PARP in the neuropathogenesis of cytomegalovirus infection - Possible role and therapeutic perspective.

Cytomegalovirus infects the majority of the population globally. Congenital CMV infection acquired through primary maternal infection in pregnancy is the most common intrauterine infection with a high mortality rate due to severe long-term neurodevelopmental sequelae. The demyelination and neuroinflammation during CMV infection have been attributed to altered immune response and ROS-mediated apoptosis. PARP-1 protein is linked to apoptotic neuronal loss with subsequent neurotoxicity and CNS injury as a result of PARP hyperactivation. PARP-1 play a critical role in the establishment of latency including EBV, HHV-8 and HIV. Research on PARP inhibitors recently shows significant progress against neurodegenerative diseases such as Alzheimer's disease and cancer therapy including malignant lymphoma and hepatitis B virus-induced hepatocellular carcinoma. The role of PARP1 in the neuropathogenesis of CMV and the potential of PARP inhibitors in the prevention of neurological sequelae is still elusive. Further studies on the role of PARP on the neuropathogenesis of CMV infection can help thwart neurodegeneration through the potential development of PARP inhibitors such as small molecule inhibitors.

Iron Oxide Nanoparticles Affects Behaviour and Monoamine Levels in Mice.

Iron oxide (Fe2O3) nanoparticles (NPs) attract the attention of clinicians for its unique magnetic and paramagnetic properties, which are exclusively used in neurodiagnostics and therapeutics among the other biomedical applications. Despite numerous research findings has already proved neurotoxicity of Fe2O3-NPs, factors affecting neurobehaviour has not been elucidated. In this study, mice were exposed to Fe2O3-NPs (25 and 50 mg/kg body weight) by oral intubation daily for 30 days. It was observed that Fe2O3-NPs remarkably impair motor coordination and memory. In the treated brain regions, mitochondrial damage, depleted energy level and decreased ATPase (Mg2+, Ca2+ and Na+/K+) activities were observed. Disturbed ion homeostasis and axonal demyelination in the treated brain regions contributes to poor motor coordination. Increased intracellular calcium ([Ca2+]i) and decreased expression of growth associated protein 43 (GAP43) impairs vesicular exocytosis could result in insufficient signal between neurons. In addition, levels of dopamine (DA), norepinephrine (NE) and epinephrine (EP) were found to be altered in the subjected brain regions in correspondence to the expression of monoamine oxidases (MAO). Along with all these factors, over expression of glial fibrillary acidic protein (GFAP) confirms the neuronal damage, suggesting the evidences for behavioural changes.

Production of highly thermo-tolerant laccase from novel thermophilic bacterium Bacillus sp. PC-3 and its application in functionalization of chitosan film.

In this study, a novel thermophilic bacterial strain was isolated from Tattapani hot spring located in the Chhattisgarh state of India. The laccase was produced via submerged fermentation and purified by ammonium sulfate precipitation and anion exchange chromatography up to 13.7 fold. The 16S rRNA gene sequence and biochemical analysis revealed that the bacterial isolate is Bacillus sp. strain PC-3. The activity of extracellular crude laccase was determined to be 11.2 U/mL using 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) as a substrate. The SDS-PAGE revealed that the enzyme consists of single subunit with molecular size of 36 kDa. The laccase exhibited the maximum enzyme activity at temperature of 60°C and pH 7. Moreover, the laccase retained 99.1% of its original activity for 180 min and exhibited half-life of 3.75 h at 60°C. Similarly, the laccase retained 95% activity at pH 7 for 240 min and displayed significant activity at wider pH range. In addition, the laccase was used for functionalization of chitosan film and characterized for antioxidant and antimicrobial activity. Interestingly, the functionalized chitosan film showed the improved antioxidant and antimicrobial activity.

Iron Oxide Nanoparticles Induces Cell Cycle-Dependent Neuronal Apoptosis in Mice.

Iron oxide (Fe2O3) nanoparticles (NPs) with its unique magnetic and paramagnetic properties are popular in biomedical applications. Some of their neurotoxic mechanisms due to repeated administration are proven. However, we speculate that the neuronal damage might be due to apoptosis resulting from unusual cell cycle entry. Moreover, iron accumulation has been shown to be closely associated with most of the neurodegenerative disorders. Thus, in the current study, mice were orally (po) treated with the Fe2O3-NPs to investigate cell cycle-associated events/components and occurrence of apoptosis. A subsequent increase in oxidant levels was observed with the iron accumulation due to Fe2O3-NPs exposure. The accumulated ß-amyloid and reduced level of cdk5 seem to aid in the cell cycle entry and forcing progression towards apoptosis. Expression of Cyclin D1 and pRb (Ser 795) indicate the cell cycle re-entry of neurons. Overexpression of RNA Pol II and PARP cleavage suggests DNA damage due to Fe2O3-NPs exposure. Further, hyperphosphorylation of p38 (Thr 180/Tyr 182) confirms the activation of DNA damage-dependent checkpoint. Expression patterns of pro- and anti-apoptotic markers, TUNEL and TEM indicate the occurrences of apoptosis.

Neurobehavioural Toxicity of Iron Oxide Nanoparticles in Mice.

Iron oxide nanoparticles (Fe2O3-NPs) are widely used in various biomedical applications, extremely in neurotheranostics. Simultaneously, Fe2O3-NP usage is of alarming concern, as its exposure to living systems causes deleterious effects due to its redox potential. However, study on the neurobehavioural impacts of Fe2O3-NPs is very limited. In this regard, adult male mice were intraperitoneally administered with Fe2O3-NPs (25 and 50 mg/kg body weight) once a week for 4 weeks. A significant change in locomotor behaviour and spatial memory was observed in Fe2O3-NP-treated animals. Damages to blood-brain barrier permeability by Fe2O3-NPs and their accumulation in brain regions were evidenced by Evan's blue staining, iron estimation and Prussian blue staining. Elevated nitric oxide, acetylcholinesterase, lactate dehydrogenase leakage and demyelination were observed in the Fe2O3-NP-exposed brain tissues. Imbalanced levels of ROS generation and antioxidant defence mechanism (superoxide dismutase and catalase) cause damages to lipids, proteins and DNA. PARP and cleaved caspase 3 expression levels were found to be increased in the Fe2O3-NP-exposed brain regions which confirms DNA damage and apoptosis. Thus, repeated Fe2O3-NP exposure causes neurobehavioural impairments by nanoparticle accumulation, oxidative stress and apoptosis in the mouse brain.

Recurrent exposure to ferric oxide nanoparticles alters myocardial oxidative stress, apoptosis and necrotic markers in male mice.

The cardiotoxicity of iron oxide nanoparticles (Fe2O3-NPs) in mice was investigated. The mice were intraperitoneally administered with Fe2O3-NPs at the dose of 25 and 50 mg/kg bw for 30 days at seven days interval. In vivo MRI analysis reveals the Fe2O3-NPs accumulation in the cardiac system. Also, serum iron estimation and Prussian blue staining confirms the iron deposition in circulatory system. Cardiac dysfunction was assessed by ECG analysis and further validated by evaluating the functional markers such as cardiac Troponin-1 (cTnI) expression, AChE activity and levels of LDH and CK-MB in cardiac tissue. Fe2O3-NPs exposure disturbs the balance between the oxidants and antioxidants resulting in oxidative myocardial damages. In consequence, damaged mitochondria, diminished ATP level and NOX4 over expression were observed in the intoxicated groups indicating the role of Fe2O3-NPs in oxidative stress. A dose dependant increase in oxidative stress mediates apoptosis through upregulation of Bax, cytochrome c and cleaved caspase 3 in the 25 mg/kg treated group. Sustained oxidative stress suggest the occurrence of necrosis in addition to apoptosis in 50 mg/kg treated group evidenced by altered expression pattern of cleaved PARP, cytochrome c, Bax and cleaved caspase 3. In addition, triphenyl tetrazolium chloride (TTC) staining confirms cardiac necrosis in 50 mg/kg Fe2O3-NPs treated group.