scholarly journals The stimuli-specific role of vasopressin in the hypothalamus–pituitary–adrenal axis response to stress

2009 ◽  
Vol 202 (2) ◽  
pp. 263-278 ◽  
Author(s):  
Dóra Zelena ◽  
Ágnes Domokos ◽  
Subodh Kumar Jain ◽  
Ryan Jankord ◽  
Ludmila Filaretova

Adaptation to a constantly changing environment is fundamental to every living organism. The hypothalamic–pituitary–adrenocortical (HPA) axis is a key component of the adaptation process. The present study tests the hypothesis that vasopressin (AVP) is required for the HPA response to acute stimuli. To accomplish this, naturally AVP-deficient Brattleboro rats were exposed to a wide range of stimuli and their HPA response was compared with heterozygous littermattes. The circadian rhythmicity of plasma ACTH and corticosterone was not different between the two genotypes. The ACTH and corticosterone response to volume load, restraint or aggressive attack were decreased in AVP-deficient rats. The stress-induced increase in ACTH, but not corticosterone, was significantly impaired in AVP-deficient animals after novelty, elevated plus-maze, forced swim, hypoglycaemia, ulcerogenic cold immobilisation, lipopolysaccharide, hypertonic saline and egg white injection. The HPA response to social avoidance, ether inhalation and footshock was not different between the genotypes. In vitro, the hypophysis of AVP-deficient animals showed a reduction in stimulated ACTH production and their adrenal glands were hyporeactive to ACTH. A dissociation between the ACTH and corticosterone response was observed in several experiments and could not be explained by an earlier ACTH peak or enhanced adrenal sensitivity, suggesting the existence of paraadenohypophyseal neuroendocrine regulators. Loss of AVP affected the HPA response to a wide variety of stressors. Interestingly, the contribution of AVP to the HPA response was not specific for, nor limited to, a known stressor category. Thus, there is a context-specific requirement for AVP in stress-induced activation of the HPA axis.

2021 ◽  
Vol 118 (27) ◽  
pp. e2106868118
Author(s):  
Irene Cimino ◽  
Hanna Kim ◽  
Y. C. Loraine Tung ◽  
Kent Pedersen ◽  
Debra Rimmington ◽  
...  

An acute increase in the circulating concentration of glucocorticoid hormones is essential for the survival of severe somatic stresses. Circulating concentrations of GDF15, a hormone that acts in the brain to reduce food intake, are frequently elevated in stressful states. We now report that GDF15 potently activates the hypothalamic–pituitary–adrenal (HPA) axis in mice and rats. A blocking antibody to the GDNF-family receptor α-like receptor completely prevented the corticosterone response to GDF15 administration. In wild-type mice exposed to a range of stressful stimuli, circulating levels of both corticosterone and GDF15 rose acutely. In the case of Escherichia coli or lipopolysaccharide injections, the vigorous proinflammatory cytokine response elicited was sufficient to produce a near-maximal HPA response, regardless of the presence or absence of GDF15. In contrast, the activation of the HPA axis seen in wild-type mice in response to the administration of genotoxic or endoplasmic reticulum toxins, which do not provoke a marked rise in cytokines, was absent in Gdf15−/− mice. In conclusion, consistent with its proposed role as a sentinel hormone, endogenous GDF15 is required for the activation of the protective HPA response to toxins that do not induce a substantial cytokine response. In the context of efforts to develop GDF15 as an antiobesity therapeutic, these findings identify a biomarker of target engagement and a previously unrecognized pharmacodynamic effect, which will require monitoring in human studies.


2011 ◽  
Vol 378-379 ◽  
pp. 711-714 ◽  
Author(s):  
Zhe Wei Huang ◽  
Ting Ting Ding ◽  
Jiao Sun

Hydroxyapatite (HAP) and tricalcium phosphate (TCP) nanoparticles (NPs) are in current use covering a wide range of medical applications, hence, it is indispensable to study the potential side effect acting on living organism, and to figure out the biocompatibility evaluation model of nanoparticles for standardization and methodology. In the present study, HAP and TCP NPs were selected and their diameters were within 30-80nm. Cytotoxicity in vitro was analyzed by agar overlay and direct contact exposure test was conducted to evaluate potential toxicity to SD rat macrophages, and hemolysis test of NPs was performed in compliance with ISO 10993-12 guidelines. The results showed that both HAP and TCP NPs could inhibit proliferation of macrophages when their concentration was reached to 20 µg/ml, and the extent of haemolysis would be increased more than 5% while 1000µg/ml NPs were contacted with rabbit blood cells. Furthermore, TCP NPs could induce obvious hemolysis reaction and inhibit proliferation of macrophages compared with group of HAP NPs at the same concentration.


2021 ◽  
Vol 118 (11) ◽  
pp. e2021888118
Author(s):  
Tessa Sinnige ◽  
Georg Meisl ◽  
Thomas C. T. Michaels ◽  
Michele Vendruscolo ◽  
Tuomas P. J. Knowles ◽  
...  

Protein aggregation is associated with a wide range of degenerative human diseases with devastating consequences, as exemplified by Alzheimer’s, Parkinson’s, and Huntington’s diseases. In vitro kinetic studies have provided a mechanistic understanding of the aggregation process at the molecular level. However, it has so far remained largely unclear to what extent the biophysical principles of amyloid formation learned in vitro translate to the complex environment of living organisms. Here, we take advantage of the unique properties of a Caenorhabditis elegans model expressing a fluorescently tagged polyglutamine (polyQ) protein, which aggregates into discrete micrometer-sized inclusions that can be directly visualized in real time. We provide a quantitative analysis of protein aggregation in this system and show that the data are described by a molecular model where stochastic nucleation occurs independently in each cell, followed by rapid aggregate growth. Global fitting of the image-based aggregation kinetics reveals a nucleation rate corresponding to 0.01 h−1 per cell at 1 mM intracellular protein concentration, and shows that the intrinsic molecular stochasticity of nucleation accounts for a significant fraction of the observed animal-to-animal variation. Our results highlight how independent, stochastic nucleation events in individual cells control the overall progression of polyQ aggregation in a living animal. The key finding that the biophysical principles associated with protein aggregation in small volumes remain the governing factors, even in the complex environment of a living organism, will be critical for the interpretation of in vivo data from a wide range of protein aggregation diseases.


2020 ◽  
Author(s):  
Tessa Sinnige ◽  
Georg Meisl ◽  
Thomas C. T. Michaels ◽  
Michele Vendruscolo ◽  
Tuomas P.J. Knowles ◽  
...  

AbstractThe accumulation of insoluble protein aggregates containing amyloid fibrils has been observed in many different human protein misfolding diseases1,2, and their pathological features have been recapitulated in diverse model systems3. In vitro kinetic studies have provided a quantitative understanding of how the fundamental molecular level processes of nucleation and growth lead to amyloid formation4. However, it is not yet clear to what extent these basic biophysical processes translate to amyloid formation in vivo, given the complexity of the cellular and organismal environment. Here we show that the aggregation of a fluorescently tagged polyglutamine (polyQ) protein into µm-sized inclusions in the muscle tissue of living C. elegans can be quantitatively described by a molecular model where stochastic nucleation occurs independently in each cell, followed by rapid aggregate growth. Global fitting of the image-based aggregation kinetics reveals a nucleation rate corresponding to 0.01 h-1 per cell at 1 mM intracellular protein concentration, and shows that the intrinsic stochasticity of nucleation accounts for a significant fraction of the observed animal-to-animal variation. Our results are consistent with observations for the aggregation of polyQ proteins in vitro5 and in cell culture6, and highlight how nucleation events control the overall progression of aggregation in the organism through the spatial confinement into individual cells. The key finding that the biophysical principles associated with protein aggregation in small volumes remain the governing factors, even in the complex environment of a living organism, will be critical for the interpretation of in vivo data from a wide range of protein aggregation diseases.


1991 ◽  
Vol 30 (01) ◽  
pp. 35-39 ◽  
Author(s):  
H. S. Durak ◽  
M. Kitapgi ◽  
B. E. Caner ◽  
R. Senekowitsch ◽  
M. T. Ercan

Vitamin K4 was labelled with 99mTc with an efficiency higher than 97%. The compound was stable up to 24 h at room temperature, and its biodistribution in NMRI mice indicated its in vivo stability. Blood radioactivity levels were high over a wide range. 10% of the injected activity remained in blood after 24 h. Excretion was mostly via kidneys. Only the liver and kidneys concentrated appreciable amounts of radioactivity. Testis/soft tissue ratios were 1.4 and 1.57 at 6 and 24 h, respectively. Testis/blood ratios were lower than 1. In vitro studies with mouse blood indicated that 33.9 ±9.6% of the radioactivity was associated with RBCs; it was washed out almost completely with saline. Protein binding was 28.7 ±6.3% as determined by TCA precipitation. Blood clearance of 99mTc-l<4 in normal subjects showed a slow decrease of radioactivity, reaching a plateau after 16 h at 20% of the injected activity. In scintigraphic images in men the testes could be well visualized. The right/left testis ratio was 1.08 ±0.13. Testis/soft tissue and testis/blood activity ratios were highest at 3 h. These ratios were higher than those obtained with pertechnetate at 20 min post injection.99mTc-l<4 appears to be a promising radiopharmaceutical for the scintigraphic visualization of testes.


1997 ◽  
Vol 77 (04) ◽  
pp. 725-729 ◽  
Author(s):  
Mario Colucci ◽  
Silvia Scopece ◽  
Antonio V Gelato ◽  
Donato Dimonte ◽  
Nicola Semeraro

SummaryUsing an in vitro model of clot lysis, the individual response to a pharmacological concentration of recombinant tissue plasminogen activator (rt-PA) and the influence on this response of the physiological variations of blood parameters known to interfere with the fibrinolytic/thrombolytic process were investigated in 103 healthy donors. 125I-fibrin labelled blood clots were submersed in autologous plasma, supplemented with 500 ng/ml of rt-PA or solvent, and the degree of lysis was determined after 3 h of incubation at 37° C. Baseline plasma levels of t-PA, plasminogen activator inhibitor 1 (PAI-1), plasminogen, α2-anti-plasmin, fibrinogen, lipoprotein (a), thrombomodulin and von Willebrand factor as well as platelet and leukocyte count and clot retraction were also determined in each donor. rt-PA-induced clot lysis varied over a wide range (28-75%) and was significantly related to endogenous t-PA, PAI-1, plasminogen (p <0.001) and age (p <0.01). Multivariate analysis indicated that both PAI-1 antigen and plasminogen independently predicted low response to rt-PA. Surprisingly, however, not only PAI-1 but also plasminogen was negatively correlated with rt-PA-ginduced clot lysis. The observation that neutralization of PAI-1 by specific antibodies, both in plasma and within the clot, did not potentiate clot lysis indicates that the inhibitor, including the platelet-derived form, is insufficient to attenuate the thrombolytic activity of a pharmacological concentration of rt-PA and that its elevation, similarly to the elevation of plasminogen, is not the cause of clot resistance but rather a coincident finding. It is concluded that the in vitro response of blood clots to rt-PA is poorly influenced by the physiological variations of the examined parameters and that factors other than those evaluated in this study interfere with clot dissolution by rt-PA. In vitro clot lysis test might help to identify patients who may be resistant to thrombolytic therapy.


2020 ◽  
Author(s):  
Tyler Colasante ◽  
Lauren Lin ◽  
Kalee DeFrance ◽  
Tom Hollenstein

In the current digital age, emotional support is increasingly received through digital devices. However, virtually all studies assessing the benefits of emotional support have focused on in-person support. Using an experience sampling methodology, we assessed participants’ negative emotions, digital and in-person support for those emotions, and success in regulating them three times per day for 14 days, thus covering a wide range of digital support scenarios (N = 164 participants with 6,530 collective measurement occasions). We also considered whether participants were alone versus with others at the time of their negative emotion and higher versus lower in social avoidance as plausible moderators of when digital support was utilized and effective. We expected more pronounced use and efficacy of digital support when participants were alone and higher in trait social avoidance. However, digital support was used and perceived as effective for regulating negative emotions regardless of these factors and its beneficial effects were on par with those of traditional in-person support. The unique benefits of digital support may not be restricted to socially isolated or socially avoidant users. These findings are timely given the widespread anxiety and isolation under the current COVID-19 pandemic. If transcending time and space with digital emotional support is the new norm, the good news is that it seems to be working.


Growth regulators, phytohormones, both natural and artificial, are the main means to control plant ontogenesis. They are involved in regulating the processes of cell differentiation and cell divisions, the formation of tissues and organs, the changes in the rate of growth and development, the duration of the certain stages of ontogenesis. The main classes of phytohormones used in plant biotechnology, in particular, in the induction of haploid structures, are auxins and cytokinins. The mechanism of action of phytohormones on a cell is rather complicated and may have a different character. Understanding the characteristics of the action of phytohormones is complicated by the fact that the system of hormonal regulation of plant life is multicomponent. This is manifested in the fact that the same physiological process is most often influenced not by one, but by several phytohormones, covering a wide range of aspects of cell metabolism. In connection with the foregoing, the purpose of our work was to test a set of nutrient media with different basic composition and different proportions of phytohormones to determine the patterns of their influence on the processes of haploid structure induction in rape anther culture using accessions, developed at the Institute of Oilseed Crops NAAS. The material used was two accessions of winter rapeseed (No. 1 and No. 2) and one sample of spring rapeseed, provided by the Rapeseed Breeding laboratory of the Institute of Oilseed Crops. Incised inflorescences were kept against the background of low temperature of 6–8 ° C for several days, and then, under aseptic conditions, anthers with unripe pollen grains were isolated and planted on nutrient media differing in both basic mineral composition and content of phytohormones. MS (Murashige & Skoog 1962) and B5 (Gamborg et al 1968) media were used as basic media. Phytohormones were added to the basic media in various combinations – BA, 2,4-D, NAA at the concentrations of 0.1-0.6 mg/l. In each treatment up to 300 anthers were cultivated. Differences between treatments were evaluated using standard t-test. Studies have shown that in the anther culture of rapeseed on the tested nutrient media, morphogenic structures of different types (embryoids and callus) were originated. Synthetic auxin 2,4-D, regardless of the composition of the basic medium, caused the formation of structures of both types, though with a low frequency. Phytohormone BA of the cytokinin type had a similar effect. In this case, the frequency of structures was slightly higher, and the developed structures were represented mainly by embryoids. The joint action of cytokinin and auxin was the most favorable for the initiation of morphogenic structures. Such combination of phytohormones caused the formation of these structures with a frequency of 24.5-14.7% in the studied genotypes of winter rape. A similar effect of phytohormones on the induction and development of morphogenic structures was also observed in spring rape. In this case, a single basic MS medium was used. The experiment included treatments where phytohormones were absent (control), as well as various combinations of auxin and cytokinin. In the control treatment, the formation of new structures was not noted. In treatments with phytohormones, in addition to the medium with the combination of auxin and cytokinin, the medium in which only cytokinin was present was also rather effective. The treatment in which the action of auxin 2,4-D was combined with the action of another auxin, NAA, turned out to be practically ineffective. Thus, it was found that for the induction of morphogenic structures from microspores in rape anther culture of the tested genotypes, the combination of cytokinin with auxin, or the use of only single cytokinin BA without other phytohormones, had the most positive effect.


Author(s):  
Roohi Mohi-ud-din ◽  
Reyaz Hassan Mir ◽  
Prince Ahad Mir ◽  
Saeema Farooq ◽  
Syed Naiem Raza ◽  
...  

Background: Genus Berberis (family Berberidaceae), which contains about 650 species and 17 genera worldwide, has been used in folklore and various traditional medicine systems. Berberis Linn. is the most established group among genera with around 450-500 species across the world. This comprehensive review will not only help researchers for further evaluation but also provide substantial information for future exploitation of species to develop novel herbal formulations. Objective: The present review is focussed to summarize and collect the updated review of information of Genus Berberis species reported to date regarding their ethnomedicinal information, chemical constituents, traditional/folklore use, and reported pharmacological activities on more than 40 species of Berberis. Conclusion: A comprehensive survey of the literature reveals that various species of the genus possess various phytoconstituents mainly alkaloids, flavonoid based compounds isolated from different parts of a plant with a wide range of pharmacological activities. So far, many pharmacological activities like anti-cancer, anti-hyperlipidemic, hepatoprotective, immunomodulatory, anti-inflammatory both in vitro & in vivo and clinical study of different extracts/isolated compounds of different species of Berberis have been reported, proving their importance as a medicinal plant and claiming their traditional use.


2019 ◽  
Vol 20 (12) ◽  
pp. 1227-1243
Author(s):  
Hina Qamar ◽  
Sumbul Rehman ◽  
D.K. Chauhan

Cancer is the second leading cause of morbidity and mortality worldwide. Although chemotherapy and radiotherapy enhance the survival rate of cancerous patients but they have several acute toxic effects. Therefore, there is a need to search for new anticancer agents having better efficacy and lesser side effects. In this regard, herbal treatment is found to be a safe method for treating and preventing cancer. Here, an attempt has been made to screen some less explored medicinal plants like Ammania baccifera, Asclepias curassavica, Azadarichta indica, Butea monosperma, Croton tiglium, Hedera nepalensis, Jatropha curcas, Momordica charantia, Moringa oleifera, Psidium guajava, etc. having potent anticancer activity with minimum cytotoxic value (IC50 >3μM) and lesser or negligible toxicity. They are rich in active phytochemicals with a wide range of drug targets. In this study, these medicinal plants were evaluated for dose-dependent cytotoxicological studies via in vitro MTT assay and in vivo tumor models along with some more plants which are reported to have IC50 value in the range of 0.019-0.528 mg/ml. The findings indicate that these plants inhibit tumor growth by their antiproliferative, pro-apoptotic, anti-metastatic and anti-angiogenic molecular targets. They are widely used because of their easy availability, affordable price and having no or sometimes minimal side effects. This review provides a baseline for the discovery of anticancer drugs from medicinal plants having minimum cytotoxic value with minimal side effects and establishment of their analogues for the welfare of mankind.


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