Endogenous Peptide Hormone Research Articles

Neuronostatin Promotion Soluble Aβ1-42 Oligomers: Induced Dysfunctional Brain Glucose Metabolism in Mice.

Neuronostatin (NST) is an endogenous peptide hormone, it has the ability to improve oligomeric Aβ (oAβ)-induced cognitive impairments and increase blood glucose levels in mice. However, the relationship between NST and oAβ regarding brain glucose metabolism has not yet been established. The present study defined the contributions of NST and oAβ in the brain glucose metabolism in mice. It was found that i.c.v. co-administration of NST (3nmol/mouse) and oAβ (1nmol/mouse) decreased the mRNA expressions of glucose-6-phosphate dehydrogenase and phosphofructokinase. The treatments were observed to reduce ATP production and the enzyme activities of glucose-6-phosphate dehydrogenase and hexokinase in both the cortex and hippocampus. Simultaneously, co-injection of NST and oAβ inhibited the mRNA and protein expression of glucose transporters GLUT3 and GLUT1 in the cortex and hippocampus. NST promoted the oAβ-induced decreased the cortical NeuN staining, while oAβ increased the levels of NST in both the cortex and hippocampus. I.c.v. co-administration of NST and oAβ led to increase the levels of GPR107 expression and the phosphorylation of PKA, Akt, PERK and eIF-2α in the cortex. These findings suggest that NST promoted oAβ-induced dysfunctional glucose metabolism through the GPR107/PKA/Akt signaling pathway and PERK/eIF2α axis in the brain, which thus contributes to metabolic dysfunction and Alzheimer's disease (AD) pathophysiology.

Expression of Iron-Regulatory Hormone Hepcidin and Iron Transporters Ferroportin and ZIP8 in Patients With and Without Chronic Rhinosinusitis.

Airway epithelia express intrinsic antimicrobial and nutrient-sequestering factors, which contribute to the host defense of the respiratory tract. Hepcidin is an endogenous peptide hormone that serves as a key regulator of iron metabolism, and ferroportin and ZIP8 are iron transporters. All exhibit innate antimicrobial activity. The purpose of this pilot study is to determine if molecules involved in iron regulation are expressed within sinus epithelia and to compare levels of expression between patients with and without chronic rhinosinusitis (CRS). Sinus mucosa was obtained from patients with (n = 19) and without (n = 14) CRS. Real-time polymerase chain reaction following RNA extraction was used to quantify expression of hepcidin, ferroportin, and ZIP8 mRNA. Hepcidin, ferroportin, and ZIP8 were all detected in the sinus epithelia of patients with and without CRS. However, only ZIP8 was significantly changed in CRS, with a 2.5-fold mean increase in mRNA expression relative to controls (P = .005). These findings suggest that ZIP8 may play a role in the innate epithelial defense of the paranasal sinuses.

1091-P: PK/PD of Glucagon and the Novel Glucagon Analog Dasiglucagon in Aqueous or Nonaqueous Formulations following SC Administration in Rats

Endogenous peptide hormones, such as glucagon used for treatment of severe hypoglycemia events in patients with diabetes, are commonly unstable in aqueous solution making development of ready-to-use injection solutions a challenge. Analogs of endogenous peptide hormones can be designed to increase the stability of the molecules. Another approach to enable easy administration of unstable peptides is to formulate them in non-aqueous formulations, such as DMSO (dimethyl sulfoxide). The current study was conducted to compare the PK/PD of glucagon following SC administration in rats when formulated in DMSO or an aqueous formulation (Phosphate buffered solution (PBS)). The PD data were compared to data generated for the stable glucagon analog dasiglucagon in rats. Four to six male Sprague-Dawley rats received 3 nmol/kg of glucagon in DMSO or in a PBS formulation or dasiglucagon at 2 nmol/kg in a PBS formulation. Blood samples for bioanalysis (glucagon groups only) and blood glucose measurement were taken at pre-dose (0) and 15, 30, 45, 60, 75, 90, 105 and 120 min post dose. Glucagon in PBS demonstrated a faster absorption, a higher Cmax (98.3 versus 39.9 pmol/L) and faster Tmax (15 versus 45 minutes) compared to glucagon in DMSO. The increase in blood glucose was similar for glucagon and dasiglucagon in PBS and faster compared to glucagon in DMSO. Disclosure C. Wenander: Employee; Self; Zealand Pharma A/S. A.H. Valeur: Employee; Self; Zealand Pharma A/S. M. Elander: Employee; Self; Zealand Pharma A/S.

Administration study of recombinant human relaxin-2 in horse for doping control purpose.

The insulin-like peptide relaxin (RLX), an endogenous peptide hormone produced in human for pregnancy and reproduction, is also known to exert a range of physiological and pathological effects. Its use is banned in human sports, horseracing, and equestrian competitions due to its potential performance enhancing effect through vasodilation resulting in the increase of blood and oxygen supplies to muscles. Little is known about the biotransformation and elimination of RLX in horses. This paper describes an administration study of rhRLX-2 and its elimination in horses, and the development of sensitive methods for the detection and confirmation of rhRLX-2 in both horse plasma and urine by nano-liquid chromatography/high resolution mass spectrometry (nano-LC/HRMS) after immunoaffinity extraction with the objective of controlling the abuse of rhRLX-2 in horses. The limits of detection in plasma and urine are 2pg/mL and 5pg/mL, respectively. Two thoroughbred geldings were each administered one dose of 10mg rhRLX-2 subcutaneously daily for 3 consecutive days. The rhRLX-2 could be detected and confirmed in the plasma and urine samples collected 105h and 80h, respectively, after the last dose of administration. For doping control purposes, rhRLX-2 ELISA could be used as a screening test to identify potential positive samples for further investigation using the nano-LC/HRMS methods.

Attribution of Ghrelin to Cancer; Attempts to Unravel an Apparent Controversy.

Ghrelin is an endogenous peptide hormone mainly produced in the stomach. It has been known to regulate energy homeostasis, stimulate secretion of growth hormone, and mediate many other physiologic effects. Various effects attributed to ghrelin contribute to many aspects of cancer development and progression. Accordingly, a large body of evidence has emerged about the association of ghrelin with several types of cancer in scales of cell-line, animal, and human studies. However, existing data are controversial. This controversy occurs in two main domains: one is the controversial results in local effects of ghrelin on different types of human cancer cell-lines; the second is the apparent disagreement in the results of in-vitro and clinical studies that investigated ghrelin association to one type of cancer. These inconsistencies have hampered the indications to consider ghrelin as a potential tumor biomarker or therapeutic agent in cancer patients. Previous studies have reviewed different parts of current literature about the ghrelin-cancer relationship. Although they have highlighted these controversial results in various ways, no specific recommendations have been given to address it. In this study, we comprehensively reviewed in-vitro, in-vivo, and clinical studies and attempted to use the following approaches to unravel the inconsistencies detected: (a) to distinguish local and systemic effects of ghrelin in interpreting its summary clinical role in each cancer; (b) scrutinizing factors that regulate local effects of ghrelin and could justify different effects of ghrelin on different cancer cell-lines. These approaches could have notable implications for future in-vitro and clinical studies.

Glucagon receptor family (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The glucagon family of receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on the Glucagon receptor family [159]) are activated by the endogenous peptide (27-44 aa) hormones glucagon, glucagon-like peptide 1, glucagon-like peptide 2, glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory polypeptide), GHRH and secretin. One common precursor (GCG) generates glucagon, glucagon-like peptide 1 and glucagon-like peptide 2 peptides [116]. For a recent review on review the current understanding of the structures of GLP-1 and GLP-1R, the molecular basis of their interaction, and the signaling events associated with it, see de Graaf et al., 2016 [87].

Abstract P3006: Angiotensin-(1-7) Prevents Doxorubicin-Induced Aortic Dysfunction Through Anti-Fibrotic Mechanisms in Juvenile Male and Female Sprague Dawley Rats

Doxorubicin (Dox) is an effective, anthracycline chemotherapeutic administered for a variety of malignancies, but clinical use of the drug is limited by a cumulative, dose-dependent cardiotoxicity. Thus, adjuvant therapies are needed to mitigate Dox-induced cardiovascular damage in cancer patients, especially in pediatric patients with decades of life ahead. Our group showed that angiotensin-(1-7) [Ang-(1-7)], an endogenous peptide hormone with anti-cancer properties, improved vascular dysfunction in coronary vessels and cremaster muscle microvessels in Ang II-infused rats. In this study, juvenile male and female Sprague Dawley rats (n = 8-10) were administered a clinically equivalent dose of Dox (21-24 mg/kg) over 6 weeks, in the presence or absence of Ang-(1-7) [24 μg/kg/h]. Aortic function was measured using echocardiography. In both sexes, Ang-(1-7) blocked the Dox-mediated increase in pulse wave velocity (PWV), a measure of arterial stiffness (75% in males and 179% in females, p<0.05 and p<0.001). Dox decreased aortic lumen diameter (by 18%, p<0.01) and increased wall thickness at systole (p<0.01) in males, which was attenuated by Ang-(1-7). In male but not female aortas, Dox increased media hypertrophy by 16% (p<0.01) and reduced elastin content by 17% compared to control rats (p<0.001), changes prevented by Ang-(1-7). Conversely, collagen deposition was increased 2.5-fold in the aortic arches of female rats treated with Dox (p<0.001), which was blocked by Ang-(1-7). Dox increased nuclear ERK1/2 by 2-fold in the aortic media of male rats (p<0.01) and Ang-(1-7) significantly attenuated nuclear ERK1/2 localization. In contrast, neither Dox nor Ang-(1-7) changed total or nuclear ERK1/2 in the aortic arches of female rats. Dox increased nuclear pSMAD2 4-fold in males (p<0.05) and 3-fold in females (p<0.05); prophylactic treatment with Ang-(1-7) reduced the Dox-induced increases in nuclear pSMAD2 while the heptapeptide hormone had no effect alone. These results demonstrate that Ang-(1-7) prevented Dox-induced aortic dysfunction in both sexes, albeit through different mechanisms, suggesting that treatment with Ang-(1-7) may serve as an effective adjuvant to improve Dox-induced vascular dysfunction in pediatric patients.

Involvement of α-Melanocyte–Stimulating Hormone–Thromboxane A2 System on Itching in Atopic Dermatitis

α-Melanocyte-stimulating hormone (α-MSH) is an endogenous peptide hormone involved in cutaneous pigmentation in atopic dermatitis (AD) with severe itching. α-MSH elicits itch-related responses in mice. We, therefore, investigated whether α-MSH was involved in itching in AD. In the skin of AD patients and mice with atopy-like dermatitis, α-MSH and the prohormone convertase 2, which is the key processing enzyme for the production of α-MSH, were distributed mainly in keratinocytes. In the skin of mice with dermatitis, melanocortin receptors (MC1R and MC5R) were expressed at the mRNA level and were distributed in the dermis. In the dorsal root ganglion of mice with dermatitis, mRNAs encoding MC1R, MC3R, and MC5R were also expressed. MC1R antagonist agouti-signaling protein inhibited spontaneous scratching in mice with dermatitis. In healthy mice, intradermal α-MSH elicited itch-associated responses, which were inhibited by thromboxane (TX) A2 receptor antagonist ONO-3708. In mouse keratinocytes, α-MSH increased the production of TXA2, which was inhibited by adenylyl cyclase inhibitor SQ-22536 and Ca2+ chelator EGTA. In mouse keratinocytes treated with siRNA for MC1R and/or MC5R, α-MSH-induced TXA2 production was decreased. α-MSH increased intracellular Ca2+ ion concentration in dorsal root ganglion neurons and keratinocytes. These results suggest that α-MSH is involved in itching during AD and may elicit itching through the direct action of primary afferents and TXA2 production by keratinocytes.

Structure-based exploration of an allosteric binding pocket in the NTS1 receptor using bitopic NT(8-13) derivatives and molecular dynamics simulations.

Crystal structures of neurotensin receptor subtype 1 (NTS1) allowed us to visualize the binding mode of the endogenous peptide hormone neurotensin and its pharmacologically active C-terminal fragment NT(8-13) within the orthosteric binding pocket of NTS1. Beneath the orthosteric binding pocket, we detected a cavity that exhibits different sequences in the neurotensin receptor subtypes NTS1 and NTS2. In this study, we explored this allosteric binding pocket using bitopic test peptides of type NT(8-13)-Xaa, in which the C-terminal part of NT(8-13) is connected to different amino acids that extend into the newly discovered pocket. Our test compounds showed nanomolar affinities for NTS1, a measurable increase in subtype selectivity compared to the parent peptide NT(8-13), and the capacity to activate the receptor in an IP accumulation assay. Computational investigation of the selected test compounds at NTS1 showed a conserved binding mode within the orthosteric binding pocket, whereas the allosteric cavity was able to adapt to different residues, which suggests a high degree of structural plasticity within that cavity of NTS1.

Somatostatin and the “Small-For-Size” Liver

“Small-for-size” livers arising in the context of liver resection and transplantation are vulnerable to the effects of increased portal flow in the immediate postoperative period. Increased portal flow is an essential stimulus for liver regeneration. If the rise in flow and stimulus for regeneration are excessive; however, liver failure and patient death may result. Somatostatin is an endogenous peptide hormone that may be administered exogenously to not only reduce portal blood flow but also offer direct protection to different cells in the liver. In this review article, we describe key changes that transpire in the liver following a relative size reduction occurring in the context of resection and transplantation and the largely beneficial effects that peri-operative somatostatin therapy may help achieve in this setting.

Proinsulin C-peptide as an alternative or combined treatment with insulin for management of testicular dysfunction and fertility impairments in streptozotocin-induced type 1 diabetic male rats.

Diabetes mellitus (DM) is closely associated with male infertility and sexual dysfunction. Recent data indicate that the proinsulin C-peptide (CP) exerts important physiological effects and shows the characteristics of an endogenous peptide hormone. So, this study was done to investigate the effect of C-peptide with or without insulin treatment on testicular function and architecture in diabetic rats. Rats were divided into the following groups: control, diabetic, and diabetic groups treated with either CP alone or combined with insulin. Tested parameters included, estimation of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and glucose levels, testicular samples for histopathology and estimation of malondialdehyde (MDA), total antioxidant capacity (TAC), and B-cell leukemia/lymphoma-2 (BCL-2) levels as well as sperm count and motility. Results showed that DM caused a severe alteration in hormonal profile and reduced sperm parameters along with increased MDA and decrease in both TAC and BCL-2 levels. CP alone or with insulin treatment efficiently reversed all the negative effects of DM on rat testes, with maximum improvement in the combined regimen. Proposed mechanisms may involve its hypoglycemic, antioxidant, and antiapoptotic properties. Thus, CP could substitute for or better combined with insulin to prevent or retard diabetic-induced testicular dysfunction.

Differential engagement of polar networks in the glucagon-like peptide 1 receptor by endogenous variants of the glucagon-like peptide 1

The glucagon-like peptide 1 receptor (GLP-1R) can be activated by a number of endogenous peptide hormones, including extended, processed, glycine extended and carboxy-terminally amidated versions of glucagon-like peptide 1 (GLP-1). While the main focus of the literature has been on the processed, amidated form, GLP-1(7-36)NH2, the other forms of this peptide are likely to be secreted in physiologically relevant amounts under certain circumstances. This study builds on our existing work examining the effect of mutation of conserved transmembrane polar residues within the receptor to understand the nature of binding and pleiotropic signaling in response to these alternatively processed versions of this important incretin hormone. We show that extended and processed peptides differ not only in their binding to the receptor but also in the way the receptor is engaged for activation that leads to differential signaling bias exhibited by these peptides.

The Guanylate Cyclase C-cGMP Signaling Axis Opposes Intestinal Epithelial Injury and Neoplasia.

Guanylate cyclase C (GUCY2C) is a transmembrane receptor expressed on the luminal aspect of the intestinal epithelium. Its ligands include bacterial heat-stable enterotoxins responsible for traveler's diarrhea, the endogenous peptide hormones uroguanylin and guanylin, and the synthetic agents, linaclotide, plecanatide, and dolcanatide. Ligand-activated GUCY2C catalyzes the synthesis of intracellular cyclic GMP (cGMP), initiating signaling cascades underlying homeostasis of the intestinal epithelium. Mouse models of GUCY2C ablation, and recently, human populations harboring GUCY2C mutations, have revealed the diverse contributions of this signaling axis to epithelial health, including regulating fluid secretion, microbiome composition, intestinal barrier integrity, epithelial renewal, cell cycle progression, responses to DNA damage, epithelial-mesenchymal cross-talk, cell migration, and cellular metabolic status. Because of these wide-ranging roles, dysregulation of the GUCY2C-cGMP signaling axis has been implicated in the pathogenesis of bowel transit disorders, inflammatory bowel disease, and colorectal cancer. This review explores the current understanding of cGMP signaling in the intestinal epithelium and mechanisms by which it opposes intestinal injury. Particular focus will be applied to its emerging role in tumor suppression. In colorectal tumors, endogenous GUCY2C ligand expression is lost by a yet undefined mechanism conserved in mice and humans. Further, reconstitution of GUCY2C signaling through genetic or oral ligand replacement opposes tumorigenesis in mice. Taken together, these findings suggest an intriguing hypothesis that colorectal cancer arises in a microenvironment of functional GUCY2C inactivation, which can be repaired by oral ligand replacement. Hence, the GUCY2C signaling axis represents a novel therapeutic target for preventing colorectal cancer.

Integrated insights into the role of alpha-melanocyte stimulatory hormone in the control of food intake and glycaemia

Identifying peptide hormones with multipotent actions on both weight and glycaemia can have a significant impact on therapeutic options in the treatment of obesity and diabetes. This has been exemplified by recent advances involving pharmacological exploitation of glucagon-like peptide 1 biology. Herein, we summarise evidence supporting the potential candidacy in this light of alpha-melanocyte stimulatory hormone, an endogenous peptide hormone and a breakdown product of the neuropeptide pro-opiomelanocortin. We reference its well described central actions in the control of food intake and moreover highlight new data pointing to an important role for this peptide hormone in the periphery, in relation to glycaemic control.

Abstract P527: Angiotensin-(1-7) Attenuates Doxorubicin-Induced Aortic Dysfunction in Male and Female Rats by Distinct Mechanisms

Doxorubicin (Dox), a commonly used and effective chemotherapeutic agent, often produces cumulative dose-dependent cardiovascular toxicity, resulting in long-term hypertrophy and fibrosis which can lead to heart failure. Adjunct therapies are thus needed to reduce Dox-induced cardiovascular toxicity and enhance long-term quality-of-life in cancer patients, especially in pediatric patients. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous peptide hormone of the renin-angiotensin system that improves cardiac and vascular function by reducing hypertrophy and fibrosis in various animal models. In this study, juvenile Sprague-Dawley rats (male and female, n = 8-10) were administered Dox (cumulative dose of 22 mg/kg) for 6 week, in the presence and absence of Ang-(1-7) [24 μg/kg/h]. Aortic function was measured using a Vevo 2100 small animal ultrasound system. In both males and females, Dox administration increased pulse wave velocity (PWV), a measure of arterial stiffness, and co-treatment with Ang-(1-7) attenuated the Dox-induced increase (Males - 5.6 ± 0.5, Sham; 9.7 ± 1.4, Dox; 7.8 ± 0.6 m/s, Dox/Ang-(1-7), p < 0.01; Females - 5.1 ± 0.5, Sham; 14.3 ± 1.5, Dox; 7.7 ± 1.2 m/s, Dox/Ang-(1-7), p < 0.001); Ang-(1-7) alone had no effect. Dox increased aortic thickness and decreased aortic diameter at systole in males only, which was attenuated by Ang-(1-7) (aortic thickness - 0.28 ± 0.01, Sham; 0.33 ± 0.01, Dox; 0.28 ± 0.01 mm, Dox/Ang-(1-7), p < 0.01; aortic diameter - 2.8 ± 0.6, Sham; 2.3 ± 0.1, Dox; 2.5 ± 0.1 mm, Dox/Ang-(1-7); p < 0.01). No change in aortic thickness or diameter was observed following treatment with Ang-(1-7) alone. Conversely, Dox increased fibrosis in female aorta only, measured by immunohistochemistry with Picrosirius red, which was attenuated by Ang-(1-7) (5.4 ± 0.3, Sham; 7.2 ± 0.6, Ang-(1-7); 12.8 ± 2.0, Dox; 8.0 ± 1.0%, Dox/Ang-(1-7); p < 0.001). These results demonstrate that Dox causes aortic dysfunction in both males and females, albeit through different mechanisms—an increase in aortic hypertrophy in males and aortic fibrosis in females. Ang-(1-7) attenuated both the hypertrophy and fibrosis, suggesting that treatment with the heptapeptide hormone may serve as an effective adjuvant to improve Dox-induced aortic dysfunction.

Adropin Is a Key Mediator of Hypoxia Induced Anti-Dipsogenic Effects via TRPV4-CamKK-AMPK Signaling in the Circumventricular Organs of Rats.

Water intake reduction (anti-dipsogenic effects) under hypoxia has been well established, but the underlying reason remains unknown. Our previous report indicated that activated TRPV4 neurons in SFO are associated with anti-dipsogenic effects under hypoxia. Although low partial pressure of blood oxygen directly activates TRPV4, humoral factors could also be involved. In the present study, we hypothesize that adropin, a new endogenous peptide hormone, was rapidly increased (serum and brain) concomitant with reduced water intake in early hypoxia. Also, the nuclear expression of c-Fos, a marker for neuronal activation, related to water-consumption (SFO and MnPO) was inhibited. These effects were mitigated by a scavenger, rat adropin neutralizing antibody, which effectively neutralized adropin under hypoxia. Interestingly, injection of recombinant adropin in the third ventricle of the rats also triggered anti-dipsogenic effects and reduced c-Fos positive cells in SFO, but these effects were absent when TRPV4 was knocked down by shRNA. Moreover, adropin-activated CamKK-AMPK signaling related to TRPV4 calcium channel in SFO in normoxia. These results revealed that dissociative adropin was elevated in acute hypoxia, which was responsible for anti-dipsogenic effects by altering TRPV4-CamKK-AMPK signaling in SFO.

Preparation of a Orexin Precursor Protein by Chemical Digestion

Endogenous peptide hormones are often produced in vivo in the form of precursor proteins that contain pre- and pro-leader sequences, which are subsequently processed into the biologically active mature peptide. Therefore, it is important to study the folding of precursor proteins to understand the mechanisms of post-translational modifications and the formation of the active conformation of the mature peptide. However, it is generally difficult to obtain precursor proteins from intact organs because only small amounts are produced in vivo. To overcome this issue, an E. coli expression system is employed to prepare recombinant proteins.Pro-orexin consists of orexin A, B, and a C-terminal peptide. To investigate the mechanism responsible for the processing and post-translational modifications of orexin peptides, we tried to express the recombinant pro-orexin in E. coli cells. However, recombinant pro-orexin was not expressed in E. coli cells. In addition, it was also difficult to obtain pro-orexin, even though Trx-fused pro-orexin was readily produced in E. coli cells because the digestion of Trx-fused pro-orexin with an enzyme yielded significant amounts of non-specific digests. Therefore, to solve this issue, we employed a chemical method to release pro-orexin from fusion proteins.K. Pane et al. recently reported a chemical method to obtain a target protein from an onconase-fused (ONC-fused) protein. They applied a chemical cleavage of the fusion protein at the Asp-Pro sequence with acetic acid. We employed this chemical method to produce recombinant pro-orexin. ONC-fused pro-orexin was successfully over-expressed as an inclusion body in E. coli BL21(DE3) cells and treated with acids under several sets of conditions to cleave the Asp-Pro sequence of ONC-fused pro-orexin. The results will be discussed in this paper.

Abstract 023: Angiotensin-(1-7) Reduces Doxorubicin-Induced Cardiac Fibrosis

Doxorubicin (Dox) is a commonly used and effective chemotherapeutic agent for childhood leukemias and sarcomas. However, Dox administration often results in cumulative dose-dependent cardiotoxicity that manifests as cardiomyopathy with marked fibrosis that leads to reduced cardiovascular function and heart failure. Consequently, there is a need for adjunct therapies to reduce Dox-induced cardiotoxicity and enhance long-term quality-of-life in cancer patients, especially in pediatric patients. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous peptide hormone of the renin-angiotensin system with cardioprotective properties; studies by us and others showed that Ang-(1-7) reduces cardiac fibrosis and improves cardiac function in various animal models. In this study, we investigated whether adjunct Ang-(1-7) attenuates cardiotoxicity resulting from an acute (6 week) exposure of juvenile Sprague-Dawley rats (male, n = 8-10) to Dox (22 mg/kg). Dox treatment reduced body mass, cardiac weight and cardiomyocyte size, while Ang-(1-7) co-administration had no effect on these changes. However, co-administration of Ang-(1-7) prevented Dox-mediated increases in cardiac fibrosis (interstitial fibrosis: 1.4 ± 0.1% to 2.5 ± 0.3%; perivascular fibrosis: 15.8 ± 1.4% to 23.2 ± 1.6%; p < 0.01) and coronary vessel hypertrophy (media-to-lumen ratio: 2.4 ± 0.2 to 3.3 ± 0.3; p < 0.05). Administration of Dox significantly increased E/E’ by 47%, a marker of diastolic dysfunction, and pulse wave velocity by 74%, as a measure of arterial stiffness, quantified using a Vevo 2100 small animal ultrasound system; co-administration of Ang-(1-7) prevented the Dox-induced increases in diastolic dysfunction and arterial stiffness. In contrast, Ang-(1-7) had no effect on the Dox-mediated reductions in ventricular diameter, parasternal wall thickness, stroke volume and cardiac output. The anti-fibrotic and anti-hypertrophic effects of Ang-(1-7) may account for the improvement in diastolic and arterial function. Collectively, these results suggest that adjuvant Ang-(1-7) may attenuate cardiac fibrosis and toxicity induced by Dox administration.

Surface-enhanced Raman studies of bradykinin using colloidal gold

In this paper, bradykinin (BK), an endogenous peptide hormone, which is involved in a number of physiological and pathophysiological processes was deposited onto the colloidal Au nanoparticles. The surface-enhanced Raman spectroscopy (SERS) was used to determine the adsorption mode of BK under different environmental conditions, including: excitation wavelengths (514.5nm and 785.0nm), pH of aqueous sol solutions (from pH=3 to pH=11), and size of the colloidal nanoparticles (10, 20, and 50nm). The metal surface plasmon of the colloidal suspended Au nanoparticles was examined by ultraviolet-visible (UV–vis) spectroscopy. The results showed that the C-terminal part of BK plays a crucial role in the adsorption process onto the colloidal suspended Au particles. The Phe5/8 and Arg9 residues of BK mainly participate in the interactions with the colloidal Au nanoparticles. At acidic pH of the solution (pH=3), the BK COO− terminal group through the both oxygen atoms strongly binds to the Au nanoparticles. The Phe5/Phe8 rings adopt tilted orientation with respect to the colloidal Au nanoparticles with diameters of 10 and 20nm. As the particle size increases to 50nm, the flat orientation of the Phe ring(s) with respect to the Au nanoparticles is observed.

Percutaneous delivery of α-melanocyte-stimulating hormone for the treatment of imiquimod-induced psoriasis

Purpose: α-Melanocyte-stimulating hormone (α-MSH) is an endogenous peptide hormone with anti-inflammatory responses. We developed topical formulation(s) of α-MSH to reduce psoriasis-related inflammation.Methods: Transcutol (TC) and n-methyl 2-pyrrolidone (NMP) were used to formulate a gel for α-MSH. Skin permeation and dermal microdialysis of the solution and optimized gel were performed. The inflammatory response of α-MSH gel was investigated in imiquimod-induced psoriasis mouse model. Histology and immunohistochemistry were then performed on treated skin.Results: Solution comprising 50%w/w TC and 10%w/w NMP showed higher (p < 0.05) skin retention (0.27 ± 0.024 µg of α-MSH/mg of skin) than solutions containing either 50% w/w TC or 10% w/w NMP at 24 h. Dispersion of α-MSH in Carbopol Ultrez 10 produced a uniform dispersion. α-MSH gel showed pseudoplastic flow with thixotropic behavior. Dermal microdialysis results suggested that skin permeation of gel after 5 h was 1.9-folds higher than the solution. Further, gel-treated psoriatic-like plaque skin sections showed significant (p < 0.05) decrease in the expression of a melanocortin receptor, in the psoriasis area and severity index score and transepidermal water loss compared to the solution.Conclusion: TC, NMP and Carbopol Ultrez 10 form a stable gel with improved skin permeation of α-MSH for a reduction in psoriasis-associated inflammation.