scholarly journals Role of Bradykinin Type 2 Receptors in Human Sweat Secretion: Translational Evidence Does Not Support a Functional Relationship

2021 ◽  
Vol 34 (3) ◽  
pp. 162-166
Author(s):  
Thad E. Wilson ◽  
Seetharam Narra ◽  
Kristen Metzler-Wilson ◽  
Artur Schneider ◽  
Kelsey A. Bullens ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Sweat Rate ◽  
Sweat Glands ◽  
Potential Therapeutic Target ◽  
Sweat Secretion ◽  
Hoe 140 ◽  
A Current

Bradykinin increases skin blood flow via a cGMP mechanism but its role in sweating in vivo is unclear. There is a current need to translate cell culture and nonhuman paw pad studies into in vivo human preparations to test for therapeutic viability for disorders affecting sweat glands. Protocol 1: physiological sweating was induced in 10 healthy subjects via perfusing warm (46–48°C) water through a tube-lined suit while bradykinin type 2 receptor (B2R) antagonist (HOE-140; 40 μM) and only the vehicle (lactated Ringer’s) were perfused intradermally via microdialysis. Heat stress increased sweat rate (HOE-140 = +0.79 ± 0.12 and vehicle = +0.64 ± 0.10 mg/cm<sup>2</sup>/min), but no differences were noted with B2R antagonism. Protocol 2: pharmacological sweating was induced in 6 healthy subjects via intradermally perfusing pilocarpine (1.67 mg/mL) followed by the same B2R antagonist approach. Pilocarpine increased sweating (HOE-140 = +0.38 ± 0.16 and vehicle = +0.32 ± 0.12 mg/cm<sup>2</sup>/min); again no differences were observed with B2R antagonism. Last, 5 additional subjects were recruited for various control experiments which identified that a functional dose of HOE-140 was utilized and it was not sudorific during normothermic conditions. These data indicate B2R antagonists do not modulate physiologically or pharmacologically induced eccrine secretion volumes. Thus, B2R agonist/antagonist development as a potential therapeutic target for hypo- and hyperhidrosis appears unwarranted.

scholarly journals Role of bradykinin type 2 receptors in human sweat secretion: translational evidence does not support a functional relationship

2020 ◽  
Author(s):  
Thad E. Wilson ◽  
Seetharam Narra ◽  
Kristen Metzler-Wilson ◽  
Artur Schneider ◽  
Kelsey A. Bullens ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Sweat Rate ◽  
Sweat Glands ◽  
Potential Therapeutic Target ◽  
Sweat Secretion ◽  
Hoe 140 ◽  
A Current

AbstractBradykinin increases skin blood flow via a cGMP mechanism but its role in sweating in vivo is unclear. There is a current need to translate cell culture and non-human paw pad studies into in vivo human preparations to test for therapeutic viability for disorders affecting sweat glands. Protocol 1: physiological sweating was induced in 10 healthy subjects via perfusing warm (46-48°C) water through a tube-lined suit while bradykinin type 2 receptor (B2R) antagonist (HOE-140; 40 μM) and only the vehicle (lactated Ringer’s) were perfused intradermally via microdialysis. Heat stress increased sweat rate (HOE-140 = +0.79±0.12 and vehicle = +0.64±0.10 mg/cm2/min), but no differences were noted with B2R antagonism. Protocol 2: pharmacological sweating was induced in 6 healthy subjects via intradermally perfusing pilocarpine (1.67 mg/ml) followed by the same B2R antagonist approach. Pilocarpine increased sweating (HOE-140 = +0.38±0.16 and vehicle = +0.32±0.12 mg/cm2/min); again no differences were observed with B2R antagonism. Lastly, 5 additional subjects were recruited for various control experiments which identified that a functional dose of HOE-140 was utilized and it was not sudorific during normothermic conditions. These data indicate B2R antagonists do not modulate physiologically-or pharmacologically-induced eccrine secretion volumes. Thus, B2R agonist/antagonist development as a potential therapeutic target for hypo- and hyperhidrosis appears unwarranted.

Role of calcium in cholinergic and adrenergic mechanisms of eccrine sweat secretion

1981 ◽  
Vol 241 (3) ◽  
pp. C113-C120 ◽  
Author(s):  
K. Sato ◽  
F. Sato
Keyword(s):  
Sweat Rate ◽  
Sweat Glands ◽  
Hyperbolic Function ◽  
Ionophore A23187 ◽  
Secretory Rate ◽  
Sweat Secretion ◽  
Eccrine Sweat Glands ◽  
Eccrine Sweat

The role of Ca2+ in eccrine sweat secretion was studied using isolated cannulated monkey palm eccrine sweat glands in vitro. Removal of Ca2+ from the incubation medium promptly abolished sweat secretion induced by methacholine or phenylephrine. In contrast, isoproterenol-induced sweat secretion lasted from 40 to 220 min in a Ca2+-free medium. The methacholine-induced maximal sweat rate was a hyperbolic function of the Ca2+ concentration in the bath and reached a plateau at 1 mM Ca2+. Higher Ca2+ concentrations rather suppressed the secretory rate. The Ca2+ ionophore A23187, but not X537A, at 3 X 10(-6) M induced copious prolonged sweat secretion after a latent period of 10 min. A23187-induced sweat secretion was not inhibited by either atropine or propranolol. D 600 (methoxyverapamil) at 10(-3) M inhibited sweat secretion induced by methacholine or by isoproterenol, although the latter lasted longer than methacholine sweating (20 vs. 5 min) in the presence of D 600. The data support the notion that Ca2+ influx into the cell plays a crucial role in cholinergic and alpha-adrenergic sweating, whereas a partial supply of Ca2+ for isoproterenol-induced sweating is derived from an intracellular store.

scholarly journals YAP inhibits autophagy and promotes progression of colorectal cancer via upregulating Bcl-2 expression

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Lan Jin ◽  
Yunhe Chen ◽  
Dan Cheng ◽  
Zhikai He ◽  
Xinyi Shi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Transcriptional Coactivator ◽  
Inhibitory Protein ◽  
Potential Therapeutic Target ◽  
Related Cell ◽  
Autophagy Inhibition

AbstractColorectal cancer (CRC) is one of the most aggressive and lethal cancers. The role of autophagy in the pathobiology of CRC is intricate, with opposing functions manifested in different cellular contexts. The Yes-associated protein (YAP), a transcriptional coactivator inactivated by the Hippo tumor-suppressor pathway, functions as an oncoprotein in a variety of cancers. In this study, we found that YAP could negatively regulate autophagy in CRC cells, and consequently, promote tumor progression of CRC in vitro and in vivo. Mechanistically, YAP interacts with TEAD forming a complex to upregulate the transcription of the apoptosis-inhibitory protein Bcl-2, which may subsequently facilitate cell survival by suppressing autophagy-related cell death; silencing Bcl-2 expression could alleviate YAP-induced autophagy inhibition without affecting YAP expression. Collectively, our data provide evidence for YAP/Bcl-2 as a potential therapeutic target for drug exploration against CRC.

scholarly journals Acute plasma glucose increase, but not early insulin response, regulates plasma ghrelin

2003 ◽  
pp. 403-406 ◽  
Author(s):  
L Briatore ◽  
G Andraghetti ◽  
R Cordera
Keyword(s):  
Plasma Glucose ◽  
Healthy Subjects ◽  
Insulin Response ◽  
Glucose Levels ◽  
Healthy Control ◽  
Early Insulin Response ◽  
Effect Of Glucose ◽  
Type 2 Diabetic

OBJECTIVE: The independent role of glucose and insulin in ghrelin regulation is still controversial; this is also because in healthy subjects it is difficult to isolate the increase of glucose from that of insulin. The aim of this study was to discriminate the effect of glucose increase alone and early insulin response on plasma ghrelin, comparing ghrelin variation after i.v. glucose between healthy subjects and type 2 diabetic (T2DM) subjects, in whom the early insulin response to i.v. glucose is abolished. METHODS: Plasma glucose, insulin and ghrelin levels were measured 0, 3, 5, 10, 30, 45 and 60 min after a 5 g glucose i.v. bolus in seven healthy control subjects and eight T2DM subjects. RESULTS: There were no significant differences in body mass index, basal insulin and basal ghrelin between T2DM and healthy subjects. Basal glucose levels were higher in T2DM subjects than in controls. After i.v. glucose administration, plasma glucose increased significantly in both groups and the glucose peak was higher in T2DM subjects than in controls (9.67+/-1.25 (s.d.) vs 6.88+/-1.00 mmol/l, P<0.01). Insulin increased rapidly in controls, while in T2DM subjects, plasma insulin did not rise in the first 10 min. After the glucose bolus, plasma ghrelin showed a significant reduction both in controls and in T2DM subjects after 5 min. CONCLUSION: These findings indicate that a low-dose i.v. glucose bolus reduces ghrelin both in controls and in T2DM subjects and therefore that early insulin response does not affect plasma ghrelin.

Effect of physical training on peripheral sweat production

1988 ◽  
Vol 65 (2) ◽  
pp. 811-814 ◽  
Author(s):  
M. J. Buono ◽  
N. T. Sjoholm
Keyword(s):  
Physical Training ◽  
Sweat Gland ◽  
Sweat Rate ◽  
Secretory Activity ◽  
Sweat Glands ◽  
Trained Subjects ◽  
Peripheral Mechanism ◽  
Sweat Production ◽  
Sedentary Women

The purpose of this study was to determine the in vivo secretory activity of sweat glands from sedentary and trained subjects. Peripheral sweat production was determined using pilocarpine iontophoresis in 40 volunteers (10 sedentary men, 10 endurance-trained men, 10 sedentary women, 10 endurance-trained women). Peripheral sweat rate was significantly (P less than 0.05) greater in trained men [6.9 +/- 0.6 (SE) g.m2.min-1] and women (6.1 +/- 0.7) compared with sedentary men (3.1 +/- 0.5) and women (2.5 +/- 0.4). Furthermore, peripheral sweat rate was significantly correlated (r = 0.73) with maximal O2 uptake. The above two findings would suggest that physical training improves the secretory activity of the human sweat gland. Such a result supports previous findings that have suggested that the potentiation in sweating seen after training is achieved via a peripheral mechanism. In addition, several gender-related differences were found in the sudorific response of men and women. Specifically, women have a significantly greater sweat gland density, whereas men have a greater sweat production per gland.

scholarly journals Integrin α10, a Novel Therapeutic Target in Glioblastoma, Regulates Cell Migration, Proliferation, and Survival

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 587 ◽  
Author(s):  
Matilda Munksgaard Thorén ◽  
Katarzyna Chmielarska Masoumi ◽  
Cecilia Krona ◽  
Xiaoli Huang ◽  
Soumi Kundu ◽  
...  
Keyword(s):  
Cell Death ◽  
Therapeutic Target ◽  
Functional Role ◽  
Treatment Strategies ◽  
Antibody Drug Conjugate ◽  
Potential Therapeutic Target ◽  
Sphere Formation

New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10β1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody–drug conjugate (ADC), an integrin α10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin α10β1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins α3, α6, and α7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin α10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin α10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin α10β1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM.

scholarly journals PPARδActivity in Cardiovascular Diseases: A Potential Pharmacological Target

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-9 ◽  
Author(s):  
Angela Tesse ◽  
Ramaroson Andriantsitohaina ◽  
Thierry Ragot
Keyword(s):  
Metabolic Diseases ◽  
Peroxisome Proliferator ◽  
In Vivo Models ◽  
Pharmacological Target ◽  
Cardiovascular Cells ◽  
Peroxisome Proliferator Activated Receptors

Activation of peroxisome proliferator-activated receptors (PPARs), and particularly of PPARαand PPARγ, using selective agonists, is currently used in the treatment of metabolic diseases such as hypertriglyceridemia and type 2 diabetes mellitus. PPARαand PPARγanti-inflammatory, antiproliferative and antiangiogenic properties in cardiovascular cells were extensively clarified in a variety of in vitro and in vivo models. In contrast, the role of PPARδin cardiovascular system is poorly understood. Prostacyclin, the predominant prostanoid released by vascular cells, is a putative endogenous agonist for PPARδ, but only recently PPARδselective synthetic agonists were found, improving studies about the physiological and pathophysiological roles of PPARδactivation. Recent reports suggest that the PPARδactivation may play a pivotal role to regulate inflammation, apoptosis, and cell proliferation, suggesting that this transcriptional factor could become an interesting pharmacological target to regulate cardiovascular cell apoptosis, proliferation, inflammation, and metabolism.

scholarly journals Fibrinolytic niche is requested for alveolar type 2 cell-mediated alveologenesis and injury repair

2020 ◽  
Author(s):  
Ali Gibran ◽  
Runzhen Zhao ◽  
Mo Zhang ◽  
Krishan G. Jain ◽  
Jianjun Chang ◽  
...  
Keyword(s):  
Alveolar Epithelium ◽  
Influenza Viruses ◽  
Alveolar Type ◽  
Differential Rate ◽  
Alveolar Epithelial ◽  
Proliferation And Differentiation ◽  
Marked Suppression

ABSTRACTCOVID-19, SARS, and MERS are featured by fibrinolytic dysfunction. To test the role of the fibrinolytic niche in the regeneration of alveolar epithelium, we compared the self-renewing capacity of alveolar epithelial type 2 (AT2) cells and its differentiation to AT1 cells between wild type (wt) and fibrinolytic niche deficient mice (Plau−/− and Serpine1Tg). A significant reduction in both proliferation and differentiation of deficient AT2 cells was observed in vivo and in 3D organoid cultures. This decrease was mainly restored by uPA derived A6 peptide, a binding fragment to CD44 receptors. The proliferative and differential rate of CD44+ AT2 cells was greater than that of CD44− controls. There was a reduction in transepithelial ion transport in deficient monolayers compared to wt cells. Moreover, we found a marked suppression in total AT2 cells and CD44+ subpopulation in lungs from brain dead patients with acute respiratory distress syndrome (ARDS) and a mouse model infected by influenza viruses. Thus, we demonstrate that the fibrinolytic niche can regulate AT2-mediated homeostasis and regeneration via a novel uPA-A6-CD44+-ENaC cascade.

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