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PubMed1994

Daily exercise improved blood pressure homeostasis of rats subjected to surgical stress.

The effect of daily spontaneous running on blood pressure homeostasis (BPH) was evaluated in 19 male and 13 female control rats and 7 male and 13 female daily spontaneous running rats subjected to surgery and subsequent repetitive hemodynamic disturbances. BPH was operationally defined as the ability to maintain mean arterial pressure above 60 mmHg during the experimental protocol. The length of time the rats maintained BPH was compared across males and females and trained and control groups. Significant sex (P = 0.01) and training (P = 0.05) effects were found. Females maintained homeostasis longer than males and trained longer than controls. Sex effects were not due to differences in the body mass. The mechanisms responsible for the higher resistance to deterioration of homeostasis merit further investigation.

Animals↗
PubMed2000

CO(2) homeostasis during periodic breathing in obstructive sleep apnea.

The contribution of apnea to chronic hypercapnia in obstructive sleep apnea (OSA) has not been clarified. Using a model (D. M. Rapoport, R. G. Norman, and R. M. Goldring. J. Appl. Physiol. 75: 2302-2309, 1993), we previously illustrated failure of CO(2) homeostasis during periodic breathing resulting from temporal dissociation between ventilation and perfusion ("temporal V/Q mismatch"). This study measures acute kinetics of CO(2) during periodic breathing and addresses interapnea ventilatory compensation for maintenance of CO(2) homeostasis in 11 patients with OSA during daytime sleep (37-171 min). Ventilation and expiratory CO(2) and O(2) fractions were measured on a breath-by-breath basis by means of a tight-fitting full facemask. Calculations included CO(2) excretion, metabolic CO(2) production, and CO(2) balance (metabolic CO(2) production - exhaled CO(2)). CO(2) balance was tabulated for each apnea/hypopnea event-interevent cycle and as a cumulative value during sleep. Cumulative CO(2) balance varied (-3,570 to +1,388 ml). Positive cumulative CO(2) balance occurred in the absence of overall hypoventilation during sleep. For each cycle, positive CO(2) balance occurred despite increased interevent ventilation to rates as high as 45 l/min. This failure of CO(2) homeostasis was dependent on the event-to-interevent duration ratio. The results demonstrate that 1) periodic breathing provides a mechanism for acute hypercapnia in OSA, 2) acute hypercapnia during periodic breathing may occur without a decrease in average minute ventilation, supporting the presence of temporal V/Q mismatch, as predicted from our model, and 3) compensation for CO(2) accumulation during apnea/hypopnea may be limited by the duration of the interevent interval. The relationship of this acute hypercapnia to sustained chronic hypercapnia in OSA remains to be further explored.

Adult↗
PubMed2001

Ren1d and Ren2 cooperate to preserve homeostasis: evidence from mice expressing GFP in place of Ren1d.

To distinguish the contributions of Ren1(d) and Ren2 to kidney development and blood pressure homeostasis, we placed green fluorescent protein (GFP) under control of the Ren1(d) renin locus by homologous recombination in mice. Homozygous Ren1(d)-GFP animals make GFP mRNA in place of Ren1(d) mRNA in the kidney and maintain Ren2 synthesis in the juxtaglomerular (JG) cells. GFP expression provides an accurate marker of Ren1(d) expression during development. Kidneys from homozygous animals are histologically normal, although with fewer secretory granules in the JG cells. Blood pressure and circulating renin are reduced in Ren1(d)-GFP homozygotes. Acute administration of losartan decreases blood pressure further, suggesting a role for Ren2 protein in blood pressure homeostasis. These studies demonstrate that, in the absence of Ren1(d), Ren2 preserves normal kidney development and prevents severe hypotension. Chronic losartan treatment results in compensation via recruitment of both Ren1(d)- and Ren2-expressing cells along the preglomerular vessels. This response is achieved by metaplastic transformation of arteriolar smooth muscle cells, a major mechanism to control renin bioavailability and blood pressure homeostasis.

Angiotensin Receptor Antagonists↗
PubMed2026

GFER Represents a Target for Dual Disruption of Redox Homeostasis and Reactivation of the Immune Response in Pancreatic Adenocarcinoma.

UNLABELLED: Both metabolic dysregulation and the immunosuppressive tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) contribute to the recalcitrance of this lethal disease to treatment. Accordingly, we aimed to identify and characterize a target that elicits an anticancer response through both disrupting cancer cell redox homeostasis and increasing the immunogenicity of PDAC. First, mitochondrial metabolic dependencies in PDAC were identified by using a CRISPR-Cas9 screening system with a custom single-guide RNA library. Functional validation analyses revealed GFER, a mitochondrial FAD-dependent sulfhydryl oxidase, as an essential regulator of tumor growth. In vitro and in vivo methodologies demonstrated that GFER depletion perturbed redox homeostasis and stimulated tumor immunogenicity, including sensitization to immune checkpoint blockade. In patient-derived xenograft models of PDAC, the growth-inhibitory response induced by GFER depletion was mediated by an altered oxidative balance that released damaged mitochondrial DNA into the cytoplasm of tumor cells, leading to the activation of the cGAS-STING pathway and expression of type I IFNs. This effect was recapitulated in a mouse immunocompetent syngeneic PDAC model, in which GFER depletion suppressed tumor growth and promoted T-cell infiltration to enhance tumor-killing effects. Consequently, GFER depletion significantly increased the antitumor efficacy of immune checkpoint blockade. Overall, these findings identify GFER as a critical node for both mitochondrial redox homeostasis and immunomodulation in PDAC and reveal a therapeutic opportunity for sensitizing PDAC to immune checkpoint blockade. SIGNIFICANCE: GFER is essential for mitochondrial redox balance and suppressing tumor immunogenicity in pancreatic tumors, with the combination of GFER inhibition with immune checkpoint blockade resulting in a strong antitumor response.

Animals↗
PubMed1998

The concept of an immune mechanism of chemical homeostasis and its importance in biology and medicine.

This paper outlines research that has led to the concept of the inevitable participation of the immune system in an organism's chemical homeostasis. This function of the immune system is tentatively named the 'immune mechanism of the chemical homeostasis' (IMCH). It is based on the theory of a permanent physiological synthesis of antibodies to endogenous biologically active substances. Minimal accumulation of biologically active substances as a result of the influence of different factors specifically activates the immune system in order to maintain its chemical homeostasis. The concept suggests the necessity of widening the notion of the range of the immune system's censorial functions. The concept explains the preexistence of immunocompetent cells preadapted to biologically active substances and autoantibodies specific to them; the natural clonality of the B lymphocyte pool; the polyclonal lymphocyte activation triggered by mitogens, foreign proteins, erythrocytes, and microbes, and tolerance to drugs.

Animals↗
PubMed2005

Chronically administered islet amyloid polypeptide in rats serves as an adiposity inhibitor and regulates energy homeostasis.

AIMS/HYPOTHESIS: Islet amyloid polypeptide (IAPP) reduces food intake and body weight in laboratory animals. In addition, IAPP appears to regulate nutrient metabolism. In the present studies, we investigated the effect of chronic IAPP treatment on different aspects of energy homeostasis. METHODS: IAPP was infused (25 pmol/kg/min) from subcutaneous osmotic pumps for 2-7 days. Rats in 2 saline-infused control groups were fed ad libitum (AF) or pair-fed (PF) against the IAPP-treated rats. RESULTS: As expected, the IAPP infusion reduced food intake and body weight gain. In addition, the IAPP treatment decreased the epididymal fat pad (vs. PF rats, p < 0.05) and lowered circulating levels of triglycerides (vs. PF rats, p < 0.05), free fatty acids (vs. PF rats, p < 0.05), leptin (vs. both AF and PF rats, p < 0.05) and insulin (vs. AF rats, p < 0.05). In contrast, glucose and protein metabolism in the IAPP-treated rats was largely unchanged, as shown in results regarding serum glucose, glucose transport in skeletal muscle, blood urea nitrogen, and glycogen and protein content in the liver and in skeletal muscle. CONCLUSION/INTERPRETATION: In summary, chronic IAPP exposure led to a changed lipid metabolism, which was characterized by decreased adiposity, hypolipidemia and hypoleptinemia, and to unchanged glucose and protein homeostasis. These results were similar to those seen in rodents during chronic exposure to another satiety/adiposity regulator, leptin. In conclusion, chronically administered IAPP plays a role as a satiety and adiposity signal in rats, and helps regulate energy homeostasis.

Adipose Tissue↗
PubMed2005

Homeostasis as basis of acute stroke treatment: stroke units are the key.

INTRODUCTION: Several studies suggest that the control of blood pressure (BP), blood glucose level, body temperature, and oxygen saturation, when analyzed separately, is related with successful acute stroke outcome. However, in a biological system these parameters are interrelated and could influence the process. Recent studies highlight the importance of the appropriate maintenance of these variables that are involved in homeostasis in patients with stroke and the influence they have on outcome. METHODS: A review was conducted of published studies which analyzed the influence of control of these physiological variables in acute stroke, whether in isolation or combinations, and we have contributed our own data derived from observational studies. RESULTS: The maintenance of homeostasis forms the basis of acute stroke treatment, in what is termed nonpharmacological neuroprotection. Stroke units (SU) are the ideal environment for this therapeutic approach since their favorable influence on the correct management of BP, body temperature, oxygen saturation, and blood glucose in the progress of stroke patients have been proved. CONCLUSIONS: The proper management of physiological variables (homeostasis) such as BP, body temperature, blood glucose, and oxygen saturation is the basis of acute stroke treatment, and SU are the key to this approach.

Blood Glucose↗
PubMed1995

Effects of growth hormone on phosphocalcium homeostasis and bone metabolism.

In this review the effects of growth hormone (GH) on phosphocalcium homeostasis and bone metabolism are reported. Some in vitro effects of GH on chondrocytes and osteoblasts are discussed too. The main GH effects on phosphocalcium homeostasis are the permissive action on renal 1 alpha-hydroxylase activity by the hypophosphatemic stimulus and the antiphosphaturic effect by the stimulation of the maximum rate of renal tubular reabsorption of phosphate. On bone, GH is able to stimulate bone turnover and to increase bone mass. In addition, GH stimulates type I and type III collagen metabolism. In vitro, GH increases the proliferation of chondrocytes from the human growing cartilage together with the levels of interleukin-6 in the supernatant. The hormone increases also the proliferation of the human osteosarcoma-derived osteoblast-like cells and augments the osteocalcin levels in the supernatant. Thus, GH markedly influences phosphocalcium homeostasis and bone metabolism in childhood and adolescence. In addition, it is possible that GH continues to play a role in bone physiology during adulthood when final height is reached.

Animals↗
PubMed2003

Decoding transcriptional programs regulated by PPARs and LXRs in the macrophage: effects on lipid homeostasis, inflammation, and atherosclerosis.

Macrophages play essential roles in immunity and homeostasis. As professional scavengers, macrophages phagocytose microbes and apoptotic and necrotic cells and take up modified lipoprotein particles. These functions require tightly regulated mechanisms for the processing and disposal of cellular lipids. Under pathological conditions, arterial wall macrophages become foam cells by accumulating large amounts of cholesterol, contributing to the development of atherosclerosis. Peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs) are members of the nuclear receptor superfamily of transcription factors that have emerged as key regulators of macrophage homeostasis. PPARs and LXRs control transcriptional programs involved in processes of lipid uptake and efflux, lipogenesis, and lipoprotein metabolism. In addition, PPARs and LXRs negatively regulate transcriptional programs involved in the development of inflammatory responses. This review summarizes recent efforts to decode the differential and overlapping roles of PPARs and LXRs in the context of macrophage lipid homeostasis and the control of inflammation.

Animals↗
PubMed1999

Angiotensin II type 1 receptor antisense gene therapy prevents altered renal vascular calcium homeostasis in hypertension.

Intracellular Ca2+ ([Ca2+]i) homeostasis regulates vascular smooth muscle tone, and alteration in [Ca2+]i handling is associated with the development and establishment of hypertension. We have previously established in the spontaneously hypertensive rat (SHR) that virally mediated delivery of angiotensin II type 1 receptor antisense (AT1R-AS) prevents the development of high blood pressure and some pathophysiology associated with hypertension for 120 days. In light of this, our objectives in this study were to determine whether AT1R-AS gene therapy (1) could have a longer duration in the prevention of hypertension and (2) would attenuate the alterations in renal vascular Ca2+ homeostasis and therefore vasoconstriction, characteristics of hypertension. Intracardiac delivery of AT1R-AS in neonates prevented the development of hypertension in SHR for at least 210 days. At this time, untreated SHR renal resistance arterioles showed a significantly enhanced contractile response to KCl and angiotensin II (Ang II) when compared with normotensive Wistar-Kyoto rats. In addition, L-type Ca2+ current density and Ang II-dependent increases in [Ca2+]i were significantly increased in cells dissociated from renal resistance arterioles of the untreated SHR. AT1R-AS treatment prevented all of the above vascular alterations associated with the hypertensive state in SHR. Finally, Western blot analysis of L-type Ca2+ channel (alpha1C) protein levels in renal resistance arterioles of untreated SHR showed no significant difference when compared with control. These results are novel and demonstrate that viral-mediated delivery of AT1R-AS not only attenuates the development of hypertension on a long-term basis but prevents changes in renal vascular Ca2+ homeostasis associated with the disease.

Angiotensin II↗
PubMed1986

Role of changes in insulin and glucagon in glucose homeostasis in exercise.

This experiment was performed to determine if plasma glucose homeostasis is maintained in normal human volunteers during light exercise (40% maximal oxygen consumption [VO2 max]) when changes in insulin and glucagon are prevented. Hormonal control was achieved by the infusion of somatostatin, insulin, and glucagon. Glucose kinetics and oxidation rates were determined with stable isotopic tracers of glucose, and by indirect calorimetry. Two different rates of replacement of insulin and glucagon were used; in one group, insulin was clamped at 19.8 +/- 2.6 microU/ml (high-insulin group), and in the other group insulin was clamped at 9.2 +/- 1.3 microU/ml (low-insulin group). Glucagon was maintained at 261 +/- 16.2 and 124 +/- 6.4 pg/ml, respectively, in the high-insulin and low-insulin groups. Without hormonal control, plasma glucose homeostasis was maintained during exercise because the increase in glucose uptake was balanced by a corresponding increase in glucose production. When changes in insulin and glucagon were prevented, plasma glucose concentration fell, particularly in the high-insulin group. Glucose uptake increased to a greater extent than when hormones were not controlled, and glucose production did not increase sufficiently to compensate. The increase in glucose uptake in the hormonal control groups was associated with an increased rate of glucose oxidation. When euglycemia was maintained by glucose infusion in the hormonal control subjects, the modest increase in glucose production that otherwise occurred was prevented. It is concluded that during light exercise there must be a reduction in insulin concentration and/or an increase in glucagon concentration if plasma glucose homeostasis is to be maintained. If such changes do not occur, hypoglycemia, and hence exhaustion, may occur.

Blood Glucose↗
PubMed1988

Alterations in cation homeostasis in cultured chick ventricular cells during and after recovery from adenosine triphosphate depletion.

Alterations in cation homeostasis during and after recovery from myocardial ischemia may account for some of the reversible and irreversible components of myocardial cell injury. To investigate possible mechanisms involved, we exposed cultured layers of spontaneously contracting chick embryo ventricular cells to media containing 1 mM cyanide (CN) and 20 mM 2-deoxyglucose (2-DG), and zero glucose for up to 6 h, and then allowed cultured cells to recover in serum-free culture medium for 24 h. Changes in Na, K, and Ca contents, 42K uptake and efflux, ATP content, cell water content, and lactate dehydrogenase (LDH) release were measured, and compared with changes produced by exposure to 10(-3) M ouabain and severe hypoxia. Exposure to CN and 2-DG caused marked increase in cell Na (sevenfold) and Ca (fivefold) contents, and a decrease in K content (one-fifth normal), coincident with ATP depletion to one-tenth normal levels. This produced only slight cell injury, evidenced by increased LDH release. Recovery for 24 h resulted in return to near normal values (expressed in nanomoles per milligram of protein) of Na, Ca, and ATP contents. However, there was failure of cell K content to return to normal, associated with a persistent reduced net uptake of 42K, and an increase in the rate of 42K efflux. These abnormalities in K homeostasis were associated with a decrease in cell volume and water content per milligram of protein. More marked ATP depletion (to 1/100 normal values) was produced by hypoxia plus 2-DG and zero glucose, and was associated with much more severe cell injury manifested by LDH loss. Ouabain exposure resulted in a much greater Ca gain (20-30-fold), relative to increase in Na content, than did either CN and 2-DG or hypoxia; and ouabain effects were not reversible (after a 15-fold or greater increase in Ca content was produced) and were associated with significant LDH release. We conclude that these cells are resistant to cell injury caused by moderately severe Ca overload and ATP depletion produced by exposure to CN and 2-DG. However, metabolic inhibition of ATP production produces persistent abnormalities in K homeostasis, associated with functional abnormalities.

Adenosine Triphosphate↗
PubMed2006

Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure.

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) control glucose homeostasis through well-defined actions on the islet beta cell via stimulation of insulin secretion and preservation and expansion of beta cell mass. We examined the importance of endogenous incretin receptors for control of glucose homeostasis through analysis of Glp1r(-/-), Gipr(-/-), and double incretin receptor knockout (DIRKO) mice fed a high-fat (HF) diet. DIRKO mice failed to upregulate levels of plasma insulin, pancreatic insulin mRNA transcripts, and insulin content following several months of HF feeding. Both single incretin receptor knockout and DIRKO mice exhibited resistance to diet-induced obesity, preservation of insulin sensitivity, and increased energy expenditure associated with increased locomotor activity. Moreover, plasma levels of plasminogen activator inhibitor-1 and resistin failed to increase significantly in DIRKO mice after HF feeding, and the GIP receptor agonist [D-Ala(2)]GIP, but not the GLP-1 receptor agonist exendin-4, increased the levels of plasma resistin in studies of both acute and chronic administration. These findings extend our understanding of how endogenous incretin circuits regulate glucose homeostasis independent of the beta cell via control of adipokine secretion and energy expenditure.

Animals↗
PubMed2007

The role of gut hormones in glucose homeostasis.

The gastrointestinal tract has a crucial role in the control of energy homeostasis through its role in the digestion, absorption, and assimilation of ingested nutrients. Furthermore, signals from the gastrointestinal tract are important regulators of gut motility and satiety, both of which have implications for the long-term control of body weight. Among the specialized cell types in the gastrointestinal mucosa, enteroendocrine cells have important roles in regulating energy intake and glucose homeostasis through their actions on peripheral target organs, including the endocrine pancreas. This article reviews the biological actions of gut hormones regulating glucose homeostasis, with an emphasis on mechanisms of action and the emerging therapeutic roles of gut hormones for the treatment of type 2 diabetes mellitus.

Adenosine Deaminase↗
PubMed2003

IL-15 is an essential mediator of peripheral NK-cell homeostasis.

Several distinct classes of surface receptors can, on ligand binding, transmit signals that modulate the survival, proliferation, and apoptosis of peripheral B, T, and natural killer (NK) cells. At the population level, dynamic changes in lymphocyte cell numbers are strictly regulated to maintain a steady state, a process referred to as homeostasis. Although several studies have investigated the signals that regulate B- and T-cell homeostasis, little is known about the mechanisms that control the survival and proliferation of peripheral NK cells. Using an adoptive transfer system, we have investigated the role of gammac-dependent cytokines, in particular interleukin 7 (IL-7) and IL-15, and major histocompatibility complex (MHC) class I molecules in peripheral NK-cell homeostasis. We observed that IL-15 plays a dominant role in the survival of peripheral NK cells, via maintenance of the antiapoptotic factor Bcl-2. IL-15 availability, however, also plays an important role because endogenous NK cells in the recipient mice influence the behavior of adoptively transferred NK cells. Finally, although NK cells bear functional inhibitory Ly49 receptors for MHC class I molecules, the presence or absence of specific ligands on host cells did not influence the survival or homeostatic expansion of donor NK cells.

Adoptive Transfer↗
PubMed2003

Elevated interleukin-7 levels not sufficient to maintain T-cell homeostasis during simian immunodeficiency virus-induced disease progression.

Elevated levels of interleukin 7 (IL-7) have been correlated with various T-cell depletion conditions, including HIV infection, and suggested as an indicator of HIV disease progression (AIDS and death). Here, the assessment of pathogenic simian immunodeficiency virus (SIVmac239) infection in rhesus macaques demonstrated a clear association between a significant elevation in IL-7 levels and disease progression. In 5 macaques that progressed to simian AIDS and death, elevated IL-7 levels were unable to restore T-cell homeostasis. In contrast, increased IL-7 levels were followed by relatively high and stable T-cell numbers in the SIV-infected macaques with a slow-progressing phenotype. Further, studies in sooty mangabeys that do not progress to simian AIDS and that maintain stable T-cell numbers despite high levels of viral replication support the importance of IL-7 and T-cell homeostasis in disease progression. These data suggest that during pathogenic SIV infection with high viral replication, elevated IL-7 levels are unable to recover T-cell homeostasis, thereby leading to disease progression. The utility of IL-7 as a potential immunotherapeutic agent to improve HIV/SIV-related T-cell depletion may therefore depend on controlling the pathogenic effects of viral replication prior to the administration of IL-7.

Animals↗
PubMed2005

Characterization of the yeast ionome: a genome-wide analysis of nutrient mineral and trace element homeostasis in Saccharomyces cerevisiae.

BACKGROUND: Nutrient minerals are essential yet potentially toxic, and homeostatic mechanisms are required to regulate their intracellular levels. We describe here a genome-wide screen for genes involved in the homeostasis of minerals in Saccharomyces cerevisiae. Using inductively coupled plasma-atomic emission spectroscopy (ICP-AES), we assayed 4,385 mutant strains for the accumulation of 13 elements (calcium, cobalt, copper, iron, potassium, magnesium, manganese, nickel, phosphorus, selenium, sodium, sulfur, and zinc). We refer to the resulting accumulation profile as the yeast 'ionome'. RESULTS: We identified 212 strains that showed altered ionome profiles when grown on a rich growth medium. Surprisingly few of these mutants (four strains) were affected for only one element. Rather, levels of multiple elements were altered in most mutants. It was also remarkable that only six genes previously shown to be involved in the uptake and utilization of minerals were identified here, indicating that homeostasis is robust under these replete conditions. Many mutants identified affected either mitochondrial or vacuolar function and these groups showed similar effects on the accumulation of many different elements. In addition, intriguing positive and negative correlations among different elements were observed. Finally, ionome profile data allowed us to correctly predict a function for a previously uncharacterized gene, YDR065W. We show that this gene is required for vacuolar acidification. CONCLUSION: Our results indicate the power of ionomics to identify new aspects of mineral homeostasis and how these data can be used to develop hypotheses regarding the functions of previously uncharacterized genes.

Elements↗
PubMed2005

Reevaluation of the role of the multidrug-resistant P-glycoprotein in cellular cholesterol homeostasis.

The multidrug resistance P-glycoprotein (P-gp) was recently proposed to redistribute cholesterol in the plasma membrane, suggesting that P-gp could modulate cholesterol efflux to cholesterol acceptors. To address this hypothesis and to reevaluate the role of P-gp in cholesterol homeostasis, we first analyzed the role of P-gp expression on cholesterol efflux in P-gp stably transfected drug-selected LLC-MDR1 cells. Cholesterol efflux to methyl-beta-cyclodextrin (CD) was 4-fold higher in LLC-MDR1 cells compared with control LLC-PK1 cells, indicating that the accessible pool of plasma membrane cholesterol was increased by P-gp expression. However, using the P-gp-inducible cells lines HeLa MDR-Tet and 77.1 MDR-Tet, cholesterol efflux to CD, apolipoprotein A-I, or HDL was not associated with P-gp expression. In addition, we did not observe any effect of P-gp expression on cellular free and esterified cholesterol content, cholesteryl ester uptake from LDL and HDL particles, or acyl-CoA:cholesterol acyltransferase activity. Therefore, we conclude that P-gp expression does not play a major role in cholesterol homeostasis in P-gp-inducible cells and that the effects of P-gp on cholesterol homeostasis previously described in drug-selected cells might result from non-P-gp pathways that were also induced by selection for drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗