目的:NOD样受体热蛋白结构域相关蛋白6(NOD-like receptor thermal protein domain associated protein 6,NLRP6)是新发现的寡聚化核苷酸结合结构域样受体家族成员,广泛表达于肠道、肝脏、肾脏、脾脏和肌肉等组织器官,在炎症、焦亡和自...目的:NOD样受体热蛋白结构域相关蛋白6(NOD-like receptor thermal protein domain associated protein 6,NLRP6)是新发现的寡聚化核苷酸结合结构域样受体家族成员,广泛表达于肠道、肝脏、肾脏、脾脏和肌肉等组织器官,在炎症、焦亡和自噬等多种生物过程发挥广泛的调节作用。近期研究表明,NLRP6在应激条件下对多种组织器官的疾病表型具有重要影响。然而,NLRP6对组织器官生长发育的影响尚未可知。方法:采用CRISPR/Cas9基因编辑技术构建NLRP6基因敲除小鼠,饲养并记录小鼠的生长和繁殖情况。将小鼠的脾、肝、心、肾、脑、四肢和后背皮肤等组织器官进行解剖和切片染色,以评估NLRP6基因敲除对实质器官的宏观发育影响和对组织结构的微观影响。结果:在自然状态下,NLRP6基因敲除缩短了雄鼠的性成熟期并使成年雄鼠的睾丸发生不可逆的破溃与萎缩。在四肢发育上,NLRP6基因敲除诱导成年雄鼠后肢横纹肌断裂,导致后肢明显萎缩。在脾脏发育上,NLRP6基因敲除不仅显著增加了雄鼠的脾脏体积(P<0.01)还诱导雄鼠脾脏出现炎性细胞浸润。在后背皮肤上,NLRP6基因敲除引发雄鼠后背皮肤出现明显的溃疡损伤、胶原纤维增生和炎性细胞浸润。结论:在自然生长发育条件下,NLRP6基因敲除选择性影响小鼠的生殖器发育与性成熟期、后肢肌肉发育、脾脏大小及其炎症免疫状态以及后背皮肤的结构完整性,而且这一作用具有明显的雄激素依赖性。展开更多
Heavy alcohol consumption results in alcoholic liver disease(ALD)with inadequate therapeutic options.Here,we first report the potential beneficial effects of ginsenoside Rk2(Rk2),a rare dehydroprotopanaxadiol saponin ...Heavy alcohol consumption results in alcoholic liver disease(ALD)with inadequate therapeutic options.Here,we first report the potential beneficial effects of ginsenoside Rk2(Rk2),a rare dehydroprotopanaxadiol saponin isolated from streamed ginseng,against alcoholic liver injury in mice.Chronic-plus-single-binge ethanol feeding caused severe liver injury,as manifested by significantly elevated serum aminotransferase levels,hepatic histological changes,increased lipid accumulation,oxidative stress,and inflammation in the liver.These deleterious effects were alleviated by the treatment with Rk2(5 and 30 mg/kg).Acting as an nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3(NLRP3)inhibitor,Rk2 ameliorates alcohol-induced liver inflammation by inhibiting NLRP3 inflammasome signaling in the liver.Meanwhile,the treatment with Rk2 alleviated the alcohol-induced intestinal barrier dysfunction via enhancing NLRP6 inflammasome in the intestine.Our findings indicate that Rk2 is a promising agent for the prevention and treatment of ALD and other NLPR3-driven diseases.展开更多
BACKGROUND About one-third of refractory irritable bowel syndrome(IBS)cases are caused by gastrointestinal(GI)infection/inflammation,known as post-infectious/postinflammatory IBS(PI-IBS).Although it is known that inte...BACKGROUND About one-third of refractory irritable bowel syndrome(IBS)cases are caused by gastrointestinal(GI)infection/inflammation,known as post-infectious/postinflammatory IBS(PI-IBS).Although it is known that intestinal microbiota and host NOD-like receptor family pyrin domain containing 6(NLRP6)inflammsome signaling are closely related to PI-IBS and moxibustion has a therapeutic effect on PI-IBS,whether moxibustion regulates the intestinal flora and host NLRP6 events in PI-IBS remains unclear.AIM To examine the regulatory effect of moxibustion on intestinal microbiota and host NLRP6 inflammatory signaling in PI-IBS.METHODS Sprague-Dawley rats were divided into a normal control group,a model control group,a mild moxibustion group,and a sham mild moxibustion group.PI-IBS rats in the mild moxibustion group were treated with moxibusiton at bilateral Tianshu(ST 25)and Zusanli(ST36)for 7 consecutive days for 10 min each time.The sham group rats were given the same treatment as the mild moxibustion group except the moxa stick was not ignited.Abdominal withdrawal reflex(AWR)score was measured to assess the visceral sensitivity,and colon histopathology and ultrastructure,colonic myeloperoxidase(MPO)activity,and serum C-reactive protein(CRP)level were measured to evaluate low-grade colonic inflammation in rats.The relative abundance of selected intestinal bacteria in rat feces was detected by 16S rDNA PCR and the NLRP6 inflammsome signaling in the colon was detected by immunofluorescence,qRTPCR,and Western blot.RESULTS The AWR score was significantly decreased and the low-grade intestinal inflammation reflected by serum CRP and colonic MPO levels was inhibited in the mild moxibustion group compared with the sham group.Mild moxibustion remarkably increased the relative DNA abundances of Lactobacillus,Bifidobacterium,and Faecalibacterium prausnitzii but decreased that of Escherichia coli in the gut of PI-IBS rats.Additionally,mild moxibustion induced mRNA and protein expression of intestine lectin 1 but inhibited the expression of IL-1β,IL-18,and resistance-like moleculeβby promoting the NLRP6 and reducing the mRNA and protein expression of apoptosis-associated speck-like protein containing CARD(ASC)and cysteinyl-aspartate-specific proteinase 1(Caspase-1).The relative DNA abundances of Lactobacillus,Bifidobacteria,Faecalibacterium prausnitzii,and Escherichia coli in each group were correlated with the mRNA and protein expression of NLRP6,ASC,and Caspase-1 in the colon.CONCLUSION These findings indicated that mild moxibustion can relieve low-grade GI inflammation and alleviate visceral hypersensitivity in PI-IBS by regulating intestinal microbes and controlling NLRP6 inflammasome signaling.展开更多
Objective:Inflammasomes promote carcinogenesis through an extrinsic pathway and maintain the malignant cancer microenvironment through an intrinsic pathway.Moreover,inflammasomes exert anticancer effects by pyroptosis...Objective:Inflammasomes promote carcinogenesis through an extrinsic pathway and maintain the malignant cancer microenvironment through an intrinsic pathway.Moreover,inflammasomes exert anticancer effects by pyroptosis and immune regulatory functions.Until now,there have been few studies about how inflammasomes contribute to hepatocellular carcinoma(HCC)development.展开更多
核苷酸结合寡聚化结构域样受体(nucleotide-binding and oligomerization domain-like receptors,NLRs)是一种模式识别受体,其中NLRP6是NLRs家族的新成员,可与caspase-1和含半胱天冬酶激活和募集结构域(caspase activation and recruitm...核苷酸结合寡聚化结构域样受体(nucleotide-binding and oligomerization domain-like receptors,NLRs)是一种模式识别受体,其中NLRP6是NLRs家族的新成员,可与caspase-1和含半胱天冬酶激活和募集结构域(caspase activation and recruitment domain,CARD)的凋亡相关颗粒样蛋白(apoptosis-associated speck-like protein containing a CARD,ASC)构成蛋白复合物,在维持肠道上皮完整性和调控肠道菌群中均有重要的作用。已有研究初步证实,NLRP6在多种恶性肿瘤中扮演重要角色。本文着重介绍NLRP6的结构、功能、激活机制以及其在各种肿瘤中的研究进展。展开更多
Neurogenesis decline in hippocampal dentate gyrus(DG)participates in stress-induced depressive-like behaviors,but the underlying mechanism remains poorly understood.Here,we observed low-expression of NOD-like receptor...Neurogenesis decline in hippocampal dentate gyrus(DG)participates in stress-induced depressive-like behaviors,but the underlying mechanism remains poorly understood.Here,we observed low-expression of NOD-like receptor family pyrin domain containing 6(NLRP6)in hippocampus of stress-stimulated mice,being consistent with high corticosterone level.NLRP6 was found to be abundantly expressed in neural stem cells(NSCs)of DG.Both Nlrp6 knockout(Nlrp6^(-/-))and NSCconditional Nlrp6 knockout(Nlrp6CKO)mice were susceptible to stress,being more likely to develop depressive-like behaviors.Interestingly,NLRP6 was required for NSC proliferation in sustaining hippocampal neurogenesis and reinforcing stress resilience during growing up.Nlrp6 deficiency promoted esophageal cancer-related gene 4(ECRG4)expression and caused mitochondrial dysfunction.Corticosterone as a stress factor significantly down-regulated NLRP6 expression,damaged mitochondrial function and suppressed cell proliferation in NSCs,which were blocked by Nlrp6 overexpression.ECRG4 knockdown reversed corticosterone-induced NSC mitochondrial function and cell proliferation disorders.Pioglitazone,a well-known clinical drug,up-regulated NLRP6 expression to inhibit ECRG4 expression in its protection against corticosterone-induced NSC mitochondrial dysfunction and proliferation restriction.In conclusion,this study demonstrates that NLRP6 is essential to maintain mitochondrial homeostasis and proliferation in NSCs,and identifies NLRP6 as a promising therapeutic target for hippocampal neurogenesis decline linked to depression.展开更多
文摘目的:NOD样受体热蛋白结构域相关蛋白6(NOD-like receptor thermal protein domain associated protein 6,NLRP6)是新发现的寡聚化核苷酸结合结构域样受体家族成员,广泛表达于肠道、肝脏、肾脏、脾脏和肌肉等组织器官,在炎症、焦亡和自噬等多种生物过程发挥广泛的调节作用。近期研究表明,NLRP6在应激条件下对多种组织器官的疾病表型具有重要影响。然而,NLRP6对组织器官生长发育的影响尚未可知。方法:采用CRISPR/Cas9基因编辑技术构建NLRP6基因敲除小鼠,饲养并记录小鼠的生长和繁殖情况。将小鼠的脾、肝、心、肾、脑、四肢和后背皮肤等组织器官进行解剖和切片染色,以评估NLRP6基因敲除对实质器官的宏观发育影响和对组织结构的微观影响。结果:在自然状态下,NLRP6基因敲除缩短了雄鼠的性成熟期并使成年雄鼠的睾丸发生不可逆的破溃与萎缩。在四肢发育上,NLRP6基因敲除诱导成年雄鼠后肢横纹肌断裂,导致后肢明显萎缩。在脾脏发育上,NLRP6基因敲除不仅显著增加了雄鼠的脾脏体积(P<0.01)还诱导雄鼠脾脏出现炎性细胞浸润。在后背皮肤上,NLRP6基因敲除引发雄鼠后背皮肤出现明显的溃疡损伤、胶原纤维增生和炎性细胞浸润。结论:在自然生长发育条件下,NLRP6基因敲除选择性影响小鼠的生殖器发育与性成熟期、后肢肌肉发育、脾脏大小及其炎症免疫状态以及后背皮肤的结构完整性,而且这一作用具有明显的雄激素依赖性。
基金supported by grants from the Research Committee of the University of Macao(Grant No.:MYRG2022-00020-ICMS)the Science and Technology Development Fund,Macao SAR,China(File No.:0074/2021/AFJ and 0052/2022/A1).
文摘Heavy alcohol consumption results in alcoholic liver disease(ALD)with inadequate therapeutic options.Here,we first report the potential beneficial effects of ginsenoside Rk2(Rk2),a rare dehydroprotopanaxadiol saponin isolated from streamed ginseng,against alcoholic liver injury in mice.Chronic-plus-single-binge ethanol feeding caused severe liver injury,as manifested by significantly elevated serum aminotransferase levels,hepatic histological changes,increased lipid accumulation,oxidative stress,and inflammation in the liver.These deleterious effects were alleviated by the treatment with Rk2(5 and 30 mg/kg).Acting as an nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3(NLRP3)inhibitor,Rk2 ameliorates alcohol-induced liver inflammation by inhibiting NLRP3 inflammasome signaling in the liver.Meanwhile,the treatment with Rk2 alleviated the alcohol-induced intestinal barrier dysfunction via enhancing NLRP6 inflammasome in the intestine.Our findings indicate that Rk2 is a promising agent for the prevention and treatment of ALD and other NLPR3-driven diseases.
基金Supported by the National Natural Science Foundation of China,No.81503656the National Key Basic Research Program of China(973 Program),No.2015CB554501 and No.2009CB522900
文摘BACKGROUND About one-third of refractory irritable bowel syndrome(IBS)cases are caused by gastrointestinal(GI)infection/inflammation,known as post-infectious/postinflammatory IBS(PI-IBS).Although it is known that intestinal microbiota and host NOD-like receptor family pyrin domain containing 6(NLRP6)inflammsome signaling are closely related to PI-IBS and moxibustion has a therapeutic effect on PI-IBS,whether moxibustion regulates the intestinal flora and host NLRP6 events in PI-IBS remains unclear.AIM To examine the regulatory effect of moxibustion on intestinal microbiota and host NLRP6 inflammatory signaling in PI-IBS.METHODS Sprague-Dawley rats were divided into a normal control group,a model control group,a mild moxibustion group,and a sham mild moxibustion group.PI-IBS rats in the mild moxibustion group were treated with moxibusiton at bilateral Tianshu(ST 25)and Zusanli(ST36)for 7 consecutive days for 10 min each time.The sham group rats were given the same treatment as the mild moxibustion group except the moxa stick was not ignited.Abdominal withdrawal reflex(AWR)score was measured to assess the visceral sensitivity,and colon histopathology and ultrastructure,colonic myeloperoxidase(MPO)activity,and serum C-reactive protein(CRP)level were measured to evaluate low-grade colonic inflammation in rats.The relative abundance of selected intestinal bacteria in rat feces was detected by 16S rDNA PCR and the NLRP6 inflammsome signaling in the colon was detected by immunofluorescence,qRTPCR,and Western blot.RESULTS The AWR score was significantly decreased and the low-grade intestinal inflammation reflected by serum CRP and colonic MPO levels was inhibited in the mild moxibustion group compared with the sham group.Mild moxibustion remarkably increased the relative DNA abundances of Lactobacillus,Bifidobacterium,and Faecalibacterium prausnitzii but decreased that of Escherichia coli in the gut of PI-IBS rats.Additionally,mild moxibustion induced mRNA and protein expression of intestine lectin 1 but inhibited the expression of IL-1β,IL-18,and resistance-like moleculeβby promoting the NLRP6 and reducing the mRNA and protein expression of apoptosis-associated speck-like protein containing CARD(ASC)and cysteinyl-aspartate-specific proteinase 1(Caspase-1).The relative DNA abundances of Lactobacillus,Bifidobacteria,Faecalibacterium prausnitzii,and Escherichia coli in each group were correlated with the mRNA and protein expression of NLRP6,ASC,and Caspase-1 in the colon.CONCLUSION These findings indicated that mild moxibustion can relieve low-grade GI inflammation and alleviate visceral hypersensitivity in PI-IBS by regulating intestinal microbes and controlling NLRP6 inflammasome signaling.
文摘Objective:Inflammasomes promote carcinogenesis through an extrinsic pathway and maintain the malignant cancer microenvironment through an intrinsic pathway.Moreover,inflammasomes exert anticancer effects by pyroptosis and immune regulatory functions.Until now,there have been few studies about how inflammasomes contribute to hepatocellular carcinoma(HCC)development.
文摘核苷酸结合寡聚化结构域样受体(nucleotide-binding and oligomerization domain-like receptors,NLRs)是一种模式识别受体,其中NLRP6是NLRs家族的新成员,可与caspase-1和含半胱天冬酶激活和募集结构域(caspase activation and recruitment domain,CARD)的凋亡相关颗粒样蛋白(apoptosis-associated speck-like protein containing a CARD,ASC)构成蛋白复合物,在维持肠道上皮完整性和调控肠道菌群中均有重要的作用。已有研究初步证实,NLRP6在多种恶性肿瘤中扮演重要角色。本文着重介绍NLRP6的结构、功能、激活机制以及其在各种肿瘤中的研究进展。
基金National Key R&D Program of China(2022YFC3500303)National Natural Science Foundation of China(81991522)partly by the Open Project of State Key Laboratory of Natural Medicine,No.SKLNMKF202204,China。
文摘Neurogenesis decline in hippocampal dentate gyrus(DG)participates in stress-induced depressive-like behaviors,but the underlying mechanism remains poorly understood.Here,we observed low-expression of NOD-like receptor family pyrin domain containing 6(NLRP6)in hippocampus of stress-stimulated mice,being consistent with high corticosterone level.NLRP6 was found to be abundantly expressed in neural stem cells(NSCs)of DG.Both Nlrp6 knockout(Nlrp6^(-/-))and NSCconditional Nlrp6 knockout(Nlrp6CKO)mice were susceptible to stress,being more likely to develop depressive-like behaviors.Interestingly,NLRP6 was required for NSC proliferation in sustaining hippocampal neurogenesis and reinforcing stress resilience during growing up.Nlrp6 deficiency promoted esophageal cancer-related gene 4(ECRG4)expression and caused mitochondrial dysfunction.Corticosterone as a stress factor significantly down-regulated NLRP6 expression,damaged mitochondrial function and suppressed cell proliferation in NSCs,which were blocked by Nlrp6 overexpression.ECRG4 knockdown reversed corticosterone-induced NSC mitochondrial function and cell proliferation disorders.Pioglitazone,a well-known clinical drug,up-regulated NLRP6 expression to inhibit ECRG4 expression in its protection against corticosterone-induced NSC mitochondrial dysfunction and proliferation restriction.In conclusion,this study demonstrates that NLRP6 is essential to maintain mitochondrial homeostasis and proliferation in NSCs,and identifies NLRP6 as a promising therapeutic target for hippocampal neurogenesis decline linked to depression.
