Inhibition Of TGF-β1 Research Articles

Linc00513 sponges miR-7 to modulate TGF-β signaling in azoospermia.

Azoospermia, or the complete absence of sperm in the ejaculate, affects about 1% of men worldwide and is a significant fertility challenge. This study investigates Linc00513, a long non-coding RNA, and its potential role in regulating the TGF-β signaling pathway, a key player in spermatogenesis, in the context of azoospermia. We show that Linc00513 expression is significantly lower in testicular tissues from azoospermic patients than in HS1 controls. Linc00513 interacts directly with microRNA-7 (miR-7) via complementary base pairing, acting as a competing endogenous RNA (ceRNA). This interaction effectively inhibits miR-7's inhibitory action on the TGF-β receptor 1 (TGFBR1), a critical component of the TGF-β signaling cascade. Downregulating Linc00513 reduces TGFBR1 repression and increases TGF-β signaling in azoospermic testes. Functional assays with spermatogonial cell lines support these findings. Silencing Linc00513 leads to increased cell proliferation and decreased apoptosis, similar to TGF-β inhibition. Overexpression of miR-7 inhibits the effects of Linc00513 on TGF-β signaling. Our study sheds new light on how Linc00513, miR-7, and the TGF-β signaling pathway interact in azoospermia. Linc00513 regulates TGFBR1 expression and thus influences spermatogonial cell fate by acting as a miR-7 ceRNA. These findings identify a potential therapeutic target for azoospermia treatment, paving the way for future research into restoring fertility in affected individuals.

Lung Cancer Organoid System to Evaluate the Cytotoxicity of Natural Killer Cells.

Natural killer (NK) cells are gaining growing attention due to their promise for immunotherapy. A fast and accurate system is needed to test NK cell biology and their therapeutic application. Here, we report a lung cancer organoid-based system to evaluate NK cells' cytotoxicity. We first established the lung cancer organoids on top of Matrigel, which allows the co-culture with NK cells. When co-cultured, NK cells moved close to and inside the lung cancer organoids. When we analyzed by flow cytometry, co-culture of NK cells induced a significantly higher ratio of cell death of lung cancer organoids, suggesting that lung cancer organoids can be employed to test the cytotoxicity of NK cells. Finally, the pretreatment of NK cells with A83-01, a TGFβ inhibitor, significantly enhanced the cell death of lung cancer organoids by NK cells, indicating that lung cancer organoid-based system faithfully recapitulates cell line-based system in evaluating the in vitro cytotoxicity of NK cells. These data represent that cancer organoid-based NK cell co-culture system is a reliable platform for studying NK cell biology and evaluating their cytotoxicity for screening for NK cell immunotherapy.

A Whole-Course-Repair System Based on Stimulus-Responsive Multifunctional Hydrogels for Myocardial Tissue Regeneration.

Myocardial infarction (MI) has emerged as the predominant cause of cardiovascular morbidity globally. The pathogenesis of MI unfolds as a progressive process encompassing three pivotal phases: inflammation, proliferation, and remodeling. Smart stimulus-responsive hydrogels have garnered considerable attention for their capacity to deliver therapeutic drugs precisely and controllably at the MI site. Here, a smart stimulus-responsive hydrogel with a dual-crosslinked network structure is designed, which enables the precise and controlled release of therapeutic drugs in different pathological stages for the treatment of MI. The hydrogel can rapidly release curcumin (Cur)in the inflammatory phase of MI to exert anti-apoptotic/anti-inflammatory effects. Recombinant humanized collagen type III (rhCol III) is loaded in the hydrogel and released as the hydrogel swelled/degraded during the proliferative phase to promote neovascularization. RepSox (a selective TGF-β inhibitor) releases from Pluronic F-127 grafted with aldehyde nanoparticles (PF127-CHO@RepSox NPs) in the remodeling phase to against fibrosis. The results in vitro and in vivo suggest that the hydrogel improves cardiac function and alleviates cardiac remodeling by suppressing inflammation and apoptosis, promoting neovascularization, and inhibiting myocardial fibrosis. A whole-course-repair system, leveraging stimulus-responsive multifunctional hydrogels, demonstrates notable effectiveness in enhancing post-MI cardiac function and facilitating the restoration of damaged myocardial tissue.

TGFβ in Pancreas and Colorectal Cancer: Opportunities to Overcome Therapeutic Resistance.

TGFβ is a pleiotropic signaling pathway that plays a pivotal role in regulating a multitude of cellular functions. TGFβ has a dual role in cell regulation where it induces growth inhibition and cell death; however, it can switch to a growth-promoting state under cancerous conditions. TGFβ is upregulated in colorectal cancer and pancreatic cancer, altering the tumor microenvironment and immune system and promoting a mesenchymal state. The upregulation of TGFβ in certain cancers leads to resistance to immunotherapy, and attempts to inhibit TGFβ expression have led to reduced therapeutic resistance when combined with chemotherapy and immunotherapy. Here, we review the current TGFβ inhibitor drugs in clinical trials for pancreatic and colorectal cancer, with the goal of uncovering advances in improving clinical efficacy for TGFβ combinational treatments in patients. Furthermore, we discuss the relevance of alterations in TGFβ signaling and germline variants in the context of personalizing treatment for patients who show lack of response to current therapeutics.

TGF-β1 inhibitor enhances the therapeutic effect of microwave ablation on hepatocellular carcinoma

Background Microwave ablation (MWA) is a widely adopted treatment technique for hepatocellular carcinoma (HCC). However, MWA alone is of limited use and has a high recurrence rate. Transforming growth factor-β1 (TGF-β1) is recognized as a potential therapeutic target for HCC patients. Therefore, this study was designed to investigate whether the TGF-β1 inhibitor could increase the efficacy of MWA therapy for HCC treatment. Methods In vitro, HCC cells challenged with TGF-β1 inhibitor (SB-525334), or normal saline were then heated by microwave. Methyl tetrazolium assays were performed to detect cell survival rate and half-maximal drug inhibitory concentration (IC50). Cell viability and apoptosis were detected by cell counting kit-8 assays, flow cytometry and western blotting. In vivo, the mice injected with HepG2 cells received oral gavage of SB-525334 (20 mg/kg) or normal saline and MWA at a power of 15 W. Tumor volume was recorded. Expression of Ki67 and apoptosis-related proteins were detected by immunohistochemistry and western blotting. TUNEL assays were used to detect cell death ratio. Histopathological changes were examined by hematoxylin and eosin staining. The mechanisms associated with the function of MWA combined with TGF-β1 inhibitor in HCC development were explored by western blotting. Results Combination of MWA and SB-525334 decreased the survival rate and promoted the apoptosis of HCC cells compared with MWA alone. SB-525334 enhanced the suppressive effect of MWA on tumor growth and amplified cell apoptosis. Mechanistically, MWA collaborated with SB-525334 inhibitor inactivated the TGF-β1/Smad2/Smad3 pathway. Conclusion TGF-β1 inhibitor enhances the therapeutic effect of MWA on HCC.

Targeted delivery of type I TGF-β receptor-mimicking peptide to fibrotic kidney for improving kidney fibrosis therapy via enhancing the inhibition of TGF-β1/Smad and p38 MAPK pathways

Renal fibrosis is a representative pathological feature of various chronic kidney diseases, and efficient treatment is needed. Interstitial myofibroblasts are a key driver of kidney fibrosis, which is dependent on the binding of TGF-β1 to type I TGF-β receptor (TβRI) and TGF-β1-related signaling pathways. Therefore, attenuating TGF-β1 activity by competing with TGF-β1 in myofibroblasts is an ideal strategy for treating kidney fibrosis. Recently, a novel TβRI-mimicking peptide RIPΔ demonstrated a high affinity for TGF-β1. Thus, it could be speculated that RIPΔ may be used for anti-fibrosis therapy. Platelet-derived growth factor β receptor (PDGFβR) is highly expressed in fibrotic kidney. In this study, we found that target peptide Z-RIPΔ, which is RIPΔ modified with PDGFβR-specific affibody ZPDGFβR, was specifically and highly taken up by TGF-β1-activated NIH3T3 fibroblasts. Moreover, Z-RIPΔ effectively inhibited the myofibroblast proliferation, migration and fibrosis response in vitro. In vivo and ex vivo experiments showed that Z-RIPΔ specifically targeted fibrotic kidney, improved the damaged renal function, and ameliorated kidney histopathology and renal fibrosis in UUO mice. Mechanistic studies showed that Z-RIPΔ hold the stronger inhibition of the TGF-β1/Smad and TGF-β1/p38 pathways than unmodified RIPΔ in vitro and in vivo. Furthermore, systemic administration of Z-RIPΔ to UUO mice led to minimal toxicity to major organs. Taken together, RIPΔ modified with ZPDGFβR increased its therapeutic efficacy and reduced its systemic toxicity, making it a potential candidate for targeted therapy for kidney fibrosis.

Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of SAR439459, a TGFβ inhibitor, as monotherapy and in combination with cemiplimab in patients with advanced solid tumors: Findings from a phase 1/1b study.

SAR439459 (SAR'459), a "second-generation" human anti-transforming growth factor beta (TGFβ) monoclonal antibody, enhances the activity of immune checkpoint inhibitors. In this phase I/Ib study, we evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of SAR'459 ± cemiplimab (intravenous) in patients with advanced solid tumors. Increasing doses of SAR'459 were administered every 2 or 3 weeks (Q2W, Q3W) alone (Part 1A) or with 3 mg/kg cemiplimab Q2W or 350 mg Q3W (Part 1B). In Part 2A (dose expansion), melanoma patients were randomly (1:1) administered 22.5 or 7.5 mg/kg SAR'459. In Part 2B (dose expansion), 22.5 mg/kg SAR'459 and 350 mg cemiplimab Q3W were administered. The primary end points were maximum tolerated dose (MTD) or maximum administered dose (MAD; Part 1), preliminary antitumor activity (Part 2B), and optimal monotherapy dose (Part 2A). Twenty-eight and 24 patients were treated in Parts 1A and 1B, respectively; MTD was not reached, MAD was 15 (Q2W) and 22.5 mg/kg (Q3W) alone and in combination, respectively. Fourteen and 95 patients, including 14 hepatocellular carcinoma (HCC) patients, were treated in Parts 2A and 2B, respectively. The population PK model yielded satisfactory goodness-of-fit plots and adequately described the observed data by a two-compartment PK model with linear elimination. Objective responses were not observed in Parts 1 and 2A. In Part 2B, objective response rate was 8.4% and 7.1% across tumor types and the HCC cohort, respectively. The most frequent treatment-emergent adverse effects were hemorrhagic events (43.5%), keratoacanthoma (6.8%), and skin neoplasms (6.2%). Fatal bleeding occurred in 21.4% HCC patients despite the implementation of mitigation measures. SAR'459 monotherapy and combination with cemiplimab appeared relatively safe and tolerable in limited number of patients in dose escalation. However, the study was discontinued due to the unclear efficacy of SAR'459 and bleeding risk, particularly in HCC patients.

The role and mechanism of circadian clock gene BMAL1 in the proliferation and metastasis of nasopharyngeal carcinoma by inhibition TGF-β1/Smads pathway.

6027 Background: To explore the molecular mechanism of biological clock gene BMAL1 inhibiting the proliferation and metastasis of nasopharyngeal carcinoma(NPC). Methods: 1. IHC detected the expression of BMAL1 in 41 cases of nasopharyngeal chronic inflammatory tissue and 71 cases of NPCtissue. PCR and Western blot measured the expression levels of BMAL1 in NP69 in NPC cells and human immortalized nasopharyngeal epithelial cells, respectively. 2. To detect the effect of BMAL1 on the proliferation capacity of NPCcells in vitro and in vivo; Scratch healing and Transwell invasion migration experiments detected the effect of BMAL1 on the invasion and migration ability of NPCcells in vitro. Fluorescence in vivo imaging and HE staining to determine the transfer of nude mouse tail intravenous injection model. PCR and Western blot detect the effect of BMAL1 on the expression of EMT-related markers at the transcriptional and protein levels in NPC cells. 3. A series of molecular biological means such as bioinformatics technology, ChIP experiment, double luciferase reporter gene experiment, immunofluorescence colocalization experiment and Co-IP were used to verify its mechanism. Results: 1. The expression of BMAL1 in NPCtissues and cells is reduced. The expression of BMAL1 in NPC tissues was associated with the M stage of nasopharyngeal carcinoma patients (p=0.006). 2. Overexpression of BMAL1 can inhibit the proliferation, invasion and migration ability of nasopharyngeal cancer cells, while knocking down BMAL1 is the opposite. Overexpression of BMAL1 inhibits EMT of NPCcells. 3. There are 5 BMAL1 binding sites in the TGF-β1promoter region, and BMAL1 can directly bind to the TGF-β1promoter region, which can inhibit the transcriptional activity of TGF-β1. Overexpression of BMAL1 inhibits TGF-β1/Smads pathway activity. Under the induction of recombinant human TGF-β1, the proliferation ability of NPC cells was enhanced, the activity of TGF-β1/Smads signaling pathway was enhanced, and nasopharyngeal cancer cells underwent EMT, and cell invasion and migration capacity increased. After overexpression of BMAL1, TGF-β1 no longer promotes TGF-β1/Smads signaling pathway activity, EMT is inhibited, and cell invasion and migration ability is weakened. BMAL1 combined with TGF-β1 has certain diagnostic value in predicting whether nasopharyngeal carcinoma metastasis. Conclusions: BMAL1 expression is downregulated in nasopharyngeal carcinoma, and its expression level is related to the development and metastasis of nasopharyngeal carcinoma. BMAL1 can inhibit the proliferation, epithelial-mesenchymal transformation and invasion and metastasis ability of NPC cells, and its mechanism is related to the inhibition of TGF-β1/Smads signaling pathway activity. It is speculated that it may become a new prognostic marker and therapeutic target for nasopharyngeal carcinoma.

Phase 1 study (DRAGON) of SRK-181 (linavonkibart), a latent TGFβ1 inhibitor, combined with pembrolizumab in patients with anti-PD1 resistant advanced solid tumors: Updated results of expansion part.

Phase 1 study (DRAGON) of SRK-181 (linavonkibart), a latent TGFβ1 inhibitor, combined with pembrolizumab in patients with anti-PD1 resistant advanced solid tumors: Updated results of expansion part.

Mechanistic insight into the hepatoprotective effect of Moringa oleifera Lam leaf extract and telmisartan against carbon tetrachloride-induced liver fibrosis: plausible roles of TGF-β1/SMAD3/SMAD7 and HDAC2/NF-κB/PPARγ pathways

The increasing prevalence and limited therapeutic options for liver fibrosis necessitates more medical attention. Our study aims to investigate the potential molecular targets by which Moringa oleifera Lam leaf extract (Mor) and/or telmisartan (Telm) alleviate carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Liver fibrosis was induced in male Sprague-Dawley rats by intraperitoneal injection of 50% CCl4 (1 ml/kg) every 72 hours, for 8 weeks. Intoxicated rats with CCl4 were simultaneously orally administrated Mor (400 mg/kg/day for 8 weeks) and/or Telm (10 mg/kg/day for 8 weeks). Treatment of CCl4-intoxicated rats with Mor/Telm significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities compared to CCl4 intoxicated group (P < 0.001). Additionally, Mor/Telm treatment significantly reduced the level of hepatic inflammatory, profibrotic, and apoptotic markers including; nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), transforming growth factor-βeta1 (TGF-β1), and caspase-3. Interestingly, co-treatment of CCl4-intoxicated rats with Mor/Telm downregulated m-RNA expression of histone deacetylase 2 (HDAC2) (71.8%), and reduced protein expression of mothers against decapentaplegic homolog 3 (p-SMAD3) (70.6%) compared to untreated animals. Mor/Telm regimen also elevated p-SMAD7 protein expression as well as m-RNA expression of peroxisome proliferator-activated receptor γ (PPARγ) (3.6 and 3.1 fold, respectively p < 0.05) compared to CCl4 intoxicated group. Histopathological picture of the liver tissue intoxicated with CCl4 revealed marked improvement by Mor/Telm co-treatment. Conclusively, this study substantiated the hepatoprotective effect of Mor/Telm regimen against CCl4-induced liver fibrosis through suppression of TGF-β1/SMAD3, and HDAC2/NF-κB signaling pathways and up-regulation of SMAD7 and PPARγ expression.

Intermittent compressive force regulates matrix metalloproteinases and tissue inhibitors of metalloproteinases expression in human periodontal ligament cells

ObjectiveThis study aims to evaluate the effects of intermittent compressive force (ICF) on the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) by human periodontal ligament cells (hPDLCs). DesignhPDLCs were subjected to ICF with a magnitude of 1.5 g/cm2 and loaded for 24 h. mRNA and protein expression of several MMPs and TIMPs were assessed using RT-PCR and ELISA analyses. An inhibitor of TGF-β (SB431542) was used to assess a possible role of TGF-β in the expression of MMPs and TIMPs under ICF. ResultsmRNA and protein analyses showed that ICF significantly induced expression of TIMP1 and TIMP3, but decreased expression of MMP1. Incubation with the TGF-β inhibitor and applied to ICF showed a downregulation of TIMP3, but expression of MMP1 was not affected. ConclusionICF is likely to affect ECM homeostasis by hPDLCs by regulating the expression of MMP1 and TIMPs. Moreover, TGF-β1 regulated expression of TIMP3. These findings suggest ICF may decrease the degradation of ECM and may thus be essential for maintaining PDL homeostasis.

#2161 Phosphodiesterase V inhibitor attenuates the fibrotic gene expression of human renal fibroblast derived from IgA nephropathy: an in-vitro study

Abstract Background and Aims Renal fibrosis (RF) is the final common pathway that determines the progression of many glomerular disease including IgA nephropathy (IgAN). Till date there is no definite therapy available to retard RF. Being the key mediator of fibrosis, TGF-β is being targeted in many studies. Phosphodiesterase V inhibitor (PDE5i) is known to inhibit TGF-β but its role in RF is yet to be established. Hence, in the current in-vitro study we wish to establish the role of PDE5 inhibitor as an inhibitor of TGF-β and hence the RF. Method This is a pilot study to evaluate the efficacy of ‘Phosphodiesterase V inhibitor’ on TGFβ1 induced fibrosis on fibroblasts derived from biopsy specimen of IgA nephropathy patients. Renal fibroblasts were cultured from six IgA patients. The fibroblasts cells were treated with PDE5i inhibitor (tadalafil) (at different doses of 1 µm, 5 µm, 10 µm and 15 µm), both before and after stimulation with transforming growth factor beta-1 (TGF-b1) (at doses of 5 ng/ml, 10 ng/ml, 15 ng/ml and 20 ng/ml). Gene expression was studied by real-time polymerase chain reaction (RT-PCR) for messenger ribonucleic acid (mRNA) of pro-fibrotic genes Col1a1, Col1a2, FN1, CTGF, ASMA, TIMP1, and anti-fibrotic MMP2. Objectives Results Our results shows that TGFβ significantly increased the expression of profibrotic gene (Col1a1, Col1a2, ASMA, CTGF, FN and TIMP1) at concentration of 10 ng/ml in the fibroblast cells derived from IgAN patients. Treatment of fibroblast cells with Tadalafil (PDE5 inhibitor) significantly decreased the pro-fibrotic gene mRNA expression (Col1a1, Col1a2, ASMA, CTGF, FN and TIMP1) with increased anti-fibrotic gene expression (MMP2) at the dose of 5 µm and 10 µm concentration in the fibroblast cells (Fig. 1). Conclusion This study may provide potential therapeutic target for prevention of renal fibrosis in IgAN patients. Till date PDE5 inhibitors were not used for IgAN. We found that, PDE5 inhibitor reduces the fibrosis in this in vitro study, this drug may be proposed as a potential therapy for IgAN.

Lack of TGFβ signaling competency predicts immune poor cancer conversion to immune rich and response to checkpoint blockade.

Transforming growth factor beta (TGFβ) is well-recognized as an immunosuppressive player in the tumor microenvironment but also has a significant impact on cancer cell phenotypes. Loss of TGFβ signaling impairs DNA repair competency, which is described by a transcriptomic score, βAlt. Cancers with high βAlt have more genomic damage and are more responsive to genotoxic therapy. The growing appreciation that cancer DNA repair deficits are important determinants of immune response prompted us to investigate the association of βAlt with response to immune checkpoint blockade (ICB). We predicted that high βAlt tumors would be infiltrated with lymphocytes because of DNA damage burden and hence responsive to ICB. We analyzed public transcriptomic data from clinical trials and preclinical models using transcriptomic signatures of TGFβ targets, DNA repair genes, tumor educated immune cells and interferon. A high βAlt, immune poor mammary tumor derived transplant model resistant to programmed death ligand 1 (PD-L1) antibodies was studied using multispectral flow cytometry to interrogate the immune system. Metastatic bladder patients in IMvigor 210 who responded to ICB had significantly increased βAlt scores and experienced significantly longer overall survival compared to those with low βAlt scores (hazard ratio 0.62, P=0.011) . Unexpectedly, 75% of high βAlt cancers were immune poor as defined by low expression of tumor educated immune cell and interferon signatures. The association of high βAlt with immune poor cancer was also evident in TCGA and preclinical cancer models. We used a high βAlt, immune poor cancer to test therapeutic strategies to overcome its inherent anti-PD-L1 resistance. Combination treatment with radiation and TGFβ inhibition were necessary for lymphocytic infiltration and activated NK cells were required for ICB response. Bioinformatic analysis identified high βAlt, immune poor B16 and CT26 preclinical models and paired biopsies of cancer patients that also demonstrated NK cell activation upon response to ICB. Our studies support βAlt as a biomarker that predicts response to ICB albeit in immune poor cancers, which has implications for the development of therapeutic strategies to increase the number of cancer patients who will benefit from immunotherapy.

Computational Exploration of Naturally Occurring Flavonoids as TGF-β Inhibitors in Breast Cancer: Insights from Docking and Molecular Dynamics Simulations and In-vitro Cytotoxicity Study.

Breast cancer is a global health concern, demanding innovative treatments. Targeting the Transforming Growth Factor-beta (TGF-β) signaling pathway, pivotal in breast cancer, is a promising approach. TGF-β inhibits proliferation via G1 phase cell cycle arrest, acting as a suppressor initially, but in later stages, it promotes progression by enhancing motility, invasiveness, and metastasis formation. This study explores naturally occurring flavonoids' interactions with TGF-β. Using molecular docking against the protein's crystal structure (PDB Id: 1PY5), Gossypin showed the highest docking score and underwent molecular dynamics simulation, revealing complex flexibility and explaining how flavonoids impede TGF-β signaling in breast cancer. ADMET predictions adhered to Lipinski's rule of Five. Insights into flavonoid-TGF-β binding offer a novel angle for breast cancer treatment. Flavonoids having a good docking score like gossypin, morin, luteolin and taxifolin shown potent cytotoxic effect on breast cancer cell line, MCF-7. Understanding these interactions could inspire flavonoid-based therapies targeting TGF-β to halt breast cancer growth. These findings pave the way for personalized, targeted breast cancer therapies, offering hope against this formidable disease.

Pre-Clinical Assessment of SAR442257, a CD38/CD3xCD28 Trispecific T Cell Engager in Treatment of Relapsed/Refractory Multiple Myeloma.

Current treatment strategies for multiple myeloma (MM) are highly effective, but most patients develop relapsed/refractory disease (RRMM). The anti-CD38/CD3xCD28 trispecific antibody SAR442257 targets CD38 and CD28 on MM cells and co-stimulates CD3 and CD28 on T cells (TCs). We evaluated different key aspects such as MM cells and T cells avidity interaction, tumor killing, and biomarkers for drug potency in three distinct cohorts of RRMM patients. We found that a significantly higher proportion of RRMM patients (86%) exhibited aberrant co-expression of CD28 compared to newly diagnosed MM (NDMM) patients (19%). Furthermore, SAR442257 mediated significantly higher TC activation, resulting in enhanced MM killing compared to bispecific functional knockout controls for all relapse cohorts (Pearson's r = 0.7). Finally, patients refractory to anti-CD38 therapy had higher levels of TGF-β (up to 20-fold) compared to other cohorts. This can limit the activity of SAR442257. Vactoserib, a TGF-β inhibitor, was able to mitigate this effect and restore sensitivity to SAR442257 in these experiments. In conclusion, SAR442257 has high potential for enhancing TC cytotoxicity by co-targeting CD38 and CD28 on MM and CD3/CD28 on T cells.

TGF β1 promotes the polarization of M2-type macrophages and activates PI3K/mTOR signaling pathway by inhibiting ISG20 to sensitize ovarian cancer to cisplatin

The involvement of Interferon-stimulated exonuclease gene 20 (ISG20) has been reported in renal clear cell carcinoma, hepatocellular carcinoma, and cervical cancer. However, its role in ovarian cancer chemotherapy remains unclear. In this study, we conducted a comparative analysis of TGF-β1 and ISG20 in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells and tissues using qRT-PCR and a tissue immunofluorescence analysis. We also investigated the impact of ISG20-targeted drugs (IFN-γ) and TGF-β1 inhibitors on cisplatin response both in vivo and in vitro. Additionally, we assessed the effects of TGF-β1 or ISG20 on the polarization of tumor-associated macrophages through flow cytometry and ELISA analysis. Our findings revealed that ISG20 expression was lower in cisplatin-resistant tissues compared to cisplatin-sensitive tissues; however, overexpression of ISG20 sensitized ovarian cancer to cisplatin treatment. Furthermore, activation of ISG20 expression with IFN-γ or TGF-β1 inhibitors enhanced the sensitivity of ovarian cancer cells to cisplatin therapy. Notably, our results demonstrated that TGF-β1 promoted M2-type macrophage polarization as well as PI3K/mTOR pathway activation by suppressing ISG20 expression both in vivo and in vitro. In conclusion, our study highlights the critical role played by ISG20 within the network underlying cisplatin resistance in ovarian cancer. Targeting ISG20 using IFN-γ or TGF-β1 inhibitors may represent a promising therapeutic strategy for treating ovarian cancer.

Available Therapeutic Options for Corneal Neovascularization: A Review

Corneal neovascularization can impair vision and result in a poor quality of life. The pathogenesis involves a complex interplay of angiogenic factors, notably vascular endothelial growth factor (VEGF). This review provides a comprehensive overview of potential therapies for corneal neovascularization, covering tissue inhibitors of metalloproteinases (TIMPs), transforming growth factor beta (TGF-β) inhibitors, interleukin-1L receptor antagonist (IL-1 Ra), nitric oxide synthase (NOS) isoforms, galectin-3 inhibitors, retinal pigment epithelium-derived factor (PEDF), platelet-derived growth factor (PDGF) receptor inhibitors, and surgical treatments. Conventional treatments include anti-VEGF therapy and laser interventions, while emerging therapies such as immunosuppressive drugs (cyclosporine and rapamycin) have been explored. Losartan and decorin are potential antifibrotic agents that mitigate TGF-β-induced fibrosis. Ocular nanosystems are innovative drug-delivery platforms that facilitate the targeted release of therapeutic agents. Gene therapies, such as small interfering RNA and antisense oligonucleotides, are promising approaches for selectively inhibiting angiogenesis-related gene expression. Aganirsen is efficacious in reducing the corneal neovascularization area without significant adverse effects. These multifaceted approaches underscore the corneal neovascularization management complexity and highlight ideas for enhancing therapeutic outcomes. Furthermore, the importance of combination therapies and the need for further research to develop specific inhibitors while considering their therapeutic efficacy and potential adverse effects are discussed.

Tumor-associated macrophage enhances PD-L1-mediated immune escape of bladder cancer through PKM2 dimer-STAT3 complex nuclear translocation

Tumor-associated macrophages (TAMs) are important components of the tumor microenvironment (TME) and strongly associated with poor prognosis and drug resistance, including checkpoint blockade immunotherapy in solid tumor patients. However, the mechanism by which TAM affects immune metabolism reprogramming and immune checkpoint signalling pathway in the TME remains elusive. In this study we found that transforming growth factor-beta (TGF-β) secreted by M2-TAMs increased the level of glycolysis in bladder cancer (BLCA) and played important role in PD-L1-mediated immune evasion through pyruvate kinase isoenzymes M2 (PKM2). Mechanistically, TGF-β promoted high expression of PKM2 by promoting the nuclear translocation of PKM2 dimer in conjunction with phosphorylated signal transducer and activator of transcription (p-STAT3), which then exerted its kinase activity to promote PD-L1 expression in BLCA. Moreover, SB-431542 (TGF-β blocker) and shikonin (PKM2 inhibitor) significantly reduced PD-L1 expression and inhibited BLCA growth and organoids by enhancing anti-tumor immune responses. In conclusion, M2-TAM-derived TGF-β promotes PD-L1-mediated immune evasion in BLCA by increasing the PKM2 dimer-STAT3 complex nuclear translocation. Combined blockade of the TGF-β receptor and inhibition of PKM2 effectively prevent BLCA progression and immunosuppression, providing a potential targeted therapeutic strategy for BLCA.

Therapeutic Effect of Desmodium caudatum Extracts on Alleviating Diabetic Nephropathy Mice.

Desmodium caudatum extracts (DCE) were investigated for their potential therapeutic effects on diabetic nephropathy (DN). In our study, the high-fat diet (HFD) / streptozotocin (STZ)-induced DN model in C57BL/6 mice was treated with 100mg/kg, 200mg/kg DCE. The results showed that DCE decreased biochemical parameters and proteinuria levels. The kidney sections staining indicated that DCE treatment recovered glomerular atrophy and alleviated lipid droplets in the glomerular. Additionally, DCE inhibited lipid and glycogen accumulation down-regulated the expression of sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FAS) proteins. DCE also reduced collagenous fibrous tissue and the expression of transforming growth factor-β1 (TGF-β1) and alpha-smooth muscle actin (α-SMA) through Masson's trichrome staining and immunohistochemical analysis. We found that DCE alleviated hydroxyproline content, and epithelial-mesenchymal transition (EMT). Besides, the results shown that DCE enhanced the antioxidant enzymes to mitigate fibrosis by reducing oxidative stress. In conclusion, our study provided evidence of the protective effect of DCE which down-regulated hyperglycemia, hyperlipidemia and inhibition of TGF-β1 and EMT pathway but elevated antioxidant, suggesting its therapeutic implication for DN.

Galunisertib downregulates mutant type I collagen expression and promotes MSCs osteogenesis in pediatric osteogenesis imperfecta

Qualitative alterations in type I collagen due to pathogenic variants in the COL1A1 or COL1A2 genes, result in moderate and severe Osteogenesis Imperfecta (OI), a rare disease characterized by bone fragility. The TGF-β signaling pathway is overactive in OI patients and certain OI mouse models, and inhibition of TGF-β through anti-TGF-β monoclonal antibody therapy in phase I clinical trials in OI adults is rendering encouraging results. However, the impact of TGF-β inhibition on osteogenic differentiation of mesenchymal stem cells from OI patients (OI-MSCs) is unknown. The following study demonstrates that pediatric skeletal OI-MSCs have imbalanced osteogenesis favoring the osteogenic commitment. Galunisertib, a small molecule inhibitor (SMI) that targets the TGF-β receptor I (TβRI), favored the final osteogenic maturation of OI-MSCs. Mechanistically, galunisertib downregulated type I collagen expression in OI-MSCs, with greater impact on mutant type I collagen, and concomitantly, modulated the expression of unfolded protein response (UPR) and autophagy markers. In vivo, galunisertib improved trabecular bone parameters only in female oim/oim mice. These results further suggest that type I collagen is a tunable target within the bone ECM that deserves investigation and that the SMI, galunisertib, is a promising new candidate for the anti-TGF-β targeting for the treatment of OI.