Tranilast Inhibits TRPV2 and Suppresses Fibrosis Progression and Weight Gain in a NASH Model Mouse.

BACKGROUND/AIM: This study aimed to investigate the role of transient receptor potential vanilloid 2 (TRPV2) in a mouse model with non-alcoholic steatohepatitis (NASH) and to examine the effects of tranilast on TRPV2 and fibrosis-related cytokines. MATERIALS AND METHODS: C57BL/6N mice were fed a Gubra-Amylin NASH (GAN) diet for 20 weeks to induce NASH. The tranilast groups received oral administration of tranilast at doses of 300, 400 and 500 mg/kg/day, five days per week for 20 weeks, in addition to the GAN diet. The effects of tranilast were assessed based on the dosage of food intake, changes in body weight, liver weight, blood biochemical parameters, histopathological examination, and expression of TRPV2 and inflammatory cytokines. RESULTS: Hepatic expression of TRPV2 was observed in the GAN-fed NASH mouse model. The tranilast groups showed significantly suppressed increases in body and liver weights. The development of intrahepatic fat deposition and liver fibrosis, assessed histopathologically, was inhibited. Tranilast administration improved the expression of TRPV2 and inflammatory cytokines in the liver. Additionally, blood tests indicated a reduction in elevated liver enzyme levels. CONCLUSION: In GAN diet NASH models, TRPV2 was up-regulated in the liver and tranilast inhibited TRPV2 and suppressed fibrosis. Therefore, it might prevent the incidence of hepatocellular carcinoma associated with NASH.

Unlocking the potential of tranilast: Targeting fibrotic signaling pathways for therapeutic benefit.

Fibrosis is the excessive deposition of extracellular matrix in an organ or tissue that results from an impaired tissue repair in response to tissue injury or chronic inflammation. The progressive nature of fibrotic diseases and limited treatment options represent significant healthcare challenges. Despite the substantial progress in understanding the mechanisms of fibrosis, a gap persists translating this knowledge into effective therapeutics. Here, we discuss the critical mediators involved in fibrosis and the role of tranilast as a potential antifibrotic drug to treat fibrotic conditions. Tranilast, an antiallergy drug, is a derivative of tryptophan and has been studied for its role in various fibrotic diseases. These include scleroderma, keloid and hypertrophic scars, liver fibrosis, renal fibrosis, cardiac fibrosis, pulmonary fibrosis, and uterine fibroids. Tranilast exerts antifibrotic effects by suppressing fibrotic pathways, including TGF-ß, and MPAK. Because it disrupts fibrotic pathways and has demonstrated beneficial effects against keloid and hypertrophic scars, tranilast could be used to treat other conditions characterized by fibrosis.

Tranilast alleviates visceral hypersensitivity and colonic hyperpermeability by suppressing NLRP3 inflammasome activation in irritable bowel syndrome rat models.

Visceral hypersensitivity resulting from compromised gut barrier with activated immune system is a key feature of irritable bowel syndrome (IBS). Corticotropin-releasing factor (CRF) and Toll-like receptor 4 (TLR4) activate proinflammatory cytokine signaling to induce these changes, which is one of the mechanisms of IBS. As activation of the NLRP3 inflammasome by lipopolysaccharide (LPS) or TLR4 leads to release interleukin (IL)-1ß, the NLRP3 inflammasome may be involved in the pathophysiology of IBS. Tranilast, an anti-allergic drug has been demonstrated to inhibit the NLRP3 inflammasome, and we evaluated the impact of tranilast on visceral hypersensitivity and colonic hyperpermeability induced by LPS or CRF (IBS rat model). Visceral pain threshold caused by colonic balloon distention was measured by monitoring abdominal muscle contractions electrophysiologically. Colonic permeability was determined by quantifying the absorbed Evans blue within the colonic tissue. Colonic protein levels of NLRP3 and IL-1ß were assessed by immunoblot or ELISA. Intragastric administration of tranilast (20-200 mg/kg) for 3 days inhibited LPS (1 mg/kg)-induced visceral hypersensitivity and colonic hyperpermeability in a dose-dependent manner. Simultaneously, tranilast also abolished these alterations induced by CRF (50 µg/kg). LPS increased colonic protein levels of NLRP3 and IL-1ß, and tranilast inhibited these changes. ß-hydroxy butyrate, an NLRP3 inhibitor, also abolished visceral hypersensitivity and colonic hyperpermeability caused by LPS. In contrast, IL-1ß induced similar GI alterations to LPS, which were not modified by tranilast. In conclusion, tranilast improved visceral pain and colonic barrier by suppression of the NLRP3 inflammasome in IBS rat models. Tranilast may be useful for IBS treating.

Targeting epigenetic and post-translational modifications regulating pyroptosis for the treatment of inflammatory diseases.

Inflammatory diseases, including infectious diseases, diabetes-related diseases, arthritis-related diseases, neurological diseases, digestive diseases, and tumor, continue to threaten human health and impose a significant financial burden despite advancements in clinical treatment. Pyroptosis, a pro-inflammatory programmed cell death pathway, plays an important role in the regulation of inflammation. Moderate pyroptosis contributes to the activation of native immunity, whereas excessive pyroptosis is associated with the occurrence and progression of inflammation. Pyroptosis is complicated and tightly controlled by various factors. Accumulating evidence has confirmed that epigenetic modifications and post-translational modifications (PTMs) play vital roles in the regulation of pyroptosis. Epigenetic modifications, which include DNA methylation and histone modifications (such as methylation and acetylation), and post-translational modifications (such as ubiquitination, phosphorylation, and acetylation) precisely manipulate gene expression and protein functions at the transcriptional and post-translational levels, respectively. In this review, we summarize the major pathways of pyroptosis and focus on the regulatory roles and mechanisms of epigenetic and post-translational modifications of pyroptotic components. We also illustrate these within pyroptosis-associated inflammatory diseases. In addition, we discuss the effects of novel therapeutic strategies targeting epigenetic and post-translational modifications on pyroptosis, and provide prospective insight into the regulation of pyroptosis for the treatment of inflammatory diseases.

Wnt dose escalation during the exit from pluripotency identifies tranilast as a regulator of cardiac mesoderm.

Wnt signaling is a critical determinant of cell lineage development. This study used Wnt dose-dependent induction programs to gain insights into molecular regulation of stem cell differentiation. We performed single-cell RNA sequencing of hiPSCs responding to a dose escalation protocol with Wnt agonist CHIR-99021 during the exit from pluripotency to identify cell types and genetic activity driven by Wnt stimulation. Results of activated gene sets and cell types were used to build a multiple regression model that predicts the efficiency of cardiomyocyte differentiation. Cross-referencing Wnt-associated gene expression profiles to the Connectivity Map database, we identified the small-molecule drug, tranilast. We found that tranilast synergistically activates Wnt signaling to promote cardiac lineage differentiation, which we validate by in vitro analysis of hiPSC differentiation and in vivo analysis of developing quail embryos. Our study provides an integrated workflow that links experimental datasets, prediction models, and small-molecule databases to identify drug-like compounds that control cell differentiation.

NY-ESO-1-specific T cell receptor-engineered T cells and Tranilast, a TRPV2 antagonist bivalent treatment enhances the killing of esophageal cancer: a dual-targeted cancer therapeutic route.

BACKGROUND: Esophageal cancer (EC) is a global canker notorious for causing high mortality due to its relentless incidence rate, convoluted with unyielding recurrence and metastasis. However, these intricacies of EC are associated with an immoderate expression of NY-ESO-1 antigen, presenting a lifeline for adoptive T cell therapy. We hypothesized that naturally isolated higher-affinity T cell receptors (TCRs) that bind to NY-ESO-1 would allow T lymphocytes to target EC with a pronounced antitumor response efficacy. Also, targeting TRPV2, which is associated with tumorigenesis in EC, creates an avenue for dual-targeted therapy. We exploited the dual-targeting antitumor efficacy against EC. METHODS: We isolated antigen-specific TCRs (asTCRs) from a naive library constructed with TCRs obtained from enriched cytotoxic T lymphocytes. The robustness of our asTCRs and their TCR-T cell derivatives, Tranilast (TRPV2 inhibitor), and their bivalent treatment were evaluated with prospective cross-reactive human-peptide variants and tumor cells. RESULTS: Our study demonstrated that our naive unenhanced asTCRs and their TCR-Ts perpetuated their cognate HLA-A*02:01/NY-ESO-1(157-165) specificity, killing varying EC cells with higher cytotoxicity compared to the known affinity-enhanced TCR (TCRe) and its wild-type (TCR0) which targets the same NY-ESO-1 antigen. Furthermore, the TCR-Ts and Tranilast bivalent treatment showed superior EC killing compared to any of their monovalent treatments of either TCR-T or Tranilast. CONCLUSION: Our findings suggest that dual-targeted immunotherapy may have a superior antitumor effect. Our study presents a technique to evolve novel, robust, timely therapeutic strategies and interventions for EC and other malignancies.

Cancer Stem Cells of Esophageal Adenocarcinoma are Suppressed by Inhibitors of TRPV2 and SLC12A2.

BACKGROUND: The potential of membrane transporters activated in cancer stem cells (CSCs) as new therapeutic targets for cancer is attracting increasing interest. Therefore, the present study examined the expression profiles of ion transport-related molecules in the CSCs of esophageal adenocarcinoma (EAC). METHODS: Cells that highly expressed aldehyde dehydrogenase 1 family member A1 (ALDH1A1) were separated from OE33 cells, a human Barrett's EAC cell line, by fluorescence-activated cell sorting. CSCs were identified based on the formation of tumorspheres. Gene expression profiles in CSCs were examined by a microarray analysis. RESULTS: Among OE33 cells, ALDH1A1 messenger RNA levels were higher in CSCs than in non-CSCs. Furthermore, CSCs exhibited resistance to cisplatin and had the capacity to redifferentiate. The results of the microarray analysis of CSCs showed the up-regulated expression of several genes related to ion channels/transporters, such as transient receptor potential vanilloid 2 (TRPV2) and solute carrier family 12 member 2 (SLC12A2). The cytotoxicities of the TRPV2 inhibitor tranilast and the SLC12A2 inhibitor furosemide were higher at lower concentrations in CSCs than in non-CSCs, and both markedly reduced the number of tumorspheres. The cell population among OE33 cells that highly expressed ALDH1A1 also was significantly decreased by these inhibitors. CONCLUSIONS: Based on the present results, TRPV2 and SLC12A2 are involved in the maintenance of CSCs, and their specific inhibitors, tranilast and furosemide, respectively, have potential as targeted therapeutic agents for EAC.

Therapeutic Effects of Long-Term Administration of Tranilast in an Animal Model for the Treatment of Fibroids.

Tranilast (N-3, 4-dimethoxycinnamoyl anthranilic acid) is an orally administered drug with antiallergic properties and approved in Japan and the Republic of Korea for the treatment of asthma and hypertrophic scars. Previous in vitro studies indicated that tranilast reduced fibroid growth through its inhibitory effects on cell proliferation and induction of apoptosis. The objective of this study was to determine the efficacy of tranilast for treatment of human-derived fibroids in a mouse model. SCID mice (ovariectomized, supplemented with estrogen and progesterone) were implanted with fibroid explants and treated for two months with tranilast (50 m/kg/daily) or the vehicle. After sacrifice, xenografts were excised and analyzed. Tranilast was well tolerated without adverse side effects. There was a 37% reduction in tumor weight along with a significant decrease in staining for Ki67, CCND1, and E2F1; a significant increase in nuclear staining for cleaved caspase 3; and reduced staining for TGF-ß3 and Masson's trichrome in the tranilast treated mice. There was a significant inhibition of mRNA and protein expression of fibronectin, COL3A1, CCND1, E2F1, and TGF-ß3 in the xenografts from the tranilast-treated mice. These promising therapeutic effects of tranilast warrant additional animal studies and human clinical trials to evaluate its efficacy for treatment of fibroids.

Identification of 5-[5-cyano-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamido] thiazole-4-carboxylic acid as a promising dual inhibitor of urate transporter 1 and xanthine oxidase.

In combination with allopurinol, tranilast is used as an urate transporter 1 (URAT1) inhibitor for the treatment of hyperuricemia, but its structure-activity relationship concerning URAT1 inhibitory activity is rarely studied. In this paper, analogs 1-30 were designed and synthesized using scaffold hopping strategy on the basis of tranilast and the privileged scaffold indole. Then, URAT1 activity was evaluated using 14C-uric acid uptake assay with HEK293-URAT1 overexpressing cells. Compared with tranilast (inhibitory rate = 44.9% at 10 µM), most compounds displayed apparent inhibitory effects, ranging from 40.0% to 81.0% at 10 µM on URAT1. Surprisingly, along with the bringing in of a cyano group at the 5-position of indole ring, compounds 26 and 28-30 exerted xanthine oxidase (XO) inhibitory activity. In particular, compound 29 presented potency on URAT1 (48.0% at 10 µM) and XO (IC50 = 1.01 µM). Molecular simulation analysis revealed that the basic structure of compound 29 had an affinity with URAT1, and XO. Furthermore, compound 29 demonstrated a significant hypouricemic effect in a potassium oxonate-induced hyperuricemia rat model at an oral dose of 10 mg/kg during in vivo tests. In summary, tranilast analog 29 was identified as a potent dual-target inhibitor of URAT1 and XO, and a promising lead compound for further investigation.

Tranilast reduces cardiomyocyte injury induced by ischemia­reperfusion via Nrf2/HO­1/NF­κB signaling.

Tranilast, a synthetic derivative of a tryptophan metabolite, can be used to treat heart diseases. However, the specific mechanism underlying the effect of tranilast on ischemia-reperfusion (I/R) injury-induced cardiomyocyte apoptosis remains unclear. Therefore, the present study aimed to determine if tranilast could attenuate I/R-induced cardiomyocyte injury. A hypoxia/reoxygenation (H/R) model of H9c2 cardiomyocytes was established to simulate I/R-induced cardiomyocyte injury. The viability, apoptosis, inflammation and oxidative stress in H/R-induced H9c2 cells following treatment with tranilast were evaluated by Cell Counting Kit-8 and TUNEL assay. Commercially available kits were used to detect the levels of inflammatory markers and oxidative stress indicators. In addition, the expression levels of the apoptosis- and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/NF-κB signalling pathway-associated proteins were detected by western blotting. The levels of reactive oxygen species were determined using 2',7'-dichlorofluorescin diacetate assay kit. The viability of H9c2 cells was decreased following induction with H/R. However, treatment with tranilast increased viability while decreasing apoptosis, oxidative stress and inflammatory response in H/R-induced H9c2 cells by activating Nrf2/HO-1/NF-κB signalling. Furthermore, treatment with ML-385, an Nrf2 inhibitor, reversed the effects of tranilast on H/R-induced H9c2 cells. In conclusion, the results of the present study suggested that tranilast could attenuate I/R-induced cardiomyocyte injury via the Nrf2/HO-1/NF-κB signalling pathway.

Importance of Mast Cell Activation Control for Preventing Scar Formation in Severe Acne.

Post-acne scarring in severe acne is a major aesthetic problem that can impair a patient's quality of life. It has been pointed out that blocking mast cell function with tranilast can prevent or minimize scarring and can be a satisfactory therapeutic strategy. Mast cells are prominent in acne lesions, and their involvement in scar formation has also been specified. Here, we discuss the importance of mast cell control in suppressing post-acne scar formation.

Impact of the TRPV2 Inhibitor on Advanced Heart Failure in Patients with Muscular Dystrophy: Exploratory Study of Biomarkers Related to the Efficacy of Tranilast.

Cardiomyopathy is the leading cause of death in patients with muscular dystrophy (MD). Tranilast, a widely used anti-allergic drug, has displayed inhibitory activity against the transient receptor potential cation channel subfamily V member 2 and improved cardiac function in MD patients. To identify urinary biomarkers that assess improved cardiac function after tranilast administration, we performed a urinary metabolomic study focused on oxidative fatty acids. Accompanying the clinical trial of tranilast, urine specimens were collected over 24 weeks from MD patients with advanced heart failure. Urinary levels of tetranor-PGDM (tetranor-prostaglandin D metabolite), a metabolite of prostaglandin D2, significantly decreased 12 weeks after tranilast administration and were correlated with BNP. These results suggest that prostaglandin-mediated inflammation, which increases with the pathological progression of heart failure in MD patients, was attenuated. Urinary prostaglandin E3 (PGE3) levels significantly increased 4 weeks after tranilast administration. There were positive correlations between the urinary levels of PGE3 and 8-hydroxy-2'-deoxyguanosine, an oxidative stress marker. High PGE3 levels may have a protective effect against cardiomyopathy in MD patients with high oxidative stress. Although further validation studies are necessary, urinary tetranor-PGDM and PGE3 levels may help the current understanding of the extent of advanced heart failure in patients with MD after tranilast administration.

Tranilast-matrine co-amorphous system: Strong intermolecular interactions, improved solubility, and physiochemical stability.

There is a great interest to develop co-amorphous drug delivery systems to enhance the solubility of biopharmaceutics classification system (BCS) class II and IV drugs. However, most reported systems only resulted in severalfold solubility improvement. Tranilast (TRA) is an anti-allergic drug used to treat bronchial asthma and allergic rhinitis. It is a BCS class II drug and its poor aqueous solubility affects its absorption in vivo. To address this issue, a natural alkaloid matrine (MAR) with interesting biological activities was chosen to form a co-amorphous system with TRA, based on the solubility parameter and phase solubility experiment. The TRA-MAR drug-drug co-amorphous system was prepared by the solvent evaporation method, and further characterized by powder X-ray diffraction and modulated temperature differential scanning calorimetry. Fourier transform infrared spectroscopy, FT-Raman, and X-ray photoelectron spectroscopy revealed the formation of salt and the presence of strong intermolecular interactions in the TRA-MAR co-amorphous system, which are also supported by molecular dynamics simulations, showing ionic and hydrogen bonding interactions. This co-amorphous system exhibited excellent physical stability at both 25 °C and 40 °C under anhydrous silica gel condition. Finally, co-amorphous TRA-MAR showed greatly enhanced solubility (greater than 100-fold) and rapid release behavior in the vitro release experiments. NMR spectroscopy revealed the strong intermolecular interactions between TRA and MAR in both DMSO­d6 and D2O. Our study resulted in a TRA-MAR co-amorphous drug system with significant solubility improvement and showcased the great potential to improve the dissolution behaviors of BCS class II and IV drugs through the co-amorphization approach.

Mechanism of anti-hyperuricemia of isobavachin based on network pharmacology and molecular docking.

BACKGROUND: Hyperuricemia is a more popular metabolic disease caused by a disorder of purine metabolism. Our previous study firstly screened out a natural product Isobavachin as anti-hyperuricemia targeted hURAT1 from a Chinese medicine Haitongpi (Cortex Erythrinae). In view of Isobavachin's diverse pharmacological activities, similar to the Tranilast (as another hURAT1 inhibitor), our study focused on its potential targets and molecular mechanisms of Isobavachin anti-hyperuricemia based on network pharmacology and molecular docking. METHODS: First of all, the putative target genes of compounds were screen out based on the public databases with different methods, such as SwissTargetPerdiction, PharmMapper and TargetNet,etc. Then the compound-pathways were obtained by the compounds' targets gene from David database for Gene Ontology (GO) function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis. The cross pathways of compound-pathways and the diseases pathways of hyperuricemia from Comparative Toxicogenomics Database were be considered as the compound-disease pathways. Next, based on the compound-disease pathways and the PPI network, the core targets were identified based on the retrieved disease-genes. Finally, the compound-target-pathway-disease network was constructed by Cytoscape and the mechanism of isobavachin anti-hyperuricemia was discussed based on the network analysis. RESULTS: Our study demonstrated that there were five pathways involved in Isobavachin against hyperuricemia, including Drug metabolism-other enzymes, Metabolic pathways, Bile secretion, Renin-angiotensin system and Renin secretion. Among the proteins involved in these pathways, HPRT1, REN and ABCG2 were identified as the core targets associated with hyperuricemia, which regulated the five pathways mentioned above. It is quite different from that of Tranilast, which involved in the same pathways except Bile secretion instead of purine metabolism. CONCLUSION: This study revealed Isobavachin could regulate the pathways including Drug metabolism-other enzymes, Metabolic pathways, Bile secretion, Renin-angiotensin system, Renin secretion by core targets HPRT1, REN and ABCG2, in the treatment of hyperuricemia effect. Among them, the Bile secretion regulated by ABCG2 probably would be a novel pathway. Our work provided a theoretical basis for the pharmacological study of Isobavachin in lowering uric acid and further basic research.

Effect of Tranilast on the Frequency of Invasive Treatment for Extra-Abdominal Desmoid Fibromatosis.

BACKGROUND: Active surveillance (AS) has been suggested for managing extra-abdominal desmoid fibromatosis (EADF), but a substantial percentage of such patients transitioned to invasive secondary treatments. The anti-keloid medication tranilast is frequently used in Japan but its effectiveness for EADF is not well understood. METHODS: We retrospectively analyzed the medical records of EADF patients treated with tranilast between January 2009 and March 2021. EADF has been reported to shrink spontaneously, so the effects of all drugs must be compared with AS. To assess the effect of tranilast, we compared the clinical courses of patients receiving tranilast with those managed by AS (as identified in a systematic review). A systematic review of AS outcomes was conducted on July 22, 2021, in accordance with PRISMA guidelines. The primary endpoint was rate of conversion to secondary treatment. Secondary endpoints were progression-free survival, objective response rate (ORR), disease control rate (DCR), and adverse events. The rates of conversion to secondary treatment, ORRs, and DCRs were compared between the two groups by using the Fisher exact test. RESULTS: Eighteen patients who received tranilast as initial treatment for EADF were included. Two patients (11.1%) underwent surgical resection for treatment of tumor growth and persistent pain. The rate of conversion to secondary treatment was significantly lower for tranilast than for a pure AS approach (40.1%; p = 0.01). ORR and DCR did not differ between groups. CONCLUSIONS: Tranilast was better than AS for initial management of EADF.

Seasonal facial erythema in a patient with allergic rhinitis treated using a combination of tranilast and roxithromycin.

OBJECTIVE: A competitive effect with suppression of Th2 immune responses of the tranilast and roxithromycin combination is examined in an allergic rhinitis patient. PATIENT AND METHODS: A 42-year-old female patient with allergic rhinitis caused by cedar pollen, which is one of the most common allergies during the spring, exhibited facial erythema with itching, particularly on both cheeks, and rhinitis symptoms, such as nasal discharge, and 200 mg/day of tranilast (original) and 300 mg/day of roxithromycin were administered. RESULTS: After 2 weeks, the patient's skin lesions were mostly eliminated, with the skin appearing almost normal; itching was nearly absent; and rhinitis symptoms disappeared. CONCLUSION: This combination may be a promising new therapeutic strategy for allergic rhinitis.

Nanomechanical properties of solid tumors as treatment monitoring biomarkers.

Many tumors, such as types of sarcoma and breast cancer, stiffen as they grow in a host healthy tissue, while individual cancer cells are becoming softer. Tumor stiffening poses major pathophysiological barriers to the effective delivery of drugs and compromises treatment efficacy. It has been established that normalization of the mechanical properties of a tumor by targeting components of the tumor microenvironment (TME) enhances the delivery of anti-cancer agents and consequently the therapeutic outcome. Consequently, there is an urgent need for the development of biomarkers, which characterize the mechanical state of a particular tumor for the development of personalized treatments or for monitoring therapeutic strategies that target the TME. In this work, Atomic Force Microscopy (AFM) was used to assess human and murine nanomechanical properties from tumor biopsies. In the case of murine tumor models, the nanomechanical properties during tumor progression were measured and a TME normalization drug (tranilast) along with chemotherapy doxorubicin were employed in order to investigate whether AFM has the ability to capture changes in the nanomechanical properties of a tumor during treatment. The nanomechanical data were further correlated with ex vivo characterization of structural components of the TME. The results highlighted that nanomechanical properties alter during cancer progression and AFM measurements are sensitive enough to capture even small alterations during different types of treatments, namely normalization and chemotherapy. The identification of unique AFM-based nanomechanical properties can lead to the development of biomarkers for treatment prediction and monitoring. STATEMENT OF SIGNIFICANCE: Cancer progression is associated with vast remodeling of the tumor microenvironment resulting in changes in the mechanical properties of the tissue. Indeed, many tumors stiffen as they grow and this stiffening compromises treatment efficacy. As a result, a number of treatments target tumor microenvironment in order to normalize its mechanical properties. Consequently, there is an urgent need for the development of innovative tools that can assess the mechanical properties of a particular tumor and monitor tumor progression and treatment outcomes. This work highlights the use of atomic force microscopy (AFM) for assessing the elasticity spectrum of solid tumors at different stages and during treatment. This knowledge is essential for the development of AFM-based nanomechanical biomarkers for treatment prediction and monitoring.

A multi-target directed ligands strategy for the treatment of Alzheimer's disease: Dimethyl fumarate plus Tranilast modified Dithiocarbate as AChE inhibitor and Nrf2 activator.

Alzheimer's disease (AD) possessed intricate pathogenesis. Currently, multi-targeted drugs were considered to have the potential to against AD by simultaneously triggering molecules in functionally complementary pathways. Hence, a series of molecules based on the pharmacophoric features of Dimethyl fumarate, Tranilast, and Dithiocarbate were designed and synthesized. These compounds showed significant AChE inhibitory activity in vitro. Among them, compound 4c2 displayed the mighty inhibitory activity to hAChE (IC50 = 0.053 µM) and held the ability to cross the BBB. Kinetic study and molecular docking pointed out that 4c2 bound well into the active sites of hAChE, forming steady and sturdy interactions with key residues in hAChE. Additionally, 4c2 as an Nrf2 activator could promote the nuclear translocation of Nrf2 protein and induce the expressions of Nrf2-dependent enzymes HO-1, NQO1, and GPX4. Moreover, 4c2 rescued BV-2 cells from H2O2-induced injury and inhibited ROS accumulation. For the anti-neuroinflammatory potential of 4c2, we observed that 4c2 could lower the levels of pro-inflammatory cytokines (NO, IL-6 and TNF-α) and suppressed the expressions of iNOS and COX-2. In particular, 4c2 was well tolerated in mice (2500 mg/kg, p.o.) and efficaciously recovered the memory impairment in a Scopolamine-induced mouse model. Overall, these results highlighted that 4c2 was a promising multi-targeted agent for treating AD.

Drug repositioning of tranilast to sensitize a cancer therapy by targeting cancer-associated fibroblast.

Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment that mediate resistance of cancer cells to anticancer drugs. Tranilast is an antiallergic drug that suppresses the release of cytokines from various inflammatory cells. In this study, we investigated the inhibitory effect of tranilast on the interactions between non-small cell lung cancer (NSCLC) cells and the CAFs in the tumor microenvironment. Three EGFR-mutant NSCLC cell lines, two KRAS-mutant cell lines, and three CAFs derived from NSCLC patients were used. To mimic the tumor microenvironment, the NSCLC cells were cocultured with the CAFs in vitro, and the molecular profiles and sensitivity to molecular targeted therapy were assessed. Crosstalk between NSCLC cells and CAFs induced multiple biological effects on the NSCLC cells both in vivo and in vitro, including activation of the STAT3 signaling pathway, promotion of xenograft tumor growth, induction of epithelial-mesenchymal transition (EMT), and acquisition of resistance to molecular-targeted therapy, including EGFR-mutant NSCLC cells to osimertinib and of KRAS-mutant NSCLC cells to selumetinib. Treatment with tranilast led to inhibition of IL-6 secretion from the CAFs, which, in turn, resulted in inhibition of CAF-induced phospho-STAT3 upregulation. Tranilast also inhibited CAF-induced EMT in the NSCLC cells. Finally, combined administration of tranilast with molecular-targeted therapy reversed the CAF-mediated resistance of the NSCLC cells to the molecular-targeted drugs, both in vitro and in vivo. Our results showed that combined administration of tranilast with molecular-targeted therapy is a possible new treatment strategy to overcome drug resistance caused by cancer-CAF interaction.

Nanomicelle-generating Microneedles Loaded With Tranilast for Treatment of Hypertrophic Scars in a Rabbit Model.

BACKGROUND/AIM: Hypertrophic scars (HS) are the result of pathological wound healing characterized by a red, raised scar formation. The goal of this research was development of a new method for treatment of HS formation. MATERIALS AND METHODS: A tranilast-loaded microneedle (TMN) was developed and applied in a rabbit ear model to treat an induced HS. Scar elevation index, the thickness of dorsal skin by hematoxylin and eosin staining, collagen deposition by Masson trichrome staining and expression of myofibroblast biomarker proteins were evaluated. RESULTS: The 12×12 array of the TMN containing 2.9 µg tranilast per needle released more than 80% of the drug within 30 min. During the procedure, control, non-loaded MN and TMN loaded with three different doses of tranilast (low: 2.5-3, medium: 25-30, and high: 100-150 µg) were applied to the HS in rabbit ears. High-level TMN led to a clear and natural appearance of skin, a decrease in scar elevation index by 47% and decline in the thickness of the epidermis from 69.27 to 15.92 µm when compared to the control group. Moreover, the collagen density also decreased in groups treated with medium- or high-level TMNs, by 10.2% and 9.06%, respectively. Furthermore, the expression of transforming growth factor-ß, collagen-1, and α-smooth muscle actin proteins was reduced in TMN-treated HSs compared to the control. CONCLUSION: The findings show the overall efficacy of TMNs in inhibiting HS. Thus, use of TMN is a simple and cosmetic remedy for HS, with good protection and reliability.