Search Results (74)

The current known data on the involvement of the peptidergic systems in breast cancer progression is overwhelmingly vast. Peptidergic systems are useful tools for imaging, diagnosis, prognosis and treatment of breast cancer. These systems play a crucial role in both basic and clinical breast cancer research by enabling the exploration of novel molecular mechanisms, signaling pathways, and the development of effective drug design strategies. Breast cancer cells overexpress peptide receptors; at the same time they are known to interact with peptides that (a) exert an oncogenic action (adrenomedullin 2, endothelin, gastrin-releasing peptide, neurokinin A, neuromedin, neuropeptide Y, neurotensin, substance P, vasoactive intestinal peptide), (b) exert an anticancer action (angiotensin (1–7), ghrelin, peptide YY) or (c) exert dual oncogenic and anticancer effects (adrenomedullin, angiotensin II, bradykinin, corticotropin-releasing factor, β-endorphin, glucagon-like peptide 1, gonadotropin-releasing hormone, kisspeptin, methionine-enkephalin, oxytocin). This indicates that peptides, as well as peptide receptor agonists and antagonists, may serve as antitumor agents due to their diverse actions against breast cancer development, including the inhibition of cell proliferation, migration and invasion, induction of apoptosis, and anti-angiogenesis. Multiple strategies have been developed to combat breast cancer, including peptide receptor silencing; antibodies conjugated to specific signaling proteins; antibodies targeting specific peptide receptors or oncogenic peptides; and the use of peptides or peptide receptor agonists/antagonists loaded with antitumor cargo. Future lines of research are suggested in breast cancer using promising anti-breast-cancer peptide receptor antagonists (HOE-140, exendin (9–39), bosentan, macitentan, PD168,368, CGP71,683A, SR48,692, aprepitant) or agonists (FR190,997, semaglutide, exendin 4, goserelin) mentioned in this review. Peptidergic systems have tremendous anti-breast-cancer clinical potential which must be exploited and developed. Taken together, the available data highlight the enormous promise of translational research into breast cancer and peptidergic systems for the development of effective treatments. A full understanding of the roles played by the peptidergic systems in breast cancer will serve to improve diagnosis and treatment. Full article

We developed and validated a capillary electrophoresis (CE) method for the separation of two opioid–neurotensin hybrid peptides, recently presented as potent analgesics being decapeptides with a hybridic nature (i.e., H-Dmt-D-Lys-Phe-Phe-Lys-Lys-Pro-Phe-Tle-Leu-OH; PK20 and its structural analogue H-Dmt-D-Lys-Phe-Phe-Lys-Lys-Pro-Phe-Ile-Leu-OH; [Ile9]PK20). As these two chimeras differ by only one amino acid, Tle→Ile, and are characterized by possessing the same molecular weight while having different spatial conformations, the aim of the study was to determine their potential separation in terms of the presence of any differences resulting from this structural modification. The separation process was performed using an eCAP fused silica capillary at a detection wavelength of 200 nm in 25 mM phosphate buffer at pH 2.5. The analysis was performed at 25 °C and 10 kV. The developed method was validated by assessing linearity in the concentration range from 50 to 5000 ng/mL. Very good linearity was obtained, with the coefficient of determination (R²) ranging from 0.9991 to 0.9999 for both analyzed derivatives. The method demonstrated baseline resolution (Rs = 1.4). The limit of quantification ranged from 34.72 ng/mL to 34.98 ng/mL. The recoveries of all derivatives ranged from 94.8% to 100%. The total analysis time was only 6 min. The developed method enables the determination of PK20 and [Ile9]PK20 derivatives both in aqueous solutions and in serum. Full article

Background/Objectives: This pilot study aimed to investigate the relationship between salivary neuropeptides levels, adverse childhood experiences (ACEs), and altruism in a sample of medical students. Additionally, the study examined potential sex differences in these relationships. Methods: Sixty medical students (36.6% men, 63.3% women) provided saliva samples to measure oxytocin, α-MSH, β-endorphin, neurotensin, and substance P using a custom 5-plex human peptide assay. Participants completed the ACE Survey and Compassionate Love Scale for Humanity (CLS-H) Altruism Survey. Descriptive statistics characterized demographics and survey data, with out-of-range values adjusted to the standard curve maximum. Data normality was assessed with the Jarque–Bera test; due to non-normality, values were log-transformed. Differences between male and female salivary, ACE score, and CLS-H altruism score were tested using t-tests and Mann–Whitney U-tests, while correlations were evaluated with Pearson and Spearman coefficients. Results: The five neuropeptides, while highly correlated with each other, did not exhibit significant relationships with altruism, as measured by the CLS-H Altruism Survey. Finally, female participants demonstrated greater altruistic tendencies compared with male participants with marginal significance. Conclusions: While there were no significant relationships between the fives neuropeptides, ACEs, or altruism; women demonstrated higher levels of altruism compared with men. The data reported in this pilot study did not strongly support the conclusion that neuropeptides influence social behavior and trauma response. Furthermore, future studies with larger, more diverse samples and multiple time point measurements of neuropeptides could be beneficial to better understand the relationships between neuropeptides and any potential implications for mental health interventions. Full article

Artificial sweeteners, or non-caloric sweeteners (NCSs), are widely consumed as sugar substitutes to reduce energy intake and manage obesity. Once considered inert, accumulating evidence now shows that NCSs interact with host physiology, altering gut microbiota composition and neural circuits that regulate feeding. This review synthesizes current knowledge on how NCSs disrupt the gut–brain axis (GBA), with particular focus on microbiota-mediated effects and neural reward processing. In homeostatic regulation, NCS-induced dysbiosis reduces beneficial taxa such as Akkermansia muciniphila and Faecalibacterium prausnitzii, diminishes short-chain fatty acid production, impairs gut barrier integrity, and promotes systemic inflammation. These changes blunt satiety signaling and favor appetite-promoting pathways. Beyond homeostasis, NCSs also rewire hedonic circuits: unlike caloric sugars, which couple sweet taste with caloric reinforcement to robustly activate dopaminergic and hypothalamic pathways, NCSs provide sensory sweetness without energy, weakening reward prediction error signaling and altering neuropeptidergic modulation by orexin, neurotensin, and oxytocin. Microbial disruption further exacerbates dopaminergic instability by reducing precursors and metabolites critical for reward regulation. Together, these top-down (neural) and bottom-up (microbial) mechanisms converge to foster maladaptive food seeking, metabolic dysregulation, and increased vulnerability to overeating. Identifying whether microbiome-targeted interventions can counteract these effects is a key research priority for mitigating the impact of NCSs on human health. Full article

Background/Objectives: Receptor-mediated transcytosis utilizing the native transporters at the blood–brain barrier (BBB) is a growing strategy for the delivery of therapeutics to the brain. One of the major challenges in identifying appropriate human transcytosis targets is that there is a species-specific transporter expression profile at the BBB, complicating translation of successful preclinical candidates into humans. In an effort to overcome this obstacle and identify proteins capable of binding human-relevant BBB ligands, we generated and screened a BBB-targeting library against human-induced pluripotent stem cell-derived brain microvascular endothelial-like cells (iPSC-derived BMEC-like cells). As targeting molecules, we used lamprey antibodies, known as variable lymphocyte receptors (VLRs), and generated a VLR library by immunizing lamprey with iPSC-derived BMEC-like cells, and inserting the resultant VLR repertoire into the yeast surface display system. Methods: The yeast displayed VLR library was then panned against human iPSC-derived BMEC-like cells and lead VLRs were validated using human in vitro models and mouse and human ex vivo brain tissue sections. Results: Finally, brain uptake for a set of VLRs was validated in mice. Of the 15 lead VLR candidates, 14 bound to human BBB antigens, and 10 bound to the murine BBB. Pharmacodynamic testing using the neuroactive peptide neurotensin indicated that the lead candidate, VLR2G, could cross the mouse BBB after intravenous injection and deliver sufficient neurotensin payload to generate a pharmacological response and lower systemic body temperature. Conclusions: Together, these results demonstrate the application of a novel screening technique capable of identifying a VLR with human relevance that can cross the BBB and deliver a payload. Full article

Objective: Pain response scores were evaluated by associating pain biomarkers with several parameters affecting radiotherapy (RT)-induced pain response in patients with bone metastases. Methods: A newly developed ‘revised pain and response scale’ based on standardized scales was used for pain scoring. TRPV1, β-endorphin (bEP), neurotensin (NT), and orexin A (OXA) biomarkers were determined by ELISA before and after RT. Results: Pain response rates were 44.75% (n = 47) poor response, 10.5% (n = 11) moderate response, 44.75% (n = 47) good response. NLR before RT was higher in patients with poor response than those with good response (4.0 (1.3–36.7) vs. 2.6 (1.2–11.4), respectively (p = 0.036). NLR after RT was lower in patients with good response than in patients with poor response (3.1 (1.2–10.8) and 3.9 (0.8–37.2), respectively (p = 0.047). There was a significant correlation between response scores and NT, bEP, and TRPV1. In patients with good response, NT and bEP decreased, while TRPV1 increased, both of which were significant. Pre-RT and post-RT values were, respectively, NT: 631.4 (39.7–2863.0) vs. 400.3 (79.1–1479.0) p = 0.006) and bEP: 92.1 (18.7–228.8) vs. 49.1 (13.3–135.6) p ≤ 0.001). TRPV1 values: 321.7 (48.1–1100.7) vs. 352.8 (119.3–1510.9) p ≤ 0.001). Conclusions: The study found no difference in pain response scores between the different fractionation treatments. Significant changes in NT, bEP, and TRPV1 levels were seen in patients with a ‘good response’. Pain response ratings were potentially least affected by OXA. Changes in NT, TRPV1, and bEP levels represent RT’s pain response efficacy and patients’ pain perception. These pain biomarkers may be included in guidelines as part of pain response monitoring strategies in the future. Full article

Introduction: Prolonged fasting induces histological and ultrastructural changes of the intestinal mucosa that may reduce absorption in malnourished patients with high risk of refeeding syndrome. Endocrine function of the intestinal mucosa may be affected by starvation with potential implications for nutritional support. Objective: The present study aims to evaluate the expression of gastrointestinal hormones in duodenal enteroendocrine cells (EECs) of patients after a long starvation period and to assess the changes in EEC hormonal expression after enteral refeeding in the same individuals. Methods: This was an observational prospective controlled study. Adult patients submitted to endoscopic gastrostomy (PEG) with an ingestion below 50% of daily needs for at least one month were enrolled. Duodenal biopsies were collected before gastrostomy (T0) and after 3–6 months of PEG feeding (T1). Biopsies underwent immunohistochemical analysis for chromogranin-A (CgA), neurotensin and incretin (GLP-1 and GIP) tissue expression. Normal duodenum biopsies were used as controls. Results: A total of 30 patients (16 men/14 women) aged 67.1 ± 13.5 years were included, and 14 patients completed follow-up at both periods (46.7%). Malnutrition was diagnosed in all patients according to GLIM criteria. T0 tissue expression defined by median stained area for CgA, GLP-1, and GIP were significantly higher in patients compared to controls (CgA: 1.04% vs. 0.41%; GLP-1: 0.17% vs. 0.03%; GIP: 0.19% vs. 0.03%) (p < 0.001) without differences for neurotensin (0.01%) (p = 0.96). T1 hormonal tissue expression was not significantly reduced after 3–6 months of enteral refeeding (p > 0.05). Conclusions: Prolonged fasting induces increased expression of incretins and chromogranin-A in the duodenum that probably reflect an adaptative response to maintain the anabolic insulin effect under nutritional deficiency. Hormonal expression does not normalize after PEG refeeding during a short period. Full article

Diabetes represents one of the major challenges in preserving health in the 21st century. It has been estimated that in 2050, 853 million subjects will live with diabetes. It was also reported that 3.4 million adults died from diabetes and related comorbidities. Chronic hyperglycemia, if not properly managed, leads to skeletal fragility with fracture risk that augments with age. In type 1 diabetes (T1D), the augmented fracture risk can be partially explained by lower areal bone mineral density (aBMD). Interestingly, in type 2 diabetes (T2D), the risk of fractures increases with normal or elevated aBMD. In this review, the recent updates on diabetes and bone health (2023–2025) are reported, thus describing bone quality and the role of mediators involved in diabetes pathogenesis. Consequently, the role of Vitamin D, Incretins, Glucagon-like peptide-2 (GLP-2), neurotensin, asprosin, irisin, and Thioredoxin-interacting protein (TXNIP) will be described considering the interplay between diabetes and bone health. The importance of monitoring diabetic patients’ bone health is underlined, together with the therapeutic approaches to avoid fractures. Full article

Background/Objectives: Neurotensin receptors (NTSRs), members of the G protein-coupled receptor (GPCR) family, have been found to be overexpressed in several types of human cancers, including breast, colon, lung, liver, prostate, and pancreatic cancer. In particular, NTSR1 is overexpressed in at least 75% of pancreatic ductal adenocarcinomas. The aim of the present study was the development and evaluation of new ^99mTc-labeled nonpeptide NTSR1-antagonists for SPECT imaging of NTSR-positive tumors. Methods: Multistep syntheses of NTSR1 antagonist derivatives were performed following our previously described procedure. Two different chelating strategies were applied for ^99mTc radiolabeling to provide the [^99mTc]Tc-HYNIC complex [^99mTc]1 and the [^99mTc]Tc-tricarbonyl complex [^99mTc]2. Receptor binding assays were performed using hNTSR1-expressing CHO cells. Radiochemical yields (RCYs) were determined by radio-HPLC. For [^99mTc]1 and [^99mTc]2, log D_7.4, plasma protein binding, stability in human plasma and serum, and cellular uptake in HT-29 cells were determined. Biodistribution studies and small animal SPECT studies were performed in HT-29 tumor-bearing nude mice. Results: The radiosynthesis of [^99mTc]1 (log D_7.4 = −0.27) and [^99mTc]2 (log D_7.4 = 1.00) was successfully performed with RCYs of 94–96% (decay-corrected). Both radioligands were stable in human serum and plasma, showed plasma protein binding of 72% ([^99mTc]1) and 82% ([^99mTc]2), and exhibited high and specific uptake in HT-29 cells. Biodistribution studies in HT-29 tumor-bearing mice showed a higher tumor accumulation of [^99mTc]1 compared to [^99mTc]2 (8.8 ± 3.4 %ID/g vs. 2.7 ± 0.2 %ID/g at 2 h p.i.). [^99mTc]2 showed exceptionally high intestinal accumulation (49 ± 22 %ID/g at 1 h p.i.) and was therefore considered unfavorable. In the SPECT/CT imaging of HT-29 tumor xenografts, [^99mTc]1 showed a higher NTSR1-specific tumor uptake than [^99mTc]2 at all time points after tracer injection, with 12 ± 2.8 %ID/g for [^99mTc]1 vs. 3.1 ± 1.1 %ID/g for [^99mTc]2 at 4 h p.i. and adequate tumor-to-background ratios. Conclusions: In particular, the [^99mTc]Tc-HYNIC ligand ([^99mTc]1) showed promising preclinical results, being a potential candidate for SPECT imaging and, therefore, appropriate for translation into the clinic. Full article

Polymer coatings as thin films stand out as a commonly used strategy to modify biosensor surfaces for improving detection performance; however, nonspecific biomolecule interactions and the limited degree of ligand conjugation on the surface have necessitated the development of innovative methods for surface modification. To this end, methacrylated tethered telechelic polyethylene glycol (PEG-diMA) chains of three different molecular weights (2, 6, and 10 kDa) were synthesized herein and used for obtaining thiolated nanoparticles (NPs) upon adding excess amounts of a tetra-thiol crosslinker. Characterized according to their size, surface charge, morphology, and thiol amounts, these nanoparticles were immobilized on gold surfaces that mimicked gold-coated mass sensor platforms. The PEG-based nanoparticles, prepared especially by PEG6K-diMA polymers, were shown to result in the preparation of a monolayer and smooth coating of 80–120 nm thickness. Cysteine-modified NTS(8–13) peptide (RRPYIL) was conjugated to thiolated NP with reversible disulfide bonds and it was demonstrated that its cleavage with a reducing agent such as dithiothreitol (DTT) restores the NP-immobilized gold surface for at least two cycles. Together with its binding studies to NTSR2 antibodies, it was revealed that the peptide-conjugated NP-modified gold surface could be employed as a model for a reusable sensor surface for the detection of biomarkers of same or different types. Full article

The peptidergic systems are involved in neuroblastoma. Peptides (angiotensin II, neuropeptide Y, neurotensin, substance P) act as oncogenic agents in neuroblastoma, whereas others (adrenomedullin, corticotropin-releasing factor, urocortin, orexin) exert anticancer effects against neuroblastoma. This plethora of peptidergic systems show the functional complexity of the mechanisms regulated by peptides in neuroblastoma. Peptide receptor antagonists act as antineuroblastoma agents since these compounds counteracted neuroblastoma cell growth and migration and the angiogenesis promoted by oncogenic peptides. Other therapeutic approaches (signaling pathway inhibitors, focal adhesion kinase inhibitors, peptide receptor knockdown, acetic acid analogs) that also counteract the beneficial effects mediated by the oncogenic peptides in neuroblastoma are discussed, and future research lines to be developed in neuroblastoma (interactions between oncogenic and anticancer peptides, combination therapy using peptide receptor antagonists and chemotherapy/radiotherapy) are also suggested. Although the data regarding the involvement of the peptidergic systems in neuroblastoma are, in many cases, fragmentary or very scarce for a particular peptidergic system, taken together, they are quite promising with respect to potentiating and developing this research line with the aim of developing new therapeutic strategies to treat neuroblastoma in the future. Peptidergic systems are potential and promising targets for the diagnosis and treatment of neuroblastoma. Full article

Background/Objectives: Radiotheranostics of neurotensin subtype 1 receptor (NTS₁R)-expressing tumors, like pancreatic, gastrointestinal, or prostate cancer, has attracted considerable attention in recent years. Still, the fast degradation of neurotensin (NT)-based radioligands, by angiotensin-converting enzyme (ACE), neprilysin (NEP), and other proteases, has considerably compromised their efficacy. The recently introduced [^99mTc]Tc-DT11 (DT11, N₄-Lys(MPBA-PEG4)-Arg-Arg-Pro-Tyr-Ile-Leu-OH; N₄, 6-(carboxy)-1,4,8,11-tetraazaundecane) has displayed promising uptake in NTS₁R-positive tumors in mice and enhanced resistance to both ACE and NEP by virtue of the lateral MPBA-PEG4 (MPBA, 4-(4-methylphenyl)butyric acid; PEG4, 14-amino-3,6,9,12-tetraoxatetradecan-1-oic acid) chain attached to the ε-NH₂ of Lys⁷. We were next interested in investigating whether these qualities could be retained in DT14D, likewise modified at Lys⁷ but carrying the universal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) via a (βAla)₃ spacer at the α-NH₂ of Lys⁷. This chelator switch enables the labeling of DT14D with a wide range of trivalent radiometals suitable for true theranostic applications, not restricted to the diagnostic imaging of NTS₁R-positive lesions only by single-photon emission computed tomography (SPECT). Methods: DT14D was labeled with Ga-67 (a surrogate for the positron emission tomography radionuclide Ga-68), In-111 (for SPECT), and Lu-177 (applied in radiotherapy). The resulting radioligands were tested in NTS₁R-expressing pancreatic cancer AsPC-1 cells and mice models. Results: [⁶⁷Ga]Ga/[¹¹¹In]In/[¹⁷⁷Lu]Lu-DT14D displayed high affinity for human NTS₁R and internalization in AsPC-1 cells. They remained >70% intact 5 min after entering the mice’s circulation, displaying NTS₁R-specific uptake in AsPC-1 xenografts. Conclusions: Suitably side-chain modified NT analogs show enhanced metabolic stability and hence better prospects for radiotheranostic application in NTS₁R-positive cancer. Full article

Afferent vagal neurons convey gut–brain signals related to the mechanical and chemical sensing of nutrients, with the latter also mediated by gut hormones secreted from enteroendocrine cells. Cell bodies of these neurons are located in the nodose ganglia (NG), with the right NG playing a key role in metabolic regulation. Notably, glucagon-like peptide-1 receptor (GLP1R) neurons primarily innervate the muscle layer of the stomach, distant from glucagon-like peptide-1 (GLP-1)-secreting gut cells. However, the co-expression of gut hormone receptors in these NG neurons remains unclear. Using RNAscope combined with immunohistochemistry, we confirmed GLP1R expression in a large population of NG neurons, with Glp1r, cholecystokinin A receptor (Cckar), and Neuropeptide Y Y2 Receptor (Npy2r) being more highly expressed in the right NG, while neurotensin receptor 1 (Ntsr), G protein-coupled receptor (Gpr65), and 5-hydroxytryptamine receptor 3A (5ht3a) showed equal expressions in the left and right NG. Co-expression analysis demonstrated the following: (i) most Glp1r, Cckar, and Npy2r neurons co-expressed all three receptors; (ii) nearly all Ntsr1- and Gpr65-positive neurons co-expressed both receptors; and (iii) 5ht3a was expressed in subpopulations of all peptide-hormone-receptor-positive neurons. Retrograde labeling demonstrated that the anterior part of the stomach was preferentially innervated by the left NG, while the right NG innervated the posterior part. The entire gastrointestinal (GI) tract, including the distal colon, was strongly innervated by NG neurons. Most importantly, dual retrograde labeling with two distinct tracers identified a population of neurons co-expressing Glp1r, Cckar, and Npy2r that innervated both the stomach and the colon. Thus, neurons co-expressing GLP-1, cholecystokinin (CCK), and peptide YY (PYY) receptors, predominantly found in the right NG, sample chemical, nutrient-induced signals along the entire GI tract and likely integrate these with mechanical signals from the stomach. Full article

Background/Objectives: Obesity is linked to a higher risk of cognitive impairment. The objective of this single blind randomized trial was to evaluate the impact of dark sweet cherry (DSC) intake on cognitive function in obese adults. Methods: Participants (body mass index (BMI): 30–40 kg/m², >18 years, without chronic diseases and/or antibiotic use) consumed 200 mL of DSC drink with 3 g of cherry powder (n = 19) or an isocaloric placebo drink (n = 21) twice daily for 30 days. Cognitive function was assessed at Day 1 (D1) and Day 30 (D30) using standardized cognitive tests and the NeuroTracker (NT) 3D training program. Blood biomarkers related to cognitive health (neurotensin, substance p, and oxytocin) and circadian rhythm (melatonin and cortisol) were assessed at D1 and D30 using a Luminex multiplex bead-based immunoassay. Results: DSC supplementation significantly improved working memory and concentration, as indicated by higher scores in the digit span forward (DSF, p = 0.006) and backward (DSB, p = 0.01) tests. However, processing speed, sustained attention, and visual spatial skills, assessed through the trail making (TMT) and digit symbol substitution (DSST) tests, as well as visual cognitive performance (VCP) evaluated by the NT program, showed no significant differences between groups. Neurotensin, associated with cognitive deficits, increased in both cherry and placebo groups but was significant only in the placebo group (p = 0.007). Similarly, melatonin increased in both groups, reaching significance only in the placebo group (p = 0.02), and it correlated positively with IFNγ, suggesting a compensatory response to inflammation. Conclusions: These findings suggest DSC supplementation may enhance specific cognitive functions in obese adults. Further clinical trials are needed to confirm these results. Full article

Neurotensin (NT) is a peptide involved in digestion, neuromodulation, and cancer progression. NT and its receptors (NTR1 and SORT1 mainly) have been widely studied in oncology. Data show that NT expression is under the control of sex steroid hormones, in particular estradiol. We focused on its involvement in three main female hormone-sensitive cancers, breast, ovarian, and endometrial cancer, in a narrative review. NT, NTR1, and SORT1 are mostly expressed in these three cancers, and their involvement in oncologic processes such as proliferation and invasion seems to match, as does their impact on prognosis for most. The development of NT receptor-targeted therapies, including theranostics and radioligand treatments, presents a promising avenue for personalized cancer treatment. Full article