Peptide Antagonist Research Articles

Double-blinded, randomized tolerance study of a biologically enhanced Nanogel with endothelin-1 and bradykinin receptor antagonist peptides via intra-articular injection for osteoarthritis treatment in horses

BackgroundOsteoarthritis is a leading cause of pain and retirement in athletic horses. Hydro-expansive functionalized nanogels, acting as Drug Delivery Systems, constitute one of the current therapeutic prospects. These nanogels have the potential to combine mechanical benefits through polymers with the biological effect of prolonged release of bioactive molecules. The purpose of this double-blinded randomized tolerance study versus negative control was to evaluate the response of healthy joints to a single injection of the expected efficient dose (further referred to as the trial dose) and overdose of nanogels composed of chitosan and hyaluronic acid and featuring a type A endothelin receptor antagonist and a type B1 bradykinin receptor antagonist. The metacarpophalangeal joints of 8 healthy horses were randomly injected with 2.4 mL of functionalized nanogels and 2.4 mL of saline as control on the contralateral limb. Injections were repeated twice at one-week intervals, followed by injection of a triple dose of nanogel on week four. Clinical, ultrasonographic and synovial fluid cellular and biochemical follow-ups were performed up to three months following the first injection.ResultsNo change in general clinical parameters, lameness or sensitivity to passive flexion of the fetlocks was noted. Mild to moderate synovitis was noted on the day following injection in the treated group, with a significant difference (p < 0.05) compared to the control group. It spontaneously resolved on day 3 following the injections and did not increase with repeated injections. Similar effects were noted after injection of the triple dose but lasted for a week. Synovial fluid markers of inflammation also showed a transient significant increase in the treated group one week after each injection, but no differences were detected at the end of the study.ConclusionsInjections of the expected therapeutic dose of functionalized nanogel in healthy joints induced a mild transient inflammatory response in the joint. Three injections of the trial dose at one-week intervals and injection of thrice the trial dose induce a mildly greater inflammation without harmful effects on joints. Functionalized nanogels are well tolerated prospects for the treatment of osteoarthritis in horses. Their beneficial effects on arthritic joints have yet to be evaluated to determine their therapeutic potential.

Spinal pituitary adenylate cyclase-activating polypeptide and PAC1 receptor signaling system is involved in the oxaliplatin-induced acute cold allodynia in mice

Chemotherapy-induced peripheral neuropathy (CIPN) is a type of peripheral neuropathy that develops in patients treated with certain anticancer drugs. Oxaliplatin (OXA) causes CIPN in approximately 80–90 % of patients; thus, it is necessary to elucidate its underlying mechanism and develop effective treatments and prevention methods. The purpose of this study was to determine whether the pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1 receptor system in the spinal dorsal horn is involved in OXA-induced acute cold allodynia and examine the effect of a PAC1 receptor antagonist. Administration of OXA induced acute cold allodynia in wild-type mice, but not in PACAP-/- mice. In the dorsal root ganglia, OXA upregulated PACAP expression, particularly in small-sized neurons. OXA-induced cold allodynia was ameliorated by intrathecal (i.t.) injection of PACAP6–38 (peptide antagonist for PACAP receptor) and PA-8 (small-molecule antagonist specific for PAC1 receptor). I.t. PACAP, but not vasoactive intestinal polypeptide, resulted in cold allodynia, which was blocked by PA-8. OXA induced the activation of spinal astrocytes in a PAC1 receptor-dependent manner. The results suggest that spinal PACAP/PAC1 receptor systems are involved in OXA-induced acute cold allodynia through astrocyte activation. Furthermore, we demonstrated that the systemic administration of PA-8 resulted in therapeutic and preventative effects on OXA-induced acute cold allodynia. Because PA-8 did not affect the anticancer effects of OXA, we propose PAC1 receptor inhibition as a new strategy for the treatment and prevention of CIPN. PerspectiveCold allodynia is a hallmark of OXA-induced peripheral neuropathy. This study demonstrated the involvement of spinal PACAP/PAC1 receptors in OXA-induced acute cold allodynia. We propose PAC1 receptor inhibition as a new strategy for the treatment and prevention of OXA-induced acute cold allodynia.

The antidepressant-like effects of kisspeptin-10 are reversed by kisspeptin antagonist peptide 234 in male rats.

Kisspeptins are reported to be the most potent activators of the hypothalamus-pituitary-gonadal (HPG) axis known to date. Kisspeptin potently elicits gonadotropin-releasing hormone (GnRH) release and luteinizing hormone (LH) secretion, even in the pre-pubertal period. Beyond the hypothalamus, kisspeptin is also expressed in limbic and paralimbic brain regions, which are areas of the neurobiological network primarily implicated in emotional behaviors alongside sexual functions. Therefore, an increasing body of studies has implicated kisspeptin as having many influences on emotional behaviors. The study was set out to explore if the kisspeptin/GPR54 signaling system is required for the anti-depressant-like effect of kisspeptin-10 (KP-10), besides the regulation of the HPG axis. To test this concept, peptide 234 (P234), a kisspeptin antagonist, was given to the male rats, and its modulatory effect on the anti-depressant-like effects of kisspeptin was investigated by using a forced swimming test (FST). The study has also sought to know whether kisspeptin can exert its effects through adrenergic and serotonergic receptors. To investigate this, the agents yohimbine (Yoh), an alpha-2 adrenergic receptor antagonist, and cyproheptadine (Cry), a non-selective 5-HT2 serotonergic receptor antagonist, were administered in the experiments. Our results indicate that, in rats, the anti-depressant-like effects of KP-10 in a modified rat FST are mediated by GPR54 receptors, since the kisspeptin antagonist peptide 234 reversed kisspeptin-induced anti-depressant-like effects. Our data also demonstrate that the anti-depressant-like effects of kisspeptin, at least in part, are mediated by an interaction of the alpha-2 adrenergic and 5-HT2 serotonergic receptors.

Designed Cell-Penetrating Peptide Constructs for Inhibition of Pathogenic Protein Self-Assembly.

Peptides possess a number of pharmacologically desirable properties, including greater chemical diversity than other biomolecule classes and the ability to selectively bind to specific targets with high potency, as well as biocompatibility, biodegradability, and ease and low cost of production. Consequently, there has been considerable interest in developing peptide-based therapeutics, including amyloid inhibitors. However, a major hindrance to the successful therapeutic application of peptides is their poor delivery to target tissues, cells or subcellular organelles. To overcome these issues, recent efforts have focused on engineering cell-penetrating peptide (CPP) antagonists of amyloidogenesis, which combine the attractive intrinsic properties of peptides with potent therapeutic effects (i.e., inhibition of amyloid formation and the associated cytotoxicity) and highly efficient delivery (to target tissue, cells, and organelles). This review highlights some promising CPP constructs designed to target amyloid aggregation associated with a diverse range of disorders, including Alzheimer's disease, transmissible spongiform encephalopathies (or prion diseases), Parkinson's disease, and cancer.

Identification and characterization of vasoactive intestinal peptide receptor antagonists with high-affinity and potent anti-leukemia activity.

Vasoactive intestinal peptide (VIP) is a neuropeptide involved in tumor growth and immune modulating functions. Previous research indicated that a VIP antagonist (VIPhyb) enhances T-cell activation and induces T-cell-dependent anti-leukemic activity in mice. We created a combinatorial library of VIPhyb C-terminal sequence variations to develop a more potent VIP-receptor (VIP-R) antagonist, hypothesizing that specific amino acid substitutions would improve receptor binding and plasma stability. In silico screening analyses identified sequences with improved docking scores predicting increased binding affinity to human VIP receptors VPAC1 and VPAC2. Fifteen peptides were synthesized and tested for their ability to potentiate activation of purified mouse and human T cells and enhance T cell-dependent anti-leukemia responses in murine models of acute myeloid leukemia. Treating C57Bl/6 mice engrafted with a C1498 myeloid leukemia cell line with daily subcutaneous injections of VIP-R antagonist peptides induced T cell activation resulting in specific anti-leukemia responses. Strikingly, the predicted binding affinity of the VIP-R antagonists to VIP receptors correlated positively with their ability to augment mouse T-cell proliferation and anti-leukemia activity. ANT308 and ANT195 emerged as top candidates due to their high predicted VIP-R binding, low EC 50 for in vitro T cell activation, and potent anti-leukemia activities. ANT308 decreased CREB phosphorylation, a downstream signaling pathway of the VIP receptor, and stimulated granzyme B and perforin expression in CD8+ T cells from AML patients. Combining in silico modeling, in vitro T cell activation properties, and in vivo anti-leukemia activity has identified promising VIP-R antagonist candidates for further development as novel immunotherapies for AML, especially for patients with relapsed disease.

EXTH-18. ADAPTER CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY TARGETING SSTR2 IN MENINGIOMA

Abstract Effective treatment options for meningioma patients beyond surgical resection and radiotherapy are limited. This study presents preclinical and translational evidence supporting the efficacy of an adaptor CAR-T cell system targeting Somatostatin Receptor (SSTR) 2 in otherwise untreatable meningiomas. Tissue microarray analysis revealed that SSTR2 expression was generally heterogeneous but high or intermediate in most World Health Organization (WHO) grade 2 (87.8%) and grade 3 (87.5%) meningiomas. The fluorescein-linked, SSTR2 antagonist peptide octofluo was used in conjunction with adaptor FITC (AdFITC) CAR-T cells to treat experimental meningiomas. In vitro, 10 nM octofluo induced tumor cell killing within 72 hours at effector-target cell ratios (E:T) as low as 1:100. This was observed in two human meningioma cell lines, Ben-Men-1 (CAR-T cells vs. untransduced T-cells [UTT]: 47.9% vs. 4.7%, P &amp;lt; 0.001) and IOMM-Lee (CAR-T cells vs. UTT: 40.2% vs. 4.9%, P &amp;lt; 0.001). In vivo, the AdFITC CAR-T cell system inhibited meningioma growth (P = 0.002) and prolonged survival (P = 0.003) in the IOMM-Lee orthotopic model compared to PBS. In a genetically engineered murine meningioma model, the AdFITC CAR-T cell system not only restricted tumor growth (P = 0.0018) and improved survival (P &amp;lt; 0.0001), but cured a substantial proportion of meningioma bearing mice. This treatment also induced the expansion of both CD8+ CAR-T cells (P = 0.0041) and a host T-cell response. Preliminary ex vivo killing assays, involving co-culture of the AdFITC CAR-T cell system with patient-derived meningioma tissue, showed specific lysis rates of 15-20% (ET 1:1) within 12 hours. Targeting SSTR2 with the AdFITC CAR-T cell system emerges as a promising therapeutic approach for meningioma, an early phase clinical trial is warranted.

Antagonistic CLE peptide pathways shape root meristem tissue patterning.

Secreted CLAVATA3/EMBRYO SURROUNDING REGION (CLE) peptide ligands dimension the stem cell niche of Arabidopsis shoot meristems by signalling through redundant and cross-compensating CLAVATA1 (CLV1)-type receptor kinases. In the root meristem, the CLV1 homologues BARELY ANY MERISTEM 1 (BAM1) and BAM2 drive CLE13/16-mediated formative divisions that produce the ground tissue layers. Here we report that BAM1/2 are also required to initiate the vascular phloem lineage and that cross-compensation between CLV1-type receptors as observed in the shoot does not operate similarly in the root. Rather, we find that BAM3-mediated CLE45 signalling antagonizes BAM1/2-mediated CLE11/12/13 signalling in the phloem initials but not in the ground tissue. We further observe spatiotemporally contrasting CLE signalling requirements for phloem initiation and differentiation, which are shaped by the SHORT ROOT (SHR) pathway. Our findings thus suggest an intricate quantitative interplay between distinct and antagonistic CLE signalling pathways that organizes tissue layer formation in the Arabidopsis root meristem.

Human adipose-derived stem cells promote migration of papillary thyroid cancer cell via leptin pathway

Introduction Obesity is associated with the incidence and poor prognosis of thyroid cancer, but the mechanism is not fully understood. The aim of this study was to investigate the effects of human adipose-derived stem cells (ADSCs) on the invasion and migration of thyroid cancer cells. Methods ADSCs-conditioned medium (ADSC-CM) was collected to culture thyroid cancer cell lines TPC-1 cells and BCPAP cells. The effects of ADSCs on thyroid cancer cell proliferation were determined by CCK8 and EdU assays, and the effects on migration were determined by Transwell and wound closure assays. Leptin neutralizing antibodies (NAB) were added to ADSC-CM to block leptin. In animal experiments, TPC-1 cells and BCPAP cells were injected into the tail vein of nude mice, and the leptin receptor antagonist peptide allo-aca was injected subcutaneously to block the leptin pathway. The number and size of metastatic lung tumours were observed after 8 weeks. Results ADSC-CM significantly promoted the invasion and migration of thyroid cancer cells and upregulated their matrix metalloproteinase 2 (MMP-2) levels, while NAB with the addition of leptin reduced the invasion and migration of thyroid cancer cells and downregulated MMP-2 levels. Allo-aca treatment reduced the number of metastatic lung nodules formed by thyroid cancer cells in nude mice and reduced the diameter of metastatic lesions. Conclusion ADSCs upregulate MMP-2 levels of thyroid cancer cells through exocrine leptin, thereby promoting cancer cell migration, which may be one of the key mechanisms by which obesity increases the invasiveness of thyroid cancer.

Hippocampal Nogo66-NgR1 signaling activation restricts postsynaptic assembly in aged mice with postoperative neurocognitive disorders.

Postoperative neurocognitive disorders (pNCD) are a common neurological complication, especially in elderly following anesthesia and surgery. Yet, the underlying mechanisms of pNCD remain elusive. This study aimed to investigate the molecular mechanisms that compromise synaptic metaplasticity in pNCD development with a focus on the involvement of Nogo-66 receptor 1 (NgR1) in the pathogenesis of pNCD in aged mice. Aged mice subjected to anesthesia and laparotomy surgery exhibited anxiety-like behavior and contextual fear memory impairment. Moreover, the procedure significantly increased NogoA and NgR1 expressions, particularly in the hippocampal CA1 and CA3 regions. This increase led to the depolymerization of F-actin, attributed to the activation of the RhoA-GTPase, resulting in a reduction of dendritic spines and changes in their morphology. Additionally, these changes hindered the efficient postsynaptic delivery of the subunit GluA1 and GluA2 of AMPA receptors (AMPARs), consequently diminishing excitatory neurotransmission in the hippocampus. Importantly, administering the competitive NgR1 antagonist peptide NEP1-40 (Nogo-A extracellular peptide residues 1-40 amino acids of Nogo-66) and Fasudil (a Rho-kinase inhibitor) effectively mitigated synaptic impairments and reversed neurocognitive deficits in aged mice following anesthesia and surgery. Our work indicates that high hippocampal Nogo66-NgR1 signaling disrupts postsynaptic AMPA receptor surface delivery due to F-actin depolymerization in the pathophysiology of pNCD.

Unbiased high-throughput screening of drug-repurposing libraries identifies small-molecule inhibitors of clot retraction

AbstractPlatelet clot retraction, the ultimate phase of platelet thrombus formation, is critical for clot stabilization. It requires functional αIIbβ3 receptors, fibrin, and the integrated actions of the actin-myosin contractile and cytoskeletal systems. Disturbances in clot retraction have been associated with both bleeding and thrombosis. We recently demonstrated that platelets treated with the αIIbβ3 antagonist peptide RGDW, which eliminates fibrinogen-mediated platelet aggregation, are still able to retract clots. We have exploited this observation to develop an unbiased, functional high-throughput assay to identify small-molecule inhibitors of fibrin-mediated clot retraction adapted for a 384-well plate format. We tested 9710 compounds from drug-repurposing libraries (DRLs). These libraries contain compounds that are either US Food and Drug Administration approved or have undergone preclinical/clinical development. We identified 27 compounds from the Library of Pharmacologically Active Compounds library as inhibitors of clot retraction, of which 14 are known inhibitors of platelet function. From the DRLs, we identified 135 compounds (1.6% hit rate). After extensive curation, these compounds were categorized based on the activity of their reported target. Multiple kinase and phosphodiesterase inhibitors with known antiplatelet effects were identified, along with multiple deubiquitination and receptor inhibitors, as well as compounds that have not previously been reported to have antiplatelet activity. Studies of 1 of the deubiquitination inhibitors (degrasyn) suggest that its effects are downstream of thrombin-induced platelet-fibrinogen interactions and thus may permit the separation of platelet thrombin-induced aggregation-mediated events from clot retraction. Additional studies of the identified compounds may lead to novel mechanisms of inhibiting thrombosis.

GAP JUNCTION FUNCTION IS ESSENTIAL FOR SURVIVAL OF ACUTE LYMPHOBLASTIC LEUKEMIA CELLS.

Acute lymphoblastic leukemia has an intimate physical relationship with nonmalignant bone marrow stromal cells. We have recently demonstrated that stromal cells contribute to the survival of leukemia cells and that there is a bidirectional transfer of intracellular material between them. Understanding the mechanisms of stromal support of leukemia may provide insights into new therapies. To test the hypothesis that gap junctions are formed between acute lymphoblastic leukemia cells and nonmalignant stromal cells, and that gap junction function is essential for the survival of leukemia cells. We employed a well-characterized in vitro model of human bone marrow stromal cells and primary human B lymphoblastic leukemia cells and measured leukemia cell survival in coculture using flow cytometry. We measured the effects of gap junction antagonist peptides, carbenoxolone (a drug known to interfere with the gap junction function), and several leukemia chemotherapy drugs including methotrexate upon leukemia cell survival. We demonstrated that stromal cells need to be alive and metabolically active to keep leukemia cells alive. Physical contact between stromal and leukemia cells leads to an increase in gap junction proteins in leukemia cells. Gap junction inhibitory peptides impaired leukemia cell survival as did carbenoxolone, a nonpeptide inhibitor of the gap junction function. Stromal cell survival was not affected. We observed a very modest enhancement of methotrexate antileukemia activity by low-dose carbenoxolone but no significant interactions with dexamethasone, vincristine, mercaptopurine, or doxorubicin. These studies demonstrate that acute lymphoblastic cell survival is impaired by interference with the gap junction function. The development of drugs targeting gap junctions may provide a novel approach to the therapy of acute lymphoblastic leukemia.

Evaluation of rimegepant utilization patterns and patient characteristics among new users: a United States administrative claims-based study

Objective To assess tablet utilization patterns and describe pre-treatment characteristics among new users of rimegepant. Background Rimegepant is the only oral calcitonin gene-related peptide antagonist approved in the United States for both the acute and preventive treatment of migraine. Methods We conducted a retrospective cohort study of people with migraine who initiated treatment with rimegepant using two US commercial claims databases (MarketScan and Optum). Patients (≥18 years old) with migraine who newly initiated rimegepant were included. Patients were stratified into two groups representing acute (quantity = 8) and prevention (quantity = 15 or 16) use cohorts. Baseline characteristics and medication use history were assessed on index and during the 365-day pre-index period. Rimegepant utilization periods were calculated based on days supplied and varying approaches to define use periods. Tablet quantity per 30 days was reported separately for both acute and prevention cohorts. Results In MarketScan, a total of 14,037 rimegepant users were identified; 11,195 (79.8%) in the acute group and 1,880 (13.4%) in the prevention group. Rimegepant utilization for acute use was 4.9 ± 2.1 tablets per 30 days and for preventive use was 13.1 ± 7.7 tablets per 30 days. There was high baseline prevalence of triptan contraindications, warnings, and high cardiovascular risk, with a combined 46.2% meeting one or more of these criteria. Acute medication overuse was also common (25.1%) prior to rimegepant initiation. Results were consistent in the Optum database. Conclusion Our analysis provides the first real-world data available on tablet utilization and characteristics of new users of rimegepant.

Concomitant use of calcitonin gene-related peptide (CGRP) antagonists with azole antifungals in patients with hematological malignancies.

Small molecule calcitonin gene-related peptide (CGRP) antagonists such as rimegepant, ubrogepant, and atogepant have been approved for migraine treatment and/or prevention. These molecules are metabolized by cytochrome P-450 3A4 (CYP3A4) enzymes in vivo, hence they are contraindicated or recommended to be avoided in combination with strong/moderate CYP3A4 inhibitors, namely posaconazole (strong) and isavuconazonium (moderate). However, no literature has been published on the impact this interaction has on patient safety and tolerability. In this case series, we report five cases in which CGRP antagonists and azole antifungal therapy were given concurrently, to provide real-world outcomes of this interaction. Electronic medical records at our hospital system were reviewed between January 2021 and December 2023 to find patients who met the criteria of hematological malignancy, taking CGRP-antagonist and azole antifungal therapy. Records were then further investigated to find cases where CGRP antagonists and azole antifungals were used concomitantly. Concurrent use of CGRP antagonists and azole antifungal therapy was feasible for patients with migraines and hematological malignancies. None of the patients experienced any grade 3 or higher non-hematological toxicity from the proposed over-exposure to CGRP antagonist. The combination was well tolerated without any need for therapy discontinuation or dose modifications. It is recommended to follow the manufacturers' guidance on drug interactions, however, in the setting where there are no other options, concomitant use of CGRP antagonists with azole antifungals is possible with monitoring and observation for adverse effects.

A Retrospective Analysis of Disease Epidemiology, Comorbidity Burden, Treatment Patterns, and Healthcare Resource Utilization of Migraine in the United Arab Emirates.

Migraine is a recurrent, disabling neurological disorder with a substantial global disease burden. However, limited real-world data are available on the patient characteristics, treatment patterns, comorbidities, and economic burden of migraine in the United Arab Emirates (UAE). In this study, we evaluated the disease burden, comorbidities, treatment patterns, specialties involved in migraine diagnosis, and healthcare resource utilization (HCRU) and associated costs in patients with migraine in Dubai, UAE. A retrospective, secondary database cohort study was conducted from 01 January 2014 to 31 March 2022 using the Dubai Real-World Database. Patients aged ≥ 18years with at least one diagnosis claim for migraine with continuous enrollment during the study period were included. Patients were stratified into treatment sub-cohorts. Outcomes were evaluated in terms of clinical characteristics, comorbidities, specialists visited, treatment patterns, and HCRU. The study included 203,222 patients (mean age: 40years), with male predominance (55.4%). About 13.4% of patients had specific cardiovascular comorbidities. Frequently prescribed drug classes were nonsteroidal anti-inflammatory drugs (84.4%), triptans (29.8%), and beta-blockers (12.8%), while only 1.0% of patients with migraine were prescribed newer medications like calcitonin gene-related peptide antagonists. General medicine was the most frequently visited specialty on the index date (51.5%). The all-cause and migraine-specific median gross costs during the 12-month post-index period were US $1252.6 (2.4-564,740.7) and US $198.1 (0-168,903.3) respectively, with maximum contribution from inpatients. The contribution of migraine-specific median costs to all-cause median costs was highest for the diagnosis-related group (64.9%), followed by consumables (35.2%), medications (32.0%), procedures (24.5%), and services (24.5%). Migraine significantly impacts healthcare costs in the UAE. The role of newer therapies in migraine management should be explored to reduce the associated socioeconomic burden and improve patients' quality of life.

Elucidation of neuronal activity in mouse models of temporomandibular joint injury and inflammation by in vivo GCaMP Ca2+ imaging of intact trigeminal ganglion neurons.

Patients with temporomandibular disorders (TMDs) typically experience facial pain and discomfort or tenderness in the temporomandibular joint (TMJ), causing disability in daily life. Unfortunately, existing treatments for TMD are not always effective, creating a need for more advanced, mechanism-based therapies. In this study, we used in vivo GCaMP3 Ca2+ imaging of intact trigeminal ganglia (TG) to characterize functional activity of the TG neurons in vivo, specifically in mouse models of TMJ injury and inflammation. This system allows us to observe neuronal activity in intact anatomical, physiological, and clinical conditions and to assess neuronal function and response to various stimuli. We observed a significant increase in spontaneously and transiently activated neurons responding to mechanical, thermal, and chemical stimuli in the TG of mice with TMJ injection of complete Freund adjuvant or with forced mouth opening (FMO). An inhibitor of the calcitonin gene-related peptide receptor significantly attenuated FMO-induced facial hypersensitivity. In addition, we confirmed the attenuating effect of calcitonin gene-related peptide antagonist on FMO-induced sensitization by in vivo GCaMP3 Ca2+ imaging of intact TG. Our results contribute to unraveling the role and activity of TG neurons in the TMJ pain, bringing us closer to understanding the pathophysiological processes underlying TMJ pain after TMJ injury. Our study also illustrates the utility of in vivo GCaMP3 Ca2+ imaging of intact TG for studies aimed at developing more targeted and effective treatments for TMJ pain.

Antagonistic insulin-like signaling influencing glucose regulation in C. elegans

The insulin/ IGF-signaling (IIS) is an evolutionary conserved signaling pathway within eukaryotic organisms that regulates glucose metabolism and cell division. The nematode, C. elegans is an excellent model for exploring IIS as they have 40 insulin-like peptides that act on a single receptor, DAF-2. We aim to explore the relationships between IIS and glucose metabolism, focusing on the antagonistic insulin-like peptide, INS-17 and its influence over FDGT-1 (facilitated glucose transporter 1). FDGT-1 is expressed throughout the nematode, including the basolateral membrane of intestinal cells and where it is theorized to export glucose to the surrounding somatic cells rather than absorb it from the intestinal tract. We hypothesize that IIS controls transcription of FDGT-1 and antagonistic peptides should lead to a decrease in FDGT-1 transcription, resulting in the increased lifespan and increased fat accumulation observed in daf-2(lf) loss of function and ins-17(oe) over expressing strains. In this study, survival assays are used to assess the impact which high-glucose content has on lifespan, along with Oil Red O (ORO) lipid staining to visualize lipid accumulation amongst conditions and protein quantification of FDGT-1:GFP to evaluate FDGT-1 protein levels. Our findings are consistent with the idea of low insulin signaling leading to extended lifespan as daf-2(lf) lived significantly longer than WT in both 0% and 2% glucose conditions and ins-17(oe) living significantly longer than wildtype in 2% glucose conditions. The ORO lipid staining revealed that high glucose conditions and low insulin signaling result in lipid accumulation within the nematode. Using the fdgt-1:gfp strain, we were able to determine an increase in the FDGT-1 in the presence of glucose, suggesting FDGT-1 expression is influenced by glucose. These findings aim to further our understanding of IIS regulating glucose uptake and metabolism, along with the significance of the FDGT-1 glucose transporter.

GDF15 Targeting for Treatment of Hyperemesis Gravidarum.

Nausea and vomiting during pregnancy (NVP), particularly its severe form, Hyperemesis gravidarum (HG), affects up to 70% of pregnancies and significantly impacts the quality of life for those with the condition as well as generates a great economic burden, with annual costs exceeding $1.7 billion in the United States. Despite the available treatments targeting neurotransmitters like serotonin and dopamine, many patients experience inadequate relief and suffer from severe side effects, including headaches and dizziness. Recent research has underscored the role of GDF15, a protein mainly produced by the placenta and linked to NVP symptoms. This protein, part of the TGF-β superfamily, has been implicated in appetite and weight regulation and is altered in those with HG due to specific genetic mutations. Addressing the challenges of delivering effective treatments, current innovations focus on targeting GDF15 to reduce symptoms while ensuring fetal safety. Promising therapeutic strategies include non-IgG immunotherapies, small peptide and molecule antagonists, and novel administration methods such as transdermal patches. These approaches aim to optimize dosage and reduce adverse effects. The effective development and testing of these treatments necessitate advanced animal models that closely resemble human pregnancy physiology, highlighting the need for further research and funding. This ongoing research holds significant potential to improve the clinical outcomes for HG patients and decrease the economic impact on healthcare systems, urging a dedicated response from the scientific and medical communities to advance these promising treatments.

Cyclic Peptides KS-133 and KS-487 Multifunctionalized Nanoparticles Enable Efficient Brain Targeting for Treating Schizophrenia.

Establishing drug delivery systems (DDSs) for transporting drugs from peripheral tissues to the brain is crucial for treating central nervous system diseases. We previously reported the interactions of (1) KS-133, a selective antagonist peptide, with vasoactive intestinal peptide receptor 2 (VIPR2), a drug target for schizophrenia, and (2) KS-487, a selective binding peptide, with the cluster IV domain of low-density lipoprotein receptor-related protein 1 (LRP1), which is involved in crossing the blood-brain barrier. We developed a novel DDS-based strategy for treating schizophrenia using KS-487 as a brain-targeting peptide and KS-133 as a drug. Dibenzocyclooctyne-KS-487 was conjugated with N3-indocyanine green (ICG) using a click reaction and administered intravenously into mice. Fluorescence was clearly observed from ICG in the brains of the mice. Nanoparticles (NPs) encapsulating ICG and displaying KS-487 were prepared and subcutaneously administered to mice, resulting in a significant accumulation of ICG in the brain. Pharmacokinetic analysis of NPs containing KS-133 and displaying KS-487 (KS-133/KS-487 NPs) revealed the time-dependent transport of KS-133 into the brain. KS-133/KS-487 NPs were subcutaneously administered to mouse models of schizophrenia, which significantly improved cognitive dysfunction. This is the first study to demonstrate the potential therapeutic efficacy of a multifunctionalized multipeptide NP in inhibiting VIPR2.

Old and New Biologics and Small Molecules in Inflammatory Bowel Disease: Anti Integrins

Recently, novel biologics or small molecular drugs have been introduced for overcoming the unmet needs associated with anti-tumor necrosis factor α agents for inflammtory bowel disease (IBD) treatment. Among these novel drugs, anti integrin agents block leukocyte trafficking to the intestine by blocking the interaction between integrin and cell adhesion molecules. Vedolizumab (anti-α4β7) is most widely used anti-integrin approved in both ulcerative colitis and Crohn's disease .It has been shown to be effective in both induction and maintenance therapy with a favorable safety profile due to gut selectivity. Several models incorporating clinical, genetic, immune and gut microbial markers to predict response to vedolizumab in IBD have been developed. Etrolizumab (anti-β7) blocks leukocyte trafficking via α4β7 and cell adhesion via αEβ7 integrins. In addition, the introduction of subcutaneous vedolizumab showed similar efficacy and safety with improved patients' convenience. Other investigational anti-integrin therapies include abrilumab (anti-α4β7 IgG2), PN-943 (orally administered and gut-restricted α4β7 antagonist peptide), AJM300 (orally active small molecule inhibitor of α4), and ontamalimab (anti-MAdCAM-1 IgG).

Role of Cholecystokinin (cck) in Feeding Regulation of Largemouth Bass (Micropterus salmoides): Peptide Activation and Antagonist Inhibition.

This study investigated the role of cholecystokinin (cck) in the feeding regulation of largemouth bass (Micropterus salmoides) via peptide activation and antagonist inhibition. The results show that the cck gene was expressed in various tissues, with the highest expression level occurring in the brain. Feeding, continuous feeding, and refeeding after fasting could significantly improve the mRNA levels of cck in the brain. Moreover, the activation of cck via injecting an exogenous CCK peptide could inhibit feed intake by regulating the mRNA levels of anorexigenic and feed-promoting factors in the brain and intestine. Furthermore, the CCK peptide reduced feed intake; however, the presence of an antagonist (Ly225910-CCK1R and devazepide-CCK2R) could reverse this effect through regulating the mRNA levels of anorexigenic and feed-promoting factors in the brain and intestine. Treatment with devazepide + CCK (CCK2R) reversed feed intake more effectively than Ly225910 + CCK (CCK1R) treatment. In summary, cck could regulate the feed intake of largemouth bass through regulating feeding-related genes in the brain and intestine. In addition, cck required binding with the receptor to inhibit feed intake more effectively in largemouth bass, and the binding effect of CCK1R was better than that of CCK2R.