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copper-mediated chemodynamic therapy with ultra-low copper consumption by doping cupric ion on cross-linked(R)-(+)-lipoic acid nanoparticles

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Regenerative Biomaterials 2023年第1期10卷 670-677页

作者： Rong Cui Bing Li Chunyan Liao Shiyong Zhang College of Biomedical Engineering National Engineering Research Center for BiomaterialsSichuan UniversityChengdu 610064China Hubei Key Laboratory of Wudang Local Chinese Medicine Research School of Pharmaceutical SciencesHubei University of MedicineShiyan 442000HubeiChina

Cu-mediated chemodynamic therapy(CDT)has attracted prominent attention owing to its advantages of pH independence and high efficiency comparing to Fe-mediated CDT,while the application of Cu-based CDT agents was impeded due to the high copper consumption caused by the metabolism loss of copper and the resultant potential ***,we developed a new copper-mediated CDT agent with extremely low Cu usage by anchoring copper on cross-linked lipoic acid nanoparticles(Cu@cLAs).After endocytosis into tumor cells,the Cu@cLAs were dissociated into LA and dihydrolipoic acid(DHLA)(reduced form of LA)and released Cu^(2+)and Cu+(oxidized form of Cu^(2+)),the two redox couples recycled each other in cells to achieve the efficient killing of cancer cells by delaying metabolic loss and increasing the ROS level of tumor *** self-recycling was confirmed in cells by the sustained high Cu/DHLA content and persistent ROS generation *** antitumor study based on the MCF-7/R nude mice gave the Cu@cLAs a tumor inhibitory rate up to 77.9%at the copper of 0.05 mg kg^(−1),the first dosage reported so far lower than that of normal serum copper(0.83±0.21 mg kg^(−1)).This work provides not only a new promising clinical strategy for the copper excessive use in copper-mediated CDT,but also gives a clue for other metal mediated disease therapies with the high metal consumption.

关键词： chemodynamic therapy copper metabolism (R)-(+)-lipoic acid nanodrug

Diagnostic criteria for acute liver failure due to Wilson disease

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World Journal of Gastroenterology 2007年第11期13卷 1711-1714页

作者： Christoph Eisenbach Olivia Sieg Wolfgang Stremmel Jens Encke Uta Merle University Hospital of Heidelberg Department of Gastroenterology and Hepatology Im Neuenheimer Feld 410 Heidelberg D-69120 Germany

AIM： To describe the diagnostic criteria for acute liver failure due to Wilson disease （WD）, which is an uncommon cause of acute liver failure （ALF）. METHODS： We compared findings of patients presenting with ALF due to WD to those with ALF of other etiologies. RESULTS： Previously described criteria, such as low alkaline phosphatase activity, ratio of low alkaline phosphatase to total bilirubin or ratio of high aspartate arninotransferase （AST） to alanine arninotransferase （ALT）, failed to identify patients with ALF due to WD. There were significant differences in low ALT and AST activities （53 ± 43 vs 1982 ± 938, P 〈 0.0001 and 87 ± 44 vs 2756 ± 2941, P = 0.037, respectively）, low choline esterase activity （1.79 ± 1.2 vs 4.30 ± 1.2, P = 0.009）, high urine copper concentrations （93.4 ± 144.0 vs 3.5 ± 1.8, P = 0.001） and low hemoglobin （7.0 ± 2.2 vs 12.6 ± 1.8, P 〈 0.0001） in patients with ALF caused by WD as compared with other etiologies. Interestingly, 4 of 7 patients with ALF due to WD survived without liver transplantation. CONCLUSION： In ALF, these criteria can help establish a diagnosis of WD. Where applicable, slitlamp examination for presence of Kayser-Fleischer rings and liver biopsy for determination of hepatic copper concentration still remain important for the diagnosis of ALF due to WD. The need for liver transplantation should be evaluated carefully as the prognosis is not necessarily fatal.

关键词： Acute liver failure copper metabolism Fulminant hepatic failure Wilson disease Liver transplantation

Novel ATP7B gene mutations in Chinese Han patients with hepatolenticular degeneration

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Neural Regeneration Research 2010年第12期5卷 933-937页

作者： Yuancheng Bao Lijuan Chen Yuanxun Yu Huaizhou Jiang Ting Guan Changshui Fang Department of Neurology FirstAffiliated Hospital of Anhui Traditional Chinese Medical College Hefei 230031 Anhui Province China Anhui Center for Medical Genetics Hefei 230061 Anhui Province China

BACKGROUND： ATP7B gene exon 8 Arg778Leu and exon 12 Arg952Lys are gene mutation hot spots in Chinese Han patients with hepatolenticular degeneration, or Wilson＇s disease （WD）. However, the gene fragments are too short for detection and the mutation detection rate remains low. OBJECTIVE： To analyze DNA sequences of ATP7B gene exon 8-exon 9 and exon 10-exon 12 sections. DESIGN, TIME AND SE＇I-rlNG： A concurrent, non-randomized, controlled, genetic polymorphism study was performed at the Anhui Medical Genetics Center, Anhui, China from March to July in 2009. PARTICIPANTS： Fifty patients, who were admitted to the Department of Neurology at the First Affiliated Hospital of Anhui Traditional Chinese Medical College between March and July in 2009, were diagnosed with WD. The WD group comprised 32 males and 18 females, with an average age of （18.8 ± 8.3） years. WD was confirmed by clinical observation, as well as physical, imaging, and biochemical examinations, including testing for serum copper, ceruloplasmin, and copper oxidase. The control group comprised 20 normal subjects, who underwent physical examination at the First Affiliated Hospital of Anhui Traditional Chinese Medical College, and included 13 males and 7 females, with an average age of （27.9 ± 2.4） years. All subjects were Chinese Han population. METHODS： Genomic DNA was extracted from 50 WD patients and 20 normal controls. Polymerase chain reaction amplification of ATP7B gene exon 8-exon 9 （about 1 100 bp） and exon 10-exon 12 （about 850 bp） segments was performed. DNA exon-intron amplification products from all subjects were processed through direct bidirectional sequencing, and sequencing results were analyzed. MAIN OUTCOME MEASURES： Sequence changes of ATPTB gene exon 8-exon 9 and exon 10-exon 12 segments. RESULTS： In the 50 included WD patients, ATP7B gene intron 8 nt53592A → G with nt53671G→ A homozygous mutation was detected between exon 8-exon 9 in seven cases; exon 8 Arg778Leu mutations with Leu770Leu sy

关键词： hepatolenticular degeneration Wilson's disease gene DNA mutation copper metabolism genetics neural regeneration

Wilson disease-the impact of hyperimmunity on disease activity:A case report

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World Journal of Clinical Cases 2021年第6期9卷 1386-1393页

作者： Wolfgang Stremmel Thomas Longerich RenéLiere Vladimir Vacata Josef van Helden Ralf Weiskirchen Pracice for Gastroenterology Medical Center Baden-BadenBaden-Baden D-76530Germany Department of General Pathology University Heidelberg HospitalInstitute of PathologyUniversity of HeidelbergHeidelberg D-69115Germany MVZ Dr.Stein+Kollegen Labor MönchengladbachMönchengladbach D-41069Germany Institute of Molecular Pathobiochemistry Experimental Gene Therapy and Clinical ChemistryRheinisch-Westfaelische Technische Hochschule University Hospital AachenAachen D-52074Germany

BACKGROUND In Wilson disease lack of biliary copper excretion causes hepatocellular injury by accumulation of free toxic *** overspill to serum accounts for neuronal damage as second common *** with copper chelators or zinc targets the removal of this free ***,in some patients liver disease persists for unknown reason despite normalized free *** discovery of a hyperimmunity as a contributing pathogenetic factor was discovered in this case report with implication also for other liver *** SUMMARY A 9-year-old girl was diagnosed in August 2009 by family screening of having asymptomatic Wilson disease with elevated *** at time of diagnosis antinuclear antibodies(ANA)were elevated without hyperimmunoglobulinemia(immunoglobulin G,IgG).After one year of therapy with Dpenicillamine transaminases normalized together with free serum *** continuous therapy with copper chelators free copper remained normal until today,whereas transaminases raised to alanine aminotransferase values of 571 U/L in December *** hyperimmunity a tentative steroid course on top of Dpenicillamine improved ***,hyperimmunity may have impact on liver inflammation after control of the metabolic disturbance.A retrospective cohort study confirmed the common association of elevated transaminases with ANA,but no IgG *** This hyperimmune-triggered condition may represent a new entity which per se or on top of other liver diseases induces liver inflammation responsive to steroids.

关键词： Wilson disease copper metabolism Antinuclear antibodies Diagnosis Steroid therapy Case report

The mechanism of copper homeostasis and its role in disease

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iLABMED 2023年第2期1卷 109-120页

作者： Yunhui Li Jing Liang Yuan Chen Yajie Wang Department of Clinical Laboratory Beijing Ditan HospitalCapital Medical UniversityBeijingChina

copper(Cuprum)is an essential trace metal indispensable for the function of numerous enzymatic molecules implicated in cellular *** evidence has demonstrated the role of copper in angiogenesis and cellular ***,raised copper levels have been detected in hepatocellular carcinoma and other *** inherited or acquired copper imbalance,including inadequately low or excessively high copper levels,as well as inappropriate copper distribution in the body,is implicated in a number of *** addition,a recent groundbreaking study identified a copperinduced type of programmed cell death named cuprotosis,the mechanism of which greatly deferred from that of other known cell death *** first part provides an overview of the regulation of copper homeostasis and discusses the underlying mechanisms of *** the second part,the authors focus on the functions of copper in liver diseases and other metabolic disorders,before discussing how this knowledge could contribute to the development of effective targets to treat such diseases.

关键词： copper homeostasis copper metabolism cuprotosis