scholarly journals The Effects ofN-Butyl-1-(4-dimethylamino)phenyl-1,2,3,4-tetrahydro-β-carboline-3-carboxamide againstLeishmania amazonensisAre Mediated by Mitochondrial Dysfunction

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Hélito Volpato ◽  
Vânia Cristina Desoti ◽  
Juliana Cogo ◽  
Manuela Ribeiro Panice ◽  
Maria Helena Sarragiotto ◽  
...  
Keyword(s):  
Side Effects ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Membrane ◽  
Membrane Integrity ◽  
Chemotherapeutic Agents ◽  
Superoxide Anions ◽  
High Toxicity ◽  
Cell Membrane Integrity ◽  
Mitochondrial Superoxide ◽  
New Chemotherapeutic Agents

Leishmaniasis is a disease that affects millions of people worldwide. The drugs that are available for the treatment of this infection exhibit high toxicity and various side effects. Several studies have focused on the development of new chemotherapeutic agents that are less toxic and more effective against trypanosomatids. We investigated the effects ofN-butyl-1-(4-dimethylamino)phenyl-1,2,3,4-tetrahydro-β-carboline-3-carboxamide (C4) and its possible targets againstL. amazonensis. The results showed morphological and ultrastructural alterations, depolarization of the mitochondrial membrane, the loss of cell membrane integrity, and an increase in the formation of mitochondrial superoxide anions inL. amazonensistreated withC4. Our results indicate thatC4is a selective antileishmanial agent, and its effects appear to be mediated by mitochondrial dysfunction.

Vitamin E prevents hypobaric hypoxia-induced mitochondrial dysfunction in skeletal muscle

2007 ◽  
Vol 113 (12) ◽  
pp. 459-466 ◽  
Author(s):  
José Magalhães ◽  
Rita Ferreira ◽  
Maria J. Neuparth ◽  
Paulo J. Oliveira ◽  
Franklim Marques ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Vitamin E ◽  
Mitochondrial Dysfunction ◽  
Hypobaric Hypoxia ◽  
Mitochondrial Membrane ◽  
Mitochondrial Protein ◽  
Membrane Integrity ◽  
Outer Mitochondrial Membrane ◽  
Hypoxia Exposure

In the present study, the effect of vitamin E (α-tocopherol) on mice skeletal muscle mitochondrial dysfunction and oxidative damage induced by an in vivo acute and severe hypobaric hypoxic insult (48 h at a barometric pressure equivalent to 8500 m) has been investigated. Male mice (n=24) were randomly divided into the following four groups (n=6): control (C), hypoxia (H), vitamin E (VE; 60 mg/kg of body weight intraperitoneally, three times/week for 3 weeks) and hypoxia+VE (HVE). A significant increase in mitochondrial protein CGs (carbonyl groups) was found in the H group compared with the C group. Confirming previous observations from our group, hypoxia induced mitochondrial dysfunction, as identified by altered respiratory parameters. Hypoxia exposure increased Bax content and decreased the Bcl-2/Bax ratio, whereas Bcl-2 remained unchanged. Inner and outer mitochondrial membrane integrity were significantly affected by hypoxia exposure; however, vitamin E treatment attenuated the effect of hypoxia on mitochondrial oxidative phosphorylation and on the levels of CGs. Vitamin E supplementation also prevented the Bax and Bcl-2/Bax ratio impairments caused by hypoxia, as well as the decrease in inner and outer mitochondrial membrane integrity. In conclusion, the results suggest that vitamin E prevents the loss of mitochondrial integrity and function, as well as the increase in Bax content, which suggests that mitochondria are involved in increased cell death induced by severe hypobaric hypoxia in mice skeletal muscle.

Side Effects and Good Effects from New Chemotherapeutic Agents

2005 ◽  
Vol 23 (10) ◽  
pp. 2425-2426 ◽  
Author(s):  
Masahiro Onozawa ◽  
Satoshi Hashino ◽  
Susumu Sogabe ◽  
Masahira Haneda ◽  
Hiromasa Horimoto ◽  
...  
Keyword(s):  
Side Effects ◽  
Chemotherapeutic Agents ◽  
New Chemotherapeutic Agents

Side Effects and Good Effects from New Chemotherapeutic Agents

2005 ◽  
Vol 23 (10) ◽  
pp. 2423-2424 ◽  
Author(s):  
Neil C. Nagaria ◽  
Janet Cogswell ◽  
Jin K. Choe ◽  
Basil Kasimis
Keyword(s):  
Side Effects ◽  
Chemotherapeutic Agents ◽  
New Chemotherapeutic Agents

scholarly journals Molecular Toxicological Mechanisms of Synthetic Cathinones on C2C12 Myoblasts

2019 ◽  
Vol 20 (7) ◽  
pp. 1561 ◽  
Author(s):  
Xun Zhou ◽  
Dino Luethi ◽  
Gerda Sanvee ◽  
Jamal Bouitbir ◽  
Matthias Liechti ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Membrane ◽  
Complex I ◽  
Membrane Integrity ◽  
Synthetic Cathinones ◽  
Cellular Respiration ◽  
Dependent Manner ◽  
C2c12 Myoblasts ◽  
Cell Membrane Integrity ◽  
Mitochondrial Superoxide

Synthetic cathinones are popular psychoactive substances that may cause skeletal muscle damage. In addition to indirect sympathomimetic myotoxicity, these substances could be directly myotoxic. Since studies in myocytes are currently lacking, the aim of the present study was to investigate potential toxicological effects by synthetic cathinones on C2C12 myoblasts (mouse skeletal muscle cell line). We exposed C2C12 myoblasts to 3-methylmethcathinone, 4-methylmethcathinone (mephedrone), 3,4-methylenedioxymethcathinone (methylone), 3,4-methylenedioxypyrovalerone (MDPV), alpha-pyrrolidinovalerophenone (α-PVP), and naphthylpyrovalerone (naphyrone) for 1 or 24 h before cell membrane integrity, ATP content, mitochondrial oxygen consumption, and mitochondrial superoxide production was measured. 3,4-Methylenedioxymethamphetamine (MDMA) was included as a reference compound. All investigated synthetic cathinones, as well as MDMA, impaired cell membrane integrity, depleted ATP levels, and increased mitochondrial superoxide concentrations in a concentration-dependent manner in the range of 50–2000 μM. The two pyrovalerone derivatives α-PVP and naphyrone, and MDMA, additionally impaired basal and maximal cellular respiration, suggesting mitochondrial dysfunction. Alpha-PVP inhibited complex I, naphyrone complex II, and MDMA complex I and III, whereas complex IV was not affected. We conclude that, in addition to sympathetic nervous system effects and strenuous muscle exercise, direct effects of some cathinones on skeletal muscle mitochondria may contribute to myotoxicity in susceptible synthetic cathinone drugs users.

The leishmanicidal activity of artemisinin is mediated by cleavage of the endoperoxide bridge and mitochondrial dysfunction

Parasitology ◽  
2018 ◽  
Vol 146 (4) ◽  
pp. 511-520 ◽  
Author(s):  
Sritama De Sarkar ◽  
Deblina Sarkar ◽  
Avijit Sarkar ◽  
Aishwarya Dighal ◽  
Sasanka Chakrabarti ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Membrane ◽  
Therapeutic Strategy ◽  
Atp Hydrolysis ◽  
Underlying Mechanism ◽  
Oxygen Species ◽  
High Iron Content ◽  
Mitochondrial Superoxide ◽  
Transport Chain ◽  
Anti Oxidant

AbstractEndoperoxides kill malaria parasitesviacleavage of their endoperoxide bridge by haem or iron, leading to generation of cytotoxic oxygen-centred radicals. In view of theLeishmaniaparasites having a relatively compromised anti-oxidant defense and high iron content, this study aims to establish the underlying mechanism(s) accounting for the apoptotic-like death ofLeishmaniapromastigotes by artemisinin, an endoperoxide. The formation of reactive oxygen species was confirmed by flow cytometry and was accompanied by inhibition of mitochondrial complexes I–III and II–III. However, this did not translate into a generation of mitochondrial superoxide or decrease in oxygen consumption, indicating minimal impairment of the electron transport chain. Artemisinin caused depolarization of the mitochondrial membrane along with a substantial depletion of adenosine triphosphatase (ATP), but it was not accompanied by enhancement of ATP hydrolysis. Collectively, the endoperoxide-mediated radical formation by artemisinin inLeishmaniapromastigotes was the key step for triggering its antileishmanial activity, leading secondarily to mitochondrial dysfunction indicating that endoperoxides represent a promising therapeutic strategy againstLeishmaniaworthy of pharmacological consideration.

scholarly journals Folate metabolism: a re-emerging therapeutic target in haematological cancers

Leukemia ◽  
2021 ◽  
Author(s):  
Martha M. Zarou ◽  
Alexei Vazquez ◽  
G. Vignir Helgason
Keyword(s):  
Side Effects ◽  
De Novo ◽  
Therapeutic Strategies ◽  
Chemotherapeutic Agents ◽  
Cellular Level ◽  
Folate Metabolism ◽  
Methionine Cycle ◽  
Paediatric Leukaemia ◽  
Thymidylate Synthesis ◽  
New Chemotherapeutic Agents

AbstractFolate-mediated one carbon (1C) metabolism supports a series of processes that are essential for the cell. Through a number of interlinked reactions happening in the cytosol and mitochondria of the cell, folate metabolism contributes to de novo purine and thymidylate synthesis, to the methionine cycle and redox defence. Targeting the folate metabolism gave rise to modern chemotherapy, through the introduction of antifolates to treat paediatric leukaemia. Since then, antifolates, such as methotrexate and pralatrexate have been used to treat a series of blood cancers in clinic. However, traditional antifolates have many deleterious side effects in normal proliferating tissue, highlighting the urgent need for novel strategies to more selectively target 1C metabolism. Notably, mitochondrial 1C enzymes have been shown to be significantly upregulated in various cancers, making them attractive targets for the development of new chemotherapeutic agents. In this article, we present a detailed overview of folate-mediated 1C metabolism, its importance on cellular level and discuss how targeting folate metabolism has been exploited in blood cancers. Additionally, we explore possible therapeutic strategies that could overcome the limitations of traditional antifolates.

scholarly journals Scutellaria baicalensisExtracts and Flavonoids Protect Rat L6 Cells from Antimycin A-Induced Mitochondrial Dysfunction

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
A-Rang Im ◽  
Young-Hwa Kim ◽  
Md. Romij Uddin ◽  
Hye Won Lee ◽  
Seong Wook Chae ◽  
...  
Keyword(s):  
Protein Expression ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Membrane ◽  
Treated Group ◽  
Antimycin A ◽  
Oxygen Species ◽  
Atp Production ◽  
L6 Cells ◽  
Mitochondrial Superoxide ◽  
Ros Formation

Antimycin A (AMA) damages mitochondria by inhibiting mitochondrial electron transport and can produce reactive oxygen species (ROS). ROS formation, aging, and reduction of mitochondrial biogenesis contribute to mitochondrial dysfunction. The present study sought to investigate extracts ofScutellaria baicalensisand its flavonoids (baicalin, baicalein, and wogonin), whether they could protect mitochondria against oxidative damage. The viability of L6 cells treated with AMA increased in the presence of flavonoids and extracts ofS. baicalensis. ATP production decreased in the AMA treated group, but increased by 50% in cells treated with flavonoids (except wogonin) and extracts ofS. baicalensiscompared to AMA-treated group. AMA treatment caused a significant reduction (depolarized) in mitochondrial membrane potential (MMP), whereas flavonoid treatment induced a significant increase in MMP. Mitochondrial superoxide levels increased in AMA treated cells, whereas its levels decreased when cells were treated with flavonoids or extracts ofS. baicalensis. L6 cells treated with flavonoids and extracts ofS. baicalensisincreased their levels of protein expression compared with AMA-treated cells, especially water extracts performed the highest levels of protein expression. These results suggest that theS. baicalensisextracts and flavonoids protect against AMA-induced mitochondrial dysfunction by increasing ATP production, upregulating MMP, and enhancing mitochondrial function.

Side Effects and Good Effects from New Chemotherapeutic Agents

2005 ◽  
Vol 23 (10) ◽  
pp. 2426-2428 ◽  
Author(s):  
C.S. Chim ◽  
G.C. Ooi ◽  
F. Loong ◽  
A.W.M. Au ◽  
A.K.W. Lie
Keyword(s):  
Side Effects ◽  
Chemotherapeutic Agents ◽  
New Chemotherapeutic Agents

scholarly journals Antibiotic drug piperacillin induces neuron cell death through mitochondrial dysfunction and oxidative damage

2018 ◽  
Vol 96 (6) ◽  
pp. 562-568 ◽  
Author(s):  
Shan Jiang ◽  
Tong Li ◽  
Xiao Zhou ◽  
Wenjun Qin ◽  
Zijun Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Side Effects ◽  
Oxidative Damage ◽  
Mitochondrial Dysfunction ◽  
Antibiotic Treatment ◽  
Membrane Lipids ◽  
Atp Production ◽  
Mitochondrial Superoxide ◽  
Antibiotic Drug ◽  
Underlying Mechanisms

Although nerve damage/toxicity has been shown to be one of the side effects in patients given prolonged antibiotic treatment, the mechanisms of the action of antibiotics on neuron cells are not clear. In this work, we investigated the toxicity of piperacillin (an antibiotic that can penetrate the blood–brain barrier) on neuron cells and its underlying mechanisms. We show that clinically relevant doses of piperacillin induce apoptosis in SH-SY5Y and human primary neuron cells through activating caspase-3 activity and decreasing Mcl-1 and Bcl-2 levels. In addition, piperacillin causes mitochondrial dysfunction in neuron cells as shown by the reduction of mitochondrial respiration, membrane potential, and ATP production. We further demonstrate that piperacillin increases accumulation of mitochondrial superoxide and reactive oxygen species, suggesting the oxidative stress in neuron cells. Consistently, oxidative damage to DNA, proteins, and membrane lipids are observed in neuron cells exposed to piperacillin. The deleterious effects of piperacillin are abolished in neuron cells by antioxidant N-acetyl-l-cysteine, further confirming that piperacillin causes neuron cell death through inducing mitochondrial dysfunction and oxidative damage. Our work demonstrates the role of piperacillin in inducing oxidative damage in neuron cells and also provides a therapeutic strategy to prevent the side effects of antibiotic treatment.

Prostatic Acid Phosphatase (PAP) Differentiated Ultracytochemically from Lysosomal Acid Phosphate in the Rat with a PAP/Specific Substrate, Phosphorylcholine

1975 ◽  
Vol 33 ◽  
pp. 450-451
Author(s):  
W. Allen Shannon ◽  
José A. Serrano ◽  
Hannah L. Wasserkrug ◽  
Anna A. Serrano ◽  
Arnold M. Seligman
Keyword(s):  
Acid Phosphatase ◽  
Phosphate Buffer ◽  
Prostatic Carcinoma ◽  
Prostatic Acid Phosphatase ◽  
Chemotherapeutic Agents ◽  
Specific Substrate ◽  
Acid Phosphate ◽  
Lysosomal Acid ◽  
Design And Synthesis ◽  
New Chemotherapeutic Agents

During the design and synthesis of new chemotherapeutic agents for prostatic carcinoma based on phosphorylated agents which might be enzyme-activated to cytotoxicity, phosphorylcholine, [(CH3)3+NCH2CH2OPO3Ca]Cl-, has been indicated to be a very specific substrate for prostatic acid phosphatase (PAP). This phenomenon has led to the development of specific histochemical and ultracytochemical methods for PAP using modifications of the Gomori lead method for acid phosphatase. Comparative histochemical results in prostate and kidney of the rat have been published earlier with phosphorylcholine (PC) and β-glycerophosphate (βGP). We now report the ultracytochemical results.Minced tissues were fixed in 3% glutaraldehyde-0.1 M phosphate buffered (pH 7.4) for 1.5 hr and rinsed overnight in several changes of 0.05 M phosphate buffer (pH 7.0) containing 7.5% sucrose. Tissues were incubated 30 min to 2 hr in Gomori acid phosphatase medium (2) containing 0.1 M substrate, either PC or βGP.

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