Experimental studies and computational modeling on cytochrome c reduction by quercetin: The role of oxidability and binding affinity

Zazeri, Gabriel; Povinelli, Ana Paula Ribeiro; Pavan, Nathália Mariana; Carvalho, Daniella Romano de; Cardoso, Cármen Lúcia; Ximenes, Valdecir Farias

doi:10.1016/j.molstruc.2021.130995

Cited by 9 publications

(11 citation statements)

References 58 publications

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“…The ratio of Bax/Bcl‐2 was significantly ( p <.01) increased in a dose–response manner, which suggested that the down‐regulation of Bcl‐2 and the up‐regulation of Bax were the key regulatory events in glyoxal‐induced apoptosis. When pro‐apoptotic signals are released, mitochondria respond to pro‐apoptotic signals by releasing Cytochrome C, a powerful apoptotic catalyst that triggers the formation of apoptosomes, leading to the activation of caspases 66 . Caspase‐3 is the executor of apoptosis, and caspase‐3 induces apoptosis after activation 63 .…”

Section: Resultsmentioning

confidence: 99%

Investigating the molecular mechanisms of glyoxal‐induced cytotoxicity in human embryonic kidney cells: Insights from network toxicology and cell biology experiments

Liu

Chen

Xie

et al. 2022

Environmental Toxicology

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Glyoxal, a reactive carbonyl species, can be generated both endogenously (glucose metabolism) and exogenously (cigarette smoke and food system). Increasing evidence demonstrates that glyoxal exacerbates the development and progression of diabetic nephropathy, but the underlying mechanisms of glyoxal toxicity to human embryonic kidney (HEK293) cells remain unclear. In this work, the molecular mechanisms of glyoxal-induced cytotoxicity in HEK293 cells were explored with network toxicology and cell biology experiments. Network toxicology results showed that oxidative stress and advanced glycation end products (AGEs)/RAGE signaling pathways played a crucial role in glyoxal toxicity. Next, further validation was performed at the cellular level. Glyoxal activated the AGEs-RAGE signaling pathway, caused the increase of cellular ROS, and activated the p38MAPK and JNK signaling pathways, causing cellular oxidative stress. Furthermore, glyoxal caused the activation of the NF-κB signaling pathway and increased the expression of TGF-β1, indicating that glyoxal caused cellular inflammation. Moreover, glyoxal caused cellular DNA damage accompanied by the activation of DNA damage response pathways. Finally, the mitochondrial apoptosis pathway was activated. The results that obtained in cell biology were consistent with network toxicology, which corroborated each other and together indicated that glyoxal induced HEK293 cells damage via the process of oxidative stress, the AGEs-RAGE pathway, and their associated signaling pathways. This study provides the experimental basis for the cytotoxicity of glyoxal on HEK293 cells.

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Section: Resultsmentioning

confidence: 99%

Investigating the molecular mechanisms of glyoxal‐induced cytotoxicity in human embryonic kidney cells: Insights from network toxicology and cell biology experiments

Liu

Chen

Xie

et al. 2022

Environmental Toxicology

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“…To elucidate this question, circular dichroism (CD) experiment was employed. The (CD) spectrum of IL6 ( Figure 5 ) presented negative bands at 208 nm (π-π* transition) and 222 nm (n-π* transition), which are characteristics of alpha helix content [ 29 ], [ 30 ]. The same pattern of CD spectrum of IL6 in the absence of the ligand was obtained by Kruttgen, A. et al [ 31 ] for human IL6, and by Zhang, J. et al [ 32 ] for murine IL6.…”

Section: Resultsmentioning

confidence: 99%

A Computational–Experimental Investigation of the Molecular Mechanism of Interleukin-6-Piperine Interaction

Povinelli

Zazeri

Jones

et al. 2022

IJMS

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Herein, we elucidate the biophysical aspects of the interaction of an important protein, Interleukin-6 (IL6), which is involved in cytokine storm syndrome, with a natural product with anti-inflammatory activity, piperine. Despite the role of piperine in the inhibition of the transcriptional protein NF-κB pathway responsible for activation of IL6 gene expression, there are no studies to the best of our knowledge regarding the characterisation of the molecular interaction of the IL6-piperine complex. In this context, the characterisation was performed with spectroscopic experiments aided by molecular modelling. Fluorescence spectroscopy alongside van’t Hoff analyses showed that the complexation event is a spontaneous process driven by non-specific interactions. Circular dichroism aided by molecular dynamics revealed that piperine caused local α-helix reduction. Molecular docking and molecular dynamics disclosed the microenvironment of interaction as non-polar amino acid residues. Although piperine has three available hydrogen bond acceptors, only one hydrogen-bond was formed during our simulation experiments, reinforcing the major role of non-specific interactions that we observed experimentally. Root mean square deviation (RMSD) and hydrodynamic radii revealed that the IL6-piperine complex was stable during 800 ns of simulation. Taken together, these results can support ongoing IL6 drug discovery efforts.

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“…Our results are supported by the results of other scientists who have also investigated the role of cytochrome c redox state in the occurrence of apoptosis. Zazeri et al indicated that quercetin possesses cytochrome-c-reducing properties, and that the potency of quercetin is related to its ability as a reducing agent and the appropriate molecular interplay between the protein and flavonoid [56]. The fact that dicaffeoylquinic-acid-rich fractions from Artemisia herb acetone extracts may regulate the mitochondrial redox state of cytochrome c is undoubtedly relevant for future research of mitochondrial-targeted plant compounds, because the regulation of the mitochondrial redox state of cytochrome c enables regulation of the intrinsic pathway of apoptosis, as was shown by Brown et al in 2008 [54].…”

Section: Discussionmentioning

confidence: 99%

Antioxidant and Mitochondria-Targeted Activity of Caffeoylquinic-Acid-Rich Fractions of Wormwood (Artemisia absinthium L.) and Silver Wormwood (Artemisia ludoviciana Nutt.)

et al. 2021

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Caffeoylquinic acids are some of the chemophenetically significant specialized metabolites found in plants of the family Asteraceae Dumort., possessing a broad spectrum of biological activities. As they might be potential mitochondria-targeted antioxidants, effective preparation methods—including extraction, isolation, and purification of caffeoylquinic acids from plant sources—are in great demand. The aim of this study was to fractionate the caffeoylquinic acids from cultivated wormwood (Artemisia absinthium L.) and silver wormwood (Artemisia ludoviciana Nutt.) herb acetone extracts and evaluate their phytochemical profiles, antioxidant activity (radical scavenging and reducing activities), effects on kidney mitochondrial functions, and cytochrome-c-reducing properties. The main findings of our study are as follows: (1) Aqueous fractions purified from wormwood and silver wormwood herb acetone extracts are rich in monocaffeoylquinic acids (chlorogenic acid, neochlorogenic acid, 4-O-caffeoylquinic acid), while methanolic fractions purified from wormwood and silver wormwood herb acetone extracts are rich in dicaffeoylquinic acids (4,5-dicaffeoylquinic acid, 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid). Aqueous fractions purified from wormwood and silver wormwood herb acetone extracts were solely composed of monocaffeoylquinic acids. Methanolic fractions purified from wormwood and silver wormwood herb acetone extracts contained only dicaffeoylquinic acids. (2) Fractions purified from silver wormwood herb acetone extracts stood out as having the greatest content of caffeoylquinic acids. (3) The greatest radical scavenging activity was determined in the dicaffeoylquinic-acid-rich fraction purified from silver wormwood herb acetone extract; the greatest reducing activity was determined in the dicaffeoylquinic-acid-rich fraction purified from wormwood herb acetone extract. (4) The effect of both fractions on mitochondrial functions was dose-dependent; lower concentrations of caffeoylquinic-acid-rich fractions had no effect on mitochondrial functions, whereas higher concentrations of caffeoylquinic-acid-rich fractions reduced the state 3 respiration rate (with the complex-I-dependent substrate glutamate/malate). (5) Both monocaffeoylquinic- and dicaffeoylquinic-acid-rich fractions possessed cytochrome-c-reducing properties; the greatest cytochrome c reduction properties were determined in the dicaffeoylquinic-acid-rich fraction purified from wormwood herb acetone extract. In summary, these findings show that caffeoylquinic acids might be beneficial as promising antioxidant and cytochrome-c-reducing agents for the modulation of mitochondria and treatment of various mitochondrial-pathway-associated pathologies.

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Experimental studies and computational modeling on cytochrome c reduction by quercetin: The role of oxidability and binding affinity

Cited by 9 publications

References 58 publications

Investigating the molecular mechanisms of glyoxal‐induced cytotoxicity in human embryonic kidney cells: Insights from network toxicology and cell biology experiments

Investigating the molecular mechanisms of glyoxal‐induced cytotoxicity in human embryonic kidney cells: Insights from network toxicology and cell biology experiments

A Computational–Experimental Investigation of the Molecular Mechanism of Interleukin-6-Piperine Interaction

Antioxidant and Mitochondria-Targeted Activity of Caffeoylquinic-Acid-Rich Fractions of Wormwood (Artemisia absinthium L.) and Silver Wormwood (Artemisia ludoviciana Nutt.)

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