School Of Health Sciences
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Item Understanding the neuronal synapse and challenges associated with the mitochondrial dysfunction in mild cognitive impairment and Alzheimer's disease(Elsevier B.V., 2023-09-13T00:00:00) Verma, Harkomal; Gangwar, Prabhakar; Yadav, Anuradha; Yadav, Bharti; Rao, Rashmi; Kaur, Sharanjot; Kumar, Puneet; Dhiman, Monisha; Taglialatela, Giulio; Mantha, Anil KumarSynaptic mitochondria are crucial for maintaining synaptic activity due to their high energy requirements, substantial calcium (Ca2+) fluctuation, and neurotransmitter release at the synapse. To provide a continuous energy supply, neurons use special mechanisms to transport and distribute healthy mitochondria to the synapse while eliminating the damaged mitochondria from the synapse. Along the neuron, mitochondrial membrane potential (?) gradient exists and is highest in the somal region. Lower ? in the synaptic region renders mitochondria more vulnerable to oxidative stress-mediated damage. Secondly, mitochondria become susceptible to the release of cytochrome c, and mitochondrial DNA (mtDNA) is not shielded from the reactive oxygen species (ROS) by the histone proteins (unlike nuclear DNA), leading to activation of caspases and pronounced oxidative DNA base damage, which ultimately causes synaptic loss. Both synaptic mitochondrial dysfunction and synaptic failure are crucial factors responsible for Alzheimer's disease (AD). Furthermore, amyloid beta (A?) and hyper-phosphorylated Tau, the two leading players of AD, exaggerate the disease-like pathological conditions by reducing the mitochondrial trafficking, blocking the bi-directional transport at the synapse, enhancing the mitochondrial fission via activating the mitochondrial fission proteins, enhancing the swelling of mitochondria by increasing the influx of water through mitochondrial permeability transition pore (mPTP) opening, as well as reduced ATP production by blocking the activity of complex I and complex IV. Mild cognitive impairment (MCI) is also associated with decline in cognitive ability caused by synaptic degradation. This review summarizes the challenges associated with the synaptic mitochondrial dysfunction linked to AD and MCI and the role of phytochemicals in restoring the synaptic activity and rendering neuroprotection in AD. � 2023 Elsevier B.V. and Mitochondria Research Society. All rights reserved.Item Serum Albumin Levels in Breast Cancer: Correlation with Overall Survival(SciTechnol, 2017) Kaur, Raman Preet; Rubal; Dhiman, Monisha; Vashitstha, Rajesh; Munshi, AnjanaIntroduction: Albumin in an important biomarker that indicates malnutrition as well as inflammation. The aim of the study was to evaluate the albumin levels in breast cancer patients and its association with overall survival among breast cancer patients of Malwa region of Punjab. Material and methods: The study was planned in Malwa region of Punjab. Sampling was done from Guru Gobind Singh Medical College and Hospital and Max Hospital. The estimation of albumin levels was done at Central University of Punjab. 250 patients with breast cancer and 250 age and sex matched controls were involved in the study. Albumin levels were estimated using fully automated bio analyzer Erba 200. Follow-up interviews were conducted at an interval of 3, 6, 12 and 15 months to determine the outcome among breast cancer patients. Results: Low levels of albumin was found among the diseased in comparison with controls (p<0.000). Higher albumin levels associated significantly with overall survival in breast cancer patients [χ2: 11.95, p<0.000; odds ratio: 7.636 (95% CI, 2.047- 28.49)]. Conclusion: Elevated levels of albumin (>3.5 g/dl) are associated significantly with increased overall survival among breast cancer patients. Albumin estimation may be a simple and inexpensive tool for the risk assessment and outcome of the disease in Malwa region of Punjab where the incidence of breast cancer is reported to be very high.Item Immunomodulatory and antibacterial effects of cystatin 9 against Francisella tularensis(2013) Eaves-Pyles, Tonyia; Patel, Jignesh; Arigi, Emma; Cong, Yingzi; Cao, Anthony; Garg, Nisha; Dhiman, Monisha; Pyles, Richard B.; Arulanandam, Bernard; Miller, Aaron L.; Popov, Vsevolod L.; Soong, Lynn; Carlsen, Eric D.; Coletta, Ciro; Szabo, Csaba; Almeida, Igor C.Cystatin 9 (CST9) is a member of the type 2 cysteine protease inhibitor family, which has been shown to have immunomodulatory effects that restrain inflammation, but its functions against bacterial infections are unknown. Here, we report that purified human recombinant (r)CST9 protects against the deadly bacterium Francisella tularensis (Ft) in vitro and in vivo. Macrophages infected with the Ft human pathogen Schu 4 (S4), then given 50 pg of rCST9 exhibited significantly decreased intracellular bacterial replication and increased killing via preventing the escape of S4 from the phagosome. Further, rCST9 induced autophagy in macrophages via the regulation of the mammalian target of rapamycin (mTOR) signaling pathways. rCST9 promoted the upregulation of macrophage proteins involved in antiinflammation and antiapoptosis, while restraining proinflammatory-associated proteins. Interestingly, the viability and virulence of S4 also was decreased directly by rCST9. In a mouse model of Ft inhalation, rCST9 significantly decreased organ bacterial burden and improved survival, which was not accompanied by excessive cytokine secretion or subsequent immune cell migration. The current report is the first to show the immunomodulatory and antimicrobial functions of rCST9 against Ft. We hypothesize that the attenuation of inflammation by rCST9 may be exploited for therapeutic purposes during infection.Item Oxidative Stress Events and Neuronal Dysfunction in Alzheimer’s Disease: Focus on APE1/Ref-1-Mediated Survival Strategies(Springer, 2014) Kaur, Navrattan; Sarkar, Bibekananda; Mittal, Sunil; Dhiman, Monisha; Taglialatela, Gulio; Perez-polo, Regino J.; Mantha, Anil K.Alzheimer’s disease (AD) is an important public health problem which affects millions of people worldwide. The major pathological hallmarks associated with AD are the accumulation of amyloid beta (Aβ) in senile plaques and neurofibrillary tangles (NFT) made up of hyperphosphorylated tau proteins. New findings suggest that oligomeric Aβ is a more toxic species than fibrillar Aβ relevant to AD pathology. Although the molecular mechanism(s) underlying the disease is not identified completely, various factors have been implicated in the development of AD. Accumulating evidences point towards the role of oxidative stress and mitochondrial dysfunction in the pathogenesis of AD and recognise them as an early event in AD development. Ageing is considered the greatest risk factor for AD and is linked to oxidative stress which causes accumulation of somatic mutations in mitochondrial DNA (mtDNA) over time and leads to genome instability and mitochondrial dysfunction. Recent studies on AD patients and transgenic mouse models suggest that amyloid precursor protein (APP) and Aβ localise to mitochondria, interact with mitochondrial proteins, disrupt electron transport chain (ETC), increases reactive oxygen species (ROS) level, impair axonal mitochondrial trafficking, thus leading to synaptic damage and cognitive decline associated with AD. It is not known whether accumulation of Aβ is the cause or outcome of declining mitochondrial function in AD. In order to counteract oxidative stress and maintain genome integrity, various DNA repair pathways exist, base excision repair (BER) pathway being the predominant pathway for repairing oxidised base lesions in neuronal cells. APE1 is the central enzyme of the BER pathway, having both repair and redox activities and shown to enhance neuronal survival after oxidative stress. Newer studies are revealing the role of APE1 in maintenance of mitochondrial genome repair and function. In this scenario, antioxidant-based therapy, which could reduce oxidative stress and modulate the activities of APE1, can serve as effective treatment providing neuroprotection in AD. This book chapter summarises some recent developments in understanding the pathogenesis of AD linking Aβ-induced oxidative stress, mitochondrial dysfunction, role of APE1 and phytochemicals toward AD therapeutics.Item P47 phox2/2 Mice Are Compromised in Expansion and Activation of CD8 + T Cells and Susceptible to Trypanosoma cruzi Infection(Public Library of Science (PLOS), 2014) Dhiman, Monisha; Garg, Nisha JainMacrophage activation of NAD(P)H oxidase (NOX2) and reactive oxygen species (ROS) is suggested to kill Trypanosoma cruzi that causes Chagas disease. However, the role of NOX2 in generation of protective immunity and whether these mechanisms are deregulated in the event of NOX2 deficiency are not known, and examined in this study. Our data showed that C57BL/6 p47phox−/− mice (lack NOX2 activity), as compared to wild-type (WT) mice, succumbed within 30 days post-infection (pi) to low doses of T. cruzi and exhibited inability to control tissue parasites. P47phox−/− bone-marrow and splenic monocytes were not compromised in maturation, phagocytosis and parasite uptake capacity. The deficiency of NOX2 mediated ROS was compensated by higher level of inducible nitric oxide synthase (iNOS) expression, and nitric oxide and inflammatory cytokine (TNF-α, IFN-γ, IL-1β) release by p47phox−/− macrophages as compared to that noted in WT controls infected by T. cruzi. Splenic activation of Th1 CD4+T cells and tissue infiltration of immune cells in T. cruzi infected p47phox−/− mice were comparable to that noted in infected control mice. However, generation and activation of type 1 CD8+T cells was severely compromised in p47phox−/− mice. In comparison, WT mice exhibited a robust T. cruzi-specific CD8+T cell response with type 1 (IFN-γ+TNF-α>IL-4+IL-10), cytolytic effector (CD8+CD107a+IFN-γ+) phenotype. We conclude that NOX2/ROS activity in macrophages signals the development of antigen-specific CD8+T cell response. In the event of NOX2 deficiency, a compromised CD8+T cell response is generated, leading to increased parasite burden, tissue pathogenesis and mortality in chagasic mice.Item Innate Immune Responses and Antioxidant/Oxidant Imbalance Are Major Determinants of Human Chagas Disease(Public Library of Science, 2013) Dhiman, Monisha; Coronado, Yun A.; Vallejo, Cecillia K.; Peterson, John R.; Ejilemele, Adetoun; Nunez, Sonia; Zago, Maria Paola; Spratt, Hiedi; Garg, Nisha JainBackground:We investigated the pathological and diagnostic role of selected markers of inflammation, oxidant/antioxidant status, and cellular injury in human Chagas disease.Methods:Seropositive/chagasic subjects characterized as clinically-symptomatic or clinically-asymptomatic (n = 116), seronegative/cardiac subjects (n = 102), and seronegative/healthy subjects (n = 45) were analyzed for peripheral blood biomarkers.Results:Seropositive/chagasic subjects exhibited an increase in sera or plasma levels of myeloperoxidase (MPO, 2.8-fold), advanced oxidation protein products (AOPP, 56%), nitrite (5.7-fold), lipid peroxides (LPO, 12-17-fold) and malondialdehyde (MDA, 4-6-fold); and a decline in superoxide dismutase (SOD, 52%) and glutathione (GSH, 75%) contents. Correlation analysis identified a significant (p<0.001) linear relationship between inflammatory markers (AOPP/nitrite: r = 0.877), inflammation and antioxidant/oxidant status (AOPP/glutathione peroxidase (GPX): r = 0.902, AOPP/GSH: r = 0.806, Nitrite/GPX: 0.773, Nitrite/LPO: 0.805, MDA/MPO: 0.718), and antioxidant/oxidant levels (GPX/MDA: r = 0.768) in chagasic subjects. Of these, MPO, LPO and nitrite biomarkers were highly specific and sensitive for distinguishing seropositive/chagasic subjects from seronegative/healthy controls (p<0.001, training and fitting AUC/ROC >0.95). The MPO (r = 0.664) and LPO (r = 0.841) levels were also correlated with clinical disease state in chagasic subjects (p<0.001). Seronegative/cardiac subjects exhibited up to 77% decline in SOD, 3-5-fold increase in LPO and glutamate pyruvate transaminase (GPT) levels, and statistically insignificant change in MPO, AOPP, MDA, GPX, GSH, and creatine kinase (CK) levels.Conclusions:The interlinked effects of innate immune responses and antioxidant/oxidant imbalance are major determinants of human Chagas disease. The MPO, LPO and nitrite are excellent biomarkers for diagnosing seropositive/chagasic subjects, and MPO and LPO levels have potential utility in identifying clinical severity of Chagas disease. ? 2013 Dhiman et al.