RPEP-12245 · 2025Wheat oligopeptides (WOPs) demonstrated potent ACE inhibitory activity, achieving 77% inhibition at 2.5 mg/mL, and produced marked reductions in systolic (SBP), diastolic (DBP), and mean arterial blood pressure (MBP) in spontaneously hypertensive rats.
The peptides worked through multiple mechanisms: activating the Nrf2/Keap1 pathway to reduce oxidative stress in kidneys and heart tissue, lowering serum levels of six inflammatory markers (TNF-α, IL-6, IL-1β, ET-1, VEGF-A, CD62E), and modulating the PI3K/AKT signaling pathway along with AT1R, ACE, and eNOS signaling proteins to protect organ tissue from hypertension-related damage.
Liu, Wenying; Wang, Xinze; Meng, Ganlu; Yang, Chengjun; Zhang, Xinxue ·
RPEP-12246 · 2025By tuning the surface hydrophilicity of inhaled liposome nanoparticles, researchers achieved two distinct delivery outcomes from the same lung-based platform. Low-hydrophilic liposomes loaded with GLP-1 receptor agonists (liraglutide or semaglutide) delivered the peptides systemically into the bloodstream, producing excellent blood sugar-lowering effects in diabetic mice. High-hydrophilic liposomes loaded with budesonide stayed in the lungs longer, treating asthma while reducing dosing frequency.
The mechanism: less hydrophilic particles crossed through alveolar epithelial cells more efficiently for systemic absorption, while more hydrophilic particles resisted both cellular transport and macrophage clearance, staying in the lungs longer.
Liu, Xi; Zhang, Lie; Li, Sa; Xing, Liyun; Ni, Mingjie; Huang, Minyi; Huang, Yuan · Animal
RPEP-12248 · 2025Daily acupuncture around full-thickness skin wounds in mice significantly improved wound closure, collagen deposition, and tissue repair quality over 10 days. The treatment enhanced M2 macrophage polarization (the healing-promoting type) within wounds, reduced systemic macrophage burden in the spleen, and lowered both local and systemic levels of the inflammatory cytokines IL-1β and IL-6.
The mechanism was identified as the CGRP-RAMP1-TSP-1 signaling pathway. Blocking this pathway with the CGRP receptor antagonist BIBN4096 abolished acupuncture's effects on macrophage reprogramming and wound healing. However, the anti-inflammatory cytokine suppression was only partially CGRP-dependent, indicating that acupuncture also works through additional neuropeptide or neuronal pathways that remain to be identified.
Liu, Xiaoer; Chen, Junsheng; Zou, Lingyue; Lu, Xiaohan; Zhu, Boran; Li, Jingwen; Zhu, Yuyan; Jiang, Minjiao; Peng, Rou; Guo, Yifan; Lu, Shengfeng ·
RPEP-12254 · 2025In mice with myocardial ischemia-reperfusion (45 min LAD ligation + 24 h reperfusion):
- Semaglutide enhanced cardiac function recovery (ultrasound assessment)
- Reduced cardiac fibrosis (Masson's staining)
- Mitigated oxidative stress in cardiomyocytes
- Inhibited ferroptosis in cardiomyocytes
- RNA sequencing identified S100A9 (S100 calcium-binding protein A9) as the target gene
- In vitro confirmation: semaglutide activated PKC (Protein Kinase C) pathway, which decreased S100A9 expression, thereby inhibiting ferroptosis
The PKC → S100A9 → ferroptosis inhibition axis represents a novel mechanism for semaglutide's cardioprotective effects.
Liu, Yan; Li, Zixuan; Xu, Xinhe; Zou, Yan; Zhang, Miaomiao; Chen, Yingyu; Zhu, Wenwu; Han, Bing ·
RPEP-12258 · 2025Sesame protein hydrolysates with 12% degree of hydrolysis (SPHDH12) formed optimal self-assembling nanoparticles for beta-carotene delivery:
- Nanoparticle size: 50.30 ± 0.43 nm
- Encapsulation efficiency: 75.23 ± 0.92%
- Drug loading capacity: 11.14 ± 0.14%
- Beta-carotene encapsulation caused structural shifts: 33.8% decrease in α-helix and 41.9% increase in β-sheet content
- Peptidomics identified five core peptides responsible for self-assembly via hydrophobic interactions
- In vitro digestion: prolonged beta-carotene release (26.76% cumulative)
- In vivo (rats): peak plasma concentration 64.98 ng/mL, 2.73-fold higher bioavailability versus free beta-carotene
Liu, Yaqi; Zhu, Zehui; Ai, Xin; Pan, Fei; Tian, Wenli; Zhao, Lei; Zhao, Liang ·
RPEP-12268 · 2025CRAMP levels were reduced in infarcted cardiac tissue and in cardiomyocytes exposed to ferroptosis inducers. Overexpressing CRAMP or pretreating cells with LL-37 peptide alleviated ferroptosis, while CRAMP knockdown worsened cell death. The mechanism involves CRAMP inhibiting cathepsin L (CTSL) activity, which preserves PDIA4 — a protein that suppresses ferroptosis. In the mouse myocardial infarction model, both CRAMP overexpression and direct CRAMP peptide administration significantly reduced myocardial injury and improved cardiac function.
Liu, Zhantao; Zhang, Qingsong; Su, Dan; Chen, Hong; Wang, Bowen; Ye, Lin; Wang, Peiyan; Wu, Jingnan; Jia, Wencan; Liu, Lijun; Wang, Jianxun; Miao, Shuo ·
RPEP-12269 · 2025GLP-1 receptor agonists work through multiple mechanisms: stimulating insulin secretion, suppressing glucagon release, delaying gastric emptying, and reducing appetite via GLP-1 receptor activation. These agents have demonstrated significant efficacy for type 2 diabetes and obesity management.
Dual GLP-1/GIP receptor agonists like tirzepatide activate both GLP-1 and GIP receptors simultaneously, providing enhanced glycemic control, greater weight loss, and improved metabolic function compared to single-target agents. Beyond metabolic effects, emerging evidence supports cardiovascular protection, neuroprotective benefits, and positive effects on mental health for these drug classes. The review also covers advances in triple receptor agonists targeting GLP-1, GIP, and glucagon receptors.
Liu, Zhao; Yu, Shanshan; Jin, Xinyan; Sheng, Luguang; YanMu, Mai Re; Gao, Jie; Lu, Jun; Lei, Tao ·
RPEP-12273 · 2025Over the past decade, MMP-triggered self-assembling peptides have been successfully developed for multiple biomedical applications:
1. Hydrogels: MMP-responsive peptides form hydrogels at disease sites for treating cancer, inflammation, wound healing, myocardial infarction, and central nervous system diseases.
2. Nanostructures: MMPs trigger peptide assembly into nanostructures that serve as biosensors, drug delivery vehicles, and biological response modulators. Incorporating enzyme cleavage sequences allows controlled drug release.
3. Smart biomaterials: These peptides function as intelligent biomaterials — they sense the disease environment (elevated MMP levels), activate at the target site, deliver therapeutic cargo, and modulate biological responses, all triggered by the same disease-associated enzymes.
Liu, Zhuyun; Yu, Chunlin; Li, Zhenjia; Wang, Xiaorui; Shang, Dejing; Dong, Weibing ·
RPEP-12274 · 2025Across 45 articles containing 119 comparisons, semaglutide was dominant or cost-effective in 73.9% of all analyses against within-study willingness-to-pay thresholds. However, sponsor type dramatically influenced results:
- **Novo Nordisk-sponsored**: 100% found semaglutide dominant/cost-effective
- **Non-industry sponsored**: 50% found semaglutide cost-effective
- **Other industry sponsors**: 0% found semaglutide cost-effective
Semaglutide was more likely to appear cost-effective in high-income countries, studies with longer time horizons, broader perspectives, and lower discount rates. Results remained consistent when converted to a common US$50,000/QALY willingness-to-pay threshold.
Liu, Ziyun; Zeng, Baoqi; Sun, Feng; Xia, Qing ·
RPEP-12276 · 2025A 47-year-old Caucasian female (BMI 27.92) with no systemic risk factors developed progressive NAION one month after initiating liraglutide therapy for weight loss. Initial presentation showed BCVA of 20/40 with optic nerve head swelling and inferior visual field defects. Despite oral corticosteroid treatment (discontinued due to poor glycemic control), the condition progressed.
After three months, she was switched to semaglutide due to poor weight loss results. Eight months later, vision had deteriorated to 20/400 with persistent ONH edema confirmed on OCT and worsened visual field defects. Given the absence of any anatomical or systemic risk factors, NAION was attributed to GLP-1 receptor agonist therapy, with liraglutide as the likely initial trigger and semaglutide as a contributing factor in progression.
Lixi, Filippo; Calabresi, Valerio; Cukurova, Feyza; Giannaccare, Giuseppe ·
RPEP-12288 · 2025The patient had an IGF-2:IGF-1 ratio of 60.7 (normal <10) with low insulin and C-peptide levels, confirming non-islet cell tumor hypoglycemia caused by the adrenal mass. Symptomatic hypoglycemia developed within 5 hours of a supervised fast. The tumor also caused biochemical hyperandrogenism with elevated testosterone, estradiol, and adrenal androgens, leading to endometrial hyperplasia and postmenopausal bleeding.
Postoperative pathology confirmed adrenocortical carcinoma with a Ki67 proliferation index of 12% and positive immunostaining for IGF-2, providing direct histological evidence that the tumor was producing this peptide growth factor.
Lonergan, Eibhlín Marie; Tan, Lok Yi Joyce; O'Sullivan, Adrian; Kanazaki, Keizo; Morita, Miwa; O'Halloran, Domhnall ·
RPEP-12292 · 2025Tirzepatide produced a 21.3% reduction in total body weight at 72 weeks, composed of a 33.9% loss in fat mass and a 10.9% loss in lean mass. In the placebo group, these figures were 5.3%, 8.2%, and 2.6% respectively (p < 0.001 for all comparisons).
Critically, the composition of weight lost was approximately 75% fat mass and 25% lean mass in both the tirzepatide and placebo groups. This ratio remained consistent across subgroups defined by sex, age, baseline BMI, and baseline fat mass.
Look, Michelle; Dunn, Julia P; Kushner, Robert F; Cao, Dachuang; Harris, Charles; Gibble, Theresa Hunter; Stefanski, Adam; Griffin, Ryan ·
RPEP-12299 · 2025In a neonatal mouse model of GBS pneumonia, neutrophils were recruited to infected lungs but their phenotype differed based on disease severity. Pups with moderate disease developed SiglecFhi neutrophils — a phenotype with enhanced phagocytic capacity and superior bacterial clearance. Pups with severe disease failed to develop this protective neutrophil type.
The key difference was CGRP: severely affected pups showed increased CGRP expression in the lungs. CGRP directly suppressed neutrophil activation into the SiglecFhi phenotype, limiting their antibacterial function. This represents a neuroimmune axis that GBS exploits to evade host immunity — the bacteria essentially co-opt a neural signaling molecule to shut down the most effective form of immune defense.
Lorga, Inês; Teixeira, Ana Sofia; Carvalho, Bárbara; Soares, Joana; Ribeiro, Nuno; Cardoso, Marcos S; Cunha, Joana; Santos, Joana; Silva, Regina A; Vilanova, Manuel; Bonifácio Andrade, Elva ·
RPEP-12305 · 2025The subcutaneously injected lipid nanoparticle-DNA system successfully expressed both exendin-4 (EX4) and a modified natural GLP-1 peptide in obese diabetic mice. Key outcomes included sustained weight loss, decreased food intake, reduced insulin resistance, and improved glycemic control. The transgene expression remained localized to the subcutaneous injection site for over 6 months — a critical safety feature ensuring the therapy doesn't spread systemically.
Transcriptomic analysis confirmed that efficacy was mediated through the GLP-1 receptor pathway, validating the mechanism. Blood-based biomarkers of liver function, pancreatic function, systemic inflammation, and muscle injury were all normal, confirming systemic tolerability. The steady-state peptide production avoids the pharmacokinetic spikes from repeated injections that cause GI side effects and contribute to the ~70% one-year discontinuation rate of current GLP-1 therapies.
Lourie, Jared; Goraltchouk, Alex; Hollander, Judith M; Berger, Nicolas J; Rosen, H Grace; Fujishiro, Atsutaro A; Luppino, Francesco; Seregin, Alexey; Rhym, Luke; Zou, Kai ·
RPEP-12317 · 2025Two novel GLP-1 peptides created using a simpler manufacturing method — tryptophan-selective lipidation with miniPEG linkers — performed comparably to liraglutide in both cell studies and animal models. Peptide A (one miniPEG linker) matched liraglutide across all measures: cAMP production, insulin secretion, blood glucose lowering, gastrointestinal motility suppression, satiety neuron activation, food intake reduction, and body weight loss. Peptide B (three miniPEG linkers) was equally effective for glucose control but somewhat less potent for appetite suppression.
Under long-term high-fat diet conditions, both peptides improved glucose tolerance and insulin sensitivity comparably to liraglutide.
Lu, Xuejing; Harada, Norio; Yasuda, Takuma; Ikeguchi-Ogura, Eri; Kobayashi, Daishiro; Denda, Masaya; Seno, Yohei; Yamane, Shunsuke; Yabe, Daisuke; Otaka, Akira; Inagaki, Nobuya · Animal
RPEP-12319 · 2025In the GLP-1 RA versus SGLT2i matched cohort (21,362 pairs), overall cancer risk was not significantly different (HR 1.03; 95% CI: 0.95-1.12). However, GLP-1 RA users had significantly increased kidney cancer risk (HR 1.43; 95% CI: 1.06-1.92).
In the GLP-1 RA versus DPP4i matched cohort (20,962 pairs), overall cancer risk was again not different (HR 0.96; 95% CI: 0.89-1.04). However, endometrial cancer risk was significantly elevated (HR 1.55; 95% CI: 1.01-2.37). The nine cancers analyzed were thyroid, pancreatic, bladder, colorectal, lung, kidney, breast, endometrial, and prostate — all considered obesity-associated cancers.
Lu, Ying; Dai, Hao; Tang, Huilin; Donahoo, William T; George, Thomas J; Sun, Ramon C; Jiang, Sizun; Tan, Aik Choon; Guo, Yi; Licht, Jonathan D; Allen, John M; Lee, Kelvin P; Guo, Jingchuan; Bian, Jiang ·
RPEP-12327 · 2025The review identifies several key advantages of small molecule GLP-1 receptor agonists over traditional peptide-based versions:
1. Enhanced oral bioavailability without the absorption enhancers needed by oral semaglutide
2. Better tissue permeability, potentially reaching organs that peptide drugs cannot easily access
3. Extended half-lives enabling convenient once-daily or potentially less frequent oral dosing
4. The ability to create fixed-dose combination pills with other diabetes or cardiovascular drugs
5. Lower manufacturing costs compared to recombinant peptide production
These advantages could address major barriers to GLP-1 therapy adoption, including needle aversion, adherence challenges, and limited combination therapy options with injectable formulations.
Luna Ceron, Eder; Reddy, Sparsha Duvuru; Kattamuri, Lakshmi; Muvva, Durga Mounika; Chozet, Luis; Bright, Tamis ·
RPEP-12329 · 2025The SOUL cardiovascular outcome trial demonstrated a 14% reduction in major adverse cardiovascular events (MACE) with oral semaglutide versus placebo in high-risk type 2 diabetes patients. This is the first CVOT to confirm cardiovascular protection with an oral GLP-1 receptor agonist, reinforcing the cardioprotective class effect of GLP-1RAs. The findings suggest improved accessibility for patient populations underrepresented in prior injection-based trials. However, gastrointestinal side effects and strict dosing requirements (taken on an empty stomach with minimal water) challenge long-term adherence.
Luna-Ceron, Eder; Kattamuri, Lakshmi; Duvvuru, Sparsha Reddy; Mukherjee, Debabrata ·
RPEP-12334 · 2025The novel dual CCK/GLP-1 receptor agonist demonstrated multiple neuroprotective effects in 5×FAD Alzheimer's mice:
- Improved cognitive deficits (memory and learning)
- Reduced amyloid-beta (Aβ) accumulation in the brain
- Alleviated mitochondrial damage through induction of mitophagy
- Regulated PINK1/Parkin-mediated mitophagy pathway (confirmed in both in vivo and Aβ-treated cell models)
- Outperformed the GLP-1 analogue liraglutide on certain indicators
This is the first demonstration that a CCK/GLP-1 dual agonist modulates mitophagy via the PINK1/Parkin pathway to enhance cognitive function in an Alzheimer's model.
Luo, Rihong; Kang, Yuhan; Ma, He; Zhang, Zhenqiang; Hölscher, Christian; Hao, Li; Zhang, Zijuan ·
RPEP-12335 · 2025A peptide mimicking the Insig1/2 loop 1 region blocked the interaction between PCK1 and Insig1/2, shutting down the SREBP1 pathway that cancer cells use to produce the lipids they need to grow. When delivered intravenously in liposomal nanoparticles, the peptide suppressed tumor growth and extended survival in mice without apparent side effects. Combining the peptide with either lenvatinib (a cancer drug) or semaglutide (an anti-obesity drug) produced additive anti-tumor effects. This is the first demonstration that SREBP — previously considered 'untargetable' — can be inhibited with a peptide therapeutic.
Luo, Shudi; Yang, Huang; Jiang, Xiaoming; Wang, Zheng; He, Xuxiao; Meng, Ying; Li, Shan; Li, Min; Xu, Daqian; Mao, Zhengwei; Lu, Zhimin ·
RPEP-12337 · 2025Over 20 AMPs derived from Cathelicidin-DM were designed with variations in sequence size, amino acid composition, amphiphilicity, and amidation. Key finding: hydrophobic amino acid substitution was the most significant factor for improving biological activity. Lead candidates demonstrated antimicrobial activity both in vitro and in vivo, anti-inflammatory properties, acceptable safety profiles, and structural stability. Structure-function analysis clarified the relationships between peptide design parameters and functional outcomes.
Luo, Ying; Dong, Zhan; Shi, Yaoqiang; Wang, Lei; Chen, Zhizhi; Yan, Shuo; Wang, Guanlin; Han, Qinqin; Zhang, Jinyang; Li, Chao; Song, Yuzhu ·
RPEP-12340 · 2025Semaglutide treatment (40 μg/kg for 4 weeks) in diabetic mice reversed pancreatic damage, enhanced islet cell proliferation, and restored both alpha- and beta-cell masses to near-normal levels. At the molecular level, semaglutide upregulated the m6A methyltransferase METTL14, which regulated PDX-1 expression in an m6A-dependent manner — a previously unknown mechanism for semaglutide's beta cell protection.
The drug also significantly altered gut microbiota composition, decreasing Firmicutes, Actinobacteriota, and Lactobacillus abundance while increasing Bacteroides and norank_f_Muribaculaceae. Short-chain fatty acid production was also boosted, suggesting a gut-pancreas signaling axis.
Luo, Yunfei; Li, Jin-E; Zeng, Haixia; Zhang, Yuying; Yang, Shiqi; Liu, Jianping ·
RPEP-12342 · 2025Among 77 participants (53 OSA patients, 24 controls), serum MOTS-c levels were significantly correlated with BMI, AHI (Apnea-Hypopnea Index), and ODI (Oxygen Desaturation Index) independent of age. MOTS-c levels decreased progressively with OSA severity: patients with severe OSA had lower levels than those with moderate OSA, who had lower levels than those with mild OSA.
Critically, ANCOVA analysis with BMI as a covariate demonstrated that OSA severity was an independent factor influencing serum MOTS-c levels — meaning the relationship isn't simply explained by obesity. This suggests a direct biological connection between the intermittent oxygen deprivation in OSA and mitochondrial peptide production.
Luo, Zhuoding; Ji, Rui; Ye, Renjing; Shi, Yawen; Pang, Qingfeng; Yin, Min ·
RPEP-12344 · 2025Amylin's primary eating-related effect is rapid, short-lasting satiation that controls meal size, directly reflecting meal-induced rises in circulating amylin. This effect is mediated by humoral (blood-borne) action in the central nervous system, with the area postrema in the caudal hindbrain being the key target region. Amylin also reduces food reward, specifically reducing high-fat food intake in certain conditions. In humans, amylin receptor agonists have reduced binge eating episodes. Long-acting amylin receptor agonists combined with GLP-1 receptor agonists (particularly semaglutide) have emerged as highly promising obesity therapeutics.
Lutz, Thomas A ·
RPEP-12347 · 2025The GLP-1 receptor (GLP-1R) does not undergo significant desensitization in physiologically relevant tissues in vivo, instead producing robust and prolonged cAMP signals through Gs protein coupling. This contrasts sharply with the GIP receptor (GIPR), which extensively uses βarrestin signaling and undergoes significant desensitization, internalization, and downregulation.
The GLP-1R's resistance to desensitization may be explained by its unique property of constantly cycling between the cell membrane and caveolae/lipid rafts. The review argues this makes GLP-1R a functionally Gs-selective receptor — a distinction with major implications for designing next-generation multi-receptor agonist drugs (poly-ligands) targeting obesity.
Lymperopoulos, Anastasios; Altsman, Victoria L; Stoicovy, Renee A ·
RPEP-12349 · 2025Shank3 mutant mother dogs exhibited significantly fewer and shorter licking bouts and reduced nursing frequency compared to wild-type dams. Blood oxytocin concentrations were significantly decreased in mutant dams. A two-week vehicle-controlled intranasal oxytocin treatment, starting on postpartum day 8, significantly rescued the licking behavior deficits both acutely and chronically. This demonstrates that the maternal behavior impairments in these autism-model dogs are at least partly driven by oxytocin system dysfunction.
Lyu, Wen; Li, Yuan; Yao, Aiyu; Tan, Qing-Quan; Zhang, Rong; Zhao, Jian-Ping; Guo, Kun; Jiang, Yong-Hui; Tian, Rui; Zhang, Yong Q ·
RPEP-12352 · 2025In 227,866 individuals with AUD (63.5% male, mean age 40, median follow-up 8.8 years), within-individual comparisons showed:
- Semaglutide (4,321 users): 36% reduced AUD hospitalization risk (aHR 0.64, 95% CI: 0.50-0.83), 32% reduced any SUD hospitalization (aHR 0.68, 95% CI: 0.54-0.85), 22% reduced somatic hospitalization (aHR 0.78, 95% CI: 0.68-0.90)
- Liraglutide (2,509 users): 28% reduced AUD hospitalization risk (aHR 0.72, 95% CI: 0.57-0.92), 22% reduced any SUD hospitalization (aHR 0.78, 95% CI: 0.64-0.97), 21% reduced somatic hospitalization (aHR 0.79, 95% CI: 0.69-0.91)
- Approved AUD medications: Only 2% reduced AUD hospitalization (aHR 0.98, 95% CI: 0.96-1.00)
- Neither drug was significantly associated with suicide attempt risk
Lähteenvuo, Markku; Tiihonen, Jari; Solismaa, Anssi; Tanskanen, Antti; Mittendorfer-Rutz, Ellenor; Taipale, Heidi ·
RPEP-12355 · 2025In C. elegans, low-molecular-weight bovine collagen hydrolysate (2 mg/mL) significantly reduced fat accumulation and reactive oxygen species, slowed aging (measured by lipofuscin), and extended median lifespan.
In 32 male diet-induced obese C57BL/6 mice, 8 weeks of daily supplementation (1 mg/animal/day) produced significant reductions in adipose tissue: mesenteric fat decreased 28%, visceral fat decreased 15%, and total adipose tissue decreased 18%. Glucose tolerance improved markedly, with a 26% reduction in area under the curve on glucose tolerance testing (p < 0.05). The collagen peptides also significantly increased gut microbiota diversity and shifted bacterial populations toward beneficial species.
López-Yoldi, Miguel; Aranaz, Paula; Riezu-Boj, José I; González-Salazar, Itxaso; Izco, Jesús M; Recalde, José I; González-Navarro, Carlos J; Milagro, Fermín I · Animal Study
RPEP-12357 · 2025When semaglutide's benefits are measured only by its primary endpoint of major adverse cardiovascular events (MACE), 58 patients need treatment for 4 years to prevent one event (NNT=58). But when the analysis includes hospitalizations, coronary revascularization, non-cardiovascular death, new diabetes onset, and kidney outcomes, only 11 patients need treatment for 4 years to prevent one adverse outcome (NNT=11).
The composite risk reductions were 20% for MACE alone, 20% for the extended composite, and 41% when cardiorenal-metabolic outcomes were included. At just 1 year, the broadest composite NNT was already 20, meaning one patient benefits for every 20 treated.
Lübker, Christopher; Bhavsar, Jigish; Duque do Vale, Ruben; Emerson, Scott S; Nørtoft, Emil; Plutzky, Jorge; Roberts, Geraint; Tarp, Jens Magelund; Lincoff, A Michael · Secondary Analysis
RPEP-12364 · 2025Eight weeks of tirzepatide treatment (10 nmol/kg) in diabetic db/db mice produced:
Metabolic improvements: decreased fasting blood glucose, HbA1c, body weight, food intake, blood lipids, and liver function markers
Kidney protection: improved renal function markers (serum creatinine and urinary albumin/creatinine ratio)
Microbiome changes: reversed gut dysbiosis, increasing beneficial genera (Clostridium_sensu_stricto_1, Romboutsia) and reducing pathogenic genera (Erysipelatoclostridium, Bacteroides). These microbiome changes correlated significantly with kidney function markers.
Critical validation: when gut microbiota was depleted with antibiotics prior to tirzepatide treatment (ABX-db/db-T group), the renoprotective effects were attenuated — demonstrating the gut microbiome is a necessary mediator of tirzepatide's kidney protection.
Ma, Jun; Tao, Mengyuan; Zhang, Wencheng; Zhou, Li; Zhang, Henglu; Li, Fei; Zhang, Hongman; Yao, Di; Lu, Weiping; Wang, Min ·
RPEP-12366 · 2025The review proposes an integrative framework connecting acupuncture to obesity treatment through the microbiota-gut-brain axis, identifying shared targets with dietary interventions:
- Short-chain fatty acids (SCFAs) produced by gut bacteria
- Glucagon-like peptide-1 (GLP-1) — the same peptide hormone targeted by semaglutide and other obesity drugs
- G protein-coupled receptors, particularly GPR43, which mediates SCFA and metabolic signaling
Acupuncture is proposed to improve microbial diversity, enhance gut barrier integrity, regulate nutrient-derived signaling molecules, and influence appetite control and inflammatory responses through neural, endocrine, and immune networks within the gut-brain axis.
Ma, Kun; Wang, Feifei; Zhang, Xinying; Guo, Liangqing; Huang, Yanqin ·
RPEP-12368 · 2025Arginine-rich cell-penetrating peptides exhibit higher transmembrane efficiency compared to other CPP types due to bidentate bonding between the guanidinium groups of arginine residues and negatively charged components on cell surfaces. This creates a particularly strong and specific interaction with cell membranes.
A second critical function is endosome escape: when peptides are taken up by cells through endocytosis, they typically become trapped in endosomes that eventually fuse with lysosomes for degradation. Arginine-rich CPPs can disrupt endosomal membranes, allowing the delivered cargo — drugs, nucleic acids, or macromolecules — to escape into the cytoplasm where it can exert its therapeutic effect.
Ma, Minghai; Zhao, Ruizhao; Li, Xing; Jing, Minxuan; Song, Rundong; Fan, Jinhai ·
RPEP-12371 · 2025Both semaglutide and tirzepatide reduced body weight, improved lipid profiles, and enhanced insulin sensitivity in obese mice. However, their transcriptomic effects on brown adipose tissue were dramatically different: semaglutide modulated 467 differentially expressed genes (199 down, 268 up) compared to only 40 for tirzepatide (20 down, 20 up).
Three shared targets were identified (Cyp1a1, Hsd11b1, Atp1a3) that enhance insulin sensitivity and metabolism. Tirzepatide uniquely modulated three additional targets — Tfrc (transferrin receptor, involved in iron metabolism), Ptger4 (prostaglandin receptor, anti-inflammatory), and Il1b (interleukin-1β, a key inflammatory mediator) — potentially explaining tirzepatide's enhanced anti-inflammatory and metabolic regulatory effects compared to GLP-1-only agonists.
Ma, Tianyi; Song, Fanfan; Pan, Yongning; He, Ying; Cao, Xinming; Zhang, Yan; Song, Guangyao; Ren, Luping ·
RPEP-12372 · 2025Functionalized peptide hydrogels can be engineered to address all five key phases of wound healing through stage-specific bioactivities. Antimicrobial peptides like EPL, LL37, and TCP-25 not only kill pathogens but also direct macrophage behavior to reduce excessive inflammation. Angiogenic factors (VEGF, SDF-1) can be sustainably released from the hydrogel to promote new blood vessel growth. MMP-responsive components balance collagen deposition and degradation during tissue remodeling, while integrin-binding motifs like RGD enhance cell adhesion and migration to accelerate skin regrowth.
These hydrogels possess self-healing properties, can be injected through narrow openings, and respond to microenvironmental cues including pH changes, enzyme activity, and reactive oxygen species (ROS) levels — allowing them to adapt their therapeutic activity to the dynamic conditions within a healing wound.
Ma, Xi-Kun; Peng, Qi; Miao, Gui-Hua; Zhang, Xiu-Zhen ·
RPEP-12376 · 2025Following coronary ligation in adult mice, systemic TB4 injection led to a significant increase in miR-139-5p expression in heart tissue. The researchers identified ROCK1 as a downstream target of this miRNA pathway. Using real-time PCR, Western blot, and immunostaining in both mouse hearts and human cardiac cells, they confirmed that TB4 modulates ROCK1 protein levels both in vivo and in vitro.
Additionally, TB4 appeared to reverse or inhibit the transformation of fibroblasts into myofibroblasts — the cells primarily responsible for pathological scarring in the heart. The downstream mechanisms by which TB4 acts through ROCK1 were found to be cell-type specific, suggesting nuanced regulatory effects across different cardiac cell populations.
Maar, Klaudia; Thatcher, Jeffrey E; Karpov, Egor; Rendeki, Szilard; Gallyas, Ferenc; Bock-Marquette, Ildiko ·
RPEP-12380 · 2025A diabetic patient developed non-arteritic anterior ischemic optic neuropathy (NAION) — a condition that causes sudden, painless vision loss due to reduced blood flow to the optic nerve — while taking semaglutide. The authors reviewed the existing literature on this possible association and found conflicting results: the original semaglutide clinical trials did not show increased NAION risk, but a subsequent retrospective cohort study suggested a possible link. The overall evidence remains controversial, with studies presenting opposing conclusions.
Maceroni, Martina; Sasso, Paola; Giarletti, Matteo; Bruno, Valentina; Minnella, Angelo Maria · Case Report + Literature Review
RPEP-12390 · 2025Chronic liraglutide treatment (300 μg/kg/day subcutaneous for 28 days) in high-fat diet obese rats produced multiple neuropsychiatric improvements:
- Reversed depressive-like behavior in sucrose preference test and forced swimming test
- Improved cognitive deficits in Morris water maze test
- Increased hippocampal BDNF, PI3K, Akt, phospho-Akt, and phospho-mTOR expression
- Downregulated autophagy markers (Beclin-1, LC3)
- Reduced inflammatory markers (TNF-α, IL-6)
- Ameliorated HFD-induced hippocampal neurodegeneration
The benefits were mediated through restoration of PI3K/Akt/mTOR signaling and reduction of excessive autophagy-mediated neurodegeneration.
Magdy, Yosra M; Kamar, Sherif A; Habib, Mohamed Z; Rady, Hagar Yousry; Rabei, Mohammed R; Khedr, Sara ·
RPEP-12394 · 2025After screening 797 records and including 20 studies from cardiovascular outcome trials, the review found that preclinical evidence supports potential bone-protective effects of GLP-1 receptor agonists, including increased bone mass, improved bone microarchitecture, and reduced bone resorption. However, human clinical evidence was inconsistent — some studies suggested possible fracture risk reduction with long-term GLP-1 RA therapy, while others did not confirm this benefit. The authors concluded that more targeted research is needed to clarify the role of these drugs in bone metabolism and fracture prevention for people with type 2 diabetes.
Mahalingasivam, Aksayan Arunanthy; Rasmussen, Nicklas Højgaard-Hessellund ·
RPEP-12403 · 2025Among 69,049 adults who started GLP-1 receptor agonists, comorbidities significantly influenced first-year adherence. Patients with diabetes who also had hyperlipidemia (OR 1.17), chronic kidney disease (OR 1.14), or hypertension (OR 1.06) were more likely to stay on their GLP-1 medication. Conversely, cardiovascular disease (OR 0.90) and digestive side effects (OR 0.94) reduced adherence.
Similar patterns held for patients with obesity. Findings were consistent across different GLP-1 RA brands, suggesting these adherence patterns are class-wide rather than drug-specific.
Mai, Ziyang; Kornak, John; Dufault, Suzanne M; Strand, Michael W; Reikes, Andrew R; Watanabe, Jonathan H · Observational
RPEP-12404 · 2025A patient with metastatic intrahepatic cholangiocarcinoma (bile duct cancer) — a typically fatal cancer with few treatment options — has remained tumor-free for more than 8 years after repeated surgery and two successive personalized peptide vaccines. Immune analysis revealed a dominant CD4+ T-cell response against vaccine antigens that persisted for years after the last vaccination, with immune cells infiltrating the tumor site. The patient also developed spontaneous immune responses against tumor neoantigens (CD4+ and CD8+ T cells), which may have contributed to the exceptional outcome. This case highlights both personalized peptide vaccination targeting non-mutated antigens and the central role of CD4+ T cells in antitumor immunity.
Maia, Ana; Schuhmacher, Juliane; Nadalin, Silvio; Königsrainer, Alfred; Thiel, Karolin; Nelde, Annika; Zinser, Raphael S; Schroeder, Christopher; Mattern, Sven; Singer, Stephan; Bösmüller, Hans; Rammensee, Hans-Georg; Löffler, Markus W; Gouttefangeas, Cécile · Case Report
RPEP-12414 · 2025Engineered buccal (inner cheek) devices can overcome the mucosal permeability barrier to deliver therapeutic peptides through the mouth lining. These devices use multiple mechanisms — physical epithelial disruption, convection-based mass transfer, and combined physicochemical strategies — to achieve fast, efficient peptide absorption. Importantly, minimally invasive devices can be self-applied by patients and maintain the mucosal barrier integrity after use. The buccal route avoids both the harsh gastrointestinal environment and liver first-pass metabolism that limit oral peptide delivery.
Malhotra, Sahil; Lijnse, Thomas; Cearbhaill, Eoin O'; Brayden, David J ·
RPEP-12422 · 2025In participants with obesity and no prior cardiovascular disease, the average baseline 10-year CVD risk score was 9.3%. After 72 weeks of treatment:
- Tirzepatide reduced predicted 10-year CVD risk by 2.4% (absolute reduction from baseline)
- Semaglutide reduced predicted 10-year CVD risk by 1.4% (absolute reduction from baseline)
- The difference was statistically significant (P < 0.001)
Projected to the ~85 million treatment-eligible Americans without prior CVD, tirzepatide could potentially prevent ~2 million CVD events over 10 years, compared to ~1.15 million with semaglutide.
Mamas, Mamas A; Bays, Harold; Li, Runjia; Upadhyay, Navneet; Irani, Tanya; Senyucel, Cagri; Dunn, Julia P; Liu-Seifert, Hong ·
RPEP-12428 · 2025In 36 frail insulin-treated older adults (mean age 79.6) switched to IDegLira for 6 months:
Insulin reduction:
- Total insulin dropped from 34.52 to 24.30 U/day
- Bolus insulin nearly discontinued
- IDegLira titrated from 15.66 to 22.41 units/day
Body composition improvements (adjusted for covariates):
- Fat-free mass: +3.17 kg/m
- Body cell mass: +7.82 kg/m
- Phase angle: +1.75° (cellular health marker)
- Basal metabolic rate: +217.6 kcal
- Fat mass: decreased significantly (P < 0.001)
Metabolic improvements:
- HbA1c: 7.29% → 7.05% (P = 0.089, favorable trend)
- Insulin resistance (METS-IR): 42.39 → 32.84 (P < 0.0001)
Mancinetti, Francesca; Xenos, Dionysios; De Fano, Michelantonio; Mazzieri, Alessio; Ercolani, Sara; Mecocci, Patrizia; Porcellati, Francesca; Boccardi, Virginia ·
RPEP-12435 · 2025Across 13 phase 2/3 RCTs with 1,811 participants:
- MASH resolution without worsening fibrosis (3 RCTs, biopsy-confirmed): OR 3.48 (95% CI: 2.69-4.51, I²=0%) — 3.5 times more likely with GLP-1RAs
- Fibrosis improvement without worsening MASH: OR 1.79 (95% CI: 1.37-2.35, I²=0%) — 1.8 times more likely
- Liver fat reduction by MRI (9 RCTs): -4.50% (95% CI: -6.60 to -2.40, I²=95.9%)
- Semaglutide 2.4 mg/week was the most studied and effective agent
- Critical exception: In 1 RCT of MASH-related compensated cirrhosis, semaglutide did NOT achieve MASH resolution or fibrosis improvement vs. placebo
Mantovani, Alessandro; Morandin, Riccardo; Fiorio, Veronica; Lando, Maria Giovanna; Stefan, Norbert; Tilg, Herbert; Byrne, Christopher D; Targher, Giovanni ·
RPEP-12436 · 2025JMV2894, a pseudopeptide growth hormone secretagogue, showed remarkable anti-atrophic effects in a severe mouse model of Duchenne muscular dystrophy (D2-mdx). At the lower dose (640 µg/kg), it significantly increased muscle fiber size and decreased expression of muscle-wasting genes (Atrogin and MuRF1).
The treatment partially improved hind limb muscle function, reduced muscle echo-density (a measure of tissue damage), and decreased expression of matrix-remodeling genes including MMP-9, ADAMTS-5, TGF-β1, and type I collagen. However, the anti-fibrotic effect was only mild histologically despite the gene expression changes.
The mechanism appears to be GH-mediated: JMV2894 increased IGF-1 gene expression and plasma levels, along with IGF-1 receptor and downstream signaling proteins. The treatment was well-tolerated at both doses over 6 weeks, though limited muscle drug exposure suggests improved formulations could enhance results.
Mantuano, Paola; Boccanegra, Brigida; Marinelli, Manuel; Cristiano, Enrica; Lenti, Roberta; Tulimiero, Lisamaura; De Bellis, Michela; Fehrentz, Jean-Alain; Denoyelle, Séverine; Bresciani, Elena; Torsello, Antonio; Mele, Antonietta; Liantonio, Antonella; Cappellari, Ornella; De Luca, Annamaria · Animal Study
RPEP-12439 · 2025GLP-1 agonist users had a significantly lower incidence of obesity-related cancer at 7.5 per 1,000 person-years versus 8.1 for other glucose-lowering drugs, translating to an adjusted hazard ratio of 0.87 (95% CI: 0.83–0.91). The association was consistent across all comparator drugs: HR 0.90 vs metformin, 0.88 vs DPP-4 inhibitors, 0.84 vs thiazolidinediones, 0.81 vs sulfonylureas, 0.73 vs SGLT2 inhibitors, and 0.70 vs insulin.
The risk reduction showed a dose-response relationship with body weight: overweight patients had an HR of 0.95 (not statistically significant), mild-to-moderate obesity had HR 0.90, and severe obesity had HR 0.82 (interaction P = 0.032). This suggests the cancer-protective association strengthens as obesity severity increases.
Mao, Xianhua; Zhang, Xinrong; Henry, Linda; Cheung, Ka Shing; Yuen, Man-Fung; Cheung, Ramsey; Seto, Wai-Kay; Nguyen, Mindie H ·
RPEP-12447 · 2025Individuals meeting the responsive NBEA genetic score threshold were 82% more likely to be highly responsive (top 20th percentile for weight loss) on liraglutide (FDR p = 1.8 × 10⁻⁶), validated in the UK Biobank (OR = 2.37, p = .008). For semaglutide, the responsive threshold showed OR = 1.63 in discovery and OR = 2.21 in validation. For non-responsiveness on liraglutide, the NBEA score predicted those with no weight loss (OR significant in both cohorts, p < .041), though the non-response score did not validate for semaglutide.
Mariam-Smith, Arshiya; Breeyear, Joseph H; Daniels, Noah J; Pantalone, Kevin M; Griebeler, Marcio L; Motsinger-Reif, Alison A; Rotroff, Daniel M ·
RPEP-12448 · 2025Semaglutide reduced weight gain and food efficiency in high-fat-fed mice. It lowered plasma TNF-α, MCP1, and resistin. In the hypothalamus, semaglutide suppressed pro-inflammatory genes (Tlr4, Mcp1, Il6, Tnfa), inflammasome complex genes (Nlrp3, Caspase 1, Il1b, Il18), and microglial activation markers (Iba1, Cd68, Arg1). Principal components analysis revealed that pair-fed mice (same weight loss, no drug) clustered with untreated obese mice — not with semaglutide-treated mice — demonstrating that the neuroinflammatory benefits are drug-specific and weight-loss-independent.
Marinho, Thatiany S; Fabiano, Matheus M; Aguila, Marcia B; Mandarim-de-Lacerda, Carlos A ·
RPEP-12451 · 2025The LightCPPgen pipeline integrates a LightGBM machine learning model (using 20 explainable physicochemical features) with a genetic algorithm to systematically design cell-penetrating peptide sequences. The system can take a non-penetrating peptide and optimize it for cell entry while maximizing similarity to the original sequence — preserving its intended biological function. The approach prioritizes explainability, allowing researchers to understand which molecular features drive cell penetration, rather than relying on opaque deep learning models.
Maroni, Gabriele; Stojceski, Filip; Pallante, Lorenzo; Deriu, Marco A; Piga, Dario; Grasso, Gianvito ·
RPEP-12456 · 2025The review synthesizes evidence that glutamate acts as an upstream trigger for CGRP release in the trigeminovascular system. Elevated glutamate levels contribute to both peripheral sensitization (nerve activation around blood vessels) and central sensitization (amplified pain processing in the brain), potentially driving the transition from episodic to chronic migraine. The CGRP-glutamate relationship is bidirectional, with CGRP also capable of enhancing glutamate signaling, creating a feedforward loop that perpetuates migraine.
Martami, Fahimeh; Holton, Kathleen F ·