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Stroke is one of the leading causes of mortality and morbidity in advanced countries of the world. Despite the fact that reactive oxygen and nitrogen species (ROS and RNS) are the by-products of normal metabolic processes and mediate important physiological processes, they can inflict damage to the cell if produced in excess due to oxidative stress. In the present review, we focus on the cellular and molecular aspects of ROS and RNS generation and its role in the pathogenesis of stroke produced by hypoxia-reperfusion (H-R) phenomena that elicit oxidative stress. We outline the reasons for the vulnerability of the brain to ischaemic insult, chronic infection and inflammation as well as the natural defence mechanisms against radical mediated injury. We deal with the effect of ROS and RNS on intracellular signaling pathways together with the phenomena of apoptosis, mitochondrial injury and survival associated with these pathways. The intracellular signaling mechanisms influenced by reactive species can have significant effects on the outcome of the condition. Future studies should focus on understanding the molecular mechanisms involved in the action of anti-radicals agents, and their mode of action.

We read with great interest the letter by Ji et al. 1 Obesity is a wellrecognized risk factor for the development of non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated liver disease (MAFLD) and is associated with adverse outcomes in COVID-19 patients. 2,3 Qatar's population has a high prevalence of obesity 4 and also has one of the highest rates of COVID-19 cases per million population, with one of the lowest mortality rates. 5 We hypothesized that NAFLD is an independent risk factor for worse outcomes in hospitalized COVID-19 patients in our population.

The crude extract of aerial parts of St John's wort (Hypericum perforatum) (Hp.Cr) and its fractions were studied in vitro for its possible spasmolytic and bronchodilator activities to rationalize some of its medicinal uses. In rabbit jejunum preparations, Hp.Cr caused a concentration-dependent relaxation of both spontaneous and K+ (80 mm)-induced contractions at a similar concentration range (0.1-1.0 mg/mL), similar to that produced by papaverine, whereas verapamil was relatively potent against K+-induced contractions. Hp.Cr shifted the Ca2+ concentration-response curves (CRCs) to the right, similar to that caused by papaverine or verapamil and also caused leftward shift of isoprenaline-induced inhibitory CRCs, similar to papaverine. In guinea-pig tracheal preparations, Hp.Cr caused relaxation of carbachol and K+-induced contractions at similar concentrations (0.01-0.3 mg/mL) and also shifted the isoprenaline-induced inhibitory CRCs to the left, similar to that caused by papaverine. In rabbit aorta preparations at rest, Hp.Cr produced a moderate vasoconstriction, while exhibited vasodilator effect against phenylephrine and K+-induced contractions. Papaverine and verapamil also produced similar non-specific vasodilation, but were devoid of any vasoconstrictor effect. Hp.Cr caused suppression of atrial force of contractions at concentrations about 20 times higher than those that produced inhibitory effect in smooth muscle preparations, similar to papaverine. These results suggest that the spasmolytic effects of Hp.Cr are mediated through dual inhibition of calcium influx and phosphodiesterase (PDE)-like mechanisms, which might explain the medicinal use of St John's wort in the disorders of gastrointestinal and respiratory tracts. Furthermore, the presence of Ca2+ antagonist and PDE inhibitory-like constituents might also be contributing to some extent in the well established use of plant in depression.

JC virus (JCV) is the etiological agent of an opportunistic brain infection, progressive multifocal leukoencephalopathy (PML), in AIDS. PML is fatal in approximately 4% of HIV-infected individuals, and although the overall incidence has fallen due to highly aggressive antiretroviral therapy (HAART), this percent has remained steady. It has been shown that the Tat protein of human immunodeficiency virus-1 (HIV-1) interacts in cells with cellular protein Puralpha. This interaction can stimulate transcription of both HIV-1 and JCV genes. HIV-1, however, infects primarily microglia and astrocytes in the brain, whereas JCV infects primarily oligodendrocytes. Although HIV-1 has been shown capable of infecting oligodendrocytes in vitro (Albright et al., 1996), no instance of viral coinfection of such cells with JCV has been reported. Tat is known to be secreted from cells in which it is made. Here we ask whether such exogenous Tat can influence JCV replication in oligodendrocytes. We find that glial cells infected with either HIV-1 or JCV are in proximity at the outer edge of PML lesions. Exogenous Tat is avidly incorporated into cultured KG-1 oligodendroglioma cells over a 72-h period and is colocalized with endogenous Puralpha both nuclear and juxtanuclear. At concentrations in the medium well below the pM range, Tat stimulates several-fold the replication in vivo of DNA initiated at the JCV origin. These results define a pathway by which a protein made by HIV-1 can directly affect the course of infection by another disease-causing virus.

Niclosamide (NCS) is an oral anthelminthic drug having low solubility and hence low bioavailability. Current investigation shows an approach to fabricate solid lipid nanoparticles (SLNs) of NCS and evaluated for pharmaceutical, in vitro and in vivo characterization. NFM-3 showed particle size 204.2 ± 2.2 nm, polydispersity index 0.328 ± 0.02 and zeta potential -33.16 ± 2 mV. Entrapment efficiency and drug loading capacity were 84.4 ± 0.02% and 5.27 ± 0.03%, respectively. Scanning electron microscopy image indicated that particles were nanoranged. DSC and P-XRD results showed change in physicochemical properties of NCS. FT-IR spectra confirmed compatibility between NCS and excipients. The drug release profile showed sustained release (93.21%) of NCS in 12 h. Different kinetic models showed zero-order kinetics and Case-II transport mechanism. Study showed maximum stability at refrigerated temperature. In vivo pharmacokinetic study showed 2.15-fold increase in NCS peak plasma concentration as solid lipid nanoparticle formulation (NFM-3) compared to commercial product while relative bioavailability was 11.08. Results including in vitro and in vivo release studies of NCS confirmed that SLNs system is suitable to improve oral delivery of NCS with increased aqueous solubility, permeability and finally bioavailability.

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