The living record of
peptide science.

Dietary Strategies and Nutritional Management in Patients Receiving GLP-1 and Dual GIP/GLP-1 Receptor Agonists as Adjuncts to Lifestyle Interventions: A Systematic Review of Randomised Clinical Trials.

Diabetes Obes Metab

Rayanne Santos de Paulo, Dandara Baia Bonifácio, Matheus Henrique Lana de Carvalho +1 more

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GIP/GLP-1 RAs are widely used to manage obesity, prediabetes and type 2 diabetes, typically in combination with lifestyle interventions. Their nutritional implications, however, remain unclear. This systematic review summarised evidence from randomised clinical trials investigating dietary strategies and nutritional management in individuals treated with these medications.

Glucagon-Like Peptide-1 Receptor Agonists for Bile Acid Diarrhea: Emerging Evidence and Clinical Implications.

Cureus

Eunice K Omeludike, Cherechi O Nwabueze, Nneoma Ubah +7 more

Bile acid diarrhea (BAD) is an underrecognized cause of chronic diarrhea that makes a significant contribution to the symptom burden and impaired quality of life. Despite increasing awareness, BAD is frequently misdiagnosed as diarrhoea-predominant irritable bowel syndrome (IBS-D), leading to delayed diagnosis and incomplete symptom control. Current management relies primarily on bile acid sequestrants, which are effective for many patients but limited by poor tolerability, variable adherence, and incomplete response in a subset, prompting interest in alternative therapeutic approaches targeting bile acid dysregulation. Advances in understanding enterohepatic signaling have highlighted the role of the farnesoid X receptor-fibroblast growth factor 19 (FXR-FGF19) axis in regulating bile acid synthesis, secretion, and motility. In parallel, glucagon-like peptide-1 (GLP-1) receptor agonists, which are commonly used in the treatment of metabolic diseases, affect gastrointestinal motility, secretion, and neurohormonal signaling by mechanisms that overlap with those that are implicated in BAD. Emerging clinical studies, including randomized trials comparing GLP-1-based therapy with established bile acid sequestrants, have begun to explore their potential role in BAD, although the current evidence base remains limited and investigational. This narrative review synthesizes peer-reviewed evidence examining the biological rationale, diagnostic context, and clinical data relevant to GLP-1 receptor agonists in BAD. Literature was identified primarily by PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE) searches supplemented by manual screening of reference lists of key reviews and clinical studies and integrated narratively because of heterogeneity of study design, exposure definitions, and outcome measures. Current evidence suggests that GLP-1 receptor agonists represent a biologically plausible area of investigation for selected patients with persistent symptoms despite standard therapy. This review does not advocate routine clinical use but aims to contextualize emerging BAD-specific and mechanistic data to inform hypothesis generation, patient selection, and future research. Available data are still limited, and GLP-1 receptor agonists have not been established as a treatment for BAD. Further prospective studies with standardized outcomes are needed to clarify their role and inform evidence-based clinical practice.

Familial partial lipodystrophy type 2 associated with a novel LMNA variant (c.604G>C; p.Glu202Gln): a Colombian family case series.

Front Endocrinol (Lausanne)

Carolina Mendoza, Raquel Cano, Luis Burgos +1 more

Familial partial lipodystrophy type 2 (FPLD2) is a rare autosomal dominant laminopathy caused by LMNA gene variants. It is characterized by progressive gluteofemoral lipoatrophy and severe metabolic derangements, including insulin resistance and metabolic dysfunction-associated steatotic liver disease.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) in dermatology: cutaneous adverse events and emerging efficacy in inflammatory skin diseases.

Expert Rev Clin Immunol

Meng Jie Ho, Choon Fong Liew, Nguan Soon Tan +2 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and next-generation incretin therapies are increasingly used for diabetes and obesity, yet cutaneous adverse events remain incompletely characterized. New-onset dermatological manifestations after GLP-1RA initiation such as rash or alopecia may be misattributed to baseline inflammatory skin disease rather than drug-induced toxicity.

Pink1 at the crossroads of aging, exercise, and diet in Parkinson's disease: a mechanistic review.

Front Aging Neurosci

Ying Lin, Deng-Tai Wen

Pink1 (PTEN-induced kinase 1) is a key guardian of mitochondrial quality via mitophagy; its mutations are tightly linked to early-onset PD. This review synthesizes how aging, exercise, and high-fat diet (HFD) modulate Pink1 activity and thereby PD risk. Aging down-regulates Pink1, impairing clearance of damaged mitochondria and promoting α-synuclein aggregation. Exercise up-regulates Pink1-Parkin signaling, enhances PGC-1α and brain-derived neurotrophic factor (BDNF), and protects dopaminergic neurons in humans and rodents. Conversely, chronic HFD suppresses Pink1, exacerbates oxidative stress, microglial activation and insulin resistance, accelerating Parkinson's disease pathology. Cross-species cautions (mouse vs. primate) are highlighted. Targeting Pink1-mediated mitophagy through lifestyle interventions offers a non-pharmacological strategy to delay PD onset and progression in aging populations.

The senescent niche hypothesis: microglial dysfunction and replacement strategies in drug-resistant epilepsy.

Front Immunol

Jingheng Wu, Miaomiao Li, Yetong Shi +1 more

Epilepsy is one of the most prevalent neurological disorders, affecting over 70 million individuals worldwide. However, despite the introduction of more than 30 anti-seizure medications over three decades, approximately 30% of patients continue to suffer from drug-resistant epilepsy (DRE). Here, we advance the "Senescent Niche Hypothesis," proposing that the epileptogenic focus in DRE harbors a pathological accumulation of senescent microglia that have lost homeostatic surveillance capacity and acquired a toxic secretory phenotype. We present the "Iron-Senescence Axis" as the mechanistic driver: recurrent seizure-induced blood-brain barrier disruption leads to chronic parenchymal iron deposition; microglia accumulate iron through erythrophagocytosis and sustain sub-lethal ferroptotic stress-characterized by lipid peroxidation, mitochondrial dysfunction, and DNA damage-that drives their irreversible transition to a senescent state rather than acute cell death. Once senescent, these microglia paradoxically acquire resistance to ferroptosis through lysosomal iron sequestration, occupy the niche indefinitely, and perpetuate epileptogenesis via the senescence-associated secretory phenotype (SASP), establishing a positive feedback loop. Converging transcriptomic and experimental evidence from both human surgical specimens and rodent models substantiates this framework, demonstrating that senolytic clearance of senescent cells significantly reduces seizure burden and can prevent epilepsy development. Building on these findings, we evaluate two complementary therapeutic strategies: senolytic therapy using dasatinib plus quercetin (D+Q) for selective elimination of senescent cells, and the Microglial Intervention Strategy for Therapy and Enhancement by Replacement (MISTER) for comprehensive niche reconstitution through CSF1R inhibitor-mediated microglial depletion followed by donor cell engraftment. We critically assess donor cell sources, advances in non-genotoxic conditioning, and CSF1R-inhibitor resistant donor cells that may enable clinical translation. This synthesis argues that targeting the senescent microglial niche may represent a disease-modifying approach that shifts the therapeutic focus from seizure suppression to neuroimmune niche restoration.

Immunosenescence and Inflammaging as Drivers of Neurodegeneration: Cellular Mechanisms, Neuroimmune Crosstalk, and Therapeutic Implications.

Cells

Gianmarco Bertoni, Sara Ristori, Daniela Monti

Aging is accompanied by profound alterations in immune function, termed immunosenescence, and by a chronic, low-grade inflammatory state known as inflammaging. These processes are increasingly recognized as central drivers of age-related neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis and Multiple Sclerosis. In the central nervous system, senescent microglia and astrocytes lose their homeostatic and neuroprotective functions, while systemic immune aging and blood-brain barrier dysfunction further amplify neuroinflammation and impair protein aggregate clearance. This sustained pro-inflammatory environment promotes synaptic dysfunction, neuronal loss and cognitive decline. Here, we synthesize current knowledge of the mechanistic links among immunosenescence, inflammaging, and neurodegeneration, highlighting innate and adaptive immune dysregulation, mitochondrial impairment, and failed resolution pathways. We further discuss emerging therapeutic strategies, including senolytics, immunoceuticals, microbiome-based interventions and advanced drug delivery systems, aimed at restoring immune homeostasis and enhancing brain resilience. By integrating mechanistic and translational insights, this review provides a framework for developing novel interventions to target immune aging in neurodegenerative diseases.

Retinal Pigment Epithelium Ageing: Cellular and Molecular Mechanisms of Long-Term Homeostasis and Age-Related Dysfunction.

Cells

Yijing Yang, Pei Liu, Jiangwei Li +4 more

The retinal pigment epithelium (RPE) is a long-lived, highly polarised epithelial monolayer that performs essential functions in retinal homeostasis, including outer blood-retina barrier maintenance, visual cycle activity, metabolic exchange, phagocytic clearance of photoreceptor outer segments, and regulation of oxidative and immune balance. Because RPE cells persist for decades under conditions of sustained oxidative, metabolic, and phagocytic stress, this tissue provides a valuable model for examining how long-lived post-mitotic cells preserve function over time and how age-related dysfunction emerges when that balance weakens. Although much of the current literature on RPE ageing has been shaped by age-related macular degeneration (AMD), age-dependent change in the RPE should not be understood solely as a preclinical stage of disease. Rather, the ageing RPE offers a broader framework for studying cellular maintenance under chronic physiological load. In this review, we synthesise current evidence on RPE ageing across four interrelated domains: structural remodelling, mitochondrial and metabolic imbalance, proteostatic and lysosomal burden, and chronic inflammatory dysregulation. Across these processes, ageing in the RPE is expressed less as widespread cell loss than as progressive decline in cellular organisation, buffering capacity, and functional precision. Structural irregularity, altered mitochondrial regulation, incomplete degradative clearance, and persistent low-grade inflammatory signalling together reduce the ability of the RPE to maintain long-term homeostasis and increase vulnerability to age-related retinal dysfunction. We further argue that ageing in the RPE is best understood not as abrupt failure of isolated pathways, but as gradual loss of system coherence among interacting homeostatic systems that remain active while operating under increasing constraint. This view helps integrate diverse cellular and molecular findings and highlights the RPE as an informative model for understanding ageing in long-lived post-mitotic tissues.

Autoimmune Features of Post-COVID-19 Vaccination Syndrome and Their Impacts on the Renin-Angiotensin System.

Vaccines (Basel)

Paolo Bellavite, Giuseppe Di Fede, Mauro Mantovani +1 more

One of the most critical aspects of post-acute COVID-19 syndrome (PACS) and post-acute COVID-19 vaccination syndrome (PACVS) is the presence of autoantibodies. These autoantibodies are directed against various receptors in the autonomic and cardiovascular systems, including those targeting proteins of the renin-angiotensin system (RAS). The RAS plays a central role in regulating vascular homeostasis, inflammation, and endothelial function. During SARS-CoV-2 infection, the interaction of the spike (S) protein with angiotensin-converting enzyme 2 (ACE2) can alter the balance of the RAS, favoring an imbalance towards the ACE/Angiotensin II/AT1R axis, known for its pro-inflammatory, pro-thrombotic, and vasoconstrictive properties. Similar pathological mechanisms also come into play in response to vaccinations that use the S protein as an antigen. Studies conducted by other groups and us on patients with PACS and PACVS have revealed the presence of autoantibodies directed against these RAS components and the mechanisms by which these antibodies can worsen the clinical situation. In particular, anti-ACE2, presumably formed by the anti-idiotype network or molecular mimicry, is correlated with PACVS symptoms in many patients. Furthermore, the presence of anti-MAS1 antibodies can reduce the efficiency of the ACE2/Angiotensin-(1-7)/MAS1 axis, which normally acts as a counter-regulator. Considering this evidence, an analysis of RAS molecules and the autoantibodies implicated in reactions to them may be useful for evaluating a state of persistent dysregulation associated with post-vaccination symptoms such as asthenia, headache, skin edema and bruising, cardiovascular alterations, and neurovegetative manifestations. Finally, we offer insights into diagnosing these multifaceted syndromes and working hypotheses to guide research into possible therapeutic approaches.

Sushi, von Willebrand Factor Type A, EGF and Pentraxin Domain-Containing Protein 1: A Novel Fibroblast-Derived Circulating Biomarker Reflecting Cardiac Fibrosis.

J Am Heart Assoc

Naoya Kuwahara, Manabu Nagao, Yu Izawa +9 more

Cardiac fibrosis is a hallmark of heart failure and can be quantified by the extracellular volume fraction (ECV) derived from diagnostic imaging. However, noninvasive assessment is limited by the lack of specific circulating biomarkers. Recent large plasma proteome analyses have identified SVEP1 (Sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1) as candidate molecules reflecting cardiac fibrosis. This study aimed to evaluate SVEP1 as a biomarker for cardiac fibrosis.

[Tirzepatide in real-world clinical practice: changes in body composition and muscle function in patients with obesity].

Nutr Hosp

Jorge Blanco Anesto, Keyla María Dotres Fallat, Joana Nicolau

obesity is a chronic and relapsing disease. Tirzepatide, a dual GLP-1 and GIP receptor agonist, has demonstrated weight loss exceeding 20 % at higher doses. However, real-world data remain limited, particularly regarding body composition and muscle function.

The 40th Minute Cortisol Measurement is the Key Time-Point in the Low-Dose Synacthen Stimulation Test: A Large, Assay-Specific Pediatric Validation Study.

J Clin Res Pediatr Endocrinol

Busra Gurpinar Tosun, Hazal Arikan Gacemer, Didem Helvacioglu +3 more

Low-dose synacthen stimulation test (LDSST) is widely used to assess central adrenal insufficiency (CAI). With the adoption of monoclonal antibody (mAb) cortisol immunoassays, lower basal and peak cortisol concentration thresholds require external validation under real-world clinical conditions.

Molecular and Cellular Mechanisms of Anti-Obesity Agents: An Integrative Review.

FASEB J

Harmandeep Kaur, Deepika Kaushik, Prasad Rasane +3 more

Genes play a pivotal role in appetite regulation and energy homeostasis during a person's obesity. LEP (Leptin) and POMC (Proopiomelanocortin) are vital for appetite suppression and promoting satiety, while AgRP (Agouti-related peptide) and NPY (Neuropeptide Y) serve to stimulate appetite, creating a balanced interplay between hunger and satiety signals. GHRL (Ghrelin) further promotes hunger, emphasizing the complexity of these regulatory mechanisms. BDNF (Brain-derived neurotrophic factor) shows a dual role, impacting energy homeostasis not only in the brain but also in adipose tissue, thereby influencing lipid metabolism. PCSK1 (Proprotein Convertase Subtilisin/Kexin Type 1) is critical for the processing of neuropeptides that modulate energy balance. IGF2BP2 (Insulin-like Growth Factor 2 mRNA-Binding Protein 2) and MAP2K5 (Mitogen-Activated Protein Kinase 5) contribute to metabolic processes involved in fat accumulation and glucose regulation. Thus, emphasizing the significance of these mechanisms offers valuable insights that could lead to effective interventions for obesity prevention and management.

Obesity and Heart Failure: Introducing the Theme.

J Cardiovasc Dev Dis

Francesco Monitillo, Paolo Basile, Giuseppe Lisco

Obesity is a chronic, highly prevalent disease affecting nearly one-third of the global population and represents a major independent risk factor for heart failure (HF), particularly heart failure with preserved ejection fraction (HFpEF). Excess adiposity-especially visceral and epicardial adipose tissue (EAT)-acts as an active endocrine and immune organ, promoting chronic low-grade inflammation, oxidative stress, endothelial dysfunction, and adverse myocardial remodeling. Expanded EAT exerts both paracrine inflammatory effects and mechanical constraint on the myocardium, contributing to diastolic dysfunction, microvascular impairment, atrial arrhythmogenesis, and elevated filling pressures despite preserved systolic function. Evidence demonstrates a dose-response relationship between increasing body mass index and incident HF. Clinically, obesity-related HFpEF is characterized by concentric left ventricular hypertrophy, impaired relaxation, increased plasma volume, reduced exercise tolerance, and relatively low natriuretic peptide levels, complicating diagnosis. HF management includes traditional treatment with diuretics, renin-angiotensin system inhibitors, β-blockers, mineralocorticoid receptor antagonists, and angiotensin receptor-neprilysin inhibitors. These agents widely remain foundational as they primarily target hemodynamic and neurohormonal pathways in HF. In contrast, sodium-glucose cotransporter 2 inhibitors consistently reduce HF hospitalizations across the ejection fraction spectrum, while glucagon-like peptide-1 receptor agonists and dual incretin therapies (e.g., tirzepatide) promote substantial weight loss, improve symptoms, and demonstrate promising anti-remodeling effects in obesity-related HFpEF. Recognizing obesity-driven HF as a distinct cardiometabolic entity supports an integrated therapeutic strategy combining structured weight reduction with guideline-directed HF polypharmacotherapy to address both hemodynamic burden and upstream adiposity-related mechanisms.

Medical Nutrition in the Glucagon-Like Peptide-1 (GLP-1) Era: Protein Strategies, Micronutrient Monitoring, and Lean Mass Preservation.

Clin Nutr ESPEN

Sedat Arslan

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 agents produce substantial, sustained weight loss primarily by suppressing appetite and lowering ad libitum energy intake. While fat mass loss predominates, randomized trials with body-composition substudies indicate a clinically relevant reduction in absolute lean mass. Concurrently, baseline micronutrient inadequacies are common in people with obesity and may be exacerbated by reduced intake, nausea, or vomiting during therapy. This narrative review synthesizes evidence on energy/macronutrient dynamics, body-composition outcomes, and guideline-informed protein targets to present a practical, dietitian-led framework for care. We propose pragmatic energy floors to preserve micronutrient adequacy; daily protein intakes of ≥1.2 g/kg (up to 1.6 g/kg in appropriate adults without chronic kidney disease (CKD)) with meal-wise targets of ∼0.3-0.4 g/kg and ∼2.5-3 g leucine; a structured laboratory panel (vitamin D, B12, iron studies, folate, zinc, and thiamine in high-risk patients); and integration of progressive resistance training. We also outline monitoring schedules using dual-energy X-ray absorptiometry (DXA)/bioelectrical impedance analysis (BIA) and adaptations for special populations (older adults, type 2 diabetes, CKD, vegetarian/vegan, sarcopenic obesity). The goal is to preserve lean mass, prevent deficiencies, and optimize outcomes of GLP-1-based obesity pharmacotherapy.

[Wheat bran reduces oxidative stress and promotes glucagon-like peptide-1 secretion in high-fat-fed rats].

Wei Sheng Yan Jiu

Aisikaier Rukeye, Ting Shang, Kuerbanjiang Maierheba +5 more

This study aimed to investigate the effects of wheat bran intervention on oxidative stress status and glucagon-like peptide-1(GLP-1) secretion in rats fed a high-fat diet(HFD).

The novel PDE5 inhibitor CPD1 attenuates pulmonary arterial hypertension through dual modulation of cGMP and TRPM8-mediated pathways.

Bioorg Chem

Yunping Mu, Jinlin Sun, Xindan Zhang +7 more

Pulmonary arterial hypertension (PAH) remains a fatal condition with limited treatment options. While phosphodiesterase-5 (PDE5) inhibitors such as sildenafil and tadalafil are standard treatments, their therapeutic efficacy is limited by poor aqueous solubility and an incomplete understanding of the mechanisms underlying their long-term benefits on vascular remodeling. To overcome these critical limitations, we developed a novel, highly water-soluble potassium salt polymorph of a PDE5 inhibitor, designated CPD1. In a monocrotaline-induced rat model of PAH, CPD1 demonstrated superior in vivo efficacy. It dose-dependently alleviated key pathological hallmarks by significantly reducing pulmonary arterial pressure, reversing right ventricular hypertrophy, and inhibiting the remodeling of small muscular pulmonary arteries. At the vascular level, CPD1 significantly attenuated the enhanced contractile responses to endothelin-1, cyclopiazonic acid, and 1-oleoyl-2-acetyl-sn-glycerol in endothelium-denuded arteries. Mechanistically, we reveal a novel dual-pathway mechanism: in addition to elevating cyclic guanosine monophosphate (cGMP) through PDE5 inhibition, CPD1 uniquely and dose-dependently upregulates the expression of the transient receptor potential melastatin-8 (TRPM8) channel. This upregulation sensitizes the pulmonary vasculature, markedly enhancing vasodilation induced by TRPM8 activation. Our findings position CPD1 not merely as a more soluble PDE5 inhibitor but as a first-in-class agent that simultaneously modulates the cGMP pathway and the TRPM8 channel, offering a promising new therapeutic strategy to correct dysregulated calcium homeostasis and reverse vascular remodeling in PAH.

Using biomarkers to detect intramammary infections in dairy cows at dry-off.

Res Vet Sci

Lorenzo Viora, P Theo Pepler, Emily L O'Reilly +3 more

Prevention and treatment of intramammary infections (IMI) associated with subclinical mastitis (SCM) are among the leading reasons for antimicrobial usage (AMU) in dairy cows, especially at dry-off. By adopting a selective dry cow therapy ((S)DCT), only cows or quarters with a demonstrable risk of IMI would be treated and AMU would be decreased. Several tools have been proposed to identify cows for SDCT, including algorithms based on clinical mastitis and somatic cell count (SCC). The potential of milk proteins as biomarkers for IMI at dry-off has not been fully evaluated. In this study, biomarkers in 185 milk samples collected aseptically at drying off were quantified and their value in detecting IMI was evaluated (individually and in combination) in comparison to SCC and California Mastitis test using a case-control design with culture-based detection of IMI as gold standard comparator. Biomarkers quantified were lactoferrin, α-lactalbumin, haptoglobin, mammary amyloid A, C-reactive protein and cathelicidin. Of the six biomarkers examined, three had accuracies greater than 61% based on univariate biomarker trees (62%, 65% and 65% for haptoglobin, cathelicidin and milk amyloid A, respectively). A two-biomarker decision tree combining cathelicidin and milk amyloid A improved overall accuracy to 70% (sensitivity 72%, specificity 67%), comparable in performance to SCC, maintaining an acceptable level of sensitivity, but with greater specificity - an attribute desirable for SDCT. This performance highlights its potential use as a practical tool to reduce unnecessary antimicrobial treatments at dry-off, supporting selective dry cow therapy without compromising detection of infected quarters.

Preserving brain health in aging: structural and biochemical benefits of water based resistance training, a randomized controlled trial.

BMC Geriatr

Mahdiyeh Haj Hosseini, Masoumeh Baghalishahi, Mandana Moshrefi +7 more

Brain aging leads to structural changes, especially atrophy, which can result in dysfunction. Mitochondrial dysfunction is thought to explain the structural changes in brain aging.

The joint association of intrinsic capacity and physical activity with cardiovascular risk in older adults: evidence from four longitudinal cohorts.

BMC Geriatr

Zhengqiu Zhang, Ziyin Liu, Feng Ye +8 more