Self-intravenous drinking and regulation of hydromineral balance in rats recovering from lesions of the lateral hypothalamus

Rats recovering after lesions of the lateral hypothalamic area (LHA) were tested for their ability to regulate hydromineral balance by the control of intakes. In the first experiment these animals learned to self inject water intravenously, and maintained themselves in the prolonged absence of oral water. It was also found that these rats preferred to take water IV rather than orally. In a second experiment LHA rats were provided with all of their fluid requirements by a continuous IV infusion. Under these conditions, oral drinking was very much suppressed, while food intake remained normal. It would thus appear that given the chance not to ingest oral water, the LHA rat does not. It also follows that the LHA rat must be sensitive to its hydrational state, and can appropriately modify drinking behavior. The LHA rat may find the taste of water in some way unpleasant, which could account for these and other results.     

Regulatory drinking in rats with permanent access to a bitter fluid source.

Male rats were given a quinine adulterated fluid as their sole source of liquid for over 60 days. After a latency of a few days, fluid intake stabilised at about 20 ml/day, with the water to food ratio close to 1.0 ml/g. Bodyweights fell to 90 percent of control levels (rats drinking unadulterated water). A battery of dipsogenic challenges was administered. Compared to controls, the ingestive responses during elevated ambient temperature, hyperosmotic salty food, after fluid deprivation, and to extracellular fluid depletion, were all attentuated. Drinking to acute NaCl injections was totally abolished. The intake of the adulterated fluid was near zero during food deprivation, and when a vegetable and fruit diet was available. Body fluid changes were suggestive of a net dehydration in the quinine drinking rats. Parallels with self intravenous drinking rats and rats recovered from lateral hypothalamic lesions were considered, and possible fundamental differences between natural and nonatural thirst stimuli.     

Zona incerta lesions: regulatory drinking deficits to intravenous NaCl, angiotensin, but not to salt in the food

Rats with bilateral damage to the anterior zona incerta (ZI) showed small and delayed drinking responses after IP hypertonic NaCl injection, but they normally excreted most of the salt load within 6 hr. The impaired drinking responses were also evident after nonpainful intravenous (IV) NaCl infusions. After nephrectomy, rats with complete ZI lesions did not drink within 24 hr of the NaCl infusion. Rats with less complete lesions showed reduced and delayed drinking. In contrast to these profound osmoregulatory drinking impairments, all of the lesioned rats increased their water to food ratio when fed a 3% NaCl-supplemented diet. ZI lesioned rats did not drink in response to IV infusions of angiotensin II. The role of the ZI in drinking behavior is discussed in terms of the paradigm-dependent nature of these results, and parallels with other findings are considered.     

Transection of fibers crossing the lateral border of the lateral hypothalamus: fragmented spontaneous ingestive patterns and reanalysis of "regulatory deficits" in rats with sagittal knife cuts.

Rats bearing sagittal knife cuts lateral to the LH showed fragmented meal patterns. Both drinking and locomotor activity occurred during the interruptions in dry chow meals. This fragmented pattern resembles that found in rats with LH lesions, yet it is anatomically unlikely these knife cut animals sustain damage to any known salivary pathway. The cut animals were also found to show delayed drinking responses after intracellular or extracellular dehydration, yet they increased their water intake normally when offered a salty chow. They showed impaired glucoprivic feeding. The similarities of these findings to those in LH and other preparations are discussed.     

Alterations in regulatory T-cells: Rediscovered pathways in immunotoxicology

In addition to the effector T-cells subsets, T-cells can also differentiate into cells that play a suppressive or regulatory role in adaptive immune responses. The cell types currently identified as regulatory T-cells (T_regs) include natural or thymic-derived T_regs, T-cells which express Foxp3⁺CD25⁺CD4⁺ and can suppress immune responses to autoreactive T-cells, as well as inducible T_regs, that are generated from naïve T-cells in the periphery after interaction with antigens presented by dendritic cells. Inducible T_regs include T_H3 cells, T_r1 cells, and Foxp3⁺-inducible T_regs. T_regs have been shown to be critical in the maintenance of immune responses and T-cell homeostasis. These cells play an important role in suppressing responses to self-antigens and in controlling inappropriate responses to non-self-antigens, such as commensal bacteria or food in the gut. For example, depletion of CD4⁺CD25⁺ T_regs from mice resulted in the development of multi-organ autoimmune diseases. CD4⁺CD25⁺ T_regs and/or IL-10-producing T_r1 cells are capable of suppressing or attenuating T_H2 responses to allergens. Moreover, adoptive transfer of CD4⁺CD25⁺ T_regs from healthy to diseased animals resulted in the prevention or cure of certain autoimmune diseases, and was able to induce transplantation tolerance. Clinical improvement seen after allergen immunotherapy for allergic diseases such as rhinitis and asthma is associated with the induction of IL-10- and TGFβ-producing T_r1 cells as well as FoxP3-expressing IL-10 T-cells, with resulting suppression of the T_H2 cytokine milieu. Activation, expansion, or suppression of CD4⁺CD25⁺ T_regs in vivo by xenobiotics, including drugs, may therefore represent a relevant mechanism underlying immunotoxicity, including immunosuppression, allergic asthma, and autoimmune diseases.     

Mechanisms of tolerance induced by TGF beta-treated APC: CD4 regulatory T cells prevent the induction of the immune response possibly through a mechanism involving TGF beta

Transforming growth factor beta (TGF beta)-treated antigen-presenting cells (APC) pulsed with antigen induce tolerance in mice, i.e. inhibition of IFN-gamma production and delayed type hypersensitivity response. Although evidence suggests that regulatory T cells are involved, their mechanism of action is currently unknown and is the subject of the present study. Both CD4 and CD8 splenic T cells from mice injected i.v. with adherent thioglycolate-elicited peritoneal exudate cells cultured with TGF beta(2) and antigen (TGF beta-treated APC) transferred tolerance to naive recipients. Interestingly, TGF beta-treated APC from class II knockout mice were unable to induce tolerance in wild-type mice, whereas wild-type TGF beta-treated APC could induce tolerance in CD8 knockout mice. TGF beta was detected in cultures of lymphoid cells from mice injected with TGF beta-treated APC, and treatment with anti-TGF beta antibody in vivo impaired tolerance induction. TGF beta appeared to be involved in both the development of CD4 regulatory T cells and the effector function of the CD4 regulatory T cells. In summary, the important findings in this study are that CD4, and not CD8, regulatory T cells are required for tolerance induced by TGF beta-treated APC in naive mice, and tolerance appears to be mediated by a mechanism involving TGF beta.     

Safety assessment of immunomodulatory biologics: The promise and challenges of regulatory T-cell modulation

Regulatory T-cell (T_reg) modulation is developing as an important therapeutic opportunity for the treatment of a number of important diseases, including cancer, autoimmunity, infection, and organ transplant rejection. However, as demonstrated with IL-2 and TGN-1412, our understanding of the complex immunological interactions that occur with T_reg modulation in both non-clinical models and in patients remains limited and appears highly contextual. This lack of understanding will challenge our ability to identify the patient population who might derive the highest benefit from T_reg modulation and creates special challenges as we transition these therapeutics from non-clinical models into humans. Thus, in vivo testing in the most representative animal model systems, with careful progress in the clinic, will remain critical in developing therapeutics targeting T_reg and understanding their clinical utility. Moreover, toxicology models can inform some of the potential liabilities associated with T_reg modulation, but not all, suggesting a continued need to explore and validate predictive models.     

Restoring the balance: harnessing regulatory T cells for therapy in rheumatoid arthritis

Treg play a vital role in the maintenance of tolerance to self antigens, thereby preventing disease through the active suppression of proliferation and pro-inflammatory cytokine production by autoreactive T cells. Here we discuss strategies aimed at enhancing Treg function in patients with rheumatoid arthritis with the ultimate aim of restoring lasting tolerance but without increasing the risk of infections or cancer.     

Conditioned drinking: A specific or nonspecific response?

Results of several recent reports indicate that drinking which follows subcutaneous injection of hypertonic saline in a distinctive test chamber will occur after repeated administrations in the absence of hypertonic saline. This so-called conditioned drinking in response to a complex stimulus is highly resistant to extinction and persists for as long as 55 nonreinforced daily test sessions. The present study is an attempt to determine if the conditioning effect is specific to drinking. Results of two experiments are reported and indicate that rats, if given the opportunity, will run in activity wheels and consume significant amounts of food during extinction in addition and, under some conditions, in preference to drinking water. Also, it seems unlikely that animals drink during extinction to avoid “strong thirst” as previously reported. Removal of food during the one hour of water deprivation which precedes testing decreased drinking and indicates that a food associated dry mouth contributes to increased drinking in the test sessions. This still perplexing effect might be more parsimoniously explained in terms of a conditioned nonspecific increase in motor excitability attributed to the administration of the hypertonic saline.     

Ontogenetic role of angiontensin-converting enzyme in rats: Thirst and sodium appetite evaluation

We investigated the influence of captopril (an angiotensin converting enzyme inhibitor) treatment during pregnancy and lactation period on hydromineral balance of the male adult offspring, particularly, concerning thirst and sodium appetite. We did not observe significant alterations in basal hydromineral (water intake, 0.3 M NaCl intake, volume and sodium urinary concentration) or cardiovascular parameters in adult male rats perinatally treated with captopril compared to controls. However, male offspring rats that perinatally exposed to captopril showed a significant attenuation in water intake induced by osmotic stimulation, extracellular dehydration and beta-adrenergic stimulation. Moreover, captopril treatment during perinatal period decreased the salt appetite induced by sodium depletion. This treatment also attenuated thirst and sodium appetite aroused during inhibition of peripheral angiotensin II generation raised by low concentration of captopril in the adult offspring. Interestingly, perinatal exposure to captopril did not alter water or salt intake induced by i.c.v. administration of angiotensin I or angiotensin II. These results showed that chronic inhibition of angiotensin converting enzyme during pregnancy and lactation modifies the regulation of induced thirst and sodium appetite in adulthood.     

Targeting regulatory T cell metabolism in disease: Novel therapeutic opportunities

Regulatory T cells (Tregs) are essential for immune homeostasis and suppression of pathological autoimmunity but can also play a detrimental role in cancer progression via inhibition of anti-tumor immunity. Thus, there is broad applicability for therapeutic Treg targeting, either to enhance function, for example, through adoptive cell therapy (ACT), or to inhibit function with small molecules or antibody-mediated blockade. For both of these strategies, the metabolic state of Tregs is an important consideration since cellular metabolism is intricately linked to function. Mounting evidence has shown that targeting metabolic pathways can selectively promote or inhibit Treg function. This review aims to synthesize the current understanding of Treg metabolism and discuss emerging metabolic targeting strategies in the contexts of transplantation, autoimmunity, and cancer. We discuss approaches to gene editing and cell culture to manipulate Treg metabolism during ex vivo expansion for ACT, as well as in vivo nutritional and pharmacological interventions to modulate Treg metabolism in disease states. Overall, the intricate connection between metabolism and phenotype presents a powerful opportunity to therapeutically tune Treg function.     

Taste-evoked drinking in the rat: The influence of maintenance diet

Non-deprived rats consume substantial amounts of a sweet solution offered for 1 hr a day, when maintained on pelleted food. Under these conditions, amount ingested varies inversely with carbohydrate concentration offered over the hypertonic range, just as it does in deprived rats. It is shown here that such “taste-evoked drinking” is maintained when a bland liquid diet is substituted for pelleted food. But such drinking is sharply reduced when a sweet liquid diet is used as maintenance fare. In addition, the effect of concentration on volume intake changes from inverse to direct. We conclude (1) that such drinking is taste-evoked, not texture-evoked; (2) that it depends on a contrast between the solution offered during the test and the maintenance diet available at other times; and (3) the use of a palatable maintenance diet, by discouraging large intakes which bring postingestive controls into play, uncovers the positive effect of taste factors on volume intake.     

Anal atresia: Effect of smoking and drinking habits during pregnancy

Summary Using data compiled from 216,707 births from the population-based Kanagawa Birth Defects Monitoring Program (KAMP), we conducted a case-control study to evaluate the effect of maternal smoking and/or drinking during pregnancy on the risk of infants' anal atresia in 1989–1994. The frequency of maternal smoking (including passive smoking) and/or maternal drinking during pregnancy among 84 infants with anal atresia was compared with 174 matched controls. The 84 anal atresias include 49 cases of isolated anal atresia and 35 cases of syndromal anal atresia. Our findings suggest that maternal drinking during early pregnancy is associated with an increased risk of isolated anal atresia (OR=4.8, 95% CI 1.2 to 19.1, p<0.05). A slightly increased trend was also observed in the association of maternal smoking during pregnancy with both in the pooled groups of anal atresia (OR=1.4, 95% CI 0.5 to 3.6).     

神经嵴细胞发育分子调控网络的生物信息学分析

BACKGROUND: Development of neural crest cells, which is regulated by various genes, plays an important role in the formation of central nervous system, heart, craniofacial organs and other tissues. However, the relationship among these genes is unclear. OBJECTIVE: To investigate the molecular regulatory networks involved in the process of neural crest cell development based on a bioinformatic analysis. METHODS: Totally 500 differentially expressed genes during the process of neural crest cell development were obtained from the GEO on-line database. Then the DAVID and STRING on-line databases were used to evaluate the relationship among these genes. RESULTS AND CONCLUSION: Totally 500 differentially expressed genes during the process of neural crest cell development could be enriched into different subgroups based on the analysis of DAVID database, including “transforming growth factor β signal pathway”, “WNT signal pathway”, “homeobox gene” , “neural crest cell differentiation” and “neural tube development”. Additionally, 12 genes molecular networks were built based on the analysis of STRING database, such as DLX5, MSX2, SNAIL2, PAX7, SHH, SOX9, NOG, GSC, KAL1, bone morphogenetic protein 5, fibroblast growth factor 8 and WNT3a .These genes exhibited interactions by co-expression, activation and antagonism. Therefore, many genes involved in the process of neural crest cell development were interacted and formed the networks. These findings imply that we should understand these neural crest-related diseases from a holistic view of the signaling pathway and molecular regulatory networks. 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

PD‐1 is not required for natural or peripherally induced regulatory T cells: Severe autoimmunity despite normal production of regulatory T cells

The expression of the coinhibitor PD‐1 on T cells is important for the establishment of immune homeostasis. We previously found that PD‐1 is particularly critical for the control of self‐tolerance during lymphopenia‐induced proliferation of recent thymic emigrants (RTEs). Previous studies suggested that PD‐1 modulates the generation of Treg cells, particularly peripherally induced Treg (pTreg) cells, and controls Th17 cells. However, these conclusions were derived indirectly from studies on the ligand PD‐L1, and not PD‐1 itself. Herein we directly tested whether T‐cell PD‐1 expression was needed for Treg cell generation and examined if a paucity of Treg cells or enhanced Th17 cells could explain the severe lymphopenia‐potentiated autoimmunity caused by PD‐1 KO RTEs. Employing the murine FoxP3^EGFP reporter system to simultaneously monitor conversion of WT and PD‐1 KO T cells to pTreg cells in the same animal, we found that PD‐1 deficiency did not inhibit pTreg cell generation or lead to Th17‐cell‐mediated autoimmunity. Surprisingly, pTreg cell numbers were increased in PD‐1 KO versus WT cell populations. Furthermore, we noted an increased conversion to pTreg cells by RTEs. Our data suggest that the primary role for PD‐1 is to restrain T‐cell activation/proliferation to self‐Ags rather than promote generation of Treg cells.     

Avian CD4CD25 regulatory T cells: Properties and therapeutic applications

Regulatory T cells (Tregs) are a subset of T cells that specialize in immune suppression. CD4⁺CD25⁺FoxP3⁺ T cells have been characterized as Tregs and extensively studied in mammals. In the absence of a putative FoxP3 ortholog in avians, CD4⁺CD25⁺ cells is characterized as Tregs in avians. Avian CD4⁺CD25⁺ cells produce high amounts of IL-10, TGF-β, CTLA-4, and LAG-3 mRNA; lack IL-2 mRNA; and suppress T cell proliferation in vitro through both contact-dependent and -independent pathways. Depleting avian CD4⁺CD25⁺ cells increases the proliferation of, IL-2 amount, and IFNγ mRNA amount of CD4⁺CD25⁻ cells. Avian CD4⁺CD25⁺ cells lose their suppressive properties immediately after inflammation and acquire supersuppressive properties once inflammation subsides. Although Treg activity could be beneficial to the host, Tregs simultaneously inhibit host immunity and cause persistent infections of certain pathogens. Therapy targeted toward alleviating Treg mediated immune suppression can improve host immunity against those persistent pathogens and benefit poultry production.     

Systemic infection with Candida albicans in breast tumor bearing mice: Cytokines dysregulation and induction of regulatory T cells

Objective

The effect of candidemia on immunologic parameters in breast tumor bearing patients is not well studied. Here, we hypothesised that candidemia in the tumor background may change the outcome of immunologic parameters and tumor condition.

Biosynthesis of sulphur amino acids in Saccharomyces cerevisiae: regulatory roles of methionine and S-adenosylmethionine reassessed

Summary cys4-1, a mutation in the reverse trans-sulphuration pathway, relieves the sulphate assimilation pathway and homocysteine synthase from methionine-mediated repression. Since the mutation blocks the synthesis of cysteine from methionine downstream from homocysteine, this indicates that neither methionine nor S-adenosylmethionine serve as low-molecular-mass effectors in this regulatory system, contradicting earlier hypotheses.