The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing nonclassical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown, and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this Review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore nonclassical platinum(II) complexes with trans geometry or with a monofunctional coordination mode, polynuclea...

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

Insulin receptors (IRs) and insulin signaling proteins are widely distributed throughout the central nervous system (CNS). To study the physiological role of insulin signaling in the brain, we created mice with a neuron-specific disruption of the IR gene (NIRKO mice). Inactivation of the IR had no impact on brain development or neuronal survival. However, female NIRKO mice showed increased food intake, and both male and female mice developed diet-sensitive obesity with increases in body fat and plasma leptin levels, mild insulin resistance, elevated plasma insulin levels, and hypertriglyceridemia. NIRKO mice also exhibited impaired spermatogenesis and ovarian follicle maturation because of hypothalamic dysregulation of luteinizing hormone. Thus, IR signaling in the CNS plays an important role in regulation of energy disposal, fuel metabolism, and reproduction.

Role of brain insulin receptor and control of body weight and reproduction

The mitochondrial permeability transition (PT) is a permeability increase of the inner mitochondrial membrane mediated by a channel, the permeability transition pore (PTP). After a brief historical introduction, we cover the key regulatory features of the PTP and provide a critical assessment of putative protein components that have been tested by genetic analysis. The discovery that under conditions of oxidative stress the F-ATP synthases of mammals, yeast, and Drosophila can be turned into Ca2+-dependent channels, whose electrophysiological properties match those of the corresponding PTPs, opens new perspectives to the field. We discuss structural and functional features of F-ATP synthases that may provide clues to its transition from an energy-conserving into an energy-dissipating device as well as recent advances on signal transduction to the PTP and on its role in cellular pathophysiology.

/pdf/the-mitochondrial-permeability-transition-pore-channel-elqbd03hr1.pdf

The Mitochondrial Permeability Transition Pore: Channel Formation by F-ATP Synthase, Integration in Signal Transduction, and Role in Pathophysiology

https://repository.up.ac.za/bitstream/handle/2263/36828/Esposito_Interactions_2014.pdf?sequence=1

Interactions between negative energy balance, metabolic diseases, uterine health and immune response in transition dairy cows

Glutathione (GSH) is the main nonprotein thiol in cells whose functions are dependent on the redox-active thiol of its cysteine moiety that serves as a cofactor for a number of antioxidant and detoxifying enzymes. While synthesized exclusively in the cytosol from its constituent amino acids, GSH is distributed in different compartments, including mitochondria where its concentration in the matrix equals that of the cytosol. This feature and its negative charge at physiological pH imply the existence of specific carriers to import GSH from the cytosol to the mitochondrial matrix, where it plays a key role in defense against respiration-induced reactive oxygen species and in the detoxification of lipid hydroperoxides and electrophiles. Moreover, as mitochondria play a central strategic role in the activation and mode of cell death, mitochondrial GSH has been shown to critically regulate the level of sensitization to secondary hits that induce mitochondrial membrane permeabilization and release of proteins confined in the intermembrane space that once in the cytosol engage the molecular machinery of cell death. In this review, we summarize recent data on the regulation of mitochondrial GSH and its role in cell death and prevalent human diseases, such as cancer, fatty liver disease and Alzheimer’s disease.

/pdf/glutathione-and-mitochondria-3f51ydk63k.pdf

Glutathione and mitochondria.

Early lactation in dairy cattle is a period of severe negative energy balance (NEB) characterized by reduced blood glucose and insulin concentrations and elevated blood GH concentrations. The liver is refractory to GH during NEB and this uncoupling of the GH-IGF axis results in diminished plasma concentrations of IGF-I. Our objectives were to examine the effects of insulin administration during the immediate postpartum period on plasma IGF-I and GH concentrations and to examine the hepatic expression of total GH receptors (all GH receptor transcripts), GH receptor 1A (GHR 1A) and IGF-I. In addition, we examined adipose tissue for total GH receptor and IGF-I mRNA levels to establish the effects of chronic hyperinsulinemia on an insulin-responsive peripheral tissue. Holstein cows (n=14) were subjected to either a hyperinsulinemic-euglycemic clamp (insulin; INS) or saline infusion (control; CTL) for 96 h starting on day 10 postpartum. Insulin was infused i.v. (1 micro g/kg body weight per h), blood samples were collected hourly, and euglycemia was maintained by infusion of glucose. Insulin concentrations during the infusions were increased 8-fold in INS compared with CTL cows (2.33+/-0.14 vs 0.27+/-0.14 ng/ml (S.E.M.); P 0.1). Plasma IGF-I increased continuously during the insulin infusion, and reached the highest concentrations at the end of the clamp, being almost 4-fold higher in INS compared with CTL cows (117+/-4 vs 30+/-4 ng/ml; P 0.1). Insulin appears to be a key metabolic signal in coupling the GH-IGF axis, thus orchestrating a marked elevation in circulating IGF-I concentrations.

/pdf/insulin-restores-gh-responsiveness-during-lactation-induced-4a30il14r7.pdf

Insulin restores GH responsiveness during lactation-induced negative energy balance in dairy cattle: effects on expression of IGF-I and GH receptor 1A.

Molecular events that regulate cellular biosynthesis of steroid hormones have been a topic of intense research for more than half a century. It has been established that transport of cholesterol into the mitochondria forms the rate-limiting step in steroid hormone production. In current models, both the steroidogenic acute regulatory protein (StAR) and the translocator protein (TSPO) have been implicated to have a concerted and indispensable effort in this cholesterol transport. Deletion of StAR in mice resulted in a critical failure of steroid hormone production, but deletion of TSPO in mice was found to be embryonic lethal. As a result, the role of TSPO in cholesterol transport has been established only using pharmacologic and genetic tools in vitro. To allow us to explore in more detail the function of TSPO in cell type-specific experimental manipulations in vivo, we generated mice carrying TSPO floxed alleles (TSPOfl/fl). In this study we made conditional knockout mice (TSPOcΔ/Δ) with TSPO deletion in testicular Leydig cells by crossing with an anti-Mullerian hormone receptor type II cre/+ mouse line. Genetic ablation of TSPO in steroidogenic Leydig cells in mice did not affect testosterone production, gametogenesis, and reproduction. Expression of StAR, cytochrome P450 side chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase type I, and TSPO2 in TSPOcΔ/Δ testis was unaffected. These results challenge the prevailing dogma that claims an essential role for TSPO in steroid hormone biosynthesis and force reexamination of functional interpretations made for this protein. This is the first study examining conditional TSPO gene deletion in mice. The results show that TSPO function is not essential for steroid hormone biosynthesis.

https://www.researchgate.net/profile/Vimal_Selvaraj/publication/258204532_Translocator_ProteinPeripheral_Benzodiazepine_Receptor_Is_Not_Required_for_Steroid_Hormone_Biosynthesis/links/55f8a27108aec948c483e834.pdf

Translocator protein/peripheral benzodiazepine receptor is not required for steroid hormone biosynthesis.

Peripheral benzodiazepine receptor/translocator protein global knock-out mice are viable with no effects on steroid hormone biosynthesis.

Energy balance, metabolic status, and the first postpartum ovarian follicle wave in cows administered propylene glycol.

Prolonged anovulation following parturition has a negative impact on fertility in dairy cows. Insulin plays an important role in ovarian function in many species, and is profoundly depressed in dairy cows during early lactation. We hypothesized that hypoinsulinemia during early lactation represents a key indicator of nutritional status, resulting in delayed ovulation. Holstein cows (n = 10) were subjected to either a hyperinsulinemic-euglycemic clamp (INS) or saline infusion (CTL) for 96 h, beginning on day 10 after parturition during the first postpartum follicular wave. Insulin was infused continuously (0.3 microg/kg body weight per h) via a jugular catheter, and euglycemia was maintained by infusion of glucose. Circulating insulin concentrations were elevated 2.6-fold in INS cows compared with CTL cows (0.73 +/- 0.026 vs 0.28 +/- 0.026 ng/ml; P 0.05) luteinizing hormone (LH) pulse frequency, pulse amplitude or mean circulating LH. Circulating estradiol was elevated in INS cows (P < 0.01) and circulating testosterone also tended to be higher. The ratio of testosterone to estradiol was not different between treatments for the initial 30 h of infusion, but was significantly reduced thereafter in response to insulin (P < 0.01), suggesting that hyperinsulinemia increased follicular aromatase activity. Insulin treatment also resulted in reduced circulating nonesterified fatty acids, and increased circulating total and free insulin-like growth factor-I concentrations. Insulin infusion increased estradiol secretion by the dominant follicle of the first postpartum follicular wave in dairy cows, and this effect appears not to be mediated through changes in pulsatile LH release.

/pdf/insulin-increases-17b-estradiol-production-by-the-dominant-2um01r8qq6.pdf

Susanne H. Pelton

Papers

Insulin restores GH responsiveness during lactation-induced negative energy balance in dairy cattle: effects on expression of IGF-I and GH receptor 1A.

Translocator protein/peripheral benzodiazepine receptor is not required for steroid hormone biosynthesis.

Peripheral benzodiazepine receptor/translocator protein global knock-out mice are viable with no effects on steroid hormone biosynthesis.

Energy balance, metabolic status, and the first postpartum ovarian follicle wave in cows administered propylene glycol.

Insulin increases 17β-estradiol production by the dominant follicle of the first postpartum follicle wave in dairy cows