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Transcript
Role of Cell Apoptosis in Drug Abuse and Human Diseases
Deling Yin M.D., Ph.D.
Associate Professor
Department of Internal Medicine
College of Medicine
East Tennessee State University
Johnson City, TN 37614
Apoptosis
Apoptosis is an active process that results in membrane blebbing,
DNA fragmentation. It is gene-directed process responsible for a
number of membrane receptors and cytoplamic proteins.
Apoptosis plays a fundamental role in a variety of physiological
process and its deregulation contributes to many diseases, including
AIDS and autoimmune diseases.
Growing evidence demonstrated that HIV-1/AIDS and opioid drugs
are capable to induce apoptosis of immune cells, but the mechanism
is not clear.
Apoptosis
Programmed Cell Death
Flow cytometry is a powerful tool to
determine the number of apoptotic cells.
Two years ago, Dr. Junying Yuan’s group reported for the first
time that “necroptosis” contributes to delayed mouse ischemic
brain injury in vivo (Nature Chemical Biology. 2005. 1, 112119). “Necroptosis” is from necrosis and apoptosis.
Absence of trophic factor: Caspase activation
Opioids
Opioids (e.g. morphine)
are an old class of drugs derived
from the poppy of opium plant
Papaver somniferum.
Opioids have been used for centuries as pain relievers.
Opioids have effects on perception of pain, consciousness, and
motor control.
Long-term use of opioid leads to tolerance, dependence, and addiction
and their mechanisms remain to be elucidated. Previous research
suggested that the abnormal gene expression in brain, impairment of
neuronal cells and changes in the plasticity of neuron may play important
roles in the development of opioid addiction.
30% of HIV-1 infected individuals are drug abuse, and most of these
individuals abuse opioids.
Opioids induce specific signal transduction processes through specific
opioid receptors.
Although the last 30 years extraordinary progress have been marked in
efforts to deal with the interactions of opioid abuse and HIV-1/AIDS, we
still lack fundamental knowledge of the cause of addiction, and certainly
lack definitive treatments and cures for many patients.
Opioids Receptors
Opioid receptors belong to G protein-coupled receptors (GPCRs)
Morphine, heroin, and many related synthetic opioids produce their major
effects through specific cell surface opioid receptors.
Opioid receptors and their agonists and antagonists
µ
Agonists
Antagonists
DAMGO
Endormorphine-1
Endormorphine-2
CTAP
BetaFunaltrexamine
Naloxonazine
қ
δ
All
other
U69593
Dynorphine A
U-50,488H
RU51599
Phenylacetamine
Methylpiperidine
DADLE
DPDPE
DSLET
SNC 80
SNC 121
Morphine
Etorphine
Codeine
Enkephalin
Endorphine
Dynorphine
Nociceptin
(orphanin
FQ)
(ORL1)
DIPPA
Norbinaltorphimine
ICI-154,129
DALCE
Natrindole
TIPP
Natrexone
Naloxone
Diprenorphine
Nocistatin
BNTXmaleate
Note: µ-receptor is the main receptor for morphine, heroin and other opioids
Mu-Opioid Receptor Mediated Signaling
HIV-1/AIDS and Apoptosis
HIV-1 is a retrovirus. Continuous HIV-1 replication leads to the destruction
Of immune cells, profound immune dysfunction, and finally, progression
to AIDS.
Disease progression during HIV-1 infection correlates with both elevated
levels of apoptosis and increased virus load. However, the molecular
mechanisms of the HIV-1-assocaite loss of CD4+ T cells in HIV-1
Infected individuals.
Gp120, the HIV-1 envelope glycoprotein, stimulates pro-apoptotic
signaling.
Further understanding of the regulation of apoptosis in HIV-1 disease
Will lead to the development of novel immune-based therapies for HIV-1
Infection and AIDS treatment.
Opioid Drug Abuse and HIV-1 Interactions
Injection drug users comprise over 30% of the HIV-1-infected population,
and many of subjects abuse opioids
Opioid drugs (e.g. morphine, heroin) are major risk factors and are the
fastest growing means for spread of HIV-1 infection.
A few studies have demonstrated that morphine significantly increase
Gp120-induced cell apoptosis through the p38 mitogen-activated protein
kinase (MAPK) signaling pathway.
However, the molecular mechanism by which gp120 affects the immune
response, particularly in the opioid-addicted individual, remains to be
defined.
Mechanisms of HIV-1 Gp120-Induced Apoptosis
β-Arrestin-Mediated Signaling
Lefkowitz RJ et al. Science. 2005;308:512-517
Beta-Arrestin-Mediated Signaling in the Heart
Critical involvement of beta-arr 1 in experimental autoimmune
encephalomyelitis (for multiple sclerosis)
Nat Immunol. 2007 Aug;8(8):817-24
Beta-Arr2 Deficiency Promotes Lung Tumor Growth,
Lung Metastasis, and Mortality
J. Immunol. 2008;180;5699-5706.
Model of β-arrestin Mediated Migration and Metastasis