Targeting acute inflammation to complement spinal cord repair

Immune effector mechanisms play key roles in the progressive（secondary）neurodegenerative changes that follow spinal cord injury（SCI）.In our recent paper（Brennan et al.,2015）,we showed that the inflammatory response to SCI includes rapid and robust activation of the innate immune complement system, with tissue levels of complement component 5a （C5a - an activation product generated by the proteolysis of complement factor 5 （C5）） peaking 12 to 24 hours post-iniurv.

An integrated quantitative proteomics strategy reveals the dual mechanisms of celastrol against acute inflammation

Inflammation is a defense mechanism associated with a wide range of diseases.Celastrol is a small molecule isolated from traditional Chinese medicine with potent anti-inflammation activity.In this study,we established an integrated quantitative proteomics strategy to investigate the acute response to celastrol treatment in a rat macrophage cell line challenged with lipopolysaccharide(LPS).Both stableisotopic based non-targeted quantitative profiling and PRM-based targeted quantitation methods were employed.Dimethyl-labeling based non-targeted profiling revealed 28 and 52 proteins that significantly up-and down-regulated by celastrol.Bioinformatics analysis pinpoint key signaling pathways affected.Seven proteins were selected for examining their time-dependent regulatory pattern in response to celastrol using targeted PRM quantitation.The abundance of mRNA at multiple time-points of selected proteins was also examined.Celastrol induced an acute response of selected key transcriptional factors in terms of mRNA or protein abundance within one hour.Interestingly,regulatory trend of mRNA and protein abundance suggested a novel dual mechanism of celastrol in the terms of acute antiinflammation.The integrated quantitative proteomic strategy established in this study constitutes an efficient workflow to characterize key components and their time-dependent regulatory pattern for monitoring drug response.

BRD7 plays an anti-inflammatory role during early acute inflammation by inhibiting activation of the NF-кB signaling pathway

Increasing evidence has shown a strong association between tumor-suppressor genes and inflammation.However,the role of BRD7 as a novel tumor suppressor in inflammation remains unknown.In this study,by observing BRD7 knockout mice for 6–12 months,we discovered that compared with BRD7+/+mice,BRD7^(−/−)mice were more prone to inflammation,such as external inflammation and abdominal abscess.By using mouse embryo fibroblast(MEF)cells from the BRD7 knockout mouse,an in vitro lipopolysaccharide(LPS)-stimulated MEF cell line was established.The mRNA levels of interleukin-6(IL-6),tumor necrosis factor-α(TNF-α),chemokine(C-X-C motif)ligand 1(CXCL-1)and inducible nitric oxide synthase(iNOS)were significantly increased in BRD7^(−/−)MEF cells compared with BRD7+/+MEF cells after LPS stimulation for 1 or 6 h.In addition,the cytoplasm-to-nucleus translocation of nuclear factor kappa-B(NF-κB;p65)and an increased NF-κB reporter activity were observed in BRD7^(−/−)MEF cells at the 1 h time point but not at the 6 h time point.Furthermore,an in vivo dextran sodium sulfate(DSS)-induced acute colitis model was created.As expected,the disease activity index(DAI)value was significantly increased in the BRD7^(−/−)mice after DSS treatment for 1–5 days,which was demonstrated by the presence of a significantly shorter colon,splenomegaly and tissue damage.Moreover,higher expression levels of IL-6,TNF-α,p65,CXCL-1 and iNOS,and an increased level of NF-κB(p65)nuclear translocation were also found in the DSS-treated BRD7^(−/−)mice.These findings suggest that BRD7 has an anti-inflammatory role during early acute inflammation by inhibiting activation of the NF-кB signaling pathway,which provides evidence to aid in understanding the therapeutic effects of BRD7 on inflammatory diseases.

Anti-inflammatory evaluation and acute toxicity of three food supplements that contain Moussonia deppeana

Objective:To identify the anti-inflammatory activity through two murine models and in the median Lethal Dose(LD_(50)) of three dietary supplements that contain Moussonia deppeana.Methods:The anti-inflammatory activity of three dietary supplements(Cicatrisan/Gastricus^(R),Gastinol^(R),and Gastrovita^(R)) EtOH extracts was evaluated by TPA and by carrageenan murine models;also,median Lethal Dose(LD_(50)) was determined.Verbascoside was quantified by High-Performance Liquid Chromatography.β-sitosterol,stigmasterol and the mixture of ursolic and oleanolic acids were identified in all supplements by TLC;however,none of these dietary supplements contain verbascoside.Results:For the TPA model,Cicatrisan/Gastricus^(R)generated a notable effect with 38.24%inhibition.While in the carrageenan model,it also exhibited noteworthy anti-inflammatory activity of ear edema with 66.39%of paw edema inhibition at 150 mg/kg,followed by Gastinol^(R) and Gastrovita^(R) with 50%at 300 mg/kg.Finally,LD_(50) was >2 g/kg for all supplements,when was administered intragastrically and Body Weight(BW) gain in mice was not altered after 14 days.Conclusions:Of the three food supplements containing M.deppeana,only the EtOH extract from the Cicatrisan/Gastricus^(R)formulation(tablets) showed significant anti-inflammatory activity in both experimental models and the LD_(50) was > 2 g/kg.

Acute-on-chronic liver failure：recent update

Acute on chronic liver failure（ACLF） was first described in 1995 as a clinical syndrome distinct to classic acute decompensation.Characterized by complications of decompensation,ACLF occurs on a background of chronic liver dysfunction and is associated with high rates of organ failure and significant short-term mortality estimated between45%and 90%.Despite the clinical relevance of the condition,it still remains largely undefined with continued disagreement regarding its precise etiological factors,clinical course,prognostic criteria and management pathways.It is concerning that,despite our relative lack of understanding of the condition,the burden of ACLF among cirrhotic patients remains significant with an estimated prevalence of 30.9%.This paper highlights our current understanding of ACLF,including its etiology,diagnostic and prognostic criteria and pathophysiology.It is evident that further refinement of the ACLF classification system is required in order to detect high-risk patients and improve short-term mortality rates.The field of metabolomics certainly warrants investigation to enhance diagnostic and prognostic parameters,while the use of granulocyte-colony stimulating factor is a promising future therapeutic intervention for patients with ACLF.

Genome editing of PAR2 through targeted delivery of CRISPR-Cas9 system for alleviating acute lung inflammation via ERK/NLRP3/IL-1β and NO/iNOS signalling

Excessive and uncontrollable inflammatory responses in alveoli can dramatically exacerbate pulmonary disease progressions through vigorous cytokine releases,immune cell infiltration and protease-driven tissue damages.It is an urgent need to explore potential drug strategies for mitigating lung inflammation.Protease-activated receptor 2(PAR2)as a vital molecular target principally participates in various inflammatory diseases via intracellular signal transduction.However,it has been rarely reported about the role of PAR2 in lung inflammation.This study applied CRISPR-Cas9 system encoding Cas9 and sg RNA(p Cas9-PAR2)for PAR2 knockout and fabricated an anionic human serum albuminbased nanoparticles to deliver p Cas9-PAR2 with superior inflammation-targeting efficiency and stability(TAP/p Cas9-PAR2).TAP/p Cas9-PAR2 robustly facilitated p Cas9-PAR2 to enter and transfect inflammatory cells,eliciting precise gene editing of PAR2 in vitro and in vivo.Importantly,PAR2 deficiency by TAP/p Cas9-PAR2 effectively and safely promoted macrophage polarization,suppressed proinflammatory cytokine releases and alleviated acute lung inflammation,uncovering a novel value of PAR2.It also revealed that PAR2-mediated pulmonary inflammation prevented by TAP/p Cas9-PAR2was mainly dependent on ERK-mediated NLRP3/IL-1β and NO/i NOS signalling.Therefore,this work indicated PAR2 as a novel target for lung inflammation and provided a potential nanodrug strategy for PAR2 deficiency in treating inflammatory diseases.

Increasing stiffness promotes pulmonary retention of ligand-directed dexamethasone-loaded nanoparticle for enhanced acute lung inflammation therapy

Inhaled nanoparticles(NPs)need to penetrate the bronchial mucosa to deliver drug payloads deeply in the lung for amplified local therapy.However,the bronchial mucociliary barrier eliminates NPs rapidly,which considerably limits their mucosal penetration.In this study,we find that surface ligand modification and stiffness adjustment of NPs contribute to the significantly enhanced bronchial mucosal absorption and pulmonary retention of inhaled drugs.We utilize neonatal Fc receptor ligand(FcBP)to modify the rationally designed low stiffness NPs(Soft-NP)and high stiffness NPs(Stiff-NP)to target bronchial mucosa.In an acute lung inflammation rat model,after intranasal administration with dexamethasone-loaded NPs,Stiff-NP endowed with FcBP displays superior therapeutic effects.The in vitro data demonstrate that the promotion effect of FcBP to bronchial mucosal absorption of Stiff-NP dominates over Soft-NP.This could be attributed to the higher affinity between ligand-receptor when incorporating FcBP on the Stiff-NP surface.Meanwhile,high stiffness modulates more actin filaments aggregation to mediate endocytosis,along with strengthened Ca2+signal to enhance exocytosis.Conclusively,we highlight that FcBP-modified NPs with higher stiffness would be a potential pulmonary drug delivery system.

Tectorigenin inhibits the inflammation of LPS-induced acute lung injury in mice

AIM: In a previous study, the anti-inflammatory effects of tectorigenin were disclosed. In this study, the anti-inflammatory effects of tectorigenin on acute lung injury using a lipopolysaccharide(LPS)-induced acute lung injury(ALI) mouse model were investigated. METHOD: The cell-count in the bronchoalveolar lavage fluid(BALF) was measured. The animal lung edema degree was evaluated by the wet/dry weight(W/D) ratio. The superoxidase dismutase(SOD) activity and myeloperoxidase(MPO) activity was assayed using SOD and MPO kits, respectively. The levels of inflammatory mediators, including tumor necrosis factor-α(TNF-α), IL-1β, and IL-6 were assayed using an enzyme-linked immunosorbent assay method. Pathological changes of lung tissues were observed through HE staining. The inflammatory signal pathway related protein nuclear factor NF-κB p65 mR NA expression was measured by real-time PCR, and the protein level of NF-κB p65 was measured using Western blotting analysis. RESULTS: The data showed that treatment with the tectorigenin markedly attenuated the inflammatory cell numbers in the BALF, decreased nuclear factor NF-κB p65 mR NA level and protein level in the lungs, and improved SOD activity and inhibited MPO activity. Histological studies showed that tectorigenin substantially inhibited LPS-induced neutrophils in lung tissue compared with the model group. CONCLUSION: The results indicated that tectorigenin had a protective effect on LPS-induced ALI in mice.

Pandemic and modern medicine:Time to recognize and correct previous misconceptions

A sudden increase in the number of viral pneumonias with the onset of the COVID-19 pandemic revealed defects in the provision of medical care for acute pneumonia in the lungs.Localization of the inflammatory process and its functional consequences indicate the identity of all forms of acute pneumonia,regardless of the etiology,and the need to develop treatment principles based on the pathogenesis of the disease.

Dynamic development of microglia and macrophages after spinal cord injury

Secondary injury following spinal cord injury is primarily characterized by a complex inflammatory response,with resident microglia and infiltrating macrophages playing pivotal roles.While previous studies have grouped these two cell types together based on similarities in structure and function,an increasing number of studies have demonstrated that microglia and macrophages exhibit differences in structure and function and have different effects on disease processes.In this study,we used single-cell RNA sequencing and spatial transcriptomics to identify the distinct evolutionary paths of microglia and macrophages following spinal cord injury.Our results showed that microglia were activated to a pro-inflammatory phenotype immediately after spinal cord injury,gradually transforming to an anti-inflammatory steady state phenotype as the disease progressed.Regarding macrophages,our findings highlighted abundant communication with other cells,including fibroblasts and neurons.Both pro-inflammatory and neuroprotective effects of macrophages were also identified;the pro-inflammatory effect may be related to integrin β2(Itgb2) and the neuroprotective effect may be related to the oncostatin M pathway.These findings were validated by in vivo experiments.This research underscores differences in the cellular dynamics of microglia and macrophages following spinal cord injury,and may offer new perspectives on inflammatory mechanisms and potential therapeutic targets.

The role of inflammatory stress in acute coronary syndrome

Objective To summarize current understanding of the roles of anti-inflammatory and proinflammatory mechanisms in the development of atherosclerosis and acute coronary syndrome and to postulate the novel concept of inflammation stress as the most important factor triggering acute coronary syndrome. Moreover,markers of inflammation stress and ways to block involved pathways are elucidated. Data sources A literature search (MEDLINE 1997 to 2002) was performed using the key words “inflammation and cardiovascular disease”. Relevant book chapters were also reviewed. Study selection Well-controlled,prospective landmark studies and review articles on inflammation and acute coronary syndrome were selected. Data extraction Data and conclusions from the selected articles providing solid evidence to elucidate the mechanisms of inflammation and acute coronary syndrome were extracted and interpreted in the light of our own clinical and basic research. Data synthesis Inflammation is closely linked to atherosclerosis and acute coronary syndrome. Chronic and long-lasting inflammation stress,present both systemically or in the vascular walls,can trigger acute coronary syndrome. Conclusions Inflammation stress plays an important role in the process of acute coronary syndrome. Drugs which can modulate the balance of pro- and anti-inflammatory processes and attenuate inflammation stress,such as angiotensin-converting enzyme (ACE) inhibitors/angiotensin Ⅱ receptor blockers,statins,and cytokine antagonists may play active roles in the prevention and treatment of acute coronary syndrome when used in addition to conventional therapies (glycoprotein Ⅱb/Ⅲa receptor antagonists,mechanical intervention strategies, etc).