Summary Background We have previously demonstrated that human bronchial epithelial cells engulf apoptotic eosinophils. Objectives To compare and contrast the phagocytic capabilities of monocyte‐derived macrophage and primary airway epithelial cells for apoptotic granulocytes. Results Here we compared phagocytosis of human apoptotic eosinophils and neutrophils by small and large airway epithelial cells (SAEC and LAEC) and monocyte‐derived macrophages. Confocal microscopy of F‐actin staining and scanning and transmission electron microscopy revealed phagocytic cup formation around apoptotic eosinophils by airway epithelial cells (AEC) membranes with evidence of their digestion. Resting and cytokine‐stimulated AEC did not recognize and ingest apoptotic neutrophils. The latter were phagocytosed by macrophages that exhibited greater ingestion of and higher capacity for, apoptotic eosinophils over apoptotic neutrophils. Cytochalasin D completely abolished uptake of apoptotic eosinophils by SAEC, LAEC or macrophage monolayers. Ligation of epithelial cell CD44 receptors for 24 h increased phagocytosis of apoptotic eosinophils by SAEC and LAEC with a potency comparable with that of IL‐1. Phagocytosis was a specific receptor‐mediated process involving integrin‐ (αvβ3, αvβ5, CD36), phosphatidylserine receptor‐ and lectin‐dependent mechanisms. No significant differences were observed in avarice for apoptotic eosinophils by SAEC or LAEC either resting, CD44 monoclonal antibodies‐ or cytokine‐ stimulated, or in their usage and expression of recognition receptors. Conclusion These findings further suggest and define an important role for the bronchial epithelium in the selective removal of apoptotic eosinophils from the airways in asthma.

Piceatannol (PIC), a naturally occurring polyphenolic stilbene, has pleiotropic pharmacological activities. It has reported cytotoxic activities against different cancer cells. In the present study, PIC emulsomes (PIC-E) were formulated and assessed for cytotoxic activity. A Box–Behnken design was employed to investigate the influence of formulation factors on particle size and drug entrapment. After optimization, the formulation had a spherical shape with a particle size of 125.45 ± 1.62 nm and entrapment efficiency of 93.14% ± 2.15%. Assessment of cytotoxic activities indicated that the optimized PIC-E formula exhibited significantly lower IC50 against HCT 116 cells. Analysis of the cell cycle revealed the accumulation of cells in the G2-M phase as well as increased cell fraction in the sub-G1 phase, an indication of apoptotic-enhancing activity. Staining of cells with Annexin V indicated increased early and late apoptosis. Further, the cellular contents of caspase - 3 and Bax/Bcl-2 mRNA expression were significantly elevated by PIC-E. In addition, the mitochondrial membrane potential (MMP) was disturbed and reactive oxygen species (ROS) production was increased. In conclusion, PIC-E exhibited superior cell death-inducing activities against HCT 116 cells as compared to pure PIC. This is mediated, at least partly, by enhanced pro-apoptotic activity, disruption of MMP, and stimulation of ROS generation.

Flibanserin (FLB) is a multifunctional serotonergic agent that was recently approved by the FDA for the oral treatment of premenopausal women with hypoactive sexual desire disorder. FLB is a centrally acting drug that has a low oral bioavailability of 33% owing to its exposure to the hepatic first-pass effect, as well as its pH-dependent solubility, which could be an obstacle hindering the drug dissolution and absorption via mucosal barriers. Thus, this work aimed at overcoming the aforementioned drawbacks and promoting the nose-to-brain delivery of FLB via the formulation of an intra-nasal in situ niosomal gel. The Box–Behnken design was employed to study the impact of Span® 85 concentration (X1), hydration time (X2), and pH of the hydrating buffer (X3) on the vesicle size and drug entrapment. The optimized formulation exhibited a spherical shape with a vesicular size of 46.35 nm and entrapment efficiency of 92.48%. The optimized FLB niosomes integrated into gellan gum-based in situ gel exhibited enhanced ex vivo permeation and improved plasma and brain concentrations after nasal administration in rats compared to raw FLB. These findings highlight the capability of the proposed intra-nasal FLB niosomal in situ gel to boost the drug bioavailability and to promote its direct delivery to the brain.

Statins, including simvastatin (SMV), are commonly used for the control of hyperlipidaemia and have also proven therapeutic and preventative effects in cardiovascular diseases. Besides that, there is an emerging interest in their use as antineoplastic drugs as demonstrated by different studies showing their cytotoxic activity against different cancer cells. In this study, SMV-loaded emulsomes (SMV-EMLs) were formulated and evaluated for their cytotoxic activity in MCF-7 breast cancer cells. The emulsomes were prepared using a modified thin-film hydration technique. A Box–Behnken model was used to investigate the impact of formulation conditions on vesicle size and drug entrapment. The optimized formulation showed a spherical shape with a vesicle size of 112.42 ± 2.1 nm and an entrapment efficiency of 94.34 ± 1.11%. Assessment of cytotoxic activities indicated that the optimized SMV-EMLs formula exhibited significantly lower half maximal inhibitory concentration (IC50) against MCF-7 cells. Cell cycle analysis indicated the accumulation of cells in the G2-M phase as well as increased cell fraction in the pre-G1 phase, suggesting an enhancement of anti-apoptotic activity of SMV. The staining of cells with Annex V revealed an increase in early and late apoptosis, in line with the increased cellular content of caspase-3 and Bax. In addition, the mitochondrial membrane potential (MMP) was significantly decreased. In conclusion, SMV-EMLs demonstrated superior cell death-inducing activity against MCF-7 cells compared to pure SMV. This is mediated, at least in part, by enhanced pro-apoptotic activity and MMP modulation of SMV.

Background. Cardiac complications may develop in a proportion of patients with the novel coronavirus disease (COVID-19), which may influence their prognosis. Objectives. To assess the role of cardiac injury biomarkers measured on admission and during hospitalization as risk factors for subsequent death in COVID-19 patients. Methods. A systematic review and meta-analysis was carried out involving cohort studies that compared the levels of cardiac injury biomarkers in surviving and dead COVID-19 patients. Cardiac injury is defined as an elevation of the definitive markers (cardiac troponin (cTnI and cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP)) above the 99th percentile upper reference limit. Secondary markers included creatine kinase-myocardial bound (CK-MB), myoglobin, interleukin-6 (IL-6), and C-reactive protein (CRP). The risk of death and the differences in marker concentrations were analyzed using risk ratios (RRs) and standardized mean differences (SMDs), respectively. Results. Nine studies met the inclusion criteria (1799 patients, 53.36% males, 20.62% with cardiac injury). The risk of death was significantly higher in patients with elevated cTn than those with normal biomarker levels (RR = 5.28, P < 0.0001 ). Compared to survivors, dead patients had higher levels of cTn (SMD = 2.15, P = 0.001 ), IL-6 (SMD = 3.13, P = 0.03 ), hs-CRP (SMD = 2.78, P < 0.0001 ), and CK-MB (SMD = 0.97, P < 0.0001 ) on admission and a significant rise of plasma cTnT during hospitalization. Conclusion. COVID-19 patients with elevated cTn on admission, possibly due to immune-mediated myocardial injury, are at increased risk for mortality. This requires further radiographic investigations, close monitoring, and aggressive care to reduce the risk of severe complications and death.

The outbreak of the COVID-19 pandemic in China has become an urgent health and economic challenge. The objective of the current work was to evaluate the efficacy of the combined complex of Sitagliptin (SIT) with melittin (MEL) against SARS-CoV-2 virus. SIT-MEL nano-conjugates were optimized by a full three-factor bi-level (23) factorial design. In addition, SIT concentration (mM, X1), MEL concentration (mM, X2), and pH (X3) were selected as the critical factors. Particle size (nm, Y1) and zeta potential (mV, Y2) were assessed as responses. Characterization of the optimized formula for Fourier-transformed infrared (FTIR) was carried out. The optimized formula showed particle size and zeta potential values of 77.42 nm and 27.67 mV, respectively. When compared with SIT and MEL, the combination of SIT-MEL complex has shown anti-viral potential against isolate of SARS-CoV-2 with IC50 values of 8.439 μM with significant improvement (p < 0.001). In addition, the complex showed IC50 in vitro 3CL-protease inhibition with IC50 7.216 µM. Molecular docking has revealed that formula components have good predicted pocket accommodation of the SARS-CoV-2 3-CL protease. An optimized formulation of SIT-MEL could guarantee both enhanced delivery to the target cells and the enhanced cellular uptake with promising activities against SARS-CoV-2.

The inappropriate accumulation of eosinophils and the subsequent release of their potent pro-inflammatory mediator arsenal are thought to be important contributors to the pathogenesis of asthma and other allergic diseases. It is also becoming apparent that eosinophils may play a role in the orchestration of immune responses in the asthmatic lung. There is therefore much interest in the development of strategies to limit or prevent eosinophil-induced toxicity. The mechanisms by which eosinophils accumulate in the peribronchial tissues of the lung are complex and include enhanced differentiation and release from the bone marrow, selective adhesion and transendothelial migration, directed movement in response to specific chemotactic mediators and finally prolonged survival as a consequence of delayed apoptosis. Thus it can be appreciated that there are many points at which the toxicity of eosinophils can be limited or even prevented. Important areas for potential advances in glucocorticoid (GC) development include efforts to dissociate their anti-inflammatory effects from unwanted side effects. Other areas include the development of humanized monoclonal antibodies against IL-4, IL-13 and IL-5 together with the inhibition of adhesion pathways and/or chemokines responsible for eosinophil accumulation in the asthmatic lung. Several avenues of research are currently underway in an attempt to define mechanisms by which pro-inflammatory cells such as eosinophils can be safely removed from the asthmatic lung through apoptosis induction and their subsequent ingestion by phagocytes. This review will discuss both the potential and shortcomings of these diverse approaches to limit eosinophil toxicity in the asthmatic lung.

Two new ergosterol derivatives namely, chlamydosterols A [(22E,24R)-ergosta-7,22diene-3β,5α,6β-triol 6-decanoate] (1) and B [5α,6β,25-trihydroxy-(22E,24R)-ergosta-7,22dien-3-one] (5) and three known ergosterols: ergosta-7,22-dien-3-ol (2), ergosta-5,7,22triene-3-ol (3), and ergosta-7,22-diene-3,5α,6-triol (4) were separated from the EtOAc extract of the endophytic fungus Fusarium chlamydosporum isolated from Anvillea garcinii (Asteraceae) leaves growing in Saudi Arabia. Their structural assignment was accomplished by various spectroscopic analyses, as well as comparing with the published data. The 5-lipoxygenase (5-LOX) inhibitory potential of the isolated metabolites was assessed. Compounds 1 and 3 displayed moderate 5-LOX inhibitory potential with IC 50 s 3.06 and 3.57 µM, respectively compared to indomethacin (IC 50 1.13 µM).