Dual Active Center-Assembled Cu31S16-Co9-xNixS8 Heterodimers: Coherent Interface Engineering Induces Multihole Accumulation for Light-Enhanced Electrocatalytic Oxygen Evolution.

The design of low-cost yet highly efficient electrocatalysts plays a critical role in energy storage and conversion reactions. The oxygen evolution reaction (OER) is considered a bottleneck of electrochemical water splitting for hydrogen fuel generation. It is still challenging to extract a high density of charge carriers in noble-metal-free alternative catalysts to facilitate sluggish kinetics. Herein, we report the rational design and coherent interface engineering for combining light-harvesting Cu31S16 with electroactive Co9-xNixS8 (x = 0-9) to form novel Cu31S16-Co9-xNixS8 heterodimers. By delicately controlling the kinetic growth in a seed-mediated growth method, the bifunctional centers, even with two distinct crystal phases, were integrated into a synergistic architecture, which achieved full-spectrum solar energy capture and light conversion to drive and activate the electrochemical reaction. Benefiting from the well-defined structure, high-quality interface, oriented attachment, and optimal Co/Ni bimetal ratio, Cu31S16-Co7.2Ni1.8S8 produces a dramatically reduced overpotential (242 mV at 10 mA cm-2) with a shift of 83 mV under visible-light excitation, achieving a 4.5-fold higher turnover frequency than that of its unirradiated Co7.2Ni1.8S8 counterpart. This enhanced performance also far exceeds commercial RuO2 (358 mV at 10 mA cm-2) and most nonprecious-metal nanocatalysts. Further mechanistic studies reveal that coherent interface engineering leads to a strong photo/electricity coupling effect and efficient spatial charge separation, which induces sufficient hot holes that eventually accumulate at the electroactive sites to accelerate the multihole-involved OER. This work would open up new opportunities for the fabrication of non-noble metal electrocatalysts and management of charge carriers.

SIRT3 is a downstream target of PPAR-α implicated in high glucose-induced cardiomyocyte injury in AC16 cells.

Diabetic cardiomyopathy (DCM) is a worldwide public health concern that continues to display rapid growth trends. This study investigated the function of sirtuin 3 (SIRT3), a primary mitochondrial deacetylase with important roles in antioxidant defense and oxidative metabolism, during high glucose-induced cardiomyocyte (AC16 cell) injury. Peroxisome proliferator-activated receptor-α (PPAR-α) is directly related to the occurrence of DCM. Hence, we further examined the relationship between SIRT3 and PPAR-α. AC16 cells were treated with various concentrations of glucose. Relative mRNA expression and protein levels were detected by RT-qPCR and western blot analysis, respectively. Cell proliferation and apoptosis were assessed using CCK8 and Annexin V-FITC apoptosis detection kits, respectively. DCFH-DA assay was used to measure reactive oxygen species (ROS) accumulation. The results indicated that high glucose treatment reduced the expression of mRNA and protein of SIRT3 and PPAR-α in AC16 cells. Moreover, high glucose inhibited cell proliferation, as well as induced apoptosis, intracellular hydrogen peroxide production, and JNK1/2 phosphorylation. These effects were antagonized by SIRT3 overexpression or treatment with the PPAR-α agonist, Wy14643. Conversely, inhibition of SIRT3 via 3-TYP led to similar phenomena as those induced by high glucose treatment in AC16 cells, which were blocked by Wy14643. Lastly, chromatin immunoprecipitation (ChIP) and luciferase assays demonstrated SIRT3 as a direct target of PPAR-α. Taken together, the results provide evidence for an important role of SIRT3 in high glucose-induced cardiomyocyte injury and regulation of JNK1/2 signaling. Further, SIRT3 is a direct downstream target of PPAR-α.

Author Correction: Improved ethanol electrooxidation performance by shortening Pd-Ni active site distance in Pd-Ni-P nanocatalysts.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Tailoring N-Coordination Environment by Ligand Competitive Thermolysis Strategy for Efficient Oxygen Reduction.

The synergy of fully exposed active sites and optimized N-dopant configurations in three-dimensional (3D) N-doped carbon (N/C) is highly pivotal for efficient catalysis and energy conversion but lacks effective methods. Meanwhile, to understand the active sites, excluding the size effect of the π-conjugated system, especially in N/C derived from metal-organic frameworks (MOFs) is significant but challenging. Herein, an elegant and general strategy, ligand competitive thermolysis, was developed to construct hierarchical pore structures and tailor their N-coordination environment in the MOF-derived 3D N/C catalysts. Due to sufficient interior mesopores and predominant active N species, the metal-free catalysts achieved an efficient activity (E1/2 = 0.84 V) and impressive durability (20,000 cycles, ΔE1/2 = 5 mV). The relationship between half-wave potential and the content of N species was also investigated. This work not only offers valuable inspiration for developing high-performance electrocatalysts but also motivates deep understanding of the active sites in N/C catalysts.

Edge-Contact Geometry and Anion-Deficit Construction for Activating Ultrathin MoS2 on W17O47 in the Hydrogen Evolution Reaction.

Rational design and precise fabrication of catalysts with high active site exposure and efficient charge transport are highly desirable but challenging. Herein, we report a unique strategy to construct well-defined and mixed-dimensional W17O47-MoS2 heterostructures, where ultrathin MoS2 nanolayers vertically rooted onto W17O47 nanowires in edge-contact geometry. The in situ etching approach simultaneously created high accessible anion-deficit sites for refined electronic structures and intimate heterointerface for spatial charge-flow-steering. The best W17O47-MoS2, with optimized MoS2 loading, exhibited a MoS2 mass activity 116-fold higher than that of pure MoS2 in electrocatalytic hydrogen evolution reaction. Density functional theory calculations unveiled that low-coordination sites and intimate interfaces induced the synergy of interface-O and edge-Mo atoms, substantially regulating the electron distribution of active sites in the critical hydrogen activation step. This work not only provided a platform for understanding the origin of catalytic activity, but also brought instructive design criteria for constructing heterostructures in catalysis, photonics, and electronics.

Edge-Site Engineering of Atomically Dispersed Fe-N4 by Selective C-N Bond Cleavage for Enhanced Oxygen Reduction Reaction Activities.

Single-atom metal-nitrogen-carbon (M-N-C) catalysts have sparked intense interests, but the catalytic contribution of N-bonding environment neighboring M-N4 sites lacks attention. Herein, a series of Fe-N-C nanoarchitectures have been prepared, which confer adjustable numbers of atomically dispersed Fe-N4 sites, tunable hierarchical micro-mesoporous structures and intensified exposure of interior active sites. The optimization between Fe-N4 single sites and carbon matrix delivers superior oxygen reduction reaction activity (half-wave potential of 0.915 V vs RHE in alkaline medium) with remarkable stability and high atom-utilization efficiency (almost 10-fold enhancement). Both experiments and theoretical calculations verified the selective C-N bond cleavage adjacent to Fe center induced by porosity engineering could form edge-hosted Fe-N4 moieties, and therefore lower the overall oxygen reduction reaction barriers comparing to intact atomic configuration. These findings provide a new pathway for the integrated engineering of geometric and electronic structures of single-atom materials to improve their catalytic performance.

Embedding Nanocluster in MOF via Crystalline Ion-Triggered Growth Strategy for Improved Emission and Selective Sensing.

Metal-organic frameworks (MOFs) containing metal nanoclusters (NCs) display great potentials, but the fabrication faces challenges because of the serious agglomeration of NCs during the MOF growth. We report a crystalline ion-triggered growth strategy for embedding AuNCs in ZIF-8. As control, when the encapsulation was triggered with other metal ions (e.g., Ca2+, Pb2+, Cd2+, Na+, Fe3+, Cu2+, and Ni2+), the AuNCs failed to be encapsulated. The quantum yields and lifetime of AuNCs were greatly enhanced after embedding in ZIF-8. The AuNCs@ZIF-8 were then successfully applied for the selective sensing of H2S both in liquid and gas phases. This crystalline ion-triggered growth strategy was easily extended to other systems, such as AgNCs@ZIF-8 and AuNCs@ZIF-67, indicating the general adaptability of this design protocol.

Improved ethanol electrooxidation performance by shortening Pd-Ni active site distance in Pd-Ni-P nanocatalysts.

Incorporating oxophilic metals into noble metal-based catalysts represents an emerging strategy to improve the catalytic performance of electrocatalysts in fuel cells. However, effects of the distance between the noble metal and oxophilic metal active sites on the catalytic performance have rarely been investigated. Herein, we report on ultrasmall (∼5 nm) Pd-Ni-P ternary nanoparticles for ethanol electrooxidation. The activity is improved up to 4.95 A per mgPd, which is 6.88 times higher than commercial Pd/C (0.72 A per mgPd), by shortening the distance between Pd and Ni active sites, achieved through shape transformation from Pd/Ni-P heterodimers into Pd-Ni-P nanoparticles and tuning the Ni/Pd atomic ratio to 1:1. Density functional theory calculations reveal that the improved activity and stability stems from the promoted production of free OH radicals (on Ni active sites) which facilitate the oxidative removal of carbonaceous poison and combination with CH3CO radicals on adjacent Pd active sites.

3D nickel-cobalt diselenide nanonetwork for highly efficient oxygen evolution.

Active, stable and low-cost oxygen evolution reaction (OER) catalyst for electrochemical water splitting is key to efficient energy conversion and storage. Here, we report a three-dimensional (3D) nanonetwork as noble-metal-free electrode consisting of nickel cobalt diselenide (NiCoSe2) nanobrush arrays on Ni foam (NF) through the initial hydrothermal reaction and subsequent thermal selenization process. Introducing ammonium fluoride as surface controller, different NiCoSe2 hierarchical architecture can be modulated from nanorods, nanobrush to nanosheets. The unique brush-like NiCoSe2 possesses high surface area for mass transfer, rough surface with rich active sites, 3D nanostructure preventing the accumulation of O2 bubbles. Compared to NiCoSe2 nanorods/NF, NiCoSe2 nanosheets/NF and commercial RuO2, NiCoSe2 nanobrush/NF exhibits an enhanced OER performance in alkaline media to reach a low overpotential of 274mV at the current density of 10mA/cm2, small Tafel slope and a long-term stability. The developed 3D nanonetwork highlights the nanoscale engineering and offers a promising alternative to noble metal catalysts for electrochemical water oxidation.

Rapamycin Inhibits Cardiac Hypertrophy by Promoting Autophagy via the MEK/ERK/Beclin-1 Pathway.

Rapamycin, also known as sirolimus, is an antifungal agent and immunosuppressant drug used to prevent organ rejection in transplantation. However, little is known about the role of rapamycin in cardiac hypertrophy and the signaling pathways involved. Here, the effect of rapamycin was examined using phenylephrine (PE) induced cardiomyocyte hypertrophy in vitro and in a rat model of aortic banding (AB) - induced hypertrophy in vivo. Inhibition of MEK/ERK signaling reversed the effect of rapamycin on the up-regulation of LC3-II, Beclin-1 and Noxa, and the down-regulation of Mcl-1 and p62. Silencing of Noxa or Beclin-1 suppressed rapamycin-induced autophagy, and co-immunoprecipitation experiments showed that Noxa abolishes the inhibitory effect of Mcl-1 on Beclin-1, promoting autophagy. In vivo experiments showed that rapamycin decreased AB-induced cardiac hypertrophy in a MEK/ERK dependent manner. Taken together, our results indicate that rapamycin attenuates cardiac hypertrophy by promoting autophagy through a mechanism involving the modulation of Noxa and Beclin-1 expression by the MEK/ERK signaling pathway.

Integrin αvß6 and matrix metalloproteinase 9 correlate with survival in gastric cancer.

AIM: To investigate the expression of integrin αvß6 and matrix metalloproteinase 9 (MMP-9), their association with prognostic factors and to assess their predictive role in gastric cancer patients. METHODS: Immunohistochemistry was used to determine the expressions of integrin αvß6 and MMP-9 in 126 specimens from patients with primary gastric carcinoma. Associations between immunohistochemical staining and various clinic pathologic variables of tissue specimens were evaluated by the χ(2) test and Fisher's exact test. Expression correlation of αvß6 and MMP-9 was assessed using bivariate correlation analysis. The patients were followed-up every 3 mo in the first two years and at least every 6 mo afterwards, with a median follow-up of 56 mo (ranging from 2 mo to 94 mo). Four different combinations of αvß6 and MMP-9 levels (that is, both markers positive, both markers negative, αvß6 positive with MMP-9 negative, and αvß6 negative with MMP-9 positive) were evaluated for their relative effect on survival. The difference in survival curves was evaluated with a log-rank test. Survival analysis was conducted using the Kaplan-Meier survival and Cox proportional hazards model analysis. RESULTS: The expressions of integrin αvß6 and MMP-9 were investigated in 126 cases, among which 34.92% were positive for αvß6 expression, and 42.06% for MMP-9 expression. The expression of αvß6 was associated with Lauren type, differentiation, N stage, and TNM stage (the P values were 0.006, 0.038, 0.016, and 0.002, respectively). While MMP-9 expression was associated with differentiation, T stage, N stage, and TNM stage (the P values were 0.039, 0.014, 0.033, and 0.008, respectively). The positive correlation between αvß6 and MMP-9 in gastric cancer was confirmed by a correlation analysis. The Kaplan-Meier survival analysis showed that patients with expression of αvß6 or MMP-9 alone died earlier than those with negative expression and that patients who were both αvß6 and MMP-9 positive had a shorter overall survival than those with the opposite pattern (both αvß6 and MMP-9 negative) (P = 0.000). A Cox model indicated that positive expression of αvß6 and MMP-9, diffuse Lauren type, as well as a senior grade of N stage, M stage, and TNM stage were predictors of a poor prognosis in univariate analysis. Only αvß6 and MMP-9 retained their significance when adjustments were made for other known prognostic factors in multivariate analysis (RR = 2.632, P = 0.003 and RR = 1.813, P = 0.007). CONCLUSION: The expression of αvß6 and MMP-9 are closely correlated, and the combinational pattern of αvß6 and MMP-9 can serve as a more effective prognostic index for gastric cancer patients.

Synergetic Integration of Cu1.94S-ZnxCd1-xS Heteronanorods for Enhanced Visible-Light-Driven Photocatalytic Hydrogen Production.

In this Communication, we present the integration of synergetic designs into high-quality, well-defined Cu1.94S-ZnxCd1-xS heteronanorods (0 ≤ x ≤ 1) for enhanced photocatalytic hydrogen evolution. These heteronanorods possess two light absorbers, intimate heterointerfaces, tunable band gaps over a wide range, and uniform one-dimensional morphology. As verified by experimental and density functional theory studies, these heteronanorods with continuous composition adjustment fully exploit the benefits of both interfacial charge separation and optimized band alignments. Even without any cocatalysts, Cu1.94S-Zn0.23Cd0.77S heteronanorods exhibit efficient hydrogen production activity (7735 µmol h(-1) g(-1)) under visible-light irradiation (λ > 420 nm), representing a 59-fold enhancement compared with the pristine CdS catalyst. Meanwhile, deposition of a Pt cocatalyst on the Cu1.94S-ZnxCd1-xS surface substantially enhances the hydrogen production performance (13 533 µmol h(-1) g(-1)) with an apparent quantum efficiency of 26.4% at 420 nm, opening up opportunities to promote the overall photocatalytic performance using rationally designed nanostructures.

Deceleration and acceleration capacities of heart rate associated with heart failure with high discriminating performance.

Accurate measurements of autonomic nerve regulation in heart failure (HF) were unresolved. The discriminating performance of deceleration and acceleration capacities of heart rate in HF was evaluated in 130 HF patients and 212 controls. Acceleration capacity and deceleration capacity were independent risk factors for HF in males, evaluated by multiple logistic regression analysis, with odds ratios (ORs) of 5.94 and 0.13, respectively. Acceleration capacity was also an independent risk factor for HF in females, with an OR of 8.58. Deceleration capacity was the best cardiac electrophysiological index to classify HF in males, with an area under the receiver operating characteristic curve (AUC) of 0.88. Deceleration capacity was the best classification factor of HF in females with an AUC of 0.97, significantly higher than even left ventricular ejection fraction (LVEF). Acceleration capacity also showed high performance in classifying HF in males (0.84) and females (0.92). The cut-off values of deceleration capacity for HF classification in males and females were 4.55 ms and 4.85 ms, respectively. The cut-off values of acceleration capacity for HF classification in males and females were -6.15 ms and -5.75 ms, respectively. Our study illustrates the role of acceleration and deceleration capacity measurements in the neuro-pathophysiology of HF.

Resveratrol-induced autophagy promotes survival and attenuates doxorubicin-induced cardiotoxicity.

Resveratrol (RSV) has many biological effects, including antitumor and antiviral activities, and vascular protection. Recent studies have suggested that RSV exerts its antitumor effects through induction of autophagy by an unknown mechanism. Doxorubicin (DOX) is a wide spectrum antitumor drug, but its clinical application is limited by its cardiotoxicity. This study evaluated whether the manipulation of autophagy could attenuate the cardiotoxic effects of DOX in vitro as well as in a rat model of DOX-induced cardiotoxicity. We found that DOX induced H9C2 cell apoptosis by inhibiting AMPK activation and promoting pro-apoptotic protein expression through p38MAPK/p53 signaling. RSV-treated H9C2 cells showed increased autophagy through the AMPK/mTOR/Ulk1 pathway. When DOX and RSV were combined, apoptosis was decreased, despite a slight increase in the autophagy ratio. The same result was observed in the rat model of DOX-induced cardiotoxicity. Injection with DOX or RSV alone, or in combination, for a week, resulted in a reduced apoptotic ratio in the combination group compared with the DOX alone group. Our results strongly indicate that this co-treatment strategy with RSV can attenuate the cardiotoxic effects of DOX. Our findings may have important clinical implications.

High level of serum AFP is an independent negative prognostic factor in gastric cancer.

BACKGROUND: Gastric cancer with a high level of serum alpha fetoprotein (AFP) is uncommon and has unique clinicopathological features and a poorer prognosis. The aim of this research was to elucidate the clinicopathological and prognostic features of gastric cancer with a high level of AFP. METHODS: The sera from 1,286 patients with gastric cancer treated at Qilu Hospital of Shandong University from January 2004 to December 2008 were analyzed preoperatively for AFP, CEA and CA19-9 levels after excluding active or chronic hepatitis, liver cirrhosis and hepatocellular carcinoma as well as preoperative distant metastasis. Patients were divided into 2 groups: 86 serum AFP-positive patients and 1,200 serum AFP-negative patients according to a cutoff of 20 ng/mL. The clinicopathological features and prognostic factors were compared between the groups. RESULTS: A higher incidence of serosal invasion, lymph node metastasis and liver metastasis and poorer prognosis was observed in the AFP-positive group compared with the AFP-negative group (all p<0.05). Serum AFP showed the highest specificity (93.66%) and diagnostic accuracy (92.38%) for predicting liver metastasis among the 3 tumor markers examined. Multivariate survival analysis revealed that AFP positivity was an independent prognostic factor in all 1,286 gastric cancer patients. The prognosis of AFP-positive gastric cancer was poorer than that of AFP-negative gastric cancer (p<0.05). CONCLUSIONS: A high level of serum AFP is an independent prognostic factor in gastric cancer and can be used for evaluating the prognosis of gastric cancers whether in the presence or absence of liver metastasis.

Risk factor panels associated with hypertension in obstructive sleep apnea patients with different body mass indexes.

Although hypertension (HTN), obstructive sleep apnea (OSA), and obesity frequently co-occur, the precise role of obesity in this interrelationship is not completely understood. A total of 727 OSA patients were assigned to body mass index (BMI) <25 (27.6%; n = 201), 25≤ BMI <29.99 (53.4%; n = 388), and BMI ≥30 (19%; n = 138). HTN risk factors in each group were evaluated. A total of 244 (33.6%) patients exhibited co-morbid HTN, of whom 20.5% (50/244), 52.9% (129/244), and 26.6% (65/244) were distributed between the BMI <25, 25≤ BMI <29.99, and BMI ≥30 groups, respectively. Multiple logistic regression indicated that age, male gender, triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and apnea-hypopnea index (AHI) scores were HTN risk factors for the BMI<25 group. In the 25≤ BMI <29.99 group, risk factors were age, BMI, diabetes, and AHI. Finally, in the BMI ≥30 group, risk factors were age, diabetes, TG, LDL-C and AHI. These results demonstrate that different risk factor panels were associated with HTN in OSA patients with different BMIs.

miRNA-130b is required for the ERK/FOXM1 pathway activation-mediated protective effects of isosorbide dinitrate against mesenchymal stem cell senescence induced by high glucose.

The present study was carried out to investigate the hypothesis that organic nitrates can attenuate the senescence of mesenchymal stem cells (MSCs), a superior cell source involved in the regeneration and repair of damaged tissue. MSCs were treated with high glucose (HG) in order to induce senescence, which was markedly attenuated by pre-treatment with isosorbide dinitrate (ISDN), a commonly used nitrate, as indicated by senescence-associated galactosidase (SA-ß-gal) activity, p21 expression, as well as by the mRNA levels of DNA methyltransferase 1 (DNMT1) and differentiated embryo chondrocyte expressed gene 1 (DEC1), which are senescence-related biomarkers. It was also found that the senescent MSCs (induced by HG glucose) exhibited a marked downregulation in ERK activity and forkhead box M1 (FOXM1) expression, which was reversed by ISDN preconditioning. Of note, the inhibition of ERK phosphorylation or the downregulation of FOXM1 statistically abolished the favourable effects of ISDN. In addition, the investigation of the senescence-associated miR-130 family suggested that miR-130b mediates the beneficial effects of ISDN; it was found that the protective effects of ISDN against the senescence of MSCs were prominently reversed by the knockdown of miR-130b. Furthermore, the downregulation of ERK phosphorylation or FOXM1 expression decreased the miR-130b expression level; however, the suppression of miR-130b demonstrated no significant impact on ERK phosphorylation or FOXM1 expression. Taken together, to the best of our knowledge, the present study is the first to demonstrate the favourable effects of ISDN against HG-induced MSC senescence, which are mediated through the activation of the ERK/FOXM1 pathway and the upregulation of miR-130b.

Pachymic acid inhibits tumorigenesis in gallbladder carcinoma cells.

BACKGROUND: Gallbladder cancer, with high aggressivity and extremely poor prognosis, is the most common malignancy of the bile duct. Thus, seeking targets gallbladder tumor cells is an attractive goal towards improving clinical treatment. MATERIAL AND METHODS: In this study, we investigated the effects of pachymic acid (PA) on the tumorigenesis of human gallbladder cancer cells. RESULTS: We found that PA significantly reduced cell growth in a dose- and time-dependent fashion. Meanwhile, cell cycle arrest at G0 phase was induced by PA. PA also significantly inhibited cancer cell migration, invasion in a dose-dependent manner. Interestingly, we demonstrated that cancer cell adhesion ability was suppressed dose-dependently, which may contribute to the inhibition of cell invasion. Finally, we showed that PA inhibited AKT and ERK signaling pathways. And oncoproteins, such as PCNA, ICAM-1 and RhoA which are involved intumorigenesis, were also downregulated by PA. CONCLUSION: Our study reveals that PA is able to inhibit gallbladder cancer tumorigenesis involving affection of AKT and ERK signaling pathways. Together, these results encourage further studies of PA as a promising candidate for gallbladder cancer therapy.

Distinct associations between hypertension and obstructive sleep apnea in male and female patients.

Obstructive sleep apnea (OSA) is highly associated with hypertension. However, the correlation between hypertension and OSA at different levels of severity and the influence of gender on that correlation are unclear. A total of 996 patients (776 males and 190 females) with OSA were recruited. The influence of gender on the correlation between hypertension and OSA at different stratifications of severity, based on the apnea-hypopnea index (AHI), was fully evaluated together with the major health risk factors obesity, age, and diabetes. Females with OSA were significantly older on average than males with OSA. Moreover, females had milder degrees of OSA on average than the extent of severity seen in males. The proportion of females with diabetes or hypertension was higher than that of males. The proportion of males with hypertension and obesity increased significantly with OSA, and age also increased with OSA. The percentage of females with hypertension at different degrees of OSA severity was stable at about 26% in the mild, moderate, and severe OSA groups. Among females, age was increased significantly in the moderate relative to the mild OSA group. Moreover, the proportion of obese subjects was increased significantly in the severe compared with the moderate OSA group. The proportions of males and females with diabetes were not significantly different among all OSA severity groups. An ordinal multivariate logistic regression analysis confirmed that hypertension, age, and obesity were associated with OSA severity in males, whereas only age and obesity were associated with OSA severity in females. Although the proportion of subjects with hypertension was higher in females with OSA than in males with OSA, the proportion of subjects with hypertension increased as the severity of OSA increased in males but not in females.

Resveratrol attenuates doxorubicin-induced cardiomyocyte apoptosis in lymphoma nude mice by heme oxygenase-1 induction.

Doxorubicin (DOX) has been used in a variety of human malignancies for decades, in particular of lymphoma. But increased cardiomyocyte apoptosis has been implicated in its cardiotoxicity. Resveratrol (RES) generates cardiovascular protective effects by heme oxygenase-1(HO-1)-mediated mechanism. The present study was designed to determine whether RES protected cardiomyocyte against apoptosis through induction of HO-1 in lymphoma nude mouse in vivo. After being developed into lymphoma model, 40 male Balb/c nude mice were randomized to one of the following four treatments (10 mice per group): control, DOX, DOX + RES and DOX + RES + HO-1 inhibitor (zinc protoporphyrin IX, ZnPP). The results showed that DOX injection markedly decreased the body weight, the heart weight and the ratio of heart weight to body weight, but inversely increased cardiomyocyte apoptosis and the level of serum lactate dehydrogenase and creatine kinase. Moreover, DOX injection attenuated HO-1 expression and enzymatic activity as well as increased P53 expression, modulated Bcl-2/Bax expression and enhanced caspase 3 activity. These cardiotoxic effects of DOX were ameliorated by its combination with RES. However, the protective effects of RES were reversed by the addition of ZnPP. Taken together, it is concluded that HO-1 plays a core role for protective action of RES in DOX-induced cardiomyocyte apoptosis in lymphoma nude mice.