Login Register Cart 0
Research Article

褪黑素和丰富的环境改善了IGF-1和mtor信号通路及自噬抑制作用引起的低蛋白诱导的宫内发育迟缓。

卷 21, 期 3, 2021

发表于: 26 July, 2020

页: [246 - 256] 页: 11

弟呕挨: 10.2174/1566524020666200726221735

价格: $65

摘要

目的：本研究调查了褪黑激素（MEL）和丰富的环境（EE）是否可以预防大鼠子宫内发育迟缓（IUGR）。 方法：将Sprague-Dawley大鼠随机分为3组：对照组（C），模型（M）和EE + MEL组。将动物饲养在丰富的环境中（EE + MEL组）或留在标准环境中（C组，M组）。 IUGR大鼠模型是通过在孕期喂养低蛋白饮食而建立的。 MEL是通过管饲法施用的。出生后第1天，测定胎鼠的基线特征和血清生化参数，肝和小肠的形态，酶活性和mRNA表达水平。通过蛋白质印迹分析确定自噬标记物LC3和Beclin1。 结果：EE + MEL明显改善了IUGR胎儿的基线特征，肝和肠形态。此外，EE + MEL显着增加了胎儿肠道中的乳糖酶活性。血清生长抑素（SST），生长激素（GH），生长激素释放激素（GHRH），胰岛素样生长因子1（IGF-1），三碘甲状腺素（T3）和四碘甲状腺素（T4）的水平可通过以下方法恢复EE + MEL。此外，EE + MEL还显着改善了SST，GHRH和GHRH受体（GHRHR），GH，GHR，IGF-1和IGF-1受体（IGF1R），IGF结合蛋白1（IGFBP1）的mRNA表达，哺乳动物雷帕霉素（mTOR），S6激酶1（S6K1）和真核起始因子4E（eIF4E）结合蛋白1（4EBP1）的哺乳动物靶标。在IUGR胎儿肝脏中，出生时LC3和Beclin1升高，而EE + MEL组中LC3和Beclin1明显降低。 结论：EE + MEL可以改善胎鼠的基线特征，血清生化指标，出生体重，肠道和肝脏的形态以及酶活性。这些效应可以通过激活IGF-1 / IGFBP1和IGF-1 / mTOR / S6K1 / 4EBP1信号通路以及自噬抑制来解释。

关键词: 褪黑激素，丰富的环境，宫内生长受限，胰岛素样生长因子-1，mTOR，自噬。

« Previous Next »
[1]
Figueras F, Gratacós E. Update on the diagnosis and classification of fetal growth restriction and proposal of a stage-based management protocol. Fetal Diagn Ther 2014; 36(2): 86-98.
[http://dx.doi.org/10.1159/000357592] [PMID: 24457811]
[2]
Faraci M, Renda E, Monte S, et al. Fetal growth restriction: current perspectives. J Prenat Med 2011; 5(2): 31-3.
[PMID: 22439073]
[3]
Li HP, Chen X, Li MQ. Gestational diabetes induces chronic hypoxia stress and excessive inflammatory response in murine placenta. Int J Clin Exp Pathol 2013; 6(4): 650-9.
[PMID: 23573311]
[4]
Biri A, Bozkurt N, Turp A, Kavutcu M, Himmetoglu O, Durak I. Role of oxidative stress in intrauterine growth restriction. Gynecol Obstet Invest 2007; 64(4): 187-92.
[http://dx.doi.org/10.1159/000106488] [PMID: 17664879]
[5]
Hardeland R, Madrid JA, Tan DX, Reiter RJ. Melatonin, the circadian multioscillator system and health: the need for detailed analyses of peripheral melatonin signaling. J Pineal Res 2012; 52(2): 139-66.
[http://dx.doi.org/10.1111/j.1600-079X.2011.00934.x] [PMID: 22034907]
[6]
de Farias Tda S, de Oliveira AC, Andreotti S, et al. Pinealectomy interferes with the circadian clock genes expression in white adipose tissue. J Pineal Res 2015; 58(3): 251-61.
[http://dx.doi.org/10.1111/jpi.12211] [PMID: 25626464]
[7]
Kedziora-Kornatowska K, Szewczyk-Golec K, Czuczejko J, et al. Effect of melatonin on the oxidative stress in erythrocytes of healthy young and elderly subjects. J Pineal Res 2007; 42(2): 153-8.
[http://dx.doi.org/10.1111/j.1600-079X.2006.00394.x] [PMID: 17286747]
[8]
Kedziora-Kornatowska K, Szewczyk-Golec K, Kozakiewicz M, et al. Melatonin improves oxidative stress parameters measured in the blood of elderly type 2 diabetic patients. J Pineal Res 2009; 46(3): 333-7.
[http://dx.doi.org/10.1111/j.1600-079X.2009.00666.x] [PMID: 19317795]
[9]
Manchester LC, Coto-Montes A, Boga JA, et al. Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res 2015; 59(4): 403-19.
[http://dx.doi.org/10.1111/jpi.12267] [PMID: 26272235]
[10]
Mauriz JL, Collado PS, Veneroso C, Reiter RJ, González-Gallego J. A review of the molecular aspects of melatonin’s anti-inflammatory actions: recent insights and new perspectives. J Pineal Res 2013; 54(1): 1-14.
[http://dx.doi.org/10.1111/j.1600-079X.2012.01014.x] [PMID: 22725668]
[11]
Renshall LJ, Morgan HL, Moens H, et al. Melatonin Increases Fetal Weight in Wild-Type Mice but Not in Mouse Models of Fetal Growth Restriction. Front Physiol 2018; 9: 1141.
[http://dx.doi.org/10.3389/fphys.2018.01141] [PMID: 30158878]
[12]
Polglase GR, Barbuto J, Allison BJ, et al. Effects of antenatal melatonin therapy on lung structure in growth-restricted newborn lambs. J Appl Physiol 2017; 123(5): 1195-203.
[13]
Nawathe A, David AL. Prophylaxis and treatment of foetal growth restriction. Best Pract Res Clin Obstet Gynaecol 2018; 49: 66-78.
[http://dx.doi.org/10.1016/j.bpobgyn.2018.02.007] [PMID: 29656983]
[14]
Castillo-Melendez M, Yawno T, Sutherland A, Jenkin G, Wallace EM, Miller SL. Effects of Antenatal Melatonin Treatment on the Cerebral Vasculature in an Ovine Model of Fetal Growth Restriction. Dev Neurosci 2017; 39(1-4): 323-37.
[http://dx.doi.org/10.1159/000471797] [PMID: 28467985]
[15]
Marseglia L, D’Angelo G, Manti S, Reiter RJ, Gitto E. Potential Utility of Melatonin in Preeclampsia, Intrauterine Fetal Growth Retardation, and Perinatal Asphyxia. Reprod Sci 2016; 23(8): 970-7.
[http://dx.doi.org/10.1177/1933719115612132] [PMID: 26566856]
[16]
Miller SL, Yawno T, Alers NO, et al. Antenatal antioxidant treatment with melatonin to decrease newborn neurodevelopmental deficits and brain injury caused by fetal growth restriction. J Pineal Res 2014; 56(3): 283-94.
[http://dx.doi.org/10.1111/jpi.12121] [PMID: 24456220]
[17]
Yuan M, Liu LJ, Xu LZ, Guo TY, Yue XD, Li SX. Effects of environmental stress on the depression-like behaviors and the diurnal rhythm of corticosterone and melatonin in male rats. Sheng Li Xue Bao 2016; 68(3): 215-23.
[PMID: 27350193]
[18]
Montes S, Yee-Rios Y, Páez-Martínez N. Environmental enrichment restores oxidative balance in animals chronically exposed to toluene: Comparison with melatonin. Brain Res Bull 2019; 144: 58-67.
[http://dx.doi.org/10.1016/j.brainresbull.2018.11.007] [PMID: 30453037]
[19]
Gong X, Chen Y, Chang J, Huang Y, Cai M, Zhang M. Environmental enrichment reduces adolescent anxiety- and depression-like behaviors of rats subjected to infant nerve injury. J Neuroinflammation 2018; 15(1): 262.
[http://dx.doi.org/10.1186/s12974-018-1301-7] [PMID: 30208926]
[20]
Illa M, Brito V, Pla L, et al. Early Environmental Enrichment Enhances Abnormal Brain Connectivity in a Rabbit Model of Intrauterine Growth Restriction. Fetal Diagn Ther 2018; 44(3): 184-93.
[http://dx.doi.org/10.1159/000481171] [PMID: 29020672]
[21]
Chamson-Reig A, Thyssen SM, Arany E, Hill DJ. Altered pancreatic morphology in the offspring of pregnant rats given reduced dietary protein is time and gender specific. J Endocrinol 2006; 191(1): 83-92.
[http://dx.doi.org/10.1677/joe.1.06754] [PMID: 17065391]
[22]
Rahmeier FL, Zavalhia LS, Tortorelli LS, et al. The effect of taurine and enriched environment on behaviour, memory and hippocampus of diabetic rats. Neurosci Lett 2016; 630: 84-92.
[http://dx.doi.org/10.1016/j.neulet.2016.07.032] [PMID: 27471162]
[23]
Liu P, Che L, Yang Z, et al. A Maternal High-Energy Diet Promotes Intestinal Development and Intrauterine Growth of Offspring. Nutrients 2016; 8(5): 258.
[http://dx.doi.org/10.3390/nu8050258] [PMID: 27164130]
[24]
Zhao P, Bu X, Wei X, et al. Dendritic cell immunotherapy combined with cytokine-induced killer cells promotes skewing toward Th2 cytokine profile in patients with metastatic non-small cell lung cancer. Int Immunopharmacol 2015; 25(2): 450-6.
[http://dx.doi.org/10.1016/j.intimp.2015.02.010] [PMID: 25698555]
[25]
Moody JL, Xu L, Helgason CD, Jirik FR. Anemia, thrombocytopenia, leukocytosis, extramedullary hematopoiesis, and impaired progenitor function in Pten+/-SHIP-/- mice: a novel model of myelodysplasia. Blood 2004; 103(12): 4503-10.
[http://dx.doi.org/10.1182/blood-2003-09-3262] [PMID: 15001465]
[26]
Cao M, Che L, Wang J, et al. Effects of maternal over- and undernutrition on intestinal morphology, enzyme activity, and gene expression of nutrient transporters in newborn and weaned pigs. Nutrition 2014; 30(11-12): 1442-7.
[http://dx.doi.org/10.1016/j.nut.2014.04.016] [PMID: 25280425]
[27]
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method Methods 2001; 25(4): 402-8.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID: 11846609]
[28]
He J, Niu Y, Wang F, et al. Dietary curcumin supplementation attenuates inflammation, hepatic injury and oxidative damage in a rat model of intra-uterine growth retardation. Br J Nutr 2018; 120(5): 537-48.
[http://dx.doi.org/10.1017/S0007114518001630] [PMID: 30043720]
[29]
Wang T-Y, Li Y, Wu X, et al. Protective Effects of Melatonin on CCl4-Induced Acute Liver Damage and Testicular Toxicity in RatsIndian Journal of Pharmaceutical Sciences. Indian J Pharm Sci 2018; 80(6): 1100-7.
[http://dx.doi.org/10.4172/pharmaceutical-sciences.1000461]
[30]
Manning J, Vehaskari VM. Low birth weight-associated adult hypertension in the rat. Pediatr Nephrol 2001; 16(5): 417-22.
[http://dx.doi.org/10.1007/s004670000560] [PMID: 11405116]
[31]
González-Candia A, Veliz M, Araya C, et al. Potential adverse effects of antenatal melatonin as a treatment for intrauterine growth restriction: findings in pregnant sheep. Am J Obstet Gynecol 2016; 215(2): 245.e1-7.
[http://dx.doi.org/10.1016/j.ajog.2016.02.040] [PMID: 26902986]
[32]
Green A, Esser MJ, Perrot TS. Developmental expression of anxiety and depressive behaviours after prenatal predator exposure and early life homecage enhancement. Behav Brain Res 2018; 346: 122-36.
[http://dx.doi.org/10.1016/j.bbr.2017.11.028] [PMID: 29183765]
[33]
Xu H, Rajsombath MM, Weikop P, Selkoe DJ. Enriched environment enhances β-adrenergic signaling to prevent microglia inflammation by amyloid-β. EMBO Mol Med 2018; 10(9)e8931
[http://dx.doi.org/10.15252/emmm.201808931] [PMID: 30093491]
[34]
Carlomagno G, Minini M, Tilotta M, Unfer V. From Implantation to Birth: Insight into Molecular Melatonin Functions. Int J Mol Sci 2018; 19(9): 2802.
[http://dx.doi.org/10.3390/ijms19092802] [PMID: 30227688]
[35]
Bauer MK, Breier BB, Bloomfield FH, Jensen EC, Gluckman PD, Harding JE. Chronic pulsatile infusion of growth hormone to growth-restricted fetal sheep increases circulating fetal insulin-like growth factor-I levels but not fetal growth. J Endocrinol 2003; 177(1): 83-92.
[http://dx.doi.org/10.1677/joe.0.1770083] [PMID: 12697039]
[36]
Dong L, Zhong X, Ahmad H, et al. Intrauterine Growth Restriction Impairs Small Intestinal Mucosal Immunity in Neonatal Piglets. J Histochem Cytochem 2014; 62(7): 510-8.
[http://dx.doi.org/10.1369/0022155414532655] [PMID: 24710659]
[37]
Rodríguez-Castelán J, Zepeda-Pérez D, Méndez-Tepepa M, et al. Hypothyroidism Alters the Uterine Lipid Levels in Pregnant Rabbits and Affects the Fetal Size. Endocr Metab Immune Disord Drug Targets 2019; 19(6): 818-25.
[http://dx.doi.org/10.2174/1871530318666181102093621] [PMID: 30387404]
[38]
Forhead AJ, Fowden AL. Thyroid hormones in fetal growth and prepartum maturation. J Endocrinol 2014; 221(3): R87-R103.
[http://dx.doi.org/10.1530/JOE-14-0025] [PMID: 24648121]
[39]
Wrutniak C, Cabello G. Changes in the concentration of thyroxine in the plasma of rat fetuses during late gestation: influence of ligation of the maternal uterine vein and artery. J Endocrinol 1983; 99(2): 233-8.
[http://dx.doi.org/10.1677/joe.0.0990233] [PMID: 6655406]
[40]
Bongers-Schokking JJ, Schopman W. Thyroid function in healthy normal, low birthweight and preterm infants. Eur J Pediatr 1984; 143(2): 117-22.
[http://dx.doi.org/10.1007/BF00445798] [PMID: 6335089]
[41]
Jacobsen BB, Hummer L. Changes in serum concentrations of thyroid hormones and thyroid hormone-binding proteins during early infancy. Studies in healthy fullterm, small-for-gestational age and preterm infants aged 7 to 240 days. Acta Paediatr Scand 1979; 68(3): 411-8.
[http://dx.doi.org/10.1111/j.1651-2227.1979.tb05029.x] [PMID: 108916]
[42]
De Blasio MJ, Gatford KL, Robinson JS, Owens JA. Placental restriction alters circulating thyroid hormone in the young lamb postnatally. Am J Physiol Regul Integr Comp Physiol 2006; 291(4): R1016-24.
[http://dx.doi.org/10.1152/ajpregu.00103.2006] [PMID: 16627695]
[43]
Garcia-Marin R, Fernandez-Santos JM, Morillo-Bernal J, et al. Melatonin in the thyroid gland: regulation by thyroid-stimulating hormone and role in thyroglobulin gene expression. J Physiol Pharmacol 2015; 66(5): 643-52.
[PMID: 26579570]
[44]
Arıcıgil M, Dündar MA, Yücel A, et al. Melatonin prevents possible radiotherapy-induced thyroid injury. Int J Radiat Biol 2017; 93(12): 1350-6.
[http://dx.doi.org/10.1080/09553002.2017.1397296] [PMID: 29095094]
[45]
Li C, Jenkins S, Mattern V, et al. Effect of moderate, 30 percent global maternal nutrient reduction on fetal and postnatal baboon phenotype. J Med Primatol 2017; 46(6): 293-303.
[http://dx.doi.org/10.1111/jmp.12290] [PMID: 28744866]
[46]
Álvarez-Nava F, Lanes R. Review and Considerations on Possible Therapeutic Options Int J Mol Sci 2017; 18(10): 1624.
[http://dx.doi.org/10.3390/ijms18101624]
[47]
Fu Q, Yu X, Callaway CW, Lane RH, McKnight RA. Epigenetics: intrauterine growth retardation (IUGR) modifies the histone code along the rat hepatic IGF-1 gene. FASEB J 2009; 23(8): 2438-49.
[http://dx.doi.org/10.1096/fj.08-124768] [PMID: 19364764]
[48]
Forbes K, Westwood M, Baker PN, Aplin JD. Insulin-like growth factor I and II regulate the life cycle of trophoblast in the developing human placenta. Am J Physiol Cell Physiol 2008; 294(6): C1313-22.
[http://dx.doi.org/10.1152/ajpcell.00035.2008] [PMID: 18400990]
[49]
Han VK, Matsell DG, Delhanty PJ, Hill DJ, Shimasaki S, Nygard K. IGF-binding protein mRNAs in the human fetus: tissue and cellular distribution of developmental expression. Horm Res 1996; 45(3-5): 160-6.
[http://dx.doi.org/10.1159/000184780] [PMID: 8964576]
[50]
Tapanainen PJ, Bang P, Wilson K, Unterman TG, Vreman HJ, Rosenfeld RG. Maternal hypoxia as a model for intrauterine growth retardation: effects on insulin-like growth factors and their binding proteins. Pediatr Res 1994; 36(2): 152-8.
[http://dx.doi.org/10.1203/00006450-199408000-00004] [PMID: 7526325]
[51]
Chard T. Insulin-like growth factors and their binding proteins in normal and abnormal human fetal growth. Growth Regul 1994; 4(3): 91-100.
[PMID: 7532055]
[52]
Giudice LC, de Zegher F, Gargosky SE, et al. Insulin-like growth factors and their binding proteins in the term and preterm human fetus and neonate with normal and extremes of intrauterine growth. J Clin Endocrinol Metab 1995; 80(5): 1548-55.
[PMID: 7538146]
[53]
Leger J, Oury JF, Noel M, et al. Growth factors and intrauterine growth retardation. I. Serum growth hormone, insulin-like growth factor (IGF)-I, IGF-II, and IGF binding protein 3 levels in normally grown and growth-retarded human fetuses during the second half of gestation. Pediatr Res 1996; 40(1): 94-100.
[http://dx.doi.org/10.1203/00006450-199607000-00017] [PMID: 8798253]
[54]
Godfrey KM, Hales CN, Osmond C, Barker DJ, Taylor KP. Relation of cord plasma concentrations of proinsulin, 32-33 split proinsulin, insulin and C-peptide to placental weight and the baby’s size and proportions at birth. Early Hum Dev 1996; 46(1-2): 129-40.
[http://dx.doi.org/10.1016/0378-3782(96)01752-5] [PMID: 8899361]
[55]
Jonker SS, Kamna D, LoTurco D, Kailey J, Brown LD. IUGR impairs cardiomyocyte growth and maturation in fetal sheep. J Endocrinol 2018; 239(2): 253-65.
[http://dx.doi.org/10.1530/JOE-18-0382] [PMID: 30143557]
[56]
Gupta MB, Abu Shehab M, Nygard K, et al. IUGR is associated with marked hyperphosphorylation of decidual and maternal plasma IGFBP-1. J Clin Endocrinol Metab 2019; 104(2): 408-22.
[http://dx.doi.org/10.1210/jc.2018-00820] [PMID: 30124960]
[57]
Mejia C, Lewis J, Jordan C, et al. Decreased activation of placental mTOR family members is associated with the induction of intrauterine growth restriction by secondhand smoke in the mouse. Cell Tissue Res 2017; 367(2): 387-95.
[http://dx.doi.org/10.1007/s00441-016-2496-5] [PMID: 27613305]
[58]
Roos S, Kanai Y, Prasad PD, Powell TL, Jansson T. Regulation of placental amino acid transporter activity by mammalian target of rapamycin. Am J Physiol Cell Physiol 2009; 296(1): C142-50.
[http://dx.doi.org/10.1152/ajpcell.00330.2008] [PMID: 18987252]
[59]
Xu X, Hueckstaedt LK, Ren J. Deficiency of insulin-like growth factor 1 attenuates aging-induced changes in hepatic function: role of autophagy. J Hepatol 2013; 59(2): 308-17.
[http://dx.doi.org/10.1016/j.jhep.2013.03.037] [PMID: 23583271]
[60]
Young AR, Narita M, Narita M. Spatio-temporal association between mTOR and autophagy during cellular senescence. Autophagy 2011; 7(11): 1387-8.
[http://dx.doi.org/10.4161/auto.7.11.17348] [PMID: 21799306]
[61]
Rouschop KM, Wouters BG. Regulation of autophagy through multiple independent hypoxic signaling pathways. Curr Mol Med 2009; 9(4): 417-24.
[http://dx.doi.org/10.2174/156652409788167131] [PMID: 19519399]
[62]
Zhang QX, Na Q, Song W. Altered expression of mTOR and autophagy in term normal human placentas. Rom J Morphol Embryol 2017; 58(2): 517-26.
[PMID: 28730238]
[63]
Wang C, Zhang R, Zhou L, et al. Intrauterine growth retardation promotes fetal intestinal autophagy in rats via the mechanistic target of rapamycin pathway. J Reprod Dev 2017; 63(6): 547-54.
[http://dx.doi.org/10.1262/jrd.2017-050] [PMID: 28855439]
[64]
Long B, Yin C, Fan Q, et al. Global Liver Proteome Analysis Using iTRAQ Reveals AMPK-mTOR-Autophagy Signaling Is Altered by Intrauterine Growth Restriction in Newborn Piglets. J Proteome Res 2016; 15(4): 1262-73.
[http://dx.doi.org/10.1021/acs.jproteome.6b00001] [PMID: 26967195]
[65]
Kuma A, Hatano M, Matsui M, et al. The role of autophagy during the early neonatal starvation period. Nature 2004; 432(7020): 1032-6.
[http://dx.doi.org/10.1038/nature03029] [PMID: 15525940]
[66]
Gong JS, Kim GJ. The role of autophagy in the placenta as a regulator of cell death. Clin Exp Reprod Med 2014; 41(3): 97-107.
[http://dx.doi.org/10.5653/cerm.2014.41.3.97] [PMID: 25309853]
[67]
Stewart T, Kallash M, Vehaskari VM, Hodgeson SM, Aviles DH. Increased Autophagy and Apoptosis in the Kidneys of Intrauterine Growth Restricted Rats. Fetal Pediatr Pathol 2019; 38(3): 185-94.
[http://dx.doi.org/10.1080/15513815.2018.1564160] [PMID: 30741571]
[68]
Zhu YH, Lin G, Dai ZL, et al. Developmental changes in polyamines and autophagic marker levels in normal and growth-restricted fetal pigs. J Anim Sci 2015; 93(7): 3503-11.
[http://dx.doi.org/10.2527/jas.2014-8743] [PMID: 26440019]
[69]
Tanida I, Ueno T, Kominami E. LC3 and Autophagy. Methods Mol Biol 2008; 445: 77-88.
[http://dx.doi.org/10.1007/978-1-59745-157-4_4] [PMID: 18425443]
[70]
Wirth M, Joachim J, Tooze SA. Autophagosome formation--the role of ULK1 and Beclin1-PI3KC3 complexes in setting the stage. Semin Cancer Biol 2013; 23(5): 301-9.
[http://dx.doi.org/10.1016/j.semcancer.2013.05.007] [PMID: 23727157]
[71]
Katsuragi Y, Ichimura Y, Komatsu M. p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. FEBS J 2015; 282(24): 4672-8.
[http://dx.doi.org/10.1111/febs.13540] [PMID: 26432171]
[72]
Zhang SH, Wu HM, Li S, Wang MZ, Fang L, Liu RY. Melatonin enhances autophagy and decreases apoptosis induced by nanosilica in RAW264.7 cells. IUBMB Life 2019; 71(7): 1021-9.
[http://dx.doi.org/10.1002/iub.2055] [PMID: 31018046]
[73]
Li H, Zhang Y, Liu S, et al. Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia. Stem Cells 2019; 37(4): 504-15.
[http://dx.doi.org/10.1002/stem.2968] [PMID: 30644149]

Rights & Permissions Print Cite
Article Metrics
20
1
© 2024 Bentham Science Publishers | Privacy Policy