Fisetin provides antidepressant effects by activating the tropomyosin receptor kinase B signal pathway in mice.

Depression has been associated with a low-grade chronic inflammatory state, suggesting a potential therapeutic role for anti-inflammatory agents. Fisetin is a naturally occurring flavonoid in strawberries that has anti-inflammatory activities, but whether fisetin has antidepressant effects is unknown. In this study, we exposed mice to spatial restraint for 2 weeks with or without treatment with fisetin.

Exogenous Adipokine Peptide Resistin Protects Against Focal Cerebral Ischemia/Reperfusion Injury in Mice.

Previous studies have demonstrated that plasma resistin levels were increased in patients with acute ischemic stroke. However, the role of resistin after ischemic brain injury is still unclear. In this study, we investigated the protective effects of resistin on cerebral ischemia/reperfusion injury in a middle cerebral artery occlusion mouse model.

β-arrestin 2 attenuates cardiac dysfunction in polymicrobial sepsis through gp130 and p38.

Sepsis is an exaggerated systemic inflammatory response to persistent bacteria infection with high morbidity and mortality rate clinically. β-arrestin 2 modulates cell survival and cell death in different systems. However, the effect of β-arrestin 2 on sepsis-induced cardiac dysfunction is not yet known.

7,8-Dihydroxy-4-methylcoumarin provides neuroprotection by increasing hippocalcin expression.

7,8-Dihydroxy-4-methylcoumarin (Dhmc) is a precursor in the synthesis of derivatives of 4-methyl coumarin, which has excellent radical scavenging properties. In this study, we investigated whether Dhmc protects against oxidative stress and ischemic brain injury. We found that Dhmc protected against glutamate toxicity in hippocampal HT-22 cells in a concentration-dependent manner in vitro.

Increased oligodendrogenesis by humanin promotes axonal remyelination and neurological recovery in hypoxic/ischemic brains.

Oligodendrocytes are the predominant cell type in white matter and are highly vulnerable to ischemic injury. The role of oligodendrocyte dysfunction in ischemic brain injury is unknown. In this study, we used a 24-amino acid peptide S14G-Humanin (HNG) to examine oligodendrogenesis and neurological functional recovery in a hypoxic/ischemic (H/I) neonatal model.

β-arrestin2/miR-155/GSK3β regulates transition of 5'-azacytizine-induced Sca-1-positive cells to cardiomyocytes.

Stem-cell antigen 1-positive (Sca-1+) cardiac stem cells (CSCs), a vital kind of CSCs in humans, promote cardiac repair in vivo and can differentiate to cardiomyocytes with 5'-azacytizine treatment in vitro. However, the underlying molecular mechanisms are unknown. β-arrestin2 is an important scaffold protein and highly expressed in the heart.

Antioxidant activity of 7,8-dihydroxyflavone provides neuroprotection against glutamate-induced toxicity.

Glutamate, an excitatory neurotransmitter in the central nervous system, plays an important role in neurological disorders. Previous studies have shown that excess glutamate can cause oxidative stress in a hippocampal HT-22 cell line. 7,8-Dihydroxyflavone (7,8-DHF), a member of the flavonoid family, is a selective tyrosine kinase receptor B (TrkB) agonist that has neurotrophic effects in various neurological diseases such as stroke and Parkinson's disease.

Synergistic protective effects of humanin and necrostatin-1 on hypoxia and ischemia/reperfusion injury.

Since several different pathways are involved in cerebral ischemia/reperfusion injury, combination therapy rather than monotherapy may be required for efficient neuroprotection. In this study, we examined the protective effects of an apoptosis inhibitor Gly(14)-humanin (HNG) and a necroptosis inhibitor necrostatin-1 (Nec-1) on hypoxia/ischemia/reperfusion injury. Cultured mouse primary cortical neurons were incubated with Nec-1, HNG or both in a hypoxia chamber for 60 min.

The role of PARP activation in glutamate-induced necroptosis in HT-22 cells.

Oxidative cell death contributes to neuronal cell death in many neurological diseases such as stroke, brain trauma, and Alzheimer's disease. In this study, we explored the involvement of poly(ADP-ribose)-polymerase (PARP) in oxidative stress-induced necroptosis. We showed that PJ34, a potent and specific inhibitor of PARP, can completely inhibit glutamate-induced necroptosis in HT-22 cells.

Manipulation of death pathways in desmin-related cardiomyopathy.

Rationale: Transgenic mice with cardiac specific overexpression of mutated alphaB-crystallin (CryAB(R120G)) display Desmin-related myopathy (DRM) with dilated cardiomyopathy and heart failure. Our previous studies showed the presence of progressive mitochondrial abnormalities and activation of apoptotic cell death in CryAB(R120G) transgenic hearts. However, the role of mitochondrial dysfunction and apoptosis in the overall course of the disease was unclear.

Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxdiase 1.

Free-radical generation is one of the primary causes of myocardial ischemia/reperfusion (I/R) injury. Melatonin is an efficient free-radical scavenger and induces the expression of antioxidant enzymes. We have previously shown that melatonin can prevent free-radical-induced myocardial injury.

Attenuation of doxorubicin-induced cardiac injury by mitochondrial glutaredoxin 2.

While the cardiotoxicity of doxorubicin (DOX) is known to be partly mediated through the generation of reactive oxygen species (ROS), the biochemical mechanisms by which ROS damage cardiomyocytes remain to be determined. This study investigates whether S-glutathionylation of mitochondrial proteins plays a role in DOX-induced myocardial injury using a line of transgenic mice expressing the human mitochondrial glutaredoxin 2 (Glrx2), a thiotransferase catalyzing the reduction as well as formation of protein-glutathione mixed disulfides, in cardiomyocytes. The total glutaredoxin (Glrx) activity was increased by 76% and 53 fold in homogenates of whole heart and isolated heart mitochondria of Glrx2 transgenic mice, respectively, compared to those of nontransgenic mice.

Over-expression of a modified bifunctional apoptosis regulator protects against cardiac injury and doxorubicin-induced cardiotoxicity in transgenic mice.

Aims: Bifunctional apoptosis regulator (BAR) is an endoplasmic reticulum protein that interacts with both the extrinsic and intrinsic apoptosis pathways. We hypothesize that over-expression of BAR Delta RING prevents apoptosis and injury following ischaemia/reperfusion (I/R) and attenuates doxorubicin (DOX)-induced cardiotoxicity.

Methods And Results: We generated a line of transgenic mice that carried a human BAR Delta RING transgene under the control of the mouse alpha-myosin heavy chain promoter.

Glutathione peroxidase 1-deficient mice are more susceptible to doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX)-induced cardiotoxicity is thought to be mediated by the generation of superoxide anion radicals (superoxide) from redox cycling of DOX in cardiomyocyte mitochondria. Reduction of superoxide generates H(2)O(2), which diffuses throughout the cell and potentially contributes to oxidant-mediated cardiac injury. The mitochondrial and cytosolic glutathione peroxidase 1 (Gpx1) primarily functions to eradicate H(2)O(2).

Neuroprotective effect of humanin on cerebral ischemia/reperfusion injury is mediated by a PI3K/Akt pathway.

Humanin (HN) is an anti-apoptotic peptide that suppresses neuronal cell death induced by Alzheimer's disease, prion protein fragments, and serum deprivation. Recently, we demonstrated that Gly14-HN (HNG), a variant of HN in which the 14th amino acid serine is replaced with glycine, can decrease apoptotic neuronal death and reduce infarct volume in a focal cerebral ischemia/reperfusion mouse model. In this study, we postulate that the mechanism of HNG's neuroprotective effect is mediated by the PI3K/Akt pathway.

Resistin, an adipocytokine, offers protection against acute myocardial infarction.

Resistin, an adipocyte-derived hormone, is thought to represent a link between obesity and insulin-resistant diabetes. The potential role of resistin as a cardioprotective agent has not been explored. Our hypothesis is that resistin has a cardioprotective effect that is mediated by the resistin receptor-coupled activation of PI3K/Akt/PKC/K(ATP) dependent pathways.

Targeted disruption of the glutaredoxin 1 gene does not sensitize adult mice to tissue injury induced by ischemia/reperfusion and hyperoxia.

To understand the physiological function of glutaredoxin, a thiotransferase catalyzing the reduction of mixed disulfides of protein and glutathione, we generated a line of knockout mice deficient in the cytosolic glutaredoxin 1 (Grx1). To our surprise, mice deficient in Grx1 were not more susceptible to acute oxidative insults in models of heart and lung injury induced by ischemia/reperfusion and hyperoxia, respectively, suggesting that either changes in S-glutathionylation status of cytosolic proteins are not the major cause of such tissue injury or developmental adaptation in the Glrx1-knockout animals alters the response to oxidative insult. In contrast, mouse embryonic fibroblasts (MEFs) isolated from Grx1-deficient mice displayed an increased vulnerability to diquat and paraquat, but they were not more susceptible to cell death induced by hydrogen peroxide (H(2)O(2)) and diamide.

Necrostatin-1 protects against glutamate-induced glutathione depletion and caspase-independent cell death in HT-22 cells.

Glutamate, a major excitatory neurotransmitter in the CNS, plays a critical role in neurological disorders such as stroke and Parkinson's disease. Recent studies have suggested that glutamate excess can result in a form of cell death called glutamate-induced oxytosis. In this study, we explore the protective effects of necrostatin-1 (Nec-1), an inhibitor of necroptosis, on glutamate-induced oxytosis.

Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure.

Loss of cardiac myocytes in heart failure is thought to occur largely through an apoptotic process. Here we show that heart failure can also be precipitated through myocyte necrosis associated with Ca2+ overload. Inducible transgenic mice with enhanced sarcolemmal L-type Ca2+ channel (LTCC) activity showed progressive myocyte necrosis that led to pump dysfunction and premature death, effects that were dramatically enhanced by acute stimulation of beta-adrenergic receptors.

Overexpression of IAP-2 attenuates apoptosis and protects against myocardial ischemia/reperfusion injury in transgenic mice.

Inhibitors of apoptosis proteins (IAPs) are key intrinsic regulators of caspases-3 and -7. During ischemia, IAP-2 is upregulated dramatically, while the other IAPs show little or no change. To test whether IAP-2 prevents cardiac apoptosis and injury following ischemia/reperfusion, we generated a line of transgenic mice that carried a mouse IAP-2 transgene.

Humanin is a novel neuroprotective agent against stroke.

Background And Purpose: Humanin (HN) is a 24-amino acid peptide best known for its ability to protect neurons from damage caused by Alzheimer disease-related proteins. This study examines the neuroprotective effects of HNG (a potent form of HN) on focal cerebral ischemia/reperfusion injury in mice.

Methods: Mice underwent middle cerebral artery occlusion for 75 minutes followed by 24-hour reperfusion.

Attenuation of doxorubicin-induced contractile and mitochondrial dysfunction in mouse heart by cellular glutathione peroxidase.

The cardiac toxicity of doxorubicin (DOX), a potent anticancer anthracycline antibiotic, is believed to be mediated through the generation of reactive oxygen species (ROS) in cardiomyocytes. This study aims to determine the function of cellular glutathione peroxidase (Gpx1), which is located in both mitochondria and cytosol, in defense against DOX-induced cardiomyopathy using a line of transgenic mice with cardiac overexpression of Gpx1. The Gpx1-overexpressing hearts were markedly more resistant than nontransgenic hearts to DOX-induced acute functional derangements, including impaired contractility and diastolic properties, decreased coronary flow rate, and reduced heart rate.

Multiple actions of pifithrin-alpha on doxorubicin-induced apoptosis in rat myoblastic H9c2 cells.

Doxorubicin (Dox) is a chemotherapeutic agent that causes significant cardiotoxicity. We showed previously that Dox activates p53 and induces apoptosis in mouse hearts. This study was designed to elucidate the molecular events that lead to p53 stabilization, to examine the pathways involved in Dox-induced apoptosis, and to evaluate the effectiveness of pifithrin-alpha (PFT-alpha), a p53 inhibitor, in blocking apoptosis of rat H9c2 myoblasts.

Pifithrin-alpha protects against doxorubicin-induced apoptosis and acute cardiotoxicity in mice.

The present experiments were designed to evaluate the effects of pifithrin-alpha (PFT-alpha), which is a p53 inhibitor, on doxorubicin (DOX)-induced apoptosis and cardiac injury. Administration of DOX (22.5 mg/kg ip) in mice upregulated the mRNA levels of Bax and MDM2, whereas PFT-alpha attenuated those levels when administered at a total dose of 4.