Search Results (220)

Skeletal muscle atrophy is a critical health issue affecting the quality of life of elderly individuals and patients with chronic diseases. These conditions induce dysregulation of glucocorticoid (GC) secretion. GCs play a critical role in maintaining homeostasis in the stress response and glucose metabolism. However, prolonged exposure to GC is directly linked to muscle atrophy, which is characterized by a reduction in muscle size and weight, particularly affecting fast-twitch muscle fibers. The GC-activated glucocorticoid receptor (GR) decreases protein synthesis and facilitates protein breakdown. Numerous antagonists have been developed to mitigate GC-induced muscle atrophy, including 11β-HSD1 inhibitors and myostatin and activin receptor blockers. However, the clinical trial results have fallen short of the expected efficacy. Recently, several emerging pathways and targets have been identified. For instance, GC-induced sirtuin 6 isoform (SIRT6) expression suppresses AKT/mTORC1 signaling. Lysine-specific demethylase 1 (LSD1) cooperates with the GR for the transcription of atrogenes. The kynurenine pathway and indoleamine 2,3-dioxygenase 1 (IDO-1) also play crucial roles in protein synthesis and energy production in skeletal muscle. Therefore, a deeper understanding of the complexities of GR transactivation and transrepression will provide new strategies for the discovery of novel drugs to overcome the detrimental effects of GCs on muscle tissues. Full article

Transforming growth factor-β (TGF-β) is a key protein family member that includes activins, inhibins, and bone morphogenetic proteins (BMPs). It is essential in numerous biological processes, such as chemotaxis, apoptosis, differentiation, growth, and cell migration. TGF-β receptors initiate signaling through two primary pathways: the canonical pathway involving Smad proteins and non-canonical pathways that utilize alternative signaling mechanisms. When TGF-β signaling is disrupted, it has been shown to contribute to the development of various diseases, including cancer. Initially, TGF-β effectively inhibits the cell cycle and promotes apoptosis. However, its role can transition to facilitating tumor growth and metastasis as the disease progresses. Moreover, TGF-β drives cancer progression through epithelial–mesenchymal transition (EMT), modulation of factor expression, and evasion of immune responses. This complexity establishes the need for further research, particularly into pharmacological agents targeting TGF-β, which are emerging as promising therapeutic options. Current clinical and preclinical studies are making significant strides toward mitigating the adverse effects of TGF-β. This underscores the critical importance of understanding its underlying mechanisms to enhance treatment effectiveness and improve survival rates for cancer patients. Full article

Estrogens regulate many physiological processes in the human body, including the cardiovascular system. Importantly, Estradiol (E2) exerts its vascular protective actions, in part, by promoting endothelial repair via induction of endothelial cell (EC) proliferation, migration and angiogenesis. Recent evidence that microRNAs (miRNAs) play an important role in vascular health and disease as well as in regulating Estrogen actions in many cell types. We hypothesize that E2 may mediate its vascular protective actions via the regulation of miRNAs. Following initial screening, we found that E2 downregulates the levels of miR-193a-3p in ECs. Moreover, miR-193a-3p downregulation by miR-193a-3p-antimir mimicked the effects as E2 on EC growth, migration, and capillary formation. Restoring miR-193a-3p levels with mimics after E2 treatment abrogated the vasculogenic actions of E2, suggesting a key role of miR-193a-3p in E2-mediated EC-growth-promoting effects. We further investigated the cellular mechanisms involved and found that miR-193a-3p inhibits angiogenesis by blocking phosphoinositide-3-kinase (PI3K)/Akt-vascular endothelial growth factor (VEGF) and Activin receptor-like kinase 1 (ALK1)/SMAD1/5/8 signaling in ECs, both pathways that are important in E2-mediated vascular protection. Additionally, using reverse transcription polymerase chain reaction (RT-PCR), we demonstrate that E2 downregulates miR-193a-3p in ECs via Estrogen Receptor (ER)α, but not ERβ or G protein-coupled estrogen receptor (GPER). Moreover, these actions occur post-transcriptionally, as the expression of pri-miR-193a-3p was not affected. The anti-angiogenic actions of miR-193a-3p were also observed in in vivo Matrigel implant-based capillary formation studies in ovariectomized mice where E2 induced capillary formation, and these effects were abrogated in the presence of miR-193a-3p, but not in the control mimic. Assessment of miR-193a-3p levels in plasma collected from in vitro fertilization (IVF) subjects with low and high E2 levels showed significantly lower miR-193a-3p levels in responders during the high E2 period. Hence, our findings provide the first evidence that miR-193a-3p mimic inhibits angiogenesis whereas its antimir is angiogenic. Importantly, E2 mediates its regenerative actions on ECs/capillary formation by downregulating endogenous miR-193a-3p expression. Both miR-193a-3p mimic or antimir may represent important therapeutic molecules to prevent or to induce endothelial function in treating pathophysiologies associated with capillary growth. Full article

Holothuria scabra has long been acknowledged in traditional medicine for its therapeutic properties. The transforming growth factor-beta (TGF-β) superfamily is crucial in regulating cellular processes, including differentiation, proliferation, and immune responses. This study marks the first exploration of the gene expression localization, sequence conservation, and functional roles of H. scabra TGF-β proteins, specifically activin (HolscActivin), inhibin (HolscInhibin), and the TGF-β receptor (HolscTGFBR), across various organs. In situ hybridization indicated that HolscActivin and HolscInhibin are expressed in the intestine, respiratory tree, ovary, testis, and inner body wall. This suggests their roles in nutrient absorption, gas exchange, reproduction, and extracellular matrix remodeling. Notably, HolscTGFBR demonstrated a similar tissue-specific expression pattern, except for its absence in the respiratory tree. Bioinformatics analysis reveals that HolscTGFBR shares significant sequence similarity with HomsaTGFBR, especially in regions essential for signal transduction and inhibition. Molecular docking results indicate that HolscActivin may promote receptor activation, while HolscInhibin functions as a natural antagonist, reflecting the signaling mechanisms of human TGF-β proteins. Interestingly, cross-species ternary complex docking with human TGF-β receptors further supports these findings, showing that HolscActivin moderately engages the receptors, whereas HolscInhibin exhibits strong binding, suggestive of competitive inhibition. These results indicate that H. scabra TGF-β proteins retain the structural and functional features of vertebrate TGF-β ligands, supporting their potential applications as natural modulators in therapeutic and functional food development. Full article

Pulmonary hypertension (PH) is broadly defined as a mean pulmonary arterial pressure (mPAP) exceeding 20 mm Hg at rest. Pulmonary arterial hypertension (PAH) is a specific subset of PH characterized by a normal pulmonary arterial wedge pressure (PAWP), combined with elevated mPAP and increased pulmonary vascular resistance (PVR), without other causes of pre-capillary hypertension such as lung diseases or chronic thromboembolic pulmonary hypertension. The majority of PAH cases are idiopathic; other common etiologies include connective tissue disease-associated PAH, congenital heart disease, and portopulmonary hypertension. To a lesser extent, genetic and familial forms of PAH can also occur. The pathophysiology of PAH involves the following four primary pathways: nitric oxide, endothelin-1, prostacyclin, and activin/bone morphogenetic protein (BMP). Dysregulation of these pathways leads to a progressive vasculopathy marked by vasoconstriction, vascular proliferation, elevated right heart afterload, and ultimately right-sided heart failure. Diagnosing PAH is challenging and often occurs at advanced stages. The gold standard for diagnosis remains invasive right heart catheterization. Along with invasive hemodynamic measurements, several noninvasive imaging modalities such as echocardiography and ventilation-perfusion scanning are key adjunct techniques. Also, recent advancements in cardiac magnetic resonance (CMR) have opened a new era for PAH management. Additionally, CMR and echocardiography not only enable diagnosis but also aid in evaluating disease severity and monitoring treatment responses. Current PAH treatments focus on targeting molecular pathways, reducing inflammation, and inhibiting right-sided heart failure. Integrating imaging with basic science techniques is crucial for enhanced patient diagnosis, and precision medicine is emerging as a key strategy in PAH management. Additionally, the incorporation of artificial intelligence into both molecular and imaging approaches holds significant potential. There is a growing need to integrate new imaging modalities with high resolution and reduced radiation exposure into clinical practice. In this review, we discuss the molecular pathways involved in PAH, the imaging modalities utilized for diagnosis and monitoring, and current targeted therapies. Advances in molecular understanding and imaging technologies, coupled with precision medicine, could hold promise in improving patient outcomes and revolutionizing the management of PAH patients. Full article

The transforming growth factor beta (TGF-$\mathsf{\beta }$) gene family is widely distributed across the animal kingdom, playing a crucial role in various cellular processes and maintaining overall health and homeostasis. The present study identified 34 TGF-$\mathsf{\beta }$ family genes based on the genome sequence in Tupaia belangeri, which were classified into the TGF-$\mathsf{\beta }$, bone morphogenetic protein (BMP), growth differentiation factor (GDF), glial cell-derived neurotrophic factor (GDNF), and Activin/Inhibin subfamilies. A phylogenetic analysis revealed the evolutionary relationships among members of the TGF-$\mathsf{\beta }$ family in T. belangeri and their homologous genes in Homo sapiens, Mus musculus, and Pan troglodytes, indicating a high degree of conservation throughout evolution. A chromosomal distribution and collinearity analysis demonstrated the localization of these genes within the genome of T. belangeri and their collinearity with genes from other species. A gene structure and motif analysis further illustrated the conservation and diversity among TGF-$\mathsf{\beta }$ family members. A protein interaction network analysis highlighted the central roles of TGFB1, TGFB3, BMP7, and BMP2 in signal transduction. A functional enrichment analysis underscored the significance of the TGF-$\mathsf{\beta }$ signaling pathway in the biological processes of T. belangeri, particularly in cell proliferation, differentiation, and apoptosis. We assessed the impact of cold acclimation treatment on the expression of TGF-$\mathsf{\beta }$ family proteins in the adipose tissue (white adipose tissue [WAT] and brown adipose tissue [BAT]) of T. belangeri using ELISA technology, finding that protein expression levels in the experimental group were significantly higher than those of in the control group. These results suggested that cold acclimation may enhance the adaptability of T. belangeri to cold environments by modulating the expression of TGF-$\mathsf{\beta }$ family genes. This study offers new insights into the role of the TGF-$\mathsf{\beta }$ family in the cold acclimation adaptation of T. belangeri, providing a scientific foundation for future genetic improvements and strategies for cold acclimation. Full article

Patients on standard hemodialysis (HD) show insufficient clearance of medium-molecular-weight uremic toxins, resulting in long-term complications. In this study we investigated the effectiveness of expanded HD (xHD) in the clearance of medium-molecular-weight uremic substances. This prospective study included patients on standard thrice-weekly HD. Participants were treated with xHD for 4 weeks, and the clearance of urea and β2-microglobulin was measured at the beginning and at the end of the study and compared with standard HD (sHD). Moreover, we investigated the clearance of Su-PAR, MCP-1, and activin, comparing sHD, xHD, and online hemodiafiltration (HDF). xHD had the same efficiency in the removal of low-molecular-weight substances compared to sHD but led to a significant decrease in β2-microglobulin levels from the first application of the method (sHD: from 36.9 ± 10.6 to 39.7 ± 18.9 mg/dL, p = 0.595 vs. 1st xHD: from 40 (36.5, 41.8) to 11 (9.8, 13.2) mg/dL, p = 0.008 vs. after 4 weeks on xHD: from 31.5 (28.5, 34.5) to 8.7 (8.2, 9.0) mg/dL, p = 0.008). Moreover, pre-session β2-microglobulin levels significantly decreased after 4 weeks on xHD. Su-PAR, MCP-1, and activin during xHD were also significantly reduced. xHD leads to a significant and cumulative reduction in medium-molecular-weight uremic toxins compared to standard HD. Full article

Definitive endoderm (DE) differentiation leads to the development of the major internal organs including the liver, intestines, pancreas, gall bladder, prostate, bladder, thyroid, and lungs. The two primary methods utilized for in vitro differentiation of induced pluripotent stem cells (iPSCs) into DE cells are the growth factor (GF) and the small molecule (SM) approaches. The GSK-3 inhibitor (CHIR99021) is a key factor for the SM approach. Activin A and Wnt3a are utilized in the GF approach. In this study, both the GF and SM protocols were compared to each other. The results show that both the GF and SM protocol produce DE with a similar morphological phenotype, gene and protein expression, and a similar level of homogeneity and functionality. However, on both the gene expression and proteomic level, there is a divergence between the two protocols during hepatic specification. Proteomic analysis shows that hepatoblasts from the GF protocol have significantly differentially expressed proteins (DEPs) involved in liver metabolic pathways compared to the SM protocol. Well-validated DE differentiation protocols are needed to fully unlock the clinical potential of iPSCs. In the first step of generating DE-derived tissue, either protocol can be utilized. However, for hepatic specification, the GF protocol is more effective. Full article

Sotatercept selectively binds free activins and growth differentiation factors by reproducing the binding domain of the activin receptor type IIA (ACTRIIA). The sequester of activins blunts the downstream signaling pathway, resulting in the reactivation of the bone morphogenic protein (BMP) receptor type 2 signaling and inhibition of pathological remodeling in pulmonary circulation. The balance between proliferative and antiproliferative pathways is restored, with a favorable impact on the progression of pulmonary arterial hypertension (PAH). Sotatercept, first approved for the treatment of hematological disorders such as anemia, has recently received approval as a drug in the treatment of group 1 PAH, either in United States or Europe. In this review, we will discuss the application of sotatercept and its cross reactivity in function alone or in combination with other drugs currently used for PAH. We will try also to further discuss what is known regarding the hematological effects of sotatercept, both from preclinical and clinical studies points of view, since they are the root of the side effects seen in PAH trials, such as bleeding and increased hemoglobin. Full article

Spermatogenesis is a complex and highly regulated process involving the proliferation, differentiation, and apoptosis of germ cells. This process is controlled by various hormonal, genetic, and environmental factors, including temperature. In hormonal regulation, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) are essential for correct spermatogenesis development from the early stages and spermatogonia proliferation to germ cell maturation. Other hormones, like inhibin and activin, finely participate tuning the process of spermatogenesis. Genetic regulation involves various transcription factors, such as SOX9, SRY, and DMRT1, which are crucial for the development and maintenance of the testis and germ cells. MicroRNAs (miRNAs) play a significant role by regulating gene expression post-transcriptionally. Epigenetic modifications, including DNA methylation, histone modifications, and chromatin remodelling, are also vital. Temperature regulation is another critical aspect, with the testicular temperature maintained around 2–4 °C below body temperature, essential for efficient spermatogenesis. Heat shock proteins (HSPs) protect germ cells from heat-induced damage by acting as molecular chaperones, ensuring proper protein folding and preventing the aggregation of misfolded proteins during thermal stress. Elevated testicular temperature can impair spermatogenesis, increasing germ cell apoptosis and inducing oxidative stress, DNA damage, and the disruption of the blood–testis barrier, leading to germ cell death and impaired differentiation. The cellular mechanisms of germ cell proliferation, differentiation, and death include the mitotic divisions of spermatogonia to maintain the germ cell pool and produce spermatocytes. Spermatocytes undergo meiosis to produce haploid spermatids, which then differentiate into mature spermatozoa. Apoptosis, or programmed cell death, ensures the removal of defective germ cells and regulates the germ cell population. Hormonal imbalance, genetic defects, and environmental stress can trigger apoptosis during spermatogenesis. Understanding these mechanisms is crucial for addressing male infertility and developing therapeutic interventions. Advances in molecular biology and genetics continue to uncover the intricate details of how spermatogenesis is regulated at multiple levels, providing new insights and potential targets for treatment. Full article

3D-printed microdevices have become increasingly important to the advancement of point-of-care (POC) immunoassays. Despite its great potential, using 3D-printed surfaces on the solid support for immunorecognition has been limited due to the non-ideal adsorption properties for many photocurable resins. In this work, we report a simple surface modification protocol that works for diverse commercial photocurable resins, improving ELISAs performed directly on 3D-printed devices. This surface modification strategy involves surface activation via air plasma followed by the one-step incubation of GLYMO-labeled streptavidin. We successfully immobilized biotinylated anti-activin A antibodies on the 3D-printed surfaces and performed the complete ELISA protocol on the 3D-printed surfaces. We demonstrated that this protocol achieved an improved performance over passive adsorption for ELISAs. The present method is also compatible with diverse commercial resins and works with both microwells and microchannels. Finally, this method demonstrated a comparable limit of detection to the ELISA performed using commercial microwells. We believe the simplicity and broad compatibility of the present surface modification strategy will facilitate the development of 3D-printed POC ELISA devices. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable chronic interstitial lung disease characterized by excessive fibrosis and impaired lung function. Current treatments, such as pirfenidone and nintedanib, slow disease progression but fail to halt or reverse fibrosis, highlighting the need for novel approaches. Activin A, which belongs to the TGF-β superfamily, is implicated in various fibrosis-related mechanisms, including epithelial–mesenchymal transition (EMT), a process where epithelial cells acquire mesenchymal characteristics, and fibroblast–myofibroblast transformation (FMT), in which fibroblasts differentiate into contractile myofibroblasts. It also promotes inflammatory cytokine release and extracellular matrix buildup. This study aimed to inhibit Activin A activity using synthetic peptides identified through phage display screening. Of the ten peptides isolated, A7, B9, and E10 demonstrated high binding affinity and inhibitory activity. Computational modeling confirmed that these peptides target the receptor-binding domain of Activin A, with peptide E10 exhibiting superior efficacy. Functional assays showed that E10 reduced cell migration, inhibited EMT in A549 cells, and suppressed FMT in fibroblast cultures, even under pro-fibrotic stimulation with TGF-β. These findings underscore the therapeutic potential of targeting Activin A with synthetic peptides, offering a promising avenue for IPF treatment and expanding the arsenal of anti-fibrotic strategies. Full article

The present study was designed to investigate the potential role of inhibin immunization on plasma hormone concentration and testicular histoarchitecture of Dezhou donkeys in the nonbreeding season (November–February). For this purpose, adult Dezhou donkeys (n = 30) were equally divided into groups A, B, and C. Group A was actively immunized with 3 mg inhibin, group B with (1.5 mg), and group C was immunized with Bovine serum albumin (BSA) and served as a control. All animals in groups A and B were given a primary dose of inhibin (INH) antigen, i.e., 3 mg and 1.5 mg on day 1, followed by a booster dose on the 23rd day of the experiment. Blood samples were collected on the 21st, 28th, 34th, and 40th days of the experiment. Primary and booster INH immunization (3 mg and 1.5 mg) slightly elevated the plasma hormone concentrations of FSH, LH, AMH, and Activin A. The number of spermatogonia was significantly higher in group A as compared to group C on the 28th day of the experiment. Inhibin immunization also caused apoptosis in testicular histoarchitecture. In conclusion, Inhibin immunization can potentially improve the reproductive efficiency of Dezhou donkeys in a nonbreeding season by elevating plasma hormone concentrations of FSH, LH, AMH, and Activin A. Full article

Primary pulmonary hypertension (PPH), now known as pulmonary arterial hypertension (PAH), has induced significant treatment breakthroughs in the past decade. Treatment has focused on improving patient survival and quality of life, and delaying disease progression. Current therapies are categorized based on targeting different pathways known to contribute to PAH, including endothelin receptor antagonists (ERAs), phosphodiesterase-5 inhibitors (PDE-5 inhibitors), prostacyclin analogs, soluble guanylate cyclase stimulators, and activin signaling inhibitors such as Sotatercept. The latest addition to treatment options is soluble guanylate cyclase stimulators, such as Riociguat, which directly stimulates the nitric oxide pathway, facilitating vasodilation. Looking to the future, advancements in PAH treatment focus on precision medicine involving the sub-stratification of patients through a deep characterization of altered Transforming Growth Factor-β(TGF-β) signaling and molecular therapies. Gene therapy, targeting specific genetic mutations linked to PAH, and cell-based therapies, such as mesenchymal stem cells, are under investigation. Besides prevailing therapies, emerging PH treatments target growth factors and inflammation-modulating pathways, with ongoing trials assessing their long-term benefits and safety. Hence, this review explores current therapies that delay progression and improve survival, as well as future treatments with curative potential. Full article

Viper bite envenoming often results in prominent skeletal muscle damage. According to our previous studies, the prolonged presence of Crotalus atrox venom toxins induced extensive muscle damage, which mimicked the outcome of chronic muscle damage often seen in human muscular dystrophies. In the case of chronic muscle damage, two critical processes occur: muscle regeneration is impaired, and fibrosis develops. Myostatin/activin signalling is a key regulator of both of these processes. Myostatin and its closely related molecules, in particular activin, inhibit the proliferation and differentiation of myocytes while promoting proliferation of fibroblasts and expression of extracellular matrix proteins. Thus, attenuating myostatin/activin signalling offers an attractive means of promoting muscle development while decreasing fibrosis. Hence, we have used the soluble activin receptor type IIb, which acts as a ligand trap for both myostatin and activin, to dampen signalling and assessed whether this intervention could alter the pathological trajectory of C. atrox venom-induced muscle damage in mice. We report that the soluble activin receptor type IIb treatment increased the size of regenerating fibres while reducing the level of fibrotic tissues in venom-damaged muscle. Full article