Screening potential anaphylactoid components in vinpocetine injection using a high expression Mas-related G-protein-coupled receptor X2 cell membrane chromatography.

Vinpocetine injection is often used in clinical treatment of acute cardiovascular and cerebrovascular diseases. However, it was reported that vinpocetine injection caused allergic reactions in clinical use; therefore, its safety needs urgent attention. Until now, research on its sensitization is rarely reported. Here, the components contained in three vinpocetine injections were examined. It was found that besides vinpocetine, the synthetic raw material vincamine, the excipients benzyl alcohol and ethyl p-toluenesulfonate, and the impurities A, B, C, and D, which are excipients specified in the European Pharmacopoeia, were also present in them. Then the Mas-related G-protein-coupled receptor X2 (MRGPRX2)-HEK293 cell membrane chromatography was used to investigate the affinity of them with MRGPRX2 and found that vinpocetine, vincamine, and impurities A, B, C, and D bind to MRGPRX2. Afterwards, these compounds were further used to investigate the local sensitization ability in vivo. The results showed that vinpocetine, vincamine, and impurity C could induce swelling of the paw and decrease body temperature in mice, but only impurity C could cause local skin mast cell degranulation and serum histamine release increase. In vitro, the results also indicated that impurity C could increase intracellular [Ca2+ ] in MRGPRX2-HEK293 cells, whereas vinpocetine and vincamine did not. Therefore, the impurity C was the potential anaphylactoid component in vinpocetine injection, which may be one of the reasons for the occurrence of allergic reactions in the clinical use of vinpocetine injection. This work provides evidence on the sensitization of impurity C and also contributes to promoting the clinical safety of vinpocetine injection.

Anti-pseudo-allergic components in licorice extract inhibit mast cell degranulation and calcium influx.

Pseudo-allergic reactions (PARs) widely occur upon application of drugs or functional foods. Anti-pseudo-allergic ingredients from natural products have attracted much attention. This study aimed to investigate anti-pseudo-allergic compounds in licorice. The anti-pseudo-allergic effect of licorice extract was evaluated in rat basophilic leukemia 2H3 (RBL-2H3) cells. Anti-pseudo-allergic compounds were screened by using RBL-2H3 cell extraction and the effects of target components were verified further in RBL-2H3 cells, mouse peritoneal mast cells (MPMCs) and mice. Molecular docking and human MRGPRX2-expressing HEK293T cells (MRGPRX2-HEK293T cells) extraction were performed to determine the potential ligands of MAS-related G protein-coupled receptor-X2 (MRGPRX2), a pivotal target for PARs. Glycyrrhizic acid (GA) and licorice chalcone A (LA) were screened and shown to inhibit Compound48/80-induced degranulation and calcium influx in RBL-2H3 cells. GA and LA also inhibited degranulation in MPMCs and increase of histamine and TNF-α in mice. LA could bind to MRGPRX2, as determined by molecular docking and MRGPRX2-HEK293T cell extraction. Our study provides a strong rationale for using GA and LA as novel treatment options for PARs. LA is a potential ligand of MRGPRX2.

Anti-pseudo-allergic components in licorice extract inhibit mast cell degranulation and calcium influx / 中国天然药物

Pseudo-allergic reactions (PARs) widely occur upon application of drugs or functional foods. Anti-pseudo-allergic ingredients from natural products have attracted much attention. This study aimed to investigate anti-pseudo-allergic compounds in licorice. The anti-pseudo-allergic effect of licorice extract was evaluated in rat basophilic leukemia 2H3 (RBL-2H3) cells. Anti-pseudo-allergic compounds were screened by using RBL-2H3 cell extraction and the effects of target components were verified further in RBL-2H3 cells, mouse peritoneal mast cells (MPMCs) and mice. Molecular docking and human MRGPRX2-expressing HEK293T cells (MRGPRX2-HEK293T cells) extraction were performed to determine the potential ligands of MAS-related G protein-coupled receptor-X2 (MRGPRX2), a pivotal target for PARs. Glycyrrhizic acid (GA) and licorice chalcone A (LA) were screened and shown to inhibit Compound48/80-induced degranulation and calcium influx in RBL-2H3 cells. GA and LA also inhibited degranulation in MPMCs and increase of histamine and TNF-α in mice. LA could bind to MRGPRX2, as determined by molecular docking and MRGPRX2-HEK293T cell extraction. Our study provides a strong rationale for using GA and LA as novel treatment options for PARs. LA is a potential ligand of MRGPRX2.

When topical therapy of atopic dermatitis fails: a guide for the clinician.

INTRODUCTION: While topical medications are the first line of treatment for mild-to-moderate atopic dermatitis, they are ineffective in individuals with diffuse disease and moderate-to-severe atopic itch. For these individuals, as well as those who do not respond to topical treatments, systemic medicines are typically essential and helpful. AREAS COVERED: We conducted a review of the literature to identify established systemic therapies, novel biologic agents, and recent advances in the pathophysiology of atopic dermatitis. The review discusses these data, which show that the majority of atopic itch medications now in development target the type 2 immune axis and brain sensitization, two main etiologies of atopic itch. We emphasize the evidence, efficacy, and side effect profiles of currently available systemic medications for atopic itch, as well as future potential for tailored therapy. EXPERT OPINION: We give our professional opinion on the current state of knowledge about atopic eczema pathogenesis and the innovative targets and therapies for atopic itch that include MRGPRX2, periostin, gabaergic medicines, and JAK/STAT inhibitors. Additionally, we discuss patient populations that stand to benefit the most from targeting these molecules or utilizing these drugs, as well as those who may face a disproportionate weight of adverse effects.

Regulación de la actividad GnRH. Los sistemas Kisspeptina/GPR54 y GnIH/GPR147 / GnRH activity regulation. Kisspeptin/GPR54 and GnIH/GPR147 systems

OBJETIVO: Revisar y actualizar la fisiología de la regulación de fertilidad y reproducción, poniendo especial énfasis en los factores neuroendocrinos que controlan la secreción pulsátil de GnRH. MATERIAL Y MÉTODOS: Revisión bibliográfica, utilizando como palabras clave «GnRH», «Kisspeptin», «GnIH», «RF-amide» y RPRF-3, entre otras. RESULTADOS: Siendo la secreción pulsátil de GnRH el elemento clave para el control de la secreción de gonadotrofinas, se describen los mecanismos neuroendocrinos (Kisspeptina, GnIH) que regulan la actividad de las neuronas GnRH

OBJECTIVE: To Review and update the physiology regulating fertility and reproduction, with particular emphasis on neuroendocrine factors controlling the pulsatile secretion of GnRH. MATERIAL AND METHODS: Review of the literature, using as key words «GnRH», «Kisspeptin», «GnIH», «RF-amide» and RPRF-3, among others. RESULTS: Being the pulsatile secretion of GnRH the key element for the control of gonadotrophin secretion, the neuroendocrine mechanisms (Kisspeptine, GnIH) that regulate the activity of GnRH neurons are described

La neurohormona GnRH en la mujer / Neurohormone GnRH in the woman

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Activation of GABAergic pathway by hypocretin in the median raphe nucleus (MRN) mediates stress-induced theta rhythm in rats.

The frequency of electroencephalograms (EEGs) is predominant in theta rhythm during stress (e.g., footshock) in rats. Median raphe nucleus (MRN) desynchronizes hippocampal theta waves via activation of GABAergic neurons in the medial septum-diagonal band of Broca (MS-DBB), a theta rhythm pacemaker. Increased hypocretin mediates stress responses in addition to the maintenance of wakefulness. Hypocretin receptors are abundant in the MRN, suggesting a possible role of hypocretin in modulating stress-induced theta rhythm. Our results indicated that the intensity of theta waves was enhanced by footshock and that a hypocretin receptor antagonist (TCS1102) suppressed the footshock-induced theta waves. Administration of hypocretin-1 (1 and 10 µg) and hypocretin-2 (10 µg) directly into the MRN simulated the effect of footshock and significantly increased theta waves. Co-administration of GABA(A) receptor antagonist, bicuculline, into the MRN blocked the increase of theta waves induced by hypocretins or footshock. These results suggested that stress enhances the release of hypocretins, activates GABAergic neurons in the MRN, blocks the ability of MRN to desynchronize theta waves, and subsequently increases the intensity of theta rhythm.

[Amyloid-beta peptide metabolism and Alzheimer's disease].

The deposition of amyloid-beta peptide (Abeta) causes the long-term pathological cascade of Alzheimer's disease (AD). Neprilysin is a rate-limiting peptidase, which participates in Abeta degradation in brain. As demonstrated by reverse genetics, the disruption of neprilysin gene causes an elevation in endogenous Abeta levels in the mouse brain in a gene-dose-dependent manner. Therefore, a reduction of neprilysin activity will contribute to Abeta deposition and thus to AD development. Neprilysin is localized at presynapses and on axons, and its expression levels are decreased at the terminal zones and on axons of the lateral perforant pathway and the mossy fibers with aging in mice, suggesting that local concentrations of Abeta are likely to be elevated at the sites, which play crucial roles on certain forms of learning and memory and are highly vulnerable to AD. Overexpression of neprilysin decreased both extracellular and intracellular Abeta levels in primary cortical neurons. These results indicate that up-regulation of neprilysin activity would be a relevant strategy for therapy and prevention through reduction of the Abeta levels. Recently, we have found that a certain neuropeptide regulates the expression of neprilysin in primary neurons. Since a number of receptors for neuropeptides are G-protein-coupled receptors, we would control brain Abetalevels pharmacologically by the manipulation of neprilysin activity.

Pharmacotherapy for intestinal motor and sensory disorders.

Motor disorders of the gastrointestinal tract are characterized by definable impairments of gut contractile function. Other conditions exhibit specific disturbances of visceral afferent and efferent activity, which may underlie selected symptom complexes. Medications in several classes have been developed to treat these disorders of gastrointestinal function. Prokinetic agents are effective therapies for ailments with reduced motor function, whereas antispasmodic drugs reduce symptoms in conditions with exaggerated pressure wave activity. Recently, medications designed to blunt transmission in visceral sensory pathways have been proposed for use in the functional bowel disorders. Finally, some patients may benefit from initiation of nonspecific therapies, which have no appreciable effect on gut motor or sensory function.