Aims/Background Pneumonia is a complex condition with rapid progression, often leading to multiple organ dysfunction syndrome (MODS), which significantly impacts patient quality of life and prognosis. This study aims to identify risk factors closely associated with the development of MODS by conducting a retrospective analysis of clinical data from 150 patients with pneumonia, providing insights for informing the prevention and treatment of pneumonia. Methods We recruited 150 patients with pneumonia admitted to Huzhou Third Municipal Hospital, the Affiliated Hospital of Huzhou University between 2019 and 2022. The patients were divided into two groups according to whether they had developed MODS: the non-MODS group (n = 100) and the MODS group (n = 50). Patients' data, such as their demographic information, clinical characteristics, laboratory test results, treatment course and outcomes, were collected. Logistic regression analysis was conducted to determine the independent predictors of MODS occurrence. Results After propensity score matching, the baseline data of the two groups of patients presented no significant difference (p > 0.05). The predominant clinical and laboratory manifestations of both groups of patients were fever, cough, decreased arterial partial pressure of oxygen (PaO2), as well as elevated white blood cell (WBC) count, C-reactive protein (CRP) level, and procalcitonin (PCT) level, but inter-group differences in these metrics were not statistically significant (p > 0.05). However, the clinical manifestation of dyspnea was significantly more prevalent in the MODS group (p < 0.01). The MODS group also had a significantly higher likelihood of receiving mechanical ventilation and renal replacement therapy (p < 0.001), as well as experiencing respiratory failure, cardiac failure, and death (p < 0.01). Univariate analysis indicated that factors including age ≥65 years, WBC count ≥15 × 109/L, PCT ≥2 ng/mL, PaO2 ≤60 mmHg, arterial partial pressure of carbon dioxide (PaCO2) ≥50 mmHg, severe pneumonia, and dyspnea were associated with a significantly increased risk of MODS (p < 0.05). These factors, except for the PCT, were validated as independent risk factors for MODS in the multivariate logistic regression analysis (p < 0.05). Conclusion Age ≥65 years, WBC count ≥15 × 109/L, PaO2 ≤60 mmHg, PaCO2 ≥50 mmHg, severe pneumonia, and dyspnea are independent risk factors for developing MODS in patients with pneumonia. Patients with MODS presenting respiratory failure as the main manifestation have a high mortality rate, and timely mechanical ventilation and supportive treatment are essential to improve the prognosis.

Coronavirus disease 2019 (COVID-19) presents with various symptoms, and some patients develop post-COVID-19 condition (PCC). Vitamin D has shown therapeutic potential in COVID-19 and may offer benefits for PCC. The aim of this study was to evaluate the differences associated with two supplementation strategies (bolus and daily) on interleukin-6 (IL-6) levels, glutathione peroxidase (GPx) activity, and clinical outcomes in PCC patients, regardless of whether target 25 (OH) D levels reached the ideal range. We conducted a self-controlled study in which 54 participants with PCC were supplemented with vitamin D3 (n = 28 bolus and n = 26 daily) for 2 months. Blood samples were collected to measure IL-6 levels and GPx activity using spectrophotometric methods. The Hospital Anxiety and Depression Scale (HADS) was used to assess mental function. Both bolus and daily vitamin D supplementation were significantly associated with increased GPx activity and decreased IL-6 levels. Daily supplementation was additionally associated with a significant reduction in anxiety and depression scores. However, neither regimen was associated with improvements in cough, dyspnea, or fatigue. These findings suggest a potential association between vitamin D supplementation and improvements in antioxidant and neuropsychiatric parameters in PCC, possibly mediated by its immunomodulatory and antioxidant properties. Further placebo-controlled trials are warranted to determine whether these observed associations reflect causal relationships.

Inflammation plays a fundamental role in the development and bidirectional association of di-verse diseases, such as periodontitis and type 2 diabetes mellitus (T2DM), which generates important clinical complications, where chronic exposure to high levels of blood glucose affects the repair process of periodontal tissues. Likewise, it has been observed that comorbidity, between these two diseases, influences the development of the COVID-19 disease towards a more severe course. However, there is currently very little scientific evidence on the relationship between periodontitis, T2DM and COVID-19 disease. This narrative review aims to provide an understanding of the current and most relevant aspects of the relationship between periodontitis, T2DM and COVID-19 disease. A narrative review was performed through a systematic search of published studies, without date restrictions, indexed in the electronic databases of PubMed, for the inclusion of articles in English, and LILACS for the inclusion of articles in Spanish. This review included different articles, which addressed the most important aspects to present a current perspective on the relationship and influence between periodontitis, T2DM and COVID-19 disease. Comorbidity between periodontitis and T2DM represents a greater risk of developing a more severe course of COVID-19 disease, because these three diseases share three important axes: a clinicopathological axis; an axis associated with glycemia, and an immunological axis associated with inflammation.

Acute kidney injury (AKI) has emerged as a significant complication in patients with coronavirus disease 2019 (COVID-19). The pathophysiology of COVID-19-associated AKI is multifactorial, involving both direct viral effects on renal cells and indirect mechanisms such as systemic inflammation and cytokine storms. This highlights the critical need for early detection and effective management strategies to mitigate kidney injury and improve patient outcomes. The aim of our study is to assess the potential predictive role of inflammatory biomarkers in determining the risk of developing COVID-19-associated AKI in patients with and without pre-existing CKD.

This study included 84 patients stratified by pre-existing chronic kidney disease (CKD) status. Demographic, clinical, and laboratory data were collected, including vital signs, hematological profiles, renal function markers, inflammatory biomarkers, coagulation parameters, and treatments. Outcomes such as acute kidney injury (AKI) and in-hospital mortality were documented.

In patients with pre-existing CKD, IL-6 and NLR demonstrated high predictive accuracy for AKI onset. In patients without pre-existing CKD, white blood cell (WBC) count emerged as a significant predictor of AKI onset.

The differential roles of IL-6, NLR, and WBC in predicting AKI onset highlight distinct physiopathological pathways influenced by COVID-19. In CKD+ patients, chronic inflammation and immune dysregulation are key drivers of AKI, with IL-6 and NLR serving as robust markers of this inflammatory state. In contrast, in CKD- patients, AKI may be more influenced by acute inflammatory responses and infectious factors, as reflected by WBC count.

The pandemic outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has threatened human health worldwide. Among protective immune reactions, T cell responses are diverse among individuals, which is related to the differences in severity. A T cell subset, regulatory T (Treg) cells, is crucial for limiting excessive immune responses. If SARS-CoV-2-specific Tregs are developed during infection, they may counteract antiviral immunity and cause severe symptoms. To address this possibility, we conducted single-cell TCR-RNA-sequencing of peripheral blood mononuclear cells from convalescent Coronavirus disease 2019 (COVID-19) patients. Among 13 donors, one with severe symptoms had substantially more FOXP3-expressing Treg clonotypes activated in the presence of SARS-CoV-2 virion or other major antigen proteins. To define the reactivity of these Treg clonotypes, 15 highly expanded Treg clonotypes were reconstituted into reporter cells and stimulated with 27 distinct peptide pools that cover all SARS-CoV-2 proteins. However, none of these clonotypes react to any SARS-CoV-2 antigens. Instead, the reporter cells expressing one TCR clonotype (23599) were activated in the presence of Epstein-Barr virus-transformed B cells without adding exogenous antigens. Furthermore, 23599 TCR-expressing cells were activated by non-transformed naïve syngeneic B cells in a DQA1*03:03-DQB1*04:01-dependent manner, suggesting that clonotype 23599 may be autoreactive. This Treg clonotype, 23599, was also detected in a public TCR database and significantly expanded in COVID-19 patients compared to healthy donors. These results suggest that SARS-CoV-2 is not the dominant antigen inducing Treg cells during infection.

Simnotrelvir/ritonavir and nirmatrelvir/ritonavir are major treatments for COVID-19, but their comparative efficacy and safety, especially in patients with moderate to severe COVID-19, remain unclear.

This was a retrospective cohort study using electronic medical record data. From May 30, 2023, to October 8, 2023, 115 patients with moderate to severe COVID-19 were retrospectively collected from Wenzhou Central Hospital. They were treated with simnotrelvir/ritonavir or nirmatrelvir/ritonavir. The clinical effectiveness and adverse reactions were analyzed and compared between the two groups.

A total of 115 hospitalized patients were included in the study. They were 65 (56.5%) men and 50 (43.5%) women, with a mean age of 61 years. 58 (50.4%) were treated with simnotrelvir/ritonavir and 57 (49.6%) with nirmatrelvir/ritonavir. There was a similar rate of composite disease progression (10.3% vs. 7.0%, χ2 = 0.401, p = 0.527) and mortality (5.2% vs. 3.5%, χ2 = 0.191, p = 0.662) between the two groups. The progression rate from moderate COVID-19 to severe COVID-19 was not significantly different between the two groups (4.5% vs. 6.4%, χ2 = 0.148, p = 0.701). Median time for hospitalization was 7.0 (6.0, 8.0) days and 9.0 (8.0, 10.0) days (p = 0.338), and time for SARS-CoV-2 negative conversion was 6.0 (6.0, 7.0) days and 7.0 (6.0, 7.0) days (p = 0.934) in the simnotrelvir/ritonavir group and nirmatrelvir/ritonavir group, respectively. Among moderate patients, time for hospitalization was shorter in the simnotrelvir/ritonavir group [6.0 (6.0, 7.0) vs. 8.0 (8.0, 10.0) days, log-rank p = 0.004, HR = 1.838 (95% CI 1.199-2.815)]. And 5 (8.6%) had adverse drug reactions (ADRs) in the simnotrelvir/ritonavir group and 6 (10.5%) had ADRs in the nirmatrelvir/ritonavir group.

This is the first study comparing the effectiveness of simnotrelvir/ritonavir and nirmatrelvir/ritonavir in moderate and severe COVID-19 patients. Patients who received simnotrelvir/ritonavir exhibited shorter hospitalization. Disease progression, viral clearance times, and symptom resolution time were similar between the two groups.

Particulate matter 2.5 (PM2.5) pollution and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic are the greatest environmental health issues worldwide. Several statistics revealed the significant positive correlation between the morbidity of coronavirus disease-19 (COVID-19) and the levels of air pollution. Nevertheless, there is no direct experimental evidence to indicate the effect of PM2.5 exposure on SARS-CoV-2 infection. The objective of this study was to evaluate whether the infection of SARS-CoV-2 affected by PM2.5 through angiotensin-converting enzyme II (ACE2) expression enhances and investigate the function of ACE2 in lung injury induced by PM2.5. An animal model of PM2.5-induced lung injury was established using wild-type (WT, C57BL/6), human ACE2 transgenic (K18-hACE2 TG), and murine ACE2 gene knockout (mACE2 KO) mice. The results indicate that PM2.5 exposure facilitates SARS-CoV-2 infection through inducing ACE2 expression in vitro (10 μg/mL) and in vivo (6.25 mg/kg/day in 50 μL saline). The levels of ACE, inflammatory cytokines, and mitogen-activated protein kinase (MAPK) proteins in WT, K18-hACE TG and mACE2 KO mice were significantly increased after PM2.5 instillation. The severest PM2.5-induced lung damage was observed in mACE2 KO mice. In summary, ACE2 plays a double-edged sword role in lung injury, PM2.5 exposure contributed to SARS-CoV-2 infection through inducing ACE2 expression, but ACE2 also protected pulmonary inflammation from PM2.5 challenge.

The complex link between COVID-19 and immunometabolic diseases demonstrates the important interaction between metabolic dysfunction and immunological response during viral infections. Severe COVID-19, defined by a hyperinflammatory state, is greatly impacted by underlying chronic illnesses aggravating the cytokine storm caused by increased levels of Pro-inflammatory cytokines. Metabolic reprogramming, including increased glycolysis and altered mitochondrial function, promotes viral replication and stimulates inflammatory cytokine production, contributing to illness severity. Mitochondrial metabolism abnormalities, strongly linked to various systemic illnesses, worsen metabolic dysfunction during and after the pandemic, increasing cardiovascular consequences. Long COVID-19, defined by chronic inflammation and immune dysregulation, poses continuous problems, highlighting the need for comprehensive therapy solutions that address both immunological and metabolic aspects. Understanding these relationships shows promise for effectively managing COVID-19 and its long-term repercussions, which is the focus of this review paper.

The SARS-CoV-2 pandemic has resulted in 762 million infections worldwide from 2020 to date, of which approximately ten percent are suffering from the effects after infection in 2019 (COVID-19) [1, 40]. In Germany, it is now assumed that at least one million people suffer from post-COVID condition with long-term consequences. These have been previously reported in diseases like Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS). Symptoms show a changing variability and recent surveys in the COVID context indicate that 10-30 % of outpatients, 50 to 70% of hospitalised patients suffer from sequelae. Recent data suggest that only 13% of all ill people were completely free of symptoms after recovery [3, 9]. Current hypotheses consider chronic inflammation, mitochondrial dysfunction, latent viral persistence, autoimmunity, changes of the human microbiome or multilocular sequelae in various organ system after infection. Hyperbaric oxygen therapy (HBOT) is applied since 1957 for heart surgery, scuba dive accidents, CO intoxication, air embolisms and infections with anaerobic pathogens. Under hyperbaric pressure, oxygen is physically dissolved in the blood in higher concentrations and reaches levels four times higher than under normobaric oxygen application. Moreover, the alternation of hyperoxia and normoxia induces a variety of processes at the cellular level, which improves oxygen supply in areas of locoregional hypoxia. Numerous target gene effects on new vessel formation, anti-inflammatory and anti-oedematous effects have been demonstrated [74]. The provision of intermittently high, local oxygen concentrations increases repair and regeneration processes and normalises the predominance of hyperinflammation. At present time only one prospective, randomized and placebo-controlled study exists with positive effects on global cognitive function, attention and executive function, psychiatric symptoms and pain interference. In conclusion, up to this date HBO is the only scientifically proven treatment in a prospective randomized controlled trial to be effective for cognitive improvement, regeneration of brain network and improvement of cardiac function. HBOT may have not only theoretical but also potential impact on targets of current pathophysiology of Post COVID condition, which warrants further scientific studies in patients.

Sepsis, a systemic syndrome often culminating in multiple organ failure (MOF), poses a substantial global health threat. However, the gene expression pattern of various tissues associated with severe sepsis remains elusive.

Applying the summary data-based Mendelian randomization (SMR) method, we integrated sepsis genome-wide association study (GWAS) data and expression quantitative trait loci (eQTLs) summaries. This facilitated the investigation of gene causality across 12 tissue types within 26 cohorts linked to adverse sepsis outcomes, including critical care and 28-day mortality. Additionally, trans-omics analyses, including blood transcriptome and single-cell RNA sequencing, were conducted to examine cellular origins and gene functions. The effects of ST7L on sepsis were validated in vivo and in vitro.

We identified 127 genes associated with severe sepsis across diverse tissues. Cross-tissue analysis highlighted ST7L as a significant pan-tissue risk factor for severe sepsis, displaying significance across 11 tissues for both critical care sepsis (meta OR 1.19, 95 % CI: 1.14-1.25, meta p < 0.0001) and 28-day-death sepsis (meta OR: 1.22, 95 % CI: 1.17-1.27, meta p < 0.0001). Notably, independent blood single-cell RNA sequencing data showed specific expression of ST7L in dendritic cells (DCs). ST7L+ DCs were elevated in non-surviving sepsis patients and exhibited an augmented inflammatory molecular pattern compared to ST7L- DCs. Both transcription and translation level of ST7L in DCs exhibited a dose-dependent pattern with LPS. Knocking down ST7L by siRNA was sufficient to alleviate the inflammation phenotype of DCs, including inhibiting p65/NF-kB pathway and inflammatory factors.

Our findings underscore ST7L as a pan-tissue risk factor for severe sepsis, specifically manifested in DCs and associated with an inflammatory phenotype. These results offer essential insights into the gene expression profiles across multiple tissues in severe sepsis, potentially identifying therapeutic targets for effective sepsis management.

In this mini review, we explore the complex network of inflammatory reactions incited by SARS-CoV-2 infection, which extends its reach well beyond the respiratory domain to influence various organ systems. Synthesizing existing literature, it elucidates how the hyperinflammation observed in COVID-19 patients affects multiple organ systems leading to physiological impairments that can persist over long after the resolution of infection. By exploring the systemic manifestations of this inflammatory cascade, from acute respiratory distress syndrome (ARDS) to renal impairment and neurological sequelae, the review highlights the profound interplay between inflammation and organ dysfunction. By synthesizing recent research and clinical observations, this mini review aims to provide an overview of the systemic interactions and complications associated with COVID-19, underscoring the need for an integrated approach to treatment and management. Understanding these systemic effects is crucial for improving patient outcomes and preparing for future public health challenges.

Lung endothelium plays a pivotal role in the orchestration of inflammatory responses to acute pulmonary insults. Mammalian sterile 20-like kinase 1 (Mst1) is a serine/threonine kinase that has been shown to play an important role in the regulation of apoptosis, stress responses, and organ growth. This study investigated the role of Mst1 in lung endothelial activation and acute lung injury (ALI). We found that Mst1 was significantly activated in inflamed lung endothelial cells (ECs) and mouse lung tissues. Overexpression of Mst1 promoted nuclear factor κ-B (NF-κB) activation through promoting JNK and p38 activation in lung ECs. Inhibition of Mst1 by either its dominant negative form (DN-Mst1) or its pharmacological inhibitor markedly attenuated cytokine-induced expression of cytokines, chemokines, and adhesion molecules in lung ECs. Importantly, in a mouse model of lipopolysaccharide-induced (LPS-induced) ALI, both deletion of Mst1 in lung endothelium and treatment of WT mice with a pharmacological Mst1 inhibitor significantly protected mice from LPS-induced ALI. Together, our findings identified Mst1 kinase as a key regulator in controlling lung EC activation and suggest that therapeutic strategies aimed at inhibiting Mst1 activation might be effective in the prevention and treatment of inflammatory lung diseases.

Previous studies have suggested that perioperative anesthesia could have direct impacts on cancer cell biology. The present study investigated the effects of ropivacaine administration on lung adenocarcinoma cells.

Ropivacaine was administered to A549 cells at concentrations of 0.1, 1, and 6 mM for 2 h. Angiotensin-converting enzyme 2 (ACE2) small interfering RNA (siRNA) transfection was performed 6 h prior to ropivacaine administration. Cell proliferation and migration were assessed with cell counting kit 8 (CCK-8) and a wound healing assay at 0 and 24 h after anesthesia exposure. PCR arrays were performed, followed by PCR validation.

Ropivacaine administration inhibited A549 cell proliferation and migration in a concentration-dependent manner, with ACE2 upregulation and HIF1α (hypoxia-inducible factor 1α) downregulation. The anticancer effect of ropivacaine was canceled out via ACE2 siRNA transfection. PCR arrays showed specific gene change patterns in the ropivacaine and respective ACE2-knockdown groups. EGFR (epidermal growth factor receptor), BAX (Bcl-2-associated X protein) and BCL2 (B-cell/CLL lymphoma 2) were suppressed with ropivacaine administration; these effects were reversed via ACE2 siRNA induction.

Ropivacaine administration inhibited A549 cell biology in conjunction with ACE2 upregulation via the inhibition of the Wnt1 (wingless/Integrated 1) pathway.

Proteases are produced and released in the mucosal cells of the respiratory tract and have important physiological functions, for example, maintaining airway humidification to allow proper gas exchange. The infectious mechanism of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), takes advantage of host proteases in two ways: to change the spatial conformation of the spike (S) protein via endoproteolysis (e.g., transmembrane serine protease type 2 (TMPRSS2)) and as a target to anchor to epithelial cells (e.g., angiotensin-converting enzyme 2 (ACE2)). This infectious process leads to an imbalance in the mucosa between the release and action of proteases versus regulation by anti-proteases, which contributes to the exacerbation of the inflammatory and prothrombotic response in COVID-19. In this article, we describe the most important proteases that are affected in COVID-19, and how their overactivation affects the three main physiological systems in which they participate: the complement system and the kinin-kallikrein system (KKS), which both form part of the contact system of innate immunity, and the renin-angiotensin-aldosterone system (RAAS). We aim to elucidate the pathophysiological bases of COVID-19 in the context of the imbalance between the action of proteases and anti-proteases to understand the mechanism of aprotinin action (a panprotease inhibitor). In a second-part review, titled "Aprotinin (II): Inhalational Administration for the Treatment of COVID-19 and Other Viral Conditions", we explain in depth the pharmacodynamics, pharmacokinetics, toxicity, and use of aprotinin as an antiviral drug.

SARS-CoV-2 can damage human placentas, leading to pregnancy complications, such as preeclampsia and premature birth. This study investigates the histopathological changes found in COVID-19-affected placentas.

This study included 23 placentas from patients with active COVID-19 during delivery and 22 samples from patients without COVID-19 infection in their medical history. The samples underwent histopathological examination for pathology, such as trophoblast necrosis, signs of vessel damage, or fetal vascular malperfusion.

Newborns from the research group have lower weights and Apgar scores than healthy newborns. In the COVID-19 group, calcifications and collapsed intervillous space were more frequent, and inflammation was more severe than in the healthy group. At the same time, the placenta of SARS-CoV-2-positive patients showed signs of accelerated vascular maturation. Trophoblast necrosis was found only in the placentas of the research group. The expression of CD68+ was elevated in the COVID-19 cohort, suggesting that macrophages constituted a significant part of the inflammatory infiltrate. The increase in lymphocyte B markers was associated with placental infarctions, while high levels of CD3+, specific for cytotoxic T lymphocytes, correlated with vascular injury.

SARS-CoV-2 is associated with pathological changes in the placenta, including trophoblast necrosis, calcification, and accelerated villous maturation. Those changes appear to be driven by T cells and macrophages, whose increased expression reflects ongoing histiocytic intervillositis in the placenta.

Studies investigating the effects of SARS-CoV-2 on male reproductive function are few and heterogeneous, and results are often conflicting. This systematic review and meta-analysis was carried out on studies conducted in men with active or anamnestic SARS-CoV-2 infection to evaluate its consequences on the male sex hormone profile and semen parameters.

This meta-analysis follows the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) protocols. PubMed, Scopus, Cochrane, and Embase databases were searched to identify relevant studies. We originally selected 3553 articles. After the eligibility phase, 16 articles met our inclusion criteria encompassing 11 case-control studies and 5 cohort studies (2 prospective and 3 retrospective studies). We performed the quantitative analysis with Comprehensive Meta-Analysis Software. Cochran-Q and heterogeneity (I2) indexes were used to assess statistical heterogeneity. Sensitivity analysis and publication bias tests were also performed.

Overall, 1250 patients with active or recent (up to 80 days before) COVID-19 infection and 1232 matched healthy controls were included. Sperm concentration, total sperm count, and total motility were significantly lower in patients compared with controls. Patients also showed lower levels of total testosterone and follicle-stimulating hormone, and higher levels of luteinizing hormone, 17β-estradiol, and prolactin compared with healthy controls. None of the included studies found the presence of SARS-CoV-2 mRNA in the semen of infected patients.

The present systematic review and meta-analysis suggests the presence of an association between SARS-CoV-2 infection and primary testicular damage manifested with a picture of altered steroidogenesis and worsening spermatogenesis. The absence of the virus in the seminal fluid indicates a low possibility of sexual transmission of the infection to partners and offspring. However, our findings mostly show short-term follow-up, while few studies have considered the long-term consequences of the viral infection, thus further studies are needed to evaluate the long-term consequences on male reproductive health.

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.

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.

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.

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.

Human kidneys are an important target of SARS-CoV-2 infection, and many renal abnormalities have been found in patients with SARS-CoV-2 infection, including proteinuria, hematuria, and acute kidney injury. Acute kidney injury is now considered a common complication of COVID-19, and the epidemiology of AKI in SARS-CoV-2-infected patients continues to be controversial.

We have carried out a narrative review to evaluate the frequency and risk factors for AKI among patients hospitalized due to COVID-19, and the latest surveys on this topic have been included. The mechanisms by which AKI occurs in COVID-19 patients have also been reviewed.

Multiple risk factors for the development of AKI in patients with SARS-CoV-2 infection have been identified; these have been classified in various groups (management and background factors, among others). SARS-CoV-2 targets the kidneys by indirect activity, but SARS-CoV-2 infects tubular epithelial cells and podocytes. We retrieved 24 reports (n = 502,593 unique patients with SARS-CoV-2 infection) and found an incidence of AKI of 31.8% (range, 0.5% to 56.9%). Only a minority (n = 2) of studies had a prospective design. We found that the AKI risk was greater in SARS-CoV-2 patients who underwent in-hospital deaths vs. those who survived; the summary estimate of the unadjusted RR of AKI was 2.63 (95% CI, 2.37; 2.93) (random-effects model). A stratified analysis showed that the incidence of AKI was greater in those reports where the frequency of COVID-19-positive patients having comorbidities (diabetes mellitus, arterial hypertension, and advanced age) was high. The unadjusted relative risk (aRR) of AKI was greater in SARS-CoV-2 patients who underwent ICU admission vs. those who did not; the pooled estimate of AKI risk was 2.64 (95% CI, 1.96; 3.56) according to the random-effects model.

AKI is a common complication of hospitalized SARS-CoV-2-infected patients, and some comorbidities are important risk factors for it. The direct activity of the virus on the kidneys has been mentioned in the pathogenesis of AKI in SARS-CoV-2 patients. Further studies are ongoing in order to identify the mechanisms underlying the kidney injury in this population. The role of AKI on survival in SARS-CoV-2-infected patients is another area of active investigation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19), a complex and multifaceted illness. COVID-19 is associated with various ocular manifestations including conjunctivitis, retinal vein occlusion and optic neuritis. However, the case of Vogt-Koyanagi-Harada (VKH) disease associated with SARS-CoV-2 is infrequent, and the specific association is still unclear.

In the present study, a 35-year-old female patient without any significant medical history presented with 1 week of bilateral blurred vision, occurring 2 weeks after a clinical course of COVID-19. Upon examination, both eyes exhibited bullous serous retinal detachments. She was diagnosed with incomplete VKH disease. Early diagnosis and treatment of VKH disease are essential for the visual prognosis of this aggressive disease. In this particular patient, ocular inflammatory signs and visual acuity improved via corticosteroid therapy. It is worth noting that the occurrence of VKH disease associated with SARS-CoV-2 is uncommon, and the specific connection between the two remains unknown. We review and summarize the clinical characteristics of VKH disease following SARS-CoV-2 infection, and discuss the potential mechanisms that may explain this phenomenon, based on similar studies previously reported.

Despite the unclear causality, it is important for ophthalmologists and physicians to be recognizant of the possible association between VKH disease and COVID-19. SARS-CoV-2 may play a potential immunological triggering role in VKH disease. However, further in-depth research is necessary to investigate the clinical and epidemiological features, as well as the underlying mechanisms of this association.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third human coronavirus to cause acute respiratory distress syndrome (ARDS) and contains four structural proteins: spike, envelope, membrane, and nucleocapsid. An increasing number of studies have demonstrated that all four structural proteins of SARS-CoV-2 are capable of causing lung injury, even without the presence of intact virus. Therefore, the topic of SARS-CoV-2 structural protein-evoked lung injury warrants more attention. In the current article, we first synopsize the structural features of SARS-CoV-2 structural proteins. Second, we discuss the mechanisms for structural protein-induced inflammatory responses in vitro. Finally, we list the findings that indicate structural proteins themselves are toxic and sufficient to induce lung injury in vivo. Recognizing mechanisms of lung injury triggered by SARS-CoV-2 structural proteins may facilitate the development of targeted modalities in treating COVID-19.

The combined effects of lead exposure and the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and how they cause cardiovascular dysfunction are examined in this viewpoint manuscript. Lead was picked as a representative environmental contaminant because it has been studied extensively for more than 40 years, while SARS-CoV-2 illustrates the unpredictability of a new infectious agent that can quickly increase the environmental burden on communities. Given that this interaction represents a plausible combined exposure for many people, it is crucial to discuss how it might happen at a mechanistic level. SARS-CoV-2 causes the coronavirus disease 2019 (COVID-19), which can spread by contact and respiratory droplets. One may be exposed to lead and SARS-CoV-2 simultaneously depending on their living situation. Uncertainty exists regarding the consequences of this exposure on cardiovascular disease and its underlying processes. This paper aims to investigate these mechanisms and provide potential causes behind them. The interaction of lead with SARS-CoV-2 and its effects on the cardiovascular system are likely caused by direct damage, the promotion of reactive oxygen species (ROS) production, oxidative stress, and inflammation. In particular, the stimulation of nuclear factor kappa B (NF-B), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF) were all identified as potentially important pathways. Blood clotting, cytokine storm cycle development, and increased hypoxia may also be the results of this. In summary, the effects on the immune system, coagulation, the renin-angiotensin-aldosterone system, and cardiac contractility were the four primary areas identified.

To explore the effects of long-term oral ACEIs/ARBs on the incidence of exacerbation and in-hospital mortality in elderly COVID-19 Omicron BA.2 patients with hypertension, especially patients aged 80 years or older.

In this retrospective study, patients suffering mild and rcommon COVID-19 with hypertension who were hospitalized in the Shanghai Fourth People's Hospital between April 2022 and June 2022 were enrolled. Primary outcomes included the incidence of exacerbation and in-hospital mortality. Secondary outcomes included the incidence of respiratory failure of patients, use of mechanical ventilation, nucleic acid conversion time (NCT), hospitalization costs, and the temporal trend of the incidence of exacerbations and in-hospital mortality in different age groups. The data were analysed using propensity score weighting (PSW).

In the entire cohort, there were 298 ACEI/ARB users and 465 non-ACEI/ARB users. The ACEI/ARB group showed a lower incidence of exacerbation (OR = 0.64, 95% CI for OR: 0.46-0.89, P = 0.0082) and lower in-hospital mortality (OR = 0.49, 95% CI for OR: 0.27-0.89, P = 0.0201) after PSW. Sensitivity analysis obtained the same results. The results of the subgroup of patients aged 80 years and older obtained a similar conclusion as the whole cohort. Most of the study indicators did not differ statistically significantly in the subgroup of patients aged 60 to 79 years except for rates of mechanical ventilation and respiratory failure.

Antihypertensive therapy with ACEIs/ARBs might reduce the incidence of exacerbation and in-hospital mortality. The findings of this study support the use of ACEIs/ARBs in COVID-19 patients infected by Omicron BA.2, especially in patients aged 80 years or older with hypertension.

Exacerbated inflammatory responses can be detrimental and pose fatal threats to the host, as exemplified by the global impact of the COVID-19 pandemic, resulting in millions of fatalities. Developing novel drugs to combat the damaging effects of inflammation is essential for both preventive measures and therapeutic interventions. Accumulating evidence suggests that Angiotensin Converting Enzyme 2 (ACE2) possesses the ability to optimize inflammatory responses. However, the clinical applicability of this potential is limited due to the lack of dependable ACE2 activators. In this study, we conducted a screening of an FDA-approved drug library and successfully identified a novel ACE2 activator, termed H4. The activator demonstrated the capability to mitigate lung inflammation caused by bacterial lung infections, effectively modulating neutrophil infiltration. Importantly, to improve the clinical applicability of the poorly water-soluble H4, we developed a prodrug variant with significantly enhanced water solubility while maintaining a similar level of efficacy as H4 in attenuating inflammatory responses in the lungs of mice exposed to bacterial infections. This finding highlights the potential of formulated H4 as a promising candidate for the treatment and prevention of inflammatory diseases, including lung-related conditions.

Immense attention has been given to the outcome of COVID-19 infection. However, comprehensive studies based on large populational cohort with long-term follow-up are still lacking. This study aimed to investigate the risk of various short-term comorbidities (within one month) and long-term sequelae (above one month) after COVID-19 infection.

In this large prospective cohort study with 14 months follow-up information based on UK biobank, we included 16,776 COVID-19-positive participants and 58,281 COVID-19-negative participants matched for comparison. The risk of each comorbidity and sequela was evaluated by multivariable logistic regression analysis and presented as hazard ratio (HR) and 95% confidence interval (95% CI).

COVID-19-positive individuals had a higher risk of 47 types of comorbidities within one month following COVID-19 infection, especially those who were older, male, overweight/obese, ever-smoked, with more pre-existing comorbidities and hospitalized. About 70.37% of COVID-19 patients with comorbidities had more than one co-occurring comorbidities. Additionally, only 6 high-risk sequelae were observed after one month of COVID-19 infection, and the incidence was relatively low (< 1%).

In addition to long-term sequelae following COVID-19 infection, plenty of comorbidities were observed, especially in patients with older age, male gender, overweight/obese, more pre-existing comorbidities and severe COVID-19, indicating that more attention should be given to these susceptible persons within this period.

SARS-CoV-2 Envelope protein (E) is one of the crucial components in virus assembly and pathogenesis. The current study investigated its role in the SARS-CoV-2-mediated cell death and inflammation in lung and gastrointestinal epithelium and its effect on the gastrointestinal-lung axis. We observed that transfection of E protein increases the lysosomal pH and induces inflammation in the cell. The study utilizing Ethidium bromide/Acridine orange and Hoechst/Propidium iodide staining demonstrated necrotic cell death in E protein transfected cells. Our study revealed the role of the necroptotic marker RIPK1 in cell death. Additionally, inhibition of RIPK1 by its specific inhibitor Nec-1s exhibits recovery from cell death and inflammation manifested by reduced phosphorylation of NFκB. The E-transfected cells' conditioned media induced inflammation with differential expression of inflammatory markers compared to direct transfection in the gastrointestinal-lung axis. In conclusion, SARS-CoV-2 E mediates inflammation and necroptosis through RIPK1, and the E-expressing cells' secretion can modulate the gastrointestinal-lung axis. Based on the data of the present study, we believe that during severe COVID-19, necroptosis is an alternate mechanism of cell death besides ferroptosis, especially when the disease is not associated with drastic increase in serum ferritin.

Antiviral treatment reduces the severity and mortality of SARS-CoV-2 infection; however, its effectiveness against long COVID-19 is unclear. This study aimed to evaluate the effectiveness of antiviral drugs in preventing long COVID and related hospitalizations/deaths. Scientific and medical databases were searched from 1 January 2020 to 30 June 2023. We included observational cohort studies comparing individuals receiving early antiviral therapy for COVID-19 and those receiving supportive treatment. A fixed-effects model was used to merge the effects reported in two or more studies. The risk of post-acute sequelae of COVID-19 (PASC) was combined as an odds ratio (OR). Six studies were selected, including a total of 3,352,235 participants. The occurrence of PASC was 27.5% lower in patients who received antiviral drugs during the early stages of SARS-CoV-2 infection (OR = 0.725; 95% confidence interval [CI] = 0.409-0.747) than in the supportive treatment group. Moreover, the risk of PASC-associated hospitalization and mortality was 29.7% lower in patients receiving early antiviral therapy than in the supportive treatment group (OR = 0.721; 95% CI = 0.697-0.794). Early antiviral therapy was associated with a reduced risk of PASC and related hospitalization or death. Thus, early antiviral therapy is recommended for at-risk individuals.

COVID-19 has been shown to induce inflammatory disorders and CNS manifestations. Swift and efficient treatment strategies are urgently warranted for the management of COVID, inflammatory and neurological disorders. Hydrogen sulfide (H2S) has been associated with several clinical disorders due to its potential to influence a broad range of biological signalling pathways. According to recent clinical studies, COVID patients with lower physiological H2S had higher fatality rates. These findings clearly demonstrate an inverse correlation between H2S levels and the severity of COVID-19. H2S has been proposed as a protective molecule because of its antioxidant, anti-inflammatory, and antiviral properties. Various H2S-releasing prodrugs, hybrids and natural compounds have been tested for their therapeutic efficacy in viral infections and inflammatory disorders. In this review, I am highlighting the rationale for using H2S-based interventions for the management of COVID-19 and post-infection inflammatory disorders including neuroinflammation. I am also proposing therepurposing of existing H2S-releasing prodrugs, developing new NO-H2S-hybrids, targeting H2S metabolic pathways, and using H2S-producing dietary supplements as viable defensive strategies against SARS-CoV-2 infection and COVID-19 pathologies.

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, poses a significant threat to public health. Angiotensin-converting enzyme 2 (ACE2) is a key receptor for SARS-CoV-2 infection. Recombinant human ACE2 (RhACE2), as a soluble supplement for human ACE2, can competitively block SARS-CoV-2 infection. In this study, a mouse organ in situ rhACE2 high aggregation model was constructed for the first time, and in vivo real-time positron emission tomography (PET) imaging of rhACE2 in the mouse model was performed using an ACE2-specific agent 68 Ga-HZ20. This radiotracer exhibits reliable radiochemical properties in vitro and maintains a high affinity for rhACE2 in vivo. In terms of probe uptake, 68 Ga-HZ20 showed a good target-to-nontarget ratio and was rapidly cleared from the circulatory system and excreted by the kidneys and urinary system. PET imaging with this radiotracer can noninvasively and accurately monitor the content and distribution of rhACE2 in the body, which clarifies that rhACE2 can aggregate in multiple organs, suggesting the preventive and therapeutic potential of rhACE2 for SARS-CoV-2 and COVID-19.

Lung endothelium plays a pivotal role in the orchestration of inflammatory and injury responses to acute pulmonary insults. Mammalian sterile 20-like kinase 1 (Mst1), a mammalian homolog of Hippo, is a serine/threonine kinase that is ubiquitously expressed in many tissues and has been shown to play an important role in the regulation of apoptosis, inflammation, stress responses, and organ growth. While Mst1 exhibits high expression in the lung, its involvement in the endothelial response to pulmonary insults remains largely unexplored.

Mst1 activity was assessed in lung endothelium by western blot. Mst1 endothelial specific knockout mice and a pharmacological inhibitor were employed to assess the effects of Mst1 on homeostatic and lipopolysaccharide (LPS)-induced endothelial responses. Readouts for these studies included various assays, including NF-κB activation and levels of various inflammatory cytokines and adhesion molecules. The role of Mst1 in lung injury was evaluated in a LPS-induced murine model of acute lung injury (ALI).

Mst1 phosphorylation was significantly increased in lung endothelial cells after exposure to tumor necrosis factor (TNF)-alpha (TNF-α) and mouse lung tissues after LPS exposure. Overexpression of full length Mst1 or its kinase domain promoted nuclear factor kappaB (NF-κB) activation through promoting JNK and p38 activation, whereas dominant negative forms of Mst1 (DN-Mst1) attenuated endothelial responses to TNF-α and interleukin-1β. Consistent with this, targeted deletion of Mst1 in lung endothelium reduced lung injury to LPS in mice. Similarly, wild-type mice were protected from LPS-induced lung injury following treatment with a pharmacological inhibitor of Mst1/2.

Our findings identified Mst1 kinase as a key regulator in the control of lung EC activation and suggest that therapeutic strategies aimed at inhibiting Mst1 activation might be effective in the prevention and treatment of lung injury to inflammatory insults.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), showing high infectiousness, resulted in an ongoing pandemic termed coronavirus disease 2019 (COVID-19). COVID-19 cases often experience acute respiratory distress syndrome, which has caused millions of deaths. Apart from triggering inflammatory and immune responses, many viral infections can cause programmed cell death in infected cells. Cell death mechanisms have a vital role in maintaining a suitable environment to achieve normal cell functionality. Nonetheless, these processes are dysregulated, potentially contributing to disease pathogenesis. Over the past decades, multiple cell death pathways are becoming better understood. Growing evidence suggests that the induction of cell death by the coronavirus may significantly contributes to viral infection and pathogenicity. However, the interaction of SARS-CoV-2 with cell death, together with its associated mechanisms, is yet to be elucidated. In this review, we summarize the existing evidence concerning the molecular modulation of cell death in SARS-CoV-2 infection as well as viral-host interactions, which may shed new light on antiviral therapy against SARS-CoV-2.

In a short time, several types of injectable and oral therapeutics have been developed and used to effectively manage patients with coronavirus disease 2019 (COVID-19). BEN815 is an improved mixture of three extracts (Psidium guajava, Camellia sinensis, and Rosa hybrida) recognized by the Ministry of Food and Drug Safety of Korea as a health food ingredient that alleviates allergic rhinitis. The current animal efficacy study was performed to assess its probability of improving COVID-19 symptoms. BEN815 treatment significantly increased the survival of K18-hACE2 transgenic mice and reduced viral titers in the lungs at 5 days post infection (DPI). Furthermore, the lungs of the treated mice showed mild tissue damage at 5 DPI and nearly complete recovery from COVID-19 at 14 DPI. BEN815 appears to be an effective and minimally toxic anti-SARS-CoV-2 agent in mice and has potential for clinical applications.

Since its spread at the beginning of 2020, the coronavirus disease 2019 (COVID‑19) pandemic represents one of the major health problems. Despite the approval, testing, and worldwide distribution of anti‑severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) vaccines, the development of specific antiviral agents targeting the SARS‑CoV‑2 life cycle with high efficiency, and/or interfering with the associated 'cytokine storm', is highly required. A recent study, conducted by the authors' group indicated that sulforaphane (SFN) inhibits the expression of IL‑6 and IL‑8 genes induced by the treatment of IB3‑1 bronchial cells with a recombinant spike protein of SARS‑CoV‑2. In the present study, the ability of SFN to inhibit SARS‑CoV‑2 replication and the expression of pro‑inflammatory genes encoding proteins of the COVID‑19 'cytokine storm' was evaluated. SARS‑CoV‑2 replication was assessed in bronchial epithelial Calu‑3 cells. Moreover, SARS‑CoV‑2 replication and expression of pro‑inflammatory genes was evaluated by reverse transcription quantitative droplet digital PCR. The effects on the expression levels of NF‑κB were assessed by western blotting. Molecular dynamics simulations of NF‑kB/SFN interactions were conducted with Gromacs 2021.1 software under the Martini 2 CG force field. Computational studies indicated that i) SFN was stably bound with the NF‑κB monomer; ii) a ternary NF‑kB/SFN/DNA complex was formed; iii) the SFN interacted with both the protein and the nucleic acid molecules modifying the binding mode of the latter, and impairing the full interaction between the NF‑κB protein and the DNA molecule. This finally stabilized the inactive complex. Molecular studies demonstrated that SFN i) inhibits the SARS‑CoV‑2 replication in infected Calu‑3 cells, decreasing the production of the N‑protein coding RNA sequences, ii) decreased NF‑κB content in SARS‑CoV‑2 infected cells and inhibited the expression of NF‑kB‑dependent IL‑1β and IL‑8 gene expression. The data obtained in the present study demonstrated inhibitory effects of SFN on the SARS‑CoV‑2 life cycle and on the expression levels of the pro‑inflammatory genes, sustaining the possible use of SFN in the management of patients with COVID‑19.

The benefits and harms of vitamin D supplementation in the treatment of COVID-19 have not yet been fully documented. In this study, we aimed to evaluate the effects of high-dose vitamin D supplementation on liver function tests in COVID-19.

This double-blinded randomized clinical trial was conducted on 140 hospitalized patients aged > 30 years. Patients were randomly allocated to receive either intervention group (n = 70 receiving 50,000 IU of vitamin D capsules orally as a single dose and then 10,000 IU syrup daily from the second day of admission for 30 days) and the control group (n = 70 receiving 1000 IU vitamin D syrup orally per day). Liver function tests (LFT), including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and Lactate Dehydrogenase (LDH) were evaluated at baseline and at the end of the intervention. Decision tree analysis was performed to identify the predictors for change in liver enzymes.

Among COVID-19 patients, a significant decrease was observed in serum level of ALP between intervention and placebo groups (p = 0.04). In addition, decision tree analysis revealed that GGT, temperature, serum magnesium level at baseline and gender were the most important predictors of ALT changes in COVID-19 patients.

High-dose vitamin D supplementation improved ALP markers among COVID-19 patients. More randomized controlled trials with longer follow-up times will be required.

Probiotic bacteria are able to modulate general antiviral responsiveness, including barrier functionality and innate and adaptive immune responses. The COVID-19 pandemic, resulting from SARS-CoV-2 infection, has created a need to control and treat this viral infection and its ensuing immunopathology with a variety of approaches; one such approach may involve the administration of probiotic bacteria. As with most viral infections, its pathological responses are not fully driven by the virus, but are significantly contributed to by the host's immune response to viral infection. The potential adoption of probiotics in the treatment of COVID-19 will have to appreciate the fine line between inducing antiviral immunity without over-provoking immune inflammatory responses resulting in host-derived immunopathological tissue damage. Additionally, the effect exerted on the immune system by SARS-CoV-2 evasion strategies will also have to be considered when developing a robust response to this virus. This review will introduce the immunopathology of COVID-19 and the immunomodulatory effects of probiotic strains, and through their effects on a range of respiratory pathogens (IAV, SARS-CoV, RSV), as well as SARS-CoV-2, will culminate in a focus on how these bacteria can potentially manipulate both infectivity and immune responsiveness via barrier functionality and both innate and adaptive immunity. In conclusion, the harnessing of induction and augmentation of antiviral immunity via probiotics may not only act as an ingestible adjuvant, boosting immune responsiveness to SARS-CoV-2 infection at the level of barrier integrity and innate and adaptive immunity, but also act prophylactically to prevent infection and enhance protection afforded by current vaccine regimens.

Although rotavirus A (RVA) is the primary cause of acute viral gastroenteritis in children and young animals, mechanisms of its replication and pathogenesis remain poorly understood. We previously demonstrated that the neuraminidase-mediated removal of terminal sialic acids (SAs) significantly enhanced RVA-G9P[13] replication, while inhibiting RVA-G5P[7] replication. In this study, we compared the transcriptome responses of porcine ileal enteroids (PIEs) to G5P[7] vs. G9P[13] infections, with emphasis on the genes associated with immune response, cholesterol metabolism, and host cell attachment. The analysis demonstrated that G9P[13] infection led to a robust modulation of gene expression (4093 significantly modulated genes vs. 488 genes modulated by G5P[7]) and a significant modulation of glycosyltransferase-encoding genes. The two strains differentially affected signaling pathways related to immune response, with G9P[13] mostly upregulating and G5P[7] inhibiting them. Both RVAs modulated the expression of genes encoding for cholesterol transporters. G9P[13], but not G5P[7], significantly affected the ceramide synthesis pathway known to affect both cholesterol and glycan metabolism. Thus, our results highlight the unique mechanisms regulating cellular response to infection caused by emerging/re-emerging and historical RVA strains relevant to RVA-receptor interactions, metabolic pathways, and immune signaling pathways that are critical in the design of effective control strategies.

Coronavirus disease 2019 (COVID-19) is a highly contagious respiratory disease that has posed a serious threat to people's daily lives and caused an unprecedented challenge to public health and people's health worldwide. Lung squamous cell carcinoma (LUSC) is a common type of lung malignancy with a highly aggressive nature and poor prognosis. Patients with LUSC could be at risk for COVID-19, We conducted this study to examine the potential for naringenin to develop into an ideal medicine and investigate the underlying action mechanisms of naringenin in COVID-19 and LUSC due to the anti-viral, anti-tumor, and anti-inflammatory activities of naringenin.

LUSC related genes were obtained from TCGA, PharmGKB, TTD,GeneCards and NCBI, and then the transcriptome data for COVID-19 was downloaded from GEO, DisGeNET, CTD, DrugBank, PubChem, TTD, NCBI Gene, OMIM. The drug targets of Naringenin were revealed through CTD, BATMAN, TCMIP, SymMap, Chemical Association Networks, SwissTargetPrediction, PharmMapper, ECTM, and DGIdb. The genes related to susceptibility to COVID-19 in LUSC patients were obtained through differential analysis. The interaction of COVID-19/LUSC related genes was evaluated and demonstrated using STRING to develop a a COX risk regression model to screen and evaluate the association of genes with clinical characteristics. To investigate the related functional and pathway analysis of the common targets of COVID-19/LUSC and Naringenin, KEGG and GO enrichment analysis were employed to perform the functional analysis of the target genes. Finally, The Hub Gene was screened and visualized using Cytoscape, and molecular docking between the drug and the target was performed using Autodock.

We discovered numerous COVID-19/LUSC target genes and examined their prognostic value in LUSC patients utilizing a variety of bioinformatics and network pharmacology methods. Furthermore, a risk score model with strong predictive performance was developed based on these target genes to assess the prognosis of LUSC patients with COVID-19. We intersected the therapeutic target genes of naringenin with the LUSC, COVID-19-related targets, and identified 354 common targets, which could be used as potential target genes for naringenin to treat COVID-19/LUSC. The treatment of COVID-19/LUSC with naringenin may involve oxidative stress, anti-inflammatory, antiviral, antiviral, apoptosis, immunological, and multiple pathways containing PI3K-Akt, HIF-1, and VEGF, according to the results of the GO and KEGG enrichment analysis of these 354 common targets. By constructing a PPI network, we ascertained AKT1, TP53, SRC, MAPK1, MAPK3, and HSP90AA1 as possible hub targets of naringenin for the treatment of COVID-19/LUSC. Last but not least, molecular docking investigations showed that naringenin has strong binding activity in COVID-19/LUSC.

We revealed for the first time the pharmacological targets and potential molecular processes of naringenin for the treatment of COVID-19/LUSC. However, these results need to be confirmed by additional research and validation in real LUSC patients with COVID-19.

Although the clinical manifestation of COVID-19 is mainly respiratory symptoms, approximately 20% of patients suffer from cardiac complications. COVID-19 patients with cardiovascular disease have higher severity of myocardial injury and poor outcomes. The underlying mechanism of myocardial injury caused by SARS-CoV-2 infection remains unclear. Using a non-transgenic mouse model infected with Beta variant (B.1.351), we found that the viral RNA could be detected in lungs and hearts of infected mice. Pathological analysis showed thinner ventricular wall, disorganized and ruptured myocardial fiber, mild inflammatory infiltration, and mild epicardia or interstitial fibrosis in hearts of infected mice. We also found that SARS-CoV-2 could infect cardiomyocytes and produce infectious progeny viruses in human pluripotent stem cell-derived cardiomyocyte-like cells (hPSC-CMs). SARS-CoV-2 infection caused apoptosis, reduction of mitochondrial integrity and quantity, and cessation of beating in hPSC-CMs. In order to dissect the mechanism of myocardial injury caused by SARS-CoV-2 infection, we employed transcriptome sequencing of hPSC-CMs at different time points after viral infection. Transcriptome analysis showed robust induction of inflammatory cytokines and chemokines, up-regulation of MHC class I molecules, activation of apoptosis signaling and cell cycle arresting. These may cause aggravate inflammation, immune cell infiltration, and cell death. Furthermore, we found that Captopril (hypotensive drugs targeting ACE) treatment could alleviate SARS-CoV-2 induced inflammatory response and apoptosis in cardiomyocytes via inactivating TNF signaling pathways, suggesting Captopril may be beneficial for reducing COVID-19 associated cardiomyopathy. These findings preliminarily explain the molecular mechanism of pathological cardiac injury caused by SARS-CoV-2 infection, providing new perspectives for the discovery of antiviral therapeutics.