Immunology of Kidney Disease.

The immune system and the kidneys are closely related. Immune components mediate acute kidney disease and are crucial to the progression of chronic kidney disease. Beyond its pathogenic functions, the immune system supports immunological homeostasis in healthy kidneys. The kidneys help maintain immune equilibrium by removing metabolic waste products and toxins, thereby limiting local and systemic inflammation. In this review, we describe the close relationship between the immune system and the kidneys. We discuss how the imbalance in the immune response can be deleterious to the kidneys and how immunomodulation can be important in preventing end-stage renal disease. In addition, recent tools such as in silico platforms and kidney organoids can help unveil the relationship between immune cells and kidney homeostasis.

The Global Evolution and Impact of Systems Biology and Artificial Intelligence in Stem Cell Research and Therapeutics Development: A Scoping Review.

Advanced bioinformatics analysis, such as systems biology (SysBio) and artificial intelligence (AI) approaches, including machine learning (ML) and deep learning (DL), is increasingly present in stem cell (SC) research. An approximate timeline on these developments and their global impact is still lacking. We conducted a scoping review on the contribution of SysBio and AI analysis to SC research and therapy development based on literature published in PubMed between 2000 and 2024. We identified an 8-10-fold increase in research output related to all three search terms between 2000 and 2021, with a 10-fold increase in AI-related production since 2010. Use of SysBio and AI still predominates in preclinical basic research with increasing use in clinically oriented translational medicine since 2010. SysBio- and AI-related research was found all over the globe, with SysBio output led by the United States (US, n=1487), United Kingdom (UK, n=1094), Germany (n=355), The Netherlands (n=339), Russia (n=215), and France (n=149), while for AI-related research the US (n=853) and UK (n=258) take a strong lead, followed by Switzerland (n=69), The Netherlands (n=37), and Germany (n=19). The US and UK are most active in SCs publications related to AI/ML and AI/DL. The prominent use of SysBio in ESC research was recently overtaken by prominent use of AI in iPSC and MSC research. This study reveals the global evolution and growing intersection between AI, SysBio, and SC research over the past two decades, with substantial growth in all three fields and exponential increases in AI-related research in the past decade.

Lisdexamfetamine dimesylate-exposition in male rats during the peripubertal period impairs inflammatory mechanisms, antioxidant activity, and apoptosis process in kidneys of male pubertal rats.

Lisdexamfetamine dimesylate (LDX) is a prodrug of dextroamphetamine, which has been widely recommended for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). There are still no data in the literature relating the possible toxic effects of LDX in the kidney. Therefore, the present study aims to evaluate the effects of LDX exposure on morphological, oxidative stress, cell death and inflammation parameters in the kidneys of male pubertal Wistar rats, since the kidneys are organs related to the excretion of most drugs. For this, twenty male Wistar rats were distributed randomly into two experimental groups: LDX group-received 11,3 mg/kg/day of LDX; and Control group-received tap water. Animals were treated by gavage from postnatal day (PND) 25 to 65. At PND 66, plasma was collected to the biochemical dosage, and the kidneys were collected for determinations of the inflammatory profile, oxidative status, cell death, and for histochemical, and morphometric analyses. Our results show that there was an increase in the number of cells marked for cell death, and a reduction of proximal and distal convoluted tubules mean diameter in the group that received LDX. In addition, our results also showed an increase in MPO and NAG activity, indicating an inflammatory response. The oxidative status showed that the antioxidant system is working undisrupted and avoiding oxidative stress. Therefore, LDX-exposition in male rats during the peripubertal period causes renal changes in pubertal age involving inflammatory mechanisms, antioxidant activity and apoptosis process.

Prenatal Stress and Ethanol Exposure: Microbiota-Induced Immune Dysregulation and Psychiatric Risks.

Changes in maternal gut microbiota due to stress and/or ethanol exposure can have lasting effects on offspring's health, particularly regarding immunity, inflammation response, and susceptibility to psychiatric disorders. The literature search for this review was conducted using PubMed and Scopus, employing keywords and phrases related to maternal stress, ethanol exposure, gut microbiota, microbiome, gut-brain axis, diet, dysbiosis, progesterone, placenta, prenatal development, immunity, inflammation, and depression to identify relevant studies in both preclinical and human research. Only a limited number of reviews were included to support the arguments. The search encompassed studies from the 1990s to the present. This review begins by exploring the role of microbiota in modulating host health and disease. It then examines how disturbances in maternal microbiota can affect the offspring's immune system. The analysis continues by investigating the interplay between stress and dysbiosis, focusing on how prenatal maternal stress influences both maternal and offspring microbiota and its implications for susceptibility to depression. The review also considers the impact of ethanol consumption on gut dysbiosis, with an emphasis on the effects of prenatal ethanol exposure on both maternal and offspring microbiota. Finally, it is suggested that maternal gut microbiota dysbiosis may be significantly exacerbated by the combined effects of stress and ethanol exposure, leading to immune system dysfunction and chronic inflammation, which could increase the risk of depression in the offspring. These interactions underscore the potential for novel mental health interventions that address the gut-brain axis, especially in relation to maternal and offspring health.

Cisplatin Toxicity Causes Neutrophil-Mediated Inflammation in Zebrafish Larvae.

Cisplatin is an antineoplastic agent used to treat various tumors. In mammals, it can cause nephrotoxicity, tissue damage, and inflammation. The release of inflammatory mediators leads to the recruitment and infiltration of immune cells, particularly neutrophils, at the site of inflammation. Cisplatin is often used as an inducer of acute kidney injury (AKI) in experimental models, including zebrafish (Danio rerio), due to its accumulation in kidney cells. Current protocols in larval zebrafish focus on studying its effect as an AKI inducer but ignore other systematic outcomes. In this study, cisplatin was added directly to the embryonic medium to assess its toxicity and impact on systemic inflammation using locomotor activity analysis, qPCR, microscopy, and flow cytometry. Our data showed that larvae exposed to cisplatin at 7 days post-fertilization (dpf) displayed dose-dependent mortality and morphological changes, leading to a decrease in locomotion speed at 9 dpf. The expression of pro-inflammatory cytokines such as interleukin (il)-12, il6, and il8 increased after 48 h of cisplatin exposure. Furthermore, while a decrease in the number of neutrophils was observed in the glomerular region of the pronephros, there was an increase in neutrophils throughout the entire animal after 48 h of cisplatin exposure. We demonstrate that cisplatin can have systemic effects in zebrafish larvae, including morphological and locomotory defects, increased inflammatory cytokines, and migration of neutrophils from the hematopoietic niche to other parts of the body. Therefore, this protocol can be used to induce systemic inflammation in zebrafish larvae for studying new therapies or mechanisms of action involving neutrophils.

Transcriptome analysis of six tissues obtained post-mortem from sepsis patients.

Septic shock is a life-threatening clinical condition characterized by a robust immune inflammatory response to disseminated infection. Little is known about its impact on the transcriptome of distinct human tissues. To address this, we performed RNA sequencing of samples from the prefrontal cortex, hippocampus, heart, lung, kidney and colon of seven individuals who succumbed to sepsis and seven uninfected controls. We identified that the lungs and colon were the most affected organs. While gene activation dominated, strong inhibitory signals were also detected, particularly in the lungs. We found that septic shock is an extremely heterogeneous disease, not only when different individuals are investigated, but also when comparing different tissues of the same patient. However, several pathways, such as respiratory electron transport and other metabolic functions, revealed distinctive alterations, providing evidence that tissue specificity is a hallmark of sepsis. Strikingly, we found evident signals of accelerated ageing in our sepsis population.

Chronic environmental hypoxia attenuates innate immunity activation and renal injury in two CKD models.

Tissue hypoxia has been pointed out as a major pathogenic factor in chronic kidney disease (CKD). However, epidemiological and experimental evidence inconsistent with this notion has been described. We have previously reported that chronic exposure to low ambient Po2 promoted no renal injury in normal rats and in rats with 5/6 renal ablation (Nx) unexpectedly attenuated renal injury. In the present study, we investigated whether chronic exposure to low ambient Po2 would also be renoprotective in two additional models of CKD: adenine (ADE) excess and chronic nitric oxide (NO) inhibition. In both models, normobaric ambient hypoxia attenuated the development of renal injury and inflammation. In addition, renal hypoxia limited the activation of NF-κB and NOD-like receptor family pyrin domain containing 3 inflammasome cascades as well as oxidative stress and intrarenal infiltration by angiotensin II-positive cells. Renal activation of hypoxia-inducible factor (HIF)-2α, along with other adaptive mechanisms to hypoxia, may have contributed to these renoprotective effects. The present findings may contribute to unravel the pathogenesis of CKD and to the development of innovative strategies to arrest its progression.NEW & NOTEWORTHY Hypoxia is regarded as a major pathogenic factor in chronic kidney disease (CKD). In disagreement with this view, we show here that sustained exposure to low ambient Po2 lessened kidney injury and inflammation in two CKD models: adenine (ADE) excess and chronic nitric oxide (NO) inhibition. Together with our previous findings in the remnant kidney, these observations indicate that local changes elicited by hypoxia may exert renoprotection in CKD, raising the prospect of novel therapeutic strategies for this disease.

Integrative systems immunology uncovers molecular networks of the cell cycle that stratify COVID-19 severity.

Several perturbations in the number of peripheral blood leukocytes, such as neutrophilia and lymphopenia associated with Coronavirus disease 2019 (COVID-19) severity, point to systemic molecular cell cycle alterations during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. However, the landscape of cell cycle alterations in COVID-19 remains primarily unexplored. Here, we performed an integrative systems immunology analysis of publicly available proteome and transcriptome data to characterize global changes in the cell cycle signature of COVID-19 patients. We found significantly enriched cell cycle-associated gene co-expression modules and an interconnected network of cell cycle-associated differentially expressed proteins (DEPs) and genes (DEGs) by integrating the molecular data of 1469 individuals (981 SARS-CoV-2 infected patients and 488 controls [either healthy controls or individuals with other respiratory illnesses]). Among these DEPs and DEGs are several cyclins, cell division cycles, cyclin-dependent kinases, and mini-chromosome maintenance proteins. COVID-19 patients partially shared the expression pattern of some cell cycle-associated genes with other respiratory illnesses but exhibited some specific differential features. Notably, the cell cycle signature predominated in the patients' blood leukocytes (B, T, and natural killer cells) and was associated with COVID-19 severity and disease trajectories. These results provide a unique global understanding of distinct alterations in cell cycle-associated molecules in COVID-19 patients, suggesting new putative pathways for therapeutic intervention.

Loss of mTORC2 Activity in Neutrophils Impairs Fusion of Granules and Affects Cellular Metabolism Favoring Increased Bacterial Burden in Sepsis.

Sepsis is a complex infectious syndrome in which neutrophil participation is crucial for patient survival. Neutrophils quickly sense and eliminate the pathogen by using different effector mechanisms controlled by metabolic processes. The mammalian target of rapamycin (mTOR) pathway is an important route for metabolic regulation, and its role in neutrophil metabolism has not been fully understood yet, especially the importance of mTOR complex 2 (mTORC2) in the neutrophil effector functions. In this study, we observed that the loss of Rictor (mTORC2 scaffold protein) in primary mouse-derived neutrophils affects their chemotaxis by fMLF and their microbial killing capacity, but not the phagocytic capacity. We found that the microbicidal capacity was impaired in Rictor-deleted neutrophils because of an improper fusion of granules, reducing the hypochlorous acid production. The loss of Rictor also led to metabolic alterations in isolated neutrophils, increasing aerobic glycolysis. Finally, myeloid-Rictor-deleted mice (LysMRic Δ/Δ) also showed an impairment of the microbicidal capacity, increasing the bacterial burden in the Escherichia coli sepsis model. Overall, our results highlight the importance of proper mTORC2 activation for neutrophil effector functions and metabolism during sepsis.

Role of proton-activated G protein-coupled receptors in pathophysiology.

Local acidification is a common feature of many disease processes such as inflammation, infarction, or solid tumor growth. Acidic pH is not merely a sequela of disease but contributes to recruitment and regulation of immune cells, modifies metabolism of parenchymal, immune and tumor cells, modulates fibrosis, vascular permeability, oxygen availability, and consumption, invasiveness of tumor cells, and impacts on cell survival. Thus, multiple pH-sensing mechanisms must exist in cells involved in these processes. These pH sensors play important roles in normal physiology and pathophysiology, and hence might be attractive targets for pharmacological interventions. Among the pH-sensing mechanisms, OGR1 (GPR68), GPR4 (GPR4), and TDAG8 (GPR65) have emerged as important molecules. These G protein-coupled receptors are widely expressed, upregulated in inflammation and tumors, sense changes in extracellular pH in the range between pH 8 and 6, and are involved in modulating key processes in inflammation, tumor biology, and fibrosis. This review discusses key features of these receptors and highlights important disease states and pathways affected by their activity.

Cytokines and Immune Cells Profile in Different Tissues of Rodents Induced by Environmental Enrichment: Systematic Review.

Environmental Enrichment (EE) is based on the promotion of socio-environmental stimuli, which mimic favorable environmental conditions for the practice of physical activity and health. The objective of the present systematic review was to evaluate the influence of EE on pro-and anti-inflammatory immune parameters, but also in cell activation related to the innate and acquired immune responses in the brain and peripheral tissues in rodents. Three databases [PubMed (2209 articles), Scopus (1154 articles), and Science Direct (1040 articles)] were researched. After applying the eligibility criteria, articles were selected for peer review, independently, as they were identified by September 2021. The protocol for this systematic review was registered in the PROSPERO. Of the 4417 articles found, 16 were selected for this systematic review. In the brain, EE promoted a reduction in proinflammatory cytokines and chemokines. In the blood, EE promoted a higher percentage of leukocytes, an increase in CD19+ B lymphocytes, and the proliferation of Natura Killer (NK cells). In the bone marrow, there was an increase in the number of CD27- and CD11b+ mature NK cells and a reduction in CD27- and CD11b+ immature Natural Killer cells. In conclusion, EE can be an immune modulation approach and plays a key role in the prevention of numerous chronic diseases, including cancer, that have a pro-inflammatory response and immunosuppressive condition as part of their pathophysiology.

Increased lacrimal inflammatory mediators in patients with keratoconus.

Purpose: This study aimed to characterize the tear film immunologic profile in keratoconus (KC) patients compared with healthy individuals (control group) and to investigate the correlation between the tear film immunologic profile and atopy, disease severity, and disease status over time. Methods: The study involved 30 KC patients and 18 healthy individuals. Tear collection was obtained using microcapillary tubes. Tear film levels of fractalkine, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ, interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17A, IL-21, IL-23, interferon-inducible T-cell alpha chemoattractant (ITAC), macrophage inflammatory protein-1 alpha (MIP-1α), MIP-1ß, MIP-3α, and tumor necrosis factor (TNF)-α were detected. Keratometric measurements and topographic patterns were used to diagnose and define disease progression. Tear immunologic profiles were compared, emphasizing the presence or absence of ocular allergy. Correlations between the cytokine profile, disease severity, and disease status were also analyzed longitudinally in the KC patients. Results: Lacrimal cytokine concentrations were higher in the KC patients than they were in the controls in 14 of 21 cytokines analyzed. IL-6 was the most relevant cytokine found in KC patients, especially when associated with ocular allergy. There was no correlation between KC progression and the level of inflammatory cytokines when analyzed longitudinally. KC severity correlated with IL-6 concentration, where the more severe KC presented a higher IL-6 concentration in tears. Conclusions: Inflammatory activity seems to be involved in the pathogenesis of KC. Out of 21 cytokines, 14 were more concentrated in the tears of KC patients than healthy subjects. IL-6 was significantly higher in KC patients' tears and was related to disease severity. Disease progression did not correlate with cytokine levels when analyzed longitudinally.

Distinct macrophage phenotypes and redox environment during the fin fold regenerative process in zebrafish.

In contrast to mammals, zebrafish (Danio rerio) has the ability to regenerate injured sites such as different tissues present in the fin. It is known that cells of the innate immune system play essential roles in regeneration; however, some aspects of the molecular mechanisms by which these cells orchestrate regeneration remain unknown. This study aimed to evaluate the infiltration dynamics of neutrophils and macrophages in the regenerative process of fin fold in regard to the influence of the redox environment and oxidative pathways. Fin fold amputation was performed on transgenic larvae for macrophage-expressed gene 1 (mpeg1), lysozyme (lyz), myeloperoxidase (mpo) and tumour necrosis factor alpha (TNFα) at 3 days post-fertilization, followed by confocal microscopy imaging and measurement of the activities of oxidant and antioxidant enzymes. We observed initially an increase in the number of neutrophils (lyz:DsRed+/mpx:GFP+) and then macrophages (mpeg1+) in the injury site followed by a decrease in neutrophils at 7 days post-amputation (dpa). Moreover, macrophages switch from a pro-inflammatory to an anti-inflammatory profile throughout the process, while the activity of superoxide dismutase (SOD) increased at 1 dpa and catalase (CAT) at 5 dpa. Higher levels of lipid peroxidation were also detected during regeneration. Despite oxidative stress, there is, therefore, an antioxidant response throughout the regeneration of the caudal fin. The present work can contribute to future studies on the development of cell therapies, achieving greater effectiveness in the treatment of diseases related to the formation of fibrotic tissue.

Inflammatory effect of Bothropstoxin-I from Bothrops jararacussu venom mediated by NLRP3 inflammasome involves ATP and P2X7 receptor.

Muscle tissue damage is one of the local effects described in bothropic envenomations. Bothropstoxin-I (BthTX-I), from Bothrops jararacussu venom, is a K49-phospholipase A2 (PLA2) that induces a massive muscle tissue injury, and, consequently, local inflammatory reaction. The NLRP3 inflammasome is a sensor that triggers inflammation by activating caspase 1 and releasing interleukin (IL)-1ß and/or inducing pyroptotic cell death in response to tissue damage. We, therefore, aimed to address activation of NLRP3 inflammasome by BthTX-I-associated injury and the mechanism involved in this process. Intramuscular injection of BthTX-I results in infiltration of neutrophils and macrophages in gastrocnemius muscle, which is reduced in NLRP3- and Caspase-1-deficient mice. The in vitro IL-1ß production induced by BthTX-I in peritoneal macrophages (PMs) requires caspase 1/11, ASC and NLRP3 and is dependent on adenosine 5'-triphosphate (ATP)-induced K+ efflux and P2X7 receptor (P2X7R). BthTX-I induces a dramatic release of ATP from C2C12 myotubes, therefore representing the major mechanism for P2X7R-dependent inflammasome activation in macrophages. A similar result was obtained when human monocyte-derived macrophages (HMDMs) were treated with BthTX-I. These findings demonstrated the inflammatory effect of BthTX-I on muscle tissue, pointing out a role for the ATP released by damaged cells for the NLRP3 activation on macrophages, contributing to the understanding of the microenvironment of the tissue damage of the Bothrops envenomation.

Macrophage inflammatory state in Type 1 diabetes: triggered by NLRP3/iNOS pathway and attenuated by docosahexaenoic acid.

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by insulin-producing pancreatic ß-cell destruction and hyperglycemia. While monocytes and NOD-like receptor family-pyrin domain containing 3 (NLRP3) are associated with T1D onset and development, the specific receptors and factors involved in NLRP3 inflammasome activation remain unknown. Herein, we evaluated the inflammatory state of resident peritoneal macrophages (PMs) from genetically modified non-obese diabetic (NOD), NLRP3-KO, wild-type (WT) mice and in peripheral blood mononuclear cells (PBMCs) from human T1D patients. We also assessed the effect of docosahexaenoic acid (DHA) on the inflammatory status. Macrophages from STZ-induced T1D mice exhibited increased inflammatory cytokine/chemokine levels, nitric oxide (NO) secretion, NLRP3 and iNOS protein levels, and augmented glycolytic activity compared to control animals. In PMs from NOD and STZ-induced T1D mice, DHA reduced NO production and attenuated the inflammatory state. Furthermore, iNOS and IL-1ß protein expression levels and NO production were lower in the PMs from diabetic NLRP3-KO mice than from WT mice. We also observed increased IL-1ß secretion in PBMCs from T1D patients and immortalized murine macrophages treated with advanced glycation end products and palmitic acid. The present study demonstrated that the resident PMs are in a proinflammatory state characterized by increased NLRP3/iNOS pathway-mediated NO production, up-regulated proinflammatory cytokine/chemokine receptor expression and altered glycolytic activity. Notably, ex vivo treatment with DHA reverted the diabetes-induced changes and attenuated the macrophage inflammatory state. It is plausible that DHA supplementation could be employed as adjuvant therapy for treating individuals with T1D.

Interleukin-6 and the Gut Microbiota Influence Melanoma Progression in Obese Mice.

There is a strong correlation between obesity and cancer. Here, we investigated the influence of IL-6 and gut microbiota of obese mice in melanoma development. We first evaluated B16F10 melanoma growth in preclinical models for obesity: mice deficient for leptin (ob/ob) or adiponectin (AdpKO) and in wild-type mice (WT, C57BL/6J) fed a high-fat diet (HFD; 60% kcal from fat) for 12 weeks. The survival rates of ob/ob and HFD-fed mice were lower than those of their respective controls. AdpKO mice also died earlier than WT control mice. We then verified the involvement of IL-6 signaling in obese mice that were inoculated with melanoma cells. Both ob/ob and AdpKO mice had higher circulating IL-6 levels than wild-type mice. Melanoma tumor volumes in IL-6 KO mice fed an HFD were reduced compared to those of WT mice subjected to the same diet. Also evaluated the effect of microbiota in tumor development. Cohousing and fecal matter transfer experiments revealed that microbiota from ob/ob mice can stimulate tumor development in lean WT mice. Taken together, our data show that in some conditions IL-6 and the gut microbiota are key mediators that link obesity and melanoma.

Chronic exposure to PM2.5 aggravates SLE manifestations in lupus-prone mice.

BACKGROUND: Air pollution causes negative impacts on health. Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations and multifactorial etiology. Recent studies suggest that air pollution can trigger SLE and induce disease activity. However, this association has not been deeply investigated. Thus, the aim of this study was to evaluate whether exposure to fine particulate matter (PM2.5) exacerbates SLE manifestations, focusing on renal complications, in a lupus-prone animal model. Female NZBWF1 mice were exposed daily to 600 µg/m3 of inhaled concentrated ambient particles (CAP) or filtered air (FA). Survival rate, body weight, weight of organs (kidney, spleen, thymus, liver and heart), blood cell count, proteinuria, kidney stereology, renal histopathology, gene expression and oxidative stress were analyzed. RESULTS: Female NZBW mice exposed to CAP showed decreased survival, increased circulating neutrophils, early onset of proteinuria and increased kidney weight with renal cortex enlargement when compared to NZBW mice exposed to FA. CONCLUSIONS: This work shows that air pollution aggravates some SLE manifestations in lupus-prone mice. These results reinforce the need of reducing air pollutant levels in order to promote a better quality of life for individuals diagnosed with SLE.

Renal lipotoxicity: Insights from experimental models.

In recent decades, there has been a progressive increase in the prevalence of obesity and chronic kidney disease. Renal lipotoxicity has been associated with obesity. Although lipids play fundamental physiological roles, the accumulation of lipids in kidney cells may cause dysfunction and/or renal fibrosis. Adipose tissue that exceeds their lipid storage capacity begins to release triglycerides into the bloodstream that can get stored in several organs, including the kidneys. The mechanisms underlying renal lipotoxicity involve intracellular lipid accumulation and organelle dysfunction, which trigger oxidative stress and inflammation that consequently result in insulin resistance and albuminuria. However, the specific pathways involved in renal lipotoxicity have not yet been fully understood. We aimed to summarize the current knowledge on the mechanisms by which lipotoxicity affects the renal morphology and function in experimental models of obesity. The accumulation of fatty acids in tubular cells has been described as the main mechanism of lipotoxicity; however, lipids and their metabolism also affect the function and the survival of podocytes. In this review, we presented indication of mitochondrial, lysosomal and endoplasmic reticulum alterations involved in kidney damage caused by obesity. The kidney is vulnerable to lipotoxicity, and studies of the mechanisms underlying renal injury caused by obesity can help identify therapeutic targets to control renal dysfunction.

Carbon monoxide protects the kidney through the central circadian clock and CD39.

Ischemia reperfusion injury (IRI) is the predominant tissue insult associated with organ transplantation. Treatment with carbon monoxide (CO) modulates the innate immune response associated with IRI and accelerates tissue recovery. The mechanism has been primarily descriptive and ascribed to the ability of CO to influence inflammation, cell death, and repair. In a model of bilateral kidney IRI in mice, we elucidate an intricate relationship between CO and purinergic signaling involving increased CD39 ectonucleotidase expression, decreased expression of Adora1, with concomitant increased expression of Adora2a/2b. This response is linked to a >20-fold increase in expression of the circadian rhythm protein Period 2 (Per2) and a fivefold increase in serum erythropoietin (EPO), both of which contribute to abrogation of kidney IRI. CO is ineffective against IRI in Cd39-/- and Per2-/- mice or in the presence of a neutralizing antibody to EPO. Collectively, these data elucidate a cellular signaling mechanism whereby CO modulates purinergic responses and circadian rhythm to protect against injury. Moreover, these effects involve CD39- and adenosinergic-dependent stabilization of Per2. As CO also increases serum EPO levels in human volunteers, these findings continue to support therapeutic use of CO to treat IRI in association with organ transplantation, stroke, and myocardial infarction.

New perspectives on natural flavonoids on COVID-19-induced lung injuries.

The SARS-CoV-2 virus, responsible for COVID-19, spread rapidly worldwide and became a pandemic in 2020. In some patients, the virus remains in the respiratory tract, causing pneumonia, respiratory failure, acute respiratory distress syndrome (ARDS), and sepsis, leading to death. Natural flavonoids (aglycone and glycosides) possess broad biological activities encompassing antiinflammatory, antiviral, antitumoral, antiallergic, antiplatelet, and antioxidant effects. While many studies have focused on the effects of natural flavonoids in experimental models, reports based on clinical trials are still insufficient. In this review, we highlight the effects of flavonoids in controlling pulmonary diseases, particularly the acute respiratory distress syndrome, a consequence of COVID-19, and their potential use in coronavirus-related diseases. Furthermore, we also focus on establishing a relationship between biological potential and chemical aspects of related flavonoids and discuss several possible mechanisms of action, pointing out some possible effects on COVID-19.