Pancreatic ductal adenocarcinoma(PDAC) is an incurable lethal disease whose incidence rate is growing. There is no effective screening for detection of early stage tumors and,in most cases,PDAC is diagnosed at advance...Pancreatic ductal adenocarcinoma(PDAC) is an incurable lethal disease whose incidence rate is growing. There is no effective screening for detection of early stage tumors and,in most cases,PDAC is diagnosed at advanced disease stages,when radical pancreatic resection is not possible. The aggressive nature of pancreatic tumor cells lies in the complex genetic mechanisms behind their uncontrolled capability to grow and metastasize,which involve essential adaptive changes in cellular metabolism,signaling,adhesion and immunoediting. In addition,PDAC cells promote a dense functional stroma that facilitates tumor resistance to chemotherapy and radiation. During the last two decades,gemcitabine has been the reference for the systemic treatment of PDAC. However,recently,a regimen combining fluorouracil,irinotecan,oxaliplatin,and leucovorin(FOLFIRINOX) and another combining albumin-bound paclitaxel with gemcitabine have shown clear therapeutic advantage in advanced PDAC,with survival outcomes of 11.3 and 8.5 mo on phase Ⅲ trials,respectively,over singleagent gemcitabine. With the pending issue of their higher toxicities,these regimens set the reference for ongoing and future clinical studies in advanced PDAC. In addition,the efficacy of oral fluoropyrimidine(S-1) has been well documented in Asiatic PDAC patients. The development of therapeutic approaches other than cytotoxic drugs has proven difficult in the past,with only one drug(erlotinib) approved to date. Besides,a number of agents targeting signaling pathways in tumor or stroma cells are being investigated. Likewise,immunotherapies that target PDAC in various ways are the subject of a number of clinical trials. The search for reliable biomarkers with diagnostic and prognostic value using genomics and mass spectrometry methods may facilitate monitoring and refinement of therapies. This review focuses on current understanding of the pathogenesis of PDAC and the latest developments in the treatment of advanced PDAC.展开更多
Inflammatory bowel diseases(IBDs),such as ulcerative colitis and Crohn's disease,are chronic pathologies associated with a deregulated immune response in the intestinal mucosa,and they are triggered by environment...Inflammatory bowel diseases(IBDs),such as ulcerative colitis and Crohn's disease,are chronic pathologies associated with a deregulated immune response in the intestinal mucosa,and they are triggered by environmental factors in genetically susceptible individuals.Exogenous glucocorticoids(GCs)are widely used as anti-inflammatory therapy in IBDs.In the past,patients with moderate or severe states of inflammation received GCs as a first line therapy with an important effectiveness in terms of reduction of the disease activity and the induction of remission.However,this treatment often results in detrimental side effects.This downside drove the development of second generation GCs and more precise(non-systemic)drugdelivery methods.Recent clinical trials show that most of these new treatments have similar effectiveness to first generation GCs with fewer adverse effects.The remaining challenge in successful treatment of IBDs concerns the refractoriness and dependency that some patients encounter during GCs treatment.A deeper understanding of the molecular mechanisms underlying GC response is key to personalizing drug choice for IBDs patients to optimize their response to treatment.In this review,we examine the clinical characteristics of treatment with GCs,followed by an in depth analysis of the proposed molecular mechanisms involved in its resistance and dependence associated with IBDs.This thorough analysis of current clinical and biomedical literature may help guide physicians in determining a course of treatment for IBDs patients and identifies important areas needing further study.展开更多
Chronic infection with the hepatitis B virus(HBV) is the leading risk factor for the development of hepatocellular carcinoma(HCC). With nearly 750000 deaths yearly, hepatocellular carcinoma is the second highest cause...Chronic infection with the hepatitis B virus(HBV) is the leading risk factor for the development of hepatocellular carcinoma(HCC). With nearly 750000 deaths yearly, hepatocellular carcinoma is the second highest cause of cancer-related death in the world. Unfortunately, the molecular mechanisms that contribute to the development of HBV-associated HCC remain incompletely understood. Recently, micro RNAs(mi RNAs), a family of small non-coding RNAs that play a role primarily in post-transcriptional gene regulation, have been recognized as important regulators of cellular homeostasis, and altered regulation of mi RNA expression has been suggested to play a significant role in virus-associated diseases and the development of many cancers. With this in mind, many groups have begun to investigate the relationship between mi RNAs and HBV replication and HBV-associated disease. Multiple findings suggest that some mi RNAs, such as mi R-122, and mi R-125 and mi R-199 family members, are playing a role in HBV replication and HBV-associated disease, including the development of HBV-associated HCC. In this review, we discuss the current state of our understanding of the relationship between HBV and mi RNAs, including how HBV affects cellular mi RNAs, how these mi RNAs impact HBV replication, and the relationship between HBV-mediated mi RNA regulation and HCC development. We also address the impact of challenges in studying HBV, such as the lack of an effective model system for infectivity and a reliance on transformed cell lines, on our understanding of the relationship between HBV and mi RNAs, and proposepotential applications of mi RNA-related techniques that could enhance our understanding of the role mi RNAs play in HBV replication and HBV-associated disease, ultimately leading to new therapeutic options and improved patient outcomes.展开更多
Chondroitin sulfate proteoglycan-4（CSPG4） is a surface component of two key cell types（oligodendrocyte progenitor cells（OPCs） and myeloid cells） present in lysolecithin-induced lesions in mouse spinal cord.Two t...Chondroitin sulfate proteoglycan-4（CSPG4） is a surface component of two key cell types（oligodendrocyte progenitor cells（OPCs） and myeloid cells） present in lysolecithin-induced lesions in mouse spinal cord.Two types of CSPG4 manipulations have been used to study the roles of these cells in myelin damage and repair：（1） OPC and myeloid-specific ablation of CSPG4,and（2） transplantation of enhanced green fluorescent protein（EGFP）-labeled progenitors to distinguish between bone marrow-derived macrophages and resident microglia.Ablation of CSPG4 in OPCs does not affect myelin damage,but decreases myelin repair,due to reduced proliferation of CSPG4-null OPCs that diminishes generation of mature oligodendrocytes for remyelination.Ablation of CSPG4 in myeloid cells greatly decreases recruitment of macrophages to spinal cord lesions,resulting in smaller initial lesions,but also in significantly diminished myelin repair.In the absence of macrophage recruitment,OPC proliferation is greatly impaired,again leading to decreased generation of myelinating oligodendrocytes.Macrophages may promote OPC proliferation via phagocytosis of myelin debris and/or secretion of factors that stimulate OPC mitosis.Microglia are not able to substitute for macrophages in promoting OPC proliferation.An additional feature of lesions in myeloid-specific CSPG4 null mice is the persistence of poorly-differentiated platelet-derived growth factor receptor α（PDGFRα） ＋ macrophages that may prolong damage.展开更多
Corneal transplantation is the most common surgical procedure amongst solid organ transplants with a high survival rate of 86% at 1-year post-grafting. This high success rate has been attributed to the immune privileg...Corneal transplantation is the most common surgical procedure amongst solid organ transplants with a high survival rate of 86% at 1-year post-grafting. This high success rate has been attributed to the immune privilege of the eye. However, mechanisms originally thought to promote immune privilege, such as the lack of antigen presenting cells and vessels in the cornea, are challenged by recent studies. Nevertheless, the immunological and physiological features of the cornea promoting a relatively weak alloimmune response is likely responsible for the high survival rate in "low-risk" settings. Furthermore, although corneal graft survival in "lowrisk" recipients is favourable, the prognosis in "high-risk" recipients for corneal graft is poor. In "high-risk" grafts, the process of indirect allorecognition is accelerated by the enhanced innate and adaptive immune responses due to pre-existing inflammation and neovascularization of the host bed. This leads to the irreversible rejection of the allograft and ultimately graft failure. Many therapeutic measures are being tested in pre-clinical and clinical studies to counter the immunological challenge of "high-risk" recipients. Despite the prevailing dogma, recent data suggest that tissue matching together with use of systemic immunosuppression may increase the likelihood of graft acceptance in "high-risk" recipients. However, immunosuppressive drugs are accompanied with intolerance/side effects and toxicity, and therefore, novel cell-based therapies are in development which target host immune cells and restore immune homeostasis without significant side effect of treatment. In addition, developments in regenerative medicinemay be able to solve both important short comings of allotransplantation:(1) graft rejection and ultimate graft failure; and(2) the lack of suitable donor corneas. The advances in technology and research indicate that wider therapeutic choices for patients may be available to address the worldwide problem of corneal blindness in both "low-risk" and "high-risk" hosts.展开更多
OBJECTIVE To investigate the genome protective effects of anti-malaria drug,artesunate in an experimental allergic asthma model.METHODS Mice were sensitized on day 0 and 7 and challenged on day 14 with 100μg house du...OBJECTIVE To investigate the genome protective effects of anti-malaria drug,artesunate in an experimental allergic asthma model.METHODS Mice were sensitized on day 0 and 7 and challenged on day 14 with 100μg house dust mite(HDM)via intratracheal administration.Artesunate(30mg·kg-1)was administered intra-peritoneally on day 6,7,8,13,14 and 15.Samples were collected on day 1,3 and 5 post last HDM-challenge for analysis of air way inflammation and DNA damage.Lung sections were immunofluorescence(IF)-stained for DNA double strand breaks(DSBs)markers,γH2AX and 53BP1.Levels of DNA repair proteins Ku70 and Rad51,which are involved in non-homologous end joining(NHEJ)and homologous recombination(HR)DNA DSB repair pathways respectively,were measured.To quantify cell death in asthmatic lung,TUNEL staining was performed.Comet assay,a single cell gel electrophoresis was employed to detect DNA damage induced by HDM in BEAS-2Bhuman bronchial epithelial cell line,in vitro.RESULTS Artesunate treatment significantly reduces immune cells infiltration in BAL fluid of asthmatic mice,collected on day 3 and 5 post-challenge.Importantly,artesuante is able to protect bronchial epithelium from DNA DSBs induced by asthma,as detected by the reduced level of γH2AX and 53BP1 foci formation in the nucleus.This genome protective effect is evident even on day 1 post-challenge,when immune cells infiltration remained high.This indicates that artesunate confers protection on bronchial epithelium in the presence of inflammation.Additionally,artesunate is also able to reduce cell death in asthmatic lung revealed by TUNEL assay and cleaved caspase 3 level.Interestingly,the levels of DNA repair proteins in artesuante-treated asthmatic mice are unchanged as compared to HDM-only mice,suggesting that artesunate treatment does not augment the level of DNA repair proteins.When human bronchial epithelial BEAS-2 Bcells were exposed to HDMin vitro,we observed an increase in the levels of DNA damage.Artesunate(60μmol·L-1)co-incubated with HDM is not able to prevent direct DNA damage induced by the allergen.Together,these studies suggest that the genome protective effect of artesunate in vivo may be attributed to physiological effects(such as its anti-inflammatory effects)rather than serving to directly prevent DNA damage.CONCULSION This study highlights a novel role for artesunate in protecting bronchial epithelial cells from asthma-induced DNA damage.展开更多
Obstructive airway disease is a complex disease entity including several maladies characterized by bronchoconstriction and abnormal airway inflammation. Reversing bronchoconstriction leads to symptomatic relief and im...Obstructive airway disease is a complex disease entity including several maladies characterized by bronchoconstriction and abnormal airway inflammation. Reversing bronchoconstriction leads to symptomatic relief and improvement in quality of life, both in reversible(bronchial asthma) and partially reversible(chronic obstructive airway disease) obstructive airway diseases. β2-adrenoceptor expressed in human airway is the main β-receptor subtype, and its activation in airway smooth muscle cells leads to bronchodilatation. Drugs targeting β-adrenoceptors have been around for many years, for which agonists of the receptors are used in bronchodilation while antagonists are used in cardiovascular diseases. This review article summarizes the effect and usage of β2-agonist in obstructive airway disease, addressing the benefits and potential risks of β2-agonist. The article also looks at the safety of β-blocker usage for cardiovascular disease in patients with obstructive airway disease. There is also emerging evidence that non-selective β-blockers with inverse agonism ironically can have longterm beneficial effects in obstructive airway disease that is beyond cardiovascular protection. Further trials are urgently needed in this area as it might lead to a dramatic turnaround in clinical practice for obstructive airway diseases as has already been seen in the usage of β-blockers for heart failure.展开更多
Background: Cervical cancer is the second most common cancer in women worldwide [1]. Photodynamic therapy has been used for cervical intraepithelial neoplasia with good responses, but few studies have used newer photo...Background: Cervical cancer is the second most common cancer in women worldwide [1]. Photodynamic therapy has been used for cervical intraepithelial neoplasia with good responses, but few studies have used newer phototherapeutics. We evaluated the effectiveness of photodynamic therapy using Pc 4 in vitro and in vivo against human cervical cancer cells. Methods: CaSki and ME-180 cancer cells were grown as monolayers and spheroids. Cell growth and cytotoxicity were measured using a methylthiazol tetrazolium assay. Pc 4 cellular uptake and intracellular distribution were determined. For in vitro Pc 4 photodynamic therapy, cells were irradiated at 667 nm at a fluence of 2.5 J/cm<sup>2</sup> at 48 h. SCID mice were implanted with CaSki and ME-180 cells both subcutaneously and intracervically. Forty-eight hours after Pc 4 photodynamic therapy was administered at 75 and 150 J/cm<sup>2</sup>. Results: The IC<sub>50</sub>s for Pc 4 and Pc 4 photodynamic therapy for CaSki and ME-180 cells as monolayers were, 7.6 μM and 0.016 μM and >10 μM and 0.026 μM;as spheroids, IC<sub>50</sub>s of Pc 4 photodynamic therapy were, 0.26 μM and 0.01 μM. Pc 4 was taken up within cells and widely distributed in tumors and tissues. Intracervical photodynamic therapy resulted in tumor death, however mice died due to gastrointestinal toxicity. Photodynamic therapy resulted in subcutaneous tumor death and growth delay. Conclusions: Pc 4 photodynamic therapy caused death within cervical cancer cells and xenografts, supporting development of Pc 4 photodynamic therapy for treatment of cervical cancer. Support: P30-CA47904, CTSI BaCCoR Pilot Program.展开更多
OBJECTIVE Steroid-resistant airway hyper-responsiveness(AHR)has been proposed to be related to the activation of innate host defense pathways such as those induced by LPS,IFN-γ,and LPS/IFN-γ-stimulated essential med...OBJECTIVE Steroid-resistant airway hyper-responsiveness(AHR)has been proposed to be related to the activation of innate host defense pathways such as those induced by LPS,IFN-γ,and LPS/IFN-γ-stimulated essential mediator IL-27.We investigated whether andrographolide,apreviously demonstrated anti-inflammatory bioactive molecule extracted from the plant Andrographis paniculata,could restore steroid sensitivity to block LPS/IFN-γ-induced IL-27 production and AHR viaits anti-oxidative property.METHODS Mouse macrophage cell line Raw264.7,mouse primary pulmonary monocyte/macrophage,and BALB/c mouse were treated with LPS/IFN-γ,in the presence and absence of increasing doses of dexamethasone and/or andrographolide.mRNA and protein levels of IL-27 in vitro and in vivo were examined,and mouse AHR was assessed.RESULTS Dexamethasone alone failed to inhibit LPS/IFN-γ-induced IL-27 and AHR in mice.Andrographolide significantly facilitated the suppressive effect of dexamethasone on LPS/IFN-γ-induced IL-27 level in macrophage cell line and primary monocyte/macrophage,mouse bronchoalveolar lavage fluid and lung tissue,and furthermore on the incurring AHR.LPS/IFN-γdid not impede nuclear translocation of glucocorticoid receptors but diminishthe protein level of histone deacetylase-2(HDAC2),an essential epigenetic enzymeresponsible for steroid anti-inflammatory action.Andrographolide at low doses(5μmol·L-1 in vitro;1mg·kg-1,ip in vivo)restored nuclear HDAC2 protein levels both in cells and in mouse lungs,possibly via suppression of PI3K/Akt signaling pathway and up-regulation of the anti-oxidative transcription factor Nrf-2level.CONCLUSION Our data suggest that andrographolide may resensitize steroid action on blocking LPS/IFN-γ-induced IL-27 and resultant AHR by restoring HDAC2 level.展开更多
The host immune system is comprised of many unique cell types that respond to pathogen-derived molecules （foreign antigens） and play key roles in combating infection. Immune cells have been historically classified i...The host immune system is comprised of many unique cell types that respond to pathogen-derived molecules （foreign antigens） and play key roles in combating infection. Immune cells have been historically classified into two groups. Innate immune ceils, such as macrophages and dendritic cells, recognize biochemical patterns within compounds or proteins expressed by microorganisms, and upon activation secrete proinflammatory cytokines im- mediately or within hours following infection. On the other hand, adaptive immune cells, such as B and T cells, react with exquisite specificity to small protein determinants encoded by patho- gens and clonally expand in numbers over the course of seven to ten days following infection or vaccination.展开更多
OBJECTIVE Cigarette smoke-induced chronic obstructive pulmonary disease(COPD)is a leading cause of death,where inflammation and oxidative stress are involved in the pathogenesis.Vitamin E isoformγ-tocotrienol possess...OBJECTIVE Cigarette smoke-induced chronic obstructive pulmonary disease(COPD)is a leading cause of death,where inflammation and oxidative stress are involved in the pathogenesis.Vitamin E isoformγ-tocotrienol possesses both anti-oxidative and anti-inflammatory properties.We hypothesized thatγ-tocotrienol may have protective effects against COPD.METHODS BALB/c mice were exposedto cigarette smoke daily for 2 weeks with oralγ-tocotrienol treatment in the second week.Bronchoalveolar lavage(BAL)fluid was assessed for total and differential cell counts,oxidative damage biomarkers,and cytokine levels.Lung tissues were examined for the expression of antioxidants and pro-inflammatory biomarkers.In order to measure changes in lung functions in COPD,another set of mice was exposed to cigarette smoke for 2 months with oralγ-tocotrienol treatment in the last 2 weeks.RESULTSγ-Tocotrienol dose-dependently abated cigarette smoke-induced elevation of BAL fluid total and neutrophil cell counts,cytokine and chemokine(IL-1β,IL-6,IL-17,LIX,G-CSF,KC,RANTES and VEGF)levels,as well as oxidative/nitrosative damage biomarker(advanced oxidation of protein products,8-isoprostane,8-hydroxy-2-deoxyguanosine and 3-nitrotyrosine)levels.γ-Tocotrienol promoted total lung antioxidant capacity and endogenous antioxidant activities of superoxide dismutase,catalase and glutathione peroxidase.More importantly,γ-tocotrienol markedly restored work of breathing and lung functions(total lung capacity,static compliance and FEV100/FVC)in chronic experimental COPD.Furthermore,γ-tocotrienol demonstrated better anti-oxidative,anti-inflammatory,and restoration of lung functions in COPD than prednisolone.CONCLUSION We have shown for the first time the efficacy of vitamin E isomerγ-tocotrienol in protection against cigarette smoke-induced COPD by direct neutralization of free radicals,abating oxidative damage,and restoring antioxidants activities,coupled with anti-inflammatory actions in the inflamed airways.展开更多
Inhaled corticosteroid is the first-line controller for asthma and COPD.However,about 10% of the asthmatics(severe/refractory asthma) and most of the COPD patients are resistant to the beneficial effects of corticoste...Inhaled corticosteroid is the first-line controller for asthma and COPD.However,about 10% of the asthmatics(severe/refractory asthma) and most of the COPD patients are resistant to the beneficial effects of corticosteroids.There is a pressing unmet medical need to develop novel therapeutic agents to restore corticosteroid efficacy in affected patients.There have been reports showing the promise of theophylline and rapamycin in reversing steroid resistance in COPD.Our laboratory has demonstrated that andrographolide,a bioactive diterpenoid lactone isolated from the plant Andrographis paniculata,is an effective anti-inflammatory and anti-oxidative compound in both asthma and COPD experimental models.In a severe asthma mouse model using combined IFN-γ/LPS exposure,production of IL-27 and methacholine-induced airway hyperresponsiveness(AHR) were found to be corticosteroid-resistant.Andrographolide was found to restore the anti-inflammatory effect of dexamethasone in LPS/IFN-γ-induced IL-27 levels in bronchoalveolar lavage(BAL) fluid and AHR in mice.LPS/IFN-γ markedly reduced the nuclear level of histone deacetylase-2(HDAC2),an essential epigenetic enzyme that mediates corticosteroid anti-inflammatory actions.Andrographolide significantly restored nuclear HDAC2 levels and diminished total HAT/HDAC activity ratio in mouse lungs exposed to LPS/IFN-γ,probably via suppression of PI3K/Akt/HDAC2 phosphorylation and up-regulation of the antioxidant transcription factor Nrf2 level.In a cigarette smoke(CS)-induced COPD model,andrographolide markedly restored dexamethasone actions in inhibiting CS-induced lung neutrophilia.In addition,andrographolide facilitated dexamethasone actions to suppress BAL fluid IL-6,IL-1b,KC and IL-17 levels.In lung lysates,andrographolide markedly restored total nuclear HDAC activity.The complete steroid re-sensitization mechanism of andrographolide remains to be unraveled.Nevertheless,our existing data strongly implicate a potentially novel steroid re-sensitizing activity of andrographolide in both severe asthma and COPD models.展开更多
OBJECTIVE To develop a 2-week cigarette smoke(CS)acute lung injury model exacerbated by haemophilus influenzae(NTHi)and study the protective effect of andrographolide in this COPD model.METHODS Female BALB/c mice,6-8-...OBJECTIVE To develop a 2-week cigarette smoke(CS)acute lung injury model exacerbated by haemophilus influenzae(NTHi)and study the protective effect of andrographolide in this COPD model.METHODS Female BALB/c mice,6-8-week-old,were exposed to 4% 3R4 FCS delivered using aperistaltic pump daily for 2 weeks to induce an acute lung injury model.After 2 weeks of smoking,mice were inoculated intratracheally with NTHi to induce exacerbation on the model.Mice were sacrificed 48 h after last bacteria challenge and lung samples were collected for various analyses.RESULTS After developing a 2-week CS acute lung injury model exacerbated by NTHi,the CS+NTHi group was shown to have a higher inflammatory response,higher bacterial clearance,an upregulation of MMP12 mRNA levels and decrease in TIMP1 mRNA levels in the lungs.Administration of Andrographolide suppressed BALF lung cellular infiltrates,TNF-α,CXCL1/KC,IL-1βand 8-OHdG protein levels,together with increased HO-1 and GR mRNA levels and decreased MMP-8 and MMP-9 mRNA levels.Andrographolide was able to ameliorate lung histopathology as observed with H&E staining and inflammation scoring.Andrographolide was also shown to reduce Keap-1 level in lungs without affecting DJ-1 level.CONCLUSION This study demonstrates the protective effect of andrographolide in a novel 2-week CS acute lung injury model exacerbated by NTHi and presents it as a potential therapeutic for COPD.展开更多
Andrographis paniculata contains two main diterpenoid constituents,andrographolide(AGP)and 14-deoxy-11,12-didehydroandrographolide(DDAG),which were found to exhibit antiasthma effects in a mouse asthma model.However,d...Andrographis paniculata contains two main diterpenoid constituents,andrographolide(AGP)and 14-deoxy-11,12-didehydroandrographolide(DDAG),which were found to exhibit antiasthma effects in a mouse asthma model.However,due to inadequacies of both compounds in terms of drug-likeness,DDAG analogues were semisynthesised to tackle these shortcomings.The objective of the study was to investigate the potential of DDAG analogues as new antiasthma agents.Among the analogues,(SRS27)was proven to inhibit cysteinyl leukotrienes(CysLT)and nitric oxide(NO)synthesis in mouse macrophages,like AGP.DDAG,on the other hand,failed to exhibit such activities.SRS27 is less cytotoxic than AGP,suggests that a simple chemical modification of DDAG produces a compound with CysLT and NO inhibitory activites similar to AGP while maintaining toxicity profile similar to DDAG.It is interesting to note that other analogues such as SRS28,SRS49,SRS76 and SRS83 with chemical modifications on the same carbon numbers 3 and 19 of DDAG were unable to show inhibition of CysLT and NO synthesis.Consequently,the potential anti-inflammatory effect of SRS27 was investigated in ovalbumin(OVA)-induced mouse asthma model.The compound was administered in a prophylactic manner and showed a substantial decrease in mouse asthma model parameters.SRS27 at 3mg·kg-1 significantly reduced OVA-induced total cell such as macrophages,eosinophils,lymphocytes and neutrophils,as well as inflammatory cytokines such as IL-4,IL-5,IL-13 and eotaxin in bronchoalveolar lavage BAL fluid.The compound also suppressed serum IgE production.In addition,SRS27 suppressed mucus hyper-secretion and expression of inflammatory mediators such as TNF-α,MCP-1,Muc5 ac,RANTES,IL-33 and iNOS.SRS27 is the first known DDAG derivative tested positive in mouse asthma model and as such SRS27 could serve as a prototype prophylactic agent.展开更多
Since the derivation of embryonic stem （ES） cell lines from human blastocysts in 1998 [1], ES cells have emerged as a potential source of cells and tissues that could be used for cell replacement therapy of incurabl...Since the derivation of embryonic stem （ES） cell lines from human blastocysts in 1998 [1], ES cells have emerged as a potential source of cells and tissues that could be used for cell replacement therapy of incurable degenerative diseases. This is due to their remarkable pluripotency, which enables them to differentiate into any adult cell type of the three embryonal germ layers. Indeed, several groups have reported the successful differentiation of ES cells into adult-type cell lineages including, but not limited to： cardiomyocytes, hematopoietic cells, hepatocytes,展开更多
Multiple myeloma (MM) is a plasma cell neoplasm characterized for its fast evolution and for being practically incurable, presenting a strong need for the development of therapies to target it. Among those under study...Multiple myeloma (MM) is a plasma cell neoplasm characterized for its fast evolution and for being practically incurable, presenting a strong need for the development of therapies to target it. Among those under study are lenalidomide and arsenic trioxide (ATO) which show individual clinical promise, although never tested together. However, the combination of ATO with thalidomide, another immunomodulatory drug and lenalidomide’s structural albeit less potent analog, have been tried clinically with some success. Therefore, we investigated the effect the combination of lenalidomide and ATO have on the MM-derived U266 and RPMI 8226 cell lines. We observed that both compounds have separate, non-interfering, anti-myeloma mechanisms with ATO demonstrating strong cytotoxic effects while lenalidomide’s role remains cytostatic and immunomodulatory. However, ATO decreases cdc25c, which helps sensitize cells to lenalidomide effects enhancing the efficacy of their interaction. Mechanistically the combination of these two agents decreased the expression of MDM2, without affecting p53 activation or its expression. Therefore, this short study provides the foundation to continue mechanistic studies of the combination of lenalidomide and ATO as a foundation for future clinical application.展开更多
In the current issue of the Journal of Sport and Health Science,Wang et al.^(1)describe their prospective study,where they analyzed whether or not multiple pregnancies would influence glycemia and the glycemic respons...In the current issue of the Journal of Sport and Health Science,Wang et al.^(1)describe their prospective study,where they analyzed whether or not multiple pregnancies would influence glycemia and the glycemic response to physical exercise in gestational diabetes mellitus(GDM).2 Multiparous women are known to be at a higher risk for GDM than primiparas.GDM carries an increased risk for adverse perinatal outcomes,not only for the mothers but also for the newborn babies.Due to a contemporary environment that is conducive to a sedentary lifestyle and obesity,the incidence of GDM among pregnant women is increasing.展开更多
Sjogren’s syndrome is a chronic autoimmune exocrinopathy associated with dry eyes and dry mouth as major clinical manifestations. It is characterized by lymphocytic infiltration of lacrimal and salivary glands and au...Sjogren’s syndrome is a chronic autoimmune exocrinopathy associated with dry eyes and dry mouth as major clinical manifestations. It is characterized by lymphocytic infiltration of lacrimal and salivary glands and autoantibody production, especially anti-Ro (or SSA) and anti-La (or SSB). Lymphoproliferative disorders are a feature of Sjogren’s syndrome, and can be considered an extraglandular manifestation of the disease. Kikuchi-Fujimoto disease or histiocytic necrotizing lymphadenitis is a rare form of lymphadenitis. It is reported more often in young adult women with localized lymphadenopathy (usually cervical), fever, rashes, and leukopenia. It is a self-limiting disease with resolution within 1 - 4 months in almost all patients. Sjogren’s syndrome has been reported in patients with other systemic diseases including SLE and lymphomas. Here we present a patient with Kikuchi-Fujimoto disease who developed Sjogren’s Syndrome 8 years after her diagnosis of Kikuchi-Fujimoto disease.展开更多
文摘Pancreatic ductal adenocarcinoma(PDAC) is an incurable lethal disease whose incidence rate is growing. There is no effective screening for detection of early stage tumors and,in most cases,PDAC is diagnosed at advanced disease stages,when radical pancreatic resection is not possible. The aggressive nature of pancreatic tumor cells lies in the complex genetic mechanisms behind their uncontrolled capability to grow and metastasize,which involve essential adaptive changes in cellular metabolism,signaling,adhesion and immunoediting. In addition,PDAC cells promote a dense functional stroma that facilitates tumor resistance to chemotherapy and radiation. During the last two decades,gemcitabine has been the reference for the systemic treatment of PDAC. However,recently,a regimen combining fluorouracil,irinotecan,oxaliplatin,and leucovorin(FOLFIRINOX) and another combining albumin-bound paclitaxel with gemcitabine have shown clear therapeutic advantage in advanced PDAC,with survival outcomes of 11.3 and 8.5 mo on phase Ⅲ trials,respectively,over singleagent gemcitabine. With the pending issue of their higher toxicities,these regimens set the reference for ongoing and future clinical studies in advanced PDAC. In addition,the efficacy of oral fluoropyrimidine(S-1) has been well documented in Asiatic PDAC patients. The development of therapeutic approaches other than cytotoxic drugs has proven difficult in the past,with only one drug(erlotinib) approved to date. Besides,a number of agents targeting signaling pathways in tumor or stroma cells are being investigated. Likewise,immunotherapies that target PDAC in various ways are the subject of a number of clinical trials. The search for reliable biomarkers with diagnostic and prognostic value using genomics and mass spectrometry methods may facilitate monitoring and refinement of therapies. This review focuses on current understanding of the pathogenesis of PDAC and the latest developments in the treatment of advanced PDAC.
基金Supported by National Fund for Scientific and Technological Development No.1170648(MHR)Clínica Las Condes Academic Project PI2013-B002,UApoya No.560959(RQ)National Commission for Scientific and Technological Research scholarship No.21150264(DDJ),No.21120682(MOM),MECESUP Scholarship No.UCH 0714(KDC)
文摘Inflammatory bowel diseases(IBDs),such as ulcerative colitis and Crohn's disease,are chronic pathologies associated with a deregulated immune response in the intestinal mucosa,and they are triggered by environmental factors in genetically susceptible individuals.Exogenous glucocorticoids(GCs)are widely used as anti-inflammatory therapy in IBDs.In the past,patients with moderate or severe states of inflammation received GCs as a first line therapy with an important effectiveness in terms of reduction of the disease activity and the induction of remission.However,this treatment often results in detrimental side effects.This downside drove the development of second generation GCs and more precise(non-systemic)drugdelivery methods.Recent clinical trials show that most of these new treatments have similar effectiveness to first generation GCs with fewer adverse effects.The remaining challenge in successful treatment of IBDs concerns the refractoriness and dependency that some patients encounter during GCs treatment.A deeper understanding of the molecular mechanisms underlying GC response is key to personalizing drug choice for IBDs patients to optimize their response to treatment.In this review,we examine the clinical characteristics of treatment with GCs,followed by an in depth analysis of the proposed molecular mechanisms involved in its resistance and dependence associated with IBDs.This thorough analysis of current clinical and biomedical literature may help guide physicians in determining a course of treatment for IBDs patients and identifies important areas needing further study.
基金Supported by Pennsylvania state CURE grant,No.4100057658,[to Steel LF and Bouchard MJ(partially)]a Ruth L Kirschstein(F31)Predoctoral Fellowship,No.5F31CA171712-03,[to Lamontagne J(partially)]
文摘Chronic infection with the hepatitis B virus(HBV) is the leading risk factor for the development of hepatocellular carcinoma(HCC). With nearly 750000 deaths yearly, hepatocellular carcinoma is the second highest cause of cancer-related death in the world. Unfortunately, the molecular mechanisms that contribute to the development of HBV-associated HCC remain incompletely understood. Recently, micro RNAs(mi RNAs), a family of small non-coding RNAs that play a role primarily in post-transcriptional gene regulation, have been recognized as important regulators of cellular homeostasis, and altered regulation of mi RNA expression has been suggested to play a significant role in virus-associated diseases and the development of many cancers. With this in mind, many groups have begun to investigate the relationship between mi RNAs and HBV replication and HBV-associated disease. Multiple findings suggest that some mi RNAs, such as mi R-122, and mi R-125 and mi R-199 family members, are playing a role in HBV replication and HBV-associated disease, including the development of HBV-associated HCC. In this review, we discuss the current state of our understanding of the relationship between HBV and mi RNAs, including how HBV affects cellular mi RNAs, how these mi RNAs impact HBV replication, and the relationship between HBV-mediated mi RNA regulation and HCC development. We also address the impact of challenges in studying HBV, such as the lack of an effective model system for infectivity and a reliance on transformed cell lines, on our understanding of the relationship between HBV and mi RNAs, and proposepotential applications of mi RNA-related techniques that could enhance our understanding of the role mi RNAs play in HBV replication and HBV-associated disease, ultimately leading to new therapeutic options and improved patient outcomes.
基金supported by National Institutes of Health R01 CA095287(WBS)Sanford Burnham Prebys Medical Discovery Institute Lab Funding Initiative(WBS)
文摘Chondroitin sulfate proteoglycan-4（CSPG4） is a surface component of two key cell types（oligodendrocyte progenitor cells（OPCs） and myeloid cells） present in lysolecithin-induced lesions in mouse spinal cord.Two types of CSPG4 manipulations have been used to study the roles of these cells in myelin damage and repair：（1） OPC and myeloid-specific ablation of CSPG4,and（2） transplantation of enhanced green fluorescent protein（EGFP）-labeled progenitors to distinguish between bone marrow-derived macrophages and resident microglia.Ablation of CSPG4 in OPCs does not affect myelin damage,but decreases myelin repair,due to reduced proliferation of CSPG4-null OPCs that diminishes generation of mature oligodendrocytes for remyelination.Ablation of CSPG4 in myeloid cells greatly decreases recruitment of macrophages to spinal cord lesions,resulting in smaller initial lesions,but also in significantly diminished myelin repair.In the absence of macrophage recruitment,OPC proliferation is greatly impaired,again leading to decreased generation of myelinating oligodendrocytes.Macrophages may promote OPC proliferation via phagocytosis of myelin debris and/or secretion of factors that stimulate OPC mitosis.Microglia are not able to substitute for macrophages in promoting OPC proliferation.An additional feature of lesions in myeloid-specific CSPG4 null mice is the persistence of poorly-differentiated platelet-derived growth factor receptor α（PDGFRα） ＋ macrophages that may prolong damage.
基金Supported by Saving Sight in Grampian,Development Trust of University of Aberdeen,United KingdomAction Medical Research United Kingdom(grant SP4328)Link?ping University,Sweden
文摘Corneal transplantation is the most common surgical procedure amongst solid organ transplants with a high survival rate of 86% at 1-year post-grafting. This high success rate has been attributed to the immune privilege of the eye. However, mechanisms originally thought to promote immune privilege, such as the lack of antigen presenting cells and vessels in the cornea, are challenged by recent studies. Nevertheless, the immunological and physiological features of the cornea promoting a relatively weak alloimmune response is likely responsible for the high survival rate in "low-risk" settings. Furthermore, although corneal graft survival in "lowrisk" recipients is favourable, the prognosis in "high-risk" recipients for corneal graft is poor. In "high-risk" grafts, the process of indirect allorecognition is accelerated by the enhanced innate and adaptive immune responses due to pre-existing inflammation and neovascularization of the host bed. This leads to the irreversible rejection of the allograft and ultimately graft failure. Many therapeutic measures are being tested in pre-clinical and clinical studies to counter the immunological challenge of "high-risk" recipients. Despite the prevailing dogma, recent data suggest that tissue matching together with use of systemic immunosuppression may increase the likelihood of graft acceptance in "high-risk" recipients. However, immunosuppressive drugs are accompanied with intolerance/side effects and toxicity, and therefore, novel cell-based therapies are in development which target host immune cells and restore immune homeostasis without significant side effect of treatment. In addition, developments in regenerative medicinemay be able to solve both important short comings of allotransplantation:(1) graft rejection and ultimate graft failure; and(2) the lack of suitable donor corneas. The advances in technology and research indicate that wider therapeutic choices for patients may be available to address the worldwide problem of corneal blindness in both "low-risk" and "high-risk" hosts.
基金The project supported by a NMRC grant NMRC/CBRG/0027/2012from the National Medical Research Council of Singapore,with additional support from the Singapore-MIT Alliance for Research and Technology
文摘OBJECTIVE To investigate the genome protective effects of anti-malaria drug,artesunate in an experimental allergic asthma model.METHODS Mice were sensitized on day 0 and 7 and challenged on day 14 with 100μg house dust mite(HDM)via intratracheal administration.Artesunate(30mg·kg-1)was administered intra-peritoneally on day 6,7,8,13,14 and 15.Samples were collected on day 1,3 and 5 post last HDM-challenge for analysis of air way inflammation and DNA damage.Lung sections were immunofluorescence(IF)-stained for DNA double strand breaks(DSBs)markers,γH2AX and 53BP1.Levels of DNA repair proteins Ku70 and Rad51,which are involved in non-homologous end joining(NHEJ)and homologous recombination(HR)DNA DSB repair pathways respectively,were measured.To quantify cell death in asthmatic lung,TUNEL staining was performed.Comet assay,a single cell gel electrophoresis was employed to detect DNA damage induced by HDM in BEAS-2Bhuman bronchial epithelial cell line,in vitro.RESULTS Artesunate treatment significantly reduces immune cells infiltration in BAL fluid of asthmatic mice,collected on day 3 and 5 post-challenge.Importantly,artesuante is able to protect bronchial epithelium from DNA DSBs induced by asthma,as detected by the reduced level of γH2AX and 53BP1 foci formation in the nucleus.This genome protective effect is evident even on day 1 post-challenge,when immune cells infiltration remained high.This indicates that artesunate confers protection on bronchial epithelium in the presence of inflammation.Additionally,artesunate is also able to reduce cell death in asthmatic lung revealed by TUNEL assay and cleaved caspase 3 level.Interestingly,the levels of DNA repair proteins in artesuante-treated asthmatic mice are unchanged as compared to HDM-only mice,suggesting that artesunate treatment does not augment the level of DNA repair proteins.When human bronchial epithelial BEAS-2 Bcells were exposed to HDMin vitro,we observed an increase in the levels of DNA damage.Artesunate(60μmol·L-1)co-incubated with HDM is not able to prevent direct DNA damage induced by the allergen.Together,these studies suggest that the genome protective effect of artesunate in vivo may be attributed to physiological effects(such as its anti-inflammatory effects)rather than serving to directly prevent DNA damage.CONCULSION This study highlights a novel role for artesunate in protecting bronchial epithelial cells from asthma-induced DNA damage.
基金Supported by NMRC/CBRG/0027/2012 from the National Medical Research Council of Singapore(in part)by NUHS Seed Fund R-184-000-238-112
文摘Obstructive airway disease is a complex disease entity including several maladies characterized by bronchoconstriction and abnormal airway inflammation. Reversing bronchoconstriction leads to symptomatic relief and improvement in quality of life, both in reversible(bronchial asthma) and partially reversible(chronic obstructive airway disease) obstructive airway diseases. β2-adrenoceptor expressed in human airway is the main β-receptor subtype, and its activation in airway smooth muscle cells leads to bronchodilatation. Drugs targeting β-adrenoceptors have been around for many years, for which agonists of the receptors are used in bronchodilation while antagonists are used in cardiovascular diseases. This review article summarizes the effect and usage of β2-agonist in obstructive airway disease, addressing the benefits and potential risks of β2-agonist. The article also looks at the safety of β-blocker usage for cardiovascular disease in patients with obstructive airway disease. There is also emerging evidence that non-selective β-blockers with inverse agonism ironically can have longterm beneficial effects in obstructive airway disease that is beyond cardiovascular protection. Further trials are urgently needed in this area as it might lead to a dramatic turnaround in clinical practice for obstructive airway diseases as has already been seen in the usage of β-blockers for heart failure.
文摘Background: Cervical cancer is the second most common cancer in women worldwide [1]. Photodynamic therapy has been used for cervical intraepithelial neoplasia with good responses, but few studies have used newer phototherapeutics. We evaluated the effectiveness of photodynamic therapy using Pc 4 in vitro and in vivo against human cervical cancer cells. Methods: CaSki and ME-180 cancer cells were grown as monolayers and spheroids. Cell growth and cytotoxicity were measured using a methylthiazol tetrazolium assay. Pc 4 cellular uptake and intracellular distribution were determined. For in vitro Pc 4 photodynamic therapy, cells were irradiated at 667 nm at a fluence of 2.5 J/cm<sup>2</sup> at 48 h. SCID mice were implanted with CaSki and ME-180 cells both subcutaneously and intracervically. Forty-eight hours after Pc 4 photodynamic therapy was administered at 75 and 150 J/cm<sup>2</sup>. Results: The IC<sub>50</sub>s for Pc 4 and Pc 4 photodynamic therapy for CaSki and ME-180 cells as monolayers were, 7.6 μM and 0.016 μM and >10 μM and 0.026 μM;as spheroids, IC<sub>50</sub>s of Pc 4 photodynamic therapy were, 0.26 μM and 0.01 μM. Pc 4 was taken up within cells and widely distributed in tumors and tissues. Intracervical photodynamic therapy resulted in tumor death, however mice died due to gastrointestinal toxicity. Photodynamic therapy resulted in subcutaneous tumor death and growth delay. Conclusions: Pc 4 photodynamic therapy caused death within cervical cancer cells and xenografts, supporting development of Pc 4 photodynamic therapy for treatment of cervical cancer. Support: P30-CA47904, CTSI BaCCoR Pilot Program.
基金The project supported by National Medical Research Council of Singapore(NMRC/CBRG/0027/2012)
文摘OBJECTIVE Steroid-resistant airway hyper-responsiveness(AHR)has been proposed to be related to the activation of innate host defense pathways such as those induced by LPS,IFN-γ,and LPS/IFN-γ-stimulated essential mediator IL-27.We investigated whether andrographolide,apreviously demonstrated anti-inflammatory bioactive molecule extracted from the plant Andrographis paniculata,could restore steroid sensitivity to block LPS/IFN-γ-induced IL-27 production and AHR viaits anti-oxidative property.METHODS Mouse macrophage cell line Raw264.7,mouse primary pulmonary monocyte/macrophage,and BALB/c mouse were treated with LPS/IFN-γ,in the presence and absence of increasing doses of dexamethasone and/or andrographolide.mRNA and protein levels of IL-27 in vitro and in vivo were examined,and mouse AHR was assessed.RESULTS Dexamethasone alone failed to inhibit LPS/IFN-γ-induced IL-27 and AHR in mice.Andrographolide significantly facilitated the suppressive effect of dexamethasone on LPS/IFN-γ-induced IL-27 level in macrophage cell line and primary monocyte/macrophage,mouse bronchoalveolar lavage fluid and lung tissue,and furthermore on the incurring AHR.LPS/IFN-γdid not impede nuclear translocation of glucocorticoid receptors but diminishthe protein level of histone deacetylase-2(HDAC2),an essential epigenetic enzymeresponsible for steroid anti-inflammatory action.Andrographolide at low doses(5μmol·L-1 in vitro;1mg·kg-1,ip in vivo)restored nuclear HDAC2 protein levels both in cells and in mouse lungs,possibly via suppression of PI3K/Akt signaling pathway and up-regulation of the anti-oxidative transcription factor Nrf-2level.CONCLUSION Our data suggest that andrographolide may resensitize steroid action on blocking LPS/IFN-γ-induced IL-27 and resultant AHR by restoring HDAC2 level.
文摘The host immune system is comprised of many unique cell types that respond to pathogen-derived molecules （foreign antigens） and play key roles in combating infection. Immune cells have been historically classified into two groups. Innate immune ceils, such as macrophages and dendritic cells, recognize biochemical patterns within compounds or proteins expressed by microorganisms, and upon activation secrete proinflammatory cytokines im- mediately or within hours following infection. On the other hand, adaptive immune cells, such as B and T cells, react with exquisite specificity to small protein determinants encoded by patho- gens and clonally expand in numbers over the course of seven to ten days following infection or vaccination.
基金The project supported in part by NMRC/CBRG/0027/2012from the National Medical Research Council of Singapore and by NUHS Seed Fund R-184-000-238-112
文摘OBJECTIVE Cigarette smoke-induced chronic obstructive pulmonary disease(COPD)is a leading cause of death,where inflammation and oxidative stress are involved in the pathogenesis.Vitamin E isoformγ-tocotrienol possesses both anti-oxidative and anti-inflammatory properties.We hypothesized thatγ-tocotrienol may have protective effects against COPD.METHODS BALB/c mice were exposedto cigarette smoke daily for 2 weeks with oralγ-tocotrienol treatment in the second week.Bronchoalveolar lavage(BAL)fluid was assessed for total and differential cell counts,oxidative damage biomarkers,and cytokine levels.Lung tissues were examined for the expression of antioxidants and pro-inflammatory biomarkers.In order to measure changes in lung functions in COPD,another set of mice was exposed to cigarette smoke for 2 months with oralγ-tocotrienol treatment in the last 2 weeks.RESULTSγ-Tocotrienol dose-dependently abated cigarette smoke-induced elevation of BAL fluid total and neutrophil cell counts,cytokine and chemokine(IL-1β,IL-6,IL-17,LIX,G-CSF,KC,RANTES and VEGF)levels,as well as oxidative/nitrosative damage biomarker(advanced oxidation of protein products,8-isoprostane,8-hydroxy-2-deoxyguanosine and 3-nitrotyrosine)levels.γ-Tocotrienol promoted total lung antioxidant capacity and endogenous antioxidant activities of superoxide dismutase,catalase and glutathione peroxidase.More importantly,γ-tocotrienol markedly restored work of breathing and lung functions(total lung capacity,static compliance and FEV100/FVC)in chronic experimental COPD.Furthermore,γ-tocotrienol demonstrated better anti-oxidative,anti-inflammatory,and restoration of lung functions in COPD than prednisolone.CONCLUSION We have shown for the first time the efficacy of vitamin E isomerγ-tocotrienol in protection against cigarette smoke-induced COPD by direct neutralization of free radicals,abating oxidative damage,and restoring antioxidants activities,coupled with anti-inflammatory actions in the inflamed airways.
基金supported by a CREATE Grant R-184-000-269-592 by the National Research Foundation(NRF) of Singapore to W.S.F.W
文摘Inhaled corticosteroid is the first-line controller for asthma and COPD.However,about 10% of the asthmatics(severe/refractory asthma) and most of the COPD patients are resistant to the beneficial effects of corticosteroids.There is a pressing unmet medical need to develop novel therapeutic agents to restore corticosteroid efficacy in affected patients.There have been reports showing the promise of theophylline and rapamycin in reversing steroid resistance in COPD.Our laboratory has demonstrated that andrographolide,a bioactive diterpenoid lactone isolated from the plant Andrographis paniculata,is an effective anti-inflammatory and anti-oxidative compound in both asthma and COPD experimental models.In a severe asthma mouse model using combined IFN-γ/LPS exposure,production of IL-27 and methacholine-induced airway hyperresponsiveness(AHR) were found to be corticosteroid-resistant.Andrographolide was found to restore the anti-inflammatory effect of dexamethasone in LPS/IFN-γ-induced IL-27 levels in bronchoalveolar lavage(BAL) fluid and AHR in mice.LPS/IFN-γ markedly reduced the nuclear level of histone deacetylase-2(HDAC2),an essential epigenetic enzyme that mediates corticosteroid anti-inflammatory actions.Andrographolide significantly restored nuclear HDAC2 levels and diminished total HAT/HDAC activity ratio in mouse lungs exposed to LPS/IFN-γ,probably via suppression of PI3K/Akt/HDAC2 phosphorylation and up-regulation of the antioxidant transcription factor Nrf2 level.In a cigarette smoke(CS)-induced COPD model,andrographolide markedly restored dexamethasone actions in inhibiting CS-induced lung neutrophilia.In addition,andrographolide facilitated dexamethasone actions to suppress BAL fluid IL-6,IL-1b,KC and IL-17 levels.In lung lysates,andrographolide markedly restored total nuclear HDAC activity.The complete steroid re-sensitization mechanism of andrographolide remains to be unraveled.Nevertheless,our existing data strongly implicate a potentially novel steroid re-sensitizing activity of andrographolide in both severe asthma and COPD models.
基金The project supported by National Medical Research Council(NMRC/CBRG/0027/2012)
文摘OBJECTIVE To develop a 2-week cigarette smoke(CS)acute lung injury model exacerbated by haemophilus influenzae(NTHi)and study the protective effect of andrographolide in this COPD model.METHODS Female BALB/c mice,6-8-week-old,were exposed to 4% 3R4 FCS delivered using aperistaltic pump daily for 2 weeks to induce an acute lung injury model.After 2 weeks of smoking,mice were inoculated intratracheally with NTHi to induce exacerbation on the model.Mice were sacrificed 48 h after last bacteria challenge and lung samples were collected for various analyses.RESULTS After developing a 2-week CS acute lung injury model exacerbated by NTHi,the CS+NTHi group was shown to have a higher inflammatory response,higher bacterial clearance,an upregulation of MMP12 mRNA levels and decrease in TIMP1 mRNA levels in the lungs.Administration of Andrographolide suppressed BALF lung cellular infiltrates,TNF-α,CXCL1/KC,IL-1βand 8-OHdG protein levels,together with increased HO-1 and GR mRNA levels and decreased MMP-8 and MMP-9 mRNA levels.Andrographolide was able to ameliorate lung histopathology as observed with H&E staining and inflammation scoring.Andrographolide was also shown to reduce Keap-1 level in lungs without affecting DJ-1 level.CONCLUSION This study demonstrates the protective effect of andrographolide in a novel 2-week CS acute lung injury model exacerbated by NTHi and presents it as a potential therapeutic for COPD.
基金The project supported by grant(BMRC/09/1/21/19/595)from the BioMedical Research Council of SingaporeResearch University Grant Scheme(RUGS)(04-02-12-2017RU)from the Ministry of Higher Education of Malaysia
文摘Andrographis paniculata contains two main diterpenoid constituents,andrographolide(AGP)and 14-deoxy-11,12-didehydroandrographolide(DDAG),which were found to exhibit antiasthma effects in a mouse asthma model.However,due to inadequacies of both compounds in terms of drug-likeness,DDAG analogues were semisynthesised to tackle these shortcomings.The objective of the study was to investigate the potential of DDAG analogues as new antiasthma agents.Among the analogues,(SRS27)was proven to inhibit cysteinyl leukotrienes(CysLT)and nitric oxide(NO)synthesis in mouse macrophages,like AGP.DDAG,on the other hand,failed to exhibit such activities.SRS27 is less cytotoxic than AGP,suggests that a simple chemical modification of DDAG produces a compound with CysLT and NO inhibitory activites similar to AGP while maintaining toxicity profile similar to DDAG.It is interesting to note that other analogues such as SRS28,SRS49,SRS76 and SRS83 with chemical modifications on the same carbon numbers 3 and 19 of DDAG were unable to show inhibition of CysLT and NO synthesis.Consequently,the potential anti-inflammatory effect of SRS27 was investigated in ovalbumin(OVA)-induced mouse asthma model.The compound was administered in a prophylactic manner and showed a substantial decrease in mouse asthma model parameters.SRS27 at 3mg·kg-1 significantly reduced OVA-induced total cell such as macrophages,eosinophils,lymphocytes and neutrophils,as well as inflammatory cytokines such as IL-4,IL-5,IL-13 and eotaxin in bronchoalveolar lavage BAL fluid.The compound also suppressed serum IgE production.In addition,SRS27 suppressed mucus hyper-secretion and expression of inflammatory mediators such as TNF-α,MCP-1,Muc5 ac,RANTES,IL-33 and iNOS.SRS27 is the first known DDAG derivative tested positive in mouse asthma model and as such SRS27 could serve as a prototype prophylactic agent.
文摘Since the derivation of embryonic stem （ES） cell lines from human blastocysts in 1998 [1], ES cells have emerged as a potential source of cells and tissues that could be used for cell replacement therapy of incurable degenerative diseases. This is due to their remarkable pluripotency, which enables them to differentiate into any adult cell type of the three embryonal germ layers. Indeed, several groups have reported the successful differentiation of ES cells into adult-type cell lineages including, but not limited to： cardiomyocytes, hematopoietic cells, hepatocytes,
文摘Multiple myeloma (MM) is a plasma cell neoplasm characterized for its fast evolution and for being practically incurable, presenting a strong need for the development of therapies to target it. Among those under study are lenalidomide and arsenic trioxide (ATO) which show individual clinical promise, although never tested together. However, the combination of ATO with thalidomide, another immunomodulatory drug and lenalidomide’s structural albeit less potent analog, have been tried clinically with some success. Therefore, we investigated the effect the combination of lenalidomide and ATO have on the MM-derived U266 and RPMI 8226 cell lines. We observed that both compounds have separate, non-interfering, anti-myeloma mechanisms with ATO demonstrating strong cytotoxic effects while lenalidomide’s role remains cytostatic and immunomodulatory. However, ATO decreases cdc25c, which helps sensitize cells to lenalidomide effects enhancing the efficacy of their interaction. Mechanistically the combination of these two agents decreased the expression of MDM2, without affecting p53 activation or its expression. Therefore, this short study provides the foundation to continue mechanistic studies of the combination of lenalidomide and ATO as a foundation for future clinical application.
文摘In the current issue of the Journal of Sport and Health Science,Wang et al.^(1)describe their prospective study,where they analyzed whether or not multiple pregnancies would influence glycemia and the glycemic response to physical exercise in gestational diabetes mellitus(GDM).2 Multiparous women are known to be at a higher risk for GDM than primiparas.GDM carries an increased risk for adverse perinatal outcomes,not only for the mothers but also for the newborn babies.Due to a contemporary environment that is conducive to a sedentary lifestyle and obesity,the incidence of GDM among pregnant women is increasing.
文摘Sjogren’s syndrome is a chronic autoimmune exocrinopathy associated with dry eyes and dry mouth as major clinical manifestations. It is characterized by lymphocytic infiltration of lacrimal and salivary glands and autoantibody production, especially anti-Ro (or SSA) and anti-La (or SSB). Lymphoproliferative disorders are a feature of Sjogren’s syndrome, and can be considered an extraglandular manifestation of the disease. Kikuchi-Fujimoto disease or histiocytic necrotizing lymphadenitis is a rare form of lymphadenitis. It is reported more often in young adult women with localized lymphadenopathy (usually cervical), fever, rashes, and leukopenia. It is a self-limiting disease with resolution within 1 - 4 months in almost all patients. Sjogren’s syndrome has been reported in patients with other systemic diseases including SLE and lymphomas. Here we present a patient with Kikuchi-Fujimoto disease who developed Sjogren’s Syndrome 8 years after her diagnosis of Kikuchi-Fujimoto disease.
