Dr. Nagendra S Ningaraj

Transforming challenges into great opportunities

Read More

Blog

Scientific Articles

Evidence of BKCa Channelopathy-Driven Breast Cancer Metastasis to Brain

November 26, 2019 | Scientific Articles | No Comments

Abstract KCNMA1 encodes the a-subunit of the large conductance, voltage and Ca2+-activated and Voltage-dependent potassium channel (BKCa) and was shown by others and us to be a potential drug target gene in several cancers, including breast cancer. In addition, we studied the role of alternative pre-mRNA splicing events of KCNMA1 in migration, invasion, proliferation and […]

Primary and Metastatic Brain Tumors Dissipate – Understanding and Intervention

November 20, 2019 | Scientific Articles | No Comments

ABSTRACT We researched and reviewed peer-reviewed articles to provide an overview of the primary and metastatic brain tumor growth, dissemination mechanisms in their microenvironment. We studied the role of alternative pre-mRNA splicing events of KCNMA1, which encodes the pore forming α-subunit of calcium-activated voltage-sensitive potassium (BKCa) channels, in migration, invasion, proliferation, dispersal of brain tumor. […]

Role of glutathione reductase system in disulfiram conversion to diethyldithiocarbamate

October 10, 2019 | Scientific Articles | No Comments

Experiments were carried out to establish the role of glutathione reductase (GR), if any, in the metabolic conversion of disulfiram (DS) to diethyldithiocarbamate (DDC). It was observed that, under standard assay conditions, whereas DS was incorporated as a substrate instead of oxidised glutathione (GSSG), the enzymes from both human liver extract and yeast sources failed […]

Effect of disulfiram administration on brain tryptophan, serotonin and peripheral tryptophan content

October 10, 2019 | Scientific Articles | No Comments

The prophylactic deterrent effect of disulfiram (DS) has been attributed to its ability to exacerbate sympathetic function. Though there are reports to indicate that DS administration could as well affect the neurotransmitter metabolism, few reports implicate the possibility of central nervous system (CNS) mediated anticraving effect of the drug. The present study involving the oral […]

Effect of disulfiram administration on rat brain glutathione metabolism

October 10, 2019 | Scientific Articles | No Comments

Chronic administration of disulfiram (DS) to rats was found to affect glutathione (GSH) metabolism. Glutathione was measured in the rat brain following DS administration. Reduced glutathione was decreased significantly (1.52 ± 0.3 μmol/g; p < 0.001), with a concomitant increase in oxidised glutathione (GSSG) content (0.12 ± 0.013 μmol/g; p < 0.001) in the brain as a consequence of DS treatment. […]

Effect of disulfiram administration on rat glutathione metabolism

October 10, 2019 | Scientific Articles | No Comments

Chronic administration of disulfiram (DS) to rats was found to affect glutathione (GSH) metabolism. Glutathione was measured in the rat brain following DS administration. Reduced glutathione was decreased significantly (1.52 +/- 0.3 mumol/g; p < 0.001), with a concomitant increase in oxidised glutathione (GSSG) content (0.12 +/- 0.013 mumol/g; p < 0.001) in the brain […]

Disulfiram lowers Ca2+, Mg(2+)-ATPase activity of rat brain synaptosomes

October 10, 2019 | Scientific Articles | No Comments

The chronic administration of disulfiram (DS) to rats resulted in significant decrease of synaptosomal Ca2+, Mg(2+)-ATPase activity. In vitro studies indicated that DS (ID50 = 20 microM) produced a dose-dependent inhibition of Ca2+, Mg(2+)-ATPase. However, diethyldithio-carbamate, a metabolite of DS, failed to modify Ca2+, Mg(2+)-ATPase activity, implying that the decrease in ATPase activity in DS […]

Monoamine oxidase isoenzymes in rat brain: Differential changes during postnatal development but not aging

October 10, 2019 | Scientific Articles | No Comments

Differential development of monoamine oxidase (MAO) isoenzymes in rat whole brain is described in postnatally developing Sprague-Dawley rats. Total MAO and isoenzyme activity was measured using nonspecific and specific substrates. Total MAO activity measured using tyramine, increased postnatally up to 24 weeks of age and attained a plateau afterward. The increase in total MAO activity […]

EFFECT OF DISULFIRAM ADMINISTRATION ON GLUTAMATE UPTAKE BY SYNAPTOSOMES IN THE RAT BRAIN

October 10, 2019 | Scientific Articles | No Comments

Abstract Although disulfiram used as a pharmacological agent in the treatment of alcoholism is reported to act on both peripheral and central nervous systems with several adverse effects, the ncurotoxic property of the drug has not been properly elucidated. We observed that the chronic administration of the drug to rats significantly inhibited synaptosomal (Na+,K+)-ATPase and […]

Disulfiram Augments Oxidative Stress in Rat Brain following Bilateral Carotid Artery Occlusion

October 10, 2019 | Scientific Articles | No Comments

Abstract We examined the brain oxidative stress which accompanies 30 min of bilateral carotid artery ligation (BCAL) in terms of changes in brain levels of glutathione; reduced (GSH) and oxidized (GSSG) forms and the exacerbation of oxidative stress by disulfiram (DSF). These results indicate that BCAL alone decreases GSH content and limits glutathione reductase (GR) […]

Glutathione carbamoylation with S-methyl N,N-diethylthiolcarbamate sulfoxide and sulfone. Mitochondrial low Km aldehyde dehydrogenase inhibition and implications for its alcohol-deterrent action.

October 9, 2019 | Scientific Articles | No Comments

Abstract S-Methyl N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO) and sulfone (DETC-MeSO2) both inhibit rat liver low Km aldehyde dehydrogenase (ALDH2) in vitro and in vivo (Nagendra et al., Biochem Pharmacol 47: 1465-1467, 1994). DETC-MeSO has been shown to be a metabolite of disulfiram, but DETC-MeSO2 has not. Studies were carried out to further investigate the inhibition of ALDH2 […]

Effect of disulfiram administration on glutamate uptake by synaptosomes in the rat brain

October 9, 2019 | Scientific Articles | No Comments

Abstract Although disulfiram used as a pharmacological agent in the treatment of alcoholism is reported to act on both peripheral and central nervous systems with several adverse effects, the neurotoxic property of the drug has not been properly elucidated. We observed that the chronic administration of the drug to rats significantly inhibited synaptosomal (Na+,K+)-ATPase and […]

Glutathione Carbamoylation with S-Methyl N,N-diethylthiolcarbamate Sulfoxide and Sulfone: Mitochondrial Low Km Aldehyde Dehydrogenase Inhibition and Implications for Its Alcohol-Deterrent Action

October 9, 2019 | Scientific Articles | No Comments

Abstract S-Methyl N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO) and sulfone (DETC-MeSO2) both inhibit rat liver low Km aldehyde dehydrogenase (ALDH2) in vitro and in vivo (Nagendra et al., Biochem Pharmacol 47: 1465–1467, 1994). DETC-MeSO has been shown to be a metabolite of disulfiram, but DETC-MeSO2 has not. Studies were carried out to further investigate the inhibition of ALDH2 by DETC-MeSO and DETC-MeSO2. In an in vitro system containing hydrogen peroxide and horseradish […]

Neurotoxic effect of acamprosate, N-Acetyl-Homotaurine, in cultured neurons

October 9, 2019 | Scientific Articles | No Comments

Abstract Acamprosate (AC), N-acetyl-homotaurine, has recently been introduced for treating alcohol craving and reducing relapses in weaned alcoholics. AC may exert its action through the taurine system rather than the glutamatergic or GABAergic system. This conclusion is based on the observations that AC strongly inhibits the binding of taurine to taurine receptors while it has […]

Targeting Brain Tumors with Nanomedicines: Overcoming Blood Brain Barrier Challenges

September 29, 2019 | Scientific Articles | No Comments

Abstract This review elucidates ongoing research, which show improved delivery of anticancer drugs alone and/ or enclosed in carriers collectively called nanomedicines to cross the BBB/ BTB to kill tumor cells and impact patient survival. We highlighted various advances in understanding the mechanism of BTB function that has an impact on anticancer therapeutics delivery. We […]

Inflection point in glioma growth and angiogenesis driven by potassium channels

September 29, 2019 | Scientific Articles | No Comments

Background and Aim The overexpression and alternative splicing of calcium-activated potassium channel subunit alpha-1 (KCNMA1) that encodes large-conductance calcium-activated voltage-sensitive potassium (BKCa) channels are implicated in the development of human cancers. Dysfunctional angiogenesis in hypoxic tumors is a challenge to intravenous anticancer drug treatments. Hypoxic factors also lead to abnormal vascular functions posing hurdle for […]

Evidence of calcium‑activated potassium channel subunit alpha‑1 as a key promoter of glioma growth and tumorigenicity

September 29, 2019 | Scientific Articles | No Comments

Introduction Brain tumors are the most common type of solid tumor in both children and adults. It is estimated that 78,980 new cases of primary malignant and nonmalignant brain tumor and other central nervous system tumors will be diagnosed in the United States in 2019. This includes an estimated 23,830 primary malignant brain tumors and […]

Elacridar as Adjuvant with Anticancer Drugs for Brain Tumors – Delivery, Safety, Efficacy and Toxicity

September 29, 2019 | Scientific Articles | No Comments

Elacridar (N-(4-(2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl)phenyl)-9,10-dihydro-5-methoxy- 9-oxo-4-acridine carboxamide) is a potent inhibitor of P-glycoprotein (PgP) and breast cancer resistance protein (BCRP). It has been investigated as modulator of efflux transporters, which are shown to be very active in various cancers. The PgP is over expressed on tumor cells and plays a key role cancer resistance to anti-cancer drugs, specifically […]

Recent advances in understanding of blood–brain tumor barrier (BTB) permeability mechanisms that enable better detection and treatment of brain tumors

September 29, 2019 | Scientific Articles | No Comments

Introduction Blood–Brain Barrier Permeability The blood–brain barrier (BBB) is a cerebrovascular permeability barrier that strictly regulates the entry of variety of substances, including therapeutics and imaging agents into the brain. Unlike blood vessels that circulate blood to other areas of the body, the microvessels that perfuse the brain consist of special endothelial cells and pericytes […]

Differential Epigenetic Inactivation of Genes in Gliomas

September 29, 2019 | Scientific Articles | No Comments

Normal epigenetic modifications such as DNA methylation or histone modifications regulate normal cell differentiation while abnormal epigenetic changes could lead to oncogenic transformation of normal cells. Aberrant or altered DNA methylation cause genomic stability, which is often linked to various pathologies including cancer. Specifically, in glioma epigenetic dysfunctions are often shown to drive oncogenic transformation […]

Role of an Alternatively Spliced KCNMA1 Variant in Glioma Growth

September 29, 2019 | Scientific Articles | No Comments

Gliomas develop genetic traits to rapidly form aggressive phenotypes. Hence, management of gliomas is complicated and difficult. Besides genetic aberrations such as oncogenic copy number variation and mutations, alternative mRNA splicing triggers prooncogenic episodes in many cancers. In gliomas, we found alternative splicing at the KCNMA transcription process. KCNMA1 encodes the pore forming α-subunit of […]

Modulation of KCa channels increases anticancer drug delivery to brain tumors and prolongs survival in xenograft model

September 29, 2019 | Scientific Articles | No Comments

Most anticancer drugs fail to impact patient survival since they fail to cross the blood-brain tumor barrier (BTB) at therapeutic levels. For example, Temozolomide (TMZ) exhibits some anti-tumor activity against brain tumors, so does Trastuzumab (Herceptin, Her-2 inhibitor), which might be effective against Her2 neu overexpressing gliomas. Nevertheless, intact BTB and active efflux system may […]

Activation of KATP channels increases anticancer drug delivery to brain tumors and survival

September 29, 2019 | Scientific Articles | No Comments

Several anticancer drugs are ineffective against brain tumor and do not impact patient survival because they fail to cross the blood-brain tumor barrier (BTB) effective levels. One such agent temozolomide is commonly used in brain tumor patients, which works better when combined with radiation or other anticancer agents. Likewise, trastuzumab (Herceptin, Her-2 inhibitor), which might […]

Drug delivery to brain tumours: challenges and progress

September 29, 2019 | Scientific Articles | No Comments

Nearly 12.5 million new cancer cases are diagnosed worldwide each year. Although new treatments have been developed, most new anticancer drugs that are effective outside the brain have failed in clinical trials against brain tumours, in part due to poor penetration across the blood–brain barrier and the blood–brain tumour barrier. This review will discuss the […]

Targeted Brain Tumor Treatment-Current Perspectives

September 29, 2019 | Scientific Articles | No Comments

Brain tumor is associated with poor prognosis. The treatment option is severely limited for a patient with brain tumor, despite great advances in understanding the etiology and molecular biology of brain tumors have lead to breakthroughs in developing pharmaceutical strategies, and ongoing NCI/Pharma-sponsored clinical trials. We reviewed the literature on molecular targeted agents in preclinical […]

Regulation of Blood-Brain Tumor Barrier Permeability by Calcium-Activated Potassium Channels

September 29, 2019 | Scientific Articles | No Comments

The blood-brain tumor barrier (BTB) limits the delivery of therapeutic drugs to brain tumors. We demonstrate in a rat brain tumor (RG2) model an enhanced drug delivery to brain tumor following intracarotid infusion of bradykinin (BK), nitric oxide (NO) donors, or agonists of soluble guanylate cyclase (sGC) and calcium-dependent potassium (KCa) channels. We modulated KCa […]

Drug delivery to brain tumours: challenges and progress

September 29, 2019 | Scientific Articles | No Comments

Nearly 12.5 million new cancer cases are diagnosed worldwide each year. Although new treatments have been developed, most new anticancer drugs that are effective outside the brain have failed in clinical trials against brain tumours, in part due to poor penetration across the blood–brain barrier and the blood–brain tumour barrier. This review will discuss the […]

Adenosine 5 – triphosphate-sensitive Potassium Channel-mediated Blood-Brain Tumor Barrier Permeability Increase in a Rat Brain Tumor Model

September 29, 2019 | Scientific Articles | No Comments

INTRODUCTION Understanding the biochemical regulation of the blood-brain barrier (BBB) and blood-brain tumor barrier (BTB) is critical to developing methods to deliver therapeutic compounds to central nervous system targets. Despite evidence of the antineoplastic effect of drugs such as Trastuzumab, a humanized anti-Her-2 monoclonal antibody (MAb; developed by Genentech, Inc., San Francisco, CA), alone or […]

Modulation of Brain Tumor Capillaries for Enhanced Drug Delivery Selectively to Brain Tumor

September 29, 2019 | Scientific Articles | No Comments

Background: The blood-brain tumor barrier (BTB) significantly impedes delivery of most hydrophilic molecules to brain tumors. Several promising strategies, however, have been developed to overcome this problem. Methods: We discuss several drug delivery methods to brain tumor, including intracerebroventricular, convectionenhanced delivery, BBB/BTB disruption, and BTB permeability modulation, which was developed in our laboratory. Results: Using […]

Role of KCNMA1 gene in breast cancer invasion and metastasis to brain

September 29, 2019 | Scientific Articles | No Comments

Background: The prognosis for patients with breast tumor metastases to brain is extremely poor. Identification of prognostic molecular markers of the metastatic process is critical for designing therapeutic modalities for reducing the occurrence of metastasis. Although ubiquitously present in most human organs, large-conductance calcium- and voltage-activated potassium channel (BKCa) channels are significantly upregulated in breast […]