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Background: Ischemic stroke presents a significant threat to human health due to its high disability rate and mortality. Currently, the clinical treatment drug, rt-PA, has a narrow therapeutic window and carries a high risk of bleeding. There is an urgent need to find new effective therapeutic drugs for ischemic stroke. Icariin (ICA), a key ingredient in the traditional Chinese medicine Epimedium, undergoes metabolism in vivo to produce Icaritin (ICT). While ICA has been reported to inhibit neuronal apoptosis after cerebral ischemia-reperfusion (I/R), yet its underlying mechanism remains unclear., Methods: PC-12 cells were treated with 200 µM H 2 O 2 for 8 h to establish a vitro model of oxidative damage. After administration of ICT, cell viability was detected by Thiazolyl blue tetrazolium Bromide (MTT) assay, reactive oxygen species (ROS) and apoptosis level, mPTP status and mitochondrial membrane potential (MMP) were detected by flow cytometry and immunofluorescence. Apoptosis and mitochondrial permeability transition pore (mPTP) related proteins were assessed by Western blotting. Middle cerebral artery occlusion (MCAO) model was used to establish I/R injury in vivo. After the treatment of ICA, the neurological function was scored by ZeaLonga socres; the infarct volume was observed by 2,3,5-Triphenyltetrazolium chloride (TTC) staining; HE and Nissl staining were used to detect the pathological state of the ischemic cortex; the expression changes of mPTP and apoptosis related proteins were detected by Western blotting., Results: In vitro: ICT effectively improved H 2 O 2 -induced oxidative injury through decreasing the ROS level, inhibiting mPTP opening and apoptosis. In addition, the protective effects of ICT were not enhanced when it was co-treated with mPTP inhibitor Cyclosporin A (CsA), but reversed when combined with mPTP activator Lonidamine (LND). In vivo: Rats after MCAO shown cortical infarct volume of 32-40%, severe neurological impairment, while mPTP opening and apoptosis were obviously increased. Those damage caused was improved by the administration of ICA and CsA., Conclusions: ICA improves cerebral ischemia-reperfusion injury by inhibiting mPTP opening, making it a potential candidate drug for the treatment of ischemic stroke., (© 2024. The Author(s).)

Gastric carcinoma is one of the most lethal malignant tumors. As part of our long-term efforts on seeking effective diagnosis and therapeutic strategies of gastric cancer, we present herein novel ternary copper-based chalcogenide nanoplatform CuS-NiS 2 nanomaterials with outstanding photothermal (PT)/photodynamic (PD) property that could effectively suppress human gastric cancer in vitro and in vi vo without obvious side effects. We revealed that CuS-NiS 2 induced reactive oxygen species (ROS) generation, leading to apoptosis through Bcl-2/Bax pathway of human gastric cancer cells under 808 nm near-infrared (NIR) irradiation. In addition, we also confirmed that the combination of CuS-NiS 2 and 808 nm NIR laser treatment triggered necroptosis by regulating the novel pathway MLKL/CAPG of human gastric cancer cells. Moreover, the CuS-NiS 2 exhibited excellent contrast enhancement according to magnetic resonance imaging (MRI). Taken together, we reported new ternary copper-based chalcogenide nanomaterials CuS-NiS 2 , which could be successfully applied for MRI-guided PT/PD therapy of gastric carcinoma through mitochondria-mediated apoptosis and MLKL/CAPG-mediated necroptosis.

Chemotherapy is recognized as one of the indispensable treatment for solid tumors. However, the emergent drug resistance and undesirable side effects have become a substantial challenge and the bottleneck of cancer chemotherapy. Magnolol (MAG) is a natural polyphenol with various bioactivities. Sulforaphane (SFN) is identified as one of the most effective naturally occurring anticancer agents. In this study, we successfully synthesized the magnolol-sulforaphane (MAG-SFN) hybrid CT1-3, showcasing more efficient anticancer activity than its lead compounds MAG and SFN with IC 50 values ranging from 5.10 to 14.06 μM in multiple cancer cells. We also demonstrated that CT1-3 elicited a strong antitumor effect in vivo but has no hepatic and renal toxicity. Furthermore, we found out CT1-3 treatment resulted in reduction of Bcl-2 and XIAP levels, in addition to increase of phospho-JNK and Bax levels, leading to mitochondria-mediated apoptosis in human cancer cells. Moreover, we revealed that CT1-3 could reduce the capacity of migration and invasion of human cancer cells via regulating the E-cadherin/Snail axis. Taken together, we provided strong evidences that the first example of MAG-SFN hybrid CT1-3 is a promising anticancer drug candidate without apparent adverse effects, which suppresses tumorigenesis partly through inducing mitochondria-mediated apoptosis and inhibiting epithelial mesenchymal transition (EMT)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Magnolol, a major bioactive component found in Magnolia officinalis with anti-inflammation and anti-oxidation activities as well as minimized cytotoxic effects. Although magnolol has a wide range of clinical applications, the anti-tumor activity of magnolol is not efficient. Herein, we reported the synthesis and anti-cancer activities of three novel magnolol analogues CT2-1, CT2-2, CT2-3, among which CT2-3 revealed more efficient anti-non-small cell lung cancer (NSCLC) activity than magnolol. Our data showed that CT2-3 could significantly inhibit the proliferation of human NSCLC cells in a dose-dependent manner. In addition, we revealed CT2-3 could induce cell cycle arrest through down-regulating mRNA expression of CDK4, CDK6 and cyclin D1. Moreover, we verified that CT2-3 could cause ROS generation, leading to apoptosis of human NSCLC cells. Further more, we also provided strong evidences that CT2-3 down-regulates the expression of c-Myc and topoisomerases, and contributes to the apoptosis of human NSCLC cells. Taken together, the current study is the first to report a promising new chemotherapeutic drug candidate CT2-3 that can efficiently eliminate human NSCLC cells through triggering cell cycle arrest as well as ROS-mediated and c-Myc/topoisomerases-mediated apoptosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Lung cancer is the most common cause of cancer death, approximately 85% of which are non-small cell lung cancer (NSCLC). Here we found that artemether (ART), a natural derivative of artemisinin, significantly inhibits the proliferation of NSCLC cells in a dose- and time-dependent manner. We also demonstrated that high concentration of ART induces apoptosis in NSCLC cells through down-regulating the level of anti-apoptotic protein B-cell lymphoma-2 (Bcl-2), cellular inhibitor of apoptosis protein 1 (cIAP1) and cellular inhibitor of apoptosis protein 2 (cIAP2). While low concentration of ART inhibits the mRNA level of cell cycle related genes including cyclin-dependent kinase 1 (CDK1), cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 6 (CDK6), cyclin A2, cyclin B1 and cyclin D1, leading to cell cycle arrest in NSCLC cells. Moreover, we confirmed that low concentration of ART induces DNA double-stranded breaks (DSBs), as well as promoting cellular senescence in NSCLC cells by up-regulating the mRNA and protein level of p16. Taken together, ART represents a promising new anti-NSCLC drug candidate that could attenuate progression of NSCLC cells in a p53-independent manner through inducing apoptosis, cell cycle arrest and promoting cellular senescence.

Background: Salidroside, an active ingredient of Rhodiola rosea, exhibits antiproliferative effect in gastric cancer (GC) cells. However, the involvement of salidroside in apoptosis and autophagy of GC cells has not been elucidated. Materials and Methods: Cell viability of BGC-823 cells was assessed by CCK-8 assay, and apoptosis was analyzed with terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling assay and flow cytometry. The apoptosis- and autophagy-associated proteins and mitogen-activated protein kinases (MAPKs) were determined by Western blot analysis. Autophagy was evaluated by green fluorescent protein-fused LC3 punctate formation. Results: Salidroside inhibited proliferation and promoted apoptosis and autophagy of BGC-823 cells in a dose-dependent manner. In addition, salidroside enhanced the phosphorylation of p38 MAPK, ERK1/2, and JNK. Furthermore, inhibition of MAPKs significantly abolished the effects of salidroside in BGC-823 cells. Conclusion: Salidroside induced apoptosis and autophagy of BGC-823 cells via activation of MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Curcumol was presented to unleash antitumor effects in a variety of cancers, including gastric cancer. However, the relevance between curcumol and cisplatin resistance in gastric cancer still remains unclear. Therefore, the current research was performed to survey the role of curcumol in cisplatin sensitivity in gastric cancer. Methods: First, BGC‐823 and BGC‐823/DDP cells were incubated with cisplatin for 48 hr and 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide (MTT) analysis was applied to determine the inhibition rate of cell proliferation and the half‐maximal inhibitory concentration (IC50) of cisplatin. In addition, BGC‐823 and BGC‐823/DDP cells were treated with curcumol for 48 hr followed with detection of cell viability and apoptosis using MTT and flow cytometry assay, respectively. Moreover, MTT analysis was applied to test the effects of curcumol on cisplatin sensitivity in gastric cancer cells. Lastly, Western blot assay and qRT‐PCR analysis were utilized to check the functions of curcumol on PI3K/AKT pathway‐related markers. Results: We found that BGC‐823/DDP cells exhibited stronger resistance to cisplatin compared with BGC‐823 cells. Furthermore, curcumol evidently reduced cell proliferation and facilitated cell apoptosis in BGC‐823/DDP and BGC‐823 cells. Moreover, results from MTT assay demonstrated that curcumol notably promoted the suppression effect of cisplatin and decreased the IC50 of cisplatin in BGC‐823/DDP and BGC‐823 cells. It was also presented that curcumol suppressed the PI3K/AKT pathway dose‐dependently in BGC‐823/DDP and BGC‐823 cells. Conclusion: The findings in the current research demonstrated that curcumol could promote the sensitivity of gastric cancer cells to cisplatin‐based chemotherapies via inhibiting the phosphatidylinositol 3‐kinase (PI3K)/Protein Kinase B (AKT) pathway. [ABSTRACT FROM AUTHOR]

Gastric carcinoma is one of the most lethal malignant tumors. As part of our long-term efforts on seeking effective diagnosis and therapeutic strategies of gastric cancer, we present herein novel ternary copper-based chalcogenide nanoplatform CuS–NiS2 nanomaterials with outstanding photothermal (PT)/photodynamic (PD) property that could effectively suppress human gastric cancer in vitro and in vivo without obvious side effects. We revealed that CuS–NiS2 induced reactive oxygen species (ROS) generation, leading to apoptosis through Bcl-2/Bax pathway of human gastric cancer cells under 808 nm near-infrared (NIR) irradiation. In addition, we also confirmed that the combination of CuS–NiS2 and 808 nm NIR laser treatment triggered necroptosis by regulating the novel pathway MLKL/CAPG of human gastric cancer cells. Moreover, the CuS–NiS2 exhibited excellent contrast enhancement according to magnetic resonance imaging (MRI). Taken together, we reported new ternary copper-based chalcogenide nanomaterials CuS–NiS2, which could be successfully applied for MRI-guided PT/PD therapy of gastric carcinoma through mitochondria-mediated apoptosis and MLKL/CAPG-mediated necroptosis. [ABSTRACT FROM AUTHOR]

Purpose: Berberine chloride (BBC) is a well-known plant isoquinoline alkaloid derived from Berberis aristata. In this study, we aim to explore the effect of BBC on non-small cell lung cancer (NSCLC), and further expound the underlying mechanism of BBC induces NSCLC cell death in vitro and in vivo.Methods: CCK-8 assay and colony formation assay were used to test the viability and colony formation ability of NSCLC cells. Apoptosis analysis was used to analyze the apoptotic cells. siRNAs were utilized to disturb the expression of Sin3A. qPCR and Western blot analysis were employed to determine mRNA and protein levels of related genes and proteins. Tumor xenografts model was used for in vivo detection.Results: BBC inhibited the proliferation and colony formation of human NSCLC cells in a dose- and time-dependent manner. In addition, BBC induced DNA double-stranded breaks (DSBs) through downregulating TOP2B level, leading to apoptosis in human NSCLC cells. The Chip-seq data of A549 cells obtained from the ENCODE consortium indicate that Sin3A binds on the promoters of TOP2B. Knockdown of Sin3A led to downregulation of TOP2B in human NSCLC cells. Furthermore, BBC decreased Sin3A expression and shortened the half-life of Sin3A, results in downregulation of TOP2B in human NSCLC cells.Conclusion: In this study, we demonstrated a new mechanism that BBC suppresses human NSCLC by deregulating Sin3A/TOP2B pathway, leading to DNA damage and apoptosis in human NSCLC in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Ovarian carcinoma (OC) begins in the ovaries and remains a highly lethal malignancy. Despite great efforts have been made to fight against OC, there still remain limited therapeutic options owing to chemotherapy drug resistance and serious side effects. Osthole is a derivative of coumarin and extracted from Cnidium monnieri (L.) Cusson, which has been drawn more attention due to its high biological activity in various disease. However, the underlying mechanism of osthole in OC is still unclear. In this study, we aim to evaluate the mechanism of osthole against OC cells. Methodologically, Cell Counting Kit-8 (CCK-8) and LIVE/DEAD™ Cell Imaging experiments were employed to assess cell viability. 2′,7′-Dichlorofluorescin diacetate (DCFH-DA) staining, flow cytometry, Hoechst staining, JC-1 staining assay and western blotting were performed to study apoptosis. Transmission electron microscopy, western blotting and monodansyl cadaverine (MDC) staining assay were used to study autophagy. Western blotting and microscopy image were employed to determine pyroptosis. Our results demonstrated that osthole could significantly suppress OC cells growth in a dose-dependent manner. We further proved that osthole could inhibit OC cells growth by mitochondria-mediated apoptosis. Meanwhile, we also discovered that osthole could trigger cell autophagy and lead to cell death. Furthermore, our study revealed that osthole could lead to pyroptosis through inducing the cleavage of gasdermin E (c-GSDME) level. Taken together, Osthole could significantly suppress the growth of OC cells and induce OC cells death via apoptosis, pyroptosis and autophagy, which is a promising new drug for the treatment of OC. Image 1 • Osthole, is a derivative of coumarin and extracts from Cnidium monnieri (L.) Cusson with a chemical formula C 15 H 16 O 3. • Osthole could trigger pyroptosis through prompting cleavage of GSDME. • Osthole could cause the cell autophagy to eat away cell organelles leading to cell death. • Osthole demonstrates a promising new drug for the treatment of ovarian carcinoma. [ABSTRACT FROM AUTHOR]