Microglia are the predominant resident innate immune cells of the brain that maintain homeostasis and mitigate damage caused by injury and pathogens. Synthetic variants of host defence peptides, also termed antimicrobial peptides, are designed based on their endogenous counterparts and have been demonstrated to exhibit enhanced immunomodulatory activities, including an ability to selectively modulate the release of cytokines by monocytic cells. These peptides exert therapeutic benefits in a murine brain injury model, but it is unknown whether they can modulate microglial immune responses. We tested the effects of three host defence peptides, namely innate defence regulators (IDR)-1002, IDR-1018 and D-3006, on selected functions of BV-2 murine microglial cells, as well as differentiated HL-60 monocytic cells, which were used as a human model of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) production. It was demonstrated here that IDR-1002, IDR-1018 and D-3006 reduced the production of nitric oxide, tumor necrosis factor-α (TNF), ROS, and cytotoxic factors, depending on whether the cells were stimulated with lipopolysaccharide (LPS), interferon (IFN)-γ, or their combination. All three IDRs also reduced LPS-induced phagocytic activity of BV-2 microglia, while IDR-1018 and D-3006 increased this function in unstimulated cells, though our findings are limited to cell lines and require validation in primary or human microglia. By altering selected inflammatory, cytotoxic, and phagocytic readouts of microglial cells in a context-dependent manner, synthetic host defence peptides such as IDRs warrant further investigation as candidate modulators of neuroinflammation, including in animal models of relevant neurological disorders.

The glucose-dependent insulinotropic polypeptide receptor (GIPR) has emerged as a central target in next-generation anti-obesity drug development. Its pharmacology, however, presents an apparent paradox: sustained GIPR agonism and GIPR antagonism can both lower body weight, and both can augment weight loss produced by glucagon-like peptide-1 receptor (GLP-1R) agonism. For this structured narrative review, PubMed/MEDLINE and ClinicalTrials.gov were searched from database inception through 1 August 2026 using prespecified terms for receptors, interventions, obesity, and bariatric surgery to identify basic, translational, and clinical studies available. Retrieved records underwent staged title/abstract screening and full-text eligibility assessment. The evidence was integrated across three levels: selective GIPR modulation, combined GIPR and GLP-1R modulation, and applications after metabolic and bariatric surgery. Recent rodent studies support a working model in which long-acting GIPR agonism engages GABAergic and area-postrema-related circuits, whereas the added weight-lowering effect of GIPR antagonism in several GLP-1R-containing combination models depends on intact GLP-1R signaling and hypothalamic GIPR networks. These mechanisms remain incompletely validated in humans. Clinically, tirzepatide has demonstrated the efficacy of GIPR/GLP-1R co-agonism, whereas maridebart cafraglutide provides phase 2 evidence for GIPR antagonism combined with GLP-1R agonism; nevertheless, the efficacy of these multi-receptor agents cannot be attributed simply to a single GIPR component. Metabolic and bariatric surgery is discussed as a translational context in which altered incretin physiology limits direct extrapolation from nonsurgical obesity trials. Future studies should use stratified designs grounded in receptor pharmacology, brain-region specificity, type of bariatric procedure, and postoperative metabolic phenotype, while assessing fat mass, lean mass, hepatic fat, bone metabolism, gastrointestinal tolerability, hypoglycemia, and weight regain after treatment withdrawal.

Antimicrobial peptides (AMPs) have garnered considerable attention as promising alternatives to conventional antibiotics, resulting in extensive experimental and computational studies that have generated large volumes of data on peptide sequences, biological activities, structural features, and experimental conditions. To organize and facilitate the use of these data, several AMP databases have been developed; however, they differ markedly in scope, data organization, annotation depth, searchability, data accessibility, usability, and support for computational analysis. In this review, we critically compare five widely used general AMP databases-APD, CAMP, DBAASP, dbAMP, and DRAMP-by analyzing database publications and directly evaluating their current data content, web interfaces, search systems, analytical tools, and suitability for different research workflows. The comparison shows that no single database fully addresses all research needs, as the resources offer complementary strengths in biological annotation, sequence and family analysis, experimental activity data, computational discovery, and therapeutic-development information. These findings highlight the need for more standardized and interoperable database strategies that improve data consistency, annotation quality, searchability, tool reliability, and the comparison, integration, and reuse of AMP data in experimental and computational research.

The BMP7-derived peptide p[63-82] improves a healthy chondrocyte phenotype and attenuates chondrocyte hypertrophy in human osteoarthritic chondrocytes. In cartilage regeneration strategies, chondrogenic differentiation of progenitor cells is often hampered by hypertrophic differentiation of the newly formed cartilaginous tissue. In this study, we explored the pro-chondrogenic and anti-hypertrophic effects of peptide p[63-82] in different progenitor-based chondrogenic differentiation models. Chondrogenic differentiation was induced in ATDC5 cells, human bone marrow-derived stem cells (hBMSCs), and rabbit periosteal progenitor cells (rPCs) in the absence or presence of peptide p[63-82]. In all models, increased gene expression of Sox9, Nkx3.2, Col2a1, Acan and GAG content was observed in the peptide p[63-82] condition, indicative of a pro-chondrogenic effect. Expression of hypertrophic genes Runx2, Col10a1, Alpl and Rmrp and ALP enzyme activity were prevented by the p[63-82] peptide-exposed cultures. Nkx3.2 signaling is, partly, responsible for the observed p[63-82] effects. The peptide p[63-82] was thus able to promote a chondrogenic phenotype, whilst preventing the development of chondrocyte hypertrophy in ATDC5 cells, hBMSCs and rPCs. The p[63-82] peptide could be a promising candidate for optimizing cell-based cartilage repair strategies after validation in in vivo models.

The comorbidity burden of obesity and cardiovascular disease (CVD) is escalating globally. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been consistently demonstrated to reduce the risk of major adverse cardiovascular events (MACE) significantly, it remains unclear whether their cardiovascular benefits are entirely mediated by weight loss. This review synthesizes current clinical evidence supporting the weight-loss-independent cardiovascular protection of GLP-1RAs in patients with obesity and CVD, with a focus on the underlying molecular mechanisms, thereby providing a foundation for future mechanistic research and precise clinical application. Analysis of major cardiovascular outcome trials (CVOTs), including LEADER, SUSTAIN-6, and SELECT, and their prespecified subgroup analyses reveals that GLP-1RAs exhibit consistent cardiovascular benefits across different baseline body mass index (BMI) subgroups. Exploratory mediation analyses suggest that 35%-55% of these benefits may not be explained by weight loss; however, these estimates depend on model assumptions and do not establish a causal pathway. Mechanistic studies support that GLP-1RAs exert cardiovascular protection through multiple weight-loss-independent pathways, including preservation of endothelial function, anti-atherosclerotic effects, preclinically supported direct myocardial protection with ongoing disputes regarding human translation, anti-inflammation and immunomodulatory effects, and improved microcirculatory perfusion. In conclusion, GLP-1RAs have demonstrated cardiovascular protective effects in patients with obesity and CVD, and a proportion of these benefits may be attributable to mechanisms beyond weight reduction. Future rigorously designed clinical trials are warranted to further validate these pathways, clarify the tissue-specific functions of GLP-1 receptors, and identify novel molecular targets.

Stress-related dysregulation of the brain-gut axis may help explain the frequent co-occurrence of gastrointestinal disorders and neuropsychiatric phenotypes, including anxiety and depression. Acute and chronic stress can alter gastrointestinal motility, visceral sensation, mucosal barrier integrity, and central affective circuits through the hypothalamic-pituitary-adrenal (HPA) axis, the autonomic nervous system (ANS), immune and inflammatory signaling, and changes in gut microbial ecology. Galanin is distributed across central stress-related nuclei, the enteric nervous system, visceral afferent pathways, and mucosal immune cells, positioning the galanin system as a potential integrator of bidirectional brain-gut signaling. This review examines the expression, receptor biology, and regulatory actions of galanin and its three receptors-galanin receptor 1 (GalR1), galanin receptor 2 (GalR2), and galanin receptor 3 (GalR3)-in stress-induced brain-gut axis dysregulation, while galanin-like peptide (GALP) and spexin provide additional endogenous-ligand context for interpreting GalR pharmacology. The galanin system is neither uniformly protective nor uniformly detrimental. Its functional effects depend on ligand identity, receptor subtype, cell type, anatomical site, stress stage, and inflammatory state, as well as receptor complexes and downstream signaling bias. This context-dependent framework may help identify settings in which galanin-pathway modulation is most mechanistically plausible according to stress stage, inflammatory status, visceral sensitivity, and barrier function. Future studies should prioritize subtype-directed, tissue-restricted, and signaling-biased strategies while maintaining a clear distinction between experimental pharmacological utility, preclinical therapeutic potential, and clinical applicability.

Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of metabolic dysfunction-associated steatotic liver disease, is characterized by hepatocellular injury, chronic inflammation, and fibrosis, yet effective antifibrotic therapies remain limited. The urotensin II (UII)/urotensin II receptor (UTR) system has been implicated in injury and tissue remodeling in several chronic liver conditions, but its role in MASH remains unclear. We examined KR-36996, an orally active UTR antagonist, in a methionine- and choline-deficient (MCD) diet-induced mouse model of fibrosing steatohepatitis. Male C57BL/6 mice were fed the MCD diet for 4 weeks and treated orally with KR-36996 at 30 mg/kg/day. Liver injury, steatosis, inflammation, fibrosis, hepatic UII/UTR expression, and MAPK signaling were assessed by serum biochemistry, histology, immunohistochemistry, RT-qPCR, and Western blotting. KR-36996 reduced serum alanine aminotransferase and aspartate aminotransferase levels and attenuated hepatic inflammation, with fewer inflammatory foci, reduced F4/80-positive macrophage accumulation, and lower Il1b, Ccl2, and Tnf expression. It also decreased collagen deposition, α-smooth muscle actin immunoreactivity, and the fibrogenic markers Col1a1 and Timp1. MCD feeding increased hepatic UII and UTR protein levels and enhanced JNK phosphorylation; KR-36996 reduced JNK phosphorylation, whereas ERK and p38 phosphorylation remained unchanged. These findings indicate that UTR antagonism primarily attenuates inflammatory and fibrogenic responses, whereas evidence for an antisteatotic effect was limited in this model, and support further evaluation of the UII/UTR axis as a potential therapeutic target for the inflammatory and fibrotic components of steatohepatitis.

Acute pancreatitis is an inflammatory disease of the pancreas characterized by oxidative stress and apoptotic cell death. Phoenixin-14 (PNX-14) is an endogenous neuropeptide suggested to regulate these processes in peripheral tissues. This study investigated the protective effects of PNX-14 against L-arginine-induced acute pancreatitis by evaluating inflammatory, oxidative stress, and apoptotic responses. Twenty-eight rats were divided into three groups: control (n = 8), L-arginine (n = 10), and L-arginine + PNX-14 (n = 10). The control group received saline(0, 1, and 2 h); the L-arginine group received L-arginine(250 mg/100 g; 1 and 2 h); and the L-arginine + PNX-14 group received L-arginine(250 mg/100 g; 1 and 2 h)and PNX-14(50 µg/kg; 0 and 2 h), all administered intraperitoneally. Serum and pancreatic tissue levels of IL-1β, IL-6, and IL-10 were measured using ELISA. Pancreatic tissue levels of SOD, MDA, and MPO were also determined by ELISA. Serum amylase, lipase, and glucose levels were measured using standard biochemical methods. Histopathological damage was assessed, and apoptosis was evaluated using TUNEL assay and caspase-3 immunohistochemistry. PNX-14 reduced serum IL-1β and IL-6 levels and increased serum IL-10 levels (p < 0.05), whereas pancreatic tissue IL-10 levels were significantly reduced following PNX-14 treatment (p < 0.05). Moreover, PNX-14 decreased the levels of amylase and lipase. The treatment group had significantly lower glucose levels than the control group (p < 0.05). PNX-14 treatment significantly increased SOD levels and decreased MPO levels (p < 0.05), while MDA levels showed a decreasing trend that did not reach statistical significance. Furthermore, PNX-14 significantly reduced histopathological pancreatic damage and caspase-3 immunoreactivity (p < 0.05). Overall, these findings suggest that PNX-14 exerts protective effects against acute pancreatitis by attenuating inflammation, oxidative stress, and apoptosis in pancreatic tissue.

This paper is the forty-eighth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2025 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).

Sulfakinin (SK) peptides are the insect members of the ancient cholecystokinin (CCK)/gastrin superfamily, defined by a sulfated tyrosine near the C-terminus and a C-terminally amidated heptapeptide core, the modifications essential for receptor activity. Although SK peptides share C-terminal similarity with vertebrate CCK-8 and gastrin, this homology is pharmacologically incomplete: both Drosophila sulfakinin receptors cluster in an arthropod-specific clade absent from vertebrate receptor families, and cross-species bioassays confirm receptor-level incompatibility. This review synthesizes current knowledge of SK structure, receptor biology, signal transduction, and physiological function across insect orders to evaluate the SK-receptor axis with emphasis on factors that may guide future pest-management applications. SKR complement ranges from one gene in Hymenoptera and Lepidoptera to two paralogous receptors in several Diptera and Coleoptera, arising from independent lineage-specific duplications. Both Ca²⁺ and cAMP second messenger arms are engaged in species-dependent combinations governed by G-protein coupling selectivity. SK peptides regulate meal termination, fat body lipid and glycogen metabolism, ecdysteroid-mediated moulting, reproductive behaviour, and agonistic signalling, with these functions partitioned among specific receptor subtypes, neural circuits, and peripheral tissues. In laboratory studies of economically significant pest species, RNAi-mediated SK-receptor silencing disrupts feeding, development, and fecundity, whereas biostable peptidomimetics represent a promising but still exploratory chemical approach. Receptor coupling identity in phytophagous crop pests, validated field-compatible dsRNA delivery, and ecological safety remain major unresolved barriers to practical application.

The glucose-dependent insulinotropic polypeptide receptor (GIPR) is a class B1 G protein-coupled receptor (GPCR) that promotes glucose-dependent insulin secretion upon activation by GIP. Dual agonism of GIPR and glucagon-like peptide-1 receptor (GLP-1R) has emerged as a breakthrough therapeutic strategy for type 2 diabetes and obesity, improving glycaemic control and promoting weight loss. Although GIPR is widely expressed in the central nervous system, endogenous GIP expression in the brain is controversial, and peripherally-administered fluorescent GIPR/GLP-1R agonists predominantly localise to circumventricular organs, suggesting a lack of GIP-ligand for receptors shielded by the blood-brain barrier. Here, we considered the existence of alternative endogenous ligands for GIPR, potentially modulated by receptor activity-modifying proteins (RAMPs). Ligand activity was profiled at heterologously expressed human GIPR using cAMP accumulation, calcium mobilisation, and cAMP inhibition assays. Among the 42 ligands tested, glicentin was the only non-proGIP-derived peptide to elicit a cAMP response at GIPR (EC50 = 877 nM). No ligand-induced calcium mobilisation or cAMP inhibition was observed. Glicentin also activated human GLP-1R and glucagon receptor (GCGR), with receptor-specific antibody blockade reducing potency by 10-20-fold at all three receptors. Glicentin's activity was conserved at rodent GIPRs, albeit with reduced potency. Co-expression with RAMP2 or RAMP3 attenuated cAMP responses to GIPR-active ligands, including glicentin, but did not affect other ligands tested. These findings show that the GIPR is highly selective and identifies glicentin as a low-potency, cross-reactive agonist at GIPR, GLP-1R and GCGR, although its high EC50 makes it unlikely to act as a physiological ligand under basal conditions.

Appetite regulation in vertebrates involves central neuropeptides and peripheral metabolic and endocrine signals that act together to maintain energy homeostasis. These include orexigenic (e.g., neuropeptide Y, orexin, ghrelin) and anorexigenic (e.g., cocaine- and amphetamine-regulated transcript, corticotropin-releasing factor, cholecystokinin, leptin) factors coordinate feeding behavior. Intelectin-1 (ITLN1), a protein implicated in innate immunity and metabolic signaling in mammals, has not yet been investigated in the context of fish feeding physiology. This study examined the potential role of ITLN1 in appetite regulation and energy metabolism in goldfish (Carassius auratus). We first determined tissue distribution of itln1, which showed highest mRNA levels in spleen and liver and lower expression in brain, intestine, kidney, and gonads. Short-term fasting reduced itln1 expression in the hypothalamus and intestine, but not in liver. Peripheral administration of recombinant human ITLN1 (250-500 ng/g) significantly reduced food intake without altering blood glucose. At the highest dose (500 ng/g), ITLN1 increased brain expression of anorexigenic neuropeptides cart1, crf, trh, cck and lep2, intestinal expression of cck and inflammatory markers (tnfa, il1b) and hepatic lep2 and glycogen synthase (gs) expressions, with no effect on orexigenic peptides or glucose transporters. These findings suggest that ITLN1 might act as a peripheral satiety signal in goldfish, modulating the expression of anorexigenic neuropeptides, gut hormones, and hepatic metabolic genes. This study provides initial evidence that ITLN1 may contribute to appetite regulation in a teleost, suggesting a potential role in coordinating immunity, nutrient metabolism, and central pathways involved in feeding.