CA : A Cancer Journal for Clinicians

Ischemia and reperfusion-elicited tissue injury contributes to morbidity and mortality in a wide range of pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease and sleep apnea. Ischemia-reperfusion injury is also a major challenge during organ transplantation and cardiothoracic, vascular and general surgery. An imbalance in metabolic supply and demand within the ischemic organ results in profound tissue hypoxia and microvascular dysfunction. Subsequent reperfusion further enhances the activation of innate and adaptive immune responses and cell death programs. Recent advances in understanding the molecular and immunological consequences of ischemia and reperfusion may lead to innovative therapeutic strategies for treating patients with ischemia and reperfusion-associated tissue inflammation and organ dysfunction.

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Ischemia and reperfusion—from mechanism to translation

We describe a rapid, sensitive process for comprehensively identifying proteins in macromolecular complexes that uses multidimensional liquid chromatography (LC) and tandem mass spectrometry (MS/MS) to separate and fragment peptides. The SEQUEST algorithm, relying upon translated genomic sequences, infers amino acid sequences from the fragment ions. The method was applied to the Saccharomyces cerevisiae ribosome leading to the identification of a novel protein component of the yeast and human 40S subunit. By offering the ability to identify >100 proteins in a single run, this process enables components in even the largest macromolecular complexes to be analyzed comprehensively.

Direct analysis of protein complexes using mass spectrometry

Protein Kinase C: Structure, Function, and Regulation

https://pure.mpg.de/pubman/item/item_3230146_1/component/file_3230147/Chang%20et%20al..pdf

Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis

The aldehyde dehydrogenase (ALDH) enzyme family metabolizes and detoxifies both exogenous and endogenous aldehydes Since chemotherapeutic agents, such as cisplatin, generate cytotoxic aldehydes and oxidative stress, and chemoresistant cancer cells express high levels of ALDH enzymes, we hypothesized that different ALDH expression within cells may show different chemosensitivity ALDH2 has the lowest Km for acetaldehyde among ALDH isozymes and detoxifies acetaldehydes in addition to other reactive aldehydes, such as 4-hydroxy-nonenal, malondialdehyde and acrolein produced from lipid peroxidation by reactive oxygen species (ROS) Thus, cells with an ALDH2 variant may sensitize them to these ROS-inducing chemotherapy drugs Here, we used wild type C57BL/6 mice and ALDH2*2 knock-in mutant mice and compared the basal level of ROS in different tissues Then, we treated the mice with cisplatin, isolated cells from organs and fractionated them into lysates containing mitochondrial and cytosolic fractions, treated with cisplatin again in vitro, and compared the level of ROS generated We show that overall ROS production increases with cisplatin treatment in cells with ALDH2 mutation The treatment of cisplatin in the wild type mice did not change the level of ROS compared to PBS treated controls In contrast, ALDH2*2 knock-in mutant mice showed a significantly increased level of ROS compared to wild type mice in tongue, lung, kidney and brain tissues without any treatment ALDH2*2 mutant mice showed 20% of the ALDH2 activity in the kidney compared to wild type mice Treatment of ALDH2*2 mutant mice with cisplatin showed increased ROS levels in the mitochondrial fraction of kidney In the cytosolic fraction, treatment of mutant mice with cisplatin increased ROS levels in lung and brain compared to PBS treated controls Furthermore, ALDH2*2 mutant mice treated with cisplatin showed increased cytotoxicity in the kidney cells compared to PBS treated mutant controls These data indicate that deficiency in ALDH2 activity may contribute to increased cisplatin sensitivity and cytotoxicity by producing more ROS by the treatment Based on these data, the amount of cisplatin used in patients may need to be adjusted based on their ALDH2 variant profile

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Aldehyde dehydrogenase 2*2 knock-in mice show increased reactive oxygen species production in response to cisplatin treatment

Characterization of the binding and phosphorylation of cardiac calsequestrin by epsilon protein kinase C.

Aims We previously demonstrated that acute ethanol administration protects the heart from ischaemia/reperfusion (I/R) injury thorough activation of aldehyde dehydrogenase 2 (ALDH2). Here, we characterized the role of acetaldehyde, an intermediate product from ethanol metabolism, and its metabolizing enzyme, ALDH2, in an ex vivo model of cardiac I/R injury. Methods and results We used a combination of homozygous knock-in mice (ALDH2*2), carrying the human inactivating point mutation ALDH2 (E487K), and a direct activator of ALDH2, Alda-1, to investigate the cardiac effect of acetaldehyde. The ALDH2*2 mice have impaired acetaldehyde clearance, recapitulating the human phenotype. Yet, we found a similar infarct size in wild type (WT) and ALDH2*2 mice. Similar to ethanol-induced preconditioning, pre-treatment with 50 μM acetaldehyde increased ALDH2 activity and reduced cardiac injury in hearts of WT mice without affecting cardiac acetaldehyde levels. However, acetaldehyde pre-treatment of hearts of ALDH2*2 mice resulted in a three-fold increase in cardiac acetaldehyde levels and exacerbated I/R injury. Therefore, exogenous acetaldehyde appears to have a bimodal effect in I/R, depending on the ALDH2 genotype. Further supporting an ALDH2 role in cardiac preconditioning, pharmacological ALDH2 inhibition abolished ethanol-induced cardioprotection in hearts of WT mice, whereas a selective activator, Alda-1, protected ALDH2*2 against ethanol-induced cardiotoxicity. Finally, either genetic or pharmacological inhibition of ALDH2 mitigated ischaemic preconditioning. Conclusion Taken together, our findings suggest that low levels of acetaldehyde are cardioprotective whereas high levels are damaging in an ex vivo model of I/R injury and that ALDH2 is a major, but not the only, regulator of cardiac acetaldehyde levels and protection from I/R.

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Cardioprotection induced by a brief exposure to acetaldehyde: role of aldehyde dehydrogenase 2.

Aldehyde dehydrogenase 2 (ALDH2) is a non-cytochrome P450 mitochondrial aldehyde oxidizing enzyme. It is best known for its role in the metabolism of acetaldehyde, a common metabolite from alcohol drinking. More evidences have been accumulated in recent years to indicate a greater role of ALDH2 in the metabolism of other endogenous and exogenous aldehydes, especially lipid peroxidation-derived reactive aldehyde under oxidative stress. Many cardiovascular diseases are associated with oxidative stress and mitochondria dysfunction. Considering that an estimated 560 million East Asians carry a common ALDH2 deficient variant which causes the well-known alcohol flushing syndrome due to acetaldehyde accumulation, the importance of understanding the role of ALDH2 in these diseases should be highlighted. There are several unfavorable cardiovascular conditions that are associated with ALDH2 deficiency. This chapter reviews the function of ALDH2 in various pathological conditions of the heart in relation to aldehyde toxicity. It also highlights the importance and clinical implications of interaction between ALDH2 deficiency and alcohol drinking on cardiovascular disease among the East Asians.

ALDH2 and Cardiovascular Disease.

The present disclosure provides compounds that function as modulators of aldehyde dehydrogenase (ALDH) enzymatic activity, as well as compositions and formulations comprising the compounds. The present disclosure provides therapeutic methods involving administering a subject compound, or a subject pharmaceutical composition.

Che-Hong Chen

Papers

Aldehyde dehydrogenase 2*2 knock-in mice show increased reactive oxygen species production in response to cisplatin treatment

Characterization of the binding and phosphorylation of cardiac calsequestrin by epsilon protein kinase C.

Cardioprotection induced by a brief exposure to acetaldehyde: role of aldehyde dehydrogenase 2.

ALDH2 and Cardiovascular Disease.

Modulators of Aldehyde Dehydrogenase and Methods of Use Thereof