Please wait a minute...
 Home  About the Journal Editorial Board Aims & Scope Peer Review Policy Subscription Contact us
Early Edition  //  Current Issue  //  Open Special Issues  //  Archives  //  Most Read  //  Most Downloaded  //  Most Cited
Aging and Disease    2017, Vol. 8 Issue (5) : 546-557     DOI: 10.14336/AD.2017.0110
Original Article |
Parity History Determines a Systemic Inflammatory Response to Spread of Ovarian Cancer in Naturally Aged Mice
Ulises Urzua1,4,5,*,Carlos Chacon1,Luis Lizama2,Sebastián Sarmiento1,Pía Villalobos1,Belén Kroxato1,Katherine Marcelain3,5,María-Julieta Gonzalez4
1Laboratorio de Genómica Aplicada, Facultad de Medicina, Universidad de Chile
2Programa de Virología, ICBM
3Programa de Genética Humana, ICBM
4Programa de Biología Celular y Molecular, ICBM
5Departamento de Oncología Básica y Clínica, Facultad de Medicina, Universidad de Chile, Santiago, Chile
Download: PDF(820 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks    

Aging intersects with reproductive senescence in women by promoting a systemic low-grade chronic inflammation that predisposes women to several diseases including ovarian cancer (OC). OC risk at menopause is significantly modified by parity records during prior fertile life. To date, the combined effects of age and parity on the systemic inflammation markers that are particularly relevant to OC initiation and progression at menopause remain largely unknown. Herein, we profiled a panel of circulating cytokines in multiparous versus virgin C57BL/6 female mice at peri-estropausal age and investigated how cytokine levels were modulated by intraperitoneal tumor induction in a syngeneic immunocompetent OC mouse model. Serum FSH, LH and TSH levels increased with age in both groups while prolactin (PRL) was lower in multiparous respect to virgin mice, a finding previously observed in parous women. Serum CCL2, IL-10, IL-5, IL-4, TNF-α, IL1-β and IL-12p70 levels increased with age irrespective of parity status, but were specifically reduced following OC tumor induction only in multiparous mice. Animals developed hemorrhagic ascites and tumor implants in the omental fat band and other intraperitoneal organs by 12 weeks after induction, with multiparous mice showing a significantly extended survival. We conclude that previous parity history counteracts aging-associated systemic inflammation possibly by reducing the immunosuppression that typically allows tumor spread. Results suggest a partial impairment of the M2 shift in tumor-associated macrophages as well as decreased stimulation of regulatory B-cells in aged mice. This long term, tumor-concurrent effect of parity on inflammation markers at menopause would be a contributing factor leading to decreased OC risk.

Keywords age      parity      ovarian cancer      menopause      cytokine      inflammation      mouse model     
Corresponding Authors: Ulises Urzua   
Just Accepted Date: 25 January 2017   Issue Date: 26 September 2017
E-mail this article
E-mail Alert
Articles by authors
Ulises Urzua
Carlos Chacon
Luis Lizama
Sebastián Sarmiento
Pía Villalobos
Belén Kroxato
Katherine Marcelain
María-Julieta Gonzalez
Cite this article:   
Ulises Urzua,Carlos Chacon,Luis Lizama, et al. Parity History Determines a Systemic Inflammatory Response to Spread of Ovarian Cancer in Naturally Aged Mice[J]. A&D, 2017, 8(5): 546-557.
URL:     OR
Figure 1.  Study design and parity records

(A) Two groups of C57BL6 female mice (n=70 per group) were maintained from 3-20 months old in virgin (nulliparous) or multiparous conditions. A smaller third group, composed of young adult 4 months old virgin mice (n=6), was used as reference controls in some assays. Multiparous mice were allowed to breastfeed their pups until 21-days old. Circulating cytokines and hormones were measured once per month in 3-4 distinct, randomly taken mice aged 15-19 months old. Tumor induction was initiated at 16 months old (n=8 per condition) with cytokines and hormones measured similarly. The age scale shown is not proportional. See Methods section for additional details. (B) Chart corresponds to the total number of litters as a function of age. (C) depicts the distribution of number of litters per individual mice over the reproductive period, both data-sets for the entire multiparous group.

Figure 2.  Circulating pituitary hormones in aged mice

Serum levels of the indicated hormones were measured monthly in 4 randomly chosen female mice 15-19 months old. The reference group, was 4 months old young adults (n=6) was. Bars represent mean with SEM corresponding to the above-mentioned time period. (*) p<0.05, (**) p<0.01, (***) p<0.005, (§) 0.05<p<0.10. Further details in Methods.

Figure 3.  Circulating cytokines in control and tumor-induced aged mice

Serum levels of the indicated cytokines were measured monthly from 15-19 months old in 3-4 randomly chosen female mice per group. Cytokines in the tumor-induced conditions (dashed bars, n=8 per group) were measured from the time of injection (16 months old) until time of death (19-19.5 months old). The young adult reference group (n=6) was 4 months old. Bars represent the mean with SEM corresponding to the above-mentioned time periods. (*) p<0.05, (**) p<0.01, (***) p<0.005, (§) 0.05<p<0.10. Further details in Methods.

Figure 4.  Tumor spread and survival of host aged mice

(A) Demonstrative image of intraperitoneal tumor implants formed in a 19 months-old virgin C57BL6 female mouse injected with MOSE cells. Tumor implants in the omental fat band are shown pulled-out with clamps. (B) Survival plots of virgin and multiparous aged mice injected with IG-10 MOSE cells; day 0 corresponds to 16.1 ± 0.3 months of age for the two groups. Median survivals were 98 and 87 days for the multiparous and virgin groups, respectively. The p value of log-rank (Mantel-Cox) is shown. Both the log-rank and the Gehan-Breslow-Wilcoxon (p=0.038) tests were performed in GraphPad Prism 5 with 95% CI of 0.7638-1.489 for ratios of survival.

[1] Franceschi C, Campisi J (2014). Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci, 69 (Suppl 1): S4-9
[2] Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013). The hallmarks of aging. Cell, 153: 1194-1217
[3] Abu-Taha M, Rius C, Hermenegildo C, Noguera I, Cerda-Nicolas JM, Issekutz AC, et al. (2009). Menopause and ovariectomy cause a low grade of systemic inflammation that may be prevented by chronic treatment with low doses of estrogen or losartan. J Immunol, 183: 1393-1402
[4] Benedusi V, Meda C, Della Torre S, Monteleone G, Vegeto E, Maggi A (2012). A lack of ovarian function increases neuroinflammation in aged mice. Endocrinology, 153: 2777-2788
[5] Cannon JG, Cortez-Cooper M, Meaders E, Stallings J, Haddow S, Kraj B, et al. (2010). Follicle-stimulating hormone, interleukin-1, and bone density in adult women. Am J Physiol Regul Integr Comp Physiol, 298: R790-798
[6] Lobo RA, Davis SR, De Villiers TJ, Gompel A, Henderson VW, Hodis HN, et al. (2014). Prevention of diseases after menopause. Climacteric, 17: 540-556
[7] Kim OY, Chae JS, Paik JK, Seo HS, Jang Y, Cavaillon JM, et al. (2012). Effects of aging and menopause on serum interleukin-6 levels and peripheral blood mononuclear cell cytokine production in healthy nonobese women. Age (Dordr), 34: 415-425
[8] Clendenen TV, Koenig KL, Arslan AA, Lukanova A, Berrino F, Gu Y, et al. (2011). Factors associated with inflammation markers, a cross-sectional analysis. Cytokine, 56: 769-778
[9] Malutan AM, Dan M, Nicolae C, Carmen M (2014). Proinflammatory and anti-inflammatory cytokine changes related to menopause. Prz Menopauzalny, 13: 162-168
[10] Yasui T, Maegawa M, Tomita J, Miyatani Y, Yamada M, Uemura H, et al. (2007). Changes in serum cytokine concentrations during the menopausal transition. Maturitas, 56: 396-403
[11] Vural P, Canbaz M, Akgul C (2006). Effects of menopause and postmenopausal tibolone treatment on plasma TNFalpha, IL-4, IL-10, IL-12 cytokine pattern and some bone turnover markers. Pharmacol Res, 53: 367-371
[12] Cioffi M, Esposito K, Vietri MT, Gazzerro P, D’Auria A, Ardovino I, et al. (2002). Cytokine pattern in postmenopause. Maturitas, 41: 187-192
[13] Deguchi K, Kamada M, Irahara M, Maegawa M, Yamamoto S, Ohmoto Y, et al. (2001). Postmenopausal changes in production of type 1 and type 2 cytokines and the effects of hormone replacement therapy. Menopause, 8: 266-273
[14] Tani A, Yasui T, Matsui S, Kato T, Kunimi K, Tsuchiya N, et al. (2013). Different circulating levels of monocyte chemoattractant protein-1 and interleukin-8 during the menopausal transition. Cytokine, 62: 86-90
[15] Ose J, Schock H, Tjonneland A, Hansen L, Overvad K, Dossus L, et al. (2015). Inflammatory Markers and Risk of Epithelial Ovarian Cancer by Tumor Subtypes: The EPIC Cohort. Cancer Epidemiol Biomarkers Prev, 24: 951-961
[16] Trabert B, Pinto L, Hartge P, Kemp T, Black A, Sherman ME, et al. (2014). Pre-diagnostic serum levels of inflammation markers and risk of ovarian cancer in the prostate, lung, colorectal and ovarian cancer (PLCO) screening trial. Gynecol Oncol, 135: 297-304
[17] Charbonneau B, Goode EL, Kalli KR, Knutson KL, Derycke MS (2013). The immune system in the pathogenesis of ovarian cancer. Crit Rev Immunol, 33: 137-164
[18] Aune G, Stunes AK, Lian AM, Reseland JE, Tingulstad S, Torp SH, et al. (2012). Circulating interleukin-8 and plasminogen activator inhibitor-1 are increased in women with ovarian carcinoma. Results Immunol, 2: 190-195
[19] Mertens-Walker I, Baxter RC, Marsh DJ (2012). Gonadotropin signalling in epithelial ovarian cancer. Cancer Lett, 324: 152-159
[20] Kass AS, Lea TE, Torjesen PA, Gulseth HC, Forre OT (2010). The association of luteinizing hormone and follicle-stimulating hormone with cytokines and markers of disease activity in rheumatoid arthritis: a case-control study. Scand J Rheumatol, 39: 109-117
[21] Tsilidis KK, Allen NE, Key TJ, Dossus L, Lukanova A, Bakken K, et al. (2011). Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European Prospective Investigation into Cancer and Nutrition. Br J Cancer, 105: 1436-1442
[22] Bodelon C, Wentzensen N, Schonfeld SJ, Visvanathan K, Hartge P, Park Y, et al. (2013). Hormonal risk factors and invasive epithelial ovarian cancer risk by parity. Br J Cancer, 109: 769-776
[23] Hunn J, Rodriguez GC (2012). Ovarian cancer: etiology, risk factors, and epidemiology. Clin Obstet Gynecol, 55: 3-23
[24] Murdoch WJ, Martinchick JF (2004). Oxidative damage to DNA of ovarian surface epithelial cells affected by ovulation: carcinogenic implication and chemoprevention. Exp Biol Med (Maywood), 229: 546-552
[25] Syed V, Ho SM (2003). Progesterone-induced apoptosis in immortalized normal and malignant human ovarian surface epithelial cells involves enhanced expression of FasL. Oncogene, 22: 6883-6890
[26] Diep CH, Charles NJ, Gilks CB, Kalloger SE, Argenta PA, Lange CA (2013). Progesterone receptors induce FOXO1-dependent senescence in ovarian cancer cells. Cell Cycle, 12: 1433-1449
[27] Fleming JS, McQuillan HJ, Millier MJ, Beaugie CR, Livingstone V (2007). E-cadherin expression and bromodeoxyuridine incorporation during development of ovarian inclusion cysts in age-matched breeder and incessantly ovulated CD-1 mice. Reprod Biol Endocrinol, 5: 14
[28] Caligioni CS (2009). Assessing reproductive status/stages in mice. Curr Protoc Neurosci, Appendix 4: Appendix 4I
[29] Golde WT, Gollobin P, Rodriguez LL (2005). A rapid, simple, and humane method for submandibular bleeding of mice using a lancet. Lab Anim (NY), 34: 39-43
[30] Roby KF, Taylor CC, Sweetwood JP, Cheng Y, Pace JL, Tawfik O, et al. (2000). Development of a syngeneic mouse model for events related to ovarian cancer. Carcinogenesis, 21: 585-591
[31] Morton DB, Griffiths PH (1985). Guidelines on the recognition of pain, distress and discomfort in experimental animals and an hypothesis for assessment. Vet Rec, 116: 431-436
[32] Martinez de Toda I, Mate I, Vida C, Cruces J, De la Fuente M (2016). Immune function parameters as markers of biological age and predictors of longevity. Aging (Albany NY), 8: 3110-3119
[33] Finch CE (2014). The menopause and aging, a comparative perspective. J Steroid Biochem Mol Biol, 142: 132-141
[34] Clendenen TV, Arslan AA, Lokshin AE, Liu M, Lundin E, Koenig KL, et al. (2013). Circulating prolactin levels and risk of epithelial ovarian cancer. Cancer Causes Control, 24: 741-748
[35] Ben-Jonathan N, LaPensee CR, LaPensee EW (2008). What can we learn from rodents about prolactin in humans?. Endocr Rev, 29: 1-41
[36] Musey VC, Collins DC, Musey PI, Martino-Saltzman D, Preedy JR (1987). Long-term effect of a first pregnancy on the secretion of prolactin. N Engl J Med, 316: 229-234
[37] Carvalho-Freitas MI, Anselmo-Franci JA, Palermo-Neto J, Felicio LF (2013). Prior reproductive experience alters prolactin-induced macrophage responses in pregnant rats. J Reprod Immunol, 99: 54-61
[38] Tripathi A, Sodhi A (2007). Production of nitric oxide by murine peritoneal macrophages in vitro on treatment with prolactin and growth hormone: involvement of protein tyrosine kinases, Ca(++), and MAP kinase signal transduction pathways. Mol Immunol, 44: 3185-3194
[39] Shelly S, Boaz M, Orbach H (2012). Prolactin and autoimmunity. Autoimmun Rev, 11: A465-470
[40] Chen KH, Walker AM (2016). Prolactin inhibits a major tumor-suppressive function of wild type BRCA1. Cancer Lett, 375: 293-302
[41] Hennessey JV, Espaillat R (2015). Diagnosis and Management of Subclinical Hypothyroidism in Elderly Adults: A Review of the Literature. J Am Geriatr Soc, 63: 1663-1673
[42] Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al. (2002). Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab, 87: 489-499
[43] Geng H, Zhang X, Wang C, Zhao M, Yu C, Zhang B, et al. (2015). Even mildly elevated TSH is associated with an atherogenic lipid profile in postmenopausal women with subclinical hypothyroidism. Endocr Res, 40: 1-7
[44] Thibault B, Castells M, Delord JP, Couderc B (2014). Ovarian cancer microenvironment: implications for cancer dissemination and chemoresistance acquisition. Cancer Metastasis Rev, 33: 17-39
[45] Nio-Kobayashi J, Kudo M, Sakuragi N, Kimura S, Iwanaga T, Duncan WC (2015). Regulated C-C motif ligand 2 (CCL2) in luteal cells contributes to macrophage infiltration into the human corpus luteum during luteolysis. Mol Hum Reprod, 21: 645-654
[46] Cohen CA, Shea AA, Heffron CL, Schmelz EM, Roberts PC (2013). The parity-associated microenvironmental niche in the omental fat band is refractory to ovarian cancer metastasis. Cancer Prev Res (Phila), 6: 1182-1193
[47] Grandi G, Mueller M, Bersinger N, Papadia A, Nirgianakis K, Cagnacci A, et al. (2016). Progestin suppressed inflammation and cell viability of tumor necrosis factor-alpha-stimulated endometriotic stromal cells. Am J Reprod Immunol, 76: 292-298
[48] Remus EW, Sayeed I, Won S, Lyle AN, Stein DG (2015). Progesterone protects endothelial cells after cerebrovascular occlusion by decreasing MCP-1- and CXCL1-mediated macrophage infiltration. Exp Neurol, 271: 401-408
[49] Mikula-Pietrasik J, Uruski P, Szubert S, Moszynski R, Szpurek D, Sajdak S, et al. (2016). Biochemical composition of malignant ascites determines high aggressiveness of undifferentiated ovarian tumors. Med Oncol, 33: 94
[50] Mahbub S, Deburghgraeve CR, Kovacs EJ (2012). Advanced age impairs macrophage polarization. J Interferon Cytokine Res, 32: 18-26
[51] Mansfield AS, Nevala WK, Dronca RS, Leontovich AA, Shuster L, Markovic SN (2012). Normal aging is associated with an increase in Th2 cells, MCP-1 (CCL1) and RANTES (CCL5), with differences in sCD40L and PDGF-AA between sexes. Clin Exp Immunol, 170: 186-193
[52] Challis JR, Lockwood CJ, Myatt L, Norman JE, Strauss JF3rd, Petraglia F (2009). Inflammation and pregnancy. Reprod Sci, 16: 206-215
[53] Sica A, Mantovani A (2012). Macrophage plasticity and polarization: in vivo veritas. J Clin Invest, 122: 787-795
[54] Deng X, Zhang P, Liang T, Deng S, Chen X, Zhu L (2015). Ovarian cancer stem cells induce the M2 polarization of macrophages through the PPARgamma and NF-kappaB pathways. Int J Mol Med, 36: 449-454
[55] Schumacher A, Costa SD, Zenclussen AC (2014). Endocrine factors modulating immune responses in pregnancy. Front Immunol, 5: 196
[56] Lissauer D, Eldershaw SA, Inman CF, Coomarasamy A, Moss PA, Kilby MD (2015). Progesterone promotes maternal-fetal tolerance by reducing human maternal T-cell polyfunctionality and inducing a specific cytokine profile. Eur J Immunol, 45: 2858-2872
[57] Muzzio DO, Soldati R, Ehrhardt J, Utpatel K, Evert M, Zenclussen AC, et al. (2014). B cell development undergoes profound modifications and adaptations during pregnancy in mice. Biol Reprod, 91: 115
[58] Bommer I, Muzzio DO, Zygmunt M, Jensen F (2016). Progesterone and estradiol exert an inhibitory effect on the production of anti-inflammatory cytokine IL-10 by activated MZ B cells. J Reprod Immunol, 116: 113-116
[59] Schwartz M, Zhang Y, Rosenblatt JD (2016). B cell regulation of the anti-tumor response and role in carcinogenesis. J Immunother Cancer, 4: 40
[60] Wei X, Jin Y, Tian Y, Zhang H, Wu J, Lu W, et al. (2016). Regulatory B cells contribute to the impaired antitumor immunity in ovarian cancer patients. Tumour Biol, 37: 6581-6588
[61] Kioi M, Takahashi S, Kawakami M, Kawakami K, Kreitman RJ, Puri RK (2005). Expression and targeting of interleukin-4 receptor for primary and advanced ovarian cancer therapy. Cancer Res, 65: 8388-8396
[62] Michaud M, Balardy L, Moulis G, Gaudin C, Peyrot C, Vellas B, et al. (2013). Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc, 14: 877-882
[63] Bradley JR (2008). TNF-mediated inflammatory disease. J Pathol, 214: 149-160
[64] Gupta M, Babic A, Beck AH, Terry K (2016). TNF-alpha expression, risk factors, and inflammatory exposures in ovarian cancer: evidence for an inflammatory pathway of ovarian carcinogenesis?. Hum Pathol, 54: 82-91
[65] Kolomeyevskaya N, Eng KH, Khan AN, Grzankowski KS, Singel KL, Moysich K, et al. (2015). Cytokine profiling of ascites at primary surgery identifies an interaction of tumor necrosis factor-alpha and interleukin-6 in predicting reduced progression-free survival in epithelial ovarian cancer. Gynecol Oncol, 138: 352-357
[66] Kulbe H, Thompson R, Wilson JL, Robinson S, Hagemann T, Fatah R, et al. (2007). The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells. Cancer Res, 67: 585-592
[67] Garlanda C, Dinarello CA, Mantovani A (2013). The interleukin-1 family: back to the future. Immunity, 39: 1003-1018
[68] Gerard N, Caillaud M, Martoriati A, Goudet G, Lalmanach AC (2004). The interleukin-1 system and female reproduction. J Endocrinol, 180: 203-212
[69] Song X, Voronov E, Dvorkin T, Fima E, Cagnano E, Benharroch D, et al. (2003). Differential effects of IL-1 alpha and IL-1 beta on tumorigenicity patterns and invasiveness. J Immunol, 171: 6448-6456
[70] Sun L, Peng Y, Sharrow AC, Iqbal J, Zhang Z, Papachristou DJ, et al. (2006). FSH directly regulates bone mass. Cell, 125: 247-260
[71] Stilley JA, Christensen DE, Dahlem KB, Guan R, Santillan DA, England SK, et al. (2014). FSH receptor (FSHR) expression in human extragonadal reproductive tissues and the developing placenta, and the impact of its deletion on pregnancy in mice. Biol Reprod, 91: 74
[72] Gartrell BA, Tsao CK, Galsky MD (2013). The follicle-stimulating hormone receptor: a novel target in genitourinary malignancies. Urol Oncol, 31: 1403-1407
[73] Zheng H, Ban Y, Wei F, Ma X (2016). Regulation of Interleukin-12 Production in Antigen-Presenting Cells. Adv Exp Med Biol, 941: 117-138
[74] Watkins SK, Egilmez NK, Suttles J, Stout RD (2007). IL-12 rapidly alters the functional profile of tumor-associated and tumor-infiltrating macrophages in vitro and in vivo. J Immunol, 178: 1357-1362
[75] Cohen CA, Shea AA, Heffron CL, Schmelz EM, Roberts PC (2016). Interleukin-12 Immunomodulation Delays the Onset of Lethal Peritoneal Disease of Ovarian Cancer. J Interferon Cytokine Res, 36: 62-73
[76] Hernandez-Alcoceba R, Poutou J, Ballesteros-Briones MC, Smerdou C (2016). Gene therapy approaches against cancer using in vivo and ex vivo gene transfer of interleukin-12. Immunotherapy, 8: 179-198
[77] Liu M, Guo S, Stiles JK (2011). The emerging role of CXCL10 in cancer (Review). Oncol Lett, 2: 583-589
[78] Campisi J, Andersen JK, Kapahi P, Melov S (2011). Cellular senescence: a link between cancer and age-related degenerative disease?. Semin Cancer Biol, 21: 354-359
[79] Asano Y (2012). Age-related accumulation of non-heme ferric and ferrous iron in mouse ovarian stroma visualized by sensitive non-heme iron histochemistry. J Histochem Cytochem, 60: 229-242
[80] Briley SM, Jasti S, McCracken JM, Hornick JE, Fegley B, Pritchard MT, et al. (2016). Reproductive age-associated fibrosis in the stroma of the mammalian ovary. Reproduction, 152: 245-260
[1] Yiwei Cao,Rui-Hong Wang. Associations among Metabolism, Circadian Rhythm and Age-Associated Diseases[J]. A&D, 2017, 8(3): 314-333.
[2] Mohammed Hussain,Neil Datta,Zhe Cheng,David Dornbos,Asif Bashir,Ibrahim Sultan,Tapan Mehta,Faris Shweikeh,Paul Mazaris,Nora Lee,Amre Nouh,Xiaokun Geng,Yuchuan Ding. Spanning from the West to East: An Updated Review on Endovascular Treatment of Intracranial Atherosclerotic Disease[J]. A&D, 2017, 8(2): 196-202.
[3] Zohara Sternberg,Zihua Hu,Daniel Sternberg,Shayan Waseh,Joseph F. Quinn,Katharine Wild,Kaye Jeffrey,Lin Zhao,Michael Garrick. Serum Hepcidin Levels, Iron Dyshomeostasis and Cognitive Loss in Alzheimer’s Disease[J]. A&D, 2017, 8(2): 215-227.
[4] Ruijun Su,Min Sun,Wei Wang,Jianliang Zhang,Li Zhang,Junli Zhen,Yanjing Qian,Yan Zheng,Xiaomin Wang. A Novel Immunosuppressor, (5R)-5-Hydroxytriptolide, Alleviates Movement Disorder and Neuroinflammation in a 6-OHDA Hemiparkinsonian Rat Model[J]. A&D, 2017, 8(1): 31-43.
[5] Taisia Rolova,Hiramani Dhungana,Paula Korhonen,Piia Valonen,Natalia Kolosowska,Henna Konttinen,Katja Kanninen,Heikki Tanila,Tarja Malm,Jari Koistinaho. Deletion of Nuclear Factor kappa B p50 Subunit Decreases Inflammatory Response and Mildly Protects Neurons from Transient Forebrain Ischemia-induced Damage[J]. A&D, 2016, 7(4): 450-465.
[6] Xin Fu,QiuHong Wang,ZhiBin Wang,HaiXue Kuang,Pinghui Jiang. Danggui-Shaoyao-San: New Hope for Alzheimer's Disease[J]. A&D, 2016, 7(4): 502-513.
[7] Liwei Ma,Hongjun Wang,Chunyan Wang,Jing Su,Qi Xie,Lu Xu,Yang Yu,Shibing Liu,Songyan Li,Ye Xu,Zhixin Li. Failure of Elevating Calcium Induces Oxidative Stress Tolerance and Imparts Cisplatin Resistance in Ovarian Cancer Cells[J]. A&D, 2016, 7(3): 254-266.
[8] Isaac G. Onyango,Jameel Dennis,Shaharyah M. Khan. Mitochondrial Dysfunction in Alzheimer’s Disease and the Rationale for Bioenergetics Based Therapies[J]. A&D, 2016, 7(2): 201-214.
[9] Xavier Castellon,Vera Bogdanova. Chronic Inflammatory Diseases and Endothelial Dysfunction[J]. A&D, 2016, 7(1): 81-89.
[10] Chandrasekharam N. Nagineni,Vijay K. Kommineni,Nader Ganjbaksh,Krishnasai K. Nagineni,John J. Hooks,Barbara Detrick. Inflammatory Cytokines Induce Expression of Chemokines by Human Retinal Cells: Role in Chemokine Receptor Mediated Age-related Macular Degeneration[J]. A&D, 2015, 6(6): 444-455.
[11] Juliana B. Hoppe,Christianne G. Salbego,Helena Cimarosti. SUMOylation: Novel Neuroprotective Approach for Alzheimer’s Disease?[J]. A&D, 2015, 6(5): 322-330.
[12] Tatiana Barichello,Jaqueline S. Generoso,Jessica A. Goularte,Allan Collodel,Meagan R. Pitcher,Lutiana R. Simões,João Quevedo,Felipe Dal-Pizzol. Does Infection-Induced Immune Activation Contribute to Dementia?[J]. A&D, 2015, 6(5): 342-348.
[13] Amandine E. Bonnet,Yannick Marchalant. Potential Therapeutical Contributions of the Endocannabinoid System towards Aging and Alzheimer’s Disease[J]. A&D, 2015, 6(5): 400-405.
[14] Ahmed H Abdelhafiz,Leocadio Rodríguez-Mañas,John E. Morley,Alan J Sinclair. Hypoglycemia in Older People - A Less Well Recognized Risk Factor for Frailty[J]. A&D, 2015, 6(2): 156-167.
[15] Costa Elísio,Fernandes João,Ribeiro Sandra,Sereno José,Garrido Patrícia,Rocha-Pereira Petronila,Coimbra Susana,Catarino Cristina,Belo Luís,Bronze-da-Rocha Elsa,Vala Helena,Alves Rui,Reis Flávio,Santos-Silva Alice. Aging is Associated with Impaired Renal Function, INF-gamma Induced Inflammation and with Alterations in Iron Regulatory Proteins Gene Expression[J]. Aging and Disease, 2014, 5(6): 356-365.
Full text



Copyright © 2014 Aging and Disease, All Rights Reserved.
Address: Aging and Disease Editorial Office 3400 Camp Bowie Boulevard Fort Worth, TX76106 USA
Fax: (817) 735-0408 E-mail:
Powered by Beijing Magtech Co. Ltd