The role of mitochondria in pharmacotoxicology: a reevaluation of an old, newly emerging topic

In addition to their well-known critical role in energy metabolism, mitochondria are now recognized as the location where various catabolic and anabolic processes, calcium fluxes, various oxygen-nitrogen reactive species, and other signal transduction pathways interact to maintain cell homeostasis and to mediate cellular responses to different stimuli. It is important to consider how pharmacological agents affect mitochondrial biochemistry, not only because of toxicological concerns but also because of potential therapeutic applications. Several potential targets could be envisaged at the mitochondrial level that may underlie the toxic effects of some drugs. Recently, antiviral nucleoside analogs have displayed mitochondrial toxicity through the inhibition of DNA polymerase-γ (pol-γ). Other drugs that target different components of mitochondrial channels can disrupt ion homeostasis or interfere with the mitochondrial permeability transition pore. Many known inhibitors of the mitochondrial electron transfer chain act by interfering with one or more of the respiratory chain complexes. Nonsteroidal anti-inflammatory drugs (NSAIDs), for example, may behave as oxidative phosphorylation uncouplers. The mitochondrial toxicity of other drugs seems to depend on free radical production, although the mechanisms have not yet been clarified. Meanwhile, drugs targeting mitochondria have been used to treat mitochondrial dysfunctions. Importantly, drugs that target the mitochondria of cancer cells have been developed recently; such drugs can trigger apoptosis or necrosis of the cancer cells. Thus the aim of this review is to highlight the role of mitochondria in pharmacotoxicology, and to describe whenever possible the main molecular mechanisms underlying unwanted and/or therapeutic effects.

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MicroRNA-892a regulates laryngocarcinoma cell proliferation via Dicer

Experimental Biology and Medicine ◽

10.1177/1535370220934036 ◽

2020 ◽

Vol 245 (14) ◽

pp. 1222-1232

Author(s):

Jinhui Dong ◽

Jianxing Wang ◽

Chunguang Shan ◽

Haizhong Zhang ◽

Ou Xu

Keyword(s):

Cell Proliferation ◽

Cancer Cells ◽

Cancer Cell ◽

Laryngeal Cancer ◽

Molecular Mechanisms ◽

Critical Role ◽

Luciferase Reporter ◽

Epithelial Cell Line ◽

Dicer Expression

MicroRNA (miR) plays a critical role in the progression of multiple malignancies. Nevertheless, knowledge of the role it plays in laryngeal cancer is limited. In this study, we explored the role of miR-892a in laryngeal cancer cell proliferation and apoptosis. miR-892a expression was increased in 17 laryngeal cancer samples and cells compared with that in healthy tissues, laryngeal cancer normal surrounding tissues, and the NP69 human nasopharyngeal epithelial cell line. Conversely, Dicer expression was downregulated in human laryngeal cancer samples as well as in the laryngeal cancer cell lines. CCK-8 assays and colony formation assay confirmed that depleted miR-892a expression damaged the proliferation and growth of TU212 and M4E cells. Annexin V/PI flow cytometry displayed that miR-892a inhibition led to increased apoptosis of TU212 and M4E cells. By conducting bioinformatic analysis and dual-luciferase reporter assay, it was revealed that that miR-892a targets Dicer 3′-UTR for silencing. Dicer expression inhibition offsets the effect of miR-892a on the growth and apoptosis of laryngeal cancer cells. Dicer overexpression displayed similar phenotype with miR-892a inhibition on the properties of laryngeal cancer cells. Results of in vivo experiments further confirmed that miR-892a silencing suppressed tumor growth in a mouse model. Hence, the results of this study provide new ideas about the biological and molecular mechanisms behind laryngeal cancer progression, thereby obtaining novel laryngeal cancer treatments. Impact statement This work expanded the knowledge of the molecular mechanisms underlying LC progression by exploring the role of miR-892a in the viability of TU212 and M4E cells. The results showed that miR-892a, which exhibited elevated expression in LC cells and tissue specimens of patients with LC, exerted an inhibitory effect on Dicer expression, whereas silencing of miR-892a in TU212 and M4E cells hindered cell proliferation and growth and promoted apoptosis. Furthermore, miR-892a was demonstrated to directly target Dicer 3′-UTR and inhibit its expression. These findings demonstrated that miR-892a acted as an LC oncogene via its action on Dicer, which further confirmed that miR-892a can serve as a diagnostic indicator or promising agent for LC treatment.

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The Role of the Endothelium in Premature Atherosclerosis: Molecular Mechanisms

Current Medicinal Chemistry ◽

10.2174/0929867326666190911141951 ◽

2020 ◽

Vol 27 (7) ◽

pp. 1041-1051 ◽

Cited By ~ 1

Author(s):

Michael Spartalis ◽

Eleftherios Spartalis ◽

Antonios Athanasiou ◽

Stavroula A. Paschou ◽

Christos Kontogiannis ◽

...

Keyword(s):

Molecular Mechanisms ◽

Low Density Lipoprotein ◽

Critical Role ◽

Density Lipoprotein ◽

Number Of Genes ◽

Causes Of Mortality ◽

Artery Disease ◽

Genetic And Environmental Factors ◽

Made In

Atherosclerotic disease is still one of the leading causes of mortality. Atherosclerosis is a complex progressive and systematic artery disease that involves the intima of the large and middle artery vessels. The inflammation has a key role in the pathophysiological process of the disease and the infiltration of the intima from monocytes, macrophages and T-lymphocytes combined with endothelial dysfunction and accumulated oxidized low-density lipoprotein (LDL) are the main findings of atherogenesis. The development of atherosclerosis involves multiple genetic and environmental factors. Although a large number of genes, genetic polymorphisms, and susceptible loci have been identified in chromosomal regions associated with atherosclerosis, it is the epigenetic process that regulates the chromosomal organization and genetic expression that plays a critical role in the pathogenesis of atherosclerosis. Despite the positive progress made in understanding the pathogenesis of atherosclerosis, the knowledge about the disease remains scarce.

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LncRNA SNHG12 Improves Cerebral Ischemic-reperfusion Injury by Activating SIRT1/FOXO3a Pathway through I nhibition of Autophagy and Oxidative Stress

Current Neurovascular Research ◽

10.2174/1567202617666200727142019 ◽

2020 ◽

Vol 17 (4) ◽

pp. 394-401

Author(s):

Yuanhua Wu ◽

Yuan Huang ◽

Jing Cai ◽

Donglan Zhang ◽

Shixi Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Molecular Mechanisms ◽

Ischemia Reperfusion ◽

Critical Role ◽

Cell Activity ◽

Ht22 Cells ◽

Cerebral Ischemic ◽

Cerebral Ischemic Reperfusion ◽

And Oxidative Stress

Background: Ischemia/reperfusion (I/R) injury involves complex biological processes and molecular mechanisms such as autophagy. Oxidative stress plays a critical role in the pathogenesis of I/R injury. LncRNAs are the regulatory factor of cerebral I/R injury. Methods: This study constructs cerebral I/R model to investigate role of autophagy and oxidative stress in cerebral I/R injury and the underline regulatory mechanism of SIRT1/ FOXO3a pathway. In this study, lncRNA SNHG12 and FOXO3a expression was up-regulated and SIRT1 expression was down-regulated in HT22 cells of I/R model. Results: Overexpression of lncRNA SNHG12 significantly increased the cell viability and inhibited cerebral ischemicreperfusion injury induced by I/Rthrough inhibition of autophagy. In addition, the transfected p-SIRT1 significantly suppressed the release of LDH and SOD compared with cells co-transfected with SIRT1 and FOXO3a group and cells induced by I/R and transfected with p-SNHG12 group and overexpression of cells co-transfected with SIRT1 and FOXO3 further decreased the I/R induced release of ROS and MDA. Conclusion: In conclusion, lncRNA SNHG12 increased cell activity and inhibited oxidative stress through inhibition of SIRT1/FOXO3a signaling-mediated autophagy in HT22 cells of I/R model. This study might provide new potential therapeutic targets for further investigating the mechanisms in cerebral I/R injury and provide.

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The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons

Molecular Psychiatry ◽

10.1038/s41380-021-01137-7 ◽

2021 ◽

Author(s):

Hongsheng Wang ◽

Wanpeng Cui ◽

Wenbing Chen ◽

Fang Liu ◽

Zhaoqi Dong ◽

...

Keyword(s):

Ventral Tegmental Area ◽

Molecular Mechanisms ◽

Critical Role ◽

Coping With Stress ◽

Chemical Genetic ◽

Chronic Social Defeat Stress ◽

Ventral Tegmental ◽

Laterodorsal Tegmentum ◽

Specific Deletion

AbstractDopamine (DA) neurons in the ventral tegmental area (VTA) are critical to coping with stress. However, molecular mechanisms regulating their activity and stress-induced depression were not well understood. We found that the receptor tyrosine kinase ErbB4 in VTA was activated in stress-susceptible mice. Deleting ErbB4 in VTA or in DA neurons, or chemical genetic inhibition of ErbB4 kinase activity in VTA suppressed the development of chronic social defeat stress (CSDS)-induced depression-like behaviors. ErbB4 activation required the expression of NRG1 in the laterodorsal tegmentum (LDTg); LDTg-specific deletion of NRG1 inhibited depression-like behaviors. NRG1 and ErbB4 suppressed potassium currents of VTA DA neurons and increased their firing activity. Finally, we showed that acute inhibition of ErbB4 after stress attenuated DA neuron hyperactivity and expression of depression-like behaviors. Together, these observations demonstrate a critical role of NRG1-ErbB4 signaling in regulating depression-like behaviors and identify an unexpected mechanism by which the LDTg-VTA circuit regulates the activity of DA neurons.

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Low Intensity Shockwave Treatment Modulates Macrophage Functions Beneficial to Healing Chronic Wounds

International Journal of Molecular Sciences ◽

10.3390/ijms22157844 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7844

Author(s):

Jason S. Holsapple ◽

Ben Cooper ◽

Susan H. Berry ◽

Aleksandra Staniszewska ◽

Bruce M. Dickson ◽

...

Keyword(s):

Macrophage Activation ◽

Molecular Mechanisms ◽

Chronic Wounds ◽

Immunohistochemical Analysis ◽

Therapeutic Effects ◽

Gene Expressions ◽

Extracorporeal Shock Wave

Extracorporeal Shock Wave Therapy (ESWT) is used clinically in various disorders including chronic wounds for its pro-angiogenic, proliferative, and anti-inflammatory effects. However, the underlying cellular and molecular mechanisms driving therapeutic effects are not well characterized. Macrophages play a key role in all aspects of healing and their dysfunction results in failure to resolve chronic wounds. We investigated the role of ESWT on macrophage activity in chronic wound punch biopsies from patients with non-healing venous ulcers prior to, and two weeks post-ESWT, and in macrophage cultures treated with clinical shockwave intensities (150–500 impulses, 5 Hz, 0.1 mJ/mm2). Using wound area measurements and histological/immunohistochemical analysis of wound biopsies, we show ESWT enhanced healing of chronic ulcers associated with improved wound angiogenesis (CD31 staining), significantly decreased CD68-positive macrophages per biopsy area and generally increased macrophage activation. Shockwave treatment of macrophages in culture significantly boosted uptake of apoptotic cells, healing-associated cytokine and growth factor gene expressions and modulated macrophage morphology suggestive of macrophage activation, all of which contribute to wound resolution. Macrophage ERK activity was enhanced, suggesting one mechanotransduction pathway driving events. Collectively, these in vitro and in vivo findings reveal shockwaves as important regulators of macrophage functions linked with wound healing. This immunomodulation represents an underappreciated role of clinically applied shockwaves, which could be exploited for other macrophage-mediated disorders.

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Cationicity and hydrophobicity enhance the cytotoxic potency of Phoratoxin C anticancer peptide analogues against triple negative breast cancer cells

Current Bioactive Compounds ◽

10.2174/1573407217999210112180404 ◽

2021 ◽

Vol 17 ◽

Author(s):

Chu Xin Ng ◽

Cheng Foh Le ◽

Sau Har Lee

Keyword(s):

Cancer Cells ◽

Anticancer Agents ◽

Breast Cancer Cells ◽

Critical Role ◽

Three Dimensional ◽

Vero Cells ◽

Anticancer Peptides ◽

Α Helix ◽

Peptide Analogues

Background: Anticancer peptides (ACPs) have received increasing attention as a promising class of novel anticancer agents owing to its potent and rapid cytotoxic properties. In this study, we aim to investigate the effects of cationicity and hydrophobicity in modulating the cytotoxicity of PtxC, a class of ACP from the leafy mistletoe Phoradendron tomentosum against the MDA-MB-231 and Vero cells. Method: We designed a series of four PtxC analogues (PA1 – PA4) by residual substitutions with specific amino acids to introduce the specific charge and hydrophobicity alterations to the analogues. The cytotoxicity strength of the PtxC analogues on MDA-MB-231 and Vero cells were tested by using MTT assay at 24 hours post treatment. Results: PA1, PA2 and PA4 displayed marked increases in cytotoxicity against both MDA-MB-231 and Vero cells and can be ranked in the order of PA2 > PA4 > PA1 > PtxC > PA3. Sequence-activity relationship analyses of the designed analogues showed that an increase in the level of cationicity and hydrophobicity correlated well with the enhanced cytotoxic activity of PtxC analogues. This was observed with PA1 (netC +8) and PA2 (netC +10) in comparison to PtxC (netC +7). Similar finding was observed for PA4 (GRAVY +0.070) in contrast to PtxC (GRAVY -0.339). Three-dimensional modelling predicted a double α-helix structure in PtxC class of ACP. The larger first helix in PA2 and PA4 was suggested to be responsible for the enhanced cytotoxicity observed. Conclusion: The critical role of cationicity and hydrophobicity in enhancing cytotoxicity of PtxC class of ACPs were clearly demonstrated in our study. The current findings could be extrapolated to benefit peptide design strategy in other classes of ACPs toward the discovery of highly potent ACPs against cancer cells as potential novel therapeutic agents.

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Down regulation of Pinkbar/pAKT and MMP2/MMP9 expression in MDA-MB-231 breast cancer cells as potential targets in cancer therapy by hAMSCs secretome

Cells Tissues Organs ◽

10.1159/000520370 ◽

2021 ◽

Author(s):

Termeh Shakery ◽

Fatemeh Safari

Keyword(s):

Breast Cancer ◽

Cancer Therapy ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Molecular Mechanisms ◽

Growth Factor Receptor ◽

3D Cell Culture ◽

Therapeutic Effects ◽

Down Regulation ◽

Egfr Signaling Pathway

Breast cancer (BC) is one of the most causes of cancer-related death among women worldwide. Cancer therapy based on stem cells was considered as a novel and promising platform. In present study, we explored the therapeutic effects of human amniotic mesenchymal stromal cells (hAMSCs) through Pinkbar (planar intestinal-and kidney-specific BAR domain protein), pAKT, and matrix metalloproteinases including MMP2, MMP9 on MDA-MB-231 breast cancer cells. To do so, we employed a co-culture system using 6 well plates transwell with a diameter of 0.4 μm pore sized. After 72h hAMSCs-treated MDA-MB-231 breast cancer cells, the expression of Epidermal growth factor receptor (EGFR), and c-Src (a key mediator in EGFR signaling pathway), Pinkbar, pAKT, MMP2, and MMP9 was analyzed by using quantitative real time PCR (qRT-PCR) and western blot methods. Based on using 2D and 3D cell culture models, the significant reduction of tumor cell growth and motility through down regulation of EGFR, c-Src, Pinkbar, pAKT, MMP2, and MMP9 in MDA-MB-231 breast cancer cells was shown. Also, the induction of cellular apoptosis also found. Our finding indicates that the hAMSCS secretome has therapeutic effects on cancer cells. To identify the details of the molecular mechanisms, more experiments will be required.

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Critical Role of Reactive Oxygen Species and Mitochondrial Permeability Transition in Microcystin-Induced Rapid Apoptosis in Rat Hepatocytes

Hepatology ◽

10.1053/jhep.2000.16183 ◽

2000 ◽

Vol 32 (3) ◽

pp. 547-555 ◽

Cited By ~ 179

Author(s):

Wen-Xing Ding ◽

Han-Ming Shen ◽

Choon-Nam Ong

Keyword(s):

Reactive Oxygen Species ◽

Mitochondrial Permeability Transition ◽

Critical Role ◽

Reactive Oxygen ◽

Permeability Transition ◽

Rat Hepatocytes ◽

Oxygen Species ◽

Mitochondrial Permeability

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Suppression of eNOS-derived superoxide by caveolin-1: a biopterin-dependent mechanism

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00936.2010 ◽

2011 ◽

Vol 301 (3) ◽

pp. H903-H911 ◽

Cited By ~ 33

Author(s):

Kanchana Karuppiah ◽

Lawrence J. Druhan ◽

Chun-an Chen ◽

Travis Smith ◽

Jay L. Zweier ◽

...

Keyword(s):

Gene Silencing ◽

Oxidase Activity ◽

Molecular Mechanisms ◽

Critical Role ◽

Caveolin 1 ◽

Calcium Calmodulin Dependent ◽

Enos Uncoupling ◽

Nadph Oxidation ◽

Interfering Rna

In the vasculature, nitric oxide (NO) is generated by endothelial NO synthase (eNOS) in a calcium/calmodulin-dependent reaction. In the absence of the requisite eNOS cofactor tetrahydrobiopterin (BH4), NADPH oxidation is uncoupled from NO generation, leading to the production of superoxide. Although this phenomenon is apparent with purified enzyme, cellular studies suggest that formation of the BH4 oxidation product, dihydrobiopterin, is the molecular trigger for eNOS uncoupling rather than BH4 depletion alone. In the current study, we investigated the effects of both BH4 depletion and oxidation on eNOS-derived superoxide production in endothelial cells in an attempt to elucidate the molecular mechanisms regulating eNOS oxidase activity. Results demonstrated that pharmacological depletion of endothelial BH4 does not result in eNOS oxidase activity, whereas BH4 oxidation gave rise to significant eNOS-oxidase activity. These findings suggest that the endothelium possesses regulatory mechanisms, which prevent eNOS oxidase activity from pterin-free eNOS. Using a combination of gene silencing and pharmacological approaches, we demonstrate that eNOS-caveolin-1 association is increased under conditions of reduced pterin bioavailability and that this sequestration serves to suppress eNOS uncoupling. Using small interfering RNA approaches, we demonstrate that caveolin-1 gene silencing increases eNOS oxidase activity to 85% of that observed under conditions of BH4 oxidation. Moreover, when caveolin-1 silencing was combined with a pharmacological inhibitor of AKT, BH4 depletion increased eNOS-derived superoxide to 165% of that observed with BH4 oxidation. This study identifies a critical role of caveolin-1 in the regulation of eNOS uncoupling and provides new insight into the mechanisms through which disease-associated changes in caveolin-1 expression may contribute to endothelial dysfunction.

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