Natural small molecule compounds have become the alternative options for developing antiviral reagent due to their broad-spectrum antiviral properties and low toxicity. Eugenol is a natural volatile phenolic aromatic compound primarily derived from clove oil. The small compound is well-recognized for its local anesthetic, anti-inflammatory, and preservative properties, making it a common choice for oral disinfection and as an adjunctive treatment for periodontitis. Clinical and experimental evidence shows that eugenol exhibits significant inhibitory effects against a variety of pathogenic microorganisms, including bacteria, fungi, and the viruses. In viral infectious diseases, eugenol can directly interact with pathogenic antigens in viral structures to prevent viral invasion. Additionally, it offers anti-inflammatory and antioxidant benefits by inhibiting multiple inflammatory mediators, thereby reducing organ damage. To the best of our knowledge, recent advancements in the antiviral properties of eugenol have not been solely addressed. This review aims to offer a new insight into the antiviral activity of eugenol and its potential mechanisms of action. Based on the literature review, we suggest that the antiviral mechanisms of eugenol are associated with cellular autophagy, and that the nuclear factor kappa-B (NF-κB) signaling pathway is the primary inflammatory pathway regulated by eugenol. These findings highlight the need for further investigation through rigorously designed experimental studies focused on specific viruses.

The pandemic of COVID-19 has ignited a global race to locate effective therapies with drug repositioning emerging as a leading strategy due to its cost-effectiveness and established safety profiles. Remdesivir, Favipiravir, Hydroxychloroquine, and Chloroquine have been the focus of rigorous clinical trials to determine their therapeutic potential against SARS-CoV-2. This article delves into the innovative synthetic strategies behind these drugs, providing a blueprint for researchers navigating the complex landscape of antiviral development. Beyond synthesis, we explore the fascinating mechanisms of action: hydroxychloroquine and chloroquine elevate lysosomal pH to impede autophagy and viral replication; favipiravir, a nucleoside analogue, induces lethal mutagenesis or RNA chain termination and remdesivir disrupts viral RNA synthesis through delayed chain termination. By merging synthetic methodologies with mechanistic insights, this article offers a comprehensive resource aimed at accelerating the development of potent COVID-19 therapies and underscores the crucial part that chemistry in addressing global health emergencies. It also underscores the vital function of chemistry in addressing global health emergencies and highlights how innovative drug design and repurposing can provide rapid responses to emerging infectious diseases. This fusion of chemistry and virology not only advances our understanding of drug action but also paves the way for the discovery of new therapeutic agents crucial in future pandemics.

Background/Objectives: SARS-CoV-2 infection has the potential to cause multi-organ involvement and, when associated with Epstein-Barr virus (EBV) coinfection, may worsen the course of disease in pediatric patients by influencing the immune response. Methods: Our retrospective-observational study included 406 hospitalized children with post-COVID-19 status or SARS-CoV-2/EBV coinfection. Results: Hypovitaminosis D was more common in the coinfected sublot (59.18%) than in the COVID-19 one (50.74%), with a higher frequency of severe vitamin D deficiency (16.33% vs. 7.35%). Hypovitaminosis D was significantly associated with female sex (p = 0.033) only in the COVID-19 subgroup. Hypervitaminosis D, although rare, was only associated with severe forms of the disease (7.69%). Between clinical severity and vitamin D level, a statistically significant association of moderate intensity was identified only in the COVID-19 subgroup (χ2 = 11.708, φ = 0.293, p = 0.020). In the same subgroup, a significant correlation was found between vitamin D levels and serum potassium values (χ2 = 10.527, p = 0.032). Moreover, in the COVID-19 subgroup, an association between abnormal sodium levels and increased D-dimer levels was found (χ2 = 7.074, p = 0.029). Conclusions: These results underline the importance of monitoring immunologic, vitamin, and electrolyte imbalance in the management of these cases and highlight the need for personalized therapeutic strategies to prevent long-term complications.

Background: Breast cancer and chronic bacterial infections are pressing global health issues, and traditional treatments are often hampered by resistance and adverse side effects. This study sought to create silver nanoparticles (AgNPs) through eco-friendly synthesis using Hibiscus rosa sinensis (HRS) flower extract and to assess their antibacterial, antibiofilm, and anticancer properties. Methods: HRS extract functioned as both a reducing and stabilizing agent in the synthesis of AgNPs. The nanoparticles were characterized using ultraviolet-visible spectroscopy (UV-Vis), Fourier-transform infrared (FTIR) spectroscopy, and transmission electron microscopy (TEM). Antibacterial and antibiofilm properties were evaluated against gram-positive (Staphylococcus aureus and Enterococcus faecalis) and gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacteria using agar well diffusion and XTT reduction assays. The cytotoxic effects on MDMB-231 breast cancer cells and normal splenocytes were measured using the MTT assay, whereas fluorescence microscopy was used to observe reactive oxygen species (ROS) production, changes in mitochondrial membrane potential, and caspase-3 activation. Results: The synthesized HRS-AgNPs, primarily ranging from 10 to 50 nm, displayed a distinct surface plasmon resonance (SPR) peak at 428 nm. They exhibit notable antibacterial activity, especially against gram-positive bacteria, and effectively disrupt bacterial biofilms. Cytotoxicity evaluations showed that HRS-AgNPs decreased the viability of MDMB-231 cells in a dose-dependent manner, with minimal toxicity observed in normal splenocytes. The increase in ROS levels, reduction in mitochondrial membrane potential, and heightened caspase-3 activity collectively suggest apoptosis-driven cell death in cancer cells. Conclusions: HRS-AgNPs demonstrated dual functionality, with strong antibacterial and selective anticancer effects. Their environmentally friendly synthesis, stability, and significant biological activities suggest their potential for further development, including in vivo safety and efficacy assessments for clinical applications in treating infections and breast cancer.

Significant efforts were currently being made worldwide to develop a tool capable of distinguishing between various harmful viruses through simple analysis. In this study, we utilized fluorescence excitation-emission matrix (EEM) spectroscopy as a rapid and specific tool with high sensitivity, employing a straightforward methodological approach to identify spectral differences between samples of respiratory infection viruses. To achieve this goal, the fluorescence EEM spectral data from eight virus samples was divided into training and test sets, which were then analyzed using random forest and support vector machine classification models. We proposed a novel strategy for data fusion based on fast Fourier transform (FFT) and wavelet transform (WT) methods, which significantly enhanced classification accuracy from 45 % to 75 %. This approach improved the classification capability for similar spectral characteristics of viruses. Rhinovirus was further differentiated from rotavirus, while influenza A virus was distinguished from inactivated poliovirus vaccines and rhinovirus. This study demonstrated that the integration of fluorescence EEM spectroscopy with machine learning algorithms presented significant potential for the detection of unidentified harmful substances in the ambient environment.

The Coronavirus disease (COVID-19) has impacted pregnant women significantly, with increased mortality and morbidity. The implications of this virus are linked to extracellular vesicles (EVs) and maternal inflammation due to the cytokine storm. Hence, this study aims to investigate the impact of COVID-19 on the pro-inflammatory cytokine profile in both plasma and EVs of South African pregnant women.

Plasma samples were obtained from pregnant women in the third trimester, from which EVs were extracted using the Invitrogen Total Exosome Isolation Kit. These plasma-derived EVs were characterised using transmission electron microscopy and nanoparticle tracking analysis (NTA).

COVID-19 infection in pregnancy did not significantly affect the average particle size and concentration of isolated EVs. The levels of IFN gamma, IL-6, MIP-1 alpha and TNF alpha were analysed in the plasma and circulating EVs through a multiplex assay. Compared to the control group, a significant increase in IL-6, IFN-γ, TNF-α and MIP-1α levels were observed in both plasma and EVs content of COVID-19 pregnancies.

These findings suggest that COVID-19 infection impacts the pro-inflammatory cytokine profile in the plasma and EVs of South African pregnant women.

Evaluating long-term immunity after COVID-19 infection and vaccination is critical for managing potential outbreaks. The aim of this study was to develop a cost-effective in-house enzyme-linked immunosorbent assay (ELISA) based on Escherichia coli-expressed SARS-CoV-2 spike protein (E-S1) for antibody detection and to evaluate its performance. The system was validated by comparing the in-house ELISA results with those obtained using a commercial ELISA with HEK293-expressed spike protein (H-S1). Recombinant SARS-CoV-2 spike protein was produced in E. coli, purified, and validated for antigenicity via ELISA. Indirect ELISAs with both E-S1 and H-S1 antigens were performed on 386 serum samples from COVID-19 survivors, vaccinated individuals, and pre-pandemic controls collected at different time points. The E-S1 ELISA showed a statistically significant but weak correlation with H-S1 ELISA across all samples (r=0.205; p=0.0001). Stronger correlations were observed among vaccinated individuals with prior infection on day 90 (r=0.6017; p<0.001) and in naïve vaccine recipients on day 30 (r=0.5361; p=0.0003). Pre-pandemic sera from a rural population in Sumba Island exhibited high background reactivity in E-S1 ELISA, likely due to anti-E. coli antibodies, while urban pre-pandemic sera from Jakarta showed a stronger correlation with H-S1 ELISA. This suggests potential regional or immune background differences influencing assay performance. Although E-S1 retained antigenic properties, its diagnostic utility is limited by non-specific reactivity and reduced sensitivity compared to H-S1. In conclusion, E. coli expression systems may not be ideal for producing spike protein-based ELISA antigens specific to SARS-CoV-2. Alternative expression systems, such as human or baculovirus, could enhance diagnostic accuracy and specificity for COVID-19 antibody detection.

Vaccination against COVID-19 is safe for patients greater than 6 months of age and reduces virus infectivity and severity. One strategy for protecting children unable to be vaccinated is cocooning, a concept that protects at-risk individuals by vaccinating adult caregivers (ACs). This study evaluates AC characteristics of those receiving COVID-19 vaccination in pediatric healthcare clinics.

This study is a retrospective chart review that identified ACs greater than 21 years of age who received a COVID-19 vaccine at one of six UFHealth pediatric offices between March 2021-April 2022. Investigators collected demographic information of the AC and corresponding child.

The AC sample was predominantly female (79.8%), parents (75.3% mothers, 19.3% fathers), White (48.2%) or Black/African American (33.7%). Those who completed both primary doses had higher rates of children less than 5 years compared to those who did not (48.2%, 37.2%; p-value: 0.0225). ACs completing both primary doses were also younger compared to their counterparts (37.0, 39.9 years; p-value: 0.0017), with double the rate of government-funded insurance (42.9%, 20.9%; p-value: <0.0001), and significantly different racial/ethnic distribution (p-value 0.0021).

ACs who completed both primary doses were younger females and had higher rates of children under 5 years old. We believe these results reflect the convenience of offering AC vaccines at pediatric healthcare clinics because of the high frequency of well-child checks within the first 5 years of life. This cohort also had double the rate of government-funded insurance, attributable to the free administration of COVID-19 vaccines at UF-affiliated pediatric clinics.

Janus kinase inhibitors (JAKis) represent a relatively new class of immunomodulatory drugs with potent effects on various cytokine signalling pathways. They have revolutionized the treatment landscape for autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. However, their ability to modulate immune responses presents a dual-edged nature, influencing both protective immunity and pathological inflammation. This review explores the complex role of JAKis in infectious settings, highlighting both beneficial and detrimental effects. On the one hand, experimental models suggest that JAK inhibition can impair host defence mechanisms, increasing susceptibility to certain bacterial and viral infections. For example, tofacitinib-treated mice exhibited more severe joint erosions in Staphylococcus aureus (S. aureus) septic arthritis and showed impaired viral clearance in herpes simplex encephalitis. Additionally, clinical data confirm an increased risk of herpes zoster in patients receiving JAKis, underscoring the need for rigorous monitoring. On the other hand, JAK inhibition has demonstrated protective effects in certain infectious and hyperinflammatory conditions. In sepsis models, including cecal ligation and puncture (CLP) and S. aureus bacteraemia, tofacitinib improved survival by attenuating excessive inflammation. Furthermore, JAKis, particularly baricitinib, have shown substantial efficacy in mitigating cytokine storms during severe COVID-19 infections, leading to improved clinical outcomes and reduced mortality. These observations suggest that JAKis have a role in modulating hyperinflammatory responses in select infectious contexts. In conclusion, JAKis present a complex interplay between immunosuppression and immunomodulation. While they increase the risk of certain infections, they also show potential in managing hyperinflammatory conditions such as cytokine storms. The key challenge is determining which patients and situations benefit most from JAKis while minimizing risks, requiring a careful and personalized treatment approach.

Platelets, known for maintaining blood balance, also participate in antimicrobial defense. Upon severeacute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, platelets become hyperactivated, releasing molecules such as cytokines, granule contents, and bioactive lipids. The key effector biolipids produced by platelets include 12-hydroxyeicosatetraenoic acid (12-HETE) and 12-hydroxyeicosatrienoic acid (12-HETrE), produced by 12-lipoxygenase (12-LOX), and prostaglandins and thromboxane, produced by cyclooxygenase-1. While prostaglandin E2 and thromboxane B2 were previously associated with lung inflammation in severe COVID-19, the role of platelet 12-LOX in SARS-CoV-2 infection remains unclear. Using mice deficient for platelets' 12-LOX, we report that SARS-CoV-2 infection resulted in higher lung inflammation characterized by histopathological tissue analysis, increased leukocyte infiltrates, and cytokine production relative to wild-type mice. In addition, distinct platelet and lung transcriptomic changes, including alterations in NOD-like receptor (NLR) family pyrin domain-containing 1 (NLRP1) inflammasome-related gene expression, were observed. Mass spectrometry lipidomic analysis in 12-LOX-deficient-infected mice revealed significant changes in bioactive lipid content, including reduced levels of 12-HETrE that inversely correlated with disease severity. Finally, platelet 12-LOX deficiency was associated with increased morbidity and lower survival rates relative to wild type (WT) mice. Overall, this study highlights the complex interplay between 12-LOX-related lipid metabolism and inflammatory responses during SARS-CoV-2 infection. The findings provide valuable insights into potential therapeutic targets aimed at mitigating severe outcomes, emphasizing the pivotal role of platelet enzymes in the host response to viral infections.

SARS-CoV-2 and Mycobacterium tuberculosis (Mtb) share similarities in their modes of transmission, pathophysiological symptoms, and clinical manifestations. An imbalance in the immune response characterised by elevated levels of some inflammatory cytokines caused by tuberculosis (TB) and COVID-19 may increase the risk of developing a severe disease-like condition. It has been reported that TB increases the expression levels of Ace2 (angiotensin converting enzyme 2) and Tmprss2 (transmembrane protease serine 2) proteins, which are essential for COVID-19 pathogenesis. Single nucleotide polymorphisms (SNPs) variants of ace2 and tmprss2 genes can impact virus and host-cell interactions and alter immune responses by modulating cytokine production. This may modify the susceptibility and/or severity in COVID-19-infected people. The role of SNPs in ace2 and tmprss2 in relation to Mtb and SARS-CoV-2 co-infection is relatively underexplored.

In this study, genotype frequency of 10 SNPs of ace2 and 03 SNPs of tmprss2 genes in a Cameroonian cohort consisting of COVID-19-positive (n = 31), TB-positive (n = 43), TB-COVID-19 co-infected (n = 21), and a control group (n = 24) were studied. The immune response was estimated by quantitating inflammatory cytokine levels alongside self-reported and clinically diagnosed symptoms. The relationship between specific genetic mutations in these ace2 gene SNPs and their impact on cytokine expression levels in Mtb and SARS-CoV-2 co-infected patients was investigated.

We identified wild-type, heterozygous, and double-mutant genotypes in seven SNPs (rs2285666, rs6632677, rs4646116, rs4646140, rs147311723, rs2074192 and rs4646142) in ace2 gene, which showed significant variations in distribution across the study groups. Our most significant findings include the association of double mutant alleles (AA) of rs4646140 and rs2074192 in the ace2 gene with decreased IL-6 and IL-2 expression levels respectively in TB-COVID-19 participants. Also, the double mutant alleles (AA) of rs4646116 were responsible for increased expression level of IL-2 in TB-COVID-19 patients. Additionally, elevated serum levels of AST, urea, and D-dimer, as well as increased plasma concentrations of IL-10, IFN-γ, and TNF-α, have been associated with co-infections involving Mtb and SARS-CoV-2.

These biomarkers may reflect the complex interplay between the two pathogens and their impact on host immune responses and disease progression. This study highlights the critical role of genetic and immunological factors in shaping altered immune responses during co-infections involving Mtb and SARS-CoV-2. By elucidating these factors, the findings provide a foundation for a deeper understanding of host-pathogen interactions and their implications for disease progression and outcomes. Furthermore, this research has the potential to drive advancements in diagnostic approaches enabling more accurate detection and monitoring of co-infections.

The COVID-19 pandemic highlighted SARS-CoV-2 variants with increased transmissibility and immune evasion. In Ethiopia, where cases surged, the understanding of the virus's dynamics was limited. This study analyzed SARS-CoV-2 variants during the fifth wave, crucial for guiding vaccines, therapeutics, diagnostics, and understanding disease severity.

From June to August 2022, 150 SARS-CoV-2-positive samples were randomly selected from the Ethiopian Public Health Institute repository. Sixty-three high-quality genome sequences were analyzed.

Of the 63 sequences, 70% were from males and 30% from females, with a median age of 34. Omicron dominated (97%, 61/63), primarily clade 22A (64%, 40/63), followed by 22B (18%, 11/63) and 21K (14%, 9/63). Delta accounted for 3.2% (2/63). Omicron was identified in all (25) vaccinated study participants. Ethiopian sequences showed limited evolutionary divergence and lower genetic diversity compared to global sequences.

Omicron was the predominant variant during Ethiopia's fifth wave, indicating recent community transmission. Despite minor genetic diversity differences, ongoing surveillance remains critical for tracking variants and informing public health interventions.

The Omicron variant of SARS-CoV-2 has been associated with unique clinical presentations in children, including croup-like symptoms such as barking cough, hoarseness, and respiratory distress. This study aimed to compare the clinical, laboratory, and treatment characteristics of hospitalized pediatric patients with croup who tested positive or negative for COVID-19 during the Omicron wave.

A retrospective, descriptive-analytical study was conducted on 111 pediatric patients hospitalized with croup at Bahrami Children's Hospital and the Children's Medical Center in Iran from January 21 to March 20, 2022. Patients were categorized into two groups: PCR-positive (Omicron group, n = 30) and PCR-negative (non-Omicron group, n = 81). Data on demographics, clinical severity, laboratory indices, treatments, and outcomes were extracted and analyzed using SPSS version 20.

The mean age of the Omicron group was significantly younger (16.93 ± 24.80 months) compared to the non-Omicron group (32.58 ± 37.26 months; p = 0.049). Symptom severity was higher in the Omicron group, with moderate to severe symptoms observed in 73.4% of patients, compared to 32.1% in the non-Omicron group (p = 0.001). The Omicron group had longer hospital stays (2.59 ± 3.93 vs. 2.11 ± 2.75 days; p = 0.016) and required more nebulized epinephrine (2.47 ± 1.27 vs. 1.77 ± 1.003 days; p = 0.003) and repeat corticosteroid doses (83.3% vs. 38.3%; p = 0.0001). Laboratory findings showed no significant differences between the groups (all p > 0.05).

Children with croup during the Omicron surge exhibited increased symptom severity, required more intensive treatment, and experienced longer hospital stays compared to those without COVID-19. These findings emphasize the need for heightened clinical awareness and tailored management strategies for Omicron-related croup in pediatric populations.

Immunocompromised patients are at increased risk for severe outcomes from COVID-19 due to their altered immune responses, yet their inflammatory profiles and the interplay between immunosuppression remain poorly understood. We aimed to illustrate the inflammation profile and clinical outcomes of hospitalized immunocompromised patients with COVID-19.

We conducted a retrospective study using a multicenter database and included adult hospitalized patients with Corona virus disease 2019 (COVID-19) in China's late 2022 COVID-19 wave. Crude and adjusted 28- and 60-day mortality was compared between the two groups. Inflammatory phenotypes were evaluated by serum interleukin-6 (IL-6) and C-reactive protein (CRP) level. The interplay between overt inflammation and immunosuppression was analyzed.

Among the 4078 included patients, 348 (8.5%) were immunocompromised. Immunocompromised patients had lower crude mortality but higher adjusted mortality at 28-day (hazard ratio [HR] = 1.55; 95% CI 1.08 to 2.23) and 60-day (HR = 1.47; 95% CI 1.05 to 2.06). Besides, immunocompromised patients had a higher risk of developing hyperinflammation (odd ratio [OR] =1.92; 95% CI 1.47 to 2.50, p <0.001). Moreover, hyperinflammation mediated a major part of the deleterious survival effect of immunosuppression on COVID-19.

Immunodeficiency not only increases short-term mortality risk but also predisposes patients to hyperinflammation. The complex interplay between immunosuppression, hyperinflammation, and COVID-19 outcomes warrants more detailed profiling of inflammation and immunity in this population.

Respiratory tract infection (RTI) is the most important cause of visiting both public and private medical care services. During the decade preceding Covid-19, in developing countries, there was a gap in the epidemiology of respiratory viral infections, probably due to the difficulty of detecting viral agents in clinical microbiology laboratories routine, at that time. In this context, the aim of this study was to describe the occurrence of virus, demographic factors associated and the likelihood of coinfections detection by multiplex PCR methods. The target also was to determine the involvement of respiratory viruses other than SARS-CoV-2 as agents of upper respiratory tract infections (URTIs) using rapid respiratory panels by multiplex real time PCR with flow chip methodology. Samples of SARSs patients, 530 in total, were tested between 2022 and 2023, obtained from nasopharyngeal swabs, nasopharyngeal exudates or nasopharyngeal aspirates. Of 530 tests, 30% was human rhinovirus, the most prevalent, followed by respiratory syncytial virus B (21.5%) and human adenovirus (17.4%). Among the total of positive samples, 83.8% belonged to patients aged between 0 and 10 years, 62.6% of whom were aged between 1 and 10 years. Multiple virus detection was found in 50.4% of the samples tested, 93.1% of which were from patients under the age of 18. Viral co-infection was evident in the finding and was higher (88.7%) in patients under the age of 18 yeas.

Lung disease is an infection that causes chronic inflammation of the human lung cells, which is one of the major causes of death around the world. Thoracic X-ray medical image is a well-known cheap screening approach used for lung disease detection. Deep learning networks, which are used to identify disease features in X-rays medical images, diagnosing a variety of lung diseases, are playing an increasingly important role in assisting clinical diagnosis. This paper proposes an explainable transformer with a hybrid network structure (LungMaxViT) combining CNN initial stage block with SE block to improve feature recognition for predicting Chest X-ray images for multiple lung disease classification. We contrast four classical pre-training models (ResNet50, MobileNetV2, ViT and MaxViT) through transfer learning based on two public datasets. The LungMaxVit, based on maxvit pre-trained with ImageNet 1K datasets, is a hybrid transformer with fine-tuning hyperparameters on the both X-ray datasets. The LungMaxVit outperforms all the four mentioned models, achieving a classification accuracy of 96.8%, AUC scores of 98.3%, and F1 scores of 96.7% on the COVID-19 dataset, while AUC scores of 93.2% and F1 scores of 70.7% on the Chest X-ray 14 dataset. The LungMaxVit distinguishes by its superior performance in terms of Accuracy, AUC and F1-score compared with other hybrids Networks. Several enhancement techniques, such as CLAHE, flipping and denoising, are employed to improve the classification performance of our study. The Grad-CAM visual technique is leveraged to represent the heat map of disease detection, explaining the consistency among clinical doctors and neural network models in the treatment of lung disease from Chest X-ray. The LungMaxVit shows the robust results and generalization in detecting multiple lung lesions and COVID-19 on Chest X-ray images.

The intricacies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing acute lung injury (ALI) and modulating inflammatory factor dynamics in vivo remain poorly elucidated. The present study endeavors to explore the impact of the recombinant SARS-CoV-2 spike protein S1 subunit (S1SP) on ALI and inflammatory factor profiles in mice, aiming to uncover potential therapeutic targets and intervention strategies for the prevention and management of Coronavirus Disease 2019 (COVID-19).

To mimic COVID-19 infection, K18-hACE2 transgenic mice were intratracheally instilled with S1SP, while C57BL/6 mice were administered LPS to form a positive control group. This setup facilitated the examination of lung injury severity, inflammatory factor levels, and alterations in signaling pathways in mice mimicking COVID-19 infection. Histopathological assessment through HE staining, along with analysis of lung wet/dry ratio and ultrasound imaging, revealed severe lung injury.

After molding, K18-hACE2 mice exhibited a pronounced reduction in body weight and showed more significant lung injury (P < 0.05). Notably, there was a significant elevation in vascular permeability, total protein, and total white blood cells in bronchoalveolar lavage fluid (BALF) (P < 0.05), indicative of tissue damage. Additionally, the tight junction of lung tissue was compromised (P < 0.05), accompanied by intense oxidative stress marked by decreased SOD activity and elevated MDA content (P < 0.05). Cytokine levels, including IL-6, IL-1β, TNF-α, and MIG, were significantly upregulated in both BALF and serum of S1SP + K18 mice (P < 0.05). Furthermore, S1SP prominently augmented the expression of p-p65/P65 and attenuated IκBα expression in the NF-κB signaling pathway of humanized mice (P < 0.05), corroborating a heightened inflammatory response at the tissue level (P < 0.05).

The administration of S1SP to K18-hACE2 mice resulted in severe lung injury, enhanced vascular permeability, and compromised epithelial barrier function in vivo. This was accompanied by disruption of lung tight junctions, the manifestation of severe oxidative stress and a cytokine storm, as well as the activation of the NF-κB signaling pathway, highlighting key pathological processes underlying COVID-19-induced lung injury.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is intricately related to the reprogramming of host metabolism. However, existing studies have mainly focused on peripheral blood samples and barely identified specific metabolites that are critically involved in the pathology of coronavirus disease 2019 (COVID-19). In the current small-scale study, we performed metabolic profiling in plasma (n = 61) and paired bronchoalveolar lavage fluid (BALF) samples (n = 20) using parallel two-dimensional liquid chromatography-mass spectrometry (2DLC-MS). In addition, we studied how an identified metabolite regulates the immunopathogenesis of COVID-19. The results unveiled distinct metabolome changes between healthy donors, and moderate and severe patients in both plasma and BALF, indicating that locations and disease severity play critical roles in COVID-19 metabolic alteration. Notably, a vital metabolite, indoxyl sulfate, was found to be elevated in both the plasma and BALF of severe COVID-19 patients. Indoxyl sulfate selectively induced TNF-α production, reduced co-stimulatory signals, and enhanced apoptosis in human monocytes. Moreover, its levels negatively correlated with the strength of co-stimulatory signals and antigen presentation capability in monocytes of COVID-19 patients. Collectively, our findings suggest that the levels of indoxyl sulfate could potentially serve as a functional biomarker to monitor COVID-19 disease progression and guide more individualized treatment for COVID-19 patients.

Since the emergence of SARS-CoV-2 and the COVID-19 pandemic, a wide range of treatment options have been evaluated in preclinical studies and clinical trials, with several being approved for use in humans. Immunomodulatory drugs have shown success in dampening the deleterious inflammatory response seen in severe COVID-19 patients, but there remains an urgent need for development of additional therapeutic options for COVID-19 treatment. A potential drug target is the CCR5-CCL5 axis, and blocking this pathway may protect against severe disease. Here we evaluated whether OB-002, an analog of human CCL5 and a potent antagonist of CCR5, provides therapeutic benefit in SARS-CoV-2 infected Syrian hamsters. Daily treatment with OB-002 altered immune gene transcription in the lungs, and reduced pathology following infection, but did not prevent weight loss or viral replication in the lungs of infected animals, even in combination with the antiviral drug remdesivir. Our data suggest that targeting the CCR5-CCL5 pathway in SARS-CoV-2 infection in hamsters is insufficient to significantly impact disease development in this model.

The 2019 coronavirus illness (COVID 2019) first manifests as a newly identified pneumonia and may quickly escalate to acute respiratory distress syndrome, which has caused a global pandemic. Except for individualized supportive care, no curative therapy has been steadfastly advised for COVID-19 up until this point. T cells and virus-specific T lymphocytes are required to guard against viral infection, particularly COVID-19. Delayed immunological reconstitution (IR) and cytokine storm (CS) continue to be significant barriers to COVID-19 cure. While severe COVID-19 patients who survived the disease had considerable lymphopenia and increased neutrophils, especially in the elderly, their T cell numbers gradually recovered. Exhausted T lymphocytes and elevated levels of pro-inflammatory cytokines, including IL6, IL10, IL2, and IL17, are observed in peripheral blood and the lungs. It implies that while convalescent plasma, IL-6 blocking, mesenchymal stem cells, and corticosteroids might decrease CS, Thymosin α1 and adaptive COVID-19-specific T cells could enhance IR. There is an urgent need for more clinical research in this area throughout the world to open the door to COVID-19 treatment in the future.

In December 2022, China ceased the zero-COVID-19 policy, resulting in an increase in hospitalizations and deaths due to COVID-19, particularly among the elderly population. Predicting non-survivors aims to identify high-risk patients and enable targeted interventions to improve survival rates. Additionally, understanding factors affecting prognosis provides essential insights for further research and optimization of treatment strategies. We applied 4D-DIA mass spectrometry for serum proteome analysis and provided a comprehensive characterization of disease features in elderly patients within the Chinese population. Our study elucidated that immune disorders, lung damage, and cardiovascular disorders are predominant causes of death in these patients. Compared to clinical indices, proteomic analysis is more sensitive in tracing these disorders. We also provided a prediction panel for survival outcomes of elderly patients using levels of CXCL10, CXCL16 and IL1RA, which were validated by ELISA. These biomarkers will help improve predictive efficacy for survival outcomes in elderly patients.

Microthrombus formation is associated with COVID-19 severity; however, the detailed mechanism remains unclear. In this study, we investigated mouse models with severe pneumonia caused by SARS-CoV-2 infection by using our in vivo two-photon imaging system. In the lungs of SARS-CoV-2-infected mice, increased expression of adhesion molecules in intravascular neutrophils prolonged adhesion time to the vessel wall, resulting in platelet aggregation and impaired lung perfusion. Re-analysis of scRNA-seq data from peripheral blood mononuclear cells from COVID-19 cases revealed increased expression levels of CD44 and SELL in neutrophils in severe COVID-19 cases compared to a healthy group, consistent with our observations in the mouse model. These findings suggest that pulmonary perfusion defects caused by neutrophil adhesion to pulmonary vessels contribute to COVID-19 severity.

This review summarizes findings presented at the 19th World Congress of Basic & Clinical Pharmacology 2023 (Glasgow, Scotland, July 3rd to 7th, 2023) from 8 speakers in the field of resolution of inflammation, resolution pharmacology and resolution biology. It is now accepted that the acute inflammatory response is protective to defend the host against infection or tissue injury. Acute inflammation is self-limited and programmed to be limited in space and time: this is achieved through endogenous resolution processes that ensure return to homeostasis. Resolution is brought about by agonist mediators that include specialized pro-resolving lipid mediators (SPMs) and pro-resolving proteins and peptides such as annexin A1 and angiotensin-(1-7), all acting to initiate anti-inflammatory and pro-resolving processes. If the inflammatory reaction remains unchecked through dysfunctional resolution mechanism, it can become chronic and contribute to a plethora of human diseases, including respiratory, cardiovascular, metabolic, allergic diseases, and arthritis. Herein, we discuss how non-resolving inflammation plays a role in the pathogenesis of these diseases. In addition to SPMs, we highlight the discovery, biosynthesis, biofunctions, and latest research updates on innovative therapeutics (including annexin-A1 peptide-mimetic RTP-026, small molecule FPR2 agonist BM-986235/LAR-1219, biased agonist for FPR1/FPR2 Cmpd17b, lipoxin mimetics AT-01-KG and AT-02-CT, melanocortin receptor agonist AP1189, gold nanoparticles, angiotensin-(1-7), and CD300a) that can promote resolution of inflammation directly or through modulation of SPMs production. Drug development strategies based on the biology of the resolution of inflammation can offer novel therapeutic means and/or add-on therapies for the treatment of chronic diseases.

SARS-CoV-2 has posed serious global health challenges not only because of the high degree of virus transmissibility but also due to its severe effects on the respiratory system, such as inducing changes in multiple organs through the ACE2 receptor. This virus makes changes to gene expression at the single-cell level and thus to cellular functions and immune responses in a variety of cell types. Previous studies have not been able to resolve these mechanisms fully, and so our study tries to bridge knowledge gaps about the cellular responses under conditions of infection. We performed single-cell RNA-sequencing of nasopharyngeal swabs from COVID-19 patients and healthy controls. We assembled a dataset of 32,588 cells for 58 subjects for analysis. The data were sorted into eight cell types: ciliated, basal, deuterosomal, goblet, myeloid, secretory, squamous, and T cells. Using machine learning, including nine feature ranking algorithms and two classification algorithms, we classified the infection status of single cells and analyzed gene expression to pinpoint critical markers of SARS-CoV-2 infection. Our findings show distinct gene expression profiles between infected and uninfected cells across diverse cell types, with key indicators such as FKBP4, IFITM1, SLC35E1, CD200R1, MT-ATP6, KRT13, RBM15, and FTH1 illuminating unique immune responses and potential pathways for viral spread and immune evasion. The machine learning methods effectively differentiated between infected and non-infected cells, shedding light on the cellular heterogeneity of SARS-CoV-2 infection. The findings will improve our knowledge of the cellular dynamics of SARS-CoV-2.

COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), lead to a global health crisis with a spectrum of clinical manifestations. A potentially vulnerable category for SARS-CoV-2 infection was identified in patients with other medical conditions. Intriguingly, parallels exist between COVID-19 and cancer at the pathophysiological level, suggesting a possible connection between them. This review discusses all possible associations between COVID-19 and cancer. Expression of receptors like angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) increases COVID-19 susceptibility. SARS-CoV-2 infection might increase cancer susceptibility and accelerate cancer progression through mechanisms involving cytokine storm, tissue hypoxia, impaired T-cell responses, autophagy, neutrophil activation, and oxidative stress. These mechanisms collectively contribute to immune suppression, hindered apoptosis, and altered cellular signaling in the tumor microenvironment, creating conditions favorable for tumor growth, metastasis, and recurrence. Approved vaccines and their impact on cancer patients along-with new clinical trials are also described.

This study compares the period during which thromboembolic disease develops after contact with the virus before, during, and after the pandemic.

In this study, the medical records of patients with a preliminary diagnosis of myocardial infarction (MI), pulmonary embolism (PE), and ischemic stroke who presented to the Emergency Department before, during, and after the pandemic (when vaccination rates increased) were retrospectively examined. Data on whether these patients had COVID-19 or were vaccinated, the time interval between infection/vaccination and the onset of these conditions, and the prognosis were analyzed.

In the MI group, patients developed embolism the longest after infection and the shortest after vaccination. Among MI patients, the rate of those who received the BioNTech vaccine during the normalization period was higher than that of those who received Sinovac (p = 0.005). In stroke patients, during the pandemic, the time to post-vaccine embolism was shorter (p < 0.001). Additionally, infection and vaccination increased the mortality rate in stroke and PE patients (p < 0.001).

This study demonstrates that thromboembolic events can occur at varying rates and durations after exposure to the virus. While the causes of thrombosis are multifactorial, contact with the virus may act as a triggering factor, even if COVID-19 does not have a direct effect.

Post-covid pulmonary fibrosis (PCPF) is an essential cause of hypoxic respiratory failure, especially in patients with severe COVID-19 infection. In our study, we aimed to compare the effectiveness of methylprednisolone and methotrexate treatments in patients diagnosed with PCPF and in whom progression was observed despite nintedanib treatment.  Methods: Forty-eight patients diagnosed with PCPF between April 2022 and February 2023 were followed up in our study. Progressive pulmonary fibrosis was observed in 18 of these patients despite nintedanib treatment. Nintedanib + methylprednisolone treatment was started in Group 1 patients, and nintedanib + methotrexate treatment was started in Group 2 patients, and after three months, a respiratory function test (PFT), 6-minute walk test (6MWT), saturation, pulse, and side effect levels were compared.

In comparing the groups at the end of the 3rd month, the change in PFT parameters was higher in Group 2 patients than in Group 1 patients. However, there was no statistically significant difference. However, the increase in fingertip saturation, 6MWT levels, and decrease in pulse levels were statistically significantly different in Group 2 patients compared to Group 1 patients (p=0.001 for all).  It was observed that complaints of muscle and joint pain, weight gain, and atrophy in peripheral extremities in Group 1 patients were statistically significantly higher than in Group 2 patients (p=0.001, 0.002, 0.001, respectively).

Methotrexate can be used as an alternative to methylprednisolone in PCPF due to its low side effect profile and its effectiveness in PFT, 6MWT, and saturation levels.

SARS-CoV-2 is a highly transmissible virus that causes COVID-19 disease. Mechanisms of viral pathogenesis include excessive inflammation and viral-induced cell death, resulting in tissue damage. Here we show that the host E3-ubiquitin ligase TRIM7 acts as an inhibitor of apoptosis and SARS-CoV-2 replication via ubiquitination of the viral membrane (M) protein. Trim7-/- mice exhibit increased pathology and virus titers associated with epithelial apoptosis and dysregulated immune responses. Mechanistically, TRIM7 ubiquitinates M on K14, which protects cells from cell death. Longitudinal SARS-CoV-2 sequence analysis from infected patients reveal that mutations on M-K14 appeared in circulating variants during the pandemic. The relevance of these mutations was tested in a mouse model. A recombinant M-K14/K15R virus shows reduced viral replication, consistent with the role of K15 in virus assembly, and increased levels of apoptosis associated with the loss of ubiquitination on K14. TRIM7 antiviral activity requires caspase-6 inhibition, linking apoptosis with viral replication and pathology.

Pregnancy is a risk factor for increased severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory infections, but the mechanisms underlying this risk are poorly understood. To gain insight into the role of pregnancy in modulating immune responses at baseline and upon SARS-CoV-2 infection, we collected peripheral blood mononuclear cells and plasma from 226 women, including 152 pregnant individuals and 74 non-pregnant women. We find that SARS-CoV-2 infection is associated with altered T cell responses in pregnant women, including a clonal expansion of CD4-expressing CD8+ T cells, diminished interferon responses, and profound suppression of monocyte function. We also identify shifts in cytokine and chemokine levels in the sera of pregnant individuals, including a robust increase of interleukin-27, known to drive T cell exhaustion. Our findings reveal nuanced pregnancy-associated immune responses, which may contribute to the increased susceptibility of pregnant individuals to viral respiratory infection.

Macrophage engineering with chimeric antigen receptor is a promising technique first applied to the treatment of tumours and recently suggested as a possible immunotherapeutic route against the COVID-19 disease. Four immunotherapies based on engineered macrophages have been tested in vitro revealing promising, with one of them acting without increasing the cytokines level. We present a mathematical model aimed at the evaluation of both the SARS-CoV-2 virions dynamics and the cytokines production induced, while such newly developed constructs interact with the immune system once administered. The importance of the study lies both in monitoring the dynamics of the infection and in evaluating the cytokine production, since clinical studies show that in critical COVID-19 patients an abnormal cytokines production occurs, a concern to be accounted for in designing appropriate therapeutic strategies. The mathematical model was built in the context of the continuum approach of the mass conservation, while the numerical simulations have been performed introducing parameters deduced from the experiments, using the finite element method. The model simulations allow to analyse and to compare the immune mechanisms underlying the virus dynamics, deepening the investigation for two selected immunotherapies, suggesting that a synergistic work of involved cytokines with phagocytic activity of macrophages occurs. The best SARS-CoV-2 clearance relies not only on the phagocytic capacity of the engineered macrophages, but also on the production of T-lymphocytes, pro- and anti-inflammatory cytokines which in the two cases examined in depth can decrease by 99.7 %, 99.6 % and 69 % respectively, passing from the most effective immunotherapy to the least effective one. This study is the first mathematical model that analyses the dynamics of macrophages engineered to fight the COVID-19, and paves the way for their possible exploitation against such a challenging disease, going beyond existing models involving other immune cells.

Azvudine, a repurposed oral small molecule antiviral drug, has potential effects in combating the SARS-CoV-2 virus. However, studies on its clinical efficacy in patients with COVID-19 are still limited and controversial, and further research and validation are necessary.

A retrospective cohort study was conducted on COVID-19 patients who were hospitalized in the General Hospital of Central Theater Command from 1 December 2022 to 31 January 2023. We included 132 patients treated with Azvudine and 132 controls after screening and propensity score matching. The primary outcomes including all-cause mortality and a composite outcome of disease progression such as non-invasive respiratory support, invasive respiratory support, admission to intensive care unit (ICU), and death were compared.

Azvudine recipients had a much lower incidence rate of composite disease progression outcome than controls (13.9075/1000 person-days versus 25.7731/1000 person-days, P<0.05). Azvudine recipients also possessed a lower all-cause mortality rate than controls (2.6797/1000 person-days versus 8.5910/1000 person-days, P<0.01). Azvudine treatment significantly reduced the risk of composite disease progression (HR: 0.37, 95% CI: 0.16-0.84, P=0.017) and all-cause death (HR: 0.25, 95% CI: 0.08-0.81, P=0.021) after adjusting potential confounding factors such as age, sex, severity of COVID-19, complications, concomitant therapy, time from symptoms to treatment, and important laboratory indicators. The subgroup analyses of composite disease progression outcome and all-cause death indicated robustness of Azvudine's in treating COVID-19 patients in general.

Our study demonstrates that Azvudine has a significant positive impact on the clinical recovery of hospitalized patients with COVID-19. These findings provide important support for the use of Azvudine as a therapeutic option for COVID-19, given the current divergent views on its therapeutic efficacy and its importance in public health and medical care.

COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) represents the biggest global health emergency in recent decades. The host immune response to SARS-CoV-2 seems to play a key role in disease pathogenesis and clinical manifestations, with Natural Killer (NK) lymphocytes being among the targets of virus-induced regulation.

This study performed a single-cell multi-omics analysis of transcripts and proteins of NK lymphocytes in COVID-19 patients, for the characterization of the innate immunological response to infection. NK cells were isolated from peripheral blood samples collected from adult subjects divided into 3 study groups: (1) non-infected subjects (Naïve group, n = 3), (2) post COVID-19 convalescent subjects (Healed group, n = 3) and (3) patients that were vaccinated against SARS-CoV-2 (Vaccine group, n = 3). Cells were then analysed by the BD Rhapsody System for the single-cell multi-omics investigation of transcriptome and membrane proteins.

The bioinformatic analysis identified 5 cell clusters which differentially expressed gene/protein markers, defining NK cell subsets as "Active NK cells" and "Mature NK cells". Calculating the relative proportion of each cluster within patient groups, more than 40% of the Naïve group cell population was found to belong to Mature NKs, whereas more than 75% of the Vaccine group cell population belonged to the cluster of Active NKs. Regarding the Healed group, it seemed to show intermediate phenotype between Active and Mature NK cells. Differential expression of specific genes, proteins and signaling pathways was detected comparing the profile of the 3 experimental groups, revealing a more activated NK cell phenotype in vaccinated patients versus recovered individuals.

The present study detected differential expression of NK cell markers in relation to SARS-CoV-2 infection and vaccine administration, suggesting the possibility to identify key molecular targets for clinical-diagnostic use of the individual response to viral infection and/or re-infection.