Hydroethanolic Extract of Prunus domestica L.: Metabolite Profiling and In Vitro Modulation of Molecular Mechanisms Associated to Cardiometabolic Diseases

High consumption of fruit and vegetables has an inverse association with cardiometabolic risk factors. This study aimed to chemically characterize the hydroethanolic extract of P. domestica subsp. syriaca fruit pulp and evaluate its inhibitory activity against metabolic enzymes and production of proinflammatory mediators. Ultra-high-performance liquid chromatography high-resolution mass spectrometry(UHPLC-HRMS) analysis showed the presence of hydroxycinnamic acids, flavanols, and glycoside flavonols, while nuclear magnetic resonance(NMR) analysis showed, among saccharides, an abundant presence of glucose. P. domestica fruit extract inhibited α-amylase, α-glucosidase, pancreatic lipase, and HMG CoA reductase enzyme activities, with IC50 values of 7.01 mg/mL, 6.4 mg/mL, 6.0 mg/mL, and 2.5 mg/mL, respectively. P. domestica fruit extract inhibited lipopolysaccharide-induced production of nitrite, interleukin-1 β and PGE2 in activated J774 macrophages. The findings of the present study indicate that P. domestica fruit extracts positively modulate in vitro a series of molecular mechanisms involved in the pathophysiology of cardiometabolic diseases. Further research is necessary to better characterize these properties and their potential application for human health.

Regulation of Trafficking and Signaling of the High Affinity IgE Receptor by FcεRIβ and the Potential Impact of FcεRIβ Splicing in Allergic Inflammation

Mast cells are tissue-resident immune cells that function in both innate and adaptive immunity through the release of both preformed granule-stored mediators, and newly generated proinflammatory mediators that contribute to the generation of both the early and late phases of the allergic inflammatory response. Although mast cells can be activated by a vast array of mediators to contribute to homeostasis and pathophysiology in diverse settings and contexts, in this review, we will focus on the canonical setting of IgE-mediated activation and allergic inflammation. IgE-dependent activation of mast cells occurs through the high affinity IgE receptor, FcεRI, which is a multimeric receptor complex that, once crosslinked by antigen, triggers a cascade of signaling to generate a robust response in mast cells. Here, we discuss FcεRI structure and function, and describe established and emerging roles of the β subunit of FcεRI (FcεRIβ) in regulating mast cell function and FcεRI trafficking and signaling. We discuss current approaches to target IgE and FcεRI signaling and emerging approaches that could target FcεRIβ specifically. We examine how alternative splicing of FcεRIβ alters protein function and how manipulation of splicing could be employed as a therapeutic approach. Targeting FcεRI directly and/or IgE binding to FcεRI are promising approaches to therapeutics for allergic inflammation. The characteristic role of FcεRIβ in both trafficking and signaling of the FcεRI receptor complex, the specificity to IgE-mediated activation pathways, and the preferential expression in mast cells and basophils, makes FcεRIβ an excellent, but challenging, candidate for therapeutic strategies in allergy and asthma, if targeting can be realized.

Aviptadil: Class Effect of a Synthetic Vasoactive Intestinal Peptide as a Treatment Option in Patients with COVID-19 with Severe Respiratory Failure

Despite dynamic drug and vaccine development processes to reduce the disease burden of COVID-19, the treatment options are still very limited. Vasoactive intestinal peptide (VIP) has a diversified physiological action with specific features of lung protection-related activities. VIP inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gene replication in human monocytes and the viral replication in Calu-3 cells, thus further reducing the generation of proinflammatory mediators. Aviptadil, a synthetic form of VIP, is the only pulmonary therapeutic agent to have been granted ‘fast track’ status by the U.S. Food and Drug Administration (FDA) and to be allowed into both Phase II and III clinical trials. Initial binding of Aviptadil with non-structural protein (nsp) 10 and nsp16, which may inhibit the 2’-O-methyltransferase activity of the SARS-CoV-2 nsp10 and nsp16 complex. Aviptadil has already proved to be an effective option in the treatment of severe respiratory failures due to sepsis and other related lung injuries. Interim analysis results of this drug used in respiratory failure caused by SARS-CoV-2 has evolved a new hope in regard to safety and efficacy. The final results from a recently completed trial, as well as all currently ongoing trials, will clarify the class effect of this drug in the treatment of COVID-19 in future days.

HMGB-1 in Psoriasis

Psoriasis is a multifactorial pathology linked to systemic inflammation. Enhanced keratinocytes proliferation and a minor maturation state of the cells are typical features. Perivascular T cells, dendritic cells, macrophages, and neutrophilic granulocytes are part of the scenario completed by apoptosis dysregulation. Several proinflammatory mediators, alarmins and growth factors are increased too, both in the skin and the patients’ blood. HMGB1 is important as an alarmin in several inflammatory conditions. Released after cellular damage, HMGB1 acts as a danger signal. Several studies have considered its role in psoriasis pathogenesis. We evaluated its level in psoriasis and the potential of the alarmin blockade through standard therapies, biological treatments and using monoclonal antibodies. PV patients were shown to have significantly increased levels of HMGB1 both in lesional skin and in serum, which were linked, in some cases, to other pro-inflammatory markers and alarmins. In most cases these parameters were correlated with PASI score. Data demonstrated that blocking HMGB1 is effective in ameliorating psoriasis. Focusing on this approach could be valuable in terms of a therapeutic option for counteracting immune-related diseases in a way unthinkable until few years ago.

Celastrol and thymoquinone alleviate aluminum chloride-induced neurotoxicity: behavioral psychomotor performance, neurotransmitter level and oxidative-inflammatory burden in brain of rats

The exposure to metal aluminum such as aluminum chloride (AlCl3) induces inflammatory-oxidative reactions with progressive neurodegeneration in different brain regions in animal models. The current study was designed to assess the role of celastrol or thymoquinone (TQ) in alleviating AlCl3 induced behavioral psychomotor changes and oxidative-inflammatory burden in albino male rats. Four groups were used in this study, (i) vehicle control group, (ii) AlCL3 control group: rats received intraperitoneal injection (i.p.) of AlCl3 (10 mg/kg), (iii) AlCl3+TQ (10 mg/kg, i.p.) group and (iv) AlCl3+celastrol (1 mg/kg, i.p.) group. In general, all injections remained for 6 weeks. Behavioral psychomotor evaluation (open field test, rotarod test and forced Swimming test) were done to assess locomotor, motor coordination, anxiety-like behavior and depressive-like behavioral. Markers of oxidative stress, malondialdehyde (MDA), total antioxidant capacity (TAC) and catalase enzyme activity (CAT) and the proinflammatory mediators, tumor necrosis factor-α (TNF-α) and interlukin-6 (IL-6) were measured in the rat brains. Neurotransmitters including acetylcholine (ACh), dopamine and serotonin in addition to acetylcholinesterase enzyme (AChE) level were measured in brain homogenates. Our results demonstrated that daily injection of TQ or celastrol significantly improved behavior psychomotor deficits, decreased AChE activity towards their normal levels. Tissue oxidative stress and proinflammatory markers were modulated by TQ and celastrol. These results concluded that TQ and celastrol have useful in alleviating AlCl3-induced neurotoxicity by their antioxidant and anti-inflammatory properties. Hence, they are looking promising for investigating their preventive effect in animal models of neurodegenerative diseases.

Capsaicin and TRPV1 Channels in the Cardiovascular System: The Role of Inflammation

Capsaicin is a potent agonist of the Transient Receptor Potential Vanilloid type 1 (TRPV1) channel and is a common component found in the fruits of the genus Capsicum plants, which have been known to humanity and consumed in food for approximately 7000–9000 years. The fruits of Capsicum plants, such as chili pepper, have been long recognized for their high nutritional value. Additionally, capsaicin itself has been proposed to exhibit vasodilatory, antimicrobial, anti-cancer, and antinociceptive properties. However, a growing body of evidence reveals a vasoconstrictory potential of capsaicin acting via the vascular TRPV1 channel and suggests that unnecessary high consumption of capsaicin may cause severe consequences, including vasospasm and myocardial infarction in people with underlying inflammatory conditions. This review focuses on vascular TRPV1 channels that are endogenously expressed in both vascular smooth muscle and endothelial cells and emphasizes the role of inflammation in sensitizing the TRPV1 channel to capsaicin activation. Tilting the balance between the beneficial vasodilatory action of capsaicin and its unwanted vasoconstrictive effects may precipitate adverse outcomes such as vasospasm and myocardial infarction, especially in the presence of proinflammatory mediators.

The α-Gal Syndrome and Potential Mechanisms

The α-Gal syndrome is a complex allergic disease characterized by the development of specific IgE antibodies against the carbohydrate galactose-α-1,3-galactose (α-Gal), an oligosaccharide present in cells and tissues of non-primate mammals. Individuals with IgE antibodies to α-Gal suffer from a delayed form of anaphylaxis following red meat consumption. There are several features that make the α-Gal syndrome such a unique allergic disease and distinguish it from other food allergies: (1) symptoms causing IgE antibodies are directed against a carbohydrate moiety, (2) the unusual delay between the consumption of the food and the onset of the symptoms, and (3) the fact that primary sensitization to α-Gal occurs via tick bites. This review takes a closer look at the immune response against α-Gal, in healthy and in α-Gal allergic individuals. Furthermore, the similarities and differences between immune response against α-Gal and against the other important glycan moieties associated with allergies, namely cross-reactive carbohydrate determinants (CCDs), are discussed. Then different mechanisms are discussed that could contribute to the delayed onset of symptoms after consumption of mammalian meat. Moreover, our current knowledge on the role of tick bites in the sensitization process is summarized. The tick saliva has been shown to contain proteins carrying α-Gal, but also bioactive molecules, such as prostaglandin E2, which is capable of stimulating an increased expression of anti-inflammatory cytokines while promoting a decrease in the production of proinflammatory mediators. Together these components might promote Th2-related immunity and trigger a class switch to IgE antibodies directed against the oligosaccharide α-Gal. The review also points to open research questions that remain to be answered and proposes future research directions, which will help to get a better understanding and lead to a better management of the disease.

INCREASED CIRCULATING COPEPTIN LEVELS ARE ASSOCIATED WITH VASO-OCCLUSIVE CRISIS AND RIGHT VENTRICULAR DYSFUNCTION IN SICKLE CELL ANEMIA

Objective Vaso-occlusive crisis (VOC) is a common clinical manifestation of sickle cell anemia (SCA) and is associated with increased proinflammatory mediators. Copeptin is the C-terminal part of the prohormone for pro-vasopressin and seems clinically relevant in various clinical conditions. Right ventricular (RV) dysfunction significantly appears in SCA patients due to pulmonary hypertension. This study aimed to investigate the association of copeptin levels in VOC patients and evaluate RV dysfunction. Materials and Methods A total of 108 patients were enrolled in the study. Twenty-eight SCA patients in steady state (30.2±10.9 years), 25 SCA patients in VOC (36.8±11.8 years), and 55 healthy individuals (31.9±9.4 years) with HbAA genotype were included. Clinical, echocardiographic, and laboratory data were recorded. ELISA was used for the determination of serum levels of copeptin. Results VOC patients had significantly higher copeptin level compared both with controls and SCA subjects in steady-state (22.6±13.0 vs. 11.3±5.7 pmol/l, 22.6±13.0 vs. 12.4±5.8 pmol/l, p=0.009 for both). Additionally, the copeptin level was significantly higher in SCA patients with RV dysfunction than those without RV dysfunction (23.2±12.2 vs. 15.3±9.5 pmol/l, p=0.024). Multiple logistic regression analysis revealed that hs-CRP and copeptin levels were found to be associated with VOC. Conclusion The study showed that copeptin and hs-CRP levels were increased in patients with VOC, and a significant relationship was found between RV dysfunction in VOC patients. As a conclusion copeptin can be used as a potential biomarker in predicting VOC crisis in SCA patients and in early detection of patients with SCA who have the potential to develop RV dysfunction.

A peripheral lipid sensor GPR120 remotely contributes to suppression of PGD2-microglia-provoked neuroinflammation and neurodegeneration in the mouse hippocampus

Background Neuroinflammation is a key pathological component of neurodegenerative disease and is characterized by microglial activation and the secretion of proinflammatory mediators. We previously reported that a surge in prostaglandin D2 (PGD2) production and PGD2-induced microglial activation could provoke neuroinflammation. We also reported that a lipid sensor GPR120 (free fatty acid receptor 4), which is expressed in intestine, could be activated by polyunsaturated fatty acids (PUFA), thereby mediating secretion of glucagon-like peptide-1 (GLP-1). Dysfunction of GPR120 results in obesity in both mice and humans. Methods To reveal the relationship between PGD2-microglia-provoked neuroinflammation and intestinal PUFA/GPR120 signaling, we investigated neuroinflammation and neuronal function with gene and protein expression, histological, and behavioral analysis in GPR120 knockout (KO) mice. Results In the current study, we discovered notable neuroinflammation (increased PGD2 production and microglial activation) and neurodegeneration (declines in neurogenesis, hippocampal volume, and cognitive function) in GPR120 KO mice. We also found that Hematopoietic–prostaglandin D synthase (H-PGDS) was expressed in microglia, microglia were activated by PGD2, H-PGDS expression was upregulated in GPR120 KO hippocampus, and inhibition of PGD2 production attenuated this neuroinflammation. GPR120 KO mice exhibited reduced intestinal, plasma, and intracerebral GLP-1 contents. Peripheral administration of a GLP-1 analogue, liraglutide, reduced PGD2-microglia-provoked neuroinflammation and further neurodegeneration in GPR120 KO mice. Conclusions Our results suggest that neurological phenotypes in GPR120 KO mice are probably caused by dysfunction of intestinal GPR120. These observations raise the possibility that intestinal GLP-1 secretion, stimulated by intestinal GPR120, may remotely contributed to suppress PGD2-microglia-provoked neuroinflammation in the hippocampus.

Myeloid Protease-Activated Receptor-2 Contributes to Influenza A Virus Pathology in Mice

BackgroundInnate immune responses to influenza A virus (IAV) infection are initiated in part by toll-like receptor 3 (TLR3). TLR3-dependent signaling induces an antiviral immune response and an NFκB-dependent inflammatory response. Protease-activated receptor 2 (PAR2) inhibits the antiviral response and enhances the inflammatory response. PAR2 deficiency protected mice during IAV infection. However, the PAR2 expressing cell-types contributing to IAV pathology in mice and the mechanism by which PAR2 contributes to IAV infection is unknown.MethodsIAV infection was analyzed in global (Par2-/-), myeloid (Par2fl/fl;LysMCre+) and lung epithelial cell (EpC) Par2 deficient (Par2fl/fl;SPCCre+) mice and their respective controls (Par2+/+ and Par2fl/fl). In addition, the effect of PAR2 activation on polyinosinic-polycytidylic acid (poly I:C) activation of TLR3 was analyzed in bone marrow-derived macrophages (BMDM). Lastly, we determined the effect of PAR2 inhibition in wild-type (WT) mice.ResultsAfter IAV infection, Par2-/- and mice with myeloid Par2 deficiency exhibited increased survival compared to infected controls. The improved survival was associated with reduced proinflammatory mediators and reduced cellular infiltration in bronchoalveolar lavage fluid (BALF) of Par2-/- and Par2fl/fl;LysMCre+ 3 days post infection (dpi) compared to infected control mice. Interestingly, Par2fl/fl;SPCCre+ mice showed no survival benefit compared to Par2fl/fl. In vitro studies showed that Par2-/- BMDM produced less IL6 and IL12p40 than Par2+/+ BMDM after poly I:C stimulation. In addition, activation of PAR2 on Par2+/+ BMDM increased poly I:C induction of IL6 and IL12p40 compared to poly I:C stimulation alone. Importantly, PAR2 inhibition prior to IAV infection protect WT mice.ConclusionGlobal Par2 or myeloid cell but not lung EpC Par2 deficiency was associated with reduced BALF inflammatory markers and reduced IAV-induced mortality. Our study suggests that PAR2 may be a therapeutic target to reduce IAV pathology.