PARP1-MGMT complex underpins pathway crosstalk in O-methylguanine repair.

DNA lesions induced by alkylating agents are repaired by two canonical mechanisms, base excision repair dependent on poly(ADP) ribose polymerase 1 (PARP1) and the other mediated by O-methylguanine (OmeG)-DNA methyltransferase (MGMT) in a single-step catalysis of alkyl-group removal. OmeG is the most cytotoxic and mutagenic lesion among the methyl adducts induced by alkylating agents. Although it can accomplish the dealkylation reaction all by itself as a single protein without associating with other repair proteins, evidence is accumulating that MGMT can form complexes with repair proteins and is highly regulated by a variety of post-translational modifications, such as phosphorylation, ubiquitination, and others.

Mitochondrial TrxR2 regulates metabolism and protects from metabolic disease through enhanced TCA and ETC function.

Mitochondrial dysfunction is a key driver of diabetes and other metabolic diseases. Mitochondrial redox state is highly impactful to metabolic function but the mechanism driving this is unclear. We generated a transgenic mouse which overexpressed the redox enzyme Thioredoxin Reductase 2 (TrxR2), the rate limiting enzyme in the mitochondrial thioredoxin system.

Nanoformulation of Talazoparib Increases Maximum Tolerated Doses in Combination With Temozolomide for Treatment of Ewing Sarcoma.

The Pediatric Preclinical Testing Program previously identified the PARP inhibitor talazoparib (TLZ) as a means to potentiate temozolomide (TMZ) activity for the treatment of Ewing sarcoma. However, the combination of TLZ and TMZ has been toxic in both preclinical and clinical testing, necessitating TMZ dose reduction to ~15% of the single agent maximum tolerated dose. We have synthesized a nanoparticle formulation of talazoparib (NanoTLZ) to be administered intravenously in an effort to modulate the toxicity profile of this combination treatment.

Dual targeting of androgen receptor and mTORC1 by salinomycin in prostate cancer.

Androgen receptor (AR) and PI3K/AKT/mTORC1 are major survival signals that drive prostate cancer to a lethal disease. Reciprocal activation of these oncogenic pathways from negative cross talks contributes to low/limited success of pathway-selective inhibitors in curbing prostate cancer progression. We report that the antibiotic salinomycin, a cancer stem cell blocker, is a dual-acting AR and mTORC1 inhibitor, inhibiting PTEN-deficient castration-sensitive and castration-resistant prostate cancer in culture and xenograft tumors.

Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions.

Orally delivered small-molecule therapeutics are metabolized in the liver and intestine by phase I and phase II drug-metabolizing enzymes (DMEs), and transport proteins coordinate drug influx (phase 0) and drug/drug-metabolite efflux (phase III). Genes involved in drug metabolism and disposition are induced by xenobiotic-activated nuclear receptors (NRs), i.e.

Developmental expression of Toll-like receptors-2 and -4 in preterm baboon lung.

Preterm babies are susceptible to respiratory infection due to immature lung and immune system. Immune cells express Toll-like receptors (TLRs), which may be important in local host defense of preterm infants. We studied the expression of TLR2 and TLR4 in lung tissues of fetal baboons delivered at 125, 140, and 175 days of gestation (dGA; term=185+/-2 days) and preterm baboons that became naturally infected with bacterial/fungal pathogens.

Immunophenotype and functions of fetal baboon bone-marrow derived dendritic cells.

Dendritic cells (DCs) are unique antigen-presenting cells that can take up pathogens, pathogens-derived and stress-antigens and stimulate antigen-specific immune response. Here we investigated the immunobiology of fetal DCs and compared their phenotype and activation status against infectious stimuli with those of young and adult baboons. The DCs were obtained from femoral bone-marrow (BMDCs) of fetus (140 and 175 days of gestation), young (4-5 years old) and mature adult (10-35 years old) baboons.

Temporal regulation of agonist efficacy at 5-hydroxytryptamine (5-HT)1A and 5-HT 1B receptors.

Coactivation of purinergic (P 2Y) receptors reduces agonist efficacy at serotonin 1B (5-HT 1B), but not 5-HT 1A receptors. Herein, we report that pretreatment for 5 min with the P 2Y receptor agonist ATP reduced agonist responsiveness at the 5-HT 1A, but not at the 5-HT 1B, receptor. The effect of ATP pretreatment on the 5-HT 1A receptor response rapidly reversed within a 10 min time frame between P 2Y receptor and 5-HT 1A receptor activation.