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Sirt6, a class III NAD+-dependent deacetylase of the sirtuin family, is a highly specific H3 deacetylase and plays important roles in regulating cellular growth and death. The induction of oxidative stress and death is the critical mechanism involved in cardiomyocyte injury and cardiac dysfunction in doxorubicin-induced cardiotoxicity, but the regulatory role of Sirt6 in the fate of DOX-impaired cardiomyocytes is poorly understood. In the present study, we exposed Sirt6 heterozygous (Sirt6+/−) mice and their littermates as well as cultured neonatal rat cardiomyocytes to DOX, then investigated the role of Sirt6 in mitigating oxidative stress and cardiac injury in the DOX-treated myocardium. Sirt6 partial knockout or silencing worsened cardiac damage, remodeling, and oxidative stress injury in mice or cultured cardiomyocytes with DOX challenge. Cardiomyocytes infected with adenoviral constructs encoding Sirt6 showed reversal of this DOX-induced damage. Intriguingly, Sirt6 reduced oxidative stress injury by upregulating endogenous antioxidant levels, interacted with oxidative stress-stirred p53, and acted as a co-repressor of p53 in nuclei. Sirt6 was recruited by p53 to the promoter regions of the target genes Fas and FasL and further suppressed p53 transcription activity by reducing histone acetylation. Sirt6 inhibited Fas/FasL signaling and attenuated both Fas-FADD-caspase-8 apoptotic and Fas-RIP3 necrotic pathways. These results indicate that Sirt6 protects the heart against DOX-induced cardiotoxicity by upregulating endogenous antioxidants, as well as suppressing oxidative stress and cell death signaling pathways dependent on ROS-stirred p53 transcriptional activation, thus reducing Fas–FasL-mediated apoptosis and necrosis.

Ovarian cancer is a serious threat to women's life and health, with a high mortality rate. Therefore, in addition to improving surgery for ovarian cancer, it is particularly important to develop novel drug treatments. In the present study, the anticancer effects of cucurbitacin I, a natural product, were investigated. Cucurbitacin I impaired the viability of SKVO3 cells in a concentration‑ and time‑dependent manner. Apoptosis was involved in the process of cucurbitacin I‑induced cell death, with an increase observed in cleaved‑caspase 3 and BAX, and a decrease in Bcl‑2. Cucurbitacin I caused a notable increase in intracellular reactive oxygen species, and regulated Kelch‑like ECH‑associated protein 1 and nuclear factor erythroid‑derived 2‑like 2 to decrease the expression of antioxidant‑related genes. In addition, Cucurbitacin I induced cell shrinkage by regulating the p190BRhoGAP (p190B)‑Rac1 signaling axis related to the cytoskeleton. In brief, these results suggested that cucurbitacin I induced cell death through oxidative stress and the p190B‑Rac1 signaling axis in SKVO3 cells. The results may provide novel evidence for the treatment of ovarian cancer.

Background Abnormalities of the L-arginine-nitric oxide pathway induce hypertension. 5-Lipoxygenase (5-LO) is the key enzyme involved in synthesis of leukotrienes (LTs). However, whether nitricoxide synthase dysfunction induces hypertensive vascular remodeling by regulating 5-LO activity and its downstream inflammatory metabolites remains unknown. Methods and results Six-week L-NAME treatment significantly induced hypertension and vascular remodeling in both wild-type (WT) and 5-LO–knockout (5-LO–KO) mice, and blood pressure in caudal and carotid arteries was lower in 5-LO–KO than WT mice with L-NAME exposure. On histology, L-NAME induced less media thickness, media-to-lumen ratio, and collagen deposition and fewer Ki-67–positive vascular smooth muscle cells (VSMCs) but more elastin expression in thoracic and mesenteric aortas of 5-LO–KO than L-NAME–treated WT mice. L-NAME significantly increased LT content, including LTB4 and cysteinyl LT (CysLTs), in plasma and neutrophil culture supernatants from WT mice. On immunohistochemistry, L-NAME promoted the colocalization of 5-LO and 5-LO–activating protein on the nuclear envelope of cultured neutrophils, which was accompanied by elevated LT content in culture supernatants. In addition, LTs significantly promoted BrdU incorporation, migration and phenotypic modulation in VSMCs. Conclusion L-NAME may activate the 5-LO/LT pathway in immune cells, such as neutrophils, and promote the products of 5-LO metabolites, including LTB4 and CysLTs, which aggravate vascular remodeling in hypertension. 5-LO deficiency may protect against hypertension and vascular remodeling by reducing levels of 5-LO downstream inflammatory metabolites.

Ovarian cancer is a very common gynecological malignant tumor. Natural products are important sources of chemotherapy drugs for ovarian cancer. Damnacanthal is an anthraquinone derivative with anti-cancer pharmacological properties.This study aimed to investigate the mechanisms underlying damnacanthal's effects against ovarian cancer.In vitro experiments, CCK8, colony formation and flow cytometry assays were used to evaluate the anti-ovarian cancer effect of damnacanthal on SKVO3 and A2780 cells. The wound healing tests and the transwell invasion assays were used to detect the migration and infiltration of ovarian cancer cells. Western Blot assays and immunofluorescence staining were used to measure autophagy levels. In vivo experiments, the anti-ovarian cancer effect of damnacanthal was further evaluated in a xenograft nude mouse model of SKVO3 cells.Damnacanthal induced significant cell death and apoptosis, as well as significant inhibition in migration and invasion, in SKVO3 and A2780 cells, Furthermore, damnacanthal induced cell cycle arrest by increasing the protein levels of p27Kip1 and decreasing cyclin D1 levels. In addition, damnacanthal induced a significant accumulation of autophagosomes, accompanied with an increase in LC3II protein levels, and a decrease in p62 protein levels. 3-methyladenine, an autophagy formation inhibitor, significantly mitigated the damnacanthal-induced apoptosis and migration hindrance, as well as the decline in cell viability. Furthermore, the inactivation of ERK and its downstream effector mTOR signaling pathways, rather than Akt or P38 pathway, were involved in damnacanthal's activation in autophagy. In addition, TBHQ, an ERK activator, significantly inhibited damnacanthal-boosted LC3 II levels and autophagosome accumulation, and reversed damnacanthal-induced cell death, apoptosis, cell cycle arrest and migration hindrance. Finally, the anti-ovarian cancer effect of damnacanthal was confirmed in the orthotopic xenograft model of SKVO3 cells in nude mice, with tumor growth being significantly inhibited comparably to the efficacy of cisplatin. Damnacanthal was also synergistic with cisplatin and showed inhibition in cisplatin-resistant ovarian cancer cells.Damnacanthal inhibited the growth of ovarian cancer via the ERK/mTOR/autophagy signaling cascade, indicating that it may be a potential anti-ovarian cancer drug candidate.

Sirt6, a class III NAD+-dependent deacetylase of the sirtuin family, is a highly specific H3 deacetylase and plays important roles in regulating cellular growth and death. The induction of oxidative stress and death are the crucial mechanisms involved in cardiomyocyte damage and cardiac dysfunction in doxorubicin-induced cardiotoxocity, but the regulatory role of Sirt6 in the fate of DOX-impaired cardiomyocytes is poorly understood. In this study, we exposed heterozygous Sirt6 knockout (Sirt6+/−) mice and their littermates as well as cultured neonatal rat cardiomyocytes to DOX, then investigated how Sirt6 mitigates oxidative stress and myocardial injury in the DOX-treated myocardium. Sirt6 partial knockout or silencing worsened myocardial damage, cardiac remodeling, and oxidative stress in mice or cultured cardiomyocytes with DOX challenge. Cardiomyocytes infected with adenoviral constructs encoding Sirt6 showed reversal of this DOX-induced damage. Intriguingly, Sirt6 reduced oxidative stress injury by upregulating endogenous antioxidant levels, interacted with oxidative stress-stirred p53, and acted as a co-repressor of p53 in nuclei. Sirt6 was recruited by p53 to the promoter regions of the target genes Fas and FasL and further suppressed p53 transcription activity by reducing histone acetylation. Sirt6 inhibited Fas/FasL signaling and attenuated both Fas-FADD-caspase-8 apoptotic and Fas-RIP3 necrotic pathways. These results suggest that Sirt6 protects the heart against DOX-induced cardiotoxity by upregulating endogenous antioxidants, as well as suppressing oxidative stress and cell death signaling pathways dependent on ROS-stirred p53 transcriptional activation, thus reducing Fas-FasL–mediated apoptosis and necrosis.

Objectives To summarise the ingredients of Luo Han Guo extract and the different pharmacological activity of the different ingredients. Find and evaluate the research value of Luo Han Guo extract as a therapeutic drug. Key findings Siraitia grosvenorii is a fruit native to China and has many years of medicinal history. Because of its low-calorie and sugar-free properties, it is approved as a sweetener substitute in foods for obese and diabetic patients. Experiments have shown that this sweetener is non-toxic. This article summarises much literature on S. grosvenorii extracts, briefly introduces their chemical composition and metabolic distribution and summarises the possible pharmacological effects of each S. grosvenorii extract. Siraitia grosvenorii extract has anti-diabetic, anti-tumour, anti-inflammatory, antioxidant, neuroprotective and lipogenic inhibitory effects. These pharmacological activities suggest the medicinal value of S. grosvenorii. Summary Luo Han Guo extract is a low-calorie, non-toxic substance, and its pharmacological activity and its potential medicinal properties support its further utilisation and research.

Cardiac hypertrophy is the main cause of heart failure and sudden death in patients. But the pathogenesis is unclear. Angiotensin II may contribute to cardiac hypertrophy in response to pressure overload. In angiotensin II-treated cardiomyocytes, there is a larger cross-sectional area, more apoptosis cells, and a reduction of irisin expression. An increase in P62, an autophagy flux index, as well as LC3II, were observed in cardiomyocytes after angiotensin II-induced injury. Surprisely, irisin supplementation increased LC3II expression and decreased P62 expression, consisted of results of RFP-GFP-LC3B adenovirus transfection, and reduced cardiomyocyte apoptosis, meanwhile, the protection of irisin was reversed by the autophagy inhibitor 3-methyladenine. In animal experiments, overexpression of irisin reduced cardiomyocyte apoptosis and alleviated myocardial hypertrophy caused by pressure overload. The above results indicate that irisin-induced protective autophagy and alleviated the apoptosis signaling pathway in cardiomyocytes, consequently reducing cardiomyocyte apoptosis after angiotensin II-induced injury. Hence, increasing irisin expression may be a new way to improve cardiac function and quality of life in patients with cardiac hypertrophy.

Endoplasmic reticulum stress (ERS) is usually involved in tumor development and progression, and anticancer agents have recently been recognized to induce ERS. Cucurbitacin-I showed a potent anticancer action by inducing apoptosis through the inhibition of signal transducer and activator of transcription 3 pathway and triggering autophagic cell death. It is not known whether ERS mediates the cancer cell death induced by cucurbitacin-I. Here, we investigated the role of ERS in cucurbitacin-I-treated SKOV3 ovarian cancer cells and PANC-1 pancreatic cancer cells. We confirmed that cucurbitacin-I caused cell death and stirred excessive ERS levels by activating inositol requiring enzyme 1α (IRE1α) and protein kinase R-like endoplasmic reticulum kinase (PERK), as well as PERK downstream factors, including IRE1α and C/EBP homologous protein, but not activating transcription factor 6 (ATF6α) pathway, which was in parallel with the increased Bax and caspase-12-dependent ERS-associated apoptosis, autophagy and autophagy flux levels and caspase-independent nonapoptotic cell death. Furthermore, 4-phenylbutyrate, an ERS inhibitor, suppressed cucurbitacin-I-induced apoptosis, autophagy, autophagy flux, and autophagic cell death. Simultaneously, there are positive correlations among ERS and cucurbitacin-I-induced reactive oxygen species and Ca 2+. Our results suggested that cucurbitacin-I-induced cancer cell death through the excessive ERS and CHOP-Bax and caspase-12-dependent ERS-associated apoptosis, as well as ERS-dependent autophagy, autophagy flux, and caspase-independent nonapoptotic cell death. These novel signaling insights may be useful for developing new, effective anticancer strategies in oncotherapy.

In hypertrophic hearts, autophagic flux insufficiency is recognized as a key pathology leading to maladaptive cardiac remodeling and heart failure. This study aimed to illuminate the cardioprotective role and mechanisms of a new myokine and adipokine, irisin, in cardiac hypertrophy and remodeling. Adult male wild-type, mouse-FNDC5 (irisin-precursor)-knockout and FNDC5 transgenic mice received 4 weeks of transverse aortic constriction (TAC) alone or combined with intraperitoneal injection of chloroquine diphosphate (CQ). Endogenous FNDC5 ablation aggravated and exogenous FNDC5 overexpression attenuated the TAC-induced hypertrophic damage in the heart, which was comparable to the protection of irisin against cardiomyocyte hypertrophy induced by angiotensin II (Ang II) or phenylephrine (PE). Accumulated autophagosome and impaired autophagy flux occurred in the TAC-treated myocardium and Ang II- or PE-insulted cardiomyocytes. Irisin deficiency caused reduced autophagy and aggravated autophagy flux failure, whereas irisin overexpression or supplementation induced protective autophagy and improved autophagy flux, which were reversed by autophagy inhibitors Atg5 siRNA, 3-MA and CQ. Irisin boosted the activity of only AMPK but not Akt and MAPK family members in hypertrophic hearts and cultured cardiomyocytes and further activated ULK1 at Ser555 but not Ser757 and did not affect the mTOR-S6K axis. Blockage of AMPK and ULK1 with compund C and SBI-0206965, respectively, both abrogated irisin's protection against cardiomyocyte hypertrophic injury and reversed its induction of both autophagy and autophagy flux. Our results suggest that irisin protects against pressure overload-induced cardiac hypertrophy by inducing protective autophagy and autophagy flux via activating AMPK-ULK1 signaling.

Doxorubicin (DOX) is a wide spectrum antitumor drug, but its clinical application is limited by the cardiotoxicity. Ghrelin, a multi-functional peptide hormone with metabolic regulation in energy homeostasis, plays important roles in cardiovascular protection. Now, the underlying mechanisms of ghrelin against DOX-induced cardiomyocyte apoptosis and atrophy are still not clear. In the present study, we revealed an autophagy-dependent mechanism involved in ghrelin's protection against DOX-induced cardiomyocyte death and size decrease. We observed that DOX insult induced remarkable mortality and cardiac dysfunction in mice, and increase in LDH leakage, cardiomyocyte apoptosis and decrease in cell viability and size in mouse hearts and H9c2 cell cultures, which were effectively improved by ghrelin supplement. We further observed that the strong autophagy stirred by DOX exposure was paralleling with the serious apoptosis and size decrease in cardiomyocytes. Ghrelin, like an autophagy inhibitor, 3-MA, inhibited the DOX-induced autophagy and attenuated cardiomyocyte apoptosis and size decrease. Furthermore, ghrelin significantly reduced the intercellular oxidative stress level, a strong autophagy trigger, partly by augmenting the expression and activities of the endogenous anti-oxidative enzymes. After the further investigation in the post signaling pathways of ghrelin receptors in H9c2 cells, including ERK, p38/MAPK, JNK, AMPK and Akt, we observed that ghrelin supplement only reduced the DOX-activated AMPK and augmented the DOX-down regulated p38-MAPK and mTOR phosphorylation. Our results indicated that ghrelin effectively improved the cardiomyocyte survival and size maintenance by suppressing the excessive autophagy through both ROS inhibition and mTOR induction through suppressing AMPK activity and stimulating p38-MAPK activity.

Cucurbitacin-I, a natural triterpenoids initially identified in medicinal plants, shows a potent anticancer effect on a variety of cancer cell types. Nevertheless, the cardiotoxicity of cucurbitacin-I has not heretofore been reported. In this study, the mechanisms of cucurbitacin-I-induced cardiotoxicity were examined by investigating the role of MAPK-autophagy-dependent pathways. After being treated with 0.1-0.3μM cucurbitacin-I for 48h, H9c2 cells showed a gradual decrease in the cell viabilities, a gradual increase in cell size, and mRNA expression of ANP and BNP (cardiac hypertrophic markers). Cucurbitacin-I concentration-dependent apoptosis of H9c2 cells was also observed. The increased apoptosis of H9c2 cells was paralleling with the gradually strong autophagy levels. Furthermore, an autophagy inhibitor, 3-MA, was used to block the cucurbitacin-I-stirred autophagy, and then the hypertrophy and apoptosis induced by 0.3μM cucurbitacin-I were significantly attenuated. In addition, cucurbitacin-I exposure also activated the MAPK signaling pathways, including ERK1/2, JNK, and p38 kinases. Interestingly, only the ERK inhibitor U0126, but not the JNK inhibitor SP600125 and p38 MAPK inhibitor SB203580, weakened the induction of 0.3μM cucurbitacin-I in hypertrophy, autophagy and apoptosis. Our findings suggest that cucurbitacin-I can increase the autophagy levels of H9c2 cells, most likely, through the activation of an ERK-autophagy dependent pathway, which results in the hypertrophy and apoptosis of cardiomyocytes.

Doxorubicin (DOX) is a potent available antitumor drug; however, its clinical use is limited by the cardiotoxicity. Salidroside (SLD), with strong antioxidative and cytoprotective actions, is of particular interest in the development of antioxidative therapies for oxidative injury in cardiac diseases. Now, the protection and underlying mechanisms of SLD against DOX-induced cardiotoxicity are still unknown. In the present study, we revealed both antioxidative mechanism and Bcl2-dependent survival signaling involved in SLD's protection. We observed that DOX exposure induced mortality elevation, body weight loss, and cardiac dysfunction in mice, increased lactate dehydrogenase leakage and cardiomyocyte apoptosis, but decreased cell viability and size in cardiac tissues and cultured H9c2 cells, respectively, which were effectively antagonized by SLD supplement. We further observed that SLD significantly reduced the intercellular oxidative stress level, partly by inhibiting NOX1 expression and augmenting the expression and activities of the endogenous antioxidative enzymes, catalase, and manganese superoxide dismutase. In addition, SLD treatment upregulated the antiapoptotic Bcl2 and downregulated the proapoptotic Bax and inhibited a downstream pathway of Bcl2/Bax and caspase-3 activity. Our results indicated that SLD effectively protected the cardiomyocytes against DOX-induced cardiotoxicity by suppressing the excessive oxidative stress and activating a Bcl2-mediated survival signaling pathway.

Publisher Summary The homogeneous distribution of two metal components on the support surface is very important for high catalytic activities or selectivities of bimetallic catalysts. However, it is difficult to use the conventional preparation method using metal salts as the catalyst precursors to obtain the homogeneity. A method has been tried to prepare the catalysts with high dispersion and homogeneous distribution of Pt and Sn by pyrolysis of well-defined Pt–Sn clusters. In this chapter, the comparative studies of the catalytic properties in n-hexane conversion and cumene hydrocracking using the catalysts derived from different Pt–Sn clusters and the catalysts prepared from H 2 PtCl 6 and SnCl 2 are reported, and the effect of Sn/Pt ratio on the activity and selectivity is discussed. Both the catalysts derived from Pt–Sn clusters exhibited excellent activities in the isomerization and aromatization of n-hexane although their acidities were weaker.