No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
A novel ferulic acid derivative attenuates myocardial cell hypoxia reoxygenation injury through a succinate dehydrogenase dependent antioxidant mechanism
Abstract
The molecular structure optimization aimed at definite target is expected to improve its anti-myocardial ischemia reperfusion (I/R) injury. Ferulic acid derivatives could probably attenuate myocardial I/R injury when optimized on account of definite target succinate dehydrogenase (SDH). Herein, an original compound hmy-paa (3-(4-hydroxy-3-methoxyphenyl)-N-(1H-pyrazol-3-yl)acrylamide), a combination of ferulic acid and active groups of enzyme inhibitor was synthesized, myocardial cell hypoxia reoxygenation (H/R) model were built, and SDH activity of myocardial cell was detected to investigate the effect of the derivative. Intriguingly, it could selectively inhibit SDH activity, and efficiently abate myocardial cell H/R injury. SDH is located in the mitochondrial inner membrane, and fluorescent hmy-paa could be observed to accumulate in cell and mitochondria through fluorescence inversion microscopy, which allows for more efficient SDH inhibition efficacy. By inhibiting SDH activity, hmy-paa could reduce oxidative damage by preventing excess production of intracellular reactive oxygen species as well as ensure energy production through the regulation of ATP level. The computational docking simulation exhibits a tightly bound mode between hmy-paa and SDH. Consequently, ferulic acid derivative hmy-paa is a new candidate for the treatment of myocardial H/R injury that exerts its therapeutic effect through a SDH dependent antioxidant mechanism. SDH could probably be a new target for drug discovery to alleviate myocardial I/R injury.
... It has also been reported that they protect the human body from a variety of diseases, ranging from specific types of cancer to cardiovascular diseases. Ferulic acid derivative has been shown to reduce myocardial ischemia-reperfusion injury [13], protect human endothelial umbilical cord vein cells from oxidative damage [14], prevent Alzheimer's disease [15], induce nitric oxide synthase [16], protect against oxidative stress-related diseases caused by various reactive oxygen species [17], neuroprotective effect against H 2 O 2 -induced cell death in SH-SY5Y cells [18], antimicrobial activity [19], nonsteroidal anti-inflammatory drug activity [20], tyrosine kinase activity [21]. Medicinal plants have long been used to improve human health [22]. ...
... Compounds were purified by column chromatography using EtOAc: Hexane (40:60). 13 C NMR spectrograms and FTIR spectrum of synthesized amide derivatives (4a-4g; 5a-5b) N-Benzyl-3-(4-hydroxy-3-methoxy-phenyl)-acrylamide ...
... The synthesis of a series of amide derivatives of ferulic acid (1) and p-coumaric acid (2) was accomplished through simple condensation of ferulic acid/pcoumaric acid with corresponding amines via two step coupling using ethyl chloroformate to yield corresponding products between 40 and 60 %. The structures of all the newly synthesized compounds were confirmed by the, 1 H NMR, 13 C NMR which were in full agreement with their structures. The structural information obtained from spectra has properly supported the chemical structures assigned to the compounds reported in the experimental section. ...
Ferulic acid and p-coumaric acid, cinnamic derivatives of phenolic acid, have antibacterial, prooxidant, and antioxidant effects. In this study ferulic acid and p-coumaric acid amide derivatives were investigated for their antibacterial and antioxidant properties are described in this communication. The most effective conjugates against B subtilis were 5b (IC 50 : 215 AE 1.3 μM) and 4d (IC 50 : 336 AE 2.7 μM) and against P. aeruginosa were 4b (IC 50 : 365 AE 2.8 μM) and 5b (IC 50 : 341 AE 3.6 μM), whereas the none of conjugates were more effective against E. coli than reference Kanamycin. Conjugates 5b was the most effective against B subtilis of all the synthesized conjugates, with IC 50 values of (IC 50 : 215 AE 1.3 μM). The free radical scavenging capacity of each compound was determined using the DPPH and ABTS assays. Conjugates 4b (IC 50 : 53 AE 3.6 μM), 4c (IC 50 : 58 AE 1.3 μM), 4d (IC 50 : 57 AE 2.5 μM), 5b (IC 50 : 29 AE 1.5 μM) and 4a (IC 50 : 56 AE 4.3 μM) have greater antioxidant capacity than ferulic acid and ascorbic acid in the DPPH assay. Whereas in the ABTS assay, compounds 4b (IC 50 : 7 AE 1.8 μM), 5b (IC 50 : 5 AE 0.7 μM), 4a (IC 50 : 9 AE 3.2 μM), 4g (IC 50 : 7 AE 2.3 μM), and 5a (IC 50 : 8 AE 4.3 μM) showed more antioxidant activity than ferulic acid, p-coumaric acid and ascorbic acid. Thus, a large library of compounds derived from bile acid can be easily synthesized for extensive structure-activity relationship studies in order to identify the most appropriate antibacterial and antioxidant agents.
... However, its therapeutic efficacy remains limited, indicating its insufficiency as a viable drug candidate. Recent studies, however, highlighted the potential of FA derivatives as enhanced therapeutic agents [32,33]. Novel compounds, such as hmy-paa [32] and NCX2057 [33], demonstrated protective effects against myocardial I/R injury and neuroinflammation by inhibiting ROS production and modulating key inflammatory pathways. ...
... Recent studies, however, highlighted the potential of FA derivatives as enhanced therapeutic agents [32,33]. Novel compounds, such as hmy-paa [32] and NCX2057 [33], demonstrated protective effects against myocardial I/R injury and neuroinflammation by inhibiting ROS production and modulating key inflammatory pathways. These findings suggest that molecular modifications of FA can significantly improve its therapeutic efficacy. ...
Dysphagia is a serious complication of stroke, yet effective pharmacological treatments remain limited. This study investigated the effects of FAD012 (3,5-dimethyl-4-hydroxy cinnamic acid), a synthetic derivative of ferulic acid (FA), on cerebral damage and swallowing dysfunction in a rat model of bilateral common carotid artery occlusion (2VO). Sprague–Dawley rats were orally administered FAD012 (3 or 10 mg/kg), FA (10 mg/kg), or 0.5% carboxymethyl cellulose (CMC, suspension vehicle) starting one week before 2VO. Two weeks after 2VO surgery, which was performed under isoflurane anesthesia, reflex swallowing was assessed by electromyographic recordings of the mylohyoid muscle under urethane anesthesia. Two weeks after 2VO, cerebral blood flow (CBF) declined to approximately 40% of baseline, and the number of reflex swallowing responses was significantly reduced in the CMC group. Additionally, 2VO induced O2⁻ production, apoptotic cell death in the striatum, and a reduction in tyrosine hydroxylase expression. Substance P (SP) levels in the laryngopharyngeal mucosa, positively regulated by dopaminergic signaling in the basal ganglia, also decreased. FAD012 (10 mg/kg) effectively prevented the 2VO-induced reduction in CBF, enhanced the reflex swallowing, and preserved the dopamine-SP system. Notably, FAD012 exerted significantly stronger effects than FA at the same dose. These findings suggest that FAD012 maintains CBF under cerebral hypoperfusion and enhances the swallowing reflex by maintaining neuronal function in the striatal and laryngopharyngeal regions of 2VO rats.
... Additionally, during I/R injury, FA demonstrated its ability to attenuate myocardial oxidative damage by inhibiting SDH. This inhibition led to a reduction in succinate levels, thereby mitigating excessive intracellular ROS production and OS [236]. ...
... Lignans of Sesame DOX-induced mice Activation of SIRT1 [220] SHR rats Up-regulation eNOS and down-regulation p22/p47 [221] HUVECs Activation of CaMKKβ/Akt/AMPK [222] DOCA/salt rats Inhibition of JNK/MAPK [223] HAECs Inhibition of OS/IKKα/p53 [224] CHO cells Activation of PPARα/PPARγ/LXRα [225] Phillyrin and Forsythin H9c2 cells Inhibition of p38/ERK1/2MAPK and Akt/NF-kB [226] RAW264.7 Inhibition of JAK-STA T/p38MAPK [227] Cinnamic acid IHD rats Up-regulation SOD and NO of expression [229] MI / RI rats Inhibition of NLRP3/Caspase1/GSDMD [230] HUVECs Activation of NO/cGMP/PKG and inhibition of Rho-kinase [231,232] VSMCs in rats Inhibition of MAPK/Akt pathways and NF-κB [234] DOX-induced rats Activation of Nrf-2/HO-1, PI3K/Akt/mTOR and inhibition of MAPK/NF-κB [235] H9c2 cells Inhibition of SDH [236] Syringic acid MI rats Up-regulated antioxidant capacity and anti-lipid peroxidation [237,238] MIRI rats Activation of PI3K/Akt/GSK-3β [239] MI rats Inhibition of NF-kB and TNF-α [240] Oleanolic acid HUVECs Activation of Nrf2/HO-1 [243] HUVECs Activation of Akt/eNOS [244] Baicalin Arterial ligation mice Upregulation of SM22α expression and inhibition ERK [249] PASMCs Inhibition of PI3K/Akt/HIF-1α and upregulation of P27 expression [250] A2AR-deficient nice Upregulation of SDF-1/CXCR4 expression and inhibition PI3K/Akt [251] HUVECs Activation of PI3K/Akt/eNOS [252] ATO-induced mice Inhibition of TLR4/NF-κB [254] CMECs Activation of PI3K/Akt/ eNOS [255] AS rabbit Activation of PPARγ/LXRα [256] Quercetin AS mice Upregulation of HO-1 expression [261] HUVECs Activation of Nrf2/HO-1 and upregulation of HO-1 expression [262] HUVECs Activation of ADMA/DDAHII [263] Human cardiomyocytes Activation of SIRT1/TMBIM6 [264] TAC mice Activation of SIRT5 [265] MIRI rats Activation of SIRT1/PGC-1α [268] MIRI rats Activation of JAK2/STAT3 [269] Luteolin HUVECs Inhibition of STAT3 [270] HUVECs Activation of AMPK/PKC [271] HUVECs Inhibition of NOX4/ROS/NF-κB [272] HUVECs Activation of ADMA/DDAHII [273] Diabetic Rat Activation of Keap1/Nrf2 [274] H9C2 cells Activation of Nrf2 and inhibition of NF-κB [275] ISO-induced mice Activation of Kim-1/NF-kB/Nrf2 [276] Activation Activation of STAT3 [277] Diabetic rats Activation of Sestrin2 and Nrf2 [278] HPH rats Activation of PI3K/Akt and inhibition of HIF-2α [279] MCT rats Inhibition of PI3K/Akt [280] Naringin HUVECs Activation of PI3K/Akt/mTOR [282] H9C2 cells Activation of HIF-1α/BNIP3 [283] myocardial infarct size through activation of the Akt/ eNOS signaling pathway. Moreover, LBP demonstrates anti-apoptotic effects and mitigates oxidative stress [306]. ...
Cardiovascular diseases (CVDs) continue to exert a significant impact on global mortality rates, encompassing conditions like pulmonary arterial hypertension (PAH), atherosclerosis (AS), and myocardial infarction (MI). Oxidative stress (OS) plays a crucial role in the pathogenesis and advancement of CVDs, highlighting its significance as a contributing factor. Maintaining an equilibrium between reactive oxygen species (ROS) and antioxidant systems not only aids in mitigating oxidative stress but also confers protective benefits on cardiac health. Herbal monomers can inhibit OS in CVDs by activating multiple signaling pathways, such as increasing the activity of endogenous antioxidant systems and decreasing the level of ROS expression. Given the actions of herbal monomers to significantly protect the normal function of the heart and reduce the damage caused by OS to the organism. Hence, it is imperative to recognize the significance of herbal monomers as prospective therapeutic interventions for mitigating oxidative damage in CVDs. This paper aims to comprehensively review the origins and mechanisms underlying OS, elucidate the intricate association between CVDs and OS, and explore the therapeutic potential of antioxidant treatment utilizing herbal monomers. Furthermore, particular emphasis will be placed on examining the cardioprotective effects of herbal monomers by evaluating their impact on cardiac signaling pathways subsequent to treatment.
Graphical Abstract
... [27] Amide + pyrazole Antioxidant and myocardial cell hypoxia reoxygenation. [133] Amino acid Anti-inflammatory, antioxidant. ...
... [27] Amide + pyrazole Antioxidant and myocardial cell hypoxia reoxygenation. [133] Amino acid Anti-inflammatory, antioxidant. [110] Aniline Antimicrobial. ...
Ferulic acid has numerous beneficial effects on human health, which are frequently attributed to its antioxidant behavior. In this report, many of them are reviewed, and 185 new ferulic acid derivatives are computationally designed using the CADMA-Chem protocol. Consequently, their chemical space was sampled and evaluated. To that purpose, selection and elimination scores were used, which are built from a set of descriptors accounting for ADME properties, toxicity, and synthetic accessibility. After the first screening, 12 derivatives were selected and further investigated. Their potential role as antioxidants was predicted from reactivity indexes directly related to the formal hydrogen atom transfer and the single electron transfer mechanisms. The best performing molecules were identified by comparisons with the parent molecule and two references: Trolox and α-tocopherol. Their potential as polygenic neuroprotectors was investigated through the interactions with enzymes directly related to the etiologies of Parkinson’s and Alzheimer’s diseases. These enzymes are acetylcholinesterase, catechol-O-methyltransferase, and monoamine oxidase B. Based on the obtained results, the most promising candidates (FA-26, FA-118, and FA-138) are proposed as multifunctional antioxidants with potential neuroprotective effects. The findings derived from this investigation are encouraging and might promote further investigations on these molecules.
... For example, ferulic acid methyl ester, a derivative of ferulic acid, possesses antioxidant, antibacterial, and anti-inflammatory properties [25,26]. A previous study demonstrated that ferulic acid methyl ester has higher activity, lower toxicity, and better protection against hypoxic damage to cardiomyocytes than ferulic acid [27]. ...
A broadly targeted metabolomics approach based on UPLC-MS/MS was employed to investigate the changes in chemical composition and in vitro activity of highland barley Monascus tea decoction before and after simulated digestion. The characteristic metabolites of the tea decoction before and after in vitro-simulated digestion were identified, and the in vitro antioxidant and enzyme inhibitory activities of the tea decoction were further analyzed. The study detected 1431 metabolites, including amino acids and their derivatives, alkaloids, organic acids, nucleotides and their derivatives, lipids, terpenoids, and phenolic acids. A total of 136 differential compounds were identified, primarily distributed in amino acids and their derivatives, alkaloids, organic acids, phenolics, and lipids. in vitro-simulated digestion significantly increased the content of amino acids, alkaloids, lipids, and phenolics in the tea. The differential metabolic compounds were primarily assigned to 20 metabolic pathways, mainly involving the metabolism of amino acids, nucleotides, carbohydrates, fatty acids, and other compounds. Additionally, after simulated digestion in vitro, the comprehensive antioxidant index (60.53%), α-glucosidase inhibitory activity (54.35%), and pancreatic lipase inhibitory activity (4.06%) was significantly improved. The highland barley Monascus tea decoction showed potential hypoglycemic and hypolipidemic efficacy. This study can provide a theoretical basis for the high-value utilization of highland barley and the development of healthy grain tea.
... It was found that my-paa can enter cardiomyocytes and accumulate in mitochondria, which has strong antioxidant activity and maybe a potential drug for the treatment of myocardial ischemia-reperfusion injury. [99] Hassan et al. reported Cu(I)-catalyzed click dipolar cycloaddition for the synthesis of esters of ferulic acid containing 1,2,3-triazole moieties and different sugar fractions. The synthesized compounds have good antibacterial activity for the development of antibacterial drugs. ...
The ever‐increasing prevalence of diseases and inadequate resources on Earth are threats to society. Biomass is an abundant resource, and bioactive compounds produced from biomass are environmentally benign in contrast to conventional chemical synthesis methods, which frequently depend on non‐renewable resources. In addition, the functionalized monomers from biomass allow the atom economical synthesis of bioactive molecules. This review aims to provide insight into the synthesis of bioactive molecules from the lignocellulose‐derived platform chemicals. Existing methodology and catalytic systems are summarized for the synthesis of targeted bioactive molecules from cellulose, hemicellulose, and lignin‐derived platform chemicals. The biological activities of bioactive molecules obtained from biomass, such as antioxidant, anti‐inflammatory, and anticancer properties, are discussed.
... [156] Amide + pyrazole Antioxidant, and myocardial cell hypoxia reoxygenation. [262] Amino acid Anti-inflammatory, antioxidant. [239] Aniline Antimicrobial. ...
Ferulic acid has numerous beneficial effects for human health, which are frequently attributed to its antioxidant behavior. In this report many of them are reviewed and 185 new ferulic acid derivatives are computationally designed, using the CADMA-Chem protocol. For the later, the chemical space was sampled and evaluated. To that purpose selection and elimination scores were used, which are built from a set of descriptors accounting for ADME properties, toxicity, and synthetic accessibility. After the first screening, 12 derivatives were selected and further investigated. Their potential role as antioxidants was predicted from reactivity indexes, directed related with the formal hydrogen atom transfer and the single electron transfer mechanisms. The best performing molecules were identified by comparisons with the parent molecule and two references: Trolox and alpha-tocopherol. Their potential as polygenic neuroprotectors was investigated through the interactions with enzymes directed related with the etiologies of Parkinson’s and Alzheimer’s diseases. They are acetylcholinesterase, catechol-O-methyltransferase, and monoamine oxidase B. Based on the obtained results, the most promising candidates (FA-26, FA-118, and FA-138) are proposed as multifunctional antioxidants with potential neuroprotective effects. The findings derived from this investigation are encouraging and might promote further investigations on these molecules.
... After the cells entered the exponential growth phase, the DMEM was replaced with EBSS balanced salt solution. The cells were cultured in a 95% N 2 and 5% CO 2 incubator for 7 h, the EBSS balanced salt solution was replaced with fresh DMEM (containing 10% FBS), and the cells were cultured in a 95% O 2 and 5% CO 2 incubator for 6 h [27]. ...
Myocardial ischemia–reperfusion injury(MIRI) is one of the common complications after myocardial infarction surgery, Oxidative stress is among the main mechanisms of myocardial ischemia–reperfusion injury. Plantamajoside (PMS), the main effective ingredient in the genus Plantain, has been reported to possess an antioxidation, anti-inflammatory and anti-apoptosis role. However, whether PMS can attenuate myocardial ischemia–reperfusion injury is not yet known. Herein, we explored the effects of PMS on hypoxia-reoxygenation (H/R) injury in H9c2 cardiomyocytes and the underling molecular mechanisms of the treatment. Network pharmacological analysis screened the top 31 key genes in the treatment of MIRI disease treated with PMS, and the result of molecular docking further illustrated the roles that the PMS play in the treatment of MIRI through its interference with integrin-linked kinase (ILK) target protein. PMS was not cytotoxic in the concentration range of 5–40 μM and increased cell survival after H/R injury in a concentration-dependent manner without affecting proliferation or growth. PMS significantly reduced the levels of lactate dehydrogenase, malonic dialdehyde, reactive oxygen species and cell apoptosis, and increased soperoxide dismutase activity compared with those of the H/R injury group. PMS promoted the protein and mRNA expression of ILK and Bcl-2, the protein expression of p-Akt, and reduced the protein and mRNA expression of Bax, Caspase-3, and Cytochrome c, the protein expression of p–c-Src. PMS has protective effects against H/R injury in H9c2 cells, and its protective mechanism may be related to reactive oxygen species clearance, activation of the ILK/c-Src/Akt pathway and inhibition of the mitochondrial apoptosis.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12906-023-03880-6.
... For example, it was found that sodium ferulate could protect human corneal endothelial cells from the oxidative damage induced by lidocaine, which causes corneal thickening, opacification, and corneal endothelial cell loss [51]. In another study a derivative of FA, hmy-paa (3-(4-hydroxy-3-methoxyphenyl)-N-(1H-pyrazol-3-yl) acrylamide), was demonstrated to selectively inhibit succinate dehydrogenase activity and efficiently abate myocardial cell injury caused by hypoxia [52]. On the other hand, the protective effect of FA derivatives on the skin was presented by Di Domenico et al. ...
Ferulic acid (FA) has been widely used in the pharmaceutical and cosmetics industry due to its, inter alia, antioxidant, antiaging and anti-inflammatory effects This compound added to cosmetic preparations can protect skin because of its photoprotective activity. However, the usefulness of FA as a therapeutic agent is limited due to its low solubility and bioavailability. The paper presents the synthesis, identification, and physicochemical properties of new FA derivatives with propyl esters of three amino acids, glycine (GPr[FA]), L-leucine (LPr[FA]), and L-proline (PPr[FA]). The NMR and FTIR spectroscopy, DSC, and TG analysis were used as analytical methods. Moreover, water solubility of the new conjugates was compared with the parent acid. Both ferulic acid and its conjugates were introduced into hydrogel and emulsion, and the resulting formulations were evaluated for stability. Additionally, in vitro penetration of all studied compounds from both formulations and for comparative purposes using Franz diffusion cells was evaluated from the solution in 70% (v/v) ethanol. Finally, cytotoxicity against murine fibroblasts L929 was tested. All of the analyzed compounds permeated pig skin and accumulated in it. LPr[FA] and PPr[FA] were characterized by much better permeability compared to the parent ferulic acid. Additionally, it was shown that all the analyzed derivatives are characterized by high antioxidant activity and lack of cytotoxicity. Therefore, they can be considered as an interesting alternative to be applied in dermatologic and cosmetic preparations.
... 11 It has been reported that FA improves myocardial I/R injury through succinate dehydrogenase-dependent antioxidant activity. 12 Moreover, FA also activates AMPK to produce an anti-inflammatory function. 13 Nevertheless, whether FA prevents myocardial I/R injury in rats has not been clarified. ...
Ferroptosis, a recently discovered form of regulated cell death that is characterized by iron accumulation and excessive ROS generation, has been favoured by the majority of researchers. Increasing evidence suggest that ferulic acid could exert markedly effects to myocardial ischemia reperfusion injury, while the understanding of its molecular mechanism is still limited. In our study, the myocardial ischemia reperfusion injury model was established to explore the relationship between ischemia reperfusion injury and ferroptosis. First, we successfully constructed myocardial ischemia reperfusion injury model with changes in ST segment, increased CK,LDH activities and NT-proBNP content, and a significantly larger infarct size. Then, the increased levels of the Ptgs2 mRNA, Fe2+ accumulation, and a decreased GSH/GSSG ratio were detected in ischemia-reperfusion-injuryed heart which highly consistent with ferroptosis. However, these effects were significantly improved after ferulic acid treatment. Based on these results, ferulic acid increased the activities of the antioxidant enzymes SOD, CAT and GSH-Px, decreased the MDA level, ameliorated the production of ROS and promoted the generation of ATP. These effects of ferulic acid are similar to those of the ferroptosis inhibitor ferrostatin-1 (Fer-1). Upregulation of AMPKα2 and GPx4 expression were also observed in the FA group. Compound C, a specific AMPK inhibitor, significantly blocked the protective effect of ferulic acid. These findings underlined that FA inhibits ferroptosis by upregulating the expression of AMPKα2 serves as a cardioprotective strategy.
... It was mentioned that mitochondrial ROS production is involved in ischemia/reperfusion injury, and the Complex II (SDH) inhibitors atpenin A5, malonate, or the new mitochondria-targeted Complex II (SDH) inhibitor tanshinone IIA exert protective effects in different cases of ischemia/reperfusion [41][42][43]. Wang et al. showed that a new ferulic acid derivative is protective in ischemia/reperfusion oxidative injury [44]. ...
To improve ischemia/reperfusion tolerance, a lot of attention has been focused on natural antioxidants. Caffeic acid phenethyl ester (CAPE), an active component of the resinous exudates of the buds and young leaves of Populus nigra L., Baccharis sarothroides A., etc., and of propolis, possesses unique biological activities such as anti-inflammatory, antioxidant, immunomodulating, and cardioprotective effects, among others. There is a lack of studies showing a link between the antioxidant potential of CAPE and the mechanism of protective action of CAPE at the level of mitochondria, which produces the main energy for the basic functions of the cell. In the kidney, ischemia/reperfusion injury contributes to rapid kidney dysfunction and high mortality rates, and the search for biologically active protective compounds remains very actual. Therefore, the aim of this study was to identify the antioxidant potential of CAPE and to investigate whether CAPE can protect rat kidney mitochondria from in vivo kidney ischemia/reperfusion induced injury. We found that CAPE (1) possesses antioxidant activity (the reducing properties of CAPE are more pronounced than its antiradical properties); CAPE effectively reduces cytochrome c; (2) protects glutamate/malate oxidation and Complex I activity; (3) preserves the mitochondrial outer membrane from damage and from the release of cytochrome c; (4) inhibits reactive oxygen species (ROS) generation in the Complex II (SDH) F site; (5) diminishes ischemia/reperfusion-induced LDH release and protects from necrotic cell death; and (6) has no protective effects on succinate oxidation and on Complex II +III activity, but partially protects Complex II (SDH) from ischemia/reperfusion-induced damage. In summary, our study shows that caffeic acid phenethyl ester protects kidney mitochondrial oxidative phosphorylation and decreases ROS generation at Complex II in an in vivo ischemia/reperfusion model, and shows potential as a therapeutic agent for the development of pharmaceutical preparations against oxidative stress-related diseases.
... All the water molecules except coordinated water were removed and charges were assigned to the molecule file. The remaining genetic algorithm (GA) parameters were set as default values, except the genetic algorithm adjusted to run at 100 [26]. ...
Purpose
Hypoxic microenvironment plays a vital role in myocardial ischemia injury, generally leading to the resistance of chemotherapeutic drugs. This induces an intriguing study on mechanism exploration and prodrug design to overcome the hypoxia-induced drug resistance.
Methods
In this study, we hypothesized that the overexpression of carbonic anhydrase 9 (CAIX) in myocardial cells is closely related to the drug resistance. Herein, bioinformatics analysis, gene knockdown, and overexpression assay certificated the correlation between CAIX overexpression and hypoxia. An original aspirin-containing CAIX inhibitor AcAs has been developed.
Results
Based on the downregulation of CAIX level, both in vitro and in vivo, AcAs can overcome the acquired resistance and more effectively attenuate myocardial ischemia and hypoxia injury than that of aspirin. CAIX inhibitor is believed to recover the extracellular pH value so as to ensure the stable effect of aspirin.
Conclusion
Results indicate great potential of CAIX inhibitor for further application in myocardial hypoxia injury therapy.
... Mitochondria-targeted tanshinone IIA, a new CII inhibitor, was developed and showed to be protective in I/R oxidative injury [97]. A similar effect was shown for the ferulic acid derivative hmy-paa (3-(4-hydroxy-3-methoxyphenyl)-N-(1H-pyrazol-3yl)acrylamide) [98]. This is because during the ischemic phase of I/R accumulated succinate is quickly oxidized upon oxygen availability, resulting in massive RET and ROS generation at CI. CII inhibitors, such as malonate, that prevent electron transfer through CII to the ubiquonine pool, therefore, prevent RET and ROS production, are protective during I/R or cold ischemia [99,100]. ...
Increasing evidence points to the respiratory Complex II (CII) as a source and modulator of reactive oxygen species (ROS). Both functional loss of CII as well as its pharmacological inhibition can lead to ROS generation in cells, with a relevant impact on the development of pathophysiological conditions, i.e. cancer and neurodegenerative diseases. While the basic framework of CII involvement in ROS production has been defined, the fine details still await clarification. It is important to resolve these aspects to fully understand the role of CII in pathology and to explore its therapeutic potential in cancer and other diseases.
... The gallic and vanillic acids were undetected in IBO and SO. Ferulic acid, with its promising antioxidant and cardiovascular protective effects at the cellular level, has been widely applied in pharmacology (Wang et al., 2019). Its effectiveness against UV radiation was also reported so that it can be added into sunscreens to improve the sun protection factor and prevent inflammatory reactions. ...
The effects of different ethanol (50%, 80% and 100%) and methanol (50%, 80% and 100%) aqueous solutions on extraction efficiency of flavonoids from sweet orange (SO) peels, ripe bitter orange (RBO) and immature bitter orange (IBO) were investigated. The highest amount of naringin was found in SO peels, compared to RBO and IBO. UHPLC‐HRMS/MS results confirmed the presence of p‐coumaric acid and quinic acid in all the three types of oranges while there were 90.91% and 20% possibilities for detecting caffeic acid in RBO and SO, respectively. The probabilities of detecting naringenin from IBO, RBO and SO were 100%, 63.64% and 40%, respectively. The highest neohesperidin and naringin amounts were obtained in RBO. Using 80% methanol was recommended for extracting flavonoids from SO to obtain the highest Soxhlet and precipitation yields whereas 100% ethanol was the most suitable solvent to extract flavonoids from RBO and IBO.
... In ischemic tissues of I/R injury, the accumulation of leukocytes will cause the final injury of organs when encountered hemorrhagic shock, and finally leads to organ failure [3]. Owing to a misty target and poor permeability of cytomembrane, the clinical efficacy of existing drugs in reducing I/R injury is limited [4]. Therefore, it is urgent to explore an therapeutic targets to improve the prognosis of the disease. ...
Objectives: Long non-coding RNAs (lncRNAs) serve pivotal roles in heart disease, while the role of lncRNA hypoxia inducible factor 1α-antisense RNA 1 (HIF1A-AS1) is rarely mentioned. Therefore, the objective of this study was to investigate the mechanism of lncRNA HIF1A-AS1 regulating suppressor of cytokine signaling 2 (SOCS2) expression by adsorption of microRNA-204 (miR-204) on ventricular remodeling after myocardial ischemia-reperfusion (I/R) injury in mice.
Methods: The mouse model of I/R was established by left coronary artery occlusion. The expression of HIF1A-AS1, miR-204 and SOCS2 was determined. The mice were injected with HIF1A-AS1-siRNA, miR-204 mimics or their controls to investigate their effects on cardiac function and ventricular remodeling of mice after I/R injury. The binding relationship between HIF1A-AS1 and miR-204 as well as between miR-204 and SOCS2 were verified.
Results: HIF1A-AS1 and SOCS2 were upregulated and miR-204 was downregulated in myocardial tissues in mice after I/R injury. LVEDD, LVEDS, LVEDP, LVMI and RVMI expression reduced while LVEF, LVFS, +dp/dt max and -dp/dt max increased through knockdown HIF1A-AS1 and upregulated miR-204. The expression of BNP, cTnI, LDH, CK, TNF-α, IL-1β, IL-6 and β-MHC reduced, and the expression of α-MHC increased when HIF1A-AS1 was poorly expressed and miR-204 was highly expressed. Silencing HIF1A-AS1 and upregulating miR-204 inhibited apoptosis of cells. LncRNA HIF1A-AS1 could act as ceRNA to adsorb miR-204 to suppress miR-204 expression and elevate SOCS2 expression.
Conclusion: Our study provides evidence that downregulation of HIF1A-AS1 and upregulation of miR-204 could alleviate ventricular remodeling and improve cardiac function in mice after myocardial I/R injury via regulating SOCS2.
Coffee is not only a delicious beverage but also an important dietary source of natural antioxidants. We live in a world where it is impossible to avoid pollution, stress, food additives, radiation, and other sources of oxidants that eventually lead to severe health disorders. Fortunately, there are chemicals in our diet that counteract the hazards posed by the reactive species that trigger oxidative stress. They are usually referred to as antioxidants; some of them can be versatile compounds that exert such a role in many ways. This review summarizes, from a chemical point of view, the antioxidant effects of relevant molecules found in coffee. Their mechanisms of action, trends in activity, and the influence of media and pH in aqueous solutions, are analyzed. Structure-activity relationships are discussed, and the protective roles of these compounds are examined. A particular section is devoted to derivatives of some coffee components, and another one to their bioactivity. The data used in the analysis come from theoretical and computational protocols, which have been proven to be very useful in this context. Hopefully, the information provided here will pro-mote further investigations into the amazing chemistry contained in our morning coffee cup. Resumen. El café no solo es una bebida deliciosa, sino también una importante fuente dietética de antioxidantes naturales. Vivimos en un mundo donde es imposible evitar la contaminación, el estrés, los aditivos alimentarios, la radiación y otras fuentes de oxidantes que eventualmente conducen a trastornos de salud graves. Afortunadamente, existen sustancias químicas en nuestra dieta que contrarrestan los peligros planteados por las especies reactivas que desencadenan el estrés oxidativo. Por lo general, se les denomina antioxidantes; algunos de ellos pueden ser compuestos versátiles que ejercen dicho papel de muchas maneras. Este artículo de revisión resume, desde un punto de vista químico, los efectos antioxidantes de moléculas relevantes encontradas en el café. Se analizan sus mecanismos de acción, tendencias en la actividad y la influencia del medio y el pH en soluciones acuosas. Se discuten las relaciones estructura-actividad, y se examinan los roles protectores de estos compuestos. Se dedica una sección particular a los derivados de algunos componentes del café, y otra a su bioactividad. Los datos utilizados en el análisis provienen de protocolos teóricos y computacionales, que han demostrado ser muy útiles en este contexto. Se espera que la información proporcionada aquí promueva investigaciones futuras sobre la química contenida en nuestra taza de café matutina.
Coffee is not only a delicious beverage but also an important dietary source of natural antioxidants. We live in an oxidative world where it is impossible to avoid pollution, stress, food additives, radiation, and other sources of oxidants that eventually lead to severe health disorders. Fortunately, there are chemicals in our diet that counteract the hazards posed by the reactive species that trigger oxidative stress. They are usually referred to as antioxidants; some of them can be versatile compounds that exert such a role in various ways. This review summarizes, from a chemical point of view, the antioxidant effects of relevant molecules found in coffee. Their ways of action and trends in activity are analyzed, considering the data gathered so far from both theory and experiments. The influence of the media and pH in aqueous solution, and structure-activity relationships are discussed. The protective role of the explored compounds is examined. A particular section is devoted to derivatives of some coffee components, and another one to their bioactivity. The data used in the analysis come from theoretical anc computational protocols, which have been proven to be very usefull in this context. Hopefully, the information provided here will promote further investigations into the amazing chemistry contained in our morning cup.
Coffee is not only a delicious beverage but also an important dietary source of natural antioxidants. We live in an oxidative world where it is impossible to avoid pollution, stress, food additives, radiation, and other sources of oxidants that eventually lead to severe health disorders. Fortunately, there are chemicals in our diet that counteract the hazards posed by the reactive species that trigger oxidative stress. They are usually referred to as antioxidants; some of them can be versatile compounds that exert such a role in various ways. This review summarizes, from a chemical point of view, the antioxidant effects of relevant molecules found in coffee. Their ways of action and trends in activity are analyzed, considering the data gathered so far from both theory and experiments. The influence of the media and pH in aqueous solution, and structure-activity relationships are discussed. The protective role of the explored compounds is examined. A particular section is devoted to derivatives of some coffee components, and another one to their bioactivity. Hopefully, the information provided here will promote further investigations into the amazing chemistry contained in our morning cup.
Cardiovascular diseases are one of the leading causes of mortality in developed countries. Among cardiovascular disorders, myocardial infarction remains a life-threatening problem predisposing to the development and progression of ischemic heart failure. Ischemia/reperfusion (I/R) injury is a critical cause of myocardial injury. In recent decades, many efforts have been made to find the molecular and cellular mechanisms underlying the development of myocardial I/R injury and post-ischemic remodeling. Some of these mechanisms are mitochondrial dysfunction, metabolic alterations, inflammation, high production of ROS, and autophagy deregulation. Despite continuous efforts, myocardial I/R injury remains a major challenge in medical treatments of thrombolytic therapy, heart disease, primary percutaneous coronary intervention, and coronary arterial bypass grafting. The development of effective therapeutic strategies to reduce or prevent myocardial I/R injury is of great clinical significance.
Cardiac inflammation is easily accompanied by hypoxia, while hypoxia-induced injury and microenvironmental variations limit the efficacy of common anti-inflammatory drugs. In order to effectively attenuate myocardial injury caused by hypoxic and inflammatory injury, we designed and synthesized a kind of anti-inflammatory compounds by coupling cyclooxygenase (COX) and carbonic anhydrase (CA) inhibitors, and evaluated the activity and their mechanism in vitro and in vivo. It was found that these compounds were structurally stable and had two enzymatic inhibition activities. By inhibiting the activity of overexpressed CA under hypoxia, the acidic microenvironment can be regulated to inhibit the hypoxic injury, in which the pH-dependent primary drug resistance can be overcome to improve the anti-inflammatory effect of the COX inhibitor. Consequently, this study provides a new strategy for the treatment of cardiac inflammation accompanied by hypoxia.
Background:
Sodium ferulate (SF), a derivative of ferulic acid, is one of the active constituents in medicinal plants thought to be useful in fighting cardiovascular diseases. However, there still lacks a systematic review of the efficacy and safety of SF in treating coronary heart disease (CHD). It is therefore the purpose of this study to comprehensively review all clinical randomized controlled trials (RCTs) of SF in CHD to assess its efficacy and safety.
Methods:
All analysis is based on 8 databases as of February 2023, which includes 35 outcomes of RCTs that investigate the effect of SF combination therapy in CHD. The present study evaluates the quality and bias of selected literature by the Jadad scale and Cochrane Collaboration's tools, and also the quality of evidence by GRADE Profiler. Furthermore, it applies sensitivity analysis to assess the high heterogeneity impact of outcomes and conducted subgroup analysis to estimate the influence factors in these studies. The study protocol was set documented, and published beforehand in PROSPERO (Registration No.CRD42022348841).
Results:
The meta-analysis of 36 studies (with 3207 patients) shows that SF combined with conventional drugs has improved clinical effectiveness for patients with CHD [RR: 1.21 (95% CI 1.17,1.26); p < 0.00001]. Statistically significant results of meta-analyses are also seen in electrocardiography (ECG) efficacy, frequency of angina attacks, endothelium-dependent flow-mediated vasodilation (FMD), nitric oxide (NO), endothelin (ET), whole Blood low shear rate (LS), platelet aggregation test (PAgT), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL6), triglyceride (TG). Adverse events are reported in 6 RCTs. By GRADE approaches, 2 outcomes (clinical efficacy, CRP) indicate a moderate quality of evidence, 17 outcomes indicate low quality of evidence, with the other 16 very low-quality.
Conclusion:
SF combination therapy has a better curative effect than conventional therapy. However, due to items with low-quality evidence demonstrated in the study, the presence of clinical heterogeneity, and imprecision in partial outcome measures, all these led to limitations in the evidence of this study. Thus, the conclusion needs to be further verified by more in-depth research.
Cardiac inflammation is generally accompanied by hypoxia, while myocardial injury and an abnormal microenvironment caused by hypoxia tend to suppress the efficacy of common anti-inflammatory drugs. To improve the anti-inflammatory effect under hypoxia, a hypoxia-activated prodrug HAP1 consisting of a cyclooxygenase-2 (COX-2) inhibitor Ind and a carbonic anhydrase (CA) inhibitor Ace was synthesized. HAP1 was found to be activated by nitroreductase (NTR) under hypoxia to release two pharmacophores and achieve the combinatory medication intensively at the hypoxic site, better than Ind or Ace alone. When NTR activity was inhibited by Na2WO4 under hypoxia, no pharmacophores were found to release from HAP1 without exhibiting its activity. However, the efficacy of the Ind and Ace combination group (I&A) was not affected. Furthermore, HAP1 showed advantages over I&A in vivo not only in improving bioavailability but also in reducing side effects. The HAP approach turns out to inhibit cardiac inflammation efficiently and safely under hypoxia.
Patients with ischemic heart disease receiving reperfusion therapy still need to face left ventricular remodeling and heart failure after myocardial infarction. Reperfusion itself paradoxically leads to further cardiomyocyte death and systolic dysfunction. Ischemia/reperfusion (I/R) injury can eliminate the benefits of reperfusion therapy in patients and causes secondary myocardial injury. Mitochondrial dysfunction and structural disorder are the basic driving force of I/R injury. We summarized the basic relationship and potential mechanisms of mitochondrial injury in the development of I/R injury. Subsequently, this review summarized the natural products (NPs) that have been proven to targeting mitochondrial therapeutic effects during I/R injury in recent years and related cellular signal transduction pathways. We found that these NPs mainly protected the structural integrity of mitochondria and improve dysfunction, such as reducing mitochondrial division and fusion abnormalities, improving mitochondrial Ca²⁺ overload and inhibiting reactive oxygen species overproduction, thereby playing a role in protecting cardiomyocytes during I/R injury. This data would deepen the understanding of I/R-induced mitochondrial pathological process and suggested that NPs are expected to be transformed into potential therapies targeting mitochondria.
Mitochondrial dysfunction is the common pathological basis of myocardial ischemia/reperfusion (I/R) injury, which induces an intriguing study on mitochondrial-targeting compounds to treat mitochondrial dysfunction related diseases. Herein, a novel mitochondrial targeting compound Tan-TPP was synthesized based on tanshinone IIA (Tan), an active constituent of Chinese medicine salvia miltiorrhiza. We employed TMT labeled quantitative mass spectrometry, bioinformatics analysis, gene knockdown and overexpression assays to explore the regulation mechanism of Tan-TPP on attenuating myocardial I/R injury. Intriguingly, Tan-TPP could accumulate in mitochondria and significantly attenuate myocardial H/R injury at cellular level and I/R injury in vivo. It can regulate the expression of mitochondrial protein GUF1, thereby reducing SDHA expression level to attenuate oxidative injury. Consequently, this study expands our understanding on the mechanism of mitochondrial-targeting molecules to attenuate myocardial I/R injury, and it also provides a new strategy to improve the efficacy of Chinese medicine.
Ferulic acid, a kind of phenolic substance widely existing in plants, is an important active component of many traditional Chinese medicines. So far, it has been proved that ferulic acid has a variety of biological activities, especially in oxidative stress, inflammation, vascular endothelial injury, fibrosis, apoptosis and platelet aggregation. Many studies have shown that ferulic acid can inhibit PI3K/AKT pathway, the production of ROS and the activity of aldose reductase. The anti-inflammatory effect of ferulic acid is mainly related to the levels of PPAR γ, CAM and NF-κ B and p38 MAPK signaling pathways. Ferulic acid not only protects vascular endothelium by ERK1/2 and NO/ET-1 signal, but also plays an anti-fibrosis role by TGF-β/Smad and MMPs/TIMPs system. Moreover, ferulic acid has ant-apoptotic and anti-platelet effects. In addition to the pharmacological effects of ferulic acid, its pharmacokinetics and derivatives were also discussed in this paper. This review provides the latest summary of the latest research on ferulic acid.
The ongoing COVID-19 pandemic has been unprecedented on many levels, not least of which are the challenges in understanding the pathophysiology of these new critically ill patients. One widely-reported phenomenon is that of a profoundly hypoxemic patient with minimal to no dyspnea out of proportion to the extent of radiographic abnormalities and changes in lung compliance. This apparently unique presentation, sometimes called "happy hypoxemia or hypoxia" but better described as "silent hypoxemia", has led to the speculation of underlying pathophysiologic differences between COVID-19 lung injury and ARDS from other causes. We explore three proposed distinctive features of COVID-19 that likely bear on the genesis of silent hypoxemia, including differences in lung compliance, pulmonary vascular responses to hypoxia, and nervous system sensing and response to hypoxemia. In the context of known principles of respiratory physiology and neurobiology, we discuss whether these particular findings are due to direct viral effects or, equally plausible, are within the spectrum of typical ARDS pathophysiology and the wide range of hypoxic ventilatory and pulmonary vascular responses, and dyspnea perception in healthy people. Comparisons between lung injury patterns in COVID-19 and other causes of ARDS are clouded by the extent and severity of this pandemic, which may underlie the description of "new" phenotypes while limiting our ability to confirm these phenotypes by more invasive and longitudinal studies. However, given the uncertainty about anything unique in the pathophysiology of COVID-19 lung injury, there are no compelling pathophysiologic reasons at present to support a different therapeutic approach for these patients to the proven standards of care in ARDS.
Purpose Hypoxic microenvironment plays a vital role in myocardial ischemia injury, generally leading to the resistance of chemotherapeutic drugs. This induces an intriguing study on mechanism exploration and prodrug design to overcome the hypoxia induced drug resistance.
Methods In this study, we hypothesized that the overexpression of carbonic anhydrase 9 (CAIX) in myocardial cells is closely related to the drug resistance. Herein, bioinformatics analysis, gene knockdown and overexpression assay certificated the correlation between CAIX overexpression and hypoxia. An original aspirin-containing CAIX inhibitor AcAs has been developed.
Results Based on the downregulation of CAIX level, both in vitro and in vivo, AcAs can overcome the acquired resistance, and more effectively attenuate myocardial ischemia and hypoxia injury than that of aspirin. CAIX inhibitor is believed to recover the extracellular pH value so as to ensure the stable effect of aspirin.
Conclusion Results indicate great potential of CAIX inhibitor for further application in myocardial hypoxia injury therapy.
Succinate accumulates during ischemia, and its oxidation at reperfusion drives injury. The mechanism of ischemic succinate accumulation is controversial and is proposed to involve reversal of mitochondrial complex II. Herein, using stable-isotope-resolved metabolomics, we demonstrate that complex II reversal is possible in hypoxic mitochondria but is not the primary succinate source in hypoxic cardiomyocytes or ischemic hearts. Rather, in these intact systems succinate primarily originates from canonical Krebs cycle activity, partly supported by aminotransferase anaplerosis and glycolysis from glycogen. Augmentation of canonical Krebs cycle activity with dimethyl-α-ketoglutarate both increases ischemic succinate accumulation and drives substrate-level phosphorylation by succinyl-CoA synthetase, improving ischemic energetics. Although two-thirds of ischemic succinate accumulation is extracellular, the remaining one-third is metabolized during early reperfusion, wherein acute complex II inhibition is protective. These results highlight a bifunctional role for succinate: its complex-II-independent accumulation being beneficial in ischemia and its complex-II-dependent oxidation being detrimental at reperfusion.
Mitochondria are key regulators of cell fate during disease. They control cell survival via the production of ATP that fuels cellular processes and, conversely, cell death via the induction of apoptosis through release of pro-apoptotic factors such as cytochrome C. Therefore, it is essential to have stringent quality control mechanisms to ensure a healthy mitochondrial network. Quality control mechanisms are largely regulated by mitochondrial dynamics and mitophagy. The processes of mitochondrial fission (division) and fusion allow for damaged mitochondria to be segregated and facilitate the equilibration of mitochondrial components such as DNA, proteins, and metabolites. The process of mitophagy are responsible for the degradation and recycling of damaged mitochondria. These mitochondrial quality control mechanisms have been well studied in chronic and acute pathologies such as Parkinson’s disease, Alzheimer’s disease, stroke, and acute myocardial infarction, but less is known about how these two processes interact and contribute to specific pathophysiologic states. To date, evidence for the role of mitochondrial quality control in acute and chronic disease is divergent and suggests that mitochondrial quality control processes can serve both survival and death functions depending on the disease state. This review aims to provide a synopsis of the molecular mechanisms involved in mitochondrial quality control, to summarize our current understanding of the complex role that mitochondrial quality control plays in the progression of acute vs chronic diseases and, finally, to speculate on the possibility that targeted manipulation of mitochondrial quality control mechanisms may be exploited for the rationale design of novel therapeutic interventions.
Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here, we demonstrate that upon lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to drive mitochondrial reactive oxygen species (ROS) production. RNA sequencing reveals that this combination induces a pro-inflammatory gene expression profile, while an inhibitor of succinate oxidation, dimethyl malonate (DMM), promotes an anti-inflammatory outcome. Blocking ROS production with rotenone by uncoupling mitochondria or by expressing the alternative oxidase (AOX) inhibits this inflammatory phenotype, with AOX protecting mice from LPS lethality. The metabolic alterations that occur upon activation of macrophages therefore repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state.
Melatonin is uncommonly effective in reducing oxidative stress under a remarkably large number of circumstances. It achieves this action via a variety of means: direct detoxification of reactive oxygen and reactive nitrogen species and indirectly by stimulating antioxidant enzymes while suppressing the activity of pro-oxidant enzymes. In addition to these well-described actions, melatonin also reportedly chelates transition metals which are involved in the Fenton/Haber-Weiss reactions; in doing so, melatonin reduces the formation of the devastatingly toxic hydroxyl radical resulting in the reduction of oxidative stress. Melatonin's ubiquitous but unequal intracellular distribution, including its high concentrations in mitochondria, likely aid in its capacity to resist oxidative stress and cellular apoptosis. There is credible evidence to suggest that melatonin should be classified as a mitochondria-targeted antioxidant. Melatonin's capacity to prevent oxidative damage and the associated physiological debilitation is well documented in numerous experimental ischemia/reperfusion (hypoxia/reoxygenation) studies especially in the brain (stroke) and in the heart (heart attack). Melatonin, via its anti-radical mechanisms, also reduces the toxicity of noxious prescription drugs and of methamphetamine, a drug of abuse. Experimental findings also indicate that melatonin renders treatment-resistant cancers sensitive to various therapeutic agents and may be useful, due to its multiple antioxidant actions, in especially delaying and perhaps treating a variety of age-related diseases and dehumanizing conditions. Melatonin has been effectively used to combat oxidative stress, inflammation and cellular apoptosis and to restore tissue function in a number of human trials; its efficacy supports its more extensive use in a wider variety of human studies. The uncommonly high safety profile of melatonin also bolsters this conclusion. It is the current feeling of the authors that, in view of the widely-diverse beneficial functions that have been reported for melatonin, these may be merely epiphenomena of the more fundamental, yet-to-be identified basic action(s) of this ancient molecule. This article is protected by copyright. All rights reserved.
Ischemia-reperfusion (IR) injury occurs when blood supply to an organ is disrupted-ischemia-and then restored-reperfusion-leading to a burst of reactive oxygen species (ROS) from mitochondria. It has been tacitly assumed that ROS production during IR is a non-specific consequence of oxygen interacting with dysfunctional mitochondria upon reperfusion. Recently, this view has changed, suggesting that ROS production during IR occurs by a defined mechanism. Here we survey the metabolic factors underlying IR injury and propose a unifying mechanism for its causes that makes sense of the huge amount of disparate data in this area and provides testable hypotheses and new directions for therapies.
The TET enzymes are members of the 2-oxoglutarate-dependent dioxygenase family and comprise three isoenzymes in humans: TETs
1-3. These TETs convert 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) in DNA, and high 5-hmC levels are associated with
active transcription. The importance of the balance in these modified cytosines is emphasized by the fact that TET2 is mutated
in several human cancers, including myeloid malignancies such as acute myeloid leukemia (AML). We characterize here the kinetic
and inhibitory properties of Tets and show that the Km value of Tets 1 and 2 for O2 is 30 μM, indicating that they retain high activity even under hypoxic conditions. The AML-associated mutations in the Fe2+ and 2-oxoglutarate-binding residues increased the Km values for these factors 30-80 fold and reduced the Vmax values. Fumarate and succinate, which can accumulate to millimolar levels in succinate dehydrogenase and fumarate hydratase-mutant
tumors, were identified as potent Tet inhibitors in vitro, with IC50 values ~400-500 μM. Fumarate and succinate also down-regulated global 5-hmC levels in neuroblastoma cells and the expression
levels of some hypoxia-inducible factor (HIF) target genes via TET inhibition, despite simultaneous HIFα stabilization.
The combination of fumarate or succinate treatment with TET1 or TET3 silencing caused differential effects on the expression
of specific HIF target genes. Altogether these data show that hypoxia-inducible genes are regulated in a multilayered manner
that includes epigenetic regulation via TETs and 5-hmC levels in addition to HIF stabilization.
Ischaemia-reperfusion (IR) injury occurs when blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death, and aberrant immune responses through generation of mitochondrial reactive oxygen species (ROS)1-5. Although mitochondrial ROS production in IR is established, it has generally been considered a non-specific response to reperfusion1,3. Here, we developed a comparative in vivo metabolomic analysis and unexpectedly identified widely conserved metabolic pathways responsible for mitochondrial ROS production during IR. We showed that selective accumulation of the citric acid cycle (CAC) intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase (SDH), which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. Upon reperfusion, the accumulated succinate is rapidly re-oxidised by SDH, driving extensive ROS generation by reverse electron transport (RET) at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo IR injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of IR injury. Furthermore, these findings reveal a novel pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation upon subsequent reperfusion is a potential therapeutic target to decrease IR injury in a range of pathologies.
Acute myocardial infarction (MI) is a major cause of mortality and disability worldwide. In patients with MI, the treatment option for reducing acute myocardial ischemic injury and limiting MI size is timely and effective myocardial reperfusion using either thombolytic therapy or primary percutaneous coronary intervention (PCI). However, the procedure of reperfusion itself induces cardiomyocyte death, known as myocardial reperfusion injury, for which there is still no effective therapy. Recent evidence has depicted a promising role of melatonin, which possesses powerful anti-oxidative and anti-inflammatory properties, in the prevention of ischemia-reperfusion (IR) injury and the protection against cardiomyocyte death. A number of reports explored the mechanism of action behind melatonin-induced beneficial effects against myocardial IR injury. In this review, we summarize the research progress related to IR injury and discuss the unique actions of melatonin as a protective agent. Furthermore, the possible mechanisms responsible for the myocardial benefits of melatonin against reperfusion injury are listed with the prospect of the use of melatonin in clinical application.
Limb remote ischemic preconditioning (RIPC) is an effective means of protection against ischemia/reperfusion (IR)- induced injury to multiple organs. Many studies are focused on identifying endocrine mechanisms that underlie the cross-talk between muscle and RIPC-mediated organ protection. We report that RIPC releases irisin, a myokine derived from the extracellular portion of fibronectin domain-containing 5 protein (FNDC5) in skeletal muscle, to protect against injury to the lung. Human patients with neonatal respiratory distress syndrome show reduced concentrations of irisin in the serum and increased irisin concentrations in the bronchoalveolar lavage fluid, suggesting transfer of irisin from circulation to the lung under physiologic stress. In mice, application of brief periods of ischemia preconditioning stimulates release of irisin into circulation and transfer of irisin to the lung subjected to IR injury. Irisin, via lipid raft-mediated endocytosis, enters alveolar cells and targets mitochondria. Interaction between irisin and mitochondrial uncoupling protein 2 (UCP2) allows for prevention of IR-induced oxidative stress and preservation of mitochondrial function. Animal model studies show that intravenous administration of exogenous irisin protects against IR-induced injury to the lung via improvement of mitochondrial function, whereas in UCP2-deficient mice or in the presence of a UCP2 inhibitor, the protective effect of irisin is compromised. These results demonstrate that irisin is a myokine that facilitates RIPC-mediated lung protection. Targeting the action of irisin inmitochondria presents a potential therapeutic intervention for pulmonary IR injury.
The identification of novel succinate dehydrogenase (SDH) inhibitors represents one of the most attractive directions in the field of fungicide research and development. During our continuous efforts to pursue inhibitors belonging to this class, some structurally novel pyrazole-furan carboxamide and pyrazole-pyrrole carboxamide derivatives have been discovered via introducing scaffold hopping and bioisosterism to compound 1, a remarkably potent lead obtained by pharmacophore-based virtual screening. As a result of the evaluation against three destructive fungi, including Sclerotinia sclerotiorum, Rhizoctonia solani and Pyricularia grisea, a majority of them displayed potent fungicidal activities. In particular, compound 12I-i, 12III-f and 12III-o exhibited excellent fungicidal activity against S. sclerotiorum and R. solani comparable to that of commercial SDHI thifluzamide and 1.
A novel series of pyrazole carboxamide derivatives had been designed, synthesized and some of them exhibited good nematocidal activity.
Hypercholesterolaemia is considered to be a principle risk factor for cardiovascular disease, having direct negative effects on the myocardium itself, in addition to the development of atherosclerosis. Since hypercholesterolaemia affects the global cardiac gene expression profile, among many other factors, it results in increased myocardial oxidative stress, mitochondrial dysfunction and inflammation triggered apoptosis, all of which may account for myocardial dysfunction and increased susceptibility of the myocardium to infarction. In addition, numerous experimental and clinical studies have revealed that hyperlcholesterolaemia may interfere with the cardioprotective potential of conditioning mechanisms. Although not fully elucidated, the underlying mechanisms for the lost cardioprotection in hypercholesterolaemic animals have been reported to involve dysregulation of the endothelial NOS-cGMP, reperfusion injury salvage kinase, peroxynitrite-MMP2 signalling pathways, modulation of ATP-sensitive potassium channels and apoptotic pathways. In this review article, we summarize the current knowledge on the effect of hypercholesterolaemia on the non-ischaemic and ischaemic heart as well as on the cardioprotection induced by drugs or ischaemic preconditioning, postconditioning and remote conditioning. Future perspectives concerning the mechanisms and the design of preclinical and clinical trials are highlighted.
Linked articles:
This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.
Mitochondria are the powerhouses of the cell and are involved in essential functions of the cell, including ATP production, intracellular Ca2 + regulation, reactive oxygen species production & scavenging, regulation of apoptotic cell death and activation of the caspase family of proteases. Mitochondrial dysfunction and oxidative stress are largely involved in aging, cancer, age-related neurodegenerative and metabolic syndrome. In the last decade, tremendous progress has been made in understanding mitochondrial structure, function and their physiology in metabolic syndromes such as diabetes, obesity, stroke and hypertension, and heart disease. Further, progress has also been made in developing therapeutic strategies, including lifestyle interventions (healthy diet and regular exercise), pharmacological strategies and mitochondria-targeted approaches. These strategies were mainly focused to reduce mitochondrial dysfunction and oxidative stress and to maintain mitochondrial quality in metabolic syndromes. The purpose of our article is to highlight the recent progress on the mitochondrial role in metabolic syndromes and also summarize the progress of mitochondria-targeted molecules as therapeutic targets to treat metabolic syndromes. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy.
Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are powerful signaling molecules that play a variety of roles in mammalian biology. Collectively called gasotransmitters, these gases have wide-ranging therapeutic potential, but their clinical use is limited by their gaseous nature, extensive reactivity, short half-life, and systemic toxicity. Strategies for gasotransmitter delivery with control over the duration and location of release are therefore vital for developing effective therapies. An attractive strategy for gasotransmitter delivery is though injectable or implantable gels, which can ideally deliver their payload over a controllable duration and then degrade into benign metabolites. Self-assembling peptide-based gels are well-suited to this purpose due to their tunable mechanical properties, easy chemical modification, and inherent biodegradability. In this review we illustrate the biological roles of NO, CO, and H2S, discuss their therapeutic potential, and highlight recent efforts toward their controlled delivery with a focus on peptide-based delivery systems.
Mitochondrial dysfunctions are recognized as major factors for various diseases including cancer, cardiovascular diseases, diabetes, neurological disorders, and a group of diseases so called “mitochondrial dysfunction related diseases”. One of the major hurdles to gain therapeutic efficiency in diseases where the targets are located in the mitochondria is the accessibility of the targets in this compartmentalized organelle that imposes barriers toward internalization of ions and molecules. Over the time, different tools and techniques were developed to improve therapeutic index for mitochondria acting drugs. Nanotechnology has unfolded as one of the logical and encouraging tools for delivery of therapeutics in controlled and targeted manner simultaneously reducing side effects from drug overdose. Tailor-made nanomedicine based therapeutics can be an excellent tool in the toolbox for diseases associated with mitochondrial dysfunctions. In this review, we present an extensive coverage of possible therapeutic targets in different compartments of mitochondria for cancer, cardiovascular, and mitochondrial dysfunction related diseases.
A novel and robust automated docking method that predicts the bound conformations of flexible ligands to macromolecular targets has been developed and tested, in combination with a new scoring function that estimates the free energy change upon binding. Interestingly, this method applies a Lamarckian model of genetics, in which environmental adaptations of an individual's phenotype are reverse transcribed into its genotype and become . heritable traits sic . We consider three search methods, Monte Carlo simulated annealing, a traditional genetic algorithm, and the Lamarckian genetic algorithm, and compare their performance in dockings of seven protein)ligand test systems having known three-dimensional structure. We show that both the traditional and Lamarckian genetic algorithms can handle ligands with more degrees of freedom than the simulated annealing method used in earlier versions of AUTODOCK, and that the Lamarckian genetic algorithm is the most efficient, reliable, and successful of the three. The empirical free energy function was calibrated using a set of 30 structurally known protein)ligand complexes with experimentally determined binding constants. Linear regression analysis of the observed binding constants in terms of a wide variety of structure-derived molecular properties was performed. The final model had a residual standard y1 y1 .
Melatonin is remarkably functionally-diverse with actions as a free radical scavenger and antioxidant, circadian rhythm regulator, anti-inflammatory and immuno-regulating molecule and as an oncostatic agent. We hypothesize that the initial and primary function of melatonin in photosynthetic cyanobacteria, which appeared on Earth 3.5-3.2 billion years ago, was as an antioxidant. The evolution of melatonin as an antioxidant by this organism was necessary since photosynthesis is associated with the generation of toxic free radicals. The other secondary functions of melatonin came about much later in evolution. We also surmise that mitochondria and chloroplasts may be primary sites of melatonin synthesis in all eukaryotic cells that possess these organelles. This prediction is made on the basis that mitochondria and chloroplasts of eukaryotes developed from purple non-sulfur bacteria (which also produce melatonin) and cyanobacteria when they were engulfed by early eukaryotes. Thus, we speculate that the melatonin-synthesizing actions of the engulfed bacteria were retained when these organelles became mitochondria and chloroplasts, respectively. That mitochondria are likely sites of melatonin formation is supported by the observation that this organelle contains high levels of melatonin that are not impacted by blood melatonin concentrations. Melatonin has a remarkable array of means by which it thwarts oxidative damage. It, as well as its metabolites, is differentially effective in scavenging a variety of reactive oxygen and reactive nitrogen species. Moreover, melatonin and its metabolites modulate a large number of antioxidative and pro-oxidative enzymes, leading to a reduction in oxidative damage. The actions of melatonin on radical metabolizing/producing enzymes may be mediated by the Keap1-Nrf2-ARE pathway. Beyond its direct free radical scavenging and indirect antioxidant effects, melatonin has a variety of physiological and metabolic advantages that may enhance its ability to limit oxidative stress. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Background
Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher levels.
Hypoxia-inducible factors (HIFs) are stabilized during adverse inflammatory processes associated with disorders such as inflammatory bowel disease, pathogen infection and acute lung injury, as well as during ischaemia-reperfusion injury. HIF stabilization and hypoxia-induced changes in gene expression have a profound impact on the inflamed tissue microenvironment and on disease outcomes. Although the mechanism that initiates HIF stabilization may vary, the final molecular steps that control HIF stabilization converge on a set of oxygen-sensing prolyl hydroxylases (PHDs) that mark HIFs for proteasomal degradation. PHDs are therefore promising therapeutic targets. In this Review, we discuss the emerging potential and associated challenges of targeting the PHD-HIF pathway for the treatment of inflammatory and ischaemic diseases.
Ferulic acid (FA) belongs to the family of phenolic acids and is very abundant in fruits and vegetables. Over the past years, several studies have shown that FA acts as a potent antioxidant by scavenging free radicals and enhancing the cell stress response through the up-regulation of cytoprotective systems, e.g. heme oxygenase-1, heat shock protein 70, extracellular signal-regulated kinase 1/2 and the proto-oncogene, Akt. Furthermore, FA was shown to inhibit the expression and/or activity of cytotoxic enzymes, including inducible nitric oxide synthase, caspases and cyclooxygenase-2. Based on this evidence, FA has been proposed as a potential treatment for many disorders including Alzheimer's disease, cancer, cardiovascular diseases, diabetes mellitus and skin disease. However, despite the great abundance of preclinical research, only a few studies were carried out in humans, the majority of which used foods containing FA, and therefore the clinical efficacy of this mode of administration needs to be further documented. New efforts and resources are needed in clinical research for the complete evaluation of FA therapeutic potential in chronic diseases.
Ferulic acid (FA) is an abundant dietary antioxidant which may offer beneficial effects against cancer, cardiovascular disease, diabetes and Alzheimer's disease. The impact of FA on health depends on its intake and pharmacokinetic properties. In this article, the literature pertaining to chemistry, natural sources, dietary intake and pharmacokinetic properties of FA is critically reviewed. High levels of FA are found in both free and bound forms in vegetables, fruits, cereals, and coffee. We have estimated that consumption of these foods may result in approximately 150-250mg/day of FA intake. FA can be absorbed along the entire gastrointestinal tract and metabolized mainly by the liver. The absorption and metabolism of FA seem to be dose dependent at least in experimental settings. Further pharmacokinetic and pharmacodynamic studies are required to characterize the impact of FA on human health.
Copyright © 2008. Published by Elsevier Ltd.