Phloretin ameliorates arsenic trioxide induced mitochondrial dysfunction in H9c2 cardiomyoblasts mediated via alterations in membrane permeability and ETC complexes

Vineetha, Vadavanath Prabhakaran; Soumya, Rema Sreenivasan; Raghu, Kozhiparambil Gopalan

doi:10.1016/j.ejphar.2015.02.036

Cited by 40 publications

(37 citation statements)

References 44 publications

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“…It has also been suggested that their hydrophobic properties may make them likely to interact non‐specifically with cellular proteins (Solimani, ). Phloretin has been demonstrated to be a highly bioactive compound in numerous mammalian studies (Shao et al ., ; Huang et al ., ; Vineetha et al ., ), but its effects on plant physiology are less clear. Phloretin accumulation may be deleterious to the plant as its polar surface area (98 Å 2 ) suggests that it is considerably more hydrophobic than phloridzin (177 Å 2 ).…”

Section: Discussionmentioning

confidence: 99%

Silencing a phloretin‐specific glycosyltransferase perturbs both general phenylpropanoid biosynthesis and plant development

et al. 2017

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The polyphenol profile of apple (Malus × domestica) is dominated by the dihydrochalcone glycoside phloridzin, but its physiological role is yet to be elucidated. Biosynthesis of phloridzin occurs as a side branch of the main phenylpropanoid pathway, with the final step mediated by the phloretin-specific glycosyltransferase UGT88F1. Unexpectedly, given that UGTs are sometimes viewed as 'decorating enzymes', UGT88F1 knockdown lines were severely dwarfed, with greatly reduced internode lengths, narrow lanceolate leaves, and changes in leaf and fruit cellular morphology. These changes suggested that auxin transport had been altered in the knockdown lines, which was confirmed in assays showing that auxin flux from the shoot apex was increased in the transgenic lines. Metabolite analysis revealed no accumulation of the phloretin aglycone, as well as decreases in many non-target phenylpropanoid compounds. This decreased accumulation of metabolites appeared to be mediated by the repression of the phenylpropanoid pathway via a reduction in key transcript levels (e.g. phenylalanine ammonia lyase, PAL) and enzyme activities (PAL and chalcone synthase). Application of exogenous phloridzin to the UGT88F1 knockdown lines in tissue culture enhanced axial leaf growth and partially restored some aspects of 'normal' apple leaf growth. Together, our results strongly implicate dihydrochalcones as critical compounds in modulating phenylpropanoid pathway flux and establishing auxin patterning early in apple development.

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Section: Discussionmentioning

confidence: 99%

Silencing a phloretin‐specific glycosyltransferase perturbs both general phenylpropanoid biosynthesis and plant development

et al. 2017

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“…2014; Vineetha et al. 2015). Several studies also showed that arsenic trioxide triggered ER stress in different types of nonmalignant cells such as myoblasts, vascular endothelial cells, pancreatic β ‐cells, neutrophils, and macrophages (Binet et al.…”

Section: Introductionmentioning

confidence: 99%

“…2008; Vineetha et al. 2015), ROS released from mitochondria could thus play a significant role in arsenic trioxide‐induced ER stress. However, arsenic trioxide might also directly induce ER stress because some authors showed with in vitro assays that this compound was able to impair protein folding (Ramadan et al.…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

188

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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“…In addition, high concentrations of As 2 O 3 (30, 60, and 90 μM) for various periods (24, 48, and 72 h) caused apoptosis in primary cardiomyocytes [ 35 ]. As 2 O 3 (5–7 μM) also increased oxidative stress, mitochondrial dysfunctions, or apoptosis in H9c2 cardiomyoblasts [ 36 – 38 ]. On the other hand, our previous studies showed that C2C12 myoblasts and primary mouse and human myoblasts cultured in differentiation media with As 2 O 3 (0.1–0.5 μM) for 4 days significantly inhibited the myoblast differentiation [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Low-Concentration Arsenic Trioxide Inhibits Skeletal Myoblast Cell Proliferation via a Reactive Oxygen Species-Independent Pathway

et al. 2015

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Myoblast proliferation and differentiation are essential for skeletal muscle regeneration. Myoblast proliferation is a critical step in the growth and maintenance of skeletal muscle. The precise action of inorganic arsenic on myoblast growth has not been investigated. Here, we investigated the in vitro effect of inorganic arsenic trioxide (As2O3) on the growth of C2C12 myoblasts. As2O3 decreased myoblast growth at submicromolar concentrations (0.25–1 μM) after 72 h of treatment. Submicromolar concentrations of As2O3 did not induce the myoblast apoptosis. Low-concentration As2O3 (0.5 and 1 μM) significantly suppressed the myoblast cell proliferative activity, which was accompanied by a small proportion of bromodeoxyuridine (BrdU) incorporation and decreased proliferating cell nuclear antigen (PCNA) protein expression. As2O3 (0.5 and 1 μM) increased the intracellular arsenic content but did not affect the reactive oxygen species (ROS) levels in the myoblasts. Cell cycle analysis indicated that low-concentrations of As2O3 inhibited cell proliferation via cell cycle arrest in the G1 and G2/M phases. As2O3 also decreased the protein expressions of cyclin D1, cyclin E, cyclin B1, cyclin-dependent kinase (CDK) 2, and CDK4, but did not affect the protein expressions of p21 and p27. Furthermore, As2O3 inhibited the phosphorylation of Akt. Insulin-like growth factor-1 significantly reversed the inhibitory effect of As2O3 on Akt phosphorylation and cell proliferation in the myoblasts. These results suggest that submicromolar concentrations of As2O3 alter cell cycle progression and reduce myoblast proliferation, at least in part, through a ROS-independent Akt inhibition pathway.

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Phloretin ameliorates arsenic trioxide induced mitochondrial dysfunction in H9c2 cardiomyoblasts mediated via alterations in membrane permeability and ETC complexes

Cited by 40 publications

References 44 publications

Silencing a phloretin‐specific glycosyltransferase perturbs both general phenylpropanoid biosynthesis and plant development

Silencing a phloretin‐specific glycosyltransferase perturbs both general phenylpropanoid biosynthesis and plant development

Role of endoplasmic reticulum stress in drug‐induced toxicity

Low-Concentration Arsenic Trioxide Inhibits Skeletal Myoblast Cell Proliferation via a Reactive Oxygen Species-Independent Pathway

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