RPEP-03164 · 2016The review synthesizes evidence on the teneurin/TCAP-latrophilin system with several key findings:
• TCAP peptides (1-4) are bioactive sequences embedded within teneurin proteins that are structurally similar to corticotropin-releasing factor (CRF), a peptide central to stress and mood disorders
• Synthetic TCAP-1 induces long-term changes in neuronal structure in hippocampal cultures: increased neurite outgrowth, dendritic branching, and axon growth via an association with dystroglycans
• In rodent behavioral models, TCAP-1 reduced anxiety responses in the elevated plus-maze, open-field test, and acoustic startle test
• TCAP-1 inhibited CRF-mediated cocaine-seeking behavior
• Teneurins interact with latrophilins (adhesion GPCRs) forming transsynaptic adhesion pairs, providing a structural and signaling basis for mood regulation
Woelfle, Rebecca; D'Aquila, Andrea L; Lovejoy, David A ·
RPEP-03169 · 2016Single-dose oxytocin administration has consistently shown significant positive effects on experimental measures related to core autism spectrum disorder (ASD) symptoms in clinical trials. However, randomized clinical trials of continuous (multi-dose) oxytocin treatment have failed to show significant improvements in clinically meaningful endpoints — such as how individuals with ASD actually interact with other people in real-world situations.
The review identifies critical unresolved issues: optimal dose and duration remain unknown, the intranasal delivery system needs optimization, individual response variability is not well understood, and there is a lack of objective, reliable measurement tools for the core social symptoms of ASD.
Yamasue, Hidenori · Review
RPEP-03170 · 2016Substance P protected mouse corneal epithelial cells from hyperosmotic stress-induced apoptosis through multiple mechanisms working through the NK-1 receptor:
- Restored phosphorylated Akt levels (cell survival signaling)
- Recovered mitochondrial membrane potential
- Normalized intracellular calcium levels
- Scavenged reactive oxygen species (ROS)
- Restored glutathione levels (antioxidant defense)
Blocking the NK-1 receptor with an antagonist impaired both Akt activation and ROS scavenging, confirming that substance P's protective effects are mediated specifically through this receptor. Akt inhibition or glutathione depletion partially suppressed the anti-apoptotic capacity, demonstrating both pathways contribute to protection.
Yang, Lingling; Sui, Wenjie; Li, Yunqiu; Qi, Xia; Wang, Yao; Zhou, Qingjun; Gao, Hua ·
RPEP-03172 · 2016At one year post-surgery, the duodenal-jejunal bypass with sleeve gastrectomy (DJB-SG) group achieved 62% complete diabetes remission (HbA1c < 6.0%) compared to 32% in the sleeve gastrectomy (SG) group (P < 0.05), despite similar total body weight loss (25.7% vs. 22%). The DJB-SG group showed significantly lower postprandial blood glucose levels and lower C-peptide levels during mixed-meal tolerance testing, indicating improved glycemic control with reduced beta-cell secretory demand.
No significant differences were found in appetite sensations between groups, suggesting the metabolic benefit of duodenal-jejunal exclusion operates through gut hormone signaling pathways rather than changes in food intake behavior.
Zachariah, Pulimuttil James; Chen, Chih-Yen; Lee, Wei-Jei; Chen, Shu-Chu; Ser, Kong-Han; Chen, Jung-Chien; Lee, Yi-Chih ·
RPEP-03178 · 2016Fasting plasma ghrelin levels were significantly higher during a high-salt diet (320.7 ± 30.6 pg/mL) compared to a low-salt diet (172.9 ± 8.9 pg/mL, p<0.01) in 38 healthy, non-obese adults. This represents an approximate 85% increase in the hunger hormone. A positive correlation between 24-hour urinary sodium excretion and fasting ghrelin levels was also demonstrated, suggesting a dose-response relationship between salt intake and ghrelin production.
Zhang, Yong; Li, Fenxia; Liu, Fu-Qiang; Chu, Chao; Wang, Yang; Wang, Dan; Guo, Tong-Shuai; Wang, Jun-Kui; Guan, Gong-Chang; Ren, Ke-Yu; Mu, Jian-Jun ·
RPEP-03179 · 2016Prenatal nicotine exposure (PNE) significantly upregulated both mRNA and protein levels of NK1R (Substance P receptor) and TRPV1 in the nodose/jugular ganglia, and NK1R mRNA specifically in pulmonary C-neurons. This upregulation prolonged apneic responses to capsaicin. The NK1R antagonist SR140333 significantly shortened the PNE-induced prolonged apnea, confirming NK1R's functional role.
The mechanism was traced to nicotinic acetylcholine receptors: both mecamylamine (general nAChR antagonist) and methyllycaconitine (selective α7nAChR antagonist) eliminated the PNE-evoked receptor upregulation, identifying α7nAChR as the key mediator of nicotine's effect on peptide receptor expression.
Zhao, Lei; Zhuang, Jianguo; Zang, Na; Lin, Yong; Lee, Lu-Yuan; Xu, Fadi ·
RPEP-03184 · 2016IMD1-53 (0.5 μg/kg) administered to septic shock rats demonstrated:
• Significantly improved animal survival with both early (immediately after CLP) and late (12 hours after CLP) administration
• Increased cardiac contractility and function
• Improved tissue perfusion and oxygen delivery
• Early administration produced better results than late administration
Mechanistically, IMD1-53 acted through two pathways:
1. Rho kinase/TnI pathway: IMD1-53 increased Rho kinase expression in cardiac muscle and inhibited troponin I (TnI) phosphorylation
2. BKCa channel pathway: IMD1-53 inhibited BKCa channel currents and reduced intracellular calcium concentration in cardiomyocytes
Both pathways were confirmed by pharmacological blockade — a Rho kinase inhibitor (Y-27632) or BKCa opener (NS1619) abolished IMD1-53's protective effects.
Zhu, Yu; Wu, Huiling; Wu, Yue; Zhang, Jie; Peng, Xiaoyong; Zang, Jiatao; Xiang, Xinming; Liu, Liangming; Li, Tao ·
RPEP-03185 · 2016BPC 157 prevented and counteracted bupivacaine cardiotoxicity in rats across an extremely wide dose range (10 pg/kg to 50 µg/kg). Given 30 minutes before or 1 minute after bupivacaine (100 mg/kg), it largely counteracted bradycardia, AV-block, ventricular arrhythmias, T-wave elevation, and asystole. Even when given 6 minutes after bupivacaine (after prolonged QRS had developed), it markedly postponed fatal outcomes. In vitro, BPC 157 (1 µM) inhibited bupivacaine-induced cell membrane depolarization in HEK293 cells.
Zivanovic-Posilovic, Gordana; Balenovic, Diana; Barisic, Ivan; Strinic, Dean; Stambolija, Vasilije; Udovicic, Mario; Uzun, Sandra; Drmic, Domagoj; Vlainic, Josipa; Bencic, Martina Lovric; Sindic, Aleksandra; Seiwerth, Sven; Sikiric, Predrag ·
RPEP-03204 · 2017Different classes of diabetes medications have similar effects on HbA1c but vary significantly in how well they control after-meal blood sugar spikes. Short-acting GLP-1 receptor agonists like exenatide twice daily and lixisenatide have a stronger effect on postprandial glucose than longer-acting GLP-1 drugs, primarily because they slow stomach emptying more. Injectable options including prandial insulin analogs, GLP-1 receptor agonists, and the amylin analog pramlintide all effectively target post-meal blood sugar. DPP-4 inhibitors and SGLT2 inhibitors also reduce postprandial spikes.
Aronoff, Stephen L · Review
RPEP-03216 · 2017GI side effects from GLP-1 receptor agonists are dose-dependent: higher doses cause more nausea (p=0.0017 across all agents) and diarrhea (p=0.031). Adding metformin as background treatment significantly worsened nausea (p=0.04) and vomiting (p=0.0009). Long-acting GLP-1 drugs (like liraglutide, dulaglutide, exenatide weekly) caused less nausea and vomiting than short-acting ones (like exenatide twice daily), but caused more diarrhea. Among long-acting agents, albiglutide and exenatide weekly had less nausea than liraglutide, while dulaglutide was similar to liraglutide.
Bettge, Karolin; Kahle, Melanie; Abd El Aziz, Mirna S; Meier, Juris J; Nauck, Michael A ·
RPEP-03223 · 2017The skin expresses antimicrobial peptides both constitutively (always on) and in response to pathogenic microbial stimuli. These AMPs are differentially effective against various bacterial and fungal skin colonizers — meaning different peptides target different microbes.
Commensal bacterial colonization of the skin is vital for training and maintaining both innate and adaptive immune functions. The skin's AMP defense works alongside its physical barrier to prevent pathogen colonization. The review identifies a gap between descriptive disease-state studies and single-species in vitro experiments, calling for research that better mimics natural skin conditions.
Brandwein, Michael; Bentwich, Zvi; Steinberg, Doron ·
RPEP-03229 · 2017GLP-1 receptor agonists target the gut-brain axis to regulate appetite and promote weight loss. Liraglutide 3.0 mg was approved for obesity treatment in adults with BMI ≥27 kg/m² and comorbidities. The review covers how GLP-1 — a peptide naturally produced in the gut — coordinates appetite regulation through brain signaling, and how pharmacological GLP-1 RAs amplify these effects to produce clinically meaningful weight loss. Other GLP-1 RAs were identified as promising future obesity treatments.
Burcelin, R; Gourdy, P ·
RPEP-03230 · 2017Human microglia and astrocytes constitutively express robust levels of the full-length neurokinin-1 receptor (NK-1R) isoform. Bacterial pathogens further elevated NK-1R expression in astrocytes. Substance P activated NF-κB signaling in microglia and augmented inflammatory cytokine release and neurotoxic mediator production by astrocytes in response to bacterial pathogens.
These findings were confirmed across multiple systems: nonhuman primate brain explants, primary human microglia and astrocytes, and immortalized human glial cell lines, using RT-PCR, immunoblotting, immunofluorescence, flow cytometry, ELISA, and neuronal toxicity assays. Previous work by the same group showed NK-1R antagonists could limit neuroinflammatory damage in bacterial meningitis models.
Burmeister, Amanda R; Johnson, M Brittany; Chauhan, Vinita S; Moerdyk-Schauwecker, Megan J; Young, Ada D; Cooley, Ian D; Martinez, Alejandra N; Ramesh, Geeta; Philipp, Mario T; Marriott, Ian ·
RPEP-03236 · 2017The calcium-chelating peptide complex (CPC) from tilapia skin hydrolysates outperformed calcium carbonate on multiple bone-related measures in calcium-deficient mice after 4 weeks of feeding. Mice receiving CPC showed significantly greater femur length, femur weight, bone calcium content, hydroxyproline content (a marker of collagen), calcium absorption, and body weight gain compared to CaCO3-fed mice.
Interestingly, serum biochemistry and bone mineral density showed no significant differences between the two groups — the improvements were specifically in bone structure, composition, and calcium uptake. Structural analysis confirmed that calcium ions bind to the peptides through NH and CN groups, creating a stable chelate complex with molecular weights mainly between 180 and 2000 Da.
Chen, Jun; Qiu, Xujian; Hao, Gengxin; Zhang, Meng; Weng, Wuyin ·
RPEP-03241 · 2017This review examines peptide-based approaches to treating traumatic brain injury, highlighting arginine-rich peptides as a particularly promising new class of neuroprotective agents. While traditional single-action drugs and combination therapies have failed in TBI clinical trials, arginine-rich cationic peptides appear to work through multiple neuroprotective mechanisms simultaneously.
These peptides have already shown protective effects against ischemic stroke in animal models, providing a reasonable basis to investigate their potential in TBI. The review argues that arginine-rich peptides' ability to target multiple injury cascades at once may make them better suited to TBI's complex pathophysiology than conventional drugs.
Chiu, Li Shan; Anderton, Ryan S; Knuckey, Neville W; Meloni, Bruno P · Review
RPEP-03243 · 2017The hybrid hydrogels achieved mechanical properties spanning 10-200 kPa by varying β-sheet peptide graft density and concentration — covering the stiffness range of many soft tissues. The non-covalent β-sheet cross-links provided a critical advantage: after being strained to failure, the hydrogels self-healed, recovering all of their original storage moduli in most cases.
Spectroscopic analysis confirmed the presence of β-sheet secondary structure within the hydrogels, verifying that the peptide cross-links maintained their intended architecture. Only 15% functionalization of the polymer's repeating units with β-sheet peptides was needed to form a gel, leaving the remaining sites available for incorporating biological epitopes for cell signaling or tissue-specific functionality.
Clarke, David E; Pashuck, E Thomas; Bertazzo, Sergio; Weaver, Jonathan V M; Stevens, Molly M ·
RPEP-03247 · 2017Review consolidating evidence that kisspeptin enhances limbic brain activity to sexual stimuli, reduces negative mood, and modulates brain responses to attraction cues, expanding its role beyond reproductive axis regulation.
Comninos, Alexander N; Dhillo, Waljit S · Review
RPEP-03250 · 2017The antimicrobial peptide LL37 (cathelicidin) and the protein ADAMTSL5 — both identified as psoriasis autoantigens — were significantly upregulated in active psoriatic skin lesions (P < 0.05). Both were co-expressed by dendritic cells, macrophages, and some T cells in the dermis.
Critically, both ADAMTSL5 and LL37 were significantly reduced by IL-17 blockade and TNF-α blockade (etanercept), suggesting a feed-forward loop: the inflammatory cytokines that drive psoriasis also drive production of the autoantigens that trigger it. LL37 gene expression was significantly upregulated in lesional skin and significantly downregulated following etanercept treatment.
Fuentes-Duculan, Judilyn; Bonifacio, Kathleen M; Hawkes, Jason E; Kunjravia, Norma; Cueto, Inna; Li, Xuan; Gonzalez, Juana; Garcet, Sandra; Krueger, James G · Basic Research
RPEP-03252 · 2017Comparing 12 cathelicidins from 6 different species under identical lab conditions revealed that these antimicrobial peptides differ significantly in their functions — both between species and within the same species. Most cathelicidins killed E. coli and/or MRSA effectively, but a surprising finding emerged: under more realistic physiological conditions, antimicrobial activity against E. coli dropped for nearly all cathelicidins while activity against MRSA actually increased.
Seven of 12 cathelicidins could neutralize bacterial LPS (a toxin from gram-negative bacteria), and 7 could neutralize LTA (from gram-positive bacteria), but there was no correlation between the two abilities. Only 4 of 12 enhanced DNA-induced TLR9 activation, showing that immune-modulating functions are not universal across cathelicidins.
Coorens, Maarten; Scheenstra, Maaike R; Veldhuizen, Edwin J A; Haagsman, Henk P · In Vitro Study
RPEP-03256 · 2017Leptin resistance and ghrelin resistance are both hallmarks of obesity and operate through distinct but interconnected cellular mechanisms. Leptin resistance involves impaired signaling through the JAK-STAT pathway in hypothalamic neurons, while ghrelin resistance involves disrupted cAMP signaling. Both forms of resistance contribute to a dysfunctional energy homeostasis system that perpetuates weight gain.
The review identifies several molecular targets within these resistance pathways that could potentially be exploited for pharmacological intervention in obesity treatment.
Cui, Huxing; López, Miguel; Rahmouni, Kamal ·
RPEP-03274 · 2017The review identifies three major mechanisms for natriuretic peptide system failure in chronic heart failure: (1) reduced availability of biologically active BNP due to increased processing into inactive forms, (2) diminished target organ responsiveness to NPs, and (3) overstimulation of counter-regulatory systems (RAAS, sympathetic nervous system, and endothelin-1) that overpower NP effects.
Sacubitril/valsartan addresses this by simultaneously inhibiting neprilysin (the enzyme that degrades NPs) and blocking angiotensin receptors (countering RAAS activation). Clinical data show this combination increases NP levels and their intracellular mediator cGMP, suggesting genuine restoration of NP system effectiveness — translating into reduced mortality and morbidity.
Díez, Javier ·
RPEP-03278 · 2017UVB irradiation of the rat heel rapidly altered neuropeptide levels in pain-processing areas. Galanin-positive neurons in the dorsal root ganglia (DRG) decreased significantly at most time points (2-96h), while galanin immunoreactivity increased in the spinal cord dorsal horn, central canal area, and lateral spinal nucleus from 12-96h. Substance P levels in DRG neurons remained unchanged, but substance P immunoreactivity increased in the dorsal spinal cord at 48h. The neuronal activation marker c-fos appeared in the dorsal horn and central canal area at 24-48h — the same timeframe when hyperalgesia peaks. Skin blood flow nearly doubled 24h after irradiation.
Etemadi, Leila; Pettersson, Lina M E; Danielsen, Nils ·
RPEP-03283 · 2017Relaxin and insulin-like peptide 3 (INSL3) — two peptide hormones traditionally associated with pregnancy and testicular function — appear to play important roles in bone and muscle health. Relaxin is involved in bone remodeling (balancing bone formation and breakdown), helps heal injured ligaments, and promotes skeletal muscle regeneration. INSL3, a male-specific hormone from testicular Leydig cells, also participates in bone remodeling.
Both peptides may help explain sex differences in osteoporosis and sarcopenia risk, and could represent new therapeutic targets for musculoskeletal diseases.
Ferlin, Alberto; De Toni, Luca; Sandri, Marco; Foresta, Carlo · Narrative Review
RPEP-03287 · 2017Meta-xylyl stapled peptides targeting the CaV α-interaction domain (AID) were developed and characterized:
- Structural: Staples enhanced helical structure (CD spectroscopy) and maintained native-like AID:CaVβ binding geometry (X-ray crystallography)
- Thermodynamic: Stapling reduced the entropic penalty of binding (ITC), improving affinity
- Functional: Stapled AID peptides effectively inhibited the CaVα1:CaVβ protein-protein interaction
- Selectivity: Modulation was CaVβ isoform-selective, demonstrating that different beta subunits can be preferentially targeted
This represents the first proof-of-concept for using protein-protein interaction inhibitors to control voltage-gated ion channel function.
Findeisen, Felix; Campiglio, Marta; Jo, Hyunil; Abderemane-Ali, Fayal; Rumpf, Christine H; Pope, Lianne; Rossen, Nathan D; Flucher, Bernhard E; DeGrado, William F; Minor, Daniel L ·
RPEP-03290 · 2017Central kisspeptin delivery caused robust growth hormone (GH) release in fasted sheep but not in fed sheep. The proposed mechanism involves a cascade of peptide interactions:
1. During fasting, systemic ghrelin rises and NPY expression in the arcuate nucleus increases
2. Kisspeptin activates NPY neurons (confirmed by c-Fos activation)
3. NPY stimulates GHRH neurons and inhibits somatostatin neurons
4. This results in GH release
Critical evidence:
- NPY Y1 receptor antagonist (BIBO 3304) blocked kisspeptin-induced GH release
- Kisspeptin induced c-Fos in NPY and GHRH cells of the arcuate nucleus
- Kisspeptin reduced c-Fos in somatostatin cells
- Blocking ghrelin (systemically or at its receptor) eliminated or reduced kisspeptin-induced GH release
- Effects were similar at 24h and 72h fasting, indicating response to food loss rather than severe energy deficit
Foradori, Chad D; Whitlock, Brian K; Daniel, Jay A; Zimmerman, Arthur D; Jones, Melaney A; Read, Casey C; Steele, Barbara P; Smith, Jeremy T; Clarke, Iain J; Elsasser, Theodore H; Keisler, Duane H; Sartin, James L ·
RPEP-03295 · 2017GHRH and its agonistic analog MR-409 attenuated cardiac hypertrophy both in vitro and in vivo. In cell models (H9c2 cardiac cells, adult rat ventricular myocytes, and human iPSC-derived cardiomyocytes), GHRH reduced phenylephrine-induced hypertrophy by blocking Gq signaling and its downstream components (phospholipase Cβ, PKCε, calcineurin, phospholamban) while activating Gαs/cAMP/PKA and inhibiting Epac1. In vivo, MR-409 mitigated cardiac hypertrophy in mice with pressure overload from transverse aortic constriction, improved cardiac function, and restored cardiomyocyte contractility and sarcolemmal structure.
Gesmundo, Iacopo; Miragoli, Michele; Carullo, Pierluigi; Trovato, Letizia; Larcher, Veronica; Di Pasquale, Elisa; Brancaccio, Mara; Mazzola, Marta; Villanova, Tania; Sorge, Matteo; Taliano, Marina; Gallo, Maria Pia; Alloatti, Giuseppe; Penna, Claudia; Hare, Joshua M; Ghigo, Ezio; Schally, Andrew V; Condorelli, Gianluigi; Granata, Riccarda ·
RPEP-03309 · 2017A single intranasal dose of oxytocin restored social interaction deficits for up to 2 hours in VPA-exposed mice. A 2-week course of daily intranasal oxytocin extended this improvement to at least 24 hours after the last dose. Neither single nor repeated administration improved recognition memory impairments.
Immunohistochemical analysis revealed that oxytocin increased c-Fos expression (a marker of neuronal activation) in the paraventricular nuclei (PVN), prefrontal cortex, and somatosensory cortex of VPA-exposed mice, but not in hippocampal CA1 or CA3 regions. This selective activation pattern explains the differential effects — social circuits were engaged while memory circuits were not. Importantly, oxytocin had no effect on social behavior in control mice, suggesting it specifically corrects the deficit rather than broadly enhancing sociality.
Hara, Yuta; Ago, Yukio; Higuchi, Momoko; Hasebe, Shigeru; Nakazawa, Takanobu; Hashimoto, Hitoshi; Matsuda, Toshio; Takuma, Kazuhiro ·
RPEP-03321 · 2017Ghrelin's central brain signaling is critical for its effects on appetite, body weight, and food reward. However, multiple factors have prevented successful drug development: GHSR-1a receptor internalization and heterodimerization create complex pharmacology, biased ligand interactions produce unpredictable effects, compensatory neuroendocrine outputs counteract drug effects, and the receptor's ubiquitous expression makes it impossible to target appetite without affecting peripheral ghrelin functions. Improving blood-brain barrier penetration of ghrelin ligands, particularly to reach mesolimbic reward circuitry, is identified as a key priority.
Howick, Ken; Griffin, Brendan T; Cryan, John F; Schellekens, Harriët ·
RPEP-03322 · 2017BPC-157 promotes the growth of new blood vessels (angiogenesis) through a specific molecular mechanism: it increases the expression and internalization of VEGFR2, a key receptor for blood vessel growth, and activates the downstream VEGFR2-Akt-eNOS signaling pathway.
The study demonstrated this across multiple experimental models. In a chick embryo membrane assay, BPC-157 increased vessel density. In human endothelial cell cultures, it enhanced tube formation (a measure of blood vessel growth). Most notably, in rats with restricted blood flow to a hind limb (ischemia model), BPC-157 accelerated blood flow recovery and increased the number of blood vessels, with enhanced VEGFR2 expression confirmed by tissue analysis.
Importantly, BPC-157 upregulated the VEGFR2 receptor itself but not the VEGF-A ligand — meaning it works by making cells more responsive to existing growth signals rather than producing more growth factor. Blocking endocytosis with dynasore inhibited BPC-157's effects, confirming that receptor internalization is a required step in the mechanism.
Hsieh, Ming-Jer; Liu, Hsien-Ta; Wang, Chao-Nin; Huang, Hsiu-Yun; Lin, Yuling; Ko, Yu-Shien; Wang, Jong-Shyan; Chang, Vincent Hung-Shu; Pang, Jong-Hwei S · Animal/In Vitro Study
RPEP-03326 · 2017Researchers synthesized multiple peptide variants derived from bovine lactoferricin — a natural antimicrobial peptide found in cow's milk — and tested their antibacterial activity. The dimeric peptide (RRWQWR)₂K-Ahx showed the strongest overall activity against the tested bacteria. Monomeric, cyclic, tetrameric, and palindromic peptides containing the RWQWR motif all showed high and specific activity against E. coli.
Different peptide architectures (linear, dimeric, tetrameric, cyclic) produced different activity profiles, demonstrating that how you arrange the same antimicrobial sequence significantly affects which bacteria it kills. The peptides were effective against both E. coli and Salmonella enteritidis but showed varying activity against Stenotrophomonas maltophilia.
Huertas Méndez, Nataly De Jesús; Vargas Casanova, Yerly; Gómez Chimbi, Anyelith Katherine; Hernández, Edith; Leal Castro, Aura Lucia; Melo Diaz, Javier Mauricio; Rivera Monroy, Zuly Jenny; García Castañeda, Javier Eduardo · In Vitro
RPEP-03331 · 2017The review evaluated multiple strategies for oral delivery of antidiabetic peptides (insulin, GLP-1, and GLP-1 analogs), identifying two main barriers that must be overcome: degradation by proteolytic enzymes in the gastrointestinal tract and poor absorption through the intestinal wall.
Among all approaches reviewed — including absorption enhancers, enzyme inhibitors, chemical modifications, and various carrier systems — nanocarrier systems emerged as the most promising platform. These include polymeric nanoparticles, solid lipid nanoparticles, liposomes, and micelles, each with distinct advantages for protecting peptides from degradation and enhancing their absorption. However, the authors noted that no FDA-approved oral antidiabetic peptide delivery system existed at the time of publication, and further development was needed.
Ismail, Ruba; Csóka, Ildikó · Review
RPEP-03335 · 2017In a mouse radiculopathy model, fullerol at 10 or 100 μM counteracted pain sensitization and inflammatory responses when disc material was pretreated before implantation. While macrophage infiltration (IBA1+) was similar across groups, IL-1β and IL-6 expression was decreased in the fullerol-treated group.
In dorsal root ganglion (DRG) explant cultures treated with TNF-α, fullerol significantly reversed the increased expression of IL-1β, NLRP3, and caspase 1, identifying the NLRP3 inflammasome as a key target. Critically, fullerol also decreased expression of the pain neuropeptides substance P and CGRP in cultured DRGs, explaining its analgesic effect.
Jin, Li; Ding, Mengmeng; Oklopcic, Azra; Aghdasi, Bayan; Xiao, Li; Li, Ziyi; Jevtovic-Todorovic, Vesna; Li, Xudong ·
RPEP-03338 · 2017In a randomized, double-blind, placebo-controlled trial of 75 adults with type 2 diabetes, 12 weeks of once-weekly semaglutide (1.0 mg) significantly improved beta cell function. First-phase insulin secretion tripled (treatment ratio 3.02, 95% CI 2.53–3.60) and second-phase insulin secretion doubled (treatment ratio 2.10, 95% CI 1.86–2.37) compared to placebo, both P<0.0001. Semaglutide also significantly reduced 24-hour glucose and glucagon responses (P<0.0001), and an arginine stimulation test showed increased maximal insulin capacity. Remarkably, during a graded glucose infusion test, semaglutide restored insulin secretion rates to levels similar to those seen in healthy participants without diabetes.
Kapitza, Christoph; Dahl, Kirsten; Jacobsen, Jacob B; Axelsen, Mads B; Flint, Anne ·
RPEP-03344 · 2017Researchers tested whether lactam stapling — a chemical modification that locks peptides into a helical shape — improves cell-penetrating peptide (CPP) performance. The results were mixed: of four stapled peptides tested, only one (MAP-1) showed clear improvement. Stapling MAP-1 enhanced its helical structure in both water and lipid environments, eliminated membrane leakage (a proxy for toxicity), and maintained high cellular uptake in HEK293 and HeLa cells.
The other three peptides (DRIM, WWSP, KFGF) didn't improve with stapling. Critically, the study found that a CPP's ability to enter cells correlates with how helical it becomes when interacting with membranes — not how helical it is free in solution. Nearly all stapled peptides caused less membrane damage (less vesicle leakage, hemolysis, and bacterial lysis) than their linear versions.
Klein, Marco J; Schmidt, Samuel; Wadhwani, Parvesh; Bürck, Jochen; Reichert, Johannes; Afonin, Sergii; Berditsch, Marina; Schober, Tim; Brock, Roland; Kansy, Manfred; Ulrich, Anne S · In Vitro
RPEP-03351 · 2017Peptide-based cancer vaccines have historically underperformed in clinical trials, largely because they produced weak immune responses and couldn't overcome the tumor's ability to suppress the immune system. However, the success of immune checkpoint inhibitors (like PD-1 blockers) has reinvigorated the field by showing that T cells really can fight cancer — they just need the right activation.
The authors describe optimized approaches to peptide vaccine design, including better antigen selection (choosing the right tumor protein fragments), improved adjuvants (immune-boosting additives), and smarter administration strategies. These advances aim to generate more powerful tumor-reactive T cell responses that can work alongside checkpoint inhibitors.
Kumai, Takumi; Fan, Aaron; Harabuchi, Yasuaki; Celis, Esteban · Review
RPEP-03352 · 2017The tripeptide CWR (Cys-Trp-Arg) was identified through molecular docking and demonstrated multiple levels of SIRT1 activation:
- Biochemical: Enhanced activity of purified recombinant SIRT1 by lowering the Michaelis constant (Km), indicating an allosteric activation mechanism
- Clinical relevance: Increased SIRT1 activity in serum from Alzheimer's disease patients
- Cellular: Decreased acetylation of p53 (a SIRT1 substrate) in IMR-32 neuroblastoma cells, confirming intracellular SIRT1 activation
- Neuroprotection: Protected neuronal cells from amyloid-beta fragment-induced cell death (MTT assay)
The peptide works allosterically — binding at a site different from the active site to enhance enzyme activity.
Kumar, Rahul; Nigam, Lokesh; Singh, Amrendra Pratap; Singh, Kusum; Subbarao, Naidu; Dey, Sharmistha ·
RPEP-03353 · 2017Adding chemical caps to both ends of the antimicrobial peptide tachyplesin I (N-terminal acetylation and C-terminal amidation) increased its cell-killing potency against tumor cells and made it resistant to enzymatic breakdown in human serum. However, the modifications also increased toxicity toward normal cells and red blood cells (hemolysis), presenting a double-edged sword for anticancer development.
Kuzmin, D V; Emelianova, A A; Kalashnikova, M B; Panteleev, P V; Ovchinnikova, T V ·
RPEP-03354 · 2017The GHRH receptor splice variant SV1 was detected in human endometrial tissue, with the highest expression found in the uterine lining of patients who had endometriosis (eutopic endometrium) compared to the endometriosis lesions themselves (ectopic tissue) or normal endometrium. Interestingly, GHRH itself was most highly expressed in ectopic endometriosis lesions.
In the mouse model, daily treatment with 10 μg MIA-602 resulted in significantly smaller human endometrial xenotransplants after 4 weeks compared to vehicle-treated controls. In cell culture, 1 μM MIA-602 decreased proliferation of endometrial stromal cells and two endometriosis cell lines (12-Z and 49-Z) after 72 hours. The drug reduced epidermal growth factor receptor protein levels and decreased activation of the MAP kinases ERK-1/2, identifying a specific signaling mechanism.
Köster, Frank; Jin, Li; Shen, Yuanming; Schally, Andrew V; Cai, Ren-Zhi; Block, Norman L; Hornung, Daniela; Marschner, Gabriele; Rody, Achim; Engel, Jörg B; Finas, Dominique ·
RPEP-03359 · 2017C-peptide is produced in equal amounts to insulin but is excreted more steadily, making it a reliable marker of how much insulin the pancreas is actually producing. A C-peptide level below 0.2 nmol/L is strongly associated with a diagnosis of type 1 diabetes. The authors recommend glucagon stimulation testing as the best balance of sensitivity and practicality among available methods. C-peptide levels also correlate with microvascular and macrovascular complications, future need for insulin therapy, and likely response to individual treatments.
Leighton, Emma; Sainsbury, Christopher Ar; Jones, Gregory C ·
RPEP-03361 · 2017The neuropeptide fragment TLQP-62 (derived from the VGF protein) prevented inflammation-induced memory deficits, depression-like behavior, and anxiety-like behavior in mice when injected into the brain before an inflammatory challenge (LPS). TLQP-62 also reduced neuroinflammation and oxidative stress markers. Critically, when BDNF expression was knocked down using a viral vector, TLQP-62's protective effects were blocked — demonstrating that the peptide works through the BDNF/TrkB signaling pathway.
Li, Chenli; Li, Mengmeng; Yu, Hanjie; Shen, Xinbei; Wang, Jinting; Sun, Xin; Wang, Qinwen; Wang, Chuang · Animal
RPEP-03364 · 2017PepGel (h9e peptide) formed a hydrogel triggered by BSA-linked cisplatin (BSA-CP), with BSA-CP serving dual roles as gelation trigger and drug payload. Fluorescence studies showed strong interaction between PepGel and BSA's hydrophobic subdomain. TEM and confocal microscopy confirmed BSA-CP dispersal within PepGel nanofibers with enhanced fiber aggregation. PepGel effectively inhibited BSA-CP diffusion even at concentrations below 0.3 wt%. Drug release rate was controllable by adjusting PepGel concentration. HeLa cell viability data was consistent with drug release kinetics, confirming maintained anti-cancer activity.
Liang, Jun; Liu, Gang; Wang, Jing; Sun, Xiuzhi Susan ·
RPEP-03368 · 2017NPFFR2 agonists (dNPA administered ICV and AC-263093 administered IP) increased serum corticosteroid levels in a time-dependent manner (rats) and dose-dependent manner (mice). These effects were blocked by:
- RF9 (NPFF receptor antagonist, ICV)
- α-helical CRF(9-41) (CRF receptor antagonist, IV)
AC-263093 also increased c-Fos expression in the hypothalamic paraventricular nucleus (confirming neuronal activation in the HPA axis command center) and induced anxiogenic effects in mice on the elevated plus maze. This is the first demonstration that NPFFR2 directly activates the HPA axis and triggers anxiety-like behaviors.
Lin, Ya-Tin; Yu, Yu-Lian; Hong, Wei-Chen; Yeh, Ting-Shiuan; Chen, Ting-Chun; Chen, Jin-Chung ·
RPEP-03379 · 2017The antimicrobial peptide LL-37 was elevated in muscle tissue of patients with polymyositis (PM) and dermatomyositis (DM) compared to healthy controls, primarily released by infiltrating neutrophils. Plasmacytoid dendritic cells (BDCA-2+, the main type I interferon producers) and the interferon marker MxA were also elevated in affected muscle. All PM/DM patients with short disease duration had low vitamin D levels. The findings support the hypothesis that LL-37 may trigger the type I interferon system in these autoimmune muscle diseases, similar to its known role in lupus (SLE).
Lu, Xin; Tang, Quan; Lindh, Monica; Dastmalchi, Maryam; Alexanderson, Helene; Popovic Silwerfeldt, Karin; Agerberth, Birgitta; Lundberg, Ingrid E; Wick, Cecilia · Observational
RPEP-03382 · 2017The review assessed therapeutic strategies targeting neurogenic inflammation mediators in migraine:
- CGRP pathway: Phase III clinical trials of monoclonal antibodies against CGRP and the CGRP receptor showed the most promise — these would later become approved drugs (erenumab, fremanezumab, galcanezumab)
- Substance P: Preclinical and clinical studies targeting SP were all terminated with no significant benefit over placebo
- Nitric oxide synthase (NOS): Clinical trials targeting NOS were similarly terminated without significant results
- PACAP and PAC1 receptor: Identified as a promising new therapeutic target based on emerging evidence of PACAP's role in migraine
- Kynurenic acid (KYNA) analogs: Highlighted as another novel approach worth pursuing
Lukacs, Melinda; Tajti, Janos; Fulop, Ferenc; Toldi, Jozsef; Edvinsson, Lars; Vecsei, Laszlo ·
RPEP-03385 · 2017Melanoma cells expressed variable levels of antimicrobial peptide mRNA, with LL-37 (cathelicidin) generally increased and hBD-4 (β-defensin 4) decreased in most melanoma cell lines compared to primary uveal melanocytes. However, neither HNP-1 (α-defensin) nor LL-37 had an observable influence on tumor cell migration in scratch assays.
Aggressive cutaneous melanoma cells exhibited vasculogenic mimicry (forming blood vessel-like channels) in 3D culture, but AMP exposure did not alter this process. Overall, despite altered expression patterns, antimicrobial peptides had little influence on the major characteristics contributing to melanoma aggressiveness and progression.
Manarang, Joseph C; Otteson, Deborah C; McDermott, Alison M ·
RPEP-03389 · 2017In rats with inferior alveolar nerve (IAN) injury:
- Nerve injury alone increased expression of TRPV1 (pain receptor) and substance P in the trigeminal ganglion, but did not change GluA1, GluA2 (AMPA receptors), or CGRP expression
- Low-level laser therapy (LLLT) produced multiple changes:
- Decreased TRPV1 expression (pain receptor)
- Decreased substance P expression (pain neuropeptide)
- Decreased CGRP expression (pain neuropeptide)
- Increased GluA1 and GluA2 expression (AMPA receptors)
The combined pattern suggests LLLT counteracts the molecular changes that drive pain sensitization after nerve injury.
Martins, D O; Santos, F M; Britto, L R G; Lemos, J B D; Chacur, M ·
RPEP-03395 · 2017The synthetic peptide Semax — composed of the ACTH(4-7) fragment plus the tripeptide Pro-Gly-Pro (PGP) — protects rat brains during ischemic stroke primarily through immune system modulation. Genome-wide transcriptome analysis of the cerebral cortex revealed that Semax's most significant effect was on immune response genes.
Specifically, Semax enhanced antigen presentation pathways, intensified interferon signaling already activated by ischemia, affected immunoglobulin synthesis, and significantly increased expression of immunoglobulin heavy chain genes. It also strongly affected cytokine, stress response, and ribosomal protein genes after stroke.
Interestingly, the PGP tripeptide component alone had the opposite effect — it suppressed immune activity and neurotransmission in the central nervous system. This suggests the two components of Semax may have distinct and potentially complementary roles in neuroprotection.
Medvedeva, Ekaterina V; Dmitrieva, Veronika G; Limborska, Svetlana A; Myasoedov, Nikolay F; Dergunova, Lyudmila V · Animal Study
RPEP-03396 · 2017In rats given toxic magnesium sulfate (560 mg/kg IP):
- **BPC 157 (10 μg or 10 ng/kg)** given 15 minutes before magnesium completely abrogated hypermagnesemia, muscle weakness, muscle and brain lesions, elevated serum enzymes, and hyperkalaemia.
- **L-NAME (NOS blocker)** and **L-arginine (NOS substrate)** each worsened all magnesium-induced disturbances when given alone.
- **L-NAME + L-arginine together** paradoxically normalized all values.
- **BPC 157** counteracted the aggravated toxicity caused by either L-NAME or L-arginine in combination with magnesium.
- In HEK293 cells, increasing magnesium from 1 to 5 mM depolarized cells by 1.75 ± 0.44 mV; BPC 157 (1 μM) inhibited this depolarization in vitro.
Medvidovic-Grubisic, Maria; Stambolija, Vasilije; Kolenc, Danijela; Katancic, Jadranka; Murselovic, Tamara; Plestina-Borjan, Ivna; Strbe, Sanja; Drmic, Domagoj; Barisic, Ivan; Sindic, Aleksandra; Seiwerth, Sven; Sikiric, Predrag ·
RPEP-03397 · 2017In high-frequency episodic migraine, the reduction in monthly migraine days from baseline versus placebo at end of treatment was:
- Eptinezumab (ALD403): -1.0 days (weeks 5-8)
- Erenumab (AMG334): -1.1 days (weeks 9-12)
- Galcanezumab (LY2951742): -1.2 days (weeks 9-12)
- Fremanezumab (TEV48125, 225 mg): -2.6 days (weeks 9-12)
Numbers needed to treat (NNT) for responders were 4.7, 6.2, 4.0, and 4.0 respectively — all clinically meaningful. The odds ratios for any adverse event were remarkably close to 1.0 (1.09, 0.96, 1.07, 1.05), indicating that side effects were essentially no different from placebo. The authors noted that overall efficacy was comparable to existing oral preventive migraine medications, but the safety and tolerability advantages were the key differentiator.
Mitsikostas, Dimos D; Reuter, Uwe ·
RPEP-03399 · 2017A single intraperitoneal injection of amylin in Tg2576 Alzheimer's mice significantly increased amyloid-beta (Aβ) serum levels, indicating enhanced brain-to-blood clearance. This effect was abolished by AC253 (an amylin receptor antagonist), confirming receptor dependence.
Mechanistic studies using a blood-brain barrier (BBB) cell model showed:
- Amylin enhanced Aβ transport across the BBB
- Two amylin antagonists and siRNA knockdown of the Ramp3 receptor component all blocked this effect
- Amylin treatment induced LRP1 (a major Aβ efflux receptor) translocation from intracellular pools to the plasma membrane
- This LRP1 membrane enrichment explains the enhanced Aβ uptake and transport
The complete mechanism: amylin → amylin receptor activation → LRP1 subcellular translocation to BBB endothelial membrane → enhanced Aβ brain-to-blood clearance.
Mohamed, Loqman A; Zhu, Haihao; Mousa, Youssef M; Wang, Erming; Qiu, Wei Qiao; Kaddoumi, Amal ·