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Currently, surgical resection remains the primary approach for treating oral squamous cell carcinoma (OSCC), with limited options for effective drug therapy. Cardamonin, a principal compound derived from Myristica fragrans of the Zingiberaceae family, has garnered attention for its potential to suppress the onset and progression of various malignancies encompassing breast cancer, hepatocellular carcinoma, and ovarian cancers. Nevertheless, the involvement of cardamonin in the treatment of OSCC and its underlying mechanisms are yet to be elucidated. This research explored the possible target of cardamonin in treating OSCC via network pharmacological analysis. Subsequently, this research investigated the impact of cardamonin on OSCC cells via in vitro experiments, revealing its capacity to impede the migration, proliferation, and invasion of OSCC cells. Additionally, western blotting analysis demonstrated that cardamonin facilitates apoptosis by regulating the PI3K/AKT pathway. The findings suggest that MMP9 and the PI3K/AKT signaling pathway may serve as the target and pathway of cardamonin in treating OSCC. To summarize, the research findings suggest that cardamonin may facilitate apoptosis in OSCC cells by inhibition of PI3K/AKT pathway activation. These outcomes offer a theoretical basis for the utilization of cardamonin as a natural drug for treating OSCC., (© 2024. The Author(s).)

Idebenone, an antioxidant used in treating oxidative damage-related diseases, has unclear neuroprotective mechanisms. Oxidative stress affects cell and mitochondrial membranes, altering Adp-ribosyl cyclase (CD38) and Silent message regulator 3 (SIRT3) protein expression and possibly impacting SIRT3's ability to deacetylate Tumor protein p53 (P53). This study explores the relationship between CD38, SIRT3, and P53 in H 2 O 2 -injured HT22 cells treated with Idebenone. Apoptosis was detected using flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining after determining appropriate H 2 O 2 and Idebenone concentrations.In this study, Idebenone was found to reduce apoptosis and decrease P53 and Caspase3 expression in H 2 O 2 -injured HT22 cells by detecting apoptosis-related protein expression. Through bioinformatics methods, CD38 was identified as the target of Idebenone, and it further demonstrated that Idebenone decreased the expression of CD38 and increased the level of SIRT3. An increased NAD + /NADH ratio was detected, suggesting Idebenone induces SIRT3 expression and protects HT22 cells by decreasing apoptosis-related proteins. Knocking down SIRT3 downregulated acetylated P53 (P53Ac), indicating SIRT3's importance in P53 deacetylation.These results supported that CD38 was used as a target of Idebenone to up-regulate SIRT3 to deacetylate activated P53, thereby protecting HT22 cells from oxidative stress injury. Thus, Idebenone is a drug that may show great potential in protecting against reactive oxygen species (ROS) induced diseases such as Parkinson's disease, and Alzheimer's disease. And it might be able to compensate for some of the defects associated with CD38-related diseases., (© 2024. The Author(s).)

Apoptosis repressor with caspase recruitment domain (ARC) is a highly potent and multifunctional suppressor of various types of programmed cell death (PCD) (e.g. apoptosis, necroptosis, and pyroptosis) and plays a key role in determining cell fate. Under physiological conditions, ARC is predominantly expressed in terminally differentiated cells, such as cardiomyocytes and skeletal muscle cells. Its expression and activity are tightly controlled by a complicated system consisting of transcription factor (TF), non-coding RNA (ncRNA), and post-translational modification (PTM). ARC dysregulation has been shown to be closely associated with many chronic diseases, including cardiovascular disease, cancer, diabetes, and neurodegenerative disease. However, the detailed mechanisms of ARC involved in the progression of these diseases remain unclear to a large extent. In this review, we mainly focus on the regulatory mechanisms of ARC expression and activity and its role in PCD. We also discuss the underlying mechanisms of ARC in health and disease and highlight the potential implications of ARC in the clinical treatment of patients with chronic diseases. This information may assist in developing ARC-based therapeutic strategies for patients with chronic diseases and expand researchers' understanding of ARC.

The rising incidences of atherosclerosis have necessitated efforts to identify novel targets for therapeutic interventions. In the present study, we observed increased expression of the mechanosensitive calcium channel Piezo1 transcript in mouse and human atherosclerotic plaques, correlating with infiltration of PIEZO1-expressing macrophages. In vitro administration of Yoda1, a specific agonist for PIEZO1, led to increased foam cell apoptosis and enhanced phagocytosis by macrophages. Mechanistically, PIEZO1 activation resulted in intracellular F-actin rearrangement, elevated mitochondrial ROS levels and induction of mitochondrial fragmentation upon PIEZO1 activation, as well as increased expression of anti-inflammatory genes. In vivo, ApoE -/- mice treated with Yoda1 exhibited regression of atherosclerosis, enhanced stability of advanced lesions, reduced plaque size and necrotic core, increased collagen content, and reduced expression levels of inflammatory markers. Our findings propose PIEZO1 as a novel and potential therapeutic target in atherosclerosis., (© 2024. The Author(s).)

In this study, we prepared a bionic nanosystem of trastuzumab-functionalized SK-BR-3 cell membrane hybrid liposome-coated pyrotinib (Ptb-M-Lip-Her) for the treatment of HER2-positive breast cancer. Transmission electron microscopy, dynamic light scattering, polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting were used to verify the successful preparation of Ptb-M-Lip-Her. In vitro drug release experiments proved that Ptb-M-Lip-Her had a sustained release effect. Cell uptake experiments and in vivo imaging experiments proved that Ptb-M-Lip-Her had good targeting ability to homologous tumor cells (SK-BR-3). The results of cell experiments such as MTT, flow cytometry, immunofluorescence staining and in vivo antitumor experiments showed that Ptb-M-Lip-Her could significantly promote apoptosis and inhibit the proliferation of SK-BR-3 cells. These results clearly indicated that Ptb-M-Lip-Her may be a promising biomimetic nanosystem for targeted therapy of HER2-positive breast cancer., (© 2024. The Author(s).)

Yinchenhao Decoction (YCHD) is a classic prescription in traditional Chinese medicine (TCM). It appears to play an important role in anti-inflammation and autoimmunity protection. As one of the key active ingredients in YCHD, quercetin is a novel anti-inflammatory metabolite that exerts protective effects in many autoimmune diseases. However, its role in autoimmune hepatitis (AIH)-related hepatic injury has not been studied. The aim of this study was to reveal the hepatocyte protective mechanism of quercetin. In this study, we used Concanavalin A (Con A) to establish an in vitro hepatocyte injury-associated AIH model. Brl3a hepatocyte injury was induced by the supernatant of J774A.1 cells treated with Con A. We found that quercetin mitigated Con A-induced via macrophage-mediated Brl3a hepatocyte injury. Quercetin administration reduced the levels of alanine transaminase (ALT) and aspartate transaminase (AST) in the supernatant of Con A-treated Brl3a cells and attenuated the infiltration of J774A.1 macrophages induced by Con A. Moreover, quercetin effectively inhibited the expression of proinflammatory cytokines including interleukin-1β (IL-1β) by Con A. Furthermore, quercetin decreased hepatocyte apoptosis and ferroptosis levels in the macrophage-induced hepatocyte injury model. In conclusion, our study indicates that quercetin alleviates macrophage-induced hepatocyte damage by reducing the inflammatory response, apoptosis and ferroptosis. Our work suggests that quercetin might be a potential therapeutic strategy for AIH.

Background: Respiratory syncytial virus (RSV), which is the predominant viral pathogen responsible for causing acute lower respiratory tract infections in children, currently lacks specific therapeutic drugs. Despite andrographolide's demonstrated effectiveness against various viral infections, its effects on RSV infection remain unclear., Methods: In this study, RSV infection and andrographolide-intervened A549 cell lines were used. The virus load of RSV and the levels of IL-6 and IL-8 in the cell supernatant were quantified. The potential targets of andrographolide in the treatment of RSV-infected airway epithelial cells were analyzed using the Gene Expression Omnibus (GEO) database and the PharmMapper Database, and the changes in mRNA expression of these target genes were measured. To further illustrate the effect of andrographolide on the death pattern of RSV-infected airway epithelial cells, Annexin V-FITC/PI apoptosis assays and Western blotting were conducted., Results: Andrographolide decreased the viral load and attenuated IL-6 and IL-8 levels in cell supernatant post-RSV infection. A total of 25 potential targets of andrographolide in the treatment of RSV-infected airway epithelial cells were discovered, and CASP1, CCL5, JAK2 , and STAT1 were identified as significant players. Andrographolide noticeably suppressed the increased mRNA expressions of these genes post-RSV infection as well as IL-1β. The flow cytometry analysis demonstrated that andrographolide alleviated apoptosis in RSV-infected cells. Additionally, RSV infection decreased the protein levels of caspase-1, cleaved caspase-1, cleaved IL-1β, N-terminal of GSDMD, and Bcl-2. Conversely, andrographolide increased their levels., Conclusion: These results suggest that andrographolide may reduce RSV-induced inflammation by suppressing apoptosis and promoting pyroptosis in epithelial cells, leading to effective viral clearance., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cancer is a leading disease-related cause of death worldwide. Despite advances in therapeutic interventions, cancer remains a major global public health problem. Cancer pathogenesis is extremely intricate and largely unknown. Fas-associated protein with death domain (FADD) was initially identified as an adaptor protein for death receptor-mediated extrinsic apoptosis. Recent evidence suggests that FADD plays a vital role in non-apoptotic cellular processes, such as proliferation, autophagy, and necroptosis. FADD expression and activity of are modulated by a complicated network of processes, such as DNA methylation, non-coding RNA, and post-translational modification. FADD dysregulation has been shown to be closely associated with the pathogenesis of numerous types of cancer. However, the detailed mechanisms of FADD dysregulation involved in cancer progression are still not fully understood. This review mainly summarizes recent findings on the structure, functions, and regulatory mechanisms of FADD and focuses on its role in cancer progression. The clinical implications of FADD as a biomarker and therapeutic target for cancer patients are also discussed. The information reviewed herein may expand researchers' understanding of FADD and contribute to the development of FADD-based therapeutic strategies for cancer patients., (© 2022. The Author(s).)

Ginsenoside Rh2 (G‑Rh2) is a monomeric compound that extracted from ginseng and possesses anti‑cancer activities both in vitro and in vivo . Previously, we reported that G‑Rh2 induces apoptosis in HeLa cervical cancer cells and that the process was related to reactive oxygen species (ROS) accumulation and mitochondrial dysfunction. However, the upstream mechanisms of G‑Rh2, along with its cellular targets, remain to be elucidated. In the present study, the Cell Counting Kit‑8 assay, flow cytometry and Hoechst staining revealed that G‑Rh2 significantly inhibited cell viability and induced apoptosis of cervical cancer cells. However, G‑Rh2 was demonstrated to be non‑toxic to End1/e6e7 cells. JC‑1, rhodamine 123 staining, oxidative phosphorylation and glycolysis capacity assays demonstrated that G‑Rh2 exposure caused an immediate decrease in mitochondrial transmembrane potential due to its inhibition of mitochondrial oxidative phosphorylation, as well as glycolysis, both of which reduced cellular ATP production. Western blotting and electron transport chain (ETC) activity assays revealed that G‑Rh2 significantly inhibited the activity of ETC complexes I, III and V. Overexpression of ETC complex III partially significantly restored mitochondrial ROS and inhibited the apoptosis of cervical cancer cells induced by G‑Rh2. The predicted results of binding energy in molecular docking, confirmed that G‑Rh2 was highly likely to induce mitochondrial ROS production and promote cell apoptosis by targeting the ETC complex, especially for ETC complex III. Taken together, the present results revealed the potential anti‑cervical cancer activity of G‑Rh2 and provide direct evidence for the contribution of impaired ETC complex activity to cervical cancer cell death.

Parkinson's disease (PD), a common multifactorial neurodegenerative disease, is characterized by irreversible loss of dopaminergic neurons in the substantia nigra. In‑depth study of the pathogenesis of PD is of great importance. High‑mobility group AT‑hook 2 (HMGA2) has been proposed to be implicated with neuronal differentiation and impairment of cognitive function. However, whether HMGA2 plays a role in PD is rarely explored. In the present study, N‑methyl‑4‑phenyl‑1,2,3,6‑tetrahydropyridine (MPTP)‑treated PD mice models and N‑methyl‑4‑ phenylpyridinium (MPP + )‑treated SH‑SY5Y cell models were established. Reverse transcription‑quantitative PCR showed that HMGA2 displayed low levels in brain tissues of MPTP‑treated mice and MPP + ‑treated SH‑SY5Y cells. Moreover, HMGA2 overexpression suppressed SH‑SY5Y cell apoptosis. Additionally, let‑7b‑5p bound with HMGA2 3' untranslated region (UTR), and its expression was negatively correlated with HMGA2 level. Moreover, let‑7b‑5p presented high levels in brain tissues of PD mice and MPP+‑treated SH‑SY5Y cells, and knockdown of let‑7b‑5p inhibited SH‑SY5Y cell apoptosis. Rescue assays illustrated that HMGA2 neutralized the promotive effects of let‑7b‑5p mimics on SH‑SY5Y cell apoptosis. In conclusion, the present study demonstrated that let‑7b‑5p contributes to cell apoptosis in PD by targeting HMGA2, which offers a potential theoretical basis for the study of effective therapy in PD.

Recent studies suggest that RRP15 (Ribosomal RNA Processing 15 Homolog) might be a potential target for cancer therapy. However, the role of RRP15 in hepatocarcinogenesis remains poorly delineated. In this study, we aimed to evaluate the expression and biological function of RRP15 in human hepatocellular carcinoma (HCC). We show that RRP15 was up regulated in HCC cell lines and tumours. Up-regulation of RRP15 in HCC tumours was also correlated with unfavorable prognosis. We further show that the frequent up-regulation of RRP15 in HCCs is at least partly driven by recurrent gene copy gain at chromosome 1q41. Functional studies indicated that RRP15 knockdown suppresses HCC proliferation and growth both in vitro and in vivo. Mechanistically, RRP15 depletion in p53-wild-type HepG2 cells induced senescence via activation of the p53-p21 signalling pathway through enhanced interaction of RPL11 with MDM2, as well as inhibition of SIRT1-mediated p53 deacetylation. Moreover, RRP15 depletion in p53-mutant PLC5 and p53-deleted Hep3B cells induced metabolic shift from the glycolytic pentose-phosphate to mitochondrial oxidative phosphorylation via regulating a series of key genes such as HK2 and TIGAR, and thus, promoted the generation of ROS and apoptosis. Taken together, our findings provide evidence for an important role of the RRP15 gene in hepatocarcinogenesis through regulation of HCC proliferation and growth, raising the possibility that targeting RRP15 may represent a potential therapeutic strategy for HCC treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Apoptosis, inflammation, and fibrosis contribute to vascular remodeling and injury. Elabela (ELA) serves as a crucial regulator to maintain vascular function and has been implicated in the pathogenesis of hypertensive vascular remodeling. This study aims to explore regulatory roles and underlying mechanisms of ELA in rat aortic adventitial fibroblasts (AFs) in response to angiotensin II (ATII). In cultured AFs, exposure to ATII resulted in marked decreases in mRNA and protein levels of ELA, fibroblast growth factor 21 (FGF21), and angiotensin-converting enzyme 2 (ACE2) as well as increases in apoptosis, inflammation, oxidative stress, and cellular migration, which were partially blocked by the exogenous replenishment of ELA and recombinant FGF21, respectively. Moreover, treatment with ELA strikingly reversed ATII-mediated the loss of FGF21 and ACE2 levels in rat aortic AFs. FGF21 knockdown with small interfering RNA (siRNA) significantly counterbalanced protective effects of ELA on ATII-mediated the promotion of cell migration, apoptosis, inflammatory, and oxidative injury in rat aortic AFs. More importantly, pretreatment with recombinant FGF21 strikingly inhibited ATII-mediated the loss of ACE2 and the augmentation of cell apoptosis, oxidative stress, and inflammatory injury in rat aortic AFs, which were partially prevented by the knockdown of ACE2 with siRNA. In summary, ELA exerts its anti-apoptotic, anti-inflammatory, and anti-oxidant effects in rat aortic AFs via activation of the FGF21-ACE2 signaling. ELA may represent a potential candidate to predict vascular damage and targeting the FGF21-ACE2 signaling may be a promising therapeutic intervention for vascular adventitial remodeling and related disorders., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

The neurotoxicity of local anesthetics (LAs) has attracted more and more attention, However, they lack preventive and therapeutic measures. Many studies have shown that apoptosis plays an important role in the process of LA-induced neurotoxicity. As an important signaling molecule to activate apoptosis, p53 has been proved to be involved in the neurotoxicity induced by LAs, but the mechanism is unclear. In this study, we explored the effect of pifithrin-α (PFT-α), a p53 inhibitor, on apoptosis by ropivacaine (Rop) in vivo and in vitro. Cell viability and apoptosis detected by CCK-8 and a JC-1 apoptosis detection kit, the changes of spinal cord structure observed after hematoxylin and eosin staining, apoptosis of the spinal cord measured by terminal deoxynucleotidyl transferase dUTP nick end labeling staining, behavioral assessment of the nerve Injury evaluated by the detection of sciatic nerve conduction velocity (SNCV) andmechanical withdrawal threshold (MWT), the expression of p53 and many apoptosis-related genes included Bax, Bcl-2, and caspase-3 detected by quantitative real-time polymerase chain reaction, Western blot analysis, immunofluorescence, and immunohistochemistry. Results showed that PC12 cell viability decreased because of Rop, but the pretreatment of PFT-α could protect it. And PFT-α reduced the injuries in the spinal cord by Rop included vacuoles or edema. The results of immunofluorescence and immunohistochemistry testing showed that PFT-α inhibited the p53 protein upregulated by Rop. Apoptosis rate and many proapoptotic genes include p53, Bax, caspase-3 messenger RNA, and proteins were increased by Rop, but PFT-α could decrease it. In conclusion, PFT-α inhibited cell apoptosis and spinal cord injuries induced by Rop., (© 2021 Wiley Periodicals LLC.)

Background: Human adipose mesenchymal stem cells (hADSCs) show poor survival after transplantation, limiting their clinical application. Tissue regeneration resulting from stem cell treatment may be caused by attenuation of hypoxia-inducible factor-1α (HIF-1α). In this study, we constructed hADSCs stably expressing HIF-1α and investigated the potential effects of HIF-1α expression in the ischemic microenvironment on mitochondrial apoptosis and survival of hADSCs, and studied the mechanisms involved., Method: Apoptosis was induced by an ischemic microenvironment in vitro. ADSCs with stable HIF-1α expression were established. Cell survival and apoptosis were observed by CCK-8 assay, western blotting, flow cytometry, and fluorescence staining. ADSCs were subcutaneously transplanted into nude mice in the location where a hypoxia ischemic microenvironment was simulated in vivo. After 1, 3, and 7 d, mitochondrial apoptotic proteins were evaluated by immunohistochemistry and immunofluorescence staining., Results: Exogenous HIF-1α downregulated mitochondrial reactive oxygen species, cytochrome c, caspase-9, and caspase-3, but inhibited mitochondrial membrane potential depolarization and increased the Bcl-2/bax ratio. HIF-1α prevented apoptosis and promoted vascular endothelial growth factor (VEGF) secretion as demonstrated by enzyme-linked immunosorbent assay (ELISA), terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and flow cytometry analysis. HIF-1α enhanced the survival of transplanted ADSCs in nude mice., Conclusion: We have shown that through inhibition of the mitochondria-mediated apoptotic pathway and promotion of VEGF secretion in hADSCs in an ischemic microenvironment, HIF-1α may potentially be applied in clinical therapy and as an alternative strategy for improving hADSC therapy., Competing Interests: Declaration of competing Interest The authors declare that they have no competing interests, (Copyright © 2020 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Glycine is a well-known free radical scavenger in the cellular antioxidant system that prevents oxidative damage and apoptosis. Excessive fluoride exposure is associated with multiple types of cellular damage in humans and animals. The objective of the present study was to investigate the protective effects of glycine on sodium fluoride (NaF) exposure and the possible underlying mechanisms in a porcine testicular Sertoli cell line model. Cellular viability and proliferation were examined following NaF exposure and glycine supplementation, and glycine dramatically ameliorated the decreases in NaF-induced porcine testicular Sertoli cell viability and proliferation. Further investigations revealed that glycine decreased NaF-induced intracellular reactive oxygen species production, DNA fragment accumulation and the apoptosis incidence in the porcine testicular Sertoli cell line; in addition, glycine improved mitochondrial function and ATP production. Notably, results of the SPiDER-β-Gal analysis suggested that glycine alleviated NaF-induced cellular senescence and downregulated P53, P21, HMGA2 and P16INK4a gene expression in the porcine testicular Sertoli cell line. Collectively, the beneficial effects of glycine alleviate NaF-induced oxidative stress, apoptosis and senescence, and together with our previous findings, support the hypothesis that glycine plays an important role in protecting against NaF exposure-induced impairments in the porcine testicular Sertoli cell line., (© 2021 Wiley-VCH GmbH.)

The cysteine-containing aspartate specific proteinase (caspase) family plays important roles in apoptosis and the maintenance of homeostasis in lampreys. We conducted genomic and functional comparisons of six distinct lamprey caspase groups with human counterparts to determine how these expanded molecules evolved to adapt to the changing caspase-mediated signaling pathways. Our results showed that lineage-specific duplication and rearrangement were responsible for expanding lamprey caspases 3 and 7, whereas caspases 1, 6, 8, and 9 maintained a relatively stable genome and protein structure. Lamprey caspase family molecules displayed various expression patterns and were involved in the innate immune response. Caspase 1 and 7 functioned as a pattern recognition receptor with a broad-spectrum of microbial recognition and bactericidal effect. Additionally, caspases 1 and 7 may induce cell apoptosis in a time- and dose-dependent manner; however, apoptosis was inhibited by caspase inhibitors. Thus, these molecules may reflect the original state of the vertebrates caspase family. Our phylogenetic and functional data provide insights into the evolutionary history of caspases and illustrate their functional characteristics in primitive vertebrates., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Tumor necrosis factor-α-induced protein-8 like-2 (TNFAIP8L2, TIPE2), a member of TNFAIP8 family, functions as a regulator in inflammation. Our previous studies showed that TIPE2 can negatively regulate HBV-specific CD8 + T lymphocyte functions. But the effect of TIPE2 on the apoptosis of HBV-infected hepatocytes which is very important for eliminating viruses remains unclear. Using gene expression microarray analysis, we find that TIPE2 deficiency can regulate the expression of apoptotic genes in liver tissues from HBV hydrodynamic injection (HI) mouse model. TIPE2 protein was detected in TUNEL staining positive hepatocytes in HBV-infected C57 mice. Interestingly, the TIPE2 expressed hepatocytes were just the HBV infected cells. Furthermore, TIPE2 upregulates the mRNA levels of FasL, Bim and TNFRsF1b which promote cells death, when TIPE2 was transfected into HepG2 cells in vitro. As a result, TIPE2 overexpression cells showed a higher number of apoptotic cells and increased level of cleavage caspase3 compared to controls. Those results indicate that TIPE2 participates in HBV infection by regulating apoptosis of virus-infected hepatocytes., (Copyright © 2020. Published by Elsevier Ltd.)

Paris saponin VII (PSVII), a bioactive constituent extracted from Trillium tschonoskii Maxim., is cytotoxic to several cancer types. This study was designed to explore whether PSVII prevents non-small-cell lung cancer (NSCLC) proliferation and to investigate its molecular target. AMP-activated protein kinase (AMPK) has been implicated in the activation of autophagy in distinct tissues. In cultured human NSCLC cell lines, PSVII induces autophagy by activating AMPK and inhibiting mTOR signaling. Furthermore, PSVII-induced autophagy activation was reversed by the AMPK inhibitor compound C. Computational docking analysis showed that PSVII directly interacted with the allosteric drug and metabolite site of AMPK to stabilize its activation. Microscale thermophoresis assay and drug affinity responsive target stability assay further confirmed the high affinity between PSVII and AMPK. In summary, PSVII acts as a direct AMPK activator to induce cell autophagy, which inhibits the growth of NSCLC cells. In the future, PSVII therapy should be applied to treat patients with NSCLC., (Copyright © 2021 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Cisplatin, a proven effective chemotherapeutic agent, has been used clinically to treat malignant solid tumors, whereas its clinical use is limited by serious side effect including nephrotoxicity. Platycodin D (PD), the major and marked saponin isolated from Platycodon grandiflorum, possesses many pharmacological effects. In this study, we evaluated its protective effect against cisplatin-induced human embryonic kidney 293 (HEK-293) cells injury and elucidated the related mechanisms. Our results showed that PD (0.25, 0.5, and 1 μM) can dose-dependently alleviate oxidative stress by decreasing malondialdehyde and reactive oxygen species, while increasing the levels of glutathione, superoxide dismutase, and catalase. Moreover, the elevation of apoptosis including Bax, Bad, cleaved caspase-3,-9, and decreased protein levels of Bcl-2, Bcl-XL induced by cisplatin were reversed after PD treatment. Importantly, PD pretreatment can also regulate PI3K/Akt and ERK/JNK/p38 signaling pathways. Furthermore, PD was found to reduce NF-κB-mediated inflammatory relative proteins. Our finding indicated that PD exerted significant effects on cisplatin induced oxidative stress, apoptosis and inflammatory, which will provide evidence for the development of PD to attenuate cisplatin-induced nephrotoxicity., (© 2020 Wiley Periodicals LLC.)

20(S)‑Ginsenoside Rh2 [20(S)‑GRh2], one of the main active components of Panax ginseng, induces apoptosis in a wide range of cancer cell types. The present study found that 20(S)‑GRh2 reduces mitochondrial membrane potential, decreases adenosine triphosphate generation and induces reactive oxygen species in HeLa cervical cancer cells. In addition, 20(S)‑GRh2 activated mitochondrion‑dependent apoptosis and inhibited both mitochondrial oxidative phosphorylation and glycolysis in HeLa cells. It was found that voltage‑dependent anion channel 1 (VDAC1) expression was significantly upregulated by 20(S)‑GRh2 treatment, while hexokinase 2 expression was downregulated and segregated from the mitochondria. Furthermore, 20(S)‑GRh2 promoted Bax transport from the cytoplasm to the mitochondria, and knockdown of VDAC1 inhibited Bax transport and apoptosis. These results suggest that VDAC1 is a novel target of 20(S)‑GRh2. The present study provides a better understanding of the mechanistic link between cervical cancer metabolism and growth control, and these results may facilitate the development of new treatments for cervical cancer.

Abnormal aortic adventitial fibroblasts (AFs) play essential roles in the development of vascular remodeling and disorders. Previous studies revealed that microRNA-122 (miR-122) levels were elevated in the aortic adventitia of hypertensive rats with vascular injury. Here, we aim to evaluate the biological effects and underlying mechanisms of miR-122 in rat AFs. Exposure to angiotensin II (ATII) in rat AFs resulted in decreased levels of sirtuin 6 (SIRT6), elabela (ELA), and angiotensin-converting enzyme 2 (ACE2). Additionally, stimulation with ATII contributed to a decline in autophagic flux and obvious increases in cellular migration, oxidative stress, and apoptosis, which were exacerbated by the transfection of miR-122-5p mimic but were rescued by miR-122-5p inhibitor, exogenous replenishment of ELA, and recombinant adeno-associated virus expressing SIRT6 (rAAV-SIRT6), respectively. Moreover, stimulation with miR-122-5p mimic led to a marked reduction in the levels of SIRT6 and ELA in rat AFs, which were elevated by stimulation with rAAV-SIRT6. Furthermore, miR-122-5p inhibitor-mediated pro-autophagic, anti-oxidant and anti-apoptotic effects in rat AFs were partially suppressed by 3-methyladenine, SIRT6 small interfering RNA (siRNA) and ELA siRNA, which were linked with the downregulation in the protein levels of LC3-II, beclin-1, and ACE2 and the upregulation of p62 expression and bax/bcl-2 ratio. Our findings indicated that miR-122-5p inhibition prevented ATII-mediated loss of autophagy, and the promotion of apoptosis and oxidative stress via activating the SIRT6-ELA-ACE2 signaling. MiR-122-5p may be a novel predictive biomarker of adventitial injury, and targeting the SIRT6-ELA-ACE2 signaling may have the potential therapeutic importance of controlling vascular remodeling and disorders., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Following the recent discovery that microRNA-134-5p (miR-134-5p) is elevated in the early stages of acute myocardial infarction (AMI), we examined the specific role of miR-134-5p in cardiomyocytes during AMI., Methods: To study miR-134-5p's role in the context of AMI, we used a combination of in vitro experiments in H 2 O 2 -treated or hypoxic cardiomyocyte cell cultures as well as in vivo experiments in a murine model of AMI., Results: H 2 O 2 - and hypoxia-induced cardiomyocyte injury upregulated miR-134-5p expression. miR-134-5p overexpression increased cardiomyocyte apoptosis, whereas miR-134-5p inhibition reduced cardiomyocyte apoptosis. We discovered that the transcription factor cAMP-responsive element binding protein 1 (Creb1) is a functional target of miR-134-5p responsible for regulating cardiomyocyte apoptosis. In vivo AMI resulted in the upregulation and downregulation of miR-134-5p and Creb1 in the infarct area, respectively. Circulating miR-134-5p levels were also increased at days 1 and 2 post-AMI. Modulation of myocardial miR-124-5p expression by intramyocardial injection of antagomiR-134-5p or agomiR-134-5p significantly affected cardiomyocyte apoptosis, infarct size, and cardiac function in vivo., Conclusions: miR-134-5p/Creb1 axis dysregulation plays a role in hypoxia- or oxidative stress-induced cardiomyocyte apoptosis as well as AMI. Circulating miR-134-5p may show promise as a biomarker for AMI or post-AMI cardiac dysfunction. Manipulating the miR-134-5p/Creb1 axis through either inhibition of miR-134-5p or overexpression of Creb1 may show promise as a novel therapeutic strategy to attenuate cardiac dysfunction following AMI., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier Inc.)

Hepatocellular carcinoma (HCC) is the sixth most common malignancy with limited treatment options. Hinokiflavone (HF), a natural biflavonoid, has shown to inhibit the proliferation of melanoma, whereas its antitumour effect against HCC and the underlying mechanisms remain elusive. Here, we aimed at evaluating its antitumour effect against HCC in both in vitro and in vivo. Cell counting kit 8, colony formation assay, PI/RNase staining and Western blotting revealed that HF inhibited the proliferation of HCC cells via G0/G1 cell cycle arrest with p21/p53 up-regulation. DAPI staining, Annexin V-FITC/PI staining and Western blotting confirmed that HF triggered caspase-dependent apoptosis. Moreover, HF increased the levels of mitochondrial reactive oxygen species (mtROS) and activated c-Jun N-terminal kinase (JNK) pathway, as measured by MitoSOX Red staining and Western blotting. After respectively inhibiting mtROS (Mito-TEMPO) and JNK (SP600125), HF-induced apoptosis was reversed. Additionally, Western blotting documented that HF suppressed nuclear factor kappa B (NF-κB) activity and the anti-apoptotic genes downstream, contributing to cell apoptosis. Finally, in vivo studies demonstrated that HF significantly impaired tumour growth in HCC xenograft. Collectively, these findings suggested that HF induced apoptosis through activating mtROS/JNK/caspase pathway and inhibiting NF-κB signalling, which may represent a novel therapeutic agent for treating HCC., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Because conventional chemotherapy is not sufficiently effective against prostate cancer, various examinations have been performed to identify anticancer activity of naturally occurring components and their mechanisms of action. The (+)-brevipolide H, an α-pyrone-based natural compound, induced potent and long-term anticancer effects in human castration-resistant prostate cancer (CRPC) PC-3 cells. Flow cytofluorometric analysis with propidium iodide staining showed (+)-brevipolide H-induced G1 arrest of cell cycle and subsequent apoptosis through induction of caspase cascades. Since Akt/mTOR pathway has been well substantiated in participating in cell cycle progression in G1 phase, its signaling and downstream regulators were examined. Consequently, (+)-brevipolide H inhibited the signaling pathway of Akt/mTOR/p70S6K. The c-Myc inhibition and downregulation of G1 phase cyclins were also attributed to (+)-brevipolide H action. Overexpression of myristoylated Akt significantly rescued mTOR/p70S6K and downstream signaling under (+)-brevipolide H treatment. ROS and Ca 2+ , two key mediators in regulating intracellular signaling, were determined, showing that (+)-brevipolide H interactively induced ROS production and an increase of intracellular Ca 2+ levels. The (+)-Brevipolide H also induced the downregulation of anti-apoptotic Bcl-2 family proteins (Bcl-2 and Bcl-xL) and loss of mitochondrial membrane potential, indicating the contribution of mitochondrial dysfunction to apoptosis. In conclusion, the data suggest that (+)-brevipolide H displays anticancer activity through crosstalk between ROS production and intracellular Ca 2+ mobilization. In addition, suppression of Akt/mTOR/p70S6K pathway associated with downregulation of G1 phase cyclins contributes to (+)-brevipolide H-mediated anticancer activity, which ultimately causes mitochondrial dysfunction and cell apoptosis. The data also support the biological significance and, possibly, clinically important development of natural product-based anticancer approaches.

Demyelination resulting from Schwann cell injury is a main pathological feature of diabetic neuropathy, and a key contributor to this process may be inflammation due to advanced glycation end products (AGEs). Therefore, protection by anti-inflammation agents is anticipated. In this study, we showed that interleukin-10 (IL-10), an anti-inflammatory cytokine, inhibits apoptosis of Schwann cells induced by AGEs in vitro . We isolated and cultured Schwann cells from rat sciatic nerves. As detected by flow cytometry, apoptosis of Schwann cells markedly increased following incubation with AGEs for 48 h. However, pretreatment with IL-10 inhibited AGE-induced apoptosis. The effect of IL-10 on NF-κB, which is a very important regulator of inflammation, was also evaluated, and results showed high levels of phospho-NF-κB and nuclear localization of NF-κB in cells incubated with AGEs but low levels of phospho-NF-κB and cytoplasmic localization in the cells incubated with IL-10, indicating the activation of NF-κB by AGEs and inhibition of NF-κB by IL-10. Moreover, incubating Schwann cells with an NF-κB inhibitor (caffeic acid phenethyl ester) for 30 min before adding AGEs mimicked IL-10, lowering the amount of reactive oxygen species and activity of caspase-3 and also decreasing apoptosis in Schwann cells. These results indicate that IL-10 may protect Schwann cells against AGE-induced apoptosis by attenuating oxidative stress via the inhibition of activation of NF-κB., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Histone demethylase KDM7A regulates neuronal differentiation and development in mammals. In this study, we found that KDM7A was also required for breast cancer stem cells (BCSCs) maintenance. Silencing KDM7A significantly reduced the BCSCs population and mamosphere formation in vitro, and inhibited breast tumor growth in vivo. Restoring KDM7A expression rescued the defect in stem cell maintenance. Our mechanism analysis suggested that KDM7A upregulated the stemness-associated factors KLF4 and c-MYC for BCSCs maintenance. In addition, KDM7A knockdown promoted apoptosis through decreasing BCL2 expression and BAD phosphorylation in breast cancer (BrCa). Furthermore, restoring KDM7A and BCL2 expression rescued apoptosis inhibition in breast cancer, suggesting that KDM7A inhibited apoptosis by upregulating the BCL2 level in breast cancer. In conclusion, KDM7A promotes cancer stem cell maintenance and apoptosis inhibition in breast cancer., (© 2019 Wiley Periodicals, Inc.)

Metallic nanoparticles were extensively examined to explore their impending exploitations over pharmaceutical purposes. Current work attempting to explores the cytotoxic capacity of zinc oxide (ZnO) nanoparticles besides to human melanoma cell line (A375). Viability of cells was resoluted, and the promising cytotoxicity potential was exhibited by zinc oxide nanoparticles. Cellular adhesion and morphology was determined by propidium iodide assay. Characterization studies like UV-Spectroscopy, X-ray diffraction (XRD) investigation, transmission electron microscope (TEM), energy dispersive X-ray (EDX) Spec, and Fourier transform infrared (FT-IR) examination confirms the accessibility of measurement, form and volume. The mRNA expression of apoptotic genes like caspase 3, 8 and 9 was elevated followed by the exposure to ZnO nanoparticles and it was narrowly proved that ZnO nanoparticles stimulates the apoptotic cell necrosis at the transcriptional stage. Cardiospermum halicacabum down regulated the apoptotic gene expressions. Reactive oxygen species (ROS) accumulation was augmented at concentration reliant mode, that changed normalize numerous indicator pathways and manipulate the kinetic cellular actions. ZnO nanoparticle synthesized Cardiospermum halicacabum might persuades programmed cell necrosis via elevated ROS levels in cells. CH-ZnONPs was further stimulates the markers of apoptosis and aggravates necrosis of cancerous cells, toxicity to cells, and accretion of ROS. With sourced on above whole data, this might accomplished that CH-ZnONPs amalgamated Cardiospermum halicacabum appreciably possessed a toxicity to human melanoma cells (A375) via provoking the apoptotic cell necrosis, entailed feasible efficacy of CH-ZnONPs besides malignancy management., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Oxidative stress is considered as a major factor in aging and exacerbates aging process through a variety of molecular mechanisms. D-galactose, a normal reducing sugar with high dose can cause the accumulation of reactive oxygen species (ROS) or stimulate free radical production indirectly by the formation of advanced glycation end products in tissues, finally resulting in oxidative stress. 20(R)-ginsenoside Rg3 (20(R)-Rg3), a major and representative component isolated from red ginseng ( Panax ginseng C.A Meyer), has been shown to observably have an anti-oxidative effect. We thereby investigated the beneficial effects of 20(R)-Rg3 on D-galactose-induced oxidative stress injury and its underlying mechanisms. Our results showed that continuous injection of D-galactose with 800[Formula: see text]mg/kg/day for 8 weeks increased the levels of alanine aminotransferase (ALT) and blood urea nitrogen (BUN). However, such increases were attenuated by the treatment of 20(R)-Rg3 for 4 weeks. Meanwhile, 20(R)-Rg3 markedly inhibited D-galactose-caused oxidative stress in liver and kidney. The anti-oxidants, including catalase (CAT) and superoxide dismutase (SOD), were elevated in the mice from 20(R)-Rg3-treated group compared with that from D-galactose group. In contrast, a significant decrease in levels of cytochrome P450 E1 (CYP2E1) and the lipid peroxidation product malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) were observed in the 20(R)-Rg3-treated group. These effects were associated with a significant increase of AGEs. More importantly, 20(R)-Rg3 effectively attenuated D-galactose induced apoptosis in liver and kidney via restoring the upstream PI3K/AKT signaling pathway. Taken together, our study suggests that 20(R)-Rg3 may be a novel and promising anti-oxidative therapeutic agent to prevent aging-related injuries in liver and kidney.

Accumulating evidence has established that long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) is a tumor regulator in many cancers. Here, we aimed to investigate the possible function of lncRNA PVT1 in esophageal carcinoma (EC) via targeting of microRNA-145 (miR-145). Initially, microarray-based gene expression profiling of EC was employed to identify differentially expressed genes. Moreover, the expression of lncRNA PVT1 was examined and the cell line presenting with the highest level of lncRNA PVT1 expression was selected for subsequent experiments. We then proceeded to examine interaction among lncRNA PVT1, FSCN1, and miR-145. The effect of lncRNA PVT1 on viability, migration, invasion, apoptosis, and tumorigenesis of transfected cells was examined with gain-of-function and loss-of-function experiments. We observed that lncRNA PVT1 was robustly induced in EC. lncRNA PVT1 could bind to miR-145 and regulate its expression, and FSCN1 is a target gene of miR-145. Overexpression of miR-145 or silencing of lncRNA PVT1 was revealed to suppress cell viability, migration, and invasion abilities, while also stimulating cell apoptosis. Furthermore, our in vivo results showed that overexpression of miR-145 or silencing of lncRNA PVT1 resulted in decreased tumor growth in nude mice. In conclusion, our research reveals that down-regulation of lncRNA PVT1 could potentially promote expression of miR-145 to repress cell migration and invasion, and promote cell apoptosis through the inhibition of FSCN1. This highlights the potential of lncRNA PVT1 as a therapeutic target for EC treatment., (© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Background: Zinc oxide nanoparticles (ZnO NPs) are used in modern cancer therapy based on their specific target, efficacy, low toxicity and biocompatibility. The photocatalytic performance of Zinc oxide (ZnO) nanocomposites with hyaluronic acid (HA) was used to study anticancer properties against various human cancer cell lines., Methods: Zinc oxide (ZnO) nanocomposites functionalized by hyaluronic acid (HA) were prepared by a co-precipitation method (HA-ZnONcs). The submicron-flower-shaped nanocomposites were further functionalized with ginsenoside Rh2 by a cleavable ester bond via carbodiimide chemistry to form Rh2HAZnO. The physicochemical behaviors of the synthesized ZnO nanocomposites were characterized by various analytical and spectroscopic techniques. We carried out 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay to evaluate the toxicity of Rh2HAZnO in various human cancer cells (A549, MCF-7, and HT29). Furthermore, to confirm the apoptotic effects of Rh2HAZnO and to determine the role of the Caspase-9/p38 MAPK pathways by various molecular techniques such as RT-PCR and Western blotting. Furthermore, Rh2HAZnO induced morphological changes of these cell lines, mainly intracellular reactive oxygen species (ROS) were observed by ROS staining and nucleus by Hoechst staining., Results: We confirmed that Rh2HAZnO exhibits the anti-cancer effects on A549 lung cancer, HT29 colon cancer, and MCF7 breast cancer cells. Moreover, intracellular reactive oxygen species (ROS) were observed in three cancer cell lines. Rh2HAZnO induced apoptotic process through p53-mediated pathway by upregulating p53 and BAX and downregulating BCL2. Specifically, Rh2HAZnO induced activation of cleaved PARP (Asp214) in A549 lung cancer cells and upregulated Caspase-9/phosphorylation of p38 MAPK in other cell lines (HT29 and MCF-7). Furthermore, Rh2HAZnO induced morphological changes in the nucleus of these cell lines., Conclusion: These results suggest that the potential anticancer activity of novel Rh2HAZnO nanoparticles might be linked to induction of apoptosis through the generation of ROS by activation of the Caspase-9/p38 MAPK pathway., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Kim et al.)

Oral squamous cell carcinoma (OSCC) is the fifth common cause of cancer mortality in Taiwan with high incidence and recurrence and needs new therapeutic strategies. In this study, ursolic acid (UA), a triterpenoid, was examined the antitumor potency in OSCC cells. Our results showed that UA inhibited the proliferation of OSCC cells in a dose- and time-dependent manner in both Ca922 and SCC2095 oral cancer cells. UA induced caspase-dependent apoptosis accompanied with the modulation of various biological biomarkers including downregulating Akt/mTOR/NF-κB signaling, ERK, and p38. In addition, UA inhibited angiogenesis as evidenced by abrogation of migration/invasion and blocking MMP-2 secretion in Ca922 cells. Interestingly, UA induced autophagy in OSCC cells, as manifested by LC3B-II conversion and increased p62 expression and accumulation of autophagosomes. Inhibition by autophagy inhibitor enhanced UA-mediated apoptosis in Ca922 cells. The experiment provides a rationale for using triterpenoid in the treatment of OSCC., (© 2019 Wiley Periodicals, Inc.)

Accumulation of amyloid-β (Aβ), which results in the formation of senile plaques that cause oxidative damage and neuronal cell death, has been accepted as the major pathological mechanism of Alzheimer's disease (AD). Hence, inhibition of Aβ-induced oxidative damage and neuronal cell apoptosis represents the effective strategies in combating AD. Ginsenoside Re (Re) has pharmacological effects against Aβ-induced neurotoxicity. However, its molecular mechanism remains elusive. The present study evaluated the effect of Re against Aβ-induced cytotoxicity and apoptosis in SH-SY5Y cells, and investigated the underlying mechanism. We demonstrate that Re inhibits the Aβ-triggered mitochondrial apoptotic pathway, as indicated by maintenance of mitochondrial functional, elevated Bcl-2/Bax ratio, reduced cytochrome c release, and inactivation of caspase-3/9. Re attenuated Aβ-evoked reactive oxygen species (ROS) production, apoptosis signal-regulating kinase 1 (ASK1) phosphorylation, and JNK activation. ROS-scavenging abrogated the ability of Re to alter ASK-1 activation. Simultaneously, inhibition of JNK abolished Re-induced Bax downregulation in Aβ-challenged SH-SY5Y cells. In addition, Re enhanced activation of the nuclear factor-E2-related factor 2 (Nrf2) in Aβ-induced SH-SY5Y cells. Knockdown of Nrf2 by small interfering RNA targeting Nrf2 abolished the protective effect of Re. Our findings indicate that Re could be a potential therapeutic approach for the treatment of AD.

Objective: In this study, we investigated the effects of delivering small interfering RNA (siRNA) for efficient STAT3 downregulation on propagation and apoptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS)., Methods: The FLSs were transfected with three different siRNAs. RNAi-1 was selected for further experiments. The expression levels of both STAT3 messenger RNA (mRNA) and its protein were detected by a real-time polymerase chain reaction and Western blot analysis. The proliferation of FLSs was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The apoptosis of FLSs was examined by flow cytometry. The expression levels of cell apoptotic-related genes Bcl-2, Bax, and caspase-3 were detected by Western blot analysis., Results: RNAi-1 was selected as the RNAi group for its lowest expression levels of STAT3 mRNA. In RNAi group, the proliferation of synoviocytes was much lower and the apoptosis rate was significantly higher. FLSs of RNAi-1 group showed significantly lower expression level of apoptotic-inhibiting gene Bcl-2 and significantly higher expression levels of proapoptotic gene Bax and apoptotic protease caspase-3., Conclusion: Transfection with targeted STAT3 recombinant plasmids effectively inhibited the expression of STAT3 mRNA and its protein in RA-FLSs. RNAi-mediated silencing of STAT3 reduced the proliferation and promoted the apoptosis of FLSs., (© 2018 Wiley Periodicals, Inc.)

Glutathione peroxidase 4 (GPX4) is essential for cell membrane repair, inflammation suppression, and ferroptosis inhibition. GPX4 upregulation provides unique drug discovery opportunities for inflammation and ferroptosis-related diseases. However, rational design of protein activators is challenging. Until now, no compound has been reported to activate the enzyme activity of GPX4. Here, we identified a potential allosteric site in GPX4 and successfully found eight GPX4 activators using a novel computational strategy and experimental studies. Compound 1 from the virtual screen increased GPX4 activity, suppressed ferroptosis, reduced pro-inflammatory lipid mediator production, and inhibited NF-κB pathway activation. Further chemical synthesis and structure-activity relationship studies revealed seven more activators. The strongest compound, 1d4, increased GPX4 activity to 150% at 20 μM in the cell-free assay and 61 μM in cell extracts. Therefore, we demonstrated that GPX4 can be directly activated using chemical compounds to suppress ferroptosis and inflammation. Meanwhile, the discovery of GPX4 activators verified the possibility of rational design of allosteric activators.

Background: Long non-coding RNA (lncRNA) distal-less homeobox 6 antisense 1 (DLX6-AS1) was reported to be dysregulated in lung cancer. However, detailed roles of DLX6-AS1 in the pathogenesis of non-small cell lung cancer (NSCLC) were largely unknown., Methods: The expression of DLX6-AS1 was measured in NSCLC tissues and cells by quantitative real-time PCR (qRT-PCR). The abundance of proline rich 11 (PRR11) were detected by qRT-PCR and western blot, respectively. The effects of DLX6-AS1 and PRR11 on cell proliferation, migration, invasion and apoptosis were explored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), transwell and flow cytometry analysis, respectively. Luciferase reporter assay, qRT-PCR and western blot were performed to confirm the interaction between miR-144 and DLX6-AS1 or PRR11. Tumor xenograft assay was performed to verify the role of DLX6-AS1 in NSCLC in vivo., Results: DLX6-AS1 and PRR11 were elevated in NSCLC tissues and cells. DLX6-AS1 was positively correlated with PRR11 mRNA expression in NSCLC tissues. Knockdown of DLX6-AS1 and PRR11 significantly suppressed cell proliferation, migration and invasion and induced apoptosis in NSCLC cells, which was reversed by PRR11 overexpression. In addition, DLX6-AS1 and PRR11 were demonstrated to interact with microRNA-144 (miR-144) and DLX6-AS1 upregulated PRR11 expression by acting as a competing endogenous RNA (ceRNA) of miR-144 in NSCLC cells. Furthermore, DLX6-AS1 knockdown suppressed tumor growth in NSCLC in vivo by upregulating miR-144 and downregulating PRR11., Conclusion: Knockdown of DLX6-AS1 inhibited cell proliferation, migration, invasion and promoted apoptosis by downregulating PRR11 expression and upregulating miR-144 in NSCLC., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The aim of this study was to evaluate the potential cytotoxicity of self-adhesive resin cements with or without light irradiation on human periodontal ligament fibroblasts (HPDLFs) in vitro . Three self-adhesive resin cements (RelyX U200, Maxcem Elite and Multilink Speed) were cured with light or not. Cured cements were stored at 37°C for 24 h in water or Dulbecco's modified eagle medium (DMEM) medium. Their chromatographic analysis of water-based extract solution was made and then the DMEM-based extract solution was diluted in complete DMEM {1:5, 1:10, 1:20, 1:40, 1:80 (v/v)} for evaluating cell relative growth rate and cell apoptosis/necrosis rate of HPDLFs. The data was analyzed by one-way ANOVA and independent T test. Regardless of light irradiation, cell relative growth rate increased, and the apoptosis/necrosis rate of each resin cement decreased with the increase of gradient dilution. Regardless of gradient dilution, the cell relative growth rate and apoptosis/necrosis rate of RelyX U200 and Maxcem Elite with light irradiation were higher than those without light irradiation. Besides, without light irradiation, Multilink Speed showed higher cell relative growth rate and lower apoptosis/necrosis rate than other cements. Light irradiation and composition difference of self-adhesive resin cements could affect their cytotoxicity on HPDLFs.

We investigated the protective effects and possible mechanisms of Aplysin against alcohol-induced liver injury. Rats were given daily either alcohol only (alcohol model group; 8 to 12 mL/kg body weight), one of three doses of Aplysin (50, 100, or 150 mg/kg Aplysin) plus alcohol, or volume-matched saline. After 6 weeks, the effects of Aplysin were assessed in terms of changes in histology, biochemical indices, and DNA oxidative damage. Potential mechanisms were analyzed through measurements of lipid peroxidation, antioxidant defense systems, expression of cytochrome P450 2E1, and expression of apoptosis-related genes. We found that Aplysin significantly protected the liver against alcohol-induced oxidative injury, evidenced by improved hepatic histological structure, inhibited alcohol-induced elevation of serum biochemical indices, attenuated extents of hepatocellular DNA damage. At a mechanistic level, Aplysin alleviated alcohol-induced oxidative stress as illustrated by the revivification of erythrocyte membrane fluidity, the attenuation of glutathione depletion, the restoration of antioxidase activities, and reduced malondialdehyde overproduction. Furthermore, the mRNA levels of Bax, cytochrome c, and cytochrome P450 2E1 were significantly down-regulated, whereas those of Bcl-2 and caspase-9 and caspase-3 were markedly up-regulated. These findings suggest that Aplysin provides significant protection against alcohol-induced liver injury, possibly through alleviating oxidative damage and modulating endogenous apoptosis-related genes expression., Practical Application: Many natural components derived from alga have been used in the food, cosmetics, and biomedicine industries. Aplysin, a marine bromosesquiterpene, was extracted from the red alga Laurencia tristicha, which could effectively protect against alcohol-induced liver injury, might be a potential natural sources for preventing alcoholic liver damage., (© 2018 Institute of Food Technologists®.)

Previous studies have shown that microcystin-LR (MCLR) is a reproductive toxicant that induces germ cell apoptosis in the testes, but the underlying mechanisms have not been well understood. In this study, we investigated that MCLR induces germ cell apoptosis is through activation of endoplasmic reticulum (ER) stress and N-acetylcysteine (NAC), an antioxidant could protect against germ cell apoptosis by inhibiting the ER stress. Healthy male zebrafish were intraperitoneally injected with NAC (500 nM), beginning at 2 h before different doses of MCLR (0, 50, 100, 200 μg/kg). As expected, acute MCLR exposure resulted in oxidative stress and germ cell apoptosis in zebrafish testes. Further analysis showed that NAC significantly alleviated MCLR-induced testicular germ cell apoptosis and inhibited the caspase-dependent apoptotic proteins. Meanwhile H&E staining showed that NAC could rescue testicular damage induced by MCLR. Moreover, MCLR induced activation of ER stress which consequently triggered apoptosis in zebrafish testes. Interestingly, NAC was effective in improving the total antioxidant capacity (T-AOC) level and activity of antioxidant enzymes in NAC pretreated groups. NAC significantly attenuated MCLR-induced upregulation of GRP78 in testes. In addition, NAC significantly attenuated MCLR-triggered testicular eIF2s1 and MAPK8 activation, indicating that NAC counteracts MCLR-induced unfolded protein response (UPR) in testes. Taken together, the results observed in this study suggested that ER stress plays a critical role in germ cell apoptosis exposed to MCLR and NAC could protect against apoptosis via inhibiting ER stress in zebrafish testes., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Type 2 diabetes (T2D) arises when the pancreatic beta-cell fails to compensate for increased insulin needs due to insulin resistance. Glucolipotoxicity (GLT) has been proposed to induce beta-cell dysfunction in T2D by formation of reactive oxygen species (ROS). Here, we examined if modeling glucolipotoxic conditions by high glucose-high free fatty acid (FFA) exposure (GLT) regulates beta-cell iron transport, by increasing the cytosolic labile iron pool (LIP). In isolated mouse islets, the GLT-induced increase in the LIP catalyzed cytosolic ROS formation and induced apoptosis. We show that GLT-induced ROS production is regulated by an increased LIP associated with elevated expression of genes regulating iron import. Using pharmacological and transgenic approaches, we show that iron reduction and decreased iron import protects from GLT-induced ROS production, prevents impairment of the mitochondrial membrane potential (MMP) and inhibits apoptosis. This study identifies a novel pathway underlying GLT-induced apoptosis involving increased iron import, generation of hydroxyl radicals from hydrogen peroxide through the Fenton reaction in the cytosolic compartment associated with dissipation of the MMP and beta-cell apoptosis., (© 2018 Society for Endocrinology.)

Background: Rheumatoid arthritis (RA) is the most common inflammatory arthritis and is a major cause of disability. The nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway has been reported to be involved in the pathogenesis of RA with unclear mechanisms. Therefore, this study aims to explore the effect of NF-κB pathway on proliferation, apoptosis, and angiogenesis of human fibroblast-like synovial cells (HFLS) in RA., Methods: Normal HFLS and RA-HFLS were selected as the normal and control groups, respectively. RA-HFLS were treated by BAY11-7082 (an inhibitor of NF-κB) in different concentrations, namely 2.5 μmol/L BAY11-7082, 5 μmol/LBAY11-7082 and 10 μmol/L BAY11-7082. MTT assay was employed to detect cell proliferation. Cell apoptosis was determined by flow cytometry at 24, 48, and 72 hours after culture. Western blot analysis was employed to detect the expressions of NF-κB, angiogenesis-related factors (VEGF, Ang1, and Ang2)., Results: Initially, we found that BAY11-7082 inhibited NF-κB expression in a concentration-dependent manner. According to the findings of MTT assay and flow cytometry, we understood that RA-HFLS treated by BAY11-7082 (an inhibitor of NF-κB), the inhibition of NF-κB pathway, suppressed RA-HFLS proliferation and induced RA-HFLS apoptosis in a concentration and time-dependent manner. Furthermore, RA-HFLS treated by BAY11-7082 presented decreased VEGF, Ang1 and Ang2 expressions in a concentration-dependent manner., Conclusion: The study concluded that inhibition of NF-κB pathway induced cell apoptosis and suppressed proliferation and angiogenesis of RA-HFLS, which could serve as a novel target in the treatment of RA.

In the present study, effects of cis-9,10-epoxy stearic acid (ESA) generated by the thermal oxidation of oleic acid on HepG2 cells, including cytotoxicity, apoptosis, and oxidative stress, were investigated. Our results revealed that ESA decreased the cell viability and induced cell death. Cell cycle analysis with propidium iodide staining showed that ESA induced cell cycle arrest at the G0/G1 phase in HepG2 cells. Cell apoptosis analysis with annexin V and propidium iodide staining demonstrated that ESA induced HepG2 cell apoptotic events in a dose- and time-dependent manner; the apoptosis of cells after treated with 500 μM ESA for 12, 24, and 48 h was 32.16, 38.70, and 65.80%, respectively. Furthermore, ESA treatment to HepG2 cells resulted in an increase in reactive oxygen species and malondialdehyde (from 0.84 ± 0.02 to 8.90 ± 0.50 nmol/mg of protein) levels and a reduction in antioxidant enzyme activity, including superoxide dismutase (from 1.34 ± 0.27 to 0.10 ± 0.007 units/mg of protein), catalase (from 100.04 ± 5.05 to 20.09 ± 3.00 units/mg of protein), and glutathione peroxidase (from 120.44 ± 7.62 to 35.84 ± 5.99 milliunits/mg of protein). These findings provide critical information on the effects of ESA on HepG2 cells, particularly cytotoxicity and oxidative stress, which is important for the evaluation of the biosafety of the oxidative product of oleic acid.

The development of nephrotoxicity largely limits the clinical use of chemotherapy. MiRNAs are able to target various genes and involved in the regulation of diverse cellular processes, including cell apoptosis and death. Our study showed that miR-181a expression was significantly increased after 5-fluorouracil (5-FU) treatment in renal mesangial cells and kidney tissue, which was associated with decreased baculoviral inhibition of apoptosis protein repeat-containing 6 (BIRC6) expression and increased apoptotic rate. Enforced miR-181a expression enhanced 5-FU-induced p53-dependent mitochondrial apoptosis, including declined Bcl-2/Bax ratio, loss of mitochondrial membrane potential, cytochrome c release, and caspase-9 and caspase-3 activation. However, inhibition of miR-181a was associated with reduced p53-mediated mitochondrial apoptosis induced by 5-FU. Moreover, miR-181a increased BIRC6 downstream gene p53 protein expression and transcriptional activity by reducing ubiquitin-mediated protein degradation. We found that miR-181a directly targeted 3'-UTR of BIRC6 mRNA and negatively regulated BIRC6 expression. In vivo study, knockdown of miR-181a with adeno-associated virus harboring miR-181a-tough decoy attenuated 5-FU-induced renal cell apoptosis, inflammation and kidney injury. In conclusion, these results demonstrate that miR-181a increases p53 protein expression and transcriptional activity by targeting BIRC6 and promotes 5-FU-induced apoptosis in mesangial cells. Inhibition of miR-181a ameliorates 5-FU-induced nephrotoxicity, suggesting that miR-181a may be a novel therapeutic target for nephrotoxicity treatment during chemotherapy.

Ethnopharmacological Relevance: Schisandra chinensis (Turcz.) Baill is a frequently used traditional Chinese medicine, and modern pharmacological research has proven that S. chinensis has antioxidant, anti-hepatotoxity, anti-inflammatory, and anti-nephrotoxic effects. Cisplatin is widely used as antineoplastic drug at present, but the clinical application is limited owing to its nephrotoxicity., Aim of the Study: To demonstrate the renoprotective activity of the extract of the stems of S. chinensis (SCE) in mice established by cisplatin-triggering acute kidney injury (AKI). The possible molecular mechanism of nephroprotection exhibited by SCE was evaluated for the first time., Materials and Methods: Mice in SCE groups were pre-treated with SCE for 10 consecutive days, and on 7th day 1 h after final administration, following intraperitoneal injection of cisplatin with 20 mg/kg was treated to cisplatin group and SCE groups. On the 10th day, renal function, histopathological change, and oxidative stress markers were investigated., Results: Renal oxidative stress level characterized by elevated heme oxygenase 1 (HO-1), cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) expression was obviously reduced by SCE pre-treatment. In addition, SCE was found to suppress inflammatory response through the reduction of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) p65 activation. SCE treatment also inhibited activation of apoptotic pathways through down-regulating Bax, cleaved caspase-3, 8, 9 and up-regulating Bcl-2 expression levels., Conclusion: These findings illustrated that SCE possessed powerful protective effect on AKI caused by cisplatin via amelioration of oxidative stress, inflammation and apoptosis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Psoriasis is a chronic auto-immune inflammation disease with skin lesions and abnormal keratinocyte proliferation. Sunitinib, a multi-targeted tyrosine kinase inhibitor, is known to selectively inhibit several growth factor receptors, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor and stem cell factor. It was reported that a patient with renal cell carcinoma (RCC) whose psoriatic lesion was resolved dramatically during treatment with Sunitinib, however, the mechanism is still unclear. We applied Sunitinib ointment to treat imiquimod-induced mouse model of psoriasis and found that Sunitinib ointment could alleviate imiquimod-induced psoriasis-like inflammation and reduce the Ki67 expression, while Sunitinib ointment couldn't reduce imiquimod-induced splenomegaly of the mouse model, then we concentrated on studying the effect of Sunitinib on the proliferation and apoptosis of keratinocytes, we cultivated HaCaT cells with epidermal growth factor (HaCaT/E cells) to represent as a state of highly proliferative psoriatic keratinocytes. We found that Sunitinib could inhibit the proliferation of Hacat/E cell in a time and concentration dependent manner by influencing the expression level of cell cycle protein D1, cycle protein E1, in addition, Sunitinib could induce the apoptosis of Hacat/E cell and up-regulate the expression of poly ADP-ribose polymerase (PARP). Sunitinib down-regulated the expression of phosphorylated signal transduction and activator of transcription 3 (p-Stat3) of Hacat/E cells significantly. We conclude that Sunitinib alleviates imiquimod-induced psoriasis-like inflammation by regulating the proliferation and apoptosis of HaCaT cells through inhibiting the expression of p-Stat3., (Copyright © 2018. Published by Elsevier B.V.)

Background: Exposure to cold weather is associated with infaust cardiovascular responses, including myocardial infarction and arrhythmias. However, the exact mechanisms of these adverse changes in the myocardium under cold stress are unknown. This study was designed to investigate the mechanisms of cardiac injury induced by cold stress in mice., Methods: The mice were randomly divided into three groups, normal control (no handling), 1-week cold stress and 2-week cold stress. We observed physiological changes of the mice and morphological changes of myocardium tissues, and we measured the changes of 3'-nitrotyrosine and 4-hydroxynonenal, the expression levels of superoxide dismutase-1, superoxide dismutase-2, Bax, Bad, Bcl-2, Nuclear factor erythroid-derived 2-like 2 (Nrf2) and Kelch like-ECH-associated protein 1 (Keap1) in myocardium by western blot. Besides, we detected mRNA of superoxide dismutase-1, superoxide dismutase-2, Bax, Bad, Bcl-2, Nrf2 and Keap1 by real-time PCR. One-way analysis of variance, followed by LSD-t test, was used to compare each variable for differences among the groups., Results: Echocardiography analyses demonstrated left ventricle dysfunction in the groups receiving cold stress. Histological analyses witnessed inflammation, vacuolar and eosinophilic degeneration occurred in left ventricle tissues. Western blotting results showed increased 3'-nitrotyrosine and 4-hydroxynonenal and decreased antioxidant enzymes (superoxide dismutase-1 and superoxide dismutase-2) in the myocardium. Expression of Nrf2 and Keap1 followed a downward trend under cold exposure, as indicated by western blotting and real-time PCR. Expression of anti-apoptotic protein Bcl-2 also showed the same trend. In contrast, expression of pro-apoptotic proteins Bax and Bad followed an upward trend under cold exposure. The results of real-time PCR were consistent with those of western blotting., Conclusions: These findings were very significant, showing that cold exposure induced cardiac injury by inhibiting the Nrf2-Keap1 signaling pathway.

Background Aims: Imatinib (IM), a tyrosine kinase inhibitor targeting the BCR-ABL oncoprotein, remains a major therapeutic strategy for patients with chronic myelogenous leukemia (CML). However, IM resistance is still a challenge in the treatment of CML. Recently, it was reported that exosomes (Exo) were involved in drug resistance. Therefore, the present study investigated whether Exo secreted by human umbilical cord mesenchymal stromal cells (hUC-MSC-Exo) affected the sensitivity of K562 cells to IM., Methods: hUC-MSC-Exo were isolated and identified. K562 cells were then treated or not with IM (1 µmol/L) in combination with hUC-MSC-Exo (50 µg/mL). Cell viability and apoptosis were determined by cell counting kit 8 (CCK-8) and annexin V/propidium iodide (PI) double staining, respectively. Apoptotic proteins, caspase and their cleaved forms were detected by Western blot., Results: It was shown that hUC-MSC-Exo alone had no effect on cell viability and apoptosis of K562 cells. However, hUC-MSC-Exo promoted IM-induced cell viability inhibition and apoptosis. Moreover, hUC-MSC-Exo enhanced the increased Bax expression and the decreased Bcl-2 expression that were induced by IM. Compared with IM alone, caspase-9 and caspase-3 were further activated by combination of hUC-MSC-Exo with IM. Finally, the effects of hUC-MSC-Exo on K562 cells could be reversed by pretreatment of K562 cells with caspase inhibitor Z-VAD-FMK (30 µmol/L) DISCUSSION: These results indicate that hUC-MSC-Exo enhanced the sensitivity of K562 cells to IM via activation of caspase signaling pathway. Therefore, combining IM with hUC-MSC-Exo could be a promising approach to improve the efficacy of CML treatment., (Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

MicroRNAs (miRNAs) exhibit a crucial role in the regulation of angiogenesis and tumor progression, of which miR-199a-5p (miR-199a) has been reported to function as a tumor suppressor in multiple malignancies. However, the precise mechanisms underlying miR-199a in hemangiomas (HAs) remain elusive. In this study, we found that miR-199a had low expression level, while proliferating cell nuclear antigen (PCNA) had high expression level in proliferating-phase HAs compared with the involuting-phase HAs and normal tissues. Spearman correlation analysis revealed the negative correlation of miR-199a with PCNA expression in proliferating-phase HAs. In vitro experiments showed that restoration of miR-199a suppressed cell proliferation capability and induced cell apoptosis in HA-derived endothelial cells (HDEC) and CRL-2586 EOMA cells, followed with decreased PCNA expression and increased cleaved caspase-3 expression, but miR-199a inhibitor reversed these effects. Furthermore, HIF1A was identified as a target of miR-199a and had negative correlation with miR-199a expression in proliferating-phase HAs. Overexpression of HIF1A attenuated the anti-proliferation effect of miR-199a mimic in HAs cells. Taken together, our findings demonstrate that miR-199a may inhibit proliferation and induce apoptosis in HAs cells via targeting HIF1A and provide a potential therapeutic target for HAs.

Endoplasmic reticulum stress (ERs) has been regarded as an important cause for the pathogenesis of non-small-cell lung cancer (NSCLC). β-elemene is an active component in the essential oil extracted from a medicinal herb, Curcuma wenyujin, and has been reported to be effective against non-small-cell lung cancer (NSCLC). However, the potential effect and underlying mechanisms of β-elemene on regulating ERs to inhibit NSCLC are still unclear. In the present study, A549 cells and Lewis tumor-bearing C57BL/6J mice were established to evaluate this effect. Visualsonics Vevo 2100 Small Animal Dedicated High-frequency Color Ultrasound was performed to observe tumor volume in vivo. 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) was used to evaluate cell vitality of A549 cells. Furthermore, western blotting (WB), immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (q-PCR) were applied to detect the ERs-related proteins. Flow cytometry was also applied to detect cell apoptosis and assay kit for reactive oxygen species (ROS) generation. Our results showed that β-elemene inhibited lung cancer tumor growth and cell vitality in a dose- and time-dependent manner. Not only that, β-elemene could up-regulate ERs-related proteins like PERK, IRE1α, ATF6, ATF4, CHOP and down-regulate the Bcl-2 expression. More importantly, ERs inhibitor 4-PBA, IRE1α inhibitor STF-083010, ATF6 inhibitor Anti-ATF6 and PERK inhibitor GSK2656157 can all reduce the amplitude of protein expression changes and apoptosis rates, then weaken the anti-tumor effect of β-elemene. Therefore, the present in vivo and in vitro study revealed that the anti-NSCLC effect of β-elemene is closely related to the activation of ERs through PERK/IRE1α/ATF6 pathway, and this might be beneficial for clinical therapy of NSCLC., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Streptococcus pneumoniae meningitis is a serious inflammatory disease of the central nervous system (CNS) and is associated with high morbidity and mortality rates. The inflammatory processes initiated by recognition of bacterial components contribute to apoptosis in the hippocampal dentate gyrus. Brain-derived neurotrophic factor (BDNF) has long been recommended for the treatment of CNS diseases due to its powerful neuro-survival properties, as well as its recently reported anti-inflammatory and anti-apoptotic effects in vitro and in vivo., Methods: In this study, we investigated the effects of BDNF-related signaling on the inflammatory response and hippocampal apoptosis in experimental models of pneumococcal meningitis. Pretreatment with exogenous BDNF or the tropomyosin-receptor kinase B (TrkB) inhibitor k252a was performed to assess the activation or inhibition of the BDNF/TrkB-signaling axis prior to intracisternal infection with live S. pneumoniae. At 24 h post-infection, rats were assessed for clinical severity and sacrificed to harvest the brains. Paraffin-embedded brain sections underwent hematoxylin and eosin staining to evaluate pathological severity, and cytokine and chemokine levels in the hippocampus and cortex were evaluated by enzyme-linked immunosorbent assay. Additionally, apoptotic neurons were detected in the hippocampal dentate gyrus by terminal deoxynucleotidyl transferase dUTP-nick-end labeling, key molecules associated with the related signaling pathway were analyzed by real-time polymerase chain reaction and western blot, and the DNA-binding activity of nuclear factor kappa B (NF-κB) was measured by electrophoretic mobility shift assay., Results: Rats administered BDNF exhibited reduced clinical impairment, pathological severity, and hippocampal apoptosis. Furthermore, BDNF pretreatment suppressed the expression of inflammatory factors, including tumor necrosis factor α, interleukin (IL)-1β, and IL-6, and increased the expression of the anti-inflammatory factor IL-10. Moreover, BDNF pretreatment increased TrkB expression, activated downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling, and inhibited the myeloid differentiation primary response gene 88 (MyD88)/NF-κB-signaling pathway., Conclusions: These data suggested that BDNF administration exerted anti-inflammatory and anti-apoptotic effects on an experimental pneumococcal meningitis model via modulation of MyD88/NF-κB- and PI3K/AKT-signaling pathways. Our results indicated that treatment with exogenous BDNF might constitute a potential therapeutic strategy for the treatment of bacterial meningitis.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a human oncoprotein that is overexpressed in multiple kinds of tumors including gastric cancer (GC). Mammalian target of rapamycin complex 1 (mTORC1) over-activation is detected in GC and many other cancers. Previous study found that CIP2A/mTORC1 controls cell growth and autophagy through direct association. CIP2A plays an 'oncogenic nexus' in several cancer types to participate in the tumorigenic transformation and chemoresistance. In the present study, we investigated whether Cucurbitacin B (CuB), a natural compound found in Cucurbitaceae, can be used in cisplatin (DDP)-resistant human GC cell line SGC7901/DDP. Results demonstrated that CuB treatment significantly suppressed SGC7901/DDP cell proliferation, induced caspase-dependent apoptosis, and autophagy. The activation of autophagy was mediated through CuB-induced inhibition of mTORC1. Furthermore, CuB inhibited mTORC1 via the activation of protein phosphatase 2A (PP2A) which is mediated by CIP2A inhibition. These findings indicated that CuB can inhibit the proliferation, induce caspase-dependent apoptosis, and autophagy of SGC7901/DDP cells by suppressing CIP2A/PP2A/mTORC1 signaling axis. Thus, CuB may be a novel effective candidate to treat DDP-resistant human GC cells.