BACKGROUND Duchenne muscular dystrophy(DMD)is a severe lethal X-linked monogenic recessive congenital muscular dystrophy caused by various types of mutations in the dystrophin gene(DG).It is one of the most common hum...BACKGROUND Duchenne muscular dystrophy(DMD)is a severe lethal X-linked monogenic recessive congenital muscular dystrophy caused by various types of mutations in the dystrophin gene(DG).It is one of the most common human genetic diseases and the most common type of muscular dystrophy,in part because DG is one of the largest protein-coding genes in the human genome with a relatively high risk of being affected by a large palette of mutations.Long-term corticosteroid therapy(LTCT)with deflazacort started at age 4 is the most accessible and used pharmacological therapy for DMD in Romania."Asea®redox supplement"(ARS)is an approved dietary supplement in the European Union.Several studies have shown that it is a very potent selective NRF2 activator,and thus a very potent,albeit indirect,antioxidant,with no toxicity up to high doses,in contrast to LTCT.CASE SUMMARY This paper presents a 3-case series on the effects of ARS in a 4-year-old,5-year-old and 3-year-old boy all with DMD from Bucharest or Slobozia(Romania).This is the first report of this type worldwide.The parents of these boys had refused LTCT.They were treated with relatively high doses of ARS(3-7 mL/kg/day).For two patients,ARS was administered in combination with medium doses of Lcarnitine and omega-3 fatty acids for various intellectual disabilities.Periodic consults and assessments for rhabdomyolysis,medullar and liver toxicity markers(blood count,gamma-glutamyl transferase,aspartate aminotransferase,alanine transaminase,lactate dehydrogenase,creatine kinase,creatine kinase-MB and serum myoglobin)were performed.In vitro studies showed that ARS is a very potent and selective NRF2 activator,and thus a very potent indirect antioxidant.The in vivo studies also support this main pharmacological mechanism of ARS,with no toxicity at high doses,in contrast with much more toxic corticosteroids which are often refused by parents for their children with DMD.Although they were three distinct ages and carried three distinct DG mutations,from the first months of ARS-based treatment,the children responded similarly to ARS.The rhabdomyolysis markers,which were initially very high,significantly dropped,and there was no evidence for medullar and/or hepatic toxicity in any of the 3 patients.CONCLUSIONS ARS has significant indirect antioxidant effects via NRF2 and deserves extensive trials in children with DMD,as an adjuvant to corticoids or as a substitute in DMD patients who refuse corticoids.Future trials should also focus on ARS as an adjuvant in many types of acute/chronic infectious/non-infectious diseases where cellular oxidative stress is involved.展开更多
Niemann-Pick type C2(NPC2) is a lysosome luminal protein that functions in concert with NPC1 to mediate egress of lowdensity lipoprotein-derived cholesterol from lysosome. The nuclear factor kappa B subunit 2(NF-κB2)...Niemann-Pick type C2(NPC2) is a lysosome luminal protein that functions in concert with NPC1 to mediate egress of lowdensity lipoprotein-derived cholesterol from lysosome. The nuclear factor kappa B subunit 2(NF-κB2) protein is a component of NF-κB transcription factor complex critically implicated in immune and inflammatory responses. Here, we report that NF-κB2 regulates intracellular cholesterol transport by controlling NPC2 expression. RNAi-mediated disruption of NF-κB2, as well as other signaling members of the non-canonical NF-κB pathway, caused intracellular cholesterol accumulation. Blockage of the non-canonical NF-κB pathway suppressed NPC2 expression, whereas Lymphotoxin β receptor(LTβR) activation or Baff receptor(BaffR) stimulation up-regulated the mRNA abundance and protein level of NPC2. Further, NF-κB2 activated NPC2 transcription through direct binding to its promoter region. We also observed cholesterol accumulation in NF-κB2-deficient zebrafish embryo and NF-κB2 mutant mice. Collectively, these data identify a regulatory role for the non-canonical NF-κB pathway in intracellular cholesterol trafficking and suggest a link between cholesterol transport and immune system.展开更多
文摘BACKGROUND Duchenne muscular dystrophy(DMD)is a severe lethal X-linked monogenic recessive congenital muscular dystrophy caused by various types of mutations in the dystrophin gene(DG).It is one of the most common human genetic diseases and the most common type of muscular dystrophy,in part because DG is one of the largest protein-coding genes in the human genome with a relatively high risk of being affected by a large palette of mutations.Long-term corticosteroid therapy(LTCT)with deflazacort started at age 4 is the most accessible and used pharmacological therapy for DMD in Romania."Asea®redox supplement"(ARS)is an approved dietary supplement in the European Union.Several studies have shown that it is a very potent selective NRF2 activator,and thus a very potent,albeit indirect,antioxidant,with no toxicity up to high doses,in contrast to LTCT.CASE SUMMARY This paper presents a 3-case series on the effects of ARS in a 4-year-old,5-year-old and 3-year-old boy all with DMD from Bucharest or Slobozia(Romania).This is the first report of this type worldwide.The parents of these boys had refused LTCT.They were treated with relatively high doses of ARS(3-7 mL/kg/day).For two patients,ARS was administered in combination with medium doses of Lcarnitine and omega-3 fatty acids for various intellectual disabilities.Periodic consults and assessments for rhabdomyolysis,medullar and liver toxicity markers(blood count,gamma-glutamyl transferase,aspartate aminotransferase,alanine transaminase,lactate dehydrogenase,creatine kinase,creatine kinase-MB and serum myoglobin)were performed.In vitro studies showed that ARS is a very potent and selective NRF2 activator,and thus a very potent indirect antioxidant.The in vivo studies also support this main pharmacological mechanism of ARS,with no toxicity at high doses,in contrast with much more toxic corticosteroids which are often refused by parents for their children with DMD.Although they were three distinct ages and carried three distinct DG mutations,from the first months of ARS-based treatment,the children responded similarly to ARS.The rhabdomyolysis markers,which were initially very high,significantly dropped,and there was no evidence for medullar and/or hepatic toxicity in any of the 3 patients.CONCLUSIONS ARS has significant indirect antioxidant effects via NRF2 and deserves extensive trials in children with DMD,as an adjuvant to corticoids or as a substitute in DMD patients who refuse corticoids.Future trials should also focus on ARS as an adjuvant in many types of acute/chronic infectious/non-infectious diseases where cellular oxidative stress is involved.
基金supported by National Natural Science Foundation of China (91754102, 31771568, 31701030, 31601147, 31600651)111 Project of Ministry of Education of China (B16036)Natural Science Foundation of Hubei Province (2016CFA012)
文摘Niemann-Pick type C2(NPC2) is a lysosome luminal protein that functions in concert with NPC1 to mediate egress of lowdensity lipoprotein-derived cholesterol from lysosome. The nuclear factor kappa B subunit 2(NF-κB2) protein is a component of NF-κB transcription factor complex critically implicated in immune and inflammatory responses. Here, we report that NF-κB2 regulates intracellular cholesterol transport by controlling NPC2 expression. RNAi-mediated disruption of NF-κB2, as well as other signaling members of the non-canonical NF-κB pathway, caused intracellular cholesterol accumulation. Blockage of the non-canonical NF-κB pathway suppressed NPC2 expression, whereas Lymphotoxin β receptor(LTβR) activation or Baff receptor(BaffR) stimulation up-regulated the mRNA abundance and protein level of NPC2. Further, NF-κB2 activated NPC2 transcription through direct binding to its promoter region. We also observed cholesterol accumulation in NF-κB2-deficient zebrafish embryo and NF-κB2 mutant mice. Collectively, these data identify a regulatory role for the non-canonical NF-κB pathway in intracellular cholesterol trafficking and suggest a link between cholesterol transport and immune system.
