INTRODUCTION:Rosacea is a chronic inflammatory skin disorder characterized by symptoms like itching, redness, and impaired skin barrier function. Mast cell activation plays a crucial role in its pathogenesis. Recent evidence shows higher expression of mast cell receptor MRGPRX2/MRGPRB2 in rosacea patients' skin tissues and its potential as a novel drug target. We evaluated the therapeutic effect of a novel small-molecule MRGPRX2/MRGPRB2 antagonist in a mouse model of rosacea and itch. METHODS:The therapeutic effects of GE1111 were evaluated in vivo on wildtype and MRGPRB2 knock-out mice with LL-37-induced rosacea. Serum MCP-1 level and histochemistry measured inflammation and mast cell degranulation in skin tissue. Functional in vitro cell culture assays were developed using MRGPRX2/MRGPRB2 agonist LL-37, mast cells, keratinocytes, and macrophage cell lines. RESULTS:LL-37-treated mice showed redness, increased serum MCP-1, and epidermal thickness of skin tissue, while these changes were absent in LL-37-treated MRGPRB2 knock-out mice. Treatment with GE1111 reduced rosacea symptoms, epidermal thickness, and serum MCP-1 levels. GE1111 protected tight junction protein expression and reduced mast cell degranulation and inflammatory cytokine gene and protein expression in skin lesions. GE1111 treatment reduced the number and duration of itch in the compound 48/80 induced itch model. In vitro evidence showed GE1111's mechanism by inhibiting inflammatory interaction of mast cells with keratinocytes and macrophages. CONCLUSION:GE1111 showed promising therapeutic effects in rosacea via targeting interactions between mast cells, keratinocytes, and macrophages and inhibiting inflammatory cytokines. These findings open possibilities for developing MRGPRX2/MRGPRB2 antagonists as novel treatments for rosacea.

Purpose of review Despite their prevalence and potential severity, non-IgE-mediated drug-induced hypersensitivity reactions (DHRs) are under-researched and poorly defined, particularly in children. Presentations range from mild cutaneous reactions to severe systemic diseases, with pathophysiological mechanisms and reliable diagnostic markers not well established. The lack of validated tests often leads to permanent drug restrictions, reliance on second-line drugs, and increased costs. Focusing on recent advancements and areas needing further research, this review aims to enhance children's recognition, diagnosis, and management of non-IgE-mediated DHRs. Recent findings Recent studies have enhanced the understanding of immediate and delayed non-IgE-mediated drug reactions. Key findings include the Mas-related G protein-coupled receptor X2 in mast cells and the identification of HLA alleles linked to severe cutaneous adverse reactions, such as Stevens–Johnson syndrome and toxic epidermal necrolysis. Improved diagnostic techniques, including skin testing, show promise in identifying immediate and delayed non-IgE DHRs. Additionally, research highlights the impact of cofactors, drug metabolites, and co-infections on these DHRs and explores potential biomarkers for predicting reaction severity. Summary Non-IgE-mediated DHRs are a significant cause of morbidity and treatment changes in pediatric patients. Recent research underscores their clinical presentations and mechanisms, paving the way for more precise diagnostic and therapeutic strategies to improve patient outcomes.

IntroductionAtopic dermatitis (AD) is a chronic inflammatory skin disorder characterised by itching, erythema, and epidermal barrier dysfunction. The pathogenesis of AD is complex and multifactorial; however,mast cell (MC) activation has been reported to be one of the crucial mechanisms in the pathogenesis of AD. The MC receptor Mas related G protein-coupled receptor-X2 (MRGPRX2) has been identified as a prominent alternative receptor to the IgE receptor in causing MC activation and the subsequent release of inflammatory mediators. The current study aimed to evaluate the therapeutic effect of a novel small molecule MRGPRX2 antagonist GE1111 in AD using in vitro and in vivo approaches. MethodsWe developed an in vitro cell culture disease model by using LAD-2 MC, HaCaT keratinocytes and RAW 264.7 macrophage cell lines. We challenged keratinocytes and macrophage cells with CST-14 treated MC supernatant in the presence and absence of GE1111 and measured the expression of tight junction protein claudin 1, inflammatory cytokines and macrophage phagocytosis activity through immunohistochemistry, western blotting, RT-qPCR and fluorescence imaging techniques. In addition to this, we developed a DFNB-induced AD model in mice and evaluated the protective effect and underlying mechanism of GE1111.Results and DiscussionOur in vitro findings demonstrated a potential therapeutic effect of GE1111, which inhibits the expression of TSLP, IL-13, MCP-1, TNF-a, and IL-1ß in MC and keratinocytes. In addition to this, GE1111 was able to preserve the expression of claudin 1 in keratinocytes and the phagocytotic activity of macrophage cells. The in vivo results demonstrated that GE1111 treatment significantly reduced phenotypic changes associated with AD (skin thickening, scaling, erythema and epidermal thickness). Furthermore, immunohistochemical analysis demonstrated that GE1111 treatment preserved the expression of the tight junction protein Involucrin and reduced the expression of the inflammatory mediator periostin in the mouse model of AD. These findings were supported by gene and protein expression analysis, where GE1111 treatment reduced the expression of TSLP, IL-13, and IL-1ß, as well as downstream signalling pathways of MRGPRX2 in AD skin lesions. In conclusion, our findings provide compelling in vitro and in vivo evidence supporting the contribution of MRGPRX2-MC interaction with keratinocytes and macrophages in the pathogenesis of AD.

Chronic spontaneous urticaria (CSU) often remains under-treated and significantly impacts quality of life [1-3]. The mainstay of treatment involves use of various mast cell-targeting medications, aiming for complete disease control [1, 4]. Although the use of patient-reported outcomes such as the weekly Urticaria Activity Score (UAS7) have been advocated, more objective biomarkers are needed [1, 4, 5]. Recent evidence have implicated the role of Mas-related G-protein coupled receptor-X2 (MRGPRX2) in CSU pathogenesis, with levels reported to correlate with disease severity [6, 7]. Blood tests such as MRGPRX2 are attractive biomarkers, given their ease of measurement and availability of commercial assays. However, to the best of our knowledge, studies correlating MRGPRX2 with CSU has not been validated beyond Korean patients [6]. Therefore, we conducted this study on a Chinese cohort to investigate the extended validity of serum MRGPRX2 as a biomarker, as well as its relationship with chemokine (C–C motif) ligand 2 (CCL-2), another potential biomarker reported to play a major role in CSU pathogenesis [8]. We enrolled newly diagnosed CSU patients referred to the Urticaria Clinic of the Hospital Authority Hong Kong West Cluster between 1 January 2023 and 31 July 2023. All patients were diagnosed according to the regional and international recommendations [1, 4]. Patient demographics, baseline characteristics, medication history and UAS7 were collected by standardised questionnaires with simultaneous bloods taken at first visit. To align with previous studies, UAS7 ≥28 and <28 patients were classified as 'severe' and 'nonsevere', respectively [1]. Treatment-naïve was defined by patients not taking any regular CSU medications for at least 1 month prior to enrolment. Serum MRGPRX2 levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit (MyBioSource, Inc., San Diego, CA, USA), and CCL2 levels were measured using Human CCL-2/MCP-1 instant ELISA kit (Thermo Fisher Scientific, MA, USA). No reference range was available for MRGPRX2, whereas CCL-2 levels ≥250 pg/mL were considered elevated based on previous studies. Statistical analyses were performed using IBM SPSS v22 (SPSS Inc., Chicago, IL, USA). Mann–Whitney U tests were used to determine the relation between baseline MRGPRX2 levels of severe and nonsevere patients; chi-squared tests were used to determine the relationship between CSU disease activity and CCL-2 levels; Pearson correlations were used to determine correlation between MRGPRX2 with UAS7 and CCL-2. Cut-off for significance levels for all tests were p < 0.05. Written informed consent was obtained from all study subjects. The study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster. A total of 95 patients were recruited, of which 47 (49%) were treatment-naïve. 75 (79%) and 20 (21%) of patients had severe and nonsevere disease at recruitment, respectively. Median age was 53 (19–20) years and the male: female ratio was 1:6.3. Overall, patients with severe disease had higher serum MRGPRX2 levels (severe: 41.06 ± 26.98; nonsevere: 26.64 ± 15.91 p = 0.011). Similarly, more patients with severe disease had elevated CCL-2 levels (70.0% vs 42.7%, p = 0.030) compared with nonsevere patients. Subgroup analysis demonstrated that MRGPRX2 was only significantly higher among treatment-naïve patients (severe: 58.15 ± 38.53, nonsevere: 25.91 ± 15.07; p = 0.034), rather than those on regular CSU medications (severe: 36.79 ± 22.98, nonsevere: 27.64 ± 17.15, p = 0.092). In contrast, differences in CCL2 did not reach statistical significance when analysing treatment-naïve patients (100.0% vs 58.1%, p = 0.283). Overall, serum MRGPX2 levels also showed significant correlation with CCL-2; but subgroup analysis revealed this correlation only remained significant among treatment-naïve patients as opposed to patients on regular CSU treatment (Figure 1 and https://osf.io/mz29q). Our study supports that both MRGPRX2 and CCL-2 may be potential biomarkers for CSU. We found that both serum markers were also strongly intercorrelated, but only among treatment-naïve patients. Similarly, MRGPRX2 was only significantly different among treatment-naïve patients, rather than those on regular CSU treatment. Alike other secreted substances, we postulate that medications used in the treatment of CSU (such as H1-antihistamines, mast cell stabilisers, anti-IgE biologics etc.) may interfere with mast cell degranulation/exocytosis of MRGPRX2-containing vesicles, therefore affecting measurable serum MRGPX2 levels among patients on treatment [9]. In contrast, CCL2 has been postulated to be a chemokine secreted by other cell types (such as monocytes) creating a proinflammatory environment in CSU and therefore may be less affected by medications [8]. There were several limitations to this study. Firstly, was its observational nature and patients were recruited on a consecutive basis, and there remains a possibility of ascertainment bias (e.g., patients with milder disease were more likely to be treatment-naïve). Secondly, as not all patient-reported outcome measures in traditional Chinese had been validated during recruitment, only UAS7 was included in analysis. Third, the cohort size was small and direct correlation between UAS7 or further subgroup analysis could not be performed (e.g., stratifying different treatment modalities, medical comorbidities or CSU subtypes). Fourth, all patients were ethnically Chinese and from a centre in Hong Kong which limits external. Similarly, no reference range was available for MRGPRX2 and there is possibility of inter-individual or -ethnic variability. These limitations highlight the need for further dedicated, prospective and multicentre studies on MRGPX2 and CCL2 among CSU patients. We propose that serum MRGPX2 and CCL-2 may be potential biomarkers reflecting CSU severity. It is important to note that, unlike CCL-2, MRGPRX2 may be more useful among treatment-naïve CSU patients (e.g., newly diagnosed CSU patients before treatment or after temporary cessation of medications) for more objective assessment and may also be used to indirectly measure adherence to treatment. The potential complimentary role of both these novel biomarkers warrants further study in larger, longitudinal studies which are currently underway. The author takes full responsibility for this article. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.

The mast cell receptor Mrgprb2, a mouse orthologue of human Mrgprx2, is known as an inflammatory receptor and its elevated expression is associated with various diseases such as ulcerative colitis. We aimed to elucidate the role of Mrgprb2/x2 and the effect of its ligands on a chemically induced murine colitis model. We showed that in Mrgprb2-/- mice, there is a differential regulation of cytokine releases in the blood plasma and severe colonic damages after DSS treatment. Unexpectedly, we demonstrated that known Mrgprb2/x2 agonists (peptide P17, P17 analogues and CST-14) and antagonist (GE1111) similarly increased the survival rate of WT mice subjected to 4% DSS-induced colitis, ameliorated the colonic damages of 2.5% DSS-induced colitis, restored major protein mRNA expression involved in colon integrity, reduced CD68+ and F4/80+ immune cell infiltration and restored cytokine levels. Collectively, our findings highlight the eminent role of Mrpgrb2/x2 in conferring a beneficial effect in the colitis model, and this significance is demonstrated by the heightened severity of colitis with altered cytokine releases and inflammatory immune cell infiltration observed in the Mrgprb2 knockout mice. Elevated expression of Mrgprb2 in WT colitis murine models may represent the organism’s adaptive protective mechanism since Mrgprb2 knockout results in severe colitis. On the other hand, both agonist and antagonist of Mrgprb2 analogously mitigated the severity of colitis in DSS-induced colitis model by altering Mrgprb2 expression, immune cell infiltration and inflammatory cytokine releases.

Chronic spontaneous urticaria (CSU), atopic dermatitis (AD), psoriasis and rosacea are highly prevalent inflammatory skin conditions which impose a significant burden on patients' quality of life. Their pathophysiology is likely multifactorial, involving genetic, immune and environmental factors. Recent advancements in the field have demonstrated the key role of mast cells (MC) in the pathophysiology of these conditions. The Mas-related G protein-coupled receptor X2 (MRGPRX2) has emerged as a promising non-IgE-mediated MC activation receptor. MRGPRX2 is predominately expressed on MC and activated by endogenous and exogenous ligands, leading to MC degranulation and release of various pro-inflammatory mediators. Mounting evidence on the presence of endogenous MRGPRX2 agonists (substance P, cortistatin-14, LL37, PAMP-12 and VIP) and its high expression among patients with CSU, AD, rosacea, psoriasis and chronic pruritus emphasizes the pathogenic role of MRGPRX2 in these conditions. Despite the currently available treatments, there remains a pressing need for novel drug targets and treatment options for these chronic inflammatory skin conditions. Here, we reviewed the pathogenic role of MRGPRX2 and its potential as a novel therapeutic target and provided an update on future research directions.

Diabetes is a hyperglycemic metabolic condition. Diabetes may lead to obesity and neuropathic changes in a patient. Damage to any neurological part or organ during diabetes causes diabetic neuropathy. Neuropathy occurs due to hypersensitivity in nerves because of abnormal epinephrine-mediated transmission of the impulse from axon to axon. In 1864, Marchal de Calvi explained that diabetes causes neurologic lesions by observing the pain in sciatic distribution and peripheral areas of anesthesia. Anti-hyperglycemic components, polypeptide-p and osmotin, can not only reduce the blood glucose level of mice but have also proven to be without any side effect or negative impact as they reduce oxidative stress level, improve the activities of endogenous antioxidants, and positively alter the activities of neurotransmitters, like cholinesterase, serotonin, and β - aminobutyric acid (GABA).

Anxiety and depression are the major psychological disorders globally, increasing the risk of morbidity and mortality and considerably leading to a socioeconomic burden by 2030. Both disorders impact day-to-day life via several symptoms (fear, insomnia, anorexia, irritability, loss of concentration, and inability to think). The available treatment strategy for psychological disorders has shown major adverse effects, which limits its use and paves the way for the development of the herbal drug-based novel drug. Natural compounds are offered as the most contented option because they possess very least side effects, are easily available, and are of low cost with high therapeutic activity. In the present chapter, we focus on the pharmacology of a plant polyphenol, Rosmarinic acid (RA), against psychological disorders. Specific plant constituents of Rosmarinus officinalis (rosmarinic acid) help treat anxiety and depression by reducing oxidative stress and inflammatory mediators. Other important targets, such as neurotransmitters (noradrenaline, 5-HT, and dopamine), neuroendocrine (Hypothalamus-pituitary-adrenal-axis), brain-derived neurotrophic factor, T-type calcium channels, mitogen kinase protein-1, and phosphorylated extracellular regulated kinase 1 and 2 protein, are also involved in the pathophysiology of psychological disorders (anxiety and depression). Thus, in this chapter, we have illustrated the pharmacology of RA in major psychological disorders, including anxiety and depression.

Background: P17, a peptide isolated from Tetramorium bicarinatum ant venom, is known to induce an alternative phenotype of human monocyte-derived macrophages via activation of an unknown G protein-coupled receptor (GPCR). Objective: We sought to investigate the mechanism of action and the immunomodulatory effects of P17 mediated through MRGPRX2 (Mas-related G protein-coupled receptor X2). Methods: To identify the GPCR for P17, we screened 314 GPCRs. Upon identification of MRGPRX2, a battery of in silico, in vitro, ex vivo, and in vivo assays along with the receptor mutation studies were performed. In particular, to investigate the immunomodulatory actions, we used beta-hexosaminidase release assay, cytokine releases, quantification of mRNA expression, cell migration and differentiation assays, immunohistochemical labeling, hematoxylin and eosin, and immunofluorescence staining. Results: P17 activated MRGPRX2 in a dose-dependent manner in beta-arrestin recruitment assay. In LAD2 cells, P17 induced calcium and beta-hexosaminidase release. Quercetin- and short hairpin RNA-mediated knockdown of MRGPRX2 reduced P17-evoked beta-hexosaminidase release. In silico and in vitro mutagenesis studies showed that residue Lys(8) of P17 formed a cation-pi interaction with the Phe(172) of MRGPRX2 and [Ala(8)] P17 lost its activity partially. P17 activated LAD2 cells to recruit THP-1 and human monocytes in Transwell migration assay, whereas MRGPRX2-impaired LAD2 cells cannot. In addition, P17-treated LAD2 cells stimulated differentiation of THP-1 and human monocytes, as indicated by the enhanced expression of macrophage markers cluster of differentiation 11b and TNF-alpha by quantitative RT-PCR. Immunohistochemical and immunofluorescent staining suggested monocyte recruitment in mice ears injected with P17. Conclusions: Our data provide novel structural information regarding the interaction of P17 with MRGPRX2 and intracellular pathways for its immunomodulatory action.

Psychiatric disorders and associated cardiac comorbidities have increased the risk of mortality worldwide. Researchers reported that depression increases the possibility of future cardiac abnormalities by approximately 30%. Therefore, there is an unmet need to develop therapeutic interventions to treat depression and associated cardiac abnormalities. The present study was conducted to evaluate the prophylactic effect of rosmarinic acid (RA) against chronic unpredictable stress (CUS)-induced depression associated cardiac abnormalities in Wistar rats. The CUS paradigm, which comprised several stressors, was employed for 40 days to induce depressive-like behavior and associated cardiac abnormalities in rats. Along with CUS, RA at a dose of 25 and 50 mg/kg was administered orally to two groups of animals for 40 days. Behavioral tests (forced swim test and sucrose consumption test) and molecular biomarkers (corticosterone and serotonin) were performed. Electrocardiography was performed before CUS (Day 0), Day 20, and Day 40 to study electrocardiogram parameters. Furthermore, changes in body weight, organ weight, tissue lipid peroxidation, glutathione, catalase, cTn-I, MMP-2, and proinflammatory cytokines (TNF-alpha and IL-6) were estimated. Our results showed that RA treatment caused a reduction in immobility period, adrenal hyperplasia, corticosterone level, tissue lipid peroxidation, cTn-I, MMP-2, proinflammatory cytokines, and QRS complex duration, while an increase in sucrose consumption, brain serotonin level, T-wave width, glutathione, and catalase activity as compared with the CUS-control group. The results of our study proved that RA administration ameliorates CUS-induced depression-associated cardiac abnormalities in rats via serotonergic, oxidative, and inflammatory pathways.

Background: Activation of Mas-related G protein-coupled receptor X2 (MRGPRX2) is a crucial non-IgE pathway for mast cell activation associated with allergic reactions and inflammation. Only a few peptides and small compounds targeting MRGPRX2 have been reported, with limited information on their pharmacologic activity. Objective: We sought to develop novel small molecule MRGPRX2 antagonists to treat MRGPRX2-mediated allergies and inflammation.Methods: A computational approach was used to design novel small molecules as MRGPRX2 antagonists. The short-listed molecules were synthesized and characterized by liquid chromatography and mass spectrometry as well as nuclear magnetic resonance. Inhibitory activity on MRGPRX2 signaling was assessed in vitro by using functional bioassays (b-hexosaminidase, calcium flux, and chemokine synthesis) and receptor activation assays (b-arrestin recruitment and Western blot analysis) in human LAD-2 mast cells and HTLA cells. In vivo effects of the novel MRGPRX2 antagonists were assessed using a mouse model of acute allergy and systemic anaphylaxis.Results: The novel small molecules demonstrated higher binding affinity with MRGPRX2 in the docking study. The half -maximal inhibitory concentration is in the low micromolar range (5-21 mM). The small molecules inhibited not only the early phase of mast cell activation but also the late phase, associated with chemokine and prostaglandin release. Further, Western blot analysis revealed inhibition of downstream phospholipase C -g, extracellular signal-regulated protein kinase 1/2, and Akt signaling pathway. Moreover, in the mouse models of allergies, small molecule administration effectively blocks acute, systemic allergic reactions and inflammation and prevents systemic anaphylaxis.Conclusion: The small molecules might hold a significant therapeutic promise to treat MRGPRX2-mediated allergies and inflammation. (J Allergy Clin Immunol 2023;151:1110-22.)

Mas-related G-protein coupled receptor member X2 (MRGPRX2) is a class A GPCR expressed on mast cells. Mast cells are granulated tissue-resident cells known for host cell response, allergic response, and vascular homeostasis. Immunoglobulin E receptor (FcεRI)-mediated mast cell activation is a well-studied and recognized mechanism of allergy and hypersensitivity reactions. However, non-IgE-mediated mast cell activation is less explored and is not well recognized. After decades of uncertainty, MRGPRX2 was discovered as the receptor responsible for non-IgE-mediated mast cells activation. The puzzle of non-IgE-mediated pseudo-allergic reaction is unlocked by MRGPRX2, evidenced by a plethora of reported endogenous and exogenous MRGPRX2 agonists. MRGPRX2 is exclusively expressed on mast cells and exhibits varying affinity for many molecules such as antimicrobial host defense peptides, neuropeptides, and even US Food and Drug Administration-approved drugs. The discovery of MRGPRX2 has changed our understanding of mast cell biology and filled the missing link of the underlying mechanism of drug-induced MC degranulation and pseudo-allergic reactions. These non-canonical characteristics render MRGPRX2 an intriguing player in allergic diseases. In the present article, we reviewed the emerging role of MRGPRX2 as a non-IgE-mediated mechanism of mast cell activation in pseudo-allergic reactions. We have presented an overview of mast cells, their receptors, structural insight into MRGPRX2, MRGPRX2 agonists and antagonists, the crucial role of MRGPRX2 in pseudo-allergic reactions, current challenges, and the future research direction.

Aim For the treatment of cerebral ischaemia, vitamin-D(3)loaded nanoemulsions were developed. Method Tween 20 and polyethylene glycol were chosen as surfactant/co-surfactant, while oleic acid as the oil phase. The formulation was characterised for variousin-vitroparameters. Targeting efficiency was investigated through radiometry, gamma scintigraphy and efficacy was studied in transient middle cerebral artery occlusion (MCAo) rat model. Result Vitamin D-3-nanoemulsion showed a mean size range of 49.29 +/- 10.28 nm with polydispersity index 0.17 +/- 0.04 and zeta potential 13.77 mV. The formulation was found stable during thermodynamic stability study and permeated within 180 min through sheep nasal mucosa (permeation coefficient 7.873 +/- 0.884 cm/h). Gamma scintigraphy and radiometry assay confirmed better percentage deposition (2.53 +/- 0.17%) of(99m)Tc-vitamin D-3-nanoemulsion through nasal route compared to IV administered(99m)Tc-vitamin D(3)solution (0.79 +/- 0.03%). Magnetic Resonance Imaging (MRI) of the ischaemic model confirmed better efficacy of vitamin D-3-nanoemulsion. Conclusion This work demonstrated better permeation, deposition, and efficacy of vitaminD(3)-nanoemulsion through the intranasal route.

Anaphylactoid shock is a fatal hypersensitivity response caused by non-IgE mediated mast cell activation. These reactions are mediated by a family of G protein-coupled receptors (GPCRs) known as Mas related GPCRX2 (MRGPRX2). Several US FDA approved drugs which are used in day to day life have been reported to cause anaphylactoid shock. Surprisingly, no therapeutic drugs are available which can directly target MRGPRX2 for treatment of anaphylactoid shock. Genistein is a non-steroidal polyphenol known for its diverse physiological and pharmacological activities. In recent studies, Genistein has been reported for its anti-inflammatory activity on mast cells. However, the effects and mechanistic pathways of Genistein on anaphylactoid reaction remain unknown. In the present study, we designed a battery of in-vitro, in-silico and in-vivo experiments to evaluate the anti-anaphylactoid activity of Genistein in order to understand the possible molecular mechanisms of its action. The in-vitro results demonstrated the inhibitory activity of Genistein on MRGPRX2 activation. Further, a mouse model of anaphylactoid shock was used to evaluate the inhibitory activity of Genistein on blood vessel leakage and hind paw edema. Taken together, our findings have demonstrated a therapeutic potential of Genistein as a lead compound in the treatment of anaphylactoid shock via MRGPRX2.

BACKGROUND:The association between new-onset left ventricular (LV) dysfunction during sepsis with long-term heart failure outcomes is lesser understood.METHODS:Retrospective cohort study of all adult patients with severe sepsis and septic shock between 2007 and 2014 who underwent echocardiography within 72 h of admission to the intensive care unit. Patients with prior heart failure, LV dysfunction, and structural heart disease were excluded. LV systolic dysfunction was defined as LV ejection fraction <50% and LV diastolic dysfunction as ≥grade II. Primary composite outcome included new hospitalization for acute decompensated heart failure and all-cause mortality at 2-year follow-up. Secondary outcomes included persistent LV dysfunction, and hospital mortality and length of stay.RESULTS:During this 8-year period, 434 patients with 206 (48%) patients having LV dysfunction were included. The two groups had similar baseline characteristics, but those with LV dysfunction had worse function as demonstrated by worse LV ejection fraction, cardiac index, and LV diastolic dysfunction. In the 331 hospital survivors, new-onset acute decompensated heart failure hospitalization did not differ between the two cohorts (15% vs. 11%). The primary composite outcome was comparable at 2-year follow-up between the groups with and without LV dysfunction (P = 0.24). Persistent LV dysfunction was noted in 28% hospital survivors on follow-up echocardiography. Other secondary outcomes were similar between the two groups.CONCLUSIONS:In patients with severe sepsis and septic shock, the presence of new-onset LV dysfunction did not increase the risk of long-term adverse heart failure outcomes.

OBJECTIVES:To evaluate the epidemiology of hyperammonemia unrelated to liver failure in the critical care setting. DESIGN:Retrospective case series. SETTING:Critically ill patients admitted to ICUs at Mayo Clinic, Rochester, MN (medical ICU, two mixed medical-surgical ICUs, coronary care unit, or the cardiosurgical ICU) between July 1, 2004, and October 31, 2015. PATIENTS:Adult critically ill patients with hyperammonemia not related to acute or chronic liver failure. We excluded patients with diagnosis of moderate or severe liver disease, hyperbilirubinemia, and patients who denied the use of their medical records. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Of 3,908 ICU patients with hyperammonemia, 167 (4.5%) had no evidence of acute or chronic liver failure. One-hundred one patients (60.5%) were male with median age of 65.7 years (interquartile range, 50-74.5 yr) and median serum ammonia level of 68 µg/dL (interquartile range, 58-87 µg/dL). Acute encephalopathy was present in 119 patients (71%). Predisposing conditions included malnutrition 27 (16%), gastric bypass six (3.6%), total parenteral nutrition four (2.4%); exposure to valproic acid 17 (10%); status epilepticus 11 (6.6%), high tumour burden 19 (11.3%), and renal failure 82 (49.1%). Urea cycle defects were diagnosed in seven patients (4.1%). Hospital mortality was high (30%), and median ammonia level was higher among the nonsurvivors (74 vs 67 µg/dL; p = 0.05). Deaths were more likely in hyperammonemic patients who were older (p = 0.016), had greater illness severity (higher Acute Physiology and Chronic Health Evaluation III score, p < 0.01), malignancy (p < 0.01), and solid organ transplantation (p = 0.04), whereas seizure disorder was more common in survivors (p = 0.02). After adjustment, serum ammonia level was not associated with increased mortality. CONCLUSIONS:Hyperammonemia occurs in a substantial minority of critically ill patients without liver failure. These patients have a poor prognosis, although ammonia level per se is not independently associated with mortality. Serum ammonia should be measured when risk factors are present, such as nutritional deficiencies and protein refeeding, treatment with valproic acid, high tumour burden, and known or suspected urea cycle abnormalities.

Background To evaluate the clinical features and outcomes of acute cardiorenal syndrome type-5 in patients with severe sepsis and septic shock. Methods Historical cohort study of all adult patients with severe sepsis and septic shock admitted to the intensive care units (ICU) at Mayo Clinic Rochester from January 1, 2007 through December 31, 2014. Patients with prior renal or cardiac dysfunction were excluded. Patients were divided into groups with and without cardiorenal syndrome type-5. Acute Kidney Injury (AKI) was defined by both serum creatinine and urine output criteria of the AKI Network and the cardiac injury was determined by troponin-T levels. Outcomes included in-hospital mortality, ICU and hospital length of stay, and one-year survival. Results Of 602 patients meeting the study inclusion criteria, 430 (71.4%) met criteria for acute cardiorenal syndrome type-5. Patients with cardiorenal syndrome type-5 had higher severity of illness, greater vasopressor and mechanical ventilation use. Cardiorenal syndrome type-5 was associated higher unadjusted in-hospital mortality, ICU and hospital lengths of stay, and lower one-year survival. When adjusted for age, gender, severity of illness and mechanical ventilation, cardiorenal syndrome type-5 was independently associated with 1.7-times greater odds of in-hospital mortality (p = .03), but did not predict one-year survival (p = .06) compared to patients without cardiorenal syndrome. Conclusions In sepsis, acute cardiorenal syndrome type-5 is associated with worse in-hospital mortality compared to patients without cardiorenal syndrome.

BACKGROUND & OBJECTIVE:Alzheimer's disease (AD) and Parkinson's disease (PD) affect an increasing number of the elderly population worldwide. The existing treatments mainly improve the core symptoms of AD and PD in a temporary manner and cause alarming side effects. Naturally occurring flavonoids are well-documented for neuroprotective and neurorestorative effects against various neurodegenerative diseases. Thus, we analyzed the pharmacokinetics of eight potent natural products flavonoids for the druggability and discussed the neuroprotective and neurorestorative effects and the underlying mechanisms.CONCLUSION:This review provides valuable clues for the development of novel therapeutics against neurodegenerative diseases.

The blood–brain barrier (BBB) is a stealth barrier that protects the brain, and allows the entry of only a select pool of compounds into the brain and functions towards the maintenance of brain homeostasis. Brain tumors are one of the most prevalent tumors of the central nervous system that affect all age groups, and they have recently surpassed leukemia as the leading cause of cancer death. Due to the low permeability and high selectivity of the BBB to conventional anticancer drugs, effective treatments for brain tumors remain a challenge. In the last 20 years, tremendous efforts have been made to fabricate novel delivery strategies against brain cancer, and, amongst them, nanotechnology-mediated targeted delivery approaches have shown promising outcomes. In this chapter, we have summarized the role of the BBB and various nanotechnologies used to target drugs for the treatment of brain tumor. Herein, we also briefly discussed the hurdles, challenges, and safety considerations in using nanotechnology-mediated targeted delivery for brain tumors.