Background and Objective: Interleukin-1 (IL-1) binds to 2 distinct and separate receptors, types I and II (IL-1RI and IL-1RII, respectively). The binding of IL-1 to IL-1RI induces cellular signaling and biological eff...Background and Objective: Interleukin-1 (IL-1) binds to 2 distinct and separate receptors, types I and II (IL-1RI and IL-1RII, respectively). The binding of IL-1 to IL-1RI induces cellular signaling and biological effects, whereas binding to IL-1RII does not induce cellular signaling and indirectly inhibits IL-1 biological activities such as that of the decoy receptor. Recently, Suzukiet al.reported that soluble IL-1RII (sIL-1RII) was detected in gingival crevicular fluid from a periodontitis patient. However, it remains unclear which cells produce sIL-1RII detected in periodontal tissues. We examined the localization of IL-1RII producing cells in gingival tissues as well as related production control mechanisms. Material and Methods: IL-1RII mRNA expression in gingival epithelial cells (GE1) was performed by real-time PCR analysis, while the amount of sIL-1RII production in supernatant from GE1 cells was examined by dot-blot analysis. Involvement of the phosphorylation of STAT6 in the signaling pathway was determined by western blot analysis. Statistical analysis was performed with Student’st-test. Results: Culturing with IL-4 and IL-13 significantly increased IL-1RII mRNA to levels 10.5-and 8.89-fold, respectively, above that of the control (p< 0.01), while addition of interferon-γ (IFN-γ) significantly suppressed IL-1RII mRNA by 0.22-fold as compared to the control (p< 0.05). Soluble IL-1RII in the supernatant of cultured GE1 cells was increased by IL-4 and IL-13, and decreased by IFN-γ, while western blotting determines the suppression of IL-1RII production by IFN-γ. Without the addition of IL-4 or IL-13 with or without IFN-γ, P-Tyr-STAT6 was not detected. Conclusion: IL-1RII mRNA expression and sIL-1RII production were increased by IL-4 and IL-13, and decreased by IFN-γ. Finally, IL-4 signaling was regulated by IFN-γ through phosphorylation of STAT6 and IL-13 signaling blockage by IFN-γ downstream of STAT6 translocation.展开更多
Background:The objective of this study is to evaluate the implications of interleukin-1β(IL-1β)in photoreceptor degeneration using a model of blue light in rodents.Methods:CD-1 mice(12-16 weeks-old)were exposed to b...Background:The objective of this study is to evaluate the implications of interleukin-1β(IL-1β)in photoreceptor degeneration using a model of blue light in rodents.Methods:CD-1 mice(12-16 weeks-old)were exposed to blue LED light(6000 lux at 450 nm)for 1 hour and then sacrificed at day 3 post-illumination.Mice were intraperitoneally treated or not with a peptide antagonist of the IL-1βreceptor,named Rytvela(or 101.10)twice per day until sacrifice.Several markers related to the inflammatory process such as F4/80,NLRP3,Caspase-1,IL-1βand glial fibrillary acidic protein(GFAP)were evaluated by immunohistochemistry.Photoreceptor cell death was assessed by TUNEL assay and Caspase-3 immunofluorescence.Results:Immunofluorescence experiments revealed an infiltration of positive F4/80 cells(microglia and macrophages)into the subretinal space in mice exposed to blue light,which was significantly(P<0.01)abrogated with Rytvela treatment.Co-localization of NLRP3,Caspase-1,and IL-1βwith F4/80 positive cells was clearly detected in the subretinal space,suggesting that these inflammatory cells are the main source of IL-1β.Interestingly,GFAP immunoreactivity,a marker of stress in Müller cells,was augmented in retinas exposed to the blue light,and reduced with Rytvela administration.The TUNEL assay showed that Rytvela prevents photoreceptor apoptosis in the retina of mice exposed to blue light.Likewise,co-culture of retinal explants with LPS-ATP activated bone marrow-derived macrophages resulted in a high number of TUNEL positive photoreceptors,which was reduced by treatment with Rytvela.Conclusions:These results show that Rytvela attenuated the inflammatory response and prevented the death of photoreceptors in a model of dry AMD.Modulation of IL-1βsignaling would be a useful therapeutic avenue for dry AMD,for which no approved treatment currently exists.展开更多
Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0...Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.展开更多
Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has b...Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.展开更多
Intracerebral hemorrhage(ICH)is a common severe emergency in neurosurgery,causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically,especially...Intracerebral hemorrhage(ICH)is a common severe emergency in neurosurgery,causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically,especially among patients with poor functional outcomes.ICH is often accompanied by decreased consciousness and limb dysfunction.This seriously affects patients’ability to live independently.Although rapid advances in neurosurgery have greatly improved patient survival,there remains insufficient evidence that surgical treatment significantly improves long-term outcomes.With in-depth pathophysiological studies after ICH,increasing evidence has shown that secondary injury after ICH is related to long-term prognosis and that the key to secondary injury is various immune-mediated neuroinflammatory reactions after ICH.In basic and clinical studies of various systemic inflammatory diseases,triggering receptor expressed on myeloid cells 1/2(TREM-1/2),and the TREM receptor family is closely related to the inflammatory response.Various inflammatory diseases can be upregulated and downregulated through receptor intervention.How the TREM receptor functions after ICH,the types of results from intervention,and whether the outcomes can improve secondary brain injury and the long-term prognosis of patients are unknown.An analysis of relevant research results from basic and clinical trials revealed that the inhibition of TREM-1 and the activation of TREM-2 can alleviate the neuroinflammatory immune response,significantly improve the long-term prognosis of neurological function in patients with cerebral hemorrhage,and thus improve the ability of patients to live independently.展开更多
BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis th...BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis through binding to dif-ferent ligands.AIM To evaluate the correlation between single nucleotide polymorphisms(SNPs)of ACVR1C and susceptibility to esophageal squamous cell carcinoma(ESCC)in Chinese Han population.METHODS In this hospital-based cohort study,1043 ESCC patients and 1143 healthy controls were enrolled.Five SNPs(rs4664229,rs4556933,rs77886248,rs77263459,rs6734630)of ACVR1C were assessed by the ligation detection reaction method.Hardy-Weinberg equilibrium test,genetic model analysis,stratified analysis,linkage disequi-librium test,and haplotype analysis were conducted.RESULTS Participants carrying ACVR1C rs4556933 GA mutant had significantly decreased risk of ESCC,and those with rs77886248 TA mutant were related with higher risk,especially in older male smokers.In the haplotype analysis,ACVR1C Trs4664229Ars4556933Trs77886248Crs77263459Ars6734630 increased risk of ESCC,while Trs4664229Grs4556933Trs77886248Crs77263459Ars6734630 was associated with lower susceptibility to ESCC.CONCLUSION ACVR1C rs4556933 and rs77886248 SNPs were associated with the susceptibility to ESCC,which could provide a potential target for early diagnosis and treatment of ESCC in Chinese Han population.展开更多
This editorial discusses Christodoulidis et al's article,which appeared in the most recent edition.The clinical trials have demonstrated the programmed cell death receptor 1(PD-1)inhibitor Pembrolizumab involved c...This editorial discusses Christodoulidis et al's article,which appeared in the most recent edition.The clinical trials have demonstrated the programmed cell death receptor 1(PD-1)inhibitor Pembrolizumab involved combination therapy can improve the efficacy of advanced gastric cancer(AGC).Pembrolizumab combined with chemotherapy can enhance its sensitivity,and further eliminate tumor cells that develop resistance to chemotherapy.The combination of Pembrolizumab and Trastuzumab targeting human epidermal growth factor receptor 2 showed improved prognosis.The overall toxic effects of Pembrolizumab are significantly lower than traditional chemotherapy,and the safety is controllable.PD-1 inhibitor Pembrolizumab sheds a light on the treatment of AGC and brings new hope to the clinical practice.展开更多
BACKGROUND With accumulating evidence showing a benefit in the renal and cardiovascular systems,diabetes guidelines recommend that patients with diabetes and chronic kidney disease(CKD)be treated with sodium-glucose c...BACKGROUND With accumulating evidence showing a benefit in the renal and cardiovascular systems,diabetes guidelines recommend that patients with diabetes and chronic kidney disease(CKD)be treated with sodium-glucose cotransporter-2 inhibitor(SGLT2i)and/or glucagon like peptide-1 receptor agonists(GLP-1RAs)for renal protection.The real-world efficacy of the two medications on the urinary albumin-creatinine ratio(UACR)and estimated glomerular filtration rate(eGFR)remains to be explored.AIM To evaluate the SGLT2i and GLP-1RA application rates and UACR alterations after intervention in a real-world cohort of patients with diabetes.METHODS A cohort of 5482 patients with type 2 diabetes were enrolled and followed up at the Integrated Care Clinic for Diabetes of Peking University First Hospital for at least 6 months.Propensity score matching was performed,and patients who were not recommended for GLP-1RA or SGLT2i with comparable sex categories and ages were assigned to the control group at a 1:2 ratio.Blood glucose,body weight,UACR and eGFR were evaluated after 6 months of treatment in real-world clinical practice.RESULTS A total of 139(2.54%)patients started GLP-1RA,and 387(7.06%)received SGLT2i.After 6 months,the variations in fasting blood glucose,prandial blood glucose,and glycosylated hemoglobin between the GLP-1RA group and the SGLT2i and control groups were not significantly different.UACR showed a tendency toward a greater reduction compared with the control group,although this difference was not statistically significant(GLP-1RA vs control,-2.20 vs 30.16 mg/g,P=0.812;SGLT2i vs control,-20.61 vs 12.01 mg/g,P=0.327);eGFR alteration also showed no significant differences.Significant weight loss was observed in the GLP-1RA group compared with the control group(GLP-1RA vs control,-0.90 vs 0.27 kg,P<0.001),as well as in the SGLT2i group(SGLT2i vs control,-0.59 vs-0.03 kg,P=0.010).CONCLUSION Compared with patients who received other glucose-lowering drugs,patients receiving SGLT2i or GLP-1RAs presented significant weight loss,a decreasing trend in UACR and comparable glucose-lowering effects in realworld settings.展开更多
Objective To define the functional significance of IL-1 receptor antagonist (IL-1ra) gene polymorphism and to investigate, the production of IL-1ra by monocytes from individuals with different genotypes of IL-1.Method...Objective To define the functional significance of IL-1 receptor antagonist (IL-1ra) gene polymorphism and to investigate, the production of IL-1ra by monocytes from individuals with different genotypes of IL-1.Methods The genotype of IL-1ra was detected by polymerase chain reaction (PCR). Peripheral monocytes obtained from patients with immunoglobin A nephropathy (IgAN), Henoch-Schonlein purpura nephritis (HSPN) and normal subjects were matched in sex and age between the IL1RN-2 allele carriers and non-carriers. The secretion of IL-1ra, IL-1α and IL-1β in the supernatant of GM-CSF (10ng/ml) treated and untreated monocytes were measured by ELISA.Results The secretion of IL-1ra by monocytes stimulated with GM-CSF was significantly higher in the IL1RN-2 allele non-carriers than those of carriers both in IgAN (21.55±3.08 vs 13.85±2.24ng/ml, P<0.001) and HSPN (23.72±6.68 vs 12.67±2.24ng/ml, P<0.01) as well as in normal controls (20.29±1.45 vs 10.51±2.3ng/ml, P<0.001). All showed no significant differences in monocyte secretion of IL-1α and IL-1β by GM-CSF stimulation between the IL1RN-2 allele carriers and non-carriers. Conclusions These results indicate that a functional correlation of the IL1RN-2 allele and IL-1ra production is present in patients with IgAN and HSPN. This gene polymorphism control of IL-1ra production may contribute to the variety of clinical responses to inflammatory stimulation in individuals with different genotype of IL-1ra.展开更多
文摘Background and Objective: Interleukin-1 (IL-1) binds to 2 distinct and separate receptors, types I and II (IL-1RI and IL-1RII, respectively). The binding of IL-1 to IL-1RI induces cellular signaling and biological effects, whereas binding to IL-1RII does not induce cellular signaling and indirectly inhibits IL-1 biological activities such as that of the decoy receptor. Recently, Suzukiet al.reported that soluble IL-1RII (sIL-1RII) was detected in gingival crevicular fluid from a periodontitis patient. However, it remains unclear which cells produce sIL-1RII detected in periodontal tissues. We examined the localization of IL-1RII producing cells in gingival tissues as well as related production control mechanisms. Material and Methods: IL-1RII mRNA expression in gingival epithelial cells (GE1) was performed by real-time PCR analysis, while the amount of sIL-1RII production in supernatant from GE1 cells was examined by dot-blot analysis. Involvement of the phosphorylation of STAT6 in the signaling pathway was determined by western blot analysis. Statistical analysis was performed with Student’st-test. Results: Culturing with IL-4 and IL-13 significantly increased IL-1RII mRNA to levels 10.5-and 8.89-fold, respectively, above that of the control (p< 0.01), while addition of interferon-γ (IFN-γ) significantly suppressed IL-1RII mRNA by 0.22-fold as compared to the control (p< 0.05). Soluble IL-1RII in the supernatant of cultured GE1 cells was increased by IL-4 and IL-13, and decreased by IFN-γ, while western blotting determines the suppression of IL-1RII production by IFN-γ. Without the addition of IL-4 or IL-13 with or without IFN-γ, P-Tyr-STAT6 was not detected. Conclusion: IL-1RII mRNA expression and sIL-1RII production were increased by IL-4 and IL-13, and decreased by IFN-γ. Finally, IL-4 signaling was regulated by IFN-γ through phosphorylation of STAT6 and IL-13 signaling blockage by IFN-γ downstream of STAT6 translocation.
文摘Background:The objective of this study is to evaluate the implications of interleukin-1β(IL-1β)in photoreceptor degeneration using a model of blue light in rodents.Methods:CD-1 mice(12-16 weeks-old)were exposed to blue LED light(6000 lux at 450 nm)for 1 hour and then sacrificed at day 3 post-illumination.Mice were intraperitoneally treated or not with a peptide antagonist of the IL-1βreceptor,named Rytvela(or 101.10)twice per day until sacrifice.Several markers related to the inflammatory process such as F4/80,NLRP3,Caspase-1,IL-1βand glial fibrillary acidic protein(GFAP)were evaluated by immunohistochemistry.Photoreceptor cell death was assessed by TUNEL assay and Caspase-3 immunofluorescence.Results:Immunofluorescence experiments revealed an infiltration of positive F4/80 cells(microglia and macrophages)into the subretinal space in mice exposed to blue light,which was significantly(P<0.01)abrogated with Rytvela treatment.Co-localization of NLRP3,Caspase-1,and IL-1βwith F4/80 positive cells was clearly detected in the subretinal space,suggesting that these inflammatory cells are the main source of IL-1β.Interestingly,GFAP immunoreactivity,a marker of stress in Müller cells,was augmented in retinas exposed to the blue light,and reduced with Rytvela administration.The TUNEL assay showed that Rytvela prevents photoreceptor apoptosis in the retina of mice exposed to blue light.Likewise,co-culture of retinal explants with LPS-ATP activated bone marrow-derived macrophages resulted in a high number of TUNEL positive photoreceptors,which was reduced by treatment with Rytvela.Conclusions:These results show that Rytvela attenuated the inflammatory response and prevented the death of photoreceptors in a model of dry AMD.Modulation of IL-1βsignaling would be a useful therapeutic avenue for dry AMD,for which no approved treatment currently exists.
基金supported by the National Natural Science Foundation of China,Nos.82204360(to HM)and 82270411(to GW)National Science and Technology Innovation 2030 Major Program,No.2021ZD0200900(to YL)。
文摘Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.
文摘Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.
基金Supported by Shanxi Provincial Key Research and Development Plan Project,No.2020ZDLSF01-02Doctor Foundation of the Second Affiliated Hospital of Xi’an Medical University,No.X2Y-R11.
文摘Intracerebral hemorrhage(ICH)is a common severe emergency in neurosurgery,causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically,especially among patients with poor functional outcomes.ICH is often accompanied by decreased consciousness and limb dysfunction.This seriously affects patients’ability to live independently.Although rapid advances in neurosurgery have greatly improved patient survival,there remains insufficient evidence that surgical treatment significantly improves long-term outcomes.With in-depth pathophysiological studies after ICH,increasing evidence has shown that secondary injury after ICH is related to long-term prognosis and that the key to secondary injury is various immune-mediated neuroinflammatory reactions after ICH.In basic and clinical studies of various systemic inflammatory diseases,triggering receptor expressed on myeloid cells 1/2(TREM-1/2),and the TREM receptor family is closely related to the inflammatory response.Various inflammatory diseases can be upregulated and downregulated through receptor intervention.How the TREM receptor functions after ICH,the types of results from intervention,and whether the outcomes can improve secondary brain injury and the long-term prognosis of patients are unknown.An analysis of relevant research results from basic and clinical trials revealed that the inhibition of TREM-1 and the activation of TREM-2 can alleviate the neuroinflammatory immune response,significantly improve the long-term prognosis of neurological function in patients with cerebral hemorrhage,and thus improve the ability of patients to live independently.
基金Supported by The National Natural Science Foundation of China,No.82350127 and No.82241013the Shanghai Natural Science Foundation,No.20ZR1411600+2 种基金the Shanghai Shenkang Hospital Development Center,No.SHDC2020CR4039the Bethune Ethicon Excellent Surgery Foundation,No.CESS2021TC04Xuhui District Medical Research Project of Shanghai,No.SHXH201805.
文摘BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis through binding to dif-ferent ligands.AIM To evaluate the correlation between single nucleotide polymorphisms(SNPs)of ACVR1C and susceptibility to esophageal squamous cell carcinoma(ESCC)in Chinese Han population.METHODS In this hospital-based cohort study,1043 ESCC patients and 1143 healthy controls were enrolled.Five SNPs(rs4664229,rs4556933,rs77886248,rs77263459,rs6734630)of ACVR1C were assessed by the ligation detection reaction method.Hardy-Weinberg equilibrium test,genetic model analysis,stratified analysis,linkage disequi-librium test,and haplotype analysis were conducted.RESULTS Participants carrying ACVR1C rs4556933 GA mutant had significantly decreased risk of ESCC,and those with rs77886248 TA mutant were related with higher risk,especially in older male smokers.In the haplotype analysis,ACVR1C Trs4664229Ars4556933Trs77886248Crs77263459Ars6734630 increased risk of ESCC,while Trs4664229Grs4556933Trs77886248Crs77263459Ars6734630 was associated with lower susceptibility to ESCC.CONCLUSION ACVR1C rs4556933 and rs77886248 SNPs were associated with the susceptibility to ESCC,which could provide a potential target for early diagnosis and treatment of ESCC in Chinese Han population.
基金Supported by Jilin Provincial Natural Science Foundation,No.YDZJ202401650ZYTS。
文摘This editorial discusses Christodoulidis et al's article,which appeared in the most recent edition.The clinical trials have demonstrated the programmed cell death receptor 1(PD-1)inhibitor Pembrolizumab involved combination therapy can improve the efficacy of advanced gastric cancer(AGC).Pembrolizumab combined with chemotherapy can enhance its sensitivity,and further eliminate tumor cells that develop resistance to chemotherapy.The combination of Pembrolizumab and Trastuzumab targeting human epidermal growth factor receptor 2 showed improved prognosis.The overall toxic effects of Pembrolizumab are significantly lower than traditional chemotherapy,and the safety is controllable.PD-1 inhibitor Pembrolizumab sheds a light on the treatment of AGC and brings new hope to the clinical practice.
基金Peking University First Hospital Institutional Review Board(No.2018104).
文摘BACKGROUND With accumulating evidence showing a benefit in the renal and cardiovascular systems,diabetes guidelines recommend that patients with diabetes and chronic kidney disease(CKD)be treated with sodium-glucose cotransporter-2 inhibitor(SGLT2i)and/or glucagon like peptide-1 receptor agonists(GLP-1RAs)for renal protection.The real-world efficacy of the two medications on the urinary albumin-creatinine ratio(UACR)and estimated glomerular filtration rate(eGFR)remains to be explored.AIM To evaluate the SGLT2i and GLP-1RA application rates and UACR alterations after intervention in a real-world cohort of patients with diabetes.METHODS A cohort of 5482 patients with type 2 diabetes were enrolled and followed up at the Integrated Care Clinic for Diabetes of Peking University First Hospital for at least 6 months.Propensity score matching was performed,and patients who were not recommended for GLP-1RA or SGLT2i with comparable sex categories and ages were assigned to the control group at a 1:2 ratio.Blood glucose,body weight,UACR and eGFR were evaluated after 6 months of treatment in real-world clinical practice.RESULTS A total of 139(2.54%)patients started GLP-1RA,and 387(7.06%)received SGLT2i.After 6 months,the variations in fasting blood glucose,prandial blood glucose,and glycosylated hemoglobin between the GLP-1RA group and the SGLT2i and control groups were not significantly different.UACR showed a tendency toward a greater reduction compared with the control group,although this difference was not statistically significant(GLP-1RA vs control,-2.20 vs 30.16 mg/g,P=0.812;SGLT2i vs control,-20.61 vs 12.01 mg/g,P=0.327);eGFR alteration also showed no significant differences.Significant weight loss was observed in the GLP-1RA group compared with the control group(GLP-1RA vs control,-0.90 vs 0.27 kg,P<0.001),as well as in the SGLT2i group(SGLT2i vs control,-0.59 vs-0.03 kg,P=0.010).CONCLUSION Compared with patients who received other glucose-lowering drugs,patients receiving SGLT2i or GLP-1RAs presented significant weight loss,a decreasing trend in UACR and comparable glucose-lowering effects in realworld settings.
文摘Objective To define the functional significance of IL-1 receptor antagonist (IL-1ra) gene polymorphism and to investigate, the production of IL-1ra by monocytes from individuals with different genotypes of IL-1.Methods The genotype of IL-1ra was detected by polymerase chain reaction (PCR). Peripheral monocytes obtained from patients with immunoglobin A nephropathy (IgAN), Henoch-Schonlein purpura nephritis (HSPN) and normal subjects were matched in sex and age between the IL1RN-2 allele carriers and non-carriers. The secretion of IL-1ra, IL-1α and IL-1β in the supernatant of GM-CSF (10ng/ml) treated and untreated monocytes were measured by ELISA.Results The secretion of IL-1ra by monocytes stimulated with GM-CSF was significantly higher in the IL1RN-2 allele non-carriers than those of carriers both in IgAN (21.55±3.08 vs 13.85±2.24ng/ml, P<0.001) and HSPN (23.72±6.68 vs 12.67±2.24ng/ml, P<0.01) as well as in normal controls (20.29±1.45 vs 10.51±2.3ng/ml, P<0.001). All showed no significant differences in monocyte secretion of IL-1α and IL-1β by GM-CSF stimulation between the IL1RN-2 allele carriers and non-carriers. Conclusions These results indicate that a functional correlation of the IL1RN-2 allele and IL-1ra production is present in patients with IgAN and HSPN. This gene polymorphism control of IL-1ra production may contribute to the variety of clinical responses to inflammatory stimulation in individuals with different genotype of IL-1ra.
