scholarly journals Gypenosides Attenuate Pulmonary Fibrosis by Inhibiting the AKT/mTOR/c-Myc Pathway

2022 ◽  
Vol 12 ◽  
Author(s):  
Suqing Liu ◽  
Qingqing Yang ◽  
Binbin Dong ◽  
Chunhui Qi ◽  
Tao Yang ◽  
...  

Gypenosides (Gyps), the major active constituents isolated from Gynostemma pentaphyllum, possess anti-inflammatory and antioxidant activities. Previous studies have demonstrated that Gyps displayed potent ameliorative effects on liver fibrosis and renal fibrosis. In this study, we found that Gyps significantly reduced the mortality of bleomycin-induced pulmonary fibrosis mice (40% mortality rate of mice in the model group versus 0% in the treatment group). Masson staining showed that Gyps could reduce the content of collagen in the lung tissue of pulmonary fibrosis mice Masson staining and immunohistochemistry demonstrated that the expression of the collagen gene α-SMA and fibrosis gene Col1 markedly decreased after Gyps treatment. The active mitosis of fibroblasts is one of the key processes in the pathogenesis of fibrotic diseases. RNA-seq showed that Gyps significantly inhibited mitosis and induced the G2/M phase cell cycle arrest. The mTOR/c-Myc axis plays an important role in the pathological process of pulmonary fibrosis. RNA-seq also demonstrated that Gyps inhibited the mTOR and c-Myc signaling in pulmonary fibrosis mice, which was further validated by Western blot and immunohistochemistry. AKT functions as an upstream molecule that regulates mTOR. Our western blot data showed that Gyps could suppress the activation of AKT. In conclusion, Gyps exerted anti-pulmonary fibrosis activity by inhibiting the AKT/mTOR/c-Myc pathway.

2019 ◽  
Vol 19 (1) ◽  
pp. 66-91 ◽  
Author(s):  
Ferda Kaleağasıoğlu ◽  
Maya M. Zaharieva ◽  
Spiro M. Konstantinov ◽  
Martin R. Berger

Background:Alkylphospholipids (APLs) are synthetically derived from cell membrane components, which they target and thus modify cellular signalling and cause diverse effects. This study reviews the mechanism of action of anticancer, antiprotozoal, antibacterial and antiviral activities of ALPs, as well as their clinical use.Methods:A literature search was used as the basis of this review.Results:ALPs target lipid rafts and alter phospholipase D and C signalling cascades, which in turn will modulate the PI3K/Akt/mTOR and RAS/RAF/MEK/ERK pathways. By feedback coupling, the SAPK/JNK signalling chain is also affected. These changes lead to a G2/M phase cell cycle arrest and subsequently induce programmed cell death. The available knowledge on inhibition of AKT phosphorylation, mTOR phosphorylation and Raf down-regulation renders ALPs as attractive candidates for modern medical treatment, which is based on individualized diagnosis and therapy. Corresponding to their unusual profile of activities, their side effects result from cholinomimetic activity mainly and focus on the gastrointestinal tract. These aspects together with their bone marrow sparing features render APCs well suited for modern combination therapy. Although the clinical success has been limited in cancer diseases so far, the use of miltefosine against leishmaniosis is leading the way to better understanding their optimized use.Conclusion:Recent synthetic programs generate congeners with the increased therapeutic ratio, liposomal formulations, as well as diapeutic (or theranostic) derivatives with optimized properties. It is anticipated that these innovative modifications will pave the way for the further successful development of ALPs.


Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 501
Author(s):  
So Hyun Park ◽  
Ji-Young Hong ◽  
Hyen Joo Park ◽  
Sang Kook Lee

Oxypeucedanin (OPD), a furocoumarin compound from Angelica dahurica (Umbelliferae), exhibits potential antiproliferative activities in human cancer cells. However, the underlying molecular mechanisms of OPD as an anticancer agent in human hepatocellular cancer cells have not been fully elucidated. Therefore, the present study investigated the antiproliferative effect of OPD in SK-Hep-1 human hepatoma cells. OPD effectively inhibited the growth of SK-Hep-1 cells. Flow cytometric analysis revealed that OPD was able to induce G2/M phase cell cycle arrest in cells. The G2/M phase cell cycle arrest by OPD was associated with the downregulation of the checkpoint proteins cyclin B1, cyclin E, cdc2, and cdc25c, and the up-regulation of p-chk1 (Ser345) expression. The growth-inhibitory activity of OPD against hepatoma cells was found to be p53-dependent. The p53-expressing cells (SK-Hep-1 and HepG2) were sensitive, but p53-null cells (Hep3B) were insensitive to the antiproliferative activity of OPD. OPD also activated the expression of p53, and thus leading to the induction of MDM2 and p21, which indicates that the antiproliferative activity of OPD is in part correlated with the modulation of p53 in cancer cells. In addition, the combination of OPD with gemcitabine showed synergistic growth-inhibitory activity in SK-Hep-1 cells. These findings suggest that the anti-proliferative activity of OPD may be highly associated with the induction of G2/M phase cell cycle arrest and upregulation of the p53/MDM2/p21 axis in SK-HEP-1 hepatoma cells.


2022 ◽  
Author(s):  
Selvaraj Shyamsivappan ◽  
Raju Vivek ◽  
Thangaraj Suresh ◽  
Palanivel Naveen ◽  
Kaviyarasu Adhigaman ◽  
...  

A progression of new N-(3'-acetyl-8-nitro-2,3-dihydro-1H,3'H-spiro[quinoline-4,2'-[1,3,4]thiadiazol]-5'-yl) acetamide derivatives were synthesized from potent 8-nitro quinoline-thiosemicarbazones. The synthesized compounds were characterized by different spectroscopic studies and single X-ray crystallographic studies. The compounds were...


2018 ◽  
Vol 49 (2) ◽  
pp. 501-511 ◽  
Author(s):  
Hao Liu ◽  
Yi He ◽  
Zhaolei Jiang ◽  
Saie Shen ◽  
Ju Mei ◽  
...  

Background/Aims: Pulmonary fibrosis is a common outcome of various interstitial lung diseases. Prodigiosin (PG) is a series of red pigment with methoxypyrrole ring. This studyinvestigates therole of prodigiosin in pulmonary fibrosis and its underlying mechanisms. Methods: A pulmonary fibrosis rat model was established by intra-trachealinjection ofbleomycin A5. Rats were divided into 4 groups: Normal group, pulmonary fibrosis Model group, Prodigiosin treatment group and hydrocortisone treatmentgroup. HE and Masson staining were carried outto evaluate histopathological changes. The content of hydroxyproline in lung tissue was determined by alkaline hydrolysis. The expression of PICP and PIIINP was examined by ELISA. The mRNA expression of miR-410, TGF-β1 and ADAMTS1 in lung homogenate were detected by RT-PCR. The bronchoalveolar lavage fluid (BALF) and lung tissues of rats were collected and analyzed. Human embryonic pulmonary fibroblast (HEPF) was used for study in vitro. A dual-luciferase reporter assay was conducted to examine the effect of miR-410 on ADAMTS1 expression. Cell transfection was conducted to inhibit miR-410. MTT assay was performed to investigate cell proliferation. The expressions of miR-410, TGF-β1, ADAMTS1and other fibrosis related biomarkers (Col I, Col III, and α-SMA) wereexamined by RT-PCR and Western Blot. Results: HE and Masson staining showed thickened alveolar septum, hyperplasticcapillaries, and large areas of collagen fiber deposition in pulmonary fibrosis model rats. Rats in prodigiosin and hydrocortisone treatment groups had alleviated symptoms. There was high hydroxyproline expression in model rats, whereas the expression of hydroxyproline reduced after prodigiosin or hydrocortisone treatments. RT-PCR results showed high miR-410,high TGF-β1 and low ADAMTS1 in lung tissue of model rats. The expression of PICP and PIIINP werehigher in BALF of model group than in treatment groups. Prodigiosin and hydrocortisone treatment significantly reduced PICP and PIIINP content. RT-PCR and Western Blot analysis showed that prodigiosin inhibited expression of miR-410 and TGF-β1, but up-regulated ADAMTS1 expression. MTT assay indicated that prodigiosin inhibited HEPF proliferation induced by miR-410 overexpression. Conclusion: Prodigiosin down-regulates the expression of miR-410 and TGF-β1, up-regulates ADAMTS1, leading to decrease accumulation of fibrotic proteins. It could be used in alleviating pulmonary fibrosis.


2021 ◽  
Author(s):  
Selvaraj Shyamsivappan ◽  
Raju Vivek ◽  
Thangaraj Suresh ◽  
Adhigaman Kaviyarasu ◽  
Sundarasamy Amsaveni ◽  
...  

Abstract A progression of novel thiadiazoline spiro quinoline derivatives were synthesized from potent thiadiazoline spiro quinoline derivatives . The synthesized compounds portrayed by different spectroscopic studies and single X-ray crystallographic studies. The compounds were assessed for in vitro anticancer properties towards MCF-7 and HeLa cells. The compounds showed superior inhibition action MCF-7 malignant growth cells. Amongst, the compound 4a showed significant inhibition activity, the cell death mechanism was evaluated by fluorescent staining, and flow cytometry, RT-PCR, and western blot analyses. The in vitro anticancer results revealed that the compound 4a induced apoptosis by inhibition of estrogen receptor alpha (ERα) and G2/M phase cell cycle arrest. The binding affinity of the compounds with ERα and pharmacokinetic properties were confirmed by molecular docking studies.


Pharmaceutics ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 512 ◽  
Author(s):  
Sanchez-Carranza ◽  
González-Maya ◽  
Razo-Hernández ◽  
Salas-Vidal ◽  
Nolasco-Quintana ◽  
...  

Multidrug resistance (MDR) has become a major obstacle in the treatment of cancer, and is associated with mechanisms such as increased drug outflow, reduction of apoptosis, and/or altered drug metabolism. These problems can be mitigated by the coadministration of agents known as chemosensitizers, as they can reverse resistance to anticancer drugs and eventually resensitize cancer cells. We explore the chemosensitizing effect of Achillin, a guaianolide-type sesquiterpene lactone isolated from the Mexican medicinal plant Artemisia ludovisiana, to reverse MDR in Hep3B/PTX cells of hepatocellular carcinoma, which present resistance to paclitaxel (PTX). Achillin showed an important effect as chemosensitizer; indeed, the cytotoxic effect of PTX (25 nM) was enhanced, and the induction of G2/M phase cell cycle arrest and apoptosis were potentiated when combining with Achillin (100 μM). In addition, we observed that Achillin decreases P-gp levels and increases the intracellular retention of doxorubicin in Hep3B/PTX cells; in addition, homology structural modeling and molecular docking calculations predicted that Achillin interacts in two regions (M-site and R-site) of transporter drug efflux P-glycoprotein (P-gp). Our results suggest that the chemosensitizer effect demonstrated for Achillin could be associated with P-gp modulation. This work also provides useful information for the development of new therapeutic agents from guaianolide-type sesquiterpene lactones like Achillin.


2020 ◽  
Vol 97 ◽  
pp. 103709 ◽  
Author(s):  
Selvaraj Shyamsivappan ◽  
Raju Vivek ◽  
Arjunan Saravanan ◽  
Thangaraj Arasakumar ◽  
Thangaraj Suresh ◽  
...  

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