Tumor necrosis factor-alpha(TNF-α) in spotted halibut Verasper variegatus at the embryonic and metamorphic stages

As an aquatic fish,the spotted halibut Verasper variegatus is highly susceptible to bacterial and virus infections.Tumor necrosis factor-alpha(TNF-α)as a cytokine could control the inflammatory responses.The functions of TNF-αin many species have been widely studied,particularly in mammals.However,little is known about the TNF-αfunctions in V.variegatus.We first cloned and sequenced the TNF-αgene in V.variegatus(VvTNF-α).The two conserved cysteine residues,transmembrane sequence,Thr-Leu motif,and TNF family signature,as well as the TA-rich motifs of its proteins related to inflammatory responses had high similarity to those of the other teleost and mammalian TNF-α.The phylogenetic analysis showed that VvTNF-αwas consistent with TNF-αgenes of other vertebrates.The VvTNF-αtranscripts were extensively distributed in the peripheral blood leukocytes(PBLs),spleen,and gill,indicating that the VvTNF-αhad a role in immune function.Furthermore,treatment with pathogen-associated molecular patterns(PAMPs)could induce a rapid and significant increase of VvTNF-αin the PBLs,which reveals that VvTNF-αdoes participate in the host immune responses against bacterial and viral pathogens.We found that VvTNF-αhad an interesting expression pattern during metamorphosis,showing that the flatfish TNF-αmay have some novel functions during specific developmental stages.In addition,the 3 D structure prediction of VvTNF-αprovided an indication of how it is likely to interact with other proteins.Therefore,VvTNF-αhas multiple functions,and provides valuable information to explore novel functions of TNF-α.

Anti Cervix Cancer Activity of Co-immobilized Tumor Necrosis Factor-α and Interferon-γ

Tumor necrosis factor α （TNF-α） and interferon-γ （IFN-γ） are cytokines with strong antitumor activities. They were reacted with a photoactive arylazide-4-azidobenzoic acid, resulting in photoactive TNF-α and IFN-γ. The infrared （IR） spectra of these products showed the characteristic absorption of an azido group at 2127 cm^-1. By photo-immobilization, this modified TNF-α and IFN-γ were immobilized on polystyrene membranes for cell culture to prepare biomaterials. The micro-morphology of photoactive cytokines was observed with a scanning electron microscope （SEM）. The inhibitory effect on growth of Hela cells and inducing apoptosis activity of these two cytokines were analyzed by growth curve, transmission electron microscope （TEM） and fluorescence active cell sorter （FACS）. The results showed that co-immobilization of IFN-γ and TNF-α had significant inhibitory effect on growth of Hela cells, inhibitory rate up to 82%, and IFN-γ had obviously synergistic action.

Secoemestrin C Ameliorates Psoriasis-like Skin Inflammation in Mice by Suppressing the TNF-α/NF-κB Signaling Pathway

Objective Secoemestrin C(SC),an epitetrathiodioxopiperazine isolated from Aspergillus nidulans,has been previously reported to have immunomodulatory and hepatoprotective effects against acute autoimmune hepatitis.However,the effect of SC on regulating the inflammation and its underlying mechanisms in the pathogenesis of psoriasis remain unclear.This study aimed to evaluate the effects of SC on inflammatory dermatosis both in vitro and in vivo.Methods In vitro,HaCaT cells were induced with tumor necrosis factor-alpha(TNF-α,10 ng/mL)to establish an inflammatory injury model,and the expression of nuclear transcription factor-κB(NF-κB)pathway components was measured using qRT-PCR and Western blotting.An in vivo mouse model of imiquimod(IMQ)-induced psoriasis-like skin inflammation was used to evaluate the effectiveness of SC in alleviating psoriasis.Results SC significantly blocked the activation of NF-κB signaling in TNF-α-stimulated HaCaT cells.In addition,systemic and local administration of SC improved psoriatic dermatitis in the IMQ-induced mouse model.SC reduced skin scale and significantly inhibited the secretion of inflammatory factors in skin lesions.Conclusion The protective effect of SC against psoriatic-associated inflammation reveals its potential therapeutic value for treating psoriasis.

Roles of tumor necrosis factor alpha on sperm acrosin activity and acrosome reaction

Aim: To study the roles of tumor necrosis factor alpha (TNF-α) on the sperm acrosin activity and acrosome reaction. Methods: The sperm acrosin activity was tested by the method of BAEE/ ADH Unity and the acrosome reaction by the Triple-stain technique. Results: TNF-α decreased the sperm acrosin activity and acrosome reaction (P<0.01; P<0.01, respectively); it also inhibited the Ca2+-ATPase activity and SOD activity in sperm (P< 0.05; P<0.001, respectively), but increased the NOS activity and the amount of NO in sperm (P<0.001; P<0.001, respectively). While it had a less significant effect on the activity of Na+-K+-ATPase (P>0.05). Conclusion: TNF-α inhibits the sperm acrosin activity and acrosome reaction.

THE CHANGE OF SERUM TUMOR NECROSIS FACTOR-α LEVEL AND ITS CLINICAL SIGNIFICANCE DURING THE TREATMENT OF CHRONIC HEPATITIS B WITH LAMIVUDINE

Objective To evaluate the effect of lamivudine on immunity of chronic hepatitis B by observing the sequential changes of serum TNF-α and HBV-DNA level. Methods 31 CHB patients with elevated serum ALT/AST level and HBVDNA level higher than 106 copies/mL were treated with lamivudine (100mg/day) for one year. The sequential serum samples, which were taken at the 0, 3 rd, 6 th, 12 th month after initiation of therapy, were used to detect serum level of TNF-α and quantity of HBV-DNA respectively. Results ① The serum TNF-α levels were higher than normal value before treatment in all patients; ② At In the 3 rd month of treatment, The the serum HBV-DNA level began to decline and became negative in the 54.9% of all patients. At the end of treatment, HBV-DNA was negative in 48.4% of all patients; ③ The decrease of TNF-α level was later than HBVDNA level drop. TNF-α level began to decline after 6 months treatment. At the end of treatment, TNF-α level was lower than that at in 6 th month, TNF-α level returned to normal in the 38.7% of all patients; ④ The TNF-α level decreased significantly after 6 months treatment in the patients with ALT>80IU/L at the beginning of treatment. But in the patients with ALT≤80IU/L, the TNF-α level decreased just after 12 months treatment; ⑤ TNF-α level fell obviously and early in patients whose HBVDNA became negative at in the 3 rd month. Conclusion Lamivudine can suppress the replication of HBVDNA quickly, and decrease TNF-α level in the serum TNF-α level. It suggests that lamivudine can modulate immune response directly or indirectly. The changes of serum TNF-α level may be used to evaluate the clinical efficacy of lamivudine.

Promising Effects of Zerumbone on the Regulation of Tumor-promoting Cytokines Induced by TNF-α-activated Fibroblasts

Inflammation plays an important role in the development of several cancers.Inflammatory cytokines,including tumor necrosis factor-α(TNF-α),are associated with the induction of inflammation.Chronic inflammation contributes to the progression of cancer through several mechanisms,including increased cytokine production and activation of transcription factors,such as nuclear factor-κB(NF-κB).Zerumbone(ZER),a component of subtropical ginger(Zingiber zerumbet Smith),seems to have anti-inflammatory,anti-cancer,and antioxidant activities.In this study,we aimed to explore the protective function and mechanisms of ZER against TNF-α-induced cancer-promoting cytokines.We found that the viability of stimulated human fibroblast cell lines was reduced after treatment with ZER(IC50=18µmol/L),compared to un-stimulated fibroblasts(IC50=40µmol/L).Besides,ZER inhibited mRNA expression and protein secretion of transforming growth factor-β(TGF-β),interleukin-33(IL-33),monocyte chemoattractant protein-1(MCP-1),and stromal cell-derived factor 1(SDF-1),which were produced by TNF-α-induced fibroblasts,as measured by quantitative real time-PCR(qRT-PCR)and ELISA assays.The mRNA expression levels of TGF-β,IL-33,SDF-1,and MCP-1 showed 8,5,2.5,and 4-fold reductions,respectively.Moreover,secretion of TGF-β,IL-33,SDF-1,and MCP-1 was reduced to 3.65±0.34 ng/mL,6.3±0.26,1703.6±295.2,and 5.02±0.18 pg/mL,respectively,compared to the untreated group.In addition,the conditioned media(CM)of TNF-α-stimulated fibroblasts increased the NF-κB expression in colorectal cancer cell lines(HCT-116 and Sw48),while in the vicinity of ZER,the expression of NF-κB was reversed.Considering the significant effects of ZER,this component can be used as an appropriate alternative herbal treatment for cancer-related chronic inflammation.

酸脂清胶囊对尿酸性肾病大鼠肾功能及TNF-α的影响

目的:观察酸脂清胶囊对尿酸性肾病大鼠肾功能及TNF-α的影响,探讨其作用的机理。方法:将6周龄SD雄性大鼠分为5组,分别为正常组、模型组、生理盐水组、酸脂清治疗组、别嘌醇治疗组。后4组用腺嘌呤、乙胺丁醇造模,成功后分别给予生理盐水、酸脂清、别嘌醇灌胃给药,3周后检测各组大鼠血中尿素氮(BUN)、肌酐(Cr)、尿酸(UA),同时用酶联反应法(Elisa法)测量各组肾脏组织中肿瘤坏死因子α(TNF-α)的含量。结果:1)造模2周后,与正常组比较,模型组大鼠血中BUN、Cr、UA均明显升高(P<0.05),证实造模成功。2)治疗3周后,与生理盐水组相比,酸脂清治疗组、别嘌醇治疗组大鼠血中BUN、UA均明显下降(P<0.05),酸脂清治疗组和别嘌醇治疗组Cr均有下降,但只有酸脂清治疗组有统计学意义(P<0.05)。3)酸脂清治疗组和别嘌醇治疗组血中BUN、Cr、UA相比,差异无统计学意义(P>0.05)。4)Elisa法测定各组TNF-α的浓度,与正常组相比,生理盐水组TNF-α明显升高(P<0.05);与生理盐水组相比,酸脂清治疗组、别嘌醇治疗组TNF-α含量明显减少(P<0.05);5)肾组织病理切片显示:与模型组相比,酸脂清治疗组、别嘌醇治疗组尿酸盐结晶沉积、炎性细胞浸润均明显减少,肾小管扩张改善。结论:酸脂清胶囊能够降低尿酸性肾病大鼠血中BUN、Cr、UA的含量,减少尿酸盐结晶在肾小管中沉积及炎性细胞浸润,降低TNF-α在肾组织中的含量,从而达到治疗的作用。

TIME-AND DOSE-DEPENDENT UP-REGULATION OF TNF-α mRNA AFTER IRRADIATION OF HUMAN NSCLC CELL LINES IN VITRO

Objective： Even though radiotherapy plays a major role in the local treatment of non-small cell lung cancer （NSCLC）, little is known about the molecular effects of irradiation in this tumor. In the present study, we examined two NSCLC cell lines for their endogenous production of TNF-α after irradiation. To investigate the radiation-induced TNF-α production in NSCLC cell lines. Methods： Two human NSCLC cell lines （A549： squamous; NCI-H596： adenosquamous） were investigated for their TNF-α mRNA （real-time RT-PCR） after exposure to different irradiation doses （2, 5, 10, 20, 30, 40 Gy） and time intervals （1, 3, 6, 12, 24, 48 or 72 h）. The TNF-α mRNA expression was quantified by real-time RT-PCR. The clonogenic survival was evaluated after irradiation with 2, 4, 6 and 8 Gy. Results： Non-irradiated NSCLC cells exhibited no or very low TNF-α expression. For the NCI-H596 cell line, TNF-α expression was significantly elevated 1～12 h （maximum 6h： 568fold increase relative to unirradiated cells） in a time-dependent manner. The radiation-induced increase could be observed after irradiation with 2 Gy reaching maximal at 40 Gy, with 83 times higher than normal controls. The clonogenic survival of these cell lines was nearly identical. Conclusion： NCI-H596 cells produce significant quantities of TNF-α following irradiation in a time- and dose-dependent manner. The pro-inflammatory cytokine TNF-α is a key mediator for the pathogenesis of radiation pneumonitis. Radiation-induced endogenous TNF-α expression in NSCLC cells may affect the normal lung adjacent to the tumor and may be associated with an adverse clinical outcome of the patient.

The effect of spinal cord injury on the expression of TGF-β and TNF-α in rat articular cartilage

Objective： To observe the expression of TGF-β and TNF-α in the spinal cord injured rat model and discuss the significance of the articular cartilage metabolism. Methods： 36 SD female rats were randomly divided into 2 groups： Rats models of spinal cord injury were implemented by Allen method. T10 laminectomy was performed in the control group. Both groups of rats were killed respectively in 1w, 3w and 6w. Hematoxylin-eosin stain was given to each slice in the model group and control group. Immunohistochemical stain was applied by using ABC method in the expression of TGF-β and TNF-α. Those expressed level were performed in image analysis and statistics process. Results： TGF-β and TNF-α were mainly distributed on the surface layer of the articular cartilage, with a weak expression in control group. The expression of TNF-α in the model group was more significant than that in the control group in the lw, and still remained an evident difference with that in control group until the 6w（P 〈 0.05）. TGF-β expression of the model group had no remarkable difference with the control group in the lw （P 〉 0.05） and prominently became stronger at 6w（P 〈 0.05）. Conclusion： The expression of TNF-α occurred early in the development of spinal cord injury, and the expression of TGF-β became stronger with the revival of spinal neural function. Both expressions were strengthened in articular cartilage in the 3rd week.

慢性阻塞性肺疾病急性加重期血清瘦素与肺功能关系的临床研究

目的：探讨血清瘦素（ leptin ）与慢性阻塞性肺疾病（ chronic obstructive pulmonary disease， COPD）急性加重期患者肺功能的关系。方法选择COPD急性加重期患者35例、COPD稳定期患者38例及健康志愿者30例，抽取空腹血。用放免法测定血清瘦素、用酶联免疫吸附法（ELISA）测定肿瘤坏死因子-α（TNF-α）及用全自动生化仪检测C-反应蛋白（CRP）；检测肺功能，记录1 s用力呼气量（ FEVl ）、最大通气量（ MVV）、肺一氧化碳弥散量（ DLCO ）等指标、分析COPD急性加重期患者血清瘦素水平与TNF-α、CRP、肺功能等的相关性。结果①COPD急性加重期患者血清瘦素、TNF-α、CRP均明显高于COPD稳定期组和对照组，而FEVl、MVV、DLCO则明显低于后者；②COPD急性加重期患者血清瘦素与TNF-α、CRP呈正相关，与FEVl、MVV、DLCO呈负相关。结论血清瘦素可判断COPD急性加重期预后，可以评估肺功能损害风险。

中西医结合治疗脓毒症的临床疗效观察

目的：探讨益气活血解毒中药汤剂治疗脓毒症的临床疗效。方法将62例脓毒症患者采用信封随机法分为对照组（31例）、治疗组（31例）。对照组给予脓毒症西医常规治疗，治疗组在脓毒症西医常规治疗基础上加用益气活血解毒法中药汤剂中西医结合治疗。分析比较两组炎性因子、病情危重程度评分、住ICU时间及28 d病死率。结果治疗组治疗后IL-6、TNF -α水平较对照组明显下降（P＜0．05），住ICU时间较对照组明显缩短（P＜0．05），APACHEⅡ评分明显低于对照组（P＜0．05），28 d病死率低于对照组（26．7％vs 37．9％，P＝0．048）。结论益气活血解毒法可明显降低炎性因子IL-6及TNF-α水平，缩短住ICU时间，提高28 d生存率。

复方柴芩退热颗粒对发热大鼠模型退热作用的研究

目的:研究复方柴芩退热颗粒对2,4二硝基苯酚及细菌内毒素所致大鼠发热模型的退热作用,进一步明确该颗粒的退热效果,初步探讨其退热机制。方法:将SPF级SD大鼠随机分为正常对照组、模型组、酚麻美敏片组[给药剂量0.148 g/(kg·d)]、小柴胡冲剂组[给药剂量2.160 g/(kg·d)]、复方柴芩退热颗粒高、中、低剂量组[给药剂量分别为6.480、3.240、1.620 g/(kg·d)]。各给药组按相应剂量灌胃给药,正常对照组、模型组同法给予等体积的蒸馏水,每天1次,连续给药5天,第4天各组动物均开始禁食不禁水24 h,末次给药前开始造模。造模实验一:除正常对照组外,余各组大鼠均皮下注射2,4-二硝基苯酚17 mg/kg,正常对照组皮下注射同体积生理盐水;造模实验二:除正常对照组外,余各组大鼠均腹腔注射细菌内毒素80μg/kg。测大鼠各时间点的体温和血清中白细胞介素-1β(IL-1β)、前列腺素E2(PGE2)、肿瘤坏死因子-α(TNF-α)的含量。结果:实验一:与正常对照组比较,模型组大鼠造模后1 h、2 h、3 h体温上升值均显著升高,大鼠血清IL-1β、PGE2含量均显著升高(P<0.01)。与模型组比较,酚麻美敏片组、小柴胡冲剂组、复方柴芩退热颗粒高、中、低剂量组大鼠血清IL-1β、PGE2含量均明显降低(P<0.05,P<0.01);酚麻美敏片组大鼠在造模后1 h、2 h、3 h体温上升值均显著降低(P<0.05,P<0.01);小柴胡冲剂组大鼠在造模后2 h、3 h体温上升值均显著降低(P<0.05,P<0.01);复方柴芩退热颗粒高、低剂量组在造模后1 h、2 h、3 h体温上升值均明显降低(P<0.05,P<0.01);复方柴芩退热颗粒中剂量组在造模后2 h、3 h体温上升值均明显降低(P<0.05)。实验二:与正常对照组比较,模型组大鼠造模后2 h、4 h、6 h、8 h体温上升值均显著升高,大鼠血清PGE2、TNF-α含量均显著升高(P<0.01)。与模型组比较,酚麻美敏片组、小柴胡冲剂组、复方柴芩退热颗粒高、中、低剂量组大鼠血清PGE2、TNF-α含量均明显降低(P<0.05,P<0.01);酚麻美敏片组大鼠在造模后2 h、4 h、6 h体温上升值均显著降低(P<0.05,P<0.01);小柴胡冲剂组、复方柴芩退热颗粒高、中、低剂量组在造模后2 h、4 h体温上升值均明显降低(P<0.05,P<0.01)。结论:复方柴芩退热颗粒对2,4二硝基苯酚及细菌内毒素所致大鼠发热均有降温作用,能有效降低大鼠血清PGE2、IL-1β和血清TNF-α含量,对大鼠实验性高热模型有较好的解热作用。

Lipopolysaccharide “Two-hit” Induced Refractory Hypoxemia Acute Respiratory Distress Model in Rats

To establish a stable and reliable model of refractory hypoxemia acute respiratory distress syndrome （ARDS） and examine its pathological mechanisms, a total of 144 healthy male Wistar rats were randomized into 4 groups： group Ⅰ （saline control group）, group Ⅱ （LPS intravenous ＂single-hit＂ group）, group Ⅲ （LPS intratracheal ＂single-hit＂ group） and Group IV （LPS ＂two-hit＂ group）. Rats were intravenously injected or intratracheally instilled with a large dose of LPS （10 mg/kg in 0.5 mL） to simulate a single attack of ARDS, or intraperitoneally injected with a small dose of LPS （1 mg/kg） followed by tracheal instillation with median dose of LPS （5 mg/kg） to establish a ＂two-hit＂ model. Rats in each group were monitored by arterial blood gas analysis and visual inspection for three consecutive days. Arterial blood gas values, lung wet/dry weight ratio and pathological pulmonary changes were analyzed to determine the effects of each ALI/ARDS model. Concentrations of TNF-α, IL-1 and IL-10 in the bronchoalveolar lavage fluid （BALF） and blood plasma were meastired by using enzyme-linked immunosorbent assays （ELISA）. Our resulsts showed that single LPS-stimulation, whether through intravenous injection or tracheal instillation, could only induce ALl and temporary hypoxemia in rats. A two-hit LPS stimulation induces prolonged hypoxemia and specific pulmonary injury in rats, and is therefore a more ideal approximation of ARDS in the animal model. The pathogenesis of LPS two-hit-induced ARDS is associated with an uncontrolled systemic inflammatory response and inflammatory injury. It is concluded that the rat ARDS model produced by our LPS two-hit method is more stable and reliable than previous models, and closer to the diagnostic criteria of ARDS, and better mimics the pathological process of ARDS.

Dual therapy of rosiglitazone/pioglitazone with glimepiride on diabetic nephropathy in experimentally induced type 2 diabetes rats

Diabetic nephropathy is a major cause of end-stage renal disease （ESRD） in the general population. It is estimated that diabetic nephropathy will eventually develop in about 40% of all patients with diabetes; therefore, prevention is critical for delaying the development and progression of diabetic kidney disease. Despite extensive efforts, medical advances are still not successful enough to prevent the progression of the disease. In the present study, we focused on the comparison of combination therapies and whether they offered additional renoprotection. Type 2 diabetes mellitus was induced by intraperitoneally administering streptozotocin （90 mg/kg） in neonatal rats and then these rats were treated with rosiglitazone （1.0 mg/kg） in combination with glimepiride （0.5 mg/kg） or with pioglitazone （2.5 mg/kg） in combination with glimepiride （0.5 mg/kg）. Diabetic nephropathy markers were evaluated by biochemical and ELISA kits and renal structural changes were examined by light microscopy and transmission electron microscopy. Results show that the combination of pioglitazone with glimepiride is more effective in amelioration of diabetic nephropathy than rosiglitazone with glimepiride drug therapy due to glycemic control, suppressing albumin excretion rate, total protein excretion rate and augmented TNF-α signaling during the development of streptozotocin induced type 2 diabetic nephropathy.

Relationship between peritoneal macrophages and inflammatory reaction in a rat model of severe acute pancreatitis

Objective To investigate the relationship between peritoneal macrophages(PMAs)and inflammatory reaction in a rat model of severe acute pancreatitis(SAP).Methods Sprague-Dawley rats were randomly divided into control group and SAP group.To induce SAP in rats,40 g/L sodium taurocholate(0.1 mL/100 g)was injected into the pancreatic duct through retrograde exposure of pancreatic bile duct in hepatic porta.One-third of rats were sacrificed at 3,6 or 12 h after modeling.PMAs were extracted,and incubated for 24 h in a humidified 5% carbon dioxide incubator.The expressions of tumor necrosis factor alpha(TNF-α)and interleukin-1β(IL-1β)mRNA in PMAs were measured by semi-quantitative RT-PCR.The levels of TNF-α and IL-1β in culture medium and serum were evaluated.The histological changes of pancreas were examined.Results The expressions of TNF-α mRNA and IL-1β mRNA in PMAs were significantly higher in SAP group than in control group at each time point(P<0.01).The concentrations of TNF-α and IL-1β in culture medium and serum were significantly elevated in SAP group compared with control group(P<0.01).The histological analysis of pancreas indicated that the damage was more severe in SAP group than in control group(P<0.01).Conclusion PMAs secrete cytokines into pancreatitis-associated ascitic fluid,and this study demonstrates a correlation between SAP and the activation of PMAs.

Effects of External Use of Pereskia aculeate Miller on Foot Swelling of Adjuvant Arthritis in Rats

[Objectives] To study the anti-inflammatory effects and its possible action mechanism of Pereskia aculeate Miller on rats with adjuvant arthritis( AJ). [Methods] Fifty SD rats( half male and half female) were randomly divided into 5 groups: blank group,model group,positive control group( Glucosidorum Tripterygll Totorum( GTT),12 mg/kg),and P. aculeate high and low dose group( 0. 86 and0. 43 g/m L). Except the blank group,other groups were induced with complete Freund's adjuvant( CFA) to establish the AA rat model. On the 17 th day of modeling,the drug was externally applied for soaking,and the diameter of foot hole and foot joint before and after administration was measured to observe the degree of swelling. The enzyme-linked immunosorbent assay( ELISA) was adopted to determine the inflammatory cytokines interleukin-1β( IL-1β) and tumor necrosis factor-α( TNF-α). [Results] Compared with the model group,the degree of swelling of the foot sole and foot joints was reduced in the P. aculeate high dose group and the positive control group( P < 0. 05). According to ELISA test,compared with the model control group,the serum levels of IL-1β( P < 0. 05) and TNF-α( P < 0. 05) were significantly reduced in the P. aculeate high dose group and the positive control group. Compared with the positive control group,there was no significant difference( P > 0. 05). [Conclusions] P. aculeate has significant inhibitory effects on foot swelling of adjuvant arthritis in rats,and the action mechanism is possibly related to the decrease of IL-1β and TNF-α.

The efficacy and safety of thalidomide for treating metastatic breast cancer:a systematic review

Objective This systematic review was conducted to investigate the efficacy and safety of thalidomide in metastatic breast cancer(MBC).Methods Based on pre-defined inclusion and exclusion criteria,data were independently collected from different databases by three investigators.Overall,three studies were included.Results The included studies indicated that no patient achieved a partial or complete response from different thalidomide dose levels.Thalidomide was well-tolerated at doses of 100 mg,200 mg,and 400 mg.In all three studies,common side effects included constipation,somnolence,fatigue,peripheral neuropathy,and dry mouth.Circulating angiogenic factors were not significantly correlated with disease progression.Conclusion The available evidence indicates that single-agent thalidomide has little or no activity in patients with MBC.

Tannic acid assisted anti-TNF-αnanobody assembly modulating the epithelial barrier dysregulation of allergic rhinitis

The derailed nasal epithelial barrier is associated with the disorder of tight junctions(TJ)function or expression,leading to more penetration of allergens to the barrier,accompanied by the release of cytokines,which develop allergic rhinitis(AR).Considering the increasing AR disease incidence worldwide,there is still an urgent unmet medical need to develop new therapeutics.Tumor necrosis factor-alpha(TNF-α)inhibitors have been applied in treating autoimmune diseases.However,their roles in AR remain unclear.In this study,anti-TNF-αnanobody(V)was assembled with tannic acid(V/TA)as a functional antibody drug candidate which could inhibit the release of the cytokines in ovalbumin(OVA)-induced AR murine model.Upon receiving V/TA treatment,the infiltration level of inflammatory cells,and the number of mucus-secreting cells and mast cells in the nasal mucosa recovered to a relatively normal level.Preliminary mechanism of action research revealed that the efficacy of V/TA was accompanied by the restricted level of TJ molecules:zonula occluden-1(ZO-1),occludin,claudin-1,and claudin-5.The therapeutic effect of the anti-TNF-αnanobody against AR was enhanced with the tannic acid assisted without any toxicity observed.This study supplied a promising delivery strategy of TNF-αinhibitor for the effective treatment of complicated allergic rhinitis disease,with an advantage in restoring effect on the AR-caused epithelial barrier defects than the commercial drug Infliximab.

Surface charge tunable nanoparticles for TNF-α siRNA oral delivery for treating ulcerative colitis

Nanopartide （NP） drug delivery systems have been successfully designed and implemented to orally deliver small interfering RNAs （siRNAs） for inflammatory disorders. However, the influence of surface charge on orally administered siRNA nanocarriers has not been investigated. In this study, we prepared structurally related poly（ethylene glycol）-block-poly（lactic-co-glycolic acid） （PEG5K-b-PLGA10K） NPs with the assistance of a synthesized lipid featuring surface amine groups for subsequent charge tuning. NPs were prepared by a double emulsion method, and their surface charge could be tuned and controlled by a succinylation reaction to yield NPs with different surface charges, while maintaining their size and composition. The prepared NPs were termed as aminated NPs （ANPs）, plain NPs （PNPs）, or carboxylated NPs （CNPs） based on their surface charge. All NPs exhibited the desired structural stability and siRNA integrity after enzymatic degradation. In vivo studies showed that ANPs significantly accumulated in inflamed colons, and they were successful in decreasing TNF-α secretion and mRNA expression levels while maintaining colonic histology in a murine model of acute ulcerative colitis （UC）. This study described a methodology to modify the surface charge of siRNA-encapsulating polymeric NPs and highlighted the influence of surface charge on oral delivery of siRNA for localized inflammatory disorders.

MODULATION OF MACROPHAGE-MEDIATED CYTOTOXIC ACTIVITY——EFFECT OF FUSARIN C ON Mφ-CF PRODUCTION AND TNF-α mRNA EXPRESSION

Fusarium moniliforme is a predominant fungus found in fungus-contaminated food in Linxian County, China, a high risk area of esophageal. cancer. Rats fed with corn bread inoculated with Fusarium moniliforme developed papillomas and squamous-cell carcinomas