.رابطه بین کمبود ویتامین D و انتی بادی ضد مخمر نان و بیمارهای نقص ایمنی با فاکتور رشد میدکین growth factor midkine (MK) .

Midkine in vitamin D deficiency and its association with anti-Saccharomyces cerevisiae antibodies

AUTHOR(S)
Serinkan Cinemre, F.; Cinemre, Hakan; Karacaer, Cengiz; Aydemir, Birsen; Nalbant, Ahmet; Kaya, Tezcan; Tamer, Ali
PUB. DATE
February 2016
SOURCE
Inflammation Research;Feb2016, Vol. 65 Issue 2, p143
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Objectives and design: The growth factor midkine (MK) is a protein that is involved in cancer, inflammation, immunity. Vitamin D is a potent immunomodulator. Anti-Saccharomyces cerevisiae antibody (ASCA) is reported in autoimmune disorders, some of which are among the causes of vitamin D deficiency. 
 The objective of this study was to investigate a possible association of MK and ASCA with vitamin D deficiency. Materials and methods: 208 adults presented to internal medicine outpatient clinic for history and physical examination has been studied. Serum biochemistry, vitamin D, MK, ASCA-IgG and -IgA, IL-1β, IL-6, IL-8, TNF-α, PDGF, VEGF were obtained. Results: Vitamin D deficiency was 74.2 %. Serum MK level was significantly higher in vitamin D-deficient compared to vitamin D-sufficient individuals (1138.1 ± 262.8 vs 958.6 ± 189 pg/mL, respectively; P < 0.009). Serum MK levels were also significantly higher in both ASCA-IgG and -IgA positives compared to negatives (1318.5 ± 160.3 vs 1065.5 ± 256.1, P = 0.008 and 1347.7 ± 229.7 vs 1070.1 ± 250.9 pg/mL, P = 0.011, respectively). Vitamin D was significantly lower in ASCA positives ( P = 0.044).Vitamin D showed positive correlation with IL-1β ( r 0.338, P < 0.009) and negative correlation with VEGF ( r −0.366, P < 0.004). Conclusions: MK was significantly elevated in vitamin D deficiency and associated with ASCA positivity which was significantly increased in vitamin D deficiency. These findings suggested that molecular mechanism of vitamin D deficiency may be related with some inflammatory processes.
پروتینی به نام فاکتور رشد میدکین   growth factor midkine (MK) در  بدن است که جلوی التهاب اندام ها و سرطان را می گیرد در کسی که کمبود ویتامین D دارد  سیستم دفاعی بدن در برابر سرطان ومخمر نان  و بیماری های اتوایمون به درستی عمل نمی کند  و ریسک سرطان و بیماری های مزمن بالا می رود  در ضمن زمانی که شما کمبود ویتامین D دارید ماده ای ضد مخمر نان در بدن شما  ایجاد می شود که  ایین انتی بادی ضد مخمر نان بعد ها ممکن است سرطان کولون و التهابات مختلف بدهد  مثل بیماری های خود ایمنی ارتریت روماتید ام اس و دیگر بیماریها می شود

تغییرات ژنتیکی بر روی مخمرنان(ساکارومایسس سرویزیه ) برای نسل کشی انسانها را چه کسانی انجام دادند / / Saccharomyces cerevisiae /Yeast, the Spam Filter

 تغییرات ژنتیکی بر روی مخمرنان(ساکارومایسس سرویزیه ) برای نسل کشی  انسانها را چه کسانی انجام دادند / / 

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New & Noteworthy

Yeast, the Spam Filter

November 11, 2015
magine what our email inboxes would look like if we didn’t have spam filters! To find the meaningful emails, we’d have to wade through hundreds of messages about winning lottery tickets, discount medications, and other things that don’t interest us.
When it comes to sorting out meaningful mutations from meaningless variation in human genes, it turns out that our friend S. cerevisiae makes a pretty good spam filter. And as more and more human genomic sequence data are becoming available every day, this is becoming more and more important.
For example, when you look at the sequence of a gene from, say, a cancer cell, you may see many differences from the wild-type gene. How can you tell which changes are significant and which are not?
SuperBud to the rescue! Because many human proteins can work in yeast, simple phenotypes like viability or growth rate can be assayed to test whether variations in human genes affect the function of their gene products. This may be one answer to the increasingly thorny problem of variants of uncertain significance—those dreaded VUS’s.
In a new paper in GENETICS, Hamza and colleagues systematically screened for human genes that can replace their yeast equivalents, and went on to test the function of tumor-specific variants in several selected genes that maintain chromosome stability in S. cerevisiae. This work extends the growing catalog of human genes that can replace yeast genes.
More importantly, it also provides compelling evidence that yeast can help us tell which mutations in a cancer cell are driver mutations, the ones that are involved in tumorigenesis, and which are the passenger mutations, those that are just the consequence of a seriously messed up cell. Talk about a useful filter!
The researchers started by testing systematically for human genes that could complement yeast mutations. Other groups have done similar large-scale screens, but this study had a couple of different twists.
Previous work from the Hieter lab had identified genes in yeast that, when mutated, made chromosomes unstable: the CIN (Chromosome INstability) phenotype. Reduction-of-function alleles of a significant fraction (29%) of essential genes confer a CIN phenotype. The human orthologs of these genes could be important in cancer, since tumor cells often show chromosome rearrangements or loss. 
So in one experiment, Hamza and colleagues focused specifically on the set of CIN genes, starting with a set of 322 pairs of yeast CIN genes and their human homologs. They tested functional complementation by transforming plasmids expressing the human cDNAs into diploid yeast strains that were heterozygous null mutant for the corresponding CIN genes. Since all of the CIN genes were essential, sporulating those diploids would generate inviable spores—unless the human gene could step in and provide the missing function.
In addition to this one-to-one test, the researchers cast a wider net by doing a pool-to-pool transformation. They mixed cultures of diploid heterozygous null mutants in 621 essential yeast genes, and transformed the pooled strains with a mixture of 1010 human cDNAs. This unbiased strategy could identify unrecognized orthologs, or demonstrate complementation between non-orthologous genes.
In combination, these two screens found 65 human cDNAs that complemented null mutations in 58 essential yeast genes. Twenty of these yeast-human gene pairs were previously undiscovered.
The investigators looked at this group of “replaceable” yeast genes as a whole to see whether they shared any characteristics. Most of their gene products localized to the cytoplasm or cytoplasmic organelles rather than to the nucleus. They also tended to have enzymatic activity rather than, for example, regulatory roles. And they had relatively few physical interactions.
So yeast could “receive messages” from human genes, allowing us to see their function in yeast. But could it filter out the meaningful messages—variations that actually affect function—from the spam? 
The authors chose three CIN genes that were functionally complemented by their human orthologs and screened 35 missense mutations that are found in those orthologs in colorectal cancer cells. Four of the human missense variants failed to support the life of the corresponding yeast null mutant, pointing to these mutations as potentially the most significant of the set.
Despite the fact that these mutations block the function of the human proteins, a mutation in one of the yeast orthologs that is analogous to one of these mutations, changing the same conserved residue, doesn’t destroy the yeast protein’s function. This underscores that whenever possible, testing mutations in the context of the entire human protein is preferable to creating disease-analogous mutations in the yeast ortholog.
Another 19 of the missense mutations allowed the yeast mutants to grow, but at a different rate from the wild-type human gene. (Eighteen conferred slower growth, but one actually made the yeast grow faster!)
For those 19 human variants that did support life for the yeast mutants, Hamza and colleagues tested the sensitivity of the complemented strains to MMS and HU, two agents that cause DNA damage. Most of the alleles altered resistance to these chemicals, making the yeast either more or less resistant than did the wild-type human gene. This is consistent with the idea that the cancer-associated mutations in these human CIN gene orthologs affect chromosome dynamics.
As researchers are inundated by a tsunami of genomic data, they may be able to turn to yeast to help discover the mutations that matter for human disease. They can help us separate those emails touting the virtues of Viagra from those not-to-be-missed kitten videos. And when we know which mutations are likely to be important for disease, we’re one step closer to finding ways to alleviate their effects. 
by Maria Costanzo, Ph.D., Senior Biocuration Scientist, SGD

(محفظه ابر) اتاقک ابر(اتاقک ویلسون) برای رویت ذرات الفا بتا و اشعه کیهانی/Cloud Wilson chamber


کمبود «ویتامین D» احتمال گرایش به اعتیاد را بالا می برد ...


بسته بندی های رنگ وارنگ از ماده مخدر اسپایس با نام ها و اشکال زیبا برای بخور دادن به گاوهای مشکل پسند جهان در فروشگاها موجود است !.



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قابل توجه کسانی که دام داری دارند !

بخور اسپایس  برای طویله گاوهای شما  در بسته بندی های زیبا به تهران رسید  !

داداش یگهو گول بسته  بندی را نخوری ؟
روی اکثرا انها  به انگلیسی البته خیلی  ریز  نوشته : مصرف انسانی ندارد ؟Not for Human Consumption
حال این بسته بندهای زیبا و قشنگ  با وزن 1 تا 3 گرم  انهم  برای ماده ای که به عنوان کود شیمیایی و مواد صنعتی  بخور برای  دام  وارد می شود چرا باید  این همه اشکال قشنگ و رنگ وارنگ باشه   الله الم !

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  تازه وزن این ماده که به عنوان بخور برای طویله گاوها است چرا سه گرم است .
اخر  داخل  طویله به این بزرگی که من می بینم !این  سه گرم دود بشه که به  همه گاوها نمی رسه!

یعنی گاوها موقع خرید  می روند داخل فروشگاهای اسمارت  شاپ (هوشمند )  و  زمان  خرید از دیدن این عکس ها خوششون می اید و یکی را انتخاب می کنند و می خرند !
 بابا این خارجی ها گاوهاشون چقدر با هوشند !!

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 شاید یک گاوی یک زمانی  ارزو داشته مثلا فیدل کاسترو بشه و یک گاو  دیگر می خواسته  به جای گاو بودن میمون بشه !
به ما چه !

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گیاه کانابیس(ماری جوانا ) را در خارج  از ایران در بسیاری کشورها دام داری ها با مجوز دولت  برای خوراک گاو می کارند و گاو بعد از مصرف مخدر گل (ماری جوانا )اشتهای گاوی پیدا کند و کلی  چاق و چله میشه ! این هم بخور گاو است دیگه ؟
چقدر گاو های خارجی حال هول  می کنند !! خوب البته رئیس گاو داری   بعد  بیشتر از گاوها شیر می دوشه  و کلی سینه گاوها را فشار می دهد و گاو هم که تو عالم هپروت و نعشگی است حال هم می کنه !
شیر گاوه که تمام شد و مغزش هم توهم زد و دیوانه شد و جنون گاوی گرفت  رئیس گاو داری می برش برای ذبح کردن .
  و همه گاوهای ماریجوانای خورد و دود اسپایس گرفته  را پخ پخشون می کند و با گوشتش سوسیس کالباس یا بیفتک  درست می کنند
بیچاره گاوه خبر نداره اخر عاقبت این خوراک ماریجوانا دادن به جای علف  و این بخور اسپایس توی طویله   به جای بوی پشکل  اخر عاقبتش چیه !
خوب گاوه دیگه.
مثل ما و  بچه های ما که نیست ما می فهمیم  که گاو نیستیم چون  عقل و شعور داریم  
اما گاوه  که نمی فهمه گاوه !
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اقا توجه
این ها که بالا نوشتم  شوخی نبود !
  به راستی روی این بسته های زیبا با وزن بین 1 تا 5 گرم 10گرم  نوشته مصرف انسانی ندارد
Not for Human Consumption
و دارای یک ماده شیمیایی مخدر روانگردان است که صد برابر قویتر از مخدر گل  است
نام خیابانی این مواد  اسپایس یا ادویه است  و بیش از 3000 نوع بسته بندی به اشکال جالب دارد
  ماری جوانا صنعتی یعنی همان اسپایس خودمونه که صد برابر قویتر از مخدر گل است .
یک بار بزنی دیگر مخ بیمخ !
یعنی ادم با مصرف مخدر اسپایس تبدیل به گاو می شود !×!!


عوامل تشدید کننده خطر ابتلا به بیماری زوال عقل.

عوامل تشدید کننده خطر ابتلا به بیماری زوال عقل

دمانس یا زوال عقل بر اثر تخریب سلول‌های مغز به‌وجود می‌آید و باعث کاهش تدریجی عملکرد شناختی فرد می‌شود. پژوهشگران به تازگی عواملی را شناسایی کرده‌اند. شایع‌ترین نوع دمانس آلزایمر است.
29.10.14 FUGD Fit und gesund Demenz
ضعف شنوایی
زندگی اجتماعی برای سالمندانی که دچار ضعف شنوایی هستند رنج‌آور است. توانایی‌های ذهنی افرادی که دچار سنگینی گوش هستند سریع‌تر از سالمندانی که از شنوایی خوبی برخوردارند کاهش می‌یابد.
توصیه پژوهشگران آمریکایی که ارتباط بین این دو را کشف کرده‌اند این است: «سنگینی گوش را نباید دست‌کم بگیرید و بلافاصله برای استفاده از سمعک اقدام کنید.»
داروهای خواب‌آور
پژوهش‌ها نشان داده‌اند داروهایی که به میزان زیاد یا در مدت طولانی برای رفع بی‌اختیاری ادرار، بی‌خوابی یا افسردگی استفاده ‌می‌شوند (حتی بعد از قطع مصرف) فرد را برای ابتلا به دمانس مستعدتر می‌کند.
پژوهشگران توصیه می‌کنند که افراد مصرف داروهای حاوی آنتی کولینرژیک را به حداقل برسانند و تاثیرات درمانی این داروها را به‌طور مرتب کنترل کنند و در صورت مشاهده بی‌تاثیری داروها این روش درمانی را متوقف کنند.

ارتباط بین کمبود ویتامین D در زنان باردار و توانایی های یادگیری کودکان.

طبق نتایج تحقیقات دانشمندان اسکاتلندی، میزان ویتامین D در زنان باردار می تواند با برخی ناتوانایی های یادگیری کودکان مرتبط باشد.
، محققان دانشگاه گلاسکو اسکاتلند دریافته اند ناتوانی های یادگیری در کودکان متولدشده در فصل زمستان که نور کافی خورشید برای تولید ویتامین D وجود ندارد، شایع تر است.
این مطالعه نشان می دهد ۸.۹ درصد کودکان متولدشده بین ماه های دی تا اسفند دارای ناتوانی های یادگیری هستند. در عوض، تنها ۷.۶ درصد کودکان متولدشده در ماه های فصل تابستان دارای ناتوانی در یادگیری بودند.
مهم ترین ناتوانی یادگیری در بین این کودکان مربوط به اوتیسم، مشکلات فکری و مشکلات یادگیری نظیر خوانش پریشی (اختلال در روان خوانی یا درک مطلب) بود.
به گفته محققان، کمبود ویتامین D می تواند به روند رشد مغز در طول بارداری آسیب برساند.
داده های این مطالعه به طور مرتب در سطح اسکاتلند جمع آوری شد و بیش از ۸۰۰ هزار کودک حاضر در مدارس اسکاتلند بین سال های ۲۰۰۶ تا ۲۰۱۱ مورد مطالعه قرار گرفتند.

.رابطه بین کمبود ویتامین D و انتی بادی ضد مخمر نان و بیمارهای نقص ایمنی با فاکتور رشد میدکین growth factor midkine (MK) .

راه پیشگیری از ابتلای جنین به اوتیسم در دوران بارداری و ...


:کمبود «ویتامین D» احتمال گرایش به اعتیاد را بالا می برد ا

اولین درمان اعتیاد به روش سایکدلیک در ایران:کمبود «ویتامین ...

90 درصد خانواده‌های ایرانی دچار کمبود کلسیم هستند

راه پیشگیری از ابتلای جنین به اوتیسم در دوران بارداری و درمان بیماران اوتیسم و بیش فعال با ویتامین ب6 و منیزیوم Vitamin B6, Magnesium and Autism

راه پیشگیری  از ابتلای جنین به اوتیسم در دوران بارداری و درمان بیماران اوتیسم و بیش فعال  با ویتامین ب6 و منیزیوم  Vitamin B6, Magnesium and Autism

ویتامین B6 (پیریدوکسین) یک  ویتامین ضروری برای انسان  است  بدن سالم انسان برای عملکرد بیش از  60 فرآیندهای بیولوژیکی  به این ویتامین نیاز دارد 
 ویتامین B6 ) pyroxidal-5-فسفات( (PLP)، آنزیمی است که برای آزاد شدن انرژی از  نشاسته و شکستن پروتئین  ها  مورد نیاز میتوکندری های ما می باشد  این ویتامین در تولید مواد شیمیایی مهمی در مغز  لازم است 
منیزیم یک ماده معدنی ضروری است که برای حفظ  سلامت  سلول های بدن انسان به خصوص  عملکرد صحیح سلول های مغز و ماهیچه لازم است. کمبود منیزیم نادر است، اما برخی تحقیقات نشان می دهد که کودکان مبتلا به اوتیسم  و بیش فعال دارای میزان کمتری از منیزیم هستند 
برخی از والدین  بیماران مبتلا به اوتیسم و بیش فعال به عنوان یک  مکمل رژیم غذایی  ترکیبی  از  ویتامین B6 و منیزیم  را به کودکان خود می دهند 
 منیزیم در بسیاری از غذاها یافت  می شود به خصوص در سبزیجات سبز مثل ، دانه ها، آجیل و غلات بیشتر  است. می توان از انها  در رژیم غذایی  کودکان  بطور روزانه  استفاده کرد 
. در حالی که  هنوز دوز مناسب برای کودکان مبتلا به اوتیسم مشخص نیست ، یک گزارش تحقیقاتی اظهار می دارد د یک دوز 10-15 میلی گرم / کیلوگرم / روز در دو دوز منقسم  کافی است 
برخی از محققان گزارش داده اند که کودکان مبتلا به اوتیسم  کمبود منیزیم دارند. تحقیقات نشان داده است که  کودکان مبتلا به اوتیسم دارای  سطح  منیزیم  کمتری در مو و خون  نسبت به  کودکان غیر مبتلا به اوتیسم   هستند
  شواهدی وجود دارد که مکمل منیزیم و ویتامین ب6 می تواند یک اثر آرام بخش بر روی برخی از کودکان مبتلا به اختلال نقص توجه (بیش فعالی) (ADHD)  داشته باشد .

گذشته از ضرورت منیزیم برای سلامت جسمی  و  همچنین عملکرد مناسب مغز،  هنوز هیچ نظریه خاص در مورد چگونگی  عملکرد این مکمل ها ابراز نشده است 
. دو مکمل اغلب با هم داده می شود، برخی از محققان می گویند  که عوارض جانبی درمان با  ویتامین B6 توسط منیزیم حذف شده است. با این حال مطالعات  دیگر  نشان داده است که  مصرف  ویتامین B6 به تنهایی هیچ عوارض جانبی  نشده است 
دو مطالعه نشان داد که ویتامین B6 و منیزیم می تواند  اثرات مثبت قابل توجهی بر رفتار  کودکان مبتلا به اوتیسم  داشته باشد .
 یکی از این مطالعات دو سو کور، نشان می دهد که درمان با ویتامین B6 و منیزیم  می تواند رفتار در برخی کودکان مبتلا به اوتیسم را بهبود بخشد.
 در  بررسی کودکان مبتلا به اوتیسم که  با  مصرف ویتامین B6 و منیزیم  تحت درمان بودند عوارض جانبی قابل توجهی دیده نشده است 
 در کودکان مبتلا به صرع مصرف  میزان بالای ویتامین B6  به مدت شش ماه، هیچگونه  عوارض جانبی قابل توجهی نداشته است 

دوز منیزیوم dose of 10-15 mg/kg/day 
روزانه بین 10 تا 15 میلی گرم برای هر کیلو وزن بدن  در روزاست بهتر است در دو دوز تقسیم شود

دوز ویتامین ب6 =18 mg/kg body weight/day هیجده میلی گرم برای هر کیلوگرم وزن بدن  در روز است 

منیزیم می تواند  در دوز های بیشتر از 600 میلی گرم در روز  سمی باشد. اما  با این حال در ، مطالعات  با استفاده از مکمل های منیزیم در دوزهای متوسط ​​(حدود 200 میلی گرم در روز) عوارض جانبی قابل توجهی گزارش نشده است.


اهمیت ویتامین D و کلسترول HDL در دوران بارداری  در  جلوگیری از بیماری اوتیسم و تکانشگری عصبی (بیش فعالی ) و جلوگیری از اعتیاد به مواد مخدر

 مصرف  ویتامین D و کلسترول در دوران بارداری، می تواند کمک موثری برای جلوگیری از بروز اوتیسم و تکانشگری  در کودکان  بکند 
 ویتامین D و کلسترول (HDL) نقش حساس و موثری در  رشد مغز و سیستم عصبی مرکزی در دوران جنینی دارد 
. کمبود کلسترول HDL و / یا ویتامین D در دوران بارداری  ممکن است خطر ابتلا به اوتیسم را در کودکان افز ایش بدهد  
 در  یک مطالعه  یک ارتباط قابل توجه بین کلسترول و نشانه های بیماری اوتیسم و سندرم اسپرگر دیده شده است  پژوهش نشان می دهد که سطوح پایین ویتامین D در دوران بارداری و در طول دوره شیرخوارگی ممکن است خطر ابتلا به اوتیسم را افزایش دهد.

کمبود «ویتامین D» احتمال گرایش به اعتیاد را بالا می برد ...



B6 AND MAGNESIUM

Elevated cytokine levels in children with autism ... - ...

Sulphation and Autism: What are the links? | The Autism File

Brain metabolism in autism. Resting cerebral glucose utilization rates as measured with positron emission tomography.

Improvement of neurobehavioral disorders in children supplemented withmagnesium-vitamin B6. II. Pervasive developmental disorder-autism.


درمان نگهدارنده اوتیسم و بیش فعالی با ویتامین ب6 , منیزیم/Vitamin B6 (and magnesium) in the Treatment of Autism.ADHD

Treatment Overview

Vitamin B6 (pyridoxine) is an essential vitamin that is necessary for more than 60 biological processes in a healthy human body. The body converts vitamin B6 into pyroxidal-5-phosphate (PLP), an enzyme that is used to release energy from starches and break down proteins. PLP is also used in the production of important chemicals in the brain.

Sulphation and Autism: What are the links?نقش سولفوناسیون در ایجاد بیماری اوتیسم.

Sulphation and Autism: What are the links?

By Rosemary H. Waring , School of Biosciences, University of Birmingham, Birmingham   B15 2TT   U.K.

Sulphate synthesis

I have always been interested in the sulphation pathway as addition of a sulphate group can make dramatic changes to the properties of both drugs and tissue components. Our group first started working in the field of autism about 15 years ago, when we were asked to measure the metabolism of paracetamol in an autistic child. At the time, I had only heard the orthodox medical view that autism was ‘all in the mind’ and had no biochemical basis. To our great surprise, we found that children with autism, unlike the age-matched controls, were much less able to form the sulphate conjugate of paracetamol, although the other metabolic pathways were normal. We went on to look at the levels of sulphate in the blood plasma, because sulphation capacity depends on both the amount of sulphate available and also the activity of the enzyme that carries out the reaction. We found that autistic children generally had low sulphate levels, typically about 10-15% of the control values. Sulphate is produced in vivo by oxidation of methionine or cysteine, both sulphur – containing amino acids which are provided from dietary proteins, and this pathway probably provides ~ 80% of the sulphate required in man.
The first stage in this process involves the enzyme cysteine dioxygenase (CDO); cysteine sulphinic acid is formed and undergoes fission to provide sulphite (SO 3 2- ) ions which are then further oxidised to sulphate (SO 4 2- ) ions by the enzyme sulphite oxidase (SOX). Obviously, if CDO or SOX have reduced activity, the provision of sulphate will also be decreased.   The human CDO gene is localised to chromosome 5 (5q22-23) and it is interesting that analysis of 110 multiplex families with autism, where one sibling had autism and the other a diagnosis of Asperger’s syndrome or pervasive developmental disorder, suggested linkage on chromosomes 5 and 19 while a study on ADHD (attention deficit/hyperactivity disorder) found a linkage to chromosome 5q33.   The CDO protein is found in heart, thyroid and kidney, as well as brain and the liver, localisation in the CNS being particularly found in the cerebellum and the Purkinje neurons; these are known to be abnormal in patients with autistic spectrum disorders.   CDO activity is variable in human populations and there are sub-sets with lower activity (~ 30% of the population) or null activity (~ 3% of the population). 
  The null S-oxidisers are heavily over-represented in chronic disease states with an auto-immune component such as rheumatoid arthritis and primary biliary cirrhosis; in general auto-immune problems are more common in the family background of autistic children.   We now know that inflammatory cytokines such as TNF-?, which are at relatively high levels in many autistic children and in auto-immune diseases, can reduce expression of CDO and SOX and therefore reduce the supply of sulphate for conjugation with drugs and biocomponents. Expression of both CDO and SOX was inhibited in vitro at levels of 0.1 ng/ml TNF- a , concentrations which could easily occur in vivo during an infection.   This work, however has all been carried out in vitro and it is difficult to deduce from this whether the effects would also occur in vivo .   To check this, a small pilot study was carried out in this laboratory when students and staff were offered a vaccination against hepatitis B   (the antigen is in fact one of the virus coat proteins).   Volunteers were asked to take a therapeutic (1000 mg) dose of paracetamol (acetaminophen) on Day 1 before the vaccination which took place on Day 7 and paracetamol was also ingested on days 8, 10 and 15 afterwards. The vaccination had no ill effects apart from slight reddening at the injection point in some volunteers but it greatly altered the detoxication pathways for paracetamol.   In particular, the phase 2 conjugation reaction of sulphation was severely depressed, only reaching control values about a week later. It is clear that even a simple vaccination in healthy volunteers can dramatically affect some metabolic pathways, at least in the short term.   It is obvious from these results that the process of sulphate formation and sulphation itself is potentially severely disrupted in inflammation; the in vivo findings appear to correlate with those seen in vitro , suggesting that cell culture systems can act as useful models.   It is interesting that autistic children who were challenged with a paediatric dose of paracetamol were less able to form its sulphated derivative than controls of the same age although the glucuronidation pathway was unaffected.   Their general metabolic profile was very similar to that found for the adult volunteers with a Hepatitis B vaccination.   This seems to be a general finding which has been replicated in UK, Italian and USA populations and probably reflects the fact that raised cytokine levels in autism have secondary effects on sulphation of a range of substrates. 
  This may explain why some children with autism are reported as responding badly to dosage with paracetamol and with other drugs; obviously toxic effects are more likely if clearance is impaired by reduced metabolism to water-soluble derivatives.

Sulphate in the brain

Principally, sulphation is a major inactivation pathway for catecholamines such as the neurotransmitter dopamine, about 80% of which is sulphated in man.   Usually, when chemical neurotransmitters are released in the central nervous system, they act at receptor proteins and are then inactivated by sulphation or by FAD-linked mono-oxygenases or alternatively are carried by transporter proteins back into the initiating neurone. Failure of a major pathway such as sulphation will lead to a neurotransmitter imbalance and raised serum and CSF levels of dopamine and elevated urinary levels of dopamine metabolites have been found in autistic children.   In rats, high dopamine concentrations like this are associated with stereotyped and repetitive behaviour, not unlike that sometimes seen in autism.   Other catecholamines, such as noradrenalin, also control behaviour and affect mood so that changes in their levels can have obvious effects.
Sulphation also affects the synthesis of brain tissue. Sulphated polysaccharides and glycosaminoglycans are so important in the development of the foetal and neonatal brain that any alteration in their structure may have serious consequences – it is currently thought that these compounds act as ‘scaffolding’ to direct the direction and ‘wiring’ of brain neurons. Sulphate transport across the placenta increases dramatically around the time of birth when most of the glial cells are being formed and these increased levels of sulphate are associated with formation of astrocytes and oligodendrocytes from progenitor cells.
 Children have higher levels of plasma sulphate than adults (0.47 nmol/l at birth decreasing to 0.33 nmol/l at 36 months; adult levels are around 0.27 nmol/l although there can be a wide range).   This relatively high level of sulphate, as compared with the adult state and with, for instance, laboratory rats, seems to show that humans have a definite   requirement for sulphation in neuronal development both before and after birth and that reduced levels could affect brain structure and function,. Recent research suggests that brain development relies on particular patterns of sulphation occurring in the right sequence; rather like the fairy tale of ‘Goldilocks and the three bears’ we need ‘not too little, not too much but just right’! But are infections in pregnancy, which would be expected to give raised cytokine levels and potentially reduce sulphate formation, actually linked with altered brain development or function in the baby? In a small pilot survey in this laboratory which looked at 200 mothers of autistic children, it was found that they were eight times more likely to have received antibiotic treatment for an infection in pregnancy than age-matched controls and 5 times more likely to have had long-term therapy for recurrent infections. Certainly studies using rats as a model have shown that increased cytokine levels in pregnancy affect the development of neural integration in the neonate; it seems probable that one of the many factors in autism may be raised levels of cytokines or other factors, possibly released in infections,   affecting sulphation and neurodevelopment.

Sulphation and the gastrointestinal tract

The process of sulphation also affects the functioning of peptides and proteins.   Mucin proteins, which line the gastrointestinal tract, are sulphated glyco-proteins which control adhesion and absorption of nutrients.   They have long peptide backbones with repeating sub-units and also peptide side-chains, rather similar to a ‘bottle-brush’.   These amino acid sequences also have strings of   attached sugars which are sulphated like the peptides themselves.   As the addition of sulphate residues (SO 4 2- ) sticks on net negative charges, the proteins spread out since the negative charges repel each other (Figure 1).   If the sulphate residues are lost, this leads to a protein which has a more globular structure and provides less protection for the tissues from the intestinal contents as there are ‘gaps’ between the proteins.   Reduced sulphation has been linked with gut dysfunction in irritable bowel disease and Andrew Wakefield’s group showed that lower levels of sulphation of the ileal mucins occured in children with autism which probably explains why gut permeability is increased in many autistic children. Sulphation of mucins increases their resistance to colonisation by pathogenic bacteria (and viruses).   It is interesting that Helicobacter pylori , which can colonise the stomach, only does so when it has produced a sulphatase enzyme to de-sulphate the gastric mucins.   This reduced sulphation of gut proteins may make Candida infections more likely in autistic children, since the slight negative charges on Candida cells would lead to their repulsion by negatively charged sulphate groups on the mucins.
Peptides can also be sulphated, usually on tyrosine residues, and the gastric hormones gastrin and cholecystokinin are good examples of this pathway.   Both are involved in the digestive process and both are activated by sulphation.   In a complex cascade, gastrin is sulphated and, with hydrochloric acid from the stomach, causes release of cholecystokinin, which also requires sulphation.   Together with peptide fragments released from proteins by hydrochloric acid in the stomach, this acts with the peptide hormone secretin on pancreatic tissue to induce the secretion of a range of proteolytic enzymes and also amylase and lipases. (Figure 2).   Without the sulphation process to trigger the release of pancreatic proteases such as trypsin and chymotrypsin, the complete digestion of proteins to their amino acid building blocks (proteolysis) cannot take place, so that peptides, rather than amino acids, are found in the gastrointestinal tract.  
 As reduced sulphation of mucins may have made the gut more permeable, the stage is set to allow peptides to penetrate into the blood stream. At the same time, the reduced levels of pancreatic amylase alter the digestibility of starch-based foods and allow increased fermentation of pathogenic bacteria while the decreased pancreatic lipase activity promotes formation of foul-smelling fatty stools which contain undigested triglycerides. Some peptides which cross the gut wall, particularly those derived from casein and gluten, have been found to be neuroactive with effects on the brain where they act at opioid receptors, affecting behaviour, mood and responses to physical stimuli such as pain.   This ‘leaky gut’ hypothesis therefore links with the opioid theory to explain why there are peptides in the circulation rather than amino acids and why they have such ready access to the central nervous system.   Although the blood-brain barrier is usually seen as being non-permeable to many compounds, it may, like the gut, be ‘leaky’ in autism.   Several studies have reported the presence of brain-derived proteins and antibodies, such as those from myelin, within the peripheral circulation.   If relatively large proteins can cross from the brain, it seems possible that peptides and proteins could potentially be transported into the brain, although the mechanisms involved are not known.   Simple diffusion across ‘leaky’ gap junctions may be all that is necessary.

Sulphotransferase enzymes in autism

Not only is there an impaired level of sulphate in many cases of autism, there is also often a corresponding lack of sulphotransferase activity.   These are the enzymes which carry out sulphation of a wide range of substrates.   They belong to a super-family which uses PAPS (3′-phosphoadenosine-5′-phosphosulphate) as a co-factor and are widely distributed throughout the body, sulphating tissue components and signal molecules such as steroids, thyroid hormones and neurotransmitters. The major enzymes responsible for the sulphation of phenols and catecholamines are called SULT1A1 and 1A3 respectively. Sulphotransferase activity is known to be altered in some dysfunctional states, for example most patients with migraine have low SULT1A1 and sometimes low SULT1A3 activity.   They are therefore less able to sulphate dietary phenols and catecholamines. Sulphation inactivates amines – many migraine patients are susceptible to foods which contain brain-active amines (cheese/tyramine, chocolate/phenylethylamine, bananas/serotonin) or inhibit the SULT enzymes.   The increased blood levels of amines/phenols with neurotransmitter activity are thought to ‘trigger’ migraine headaches in those who are already susceptible.   It has been shown that individuals who are susceptible to migraine are metabolically unstable (with raised excitotoxic amino acid levels) so that very small changes in blood and brain catecholamine levels are sufficient to provoke a migraine attack .   SULT1A1 and 1A3 can be inhibited by flavonoids and by foods containing these compounds which typically occur in fruit and vegetables. Eating citrus fruit, especially oranges, is often reported as being a migraine ‘trigger’ and the component flavonoids (especially naringin) are inhibitors of both SULT1A1 and SULT1A3.   The inhibitory effects of flavonoids on SULT1A1 can be partially overcome by the presence of magnesium ions which enhance the enzyme activity.
Many children with autism, particularly those with g.i. tract problems, have a family background of migraine and in a small pilot study   we found that some children  with autism also had reduced sulphotransferase activity.   They would be expected to react badly to foods containing phenols, catecholamines or flavonoids and this response may underlie the benefits of the Feingold (low-phenol) diet and provide an explanation for the dietary intolerances which can be found in autism.   Anecdotally many parents of autistic children report that their condition is made worse by the same foods which affect migraine patients and that chocolate and bananas exacerbate behavioural problems.   In children ‘migraine’ often affects the gastro-intestinal tract, causing colic and cramping.   This disappears around puberty to become the classic headache syndrome and it is possible that some of the gut dysfunction seen in autism may be a version of   this juvenile presentation of migraine.
Other sulphotransferases can also be affected. The enzyme tyrosylprotein sulphotransferase (TPST) is membrane-bound and found in most tissues of the body, including the platelet and the gastrointestinal tract. TPST is the enzyme responsible for sulphation of gastrin and cholecystokinin as well as the sulphation of mucins   so it is obviously important in g.i.tract function. It is interesting that sulphated cholecystokinin (CS) has receptors in the brain as well as the gut and is required for release of the peptide hormone oxytocin.   CS levels may be low in mothers of autistic children as studies have shown that they are more likely to require pitocin (a synthetic oxytocin analogue) during the birth process .   Children with autism have lower levels of oxytocin themselves and as this hormone elicits social behaviour any deficiency may contribute to the social deficits in autistic spectrum disorders.   The digestive and neurological systems are therefore dependent on adequate supplies of sulphate (usually low in autism) and on a sufficiently active form of TPST being present to catalyse the digestive ‘cascade’ process and also activate the body’s defences against infections. Relatively little work has been done on this enzyme, but a pilot study in this laboratory with autistic children showed a mean TPST activity which was 33% of the control value.   There was a wide range of activity, some children having almost no detectable platelet TPST values while a small number (3/20) had nearly normal levels.   None of this latter group had g.i. tract dysfunction while those children who did have gut problems, including diarrhoea and constipation, all fell into the ‘low TPST activity’ category.

Conclusion

The evidence so far is incomplete but is certainly in accordance with the view that while defects in sulphation may not be the prime cause of autism, they are responsible for much of the dysregulation of biochemical and physiological processes.   Perhaps the full answer may lie somewhere in the complex interactions of the autoimmune system with neuronal development.   Autism may then reflect either in utero damage from maternal cytokines or perinatal damage caused by the actions of infections and vaccinations on a child with faulty autoimmune responses.   The aetiology of the condition might then be similar to that for eczema, asthma and allergic responses, all of which seem to be increasingly common in children.   Autism is of course heterogeneous but improved understanding of the biochemistry involved must eventually lead to novel therapeutic approaches.   Potentially, too, we should be able to identify children ‘at risk’( perhaps measuring cytokine levels at birth or before vaccinations?). They could then follow a controlled diet and possibly a different schedule of vaccinations, while infections would be avoided where possible.
Figure 1

Schematic diagram showing the structure of mucin.   The thick horizontal line represents the polypeptide “backbone” and the short vertical lines the polysaccharide side-chains which are studded with sulphate ( ˜ ) and sialic acid ( ™ ) residues.
Figure 2

The role of sulphation in digestion.   Mechanical stretching of the stomach walls coupled with chemical stimuli from the food cause the polypeptide hormone gastrin to be secreted by the pyloric glands in the stomach.   Gastrin is activated by sulphation and triggers the production of hydrochloric acid and the proteolytic enzyme pepsin.   These, in combination with digestive products, prompt the release of two more hormones: the polypeptide cholecystokinin (which also requires sulphation prior to activation) and secretin which stimulates the pancreas to produce bicarbonate which neutralizes the acid from the stomach and the enzymes necessary for digestion to continue in the small intestine.

Xenobiotics, Biotransformations, Detoxication/زیست دگرگونی و سم زدایی داروها و مواد مضر در بدن انسان چگونه صورت می گیرد

زیست دگرگونی و سم زدایی داروها و مواد مضر در  بدن انسان چگونه صورت می گیرد 

 Xenobiotics, Biotransformations, Detoxication

  1. 1. Detoxification Xenobiotics Bio-transformations Dr. Dhiraj J. Trivedi
  2. 2.  Detoxification: Biochemical process whereby the noxious substances are rendered less harmful and more water soluble  Xenobiotics: Compounds which may be accidentally ingested / taken as drugs / produced in the body by the bacterial action is rendered hydrophilic.  Biotransformation: Is a process whereby a substance is changed from one chemical form to another by a chemical reaction in the body • Detoxification is the process of biotransformation of a xenobiotic
  3. 3. Detoxification Knowledge of how to handle toxic matter at cellular level is key to learn how to survive in this adulterated and polluted world Basic to a rational understanding of Pharmacology, Toxicology, Cancer research and DRUG ADDICTION Why?
  4. 4. Few terms for better understanding • Toxin: Substance with harmful effects on living systems. • Detoxification: Removal / neutralization of toxic quality of toxins. • Xenobiotic: Chemical substance present within but not made within a living body – stranger to life • Toxic load: Sum Total toxins within a given living system
  5. 5. Few terms for better understanding • Lipophilic Toxin: Low molecular weight, non polar, fat soluble toxins. Difficult to eliminate. • Polyvinyl chloride, Bisphenols, Benzoate • Hydrophilic toxins: Water soluble, Polar toxins. Easy to be excreted. • Urea, uric acid, creatinine, bilirubindiglucuronide
  6. 6. Truth: Ubiquitous, too many to count, Complex interactions • Alter brain function, • Gut disturbance, • Reproductive effects, • Hormonal imbalance Inflammation, cancer, diabetes, Autoimmune disease, CVD, Renal disease and more… Consequences R MANY
  7. 7. Definition • Biochemical process to convert toxic lipophilic substances to less toxic or nontoxic hydrophilic form. • Easy to excrete form
  8. 8. What are the Source of Toxins? • Exogenous • Diet - addative • Drug - chemical • Abuse – toxins • Microbes - • Occupation – man made • Endogenous • Metabolism • Normal – urea, UA, Bilirubin • Abnormal – Acetae, formate
  9. 9. Bio-transformation: Substance is changed from one substance to other by a chemical reaction within the body Bio-activtion Biotransformation leading to more toxic compound than the parent -Entoxication Bio-inactivation Noxious substances rendered less harmful and more water soluble is called Detoxication and Procarcinogen / prodrug
  10. 10. What all needs detoxification? Food additives Toxins / Poisons Cosmotics Drugs Metabolites Chemicals / Dyes Pesticides Insecticides Many more…..
  11. 11. Who looks after Bio-transformations? • The liver handles 70% of the bio-transformation reactions in body. • Other sites are • Kidneys • Lungs • Skin • Intestinal cells • Endothelial cells of BBB
  12. 12. Factors that affect biotransformation • Diet • Age • Developmental status • Hormonal status • Disease • Functional status of Liver and Kidney • Genetics
  13. 13. Biotrans formation of lipophilic Toxins • Phase 1: • Reaction that add a functional group to a fat soluble toxin so the new structure can be conjugated and made hydrophilic, excretory form. • Phase 2: • Reactions that either continue the phase 1 or independent, create a water soluble compound suitable for excretion
  14. 14. Phase 1 Phase 2 Fat Soluble Oxidation/ epoxidation Conjugation with Glucuronic acid Reduction Conjugation with sulfate Hydrolysis Conjugation with Glutathione Acetylation Conjugation with Amino acid How does it happen ?
  15. 15. Phase 1 Reactions Oxidation or Hydroxylation Large number of foreign substances are destroyed by oxidation
  16. 16. Phase 1 Oxidation or Hydroxylation • Large number of foreign substances are destroyed by oxidation or hydroxylation • Reaction needs • Cytochrome P450 / Mono-oxygenase • Concentrated on smooth ER of liver • Heme containing enzyme • Inducible: By Phenobarbitone, Alcohol
  17. 17. • P450 because absorb light at 450nm • It can detoxify exogenous drugs as well endogenous steroid and eicosanoids • It is typically mono-oxygenase as it incorporates one atom of oxygen to form hydroxy derivative, Second atom is reduced to water Cytochrome - P450 RH + O2 + NADPH  ROH +H2O NADP+
  18. 18. Mechanism of mono-oxygenase NADPH+H NADP+ NADPH- Cyt P450 Reductase Ox NADPH- Cyt P450 Reductase Red Fe+3 Fe+2 Cyt P450 Cyt P450 R-H R-OH H2O O2 50% of the medicinal drugs are metabolised by Cyt P450 OX Red
  19. 19. Mechanism of Cyt P450 P450 Fe+3 R-H P450 Fe+3 R-H P450 Fe+2 R-H e O2 P450 Fe+2 R-H O2 P450 Fe+2 R-H O*2 e R-OH NADPH+H NADPH-Cyt P450 Reductase 1 2 3 4 5
  20. 20. • CYP3A is important cytochrome P450involved in drug metabolism, because of its abundance in liver and intestine it can fluctuate by almost 400-fold due to inhibition and induction, thus leading to problems with drug dosage Iso forms
  21. 21. • CYP2E1, which is induced by consumption of ethanol. This may increase the risk of carcinogenicity developing from exposure to such compounds • CYP2A6, involved in the metabolism of nicotine null alleles, who have impaired metabolism of nicotine, are apparently protected against becoming tobacco- dependent smokers Iso forms
  22. 22. Oxidation Ethanol Acetic acid Methanol Formic acid Benzyl alcohol Benzaldehyde Benzoic acid COOHCOHOH Catechol Muconic acid COOH COOH OH OH
  23. 23. Oxidation Aniline P- Amino Phenol Acetanilide P- acetyl amino phenol Ingrediant of analgesic drug which relieves pain Meprobamate Hydroxy meprobamate A Tranquilizer use for psychiatric disorder Chloral (CCl3CHO) Trichloroacetic acid Used as hypnotic, converted to TCA and excreted
  24. 24. Epoxide An epoxide is a cyclic ether with a three-atom ring. This ring approximates an equilateral triangle, which makes it highly strained. The strained ring makes epoxides more reactive than other ethers. Oxidation
  25. 25. Entoxification Vinyl chloride Vinyl chloride epoxide Potent carcinogen Benzopyrine Epoxidation Potent carcinogen Glycerol Ployethelene Potent Renal toxin Converted to oxalic acid Ethylene Glycol Hyperactive
  26. 26. Entoxification Poly cyclic Aromatic hydrocarbon (PAH) Epoxide Potent carcinogen •Iso form of Cyt P450 i.e. P448 found in lung of cigarette smokers •Cigatette smoke PAH are converted to Tar Which is procarcinogen
  27. 27. Phase 1 Reactions Reduction Nitro compounds are reduced to amines Aldehyde, Ketones are reduced to Alcohols
  28. 28. Reduction • Less important than oxidation Picric acid Picramic acid NO2 NO2 OH NO2 NH2 NO2 OH NO2 Chloral (CCl3CHO) Trichloro ethyl alcohol Used as sedetive, reduced before excreted
  29. 29. Reduction Nitro benzene Aniline NO2 NH2 H2 NH2 Glucuronic acid Aniline-N- Glucuronide Conjugation Glucuronide
  30. 30. Para nitro-phenol to Para aminophenol P-Nitro phenol P-Aminophenol NO2 NH2 H2 OH OH Reduction Disulfiram Di thio carbamic acid Tx for alcohollism
  31. 31. Phase 1 Reactions Hydrolysis Toxic molecules are broken down to smaller ones X-Y + H2O X-OH & Y-H
  32. 32. Hydrolysis Aspirin popular analgesic metabolised by hydrolysis Aspirin + H2O Salicylic acid + Acetic acid Acetanilide + H2O Aneline + Acetic acid Atropine + H2O Tropic acid + Tropine Psychoactive drug Digitalis + H2O Sugar + Digoxin(Aglycon )Cardiac glycoside drug
  33. 33. Hydrolysis Digitalis + H2O Sugar + Digoxin(Aglycon )Cardiac glycoside drug Procaine + H2O P-Amino Benzoic acid + Diethyl amino ethanol Anesthetic drug
  34. 34. Hydrolysis Esters Esterase Amides Amidase Glycosides Glycosidase
  35. 35. Phase 2 Reactions Conjugation Number of substances undergo complex formation – conjugation after phase 1 reaction, this will make them more hydrophilic and suitable for excretion
  36. 36. Conjugation 1. Conjgation with glucuronic acid 2. Conjugation with glycine 3. Conjugation with Sulfate 4. Conjugation with glutamine 5. Conjugation with Cysteine / Glutathione 6. Acetylation 7. Methylation
  37. 37. Phenol Benzoic acid Bilirubin Steroid Amide Phenyl glucuronide Benzoyl glucuronide Bilirubin diglucuronide Steroid glucuronide N-glucuronide UDP Glucuronic acid UDP Glucuronyl transferase UDP Glucuronic acid
  38. 38. • Many other drugs like – Morphine – Chloramphenicol – Indomethacin – Dapsone – Sulpathiazole are conjugated with Glucuronic acid Glucuronic acid
  39. 39. Conjugation with Glycine Cholic acid Glycocholic acid Glycine Benzoic acid Benzoyl glycine Or Hippuric acid Glycine Salicylic acid Salicyluric acid Glycine ChenodeoxyCholic acid ChenodeoxyGlycocholic acid Glycine Nicotinic acid Nicotinuric acid Glycine
  40. 40. Conjugation with Sulphate Indoxyl Indoxyl sulphate PAPS Phenol Phenoxy sulphate Ethereal sulphate PAPS Sketol Sketol sulphate PAPS Cyanide Sodium thiocynate Thiosulphate PAPS = Phospho adenosyl phospho sulphate
  41. 41. R –X + GSH GS – R + X –H Glutathione helps in conjugation reaction Isoniazide & Sulfanamide are detoxicted by Acetylation Isoniazide Acetyl-INH Sulphaniamide Acetyl sulphanilamide Acetic acid
  42. 42. Conjugation with Glutamine • Phenyl acetic acid + Glutamine  Phenyl acetylglutamine • α -KG + NH3 – Glutamate – Glutamine • Thus in hyper ammonemia NH3 toxicity is reduced.
  43. 43. Methylation • Amino, hydroxy or thiol groups are methylated • SAM act as methyl group donor • O – methyl transferases enzyme 1. Epinephrine  Metanephrine 2. Nor epinephrine  Nor metanephrine 3. Nicotinamide N- methyl nicotinamide 4. Histamine  methyl histamine 5. Pyridine N – methyl pyridine
  44. 44. Purpose Chemically modified Intermediate Parent compound Toxic , Lipophililc Phase 1 Phase 2 Excreted in Urine Urine Final metabolite Non-toxic, hydrophilic
  45. 45. Xenobiotics for some common drugs
  46. 46. Thank you
  47. Xenobiotics, Biotransformations, Detoxication - SlideShare