Dahuang Zhechong Pills Suppress Silicosis Fibrosis Progression via p38 MAPK/TGF-β1/Smad Pathway In Vitro

Background. Dahuang Zhechong pills (DHZCP) is a classic Chinese medicinal prescription in “Treatise on Cold Pathogenic and Miscellaneous Diseases (Shanghan Zabing Lun),” and it has the function of tonifying blood, nourishing Yin, and removing blood stasis. Previous studies have shown that DHZCP could alleviate SiO2 induced pulmonary fibrosis in mice. This study aims to further explore the preventive and therapeutic effects of DHZCP against silicosis fibrosis and the underlying mechanisms in vitro. Methods. We used the experimental model of SiO2-induced MH-S cells to evaluate the therapeutic potential of DHZCP. MH-S cells induced by SiO2 were intervened with the drug-containing serum of DHZCP, and the effects of drug-containing serum of DHZCP on the MH-S cells were detected by CCK8, ELISA, flow cytometry, western blot, and immunofluorescence. Results. DHZCP improved cell viability by reducing apoptosis. It also decreased the levels of TNF-α, IL-1β, IL-6 in the supernatant of MH-S cells induced by SiO2, inhibited the expression of p38 MAPK, blocked the activation of NF-κB, and controlled the upstream inflammatory response by multiple targeting. Concomitantly, we observed upregulation of Smad7 and a marked decline in TGF-β1, α-SMA, Smad2, Smad3 expression in MH-S cells treated with DHZCP. Conclusion. To sum up, we conclude that DHZCP protects against SiO2-induced silicosis by reducing the persistent irritation of inflammation, regulating the p38 MAPK/TGF-β1/Smad pathway.

Download Full-text

20(S)-ginsenoside Rh2 as agent for the treatment of LMN-CRC via regulating epithelial–mesenchymal transition

Bioscience Reports ◽

10.1042/bsr20191507 ◽

2020 ◽

Vol 40 (3) ◽

Author(s):

Yihang Yuan ◽

Jue Wang ◽

Ming Xu ◽

Yunpeng Zhang ◽

Zhiqiang Wang ◽

...

Keyword(s):

Epithelial Mesenchymal Transition ◽

Therapeutic Potential ◽

Potential Effect ◽

Therapeutic Effects ◽

Dependent Manner ◽

Ginsenoside Rh2 ◽

Mesenchymal Transition ◽

Underlying Mechanisms

Abstract The lymph node metastasis of colorectal cancer (LMN-CRC) seriously threatens the prognosis of patients. Chemotherapy, as the most common treatment, results in severe bone marrow suppression. 20(S)-ginsenoside Rh2 (SGRh2), a major effective constituent of ginseng, has demonstrated therapeutic effects on a variety of diseases, including some tumours. SGRh2 treatment had no effect on other organs. Therefore, ginsenosides are considered a safe and effective antineoplastic drug. However, the effects of SGRh2 on LMN-CRC remain unknown. The present study investigated the potential effect of SGRh2 on LMN-CRC in vitro and in vivo. SW480 and CoLo205 cell lines were treated with SGRh2. SGRh2 dose-dependently decreased CRC cell proliferation by CCK-8, colony formation and Edu assays. The Transwell and scratch assays revealed that SGRh2 inhibits the migratory and invasive abilities of CRC cells in a dose-dependent manner. Furthermore, the results of Western blotting revealed that SGRh2 decreased the expression of matrix metalloproteinase (MMP)-2 and MMP9. In terms of the underlying mechanisms, SGRh2 regulates CRC metastasis by affecting epithelial–mesenchymal transition (EMT), which significantly up-regulated epithelial biomarkers (E-cadherin) and down-regulated mesenchymal biomarkers (N-cadherin and vimentin) and EMT transcriptional factors (Smad-3, Snail-1, and Twist-1). In vivo, SGRh2 significantly inhibited LMN-CRC without affecting other normal organs. Immunohistochemical results showed that SGRh2 treats LMN-CRC by regulating EMT. These results demonstrate that SGRh2 has therapeutic potential for LMN-CRC.

Download Full-text

Phytosomal Curcumin Elicits Anti-tumor Properties Through Suppression of Angiogenesis, Cell Proliferation and Induction of Oxidative Stress in Colorectal Cancer

Current Pharmaceutical Design ◽

10.2174/1381612825666190110145151 ◽

2019 ◽

Vol 24 (39) ◽

pp. 4626-4638 ◽

Cited By ~ 13

Author(s):

Reyhaneh Moradi-Marjaneh ◽

Seyed M. Hassanian ◽

Farzad Rahmani ◽

Seyed H. Aghaee-Bakhtiari ◽

Amir Avan ◽

...

Keyword(s):

Oxidative Stress ◽

Colorectal Cancer ◽

Therapeutic Potential ◽

Vegf Signaling ◽

Anticancer Effects ◽

Inhibition Of Angiogenesis ◽

Underlying Mechanisms ◽

Apoptotic Activity

Background: Colorectal cancer (CRC) is one of the most common causes of cancer-associated mortality in the world. Anti-tumor effect of curcumin has been shown in different cancers; however, the therapeutic potential of novel phytosomal curcumin, as well as the underlying molecular mechanism in CRC, has not yet been explored. Methods: The anti-proliferative, anti-migratory and apoptotic activity of phytosomal curcumin in CT26 cells was assessed by MTT assay, wound healing assay and Flow cytometry, respectively. Phytosomal curcumin was also tested for its in-vivo activity in a xenograft mouse model of CRC. In addition, oxidant/antioxidant activity was examined by DCFH-DA assay in vitro, measurement of malondialdehyde (MDA), Thiol and superoxidedismutase (SOD) and catalase (CAT) activity and also evaluation of expression levels of Nrf2 and GCLM by qRT-PCR in tumor tissues. In addition, the effect of phytosomal curcumin on angiogenesis was assessed by the measurement of VEGF-A and VEGFR-1 and VEGF signaling regulatory microRNAs (miRNAs) in tumor tissue. Results: Phytosomal curcumin exerts anti-proliferative, anti-migratory and apoptotic activity in-vitro. It also decreases tumor growth and augmented 5-fluorouracil (5-FU) anti-tumor effect in-vivo. In addition, our data showed that induction of oxidative stress and inhibition of angiogenesis through modulation of VEGF signaling regulatory miRNAs might be underlying mechanisms by which phytosomal curcumin exerted its antitumor effect. Conclusion: Our data confirmed this notion that phytosomal curcumin administrates anticancer effects and can be used as a complementary treatment in clinical settings.

Download Full-text

Apigenin Alleviates Renal Fibroblast Activation through AMPK and ERK Signaling Pathways In Vitro

Current Pharmaceutical Biotechnology ◽

10.2174/1389201021666200320140908 ◽

2020 ◽

Vol 21 (11) ◽

pp. 1107-1118

Author(s):

Ningning Li ◽

Zhan Wang ◽

Tao Sun ◽

Yanfei Lei ◽

Xianghua Liu ◽

...

Keyword(s):

Renal Fibrosis ◽

Transforming Growth Factor ◽

Therapeutic Potential ◽

Protective Role ◽

Fibroblast Proliferation ◽

Fibroblast Activation ◽

And Function ◽

Activated Fibroblasts ◽

Tgf Β1

Objective: Renal fibrosis is a common pathway leading to the progression of chronic kidney disease. Activated fibroblasts contribute remarkably to the development of renal fibrosis. Although apigenin has been demonstrated to play a protective role from fibrotic diseases, its pharmacological effect on renal fibroblast activation remains largely unknown. Materials and Methods: Here, we examined the functional role of apigenin in the activation of renal fibroblasts response to transforming growth factor (TGF)-β1 and its potential mechanisms. Cultured renal fibroblasts (NRK-49F) were exposed to apigenin (1, 5, 10 and 20 μM), followed by the stimulation of TGF-β1 (2 ng/mL) for 24 h. The markers of fibroblast activation were determined. In order to confirm the anti-fibrosis effect of apigenin, the expression of fibrosis-associated genes in renal fibroblasts was assessed. As a consequence, apigenin alleviated fibroblast proliferation and fibroblastmyofibroblast differentiation induced by TGF-β1. Result: Notably, apigenin significantly inhibited the fibrosis-associated genes expression in renal fibroblasts. Moreover, apigenin treatment significantly increased the phosphorylation of AMP-activated protein kinase (AMPK). Apigenin treatment also obviously reduced TGF-β1 induced phosphorylation of ERK1/2 but not Smad2/3, p38 and JNK MAPK in renal fibroblasts. Conclusion: In a summary, these results indicate that apigenin inhibits renal fibroblast proliferation, differentiation and function by AMPK activation and reduced ERK1/2 phosphorylation, suggesting it could be an attractive therapeutic potential for the treatment of renal fibrosis.

Download Full-text

Concurrent YAP/TAZ and SMAD signaling mediate vocal fold fibrosis

Scientific Reports ◽

10.1038/s41598-021-92871-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ryosuke Nakamura ◽

Nao Hiwatashi ◽

Renjie Bing ◽

Carina P. Doyle ◽

Ryan C. Branski

Keyword(s):

Vocal Fold ◽

Vocal Folds ◽

Nuclear Accumulation ◽

Smad Pathway ◽

Surgical Interventions ◽

Smad Signaling ◽

Iatrogenic Damage ◽

Tgf Β1

AbstractVocal fold (VF) fibrosis is a major cause of intractable voice-related disability and reduced quality of life. Excision of fibrotic regions is suboptimal and associated with scar recurrence and/or further iatrogenic damage. Non-surgical interventions are limited, putatively related to limited insight regarding biochemical events underlying fibrosis, and downstream, the lack of therapeutic targets. YAP/TAZ integrates diverse cell signaling events and interacts with signaling pathways related to fibrosis, including the TGF-β/SMAD pathway. We investigated the expression of YAP/TAZ following vocal fold injury in vivo as well as the effects of TGF-β1 on YAP/TAZ activity in human vocal fold fibroblasts, fibroblast-myofibroblast transition, and TGF-β/SMAD signaling. Iatrogenic injury increased nuclear localization of YAP and TAZ in fibrotic rat vocal folds. In vitro, TGF-β1 activated YAP and TAZ in human VF fibroblasts, and inhibition of YAP/TAZ reversed TGF-β1-stimulated fibroplastic gene upregulation. Additionally, TGF-β1 induced localization of YAP and TAZ in close proximity to SMAD2/3, and nuclear accumulation of SMAD2/3 was inhibited by a YAP/TAZ inhibitor. Collectively, YAP and TAZ were synergistically activated with the TGF-β/SMAD pathway, and likely essential for the fibroplastic phenotypic shift in VF fibroblasts. Based on these data, YAP/TAZ may evolve as an attractive therapeutic target for VF fibrosis.

Download Full-text

GPR37 promotes the malignancy of lung adenocarcinoma via TGF-β/Smad pathway

Open Medicine ◽

10.1515/med-2021-0011 ◽

2020 ◽

Vol 16 (1) ◽

pp. 024-032

Author(s):

Jian Wang ◽

Min Xu ◽

Dan-Dan Li ◽

Wujikenayi Abudukelimu ◽

Xiu-Hong Zhou

Keyword(s):

Lung Adenocarcinoma ◽

Biological Function ◽

Migration And Invasion ◽

Loss Of Function ◽

Malignant Phenotype ◽

Smad Pathway ◽

Smad3 Phosphorylation ◽

Poor Outcomes ◽

Tgf Β1

AbstractThis paper aimed to research the function and in-depth mechanism of GPR37 in lung adenocarcinoma (LUAD). Herein, based on TCGA and Oncomine databases, we revealed that GPR37 was expressed at high levels in LUAD, and upregulation of GPR37 was related to the poor outcomes. Furthermore, biological function experiments in vitro were utilized to assess whether GPR37 impacts malignant phenotype of LUAD cells. Gain- or loss-of-function assays indicated that the upregulation of GPR37 contributed to improving the proliferation, migration, and invasion of LUAD cells in vitro, while knockdown of GPR37 can inhibit the malignant biological behaviors. Then, we found that depletion of GPR37 resulted in a decrease in the expression of TGF-β1 as well as the extents of Smad2 and Smad3 phosphorylation, while overexpression of GPR37 presented opposite outcomes. Altogether, our findings indicated that GPR37 is a potential oncogene of LUAD, and its promoting effects on the malignant progression of LUAD may be realized via TGF-β/Smad pathway.

Download Full-text

Prrx1 promotes stemness and angiogenesis via activating TGF-β/smad pathway and upregulating proangiogenic factors in glioma

Cell Death and Disease ◽

10.1038/s41419-021-03882-7 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Zetao Chen ◽

Yihong Chen ◽

Yan Li ◽

Weidong Lian ◽

Kehong Zheng ◽

...

Keyword(s):

Stem Cells ◽

Therapeutic Strategy ◽

Critical Role ◽

Glioma Stem Cells ◽

Promoter Regions ◽

Aberrant Expression ◽

Smad Pathway ◽

Tgf Β1

AbstractGlioma is one of the most lethal cancers with highly vascularized networks and growing evidences have identified glioma stem cells (GSCs) to account for excessive angiogenesis in glioma. Aberrant expression of paired-related homeobox1 (Prrx1) has been functionally associated with cancer stem cells including GSCs. In this study, Prrx1 was found to be markedly upregulated in glioma specimens and elevated Prrx1 expression was inversely correlated with prognosis of glioma patients. Prrx1 potentiated stemness acquisition in non-stem tumor cells (NSTCs) and stemness maintenance in GSCs, accompanied with increased expression of stemness markers such as SOX2. Prrx1 also promoted glioma angiogenesis by upregulating proangiogenic factors such as VEGF. Consistently, silencing Prrx1 markedly inhibited glioma proliferation, stemness, and angiogenesis in vivo. Using a combination of subcellular proteomics and in vitro analyses, we revealed that Prrx1 directly bound to the promoter regions of TGF-β1 gene, upregulated TGF-β1 expression, and ultimately activated the TGF-β/smad pathway. Silencing TGF-β1 mitigated the malignant behaviors induced by Prrx1. Activation of this pathway cooperates with Prrx1 to upregulate the expression of stemness-related genes and proangiogenic factors. In summary, our findings revealed that Prrx1/TGF-β/smad signal axis exerted a critical role in glioma stemness and angiogeneis. Disrupting the function of this signal axis might represent a new therapeutic strategy in glioma patients.

Download Full-text

Targeting necroptosis as therapeutic potential in chronic myocardial infarction

Journal of Biomedical Science ◽

10.1186/s12929-021-00722-w ◽

2021 ◽

Vol 28 (1) ◽

Author(s):

Chanon Piamsiri ◽

Chayodom Maneechote ◽

Natthaphat Siri-Angkul ◽

Siriporn C. Chattipakorn ◽

Nipon Chattipakorn

Keyword(s):

Myocardial Infarction ◽

Therapeutic Potential ◽

Coronary Perfusion ◽

Beneficial Effects ◽

Cell Death Pathways ◽

Threatening Condition ◽

Underlying Mechanisms ◽

Novel Therapeutic Strategies

AbstractCardiovascular diseases (CVDs) are considered the predominant cause of morbidity and mortality globally. Of these, myocardial infarction (MI) is the most common cause of CVD mortality. MI is a life-threatening condition which occurs when coronary perfusion is interrupted leading to cardiomyocyte death. Subsequent to MI, consequences include adverse cardiac remodeling and cardiac dysfunction mainly contribute to the development of heart failure (HF). It has been shown that loss of functional cardiomyocytes in MI-induced HF are associated with several cell death pathways, in particular necroptosis. Although the entire mechanism underlying necroptosis in MI progression is still not widely recognized, some recent studies have reported beneficial effects of necroptosis inhibitors on cell viability and cardiac function in chronic MI models. Therefore, extensive investigation into the necroptosis signaling pathway is indicated for further study. This article comprehensively reviews the context of the underlying mechanisms of necroptosis in chronic MI-induced HF in in vitro, in vivo and clinical studies. These findings could inform ways of developing novel therapeutic strategies to improve the clinical outcomes in MI patients from this point forward.

Download Full-text

Selonsertib Alleviates the Progression of Rat Osteoarthritis: An in vitro and in vivo Study

Frontiers in Pharmacology ◽

10.3389/fphar.2021.687033 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jiyuan Yan ◽

Yingchi Zhang ◽

Gaohong Sheng ◽

Bowei Ni ◽

Yifan Xiao ◽

...

Keyword(s):

Therapeutic Potential ◽

Cartilage Damage ◽

Cartilage Degradation ◽

Degenerative Joint Disease ◽

Joint Disease ◽

Therapeutic Effects ◽

Exact Role

Osteoarthritis (OA) is a prevalent degenerative joint disease. Its development is highly associated with inflammatory response and apoptosis in chondrocytes. Selonsertib (Ser), the inhibitor of Apoptosis Signal-regulated kinase-1 (ASK1), has exhibited multiple therapeutic effects in several diseases. However, the exact role of Ser in OA remains unclear. Herein, we investigated the anti-arthritic effects as well as the potential mechanism of Ser on rat OA. Our results showed that Ser could markedly prevent the IL-1β-induced inflammatory reaction, cartilage degradation and cell apoptosis in rat chondrocytes. Meanwhile, the ASK1/P38/JNK and NFκB pathways were involved in the protective roles of Ser. Furthermore, intra-articular injection of Ser could significantly alleviate the surgery induced cartilage damage in rat OA model. In conclusion, our work provided insights into the therapeutic potential of Ser in OA, indicating that Ser might serve as a new avenue in OA treatment.

Download Full-text

P13.08 Novel Thioridazine derivates: Antiproliferative and apoptosis-inducing activity on glioblastoma cells in vitro

Neuro-Oncology ◽

10.1093/neuonc/noab180.116 ◽

2021 ◽

Vol 23 (Supplement_2) ◽

pp. ii34-ii34

Author(s):

S G Schwab ◽

K Sarnow ◽

E Alme ◽

R Goldbrunner ◽

H Bjørsvik ◽

...

Keyword(s):

Imaging System ◽

Therapeutic Potential ◽

Flow Cytometric Analysis ◽

Annexin V ◽

Therapeutic Effects ◽

Cell Viability Assay ◽

Selective Cytotoxicity ◽

Viability Assay

Abstract BACKGROUND Although withdrawn from the market due to cardiotoxicity, we have shown that the antipsychotic drug Thioridazine shows chemosensitizing effects in combination with Temozolomide (TMZ) for the treatment of glioblastoma multiforme (GBM). Based on our prior observations, the aim of the presented project was through medicinal chemistry, to design and synthesize new compounds based on Thioridazines tricyclic structure, and to determine their therapeutic potential. MATERIAL AND METHODS Fourteen compounds were synthesized where variations were made within the tricyclic side chains. The newly synthesized compounds were screened for therapeutic efficacy with or without TMZ using a WST-1 cell viability assay as well as a real-time imaging system (IncuCyte). Tests were performed on both monolayer cell cultures, as well as on glioma stem cell spheroids (GSC). The therapeutic effects were also studied on human astrocytes (NHA) as well as on rat brain organoids (BO). Annexin V/propidium iodide (PI) double staining followed by flow cytometric analysis was performed after 48 hours of treatment. RESULTS Following an extensive screening, we identified two novel compounds (EA01 and EA02) that at concentrations of 4 and 9.5 µM showed a strong cytotoxicity on GBM cell lines (U-87 MG p<0,0001, U251 p<0,0001, LN18 p=0,0004) as well as on glioma stem cells (GSC) (P3 p<0,0001) compared to NHA and BOs respectively. Also, when BOs were confronted with GSC spheres in an invasion assay, a selective cytotoxicity was observed in the GSCs. Mechanistically, we show that both compounds induce apoptosis in the GBM cells. Moreover, intravenous delivery of increasing concentrations of EA01 and EA02 revealed no toxicity in animals at concentrations up to 21 mg/kg. CONCLUSION We have developed two new tricyclic therapeutic compounds that show a strong selective cytotoxicity in GBM cells with limited systemic toxicity in animals. Ongoing studies are investigating the therapeutic potential of EA01 and EA02 in orthotopic xenografts in vivo.

Download Full-text

Therapeutic Potential of 47Sc in Comparison to 177Lu and 90Y: Preclinical Investigations

Pharmaceutics ◽

10.3390/pharmaceutics11080424 ◽

2019 ◽

Vol 11 (8) ◽

pp. 424 ◽

Cited By ~ 6

Author(s):

Klaudia Siwowska ◽

Patrycja Guzik ◽

Katharina A. Domnanich ◽

Josep M. Monné Rodríguez ◽

Peter Bernhardt ◽

...

Keyword(s):

Radionuclide Therapy ◽

Therapeutic Potential ◽

Folate Receptor ◽

Tumor Growth Inhibition ◽

Therapeutic Effects ◽

Targeted Radionuclide Therapy ◽

Decay Properties ◽

Therapeutic Properties ◽

Folate Conjugate

Targeted radionuclide therapy with 177Lu- and 90Y-labeled radioconjugates is a clinically-established treatment modality for metastasized cancer. 47Sc is a therapeutic radionuclide that decays with a half-life of 3.35 days and emits medium-energy β−-particles. In this study, 47Sc was investigated, in combination with a DOTA-folate conjugate, and compared to the therapeutic properties of 177Lu-folate and 90Y-folate, respectively. In vitro, 47Sc-folate demonstrated effective reduction of folate receptor-positive ovarian tumor cell viability similar to 177Lu-folate, but 90Y-folate was more potent at equal activities due to the higher energy of emitted β−-particles. Comparable tumor growth inhibition was observed in mice that obtained the same estimated absorbed tumor dose (~21 Gy) when treated with 47Sc-folate (12.5 MBq), 177Lu-folate (10 MBq), and 90Y-folate (5 MBq), respectively. The treatment resulted in increased median survival of 39, 43, and 41 days, respectively, as compared to 26 days in untreated controls. There were no statistically significant differences among the therapeutic effects observed in treated groups. Histological assessment revealed no severe side effects two weeks after application of the radiofolates, even at double the activity used for therapy. Based on the decay properties and our results, 47Sc is likely to be comparable to 177Lu when employed for targeted radionuclide therapy. It may, therefore, have potential for clinical translation and be of particular interest in tandem with 44Sc or 43Sc as a diagnostic match, enabling the realization of radiotheragnostics in future.

Download Full-text