Novel Pharmaceuticals in Appetite Regulation: Exploring emerging gut peptides and their pharmacological prospects.

Obesity, a global health challenge, necessitates innovative approaches for effective management. Targeting gut peptides in the development of anti-obesity pharmaceuticals has already demonstrated significant efficacy. Ghrelin, peptide YY (PYY), cholecystokinin (CCK), and amylin are crucial in appetite regulation offering promising targets for pharmacological interventions in obesity treatment using both peptide-based and small molecule-based pharmaceuticals. Ghrelin, a sole orexigenic gut peptide, has a potential for anti-obesity therapies through various approaches, including endogenous ghrelin neutralization, ghrelin receptor antagonists, ghrelin O-acyltransferase, and functional inhibitors. Anorexigenic gut peptides, peptide YY, cholecystokinin, and amylin, have exhibited appetite-reducing effects in animal models and humans. Overcoming substantial obstacles is imperative for translating these findings into clinically effective pharmaceuticals. Peptide YY and cholecystokinin analogues, characterized by prolonged half-life and resistance to proteolytic enzymes, present viable options. Positive allosteric modulators emerge as a novel approach for modulating the cholecystokinin pathway. Amylin is currently the most promising, with both amylin analogues and dual amylin and calcitonin receptor agonists (DACRAs) progressing to advanced stages of clinical trials. Despite persistent challenges, innovative pharmaceutical strategies provide a glimpse into the future of anti-obesity therapies.

Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice.

The melanocortin-3 receptor (MC3R) regulates GABA release from agouti-related protein (AgRP) nerve terminals and thus tonically suppresses multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of the MC3R and the melanocortin system in regulating the response to various anorexigenic agents. The genetic deletion or pharmacological inhibition of the MC3R, or subthreshold doses of an MC4R agonist, improved the dose responsiveness to glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss. An enhanced anorectic response to the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipostatic factor leptin demonstrated that increased sensitivity to anorectic agents was a generalized result of MC3R antagonism. We observed enhanced neuronal activation in multiple hypothalamic nuclei using Fos IHC following low-dose liraglutide in MC3R-KO mice (Mc3r-/-), supporting the hypothesis that the MC3R is a negative regulator of circuits that control multiple aspects of feeding behavior. The enhanced anorectic response in Mc3r-/- mice after administration of GLP1 analogs was also independent of the incretin effects and malaise induced by GLP1 receptor (GLP1R) analogs, suggesting that MC3R antagonists or MC4R agonists may have value in enhancing the dose-response range of obesity therapeutics.

Impact of Serotonin Deficiency on Circadian Dopaminergic Rhythms.

Physiology and behavior are structured temporally to anticipate daily cycles of light and dark, ensuring fitness and survival. Neuromodulatory systems in the brain-including those involving serotonin and dopamine-exhibit daily oscillations in neural activity and help shape circadian rhythms. Disrupted neuromodulation can cause circadian abnormalities that are thought to underlie several neuropsychiatric disorders, including bipolar mania and schizophrenia, for which a mechanistic understanding is still lacking. Here, we show that genetically depleting serotonin in Tph2 knockout mice promotes manic-like behaviors and disrupts daily oscillations of the dopamine biosynthetic enzyme tyrosine hydroxylase (TH) in midbrain dopaminergic nuclei. Specifically, while TH mRNA and protein levels in the Substantia Nigra (SN) and Ventral Tegmental Area (VTA) of wild-type mice doubled between the light and dark phase, TH levels were high throughout the day in Tph2 knockout mice, suggesting a hyperdopaminergic state. Analysis of TH expression in striatal terminal fields also showed blunted rhythms. Additionally, we found low abundance and blunted rhythmicity of the neuropeptide cholecystokinin (Cck) in the VTA of knockout mice, a neuropeptide whose downregulation has been implicated in manic-like states in both rodents and humans. Altogether, our results point to a previously unappreciated serotonergic control of circadian dopamine signaling and propose serotonergic dysfunction as an upstream mechanism underlying dopaminergic deregulation and ultimately maladaptive behaviors.

Unraveling Verapamil's Multidimensional Role in Diabetes Therapy: From ß-Cell Regeneration to Cholecystokinin Induction in Zebrafish and MIN6 Cell-Line Models.

This study unveils verapamil's compelling cytoprotective and proliferative effects on pancreatic ß-cells amidst diabetic stressors, spotlighting its unforeseen role in augmenting cholecystokinin (CCK) expression. Through rigorous investigations employing MIN6 ß-cells and zebrafish models under type 1 and type 2 diabetic conditions, we demonstrate verapamil's capacity to significantly boost ß-cell proliferation, enhance glucose-stimulated insulin secretion, and fortify cellular resilience. A pivotal revelation of our research is verapamil's induction of CCK, a peptide hormone known for its role in nutrient digestion and insulin secretion, which signifies a novel pathway through which verapamil exerts its therapeutic effects. Furthermore, our mechanistic insights reveal that verapamil orchestrates a broad spectrum of gene and protein expressions pivotal for ß-cell survival and adaptation to immune-metabolic challenges. In vivo validation in a zebrafish larvae model confirms verapamil's efficacy in fostering ß-cell recovery post-metronidazole infliction. Collectively, our findings advocate for verapamil's reevaluation as a multifaceted agent in diabetes therapy, highlighting its novel function in CCK upregulation alongside enhancing ß-cell proliferation, glucose sensing, and oxidative respiration. This research enriches the therapeutic landscape, proposing verapamil not only as a cytoprotector but also as a promoter of ß-cell regeneration, thereby offering fresh avenues for diabetes management strategies aimed at preserving and augmenting ß-cell functionality.

Single-cell transcriptome analysis reveals secretin as a hallmark of human enteroendocrine cell maturation.

The traditional nomenclature of enteroendocrine cells (EECs), established in 1977, applied the "one cell - one hormone" dogma, which distinguishes subpopulations based on the secretion of a specific hormone. These hormone-specific subpopulations included S cells for secretin (SCT), K cells for glucose-dependent insulinotropic polypeptide (GIP), N cells producing neurotensin (NTS), I cells producing cholecystokinin (CCK), D cells producing somatostatin (SST), and others. In the past 15 years, reinvestigations into murine and human organoid-derived EECs, however, strongly questioned this dogma and established that certain EECs coexpress multiple hormones. Using the Gut Cell Atlas, the largest available single-cell transcriptome dataset of human intestinal cells, this study consolidates that the original dogma is outdated not only for murine and human organoid-derived EECs, but also for primary human EECs, showing that the expression of certain hormones is not restricted to their designated cell type. Moreover, specific analyses into SCT-expressing cells reject the presence of any cell population that exhibits significantly elevated secretin expression compared to other cell populations, previously referred to as S cells. Instead, this investigation indicates that secretin production is realized jointly by other enteroendocrine subpopulations, validating corresponding observations in murine EECs also for human EECs. Furthermore, our findings corroborate that SCT expression peaks in mature EECs, in contrast, progenitor EECs exhibit markedly lower expression levels, supporting the hypothesis that SCT expression is a hallmark of EEC maturation.

Cholecystokinin-expressing superficial tufted cells modulate odour representation in the olfactory bulb and olfactory behaviours.

In mammals, odour information within the olfactory bulb (OB) is processed by complex neural circuits before being ultimately represented in the action potential activity of mitral/tufted cells (M/Ts). Cholecystokinin-expressing (CCK+) superficial tufted cells (sTCs) are a subset of tufted cells that potentially contribute to olfactory processing in the OB by orchestrating M/T activity. However, the exact role of CCK+ sTCs in modulating odour processing and olfactory function in vivo is largely unknown. Here, we demonstrate that manipulating CCK+ sTCs can generate perception and induce place avoidance. Optogenetic activation/inactivation of CCK+ sTCs exerted strong but differing effects on spontaneous and odour-evoked M/T firing. Furthermore, inactivation of CCK+ sTCs disrupted M/T odour encoding and impaired olfactory detection and odour discrimination. These results establish the role of CCK+ sTCs in odour representation and olfactory behaviours. KEY POINTS: Mice could perceive the activity of CCK+ sTCs and show place avoidance to CCK+ sTC inactivation. Optical activation of CCK+ sTCs increased the percentage of cells with odour response but reduced the odour-evoked response in M/Ts in awake mice. Optical inactivation of CCK+ sTCs greatly decreased spontaneous firing and odour-evoked response in M/Ts. Inactivation of CCK+ sTCs impairs the odour decoding performance of M/Ts and disrupts odour detection and discrimination behaviours in mice. These results indicate that CCK+ sTCs participate in modulating the odour representation and maintaining normal olfactory-related behaviours.

Cholecystokinin-mediated effect of insulin pathway on the steroidogenic activity of follicular granulosa cells in Camelus bactrianus: In vitro study.

The current study aimed to explore the molecular mechanism by which the cholecystokinin (CCK)-mediated CCKAR and CCKBR, as well as the molecular mechanisms of CCK-mediated insulin signalling pathway, regulate oestrogen in the granulosa cells. Also, the expression of CCK in ovaries, uterus, hypothalamus and pituitary gland was investigated in Camelus bactrianus. Ovaries, uterus, hypothalamus and pituitary gland were collected from six, three before ovulation (control) and three after ovulation, slaughtered Camelus bactrianus. Ovulation was induced by IM injection of seminal plasma before slaughtering in the ovulated group. The results showed that there were differences in the transcription and protein levels of CCK in various tissues before and after ovulation (p < .05, p < .01). After transfection with p-IRES2-EGFP-CCK, the mRNA and protein levels of CCK, CCKAR, CCKBR and ER in follicular granulosa cells were significantly upregulated (p < .05, p < .01), and the content of E2 was significantly upregulated (p < .01); On the contrary, after transfection with si-CCK, the mRNA and protein levels of CCK, CCKAR, CCKBR and ER in follicular granulosa cells were significantly downregulated (p < .05, p < .01), and the content of E2 was significantly downregulated (p < .01). Regulating CCK can affect the mRNA levels of INS, INSR, IGF and IGF-R. In summary, regulating the expression level of CCK can activate insulin-related signalling pathways by CCKR, thereby regulating the steroidogenic activity of granulosa cells.

Cholecystokinin facilitates motor skill learning by modulating neuroplasticity in the motor cortex.

Cholecystokinin (CCK) is an essential modulator for neuroplasticity in sensory and emotional domains. Here, we investigated the role of CCK in motor learning using a single pellet reaching task in mice. Mice with a knockout of Cck gene (Cck-/-) or blockade of CCK-B receptor (CCKBR) showed defective motor learning ability; the success rate of retrieving reward remained at the baseline level compared to the wildtype mice with significantly increased success rate. We observed no long-term potentiation upon high-frequency stimulation in the motor cortex of Cck-/- mice, indicating a possible association between motor learning deficiency and neuroplasticity in the motor cortex. In vivo calcium imaging demonstrated that the deficiency of CCK signaling disrupted the refinement of population neuronal activity in the motor cortex during motor skill training. Anatomical tracing revealed direct projections from CCK-expressing neurons in the rhinal cortex to the motor cortex. Inactivation of the CCK neurons in the rhinal cortex that project to the motor cortex bilaterally using chemogenetic methods significantly suppressed motor learning, and intraperitoneal application of CCK4, a tetrapeptide CCK agonist, rescued the motor learning deficits of Cck-/- mice. In summary, our results suggest that CCK, which could be provided from the rhinal cortex, may surpport motor skill learning by modulating neuroplasticity in the motor cortex.

Gamma-glutamylation of beef protein hydrolysates to improve its overall taste and functions of gastro-intestinal hormone (CCK and GLP-1) pro-secretion and anti-inflammation.

γ-Glutamylation of beef protein hydrolysate (BPH) by L-glutaminase was carried out to improve the taste, as well as enhance the stimulating effect of gastrointestinal hormone (CCK and GLP-1) secretion and the anti-inflammatory property. Results of sensory evaluation showed that the kokumi taste, umaminess, saltiness of the γ-glutamylated product (γ-GBPH) were significantly higher (p < 0.05), whilst the bitterness was remarkably decreased (p < 0.05) than that of BPH. γ-GBPH had a better promoting effect (p < 0.05) on CCK and GLP-1 secretion and a higher inhibition (p < 0.05) on TNF-α and IL-8 production than BPH in vitro cell experiments. In γ-GBPH, 15 γ-Glutamylated amino acids (γ-[Glu](n =1/2)-AAs) and 10 γ-Glutamyl-tripeptide (γ-Glu-AA-AAs) were synthesized from the bitter amino acids and bitter peptides, respectively, and their total production yield was 140.01-170.46 mg/g and 149.06 mg/g, respectively. The synthesized γ-Glu-AA-AAs entered the binding pocket of the calcium-sensitive receptor (CaSR), and they all interacted with three reported amino acid residues (Ser147, Ala168, and Ser170) of CaSR.

CCK+ Interneurons Contribute to Thalamus-Evoked Feed-Forward Inhibition in the Prelimbic Prefrontal Cortex.

Interneurons in the medial prefrontal cortex (PFC) regulate local neural activity to influence cognitive, motivated, and emotional behaviors. Parvalbumin-expressing (PV+) interneurons are the primary mediators of thalamus-evoked feed-forward inhibition across the mouse cortex, including the anterior cingulate cortex, where they are engaged by inputs from the mediodorsal (MD) thalamus. In contrast, in the adjacent prelimbic (PL) cortex, we find that PV+ interneurons are scarce in the principal thalamorecipient layer 3 (L3), suggesting distinct mechanisms of inhibition. To identify the interneurons that mediate MD-evoked inhibition in PL, we combine slice physiology, optogenetics, and intersectional genetic tools in mice of both sexes. We find interneurons expressing cholecystokinin (CCK+) are abundant in L3 of PL, with cells exhibiting fast-spiking (fs) or non-fast-spiking (nfs) properties. MD inputs make stronger connections onto fs-CCK+ interneurons, driving them to fire more readily than nearby L3 pyramidal cells and other interneurons. CCK+ interneurons in turn make inhibitory, perisomatic connections onto L3 pyramidal cells, where they exhibit cannabinoid 1 receptor (CB1R) mediated modulation. Moreover, MD-evoked feed-forward inhibition, but not direct excitation, is also sensitive to CB1R modulation. Our findings indicate that CCK+ interneurons contribute to MD-evoked inhibition in PL, revealing a mechanism by which cannabinoids can modulate MD-PFC communication.

Effects of fasting and environmental factors on appetite regulators in pond loach Misgurnus anguillicaudatus.

The pond loach (Misgurnus anguillicaudatus) is an important aquaculture freshwater species, used as an ornamental fish, food source for humans and angling bait. Pond loaches are resistant to fasting and extreme environmental conditions, including temperature and low oxygen levels. Little is known about how these factors affect the feeding physiology and the endocrine regulation of feeding of loaches. In this study, we examined the effects of fasting, as well as increased temperature and decreased oxygen levels on food intake and transcript levels of appetite regulators. Fasted fish had lower blood glucose levels, and lower expression levels of intestine CCK and PYY, and brain CART1, but had higher levels of brain orexin and ghrelin than fed fish. Fish held at 30 °C had higher food intake, glucose levels, and mRNA levels of intestine CCK and PYY, and brain CART2, but lower brain orexin levels than fish at 20 °C. Fish held at low oxygen levels had a lower food intake, higher intestine CCKa and ghrelin, and brain orexin, CART2 and ghrelin mRNA expression levels than fish held at high O2 levels. Our results suggest that fasting and high temperatures increase the expression of orexigenic and anorexigenic factors respectively, whereas the increase in expression of both orexigenic and anorexigenic factors in low O2 environments might not be related to their role in feeding, but possibly to protection from tissue damage. The results of our study might shed new light on how pond loaches are able to cope with extreme environmental conditions such as low food availability, extreme temperatures and hypoxia.

Effect of intracerebroventricular (ICV) injection of adrenomedullin and its interaction with NPY and CCK pathways on food intake regulation in neonatal layer-type chicks.

Adrenomedullin has various physiological roles including appetite regulation. The objective of present study was to determine the effects of ICV injection of adrenomedullin and its interaction with NPY and CCK receptors on food intake regulation. In experiment 1, chickens received ICV injection of saline and adrenomedullin (1, 2, and 3 nmol). In experiment 2, birds injected with saline, B5063 (NPY1 receptor antagonist, 1.25 µg), adrenomedullin (3 nmol) and co-injection of B5063+adrenomedullin. Experiments 3 to 5 were similar to experiment 2 and only SF22 (NPY2 receptor antagonist, 1.25 µg), SML0891 (NPY5 receptor antagonist, 1.25 µg) and CCK4 (1 nmol) were injected instead of B5063. In experiment 6, ICV injection of saline and CCK8s (0.125, 0.25, and 0.5 nmol) were done. In experiment 7, chickens injected with saline, CCK8s (0.125 nmol), adrenomedullin (3 nmol) and co-injection of CCK8s+adrenomedullin. After ICV injection, birds were returned to their individual cages immediately and cumulative food intake was measured at 30, 60, and 120 min after injection. Adrenomedullin (2 and 3 nmol) decreased food intake compared to control group (P < 0.05). Coinjection of B5063+adrenomedullin amplified hypophagic effect of adrenomedullin (P < 0.05). The ICV injection of the CCK8s (0.25 and 0.5 nmol) reduced food intake (P < 0.05). Co-injection of the CCK8s+adrenomedullin significantly potentiated adrenomedullin-induced hypophagia (P < 0.05). Administration of the SF22, SML0891 and CCK4 had no effect on the anorexigenic response evoked by adrenomedullin (P > 0.05). These results suggested that the hypophagic effect of the adrenomedullin is mediated by NPY1 and CCK8s receptors. However, our novel results should form the basis for future experiments.

Cholecystokinin B receptor agonists alleviates anterograde amnesia in cholecystokinin-deficient and aged Alzheimer's disease mice.

BACKGROUND: As one major symptom of Alzheimer's disease (AD), anterograde amnesia describes patients with an inability in new memory formation. The crucial role of the entorhinal cortex in forming new memories has been well established, and the neuropeptide cholecystokinin (CCK) is reported to be released from the entorhinal cortex to enable neocortical associated memory and long-term potentiation. Though several studies reveal that the entorhinal cortex and CCK are related to AD, it is less well studied. It is unclear whether CCK is a good biomarker or further a great drug candidate for AD. METHODS: mRNA expressions of CCK and CCK-B receptor (CCKBR) were examined in two mouse models, 3xTg AD and CCK knock-out (CCK-/-) mice. Animals' cognition was investigated with Morris water maze, novel object recognition test and neuroplasticity with in-vitro electrophysiological recording. Drugs were given intraperitoneally to animals to investigate the rescue effects on cognitive deficits, or applied to brain slices directly to explore the influence in inducement of long-term potentiation. RESULTS: Aged 3xTg AD mice exhibited reduced CCK mRNA expression in the entorhinal cortex but reduced CCKBR expression in the neocortex and hippocampus, and impaired cognition and neuroplasticity comparable with CCK-/- mice. Importantly, the animals displayed improved performance and enhanced long-term potentiation after the treatment of CCKBR agonists. CONCLUSIONS: Here we provide more evidence to support the role of CCK in learning and memory and its potential to treat AD. We elaborated on the rescue effect of a promising novel drug, HT-267, on aged 3xTg AD mice. Although the physiological etiology of CCK in AD still needs to be further investigated, this study sheds light on a potential pharmaceutical candidate for AD and dementia.

Neural circuits regulation of satiation.

Terminating a meal after achieving satiation is a critical step in maintaining a healthy energy balance. Despite the extensive collection of information over the last few decades regarding the neural mechanisms controlling overall eating, the mechanism underlying different temporal phases of eating behaviors, especially satiation, remains incompletely understood and is typically embedded in studies that measure the total amount of food intake. In this review, we summarize the neural circuits that detect and integrate satiation signals to suppress appetite, from interoceptive sensory inputs to the final motor outputs. Due to the well-established role of cholecystokinin (CCK) in regulating the satiation, we focus on the neural circuits that are involved in regulating the satiation effect caused by CCK. We also discuss several general principles of how these neural circuits control satiation, as well as the limitations of our current understanding of the circuits function. With the application of new techniques involving sophisticated cell-type-specific manipulation and mapping, as well as real-time recordings, it is now possible to gain a better understanding of the mechanisms specifically underlying satiation.

Hippocampal cholecystokinin-expressing interneurons regulate temporal coding and contextual learning.

Cholecystokinin-expressing interneurons (CCKIs) are hypothesized to shape pyramidal cell-firing patterns and regulate network oscillations and related network state transitions. To directly probe their role in the CA1 region, we silenced their activity using optogenetic and chemogenetic tools in mice. Opto-tagged CCKIs revealed a heterogeneous population, and their optogenetic silencing triggered wide disinhibitory network changes affecting both pyramidal cells and other interneurons. CCKI silencing enhanced pyramidal cell burst firing and altered the temporal coding of place cells: theta phase precession was disrupted, whereas sequence reactivation was enhanced. Chemogenetic CCKI silencing did not alter the acquisition of spatial reference memories on the Morris water maze but enhanced the recall of contextual fear memories and enabled selective recall when similar environments were tested. This work suggests the key involvement of CCKIs in the control of place-cell temporal coding and the formation of contextual memories.

Use of a Fatty Meal Cholecystagogue Protocol in Hepatobiliary Scintigraphy for Chronic Functional Gallbladder Disease.

Chronic functional gallbladder disorder, characterized by biliary pain in the absence of structural pathology, poses a diagnostic challenge necessitating reliable cholecystagogues for accurate evaluation. However, recurrent shortages of synthetic cholecystokinin analogs have prompted the exploration of alternative agents. This paper describes the efficacy of Ensure Plus as a viable fatty meal substitute for hepatobiliary scintigraphy in assessing chronic functional gallbladder disorder. Through comparative studies, Ensure Plus demonstrates comparable diagnostic accuracy to cholecystokinin in similar patient populations. Furthermore, Ensure Plus demonstrates significant symptom improvement after cholecystectomy in patients with anomalous gallbladder ejection fractions. This paper offers a detailed protocol for the seamless integration of Ensure Plus into hepatobiliary scintigraphy, providing clinicians with a valuable tool to navigate cholecystokinin shortages while maintaining diagnostic precision in cases of chronic functional gallbladder disorder. The use of Ensure Plus not only addresses practical supply challenges but also underscores its potential as a cost-effective and clinically sound alternative in biliary diagnostics.

Gut hormones and appetite regulation.

PURPOSE OF REVIEW: Various gut hormones interact with the brain through delicate communication, thereby influencing appetite and subsequent changes in body weight. This review summarizes the effects of gut hormones on appetite, with a focus on recent research. RECENT FINDINGS: Ghrelin is known as an orexigenic hormone, whereas glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), postprandial peptide YY (PYY), and oxyntomodulin (OXM) are known as anorexigenic hormones. Recent human studies have revealed that gut hormones act differently in various systems, including adipose tissue, beyond appetite and energy intake, and even involve in high-order thinking. Environmental factors including meal schedule, food contents and quality, type of exercise, and sleep deprivation also play a role in the influence of gut hormone on appetite, weight change, and obesity. Recently published studies have shown that retatrutide, a triple-agonist of GLP-1, GIP, and glucagon receptor, and orforglipron, a GLP-1 receptor partial agonist, are effective in weight loss and improving various metabolic parameters associated with obesity. SUMMARY: Various gut hormones influence appetite, and several drugs targeting these receptors have been reported to exert positive effects on weight loss in humans. Given that diverse dietary and environmental factors affect the actions of gut hormones and appetite, there is a need for integrated and largescale long-term studies in this field.

Shedding light on cholecystokinin's role in hippocampal neuroplasticity and memory formation.

The hippocampus is a crucial brain region involved in the process of forming and consolidating memories. Memories are consolidated in the brain through synaptic plasticity, and a key mechanism underlying this process is called long-term potentiation (LTP). Recent research has shown that cholecystokinin (CCK) plays a role in facilitating the formation of LTP, as well as learning and memory consolidation. However, the specific mechanisms by which CCK is involved in hippocampal neuroplasticity and memory formation are complicated or poorly understood. This literature review aims to explore the role of LTP in memory formation, particularly in relation to hippocampal memory, and to discuss the implications of CCK and its receptors in the formation of hippocampal memories. Additionally, we will examine the circuitry of CCK in the hippocampus and propose potential CCK-dependent mechanisms of synaptic plasticity that contribute to memory formation.

Distribution of cionin, a cholecystokinin/gastrin family peptide, and its receptor in the central nervous system of Ciona intestinalis type A.

The cholecystokinin (CCK)/gastrin family peptides are involved in regulation of feeding and digestion in vertebrates. In the ascidian Ciona intestinalis type A (Ciona robusta), cionin, a CCK/gastrin family peptide, has been identified. Cionin is expressed exclusively in the central nervous system (CNS). In contrast, cionin receptor expression has been detected in the CNS, digestive tract, and ovary. Although cionin has been reported to be involved in ovulation, its physiological function in the CNS remains to be investigated. To elucidate its neural function, in the present study, we analyzed the expression of cionin and cionin receptors in the CNS. Cionin was expressed mainly in neurons residing in the anterior region of the cerebral ganglion. In contrast, the gene expressin of the cionin receptor gene CioR1, was detected in the middle part of the cerebral ganglion and showed a similar expression pattern to that of VACHT, a cholinergic neuron marker gene. Moreover, CioR1 was found to be expressed in cholinergic neurons. Consequently, these results suggest that cionin interacts with cholinergic neurons as a neurotransmitter or neuromodulator via CioR1. This study provides insights into a biological role of a CCK/gastrin family peptide in the CNS of ascidians.

Exploring FDA-Approved Frontiers: Insights into Natural and Engineered Peptide Analogues in the GLP-1, GIP, GHRH, CCK, ACTH, and α-MSH Realms.

Peptides continue to gain significance in the pharmaceutical arena. Since the unveiling of insulin in 1921, the Food and Drug Administration (FDA) has authorised around 100 peptides for various applications. Peptides, although initially derived from endogenous sources, have evolved beyond their natural origins, exhibiting favourable therapeutic effectiveness. Medicinal chemistry has played a pivotal role in synthesising valuable natural peptide analogues, providing synthetic alternatives with therapeutic potential. Furthermore, key chemical modifications have enhanced the stability of peptides and strengthened their interactions with therapeutic targets. For instance, selective modifications have extended their half-life and lessened the frequency of their administration while maintaining the desired therapeutic action. In this review, I analyse the FDA approval of natural peptides, as well as engineered peptides for diabetes treatment, growth-hormone-releasing hormone (GHRH), cholecystokinin (CCK), adrenocorticotropic hormone (ACTH), and α-melanocyte stimulating hormone (α-MSH) peptide analogues. Attention will be paid to the structure, mode of action, developmental journey, FDA authorisation, and the adverse effects of these peptides.