Mathematical Modeling of Severe Acute Respiratory Syndrome Coronavirus 2 Infection Network with Cytokine Storm, Oxidative Stress, Thrombosis, Insulin Resistance, and Nitric Oxide Pathways.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a systemic disease affecting not only the lungs but also multiple organ systems. Clinical studies implicate that SARS-CoV-2 infection causes imbalance of cellular homeostasis and immune response that trigger cytokine storm, oxidative stress, thrombosis, and insulin resistance. Mathematical modeling can offer in-depth understanding of the SARS-CoV-2 infection and illuminate how subcellular mechanisms and feedback loops underpin disease progression and multiorgan failure. We report here a mathematical model of SARS-CoV-2 infection pathway network with cytokine storm, oxidative stress, thrombosis, insulin resistance, and nitric oxide (NO) pathways. The biochemical systems theory model shows autocrine loops with positive feedback enabling excessive immune response, cytokines, transcription factors, and interferons, which can imbalance homeostasis of the system. The simulations suggest that changes in immune response led to uncontrolled release of cytokines and chemokines, including interleukin (IL)-1ß, IL-6, and tumor necrosis factor α (TNFα), and affect insulin, coagulation, and NO signaling pathways. Increased production of NETs (neutrophil extracellular traps), thrombin, PAI-1 (plasminogen activator inhibitor-1), and other procoagulant factors led to thrombosis. By analyzing complex biochemical reactions, this model forecasts the key intermediates, potential biomarkers, and risk factors at different stages of COVID-19. These insights can be useful for drug discovery and development, as well as precision treatment of multiorgan implications of COVID-19 as seen in systems medicine.

A New Perspective on Cancer Therapy: Changing the Treaded Path?

During the last decade, we have persistently addressed the question, "how can the innate immune system be used as a therapeutic tool to eliminate cancer?" A cancerous tumor harbors innate immune cells such as macrophages, which are held in the tumor-promoting M2 state by tumor-cell-released cytokines. We have discovered that these tumor-associated macrophages (TAM) are repolarized into the nitric oxide (NO)-generating tumoricidal M1 state by the dietary agent curcumin (CC), which also causes recruitment of activated natural killer (NK) cells and cytotoxic T (Tc) cells into the tumor, thereby eliminating cancer cells as well as cancer stem cells. Indications are that this process may be NO-dependent. Intriguingly, the maximum blood concentration of CC in mice never exceeds nanomolar levels. Thus, our results submit that even low, transient levels of curcumin in vivo are enough to cause repolarization of the TAM and recruitment NK cells as well as Tc cells to eliminate the tumor. We have observed this phenomenon in two cancer models, glioblastoma and cervical cancer. Therefore, this approach may yield a general strategy to fight cancer. Our mechanistic studies have so far implicated induction of STAT-1 in this M2→M1 switch, but further studies are needed to understand the involvement of other factors such as the lipid metabolites resolvins in the CC-evoked anticancer pathways.

Isodeoxyelephantopin, a sesquiterpene lactone from Elephantopus scaber Linn., inhibits pro-inflammatory mediators' production through both NF-κB and AP-1 pathways in LPS-activated macrophages.

Isodeoxyelephantopin (IDET) has been identified as an anti-tumor natural constituent whose anti-tumor activity and mechanism have been widely investigated. Since the occurrence and development of cancer usually accompany with inflammation, and tumor signaling shares many components with inflammation signaling, the agents with anti-tumor activity are likely to possess anti-inflammation potential. Thus, the current study aims to demonstrate the anti-inflammatory activity along with the underlying mechanism of IDET in lipopolysaccharide (LPS)-primed macrophages. By using Griess method and ELISA, we found that in both bone marrow derived macrophages and alveolar macrophage cell line, IDET, at relatively low concentrations (0.75, 1.5 and 3 µM), could inhibit LPS-induced expression of various pro-inflammatory mediators including nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS), interleukin (IL)-6, monocyte chemotactic protein-1 (MCP-1) and IL-1ß. Meanwhile, in activated MH-S cells, the inhibitory action of IDET on mRNA expression levels of these cytokines was also detected using qPCR. Mechanistically, the effects of IDET on two key inflammatory signalings, nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) pathways, were determined in LPS-activated MH-S cells by reporter gene along with western blot assays. On the one hand, IDET suppressed NF-κB signaling via down-regulating phosphorylation and degradation of inhibitor of NF-κB (IκB)-α and the subsequent p65 translocation. On the other hand, IDET dampened AP-1 signaling through attenuating phosphorylation of both c-jun N-terminal kinase 1/2 (JNK1/2) and extracellular signal regulated kinase 1/2 (ERK1/2). Our study indicates that IDET might be a promising constituent from the anti-inflammatory herb Elephantopus scaber Linn. in mitigating inflammatory conditions, especially respiratory inflammation.