Role of Nrf2 in Oxidative Stress, Neuroinflammation and Autophagy in Alzheimer's Disease: Regulation of Nrf2 by Different Signaling Pathways.

Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder and the leading cause of dementia. AD is characterized by the aggregation of amyloid-ß (Aß) peptide, increased levels of tau protein, and loss of redox homeostasis responsible for mitochondrial dysfunction, oxidative stress, and neuroinflammation. Excessive accumulation of toxic Aß plaques activates microglia, which initiates neuroinflammation and consequently accelerates synaptic damage and neuronal loss. Various proinflammatory cytokines release, microglia proliferation, reactive astrocyte, and oxidative (reactive oxygen species (ROS) production, level of antioxidant enzymes, redox homeostasis, and lipid peroxidation) stress play a major role in AD. Several studies revealed that nuclear factor erythroid 2-related factor 2 (Nrf2) regulates redox homeostasis and works as an anti-inflammatory in various neurodegenerative disorders. D-Glutamate expression of transcription factor Nrf2 and its genes (glutamate-cysteine ligase catalytic subunit (GCLC), Heme oxygenase-1 (HO-1), and NADPH quinone oxidoreductase I (NQO1)) has been found in AD. Nrf2-HO-1 enhances the expression of antioxidant genes, inhibits microglia-mediated inflammation, and boosts mitochondrial function, suggesting that modulators of this protein may be useful to manage AD. This review focuses on the role of Nrf2 in AD, with a particular emphasis on the various pathways involved in the positive and negative modulation of Nrf2, namely Phosphoinositide 3-kinase (PI3K), Glycogen synthase kinase-3 (GSK-3), Nuclear factor kappa-B (NF-κB), and p38Mitogen-activated protein kinases (p38MAPK). Also, we have discussed the progress and challenges regarding the Nrf2 activators for AD treatment.

Glabridin mitigates TiO2NP induced cognitive deficit in adult zebrafish.

Glabridin is extracted from the roots of Glycyrrhiza glabra, which has anti-oxidative and anti-inflammatory properties. We investigated the neuroprotective potential of Glabridin against the learning and memory deficit by triggering NRF2/HO-1 signaling in Titanium dioxide nanoparticles (TiO2NP) treated zebrafish. Our study suggests that Glabridin at doses of 12.5, 25, and 50 mg/kg/day for 7 days improved memory and lowered anxiety in the novel object recognition test, T-maze, and novel diving tank respectively. Biochemical analysis showed that Glabridin treatment in TiO2NP-exposed zebrafish enhanced GSH, CAT, SOD, and GPx activity and reduced MDA levels; inhibited proinflammatory mediators, namely, TNF-α, IL-1ß, and IL-6. In histopathological evaluation, Glabridin significantly reduced pycnotic neurons in TiO2NP-treated zebrafish brains. Furthermore, Glabridin upregulated NRF2 and HO-1 levels, which leads to a decline in oxidative stress and neuroinflammation and were reversed by ML385 treatment. ML385 as a probe molecule that specifically inhibit NRF2 and prevents its downstream gene expression. Thus, these considerable outcomes provide new insights into the neuroprotective effect of glabridin.

AlCl3 induced learning and memory deficit in zebrafish.

Aluminium is a metal known to cause neurotoxicity in the brain, by promoting neurodegeneration and affecting memory and cognitive ability. AlCl3 has been reported to enhance reactive oxygen species (ROS) and inflammatory markers which are further responsible for the degeneration of neurons. AlCl3 exposure to zebrafish causes behavioral, biochemical, and neurochemical changes in the brain. In our study, Zebrafish were exposed to AlCl3 at three different doses (50 µg/L, 100 µg/L, and 200 µg/L) for four consecutive days. On days 1st and 4th, a novel diving test was performed to check anxiety in zebrafish. T - maze and novel object recognition test were used to check the memory on days 3rd and 4th with the help of ANY-maze software. On the last day (4th day), zebrafishes were sacrificed and whole brains were used to perform the biochemical, neurotransmitters, histopathological, and immunohistochemistry analysis. Our study revealed that AlCl3 exposure significantly decreased the total distance traveled, and the number of entries in the top zone and increased the time spent in the bottom zone, checked through the novel diving test. In the T maze test, AlCl3 treated zebrafish showed significantly increased transfer latency to the favorable zone and time spent, and the number of entries to the unfavorable zone. The exploration time with the novel object was reduced significantly after AlCl3 treatment. Moreover, reduced glutathione (GSH) and superoxide dismutase (SOD) levels were significantly reduced in AlCl3 treated zebrafish whereas malondialdehyde (MDA) level was found to be increased, indicating high oxidative stress. The neurotransmitters level was also disturbed indicated by the significantly decreased GABA, dopamine, noradrenaline, and Serotonin levels and increased glutamate level in the brain of zebrafish treated with AlCl3. Moreover, histopathological and immunohistochemistry study shows a markedly increased number of pyknotic neurons and reduced the expression of Nrf2 in the zebrafish brain after AlCl3 exposure. These findings suggest that AlCl3 significantly causes behavioral, biochemical, neurotransmitters, morphological, and molecular changes in zebrafish, ultimately causing AD.

Structure based designing of thiazolidinone-pyrimidine derivatives as ERK2 inhibitors: Synthesis and in vitro evaluation.

Breast cancer has been associated with an overexpression of various molecular targets; accordingly, various target-specific chemotherapeutic agents have been developed. Inhibition of ERK2, a member of MAPK pathway, is an important target involved in the treatment of both oestrogen receptor-positive and triple-negative breast cancer. Thus, in continuation of our previous work on the ERK2 target, we here report novel inhibitors of this kinase. Out of three lead molecules reported in our previous study, we selected the thiazolidinone-pyrimidine scaffold for further development of small molecule inhibitors of ERK2. Analogues of the lead molecule were docked in the target kinase, followed by molecular dynamic simulations and MM-GBSA calculations. Analogues maintaining key interactions with amino acid residues in the ATP-binding domain of ERK2 were selected and duly synthesized. In vitro biochemical evaluation of these molecules against ERK2 kinase disclosed that two molecules possess significant kinase inhibitory potential with IC50 values ≤ 0.5 µM.

A review of emerging trends in the treatment of tuberculosis.

This review attempts to summarize the information available on emerging trends in the treatment of tuberculosis caused by the bacteria Mycobacterium tuberculosis. Nanostructured biomaterials, liposomes, microparticles and solid lipid nanoparticles have unique physicochemical properties such as particularly small and convenient size, sustained release, great surface area to mass ratio and high reactivity with structure. These properties can be useful in easing the administration of antimicrobial drugs, thereby reducing the number of limitations in long-established antimicrobial therapeutics. In recent years, the encapsulation of antimicrobial drugs in all carrier systems has emerged as an innovative and promising change that increases therapeutic efficiency and reduces undesirable side effects of the drugs.

Development and characterization of ligand-appended liposomes for multiple drug therapy for pulmonary tuberculosis.

Tuberculosis (TB) remains one of the oldest and deadliest diseases in the current scenario. The intracellular organism Mycobacterium tuberculosis, which mainly resides in mononuclear phagocytes, is responsible for tuberculosis in humans. A few therapies are available for the treatment of tuberculosis but they have many hurdles. To overcome these hurdles, a combination of chemotherapeutic agent-loaded vesicular systems have been prepared to overcome tuberculosis. To investigate the role of novel drug delivery systems for the treatment of pulmonary tuberculosis, ligand appended liposomals have been developed. In the present study, drug-loaded, ligand-appended liposomes and their DPI (Dry Powder Inhaler) forms have been prepared and characterized using various in vitro and in vivo parameters. The prepared ligand-appended liposomal formulation showed good entrapment efficiency, prolonged drug release, improved recovery of drugs from the target site, and proved to be more suitable for use as DPI, justifying their potential for improved drug delivery. Thus we tried our best by our project to reduce the national burden of tuberculosis, which is still a global health challenge.

Advances in pulmonary delivery of nanoparticles.

Nanotechnology has potential in the development of novel and effective delivery of drugs within lungs. Different strategies have been utilized for pulmonary delivery of drugs, including the use of lipid-based delivery systems (liposomes, ISCOMs, SLNs), use of polymeric matrix (PLGA, poly caprolactone, cynoacrylates, gelatin), development of polysaccharide particulates (chitosan, alginates, Carbopol, etc.), biocompatible metallic inorganic particles (iron, gold, zinc), etc. This paper reviews various nanopaticulate approaches in the form of lipids, polymers, metals, polysaccharides, or emulsions based for pulmonary drug delivery that could provide an increased biological efficacy and better local and systemic action.

Novel drug delivery systems: desired feat for tuberculosis.

Tuberculosis has claimed its victims throughout much of known human history and is currently the most devastating human bacterial disease. The ability to infect human population on a global scale, combined with the widespread emergence of multi-drug resistant strains, has led to the placement of Mycobacterium tuberculosis on the National Institute of Allergy and Infectious Diseases (NIAID) list of Biodefence and Emerging Infectious Disease Threats Agents. The resurgence of interest in tuberculosis (TB) has stemmed because of increased evidences from developed countries. Contrary to expectations, no country has reached the phase of elimination and in no subsection of society TB has been completely eliminated. A deeper understanding of the process will assist in the identification of the host and mycobacterial efforts involved and provide targets for therapeutic strategies against tuberculosis. The article presents a view on pathogenesis of tuberculosis and its diverse manifestations, host defense evasion, mechanisms of microbial persistence, emergence of Multiple Drug Resistance and Extensive Drug Resistance, conventional therapy used and the possible novel systems which are under extensive investigation as drug carriers for improving the cytosolic concentration of the anti-tubercular agents.

Effect of rifampicin on theophylline pharmacokinetics in human beings.

Theophylline pharmacokinetics before and after rifampicin administration was studied in 10 healthy volunteers. It was seen that Rifampicin significantly increased the volume of distribution of theophylline by 23.41% (p < 0.01) and its metabolic clearance by 47.65% (P < 0.05). This has got clinical significance in the treatment of patients of pulmonary tuberculosis with chronic obstructive airways disease where both the drugs may have to be given concurrently.

Serum adenosine deaminase in pulmonary tuberculosis, malignancy and non-tubercular respiratory diseases.

The study has been conducted to find out the serum ADA levels in 120 patients with various pulmonary diseases which included patients with tubercular pleural effusion (n = 86), lung cancer (n = 10) and patients with non-tubercular pulmonary diseases like pneumonia, etc (n = 24). Twenty healthy individuals served as control subjects. The mean (+/- SD) of ADA activity was 23.38 (4.47), 7.29 (1.08), 12.71 (1.95) and 2.23 (1.00) units/litre in tuberculosis, malignancy, non-tubercular pulmonary diseases and healthy controls respectively with significant difference between each other (P less than 0.001). Patients with tuberculosis (100%) fall in 97% sensitivity range with a lower cut off limit at 17 units/litre ADA activity, while for malignancy and non-tubercular respiratory diseases, the sensitivity was 90% and 83% respectively. Within the sensitivity limits, the serum ADA activity can be used for the differential diagnosis of pulmonary diseases.

Psycho-social study of cigarette smoking.

The present study has been carried out to assess the smoking habit among medical students and its relationship to demographic, social and psychological characteristics. Prevalence of smoking was found to be 30.79% in 854 students who responded to the questionnaire adequately. Smoking habit was more common among student who were married hailed from rural areas and the intensity of smoking increased with advancement in the career in medical profession. A strong association was observed between the habit and family history of smoking. The psychological factors associated with smoking were worry about examination unhappiness without justified cause and failure in friendship.

Ventilatory functions in tropical pulmonary eosinophilia.

A study of ventilatory function in tropical pulmonary eosinophilia was carried out. Seventy five cases and 75 healthy controls were studied. Four types of ventilatory patterns were observed-restrictive (52%), mixed (33%), obstructive (4%) and normal (10.6%).

Smoking habits of the medical students.

Smoking habits of the medical students, both undergraduates and postgraduates, were evaluated by self-administering a predesigned proforma. 854 (66.05%) of the 1293 students responded, of whom, 30.7% of them were smokers. The number of smokers and the intensity of smoking increased with the advancement of their career at college. There were more smokers amongst the married and those with a history of smoking in their family. There was no systematic correlation between the socio-economic or rural/urban background and the smoking habit.

Studies on circadian periodicity of plasma 17-hydroxycorticosteroids (17-OHCS) in tropical pulmonary eosinophilia.

Circadian periodicity of plasma 17-hydroxycorticosteroids (17-OHCS) was studied in ten healthy controls and 25 patients with tropical pulmonary eosinophilia (TPE). Subjects were synchronized for 1 week with diurnal activity from 0600 to 2200 hr and nocturnal rest; meals were taken at 0830, 1300, and 2030 hr. No medications were administered. TPE patients were divided into three subgroups of fourteen, seven, and four each according to the hour of the worsening of their symptoms. Blood samples were collected at 8-hr intervals at fixed clock hours for 24 hr, starting at 0800 in all four groups. We noted a marked rhythm in plasma 17-OHCS in controls, with significant amplitude and an acrophase at 1033 hr. Similarly, all TPE patients exhibited a definite rhythm in plasma 17-OHCS with significant amplitude irrespective of the time of worsening of symptoms, suggesting thereby no relationship between worsening of symptoms and the rhythm. Thus the circadian nature and normal concentration of plasma 17-OHCS were observed to be similar in healthy controls and TPE patients.

Circadian variations of the absolute eosinophil count and serum histaminase activity in tropical pulmonary eosinophilia.

Nine healthy volunteers and 25 tropical pulmonary eosinophilia (TPE) patients were used to study circadian variations of absolute eosinophil count (AEC) and serum histaminase activity (SHA). A marked circadian variation was found in AEC for healthy volunteers and TPE patients with the worst symptoms in the late evening and morning hours only; no rhythm could be detected in SHA for healthy subjects. However, TPE patients with worst symptoms in the late evening hours did exhibit a significant rhythm in SHA. Increased SHA in all TPE patients at all time-points of the 24 hour day-night cycle, irrespective of the worsening hours of symptoms in comparison to healthy controls, could be due to increased histamine production in such situations.