Phycocyanin (PC), a natural algal protein, is reported for having anti-oxidant and antiinfl ammatory properties. We investigated its ability to attenuate lung infl ammation in mice subjected to X-ray radiation. Male C...Phycocyanin (PC), a natural algal protein, is reported for having anti-oxidant and antiinfl ammatory properties. We investigated its ability to attenuate lung infl ammation in mice subjected to X-ray radiation. Male C57BL/6 mice were assigned to the control, total body irradiation, PC pretreatment, and PC treatment groups. Mice in the PC pretreatment group were gavaged with 200 mg/kg PC for 7 consecutive days before irradiation, and those in the PC treatment group were gavaged with 200 mg/kg PC for 7 consecutive days after irradiation. Lungs were collected on Day 7 after irradiation exposure. Hematoxylin and eosin staining of mouse lung sections showed considerable infl ammation damage 7 days after irradiation compared with the control lung but a reduction in pathological injury in the PC treatment group. Pretreatment or treatment with PC signifi cantly decreased levels of interleukin-6 and tumor necrosis factor-α in the lung, and also increased the relative mRNA expression of superoxide dismutase and glutathione. In vivo, PC signifi cantly reduced the expression of Toll-like receptor TLR2, myeloid diff erentiation primary response Myd88, and nuclear factor NF-κB, at both the transcriptional and translation level. Taken together, these data indicated that PC attenuated lung infl ammatory damage induced by radiation by blocking the TLR2- MyD88-NF-κB signaling pathway. Therefore, PC could be a protective agent against radiation-induced infl ammatory damage in normal tissues.展开更多
Ramulus Cinnamomi （RC）, a traditional Chinese herb, has been used to attenuate inflammatory responses. The purpose of this study was to investigate the effect of RC extract on lipopolysaccharide （LPS）-induced neur...Ramulus Cinnamomi （RC）, a traditional Chinese herb, has been used to attenuate inflammatory responses. The purpose of this study was to investigate the effect of RC extract on lipopolysaccharide （LPS）-induced neuroinflammation in BV2 microglial cells and the underlying mechanisms involved. BV2 cells were incubated with normal medium （control group）, LPS, LPS plus 30 pg/mL RC extract, or LPS plus 100 pg/mL RC extract. The BV2 cell morphology was observed under an optical microscope and cell viability was detected by MTT assay. Nitric oxide level in BV2 cells was detected using Griess regents, and the levels of interleukin-6, interleukin-1 β, and tumor necrosis factor u in BV2 cells were determined by ELISA. The expression levels of cyclooxygenase-2, Toll-like receptor 4 and myeloid differentiation factor 88 proteins were detected by western blot assay. Compared with the LPS group, both 30 and 100 μg/mL RC extract had no significant effect on the viability of BV2 cells. The levels of nitric oxide, interleukin-6, interleukin-1β and tumor necrosis factor ct in BV2 cells were all significantly increased after LPS induction, and the levels were significantly reversed after treatment with 30 and 100 μg/mL RC extract. Furthermore, RC extract significantly inhibited the protein expression levels of cyclooxygenase-2, Toll-like receptor 4 and myeloid differentiation factor 88 in LPS-induced BV2 cells. Our findings suggest that RC extract alleviates neuroinflammation by downregulating the TLR4/MyD88 signaling pathway.展开更多
Objective:To investigate the clinical efficacy of dexmedetomidine in the regulation of TLR4/My D88/NF-κB in the prevention of paroxysmal sympathetic over-excitation (PSH) in patients with severe head injury. Methods:...Objective:To investigate the clinical efficacy of dexmedetomidine in the regulation of TLR4/My D88/NF-κB in the prevention of paroxysmal sympathetic over-excitation (PSH) in patients with severe head injury. Methods:One hundred patients with severe head injury who were admitted to our hospital from September 2016 to May 2019 were enrolled. The randomized digital table method was divided into 50 cases in the study group and the control group. Patients in the study group were given dexmedetomidine at a dose of 1.0 μg/kg before anesthesia induction, followed by infusion at 0.4 μg / (kg·h), and the control group was injected with the same amount of normal saline. The incidence of PSH, clinical symptoms, imaging findings, mechanical ventilation time, tracheal intubation/incision duration, ICU hospitalization time, total length of hospital stay, and GCS scores three months after discharge were compared between the two groups. At the same time, the fluorescence intensity, TLR4, NF-κB expression level and tumor necrosis factor-α (TNF-α) expression levels in peripheral blood CD14+ monocytes of the two groups were detected. Results:The incidence of PSH was significantly lower in the study group than in the control group at 7 and 3 months (P<0.05). The total length of hospital stay, duration of ICU hospitalization, intraoperative tracheotomy, and mechanical ventilation time were significantly lower in the study group than in the control group. And the GCS score was higher than the control group, and the difference was statistically significant (P<0.05). In addition, the imaging results showed that there were some differences in the location of imaging lesions between the two groups. The proportion of lesions in the ventricular system and surrounding areas was higher in the control group than in the study group (P<0.05). And the T14-T3 CD14+ PBMC MyD88 fluorescence intensity, TLR4 and NK-κB positive expression rate were significantly higher than those of T0 (P<0.05), but the MyD88 fluorescence intensity, TLR4 and NK-κB positive expression rate in the study group were significantly lower than those in the control group at T1~T3 (P<0.05). The levels of serum TNF-α in T1~T3 groups were significantly higher than those in T0 (P<0.05), but the levels of serum TNF-α in T1~T3 in the study group were significantly lower than those in the control group (P< 0.05). Conclusions:Dexmedetomidine can reduce the oxidative stress response in patients with severe head injury by inhibiting TLR4/My D88/NF-κB signaling pathway, thus effectively reducing the risk of PSH and improving the prognosis of patients.展开更多
Toll-like receptors （TLRs） are sentinels of the host defense system, which recognize a large number of microbial pathogens. The host defense system may be inefficient or inflammatory diseases may develop if microbia...Toll-like receptors （TLRs） are sentinels of the host defense system, which recognize a large number of microbial pathogens. The host defense system may be inefficient or inflammatory diseases may develop if microbial recognition by TLRs and subsequent TLR-triggered cytokine production are deregulated. Activating transcription factor 4 （ATF4）, a member of the ATF/CREB transcription factor family, is an important factor that participates in several pathophysiological processes. In this report, we found that ATF4 is also involved in the TLR-mediated innate immune response, which participates in TLR4 signal transduction and mediates the secretion of a variety of cytokines. We observed that ATF4 is activated and translocates to the nucleus following l ipopolysaccharide （LPS） stimulation via the TLR4-MyD88-dependent pathway. Additionally, a cytokine array assay showed that some key inflammatory cytokines, such as I L-6, I L-8 and RANTES, are positively regulated by ATF4. We also demonstrate that c-Jun directly binds to ATF4, thereby promoting the secretion of inflammatory cytokines. Taken together, these results indicate that ATF4 acts as a positive regulator in TLR4-triggered cytokine production.展开更多
Previous studies have shown that trans fatty acids(TFA) are associated with several chronic diseases,the gut microbiota is directly influenced by dietary components and linked to chronic diseases.Our research investig...Previous studies have shown that trans fatty acids(TFA) are associated with several chronic diseases,the gut microbiota is directly influenced by dietary components and linked to chronic diseases.Our research investigated the effects of elaidic acid(EA),a typical TFA,on the gut microbiota to understand the underlying mechanisms of TFA-related chronic diseases.16S rDNA gene sequencing on faecal samples from Sprague-Dawley rats were performed to explore the composition change of the gut microbiota by EA gavage for 4 weeks.The results showed that the intake of EA increased the abundance of well-documented harmful bacteria,such as Proteobacteria,Anaerotruncus,Oscillibacter and Desulfovibrionaceae.Plus,EA induced translocation of lipopolysaccharides(LPS) and the above pathogenic bacteria,disrupted the intestinal barrier,led to gut-liver axis derangement and TLR4 pathway activation in the liver.Overall,EA induced intestinal barrier damage and regulated TLR4-MyD88-NF-κB/MAPK pathways in the liver of SD rats,leading to the activation of NLRP3 inflammasome and inflammatory liver damage.展开更多
OBJECTIVE Neuroinflammation plays a critical role in neurodegenerative disorders,although the inflammation may not the initiating factor.Parkinson disease(PD)is characterized pathologically by the accumulation of alph...OBJECTIVE Neuroinflammation plays a critical role in neurodegenerative disorders,although the inflammation may not the initiating factor.Parkinson disease(PD)is characterized pathologically by the accumulation of alpha synuclein(α-syn)and the loss of the dopamine(DA)neurons in the substantia nigra(SN),which has been reported to be induced by the stereotaxic injection of lipopolysaccharide(LPS)to the SN region in rodents.This study is to investigate the therapeutic benefit of the inhibition of miR-873 in PD.METHODS Rats received the right-unilaterally injection with concentrated LV-sponge or LV-EGFP 3 d before LPS treatment,7 or 14 d after LPS treatment.The animals were tested for rotational behavior with the dopaminergic agonist apomorphine dissolved in sterile saline at 21 d after LPS injection.The regulation of miR-873 on the genes related with cholesterol transport and inflammation was assayed in SH-SY5Y cells and U251 cells.RESULTS TLR4-My D88 signaling pathway was involved the regulation of miR-873 by LPS.The luciferase assay showed that HMGCR,ABCA1 and A20 were down-stream genes of miR-873.The transfection of miR-873 decreased the cholesterol levels in cell membrane,but increased in lysosome in SH-SY5Y cells.Compared with the control SH-SY5Y cells,cholesterol levels were higher in lysosome withα-synuclein overexpression or LPS treatment.The transfection of miR-873 increased theα-syn levels in lysosome in cel s withα-synuclein overexpression.The loss of dopaminergic neuorns induced by LPS was significantly respectively decreased by 22.8%,35.6%and 57% after the inhibition of miR-873 at 3 d before LPS treatment,7 or14 d after LPS treatment.Compared with LPS-treated group,the number of the rotation of rats was decreased by 60.4%,33.5%and 13.2%after the inhibition of miR-873 at 3 d before LPS treatment,7or 14 d after LPS treatment.The inhibition of miR-873 significantly decreased accumulation ofα-syn.The m RNA levels of HMGCR,ABCA1 and A20 in SN were decreased by LPS treatment,which was attenuated by the injection of LV-sponge.CONCLUSION The selective regulation of miR-873 can protect the dopaminergic neurons from the LPS-induced damage.The inhibition of miR-873 can attenuate the relocation of cholesterol in lysosome and the accumulation ofα-syn in neurons induced by LPS via the regulation of HMGCR,ABCA1 and A20.展开更多
Toll-like receptor 2(TLR2)mediated macrophages regulate the protective immune response to infectious microorganisms,but the aberrant activation of macrophages often leads to pathological inflammation,including tissue ...Toll-like receptor 2(TLR2)mediated macrophages regulate the protective immune response to infectious microorganisms,but the aberrant activation of macrophages often leads to pathological inflammation,including tissue damage.In this study,we identified antagonists of TLR2 by screening2100 natural products and subsequently identified Taspine,an aporphine alkaloid,as an excellent candidate.Furthermore,analysis of the 10 steps chemical synthesis route and structural optimization yielded the Taspine derivative SMU-Y6,which has higher activity,better solubility,and improved drug-feasible property.Mechanistic studies and seq-RNA analysis revealed that SMU-Y6 inhibited TLR2 over other TLRs,hindered the formation of TLR2/MyD88 complex,and blocked the downstream NF-κB and MAPK signaling pathway,thus suppressing the release of inflammatory cytokines.SMU-Y6 could stabilize TLR2 and bind to TLR2 protein with a Kdof 0.18μmol/L.Additionally,SMU-Y6 could efficiently reverse the M1 phenotype macrophage polarization,reduce the production of cytokines as well as infiltration of neutrophiles and alleviate the local inflammation in mice with acute paw edema and colitis.Collectively,we reported the first aporphine alkaloid derivative that selectively inhibits TLR2 with high binding affinity and superior drug-feasible property,thus providing an urgently-needed molecular probe and potential drug candidate for inflammatory and autoimmune disease therapy.展开更多
Pro-Glu-Trp(PEW),a whey protein-derived peptide,has been previously shown in vitro to have antihyperuricemic potential.The current study further evaluated the roles and the underlying mechanism of PEW in the managemen...Pro-Glu-Trp(PEW),a whey protein-derived peptide,has been previously shown in vitro to have antihyperuricemic potential.The current study further evaluated the roles and the underlying mechanism of PEW in the management of hyperuricemia(HUA)in rat induced by potassium oxonate(PO)and hypoxanthine.Results revealed that PEW significantly reduced the levels of uric acid(UA),creatinine(Cr),and blood urea nitrogen(BUN)in serum,and effectively suppressed the activities of xanthine oxidase(XOD)associated with UA synthesis and modulated the expression of organic ion transporters related to UA excretion.Moreover,PEW alleviated UAinduced renal inflammation by regulating oxidative stress,suppressing the level of pro-inflammatory cytokines,and inhibiting the activation of NOD-like receptor family pyrin domain-containing 3(NLRP3)inflammasome and Toll-like receptor 4/myeloid differentiation factor 88/NF-kappaB(TLR4/MyD88/NF-κB)signaling pathway.Taken together,these relults indicated that PEW improved HUA and renal inflammation by inhibiting UA synthesis,promoting renal UA excretion and suppressing NLRP3 inflammasome and TLR4/MyD88/NF-κB signaling pathways.展开更多
基金Supported by the National Key Research and Development Program of China(No.2018YFD0901102)
文摘Phycocyanin (PC), a natural algal protein, is reported for having anti-oxidant and antiinfl ammatory properties. We investigated its ability to attenuate lung infl ammation in mice subjected to X-ray radiation. Male C57BL/6 mice were assigned to the control, total body irradiation, PC pretreatment, and PC treatment groups. Mice in the PC pretreatment group were gavaged with 200 mg/kg PC for 7 consecutive days before irradiation, and those in the PC treatment group were gavaged with 200 mg/kg PC for 7 consecutive days after irradiation. Lungs were collected on Day 7 after irradiation exposure. Hematoxylin and eosin staining of mouse lung sections showed considerable infl ammation damage 7 days after irradiation compared with the control lung but a reduction in pathological injury in the PC treatment group. Pretreatment or treatment with PC signifi cantly decreased levels of interleukin-6 and tumor necrosis factor-α in the lung, and also increased the relative mRNA expression of superoxide dismutase and glutathione. In vivo, PC signifi cantly reduced the expression of Toll-like receptor TLR2, myeloid diff erentiation primary response Myd88, and nuclear factor NF-κB, at both the transcriptional and translation level. Taken together, these data indicated that PC attenuated lung infl ammatory damage induced by radiation by blocking the TLR2- MyD88-NF-κB signaling pathway. Therefore, PC could be a protective agent against radiation-induced infl ammatory damage in normal tissues.
基金supported by a grant from the National Natural Science Foundation of China,No.81473383a grant from the Medical and Health Innovation Project of Chinese Academy of Medical Sciences,No.2016-I2M-3-007a grant from Key Project of New-Drugs Creation of Science and Technology of China,No.2012ZX09103101-078 and 2017ZX09101003-003-019
文摘Ramulus Cinnamomi （RC）, a traditional Chinese herb, has been used to attenuate inflammatory responses. The purpose of this study was to investigate the effect of RC extract on lipopolysaccharide （LPS）-induced neuroinflammation in BV2 microglial cells and the underlying mechanisms involved. BV2 cells were incubated with normal medium （control group）, LPS, LPS plus 30 pg/mL RC extract, or LPS plus 100 pg/mL RC extract. The BV2 cell morphology was observed under an optical microscope and cell viability was detected by MTT assay. Nitric oxide level in BV2 cells was detected using Griess regents, and the levels of interleukin-6, interleukin-1 β, and tumor necrosis factor u in BV2 cells were determined by ELISA. The expression levels of cyclooxygenase-2, Toll-like receptor 4 and myeloid differentiation factor 88 proteins were detected by western blot assay. Compared with the LPS group, both 30 and 100 μg/mL RC extract had no significant effect on the viability of BV2 cells. The levels of nitric oxide, interleukin-6, interleukin-1β and tumor necrosis factor ct in BV2 cells were all significantly increased after LPS induction, and the levels were significantly reversed after treatment with 30 and 100 μg/mL RC extract. Furthermore, RC extract significantly inhibited the protein expression levels of cyclooxygenase-2, Toll-like receptor 4 and myeloid differentiation factor 88 in LPS-induced BV2 cells. Our findings suggest that RC extract alleviates neuroinflammation by downregulating the TLR4/MyD88 signaling pathway.
基金Nanchong city school cooperative research project in 2018(No.18SXHZ0445).
文摘Objective:To investigate the clinical efficacy of dexmedetomidine in the regulation of TLR4/My D88/NF-κB in the prevention of paroxysmal sympathetic over-excitation (PSH) in patients with severe head injury. Methods:One hundred patients with severe head injury who were admitted to our hospital from September 2016 to May 2019 were enrolled. The randomized digital table method was divided into 50 cases in the study group and the control group. Patients in the study group were given dexmedetomidine at a dose of 1.0 μg/kg before anesthesia induction, followed by infusion at 0.4 μg / (kg·h), and the control group was injected with the same amount of normal saline. The incidence of PSH, clinical symptoms, imaging findings, mechanical ventilation time, tracheal intubation/incision duration, ICU hospitalization time, total length of hospital stay, and GCS scores three months after discharge were compared between the two groups. At the same time, the fluorescence intensity, TLR4, NF-κB expression level and tumor necrosis factor-α (TNF-α) expression levels in peripheral blood CD14+ monocytes of the two groups were detected. Results:The incidence of PSH was significantly lower in the study group than in the control group at 7 and 3 months (P<0.05). The total length of hospital stay, duration of ICU hospitalization, intraoperative tracheotomy, and mechanical ventilation time were significantly lower in the study group than in the control group. And the GCS score was higher than the control group, and the difference was statistically significant (P<0.05). In addition, the imaging results showed that there were some differences in the location of imaging lesions between the two groups. The proportion of lesions in the ventricular system and surrounding areas was higher in the control group than in the study group (P<0.05). And the T14-T3 CD14+ PBMC MyD88 fluorescence intensity, TLR4 and NK-κB positive expression rate were significantly higher than those of T0 (P<0.05), but the MyD88 fluorescence intensity, TLR4 and NK-κB positive expression rate in the study group were significantly lower than those in the control group at T1~T3 (P<0.05). The levels of serum TNF-α in T1~T3 groups were significantly higher than those in T0 (P<0.05), but the levels of serum TNF-α in T1~T3 in the study group were significantly lower than those in the control group (P< 0.05). Conclusions:Dexmedetomidine can reduce the oxidative stress response in patients with severe head injury by inhibiting TLR4/My D88/NF-κB signaling pathway, thus effectively reducing the risk of PSH and improving the prognosis of patients.
文摘Toll-like receptors （TLRs） are sentinels of the host defense system, which recognize a large number of microbial pathogens. The host defense system may be inefficient or inflammatory diseases may develop if microbial recognition by TLRs and subsequent TLR-triggered cytokine production are deregulated. Activating transcription factor 4 （ATF4）, a member of the ATF/CREB transcription factor family, is an important factor that participates in several pathophysiological processes. In this report, we found that ATF4 is also involved in the TLR-mediated innate immune response, which participates in TLR4 signal transduction and mediates the secretion of a variety of cytokines. We observed that ATF4 is activated and translocates to the nucleus following l ipopolysaccharide （LPS） stimulation via the TLR4-MyD88-dependent pathway. Additionally, a cytokine array assay showed that some key inflammatory cytokines, such as I L-6, I L-8 and RANTES, are positively regulated by ATF4. We also demonstrate that c-Jun directly binds to ATF4, thereby promoting the secretion of inflammatory cytokines. Taken together, these results indicate that ATF4 acts as a positive regulator in TLR4-triggered cytokine production.
基金supported by fund from the National Natural Science Foundation of China (32172322)Shandong Provincial Natural Science Foundation (ZR2023QC291)Shandong Traditional Chinese Medicine Technology Project (Q-2023130)。
文摘Previous studies have shown that trans fatty acids(TFA) are associated with several chronic diseases,the gut microbiota is directly influenced by dietary components and linked to chronic diseases.Our research investigated the effects of elaidic acid(EA),a typical TFA,on the gut microbiota to understand the underlying mechanisms of TFA-related chronic diseases.16S rDNA gene sequencing on faecal samples from Sprague-Dawley rats were performed to explore the composition change of the gut microbiota by EA gavage for 4 weeks.The results showed that the intake of EA increased the abundance of well-documented harmful bacteria,such as Proteobacteria,Anaerotruncus,Oscillibacter and Desulfovibrionaceae.Plus,EA induced translocation of lipopolysaccharides(LPS) and the above pathogenic bacteria,disrupted the intestinal barrier,led to gut-liver axis derangement and TLR4 pathway activation in the liver.Overall,EA induced intestinal barrier damage and regulated TLR4-MyD88-NF-κB/MAPK pathways in the liver of SD rats,leading to the activation of NLRP3 inflammasome and inflammatory liver damage.
基金supported by National Natural Science Foundation of China(1673503)
文摘OBJECTIVE Neuroinflammation plays a critical role in neurodegenerative disorders,although the inflammation may not the initiating factor.Parkinson disease(PD)is characterized pathologically by the accumulation of alpha synuclein(α-syn)and the loss of the dopamine(DA)neurons in the substantia nigra(SN),which has been reported to be induced by the stereotaxic injection of lipopolysaccharide(LPS)to the SN region in rodents.This study is to investigate the therapeutic benefit of the inhibition of miR-873 in PD.METHODS Rats received the right-unilaterally injection with concentrated LV-sponge or LV-EGFP 3 d before LPS treatment,7 or 14 d after LPS treatment.The animals were tested for rotational behavior with the dopaminergic agonist apomorphine dissolved in sterile saline at 21 d after LPS injection.The regulation of miR-873 on the genes related with cholesterol transport and inflammation was assayed in SH-SY5Y cells and U251 cells.RESULTS TLR4-My D88 signaling pathway was involved the regulation of miR-873 by LPS.The luciferase assay showed that HMGCR,ABCA1 and A20 were down-stream genes of miR-873.The transfection of miR-873 decreased the cholesterol levels in cell membrane,but increased in lysosome in SH-SY5Y cells.Compared with the control SH-SY5Y cells,cholesterol levels were higher in lysosome withα-synuclein overexpression or LPS treatment.The transfection of miR-873 increased theα-syn levels in lysosome in cel s withα-synuclein overexpression.The loss of dopaminergic neuorns induced by LPS was significantly respectively decreased by 22.8%,35.6%and 57% after the inhibition of miR-873 at 3 d before LPS treatment,7 or14 d after LPS treatment.Compared with LPS-treated group,the number of the rotation of rats was decreased by 60.4%,33.5%and 13.2%after the inhibition of miR-873 at 3 d before LPS treatment,7or 14 d after LPS treatment.The inhibition of miR-873 significantly decreased accumulation ofα-syn.The m RNA levels of HMGCR,ABCA1 and A20 in SN were decreased by LPS treatment,which was attenuated by the injection of LV-sponge.CONCLUSION The selective regulation of miR-873 can protect the dopaminergic neurons from the LPS-induced damage.The inhibition of miR-873 can attenuate the relocation of cholesterol in lysosome and the accumulation ofα-syn in neurons induced by LPS via the regulation of HMGCR,ABCA1 and A20.
基金supported by Foundation National Natural Science Foundation of China(Nos.82073689,82273762)National Key Research and Development Program of China(No.2022YFC2304203)+2 种基金Key Program of National Natural Science Foundation of China(No.82130101)National Natural Science Foundation of Guangdong Province(No.2018B030312010,China)Science and Technology Program of Guangzhou(No.201904010380,China)。
文摘Toll-like receptor 2(TLR2)mediated macrophages regulate the protective immune response to infectious microorganisms,but the aberrant activation of macrophages often leads to pathological inflammation,including tissue damage.In this study,we identified antagonists of TLR2 by screening2100 natural products and subsequently identified Taspine,an aporphine alkaloid,as an excellent candidate.Furthermore,analysis of the 10 steps chemical synthesis route and structural optimization yielded the Taspine derivative SMU-Y6,which has higher activity,better solubility,and improved drug-feasible property.Mechanistic studies and seq-RNA analysis revealed that SMU-Y6 inhibited TLR2 over other TLRs,hindered the formation of TLR2/MyD88 complex,and blocked the downstream NF-κB and MAPK signaling pathway,thus suppressing the release of inflammatory cytokines.SMU-Y6 could stabilize TLR2 and bind to TLR2 protein with a Kdof 0.18μmol/L.Additionally,SMU-Y6 could efficiently reverse the M1 phenotype macrophage polarization,reduce the production of cytokines as well as infiltration of neutrophiles and alleviate the local inflammation in mice with acute paw edema and colitis.Collectively,we reported the first aporphine alkaloid derivative that selectively inhibits TLR2 with high binding affinity and superior drug-feasible property,thus providing an urgently-needed molecular probe and potential drug candidate for inflammatory and autoimmune disease therapy.
文摘Pro-Glu-Trp(PEW),a whey protein-derived peptide,has been previously shown in vitro to have antihyperuricemic potential.The current study further evaluated the roles and the underlying mechanism of PEW in the management of hyperuricemia(HUA)in rat induced by potassium oxonate(PO)and hypoxanthine.Results revealed that PEW significantly reduced the levels of uric acid(UA),creatinine(Cr),and blood urea nitrogen(BUN)in serum,and effectively suppressed the activities of xanthine oxidase(XOD)associated with UA synthesis and modulated the expression of organic ion transporters related to UA excretion.Moreover,PEW alleviated UAinduced renal inflammation by regulating oxidative stress,suppressing the level of pro-inflammatory cytokines,and inhibiting the activation of NOD-like receptor family pyrin domain-containing 3(NLRP3)inflammasome and Toll-like receptor 4/myeloid differentiation factor 88/NF-kappaB(TLR4/MyD88/NF-κB)signaling pathway.Taken together,these relults indicated that PEW improved HUA and renal inflammation by inhibiting UA synthesis,promoting renal UA excretion and suppressing NLRP3 inflammasome and TLR4/MyD88/NF-κB signaling pathways.
