Farnesoid X receptor (FXR) signaling plays an important role in liver regeneration and carcinogenesis. Dysregulation of FXR signaling is linked to the pathogenesis of hepatocellular carcinoma (HCC) while FXR knockout mice spontaneously develop HCC as they age. Ubiquitin specific peptidase 2b (USP2b) is a deubiquitinating enzyme regulating protein stability and other activities. In our recent study, we found that USP2b was significantly downregulated in subjects with HCC and exhibited both tumor-promoting and tumor suppressive activity in a context-dependent manner. However, the mechanistic link between FXR signaling and USP2b and its implications in the pathogenesis of HCC remain to be determined. In this study, we revealed that USP2b was transcriptionally regulated by FXR. Activation of FXR significantly increased while antagonizing FXR reduced USP2b mRNA and protein expression in vitro and in vivo. Consistently, USP2b expression was significantly reduced in FXR knockout (FXR-KO) mice. Further investigation showed that USP2b was transcriptionally regulated by FXR in an isoform-specific manner, predominantly by FXRα2 but not FXRα1. The transcription starting sites (TSS) of USP2 isoforms were determined by 5'RACE, which leads to the identification of the USP2b-specific promoter. An FXR response element (FXRE) was identified in the USP2b promoter and functionally characterized. FXR directly bound to the FXRE in vitro and recruited to the USP2b promoter in intact cells and in vivo. Further study revealed that upon FXR activation, co-activator-associated arginine methyltransferase 1 (CARM-1) was significantly recruited to the human USP2b promoter while coactivators glutamate receptor-interacting protein 1 (GRIP-1) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) were significantly recruited to the mouse USP2b promoter. Over-expression of USP2b in FXR-KO mice significantly slowed down tumor growth with reduced tumor size while maintained comparable tumor numbers consistent with its tumor suppressive activity. In summary, this study demonstrated that USP2b was transcriptionally regulated by FXR in an isoform-dependent manner and USP2b played a tumor-suppressive role in the pathogenesis of FXR deficiency-induced HCC.

Highlights1. Panax notoginseng saponins attenuate renal injury in STZ-induced diabetic rats.2. PNS alleviates renal oxidative stress in diabetic kidneys with miR-3185 restoration.3. MiR-3185 upregulation is linked to KRAS suppression and FOXO1-related signaling changes.4. Ginsenoside Rg1 shows the strongest antioxidative activity among tested PNS constituents.5. Rg1 protects high-glucose-treated mesangial cells in a partially miR-3185-dependent manner.

C 25 H 32 N 2 O 7 , Tetragonal, P 4 3 2 1 2, a = 9.0226 (8) Å, c = 59.048 (6) Å, V = 4806.9(10) Å 3 , Z = 8, R gt ( F ) = 0.043, wR ref ( F 2 ) = 0.112, T = 100 K.

Stroke is the leading cause of death and disability worldwide. Novel and effective therapies for ischemic stroke are urgently needed. Here, we report that melatonin receptor 1A (MT1) agonist ramelteon is a neuroprotective drug candidate as demonstrated by comprehensive experimental models of ischemic stroke, including a middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia in vivo, organotypic hippocampal slice cultures ex vivo, and cultured neurons in vitro; the neuroprotective effects of ramelteon are diminished in MT1-knockout (KO) mice and MT1-KO cultured neurons. For the first time, we report that the MT1 receptor is significantly depleted in the brain of MCAO mice, and ramelteon treatment significantly recovers the brain MT1 losses in MCAO mice, which is further explained by the Connectivity Map L1000 bioinformatic analysis that shows gene-expression signatures of MCAO mice are negatively connected to melatonin receptor agonist like Ramelteon. We demonstrate that ramelteon improves the cerebral blood flow signals in ischemic stroke that is potentially mediated, at least, partly by mechanisms of activating endothelial nitric oxide synthase. Our results also show that the neuroprotection of ramelteon counteracts reactive oxygen species-induced oxidative stress and activates the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway. Ramelteon inhibits the mitochondrial and autophagic death pathways in MCAO mice and cultured neurons, consistent with gene set enrichment analysis from a bioinformatics perspective angle. Our data suggest that Ramelteon is a potential neuroprotective drug candidate, and MT1 is the neuroprotective target for ischemic stroke, which provides new insights into stroke therapy. MT1-KO mice and cultured neurons may provide animal and cellular models of accelerated ischemic damage and neuronal cell death.

传统中药生脉饮对心血管系统具有重要保护作用,可有效治疗多种类型心血管疾病,且疗效较好.研究发现,生脉饮主要通过抗氧化、抗凋亡、调节心脏免疫微环境、降低心肌损伤、改善心肌纤维化、抑制心脏重塑及改善心肌脂质代谢等机制发挥心肌保护作用.

Ubiquitin specific peptidase-2 (USP2) plays important roles in a myriad of cellular activities through deubiquitinating target proteins and its implications in various diseases, especially cancers, are starting to emerge. Our current understanding on USP2 expression in subjects with hepatocellular carcinoma (HCC) and its roles in the pathogenesis of HCC is limited. In this study, we found that USP2 protein and mRNA levels were significantly dysregulated in HCC tumor (HCC-T) when compared to adjacent non-tumor (HCC-NT) or normal liver tissues from both human and mouse HCC model. Among the USP2 isoforms, USP2b was the predominant isoform in the normal liver and markedly down-regulated in HCC-T tissues in both human and mice. Data from overexpression, chemical inhibition and knockout studies consistently demonstrated that USP2b promoted cell proliferation, colony formation and wound healing in HepG2 and Huh 7 cells. On the other hand, USP2b exhibited proapoptotic and pronecrtotic activities through enhancing bile acid-induced apoptosis and necrosis in both HepG2 and Huh 7 cells. Unbiased proteomic analysis of USP2-knockout (KO) and parental HepG2 cells resulted in identification of USP2 regulated downstream target proteins involved in cell proliferation, apoptosis, and tumorigenesis, including serine/threonine kinase 4 (STK4), epidermal growth factor receptor (EGFR), dipeptidyl peptidase 4 (DPP4) and fatty acid binding protein 1 (FABP1). In conclusion, USP2b expression was dysregulated in subjects with HCC and contributed to the pathogenesis of HCC by promoting cell proliferation and exerting proapoptotic and pronecrotic activities. The findings provide the molecular basis for developing therapies for HCC through modulating USP2b expression or activities.

Preterm birth (PTB) is the leading cause of perinatal mortality and newborn complications. Bile acids are recognized as signaling molecules regulating a myriad of cellular and metabolic activities but have not been etiologically linked to PTB. In this study, a hospital-based cohort study with 36,755 pregnant women is conducted. We find that serum total bile acid levels directly correlate with the PTB rates regardless of the characteristics of the subjects and etiologies of liver disorders. Consistent with the findings from pregnant women, PTB is successfully reproduced in mice with liver injuries and dysregulated bile acids. More importantly, bile acids dose-dependently induce PTB with minimal hepatotoxicity. Furthermore, restoring bile acid homeostasis by farnesoid X receptor activation markedly reduces PTB and dramatically improves newborn survival rates. The findings thus establish an etiologic link between bile acids and PTB, and open an avenue for developing etiology-based therapies to prevent or delay PTB.

Alcohol use disorder (AUD) is an enormous public health problem that poses significant social, medical, and economic burdens. Under AUD, the liver is one of the most adversely affected organs. As current therapies and protective drugs for AUD-mediated liver injury are very limited, the prevention and therapy of alcoholic liver disease are urgently needed. The present study aims to investigate the beneficial effects of tartary buckwheat extract (TBE), the important component of Maopu tartary buckwheat liquor, on both alcoholic-induced acute and chronic liver injuries. We show that the TBE administration, similar to curcumin, significantly reduces the elevated serum aspartate aminotransferase and alanine aminotransferase levels, improves liver index, alleviates the elevated contents of hepatic malondialdehye, and restores the decreased contents of hepatic glutathione both in acute and chronic liver injuries in alcohol-exposed rats. Furthermore, histopathological analyses show that a medium dose of TBE (16.70 ml/kg body weight) alleviates hepatocyte morphology changes in both acute and chronic alcohol exposure models. We also show the protective effects of TBE on the cell death rates of alcohol-exposed primary cultured hepatocytes, HepG2 hepatoma, and Huh 7 hepatoma cells. Furthermore, we demonstrate that TBE exerts hepatoprotection partly through inhibiting the mitochondrial cell death pathway by reducing cytochrome c release, caspase-9 and -3 activities, and the number of TUNEL-positive cells. These effects of TBE were accompanied by enhanced levels of Bcl-2 and Bcl-xL and autophagic cell death pathway by reducing Beclin-1 expression, as well as through promoting its anti-oxidant capacity by suppressing reactive oxygen species production. This study demonstrates, for the first time, the protective effect of TBE against alcohol-induced acute and chronic liver injury in vivo and in vitro. Given the dietary nature of tartary buckwheat, pueraria, lycium barbarum, and hawthorn, the oral intake of TBE or liquor contained TBE, e.g., Maopu Tartary buckwheat liquor, compared with pure liquor consumption alone, may have the potential to alleviate alcoholic-induced liver injuries.

目的 探讨生脉饮(SMY)对蒽环类抗肿瘤药物多柔比星(DOX)诱导的心肌损伤的保护作用.方法 Balb/c小鼠40只随机分为Control组、DOX组、DOX+低SMY组、DOX+高SMY组.建立DOX损伤模型,SMY干预8 w后,心脏彩超检测心功能;HE染色检测病理改变;透射电镜观察超微结构变化;荧光酶标仪检测活性氧物质(ROS)改变;Western印迹检测凋亡相关蛋白表达水平;TUNEL法检测心肌凋亡指数(AI).结果 DOX可诱导ROS过度累积,促凋亡蛋白Bax表达量显著上升,抗凋亡蛋白Bcl-2显著下降,AI显著升高,心肌病理学及超微结构损伤,导致心功能显著下降.SMY处理可部分逆转DOX引起的上述变化.结论 SMY对DOX引起的心肌损伤具有保护作用,可能机制在于降低DOX诱导的心肌过度氧化和凋亡.

Melatonin is a neurohormone associated with sleep and wakefulness and is mainly produced by the pineal gland. Numerous physiological functions of melatonin have been demonstrated including anti-inflammation, suppressing neoplastic growth, circadian and endocrine rhythm regulation, and its potent antioxidant activity as well as its role in regeneration of various tissues including the nervous system, liver, bone, kidney, bladder, skin, and muscle, among others. In this review, we summarize the recent advances related to the multiple protective roles of melatonin receptor agonists, melatonin and N-acetylserotonin (NAS), in brain injury, liver damage, and bone health. Brain injury, including traumatic brain injury, ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and newborn perinatal hypoxia-ischemia encephalopathy, is a major cause of mortality and disability. Liver disease causes serious public health problems and various factors including alcohol, chemical pollutants, and drugs induce hepatic damage. Osteoporosis is the most common bone disease in humans. Due in part to an aging population, both the cost of care of fracture patients and the annual fracture rate have increased steadily. Despite the discrepancy in the pathophysiological processes of these disorders, time frames and severity, they may share several common molecular mechanisms. Oxidative stress is considered to be a critical factor in these pathogeneses. We update the current state of knowledge related to the molecular processes, mainly including anti-oxidative stress, anti-apoptosis, autophagy dysfunction, and anti-inflammation as well as other properties of melatonin and NAS. Particularly, the abilities of melatonin and NAS to directly scavenge oxygen-centered radicals and toxic reactive oxygen species, and indirectly act through antioxidant enzymes are disscussed. In this review, we summarize the similarities and differences in the protection provided by melatonin and/or NAS in brain, liver and bone damage. We analyze the involvement of melatonin receptor 1A (MT1), melatonin receptor 1B (MT2), and melatonin receptor 1C (MT3) in the protection of melatonin and/or NAS. Additionally, we evaluate their potential clinical applications. The multiple mechanisms of action and multiple organ-targeted properties of melatonin and NAS may contribute to development of promising therapies for clinical trials.

Bile acids are synthesized in the liver and tightly regulated through the enterohepatic circulation.Recent studies reveal that bile acids serve as hormone-like signaling molecules to activate nuclear receptors, notably farnesoid X receptor (FXR), regulating metabolic homeostasis of bile acids, cholesterol, lipids, and glucose.A connection between bile acids and nonalcoholic fatty liver disease (NAFLD) has long been recognized.Although inconsistent or even contradictory results are reported, a large body of evidence from clinical as well as preclinical studies demonstrates that bile acid homeostasis is disrupted in patients with NAFLD.The bile acid dysregulation gets worsening as NAFLD progresses from early stage simple steatosis to late stage nonalcoholic steatohepatitis (NASH) and NASH with fibrosis.As the risk factors for NAFLD, obesity and insulin resistance, which are often associated with NAFLD, contribute to the dysregulation of bile acids in patients with NAFLD.Total serum and fecal bile acid concentrations are mostly elevated in patients with NAFLD as a result of increased bile acid synthesis, elevated hepatic bile acids, and upregulation of bile acid transporters.The two negative feedback regulatory pathways for bile acid synthesis, FXR/SHP (small heterodimer partner) and fibroblast growth factor-19 (FGF19)/FGF receptor-4 (FGFR4), are impaired in patients with NAFLD.

Intraventricular hemorrhage (IVH) is a common complication of prematurity in infants born at 23-28 weeks of gestation. Survivors exhibit impaired growth of the cerebral cortex and neurodevelopmental sequeale, but the underlying mechanism(s) are obscure. Previously, we have shown that neocortical neurogenesis continues until at least 28 gestational weeks. This renders the prematurely born infants vulnerable to impaired neurogenesis. Here, we hypothesized that neurogenesis is impaired by IVH, and that signaling through GSK3β, a critical intracellular kinase regulated by Wnt and other pathways, mediates this effect. These hypotheses were tested observationally in autopsy specimens from premature infants, and experimentally in a premature rabbit IVH model. Significantly, in premature infants with IVH, the number of neurogenic cortical progenitor cells was reduced compared with infants without IVH, indicating acutely decreased neurogenesis. This finding was corroborated in the rabbit IVH model, which further demonstrated reduction of upper layer cortical neurons after longer survival. Both the acute reduction of neurogenic progenitors, and the subsequent decrease of upper layer neurons, were rescued by treatment with AR-A014418, a specific inhibitor of GSK3β. Together, these results indicate that IVH impairs late stages of cortical neurogenesis, and suggest that treatment with GSK3β inhibitors may enhance neurodevelopment in premature infants with IVH.

The function of melatonin as a protective agent against newborn hypoxic‐ischemic (H‐I) brain injury is not yet well studied, and the mechanisms by which melatonin causes neuroprotection in neurological diseases are still evolving. This study was designed to investigate whether expression of MT 1 receptors is reduced in newborn H‐I brain injury and whether the protective action of melatonin is by alterations of the MT 1 receptors. We demonstrated that there was significant reduction in MT 1 receptors in ischemic brain of mouse pups in vivo following H‐I brain injury and that melatonin offers neuroprotection through upregulation of MT 1 receptors. The role of MT 1 receptors was further supported by observation of increased mortality in MT 1 knockout mice following H‐I brain injury and the reversal of the inhibitory role of melatonin on mitochondrial cell death pathways by the melatonin receptor antagonist, luzindole. These data demonstrate that melatonin mediates its neuroprotective effect in mouse models of newborn H‐I brain injury, at least in part, by the restoration of MT 1 receptors, the inhibition of mitochondrial cell death pathways and the suppression of astrocytic and microglial activation.

Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission. Our previous studies proved that the inhibition of Drp1 may help attenuate traumatic brain injury (TBI)-induced functional outcome and cell death through maintaining normal mitochondrial morphology and inhibiting activation of apoptosis. However, the molecular mechanisms of Drp1 after TBI remain poorly understood. In this study, we investigated the role of mitochondrial division inhibitor 1 (Mdivi-1), a small molecule inhibitor of Drp1, in underlying mechanisms of general autophagy and mitochondria autophagy (mitophagy) after experimental TBI. In vivo, we found that autophagosomes accumulated in cortical neurons at 24h after TBI, owing to the enhanced autophagy indicated by the accumulation of LC3 and the decrease of p62; but Mdivi-1 reversed the enhancement. Mdivi-1 also alleviated the number of LC3 puncta and TUNEL-positive structures in cells, indicating that autophagy maybe involved in Mdivi-1's anti-apoptosis effects. Then, the expression level of mitochondrial dynamics related and mitophagy related proteins was assessed using the isolated mitochondria. The results showed that TBI-induced mitochondrial fission (represented by Drp1), mtDNA concentration down-regulation and PTEN induced putative kinase 1 (PINK1)-Parkin mediated mitophagy activation were all inhibited by Mdivi-1. In addition, TBI-induced blood-brain barrier (BBB) disruption and matrix metalloproteinases (MMP)-9 expression up-regulation were inhibited following Mdivi-1 treatment. In vitro, Mdivi-1 significantly alleviated the scratch injury-induced cell death, loss of mitochondrial membrane potential, reactive oxygen species (ROS) production and ATP reduction in primary cortical neurons (PCNs). Additionally, the lysosome inhibitor chloroquine (CQ) abrogated the Mdivi-1-induced decrease in autophagosomes accumulation and cell death at 24h both in the basal state and under the conditions of scratch cell injury. Together, these data demonstrate that Mdivi-1 mitigates TBI-induced BBB disruption and cell death at least in part by a mechanism involving inhibiting autophagy dysfunction and mitophagy activation.

目的：探讨番红花对2型糖尿病大鼠模型的降血糖作用。方法通过链脲佐菌素（ STZ）腹腔注射＋高糖饮食，成功建立了2型糖尿病Wistar大鼠模型，随机分为番红花组（低、中、高剂量）和二甲双胍组。连续给药28 d，观察番红花对血糖、蔗糖糖耐量的影响以及对钙蛋白酶10基因表达的影响。结果中、高剂量番红花可明显降低血糖，升高蔗糖糖耐量，同时钙蛋白酶10基因的表达量上升明显。结论番红花能降低高血糖2型糖尿病模型大鼠血糖，提高蔗糖糖耐量，对钙蛋白酶10基因的表达具有增强作用。

Ginsenosides are the main active constituents of Panax ginseng. Ginsenoside Re is one of the major ginsenosides; whereas hydrolysis products such as Rd appear to have higher biological activity though are present in smaller amounts. Ginsenosides, from their early use in folk medicine to modern studies, appear to exert beneficial actions against aging and even neurodegenerative disorders. Parkinson's disease is a progressive neurodegenerative movement disorder characterized by a profound loss of midbrain dopamine neurons in the substantia nigra pars compacta. Carbon tetrachloride (CCl4) exerts neurotoxic effects when present as an environmental pollutant. As a model compound it was used here to study the impact on primary nigrostriatal dopaminergic nerve cells and to investigate the neuroprotective potential of ginsenosides Rd and Re against this organic solvent. CCl4 (2.5 mM on day 12 in vitro for 48 h) significantly decreased the number of tyrosine hydroxylase (TH+) cells by 51% compared with untreated control cultures, reduced their neuritic lengths, and led to truncated degenerations of cell morphology. Ginsenosides Rd and Re (10 µM) strongly reduced cell loss and degeneration and significantly protected process lengths and numbers of neurites of TH+ cells. The anti-oxidative and anti-inflammatory potential of the cellular supernatant was lowered by CCl4 exposure. Inclusion of ginsenosides inhibited both oxidative stress and inflammation. Therefore the neuroprotective effects of ginsenosides at least partially depend on lowering oxidative stress and anti-inflammation.

Subarachnoid hemorrhage (SAH) results in significant nerve dysfunction, such as hemiplegia, mood disorders, cognitive and memory impairment. Currently, no clear measures can reduce brain nerve damage. The study of brain nerve protection after SAH is of great significance. We aim to evaluate the protective effects and the possible mechanism of methazolamide in C57BL/6J SAH animal model in vivo and in blood-induced primary cortical neuron (PCNs) cellular model of SAH in vitro. We demonstrate that methazolamide accelerates the recovery of neurological damage, effectively relieves cerebral edema, and improves cognitive function in SAH mice as well as offers neuroprotection in blood- or hemoglobin-treated PCNs and partially restores normal neuronal morphology. In addition, western blot analyses show obviously decreased expression of active caspase-3 in methazolamide-treated SAH mice comparing with vehicle-treated SAH animals. Furthermore, methazolamide effectively inhibits ROS production in PCNs induced by blood exposure or hemoglobin insult. However, methazolamide has no protective effects in morality, fluctuation of cerebral blood flow, SAH grade, and cerebral vasospasm of SAH mice. Given methazolamide, a potent carbonic anhydrase inhibitor, can penetrate the blood-brain barrier and has been used in clinic in the treatment of ocular conditions, it provides potential as a novel therapy for SAH.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss. Evidence suggests that mitochondrial dysfunction, apoptosis, oxidative stress, inflammation, glutamate excitotoxicity, and proteasomal dysfunction are all responsible for ALS pathogenesis. N-acetyl-tryptophan has been identified as an inhibitor of mitochondrial cytochrome c release and therefore is a potential neuroprotective agent. By quantifying cell death, we demonstrate that N-acetyl-l-tryptophan (L-NAT) and N-acetyl-DL-tryptophan are neuroprotective in NSC-34 motor neuron-like cells and/or primary motor neurons, while their isomer N-acetyl-d-tryptophan has no protective effect. These findings are consistent with energy minimization and molecular modeling analysis, confirming that L-NAT generates the most stable complex with the neurokinin-1 receptor (NK-1R). L-NAT inhibits the secretion of Substance P and IL-1 (Enzyme-Linked Immunosorbent Assay and/or dot blots) and mitochondrial dysfunction by effectively inhibiting the release of cytochrome c/Smac/AIF from mitochondria into the cytoplasm and activation of apoptotic pathways, including the activation of caspase-1, -9, and -3, as well as proteasomal dysfunction through restoring chymotrypsin-like, trypsin-like, and caspase-like proteasome activity. These data provide insight into the molecular mechanisms by which L-NAT offers neuroprotection in models of ALS and suggest its potential as a novel therapeutic strategy for ALS.

Background and Purpose— The extent of ischemic injury in response to cerebral ischemia is known to be affected by native vasculature. However, the nonvascular and dynamic vascular responses and their genetic basis are not well understood. Methods— We performed a genome-wide association study in 235 mice from 33 inbred strains using the middle cerebral artery occlusion model. Population structure and genetic relatedness were accounted for using the efficient mixed-model association method. Human orthologs to the genes associated with the significant and suggestive single-nucleotide polymorphisms from the mouse strain survey were examined in patients with M1 occlusions admitted with signs and symptoms of acute ischemic stroke. Results— We identified 4 genome-wide significant and suggestive single-nucleotide polymorphisms to be associated with infarct volume in mice (rs3694965, P =2.17×10 –7 ; rs31924033, P =5.61×10 –6 ; rs32249495, P =2.08×10 –7 ; and rs3677406, P =9.56×10 –6 ). rs32249495, which corresponds to angiopoietin-1 ( ANGPT1 ), was also significant in the recessive model in humans, whereas rs1944577, which corresponds to ZBTB7C , was nominally significant in both the additive and dominant genetic models in humans. ZBTB7C was shown to be upregulated in endothelial cells using both in vitro and in vivo models of ischemia. Conclusions— Genetic variations of ANGPT1 and ZBTB7C are associated with increased infarct size in both mice and humans. ZBTB7C may modulate the ischemic response via neuronal apoptosis and dynamic collateralization and, in addition to ANGPT1 , may serve as potential novel targets for treatments of cerebral ischemia.

It has been reported that ophiopogonin D (OP-D), a steroidal glycoside and an active component extracted from Ophiopogon japonicas, promotes antioxidative protection of the cardiovascular system. However, it is unknown whether OP-D exerts protective effects against doxorubicin (DOX)-induced autophagic cardiomyocyte injury. Here, we demonstrate that DOX induced excessive autophagy through the generation of reactive oxygen species (ROS) in H9c2 cells and in mouse hearts, which was indicated by a significant increase in the number of autophagic vacuoles, LC3-II/LC3-I ratio, and upregulation of the expression of GFP-LC3. Pretreatment with OP-D partially attenuated the above phenomena, similar to the effects of treatment with 3-methyladenine. In addition, OP-D treatment significantly relieved the disruption of the mitochondrial membrane potential by antioxidative effects through downregulating the expression of both phosphorylated c-Jun N-terminal kinase and extracellular signal-regulated kinase. The ability of OP-D to reduce the generation of ROS due to mitochondrial damage and, consequently, to inhibit autophagic activity partially accounts for its protective effects in the hearts against DOX-induced toxicity.