Exosomes, a type of extracellular vesicle, are commonly found in different body fluids and are rich in nucleic acids (circRNA, lncRNAs, miRNAs, mRNAs, tRNAs, etc.), proteins, and lipids. They are involved in intercellular communication. lncRNAs are responsible for the modulation of gene expression, thus affecting the pathological process of kidney injury. This review summarizes the latest knowledge on the roles of exosome lncRNAs and circulating lncRNAs in the pathogenesis, biomarker discovery, and treatment of chronic kidney disease, renal fibrosis, and acute kidney injury, providing an overview of novel regulatory approaches and lncRNA delivery systems.

Facial nerve injury can lead to significant functional impairment, emotional impacts, and difficulties in social and economic activities. Although peripheral nerves have the potential for recovery, incomplete regeneration can pose challenges. Suppressor of Mothers Against Decapentaplegic Homolog (SMAD) proteins are crucial in the nerve-regeneration process. The study aimed to investigate the changes in SMAD protein expression involved in peripheral nerve regeneration following facial nerve injury induced by compression or axotomy in a pre-clinical study conducted on Sprague Dawley rats. Facial nerve recovery was assessed at 1, 2, 3, 4, 8, and 12 weeks post-facial nerve compression and axotomy using behavioral tests, including whisker movement and eyelid blink-reflex tests. Additionally, the role of SMAD proteins in the nerve regeneration process was evaluated by analyzing the expression of SMAD1-8 proteins at 2 and 12 weeks post-injury. Behavioral tests revealed significant impairment in facial nerve function in both the Compression and Axotomy groups compared with the Sham group at early time points. Recovery was observed in the Compression group by 2 weeks, whereas the Axotomy group exhibited prolonged impairment through 12 weeks. SMAD protein analyses showed increased expression of SMAD2, SMAD7, and SMAD8 following compression injury, whereas axotomy led to more extensive increases in expression that included SMAD1, SMAD2, SMAD3, SMAD4, SMAD6, SMAD7, and SMAD8. These findings suggest that SMAD proteins play differential roles in nerve regeneration following facial nerve injuries caused by compression versus axotomy. The distinct expression patterns of SMAD proteins highlight their potential as therapeutic targets for enhancing nerve regeneration and functional recovery in peripheral nerve injuries.

Cancer persists as a ubiquitous global challenge despite the remarkable advances. It is caused by uncontrolled cell growth and metastasis. The Transforming Growth Factor-beta (TGF-β) signaling pathway is considered a primary regulator of various normal physiological processes in the human body. Recently, factors determining the nature of TGF-β response have received attention, specifically its signaling pathway which can be an attractive therapeutic target for various cancer treatments. The TGF-β receptor is activated by its ligands and undergoes transduction of signals via canonical (SMAD dependent) or non-canonical (SMAD independent) signaling pathways regulating several cellular functions. Furthermore, the cross talk of the TGF-β signaling pathway cross with other signaling pathways has shown the controlled regulation of cellular functions. This review highlights the cross talk between various major signaling pathways and TGF-β. These signaling pathways include Wnt, NF-κB, PI3K/Akt, and Hedgehog (Hh). TGF-β signaling pathway has a dual role at different stages. It can suppress tumor formation at early stages and promote progression at advanced stages. This complex behaviour of TGF-β has made it a promising target for therapeutic interventions. Moreover, many strategies have been designed to control TGF-β signaling pathways at different levels, inhibiting tumor-promoting while enhancing tumor-suppressive effects, each with unique molecular mechanisms and clinical implications. This review also discusses various therapeutic inhibitors including ligand traps, small molecule inhibitors (SMIs), monoclonal antibodies (mAbs), and antisense oligonucleotides which target specific components of TGF-β signaling pathway to inhibit TGF-β signaling and are studied in both preclinical and clinical trials for different types of cancer. The review also highlights the prospect of TGF-β signaling in normal physiology and in the case of dysregulation, TGF-β inhibitors, and different therapeutic effects in cancer therapy along with the perspective of combinational therapies to treat cancer.

Airway stenosis (AS) is a fibroinflammatory disease characterized by abnormal activation of fibroblasts and excessive synthesis of extracellular matrix, which has puzzled many doctors despite its relatively low prevalence. Traditional treatment such as endoscopic surgery, open surgery, and adjuvant therapy have many disadvantages and are limited in the treatment of patients with recurrent AS. Therefore, it is urgent to reveal the pathogenesis of AS and accelerate its clinical transformation. Based on the discovered pathogenesis, including fibrosis, inflammation, epithelial-mesenchymal transition, metabolic reprogramming, microbiome, genetic susceptibility, and other mechanisms, researchers have developed a series of treatments, such as drug therapy, gene therapy, stem cell therapy, growth factor therapy, protein therapy, and photodynamic therapy. This review introduces the classification of AS, explores the existing pathogenesis and preclinical treatments developed based on the pathogenesis, and finally summarizes the current clinical management. In addition, the prospect of exploring the interaction between different types of cells and between microorganisms and cells to identify the intersection of multiple mechanisms based on single-cell RNA sequencing, 16S rRNA gene sequencing and shotgun metagenomic sequencing is worth looking forward to.

Immune checkpoint inhibition (ICI) is highly effective for the treatment of melanoma, but intrinsic resistance is present in a subgroup of patients. TGF-β pathway activity may play a role in this resistance by preventing T-cells from entering the tumor microenvironment, causing immune escape. We investigated the association of TGF-β signal transduction pathway activity with resistance to ICI treatment in advanced melanoma. Furthermore, other pathway activities were analyzed to better understand their potential role in ICI resistance.

The activity of 8 signaling pathways (TGF-β, Hedgehog, MAPK, AR, NOTCH, PI3K, JAK/STAT1-2, and NFkB) was analyzed from tumor tissue from patients with advanced melanoma. Pathway activity scores (PAS) were explored for associations with survival and response to ICI in 34 patients (19 non-responders and 15 responders). A second, independent method to investigate the predictive value of TGF-β pathway activation was conducted by determining levels of phosphorylated SMAD2.

The mean TGF-β PAS of responders vs non-responders was 53.9 vs 56.8 (P = 0.265). No significant relation with progression-free survival was detected for TGF-β activity (P = 0.078). No association between pSMAD2 staining and treatment response or survival was identified. In contrast, Hedgehog scores of responders versus non-responders were 35.7 vs 41.6 (P = 0.038). High Hedgehog PAS was the sole significant predictor of resistance to ICI (OR 0.88, P = 0.033) and worse progression-free survival (HR 1-1.1, P = 0.012).

TGF-β pathway activation showed no significant relation with treatment response to ICI or survival in patients with advanced melanoma. Hedgehog PAS was identified as a possible biomarker associated with both treatment response and survival.

Dilated cardiomyopathy (DCM) stands as one of the most prevalent and severe causes of heart failure. Inflammation plays a pivotal role throughout the progression of DCM to heart failure, while age acts as a natural predisposing factor for all cardiovascular diseases. These two factors often interact, contributing to cardiac fibrosis, which is both a common manifestation and a pathogenic driver of adverse remodeling in DCM-induced heart failure.

Bulk RNA-seq, single-cell RNA-seq, Mendelian randomization analysis, animal model construction, and BMP6 knockdown were utilized to identify and validate potential specific markers and targets for intervention in DCM heart failure.

We found that DCM hearts exhibit pronounced inflammatory cell infiltration and fibrosis. Both bulk RNA-seq and single-cell RNA-seq analyses revealed aberrant BMP6 expression specifically in fibroblasts. The ROC curve underscores the high specificity of BMP6 in relation to DCM, while Mendelian randomization analysis further confirms BMP6 as a protective factor against DCM. Notably, BMP6 knockdown led to a decrease in SMAD6 expression and a marked elevation in COL1A1 expression levels, indicating its antifibrotic role.

BMP6 emerges as a promising biomarker for DCM, and its functional role in exerting an antifibrotic effect underscores its potential as a therapeutic target.

Diabetic cardiomyopathy (DCM) is one of the most prevalent and severe complications associated with diabetes mellitus (DM). The onset of DCM is insidious, with the symptoms being obvious only in the late stage. Consequently, the early diagnosis of DCM is a formidable challenge which significantly influences the treatment and prognosis of DCM. Thus, it becomes imperative to uncover innovative approaches to facilitate the prompt identification and diagnosis of DCM. On the traditional clinical side, we tend to use serum biomarkers as well as imaging as the most common means of diagnosing diseases because of their convenience as well as affordability. As we delve deeper into the mechanisms of DCM, a wide variety of biomarkers are becoming competitive diagnostic indicators. Meanwhile, the application of multiple imaging techniques has also made efforts to promote the diagnosis of DCM. Besides, the spurt in sequencing technology has made it possible to give hints about disease diagnosis from the genome as well as the transcriptome, making diagnosis less difficult, more sensitive, and more predictive. Overall, sequencing technology is expected to be the superior choice of plasma biomarkers for detecting lesions at an earlier stage than imaging, and its judicious utilization combined with imaging technologies will lead to a more sensitive diagnosis of DCM in the future. Therefore, this review meticulously consolidates the progress and utilization of various biomarkers, imaging methods, and sequencing technologies in the realm of DCM diagnosis, with the aim of furnishing novel theoretical foundation and guide future research endeavors towards enhancing the diagnostic and therapeutic landscape of DCM.

Liver fibrosis is a common outcome of various chronic hepatic insults, characterized by excessive extracellular matrix (ECM) deposition. The precise mechanisms, however, remain largely undefined. This study identified an elevated expression of platelet-activating factor acetylhydrolase 1B3 (Pafah1b3) in liver tissues from both carbon tetrachloride (CCl4)-treated mice and patients with cirrhosis. Deletion of Pafah1b3 significantly attenuated CCl4-induced fibrosis, hepatic stellate cell (HSC) activation, and activation of transforming growth factor-β (TGF-β) signaling. Mechanistically, PAFAH1B3 binds to mothers against decapentaplegic homolog 7 (SMAD7), disrupting SMAD7's interaction with TGF-β receptor 1 (TβR1), which subsequently decreases TβR1 ubiquitination and degradation. Pharmacological inhibition using 3-IN-P11, a specific Pafah1b3 inhibitor, conferred protective effects against CCl4-induced fibrosis in mice. Furthermore, Pafah1b3 deficiency reduced hepatic inflammation. Overall, these results establish a pivotal role for Pafah1b3 in modulating TGF-β signaling and driving HSC activation.

Bone homeostasis relies on several contributing factors, encompassing growth factors and mechanical stimuli. While bone morphogenetic protein (BMP) signaling is acknowledged for its essential role in skeletal development, its specific impact on mandibular morphogenesis remains unexplored. Here, we investigated the involvement of BMP signaling and mechanical loading through mastication in postnatal mandibular morphogenesis.

We employed conditional deletion of Bmpr1a in osteoblasts and chondrocytes via Osterix-Cre. Cre activity was induced at birth for the 3-week group and at three weeks for the 9-week and 12-week groups, respectively. The conditional knockout (cKO) and control mice were given either a regular diet (hard diet, HD) or a powdered diet (soft diet, SD) from 3 weeks until sample collection, followed by micro-CT and histological analysis.

The cKO mice exhibited shorter anterior lengths and a posteriorly inclined ramus across all age groups compared to the control mice. The cKO mice displayed an enlarged hypertrophic cartilage area along with fewer osteoclast numbers in the subchondral bone of the condyle compared to the control group at three weeks, followed by a reduction in the cartilage area in the posterior region at twelve weeks. Superimposed imaging and histomorphometrical analysis of the condyle revealed that BMP signaling primarily affects the posterior part of the condyle, while mastication affects the anterior part.

Using 3D landmark-based geometric morphometrics and histological assessments of the mandible, we demonstrated that BMP signaling and mechanical loading reciprocally contribute to the morphological alterations of the mandible and condyle during postnatal development.

Cervical cancer (CC) is a potentially lethal disorder that can have serious consequences for a woman's health. Because early symptoms are typically only present in the middle to late stages of the disease, clinical diagnosis and treatment can be challenging. Traditional Chinese medicine (TCM) has been shown to have unique benefits in terms of alleviating cancer clinical symptoms, lowering the risk of recurrence after surgery, and reducing toxic side effects and medication resistance after radiation therapy. It has also been shown to improve the quality of life for patients. Because of its improved anti-tumor effectiveness and biosafety, it could be considered an alternative therapy option. This study examines how TCM causes apoptosis in CC cells via signal transduction, including the active components and medicinal tonics. It also intends to provide a reliable clinical basis and protocol selection for the TCM therapy of CC.

The following search terms were employed in PubMed, Web of Science, Embase, CNKI, Wanfang, VIP, SinoMed, and other scientific databases to retrieve pertinent literature on "cervical cancer," "apoptosis," "signaling pathway," "traditional Chinese medicine," "herbal monomers," "herbal components," "herbal extracts," and "herbal formulas."

It has been demonstrated that herbal medicines can induce apoptosis in cells of the cervix, a type of cancer, by influencing the signaling pathways involved.

A comprehensive literature search was conducted, and 148 papers from the period between January 2017 and December 2023 were identified as eligible for inclusion. After a meticulous process of screening, elimination and summary, generalization, and analysis, it was found that TCM can regulate multiple intracellular signaling pathways and related molecular targets, such as STAT3, PI3K/AKT, Wnt/β-catenin, MAPK, NF-κB, p53, HIF-1α, Fas/FasL and so forth. This regulatory capacity was observed to induce apoptosis in cervical cancer cells. The study of the mechanism of TCM against cervical cancer and the screening of new drug targets is of great significance for future research in this field. The results of this study will provide ideas and references for the future development of Chinese medicine in the diagnosis and treatment of cervical cancer.

Infertility is a multifactorial reproductive system disorder, and most infertility cases occur in men. Semen testing is now thought to be the most important diagnostic test for infertile men; nonetheless, because of its limitations, the cause of infertility remains unknown for 40% of infertile men. Semen assessment's shortcomings indicate the need for improved and innovative diagnostic techniques and biomarkers worldwide. Non-coding RNAs with a length of roughly 18-22 nucleotides are called microRNAs (miRNAs). Most of our protein-coding genes are post-transcriptionally regulated by them. These molecules are unusual in bodily fluids, and aberrant variations in their expression can point to specific conditions like infertility. As a result, fresh potential biomarkers for the diagnosis and prognosis of various forms of male infertility may be represented by miRNAs. This review examined the most recent research revealing the association between different miRNAs' functions in male infertility and their expression patterns. Also, it aims to figure out the most recent strategies that could be applied for using such miRNAs as possible therapeutic targets for infertility treatment.

The ZDHHC13/ZDHHC17 subfamily belongs to the zinc finger DHHC-domain containing (ZDHHC) family, including ZDHHC13 and ZDHHC17. Recent studies have shown that the ZDHHC13/ZDHHC17 subfamily is involved in various pathological and physiological processes, including S-palmitoylation, Mg2+ transport, and CALCOCO1-mediated Golgiphagy. Moreover, the ZDHHC13/ZDHHC17 subfamily plays a crucial role in the occurrence and development of many diseases, including Huntington disease (HD), osteoporosis, atopic dermatitis, diabetes, and cancer. In the present review, we describe the distribution, structure, and post-translational modifications (PTMs) of the ZDHHC13/ZDHHC17 subfamily. Moreover, we effectively summarize the biological functions and associated diseases of this subfamily. Given the pleiotropy of the ZDHHC13/ZDHHC17 subfamily, it is imperative to conduct further research on its members to comprehend the pertinent pathophysiological mechanisms and to devise tactics for managing and controlling various diseases.

During wound healing, fibroblast to myofibroblast transition is required for wound contraction and remodeling. While hypoxia is an important biophysical factor in wound microenvironment, the exact regulatory mechanism underlying hypoxia and fibroblast-to-myofibroblast transition remains unclear. We previously found that tetraspanin CD9 plays an important role in oxygen sensing and wound healing. Herein, we investigated the effects of physiological hypoxia on fibroblast-to-myofibroblast transition and the biological function and mechanism of CD9 in it.

Human skin fibroblasts (HSF) and mouse dermis wounds model were established under physiological hypoxia (2% O2). The cell viability and contractility of HSF under hypoxia were evaluated by CCK8 and collagen gel retraction, respectively. The expression and distribution of fibroblast-to-myofibroblast transition markers and CD9 in HSF were detected by Western blotting and immunofluorescence. CD9 slicing and overexpressing HSFs were constructed to determine the role of CD9 by small interfering RNA and recombinant adenovirus vector. The association of TβR2 and TβR1 was measured by immunoprecipitation to explore the regulatory mechanism. Additionally, further validation was conducted on mouse dermis wounds model through histological analysis.

Enhanced fibroblast-to-myofibroblast transition and upregulated CD9 expression was observed under hypoxia in vitro and in vivo. Besides, reversal of fibroblast-to-myofibroblast transition under hypoxia was observed when silencing CD9, suggesting that CD9 played a key role in this hypoxia-induced transition. Moreover, hypoxia increased fibroblast-to-myofibroblast transition by activating TGF-β1/Smad2/3 signaling, especially increased interaction of TβR2 and TβR1. Ultimately, CD9 was determined to directly affect TβR1-TβR2 association in hypoxic fibroblast.

Collectively, these findings suggest that CD9 promotes TβR2-TβR1 association, thus driving the transition of human dermal fibroblasts to myofibroblast under hypoxia.

Histone lysine isonicotinylation (Kinic) induced by isoniazid (INH) was recently identified as a post-translational modification in cells. However, global cellular non-histone proteins Kinic remains unclear. Using proteomic technology, we identified 11,442 Kinic sites across 2,792 proteins and demonstrated that Kinic of non-histone proteins is involved in multiple function pathways. Non-histone proteins Kinic can be regulated by isonicotinyl-transferases, including CBP and Tip60, and deisonicotinylases, including HDAC8 and HDAC6. In particular, the Kinic of poly (ADP-ribose) (PAR) polymerase 1 (PARP1) can be catalyzed by CBP and deisonicotinylation can be catalyzed by HDAC8. Tip60 and HDAC6 are isonicotinyl-transferase and the deisonicotinylase of SMAD3, respectively. Importantly, we found the K378inic of SMAD3 increases its phosphorylation, activates TGFβ pathway, and promotes liver cancer cells migration and invasion. In conclusion, our study demonstrated non-histone proteins Kinic occur extensively in cells and plays an important role in regulation of various cellular functions, including cancer progression.

The BMP signaling pathway plays a crucial role in regulating early embryonic development and tissue homeostasis. SMAD6 encodes a negative regulator of BMP, and rare variants of SMAD6 are recurrently found in individuals with birth defects. However, we observed that a subset of rare pathogenic variants of SMAD6 consistently exhibited positive regulatory effects instead of the initial negative effects on the BMP signaling pathway. We sought to determine whether these SMAD6 variants have common pathogenic mechanisms. Here, we showed that pathogenic SMAD6 variants accompanying this functional reversal exhibit similar increases in deamidation. Mechanistically, increased deamidation of SMAD6 variants promotes the accumulation of the BMP receptor BMPR1A and the formation of new complexes, both of which lead to BMP signaling pathway activation. Specifically, two residues, N262 and N404, in SMAD6 were identified as the crucial sites of deamidation, which was catalyzed primarily by glutamine-fructose-6-phosphate transaminase 2 (GFPT2). Additionally, treatment of cells harboring SMAD6 variants with a deamidase inhibitor restored the inhibitory effect of SMAD6 on the BMP signaling pathway. Conversely, when wild-type SMAD6 was manually simulated to mimic the deamidated state, the reversed function of activating BMP signaling was reproduced. Taken together, these findings show that deamidation of SMAD6 plays a crucial role in the functional reversal of BMP signaling activity, which can be induced by a subset of various SMAD6 variants. Our study reveals a common pathogenic mechanism shared by these variants and provides a potential strategy for preventing birth defects through deamidation regulation, which might prevent the off-target effects of gene editing.

Transforming growth factor β (TGF-β) is a ubiquitous molecule that is extremely conserved structurally and plays a systemic role in human organism. TGF-β is a homodimeric molecule consisting of two subunits joined through a disulphide bond. In mammals, three genes code for TGF-β1, TGF-β2, and TGF-β3 isoforms of this cytokine with a dominating expression of TGF-β1. Virtually, all normal cells contain TGF-β and its specific receptors. Considering the exceptional role of fine balance played by the TGF-β in anumber of physiological and pathological processes in human body, this cytokine may be proposed for use in medicine as an immunosuppressant in transplantology, wound healing and bone repair. TGFb itself is an important target in oncology. Strategies for blocking members of TGF-β signaling pathway as therapeutic targets have been considered. In this review, signalling mechanisms of TGF-β1 action are addressed, and their role in physiology and pathology with main focus on carcinogenesis are described.

Dysregulation of the transforming growth factor-β (TGF-β) signaling pathway regulates cancer stem cells (CSCs) and drug sensitivity, whereas it remains largely unknown how feedback regulatory mechanisms are hijacked to fuel drug-resistant CSCs. Through a genome-wide CRISPR activation screen utilizing stem-like drug-resistant properties as a readout, the TGF-β receptor-associated binding protein 1 (TGFBRAP1) is identified as a TGF-β-inducible positive feedback regulator that governs sensitivity to tyrosine kinase inhibitors (TKIs) and promotes liver cancer stemness. By interacting with and stabilizing the TGF-β receptor type 1 (TGFBR1), TGFBRAP1 plays an important role in potentiating TGF-β signaling. Mechanistically, TGFBRAP1 competes with E3 ubiquitin ligases Smurf1/2 for binding to TGFΒR1, leading to impaired receptor poly-ubiquitination and proteasomal degradation. Moreover, hyperactive TGF-β signaling in turn up-regulates TGFBRAP1 expression in drug-resistant CSC-like cells, thereby constituting a previously uncharacterized feedback mechanism to amplify TGF-β signaling. As such, TGFBRAP1 expression is correlated with TGFΒR1 levels and TGF-β signaling activity in hepatocellular carcinoma (HCC) tissues, as well as overall survival and disease recurrence in multiple HCC cohorts. Therapeutically, blocking TGFBRAP1-mediated stabilization of TGFBR1 by selective inhibitors alleviates Regorafenib resistance via reducing CSCs. Collectively, targeting feedback machinery of TGF-β signaling pathway may be an actionable approach to mitigate drug resistance and liver cancer stemness.

Uterine fibroids, the most common nonmalignant tumors affecting the female genital tract, are a significant medical challenge. This article focuses on the most recent studies that attempted to identify novel non-hormonal therapeutic targets and strategies in UF therapy.

This review covers the analysis of the pharmacological and biological mechanisms of the action of natural substances and the role of the microbiome in reference to UFs. This study aimed to determine the potential role of these compounds in UF prevention and therapy.

While there are numerous approaches for treating UFs, available drug therapies for disease control have not been optimized yet. This review highlights the biological potential of vitamin D, EGCG and other natural compounds, as well as the microbiome, as promising alternatives in UF management and prevention. Although these substances have been quite well analyzed in this area, we still recommend conducting further studies, particularly randomized ones, in the field of therapy with these compounds or probiotics. Alternatively, as the quality of data continues to improve, we propose the consideration of their integration into clinical practice, in alignment with the patient's preferences and consent.

Erythropoietin-producing hepatocellular (Eph)/Ephrin cell-cell signaling is emerging as a key player in tissue fibrogenesis. The aim of this study was to test the hypothesis that the receptor tyrosine kinase EphB2 mediates dermal fibrosis in systemic sclerosis (SSc).

We assessed normal and SSc human skin biopsies for EphB2 expression. The in vivo role of EphB2 in skin fibrosis was investigated by subjecting EphB2-knockout mice to both bleomycin-induced and tight skin (Tsk1/+) genetic mouse models of skin fibrosis. EphB2 kinase-dead and overactive point mutant mice were used to evaluate the role of EphB2 forward signaling in bleomycin-induced dermal fibrosis. In vitro studies were performed on dermal fibroblasts from patients with SSc and healthy controls, which was followed by in vivo analysis of fibroblast-specific Ephb2-deficient mice.

Expression of EphB2 is up-regulated in SSc skin tissue and explanted SSc dermal fibroblasts compared with healthy controls. EphB2 expression is elevated in two animal models of dermal fibrosis. In mice, EphB2 drives dermal fibrosis in both the bleomycin and the Tsk1/+ models of skin fibrosis. EphB2 forward signaling is a critical mediator of dermal fibrosis. Transforming growth factor-β (TGF-β) cytokines up-regulate EphB2 in dermal fibroblasts via noncanonical TGF-β/mother against decapentaplegic signaling, and silencing EPHB2 in human dermal fibroblasts is sufficient to dampen TGF-β-induced fibroblast-to-myofibroblast differentiation. Moreover, mice with fibroblast-specific deletion of EphB2 showed impaired fibroblast-to-myofibroblast differentiation and reduced skin fibrosis upon bleomycin challenge.

Our data implicate TGF-β regulation of EphB2 overexpression and kinase-mediated forward signaling in the development of dermal fibrosis in SSc. EphB2 thus represents a potential new therapeutic target for SSc.

Primary membranous nephropathy (PMN) is one of the leading causes of end-stage renal disease, and the most frequent cause of massive proteinuria in nondiabetic adults, resulting in fatal complications. However, the underlying pathomechanisms of PMN remain largely unclear. Here, single-cell RNA sequencing is employed to analyze kidney biopsies from eleven PMN patients and seven healthy subjects. Profiling 44 060 cells from patients allowed us to characterize the cellular composition and cell-type-specific gene expression in the PMN kidney. The complement-induced BMP2/pSMAD1/COL4 pathway is identified as the pathogenic pathway in podocytes, bridging two key events, i.e., complement system activation and glomerular basement membrane thickening in PMN. Augmented infiltration and activation of myeloid leukocytes and B lymphocytes are found, profiling delicate crosstalk of immune cells in PMN kidneys. Overall, these results provide valuable insights into the roles of podocytes and immune cells in PMN, and comprehensive resources toward the complete understanding of PMN pathophysiology.

Transforming growth factor-β (TGF-β) plays a complex role in lung cancer pathophysiology, initially acting as a tumor suppressor by inhibiting early-stage tumor growth. However, its role evolves in the advanced stages of the disease, where it contributes to tumor progression not by directly promoting cell proliferation but by enhancing epithelial-mesenchymal transition (EMT) and creating a conducive tumor microenvironment. While EMT is typically associated with enhanced migratory and invasive capabilities rather than proliferation per se, TGF-β's influence on this process facilitates the complex dynamics of tumor metastasis. Additionally, TGF-β impacts the tumor microenvironment by interacting with immune cells, a process influenced by genetic and epigenetic changes within tumor cells. This interaction highlights its role in immune evasion and chemoresistance, further complicating lung cancer therapy. This review provides a critical overview of recent findings on TGF-β's involvement in lung cancer, its contribution to chemoresistance, and its modulation of the immune response. Despite the considerable challenges encountered in clinical trials and the development of new treatments targeting the TGF-β pathway, this review highlights the necessity for continued, in-depth investigation into the roles of TGF-β. A deeper comprehension of these roles may lead to novel, targeted therapies for lung cancer. Despite the intricate behavior of TGF-β signaling in tumors and previous challenges, further research could yield innovative treatment strategies.

Cardiac fibroblast activation contributes to adverse remodeling, fibrosis, and dysfunction in the pressure-overloaded heart. Although early fibroblast TGF-β (transforming growth factor-β)/Smad (small mother against decapentaplegic)-3 activation protects the pressure-overloaded heart by preserving the matrix, sustained TGF-β activation is deleterious, accentuating fibrosis and dysfunction. Thus, endogenous mechanisms that negatively regulate the TGF-β response in fibroblasts may be required to protect from progressive fibrosis and adverse remodeling. We hypothesized that Smad7, an inhibitory Smad that restrains TGF-β signaling, may be induced in the pressure-overloaded myocardium and may regulate fibrosis, remodeling, and dysfunction.

The effects of myofibroblast-specific Smad7 loss were studied in a mouse model of transverse aortic constriction, using echocardiography, histological analysis, and molecular analysis. Proteomic studies in S7KO (Smad7 knockout) and overexpressing cells were used to identify fibroblast-derived mediators modulated by Smad7. In vitro experiments using cultured cardiac fibroblasts, fibroblasts populating collagen lattices, and isolated macrophages were used to dissect the molecular signals responsible for the effects of Smad7.

Following pressure overload, Smad7 was upregulated in cardiac myofibroblasts. TGF-β and angiotensin II stimulated fibroblast Smad7 upregulation via Smad3, whereas GDF15 (growth differentiation factor 15) induced Smad7 through GFRAL (glial cell line-derived neurotrophic factor family receptor α-like). MFS7KO (myofibroblast-specific S7KO) mice had increased mortality, accentuated systolic dysfunction and dilative remodeling, and accelerated diastolic dysfunction in response to transverse aortic constriction. Increased dysfunction in MFS7KO hearts was associated with accentuated fibrosis and increased MMP (matrix metalloproteinase)-2 activity and collagen denaturation. Secretomic analysis showed that Smad7 loss accentuates secretion of structural collagens and matricellular proteins and markedly increases MMP2 secretion. In contrast, Smad7 overexpression reduced MMP2 levels. In fibroblasts populating collagen lattices, the effects of Smad7 on fibroblast-induced collagen denaturation and pad contraction were partly mediated via MMP2 downregulation. Surprisingly, MFS7KO mice also exhibited significant macrophage expansion caused by paracrine actions of Smad7 null fibroblasts that stimulate macrophage proliferation and fibrogenic activation. Macrophage activation involved the combined effects of the fibroblast-derived matricellular proteins CD5L (CD5 antigen-like), SPARC (secreted protein acidic and rich in cysteine), CTGF (connective tissue growth factor), ECM1 (extracellular matrix protein 1), and TGFBI (TGFB induced).

The antifibrotic effects of Smad7 in the pressure-overloaded heart protect from dysfunction and involve not only reduction in collagen deposition but also suppression of MMP2-mediated matrix denaturation and paracrine effects that suppress macrophage activation through inhibition of matricellular proteins.

The mandible is composed of several musculoskeletal tissues including bone, cartilage, and tendon that require precise patterning to ensure structural and functional integrity. Interestingly, most of these tissues are derived from one multipotent cell population called cranial neural crest cells (CNCCs). How CNCCs are properly instructed to differentiate into various tissue types remains nebulous. To better understand the mechanisms necessary for the patterning of mandibular musculoskeletal tissues we utilized the avian mutant talpid2 (ta2) which presents with several malformations of the facial skeleton including dysplastic tendons, mispatterned musculature, and bilateral ectopic cartilaginous processes extending off Meckel's cartilage. We found an ectopic epithelial BMP signaling domain in the ta2 mandibular prominence (MNP) that correlated with the subsequent expansion of SOX9+ cartilage precursors. These findings were validated with conditional murine models suggesting an evolutionarily conserved mechanism for CNCC-derived musculoskeletal patterning. Collectively, these data support a model in which cilia are required to define epithelial signal centers essential for proper musculoskeletal patterning of CNCC-derived mesenchyme.

The progression of renal fibrosis to end-stage renal disease (ESRD) is significantly influenced by transforming growth factor-beta (TGF-beta) signal pathway. This study aimed to develop nanoparticles (PMVs@PLGA complexes) with platelet membrane camouflage, which can transport interfering RNA to target and regulate the TGF-β1 pathway in damaged renal tissues. The aim is to reduce the severity of acute kidney injury and to reduce fibrosis in chronic kidney disease. Hence, we formulated PMVs@TGF-β1-siRNA NP complexes and employed them for both in vitro and in vivo therapy. From the experimental findings we know that the PMVs@siRNA NPs could effectively target the kidneys in unilateral ureteral obstruction (UUO) mice and ischemia/reperfusion injury (I/R) mice. In animal models of treatment, PMVs@siRNA NP complexes effectively decreased the expression of TGF-β1 and mitigated inflammation and fibrosis in the kidneys by blocking the TGF-β1/Smad3 pathway. Therefore, these PMVs@siRNA NP complexes can serve as a promising biological delivery system for treating kidney diseases.

Intestinal fibrosis is a prevalent complication of IBD that that can frequently be triggered by prolonged inflammation. Fibrosis in the gut can cause a number of issues, which continue as an ongoing challenge to healthcare systems worldwide. The primary causes of intestinal fibrosis are soluble molecules, G protein-coupled receptors, epithelial-to-mesenchymal or endothelial-to-mesenchymal transition, and the gut microbiota. Fresh perspectives coming from in vivo and in vitro experimental models demonstrate that fibrogenic pathways might be different, at least to some extent, independent of the ones that influence inflammation. Understanding the distinctive procedures of intestinal fibrogenesis should provide a realistic foundation for targeting and blocking specific fibrogenic pathways, estimating the risk of fibrotic consequences, detecting early fibrotic alterations, and eventually allowing therapy development. Here, we first summarize the inflammatory and non-inflammatory components of fibrosis, and then we elaborate on the underlying mechanism associated with multiple cytokines in fibrosis, providing the framework for future clinical practice. Following that, we discuss the relationship between modernization and disease, as well as the shortcomings of current studies. We outline fibrosis diagnosis and therapy, as well as our recommendations for the future treatment of intestinal fibrosis. We anticipate that the global review will provides a wealth of fresh knowledge and suggestions for future fibrosis clinical practice.

Developmental signaling pathways associated with growth factors such as TGFb are commonly dysregulated in melanoma. Here we identified a human TGFb enhancer specifically activated in melanoma cells treated with TGFB1 ligand. We generated stable transgenic zebrafish with this TGFb Induced Enhancer driving green fluorescent protein (TIE:EGFP). TIE:EGFP was not expressed in normal melanocytes or early melanomas but was expressed in spatially distinct regions of advanced melanomas. Single-cell RNA-sequencing revealed that TIE:EGFP+ melanoma cells down-regulated interferon response while up-regulating a novel set of chronic TGFb target genes. ChIP-sequencing demonstrated that AP-1 factor binding is required for activation of chronic TGFb response. Overexpression of SATB2, a chromatin remodeler associated with tumor spreading, showed activation of TGFb signaling in early melanomas. Confocal imaging and flow cytometric analysis showed that macrophages localize to TIE:EGFP+ regions and preferentially phagocytose TIE:EGFP+ melanoma cells compared to TIE:EGFP- melanoma cells. This work identifies a TGFb induced immune response and demonstrates the need for the development of chronic TGFb biomarkers to predict patient response to TGFb inhibitors.

The adult mammalian heart has limited endogenous regenerative capacity and heals through the activation of inflammatory and fibrogenic cascades that ultimately result in the formation of a scar. After infarction, massive cardiomyocyte death releases a broad range of damage-associated molecular patterns that initiate both myocardial and systemic inflammatory responses. TLRs (toll-like receptors) and NLRs (NOD-like receptors) recognize damage-associated molecular patterns (DAMPs) and transduce downstream proinflammatory signals, leading to upregulation of cytokines (such as interleukin-1, TNF-α [tumor necrosis factor-α], and interleukin-6) and chemokines (such as CCL2 [CC chemokine ligand 2]) and recruitment of neutrophils, monocytes, and lymphocytes. Expansion and diversification of cardiac macrophages in the infarcted heart play a major role in the clearance of the infarct from dead cells and the subsequent stimulation of reparative pathways. Efferocytosis triggers the induction and release of anti-inflammatory mediators that restrain the inflammatory reaction and set the stage for the activation of reparative fibroblasts and vascular cells. Growth factor-mediated pathways, neurohumoral cascades, and matricellular proteins deposited in the provisional matrix stimulate fibroblast activation and proliferation and myofibroblast conversion. Deposition of a well-organized collagen-based extracellular matrix network protects the heart from catastrophic rupture and attenuates ventricular dilation. Scar maturation requires stimulation of endogenous signals that inhibit fibroblast activity and prevent excessive fibrosis. Moreover, in the mature scar, infarct neovessels acquire a mural cell coat that contributes to the stabilization of the microvascular network. Excessive, prolonged, or dysregulated inflammatory or fibrogenic cascades accentuate adverse remodeling and dysfunction. Moreover, inflammatory leukocytes and fibroblasts can contribute to arrhythmogenesis. Inflammatory and fibrogenic pathways may be promising therapeutic targets to attenuate heart failure progression and inhibit arrhythmia generation in patients surviving myocardial infarction.

Bilateria encompass the vast majority of the animal phyla. As the name states, they are bilaterally symmetric, that is with a morphologically clear main body axis connecting their anterior and posterior ends, a second axis running between their dorsal and ventral surfaces, and with a left side being roughly a mirror image of their right side. Bone morphogenetic protein (BMP) signalling has widely conserved functions in the formation and patterning of the second, dorso-ventral (DV) body axis, albeit to different extents in different bilaterian species. Whilst initial findings in the fruit fly Drosophila and the frog Xenopus highlighted similarities amongst these evolutionarily very distant species, more recent analyses featuring other models revealed considerable diversity in the mechanisms underlying dorsoventral patterning. In fact, as phylogenetic sampling becomes broader, we find that this axis patterning system is so evolvable that even its core components can be deployed differently or lost in different model organisms. In this review, we will try to highlight the diversity of ways by which BMP signalling controls bilaterality in different animals, some of which do not belong to Bilateria. Future research combining functional analyses and modelling is bound to give us some understanding as to where the limits to the extent of the evolvability of BMP-dependent axial patterning may lie.

Small molecules are at the forefront of anticancer therapies. Successive treatments with single molecules incur drug resistance, calling for combination. Here, we explore the tough choices oncologists face - not just which drugs to use but also the best treatment plans, based on factors such as target proteins, pathways, and gene expression. We consider the reality of cancer's disruption of normal cellular processes, highlighting why it's crucial to understand the ins and outs of current treatment methods. The discussion on using combination drug therapies to target multiple pathways sheds light on a promising approach while also acknowledging the hurdles that come with it, such as dealing with pathway crosstalk. We review options and provide examples and the mechanistic basis, altogether providing the first comprehensive guide to combinatorial therapy selection.

Nucleosome assembly proteins (NAPs) have been identified as histone chaperons. Testis-Specific Protein, Y-Encoded-Like (TSPYL) is a newly arisen NAP family in mammals. TSPYL2 can be transcriptionally induced by DNA damage and TGFβ causing proliferation arrest. TSPYL1, another TSPYL family member, has been poorly characterized and is the only TSPYL family member known to be causal of a lethal recessive disease in humans. This study shows that TSPYL1 and TSPYL2 play an opposite role in TGFβ signaling. TSPYL1 partners with the transcription factor FOXA1 and histone methyltransferase EZH2, and at the same time represses TGFBR1 and epithelial-mesenchymal transition (EMT). Depletion of TSPYL1 increases TGFBR1 expression, upregulates TGFβ signaling, and elevates the protein stability of TSPYL2. Intriguingly, TSPYL2 forms part of the SMAD2/3/4 signal transduction complex upon stimulation by TGFβ to execute the transcriptional responses. Depletion of TSPYL2 rescues the EMT phenotype of TSPYL1 knockdown in A549 lung carcinoma cells. The data demonstrates the prime role of TSPYL2 in causing the dramatic defects in TSPYL1 deficiency. An intricate counter-balancing role of TSPYL1 and TSPYL2 in regulating TGFβ signaling is also unraveled.

The distinctive role of Yes-associated protein (YAP) in the nervous system has attracted widespread attention. This comprehensive review strategically uses the retina as a vantage point, embarking on an extensive exploration of YAP's multifaceted impact from the retina to the brain in development and pathology. Initially, we explore the crucial roles of YAP in embryonic and cerebral development. Our focus then shifts to retinal development, examining in detail YAP's regulatory influence on the development of retinal pigment epithelium (RPE) and retinal progenitor cells (RPCs), and its significant effects on the hierarchical structure and functionality of the retina. We also investigate the essential contributions of YAP in maintaining retinal homeostasis, highlighting its precise regulation of retinal cell proliferation and survival. In terms of retinal-related diseases, we explore the epigenetic connections and pathophysiological regulation of YAP in diabetic retinopathy (DR), glaucoma, and proliferative vitreoretinopathy (PVR). Lastly, we broaden our exploration from the retina to the brain, emphasizing the research paradigm of "retina: a window to the brain." Special focus is given to the emerging studies on YAP in brain disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), underlining its potential therapeutic value in neurodegenerative disorders and neuroinflammation.

Hepatocellular carcinoma (HCC) results from various etiologies, such as Hepatitis B and C, Alcoholic and Non-alcoholic fatty liver disorders, fibrosis, and cirrhosis. About 80 to 90% of HCC cases possess cirrhosis, which is brought on by persistent liver inflammation. TGF-β is a multifunctional polypeptide molecule that acts as a pro-fibrogenic marker, inflammatory cytokine, immunosuppressive agent, and pro-carcinogenic growth factor during the progression of HCC. The preclinical and clinical evidence illustrates that TGF-β can induce epithelial-to-mesenchymal transition, promoting progression and hepatocyte immune evasion. Therefore, targeting the TGF-β pathway can be a promising therapeutic option against HCC.

We carry out a systemic analysis of eight potentially selected culinary Indian spices: Turmeric, Black pepper, Ginger, Garlic, Fenugreek, Red pepper, Clove, Cinnamon, and their bioactives in regulation of the TGF-β pathway against liver cancer.

Turmeric and its active constituent, curcumin, possess the highest therapeutic potential in treating inflammation-induced HCC and they also have the maximum number of ongoing in-vivo and in-vitro studies.

Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into cells of different lineages to form mesenchymal tissues, which are promising in regard to treatment for bone diseases. Their osteogenic differentiation is under the tight regulation of intrinsic and extrinsic factors. Transforming growth factor β (TGF-β) is an essential growth factor in bone metabolism, which regulates the differentiation of MSCs. However, published studies differ in their views on whether TGF-β signaling regulates the osteogenic differentiation of MSCs positively or negatively. The controversial results have not been summarized systematically and the related explanations are required. Therefore, we reviewed the basics of TGF-β signaling and summarized how each of three isoforms regulates osteogenic differentiation. Three isoforms of TGF-β (TGF-β1/β2/β3) play distinct roles in regulating osteogenic differentiation of MSCs. Additionally, other possible sources of conflicts are summarized here. Further understanding of TGF-β signaling regulation in MSCs may lead to new applications to promote bone regeneration and improve therapies for bone diseases.

The problem of achieving economic efficiency in sheep breeding can be largely solved by increasing sheep productivity. Recently, the BMPRIB gene has been revealed by GWAS as a potential candidate gene for sheep body morphometric traits. Therefore, the present study aimed to investigate whether genetic polymorphisms (p.Q249R SNP and 90-bp deletion) in the BMPRIB gene are associated with sheep growth traits.

PCR-based genotyping was performed on 1,875 sheep, including 1,191 Guiqian semi-fine wool (GQSFW), 560 Luxi Blackhead (LXBH), 55 Lanzhou fat-tailed (LZFT), and 69 Weining (WN) sheep. Genotype-phenotype association was assessed using the independent samples t-test and ANOVA. The significance level was set at αoriginal < 0.05. The threshold p-value for significance was adjusted after correction for multiple comparisons using the Bonferroni correction.

After the Bonferroni correction, it was found that individuals with FecB+/FecB+ genotypes of the p.Q249R had significantly better growth traits in LXBH ewe lambs, including the body length, chest width, paunch girth, cannon circumference, and hip width (P<0.0005). Meanwhile, associations were observed between 90-bp deletion polymorphism and several growth traits (body length, body height, chest depth, and canon circumference) in GQSFW ewe adults after the Bonferroni correction (P < 0.0002), and individuals with the "DD" genotypes had greater growth traits.

Our findings align with the experimental observations from GWAS, which identified the BMPRIB gene as a potential candidate gene for body measurement traits. These findings not only confirm the previous study's results but also expand on them. Therefore, further investigations regarding the impact of BMPRIB polymorphisms on growth traits are necessary in other sheep breeds.