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The octapetide NAP alleviates intestinal and extra-intestinal anti-inflammatory sequelae of acute experimental colitis.
Peptides
Markus M Heimesaat, Eliezer Giladi, Anja A Kühl +2 more
The octapeptide NAP has been shown to exert neuroprotective properties and reduce neuro-inflammatory responses. The aim of the present study was to investigate if NAP provides anti-inflammatory effects in acute murine colitis. To address this, C57BL/6 j mice were challenged with 3.5% dextran sulfate sodium from day 0 until day 6 to induce colitis, either treated intraperitoneally with NAP or placebo (NaCl 0.9%) from day 1 until day 6 post-induction (p.i.) and subjected to in depth macroscopic, microscopic and immunological evaluations. Whereas NAP application did not alleviate macroscopic (i.e. clinical) sequelae of colitis, lower numbers of apoptotic, but higher counts of proliferating/regenerating colonic epithelial cells could be observed in NAP as compared to placebo treated mice at day 7 p.i. Furthermore, lower numbers of adaptive immune cells such as T lymphocytes and regulatory T cells were abundant in the colonic mucosa and lamina propria upon NAP versus placebo treatment that were accompanied by less colonic secretion of pro-inflammatory mediators including IFN-γ and nitric oxide at day 7 p.i. In mesenteric lymph nodes, pro-inflammatory IFN-γ, TNF and IL-6 concentrations were increased in placebo, but not NAP treated mice at day 7 p.i., whereas interestingly, elevated anti-inflammatory IL-10 levels could be observed in NAP treated mice only. The assessed anti-inflammatory properties of NAP were not restricted to the intestinal tract, given that in extra-intestinal compartments such as the kidneys, IFN-γ levels increased in placebo, but not NAP treated mice upon colitis induction. NAP induced effects were accompanied by distinct changes in intestinal microbiota composition, given that colonic luminal loads of bifidobacteria, regarded as anti-inflammatory, "health-promoting" commensal species, were two orders of magnitude higher in NAP as compared to placebo treated mice and even naive controls. In conclusion, NAP alleviates intestinal and extra-intestinal pro-inflammatory sequelae of acute experimental colitis and may provide novel treatment options of intestinal inflammatory diseases in humans.
Structural modification of the tripeptide KPV by reductive "glycoalkylation" of the lysine residue.
PLoS One
Abigael C Songok, Pradip Panta, William T Doerrler +2 more
Peptides that exhibit enzymatic or hormonal activities are regulatory factors and desirable therapeutic drugs because of their high target specificity and minimal side effects. Unfortunately, these drugs are susceptible to enzymatic degradation, leading to their rapid elimination and thereby demanding frequent dosage. Structurally modified forms of some peptide drugs have shown enhanced pharmacokinetics, improving their oral bioavailability. Here, we discuss a novel glycomimetic approach to modify lysine residues in peptides. In a model system, the ε-amine of Ts-Lys-OMe was reductively alkylated with a glucose derivative to afford a dihydroxylated piperidine in place of the amine. A similar modification was applied to H-KPV-NH2, a tripeptide derived from the α-melanocyte stimulating hormone (α-MSH) reported to have antimicrobial and anti-inflammatory properties. Antimicrobial assays, under a variety of conditions, showed no activity for Ac-KPV-NH2 or the α- or ε-glycoalkylated analogs. Glycoalkylated peptides did, however, show stability toward proteolytic enzymes.
The CRF Family of Neuropeptides and their Receptors - Mediators of the Central Stress Response.
Curr Mol Pharmacol
Nina Dedic, Alon Chen, Jan M Deussing
Dysregulated stress neurocircuits, caused by genetic and/or environmental changes, underlie the development of many neuropsychiatric disorders. Corticotropin-releasing factor (CRF) is the major physiological activator of the hypothalamic-pituitary-adrenal (HPA) axis and consequently a primary regulator of the mammalian stress response. Together with its three family members, urocortins (UCNs) 1, 2, and 3, CRF integrates the neuroendocrine, autonomic, metabolic and behavioral responses to stress by activating its cognate receptors CRFR1 and CRFR2.
Microtubule Hyperacetylation Enhances KL1-Dependent Micronucleation under a Tau Deficiency in Mammary Epithelial Cells.
Int J Mol Sci
Haruka Sudo
Enhanced microtubule acetylation has been identified as a negative prognostic indicator in breast cancer. We reported previously that primary cultured human mammary epithelial cells manifest breast cancer-related aneuploidization via the activation of severing protein katanin-like (KL)1 when tau is deficient. To address in this current study whether microtubule hyperacetylation is involved in breast carcinogenesis through mitosis, the effects of tubacin on human mammary epithelial cells were tested using immunofluorescence techniques. Tau-knockdown cells showed enhancement of KL1-dependent events, chromosome-bridging and micronucleation in response to tubacin. These enhancements were suppressed by further expression of an acetylation-deficient tubulin mutant. Consistently, using a rat fibroblast-based microtubule sensitivity test, it was confirmed that KL1 also shows enhanced activity in response to microtubule hyperacetylation as well as katanin. It was further observed in rat fibroblasts that exogenously expressed KL1 results in more micronucleation under microtubule hyperacetylation conditions. These data suggest that microtubule acetylation upregulates KL1 and induces more aneuploidy if tau is deficient. It is thus plausible that microtubule hyperacetylation promotes tumor progression by enhancing microtubule sensitivity to KL1, thereby disrupting spindle microtubules and this process could be reversed by the microtubule-binding and microtubule protective octapeptide NAPVSIPQ (NAP) which recruits tau to the microtubules.
Myostatin and activin blockade by engineered follistatin results in hypertrophy and improves dystrophic pathology in mdx mouse more than myostatin blockade alone.
Skelet Muscle
Andrea Iskenderian, Nan Liu, Qingwei Deng +15 more
Myostatin antagonists are being developed as therapies for Duchenne muscular dystrophy due to their strong hypertrophic effects on skeletal muscle. Engineered follistatin has the potential to combine the hypertrophy of myostatin antagonism with the anti-inflammatory and anti-fibrotic effects of activin A antagonism.
Ghrelin regulation of glucose metabolism.
Peptides
Anne-Laure Poher, Matthias H Tschöp, Timo D Müller
The a 28-amino acid peptide ghrelin was discovered in 1999 as a growth hormone (GH) releasing peptide. Soon after its discovery, ghrelin was found to increase body weight and adiposity by acting on the hypothalamic melanocortinergic system. Subsequently, ghrelin was found to exert a series of metabolic effects, overall testifying ghrelin a pleiotropic nature of broad pharmacological interest. Ghrelin acts through the growth hormone secretagogue-receptor (GHS-R), a seven transmembrane G protein-coupled receptor with high expression in the anterior pituitary, pancreatic islets, thyroid gland, heart and various regions of the brain. Among ghrelins numerous metabolic effects are the most prominent the stimulation of appetite via activation of orexigenic hypothalamic neurocircuits and the food-intake independent stimulation of lipogenesis, which both together lead to an increase in body weight and adiposity. Ghrelin effects beyond the regulation of appetite and GH secretion include the regulation of gut motility, sleep-wake rhythm, taste sensation, reward seeking behaviour, and the regulation of glucose metabolism. The latter received recently increasing recognition because pharmacological inhibition of ghrelin signaling might be of therapeutic value to improve insuin resistance and type 2 diabetes. In this review we highlight the multifaceted nature of ghrelin and summarize its glucoregulatory action and discuss the pharmacological value of ghrelin pathway inhibition for the treatment of glucose intolerance and type 2 diabetes.
The Safety and Efficacy of Growth Hormone Secretagogues.
Sex Med Rev
John T Sigalos, Alexander W Pastuszak
Growth hormone (GH) increases lean body mass, decreases fat mass, increases exercise tolerance and maximum oxygen uptake, enhances muscle strength, and improves linear growth. Long-term studies of GH administration offer conflicting results on its safety, which has led to strict Food and Drug Administration criteria for GH use. The potential drawbacks of exogenous GH use are believed to be due in part to impaired regulatory feedback.
Analysis of new growth promoting black market products.
Growth Horm IGF Res
Oliver Krug, Andreas Thomas, Helle Malerød-Fjeld +5 more
Detecting agents allegedly or evidently promoting growth such as human growth hormone (GH) or growth hormone releasing peptides (GHRP) in doping controls has represented a pressing issue for sports drug testing laboratories. While GH is a recombinant protein with a molecular weight of 22 kDa, the GHRPs are short (3-6 amino acids long) peptides with GH releasing properties. The endogenously produced GH (22 kDa isoform) consists of 191 amino acids and has a monoisotopic molecular mass of 22,124 Da. Within this study, a slightly modified form of GH was discovered consisting of 192 amino acids carrying an additional alanine at the N-terminus, leading to a monoisotopic mass of 22,195 Da. This was confirmed by top-down and bottom-up experiments using liquid chromatography coupled to high resolution/high accuracy mass spectrometry. Additionally, three analogues of GHRPs were identified as Gly-GHRP-6, Gly-GHRP-2 and Gly-Ipamorelin, representing the corresponding GHRP extended by a N-terminal glycine residue. The structure of these peptides was characterised by means of high resolution (tandem) mass spectrometry, and for Gly-Ipamorelin and Gly-GHRP-2 their identity was additionally confirmed by custom synthesis. Further, established in-vitro experiments provided preliminary information considering the potential metabolism after administration.
Peptide Receptor-Targeted Fluorescent Probe: Visualization and Discrimination between Chronic and Acute Ulcerative Colitis.
ACS Appl Mater Interfaces
Meiying Zeng, Andong Shao, Hui Li +7 more
The inflammatory activity of ulcerative colitis plays an important role in the medical treatment. However, accurate and real-time monitoring of the colitis activity with noninvasive bioimaging method is still challenging, especially in distinguishing between chronic and acute colitis. As a good receptor, the oligopeptide transporter (PepT1) is overexpressed in the colonic epithelial cells of chronic ulcerative colitis, which can deliver tripeptide KPV (Lys-Pro-Val, the C-terminal sequence of α-MSH) into cytosol in the intestine. Herein, we report a PepT1 peptide receptor-targeted fluorescent probe, dicyanomethylene-4H-pyran (DCM)-KPV, with the strategy of conjugating the KPV into the DCM chromophore. The diagnostic fluorescent probe bestows a specific receptor-targeted interaction with PepT1 through the KPV moiety, possessing several beneficial characteristics, such as efficient long emission, low photobleaching, negligible cytotoxicity, and high cytocompatibility in living cells. We build the overexpressed PepT1 on the cytomembrane of ulcerative colitis model Caco-2 cell as the efficient receptor to accumulate the targeted tripeptide KPV in the cytoplasm and nucleus. With the co-localization of DCM-KPV and the DNA-specific fluorophore, DAPI, the specifically long emission from chromophore DCM and efficient receptor-targeted peptide KPV, the fluorescent probe of DCM-KPV makes a breakthrough to the direct noninvasive observation of the accumulation in colon inflammation regions via intestinal mucosa, even successfully distinguishing the chronic, acute ulcerative colitis and normal groups. Compared with the traditional unenhanced magnetic resonance imaging and hematoxylin and eosin (H&E) staining, we make full use of exploiting the specific target-receptor interaction between the tripeptide unit, KPV, and the oligopeptide transporter, PepT1, for sensing selectivity. The desirable diagnostic ability of DCM-KPV can guarantee the real-time tracking and visualization of the role of intracellular KPV on ulcerative colitis, which provides an alternative to replace the time-consuming and tissue sampling-invasive H&E staining diagnosis.
Mitochondrial-Derived Peptides Exacerbate Senescence.
Rejuvenation Res
Andrew R Mendelsohn, James W Larrick
Mitochondrial-derived peptides (MDPs), encoded by mitochondrial DNA, play a cytoprotective role by helping preserve mitochondrial function and cell viability under stressful conditions. Humanin and its homologs and MOTS-c are two of several MDPs hypothesized to have antiaging activity based on correlative studies. For example, humanin plasma levels are inversely correlated with growth hormone and insulin-like growth factor 1 expression, which may promote accelerated aging. Humanin has been shown to protect cells from beta amyloid toxicity and preserve endothelial cell function in a mouse model of atherosclerosis. Furthermore, both humanin and MOTS-c improve insulin sensitivity in mouse models of type 2 diabetes. Recently it was reported that a potent analogue of humanin blocks cardiac fibrosis in aging mice. Although it has been hypothesized that MDPs might have senolytic activity, in a recent report humanin and MOTS-c both exacerbate the senescence-associated-secretory-phenotype (SASP) in senescent cells by stimulating the secretion of IL-6, IL-1β, IL-8, IL-10 and tumor necrosis factor α. It appears that the cytoprotective activity of the MDPs may be permissive for increased expression of a set of proinflammatory cytokines. Given the potential benefits of MDPs in many of the same diseases associated with the presence of senescent cells, a combination of senolytic and MDP-based treatments may be additive or synergistic. The MDPs would protect normal cells, whereas senescent cells would be eliminated by the senolytic therapy. It is even possible that MDPs by increasing the SASP phenotype would make the senescent cells more apt to be cleared by the immune system or more sensitive to senolytics. In contrast, if the MDPs actually cytoprotect the senescent cells, then the treatment can be performed serially with the senolytic used first.
Structural basis of the signal transduction via transmembrane domain of the human growth hormone receptor.
Biochim Biophys Acta Gen Subj
Eduard V Bocharov, Dmitry M Lesovoy, Olga V Bocharova +5 more
Prior studies of the human growth hormone receptor (GHR) revealed a distinct role of spatial rearrangements of its dimeric transmembrane domain in signal transduction across membrane. Detailed structural information obtained in the present study allowed elucidating the bases of such rearrangement and provided novel insights into receptor functioning.
Involvement of the cystathionine-γ-lyase/Cav3.2 pathway in substance P-induced bladder pain in the mouse, a model for nonulcerative bladder pain syndrome.
Neuropharmacology
Maho Tsubota, Yasumasa Okawa, Yuhei Irie +5 more
Hydrogen sulfide (H2S) formed by cystathionine-γ-lyase (CSE) enhances the activity of Cav3.2 T-type Ca2+ channels, contributing to the bladder pain accompanying hemorrhagic cystitis caused by systemic administration of cyclophosphamide (CPA) in mice. Given clinical and fundamental evidence for the involvement of the substance P/NK1 receptor systems in bladder pain syndrome (BPS)/interstitial cystitis (IC), we created an intravesical substance P-induced bladder pain model in mice and analyzed the possible involvement of the CSE/Cav3.2 pathway. Bladder pain/cystitis was induced by i.p. CPA or intravesical substance P in female mice. Bladder pain was evaluated by counting nociceptive behavior and by detecting referred hyperalgesia in the lower abdomen and hindpaw. The isolated bladder tissue was weighed to estimate bladder swelling and subjected to histological observation and Western blotting. Intravesical substance P caused profound referred hyperalgesia accompanied by little bladder swelling or edema 6-24 h after the administration, in contrast to i.p. CPA-induced nociceptive behavior/referred hyperalgesia with remarkable bladder swelling/edema and urothelial damage. The bladder pain and/or cystitis symptoms caused by substance P or CPA were prevented by the NK1 receptor antagonist. CSE in the bladder was upregulated by substance P or CPA, and the NK1 antagonist prevented the CPA-induced CSE upregulation. A CSE inhibitor, a T-type Ca2+ channel blocker and gene silencing of Cav3.2 abolished the intravesical substance P-induced referred hyperalgesia. The intravesical substance P-induced pain in mice is useful as a model for nonulcerative BPS, and involves the activation of the NK1 receptor/CSE/H2S/Cav3.2 cascade.
[Clinical efficacy of neuropeptides in cerebrovascular pathology].
Zh Nevrol Psikhiatr Im S S Korsakova
O A Shavlovskaya
Great value in the treatment of ischemic stroke (IS) is given for neuroprotection. When ischemic neuroprotection aims to increase the period of 'therapeutic window' and stop the cascade of pathological reactions. The neuroprotection is defined as the continuous adaptation of the neuron to new functional conditions, as the key to reducing damage to brain tissue caused by ischemia, it acts at the level of the molecular cascade leading to the dysfunction and death of neurons. Special attention is paid to the study of the properties of low molecular weight neuropeptides that penetrate through the hematoencephalitic barrier and exert a multiple effect on the Central nervous system (CNS) even in small concentrations. One of neuropeptide of cytoprotectors, is Cortexin, containing a complex of low molecular weight peptides (with mass from 1 to 10 kDa), which is optimally balanced and close to the metabolism of brain neurons (organotropic) that exert tissue-specific, regulatory and restorative effect on the cerebral cortex. The article presents data on the effectiveness purpose of Cortexin in patients with IS. It is shown that the optimal scheme for the purpose of Cortexin includes: intramuscular administration of Cortexin in the dose of 20 mg (10 mg morning + 10 mg evening) for 10 days, with a repeat the same course within 10 days after the first, since the first 6 h after the onset of stroke symptoms. The observation period is more than 2 months.
Peptidomimetic growth hormone secretagogue derivatives for positron emission tomography imaging of the ghrelin receptor.
Eur J Med Chem
Milan M Fowkes, Tyler Lalonde, Lihai Yu +3 more
The ghrelin receptor is a seven-transmembrane (7-TM) receptor known to have an increased level of expression in human carcinoma and heart failure. Recent work has focused on the synthesis of positron emission tomography (PET) probes designed to target and image this receptor for disease diagnosis and staging. However, these probes have been restricted to small-molecule quinalizonones and peptide derivatives of the endogenous ligand ghrelin. We describe the design, synthesis and biological evaluation of a series of 4-fluorobenzoylated growth hormone secretagogues (GHSs) derived from peptidic (GHRP-1, GHPR-2 and GHRP-6) and peptidomimetic (G-7039, [1-Nal4]G-7039 and ipamorelin) families in order to test locations for the insertion of fluorine-18 for PET imaging. The peptidomimetic G-7039 was found to be the most suitable for 18F-radiolabelling as its non-radioactive 4-fluorobenzoylated analogue ([1-Nal4,Lys5(4-FB)]G-7039), had both a high binding affinity (IC50 = 69 nM) and promising in vitro efficacy (EC50 = 1.1 nM). Prosthetic group radiolabelling of the precursor compound [1-Nal4]G-7039 using N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) delivered the PET probe [1-Nal4,Lys5(4-[18F]-FB)]G-7039 in an average decay-corrected radiochemical yield of 48%, a radio-purity ≥ 99% and an average molar activity of >34 GBq/μmol. This compound could be investigated as a PET probe for the detection of diseases that are characterised by overexpression of the ghrelin receptor.
Phosphorylated delta sleep inducing peptide restores spatial memory and p-CREB expression by improving sleep architecture at high altitude.
Life Sci
Koustav Roy, Garima Chauhan, Punita Kumari +5 more
Sleep loss at high altitude (HA) play major role in worsening of neuropsychological functions, such as attention, memory and decision making. This study investigates the role of phosphorylated delta sleep inducing peptide (p-DSIP) in improving sleep architecture during chronic hypobaric hypoxia (HH) exposure and restoration of spatial navigational memory.
Pharmacotherapy for Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema: A Systematic Review.
Otolaryngol Head Neck Surg
Claire M Lawlor, Ashwin Ananth, Blair M Barton +2 more
Objective Angioedema is a potentially life-threatening complication of angiotensin-converting enzyme inhibitor (ACEI) use, occurring in up to 0.5% of users. Although the pathophysiology of ACEI-induced angioedema is attributable to elevated serum bradykinin, standard management typically includes corticosteroids and antihistamines. We sought to summarize the evidence supporting pharmacotherapy for ACEI-induced angioedema. Data Sources PubMed, MEDLINE, and Embase portals. Methods A systematic literature review was conducted according to the PRISMA guidelines. Databases were queried by 3 independent reviewers for English-language studies published between 1980 and 2017. The initial search screened for all occurrences of "angioedema" and then was further refined to include studies of ACEI-related cases and exclude hereditary angioedema. Results Five articles representing 218 cases were identified, including 3 randomized controlled trials and 2 prospective case series with historical controls. One of 2 studies of icatibant (bradykinin B2 receptor antagonist) found more rapid symptom improvement than that with a control group of corticosteroids and antihistamines. Two studies of ecallantide (plasma kallikrein inhibitor) and 1 study of C1 inhibitor replacement found no significant benefit over control. No studies were identified that compared the efficacy of corticosteroids with antihistamines, of one dose with another, of fresh frozen plasma, or of combination therapy. Conclusion The efficacy of treatment of ACEI-induced angioedema with bradykinin antagonists, kallikrein inhibitor, and C1 inhibitor warrants further study. Although consistent benefit of these medications has not been demonstrated, their use has not caused harm. One study examining off-label use of icatibant has demonstrated efficacy over control. In addition, further study is needed to establish the efficacy and mechanism of action of standard pharmacotherapy such as corticosteroids and antihistamines in treatment of this condition.
Opposing effects of cationic antimicrobial peptides and divalent cations on bacterial lipopolysaccharides.
Phys Rev E
Matthew Smart, Aruna Rajagopal, Wing-Ki Liu +1 more
The permeability of the bacterial outer membrane, enclosing Gram-negative bacteria, depends on the interactions of the outer, lipopolysaccharide (LPS) layer, with surrounding ions and molecules. We present a coarse-grained model for describing how cationic amphiphilic molecules (e.g., antimicrobial peptides) interact with and perturb the LPS layer in a biologically relevant medium, containing monovalent and divalent salt ions (e.g., Mg^{2+}). In our approach, peptide binding is driven by electrostatic and hydrophobic interactions and is assumed to expand the LPS layer, eventually priming it for disruption. Our results suggest that in parameter ranges of biological relevance (e.g., at micromolar concentrations) the antimicrobial peptide magainin 2 effectively disrupts the LPS layer, even though it has to compete with Mg^{2+} for the layer. They also show how the integrity of LPS is restored with an increasing concentration of Mg^{2+}. Using the approach, we make a number of predictions relevant for optimizing peptide parameters against Gram-negative bacteria and for understanding bacterial strategies to develop resistance against cationic peptides.
Serelaxin treatment reverses vascular dysfunction and left ventricular hypertrophy in a mouse model of Type 1 diabetes.
Sci Rep
Hooi Hooi Ng, Chen Huei Leo, Darnel Prakoso +3 more
Serelaxin prevents endothelial dysfunction in the mouse aorta ex vivo and inhibits apoptosis in cardiomyocytes under acute hyperglycaemia. Less is known about the effects of serelaxin in an in vivo mouse model of diabetes. Therefore, we tested the hypothesis in streptozotocin (STZ)-treated mice that serelaxin is able to reverse diabetes-induced vascular dysfunction and cardiac remodelling. Mice were divided into citrate buffer + placebo, STZ + placebo and STZ + serelaxin (0.5 mg/kg/d, 2 weeks) groups. After 12 weeks of diabetes, sensitivity to the endothelium-dependent agonist acetylcholine (ACh) was reduced in the mesenteric artery. This was accompanied by an enhanced vasoconstrictor prostanoid contribution and a decrease in endothelium-derived hyperpolarisation (EDH)-mediated relaxation. Serelaxin restored endothelial function by increasing nitric oxide (NO)-mediated relaxation but not EDH. It also normalised the contribution of vasoconstrictor prostanoids to endothelial dysfunction and suppressed diabetes-induced hyper-responsiveness of the mesenteric artery to angiotensin II. Similarly, diabetes reduced ACh-evoked NO-mediated relaxation in the aorta which was reversed by serelaxin. In the left ventricle, diabetes promoted apoptosis, hypertrophy and fibrosis; serelaxin treatment reversed this ventricular apoptosis and hypertrophy, but had no effect on fibrosis. In summary, serelaxin reversed diabetes-induced endothelial dysfunction by enhancing NO-mediated relaxation in the mouse vasculature and attenuating left ventricular hypertrophy and apoptosis.
The "pre-assembled state" of magainin 2 lysine-linked dimer determines its enhanced antimicrobial activity.
Colloids Surf B Biointerfaces
Esteban N Lorenzón, Thatyane M Nobre, Luciano Caseli +4 more
Antimicrobial peptides (AMPs) are alternatives to conventional antibiotics against multi-drug resistant bacteria with low potential for developing microbial resistance. The design of such molecules requires understanding of the mechanisms of action, particularly the interaction with bacteria cell membranes. In this work, we determine the mechanism responsible for the higher activity against Escherichia coli of the C-terminal lysine dimer of magainin 2, (MG2)2K, in comparison to the monomeric peptide magainin 2 (MG2). Langmuir monolayers and vesicles made with the E. coli lipid extract were used to address the two possible states for the peptide-membrane interaction, namely the "binding state" and "pore state", respectively. The incorporation of MG2 and (MG2)2K in lipid monolayers at the air-water interface caused slight differences in surface pressure isotherms and polarization-modulated infrared reflection absorption (PM-IRRAS) spectra, and therefore the difference in activity is not associated with the binding state. In contrast, large differences were observed in the leakage experiments where (MG2)2K was shown to disrupt the large unilamellar vesicles to a much higher extent owing to efficient pore formation. The binding and penetration of MG2 and (MG2)2K were also probed with molecular dynamics (MD) simulations for bilayers made with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine:1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPE:POPG). (MG2)2K forms disordered toroidal pores at a significant lower concentration than for MG2. In summary, the combination of experimental and computational simulation results indicated that the "pre-assembling state" of (MG2)2K dimer leads to a reduced number of molecules and shorter time being required to kill E. coli.
Serelaxin inhibits differentiation and fibrotic behaviors of cardiac fibroblasts by suppressing ALK-5/Smad2/3 signaling pathway.
Exp Cell Res
Xue-Ping Wu, Hai-Jie Wang, Yong-Li Wang +2 more
Serelaxin, a recombinant form of human relaxin-2, is currently regarded as a novel drug for treatment of acute heart failure. However, whether therapeutic effects of serelaxin are achieved by inhibiting cardiac fibrosis remains unclear. In this study, we investigate effects of serelaxin on inhibiting cardiac fibrosis. Cardiac fibroblasts (CFs) were isolated from the hearts of adult rats. Effects of serelaxin on differentiation of CFs towards myofibroblasts (MFs) and their fibrotic behaviors after induction with TGF-β1 were examined. Synthesis and degradation of collagens, secretion of IL-10, and expression of ALK-5 and p-Smad2/3 of TGF-β1-induced cells were assessed after treatment with serelaxin. Serelaxin inhibited differentiation of TGF-β1-induced CFs towards MFs, and reduced proliferation and migration of the induced cells. Moreover, serelaxin down-regulated expression of collagen I/III and TIMP-2, and up-regulated expression of MMP-2 and MMP-9 in the cells. After treatment with serelaxin, activity of MMP-2 and MMP-9 and secretion of IL-10 increased, expression of ALK-5 and the level of Smad2/3 phosphorylation was reduced significantly. These results suggest that serelaxin can inhibit differentiation of TGF-β1-induced CFs towards MFs, reduce production of collagens by suppressing ALK-5/Smad2/3 signaling pathway, and enhance extracellular matrix degradation by increasing MMP-2/TIMP-2 ratio and IL-10 secretion. Serelaxin may be a potential therapeutic drug for inhibiting cardiac fibrosis.