Xuanfei Baidu Decoction reduces acute lung injury by regulating infiltration of neutrophils and macrophages via PD-1/IL17A pathway.
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ABSTRACT:
SUBMITTER: Wang Y
PROVIDER: S-EPMC8757644 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening symptoms in Coronavirus Disease 2019 (COVID-19) patients. Xuanfei Baidu Decoction (XFBD) is a recommend first-line traditional Chinese medicine (TCM) formula therapeutic strategy for COVID-19 patients. Prior studies demonstrated the pharmacological roles and mechanisms of XFBD and its derived effective components against inflammation and infections through multiple model systems, which provided the biological explanations for its clinical use. Our previous work revealed that XFBD inhibited macrophages and neutrophils infiltration via PD-1/IL17A signaling pathway. However, the subsequent biological processes are not well elucidated. Here, we proposed a hypothesis that XFBD can regulate the neutrophils-mediated immune responses, including neutrophil extracellular traps (NETs) formation and the generation of platelet-neutrophil aggregates (PNAs) after XFBD administration in lipopolysaccharide (LPS)-induced ALI mice. The mechanism behind it was also firstly explained, that is XFBD regulated NETs formation via CXCL2/CXCR2 axis. Altogether, our findings demonstrated the sequential immune responses of XFBD after inhibiting neutrophils infiltration, as well as shedding light on exploiting the therapy of XFBD targeting neutrophils to ameliorate ALI during the clinical course.
| S-EPMC10019344 | biostudies-literature
Project description:Statins, known for their lipid-lowering effects, also have immunomodulatory properties. This study aims to examine whether systematic simvastatin administration could decrease polymorphonuclear neutrophils (PMNs) infiltration into brain tissue, as well as alleviate neuroinflammation in a rat model of intracerebral hemorrhage (ICH). The ICH model was induced in adult male Sprague-Dawley rats by an injection of autologous blood. Animals randomly received simvastatin (i.p. 2 mg/kg) or vehicle daily from 5 days before ICH until sacrificed. Routine blood counts, brain water content, neurological scoring, immunofluorescence and RT-PCR were conducted to evaluate the anti-inflammatory effect of simvastatin following ICH. Furthermore, flow cytometric and western blotting analysis were implemented for elucidating the mechanisms involved in simvastatin-induced reduction of neutrophil brain-invading. Elevated PMNs count and neutrophil-to-lymphocyte ratio in circulation were detected in rat model of ICH, which was reversed by using simvastatin. Simvastatin effectively alleviated PMNs infiltration and proinflammatory factors release in perihematomal area, as well as attenuated ICH-induced brain edema and neurological deficits. Simvastatin significantly downregulated the expression of antiapoptotic protein-Mcl-1 while increased the level of proapoptotic protein-Bax and cleaved caspase 3 in PMNs. Simvastatin treatment significantly alleviated PMNs brain-infiltrating and subsequent neuroinflammatory reaction after ICH, in part by accelerating peripheral PMNs apoptosis through disorganized the expression of apoptotic related proteins. Our data provided new evidence for simvastatin application on patients with ICH.
| S-EPMC6315192 | biostudies-literature
Project description:Traditional Chinese herbal compound prescription in Xuanfei Baidu Tang (XBT) has obvious effects in the treatment of COVID-19. However, its effective compounds and targets for the treatment of COVID-19 remain unclear. Computer-Aided Drug Design is used to virtually screen out the anti-inflammatory or anti-viral compounds in XBT, and predict the potential targets by Discovery Studio 2020. Then, we searched for COVID-19 targets using Genecards databases and Protein Data Bank (PDB) databases and compared them to identify targets that were common to both. Finally, the target we screened out is: TP53 (Tumor Protein P53). This article also shows that XBT in the treatment of COVID-19 works in a multi-link and overall synergistic manner. Our results will help to design the new drugs for COVID-19.
| S-EPMC8373853 | biostudies-literature
Project description:PurposeThe Corona Virus Disease 2019 (COVID-19) pandemic has become a challenge of world. The latest research has proved that Xuanfei Baidu granule (XFBD) significantly improved patient's clinical symptoms, the compound drug improves immunity by increasing the number of white blood cells and lymphocytes, and exerts anti-inflammatory effects. However, the analysis of the effective monomer components of XFBD and its mechanism of action in the treatment of COVID-19 is currently lacking. Therefore, this study used computer simulation to study the effective monomer components of XFBD and its therapeutic mechanism.MethodsWe screened out the key active ingredients in XFBD through TCMSP database. Besides GeneCards database was used to search disease gene targets and screen intersection gene targets. The intersection gene targets were analyzed by GO and KEGG. The disease-core gene target-drug network was analyzed and molecular docking was used for verification. Molecular dynamics simulation verification was carried out to combine the active ingredient and the target with a stable combination. The supercomputer platform was used to measure and analyze the number of hydrogen bonds, the binding free energy, the stability of protein target at the residue level, the solvent accessible surface area, and the radius of gyration.ResultsXFBD had 1308 gene targets, COVID-19 had 4600 gene targets, the intersection gene targets were 548. GO and KEGG analysis showed that XFBD played a vital role by the signaling pathways of immune response and inflammation. Molecular docking showed that I-SPD, Pachypodol and Vestitol in XFBD played a role in treating COVID-19 by acting on NLRP3, CSF2, and relieve the clinical symptoms of SARS-CoV-2 infection. Molecular dynamics was used to prove the binding stability of active ingredients and protein targets, CSF2/I-SPD combination has the strongest binding energy.ConclusionFor the first time, it was found that the important active chemical components in XFBD, such as I-SPD, Pachypodol and Vestitol, reduce inflammatory response and apoptosis by inhibiting the activation of NLRP3, and reduce the production of inflammatory factors and chemotaxis of inflammatory cells by inhibiting the activation of CSF2. Therefore, XFBD can effectively alleviate the clinical symptoms of COVID-19 through NLRP3 and CSF2.
| S-EPMC9399524 | biostudies-literature
Project description:BackgroundInflammatory bowel disease (IBD) is becoming a global disease. A percentage of IBD patients will not react to therapy or will lose their response. Qu-Yu-Jie-Du Decoction (QYJD) is a traditional Chinese medicine formula commonly used for intestinal diseases. It has been reported that QYJD has an anti-inflammatory effect, but the mechanism is not fully understood. In this study, we mainly evaluated the anti-inflammatory effect of QYJD and explored the possible mechanisms.MethodsTwenty-four BALB/c mice were randomly divided into 4 groups according to their body weight, namely, the control group, the dextran sulfate sodium (DSS) group, the DSS + QYJD group, and the QYJD group. Mice were given 3% DSS drinking water freely, and at the same time, mice were given normal saline or QYJD (4.44 mg/g/d), respectively. Mental state, faeces, and weight were recorded every day. On the 10th day, the mice were sacrificed and collected for investigation. The length of the mice colon was measured. Histological analysis was used to detect the morphological changes in the colon. Immunohistochemistry was used to measure the infiltration of macrophages (F4/80, CD163) and neutrophils (Ly6G). Colorimetry was used to detect the myeloperoxidase (MPO) activity of colon tissues. ELISA was utilized to detect associated inflammatory cytokines and chemokines in colon tissues.ResultsQYJD alleviated the weight loss and colitis symptoms of mice caused by DSS. QYJD fought against the shortening of the intestine caused by DSS; that is, it improved the decline of intestinal compliance in mice and had a protective effect on colon tissues. The mechanisms were related to downregulating macrophages and neutrophils in colon tissues of infiltration. Besides, QYJD simultaneously reduced the activity of myeloperoxidase activity (MPO) and the contents of IL-1β, IL-6, TNF-α, TGF-β, CCL2, and CXCL2 in colon tissues.ConclusionsQYJD can ameliorate DSS-induced colitis in mice and the mechanism is connected with a reduction in neutrophil and macrophage infiltration.
| S-EPMC9747316 | biostudies-literature
Project description:BackgroundSepsis is the most common critical illness in the clinic, with a high incidence and mortality. Qingwen Baidu decoction (QWBDD) has been widely applied in the treatment of sepsis, however, there is no systematic review or meta-analysis of QWBDD in the treatment of sepsis. Hence, we provide a protocol of systematic review and meta-analysis to evaluate the efficacy and safety of QWBDD in the treatment of sepsis.MethodsThe databases including Cochrane Library, PubMed, Embase, Web of Science, Cochrane Clinical Trial Database, World Health Organization International Clinical Trial Registration Platform, CNKI, CBM, VIP, and WanFang Database will be searched from the time when the respective databases were established to January 2019. All randomized controlled trials (RTCs) published in Chinese and English assessing QWBDD for sepsis will be included. Continuity data are expressed as mean difference (MD) or standard mean difference (SMD), and dichotomous data is expressed as relative risk. Analyses will be performed by using RevMan V.5.3.5 software.ResultsThis study will provide high-quality synthesis of current evidence of QWBDD in the treatment of sepsis from the following aspects, including 28-day mortality, mean arterial pressure (MAP), blood lactate, procalcitonin (PCT), tumor necrosis factor-? (TNF-?), interleukin-6 (IL-6), hypersensitive C-reactive protein (hs-CRP), acute physiology and chronic health score (APACHE-II), intensive care unit stay, mean hospital stay, mechanical ventilation time, etc. CONCLUSION:: Our systematic review will provide evidence for judging whether QWBDD is an effective intervention for sepsis.Prospero registration numberPROSPERO CRD 42019123078.
| S-EPMC6831360 | biostudies-literature
Project description:Qingwen Baidu Decoction (QBD) is an extraordinarily "cold" formula. It was traditionally used to cure epidemic hemorrhagic fever, intestinal typhoid fever, influenza, sepsis and so on. The purpose of this study was to discover relationships between the change of the constituents in different extracts of QBD and the pharmacological effect in a rat model of acute lung injury (ALI) induced by lipopolysaccharide (LPS). The study aimed to discover the changes in constituents of different QBD extracts and the pharmacological effects on acute lung injury (ALI) induced by LPS. The results demonstrated that high dose and middle dose of QBD had significantly potent anti-inflammatory effects and reduced pulmonary edema caused by ALI in rats (p < 0.05). To explore the underlying constituents of QBD, we assessed its influence of six different QBD extracts on ALI and analyzed the different constituents in the corresponding HPLC chromatograms by a Principal Component Analysis (PCA) method. The results showed that the pharmacological effect of QBD was related to the polarity of its extracts, and the medium polarity extracts E2 and E5 in particular displayed much better protective effects against ALI than other groups. Moreover, HPLC-DAD-ESI-MSn and PCA analysis showed that verbascoside and angoroside C played a key role in reducing pulmonary edema. In addition, the current study revealed that ethyl gallate, pentagalloylglucose, galloyl paeoniflorin, mudanpioside C and harpagoside can treat ALI mainly by reducing the total cells and infiltration of activated polymorphonuclear leukocytes (PMNs).
| S-EPMC6154387 | biostudies-literature
Project description:BackgroundInterleukin (IL)17A is a member of the IL17 cytokine family, which is released by both immune and non-immune cells such as tumor and stromal cells into the tumor microenvironment. IL17 receptors are also widely expressed in different type of cells. Among all the members, IL17A is the most controversial in regulating tumor immunity. Here, we investigated how IL17A inhibition modulated macrophage differentiation and metabolism in the presence or absence of gemcitabine. Gemcitabine is the gold standard drug for treating pancreatic cancer and can increase macrophage antitumoral activities.ResultsWe observed some unique features of macrophages polarized in the absence of IL17A, in terms of RNA and protein expression of typical phenotypic markers, and we demonstrated that this paralleled specific changes in their metabolism and functions, such as the induction of an antitumor response. Interestingly, these features were almost maintained or enhanced when macrophages were treated with gemcitabine. We also demonstrated that the anti-IL17A antibody effectively reproduced features of macrophages derived from IL17A knock-out mice.ConclusionOverall, we provide a proof-of-concept that combining an anti-IL17A antibody with gemcitabine may represent an effective strategy to modulate macrophages and enhance the anti-tumor response, especially in pancreatic cancer where gemcitabine is widely used.
| S-EPMC7999796 | biostudies-literature
Project description:Severe influenza kills tens of thousands of individuals each year, yet the mechanisms driving lethality in humans are poorly understood. Here we used a unique translational model of lethal H5N1 influenza in cynomolgus macaques that utilizes inhalation of small-particle virus aerosols to define mechanisms driving lethal disease. RNA sequencing of lung tissue revealed an intense interferon response within two days of infection that resulted in widespread expression of interferon-stimulated genes, including inflammatory cytokines and chemokines. Macaques with lethal disease had rapid and profound loss of alveolar macrophages (AMs) and infiltration of activated CCR2+ CX3CR1+ interstitial macrophages (IMs) and neutrophils into lungs. Parallel changes of AMs and neutrophils in bronchoalveolar lavage (BAL) correlated with virus load when compared to macaques with mild influenza. Both AMs and IMs in lethal influenza were M1-type inflammatory macrophages which expressed neutrophil chemotactic factors, while neutrophils expressed genes associated with activation and generation of neutrophil extracellular traps (NETs). NETs were prominent in lung and were found in alveolar spaces as well as lung parenchyma. Genes associated with pyroptosis but not apoptosis were increased in lung, and activated inflammatory caspases, IL-1β and cleaved gasdermin D (GSDMD) were present in bronchoalveolar lavage fluid and lung homogenates. Cleaved GSDMD was expressed by lung macrophages and alveolar epithelial cells which were present in large numbers in alveolar spaces, consistent with loss of epithelial integrity. Cleaved GSDMD colocalized with viral NP-expressing cells in alveoli, reflecting pyroptosis of infected cells. These novel findings reveal that a potent interferon and inflammatory cascade in lung associated with infiltration of inflammatory macrophages and neutrophils, elaboration of NETs and cell death by pyroptosis mediates lethal H5N1 influenza in nonhuman primates, and by extension humans. These innate pathways represent promising therapeutic targets to prevent severe influenza and potentially other primary viral pneumonias in humans.
| S-EPMC8939778 | biostudies-literature
Project description:T-LAK cell-oriented protein kinase (TOPK) strongly promotes the malignant proliferation of cancer cells and is recognized as a promising biomarker of tumor progression. Psoriasis is a common inflammatory skin disease featured by excessive proliferation of keratinocytes. Although we have previously reported that topically inhibiting TOPK suppressed psoriatic manifestations in psoriasis-like model mice, the exact role of TOPK in psoriatic inflammation and the underlying mechanism remains elusive. GEO datasets were analyzed to investigate the association of TOPK with psoriasis. Skin immunohistochemical (IHC) staining was performed to clarify the major cells expressing TOPK. TOPK conditional knockout (cko) mice were used to investigate the role of TOPK-specific deletion in IMQ-induced psoriasis-like dermatitis in mice. Flow cytometry was used to analyze the alteration of psoriasis-related immune cells in the lesional skin. Next, the M5-induced psoriasis cell model was used to identify the potential mechanism by RNA-seq, RT-RCR, and western blotting. Finally, the neutrophil-neutralizing antibody was used to confirm the relationship between TOPK and neutrophils in psoriasis-like dermatitis in mice. We found that TOPK levels were strongly associated with the progression of psoriasis. TOPK was predominantly increased in the epidermal keratinocytes of psoriatic lesions, and conditional knockout of TOPK in keratinocytes suppressed neutrophils infiltration and attenuated psoriatic inflammation. Neutrophils deletion by neutralizing antibody greatly diminished the suppressive effect of TOPK cko in psoriasis-like dermatitis in mice. In addition, topical application of TOPK inhibitor OTS514 effectively attenuated already-established psoriasis-like dermatitis in mice. Mechanismly, RNA-seq revealed that TOPK regulated the expression of some genes in the IL-17 signaling pathway, such as neutrophils chemokines CXCL1, CXCL2, and CXCL8. TOPK modulated the expression of neutrophils chemokines via activating transcription factors STAT3 and NF-κB p65 in keratinocytes, thereby promoting neutrophils infiltration and psoriasis progression. This study identified a crucial role of TOPK in psoriasis by regulating neutrophils infiltration, providing new insights into the pathogenesis of psoriasis.
| S-EPMC11292866 | biostudies-literature