A comprehensive review of stroke-related signaling pathways and treatment in western medicine and traditional Chinese medicine.

This review provides insight into the complex network of signaling pathways and mechanisms involved in stroke pathophysiology. It summarizes the historical progress of stroke-related signaling pathways, identifying potential interactions between them and emphasizing that stroke is a complex network disease. Of particular interest are the Hippo signaling pathway and ferroptosis signaling pathway, which remain understudied areas of research, and are therefore a focus of the review. The involvement of multiple signaling pathways, including Sonic Hedgehog (SHH), nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE), hypoxia-inducible factor-1α (HIF-1α), PI3K/AKT, JAK/STAT, and AMPK in pathophysiological mechanisms such as oxidative stress and apoptosis, highlights the complexity of stroke. The review also delves into the details of traditional Chinese medicine (TCM) therapies such as Rehmanniae and Astragalus, providing an analysis of the recent status of western medicine in the treatment of stroke and the advantages and disadvantages of TCM and western medicine in stroke treatment. The review proposes that since stroke is a network disease, TCM has the potential and advantages of a multi-target and multi-pathway mechanism of action in the treatment of stroke. Therefore, it is suggested that future research should explore more treasures of TCM and develop new therapies from the perspective of stroke as a network disease.

Acute kidney injury in coronavirus infectious disease: a study of incidence, risk factors, and prognosis during the first wave of the disease in Brazil.

INTRODUCTION: Acute kidney injury (AKI) is one of the main complications of COVID-19 caused by SARS-CoV-2. This study aimed to evaluate the incidence of AKI in Brazilian hospitalized patients diagnosed with COVID-19 and identify the risk factors associated with its onset and those associated with its prognosis. METHODS: A prospective cohort study of hospitalized patients diagnosed with COVID-19 at a public and tertiary university hospital in São Paulo from March to December 2020. RESULTS: There were 347 patients hospitalized with COVID-19, 52.4% were admitted to the intensive care unit (ICU) and 47.6% were admitted to the wards. The overall incidence of AKI was 46.4%, more frequent in the ICU (68.1% vs 22.4, p < 0.01) and the overall mortality was 36.1%. Acute kidney replacement therapy was indicated in 46.6% of patients with AKI. In the general population, the factors associated with AKI were older age (OR 1.03, CI 1-1.05, p < 0.05), mechanical ventilation (OR 1.23, CI 1.06-1.83, p < 0.05), presence of proteinuria (OR 1.46, CI 1.22-1.93, p < 0.05), and use of vasoactive drugs (OR 1.26, CI 1.07-1.92, p < 0.05). Mortality was higher in the elderly (OR 1.08, CI 1.04-1.11, p < 0.05), in those with AKI (OR 1.12, CI 1.02-2.05, p < 0.05), particularly KDIGO stage 3 AKI (OR 1.10, CI 1.22-2.05, p < 0.05) and in need of mechanical ventilation (OR 1.13, CI 1.03-1.60, p < 0.05). CONCLUSION: AKI was frequent in hospitalized patients with COVID-19 and the factors associated with its development were older age, mechanical ventilation, use of vasoactive drugs, and presence of proteinuria, being a risk factor for death.

COVID-19 Invades Several Important Organs other than the Lungs: Organs Crosstalk

In December 2019, a new severe acute respiratory coronavirus (SARS-COV-2) had caused outbreaks of pneumonia in Wuhan city, China. It was known as coronavirus infected dis-ease-2019 (COVID-19). COVID-19 patients typically have a fever and respiratory syndrome, where the lung is the main target organ affected by this virus. The objective of this review is to monitor and evaluate injuries caused by the SARS-COV-2 virus on multiple organs other than the lung as the gastrointestinal tract, liver, kidney, heart, ovary, ocular, olfactory, gonad, skin, central nervous system, and sense organs. As SARS-COV-2 virus enters host cells via cell receptor an-giotensin circulating enzyme-2 (ACE2), so it is important to identify the main target cells attacked by SARS-COV-2 virus by comparing the ACE2 expression and viral upload in different organs. In conclusion, the definite role of body organs is explored in the manifestation of COVID-19 infection and crosstalk between other organs are useful tools to find any correlation between disease severity and organs dysfunction, exact prognosis, disease prevention measures, clinical care, and treatment strategies.Copyright © 2021 Bentham Science Publishers.

COVID-19: Could Irisin Become the Handyman Myokine of the 21st Century?

The ongoing Coronavirus disease 2019 (COVID-19) outbreak in China has become the world's leading health headline and is causing major panic and public concerns. After emerging in the City of Wuhan, China, COVID-19 has spread to several countries becoming a worldwide pandemia. Among the studies on COVID-19, it has been demonstrated that novel coronavirus pneumonia is closely associated with inflammatory storms. Controlling the inflammatory response may be as important as targeting the virus. Irisin is a muscle-contraction-induced immunomodulatory myokine related to physical activity. Irisin drives the "browning" of white adipocytes, so enhancing metabolic uncoupling and hence caloric expenditure. Irisin has been clearly shown to be a handyman molecule by exerting beneficial effects on adipose tissues, pancreas, and bone through "cross-talk" between skeletal muscle-adipocyte, skeletal muscle-pancreas, and skeletal muscle-bone, respectively. Irisin has been proposed as a promising strategy for early diagnosis and treatment of various types of cancers, neurological diseases and inflammatory conditions. Irisin has been demonstrated to suppress the immune response, too. The importance of irisin is demonstrated by the increase in the number of scientific papers and patents in recent years. The identification of irisin receptor should greatly facilitate the understanding of irisin's function in exercise and human health. This review examines the structure and recent advances in activi-ties of irisin, suggesting it for further studies on the prevention and cure of COVID-19. Nowadays, studies on irisin plasma levels and physical activity may be useful tools to further investigate the prevention of COVID-19. Irisin may be suggested as a potential novel intervention for COVID-19 by mitigating inflammatory storms, suppressing the immune response and simultaneously alleviating neurological dis-orders such as depression and anxiety.Copyright © 2020 Bentham Science Publishers.

Extracorporeal Carbon Dioxide Removal: From Pathophysiology to Clinical Applications; Focus on Combined Continuous Renal Replacement Therapy.

Lung-protective ventilation (LPV) with low tidal volumes can significantly increase the survival of patients with acute respiratory distress syndrome (ARDS) by limiting ventilator-induced lung injuries. However, one of the main concerns regarding the use of LPV is the risk of developing hypercapnia and respiratory acidosis, which may limit the clinical application of this strategy. This is the reason why different extracorporeal CO2 removal (ECCO2R) techniques and devices have been developed. They include low-flow or high-flow systems that may be performed with dedicated platforms or, alternatively, combined with continuous renal replacement therapy (CRRT). ECCO2R has demonstrated effectiveness in controlling PaCO2 levels, thus allowing LPV in patients with ARDS from different causes, including those affected by Coronavirus disease 2019 (COVID-19). Similarly, the suitability and safety of combined ECCO2R and CRRT (ECCO2R-CRRT), which provides CO2 removal and kidney support simultaneously, have been reported in both retrospective and prospective studies. However, due to the complexity of ARDS patients and the limitations of current evidence, the actual impact of ECCO2R on patient outcome still remains to be defined. In this review, we discuss the main principles of ECCO2R and its clinical application in ARDS patients, in particular looking at clinical experiences of combined ECCO2R-CRRT treatments.

Epigenetic and transcriptomic reprogramming in monocytes of severe COVID-19 patients reflects alterations in myeloid differentiation and the influence of inflammatory cytokines.

BACKGROUND: COVID-19 manifests with a wide spectrum of clinical phenotypes, ranging from asymptomatic and mild to severe and critical. Severe and critical COVID-19 patients are characterized by marked changes in the myeloid compartment, especially monocytes. However, little is known about the epigenetic alterations that occur in these cells during hyperinflammatory responses in severe COVID-19 patients. METHODS: In this study, we obtained the DNA methylome and transcriptome of peripheral blood monocytes from severe COVID-19 patients. DNA samples extracted from CD14 + CD15- monocytes of 48 severe COVID-19 patients and 11 healthy controls were hybridized on MethylationEPIC BeadChip arrays. In parallel, single-cell transcriptomics of 10 severe COVID-19 patients were generated. CellPhoneDB was used to infer changes in the crosstalk between monocytes and other immune cell types. RESULTS: We observed DNA methylation changes in CpG sites associated with interferon-related genes and genes associated with antigen presentation, concordant with gene expression changes. These changes significantly overlapped with those occurring in bacterial sepsis, although specific DNA methylation alterations in genes specific to viral infection were also identified. We also found these alterations to comprise some of the DNA methylation changes occurring during myeloid differentiation and under the influence of inflammatory cytokines. A progression of DNA methylation alterations in relation to the Sequential Organ Failure Assessment (SOFA) score was found to be related to interferon-related genes and T-helper 1 cell cytokine production. CellPhoneDB analysis of the single-cell transcriptomes of other immune cell types suggested the existence of altered crosstalk between monocytes and other cell types like NK cells and regulatory T cells. CONCLUSION: Our findings show the occurrence of an epigenetic and transcriptional reprogramming of peripheral blood monocytes, which could be associated with the release of aberrant immature monocytes, increased systemic levels of pro-inflammatory cytokines, and changes in immune cell crosstalk in these patients.

Evolutionary Signals in Coronaviral Structural Proteins Suggest Possible Complex Mechanisms of Post-Translational Regulation in SARS-CoV-2 Virus.

Post-translational regulation of proteins has emerged as a central topic of research in the field of functional proteomics. Post-translational modifications (PTMs) dynamically control the activities of proteins and are involved in a wide range of biological processes. Crosstalk between different types of PTMs represents a key mechanism of regulation and signaling. Due to the current pandemic of the novel and dangerous SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) virus, here we present an in silico analysis of different types of PTMs in structural proteins of coronaviruses. A dataset of PTM sites was studied at three levels: conservation analysis, mutational analysis and crosstalk analysis. We identified two sets of PTMs which could have important functional roles in the regulation of the structural proteins of coronaviruses. Additionally, we found seven interesting signals of potential crosstalk events. These results reveal a higher level of complexity in the mechanisms of post-translational regulation of coronaviral proteins and provide new insights into the adaptation process of the SARS-CoV-2 virus.

Xenogeneic support for the recovery of human donor organs.

VIDEO ABSTRACT.

Screening of cell-virus, cell-cell, gene-gene crosstalk among animal kingdom at single cell resolution.

BACKGROUND: The exact animal origin of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains obscure and understanding its host range is vital for preventing interspecies transmission. METHODS: Herein, we applied single-cell sequencing to multiple tissues of 20 species (30 data sets) and integrated them with public resources (45 data sets covering 26 species) to expand the virus receptor distribution investigation. While the binding affinity between virus and receptor is essential for viral infectivity, understanding the receptor distribution could predict the permissive organs and tissues when infection occurs. RESULTS: Based on the transcriptomic data, the expression profiles of receptor or associated entry factors for viruses capable of causing respiratory, blood, and brain diseases were described in detail. Conserved cellular connectomes and regulomes were also identified, revealing fundamental cell-cell and gene-gene cross-talks from reptiles to humans. CONCLUSIONS: Overall, our study provides a resource of the single-cell atlas of the animal kingdom which could help to identify the potential host range and tissue tropism of viruses and reveal the host-virus co-evolution.

Adipose Tissue Inflammation and Pulmonary Dysfunction in Obesity.

Obesity is a chronic disease caused by an excess of adipose tissue that may impair health by altering the functionality of various organs, including the lungs. Excessive deposition of fat in the abdominal area can lead to abnormal positioning of the diaphragm and consequent reduction in lung volume, leading to a heightened demand for ventilation and increased exposure to respiratory diseases, such as chronic obstructive pulmonary disease, asthma, and obstructive sleep apnoea. In addition to mechanical ventilatory constraints, excess fat and ectopic deposition in visceral depots can lead to adipose tissue dysfunction, which promotes metabolic disorders. An altered adipokine-secretion profile from dysfunctional adipose tissue in morbid obesity fosters systemic, low-grade inflammation, impairing pulmonary immune response and promoting airway hyperresponsiveness. A potential target of these adipokines could be the NLRP3 inflammasome, a critical component of the innate immune system, the harmful pro-inflammatory effect of which affects both adipose and lung tissue in obesity. In this review, we will investigate the crosstalk between adipose tissue and the lung in obesity, highlighting the main inflammatory mediators and novel therapeutic targets in preventing pulmonary dysfunction.

SARS-CoV-2 and cancer: the intriguing and informative cross-talk.

The COVID-19 pandemic caused by the SARS-CoV-2 virus has significantly disrupted and burdened the diagnostic workup and delivery of care, including transfusion, to cancer patients across the globe. Furthermore, cancer patients suffering from solid tumors or hematologic malignancies were more prone to the infection and had higher morbidity and mortality than the rest of the population. Major signaling pathways have been identified at the intersection of SARS-CoV-2 and cancer cells, often leading to tumor progression or alteration of the tumor response to therapy. The reactivation of oncogenic viruses has also been alluded to in the context and following COVID-19. Paradoxically, certain tumors responded better following the profound infection-induced immune modulation. Unveiling the mechanisms of the virus-tumor cell interactions will lead to a better understanding of the pathophysiology of both cancer progression and virus propagation. It would be challenging to monitor, through the different cancer registries, retrospectively, the response of patients who have been previously exposed to the virus in contrast to those who have not contracted the infection.

Evaluation in a Cytokine Storm Model In Vivo of the Safety and Efficacy of Intravenous Administration of PRS CK STORM (Standardized Conditioned Medium Obtained by Coculture of Monocytes and Mesenchymal Stromal Cells).

Our research group has been developing a series of biological drugs produced by coculture techniques with M2-polarized macrophages with different primary tissue cells and/or mesenchymal stromal cells (MSC), generally from fat, to produce anti-inflammatory and anti-fibrotic effects, avoiding the overexpression of pro-inflammatory cytokines by the innate immune system at a given time. One of these products is the drug PRS CK STORM, a medium conditioned by allogenic M2-polarized macrophages, from coculture, with those macrophages M2 with MSC from fat, whose composition, in vitro safety, and efficacy we studied. In the present work, we publish the results obtained in terms of safety (pharmacodynamics and pharmacokinetics) and efficacy of the intravenous application of this biological drug in a murine model of cytokine storm associated with severe infectious processes, including those associated with COVID-19. The results demonstrate the safety and high efficacy of PRS CK STORM as an intravenous drug to prevent and treat the cytokine storm associated with infectious processes, including COVID-19.

Regulation of Dynamic Cell Adhesion by Integrin-Integrin Crosstalk.

Most cells express several integrins. The integrins are able to respond to various cellular functions and needs by modifying their own activation state, but in addition by their ability to regulate each other by activation or inhibition. This crosstalk or transdominant regulation is strictly controlled. The mechanisms resulting in integrin crosstalk are incompletely understood, but they often involve intracellular signalling routes also used by other cell surface receptors. Several studies show that the integrin cytoplasmic tails bind to a number of cytoskeletal and adaptor molecules in a regulated manner. Recent work has shown that phosphorylations of integrins and key intracellular molecules are of pivotal importance in integrin-cytoplasmic interactions, and these in turn affect integrin activity and crosstalk. The integrin ß-chains play a central role in regulating crosstalk. In addition to Integrin-integrin crosstalk, crosstalk may also occur between integrins and related receptors, including other adhesion receptors, growth factor and SARS-CoV-2 receptors.

The Role of Fecal Microbiota Transplantation in the Treatment of Acute Graft-versus-Host Disease.

The number of allogeneic hematopoietic stem cell transplantations conducted worldwide is constantly rising. Together with that, the absolute number of complications after the procedure is increasing, with graft-versus-host disease (GvHD) being one of the most common. The standard treatment is steroid administration, but only 40-60% of patients will respond to the therapy and some others will be steroid-dependent. There is still no consensus regarding the best second-line option, but fecal microbiota transplantation (FMT) has shown encouraging preliminary and first clinically relevant results in recent years and seems to offer great hope for patients. The reason for treatment of steroid-resistant acute GvHD using this method derives from studies showing the significant immunomodulatory role played by the intestinal microbiota in the pathogenesis of GvHD. Depletion of commensal microbes is accountable for aggravation of the disease and is associated with decreased overall survival. In this review, we present the pathogenesis of GvHD, with special focus on the special role of the gut microbiota and its crosstalk with immune cells. Moreover, we show the results of studies and case reports to date regarding the use of FMT in the treatment of steroid-resistant acute GvHD.

"Reframing" dopamine signaling at the intersection of glial networks in the aged Parkinsonian brain as innate Nrf2/Wnt driver: Therapeutical implications.

Dopamine (DA) signaling via G protein-coupled receptors is a multifunctional neurotransmitter and neuroendocrine-immune modulator. The DA nigrostriatal pathway, which controls the motor coordination, progressively degenerates in Parkinson's disease (PD), a most common neurodegenerative disorder (ND) characterized by a selective, age-dependent loss of substantia nigra pars compacta (SNpc) neurons, where DA itself is a primary source of oxidative stress and mitochondrial impairment, intersecting astrocyte and microglial inflammatory networks. Importantly, glia acts as a preferential neuroendocrine-immune DA target, in turn, counter-modulating inflammatory processes. With a major focus on DA intersection within the astrocyte-microglial inflammatory network in PD vulnerability, we herein first summarize the characteristics of DA signaling systems, the propensity of DA neurons to oxidative stress, and glial inflammatory triggers dictating the vulnerability to PD. Reciprocally, DA modulation of astrocytes and microglial reactivity, coupled to the synergic impact of gene-environment interactions, then constitute a further level of control regulating midbrain DA neuron (mDAn) survival/death. Not surprisingly, within this circuitry, DA converges to modulate nuclear factor erythroid 2-like 2 (Nrf2), the master regulator of cellular defense against oxidative stress and inflammation, and Wingless (Wnt)/ß-catenin signaling, a key pathway for mDAn neurogenesis, neuroprotection, and immunomodulation, adding to the already complex "signaling puzzle," a novel actor in mDAn-glial regulatory machinery. Here, we propose an autoregulatory feedback system allowing DA to act as an endogenous Nrf2/Wnt innate modulator and trace the importance of DA receptor agonists applied to the clinic as immune modifiers.

Cytokine Profile and Anti-Inflammatory Activity of a Standardized Conditioned Medium Obtained by Coculture of Monocytes and Mesenchymal Stromal Cells (PRS CK STORM).

Intercellular communication between monocytes/macrophages and cells involved in tissue regeneration, such as mesenchymal stromal cells (MSCs) and primary tissue cells, is essential for tissue regeneration and recovery of homeostasis. Typically, in the final phase of the inflammation-resolving process, this intercellular communication drives an anti-inflammatory immunomodulatory response. To obtain a safe and effective treatment to counteract the cytokine storm associated with a disproportionate immune response to severe infections, including that associated with COVID-19, by means of naturally balanced immunomodulation, our group has standardized the production under GMP-like conditions of a secretome by coculture of macrophages and MSCs. To characterize this proteome, we determined the expression of molecules related to cellular immune response and tissue regeneration, as well as its possible toxicity and anti-inflammatory potency. The results show a specific molecular pattern of interaction between the two cell types studied, with an anti-inflammatory and regenerative profile. In addition, the secretome is not toxic by itself on human PBMC or on THP-1 monocytes and prevents lipopolysaccharide (LPS)-induced growth effects on those cell types. Finally, PRS CK STORM prevents LPS-induced TNF-A and IL-1Β secretion from PBMC and from THP-1 cells at the same level as hydrocortisone, demonstrating its anti-inflammatory potency.

Potential role of bradykinin and its receptors in COVID-19

Bradykinin (BK) is a nonapeptide that belongs to the kinin family. It is an active inflammatory mediator that exerts multiple different effects via its B1 and B2 receptors (B1R and B2R);however, its role has not been fully elucidated so far. It is known that B1R and B2R interact with angiotensin-converting enzyme (ACE)-2 protein, which acts as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). By degrading BK to its desARG9-BK metabolite, ACE2 leads to B1R activation, which triggers a release of pro-and anti-inflammatory cytokines in an immune response to infectious pathogens. On the other hand, ACE2 stimulates the expression of B2R by activating the ANG(1-7)-MasR axis which is essential for proper endothelial function. A controlled increase in B1R-mediated cytokine release during SARS-CoV-2 cell entry may be considered a normal immune response aiming to prevent infection. However, if regulatory mechanisms fail, the increase in proinflammatory cytokine release may lead to progression of infection, endothelial activation, and onset of symptoms, including organ involvement. Available data strongly suggest that BK and its receptors are involved in the pathomechanism of COVID-19 and linked by various feedback mechanisms to ACE2, ACE1, as well as angiotensin II (ANGII) and its receptors. As expression of these pathways is likely to change dynamically throughout different stages of COVID-19, novel treatment options that target these pathways along with close monitoring of their activity should be developed.

The function of specialized pro-resolving endogenous lipid mediators, vitamins, and other micronutrients in the control of the inflammatory processes: Possible role in patients with SARS-CoV-2 related infection

Inflammation is an essential protective response against harmful stimuli, such as invading pathogens, damaged cells, or irritants. Physiological inflammation eliminates pathogens and promotes tissue repair and healing. Effective immune response in humans depends on a tightly regulated balance among inflammatory and antiinflammatory mechanisms involving both innate and adaptive arms of the immune system. Excessive inflammation can become pathological and induce detrimental effects. If this process is not self-limited, an inappropriate remodeling of the tissues and organs can occur and lead to the onset of chronic degenerative diseases. A wide spectrum of infectious and non-infectious agents may activate the inflammation, via the release of mediators and cytokines by distinct subtypes of lymphocytes and macrophages. Several molecular mechanisms regulate the onset, progression, and resolution of inflammation. All these steps, even the termination of this process, are active and not passive events. In particular, a complex interplay exists between mediators (belonging to the group of Eicosanoids), which induce the beginning of inflammation, such as Prostaglandins (PGE2), Leukotrienes (LT), and thromboxane A2 (TXA2), and molecules which display a key role in counteracting this process and in promoting its proper resolution. The latter group of mediators includes: o)-6 arachidonic acid (AA)-derived metabolites, such as Lipoxins (LXs), o) -3 eicosapentaenoic acid (EPA)-derived mediators, such as Eseries Resolvins (RvEs), and o) -3 docosahexaenoic (DHA)-derived mediators, such as D-series Resolvins (RvDs), Protectins (PDs) and Maresins (MaRs). Overall, these mediators are defined as specialized pro-resolving mediators (SPMs). Reduced synthesis of these molecules may lead to uncontrolled inflammation with possible harmful effects. o)-3 fatty acids are widely used in clinical practice as rather inexpensive, safe, readily available supplemental therapy. Taking advantage of this evidence, several researchers are suggesting that SPMs may have beneficial effects in the complementary treatment of patients with severe forms of SARS-CoV-2 related infection, to counteract the "cytokine storm" observed in these individuals. Well-designed and sized trials in patients suffering from COVID-19 with different degrees of severity are needed to investigate the real impact in the clinical practice of this promising therapeutic approach.

Possible kidney-lung cross-talk in COVID-19: in silico modeling of SARS-CoV-2 infection.

BACKGROUND: Publicly available genomics datasets have grown drastically during the past decades. Although most of these datasets were initially generated to answer a pre-defined scientific question, their repurposing can be useful when new challenges such as COVID-19 arise. While the establishment and use of experimental models of COVID-19 are in progress, the potential hypotheses for mechanisms of onset and progression of COVID-19 can be generated by using in silico analysis of known molecular changes during COVID-19 and targets for SARS-CoV-2 invasion. METHODS: Selecting condition: COVID-19 infection leads to pneumonia and mechanical ventilation (PMV) and associated with acute kidney injury (AKI). There is increasing data demonstrating mechanistic links between AKI and lung injury caused by mechanical ventilation. Selecting targets: SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) for cell entry. We hypothesized that expression of ACE2 and TMPRSS2 would be affected in models of AKI and PMV. We therefore evaluated expression of ACE2 and TMPRSS2 as well as other novel molecular players of AKI and AKI-lung cross-talk in the publicly available microarray datasets GSE6730 and GSE60088, which represent gene expression of lungs and kidneys in mouse models of AKI and PMV, respectively. RESULTS: Expression of COVID-19 related genes ACE2 and TMPRSS2 was downregulated in lungs after 6 h of distant AKI effects. The expression of ACE2 decreased further after 36 h, while expression of TMPRSS2 recovered. In kidneys, both genes were downregulated by AKI, but not by distant lung injury. We also identified 53 kidney genes upregulated by PMV; and 254 lung genes upregulated by AKI, 9 genes of which were common to both organs. 3 of 9 genes were previously linked to kidney-lung cross-talk: Lcn2 (Fold Change (FC)Lung (L) = 18.6, FCKidney (K) = 6.32), Socs3 (FCL = 10.5, FCK = 10.4), Inhbb (FCL = 6.20, FCK = 6.17). This finding validates the current approach and reveals 6 new candidates, including Maff (FCL = 7.21, FCK = 5.98). CONCLUSIONS: Using our in silico approach, we identified changes in COVID-19 related genes ACE2 and TMPRSS2 in traditional mouse models of AKI and kidney-lung cross-talk. We also found changes in new candidate genes, which could be involved in the combined kidney-lung injury during COVID-19.