Transformation of macrophages into myofibroblasts in fibrosis-related diseases: emerging biological concepts and potential mechanism.

Macrophage-myofibroblast transformation (MMT) transforms macrophages into myofibroblasts in a specific inflammation or injury microenvironment. MMT is an essential biological process in fibrosis-related diseases involving the lung, heart, kidney, liver, skeletal muscle, and other organs and tissues. This process consists of interacting with various cells and molecules and activating different signal transduction pathways. This review deeply discussed the molecular mechanism of MMT, clarified crucial signal pathways, multiple cytokines, and growth factors, and formed a complex regulatory network. Significantly, the critical role of transforming growth factor-ß (TGF-ß) and its downstream signaling pathways in this process were clarified. Furthermore, we discussed the significance of MMT in physiological and pathological conditions, such as pulmonary fibrosis and cardiac fibrosis. This review provides a new perspective for understanding the interaction between macrophages and myofibroblasts and new strategies and targets for the prevention and treatment of MMT in fibrotic diseases.

Integrated Lipidomic and transcriptomics to explore the effects of ethyl acetate extract of Herpetospermum pedunculosum on nonalcoholic fatty liver disease in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Herpetospermum pedunculosum (Ser.) C.B. Clarke (HP), a traditional Tibetan medicine used to treat hepatobiliary diseases, was confirmed that lignans-enriched ethyl acetate extract of HP (EAHP) could alleviate the hepatic injury by modern pharmacological evidence. However, the effects and potential mechanisms of EAHP against nonalcoholic fatty liver disease (NAFLD) are still unknown. AIM OF THE STUDY: To reveal the effects of EAHP on NAFLD and explore the potential mechanisms from the perspective of lipidomics and transcriptomics. MATERIALS AND METHODS: UPLC‒Q-TOF‒MS analysis was carried out to investigate the chemical components of EAHP. A Choline-deficient, L-amino acid defined, high fat diet (CDAHFD) was used to establish a NAFLD mouse model. The anti-NAFLD effects of various dosages of EAHP were evaluated by biochemical indexes and histological analysis. Hepatic lipidomic and transcriptomic analysis and multiple bioinformatics methods were used to screen biomarkers and signaling pathways. The levels of the corresponding genes were verified by qPCR. RESULTS: 36 kinds of compounds were identified by UPLC‒Q-TOF‒MS analysis. Oral treatment with EAHP significantly decrease the liver index and the levels of ALT and AST in the serum. The measurements lipid content and Oil Red O staining results suggested that EAHP ameliorated lipid metabolism disorders by reducing the content of TG and LDL-C, increasing HDL-C in the liver. H&E staining and ELISA revealed that EAHP restored hepatic inflammatory infiltration and decrease the levels of IL-1ß, IL-6, TNF-α, and increase IL-10 in the serum. Lipidomic analysis showed that EAHP could regulate CDAHFD-induced lipid metabolic disorder. The different lipid metabolites included TG, phosphatidyl choline (PC), diacylglycerol (DG), phosphatidylethanolamine (PE), phosphatidylinositol (PI), ceramide (Cer). Transcriptomic analysis revealed that Bmp8b, Nbl1, Rgma, Sphk1, Thbs1, and Ugt8a were important regulators, which were associated with TGF-ß signaling pathway and sphingolipid metabolism. The expressions of above genes detected by were qPCR consistent with transcriptomic data. CONCLUSIONS: The ameliorative effects of EAHP on NAFLD are potentially attributable to the regulation of sphingolipid metabolism and TGF-ß signaling pathway, etc., which results in abnormal hepatic lipid metabolism and inflammatory response.

DACT2 modulates atrial fibrillation through TGF/ß and Wnt signaling pathways.

Atrial fibrillation (AF) is a common cardiac arrhythmia that seriously affects the quality of life of patients. Effective treatment and prevention are important to control the morbidity and mortality of AF. It has been found that cardiac fibrosis promotes the onset and progression of AF. It is now known that transforming growth factor ß (TGF-ß), an important fibrotic cytokine, plays an important role in cardiac fibrosis by inducing myofibroblast activation via the activation of classical (SMAD-based) and non-classical (non-SMAD-based) signaling pathways. In addition, specific activation of the Wnt/ß-catenin pathway has been shown to promote the transformation of fibroblasts into myofibroblasts. In recent years, a new family of proteins, namely Disheveled-associated antagonist of beta-catenin (DACT) 2, can affect the Wnt/ß-catenin and TGF-ß signaling pathways by regulating the phosphorylation levels of these target proteins, which in turn affects the progression of fibrosis. The present study focuses on the effect of DACT2-guided ß-catenin on atrial fibrosis. It is expected that the summarized information can be helpful in the treatment of AF.

In vitro Chondrogenic Induction Promotes the Expression Level of IL-10 via the TGF-ß/SMAD and Canonical Wnt/ß-catenin Signaling Pathways in Exosomes Secreted by Human Adipose Tissue-derived Mesenchymal Stem Cells.

Current treatment approaches cannot exactly regenerate cartilage tissue. Regarding some problems encountered with cell therapy, exosomes are advantageous because of their "cell-free" nature. This study examines the relationship between IL-10 and TGF-ß and Canonical Wnt/ß-catenin signal pathways in human adipose tissue-derived MSCs exosomes (hAT-MSCs-Exos) after in vitro chondrogenic differentiation. Human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) and, as a control group, human fetal chondroblast cells (hfCCs) were differentiated chondrogenically in vitro. Exosome isolation and characterization analyses were performed. Chondrogenic differentiation was shown by Alcian Blue and Safranin O stainings. The expression levels of IL-10, TGF-ß/SMAD signaling pathway genes, and Canonical Wnt/ß-catenin signaling pathway genes, which play an essential role in chondrogenesis, were analyzed by RT-qPCR. Conditioned media cytokine levels were measured by using the TGF-ß and IL-10 ELISA kits. IL-10 expression was upregulated in both chondrogenic differentiated hAT-MSC-Exos (dhAT-MSC-Exos) (p < 0.0001). In the TGF-ß signaling pathway, TGF-ß (p < 0.0001), SMAD2 (p < 0.0001), SMAD4 (p < 0.001), ACAN (p < 0.0001), SOX9 (p < 0.05) and COL1A2 (p < 0.0001) expressions were upregulated in dhAT-MSC-Exos. SMAD3 expression was upregulated in non-differentiated hAT-MSC-Exos. In the Canonical Wnt/ß-catenin signaling pathway, WNT (p < 0.0001) and CTNNB1(p < 0.0001) expressions were upregulated in dhAT-MSC-Exos. AXIN (p < 0.0001) expression was upregulated in non-differentiated hAT-MSC-Exos. TGF-ß and IL-10 levels were higher in dhAT-MSCs) (p < 0.0001). Related to these results, IL-10 may induce TGF-ß/SMAD and Canonical Wnt/ß-catenin signaling pathways in hAT-MSC exosomes obtained after chondrogenic differentiation. Therefore, using these exosomes for cartilage regeneration can lead to the development of treatment methods.

Single-Cell RNA Sequencing Revealing that MMP12+ Macrophages are Associated with Cancer Liver Metastasis.

AIM: We aimed to explore the MMP12+ macrophages function in liver metastasis of Colorectal cancer [CRC]. BACKGROUND: CRC has a high incidence, and a great many patients develop liver metastases. Some studies have found that macrophages may participate in the liver metastasis of CRC. OBJECTIVE: This study aimed to determine the factors and major signaling pathways of MMP12+ macrophages affecting liver metastasis of CRC. METHODS: The single-cell RNA sequencing [scRNA-seq] data of CRC and bulk transcriptome data were downloaded. After filtering scRNA-seq data, dimensionality reduction and clustering were performed to identify different cell subgroups. The FindAll- Markers function was used to calculate the differentially expressed genes in each cell subgroup, and the genes in the promising set were uploaded to the DAVID database to analyze the biological processes to which these genes were enriched. Differentially expressed genes among macrophage subgroups were selected by the AverageExpression function. Then, the CIBERSORT algorithm was used to compute the proportion of each macrophage subgroup in each bulk tissue and determine the most significant macrophage subgroup. The dynamic changes of gene expression in macrophage subgroup were computed by Pseudotime. Finally, CellChat was applied to investigate the effect of the macrophage subgroup on epithelial cells and the ligand-receptor effect of B cells and T cells. RESULTS: Clustering scRNA-seq data showed a larger proportion of macrophages in liver metastases. The proportion of MMP12+ macrophage subtypes increased gradually among normal, tumor, and liver metastasis groups, and MMP12+ macrophages were associated with angiogenesis, cell migration, and inhibited T cell proliferation. The Pseudotime showed higher expression levels of genes related to angiogenesis and enhanced TGF-ß signaling pathway and the negative regulation of T cell proliferation with the occurrence of liver metastasis in MMP12+ macrophages. MMP12+ macrophages can promote the proliferation of epithelial cells and inhibit the activation of T cells and B cells. CONCLUSION: MMP12+ macrophages promoted liver metastasis of CRC by influencing angiogenesis, TGF-ß signaling pathway expression, and regulation of T cells and B cells.

The combination of paeoniflorin and metformin synergistically inhibits the progression of liver fibrosis in mice.

Liver fibrosis is a pathological process that endangers human health, for which effective treatments remain elusive to date. Paeoniflorin (PAE), a pineane-type monoter penoid compound from the traditional Chinese medicine PaeoniaeRubra Radix, and metformin (MET), an oral biguanide hypoglycemic agent, both demonstrate anti-inflammatory and hepatoprotective effects. In current work, we first discovered that the combined treatment of PAE and MET synergistically inhibited the progression of liver fibrosis in two different animal models: therapeutic and preventive. This therapeutic effect is evidenced by a reduction in the expression levels of liver fibrosis markers and an improvement in histopathological characteristics. Mechanistic exploration further revealed that this combination therapy downregulated the expression of TGF-ß1 and p-Smad2, while upregulating Smad7 expression in both models. Importantly, we also found that this combinatorial approach significantly reduced hepatotoxicity and nephrotoxicity in both models. Our findings suggest an effective combination therapy for liver fibrosis and provide the possibility of therapeutic improvement for patients with liver fibrosis.

CD5L up-regulates the TGF-ß signaling pathway and promotes renal fibrosis.

Renal fibrosis is the common final pathway of progressive renal diseases, in which the macrophages play an important role. ELISA was used to detect CD5 antigen-like (CD5L) in serum samples from end-stage renal disease (ESRD), as well as in mice serum with unilateral ureteral occlusion (UUO). Recombinant CD5L was injected into UUO mice to assess renal injury, fibrosis, and macrophage infiltration. The expression of CD5L was significantly upregulated in the serum of patients with ESRD and UUO mice. Histological analysis showed that rCD5L-treated UUO mice had more severe renal injury and fibrosis. Furthermore, rCD5L promoted the phenotypic transfer of monocytes from Ly6Chigh to LyC6low. RCD5L promoted TGF-ß signaling pathway activation by promoting Smad2/3 phosphorylation. We used Co-IP to identify HSPA5 interact with CD5L on cell membrane could inhibit the formation of the Cripto/HSPA5 complex, and promote the activation of the TGF-ß signaling pathway. The CD5L antibody could reduce the degree of renal fibrosis in UUO mice.

PF-06952229, a selective TGF-ß-R1 inhibitor: preclinical development and a first-in-human, phase I, dose-escalation study in advanced solid tumors.

BACKGROUND: PF-06952229 is a selective small-molecule inhibitor of transforming growth factor-ß (TGF-ß) receptor 1. We evaluated its antitumor activity in preclinical studies and its safety, tolerability, pharmacokinetics, and pharmacodynamics in a phase I study (NCT03685591). PATIENTS AND METHODS: In vitro and in vivo preclinical studies were conducted. Patients (aged ≥18 years) received PF-06952229 monotherapy [20-500 mg, oral b.i.d., 7 days on/7 days off, 28-day cycles, Part 1A (P1A)] for advanced/metastatic solid tumors and combination therapy [250/375 mg with enzalutamide, Part 1B (P1B)] for metastatic castration-resistant prostate cancer (mCRPC). Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and laboratory abnormalities. Efficacy, pharmacokinetic parameters, and biomarker modulation were assessed. RESULTS: PF-06952229 showed activity in preclinical murine tumor models including pSMAD2 modulation in tumors. The study (NCT03685591) enrolled 49 patients (P1A, n = 42; P1B, n = 7). DLTs were reported in 3/35 (8.6%) P1A patients receiving PF-06952229 375 mg (anemia, intracranial tumor hemorrhage, and anemia and hypertension, all grade 3, n = 1 each). The most frequent grade 3 treatment-related AEs (TRAEs) were alanine aminotransferase increased and anemia (9.5% each). There were no grade 4-5 TRAEs. Plasma PF-06952229 exposures were dose proportional between 80 and 375 mg. Pharmacodynamic studies confirmed target modulation of pSMAD2/3 (peripheral monocytes). One P1A patient with prostate cancer receiving PF-06952229 375 mg monotherapy achieved confirmed partial response (31-month duration of response). A total of 8 patients (P1A, n = 6; P1B, n = 2) achieved stable disease. CONCLUSIONS: Antitumor activity of PF-06952229 was observed in preclinical studies. PF-06952229 was generally well tolerated with manageable toxicity; a small group of patients achieved durable responses and/or disease stabilization.

Towards an enhanced understanding of osteoanabolic effects of PTH-induced microRNAs on osteoblasts using a bioinformatic approach.

In this study, we used a bioinformatic approach to construct a miRNA-target gene interaction network potentially involved in the anabolic effect of parathyroid hormone analogue teriparatide [PTH (1-34)] on osteoblasts. We extracted a dataset of 26 microRNAs (miRNAs) from previously published studies and predicted miRNA target interactions (MTIs) using four software tools: DIANA, miRWalk, miRDB, and TargetScan. By constructing an interactome of PTH-regulated miRNAs and their predicted target genes, we elucidated signaling pathways regulating pluripotency of stem cells, the Hippo signaling pathway, and the TGF-beta signaling pathway as the most significant pathways in the effects of PTH on osteoblasts. Furthermore, we constructed intersection of MTI networks for these three pathways and added validated interactions. There are 8 genes present in all three selected pathways and a set of 18 miRNAs are predicted to target these genes, according to literature data. The most important genes in all three pathways were BMPR1A, BMPR2 and SMAD2 having the most interactions with miRNAs. Among these miRNAs, only miR-146a-5p and miR-346 have validated interactions in these pathways and were shown to be important regulators of these pathways. In addition, we also propose miR-551b-5p and miR-338-5p for further experimental validation, as they have been predicted to target important genes in these pathways but none of their target interactions have yet been verified. Our wet-lab experiment on miRNAs differentially expressed between PTH (1-34) treated and untreated mesenchymal stem cells supports miR-186-5p from the literature obtained data as another prominent miRNA. The meticulous selection of miRNAs outlined will significantly support and guide future research aimed at discovering and understanding the crucial pathways of osteoanabolic PTH-epigenetic effects on osteoblasts. Additionally, they hold potential for the discovery of new PTH target genes, innovative biomarkers for the effectiveness and safety of osteoporosis-affected treatment, as well as novel therapeutic targets.

NOR1 promotes the osteoblastic differentiation of human periodontal ligament stem cells via TGF-ß signaling pathway.

Alveolar bone loss is a main manifestation of periodontitis. Human periodontal ligament stem cells (PDLSCs) are considered as optimal seed cells for alveolar bone regeneration due to its mesenchymal stem cell like properties. Osteogenic potential is the premise for PDLSCs to repair alveolar bone loss. However, the mechanism regulating osteogenic differentiation of PDLSCs remain elusive. In this study, we identified Neuron-derived orphan receptor 1 (NOR1), was particularly expressed in PDL tissue in vivo and gradually increased during osteogenic differentiation of PDLSCs in vitro. Knockdown of NOR1 in hPDLSCs inhibited their osteogenic potential while NOR1 overexpression reversed this effect. In order to elucidate the downstream regulatory network of NOR1, RNA-sequencing was used. We found that downregulated genes were mainly enriched in TGF-ß, Hippo, Wnt signaling pathway. Further, by western blot analysis, we verified that the expression level of phosphorylated-SMAD2/3 and phosphorylated-SMAD4 were all decreased after NOR1 knockdown. Additionally, ChIP-qPCR and dual luciferase reporter assay indicated that NOR1 could bind to the promoter of TGFBR1 and regulate its activity. Moreover, overexpression of TGFBR1 in PDLSCs could rescue the damaged osteogenic potential after NOR1 knockdown. Taken together, our results demonstrated that NOR1 could activate TGF-ß/SMAD signaling pathway and positively regulates the commitment of osteoblast lineages of PDLSCs by targeting TGFBR1 directly.

Hepatitis B virus X protein and TGF-ß: partners in the carcinogenic journey of hepatocellular carcinoma.

Hepatitis B infection is substantially associated with the development of liver cancer globally, with the prevalence of hepatocellular carcinoma (HCC) cases exceeding 50%. Hepatitis B virus (HBV) encodes the Hepatitis B virus X (HBx) protein, a pleiotropic regulatory protein necessary for the transcription of the HBV covalently closed circular DNA (cccDNA) microchromosome. In previous studies, HBV-associated HCC was revealed to be affected by HBx in multiple signaling pathways, resulting in genetic mutations and epigenetic modifications in proto-oncogenes and tumor suppressor genes. In addition, transforming growth factor-ß (TGF-ß) has dichotomous potentials at various phases of malignancy as it is a crucial signaling pathway that regulates multiple cellular and physiological processes. In early HCC, TGF-ß has a significant antitumor effect, whereas in advanced HCC, it promotes malignant progression. TGF-ß interacts with the HBx protein in HCC, regulating the pathogenesis of HCC. This review summarizes the respective and combined functions of HBx and TGB-ß in HCC occurrence and development.

TGF-ß-Based Therapies for Treating Ocular Surface Disorders.

The cornea is continuously exposed to injuries, ranging from minor scratches to deep traumas. An effective healing mechanism is crucial for the cornea to restore its structure and function following major and minor insults. Transforming Growth Factor-Beta (TGF-ß), a versatile signaling molecule that coordinates various cell responses, has a central role in corneal wound healing. Upon corneal injury, TGF-ß is rapidly released into the extracellular environment, triggering cell migration and proliferation, the differentiation of keratocytes into myofibroblasts, and the initiation of the repair process. TGF-ß-mediated processes are essential for wound closure; however, excessive levels of TGF-ß can lead to fibrosis and scarring, causing impaired vision. Three primary isoforms of TGF-ß exist-TGF-ß1, TGF-ß2, and TGF-ß3. Although TGF-ß isoforms share many structural and functional similarities, they present distinct roles in corneal regeneration, which adds an additional layer of complexity to understand the role of TGF-ß in corneal wound healing. Further, aberrant TGF-ß activity has been linked to various corneal pathologies, such as scarring and Peter's Anomaly. Thus, understanding the molecular and cellular mechanisms by which TGF-ß1-3 regulate corneal wound healing will enable the development of potential therapeutic interventions targeting the key molecule in this process. Herein, we summarize the multifaceted roles of TGF-ß in corneal wound healing, dissecting its mechanisms of action and interactions with other molecules, and outline its role in corneal pathogenesis.

Serial Changes of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab.

Immune checkpoint inhibitors have promising outcomes in patients with hepatocellular carcinoma (HCC); however, there is no reliable biomarker for predicting disease progression. Circulating tumor cells (CTCs) derived from peripheral blood have attracted attention in monitoring therapeutic efficacy. In this study, CTCs were serially collected from HCC patients undergoing atezolizumab plus bevacizumab (Atezo+Bev), and changes in molecular expression and CTC numbers were analyzed to identify effective biomarkers. Changes in CTC numbers during Atezo+Bev reflected the tumor volume. Targeted RNA sequencing with next-generation sequencing (NGS) revealed that patients with elevated transforming growth factor (TGF)-ß signaling molecules had a poorer response, whereas those with elevated apoptosis signaling molecules had a favorable response. In addition, compared with changes in CTC counts, changes in TGF-ß signaling molecule expression in CTCs accurately and promptly predicted treatment response. Overall, NGS analysis of CTC-derived RNA showed that changes in TGF-ß signaling molecules predict treatment response earlier than changes in CTC counts. These findings suggest that changes in the expression of TGF-ß molecules in CTCs could serve as novel biomarkers for the early prediction of therapeutic response in patients with unresectable HCC undergoing Atezo+Bev.

MicroRNA-19b exacerbates systemic sclerosis through promoting Th9 cells.

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis of the skin and multiple vital organs, but the immunological pathogenesis of SSc remains unclear. We show here that miR-19b promotes Th9 cells that exacerbate SSc. Specifically, miR-19b and interleukin (IL)-9 increase in CD4+ T cells in experimental SSc in mice induced with bleomycin. Inhibiting miR-19b reduces Th9 cells and ameliorates the disease. Mechanistically, transforming growth factor beta (TGF-ß) plus IL-4 activates pSmad3-Ser213 and TRAF6-K63 ubiquitination by suppressing NLRC3. Activated TRAF6 sequentially promotes TGF-ß-activated kinase 1 (TAK1) and nuclear factor κB (NF-κB) p65 phosphorylation, leading to the upregulation of miR-19b. Notably, miR-19b activated Il9 gene expression by directly suppressing atypical E2F family member E2f8. In patients with SSc, higher levels of IL9 and MIR-19B correlate with worse disease progression. Our findings reveal miR-19b as a key factor in Th9 cell-mediated SSc pathogenesis and should have clinical implications for patients with SSc.

Single cell transcriptomic analysis reveals tumor immune infiltration by NK cells gene signature in lung adenocarcinoma.

Background: Natural Killer (NK) cells are vital components of the innate immune system, crucial for combating infections and tumor growth, making them pivotal in cancer prognosis and immunotherapy. We sought to understand the diverse characteristics of NK cells within lung adenocarcinoma (LUAD) by conducting single-cell RNA sequencing analyses. Methods: Using the scRNA-seq dataset for multiple primary lung cancers (MPLCs), we examined two major NK cell groups, NK1 and NK2, comparing the expression profiles of 422 differentially expressed NK signature genes. We identified eight genes (SPON2, PLEKHG3, CAMK2N1, RAB27B, CTBP2, EFHD2, GOLM1, and PLOD1) that distinguish NK1 from NK2 cells. A prognostic signature, the NK gene signature (NKGS) score, was established through LASSO Cox regression. High NKGS scores were linked to poorer overall survival in TCGA-LUAD patients and consistently validated in other datasets (GSE31210 and GSE14814). Results: Functional analysis revealed an enrichment of genes related to the TGF-ß signaling pathway in the high NKGS score group. Moreover, a high NKGS score correlated with an immunosuppressive tumor microenvironment (TME) driven by immune evasion mechanisms. We also observed reduced T-cell receptor (TCR) repertoire diversity in the high-risk NKGS group, indicating a negative association between inflammation and risk score. Conclusion: This study introduced the innovative NKGS score, differentiating NK1 from NK2 cells. High NKGS scores were associated with the TGF-ß pathway and provided insights into LUAD prognosis and immune activities.

Investigating the impact of SMAD2 and SMAD4 downregulation in colorectal cancer and their correlation with immune markers, prognosis, and drug resistance and sensitivity.

BACKGROUND: While many genes linked to colorectal cancer (CRC) contribute to cancer development, a thorough investigation is needed to explore crucial hub genes yet to be fully studied. A pivotal pathway in CRC is transforming growth factor-beta (TGF-ß). This study aimed to assess SMAD2 and SMAD4 gene expression from this pathway. METHODS AND RESULTS: Counted data from the Cancer Genome Atlas (TCGA) were examined, comparing 483 tumor and 41 normal samples. Using clinical data, genes impacting overall survival (OS) were evaluated. GSE39582 was employed to confirmed the levels of genes in CRC compared to the normal samples. Additionally, employing unhealthy samples and the RT-qPCR means our outcomes was validated. Finally, PharmacoGx information were utilized to connect the levels of potential genes to drug tolerance and susceptibility. Our findings showed SMAD2 and SMAD4 levels in TGF-ß signaling were more significant than other pathway genes. Our findings indicated that the protein levels of these genes were lower in malignant tissues than in healthy tissues. Results revealed a significant correlation between low levels of SMAD2 and unfavorable OS in CRC individuals. RT-qPCR results demonstrated decreased expressions of both SMAD2 and SMAD4 in cancer tissues compared to elevated levels in adjacent normal samples. Our results showed significant association between selected genes and immune cell infiltration markers such as CD8+, and B-cells. Our results indicated a potential association among the levels of SMAD2 and SMAD4 genes and tolerance and susceptibility to Nilotinib and Panobinostat drugs. CONCLUSION: Reduced expression of SMAD2 and SMAD4 may be pivotal in CRC progression, impacting downstream genes unrelated to patient OS. These findings suggest a potential role for SMAD2 and SMAD4 as predictive markers for drug response in CRC patients.

α-Mangostin reduces hypertension in spontaneously hypertensive rats and inhibits EMT and fibrosis in Ang II-induced HK-2 cells.

Hypertension affects a large number of individuals globally and is a common cause of nephropathy, stroke, ischaemic heart disease and other vascular diseases. While many anti-hypertensive medications are used safely and effectively in clinic practice, controlling hypertensive complications solely by reducing blood pressure (BP) can be challenging. α-Mangostin, a xanthone molecule extracted from the pericarp of Garcinia mangostana L., has shown various beneficial effects such as anti-tumor, anti-hyperuricemia, and anti-inflammatory properties. However, the effects of α-Mangostin on hypertension remain unknown. In this study, we observed that α-Mangostin significantly decreased systolic and diastolic blood pressure in spontaneously hypertensive rats (SHR), possibly through the down-regulation of angiotensin II (Ang II). We also identified early markers of hypertensive nephropathy, including urinary N-acetyl-ß-D-glucosaminidase (NAG) and ß2-microglobulin (ß2-MG), which were reduced by α-Mangostin treatment. Mechanistic studies suggested that α-Mangostin may inhibit renal tubular epithelial-to-mesenchymal transformation (EMT) by down-regulating the TGF-ß signaling pathway, thus potentially offering a new therapeutic approach for hypertension and hypertensive nephropathy.

Structure, unique biological properties, and mechanisms of action of transforming growth factor ß.

Transforming growth factor ß (TGF-ß) is a ubiquitous molecule that is extremely conserved structurally and plays a systemic role in human organism. TGF-ß is a homodimeric molecule consisting of two subunits joined through a disulphide bond. In mammals, three genes code for TGF-ß1, TGF-ß2, and TGF-ß3 isoforms of this cytokine with a dominating expression of TGF-ß1. Virtually, all normal cells contain TGF-ß and its specific receptors. Considering the exceptional role of fine balance played by the TGF-ß 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-ß signaling pathway as therapeutic targets have been considered. In this review, signalling mechanisms of TGF-ß1 action are addressed, and their role in physiology and pathology with main focus on carcinogenesis are described.

Disruption of TGF-ß signaling pathway is required to mediate effective killing of hepatocellular carcinoma by human iPSC-derived NK cells.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Transforming growth factor beta (TGF-ß) is highly expressed in the liver tumor microenvironment and is known to inhibit immune cell activity. Here, we used human induced pluripotent stem cells (iPSCs) to produce natural killer (NK) cells engineered to mediate improved anti-HCC activity. Specifically, we produced iPSC-NK cells with either knockout TGF-ß receptor 2 (TGFBR2-KO) or expression of a dominant negative (DN) form of the TGF-ß receptor 2 (TGFBR2-DN) combined with chimeric antigen receptors (CARs) that target either GPC3 or AFP. The TGFBR2-KO and TGFBR2-DN iPSC-NK cells are resistant to TGF-ß inhibition and improved anti-HCC activity. However, expression of anti-HCC CARs on iPSC-NK cells did not lead to effective anti-HCC activity unless there was also inhibition of TGF-ß activity. Our findings demonstrate that TGF-ß signaling blockade is required for effective NK cell function against HCC and potentially other malignancies that express high levels of TGF-ß.

MALAT1 Knockdown Inhibits the Proliferation, Migration, and Collagen Deposition of Human Hypertrophic Scar Fibroblasts via Targeting miR-29a-3p/Smurf2 Axis.

Purpose: Hypertrophic scarring (HS) is commonly described as an abnormal post-traumatic tissue repair characterized by excessive hypercellularity and extracellular matrix (ECM) deposition. Mounting evidence suggests that MALAT1 is maladjusted in many fibrotic diseases, but its contribution to HS progression remains poorly understood. Hence, we sought to elucidate the fundamental role of MALAT1 in HS. Methods: The expression of MALAT1, miR-29a-3p, and Smurf2 in skin tissues and fibroblasts was assessed by RT-qPCR and Western blotting. Furthermore, lentiviruses, RNAi, or plasmids were utilized to transfect hypertrophic scar fibroblasts (HSFs) for gene overexpression or downregulation. The biological behaviors of HSFs were quantified by the CCK-8 assay, wound healing assay, transwell assay, and flow cytometry. Mechanistically, bioinformatics analysis, dual-luciferase reporter assays, and rescue experiments were performed to verify the relationship between miR-29a-3p and MALAT1 or Smurf2. Results: Our data indicate that MALAT1, Smurf2 were overexpressed while miR-29a-3p was suppressed in HS tissues and fibroblasts. Downregulation of MALAT1 may lead to decreased proliferation, migration, and invasion of fibroblasts, accompanied by enhanced apoptosis, reduced TGF-ß signal transduction, and ECM accumulation in HSFs, by enhancing miR-29a-3p and suppressing Smurf2 expression. Mechanistically, MALAT1 acted as a sponge for miR-29a-3p, while miR-29a-3p directly targeted Smurf2. More importantly, rescue experiments suggested that MALAT1 downregulation induced impact on the proliferation, migration, and invasion of HSFs could be partially overturned through miR-29a-3p knockdown or Smurf2 overexpression. Conclusion: MALAT1 knockdown inhibits the proliferation, migration, invasion, and collagen deposition of HSFs via targeting the miR-29a-3p/Smurf2 axis, which may reveal a promising therapeutic exploitable vulnerability to HS.