RPEP-12458 · 2025Perinatal exposure to four major categories of environmental toxicants — flame retardants, pesticides, plastics (including BPA and phthalates), and air pollution — all induce measurable changes to oxytocin (OT) and arginine vasopressin (AVP) systems in the developing brain. These changes affect the neuropeptides themselves as well as their central receptors (oxytocin receptor and vasopressin V1a receptor).
Two primary biological mechanisms were identified: endocrine disruption (toxicants mimicking or blocking hormones) and maternal immune activation (toxicant-triggered inflammation in the mother affecting fetal brain development). Key resilience factors include positive psychosocial experiences for mothers, sex-dependent differences in vulnerability, a healthy gut microbiome, and the timing and dose of exposure. The gut microbiome emerged as a particularly promising target for intervention.
Martin, Elise M; Xue, Jason; Smith, Caroline J ·
RPEP-12463 · 2025Retrograde tracing in rats confirmed that some trigeminal ganglion (TG) cells send bifurcated projections through both V1 (meningeal/ophthalmic) and V2 (infraorbital/facial) branches. Triple-labeling showed some of these dual-projecting cells expressed both CGRP and oxytocin receptors (OTR). At the meningeal level, OTR was expressed perivascularly and on CGRPergic nerve fibers, suggesting oxytocin could modulate CGRP release at the meningeal vasculature — a key site of migraine pain generation.
Martínez-Lorenzana, Guadalupe; Córdova-Quiroga, Aketzalli; Condés-Lara, Miguel; González-Hernández, Abimael ·
RPEP-12475 · 2025Temporal transcriptomics revealed that the phage shock protein (Psp) system is highly expressed in intracellular Salmonella Typhimurium with sustained expression throughout macrophage infection. The Psp system is regulated by the virulence-associated two-component system SsrA-SsrB, coordinating its expression with other immune evasion functions.
Functional assays demonstrated that the Psp system mediates resistance specifically to host antimicrobial peptides, including cathelicidin-related antimicrobial peptide (CRAMP). This resistance supports bacterial persistence in host tissues and survival within macrophages. The findings establish the Psp system as a new adaptive mechanism for evading host antimicrobial peptide defenses.
Massicotte, Marie-Ange; Fiebig, Aline A; Bogza, Andrei; Coombes, Brian K ·
RPEP-12476 · 2025Compared to placebo, tirzepatide reduced hsCRP by 32.9% (95% CI: -33.6 to -32.2; I²=15.3%) and IL-6 by 17.8% (95% CI: -24.3 to -11.3; I²=1.6%). The hsCRP reduction was significant at all doses: 15 mg (-32.9%), 10 mg (-33.9%), and 5 mg (-20.3%). IL-6 reductions were also significant at all doses: 5 mg (-18.8%), 10 mg (-17.9%), and 15 mg (-16.8%). Low heterogeneity (I² values mostly under 20%) suggests consistent effects across studies.
Masson, Walter; Lobo, Martín; Nogueira, Juan P; Barbagelata, Leandro; Touzas, Pedro; Frías, Juan P ·
RPEP-12477 · 2025Semaglutide showed significantly elevated reporting of vision impairment compared to multiple drug classes in the FDA Adverse Event Reporting System (FAERS):
- vs. other GLP-1 receptor agonists: reporting odds ratio (rOR) 1.95 (95% CI 1.75–2.17, p < 0.0001)
- vs. DPP-4 inhibitors: rOR 2.46 (95% CI 2.12–2.86, p < 0.0001)
- vs. SGLT2 inhibitors: rOR 3.89 (95% CI 3.35–4.51, p < 0.0001)
- vs. metformin: rOR 2.23 (95% CI 1.90–2.62, p < 0.0001)
- vs. phentermine: rOR 1.57 (95% CI 1.07–2.31, p = 0.026)
- vs. orlistat: rOR 3.77 (95% CI 2.96–4.81, p < 0.0001)
Only topiramate had higher vision impairment reporting than semaglutide (rOR 0.30, p < 0.0001).
Massy, Marine; Marti, Stefanie; Hammer, Helly; Hoepner, Robert ·
RPEP-12483 · 2025Among 166 patients with metastatic pancreatic neuroendocrine tumors, 100 received PRRT. Overall survival for the entire cohort was 79 months. Patients receiving 4 or more cycles of PRRT achieved a median overall survival of 87 months, while those receiving 5 or more cycles reached 100 months.
Tumor grade was a significant factor: patients with grade 1 or 2 tumors had a median survival of 97 months compared to 74.5 months for grade 3 tumors (p=0.0055). Bone metastases also predicted worse outcomes — patients with bone metastases who received PRRT survived a median of 74 months versus 89 months for those without (p=0.013). Whether the tumor was functioning or non-functioning did not significantly affect survival after PRRT.
Mathew, Annie; Kersting, David; Fendler, Wolfgang P; Braegelmann, Johanna; Fuhrer, Dagmar; Lahner, Harald ·
RPEP-12493 · 2025This review synthesizes research on using venom-derived peptides as targeting agents for drug delivery. Chlorotoxin (from scorpion venom) and exendin-4 (from Gila monster venom) have shown the most promise. Venom peptides have been incorporated into nanoparticles and bioconjugates to deliver therapeutic and diagnostic agents, primarily targeting cancer and nervous system conditions. Their evolutionary refinement provides high potency and specificity for human biomolecules.
Mazurs, Austris; Mauriņa, Baiba; Bandere, Dace; Logviss, Konstantīns ·
RPEP-12499 · 2025The updated Cardiff T2D model incorporated three key changes: (1) a holistic therapy selection/escalation module considering cardiovascular risk, comorbidities, and bodyweight — not just HbA1c; (2) updated risk factor progression equations based on UKPDS90 data; (3) novel risk equations capturing cardio-kidney-metabolic benefits of SGLT2 inhibitors and GLP-1 receptor agonists derived from clinical outcomes trial data.
Comparing holistic vs. conventional (glucose-centric) approaches for a newly diagnosed T2D population, the holistic model enabled earlier introduction of SGLT2i and GLP-1 RA — primarily driven by elevated cardiovascular risk. This resulted in fewer predicted clinical events (cardiovascular, renal) and additional health benefits compared to the glucose-focused approach.
McEwan, Phil; Foos, Volker; Roberts, Geraint; Jenkins, Robert H; Evans, Marc; Wheeler, David C; Chen, Jieling ·
RPEP-12502 · 2025Among 9,650 randomized participants with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both:
- **Primary outcome (MACE)**: 12.0% in the oral semaglutide group vs. 13.8% in the placebo group (HR 0.86; 95% CI 0.77-0.96; P = 0.006)
- Incidence rates: 3.1 vs. 3.7 events per 100 person-years
- Mean follow-up: 47.5 months (median 49.5 months)
- The confirmatory secondary outcome of major kidney disease events did not differ significantly between groups
- Serious adverse events: 47.9% vs. 50.3% (numerically lower with semaglutide)
- Gastrointestinal disorders: 5.0% vs. 4.4% (slightly higher with semaglutide, as expected)
McGuire, Darren K; Marx, Nikolaus; Mulvagh, Sharon L; Deanfield, John E; Inzucchi, Silvio E; Pop-Busui, Rodica; Mann, Johannes F E; Emerson, Scott S; Poulter, Neil R; Engelmann, Mads D M; Ripa, Maria Sejersten; Hovingh, G Kees; Brown-Frandsen, Kirstine; Bain, Stephen C; Cavender, Matthew A; Gislum, Mette; David, Jens-Peter; Buse, John B ·
RPEP-12503 · 2025BPC-157 activates several key healing pathways in animal models: VEGFR2 and nitric oxide synthesis via the Akt-eNOS axis (promoting blood vessel growth), ERK1/2 signaling (facilitating tissue repair), fibroblast activation, and anti-inflammatory effects. These mechanisms are particularly relevant for poorly vascularized tissues like tendons and myotendinous junctions, which heal slowly.
However, the review found a stark gap between preclinical promise and clinical evidence. Only three small pilot studies have examined BPC-157 in humans: for knee pain (intraarticular), interstitial cystitis, and IV safety/pharmacokinetics. No adverse effects were reported in any human study, but none were powered to assess efficacy. The review concludes that BPC-157 should be considered investigational until well-designed clinical trials are completed.
McGuire, Flynn P; Martinez, Riley; Lenz, Annika; Skinner, Lee; Cushman, Daniel M · Scoping Review
RPEP-12505 · 2025Using the WHO VigiBase database, reporting odds ratios (ROR) showed a mixed pattern:
**Increased ROR (more reports than expected):**
- Suicidal ideation: semaglutide (5.82), liraglutide (4.03), tirzepatide (2.25)
- Depression/suicidal: semaglutide (14.74), liraglutide (5.86)
- Suicidal behavior: semaglutide (6.52), liraglutide (3.90)
**Decreased ROR (fewer reports than expected):**
- Suicide attempts: semaglutide (0.11), dulaglutide (0.075), exenatide (0.047), liraglutide (0.15)
- Completed suicide: semaglutide (0.01), dulaglutide (0.003), exenatide (0.002), liraglutide (0.008)
This paradoxical pattern — more reports of suicidal thoughts but dramatically fewer actual attempts and deaths — differs from what was found in the FDA's FAERS database.
McIntyre, Roger S; Mansur, Rodrigo B; Rosenblat, Joshua D; Rhee, Taeho Greg; Cao, Bing; Teopiz, Kayla M; Wong, Sabrina; Le, Gia Han; Ho, Roger; Kwan, Angela T H ·
RPEP-12510 · 2025Using fiber photometry in live mice, researchers discovered that GIP and GLP-1 play distinct roles in appetite regulation through AgRP neurons — the brain's key hunger-promoting cells. Endogenous GIP (but not GLP-1) was required for normal nutrient-triggered suppression of these hunger neurons. However, at pharmacologic doses, both GIP and GLP-1 analogs inhibited AgRP neurons.
Critically, dual GIP and GLP-1 receptor agonism (as in tirzepatide) more potently inhibited AgRP neurons and suppressed food intake than either agonist alone. The degree of neural inhibition directly correlated with how much each drug reduced eating.
McMorrow, Hayley E; Cohen, Andrew B; Lorch, Carolyn M; Hayes, Nikolas W; Fleps, Stefan W; Frydman, Joshua A; Xia, Jessica L; Samms, Ricardo J; Beutler, Lisa R · Animal Study
RPEP-12521 · 2025GLP-1 receptor agonists like semaglutide and tirzepatide suppress appetite and delay gastric emptying, which can further reduce protein and micronutrient intake in patients already at nutritional risk from weight loss. Despite guidelines recommending 60-120 g/day of protein, many patients on GLP-1RAs fall short of this target.
Protein deficiency is particularly dangerous for surgical patients because it impairs collagen production, angiogenesis (new blood vessel formation), and immune function — all critical for wound healing. Laparoscopic sleeve gastrectomy, while causing fewer malabsorption issues than gastric bypass, still predisposes patients to iron, B12, and protein deficiencies due to reduced food intake and food intolerance.
Mehta, Meeti; Rometo, David; Gusenoff, Jeffrey; Rubin, J Peter ·
RPEP-12525 · 2025The review identifies anemia as a prevalent but under-recognized complication in type 2 diabetes, particularly in patients with chronic kidney disease. It examines three classes of newer antidiabetic agents — SGLT2 inhibitors, GLP-1 receptor agonists, and combined GLP-1 RA/GIP agonists — for their potential effects on anemia risk.
The authors highlight that current clinical guidelines lack specific recommendations for anemia prevention and management in the context of these newer therapies, representing a significant gap in diabetes care. Early detection and management of anemia is emphasized as important for glycemic control, cardiovascular outcomes, and overall treatment success.
Meliš, Petra; Cigrovski Berkovic, Maja ·
RPEP-12531 · 2025PeptideMiner uses profile-hidden Markov models to discover peptide families across species despite high sequence divergence. Benchmarking showed it outperformed existing methods.
Applied to venom transcriptomes (including 24 previously unpublished datasets), PeptideMiner identified 10 novel natriuretic peptides from distantly related species and 57 novel insulin-like sequences from marine cone snails. Chemical synthesis and testing of newly identified conoinsulins at human insulin receptors confirmed biological activity, validating the approach for discovering pharmacologically relevant peptides.
Mendel, Helen C; Hopping, Gene; Undheim, Eivind A B; Zuegg, Johannes; Lewis, Richard J; Forbes, Briony E; Kaas, Quentin; Muttenthaler, Markus ·
RPEP-12532 · 2025Patients with MDD show systemic and localized glucose metabolism impairments across multiple processes: glucose uptake, glycoprotein transport, glycolysis, the TCA cycle, and oxidative phosphorylation. These impairments stem from insulin resistance, hyperglycemia-induced damage, oxidative stress, astrocyte dysfunction, and mitochondrial dysfunction.
The downstream consequences include insufficient energy supply to neurons, altered synaptic plasticity, neuronal cell death, and functional/structural damage to brain reward networks — all of which contribute to depressive symptoms. GLP-1 receptor agonists, liraglutide, metformin, topical insulin, and pioglitazone are identified as potential pharmacological interventions that target these metabolic pathways.
Meng, Fanhao; Wang, Jing; Wang, Long; Zou, Wei ·
RPEP-12541 · 2025The patient, an elderly woman with a metastatic pancreatic neuroendocrine tumor (pNET), developed acute myeloid leukemia (AML) while receiving peptide receptor radionuclide therapy (PRRT) with octreotide. The AML diagnosis was complicated by pancytopenia that initially masked the leukemia.
She was treated with a non-chemotherapy regimen of azacitidine and venetoclax, which achieved remission of both the AML and the neuroendocrine tumor simultaneously. This dual response demonstrates the potential for non-intensive therapeutic approaches in managing therapy-related AML in complex oncology patients.
Menon, Abhinav; Harindran Vallathol, Dilip; Charles, Deepak; Nair, Shagos; Kundil Veetil, Karthika; Komaranchath, Ashok S; Warrier, Arun R ·
RPEP-12543 · 2025After a median 8.7 months of tirzepatide treatment in 17 lipodystrophy patients (14 with FPLD): BMI decreased by median 1.7 kg/m² (p=0.008), HbA1c decreased by median 1.1% (range -6.3% to -0.1%, p<0.001), triglycerides decreased by median 65 mg/dL (with one patient dropping 3,820 mg/dL; p=0.003), and total daily insulin requirements decreased by median 109 units (range -315 to 0 units, p=0.002). Three additional patients with rarer lipodystrophy forms (atypical PL, acquired GL) also showed robust responses. Side effects were limited to benign gastrointestinal symptoms.
Meral, Rasimcan; Celik Guler, Merve; Kaba, Diarratou; Prativadi, Jeevitha; Frontera, Eric D; Foss-Freitas, Maria Cristina; Nachawi, Noura; Broome, David T; Lightbourne, Marissa; Brown, Rebecca J; Taylor, Simeon I; Oral, Elif A ·
RPEP-12547 · 2025Animal studies revealed contradictory GLP-1 effects on female reproduction:
Stimulatory effects (intracerebroventricular GLP-1):
• Increased luteinizing hormone surge amplitude
• Increased FSH secretion
• Elevated serum progesterone
• Up-regulated Kiss-1r expression in hypothalamus
• Increased ovarian Graafian follicles and corpora lutea
Inhibitory effects (GLP-1 RA drugs):
• Intracerebroventricular Exendin-4 and subcutaneous liraglutide produced opposite effects to native GLP-1
• GLP-1 suppressed FSH-induced progesterone synthesis in granulosa cells despite up-regulating FSH receptor expression
Uterine effects (controversial):
• Some studies: beneficial antifibrotic effect, reducing collagen deposition in intrauterine adhesion models
• Other studies: destruction of luminal epithelium and shrinkage of muscle fibers
Merhi, Zaher ·
RPEP-12548 · 2025In animal models, GLP-1 receptor agonists caused lower ovarian weights, increased follicular atresia (egg cell death), and reduced serum steroid levels. They also downregulated kiss-1 and kiss-1r expression in the hypothalamus, leading to lower luteinizing hormone levels and delayed puberty. In the uterus, these drugs negatively affected the epithelial lining, though they reduced fibrosis in an intrauterine adhesion model. No human studies on fertility outcomes in non-PCOS women have been published to date.
Merhi, Zaher ·
RPEP-12550 · 2025In 42 overweight/obese adults with type 1 diabetes, once-weekly semaglutide produced a mean relative weight loss of 13.3% over 12 months — comparable to results seen in type 2 diabetes and obesity trials. Glycemic control also improved, and the proportion of patients with significant liver stiffness (>8 kPa, suggesting liver scarring) dropped dramatically from 20.6% to just 4.5%.
Total daily insulin requirements decreased by 13.6%, suggesting that semaglutide reduces insulin resistance even in the type 1 diabetes setting where insulin production is absent. Eight of 42 patients (19%) discontinued treatment, mainly due to gastrointestinal intolerance. The study provides the first substantial real-world evidence that semaglutide is safe and effective in type 1 diabetes, a population for which it is not currently approved.
Mertens, Jonathan; De Winter, Hennah T; Dirinck, Eveline; Francque, Sven; De Block, Christophe · Observational / Real World Study
RPEP-12551 · 2025Among 26 studies (n=3,020), 5 evaluated psychiatric symptoms as primary outcomes and 21 as secondary outcomes:
Primary psychiatric outcomes: Exenatide 2 mg weekly reduced cocaine craving in a case series but showed no significant change in a separate study (n=12, p=0.46). Dulaglutide 1.5 mg weekly did not significantly affect smoking cessation (RR=0.87, p=0.25) but reduced alcohol consumption by 29% in a secondary analysis.
Secondary psychiatric outcomes: Liraglutide 1.8 mg/day significantly improved depression and anhedonia. Semaglutide improved diabetes-related quality of life and anxiety (Cohen's d=0.48) compared to dulaglutide. Exenatide showed mixed results, with one RCT finding significant BDI score reduction (Δ=-5.2).
Overall: Only 3 of 9 included RCTs reported significant effects on primary psychiatric outcomes; 6 reported null findings.
Meshkat, Shakila; Di Luciano, Corinna; Swiderski, Alyssa; Li, Gloria; Aguilar, Reinhard Janssen; Dunkley, Benjamin T; Reichelt, Amy C; Zhang, Yanbo; Greenshaw, Andrew; Vermetten, Eric; Jetly, Rakesh; Dash, Satya; Agarwal, Sri Mahavir; Swainson, Jennifer; Bhat, Venkat ·
RPEP-12552 · 2025Across four RCTs with 514 Parkinson's patients testing three different GLP-1 agonists:
- Motor function (OFF-medication state): Significantly improved (MD = -3.29, 95% CI -5.17 to -1.42, p=0.0006)
- Quality of life (PDQ-39): No significant improvement (MD = -0.54, 95% CI -2.07 to 0.99, p=0.49)
- Adverse effects significantly higher in GLP-1 group: nausea (RR 1.98, p=0.0008), vomiting (RR 6.65, p=0.0008), constipation (RR 1.45, p=0.01), and weight loss (RR 2.11, p=0.03)
- No other adverse effects were significantly increased
Messak, Mark; Abdelmageed, Ahmed; Senbel, Abdelrahman A; Khattab, Youssef A; Mandour, Youssef; Shaker, Omar; Rehan, Ahmed Hamed; Oransa, Samir; Nasr, Mohamed; Shabeeb, Abdullah Emad; Rezq, Ziyad; Hossam, Fares; Abouelmagd, Moaz Elsayed ·
RPEP-12569 · 2025Using ribosome profiling (RiboSeq) to capture the complete set of actively translated proteins in the medial prefrontal cortex after antidepressant-dose ketamine, researchers identified VPAC2 — the receptor for the neuropeptide vasoactive intestinal peptide (VIP) — as a novel target for antidepressant action.
VPAC2 expression in the prefrontal cortex was found to be limited to somatostatin-positive inhibitory neurons. When a VPAC2 agonist was administered in vivo, it bidirectionally modulated pyramidal neuron activity and disrupted coordinated neural activity patterns. Critically, VPAC2 agonism alone was sufficient to drive an antidepressant response in mice, validating this neuropeptide receptor as a potential drug target independent of ketamine itself.
Miller, Oliver H; Grabole, Nils; Wells, Isabelle; Bellier, Ludovic; Nassi, Jonathan J; Hall, Benjamin J ·
RPEP-12570 · 2025After one year of subcutaneous semaglutide treatment (titrated from 0.25 mg to 1 mg weekly), 168 type 2 diabetes patients showed significant improvements across all measured metabolic parameters. Median weight decreased from 100.0 kg to 91.5 kg (p<0.001), median BMI from 33.6 to 30.9 kg/m² (p<0.001), and HbA1c from 7.80% to 6.90% (p<0.001).
At baseline, 92.3% of patients had obesity (BMI ≥30), with 53.6% in Obesity Class 1. After treatment, 81 patients transitioned to lower obesity classes, though 15 remained in Class 3 obesity.
Milushewa, Petya; Mitreva, Yoanna; Chakarova, Nevena; Tankova, Tsvetalina; Naseva, Emilia; Petkova, Valentina ·
RPEP-12571 · 2025A 69-year-old woman with prurigo nodularis achieved complete skin lesion resolution with nemolizumab. Discontinuation of pregabalin (prescribed for coexisting sciatic pain) led to pruritus recurrence within 2 months despite continued absence of visible lesions. Reintroduction of low-dose pregabalin stabilized symptoms within 2 months. The proposed mechanism is pregabalin's inhibition of α2δ voltage-gated calcium channel subunits, suppressing release of excitatory neuropeptides including substance P and CGRP.
Mima, Yoshihito; Yamamoto, Masako; Iozumi, Ken ·
RPEP-12574 · 2025This comprehensive review maps the pharmacokinetics and drug interactions of all approved GLP-1 receptor agonists (exenatide, liraglutide, dulaglutide, semaglutide) plus tirzepatide (the dual GLP-1/GIP agonist). Native GLP-1 has a half-life of just 2 minutes — the structural modifications that extend this (amino acid substitutions, fatty acid conjugation, albumin binding, Fc fusion) vary by drug and produce dramatically different pharmacokinetic profiles.
The review finds that most drug-drug interactions (DDIs) with GLP-1 RAs are clinically insignificant — they don't interfere with liver enzymes or drug transporters. The main DDI mechanism is delayed gastric emptying, which slows absorption of co-administered oral drugs. However, two notable exceptions require monitoring: tirzepatide significantly altered oral contraceptive exposure, and oral semaglutide affected levothyroxine levels. Additionally, GLP-1 drug-induced changes in body fat, kidney filtration, and liver enzyme activity could affect other drugs in ways not yet well understood.
Min, Jee Sun; Jo, Seong Jun; Lee, Sangyoung; Kim, Duk Yeon; Kim, Da Hyun; Lee, Chae Bin; Bae, Soo Kyung · Review
RPEP-12587 · 2025Across three clinical trials screening 1,082 patients (691 randomized: 510 retatrutide, 130 placebo), the 12 mg weekly dose produced the most significant results:
• Greatest reductions in body weight, BMI, and waist circumference across all dose groups
• Higher proportion of patients achieving weight loss thresholds of ≥5%, ≥10%, ≥15%, and ≥20%
• Significant metabolic improvements compared to placebo
• Gastrointestinal adverse effects were the most commonly reported side effects
The study population averaged 54.26 years of age with a near-equal gender split (48% men, 52% women).
Misra, Saurav; Narayan, Ravi Kant; Kaur, Manmeet ·
RPEP-12589 · 2025All-atom molecular dynamics simulations of the wild-type hLL-37₁₇₋₂₉ peptide and five I24 mutants revealed a biphasic aggregation process: rapid small oligomer formation via hydrophobic collapse, followed by structural reorganization.
Mutant-specific behaviors were striking: I24D (aspartate) and I24Q (glutamine) were strongly aggregation-prone, I24K (lysine) was aggregation-resistant with strong solvation and minimal clumping, and I24A (alanine) and I24S (serine) showed intermediate behavior. Mutations destabilized the amphipathic α-helix critical for membrane activity, especially charged variants, with helix unfolding concentrated near the peptide termini. Aggregate morphology remained predominantly fibrillar across all systems, but internal order varied. Aggregation was governed by a balance between electrostatic and van der Waals forces, with each mutation shifting this balance differently.
Mitra, Aritra; Paul, Sandip ·
RPEP-12598 · 2025GLP-1 receptor agonists show broad neuroprotective potential across multiple neurodegenerative diseases. In preclinical models, they reduce amyloid-β and tau pathology in Alzheimer's, preserve dopaminergic neurons in Parkinson's, protect brain cells after stroke, and alleviate depression. These effects are mediated through cAMP/PKA, PI3K/Akt, and MAPK signaling pathways that promote neuronal survival, reduce neuroinflammation, inhibit apoptosis, and enhance synaptic plasticity. Early clinical trials show attenuation of cortical atrophy and preserved brain glucose metabolism, though core AD biomarker changes remain inconclusive.
Moaket, Osama Sobhi; Obaid, Sarah Eyad; Obaid, Fawaz Eyad; Shakeeb, Yusuf Abdulkarim; Elsharief, Samir Mohammed; Tania, Afrin; Darwish, Radwan; Butler, Alexandra E; Moin, Abu Saleh Md ·
RPEP-12599 · 2025The G protein-biased agonist acyl-ExF1, when given peripherally for 6 weeks, prevented body weight gain and reduced plasma glucose levels, while the β-arrestin-biased agonist acyl-ExD3 did not. However, neither agonist significantly affected circulating lipid levels when given peripherally.
In contrast, when administered directly into the brain (intracerebroventricular infusion for 18 days), both agonists strongly reduced plasma triglyceride and cholesterol levels but did not affect glucose levels. Both increased fatty acid uptake by adipose tissue — acyl-ExD3 significantly in brown adipose tissue, acyl-ExF1 in white adipose tissue. The key finding is that signaling bias at the GLP-1 receptor does not differentially affect lipid metabolism.
Modder, Melanie; Tomas, Alejandra; Afkir, Salwa; Pronk, Amanda C M; Streefland, Trea C M; Lalai, Reshma A; van Eenige, Robin; Rensen, Patrick C N; Jones, Ben; Kooijman, Sander ·
RPEP-12601 · 2025At 6-month follow-up, 69% of the overall cohort achieved HbA1c <7%, rising to 77% in the GLP-1 RA-naïve subgroup. Mean weight changes by subgroup were:
- Overall cohort: -6.3 kg
- Baseline HbA1c <7%: -7.1 kg
- GLP-1 RA-naïve: -8.1 kg
More pronounced HbA1c reductions occurred in GLP-1 RA-naïve patients and those with higher baseline HbA1c (≥7%), while greater weight loss was seen in GLP-1 RA-naïve patients and those with lower baseline HbA1c (<7%). The cohort was 58% female, mean age 54, and 54% were already on a GLP-1 RA at baseline.
Mody, Reema; Desai, Karishma; Teng, Chia-Chen; Reznor, Gally; Stockbower, Grace; Grabner, Michael; Benneyworth, Brian D ·
RPEP-12603 · 2025At baseline, 44.6% of 884 ischemic stroke patients had normoglycemia, 33.9% had prediabetes, and 21.5% had type 2 diabetes. After 1 year, normoglycemia decreased by 12.1 percentage points while prediabetes increased by 10.2 points and diabetes by 1.9 points. Statin therapy was the only significant risk factor for glycemic progression.
23.4% (n=207) of the cohort would have met eligibility criteria for the SELECT trial on semaglutide in obese non-diabetics with prior cardiovascular disease. However, only one ongoing clinical trial is evaluating short-term cardiovascular risk reduction with these drugs in stroke patients specifically.
Moelgg, Kurt; Karisik, Anel; Scherer, Lukas; Buergi, Lucie; Dejakum, Benjamin; Komarek, Silvia; Granna, Julian; Boehme, Christian; Pechlaner, Raimund; Toell, Thomas; Knoflach, Michael; Kiechl, Stefan; Kaser, Susanne; Egger, Alexander; Griesmacher, Andrea; Mayer-Suess, Lukas ·
RPEP-12606 · 2025Meta-analysis of 13 RCTs of GLP-1 RAs in obese/overweight patients without diabetes found:
- Body weight reduction: -12.79% (95% CI: -15.12 to -10.46)
- BMI reduction: -4.80 kg/m² (95% CI: -6.24 to -3.36)
- Waist circumference: -9.78 cm (95% CI: -11.47 to -8.09)
- Systolic BP: -6.32 mmHg (95% CI: -7.92 to -4.72)
- Diastolic BP: -1.95 mmHg (95% CI: -3.21 to -0.69)
Weight loss thresholds vs. placebo (risk ratios):
- ≥5% weight loss: RR 2.98
- ≥10% weight loss: RR 5.56
- ≥15% weight loss: RR 9.50
- ≥20% weight loss: RR 15.00
Tirzepatide showed greater reductions than semaglutide across outcomes.
Mohamed Ali Elbashir, Roaa; Elbashir, Azza; Urimuke Basake, Robert; Zakaria Ahmed Mohieldin, Amna; I A Elhaj, Najla; Ebrahim Mohamed Ebrahim, Fatima; Gase Ahmed, Waad; Abdelrahim Mohamed Mahgoub, Ola ·
RPEP-12609 · 2025Mu-17 (LFRLIPSLIKRLISAFK, 17 residues) showed broad-spectrum antimicrobial activity with MICs of 1.5-5 μM against Gram-positive bacteria (Bacillus sp., Staphylococcus sp.), Gram-negative bacteria (E. coli), and Candida albicans. It inhibited breast cancer cell proliferation with an IC50 of 13 μM. Hemolytic activity was only 18% at 100 μM — significantly lower than many potent AMPs. The peptide forms an amphipathic alpha-helix and likely kills through membrane interaction. Recombinant production in E. coli was successfully optimized.
Mohammadi, Zahra; Ayat, Hoda; Ahadi, Ali Mohammad ·
RPEP-12618 · 2025By constraining computer-assisted synthesis planning with hierarchical reaction logic — dictating which subsets of reactions to apply at different planning stages — the algorithm successfully designed complete synthesis routes for complex peptide targets within minutes.
The approach was validated on clinically relevant targets including vancomycin (a complex glycopeptide antibiotic) and semaglutide (a large GLP-1 receptor agonist used for diabetes and obesity). Despite not being trained on any literature precedents, the computationally designed routes mimicked strategies used by human expert chemists.
The system incorporates protecting-group strategies and realistic pathway pricing, and supports both solid-phase and solution-phase synthesis modes, including C-to-N and N-to-C peptide extension strategies.
Molga, Karol; Beker, Wiktor; Roszak, Rafał; Czerwiński, Andrzej; Grzybowski, Bartosz A ·
RPEP-12620 · 2025Semaglutide and tirzepatide represent two complementary but distinct approaches to obesity pharmacotherapy. Tirzepatide (dual GIP/GLP-1 agonist) produces greater weight loss and broader metabolic benefits, while semaglutide (GLP-1 agonist) has demonstrated robust cardiovascular protection with dedicated outcomes data from the SELECT trial.
The review synthesizes data from the major clinical trial programs: STEP and SELECT for semaglutide, SURMOUNT and SUMMIT for tirzepatide. It frames the choice between the two drugs as a clinical decision that depends on the individual patient's priorities — maximum weight loss and metabolic improvement (favoring tirzepatide) versus proven cardiovascular risk reduction (favoring semaglutide). Both drugs require clinicians to treat obesity as a chronic disease needing ongoing pharmacological management rather than a lifestyle issue with a temporary fix.
Mondoh, Alvin; Crotty, Michael; le Roux, Carel W · Comparative Review
RPEP-12621 · 2025Researchers successfully printed self-standing, ring-shaped peptide scaffolds up to 10 mm in diameter using a self-assembling peptide bioink and a microfluidic coaxial printhead.
Murine neural stem cells encapsulated by either printing strategy showed slightly lower initial viability than controls, but viability increased over time. By day 7, the cells had adhered, sprouted, and differentiated into neurons, astrocytes, and oligodendrocytes, supporting the idea that these peptide hydrogels can function as bioinks for nervous tissue engineering.
Mondésert, Hugues; Malloggi, Chiara; Lazzaro, Andrea; Sala, Giulia; Corvaglia, Valentina; Forouharshad, Mahdi; Gelain, Fabrizio ·
RPEP-12625 · 2025In 29 MASLD patients without diabetes, after 12 weeks of matched weight loss:
Similar between groups:
- Body composition changes, ALT reduction, liver steatosis reduction, and disease activity improvement
- Subcutaneous adipose transcriptome, circulating proteome, and stool microbiome
GLP-1RA advantages:
- Improved glucose handling and fasting lipids
- Significantly decreased de novo lipogenesis (DNL)
After treatment withdrawal (12 weeks):
- GLP-1RA (but not lifestyle) group showed elevated MMP-10, IL10RB, FGF-23, and Flt3L in circulation
- Dysregulated adipose tissue gene expression
- Changes suggestive of metabolic predisposition to weight regain
Moolla, Ahmad; Poolman, Toryn; Othonos, Nantia; Dong, Jiawen; Smith, Kieran; Cornfield, Thomas; White, Sarah; Ray, David W; Mouchti, Sofia; Mózes, Ferenc E; Thomaides-Brears, Helena; Neubauer, Stefan; Cobbold, Jeremy F; Hodson, Leanne; Tomlinson, Jeremy W ·
RPEP-12629 · 2025The review identifies a paradigm shift in CKD management: obesity-associated CKD phenotypes can now be therapeutically targeted using combinations of GLP-1 receptor agonists, SGLT2 inhibitors, and finerenone added to standard RAAS blockade. These multitargeted strategies address the pathophysiological interplay between obesity, metabolic syndrome, and kidney disease, with evidence of cardio-renal protection that could substantially alter disease progression.
Morales, Enrique; Jenssen, Trond G; Bevc, Sebastjan; Miglinas, Marius; Martin, William P; Theodorakopoulou, Marieta; Buus Jørgensen, Morten; Trillini, Matias ·
RPEP-12631 · 2025Of 29 soil isolates tested, Paenibacillus profundus strains 7.5 and M4.5 showed the most potent broad-spectrum antimicrobial activity, including significant inhibition of MRSA and carbapenem-resistant Enterobacterales (CRE).
Genome mining of three producer strains using antiSMASH revealed biosynthetic gene clusters for:
- Nonribosomal peptide synthetases (NRPSs)
- Polyketide synthases (PKSs)
- Ribosomally synthesized and post-translationally modified peptides (RiPPs)
Several clusters matched known compounds (polymyxin B, paenilan, colistin, paenibacterin), while many had no known counterparts, suggesting potential for discovering novel antimicrobial peptides.
Moran, Michael; Turner, Hogan; Yanchar, Joseph; Preece, Joshua; Ahlborn, Gene; Robison, Richard ·
RPEP-12633 · 2025The review presents several lines of evidence implicating amylin in migraine:
- Amylin belongs to the same calcitonin/CGRP peptide family and shares receptor components with CGRP
- In provocation studies, amylin can trigger migraine attacks, similar to CGRP
- Some CGRP-targeting therapies also block amylin receptors, which may contribute to their efficacy
- Amylin plasma levels have been identified as a potential migraine biomarker in at least one clinical study
- Preclinical rodent studies suggest sex differences in amylin-mediated migraine mechanisms
The authors propose that understanding the distinct and overlapping mechanisms between amylin and CGRP signaling could advance migraine treatment options.
Moreno-Ajona, David; Gosalia, Helin; Hoffmann, Jan; Goadsby, Peter J ·
RPEP-12636 · 2025Among 236 patients (median age 64, BMI 33.8, baseline SU 5.2 mg/dL), oral semaglutide achieved the primary endpoint of SU < 6 mg/dL in a significant proportion at 12 months. Patients with baseline SU ≥ 6 mg/dL showed reductions of 0.6 and 0.8 mg/dL respectively (all p < 0.001). Changes were independent of metabolic control improvement, weight loss, or baseline use of GLP-1RAs or SGLT2 inhibitors. Switching from DPP-4 inhibitors was associated with particularly notable SU reductions.
Moreno-Pérez, Oscar; Tejera-Muñoz, Antonio; Carreño-Valdivia, Rubén; Rodríguez-Bedoya, María; Guillén-Morote, Cristina; Roldán-Sánchez, Ada; Andrés, Mariano ·
RPEP-12639 · 2025A single-chain IgG (scIgG) was engineered from atezolizumab (anti-PD-L1) with flexible linkers embedding the melittin sequence flanked by matriptase cleavage sites. Initial constructs with native melittin were too cytotoxic during production, leading to development of Pmod2-2, a melittin variant that retained potent pore-forming ability while being compatible with antibody fusion.
The resulting scIgG-Pmod2-2 hybrid preserved the Fab (antigen binding) and Fc (immune signaling) functionalities of atezolizumab, displayed favorable pharmacokinetics, and released the active cytotoxic peptide specifically in response to matriptase — an enzyme overexpressed in carcinomas.
Morillo, Izaskun; Zulaica, Joao; R Caballero, Asier; Auzmendi-Iriarte, Jaione; Largo, Eneko; Apellaniz, Beatriz; Carracedo, Arkaitz; Piva, Marco; Nieva, José L; Rujas, Edurne ·
RPEP-12643 · 2025Over five weeks at 6°C, all mice ate significantly more food. Wild-type and GLP-1R/GIPR double knockout mice showed increased jejunal circumference, villi length, and crypt depth — but mice lacking both GLP-1R and GLP-2R did not show these gut adaptations. This pinpoints the GLP-2 receptor as essential for cold-induced intestinal expansion. Despite elevated plasma active GLP-1 levels, villi lengthening did not occur without GLP-2R. However, GLP-1R signaling was sufficient for body weight gain even when gut structural adaptation failed.
Morrow, Nadya M; Hanson, Antonio A; Fong-McMaster, Claire; Livingston, Dawson B H; Osman, Hoda; Hamilton, Lauren; Trzaskalski, Natasha A; Locatelli, Cassandra A A; Bellefleur, Mélodie N; Messika-Zeitoun, Ethel; Cino, Sebastian M; Pulente, Serena M; Abramchuk, Iryna; Zhao, Xiaoling; Lorenzen-Schmidt, Ilka; Morissette, Arianne; Power, Krista A; Harper, Mary-Ellen; Mulvihill, Erin E ·
RPEP-12647 · 2025When the glutamate agonist NMDA and the acetylcholine agonist carbachol were each applied separately to the IGL, both caused non-photic phase shifts in circadian rhythms. Orexin alone produced only small, inconsistent shifts. However, combining carbachol and NMDA together actually inhibited each other's effects. Adding orexin to this two-drug cocktail reversed the inhibition and produced the largest phase shifts observed in the study.
Blocking acetylcholine muscarinic receptors or orexin receptors individually during sleep deprivation did not prevent phase shifting, indicating that no single arousal pathway is solely responsible — the IGL relies on redundant, convergent inputs.
Moshirpour, Mahtab; Horsley, Katelyn G; Puche Saud, Susana; McCance, Chantelle; Scotland, Maeve; Antle, Michael C ·
RPEP-12649 · 2025Antidepressant-related weight gain is a common and clinically significant problem that can worsen metabolic health in patients already at elevated risk due to depression. The review identifies several strategies to manage this:
1. **Weight-neutral alternatives**: Bupropion, fluoxetine, and the newer agent gepirone can treat depression without the weight gain associated with many other antidepressants.
2. **Genetic prediction**: Metabolizer phenotypes and inflammation markers may help predict which patients are most susceptible to weight gain on specific antidepressants.
3. **GLP-1 receptor agonists**: Liraglutide and metformin are discussed as pharmacotherapy options to counteract antidepressant-induced weight gain.
4. **Integrated behavioral interventions**: Combining lifestyle modifications with medication management can help offset metabolic risks.
Moss, Lauren; Laudenslager, Marci; Steffen, Kristine J; Sockalingam, Sanjeev; Coughlin, Janelle W · Review
RPEP-12650 · 2025Chitosan nanoparticles decorated with a high density of PDGF-β binding peptide and loaded with anti-TGF-β1 siRNA significantly reduced hepatic TGF-β1 levels by approximately 65% and fibronectin levels by approximately 63% in a CCl4-induced liver fibrosis mouse model. Pretreatment with collagenase-loaded nanoparticles (to break down the dense scar tissue barrier) further reduced both markers by an additional ~10%. Histopathological evaluation confirmed reduced portal inflammation, absence of fibroblastic proliferation between hepatocytes, and decreased collagen deposition. The nanoparticles had 92.39% siRNA encapsulation efficiency, a diameter of 103 nm, and showed no organ-specific toxicity at doses up to 120 mg/kg over 4 weeks.
Mostafa, Salma; Shetab Boushehri, Maryam A; Ezzat, Aya A; Weiskirchen, Ralf; Lamprecht, Alf; Mansour, Samar; Tammam, Salma N ·
RPEP-12664 · 2025Researchers developed Immuno-STAT (IST), a protein scaffold that delivers peptide-specific T cell receptor activation plus CD28 costimulatory signals to expand HIV-specific killer T cells from the naive immune repertoire. The IST platform succeeded where conventional dendritic cell methods failed: it expanded naive SL9-specific CD8+ T cells (targeting a key HIV epitope) that dendritic cells could not stimulate.
The IST-generated T cells showed potent cytotoxicity against HIV-infected targets, diverse T cell receptor clonotypes (suggesting broad coverage), memory-differentiated phenotypes, and polyfunctionality — all critical qualities for an effective HIV-targeting immune response.
Mueller, April L; Lamcaj, Sara; Garforth, Scott; Hiner, Christopher; Woodley, Darien; Paraiso, Kitt; Mi, Tian; Low, Simon; Youngblood, Ben; Almo, Steven C; Goldstein, Harris · In Vitro
RPEP-12671 · 2025Tirzepatide demonstrated significantly superior weight loss compared to semaglutide across 7 studies (28,980 participants). The pooled standardized mean difference was 0.75 (95% CI: 0.52–0.92) favoring tirzepatide.
At 6 months, tirzepatide achieved a mean difference of 1.33 percentage points greater weight reduction (95% CI: 0.58–2.08). Participants on tirzepatide had significantly higher odds of achieving ≥10% weight loss compared to semaglutide (OR: 0.21, 95% CI: 0.06–0.78). However, heterogeneity was very high across studies (I² >90%).
Munawar, Nazish; Mahato, Aakash; Rawat, Anurag; Gill, Fahad Shaukat; Kumar, Daksh; Katwal, Susant; Wei, Calvin R; Ali, Neelum ·