Severe COVID-19 is often associated with coagulopathy and thrombotic complications. The underlying mechanisms are complex and multifactorial, involving platelet activation, dysregulation of the complement cascade, fibrinolytic imbalance, release of pro-inflammatory cytokines, immunothrombosis, antiphospholipid antibodies, and alterations in the von Willebrand factor (vWF)/ADAMTS13 axis. These pathways are also implicated in thrombotic microangiopathies (TMAs), characterized by endothelial injury and widespread microvascular thrombosis. In this prospective monocentric observational study, we investigated whether COVID-19-associated coagulopathy meets the criteria for TMA and evaluated the roles of complement activation and vWF/ADAMTS13 imbalance in disease severity. Forty-three hospitalized COVID-19 patients were enrolled and stratified by disease severity. Blood samples collected at admission were analyzed for hematologic, coagulation, inflammatory, and complement parameters. A 30-day follow-up recorded survival and thrombotic events. All patients showed elevated vWF and factor VIII levels; however, only vWF collagen-binding activity (vWF-CBA) significantly correlated with disease severity. ADAMTS13 activity remained above 60% in all cases, and no schistocytes were detected, arguing against a diagnosis of classical TMA. Nevertheless, the vWF-CBA/ADAMTS13 ratio was significantly higher in severe cases, particularly in unvaccinated individuals, suggesting endothelial dysregulation. Complement analysis revealed increased C5a levels and decreased C3b/iC3b ratios in severe disease, consistent with complement activation and consumption. C2 levels were also lower in these patients. Although complement activation and vWF/ADAMTS13 imbalance did not directly correlate, both pathways showed a similar trend according to disease severity. Overall, our findings indicate that COVID-19-related coagulopathy does not fulfill the criteria for classical TMA but shows features of complement-mediated endothelial injury and vWF dysregulation. The vWF-CBA may serve as a rapid, standardized tool for assessing endothelial dysfunction. Activation of the complement system, particularly via the lectin and alternative pathways, appears central to the prothrombotic state in severe COVID-19.

Neutrophils, conventionally regarded as a homogeneous immune cell population, have emerged as a heterogeneous group of cells with distinct gene profiles and immune properties. Activated neutrophils release a spectrum of bioactive substances, including cytokines, chemokines, proteolytic enzymes, reactive oxygen species and neutrophil extracellular traps (NETs), which are composed of decondensed DNA and antimicrobial proteins. NETs have a pivotal role in innate immunity, including in preventing the ascent of uropathogenic bacteria into the kidneys, as they efficiently trap pathogenic microorganisms. However, although indispensable for defence against pathogens, NETs also pose risks of self-damage owing to their cytotoxicity, thrombogenicity and autoantigenicity. Accordingly, neutrophils and NETs have been implicated in the pathogenesis of various disorders that affect the kidneys, including acute kidney injury, vasculitis, systemic lupus erythematosus, thrombotic microangiopathy and in various aetiologies of chronic kidney disease. Pathological alterations in the glomerular vascular wall can promote the infiltration of neutrophils, which can cause tissue damage and inflammation through their interactions with kidney-resident cells, including mesangial cells and podocytes, leading to local cell death. Targeting neutrophil activation and NET formation might therefore represent a new therapeutic strategy for these conditions.

Aging has a profound impact on the immune system, leading to a gradual decline in its function and increased systemic inflammation, collectively known as immunosenescence and inflammaging. These changes make older adults more susceptible to infections, including COVID-19, and contribute to worse clinical outcomes, such as higher morbidity and mortality rates. This review explores immunological changes associated with aging, including impaired innate immune responses, reduced T- and B-cell function, and altered cytokine profiles. A comprehensive literature search identified relevant studies on the topic, and inclusion criteria focused on studies addressing age-related immune changes and their impact on responses to COVID-19. The findings underscore the need for targeted healthcare strategies to mitigate the negative effects of aging on immunity and improve immune resilience, and ultimately clinical outcomes and quality of life for this vulnerable population.

Coronavirus infectious disease of 2019 (COVID-19) can lead to cardiac complications, yet the molecular mechanisms driving these effects remain unclear. Protein glycosylation is crucial for viral replication, immune response, and organ function and has been found to change in the lungs and liver of patients with COVID-19. However, how COVID-19 impacts cardiac protein glycosylation has not been defined. Our study combined single nuclei transcriptomics, mass spectrometry (MS)-based glycomics, and lectin-based tissue imaging to investigate alterations in N-glycosylation in the human heart post-COVID-19. We identified significant expression differences in glycogenes involved in N-glycan biosynthesis and MS analysis revealed a reduction in high mannose and isomers of paucimannose structures post-infection, with changes in paucimannose directly correlating with COVID-19 independent of comorbidities. Our observations suggest that COVID-19 primes cardiac tissues to alter the glycome at all levels, namely, metabolism, nucleotide sugar transport, and glycosyltransferase activity. Given the role of N-glycosylation in cardiac function, this study provides a basis for understanding the molecular events leading to cardiac damage post-COVID-19 and informing future therapeutic strategies to treat cardiac complications resulting from coronavirus infections.

Long COVID (also termed postacute sequelae of SARS-CoV-2, or PASC) affects up to 10% of people recovering from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diagnosis is hampered by diffuse symptomatology, lack of biomarkers, incomplete understanding of pathogenesis, and lack of validated treatments. In terms of pathogenesis, hypothesized causes include virus persistence, the legacy of endotheliitis and thrombosis, low-grade tissue-based inflammation and/or scarring, perturbation of the host virome/microbiome, or triggering of autoimmunity. Several studies show preexisting and/or de novo production of autoantibodies after infection with SARS-CoV-2, but the persistence of these antibodies and their role in causing long COVID is debated. Here, we review the mechanisms through which autoimmune responses can arise during and after viral infection, focusing on the evidence for B-cell dysregulation and autoantibody production in acute and long COVID.

The SARS-CoV-2 virus can cause thrombotic microangiopathy (TMA) by alternate pathway activation. We present a case of a young female patient who presented with fever and dialysis-dependent acute kidney injury. On evaluation, she was diagnosed with COVID-19-induced complement-mediated thrombotic microangiopathy (CM-TMA). She was initially managed with plasma exchange (PLEX). However, because of poor response to PLEX, she was administered Inj Eculizumab. She became dialysis independent and had normal renal function on follow-up visits.

Alpha-synuclein (α-syn) is a 140-amino-acid, intrinsically disordered, soluble protein that is abundantly present in the brain. It plays a crucial role in maintaining cellular structures and organelle functions, particularly in supporting synaptic plasticity and regulating neurotransmitter turnover. However, for reasons not yet fully understood, α-syn can lose its physiological role and begin to aggregate. This altered α-syn disrupts dopaminergic transmission and causes both presynaptic and postsynaptic dysfunction, ultimately leading to cell death. A group of neurodegenerative diseases known as α-synucleinopathies is characterized by the intracellular accumulation of α-syn deposits in specific neuronal and glial cells within certain brain regions. In addition to Parkinson's disease (PD), these conditions include dementia with Lewy bodies (DLBs), multiple system atrophy (MSA), pure autonomic failure (PAF), and REM sleep behavior disorder (RBD). Given that these disorders are associated with α-syn-related neuroinflammation-and considering that SARS-CoV-2 infection has been shown to affect the nervous system, with COVID-19 patients experiencing neurological symptoms-it has been proposed that COVID-19 may contribute to neurodegeneration in PD and other α-synucleinopathies by promoting α-syn misfolding and aggregation. In this review, we focus on whether SARS-CoV-2 could act as an environmental trigger that facilitates the onset or progression of α-synucleinopathies. Specifically, we present new evidence on the potential role of SARS-CoV-2 in modulating α-syn function and discuss the causal relationship between SARS-CoV-2 infection and the development of parkinsonism-like symptoms.

Chronic hepatitis C (CHC) is a liver disease caused by the hepatitis C virus. Anti-Saccharomyces cerevisiae (S. cerevisiae) antibodies (ASCA) are frequently reported in autoimmune diseases but rarely in viral infections. We aimed to determine the frequency of ASCA in adult patients with CHC.

Eighty-eight patients with CHC and 160 healthy blood donors were included in this study. ASCA-IgG and IgA levels were determined using enzyme linked immunosorbent assay. For statistical analysis, we used open EPI version 3 as software. Correlations were determined by Spearman's test using IBM® SPSS® Statistics.

ASCA (IgG or IgA) were present in 31.8 % of patients and in 3.7 % of controls (p < 10-6). ASCA-IgG and ASCA-IgA were more frequent in patients with CHC than in healthy subjects (23.9 % vs. 3.1 %; p < 10-5 and 9.1 % vs. 0.6 %; p = 0.002, respectively). In patients, mean levels of ASCA-IgG and IgA were significantly higher than in controls (9.95 ± 11.78 U/mL vs. 2.28 ± 2.86 U/mL, p < 10-6 and 5.96 ± 7.69 U/mL vs. 0.56 ± 0.12 U/mL, p < 10-6; respectively). In patients with CHC, the mean level of ASCA-IgG was significantly higher than that of ASCA-IgA (9.95 ± 11.78 U/mL vs. 5.96 ± 7.69 U/mL, p = 0.008).

The frequency of ASCA was significantly higher in patients with CHC than in healthy controls.

Eighty years ago, the Institute of Biomedical Chemistry (IBMC) initially known as the Institute of Biological and Medical Chemistry of the Academy of Sciences of the USSR was founded. During the first decades significant studies were performed; they not only contributed to a deeper understanding of biochemical processes in the living organisms, but also laid the foundation for further development of these fields. The main directions of IBMC were focused on studies of structures of enzymes (primarily various proteases), their substrates and inhibitors, the role of enzymes of carbohydrate metabolism in the development of pathologies, study of the mechanisms of hydrolytic and oxidative-hydrolytic transformation of organic compounds, studies of connective tissue proteins, including collagens, study of amino acid metabolism. It is difficult to find papers from that period in current online literature databases, so this review will help to understand the value of studies performed at IBMC during the first 40 years after its organization, as well as their impact on modern research.

The emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to the global COVID-19 pandemic, significantly impacting the health of pregnant women. Obstetric populations, already vulnerable, face increased morbidity and mortality related to COVID-19, aggravated by preexisting comorbidities. Recent studies have shed light on the potential correlation between COVID-19 and preeclampsia (PE), a leading cause of maternal and perinatal morbidity worldwide, emphasizing the significance of exploring the relationship between these two conditions. Here, we review the pathophysiological similarities that PE shares with COVID-19, with a particular focus on severe COVID-19 cases and in PE-like syndrome cases related with SARS-CoV-2 infection. We highlight cellular and molecular mechanistic inter-connectivity between these two conditions, for example, regulation of renin-angiotensin system, tight junction and barrier integrity, and the complement system. Finally, we discuss how COVID-19 pandemic dynamics, including the emergence of variants and vaccination efforts, has shaped the clinical scenario and influenced the severity and management of both COVID-19 and PE. Continued research on the mechanisms of SARS-CoV-2 infection during pregnancy and the potential risk of developing PE from previous infections is warranted to delineate the complexities of COVID-19 and PE interactions and to improve clinical management of both conditions.

Background: Vitamin C has been used as an antioxidant and has been proven effective in boosting immunity in different diseases, including coronavirus disease (COVID-19). An increasing awareness was directed to the role of intravenous vitamin C in COVID-19. Methods: In this study, we aimed to assess the safety of high-dose intravenous vitamin C added to the conventional regimens for patients with different stages of COVID-19. An open-label clinical trial was conducted on patients with COVID-19. One hundred four patients underwent high-dose intravenous administration of vitamin C (in addition to conventional therapy), precisely 10 g in 250 cc of saline solution in slow infusion (60 drops/min) for three consecutive days. At the same time, 42 patients took the standard-of-care therapy. Results: This study showed the safety of high-dose intravenous administration of vitamin C. No adverse reactions were found. When we evaluated the renal function indices and estimated the glomerular filtration rate (eGRF, calculated with the CKD-EPI Creatinine Equation) as the main side effect and contraindication related to chronic renal failure, no statistically significant differences between the two groups were found. High-dose vitamin C treatment was not associated with a statistically significant reduction in mortality and admission to the intensive care unit, even if the result was bound to the statistical significance. On the contrary, age was independently associated with admission to the intensive care unit and in-hospital mortality as well as noninvasive ventilation (N.I.V.) and continuous positive airway pressure (CPAP) (OR 2.17, 95% CI 1.41-3.35; OR 7.50, 95% CI 1.97-28.54; OR 8.84, 95% CI 2.62-29.88, respectively). When considering the length of hospital stay, treatment with high-dose vitamin C predicts shorter hospitalization (OR -4.95 CI -0.21--9.69). Conclusions: Our findings showed that an intravenous high dose of vitamin C is configured as a safe and promising therapy for patients with moderate to severe COVID-19.

Growing evidence has highlighted the substantial effects of COVID-19 on kidneys, ranging from mild proteinuria to severe acute kidney injury. However, comprehensive assessments of histopathological features in renal allograft biopsies are lacking.

Seventeen kidney transplant recipients with COVID-19 between March 2020 and November 2022 were evaluated. Clinical characteristics, pathological findings, and outcomes were studied.

Six kidney transplant recipients (35.3%) developed acute kidney injury, leading to the requirement for hemodialysis. COVID-19 severity, as indicated by pneumonia (P = .028) and hospitalization (P = .002), was significantly associated with development of acute kidney injury. Most patients with COVID-19 (82.4%) showed considerably increased proteinuria levels (82.4%), along with presence of new-onset microscopic hematuria (35.3%) and nephrotic syndrome (58.8%). Tubular viral inclusionlike changes were detected in 47.1% of cases and were associated with a higher risk of graft loss (75%). Thrombotic microangiopathy and endothelial cell swelling in glomeruli were prevalent, highlighting extensive endothelial cell injury. Most recipients (88.2%) experienced rejection after COVID-19, with graft loss occurring in 46.7% of these cases. Biopsies revealed collapsing (n = 5), noncollapsing (n = 3), and recurrent (n = 2) focal segmental glomerulosclerosis, as well as acute tubulointerstitial nephritis (n = 3), crescentic glomerulonephritis with immunoglobulin A nephropathy (n = 1), and membranoproliferative glomerulonephritis (n = 1), in 129.7 ± 33 days. Eight patients experienced graft loss (8.2 ± 2 mo posttransplant). Hospitalization (P = .044) and viralinclusion-like nuclear changes in tubules (P = .044) significantly influenced graft survival. Collapsing (60%) and noncollapsing (66.7%) focal segmental glomerulosclerosis increased the risk of graft loss.

COVID-19 has had a multifaceted and enduring effect on renal allografts, urging the need for meticulous monitoring and tailored management strategies to mitigate the risk of severe kidney-related complications and graft loss in this vulnerable population.

Gene therapy has brought tremendous hope for patients with severe life-threatening monogenic diseases. Although studies have shown the efficacy of gene therapy, serious adverse events have also emerged, including thrombotic microangiopathy (TMA) following viral vector-based gene therapy. In this review, we briefly summarize the concept of gene therapy, and the immune response triggered by viral vectors. We also discuss the incidence, presentation, and potential underlying mechanisms, including complement activation, of gene therapy-associated TMA. Further studies are needed to better define the pathogenesis of this severe complication of gene therapy, and the optimal measures to prevent it.

Porcine reproductive and respiratory syndrome virus (PRRSV) causes a highly transmissible disease of significant concern in the pig industry. Previous studies have demonstrated that the XM-2020 strain (a lineage 1.8 PRRSV IA/2012/NADC30) can induce special hemorrhagic injury in the small intestines. However, the specific mechanism underlying this injurious effect remains incompletely understood. In this study, we examined the pathogenic properties of XM-2020 and YC-2020 strains (a lineage 1.5 PRRSV IA/2014/NADC34) in piglets. Animal pathogenic tests revealed that with either Lineage 1 PRRSVs strains XM-2020 or YC-2020 demonstrated pronounced intestinal hemorrhage and suppression of peripheral immunological organs, comparing to JXA1 infection. Transcriptome analysis of diseased small intestines unveiled that PRRSV infection stimulated oxidative and inflammatory reactions. Remarkably, we also observed activation of the complement system alongside a notable down-regulation of complement and coagulation cascade pathways in the Lineage 1 PRRSVs infection group. Based on these findings, we propose that the primary mechanism driving the hemorrhagic injury of the small intestine caused by Lineage 1 PRRSVs is the suppression of complement and coagulation cascades resulting from immunosuppression. This discovery deepens our understanding of the pathogenicity of PRRSV in the small intestine and provides promising ways out for the development of innovative strategies aimed at controlling PRRSV.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in December 2019 with staggering economic fallout and human suffering. The unique structure of SARS-CoV-2 and its underlying pathogenic mechanism were responsible for the global pandemic. In addition to the direct damage caused by the virus, SARS-CoV-2 triggers an abnormal immune response leading to a cytokine storm, culminating in acute respiratory distress syndrome and other fatal diseases that pose a significant challenge to clinicians. Therefore, potential treatments should focus not only on eliminating the virus but also on alleviating or controlling acute immune/inflammatory responses. Current management strategies for COVID-19 include preventative measures and supportive care, while the role of the host immune/inflammatory response in disease progression has largely been overlooked. Understanding the interaction between SARS-CoV-2 and its receptors, as well as the underlying pathogenesis, has proven to be helpful for disease prevention, early recognition of disease progression, vaccine development, and interventions aimed at reducing immunopathology have been shown to reduce adverse clinical outcomes and improve prognosis. Moreover, several key mutations in the SARS-CoV-2 genome sequence result in an enhanced binding affinity to the host cell receptor, or produce immune escape, leading to either increased virus transmissibility or virulence of variants that carry these mutations. This review characterizes the structural features of SARS-CoV-2, its variants, and their interaction with the immune system, emphasizing the role of dysfunctional immune responses and cytokine storm in disease progression. Additionally, potential therapeutic options are reviewed, providing critical insights into disease management, exploring effective approaches to deal with the public health crises caused by SARS-CoV-2.

With the rapid global spread of COVID-19, it has become evident that the virus can lead to multisystem complications, leading to a significant increase in related publications. Bibliometrics serves as a valuable tool for identifying highly cited literature and research hotspots within specific areas.

The aim of this study is to identify current research hotspots and future trends in COVID-19 complications.

The dataset was obtained from the Web of Science Core Collection, covering COVID-19 complications from December 8, 2019, to October 31, 2022. Various aspects, including publication general information, authors, journals, co-cited authors, co-cited references, research hotspots, and future trends, were subjected to analysis. Visual analysis was conducted using VOSviewer, The Online Analysis Platform of Literature Metrology, and Charticulator.

There were 4597 articles in the study. The top three countries with the most published articles are the USA (n = 1350, 29.4 %), China (n = 765, 16.6 %), and Italy (n = 623, 13.6 %). USA and China have the closest collaborative relationship. The institute with the largest number of publications is Huazhong University of Science and Technology, followed by Harvard Medical School. Nevertheless, half of the top 10 institutes belong to the USA. "Rezaei, Nima" published 13 articles and ranked first, followed by "Yaghi, Shadi" with 12 articles and "Frontera, Jennifer" with 12 articles. The journal with the largest number of publications is "Journal of Clinical Medicine". The top 3 co-cited authors are "Zhou, Fei", "Guan, Wei-Jie", "Huang, Chaolin". The top 3 co-cited references addressed COVID-19's clinical features in China and noticed that COVID-19 patients had a wide range of complications. We also list four research hotspots.

This study conducted a bibliometric visual analysis of the literature on COVID-19 complications and summarized the current research hotspots. This study may provide valuable insights into the complications of COVID-19.

SARS-CoV-2 infection is considered as a relapsing inflammatory process with a dysregulation of IL-6 signalling. Classic IL-6 signalling is thought to represent a defence mechanism against pathogens. In contrast, IL-6 trans-signalling has pro-inflammatory effects. In severe COVID-19, therapeutic strategies have focused on global inhibition of IL-6, with controversial results. We hypothesized that specific blockade of IL-6 trans-signalling could inhibit inflammatory response preserving the host defence activity inherent to IL-6 classic signalling.

To test the role of the specific IL-6 trans-signalling inhibition by sgp130Fc in short- and long-term consequences of COVID-19, we used the established K18-hACE2 transgenic mouse model. Histological as well as immunohistochemical analysis, and pro-inflammatory marker profiling were performed. To investigate IL-6 trans-signalling in human cells we used primary lung microvascular endothelial cells and fibroblasts in the presence/absence of sgp130Fc.

We report that targeting IL-6 trans-signalling by sgp130Fc attenuated SARS-CoV-2-related clinical symptoms and mortality. In surviving mice, the treatment caused a significant decrease in lung damage. In vitro, IL-6 trans-signalling induced strong and persisting JAK1/STAT3 activation in endothelial cells and lung fibroblasts with proinflammatory effects, which were attenuated by sgp130Fc. Our data also suggest that in those cells with scant amounts of IL-6R, the induction of gp130 and IL-6 by IL-6:sIL-6R complex sustains IL-6 trans-signalling.

IL-6 trans-signalling fosters progression of COVID-19, and suggests that specific blockade of this signalling mode could offer a promising alternative to mitigate both short- and long-term consequences without affecting the beneficial effects of IL-6 classic signalling. These results have implications for the development of new therapies of lung injury and endotheliopathy in COVID-19.

The project was supported by ISCIII, Spain (COV-20/00792 to MB, PI23/01351 to MARH) and the European Commission-Next generation EU (European Union) (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global, SGL2103029 to MB). PID2019-110587RB-I00 (MB) supported by MICIN/AEI/10.13039/501100011033/and PID2022-143034OB-I00 (MB) by MICIN/AEI/10.13039/501100011033/FEDER. MAR-H acknowledges support from ISCIII, Spain and the European Commission-Next generation EU (European Union), through CSIC's Global Health PTI.

Mortalin/GRP75 is a ubiquitous mitochondrial chaperone related to the cytosolic heat shock protein 70. It protects cells from various types of damages and from senescence. Our goal was to determine whether COVID-19 patients have circulating mortalin in their blood and to assess its prognostic value in anticipating disease severity.

Mortalin was determined by ELISA in the sera of 83 COVID-19 patients enrolled in the study. Patients were categorized into 4 groups: critical patients who died (FATAL) or required intensive care and survived (ICU), patients of mild severity (hospitalized but not critical) who required nasal oxygen support (HOSP+O2), and patients who did not need oxygen therapy (HOSP).

The mortalin concentration in the serum of all COVID-19 patients in the cohort was 194-2324 pg/mL. A comparison of the mortalin levels by peak severity among the various patient groups showed a highly significant difference between the HOSP and FATAL groups and a significant difference between the HOSP and the ICU groups. COVID-19 patients who eventually failed to survive had at hospitalization a markedly higher level of mortalin in their sera. Cox regression analysis revealed a high mortality hazard (HR=3.96, p<0.01) in patients with high mortalin circulating levels (above the median, ≥651 pg/mL). This was confirmed in survival curve analysis (Kaplan-Meier; p=0.0032, log-rank test). Mortalin remained an independent predictor of mortality even after adjusting for age and sex or various complement activation products. Complement activation data collected in an earlier study in the same cohort was compared regarding the mortalin levels. Patients with higher circulating mortalin levels also had higher levels of complement C3a but reduced levels of properdin.

This is the first report on circulating mortalin in COVID-19 patients. Higher mortalin levels were associated with more severe illnesses and a higher risk of death. We claim that quantifying the blood levels of mortalin and activated complement proteins will provide important information on the prognosis of COVID-19 patients and will serve as a useful tool for guiding their clinical management and treatment.

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.

Melittin (MLT), a peptide containing 26 amino acids, is a key constituent of bee venom. It comprises ∼40%-60% of the venom's dry weight and is the main pricing index for bee venom, being the causative factor of pain. The unique properties of MLT extracted from bee venom have made it a very valuable active ingredient in the pharmaceutical industry as this cationic and amphipathic peptide has propitious effects on human health in diverse biological processes. It has the ability to strongly impact the membranes of cells and display hemolytic activity with anticancer characteristics. However, the clinical application of MLT has been limited by its severe hemolytic activity, which poses a challenge for therapeutic use. By employing more efficient mechanisms, such as modifying the MLT sequence, genetic engineering, and nano-delivery systems, it is anticipated that the limitations posed by MLT can be overcome, thereby enabling its wider application in therapeutic contexts. This review has outlined recent advancements in MLT's nano-delivery systems and genetically engineered cells expressing MLT and provided an overview of where the MLTMLT's platforms are and where they will go in the future with the challenges ahead. The focus is on exploring how these approaches can overcome the limitations associated with MLT's hemolytic activity and improve its selectivity and efficacy in targeting cancer cells. These advancements hold promise for the creation of innovative and enhanced therapeutic approaches based on MLT for the treatment of cancer.

Coronavirus disease 2019 (COVID-19) displays clinical heterogeneity, but little information is available for patients with mild or very early disease. We aimed to characterize biomarkers that are useful for discriminating the hospitalization risk in a COVID-19 cohort from Northern Italy during the first pandemic wave. We enrolled and followed for four weeks 76 symptomatic SARS-CoV-2 positive patients and age/sex-matched healthy controls. Patients with mild disease were discharged (n.42), and the remaining patients were hospitalized (n.34). Blood was collected before any anti-inflammatory/immunosuppressive therapy and assessed for soluble C5b-9/C5a, H3-neutrophil extracellular traps (NETs), calprotectin, and DNase plasma levels via ELISA and a panel of proinflammatory cytokines via ELLA. Calprotectin and NET levels discriminate between hospitalized and non-hospitalized patients, while DNase negatively correlates with NET levels; there are positive correlations between calprotectin and both NET and neopterin levels. Neopterin levels increase in patients at the beginning of the disease and do so more in hospitalized than non-hospitalized patients. C5a and sC5b-9, and other acute phase proteins, correlate with neopterin, calprotectin, and DNase. Both NET and neopterin levels negatively correlate with platelet count. We show that calprotectin, NETs, and neopterin are important proinflammatory parameters potentially useful for discriminating between COVID-19 patients at risk of hospitalization.

With a high incidence of acute kidney injury among hospitalized COVID-19 patients, considerable attention has been focussed on whether SARS-CoV-2 specifically targets kidney cells to directly impact renal function, or whether renal damage is primarily an indirect outcome. To date, several studies have utilized kidney organoids to understand the pathogenesis of COVID-19, revealing the ability for SARS-CoV-2 to predominantly infect cells of the proximal tubule (PT), with reduced infectivity following administration of soluble ACE2. However, the immaturity of standard human kidney organoids represents a significant hurdle, leaving the preferred SARS-CoV-2 processing pathway, existence of alternate viral receptors, and the effect of common hypertensive medications on the expression of ACE2 in the context of SARS-CoV-2 exposure incompletely understood. Utilizing a novel kidney organoid model with enhanced PT maturity, genetic- and drug-mediated inhibition of viral entry and processing factors confirmed the requirement for ACE2 for SARS-CoV-2 entry but showed that the virus can utilize dual viral spike protein processing pathways downstream of ACE2 receptor binding. These include TMPRSS- and CTSL/CTSB-mediated non-endosomal and endocytic pathways, with TMPRSS10 likely playing a more significant role in the non-endosomal pathway in renal cells than TMPRSS2. Finally, treatment with the antihypertensive ACE inhibitor, lisinopril, showed negligible impact on receptor expression or susceptibility of renal cells to infection. This study represents the first in-depth characterization of viral entry in stem cell-derived human kidney organoids with enhanced PTs, providing deeper insight into the renal implications of the ongoing COVID-19 pandemic.

Utilizing a human iPSC-derived kidney organoid model with improved proximal tubule (PT) maturity, we identified the mechanism of SARS-CoV-2 entry in renal cells, confirming ACE2 as the sole receptor and revealing redundancy in downstream cell surface TMPRSS- and endocytic Cathepsin-mediated pathways. In addition, these data address the implications of SARS-CoV-2 exposure in the setting of the commonly prescribed ACE-inhibitor, lisinopril, confirming its negligible impact on infection of kidney cells. Taken together, these results provide valuable insight into the mechanism of viral infection in the human kidney.

The world continues to contend with COVID-19, fueled by the emergence of viral variants. At the same time, a subset of convalescent individuals continues to experience persistent and prolonged sequelae, known as long COVID. Clinical, autopsy, animal and in vitro studies all reveal endothelial injury in acute COVID-19 and convalescent patients. Endothelial dysfunction is now recognized as a central factor in COVID-19 progression and long COVID development. Different organs contain different types of endothelia, each with specific features, forming different endothelial barriers and executing different physiological functions. Endothelial injury results in contraction of cell margins (increased permeability), shedding of glycocalyx, extension of phosphatidylserine-rich filopods, and barrier damage. During acute SARS-CoV-2 infection, damaged endothelial cells promote diffuse microthrombi and destroy the endothelial (including blood-air, blood-brain, glomerular filtration and intestinal-blood) barriers, leading to multiple organ dysfunction. During the convalescence period, a subset of patients is unable to fully recover due to persistent endothelial dysfunction, contributing to long COVID. There is still an important knowledge gap between endothelial barrier damage in different organs and COVID-19 sequelae. In this article, we mainly focus on these endothelial barriers and their contribution to long COVID.

SARS-CoV-2, the causative agent of COVID-19, primarily affects the epithelial compartment in the upper and lower airways. There is evidence that the microvasculature in both the pulmonary and extrapulmonary systems is a major target of SARS-CoV-2. Consistent with this, vascular dysfunction and thrombosis are the most severe complications in COVID-19. The proinflammatory milieu triggered by the hyperactivation of the immune system by SARS-CoV-2 has been suggested to be the main trigger for endothelial dysfunction during COVID-19. More recently, a rapidly growing number of reports have indicated that SARS-CoV-2 can interact directly with endothelial cells through the spike protein, leading to multiple instances of endothelial dysfunction. Here, we describe all the available findings showing the direct effect of the SARS-CoV-2 spike protein on endothelial cells and offer mechanistic insights into the molecular basis of vascular dysfunction in severe COVID-19.

Severe infections induce immune defense mechanisms and initial tissue damage, which produce an inflammatory neutrophil response. Upon dysregulation of these responses, inflammation, further tissue damage, and systemic spread of the pathogen may occur. Subsequent vascular inflammation and activation of coagulation processes may cause microvascular obstruction at sites distal to the primary site of infection. Low immunoglobulin (Ig) M and IgG levels have been detected in patients with severe infections like sCAP and sepsis, associated with increased severity and mortality. Based on Ig's modes of action, supplementation with polyvalent intravenous Ig preparations (standard IVIg or IgM/IgA-enriched Ig preparations) has long been discussed as a treatment option for severe infections. A prerequisite seems to be the timely administration of Ig preparations before excessive tissue damage has occurred and coagulopathy has developed. This review focuses on nonclinical and clinical studies that evaluated tissue-protective activities resulting from interactions of Igs with neutrophils, complement, and the coagulation system. The data indicate that coagulopathy, organ failure, and even death of patients can possibly be prevented by the timely combined interactions of (natural) IgM, IgA, and IgG with neutrophils and complement.

During the coronavirus disease 2019 (COVID-19) pandemic, acute kidney injury (AKI) was a common sequela of COVID-19 infection and predicted disease severity and mortality. Extracorporeal blood purification techniques involving blood filtration devices are an emerging treatment for AKI in the setting of severe COVID-19 infections. In this review, we discuss potential mechanisms for the development of AKI in COVID-19 patients as well as the various available blood filtration devices and the role they may play in managing the AKI in COVID-19 patients. A total of seven blood filters currently available were compared based on their potential in treating AKI in COVID-19 patients. Blood filtration devices show potential as an emerging treatment modality for COVID-19-induced AKI, but further clinical trials are necessary before their widespread adoption and usage.

This report provides insight into three distinct pediatric cases exhibiting a nexus between multisystem inflammatory syndrome in children (MIS-C) and thrombotic microangiopathy (TMA) triggered by COVID-19. The aim is to underscore the range of clinical presentations and the essentiality of early interventions.

This report presents three cases aged 10 months, 7 years, and 3 years with persistent fever, diarrhea, nausea, and vomiting. The first case, a 10-month-old girl, demonstrated acute kidney injury (AKI) and microangiopathic hemolytic anemia (MAHA) following a COVID-19 infection. Despite initial negative SARS-CoV-2 RT-PCR results, her condition escalated rapidly, presenting increased levels of LDH (peaking at 4,200 U/L) and requiring renal replacement therapy (RRT) to manage deteriorating renal function. Interventions with eculizumab and anakinra led to marked improvements, with a stable follow-up of 13 months post-hospitalization. The second case involved a 7-year-old girl who developed symptoms of MIS-C, hemolytic uremic syndrome (HUS), and posterior reversible encephalopathy syndrome (PRES) post-exposure to COVID-19, evidenced by heightened LDH levels (3,522 U/L at peak). After a precarious period of deteriorating kidney function and exacerbated hypertension, she responded positively to treatments, inclusive of IVIG, steroid therapies, and eculizumab, with a favorable 6-month follow-up showcasing stable laboratory results. The third case discusses a 3-year-old boy, without any medical history, manifesting HUS symptoms and COVID-19 infection. He exhibited increased LDH levels (peaking at 3,946 U/L) alongside elevated creatinine, marking renal impairment. He responded well to hemodialysis, IVIG, and steroid therapy, showcasing substantial recovery by the 19th day of hospitalization, which marked his discharge with a tapering steroid regimen.

This case series underscores that MIS-C-associated TMA is a significant complication in pediatric COVID-19. Our findings illuminate the potential for treatment success but simultaneously emphasize the need for a more comprehensive understanding of the underlying pathophysiology.

Kidney injury is common in patients with Coronavirus Disease-19 (COVID-19), which is related to poor prognosis. We aim to summarize the clinical features, athological types, and prognosis of COVID-19 associated kidney injury caused by the Omicron strain. In this study, 46 patients with Omicron-associated kidney injury were included, 38 of whom performed renal biopsy. Patients were divided into two groups: group A for patients with onset of kidney injury after SARS-CoV-2 infection; group B for patients with pre-existing kidney disease who experienced aggravation of renal insufficiency after SARS-CoV-2 infection. The clinical, pathological, and prognostic characteristics of the patients were observed. Acute kidney injury (AKI) (35%) was the most common clinical manifestation in group A. Patients in group B mainly presented with chronic kidney disease (CKD) (55%) and nephrotic syndrome (NS) (40%). The pathological type was mainly IgA nephropathy (IgAN) (39% in group A and 45% in group B). Among all of them, one case presenting with thrombotic microangiopathy had worse kidney function at biopsy time. Mean serum C3 levels were 1.2 ± 0.5 and 1.0 ± 0.2 g/L in group A and group B, respectively. In renal tissues, C3 deposits were observed in 71.1% of patients. 11.8% (n = 2) patients experienced deterioration of renal function after treatment, but no patients developed to end-stage renal disease. In our single-center study in China, the main clinical manifestations were AKI, CKD, and NS, while the main pathological type was IgAN. Compared with previous strains of SARS-CoV-2, patients with the Omicron infection had a favorable prognosis.

The complement system is an essential part of innate immunity. It is activated by invading pathogens causing inflammation, opsonization, and lysis via complement anaphylatoxins, complement opsonin's and membrane attack complex (MAC), respectively. However, in SARS-CoV-2 infection overactivation of complement system is causing cytokine storm leading to multiple organs damage. In this study, the René Thomas kinetic logic approach was used for the development of biological regulatory network (BRN) to model SARS-CoV-2 mediated complement system signalling pathways. Betweenness centrality analysis in cytoscape was adopted for the selection of the most biologically plausible states in state graph. Among the model results, in strongly connected components (SCCs) pro-inflammatory cytokines (PICyts) oscillatory behaviour between recurrent generation and downregulation was found as the main feature of SARS-CoV-2 infection. Diversion of trajectories from the SCCs leading toward hyper-inflammatory response was found in agreement with in vivo studies that overactive innate immunity response caused PICyts storm during SARS-CoV-2 infection. The complex of negative regulators FI, CR1 and DAF in the inhibition of complement peptide (C5a) and PICyts was found desirable to increase immune responses. In modelling role of MAC and PICyts in lowering of SARS-CoV-2 titre was found coherent with experimental studies. Intervention in upregulation of C5a and PICyts by C3 was found helpful in back-and-forth variation of signalling pattern linked with the levels of PICyts. Moreover, intervention in upregulation of PICyts by C5a was found productive in downregulation of all activating factors in the normal SCCs. However, the computational model predictions require experimental studies to be validated by exploring the activation role of C3 and C5a which could change levels of PICyts at various phases of SARS-CoV-2 infection.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by hemolytic anemia, bone marrow failure, thrombophilia. COVID-19, caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with many variants including Omicron.

This study collected demographic and clinical data of 20 PNH patients with SARS-CoV-2 Omicron infection.

They all were with high disease activity, and LDH level exceeded any documented since the diagnosis of PNH, and those reported in the literature for previously stable treatment with complement inhibitors. D-dimer level elevated in 10 patients. 2 patients developed mild pulmonary artery hypertension. Glomerular filtration rate declined in 5 patients. 1 patient developed acute renal failure and underwent hemodialysis. Anemia and hemolysis were improved in 5 patients treated with eculizumab.

Hemolytic exacerbation of PNH with COVID-19 is severe and eculizumab may be an effective treatment.

The spike protein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can interact with endothelial cells. However, no studies demonstrated the direct effect of the spike protein subunit 1 (S1) in inducing lung vascular damage and the potential mechanisms contributing to lung injury. Here, we found that S1 injection in mice transgenic for human angiotensin converting enzyme 2 (ACE2) induced early loss of lung endothelial thromboresistance at 3 days, as revealed by thrombomodulin loss and von Willebrand factor (vWF) increase. In parallel, vascular and epithelial C3 deposits and enhanced C3a receptor (C3aR) expression were observed. These changes preceded diffuse alveolar damage and lung vascular fibrin(ogen)/platelets aggregates at 7 days, as well as inflammatory cell recruitment and fibrosis. Treatment with C3aR antagonist (C3aRa) inhibited lung C3 accumulation and C3a/C3aR activation, limiting vascular thrombo-inflammation and fibrosis. Our study demonstrates that S1 triggers vascular dysfunction and activates complement system, instrumental to lung thrombo-inflammatory injury. By extension, our data indicate C3aRa as a valuable therapeutic strategy to limit S1-dependent lung pathology.

The COVID-19 coronavirus, which primarily affects the lungs, is the source of the disease known as SARS-CoV-2. According to "Smoking and COVID-19: a scoping review," about 32% of smokers had a severe case of COVID-19 pneumonia at their admission time and 15% of non-smokers had this case of COVID-19 pneumonia. We were able to determine which genes were expressed differently in each group by comparing the expression of gene transcriptomic datasets of COVID-19 patients, smokers, and healthy controls. In all, 37 dysregulated genes are common in COVID-19 patients and smokers, according to our analysis. We have applied all important methods namely protein-protein interaction, hub-protein interaction, drug-protein interaction, tf-gene interaction, and gene-MiRNA interaction of bioinformatics to analyze to understand deeply the connection between both smoking and COVID-19 severity. We have also analyzed Pathways and Gene Ontology where 5 significant signaling pathways were validated with previous literature. Also, we verified 7 hub-proteins, and finally, we validated a total of 7 drugs with the previous study.

Brain fog can be described as a constellation of new-onset neuropsychiatric sequelae in the post-acute phase of COVID-19 (long COVID). The symptoms include inattention, short-term memory loss, and reduced mental acuity, which may undermine cognition, concentration, and sleep. This cognitive impairment, persisting for weeks or months after the acute phase of SARS-CoV-2 infection, can significantly impact on daily activities and the quality of life. An important role for the complement system (C) in the pathogenesis of COVID-19 has emerged since the beginning of pandemic outbreak. A number of pathophysiological characteristics including microangiopathy and myocarditis have been attributed to dysregulated C activation due to SARS-CoV-2 infection. Mannan-binding lectin (MBL), the first recognition subcomponent of the C lectin pathway, has been shown to bind to glycosylated SARS-CoV-2 spike protein, genetic variants of MBL2 are suggested to have an association with severe COVID-19 manifestations requiring hospitalization. In the present study, we evaluated MBL activity (lectin pathway activation) and levels in the sera of a cohort of COVID-19 patients, presenting brain fog or only hyposmia/hypogeusia as persistent symptoms, and compared them with healthy volunteers. We found significantly lower levels of MBL and lectin pathway activity in the sera of patients experiencing brain fog as compared to recovered COVID-19 patients without brain fog. Our data indicate that long COVID-associated brain fog can be listed among the variegate manifestations of increased susceptibility to infections and diseases contributed by MBL deficiency.

Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms.

Using measurements of ~4000 plasma proteins in two cohorts of patients hospitalized with COVID-19, we discovered and validated markers of COVID-associated AKI (stage 2 or 3) and long-term kidney dysfunction. In the discovery cohort (N = 437), we identified 413 higher plasma abundances of protein targets and 30 lower plasma abundances of protein targets associated with COVID-AKI (adjusted p < 0.05). Of these, 62 proteins were validated in an external cohort (p < 0.05, N = 261).

We demonstrate that COVID-AKI is associated with increased markers of tubular injury (NGAL) and myocardial injury. Using estimated glomerular filtration (eGFR) measurements taken after discharge, we also find that 25 of the 62 AKI-associated proteins are significantly associated with decreased post-discharge eGFR (adjusted p < 0.05). Proteins most strongly associated with decreased post-discharge eGFR included desmocollin-2, trefoil factor 3, transmembrane emp24 domain-containing protein 10, and cystatin-C indicating tubular dysfunction and injury.

Using clinical and proteomic data, our results suggest that while both acute and long-term COVID-associated kidney dysfunction are associated with markers of tubular dysfunction, AKI is driven by a largely multifactorial process involving hemodynamic instability and myocardial damage.

Sepsis is accompanied by thrombocytopenia and the severity of the thrombocytopenia is associated with mortality. This thrombocytopenia is characteristic of disseminated intravascular coagulation (DIC), the sepsis-associated coagulopathy. Many of the pathogens, both bacterial and viral, that cause sepsis also directly activate platelets, which suggests that pathogen-induced platelet activation leads to systemic thrombosis and drives the multi-organ failure of DIC. In this paper we review the mechanisms of platelet activation by pathogens and the evidence for a role for anti-platelet agents in the management of sepsis.

During 2019, the SARS-CoV-2 emerged from China, and during months, COVID-19 spread in many countries around the world. The expanding data about pathogenesis of this virus could elucidate the exact mechanism by which COVID-19 caused death in humans. One of the pathogenic mechanisms of this disease is coagulation. Coagulation disorders that affect both venous and arterial systems occur in patients with COVID-19. The possible mechanism involved in the coagulation could be excessive inflammation induced by SARS-CoV-2. However, it is not yet clear well how SARS-CoV-2 promotes coagulopathy. However, some factors, such as pulmonary endothelial cell damage and some anticoagulant system disorders, are assumed to have an important role. In this study, we assessed conducted studies about COVID-19-induced coagulopathy to obtain clearer vision of the wide range of manifestations and possible pathogenesis mechanisms.