RPEP-14322 · 2025Tirzepatide (daily subcutaneous injection for 14 days) protected C57BL/6 mice from doxorubicin-induced myocardial injury, cardiac dysfunction, and mortality. Tirzepatide significantly reduced oxidative stress and cardiomyocyte apoptosis both in vivo and in H9c2 cells. RNA sequencing and molecular analysis revealed the mechanism: doxorubicin triggers ER stress that upregulates HRD1, an E3 ubiquitin ligase that ubiquitinates and degrades Nrf2. Tirzepatide prevents ER stress-induced HRD1 upregulation, thereby preserving Nrf2 protein expression, nuclear translocation, and transcriptional activity — ultimately protecting cardiomyocytes from oxidative damage and death. Ad-Hrd1 overexpression and siNrf2 knockdown confirmed the mechanism.
Yang, Dan; Chen, Yang-Hao; Chen, Yan-Kun; Zeng, Ya-Lin; Ling, Zhi-Yu ·
RPEP-14326 · 2025Hydrocarbon-stapled analogs of the antimicrobial peptide Oce-3N-0 showed remarkable improvements in both protease resistance and antimicrobial activity compared to the unmodified parent peptide.
The stapled analog Oce-3N-5 was identified as the most promising candidate, demonstrating broad-spectrum activity against both Gram-negative and Gram-positive pathogens while maintaining structural stability. The stapling approach successfully addressed the two main barriers to clinical development of this peptide class: unstable structure and susceptibility to proteolytic degradation.
Yang, Hao; Yuan, Fei; Xie, Guangxu; Fu, Yinxue; Mi, Jia; Yu, Longjie; Liu, Weijia; Li, Yulei ·
RPEP-14332 · 2025The review identifies nine central neuropeptides that modulate astrocyte state transitions: neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), cholecystokinin (CCK), corticotropin-releasing hormone (CRH), angiotensin (Ang), oxytocin (OXT), orexin/hypocretin (OX/HCRT), and glucagon-like peptide-1 (GLP-1). These peptides influence astrocyte proliferation, morphology, and secretory functions, thereby affecting the pathogenesis of both neurodegenerative diseases (Alzheimer's, Parkinson's) and neuropsychiatric disorders (depression, anxiety). Both the neuropeptides and their receptors are positioned as promising therapeutic targets.
Yang, Meng-Jie; Jia, Min; Cai, Meng; Feng, Xiao; Huang, Li-Ning; Yang, Jian-Jun ·
RPEP-14334 · 2025The supramolecular peptide epitope vaccine encapsulated with CAR-T cells (SPEV-CAR-T) achieved multiple improvements over standard CAR-T therapy:
- The peptide hydrogel scaffold promoted CAR-T cell proliferation, cytotoxic activity, and lymphocyte subpopulation transformation (from effector to memory phenotypes)
- Complementary peptide epitopes from different extracellular domains of HER2 improved tumor antigen spreading and targeting efficiency
- Sustained release from the hydrogel maintained both vaccine and CAR-T cell delivery over time
- The system induced endogenous humoral and cellular immune responses alongside the exogenous CAR-T response
- Critically, SPEV-CAR-T generated central memory T cells in systemic immune tissues — directly addressing the poor persistence problem of CAR-T therapy
- Superior anti-tumor effects were demonstrated in an in vivo mouse model of solid tumors
Yang, Pengxiang; Yao, Xiaomin; Tian, Xue; Wang, Yuehan; Gong, Leilei; Yang, Yumin; Jie, Jing ·
RPEP-14339 · 2025From three major royal jelly proteins (MRJP1-3), 1,411 unique peptides were generated through simulated digestion. After virtual screening for bioactivity, safety, and drug-like properties, 27 candidates were selected. Two peptides — PYPDWSFAK and RPYPDWSF — showed potent ACE inhibition with IC50 values of 110 μmol/L and 204 μmol/L, respectively.
PYPDWSFAK acted as a mixed-type ACE inhibitor, forming multiple hydrogen bonds with key residues in the ACE active site and directly coordinating with the catalytic zinc ion. In cell studies, PYPDWSFAK was non-toxic, blocked angiotensin II-induced endothelial cell migration, restored the balance of nitric oxide (NO) and endothelin-1 (ET-1), and boosted antioxidant enzyme activities (SOD and GSH-Px).
Yang, Wanyu; Zou, Xinyu; Zhang, Tianrong; Liu, Qingqing; Liu, Ziyan; Li, Fan; Luo, Yuhong; Wang, Yiwen; Qiu, Zhijun; Zhang, Bin ·
RPEP-14342 · 2025Genetically predicted GLP-1R activation significantly reduced risks of CKD (OR 0.83, p=9.22E-9), IgA nephropathy (OR 0.70, p=2.11E-3), and preserved kidney function (eGFR β=0.01, p=9.11E-3). Effects on other CKD subtypes (membranous nephropathy, nephrotic syndrome, chronic glomerulonephritis) were null.
Mediation analysis revealed FGF23 suppression as the dominant pathway, mediating 26.57% of the eGFR effect and 13.50% of CKD protection. Metabolic mediators contributed modestly: BMI (2.08% for CKD, 5.51% for eGFR), HDL (0.79% for CKD), and HbA1c (8.25% for eGFR). For IgA nephropathy specifically, only BMI showed a mediation effect.
Yang, Xueying; Tang, Wenhao; Chan, Han; Wang, Mo; Yang, Haiping; Li, Qiu ·
RPEP-14344 · 2025The double-stapled and α-methylated peptide DA23-Bpy10,17Bpy21,28 demonstrated more potent and balanced dual agonist activity at both GLP-1R and GIPR compared to tirzepatide. It achieved a half-life of 30 minutes in simulated intestinal fluid, representing a significant improvement in proteolytic stability over earlier single-stapled versions.
In oral glucose tolerance tests in rodents, the peptide showed glucose-lowering activity equal to semaglutide, suggesting it could be a viable candidate for oral delivery of dual-agonist therapy.
Yang, Yifang; Lin, Qing ·
RPEP-14347 · 2025Tirzepatide (at doses of 3 and 10 nmol/kg) administered for 8 weeks to diabetic mice reduced serum creatinine, blood urea nitrogen, and advanced glycosylation end products while promoting insulin secretion. It attenuated tubular and glomerular injury, reduced kidney cell death, increased antioxidant enzymes (SOD and CAT), decreased the oxidative stress marker MDA, and lowered pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in both serum and kidney tissue.
The mechanism was traced to inhibition of the IL-17 pathway: when researchers administered an IL-17 pathway agonist (IL-17A), it reversed tirzepatide's suppressive effects on oxidative stress and inflammation, confirming this pathway as the key mediator.
Yang, Yong; Wang, Yiyong; Zhou, Yong; Deng, Jing; Wu, Lihao ·
RPEP-14348 · 2025Using 22 significant cis-eQTL single-nucleotide polymorphisms as genetic instruments, the study found that increased GLP-1R gene expression had a significant protective effect on type 1 diabetes, hypothyroidism, primary biliary cholangitis (PBC), and rheumatoid arthritis (RA). Conversely, it was associated with increased risk of Graves' disease (GD), ulcerative colitis (UC), and psoriasis.
Positive control analysis confirmed the methodology's validity: GLP-1R agonists were significantly associated with reduced obesity risk (OR = 0.826, p = 0.021) and reduced type 2 diabetes risk (OR = 0.886, p < 0.001), consistent with their known clinical effects. Results were validated across two independent databases (IEU OpenGwas and FinnGen) via meta-analysis.
Yang, Yuanyuan; Liu, Wencong; Zhang, Zechang; Zhang, Yujia; Wang, Xuebin; Wang, Jing; Cai, Huaifang; Liu, Yichan; Meng, Ran; Fu, Yuqi; Luo, Hongmin; Yang, Lei; Liu, Wenxuan ·
RPEP-14354 · 2025The short peptide KK (sequence: KIKIDPPIKIK) has an angular structure created by its proline-proline core that enables it to form a network hydrogel under neutral pH, trapping hydrophobic paclitaxel. Under the slightly acidic conditions found in tumors, the gel structure changes and releases the drug in a sustained manner.
In vitro and in vivo experiments demonstrated that the drug-loaded hydrogel improved anti-tumor efficacy while showing good biocompatibility and biological safety. The peptide's functional properties are achieved with only 10 amino acids, making it cheaper and easier to synthesize than longer peptide-based delivery systems.
Yao, Qingqing; Gao, Jie; Liu, Linsheng; Shi, Jinfang; Zafar, Hajra; Khan, Muhammad Ijaz; Zhu, Jianguo; Raza, Faisal; Zhu, Ying ·
RPEP-14355 · 2025The review proposes a hierarchical model of oxytocin's behavioral effects: it first enhances attention to salient social stimuli, then modulates cognitive, emotional, and reward processing in a person- and context-dependent manner. These effects promote interpersonal social understanding, attraction, and bonds on one hand, and social group cohesion through conformity, altruistic punishment, and moral emotions on the other. Importantly, oxytocin acts indirectly through neuromodulatory interactions with classical neurotransmitters and other peptides. Peripheral effects, particularly via the vagus nerve, may be more significant than originally understood.
Yao, Shuxia; Kendrick, Keith M ·
RPEP-14356 · 2025Adding thymosin alpha-1 (a peptide that boosts immune function) to a combination of lenvatinib (a targeted therapy) and sintilimab (a checkpoint inhibitor) significantly improved outcomes in unresectable liver cancer. Patients receiving the triple combination lived a median of 16 months compared to 11 months without thymosin alpha-1 — a 5-month survival advantage (p=0.018).
Progression-free survival nearly doubled: 7 months vs. 4 months (p=0.006). The tumor response rate was also higher at 55.8% vs. 34.7% (p=0.042). Crucially, adding thymosin alpha-1 did not increase side effects — adverse event rates were similar between groups.
Yao, Siyang; Huang, Qiangsong; Zou, Yan; Liu, Tianqi; Yang, Yongyu; Huang, Tao; Zhao, Yuanquan; Dong, Xiaofeng · Observational Study
RPEP-14358 · 2025Across 17 studies with 40,632 patients, oral semaglutide significantly reduced cardiovascular death by 23% (HR 0.77), major adverse cardiovascular events (MACE) by 18% (HR 0.82), nonfatal heart attacks by 18% (HR 0.82), and nonfatal stroke by 32% (HR 0.68) compared to placebo.
The cardiovascular benefits were most pronounced in patients who also had chronic kidney disease (CKD), with risk reductions of 24–37% compared to 13–35% in those with type 2 diabetes alone or with existing cardiovascular disease. Semaglutide also lowered systolic blood pressure by 8 mmHg and LDL cholesterol by about 13 mg/dL, though it did not significantly affect kidney function markers like eGFR or UACR.
Yao, Yanni; Liu, Nairong; Chen, Siyan; Sun, Meng; Guo, Yanjie ·
RPEP-14359 · 2025Genetically proxied GLP-1 receptor agonist exposure was significantly associated with decreased risk of two kidney diseases:
- Diabetic nephropathy: OR = 0.72 (95% CI: 0.54-0.97, p = 0.031) — a 28% risk reduction
- IgA nephropathy: OR = 0.58 (95% CI: 0.36-0.94, p = 0.027) — a 42% risk reduction
Two-stage network Mendelian randomization revealed that 34.27% (95% CI: 1.47-67.03%, p = 0.041) of the GLP-1 receptor agonist effect on IgA nephropathy was mediated through SLAMF1 (signaling lymphocytic activation molecule family member 1), an inflammatory protein. No significant associations were found with membranous nephropathy, nephrotic syndrome, chronic kidney disease, acute or chronic glomerulonephritis, or kidney stones.
Yao, Yu-Xuan; Tang, Chen; Si, Feng-Lei; Lv, Ji-Cheng; Shi, Su-Fang; Zhou, Xu-Jie; Liu, Li-Jun; Zhang, Hong ·
RPEP-14366 · 2025The review identifies three main routes by which topical eyedrops can reach the posterior segment of the eye: the corneal route, the conjunctival-vasculature route, and the conjunctival-scleral route. Different peptide-based technologies favor different pathways:
- Cell-penetrating homing peptides and lipid nanoparticle-encapsulated eyedrops primarily use the corneal route
- Cell-penetrating peptides and PepT-1-targeting ligands mainly use the conjunctival route
- Supramolecular peptide-based eyedrops, chitosan nanoparticles, and polymeric micelles can access the posterior segment through both routes
No topical eyedrop formulation has yet been clinically approved for treating ocular fundus (back-of-eye) diseases.
Ye, Yuhong; Zhang, Ye; Zhao, Pan; Shen, Yaobang; Hu, Ping; Wang, Lei; Long, Da ·
RPEP-14367 · 2025CGRP-positive nociceptive nerves were overexpressed within fibrotic lesions in both human adenomyosis patients and mouse models. The peptide CGRP activated the ERK signaling pathway in RAMP1-high CD140b+CD146+ fibroblasts, driving them toward an extracellular matrix deposition phenotype that worsens fibrosis.
Ablating nociceptive nerves reduced uterine fibrosis in mice with induced adenomyosis. Treatment with rimegepant, an FDA-approved CGRP/RAMP1 antagonist, alleviated fibrosis progression and promoted fertility restoration in the mouse model.
Ye, Zi; Zhao, Anning; Li, Xia; Hao, Yanqing; Huang, Dong; Chen, Jianmin; Li, Tiantian; Dai, Yangyang; Sun, Wenchao; Ma, Lie; Zhang, Songying; Xin, Liaobing ·
RPEP-14369 · 2025The treatment landscape for metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD) and its inflammatory progression to MASH (formerly NASH) is rapidly evolving, with peptide-based drugs playing a central role. GLP-1 receptor agonists, GLP-1/GIP dual agonists, and GIP/GLP-1/glucagon triple agonists are all being investigated as treatments that could halt or reverse liver disease progression.
These peptide therapies join other emerging drug classes including thyroid hormone receptor β agonists (recently approved), FXR agonists, and PPAR agonists. The review emphasizes that MASLD is a complex, multi-pathway disease involving insulin resistance, oxidative stress, gut-liver axis dysfunction, and genetic/epigenetic factors. When MASLD progresses unchecked, it can lead to cirrhosis and hepatocellular carcinoma (liver cancer). Lifestyle interventions remain foundational, but pharmacological options — particularly peptide-based ones — offer new hope for the large population affected.
Yeh, Hsiao-Yun; Lin, Shang-Wei; Shen, Hsiao-Chin; Li, Tzu-Hao; Tsai, Hung-Cheng; Yang, Ying-Ying; Lin, Han-Chieh; Hou, Ming-Chih · Review
RPEP-14375 · 2025For the first time, researchers provided ultrastructural evidence that neuropeptide Y (NPY) nerve terminals make direct synaptic contact with corticotropin-releasing factor (CRF) neurons in the central nucleus of the amygdala (CeA). Of 163 NPY terminals analyzed, approximately 85% formed symmetric (inhibitory) synapses with CRF dendrites, while only ~1% formed asymmetric (excitatory) synapses.
This anatomical wiring diagram reveals the physical basis for how NPY — the brain's 'stress resilience' peptide — may counteract CRF, the peptide that orchestrates the stress response. The overwhelming predominance of inhibitory-type connections suggests NPY primarily dampens CRF neuron activity.
Yerraguntla, Himavarsha; Onyekachi, Joy; Giacometti, Laura L; Goldberg, Samuel L; Barson, Jessica R; Barker, Jacqueline M; Reyes, Beverly A S · Animal Study
RPEP-14381 · 2025Pooled analysis of 29 RCTs (37,348 participants, 9 GLP-1RA-based drugs) in non-diabetic overweight/obese adults found:
**Cardiovascular Outcomes (vs. placebo):**
- Total cardiovascular events: RR 0.81 (95% CI: 0.76-0.87) — 19% reduction
- Major adverse cardiovascular events (MACE): RR 0.80 (0.72-0.89) — 20% reduction
- Myocardial infarction: RR 0.72 (0.61-0.85) — 28% reduction
- All-cause mortality: RR 0.81 (0.71-0.93) — 19% reduction
- Cardiovascular death: no significant difference
- Stroke: no significant difference
**Best-in-class for cardiometabolic parameters:**
- Systolic blood pressure: Orforglipron (-7.10 mmHg)
- BMI reduction: Tirzepatide (-6.50 kg/m²)
- HbA1c reduction: Tirzepatide (-0.39%)
- Lipid profiles: Retatrutide (most effective)
- C-reactive protein: Semaglutide (-1.20 mg/dL)
Yin, Yue; Zhang, Minghan; Cao, Qiuyu; Lin, Lin; Lu, Jieli; Bi, Yufang; Chen, Yuhong ·
RPEP-14382 · 2025Four peptides (EM-1 through EM-4) were designed from Asian elephant (Elephas maximus) cathelicidin EM. EM-1 demonstrated the best profile: low hemolytic and cytotoxicity, with significant inhibition of HSV-1 replication in U251 cells.
In C57BL/6J mice infected via footpad inoculation, EM-1 substantially reduced viral loads in brain, lung, and heart tissues and alleviated inflammatory responses and tissue damage. Mechanistically, EM-1 upregulated interferon-gamma expression and downstream antiviral genes ISG15 and MX1, revealing a dual-function profile: direct antiviral activity plus enhancement of host innate immunity.
Yisihaer, Haiche; Dong, Peng; Li, Pengpeng; Deng, Enjie; Meng, Rui; Jin, Lin; Li, Guilan ·
RPEP-14384 · 2025Across four observational studies (three cohort, one case-control):
- GLP-1 receptor agonists: pooled HR 1.07 (95% CI: 0.70–1.63) — no significant association with cholangiocarcinoma
- DPP-4 inhibitors: pooled HR 1.05 (95% CI: 0.83–1.34) — no significant association
- Pooled risk ratio analyses yielded similarly non-significant results for both drug classes
- All included studies were assessed as having low risk of bias per the Newcastle-Ottawa Scale
- Findings provide reassurance about the safety of incretin-based therapies regarding bile duct cancer risk
Yonatan, Eric Ricardo; Jusni, Louis Fabio Jonathan; Alvianto, Steven; Widjanarko, Nicolas Daniel; Usman, Steven Yulius; Muzellina, Virly Nanda ·
RPEP-14402 · 2025In 47 patients with biochemically proven hyperinsulinemic hypoglycemia, the peptide-based tracer 68Ga-NOTA-Exendin-4 PET/CT achieved 94.11% sensitivity and 95.74% accuracy for localizing insulinomas — significantly outperforming 68Ga-DOTATATE PET/CT (70.59% sensitivity, p=0.026), 18F-FDG PET/CT (50.00% sensitivity), and conventional imaging (CE-CT/CE-MRI).
Exendin-4 PET/CT also showed better imaging quality and easier interpretation than the other molecular imaging methods. Combining Exendin-4 and DOTATATE PET/CT could provide comprehensive evaluation of insulinomas.
Yu, Haonan; Bao, Xiangyuan; Gu, Yian; Pan, Meijie; He, Qing; Li, Dong; Chen, Qiusong; Yao, Shaobo ·
RPEP-14406 · 2025In this Phase II trial, combining hypofractionated radiotherapy with PD-1 inhibitor immunotherapy, GM-CSF, and the peptide thymosin-α1 achieved a 23.08% objective response rate and 65.38% disease control rate in heavily pretreated metastatic cancer patients. Median progression-free survival was 3.5 months. Notably, abscopal effects (tumor shrinkage at sites not directly irradiated) were observed in 23.08% of patients, with four achieving partial responses. Lower baseline neutrophil-to-lymphocyte ratio predicted better outcomes. The regimen was manageable with six grade 3-4 adverse events and no treatment-related deaths.
Yu, Jiamin; Yin, Li; Guo, Wenjie; Wang, Qiang; Liu, Juying; Zhang, Lansheng; Ye, Hongxun; Xia, Jianhong; Xia, Youyou; Wu, Jianfeng; Wang, Wanwei; Yang, Yanguang; Zong, Dan; He, Xia; Wang, Lijun; Jiang, Hong ·
RPEP-14422 · 2025Across 27 RCTs with 202,727 participants:
**SGLT2 inhibitors** reduced risk of:
- Pneumonia: OR 0.84 (16% reduction)
- Bronchitis: OR 0.59 (41% reduction)
- COPD: OR 0.76 (24% reduction)
- Pulmonary edema: OR 0.51 (49% reduction)
- Respiratory failure: OR 0.77 (23% reduction)
- Asthma: OR 0.55 (45% reduction)
**GLP-1 receptor agonists** were neutral in T2DM but reduced pneumonia, respiratory failure, and asthma risk in obese populations.
**DPP-4 inhibitors** were largely neutral but increased asthma risk (OR 1.70, 70% increase).
SGLT2 inhibitor benefits appeared largely independent of diabetes status.
Yu, Zhexuan; Gu, Bingyan; Zhang, Junyao; Jin, Weifeng; Wan, Haitong; Jin, Wei ·
RPEP-14426 · 2025From 284 cervical cancer samples, researchers identified 30 highly mutated genes and narrowed these to seven (TTN, PRKDC, PCLO, MUC17, HUWE1, RYR2, and CREBBP) that positively correlated with immune cell infiltration into tumors. PCLO stood out because it showed higher protein expression in tumor tissue versus normal tissue, marking it as a potential tumor antigen.
Using computational prediction algorithms (NetMHCpan-4.0 and NetCTL-1.2), two PCLO-derived peptides — SISRFTLEK (PCLOL4169F) and LSEAGHFFY (PCLOA3000S) — achieved the highest predicted immunogenicity scores. These peptides were validated experimentally: they activated T cells in vivo (confirmed by flow cytometry and RT-PCR) and stimulated immune responses in patient-derived peripheral blood mononuclear cells with matching HLA types in ELISpot assays.
Yuan, Jing; Xu, Na; Gong, Xueqi; Ai, Jihui; Li, Kezhen; Han, Yingyan ·
RPEP-14429 · 2025This comprehensive review examines how scientists have modified LL-37 — the only human cathelicidin antimicrobial peptide — to overcome its key limitations: high production costs, reduced effectiveness under real physiological conditions, vulnerability to enzymatic breakdown, and toxicity to human cells.
Multiple modification strategies have improved LL-37's clinical potential, including truncation (shortening the peptide while keeping its active region), amino acid substitutions, cyclization, and conjugation with nanocarrier delivery systems. Modified LL-37 derivatives show enhanced activity against bacterial biofilms and cell membranes, and some demonstrate synergy with traditional antibiotics.
Yuan, Yihao; Li, Jiapeng; Wei, Guotao; Shen, Ziyi; Li, Bo; Wu, Jiawei; Liu, Jing · Review
RPEP-14431 · 2025PRF applied to the sciatic nerve significantly reduced knee pain, synovitis, and inflammatory cytokines in a mouse model. Tracer studies and western blotting showed PRF inhibited axonal transport in small dorsal root ganglion neurons, suppressing secretion of CGRP and substance P into the knee joint. Critically, administering CGRP and substance P agonists completely reversed PRF's analgesic and anti-inflammatory effects, proving these neuropeptides are the essential mediators of PRF's therapeutic action.
Yuba, Tomoo; Koyama, Yoshihisa; Uematsu, Hironobu; Takahashi, Ayako; Matsuda, Yoichi; Fujino, Yuji; Shimada, Shoichi ·
RPEP-14434 · 2025The purified oyster fraction M4-2 had an ACE inhibitory IC50 of 0.774 mg/mL, 3.6 times more potent than the crude hydrolysate (IC50: 2.801 mg/mL). Ninety-one selenium-containing peptide sequences were identified by LC-MS/MS.
The two selected peptides showed strong ACE binding: SeMFRTSSK (-9.8 kcal/mol, binding via hydrogen bonds to active pocket residues) and QASeMNEATGGK (-9.0 kcal/mol, interacting with the Zn²⁺ active center). At 0.025 mg/mL in EA.hy926 endothelial cells, SeMFRTSSK and QASeMNEATGGK enhanced NO release by 202.65% and 273.45% respectively, while suppressing ET-1 secretion by 18.03% and 27.86% — outperforming captopril on both measures. Both peptides were non-cytotoxic up to 0.25 mg/mL.
Yue, Zhuangzhuang; Xia, Zhen; Xu, Fei; Chen, Bingbing; Jiao, Shufei; Liang, Xingtang; Yin, Yanzhen; Miao, Jianyin ·
RPEP-14438 · 2025Semaglutide has demonstrated efficacy in treating metabolic dysfunction-associated steatohepatitis (MASH), resolving steatohepatitis and improving hepatic fibrosis. It has been approved alongside resmetirom for treating non-cirrhotic MASH with moderate-to-advanced fibrosis. The review traces semaglutide's development from the discovery of GLP-1's role in glucose homeostasis through to its expanding clinical applications, which now include glycemic control, weight reduction, cardiovascular risk reduction, and liver disease treatment.
Zacharia, George S; Gongati, Sudharsan R; Kharel, Aayush; Jacob, Anu ·
RPEP-14442 · 2025The review establishes that sympathetic activation is both an acute arrhythmic trigger and a chronic driver of disease progression in inherited arrhythmogenic syndromes. Neuropeptide Y (NPY) and regional cardiac innervation patterns play critical roles in shaping myocardial excitability, tissue remodeling, and arrhythmogenesis.
In CPVT, arrhythmias are triggered by sympathetic stimulation in structurally normal hearts through calcium-handling abnormalities. In ACM, maladaptive autonomic remodeling including neurogenic fibrofatty infiltration creates an amplified arrhythmic substrate. The authors propose NPY antagonism as an emerging peptidergic therapy alongside β-blockade and left cardiac sympathetic denervation.
Zaglia, Tania; Perumal Vanaja, Induja; Guazzo, Anna; Mongillo, Marco ·
RPEP-14444 · 2025Clinical trial results (85 women, 84 days):
- Skin firmness: significantly improved vs placebo (P < 0.05)
- Skin elasticity: significantly improved vs placebo (P < 0.05)
- Skin hydration: improved but did not reach statistical significance
Preclinical molecular findings (human dermal fibroblasts):
- Type I procollagen gene expression: significantly increased
- Decorin and biglycan: significantly increased (these organize collagen architecture)
- Versican: decreased (shifts toward tighter collagen organization)
- MMP-1: decreased (less collagen breakdown) with increased TIMP-1 (more collagen protection)
- Hyaluronic acid: effects measured alongside other ECM components
The combination shows Col-OP promotes collagen synthesis while inhibiting its degradation.
Zague, Vivian; Pinheiro, Ana Lucia Tabarini Alves; Pinto, Juliana Rodrigues; Facchini, Gustavo; Eberlin, Samara ·
RPEP-14447 · 2025Liraglutide and semaglutide consistently produced clinically meaningful reductions in BMI, body weight, and waist circumference in adolescents with obesity, with modest improvements in systolic blood pressure and minimal effects on lipid levels or HbA1c. Newer trials have begun evaluating GLP-1RAs in children aged 6 and older.
Critical knowledge gaps include pediatric pharmacokinetics, optimal dosing strategies, long-term developmental safety (particularly musculoskeletal health), nutritional adequacy during rapid weight loss in growing children, and the risk of misuse. The review concludes that pediatric-specific protocols are essential to safely translate adult GLP-1 agonist success to younger populations.
Zaitoon, Hussein; Wauters, Aimee D; Rodriguez, Luisa M; Lynch, Jane L ·
RPEP-14448 · 2025Over 6 months, tirzepatide reduced waist circumference by 18.08 cm vs. 13.04 cm with semaglutide (p<0.001). Both drugs significantly lowered triglycerides (tirzepatide: -64.42 mg/dL, semaglutide: -70.70 mg/dL, both p<0.001). Tirzepatide showed greater improvements in fasting glucose, blood pressure, LDL, and total cholesterol. The highest digital engagement group (≥25 interactions) showed dramatically better outcomes: waist circumference -19.04 cm vs. -9.60 cm (p=0.002), triglycerides -108.56 vs. -44.49 mg/dL (p=0.02), diastolic BP -10.33 vs. -0.83 mmHg (p=0.004), and fasting glucose -18.60 vs. -2.49 mg/dL (p=0.02). The highest engagement quartile had 60% greater likelihood of metabolic syndrome reversal.
Zakaria, Hala; Jabri, Hadoun; Alshehhi, Sheikha; Caccelli, Milena; Debs, Joelle; Said, Yousef; Kattan, Joudy; Almarzooqi, Noah; Hashemi, Ali; Almarzooqi, Ihsan ·
RPEP-14450 · 2025A patient on weekly 1 mg semaglutide for one year self-injected his entire monthly prescription at once (approximately 4 times the recommended dose) during a period of dysphoria. He presented 14 days later with multiorgan failure, hypoglycemia, cholestatic liver dysfunction, two duodenal ulcers, and a two-week history of weakness, appetite loss, epigastric pain, severe diarrhea, melena, and syncope.
The authors characterize this as possible suicide-related behavior based on six criteria: the patient's prior treatment experience, ability to self-inject, awareness that a single injection is limited to the weekly dose, the intentional injection of multiple doses exceeding the monthly supply, the safety of the pen delivery system, and self-reported dysphoria before the event. The patient's clinical status improved gradually, including ulcer healing by discharge.
Zamir, Doron; Ovadia, Yaniv S; Ben-Bassat, Ofer; Zamir, Mariana; Malnick, Stephen D H ·
RPEP-14452 · 2025Researchers used machine learning and a genetic algorithm to design a brand-new antibacterial peptide called Healitide-GP1, then validated it in lab experiments. The peptide proved safe for human skin cells at concentrations above 200 µg/mL in both dermal fibroblasts (HDF) and keratinocytes (HaCaT).
In wound-closure assays, Healitide-GP1 improved wound closure by 48% in fibroblasts and 52% in keratinocytes after just 24 hours. It also showed strong antibacterial activity against two common wound pathogens: Staphylococcus aureus (MIC: 12.5 µg/mL) and Escherichia coli (MIC: 25 µg/mL).
Bioinformatics analysis revealed that Healitide-GP1 has a unique hydrophobic motif and distinct evolutionary positioning compared to known antimicrobial peptides, suggesting it may work through a novel mechanism of action.
Zare-Zardini, Hadi; Seyedjavadi, Sima Sadat · In Vitro
RPEP-14455 · 2025The review outlines a framework for understanding and managing the diabetes-kidney-heart continuum through three stages:
1. **Prevent**: Early risk stratification and intervention before vascular damage occurs
2. **Regress**: Reversing early vascular changes when detected
3. **Retard**: Slowing progression of established cardiovascular and kidney disease
Key therapeutic classes for managing this continuum include SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, lipid-lowering therapy, and RAAS blockers — all with evidence for both cardiac and renal protection. New diagnostic biomarkers (BNP, NT-proBNP, cardiac troponin, cystatin C) and technologies (single-cell transcriptome sequencing) can detect vascular complications earlier than traditional methods.
Zargar, Abdul Hamid; Balagopalan, Jayagopal Pathiyil; Bhattacharyya, Arpandev; Almeida, Alan; Taraphder, Abhijit; Bansal, Sandeep; Dani, Sameer; Deka, Nilakshi; Jain, Sanjay; Swami, Onkar C ·
RPEP-14457 · 2025In a porcine (pig) wound infection model, the antimicrobial peptide PLNC8 αβ eradicated wound infections and promoted re-epithelialization (new skin growth over the wound).
Two types of nanocellulose dressings were tested: bacterial cellulose (BC) and wood-derived TEMPO-oxidized nanocellulose (TC). Both showed effective contact killing of bacteria on the dressing surface but were less effective against bacteria floating in wound fluid.
The breakthrough came from incorporating mesoporous silica nanoparticles (MSNs) into the dressings as peptide carriers. MSN-functionalized dressings achieved significantly higher peptide loading and sustained release, resulting in improved antimicrobial efficacy against both surface and suspended bacteria. All formulations showed low cytotoxicity toward human fibroblasts and keratinocytes.
Zattarin, Elisa; Sotra, Zeljana; Wiman, Emanuel; Bas, Yagmur; Rakar, Jonathan; Berglund, Linn; Starkenberg, Annika; Björk, Emma M; Khalaf, Hazem; Oksman, Kristiina; Bengtsson, Torbjörn; Junker, Johan P E; Aili, Daniel ·
RPEP-14460 · 2025Both proline-rich antimicrobial peptides (P1 and P2) from Galleria mellonella hemolymph demonstrated antibacterial activity against Gram-negative E. coli and Gram-positive M. luteus. The P2 peptide was approximately three times more effective than P1 in both reducing M. luteus survival and permeabilizing E. coli membranes.
Microscopy imaging revealed that both peptides caused significant changes in bacterial cell morphology, surface topography, and nanomechanical properties. The peptides also affected protein and lipid composition on cell surfaces differently depending on the bacterial type, highlighting distinct mechanisms of interaction with Gram-negative vs. Gram-positive bacteria.
Zdybicka-Barabas, Agnieszka; Stączek, Sylwia; Mak, Paweł; Kapral-Piotrowska, Justyna; Skrzypiec, Krzysztof; Wydrych, Jerzy; Pawlikowska-Pawlęga, Bożena; Gruszecki, Wiesław I; Cytryńska, Małgorzata ·
RPEP-14473 · 2025In APP/PS1 transgenic Alzheimer's mice treated with semaglutide for 8 weeks:
- Cognitive function improved on Morris water maze testing
- Amyloid-beta (Aβ) plaque accumulation was reduced
- Microglial and astrocyte overactivation was inhibited
- Inflammatory mediator secretion was decreased
- AMP-activated protein kinase (AMPK) was robustly activated
- TLR4/NF-κB inflammatory signaling cascade was suppressed
Transcriptomic profiling (RNA sequencing) confirmed the anti-inflammatory mechanism at the gene expression level, providing multi-level evidence for semaglutide's neuroprotective effects.
Zhai, Yanyu; Lu, Kaili; Yuan, Yuan; Zhang, Ziyao; Xue, Lixia; Zhao, Fei; Xu, Xiaofeng; Wang, Hongmei ·
RPEP-14475 · 2025PDIA3 is highly expressed in healthy intestinal epithelial cells, particularly in goblet and Paneth cells. In patients with mesenteric artery ischemia, PDIA3 expression was reduced, correlating with disease severity.
In intestinal epithelium-specific Pdia3 knockout mice, ischemia/reperfusion injury was significantly more severe, with impaired goblet cell mucus production, reduced Paneth cell antimicrobial peptide secretion, and dysbiotic gut microbiota. Treatment with recombinant defensin α1 — an antimicrobial peptide normally secreted by Paneth cells — significantly alleviated the adverse effects of Pdia3 deficiency, restoring microbiota balance and reducing intestinal inflammation.
Zhan, Yaqing; Deng, Qiwen; Jia, Yifan; Chen, Zhaorong; Zhao, Xu; Ling, Yihong; Qiu, Yuxin; Wang, Xiwen; Wang, Fan; He, Muchen; Huang, Wenqi; Shen, Jiantong; Wen, Shihong ·
RPEP-14484 · 2025Researchers created DiWB-1, a peptide-drug conjugate that links an LHRH-receptor-targeting peptide to the PI3K inhibitor buparlisib. DiWB-1 was more potent than buparlisib alone against LHRH-receptor-positive breast cancer cells (IC50 of 1.8 μM vs 2.4 μM) while being less toxic to normal cells. In mice, DiWB-1 suppressed tumors effectively while avoiding the liver damage, kidney damage, and blood sugar spikes caused by buparlisib alone. The conjugate also showed favorable metabolic stability with a half-life of 5.6 hours, slightly longer than the established peptide drug triptorelin (4.2 hours).
Zhang, Chenyu; Zhong, Honglan; Li, Xiang; Xing, Zhenjian; Li, Siming; Yu, Rui; Deng, Xin · Animal
RPEP-14485 · 2025By conjugating a long-chain fatty acid to the N-terminus and a medium-chain fatty acid to Lys2 of the BimBH3 peptide, the optimized analogue D6 achieved:
- Potent dual PTPN1/2 inhibition (IC50 = 107.6 nM for PTPN1, 3375 nM for PTPN2)
- 40-fold improved DPP-IV stability over the parent peptide
- Plasma half-life >200 hours in rats after subcutaneous injection
- Efficient cell permeability and uptake for intracellular target engagement
- Restored insulin signaling in HepG2 liver cells
- Once-weekly glycemic control in db/db diabetic mice
Zhang, Chuanliang; Dong, Guozhen; Wu, Xiao; Chen, Jin; Wang, Yanqing; Gong, Liyan; Yang, Xianmin; Shi, Yiying; Gu, Zongwen; Gao, Xiang; Zheng, Yaning; Wu, Han; Zheng, Ke; Liu, Xiaochun; Gu, Yuchao ·
RPEP-14490 · 2025Two chicken-derived umami peptides were identified with dual functionality:
- DGGRYY: ACE inhibition IC50 = 28.71 μM (potent)
- NEFGYSNR: ACE inhibition IC50 = 283.24 μM (moderate)
Both peptides demonstrated:
- Good pH and thermal stability (suitable for food processing)
- Retention of ACE-inhibitory activity after simulated gastrointestinal digestion (DGGRYY: ~53%, NEFGYSNR: ~57%)
- Uncompetitive ACE inhibition pattern (binding outside the active pocket)
- Key binding sites: Trp59, Tyr62, Asp121, Arg124, Ser516
- Saltiness enhancement in 0.1-0.3% NaCl solutions, compensating for palatability loss from salt reduction
Zhang, Haotong; Liang, Li; Sun, Baoguo; Yang, Rui; Liu, Zunying; Mao, Xiangzhao; Zhang, Yuyu ·
RPEP-14492 · 2025HEC88473 is an Fc fusion protein that combines GLP-1 and FGF21 activity in a single molecule. In this phase 1 single-ascending dose trial:
- Pharmacokinetics: The drug splits into two active components after dosing — Fc-GLP-1 (half-life 66.5-119.5 hours) and Fc-FGF21 (half-life 28.4-41.6 hours), with peak levels at 12-14 hours
- Blood sugar: At doses ≥5.1 mg, glucose decreased during oral glucose tolerance tests on days 3 and 7. Maximum reduction was -1.829 mmol/L (placebo-adjusted) at 47.6 mg
- Adiponectin: At doses ≥10.2 mg, levels increased dose-dependently, up to 90.71% from baseline at 62.9 mg
- Triglycerides: At doses ≥17.0 mg, significant dose-dependent reductions up to -43.01% from baseline at 62.9 mg
- Safety: Well tolerated; most adverse events were mild GI disorders
Zhang, Hong; Li, Qianqian; Chen, Hong; Guo, Lingfeng; Li, Jing; Xie, Can; Yan, Jiangyu; Ding, Yanhua ·
RPEP-14500 · 2025HNP-1, produced primarily by human neutrophils, exhibits broad-spectrum antimicrobial activity against both bacteria and viruses. The review identified several key aspects:
• HNP-1 combats pathogens without leading to the resistance patterns seen with traditional antibiotics
• The peptide has multiple functions beyond direct antimicrobial killing, including immune regulatory roles
• Mass production has been a major barrier to clinical use — microbial biosynthesis systems offer a cost-effective alternative to human extraction
• Recent studies have revealed HNP-1's endogenous bactericidal mechanism, advancing understanding of how it kills pathogens
• The peptide's gene expression, distribution, and regulatory elements controlling its production are now better understood
Zhang, Jiaqi; Liu, Zhaoke; Zhou, Zhihao; Huang, Zile; Yang, Yifan; Wu, Junzhu; Liu, Yanhong ·
RPEP-14509 · 2025The review synthesizes evidence for several emerging multi-agonist peptide drug classes:
- GLP-1/GIP dual agonists (e.g., tirzepatide) have already demonstrated superior efficacy over GLP-1 monotherapy
- GLP-1/glucagon dual agonists leverage glucagon's energy-expenditure effects while offsetting its glucose-raising activity with GLP-1's insulin-promoting action
- GLP-1/GIP/glucagon triple agonists (e.g., retatrutide) target all three receptors for potentially maximal metabolic benefit
- GDF15-based approaches represent a newer pathway that reduces appetite through brainstem signaling
- Beyond metabolic effects, these agents may offer cardioprotective and anti-inflammatory benefits
Zhang, Jiudan; Sanan, Shriya; Csanalosi, Marta; Zheng, Chao; Pfeiffer, Andreas F H ·
RPEP-14512 · 2025Liraglutide significantly reduced myocarditis severity, as shown by lower heart weight/body weight ratio, reduced serum cardiac troponin T, decreased cardiac fibrosis, and diminished inflammatory infiltration. Echocardiography confirmed improved left ventricular function. Immunofluorescence and RT-qPCR showed decreased T-cell and macrophage infiltration with reduced pro-inflammatory cytokine expression. RNA sequencing identified the NLRP3 inflammasome and NF-κB pathways as the key targets modulated by liraglutide.
Zhang, Lijuan; Han, Lishuai; Lu, Yang; Chen, Quanzhou ·
RPEP-14518 · 2025High-throughput screening and microscale thermophoresis confirmed that liraglutide has high affinity for and directly binds to transthyretin (TTR) protein. In humanized ATTRv mice carrying the Val50Met mutation, 28 days of liraglutide treatment (0.3 mg/kg/day) significantly decreased TTR protein content in brain tissue compared to placebo.
However, cardiovascular endpoints showed no benefit. Plasma BNP (heart failure marker), cardiac fibrosis markers (Col1a1 and TGFβ1 expression), and pathological measures (right ventricular collagen percentage, ventricular septum thickness, left ventricular wall thickness, and left ventricular internal diameter) were all statistically comparable between liraglutide and placebo groups.
Zhang, Mengqing; Li, Zonglin; Cai, Xiaoling; Lv, Fang; Wen, Xin; Guo, Chengcheng; Lin, Chu; Ji, Linong ·
RPEP-14522 · 2025Liraglutide significantly reversed free fatty acid-induced hepatocyte steatosis (fatty liver cells) through two complementary mechanisms. First, it regulated lipid metabolism enzymes: decreasing lipogenesis proteins (FAS, ACC1) that make new fat, while increasing lipolysis proteins (ATGL, HSL, LAL) that break down stored fat.
Second, liraglutide enhanced autophagy — the cellular self-digestion process that clears accumulated lipid droplets. Both effects were AMPK-dependent and required SIRT1: when SIRT1 was knocked down, liraglutide could no longer induce autophagy or reduce lipid accumulation. This establishes the AMPK/SIRT1 axis as the critical mediator of GLP-1 receptor agonist activity against hepatic steatosis.
Zhang, Qiang; Wang, Jingyuan; Hu, Xiaojin; Lu, Wei; Cao, Yang; Niu, Chunyan; Yue, Hongqin ·
RPEP-14523 · 2025The review identifies three major innovations in peptide-based anti-aging strategies: (1) environment-responsive peptides that can be triggered by specific skin conditions like pH changes or oxidative stress, (2) biomimetic peptides designed to mimic the function of natural skin proteins and signaling molecules, and (3) advanced nano-delivery systems that overcome the skin barrier to deliver peptides effectively to target cells.
The integration of chronobiology (studying how aging processes vary with circadian rhythms) and multi-omics approaches (genomics, proteomics, metabolomics) is further refining peptide-based interventions toward personalized anti-aging treatments.
Zhang, Qianqian; Liu, Zijian; Shu, Peng; Jiang, Ligang; Ding, Wenfeng ·