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2022 ◽  
Vol 12 (4) ◽  
pp. 873-877
Author(s):  
Dongqian Xie ◽  
Zhicheng Gao ◽  
Mei Liu ◽  
Defeng Wang

Metformin is shown to have hypoglycemic effects. However, the relationship between metformin’s intervention in FFA-induced endoplasmic reticulum stress-mediated insulin resistance (IR) and insulin β-cell apoptosis under high-glucose condition remains unclear. Our study intends to assess their relationship. Human pancreatic β-cells were treated with metformin and cell proliferation and IR were detected by MTT assay along with detection of Wnt/β-catenin signaling by RT-PCR, cell cycle and apoptosis by flow cytometry. Metformin inhibited β cell proliferation which was mediated by FFA-induced endoplasmic reticulum stress in a time-dependent and dose-dependent manner as well as induced cell cycle arrest at G2/M phase. In addition, metformin inhibited β-catenin signaling activation and decreased the expression of c-myc, Dvl-2, survivin, Dvl-3, GSK-3β (p-ser9) and promoted GSK-3 (p-tyr216) and Axin-2 expression. In conclusion, metformin inhibits Wnt/β-catenin signaling and promotes FFA to induce endoplasmic reticulum stress, thereby mediating pancreatic β-cells behaviors.


2023 ◽  
Vol 83 ◽  
Author(s):  
Maryam A. Al-Ghamdi ◽  
A. AL-Enazy ◽  
E.A Huwait ◽  
A. Albukhari ◽  
S. Harakeh ◽  
...  

Abstract Colorectal cancer (CRC) is one of the most common cancers leading to comorbidities and mortalities globally. The rational of current study was to evaluate the combined epigallocatechin gallate and quercetin as a potent antitumor agent as commentary agent for therapeutic protocol. The present study investigated the effect of epigallocatechin Gallate (EGCG) (150mg) and quercetin (200mg) at different proportions on proliferation and induction of apoptosis in human colon cancer cells (HCT-116). Cell growth, colonogenic, Annexin V in addition cell cycle were detected in response to phytomolecules. Data obtained showed that, the colony formation was inhibited significantly in CRC starting from the lowest concentration tested of 10 µg/mL resulting in no colonies as visualized by a phase-contrast microscope. Data showed a significant elevation in the annexin V at 100 µg/mL EGCG(25.85%) and 150 µg/mL quercetin (48.35%). Moreover, cell cycle analysis showed that this combination caused cell cycle arrest at the G1 phase at concentration of 100 µg/mL (72.7%) and 150 µg/mL (75.25%). The combined effect of epigallocatechin Gallate and quercetin exert antiproliferative activity against CRC, it is promising in alternative conventional chemotherapeutic agent.


Nutrients ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 369
Author(s):  
Jochen Rutz ◽  
Sebastian Maxeiner ◽  
Eva Juengel ◽  
Felix K.-H. Chun ◽  
Igor Tsaur ◽  
...  

Bladder cancer patients whose tumors develop resistance to cisplatin-based chemotherapy often turn to natural, plant-derived products. Beneficial effects have been particularly ascribed to polyphenols, although their therapeutic relevance when resistance has developed is not clear. The present study evaluated the anti-tumor potential of polyphenol-rich olive mill wastewater (OMWW) on chemo-sensitive and cisplatin- and gemcitabine-resistant T24, RT112, and TCCSUP bladder cancer cells in vitro. The cells were treated with different dilutions of OMWW, and tumor growth and clone formation were evaluated. Possible mechanisms of action were investigated by evaluating cell cycle phases and cell cycle-regulating proteins. OMWW profoundly inhibited the growth and proliferation of chemo-sensitive as well as gemcitabine- and cisplatin-resistant bladder cancer cells. Depending on the cell line and on gemcitabine- or cisplatin-resistance, OMWW induced cell cycle arrest at different phases. These differing phase arrests were accompanied by differing alterations in the CDK-cyclin axis. Considerable suppression of the Akt-mTOR pathway by OMWW was observed in all three cell lines. Since OMWW blocks the cell cycle through the manipulation of the cyclin-CDK axis and the deactivation of Akt-mTOR signaling, OMWW could become relevant in supporting bladder cancer therapy.


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.


2022 ◽  
Vol 23 (2) ◽  
pp. 901
Author(s):  
Zikai Liu ◽  
Qing Cheng ◽  
Xiaoli Ma ◽  
Mingke Song

The role of calcium ion (Ca2+) signaling in tumorigenicity has received increasing attention in melanoma research. Previous Ca2+ signaling studies focused on Ca2+ entry routes, but rarely explored the role of Ca2+ extrusion. Functioning of the Na+/Ca2+ exchanger (NCX) on the plasma membrane is the major way of Ca2+ extrusion, but very few associations between NCX and melanoma have been reported. Here, we explored whether pharmacological modulation of the NCX could suppress melanoma and promise new therapeutic strategies. Methods included cell viability assay, Ca2+ imaging, immunoblotting, and cell death analysis. The NCX inhibitors SN-6 and YM-244769 were used to selectively block reverse operation of the NCX. Bepridil, KB-R7943, and CB-DMB blocked either reverse or forward NCX operation. We found that blocking the reverse NCX with SN-6 or YM-244769 (5–100 μM) did not affect melanoma cells or increase cytosolic Ca2+. Bepridil, KB-R7943, and CB-DMB all significantly suppressed melanoma cells with IC50 values of 3–20 μM. Bepridil and KB-R7943 elevated intracellular Ca2+ level of melanoma. Bepridil-induced melanoma cell death came from cell cycle arrest and enhanced apoptosis, which were all attenuated by the Ca2+ chelator BAPTA-AM. As compared with melanoma, normal melanocytes had lower NCX1 expression and were less sensitive to the cytotoxicity of bepridil. In conclusion, blockade of the forward but not the reverse NCX leads to Ca2+-related cell death in melanoma and the NCX is a potential drug target for cancer therapy.


2022 ◽  
Author(s):  
Daisuke Kaida ◽  
Takayuki Satoh ◽  
Ken Ishida ◽  
Rei Yoshimoto

Pre-mRNA splicing is indispensable for eukaryotic gene expression. Splicing inhibition causes cell cycle arrest and cell death, which are the reasons of potent anti-tumor activity of splicing inhibitors. Here, we found that truncated proteins are involved in cell cycle arrest and cell death upon splicing inhibition. We analyzed pre-mRNAs accumulated in the cytoplasm where translation occurs, and found that a truncated form of the p27 CDK inhibitor, named p27*, is translated from pre-mRNA and accumulated in G2 arrested cells. Overexpression of p27* caused G2 phase arrest through inhibiting CDK-cyclin complexes. Conversely, knockout of p27* accelerated resumption of cell proliferation after washout of splicing inhibitor. Interestingly, p27* was resistant to proteasomal degradation. We propose that cells produce truncated proteins with different nature to the original proteins via pre-mRNA translation only under splicing deficient conditions to response to the splicing deficient conditions.


Life ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 114
Author(s):  
Ahmed Al Saqr ◽  
El-Sayed Khafagy ◽  
Mohammed F. Aldawsari ◽  
Khaled Almansour ◽  
Amr S. Abu Lila

Furanodienone (FDN), a major bioactive component of sesquiterpenes produced from Rhizoma curcumae, has been repeatedly acknowledged for its intrinsic anticancer efficacy against different types of cancer. In this study, we aimed to investigate the cytotoxic potential of furanodienone against human lung cancer (NSCLC A549) cells in vitro, as well as its underlying molecular mechanisms in the induction of apoptosis. Herein, we found that FDN significantly inhibited the proliferation of A549 cells in a dose-dependent manner. In addition, treatment with FDN potentially triggered apoptosis in A549 cells via not only disrupting the nuclear morphology, but by activating capsase-9 and caspase-3 with concomitant modulation of the pro- and antiapoptotic gene expression as well. Furthermore, FDN revealed its competence in inducing cell cycle arrest at G0/G1 phase in A549 cells, which was associated with decreased expression of cyclin D1 and cyclin-dependent kinase 4 (CDK4), along with increased expression of CDK inhibitor p21Cip1. Intriguingly, FDN treatment efficiently downregulated the Wnt signaling pathway, which was correlated with increased apoptosis, as well as cell cycle arrest, in A549 cells. Collectively, FDN might represent a promising adjuvant therapy for the management of lung cancer.


2022 ◽  
Vol 20 (2) ◽  
pp. 281-286
Author(s):  
Hongmei Wang ◽  
Yina Wang

Purpose: To investigate the anticancer effects of 7-hydroxycoumarin against cisplatin-resistant ovarian cancer cell line, and the underlying mechanism(s). Methods: Cell proliferation was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The 4’,6-diamidino-2-phenylindole (DAPI) and acridine orange/ethidium bromide (AO/EB) dual staining methods were used for measuring cell apoptosis in terms of DNA damage. Flow cytometry was used for analysis of mitosis of cancer cells, while protein expression levels were assayed with western blotting. Results: The 7-hydroxycoumarin preferentially inhibited the proliferation of the ovarian cancer cells, but had significantly less prominent effects on normal cells (p < 0.05). The decrease in cell proliferation was due to induction of cell apoptosis via caspase-linked apoptotic pathway. Treatment with 7- hdoxycoumarin further led to the arrest of cancer cell cycle at G2/M stage (p < 0.05) via down-regulation of the expressions of regulatory proteins that promote mitotic entry. Conclusion: 7-Hydroxycoumarin exerts significant anticancer effect against cisplatin-resistant ovarian cancer cells via decrease in cell proliferation, induction of apoptosis and mitotic cell cycle arrest. Thus, the compound could emerge as a vital lead molecule in the treatment of cisplatin-resistant type of human ovarian cancer.


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