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Objective: This study investigated the expression of TGF-β/Smad pathway-related indices in patients with isolated iliac artery aneurysms (IIAA) complicated with iliac arteriovenous fistula (IAVF) and their relationship with prognosis., Methods: From January 2016 to June 2022, 83 patients with IIAA complicated with IAVF (Study group) and 54 patients with IIAA not complicated with IAVF (control group) were studied. The related indices of TGF-β/Smad pathway were evaluated, and the effects of each index on the formation of IAVF were analyzed. The patients were divided into the survival group (64 cases) and death group (19 cases), and the prognostic value of indices in combination was analyzed., Results: TGF-β, p-Smad2, p-Smad3, p-JNK, and p-ERK in the study group were higher than those in the control group. Abnormal increase of pSmad3 expression was a risk factor for IAVF formation in patients with IIAA. TGF-β level in the death group was higher than that in the survival group, and p-Smad3 and p-JNK proteins were higher than those in the survival group. The AUC value of indices in the TGF-β/Smad pathway in combination was greater than that of each index alone. Abnormal increased expression of pSmad3 was a risk factor for prognosis of patients with IIAA complicated with IAVF., Conclusion: The abnormal increase of TGF-β/Smad pathway-related indices is related to poor prognosis of patients with IIAA complicated with IAVF, and the combined detection of all indices has a predictive value for patients' prognosis.

Colorectal Cancer (CRC) is the third most common cancer worldwide, and the occurrence and development of CRC are influenced by the molecular biology characteristics of CRC, especially alterations in key signaling pathways. The transforming growth factor-β (TGF-β) plays a crucial role in cellular growth, differentiation, migration, and apoptosis, with SMAD4 protein serving as a key transcription factor in the TGF-β signaling pathway, thus playing a significant role in the onset and progression of CRC. CRC is one of the malignancies with a high mortality rate worldwide. Despite significant research progress in recent years, especially regarding the role of SMAD4, its dual role in the early and late stages of tumor progression has promoted further discussion on its complexity as a therapeutic target, highlighting the urgent need for a deeper analysis of its role in CRC. This review aims to explore the function of SMAD4 protein in CRC and its potential as a therapeutic target.

Sarcopenia has become a prominent health problem among the elderly because of its adverse consequence, including physical disabilities and death. Fibro-adipogenic progenitors (FAPs) exhibit adipogenic and fibrogenic potencies and regulate skeletal muscle development, which plays important role in sarcopenia. Mairin, as an ingredient of Astragalus membranaceus, has the effect of anti-fibrosis. Therefore, we predicted that mairin targeted the fibrosis of FAPs and then affected sarcopenia. To verify our ideas, mairin (30 mg/kg/day or 60 mg/kg/day) was given to senescence accelerated mouse-prone 8 (SAMP8) mice by oral administration. Aging led to loss of weight, skeletal muscle mass, strength, and function, and an increase in muscle atrophy and fibrosis, while mairin administration inhibited physiological decline caused by aging. Similarly, mairin (20 μM or 40 μM) treatment enhanced FAP proliferation but blocked the differentiation into fibroblasts. Mechanically, mairin played an anti-fibrotic role via AMP-activated protein kinase-transforming growth factor beta-drosophila mothers against decapentaplegic protein (AMPK-TGF-β-SMAD) axis, as evidenced by increased phosphorylation of AMPKα and decreased TGF-β and phosphorylated-SMAD2/3. In addition, the potential target genes of mairin were explored by mRNA sequencing in our study. In conclusion, mairin may interfere with the AMPK/TGF-β/SMAD pathway to repress the fibrosis of FAPs and eventually ameliorate sarcopenia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Fibrosis results in one-third of all deaths globally and is a major healthcare challenge. Fibrosis is scarring caused by the excess deposition of extracellular matrix proteins by fibroblasts. Inhibition of pathways downstream of transforming growth factor β (TGF-β) a pluripotent growth factor, has potent antifibrotic effects in different organs. Here we show that loss of bone morphogenetic protein (BMP-3) is a feature of kidney fibrosis, independent of the initiating injury, suggesting loss of this cytokine is a core fibrotic mechanism. TGF-β decreased BMP3 expression in human fibroblasts is possibly a feed-forward loop that contributes to increased and sustained TGF-β activity. Recombinant human BMP-3 reduced TGF-β induced fibroblast contraction, migration and invasion, pathways that lead to scarring and tissue stiffening. BMP-3 reduced TGF-β stimulated collagen cross-linking, and Ox-LDL receptor 1, a regulator of collagen deposition. BMP-3 inhibited TGF-β stimulated lysyl oxidase activity. Lysyl oxidase mediated collagen cross-linking is a critical process in TGF-β induced fibrosis. We propose that BMP-3 alters fibroblast responses to TGF-β, shifting the balance from fibrosis to repair. Recombinant human BMP-3 shows promise for development as a novel therapeutic for fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Surgical resection is the best-known approach for breast cancer treatment. However, post-operative metastases increase the rate of death. The potential effect of anesthetic drugs on long-term tumor growth, risk of metastasis, and recurrence after surgery has been investigated in cancer patients. However, the underlying mechanisms remain unclear. Therefore, we aimed to elucidate the anti-metastatic effect of lidocaine combined with common anesthetics and its mechanisms of action on lung metastasis in breast cancer models. The combination of lidocaine with propofol or sevoflurane inhibited the growth of TNBC cells compared to treatment alone. In addition, the combination effectively inhibited cancer cell migration and invasion. It suppressed tumor growth and increased the survival rate in breast 4 T1 orthotopic models. More importantly, it inhibited lung metastasis and recurrence compared with groups treated with a single anesthetic. In co-culture with TAMs and TNBC cells, lidocaine not only reduced M2-tumor-associated macrophages (TAM) that were increased by sevoflurane or propofol but also increased M1 macrophage polarization, impeding tumor growth in TNBC. Also, we found that the transforming growth factor-β (TGF-β) derived from TAMs increased EMT signaling in TNBC cells, and that lidocaine affected cancer cells as well as M2-TAMs, inducing M2 to M1 reprogramming and decreasing TGF-β/Smads-mediated EMT signaling in TNBC cells, leading to inhibition of cancer metastasis and recurrence. These findings suggest lidocaine combined with general anesthetics as a potential therapeutic approach for the inhibition of recurrence and metastasis of breast cancer patients undergoing curative resection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Integrin heterodimers containing an Integrin alpha V subunit are essential for development and play critical roles in cell adhesion and signaling. We identified biallelic variants in the gene coding for Integrin alpha V (ITGAV) in three independent families (two patients and four fetuses) that either caused abnormal mRNA and the loss of functional protein or caused mistargeting of the integrin. This led to eye and brain abnormalities, inflammatory bowel disease, immune dysregulation, and other developmental issues. Mechanistically, the reduction of functional Integrin αV resulted in the dysregulation of several pathways including TGF-β-dependent signaling and αVβ3-regulated immune signaling. These effects were confirmed using immunostaining, RNA sequencing, and functional studies in patient-derived cells. The genetic deletion of itgav in zebrafish recapitulated patient phenotypes including retinal and brain defects and the loss of microglia in early development as well as colitis in juvenile zebrafish with reduced SMAD3 expression and transcriptional regulation. Taken together, the ITGAV variants identified in this report caused a previously unknown human disease characterized by brain and developmental defects in the case of complete loss-of-function and atopy, neurodevelopmental defects, and colitis in cases of incomplete loss-of-function., (© 2024 Ghasempour et al.)

Background: Injectable platelet-rich fibrin (iPRF), a liquid form of PRF that is prepared from peripheral blood without anticoagulants, promotes tissue wound healing and regeneration. The present study focused on iPRF-like bone marrow aspirate concentrate (iBMAC) prepared without anticoagulant, and the regenerative potential of iPRF and iBMAC was compared in vitro., Methods: iPRF and iBMAC were prepared from the same New Zealand white rabbits. The cytocompatibility and regenerative potential of each concentrate were evaluated using primary rabbit gingival fibroblasts and osteoblasts., Results: Both gingival fibroblasts and osteoblasts treated with each concentrate exhibited excellent cell viability. Interestingly, compared to cells treated with iPRF, cells treated with iBMAC demonstrated significantly greater migration potential. Furthermore, higher mRNA levels of transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), and collagen I (COL1) were observed in gingival fibroblasts treated with iBMAC than in those treated with iPRF. Compared with osteoblasts treated with iPRF, osteoblasts treated with iBMAC exhibited greater differentiation potential, as indicated by increased osteocalcin (OCN) expression and mineralization capability., Conclusion: The results of the in vitro study suggest that, compared with iPRF, iBMAC may promote wound healing and bone regeneration more effectively. However, further preclinical and clinical studies are needed to confirm the regenerative potential of iBMAC in the body., Competing Interests: Declarations. Conflict of interest: No competing financial interests exist. Ethical approval: The animal studies were performed after receiving approval of the Institutional Animal Care and Use Committee (IACUC) in XXX University (IACUC approval No. 20–08-01)., (© 2024. The Author(s).)

Background: Heparin-binding protein (HBP) levels have been linked to organ failure and may represent an inflammatory biomarker of sepsis. We found disseminated intravascular coagulation (DIC) is associated with higher HBP levels in patients and in in vivo and in vitro models. This prospective, single-center observational study investigated the effects and underlying mechanisms of HBP on the coagulation cascade in sepsis., Methods: 538 patients with sepsis from June 2016 to December 2019 were enrolled. Mechanisms underlying HBP and the coagulation system were investigated in human umbilical vein endothelial cells (HUVEC) and C57 mice., Results: Increased HBP was associated with sepsis-induced DIC. The optimal cutoff value was 37.5 ng/mL (sensitivity: 56 %, specificity: 65 %). Antithrombin-III (AT-III) activity, plasmin-a2 plasmin inhibitor complex (PIC), procalcitonin (PCT), hemoglobin, and HBP ≥37.5 ng/mL were associated with of DIC occurrence. In HUVECs &C57 mice models, Western blotting, qPCR, and immunohistochemistry analysis showed that the binding between HBP and TGF-β receptor 2 (TGFBR2) caused elevation of plasminogen activator inhibitor-1 (PAI-1) levels. Furthermore, we found that mice stimulated with HBP had higher levels of fibrinogen and D-dimer in the blood. HBP treatment caused the accumulation of fibrinogen in mice lung tissue. Treatment with TGFBR2-small interfering RNAs inhibited the effects., Conclusion: Patients with sepsis having HBP ≥37.5 ng/mL at admission were more likely to develop DIC. HBP upregulates the expression of fibrinogen and PAI-1 via TGFBR2 and the TGF-β signalling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Fibrotic cataracts, the most frequent complications after phacoemulsification, cannot be cured by drugs in clinic. The primary mechanism underlying the disease is the epithelial-mesenchymal transition (EMT). Cimifugin is a natural monomer component of traditional Chinese medicines. Previous researches have demonstrated the effect of cimifugin inhibiting EMT in the lung. The purpose of this work is to evaluate the impact of cimifugin on EMT in the lens and elucidate its precise mechanism. The pathogenesis of fibrotic cataracts was simulated using TGFβ2-induced cell model of EMT and the injury-induced anterior subcapsular cataract animal model. Through H&E staining and immunofluorescence of mice eyeballs, we discovered that cimifugin can inhibit the expansion of fibrotic lesions in vivo. Furthermore, at mRNA and protein levels, we confirmed that cimifugin can allay EMT of lens epithelial cells (LECs) in vitro and in vivo. Additionally, the inhibition of cimifugin on the activation of TGFβ-related signaling pathways was certified by immunoblot. HSP90β, the target of cimifugin, was predicted by network pharmacology and verified by drug affinity responsive target stability, the cellular thermal shift assay, and microscale thermophoresis. Moreover, co-immunoprecipitation revealed the interaction between HSP90β and TGFβ receptor (TGFβR) II. Together, our findings showed that by weakening the binding of HSP90β and TGFβRII, cimifugin suppressed the TGFβ signaling pathways to alleviate fibrotic cataracts. Cimifugin is a promising medication for the treatment of fibrotic cataracts., Competing Interests: Declaration of competing interests The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The aim of the present study was to investigate the role and mechanism of endoplasmic reticulum stress (ERS) in kidney injury caused by high‑fat diet (HFD). An obese mouse model was established via HFD feeding and intervention was performed by intraperitoneal injection of the ERS inhibitor salubrinal (Sal). Changes in the body and kidney weight and serum biochemical indices of the mice were determined. Hematoxylin and eosin and Masson staining were used to observe the pathological changes of renal tissues. Reverse transcription‑quantitative PCR and western blotting were used to observe the expression of ERS‑related proteins and TGF‑β/SMAD pathway‑related proteins. Immunohistochemistry was employed to explore the distribution of these proteins. Compared with those in the control group, the weight gain, lipid metabolism disorders and deterioration of renal function in the model group were greater. Malondialdehyde was elevated and superoxide dismutase was decreased in renal tissues. The mRNA and protein levels of TGF‑β1, SMAD2/3, α‑smooth muscle actin, collagen I, glucose‑regulated protein 78 and C/EBP‑homologous protein were markedly elevated, whereas SMAD7 was markedly decreased. Sal markedly inhibited the aforementioned effects. This investigation revealed a link between ERS and renal injury caused by HFD. ERS in HFD‑fed mice triggers renal fibrosis through the TGF‑β/SMAD pathway.

In gastric cancer treatment, cancer-associated fibroblasts (CAF) may significantly influence the efficacy of immune checkpoint inhibitors by modulating PD-L1 expression. However, the precise mechanisms remain unclear. This study aims to explore the relationship between CAF and PD-L1 expression, providing new insights for improving PD-L1-targeted therapies. Using primary fibroblasts, transcriptome sequencing, ChIP-qPCR, and a lung metastasis model, we discovered that CAF secrete lysyl oxidase (LOX), which activates the TGFβ signaling pathway in gastric cancer cells, thereby promoting insulin-like growth factor 1(IGF1) expression. Upregulation of IGF1 enhances gastric cancer cell migration, epithelial-mesenchymal transition (EMT), and glycolysis. Additionally, we found that lactate accumulation leads to lysine 18 lactylation on histone H3 (H3K18la), which enriches at the PD-L1 promoter region, thus promoting PD-L1 transcription. These findings suggest that CAF may diminish the effectiveness of PD-1/PD-L1 blockade immunotherapy through LOX-induced glycolysis and lactate accumulation. Consequently, we have constructed a model of the interactions among CAF, lactate, and PD-L1 in gastric cancer progression, providing new experimental evidence for PD-L1-based immunotherapy., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: Idiopathic pulmonary fibrosis (IPF) is a disease associated with aging, where increased oxidative stress accelerates the progression of pulmonary fibrosis (PF). The specific mechanisms through which oxidative stress intensifies PF are still not fully understood., Materials and Methods: In this study, we used bleomycin (BLM)-induced PF mouse model and TGF-β-induced collagen deposition cells for in vivo and in vitro experiments, respectively. Additionally, we employed BSO, a glutathione synthesis inhibitor, to induce excess reactive oxygen species (ROS)., Key Findings: Our findings revealed that heightened ROS production significantly exacerbated PF development in mice and increased collagen deposition in A549 cells. We also showed that cellular senescence was further intensified by the combined treatment of BSO with BLM or TGF-β, as indicated by the increased levels of p53 and p21, along with an increase in β-galactosidase-positive cells. Moreover, inflammatory responses, including inflammatory cells, inflammatory cytokines, and ROS levels were dramatically increased with the BSO and BLM or TGF-β combination. Mechanistically, we found that NLRP3 inflammasome was activated more significantly by the combined treatments of BSO with BLM or TGF-β. Inhibition of NLRP3 ameliorated the aging-related phenotype and reduced p53 and p21 expression. Furthermore, we showed that N-acetylcysteine (NAC) treatment significantly attenuated BLM or BLM plus BSO-enhanced PF in vivo., Significance: Our study demonstrates that elevated ROS levels contribute to the development of PF via NLRP3-mediated cellular senescence. We also provide that targeting oxidative stress might be an effective strategy for treating PF., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with limited therapeutic options. Fibroblast growth factor receptor-4 (FGFR4) is a known receptor for several paracrine fibroblast growth factors (FGFs). FGFR4 is also the main receptor for FGF19, an endocrine FGF that was demonstrated by our group to have antifibrotic properties in the lung. We aimed to determine whether FGFR4 could modulate pulmonary fibrogenesis. We assessed FGFR4 mRNA and protein levels in IPF and control lungs. In vitro, we determined the effect of transforming growth factor-β (TGF-β), endothelin-1, and platelet-derived growth factor (PDGF) on FGFR4 expression in human lung fibroblasts. We determined the effect of FGFR4 inhibition, using a specific pharmacological inhibitor (FGF401), or genetic deletion in murine embryonic fibroblasts (MEFs) on TGF-β-induced myofibroblastic differentiation. In vivo, we evaluated the development of bleomycin-induced lung fibrosis in Fgfr4 -deficient ( Fgfr4 - /- ) mice compared with wild-type littermates (WT) and after FGF401 treatment in WT mice compared with a control group receiving the solvent only. FGFR4 was decreased in IPF lungs, as compared with control lungs, at mRNA and protein levels. In vitro, FGFR4 was downregulated after treatment with TGF-β, endothelin-1, and PDGF. In vitro, FGFR4 inhibition by FGF401 prevented TGF-β1-induced collagen and ACTA2 increase in lung fibroblasts. Similar results were observed in Fgfr4 - /- MEFs. In vivo, FGFR4 genetic deficiency or FGFR4 pharmacological inhibition did not modulate bleomycin-induced pulmonary fibrosis. Our data suggest that FGFR4 exerts profibrotic properties by enhancing TGF-β signaling in vitro. However, the inhibition of FGFR4 is not sufficient to prevent the development of pulmonary fibrosis in vivo. NEW & NOTEWORTHY FGFR4 has been reported to have antifibrotic effects in the liver. We aimed to determine the involvement of FGFR4 during IPF. Our data suggest that FGFR4 exerts profibrotic properties by enhancing TGF-β signaling in vitro. However, the inhibition of FGFR4 is not sufficient to prevent the development of pulmonary fibrosis in vivo. To our knowledge, this is the first study to assess the profibrotic action of FGFR4 during pulmonary fibrosis.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths and the fifth most common cancer worldwide. Brown algae appeared to be a rich source of efficient and safe agents against many life-threatening diseases like cancer. Thus, the scope of this study was to investigate the therapeutic effects of Turbinaria ornata against experimentally induced HCC in a rat model. Accordingly, forty male albino rats were divided into four groups. HCC was induced by intraperitoneal injection with diethylnitrosamine (DENA) followed by carbon tetrachloride (CCL 4 ). After four weeks of DENA + CCL 4 injection and two weeks of treatment with Turbinaria ornata, rats were sacrificed to collect hepatic tissue and blood samples for histopathological observations and various biochemical markers such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alpha-fetoprotein (AFP), urea, creatinine, albumin (ALB), and alkaline phosphatase (ALP). Rats that were injected for four weeks with DENA + CCL 4 showed a significant increase in AFP levels, transforming growth factor-beta (TGF-β) and tumor necrosis factor-alpha (TNF-α), as well as a high percentage of malignant changes in hepatic tissues. The extension of malignant changes in the rat liver tissues was markedly reduced using Turbinaria ornata, as the treatment displayed liver patterns similar to that of the normal control rats. Furthermore, rats with HCC fed with Turbinaria ornata extract for two weeks showed decreasing levels of TGF-β and TNF-α. These findings demonstrate that Turbinaria ornata supplement can prevent HCC development in hepatic rats; however, the exact mechanism requires further investigation., Competing Interests: Declarations Ethical approval The current work is approved by the Ethical Committee of the University of Sadat City. All animal-handling actions as well as samples gathering and discarding protocol were performed in accordance with ARRIVE guidelines, including anesthesia and euthanasia methods at the Institutional Animal Care and Use Committee (IACUC) with oversight of the faculty of Veterinary Medicine, University of Sadat City, Sadat City, Egypt (Ethical approval number: VUSC-025-1-22). Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Graves' orbitopathy (GO), a manifestation of Graves' disease, is characterized by orbital fibroblast‑induced inflammation, leading to fibrosis or adipogenesis. Histone deacetylase (HDAC) serves a central role in autoimmune diseases and fibrosis. The present study investigated HDAC inhibition in orbital fibroblasts from patients with GO to evaluate its potential as a therapeutic agent. Primary cultured orbital fibroblasts were treated with an HDAC inhibitor, panobinostat, under the stimulation of IL‑1β, TGF‑β or adipogenic medium. Inflammatory cytokines, and fibrosis‑ and adipogenesis‑related proteins were analyzed using western blotting. The effects of panobinostat on HDAC mRNA expression were measured in GO orbital fibroblasts, and specific HDACs were inhibited using small interfering RNA transfection. Panobinostat significantly reduced the IL‑1β‑induced production of inflammatory cytokines and TGF‑β‑induced production of fibrosis‑related proteins. It also suppressed adipocyte differentiation and adipogenic transcription factor production. Furthermore, it significantly attenuated HDAC7 mRNA expression in GO orbital fibroblasts. In addition, the silencing of HDAC7 led to anti‑inflammatory and anti‑fibrotic effects. In conclusion, by inhibiting HDAC7 gene expression, panobinostat may suppress the production of inflammatory cytokines, profibrotic proteins and adipogenesis in GO orbital fibroblasts. The present in vitro study suggested that HDAC7 could be a potential therapeutic target for inhibiting the inflammatory, adipogenic and fibrotic mechanisms of GO.

Background: Hepatic fibrosis is a pathological process in a variety of acute or chronic liver injuries. Catalpol (CAT), an iridoid glycoside found in Rehmannia glutinosa, has several pharmacological properties, including anti-inflammatory, antidiabetic and anti-fibrotic effects. Nevertheless, there is currently no report on whether CAT regulates the aerobic glycolysis of hepatic stellate cells (HSCs) to inhibit liver fibrosis., Objective: This study aimed to investigate the protective effects of CAT on hepatic fibrosis and elucidate its underlying mechanisms., Methods: To explore whether CAT improved liver fibrosis in vivo and in vitro, hepatic fibrosis was induced to mice by intraperitoneally injecting carbon tetrachloride (CCl 4 ). Additionally, LX-2 cells were stimulated with transforming growth factor-β (TGF-β) to simulate fibrosis in vitro. Serum markers of liver injury were examined by using an automatic biochemical analyzer. Histopathological staining, Immunofluorescence (IF) staining, Western blot (WB) analysis, co-immunoprecipitation (Co-IP), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), etc. were employed to identify the targeting between CAT and EphA2 and detect the expression of aerobic glycolysis related proteins, fiber markers and signaling pathways that are responsible for CAT's anti-fibrotic effects of CAT., Results: Results showed that CAT significantly inhibited hepatic injury, fibrogenesis and inflammation in mice treated with CCl 4 . This was demonstrated by the enhancement of fibrosis markers, liver function indices, and histopathology. In addition, CAT significantly inhibited the activation of HSCs in TGF-β-induced LX-2 cells, as indicated by decreased proliferation, migration, and expression of collagen I and a-SMA. The study results also suggested that CAT may exert anti-fibrotic effects by inhibiting glycolysis in activated HSCs and in CCl 4 -treated mice. Mechanistically, CAT directly targets Ephrin type-A receptor 2 (EphA2) to reduce binding with focal adhesion kinases (FAK) and significantly inhibits the FAK/Src pathway. In addition, the pharmacological inhibition of EphA2 cannot further increase the therapeutic effects of CAT on liver fibrosis in vivo and in vitro., Conclusion: The study findings generally demonstrated that CAT presented a novel therapeutic method to treat hepatic fibrosis; this method which inhibits the aerobic glycolysis of activated HSCs through the EphA2/FAK/Src signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Dihydrotestosterone-induced androgen receptor activation and nuclear translocation was identified as the key event in androgen alopecia, which led to dermal papilla cell damage and hair growth cycle arrest. Inhibiting androgen receptor activation or nuclear translocation thus represents a potential therapeutic strategy for reducing dermal papilla cell damage and treating androgen alopecia., Purpose: To evaluate the effects of obacunone androgen alopecia and explore the potential underlying mechanisms., Methods: The effects of obacunone on androgen receptor activation and changes in the properties of dermal papilla cells were investigated. Meanwhile, the effects of obacunone on transforming growth factor-β-induced hair follicle stem cell damage and on androgen alopecia mice induced by dihydrotestosterone were evaluated., Results: Obacunone can competitively bind to androgen receptors with dihydrotestosterone, thereby alleviating the androgen receptor dimerization and nuclear translocation. The negative effects of dihydrotestosterone on dermal papilla cell apoptosis, senescence, and cycle arrest were alleviated by obacunone. Obacunone also counteracted the proliferation and apoptosis of transforming growth factor-β-mediated hair follicle stem cells. In mice with androgen alopecia, treatment with obacunone promoted mice hair growth and inhibited TGF-β/smad signaling., Conclusion: Thus, inhibiting androgen receptor dimerization was found to be an effective strategy for alleviating androgen alopecia. Obacunone follows a novel mechanism and holds potential as a drug candidate for androgen alopecia through inhibition of the dimerization of the androgen receptor. This targeting strategy may provide a new avenue for the development of new drugs different from the existing therapeutic approaches., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Apple polyphenols (APs) have gained attention for their various bioactivities, while no studies on anti-liver fibrosis activity are reported. This study evaluated the protective effect of APs on liver fibrosis using LPS-treated activated HSC-T6 cells and alcohol-treated liver fibrosis (ALF) mice. The results indicated that APs inhibited HSC-T6 cells activation in vitro and reduced the level of serum hyaluronic acid (HA) (p < 0.05), decreased fibrogenesis marker expression (p < 0.05), thereby alleviating ALF. In addition, APs (800 mg/kg b.w.) decreased the Firmicutes/Bacteroidetes ratio (p < 0.05) in ALF mice, inhibited LPS accumulation in the liver tissue and serum (p < 0.05), and significantly inhibited the TLR4/NF-κB/TGF-β signaling in mice liver. In conclusion, APs markedly ameliorated ALF, possibly by improving gut microbiota homeostasis, decreasing the translocation of bacterial endotoxins to the blood, and suppressing the TLR4/NF-κB/TGF-β signaling pathway, indicating its potential as lead compounds for functional foods and/or drugs against ALF., Competing Interests: Declarations Competing Interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Arteriovenous fistulae (AVF) are the preferred vascular access for hemodialysis in patients with end-stage kidney disease. Chronic kidney disease (CKD) is associated with endothelial injury, impaired AVF maturation, and reduced patency, as well as utilization. Because CKD is characterized by multiple pathophysiological processes that induce endothelial-to-mesenchymal transition (EndMT), we hypothesized that CKD promotes EndMT during venous remodeling and that disruption of endothelial TGF (transforming growth factor)-β signaling inhibits EndMT to prevent AVF failure even in the end-stage kidney disease environment., Methods: The mouse 5/6 nephrectomy and aortocaval fistula models were used. CKD was created via 5/6 nephrectomy, with controls of no (0/6) or partial (3/6) nephrectomy in C57BL/6J mice. AVF were created in mice with knockdown of TGF-βR1/R2 (TGF-β receptors type 1/2) in either smooth muscle cells or endothelial cells. AVF diameters and patency were measured and confirmed by serial ultrasound examination. AVF, both murine and human, were examined using Western blot, histology, and immunofluorescence. Human and mouse endothelial cells were used for in vitro experiments., Results: CKD accelerates TGF-β activation and promotes EndMT that is associated with increased AVF wall thickness and reduced patency in mice. Inhibition of TGF-β signaling in both endothelial cells and smooth muscle cells decreased smooth muscle cell proliferation in the AVF wall, attenuated EndMT, and was associated with reduced wall thickness, increased outward remodeling, and improved AVF patency. Human AVF also showed increased TGF-β signaling and EndMT., Conclusions: CKD promotes EndMT and reduces AVF patency. Inhibition of TGF-β signaling, especially disruption of endothelial cell-specific TGF-β signaling, attenuates EndMT and improves AVF patency in mouse AVF. Inhibition of EndMT may be a therapeutic approach of translational significance to improve AVF patency in human patients with CKD., Competing Interests: None.

Inhibitor of β-catenin and T-cell factor (ICAT) is a classical inhibitor of the Wnt signaling pathway. Nonetheless, our previous work found that ICAT is overexpressed in cervical cancer (CC), resulting in the augmentation of migration and invasion capabilities of CC cells. It remains unclear what molecular mechanism underlies this phenomenon. The interaction between cancer cells and the tumor microenvironment (TME) promotes the outgrowth and metastasis of tumors. Tumor-associated macrophages (TAMs) are a major constituent of the TME and have a significant impact on the advancement of CC. Consequently, our inquiry pertains to the potential of ICAT to facilitate tumor development through its modulation of the cervical TME. In this study, we first verified that ICAT regulated the secretion of cytokines interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) in CC cells, leading to M2-like macrophage polarization and enhancement of the migration and invasion of CC cells. Furthermore, the system of co-culturing human umbilical vein endothelial cells (HUVECs) with macrophages revealed that depending on the CC cells' overexpression or inhibition of ICAT, the vascular tube formation by HUVECs can be either increased or decreased. Overall, our study indicates that ICAT stimulates M2-like polarization of TAMs via upregulating IL-10 and TGF-β, which results in increased neovascularization, tumor metastasis, and immunosuppression in CC. In upcoming times, inhibiting crosstalk between CC cells and TAMs may be a possible strategy for CC therapy., (© 2024 Wiley Periodicals LLC.)

Pediatric adrenocortical tumors (ACT) are rare aggressive neoplasms with heterogeneous prognosis. MicroRNA (miRNA) signatures have been associated with cancer diagnosis, treatment response, and outcomes of several types of cancer. However, the role played by miRNAs in pediatric ACT has been poorly explored. In this study, we have evaluated the expression of miR-483-3p and miR-630 in 67 pediatric ACT and 19 non-neoplastic adrenal samples, the effects of the modulations of these miRNAs, and their relationship with the TGF-β pathway in the H295R and H295A cell lines. Deregulation of both miRNAs was related to survival and disease advanced stages and hence to patients' prognosis. Moreover, modified miR-483-3p and miR-630 in vitro expression decreased cell viability and colony formation capacity, changed how some genes of the TGF-β pathway, such as TGFBR1, TGFBR2, and SMAD7, are expressed, and altered Smad3, pSmad3, Smad 2/3, N-cadherin, and Vimentin protein expression. Besides that, when inhibition of the TGF-β pathway was combined with miR-630 overexpression or miR-483-3p silencing, cell viability and colony formation capacity decreased, and protein expression in the TGF-β pathway changed. Together, the data indicate that both miRNAs participate in the TGF-β pathway and are therefore potential markers for predicting the prognosis of patients with pediatric ACT., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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-β and Canonical Wnt/β-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-β/SMAD signaling pathway genes, and Canonical Wnt/β-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-β 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-β signaling pathway, TGF-β (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/β-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-β and IL-10 levels were higher in dhAT-MSCs) (p < 0.0001). Related to these results, IL-10 may induce TGF-β/SMAD and Canonical Wnt/β-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., Competing Interests: Compliance with Ethical Standards Conflict of interest The authors declare that they have no conflict of interest. Consent for Publication All the authors approved the publication., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cigarette smoking is associated with worse clinical outcomes in patients with chronic hepatitis B (CHB) infection, but the effects on hepatitis B surface antigen (HBsAg) seroclearance are unclear. This study aimed to investigate the effect of active smoking on HBsAg seroclearance (SC) and its impact on peripheral blood lymphocytes in patients with CHB infection. Longitudinal follow-up data was retrieved in 7833 antiviral-treated CHB subjects identified from a centralised electronic patient record database (Part 1). Phenotypic analysis of peripheral blood mononuclear cells (PBMCs) from 27 CHB-infected patients (6 active smokers; 13 with SC) was performed by flow cytometry to assess programmed death-1 (PD-1) expression and proportion of regulatory T cells (CD4 + CD25 + CD127 lo ). Effector function of HBV-specific T cells was examined by comparing granzyme B (GZMB) and transforming growth factor beta (TGFβ) production in undepleted PBMCs and Treg-depleted PBMCs after 7 days in vitro stimulation with HBV envelope protein overlapping peptides (Part 2). Over a median follow-up of 5 years, smoking was associated with lower probability of SC (aHR 0.70, 95% CI 0.57-0.87). PD-1 expression was increased in CD4 + T cells, CD8 + T cells and CD20 + B cells among smokers compared to non-smokers and positively correlated with pack years (all p < 0.05). Treg depletion led to partial functional recovery of HBV-specific T cells, with significantly bigger magnitude in smokers (p = 0.0451, mean difference = 4.68%) than non-smokers (p = 0.012, mean difference = 4.2%). Cigarette smoking is associated with lower chance of HBsAg seroclearance, higher PD-1 expression on lymphocytes, and impairment of effector functions of HBV-specific T cells in CHB., (© 2024 The Author(s). Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Idiopathic pulmonary fibrosis (IPF) is a lifelong lung disease, but there is no specific drug for treatment. Qingfei Xieding prescription (QF) is active in the treatment of lung diseases. More comprehensive mechanisms over how QF exhibits anti-pulmonary fibrosis need to be elucidated. TGF-β was used to construct a pulmonary fibrosis cell model in vitro . Bleomycin was applied to induce a lung tissue fibrosis model in mice in vivo . Flow cytometry was used to detect cellular ROS and lipid oxidation levels. Cell substructure was observed by Transmission Electron Microscopy. ELISA was used to determine the levels of inflammatory factors. HE staining, Masson staining and immunohistochemistry were performed to evaluate the degree of fibrosis. Western Blot assay was used to determine the protein expressions of different molecules. In TGF-β-exposed lung epithelial MLE-12 cell model, α-SMA and Collagen I were significantly elevated and cell viability was reduced. QF treatment restored the cell viability decreased by exogenous TGF-β. Ferroptosis inducer Erastin administration could reverse the beneficial effects such as lipid oxidation and ROS reduction caused by QF treatment. QF was proven to inhibit ferroptosis and alleviated the process of IPF by activating ACE2 signal axis. In bleomycin induced IPF mice model, QF altered lung coefficient, body weight and the expression of inflammatory factors, which were prevented by ferroptosis activator Erastin. QF was demonstrated to affect the ACE2-ERK signaling axis in vivo . QF alleviated idiopathic pulmonary fibrosis by regulating renin-angiotensin through blocking ferroptosis. This research offers evidence for the potentiality of QF in clinical application for IPF therapy., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Objective: Mechanical loading is an essential factor for the maintenance of joint inflammatory homeostasis and the sensitive catabolic-anabolic signaling cascade involved in maintaining cartilage tissue health. However, abnormal mechanical loading of the joint structural tissues can propagate joint metabolic dysfunction in the form of low-grade inflammation. To date, few studies have attempted to delineate the early cascade responsible for the initiation and perpetuation of stress-mediated inflammation and cartilage breakdown in human joints., Design: Fifteen healthy human male participants performed a walking paradigm on a cross-tilting treadmill platform. Blood samples were collected before exercise, after 30 minutes of flat walking, after 30 minutes of tilted walking, and after an hour of rest. Serum concentrations of the following biomarkers were measured: interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor alpha (TNF)-α, matrix metalloproteinase (MMP)-1, MMP-3, MMP-9, MMP-13, transforming growth factor beta (TGF)-β, tissue inhibitor of matrix metalloproteinase 1 (TIMP)-1, and cartilage oligomeric protein (COMP)., Results: Luminex Multiplex analysis of serum showed increased concentrations of COMP, IL-1β, TNF-α, IL-10, and TGF-β from samples collected after flat and cross-tilted treadmill walking compared to baseline. Serum concentrations of MMP-1 and MMP-13 also increased, but primarily in samples collected after tilted walking. Pearson's correlation analysis showed positive correlations between the expression of COMP, TNF-α, IL-10, and MMP-13 at each study timepoint., Conclusion: Stress-mediated increases in serum COMP during exercise are associated with acute changes in pro and anti-inflammatory molecular activity and subsequent changes in molecules linked to joint tissue remodeling and repair., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Sjogren's syndrome (SS) is a chronic, progressive autoimmune disorder characterized by gland fibrosis. We previously found a close correlation between gland fibrosis and the expression of G protein-coupled receptor kinase 2 (GRK2). In this study we explored the pathological and therapeutic significance of GRK2 in SS. Submandibular gland (SMG) antigen-induced SS mouse model was established in WT and GRK2 +/- mice. We showed that the expression levels of GRK2 were significantly up-regulated in glandular tissue and positively correlated with fibrotic morphology in SS patients and mice. Hemizygous knockout of GRK2 significantly inhibited the gland fibrosis. In mouse salivary gland epithelial cells (SGECs), we demonstrated that GRK2 interacted with Smad2/3 to positively regulate the activation of TGF-β-Smad signaling with a TGF-β-GRK2 positive feedback loop contributing to gland fibrosis. Hemizygous knockout of GRK2 attenuated TGF-β-induced collagen I production in SGECs in vitro and hindered gland fibrosis in murine SS though preventing Smad2/3 nuclear translocation. Around 28 days post immunization with SMG antigen, WT SS mice were treated with a specific GRK2 inhibitor paroxetine (Par, 5 mg·kg -1 ·d -1 , i.g. for 19 days). We found that Par administration significantly attenuated gland fibrosis and alleviated the progression of SS in mice. We conclude that genetic knockdown or pharmacological inhibition of GRK2 significantly attenuates gland fibrosis and alleviates the progression of SS. GRK2 binds to Smad2/3 and positively regulates the activation of TGF-β-Smad signaling. A TGF-β-GRK2 positive feedback loop contributes to gland fibrosis. Our research points out that GRK2 could be a promising therapeutic target for treating SS., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Iguratimod is a novel synthetic, small-molecule immunosuppressive agent used to treat rheumatoid arthritis. Through ongoing exploration of its role and mechanisms of action, iguratimod has been observed to have antifibrotic effects in the lung and skin; however, its effect on renal fibrosis remains unknown. This study aimed to investigate whether iguratimod could affect renal fibrosis progression. Three different concentrations of iguratimod (30 mg/kg/day, 10 mg/kg/day, and 3 mg/kg/day) were used to intervene in unilateral ureteral obstruction (UUO) model mice. Iguratimod at 10 mg/kg/day was observed to be effective in slowing UUO-mediated renal fibrosis. In addition, stimulating bone marrow-derived macrophages with IL-4 and/or iguratimod, or with TGF-β and iguratimod or SRC inhibitors in vitro , suggested that iguratimod mitigates the progression of renal fibrosis in UUO mice, at least in part, by inhibiting the IL-4/STAT6 signaling pathway to attenuate renal M2 macrophage infiltration, as well as by impeding SRC activation to reduce macrophage-myofibroblast transition. These findings reveal the potential of iguratimod as a treatment for renal disease.

Transforming growth factor-β (TGFβ) and FoxP3 regulatory T cells (Treg) are involved in human breast carcinogenesis. This topic is not well documented in canine mammary tumors (CMT). In this work, the tumoral TGFβ expression was assessed by immunohistochemistry in 67 malignant CMT and its correlation to previously determined FoxP3, VEGF, and CD31 markers and other clinicopathologic parameters was evaluated. The high levels of TGFβ were statistically significantly associated with skin ulceration, tumor necrosis, high histological grade of malignancy (HGM), presence of neoplastic intravascular emboli and presence of lymph node metastases. The observed levels of TGFβ were positively correlated with intratumoral FoxP3 (strong correlation), VEGF (weak correlation) and CD31 (moderate correlation). Tumors that presented a concurrent high expression of TGFβ/FoxP3, TGFβ/VEGF, and TGFβ/CD31 markers were statistically significantly associated with parameters of tumor malignancy (high HGM, presence of vascular emboli and nodal metastasis). Additionally, shorter overall survival (OS) time was statistically significantly associated with tumors with an abundant TGFβ expression and with concurrent high expression of TGFβ/FoxP3, TGFβ/VEGF, and TGFβ/CD31. The presence of lymph node metastasis increased 11 times the risk of disease-related death, arising as an independent predictor of poor prognosis in the multivariable analysis. In conclusion, TGFβ and Treg cells seem involved in tumor progression emerging as potential therapeutic targets for future immunotherapy studies.

Objectives: Aplastic anemia (AA) is one of the immune-mediated bone marrow failure disorders caused by multiple factors, including the inability of CD4 + CD25 + regulatory T cells (Tregs) to negatively regulate cytotoxic T lymphocytes (CTLs). Dioscin is a natural steroid saponin that has a similar structure to steroid hormones. The purpose of this study is to look into the effect of Dioscin on the functions of CD4 + CD25+ Tregs in the AA mouse model and explore its underlying mechanism. Methods: To begin with, bone marrow failure was induced through total body irradiation and allogeneic lymphocyte infusion using male Balb/c mice. After 14 consecutive days of Dioscin orally administrated, the AA mouse model was tested for complete blood counts, HE Staining of the femur, Foxp3, IL-10 and TGF-β. Then CD4 + CD25+ Tregs were isolated from splenic lymphocytes of the AA mouse model, Tregs and the biomarkers and cytokines of Tregs were measured after 24 h of Dioscin intervention treatment in vitro. Results: Dioscin promotes the expression of Foxp3, IL-10, IL-35 and TGF-β, indicating its Tregs-promoting properties. Mechanistically, the administration of Dioscin resulted in the alteration of CD152, CD357, Perforin and CD73 on the surface of Tregs, and restored the expression of Foxp3. Conclusion: Dioscin markedly attenuated bone marrow failure, and promoted Tregs differentiation, suggesting the maintenance of theimmune balance effect of Dioscin. Dioscin attenuates pancytopenia and bone marrow failure via its Tregs promotion properties.

Background: Fibrosis is an important pathological feature of endometriotic lesions of all subtypes. Fibrosis is present in and around endometriotic lesions, and a central role in its development is played by myofibroblasts, which are cells derived mainly after epithelial-to-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT). Transforming growth factor-β (TGF-β) has a key role in this myofibroblastic differentiation. Myofibroblasts deposit extracellular matrix (ECM) and have contracting abilities, leading to a stiff micro-environment. These aspects are hypothesized to be involved in the origin of endometriosis-associated pain. Additionally, similarities between endometriosis-related fibrosis and other fibrotic diseases, such as systemic sclerosis or lung fibrosis, indicate that targeting fibrosis could be a potential therapeutic strategy for non-hormonal therapy for endometriosis., Objective and Rationale: This review aims to summarize the current knowledge and to highlight the knowledge gaps about the role of fibrosis in endometriosis. A comprehensive literature overview about the role of fibrosis in endometriosis can improve the efficiency of fibrosis-oriented research in endometriosis., Search Methods: A systematic literature search was performed in three biomedical databases using search terms for 'endometriosis', 'fibrosis', 'myofibroblasts', 'collagen', and 'α-smooth muscle actin'. Original studies were included if they reported about fibrosis and endometriosis. Both preclinical in vitro and animal studies, as well as research concerning human subjects were included., Outcomes: Our search yielded 3441 results, of which 142 studies were included in this review. Most studies scored a high to moderate risk of bias according to the bias assessment tools. The studies were divided in three categories: human observational studies, experimental studies with human-derived material, and animal studies. The observational studies showed details about the histologic appearance of fibrosis in endometriosis and the co-occurrence of nerves and immune cells in lesions. The in vitro studies identified several pro-fibrotic pathways in relation to endometriosis. The animal studies mainly assessed the effect of potential therapeutic strategies to halt or regress fibrosis, for example targeting platelets or mast cells., Wider Implications: This review shows the central role of fibrosis and its main cellular driver, the myofibroblast, in endometriosis. Platelets and TGF-β have a pivotal role in pro-fibrotic signaling. The presence of nerves and neuropeptides is closely associated with fibrosis in endometriotic lesions, and is likely a cause of endometriosis-associated pain. The process of fibrotic development after EMT and FMT shares characteristics with other fibrotic diseases, so exploring similarities in endometriosis with known processes in diseases like systemic sclerosis, idiopathic pulmonary fibrosis or liver cirrhosis is relevant and a promising direction to explore new treatment strategies. The close relationship with nerves appears rather unique for endometriosis-related fibrosis and is not observed in other fibrotic diseases., Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Although it is an effective treatment for acute myeloid leukemia (AML), chemotherapy leads to myelosuppression and poor hematopoietic reconstruction. Hematopoiesis is regulated by bone marrow (BM) endothelial cells (ECs), and BM ECs are dysfunctional in acute leukemia patients with poor hematopoietic reconstitution after allogenic hematopoietic stem cell transplantation. Thus, it is crucial to explore the underlying mechanism of EC impairment and establish strategies for targeted therapy. TGF-β signaling was found to be upregulated in ECs from AML patients in complete remission (CR ECs) and led to CR EC damage. Administration of a TGF-β inhibitor rescued the dysfunction of ECs caused by TGF-β1 expression in vitro, especially their hematopoiesis-supporting ability. Moreover, inhibition of TGF-β expression repaired the BM EC damage triggered by chemotherapy in both AML patients in vitro and in an AML-CR murine model, and restored normal hematopoiesis without promoting AML progression. Mechanistically, our data reveal alterations in the transcriptomic pattern of damaged BM ECs, accompanied by the overexpression of downstream molecules TGF-βR1, pSmad2/3, and functional genes related to adhesion, angiogenesis suppression and pro-apoptosis. Collectively, our findings reveal for the first time that the activation of TGF-β signaling leads to BM EC dysfunction and poor hematopoietic reconstitution. Targeting TGF-β represents a potential therapeutic strategy to promote multilineage hematopoiesis, thereby benefiting more cancer patients who suffer from myelosuppression after chemotherapy., Competing Interests: Declaration of competing interest The authors wish to confirm that there are no known conflicts of interest associated with this publication. All co-authors have seen and approved this version of the manuscript and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Cyclophosphamide (CP)-induced hepatotoxicity is a significant problem in clinical settings. This study aimed to evaluate the protective effect of levocabastine (LEV) on CP-induced hepatotoxicity in Swiss albino mice., Methods and Results: Mice were given CP (toxic drug) 200 mg/kg, i.p., once on the 7th day, and LEV 50 and 100 µg/kg, i.p., and fenofibrate (FF) 80 mg/kg, p.o., daily for 14 days. On the 15th day, blood and liver samples were collected to assess biological parameters. CP 200 mg/kg caused hepatotoxicity due to oxidative stress, inflammation, apoptosis, and fibrosis as manifested by a reduction in catalase, reduced glutathione (GSH), superoxide dismutase (SOD), and an increase in thiobarbituric acid reactive substance (TBARS), nitrite, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), transforming growth factor-beta 1 (TGF-β1), interleukin-1β (IL-1β), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) levels. Cleaved caspase-3 and nuclear factor kappa-B (NF-κB) expression was also increased and nuclear factor erythroid 2-related factor (Nrf2) expression was decreased as confirmed by Immunohistochemical analysis. It also caused histopathological abnormalities and fibrosis as manifested by Hematoxylin-Eosin (H&E) and Masson's trichrome (MT) staining. These alterations were returned to almost normal when treated with LEV 100 µg/kg and FF 80 mg/kg. Thus, LEV protected CP-induced hepatotoxicity by reversing inflammation, apoptosis, fibrosis, oxidative stress, hepatic injury, and histopathological damages., Conclusion: LEV can be helpful as an adjuvant in cancer patients who are on CP treatment, to minimize toxicity. However, its role in in-vivo cancer model is further needed to be confirmed., Competing Interests: Declarations. Ethical approval: The experiment was approved by the Institutional Animal Ethics Committee (IAEC) with the protocol numbers 1930/1990. It complies with the ARRIVE guidelines and is carried out in accordance with the U.K. Animals (Scientific Procedures) Act, 1986 and associated guidelines, EU Directive 2010/63/EU for animal experiments, or the National Institutes of Health guide for the care and use of Laboratory animals (NIH Publications No. 8023, revised 1978). Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Osteoarthritis (OA) is the most common degenerative joint disease characterized by cartilage degradation and various degrees of inflammation in the synovium. Growing evidence highlights that neutrophil extracellular vesicles (EVs) play a protective role in arthritic joints by promoting the resolution of inflammation and the synthesis of proteoglycans in cartilage. However, this homeostatic function is dependent on the activation state of neutrophils and the surrounding environment/tissues. Hence, we explored the chondroprotective functions of neutrophil-derived EVs under different stimulation conditions and the underlying molecular mechanism., Methods: Human blood-derived neutrophils, murine bone marrow-derived neutrophils, C-28I2 cells and primary chondrocytes were used. Neutrophils were stimulated with different cytokines, and their EVs were isolated for chondrocyte stimulation and further subjected to RNA-sequencing analysis. Two experimental murine OA models were used, and the treatment was performed by intraarticular injections., Results: Conditioned medium from neutrophils stimulated with TGF-β (N-β) had the greatest inhibitory effect on the expression of catabolic factors in stimulated chondrocytes. These protective effects were not impaired when conditioned medium of N-β from AnxA1-deficient mice was used. Consistent with these results, EVs isolated from N-β significantly reduced the expression of catabolic factors in stimulated chondrocytes. Bulk RNA-seq analysis revealed that secreted frizzled-related protein 5 (SFRP5) is upregulated in N-β-EV-stimulated chondrocytes. Furthermore, recombinant SFRP5 treatment significantly reduced the expression of catabolic factors in vitro and catabolic process in experimental murine OA models., Conclusions: The current study emphasizes the potential therapeutic application of neutrophils in OA and provides new knowledge on the molecular mechanisms underlying their function., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Inflammatory cytokines are pivotal to immune responses. Upon cytokine exposure, cells enter an "alert state" that enhances their visibility to the immune system. Here, we identified an alert-state subpopulation of ribosomes defined by the presence of the P-stalk. We show that P-stalk ribosomes (PSRs) are formed in response to cytokines linked to tumor immunity, and this is at least partially mediated by P-stalk phosphorylation. PSRs are involved in the preferential translation of mRNAs vital for the cytokine response via the more efficient translation of transmembrane domains of receptor molecules involved in cytokine-mediated processes. Importantly, loss of the PSR inhibits CD8+ T cell recognition and killing, and inhibitory cytokines like transforming growth factor β (TGF-β) hinder PSR formation, suggesting that the PSR is a central regulatory hub upon which multiple signals converge. Thus, the PSR is an essential mediator of the cellular rewiring that occurs following cytokine exposure via the translational regulation of this process., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The ALK5 (TGFBR1) receptor serine/threonine kinase transduces TGF-β (Transforming Growth Factor beta) signaling to activate SMAD2/3-dependent and -independent pathways. Here, we aimed to determine the functional consequences of ALK5 mutations in human endometrial cancer (EC). Somatic mutation data were retrieved from publicly available databases. Using seven in silico algorithms, 78.5% (11 of 14) of ALK5 kinase domain mutations in EC, including A230V-ALK5, were predicted to impact protein function. For in vitro studies, we focused on A230V-ALK5 because it was the only mutated residue located within the ATP-binding pocket, which is an important region for both ATP-binding and binding of ATP-competitive inhibitors. Constructs expressing wildtype-, constitutively-active-, kinase-dead-, or mutant A230V-ALK5, were transfected into NIH/3T3 cells. Following TGF-β1 stimulation, transient exogenous expression of A230V-ALK5 resulted in attenuated SMAD2/3 signal transduction and reduced AKT activation. We further showed that the A230V-ALK5 mutant had reduced stability resulting from increased ubiquitin-dependent protein degradation. Our structural modeling predicted that SB-431542, a small molecule ATP-competitive inhibitor of ALK5, binds to the A230V-ALK5 mutant with reduced affinity compared to wildtype-ALK5. We therefore examined the inhibitory effect of SB-431542 and galunisertib on wildtype- and mutant-ALK5 activity using a Smad-binding element (SBE) luciferase reporter assay combined with TGF-β1 stimulation, in NIH/3T3 cells and HEC-265 EC cells. SBE luciferase activity in A230V-ALK5 transfected cells was inhibited less by SB-431542 and galunisertib than in wildtype-ALK5 transfected cells indicating that A230V-ALK5 is less sensitive to inhibition by these agents than wildtype-ALK5, potentially due to changes in SB-431542/A230V-ALK5 binding affinity. Our findings are novel and show that A230V-ALK5 is a partial loss-of-function mutant that attenuates TGF-β1 signal transduction and has reduced sensitivity to ALK5 small molecule inhibitors., Competing Interests: Conflicts of Interest Disclosures: Dr. Eun-Jeong Yu has no conflicts of interest. Dr. Daphne W. Bell is an inventor on US patent no. 7,294,468, which has been licensed and provides royalty income for work performed outside the current study. "This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Purpose: This study investigates the effects of hexagonal microtextured titanium sheets on fibroblast growth and collagen synthesis, crucial factors in anastomotic healing., Materials and Methods: Hexagonal titanium sheets were fabricated using a laser microtextured machine. Mouse fibroblastic embryonic stem cells (NIH/3T3) were cultured on these sheets. Cell proliferation was assessed using a CCK8 assay, and expression of TGF-β/Smad pathway-related genes and collagen types I and III was evaluated through qRT-PCR and western blot., Results: Hexagonal titanium sheets significantly enhanced fibroblast growth and collagen synthesis. The 50-30 group, with the smallest contact angle (48 ± 2.3°), exhibited the highest cell growth rates by CCK8 assay. Gene expression analysis revealed that TGF-β1, Smad2, Smad3, Smad4, and COL1A1 were significantly upregulated in the 50-30 group on day 7. Meanwhile, type I collagen expression was significantly increased in the 50-30 group on day 7 by western blot analysis., Conclusion: Our findings demonstrate that laser-fabricated hexagonal microtextured titanium sheets enhance hydrophilicity and promote fibroblast growth, activating the TGF-β/Smad pathway to facilitate collagen synthesis. These results have important implications for tissue repair and regeneration., Competing Interests: Declarations. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The formation of transcription regulatory complexes by the association of Smad4 with Smad2 and Smad3 (Smad2/3) is crucial in the canonical TGFβ pathway. Although the central requirement of Smad4 as a common mediator is emphasized in regulating TGFβ signaling, it is not obligatory for all responses. The role of Smad2/3 independently of Smad4 remains understudied. Here, we introduce a stepwise paradigm in which Smad2/3 regulate the lineage priming and differentiation of mouse embryonic stem cells (mESCs) by collaboration with different effectors. During the naïve-to-primed transition, Smad2/3 upregulate DNA methyltransferase 3b (Dnmt3b), which establishes the proper DNA methylation patterns and, in turn, enables Smad2/3 binding to the hypomethylated centers of promoters and enhancers of epiblast marker genes. Consequently, in the absence of Smad2/3, Smad4 alone cannot initiate epiblast-specific gene transcription. When primed epiblast cells begin to differentiate, Dnmt3b becomes less actively engaged in global genome methylation, and Smad4 takes over the baton in this relay race, forming a complex with Smad2/3 to support mesendoderm induction. Thus, mESCs lacking Smad4 can undergo the priming process but struggle with the downstream differentiation. This work sheds light on the intricate mechanisms underlying TGFβ signaling and its role in cellular processes., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

While the prevalence of cancer-associated thrombosis (CAT) is high in cancer patients, its molecular mechanisms have not been fully elucidated. Moreover, the risks of recurrent CAT events and mortality remain high in cancer patients despite the introduction of anticoagulant/antiplatelet therapy. Here, we discuss the possibility that increased plasmin activity driven by anticoagulant/antiplatelet treatment might be the major mechanism responsible for the activation of an excess of cancer-derived transforming growth factor-beta (TGF-β) originating from cancer cells and the tumour microenvironment. Hence, high coagulation and fibrinolysis rates in cancer patients may be linked to high rates of TGF-β activation, especially the excess of TGF-β derived from cancer cells. In turn, high TGF-β activation could contribute directly to maintaining high thrombotic risk and CAT recurrence in cancer patients since TGF-β signalling increases gene expression and secretion of the fibrinolysis inhibitor plasminogen activator inhibitor 1 (PAI1). Thus, TGF-β could directly contribute to the high number of deaths among patients with cancer experiencing CAT, despite anticoagulant/antiplatelet treatment. In a longer-term perspective, increased TGF-β activation, by supporting a pro-coagulant cancer microenvironment, might also accelerate cancer progression. This review aims to discuss the published evidence that might support the scenario described above, and to put forward the hypothesis that cancer patients experiencing CAT events would largely benefit from anti-TGF-β therapy., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Remote limb ischemic pre-conditioning (RIPreC) can invoke potent renal protection. The involvement of oxidative stress and inflammatory pathways in renal ischemia/reperfusion injury (I/RI) was also confirmed. This study was designed to investigate the RIPreC effects on IRI-induced kidney dysfunction in rats through NFĸB/TNF-α/TGF-ꞵ/apelin signaling pathway., Methods: Renal I/RI was induced by occluding the kidney arteries for 45 min, then reperfusion for 24 h. Four similar cycles of left femoral artery ischemia (2 min)/reperfusion (3 min) before the onset of kidney ischemia were performed to create RIPreC. Animals were randomly divided into three groups: sham, I/R, and RIPreC + I/R. Following the reperfusion phase, urine and blood samples were taken, and the kidney was removed for functional, molecular, and histological examination., Results: When compared to sham rats, renal IRI resulted in decreased creatinine clearance and increased sodium fractional excretion, lower antioxidant enzyme activities, higher malondialdehyde content and higher nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), transforming growth factor-betta (TGF-β), and Apelin expression levels, and histologically damaged kidney tissue. All of the alterations, as mentioned earlier, were alleviated using the RIPreC treatment., Conclusion: Thus, RIPreC can protect against renal dysfunction after renal I/RI via modulation of the TNF-α/NF-κB/TGF-ꞵ/Apelin signaling pathway and strengthening the antioxidant defense system., Competing Interests: Declarations. Institutional review board statement: The animal study protocol was approved by the Ethics Committee of Shiraz University of Medical Sciences (ethical code: IR.SUMS.REC.1398.932). All methods are reported in accordance with the ARRIVE guidelines. Informed consent: Not Applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Overcoming resistance to therapy is a major challenge in castration-resistant prostate cancer (CRPC). Lineage plasticity towards a neuroendocrine phenotype enables CRPC to adapt and survive targeted therapies. However, the molecular mechanisms of epigenetic reprogramming during this process are still poorly understood. Here we show that the protein kinase PKCλ/ι-mediated phosphorylation of enhancer of zeste homolog 2 (EZH2) regulates its proteasomal degradation and maintains EZH2 as part of the canonical polycomb repressive complex (PRC2). Loss of PKCλ/ι promotes a switch during enzalutamide treatment to a non-canonical EZH2 cistrome that triggers the transcriptional activation of the translational machinery to induce a transforming growth factor β (TGFβ) resistance program. The increased reliance on protein synthesis creates a synthetic vulnerability in PKCλ/ι-deficient CRPC., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Hepatic metastasis is the primary cause of colorectal cancer (CRC)-induced death. Our previous results showed the anti-metastatic effects of Coptidis rhizoma using in vitro model., Aim: The present study aimed to investigate whether berberine, the main active compound of C. rhizoma, inhibits colon-liver metastasis in an animal model, and to elucidate the underlying mechanisms., Methods: Murine colon carcinoma (CT26) tumor tissue was implanted into the cecum of balb/c mice with/without oral administration of berberine (100 mg/kg) for 21 days, after which liver metastasis was evaluated. In addition, the pharmacological actions of berberine were explored using 5-fluorouracil-resistant human colon cancer cells (HCT116/R)., Result: The administration of berberine significantly decreased the number of tumor nodules in the liver, while significant activation of E-cadherin (an epithelial marker), and suppression of vimentin, Snail and TGF-β (mesenchymal markers) were observed in primary colon tumor tissues. Berberine treatment also notably lowered the levels of inflammatory cytokines (TGF-β, TNF- α, IL-6 and IL-1β) in the blood. In HCT116/R cells, berberine significantly inhibited migration and invasion and modulated the expression of TGF-β and representative molecules related to its pathway. The results obtained with a TGF-β inhibitor (SB431542) and a TGF-β siRNA, strongly suggest that the mechanism of action of berberine is linked to TGF-β signaling., Conclusion: In conclusion, berberine evidently possess an anti-colon-liver metastatic effect, and its underlying mechanisms involve the inhibition of epithelial-mesenchymal transition (EMT) through the TGF-β signaling pathway. Thus, we cautiously propose the pharmacological potential of berberine in drug research studies targeting hepatic metastasis from CRC., Competing Interests: Declarations Ethics approval and consent to participate The animal study was reviewed and approved by Institutional Animal Care and Use Committee Daejeon University (DJUARB2022-002). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Hepatic stellate cells (HSCs) are pericytes of the liver responsible for liver fibrosis and cirrhosis, which are the end stages of chronic liver diseases. TGF-β activates HSCs, leading to the differentiation of myofibroblasts in the process of liver fibrosis. While the heterogeneity of HSCs is appreciated in the fibrotic liver, it remains elusive which HSC subsets mainly contribute to fibrosis. Here, we show that the expression of the pericyte marker FoxD1 specifically marks a subset of HSCs in FoxD1-fate tracer mice. HSCs fate-mapped by FoxD1 were preferentially localized in the portal and peripheral areas of both the homeostatic and fibrotic liver induced by carbon tetrachloride. Furthermore, the deletion of Cbfβ, which is necessary for TGF-β signaling, in FoxD1-expressing cells ameliorated liver fibrosis. Thus, we identified an HSC subset that preferentially responds to liver injuries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Marfan syndrome (MFS) is an autosomal dominant connective-tissue disorder affecting multiple systems, such as skeletal, cardiovascular, and ocular systems. MFS is predominantly caused by mutations in the FBN1 gene, which encodes the fibrillin-1 protein, crucial for connective-tissue integrity. FBN1 mutations lead to defective fibrillin, resulting in structurally compromised connective tissues. Additionally, these mutations cause aberrant TGF-β expression, contributing to vascular issues and increased susceptibility to radiation-induced fibrosis. Studies about the potential radiosensitivity of MFS are rare and generally limited to case reports. Here, we aimed to investigate the radiation-induced ATM nucleo-shuttling (RIANS) model to explore the molecular and cellular radiation response in fibroblasts from MFS patients. The results showed that the MFS fibroblast cell lines tested are associated with moderate but significant radiosensitivity, high yield of micronuclei, and impaired recognition of DNA double-strand breaks (DSBs) caused by a diminished RIANS. The diminished RIANS is supported by the sequestration of ATM protein in the cytoplasm not only by mutated FBN1 protein but also by overexpressed TGF-β. This report is the first molecular and cellular characterization of the radiation response of MFS fibroblasts and highlights the importance of the FBN1-TGF-β complex after irradiation.

Helicobacter pylori (H. pylori) infection is widely acknowledged as the primary risk factor for gastric cancer, facilitating its progression via the Correa cascade. Concurrently, Hexokinase Domain Containing 1 (HKDC1) has been implicated in the mediation of aerobic glycolysis, contributing to tumorigenesis across various cancers. However, the precise role of HKDC1 in the inflammatory transformation associated with H. pylori-induced gastric cancer remains elusive. In this study, transcriptome sequencing revealed a significant correlation between HKDC1 and H. pylori-induced gastric cancer. Subsequent validation using qRT-PCR, immunohistochemistry, and Western blot analysis confirmed elevated HKDC1 expression in both human and murine gastritis and gastric tumors. Moreover, in vitro and in vivo experiments demonstrated that H. pylori infection up-regulates TGF-β1 and p-Smad2, thereby activating the epithelial-mesenchymal transition (EMT) pathway, with HKDC1 playing a pivotal role. Suppression of HKDC1 expression or pharmacological inhibition of TGF-β1 reversed EMT activation, consequently reducing gastric cancer cell proliferation and metastasis. These results underscore HKDC1's essential contribution to H. pylori-induced gastric cancer progression via EMT activation., Competing Interests: Declarations Competing interests The authors have no relevant financial or non-financial interests to disclose. Ethics approval This study was conducted in accordance with the principles outlined in the Declaration of Helsinki. Ethical approval was obtained from the Ethics Committee of Anhui Medical University. Consent to participate Written informed consent was obtained from each patient. The study complies with all ethical regulations regarding human participants. Consent to publish The authors confirm that all human research participants provided informed consent for the publication of the images included in Tables 1 and 2., (© 2024. The Author(s).)

Acanthamoeba spp. are facultative, opportunistic pathogens that are found in diverse environments. In the hosts, they lead to multi-organ disease. Recent studies reported that they may induce changes in the kidneys of hosts. The aim of the study was to determine the influence of Acanthamoeba sp. on hypoxia and collagen deposition in the kidneys of immunocompetent and immunosuppressed mice infected with Acanthamoeba sp. The results strongly suggest that Acanthamoeba sp. induces hypoxia in mice with normal and reduced immune response by increasing gene and/or protein expression of HIF1α as well as HIF2α. Additionally, the activation of these factors is probably induced via NOX2/ROS. Hypoxia promotes vessel formation, and we found that angiogenesis occurs in the kidneys of mice infected with the parasite regardless of their immunological status. The proangiogenic factors released in hypoxic conditions cause modulation and inflammation in the kidney cells, which in turn leads to collagen deposition via TGF-β. This work reveals mechanisms occurring in the hosts infected with Acanthamoeba sp., highlights as well as supports the relevance of pathophysiology in the kidneys in hosts with systematic acanthamoebiasis., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Ligands of the TGF-β/BMP superfamily are crucially involved in the regulation of growth, patterning and organogenesis and can act as long-range morphogens. Essential for understanding TGF-β/BMP signaling dynamics and regulation are tools that allow monitoring and manipulating pathway components at physiological expression levels and endogenous spatiotemporal patterns. We used genome engineering to generate a comprehensive library of endogenously epitope- or fluorescent-tagged versions of receptors, co-receptors, transcription factors and key feedback regulators of the Drosophila BMP and Activin signaling pathways. We demonstrate that the generated alleles are biologically active and can be used for assessing tissue and subcellular distribution of the corresponding proteins. Furthermore, we show that the genomic platforms can be used for in locus structure-function and cis-regulatory analyses. Finally, we present a complementary set of protein binder-based tools, which allow visualization as well as manipulation of the stability and subcellular localization of epitope-tagged proteins, providing new tools for the analysis of BMP signaling and beyond., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

TGF-β is a crucial regulator in tumor microenvironment (TME), especially for myofibroblastic cancer-associated fibroblasts (myCAFs). The myCAFs can be motivated by TGF-β signaling to erect pro-tumor TME, meanwhile, myCAFs overexpress TGF-β to mediate the crosstalk between tumor and stromal cells. The blockade of TGF-β can break cancer-associated fibroblasts barrier, consequently opening the access for drugs into tumor. The TGF-β is a promising target in anti-tumor therapy. Herein, we introduced a two-stage combination therapy (TC-Therapy), including TGF-β receptor I inhibitor SB525334 (SB) and cytotoxicity agent docetaxel micelle (DTX-M). We found that SB and DTX-M synergistically inhibited myCAFs proliferation and elevated p53 protein expression in BxPC-3/3T3 mixed cells. Gene and protein tests demonstrated that SB cut off TGF-β signaling via receptor blockade and it did not arouse TGF-β legend compensated internal autocrine. On the contrary, two agents combined decreased TGF-β secretion and inhibited myCAFs viability marked by α-SMA and FAPα. TC-Therapy was applied in BxPc-3/3T3 mixed tumor-bearing mice model. After TC-Therapy, the α-SMA + / FAPα + myCAFs faded increasingly and collagenous fibers mainly secreted by myCAFs decreased dramatically as well. More than that, the myCAFs barrier breaking helped to normalize micro-vessels and paved way for micelle penetration. The TGF-β protein level of TC-Therapy in TME was much lower than that of simplex DTX-M, which might account for TME restoration. In conclusion, TGF-β inhibitor acted as the pioneer before nano chemotherapeutic agents. The TC-Therapy of TGF-β signaling inhibition and anti-tumor agent DTX-M is a promising regimen without arising metastasis risk to treat pancreatic cancer. The therapeutic regimen focused on TGF-β related myCAFs reminds clinicians to have a comprehensive understanding of pancreatic cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background/aims: : The genetic expression in the active inflammatory regions is increased in ulcerative colitis (UC) with endoscopic activity. The aim of this study was to investigate the molecular activity of inflammation and tissue remodeling markers in endoscopically inflamed and uninflamed regions of UC., Methods: : Patients with UC (n=47) and controls (n=20) were prospectively enrolled at the Seoul National University Bundang Hospital. Inflamed tissue was obtained at the most active lesion, and uninflamed tissue was collected from approximately 15 cm above the upper end of the active lesion via colonoscopic biopsies. The messenger RNA expression levels of transforming growth factor β ( TGF-β ), interleukin ( IL)-1β , IL-6 , IL-17A , E-cadherin , olfactomedin-4 ( OLFM4 ), leucine-rich repeat-containing G protein-coupled receptor 5 ( LGR5 ), vimentin , fibroblast-specific protein-1 ( FSP1 ), and α-smooth muscle actin ( SMA ) were evaluated. Mucosal healing (MH) was defined according to a Mayo endoscopic score of 0, 1 or non-MH (Mayo endoscopic score of 2 or 3)., Results: : The messenger RNA expressions of TGF-β , IL-1β , OLFM4 , FSP1 , vimentin , and α-SMA were significantly higher, and that of E-cadherin was significantly lower in inflamed and uninflamed regions of patients with UC than those in controls. In the inflamed regions, patients in the non-MH group had significantly increased genetic expression of TGF-β , FSP1 , vimentin , and α-SMA compared to patients in the MH group. Similarly, the non-MH group had significantly higher genetic expression of TGF-β , IL-1β , IL-6 , vimentin , and α-SMA than the MH group in the uninflamed regions., Conclusions: : Endoscopic activity in UC suggests inflammation and tissue remodeling of uninflamed regions similar to inflamed regions (ClinicalTrials.gov, NCT05653011).

The pogo transposable element-derived zinc finger protein, POGZ, is notably associated with neurodevelopmental disorders through its role in gene transcription. Many proteins involved in neurological development are often dysregulated in cancer, suggesting a potential role for POGZ in tumor biology. Here, we provided experimental evidence that POGZ influences the growth and metastatic spread of triple-negative breast cancers (TNBC). In well-characterized models of TNBC, POGZ exerted a dual role, both as a tumor promoter and metastasis suppressor. Mechanistically, loss of POGZ potentiated TGFβ pathway activation to exert cytostatic effects while simultaneously increasing the mesenchymal and migratory properties of breast tumors. Although POGZ levels are elevated in human breast cancers, the most aggressive forms of TNBC tumors, including those with increased mesenchymal and metastatic properties, exhibit dampened POGZ levels, and low POGZ expression was associated with inferior clinical outcomes in these tumor types. Taken together, these data suggest that POGZ is a critical suppressor of the early stages of the metastatic cascade. Significance: The POGZ neurodevelopmental protein plays dual functions in triple-negative breast cancers as a tumor promoter and metastasis suppressor, inhibiting TGFβ-regulated EMT to limit breast cancer metastatic progression., (©2024 American Association for Cancer Research.)

Objectives: Periodontitis is associated with Fusobacterium nucleatum (F.n) infection. Although the colonization of renal tissue by F.n is well documented, its specific role in kidney disease has yet to be determined. This study aimed to investigate the potential association between F.n-induced periodontitis and renal interstitial fibrosis., Methods: The rat gingival sulcus was injected with F.n suspension, while the control group (NC) was injected with PBS. The levels of total protein (TP), albumin (ALB), creatinine, and urea nitrogen (BUN) in rat serum and/or urine were quantified using the appropriate kits. Renal interstitial fibrosis and epithelial-mesenchymal transition (EMT) were evaluated in rats using Masson staining, Periodic Schiff-Methenamine (PASM) staining, and immunohistochemical staining. The levels of fibrosis- and EMT-related proteins and the TGF-β/SMAD2/3 and β-catenin signaling pathways were determined using Western blot analysis. F.n in the kidney tissues was quantitatively determined using bacterial 16S rRNA technology., Results: Serum levels of TP, ALB, creatinine, and BUN were not significantly decreased in F.n-infected rats with periodontitis. The levels of creatinine and ALB in the urine were not statistically different between two groups. Masson and PASM staining showed that F.n-induced periodontitis could promote renal interstitial fibrosis in rats. The levels of collagen I, fibronectin (FN), vimentin, and α-SMA were upregulated in the kidney tissues of rats with F.n-induced periodontitis and in F.n-treated HK-2 cells. However, E-cadherin levels were reduced. F.n promoted renal interstitial and HK-2 cell fibrosis in rats by modulating the TGF-β/SMAD2/3 and β-catenin signaling pathways. F.n colonization increased renal interstitial fibrosis in rats., Conclusion: F.n-induced periodontitis promoted EMT by activating the TGF-β/SMAD2/3 and β-catenin signaling pathways, thus promoting renal interstitial fibrosis in rats., Competing Interests: Declaration of competing interest The author declares that there is no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)