Effects Of Hypo Research Articles

MO442ACUTE ADVERSE EFFECTS OF LOW POTASSIUM ON HEART AND KIDNEY*

Abstract Background and Aims Chronic hypokalemia causes kidney fibrosis with cystic lesions and arterial hypertension. In contrast, potassium-rich diet lowers blood pressure. The acute effects of hypo- and hyperkalemia on heart and kidney are not well understood. Method Wild-type mice were fed with low (LK), normal (NK) and high (HK) potassium diet for 4 and 20 days. Kidneys were examined for site of acute injury, inflammation and fibrosis. Blood analysis of electrolytes and kidney parameters were analyzed. Echocardiography and ECG were used to assess heart function. Further, KCNJ10 knockout mice were used to investigate kidney damage in a genetically induced hypokalemia model. Results Proximal tubule injury as detected by KIM-1+ staining and yH2AX+ DNA-damage was observed after 4 and 20 days of LK diet. Injury was associated with strong Ki-67+ proliferation of proximal tubule cells. No injury was detected in mice on NK and HK diet. After 20 days of LK diet, F4/80+ inflammation and aSMA+ extracellular matrix accumulation, typical for fibrosis, were observed. LK mice developed polyurie, volume depletion, loss of body weight and high BUN. Lower cardiac output and signs of myocardial stress was seen in echocardiography and ECG. Consistent with WT mice on LK diet, KCNJ10 knockout mice developed same pattern of kidney injury. Nine months after deletion of KCNJ10, cysts were observed in the proximal tubule in outer medzulla. Conclusion Acute hypokalemia causes kidney injury and myocardial stress. Cystic lesions originate from late proximal tubule. Hypokalemia should be corrected rapidly to stop progression into kidney fibrosis.

Modulation of Glucose Availability and Effects of Hypo- and Hyperglycemia on Status Epilepticus: What We Do Not Know Yet?

Status epilepticus (SE) can lead to serious neuronal damage and act as an initial trigger for epileptogenic processes that may lead to temporal lobe epilepsy (TLE). Besides promoting neurodegeneration, neuroinflammation, and abnormal neurogenesis, SE can generate an extensive hypometabolism in several brain areas and, consequently, reduce intracellular energy supply, such as adenosine triphosphate (ATP) molecules. Although some antiepileptic drugs show efficiency to terminate or reduce epileptic seizures, approximately 30% of TLE patients are refractory to regular antiepileptic drugs (AEDs). Modulation of glucose availability may provide a novel and robust alternative for treating seizures and neuronal damage that occurs during epileptogenesis; however, more detailed information remains unknown, especially under hypo- and hyperglycemic conditions. Here, we review several pathways of glucose metabolism activated during and after SE, as well as the effects of hypo- and hyperglycemia in the generation of self-sustained limbic seizures. Furthermore, this study suggests the control of glucose availability as a potential therapeutic tool for SE.

783-P: Can Mood and Energy Levels Be Predicted by Preceding Glucose Values? Combining Ecological Momentary Assessment (EMA) and Continuous Glucose Monitoring (CGM)

For association with glycemic control, psychosocial research almost exclusively used retrospective questionnaire data to assess psychosocial outcomes. Little is known about the immediate, real-time effects of glucose values on psychosocial outcomes. In an observational study, 152 people with type 1 diabetes were equipped with CGM and completed a Smartphone-based EMA-survey 4-times a day over 18 days. Participants rated their mood and energy level separately on a single-item scale from 0 (very poor) to 10 (very good). Glucose data 90 minutes prior to each rating was extracted and mean glucose, time in range, time in hypoglycemic ranges (<70, <55 mg/dl), time in hyperglycemic ranges (>180, >250 mg/dl), and the mean absolute difference (MAD) of consecutive glucose values were calculated. Multilevel regression analyses were conducted with mood and energy levels as dependent variables and each parameter of glycemic control (90min prior) as independent variable, controlled for the overall level of glycemic control. Better mood was significantly predicted by lower mean glucose levels (p=.003), higher time in range (p=.003), and less hyperglycemic values (>180 mg/dl: p=.021; >250 mg/dl: p=.002). No significant associations were found for hypoglycemic values and MAD. Higher energy levels were significantly predicted by lower mean glucose levels (p=.012), higher time in range (p=.001), less hypoglycemic values (<70 mg/dl: p<.001; <54 mg/dl: p=.023), less values in the severe hyperglycemic range (>250 mg/dl: p<.001). Lower MAD predicted higher energy levels (p=.047). Ratings of mood and energy were significantly affected by immediately preceding glucose levels. While hyperglycemic values were more important for mood, hypoglycemic values were more important for energy. These preliminary findings have important implications for our understanding of real-time effects of hypo- and hyperglycemic glucose levels. Disclosure D. Ehrmann: Speaker’s Bureau; Self; Abbott, Berlin-Chemie AG, Glooko, Inc. Other Relationship; Self; Dexcom, Inc., Roche Diabetes Care. A.J. Schmitt: None. P. Rubertus: None. B. Kulzer: Research Support; Self; Abbott, AstraZeneca, Berlin-Chemie AG, Roche Diabetes Care. Speaker’s Bureau; Self; Abbott, Ascensia Diabetes Care, Berlin-Chemie AG, Eli Lilly and Company, Medtronic, Novo Nordisk Inc., Roche Diabetes Care. N. Hermanns: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, AstraZeneca, Berlin-Chemie AG. Funding German Center for Diabetes Research (FKZ82DZD1102A)

Impaired Cardiovascular Function in Male Rats with Hypo- and Hyperthyroidism: Involvement of Imbalanced Nitric Oxide Synthase Levels.

All three isoforms of nitric oxide (NO) synthase (NOS) are targets for thyroid hormones in the cardiovascular system. The aim of this study was to assess the effects of hypo- and hyperthyroidism on inducible (iNOS), endothelial (eNOS), and neural (nNOS) NOS levels in aorta and heart tissues of male rats. Rats were divided into control, hypothyroid, and hyperthyroid groups; hypo- and hyperthyroidism were induced by adding propylthiouracil (500 mg/L) and L-thyroxine (12 mg/L) to drinking water for a period of 21 days. On day 21, systolic blood pressure, heart rate, left ventricular developed pressure (LVDP), peak rate of positive and negative (±dp/dt) changes in left ventricular pressure as well as NO metabolites (NOx) and iNOS, eNOS, and nNOS protein levels in aorta and heart, were all measured. Compared to controls, LVDP and ±dp/dt were lower in both hypo- and hyperthyroid rats. Compared to controls, heart rate and systolic blood pressure were lower in hypothyroid and higher in hyperthyroid rats. NOx levels in the heart of hypothyroid rats were lower (53%), whereas that in hyperthyroid rats were higher (56% and 40%) than controls. Compared to controls, hypothyroid rats had lower levels of eNOS, iNOS, and nNOS in the aorta (16%, 34%, and 15%, respectively) and lower iNOS and higher nNOS in heart tissue (27% and 46%). In hyperthyroid rats, eNOS levels were lower (54% and 30%) and iNOS were higher (63%, and 35%) in the aorta and heart while nNOS was lower in the aorta (18%). Hypothyroidism increased while hyperthyroidism decreased the ratio of eNOS/iNOS in aorta and heart; these changes of NOS levels were associated with impaired cardiovascular function.

A multi-scale model for determining the effects of pathophysiology and metabolic disorders on tumor growth

The search for efficient chemotherapy drugs and other anti-cancer treatments would benefit from a deeper understanding of the tumor microenvironment (TME) and its role in tumor progression. Because in vivo experimental methods are unable to isolate or control individual factors of the TME and in vitro models often do not include all the contributing factors, some questions are best addressed with systems biology mathematical models. In this work, we present a new fully-coupled, agent-based, multi-scale mathematical model of tumor growth, angiogenesis and metabolism that includes important aspects of the TME spanning subcellular-, cellular- and tissue-level scales. The mathematical model is computationally implemented for a three-dimensional TME, and a double hybrid continuous-discrete (DHCD) method is applied to solve the governing equations. The model recapitulates the distinct morphological and metabolic stages of a solid tumor, starting with an avascular tumor and progressing through angiogenesis and vascularized tumor growth. To examine the robustness of the model, we simulated normal and abnormal blood conditions, including hyperglycemia/hypoglycemia, hyperoxemia/hypoxemia, and hypercarbia/hypocarbia – conditions common in cancer patients. The results demonstrate that tumor progression is accelerated by hyperoxemia, hyperglycemia and hypercarbia but inhibited by hypoxemia and hypoglycemia; hypocarbia had no appreciable effect. Because of the importance of interstitial fluid flow in tumor physiology, we also examined the effects of hypo- or hypertension, and the impact of decreased hydraulic conductivity common in desmoplastic tumors. The simulations show that chemotherapy-increased blood pressure, or reduction of interstitial hydraulic conductivity increase tumor growth rate and contribute to tumor malignancy.

Both experimental hypo- and hyper-thyroidism exacerbate the adverse effects of chronic heat stress in broilers

ABSTRACT 1. The effects of hypo- and hyper-thyroidism in mitigating or exacerbating the negative changes of chronic heat stress (HS) in broilers were investigated. 2. Three-week-old broilers were distributed into six groups (n = 13 per group). Three groups were housed at ambient room temperature: control group (CN), propylthiouracil-treated group (AN) and thyroxine-treated group (TN). The other three groups were exposed to HS at 33 ± 1°C for 2 weeks: control heat stress (CH), propylthiouracil + heat stress (AH) and thyroxine + HS (TH). 3. Induced hypothyroidy significantly decreased cloacal temperature and body weight gain in the birds in both the normal and HS groups (AN, AH). Conversely, hyperthyroidy resulted in a significant elevation in cloacal temperature in the TN and TH groups and a significant decline in weight gain in the TH group. Hyperthyroidy exacerbated the HS-induced degenerative changes in jejunal mucosa and caused noticeable vascular changes. A significant increase in the expression levels of jejunal nutrient transporter genes was observed in the AH and TH groups. The hyperthyroidic state significantly upregulated the HSP70 expression level in the TH group and the reverse occurred with propylthiouracil (PTU) treatment in the AH group. 4. PTU supplementation to chicks reared under HS significantly decreased the triiodothyronine level, antibody (Ab) titre, and increased the heterophil-lymphocyte ratio. Furthermore, it induced higher hepatic glutathione peroxidase (GSH-Px) activity in the AN and AH groups and decreased the malondialdehyde content (MDA) in the AN group. Hyperthyroidy significantly increased triiodothyronine concentration, H/L ratio and decreased Hb concentration and Ab titres in the TH group. Additionally, this status increased the MDA content and decreased the GSH-Px activities. 5. In conclusion, manipulation of thyroid status is not a remedy to overcome the undesirable effects of HS in broilers.

Thyroid hormones and female reproduction.

Thyroid hormones are vital for the proper functioning of the female reproductive system, since they modulate the metabolism and development of ovarian, uterine, and placental tissues. Therefore, hypo- and hyperthyroidism may result in subfertility or infertility in both women and animals. Other well-documented sequelae of maternal thyroid dysfunctions include menstrual/estral irregularity, anovulation, abortion, preterm delivery, preeclampsia, intrauterine growth restriction, postpartum thyroiditis, and mental retardation in children. Several studies have been carried out involving prospective and retrospective studies of women with thyroid dysfunction, as well as in vivo and in vitro assays of hypo- and hyperthyroidism using experimental animal models and/or ovarian, uterine, and placental cell culture. These studies have sought to elucidate the mechanisms by which thyroid hormones influence reproduction to better understand the physiology of the reproductive system and to provide better therapeutic tools for reproductive dysfunctions that originate from thyroid dysfunctions. Therefore, this review aims to summarize and update the available information related to the role of thyroid hormones in the morphophysiology of the ovary, uterus, and placenta in women and animals and the effects of hypo- and hyperthyroidism on the female reproductive system.

Motor units at various temperatures

This review focuses on the effects of temperature on the functioning of the neuromuscular system. The changes in environmental temperature could affect the contractile acts in both ectotherms and endotherms by changing the amplitude and velocity of contractions and, accordingly, the mechanical work of skeletal muscles. In this study, we summarize the data on the effects of hypo- and hyperthermia on the supraspinal and peripheral components of regulation of the neuromuscular function.

Joseph Altman (1925–2016): A life in neurodevelopment

Joseph Altman (1925–2016): A life in neurodevelopment

Thyroid hormones regulate skeletal muscle regeneration after acute injury.

We evaluated the effects of hypo- and hyperthyroid statuses during the initial phase of skeletal muscle regeneration in rats. To induce hypo- or hyperthyroidism, adult male Wistar rats were treated with methimazole (0.03%) or T4 (10 μg/100 g), respectively, for 10 days. Three days before sacrifice, a crush injury was produced in the solear muscles of one half of the animals, while the other half remained intact. T3, T4, TSH, and leptin serum levels were not affected by the injury. Serum T3 and T4 levels were significantly increased in hyperthyroid and hyper-injury animals. Hypothyroidism was confirmed by the significant increase in serum TSH levels in hypothyroid and hypo-injury animals. Injury increased cell infiltration and macrophage accumulation especially in hyperthyroid animals. Both type 2 and type 3 deiodinases were induced by lesion, and the opposite occurred with the type 1 isoform, at least in the control and hyperthyroid groups. Injury increased both MyoD and myogenin expression in all the studied groups, but only MyoD expression was increased by thyroidal status only at the protein level. We conclude that thyroid hormones modulate skeletal muscle regeneration possibly by regulating the inflammatory process, as well as MyoD and myogenin expression in the injured tissue.

Migraine and Neurological Disorders Comorbidity-Consideration of Sinus Hypoxic Nitric Oxide Theory for Migraine

Migraine is an extremely common disorder and has co morbidity with many neurological illnesses. After reviewing the neurophysiological and biochemical basis of the research findings and hypotheses of migraine and other neurological disorders I present to the best of my knowledge the first para nasal sinus nitric oxide mediated neurobiophysiological explanation for many neurological disorders. The etiology of neurological illnesses is mainly due to neurotransmitter imbalance, neurodegenerative changes acute and chronic inflammation, effects of hypo and hyper endothelial and neuronal NO levels and genetic predisposition. According to this para nasal sinus nitric oxide based description those effects are mainly brought on by the sinorhinogenic impulse distribution of the central nervous system except genetic predisposition. Moreover, avoidance of the central neuronal influence and stress to the brain in early childhood or young age caused by migraine would help to prevent the progression or aggravation of the neurological illnesses. Indeed this article explains a new pathophysiological initiation between sino rhinogenic nitric oxide effects and neurological disorders and provides an etiologically important Neuro vascular impulse generating pathway to cause or aggravate neurological disorders. Therefore the patients who are clinically suspected of having migraine headache and neurological disorders or along with susceptible neurological disorders should receive comprehensive sinorhinological examination and evaluation based on the sinus hypoxic nitric oxide phenomena. A standard surgical and medical management of migraine that links with the sinus hypoxic nitric oxide theory are suggested to be used for even neurological disorder as a new treatment of neurological illnesses and to prevent the dysfunction of central specific neural circuits.

Effects of thyroid status on NEI concentration in specific brain areas related to reproduction during the estrous cycle

We previously showed that short-term hypo- and hyperthyroidism induce changes in neuropeptide glutamic-acid-isoleucine-amide (NEI) concentrations in discrete brain areas in male rats. To investigate the possible effects of hypo- and hyperthyroidism on NEI concentrations mainly in hypothalamic areas related to reproduction and behavior, female rats were sacrificed at different days of the estrous cycle. Circulating luteinizing hormone (LH), estradiol and progesterone concentrations were measured in control, hypothyroid (hypoT, treated with PTU during 7–9 days) and hyperthyroid (hyperT, l-T4 during 4–7 days) animals. Both treatments blunted the LH surge. Hypo- and hyperthyroidism increased estradiol concentrations during proestrus afternoon (P-PM), although hypoT rats showed lower values compared to control during proestrus morning (P-AM). Progesterone levels were higher in all groups at P-PM and in the hyperT during diestrus morning (D2). NEI concentrations were lower in hypoT rats during the estrous cycle except in estrus (E) in the peduncular part of the lateral hypothalamus (PLH). They were also reduced by both treatments in the perifornical part of the lateral hypothalamus (PeFLH) during P-PM. Hypothyroidism led to higher NEI concentrations during P-PM in the organum vasculosum of the lamina terminalis and anteroventral periventricular nucleus (OVLT+AVPV). The present results indicate that NEI concentration is regulated in a complex manner by hypo- and hyperthyroidism in the different areas studied, suggesting a correlation between NEI values and the variations of gonadal steroid levels during estrous cycle. These changes could be, in part, responsible for the alterations observed in the hypothalamic–pituitary–gonadal axis in these pathologies.

Effects of hypo- and hyperthyroid states on herpes simplex virus infectivity in the rat

Objective: Available data from in vitro studies show that thyroid hormones (THs) regulate herpes simplex virus (HSV) gene expression and may modulate latency/reactivation of the virus. Whether infectivity of the virus is also affected by THs is not known. Using animal models (in vivo study) and Vero cell culture (in vitro study), we examined the effects of alterations in THs level on HSV-1 infectivity. Methods: Rats were rendered hypo- and hyperthyroid by daily addition of methimazole and l-thyroxine into their drinking water, respectively. Euthyroid animals served as control. All animals were given a single dose of HSV-1 (107TCID50, ip) and sacrificed 3 d later. The spleen of the animals was then removed and viral particles were recovered from the tissue extract through aseptic procedures. Serial dilution of the extracts was prepared and added to Vero cell culture. For the in vitro study, the cultures were pretreated with l-thyroxine and the viral particles were then added. Virus titration was determined by Reed–Muench quantal assay. Results: The viral load of spleen in hyperthyroid rats was significantly lower (1000-fold) than that of the euthyroid rats. Similarly, in vitro presence of supraphysiologic levels of l-thyroxine in the culture media of Vero cells decreased virus infectivity. Interestingly, hypothyroid animals showed a significant increase (10-fold) in spleen viral load as compared to that of their euthyroid counterparts. Conclusions: These data clearly show that the HSV-1 infectivity is affected by THs, and suggest that THs or their analogs may have a potential application in prevention and/or treatment of viral infections.

Effects of Hypo‐ and Hyperthyroidism on Proliferation, Angiogenesis, Apoptosis and Expression of COX‐2 in the Corpus Luteum of Female Rats

Although thyroid dysfunction occurs frequently in humans and some animal species, the mechanisms by which hypo- and hyperthyroidism affect the corpus luteum have not been thoroughly elucidated. This study evaluated the levels of proliferative activity, angiogenesis, apoptosis and expression of cyclooxygenase-2 in the corpus luteum of female rats with thyroid dysfunction. These processes may be important in understanding the reproductive changes caused by thyroid dysfunction. A total of 18 adult female rats were divided into three groups (control, hypothyroid and hyperthyroid) with six animals per group. Three months after treatment to induce thyroid dysfunction, the rats were euthanized in the dioestrus phase. The ovaries were collected and immunohistochemically analysed for expression of the cell proliferation marker CDC-47, vascular endothelial growth factor (VEGF), VEGF receptor Flk-1 and cyclooxygenase-2 (COX-2). Apoptosis was evaluated using the TUNEL assay. Hypothyroidism reduced the intensity and area of COX-2 expression in the corpus luteum (p<0.05), while hyperthyroidism did not alter COX-2 expression in the dioestrus phase. Hypothyroidism significantly reduced the expression of CDC-47 in endothelial cells and pericytes in the corpus luteum, whereas hyperthyroidism did not induce a detectable change in CDC-47 expression (p>0.05). Hypothyroidism reduced the level of apoptosis in luteal cells (p<0.05) and increased VEGF expression in the corpus luteum. In contrast, hyperthyroidism increased the level of apoptosis in the corpus luteum (p<0.05). In conclusion, thyroid dysfunction differentially affects the levels of proliferative activity, angiogenesis and apoptosis and COX-2 expression in the corpus luteum of female rats.

Hyperthermia-induced micronucleus formation in a human keratinocyte cell line

Elevated temperature can cause biological effects in vitro and in vivo. Many studies on effects of hypo- and hyperthermia have been conducted, but only few studies systematically investigated the formation of genomic damage in the micronucleus test in human cells in vitro as a consequence of different temperatures.In the present study, HaCaT human keratinocytes were exposed to different temperatures from 37°C to 42°C for 24h in a regular cell culture incubator.Micronucleus frequency as a marker of genomic damage was elevated in a temperature-dependent and statistically significant manner. Apoptosis occurred at temperatures of 39°C or higher. Cell proliferation was unaffected up to 40°C and decreased at 41°C and 42°C. Expression of the heat shock protein Hsp70 was elevated, particularly at temperatures of 40°C and higher.These findings are in agreement with several in vivo studies and some in vitro studies looking at single, specific temperatures, but a systematically investigated temperature-dependent increase of genomic damage in human keratinocytes in vitro is demonstrated for the first time here.

Effects of hypo- or hyperosmotic stress on lipid synthesis and gluconeogenic activity in tissues of the crab Neohelice granulata

The present study assesses the effects of osmotic stress on phosphoenolpyruvate carboxykinase (PEPCK), fructose 1,6-bisphosphatase (FBPase) and glucose 6-phosphatase (G6Pase) activities and 14C-total lipid synthesis from 14C-glycine in the anterior and posterior gills, jaw muscle, and hepatopancreas of Neohelice granulata. In posterior gills, 24-h exposure to hyperosmotic stress increased PEPCK, FBPase and G6Pase activities. Increase in 14C-lipid synthesis was associated to the decrease in PEPCK activity after 72-h exposure to hyperosmotic stress. Hypo-osmotic stress decreased PEPCK and G6Pase activities in posterior gills; however, 14C-lipids increased after 72-h exposure to stress. In anterior gills, decreases in the G6Pase activity after 72-h of hyperosmotic stress and in 14C-lipogenesis after 144-h were observed, while PEPCK activity increased after 144h. Exposure to hypo-osmotic stress increased 14C-lipid synthesis and PEPCK activity in anterior gills. Muscle G6Pase activity increased after 72-h exposure to hypo-osmotic stress; however, no significant change was observed in the lipogenesis. PEPCK decreased in muscle after 144-h exposure to hyperosmotic, coinciding with increased 14C-lipid synthesis. In the hepatopancreas, a decrease in the 14C-lipogenesis occurred after 24-h exposure to hyperosmotic stress, accompanied by increase in 14C-lipid synthesis. Additionally, PEPCK activity returned to control levels. The hepatopancreatic lipogenesis from amino acids was not involved in the metabolic adjustment during hypo-osmotic stress. However, gluconeogenesis is one of the pathways involved in the adjustment of the intracellular concentration of nitrogenated compounds.

Effect of hypohydration and altitude exposure on aerobic exercise performance and acute mountain sickness

Hypoxia often causes body water deficits (hypohydration, HYPO); however, the effects of HYPO on aerobic exercise performance and prevalence of acute mountain sickness (AMS) at high altitude (ALT) have not been reported. We hypothesized that 1) HYPO and ALT would each degrade aerobic performance relative to sea level (SL)-euhydrated (EUH) conditions, and combining HYPO and ALT would further degrade performance more than one stressor alone; and 2) HYPO would increase the prevalence and severity of AMS symptoms. Seven lowlander men (25 ± 7 yr old; 82 ± 11 kg; mean ± SD) completed four separate experimental trials. Trials were 1) SL-EUH, 2) SL-HYPO, 3) ALT-EUH, and 4) ALT-HYPO. In HYPO, subjects were dehydrated by 4% of body mass. Subjects maintained hydration status overnight and the following morning entered a hypobaric chamber (at SL or 3,048 m, 27°C) where they completed 30 min of submaximal exercise immediately followed by a 30-min performance time trial (TT). AMS was measured with the Environmental Symptoms Questionnaire-Cerebral Score (AMS-C) and the Lake Louise Scoring System (LLS). The percent change in TT performance, relative to SL-EUH, was -19 ± 12% (334 ± 64 to 278 ± 87 kJ), -11 ± 10% (334 ± 64 to 293 ± 33 kJ), and -34 ± 22% (334 ± 64 to 227 ± 95 kJ), for SL-HYPO, ALT-EUH, and ALT-HYPO, respectively. AMS symptom prevalence was 2/7 subjects at ALT-EUH for AMS-C and LLS and 5/7 and 4/7 at ALT-HYPO for AMS-C and LLS, respectively. The AMS-C symptom severity score (AMS-C score) tended to increase from ALT-EUH to ALT-HYPO but was not significant (P = 0.07). In conclusion, hypohydration at 3,048 m 1) degrades aerobic performance in an additive manner with that induced by ALT; and 2) did not appear to increase the prevalence/severity of AMS symptoms.

Abstract 859: Hypoxia-activated CXCR4 Expression In Cardiac Progenitor Cells For Replenishing Stem Cell Pool In Acute Ischemic Myocardium

The resident cardiac progenitor cells (CPCs) have been identified in the adult myocardium, however, the CPC pool is rapidly depleted after acute myocardial infarction (AMI). The strategy to home ex vivo cultured CPCs to ischemic myocardium might be an important strategy to replenish resident CPC pool, and improve cardiac function. The CXC chemokine SDF-1α and its receptor CXCR4 have been identified as critical mediator for the ischemia-specific recruitment of progenitor cells, yet the level of CXCR4 expression in CPCs is quite low in normal conditions. Our previous studies showed that hypoxia can optimize CPCs via inducing functional CXCR4 expression in vitro, therefore, in this study, we want to investigate whether the transplantation of hypoxia treated CPCs (Hypo:CPCs) have the benefit of improving cardiac function resulted from increased cell homing in ischemic myocardium through mechanisms of hypoxia induced CXCR4 expression. To compare the homing capability between CPCs and Hypo:CPCs in response to endogenous SDF-1 signal in acute ischemic myocardium, we used retrovirus (pCL-MFG-β-gal) to label c-kit + Lin − CPCs with β-gal, and then injected labeled CPCs and Hypo:CPCs (1×10 6 ) intravenously via intra-jugular vein to mice 10 min after induction of MI in the C56BL/6 mice. We harvested the hearts 1d after cell transplantation to quantify the cell retention by chemiluminescent β-galactosidase assay. We observed that hypoxia treatment resulted in about 2.5 fold increase in β-gal cell recruitment in ischemic hearts (p&lt;0.001, n=7– 8/group), however, AMD3100 can partially reduce Hypo:CPCs homing, therefore, the beneficial effects of Hypo:CPCs transplantation were mediated primarily through increasing cell homing via SDF-1:CXCR4 binding within the ischemic hearts. In addtion, the infusion of Hypo:CPCs also led to improved left ventricular performance, as assessed by LV development pressure by Millar catheter, by 23.67% compared with CPCs at 1 month after cell therapy (p&lt;0.001, n=6/group). These results indicate that replenish CPC pool after AMI using ex vivo cultured CPC transplantation has significant beneficial effects on injured heart function dependent of hypoxia induced CXCR4 upregulation.

Changes in Osmolality Sensitize the Response to Capsaicin in Trigeminal Sensory Neurons

Changes in tonicity in the peripheral nervous system can activate nociceptors and produce pain. Under local inflammatory conditions the peripheral terminals of nociceptors are subject to deviations from isotonicity. Previously it was shown that several members of the TRP(V) family of ion channels are responsive to changes in tonicity. Here we explore how changes in tonicity affect TRPV1 receptor-mediated responses to capsaicin in dissociated rat trigeminal ganglion (TG) neurons. Using whole cell patch-clamp and calcium imaging, we found that mild anisotonicity (260 and 348 mOsm/kg for hypotonicity and hypertonicity, respectively) strikingly sensitized the capsaicin-evoked current, I(caps). Confocal immunolocalization studies also revealed a modest anisotonicity-mediated redistribution of TRPV1 toward the plasma membrane of TG neurons. With respect to downstream signaling pathways, tonicity-induced sensitization of I(caps) was dependent on whether hypo- or hypertonic stimuli were applied. Specifically, antagonism of PKA- and PI3K-activated pathways appreciably reduced the hypertonicity-induced sensitization of I(caps), whereas inhibition of PKC-mediated pathways selectively reduced the sensitization produced by hypotonic solutions. In summary, whereas the overall effects of hypo- and hypertonicity resulted in a similar pattern of potentiation of I(caps), intracellular signaling pathways were selective for hypo- versus hypertonicity-induced tuning of capsaicin-activated currents.

Effects of hypo- and hyperoxia on transcription levels of five stress genes and the glutathione system in liver of Atlantic cod Gadus morhua

The transcript levels of three genes coding for antioxidants, Cu/Zn superoxide dismutase (SOD), catalase and phospholipid hydroperoxide glutathione peroxidase (GSH-Px), and those of two stress proteins, metallothionein (MT) and CYP1A, were examined with real-time quantitative (q) RT-PCR in hepatic tissue of Atlantic cod exposed to 46% (hypoxia), 76% (normoxia) and 145% (hyperoxia) O(2) saturation (tank outlet). To evaluate the oxidative stress state, the levels of total glutathione (tGSH), reduced glutathione (GSH) and oxidized glutathione (GSSG) and subsequently the oxidative stress index (OSI), were determined in the same tissue samples. The transcript level of GSH-Px was significantly upregulated in fish exposed to hyperoxia, and significantly downregulated in fish exposed to hypoxia, compared to the normoxia group. Significant downregulation was also found for SOD and CYP1A transcriptional levels in fish exposed to hypoxia. The transcript levels of catalase and MT did not change in liver of cod exposed to suboptimal oxygen levels. No significant differences were seen between the groups for tGSH, GSH, GSSG or OSI. Prolonged exposure to unfavourable oxygen saturation levels did not alter the OSI, indicating that the antioxidant glutathione system is maintained at an unchanged level in liver of the examined cod.