Publications by authors named "Kiran Dip Gill"

51 Publications

Okadaic Acid and Hypoxia Induced Dementia Model of Alzheimer's Type in Rats.

Neurotox Res 2019 Apr 7;35(3):621-634. Epub 2019 Feb 7.

Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.

Alzheimer's disease (AD) is the most common cause of progressive decline of memory function in aged humans. To study about a disease mechanism and progression, animal models for the specific disease are needed. For AD, although highly valid animal models exist, none of the existing models recapitulates all aspects of human AD. The pathogenic mechanisms involved in AD are diverse and thus it is difficult to recapitulate human AD in model organisms. Intracerebroventricular (ICV) injection of okadaic acid (OKA), a protein phosphatase 2A (PP2A) inhibitor, in rats causes neurotoxicity associated with neurofibrillary degeneration. However, this model lacks amyloid pathology as observed in AD. We aimed at combining two different treatments and hence producing a better animal model of AD which may mimic most of the neuropathological, neurobehavioral, and neurochemical changes observed in AD. For this, OKA (200 ng) was microinjected bilaterally into the hippocampus of male Wistar rats followed by exposure of same rats to hypoxic conditions (10%) for 3 days. The result of which, the combination model exhibited tau hyperphosphorylation along with Aβ upregulation as evident by western blotting and immunohistochemistry. The observed changes were accompanied with dysfunction of neurotransmitter system, i.e., decreased acetylcholine activity and expression. This combinatorial model also exhibited cognitive deficiency which was assessed by Morris water maze and avoidance tests along with enhanced oxidative stress which is thought to be a major player in AD pathogenesis. Taken together, we established an easily reproducible and reliable rat model for sporadic dementia of Alzheimer's type in rats which allows effective testing of new therapeutic strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12640-019-0005-9DOI Listing
April 2019

Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer's disease.

Alzheimers Dement 2018 07 28;14(7):913-924. Epub 2018 Mar 28.

Department of Nuclear Medicine, Technische Universitaet München, Munich, Germany.

Introduction: Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology.

Methods: We included 3451 Aβ+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE ε4 prevalence in relation to age, sex, education, and geographical location.

Results: The APOE ε4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aβ+ cognitively normal and Aβ+ mild cognitive impairment (P < .05) but not in Aβ+ AD dementia (P = .66). The prevalence was highest in Northern Europe but did not vary by sex or education.

Discussion: The APOE ε4 prevalence in AD was higher than that in previous studies, which did not require presence of Aβ pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jalz.2018.02.009DOI Listing
July 2018

Cell cycle activation in p21 dependent pathway: An alternative mechanism of organophosphate induced dopaminergic neurodegeneration.

Biochim Biophys Acta Mol Basis Dis 2017 07 2;1863(7):1858-1866. Epub 2016 Jun 2.

Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India. Electronic address:

In the previous study, we demonstrated that dichlorvos induces oxidative stress in dopaminergic neuronal cells and subsequent caspase activation mediates apoptosis. In the present study, we evaluated the effect and mechanism of dichlorvos induced oxidative stress on cell cycle activation in NGF-differentiated PC12 cells. Dichlorvos exposure resulted in oxidative DNA damage along with activation of cell cycle machinery in differentiated PC12 cells. Dichlorvos exposed cells exhibited an increased expression of p53, cyclin-D1, pRb and decreased expression of p21suggesting a re-entry of differentiated cells into the cell cycle. Cell cycle analysis of dichlorvos exposed cells revealed a reduction of cells in the G/G phase of the cell cycle (25%), and a concomitant increase of cells in S phase (30%) and G2/M phase (43.3%) compared to control PC12 cells. Further, immunoblotting of cytochrome c, Bax, Bcl-2 and cleaved caspase-3 revealed that dichlorvos induces a caspase-dependent cell death in PC12 cells. These results suggest that Dichlorvos exposure has the potential to generate oxidative stress which evokes activation of cell cycle machinery leading to apoptotic cell death via cytochrome c release from mitochondria and subsequent caspase-3 activation in differentiated PC12 cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbadis.2016.05.014DOI Listing
July 2017

Understanding Aspects of Aluminum Exposure in Alzheimer's Disease Development.

Brain Pathol 2016 Mar 8;26(2):139-54. Epub 2015 Dec 8.

Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Aluminum is a ubiquitously abundant nonessential element. Aluminum has been associated with neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis, and dialysis encephalopathy. Many continue to regard aluminum as controversial although increasing evidence supports the implications of aluminum in the pathogenesis of AD. Aluminum causes the accumulation of tau protein and Aβ protein in the brain of experimental animals. Aluminum induces neuronal apoptosis in vivo and in vitro, either by endoplasmic stress from the unfolded protein response, by mitochondrial dysfunction, or a combination of them. Some, people who are exposed chronically to aluminum, either from through water and/or food, have not shown any AD pathology, apparently because their gastrointestinal barrier is more effective. This article is written keeping in mind mechanisms of action of aluminum neurotoxicity with respect to AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bpa.12333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028870PMC
March 2016

Quercetin protects against aluminium induced oxidative stress and promotes mitochondrial biogenesis via activation of the PGC-1α signaling pathway.

Neurotoxicology 2015 Dec 19;51:116-37. Epub 2015 Oct 19.

Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India. Electronic address:

The present investigation was carried out to elucidate a possible molecular mechanism related to the protective effect of quercetin administration against aluminium-induced oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of PGC-1α and its downstream targets, i.e. NRF-1, NRF-2 and Tfam in mitochondrial biogenesis. Aluminium lactate (10mg/kg b.wt./day) was administered intragastrically to rats, which were pre-treated with quercetin 6h before aluminium (10mg/kg b.wt./day, intragastrically) for 12 weeks. We found a decrease in ROS levels, mitochondrial DNA oxidation and citrate synthase activity in the hippocampus (HC) and corpus striatum (CS) regions of rat brain treated with quercetin. Besides this an increase in the mRNA levels of the mitochondrial encoded subunits - ND1, ND2, ND3, Cyt b, COX1, COX3 and ATPase6 along with increased expression of nuclear encoded subunits COX4, COX5A and COX5B of electron transport chain (ETC). In quercetin treated group an increase in the mitochondrial DNA copy number and mitochondrial content in both the regions of rat brain was observed. The PGC-1α was up regulated in quercetin treated rats along with NRF-1, NRF-2 and Tfam, which act downstream from PGC-1α. Electron microscopy results revealed a significant decrease in the mitochondrial cross-section area, mitochondrial perimeter length and increase in mitochondrial number in case of quercetin treated rats as compared to aluminium treated ones. Therefore it seems quercetin increases mitochondrial biogenesis and makes it an almost ideal flavanoid to control or limit the damage that has been associated with the defective mitochondrial function seen in many neurodegenerative diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuro.2015.10.002DOI Listing
December 2015

Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.

JAMA 2015 May;313(19):1924-38

Department of Neurology, Akershus University Hospital, Lørenskog, Norway.

Importance: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.

Objective: To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI).

Data Sources: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators.

Study Selection: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity.

Data Extraction And Synthesis: Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies.

Main Outcomes And Measures: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations.

Results: The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality.

Conclusions And Relevance: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2015.4668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486209PMC
May 2015

CSF ubiquitin as a specific biomarker in Alzheimer's disease.

Curr Alzheimer Res 2014 May;11(4):340-8

Department of Radiation oncology, Emory University, Atlanta, Georgia 30322.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Although, many putative biomarkers are reported for AD, only a few have been validated in the clinical setting. Ubiquitin levels increase in cerebrospinal fluid (CSF) of patients with AD, but its diagnostic value is not clear. In this present study we evaluate the performance of ubiquitin as a diagnostic marker and deduce a statistical association with disease pathology in AD. Ubiquitin levels were estimated in subjects with AD, other forms of dementias, neurological disorders and healthy age matched population. The levels of ubiquitin were significantly higher in subjects with AD when compared with other groups (p<0.0001). A significant positive correlation was observed between ubiquitin, tau and apolipoprotein Eε4 genotype; with Aβ42 the correlation was negative. By comparing the effect size of the association between ubiquitin and a diagnosis of AD, we find that high ubiquitin levels are specific for AD. We obtained an odds ratio of 5.6 (95% CI 5.0-7.7) for ubiquitin, towards a diagnosis of AD based on clinical criteria, CSF biomarker signature (Aβ42+tau) and apolipoprotein Eε4 genotype. Hence, all our findings taken together provide a strong statistical association linking ubiquitin to the pathology in AD. We also find that, the performance of ubiquitin as a diagnostic marker is comparable to that of CSF Aβ42 or tau or apolipoprotein Eε4 genotype considered individually.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1567205011666140331161027DOI Listing
May 2014

Oxidative stress and mitochondrial dysfunction in aluminium neurotoxicity and its amelioration: a review.

Neurotoxicology 2014 Mar 20;41:154-66. Epub 2014 Feb 20.

Department of Biochemistry, Maharshi Dayanand University, Rohtak, India; Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India. Electronic address:

Aluminium is light weight and toxic metal present ubiquitously on earth which has gained considerable attention due to its neurotoxic effects. The widespread use of products made from or containing aluminium is ensuring its presence in our body. There is prolonged retention of a fraction of aluminium that enters the brain, suggesting its potential for accumulation with repeated exposures. There is no known biological role for aluminium within the body but adverse physiological effects of this metal have been observed in mammals. The generation of oxidative stress may be attributed to its toxic consequences in animals and humans. The oxidative stress has been implicated in pathogenesis of various neurodegenerative conditions including Alzheimer's disease and Parkinson's disease. Though it remains unclear whether oxidative stress is a major cause or merely a consequence of cellular dysfunction associated with neurodegenerative diseases, an accumulating body of evidence implicates that impaired mitochondrial energy production and increased mitochondrial oxidative damage is associated with the pathogenesis of neurodegenerative disorders. Being involved in the production of reactive oxygen species, aluminium may impair mitochondrial bioenergetics and may lead to the generation of oxidative stress. In this review, we have discussed the oxidative stress and mitochondrial dysfunctions occurring in Al neurotoxicity. In addition, the ameliorative measures undertaken in aluminium induced oxidative stress and mitochondrial dysfunctions have also been highlighted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuro.2014.02.004DOI Listing
March 2014

Effect of Resveratrol and Nicotine on PON1 Gene Expression: In Vitro Study.

Indian J Clin Biochem 2014 Jan 1;29(1):69-73. Epub 2013 Feb 1.

Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Nehru Hospital, 4th Floor, Block F, Room 16, Chandigarh, 160012 India.

Dietary and lifestyle factors have been shown to have a profound effect on paraoxonase-1 (PON1) activity. Cigarette smoke has been shown to inhibit its mass and activity where as resveratrol has been shown to enhance it. We exposed hepatoma derived cell line (HepG2) to resveratrol and nicotine in varying doses and measured PON1 enzymatic activity and PON1 gene expression. In addition, total protein content of HepG2 cells was also measured. Resveratrol in a dose of 15 μmol/l or above significantly increased the PON1 enzyme activity (p > 0.001) where as nicotine in a dose of 1 μmol/l or higher significantly reduced it (p < 0.05). The resveratrol in this dose also enhanced the PON1 gene expression whereas nicotine decreased it as compared to controls. However, the protein conent of cells was not changed suggesting that they were not cytotoxic in the doses used. Till date the antioxidant vitamins have shown disappointing results against LDL oxidation and cardiovascular protection. However, the effect of resveratrol on PON1 gene expression and activity was significant, suggesting increase in PON1 activity and enhanced gene expression may be its alternative mechanism for offering protection against cardiovascular disease and may be an potential pharmacological agent which can be used for this.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12291-013-0300-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903941PMC
January 2014

4-Hydroxy TEMPO attenuates dichlorvos induced microglial activation and apoptosis.

ACS Chem Neurosci 2014 Feb 6;5(2):115-27. Epub 2014 Jan 6.

Department of Biochemistry, Postgraduate Institute of Medical Education and Research , Chandigarh 160012, India.

Microglial cells have been implicated in various neurodegenerative diseases. Previous studies from our lab have shown that dichlorvos (an organophosphate) could induce Parkinson's like features in rats. Recently, we have shown that dichlorvos can induce microglial activation, and if not checked in time could ultimately induce neuronal apoptosis. However, this activation does not always pose a threat to the neurons. Activated microglia also secrete various neuronal growth factors, suggesting that they have beneficial roles in CNS repair. Therefore, it is essential to control their detrimental functions selectively. Here, we tried to find out how microglial cells behave when exposed to dichlorvos in either the presence or absence of potent nitric oxide scavenger and superoxide dismutase mimetic, 4-hydroxy TEMPO (4-HT). Wistar rat pups (1 day) were used to isolate and culture primary microglial cells. We found 4-HT pretreatment successfully attenuated the dichlorvos mediated microglial activation. Moreover, 4-HT pretreatment decreased the up-regulated levels of p53 and its downstream effector, p21. The expression of various cell cycle regulators such as Chk2, CDC25a, and cyclin A remained close to their basal levels when 4-HT pretreatment was given. DNA fragmentation analysis showed significant reduction in the DNA damage of 4-HT pretreated microglia as compared to dichlorvos treated cells. In addition to this, we found 4-HT pretreatment prevented the microglial cells from undergoing apoptotic cell death even after 48 h of dichlorvos exposure. Taken together, our results showed 4-HT pretreatment could successfully ameliorate the dichlorvos induced microglial cell damage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/cn400206wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930997PMC
February 2014

CSF p-Tau levels in the prediction of Alzheimer's disease.

Biol Open 2013 4;2(11):1119-24. Epub 2013 Sep 4.

Department of Biochemistry, Post Graduate Institute of Medical Education and Research , Chandigarh , India 160 012.

The two hallmarks of Alzheimer's disease (AD) are neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles are formed due to the hyperphosphorylation of tau protein. There is an urgent need to develop a reliable biomarker for the diagnosis of AD. Cerebrospinal fluid (CSF) is surrounding the brain and reflects the major neuropathological features in the AD brain. Diagnosis, disease progression and drug actions rely on the AD biomarkers. Mainly CSF tau and phosphorylated tau (p-Tau) have been observed to serve the purpose for early AD. Keeping in view the early appearance of p-Tau in CSF, we analyzed p-Tau levels in 23 AD, 23 Non AD type dementia (NAD), 23 Neurological control (NC) and 23 Healthy control (HC) North Indian patients. The levels of p-Tau were found to be increased in AD patients (67.87±18.05 pg/ml, SEM 3.76) compared with NAD (47.55±7.85 pg/ml, SEM 1.64), NC (34.42±4.51 pg/ml, SEM 0.94) and HC (27.09±7.18 pg/ml, SEM 1.50). The resulting sensitivity for AD with NAD was 80.27% whereas with respect to the NAD, NC and HC was 85.40%. Therefore elevated levels of p-Tau in AD can be exploited as a predictive biomarker in North Indian AD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1242/bio.20135447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828758PMC
November 2013

Aluminium induced oxidative stress results in decreased mitochondrial biogenesis via modulation of PGC-1α expression.

Toxicol Appl Pharmacol 2013 Dec 29;273(2):365-80. Epub 2013 Sep 29.

Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.

The present investigation was carried out to elucidate a possible molecular mechanism related to the effects of aluminium-induced oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of Peroxisome proliferator activated receptor gamma co-activator 1α (PGC-1α) and its downstream targets i.e. Nuclear respiratory factor-1(NRF-1), Nuclear respiratory factor-2(NRF-2) and Mitochondrial transcription factor A (Tfam) in mitochondrial biogenesis. Aluminium lactate (10mg/kgb.wt./day) was administered intragastrically to rats for 12 weeks. After 12 weeks of exposure, we found an increase in ROS levels, mitochondrial DNA oxidation and decrease in citrate synthase activity in the Hippocampus (HC) and Corpus striatum (CS) regions of rat brain. On the other hand, there was a decrease in the mRNA levels of the mitochondrial encoded subunits-NADH dehydrogenase (ND) subunits i.e. ND1, ND2, ND3, Cytochrome b (Cytb), Cytochrome oxidase (COX) subunits i.e. COX1, COX3, ATP synthase (ATPase) subunit 6 along with reduced expression of nuclear encoded subunits COX4, COX5A, COX5B of Electron transport chain (ETC). Besides, a decrease in mitochondrial DNA copy number and mitochondrial content in both regions of rat brain was observed. The PGC-1α was down-regulated in aluminium treated rats along with NRF-1, NRF-2 and Tfam, which act downstream from PGC-1α in aluminium treated rats. Electron microscopy results revealed a significant increase in the mitochondrial swelling, loss of cristae, chromatin condensation and decreases in mitochondrial number in case of aluminium treated rats as compared to control. So, PGC-1α seems to be a potent target for aluminium neurotoxicity, which makes it an almost ideal target to control or limit the damage that has been associated with the defective mitochondrial function seen in neurodegenerative diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.taap.2013.09.012DOI Listing
December 2013

Therapeutics of Alzheimer's disease: Past, present and future.

Neuropharmacology 2014 Jan 25;76 Pt A:27-50. Epub 2013 Jul 25.

Department of Biochemistry, Christian Medical College, Vellore 632002, Tamilnadu, India. Electronic address:

Alzheimer's disease (AD) is the most common cause of dementia worldwide. The etiology is multifactorial, and pathophysiology of the disease is complex. Data indicate an exponential rise in the number of cases of AD, emphasizing the need for developing an effective treatment. AD also imposes tremendous emotional and financial burden to the patient's family and community. The disease has been studied over a century, but acetylcholinesterase inhibitors and memantine are the only drugs currently approved for its management. These drugs provide symptomatic improvement alone but do less to modify the disease process. The extensive insight into the molecular and cellular pathomechanism in AD over the past few decades has provided us significant progress in the understanding of the disease. A number of novel strategies that seek to modify the disease process have been developed. The major developments in this direction are the amyloid and tau based therapeutics, which could hold the key to treatment of AD in the near future. Several putative drugs have been thoroughly investigated in preclinical studies, but many of them have failed to produce results in the clinical scenario; therefore it is only prudent that lessons be learnt from the past mistakes. The current rationales and targets evaluated for therapeutic benefit in AD are reviewed in this article. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2013.07.004DOI Listing
January 2014

Attenuation of dichlorvos-induced microglial activation and neuronal apoptosis by 4-hydroxy TEMPO.

Mol Neurobiol 2014 Feb 25;49(1):163-75. Epub 2013 Jul 25.

Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.

The neurotoxic consequences of acute high-level as well as chronic low-level organophosphates exposure are associated with a range of abnormalities in nerve functions. Previously, we have shown that after 24 h of dichlorvos exposure, microglia become activated and secrete pro-inflammatory molecules like nitric oxide, tumour necrosis factor-α and interleukin-1β. Here, we extended our findings and focused on the neuronal damage caused by dichlorvos via microglial activation. For this, neurons and microglia were isolated separately from 1-day-old Wistar rat pups. Microglia were treated with dichlorvos for 24 h and supernatant was collected (dichlorvos-induced conditioned medium, DCM). However, when 4-hydroxy TEMPO (4-HT) pretreatment was given, we observed significant attenuation of dichlorvos-induced microglial activation; we also collected the supernatant of this culture (4-HT + DCM, TDCM). Next, we checked the effects of DCM on neurons and found heavy loss in viability as evident from NF-H immunostaining and MTT results, whereas dichlorvos alone-treated neurons showed comparatively less damage. However, we observed significant increase in neuronal viability when cells were treated with TDCM. Semi-quantitative PCR and western blot results revealed significant increase in p53, Bax and cytochrome c levels along with caspase 3 activation after 24 h of DCM treatment. However, TDCM-treated neurons showed significant decrease in the expression of these pro-apoptotic molecules. Taken together, these findings suggest that 4-HT can significantly attenuate dichlorvos-induced microglial activation and prevent apoptotic neuronal cell death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12035-013-8508-5DOI Listing
February 2014

Spontaneous and induced nontransgenic animal models of AD: modeling AD using combinatorial approach.

Am J Alzheimers Dis Other Demen 2013 Jun 17;28(4):318-26. Epub 2013 May 17.

Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Alzheimer's disease (AD), the most common neurodegenerative and dementing disorder, is characterized by extracellular amyloid deposition, intracellular neurofibrillary tangle formation, and neuronal loss. We are still behind in AD research in terms of knowledge regarding understanding its pathophysiology and designing therapeutics because of the lack of an accurate animal model for AD. A complete animal model of AD should imitate all the cognitive, behavioral, and neuropathological features of the disease. Partial models are currently in use, which only mimic specific and not all of the components of AD pathology. Currently the transgenic animals are the popular models for AD research, but different genetic backgrounds of these transgenic animals remain a major confounding factor. This review attempts to summarize the current literature on nontransgenic animal models of AD and to highlight the potential of exploiting spontaneous and induced animal models for neuropathological, neurochemical, neurobehavioral, and neuroprotective studies of AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1533317513488914DOI Listing
June 2013

Apolipoprotein E levels in the cerebrospinal fluid of north Indian patients with Alzheimer's disease.

Am J Alzheimers Dis Other Demen 2013 May;28(3):258-62

Radiation Oncology, Emory University, Atlanta, Georgia, USA.

The etiology of Alzheimer's disease (AD) is multifactorial involving both genetic and environmental factors. Apolipoprotein E (ApoE) gene plays a pivotal role in risk and age of onset of AD. Although it is broadly accepted that ApoE genotype is linked to the pathogenesis of AD, there are still controversial results regarding the association of ApoE levels in cerebrospinal fluid (CSF) with the occurrence of AD. Some studies have shown a positive correlation between CSF ApoE levels and AD, whereas others showed no link. In this study, we measured ApoE levels to assess the usefulness of CSF ApoE as a diagnostic marker of AD by comparing the levels in 3 patient groups and in control participants. No significant difference was observed in CSF ApoE concentrations between the patients with AD and the controls. So, it appears that CSF ApoE measurement does not offer any diagnostic advantage for AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1533317513481097DOI Listing
May 2013

Dichlorvos-induced cell cycle arrest and DNA damage repair activation in primary rat microglial cells.

J Neurosci Res 2013 Mar 26;91(3):444-52. Epub 2012 Dec 26.

Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Dichlorvos, an organophosphate (OP), is known to cause oxidative stress in the central nervous system (CNS). Previously we have shown that dichlorvos treatment promoted the levels of proinflammatory molecules and ultimately induced apoptotic cell death in primary microglial cells. Here we studied the effect of dichlorvos on crucial cell cycle regulatory proteins and the DNA damage sensor ataxia-telangiectasia mutated (ATM). We found a significant increase in p53 and its downstream target, p21, levels in dichlorvos-treated microglial cells compared with control cells. Moreover, dichlorvos exposure promoted the levels of different cell cycle regulatory proteins. These results along with flow cytometry results suggested that primary microglial cells were arrested at G1 and G2/M phase after dichlorvos exposure. We have shown in a previous study that dichlorvos can induce DNA damage in microglia; here we found that microglial cells also tried to repair this damage by inducing a DNA repair enzyme, i.e., ATM. We observed a significant increase in the levels of ATM after dichlorvos treatment compared with control.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jnr.23173DOI Listing
March 2013

Effect of acute aluminum phosphide exposure on rats: a biochemical and histological correlation.

Toxicol Lett 2012 Nov 2;215(1):62-9. Epub 2012 Oct 2.

Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Aluminum phosphide (AlP), a widely used fumigant and rodenticide leads to high mortality if ingested. Its toxicity is due to phosphine liberated when it comes in contact with moisture. The exact mechanism of action of phosphine is not known. In this study male Wistar rats were used. The animals received a single dose (20mg AlP/kg body weight i.g.) orally. Basic serum biochemical parameters, activity of mitochondrial complexes, antioxidant enzymes and parameters of oxidative stress, individual mitochondrial cytochrome levels were measured along with tissue histopathology and immunostaining for cytochrome c and compared with controls. The serum levels of creatinine kinase-MB, lactate dehydrogenase, magnesium and cortisol were higher (p<0.01); the activities of mitochondrial complexes I, II, IV were observed to be significantly decreased in liver tissue in treated rats (p<0.01). The activity of catalase was lower (p<0.05) with a significant increase in lipid peroxidation (p<0.05) whereas superoxide dismutase and glutathione peroxidase were unaffected in them. There was a significant decrease in all the cytochromes in brain and liver tissues (p<0.05) with the exception of cytochrome b in brain, the levels of which remained same. Histopathology revealed congestion in most organs with centrizonal hemorrhagic necrosis in liver. Ultra structural changes indicating mitochondrial injury was observed in heart, liver and kidney tissues. There was also a marked reduction in the cytochrome-c immunostaining compared to the controls. Toxicity due to AlP appears to result as a consequence of both-energy insufficiency and oxidative stress, with a possible and preferential interaction with the tissue cytochromes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.toxlet.2012.09.020DOI Listing
November 2012

Quercetin protects against chronic aluminum-induced oxidative stress and ensuing biochemical, cholinergic, and neurobehavioral impairments in rats.

Neurotox Res 2013 May 24;23(4):336-57. Epub 2012 Aug 24.

Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India.

In this study, we investigated the protective effect of chronic quercetin (a natural flavanoid) administration against Al-induced cognitive impairments, oxidative damage, and cholinergic dysfunction in male Wistar rats. Al lactate (10 mg/kg b.wt./day) was administered intragastrically to rats which were pre-treated with quercetin (10 mg/kg b.wt./day, intragastrically) for 12 weeks. At the end of 6 or 12 weeks of the study, several behavioral parameters were carried out to evaluate cognitive functions. Further after 12 weeks of exposure, various biochemical tests and H&E staining were performed to assess the extent of oxidative damage and neurodegeneration, respectively. Al levels were also estimated in HC and CS regions of rat brain. Chronic administration of quercetin caused significant improvement in the muscle coordination, cognition, anxiety, locomotion, and initial exploratory patterns in Al-treated rats. Quercetin supplementation to Al-treated animals also reduced oxidative stress, decreased ROS production, increased MnSOD activity and glutathione levels with decreased lipid peroxidation and protein oxidation. It increased AChE activity and ATP levels in HC and CS regions of rat brain compared to Al-treated rats. Quercetin administration ameliorates Al-induced neurodegenerative changes in Al-treated rats as seen by H&E staining. Further with the help of atomic absorption spectrophotometer, we found that quercetin supplementation to Al-treated rats also decreases the accumulation of Al in the HC and CS regions of rat brain. Taken together the results of this study show that quercetin offers neuroprotection against Al-induced cognitive impairments, cholinergic dysfunction, and associated oxidative damage in rats.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12640-012-9351-6DOI Listing
May 2013

Dichlorvos exposure results in activation induced apoptotic cell death in primary rat microglia.

Chem Res Toxicol 2012 Aug 3;25(8):1762-70. Epub 2012 Aug 3.

Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh-160012, India.

Dichlorvos [2,2-dichlorovinyl dimethyl phosphate] is one of the most common in-use organophosphate (OP) in developing nations. Previous studies from our lab have shown chronic Dichlorvos exposure leads to neuronal cell death in rats. However, the extent of damage caused by Dichlorvos to other cells of the central nervous system (CNS) is still not clear. Microglial cells are the primary threat sensors of CNS which become activated in many pathological conditions. Activation of microglial cells results in reactive microgliosis, manifested by increased cellular damage in the affected regions. Using rat primary microglial cultures, here we show that Dichlorvos exposure can activate and induce apoptotic cell death in microglia. We observed significant up-regulation of pro-inflammatory molecules like nitric oxide, TNF-α, and IL-1β when microglia were treated with Dichlorvos (10 μM). Significant up-regulation of CD11b, microglial specific activation marker, was also observed after 24 h of Dichlorvos treatment. The activated microglial cells eventually undergo cell death after 48 h of Dichlorvos treatment. The DNA fragmentation pattern of Dichlorvos treated microglia along with increased expression of Bax in mitochondria, cytochrome c release from mitochondria, and caspase-3 activation led us to assume that microglia were undergoing apoptosis. Thus, the present study showed that Dichlorvos can induce microglial activation and ultimately apoptotic cell death. These findings gave new perspective to the current knowledge of Dichlorvos (OPs) mediated CNS damage and presents microglial activation as a potential therapeutic target for preventing the OP induced neuronal damage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/tx300234nDOI Listing
August 2012

Low serum PON1 activity: an independent risk factor for coronary artery disease in North-West Indian type 2 diabetics.

Gene 2012 Apr 4;498(1):13-9. Epub 2012 Feb 4.

Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.

The paraoxonase (PON1) gene polymorphisms are known to affect the PON1 activity and coronary artery disease (CAD) risk. Studies done so far have given conflicting results. In the present study, we determined the role of PON1 genetic variants and PON1 activity in the development of CAD in North-West Indian Punjabis, a distinct ethnic group, having high incidence of both CAD and type 2 diabetes. 300 angiographically proven CAD with type 2 diabetics and 250 type 2 diabetics with no clinically evident CAD were enrolled. Serum PON1 activity and genotyping of coding (Q192R, L55M) and promoter (-909G/C, -162A/G, -108C/T) region polymorphisms were carried out and haplotypes were determined using PHASE software. The serum PON1 activity was significantly lower in CAD with type 2 diabetics as compared to diabetics alone (51.0 vs. 114.2nmol/min/ml). In logistic regression model after adjusting for confounding variables, lower PON1 activity was found to be significantly associated with CAD risk in type 2 diabetics with OR being 16.8 (95% CI: 10.2-27.7). The lower serum PON1 activity, irrespective of genotypes and haplotypes is a risk factor for development of CAD in North-West Indian Punjabis with type 2 diabetics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gene.2012.01.091DOI Listing
April 2012

siRNA against presenilin 1 (PS1) down regulates amyloid β42 production in IMR-32 cells.

J Biomed Sci 2012 Jan 3;19. Epub 2012 Jan 3.

Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Background: One of the pathological hallmarks of Alzheimer's disease (AD) is the deposition of the ~4 kDa amyloid β protein (Aβ) within lesions known as senile plaques. Aβ is also deposited in the walls of cerebral blood vessels in many cases of AD. A substantial proportion of the Aβ that accumulates in the AD brain is deposited as Amyloid, which is highly insoluble, proteinaceous material with a β-pleated-sheet conformation and deposited extracellularly in the form of 5-10 nm wide straight fibrils. As γ-secretase catalyzes the final cleavage that releases the Aβ42 or 40 from amyloid β -protein precursor (APP), therefore, it is a potential therapeutic target for the treatment of AD. γ-Secretase cleavage is performed by a high molecular weight protein complex containing presenilins (PSs), nicastrin, Aph-1 and Pen-2. Previous studies have demonstrated that the presenilins (PS1 and PS2) are critical components of a large enzyme complex that performs γ-secretase cleavage.

Methods: In this study we used RNA interference (RNAi) technology to examine the effects of small-interfering RNA (siRNA) against PS1 on expression levels of PS1 and Aβ42 in IMR-32 Cells using RTPCR, western blotting and immunofluorescence techniques.

Results: The results of the present study showed down regulation of PS1 and Aβ42 in IMR32 cells transfected with siRNA against PS1.

Conclusion: Our results substantiate the concept that PS1 is involved in γ-secretase activity and provides the rationale for therapeutic strategies aimed at influencing Aβ42 production.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1423-0127-19-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282656PMC
January 2012

Road to Alzheimer's disease: the pathomechanism underlying.

Pathobiology 2012 28;79(2):55-71. Epub 2011 Dec 28.

Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Alzheimer's disease (AD), the most common cause of dementia, results from the interplay of various deregulated mechanisms triggering a complex pathophysiology. The neurons suffer from and slowly succumb to multiple irreversible damages, resulting in cell death and thus memory deficits that characterize AD. In spite of our vast knowledge, it is still unclear as to when the disease process starts and how long the perturbations continue before the disease manifests. Recent studies provide sufficient evidence to prove amyloid β (Aβ) as the primary cause initiating secondary events, but Aβ is also known to be produced under normal conditions and to possess physiological roles, hence, the questions that remain are: What are the factors that lead to abnormal Aβ production? When does Aβ turn into a pathological molecule? What is the chain of events that follows Aβ? The answers are still under debate, and further insight may help us in creating better diagnostic and therapeutic options in AD. The present article attempts to review the current literature regarding AD pathophysiology and proposes a pathophysiologic cascade in AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000332218DOI Listing
June 2012

Protective efficacy of coenzyme Q10 against DDVP-induced cognitive impairments and neurodegeneration in rats.

Neurotox Res 2012 May 15;21(4):345-57. Epub 2011 Nov 15.

Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.

The present study was carried out to elucidate the effects of coenzyme Q(10) (CoQ(10)) against cognitive impairments induced by dichlorvos (DDVP). We have previously shown organophosphate, DDVP-induced impairments in neurobehavioral indices viz. rota rod, passive avoidance, and water maze tests. In addition to this, we have also reported that chronic DDVP exposure leads to decreased mitochondrial electron transfer activities of cytochrome oxidase along with altered mitochondrial complexes I-III activity. Administration of CoQ(10) (4.5 mg/kg, i.p. for 12 weeks prior to DDVP administration daily) to DDVP-treated rats improved cognitive performance in passive avoidance task and Morris water maze test. Furthermore, CoQ(10) treatment also reduced oxidative stress (as evident by reduced malondialdehyde, decreased ROS and increased Mn-SOD activity) in DDVP-treated rats' hippocampus region, along with enhanced activity of complexes I-III and complex IV. Electron microscope studies of rat hippocampus mitochondria revealed that CoQ(10) administration leads to near normal physiology of mitochondria with well-defined cristae compared with DDVP-treated animals where enlarged mitochondria with distorted cristae are observed. CoQ(10) administration also attenuated neuronal damage in hippocampus as evident from histopathological studies. These results demonstrate the beneficial effects of CoQ(10) against organophosphate-induced cognitive impairments and hippocampal neuronal degeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12640-011-9289-0DOI Listing
May 2012

Chronic dichlorvos exposure: microglial activation, proinflammatory cytokines and damage to nigrostriatal dopaminergic system.

Neuromolecular Med 2011 Dec 4;13(4):251-65. Epub 2011 Oct 4.

Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.

Dopaminergic cells in the substantia nigra are highly vulnerable to the neurodegenerative process of Parkinson's disease. Therefore, mechanisms that enhance their susceptibility to injury bear important implications for disease pathogenesis. We have previously shown that chronic dichlorvos exposure caused nigrostriatal dopaminergic degeneration and significant behavioral impairments. In this study, we analyzed the relationship between microglial activation and dopaminergic neurodegeneration to examine the possibility that neuroinflammation may induce dopaminergic neuronal loss in the nigrostriatal system. Chronic dichlorvos exposure causes microglial activation including induction of NADPH oxidase and a selective loss of dopaminergic neurons in rat. Microglial marker expression was increased at transcription as well as translational levels in the substantia nigra (SN) and corpus striatum (CS) of rats exposed to dichlorvos. Activated microglia were seen in SN and CS of dichlorvos-treated animals but were rarely observed in controls. Immunostaining revealed lesser number of TH-positive neurons and higher number of microglia in SN and CS regions after dichlorvos treatment. The mRNA and protein levels of the NADPH oxidase main subunit gp91(phox) were significantly increased after dichlorvos administration. Dichlorvos exposure also leads to increased level of microglial noxious mediators such as IL-1β, TNF-α and IL-6 in ventral midbrain and CS at transcription as well as translational levels. Data indicate that microglial activation and consequent induction of NADPH oxidase and proinflammatory cytokines such as TNF-α, IL-1β and IL-6 may act as risk factors for Parkinson's disease by increasing the vulnerability of dopaminergic cells to dichlorvos toxic injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12017-011-8156-8DOI Listing
December 2011

Protection of dichlorvos induced oxidative stress and nigrostriatal neuronal death by chronic coenzyme Q10 pretreatment.

Toxicol Appl Pharmacol 2011 Oct 5;256(1):73-82. Epub 2011 Aug 5.

Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.

Numerous epidemiological studies have shown an association between pesticide exposure and increased risk of developing Parkinson's diseases. Oxidative stress generated as a result of mitochondrial dysfunction has been implicated as an important factor in the etiology of Parkinson's disease. Previously, we reported that chronic dichlorvos exposure causes mitochondrial impairments and nigrostriatal neuronal death in rats. The present study was designed to test whether Coenzyme Q(10) (CoQ(10)) administration has any neuroprotective effect against dichlorvos mediated nigrostriatal neuronal death, α-synuclein aggregation, and motor dysfunction. Male albino rats were administered dichlorvos by subcutaneous injection at a dose of 2.5 mg/kg body weight over a period of 12 weeks. Results obtained there after showed that dichlorvos exposure leads to enhanced mitochondrial ROS production, α-synuclein aggregation, decreased dopamine and its metabolite levels resulting in nigrostriatal neurodegeneration. Pretreatment by Coenzyme Q(10) (4.5 mg/kg ip for 12 weeks) to dichlorvos treated animals significantly attenuated the extent of nigrostriatal neuronal damage, in terms of decreased ROS production, increased dopamine and its metabolite levels, and restoration of motor dysfunction when compared to dichlorvos treated animals. Thus, the present study shows that Coenzyme Q(10) administration may attenuate dichlorvos induced nigrostriatal neurodegeneration, α-synuclein aggregation and motor dysfunction by virtue of its antioxidant action.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.taap.2011.07.015DOI Listing
October 2011

Serum paraoxonase-1 (PON1) activities (PONase/AREase) and polymorphisms in patients with type 2 diabetes mellitus in a North-West Indian population.

Gene 2011 Nov 26;487(1):88-95. Epub 2011 Jul 26.

Department of Biochemistry, PGIMER, Chandigarh, India.

Objective: Paraoxonase-1 (PON1), an HDL-C associated enzyme, protects lipoproteins from oxidation. There is evidence that PON1 enzyme activity is reduced in the patients with type 2 diabetes mellitus (T2DM). North-West Indian Punjabis, a distinct ethnic group has high incidence of T2DM. However till date there is no information regarding PON1 enzyme activities and PON1 polymorphisms in T2DM patients of this ethnic group.

Methods: We identified polymorphisms in the coding Q192R, L55M and promoter -909G/C, -162A/G, -108C/T of the PON1 gene by using PCR-RFLP, multiplex PCR and allele specific oligonucleotide PCR assays in 250 T2DM patients and 300 healthy controls. We also assessed paraoxonase (PONase) and arylesterase (AREase) activities of PON1 enzyme.

Results: The serum PONase (114.2 vs. 178.0nmol/min/ml) and AREase (62.7 vs. 82.5μmol/min/ml) activities were significantly lower (p<0.0001) in patients as compared to controls. PONase activity was affected by all the studied PON1 polymorphisms. However, AREase activity was not affected by any of these polymorphisms. Coding Q192R and promoter -909G/C polymorphisms showed significant differences in genotypic distribution. QR, RR (Q192R) and GC, CC (-909G/C) genotypes and L-C-A-R-G, L-T-A-R-G, L-T-G-Q-C haplotypes showed significant association with type 2 diabetes. No significant linkage disequilibrium was observed among the five polymorphisms.

Conclusion: Both PONase and AREase activities are lower in patients and this could lead to increased lipid peroxidation and accelerated atherosclerosis in them. PONase activity, but not AREase activity is influenced by PON1 polymorphisms. QR, RR, GC, CC genotypes and L-C-A-R-G, L-T-A-R-G, L-T-G-Q-C haplotypes are commoner in diabetics as compared to controls and may be related to genetic susceptibility to type 2 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gene.2011.07.011DOI Listing
November 2011

Protective efficacy of mitochondrial targeted antioxidant MitoQ against dichlorvos induced oxidative stress and cell death in rat brain.

Neuropharmacology 2011 Dec 26;61(8):1193-201. Epub 2011 Jul 26.

Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.

Dichlorvos is a synthetic insecticide that belongs to the family of chemically related organophosphate (OP) pesticides. It can be released into the environment as a major degradation product of other OPs, such as trichlorfon, naled, and metrifonate. Dichlorvos exerts its toxic effects in humans and animals by inhibiting neural acetylcholinesterase. Chronic low-level exposure to dichlorvos has been shown to result in inhibition of the mitochondrial complex I and cytochrome oxidase in rat brain, resulting in generation of reactive oxygen species (ROS). Enhanced ROS production leads to disruption of cellular antioxidant defense systems and release of cytochrome c (cyt c) from mitochondria to cytosol resulting in apoptotic cell death. MitoQ is an antioxidant, selectively targeted to mitochondria and protects it from oxidative damage and has been shown to decrease mitochondrial damage in various animal models of oxidative stress. We hypothesized that if oxidative damage to mitochondria does play a significant role in dichlorvos induced neurodegeneration, then MitoQ should ameliorate neuronal apoptosis. Administration of MitoQ (100 μmol/kg body wt/day) reduced dichlorvos (6 mg/kg body wt/day) induced oxidative stress (decreased ROS production, increased MnSOD activity and glutathione levels) with decreased lipid peroxidation, protein and DNA oxidation. In addition, MitoQ also suppressed DNA fragmentation, cyt c release and caspase-3 activity in dichlorvos treated rats compared to the control group. Further electron microscopic studies revealed that MitoQ attenuates dichlorvos induced mitochondrial swelling, loss of cristae and chromatin condensation. These results indicate that MitoQ may be beneficial against OP (dichlorvos) induced neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2011.07.008DOI Listing
December 2011

Paraoxonase 1 (PON1) polymorphisms, haplotypes and activity in predicting cad risk in North-West Indian Punjabis.

PLoS One 2011 24;6(5):e17805. Epub 2011 May 24.

Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Background: Human serum paraoxonase-1 (PON1) prevents oxidation of low density lipoprotein cholesterol (LDL-C) and hydrolyzes the oxidized form, therefore preventing the development of atherosclerosis. The polymorphisms of PON1 gene are known to affect the PON1 activity and thereby coronary artery disease (CAD) risk. As studies are lacking in North-West Indian Punjabi's, a distinct ethnic group with high incidence of CAD, we determined PON1 activity, genotypes and haplotypes in this population and correlated them with the risk of CAD.

Methodology/principal Findings: 350 angiographically proven (≥ 70% stenosis) CAD patients and 300 healthy controls were investigated. PON1 activity was determined towards paraoxon (Paraoxonase; PONase) and phenylacetate (Arylesterase; AREase) substrates. In addition, genotyping was carried out by using multiplex PCR, allele specific oligonucleotide -PCR and PCR-RFLP methods and haplotyping was determined by PHASE software. The serum PONase and AREase activities were significantly lower in CAD patients as compared to the controls. All studied polymorphisms except L55M had significant effect on PONase activity. However AREase activity was not affected by them. In a logistic regression model, after adjustment for the conventional risk factors for CAD, QR (OR: 2.73 (1.57-4.72)) and RR (OR, 16.24 (6.41-41.14)) genotypes of Q192R polymorphism and GG (OR: 2.07 (1.02-4.21)) genotype of -162A/G polymorphism had significantly higher CAD risk. Haplotypes L-T-G-Q-C (OR: 3.25 (1.72-6.16)) and L-T-G-R-G (OR: 2.82 (1.01-7.80)) were also significantly associated with CAD.

Conclusions: In conclusion this study shows that CAD patients had lower PONase and AREase activities as compared to the controls. The coding Q192R polymorphism, promoter -162A/G polymorphism and L-T-G-Q-C and L-T-G-R-G haplotypes are all independently associated with CAD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017805PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101202PMC
September 2011

Aluminum phosphide poisoning: an unsolved riddle.

J Appl Toxicol 2011 Aug 24;31(6):499-505. Epub 2011 May 24.

Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Aluminum phosphide (ALP), a widely used insecticide and rodenticide, is also infamous for the mortality and morbidity it causes in ALP-poisoned individuals. The toxicity of metal phosphides is due to phosphine liberated when ingested phosphides come into contact with gut fluids. ALP poisoning is lethal, having a mortality rate in excess of 70%. Circulatory failure and severe hypotension are common features of ALP poisoning and frequent cause of death. Severe poisoning also has the potential to induce multi-organ failure. The exact site or mechanism of its action has not been proved in humans. Rather than targeting a single organ to cause gross damage, ALP seems to work at the cellular level, resulting in widespread damage leading to multiorgan dysfunction (MOD) and death. There has been proof in vitro that phosphine inhibits cytochrome c oxidase. However, it is unlikely that this interaction is the primary cause of its toxicity. Mitochondria could be the possible site of maximum damage in ALP poisoning, resulting in low ATP production followed by metabolic shutdown and MOD; also, owing to impairment in electron flow, there could be free radical generation and damage, again producing MOD. Evidence of reactive oxygen species-induced toxicity owing to ALP has been observed in insects and rats. A similar mechanism could also play a role in humans and contribute to the missing link in the pathogenesis of ALP toxicity. There is no specific antidote for ALP poisoning and supportive measures are all that are currently available.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jat.1692DOI Listing
August 2011
-->