Current Genetics

, Volume 65, Issue 2, pp 329–338 | Cite as

Genetic mechanisms of arsenic detoxification and metabolism in bacteria

  • Ge Yan
  • Xingxiang Chen
  • Shiming Du
  • Zixin Deng
  • Lianrong Wang
  • Shi ChenEmail author


Arsenic, distributed pervasively in the natural environment, is an extremely toxic substance which can severely impair the normal functions of living cells. Research on the genetic mechanisms of arsenic metabolism is of great importance for remediating arsenic-contaminated environments. Many organisms, including bacteria, have developed various strategies to tolerate arsenic, by either detoxifying this harmful element or utilizing it for energy generation. This review summarizes arsenic detoxification as well as arsenic respiratory metabolic pathways in bacteria and discusses novel arsenic resistance pathways in various bacterial strains. This knowledge provides insights into the mechanisms of arsenic biotransformation in bacteria. Multiple detoxification strategies among bacteria imply possible functional relationships among different arsenic detoxification/metabolism pathways. In addition, this review sheds light on the bioremediation of arsenic-contaminated environments and prevention of antibiotic resistance.


Arsenic resistance Arsenic detoxification Arsenic metabolism Arsenic biotransformation Bacteria 



This work was supported by Grants from the National Science Foundation of China (31720103906, 31520103902, 31670072, 31670086, and 31170070).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Human and animal rights

This work does not contain any research with human participants and/or animals.

Informed consent

Informed consent was obtained from all the authors included in the study.


  1. Abernathy CO, Liu YP, Longfellow D, Aposhian HV, Beck B, Fowler B, Goyer R, Menzer R, Rossman T, Thompson C, Waalkes M (1999) Arsenic: health effects, mechanisms of actions, and research issues. Environ Health Perspect 107:593–597CrossRefGoogle Scholar
  2. Abernathy CO, Thomas DJ, Calderon RL (2003) Health effects and risk assessment of arsenic. J Nutr 133:1536S–1538S. CrossRefGoogle Scholar
  3. Afkar E, Lisak J, Saltikov C, Basu P, Oremland RS, Stolz JF (2003) The respiratory arsenate reductase from Bacillus selenitireducens strain MLS10. FEMS Microbiol Lett 226:107–112CrossRefGoogle Scholar
  4. Ahmann D, Roberts AL, Krumholz LR, Morel FM (1994) Microbe grows by reducing arsenic. Nature 371:750. CrossRefGoogle Scholar
  5. Ayyildiz D, Arga KY, Avci FG, Altinisik FE, Gurer C, Gulsoy Toplan G, Kazan D, Wozny K, Brugger B, Mertoglu B, Sariyar Akbulut B (2017) Transcriptomic analysis displays the effect of (−)-roemerine on the motility and nutrient uptake in Escherichia coli. Curr Genet 63:709–722. CrossRefGoogle Scholar
  6. Bhattacharjee H, Rosen BP (1996) Spatial proximity of Cys113, Cys172, and Cys422 in the metalloactivation domain of the ArsA ATPase. J Biol Chem 271:24465–24470CrossRefGoogle Scholar
  7. Bhattacharjee H, Li J, Ksenzenko MY, Rosen BP (1995) Role of cysteinyl residues in metalloactivation of the oxyanion-translocating ArsA ATPase. J Biol Chem 270:11245–11250CrossRefGoogle Scholar
  8. Cansizoglu MF, Toprak E (2017) Fighting against evolution of antibiotic resistance by utilizing evolvable antimicrobial drugs. Curr Genet 63:973–976. CrossRefGoogle Scholar
  9. Cao B, Chen C, DeMott MS, Cheng Q, Clark TA, Xiong X, Zheng X, Butty V, Levine SS, Yuan G, Boitano M, Luong K, Song Y, Zhou X, Deng Z, Turner SW, Korlach J, You D, Wang L, Chen S, Dedon PC (2014) Genomic mapping of phosphorothioates reveals partial modification of short consensus sequences. Nat Commun 5:3951. CrossRefGoogle Scholar
  10. Chen Y, Rosen BP (1997) Metalloregulatory properties of the ArsD repressor. J Biol Chem 272:14257–14262CrossRefGoogle Scholar
  11. Chen CM, Misra TK, Silver S, Rosen BP (1986) Nucleotide sequence of the structural genes for an anion pump. The plasmid-encoded arsenical resistance operon. J Biol Chem 261:15030–15038Google Scholar
  12. Chen J, Bhattacharjee H, Rosen BP (2015a) ArsH is an organoarsenical oxidase that confers resistance to trivalent forms of the herbicide monosodium methylarsenate and the poultry growth promoter roxarsone. Mol Microbiol 96:1042–1052. CrossRefGoogle Scholar
  13. Chen J, Madegowda M, Bhattacharjee H, Rosen BP (2015b) ArsP: a methylarsenite efflux permease. Mol Microbiol 98:625–635. CrossRefGoogle Scholar
  14. Chen J, Yoshinaga M, Garbinski LD, Rosen BP (2016) Synergistic interaction of glyceraldehydes-3-phosphate dehydrogenase and ArsJ, a novel organoarsenical efflux permease, confers arsenate resistance. Mol Microbiol 100:945–953. CrossRefGoogle Scholar
  15. Chen C, Wang L, Chen S, Wu X, Gu M, Chen X, Jiang S, Wang Y, Deng Z, Dedon PC, Chen S (2017) Convergence of DNA methylation and phosphorothioation epigenetics in bacterial genomes. Proc Natl Acad Sci USA 114:4501–4506. CrossRefGoogle Scholar
  16. Dey S, Rosen BP (1995) Dual mode of energy coupling by the oxyanion-translocating ArsB protein. J Bacteriol 177:385–389CrossRefGoogle Scholar
  17. Dziarski R, Gupta D (2018) How innate immunity proteins kill bacteria and why they are not prone to resistance. Curr Genet 64:125–129. CrossRefGoogle Scholar
  18. Ellis PJ, Conrads T, Hille R, Kuhn P (2001) Crystal structure of the 100 kDa arsenite oxidase from Alcaligenes faecalis in two crystal forms at 1.64 A and 2.03 A. Structure 9:125–132CrossRefGoogle Scholar
  19. Endo G, Silver S (1995) CadC, the transcriptional regulatory protein of the cadmium resistance system of Staphylococcus aureus plasmid pI258. J Bacteriol 177:4437–4441CrossRefGoogle Scholar
  20. Erb TJ, Kiefer P, Hattendorf B, Gunther D, Vorholt JA (2012) GFAJ-1 is an arsenate-resistant, phosphate-dependent organism. Science 337:467–470. CrossRefGoogle Scholar
  21. Erbe JL, Taylor KB, Hall LM (1995) Metalloregulation of the cyanobacterial smt locus: identification of SmtB binding sites and direct interaction with metals. Nucleic Acids Res 23:2472–2478CrossRefGoogle Scholar
  22. Fisher E, Dawson AM, Polshyna G, Lisak J, Crable B, Perera E, Ranganathan M, Thangavelu M, Basu P, Stolz JF (2008) Transformation of inorganic and organic arsenic by Alkaliphilus oremlandii sp. nov. strain OhILAs. Ann N Y Acad Sci 1125:230–241. CrossRefGoogle Scholar
  23. Garbarino JR, Bednar AJ, Rutherford DW, Beyer RS, Wershaw RL (2003) Environmental fate of roxarsone in poultry litter. I. Degradation of roxarsone during composting. Environ Sci Technol 37:1509–1514CrossRefGoogle Scholar
  24. Gladysheva TB, Oden KL, Rosen BP (1994) Properties of the arsenate reductase of plasmid R773. Biochemistry 33:7288–7293CrossRefGoogle Scholar
  25. Hasegawa H, Rahman MA, Kitahara K, Itaya Y, Maki T, Ueda K (2010) Seasonal changes of arsenic speciation in lake waters in relation to eutrophication. Sci Total Environ 408:1684–1690. CrossRefGoogle Scholar
  26. Hernandez-Maldonado J, Stoneburner B, Boren A, Miller L, Rosen M, Oremland RS, Saltikov CW (2016) Genome sequence of the photoarsenotrophic bacterium Ectothiorhodospira sp. strain BSL-9, isolated from a hypersaline alkaline arsenic-rich extreme environment. Genome Announc 4(5):e01139–16. CrossRefGoogle Scholar
  27. Hervas M, Lopez-Maury L, Leon P, Sanchez-Riego AM, Florencio FJ, Navarro JA (2012) ArsH from the cyanobacterium Synechocystis sp. PCC 6803 is an efficient NADPH-dependent quinone reductase. Biochemistry 51:1178–1187. CrossRefGoogle Scholar
  28. Huijbers MM, Montersino S, Westphal AH, Tischler D, van Berkel WJ (2014) Flavin dependent monooxygenases. Arch Biochem Biophys 544:2–17. CrossRefGoogle Scholar
  29. Ji G, Silver S (1992a) Reduction of arsenate to arsenite by the ArsC protein of the arsenic resistance operon of Staphylococcus aureus plasmid pI258. Proc Natl Acad Sci USA 89:9474–9478CrossRefGoogle Scholar
  30. Ji G, Silver S (1992b) Regulation and expression of the arsenic resistance operon from Staphylococcus aureus plasmid pI258. J Bacteriol 174:3684–3694CrossRefGoogle Scholar
  31. Ji G, Garber EA, Armes LG, Chen CM, Fuchs JA, Silver S (1994) Arsenate reductase of Staphylococcus aureus plasmid pI258. Biochemistry 33:7294–7299CrossRefGoogle Scholar
  32. Kang YS, Bothner B, Rensing C, McDermott TR (2012) Involvement of RpoN in regulating bacterial arsenite oxidation. Appl Environ Microbiol 78:5638–5645. CrossRefGoogle Scholar
  33. Kapaj S, Peterson H, Liber K, Bhattacharya P (2006) Human health effects from chronic arsenic poisoning—a review. J Environ Sci Health Part A Tox Hazard Subst Environ Eng 41:2399–2428. CrossRefGoogle Scholar
  34. Kashyap DR, Botero LM, Franck WL, Hassett DJ, McDermott TR (2006) Complex regulation of arsenite oxidation in Agrobacterium tumefaciens. J Bacteriol 188:1081–1088. CrossRefGoogle Scholar
  35. Koechler S, Cleiss-Arnold J, Proux C, Sismeiro O, Dillies MA, Goulhen-Chollet F, Hommais F, Lievremont D, Arsene-Ploetze F, Coppee JY, Bertin PN (2010) Multiple controls affect arsenite oxidase gene expression in Herminiimonas arsenicoxydans. BMC Microbiol 10:53. CrossRefGoogle Scholar
  36. Krafft T, Macy JM (1998) Purification and characterization of the respiratory arsenate reductase of Chrysiogenes arsenatis. Eur J Biochem 255:647–653CrossRefGoogle Scholar
  37. Kuroda M, Dey S, Sanders OI, Rosen BP (1997) Alternate energy coupling of ArsB, the membrane subunit of the Ars anion-translocating ATPase. J Biol Chem 272:326–331CrossRefGoogle Scholar
  38. Laverman AM, Blum JS, Schaefer JK, Phillips E, Lovley DR, Oremland RS (1995) Growth of strain SES-3 with arsenate and other diverse electron acceptors. Appl Environ Microbiol 61:3556–3561Google Scholar
  39. Lin YF, Walmsley AR, Rosen BP (2006) An arsenic metallochaperone for an arsenic detoxification pump. Proc Natl Acad Sci USA 103:15617–15622. CrossRefGoogle Scholar
  40. Lin YF, Yang J, Rosen BP (2007) ArsD: an As(III) metallochaperone for the ArsAB As(III)-translocating ATPase. J Bioenerg Biomembr 39:453–458. CrossRefGoogle Scholar
  41. Liu G, Liu M, Kim EH, Maaty WS, Bothner B, Lei B, Rensing C, Wang G, McDermott TR (2012) A periplasmic arsenite-binding protein involved in regulating arsenite oxidation. Environ Microbiol 14:1624–1634. CrossRefGoogle Scholar
  42. Malasarn D, Keeffe JR, Newman DK (2008) Characterization of the arsenate respiratory reductase from Shewanella sp. strain ANA-3. J Bacteriol 190:135–142. CrossRefGoogle Scholar
  43. Meng YL, Liu Z, Rosen BP (2004) As(III) and Sb(III) uptake by GlpF and efflux by ArsB in Escherichia coli. J Biol Chem 279:18334–18341. CrossRefGoogle Scholar
  44. Muller D, Lievremont D, Simeonova DD, Hubert JC, Lett MC (2003) Arsenite oxidase aox genes from a metal-resistant beta-proteobacterium. J Bacteriol 185:135–141CrossRefGoogle Scholar
  45. Murphy JN, Saltikov CW (2007) The cymA gene, encoding a tetraheme c-type cytochrome, is required for arsenate respiration in Shewanella species. J Bacteriol 189:2283–2290. CrossRefGoogle Scholar
  46. Nadar SV, Yoshinaga M, Kandavelu P, Sankaran B, Rosen BP (2014) Crystallization and preliminary X-ray crystallographic studies of the ArsI C-As lyase from Thermomonospora curvata. Acta Crystallogr Sect F Struct Biol Commun 70:761–764. CrossRefGoogle Scholar
  47. Newman DK, Kennedy EK, Coates JD, Ahmann D, Ellis DJ, Lovley DR, Morel FM (1997) Dissimilatory arsenate and sulfate reduction in Desulfotomaculum auripigmentum sp. nov. Arch Microbiol 168:380–388CrossRefGoogle Scholar
  48. Nordstrom DK (2002) Public health. Worldwide occurrences of arsenic in ground water. Science 296:2143–2145. CrossRefGoogle Scholar
  49. Qin J, Rosen BP, Zhang Y, Wang G, Franke S, Rensing C (2006) Arsenic detoxification and evolution of trimethylarsine gas by a microbial arsenite S-adenosylmethionine methyltransferase. Proc Natl Acad Sci USA 103:2075–2080. CrossRefGoogle Scholar
  50. Rahman M, Tondel M, Ahmad SA, Axelson O (1998) Diabetes mellitus associated with arsenic exposure in Bangladesh. Am J Epidemiol 148:198–203CrossRefGoogle Scholar
  51. Reaves ML, Sinha S, Rabinowitz JD, Kruglyak L, Redfield RJ (2012) Absence of detectable arsenate in DNA from arsenate-grown GFAJ-1 cells. Science 337:470–473. CrossRefGoogle Scholar
  52. Rosen BP (2002) Biochemistry of arsenic detoxification. FEBS Lett 529:86–92CrossRefGoogle Scholar
  53. Rosen BP, Liu Z (2009) Transport pathways for arsenic and selenium: a minireview. Environ Int 35:512–515. CrossRefGoogle Scholar
  54. Rosen BP, Hsu CM, Karkaria CE, Owolabi JB, Tisa LS (1990) Molecular analysis of an ATP-dependent anion pump. Philos Trans R Soc Lond B Biol Sci 326:455–463CrossRefGoogle Scholar
  55. Rosenberg H, Gerdes RG, Chegwidden K (1977) Two systems for the uptake of phosphate in Escherichia coli. J Bacteriol 131:505–511Google Scholar
  56. Saltikov CW, Newman DK (2003) Genetic identification of a respiratory arsenate reductase. Proc Natl Acad Sci USA 100:10983–10988. CrossRefGoogle Scholar
  57. Santini JM, vanden Hoven RN (2004) Molybdenum-containing arsenite oxidase of the chemolithoautotrophic arsenite oxidizer NT-26. J Bacteriol 186:1614–1619CrossRefGoogle Scholar
  58. Sato T, Kobayashi Y (1998) The ars operon in the skin element of Bacillus subtilis confers resistance to arsenate and arsenite. J Bacteriol 180:1655–1661Google Scholar
  59. Sharma VK, Sohn M (2009) Aquatic arsenic: toxicity, speciation, transformations, and remediation. Environ Int 35:743–759. CrossRefGoogle Scholar
  60. Shen Z, Luangtongkum T, Qiang Z, Jeon B, Wang L, Zhang Q (2014) Identification of a novel membrane transporter mediating resistance to organic arsenic in Campylobacter jejuni. Antimicrob Agents Chemother 58:2021–2029. CrossRefGoogle Scholar
  61. Shi J, Vlamis-Gardikas A, Aslund F, Holmgren A, Rosen BP (1999) Reactivity of glutaredoxins 1, 2, and 3 from Escherichia coli shows that glutaredoxin 2 is the primary hydrogen donor to ArsC-catalyzed arsenate reduction. J Biol Chem 274:36039–36042CrossRefGoogle Scholar
  62. Sofia HJ, Burland V, Daniels DL, Plunkett G III, Blattner FR (1994) Analysis of the Escherichia coli genome. V. DNA sequence of the region from 76.0 to 81.5 minutes. Nucleic Acids Res 22:2576–2586CrossRefGoogle Scholar
  63. Tchounwou PB, Patlolla AK, Centeno JA (2003) Carcinogenic and systemic health effects associated with arsenic exposure—a critical review. Toxicol Pathol 31:575–588. Google Scholar
  64. Tisa LS, Rosen BP (1990) Molecular characterization of an anion pump. The ArsB protein is the membrane anchor for the ArsA protein. J Biol Chem 265:190–194Google Scholar
  65. Tong T, Chen S, Wang L, Tang Y, Ryu JY, Jiang S, Wu X, Chen C, Luo J, Deng Z, Li Z, Lee SY, Chen S (2018) Occurrence, evolution, and functions of DNA phosphorothioate epigenetics in bacteria. Proc Natl Acad Sci USA 115:E2988–E2996. CrossRefGoogle Scholar
  66. Walker JE, Saraste M, Runswick MJ, Gay NJ (1982) Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. EMBO J 1:945–951CrossRefGoogle Scholar
  67. Wang G, Kennedy SP, Fasiludeen S, Rensing C, DasSarma S (2004) Arsenic resistance in Halobacterium sp. strain NRC-1 examined by using an improved gene knockout system. J Bacteriol 186:3187–3194CrossRefGoogle Scholar
  68. Wang L, Chen S, Xiao X, Huang X, You D, Zhou X, Deng Z (2006) arsRBOCT arsenic resistance system encoded by linear plasmid pHZ227 in Streptomyces sp. strain FR-008. Appl Environ Microbiol 72:3738–3742. CrossRefGoogle Scholar
  69. Wang L, Chen S, Xu T, Taghizadeh K, Wishnok JS, Zhou X, You D, Deng Z, Dedon PC (2007) Phosphorothioation of DNA in bacteria by dnd genes. Nat Chem Biol 3:709–710. CrossRefGoogle Scholar
  70. Wang L, Chen S, Vergin KL, Giovannoni SJ, Chan SW, DeMott MS, Taghizadeh K, Cordero OX, Cutler M, Timberlake S, Alm EJ, Polz MF, Pinhassi J, Deng Z, Dedon PC (2011) DNA phosphorothioation is widespread and quantized in bacterial genomes. Proc Natl Acad Sci USA 108:2963–2968. CrossRefGoogle Scholar
  71. Wang L, Jiang S, Chen C, He W, Wu X, Wang F, Tong T, Zou X, Li Z, Luo J, Deng Z, Chen S (2018a) Synthetic genomes: from DNA synthesis to genome design. Angew Chemie Int Ed 57:2–11CrossRefGoogle Scholar
  72. Wang L, Jiang S, Deng Z, Dedon PC, Chen S (2018b) DNA phosphorothioate modification—a new multi-functional epigenetic system in bacteria. FEMS Microbiol Rev. Google Scholar
  73. Willsky GR, Malamy MH (1980a) Characterization of two genetically separable inorganic phosphate transport systems in Escherichia coli. J Bacteriol 144:356–365Google Scholar
  74. Willsky GR, Malamy MH (1980b) Effect of arsenate on inorganic phosphate transport in Escherichia coli. J Bacteriol 144:366–374Google Scholar
  75. Wolfe-Simon F, Switzer Blum J, Kulp TR, Gordon GW, Hoeft SE, Pett-Ridge J, Stolz JF, Webb SM, Weber PK, Davies PC, Anbar AD, Oremland RS (2011) A bacterium that can grow by using arsenic instead of phosphorus. Science 332:1163–1166. CrossRefGoogle Scholar
  76. Wu J, Rosen BP (1991) The ArsR protein is a trans-acting regulatory protein. Mol Microbiol 5:1331–1336CrossRefGoogle Scholar
  77. Wu J, Rosen BP (1993) The arsD gene encodes a second trans-acting regulatory protein of the plasmid-encoded arsenical resistance operon. Mol Microbiol 8:615–623CrossRefGoogle Scholar
  78. Wu S, Wang L, Gan R, Tong T, Bian H, Li Z, Du S, Deng Z, Chen S (2018) Signature arsenic detoxification pathways in Halomonas sp. strain GFAJ-1. mBio 9:e00515-8Google Scholar
  79. Xu C, Zhou T, Kuroda M, Rosen BP (1998) Metalloid resistance mechanisms in prokaryotes. J Biochem 123:16–23CrossRefGoogle Scholar
  80. Xue XM, Yan Y, Xu HJ, Wang N, Zhang X, Ye J (2014) ArsH from Synechocystis sp. PCC 6803 reduces chromate and ferric iron. FEMS Microbiol Lett 356:105–112. CrossRefGoogle Scholar
  81. Yang HC, Cheng J, Finan TM, Rosen BP, Bhattacharjee H (2005) Novel pathway for arsenic detoxification in the legume symbiont Sinorhizobium meliloti. J Bacteriol 187:6991–6997. CrossRefGoogle Scholar
  82. Yang J, Rawat S, Stemmler TL, Rosen BP (2010) Arsenic binding and transfer by the ArsD As(III) metallochaperone. Biochemistry 49:3658–3666. CrossRefGoogle Scholar
  83. Ye J, Yang HC, Rosen BP, Bhattacharjee H (2007) Crystal structure of the flavoprotein ArsH from Sinorhizobium meliloti. FEBS Lett 581:3996–4000. CrossRefGoogle Scholar
  84. Yoshinaga M, Rosen BP (2014) A CAs lyase for degradation of environmental organoarsenical herbicides and animal husbandry growth promoters. Proc Natl Acad Sci USA 111:7701–7706. CrossRefGoogle Scholar
  85. Yuan C, Lu X, Qin J, Rosen BP, Le XC (2008) Volatile arsenic species released from Escherichia coli expressing the AsIII S-adenosylmethionine methyltransferase gene. Environ Sci Technol 42:3201–3206CrossRefGoogle Scholar
  86. Zargar K, Hoeft S, Oremland R, Saltikov CW (2010) Identification of a novel arsenite oxidase gene, arxA, in the haloalkaliphilic, arsenite-oxidizing bacterium Alkalilimnicola ehrlichii strain MLHE-1. J Bacteriol 192:3755–3762. CrossRefGoogle Scholar
  87. Zargar K, Conrad A, Bernick DL, Lowe TM, Stolc V, Hoeft S, Oremland RS, Stolz J, Saltikov CW (2012) ArxA, a new clade of arsenite oxidase within the DMSO reductase family of molybdenum oxidoreductases. Environ Microbiol 14:1635–1645. CrossRefGoogle Scholar
  88. Zhou T, Radaev S, Rosen BP, Gatti DL (2000) Structure of the ArsA ATPase: the catalytic subunit of a heavy metal resistance pump. EMBO J 19:4838–4845. CrossRefGoogle Scholar
  89. Zhu YG, Johnson TA, Su JQ, Qiao M, Guo GX, Stedtfeld RD, Hashsham SA, Tiedje JM (2013) Diverse and abundant antibiotic resistance genes in Chinese swine farms. Proc Natl Acad Sci USA 110:3435–3440. CrossRefGoogle Scholar
  90. Zhu YG, Yoshinaga M, Zhao FJ, Rosen BP (2014) Earth abides arsenic biotransformations. Annu Rev Earth Planet Sci 42:443–467. CrossRefGoogle Scholar
  91. Zou X, Wang L, Li Z, Luo J, Wang Y, Deng Z, Du S, Chen S (2018) Genome engineering and modification toward synthetic biology for the production of antibiotics. Med Res Rev 38:229–260. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ge Yan
    • 1
    • 2
  • Xingxiang Chen
    • 1
  • Shiming Du
    • 2
  • Zixin Deng
    • 1
  • Lianrong Wang
    • 1
  • Shi Chen
    • 1
    • 2
    Email author
  1. 1.Ministry of Education Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, School of Pharmaceutical Sciences, Zhongnan HospitalWuhan UniversityWuhanChina
  2. 2.Taihe HospitalHubei University of MedicineShiyanChina

Personalised recommendations