Neutrophil-macrophage communication via extracellular vesicle transfer promotes itaconate accumulation and ameliorates cytokine storm syndrome.

Cytokine storm syndrome (CSS) is a life-threatening systemic inflammatory syndrome involving innate immune hyperactivity triggered by various therapies, infections, and autoimmune conditions. However, the potential interplay between innate immune cells is not fully understood. Here, using poly I:C and lipopolysaccharide (LPS)-induced cytokine storm models, a protective role of neutrophils through the modulation of macrophage activation was identified in a CSS model. Intravital imaging revealed neutrophil-derived extracellular vesicles (NDEVs) in the liver and spleen, which were captured by macrophages. NDEVs suppressed proinflammatory cytokine production by macrophages when cocultured in vitro or infused into CSS models. Metabolic profiling of macrophages treated with NDEV revealed elevated levels of the anti-inflammatory metabolite, itaconate, which is produced from cis-aconitate in the Krebs cycle by cis-aconitate decarboxylase (Acod1, encoded by Irg1). Irg1 in macrophages, but not in neutrophils, was critical for the NDEV-mediated anti-inflammatory effects. Mechanistically, NDEVs delivered miR-27a-3p, which suppressed the expression of Suclg1, the gene encoding the enzyme that metabolizes itaconate, thereby resulting in the accumulation of itaconate in macrophages. These findings demonstrated that neutrophil-to-macrophage communication mediated by extracellular vesicles is critical for promoting the anti-inflammatory reprogramming of macrophages in CSS and may have potential implications for the treatment of this fatal condition.

Cytokine Storm Related to CD4+ T Cells in Influenza Virus-Associated Acute Necrotizing Encephalopathy.

Acute necrotizing encephalopathy (ANE) is a rare but deadly complication with an unclear pathogenesis. We aimed to elucidate the immune characteristics of H1N1 influenza virus-associated ANE (IANE) and provide a potential therapeutic approach for IANE. Seven pediatric cases from a concentrated outbreak of H1N1 influenza were included in this study. The patients' CD4+ T cells from peripheral blood decreased sharply in number but highly expressed Eomesodermin (Eomes), CD69 and PD-1, companied with extremely high levels of IL-6, IL-8 in the cerebrospinal fluid and plasma. Patient 2, who showed high fever and seizures and was admitted to the hospital very early in the disease course, received intravenous tocilizumab and subsequently showed a reduction in temperature and a stable conscious state 24 h later. In conclusion, a proinflammatory cytokine storm associated with activated CD4+ T cells may cause severe brain pathology in IANE. Tocilizumab may be helpful in treating IANE.

High-Dose Colchicine: Key Factor in the Treatment of Morbidly Obese COVID-19 Patients.

Colchicine has long been known to possess anti-inflammatory effects by inhibiting microtubules, activation and migration of neutrophils, and most importantly, the inflammasome complex found in neutrophils and monocytes. Due to these properties, a number of clinical trials have tested the therapeutic effect of colchicine in COVID-19 patients. One common feature of these studies, however, is the low therapeutic dose used, which may explain the conflicting and disappointing results. Colchicine has the unique property of accumulating in leukocytes, which are primarily responsible for the hyperactivation of the NLRP3 inflammasome and the cytokine storm. The low-dose colchicine used to treat COVID-19 is not sufficient to reach the necessary intracellular concentration for NLRP3 inflammasome inhibition. We have reported our experience with high-dose colchicine, within the approved therapeutic range, in both ambulatory and hospitalized patients, and have shown dramatic cure rates. Here, we present our observation of an excellent therapeutic effect of high-dose colchicine in morbidly obese COVID-19 patients who are at the highest morbidity and mortality risk.

Ruxolitinib plus standard of care in severe hospitalized adults with severe fever with thrombocytopenia syndrome (SFTS): an exploratory, single-arm trial.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease, and its morbidity and mortality are increasing. At present, there is no specific therapy available. An exacerbated IFN-I response and cytokine storm are related to the mortality of patients with SFTS. Ruxolitinib is a Janus kinase (JAK) 1/2 inhibitor that can block proinflammatory cytokines and inhibit the type I IFN pathway. We aimed to explore the use of ruxolitinib plus standard of care for severe SFTS. METHODS: We conducted a prospective, single-arm study of severe SFTS. We recruited participants aged 18 years or older who were admitted to the hospital with laboratory-confirmed severe SFTS and whose clinical score exceeded 8 points within 6 days of symptom onset. Participants received oral ruxolitinib (10 mg twice a day) for up to 10 days. The primary endpoint was 28-day overall survival. The secondary endpoints included the proportion of participants who needed intensive care unit (ICU) admission, total cost, changes in neurologic symptoms and clinical laboratory parameters, and adverse events (AEs) within 28 days. A historical control group (HC group, n = 26) who met the upper criteria for inclusion and hospitalized from April 1, 2021, to September 16, 2022, was selected and 1:1 matched for baseline characteristics by propensity score matching. RESULTS: Between Sep 16, 2022, and Sep 16, 2023, 26 participants were recruited into the ruxolitinib treatment group (RUX group). The 28-day overall mortality was 7.7% in the RUX group and 46.2% in the HC group (P = 0.0017). There was a significantly lower proportion of ICU admissions (15.4% vs 65.4%, p < 0.001) and total hospitalization cost in the RUX group. Substantial improvements in neurologic symptoms, platelet counts, hyperferritinemia, and an absolute decrease in the serum SFTS viral load were observed in all surviving participants. Treatment-related adverse events were developed in 6 patients (23.2%) and worsened in 8 patients (30.8%), and no treatment-related serious adverse events were reported. CONCLUSIONS: Our findings indicate that ruxolitinib has the potential to increase the likelihood of survival as well as reduce the proportion of ICU hospitalization and being tolerated in severe SFTS. Further trials are needed. TRAIL REGISTRATION: ChiCTR2200063759, September 16, 2022.

Frontiers and hotspots evolution in cytokine storm: A bibliometric analysis from 2004 to 2022.

Background: As a fatal disease, cytokine storm has garnered research attention in recent years. Nonetheless, as the body of related studies expands, a thorough and impartial evaluation of the current status of research on cytokine storms remains absent. Consequently, this study aimed to thoroughly explore the research landscape and evolution of cytokine storm utilizing bibliometric and knowledge graph approaches. Methods: Research articles and reviews centered on cytokine storms were retrieved from the Web of Science Core Collection database. For bibliometric analysis, tools such as Excel 365, CiteSpace, VOSviewer, and the Bibliometrix R package were utilized. Results: This bibliometric analysis encompassed 6647 articles published between 2004 and 2022. The quantity of pertinent articles and citation frequency exhibited a yearly upward trend, with a sharp increase starting in 2020. Network analysis of collaborations reveals that the United States holds a dominant position in this area, boasting the largest publication count and leading institutions. Frontiers in Immunology ranks as the leading journal for the largest publication count in this area. Stephan A. Grupp, a prominent researcher in this area, has authored the largest publication count and has the second-highest citation frequency. Research trends and keyword evaluations show that the connection between cytokine storm and COVID-19, as well as cytokine storm treatment, are hot topics in research. Furthermore, research on cytokine storm and COVID-19 sits at the forefront in this area. Conclusion: This study employed bibliometric analysis to create a visual representation of cytokine storm research, revealing current trends and burgeoning topics in this area for the first time. It will provide valuable insights, helping scholars pinpoint critical research areas and potential collaborators.

The NLRP3 inflammasome is essential for IL-18 production in a model of macrophage activation syndrome.

Hyperinflammatory disease is associated with an aberrant immune response resulting in cytokine storm. One such instance of hyperinflammatory disease is known as macrophage activation syndrome (MAS). The pathology of MAS can be characterised by significantly elevated serum levels of interleukin (IL)-18 and interferon (IFN)-γ. Given the role for IL-18 in MAS, we sought to establish the role of inflammasomes in the disease process. Using a murine model of CpG-DNA induced MAS, we discovered that the expression of the NLRP3 inflammasome was increased and correlated with IL-18 production. Inhibition of the NLRP3 inflammasome, or downstream caspase-1, prevented MAS-mediated upregulation of plasma IL-18 but interestingly did not alleviate key features of hyperinflammatory disease including hyperferritinaemia and splenomegaly. Furthermore IL-1 receptor blockade with IL-1Ra did not prevent the development of CpG-induced MAS, despite being clinically effective in the treatment of MAS. These data demonstrate that in the development of MAS, the NLRP3 inflammasome was essential for the elevation in plasma IL-18, a key cytokine in clinical cases of MAS, but was not a driving factor in the pathogenesis of CpG-induced MAS.

The critical impacts of cytokine storms in respiratory disorders.

Cytokine storm (CS) refers to the spontaneous dysregulated and hyper-activated inflammatory reaction occurring in various clinical conditions, ranging from microbial infection to end-stage organ failure. Recently the novel coronavirus involved in COVID-19 (Coronavirus disease-19) caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) has been associated with the pathological phenomenon of CS in critically ill patients. Furthermore, critically ill patients suffering from CS are likely to have a grave prognosis and a higher case fatality rate. Pathologically CS is manifested as hyper-immune activation and is clinically manifested as multiple organ failure. An in-depth understanding of the etiology of CS will enable the discovery of not just disease risk factors of CS but also therapeutic approaches to modulate the immune response and improve outcomes in patients with respiratory diseases having CS in the pathogenic pathway. Owing to the grave consequences of CS in various diseases, this phenomenon has attracted the attention of researchers and clinicians throughout the globe. So in the present manuscript, we have attempted to discuss CS and its ramifications in COVID-19 and other respiratory diseases, as well as prospective treatment approaches and biomarkers of the cytokine storm. Furthermore, we have attempted to provide in-depth insight into CS from both a prophylactic and therapeutic point of view. In addition, we have included recent findings of CS in respiratory diseases reported from different parts of the world, which are based on expert opinion, clinical case-control research, experimental research, and a case-controlled cohort approach.

Mesenchymal stem cells and their derived exosomes for the treatment of COVID-19.

Coronavirus disease 2019 (COVID-19) is an acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection typically presents with fever and respiratory symptoms, which can progress to severe respiratory distress syndrome and multiple organ failure. In severe cases, these complications may even lead to death. One of the causes of COVID-19 deaths is the cytokine storm caused by an overactive immune response. Therefore, suppressing the overactive immune response may be an effective strategy for treating COVID-19. Mesenchymal stem cells (MSCs) and their derived exosomes (MSCs-Exo) have potent homing abilities, immunomodulatory functions, regenerative repair, and antifibrotic effects, promising an effective tool in treating COVID-19. In this paper, we review the main mechanisms and potential roles of MSCs and MSCs-Exo in treating COVID-19. We also summarize relevant recent clinical trials, including the source of cells, the dosage and the efficacy, and the clinical value and problems in this field, providing more theoretical references for the clinical use of MSCs and MSCs-Exo in the treatment of COVID-19.

Does your unwell patient have haemophagocytic lymphohistiocytosis?

Haemophagocytic lymphohistiocytosis is a severe systemic hyperinflammatory syndrome characterised by dysregulation of immune cells and excessive production of cytokines, also known as a cytokine storm. It has distinctive clinical features with fever, hyperferritinaemia and falling blood counts. In adults, this usually occurs secondary to an underlying driver or trigger including infection, malignancy or rheumatic diseases. Prompt treatment with immunomodulatory therapy, including corticosteroids and the recombinant IL-1 receptor antagonist anakinra, is recommended to switch off the cytokine storm. Etoposide-based regimens are sometimes needed, and newer therapies such as emapalumab and JAK inhibitors are increasingly being used. The incidence of haemophagocytic lymphohistiocytosis has increased significantly over the last 20 years which may partly reflect increased awareness of the condition. Although relatively rare, haemophagocytic lymphohistiocytosis can be encountered by a broad range of hospital physicians, so knowing how to diagnose and treat this condition is essential. This article reviews the pathogenesis, clinical features, causes, diagnosis and treatment of haemophagocytic lymphohistiocytosis to improve physician recognition and management of this condition to improve future patient outcomes.

Immunomodulating Phytochemicals: An Insight Into Their Potential Use in Cytokine Storm Situations.

Phytochemicals are compounds found in plants that possess a variety of bioactive properties, including antioxidant and immunomodulatory properties. Recent studies have highlighted the potential of phytochemicals in targeting specific signalling pathways involved in cytokine storm, a life-threatening clinical condition resulting from excessive immune cell activation and oversupply of proinflammatory cytokines. Several studies have documented the immunomodulatory effects of phytochemicals on immune function, including their ability to regulate essential cellular and molecular interactions of immune system cells. This makes them a promising alternative for cytokine storm management, especially when combined with existing chemotherapies. Furthermore, phytochemicals have been found to target multiple signalling pathways, including the TNF-α/NF-κB, IL-1/NF-κB, IFN-γ/JAK/STAT, and IL-6/JAK-STAT. These pathways play critical roles in the development and progression of cytokine storm, and targeting them with phytochemicals represents a promising strategy for controlling cytokine release and the subsequent inflammation. Studies have also investigated certain families of plant-related constituents and their potential immunomodulatory actions. In vivo and in vitro studies have reported the immunomodulatory effects of phytochemicals, which provide viable alternatives in the management of cytokine storm syndrome. The collective data from previous studies suggest that phytochemicals represent a potentially functional source of cytokine storm treatment and promote further exploration of these compounds as immunomodulatory agents for suppressing specific signalling cascade responses. Overall, the previous research findings support the use of phytochemicals as a complementary approach in managing cytokine storm and improving patient outcomes.

The Scutellaria-Coptis herb couple and its active small-molecule ingredient wogonoside alleviate cytokine storm by regulating the CD39/NLRP3/GSDMD signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: A drug pair is a fundamental aspect of traditional Chinese medicine prescriptions. Scutellaria baicalensis Georgi and Coptis chinensis Franch, commonly used as an herb couple (SBCC), are representative heat-clearing and dampness-drying drugs. They possess functions such as clearing heat, drying dampness, purging fire, and detoxifying. These herbs are used in both traditional and modern medicine for treating inflammation. AIM OF THE STUDY: This study investigated the effects of SBCC on cytokine storm syndrome (CSS) and explored its potential regulatory mechanism. MATERIALS AND METHODS: We assessed the impact of SBCC in a sepsis-induced acute lung injury mouse model by administering an intraperitoneal injection of LPS (15 mg/kg). The cytokine levels in the serum and lungs, the wet-to-dry ratio of the lungs, and lung histopathological changes were evaluated. The macrophages in the lung tissue were examined through transmission electron microscopy. Western blot was used to measure the levels of the CD39/NLRP3/GSDMD pathway-related proteins. Immunofluorescence imaging was used to assess the activation of pro-caspase-1 and ASC and their interaction. AMP-Glo™ assay was used to screen for active ingredients in SBCC targeting CD39. One of the ingredients was selected, and its effect on cell viability was assessed. We induced inflammation in macrophages using LPS + ATP and detected the levels of proinflammatory factors. The images of cell membrane large pores were captured using scanning electron microscopy, the interaction between NLRP3 and ASC was detected using immunofluorescence imaging, and the levels of CD39/NLRP3/GSDMD pathway-related proteins were assessed using Western blot. RESULTS: SBCC administration effectively mitigated LPS-induced cytokine storm, pulmonary edema and lung injury. Furthermore, it repressed the programmed death of lung tissue macrophages by inhibiting the NLRP3/GSDMD pyroptosis pathway and regulating the CD39 purinergic pathway. Based on the results of the AMP-Glo™ assay, we selected wogonoside for further valuation. Wogonoside alleviated LPS + ATP-induced inflammatory damage by regulating the inhibiting the NLRP3/GSDMD pyroptosis pathway and regulating the CD39 purinergic pathway. However, its effect on NLRP3 is not mediated though CD39. CONCLUSION: SBCC and its active small-molecule ingredient, wogonoside, improved CSS by regulating the NLRP3/GSDMD pyroptosis pathway and its upstream CD39 purinergic pathway. It is essential to note that the regulatory effect of wogonoside on NLRP3 is not mediated by CD39.

Inhibitory effect of food-functioned phytochemicals on dysregulated inflammatory pathways triggered by SARS-CoV-2: a mechanistic review.

Inflammatory cascades of the dysregulated inflammatory pathways in COVID-19 can cause excessive production of pro-inflammatory cytokines and chemokines leading to cytokine storm syndrome (CSS). The molecular cascades involved in the pathways may be targeted for discovery of new anti-inflammatory agents. Many plant extracts have been used clinically in the management of COVID-19, however, their immunosuppressive activities were mainly investigated based on in silico activity. Dietary flavonoids of the extracts such as quercetin, luteolin, kaempferol, naringenin, isorhamnetin, baicalein, wogonin, and rutin were commonly identified as responsible for their inhibitory effects. The present review critically analyzes the anti-inflammatory effects and mechanisms of phytochemicals, including dietary compounds against cytokine storm (CS) and hyperinflammation via inhibition of the altered inflammatory pathways triggered by SARS-CoV-2, published since the emergence of COVID-19 in December 2019. Only a few phytochemicals, mainly dietary compounds such as nanocurcumin, melatonin, quercetin, 6-shagoal, kaempferol, resveratrol, andrographolide, and colchicine have been investigated either in in silico or preliminary clinical studies to evaluate their anti-inflammatory effects against COVID-19. Sufficient pre-clinical studies on safety and efficacy of anti-inflammatory effects of the phytochemicals must be performed prior to proper clinical studies to develop them into therapeutic adjuvants in the prevention and treatmemt of COVID-19 symptoms.

L-AP Alleviates Liver Injury in Septic Mice by Inhibiting Macrophage Activation via Suppressing NF-κB and NLRP3 Inflammasome/Caspase-1 Signal Pathways.

Liver injury and progressive liver failure are severe life-threatening complications in sepsis, further worsening the disease and leading to death. Macrophages and their mediated inflammatory cytokine storm are critical regulators in the occurrence and progression of liver injury in sepsis, for which effective treatments are still lacking. l-Ascorbic acid 6-palmitate (L-AP), a food additive, can inhibit neuroinflammation by modulating the phenotype of the microglia, but its pharmacological action in septic liver damage has not been fully explored. We aimed to investigate L-AP's antisepticemia action and the possible pharmacological mechanisms in attenuating septic liver damage by modulating macrophage function. We observed that L-AP treatment significantly increased survival in cecal ligation and puncture-induced WT mice and attenuated hepatic inflammatory injury, including the histopathology of the liver tissues, hepatocyte apoptosis, and the liver enzyme levels in plasma, which were comparable to NLRP3-deficiency in septic mice. L-AP supplementation significantly attenuated the excessive inflammatory response in hepatic tissues of septic mice in vivo and in cultured macrophages challenged by both LPS and ATP in vitro, by reducing the levels of NLRP3, pro-IL-1ß, and pro-IL-18 mRNA expression, as well as the levels of proteins for p-I-κB-α, p-NF-κB-p65, NLRP3, cleaved-caspase-1, IL-1ß, and IL-18. Additionally, it impaired the inflammasome ASC spot activation and reduced the inflammatory factor contents, including IL-1ß and IL-18 in plasma/cultured superannuants. It also prevented the infiltration/migration of macrophages and their M1-like inflammatory polarization while improving their M2-like polarization. Overall, our findings revealed that L-AP protected against sepsis by reducing macrophage activation and inflammatory cytokine production by suppressing their activation in NF-κB and NLRP3 inflammasome signal pathways in septic liver.

Current remarks and future directions on the interactions between metabolic dysfunction-associated fatty liver disease and COVID-19.

During the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, particular interest rose regarding the interaction between metabolic dysfunction-associated fatty liver disease (MAFLD) and the COVID-19 infection. Several studies highlighted the fact that individuals with MAFLD had higher probability of severe acute respiratory syndrome coronavirus 2 infection and more severe adverse clinical outcomes. One of the proposed mechanisms is the inflammatory response pathway, especially the one involving cytokines, such as interleukin 6, which appeared particularly elevated in those patients and was deemed responsible for additional insult to the already damaged liver. This should increase our vigilance in terms of early detection, close follow up and early treatment for individuals with MAFLD and COVID-19 infection. In the direction of early diagnosis, biomarkers such as cytokeratin-18 and scoring systems such as Fibrosis-4 index score are proposed. COVID-19 is a newly described entity, expected to be of concern for the years to come, and MAFLD is a condition with an ever-increasing impact. Delineating the interaction between these two entities should be brought into the focus of research. Reducing morbidity and mortality of patients with COVID-19 and MAFLD should be the ultimate objective, and the optimal way to achieve this is by designing evidence-based prevention and treatment policies.

Cytokine storm in Chikungunya: Can we call it multisystem inflammatory syndrome associated with Chikungunya?

Paraguay is currently facing a new outbreak of Chikungunya virus. This report summarizes two severe cases of Chikungunya (CHIKV) infection, confirmed by real-time reverse transcription polymerase chain reaction. We present the cases of patients with acute CHIKV infection and multisystem involvement, with fever, rash, abdominal pain, vomiting, myocarditis, and coronary artery anomalies, very similar to the cases described in MIS-C related to SARS-CoV-2 during the COVID-19 Pandemic. Both patients received IVIG and methylprednisolone, with good clinical response. In this setting of cytokine storm in Chikungunya, can we call it "Multisystem inflammatory syndrome associated with Chikungunya"?.

Ruxolitinib-loaded cytokine nanosponge alleviated the cytokine storm and dampened macrophage overactivation for the treatment of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome characterized by a positive feedback loop between cytokine storm and macrophages and lymphocytes overactivation, which could serve as a valid therapeutic target for HLH treatment. In this study, the clinically extensively used JAK1/2 inhibitor ruxolitinib was encapsulated into macrophage membrane-coated nanoparticles (M@NP-R) with high drug-loading efficiency for targeted HLH treatment. In vitro and in vivo studies demonstrated that M@NP-R not only efficiently adsorbed extracellular proinflammation cytokines, like IFN-γ and IL-6 to alleviate the cytokine storm, but also effectively dampened macrophage activation and proliferation by intracellular JAK/STAT signaling pathway inhibition. M@NP-R treatment significantly ameliorated the clinical and laboratory manifestations of HLH in mouse models, including trilineage cytopenia, hypercytokinemia, organomegaly, hepatorenal dysfunction, and tissue inflammation. Importantly, M@NP-R significantly enhanced the survival of the lethal HLH mice. Altogether, M@NP-R successfully blocked the positive feedback loop between the cytokine storm and macrophage overactivation by depleting extracellular inflammatory cytokines and inhibiting the intracellular JAK/STAT signaling pathway, both of which worked synergistically in HLH treatment. As ruxolitinib has already been extensively used in clinics with favorable safety, and M@NP is biodegradable and highly biocompatible, M@NP-R has good prospects for clinical translation.

A case report and literature review on tocilizumab-cured acute necrotizing encephalopathy caused by influenza A virus.

Introduction: Acute Necrotizing Encephalopathy (ANE), is a kind of severe Central Nervous System Disease. The commonest pathogen is the influenza virus. The pathogenesis of ANE is bound up to genetic susceptibility and cytokine storm. Interleukin-6 (IL-6) is deemed as the core function in cytokine storm of ANE and that plays a significant role in evaluating the severity of Influenza-Related ANE. Tocilizumab, an IL-6 antagonist, is known to be safe and effective in the treatment of ANE when used early and has an essential role in improving prognosis and preventing disability. Case report: This case reports a 2 year 10 month old boy who developed ANE after being infected with influenza A virus (H1N1-2019). After treatment with Tocilizumab, the child's consciousness was clear, no convulsions occurred, the movement of limbs was improved, and the lesions of encephalopathy were significantly reduced. Conclusion: The early use of Tocilizumab is safe and effective for the treatment of ANE caused by influenza virus.

Pasteurella multocida activates apoptosis via the FAK-AKT-FOXO1 axis to cause pulmonary integrity loss, bacteremia, and eventually a cytokine storm.

Pasteurella multocida is an important zoonotic respiratory pathogen capable of infecting a diverse range of hosts, including humans, farm animals, and wild animals. However, the precise mechanisms by which P. multocida compromises the pulmonary integrity of mammals and subsequently induces systemic infection remain largely unexplored. In this study, based on mouse and rabbit models, we found that P. multocida causes not only lung damage but also bacteremia due to the loss of lung integrity. Furthermore, we demonstrated that bacteremia is an important aspect of P. multocida pathogenesis, as evidenced by the observed multiorgan damage and systemic inflammation, and ultimately found that this systemic infection leads to a cytokine storm that can be mitigated by IL-6-neutralizing antibodies. As a result, we divided the pathogenesis of P. multocida into two phases: the pulmonary infection phase and the systemic infection phase. Based on unbiased RNA-seq data, we discovered that P. multocida-induced apoptosis leads to the loss of pulmonary epithelial integrity. These findings have been validated in both TC-1 murine lung epithelial cells and the lungs of model mice. Conversely, the administration of Ac-DEVD-CHO, an apoptosis inhibitor, effectively restored pulmonary epithelial integrity, significantly mitigated lung damage, inhibited bacteremia, attenuated the cytokine storm, and reduced mortality in mouse models. At the molecular level, we demonstrated that the FAK-AKT-FOXO1 axis is involved in P. multocida-induced lung epithelial cell apoptosis in both cells and animals. Thus, our research provides crucial information with regard to the pathogenesis of P. multocida as well as potential treatment options for this and other respiratory bacterial diseases.

A curious Takotsubo cardiomyopathy after COVID-19.

We present the case of a 66-year-old woman undergoing chronic dialysis who developed pneumonia and enteritis after being infected with COVID-19 and had severe wall motion reduction similar to a left ventricular aneurysm. There was concern that the condition might worsen due to left ventricular wall thinning and curious wall motion abnormalities, but echocardiography one month later showed normalization. After four months, simultaneous binuclear myocardial scintigraphy of thallium and BMIPP showed that the mismatch had disappeared. We considered that there may be other factors specific to COVID-19 infection in addition to the stress associated with infection and reviewed the literature.

Potential Anti-Inflammatory and Anti-Fatigue Effects of an Oral Food Supplement in Long COVID Patients.

Long coronavirus disease (COVID) syndrome leads to chronic inflammatory state onset that can have a multisystem impact and compromise organ function. Moreover, long COVID syndrome is often characterized by the presence of chronic fatigue, which affects subjects' daily activities and worsens their quality of life. The aim of our double-blind, placebo-controlled randomized trial (protocol code RS 150.21, approved on 4 November 2021) was to evaluate the beneficial effects of the consumption of 2 cps/day, for two months, of an oral food supplement (OFS), based on Echinacea angustifolia, rosehip, propolis, royal jelly and zinc, in long COVID patients, compared to a two-month placebo period. The OFS's vitamin C content was equal to 22.17 mg/g (8.87 mg/capsule). The OFS's total polyphenol content was 43.98 mg/g gallic acid equivalents. At the end of the in vivo study, we highlighted a significant decrease in the inflammatory parameters in the OFS period, compared to the placebo period (neutrophil-to-lymphocyte ratio, p = 0.0455; monocyte to-lymphocyte ratio, p = 0.0005; C-reactive protein, p = 0.0145). Our study also highlighted a significant increase in vitamin D serum values (p = 0.0005) and, at the same time, an improvement in patients' life quality and a reduction in fatigue, monitored by the fatigue severity scale. This study showed the OFS's beneficial effects on the inflammatory state, fatigue and quality of life in long COVID patients.