Bisindolylpyrrole Induces a Cpr3- and Porin1/2-Dependent Transition in Yeast Mitochondrial Permeability in a Low Conductance State via the AACs-Associated Pore.

Although the mitochondrial permeability transition pore (PTP) is presumably formed by either ATP synthase or the ATP/ADP carrier (AAC), little is known about their differential roles in PTP activation. We explored the role of AAC and ATP synthase in PTP formation in using bisindolylpyrrole (BP), an activator of the mammalian PTP. The yeast mitochondrial membrane potential, as indicated by tetramethylrhodamine methyl ester signals, dissipated over 2-4 h after treatment of cells with 5 μM BP, which was sensitive to cyclosporin A (CsA) and Cpr3 deficiency and blocked by porin1/2 deficiency.

Bisindolylpyrrole triggers transient mitochondrial permeability transitions to cause apoptosis in a VDAC1/2 and cyclophilin D-dependent manner via the ANT-associated pore.

Bisindolylpyrrole at 0.1 μM is cytoprotective in 2% FBS that is counteracted by cyclosporin-A (CsA), an inhibitor of cyclophilin-D (CypD). We hypothesized that the cytoprotective effect might be due to transient mitochondrial permeability transition (tPT).

The yeast mitochondrial permeability transition is regulated by reactive oxygen species, endogenous Ca and Cpr3, mediating cell death.

We investigated the properties of the permeability transition pore (PTP) in Saccharomyces cerevisiae in agar-embedded mitochondria (AEM) and agar-embedded cells (AEC) and its role in yeast death. In AEM, ethanol-induced pore opening, as indicated by the release of calcein and mitochondrial membrane depolarization, can be inhibited by CsA, by Cpr3 deficiency, and by the antioxidant glutathione. Notably, the pore opening is inhibited, when mitochondria are preloaded by EGTA or Fluo3 to chelate matrix Ca, or are pretreated with 4-Br A23187 to extract matrix Ca, prior to agar-embedding, or when pore opening is induced in the presence of EGTA; opened pores are re-closed by sequential treatment with CsA, 4-Br A23187 plus EGTA and NADH, indicating endogenous matrix Ca involvement.

Effects of angiogenesis inhibitor TNP-470 on the development of uterine adenomyosis in mice.

Objective: To investigate the effects of angiogenesis inhibitor TNP-470 on uterine microvessels in mice. Pituitary grafting frequently induced uterine adenomyosis.

Design: In vivo experimental study.

Second window of ischemic preconditioning regulates mitochondrial permeability transition pore by enhancing Bcl-2 expression.

Objective: The second window of protection (SWOP) following brief coronary artery occlusion begins at 24 h and may last up to 72 h and occurs via many unknown mechanisms. We investigated the role of the mitochondrial permeability transition pore (PTP), a non specific pore in the inner membrane of the mitochondria in this phenomenon.

Methods: Ischemic preconditioning (IP) was induced in Wistar rats by left coronary artery occlusion (four, 3-min episodes separated by 10 min of reperfusion) on day 1.

Bisindolylmaleimide I and V inhibit necrosis induced by oxidative stress in a variety of cells including neurons.

Although free radical-mediated necrosis is implicated in many diseases such as neurodegeneration, potent anti-necrotic drugs have not yet been exploited. We found that bisindolylmaleimide I (BMI or GF 109203X), a PKC inhibitor, protected a variety of cells, including neurons, from oxidant-induced necrosis, although calphostin C, another type of PKC inhibitor, and staurosporine, a broad kinase inhibitor, had no such effect. BMI was significantly protective in neuronal cells whereas chronic application of BMI induced neurotoxicity.