group of disorders categorized into primary or secondary forms. Primary childhood glaucoma stands as the most prevalent subtype, comprising primary congenital glaucoma (PCG) and juvenile open-angle glaucoma (JOAG). Presently, multiple genes are implicated in inherited forms of primary childhood glaucoma. This comprehensive review delves into genetic investigations into primary childhood glaucoma, with a focus on identifying causative genes, understanding their inheritance patterns, exploring essential biological pathways in disease pathogenesis, and utilizing animal models to study these mechanisms. Specifically, attention is directed towards genes such as CYP1B1 (cytochrome P450 family 1 subfamily B member 1), LTBP2 (latent transforming growth factor beta binding protein 2), TEK (TEK receptor tyrosine kinase), ANGPT1 (angiopoietin 1), and FOXC1 (forkhead box C1), all associated with PCG; and MYOC (myocilin), associated with JOAG. Through exploring these genetic factors, this review aims to deepen our understanding of the intricate pathogenesis of primary childhood glaucoma, thereby facilitating the development of enhanced diagnostic and therapeutic strategies.

Novel compound heterozygous variants in LTBP2 associated with relative anterior microphthalmos.

Relative anterior microphthalmos (RAM) is a rare congenital defect associated with severe vision impairment that is primarily caused by genetic alterations. The purpose of this study was to identify the causative genetic variants in two Chinese families with RAM with an autosomal recessive inheritance pattern. DNA samples were obtained from two probands and their family members. Targeted next-generation sequencing (NGS) was used to screen 425 genes associated with inherited eye diseases to identify possible disease-causing variants in the two patients. Sanger sequencing was subsequently used to validate the results in both families. The targeted NGS panel identified potentially causative novel variants of the latent transforming growth factor beta binding protein 2 (LTBP2) gene in the two RAM families: a missense variant (c.2771C > T; p.Ala924Val) and an intronic variant (c.4582 + 9A > G) in Family A and a different missense variant (c.5239C > A; p.Arg1747Ser) and a synonymous variant (c.951G > A; p.Pro317Pro) in Family B. These four novel variants all cosegregated with the disease phenotype. To our knowledge, this is the first study to report novel LTBP2 gene variants related to RAM. Considering the importance of LTBP2 in ocular development, we provide initial insights into the potential pathogenic mechanisms of LTBP2 in RAM.

Role of vascular endothelial growth factor D in lung adenocarcinoma immunotherapy response.

To identify key genes associated with tumor-associated macrophages (TAMs), tumor immunotherapy, in the prognosis of lung adenocarcinoma (LUAD). The mRNA expression profiles of LUAD samples were obtained from The Cancer Genome Atlas (TCGA) database. The "CIBERSORT" R package was employed to calculate the proportion of innate immune cell infiltration in both tumor and adjacent normal tissues. TAM-associated genes in LUAD were identified to construct a prognostic risk model using weighted gene correlation network analysis (WGCNA), Least Absolute Shrinkage and Selection Operator (LASSO), and multivariate Cox regression analyses (COX). The IMvigor210 cohort was utilized to validate the roles of these genes as predictors of immunotherapy response. Tissue microarrays, immunofluorescence staining, and mRNA level detection methods were used to determine the correlation of risk factors in LUAD tissues. CIBERSORT analysis revealed significant differences in innate immune cells between tumor and adjacent tissues. Seventy-four differential genes linked to these cells were identified from WGCNA. Four hub genes (endothelin receptor type B, vascular endothelial growth factor D (VEGFD), latent transforming growth factor beta binding protein 4 (LTBP4), and fibroblast growth factor receptor 4 (FGFR4)) in the TAM prognostic model were identified as independent prognostic risk factors (P < 0.05). VEGFD expression was identified as a low-risk factor for LUAD prognosis prediction (P < 0.05). Moreover, low-risk patients exhibited higher sensitivity to anti-PD-L1 therapy compared to high-risk patients (P < 0.05). VEGFD levels were negatively correlated with programmed cell death 1 (PD-1) levels (r = -0.363; P < 0.05), suggesting that VEGFD may serve as a predictor for anti-PD-1 treatment. VEGFD is associated with innate immunity in LUAD, it can predict LUAD prognosis, and therefor may be a potential predictor for anti-PD-1 treatment in patients with LUAD.

LTBP1 promotes the progression of triple negative breast cancer via activating the RhoA/ROCK signaling pathway

&lt;p class="MsoNormal" style="text-align: justify;"&gt;&lt;span lang="EN-US"&gt;The latent transforming growth factor-beta (TGF-&amp;beta;) binding protein 1 (LTBP1) has been implicated in various cellular processes, but its role in triple-negative breast cancer (TNBC) remains unclear. In this study, we investigated the impact of LTBP1 on TNBC progression and its underlying mechanisms. Analysis of online datasets revealed elevated LTBP1 mRNA expression in breast cancer tissues compared to normal adjacent tissues. Kaplan-Meier Plotter analysis indicated that high LTBP1 expression was negatively correlated with relapse-free survival (RFS), distant-metastasis free survival (DMFS), and overall survival (OS) of breast cancer patients. Additionally, LTBP1 mRNA levels were associated with chemotherapy resistance. Functional assays in TNBC cells demonstrated that LTBP1 knockdown suppressed cell proliferation, induced apoptosis, and attenuated migration and invasion. In vivo studies confirmed that LTBP1 knockdown inhibited tumor growth in a xenograft mouse model. Mechanistically, LTBP1 positively correlated with genes involved in signaling regulation and organelle organization, with significant associations to GTPase binding and the RhoA/ROCK pathway. LTBP1 knockdown reduced RhoA activity and phosphorylation of Myosin Light Chain 2 (MLC2), suggesting inhibition of the RhoA/ROCK signaling pathway. Moreover, activation of the RhoA/ROCK pathway partially rescued the effects of LTBP1 knockdown on TNBC cell proliferation, apoptosis, migration, and invasion. In conclusion, our findings suggest that LTBP1 promotes TNBC progression through activation of the RhoA/ROCK signaling pathway, highlighting its potential as a therapeutic target for TNBC.&lt;/span&gt;&lt;/p&gt;

Efficient Treatment of Pulpitis via Transplantation of Human Pluripotent Stem Cell-Derived Pericytes Partially through LTBP1-Mediated T Cell Suppression.

Dental pulp pericytes are reported to have the capacity to generate odontoblasts and express multiple cytokines and chemokines that regulate the local immune microenvironment, thus participating in the repair of dental pulp injury in vivo. However, it has not yet been reported whether the transplantation of exogenous pericytes can effectively treat pulpitis, and the underlying molecular mechanism remains unknown. In this study, using a lineage-tracing mouse model, we showed that most dental pulp pericytes are derived from cranial neural crest. Then, we demonstrated that the ablation of pericytes could induce a pulpitis-like phenotype in uninfected dental pulp in mice, and we showed that the significant loss of pericytes occurs during pupal inflammation, implying that the transplantation of pericytes may help to restore dental pulp homeostasis during pulpitis. Subsequently, we successfully generated pericytes with immunomodulatory activity from human pluripotent stem cells through the intermediate stage of the cranial neural crest with a high level of efficiency. Most strikingly, for the first time we showed that, compared with the untreated pulpitis group, the transplantation of hPSC-derived pericytes could substantially inhibit vascular permeability (the extravascular deposition of fibrinogen, ** p < 0.01), alleviate pulpal inflammation (TCR+ cell infiltration, * p < 0.05), and promote the regeneration of dentin (** p < 0.01) in the mouse model of pulpitis. In addition, we discovered that the knockdown of latent transforming growth factor beta binding protein 1 (LTBP1) remarkably suppressed the immunoregulation ability of pericytes in vitro and compromised their in vivo regenerative potential in pulpitis. These results indicate that the transplantation of pericytes could efficiently rescue the aberrant phenotype of pulpal inflammation, which may be partially due to LTBP1-mediated T cell suppression.

Spatial Distribution of Non-Immune Cells Expressing Glycoprotein A Repetitions Predominant in Human and Murine Metastatic Lymph Nodes

Several types of cancer spread through the lymphatic system via the sentinel lymph nodes (LNs). Such LN-draining primary tumors, modified by tumor factors, lead to the formation of a metastatic niche associated with an increased number of Foxp3+ regulatory T cells (Tregs). These cells are expected to contribute to the elaboration of an immune-suppressive environment. Activated Tregs express glycoprotein A repetitions predominant (GARP), which binds and presents latent transforming growth factor beta 1 (TGF-β1) at their surface. GARP is also expressed by other non-immune cell types poorly described in LNs. Here, we mapped GARP expression in non-immune cells in human and mouse metastatic LNs. The mining of available (human and murine) scRNA-Seq datasets revealed GARP expression by blood (BEC)/lymphatic (LEC) endothelial, fibroblastic, and perivascular cells. Consistently, through immunostaining and in situ RNA hybridization approaches, GARP was detected in and around blood and lymphatic vessels, in (αSMA+) fibroblasts, and in perivascular cells associated with an abundant matrix. Strikingly, GARP was detected in LECs forming the subcapsular sinus and high endothelial venules (HEVs), two vascular structures localized at the interface between LNs and the afferent lymphatic and blood vessels. Altogether, we here provide the first distribution maps for GARP in human and murine LNs.

Latent transforming growth factor beta binding protein 4: A regulator of mitochondrial function in acute kidney injury.

Recently, latent transforming growth factor beta binding protein 4 (LTBP4) was implicated in the pathogenesis of renal damage through its modulation of mitochondrial dynamics. The seminal article written by Su etal. entitled "LTBP4 (Latent Transforming Growth Factor Beta Binding Protein 4) Protects Against Renal Fibrosis via Mitochondrial and Vascular Impacts" uncovers LTBP4's renoprotective role against acute kidney injury via modulating mitochondrial dynamics. Recently, LTBP4 has emerged as a driver in the mitochondrial-dependent modulation of age-related organ pathologies. This article aims to expand our understanding of LTBP4's diverse roles in these diseases in the context of these recent findings.

LTBP4 Protects Against Renal Fibrosis via Mitochondrial and Vascular Impacts.

As a part of natural disease progression, acute kidney injury (AKI) can develop into chronic kidney disease via renal fibrosis and inflammation. LTBP4 (latent transforming growth factor beta binding protein 4) regulates transforming growth factor beta, which plays a role in renal fibrosis pathogenesis. We previously investigated the role of LTBP4 in chronic kidney disease. Here, we examined the role of LTBP4 in AKI. LTBP4 expression was evaluated in human renal tissues, obtained from healthy individuals and patients with AKI, using immunohistochemistry. LTBP4 was knocked down in both C57BL/6 mice and human renal proximal tubular cell line HK-2. AKI was induced in mice and HK-2 cells using ischemia-reperfusion injury and hypoxia, respectively. Mitochondrial division inhibitor 1, an inhibitor of DRP1 (dynamin-related protein 1), was used to reduce mitochondrial fragmentation. Gene and protein expression were then examined to assess inflammation and fibrosis. The results of bioenergetic studies for mitochondrial function, oxidative stress, and angiogenesis were assessed. LTBP4 expression was upregulated in the renal tissues of patients with AKI. Ltbp4-knockdown mice showed increased renal tissue injury and mitochondrial fragmentation after ischemia-reperfusion injury, as well as increased inflammation, oxidative stress, and fibrosis, and decreased angiogenesis. in vitro studies using HK-2 cells revealed similar results. The energy profiles of Ltbp4-deficient mice and LTBP4-deficient HK-2 cells indicated decreased ATP production. LTBP4-deficient HK-2 cells exhibited decreased mitochondrial respiration and glycolysis. Human aortic endothelial cells and human umbilical vein endothelial cells exhibited decreased angiogenesis when treated with LTBP4-knockdown conditioned media. Mitochondrial division inhibitor 1 treatment ameliorated inflammation, oxidative stress, and fibrosis in mice and decreased inflammation and oxidative stress in HK-2 cells. Our study is the first to demonstrate that LTBP4 deficiency increases AKI severity, consequently leading to chronic kidney disease. Potential therapies focusing on LTBP4-associated angiogenesis and LTBP4-regulated DRP1-dependent mitochondrial division are relevant to renal injury.

Increased Chymase-Positive Mast Cells in High-Grade Mucoepidermoid Carcinoma of the Parotid Gland

It has long been known that high-grade mucoepidermoid carcinoma (MEC) has a poor prognosis, but the detailed molecular and biological mechanisms underlying this are not fully understood. In the present study, the pattern of chymase-positive mast cells, as well as chymase gene expression, in high-grade MEC was compared to that of low-grade and intermediate-grade MEC by using 44 resected tumor samples of MEC of the parotid gland. Chymase expression, as well as chymase-positive mast cells, was found to be markedly increased in high-grade MEC. Significant increases in PCNA-positive cells and VEGF gene expression, as well as lymphangiogenesis, were also confirmed in high-grade MEC. Chymase substrates, such as the latent transforming growth factor-beta (TGF-β) 1 and pro-matrix metalloproteinase (MMP)-9, were also detected immunohistologically in high-grade MEC. These findings suggested that the increased chymase activity may increase proliferative activity, as well as metastasis in the malignant condition, and the inhibition of chymase may be a strategy to improve the poor prognosis of high-grade MEC of the parotid gland.

TLE3 and TLE4-coordinated colonic macrophage-CD4+ T cell crosstalk maintains intestinal immune homeostasis

Colonic macrophages are critical for maintenance of cluster of differentiation 4 T helper (CD4+ T) cell homeostasis in the intestinal lamina propria. However, the mechanisms by which this process is regulated at the transcriptional level remain unknown. In this study, we found that the transcriptional corepressors transducin-like enhancer of split (TLE)3 and TLE4, but not TLE1 or TLE2, in colonic macrophages controlled homeostasis of CD4+ T-cell pool in the colonic lamina propria. Mice lacking TLE3 or TLE4 in myeloid cells exhibited markedly increased numbers of regulatory T (Treg) and T helper (TH) 17 cells under homeostatic conditions, rendering them more resistant to experimental colitis. Mechanistically, TLE3 and TLE4 negatively regulated matrix metalloproteinase (Mmp)9 transcription in colonic macrophages. Tle3 or Tle4 deficiency in colonic macrophages resulted in upregulated MMP9 production and thus enhanced latent transforming growth factor-beta (TGF-β) activation, which subsequently led to Treg and TH17 cell expansion. These results advanced our knowledge regarding the intricate crosstalk between the intestinal innate and adaptive immune compartments.

Microspherophakia and megalocornea with or without secondary glaucoma: A case series

AbstractPurpose: To report a case series of 6 eyes of 3 children diagnosed with microspherophakia and megalocornea with or without secondary glaucoma (MSPKA) and to discuss its clinical features and management.Methods: We reviewed 3 cases of a boy (case 1) and 2 sisters (cases 2,3) diagnosed with MSPKA from two consanguineous families. Ultrasound biomicroscopy was performed in 2 eyes and anterior‐segment swept‐source optical coherence tomography in 6 eyes.Results: Mean corneal diameter was 13 mm. Lens equatorial diameters were, in case 1, 6.2 mm in the right eye (RE) and 6.1 mm in the left eye (LE); in case 2, 7.4 mm (RE) and 7.7 mm (LE). Systemic work‐up was unremarkable.Case 1: A 6‐year‐old boy presented with bilateral lens subluxation and advanced secondary angle‐closure glaucoma (SACG). Best‐corrected visual acuity (BCVA) was 20/200 (RE) and was limited to counting fingers (LE). We performed phacoemulsification, anterior vitrectomy and retro‐pupillary iris‐claw intraocular lens implantation (RPIC‐IOL) in both eyes. At 5 months follow‐up, BCVA was 20/50 (RE) and 20/100 (LE). Intraocular pressure (IOP) decreased to 14 mmHg in both eyes.Case 2: Ophthalmologic examination in a 5‐year‐old girl showed in both eyes: a BCVA of 20/50, megalocornea, normal IOP and iridophacodonesis. Surgery with scleral fixation of the capsular bag will be considered.Case 3: An 8‐year‐old girl was referred after a bilateral lensectomy following spontaneous luxation of the lens into the anterior chamber in her RE. Examination showed bilateral megalocornea, aphakia and normal IOP. Secondary RPIC‐IOL implantation and amblyopia management were planned.Genetic testing for the Latent Transforming Growth Factor Beta Binding Protein 2 (LTBP2) gene mutation was performed in both sisters.Conclusions: MSPKA is a rare condition that can be associated with extraocular manifestations. Patients are at a high risk of lens dislocation and SACG. Surgical management remains challenging and should not be delayed.

Identification of LTBP2 gene polymorphisms and their association with thoracolumbar vertebrae number, body size, and carcass traits in Dezhou donkeys.

The number of thoracolumbar vertebrae in Dezhou donkeys varies from 22 to 24 and is associated with body size and carcass traits. In mammals, the latent transforming growth factor beta binding protein 2 (LTBP2) has been found to have some functions in the development of thoracolumbar vertebrae. The relationship between LTBP2 and TLN (the number of thoracolumbar vertebrae) of Dezhou donkeys is yet to be reported. The purposes of this study are as follows: 1) to quantify the effect of thoracolumbar vertebrae number variation of Dezhou donkeys on body size and carcass trait; 2) to study the distribution of single nucleotide variants (SNVs) in the LTBP2 gene of Dezhou donkeys; and 3) to explore whether these SNVs can be used as candidate sites to study the mechanism of Dezhou donkey muti-thoracolumbar vertebrae development. The TLN, body size, and carcass traits of 392 individuals from a Dezhou donkey breed were recorded. All animals were sequenced for LTBP2 using GBTS liquid chip and 16 SNVs were used for further analysis. We then analyzed the relationship between these SNVs with TLN, body size, and carcass traits. The results showed that: 1) c.5547 + 860C > T, c.5251 + 281 A > C, c.3769 + 40C > T, and c.2782 + 3975 A > G were complete genetic linkages and significantly associated with thoracic vertebrae number (TN) (p < 0.05) (wild-type homozygotes had more TN than heterozygotes); 2) c.1381 + 768T > G and c.1381 + 763G > T were significantly associated with lumber vertebrae number (LN) (p < 0.05); 3) c.1003 + 704C > T, c.1003 + 651C > T, c.1003 + 626 A > G, and c.812 + 22526T > G were significantly associated with chest circumference (CHC), front carcass weight (CWF), after carcass weight (CWA), and carcass weight (CW) (p < 0.05) (wild-type homozygotes were larger than other genotypes in CHC, CWF, CWA, and CW); and 4) the effect of variation is not consistent in c.565 + 11921 A > G, c.565 + 6840 A > G, c.565 + 3453C > T, and c.494 + 5808C > T. These results provide useful information that the polymorphism of LTBP2 is significantly associated with TLN, body size, and carcass traits in Dezhou donkeys, which can serve as a molecule marker to improve donkey production performance.

Identification of LTBP-2 as a plasma biomarker for right ventricular dysfunction in human pulmonary arterial hypertension.

Although right ventricular (RV) function is the primary determinant of morbidity and mortality in pulmonary arterial hypertension (PAH), the molecular mechanisms of RV remodeling and the circulating factors reflecting its function remain largely elusive. In this context, the identification of new molecular players implicated in maladaptive RV remodeling along with the optimization of risk stratification approaches in PAH are key priorities. Through combination of transcriptomic and proteomic profiling of RV tissues with plasma proteome profiling, we identified a panel of proteins, mainly related to cardiac fibrosis, similarly upregulated in the RV and plasma of patients with PAH with decompensated RV. Among these, we demonstrated that plasma latent transforming growth factor beta binding protein 2 (LTBP-2) level correlates with RV function in human PAH and adds incremental value to current risk stratification models to predict long-term survival in two independent PAH cohorts.

Autosomal recessive cutis laxa type 1C with a homozygous LTBP4 splicing variant: a case report and update of literature

Autosomal recessive cutis laxa (ARCL) is a heterogeneous disorder with three primary forms (ARCL 1, ARCL 2 and ARCL 3). Latent transforming growth factor beta binding protein 4 (LTBP4) anomalies cause ARCL1C and are connected to different problems in the skin and other organs. Herein, we present a seven month old Iranian boy with a clinical manifestation of ARCL1 with literature review of previous cases with attributes of ARCL1C. Considering the craniofacial characteristics and respiratory distress of the proband, cutis laxa (CL) was expected and whole-exome sequencing (WES) was performed. In the proband, signs of CL were mainly located in the face, thorax, and abdomen. The prenatal investigation revealed a diaphragmatic hernia and certain uncommon signs, such as an atrial septal defect and pyloric stenosis. The WES showed a novel homozygous mutation (c.533-1G > A) in exon six of the LTBP4 gene. This report showed a new variant with uncommon clinical features, such as a stenosis atrial septal defect and pyloric stenosis, which causes ARCL1C. Unfortunately, the proband developed several heart problems and died at the age of seven months and seven days. Thus, a more in-depth evaluation is needed to clarify the different aspects of CL related to LTBP4 disorder.

Elevated latent transforming growth factor beta binding protein 2 in endometriosis promotes endometrial stromal cell invasion and proliferation via the NF-kB signaling pathway

Endometriosis, defined as the abnormal growth of functional endometrium outside the uterus, is characterized by the abnormal phenotype of endometrial cells. This study aimed to investigate the role of latent transforming growth factor beta binding protein 2 (LTBP2), an extracellular matrix protein, in the occurrence and development of endometriosis. Elevated LTBP2 expression levels were observed in endometrial tissues and serum of endometriosis patients and their area under the ROC curve (AUC) values for distinguishing endometriosis were 0.9044 and 0.9534, respectively. Overexpressing-LTBP2 could promote proliferation, migration, and invasion, whereas suppressing apoptosis of endometrial stromal cells (ESCs). Moreover, LTBP2 downregulation induced the opposite effect. The supernatant from ESCs overexpressing LTBP2 promoted the tube formation of human umbilical vein endothelial cells (HUVECs), thus indicating an angiogenic effect. Furthermore, overexpression of LTBP2 facilitated the inflammation and might promote endometriosis progression through the NF-kB signaling pathway. Conclusively, LTBP2 might be a potential target in the diagnosis and treatment of endometriosis.

Immune suppressive signaling regulated by latent transforming growth factor beta binding protein 1 promotes metastasis in cervical cancer.

Although metastasis is the major cause of death in cervical cancer, the mechanism of metastasis is still unclear. The mRNA expression and protein level of latent transforming growth factor beta binding protein 1 (LTBP1) were detected in tumor tissues and paracancerous tissues from in-house samples. Cell proliferation, cell cycle, migration, and in vivo metastasis were determined after LTBP1 was knocked down. Then, 13 drugs were screened, and the changes in cell apoptosis and proliferation and tumor metastasis were detected after drug treatment in shRNA cells. In our in-house samples, LTBP1 was lowly expressed in cervical cancer tissues. After LTBP1 knockdown, cell proliferation was increased, and the ability of in vitro migration and in vivo metastasis was enhanced. At the same time, the proportion of myeloid derived suppressor cells (MDSC) in situ increased, the proportion of T cells decreased, and transforming growth factor beta-1 (TGFβ1) signaling was activated. After carboplatin treatment, LTBP1 shRNA cell line apoptosis increased, metastasis in vivo was limited, and the proportion of MDSC in situ decreased. LTBP1 was lowly expressed in cervical cancer, and the inhibition of LTBP1 can improve the malignant degree of the tumor, and this process can be blocked by carboplatin.

N-Acetylcysteine Inhibits Aortic Stenosis Progression in a Murine Model by Blocking Shear-Induced Activation of Platelet Latent Transforming Growth Factor Beta 1.

Objective: Aortic stenosis (AS) is characterized by narrowing of the aortic valve opening, resulting in peak blood flow velocity that induces high wall shear stress (WSS) across the valve. Severe AS leads to heart failure and death. There is no treatment available for AS other than valve replacement. Platelet-derived transforming growth factor beta 1 (TGF-β1) partially contributes to AS progression in mice, and WSS is a potent activator of latent TGF-β1. N-acetylcysteine (NAC) inhibits WSS-induced TGF-β1 activation in vitro. We hypothesize that NAC will inhibit AS progression by inhibiting WSS-induced TGF-β1 activation. Approach: We treated a cohort of Ldlr(-/-)Apob(100/100) low density lipoprotein receptor (LDLR) mice fed a high-fat diet with NAC (2% in drinking water) at different stages of disease progression and measured its effect on AS progression and TGF-β1 activation. Results: Short-term NAC treatment inhibited AS progression in mice with moderate and severe AS relative to controls, but not in LDLR mice lacking platelet-derived TGF-β1 (TGF-β1platlet-KO-LDLR). NAC treatment reduced TGF-β signaling, p-Smad2 and collagen levels, and mesenchymal transition from isolectin B4 and CD45-positive cells in LDLR mice. Mechanistically, NAC treatment resulted in plasma NAC concentrations ranging from 75.5 to 449.2 ng/mL, which were sufficient to block free thiol labeling of plasma proteins and reduce active TGF-β1 levels without substantially affecting reactive oxygen species-modified products in valvular cells. Conclusions: Short-term treatment with NAC inhibits AS progression by inhibiting WSS-induced TGF-β1 activation in the LDLR mouse model of AS, motivating a clinical trial of NAC and/or other thiol-reactive agent(s) as a potential therapy for AS.