Research Hub
The living record of
peptide science.
PubMed studies synced daily. Active clinical trials. Evidence updates when the science materially changes. Monthly synthesis for practitioners.
Layer 1
Study feed
Novel Cholecystokinin Secretion-Stimulating Peptides from Oat Protein Hydrolysate: Sequence Identification and Insight into the Mechanism of Action.
J Agric Food Chem
Hongdong Song, Lei Xue, Qiuyun Fu +4 more
Cholecystokinin (CCK), secreted by enteroendocrine cells, plays a vital role in suppressing appetite. This study aimed to evaluate the in vivo effect of oat protein hydrolysate (OPH) on CCK secretion and elucidate the structural characteristics of the responsible peptides and their underlying mechanism of action. OPH was prepared by a simulated gastrointestinal digestion model. Intragastric administration of OPH in mice significantly increased plasma CCK levels. Using size exclusion column chromatography and liquid chromatography-tandem mass spectrometry, ten peptides were successfully identified, and their abilities to stimulate CCK secretion were evaluated in STC-1 cells. Four novel CCK secretion-stimulating peptides, including LLL, QQVFQPQ, QGDVVALPA, and DVNNNANQLEPR, were validated. Among them, QGDVVALPA exhibited the strongest activity. Inhibition experiments demonstrated that the calcium-sensing receptor and its coupled G-protein subtype Gq were involved in QGDVVALPA-stimulated CCK secretion. Additionally, downstream signaling molecules including intracellular Ca2+ and Ca2+/CaM-dependent protein kinase (CaMKII) were also required for QGDVVALPA to induce CCK secretion. Our findings highlight the potential of oat protein-derived hydrolysate and peptides as functional food ingredients to regulate satiety.
Modulation of temporoammonic-CA1 synapses by neuropeptide Y is through Y1 receptors in mice.
Neuropeptides
Mariana A Cortes, Aundrea F Bartley, Qin Li +7 more
Reduced levels of neuropeptide Y (NPY), an abundant neuromodulator in the brain, are linked to multiple neuropsychiatric disorders, including post-traumatic stress disorder (PTSD). The CA1 region of hippocampus is important for anxiety regulation and highly expresses NPY. Injecting NPY into CA1 is anxiolytic and alleviates behavioral symptoms in a model of traumatic stress; these anxiolytic effects are blocked by a Y1 receptor antagonist. However the location of Y1Rs that mediate NPY's anxiolytic effects in CA1 remains unclear. CA1 receives inputs from entorhinal cortex through the temporammonic pathway (TA), which is important for fear learning and sensitive to stress. Our lab previously showed that NPY reduces TA-evoked synaptic responses, however, the subtype of NPY receptor mediating this reduction is unknown. Here we demonstrate that in mice both exogenous (bath-applied) and endogenously-released NPY act through Y1 receptors in the TA pathway. This is the first demonstration of Y1 receptor-mediated effect on synaptic function in CA1. Interestingly, chronic overexpression of NPY (in NPY-expressing interneurons) impairs the sensitivity of the TA-evoked synaptic response to a Y1 receptor agonist. However, the long-known NPY Y2 receptor-mediated effect on the Schaffer collateral (SC) pathway is unaffected by NPY overexpression. Therefore, NPY can have a pathway-specific impact on synaptic transmission in CA1 based on the differential expression of NPY receptors and their response to overexpression of NPY. Our results demonstrating that NPY acts at Y1 receptors in the TA pathway are consistent with the idea that the TA pathway underlies the anxiolytic effects of NPY in CA1.
Pro-adrenomedullin as an independent predictive biomarker for heart failure in atrial fibrillation and flutter.
ESC Heart Fail
Gaifeng Hu, Xiaodong Peng, Liu He +6 more
This study aimed to investigate potential biomarkers for predicting incident heart failure (HF) in patients with atrial fibrillation and flutter (AF and AFL), utilizing proteomic data from the UK Biobank Pharma Proteomics Project (UKB-PPP).
Natriuretic Peptides and Soluble ST2 Improve Echocardiographic and Invasive Long-Term Survival Prediction in Patients Evaluated for Diastolic Dysfunction.
Int J Mol Sci
Horațiu Suciu, Paul-Adrian Călburean, Adina Huțanu +8 more
This study aimed to investigate the impact of long-term survival on cardiac serum biomarkers such as natriuretic peptides (mid-regional pro-atrial natriuretic peptide [MR-proANP], B-type natriuretic peptide [BNP], N-terminal prohormone BNP [NT-proBNP]), soluble ST2 (sST2), galectin-3 and mid-regional pro-adrenomedullin (MR-proAMD). Consecutive patients hospitalized in a tertiary center, undergoing echocardiographic and invasive left cardiac catheterization for diastolic dysfunction assessment were prospectively included in this study. Cardiac biomarkers were determined from pre-procedural peripheral venous blood samples. A total of 110 patients were included, with a median follow-up of 1.66 (1.23-2.16) years during which 16 (14.5%) patients died. A total of 45.4% (50) of patients had diastolic dysfunction. In the univariate Cox regression, long-term survival was predicted by BNP (p < 0.0001, HR = 0.39 [0.20-0.53]), NT-proBNP (p < 0.0001, HR = 0.40 [0.22-0.55]), MR-proANP (p = 0.001, HR = 0.30 [0.11-0.46]), sST2 (p < 0.0001, HR = 0.47 [0.30-0.60]), but not with MR-proAMD (p = 0.77) or galectin-3 (p = 0.76). In the final stepwise multivariable Cox regression non-invasive and invasive models, NT-proBNP and sST2 remained independent predictors of survival. Natriuretic peptides (BNP and NT-proBNP) and sST2 were predictors of long-term survival, while MR-proANP, MR-proADM and galectin-3 did not have predictive values. NT-proBNP and sST2 improved survival prediction in both a non-invasive scenario (including clinical, serum and echocardiographic parameters) and an invasive clinical scenario (including left heart catheterization parameters). The sST2 pathway could provide a target for therapeutic intervention.
An orexin agonist promotes wakefulness and inhibits cataplexy through distinct brain regions.
Curr Biol
Takashi Ishikawa, Emi Kurimoto, Adam A Joyal +3 more
Narcolepsy type 1, caused by selective loss of the orexin-producing neurons, is characterized by poor maintenance of wakefulness and cataplexy. Clinical trials show that orexin receptor 2 (OX2R) agonists substantially improve narcolepsy symptoms, but the key brain regions through which OX2R signaling produces these benefits are only partially understood. To address this question, we produced recombinant mice expressing the human diphtheria toxin receptor driven by the endogenous orexin promoter (orexinDTR mice). After injection with diphtheria toxin, orexinDTR mice had severe and selective loss of the orexin neurons, leading to narcolepsy symptoms, including poor maintenance of wakefulness and cataplexy; these symptoms were substantially improved by an OX2R-selective agonist OX-201. We then crossed orexinDTR mice with OX2R transcription-disrupted (TD) mice to produce a new model lacking orexin neurons and OX2R. We focally restored OX2R expression in specific brain regions of OX2R TD::orexinDTR mice and assessed whether OX-201 improves specific aspects of narcolepsy. In mice expressing OX2R only in the tuberomammillary nucleus (TMN) or basal forebrain (BF) regions, OX-201 improved maintenance of wakefulness but did not suppress cataplexy. In contrast, in mice expressing OX2R in the ventrolateral periaqueductal gray and lateral pontine tegmentum (vlPAG/LPT), OX-201 suppressed cataplexy without improving maintenance of wakefulness. These results suggest that OX2R signaling in the TMN and BF regions can stabilize wakefulness and OX2R signaling in the vlPAG/LPT region can suppress cataplexy, providing key insights into how orexins regulate wakefulness and muscle tone and how OX2R agonists improve the symptoms of narcolepsy. VIDEO ABSTRACT.
Mice with Heterozygous Deletion of Exon 3 in the Gh Gene Demonstrate Growth Retardation Caused by Reduced Ghrhr mRNA.
Int J Mol Sci
Daisuke Ariyasu, Daisuke Higa, Ryo Tokudome +4 more
Isolated Growth Hormone Deficiency Type 2 (IGHD2) is caused by a heterozygous splice site variant in intron 3 of the GH1 gene. The resulting exon 3-skipped growth hormone (Δ3 GH), produced from the mutated allele, exerts a dominant-negative effect, leading to growth hormone (GH) deficiency. However, the precise molecular mechanisms underlying this effect remain poorly understood. While several model murine models expressing human Δ3 GH have been developed, no IGHD2 mouse models featuring variants in the endogenous Gh gene currently exist. We generated a mouse model (Gh+/Δ3) with a heterozygous deletion of exon 3 in the Gh gene using CRISPR/Cas9 system. The Gh+/Δ3 model exhibited GH deficiency caused by a dominant-negative effect at the mRNA level, characterized by reduced Gh mRNA expression. This mechanism parallels findings in our previous humanized IGHD2 mouse model, where the deficiency was driven by decreased Ghrhr mRNA expression. Transcriptome analysis of the pituitary revealed widespread downregulation of mRNAs encoding membrane and secretory proteins. The dominant-negative effect of Δ3 GH in IGHD2 is mediated by properties of Δ3 GH that are conserved across both humans and mice. This mechanism involves the downregulation of mRNAs, including those encoding membrane and secretory proteins, such as Ghrhr mRNA.
Anti-inflammatory treatment using alpha melanocyte stimulating hormone (α-MSH) does not alter osteoblasts differentiation and fracture healing.
BMC Musculoskelet Disord
Johanna Graue, Melanie Timmen, Katharina Schmitz +5 more
Alpha-melanocyte-stimulating-hormone (α-MSH) has been identified as a new anti-inflammatory treatment compound in rheumatoid arthritis (RA) and other inflammatory diseases. However, its direct effect on bone cell differentiation or on bone regeneration, which is an inflammatory process, too, has not been investigated, yet. Bone tissue is significantly affected in inflammatory joint diseases. Additionally, inflammatory signaling is essential -in bone regeneration during fracture healing. Therefore, we evaluated the impact of α-MSH-treatment on bone forming cells in an inflammatory setting in vitro and as a treatment approach in a murine fracture healing model in vivo.
A single injection of neuropeptide QRFP in the lateral hypothalamus decreased food intake.
J Psychopharmacol
Olga Zagorácz, Tamás Ollmann, László Péczely +9 more
Severe eating disorders, such as obesity, bulimia, and anorexia, keep increasing to epidemic proportions worldwide. Understanding of neuropeptides' role in complex hunger/satiety mechanisms may allow new prospects for treatment and prevention. Pyroglutamylated arginine-phenylalanine-amide peptides (QRFPs) are thought to enhance feeding following the central administration.
Ovarian premature aging: VIP as key regulator of fibro-inflammation and foamy macrophages generation.
Mol Cell Endocrinol
Lara Castagnola, Lucila Gallino, Ana Schafir +8 more
Ovarian aging is associated with fibro-inflammation, contributing to the decline in oocyte count and quality. Given the immunomodulatory properties of the vasoactive intestinal peptide (VIP) in the reproductive tract, we investigated its role in maintaining ovarian immune homeostasis and preventing premature aging. We evaluated young VIP knockout (KO) mice, comparing them to young wild type (WT) females, for signs of premature aging. Histological staining revealed aberrant ovarian morphology in VIP KO mice, characterized by increased atretic follicles and decreased ovarian reserve compared to WT controls. Moreover, VIP KO ovaries showed reduced vascularization, increased collagen deposition and elevated ROS and IL-1β levels. Foamy macrophages were significantly predominant, indicating premature aging in young VIP KO ovaries. To determine potential mechanisms behind these pathogenic changes, we conditioned peritoneal macrophages from young WT or VIP KO mice in vitro with ovarian-conditioned media from young WT or VIP KO mice to mimic the respective ovarian microenvironment. When WT or VIP KO peritoneal macrophages were conditioned with ovarian media from their respective genotypes, lipid droplet accumulation increased compared to control medium. In cross-genotype experiments, WT macrophages conditioned with media from VIP KO ovaries selectively accumulated higher levels of lipid droplets, whereas no differences were observed in VIP KO macrophages conditioned with WT ovarian media. This suggests that VIP KO macrophages are uniquely sensitized to the inflammatory environment of VIP KO ovaries, implicating both ovarian factors and macrophage status. These findings highlight the role of VIP in preventing fibro-inflammation, thereby preserving ovarian health and preventing premature aging.
The in vitro and in vivo skin-whitening activity of Ectoine through enhanced autophagy in melanocytes and keratinocytes and zebrafish model.
Biofactors
Wei-Chen Jane, Siang-Jyun Chen, Jhih-Hsuan Hseu +6 more
Ectoine, a natural bacterial osmolyte, suppressed UVA irradiated-α-melanocyte stimulating hormone (MSH) stimulated melanogenesis through antioxidant Nrf2 pathways in human keratinocytes; however, the underlying skin whitening mechanisms were not elucidated. The depigmenting efficiency of Ectoine (0-400 μM) through antimelanogenesis and melanin degradation by autophagy promotion was investigated in melanoma (B16F10) and melanin-feeding keratinocyte (HaCaT) cells and in vivo zebrafish model. MTT assay, Western blotting, GFP-LC3 puncta, AVO formation, melanin assay, immunofluorescence staining, TEM techniques, siLC3 transfection, and zebrafish model were utilized. Ectoine-induced autophagy in B16F10 and HaCaT cells was shown by enhanced LC3-II accumulation, autophagosome GFP-LC3 puncta, autolysosome AVOs formation, ATG4B downregulation, and Beclin-1/Bcl-2 dysregulation. The immunoprecipitation data revealed that Ectoine increased the association between LC3-II and p62 proteins in B16F10 and HaCaT cells. Importantly, antioxidant NAC pretreatment antagonized the Ectoine-induced ATG4B diminution in B16F10 and HaCaT cells. Ectoine inhibited melanogenesis by suppressing melanosome gp100, tyrosinase, TRP-1/-2, and/or melanin formation via autophagy in α-MSH-stimulated B16F10 and melanin-feeding HaCaT cells. TEM findings displayed that Ectoine increased melanosome-engulfing autophagosomes and autolysosomes in α-MSH-stimulated B16F10 and melanin-feeding HaCaT cells. Ectoine-inhibited melanogenesis in α-MSH-stimulated B16F10 cells and melanin-feeding HaCaT cells was reversed by pretreatment with the autophagy inhibitor 3-MA or LC3 silencing. In vivo study demonstrated that Ectoine (5 mM) suppressed endogenous body pigmentation by antimelanogenesis and melanin degradation through autophagy induction in a zebrafish model. The in vitro and in vivo study demonstrated that Ectoine inhibits melanogenesis and enhances melanin degradation by triggering autophagy. Ectoine could be utilized as a whitening ingredient in cosmetic formulations.
AhR Activation Transcriptionally Induces Anti-Microbial Peptide Alpha-Defensin 1 Leading to Reversal of Gut Microbiota Dysbiosis and Colitis.
Gut Microbes
Manikandan Palrasu, Khadija Kakar, Amarnath Marudamuthu +9 more
Alpha-defensin 1 is a small antimicrobial peptide that acts as the first line of defense against pathogens. It is induced following microbial cues and inflammatory signals in neutrophils and Paneth cells in the small intestine, which suggests that it plays a role in microbial homeostasis in the gut. The gut microbial products also serve as ligands for the aryl hydrocarbon receptor (AhR), an environmental sensor. In the current study, we investigated if there is any crosstalk between AhR and alpha-defensin 1. Interestingly, we found a positive correlation between AhR and alpha-defensin 1 protein levels in ileal tissues from active Crohn's' (CD) patients and epithelial cells (IECs) from multiple models of murine colitis. In vitro downregulation of AhR led to inhibition of α-defensin 1, while activation of AhR induced α-defensin 1 in IECs. AhR directly targeted the dioxin response element 3 (DRE3) region on the α-defensin 1 promoter in IECs. AhR-mediated induction of α-defensin 1 in colitis mice reversed the gut microbial dysbiosis and alleviated colitis. Our data identify a novel signaling pathway in which AhR acts as a transcription factor for α-defensin 1, leading to regulation of homeostasis between gut microbiota, intestinal mucosa, and mucosal immunity.
Can good sleep quality enhance the benefits of oral collagen supplementation in the prevention of skin aging? A brief report.
Arch Dermatol Res
Ellen M S Xerfan, Maingredy Rodrigues Souza, Anamaria S Facina +2 more
Collagen is essential to skin structure and integrity, and it is continually degraded with aging due to higher oxidative stress. Sleep deprivation accelerates skin aging and reduces collagen production. Good sleep may be a potential adjuvant to the efficacy of oral supplementation with collagenic peptides for the skin.
Cadmium-cardiolipin disruption of respirasome assembly and redox balance through mitochondrial membrane rigidification.
J Lipid Res
Nadiya Romanova, Kevin Sule, Travis Issler +5 more
The environmental pollutant cadmium (Cd) poses a threat to human health through the consumption of contaminated foodstuffs culminating in chronic nephrotoxicity. Mitochondrial dysfunction and excessive reactive oxygen species (ROS) are key to Cd cellular toxicity. Cd-lipid interactions have been less considered. We hypothesized Cd binding to the inner mitochondrial membrane (IMM) phospholipid cardiolipin (CL) and membrane rigidification underlies defective electron transfer by disrupted respiratory supercomplexes (SCs). In Cd-treated rat kidney cortex (rKC) mitoplasts, laurdan (lipid-water interface), and diphenylhexatriene (hydrophobic core) revealed increased and decreased membrane fluidity, respectively. Laurdan-loaded pure CL or IMM biomimetic (40 mol % POPC, 35 mol % DOPE, 20 mol % TOCL, 5 mol % SAPI) nanoliposomes were rigidified by 25 μM Cd, which was confirmed in live-cell imaging of laurdan or di-4-ANEPPDHQ loaded human proximal convoluted tubule (HPCT) cells. Blue native gel electrophoresis evidenced ∼30% loss of I+III2+IVn SC formation after 5 μM Cd for 6 h in HPCTs, which was reversed by CL-binding drug MTP-131/SS-31/elamipretide (0.1 μM), yet α-tocopherol-insensitive. Moreover, MTP-131 attenuated Cd-induced H2O2 (∼30%) and cytochrome c release (∼25%), but not osmotic swelling, in rKC mitochondria as well as Cd-induced ROS (∼25%) in HPCTs. MTP-131 binding to IMM biomimetic nanoliposomes decreased zeta potential, prevented Cd-induced liposome size increase, and membrane rigidification reported by laurdan. Heterologous CRLS1 expression reversed Cd (5 μM, 24 h) cytotoxicity (∼25%) by MTT assay, Cd (5 μM, 3 h)-induced ROS and mitochondrial membrane rigidification by Cd (1 μM, 1 h) in HPCT cells. In summary, we report a novel mechanism for Cd toxicity in which Cd-CL interactions cause IMM rigidification, thereby disrupting correct SC assembly and increasing ROS.
Ghrelin suppresses water intake with a different physiological significance from atrial natriuretic peptide in conscious seawater-acclimated eels.
J Exp Biol
Hiroyuki Kaiya, Shigenori Nobata, Yoshio Takei
In general, ghrelin is known as one of the orexigenic (increasing appetite or food intake) hormones in mammals. However, it has also been shown that ghrelin inhibits water intake, which appears to be inconsistent with its role in the feeding response. In this study, the effect of ghrelin on water intake was comprehensively addressed using conscious seawater-acclimated eels as an experimental model for water drinking behaviour. When injected intra-arterially, ghrelin inhibited copious drinking in a dose-dependent manner without affecting arterial pressure. This effect contrasted with the inhibitory effect of atrial natriuretic peptide (ANP) on drinking, which is synchronized with a vasodepressor effect. Similarly, intra-cerebroventricular injection of ghrelin also decreased the drinking rate without affecting arterial pressure. Continuous infusion of ghrelin from the ventral aorta also decreased the drinking rate, concomitant with an increase in plasma ghrelin concentration. The inhibitory effects of ghrelin on drinking were as potent and efficacious as those of ANP. The inhibitory action was not blocked by pre-treatment with a ghrelin receptor antagonist ([D-Lys3] GHRP-6); consistently, the agonist form (GHRP-6) injected intra-arterially did not show any inhibitory effect of ghrelin when injected peripherally. These results demonstrate that ghrelin is a potent anti-dipsogen in eels without baroreflex and ANP secretion, and it is possible that ghrelin's effect might be mediated through another type of ghrelin receptor that [D-Lys3] GHRP-6 or GHRP-6 do not bind.
Divergent immediate and delayed effects of juvenile exposure to doxorubicin on the thymus in C57BL/6 mice.
Sci Rep
Benu George, Korbyn J V Dahlquist, Marianne K O Grant +7 more
The long-term effects of doxorubicin (DOX) chemotherapy on thymic immune function in childhood cancer survivors remain inadequately understood. This study explores the immediate and delayed impacts of low-dose DOX on thymic immune populations using a juvenile mouse model. Male mice received intraperitoneal DOX injections (4 mg/kg/week) for three weeks, with evaluations performed at one- and five-weeks post treatment. Thymic samples were collected and analyzed using multi-parameter flow cytometry to assess changes in immune cell composition and phenotype. Additionally, real-time polymerase chain reaction (RT-PCR) was employed to measure gene expression of cytokines and senescence markers. One week after DOX administration, significant thymic atrophy was evident. While mature CD3+CD4+ T-cell frequency remained unchanged, CD3+CD8+ T-cells significantly increased, suggesting differential effects on T-cell subsets. PD1+ expression increased across naïve and memory CD4+ T-cell subsets, suggesting activation or exhaustion. Additionally, Ki67+ expression was elevated in naïve and memory CD8+ T-cells, indicating enhanced proliferation. Gene expression analysis revealed upregulation of Foxn1, Pax1, Ifnγ, and Il7 whereas Il6 and Il17 were downregulated. Furthermore, Cdkn1a (p21) expression was elevated, suggesting immune dysregulation and early immunosenescence. At five weeks, thymic weight rebounded; however, T-cell subsets displayed persistent perturbations. Central memory and effector memory CD4+ T-cells were reduced, while naïve CD4+ T-cells showed increased Ki67+ expression. In contrast, CD8+ T-cells subsets remained largely unchanged, except for a decrease in central memory cells. Although expression of thymus-related genes was normalized, p21 expression remained elevated, suggesting lingering immunosenescence. These findings highlight the complex effects of DOX, including acute thymic atrophy due to T-cell depletion, and a delayed recovery with persistent immunosenescence, underscoring the need for strategies to preserve immune function in childhood cancer survivors.
Amylin is incorporated into extracellular vesicles in an ESCRT-dependent manner and regulates senescence.
Biochim Biophys Acta Mol Basis Dis
S Iglesias-Fortes, A C Lockwood, C González-Blanco +7 more
Type 2 diabetes mellitus is a disease which initiates with insulin resistance. Then, pancreatic β cells start to counteract this situation by increasing insulin secretion, which is known as pre-diabetic state. Amylin protein or islet amyloid polypeptide (IAPP), has multiple physiological roles such as the regulation of satiety and avoiding gastric emptying. However, amylin is able to aggregate, forming insoluble structures that affects pancreatic β cell survival. Interestingly, not all the amylin from the different species has this aggregate-prone capacity. There are species, which possesses non-amyloidogenic capacity and does not aggregate such as the rodents. However, there are versions of the protein, for instance from humans and primates, which can aggregate. Previously, we observed that small oligomers could be found in extracellular vesicles (EVs). Now, we have used a pancreatic β cell which overexpresses human amylin (hIAPP) (INS1E-hIAPP) and we have explored the capacity of amylin to be incorporated into EVs and how amylin could affect to different essential signaling pathways such as the mammalian target of rapamycin complex 1, endoplasmic-reticulum stress and senescence. Here, we report that amylin can be incorporated into EVs in an endosomal sorting complexes required for transport (ESCRT)-dependent manner. When we treated the cells with the neutral sphingomyelinase inhibitor, GW4869, one of the pathways for EV biogenesis and under high glucose conditions, there was an increased incorporation of soluble amylin into vesicles. Interestingly in this condition, when we isolated the EVs, we clearly observed that the size of the vesicles was higher, compatible with microvesicles (MVs). Resveratrol increased a pro-senescent phenotype but, it was able to revert either the high glucose or GW4869-associated senescent. In summary, these results indicate that amylin can be recruited in an ESCRT-dependent manner into EVs and, resveratrol presents an important role in inducing senescence in INS1E-hIAPP pancreatic β cells.
Oxytocin lipidation expanding therapeutics for long-term reversal of autistic behaviors in rats.
Int J Pharm
Honglin Li, Ya Chen, Yue Qiu
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction and repetitive, stereotyped behaviors. There is no universally effective pharmacological treatment targeting its core symptoms.Oxytocin, an endogenous polypeptide known as the "social hormone", has shown potential in improving emotional recognition and social interactions in individuals with ASD. However, its clinical application has been limited due to its short half-life and poor blood-brain barrier penetration. To address these challenges, we utilized peptide lipidation technology to enhance the pharmacokinetic properties and brain bioavailability of oxytocin. A series of lipidated oxytocin analogs was designed and synthesized, exhibiting superior brain distribution and pharmacokinetic profiles in valproic acid-induced autistic rat models compared to unmodified oxytocin. Among theseanalogs, C16-modified oxytocin (C16-OT), administered intrathecally, achieved the most extensive brain distribution with limited presence in the blood, resulting in long-lasting improvements in autistic behaviors. These improvements, including enhanced social behaviors and reduced stereotypical actions, were sustained for up to 42 days, contrasting with the brief effects typically reported in previous studies. Furthermore, a comparison of administration routes revealed that intrathecal injection achieved higher brain concentrations and more prolonged social behavioral improvements than intranasal delivery. These findings provide robust preclinical evidence that C16-OT, through optimized lipidation and intrathecal delivery, offers sustained central nervous system activity and significant, long-term reversal of social behavioral deficits in rats with autism.
Antheraea pernyi silk nanofibrils with inherent RGD motifs accelerate diabetic wound healing: A novel drug-free strategy to promote hemostasis, regulate immunity and improve re-epithelization.
Biomaterials
Lian Duan, Ga Liu, Fuying Liao +7 more
The chronic inflammation and matrix metalloprotease (MMP)-induced tissue degradation significantly disrupt re-epithelization and delay the healing process of diabetic wounds. To address these issues, we produced nanofibrils from Antheraea pernyi (Ap) silk fibers via a facile and green treatment of swelling and shearing. The integrin receptors on the cytomembrane could specifically bind to the Ap nanofibrils (ApNFs) due to their inherent Arg-Gly-Asp (RGD) motifs, which activated platelets to accelerate coagulation and promoted fibroblast migration, adhesion and spreading. These degradable nanofibrils served as effective competitive substrates to reduce MMP-induced tissue degradation. ApNFs and their enzymatic hydrolysates could modulate macrophage polarization due to their RGD motifs. RNA sequencing further revealed that ApNFs treatment activated the JAK2-STAT5b and PI3K-Akt signaling pathways while suppressed the NF-κB, IL-17 and TNF signaling pathways in macrophages. The full-thickness skin wound experiments confirmed that ApNFs significantly accelerated wound healing in both diabetic and non-diabetic rats. Notably, in diabetic wound, ApNFs and their enzymatic hydrolysates polarized the accumulated M1-type macrophages into M2-type, which promoted the wound to get rid of the inflammatory stage and transition to the following proliferative stage, improving the wound healing percentage on day 14 from 74.9 % to 93.2 % by facilitating collagen deposition, angiogenesis and re-epithelization. These results demonstrate that ApNFs are promising drug-free diabetic wound dressings with favorable inherent immunoregulatory properties for biomedical translation.
Advances in the therapeutic potentials of ligands of the apelin receptor APJ.
Eur J Pharmacol
Gerry T M Wagenaar, Gert N Moll
Angiotensin II protein J receptor, APJ, is a type A G protein coupled receptor. Endogenous apelin and elabela peptides stimulate APJ via distinct signalling profiles. A complex signalling map of elabela-stimulated APJ was published in 2022. Dimerization or oligomerization of APJ with itself or other receptor(s) can affect APJ signalling. Apelin has been shown to tolerate mutations and/or modifications at multiple sites without abolishing activity. This offers a great opportunity to design and engineer variants with desired signalling profiles and enhanced resistance to breakdown by peptidases. Several biased agonists with enhanced therapeutic potential have been generated. APJ agonists have therapeutic potential in multiple diseases including cardiovascular, renal, pulmonary and metabolic diseases, and viral infections. APJ antagonists may have therapeutic potential in cancer and retinopathy, and in related diseases in which unwanted angiogenesis is to be halted. A growing understanding of APJ signalling pathways and the robust therapeutic potential of associated ligands for many serious diseases will stimulate the clinical development of APJ ligands.
Sex-specific alterations in emotional behavior and neurotransmitter systems in LPA1 receptor-deficient mice.
Neuropharmacology
Laura Sánchez-Marín, Violeta Jiménez-Castilla, María Flores-López +7 more
Lysophosphatidic acid (LPA) and the endocannabinoid system (ECS) are critical lipid signaling pathways involved in emotional regulation and behavior. Despite their interconnected roles and shared metabolic pathways, the specific contributions of LPA signaling through the LPA1 receptor to stress-related disorders remain poorly understood. This study investigates the effects of LPA1 receptor deficiency on emotional behavior and neurotransmitter-related gene expression, with a focus on sex-specific differences, using maLPA1-null mice of both sexes. We hypothesized LPA1 receptor loss disrupts the interplay between LPA and the endocannabinoid 2-arachidonoylglycerol (2-AG) signaling, resulting in distinct behavioral and molecular alterations. maLPA1-null mice exhibited increased anxiety-like behaviors and altered stress-coping responses compared to wild-type counterparts, with more pronounced effects observed in females. Female mice also displayed higher corticosterone levels, though no genotype-related differences were observed. Plasma analyses revealed elevated LPA levels in maLPA1-null mice, suggesting a compensatory mechanism, and reduced 2-AG levels, indicating impaired ECS signaling. Gene expression profiling in the amygdala and medial prefrontal cortex showed significant alterations in the gene expression of key components of LPA and 2-AG signaling pathways, as well as neuropeptide systems such as corticotropin-releasing hormone (CRH) and neuropeptide Y (NPY). Glutamatergic signaling components also exhibited sex-specific variations. These findings suggest that LPA1 receptor deficiency impacts behavioral response and disrupts sex-specific neurotransmitter signaling, emphasizing the importance of LPA-ECS crosstalk in emotional regulation. This study provides insights into the molecular mechanisms underlying stress-related disorders such as depression and anxiety, which may inform the development of sex-specific therapeutic approaches.