Optimized Harmonic Reduction PWM based Control Technique for Three-Phase quasi Z-Source Inverter

This paper proposes an optimized harmonic reduction pulse width modulation (HRPWM) control strategy for three-phase quasi Z-source inverter (qZSI). In traditional sinusoidal or space vector pulse width modulation techniques, the flexibility in adjustment of individual switching angles is not possible and thus, these techniques are not optimum choices for low switching frequency operations of high/medium power qZSI. In the proposed technique, adjustments of switching angles of HRPWM waveform are possible to achieve optimum performance. The optimum performance is targeted as maximization of boosting factor and simultaneous minimization of weighted total harmonic distortion (WTHD) at the output voltage of qZSI. The hybrid particle swarm optimization gravitational search algorithm (PSOGSA) is used for computation of optimum switching angles of suggested HRPWM waveform at various modulation indices. The obtained WTHDs up to 49th order harmonics and boosting factors of optimized HRPWM methodology are compared with that of the maximum boost control (MBC) technique for qZSI to justify superior performances of the suggested method in low switching frequency range. The proposed concept has been verified via simulation study. The experimentation (qZSI controlled by microcontroller) validates the working of optimized HRPWM based qZSI which agrees with software results

Mangiferin Ameliorates Cisplatin Induced Acute Kidney Injury by Upregulating Nrf-2 via the Activation of PI3K and Exhibits Synergistic Anticancer Activity With Cisplatin

Occurrence of oxidative stress is the principal cause of acute kidney injury induced by cisplatin. Mangiferin, a naturally occurring antioxidant molecule, is found to ameliorate several oxidative stress mediated pathophysiological conditions including cancer. Cisplatin induced cytotoxicity was measured in NKE cells by MTT assay and microscopic analysis. Induction of oxidative stress and regulation of proapoptotic molecules were subsequently investigated by using different spectrophotometric analyses, FACS and immunocytochemistry. Induction of nephrotoxicity was determined by analyzing different serum biomarkers and histological parameters in vivo using swiss albino mice. Activation of NF-κB mediated pro-inflammatory and caspase dependent signaling cascades were investigated by semi-quantitative RT-PCR and immunoblotting. Mangiferin was found to ameliorate cisplatin induced nephrotoxicity in vitro and in vivo by attenuating the induction of oxidative stress and upregulating Nrf-2 mediated pro-survival signaling cascades via the activation of PI3K. Additionally, mangiferin showed synergistic anticancer activity with cisplatin in cancer cell lines (MCF-7 and SKRC-45) and EAC cell induced solid tumor bearing experimental mice. The ameliorative effect of mangiferin is primarily attributed to its anti-oxidant and anti-inflammatory properties. It acts differentially in normal tissue cells and tumor cells by modulating different cell survival regulatory signaling molecules. For the first time, the study reveals a mechanistic basis of mangiferin action against cisplatin induced nephrotoxicity. Since Mangiferin shows synergistic anticancer activity with cisplatin, it can be considered as a promising drug candidate, to be used in combination with cisplatin

Perspectives of the Nrf-2 signaling pathway in cancer progression and therapy

The Nuclear factor erythroid2-related factor2 (Nrf2), a master regulator of redox homoeostasis, is a key transcription factor regulating a wide array of genes for antioxidant and detoxification enzymes. It protects organs from various kinds of toxic insults. On the other hand, activation of Nrf2 is also correlated with cancer progression and chemoresistance. Downregulation of Nrf2 activity has attracted an increasing amount of attention as it may provide an alternative cancer therapy. In this review, we examine recent studies on roles of Nrf2 in several pathophysiological conditions emphasising cancer. We discuss elaborately the current knowledge on Nrf2 regulation including KEAP1-dependent and KEAP1-independent cascades. KEAP1/Nrf2 system is a master regulator of cellular response against a variety of environmental stresses. We also highlight several tightly controlled regulations of Nrf2 by numerous proteins, small molecules, toxic metals, etc. In addition, we evaluate the possible therapeutic approaches of increasing chemosensitivity via modulating Nrf2 signaling. Keywords: Nrf2, Transcription factor, KEAP1, Oxidative stress, Cell proliferation, Carcinogenesis, Chemopreventio

Mangiferin attenuates oxidative stress induced renal cell damage through activation of PI3K induced Akt and Nrf-2 mediated signaling pathways

Background: Mangiferin is a polyphenolic xanthonoid with remarkable antioxidant activity. Oxidative stress plays the key role in tert-butyl hydroperoxide (tBHP) induced renal cell damage. In this scenario, we consider mangiferin, as a safe agent in tBHP induced renal cell death and rationalize its action systematically, in normal human kidney epithelial cells (NKE). Methods: NKE cells were exposed to 20 µM mangiferin for 2 h followed by 50 µM tBHP for 18 h. The effect on endogenous ROS production, antioxidant status (antioxidant enzymes and thiols), mitochondrial membrane potential, apoptotic signaling molecules, PI3K mediated signaling cascades and cell cycle progression were examined using various biochemical assays, FACS and immunoblot analyses. Results: tBHP exposure damaged the NKE cells and decreased its viability. It also elevated the intracellular ROS and other oxidative stress-related biomarkers within the cells. However, mangiferin dose dependently, exhibited significant protection against this oxidative cellular damage. Mangiferin inhibited tBHP induced activation of different pro-apoptotic signals and thus protected the renal cells against mitochondrial permeabilization. Further, mangiferin enhanced the expression of cell proliferative signaling cascade molecules, Cyclin d1, NFκB and antioxidant molecules HO-1, SOD2, by PI3K/Akt dependent pathway. However, the inhibitor of PI3K abolished mangiferin's protective activity. Conclusions: Results show Mangiferin maintains the intracellular anti-oxidant status, induces the expression of PI3K and its downstream molecules and shields NKE cells against the tBHP induced cytotoxicity. General significance: Mangiferin can be indicated as a therapeutic agent in oxidative stress-mediated renal toxicity. This protective action of mangiferin primarily attributes to its potent antioxidant and antiapoptotic nature

Therapeutic Targeting of Cancer Stem Cells in Lung, Head and Neck, and Bladder Cancers

Resistance to cancer therapy remains a significant obstacle in treating patients with various solid malignancies. Exposure to current chemotherapeutics and targeted agents invariably leads to therapy resistance, heralding the need for novel agents. Cancer stem cells (CSCs)—a subpopulation of tumor cells with capacities for self-renewal and multi-lineage differentiation—represent a pool of therapeutically resistant cells. CSCs often share physical and molecular characteristics with the stem cell population of the human body. It remains challenging to selectively target CSCs in therapeutically resistant tumors. The generation of CSCs and induction of therapeutic resistance can be attributed to several deregulated critical growth regulatory signaling pathways such as WNT/β-catenin, Notch, Hippo, and Hedgehog. Beyond growth regulatory pathways, CSCs also change the tumor microenvironment and resist endogenous immune attack. Thus, CSCs can interfere with each stage of carcinogenesis from malignant transformation to the onset of metastasis to tumor recurrence. A thorough review of novel targeted agents to act against CSCs is fundamental for advancing cancer treatment in the setting of both intrinsic and acquired resistance

Selective Pro-Apoptotic Activity of Novel 3,3′-(Aryl/Alkyl-Methylene)Bis(2-Hydroxynaphthalene-1,4-Dione) Derivatives on Human Cancer Cells via the Induction Reactive Oxygen Species - Fig 14

<p>a. Immunoblot analysis of different signalling molecules considered in the study. β actin was used as an internal control. Data are representative of three independent experiments. Control: untreated cells, 1j: 20 μM <b>1j</b> exposed cells. b. Densitometric analysis of the respective immunoblots. All data are mean ± SD, for 3 independent experiments and were analyzed by one-way ANOVA. ‘‘*” represents the significant difference between the normal control and <b>1j</b> exposed cells. c. Schematic representation of the most probable signalling cascade moduated due to <b>1j</b> exposure.</p

The dose dependent cytotoxic effect of 1j bis-lawsone derivative and CDDP on CCF-4 and NKE cells.

<p>a. Effects of different concentrations of <b>1j</b> ranging from 0 μM to 50μM, on both the cells viability by MTT assay. b. Effects of different concentrations of CDDP ranging from 0 μM to 50μM, on both the cells viability by MTT assay. c. Cytotoxic effect of both <b>1j</b> and CDDP on both the cancerous and normal cell line by LDH leakage assay. Each point represents mean ±SD, n = 3 (number of plates). ‘‘*” represents the significant difference compared to the control cells. (P* < 0.05).</p

IC₅₀ of the synthesized 1j derivative on six different cell lines.

<p>IC₅₀ of the synthesized 1j derivative on six different cell lines.</p

Effect of 20 μM 1j and 25 μM CDDP on ROS production in the cancerous and normal cells.

<p>a-b. DCFH-DA staining shows increased ROS production upon exposure of both the compounds in CCF-4 and NKE cells. c-d. Differential induction of ROS on CCF-4 and NKE cells upon exposure to 20 μM <b>1j</b> and 5mM NAC. e. Intracellular ROS production was detected by changes in the fluorescence intensity of DCF by fluoroscent microscopy (20X). Data are representative of three independent experiments. f. Effect on cell viability of CCF-4 cells upon exposure to 20 μM <b>1j</b> and 5mM NAC. Each column represents mean ±SD, n = 6. ‘‘*” represents the significant difference between the normal control and <b>1j</b> treated cells (P* < 0.05).</p

Effect of 20 μM 1j derivative on cell migration was observed by a phase contrast microscope (100X).

<p>a. untreated CCF-4 cells b. 1j exposed CCF-4 cells. Data are representative of three independent experiments. All data are mean ± SD, for 3 independent experiments and were analyzed by one-way ANOVA. ‘‘*” represents the significant difference between the normal control and <b>1j</b> exposed cells.</p