RPEP-02294 · 2013Infusion of the NPY Y2 receptor agonist NPY(13-36) into the lateral septum significantly increased open-arm exploration in the elevated plus-maze test — a classic indicator of reduced anxiety. This anxiolytic effect was blocked by pre-treatment with the selective Y2 receptor antagonist BIIE 0246, confirming that Y2 receptors mediate the effect.
However, the anxiolytic action was test-specific: NPY(13-36) reduced burying behavior in the shock-probe burying test but did not reduce anxiety in all threat-related behavioral measures. The Y2 antagonist blocked the plus-maze effect but not the shock-probe effect, suggesting that the anxiolytic actions of lateral septal NPY(13-36) involve Y2-dependent and Y2-independent mechanisms depending on the type of threat.
Trent, Natalie L; Menard, Janet L ·
RPEP-02296 · 2013High-protein breakfasts significantly increased circulating levels of the satiety peptides GLP-1 and PYY compared to high-fat and high-carbohydrate breakfasts. PYY levels were highest after the protein meal (p=0.005), and GLP-1 was elevated from 120 minutes onward (p=0.041). However, these hormonal differences did not translate into reduced food intake at a subsequent meal — participants ate roughly the same amount regardless of breakfast composition (~1,023 kcal after protein vs. ~1,158 kcal after carbohydrate).
Ghrelin, the hunger hormone, decreased equally after all three breakfast types.
van der Klaauw, Agatha A; Keogh, Julia M; Henning, Elana; Trowse, Victoria M; Dhillo, Waljit S; Ghatei, Mohammad A; Farooqi, I Sadaf · Rct
RPEP-02300 · 2013Nine years after surgery, gastric bypass patients had significantly higher postprandial energy expenditure (p=0.018) and total 24-hour energy expenditure (p=0.048) compared to vertical banded gastroplasty (VBG) patients, despite similar body composition and food intake. Gastric bypass also produced significantly higher postprandial levels of the gut peptide hormones PYY and GLP-1 (both p<0.001). These exaggerated peptide responses may drive the increased calorie burning that explains superior long-term weight loss maintenance.
Werling, Malin; Olbers, Torsten; Fändriks, Lars; Bueter, Marco; Lönroth, Hans; Stenlöf, Kaj; le Roux, Carel W ·
RPEP-02308 · 2013Angiotensin III (Ang III), long considered a minor degradation product of angiotensin II, actually produces physiologically relevant effects comparable to Ang II. The review establishes that Ang III is a biologically active peptide in its own right within the renin-angiotensin system (RAS), with its own spectrum of effects on blood pressure, blood volume, sodium handling, thirst, and vasopressin release.
The RAS contains multiple active peptides — angiotensinogen, Ang II, Ang III, Ang IV, and Ang-(1-7) — each with distinct physiological roles. While research has overwhelmingly focused on Ang II, emerging data shows Ang III may be equally important in driving the pathological effects seen in heart failure, hypertension, heart attack, and diabetic kidney disease.
Yugandhar, Vudhya G; Clark, Michelle A · Review
RPEP-02309 · 2013Intracerebroventricular injection of ghrelin at doses of 0.1 to 100 nmol/L inhibited the pain-relieving effect of systemic morphine (6 mg/kg) in the tail withdrawal test in mice. The GHS-R1a receptor agonists GHRP-6 and GHRP-2 similarly reduced morphine analgesia.
Critically, pretreatment with the selective GHS-R1a antagonist [d-Lys(3)]-GHRP-6 (100 nmol/L) did not block the anti-opioid effects, demonstrating that ghrelin's interference with morphine pain relief occurs through a receptor mechanism independent of GHS-R1a. This points to an unidentified receptor or signaling pathway mediating the ghrelin-opioid interaction in the brain.
Zeng, Ping; Chen, Jia-Xiang; Yang, Bei; Zhi, Xing; Guo, Fa-Xian; Sun, Meng-Li; Wang, Jing-Lei; Wei, Jie ·
RPEP-02333 · 2014Substance P levels increased in injured corneas in both the alkali burn and suture models. The NK1R antagonist Lanepitant, applied topically as eye drops, was nontoxic and reduced both blood vessel (hemangiogenesis) and lymphatic vessel (lymphangiogenesis) growth, corneal SP levels, and inflammatory cell (leukocyte) infiltration within 4 days in the alkali burn model.
Subconjunctival injection of Lanepitant was effective in the suture model (where topical drops were insufficient), reducing lymphatic vessels, leukocyte infiltration, and SP levels after 10 days. In the alkali burn model, subconjunctival Lanepitant additionally reduced corneal perforation rates, opacity, and improved tear secretion. Befetupitant also showed efficacy but its vehicle (DMSO) was toxic to the eye surface.
Bignami, Fabio; Giacomini, Chiara; Lorusso, Anna; Aramini, Andrea; Rama, Paolo; Ferrari, Giulio ·
RPEP-02335 · 2014In 62 women with fibromyalgia, current smokers (n=18) had significantly lower leptin levels than ex-smokers (n=25, P=0.002). Normally, smoking stimulates neuropeptide Y (NPY) production through nicotinic receptors, but this expected NPY increase was absent in fibromyalgia patients. Without that compensatory NPY response, smokers with fibromyalgia experienced worse outcomes: higher pain scores on VAS (P=0.04), more tender points (P=0.03), and lower pain thresholds (P=0.01). NPY levels directly correlated with pain threshold (rho=0.414) and inversely correlated with tender point counts (rho=-0.375). The findings suggest that a broken leptin-NPY feedback loop may be a key mechanism underlying chronic pain in fibromyalgia.
Bokarewa, Maria I; Erlandsson, Malin C; Bjersing, Jan; Dehlin, Mats; Mannerkorpi, Kaisa ·
RPEP-02336 · 2014The paper proposes a five-component model of body weight regulation centered on the counterregulation of insulin by leptin. Key components include: (1) the autonomic nervous system and suprachiasmatic clock coordinating energy intake and expenditure within a circadian framework; (2) interaction with brain reward circuits involving dopamine, ghrelin, melanin-concentrating hormone, and orexin-hypocretin peptides driving feeding and locomotion; (3) leptin counteracting insulin through multiple mechanisms — potentiating CCK-mediated satiation, inhibiting insulin secretion, opposing insulin's lipogenic effects with lipolytic action, and modulating insulin sensitivity; and (4) leptin's role in inhibiting bone mineral accrual, suggesting it helps maintain stability of skeletal, lean, and adipose tissue masses.
Borer, Katarina T ·
RPEP-02337 · 2014Immunohistochemistry of human hypothalamic tissue revealed:
- Dense plexuses of kisspeptin (KP), neurokinin B (NKB), and substance P (SP) immunoreactive fibers in the postinfundibular eminence and infundibular stalk
- These neuropeptide fiber networks innervated the portal capillary network and formed descending tracts to the neurohypophysis
- KP, NKB, and SP plexuses intermingled with and established occasional contacts with GnRH fiber projections
- Triple immunofluorescence revealed considerable overlap of KP, NKB, and SP signals within individual fibers, confirming they arise from the same mediobasal hypothalamic neurons
- These anatomical relationships support axo-axonal communication between neuropeptide fibers and GnRH projections in humans
Borsay, Beáta Á; Skrapits, Katalin; Herczeg, László; Ciofi, Philippe; Bloom, Stephen R; Ghatei, Mohammad A; Dhillo, Waljit S; Liposits, Zsolt; Hrabovszky, Erik ·
RPEP-02342 · 2014Three GHSR1a agonists (ulimorelin, capromorelin, CP464709) caused rapid blood pressure decreases in anesthetized rats. This effect was NOT blocked by GHSR1a antagonists (JMV2959 or YIL781) at doses that blocked other ghrelin receptor effects. Neither ghrelin nor unacylated ghrelin mimicked the hypotensive effect. The blood pressure drop preceded changes in sympathetic nerve activity and was not reduced by ganglionic blockade or baroreceptor denervation, indicating a direct vascular mechanism. Ulimorelin relaxed isolated mesenteric artery and aorta segments, with relaxation also resistant to GHSR1a antagonists. These findings indicate a novel vascular receptor activated by small-molecule GHSR1a agonists but not by the peptide ghrelin.
Callaghan, Brid; Kosari, Samin; Pustovit, Ruslan V; Sartor, Daniela M; Ferens, Dorota; Ban, Kung; Baell, Jonathan; Nguyen, Trung V; Rivera, Leni R; Brock, James A; Furness, John B ·
RPEP-02343 · 2014Beyond the known ghrelin receptor GHSR1a, evidence points to at least two additional classes of receptors: ghrelin receptor-like receptors (GRLRs) that respond to both ghrelin and its unacylated form (UAG), and UAG-specific receptors that respond only to unacylated ghrelin. These novel receptors may be heterodimers formed when GHSR1a or GHSR1b pairs with other G protein-coupled receptors, creating complexes with distinct pharmacological properties.
Effects mediated through these novel receptors include fat cell lipid accumulation, muscle cell differentiation, bone cell proliferation, insulin release, heart protection, blood vessel constriction and growth, and tumor cell proliferation — none of which can be fully explained by GHSR1a alone.
Callaghan, Brid; Furness, John B ·
RPEP-02347 · 2014In the landmark CLARINET trial, lanreotide (a long-acting somatostatin analog) cut the risk of tumor progression or death by 53% compared to placebo in patients with metastatic neuroendocrine tumors of the gut and pancreas (hazard ratio 0.47, p<0.001). After 96 weeks, 65.1% of lanreotide patients had no disease progression compared to just 33.0% on placebo.
The median progression-free survival wasn't even reached in the lanreotide group (vs. 18 months for placebo), meaning more than half the patients were still progression-free at study end. The treatment effect was consistent across subgroups, and quality of life was similar between groups.
Caplin, Martyn E; Pavel, Marianne; Cwikla, Jaroslaw B; Phan, Alexandria T; Raderer, Markus; Sedlackova, Eva; Cadiot, Guillaume; Wolin, Edward M; Capdevila, Jaume; Wall, Lucy; Rindi, Guido; Langley, Alison; Martinez, Santiago; Blumberg, Jochen; Ruszniewski, Philippe; CLARINET Investigators · Human Rct
RPEP-02348 · 2014When GLP-1 and glucagon were each given at doses too low to reduce appetite on their own (subanorectic doses), combining them produced a significant 13% reduction in food intake compared to placebo. Additionally, GLP-1 protected against glucagon's tendency to raise blood sugar, and the combination increased resting energy expenditure by 53 kcal/day.
This demonstrates a synergistic interaction between the two peptides at low doses: neither alone was effective, but together they reduced appetite, prevented hyperglycemia, and boosted metabolic rate — providing a proof-of-concept for dual GLP-1/glucagon agonist drugs.
Cegla, Jaimini; Troke, Rachel C; Jones, Ben; Tharakan, George; Kenkre, Julia; McCullough, Katherine A; Lim, Chung Thong; Parvizi, Nassim; Hussein, Mohamed; Chambers, Edward S; Minnion, James; Cuenco, Joyceline; Ghatei, Mohammad A; Meeran, Karim; Tan, Tricia M; Bloom, Stephen R · Randomized Double Blind Crossover Trial
RPEP-02352 · 2014A new method for synthesizing hydrophobic amyloid-beta peptides was developed by temporarily adding lysine residues to the C-terminus during synthesis, then removing them enzymatically with carboxypeptidase B. This produced Aβ42 of quality rivaling recombinant expression — a significant improvement over standard synthesis.
The method also enabled synthesis of Aβ46, which was found to form amyloid fibrils significantly faster than Aβ42 or Aβ40. Despite being present in low amounts in the human brain, Aβ46's enhanced amyloidogenicity suggests it could play a disproportionate role in initiating Alzheimer's plaque formation.
Chemuru, Saketh; Kodali, Ravindra; Wetzel, Ronald · Laboratory
RPEP-02353 · 2014Nerve injury completely abolished the ability of μ-opioid receptors to inhibit substance P release from pain-sensing nerve fibers in the spinal cord of rats — explaining why opioids work poorly for neuropathic pain. In contrast, this opioid-mediated inhibition of substance P release remained intact in rats with inflammatory pain and in untreated rats. The loss of opioid control was not caused by fewer opioid receptors on nerve fibers — their numbers remained unchanged. Instead, the opioid receptors appeared to lose their ability to signal properly after nerve injury, even though they were still physically present.
Chen, W; McRoberts, J A; Marvizón, J C G · Animal Study
RPEP-02360 · 2014Anamorelin hydrochloride demonstrated significant improvements across multiple cachexia endpoints in preclinical and clinical studies:
- Significant appetite enhancement via potent ghrelin receptor activation
- Improvements in body weight and lean body mass compared to placebo
- Improvements in handgrip strength (a key functional measure)
- Stimulation of growth hormone and IGF-1 secretion (anabolic effects)
Critically, the growth hormone and IGF-1 stimulation did not promote tumor growth, and overall survival was not compromised in cancer patients. The drug was well tolerated with no dose-limiting toxicities identified across studies completed at the time of this review. Phase III studies in non-small-cell lung cancer cachexia were ongoing.
Currow, David C; Abernethy, Amy P ·
RPEP-02361 · 2014Peptide drug impurities fall into three categories: (1) synthesis-related impurities from solid-phase peptide synthesis (SPPS) — including amino acid deletions, insertions, racemization, incomplete side-chain deprotection, oxidation, and dimerization; (2) degradation products from chemical instability — including β-elimination, diketopiperazine formation, pyroglutamate formation, and succinimide formation; (3) finished product impurities from API-excipient interactions. Trifluoroacetate (TFA) counter-ion contamination from SPPS purification and cross-contamination with unrelated peptides (indicating inadequate GMP) were also documented.
D'Hondt, Matthias; Bracke, Nathalie; Taevernier, Lien; Gevaert, Bert; Verbeke, Frederick; Wynendaele, Evelien; De Spiegeleer, Bart ·
RPEP-02366 · 2014The review consolidates evidence showing that Substance P is expressed during the inflammatory process of periodontal disease and contributes to alveolar bone resorption. Studies demonstrate that Substance P levels are highest in the gingival crevicular fluid from sites with active periodontal disease and bone loss.
The persistent presence of Substance P in periodontal tissues could stimulate neurogenic inflammation in susceptible tissues and cause pain. The review identifies Substance P expressed during periodontal disease as a potential risk factor for patients with systemic inflammatory pathologies, particularly chronic arthritis and rheumatoid arthritis, suggesting a neuropeptide-mediated link between oral and systemic inflammation.
de Avila, Erica Dorigatti; de Molon, Rafael Scaf; de Godoi Gonçalves, Daniela Aparecida; Camparis, Cinara Maria ·
RPEP-02368 · 2014Self-assembling EAbuK peptide hydrogel layer on sandblasted/acid-etched titanium enhanced human osteoblast adhesion (with RGD conjugate at 3.8 × 10⁻⁷ M) and proliferation (with IGF-1 at 2.1 × 10⁻⁵ M). XPS confirmed surface composition changes; contact angle measurements showed altered wettability from the peptide layer.
Dettin, M; Zamuner, A; Iucci, G; Messina, G M L; Battocchio, C; Picariello, G; Gallina, G; Marletta, G; Castagliuolo, I; Brun, P ·
RPEP-02376 · 2014Daily ghrelin injections significantly extended the lifespan of mice with inherited dilated cardiomyopathy (DCM) compared to saline-treated controls over a 30-day treatment period. Beyond survival, ghrelin improved multiple measures of heart function: it reduced left ventricular dilation, increased ejection fraction (the heart's pumping efficiency), decreased the heart-to-body weight ratio, prevented cardiac remodeling and fibrosis, and lowered brain natriuretic peptide (BNP) expression — a key marker of heart failure severity.
The mechanism appears to involve the autonomic nervous system: ghrelin suppressed the excessive sympathetic nerve activity that drives heart failure progression and restored parasympathetic (calming) nerve activity to the heart. This rebalancing of the nervous system may be central to ghrelin's cardioprotective effects.
Du, Cheng-Kun; Zhan, Dong-Yun; Morimoto, Sachio; Akiyama, Tsuyoshi; Schwenke, Daryl O; Hosoda, Hiroshi; Kangawa, Kenji; Shirai, Mikiyasu · Preclinical (Animal Study)
RPEP-02383 · 2014Lactoferrin-derived peptides, including LfcinB20-25 (RRWQWR), LIWKL, and RPYL, all inhibited angiotensin II-induced vasoconstriction in ex vivo assays. RPYL showed the highest inhibitory effect and was confirmed to directly block AT1 receptor binding using radioligand assays with [(125)I]-(Sar(1),Ile(8))-angiotensin II.
Importantly, neither the lactoferrin hydrolysate nor RPYL inhibited endothelin-1 or depolarization-induced vasoconstriction, demonstrating selectivity for the angiotensin pathway. This represents a blood pressure-lowering mechanism beyond ACE inhibition that may work synergistically with it.
Fernández-Musoles, Ricardo; Castelló-Ruiz, María; Arce, Cristina; Manzanares, Paloma; Ivorra, M Dolores; Salom, Juan B ·
RPEP-02388 · 2014Using computational design with Rosetta software, researchers created two macrocyclic (ring-shaped) peptides derived from the MD2 protein sequence that modulate TLR4 immune signaling. The cyclic peptides synergistically enhanced TLR4 activation when co-administered with LPS (bacterial endotoxin), while their linear (non-cyclized) counterparts had no such effect.
This demonstrates that peptide cyclization — making a linear peptide into a ring — can be critical for biological activity, and that computationally designed macrocyclic peptides can serve as tools for modulating innate immune signaling.
Gao, Meng; London, Nir; Cheng, Kui; Tamura, Ryo; Jin, Jialin; Schueler-Furman, Ora; Yin, Hang · In Vitro
RPEP-02390 · 2014Case reports and the FDA pharmacovigilance database indicate associations between acute pancreatitis and incretin drugs (both DPP-4 inhibitors and GLP-1 receptor agonists). However, only 1 of 8 pharmacoepidemiological studies found a statistically significant odds ratio for this association. None of the intervention trials, including two large RCTs with cardiovascular endpoints, confirmed an increased pancreatitis risk with incretin use.
Other diabetes drugs also have pancreatitis associations: metformin (in renal insufficiency), sulphonylureas (particularly glibenclamide), and phenformin have been linked in case reports or cohort studies. No link was found for metaglinide, acarbose, pramlintide, or SGLT-2 inhibitors. Thiazolidinediones may actually be protective in animal models.
Giorda, C B; Nada, E; Tartaglino, B; Marafetti, L; Gnavi, R ·
RPEP-02391 · 2014In a restricted feeding protocol, all three mutant groups (GhsrKO, Mc3rKO, and double knockouts) initially showed reduced food anticipatory activity. However, GhsrKO mice eventually developed a robust compensatory response, while Mc3rKO and double knockout mice did not recover. The continued FAA deficit in Mc3rKO mice was associated with lower expression of the orexigenic neuropeptides AgRP and NPY in the hypothalamus before mealtimes. AgRP and NPY expression positively correlated with FAA levels, and only Mc3r loss (not Ghsr loss) suppressed these hunger-signaling peptides, pointing to melanocortin-3 receptors as critical regulators of anticipatory hunger responses.
Girardet, Clemence; Mavrikaki, Maria; Southern, Mark R; Smith, Roy G; Butler, Andrew A ·
RPEP-02397 · 2014The computational analysis revealed several key relationships between peptide stapling strategy and function:
- α-helical conformation stability is critical for peptide-MDM2 binding
- Peptide sequence, cross-linker stereochemistry, alkene bridge conformation, and bridge length all affect helical stability
- WaterMap analysis identified over 100 hydration sites in the MDM2 binding pocket where displacing water releases binding free energy
- Potentials of mean force correctly ranked peptide binding affinities in agreement with experimental data
- Double staples can provide additional stability but the benefit depends on placement and chemistry
The study provides a comprehensive structure-activity relationship for stapled peptide design targeting the p53/MDM2 interaction.
Guo, Zuojun; Streu, Kristina; Krilov, Goran; Mohanty, Udayan ·
RPEP-02403 · 2014Vasoactive intestinal peptide (VIP) improved early pregnancy outcomes in non-obese diabetic (NOD) mice by shifting the immune environment at the maternal-fetal interface toward tolerance. In vitro, VIP treatment of implantation sites increased expression of immunosuppressive markers IL-10, TGF-β, and Foxp3 (a marker of regulatory T cells). It also reduced expression of IL-17 and RORγT, markers associated with inflammatory immune responses. Resorption sites (where pregnancies were failing) had lower VIP expression and reduced suppressive markers compared to viable sites. When pregnant NOD mice were injected with VIP on gestational day 6.5, they showed a more even distribution of viable implantation sites with increased IL-10, TGF-β, and Foxp3 expression by day 9.5.
Hauk, Vanesa; Azzam, Sofía; Calo, Guillermina; Gallino, Lucila; Paparini, Daniel; Franchi, Ana; Ramhorst, Rosanna; Pérez Leirós, Claudia ·
RPEP-02408 · 2014The review identifies multiple peptide systems involved in colorectal cancer growth:
- Gastrin and gastrin-releasing peptide (GRP/bombesin) promote CRC growth
- Insulin-like growth factor I and II are implicated in CRC progression
- Growth hormone-releasing hormone (GHRH) contributes to tumor growth
Experimental approaches include antagonistic analogs of bombesin/GRP, GHRH antagonists, and cytotoxic peptides that target peptide receptors on tumors to deliver chemotherapy directly to cancer cells. These peptide-based strategies complement existing VEGF and EGFR-targeting therapies.
Hohla, Florian; Winder, Thomas; Greil, Richard; Rick, Ferenc G; Block, Norman L; Schally, Andrew V ·
RPEP-02411 · 2014Key points from this early review:
- GLP-1 is involved in both peripheral and central satiety pathways
- Clinical trials showed exenatide and liraglutide have weight-lowering potential in non-diabetic obese individuals
- GLP-1 drugs may prevent diabetes development compared to other weight loss agents
- Incretin impairment exists in both obesity and diabetes, potentially linking these two conditions
- At the time of writing (2014), bariatric surgery was the only efficient obesity treatment
- The review predicted GLP-1-based therapies would play a key role in prevention and treatment of both obesity and diabetes
Iepsen, Eva W; Torekov, Signe S; Holst, Jens J ·
RPEP-02413 · 2014DPP-4 is a widely expressed enzyme that clips dipeptides from the N-terminus of peptides containing proline or alanine at position 2. Its most clinically relevant targets are the incretin hormones GLP-1 and GIP, which regulate blood glucose. Several families of DPP-4 inhibitors have been developed, and multiple gliptins are now approved for type 2 diabetes based on their ability to preserve incretin activity and improve glycemic control.
Beyond diabetes, this review highlights that DPP-4 has many other peptide substrates involved in immune regulation, inflammation, and cell signaling — suggesting gliptins could potentially be repurposed for other therapeutic areas.
Juillerat-Jeanneret, Lucienne ·
RPEP-02421 · 2014A single intraperitoneal injection of selank at 0.3 mg/kg eliminated anxiety caused by alcohol withdrawal in rats, as measured by the elevated plus maze and social interaction tests. Selank also prevented the development of mechanical allodynia (pain hypersensitivity) — a common withdrawal symptom. Notably, selank reduced withdrawal symptoms without affecting the rats' ethanol consumption, meaning it treated the withdrawal without changing drinking behavior.
Kolik, L G; Nadorova, A V; Kozlovskaya, M M ·
RPEP-02434 · 2014Peptides derived from the knuckle epitope of BMP-2, covalently conjugated to alginate hydrogels, increased alkaline phosphatase activity in osteoblasts when presented from both 2D surfaces and 3D hydrogels. In 3D hydrogels, the peptides initiated Smad signaling (the canonical BMP pathway), upregulated osteopontin production, and increased mineral deposition in murine mesenchymal stem cells. The peptides were attached via carbodiimide or sulfhydryl coupling strategies, both confirmed by NMR spectroscopy and quantified by fluorescent labeling.
Madl, Christopher M; Mehta, Manav; Duda, Georg N; Heilshorn, Sarah C; Mooney, David J ·
RPEP-02435 · 2014After 12 months, tesamorelin treatment significantly increased IGF-I compared to placebo (change: +102.9 vs +22.8 μg/L; P = 0.02). The key finding was the relationship between IGF-I increases and mitochondrial function:
- Overall correlation between IGF-I increase and phosphocreatine recovery improvement (ViPCr): R = 0.56, P = 0.01
- In tesamorelin-treated subjects only: R = 0.71, P = 0.03 (strong correlation)
- The association remained significant after controlling for age, sex, race, ethnicity, body composition, and insulin sensitivity (all P < 0.05)
Phosphocreatine recovery rate is a validated marker of mitochondrial oxidative capacity, suggesting tesamorelin improves mitochondrial function through IGF-I elevation.
Makimura, Hideo; Murphy, Caitlin A; Feldpausch, Meghan N; Grinspoon, Steven K ·
RPEP-02438 · 2014Hexarelin, a synthetic growth hormone-releasing peptide, has direct cardiovascular effects beyond growth hormone release. It activates both the ghrelin receptor (GHSR) in the brain and a specific cardiac receptor called CD36, which mediates its cardioprotective effects. Compared to the natural hormone ghrelin, hexarelin is more chemically stable and functionally more potent.
The review summarizes evidence that hexarelin can protect the heart through direct actions on cardiac and vascular tissue, independent of its growth hormone-stimulating properties.
Mao, Yuanjie; Tokudome, Takeshi; Kishimoto, Ichiro · Review
RPEP-02443 · 2014The peptide hormone ghrelin drives stress-induced vulnerability to enhanced fear learning through a novel pathway independent of the classical HPA stress axis. Stress-related increases in circulating ghrelin are both necessary and sufficient for exacerbated fear learning, acting through ghrelin receptors in the amygdala. Ghrelin's fear-enhancing effects require growth hormone (GH) in the amygdala — GH was upregulated after chronic stress, its release was enhanced by ghrelin receptor stimulation, and blocking GH receptors prevented ghrelin's fear-enhancing effects. Critically, ghrelin receptor antagonism during stress blocked enhanced fear without affecting corticosterone levels, confirming this is a separate stress response pathway.
Meyer, R M; Burgos-Robles, A; Liu, E; Correia, S S; Goosens, K A ·
RPEP-02449 · 2014Over 12 weeks, the green-plant membrane group lost significantly more weight than placebo (5.0 ± 2.3 kg vs 3.5 ± 2.3 kg, p < 0.01). The supplement also significantly reduced total cholesterol (p < 0.01) and LDL cholesterol (p < 0.05) compared to control.
Single-meal tests on days 1 and 90 showed the supplement group had increased postprandial GLP-1 release and decreased urge for sweet and chocolate on both occasions. This effect was consistent from the first day through the end of the study.
Waist circumference, body fat, and leptin decreased in both groups over the study period, but there were no significant between-group differences for these measures. The authors propose that increased GLP-1 release may be the primary mechanism behind the weight loss and appetite effects.
Montelius, Caroline; Erlandsson, Daniel; Vitija, Egzona; Stenblom, Eva-Lena; Egecioglu, Emil; Erlanson-Albertsson, Charlotte ·
RPEP-02450 · 2014The negatively charged regions of lactoferrin binding protein B (LbpB) in Neisseria meningitidis are essential for protecting the bacteria against lactoferricin, a cationic antimicrobial peptide. Removing these negatively charged regions eliminated LbpB's protective effect while maintaining the protein's structural stability. LbpB provided greater protection against lactoferricin than the bacterial polysaccharide capsule, suggesting it is a major defense mechanism against host antimicrobial peptides. The selective release of LbpB from the cell surface by the autotransporter NalP may serve primarily for immune evasion rather than iron acquisition.
Morgenthau, Ari; Beddek, Amanda; Schryvers, Anthony B ·
RPEP-02455 · 2014In PC3 androgen-independent prostate cancer cells and nude mouse xenografts:
- GHRH stimulated expression and activation of both EGFR and HER2
- GHRH caused rapid ligand-independent HER activation via cAMP/PKA and Src pathways
- GHRH also caused slow ligand-dependent HER activation via ADAM-mediated extracellular pathway
- GHRH antagonists JMR-132 and JV-1-38 abrogated GHRH-stimulated responses in vitro
- EGF reciprocally increased GHRH and GHRH receptor mRNA — bidirectional cross-talk
- In vivo: JV-1-38 inhibited tumor growth with substantial reduction in EGFR/HER2 mRNA and protein
- JV-1-38 significantly decreased phosphorylated Src levels in tumors
Muñoz-Moreno, Laura; Arenas, M Isabel; Carmena, M José; Schally, Andrew V; Prieto, Juan C; Bajo, Ana M ·
RPEP-02463 · 2014The review describes how disulfide-rich head-to-tail cyclic peptides possess exceptional thermal, chemical, and enzymatic stability due to their highly constrained structures. These naturally occurring peptide scaffolds can be utilized in two key ways for drug design:
1. Epitope grafting — inserting pharmaceutically active sequences into the stable cyclic framework to give them enhanced stability and bioavailability
2. Engineering — modifying the scaffold itself to increase selectivity and bioactivity for specific targets
These approaches open possibilities for addressing 'difficult' pharmaceutical targets that are not easily druggable by conventional small molecules or antibodies, including intracellular protein-protein interactions.
Northfield, Susan E; Wang, Conan K; Schroeder, Christina I; Durek, Thomas; Kan, Meng-Wei; Swedberg, Joakim E; Craik, David J ·
RPEP-02466 · 2014The review highlights several novel roles for tachykinin peptides discovered in the preceding five years:
1. Neurokinin B (NKB) signaling in the hypothalamus plays a crucial role in regulating gonadotropin hormone secretion and puberty onset — mutations in NKB or its receptor cause failure to enter puberty.
2. Tachykinins have newly identified roles in hematopoiesis (blood cell formation) and venous thromboembolism (blood clotting in veins).
3. Molecular studies revealed prophylactic activities of tachykinins against neurogenic movement disorders based on their molecular structure.
4. Novel connections between substance P and tendinopathy (tendon disease) and taste perception have been clarified.
Onaga, Takenori ·
RPEP-02474 · 2014Anamorelin (ANAM) is a potent, orally active ghrelin receptor agonist that significantly increased food intake, body weight, and growth hormone levels in rats at doses of 3, 10, and 30 mg/kg over 6 days. The effects were dose-dependent, with GH increases reaching significance at 10 and 30 mg/kg.
In pigs, both single-dose (3.5 mg/kg) and continuous dosing (1 mg/kg/day) increased growth hormone and IGF-1 levels. In vitro, ANAM showed strong binding affinity and agonist activity at the ghrelin receptor and stimulated GH release from rat pituitary cells. These results established ANAM as a highly specific ghrelin receptor agonist with appetite-stimulating and anabolic properties.
Pietra, Claudio; Takeda, Yasuhiro; Tazawa-Ogata, Naoko; Minami, Masashi; Yuanfeng, Xia; Duus, Elizabeth Manning; Northrup, Robert · Animal Study
RPEP-02478 · 2014Oral supplementation with specific collagen peptides (2.5 g or 5.0 g daily for 8 weeks) significantly improved skin elasticity compared to placebo in women aged 35–55. The improvement was statistically significant in both dosage groups, and the effect persisted even 4 weeks after supplementation ended — particularly in older women.
Skin moisture and transepidermal water loss showed positive trends in subgroup analyses but did not reach statistical significance overall. No side effects were reported throughout the study.
Proksch, E; Segger, D; Degwert, J; Schunck, M; Zague, V; Oesser, S · Randomized Controlled Trial
RPEP-02481 · 2014Thuricin CD, a two-peptide bacteriocin produced by Bacillus thuringiensis, showed potent targeted killing of Clostridium difficile when delivered rectally in mice. One hour after rectal administration, C. difficile numbers dropped by more than 95% (over 1.5 log units) compared to controls (P<0.001), and by 6 hours there was a further 1.5 log reduction (P<0.05).
However, oral delivery posed challenges. One of the two peptide components (Trn-β) was broken down by stomach enzymes pepsin and α-chymotrypsin, while the other (Trn-α) survived digestion and was detected in the intestines of pigs after oral feeding. Attempting to deliver the bacteriocin via spores of the producing bacterium also failed — nearly 99% of spores were excreted within 24 hours without producing detectable thuricin in the gut.
Rea, Mary C; Alemayehu, Debebe; Casey, Pat G; O'Connor, Paula M; Lawlor, Peadar G; Walsh, Maria; Shanahan, Fergus; Kiely, Barry; Ross, R Paul; Hill, Colin · Animal Study
RPEP-02486 · 2014In a surprising reversal of the normal pattern, fast eating (5 minutes) produced higher levels of the appetite-suppressing gut peptides GLP-1 and PYY in adults with Prader-Willi syndrome (PWS) compared to slow eating (30 minutes). In healthy normal-weight subjects, the expected opposite was true — slow eating produced greater peptide release and more satiety. In patients with simple obesity, neither eating rate significantly affected GLP-1 levels.
Fast eating also produced lower hunger and higher satiety ratings in PWS patients, mirroring the peptide findings. This reversed relationship suggests PWS involves a fundamentally different pathophysiological substrate governing gut-brain appetite signaling compared to simple obesity.
Rigamonti, A E; Bini, S; Grugni, G; Agosti, F; De Col, A; Mallone, M; Cella, S G; Sartorio, A · Clinical Trial
RPEP-02489 · 2014Three Fmoc-SAP (fluorenylmethyloxycarbonyl self-assembling peptide) hydrogels containing bioactive sequences from laminin and fibronectin were tested in vivo in mouse brains. All three formulations demonstrated biocompatibility, with limited foreign body response and low cytotoxicity maintained for at least 28 days after transplantation.
The peptide hydrogels effectively supported the survival of grafted cortical neural progenitor cells and showed favorable interactions with the surrounding host brain tissue, attenuating the inflammatory response at the graft-host interface.
Rodriguez, A L; Wang, T Y; Bruggeman, K F; Horgan, C C; Li, R; Williams, R J; Parish, C L; Nisbet, D R ·
RPEP-02491 · 2014Both GLP-1 drugs tested — exenatide (a GLP-1 receptor agonist) and sitagliptin (a DPP-4 inhibitor) — caused significant pancreatic injury in mice compared to controls. The damage included acinar cell injury (hypertrophy, autophagy, apoptosis, necrosis, and atrophy), vascular injury, interstitial edema and inflammation, fat necrosis, and duct changes.
Importantly, a high-fat diet made everything worse. Mice fed a high-fat diet already showed increased pancreatic changes compared to standard-diet mice, and when GLP-1 drugs were added on top of a high-fat diet, the pancreatic injury was exacerbated. Pro-inflammatory cytokines (TNFα, IL-1β, and KC) were significantly elevated in high-fat diet mice regardless of drug treatment.
Rouse, Rodney; Xu, Lin; Stewart, Sharron; Zhang, Jun · Animal Study
RPEP-02492 · 2014In the most comprehensive preclinical pancreatic safety assessment ever conducted for GLP-1-based drugs:
- More than 70 GLP-regulated toxicology studies were conducted across mice, rats, dogs, and monkeys
- Over 2,400 pancreata examined from exenatide-treated animals
- Over 1,700 pancreata examined from saxagliptin-treated animals
- Treatment lasted up to 2 years in rodents and 12 months in non-rodents
- Doses reached 130× human exposure for exenatide and 2,200× for saxagliptin
- Neither drug caused microscopic changes indicating acute or chronic pancreatic injury
- No evidence of pancreatitis, pre-neoplastic changes, or pancreatic cancer in any species
These data substantially support the pancreatic safety of GLP-1-based therapies.
Roy, D; Chadwick, K D; Tatarkiewicz, K; LaCerte, C; Bergholm, A-M; Brodie, T; Mangipudy, R S; Parkes, D; Graziano, M J; Reilly, T P ·
RPEP-02495 · 2014GHRP-6 (His-(D-Trp)-Ala-Trp-(D-Phe)-Lys-NH2) spontaneously forms long nanotubes in aqueous solution at pH 7.0 and 22°C. The nanotubes have inner and outer cross-sections of 6.7 nm and 13.4 nm respectively. Molecular dynamics simulations revealed the peptides self-assemble in a partially interdigitated structure: positively charged amino termini at the peptide-water interface, neutral carboxy termini buried in the hydrophobic core, and Lys-6 stretching its positive charge to the cylinder surface. At higher concentrations, nanotubes pack in a hexagonal arrangement with ~15 nm center-to-center spacing. The nanostructures are stable in solution and when transferred to solid supports.
Santana, Héctor; Avila, Cesar L; Cabrera, Ingrid; Páez, Rolando; Falcón, Viviana; Pessoa, Adalberto; Ventosa, Nora; Veciana, Jaume; Itri, Rosangela; Barbosa, Leandro Ramos Souza ·
RPEP-02498 · 2014Thymosin alpha-1 exposure caused human monocyte-derived macrophages to assume an activated shape and dramatically increased their ability to engulf fluorescent beads, zymosan particles, and Aspergillus niger conidia (fungal spores). The phagocytosis and killing of fungal spores began as soon as 30 minutes after exposure.
The effect was dose-dependent and notably occurred with low levels of pro-inflammatory cytokines (TNF-α and IL-6) and unchanged Toll-like receptor expression — meaning Tα1 boosted pathogen killing without triggering excessive inflammation. The mechanism depended on intact microtubules and protein kinase C activity, and operated through complement receptor-mediated phagocytosis with a distinctive pattern of vinculin and actin recruitment at the phagosome.
Serafino, Annalucia; Pica, Francesca; Andreola, Federica; Gaziano, Roberta; Moroni, Noemi; Moroni, Gabriella; Zonfrillo, Manuela; Pierimarchi, Pasquale; Sinibaldi-Vallebona, Paola; Garaci, Enrico ·
RPEP-02504 · 2014A urinary peptide-based diagnostic test called CKD273 — which measures 273 peptide fragments in urine — was validated across 9 different medical centers with remarkable consistency. The test achieved areas under the curve (AUC) of 0.95 to 1.00 for detecting diabetic nephropathy progression in type 2 diabetes patients, meaning it was nearly perfect at distinguishing those whose kidney disease would progress.
The classifier worked reliably regardless of patient age (16-89 years), gender, or what type of container was used to collect the urine. The most consistently detected peptides came from blood-derived and extracellular matrix proteins, suggesting these are the most robust biomarkers for kidney damage in diabetes.
Siwy, Justyna; Schanstra, Joost P; Argiles, Angel; Bakker, Stephan J L; Beige, Joachim; Boucek, Petr; Brand, Korbinian; Delles, Christian; Duranton, Flore; Fernandez-Fernandez, Beatriz; Jankowski, Marie-Luise; Al Khatib, Mohammad; Kunt, Thomas; Lajer, Maria; Lichtinghagen, Ralf; Lindhardt, Morten; Maahs, David M; Mischak, Harald; Mullen, William; Navis, Gerjan; Noutsou, Marina; Ortiz, Alberto; Persson, Frederik; Petrie, John R; Roob, Johannes M; Rossing, Peter; Ruggenenti, Piero; Rychlik, Ivan; Serra, Andreas L; Snell-Bergeon, Janet; Spasovski, Goce; Stojceva-Taneva, Olivera; Trillini, Matias; von der Leyen, Heiko; Winklhofer-Roob, Brigitte M; Zürbig, Petra; Jankowski, Joachim · Prospective Validation
RPEP-02505 · 2014Kisspeptin is the principal upstream regulator of GnRH secretion, critical for puberty onset, sex steroid feedback, and adult fertility in both sexes. It works through the KNDy (kisspeptin-neurokinin B-dynorphin) pathway, where neurokinin B provides stimulatory and dynorphin provides inhibitory paracrine input to control pulsatile GnRH release.
When administered to humans in various forms, routes, and doses, kisspeptin robustly stimulates LH secretion and pulse frequency. This creates two therapeutic directions: boosting LH in conditions with low pulsatility (hypothalamic amenorrhea, hypogonadotropic hypogonadism) and reducing it in conditions with excess LH (like PCOS).
Skorupskaite, Karolina; George, Jyothis T; Anderson, Richard A · Review