T cell interactions with microglia in immune-inflammatory processes of ischemic stroke

The primary mechanism of secondary injury after cerebral ischemia may be the brain inflammation that emerges after an ischemic stroke,which promotes neuronal death and inhibits nerve tissue regeneration.As the first immune cells to be activated after an ischemic stroke,microglia play an important immunomodulatory role in the progression of the condition.After an ischemic stroke,peripheral blood immune cells(mainly T cells)are recruited to the central nervous system by chemokines secreted by immune cells in the brain,where they interact with central nervous system cells(mainly microglia)to trigger a secondary neuroimmune response.This review summarizes the interactions between T cells and microglia in the immune-inflammatory processes of ischemic stroke.We found that,during ischemic stroke,T cells and microglia demonstrate a more pronounced synergistic effect.Th1,Th17,and M1 microglia can co-secrete proinflammatory factors,such as interferon-γ,tumor necrosis factor-α,and interleukin-1β,to promote neuroinflammation and exacerbate brain injury.Th2,Treg,and M2 microglia jointly secrete anti-inflammatory factors,such as interleukin-4,interleukin-10,and transforming growth factor-β,to inhibit the progression of neuroinflammation,as well as growth factors such as brain-derived neurotrophic factor to promote nerve regeneration and repair brain injury.Immune interactions between microglia and T cells influence the direction of the subsequent neuroinflammation,which in turn determines the prognosis of ischemic stroke patients.Clinical trials have been conducted on the ways to modulate the interactions between T cells and microglia toward anti-inflammatory communication using the immunosuppressant fingolimod or overdosing with Treg cells to promote neural tissue repair and reduce the damage caused by ischemic stroke.However,such studies have been relatively infrequent,and clinical experience is still insufficient.In summary,in ischemic stroke,T cell subsets and activated microglia act synergistically to regulate inflammatory progression,mainly by secreting inflammatory factors.In the future,a key research direction for ischemic stroke treatment could be rooted in the enhancement of anti-inflammatory factor secretion by promoting the generation of Th2 and Treg cells,along with the activation of M2-type microglia.These approaches may alleviate neuroinflammation and facilitate the repair of neural tissues.

Therapeutic window of Qingkailing injection for focal cerebral ischemia/reperfusion injury

The time window in which a drug is effective varies between drugs. The present study investigated the therapeutic window of Qingkailing injection for focal cerebral ischemia/reperfusion in mice. Animals underwent middle cerebral artery occlusion and were injected with Qingkailing （1.5, 3, 6 mL/kg）. Infarct volume and neurological function were assessed after 24 hours of ischemia. In addition, to establish the therapeutic time window, mice were injected with 3 mL/kg Qingkailing at 0, 1, 3, 4, 6, 9 and 12 hours after occlusion. Results revealed that Qingkailing injection significantly reduced infarct volume and improved neurological function in model mice after cerebral infarction for up to 9 hours, demonstrating that the therapeutic window of Qingkailing injection can extend to 9 hours for cerebral ischemia/reperfusion in mice.

Molecular mechanism of non-alcoholic fatty liver disease induced and aggravated by chronic stress through HSL/ATGL-FFA which promotes fat mobilization

Objective:To study the effects of social stress(CS)and social stress combined with high-fat diet on fat mobilization as a candidate mechanism for the induction or aggravation of non-alcoholic fatty liver disease(NAFLD).Methods:Thirty-two male Wistar rats(250±10 g)were randomly allocated to a blank control group(BC),a high-fat diet group(HFD),a CS group,and a combined CS and high-fat diet group(CS t HFD).Rats were sacrificed and tissues were collected after 8 weeks.Liver and body mass were measured and used to calculate the liver index.Serum aspartate aminotransferase(AST),alanine aminotransferase(ALT),and free fatty acids(FFAs)were measured.Liver sections were examined microscopically after oil red O and hematoxylin and eosin staining.The relative mRNA expression of acetyl-CoA carboxylase(ACCase),hydroxymethylglutaryl coenzyme A(HMG-CoA)reductase in liver,and hormone-sensitive lipase(HSL),and adipose triglyceride lipase(ATGL)in subcutaneous adipose tissue,were measured by real-time PCR.The liver concentrations of triglyceride,reactive oxygen species,and ACCase were measured by ELISA and HSL activity was determined using turbidimetry.Results:NAFLD developed in the CS,HFD,and CS t HFD groups,with the most severe NAFLD being in the CS t HFD group.Serum AST,ALT,and FFA,liver index,and hepatic triglyceride,FFA,and tumor necrosis factor-a were significantly higher in both the CS and CS t HFD groups.However,food intake and ACCase mRNA expression were lower.The mRNA expression of HSL and ATGL in adipose tissue was much higher,and HSL activity was higher in the CS group than in the BC group,and in the CS t HFD group than in the HFD group.Conclusion:We have successfully established two models of stress-induced NAFLD,suggesting stress can induce and aggravate NAFLD by promoting fat mobilization through upregulation of HSL and ATGL.

Qinzhi Zhudan formula improves memory and alleviates neuroinflammation in vascular dementia rats partly by inhibiting the TNFR1-mediated TNF pathway

Objective: The Qinzhi Zhudan formula(QZZD) exhibits a prominent therapeutic effect in the treatment of vascular dementia(VaD). This study combined a network pharmacology approach and experimental validation to identify the underlying biological mechanism of QZZD against VaD.Methods: Male Wistar rats received bilateral common carotid artery occlusion(BCCAO) surgery, and after4 weeks of intragastric administration of QZZD, the therapeutic effect was assessed using the Morris water maze test and cerebral blood flow(CBF) assessment. Hematoxylin and eosin staining, Nissl staining, and electron microscopy were used to measure the histopathological changes in the neurons of rats. The effect of QZZD treatment on hippocampal neurotransmitters was assessed by high-performance liquid chromatography with electrochemical detection and liquid chromatography mass spectrometry.Immunofluorescence was used to observe VaD-induced microglia activation. The inflammatory cytokine levels were assessed by enzyme linked immunosorbent assay. Western blot was used to examine the TNFR1-mediated TNF pathway, which was screened out by network pharmacology analysis.Results: QZZD treatment alleviated pathological changes and neuronal damage in VaD rats and attenuated their cognitive impairment. In addition, QZZD increased CBF and the expression of acetylcholine and 5-hydroxytryptamine in the hippocampal region. Notably, QZZD inhibited microglial activation and the expression of IL-6 and TNF-a. Network pharmacology and western blot indicated that QZZD inhibited the levels of TNFR1, NF-κBp65, p-ERK, TNF-a, and IL-6, which are related to the TNFR1-mediated TNF signaling pathway.Conclusion: QZZD clearly improved learning and memory function, reduced brain pathological damage,elevated CBF and hippocampal neurotransmitter levels, and alleviated neuroinflammation of VaD rats partly by inhibiting the TNFR1-mediated TNF pathway, indicating its potential value in the clinical therapy of VaD.

Liangxue Xiaoban decoction and its disassembled prescriptions ameliorate psoriasis-like skin lesions induced by imiquimod in mice via T cell regulation

Objective:To explore the therapeutic capacity of the Liangxue Xiaoban(LXXB)decoction and its disassembled prescriptions in the modulation of T cell subsets and recurrence-related indexes of psoriasis using a psoriasis-like mouse model.Methods:The psoriasis model was generated by the treatment of BALB/c mice(n=48)with imiquimod.Mice were divided into six groups:control,psoriasis model,tripterygium glycosides,LXXB decoction,Liangxue decoction,and Qingqi decoction.After the intervention period,the interleukin(IL)-17A,IL-22,and interferon-γ levels in mice were examined and hematoxylin and eosin staining was conducted to determine pathological changes in the skin tissues.T cell subset changes in the skin-draining lymph nodes were analyzed using flow cytometry,and the expression levels of the associated transcription factors and recurrence-related indexes in the skin tissues were determined using a polymerase chain reaction.Results:LXXB decoction attenuated the levels of CD8^(+)T,Th17,and Th1 cells and induced an increase in the Th2 and Treg cell levels.The disassembled prescriptions promoted or inhibited specific subsets of T cells to improve the symptoms of psoriasis.Notably,the LXXB and Liangxue decoctions suppressed the expression of IL-22 at both the gene and protein levels and restored the CD103 and IL-15 expressions in the skin tissue to the normal range.Conclusion:LXXB decoction exerted significant immunoregulatory effects on T cell subsets and improved the recurrence-related indexes.Interestingly,the Liangxue prescription appeared to have a therapeutic advantage in terms of Th17 modulation and psoriasis recurrence,while the Qingqi prescription performed better in Treg immunoregulation.

Paeoniflorin inhibits lipopolysaccharide-induced inflammation in LO2 cells by regulating RhoA/NLRP3 pathway

Background:Inflammation is an essential component of liver diseases.Paeoniflorin(PF),a monoterpenoid component derived from peony root(Paeonia lactiflora Pall.),has anti-inflammatory,immunoregulatory,and hepatoprotective activities.However,whether PF affects liver inflammation and its underlying mechanisms is unclear.In this study,we investigated the effects of PF on lipopolysaccharide(LPS)-induced inflammation in LO2 cells and the underlying molecular mechanism.Methods:LPS was used to induce inflammation.After PF pretreatment for 2 h,the cells were treated with PF and LPS.Cell counting kit-8 was used to measure cell viability.Tumor necrosis factor-a(TNF-a)and interleukin(IL)-6 were tested by Enzyme-linked immunosorbent assay.Western blot was used to evaluate TNF-a,Ras homolog family member A(RhoA),NOD-,LRR-and pyrin domain-containing protein 3(NLRP3),apoptosis-associated speck-like protein containing a CARD(ASC),caspase-1,and IL-1b proteins expression.Results:In LPS-induced LO2 cells,PF reduced TNF-a and IL-6 inflammatory cytokine production in a dose-dependent manner.LPS-induced TNF-a expression was also suppressed by PF.In addition,PF significantly inhibited LPS-induced RhoA activation(P=.0014).Finally,PF suppressed LPS-induced NLRP3 inflammasome activation by downregulating NLRP3,ASC,caspase-1,and IL-1b expression.Conclusion:These findings suggest that PF alleviates inflammation induced by LPS and further suggest the anti-inflammatory effect of PF may follow via reduced RhoA and NLRP3 inflammasome activity.

Biologic basis of TCM syndromes and the standardization of syndrome classification

Traditional Chinese medicine(TCM)syndrome is an integral and essential component of TCM theory,and goes beyond philosophic concepts.This article reviews the concept of TCM syndromes and summarizes research findings on the biologic foundation of syndromes.In addition,insight is provided into the promotion of standardization of syndrome classification by enforcing uniformity of TCM terminology,applying standardized diagnostic criteria and operating procedures to minimize subjective effects.Also incorporating interdisciplinary approaches such as data mining and structure modeling,as well as integrating findings on biomarker research are discussed.Consideration is made of the fundamental TCM aspects of syndrome elements,symptoms,phenotypic features,as well as diseases,to form an integral process in the diagnostic path.We believe that better understanding of the biologic basis of the TCM syndrome and standardization of syndrome classification will improve diagnosis,which in turn will enhance therapeutic efficacy and disease prognosis.

Qingre Lishi Tuihuang therapy for acute icteric hepatitis B: A systematic review

Objective:To assess the efficacy of Qingre Lishi Tuihuang therapy (QLTT) for acute icteric hepatitis B infection.Methods:Eight electronic databases were searched from inception to December 2016 with no language restrictions for reports of randomized controlled trials evaluating the effect of QLTT treating acute icteric hepatitis B.Two researchers independently extracted detailed data and assessed methodological quality.ReviewManager 5.3.0 software was used to analyze the data.Results:A total of 13 randomized controlled trials involving 2238 participants were included in this review.The methodological quality was generally poor.The results indicated that supplemented Yinchenhao decoction combined with non-specific treatments was more effective in improving the cure rate (risk ratio =1.80;95% CI 1.21-2.68) and reducing the serum levels of total bilirubin (mean difference =-29.74;95% CI-31.91 to-27.57) and aspartate aminotransferase.Other self-made prescriptions conforming to QLTT plus non-specific treatments had beneficial effect for acute icteric hepatitis B in curing this disease (risk ratio =1.48;95% CI 1.27-1.73),as well as for negative seroconversion of HBeAg (risk ratio =1.39;95% CI 1.11-1.74).Supplemented Yinchenhao decoction plus non-specific treatments was more effective than other self-made prescriptions conforming to QLTT in reducing serum total bilirubin level.Conclusion:Qingre Lishi Tuihuang therapy appears to improve effect based on non-specific treatments for the treatment of acute icteric hepatitis B.However,it is premature to draw confirmative conclusions,owing to the poor methodological quality and high clinical heterogeneity of the included trials.Further well-designed clinical randomized controlled trials with large sample sizes should be undertaken.