Dampening of the respiratory cytokine storm is promoted by inhaled budesonide in patients with early COVID-19

SummaryVaccinations against SARS-CoV-2 are effective in COVID-19. However, with limited vaccine access, vaccine hesitancy and variant breakthroughs, there is still a need for effective and safe early treatments. Two community-based clinical trials of the inhaled corticosteroid, budesonide, have recently been published showing and improvement in patients with COVID-19 treated early with budesonide1,2. To understand mechanistically how budesonide was beneficial, inflammatory mediators were assessed in the nasal mucosa of patients recruited to the Steroids in COVID (STOIC1) trial and a cohort of SARS-CoV-2 negative individuals. Here we show that in early COVID-19, elevation in viral response proteins and Th1 and Th2 inflammation occurs. Longitudinal sampling in the natural course of COVID-19 showed persistently high interferon levels and elevated concentrations of the eosinophil chemokine, CCL11. In patients who deteriorate, the initial nasal mucosal signal is characterised by a marked suppression of the early inflammatory response, with reduced concentrations of interferon and inflammatory cytokines, but elevated eosinophil chemokines. Systemic inflammation remained altered in COVID-19 patients, implying that even after symptom resolution, changes in immunological mediators do not resolve. Budesonide treatment decreased IL-33 and IFN-γ, implying a reduction in epithelial damage and dampening of the interferon response. Budesonide treatment also increased CCL17 concentrations, suggesting an improved T-cell response; and significantly alters inflammatory pathways giving further insight into how this treatment can accelerate patient recovery.Abstract Figure

Dopaminergic dysfunction in the 3xTg-AD mice model of Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by amyloid (Aβ) protein aggregation and neurofibrillary tangles accumulation, accompanied by neuroinflammation. With all the therapeutic attempts targeting these biomarkers having been unsuccessful, the understanding of early mechanisms involved in the pathology is of paramount importance. Dopaminergic system involvement in AD has been suggested, particularly through the appearance of dopaminergic dysfunction-related neuropsychiatric symptoms and an overall worsening of cognitive and behavioral symptoms. In this study, we reported an early dopaminergic dysfunction in a mouse model presenting both amyloid and Tau pathology. 3xTg-AD mice showed an increase of postsynaptic D2/3R receptors density in the striatum and D2/3-autoreceptors in SN/VTA cell bodies. Functionally, a reduction of anxiety-like behavior, an increase in locomotor activity and D2R hyper-sensitivity to quinpirole stimulation have been observed. In addition, microglial cells in the striatum showed an early inflammatory response, suggesting its participation in dopaminergic alterations. These events are observed at an age when tau accumulation and Aβ deposits in the hippocampus are low. Thus, our results suggest that early dopaminergic dysfunction could have consequences in behavior and cognitive function, and may shed light on future therapeutic pathways of AD.

Persistent hyperammonia and altered concentrations of urea cycle metabolites in a 5-day swine experiment of sepsis

We measured plasma and cerebrospinal fluid (CSF) metabolite concentrations in a 5-day porcine sepsis model of fecal peritonitis. The objectives were: (i) to verify whether the expected pathways that had emerged in previous studies pertain only to the early inflammatory response or persist for the subsequent days; (ii) to identify metabolic derangements that arise later; (iii) to verify whether CSF metabolite concentrations were altered and if these alterations were similar to those in the blood or delayed. We observed an early response to inflammation and cytokine storms with alterations in lipid and glucose metabolism. The arginine/asymmetric dimethylarginine (ADMA) and phenylalanine/tyrosine balances changed 24 h after resuscitation in plasma, and later in CSF. There was a rise in ammonia concentration, with altered concentrations of metabolites in the urea cycle. Whether persistent derangement of these pathways have a role not only on short-term outcomes but also on longer-term comorbidities, such as septic encephalopathy, should be addressed in further studies.

The CXC Chemokine Receptors in Four-Eyed Sleeper (Bostrychus sinensis) and Their Involvement in Responding to Skin Injury

CXC Chemokine signaling plays an important role in wound healing. The four-eyed sleeper (Bostrychus sinensis) is a commercially important marine fish, which is prone to suffer skin ulceration at high temperature seasons, leading to mass mortality of fish in aquaculture farms. The genetic background related to skin ulceration and wound healing has remained unknown in this fish. Herein, we identified 10 differentially expressed Bostrychus sinensis CXC chemokine receptors (BsCXCRs) in skin ulcerated fish by de novo transcriptome sequencing. The transcripts of these BsCXCRs were classified in seven types, including BsCXCR1a/1b, BsCXCR2, BsCXCR3a1/3a2, BsCXCR4a/4b, and BsCXCR5-7, and BsCXCR6 was the first CXCR6 homologue experimentally identified in teleost fish. These BsCXCRs were further characterized in gene and protein structures, as well as phylogenetics, and the results revealed that BsCXCRs have expanded to divergent homologues. Our results showed that, in healthy fish, the BsCXCR transcripts was mainly distributed in the muscle and immune related organs, and that BsCXCR1a/1b proteins located in the cytomembrane, BsCXCR4a/4b/5/6 in the cytomembrane and perinuclear region, and BsCXCR3a1/3a2/7 in the cytomembrane, perinuclear region, and nuclear membrane, respectively. In skin injured fish, the transcripts of all BsCXCRs were transiently increased within one hour after injury, suggesting the involvement of BsCXCRs into the early inflammatory response to skin injury in the four-eyed sleeper. These results are valuable for understanding the evolutionary events of fish CXCR genes and provide insights into the roles of CXCR family in fish skin injury.

Recent Approaches to Targeting Canonical NFκB Signalling in the Early Inflammatory Response to Renal IRI

Ischemia reperfusion injury (IRI) is the most common cause of in-hospital acute kidney injury and is associated with increased morbidity and mortality. IRI is associated with an early phase of inflammation primarily regulated by the canonical NFκB signalling pathway. Despite recent advances in our understanding of the pathogenesis of IRI, few therapeutic strategies have emerged. The purpose of this manuscript is to review interventions targeting NFκB following IRI. (Pubmed: NF kappaB, inhibition, ischemia reperfusion, kidney. Filter: 5 years)

Pterostilbene Supplementation Inhibits Early Inflammatory Response and Oxidative Stress in UVB-Induced BALB/C Mice

Extended dermal exposure of ultraviolet B (UVB) can induce erythema, hyperpigmentation, epidermal hyperplasia and cancer. Natural active compound such as pterostilbene (PS) is a potential UV-protecting agent as it has broad biological activities. This study aimed to evaluate the photoprotective effect of pterostilbene on ultraviolet-B-induced BALB/c mice. Twenty-four female mice were randomised into four groups (n=6/group): vehicle control (VC); UVB irradiated only (UVB only); UVB irradiation treated with pterostilbene 10 mg/kg (PS10+UVB); (iv) UVB irradiation treated with pterostilbene 20 mg/kg (PS20+UVB). The PS treatments were given for 14 days, and UVB was given at dose 250 mJ/cm2 on days 9, 11, and 13 of the treatment periods. The results showed that PS lessened redness and scaling on the skin of UVB-irradiated mice. The skinfold thickness and epidermal thickness in the PS-treated group were significantly reduced (p<0.05) in comparison with those in the UVB only group. The PS10 and PS20 groups (5.927 ± 0.354 and 5.660 ± 0.765 nmol/g, respectively) demonstrated significantly decreased MDA levels (P<0.05) relative to the UVB only group (13.343 ± 1.350 nmol/g). The GSH level in both PS10 (0.555 ± 0.020 µmol/mg) and PS20 (0.568 ± 0.055 µmol/mg) groups increased significantly (p<0.05) compared with that in the UVB only group (0.376 ± 0.025 µmol/mg). SOD activity in the PS20 group (1.388 ± 0.172 U/min/mg) increased significantly (p<0.05) compared with that in the UVB only group (0.561 ± 0.034 U/min/mg). Histological observation showed that PS reduced leukocyte infiltration and epidermal hyperplasia. Hence, oral PS may exert a photoprotective effect by acting as an anti-inflammatory and antioxidant agent on UVB-irradiated mice skin.

Modulating the Inflammatory Response to Wounds and Cancer Through Infection

The zebrafish (Danio rerio) has recently emerged as an excellent model to study cancer biology and the tumour microenvironment, including the early inflammatory response to both wounding and early cancer growth. Here, we use high-resolution confocal imaging of translucent zebrafish larvae, with novel automated tracking and cell:cell interaction software, to investigate how innate immune cells behave and interact with repairing wounds and early cancer (pre-neoplastic) cells expressing a mutant active human oncogene (HRASG12V). We show that bacterial infections, delivered either systemically or locally, induce a change in the number and behaviour of neutrophils and macrophages recruited to acute wounds and to pre-neoplastic cells, and that infection can modify cellular interactions in ways that lead to a significant delay in wound healing and a reduction in the number of pre-neoplastic cells. Besides offering insights as to how Coley’s toxins and other cancer bacteriotherapies may function to reduce cancer burden, our study also highlights novel software tools that can be easily adapted to investigate cellular behaviours and interactions in other zebrafish models.

Proteomic Analysis Revealed the Characteristics of Key Proteins Involved in the Regulation of Inflammatory Response, Leukocyte Transendothelial Migration, Phagocytosis, and Immune Process during Early Lung Blast Injury

Previous studies found that blast injury caused a significant increased expression of interleukin-1, IL-6, and tumor necrosis factor, a significant decrease in the expression of IL-10, an increase in Evans blue leakage, and a significant increase in inflammatory cell infiltration in the lungs. However, the molecular characteristics of lung injury at different time points after blast exposure have not yet been reported. Therefore, in this study, tandem mass spectrometry (TMT) quantitative proteomics and bioinformatics analysis were used for the first time to gain a deeper understanding of the molecular mechanism of lung blast injury at different time points. Forty-eight male C57BL/6 mice were randomly divided into six groups: control, 12 h, 24 h, 48 h, 72 h, and 1 w after low-intensity blast exposure. TMT quantitative proteomics and bioinformatics analysis were performed to analyze protein expression profiling in the lungs from control and blast-exposed mice, and differential protein expression was verified by Western blotting. The results demonstrated that blast exposure induced severe lung injury, leukocyte infiltration, and the production of inflammatory factors in mice. After analyzing the expression changes in global proteins and inflammation-related proteomes after blast exposure, the results showed that a total of 6861 global proteins and 608 differentially expressed proteins were identified, of which 215, 128, 187, 232, and 65 proteins were identified at 12 h, 24 h, 48 h, 72 h, and 1 week after blast exposure, respectively. Moreover, blast exposure-induced 177 differentially expressed proteins were associated with inflammatory responses, which were enriched in the inflammatory response regulation, leukocyte transendothelial migration, phagocytosis, and immune response. Therefore, blast exposure may induce early inflammatory response of lung tissue by regulating the expression of key proteins in the inflammatory process, suggesting that early inflammatory response may be the initiating factor of lung blast injury. These data can provide potential therapeutic candidates or approaches for the development of future treatment of lung blast injury.