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題名 發炎環境對粒線體功能及神經細胞活動影響之研究
The study of the effects of inflammatory milieu on mitochondrial function and neural activities
作者 林有上
Lim, Yeou-San
貢獻者 陳紹寬
Chen, Shau-Kwaun
林有上
Lim, Yeou-San
關鍵詞 下視丘
慢性發炎
POMC神經元
粒線體
脂多醣
干擾素-α
Inflammation
Hypothalamic POMC neuron
Mitochondrial morphology
Lipopolysaccharide
IFN-α
日期 2022
上傳時間 2-Sep-2022 15:06:24 (UTC+8)
摘要 發炎是當病原體入侵和組織損傷時所反應出的急性保護性反應以幫助生理系統恢復正常狀態。發炎可分為急性和慢性發炎，兩種發炎模式都有各自應對發炎的免疫功能和機制。急性發炎可保護個個體引發對抗外來病原體所必需的炎症反應，但長期慢性發炎所產生的炎症反應則會損害個體產生各種疾病問題。因此發炎是目前在已知的研究中被認為與許多神經系統疾病有間接或直接相關的成因之一。許多研究發現周邊系統的發炎會影響大腦中樞系統進而改變生理功能或其行為模式。目前研究多數在於研究周邊系統的發炎，但大腦中樞系統和大腦神經細胞處在發炎環境下所產生的改變尚未釐清。大腦下視丘弓狀核 (ARC)神經元群中的POMC/CART神經元調節著食慾，睡眠，代謝達到能量平衡等關鍵生理功能。下視丘發炎也是周邊發炎影響到大腦中樞神經系統的首要影響核區。促發炎細胞因子能夠通過血腦屏障進入下視丘中並活化小膠質細胞引發下視丘炎症。本研究旨在探討兩種不同因子造成的的不同發炎環境對POMC神經元中的粒線體的變化及POMC神經元活動的影響。本研究分為兩種不同的促發炎因子兩大部分。第一大部分探討第一種促發炎因子-脂多醣 (lipopolysaccharides) 刺激單核細胞系(monocytic lineage cells)對mHypo-POMC/GPF1神經元處在短期急性或長期慢性發炎環境下的粒線體功能及神經細胞活動之變化。 實驗結果發現POMC神經元在脂多醣的長期慢性發炎環境下導致粒線體出現型態上的變化，包括呈長條狀及出現空洞破壞等型態異變， 以及細胞內的ROS/RNS水平有上升趨勢，SOD1抗氧化酶基因和 GPX4 穀胱甘肽過氧化物酶基因的抗氧化酶的表達下降與 ROS/RNS 上升的結果是同步的。此外，也證實了在長期慢性發炎環境下會誘發黑皮質素（α-MSH）神經免疫調節肽的表現量增加。而在短期急性發炎環境下會導致MFN2 線粒體融合基因顯著下降。但脂多醣並未顯著影響POMC神經元細胞活動。另外我們透過腹腔注射脂多醣來誘導小鼠出現類疾病行為 (sickness behavior)，包括顯著增加小鼠體內的細胞因子和其食慾進食量減少，同時刺激下視丘的c-fos表現。第二大部分探討第二種促發炎因子-干擾素-α (IFN-α)。IFN-α在臨床上常被用於治療自體免疫疾病，病毒性疾病和癌症。然而長期使用IFN-α的治療患者會出現憂鬱症症狀。由於IFN-α也是另一類的促發炎因子和免疫調節因子，並且憂鬱症的症狀與大腦下視丘功能相呼應，如睡眠障礙，食慾降低或增加，疲憊等。因此IFN-α可用於探討在短期急性或長期慢性發炎環境下對下視丘POMC神經元之粒線體功能及神經細胞活動的影響。實驗結果發現IFN-α慢性長期發炎在POMC神經元上會活化STAT1傳遞訊號並促進SOCS1的表現。胰島素是POMC神經元調節代謝功能時的重要調節訊號。IFN-α逆轉了胰島素抑制細胞因子信號抑制因子3 (SOCS3)的表現。SOCS3 可以與胰島素受體結合調節胰島素敏感性，說明在IFN-α的作用下會增加胰島素敏感性。另外，過去研究發現POMC神經元在瘦素和胰島素的作用下會誘發神經活動，在本實驗中發現胰島素POMC神經元激活了神經活動(c-fos)之表現，但在IFN-α的刺激下胰島素卻顯著降低了神經活動。此外在IFN-α長期刺激下POMC神經元粒線體也產生型態上的變化，而且也觀察到POMC細胞內自噬過程，但尚未了解IFN-α對於神經細胞啟動自噬過程的相關機制，後續仍有待進一步研究。IFN-α的腹腔注射也證實誘導出小鼠出現類憂鬱行為，包括強迫游泳及懸尾僵直行為顯著增加。總而言之，本實驗結果顯示在兩種不同的發炎環境下，對下視丘POMC神經元中的粒線體和神經活動都有各別影響，而其中有幾個重要發現問題仍有待進一步研究探討及解決。
Inflammation is the biological response of the immune system to protect the body from the harms mediated by foreign pathogen infection or damaged tissues. Inflammation can be either acute or chronic, both have their own immune responses and underlying mechanisms. Acute inflammation protects our body by eliciting the inflammatory responses necessary to fight foreign pathogens. In contrast, chronic inflammation generates long-lasting inflammation responses and caused various chronic diseases, including cardiovascular and bowel diseases, diabetes, and cancer. Mounting studies have demonstrated that peripheral inflammation affects central nervous system and alters physiological functions or behavioral phenotypes. Peripheral inflammatory cytokines directly or indirectly affect the brain and activate microglia to trigger hypothalamic inflammation. POMC neurons is the neuronal population located in hypothalamic arcuate nucleus (ARC) with regulating several essential physiological functions such as appetite, sleep, glucose metabolism and energy homeostasis. In this study, we aim to investigate how pro-inflammatory milieu or cytokines influence mitochondrial function and neuronal activities in hypothalamic POMC neurons. We compared neuronal alterations induced by two different types of pro-inflammatory stimuli. In the first part, mHypoA-POMC/GFP1 cells were treated with the conditioned medium collected from LPS-activated macrophage to mimic the inflammatory milieu during hypothalamic inflammation. Our in vivo data showed that POMC neurons exposed in CMLPS-chronic inflammation milieu led to morphological changes in mitochondrial elongation. Further, the intracellular ROS/RNS levels were elevated. The reduced expression of antioxidant enzymes was synchronized with ROS/RNS levels upregulation, such as Sod1 and Gpx4 genes during chronic inflammation. In vivo studies found that after intraperitoneal injection of lipopolysaccharide significantly increased cytokines and decreased appetite in mice. The expression of c-fos was also elevated in the hypothalamus, suggesting that neuronal activities were increased. The second type of inflammatory condition is chronic administration of interferon-alpha (IFN-α). IFN-α is often used clinically to treat autoimmune diseases, viral diseases, and cancer. However, chronic administration of IFN-α also cause neurological side effects such as depression. Therefore, chronic administration of IFN-α was employed as an alternative model to investigate the
effects of chronic inflammation on mitochondrial functions and neuronal activities of hypothalamic POMC neurons. In vitro experimental results found that IFN-α activates STAT1 expression in POMC neurons. IFN-α also disrupt insulin signaling, which is a crucial regulatory signal for the metabolism-regulatory functions in POMC neurons. IFN-α treatment reversed the expression of suppressed cytokine signaling inhibitor 3 (SOCS3). Also, IFN-α significantly reduced the neural activity activated by insulin. Additionally, IFN-α-induced chronic inflammation initiated mitochondrial changes and autophagy-like alterations in POMC neurons, and need more observatory time points are necessary to further understand the autophagic status. Intraperitoneal injection of IFN-α also confirmed the induction of depression-like behaviors in mice, including significant increase in forced swimming test and tail suspension test. In summary, these two different pro-inflammatory environments get different alterations on mitochondrial and neural activity in hypothalamic POMC neurons, and several questions remain to be further exploring by more experiments.
參考文獻 Alexander WS, Starr R, Fenner JE, Scott CL, Handman E, Sprigg NS, Corbin JE, Cornish AL, Darwiche R, Owczarek CM, Kay TW, Nicola NA, Hertzog PJ, Metcalf D, Hilton DJ (1999) SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 98:597-608.
Baker RG, Hayden MS, Ghosh S (2011) NF-κB, inflammation, and metabolic disease. Cell Metab 13:11-22.
Balthasar N, Coppari R, McMinn J, Liu SM, Lee CE, Tang V, Kenny CD, McGovern RA, Chua SC, Jr., Elmquist JK, Lowell BB (2004) Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42:983-991.
Banks WA (2005) Blood-brain barrier transport of cytokines: a mechanism for neuropathology. Curr Pharm Des 11:973-984.
Banks WA, Kastin AJ (1991) Blood to brain transport of interleukin links the immune and central nervous systems. Life Sci 48:Pl117-121.
Banks WA, Kastin AJ, Gutierrez EG (1994) Penetration of interleukin-6 across the murine blood-brain barrier. Neurosci Lett 179:53-56.
Benoit SC, Air EL, Coolen LM, Strauss R, Jackman A, Clegg DJ, Seeley RJ, Woods SC (2002) The catabolic action of insulin in the brain is mediated by melanocortins. J Neurosci 22:9048-9052.
Bode JG, Ludwig S, Ehrhardt C, Albrecht U, Erhardt A, Schaper F, Heinrich PC, Häussinger D (2003) IFN-alpha antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling-3. Faseb j 17:488-490.
Borges BC, Garcia-Galiano D, Rorato R, Elias LLK, Elias CF (2016) PI3K p110β subunit in leptin receptor expressing cells is required for the acute hypophagia induced by endotoxemia. Mol Metab 5:379-391.
Bouret SG, Simerly RB (2004) Minireview: Leptin and Development of Hypothalamic Feeding Circuits. Endocrinology 145:2621-2626.
Brzózka K, Pfaller C, Conzelmann KK (2007) Signal transduction in the type I interferon system and viral countermeasures. Signal Transduct 7:5-19.
Bulua AC, Simon A, Maddipati R, Pelletier M, Park H, Kim KY, Sack MN, Kastner DL, Siegel RM (2011) Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med 208:519-533.
Carow B, Rottenberg ME (2014) SOCS3, a Major Regulator of Infection and Inflammation. Front Immunol 5:58.
Chaban Y, Boekema EJ, Dudkina NV (2014) Structures of mitochondrial oxidative phosphorylation supercomplexes and mechanisms for their stabilisation. Biochim Biophys Acta 1837:418-426.
Chen H, Chan DC (2009) Mitochondrial dynamics--fusion, fission, movement, and mitophagy--in neurodegenerative diseases. Hum Mol Genet 18:R169-176.
Chen H, Chan DC (2010) Physiological functions of mitochondrial fusion. Ann N Y Acad Sci 1201:21-25.
Chen XH, Zhao YP, Xue M, Ji CB, Gao CL, Zhu JG, Qin DN, Kou CZ, Qin XH, Tong ML, Guo XR (2010) TNF-alpha induces mitochondrial dysfunction in 3T3-L1 adipocytes. Mol Cell Endocrinol 328:63-69.
Chitnis T, Weiner HL (2017) CNS inflammation and neurodegeneration. J Clin Invest 127:3577-3587.
Cogliati S, Frezza C, Soriano ME, Varanita T, Quintana-Cabrera R, Corrado M, Cipolat S, Costa V, Casarin A, Gomes LC, Perales-Clemente E, Salviati L, Fernandez-Silva P, Enriquez JA, Scorrano L (2013) Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell 155:160-171.
Cone RD, Cowley MA, Butler AA, Fan W, Marks DL, Low MJ (2001) The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis. Int J Obes Relat Metab Disord 25 Suppl 5:S63-67.
Coupé B, Ishii Y, Dietrich MO, Komatsu M, Horvath TL, Bouret SG (2012) Loss of autophagy in pro-opiomelanocortin neurons perturbs axon growth and causes metabolic dysregulation. Cell Metab 15:247-255.
Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S, Horvath TL, Cone RD, Low MJ (2001) Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411:480-484.
Dantzer R, O`Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46-56.
De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, Saad MJ, Velloso LA (2005) Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146:4192-4199.
Degan D, Ornello R, Tiseo C, Carolei A, Sacco S, Pistoia F (2018) The Role of Inflammation in Neurological Disorders. Curr Pharm Des 24:1485-1501.
Degtyarev M, De Mazière A, Orr C, Lin J, Lee BB, Tien JY, Prior WW, van Dijk S, Wu H, Gray DC, Davis DP, Stern HM, Murray LJ, Hoeflich KP, Klumperman J, Friedman LS, Lin K (2008) Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents. J Cell Biol 183:101-116.
Dietrich MO, Liu ZW, Horvath TL (2013) Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity. Cell 155:188-199.
Elias CF, Aschkenasi C, Lee C, Kelly J, Ahima RS, Bjorbaek C, Flier JS, Saper CB, Elmquist JK (1999) Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23:775-786.
Ellacott KL, Cone RD (2006) The role of the central melanocortin system in the regulation of food intake and energy homeostasis: lessons from mouse models. Philos Trans R Soc Lond B Biol Sci 361:1265-1274.
Fenner JE, Starr R, Cornish AL, Zhang JG, Metcalf D, Schreiber RD, Sheehan K, Hilton DJ, Alexander WS, Hertzog PJ (2006) Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity. Nat Immunol 7:33-39.
Fensterl V, Sen GC (2009) Interferons and viral infections. Biofactors 35:14-20.
Fernández-Sánchez A, Madrigal-Santillán E, Bautista M, Esquivel-Soto J, Morales-González A, Esquivel-Chirino C, Durante-Montiel I, Sánchez-Rivera G, Valadez-Vega C, Morales-González JA (2011) Inflammation, oxidative stress, and obesity. Int J Mol Sci 12:3117-3132.
Frenois F, Moreau M, O`Connor J, Lawson M, Micon C, Lestage J, Kelley KW, Dantzer R, Castanon N (2007) Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior. Psychoneuroendocrinology 32:516-531.
Fukuda M, Jones JE, Olson D, Hill J, Lee CE, Gautron L, Choi M, Zigman JM, Lowell BB, Elmquist JK (2008) Monitoring FoxO1 localization in chemically identified neurons. J Neurosci 28:13640-13648.
Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, Ferrucci L, Gilroy DW, Fasano A, Miller GW, Miller AH, Mantovani A, Weyand CM, Barzilai N, Goronzy JJ, Rando TA, Effros RB, Lucia A, Kleinstreuer N, Slavich GM (2019) Chronic inflammation in the etiology of disease across the life span. Nature Medicine 25:1822-1832.
Goubau D, Deddouche S, Reis e Sousa C (2013) Cytosolic sensing of viruses. Immunity 38:855-869.
Gu W, Cui R, Ding T, Li X, Peng J, Xu W, Han F, Guo X (2017) Simvastatin alleviates airway inflammation and remodelling through up-regulation of autophagy in mouse models of asthma. Respirology 22:533-541.
Gutierrez EG, Banks WA, Kastin AJ (1993) Murine tumor necrosis factor alpha is transported from blood to brain in the mouse. J Neuroimmunol 47:169-176.
Hahn WS, Kuzmicic J, Burrill JS, Donoghue MA, Foncea R, Jensen MD, Lavandero S, Arriaga EA, Bernlohr DA (2014) Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics. Am J Physiol Endocrinol Metab 306:E1033-1045.
Hannigan GE, Williams BR (1992) Interferon-alpha activates binding of nuclear factors to a sequence element in the c-fos proto-oncogene 5`-flanking region. J Interferon Res 12:355-361.
Hart BL (1988) Biological basis of the behavior of sick animals. Neurosci Biobehav Rev 12:123-137.
Hayden MS, West AP, Ghosh S (2006) NF-κB and the immune response. Oncogene 25:6758-6780.
Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, Sheridan JF, Godbout JP (2008) Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation 5:15.
Hill JW, Elias CF, Fukuda M, Williams KW, Berglund ED, Holland WL, Cho YR, Chuang JC, Xu Y, Choi M, Lauzon D, Lee CE, Coppari R, Richardson JA, Zigman JM, Chua S, Scherer PE, Lowell BB, Brüning JC, Elmquist JK (2010) Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab 11:286-297.
Hopkins SJ, Rothwell NJ (1995) Cytokines and the nervous system. I: Expression and recognition. Trends Neurosci 18:83-88.
Hoppins S, Lackner L, Nunnari J (2007) The machines that divide and fuse mitochondria. Annu Rev Biochem 76:751-780.
Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860-867.
Howard JK, Flier JS (2006) Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol Metab 17:365-371.
Iwasa T, Matsuzaki T, Kinouchi R, Fujisawa S, Murakami M, Kiyokawa M, Kuwahara A, Yasui T, Irahara M (2010) Neonatal LPS injection alters the body weight regulation systems of rats under non-stress and immune stress conditions. Int J Dev Neurosci 28:119-124.
Iwasaki A, Medzhitov R (2015) Control of adaptive immunity by the innate immune system. Nat Immunol 16:343-353.
Jaeger LB, Dohgu S, Sultana R, Lynch JL, Owen JB, Erickson MA, Shah GN, Price TO, Fleegal-Demotta MA, Butterfield DA, Banks WA (2009) Lipopolysaccharide alters the blood-brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer`s disease. Brain Behav Immun 23:507-517.
Jais A, Brüning JC (2017) Hypothalamic inflammation in obesity and metabolic disease. J Clin Invest 127:24-32.
Jeon SW, Yoon HK, Kim YK (2019) Role of Inflammation in Psychiatric Disorders. Adv Exp Med Biol 1192:491-501.
Jung CH, Kim MS (2013) Molecular mechanisms of central leptin resistance in obesity. Arch Pharm Res 36:201-207.
Kaushik S, Arias E, Kwon H, Lopez NM, Athonvarangkul D, Sahu S, Schwartz GJ, Pessin JE, Singh R (2012) Loss of autophagy in hypothalamic POMC neurons impairs lipolysis. EMBO Rep 13:258-265.
Kazi JU, Kabir NN, Flores-Morales A, Rönnstrand L (2014) SOCS proteins in regulation of receptor tyrosine kinase signaling. Cell Mol Life Sci 71:3297-3310.
Kent S, Bluthé RM, Kelley KW, Dantzer R (1992) Sickness behavior as a new target for drug development. Trends Pharmacol Sci 13:24-28.
Khacho M, Slack RS (2018) Mitochondrial dynamics in the regulation of neurogenesis: From development to the adult brain. Dev Dyn 247:47-53.
Klionsky DJ (2007) Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8:931-937.
Könner AC, Janoschek R, Plum L, Jordan SD, Rother E, Ma X, Xu C, Enriori P, Hampel B, Barsh GS, Kahn CR, Cowley MA, Ashcroft FM, Brüning JC (2007) Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab 5:438-449.
Kowaltowski AJ, de Souza-Pinto NC, Castilho RF, Vercesi AE (2009) Mitochondria and reactive oxygen species. Free Radic Biol Med 47:333-343.
Krishnadas R, Cavanagh J (2012) Depression: an inflammatory illness? J Neurol Neurosurg Psychiatry 83:495-502.
Kubo M, Hanada T, Yoshimura A (2003) Suppressors of cytokine signaling and immunity. Nat Immunol 4:1169-1176.
Lauria F, Foà R, Raspadori D, Zinzani PL, Buzzi M, Fierro MT, Bonferroni M, Fanin R, Gallizia C, Michieli MG, et al. (1988) Treatment of hairy-cell leukaemia with alpha-interferon (alpha-IFN). Eur J Cancer Clin Oncol 24:195-200.
Laviano A, Inui A, Meguid MM, Molfino A, Conte C, Rossi Fanelli F (2008) NPY and brain monoamines in the pathogenesis of cancer anorexia. Nutrition 24:802-805.
Le Thuc O, Stobbe K, Cansell C, Nahon J-L, Blondeau N, Rovère C (2017) Hypothalamic Inflammation and Energy Balance Disruptions: Spotlight on Chemokines. Frontiers in Endocrinology 8.
Lee CH, Suk K, Yu R, Kim MS (2020) Cellular Contributors to Hypothalamic Inflammation in Obesity. Mol Cells 43:431-437.
Li F, Guo H, Yang Y, Feng M, Liu B, Ren X, Zhou H (2019) Autophagy modulation in bladder cancer development and treatment (Review). Oncol Rep 42:1647-1655.
Lin HV, Plum L, Ono H, Gutiérrez-Juárez R, Shanabrough M, Borok E, Horvath TL, Rossetti L, Accili D (2010) Divergent regulation of energy expenditure and hepatic glucose production by insulin receptor in agouti-related protein and POMC neurons. Diabetes 59:337-346.
Liu Y, Fiskum G, Schubert D (2002) Generation of reactive oxygen species by the mitochondrial electron transport chain. J Neurochem 80:780-787.
Losón OC, Song Z, Chen H, Chan DC (2013) Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell 24:659-667.
Lumeng CN, Saltiel AR (2011) Inflammatory links between obesity and metabolic disease. J Clin Invest 121:2111-2117.
Ma RJ, Tan YQ, Zhou G (2019) Aberrant IGF1-PI3K/AKT/MTOR signaling pathway regulates the local immunity of oral lichen planus. Immunobiology 224:455-461.
Marchi S, Giorgi C, Suski JM, Agnoletto C, Bononi A, Bonora M, De Marchi E, Missiroli S, Patergnani S, Poletti F, Rimessi A, Duszynski J, Wieckowski MR, Pinton P (2012) Mitochondria-ros crosstalk in the control of cell death and aging. J Signal Transduct 2012:329635.
Martín Giménez VM, de las Heras N, Ferder L, Lahera V, Reiter RJ, Manucha W (2021) Potential Effects of Melatonin and Micronutrients on Mitochondrial Dysfunction during a Cytokine Storm Typical of Oxidative/Inflammatory Diseases. Diseases 9:30.
Mears JA, Lackner LL, Fang S, Ingerman E, Nunnari J, Hinshaw JE (2011) Conformational changes in Dnm1 support a contractile mechanism for mitochondrial fission. Nat Struct Mol Biol 18:20-26.
Mizumura K, Cloonan S, Choi ME, Hashimoto S, Nakahira K, Ryter SW, Choi AM (2016) Autophagy: Friend or Foe in Lung Disease? Ann Am Thorac Soc 13 Suppl 1:S40-47.
Mohanty A, Tiwari-Pandey R, Pandey NR (2019) Mitochondria: the indispensable players in innate immunity and guardians of the inflammatory response. J Cell Commun Signal 13:303-318.
Mohr DC, Goodkin DE, Islar J, Hauser SL, Genain CP (2001) Treatment of depression is associated with suppression of nonspecific and antigen-specific T(H)1 responses in multiple sclerosis. Arch Neurol 58:1081-1086.
Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1-13.
Murphy MP (2018) Newly made mitochondrial DNA drives inflammation. Nature 560:176-177.
Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS, Greiner K, Nemeroff CB, Miller AH (2001) Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 344:961-966.
Nazarians-Armavil A, Chalmers JA, Lee CB, Ye W, Belsham DD (2014) Cellular insulin resistance disrupts hypothalamic mHypoA-POMC/GFP neuronal signaling pathways. J Endocrinol 220:13-24.
Nishikawa T, Araki E (2007) Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications. Antioxid Redox Signal 9:343-353.
Northrop NA, Yamamoto BK (2011) Neuroimmune pharmacology from a neuroscience perspective. J Neuroimmune Pharmacol 6:10-19.
O`Connor JC, Satpathy A, Hartman ME, Horvath EM, Kelley KW, Dantzer R, Johnson RW, Freund GG (2005) IL-1beta-mediated innate immunity is amplified in the db/db mouse model of type 2 diabetes. J Immunol 174:4991-4997.
Perot BP, Boussier J, Yatim N, Rossman JS, Ingersoll MA, Albert ML (2018) Autophagy diminishes the early interferon-β response to influenza A virus resulting in differential expression of interferon-stimulated genes. Cell Death Dis 9:539.
Perry VH, Cunningham C, Holmes C (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 7:161-167.
Pinto S, Roseberry AG, Liu H, Diano S, Shanabrough M, Cai X, Friedman JM, Horvath TL (2004) Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304:110-115.
Plum L et al. (2006) Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. J Clin Invest 116:1886-1901.
Qiu J, Zhang C, Borgquist A, Nestor CC, Smith AW, Bosch MA, Ku S, Wagner EJ, Rønnekleiv OK, Kelly MJ (2014) Insulin excites anorexigenic proopiomelanocortin neurons via activation of canonical transient receptor potential channels. Cell Metab 19:682-693.
Quan W, Kim HK, Moon EY, Kim SS, Choi CS, Komatsu M, Jeong YT, Lee MK, Kim KW, Kim MS, Lee MS (2012) Role of hypothalamic proopiomelanocortin neuron autophagy in the control of appetite and leptin response. Endocrinology 153:1817-1826.
Raison CL, Demetrashvili M, Capuron L, Miller AH (2005) Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs 19:105-123.
Rana I, Stebbing M, Kompa A, Kelly DJ, Krum H, Badoer E (2010) Microglia activation in the hypothalamic PVN following myocardial infarction. Brain Res 1326:96-104.
Reder AT, Feng X (2014) How type I interferons work in multiple sclerosis and other diseases: some unexpected mechanisms. J Interferon Cytokine Res 34:589-599.
Riley JS, Tait SW (2020) Mitochondrial DNA in inflammation and immunity. EMBO Rep 21:e49799.
Roger AJ, Muñoz-Gómez SA, Kamikawa R (2017) The Origin and Diversification of Mitochondria. Curr Biol 27:R1177-r1192.
Ronaldson PT, Bendayan R (2006) HIV-1 viral envelope glycoprotein gp120 triggers an inflammatory response in cultured rat astrocytes and regulates the functional expression of P-glycoprotein. Mol Pharmacol 70:1087-1098.
Roth J, Harré EM, Rummel C, Gerstberger R, Hübschle T (2004) Signaling the brain in systemic inflammation: role of sensory circumventricular organs. Front Biosci 9:290-300.
Santel A, Fuller MT (2001) Control of mitochondrial morphology by a human mitofusin. J Cell Sci 114:867-874.
Saracco G, Olivero A, Ciancio A, Carenzi S, Rizzetto M (2003) Therapy of chronic hepatitis C: a critical review. Curr Drug Targets Infect Disord 3:25-32.
Schindler C, Levy DE, Decker T (2007) JAK-STAT signaling: from interferons to cytokines. J Biol Chem 282:20059-20063.
Schroder K, Sweet MJ, Hume DA (2006) Signal integration between IFNgamma and TLR signalling pathways in macrophages. Immunobiology 211:511-524.
Seong J, Kang JY, Sun JS, Kim KW (2019) Hypothalamic inflammation and obesity: a mechanistic review. Arch Pharm Res 42:383-392.
Sergeyev V, Broberger C, Hökfelt T (2001) Effect of LPS administration on the expression of POMC, NPY, galanin, CART and MCH mRNAs in the rat hypothalamus. Brain Res Mol Brain Res 90:93-100.
Silverman AJ, Sutherland AK, Wilhelm M, Silver R (2000) Mast cells migrate from blood to brain. J Neurosci 20:401-408.
Stichel CC, Luebbert H (2007) Inflammatory processes in the aging mouse brain: participation of dendritic cells and T-cells. Neurobiol Aging 28:1507-1521.
Süß P, Hoffmann A, Rothe T, Ouyang Z, Baum W, Staszewski O, Schett G, Prinz M, Krönke G, Glass CK, Winkler J, Schlachetzki JCM (2020) Chronic Peripheral Inflammation Causes a Region-Specific Myeloid Response in the Central Nervous System. Cell Rep 30:4082-4095.e4086.
Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805-820.
Thaler JP, Choi SJ, Schwartz MW, Wisse BE (2010) Hypothalamic inflammation and energy homeostasis: resolving the paradox. Front Neuroendocrinol 31:79-84.
Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, Zhao X, Sarruf DA, Izgur V, Maravilla KR, Nguyen HT, Fischer JD, Matsen ME, Wisse BE, Morton GJ, Horvath TL, Baskin DG, Tschöp MH, Schwartz MW (2012) Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 122:153-162.
Toda C, Santoro A, Kim JD, Diano S (2017) POMC Neurons: From Birth to Death. Annu Rev Physiol 79:209-236.
Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552:335-344.
van Horssen J, van Schaik P, Witte M (2019) Inflammation and mitochondrial dysfunction: A vicious circle in neurodegenerative disorders? Neurosci Lett 710:132931.
Varela L, Horvath TL (2012) Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis. EMBO Rep 13:1079-1086.
Verma S, Nakaoke R, Dohgu S, Banks WA (2006) Release of cytokines by brain endothelial cells: A polarized response to lipopolysaccharide. Brain Behav Immun 20:449-455.
Vezzani A, Viviani B (2015) Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology 96:70-82.
Wan YJ, Levi BZ, Ozato K (1988) Induction of c-fos gene expression by interferons. J Interferon Res 8:105-112.
Wang J, Campbell IL (2002) Cytokine signaling in the brain: putting a SOCS in it? J Neurosci Res 67:423-427.
Wardlaw SL (2011) Hypothalamic proopiomelanocortin processing and the regulation of energy balance. Eur J Pharmacol 660:213-219.
Westermann B (2010) Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 11:872-884.
Westermann B (2012) Bioenergetic role of mitochondrial fusion and fission. Biochim Biophys Acta 1817:1833-1838.
White JP, Puppa MJ, Sato S, Gao S, Price RL, Baynes JW, Kostek MC, Matesic LE, Carson JA (2012) IL-6 regulation on skeletal muscle mitochondrial remodeling during cancer cachexia in the ApcMin/+ mouse. Skelet Muscle 2:14.
Williams KW, Margatho LO, Lee CE, Choi M, Lee S, Scott MM, Elias CF, Elmquist JK (2010) Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. J Neurosci 30:2472-2479.
Wispelwey B, Lesse AJ, Hansen EJ, Scheld WM (1988) Haemophilus influenzae lipopolysaccharide-induced blood brain barrier permeability during experimental meningitis in the rat. J Clin Invest 82:1339-1346.
Xu AW, Kaelin CB, Takeda K, Akira S, Schwartz MW, Barsh GS (2005) PI3K integrates the action of insulin and leptin on hypothalamic neurons. J Clin Invest 115:951-958.
Yang Z, Hulver M, McMillan RP, Cai L, Kershaw EE, Yu L, Xue B, Shi H (2012) Regulation of insulin and leptin signaling by muscle suppressor of cytokine signaling 3 (SOCS3). PLoS One 7:e47493.
Ye SM, Johnson RW (2001) An age-related decline in interleukin-10 may contribute to the increased expression of interleukin-6 in brain of aged mice. Neuroimmunomodulation 9:183-192.
Yue L, Yao H (2016) Mitochondrial dysfunction in inflammatory responses and cellular senescence: pathogenesis and pharmacological targets for chronic lung diseases. Br J Pharmacol 173:2305-2318.
Zheng LS, Kaneko N, Sawamoto K (2015) Minocycline treatment ameliorates interferon-alpha- induced neurogenic defects and depression-like behaviors in mice. Front Cell Neurosci 9:5.
描述 碩士
國立政治大學
神經科學研究所
108754002
資料來源 http://thesis.lib.nccu.edu.tw/record/#G0108754002
資料類型 thesis
dc.contributor.advisor 陳紹寬zh_TW
dc.contributor.advisor Chen, Shau-Kwaunen_US
dc.contributor.author (Authors) 林有上zh_TW
dc.contributor.author (Authors) Lim, Yeou-Sanen_US
dc.creator (作者) 林有上zh_TW
dc.creator (作者) Lim, Yeou-Sanen_US
dc.date (日期) 2022en_US
dc.date.accessioned 2-Sep-2022 15:06:24 (UTC+8)-
dc.date.available 2-Sep-2022 15:06:24 (UTC+8)-
dc.date.issued (上傳時間) 2-Sep-2022 15:06:24 (UTC+8)-
dc.identifier (Other Identifiers) G0108754002en_US
dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/141645-
dc.description (描述) 碩士zh_TW
dc.description (描述) 國立政治大學zh_TW
dc.description (描述) 神經科學研究所zh_TW
dc.description (描述) 108754002zh_TW
dc.description.abstract (摘要) 發炎是當病原體入侵和組織損傷時所反應出的急性保護性反應以幫助生理系統恢復正常狀態。發炎可分為急性和慢性發炎，兩種發炎模式都有各自應對發炎的免疫功能和機制。急性發炎可保護個個體引發對抗外來病原體所必需的炎症反應，但長期慢性發炎所產生的炎症反應則會損害個體產生各種疾病問題。因此發炎是目前在已知的研究中被認為與許多神經系統疾病有間接或直接相關的成因之一。許多研究發現周邊系統的發炎會影響大腦中樞系統進而改變生理功能或其行為模式。目前研究多數在於研究周邊系統的發炎，但大腦中樞系統和大腦神經細胞處在發炎環境下所產生的改變尚未釐清。大腦下視丘弓狀核 (ARC)神經元群中的POMC/CART神經元調節著食慾，睡眠，代謝達到能量平衡等關鍵生理功能。下視丘發炎也是周邊發炎影響到大腦中樞神經系統的首要影響核區。促發炎細胞因子能夠通過血腦屏障進入下視丘中並活化小膠質細胞引發下視丘炎症。本研究旨在探討兩種不同因子造成的的不同發炎環境對POMC神經元中的粒線體的變化及POMC神經元活動的影響。本研究分為兩種不同的促發炎因子兩大部分。第一大部分探討第一種促發炎因子-脂多醣 (lipopolysaccharides) 刺激單核細胞系(monocytic lineage cells)對mHypo-POMC/GPF1神經元處在短期急性或長期慢性發炎環境下的粒線體功能及神經細胞活動之變化。 實驗結果發現POMC神經元在脂多醣的長期慢性發炎環境下導致粒線體出現型態上的變化，包括呈長條狀及出現空洞破壞等型態異變， 以及細胞內的ROS/RNS水平有上升趨勢，SOD1抗氧化酶基因和 GPX4 穀胱甘肽過氧化物酶基因的抗氧化酶的表達下降與 ROS/RNS 上升的結果是同步的。此外，也證實了在長期慢性發炎環境下會誘發黑皮質素（α-MSH）神經免疫調節肽的表現量增加。而在短期急性發炎環境下會導致MFN2 線粒體融合基因顯著下降。但脂多醣並未顯著影響POMC神經元細胞活動。另外我們透過腹腔注射脂多醣來誘導小鼠出現類疾病行為 (sickness behavior)，包括顯著增加小鼠體內的細胞因子和其食慾進食量減少，同時刺激下視丘的c-fos表現。第二大部分探討第二種促發炎因子-干擾素-α (IFN-α)。IFN-α在臨床上常被用於治療自體免疫疾病，病毒性疾病和癌症。然而長期使用IFN-α的治療患者會出現憂鬱症症狀。由於IFN-α也是另一類的促發炎因子和免疫調節因子，並且憂鬱症的症狀與大腦下視丘功能相呼應，如睡眠障礙，食慾降低或增加，疲憊等。因此IFN-α可用於探討在短期急性或長期慢性發炎環境下對下視丘POMC神經元之粒線體功能及神經細胞活動的影響。實驗結果發現IFN-α慢性長期發炎在POMC神經元上會活化STAT1傳遞訊號並促進SOCS1的表現。胰島素是POMC神經元調節代謝功能時的重要調節訊號。IFN-α逆轉了胰島素抑制細胞因子信號抑制因子3 (SOCS3)的表現。SOCS3 可以與胰島素受體結合調節胰島素敏感性，說明在IFN-α的作用下會增加胰島素敏感性。另外，過去研究發現POMC神經元在瘦素和胰島素的作用下會誘發神經活動，在本實驗中發現胰島素POMC神經元激活了神經活動(c-fos)之表現，但在IFN-α的刺激下胰島素卻顯著降低了神經活動。此外在IFN-α長期刺激下POMC神經元粒線體也產生型態上的變化，而且也觀察到POMC細胞內自噬過程，但尚未了解IFN-α對於神經細胞啟動自噬過程的相關機制，後續仍有待進一步研究。IFN-α的腹腔注射也證實誘導出小鼠出現類憂鬱行為，包括強迫游泳及懸尾僵直行為顯著增加。總而言之，本實驗結果顯示在兩種不同的發炎環境下，對下視丘POMC神經元中的粒線體和神經活動都有各別影響，而其中有幾個重要發現問題仍有待進一步研究探討及解決。zh_TW
dc.description.abstract (摘要) Inflammation is the biological response of the immune system to protect the body from the harms mediated by foreign pathogen infection or damaged tissues. Inflammation can be either acute or chronic, both have their own immune responses and underlying mechanisms. Acute inflammation protects our body by eliciting the inflammatory responses necessary to fight foreign pathogens. In contrast, chronic inflammation generates long-lasting inflammation responses and caused various chronic diseases, including cardiovascular and bowel diseases, diabetes, and cancer. Mounting studies have demonstrated that peripheral inflammation affects central nervous system and alters physiological functions or behavioral phenotypes. Peripheral inflammatory cytokines directly or indirectly affect the brain and activate microglia to trigger hypothalamic inflammation. POMC neurons is the neuronal population located in hypothalamic arcuate nucleus (ARC) with regulating several essential physiological functions such as appetite, sleep, glucose metabolism and energy homeostasis. In this study, we aim to investigate how pro-inflammatory milieu or cytokines influence mitochondrial function and neuronal activities in hypothalamic POMC neurons. We compared neuronal alterations induced by two different types of pro-inflammatory stimuli. In the first part, mHypoA-POMC/GFP1 cells were treated with the conditioned medium collected from LPS-activated macrophage to mimic the inflammatory milieu during hypothalamic inflammation. Our in vivo data showed that POMC neurons exposed in CMLPS-chronic inflammation milieu led to morphological changes in mitochondrial elongation. Further, the intracellular ROS/RNS levels were elevated. The reduced expression of antioxidant enzymes was synchronized with ROS/RNS levels upregulation, such as Sod1 and Gpx4 genes during chronic inflammation. In vivo studies found that after intraperitoneal injection of lipopolysaccharide significantly increased cytokines and decreased appetite in mice. The expression of c-fos was also elevated in the hypothalamus, suggesting that neuronal activities were increased. The second type of inflammatory condition is chronic administration of interferon-alpha (IFN-α). IFN-α is often used clinically to treat autoimmune diseases, viral diseases, and cancer. However, chronic administration of IFN-α also cause neurological side effects such as depression. Therefore, chronic administration of IFN-α was employed as an alternative model to investigate the
effects of chronic inflammation on mitochondrial functions and neuronal activities of hypothalamic POMC neurons. In vitro experimental results found that IFN-α activates STAT1 expression in POMC neurons. IFN-α also disrupt insulin signaling, which is a crucial regulatory signal for the metabolism-regulatory functions in POMC neurons. IFN-α treatment reversed the expression of suppressed cytokine signaling inhibitor 3 (SOCS3). Also, IFN-α significantly reduced the neural activity activated by insulin. Additionally, IFN-α-induced chronic inflammation initiated mitochondrial changes and autophagy-like alterations in POMC neurons, and need more observatory time points are necessary to further understand the autophagic status. Intraperitoneal injection of IFN-α also confirmed the induction of depression-like behaviors in mice, including significant increase in forced swimming test and tail suspension test. In summary, these two different pro-inflammatory environments get different alterations on mitochondrial and neural activity in hypothalamic POMC neurons, and several questions remain to be further exploring by more experiments.		en_US
dc.description.tableofcontents 中文摘要 I
Abstract III
Abbreviation IX
Introduction 1
1.1 Inflammation 1
1.2 The innate vs. adaptive immune system 1
1.3 The inflammatory responses 2
1.4 Acute vs. chronic inflammation 2
1.5 Cytokine-induced sickness behavior in animal models 3
1.6 Pro-inflammatory cytokines 5
1.7 Interferon-alpha (IFN-α) and depression 6
1.8 Interferon alpha (IFN-α) signaling pathway 7
1.9 Hypothalamic inflammation 7
1.10 Hypothalamic POMC neuron 9
1.11 The Link between POMC and Leptin/Insulin 9
1.12 Mitochondria 10
1.13 DNA genome (mtDNA) 10
1.14 Reactive oxygen species (ROS) 11
1.15 Mitochondria morphologies 11
1.16 Mitochondria dynamics: changing shape and shaping changing 12
1.17 Mitochondria Fusion and Fission 12
1.18 Mitochondria dysfunction 13
1.19 Mitochondria and Inflammation 13
Aims and Objectives 15
2.1 Experiment Aim and Objectives 15
2.2 Experiment Design 16
Material and Methods 17
3.1 Cell culture - mHYPO-POMC/GFP-1 cell line 17
3.2 Passaging Cells 17
3.3 Counting Cells on a Hemocytometer 17
3.4 Generation of BMDM and collection of conditioned medium (CMLPS) 17
3.5 In vitro drug treatment 18
3.6 Experiment animals 18
3.7 In vivo drug treatment: IFN-α 18
3.8 In-vivo drug treatment: Lipopolysaccharides (LPS) 19
3.9 Behavioral tests 19
3.9.1 Forced Swimming Test, FST 19
3.9.2 Tail Suspension Test, TST 19
3.9.3 Social Interaction Test, SIT 19
3.10 Real time Polymerase Chain Reaction (RT-PCR) 20
3.10.1 RNA extraction and concentration determination 20
3.10.2 Reverse transcription-PCR (RT-PCR) 21
3.10.3 Quantitative Real-Time PCR (qRT-PCR) 21
3.11 Measurement of Intracellular Reactive Oxygen Species (ROS) level 22
3.12 Mitochondria Complex IV activity 22
3.13 Mitochondrial DNA/ Nuclear DNA Ratio 23
3.14 Transmission Electron Microscopy 23
3.15 Indirect Immunocytochemistry (ICC) 23
3.16 Statistical Analysis 24
Results 25
4.1 Conditioned medium collected from bone marrow derived macrophage induced with LPS provide the inflammatory environment in hypothalamic POMC neurons 25
4.2 Chronic inflammation changed different mitochondria morphologies and dynamics in CMLPS or IFNα-inflammatory milieus 25
4.3 ROS/RNS levels were elevated in POMC neurons in CMLPS- inflammatory milieu 27
4.4 Neuronal activities were elicited by CMLPS-inflammatory milieu 27
4.5 Interferon-alpha (IFN-α) activated JAK-STAT signal transduction in POMC neurons 28
Discussion 32
Experiment Figures 35
Figures 6.1. Graphical Abstract and Highlights 35
Figure 6.2. The TEM images of POMC neuron-mitochondrial morphology in the treatment of CMLPS or control 36
Figure 6.3. Abnormalities and damaged mitochondrial morphology in CMLPS-exposed POMC neuron 38
Figure 6.4. Quantification mRNA analysis of mitochondrial dynamics for fusion (Mfn1, Mfn2, Opa1) under CMLPS treatment 39
Figure 6.5. The cellular ROS levels analysis in POMC neurons under different treatment conditions 40
Figure 6.6. RT-qPCR analysis of mRNA expression levels on mitochondrial oxidative stress-related RNA expression in POMC neuron treated with CMLPS 41
Figure 6.7. The effect of Complex IV enzyme activity of mitochondrial under inflammation environment 42
Figure 6.8. Compare the mitochondrial DNA copies/nuclear DNA copies in POMC neurons 43
Figure 6.9. The neuronal alteration c-fos mRNA expression in POMC neurons after CMLPS stimulation 44
Figure 6.10. The Immunocytochemistry (ICC) staining verified co-expression of a-MSH in mHypoA-POMC/GFP cells in culture 45
Figure 6.11. CMLPS increased the expression of α-MSH in POMC neurons 47
Figure 6.12. LPS-stimulation decreased the feeding behavior on mice 48
Figure 6.13. LPS upregulated the pro-inflammatory cytokines mRNA expression of hypothalamus in mice 49
Figure 6.14. LPS-induced the c-fos gene expression in the hypothalamus of mice 50
Figure 6.15 The JAK-STAT signal transduction in POMC neurons induced by the inflammation milieu of Interferon-alpha (IFN-α) 51
Figure 6.16. Comparation the levels of SOCS3 mRNA expression of IFNα, Insulin, and IFNα+ Insulin treatment in POMC neuron 53
Figure 6.17. Significantly changes of c-Fos mRNA expression in POMC neurons 54
Figure 6.18 Interferon-alpha stimulation induces cellular autophagy-like morphology on POMC neurons 55
Figure 6.19. Chronic administration of IFN-α significantly induced depressive-like behavior in mice 57
Figure 6.20. The behavioral of Social Interaction test observing in chronic administration of IFN-α in mice 58
Figure 6.21. The hypothalamus of c-fos mRNA expression in chronic administration of IFN-α in mice 59
References: 60
Supplementary Table 66
S1: cDNA synthesis mixture solution 66
S2: Reaction master mix solution 66
S3: Primers List 66		zh_TW
dc.format.extent 3040394 bytes-
dc.format.mimetype application/pdf-
dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0108754002en_US
dc.subject (關鍵詞) 下視丘zh_TW
dc.subject (關鍵詞) 慢性發炎zh_TW
dc.subject (關鍵詞) POMC神經元zh_TW
dc.subject (關鍵詞) 粒線體zh_TW
dc.subject (關鍵詞) 脂多醣zh_TW
dc.subject (關鍵詞) 干擾素-αzh_TW
dc.subject (關鍵詞) Inflammationen_US
dc.subject (關鍵詞) Hypothalamic POMC neuronen_US
dc.subject (關鍵詞) Mitochondrial morphologyen_US
dc.subject (關鍵詞) Lipopolysaccharideen_US
dc.subject (關鍵詞) IFN-αen_US
dc.title (題名) 發炎環境對粒線體功能及神經細胞活動影響之研究zh_TW
dc.title (題名) The study of the effects of inflammatory milieu on mitochondrial function and neural activitiesen_US
dc.type (資料類型) thesisen_US
dc.relation.reference (參考文獻) Alexander WS, Starr R, Fenner JE, Scott CL, Handman E, Sprigg NS, Corbin JE, Cornish AL, Darwiche R, Owczarek CM, Kay TW, Nicola NA, Hertzog PJ, Metcalf D, Hilton DJ (1999) SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 98:597-608.
Baker RG, Hayden MS, Ghosh S (2011) NF-κB, inflammation, and metabolic disease. Cell Metab 13:11-22.
Balthasar N, Coppari R, McMinn J, Liu SM, Lee CE, Tang V, Kenny CD, McGovern RA, Chua SC, Jr., Elmquist JK, Lowell BB (2004) Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42:983-991.
Banks WA (2005) Blood-brain barrier transport of cytokines: a mechanism for neuropathology. Curr Pharm Des 11:973-984.
Banks WA, Kastin AJ (1991) Blood to brain transport of interleukin links the immune and central nervous systems. Life Sci 48:Pl117-121.
Banks WA, Kastin AJ, Gutierrez EG (1994) Penetration of interleukin-6 across the murine blood-brain barrier. Neurosci Lett 179:53-56.
Benoit SC, Air EL, Coolen LM, Strauss R, Jackman A, Clegg DJ, Seeley RJ, Woods SC (2002) The catabolic action of insulin in the brain is mediated by melanocortins. J Neurosci 22:9048-9052.
Bode JG, Ludwig S, Ehrhardt C, Albrecht U, Erhardt A, Schaper F, Heinrich PC, Häussinger D (2003) IFN-alpha antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling-3. Faseb j 17:488-490.
Borges BC, Garcia-Galiano D, Rorato R, Elias LLK, Elias CF (2016) PI3K p110β subunit in leptin receptor expressing cells is required for the acute hypophagia induced by endotoxemia. Mol Metab 5:379-391.
Bouret SG, Simerly RB (2004) Minireview: Leptin and Development of Hypothalamic Feeding Circuits. Endocrinology 145:2621-2626.
Brzózka K, Pfaller C, Conzelmann KK (2007) Signal transduction in the type I interferon system and viral countermeasures. Signal Transduct 7:5-19.
Bulua AC, Simon A, Maddipati R, Pelletier M, Park H, Kim KY, Sack MN, Kastner DL, Siegel RM (2011) Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med 208:519-533.
Carow B, Rottenberg ME (2014) SOCS3, a Major Regulator of Infection and Inflammation. Front Immunol 5:58.
Chaban Y, Boekema EJ, Dudkina NV (2014) Structures of mitochondrial oxidative phosphorylation supercomplexes and mechanisms for their stabilisation. Biochim Biophys Acta 1837:418-426.
Chen H, Chan DC (2009) Mitochondrial dynamics--fusion, fission, movement, and mitophagy--in neurodegenerative diseases. Hum Mol Genet 18:R169-176.
Chen H, Chan DC (2010) Physiological functions of mitochondrial fusion. Ann N Y Acad Sci 1201:21-25.
Chen XH, Zhao YP, Xue M, Ji CB, Gao CL, Zhu JG, Qin DN, Kou CZ, Qin XH, Tong ML, Guo XR (2010) TNF-alpha induces mitochondrial dysfunction in 3T3-L1 adipocytes. Mol Cell Endocrinol 328:63-69.
Chitnis T, Weiner HL (2017) CNS inflammation and neurodegeneration. J Clin Invest 127:3577-3587.
Cogliati S, Frezza C, Soriano ME, Varanita T, Quintana-Cabrera R, Corrado M, Cipolat S, Costa V, Casarin A, Gomes LC, Perales-Clemente E, Salviati L, Fernandez-Silva P, Enriquez JA, Scorrano L (2013) Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell 155:160-171.
Cone RD, Cowley MA, Butler AA, Fan W, Marks DL, Low MJ (2001) The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis. Int J Obes Relat Metab Disord 25 Suppl 5:S63-67.
Coupé B, Ishii Y, Dietrich MO, Komatsu M, Horvath TL, Bouret SG (2012) Loss of autophagy in pro-opiomelanocortin neurons perturbs axon growth and causes metabolic dysregulation. Cell Metab 15:247-255.
Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S, Horvath TL, Cone RD, Low MJ (2001) Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411:480-484.
Dantzer R, O`Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46-56.
De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, Saad MJ, Velloso LA (2005) Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146:4192-4199.
Degan D, Ornello R, Tiseo C, Carolei A, Sacco S, Pistoia F (2018) The Role of Inflammation in Neurological Disorders. Curr Pharm Des 24:1485-1501.
Degtyarev M, De Mazière A, Orr C, Lin J, Lee BB, Tien JY, Prior WW, van Dijk S, Wu H, Gray DC, Davis DP, Stern HM, Murray LJ, Hoeflich KP, Klumperman J, Friedman LS, Lin K (2008) Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents. J Cell Biol 183:101-116.
Dietrich MO, Liu ZW, Horvath TL (2013) Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity. Cell 155:188-199.
Elias CF, Aschkenasi C, Lee C, Kelly J, Ahima RS, Bjorbaek C, Flier JS, Saper CB, Elmquist JK (1999) Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23:775-786.
Ellacott KL, Cone RD (2006) The role of the central melanocortin system in the regulation of food intake and energy homeostasis: lessons from mouse models. Philos Trans R Soc Lond B Biol Sci 361:1265-1274.
Fenner JE, Starr R, Cornish AL, Zhang JG, Metcalf D, Schreiber RD, Sheehan K, Hilton DJ, Alexander WS, Hertzog PJ (2006) Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity. Nat Immunol 7:33-39.
Fensterl V, Sen GC (2009) Interferons and viral infections. Biofactors 35:14-20.
Fernández-Sánchez A, Madrigal-Santillán E, Bautista M, Esquivel-Soto J, Morales-González A, Esquivel-Chirino C, Durante-Montiel I, Sánchez-Rivera G, Valadez-Vega C, Morales-González JA (2011) Inflammation, oxidative stress, and obesity. Int J Mol Sci 12:3117-3132.
Frenois F, Moreau M, O`Connor J, Lawson M, Micon C, Lestage J, Kelley KW, Dantzer R, Castanon N (2007) Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior. Psychoneuroendocrinology 32:516-531.
Fukuda M, Jones JE, Olson D, Hill J, Lee CE, Gautron L, Choi M, Zigman JM, Lowell BB, Elmquist JK (2008) Monitoring FoxO1 localization in chemically identified neurons. J Neurosci 28:13640-13648.
Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, Ferrucci L, Gilroy DW, Fasano A, Miller GW, Miller AH, Mantovani A, Weyand CM, Barzilai N, Goronzy JJ, Rando TA, Effros RB, Lucia A, Kleinstreuer N, Slavich GM (2019) Chronic inflammation in the etiology of disease across the life span. Nature Medicine 25:1822-1832.
Goubau D, Deddouche S, Reis e Sousa C (2013) Cytosolic sensing of viruses. Immunity 38:855-869.
Gu W, Cui R, Ding T, Li X, Peng J, Xu W, Han F, Guo X (2017) Simvastatin alleviates airway inflammation and remodelling through up-regulation of autophagy in mouse models of asthma. Respirology 22:533-541.
Gutierrez EG, Banks WA, Kastin AJ (1993) Murine tumor necrosis factor alpha is transported from blood to brain in the mouse. J Neuroimmunol 47:169-176.
Hahn WS, Kuzmicic J, Burrill JS, Donoghue MA, Foncea R, Jensen MD, Lavandero S, Arriaga EA, Bernlohr DA (2014) Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics. Am J Physiol Endocrinol Metab 306:E1033-1045.
Hannigan GE, Williams BR (1992) Interferon-alpha activates binding of nuclear factors to a sequence element in the c-fos proto-oncogene 5`-flanking region. J Interferon Res 12:355-361.
Hart BL (1988) Biological basis of the behavior of sick animals. Neurosci Biobehav Rev 12:123-137.
Hayden MS, West AP, Ghosh S (2006) NF-κB and the immune response. Oncogene 25:6758-6780.
Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, Sheridan JF, Godbout JP (2008) Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation 5:15.
Hill JW, Elias CF, Fukuda M, Williams KW, Berglund ED, Holland WL, Cho YR, Chuang JC, Xu Y, Choi M, Lauzon D, Lee CE, Coppari R, Richardson JA, Zigman JM, Chua S, Scherer PE, Lowell BB, Brüning JC, Elmquist JK (2010) Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab 11:286-297.
Hopkins SJ, Rothwell NJ (1995) Cytokines and the nervous system. I: Expression and recognition. Trends Neurosci 18:83-88.
Hoppins S, Lackner L, Nunnari J (2007) The machines that divide and fuse mitochondria. Annu Rev Biochem 76:751-780.
Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860-867.
Howard JK, Flier JS (2006) Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol Metab 17:365-371.
Iwasa T, Matsuzaki T, Kinouchi R, Fujisawa S, Murakami M, Kiyokawa M, Kuwahara A, Yasui T, Irahara M (2010) Neonatal LPS injection alters the body weight regulation systems of rats under non-stress and immune stress conditions. Int J Dev Neurosci 28:119-124.
Iwasaki A, Medzhitov R (2015) Control of adaptive immunity by the innate immune system. Nat Immunol 16:343-353.
Jaeger LB, Dohgu S, Sultana R, Lynch JL, Owen JB, Erickson MA, Shah GN, Price TO, Fleegal-Demotta MA, Butterfield DA, Banks WA (2009) Lipopolysaccharide alters the blood-brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer`s disease. Brain Behav Immun 23:507-517.
Jais A, Brüning JC (2017) Hypothalamic inflammation in obesity and metabolic disease. J Clin Invest 127:24-32.
Jeon SW, Yoon HK, Kim YK (2019) Role of Inflammation in Psychiatric Disorders. Adv Exp Med Biol 1192:491-501.
Jung CH, Kim MS (2013) Molecular mechanisms of central leptin resistance in obesity. Arch Pharm Res 36:201-207.
Kaushik S, Arias E, Kwon H, Lopez NM, Athonvarangkul D, Sahu S, Schwartz GJ, Pessin JE, Singh R (2012) Loss of autophagy in hypothalamic POMC neurons impairs lipolysis. EMBO Rep 13:258-265.
Kazi JU, Kabir NN, Flores-Morales A, Rönnstrand L (2014) SOCS proteins in regulation of receptor tyrosine kinase signaling. Cell Mol Life Sci 71:3297-3310.
Kent S, Bluthé RM, Kelley KW, Dantzer R (1992) Sickness behavior as a new target for drug development. Trends Pharmacol Sci 13:24-28.
Khacho M, Slack RS (2018) Mitochondrial dynamics in the regulation of neurogenesis: From development to the adult brain. Dev Dyn 247:47-53.
Klionsky DJ (2007) Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8:931-937.
Könner AC, Janoschek R, Plum L, Jordan SD, Rother E, Ma X, Xu C, Enriori P, Hampel B, Barsh GS, Kahn CR, Cowley MA, Ashcroft FM, Brüning JC (2007) Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab 5:438-449.
Kowaltowski AJ, de Souza-Pinto NC, Castilho RF, Vercesi AE (2009) Mitochondria and reactive oxygen species. Free Radic Biol Med 47:333-343.
Krishnadas R, Cavanagh J (2012) Depression: an inflammatory illness? J Neurol Neurosurg Psychiatry 83:495-502.
Kubo M, Hanada T, Yoshimura A (2003) Suppressors of cytokine signaling and immunity. Nat Immunol 4:1169-1176.
Lauria F, Foà R, Raspadori D, Zinzani PL, Buzzi M, Fierro MT, Bonferroni M, Fanin R, Gallizia C, Michieli MG, et al. (1988) Treatment of hairy-cell leukaemia with alpha-interferon (alpha-IFN). Eur J Cancer Clin Oncol 24:195-200.
Laviano A, Inui A, Meguid MM, Molfino A, Conte C, Rossi Fanelli F (2008) NPY and brain monoamines in the pathogenesis of cancer anorexia. Nutrition 24:802-805.
Le Thuc O, Stobbe K, Cansell C, Nahon J-L, Blondeau N, Rovère C (2017) Hypothalamic Inflammation and Energy Balance Disruptions: Spotlight on Chemokines. Frontiers in Endocrinology 8.
Lee CH, Suk K, Yu R, Kim MS (2020) Cellular Contributors to Hypothalamic Inflammation in Obesity. Mol Cells 43:431-437.
Li F, Guo H, Yang Y, Feng M, Liu B, Ren X, Zhou H (2019) Autophagy modulation in bladder cancer development and treatment (Review). Oncol Rep 42:1647-1655.
Lin HV, Plum L, Ono H, Gutiérrez-Juárez R, Shanabrough M, Borok E, Horvath TL, Rossetti L, Accili D (2010) Divergent regulation of energy expenditure and hepatic glucose production by insulin receptor in agouti-related protein and POMC neurons. Diabetes 59:337-346.
Liu Y, Fiskum G, Schubert D (2002) Generation of reactive oxygen species by the mitochondrial electron transport chain. J Neurochem 80:780-787.
Losón OC, Song Z, Chen H, Chan DC (2013) Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell 24:659-667.
Lumeng CN, Saltiel AR (2011) Inflammatory links between obesity and metabolic disease. J Clin Invest 121:2111-2117.
Ma RJ, Tan YQ, Zhou G (2019) Aberrant IGF1-PI3K/AKT/MTOR signaling pathway regulates the local immunity of oral lichen planus. Immunobiology 224:455-461.
Marchi S, Giorgi C, Suski JM, Agnoletto C, Bononi A, Bonora M, De Marchi E, Missiroli S, Patergnani S, Poletti F, Rimessi A, Duszynski J, Wieckowski MR, Pinton P (2012) Mitochondria-ros crosstalk in the control of cell death and aging. J Signal Transduct 2012:329635.
Martín Giménez VM, de las Heras N, Ferder L, Lahera V, Reiter RJ, Manucha W (2021) Potential Effects of Melatonin and Micronutrients on Mitochondrial Dysfunction during a Cytokine Storm Typical of Oxidative/Inflammatory Diseases. Diseases 9:30.
Mears JA, Lackner LL, Fang S, Ingerman E, Nunnari J, Hinshaw JE (2011) Conformational changes in Dnm1 support a contractile mechanism for mitochondrial fission. Nat Struct Mol Biol 18:20-26.
Mizumura K, Cloonan S, Choi ME, Hashimoto S, Nakahira K, Ryter SW, Choi AM (2016) Autophagy: Friend or Foe in Lung Disease? Ann Am Thorac Soc 13 Suppl 1:S40-47.
Mohanty A, Tiwari-Pandey R, Pandey NR (2019) Mitochondria: the indispensable players in innate immunity and guardians of the inflammatory response. J Cell Commun Signal 13:303-318.
Mohr DC, Goodkin DE, Islar J, Hauser SL, Genain CP (2001) Treatment of depression is associated with suppression of nonspecific and antigen-specific T(H)1 responses in multiple sclerosis. Arch Neurol 58:1081-1086.
Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1-13.
Murphy MP (2018) Newly made mitochondrial DNA drives inflammation. Nature 560:176-177.
Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS, Greiner K, Nemeroff CB, Miller AH (2001) Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 344:961-966.
Nazarians-Armavil A, Chalmers JA, Lee CB, Ye W, Belsham DD (2014) Cellular insulin resistance disrupts hypothalamic mHypoA-POMC/GFP neuronal signaling pathways. J Endocrinol 220:13-24.
Nishikawa T, Araki E (2007) Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications. Antioxid Redox Signal 9:343-353.
Northrop NA, Yamamoto BK (2011) Neuroimmune pharmacology from a neuroscience perspective. J Neuroimmune Pharmacol 6:10-19.
O`Connor JC, Satpathy A, Hartman ME, Horvath EM, Kelley KW, Dantzer R, Johnson RW, Freund GG (2005) IL-1beta-mediated innate immunity is amplified in the db/db mouse model of type 2 diabetes. J Immunol 174:4991-4997.
Perot BP, Boussier J, Yatim N, Rossman JS, Ingersoll MA, Albert ML (2018) Autophagy diminishes the early interferon-β response to influenza A virus resulting in differential expression of interferon-stimulated genes. Cell Death Dis 9:539.
Perry VH, Cunningham C, Holmes C (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 7:161-167.
Pinto S, Roseberry AG, Liu H, Diano S, Shanabrough M, Cai X, Friedman JM, Horvath TL (2004) Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304:110-115.
Plum L et al. (2006) Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. J Clin Invest 116:1886-1901.
Qiu J, Zhang C, Borgquist A, Nestor CC, Smith AW, Bosch MA, Ku S, Wagner EJ, Rønnekleiv OK, Kelly MJ (2014) Insulin excites anorexigenic proopiomelanocortin neurons via activation of canonical transient receptor potential channels. Cell Metab 19:682-693.
Quan W, Kim HK, Moon EY, Kim SS, Choi CS, Komatsu M, Jeong YT, Lee MK, Kim KW, Kim MS, Lee MS (2012) Role of hypothalamic proopiomelanocortin neuron autophagy in the control of appetite and leptin response. Endocrinology 153:1817-1826.
Raison CL, Demetrashvili M, Capuron L, Miller AH (2005) Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs 19:105-123.
Rana I, Stebbing M, Kompa A, Kelly DJ, Krum H, Badoer E (2010) Microglia activation in the hypothalamic PVN following myocardial infarction. Brain Res 1326:96-104.
Reder AT, Feng X (2014) How type I interferons work in multiple sclerosis and other diseases: some unexpected mechanisms. J Interferon Cytokine Res 34:589-599.
Riley JS, Tait SW (2020) Mitochondrial DNA in inflammation and immunity. EMBO Rep 21:e49799.
Roger AJ, Muñoz-Gómez SA, Kamikawa R (2017) The Origin and Diversification of Mitochondria. Curr Biol 27:R1177-r1192.
Ronaldson PT, Bendayan R (2006) HIV-1 viral envelope glycoprotein gp120 triggers an inflammatory response in cultured rat astrocytes and regulates the functional expression of P-glycoprotein. Mol Pharmacol 70:1087-1098.
Roth J, Harré EM, Rummel C, Gerstberger R, Hübschle T (2004) Signaling the brain in systemic inflammation: role of sensory circumventricular organs. Front Biosci 9:290-300.
Santel A, Fuller MT (2001) Control of mitochondrial morphology by a human mitofusin. J Cell Sci 114:867-874.
Saracco G, Olivero A, Ciancio A, Carenzi S, Rizzetto M (2003) Therapy of chronic hepatitis C: a critical review. Curr Drug Targets Infect Disord 3:25-32.
Schindler C, Levy DE, Decker T (2007) JAK-STAT signaling: from interferons to cytokines. J Biol Chem 282:20059-20063.
Schroder K, Sweet MJ, Hume DA (2006) Signal integration between IFNgamma and TLR signalling pathways in macrophages. Immunobiology 211:511-524.
Seong J, Kang JY, Sun JS, Kim KW (2019) Hypothalamic inflammation and obesity: a mechanistic review. Arch Pharm Res 42:383-392.
Sergeyev V, Broberger C, Hökfelt T (2001) Effect of LPS administration on the expression of POMC, NPY, galanin, CART and MCH mRNAs in the rat hypothalamus. Brain Res Mol Brain Res 90:93-100.
Silverman AJ, Sutherland AK, Wilhelm M, Silver R (2000) Mast cells migrate from blood to brain. J Neurosci 20:401-408.
Stichel CC, Luebbert H (2007) Inflammatory processes in the aging mouse brain: participation of dendritic cells and T-cells. Neurobiol Aging 28:1507-1521.
Süß P, Hoffmann A, Rothe T, Ouyang Z, Baum W, Staszewski O, Schett G, Prinz M, Krönke G, Glass CK, Winkler J, Schlachetzki JCM (2020) Chronic Peripheral Inflammation Causes a Region-Specific Myeloid Response in the Central Nervous System. Cell Rep 30:4082-4095.e4086.
Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805-820.
Thaler JP, Choi SJ, Schwartz MW, Wisse BE (2010) Hypothalamic inflammation and energy homeostasis: resolving the paradox. Front Neuroendocrinol 31:79-84.
Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, Zhao X, Sarruf DA, Izgur V, Maravilla KR, Nguyen HT, Fischer JD, Matsen ME, Wisse BE, Morton GJ, Horvath TL, Baskin DG, Tschöp MH, Schwartz MW (2012) Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 122:153-162.
Toda C, Santoro A, Kim JD, Diano S (2017) POMC Neurons: From Birth to Death. Annu Rev Physiol 79:209-236.
Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552:335-344.
van Horssen J, van Schaik P, Witte M (2019) Inflammation and mitochondrial dysfunction: A vicious circle in neurodegenerative disorders? Neurosci Lett 710:132931.
Varela L, Horvath TL (2012) Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis. EMBO Rep 13:1079-1086.
Verma S, Nakaoke R, Dohgu S, Banks WA (2006) Release of cytokines by brain endothelial cells: A polarized response to lipopolysaccharide. Brain Behav Immun 20:449-455.
Vezzani A, Viviani B (2015) Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology 96:70-82.
Wan YJ, Levi BZ, Ozato K (1988) Induction of c-fos gene expression by interferons. J Interferon Res 8:105-112.
Wang J, Campbell IL (2002) Cytokine signaling in the brain: putting a SOCS in it? J Neurosci Res 67:423-427.
Wardlaw SL (2011) Hypothalamic proopiomelanocortin processing and the regulation of energy balance. Eur J Pharmacol 660:213-219.
Westermann B (2010) Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 11:872-884.
Westermann B (2012) Bioenergetic role of mitochondrial fusion and fission. Biochim Biophys Acta 1817:1833-1838.
White JP, Puppa MJ, Sato S, Gao S, Price RL, Baynes JW, Kostek MC, Matesic LE, Carson JA (2012) IL-6 regulation on skeletal muscle mitochondrial remodeling during cancer cachexia in the ApcMin/+ mouse. Skelet Muscle 2:14.
Williams KW, Margatho LO, Lee CE, Choi M, Lee S, Scott MM, Elias CF, Elmquist JK (2010) Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. J Neurosci 30:2472-2479.
Wispelwey B, Lesse AJ, Hansen EJ, Scheld WM (1988) Haemophilus influenzae lipopolysaccharide-induced blood brain barrier permeability during experimental meningitis in the rat. J Clin Invest 82:1339-1346.
Xu AW, Kaelin CB, Takeda K, Akira S, Schwartz MW, Barsh GS (2005) PI3K integrates the action of insulin and leptin on hypothalamic neurons. J Clin Invest 115:951-958.
Yang Z, Hulver M, McMillan RP, Cai L, Kershaw EE, Yu L, Xue B, Shi H (2012) Regulation of insulin and leptin signaling by muscle suppressor of cytokine signaling 3 (SOCS3). PLoS One 7:e47493.
Ye SM, Johnson RW (2001) An age-related decline in interleukin-10 may contribute to the increased expression of interleukin-6 in brain of aged mice. Neuroimmunomodulation 9:183-192.
Yue L, Yao H (2016) Mitochondrial dysfunction in inflammatory responses and cellular senescence: pathogenesis and pharmacological targets for chronic lung diseases. Br J Pharmacol 173:2305-2318.
Zheng LS, Kaneko N, Sawamoto K (2015) Minocycline treatment ameliorates interferon-alpha- induced neurogenic defects and depression-like behaviors in mice. Front Cell Neurosci 9:5.		zh_TW
dc.identifier.doi (DOI) 10.6814/NCCU202201421en_US