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ObjectiveTo systematically evaluate the safety of interferon β-1a for treatment of corona virus disease 2019 （COVID-19）， and to provide references for interferon β-1a's clinical application. MethodsThis study was conducted with the database from US Food and Drug Administration adverse event reporting system （FAERS） from January 1， 2015 to March 31， 2021. Information component （IC） and reporting odds ratio （ROR） methods were applied for signal mining. ResultsA total of 463 700 records of COVID-19 were selected for analysis， and 45 positive drug adverse event signals were detected. Headache （IC025=1.09， ROR025=2.28）， pyrexia （IC025=0.51， ROR025=1.51） and multiple sclerosis relapse （IC025=3.67， ROR025=14.71） were positive adverse events with higher frequency. Autoimmune disorder （IC025=4.42， ROR025=24.03）， streptococcal infection （IC025=4.12， ROR025=19.82）， and multiple sclerosis relapse （IC025=3.67， ROR025=14.71） were positive adverse events. Acute lung injury， cardio-respiratory arrest and metabolic acidosis were associated with a higher proportion and frequency of death. ConclusionThere are certain safety issues with interferon β-1a in the treatment of COVID-19， and some adverse events with high frequency and high death rate deserve further attention by medical staffs.
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Toll-like receptor 3 (TLR3) is a member of the TLR family, mediating the transcriptional induction of type I interferons (IFNs), proinflammatory cytokines, and chemokines, thereby collectively establishing an antiviral host response. Studies have shown that unlike other TLR family members, TLR3 is the only RNA sensor that is utterly dependent on the Toll-interleukin-1 receptor (TIR)-domain-containing adaptor-inducing IFN-β (TRIF). However, the details of how the TLR3-TRIF signaling pathway works in an antiviral response and how it is regulated are unclear. In this review, we focus on recent advances in understanding the antiviral mechanism of the TRIF pathway and describe the essential characteristics of TLR3 and its antiviral effects. Advancing our understanding of TLR3 may contribute to disease diagnosis and could foster the development of novel treatments for viral diseases.
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PURPOSE: In the present study, human neural stem cells (hNSCs) with tumor-tropic behavior were used as drug delivery vehicle to selectively target melanoma. A hNSC line (HB1.F3) was transduced into two types: one expressed only the cytosine deaminase (CD) gene (HB1.F3. CD) and the other expressed both CD and human interferon-β (IFN-β) genes (HB1.F3.CD. IFN-β). MATERIALS AND METHODS: This study verified the tumor-tropic migratory competence of engineered hNSCs on melanoma (A375SM) using a modified Boyden chamber assay in vitro and CM-DiI staining in vivo. The antitumor effect of HB1.F3.CD and HB1.F3.CD.IFN-β on melanoma was also confirmed using an MTT assay in vitro and xenograft mouse models. RESULTS: A secreted form of IFN-β from the HB1.F3.CD.IFN-β cells modified the epithelial-mesenchymal transition (EMT) process and metastasis of melanoma. 5-Fluorouracil treatment also accelerated the expression of the pro-apoptotic protein BAX and decelerated the expression of the anti-apoptotic protein Bcl-xL on melanoma cell line. CONCLUSION: Our results illustrate that engineered hNSCs prevented malignant melanoma cells from proliferating in the presence of the prodrug, and the form that secreted IFN-β intervened in the EMT process and melanoma metastasis. Hence, neural stem cell-directed enzyme/prodrug therapy is a plausible treatment for malignant melanoma.
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Animals , Humans , Mice , Cell Line , Cytosine Deaminase , Epithelial-Mesenchymal Transition , Flucytosine , Fluorouracil , Heterografts , In Vitro Techniques , Melanoma , Mental Competency , Neoplasm Metastasis , Neural Stem Cells , Stem CellsABSTRACT
Objective:To investigate the effect of miR-322-5p which targets Akt3 on Th17 differentiation in experimental autoimmune encephalomyelitis (EAE) interfered by interferon-β (IFN-β). Methods:The effect of IFN-β on EAE mice which were randomly divided into IFN-β group and PBS group was examine. The percents of Th17 in the two groups were compared by fluorescence activated cell sorting. The miRNA array was made to find different miRNAs between those two groups. MiR-322-5p was screened for further research. The target gene of miR-322-5p was predicted using softwares and the common predicted target gene Akt3 was got. The expression of Akt3 was detected after IFN-β intervention and miR-322-5p overexpression. The target relationship between Akt3 and miR-322-5p was verified by luciferase reporter assay. At last, the effect of Akt3 on Th17 differentiation was explored in vitro. Results:Compared to PBS group, the percent of Th17 was significantly downregulated, the expression of miR-322-5p was significantly upregulated and Akt3 was significantly downregulated in IFN-β group. The expression of Akt3 was obviously decreased after overexpressing miR-322-5p. Luciferase reporter assay showed that Akt3 was directly targeted by miR-322-5p. The percent of Th17 differentiation was greatly promoted by Akt3 in vitro. Conclusion:IFN-β significantly ameliorates the severity of EAE by affecting miR-322-5p which can inhibit Th17 differentiation by targeting Akt3.
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Objective To investigate the effect of different antibodies on Toll-like Receptor 4-High Mobility Group Box 1 and its downstream signal transductions in distant organ injuries caused by intestinal ischemia/reperfusion in mice.Methods A total of 40 mice (C57BL/6,SPF level) were by random number table method assigned into five groups:sham,control,anti-HMGB1,anti-Myeloid differentitation gene,and antiTIR domain containing adaptor inducing IFN-β (n=8).In the control,anti-HMGB1,anti-MyD88,and antiTRIF groups,the IgG,HMGB1,MyD88,and TRIF antibodies were injected,respectively,via the tail vein 30 minutes before ischemia (1 mg/kg body weight,0.025％).After anesthesia and abdomen incision,all mice,except the sham group,underwent intestinal ischemia by clamping the superior mesenteric artery for 60 minutes followed by 60 minutes of reperfusion.Sham group underwent the same surgical procedures except for clamping the artery.Serum nuclear factor-κB p65,Interleukin-6 and Tumor Necrosis Factor-α were measured.Morphological changes in the lung and intestine were evaluated.mRNA and protein expressions of HMGB1 and NF-κB in lung and intestinal tissues were assayed.Results Compared with the control group [(228.53± 24.85),(104.91±31.18),and (70.81±46.97) ng/L],HMGB1 [(145.00±33.63),(62.28±6.73),and (52.76± 5.71) ng/L],MyD88 [(191.12± 13.22),(85.90± 17.37),and (63.19 ± 5.47) ng/L],and TRIF [(183.73±10.81),(78.14±7.38),and (59.70±4.63) ng/L] significantly decreased the serum level of NF-κB (P=0.000,0.005,0.001),IL-6 (P=0.000,0.004,0.000) and TNF-α (P=0.000,0.024,0.002) after ischemia reperfusion.Tissue injuries in the lung and intestine were also alleviated by HMGB1,MyD88,and TRIF.The anti-HMGB1,anti-MyD88,and anti-TRIF groups displayed significant elevations of HMGB1 mRNA [lung (1.89±0.18),(2.35±0.31),and (2.29±0.28),ileum (4.93±0.55),(5.96± 0.73),and (5.76±0.51)],NF-κB mRNA [lung (1.42±0.23),(1.77±0.18) and (1.70±0.13),ileum (2.23±0.55),(3.11±0.38) and (2.99±0.24)] and NF-κB protein expressions in lung and ileum tissues compared to the sham group [lung HMGB1 mRNA (1.04±0.19) (P=0.000,0.000,0.000),NF-κBmRNA (1.03±0.21) (P=0.004,0.000,0.000),ileum HMGB1 mRNA (1.14±0.54) (P=0.000,0.000,0.000),NF-κB mRNA (1.03±0.23) (P=0.000,0.000,0.000)].However,incornparison with the control group [lung HMGB1 mRNA (2.67±0.23) (P=0.000,0.035,0.016),NF-κB mRNA (2.04±0.29) (P=0.000,0.039,0.012),ileum HMGB1 mRNA (6.70±0.66) (P=0.001,0.038,0.015),NF-κBmRNA (3.71±0.53) (P=0.000,0.018,0.006)],the other three groups showed a significant down-regulation,with the most remarkable decrement in the anti-HMGB1 group.Application of anti-HMGB1,anti-MyD88,and anti-TRIF could drastically attenuate the tissue injuries in ischemia reperfusion.anti-HMGB1 exhibited the most significant effect.Conclusions HMGB1 and its downstream signals play an important role in intestinal ischemia reperfusion injuries in mice.Of two downstream signals,the TRIF-dependent pathway exerts a more important effect than that of the MyD88-dependent pathway.
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Objective To research the effect of the baicalin to the expression of interferon(IFN)-α and IFN-β in the BALB/c mouse infected by respiratory syncytial virus(RSV),and discussed the antiviral of mechanism.Methods To establish the BALB/c mouse model of RSV,the effects of IFN-α and IFN-β in the BALB/c mouse infected by RSV were detected by ELISA.Results The IFN-α and IFN-β in the BALB/c mouse infected by RSV could be evaluated significantly by Baicalin.Conclusion The Baicalin regulates the level of IFN in the BALB/c mouse infected by RSV.
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AIM: To clarify the modulation of autophagy in ischemic penumbra by hydroxysafflor yellow A ( HSYA) after cerebral ischemia/reperfusion ( I/R) injury.METHODS:Male SD rats subjected to transient middle cere-bral artery occlusion for 90 min were randomly divided into 4 groups:sham-operation (sham) group, cerebral I/R (I/R) group, I/R+HSYA group and sham+HSYA group.Modified neurological severity score (mNSS) was used to evaluate the neurological deficits of the rats at 6 h, 1 d, 3 d and 7 d after reperfusion , accompanied by the detection of autophagy , apoptosis and mRNA expression of IFN-βin ischemic penumbra .RESULTS:Compared with sham group , upregulation of LC3-Ⅱand degradation of SQSTM1/P62 were observed in I/R group, indicating the activation of autophagy after I/R.The activation of autophagy in I/R+HSYA group was significantly enhanced by HSYA on day 1 and day 3, and inhibited on day 7, as compared with I/R group (P<0.05).Besides, the mRNA expression of IFN-βin I/R group was significantly upregulated at 6 h, then downregulated on day 1 and day 3, and returned to basal level on day 7, as compared with sham group (P<0.05).In I/R+HSYA group, the mRNA expression of IFN-βwas significantly upregulated on day 1 and day 3, accompanied by the inhibition of apoptosis on day 3 and the significantly decreased mNSS from day 4, as compared with I/R group (P<0.05).CONCLUSION:HSYA alleviates cerebral I/R injury by dynamically modulating the activation of autophagy and the expression of IFN-βin ischemic penumbra .
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Objective To research the toxicity of ethanol extracts from Poylgonum multiflorum Thunb(PMT)induced by en?dotoxin of Gram-negative bacteria lipopolysaccharide(LPS)in rat liver,and then investigate the hepatotoxicity mechanisms of PMT on immune inflammatory signal pathway Toll-Like receptor 4(TLR4)-interferon regulated factor3(IRF-3). Methods SD rats were randomly assigned into normal control,LPS(4 mg/kg),acetaminophen APAP(625 mg/kg),PMT 6 g/kg(PMT-L),PMT 12 g/kg (PMT-H),LPS+APAP and LPS+PMT-L/-H groups. The 4 groups later were injected LPS 4 mg/kg by caudal vein,after 2 h,the corre?sponding drugs were administered once a day for 7 consecutive days,respectively. The changes of weight of rats were observed every day. The tissue morphology of liver tissue of rats on 2 h,14 h,5 d,8 d after administration were detected by hematoxylin-eosin stain? ing respectively. Real time quantitative PCR(RT-qPCR)method and Western blotting were used to detect the expression of TLR4, TRIF and IRF3 in the TLR4 signaling pathway in liver cells. Results Two hours after the rat tail vein injection of LPS,the liver tiny granulomas of rats could be observed in LPS-induced groups,and then,the liver injury of rats in LPS group was gradually recovered. Eight Days after LPS induction,the liver tissue structure of rats in LPS group was clear and complete,but in LPS+APAP group and LPS+PMT 6 or 12 g/kg groups,the focal necrosis of hepatocytes,with inflammatory cell infiltration could be observed. The results of RT-qPCR and Western blotting showed that in oral administration of PMT groups,the expression of TLR4,TRIF and IRF-3 mRNA and protein in the liver cells had no significant change compared with the normal control group. But in 4 groups induced with LPS,the expression of TLR4, TRIF and IRF-3 mRNA and protein in the liver cells were significantly higher than that of the normal control group and LPS group(P<0.05). Conclusion PMT can cause liver damage induced by LPS,the hepatotoxicity is related to the positive regulation of TLR4/IRF-3 signaling pathways,which is not related to the dosage of PMT. The results show that activating TLR4/IRF3 signaling pathway is one of the mechanisms of liver injury of PMT in rats induced by LPS.
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Objective To research the toxicity of ethanol extracts from Poylgonum multiflorum Thunb (PMT) induced by endotoxin of Gram-negative bacteria lipopolysaccharide (LPS) in rat liver, and then investigate the hepatotoxicity mechanisms of PMT on immune inflammatory signal pathway Toll-Like receptor 4 (TLR4) -interferon regulated factor3 (IRF-3). Methods SD rats were randomly assigned into normal control, LPS (4 mg/kg), acetaminophen APAP (625 mg/kg), PMT 6 g/kg (PMT- L), PMT 12 g/kg (PMT-H), LPS+APAP and LPS+PMT-L/-H groups. The 4 groups later were injected LPS 4 mg/kg by caudal vein, after 2 h, the corresponding drugs were administered once a day for 7 consecutive days, respectively. The changes of weight of rats were observed every day. The tissue morphology of liver tissue of rats on 2 h, 14 h, 5 d, 8 d after administration were detected by hematoxylin-eosin staining respectively. Real time quantitative PCR (RT-qPCR) method and Western blotting were used to detect the expression of TLR4, TRIF and IRF3 in the TLR4 signaling pathway in liver cells. Results Two hours after the rat tail vein injection of LPS, the liver tiny granulomas of rats could be observed in LPS-induced groups, and then, the liver injury of rats in LPS group was gradually recovered. Eight Days after LPS induction, the liver tissue structure of rats in LPS group was clear and complete, but in LPS + APAP group and LPS + PMT 6 or 12 g/kg groups, the focal necrosis of hepatocytes, with inflammatory cell infiltration could be observed. The results of RT-qPCR and Western blotting showed that in oral administration of PMT groups, the expression of TLR4, TRIF and IRF-3 mRNA and protein in the liver cells had no significant change compared with the normal control group. But in 4 groups induced with LPS, the expression of TLR4, TRIF and IRF- 3 mRNA and protein in the liver cells were significantly higher than that of the normal control group and LPS group (P<0.05). Conclusion PMT can cause liver damage induced by LPS, the hepatotoxicity is related to the positive regulation of TLR4/IRF-3 signaling pathways, which is not related to the dosage of PMT. The results show that activating TLR4/IRF3 signaling pathway is one of the mechanisms of liver injury of PMT in rats induced by LPS.
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AIM:To investigate the effect of signal transducer and activator of transcription 1 ( STAT 1 ) on proliferation and interferon-β(IFN-β) sensitivity of human non-small-cell lung cancer H1299 cells.METHODS:STAT1 or EGFP gene was transfected into H1299 cells by the lentiviral vectors system.The cell number was counted under a mi-croscope and cell proliferation was tested by MTT assay.In addition, the cells transfected with STAT1 and EGFP were trea-ted with IFN-βand cell viability was measured by MTT assay.The protein levels of p-STAT1, ICAM-1 and PCNA were de-tected by Western blot.RESULTS: Over-expression of STAT1 inhibited H1299 cell proliferation (P<0.05).H1299 cells transfected with STAT1 gene had a higher sensitivity to IFN-βthan the control cells transfected with EGFP ( P <0.05).Overexpression of STAT1 increased the protein level of p-STAT1, and reduced IACM-1 expression in H1299 cells. Moreover, STAT1 enhanced STAT1 phosphorylation and downregulated the expression of PCNA in H1299 cells treated with IFN-β.CONCLUSION:STAT1 inhibits the proliferation and enhances the IFN-βsensitivity of non-small-cell lung cancer H1299 cells.
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Objective: To study the anti-influenza virus A/PR/8/34 (H1N1) activity of the volatile oil in Cinnamomi Ramulus (VOCR) and cinnamaldehyde in vitro, and to reveal the effect of TLR7 signaling pathway in anti-influenza. Methods: The IC50 and therapeutic index (TI) of VOCR and cinnamaldehyde in vitro were determined using influenza virus-infected Madin-Darby canine kidney (MDCK) cell line. ELISA was conducted to determine the level of interferon-β (IFN-β) in MDCK cells. The real-time RT-PCR was used to determine the mRNA expresstion of TLR3, TLR7, TRAF-3, interleukin-1 related acceptor kinase-4 (IRAK-4), and IFN-β. Results: Both VOCR and cinnamaldehyde had the direct virucidal activities on influenza virus; The IC50 values were 1.85 × 10-7 and 5.77 × 10-7 g/mL, respectively. The TI values were 27.04 and 9.51, respectively. Compared with the virus group, VOCR and cinnamaldehyde (0.25 × 10-5 g/mL) had the significant effects on increasing the serum level of IFN-β in infected MDCK cells (P < 0.05) and the mRNA expression of TLR7, IRAK-4, and IFN-β (P < 0.05). Conclusion: VOCR and cinnamaldehyde have good anti-influenza virus activities in the cellular level. The mechanisms are related to the activiation of TLR7 signaling pathway and IRAK-4, and leading to the high expression of IFN-β.
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Objective To investigate the effects of eritoran on the expressions of the inflammatory cytokines interleukin-1β (IL-1β),tumor necrosis factor-α (TNF-α) and interferon-[ (IFN-β) mRNA in the basilar artery after subarachnoid hemorrhage (SAH) in rabbits.Methods Atotal of 36 healthy adult male New Zealand white rabbits were randomly allocated into three groups:SAH (n =12),normal saline (n =12) and eritoran (n =12) groups.A SAH model was induced by injection of autologous arterial blood into cisterna magnatwice.An equal amount of cerebrospinal fluid was displaced with the saline in the normal saline group.An equal amount of autologous non-heparinized arterial blood was injected immediate after the replacementof cerebrospinal fluid in the SAH group.Eritoran 1.5 mg/kg was injected intravenously immediately after the blood injection via the cisterna magna each time in the eritoran group.The food intake and neurological deficit were assessed.The expressions of IL-1β,TNF-α and IFN-β mRNA in the basilar artery were detected by real-time fluorescence quantitative polymerase chain reaction.Results The food intake scores (1.20 ± 0.41 vs.2.20 ±0.61; t =53.073,P =0.002),the neurological deficit scores (1.46 ± 0.32 vs.2.6 ± 0.08; t =306.431,P =0.001),the expressions of IL-1β (1.22 ±0.48 vs.2.38 ±0.06,P =0.000),TNF-α (1.39 ±0.07 vs.3.32 ±0.21,P =0.000) and IFN-β (1.51 ±0.08 vs.2.18 ±0.05,P =0.000) in Eritoran group were all significantly lower than those in the SAH group.Conclusions Eritoran may downregnlate the expressions of inflammatory cytokines IL-1β,TNF-α and IFN-β mRNA in the basilar artery after SAH in rabbits,increasing food intake,and improving neurological deficits.
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This study investigated the expression and prognostic value of SHP-2 in cervical cancer caused by human papillomavirus (HPV) infection.Forty-five specimens from patients with cervical cancer (stage Ⅰ -Ⅲ),32 specimens from patients with cervical intraepithelial neoplasia (CIN) ( Ⅰ,Ⅱ) and 20 normal cervical samples from patients with hysteromyoma were collected in Department of Pathology for comparison.The expression levels of SHP-2 and IFN-β proteins were detected by using immunohistochemistry.The mRNA expression level of SHP-2 was detected by using quantitative real-time polymerase chain reaction (PCR).HPVs were detected by HPV GenoArray Test.The Spearman correlation was used to compare the expression level of SHP-2 in HPV infected cervical cancer vs non-HPV infected normal cervix.The level of SHP-2 protein expression in the cancer tissues (88.8％) was significantly higher than in CIN tissues (62.5％) and normal cervixes (45％) (P＜0.05 and P＜0.05,respectively).The SHP-2 mRNA levels in the cancer tissues were upregulated as compared with those in the normal cervixes (P＜0.05).Twenty-one (46.7％) cervical cancers,25 (78.1％) CINs and 17 (85％) normal cervixes showed IFN-β positive staining in cytoplasm.There was statistically significant difference in the expression rate of IFN-β between cervical cancer and normal cervix (x2=8.378,P＜0.05) as well as between cervical cancer and CIN (x2=7.695,P＜0.05).HPV16/18 infections could be found in normal cervixs (15％),CINs (68.7％) and cervical cancers (84.4％).There was a correlation between HPV infection and SHP-2 expression in cervical cancer (rs=0.653,P＜0.05).SHP-2 may be a useful prognostic and diagnostic indicator for HPV infected cervical cancer.In cervical canccrs,SHP-2 mRNA and protein overexpression was associated with IFN-β lower-expression.
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Objective To study the effect of Toll-like receptor 4(TLR4)on the expression of IRF-3 and IFN-β during the inflammatory reaction induced by cerebral ischemia reperfusion in mice.Methods Totally 144 mice were randomly divided into 3 groups:(1)ischemia reperfusion group(I group):the mice were subjected to 12 minutes ischemia by bilateral common carotid arteries(CCA)occlusion,and reperfusion without additional intervention;(2)TLR4 blocking group(T group):after 10 minutes of bilateral CCA occlusion,TLR4 antibody was injected slowly into right CCA within 2 minutes;(3)sham group(S group):no CCA occlusion was performed.At 1,2,3 and 4 d after ischemia reperfusion,the expression levels of TLR4,IRF-3 and IFN-β protein in the cortex was respectively examined by Western blot.Results In the right cortex,the expression levels of TLR4,IRF-3 and IFN-β of I group were distinctly higher than that of S and T gtoup(P<0.05);the expression levels of the 3 protein of T group were significantly higher than those of S group(P<0.05).Conclusion The cerebral ischemia reperfusion could activate TLR4 expression in the cortex of the mice.TLR4 might participate in the cerebral ischemia reperfusion through upregulating the expression of IRF-3 and IFN-β.