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Purpose: Identifying the determinants of performance is fundamental to talent identification and individualizing training prescription. Consequently, the aim of this study was to determine whether estimated muscle typology is associated with the key mechanical characteristics of track sprint cycling. Methods: Sixteen world-class and elite track cyclists (n = 7 female) completed a laboratory session wherein torque–cadence and power–cadence profiles were constructed to determine maximal power output (Pmax), optimal cadence (Fopt), and maximal cadence (Fmax), and fatigue rate per pedal stroke was determined during a 15-second maximal sprint at Fopt. Muscle typology was estimated by measuring carnosine content via proton magnetic resonance spectroscopy in the gastrocnemius and soleus. Results: Using partial correlation analysis to account for sex, greater muscle carnosine content (ie, greater estimated proportion of type II fibers) was associated with a greater Pmax (r =.68, P =.007), Fmax (r =.77, P =.0014), Fopt (r =.61, P =.0196), and absolute fatigue rate (W·stroke−1; r = −.55, P =.0418) but not relative fatigue rate (%peak power·stroke−1; r = −.33, P =.246). Conclusions: The findings from this study substantiate the mechanical differences in muscle-fiber types derived from single muscle-fiber studies and highlight the importance of estimated muscle typology for sprint cycling performance. [ABSTRACT FROM AUTHOR]

Beta-alanine is a nonessential amino acid that is commonly used to improve exercise performance. It could influence the buffering of hydrogen ions produced during intense exercise and delay fatigue, providing a substrate for increased synthesis of intramuscular carnosine. This systematic review evaluates the effects of beta-alanine supplementation on maximal intensity exercise in trained, young, male individuals. Six databases were searched on August 10, 2023, to identify randomized, double-blinded, placebo-controlled trials investigating the effect of chronic beta-alanine supplementation in trained male individuals with an age range of 18–40 years. Studies evaluating exercise performance through maximal or supramaximal intensity efforts falling within the 0.5–10 min duration were included. A total of 18 individual studies were analyzed, employing 18 exercise test protocols and 15 outcome measures in 331 participants. A significant (p =.01) result was observed with an overall effect size of 0.39 (95% confidence interval [CI] [0.09, 0.69]), in favor of beta-alanine supplementation versus placebo. Results indicate significant effects at 4 weeks of supplementation, effect size 0.34 (95% CI [0.02, 0.67], p =.04); 4–10 min of maximal effort, effect size 0.55 (95% CI [0.07, 1.04], p =.03); and a high beta-alanine dosage of 5.6–6.4 g per day, effect size 0.35 (95% CI [0.09, 0.62], p =.009). The results provide insights into which exercise modality will benefit the most, and which dosage protocols and durations stand to provide the greatest ergogenic effects. This may be used to inform further research, and professional or recreational training design, and optimization of supplementation strategies. [ABSTRACT FROM AUTHOR]

To determine how neuronal circuits encode and drive behavior, it is often necessary to measure and manipulate different aspects of neurochemical signaling in awake animals. Optogenetics and calcium sensors have paved the way for these types of studies, allowing for the perturbation and readout of spiking activity within genetically defined cell types. However, these methods lack the ability to further disentangle the roles of individual neuromodulator and neuropeptides on circuits and behavior. We review recent advances in chemical biology tools that enable precise spatiotemporal monitoring and control over individual neuroeffectors and their receptors in vivo. We also highlight discoveries enabled by such tools, revealing how these molecules signal across different timescales to drive learning, orchestrate behavioral changes, and modulate circuit activity.

Neuropeptides are ubiquitous in the nervous system. Research into neuropeptides has been limited by a lack of experimental tools that allow for the precise dissection of their complex and diverse dynamics in a circuit-specific manner. Opioid peptides modulate pain, reward and aversion and as such have high clinical relevance. To illuminate the spatiotemporal dynamics of endogenous opioid signaling in the brain, we developed a class of genetically encoded fluorescence sensors based on kappa, delta and mu opioid receptors: κLight, δLight and µLight, respectively. We characterized the pharmacological profiles of these sensors in mammalian cells and in dissociated neurons. We used κLight to identify electrical stimulation parameters that trigger endogenous opioid release and the spatiotemporal scale of dynorphin volume transmission in brain slices. Using in vivo fiber photometry in mice, we demonstrated the utility of these sensors in detecting optogenetically driven opioid release and observed differential opioid release dynamics in response to fearful and rewarding conditions.

The small G-protein Ras-related C3 botulinum toxin substrate 1 (Rac1) promotes the formation of filamentous actin (F-actin). Actin is a major component of dendritic spines, and we previously found that alcohol alters actin composition and dendritic spine structure in the nucleus accumbens (NAc) and the dorsomedial striatum (DMS). To examine if Rac1 contributes to these alcohol-mediated adaptations, we measured the level of GTP-bound active Rac1 in the striatum of mice following 7 weeks of intermittent access to 20% alcohol. We found that chronic alcohol intake activates Rac1 in the DMS of male mice. In contrast, Rac1 is not activated by alcohol in the NAc and DLS of male mice or in the DMS of female mice. Similarly, closely related small G-proteins are not activated by alcohol in the DMS, and Rac1 activity is not increased in the DMS by moderate alcohol or natural reward. To determine the consequences of alcohol-dependent Rac1 activation in the DMS of male mice, we inhibited endogenous Rac1 by infecting the DMS of mice with an adeno-associated virus (AAV) expressing a dominant negative form of the small G-protein (Rac1-DN). We found that overexpression of AAV-Rac1-DN in the DMS inhibits alcohol-mediated Rac1 signaling and attenuates alcohol-mediated F-actin polymerization, which corresponded with a decrease in dendritic arborization and spine maturation. Finally, we provide evidence to suggest that Rac1 in the DMS plays a role in alcohol-associated goal-directed learning. Together, our data suggest that Rac1 in the DMS plays an important role in alcohol-dependent structural plasticity and aberrant learning.

Schizophrenia (SZ) is a serious mental illness and neuropsychiatric brain disorder with behavioral symptoms that include hallucinations, delusions, disorganized behavior, and cognitive impairment. Regulation of such behaviors requires utilization of neurotransmitters released to mediate cell-cell communication which are essential to brain functions in health and disease. We hypothesized that SZ may involve dysregulation of neurotransmitters secreted from neurons. To gain an understanding of human SZ, induced neurons (iNs) were derived from SZ patients and healthy control subjects to investigate peptide neurotransmitters, known as neuropeptides, which represent the major class of transmitters. The iNs were subjected to depolarization by high KCl in the culture medium and the secreted neuropeptides were identified and quantitated by nano-LC-MS/MS tandem mass spectrometry. Several neuropeptides were identified from schizophrenia patient-derived neurons, including chromogranin B (CHGB), neurotensin, and natriuretic peptide. Focusing on the main secreted CHGB neuropeptides, results revealed differences in SZ iNs compared to control iN neurons. Lower numbers of distinct CHGB peptides were found in the SZ secretion media compared to controls. Mapping of the peptides to the CHGB precursor revealed peptides unique to either SZ or control, and peptides common to both conditions. Also, the iNs secreted neuropeptides under both KCl and basal (no KCl) conditions. These findings are consistent with reports that chromogranin B levels are reduced in the cerebrospinal fluid and specific brain regions of SZ patients. These findings suggest that iNs derived from SZ patients can model the decreased CHGB neuropeptides observed in human SZ.

Introduction: Melanin-concentrating hormone (MCH) neurons are essential regulators of energy and glucose homeostasis, sleep–wake behaviors, motivation, learning and memory. These neurons are anatomically distributed across the medial (MH) and lateral hypothalamus (LH), and the adjacent zona incerta (ZI), which may represent functional subgroups with distinct connectivity with different brain regions. Furthermore, MCH neurons can be classified according to co-expression of neuropeptides, such as cocaine and amphetamine- regulated transcript (CART). Methods: To identify functional similarities and differences of MCH subpopulations, we characterized their intrinsic electrophysiological properties using whole cell current clamp recording on acute brain slices from male and female mice. Results: MCH neurons were classified into subgroups according to their anatomical localization in three MCH-rich brain areas: MH, LH and ZI. Among the three brain regions, ZI MCH neurons were the least excitable while LH MCH neurons were the most excitable. Furthermore, grouping MCH neurons according to CART co-expression revealed that MCH/CART− cells are uniquely depolarized and excitable, and display H-currents. These MCH/CART− cells were mainly found in the LH, which may in part explain why LH MCH neurons are more excitable. While some sex differences were found, the majority of parameters investigated were not different. Discussion: Our results suggest that MCH/CART− cells are electrophysiologically distinct, whereas MCH/CART+ cells are largely similar despite their diffuse distribution in the hypothalamus. It is therefore a combination of intrinsic electrophysiological properties and neurochemical identities, in addition to anatomy and connectivity that are likely to be critical in defining functional subpopulations of MCH neurons. [ABSTRACT FROM AUTHOR]

The silkworm neuropeptide Orcokinin (abbreviated as BommoOK) is equipped with multiple biological functions, one of which acts as a pigmentation inhibitor. To explore the whitening efficiency of BommoOK, the inhibitory effects on tyrosinase and its adaptability on the cell for six mature peptides of BommoOK were investigated in this paper. At the same time, BommoOKA_type4, the peptide with the best melanin inhibition effect, was used as an additive to prepare a whitening cream, and the effects on skin moisture, oil content, fine lines, skin glossiness, pores, and pigment depth were determined. The results revealed that the cream added with BommoOKA_type4 peptide showed a good improvement effect on the skin, especially in significantly reducing the pigment depths of skin. The results displayed a potential application of BommoOK in whitening and skincare products as an excellent additive and provide certain references for the mechanism research of BommoOK in inhibiting melanin synthesis. [ABSTRACT FROM AUTHOR]

Almost every facet of our behavior and physiology varies predictably over the course of day and night, anticipating and adapting us to their associated opportunities and challenges. These rhythms are driven by endogenous biological clocks that, when deprived of environmental cues, can continue to oscillate within a period of approximately 1 day, hence circa - dian. Normally, retinal signals synchronize them to the cycle of light and darkness, but disruption of circadian organization, a common feature of modern lifestyles, carries considerable costs to health. Circadian timekeeping pivots around a cell-autonomous molecular clock, widely expressed across tissues. These cellular timers are in turn synchronized by the principal circadian clock of the brain: the hypothalamic suprachiasmatic nucleus (SCN). Intercellular signals make the SCN network a very powerful pacemaker. Previously, neurons were considered the sole SCN timekeepers, with glial cells playing supportive roles. New discoveries have revealed, however, that astrocytes are active partners in SCN network timekeeping, with their cell-autonomous clock regulating extracellular glutamate and GABA concentrations to control circadian cycles of SCN neuronal activity. Here, we introduce circadian timekeeping at the cellular and SCN network levels before focusing on the contributions of astrocytes and their mutual interaction with neurons in circadian control in the brain. [ABSTRACT FROM AUTHOR]

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Objective: To explore the mechanism of action of asperosaponin VI (AVI) in the treatment of rheumatoid arthritis (RA) and validate it in ex vivo experiments using network pharmacology and molecular docking methods. Methods: The predicted targets of AVI were obtained from PharmMaper, UniProt and SwissTarget Prediction platforms, the disease targets were collected from Online Mendelian Inheritance in Man, Therapeutic Target Database and GeneCards databases, the intersection targets of AVI and RA were obtained from Venny 2.1.0, and the protein-protein interaction (PPI) network was obtained from STRING database, which was analyzed by Cytoscape software and screened to obtain the core targets. Cytoscape software was used to analyze PPI network and screen the core targets. Based on the Database for Annotation, Visualization and Integrated Discovery database, Gene Ontology functional and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed, and Cytoscape software was used to construct the "Disease-Pathway-Target-Drug" network, which was finally verified by molecular docking and animal experiments. Results: Network pharmacological studies showed that AVI was able to modulate 289 targets, with 102 targets for the potential treatment of RA, with the core pathway being the AKT/PI3K signaling pathway, and the core targets being the epidermal growth factor receptor (EGFR) and matrix metalloproteinase 9 (MMP9). Molecular docking results showed that AVI could produce strong binding with both of the 2 core targets. In vitro cellular experiments showed that AVI reduced nitric oxide, prostaglandin E2, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1 β levels (P<0.05) and inhibited cyclooxygenase-2, nitric oxide synthase, EGFR, MMP9, phosphorylated phosphoinositide 3-kinase (p-PI3K), and phosphorylated serine-threonine kinase (p-AKT) proteins (P<0.05). The results of in vivo studies showed that AVI improved RA score and foot swelling thickness and decreased TNF-α, IL-6, p-PI3K and p-AKT levels in RA rats (P<0.05). Conclusion: AVI exerts anti-inflammatory and anti-RA effects which might be related to the EGFR/MMP9/AKT/PI3K pathway. [ABSTRACT FROM AUTHOR]

BACKGROUND: Obesity is a non‐communicable complex disease that is the fifth leading cause of death worldwide. According to a novel viewpoint, the brain plays a significant role in the central regulation of satiety and energy homeostasis. Because of its rich nutritional profile and versatile uses, oat (Avena sativa) is one of the most popular functional foods recommended by many nutritionists. The anti‐obesity effect of oat was hypothesized, focusing on the brain as the target organ. In the current study, the interplay between brain biomarkers, obesity, and its related complications was evaluated in diet‐induced obese rats for 25 weeks, in which 60 adult male white albino Wistar rats were divided into three control and seven treatment groups given oat extracts in a dose‐dependent manner. RESULTS: Oat significantly improved obesity‐related metabolic complications. In terms of brain function, oat significantly increased dopaminergic signaling, brain‐derived neurotrophic factor levels, vaspin, irisin, and uncoupling protein‐1 brain levels, while decreasing the expression of agouti‐related peptide and neuropeptide Y (P‐value < 0.05). CONCLUSION: The current study proposes oat supplementation as a new conceptual framework with numerous implications for hedonic and homeostatic mechanisms that control satiety. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

[Display omitted] • Intrathecal injection of 10 nmol NPFF potentiated morphine-induced analgesia. • Intrathecal injection of 10 pmol NPFF attenuated morphine-induced analgesia. • Both the pro- and anti-opioid effects of NPFF were mediated by NPFFR2. • Blockade of spinal NPFFR2 selectively regulated MOR agonists-induced analgesia. • NPFF exhibited anti-morphine effects in primary-cultured spinal neurons. Increasing evidence indicates that neuropeptide FF (NPFF) produces analgesic effects and augments opioid-induced analgesia at the spinal level. However, our recent research demonstrated that NPFF exerted complex opioid-modulating effects in an inflammatory pain model after intrathecal (i.t.) injection. Consistent with previous findings, we found that i.t. NPFF dose-dependently attenuated complete Freund's adjuvant-induced pain hypersensitivity. Interestingly, pharmacological results illustrated that NPFF exhibited opposite opioid-modulating effects at the spinal level depending on its administration dosage, wherein i.t. NPFF potentiated morphine-induced anti-allodynia at the dose of 10 nmol, while attenuated morphine analgesia at an ultra-low-dose of 10 pmol. Behavioral results obtained from neuropeptide FF receptor 2 (NPFFR2) knockout animals suggested that both pro- and anti-opioid effects of NPFF were mediated by NPFFR2. Moreover, these modulating effects of spinal NPFFR2 were selectively targeting mu-opioid receptor, had no effect on delta- and kappa-opioid receptor agonist-induced analgesia. Finally, the opioid-modulating effects of NPFF were further verified using in vitro calcium imaging assay, demonstrating that pretreated with NPFF in primary-cultured spinal neurons significantly attenuated the inhibitory effects of morphine on high-K+-induced neuronal excitability. Taken together, our results suggested that NPFF exhibited dual modulating effects on morphine-induced analgesia after i.t. administration, which provides a possible mechanism to explain the complex opioid-modulating effects of endogenous NPFF systems. [ABSTRACT FROM AUTHOR]

Copyright of Hungarian Medical Journal / Orvosi Hetilap is the property of Akademiai Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

In mammals, the central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, which transmits circadian information to other brain regions and regulates the timing of sleep and wakefulness. Neurons in the lateral hypothalamus (LH), particularly those producing melanin-concentrating hormone (MCH) and orexin, are key regulators of sleep and wakefulness. Although the SCN receives nonphotic input from other brain regions, the mechanisms of functional input from the LH to the SCN remain poorly understood. Here, we show that orexin and MCH peptides influence the circadian period within the SCN of both sexes. When these neurons are ablated, the circadian behavioral rhythms are lengthened under constant darkness. Using anterograde and retrograde tracing, we found that orexin and MCH neurons project to the SCN. Furthermore, the application of these peptides to cultured SCN slices shortened circadian rhythms and reduced intracellular cAMP levels. Additionally, pharmacological reduction of intracellular cAMP levels similarly shortened the circadian period in SCN slices. These findings suggest that orexin and MCH peptides from the LH contribute to the modulation of the circadian period in the SCN. [ABSTRACT FROM AUTHOR]

Background: Hypocretin-1 is a vital neurotransmitter in regulating the sleep–wake cycle and provides neuroprotection against cerebral ischemia. We aims to develop a poor sleep quality predictive model for elderly population with acute ischemic stroke. Methods: A total of 183 consecutively elderly patients were included in the prospective cohort study. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). Cerebrospinal fluid samples were taken within 24 h of acute ischemic stroke onset. After selecting optimal predictors via univariate analysis and bootstrapped stepwise logistic regression, the predictive model was developed. The models were internally validated and evaluated comprehensively via discrimination, calibration, and clinical utility. Results: The prevalence of poor sleep (PSQI >7) was 64.5% among elderly individuals experiencing acute ischemic stroke. The study developed a predictive model using hypocretin-1, hypertension, stroke history, the National Institutes of Health Stroke score, and depression. Adding hypocretin-1 (as continuous variable) significantly improved the model performance greatly, as the area under the receiver operating characteristic curve increased from 0.799 to 0.845 (p < 0.001). The optimal cutoff value for hypocretin-1 was 74.94 pg/mL. Adding hypocretin-1 (as binary variable) significantly improved the model performance greatly, as the AUC increased from 0.799 to 0.857 (p < 0.001). Conclusion: Reduced cerebrospinal fluid levels of hypocretin-1 at admission were an independent poor sleep quality predictor and the model demonstrated superior performance. The combination of hypocretin-1 could offer valuable prognostic information for post-stroke sleep quality in elderly patients with acute ischemic stroke. [ABSTRACT FROM AUTHOR]

Feeding behavior is regulated by a complex network of endogenous neuropeptides. In chordates, this role is suggested to be under the control of diverse factors including thyrotropin-releasing hormone (TRH). However, whether this regulatory activity of TRH is functionally conserved in non-chordate metazoans, and to what extent this process is underpinned by interactions of TRH with other neuropeptides such as cholecystokinin (CCK, known as a satiety signal), remain unclear. This study investigated the TRH signaling system in the echinoderm Apostichopus japonicus. Bioinformatic analyses and ligand-binding assays identified a functional TRH receptor (AjTRHR) that activated signaling via the MAPK/ERK1/2 pathways. Experimental administration of TRH significantly reduced feeding activity, while up-regulating CCK expression. RNA interference (RNAi) experiments confirmed that both CCK and TRH are essential components of satiety signaling, working synergistically to mediate feeding inhibition. Evolutionary analysis of TRHtype peptides revealed greater conservation of the short isoform of TRH compared to the long isoform, probably driven by strong selection acting on the functional redundancy. These findings provide compelling evidence of a TRH-mediated signaling system in non-chordate deuterostomes, expanding our understanding of neuropeptide-regulated feeding mechanisms in marine invertebrates. [ABSTRACT FROM AUTHOR]

The fall armyworm, Spodoptera frugiperda, is one of the most notorious pest insects, causing damage to more than 350 plant species, and is feared worldwide as an invasive pest species since it exhibits high adaptivity against environmental stress. Here, we therefore investigated its transcriptome responses to four different types of stresses, namely cold, heat, no water and no food. We used brain samples as our interest was in the neuroendocrine responses, while previous studies used whole bodies of larvae or moths. In general, the responses were complex and encompassed a vast array of neuropeptides (NPs) and biogenic amines (BAs). The NPs were mainly involved in ion homeostasis regulation (ITP and ITPL) and metabolic pathways (AKH, ILP), and this was accompanied by changes in BA (DA, OA) biosynthesis. Cold and no-water stress changed the NP gene expression with the same patterns of expression but clearly separated from each other, and the most divergent pattern of expression was shown after no-food stress. In conclusion, our data provide a foundation in an important model and pest insect with candidate NPs and BAs and other marker candidate genes in response to environmental stress, and also potential new targets to manage pest insects. [ABSTRACT FROM AUTHOR]

Feeding and molting are particularly important physiological processes for insects, and it has been reported that neuropeptides are involved in the nervous regulation of these 2 processes. Sulfakinin (SK) is an important neuropeptide that is widely distributed among insects and plays a pivotal role in regulating feeding, courtship, aggression, and locomotion. In this study, we investigated the involvement of SK in feeding and molting on a highly notorious pest insect, the fall armyworm, Spodoptera frugiperda. SK transcript levels were found in all larval stages and there was a predominant expression of SK in the brain of 5th instar larvae. By immunostaining, SK was detected in 2 pairs of cells in the median protocerebrum. But during prolonged periods of starvation, there was a significant reduction in SK messenger RNA levels; however, subsequent refeeding led to a notable increase. To investigate the role of SK in feeding and molting, SK was silenced in S. frugiperda larvae through RNA interference. This resulted in a significant increase in food intake, weight gain, and the molting process happened more rapidly in the double‐stranded SK‐treated larvae compared to the controls. Conversely, injection of sulfated SK peptide (sSK) caused opposite effects. Interestingly, SK‐knockdown in larvae resulted in increased levels of 20‐hydroxyecdysone and also of the expression of some of it signaling pathway genes. Altogether, this study highlights the important role played by SK in regulating feeding and molting in S. frugiperda. [ABSTRACT FROM AUTHOR]

Aim: It is known that apelin-13 is one of the major neuropeptides with a clear and crucial role in the circuits that are involved in mood disorders. In the development and/or maintenance of pathological anxiety, abnormalities of the hippocampus and amygdala play an important role. Here, we assessed the potential anxiolytic effect of apelin-13 on anxiety-like behaviors in male rats. Materials and Methods: A total of 48 male Wistar rats were divided into 4 groups (n=12). Control (C), Social Isolation (SI), Apelin-13 (A), and Social Isolation + Apelin- 13 (SI+A). In the C and A groups, four animals in each cage for 8 weeks. In the SI and SI+A groups, each animal was housed individually for 8 weeks. After that apelin-13 administration was applied by osmotic pomp. Anxiety/depression-related behaviors were evaluated using the Elevated Plus Maze (EPM), Open Field Test (OFT), and Light-Dark boxes (LDB). We also measured the expression of Apelin-13, Apelin receptor (APJ), Brain Derived Neurotrophic Factor (BDNF), Mammalian Atonal Homolog 1 (MASH1), Nestin, Doublecortin (DCX) and Neuritin in the hippocampus. These are important markers indicating the anxiety mechanism in the hippocampus. Results: The results of our study showed that apelin-13 administration reduced anxiety behaviors. Open arm entires and time spent were higher in the A group. In the open field test, grooming and rearing were lower in the SI group. Moreover, apelin-13 and APJ gene expression was higher in the A group. Conclusion: The results of the study indicate that apelin-13 infusion may lead to a decrease in anxiety-related behaviors in male rats. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) occurs in 8%-13% of reproductive-aged women and is associated with reproductive, metabolic, and psychological dysfunction. Overweight and obesity are prevalent and exacerbate the features of PCOS. The aim of this review is to evaluate the extent of evidence examining the physiological factors affecting energy homeostasis, which may impact weight gain, weight loss, and weight maintenance in PCOS, and identify research gaps and recommendations for future research. Literature searches using MEDLINE, EMBASE, PsycInfo, AMED, CINAHL, and Cochrane Central Register of Controlled Trials were conducted up to June 22, 2022. Abstracts, non–English-language articles, and reviews were excluded. A total of n = 78 (n = 55 energy intake and n = 23 energy expenditure) primary research papers were included. Papers with multiple outcomes of interest were counted as separate studies. Energy-intake studies (n = 89) focussed on assessing food, nutrient, or supplements stimuli and were grouped into the outcomes of gastrointestinal appetite hormones (n = 43), adipokines (n = 34), subjective appetite (n = 9), functional brain imaging (n = 3), and neuropeptides (n = 0). Energy-expenditure studies (n = 29) were grouped into total energy expenditure (n = 1), resting energy expenditure (n = 15), meal-induced thermogenesis (n = 3), nutrient oxidation (n = 5), and metabolic flexibility (n = 5). Across both energy-intake and -expenditure papers, 60% of the studies compared outcome responses in women with PCOS with a control group. Results were inconsistent, with 57% reporting no differences and 43% reporting altered responses in PCOS compared with controls, including blunted appetite hormone responses, metabolic inflexibility, and reduced energy expenditure. The authors identified that there is inconsistent, yet preliminary, evidence of possible altered physiological factors, which may impact energy balance and weight management. Further work is needed to act on the identified clinical and research gaps to support women with PCOS and health professionals in informing and achieving realistic weight-management goals for women with PCOS. Systematic Review Registration The protocol was prospectively registered on the Open Science Framework on February 16, 2021 (https://osf.io/9jnsm). [ABSTRACT FROM AUTHOR]

Background: Trichodynia or hair pain refers to the painful sensation occurring in the hair and or scalp in the setting of hair shedding. It has been reported mainly in association with telogen effluvium and androgenetic alopecia (AGA). Recently, trichodynia cases have been growing in numbers. Several theories have been proposed to explain the pathogenesis of trichodynia, suggesting a major role for substance P (SP) accompanied by perifollicular inflammation. Objective: To assess tissue and serum levels of SP in trichodynia occurring in AGA patients. Patients and methods: This is a case–control study that included 35 patients of trichodynia in AGA as well as 35 age-matched and sex-matched healthy participants included as controls. The diagnosis was made by clinical, trichoscopic examination, and scalp biopsy. Tissue and serum levels of SP were measured using the enzyme-linked immunoassay technique. Results: The mean tissue levels of SP were significantly higher in patients (448.11±241.24 pg/g), than in controls (75.78±11.81 pg/g) (P <0.0001). The mean serum levels of SP were significantly higher in patients (325.09±218.43 pg/ml), than in controls (171.06±42.19 pg/ml) (P =0.0002). The mean levels of SP in the tissue of patients were significantly higher among those with positive tenderness by examination (322.62±64.11123) compared to those with no tenderness (553.78±284.12157) (P =0.003). The mean levels of SP in the tissue of AGA patients were significantly higher in the group who reported a diffuse distribution of trichodynia (553.78±284.12) than in patients with localized trichodynia (322.62±64.11) (P =0.028). Conclusion: An increase of SP levels in tissue and serum of trichodynia accompanying AGA patients compared to healthy controls could have a role in trichodynia. [ABSTRACT FROM AUTHOR]

ABSTRACT Neuropeptides are key modulators of adult neurocircuits, balancing their sensitivity to both excitation and inhibition, and fine‐tuning fast neurotransmitter action under physiological conditions. Here, we reason that transient increases in neuropeptide availability and action exist during brain development for synapse maturation, selection, and maintenance. We discuss fundamental concepts of neuropeptide signaling at G protein‐coupled receptors (GPCRs), with a particular focus on how signaling at neuropeptide GPCRs could underpin neuronal morphogenesis. We use galanin, a 29/30 amino acid‐long neuropeptide, as an example for its retrograde release from the dendrites of thalamic neurons to impact the selection and wiring of sensory afferents originating at the trigeminal nucleus through galanin receptor 1 (GalR1) engagement. Thus, we suggest novel roles for neuropeptides, expressed transiently or permanently during both pre‐ and postnatal neuronal circuit development, with potentially life‐long effects on circuit layout and ensuing behavioral operations. [ABSTRACT FROM AUTHOR]

Background: Migraine is a painful neurological syndrome characterized by attacks of throbbing headache, of moderate to severe intensity, which is associated with photo- and phono- sensitivity as well as nausea and vomiting. It affects about 15% of the world's population being 2–3 times more prevalent in females. The calcitonin gene-related peptide (CGRP) is a key mediator in the pathophysiology of migraine, and a significant advance in the field has been the development of anti-CGRP therapies. The trigeminal ganglion (TG) is thought to be an important site of action for these drugs. Moreover, experimental migraine can be induced by CGRP injection in the TG. The signaling pathway induced by CGRP in the TG is not fully understood, but studies suggest that voltage-gated calcium channels contribute to CGRP effects relevant to migraine. Objective: We hypothesised that CGRP injection in the TG enhances CaV3.2 T-type calcium channel currents to contribute to the development of periorbital mechanical allodynia. Results: A Co-Immunoprecipitation assay in tsA-201 cells revealed that CaV3.2 channels form a complex with RAMP-1, a component of the CGRP receptor. Constitutive CGRPR activity was able to inhibit CaV3.2 channels and induce a depolarizing shift in both activation and inactivation curves. Incubation of TG neurons with CGRP increased T-type current density by ~ 3.6 fold, an effect that was not observed in TG neurons from CaV3.2 knockout mice. Incubation of TG neurons with Z944, a pan T-type channel blocker, resulted in an approximately 80% inhibition of T-type currents. In vivo, this treatment abolished the development of periorbital mechanical allodynia induced by CGRP in male and female mice. Likewise, CaV3.2 knockout mice did not develop periorbital mechanical allodynia after intraganglionic CGRP injection. Finally, we demonstrated that the CGRP effect depends on the activation of its canonical GPCR, followed by protein kinase A activation. Conclusion: The present study suggests that CGRP modulates CaV3.2 in the TG, an effect possibly mediated by the canonical CGRP receptor and PKA activation. The increase in T-type currents in the TG may represent a contributing factor for the initiation and maintenance of the headache pain during migraine. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is a leading cause of cancer death worldwide with an increasing incidence. Neural invasion is present in almost all pancreatic cancers. Clinically, it is translated into intractable pain and worse outcomes. Here, we highlight the importance of peripheral nerves in the pancreatic tumor microenvironment influencing the initiation and dissemination of pancreatic cancer. Furthermore, both autonomic (sympathetic and parasympathetic) and afferent nerves modulate different signaling pathways promoting tumor survival and immune escape. For this reason, exploring the potential synergistic benefits of anti-neurogenic therapies combined with chemotherapy or immunotherapy might inhibit both pancreatic cancer progression and alleviate cancer-related pain. Pancreatic cancer is an aggressive tumor with dismal prognosis. Neural invasion is one of the pathological hallmarks of pancreatic cancer. Peripheral nerves can modulate the phenotype and behavior of the malignant cells, as well as of different components of the tumor microenvironment, and thus affect tumor growth and metastasis. From a clinical point of view, neural invasion is translated into intractable pain and represents a predictor of tumor recurrence and poor prognosis. Several molecules are implicated in neural invasion and pain onset in PDAC, including neutrophins (e.g., NGF), chemokines, adhesion factors, axon-guidance molecules, different proteins, and neurotransmitters. In this review, we discuss the role of nerves within the pancreatic cancer microenvironment, highlighting how infiltrating nerve fibers promote tumor progression and metastasis, while tumor cells, in turn, drive nerve outgrowth in a reciprocal interaction that fuels tumor advancement. We outline key molecules involved in neural invasion in pancreatic cancer and, finally, explore potential therapeutic strategies to target neural invasion, aiming to both inhibit cancer progression and alleviate cancer-associated pain. [ABSTRACT FROM AUTHOR]

Introduction: The efferent vestibular system (EVS) originates in brainstem efferent vestibular nuclei (EVN) and modifies afferent vestibular signals at their source, in peripheral vestibular organs. Recent evidence suggests that EVS is also involved in the development of motion sickness symptoms, including vertigo and nausea, but the underlying mechanism is unknown. One possible link between EVN and motion sickness symptoms is through the neuropeptide calcitonin gene-related peptide (CGRP). CGRP often co-exists with substance P and pituitary adenylate cyclase-activating polypeptide (PACAP), two neuropeptides with similar vasodilatory effects. Collectively, these sensory neuropeptides have been associated with vestibular migraine pathophysiology and motion sickness. While CGRP and the fast EVS neurotransmitter, acetylcholine (ACh), have previously been identified in EVN neurons and their peripheral terminals, the presence of substance P and PACAP in the EVN has not yet been described. Methods: We used fluorescent immunohistochemistry combined with confocal microscopy to examine the distribution of these three neuropeptides in the mouse EVN. In transgenic choline acetyltransferase (ChAT)-gCaMP6f mice, EVN neurons were positively identified using the fluorescent expression of gCaMP6f. In wild-type C57/BL6 mice, EVN neurons were confirmed using ChAT immunolabelling. Results: Consistent with previous studies, CGRP was labelled in a subset of cholinergic EVN neurons. Additionally, we also show evidence for substance P and PACAP expression in EVN of transgenic and wild-type mice. Conclusion: The presence of CGRP, substance P, and PACAP in EVN neurons suggests a complex peptidergic modulation of cholinergic signalling, whose release into local blood vessels may contribute to motion sickness symptoms. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to examine whether there are sex differences in vasomotor responses and receptor localization of hormones and neuropeptides with relevance to migraine (vasopressin, oxytocin, estrogen, progesterone, testosterone, amylin, adrenomedullin and calcitonin gene-related peptide (CGRP)) in human intracranial arteries. Methods: Human cortical cerebral and middle meningeal arteries were used in this study. The tissues were removed in conjunction with neurosurgery and donated with consent. Vasomotor responses of arteries, after exposure to hormones or neuropeptides, were recorded using a wire myograph. Immunohistochemistry was performed to examine the expression and localization of their receptors within human intracranial arteries. Results: Vasopressin showed the strongest contractile responses, followed by oxytocin and progesterone. CGRP displayed the strongest vasodilatory response when compared to adrenomedullin, amylin, testosterone and estrogen. No significant differences were observed in vasomotor responses between male and female arteries. The vasomotor effects were supported by the presence of corresponding receptors in the vascular smooth muscle cells. Estrogen receptors (ERα and ERβ), progesterone receptor (PR), vasopressin 1a receptor (V1aR), and the oxytocin receptor (OTR) were expressed in the walls of both cerebral arteries overlying the cerebral cortex and intracranial arteries of the dura mater. ERα, V1aR, and PR were found to be localized in both smooth muscle cells and endothelium, whereas OTR was exclusively located within the smooth muscle cells. Conclusions: Hypothalamic, sex hormones and the pancreas hormone (amylin) receptors are expressed in the human intracranial artery walls. The vasomotor responses revealed no sex differences, however contractile responses to vasopressin was higher and more potent in MMA compared to CCA when pooling data from both sexes. Overall, the hormones estrogen, progesterone and oxytocin, which drop in circulating levels at onset of menstruation, only showed modest vasomotor responses as compared to CGRP. This suggests that their role in inducing menstrual migraine attacks is not directly related to vasomotor responses. [ABSTRACT FROM AUTHOR]

RF‐amide peptide receptors including the neuropeptide FF receptor 1 (NPFFR1) are G protein‐coupled receptors (GPCRs) that modulate diverse physiological functions. High conservation of endogenous ligands and receptors makes the identification of selective ligands challenging. Previously identified antagonists mimic the C‐terminus of peptide ligands and lack selectivity towards the closely related neuropeptide FF receptor 2 (NPFFR2) or the neuropeptide Y1 receptor (Y1R). In a high‐throughput screening, we identified the pentacyclic triterpenoid hederagenin (1) as a novel selective antagonist for the NPFFR1. Hederagenin (1) is a natural product isolated from Hedera helix (ivy). We characterized its mode of activity using in vitro and in silico methods, revealing an overlapping binding site of the small molecule with the orthosteric peptide agonists. Despite the high similarity of the orthosteric binding pockets of NPFFR1 and NPFFR2, hederagenin (1) shows strong subtype selectivity, particularly caused by slight differences in the shape of the binding pockets and the rigidity of the small molecule. Several residues inhibiting the activity of hederagenin (1) at the NPFFR2 were identified. As NPFFR1 antagonists are discussed as potential candidates for the treatment of chronic pain, these insights into the structural determinants governing subtype specificity will facilitate the development of next‐generation analgesics with improved safety and efficacy. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the leading type of dementia globally, characterized by a complex pathogenesis that involves various comorbidities. An imbalance in the production and clearance of amyloid β-protein (Aβ) peptides in the brain is a key pathological mechanism of AD, with the glymphatic system playing a crucial role in Aβ clearance. Comorbidities associated with AD, such as diabetes, depression, and hypertension, not only affect Aβ production but also impair the brain's lymphatic system. Abnormalities in the structure and function of this system further weaken Aβ clearance capabilities, and the presence of comorbidities may exacerbate this process. This paper aims to review the role and specific mechanisms of impaired Aβ clearance via the glymphatic system in the context of AD comorbidities, providing new insights for the prevention and treatment of AD. Overall, the damage to the glymphatic system primarily focuses on aquaporin-4 (AQP4) and perivascular spaces (PVS), suggesting that maintaining the health of the glymphatic system may help slow the progression of AD and its comorbidities. Additionally, given the ongoing controversies regarding the structure of the glymphatic system, this paper revisits this structure and discusses the principles and characteristics of current detection methods for the glymphatic system. [ABSTRACT FROM AUTHOR]

The circadian clock and its output pathways play a pivotal role in optimizing daily processes. To obtain insights into how diverse rhythmic physiology and behaviors are orchestrated, we have generated a comprehensive connectivity map of an animal circadian clock using the Drosophila FlyWire brain connectome. Intriguingly, we identified additional dorsal clock neurons, thus showing that the Drosophila circadian network contains ~240 instead of 150 neurons. We revealed extensive contralateral synaptic connectivity within the network and discovered novel indirect light input pathways to the clock neurons. We also elucidated pathways via which the clock modulates descending neurons that are known to regulate feeding and reproductive behaviors. Interestingly, we observed sparse monosynaptic connectivity between clock neurons and downstream higher-order brain centers and neurosecretory cells known to regulate behavior and physiology. Therefore, we integrated single-cell transcriptomics and receptor mapping to decipher putative paracrine peptidergic signaling by clock neurons. Our analyses identified additional novel neuropeptides expressed in clock neurons and suggest that peptidergic signaling significantly enriches interconnectivity within the clock network. Circadian clocks are a fundamental biological system which orchestrate various physiological and behavioral processes in response to daily environmental changes. Here, the authors utilize a multipronged approach to generate a comprehensive neural connectome of an animal circadian clock. [ABSTRACT FROM AUTHOR]

Background: Brain-derived neurotrophic factor (BDNF) is an essential protein required for neuronal growth, survival, and structural maintenance. However, there is still contradictory evidence on the responses of BDNF to exercise and its subsequent secretion. Aims: To investigate the concentration changes and associated health benefits of BDNF following aerobic exercise. Methods: A literature search was conducted on PubMed, Scopus, and Web of Science using the terms: [BDNF] AND [Exercise, Health, Cognition, Metabolism]. The responses of BDNF following aerobic exercise were examined under two clusters: short-term (< 3 weeks) and long-term (> 3 weeks) exercise interventions. Results: 210 research articles were examined, and 34 qualifying articles were included (18 short-term and 16 long-term exercise interventions). Overall, serum samples were prioritized over other biospecimens to quantify BDNF. Compared to plasma, serum samples had a relatively higher concentration of BDNF. Short-term exercise interventions significantly increased BDNF under both high and moderate-intensity. Similarly, long-term exercise interventions also increased BDNF under both high and moderate-intensity. However, multiple long-term exercise interventions reported no change in the concentration of BDNF. Conclusion: Short-term exercise interventions at moderate and high-intensity are effective at increasing the concentration of BDNF. Although these exercise-induced increases in BDNF may not be always visible following long-term exercise interventions, other health benefits related to cognitive function and overall health are attributed to long-term exercise interventions. Future studies should consider the interplay between variables such as hydration status, biospecimen collection time, and sex that may increase the variability of results in BDNF following an exercise intervention. [ABSTRACT FROM AUTHOR]

Regarding Alzheimer's disease (AD), specific neuronal populations and brain regions exhibit selective vulnerability. Understanding the basis of this selective neuronal and regional vulnerability is essential to elucidate the molecular mechanisms underlying AD pathology. However, progress in this area is currently hindered by the incomplete understanding of the intricate functional and spatial diversity of neuronal subtypes in the human brain. Previous studies have demonstrated that neuronal subpopulations with high neuropeptide (NP) co-expression are disproportionately absent in the entorhinal cortex of AD brains at the single-cell level, and there is a significant decline in hippocampal NP expression in naturally aging human brains. Given the role of NPs in neuroprotection and the maintenance of microenvironments, we hypothesize that neurons expressing higher levels of NPs (HNP neurons) possess unique functional characteristics that predispose them to cellular abnormalities, which can manifest as degeneration in AD with aging. To test this hypothesis, multiscale and spatiotemporal transcriptome data from ~1900 human brain samples were analyzed using publicly available datasets. The results indicate that HNP neurons experienced greater metabolic burden and were more prone to protein misfolding. The observed decrease in neuronal abundance during stages associated with a higher risk of AD, coupled with the age-related decline in the expression of AD-associated neuropeptides (ADNPs), provides temporal evidence supporting the role of NPs in the progression of AD. Additionally, the localization of ADNP-producing HNP neurons in AD-associated brain regions provides neuroanatomical support for the concept that cellular/neuronal composition is a key factor in regional AD vulnerability. This study offers novel insights into the molecular and cellular basis of selective neuronal and regional vulnerability to AD in human brains. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuropeptides are small molecules that play key roles in regulating various developmental, physiological, and behavioral processes in crustaceans. In this study, we focused on the Pacific white shrimp, Litopenaeus vannamei, to identify and understand the genes responsible for producing these neuropeptides. Using advanced genetic analysis techniques, we discovered 125 genes that encode neuropeptides, with 54 of them being newly identified. We found that these genes are mainly active in the shrimp's nervous system, particularly in the eyestalk, brain, and nerve ganglia. Additionally, we explored how silencing two specific genes, CHH and VIH, which are important for hormone regulation, affected the expression of other neuropeptide genes. Our results showed that silencing these genes led to a significant decrease in the activity of many neuropeptide genes, affecting pathways related to metabolism and hormone production. This research provides valuable insights into the genetic mechanisms that control shrimp growth and development, which could help improve shrimp farming practices by improving growth rates and disease resistance. Neuropeptides are pivotal in regulating a broad spectrum of developmental, physiological, and behavioral processes throughout the life cycle of crustaceans. In this comprehensive study, we utilized a multiomics approach to characterize neuropeptide precursors and to assess the expression profiles of neuropeptide-encoding genes across various tissues and developmental stages in the Pacific white shrimp, Litopenaeus vannamei. Additionally, we explored the differential expression of neuropeptide genes in the eyestalk before and after the RNA interference-mediated suppression of crustacean hyperglycemic hormone (CHH) and vitellogenesis-inhibiting hormone (VIH) gene expression. Our study identified a total of 125 neuropeptide-encoding genes in L. vannamei, with 54 of these genes previously uncharacterized in the genome. Notably, certain neuropeptide-encoding gene families showed significant expansion, as demonstrated by the discovery of 10 adipokinetic hormone/corazonin-like peptide (ACP) genes, 55 CHH superfamily genes, and 13 pigment-dispersing hormone (PDH) genes. Alternative splicing was also found to play a crucial role in generating functionally diverse neuropeptides; for example, the agatoxin and calcitonin genes undergo alternative splicing that leads to the production of three distinct agatoxin neuropeptides and two distinct calcitonin neuropeptides, respectively. Neuropeptide genes are predominantly expressed in neuroendocrine tissues, including the eyestalk, cerebral ganglia, thoracic ganglia, and ventral ganglia. During the embryonic development of L. vannamei, with the exception of the molt-inhibiting hormone (MIH) gene, all monitored genes display minimal expression from the zygote stage through to the larval in membrane (Lim) stage. In contrast, the majority of these genes exhibit a steady uptick in expression from the nauplius stage onwards, culminating in the post-larval stage. Furthermore, comparative transcriptomic analysis of the eyestalk revealed that the expression of the majority of neuropeptide genes was downregulated following the suppression of CHH and VIH gene expression. This downregulation was significantly associated with the enrichment of pathways related to amino acid metabolism and hormone synthesis. The findings of this study provide valuable insights for future research aimed at elucidating the role of neuropeptides in regulating physiological functions in L. vannamei, potentially leading to advancements in shrimp aquaculture practices. [ABSTRACT FROM AUTHOR]

The neurobiology of autism is complex, but emerging research points to potential abnormalities and alterations in neurogenesis. The aim of the present review is to describe the advances in the understanding of the role of selected neurotrophins, neuropeptides, and other compounds secreted by neuronal cells in the processes of postnatal neurogenesis in conjunction with autism. We characterize the fundamental mechanisms of neuronal cell proliferation, generation of major neuronal cell types with special emphasis on neurogenic niches – the subventricular zone and hippocampal areas. We also discuss changes in intracellular calcium levels and calcium-dependent transcription factors in the context of the regulation of neurogenesis and cell fate determination. To sum up, this review provides specific insight into the known association between alterations in the function of the entire spectrum of molecules involved in neurogenesis and the etiology of autism pathogenesis. [ABSTRACT FROM AUTHOR]