The living record of
peptide science.

Tripartite warfare: decoding the cell-virus-virophage arms race.

Crit Rev Microbiol

Ting Chu, Yongjie Wang

Giant viruses constitute a remarkable group of large double-stranded DNA (dsDNA) viruses distinguished by their exceptional structural complexity and genomic features. Their genomes can reach 2.8 Mb, encoding hundreds of proteins, and virion diameters up to 1.5 μm. They infect diverse eukaryotic hosts and establish viral factories within host cells. Virophages are small dsDNA viruses (17-34 kb; 50-75 nm) that parasitize giant viruses. These satellite viruses hijack giant virus replication machinery while suppressing giant virus progeny, benefiting the host cell and creating a parasitic-symbiotic dynamic. This review examines the tripartite relationship between host cells, giant viruses, and virophages (CVv systems), focusing on: (1) virus-host interactions in amebae, marine flagellates, and unicellular algae; (2) molecular mechanisms of these interactions; and (3) ecological and evolutionary implications. We also identify current research challenges and propose future directions, particularly the molecular basis of viral interactions in CVv systems.

P2Y12 receptor in trigeminal ganglion contributes to CFA-induced mechanical allodynia in mice.

Neuroscience

Zhishan Zou, Qianyi Shi, Lijia Mai +4 more

Chronic orofacial inflammatory pain remains a major clinical challenge, and peripheral sensitization within the trigeminal ganglion (TG) is thought to contribute to its development. This study aimed to investigate whether P2Y12 receptor signaling contributes to orofacial inflammatory pain, with particular focus on the TG as a potential peripheral site of action. A mouse model of orofacial pain was established through the subcutaneous injection of complete Freund's adjuvant (CFA) into the right whisker pad. The expression and distribution of P2Y12 receptor were characterized using single-cell RNA sequencing, immunohistochemistry, and immunofluorescence. The functional role of P2Y12 signaling was examined by systemic clopidogrel treatment in vivo and by ADP stimulation with or without the selective antagonist PSB-0739 in primary satellite glial cells (SGCs) and macrophages in vitro. P2Y12 expression in the TG was significantly upregulated 7 days after CFA injection and was predominantly expressed on SGCs and macrophages. Systemic pharmacological inhibition of P2Y12 alleviated mechanical allodynia and was associated with reduced c-Fos expression in the spinal trigeminal nucleus caudalis (SpVc). In addition, the P2Y12 inhibition was accompanied by decreased SGC activation, fewer CD86-positive macrophages, and lower interleukin-6 (IL-6) expression in the TG. In vitro assays further showed that P2Y12 activation promoted pro-inflammatory cytokine expression in both SGCs and macrophages, and this effect was attenuated by PSB-0739. Collectively, these findings suggest that P2Y12 receptor may contribute to the regulation of orofacial inflammatory pain, in part through neuroimmune alterations within the TG.

Engineered neuronal exosomes mediate α-synuclein clearance to ameliorate Parkinson's disease.

J Nanobiotechnology

Lufei Chen, Xiaoling Lin, Mingzhi Fu +10 more

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. A hallmark pathological feature of PD is the abnormal aggregation of α-synuclein (αSyn) into insoluble Lewy bodies. Consequently, developing strategies to inhibit αSyn aggregation in the brain has been a major research focus for PD treatment. This study developed a therapeutic approach using engineered neuronal exosomes. These exosomes were modified to extend their blood circulation half-life to 3.8 h and enhance targeting, with a 2.15 ± 0.09% brain signal proportion (vs. 0.78 ± 0.07% for free dye). They were then loaded with a self-developed αSyn aggregation-blocking peptide (sPep) as well as the antioxidant pyrroloquinoline quinone (PQQ). We investigated the therapeutic efficacy of this system in both in vitro and in vivo models of PD. Our experiments confirmed that the screened sPep effectively targeted and blocked αSyn aggregation both in vitro and in vivo. Neuronal exosomes, isolated by ultracentrifugation and hybridization, demonstrated strong abilities to cross the blood-brain barrier. In vivo studies revealed that the treatment significantly improved motor and cognitive functions in PD model mice. The underlying neuroprotective mechanisms included reducing αSyn aggregation, enhancing antioxidant capacity, ameliorating mitochondrial dysfunction, and suppressing cell apoptosis, collectively promoting the survival of dopaminergic neurons. These findings demonstrate that the engineered exosome-mediated delivery system exerts a protective effect against PD pathology.

Optimizing heart failure care: A machine learning-based prediction of hospital length of stay for heart failure patients.

Heart Lung

Arthur De Souza, Ray Opoku

Heart failure represents a significant global health burden, with prolonged length of stay (LoS) tied to increased mortality and costs. Accurate prediction of hospital LoS is crucial for improving resource allocation, lowering mortality and readmission rates, and enhancing patient care.

A randomised clinical trial testing the safety of and metabolic responses to short-term duodenal infusion of recombinant RORDEP1 in healthy men.

Diabetologia

Joachim Gæde, Yong Fan, Liwei Lyu +7 more

RUMTOR-derived peptides (RORDEPs) 1 and 2 are polypeptides synthesised by specific strains of the human gut commensal Ruminococcus torques. Preclinical studies have shown that RORDEPs lower blood glucose via an impact on plasma incretins and an improvement of hepatic insulin sensitivity. In a randomised, placebo-controlled, crossover trial, we here explore the safety and tolerability of, as well as any metabolic responses to, a duodenal infusion of recombinant RORDEP1 (r-RORDEP1) given to healthy men after oral intake of a liquid mixed meal.

Measuring approach-avoidance behavior in patients with panic disorder using the human elevated plus maze in mixed reality.

J Psychiatr Res

Till Dobner, Jana Christina Müller, Daniel Biedermann +2 more

Avoidance behavior is a hallmark of panic disorder (PD), yet experimental evidence remains limited due to challenges in assessing unconditioned avoidance without specific threats. The human Elevated Plus Maze (EPM), implemented in mixed reality, provides an ecologically valid paradigm to measure approach-avoidance behavior under controlled conditions.

Adrenocorticotropin hormone regulates sphingosine-1-phosphate synthesis via cortisol in bovine adrenocortical cells.

Biochem Biophys Res Commun

Zaire Belen Medina-Moctezuma, Adrian Guzmán-Sánchez, David González-Aretia +3 more

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) stimulate the synthesis of sphingosine-1 phosphate (S1P) in Gs-coupled receptors dependent manner, enabling S1P to mediate specific bioactivities of FSH and LH. Because adrenocorticotropic hormone (ACTH) also acts via a Gs-coupled receptor to regulate adrenal cortex function, we hypothesized that ACTH could induce S1P secretion in adrenocortical cells, which could then mediate the steroidogenic and number of viable cells effects associated with ACTH. Primary bovine adrenocortical cell cultures were treated with ACTH, and number of viable cells, as well as S1P and cortisol concentrations in the culture media were measured. The effects of exogenous cortisol on number of viable cells, S1P and phosphorylated SPHK1 concentrations were also determined. Results show that the addition of 0.001 μM and 0.1 μM ACTH to the culture medium increased the number of viable adrenocortical cells, and the concentration of cortisol in culture media, respectively. However, ACTH addition did not increase S1P concentrations. Interestingly, a negative correlation between S1P and cortisol concentrations in the culture medium was observed. Moreover, while addition of 0.1 ng/mL cortisol increased S1P and phosphorylated SPHK1 concentrations, increasing cortisol from 1 to 10 ng/mL did not affect phosphorylated SPHK1 but reduced S1P concentration. Thus, while our data suggest that ACTH does not promote S1P synthesis; by stimulating cortisol synthesis, ACTH could be involved in regulation of S1P levels in bovine adrenocortical cells.

Serelaxin has greater anti-fibrotic potential than perindopril but maintains its anti-fibrotic efficacy in the presence of perindopril in normotensive mouse models of heart disease.

Life Sci

Ziqiao Wang, Gang She, Chao Wang +5 more

Serelaxin (RLX), the drug form of human gene-2 relaxin, has potent anti-fibrotic properties that are currently being clinically-evaluated for the treatment of heart failure (HF). Whilst these effects can potentially be antagonised by angiotensin receptor blocker co-administration, this study determined if RLX was a suitable adjunct therapy to angiotensin converting enzyme inhibitor (ACEi) treatment. In particular, the anti-fibrotic effects of RLX were compared or combined with the clinically-used ACEi, perindopril, in murine models of isoprenaline (ISO)-induced cardiomyopathy and surgically-induced myocardial infarction (MI).

Novel Amylin-Based Therapies for Weight Management in Adults With Overweight or Obesity Without Diabetes: A Network Meta-Analysis.

Endocrinol Diabetes Metab

A B M Kamrul-Hasan, Ibrahim Khalil, Kunal Mahajan +3 more

Long-acting amylin-based therapies (ABTs) are emerging anti-obesity agents; we sought to compare their effects on weight and anthropometric outcomes in adults with overweight/obesity without diabetes, evaluate gastrointestinal (GI) safety, and rank agents and doses within a network meta-analysis (NMA) framework.

Dual orexin receptor antagonism with lemborexant enhances microglial clearance of β-amyloid in mice.

Mol Neurodegener

Ashish Sharma, Emiko Segawa, Xiaoying Chen +12 more

Sleep disturbances elevate brain amyloid-beta (Aβ) levels and represent a modifiable risk factor for Alzheimer's disease (AD). The orexin/hypocretin system regulates sleep-wake behavior and has emerged as a therapeutic target in AD; however, the effects of FDA-approved dual orexin receptor antagonists (DORAs) on amyloid pathology remain unclear. We compared lemborexant, an FDA-approved DORA, to doxepin, an antihistaminergic sleep medication, on amyloid pathology and microglial responses in PSAPP mice.

How cholesterol modulates LL-37 function: A biophysical study in eukaryotic-like membrane systems.

Biophys Chem

Juan M Giraldo-Lorza, Saúl Antonio Hernández Martínez, Francisco J Sierra-Valdez +3 more

The limited selectivity of antimicrobial peptides (AMPs) can lead to unintended damage to healthy eukaryotic cells, a process strongly influenced by membrane physicochemical properties. Cholesterol (CHO) is a key regulator of lipid packing, membrane order, and bilayer mechanical stability; however, its role in modulating AMP-membrane interactions remain incompletely understood. Here, we examine how CHO alters peptide-membrane interactions at the molecular level using eukaryotic membrane models composed of phosphatidylcholine, sphingomyelin, and increasing CHO fractions. Fourier-transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), isothermal titration calorimetry (ITC), and fluorescence spectroscopy were employed to probe both structural and thermodynamic changes upon interaction with the human cathelicidin LL-37. FT-IR and DSC revealed that LL-37 preferentially perturbs sphingomyelin-enriched membranes, inducing shifts in phase transition temperatures and signatures of domain segregation. These perturbations were pronounced in the absence of CHO and remained detectable up to 10 mol% CHO, but were markedly attenuated at 20 mol% CHO. ITC measurements confirmed a higher binding affinity of LL-37 for sphingomyelin-rich regions, whereas fluorescence permeabilization assays demonstrated a progressive increase in membrane resistance to peptide-induced disruption with increasing CHO content. Collectively, these results suggest that LL-37 preferentially partitions into cholesterol-poor membrane domains, destabilizing their structure. In contrast, cholesterol incorporation stabilizes the surface of cholesterol-rich domain without necessarily promoting peptide anchoring within the bilayer. This study provides mechanistic insights into AMP cytotoxicity toward eukaryotic membranes and underscores cholesterol's protective role offering guidance for designing peptides with enhanced therapeutic selectivity.

Effects of a 6-week subcutaneous infusion of native GIP alone or as add-on to semaglutide in people with type 2 diabetes: a single-centre, double-blind, parallel-group, randomised, placebo-controlled trial.

Lancet Diabetes Endocrinol

Mads M Helsted, Christiane Fonnesbech-Wulff, Nina L Schaltz +11 more

The long-term glycaemic effects of glucose-dependent insulinotropic polypeptide (GIP) remain unclear. We aimed to assess whether a 6-week subcutaneous infusion of GIP alone and in combination with the GLP-1 receptor agonist semaglutide would enhance glycaemic control in individuals with type 2 diabetes.

Semaglutide drives weight loss through cAMP-dependent mechanisms in GLP1R-expressing hindbrain neurons.

Nat Metab

Claire Gao, Isabelle C Geneve, Shakira Rodriguez-Gonzalez +5 more

Glucagon-like peptide 1 receptor (GLP1R) agonists, such as semaglutide, drive weight loss by binding to GLP1Rs-classically described as Gs-coupled G-protein-coupled receptors-in the brain; however, the intracellular signalling mechanisms underlying these effects remain poorly defined. Here, we find that semaglutide engages both Gs- and Gq-dependent signalling pathways in Glp1r-expressing neurons in the area postrema (APGlp1r), the primary site of semaglutide action in the brain, and differentially regulates neuronal activation across distinct neuronal clusters. Semaglutide also drives graded increases of the essential secondary messenger cyclic adenosine monophosphate (cAMP) in APGlp1r neurons through the Gs pathway. Inhibition of the cAMP-degrading enzyme phosphodiesterase 4 (PDE4) enhances and sustains these cAMP responses, and disruption of Gs or cAMP signalling in APGlp1r neurons abolishes semaglutide-induced weight loss and downstream brain-wide activation. Our systematic characterization of semaglutide's signalling mechanisms in the hindbrain reveals the intracellular signalling architecture through which semaglutide engages cAMP and calcium to regulate body weight, providing avenues for improving obesity therapeutics.

A single centre retrospective study of the long‑term weight and pregnancy-related outcomes in women of reproductive age before and after liraglutide exposure.

Int J Obes (Lond)

Tariq Chukir, Hubaib Haider, Shaunak Sarkar +4 more

The impact of GLP‑1 receptor agonist exposure prior to pregnancy on pregnancy-related outcomes remains unclear, with studies reporting mixed findings.

The pulmonary artery hypertension and cancer: PULAHYCA PILOT study. Initial prostanoid therapy in cancer patients with pulmonary hypertension: results from an observational study.

Cardiooncology

Vanesa Gregorietti, Teresa López-Fernández, Joerg Herrmann +2 more

Cancer is a leading cause of death worldwide, though new therapies have increased patient survival. These therapies, however, have also raised concerns for cardiovascular toxicities, such as cardiomyopathies, coronary artery disease, hypertension and arrhythmias. Pulmonary arterial hypertension (PAH) is a rare condition that carries a poor prognosis and is often diagnosed at an advanced stage. The annual incidence in the general population is estimated to be between 1 and 2 cases per million. The highest prevalence occurs during the third and fourth decades of life; however, there are cases whose are identified after the sixth decade. It has increasingly become evident that various cancer therapies can exacerbate pulmonary hypertension, significantly impacting patient prognosis. It is recognized that oncologic treatments can cause endothelial dysfunction, including the pulmonary vasculature, and can have thrombotic effects, worsening PAH in patients with this disease. The objective of this study is to describe our experience with patients with a concomitant diagnosis of PAH and cancer, who received prostanoid therapy to be able to complete specific cancer treatments.

Preliminary results from a phase II trial of spatially fractionated radiotherapy combined with immunotherapy and anti-angiogenic therapy in patients with bulky solid tumors: early evidence of promising efficacy and favorable safety.

Radiat Oncol

Yuntao Zhou, Yanwei Li, Hui Zhu +8 more

Bulky solid tumors present significant therapeutic challenges. Spatially fractionated radiotherapy (SFRT), a technique delivering alternating high- and low-dose subvolumes, alters the tumor microenvironment while minimizing toxicity. This phase II trial assesses the efficacy and safety of SFRT combined with immune checkpoint inhibitors (ICIs) and anti-angiogenic agents in advanced malignancies.

Projected reduction in major adverse cardiovascular events among high-risk U.S. adults with type 2 diabetes eligible for oral semaglutide: a SOUL trial-based analysis using NHANES (1988-2018) cycles.

Cardiovasc Diabetol Endocrinol Rep

Mustafa Al-Jarshawi, Andrew Cole, Rodrigo Bagur +5 more

Short-term comparative effects of semaglutide, either alone or in conjunction with canagliflozin, on early diabetic kidney disease.

Pak J Pharm Sci

Wang Long, Li Ningning, Huang Weijun

Diabetic kidney disease (DKD) is a common complication of type 2 diabetes mellitus and an important cause of end-stage renal disease. Metabolic dysfunction, albuminuria, and chronic low-grade inflammation characterize early DKD, leading to progressive renal impairment. To date, SGLT2 inhibitors and GLP-1 receptor agonists are known to provide renoprotective and metabolic benefits; however, there is limited evidence available regarding the combined use of these treatments in early DKD.

Glycaemic changes during early semaglutide treatment: a case of pancreatic adenocarcinoma.

Acta Diabetol

Işılay Taşkaldıran, Püren Gökbulut, Hasan Yiğit +1 more

Glucagon-like peptide-1 receptor agonists are widely used for the management of obesity and dysglycaemia, and current evidence does not support a causal association with pancreatic cancer. We report a 55-year old woman with obesity and prediabetes who started once-weekly semaglutide 0.25 mg for weight management and glycaemic control. Baseline fasting plasma glucose was 107 mg/dL and glycated haemoglobin was 6.0%. After one month, despite a 4 kg weight loss and no significant gastrointestinal symptoms, fasting plasma glucose increased to 169 mg/dL and glycated haemoglobin to 6.6%. Latent autoimmune diabetes in adults was excluded by negative autoantibodies and preserved C-peptide. Further evaluation revealed markedly elevated carbohydrate antigen 19-9 and pancreatic magnetic resonance imaging demonstrated a 4 × 3 cm irregular mass in the pancreatic head. Surgical exploration identified liver metastases, and biopsy confirmed metastatic pancreatobiliary adenocarcinoma. This case highlights that atypical glycaemic changes during early semaglutide treatment should be interpreted cautiously, particularly during subtherapeutic dose escalation. Such observations do not imply causality, but may warrant individualized assessment when accompanied by additional clinical suspicion.

[Glucagon-like peptide-1 agonists and heart failure].

Rev Med Suisse

Nisha Soborun, Lucie Favre, Henri Lu +1 more

Developed to treat type 2 diabetes, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been associated with a reduced risk of cardiovascular events in high-risk patients with diabetes, and later in obese patients with cardiovascular disease without diabetes. More recently, semaglutide and tirzepatide have demonstrated benefits in obese patients with heart failure (HF) with preserved or mildly reduced ejection fraction, including fewer HF hospitalisations and improvements in symptoms and functional capacity. Data remain limited in heart failure with reduced ejection fraction. This article summarises current evidence on these therapies, particularly in HF, and provides practical guidance for their prescription and follow-up.