cytochrome-c-t and baicalin

Myocardial injury after cardiac arrest (CA) often results in severe myocardial dysfunction and death involving mitochondrial dysfunction. Here, we sought to investigate whether baicalin, a natural flavonoid compound, exerts cardioprotection against CA-induced injury via regulating mitochondrial dysfunction. We subjected the rats to asphyxia CA after a daily baicalin treatment for 4 weeks. After the return of spontaneous circulation, baicalin treatment significantly improved cardiac function performance, elevated survival rate from 35% to 75%, prevented necrosis and apoptosis in the myocardium, which was accompanied by reduced phosphorylation of Drp1 at serine 616, inhibited Drp1 translocation to the mitochondria and mitochondrial fission, and improved mitochondrial function. In H9c2 cells subjected to simulated ischemia/reperfusion, increased phosphorylation of Drp1 at serine 616 and subsequently enhanced mitochondrial Drp1 translocation as well as mitochondrial fission, augmented cardiomyocyte death, increased reactive oxygen species production, released cytochrome c from mitochondria and injured mitochondrial respiration were efficiently improved by baicalin and Drp1 specific inhibitor with Mdivi-1. Furthermore, overexpression of Drp1 augmented excessive mitochondrial fission and abolished baicalin-afforded cardioprotection, indicating that the protective impacts of baicalin are linked to the inhibition of Drp1. Altogether, our findings disclose for the first time that baicalin offers cardioprotection against ischemic myocardial injury after CA by inhibiting Drp1-mediated mitochondrial fission. Baicalin might be a prospective therapy for the treatment of post-CA myocardial injury.

Topics: Animals; Cell Line; Cell Respiration; Cytochromes c; Dynamins; Flavonoids; Heart Arrest; Hemodynamics; Male; Mitochondria; Mitochondrial Dynamics; Myocardium; Rats, Sprague-Dawley; Reactive Oxygen Species; Return of Spontaneous Circulation; Treatment Outcome

The accumulation and deposition of β-amyloid peptide (Aβ) in senile plaques and cerebral vasculature is believed to facilitate the progressive neurodegeneration that occurs in the Alzheimer's disease (AD). The present study sought to elucidate possible effects of baicalin, a natural phytochemical, on Aβ toxicity in a rat model of AD. By morris water maze test, Aβ1-42 injection was found to cause learning and memory deficit in rat, which was effectively improved by baicalin treatment. Besides, histological examination showed that baicalin could attenuate the hippocampus injury caused by Aβ. The neurotoxicity mechanism of Aβ is associated with oxidative stress and apoptosis, as revealed by increased malonaldehyde generation and TUNEL-positive cells. Baicalin treatment was able to increase antioxidant capabilities by recovering activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) and up-regulating their gene expression. Moreover, baicalin effectively prevented Aβ-induced mitochondrial membrane potential decrease, Bax/Bcl-2 ratio increase, cytochrome c release, and caspase-9/-3 activation. In addition, we found that the anti-oxidative effect of baicalin was associated with Nrf2 activation. In conclusion, baicalin effectively improved Aβ-induced learning and memory deficit, hippocampus injury, and neuron apoptosis, making it a promising drug to preventive interventions for AD.

Topics: Amyloid beta-Peptides; Animals; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Caspases; Cell Nucleus; Cytochromes c; Enzyme Activation; Flavonoids; Hippocampus; Male; Malondialdehyde; Membrane Potential, Mitochondrial; Memory Disorders; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Rats, Wistar; Real-Time Polymerase Chain Reaction

We observed that treatment of prostate cancer cells for 24 h with wogonin, a naturally occurring monoflavonoid, induced cell death in a dose- and time-dependent manner. Exposure of wogonin to LNCaP cells was associated with increased intracellular levels of p21(Cip-1), p27(Kip-1), p53, and PUMA, oligomerization of Bax, release of cytochrome c from the mitochondria, and activation of caspases. We also confirmed the role of p53 by noting that knock-in in p53 expression by transfecting p53 DNA increased wogonin-induced apoptosis in p53-null PC-3 cells. To study the mechanism of PUMA up-regulation, we determined the activities of PUMA promoter in the wogonin treated and untreated cells. Increase of the intracellular levels of PUMA protein was due to increase in transcriptional activity. Data from chromatin immunoprecipitation (ChIP) analyses revealed that wogonin activated the transcription factor p53 binding activity to the PUMA promoter region. We observed that the up-regulation of PUMA mediated wogonin cytotoxicity. Further characterization of the transcriptional response to wogonin in HCT116 human colon cancer cells demonstrated that PUMA induction was p53-dependent; deficiency in either p53 or PUMA significantly protected HCT116 cells against wogonin-induced apoptosis. Also, wogonin promoted mitochondrial translocation and multimerization of Bax. Interestingly, wogonin (100 microM) treatment did not affect the viability of normal human prostate epithelial cells (PrEC). Taken together, these results indicate that p53-dependent transcriptional induction of PUMA and oligomerization of Bax play important roles in the sensitivity of cancer cells to apoptosis induced by caspase activation through wogonin.

Topics: Apoptosis; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; Caspase 3; Caspase 9; Cell Line, Tumor; Cell Survival; Cells, Cultured; Cytochromes c; DNA Fragmentation; Epithelial Cells; Flavanones; Flavonoids; Gene Expression Regulation; Humans; Male; Prostate; Proto-Oncogene Proteins; Tumor Suppressor Protein p53

Acute lymphoblastic leukemia (ALL), especially T-acute lymphoblastic leukemia (T-ALL), is a common childhood malignant neoplastic disorder. Chemotherapy agents, particularly those that can induce apoptosis, are the major intervening strategy in the treatment of ALL. In this study, we investigated in T-ALL cell line, CCRF-CEM, the in vitro cytotoxic effect and the mechanism of action of baicalin, a compound extracted from Scutellaria baicalensis Georgi and S. rivularis Benth (Labiateae). Results demonstrated that baicalin displayed a remarkable cytotoxic effect in CCRF-CEM, with an IC(50) value of 10.6 microg/ml. It triggered apoptotic effect by fragmentizing cellular DNA and arrested the cell cycle at G(0)/G(1) phase. Baicalin (37.5 microg/ml) had not effected the expression of p53 and Fas protein. It was shown to decline the expression of Bcl-2 (22.0 pg/ml), which consequently caused the loss (52.7%) of transmembrane potential (Delta Psi m) in the mitochondria after 72 hours of treatment. Baicalin (37.5 microg/ml) also elevated the amount of cytosolic cytochrome c (19.2 microg/ml), which finally triggered the activation of caspase-3 (50.1 pmol/min). In conclusion, baicalin was found to induce apoptosis in T-ALL cell lines through multiple pathways. This finding encourages further investigation of baicalin in its role as a potential candidate for chemotherapeutic agents in T-ALL.

Topics: Apoptosis; Caspase 3; Caspases; Cell Cycle; Cell Line, Tumor; Cytochromes c; DNA; Flavonoids; Flow Cytometry; Humans; Leukemia; Membrane Potentials; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53