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Chemical Science Jun 2024Synthetic methods that enable the macrocyclisation of peptides facilitate the development of effective therapeutic and diagnostic tools. Herein we report a peptide...
Synthetic methods that enable the macrocyclisation of peptides facilitate the development of effective therapeutic and diagnostic tools. Herein we report a peptide cyclisation strategy based on intramolecular interception of visible-light-mediated cysteine desulfurisation. This method allows cyclisation of unprotected peptides in an aqueous solution the installation of a hydrocarbon linkage. We explore the limits of this chemistry using a range of model peptides of increasing length and complexity, including peptides of biological/therapeutic relevance. The method is applied to replace the native disulfide of the peptide hormone, oxytocin, with a proteolytically/redox-stable hydrocarbon, and internal macrocyclisation of an MCL-1-binding peptide.
PubMed: 38939126
DOI: 10.1039/d3sc05865d -
Innovations in Clinical Neuroscience 2024Glucagon-like peptide-1 (GLP-1) receptor agonists have garnered significant attention in diabetes management, and they act by mimicking the effects of GLP-1, a hormone...
Glucagon-like peptide-1 (GLP-1) receptor agonists have garnered significant attention in diabetes management, and they act by mimicking the effects of GLP-1, a hormone that regulates insulin secretion and appetite. While these medications have become increasingly popular, their impact on mood and other psychiatric manifestations remains uncertain because of inconsistent data. It has been shown to affect brain regions involved in emotional regulation. This case report underscores the adverse mood changes possibly linked to semaglutide and the need for further study in this area.
PubMed: 38938530
DOI: No ID Found -
JACC. Advances Dec 2023Brain natriuretic peptide (BNP)/N-terminal-pro hormone brain natriuretic peptides (NT-proBNP) enable risk stratification, diagnosing, and monitoring of heart failure...
BACKGROUND
Brain natriuretic peptide (BNP)/N-terminal-pro hormone brain natriuretic peptides (NT-proBNP) enable risk stratification, diagnosing, and monitoring of heart failure patients. An additional prognostic value for BNP/NT-proBNP in nonheart failure patients and general population cohorts is described in the literature, but specific cut-off levels are only described for heart failure patients.
OBJECTIVES
This study aimed to determine thresholds for risk stratification in nonheart failure patients.
METHODS
Based on the Essen Coronary Artery Disease registry we excluded patients with known heart failure or elevated BNP/NT-pro BNP levels. The resulting cohort was divided into a derivation and validation cohort using random sampling. The prognostic value of BNP/NT-proBNP of incident mortality was evaluated in the derivation cohort using univariate and multivariable cox regression analysis. In receiver operating characteristic analysis and corresponding area under the curve the optimal threshold was determined using Youdens J index. The findings were verified in the validation cohort.
RESULTS
A total of 3,690 patients (age 62.9 ± 12.5 years, 71% male, 68% patients with coronary artery disease) were included. During a mean follow-up of 2.6 ± 3.4 years (median 1.2 [IQR: 0.4-2.88]), 169 deaths of any cause occurred. Based on Youden's J index, BNP-thresholds of 9.6 and 29pg/ml and NT-proBNP thresholds of 65 and 77pg/ml for men and women, respectively, were determined. BNP/NT-proBNP levels above these thresholds were associated with increased mortality in the derivation cohort (HR: 2.44 [95% CI: 1.32-4.53], = 0.005). The predictive value was confirmed in the validation cohort (HR: 2.78 [95% CI: 1.26-6.14], = 0.01).
CONCLUSIONS
We here describe sex-specific BNP/NT-proBNP thresholds that allow prediction of impaired survival in patients without heart failure, independent of traditional cardiovascular risk factors.
PubMed: 38938478
DOI: 10.1016/j.jacadv.2023.100688 -
Communications Biology Jun 2024Aggregation of the human islet amyloid polypeptide (hIAPP) contributes to the development and progression of Type 2 Diabetes (T2D). hIAPP aggregates within a few hours...
Aggregation of the human islet amyloid polypeptide (hIAPP) contributes to the development and progression of Type 2 Diabetes (T2D). hIAPP aggregates within a few hours at few micromolar concentration in vitro but exists at millimolar concentrations in vivo. Natively occurring inhibitors of hIAPP aggregation might therefore provide a model for drug design against amyloid formation associated with T2D. Here, we describe the combined ability of low pH, zinc, and insulin to inhibit hIAPP fibrillation. Insulin dose-dependently slows hIAPP aggregation near neutral pH but had less effect on the aggregation kinetics at acidic pH. We determine that insulin alters hIAPP aggregation in two manners. First, insulin diverts the aggregation pathway to large nonfibrillar aggregates with ThT-positive molecular structure, rather than to amyloid fibrils. Second, soluble insulin suppresses hIAPP dimer formation, which is an important early aggregation event. Further, we observe that zinc significantly modulates the inhibition of hIAPP aggregation by insulin. We hypothesize that this effect arose from controlling the oligomeric state of insulin and show that hIAPP interacts more strongly with monomeric than oligomeric insulin.
Topics: Islet Amyloid Polypeptide; Hydrogen-Ion Concentration; Humans; Zinc; Insulin; Protein Aggregates; Diabetes Mellitus, Type 2; Kinetics; Amyloid; Protein Aggregation, Pathological
PubMed: 38937578
DOI: 10.1038/s42003-024-06388-y -
Scientific Reports Jun 2024A rise in bone turnover markers (BTM) after bariatric surgery predicts poor bone health years later. This study explored factors associated with BTM and changes in BTM...
A rise in bone turnover markers (BTM) after bariatric surgery predicts poor bone health years later. This study explored factors associated with BTM and changes in BTM after bariatric surgery. Inclusion criteria were subjects 18 to 65 years of age with morbid obesity undergoing bariatric surgery. All data were measured before and 6 and 12 months after surgery. The study included 104 subjects: women/men: 83/21; mean age 43.1 (SD 8.4) years; BMI: 38.8 kg/m (SD 3.8). Surgery with Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) was performed in 84 (81%) and 20 (19%) subjects, respectively. From before to 6-12 months after surgery, procollagen type 1 N-terminal propeptid (P1NP) increased by 45.6 µg/L (95% CI 41.5-50.0, p < 0.001), and alkaline phosphatase (ALP) by 10 U/L (95% CI 7-14, p < 0.001). The increases were significantly larger after RYGB than after SG. The APOE- Ɛ3 allele was associated with low levels of BTM and high levels of leptin. There was an unfavourable increase in BTM after bariatric surgery. SG compared to RYGB and the presence of the APOE-Ɛ3 allele were associated with less unfavourable effects. The study emphasises the importance of optimal prophylactic interventions after bariatric surgery to prevent osteoporosis.
Topics: Humans; Female; Male; Adult; Middle Aged; Bone Remodeling; Biomarkers; Bariatric Surgery; Obesity, Morbid; Peptide Fragments; Procollagen; Gastrectomy; Gastric Bypass; Alkaline Phosphatase; Leptin; Aged; Adolescent
PubMed: 38937532
DOI: 10.1038/s41598-024-65952-y -
Scientific Reports Jun 2024There is no treatment for acute aortic dissection (AAD) targeting inflammatory cells. We aimed to identify the new therapeutic targets associated with inflammatory...
There is no treatment for acute aortic dissection (AAD) targeting inflammatory cells. We aimed to identify the new therapeutic targets associated with inflammatory cells. We characterized the specific distribution of myeloid cells of both human type A AAD samples and a murine AAD model generated using angiotensin II (ANGII) and β-aminopropionitrile (BAPN) by single-cell RNA sequencing (scRNA-seq). We also examined the effect of an anti-interleukin-1β (IL-1β) antibody in the murine AAD model. IL1B inflammatory macrophages and classical monocytes were increased in human AAD samples. Trajectory analysis demonstrated that IL1B inflammatory macrophages differentiated from S100A8/9/12 classical monocytes uniquely observed in the aorta of AAD. We found increased infiltration of neutrophils and monocytes with the expression of inflammatory cytokines in the aorta and accumulation of inflammatory macrophages before the onset of macroscopic AAD in the murine AAD model. In blocking experiments using an anti-IL-1β antibody, it improved survival of murine AAD model by preventing elastin degradation. We observed the accumulation of inflammatory macrophages expressing IL-1β in both human AAD samples and in a murine AAD model. Anti-IL-1β antibody could improve the mortality rate in mice, suggesting that it may be a treatment option for AAD.
Topics: Aortic Dissection; Interleukin-1beta; Animals; Humans; Macrophages; Mice; Disease Models, Animal; Male; Aminopropionitrile; Angiotensin II; Inflammation; Monocytes; Aorta; Mice, Inbred C57BL; Female
PubMed: 38937528
DOI: 10.1038/s41598-024-65931-3 -
Nature Communications Jun 2024In vertebrates, folliculogenesis and ovulation are regulated by two distinct pituitary gonadotropins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH)....
In vertebrates, folliculogenesis and ovulation are regulated by two distinct pituitary gonadotropins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Currently, there is an intriguing consensus that a single hypothalamic neurohormone, gonadotropin-releasing hormone (GnRH), regulates the secretion of both FSH and LH, although the required timing and functions of FSH and LH are different. However, recent studies in many non-mammalian vertebrates indicated that GnRH is dispensable for FSH function. Here, by using medaka as a model teleost, we successfully identify cholecystokinin as the other gonadotropin regulator, FSH-releasing hormone (FSH-RH). Our histological and in vitro analyses demonstrate that hypothalamic cholecystokinin-expressing neurons directly affect FSH cells through the cholecystokinin receptor, Cck2rb, thereby increasing the expression and release of FSH. Remarkably, the knockout of this pathway minimizes FSH expression and results in a failure of folliculogenesis. Here, we propose the existence of the "dual GnRH model" in vertebrates that utilize both FSH-RH and LH-RH.
Topics: Animals; Gonadotropin-Releasing Hormone; Follicle Stimulating Hormone; Female; Oryzias; Hypothalamus; Neurons; Luteinizing Hormone; Ovarian Follicle; Ovulation
PubMed: 38937445
DOI: 10.1038/s41467-024-49564-8 -
In Vivo (Athens, Greece) 2024When hormone therapy (HT) is combined with radiotherapy, understanding the recovery of testosterone levels after the end of HT becomes crucial for considering subsequent...
BACKGROUND/AIM
When hormone therapy (HT) is combined with radiotherapy, understanding the recovery of testosterone levels after the end of HT becomes crucial for considering subsequent therapy. The aim of this study was to determine the factors influencing the time to recovery of testosterone levels after discontinuation of HT and the likelihood of recovery.
PATIENTS AND METHODS
The study included a total of 108 patients with prostate cancer who were treated with GnRH agonist in combination with radiotherapy and followed up for at least 12 months after discontinuation of the GnRH agonist. The presence of recovery of testosterone levels and the time to recovery were investigated. Univariate and multivariate analyses were performed on several factors contributing to testosterone recovery, including age at initiation of HT, and the duration of HT.
RESULTS
Testosterone levels recovered in 61 cases (56.5%). The median time to recovery was 14.8 months. There was a significant difference in the recovery of testosterone levels between patients aged ≥71 years and those aged <71 years at the start of HT (p=0.002), and between those who had been on HT for ≥34 months and those for <34 months (p=0.031). In both univariate and multivariate analyses, age at initiation of HT and duration of HT contributed to the recovery of testosterone levels.
CONCLUSION
The rate of recovery of testosterone levels after long-term (median 34.3 months) HT was lower in patients who were older than 71 years at the start of HT.
Topics: Humans; Testosterone; Male; Aged; Prostatic Neoplasms; Middle Aged; Aged, 80 and over; Gonadotropin-Releasing Hormone; Combined Modality Therapy; Treatment Outcome; Antineoplastic Agents, Hormonal
PubMed: 38936898
DOI: 10.21873/invivo.13666 -
In Vivo (Athens, Greece) 2024Depression is associated with metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). However, the mechanisms underlying the interaction between them...
BACKGROUND/AIM
Depression is associated with metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). However, the mechanisms underlying the interaction between them are still poorly known.
MATERIALS AND METHODS
In this study, mice on a choline deficiency, L-amino acid-defined, high-fat diet (CDAHFD) developing steatosis were challenged with chronic restraint stress (CRS), a protocol widely used to induce depression. The development of depression and steatosis was evaluated using histopathology analysis, ELISA, q-PCR and Western Blot.
RESULTS
The contribution of the activated HPA axis to hepatic steatosis progress was fully established, which was validated using a hepatocyte model. Histopathological and biochemical analysis indicated that steatosis was exacerbated by CRS challenge, and behavioral tests indicated that the mice developed depression. Among the screened endocrinal pathways, the hypothalamic-pituitary-adrenal (HPA) axis was significantly activated and the synergistic effect of CDAHFD and CRS in activating the HPA axis was observed. In the hypothalamus, expression of corticotropin-releasing hormone (CRH) was increased by 86% and the protein levels of hypothalamic CRH were upregulated by 25% to 33% by CRS treatment. Plasma CRH levels were elevated by 45-56% and plasma adrenocorticotropic hormone (ACTH) levels were elevated by 29-58% by CRS treatment. In the liver, target genes of the HPA axis were activated, accompanied by disruption of the lipid metabolism and progression of steatohepatitis. The lipid metabolism in the Hepa1-6 cell line treated with endogenous corticosterone (CORT) was in accordance with the aforementioned in vivo responses.
CONCLUSION
Depression aggravated hepatic steatosis in CDAHFD-fed mice by activating the HPA axis. The risk of NAFLD development should be fully considered in depressive patients and improvement of psychotic disorders could be an etiological treatment strategy for them.
Topics: Animals; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Mice; Depression; Disease Models, Animal; Non-alcoholic Fatty Liver Disease; Male; Mice, Inbred C57BL; Corticotropin-Releasing Hormone; Diet, High-Fat; Adrenocorticotropic Hormone; Liver; Fatty Liver; Corticosterone
PubMed: 38936893
DOI: 10.21873/invivo.13618 -
ACS Chemical Biology Jun 2024The incretin gut hormone glucagon-like peptide-1 (GLP-1) has become a household name because of its ability to induce glucose-dependent insulin release with accompanying...
The incretin gut hormone glucagon-like peptide-1 (GLP-1) has become a household name because of its ability to induce glucose-dependent insulin release with accompanying weight loss in patients. Indeed, derivatives of the peptide exert numerous pleiotropic actions that favorably affect other metabolic functions, and consequently, such compounds are being considered as treatments for a variety of ailments. The ability of native GLP-1 to function as a clinical drug is severely limited because of its short half-life . All of the beneficial effects of GLP-1 come from its agonism at the cognate receptor, GLP-1R. In our quest for long-lived activation of the receptor, we hypothesized that an agonist that had the ability to covalently cross-link with GLP-1R would prove useful. We here report the structure-guided design of peptide analogues containing an electrophilic warhead that could be covalently captured by a resident native nucleophile on the receptor. The compounds were evaluated using washout experiments, and resistance to such washing serves as an index of prolonged activation and covalent capture, which we use to tabulate longevity and robust long-lived GLP-1R agonism. The addition of SulF (cross-linkable warhead), an N-terminal trifluoroethyl group (for protease protection), and a C18 diacid lipid (protractor) all contributed to the increased wash resistance of GLP-1. The most effective compound based on the wash resistance metric, , has all three elements outlined and may serve as a blueprint and a proof-of-concept scaffold for the design of clinically useful molecules.
PubMed: 38935975
DOI: 10.1021/acschembio.4c00039