195
MiR-181b Expression Levels as Molecular Biomarker for Type 2 Diabetes
Seyed Mohsen Aghaei Zarch1, Mohamad Yahya Vahidi Mehrjardi2,
Emad Babakhanzadeh1, Majid Nazari1, Mehrdad Talebi1,
Fahime Zeniali3, Mohammadreza Dehghani4
1 MSc Student in Human Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
2 PhD of Molecular Genetics, Diabetes Research Centre, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
3 PhD Student in Nutrition, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
4Associate Professor, Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
(Received March 5, 2018 ; Accepted June 23, 2019)
Abstract
Background and purpose: Type 2 diabetes mellitus (T2DM) as a progressive metabolic disorder is rising very fast around the world. Diagnosis of T2DM at early stages (prediabetic) is important in reducing the mortality associated with this disease. Several studies have shown that micro-RNAs play a major role in the pathogenesis of the T2DM. Because of the high stability of these regulatory RNA in body fluids and the availability of sensitive technology, such as Real-time PCR for detecting them, they can be used as epigenetic biomarker in the early diagnosis of T2DM. In this study, for the first time, miR - 181 expression levels were investigated in patients with T2DM in Yazd province, Iran.
Materials and methods: In this experimental study, Real-time PCR was used to quantify expression levels of miR-181b in 90 individuals including T2DM patients (n=30), prediabetic (n=30), and healthy individuals (n=30).
Results: There were significant differences in miR-181b expression levels between the groups studied.
Conclusion: Reduced miR-181b expression levels in T2DM and pre-diabetic subjects compared to healthy individuals suggests that miR-181b could be used as a new epigenetic diagnostic marker for early diagnosis of T2DM.
Keywords: type 2 diabetes, miR-181b, biomarker
J Mazandaran Univ Med Sci 2019; 29(176): 195-201 (Persian).
* Corresponding Author: Mohammadreza Dehghani - Shahid Sadoughi University of Medical Sciences, Yazd, Iran (E-mail: dehghani.dr@gmail.com)
هرود هرﺎﻤﺷ ﻢﻬﻧ و ﺖﺴﯿﺑ 176
رﻮﯾﺮﻬﺷ لﺎﺳ 1398 ) 201 - 195 (
نﺎﯿﺑ
miR-181b
ﯽﻟﻮﮑﻟﻮﻣ ﺮﮐرﺎﻣﻮﯿﺑ ﮏﯾ ناﻮﻨﻋ ﻪﺑ ود عﻮﻧ ﺖﺑﺎﯾد رد
چراز ﯽﯾﺎﻗآ ﻦﺴﺤﻣ ﺪﯿﺳ 1
يدﺮﺟﺮﻬﻣ يﺪﯿﺣو ﯽﯿﺤﯾ ﺪﻤﺤﻣ 2
هداﺰﻧﺎﺧﺎﺑﺎﺑ دﺎﻤﻋ 1
يﺮﻈﻧ ﺪﯿﺠﻣ 1
يراوﺪﻧا ﯽﺒﻟﺎﻃ دادﺮﻬﻣ 1
ﯽﻠﻨﯾز ﻪﻤﯿﻬﻓ 3
ﯽﻧﺎﻘﻫد ﺎﺿرﺪﻤﺤﻣ 4
هﺪﯿﮑﭼ
ﻪﻘﺑﺎﺳ :فﺪﻫ و عﻮﻧ ﺖﺑﺎﯾد عﻮﯿﺷ لﺎـﺣ رد يدﺎـﯾز ﺖﻋﺮـﺳ ﻪﺑ نﺎﻬﺟ ﺮﺳاﺮﺳ رد هﺪﻧوﺮﺸﯿﭘ ﮏﯿﻟﻮﺑﺎﺘﻣ لﻼﺘﺧا ﮏﯾ ناﻮﻨﻋ ﻪﺑ ود
رﺎﻤﯿﺑ ﻦﯾا ﺺﯿﺨﺸﺗ .ﺖﺳا ﺶﯾاﺰﻓا يرﺎـﻤﯿﺑ ﻦـﯾا ﺎـﺑ ﻂﺒﺗﺮـﻣ يﺎﻫﺮﯿﻣ و گﺮﻣ ﺶﻫﺎﮐرد ار ﯽﻤﻬﻣ ﺶﻘﻧ (ﯽﺘﺑﺎﯾد ﺶﯿﭘ) ﻪﯿﻟوا ﻞﺣاﺮﻣ رد ي
هداد نﺎﺸﻧ تﺎﻌﻟﺎﻄﻣ .دراد وﺮﮑﯿﻣ ﻪﮐ ﺪﻧا
ﯽـﻣ يزﺎـﺑ ود عﻮـﻧ ﺖـﺑﺎﯾد ﺰﻧژﻮﺗﺎـﭘ رد ﯽـﻤﻬﻣ ﺶـﻘﻧ ﺎﻫRNA
ﻦـﯾا يراﺪـﯾﺎﭘ ﻞـﯿﻟد ﻪـﺑ .ﺪـﻨﻨﮐ
لﻮﮑﻟﻮﻣ ﺑ سﺎﺴﺣ يژﻮﻟﻮﻨﮑﺗ ندﻮﺑ سﺮﺘﺳد رد و نﺪﺑ تﺎﻌﯾﺎﻣ رد ﯽﻤﯿﻈﻨﺗ يﺎﻫ هزاﺪﻧا ياﺮ
نآ يﺮـﯿﮔ ﯽـﻣ ،ﺎـﻫ
نآ زا ناﻮـﺗ ناﻮـﻨﻋ ﻪـﺑ ﺎـﻫ
نﺎـﯿﺑ ﯽﺳرﺮﺑ ﻪﺑ رﺎﺑ ﻦﯿﻟوا ياﺮﺑ ﻪﻌﻟﺎﻄﻣ ﻦﯾا رد .دﻮﻤﻧ هدﺎﻔﺘﺳا ود عﻮﻧ ﺖﺑﺎﯾد سردوز ﺺﯿﺨﺸﺗ رد ﯽﮑﯿﺘﻧژ ﯽﭘاﺮﮐرﺎﻣﻮﯿﺑ 181b
ردmiR-
.ﺪﺷ ﻪﺘﺧادﺮﭘ دﺰﯾ ﺖﯿﻌﻤﺟ رد ود عﻮﻧ ﺖﺑﺎﯾد ﻪﺑ ﻼﺘﺒﻣ نارﺎﻤﯿﺑ شور و داﻮﻣ :ﺎﻫ
ﻨﺳ ياﺮﺑ ﻪﻌﻟﺎﻄﻣ ﻦﯾا رد نﺎـﯿﺑ ناﺰﯿﻣ ﺶﺠ
181b
ردmiR-
30 ،ود عﻮـﻧ ﺖـﺑﺎﯾد ﻪـﺑ ﻼﺘـﺒﻣ دﺮـﻓ 30
ﺶﯿـﭘ دﺮـﻓ
و ﯽﺘﺑﺎﯾد 30 شور زا ﻢﻟﺎﺳ دﺮﻓ
Real-time PCR
.ﺪﯾدﺮﮔ هدﺎﻔﺘﺳا
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181b
هوﺮﮔ ﻦﯿﺑ ردmiR-
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:جﺎﺘﻨﺘﺳا نﺎﯿﺑ ﻪﺘﻓﺎﯾ ﺶﻫﺎﮐ 181b
ﻪـﺑ ﺖﺒـﺴﻧ ﯽﺘﺑﺎـﯾد ﺶﯿـﭘ و ود عﻮـﻧ ﺖـﺑﺎﯾد ﻪـﺑ ﻼﺘـﺒﻣ داﺮـﻓا ردmiR-
هوﺮـﮔ ﻢﻟﺎـﺳ لﺮـﺘﻨﮐ
نﺎﺸﻧ ﻪﮐ ﺖﺳا ﻦﯾا هﺪﻨﻫد 181b
.ﺖﺳا اراد ار ود عﻮﻧ ﺖﺑﺎﯾد رد ﺮﮐرﺎﻣﻮﯿﺑ ناﻮﻨﻋ ﻪﺑ هدﺎﻔﺘﺳا ﻞﯿﺴﻧﺎﺘﭘmiR-
:يﺪﯿﻠﮐ يﺎﻫ هژاو ،ود عﻮﻧ ﺖﺑﺎﯾد
181b
ﺮﮐرﺎﻣﻮﯿﺑ ،miR-
ﻪﻣﺪﻘﻣ
يرﺎﻤﯿﺑ زا ود عﻮﻧ ﺖﺑﺎﯾد ﺑﺎـﺘﻣ يﺎـﻫ
هﺪﻧوﺮـﺸﯿﭘ ﯽﮑﯿﻟﻮ
ﺖـﺳا ﺶﯾاﺰـﻓا لﺎﺣ رد ﺎﯿﻧد ﺮﺳاﺮﺳ رد نآ عﻮﯿﺷ ﻪﮐ ﺖﺳا ﯽﻣ هدز ﻦﯿﻤﺨﺗ و لﺎـﺳ ﺎﺗ ﻪﮐ دﻮﺷ
2025 ﻪـﺑ ﮏـﯾدﺰﻧ 375
ﺪـﻧدﺮﮔ ﻼﺘﺒﻣ يرﺎﻤﯿﺑ ﻦﯾا ﻪﺑ ﺮﻔﻧ نﻮﯿﻠﯿﻣ
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ﻪـﺑ ﺮـﺠﻨﻣ ﻪﮐ ﺪﺷﺎﺑ ﻪﺘﺷاد ﯽﻧﻮﺧ قوﺮﻋ يور ﺮﺑ يا هﺪﻨﻨﮐ و ﯽﺗﺎـﭘوﺮﻔﻧ ،ﯽﺗﺎـﭘﻮﻨﯿﺗر ﺮـﯿﻈﻧ رﻻﻮﮑـﺳاو وﺮﮑﯿﻣ ضراﻮﻋ ﺮـﭘ و ﻪﺘﮑـﺳ ﺮـﯿﻈﻧ رﻻﻮﮑـﺳاووﺮﮐﺎﻣ ضراﻮﻋ و ﯽﺗﺎﭘورﻮﻧ دﻮﺷ نﻮﺧ يرﺎﺸﻓ
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نﺎـﻣرد ضراﻮـﻋ ﻦﯾا ﻪﮑﯿﺗرﻮﺻ رد
ﺪﻧﻮﺸﻧ ﯽﮔﺪﻧز ﺖﯿﻔﯿﮐ و ﺪﯾﺪﻬﺗ ار دﺮﻓ ﯽـﮔﺪﻧز ﺪﻨﻧاﻮﺗ ﯽﻣ
ﯽﻧﺎﻘﻫد ﺎﺿر ﺪﻤﺤﻣ :لﻮﺌﺴﻣ ﻒﻟﻮﻣ ﯽﮑﺷﺰﭘ ﮏﯿﺘﻧژ هوﺮﮔ ،ﯽﮑﺷﺰﭘ هﺪﮑﺸﻧاد ،دﺰﯾ ﯽﮑﺷﺰﭘ مﻮﻠﻋ هﺎﮕﺸﻧاد ،ﻢﻟﺎﻋ ناﺪﯿﻣ :دﺰﯾ-
dehghani.dr@gmail.com E-mail:
1.
ﯽﻧﺎﺴﻧا ﮏﯿﺘﻧژ ﺪﺷرا ﯽﺳﺎﻨﺷرﺎﮐ يﻮﺠﺸﻧاد ﺪﺻ ﺪﯿﻬﺷ ﯽﮑﺷﺰﭘ مﻮﻠﻋ هﺎﮕﺸﻧاد ،
ناﺮﯾا ،دﺰﯾ ،دﺰﯾ ﯽﻗو
2 ﯽﻟﻮﮑﻟﻮﻣ ﮏﯿﺘﻧژ ﯽﺼﺼﺨﺗ يﺮﺘﮐد . ﯽﺗﺎﻘﯿﻘﺤﺗ ﺰﮐﺮﻣ ،
ناﺮﯾا ،دﺰﯾ ،ﺖﺑﺎﯾد ﯽﻧﺎﻣرد–
3 مﻮﻠﻋ ﯽﺼﺼﺨﺗ يﺮﺘﮐد يﻮﺠﺸﻧاد
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: ﺖﻓﺎﯾرد ﺦﯾرﺎﺗ 14
/ 12 / 1397 : تﺎﺣﻼﺻا ﺖﻬﺟ عﺎﺟرا ﺦﯾرﺎﺗ 20
/ 12 / 1397 : ﺐﯾﻮﺼﺗ ﺦﯾرﺎﺗ 2/
4/
1398
نارﺎﮑﻤﻫ و چراز ﯽﯾﺎﻗآ ﻦﺴﺤﻣ ﺪﯿﺳ
نارﺪﻧزﺎﻣ ﯽﮑﺷﺰﭘ مﻮﻠﻋ هﺎﮕﺸﻧاد ﻪﻠﺠﻣ
هرﺎﻤﺷ ،ﻢﻬﻧ و ﺖﺴﯿﺑ هرود 176
رﻮﯾﺮﻬﺷ ، 1398 197
هﺎﺗﻮﮐ شراﺰﮔ
ﻞﺣ هار زا ﯽﮑﯾ .ﺪﻨﻫد ﺶﻫﺎﮐ ار ﯽﯾﺎـﺳﺎﻨﺷ ﻞﮑﺸﻣ ﻦﯾا يﺎﻫ
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وﺮﮑﯿﻣ لﻮﮑﻟﻮﻣ ﺎﻫRNA
ﺎـﺑ ﯽﮑﭼﻮـﮐ ﯽـﻤﯿﻈﻨﺗ يﺎﻫ
لﻮﻃ 18 ﺎـﺗ 25 رد يﺰـﮐﺮﻣ رﻮﺘﮐﺎـﻓ و ﺪﻨﺘـﺴﻫ ﺪـﯿﺗﻮﺌﻠﮐﻮﻧ
نﺎـﻫﺎﯿﮔ و تﺎـﻧاﻮﯿﺣ رد ﯽـﺴﯾﻮﻧور ﺎﺴﭘ ﻢﯿﻈﻨﺗ بﺎـﺴﺣ ﻪـﺑ
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ﯽﻣ ﻞﺼﺘﻣ ﻪﻤﺟﺮﺗ رﺎﻬﻣ ﺎﯾ ﻪﯾﺰﺠﺗ ﺖﻋﺮﺳ ﺶﯾاﺰﻓا ﺎﺑ و ﺪﻧﻮﺷ
نآ نآ نﺎﯿﺑ ﯽﻔﻨﻣ ترﻮﺻ ﻪﺑ ،ﺎﻫ ﯽـﻣ ﻢﯿﻈﻨﺗ ار ﺎﻫ
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ل نﻮـﺧ رد ﺎـﻫ
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Real-time PCR
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لﻮﮑﻟﻮﻣ ﻦﯾا ﺶﻘﻧ ﺮﯾﺎـﺳ و ﯽﮑﯿﻟﻮﺑﺎﺘﻣ يﺎﻫﺪﻨﯾآﺮﻓ رد ار ﺎﻫ
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ﻦﯾﺮـﺗ
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و ﺎﺘﺷﺎﻧ
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) 10
. (
نﺪــﺷ لﺎــﻌﻓ ﯽــﻗوﺮﻋ مﻮﯿﻠﺗوﺪــﻧا رد
NF-κB
)
Nuclear Factor-κB
( نژ نﺎـــﯿﺑ ﻪـــﺑ ﺮـــﺠﻨﻣ ، يﺎـــﻫ
نژ ﺮــﯿﻈﻧ ،ﯽﺑﺎــﻬﺘﻟا ﺶﯿــﭘ ﺪــﮐ يﺎــﻫ
ﻦﯿﮐﻮﺘﯿــﺳ هﺪــﻨﻨﮐ و ﺎــﻫ
لﻮﮑﻟﻮﻣ ﯽﻣ ﯽﻟﺎﺼﺗا يﺎﻫ ﮕﻤﻫ ﻪﮐ ددﺮﮔ
رد ﯽﻤﻬﻣ ﺶﻘﻧ ﯽ
ﯽـﻣ يزﺎﺑ ﯽﻨﻤﯾا ﺦﺳﺎﭘ و بﺎﻬﺘﻟا لﻼﺘـﺧا ﻪـﺠﯿﺘﻧ رد ،ﺪـﻨﻨﮐ
لﻮﻠﺳ ﯽﻣ ﯽﻟﺎﯿﻠﺗوﺪﻧا يﺎﻫ ،ﯽﺑﺎـﻬﺘﻟا ﻂﯿـﺤﻣ دﺎـﺠﯾا ﺎـﺑ ﺪﻧاﻮﺗ
ﻪﺘـﺷاد ﺖـﺑﺎﯾد و ﯽﻨﯿﻟﻮﺴﻧا ﺖﻣوﺎﻘﻣ ﻪﻌﺳﻮﺗ رد ﯽﻤﻬﻣ ﺶﻘﻧ ﺪـــﺷﺎﺑ
) 11
.(
181b
ﺎـــﻀﻋا زاmiR-
ي هداﻮﻧﺎـــﺧ 181
miR-
ﺖــﺳا و
a/c/d
181 ﺎــﻀﻋا زاmiR-
ي د ﯾ ﺮــﮕ ا ــﯾ ﻦ هداﻮﻧﺎــﺧ ﺘﺴﻫ
ﺑ ﺶﻘﻧ .ﺪﻨ ﯿ
ژﻮﻟﻮ ﯾ ﮑ ﯽ اﯾ ﻦ ناﻮـﻨﻋ ﻪـﺑ اﺪـﺘﺑا رد هداﻮﻧﺎﺧ
ﻬﺴﺗ ﯿ ﻞ ﺎـﻤﺗ هﺪﻨﻨﮐ ﯾﺰ
لﻮﻠـﺳ ﺎـﻫ ي ﻧﻮـﺧ ﯽ ﺪـﺷ ﻪﺘﺧﺎﻨـﺷ
) 12
.(
ﻣ ــﯿ ناﺰ ﺑ ــﯿ نﺎ 181b
وmiR-
181a
ــﻣmiR-
ﯽ ﺖــﺤﺗ ﺪــﻧاﻮﺗ
ﺛﺎﺗ ﯿﺮ ﻤﮐﻮﻟ ﯽ ﮔ راﺮﻗ ﺎﻫرﻮﻣﻮﺗ عاﻮﻧا و ﺎﻣﻮﻔﻨﻟ/
ﯿ دﺮ ا ﻪـﮐ ، ـﯾ ﻦ
ﺑ طﺎﺒﺗرا هﺪﻨﻫد نﺎﺸﻧ درﻮﻣ ﯿ
ﻦ ﻈﻨﺗﺪﺑ ﯿﻤ ﯽ ﺴﻣ ﯿﺮ ﭘ ـﯿ مﺎ ﻧﺎـﺳر ﯽ
NF-κB
ﺶﻫﺎﮐ و ﺑ ـﯿ نﺎ 181b
ﺖـﺳاmiR- ) 13
ﻦﯿـﻨﭽﻤﻫ .(
181b
وﺮﮑﯿﻣ زا ﯽﮑﯾmiR-
ﺮﯿـﺴﻣ هﺪﻨﻨﮐ رﺎﻬﻣ يﺎﻫRNA
مﺎﯿﭘ ﯽﻧﺎﺳر
NF-κB
لﻮﻠﺳ رد ﺺﺨـﺸﻣ .ﺖﺳا ﯽﻟﺎﯿﻠﺗوﺪﻧا يﺎﻫ
هﺪﺷ 181b
ﻢﯿﻘﺘـﺴﻣ يﺮـﯿﮔ فﺪـﻫ ﺎﺑmiR- importin α3
يا ﻪﺘـﺴﻫ لﺎـﻘﺘﻧا ياﺮـﺑ ﻪـﮐ ﯽﻨﯿﺌﺗوﺮﭘ)
NF-κB
يروﺮـﺿ
رﺎﻬﻣ رد ﯽﻤﻬﻣ ﺶﻘﻧ ،(ﺖﺳا
NF-κB
ـﻬﺘﻟا رﺎﻬﻣ و ﺎـﻔﯾا بﺎ
ﯽﻣ ﺪﻨﮐ
) 14
.(
نﺎـﯿﺑ ﯽـﺳرﺮﺑ ،ﺮـﺿﺎﺣ ﻪـﻌﻟﺎﻄﻣ فﺪﻫ ﻦﯾاﺮﺑﺎﻨﺑ
181b
ﯽﺘﺑﺎﯾد ﺶﯿﭘ ،ود عﻮﻧ ﺖﺑﺎﯾد ﻪﺑ ﻼﺘﺒﻣ داﺮﻓا ردmiR-
يرﺎﮑﻫار ﻪﺋارا ياﺮﺑ ﻢﻟﺎﺳ داﺮﻓا و ﺺﯿﺨﺸﺗ رد ﺪﯾﺪﺟ يﺎﻫ
رد ضراﻮـﻋ زوﺮﺑ زا يﺮﯿﮔﻮﻠﺟ و ود عﻮﻧ ﺖﺑﺎﯾد سردوز ﺪﺷﺎﺑ ﯽﻣ ﺮﻄﺧ ﺮﭘ هوﺮﮔ ناﻮﻨﻋ ﻪﺑ دﺰﯾ ﺖﯿﻌﻤﺟ
) 15 .(
و داﻮﻣ شور
ﺎﻫ
ﻊﻤﺟ ﻪﻧﻮﻤﻧ يروآ ﻢﻟﺎـﺳ داﺮﻓا و نارﺎﻤﯿﺑ يﺎﻫ
ﻦـﯾا رد :
زا ،ﯽﺑﺮﺠﺗ ﻪﻌﻟﺎﻄﻣ 30
،ود عﻮﻧ ﺖﺑﺎﯾد ﻪﺑ ﻼﺘﺒﻣ رﺎﻤﯿﺑ 30
دﺮﻓ
و ﯽﺘﺑﺎﯾد ﺶﯿﭘ 30
،لﺮﺘﻨﮐ ناﻮﻨﻋ ﻪﺑ ﻢﻟﺎﺳ دﺮﻓ 5
ﯽـﻠﯿﻣ ﺮـﺘﯿﻟ
دﺎـﻘﻌﻧا ﺪـﺿ ﺎﺑ هاﺮﻤﻫ ﯽﻄﯿﺤﻣ نﻮﺧ زا هﺪـﺷ ﻪـﯿﻬﺗEDTA
ﯽﺗﺎــﻘﯿﻘﺤﺗ ﺰــﮐﺮﻣ ﯽــﺒﻃ ﺺﯿﺨــﺸﺗ هﺎﮕــﺸﯾﺎﻣزآ -
ﯽﻧﺎــﻣرد
ﺑﺎﯾد ﻊﻤﺟ دﺰﯾ ﺖ .ﺪﺷ يروآ
ا ﺑ بﺎﺨﺘﻧ ﯿ نارﺎـﻤ ﺨـﺸﺗ ﺎـﺑ ﯿ ﺺ
ﺺﺼﺨﺗ قﻮﻓ ﺪﺷ مﺎﺠﻧا دﺪﻏ
. ﻪـﻌﻟﺎﻄﻣ ﻪـﺑ دورو يﺎﻫرﺎﯿﻌﻣ
يﻻﺎــﺑ ﻦــﺳ ،ﻞﻣﺎــﺷ 35
و وﺮــﮑﯿﻣ ضراﻮــﻋ ناﺪــﻘﻓ ،لﺎــﺳ
و ﻮـﻀﻋ ﻊـﻄﻗ ،ﯽﺗﺎﭘوﺮﻔﻧ ،ﯽﺗﺎﭘﻮﻨﯿﺗر ﺮﯿﻈﻧ رﻻﻮﮑﺳاووﺮﮐﺎﻣ .دﻮــﺑ ﺮــﻧوﺮﮐ قوﺮــﻋ و ﯽﻧﻮــﻔﻋ يﺎــﻫرﺎﻤﯿﺑ ﻪــﺑ ﻼﺘــﺑا مﺪــﻋ ﺗ نارﺎﻤﯿﺑ ﮏﯿﻓاﺮﮔﻮﻣد تﺎﻋﻼﻃا لوﺪـﺟ رد ﻪـﻌﻟﺎﻄﻣ ﺖـﺤ
هرﺎﻤﺷ 1 ﺖﺳا هﺪﻣآ .
عﻮﻧ ﺖﺑﺎﯾد ﻪﺑ ﻼﺘﺒﻣ نارﺎﻤﯿﺑ ﺺﯿﺨﺸﺗ
يرﺎﯿﻌﻣ سﺎﺳا ﺮﺑ ود يﺎـﻫ
مﺎـﺠﻧا ترﻮـﺻ ﻦـﯾا ﻪـﺑWHO
:ود عﻮﻧ ﺖﺑﺎﯾد :ﺖﻓﺮﮔ )
mmol/mol
48 % ( 5/
6
HbA1c>
،
)
mmol/L
7(
mg/dl
126
FBG>
ناﺰـــﯿﻣ :ﯽﺘﺑﺎـــﯾد ﺶﯿـــﭘ ،
HbA1c
ﻦﯿـــــــــﺑ )
mmol/mol
47 - 39 % ( 4/
6 -
% 7/
5 ،
ﯿﺑFBG
ﻦ )
mmol/mol
9 /6 - 6 (
mg/dl
126 - 100 .
لوﺪﺟ هرﺎﻤﺷ 1 ﻦﯿﮕﻧﺎﯿﻣ ترﻮﺻ ﻪﺑ ﺎﻫ هداد .ﻪﻌﻟﺎﻄﻣ ﺖﺤﺗ يﺎﻬﻫوﺮﮔ ﮓﯿﻓاﺮﮔﻮﻣد تﺎﻋﻼﻃا : ﺪﻧا هﺪﺷ هداد نﺎﺸﻧ رﺎﯿﻌﻣ فاﺮﺤﻧا±
parameter Healthy (n = 30)
Pre-diabetes (n= 30) T2DM (n = 30)
يراد ﯽﻨﻌﻣ ﺢﻄﺳ
Age (years) 2/
7
± 5 / 53 7
± 7 / 56 3/
5
± 4 / 55 32
/0 P=
FBG (mg/dl) 4/
6
± 1 / 90 5/
8
± 8 / 108 24
/ 59
± 1 / 191 001
/0 P<
HbA1c 24
/0
± 1 /5 28
/0
± 04 /6 74
/1
± 62 /8 001
/0 P<
Triglycerides (mg/dl) 84
/
±30 11 / 118 34
/
±50 82 / 136 12
/
±87 1 / 206 001
P</0
cholesterol (mg/dl) 21
/
±21 61 / 147 72
/
±44 75 / 174 85
/
±53 5 / 189 04
P=/0
6/ HDL 10
± 11 / 43 5/
9
± 9 / 39 9/
10
± 31 / 35 12
/0 P=
ﯽﺋﺎﯿﻤﯿـﺷﻮﯿﺑ يﺎـﻫ ﺮﺘﻣارﺎـﭘ ﺶﺠﻨﺳ سرﺎـﭘ ﺖـﯿﮐ زا :
رﺰﯾﻻﺎﻧآﻮﺗآ هﺎﮕﺘﺳد و نﻮﻣزآ ﺎﻔﻟآ)
،نﺎﻬﻔﺻا ،ﮏﯿﺳﻼﮐ_
ﻞـﯾﺎﻓوﺮﭘ ﺶﺠﻨﺳ ياﺮﺑ (ناﺮﯾا ﯽﺋﺎﯿﻤﯿـﺷﻮﯿﺑ يﺎـﻫ
) ،يﺪـﯿﭙﯿﻟ
ﺪﺷ هدﺎﻔﺘﺳا (يﺪﻨﻗ هرﺎﻤﺷ لوﺪﺟ)
1 .(
جاﺮﺨﺘـــــﺳا ﺰﺘﻨـــــﺳ وRNA
جاﺮﺨﺘـــــﺳا :cDNA
Total RNA
ﻣﺎﺷ ﻪـــــﮐ ـــــــــ
ﻣ ﻞ ﯿ ﮑ ـــــــ وﺮ وRNA
ﻮﻃRNA
ــــﯾ ﻞ ــــﻣ ﯽ ﮐ زا هدﺎﻔﺘــــﺳا ﺎــــﺑ ﺪــــﺷﺎﺑ ــــﯿ
ﺖ
)
GeneAll (General Biosystems, Seoul, Korea
زرا ،ﺖــﻓﺮﮔ مﺎـــﺠﻧا ﻞﻤﻌﻟارﻮﺘــﺳد ﻖــﺒﻃ ــﯾ
ﺑﺎ ﯽ و هدزﺎـــﺑ
ﮐﯿ ﻔ ــﯿ ﺖ ﻘﺘــﺴﻣ رﻮــﻃ ﻪــﺑRNA
ﯿ ﻢ پاردﻮﻧﺎــﻧ هﺎﮕﺘــﺳد رد
)
Thermo Fisher Scientific
زرا ( ﯾﺑﺎ ﯽ ﻞـﻤﻋ ﺲﭙﺳ .ﺪﺷ
ﺰﺘﻨﺳ ،ناﺮﻬﺗ ،ﻪﺘﺧﺎﯾ ﻦﺑ) ﺮﯿﻣ ﻦﺑ ﺖﯿﮐ زا هدﺎﻔﺘﺳا ﺎﺑcDNA
.ﺖﻓﺮﮔ ترﻮﺻ (ناﺮﯾا ﺶﻨﮐاو
Real-Time PCR
وﺮﮑﯿﻣ نﺎﯿﺑ ﯽﺳرﺮﺑ ياﺮﺑ
زا هدﺎﻔﺘـﺳا ﺎـﺑ ﻞـﻤﻋ ﻦـﯾا :RNA BONmiR QPCR Kit
درﻮـﻣ يﺎﻫﺮﻤﯾاﺮﭘ .ﺖﻓﺮﮔ مﺎﺠﻧا (ناﺮﯾا ،ناﺮﻬﺗ ،ﻪﺘﺧﺎﯾ ﻦﺑ) هرﺎﻤـﺷ لوﺪـﺟ) ﺪـﺷ ﻪـﯿﻬﺗ ﻪـﺘﺧﺎﯾ ﻦـﺑ ﺖﮐﺮﺷ زا ﺮﻈﻧ 2
.(
ﺶﻨﮐاو
Real-Time PCR
هﺎﮕﺘـﺳد رد
Rotor Gene 6000
)
Corbett, Concorde, NSW, Australia
.ﺪـﺷ مﺎـﺠﻧا (
وﺮﮑﯿﻣ ﯽﺒﺴﻧ راﺪﻘﻣ ﺪـﺘﻣ سﺎـﺳا ﺮﺑRNA
∆∆Ct -
2^
)
livak
(
.ﺪﯾدﺮﮔ ﻪﺒﺳﺎﺤﻣ
لوﺪﺟ هرﺎﻤﺷ 2 يﺪﯿﺗﻮﺌﻠﮐﻮﻧﻮﮕﯿﻟوا يﺎﻫ ﺮﻤﯾاﺮﭘ :
فﺪﻫ نژ ﯽﻟاﻮﺗ
ﺮﻤﯾاﺮﭘ
miR-181b Forward: 5'-CAACATTCATTGCTGTCG -3'
Reverse*
SNORD 47 Forward: 5'-ATCACTGTAAAACCGTTCCA -3'
Reverse*
ﺮﻤﯾاﺮﭘ :* reverse .ﺪﺷ يراﺪﯾﺮﺧ ﻪﺘﺧﺎﯾ ﻦﺑ ﺖﮐﺮﺷ زا
: بوذ ﯽﻨﺠﻨﻣ ﺰﯿﻟﺎﻧآ ﺶﻨـﮐاو ﺖﯿـﺻﺎﺼﺘﺧا
ﺎـﺑPCR
ﺲﯾزرﻮـﻓوﺮﺘﮑﻟا لژ ﺲﭙـﺳ و بوذ ﯽـﻨﺤﻨﻣ ﺰﯿﻟﺎـﻧآ دﺎﺠﯾا هرﺎﻤﺷ رادﻮﻤﻧ) ﺪﯾدﺮﮔ ﺪﯿﯾﺎﺗ 1
.(
هرﺎﻤﺷ ﺮﯾﻮﺼﺗ 1
بوذ ﯽﻨﺤﻨﻣ : 181b
miR-
هداد يرﺎــﻣآ ﺰﯿﻟﺎــﻧآ :ﺎــﻫ
هداد ﯽﻣﺎــﻤﺗ ترﻮــﺻ ﻪــﺑ ﺎــﻫ
ﻦﯿﮕﻧﺎﯿﻣ هداد .ﺖﺳا هﺪﺷ هداد نﺎﺸﻧ رﺎﯿﻌﻣ فاﺮﺤﻧا±
ﺎـﺑ ﺎﻫ
مﺮﻧ راﺰﻓا
Prism 7
ﻪـﺘﯿﻟﺎﻣﺮﻧ ﯽﺳرﺮﺑ .ﺪﻧﺪﺷ ﻞﯿﻠﺤﺗ و ﻪﯾﺰﺠﺗ
هداد ﯿﻤﺳا نﻮﻣزآ زا هدﺎﻔﺘﺳا ﺎﺑ ﺎﻫ فﻮﻧﺮ
- )فوﺮﮕﯿﻤﻟﻮـﮐ (K-S
ﺮﯾدﺎﻘﻣ يرﺎﻣآ توﺎﻔﺗ .ﺖﻓﺮﮔ مﺎﺠﻧا 181b
داﺮﻓا ﻦﯿﺑmiR-
ﻖـﯾﺮﻃ زا لﺮـﺘﻨﮐ هوﺮـﮔ و ﯽﺘﺑﺎـﯾد ﺶﯿـﭘ ،ﺖـﺑﺎﯾد ﻪﺑ ﻼﺘﺒﻣ نﻮﻣزآ
one-way ANOVA
ﯽﮐﻮـﺗ نﻮـﻣزآ زا .ﺪﺷ ﯽﺳرﺮﺑ
)
Tukey
هوﺮﮔ ﻦﯿﺑ ﻪﺴﯾﺎﻘﻣ ياﺮﺑ ( راﺪـﻘﻣ .ﺪﺷ هدﺎﻔﺘﺳا ﺎﻫ
P
ﻢﮐ زا ﺮﺗ 05 /0 ﯽﻨﻌﻣ يرﺎﻣآ ظﺎﺤﻟ زا ﺮﻈﻧ رد راد
.ﺪﺷ ﻪﺘﻓﺮﮔ
ﺎﻫ ﻪﺘﻓﺎﯾ ﺚﺤﺑ و
نﺎـﯿﺑ ﯽـﺳرﺮﺑ ﻪـﺑ رﺎـﺑ ﻦﯿـﻟوا ياﺮـﺑ ﺮـﺿﺎﺣ ﻪﻌﻟﺎﻄﻣ رد 181b
داﺮـﻓا و ود عﻮﻧ ﺖﺑﺎﯾد ،ﯽﺘﺑﺎﯾد ﺶﯿﭘ داﺮﻓا ردmiR-
.ﺪـﺷ ﻪـﺘﺧادﺮﭘ دﺰـﯾ ﺖـﯿﻌﺟ رد ﻢﻟﺎﺳ ﺑ
ـﯿ نﺎ 181b
ردmiR-
د ﻪﺑ ﻼﺘﺒﻣ داﺮﻓا ﻞﻣﺎﮐ نﻮﺧ ﯾ
ﺖﺑﺎ عﻮﻧ ود ﭘ ، ﯿ ﺶ - ـﯾد ﺘﺑﺎ ﯽ و
شور زا هدﺎﻔﺘﺳا ﺎﺑ لﺮﺘﻨﮐ هوﺮﮔ ﺳqPCR
ﺠﻨ ﯿ هﺪ ﺎـﺑ و ﺪﺷ
ﻠﺧاد لﺮﺘﻨﮐ نژ ﯽ
SNORD
ﻟﺎﻣﺮﻧ ﯿﺰ ﺪﺷ ه .
رد ﻪـــﮐ نﺎـــﻨﭽﻤﻫ رادﻮـــﻤﻧ
هرﺎﻤـــﺷ 2 هداد نﺎـــﺸﻧ
نﺎــﯿﺑ ،ﺖــﺳا هﺪــﺷ 181b
ﯽﺘﺑﺎــﯾد ﺶﯿــﭘ داﺮــﻓا ردmiR-
) 12 /0 34±
/0
fold change =
ﻢﻟﺎـﺳ داﺮـﻓا ﻪـﺑ ﺖﺒـﺴﻧ (
نارﺎﮑﻤﻫ و چراز ﯽﯾﺎﻗآ ﻦﺴﺤﻣ ﺪﯿﺳ
نارﺪﻧزﺎﻣ ﯽﮑﺷﺰﭘ مﻮﻠﻋ هﺎﮕﺸﻧاد ﻪﻠﺠﻣ
هرﺎﻤﺷ ،ﻢﻬﻧ و ﺖﺴﯿﺑ هرود 176
رﻮﯾﺮﻬﺷ ، 1398 199
هﺎﺗﻮﮐ شراﺰﮔ
) 38 /0 05±
/1
fold change=
ﻪﻈﺣﻼﻣ ﻞﺑﺎﻗ ناﺰﯿﻣ ﻪﺑ( يا
ﺖﻓﺎﯾ ﺶﻫﺎﮐ )
001 /0
P<
( نﺎـﯿﺑ ﻦﯿﻨﭽﻤﻫ ، 181b
ردmiR-
ود عﻮـﻧ ﺖﺑﺎﯾد هوﺮﮔ )
03 /0 08±
/0
fold change =
ﻪـﺑ (
ﺶﯿـﺑ ناﺰﯿﻣ
،ﺞﯾﺎـﺘﻧ ﻦـﯾا ﺮـﺑ هوﻼـﻋ . ﺖـﻓﺎﯾ ﺶﻫﺎـﮐ يﺮـﺗ
ﯽﻨﻌﻣ ﺶﻫﺎﮐ ﺰﯿﻧ ﺖﺑﺎﯾد هوﺮﮔ و ﯽﺘﺑﺎﯾد ﺶﯿﭘ هوﺮﮔ ﻦﯿﺑ راد
ﺪﻧداد نﺎﺸﻧ )
005 /0 = .(P
healthy
pre-diabetes
T2DM 0.0
0.5 1.0 1.5 2.0
relative expression of miR-181b (fold change)
P = 0.005 P < 0.001
P < 0.001
هرﺎﻤﺷ ﺮﯾﻮﺼﺗ نﺎـﯿﺑ ن اﺰـﯿﻣ 2:
181b ﻮـﺧ ردmiR- هوﺮـﮔرد ﯽـﻄﯿﺤﻣ ن
) لﺮﺘﻨﮐ 30 (n=
) ﯽﺘﺑﺎﯾد ﺶﯿﭘ ، 30
) ود عﻮﻧ ﺖﺑﺎﯾد ، (n=
30 .( n=
بﺎﺨﺘﻧا ﻞﯾﻻد زا ﯽﮑﯾ 181b
،ﻪـﻌﻟﺎﻄﻣ ﻦـﯾا ردmiR-
ﯽﻨﯿﻟﻮـﺴﻧا ﺖـﻣوﺎﻘﻣ رد نآ يﺮـﯿﮔرد و ﯽﺑﺎـﻬﺘﻟا ﺪﺿ ﺶﻘﻧ .ﺖـﺳا هﺪـﺷ هرﺎـﺷا نآ ﻪـﺑ ﯽﻔﻠﺘﺨﻣ تﺎﻌﻟﺎﻄﻣ رد ﻪﮐ ﺖﺳا نﻮﯿﺳﻼﯾﺮﻔﺴﻓ ﺪﻌﺘﻣ ﯽﮑﯾژﻮﻟﻮﯿﺑ يﺎﻫﺪﻨﯾآﺮﻓAkt
ﺮـﯿﻈﻧ يد
ﯽﻣ ﻢﯿﻈﻨﺗ ار ﻦﯿﻟﻮﺴﻧا ﯽﻧﺎﺳر مﺎﯿﭘ ﺮﯿﺴﻣ يرﻮﻃ ﻪﺑ ،ﺪﯾﺎﻤﻧ
ﻪﮐ
نﻮﯿـــﺳﻼﯾﺮﻔﺴﻓ ﯽـــﻤﯿﻈﻨﺗ ﺪـــﺑ هﺪـــﯾد ﺖـــﺑﺎﯾد ردAkt
ﯽﻣ دﻮﺷ
) 16
. (
ﻞﻣﺎﮐ ﺖﯿﻟﺎﻌﻓ ﻪـﺸﯾر نﻮﯿـﺳﻼﯾﺮﻔﺴﻓ ﻪﺑAkt
يﺎـﻫ
Thr308
و
Ser473
ﻪﺑ يزﺎﺗﺎﻔﺴﻓ ﻪﻠﯿﺳﻮﺑ ﻪﮐ دراد ﯽﮕﺘﺴﺑ
مﺎﻧ
PHLPP2
ﯽﻣ رﺎﻬﻣ ددﺮﮔ
) 17
.(
ﻪﻌﻟﺎﻄﻣ رد ﻂﺳﻮﺗ ﻪﮐ يا
نارﺎــﮑﻤﻫ وSun )
18
ﻪــﮐ ﺪــﺷ ﺺﺨــﺸﻣ ﺖــﻓﺮﮔ مﺎــﺠﻧا(
181b
فﺪﻫ ﺎﺑmiR-
يﺮﯿﮔ
PHLPP2
ﺐـﺟﻮﻣ ﯽﻟﺎﯿﻠﺗوﺪﻧا
ﯽﻣ ﯽﻟﺎﯿﻠﺗوﺪﻧا بﺎﻬﺘﻟا و ﻦﯿﻟﻮﺴﻧا ﯽﻧﺎﺳر مﺎﯿﭘ دﻮﺒﻬﺑ .ددﺮـﮔ
د فﺮــﻃ رد ﯾ
ﺮــﮕ
Tomé-Carneiro )
19
ﻪــﮐ داد نﺎــﺸﻧ(
ناﺰﯿﻣ 181b
فﺮـﺼﻣ لﺎـﺳ ﮏﯾ ﻪﮐ ﯽﺘﺑﺎﯾد داﺮﻓا ردmiR-
لوﺮﺗاروزر ﻪﻧازور ﻟا ﺪﺿ يوراد ﮏﯾ)
ﺪﻨﺘـﺷاد ار (ﯽﺑﺎـﻬﺘ ﯽـﻣ ﺶﯾاﺰـﻓا يا ﻪـﻈﺣﻼﻣ ﻞـﺑﺎﻗ ناﺰـﯿﻣ ﻪﺑ
.ﺪـﺑﺎﯾ ﺮـﺑ هوﻼـﻋ
ﺶــﻘﻧ ﻦــﯾا 181b
ﺰــﯿﻧ ﯽﺘﺑﺎــﯾد ﯽﺗﺎــﭘﻮﯿﻣﻮﯾدرﺎﮐ ردmiR-
.ﺖــﺳا هﺪــﺷ ﺺﺨــﺸﻣ
Jiang
ﻪــﻌﻟﺎﻄﻣ ﺎــﺑ نارﺎــﮑﻤﻫ و
ﺖﺳﻼﺑوﺮﺒﯿﻓ ﻦﯿـﺴﻨﺗﻮﯾﮋﻧآ ﺎﺑ هﺪﺷ رﺎﻤﯿﺗ ﯽﺒﻠﻗ يﺎﻫ
نﺎـﺸﻧII
نﺎﯿﺑ ﻪﮐ ﺪﻧداد 181b
ﯽﻣ ﺶﻫﺎﮐmiR-
درﻮـﻣ ﻦﯾا ﻪﮐ ،ﺪﺑﺎﯾ
ﺎﺸﻧ ن ﯽﻟﺎﻤﺘﺣا ﺶﻘﻧ هﺪﻨﻫد 181b
نﺪـﺷ هزوﺮـﺒﯿﻓ ردmiR-
ﯽﻣ ﺐﻠﻗ ﺪﺷﺎﺑ
) 20 .(
ﻪــﻌﻟﺎﻄﻣ رد لﺎــﺳ رد ﻪــﮐ يا
2017 ﻂــﺳﻮﺗ
Copier
و
نارﺎــﮑﻤﻫ
) 21
ﯽﺗﺎــﭘﻮﯿﻣﻮﯾدرﺎﮐ ﯽﻧاﻮــﯿﺣ لﺪــﻣ يور ﺮــﺑ(
نﺎـﯿﺑ ﻪﮐ ﺪﺷ ﺺﺨﺸﻣ ﺖﻓﺮﮔ ترﻮﺻ ﯽﺘﺑﺎﯾد 181b
miR-
شﻮﻣ رد ﯽﻣ ﺶﻫﺎﮐ لﺮﺘﻨﮐ هوﺮﮔ ﻪﺑ ﺖﺒﺴﻧ ﻼﺘﺒﻣ يﺎﻫ ﺪـﺑﺎﯾ
هدﺎﻔﺘﺳا ﻞﯿﺴﻧﺎﺘﭘ و رد ﯽـﺼﯿﺨﺸﺗ ﺮﮐرﺎـﻣﻮﯿﺑ ﮏﯾ ناﻮﻨﻋ ﻪﺑ
.ﺖﺳا اراد ار ﯽﺘﺑﺎﯾد ﯽﺗﺎﭘﻮﯿﻣﻮﯾدرﺎﮐ نﺎﯿﺑ ﺶﻫﺎﮐ ﺮﺿﺎﺣ ﻪﻌﻟﺎﻄﻣ رد 181b
ﺖﺑﺎﯾد ردmiR-
ﺰـﯿﻧ و ﻢﻟﺎـﺳ داﺮـﻓا و ﯽﺘﺑﺎﯾد ﺶﯿﭘ هوﺮﮔ ﻪﺑ ﺖﺒﺴﻧ ،ود عﻮﻧ لﺮـﺘﻨﮐ هوﺮـﮔ ﻪـﺑ ﺖﺒﺴﻧ ﯽﺘﺑﺎﯾد ﺶﯿﭘ داﺮﻓا رد نآ ﺶﻫﺎﮐ ﯽﻣ ،ﻢﻟﺎﺳ وﺮـﮑﯿﻣ ﻦـﯾا ﯽﻟﺎـﻤﺘﺣا ﺶـﻘﻧ هﺪـﻨﻫد نﺎﺸﻧ ﺪﻧاﻮﺗ ﻪــﺑ هدﺎﻔﺘــﺳا ﻞﯿـﺴﻧﺎﺘﭘ و ﺪــﺷﺎﺑ يرﺎــﻤﯿﺑ ﺖﻓﺮـﺸﯿﭘ ردRNA
اراد ار ود عﻮــﻧ ﺖــﺑﺎﯾد رد ﯽــﺼﯿﺨﺸﺗ ﺮﮐرﺎــﻣﻮﯿﺑ ناﻮــﻨﻋ ﯽﻣ .ﺪﺷﺎﺑ لﺎﺣ ﻦﯾا ﺎﺑ ژ ﺖـﺷﻮﻧور ﺰﯿﻟﺎﻧآ مﺪﻋ ﻞﯿﻟﺪﺑ
ن يﺎـﻫ
ﻪــﻧﻮﻤﻧ داﺪــﻌﺗ ندﻮــﺑ ﻦﯿﺋﺎــﭘ و فﺪــﻫ ﻪــﺘﻓﺎﯾ ،ﺎــﻫ
ﻦــﯾا يﺎــﻫ
تﺎـﻌﻟﺎﻄﻣ ﻪـﺠﯿﺘﻧ رد .ددﺮﮔ ﺮﯿﺴﻔﺗ طﺎﯿﺘﺣا ﺎﺑ ﺪﯾﺎﺑ ﺶﯾﺎﻣزآ ﺳر ياﺮﺑ يﺮﺗ ﺶﯿﺑ وﺮـﮑﯿﻣ ﻦـﯾا ﻖـﯿﻗد ﺶﻘﻧ ﻪﺑ نﺪﯿ
RNA
.ﺖﺳا زﺎﯿﻧ ود عﻮﻧ ﺖﺑﺎﯾد ﺰﻧژﻮﺗﺎﭘ رد
يراﺰﮕﺳﺎﭙﺳ
ﺎـﺑ ﺪـﺷرا ﯽـﺳﺎﻨﺷرﺎﮐ ﻪﻣﺎﻧ نﺎﯾﺎﭘ زا ﯽﺸﺨﺑ ﻪﻌﻟﺎﻄﻣ ﻦﯾا قﻼـــﺧا ﺪـــﮐ
IR.SSU.MEDICINE.REC.1396.237
ﯽﻣ مﺎـﺠﻧا دﺰﯾ ﯽﮑﺷﺰﭘ مﻮﻠﻋ هﺎﮕﺸﻧاد يرﺎﮑﻤﻫ ﺎﺑ ﻪﮐ ﺪﺷﺎﺑ
ﻦﯾﺪﺑ ،ﺖﺳا هﺪﺷ ﯽﻧادرﺪﻗ ﻪﻃﻮﺑﺮﻣ ﻦﯿﻟﻮﺌﺴﻣزا ﻪﻠﯿﺳو
ﯽﻣ دﻮـﺷ .
و دﺰـﯾ ﺖـﺑﺎﯾد ﯽﻧﺎﻣرد ﯽﺗﺎﻘﯿﻘﺤﺗ ﺰﮐﺮﻣ ﻞﻨﺳﺮﭘ زا ﻦﯿﻨﭽﻤﻫ ﯽﻣ ﯽﻧادرﺪﻗ دﺰﯾ ﯽﮑﺷﺰﭘ هﺪﮑﺸﻧاد .دﻮﺷ
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نارﺎﮑﻤﻫ و چراز ﯽﯾﺎﻗآ ﻦﺴﺤﻣ ﺪﯿﺳ
نارﺪﻧزﺎﻣ ﯽﮑﺷﺰﭘ مﻮﻠﻋ هﺎﮕﺸﻧاد ﻪﻠﺠﻣ
هرﺎﻤﺷ ،ﻢﻬﻧ و ﺖﺴﯿﺑ هرود 176
رﻮﯾﺮﻬﺷ ، 1398 201
هﺎﺗﻮﮐ شراﺰﮔ
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