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BioChem, Volume 3, Issue 2 (June 2023) – 3 articles

Cover Story (view full-size image): Flavan-3-ol derivatives are polyphenolic compounds with multifunctional properties. We found that epicatechin-3,5-di-O-gallate and its fluorinated derivatives exhibited high toxicity against HeLa and A549 cells. The addition of fluorinated derivatives increased the amount of intracellular mitochondrial superoxide, abolished the membrane potential of mitochondria, and, interestingly, formed granular aggregates containing mitochondria. When the level of LC3-II, a marker of autophagy induction, was confirmed, it suggested that the addition of fluorinated compounds promoted autophagy. These results suggest that the novel highly cytotoxic fluorinated flavan-3-ol compound synthesized in this study promotes autophagy and induces cell death by triggering mitochondrial aggregation. View this paper
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11 pages, 1703 KiB  
Communication
DMSO Alleviates LPS-Induced Inflammatory Responses in RAW264.7 Macrophages by Inhibiting NF-κB and MAPK Activation
by Hyunju Han, Jin-Kyu Kang, Keun Jae Ahn and Chang-Gu Hyun
BioChem 2023, 3(2), 91-101; https://doi.org/10.3390/biochem3020007 - 14 Jun 2023
Cited by 1 | Viewed by 3030
Abstract
Dimethyl sulfoxide (DMSO), an amphipathic molecule composed of one highly polar sulfinyl group and two nonpolar methyl groups, is considered an excellent solvent due to its capability to dissolve many polar and nonpolar compounds. Therefore, DMSO is widely used to solubilize drugs for [...] Read more.
Dimethyl sulfoxide (DMSO), an amphipathic molecule composed of one highly polar sulfinyl group and two nonpolar methyl groups, is considered an excellent solvent due to its capability to dissolve many polar and nonpolar compounds. Therefore, DMSO is widely used to solubilize drugs for therapeutic applications. DMSO is reported to possess anti-inflammatory, anticancer, and antioxidative capacities, and the anti-inflammatory efficacy of DMSO has been intensively studied in various cell lines and animal models. An in vitro model of mouse macrophage RAW 264.7 cells has been widely used, among several experimental designs, for evaluation during the development of new anti-inflammatory drugs. DMSO, which is used to dissolve samples, is also prone to experimental errors because of its anti-inflammatory properties. Therefore, we systematically confirmed the cytotoxic and anti-inflammatory effects of DMSO and the related signaling pathways in RAW 264.7 cells. The results show that DMSO at 0.25% to 1.5% did not result in cellular toxicity, with results comparable to the control group where DMSO is absent; at concentrations 2.0%, however, it inhibited the viability of RAW264.7 cells (13.25%). The results demonstrate that pretreatment with DMSO profoundly attenuates the lipopolysaccharide (LPS)-stimulated levels of nitric oxide (NO) and prostaglandin (PG)E2, as well as the levels of pro-inflammatory cytokines, cyclooxygenase-2 (COX-2) protein, and inducible nitric oxide synthase (iNOS). Collectively, the DMSO pretreatments appear to notably alleviate LPS-induced damage by reducing phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase proteins (ERKs), nuclear factor-kappa-B (NF-κB) in addition to NF-κB/p65 nuclear translocation. Taken together, the results clearly show that DMSO attenuates the inflammatory response in LPS-induced RAW264.7 cells by regulating the activation of the MAPK and NF-κB signaling pathways. These results contribute to potentially reducing experimental errors or misjudgments when using the LPS-induced RAW 264.7 macrophage cell model for evaluation during the development of new anti-inflammatory drugs. Full article
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13 pages, 1401 KiB  
Article
Nitric Oxide Production from Nitrite plus Ascorbate during Ischemia upon Hippocampal Glutamate NMDA Receptor Stimulation
by Carla Nunes and João Laranjinha
BioChem 2023, 3(2), 78-90; https://doi.org/10.3390/biochem3020006 - 3 May 2023
Cited by 2 | Viewed by 1655
Abstract
Nitric oxide (NO), a diffusible free radical, is an intercellular messenger, playing a crucial role in several key brain physiological processes, including in neurovascular coupling (NVC). In the brain, glutamatergic activation of the neuronal nitric oxide synthase (nNOS) enzyme constitutes its [...] Read more.
Nitric oxide (NO), a diffusible free radical, is an intercellular messenger, playing a crucial role in several key brain physiological processes, including in neurovascular coupling (NVC). In the brain, glutamatergic activation of the neuronal nitric oxide synthase (nNOS) enzyme constitutes its main synthesis pathway. However, when oxygen (O2) supply is compromised, such as in stroke, ischemia, and aging, such NO production pathway may be seriously impaired. In this context, evidence suggests that, as already observed in the gastric compartment, the reduction of nitrite by dietary compounds (such as ascorbate and polyphenols) or by specific enzymes may occur in the brain, constituting an important rescuing or complementary mechanism of NO production. Here, using microsensors selective for NO, we show that nitrite enhanced the NO production in a concentration-dependent manner and in the presence of ascorbate evoked by N-methyl-D-aspartate (NMDA) and glutamate stimulation of rat hippocampal slices. Additionally, nitrite potentiated the NO production induced by oxygen-glucose deprivation (OGD). Overall, these observations support the notion of a redox interaction of ascorbate with nitrite yielding NO upon neuronal glutamatergic activation and given the critical role of NO as the direct mediator of neurovascular coupling may represents a key physiological mechanism by which NO production for cerebral blood flow (CBF) responses to neuronal activation is sustained under hypoxic/acidic conditions in the brain. Full article
(This article belongs to the Special Issue Selected Papers from XXI SPB National Congress of Biochemistry 2021)
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17 pages, 3402 KiB  
Article
Fluorinated Derivatives of Digalloyl-Flavan-3-ol Induce Autophagic Cell Death by Forming Granular Aggregates Containing Mitochondria
by Ryo Doge, Yuki Nishino and Akiko Saito
BioChem 2023, 3(2), 61-77; https://doi.org/10.3390/biochem3020005 - 17 Apr 2023
Cited by 1 | Viewed by 1643
Abstract
Flavan-3-ol derivatives are polyphenolic compounds with multifunctional properties. One of the flavan-3-ol derivatives, green tea catechin epigallocatechin gallate, is known to have anticancer activity as one of its multifunctional properties. We have studied the synthesis of flavan-3-ol derivatives and conducted structure-activity relationship studies; [...] Read more.
Flavan-3-ol derivatives are polyphenolic compounds with multifunctional properties. One of the flavan-3-ol derivatives, green tea catechin epigallocatechin gallate, is known to have anticancer activity as one of its multifunctional properties. We have studied the synthesis of flavan-3-ol derivatives and conducted structure-activity relationship studies; we found that the fluorinated derivatives exhibited high toxicity against HeLa and A549 cells. It was confirmed that the cytotoxicity was affected by the conformation of the flavan-3-ol skeleton and that the 2,3-cis form was dominant. The addition of fluorinated compounds increased the amount of intracellular mitochondrial superoxide, abolished the membrane potential of mitochondria, and, interestingly, formed granular aggregates containing mitochondria. When the level of LC3-II, a marker of autophagy induction, was confirmed, it suggested that the addition of the fluorinated compounds promoted autophagy. These results suggest that the novel highly cytotoxic fluorinated flavan-3-ol compound synthesized in this study promotes autophagy and induces cell death by triggering mitochondrial dysfunction. We believe that these results suggest the possibility of conferring more functionality through structural transformations of flavan-3-ol derivatives. Full article
(This article belongs to the Special Issue Cancer Molecular Biology and Drug Discovery)
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