Dysregulated Interferon Response and Immune Hyperactivation in Severe COVID-19: Targeting STATs as a Novel Therapeutic Strategy.

A disease outbreak in December 2019, caused by a novel coronavirus SARS-CoV-2, was named COVID-19. SARS-CoV-2 infects cells from the upper and lower respiratory tract system and is transmitted by inhalation or contact with infected droplets. Common clinical symptoms include fatigue, fever, and cough, but also shortness of breath and lung abnormalities. Still, some 5% of SARS-CoV-2 infections progress to severe pneumonia and acute respiratory distress syndrome (ARDS), with pulmonary edema, acute kidney injury, and/or multiple organ failure as important consequences, which can lead to death. The innate immune system recognizes viral RNAs and triggers the expression of interferons (IFN). IFNs activate anti-viral effectors and components of the adaptive immune system by activating members of the STAT and IRF families that induce the expression of IFN-stimulated genes (ISG)s. Among other coronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV, common strategies have been identified to antagonize IFN signaling. This typically coincides with hyperactive inflammatory host responses known as the "cytokine storm" that mediate severe lung damage. Likewise, SARS-CoV-2 infection combines a dysregulated IFN response with excessive production of inflammatory cytokines in the lungs. This excessive inflammatory response in the lungs is associated with the local recruitment of immune cells that create a pathogenic inflammatory loop. Together, it causes severe lung pathology, including ARDS, as well as damage to other vulnerable organs, like the heart, spleen, lymph nodes, and kidney, as well as the brain. This can rapidly progress to multiple organ exhaustion and correlates with a poor prognosis in COVID-19 patients. In this review, we focus on the crucial role of different types of IFN that underlies the progression of SARS-CoV-2 infection and leads to immune cell hyper-activation in the lungs, exuberant systemic inflammation, and multiple organ damage. Consequently, to protect from systemic inflammation, it will be critical to interfere with signaling cascades activated by IFNs and other inflammatory cytokines. Targeting members of the STAT family could therefore be proposed as a novel therapeutic strategy in patients with severe COVID-19.

Biodegradation of cyanide to ammonia and carbon dioxide by an industrially valuable enzyme from the newly isolated Enterobacter zs.

The biodetoxification of cyanide-rich wastewater has been suggested as an appropriate technique due to its environmental friendliness and cost effectiveness. In this research, Enterobacter zs that was newly isolated from cyanide-polluted wastewater was selected to catalyze cyanide via an enzymatic mechanism. Enzyme was purified and its activity was also determined by ammonia assay. Subsequently, the operational procedure was optimized to enhance cyanide biodegradation at variable pH values, temperatures and cyanide concentrations using response surface methodology (RSM). The results revealed that the interactions between pH and temperature, as well as those between pH and cyanide concentration, were significant, and the concentration of cyanide in a 650 mg.L-1 solution was decreased by 73%. According to this study, it can be proposed that due to its higher activity level compared with those of similar enzymes, this enzyme can prove useful in enzymatic biodegradation of cyanide which is a promising approach in the treatment of industrial effluent.

Promoting motor functions in a spinal cord injury model of rats using transplantation of differentiated human olfactory stem cells: A step towards future therapy.

Human olfactory ecto-mesenchymal stem cells (hOE-MSCs) derived from the human olfactory mucosa (OM) can be easily isolated and expanded in cultures while their immense plasticity is maintained. To mitigate ethical concerns, the hOE-MSCs can be also transplanted across allogeneic barriers, making them desirable cells for clinical applications. The main purpose of this study was to evaluate the effects of administering the hOE-MSCs on a spinal cord injury (SCI) model of rats. These cells were accordingly isolated and cultured, and then treated in the neurobasal medium containing serum-free Dulbecco's Modified Essential Medium (DMEM) and Ham's F-12 Medium (DMEM/F12) with 2% B27 for two days. Afterwards, the pre-induced cells were incubated in N2B27 with basic fibroblast growth factor (bFGF), fibroblast growth factor 8b (FGF8b), sonic hedgehog (SHH), and ascorbic acid (vitamin C) for six days. The efficacy of the induced cells was additionally evaluated using immunocytochemistry (ICC) and real-time polymerase chain reaction (RT-PCR). The differentiated cells were similarly transplanted into the SC contusions. Functional recovery was further conducted on a weekly basis for eight consecutive weeks. Moreover, cell integration was assessed via conventional histology and ICC, whose results revealed the expression of choline acetyltransferase (ChAT) marker at the induction stage. According to the RT-PCR findings, the highest expression level of insulin gene-enhancer protein (islet-1), oligodendrocyte transcription factor (Olig2), and homeobox protein HB9 was observed at the induction stage. The number of engraftment cells also rose (approximately by 2.5 % ± 0.1) in the motor neuron-like cells derived from the hOE-MSCs-grafted group compared with the OE-MSCs-grafted one. The functional analysis correspondingly revealed that locomotor and sensory scores considerably improved in the rats in the treatment group. These findings suggested that motor neuron-like cells derived from the hOE-MSCs could be utilized as an alternative cell-based therapeutic strategy for SCI.

Differentiation of human mesenchymal stem cells (MSC) to dopaminergic neurons: A comparison between Wharton's Jelly and olfactory mucosa as sources of MSCs.

The generation of dopaminergic neurons from stem cells is a potential therapeutic approach to treat neurodegenerative disorders, such as Parkinson's disease. The current study aims to investigate the potential of two different types of mesenchymal stem cells derived from human Wharton's jelly and nasal cavity for differentiation into dopaminergic neurons. The differentiation capacities of both cell types were evaluated using real-time PCR, immunocytochemistry, flow cytometry and HPLC. Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) are noted for their capability to differentiate into mesodermal and non-mesodermal cells, including neurons. However, it was demonstrated that having the same neuroectodermal origin as the nervous system, the olfactory ectomesenchymal stem cells (OE-MSCs) expressed the neural marker MAP2 as well as dopaminergic markers such as tyrosine hydroxylase (TH), dopamine transporter (DAT) and PITX3 to a greater extent than the WJ-MSCs both at the level of mRNA and protein. Furthermore, quantitative flow cytometric evaluation of these markers at 12 days post-induction supported the above-mentioned results. Finally, the assessment of the functionality of differentiated cells and their ability to synthesize dopamine measured by HPLC revealed that the OE-MSC-derived dopaminergic cells released almost the same amount of dopamine as that secreted by WJ-MSC-derived cells. Thus it showed the difference in their functionality to be negligible. Overall, it may be concluded that higher proliferation and differentiation capacity of OE-MSCs, along with their easier harvestability and autologous transplantability compared with WJ-MSCs, makes them a better cell source for stem cell therapy of neurodegenerative disorders which are caused by degeneration of dopaminergic neurons.