Hyperinflammatory Response Research Articles

TLR2 Activation as a Marker of Severe COVID-19 and a Potential Therapeutic Target.

SARS-CoV-2-induced COVID-19 has been a serious public health problem, resulting in millions of lives lost over the previous three years. Although the direct infection caused by virus invasion is important for the pathobiology of COVID-19, the hyperinflammatory response and tissue injury are major contributors in critically ill patients. As a host sensor, toll-like receptor 2 (TLR2) recognizes multiple pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), producing various inflammatory cytokines and inflammatory cell death signals, which are central to the inflammatory pathology observed in COVID-19. The objectives of this narrative review are to summarize the role of TLR2 activation during SARS-CoV-2 infection and emphasize the importance of SARS-CoV-2 viral proteins in TLR2 activation. Additionally, we presented some compounds related to TLR2 regulation clinically or experimentally, which may provide new insights into targets for pharmaceutical discovery and development.

The Impact of Infliximab on Hyperinflammation State in Hospitalized COVID-19 Patients: A Retrospective Study

Background and Objectives: Elevated levels of pro-inflammatory cytokines have been linked to increased mortality in COVID-19 patients. Infliximab, a tumor necrosis factor inhibitor, has been reported to improve outcomes in COVID-19 patients by targeting the hyperinflammatory response. Our objective was to evaluate the effectiveness of incorporating Infliximab into standard care guidelines for the management of COVID-19. Materials and Methods: A retrospective analysis was conducted on 111 participants who were moderate to severe COVID-19 patients admitted to the hospital. Among them, 74 individuals received solely standard treatment, while 37 received standard therapy plus Infliximab. The primary outcomes of the study centered around the changes in laboratory test parameters. The secondary clinical findings included clinical recovery defined as improvement in patient oxygenation, time till recovery, and assessing necessity for ICU admission, and mortality rates. Results: There was no statistical difference observed in the inflammatory markers including, LDH, Ferritin, CRP, neutrophil to lymphocyte ratio (NLR), and P/F ratio between both groups and in the clinical outcomes including clinical recovery (p = 1.0), time to improvement (p = 0.436), and mortality rate (p = 0.601). However, there was a significant increase in secondary infection (45.9%, 20.3%; p = 0.005), and in liver enzymes, ALT (79.5, 50.0 IU/L; p = 0.02) and AST (57.5, 38.0 IU/L; p = 0.019) in the Infliximab group and the standard care group, respectively. Conclusions: Infliximab therapy did not demonstrate significant benefits compared to standard of care in moderate to severe hospitalized COVID-19 patients.

CCR2+ monocytes are dispensable to resolve acute pulmonary Pseudomonas aeruginosa infections in WT and Cystic Fibrosis mice.

Extravasation of CCR2-positive monocytes into tissue and to the site of injury is a fundamental immunological response to infections. Nevertheless, exuberant recruitment and/or activity of these monocytes and monocyte-derived macrophages can propagate tissue damage, especially in chronic inflammatory disease conditions. We have previously shown that inhibiting the recruitment of CCR2-positive monocytes ameliorates lung tissue damage caused by chronic neutrophilic inflammation in cystic fibrosis (CF) mouse models. A potential concern with targeting monocyte recruitment for therapeutic benefit in CF, however, is whether they are essential for eradicating infections such as Pseudomonas aeruginosa (PA), a pathogen that commonly colonizes and damages the lungs of patients with CF. In this study, we investigated the role of CCR2-positive monocytes in the immune response to acute pulmonary PA infection. Our data show that the altered host immune response caused by the lack of monocyte recruitment to the lungs does not impact PA lung colonization, clearance, and the severity of the infection. These results also hold up in a CF mouse background, which have a hyper-inflammatory immune response, yet exhibit reduced bactericidal activity. Thus, we lay the groundwork for future studies to investigate the use of CCR2 inhibitors as a potential therapy to ameliorate lung tissue damage in CF. This could be given alone or as an adjunct therapy with CFTR modulators that significantly improve clinical outcomes for eligible patients, but do not completely resolve the persistent infection and inflammation that drive lung tissue damage.

The sympathetic nervous system drives hyperinflammatory responses to Clostridioides difficile infection

Clostridioides difficile infection (CDI) is a leading cause of hospital-acquired infections in the United States, known for triggering severe disease by hyperactivation of the host response. In this study, we determine the impact of the sympathetic nervous system (SNS) on CDI disease severity. Mouse models of CDI are administered inhibitors of SNS activity prior to CDI. Chemical sympathectomy or pharmacological inhibition of norepinephrine synthesis greatly reduces mortality and disease severity in the CDI model. Pharmacological blockade or genetic ablation of the alpha 2 adrenergic receptor ameliorates intestinal inflammation, disease severity, and mortality rate. These results underscore the role of the SNS and the alpha 2 adrenergic receptor in CDI pathogenesis and suggest that targeting neural systems could be a promising approach to therapy in severe disease.

Taking AIM at Influenza: The Role of the AIM2 Inflammasome.

Influenza A viruses (IAV) are dynamic and highly mutable respiratory pathogens that present persistent public health challenges. Inflammasomes, as components of the innate immune system, play a crucial role in the early detection and response to infections. They react to viral pathogens by triggering inflammation to promote immune defences and initiate repair mechanisms. While a strong response is necessary for early viral control, overactivation of inflammasomes can precipitate harmful hyperinflammatory responses, a defining characteristic observed during severe influenza infections. The Absent in Melanoma 2 (AIM2) inflammasome, traditionally recognised for its role as a DNA sensor, has recently been implicated in the response to RNA viruses, like IAV. Paradoxically, AIM2 deficiency has been linked to both enhanced and reduced vulnerability to IAV infection. This review synthesises the current understanding of AIM2 inflammasome activation during IAV and explores its clinical implications. Understanding the nuances of AIM2's involvement could unveil novel therapeutic avenues for mitigating severe influenza outcomes.

The Complex Landscape of Immune Dysregulation in Multisystem Inflammatory Syndrome in Children with COVID-19

Abstract The immune responses following SARS-CoV-2 infection in children are still under investigation. While coronavirus disease 2019 (COVID-19) is usually mild in the pediatric population, some children develop severe clinical manifestations or multisystem inflammatory syndrome in children (MIS-C) after infection. MIS-C, typically emerging 2-6 weeks after SARS-CoV-2 exposure, is characterized by a hyperinflammatory response affecting multiple organs. This review aims to explore the complex landscape of immune dysregulation in MIS-C, focusing on innate, T cell-, and B cell-mediated immunity, and discusses the role of SARS-CoV-2 spike protein as a superantigen in MIS-C pathophysiology. Understanding these mechanisms is crucial for improving the management and outcomes for affected children.

The Effect of Hemoadsorption with CytoSorb on Severe COVID-19 Complications

The aim of the study was to assess the effect of hemoadsorption with CytoSorb on the inflammatory response, respiratory failure, and mortality in patients with severe novel coronavirus infection.Materials and methods. A retrospective single-center cohort comparative study of hemoadsorbtion using the CytoSorb therapy included data from 124 COVID-19 ICU patients. Patients were divided into two groups: the study arm with hemoadsorption (group 1, N=93) and the control arm without hemoadsorption (group 2, N=31). Patients in group 1 had more severe respiratory failure at baseline, but were otherwise comparable to patients in group 2 in terms of clinical and demographic parameters.Results. After hemoadsorption, group 1 patients showed significant improvement in 9 of 13 monitored clinical, instrumental, and laboratory parameters: fever (P=0.005), lactate dehydrogenase (LDH) (P<0.001), C-reactive protein (CRP) (P<0.001), and IL-6 (P<0.001) levels, as well as an increase in SpO₂/FiO₂ ratio (P=0.041), leukocyte count (P<0.001) and lymphocyte count (P=0.003), as well as no significant changes in SOFA score (P=0.068). The only improvement seen in group 2 patients was a reduction in fever (P=0.003). Other significant changes in group 2 were unfavorable, such as a decrease in SpO₂/FiO₂ ratio (P=0.002), an increase in inspiratory oxygen fraction FiO₂ (P=0.001), leukocyte count (P<0.05), LDH (P=0.038), procalcitonin (P<0.001), and IL-6 (P=0.005), as well as an increase in SOFA score from 3.0 to 7.0 (95%CI, 3.0–9.0) (P=0.001). The all-cause hospital mortality rate was 37,63% in group 1 and 74.20% in group 2.Conclusion. The use of hemoadsorption with CytoSorb as a pathogenetic therapy targeting the hyperinflammatory response in the management algorithm of ICU patients with severe COVID-19 complications resulted in resolution of the inflammatory response and respiratory failure, as well as a significant reduction in mortality.

Plasma Inflammatory Proteome Profile in a Cohort of Patients with Recurrent Vulvovaginal Candidiasis in Kenya.

Vulvovaginal candidiasis (VVC) affects up to 75% of women at least once during their lifetime, and up to 8% of women suffer from frequent recurrent episodes of VVC (RVVC). A lack of a protective host response underlies vaginal Candida infections, while a dysregulated hyperinflammatory response may drive RVVC. This study aimed to investigate the systemic inflammatory protein profile in women with RVVC in an African population, considering the potential influence of hormonal contraceptive use on systemic inflammation. Using multiplex Proximity Extension Assay technology, we measured 92 circulatory inflammatory proteins in plasma samples from 158 RVVC patients and 92 asymptomatic women (controls). Hormonal contraceptive use was not found to have a statistically significant correlation with a systemic inflammatory protein profile in either RVVC patients or the asymptomatic women. RVVC women had lower circulating Fibroblast Growth Factor 21 (FGF-21) concentrations compared with healthy controls (adjusted p value = 0.028). Reduced concentrations of FGF-21 may be linked to the immune pathology observed in RVVC cases through IL-1β. This study may help to identify new biomarkers for the diagnosis and future development of novel immunomodulatory treatments for RVVC.

Effectiveness of remote ischaemic conditioning is not affected by hyper-inflammation in a rat model of stroke

The inflammation and coagulopathy during coronavirus disease (COVID-19) impairs the efficiency of the current stroke treatments. Remote ischaemic conditioning (RIC) has shown potential in recent years to protect the brain and other organs against pathological conditions. This study aimed to evaluate the efficiency of RIC in brain infarct size using TTC staining and lung injury reduction by H&E staining during the hyper-inflammatory response in rats. The inflammation and coagulopathy were assessed by sedimentation rate, haematocrit, systemic oxidative stress and clotting time. Moreover, we observed changes in the cytokine profile. The results of the first part of the experiment showed that the inflammation and lung injury are fully developed after 24 h of intratracheal LPS administration. At this time, we induced focal brain ischaemia and examined the effect of RIC pre- and post-treatment. Our results showed that RIPre-C reduced the infarct size by about 23%, while RIPost-C by about 30%. The lung injury was also reduced following both treatments. Moreover, RIC modulated systemic inflammation. The level of chemokines CINC-1, LIX and RANTES decreased after 24 h of post-ischaemic reperfusion in treated animals compared to non-treated. The RIC-mediated decrease of inflammation was reflected in improved sedimentation rate and hematocrit, as well as reduced systemic oxidative stress. The results of this work showed neuroprotective and lung protective effects of RIC with a decrease in inflammation response. On the basis of our results, we assume that immunomodulation through the chemokines CINC-1, LIX, and RANTES play a role in RIC-mediated protection.

Molecular and Functional Alterations in the Cerebral Microvasculature in an Optimized Mouse Model of Sepsis-Associated Cognitive Dysfunction.

Systemic inflammation has been implicated in the development and progression of neurodegenerative conditions such as cognitive impairment and dementia. Recent clinical studies indicate an association between sepsis, endothelial dysfunction, and cognitive decline. However, the investigations of the role and therapeutic potential of the cerebral microvasculature in sepsis-induced cognitive dysfunction have been limited by the lack of standardized experimental models for evaluating the alterations in the cerebral microvasculature and cognition induced by the systemic inflammatory response. Herein, we validated a mouse model of endotoxemia that recapitulates key pathophysiology related to sepsis-induced cognitive dysfunction, including the induction of an acute systemic hyperinflammatory response, blood-brain barrier (BBB) leakage, neurovascular inflammation, and memory impairment after recovery from the systemic inflammation. In the acute phase, we identified novel molecular (e.g., upregulation of plasmalemma vesicle-associated protein, PLVAP, a driver of endothelial permeability, and the procoagulant plasminogen activator inhibitor-1, PAI-1) and functional perturbations (i.e., albumin and small-molecule BBB leakage) in the cerebral microvasculature along with neuroinflammation. Remarkably, small-molecule BBB permeability, elevated levels of PAI-1, intra-/perivascular fibrin/fibrinogen deposition, and microglial activation persisted 1 month after recovery from sepsis. We also highlight molecular neuronal alterations of potential clinical relevance following systemic inflammation including changes in neurofilament phosphorylation and decreases in postsynaptic density protein 95 and brain-derived neurotrophic factor, suggesting diffuse axonal injury, synapse degeneration, and impaired neurotrophism. Our study serves as a standardized mouse model to support future mechanistic studies of sepsis-associated cognitive dysfunction and to identify novel endothelial therapeutic targets for this devastating condition.

Multimodal Nuclear Factor-Erythroid-2-Related Factor (NRF2) Therapy in the Context of Mammalian Target of Rapamycin (mTOR) Inhibition Reprograms the Acute Systemic and Pulmonary Immune Response after Combined Burn and Inhalation Injury.

Severe burn injuries induce acute and chronic susceptibility to infections, which is largely attributed to a hyper-pro-inflammatory response followed by a chronic anti-inflammatory response. Concurrent inhalation injury (B + I) causes airway inflammation. Pulmonary macrophages and neutrophils are "hyperactive" with increased reactive oxygen (ROS) and nitrogen species (RONS) activity, but are unable to clear infection, causing airway damage upon activation. Nuclear Factor-Erythroid-2-Related Factor (NRF2) is a critical immunomodulatory component that induces compensatory anti-inflammatory pathways when activated. On the other hand, inhibition of Mammalian Target of Rapamycin (mTOR) reduces pro-inflammatory responses. The therapeutic use of these targets is limited, as known modulators of these pathways are insoluble in saline and require long-term administration. A biocompatible NRF2 agonist (CDDO) and rapamycin (RAPA) poly (lactic-co-glycolic acid) (PLGA) microparticles (MP) were created, which we hypothesized would reduce the acute hyper-inflammatory response in our murine model of B + I injury. BI-injured mice that received CDDO-MP or both CDDO-MP and RAPA-MP (Combo-MP) an hour after injury displayed significant changes in the activation patterns of pulmonary and systemic immune genes and their associated immune pathways 48 h after injury. For example, mice treated with Combo-MP showed a significant reduction in inflammatory gene expression compared to untreated or CDDO-MP-treated mice. We also hypothesized that Combo-MP therapy would acutely decrease bacterial susceptibility after injury. BI-injured mice that received Combo-MP an hour after injury, inoculated 48 h later with Pseudomonas aeruginosa (PAO1), and sacrificed 48 h after infection, displayed significantly decreased bacterial counts in the lungs and liver versus untreated B + I mice. This reduction in infection was accompanied by significantly altered lung and plasma cytokine profiles and immune reprogramming of pulmonary and splenic cells. Our findings strongly suggest that multimodal MP-based therapy holds considerable promise for reprogramming the immune response after burn injuries, particularly by mitigating the hyper-inflammatory phase, and preventing subsequent susceptibility to infection.

Life-Saving Extracorporeal Membrane Oxygenation Combined with Hemoperfusion for a Pregnant Woman with COVID-19 Severe Acute Respiratory Distress Syndrome

The pandemic of the novel coronavirus (COVID-19) affected millions of people worldwide, causing high mortality and morbidity, especially in pregnancy. The management of COVID-19, which progresses to severe acute respiratory distress syndrome during pregnancy, is very challenging. Herein we report a 35-year-old pregnant woman in her second trimester (16 weeks of gestational age) who presented with a productive cough and progressive dyspnea. She was diagnosed with a severe COVID-19 infection, confirmed by PCR testing. During hospitalization, she developed severe acute respiratory distress syndrome (ARDS) and was referred to a tertiary hospital. Despite the use of antiviral therapy, steroids, mechanical ventilators, and muscle relaxants, she still had significant hypoxemia. Thus, she underwent veno-venous extracorporeal membrane oxygenation (VV-ECMO). Due to the limitations of immunomodulatory therapy in pregnancy, our team decided to perform extracorporeal cytokine removal therapy with HA330 adsorbent hemoperfusion to remove circulatory cytokines and proinflammatory mediators and suppress the hyperinflammatory response. After 3 consecutive days of hemoperfusion, her C-reactive protein and interleukin-6 were controlled. On the 13th day of ICU admission, her clinical conditions, including pulmonary function, were improving, and she was successfully weaned off the VV-ECMO. A chest X-ray showed she was completely free of ARDs. The patient left the hospital with good clinical status and a viable fetus. We conclude that pregnant women infected with COVID-19 who develop refractory hypoxemia with cytokine storm syndrome may benefit from combined VV-ECMO and hemoperfusion as a rescue therapy.

Impact of diabetes on COVID-19 and glucocorticoids on patients with COVID-19 and diabetes during the Omicron variant epidemic: a multicenter retrospective cohort study in South China

BackgroundTo explore the impact of diabetes on the clinical features and prognosis of COVID-19 and assess the influence of glucocorticoid use on the prognosis of patients with COVID-19 and diabetes.MethodsThis retrospective multicenter cohort study included patients admitted between December 2022 and January 2023. The patients were grouped according to diabetes and glucocorticoid use. The primary outcome was in-hospital mortality.ResultsAmong 400 patients with glucocorticoid data, 109 (27.3%) had diabetes. The inflammatory cytokines were higher in patients with diabetes, manifested by higher IL-6 (25.33 vs. 11.29 ng/L, p = 0.011), CRP (26.55 vs. 8.62 mg/L, p = 0.003), and PCT (0.07 vs. 0.04 ng/ml, p = 0.010), while CD4+ (319 vs. 506 /mL, p = 0.004) and CD8+ (141 vs. 261 /mL, p < 0.001) T lymphocytes were lower. The overall mortality rate of hospitalized COVID-19 patients with diabetes was 13.46%. The diabetic patients who received glucocorticoids vs. those who did not receive glucocorticoids had a similar mortality (15.00% vs. 11.39%, p = 0.591).ConclusionsPatients with COVID-19 and diabetes are more likely to experience hyperinflammatory response and T cell reduction, especially those with severe/critical disease. Glucocorticoid use was not associated with the prognosis of COVID-19 in patients with diabetes. Still, glucocorticoids should be used cautiously in diabetic patients with severe/critical COVID-19.

Yersinia pestis and pneumonic plague: Insight into how a lethal pathogen interfaces with innate immune populations in the lung to cause severe disease

Yersinia pestis is the causative agent of bubonic, septicemic and pneumonic plague. The historical importance and potential of plague to re-emerge as a threat worldwide are indisputable. The most severe manifestion of plague is pneumonic plague, which results in disease that is 100% lethal without treatment. Y. pestis suppresses host immune responses early in the lung to establish infection. The later stages of infection see the rapid onset of hyperinflammatory responses that prove lethal. The study of Y. pestis host/pathogen interactions have largely been investigated during bubonic plague and with attenuated strains in cell culture models. There remains a somewhat limited understanding of the interactions between virulent Y. pestis and immune populations in the lung that drive severe disease. In this review we give a broad overview of the progression of pneumonic plague and highlighting how Y. pestis interfaces with host innate immune populations in the lung to cause lethal disease.

Unravelling the potential of hydrogen in biological systems

Molecular hydrogen (H2) and oxyhydrogen (66% H2/ 33% O2) gases have been demonstrated to remediate the effects of numerous diseases in adults[1-4]. By acting as an anti-inflammatory and antioxidative agent, it is reported that H2 can improve recovery through mitigating hyperinflammatory responses and reducing oxidative stress[5-7]. As the precise mechanisms of H2 activity are currently undefined, the lack of primary target identification, coupled with difficulties regarding administration methods (e.g., dosage and dosage frequencies, and long-term effects of treatments), there is a requirement for H2 research to evidence how it can reasonably and effectively, be incorporated into healthcare.

Impact of Marijuana Use on Lung Health.

The widespread use of marijuana in the context of increasing legalization has both short- and long-term health implications. Although various modes of marijuana use-smoked, vaped, or ingested-may lead to a wide scope of potential systemic effects, we focus here on inhalational use of marijuana as the most common mode with the lung as the organ that is most directly exposed to its effects. Smoked marijuana has been associated with symptoms of chronic bronchitis and histopathologic changes in airway epithelium, but without consistent evidence of long-term decline in pulmonary function. Its role in immunomodulation, both for risk of infection and protection against a hyperinflammatory host response to infection, has been suggested in animal models and in vitro without conclusive extrapolation to humans. Marijuana smoke contains carcinogens like those found in tobacco, raising concern about its role in lung cancer, but evidence is mixed and made challenging by concurrent tobacco use. Vaping may offer a potential degree of harm reduction when compared with smoking marijuana with reduction of exposure to several toxins, including carbon monoxide, and reduction in chronic respiratory symptoms. However, these potential benefits are counterbalanced by risks including vaping-associated lung injury, potentially more intense drug exposure, and other yet not well-understood toxicities. As more states legalize marijuana and the federal government considers changing this from a Schedule I to a Schedule III controlled substance, we anticipate an increase in prospective medical studies concerning the risks related to marijuana use. This review is based on currently available data concerning the impact of inhaled marijuana on lung health.

Baricitinib and Pulse Steroids Combination Treatment in Hyperinflammatory COVID-19: A Rheumatological Approach in the Intensive Care Unit.

Hyperinflammatory Coronavirus disease 2019 (COVID-19) and rapidly-progressive interstitial lung diseases (RP-ILD) secondary to inflammatory myopathies (IIM) present important similarities. These data support the use of anti-rheumatic drugs for the treatment of COVID-19. The aim of this study was to compare the efficacy of combining baricitinib and pulse steroids with the Standard of Care (SoC) for the treatment of critically ill COVID-19 patients. We retrospectively enrolled consecutive patients admitted to the Intensive Care Unit (ICU) with COVID-19-pneumonia. Patients treated with SoC (dexamethasone plus remdesivir) were compared to patients treated with baricitinib plus 6-methylprednisolone pulses (Rheuma-group). We enrolled 246 patients: 104/246 in the SoC and 142/246 in the Rheuma-group. All patients presented laboratory findings suggestive of hyperinflammatory response. Sixty-four patients (26.1%) died during ICU hospitalization. The mortality rate in the Rheuma-group was significantly lower than in the SoC-group (15.5 vs. 40.4%, p < 0.001). Compared to the SoC-group, patients in the Rheuma-group presented significantly lower inflammatory biomarker levels after one week of treatment. Higher ferritin levels after one week of treatment were strongly associated with mortality (p < 0.001). In this large real-life COVID-19 cohort, baricitinib and pulse steroids led to a significant reduction in mortality, paralleled by a prompt reduction in inflammatory biomarkers. Our experience supports the similarities between hyperinflammatory COVID-19 and the IIM-associated RP-ILD.

Smoking and vaping alter genes related to mechanisms of SARS-CoV-2 susceptibility and severity: a systematic review and meta-analysis.

Evidence for the impact of smoking on coronavirus disease 2019 (COVID-19) is contradictory, and there is little research on vaping. Here we provide greater clarity on mechanisms perturbed by tobacco cigarette, electronic cigarette and nicotine exposures that may impact the risks of infection and/or disease severity. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the Ovid and Web of Science databases were searched. Study design and exposure-induced gene expression changes were extracted. Each study was quality assessed and higher confidence scores were assigned to genes consistently changed across multiple studies following the same exposure. These genes were used to explore pathways significantly altered following exposure. 125 studies provided data on 480 genes altered by exposure to tobacco cigarettes, e-cigarettes, nicotine or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Genes involved in both SARS-CoV-2 viral-entry and inflammation were changed following exposure. Pathway analysis revealed that many of those genes with high confidence scores are involved in common cellular processes relating to hyperinflammatory immune responses. Exposure to tobacco cigarettes, e-cigarettes or nicotine may therefore impact initial host-pathogen interactions and disease severity. Smokers and vapers of e-cigarettes with nicotine could potentially be at increased risk of SARS-CoV-2 infection, associated cytokine storm, and acute respiratory distress syndrome. However, further research is required, particularly on e-cigarettes, to determine the biological mechanisms involved in perturbation of viral-entry genes and host-pathogen interactions and subsequent responses within the respiratory tract. This will improve our physiological understanding of the impact of smoking and vaping on COVID-19, informing public health advice and providing improved guidance for management of SARS-CoV-2 and other respiratory viruses.

From nature to medicine: bioactive compounds in the battle against SARS-CoV-2

The COVID-19 pandemic has driven the search for new therapeutic agents against SARS-CoV-2. Natural products have shown promise as sources of bioactive compounds with antiviral properties. This letter highlights the potential of these compounds in developing effective COVID-19 therapies. Quercetin, found in fruits and vegetables, has demonstrated antiviral activity by inhibiting viral replication. Glycyrrhizin, from licorice root, can modulate host cell signaling to inhibit SARS-CoV-2 replication. Curcumin, from turmeric, disrupts the interaction between the virus’s spike protein and the ACE2 receptor, preventing viral entry. Additionally, compounds like resveratrol possess immunomodulatory properties that can reduce the hyperinflammatory response in severe COVID-19. Despite these promising findings, the variability of natural extracts and potential side effects necessitate rigorous clinical trials. Natural product-derived bioactive compounds represent a promising avenue for novel COVID-19 therapies, warranting further investigation and clinical validation to uncover effective treatments and enhance preparedness for future outbreaks.

Lysosomal dysfunction-derived autophagy impairment of gingival epithelial cells in diabetes-associated periodontitis with altered protein acetylation

Diabetes-associated periodontitis (DP) presents severe inflammation and resistance to periodontal conventional treatment, presenting a significant challenge in clinical management. In this study, we investigated the underlying mechanism driving the hyperinflammatory response in gingival epithelial cells (GECs) of DP patients. Our findings indicate that lysosomal dysfunction under high glucose conditions leads to the blockage of autophagy flux, exacerbating inflammatory response in GECs. Single-cell RNA sequencing and immunohistochemistry analyses of clinical gingival epithelia revealed dysregulation in the lysosome pathway characterized by reduced levels of lysosome-associated membrane glycoprotein 2 (LAMP2) and V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C) in subjects with DP. In vitro stimulation of human gingival epithelial cells (HGECs) with a hyperglycemic microenvironment showed elevated release of proinflammatory cytokines, compromised lysosomal acidity and blocked autophagy. Moreover, HGECs with deficiency in ATP6V0C demonstrated impaired autophagy and heightened inflammatory response, mirroring the effects of high glucose stimulation. Proteomic analysis of acetylation modifications identified altered acetylation levels in 28 autophagy-lysosome pathway-related proteins and 37 sites in HGECs subjected to high glucose stimulation or siATP6V0C. Overall, our finding highlights the pivotal role of lysosome impairment in autophagy obstruction in DP and suggests a potential impact of altered acetylation of relevant proteins on the interplay between lysosome dysfunction and autophagy blockage. These insights may pave the way for the development of effective therapeutic strategies against DP.