Systemic administration of sunflower oil exerts neuroprotection in a mouse model of transient focal cerebral ischaemia.

OBJECTIVES: Natural products are valuable sources of nutraceuticals for the prevention or treatment of ischemic stroke, a major cause of death and severe disability worldwide. Among the mechanisms implicated in cerebral ischemia-reperfusion damage, oxidative stress exerts a pivotal role in disease progression. Given the high antioxidant potential of most components of sunflower oil, we have explored its effects on ischemic brain injury produced in the mouse by transient occlusion of the middle cerebral artery (MCAo). KEY FINDINGS: Intraperitoneal (i.p.) administration of sunflower oil at doses of 3 ml/kg (48 h, 24 h and 1 h before MCAo) significantly reduced brain infarct volume and oedema assessed 24 h after the insult. This neuroprotective treatment schedule also prevented the elevation of brain lipid peroxidation produced by MCAo-reperfusion injury. By contrast, doses of 0.03 ml/kg of sunflower oil resulted ineffective on both cerebral damage and lipid peroxidation. Although sunflower oil did not affect serum levels of Diacron-reactive oxygen metabolites (d-ROMs), both 0.03 and 3 ml/kg dosing regimens resulted in the preservation of serum biological antioxidant potential (BAP) that was otherwise dramatically reduced 24 h after MCAo. CONCLUSIONS: Sunflower oil represents a promising source of neuroprotective extracts/compounds that can be exploited for the prevention and/or treatment of cerebral ischemia.

Prevalence of vitamin D deficiency and its prognostic impact on patients hospitalized with COVID-19.

OBJECTIVES: Although hypovitaminosis D appears to be highly prevalent in patients with coronavirus disease 2019 (COVID-19), its impact on their prognosis remains unclear. METHODS: In this study, serum 25-hydroxyvitamin D (Vit-D) level was measured in 200 patients hospitalized with COVID-19. The association between Vit-D and the composite endpoint of intensive care unit (ICU) admission/in-hospital death was explored using univariable and multivariable analyses. Also, serum Vit-D level in patients with COVID-19 was compared with that in age- and sex-balanced COVID-19-negative controls (i.e., 50 inpatients with sepsis). RESULTS: Serum Vit-D level was comparable between patients with COVID-19 and COVID-19-negative inpatients with sepsis (P = 0.397). No significant differences were found in serum Vit-D level according to COVID-19 severity at the time of hospital admission (P = 0.299). Incidence rates of the composite endpoint of ICU admission/in-hospital death did not differ significantly between patients with either Vit-D deficiency (i.e., Vit-D <20 ng/mL) or severe Vit-D deficiency (i.e., Vit-D <12 ng/mL) and those without (31% vs 35% with P = 0.649, and 34% vs 30% with P = 0.593, respectively). Vit-D level and status (i.e., Vit-D deficiency and severe Vit-D deficiency) were not prospectively associated with the risk of the composite endpoint of ICU admission/in-hospital death (P > 0.05 for all Cox regression models). CONCLUSIONS: Regardless of the potential usefulness of Vit-D measurement to guide appropriate supplementation, Vit-D does not appear to provide helpful information for the stratification of in-hospital prognosis in patients with COVID-19.

Discovery of potent p38α MAPK inhibitors through a funnel like workflow combining in silico screening and in vitro validation.

This work describes the rational discovery of novel chemotypes of p38α MAPK inhibitors using a funnel approach consisting of several computer-aided drug discovery methods and biological experiments. Among the identified hits, four compounds belonging to different chemical families showed IC50 values lower than 10 µM. In particular, the 1,4-benzodioxane derivative 5 turned out to be a potent and efficient p38α MAPK inhibitor having IC50 = 0.07 µM, and LEexp and LipE values of 0.38 and 4.8, respectively; noteworthy, the compound had also a promising kinase selectivity profile and the capability to suppress p38α MAPK effects in human immune cells. Overall, the collected findings highlight that the applied strategy has been successful in generating chemical novelty in the inhibitor kinase field, providing suitable chemical candidates for further inhibitor optimization.

Toll-like receptors as novel therapeutic targets for herpes simplex virus infection.

Seropositivity for HSV reaches more than 70% within the world population, and yet no approved vaccine exists. While HSV1 is responsible for keratitis, encephalitis, and labialis, HSV2 carriers have a high susceptibility to other STD infections, such as HIV. Induction of antiviral innate immune responses upon infection depends on a family of pattern recognition receptors called Toll-like receptors (TLR). TLRs bridge innate and adaptive immunity by sensing virus infection and activating antiviral immune responses. HSV adopts smart tricks to evade innate immunity and can also manipulate TLR signaling to evade the immune system or even confer destructive effects in favor of virus replication. Here, we review mechanisms by which HSV can trick TLR signaling to impair innate immunity. Then, we analyze the role of HSV-mediated molecular cues, in particular, NF-κB signaling, in promoting protective versus destructive effects of TLRs. Finally, TLR-based therapeutic opportunities with the goal of preventing or treating HSV infection will be discussed.

Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration.

Gene therapy mediated by recombinant adeno-associated virus (AAV) vectors is a promising treatment for systemic monogenic diseases. However, vector immunogenicity represents a major limitation to gene transfer with AAV vectors, particularly for vector re-administration. Here, we demonstrate that synthetic vaccine particles encapsulating rapamycin (SVP[Rapa]), co-administered with AAV vectors, prevents the induction of anti-capsid humoral and cell-mediated responses. This allows successful vector re-administration in mice and nonhuman primates. SVP[Rapa] dosed with AAV vectors reduces B and T cell activation in an antigen-selective manner, inhibits CD8+ T cell infiltration in the liver, and efficiently blocks memory T cell responses. SVP[Rapa] immunomodulatory effects can be transferred from treated to naive mice by adoptive transfer of splenocytes, and is inhibited by depletion of CD25+ T cells, suggesting a role for regulatory T cells. Co-administration of SVP[Rapa] with AAV vector represents a powerful strategy to modulate vector immunogenicity and enable effective vector re-administration.

Thymosin α1 represents a potential potent single-molecule-based therapy for cystic fibrosis.

Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that compromise its chloride channel activity. The most common mutation, p.Phe508del, results in the production of a misfolded CFTR protein, which has residual channel activity but is prematurely degraded. Because of the inherent complexity of the pathogenetic mechanisms involved in CF, which include impaired chloride permeability and persistent lung inflammation, a multidrug approach is required for efficacious CF therapy. To date, no individual drug with pleiotropic beneficial effects is available for CF. Here we report on the ability of thymosin alpha 1 (Tα1)-a naturally occurring polypeptide with an excellent safety profile in the clinic when used as an adjuvant or an immunotherapeutic agent-to rectify the multiple tissue defects in mice with CF as well as in cells from subjects with the p.Phe508del mutation. Tα1 displayed two combined properties that favorably opposed CF symptomatology: it reduced inflammation and increased CFTR maturation, stability and activity. By virtue of this two-pronged action, Tα1 has strong potential to be an efficacious single-molecule-based therapeutic agent for CF.

Effects of a nutraceutical combination on lipids, inflammation and endothelial integrity in patients with subclinical inflammation: a randomized clinical trial.

Cholesterol elevations are associated with systemic inflammation and endothelial fragmentation into microparticles. The cholesterol-lowering efficacy of nutraceutical combinations (NC) has not been investigated in patients with low-grade systemic inflammation and normal-borderline cholesterol levels. This is a 3-month prospective randomized open-label interventional study in patients with elevated plasma high sensitivity C-reactive protein (hsCRP) levels (>2 mg/L) and low-density lipoprotein (LDL) cholesterol of 100-160 mg/dL. The effect of either an oral cholesterol-lowering nutraceutical combination (NC) or no active treatment (noNC) was tested on LDL cholesterol, hsCRP and endothelial microparticle (EMPs) levels. Patients taking the NC had a significant reduction of total (-12%) and LDL cholesterol (-23%) compared to those who received noNC (p < 0.001 for both). Also, hsCRP and EMPs were significantly reduced by the NC (-41% and -16%, respectively). LDL cholesterol change was positively associated with hsCRP (rho = 0.21, p = 0.04) and EMP changes (rho = 0.56, p < 0.001), hsCRP and EMP changes being associated with each other (rho = 0.28, p = 0.005). Patients experiencing both LDL cholesterol and hsCRP reduction were those having the greatest EMP decrease. In conclusion, among patients with low-grade systemic inflammation, an oral NC significantly improved cholesterol profile and attenuated the degree of systemic inflammation and endothelial injury.

Topical application of soluble CD83 induces IDO-mediated immune modulation, increases Foxp3+ T cells, and prolongs allogeneic corneal graft survival.

Modulation of immune responses is one of the main research aims in transplant immunology. In this study, we investigate the local immunomodulatory properties of soluble CD83 (sCD83) at the graft-host interface using the high-risk corneal transplantation model. In this model, which mimics the inflammatory status and the preexisting vascularization of high-risk patients undergoing corneal transplantation, allogeneic donor corneas are transplanted onto sCD83-treated recipient animals. This model allows the direct and precise application of the immune modulator at the transplantation side. Interestingly, sCD83 was able to prolong graft survival after systemic application as well as after topical application, which is therapeutically more relevant. The therapeutic effect was accompanied by an increase in the frequency of regulatory T cells and was mediated by the immune-regulatory enzyme IDO and TGF-ß. In vitro, sCD83 induced long-term IDO expression in both conventional and plasmacytoid dendritic cells via autocrine or paracrine production of TGF-ß, a cytokine previously shown to be an essential mediator of IDO-dependent, long-term tolerance. These findings open new treatment avenues for local immune modulation after organ and tissue transplantation.