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1.
Am J Physiol Regul Integr Comp Physiol ; 322(2): R99-R111, 2022 02 01.
Article in English | MEDLINE | ID: covidwho-2162033

ABSTRACT

A prominent health issue nowadays is the COVID-19 pandemic, which poses acute risks to human health. However, the long-term health consequences are largely unknown and cannot be neglected. An especially vulnerable period for infection is pregnancy, when infections could have long-term health effect on the child. Evidence suggests that maternal immune activation (MIA) induced by either bacteria or viruses presents various effects on the offspring, leading to adverse phenotypes in many organ systems. This review compares the mechanisms of bacterial and viral MIA and the possible long-term outcomes for the offspring by summarizing the outcome in animal LPS and Poly I:C models. Both models are activated immune responses mediated by Toll-like receptors. The outcomes for MIA offspring include neurodevelopment, immune response, circulation, metabolism, and reproduction. Some of these changes continue to exist until later life. Besides different doses and batches of LPS and Poly I:C, the injection day, administration route, and also different animal species influence the outcomes. Here, we specifically aim to support colleagues when choosing their animal models for future studies.


Subject(s)
COVID-19/complications , COVID-19/immunology , Lipopolysaccharides/toxicity , Poly I-C/toxicity , Prenatal Exposure Delayed Effects/immunology , SARS-CoV-2 , Bacterial Infections/immunology , Female , Humans , Pregnancy
2.
Dis Markers ; 2022: 1118195, 2022.
Article in English | MEDLINE | ID: covidwho-2138216

ABSTRACT

Background: Mitochondria have been involved in host defense upon viral infections. Factor Xa (FXa), a coagulating factor, may also have influence on mitochondrial functionalities. The aim was to analyze if in human pulmonary microvascular endothelial cells (HPMEC), the SARS-CoV-2 (COVID-19) spike protein subunits, S1 and S2 (S1+S2), could alter mitochondrial metabolism and what is the role of FXA. Methods: HPMEC were incubated with and without recombinants S1+S2 (10 nmol/L each). Results: In control conditions, S1+S2 failed to modify FXa expression. However, in LPS (1 µg/mL)-incubated HPMEC, S1+S2 significantly increased FXa production. LPS tended to reduce mitochondrial membrane potential with respect to control, but in higher and significant degree, it was reduced when S1+S2 were present. LPS did not significantly modify cytochrome c oxidase activity as compared with control. Addition of S1+S2 spike subunits to LPS-incubated HPMEC significantly increased cytochrome c oxidase activity with respect to control. Lactate dehydrogenase activity was also increased by S1+S2 with respect to control and LPS alone. Protein expression level of uncoupled protein-2 (UCP-2) was markedly expressed when S1+S2 were added together to LPS. Rivaroxaban (50 nmol/L), a specific FXa inhibitor, significantly reduced all the above-mentioned alterations induced by S1+S2 including UCP-2 expression. Conclusions: In HPMEC undergoing to preinflammatory condition, COVID-19 S1+S2 spike subunits promoted alterations in mitochondria metabolism suggesting a shift from aerobic towards anaerobic metabolism that was accompanied of high FXa production. Rivaroxaban prevented all the mitochondrial metabolic changes mediated by the present COVID-19 S1 and S2 spike subunits suggesting the involvement of endogenous FXa.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Humans , Spike Glycoprotein, Coronavirus/metabolism , Factor Xa/metabolism , SARS-CoV-2 , Endothelial Cells/metabolism , Protein Subunits/metabolism , Rivaroxaban/pharmacology , Rivaroxaban/metabolism , Electron Transport Complex IV/metabolism , Lipopolysaccharides/pharmacology , Lipopolysaccharides/metabolism , Mitochondria/metabolism
3.
Immun Inflamm Dis ; 10(12): e737, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2127750

ABSTRACT

INTRODUCTION: It is important to control both inflammation and immunosuppression after severe insults, such as sepsis, trauma, and surgery. Endotoxin tolerance is one of the immunosuppressive conditions and it has been known that endotoxin tolerance relates to poorer clinical outcomes in patients with severe insults. This study investigated whether whey protein hydrolysate (WPH) mitigates inflammation and endotoxin tolerance in THP-1 human monocytic leukemia cells. METHODS: Endotoxin tolerance can be experimentally reproduced by two consecutive stimulations with lipopolysaccharide (LPS). THP-1 cells were incubated with LPS and WPH (first stimulation). After collecting the culture supernatant to evaluate the effect on inflammation, the cells were washed and restimulated by 100 ng/ml LPS (second stimulation). The culture supernatant was again collected to evaluate the effect on endotoxin tolerance. Concentrations of LPS and WPH in the first stimulation were adjusted to evaluate their dose dependency. Cytokine levels in the supernatant were determined by enzyme-linked immunosorbent assay. Statistical analysis was performed using the student's t-test or Dunnett's test. RESULTS: Five mg/ml WPH significantly decreased interleukin (IL)-6 (p = .006) and IL-10 (p < .001) levels after the first LPS stimulation (1000 ng/ml). WPH significantly increased tumor necrosis factor-alpha (p < .001) and IL-10 (p = .014) levels after the second LPS stimulation. The suppressive effect of WPH on inflammation and endotoxin tolerance was dependent on the concentrations of LPS and WPH. The effective dose of WPH for endotoxin tolerance was lower than its effective dose for inflammation. CONCLUSION: WPH mitigated both inflammation and endotoxin tolerance. Therefore, WPH might be a candidate for valuable food ingredients to control both inflammation and immunosuppression after severe insults.


Subject(s)
Interleukin-10 , Leukemia , Humans , THP-1 Cells , Protein Hydrolysates , Lipopolysaccharides , Endotoxin Tolerance , Whey , Inflammation/drug therapy , Interleukin-6
4.
Cell Rep ; 39(13): 110989, 2022 06 28.
Article in English | MEDLINE | ID: covidwho-2121651

ABSTRACT

The interleukin-12 (IL-12) family comprises the only heterodimeric cytokines mediating diverse functional effects. We previously reported a striking bimodal IL-12p70 response to lipopolysaccharide (LPS) stimulation in healthy donors. Herein, we demonstrate that interferon ß (IFNß) is a major upstream determinant of IL-12p70 production, which is also associated with numbers and activation of circulating monocytes. Integrative modeling of proteomic, genetic, epigenomic, and cellular data confirms IFNß as key for LPS-induced IL-12p70 and allowed us to compare the relative effects of each of these parameters on variable cytokine responses. Clinical relevance of our findings is supported by reduced IFNß-IL-12p70 responses in patients hospitalized with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or chronically infected with hepatitis C (HCV). Importantly, these responses are resolved after viral clearance. Our systems immunology approach defines a better understanding of IL-12p70 and IFNß in healthy and infected persons, providing insights into how common genetic and epigenetic variation may impact immune responses to bacterial infection.


Subject(s)
Interferon-beta , Interleukin-12 , Toll-Like Receptor 4 , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Cytokines/immunology , Cytokines/metabolism , Humans , Interferon-beta/immunology , Interferon-beta/metabolism , Interleukin-12/immunology , Interleukin-12/metabolism , Lipopolysaccharides/pharmacology , Proteomics , SARS-CoV-2/immunology
5.
Toxicol In Vitro ; 83: 105394, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-2115544

ABSTRACT

We previously reported that delivery of nickel nanoparticles (NiNPs) and bacterial lipopolysaccharide (LPS) into the lungs of mice synergistically increased IL-6 production and inflammation, and male mice were more susceptible than female mice. The primary goal of this study was to utilize an in vitro human lung epithelial cell model (BEAS-2B) to investigate the intracellular signaling mechanisms that mediate IL-6 production by LPS and NiNPs. We also investigated the effect of sex hormones on NiNP and LPS-induced IL-6 production in vitro. LPS and NiNPs synergistically induced IL-6 mRNA and protein in BEAS-2B cells. TPCA-1, a dual inhibitor of IKK-2 and STAT3, blocked the synergistic increase in IL-6 caused by LPS and NiNPs, abolished STAT3 activation, and reduced C/EBPß. Conversely, SC144, an inhibitor of the gp130 component of the IL-6 receptor, enhanced IL-6 production induced by LPS and NiNPs. Treatment of BEAS-2B cells with sex hormones (17ß-estradiol, progesterone, or testosterone) or the anti-oxidant NAC, had no effect on IL-6 induction by LPS and NiNPs. These data suggest that LPS and NiNPs induce IL-6 via STAT3 and C/EBPß in BEAS-2B cells. While BEAS-2B cells are a suitable model to study mechanisms of IL-6 production, they do not appear to be suitable for studying the effect of sex hormones.


Subject(s)
Lipopolysaccharides , Nanoparticles , Animals , CCAAT-Enhancer-Binding Protein-beta/metabolism , Cell Line , Epithelial Cells , Female , Humans , Interleukin-6/genetics , Interleukin-6/metabolism , Lipopolysaccharides/pharmacology , Male , Mice , Nickel , STAT3 Transcription Factor/metabolism
6.
J Cell Mol Med ; 26(21): 5506-5516, 2022 11.
Article in English | MEDLINE | ID: covidwho-2103158

ABSTRACT

Although the physiological function of receptor-interacting protein kinase (RIPK) 3 has emerged as a critical mediator of programmed necrosis/necroptosis, the intracellular role it plays as an attenuator in human lungs and human bronchial epithelia remains unclear. Here, we show that the expression of RIPK3 dramatically decreased in the inflamed tissues of human lungs, and moved from the nucleus to the cytoplasm. The overexpression of RIPK3 dramatically increased F-actin formation and decreased the expression of genes for pro-inflammatory cytokines (IL-6 and IL-1ß), but not siRNA-RIPK3. Interestingly, whereas RIPK3 was bound to histone 1b without LPS stimulation, the interaction between them was disrupted after 15 min of LPS treatment. Histone methylation could not maintain the binding of RIPK3 and activated movement towards the cytoplasm. In the cytoplasm, overexpressed RIPK3 continuously attenuated pro-inflammatory cytokine gene expression by inhibiting NF-κB activation, preventing the progression of inflammation during Pseudomonas aeruginosa infection. Our data indicated that RIPK3 is critical for the regulation of the LPS-induced inflammatory microenvironment. Therefore, we suggest that RIPK3 is a potential therapeutic candidate for bacterial infection-induced pulmonary inflammation.


Subject(s)
Lipopolysaccharides , Pseudomonas aeruginosa , Humans , Histones , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Necrosis , Inflammation/metabolism , Cytokines/metabolism
7.
Immunity ; 55(11): 2103-2117.e10, 2022 Nov 08.
Article in English | MEDLINE | ID: covidwho-2095502

ABSTRACT

The surface of the central nervous system (CNS) is protected by the meninges, which contain a dense network of meningeal macrophages (MMs). Here, we examined the role of tissue-resident MM in viral infection. MHC-II- MM were abundant neonatally, whereas MHC-II+ MM appeared over time. These barrier macrophages differentially responded to in vivo peripheral challenges such as LPS, SARS-CoV-2, and lymphocytic choriomeningitis virus (LCMV). Peripheral LCMV infection, which was asymptomatic, led to a transient infection and activation of the meninges. Mice lacking macrophages but conserving brain microglia, or mice bearing macrophage-specific deletion of Stat1 or Ifnar, exhibited extensive viral spread into the CNS. Transcranial pharmacological depletion strategies targeting MM locally resulted in several areas of the meninges becoming infected and fatal meningitis. Low numbers of MHC-II+ MM, which is seen upon LPS challenge or in neonates, corelated with higher viral load upon infection. Thus, MMs protect against viral infection and may present targets for therapeutic manipulation.


Subject(s)
COVID-19 , Lymphocytic Choriomeningitis , Animals , Mice , Lipopolysaccharides , Mice, Inbred C57BL , SARS-CoV-2 , Lymphocytic choriomeningitis virus/physiology , Macrophages , Meninges
8.
Molecules ; 27(21)2022 Oct 28.
Article in English | MEDLINE | ID: covidwho-2090286

ABSTRACT

Acute lung injury (ALI) is a kind of lung disease with acute dyspnea, pulmonary inflammation, respiratory distress, and non-cardiogenic pulmonary edema, accompanied by the mid- and end-stage characteristics of COVID-19, clinically. It is imperative to find non-toxic natural substances on preventing ALI and its complications. The animal experiments demonstrated that Lentinus edodes polysaccharides (PLE) had a potential role in alleviating ALI by inhibiting oxidative stress and inflammation, which was manifested by reducing the levels of serum lung injury indicators (C3, hs-CRP, and GGT), reducing the levels of inflammatory factors (TNF-α, IL-1ß, and IL-6), and increasing the activities of antioxidant enzymes (SOD and CAT) in the lung. Furthermore, PLE had the typical characteristics of pyran-type linked by ß-type glycosidic linkages. The conclusions indicated that PLE could be used as functional foods and natural drugs in preventing ALI.


Subject(s)
Acute Lung Injury , COVID-19 , Shiitake Mushrooms , Animals , Oxidative Stress , Acute Lung Injury/drug therapy , Inflammation/drug therapy , Polysaccharides/pharmacology , Polysaccharides/therapeutic use , Lung , Lipopolysaccharides
9.
Carbohydr Polym ; 297: 120032, 2022 Dec 01.
Article in English | MEDLINE | ID: covidwho-2068751

ABSTRACT

The cytokine storm is highly associated with inflammatory-type disease severity and patients' survival. Plant polysaccharides, the main natural phytomedicine source, have a great potential to be an effective drug to treat cytokine storm. Herein we found that a polymeric acemannan (ABPA1) isolated from Aloe Vera Barbadensis extract C (AVBEC) exerted prominent inhibitory effects on inflammation-induced cytokine storm. The results displayed that ABPA1 effectively suppressed LPS-induced proinflammatory cytokines release in vitro. Moreover, ABPA1 treatment alleviated the cytokine storm and tissue damage in LPS- and IAV-induced mouse pneumonia models, and altered the phenotypic balance of macrophages in lung tissues. Functionally, ABPA1 enhanced macrophage M2 polarization and phagocytosis in RAW264.7 cells and inhibited LPS-induced M1 polarization. Mechanistically, ABPA1 enhanced mitochondrial metabolism and OXPHOS through activated PI3K/Akt/GSK-3ß signalling pathway. Overall, our findings suggest that ABPA1 may modulate macrophage activation and mitochondrial metabolism by targeting PI3K/Akt/GSK-3ß signalling pathway, thereby alleviating cytokine storm and inflammation.


Subject(s)
Aloe , Aloe/metabolism , Animals , Cytokine Release Syndrome , Cytokines/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Lipopolysaccharides/pharmacology , Macrophages , Mannans , Mice , Phosphatidylinositol 3-Kinases/metabolism , Plant Extracts/pharmacology , Polysaccharides/pharmacology , Proto-Oncogene Proteins c-akt/metabolism
10.
Int J Mol Sci ; 23(19)2022 Oct 07.
Article in English | MEDLINE | ID: covidwho-2066142

ABSTRACT

The role of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in the regulation of energy homeostasis remains poorly understood. In this study, we used a transgenic fat-1 mouse model, which can produce n-3 PUFAs endogenously, to investigate how n-3 PUFAs regulate the morphology and function of brown adipose tissue (BAT). We found that high-fat diet (HFD) induced a remarkable morphological change in BAT, characterized by "whitening" due to large lipid droplet accumulation within BAT cells, associated with obesity in wild-type (WT) mice, whereas the changes in body fat mass and BAT morphology were significantly alleviated in fat-1 mice. The expression of thermogenic markers and lypolytic enzymes was significantly higher in fat-1 mice than that in WT mice fed with HFD. In addition, fat-1 mice had significantly lower levels of inflammatory markers in BAT and lipopolysaccharide (LPS) in plasma compared with WT mice. Furthermore, fat-1 mice were resistant to LPS-induced suppression of UCP1 and PGC-1 expression and lipid deposits in BAT. Our data has demonstrated that high-fat diet-induced obesity is associated with impairments of BAT morphology (whitening) and function, which can be ameliorated by elevated tissue status of n-3 PUFAs, possibly through suppressing the effects of LPS on inflammation and thermogenesis.


Subject(s)
Adipose Tissue, Brown , Fatty Acids, Omega-3 , Adipose Tissue, Brown/metabolism , Animals , Diet, High-Fat/adverse effects , Fatty Acids, Omega-3/metabolism , Fatty Acids, Omega-3/pharmacology , Fatty Acids, Unsaturated/metabolism , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Obesity/genetics , Obesity/metabolism , Thermogenesis
11.
Cells ; 11(19)2022 Sep 27.
Article in English | MEDLINE | ID: covidwho-2065727

ABSTRACT

Clinical success of Toll-Like receptor-4 (TLR-4) antagonists in sepsis therapy has thus far been lacking. As inhibition of a receptor can only be useful if the receptor is active, stratification of patients with active TLR-4 would be desirable. Our aim was to establish an assay to quantify phosphorylated TLR-4 using the proximity ligation assay (PLA). HEK293 TLR4/MD2/CD14 as well as THP-1 cells were stimulated with LPS and the activation of TLR-4 was measured using the PLA. Furthermore, peripheral blood mononuclear cells (PBMCs) from 25 sepsis patients were used to show the feasibility of this assay in clinical material. Activation of TLR-4 in these samples was compared to the PBMCs of 11 healthy individuals. We could show a transient activation of TLR-4 in both cell lines. Five min after the LPS stimulation, the signal increased 6.7-fold in the HEK293 cells and 4.3-fold in the THP-1 cells. The assay also worked well in the PBMCs of septic patients. Phosphorylation of TLR-4 at study inclusion was 2.9 times higher in septic patients compared to healthy volunteers. To conclude, we established a diagnostic assay that is able to quantify the phosphorylation of TLR-4 in cell culture and in clinical samples of sepsis patients. This makes large-scale stratification of sepsis patients for their TLR-4 activation status possible.


Subject(s)
Sepsis , Toll-Like Receptor 4/metabolism , HEK293 Cells , Humans , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides/metabolism , Lipopolysaccharides/pharmacology
12.
PLoS One ; 17(10): e0275838, 2022.
Article in English | MEDLINE | ID: covidwho-2065150

ABSTRACT

The World Health Organization (WHO) emphasizes that tuberculosis (TB) in children and adolescents is often overlooked by healthcare providers and difficult to diagnose. As childhood TB cases rise, finding a diagnostic high in sensitivity and specificity is critical. In this study 91 urine samples from children aged 1-10 years were analyzed for tuberculostearic acid (TBSA) by gas chromatography/mass spectrometry (GC/MS) and capture ELISA (C-ELISA). In C-ELISA the CS35/A194-01 antibody performed very poorly with both curve-based and model-based cutoffs. The area under the ROC curve (AUC) of the CS35 OD450 values was only 0.60. Replacing the capture antibody with BJ76 gave a better performance in both sensitivity and specificity (AUC = 0.95). When these samples were analyzed by GC/MS, 41 classified as 'probable/possible' for TB were distinctly TBSA positive with ten samples having <3 ng/mL LAM. However, from the 50 samples with 'unlikely' TB classification, 36 were negative but 7 had >3 ng/mL and were designated as LAM positive. This experimental assay assessment study signifies that i) the antibody pair CS35/A194-01 that has been successful for adult active TB diagnosis is not adequate when LAM level is low as in pediatric TB; ii) no one mAb appears to recognize all TB-specific LAM epitopes.


Subject(s)
HIV Infections , Mycobacterium tuberculosis , Tuberculosis , Adolescent , Adult , Antibodies , Child , Epitopes , Humans , Limit of Detection , Lipopolysaccharides , Sensitivity and Specificity , Tuberculosis/diagnosis
13.
Clin Transl Med ; 12(10): e1069, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2059366

ABSTRACT

BACKGROUND: A heterogeneous clinical phenotype is a characteristic of coronavirus disease 2019 (COVID-19). Therefore, investigating biomarkers associated with disease severity is important for understanding the mechanisms responsible for this heterogeneity and for developing novel agents to prevent critical conditions. This study aimed to elucidate the modulations of sphingolipids and glycerophospholipids, which have been shown to possess potent biological properties. METHODS: We measured the serum sphingolipid and glycerophospholipid levels in a total of 887 samples from 215 COVID-19 subjects, plus 115 control subjects without infectious diseases and 109 subjects with infectious diseases other than COVID-19. RESULTS: We observed the dynamic modulations of sphingolipids and glycerophospholipids in the serum of COVID-19 subjects, depending on the time course and severity. The elevation of C16:0 ceramide and lysophosphatidylinositol and decreases in C18:1 ceramide, dihydrosphingosine, lysophosphatidylglycerol, phosphatidylglycerol and phosphatidylinositol were specific to COVID-19. Regarding the association with maximum severity, phosphatidylinositol and phosphatidylcholine species with long unsaturated acyl chains were negatively associated, while lysophosphatidylethanolamine and phosphatidylethanolamine were positively associated with maximum severity during the early phase. Lysophosphatidylcholine and phosphatidylcholine had strong negative correlations with CRP, while phosphatidylethanolamine had strong positive ones. C16:0 ceramide, lysophosphatidylcholine, phosphatidylcholine and phosphatidylethanolamine species with long unsaturated acyl chains had negative correlations with D-dimer, while phosphatidylethanolamine species with short acyl chains and phosphatidylinositol had positive ones. Several species of phosphatidylcholine, phosphatidylethanolamine and sphingomyelin might serve as better biomarkers for predicting severe COVID-19 during the early phase than CRP and D-dimer. Compared with the lipid modulations seen in mice treated with lipopolysaccharide, tissue factor, or histone, the lipid modulations observed in severe COVID-19 were most akin to those in mice administered lipopolysaccharide. CONCLUSION: A better understanding of the disturbances in sphingolipids and glycerophospholipids observed in this study will prompt further investigation to develop laboratory testing for predicting maximum severity and/or novel agents to suppress the aggravation of COVID-19.


Subject(s)
COVID-19 , Sphingolipids , Animals , Biomarkers , Ceramides , Glycerophospholipids , Histones , Lipopolysaccharides , Lysophosphatidylcholines , Mice , Phosphatidylcholines , Phosphatidylethanolamines , Phosphatidylglycerols , Phosphatidylinositols , Sphingomyelins , Thromboplastin
14.
Mar Drugs ; 20(9)2022 Sep 06.
Article in English | MEDLINE | ID: covidwho-2039912

ABSTRACT

Three unusual diterpenes with rare sarsolenane and capnosane skeletons, namely mililatensols A-C (1-3), were isolated from the South China Sea soft coral Sarcophyton mililatensis, leading to the first record of sarsolenane and capnosane diterpenes from the title animal. The structures of compounds 1-3 were established by extensive spectroscopic analysis and comparison with the literature data. Moreover, the absolute configuration of 2 was determined by TDDFT ECD calculations. In an in vitro bioassay, none of the isolated compounds showed obvious anti-inflammatory activity on LPS-induced TNF-α release in RAW264.7 macrophages. In the preliminary virtual screening of inhibitory potential against SARS-CoV-2 by molecular docking, the results showed these three diterpenes were potential SARS-CoV-2 Mpro inhibitors.


Subject(s)
Anthozoa , COVID-19 , Diterpenes , Animals , Anthozoa/chemistry , Anti-Inflammatory Agents/pharmacology , Diterpenes/chemistry , Lipopolysaccharides , Molecular Docking Simulation , Molecular Structure , SARS-CoV-2 , Tumor Necrosis Factor-alpha
15.
J Chin Med Assoc ; 85(6): 717-722, 2022 Jun 01.
Article in English | MEDLINE | ID: covidwho-2037568

ABSTRACT

BACKGROUND: The symptoms of coronavirus disease 2019 (COVID-19) such as hyposmia, rhinorrhea, nasal obstruction, and cough are similar to those of chronic allergic rhinitis (AR). Such symptoms can easily lead AR patients to unnecessary anxiety, misdiagnosis, and invasive diagnostic tests in the COVID-19 pandemic. Interleukin-6 (IL-6) is an important mediator for chronic AR and plays a crucial role in the inflammation of COVID-19. Houttuynia cordata (HC) has been shown to reduce nasal congestion and swelling by suppressing the activation of IL-6 and is used to fight COVID-19. A novel HC-based Chinese herbal formula, Zheng-Yi-Fang (ZYF), was developed to test effects on nasal symptoms of patients with AR in the COVID-19 pandemic. METHODS: Participants aged between 20 and 60 years with at least a 2-year history of moderate to severe perennial AR were enrolled. Eligible participants were randomly allocated to either the intervention group (taking ZYF) or the control group (using regular western medicine) for 4 weeks. The Chinese version of the Rhinosinusitis Outcome Measures was used to evaluate impacts on quality of life and nasal symptoms of participants with AR. In addition, the effect of ZYF on lipopolysaccharide (LPS)-induced IL-6 was investigated. RESULTS: Participants with AR taking ZYF improved their symptoms of nasal obstruction, nasal secretion, hyposmia, and postnasal drip in comparison with those of the control group. Meanwhile, ZYF exhibited inhibition of IL-6 secretion in the LPS-induced inflammatory model. CONCLUSION: ZYF has potential effects to relieve nasal symptoms for AR during the COVID-19 pandemic.


Subject(s)
Drugs, Chinese Herbal , Houttuynia , Rhinitis, Allergic , Adult , Anosmia , COVID-19 , China , Drugs, Chinese Herbal/therapeutic use , Houttuynia/chemistry , Humans , Interleukin-6 , Lipopolysaccharides , Middle Aged , Pandemics , Quality of Life , Rhinitis, Allergic/drug therapy , Young Adult
16.
Cell Rep ; 41(1): 111441, 2022 10 04.
Article in English | MEDLINE | ID: covidwho-2031186

ABSTRACT

Biologically active small molecules can impart modulatory effects, in some cases providing extended long-term memory. In a screen of biologically active small molecules for regulators of tumor necrosis factor (TNF) induction, we identify several compounds with the ability to induce training effects on human macrophages. Rutaecarpine shows acute and long-term modulation, enhancing lipopolysaccharide (LPS)-induced pro-inflammatory cytokine secretion and relieving LPS tolerance in human macrophages. Rutaecarpine inhibits ß-glucan-induced H3K4Me3 marks at the promoters of several pro-inflammatory cytokines, highlighting the potential of this molecule to modulate chromosomal topology. Syk kinase inhibitor (SYKi IV), another screen hit, promotes an enhanced response to LPS similar to that previously reported for ß-glucan-induced training. Macrophages trained with SYKi IV show a high degree of resistance to influenza A, multiple variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and OC43 coronavirus infection, highlighting a potential application of this molecule and other SYKis as prophylactic treatments for viral susceptibility.


Subject(s)
COVID-19 , beta-Glucans , COVID-19/drug therapy , Cytokines , Humans , Indole Alkaloids , Lipopolysaccharides , Macrophages , Quinazolinones , SARS-CoV-2 , Syk Kinase , Tumor Necrosis Factor-alpha
17.
Biomed Pharmacother ; 155: 113666, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2027928

ABSTRACT

Acute lung injury (ALI) and its more serious form; acute respiratory distress syndrome are major causes of COVID-19 related mortality. Finding new therapeutic targets for ALI is thus of great interest. This work aimed to prepare a biocompatible nanoformulation for effective pulmonary delivery of the herbal drug; tanshinone-IIA (TSIIA) for ALI management. A nanoemulsion (NE) formulation based on bioactive natural ingredients; rhamnolipid biosurfactant and tea-tree oil, was developed using a simple ultrasonication technique, optimized by varying oil concentration and surfactant:oil ratio. The selected TSIIA-NE formulation showed 105.7 nm diameter and a PDI âˆ¼ 0.3. EE exceeded 98 % with biphasic sustained drug release and good stability over 3-months. In-vivo efficacy was evaluated in lipopolysaccharide (LPS)-induced ALI model. TSIIA-NE (30 µg/kg) was administered once intratracheally 2 h after LPS instillation. Evaluation was performed 7days post-treatment. Pulmonary function assessment, inflammatory, oxidative stress and glycocalyx shedding markers analysis in addition to histopathological examination of lung tissue were performed. When compared to untreated rats, in-vivo efficacy study demonstrated 1.4 and 1.9-fold increases in tidal volume and minute respiratory volume, respectively, with 32 % drop in wet/dry lung weight ratio and improved levels of arterial blood gases. Lung histopathology and biochemical analysis of different biomarkers in tissue homogenate and bronchoalveolar lavage fluid indicated that treatment may ameliorate LPS-induced ALI symptoms thorough anti-oxidative, anti-inflammatory effects and inhibition of glycocalyx degradation. TSIIA-NE efficacy was superior to free medication and blank-NE. The enhanced efficacy of TSIIA bioactive nanoemulsion significantly suggests the pharmacotherapeutic potential of bioactive TSIIA-NE as a promising nanoplatform for ALI.


Subject(s)
Acute Lung Injury , COVID-19 , Rats , Animals , Lipopolysaccharides/pharmacology , Glycocalyx/pathology , COVID-19/drug therapy , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Acute Lung Injury/pathology , Lung , Anti-Inflammatory Agents/pharmacology , Surface-Active Agents/pharmacology , Gases/adverse effects , Gases/metabolism , Tea/metabolism
18.
Physiol Rep ; 10(17): e15451, 2022 09.
Article in English | MEDLINE | ID: covidwho-2025738

ABSTRACT

With a mortality rate of 46% before the onset of COVID-19, acute respiratory distress syndrome (ARDS) affected 200,000 people in the US, causing 75,000 deaths. Mortality rates in COVID-19 ARDS patients are currently at 39%. Extrapulmonary support for ARDS aims to supplement mechanical ventilation by providing life-sustaining oxygen to the patient. A new rapid-onset, human-sized pig ARDS model in a porcine intensive care unit (ICU) was developed. The pigs were nebulized intratracheally with a high dose (4 mg/kg) of the endotoxin lipopolysaccharide (LPS) over a 2 h duration to induce rapid-onset moderate-to-severe ARDS. They were then catheterized to monitor vitals and to evaluate the therapeutic effect of oxygenated microbubble (OMB) therapy delivered by intrathoracic (IT) or intraperitoneal (IP) administration. Post-LPS administration, the PaO2 value dropped below 70 mmHg, the PaO2 /FiO2 ratio dropped below 200 mmHg, and the heart rate increased, indicating rapidly developing (within 4 h) moderate-to-severe ARDS with tachycardia. The SpO2 and PaO2 of these LPS-injured pigs did not show significant improvement after OMB administration, as they did in our previous studies of the therapy on small animal models of ARDS injury. Furthermore, pigs receiving OMB or saline infusions had slightly lower survival than their ARDS counterparts. The OMB administration did not induce a statistically significant or clinically relevant therapeutic effect in this model; instead, both saline and OMB infusion appeared to lower survival rates slightly. This result is significant because it contradicts positive results from our previous small animal studies and places a limit on the efficacy of such treatments for larger animals under more severe respiratory distress. While OMB did not prove efficacious in this rapid-onset ARDS pig model, it may retain potential as a novel therapy for the usual presentation of ARDS in humans, which develops and progresses over days to weeks.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Animals , Humans , Lipopolysaccharides/toxicity , Microbubbles , Respiration, Artificial , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/therapy , Swine
19.
Biomed Res Int ; 2022: 3510423, 2022.
Article in English | MEDLINE | ID: covidwho-2020494

ABSTRACT

Purpose: Aurantiamide acetate (AA) is a dipeptide derivative with complex pharmacological activities and remarkable effects on preventing and treating various diseases. In the current study, we aimed to investigate whether AA can exert protective effects in a mouse model of ALI induced by LPS. Materials and Methods: In this model, mice were given intranasal LPS for 3 days prior to receiving AA (2.5, 5, and 10 mg/kg) via oral gavage. An assessment of histopathological changes was performed by hematoxylin and eosin (HE). Proinflammatory cytokines were detected in bronchoalveolar lavage fluids (BALFs) by enzyme-linked immunosorbent assays (ELISAs). The effects of AA on protein expression of NF-κB and PI3K/AKT signaling pathways were determined by Western blot. In addition, lung wet/dry (W/D) weight ratio, myeloperoxidase (MPO) activity, cell counts, and protein content were also measured. Results: According to results, AA pretreatment significantly reduced lung pathological changes, W/D ratio, MPO activity, and protein content. Additionally, AA resulted in a significant reduction in the number of total cells, neutrophils, and proinflammatory cytokines in the BALF after LPS stimulation. The subsequent study revealed that pretreatment with AA dose dependently suppressed LPS-induced activation of NF-κB as well as PI3K/AKT phosphorylation. Conclusion: The results indicated that the AA had a protective effect on LPS-induced ALI in mice and could be a potential drug for ALI.


Subject(s)
Acute Lung Injury , Pneumonia , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Acute Lung Injury/metabolism , Animals , Bronchoalveolar Lavage Fluid/chemistry , Cytokines/metabolism , Dipeptides/pharmacology , Lipopolysaccharides/adverse effects , Lung/pathology , Mice , Mice, Inbred BALB C , NF-kappa B/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Pneumonia/pathology , Proto-Oncogene Proteins c-akt/metabolism
20.
J Ethnopharmacol ; 298: 115661, 2022 Nov 15.
Article in English | MEDLINE | ID: covidwho-2015648

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Shufeng Jiedu capsule (SFJDC) is a pure form of traditional Chinese medicine (TCM) that contains eight medicinal plants. Known for its anti-inflammatory and antipyretic effects, it is mostly used to treat upper respiratory tract infections and other infectious diseases, such as colds, pharyngitis, laryngitis, and tonsillitis. Both acute lung injury (ALI) and COVID-19 are closely related to lung damage, primarily manifesting as lung inflammation and epithelial cell damage. However, whether SFJDC can improve ALI and by what mechanism remain unclear. The purpose of this study was to explore whether SFJDC could be used as a prophylactic treatment for COVID-19 by improving acute lung injury. AIM OF THE STUDY: The purpose of this study was to determine whether SFJDC could protect against ALI caused by lipopolysaccharide (LPS), and we wanted to determine how SFJDC reduces inflammation and apoptosis pharmacologically and molecularly. MATERIALS AND METHODS: Preadministering SFJDC at 0.1 g/kg, 0.3 g/kg, or 0.5 g/kg for one week was followed by 5 mg/kg LPS to induce ALI in mice. Observations included the study of lung histomorphology, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) secretion, as well as the ratio of lung wet/dry weights. In addition, RAW264.7 cells were treated for 24 h with 1 µg/mL LPS after being pretreated for 1 h with 0.5 mg/mL SFJDC. In the samples, we detected TNF-α, IL-1ß, and IL-6. Cell apoptosis was detected by stimulating A549 cells for 24 h with RAW264.7 supernatant. Both in vitro and in vivo, the levels of A2A adenosine receptor (A2AAR), PKA, IκB, p-IκB, NF-κB P65 (P65), p-NF-κB P65 (p-P65), cleaved caspases-3 (Cc3), Bcl-2 associated X protein (Bax), and B-cell lymphoma-2 (Bcl-2) proteins were determined using Western blot analysis. RESULTS: Lung tissue morphology was improved as SFJDC decreased cytokine secretion, the ratio of lung wet/dry weights, and lung tissue secretion of proinflammatory cytokines. The expression of A2AAR was increased by SFJDC, and the phosphorylation of NF-κB was inhibited. TUNEL staining and flow cytometry showed that SFJDC inhibited apoptosis by reducing the expression of Cc3 and the ratio of Bax/Bcl-2. CONCLUSIONS: According to the results of this study, SFJDC can reduce inflammation and inhibit apoptosis. A2AAR activation and regulation of NF-κB expression are thought to make SFJDC anti-inflammatory and anti-apoptotic. A wide range of active ingredients may result in an anti-inflammatory and antipyretic effect with SFJDC.


Subject(s)
Acute Lung Injury , COVID-19 , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Acute Lung Injury/metabolism , Animals , Anti-Inflammatory Agents , Apoptosis , Drugs, Chinese Herbal , Inflammation/pathology , Interleukin-6/metabolism , Lipopolysaccharides/metabolism , Lipopolysaccharides/toxicity , Lung , Mice , NF-kappa B/metabolism , Receptors, Purinergic P1/metabolism , Receptors, Purinergic P1/therapeutic use , Signal Transduction , Tumor Necrosis Factor-alpha/metabolism , bcl-2-Associated X Protein/metabolism
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