The Interplay of Mitochondrial Bioenergetics and Dopamine Agonists as an Effective Disease-Modifying Therapy for Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurological ailment with a slower rate of advancement that is more common in older adults. The biggest risk factor for PD is getting older, and those over 60 have an exponentially higher incidence of this condition. The failure of the mitochondrial electron chain, changes in the dynamics of the mitochondria, and abnormalities in calcium and ion homeostasis are all symptoms of Parkinson's disease (PD). Increased mitochondrial reactive oxygen species (mROS) and an energy deficit are linked to these alterations. Levodopa (L-DOPA) is a medication that is typically used to treat most PD patients, but because of its negative effects, additional medications have been created utilizing L-DOPA as the parent molecule. Ergot and non-ergot derivatives make up most PD medications. PD is successfully managed with the use of dopamine agonists (DA). To get around the motor issues produced by L-DOPA, these dopamine derivatives can directly excite DA receptors in the postsynaptic membrane. In the past 10 years, two non-ergoline DA with strong binding properties for the dopamine D2 receptor (D2R) and a preference for the dopamine D3 receptor (D3R) subtype, ropinirole, and pramipexole (PPx) have been developed for the treatment of PD. This review covers the most recent research on the efficacy and safety of non-ergot drugs like ropinirole and PPx as supplementary therapy to DOPA for the treatment of PD.

Environment Enrichment Facilitates Long-Term Memory Consolidation through Behavioral Tagging.

The behavioral tagging (BT) hypothesis provides crucial insights into the mechanism of long-term memory (LTM) consolidation. Novelty exposure in BT is a decisive step in activating the molecular machinery of memory formation. Several studies have validated BT using different neurobehavioral tasks; however, the novelty given in all studies is open field (OF) exploration. Environment enrichment (EE) is another key experimental paradigm to explore the fundamentals of brain functioning. Recently, several studies have highlighted the importance of EE in enhancing cognition, LTM, and synaptic plasticity. Hence, in the present study, we investigated the effects of different types of novelty on LTM consolidation and plasticity-related protein (PRP) synthesis using the BT phenomenon. Novel object recognition (NOR) was used as the learning task for rodents (male Wistar rats), while OF and EE were two types of novel experiences provided to the rodents. Our results indicated that EE exposure efficiently leads to LTM consolidation through the BT phenomenon. In addition, EE exposure significantly enhances protein kinase Mζ (PKMζ) synthesis in the hippocampus region of the rat brain. However, the OF exposure did not lead to significant PKMζ expression. Further, our results did not find alterations in BDNF expression after EE and OF exposure in the hippocampus. Hence, it is concluded that different types of novelty mediate the BT phenomenon up to the same extent at the behavioral level. However, the implications of different novelties may differ at molecular levels.

Identification of the Genes Involved in Stomatal Development via Epidermal Phenotype Scoring.

Stomata are small pores on the surface of land plants that are involved in gas exchange and water vapor release, and their function is critical for plant productivity and survival. As such, understanding the mechanisms by which stomata develop and pattern has tremendous agronomic value. This paper describes two phenotypic methods using Arabidopsis cotyledons that can be used to characterize the genes controlling stomatal development and patterning. Presented first are procedures for analyzing the stomatal phenotypes using toluidine blue O-stained cotyledons. This method is fast and reliable and does not require the use of epidermal peels, which are widely used for phenotypic analyses but require specialized training. Due to the presence of multiple cysteine residues, the identification and generation of bioactive EPF peptides that have a role in stomatal development have been challenging. Thus, presented second is a procedure used to identify stomatal ligands and monitor their biological activity by bioassays. The main advantage of this method is that it produces reproducible data relatively easily while reducing the amount of peptide solution and the time required to characterize the role of the peptides in controlling stomatal patterning and development. Overall, these well-designed protocols enhance the efficiency of studying the potential stomatal regulators, including cysteine-rich secretory peptides, which require highly complex structures for their activity.

Role of melatonin and quercetin as countermeasures to the mitochondrial dysfunction induced by titanium dioxide nanoparticles.

AIM: Due to the growing commercialization of titanium dioxide nanoparticles (TNPs), it is necessary to use these particles in a manner that is safe, healthy and environmental friendly. Through reactive oxygen species (ROS) generation, it has been discovered that TNPs have a harmful effect on the brain. The aim of this study is to provide valuable insights into the possible mechanisms of TNPs induced mitochondrial dysfunction in brain and its amelioration by nutraceuticals, quercetin (QR) and melatonin (Mel) in in vitro and in vivo conditions. MATERIALS AND METHODS: Whole brain mitochondrial sample was used for in-vitro evaluation. Pre-treatment of QR (30 µM) and Mel (100 µM) at 25 °C for 1 h was given prior to TNPs (50 µg/ml) exposure. For in-vivo study, male Wistar rats were divided into four groups. Group I was control and group II was exposed to TNPs (5 mg/kg b.wt., i.v.). QR (5 mg/kg b.wt.) and Mel (5 mg/kg b.wt.) were given orally as pre-treatment in groups III and IV, respectively. Biochemical parameters, neurobehavioural paradigms, mitochondrial respiration, neuronal architecture assessment were assessed. KEY FINDINGS: QR and Mel restored the mitochondrial oxidative stress biomarkers in both the studies. Additionally, these nutraceuticals resuscitated the neurobehavioural alterations and restored the neuronal architecture alterations in TNPs exposed rats. The mitochondrial dysfunction induced by TNPs was also ameliorated by QR and Mel by protecting the mitochondrial complex activity and mitochondrial respiration rate. SIGNIFICANCE: Results of the study demonstrated that QR and Mel ameliorated mitochondrial mediated neurotoxic effects induced by TNPs exposure.

Pregnenolone Attenuates the Ischemia-Induced Neurological Deficit in the Transient Middle Cerebral Artery Occlusion Model of Rats.

Neurosteroids are apparent to be connected in the cerebral ischemic injury for their potential neuroprotective effects. We previously demonstrated that progesterone induces neuroprotection via the mitochondrial cascade in the cerebral ischemic stroke of rodents. Here, we sought to investigate whether or not pregnenolone, a different neurosteroid, can protect the ischemic injury in the transient middle cerebral artery occlusion (tMCAO) rodent model. Male Wistar rats were chosen for surgery for inducing stroke using the tMCAO method. Pregnenolone (2 mg/kg b.w.) at 1 h postsurgery was administered. The neurobehavioral tests and (TTC staining) 2, 3, 5-triphenyl tetrazolium chloride staining were performed after 24 h of the surgery. The mitochondrial membrane potential and reactive oxygen species (ROS) were measured using flow cytometry. Oxygraph was used to examine mitochondrial bioenergetics. The spectrum of neurobehavioral tests and 2, 3, 5-triphenyltetrazolium chloride staining showed that pregnenolone enhanced neurological recovery. Pregnenolone therapy after a stroke lowered mitochondrial ROS following ischemia. Our data demonstrated that pregnenolone was not able to inhibit mitochondrial permeability transition pores. There was no effect on mitochondrial bioenergetics such as oxygen consumption and respiratory coupling. Overall, the findings demonstrated that pregnenolone reduced the neurological impairments via reducing mitochondria ROS but not through the inhibition of the mitochondria permeability transition pore (mtPTP).

Mitochondria-Related Apoptosis Regulation by Minocycline: A Study on a Transgenic Drosophila Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a very complicated and multifactorial neurological disorder having limited therapeutic interventions illustrated by the impairment in memory and cognitive function. Several lines of confirmation are stoutly connected with mitochondrial function perturbation as a significant causative factor in AD, while the molecular mechanisms involved in AD pathogenesis are still poorly understood. Minocycline, a well-known antibiotic, has confirmed efficacy against mitochondrial defects and oxidative stress as a neuroprotective effect. In view of this property, we examined the remedial effect of minocycline on AD. To attain insight into the molecular machinery responsible for AD pathogenesis, we preferred the UAS/GAL4 scheme for the development of AD in flies that overexpress the Aß42 protein in the brain of Drosophila. The warning signs like the declined lifespan, locomotion deficit and memory loss, impaired mitochondrial membrane potential, and increased caspase 3 expression with mitogen-associated protein kinases linked with AD pathogenesis were examined in the existence of minocycline. Minocycline halted the Aß42-induced symptoms including behavioral changes and altered the mitochondrial membrane potential along with apoptotic factors' protein expression (JNK/p-JNK and caspase 3). Thus, the current study could be functional to find out the role of minocycline in human Aß42-overexpressed transgenic AD flies.

Modulatory Role of Quercetin in Mitochondrial Dysfunction in Titanium Dioxide Nanoparticle-Induced Hepatotoxicity.

Background : Titanium dioxide (TiO2) nanoparticles are among the largely manmade nanomaterials worldwide and are broadly used as both industrial and user products. The primary target site for several nanoparticles is the liver, including TiO2 nanoparticles (TNPs), exposed directly or indirectly through ingestion of contaminated water, food, or animals and elevated environmental contamination. Oxidative stress is a known facet of nanoparticle-induced toxicity, including TNPs. Mitochondria are potential targets for nanoparticles in several types of toxicity, such as hepatotoxicity. Nevertheless, its causal mechanism is still controversial due to scarcity of literature linking the role of mitochondria-mediated TNP-induced hepatotoxicity. Aim : The objective of the current study was to evaluate the relation of mitochondrial oxidative stress and respiratory chain mechanisms with TNP-induced mitochondrial dysfunction in vitro, and explore the hepatoprotective effect of quercetin (QR), which is a polyphenolic flavonoid abundant in fruits and vegetables with known antioxidant properties, on TNP-induced mitochondrial oxidative stress and disturbance in respiratory chain complex enzymes in the liver of rats. Results: Enzymatic and non-enzymatic antioxidant levels, oxidative stress markers, and mitochondrial complexes were assessed with regard to TNP-induced hepatotoxicity. The depleted lipid peroxidation levels and protein carbonyl content, in mitochondria, induced by TNPs were restored significantly by pretreatment with QR. QR modulated the altered non-enzymatic and enzymatic antioxidants and mitochondrial complex enzymes. Conclusion : Based on the findings, we conclude that QR, which mitigates oxidative stress caused by mitochondrial dysfunction, holds promising capability to potentially diminish TNP-induced adverse effects in the liver.

Memory related molecular signatures: The pivots for memory consolidation and Alzheimer's related memory decline.

Age-related cognitive decline is the major cause of concern due to its 70% more incidence than dementia cases worldwide. Moreover, aging is also the major risk factor of Alzheimer's disease (AD), associated with progressive memory loss. Approx. 13 million people will have Alzheimer-related memory decline by 2050. Learning and memory is the fundamental process of brain functions. However, the mechanism for the same is still under investigation. Thus, it is critical to understand the process of memory consolidation in the brain and extrapolate its understanding to the memory decline mechanism. Research on learning and memory has identified several molecular signatures such as Protein kinase M zeta (PKMζ), Calcium/calmodulin-dependent protein kinase II (CaMKII), Brain-derived neurotrophic factor (BDNF), cAMP-response element binding protein (CREB) and Activity-regulated cytoskeleton-associated protein (Arc) crucial for the maintenance and stabilization of long-term memory in the brain. Interestingly, memory decline in AD has also been linked to the abnormality in expressing these memory-related molecular signatures. Hence, in the present consolidated review, we explored the role of these memory-related molecular signatures in long-term memory consolidation. Additionally, the effect of amyloid-beta toxicity on these molecular signatures is discussed in detail.

Dodging blood brain barrier with "nano" warriors: Novel strategy against ischemic stroke.

Ischemic stroke (IS) is one of the leading causes of death and disability resulting in inevitable burden globally. Ischemic injury initiates cascade of pathological events comprising energy dwindling, failure of ionic gradients, failure of blood brain barrier (BBB), vasogenic edema, calcium over accumulation, excitotoxicity, increased oxidative stress, mitochondrial dysfunction, inflammation and eventually cell death. In spite of such complexity of the disease, the only treatment approved by US Food and Drug Administration (FDA) is tissue plasminogen activator (t-PA). This therapy overcome blood deficiency in the brain along with side effects of reperfusion which are responsible for considerable tissue injury. Therefore, there is urgent need of novel therapeutic perspectives that can protect the integrity of BBB and salvageable brain tissue. Advancement in nanomedicine is empowering new approaches that are potent to improve the understanding and treatment of the IS. Herein, we focus nanomaterial mediated drug delivery systems (DDSs) and their role to bypass and cross BBB especially via intranasal drug delivery. The various nanocarriers used in DDSs are also discussed. In a nut shell, the objective is to provide an overview of use of nanomedicine in the diagnosis and treatment of IS to facilitate the research from benchtop to bedside.

Chrysin ameliorates 3 nitropropinoic acid induced neurotoxicity targeting behavioural, biochemical and histological alterations.

BACKGROUND AND PURPOSE: Huntington disease (HD) is an autosomal dominant inheritance neurodegenerative disorder. 3-Nitropropanoic acid (3-NP) is a mitochondrial toxin that induces HD-like symptoms and thus serves as a good experimental model of HD. Chrysin (5, 7-dihydroxyflavone) is a natural flavonoid that have multiple biological activities. The present work was aimed to evaluate the neuroprotective efficacy of Chrysin in rat brain, under the influence of 3-NP treatment, by studying neurobehavioral and biochemical alterations alongwith histo-architectural changes. MATERIALS AND METHODS: Male Wistar rats (220-250 g) were used in the study and were divided into three groups following randomization. Each group comprised of nine animals. Group I animals served as control group and administered with normal saline (orally) as vehicle. Animals of Group II were treated with 3-NP for four successive days, at the dose of 20 mg/kg, intraperitoneally (i.p.). Animals that received Chrysin for the period of four consecutive days with the dose of 50 mg/kg, orally twice daily (30 min pre-treatment and 6 h post-treatment) following 3-NP administration served as Group III. After the treatment regime, animals were evaluated for neurobehavioral alterations and brain homogenates were used for estimation of neurotoxicity marker activity and neurotransmitter level along with histological assessment. RESULTS: The significant alteration in neurobehavioral, biochemical and neuronal structure in striatal part of brain was observed in the 3-NP administered (Group II) animals. It was observed that co-treatment of Chrysin with 3-NP treated rats the rotarod performance, grip strength, stride length as well as monoamine oxidase activity and serotonin levels were elevated. CONCLUSION: The results of this study reveal that Chrysin treatment alleviated the neurobehavioral, biochemical and histological alterations against HD symptoms in rats.

Harnessing the mitochondrial integrity for neuroprotection: Therapeutic role of piperine against experimental ischemic stroke.

Ischemic stroke (IS) is a rapidly increasing global burden and is associated with severe neurological decline and mortality. There is urgent requirement of the efforts, aimed to identify therapeutic strategies that are effective in clinic to promote significant recovery from IS. Studies have shown that mitochondria mediated neuroprotection can be a competent target against ischemic damage. Therefore, we examined whether mitochondrial impairment is regulated by Piperine (PIP), an alkaloid of Piper Longum, which has neuroprotective activity against ischemic brain injury. In this study, transient middle cerebral artery occlusion (tMCAO) surgery was performed on male Wistar rats for 90 min followed by 22.5 h of reperfusion for mimicking the IS condition. This study consisted of three groups: sham, tMCAO and tMCAO + PIP (10 mg/kg b.wt., p.o/day for 15 days), and studied for behavioral tests, infarct volume, brain pathological changes, mitochondrial dysfunction, inflammation alongwith cell survival status. PIP pre-treatment showed reduction in neurological alterations and infarct volume. In addition, PIP pre-treatment suppressed the mitochondrial dysfunction and might have anti-apoptotic potential by preventing Cytochrome c (Cyt c) release from mitochondria to cytoplasm and caspase 3 activation. It also regulates pro-apoptotic, Bax and anti-apoptotic, Bcl-2 proteins accompanied by glial fibrillary acidic protein (GFAP) positive cells in cortex region. Quantitative Reverse transcription-polymerase chain reaction (qRT-PCR) results also showed that PIP reduced the expression of pro-inflammatory protein, interleukin-1 ß (IL-1ß) and enhanced cell survival by restoring the activity of brain derived neurotrophic factor (BDNF) and its transcription protein, cAMP response element binding protein (CREB). Taken together, PIP reduced the mitochondrial dysfunction, neurological impairment, and enhanced neuronal survival. In conclusion, our findings reinforce PIP as an effective neuroprotective agent and provide important evidence about its role as a potential target to serve as a promising therapy for treatment of IS.

Duplicated antagonistic EPF peptides optimize grass stomatal initiation.

Peptide signaling has emerged as a key component of plant growth and development, including stomatal patterning, which is crucial for plant productivity and survival. Although exciting progress has been made in understanding EPIDERMAL PATTERNING FACTOR (EPF) signaling in Arabidopsis, the mechanisms by which EPF peptides control different stomatal patterns and morphologies in grasses are poorly understood. Here, by examining expression patterns, overexpression transgenics and cross-species complementation, the antagonistic stomatal ligands orthologous to Arabidopsis AtEPF2 and AtSTOMAGEN/AtEPFL9 peptides were identified in Triticum aestivum (wheat) and the grass model organism Brachypodium distachyon. Application of bioactive BdEPF2 peptides inhibited stomatal initiation, but not the progression or differentiation of stomatal precursors in Brachypodium. Additionally, the inhibitory roles of these EPF peptides during grass stomatal development were suppressed by the contrasting positive action of the BdSTOMAGEN peptide in a dose-dependent manner. These results not only demonstrate how conserved EPF peptides that control different stomatal patterns exist in nature, but also suggest new strategies to improve crop yield through the use of plant-derived antagonistic peptides that optimize stomatal density on the plant epidermis.

Melatonin Provides Neuroprotection Following Traumatic Brain Injury-Promoted Mitochondrial Perturbation in Wistar Rat.

Excessive mitochondrial fission has been implicated in the etiology of neuronal cell death in traumatic brain injury (TBI). In the present study, we examined the efficacy of melatonin (Mel) as a neuroprotective agent against TBI-induced oxidative damage and mitochondrial dysfunction. We assessed the impact of Mel post-treatment (10 mg/kg b.wt., i.p.) at different time intervals in TBI-subjected Wistar rats. We found that the Mel treatment significantly attenuated brain edema, oxidative damage, mitochondrial fission, and promoted mitochondrial fusion. Additionally, Mel-treated rats showed restoration of mitochondrial membrane potential and oxidative phosphorylation with a concomitant reduction in cytochrome-c release. Further, Mel treatment significantly inhibited the translocation of Bax and Drp1 proteins to mitochondria in TBI-subjected rats. The restorative role of Mel treatment in TBI rats was supported by the mitochondrial ultra-structural analysis, which showed activation of mitochondrial fusion mechanism. Mel enhanced mitochondrial biogenesis by upregulation of PGC-1α protein. Our results demonstrated the remedial role of Mel in ameliorating mitochondrial dysfunctions that are modulated in TBI-subjected rats and provided support for mitochondrial-mediated neuroprotection as a putative therapeutic agent in the brain trauma.

Cross-Talk Between Key Players in Patients with COVID-19 and Ischemic Stroke: A Review on Neurobiological Insight of the Pandemic.

The global pandemic of novel coronavirus disease 2019 (COVID-19) has taken the entire human race by surprise and led to an unprecedented number of mortalities worldwide so far. Current clinical studies have interpreted that angiotensin-converting enzyme 2 (ACE2) is the host receptor for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). In addition, ACE2 is the major component of the renin-angiotensin system. ACE2 deteriorates angiotensin II, a peptide that is responsible for the promotion of stroke. The downregulation of ACE2 further activates an immunological cascade. Thus, researchers need to explore and examine the possible links between COVID-19 and ischemic stroke (IS). Human ACE2 expression level and pattern in various tissues might be decisive for the vulnerability, symptoms, and treatment outcomes of the SARS-CoV-2 infection. The swift increase in the knowledge of SARS-CoV-2 has given creditable evidence that SARS-CoV-2 infected patients also encounter neurological deficits. As the SARS-CoV-2 binds to ACE2, it will hamper the activity of ACE2 in providing neuroprotection, especially in the case of stroke patients. Due to the downregulation of ACE2, the inflammatory response is activated in the ischemic penumbra. The COVID-19 pandemic has affected people with various pre-existing diseases, including IS, in such a way that these patients need special care and attention for their survival. Several clinical trials are currently ongoing worldwide as well as many other projects are in different stages of conceptualization and planning to facilitate the effective management of stroke patients with COVID-19 infection.

Post-ischemic administration of dopamine D2 receptor agonist reduces cell death by activating mitochondrial pathway following ischemic stroke.

AIMS: Cerebral ischemic stroke leads to mitochondrial alterations which are key factors for initiation of various cascades resulting in neuronal damage. Dopamine D2 receptor (D2R) agonist, Sumanirole (SUM) has been reported to possess anti-inflammatory, anti-oxidant, and anti-apoptotic properties. However, the role of SUM in ischemic stroke (IS) has not been studied yet. The aim of the present study was to investigate the neuroprotective efficiency of SUM against ischemic injury and its possible effect on mitochondrial restorative mechanisms. MATERIALS AND METHODS: Transient middle cerebral artery occlusion (tMCAO) was performed in Wistar rats for 90 min occlusion and 22.5 h reperfusion to mimic ischemic stroke. Post- treatment with Sumanirole (0.1 mg/kg and 1 mg/kg; s.c.) was done at 1 h, 6 h, 12 hand 18 h after surgery. In addition, neurobehavioral analysis, mitochondrial reactive oxygen species and mitochondrial membrane potential by flow cytometric analysis, mitochondrial complexes analysis, infarct size evaluation and histological analysis were performed. KEY FINDINGS: Sumanirole restored behavioural alterations as measured by rotarod performance, grip strength, adhesive tape removal analysis and neurological deficits. In addition, it also refurbished mitochondrial dysfunction by decreasing mitochondrial reactive oxygen species production, elevating mitochondrial membrane potential and by protecting the activity of mitochondrial complexes along with histological alterations. As a result, infarct sizes were markedly reduced in tMCAO surgery animals. SIGNIFICANCE: Findings from the study provide evidence that SUM promotes neuronal survival in in vivo model of IS through mitochondria mediated neuroprotective features.

Role of Mitochondrial Mechanism in Chemotherapy-Induced Peripheral Neuropathy.

BACKGROUND: Even though chemotherapeutic regimens show considerable importance, it may cause progressive, continuing and sometimes irreversible peripheral neuropathy. Chemotherapy induced peripheral neuropathy (CIPN) is comprised of sensory abnormalities that are most distressing issues. The mechanism associated with CIPN pathogenesis is not completely revealed and its treatment is still questionable. The purpose of this review was to investigate the role of mitochondria in CIPN. METHODS: This review is literature based that describes the mitochondrial mechanism underlying CIPN and the neuropathic complications associated with different antineoplastic agents. RESULTS: For severe pain, a modification towards less efficient chemotherapeutic drugs could possibly be needed and/or patients perhaps prefer to withdrawal therapeutic regimen. The epidemiology of CIPN is still debatable. The major recurrent molecules causing CIPN are platinum based drugs including cisplatin and oxaliplatin, thalidomide, bortezomib, vinka alkaloids and taxanes. Neuropathic pain is one of the symptoms of CIPN. Various neuropathic disorders as well as CIPN are due to mitochondrial impairment, relevant impairment of Ca2+ signalling pathways and reactive oxygen species (ROS) that ultimately leads to apoptosis. CONCLUSION: The pathophysiology of CIPN is complicated as chemotherapeutic medications often involve combination of drugs. With these combinatorial therapies cancer survivors develop continuing effects of CIPN which require rehabilitation strategies for the recovery of patient's condition and quality of life.

Mitochondria-mediated mitigatory role of curcumin in cisplatin-induced nephrotoxicity.

Cisplatin (CP) is one of the most potent chemotherapeutic anti-tumour drugs, and it has been implicated in renal toxicity. Oxidative stress has been proven to be involved in CP-induced toxicity including nephrotoxicity. However, there is paucity of literature involving role of mitochondria in mediating CP-induced renal toxicity, and its underlying mechanism remains unclear. Therefore, the present study was undertaken to examine the antioxidant potential of curcumin (CMN; a natural polyphenolic compound) against the mitochondrial toxicity of CP in kidneys of male rats. Acute toxicity was induced by a single intra-peritoneal injection of CP (6 mg kg(-1) ). We studied the ameliorative effect of CMN pre-treatment (200 mg kg(-1) ) on the toxicity of CP in rat kidney mitochondria. CP caused a significant elevation in the mitochondrial lipid peroxidation (LPO) levels and protein carbonyl (PC) content. Pre-treatment of rat with CMN significantly replenished the mitochondrial LPO levels and PC content. It also restored the CP-induced modulatory effects on altered enzymatic and non-enzymatic antioxidants in kidney mitochondria. We hypothesize that the reno-protective effects of CMN may be related to its predisposition to scavenge free radicals, and upregulate antioxidant machinery in kidney mitochondria.

Study on variability assessment and evolutionary relationships of glutamate racemase in Pseudomonas species.

Pseudomonas species is known to cause multiple nosocomial infections in patients and results in high morbidity and mortality rates (10%). The greatest obstacle in treating patients infected with the Pseudomonas species is the widespread emergence of antibiotic resistance. Hence, there is an urgent need to develop new compounds which can be effective against Pseudomonas species and possibly remain tolerant to drug resistance. The enzyme glutamate racemase plays an important role in cell wall synthesis of bacteria and as a rate limiting step, thus it is an excellent target for the designing of new class of antibacterial agents. The objective of this study is to investigate the variations in sequences of glutamate racemase, a potential drug target across the all 31 species of Pseudomonas. Sequence variability and conservation for functional motif identification is helpful for identifying evolutionarily important residues with functional significance; subsequently these results of variable sites were supported by entropy profile obtained from protein variability server using Shannon entropy. Phylogenetic profile among the different Pseudomonas sp. having fully/highly conserved residues was observed, suggesting possible functional similarities between them. The variation analysis in conserved and non-conserved region of the sequence can be used to predict the binding site for target specific drug discovery.