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Background: Caudal dorsomedial hindbrain detection of hypoglycemia-associated lactoprivation regulates glucose counter-regulation in male rats. In females, estradiol (E) determines hypothalamic neuroanatomical and molecular foci of hindbrain energy sensor activation. This study investigated the hypothesis that E signal strength governs metabolic neuropeptide and counter-regulatory hormone responses to hindbrain lactoprivic stimuli in hypoglycemic female rats., Methods: Ovariectomized animals were implanted with E-filled silastic capsules [30 (E-30) or 300 μg (E-300)/mL] to replicate plasma concentrations at estrous cycle nadir versus peak levels. E-30 and E-300 rats were injected with insulin or vehicle following initiation of continuous caudal fourth ventricular L-lactate infusion., Results: Hypoglycemic hypercorticosteronemia was greater in E-30 versus E-300 animals. Glucagon and corticosterone outflow was correspondingly fully or partially reversed by hindbrain lactate infusion. Insulin-injected rats exhibited lactate-reversible augmentation of norepinephrine (NE) accumulation in all preoptic/hypothalamic structures examined, excluding the dorsomedial hypothalamic nucleus (DMH) where hindbrain lactate infusion either suppressed (E-30) or enhanced (E-300) NE content. Expression profiles of hypoglycemia-reactive metabolic neuropeptides were normalized (with greater efficacy in E-300 animals) by lactate infusion. DMH RFamide-related peptide-1 and -3, arcuate neuropeptide Y and kisspeptin, and ventromedial nucleus nitric oxide synthase protein responses to hypoglycemia were E dosage-dependent., Conclusions: Distinct physiological patterns of E secretion characteristic of the female rat estrous cycle elicit differential corticosterone outflow during hypoglycemia, and establish both common and different hypothalamic metabolic neurotransmitter targets of hindbrain lactate deficit signaling. Outcomes emphasize a need for insight on systems-level organization, interaction, and involvement of E signal strength-sensitive neuropeptides in counter-regulatory functions., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Vital nerve cell functions, including maintenance of transmembrane voltage and information transfer, occur at high energy expense. Inadequate provision of the obligate metabolic fuel glucose exposes neurons to risk of dysfunction or injury. Clinical hypoglycemia rarely occurs in nondiabetic individuals but is an unfortunate regular occurrence in patients with type 1 or advanced insulin-treated type 2 diabetes mellitus. Requisite strict glycemic control, involving treatment with insulin, sulfonylureas, or glinides, can cause frequent episodes of iatrogenic hypoglycemia due to defective counter-regulation, including reduced glycemic thresholds and diminished magnitude of motor responses. Multiple components of the body's far-reaching energy balance regulatory network, including the hindbrain dorsal vagal complex, provide dynamic readout of cellular energetic disequilibrium, signals that are utilized by the hypothalamus to shape counterregulatory autonomic, neuroendocrine, and behavioral outflow toward restoration of glucostasis. The ovarian steroid hormone 17β-estradiol acts on central substrates to preserve nerve cell energy stability brain-wide, thereby providing neuroprotection against bio-energetic insults such as neurodegenerative diseases and acute brain ischemia. The current review highlights recent evidence implicating estrogen in gluco-regulation in females by control of hindbrain metabolic sensor screening and signaling of hypoglycemia-associated neuro-energetic instability. It is anticipated that new understanding of the mechanistic basis of how estradiol influences metabolic sensory input from this critical brain locus to discrete downstream regulatory network substrates will likely reveal viable new molecular targets for therapeutic simulation of hormone actions that promote positive neuronal metabolic state during acute and recurring hypoglycemia.

The synthesis of a series of 17β-estradiol-platinum(II) hybrid molecules is reported. The hybrids are made of a PEG linking chain of various length and a 2-(2'-aminoethyl)pyridine ligand. They are prepared from estrone in only 5 chemical steps with an overall yield of 22%. The length of the PEG chain does not influence the solubility of the compounds as it remains relatively constant throughout the series. MTT assays showed that the derivative with the longest PEG chain showed the best activity against two human breast cancer cell lines (MCF-7 and MDA-MB-231). The novel PEG-hybrids are also compared in terms of activities with two other families of 17β-estradiol-platinum(II) hybrids that we reported in previous studies. Molecular modeling study performed on a representative member of each family of hybrids reveals distinct molecular interactions with the estrogen receptor α which further corroborates their notably contrasting cytocidal activities on breast cancer cell lines. This study also shows that lipophilicity and the orientation of the tether chain between the estrogenic portion and the platinum(II) core contribute markedly to the biological activity of the various families of hybrids. The most active hybrids are those possessing an alkyl tether chain at position 16β of the steroid nucleus. For example, derivative 3 (p=6) is about 16 times more potent on MCF-7 breast cancer cells than the corresponding 16α-PEG-hybrids (2b) made in this study., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The synthesis of a series of 17beta-estradiol-platinum(II) hybrid molecules is reported. The hybrids are made of a PEG linking chain of various length and a 2-(2'-aminoethyl)pyridine ligand. They are prepared from estrone in five chemical steps with an overall yield of 22%. The length of the PEG chain does not influence the solubility of the compounds as it remains relatively constant throughout the series. MTT assays showed that the derivative with the longest PEG chain showed the best activity against breast cancer cell lines (MCF-7 and MDA-MB-231). Molecular modeling study rationalized the results.

We have recently reported the synthesis of a series of original 17beta-estradiol-linked platinum(II) hybrid molecules. The biological activity of these compounds was evaluated in vitro on estrogen dependent and independent (ER(+) and ER(-)) human uterine and ovarian cancers. The hybrid molecules present higher affinity than that of 17beta-estradiol for the estrogen receptor alpha (ERalpha). The cytotoxicity and the affinity of the hybrid molecules are explained using molecular modeling analysis. This study further confirms that the derivatives made of a 2-(2'-aminoethyl)pyridine ligand displayed superior activity against the cell lines particularly when the connecting arm is 8-10 carbon atoms long. Molecular modeling shows that a long side chain can facilitate the access of the platinum(II) moiety to DNA. The novel compounds also prove to be moderately cytotoxic against platinum resistant endometrial and ovarian cancer cell lines.

The synthesis of a novel series of 17beta-estradiol-linked platinum(II) complexes is described. The new molecules are linked with an alkyl chain at position 16alpha of the steroid nucleus and bear a 16beta-hydroxymethyl side chain. They are made from estrone in five chemical steps with an overall yield exceeding 28%. The biological activity of these compounds was evaluated in vitro on estrogen dependent and independent (ER+ and ER-) human breast cancers. The derivatives incorporating a 2-(2'-aminoethyl)pyridine ligand displayed good activity against the cell lines particularly when the connecting arm is 10 carbon atoms long.