生 物 物 理 学
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生 物 物 理 学. 河北工业大学 生物物理所. 第 6 章 自由基生物学. 6.1 自由基概念 6.1.1 自由基产生 6.1.2 自由基性质 6.1.3 自由基反应 6 .1.4 自由基研究方法 6.2 活性氧 6.2.1 体内活性氧的产生 6.2.2 体内活性氧的产生 6.3 自由基对人体的危害. 6.4 自由基与癌症 6 .4.1 两步致癌学说 6.4.2 各种疾病与抗氧化作用 6.5 自由基与衰老 6.5.1 衰老的进化理论 6.5.2 多劳多损论 6.5.3 端粒酶缩短短寿论 6.6 一氧化氮自由基.

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生 物 物 理 学

河北工业大学 生物物理所

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第6章自由基生物学

  • 6.1自由基概念

  • 6.1.1 自由基产生

  • 6.1.2自由基性质

  • 6.1.3自由基反应

  • 6.1.4 自由基研究方法

  • 6.2 活性氧

  • 6.2.1 体内活性氧的产生

  • 6.2.2 体内活性氧的产生

  • 6.3 自由基对人体的危害

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  • 6.4自由基与癌症

  • 6.4.1 两步致癌学说

  • 6.4.2 各种疾病与抗氧化作用

  • 6.5 自由基与衰老

  • 6.5.1 衰老的进化理论

  • 6.5.2 多劳多损论

  • 6.5.3 端粒酶缩短短寿论

  • 6.6 一氧化氮自由基

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6.1 自由基概念

  • 自由基(free radical)概念: 外层轨道上具有单个不配对电子的原子、原子团和分子的总称。

  • 自由基结构:

    平面型: 角锥型:

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6.1.1 自由基产生

电子俘获

共价键均裂

产生自由基的供能方式:

Ⅰ. 热解

(CH3CH2)4Pb 4CH3CH2.+ Pb

CH3CH2. +Cl2 CH3CH2Cl + Cl.

Δ

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Ⅱ、光解

Cl2 Cl.

易光解的化合物:P190。

Ⅲ、辐射分解(如P173,水的辐射分解)

Ⅳ、氧化还原反应:

Mn+ +R1-O-O-R2 M(n+1)+ +R1O.+R2O-

Ⅴ、加入自由基引发剂

487.5nm

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6.1.2 自由基性质

  • 顺磁(性)物质的主要特点是原子或分子中含有没有完全抵消的电子磁矩,因而具有原子或分子磁矩

  • 顺磁性:凡有未成对电子的分子,在外加磁场中磁化引起的附加磁矩的方向总是和外磁场相同 。

I 激起外磁场的电流

I分 分子电流

I ´ 由转向排列引起的束缚电流

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自由基稳定性

3o自由基>2o自由基>1o自由基

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6.1.3 自由基反应

  • 单分子自由基反应:自由基本身发生的化学反应。类型:碎裂、重排。

  • 自由基-分子相互作用

    类型:加成、取代/夺取、与氧化剂反应

  • 自由基-自由基相互作用

    类型:二聚/偶联、歧化

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1. 气相断链:

气体压力较大时占优势

2.器壁断链:

1. 热:

2. 光:

气体压力较小时占优势

3. 引发剂:

链反应的主要步骤

(1)链引发(chain initiation)-自由基生成

处于稳定态的分子吸收了外界的能量,如加热、光照,加引发剂,使它分解成自由原子或自由基等活性传递物。活化能相当于所断键的键能。

(2)链传递(chain propagation) -自由基传递

链引发所产生的活性传递物与另一稳定分子作用,在形成产物的同时又生成新的活性传递物,使反应如链条一样不断发展下去。

(3)链终止(chain termination)-自由基湮灭

两个活性传递物相碰形成稳定分子,失去传递活性;或与器壁相碰,形成稳定分子,放出的能量被器壁吸收,造成反应停止。

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6.1.4 自由基研究方法

  • 电子顺磁共振

  • 脉冲射解与停流

  • 超微弱化学发光

  • 超氧阴离子和过氧化氢的测定

  • 过氧化产物测定

  • 相关酶的活力测定(CAT、SOD等)

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6.2 活性氧

  • O2还原成水产生许多中间产物,如超氧阴离子,羟基自由基,过氧化氢,单线态氧,氢过氧基,烷氧基,烷过氧基,氢过氧化物,这些中间产物统称活性氧(Redox)。

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XOD

XOD

6.2.1 体内活性氧的产生

酶反应产生O·-2

黄嘌呤氧化酶(XOD)

+O2 + O·-2+H2O2

+ O·-2+H2O2

OH·

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非酶反应产生

  • 某些生物分子(如FMN、FAD、GSH和半胱氨酸)在氧气存在下氧化,产生O·-2

  • 氧合血红蛋白转变为高铁血红蛋白时,产生O·-2

  • 体内产生的半醌自由基与氧气反应时,产生O·-2

  • 体内产生的过氧化氢聚到过渡金属离子或者其复合物时,产生O·-2

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6.2.2 体内活性氧的产生

  • OH.的产生

  • H2O2的产生

  • 1O2的产生

  • 脂质过氧化物的产生

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6.3 自由基对人体的危害

  • 自由基破坏了细胞中的DNA,便会导致癌症的发生。

  • 自由基破坏了蛋白质,便会使体内的酶被破坏,从而导致炎症和老年化。

  • 自由基破坏了脂肪,便会发生脂质过氧化,导致动脉粥样硬化,最后发生中风或心脏病。

  • 自由基破坏了碳水化合物,便会使体内的透明质酸降解,发生关节炎。

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为什么这几年自由基疾病大量发生

(一)、环境因素

(1)空调、冰箱的大量使用,使空气中增加了大量的氟,破坏了臭氧层,使紫外光更容易侵入,产生自由基。

(2)汽车、工厂排放的二氧化氮和有毒气体,污染空气。

(3)很多杀虫剂的化学结构,都会导致自由基的产生。

(4)由于大量杀虫剂、化肥和除草剂的使用,使农作物缺乏清除自由基的维生素和微量元素,如维生素C、维生素E、β-胡萝卜素及硒和锌等。

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(二)膳食因素

(1)由于生活的节奏加快,很多人在中午只是吃快餐或方便面,因而缺乏清除自由基的维生素C、维生素E、β-胡萝卜素及微量元素。

(2)很多人只吃精制的大米和面粉,缺乏纤维素和B族维生素。

(3)由于工作繁忙,日常的饮水量减少,使侵入机体污染物和有毒物质不能排出体外。

(4)由于我国人民肉食以食猪肉为主,猪肉中脂肪含量高,容易导致自由基的产生。

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(三)生活方式

(1)适量运动,能避免自由基的侵袭,上班人锻炼太少。

(2)生活高度紧张,使应激反应增加,使得脂质过氧化增加,产生自由基。

(3)酗酒、吸毒都会促进体内自由基产生。香烟内含有大量的自由基,每吸一口烟可以吸入几百万个自由基。

(4)孤独和离群都会使脑功能退化,发生与自由基和脂质过氧化有关的疾病,如老年痴呆和阿兹海默氏病。

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6.4 自由基与癌症

  • 自由基与致癌物活化

    化学致癌物C C.+DNA

光、电、辐射或燃烧

多环芳烃,芳胺,硝基,亚硝基化合物

DNA.+C

苯并芘

DNA-C加合物

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6 4 1

6.4.1 两步致癌学说

H2O2,OH.,……

  • Step 1 诱发期:只需使用一次致癌剂,作用不可逆

  • Step 2 促进期:需多次重复使用促癌剂,作用可逆

Free radical

VE,VC等抑制促癌作用的物质也能抑制自由基产生

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6.4.2 自由基与抗癌作用

  • 抗癌药物:道诺霉素、阿霉素、黑孢霉素、博莱霉素,黄钟花醌…

  • 药物机理:癌细胞的自由基清除剂(SOD,CAT等)含量比正常细胞少,以上抗癌药物能产生自由基,这些自由基不能被癌细胞及时清除,从而造成癌细胞死亡,而药物对正常细胞的影响较小。

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Major Carotenoids

胡萝卜素

玉米黄质

虾青素

角黄素

番茄红素

隐黄素

叶黄素

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流行病学结果

  • Epidemiological studies support a varied diet, with 7 servings of fruit and vegetables, as a basis for good health.杂食保健

  • Epidemiological studies show people with high intakes of carotenoids have a reduced risk of various cancers, heart disease and cataracts(白内障). 类胡萝卜素防病

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自由基损伤部位

  • Cancer: prostate(前列腺),cervical(宫颈), breast, lung

  • Heart disease 心脏病

  • Immune system degeneration 免疫

  • Stroke(中风), cerebrovascular disease(脑血管病)

  • Respiratory function 呼吸

  • Cataracts, age-related macular degeneration 白内障

  • Memory and cognitive function 记忆和认知

  • Sun-damaged skin, wrinkles 皮肤损伤

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自由基的氧化损伤

  • Nucleic acids, leading to cancerous changes

  • Lipids, including those in membranes, and LDL in arteries(动脉)

  • Enzymes, which repair cell structures

  • Other proteins, including collagen(胶原蛋白) in skin

  • The free radical theory of aging-Harman

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自由基的体内来源

  • Cigarette smoke

  • Air pollutants, such as ozone(臭氧),nitrogen dioxide(二氧化氮)

  • Some food preservatives, including nitrites(亚硝酸盐)

  • Aerobic activity(有氧运动)

  • Metabolism of fats(脂肪代谢)

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抗氧化能力排序

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Melanocyte:黑素细胞

Estrogen:雌激素

Malignant melanoma:恶性黑素瘤

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前列腺癌与抗氧化作用

  • The second highest cause of cancer death in US men in 1997.

  • Men with lowest plasma beta-carotene had increased risk of prostate cancer. When supplemented with beta-carotene, their prostate cancer risk reduced by 36%.

  • Lycopene (from tomato products) halved the risk of prostate cancer.

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乳腺癌与抗氧化作用

  • Adding lutein(叶黄素) and zeaxanthin(玉米黄质) to breast cancer cell cultures significantly suppressed their cell division.

  • Canthaxanthin(角黄素), b-carotene and astaxanthin(虾青素) inhibit mammary tumor(乳腺瘤) growth in mice.

  • A mixture of carotenoids in the diet may prevent spread of breast cancer cells.

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心脏病与抗氧化作用

  • Free radicals, lipid peroxidation and oxidation of LDL are implicated initiatitors of atherosclerosis(动脉硬化).

  • 50 mg beta-carotene on alternate days reduced the risk of heart attacks by 40% for male physicians.

  • 25,802 men and women for up to 14 years showed the risk of heart attack increased as blood beta-carotene decreased.

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防晒与抗氧化作用

  • Free radicals contribute to wrinkles by breaking down the structure of collagen, a connective tissue protein aiding elasticity.

  • A news report from Paris this year showed that applying beta-carotene,and vitamins C and E to skin can slow wrinkle formation 23% and reduce existing wrinkles by 8%.

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免疫系统

  • Our immune system is made up of many lines of defense for our bodies

  • It includes our skin, phagocytes(吞噬细胞), T-cells, antibodies

  • It defends us against microorganisms, allergens(过敏原) and our own malignant cells

  • It usually declines with age, but this decline can be reduced with antioxidants

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嗜中性粒细胞

补体系统

巨噬细胞

浆细胞

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免疫系统与抗氧化作用

  • As part of the large physicians health study there were observations on natural killer cell activity (important in surveillance for cancer cells and fighting infections).

  • They showed men taking 50mg beta-carotene supplements on alternate days had 42% greater killer cell activity than those taking placebos(安慰剂).

  • Women on low carotenoid diets had suppressed immune responsiveness of lymphocytes(淋巴细胞). This improved when supplemented with mixed carotenoids concentrates.

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6.5 自由基与衰老

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http://www.cpawscalgary.org/education/images/galapagos-tortoise.jpg

Rockfish

Galapagos Tortoise

Myostis lucifugus棕色鼠耳蝠:

www.akmarine.org

www.borealforest.org

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6.5.1 衰老的进化理论

  • “Aging, from an evolutionary point of view, can be defined as a progressive decline in fitness (the ability to survive and reproduce) with increasing age.” –Evolutionary Theories of Aging, Sharon Phaneuf.

  • There are three major theories that describe an evolutionary mechanism for aging:

  • The Accumulated Mutations Theory(突变积累论)

  • The Antagonistic Pleiotropy Theory(忍气吞声论)

  • The Disposable Soma Theory(弃车保帅论)

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弃车保帅论

  • “DNA repair, protein turnover, antioxidant defenses, etc. are expensive for an organism.”

  • If an organism devotes more energy towards reproduction than maintaining its body (soma), it will have more reproductive success.

  • “If nine out of ten newborn wild mice die before the age of 10 months, it would make little sense to use precious metabolic resources to maintain the soma beyond the expected lifetime of the organism.” (Evolutionary Theories of Aging, Paneuf, S.)

  • This theory best explains lifespan differences between species.

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  • As extrinsic mortality increases in a species, energy devoted to somatic maintenance decreases.

  • Therefore, animals that are protected from extrinsic mortality are afforded greater maximum lifespans.

  • For example, bats and birds fly, turtles have shells, and some animals have larger body mass and therefore fewer predators to target them.

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6 5 2

6.5.2 多劳多损论

  • Chapuisat and Keller hypothesized that the minor workers would have a longer maximum lifespan.

  • The ants were counted at the callow(幼蚁) stage when they were pale colored. This allowed the researchers to be certain they were very young ants.

  • They were allowed to form three colonies from colony fragments set up in an environment where the ants had little foraging requirements in order to keep extrinsic mortality low.

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“Division of Labour Influences the Rate of Ageing in Weaver Ant Workers.”

MINOR WORKERS DARK LINE

MAJOR WORKERS LIGHT LINE

ALL COLONIES

The ant colony in graph (c) was completely destroyed by Argentine Ants at 34 weeks.

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弃车保帅论的旁证

  • The results supported the hypothesis by Chapuisat and Keller. The minor workers lived significantly longer than the major workers.

  • This finding directly supports the idea that individuals with higher rates of extrinsic mortality (major workers), have decreased longevity when compared to individuals at lower risk (minor workers).

  • This supports the Disposable Soma Theory of Aging.

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6.5.3 端粒酶缩短短寿论

  • Mϋller, W. E. G. and Mϋller, Isabel, 2002, Germany.

  • Two long lived marine sponges, Suberites domuncula and Geodia cyandonium, were analyzed for telomerase activity in vivo.

  • “Most sponge species show a continuous growth and long life span.” An extreme example is Cinachyra antarctica which may live to be 1,500 years old. There have even been estimates of sponges living 10,000 years.

  • Both S. domuncula and G. cyandonium seem to be very long living, though they have not been assigned a typical lifespan.

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海绵类动物的研究

  • Tissue samples from the sponges were shaken apart to make cellular cultures.

  • When the cells are dissociated, they cease to express telomerase, as they did before they were separated.

  • They formed primmorphs (organization of dissociated sponge cells that maintained their ability to proliferate and are proliferating).

  • Cells that have formed a primmorph regain their telomerase expression.

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结论

  • Since sponges are multicellular with more than one cell type, they must be able to control the rate of cellular growth and death in order to regulate the number of each cell type, somatic or germ.

  • Because of this, Mϋller and Mϋller propose “concomitant regulation of apoptosis and telomerase activity.”

  • A question left unanswered by this study is: do sponges have the clock that initiates the switch from immortal to senescent cells.

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Telomeres shorten more slowly in long lived birds and mammals than in short lived ones

“Telomeres Shorten More Slowly in Long-lived Birds and Mammals than in Short-lived Ones”

Mammalian Data with human inclusion

Avian Data m=+17

Z.F. T.S. A.P. C.T. S.P.

Human

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The evolution of mammalian aging

“The Evolution of Mammalian Aging”

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衰老与自由基结论

  • There are differences in longevity in many species that can be explained biochemically.

  • Research that explores the causes of differential longevity is very important to determining the causes of aging.

  • A number of negligibly senescent species also provide valuable information about the aging process.

  • In every negligibly senescent species studied, telomerase has been active, or has the ability to be activated in somatic cells.

  • The mitochondrial inefficiency models for the small mammal studied here have not, to my knowledge been comparatively studied in other species.

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  • Inside your tomato

  • Tomatoes contain a lot of nutrients, among them vitamins C and B-complex and the minerals iron(铁) and potassium(钾). Also in the mix are carotenoids (kuh-ROT-uh-noids). These include lycopene and beta carotene, which is converted in the body into vitamin A.

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Genetically identical

twins

Lifestyle

Genetics

Alcohol

Nicotine

UV

Healthy

lifestyle

Environment

Metabolism

Diet

Which parameters

affect

biological aging ?

Lawrence Journal World, 8. Jan. 2000

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6.6 一氧化氮自由基

  • First described in 1979 as a potent relaxant(松弛剂) of peripheral vascular smooth muscle(外周血管平滑肌).

  • Used by the body as a signaling molecule.

  • Serves different functions depending on body system. i.e. neurotransmitter(神经递质), vasodilator(血管扩张剂), bactericide(杀菌剂).

  • Environmental Pollutant

  • First gas known to act as a biological messenger(生物信号分子)

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一氧化氮的分子结构及特性

  • Nitric oxide is a diatomic free radical consisting of one atom of nitrogen and one atom of oxygen(双原子)

  • Lipid soluble and very small for easy passage between cell membranes(脂溶,体积小)

  • Short lived, usually degraded or reacted within a few seconds(寿命短)

  • The natural form is a gas(气态)

O

N

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COO-

COO-

COO-

+ O2

C

H

+H3N

C

H

+

NADPH

NAD+

+H3N

C

H

NO

(CH2)3

(CH2)3

(CH2)3

NOS

NOS

NH

NH

NH

+

C

NH2+

C

N

OH

C

H

H2N

H2N

O

NH2

Arginine

N-w-Hydroxyarginine

Citrulline(瓜氨酸)

一氧化氮生物合成

  • Nitric oxide is synthesized from L-arginine (精氨酸)

  • This reaction is catalyzed by nitric oxide synthase, a 1,294 aa enzyme

+H3N

河北工业大学 生物物理学


5057222

一氧化氮合酶的类型

  • NOS I(神经系统)

    • Central and peripheral neuronal cells(中心和外周神经细胞)

    • Ca+2 dependent, used for neuronal communication

  • NOS II(免疫系统)

    • Most nucleated cells, particularly macrophages(巨噬细胞)

    • Independent of intracellular Ca+2

    • Inducible in presence of inflammatory cytokines(炎症因子)

  • NOS III(循环系统)

    • Vascular endothelial cells(血管内皮细胞)

    • Ca+2 dependent

    • Vascular regulation(血管调节)

河北工业大学 生物物理学


5057222

一氧化氮在人体中的作用

  • Nitric Oxide in the human body has many uses which are best summarized under five categories.

    • NO in the nervous system

    • NO in the circulatory system

    • NO in the muscular system

    • NO in the immune system

    • NO in the digestive system

河北工业大学 生物物理学


5057222

神经系统

  • Nitric oxide as a neurotransmitter

    • NO is a signaling molecule, but not necessarily a neurotransmitter

    • NO signals inhibition of smooth muscle contraction, adaptive relaxation, and localized vasodilation(血管舒张)

  • Nitric oxide believed to play a role in long term memory

    • Synthesis mechanism involving Ca/Calmodulin activates NOS-I

    • This starts a cycle of nerve action potentials driven by NO

河北工业大学 生物物理学


5057222

循环系统

  • NO serves as a vasodilator(血管舒张剂)

    • Released in response to high blood flow rate and signaling molecules (乙酰胆碱和缓激肽)

    • If NO synthesis is inhibited, blood pressure skyrockets(暴涨)

  • NO aids in gas exchange between hemoglobin and cells

    • Hemoglobin is a vasoconstrictor, Fe scavenges NO

    • NO is protected by cysteine group when O2 binds to hemoglobin

    • During O2 delivery, NO locally dilates(扩张) blood vessels to aid in gas exchange

    • Excess NO is picked up by with hemoglobin CO2

河北工业大学 生物物理学


5057222

肌肉系统

  • NO was orginally called EDRF (血管内皮产生的松弛因子)

  • NO signals inhibition of smooth muscle contraction

    • Ca2+ is released from the vascular lumen activating NOS

    • This causes guanylyl cyclase to produce cGMP

    • A rise in cGMP causes Ca2+ pumps to be activated, thus reducing Ca2+ concentration in the cell

    • This causes muscle relaxation(肌肉松弛)

河北工业大学 生物物理学


5057222

免疫系统

  • NOS II catalyzes synthesis of NO used in host defense reactions

    • Synthesis of NO happens in most nucleated cells, particularly macrophages

    • NO is a potent inhibitor of viral(病毒) replication

  • NO is a bactericidal agent

    • NO is created from the nitrates(硝酸盐) extracted from food near the gums(齿龈)

    • This kills bacteria in the mouth that may be harmful to the body

河北工业大学 生物物理学


5057222

消化系统

NO is used in adaptive relaxation

  • NO promotes the stretching(伸展) of the stomach in response to filling.

  • When the stomach gets full, stretch receptors trigger smooth muscle relaxation through NO releasing neurons

河北工业大学 生物物理学


5057222

谢谢各位同学!

河北工业大学 生物物理学


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