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Area CA3 in the hippocampus is traditionally thought to act as a homogeneous neural circuit that is vital for spatial navigation and episodic memories. However, recent studies have revealed that CA3 pyramidal neurons in dorsal hippocampus display marked anatomic and functional heterogeneity along the proximodistal (transverse) axis. The hippocampus is also known to be functionally segregated along the dorsoventral (longitudinal) axis, with dorsal hippocampus strongly involved in spatial navigation and ventral hippocampus associated with emotion and anxiety. Surprisingly, however, relatively little is known about CA3 functional heterogeneity along the dorsoventral axis. Here, we carried out mouse-brain-slice patch-clamp recordings and morphological analyses to examine the heterogeneity of CA3 cellular properties along both proximodistal and dorsoventral axes. We find that CA3 pyramidal neurons exhibit considerable heterogeneity of somatodendritic morphology and intrinsic membrane properties, with ventral CA3 (vCA3) displaying more elaborate somatodendritic morphology, lower intrinsic excitability, smaller input resistance, greater cell capacitance, and more prominent hyperpolarization-activated current than dorsal CA3 (dCA3). Furthermore, although both dCA3 and vCA3 exhibit proximal-to-distal gradients in intrinsic properties and neuronal morphology, these proximal-to-distal gradients in vCA3 are more moderate than those in dCA3. Taken together, our results extend previous findings on the proximodistal heterogeneity of dCA3 function and uncover a complex, yet orderly, pattern of topographic organization of CA3 neuronal features that extends to multiple anatomic dimensions and may contribute to its in vivo functional diversity. NEW & NOTEWORTHY Area CA3 is a major hippocampal region that is classically thought to act as a homogeneous neural network vital for spatial navigation and episodic memories. Here, we report that CA3 pyramidal neurons exhibit marked heterogeneity of somatodendritic morphology and cellular electrical properties along both proximodistal and dorsoventral axes. These new results uncover a complex, yet orderly, pattern of topographic organization of CA3 neuronal features that may contribute to its in vivo functional diversity. [ABSTRACT FROM AUTHOR]

Morphological and functional alterations of hepatic mitochondria have been docu- mented in patients with alcoholic liver disease (ALD). Our recent study demonstrated that zinc level was decreased in whole liver and mitochondria by chronic alcohol feeding. The present study was undertaken to determine whether zinc deficiency mediates alcohol- induced mitochondrial electron transport chain (ETC) defect and whether defective ETC function may lead to generation of reactive oxygen species (ROS). Male Wistar rats were pair fed with the Lieber-DeCarli control or ethanol diet for 5 mo. Chronic alcohol exposure increased hepatic triglyceride, free fatty acid, and 4-hy- droxynonenal (4HNE) levels; meanwhile hepatic mitochondrial 4HNE level was also increased. Moreover, hepatic mitochondrial respiratory complexes I, III, IV, and V and hepatic ATP production were decreased by chronic alcohol exposure. Chronic alcohol feeding decreased peroxisome proliferator-activated receptor gamma coacti- vator-1-alpha (PGC1a.), nuclear respiratory factor 1 (NRF1), mito- chondrial transcription factor A (TFAM), and mitochondrial DNA. HepG2 cells were treated with N,N,N=,N=-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) for 6 h. Zinc deficiency significantly de- creased mitochondrial respiratory complexes I, III, and IV. In addi- tion, PGC1a., NRF1, and TFAM levels as well as mitochondrial DNA were significantly decreased by TPEN treatment. Knockdown of mitochondrial respiratory complexes I, III, or IV by shRNA caused a decrease in mitochondrial membrane potential and an increase in ROS production. These results suggest that alcohol-induced hepatic zinc deficiency could inactivate mitochondrial biogenesis pathway and decrease mitochondrial DNA replication, which, in turn, decreases mitochondrial complex protein expression. The defect of mitochon- drial respiratory complexes may worsen alcohol-induced ROS pro- duction. [ABSTRACT FROM AUTHOR]

Hepatic zinc deficiency has been well documented in alcoholic patients, but the mechanisms by which zinc deficiency mediates cell death have not been well defined. The objectives of this study were to determine whether alcohol perturbs subcellular zinc homeostasis and how organelle zinc depletion may link with cell death pathways. Wistar rats were pair-fed with the Lieber-DeCarli control or ethanol diet for 5 mo. Chronic alcohol exposure significantly reduced zinc level in isolated hepatic endoplasmic reticulum (ER) and mitochondria. Among the detected zinc transporters, ER Zrt/Irt-like protein (ZIP)13 and mitochondrial ZIP8, which transport zinc from ER and mitochondria to cytosol, were significantly increased. Mitochondrial zinc transporter (ZnT) 4, which transports zinc from cytosol to mitochondria, was also increased. ER phosphorylated eukaryotic initiation factor 2α, activating transcription factor 4, and C/EBP homologous protein were significantly upregulated, and mitochondrial cytochrome c release and Bax insertion were detected in association with caspase-3 activation and apoptotic cell death. To define the role of zinc deficiency in ER and mitochondrial stress, H4IIEC3 cells were treated with 3 μM N,N,N'=,N'=-tetrakis (2-pyridylmethyl) ethylenediamine for 6 h with or without supplementation with zinc or N-acetylcysteine (NAC). The results demonstrated that zinc deprivation induced caspase-3 activation and apoptosis in association with ER and mitochondria dysfunction, which were inhibited by zinc as low as 10 μM but not by 2 mM NAC. These results suggest that chronic ethanol exposure induced in ER and mitochondrial zinc deficiency might activate intrinsic cell death signaling pathway, which could not be effectively rescued by antioxidant treatment. [ABSTRACT FROM AUTHOR]

Zinc deficiency is a consistent phenomenon observed in patients with alcoholic liver disease, but the mechanisms have not been well defined. The objective of this study was to determine if alcohol alters hepatic zinc transporters in association with reduction of hepatic zinc levels and if oxidative stress mediates the alterations of zinc transporters. C57BL/6 mice were pair-fed with the Lieber-DeCarli control or ethanol diets for 2, 4, or 8 wk. Chronic alcohol exposure reduced hepatic zinc levels, but increased plasma and urine zinc levels, at all time points. Hepatic zinc finger proteins, peroxisome proliferator-activated receptor-α (PPAR-α) and hepatocyte nuclear factor 4α (HNF-4α), were downregulated in ethanol-fed mice. Four hepatic zinc transporter proteins showed significant alterations in ethanol-fed mice compared with the controls. ZIP5 and ZIP14 proteins were downregulated, while ZIP7 and ZnT7 proteins were upregulated, by ethanol exposure at all time points. Immunohistochemical staining demonstrated that chronic ethanol exposure upregulated cytochrome P-450 2E1 and caused 4-hydroxynonenal accumulation in the liver. For the in vitro study, murine FL-83B hepatocytes were treated with 5 μM 4-hydroxynonenal or 100 μM hydrogen peroxide for 72 h. The results from in vitro studies demonstrated that 4-hydroxynonenal treatment altered ZIP5 and ZIP7 protein abundance, and hydrogen peroxide treatment changed ZIP7, ZIP14, and ZnT7 protein abundance. These results suggest that chronic ethanol exposure alters hepatic zinc transporters via oxidative stress, which might account for ethanol-induced hepatic zinc deficiency. [ABSTRACT FROM AUTHOR]

Features a study which investigated the therapeutic effects of vanadium in diabetic rats. Overview of the mechanism of action of vanadium and vanadium theraphy; Methodology and results; Analysis of results.

Studies the effects of triiodothyronine (T3) on the electrophysiological properties of ventricular myocytes isolated from euthyroid and hypothyroid rats using whole cell patch clamp techniques. Prolonged action potential duration shown by hypothyroid ventricular myocytes; Unaffected transient outward current with the acute application of T3.

Investigates the role of epsilon protein kinase C isozyme in the regulation of cardiac sodium channels. Methods in the conduct of the study; Determination of cell excitability and velocity of action potential; Effects of phorbol 12-nyristate 13-acetate inhibition expressed in xenopus oocytes.

Examines the role of epsilon protein kinase C isozyme in the regulation of cardiac calcium ion channels. Use of novel peptide-specific inhibitors; Identification of isozymes that mediates the regulation of calcium ion channels; Evidence of the peptide translocation activator for epsilon protein kinase C.

Liver ischemia-reperfusion (I/R) injury occurs through induction of oxidative stress and release of damage-associated molecular patterns (DAMPs), including cytosolic DNA released from dysfunctional mitochondria or from the nucleus. Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) is a cytosolic DNA sensor known to trigger stimulator of interferon genes (STING) and downstream type 1 interferon (IFN-I) pathways, which are pivotal innate immune system responses to pathogen. However, little is known about the role of cGAS/STING in liver I/R injury. We subjected C57BL/6 (WT), cGAS knockout (cGAS-/-), and STING-deficient (STINGgt/gt) mice to warm liver I/R injury and that found cGAS-/- mice had significantly increased liver injury compared with WT or STINGgt/gt mice, suggesting a protective effect of cGAS independent of STING. Liver I/R upregulated cGAS in vivo and also in vitro in hepatocytes subjected to anoxia/reoxygenation (A/R). We confirmed a previously published finding that hepatocytes do not express STING under normoxic conditions or after A/R. Hepatocytes and liver from cGAS-/- mice had increased cell death and reduced induction of autophagy under hypoxic conditions as well as increased apoptosis. Protection could be restored in cGAS-/- hepatocytes by overexpression of cGAS or by pretreatment of mice with autophagy inducer rapamycin. Our findings indicate a novel protective role for cGAS in the regulation of autophagy during liver I/R injury that occurs independently of STING. [ABSTRACT FROM AUTHOR]