Progress and perspective on hydrogen sulfide donors and their biomedical applications.

Following the discovery of nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H2 S) has been identified as the third gasotransmitter in humans. Increasing evidence have shown that H2 S is of preventive or therapeutic effects on diverse pathological complications. As a consequence, it is of great significance to develop suitable approaches of H2 S-based therapeutics for biomedical applications. H2 S-releasing agents (H2 S donors) play important roles in exploring and understanding the physiological functions of H2 S. More importantly, accumulating studies have validated the theranostic potential of H2 S donors in extensive repertoires of in vitro and in vivo disease models. Thus, it is imperative to summarize and update the literatures in this field. In this review, first, the background of H2 S on its chemical and biological aspects is concisely introduced. Second, the studies regarding the H2 S-releasing compounds are categorized and described, and accordingly, their H2 S-donating mechanisms, biological applications, and therapeutic values are also comprehensively delineated and discussed. Necessary comparisons between related H2 S donors are presented, and the drawbacks of many typical H2 S donors are analyzed and revealed. Finally, several critical challenges encountered in the development of multifunctional H2 S donors are discussed, and the direction of their future development as well as their biomedical applications is proposed. We expect that this review will reach extensive audiences across multiple disciplines and promote the innovation of H2 S biomedicine.

Emodin ameliorates antioxidant capacity and exerts neuroprotective effect via PKM2-mediated Nrf2 transactivation.

Pyruvate kinase M2 (PKM2) is overexpressed in neuronal cells. However, there are few studies on the involvement of PKM2 modulators in neurodegenerative diseases. Emodin, a dominating anthraquinone derivative extracting from the rhizome of rhubarb, has received expanding consideration due to its pharmacological properties. Our data reveal that emodin could resist hydrogen peroxide- or 6-hydroxydopamine-mediated mitochondrial fission and apoptosis in PC12 cells (a neuron-like rat pheochromocytoma cell line). Notably, emodin at nontoxic concentrations significantly inhibits PKM2 activity and promotes dissociation of tetrameric PKM2 into dimers in cells. The PKM2 dimerization enhances the interaction of PKM2 and NFE2-related factor 2 (Nrf2), which further triggers the activation of the Nrf2/ARE pathway to upregulate a panel of cytoprotective genes. Modulating the PKM2/Nrf2/ARE axis by emodin unveils a novel mechanism for understanding the pharmacological functions of emodin. Our findings indicate that emodin is a potential candidate for the treatment of oxidative stress-related neurodegenerative disorders.

Natural Molecules Targeting Thioredoxin System and Their Therapeutic Potential.

Significance: Thioredoxin (Trx) and thioredoxin reductase are two core members of the Trx system. The system bridges the gap between the universal reducing equivalent NADPH and various biological molecules and plays an essential role in maintaining cellular redox homeostasis and regulating multiple cellular redox signaling pathways. Recent Advance: In recent years, the Trx system has been well documented as an important regulator of many diseases, especially tumorigenesis. Thus, the development of potential therapeutic molecules targeting the system is of great significance for disease treatment. Critical Issues: We herein first discuss the physiological functions of the Trx system and the role that the Trx system plays in various diseases. Then, we focus on the introduction of natural small molecules with potential therapeutic applications, especially the anticancer activity, and review their mechanisms of pharmacological actions via interfering with the Trx system. Finally, we further discuss several natural molecules that harbor therapeutic potential and have entered different clinical trials. Future Directions: Further studies on the functions of the Trx system in multiple diseases will not only improve our understanding of the pathogenesis of many human disorders but also help develop novel therapeutic strategies against these diseases. Antioxid. Redox Signal. 34, 1083-1107.

Nrf2: a dark horse in Alzheimer's disease treatment.

Alzheimer's disease (AD), an age-dependent neurodegenerative disorder, is the main cause of dementia. Common hallmarks of AD include the amyloid ß-peptide (Aß) aggregation, high levels of hyperphosphorylated tau protein (p-tau) and failure in redox homeostasis. To date, all proposed drugs affecting Aß and/or p-tau have been failed in clinical trials. A decline in the expression of the transcription factor Nrf2 (nuclear factor-erythroid 2-p45 derived factor 2) and its driven genes (NQO1, HO-1, and GCLC), and alteration of the Nrf2-related pathways have been observed in AD brains. Nrf2 plays a critical role in maintaining cellular redox homeostasis and regulating inflammation response. Nrf2 activation also provides cytoprotection against increasing pathologies including neurodegenerative diseases. These lines of evidence imply that Nrf2 activation may be a novel AD treatment option. Interestingly, recent studies have also demonstrated that Nrf2 interferes with several key pathogenic processes in AD including Aß and p-tau pathways. The current review aims to provide insights into the role of Nrf2 in AD. Also, we discuss the progress and challenges regarding the Nrf2 activators for AD treatment.

Antioxidant activity, acetylcholinesterase inhibitory potential and phytochemical analysis of Sarcocephalus latifolius Sm. bark used in traditional medicine in Sudan.

BACKGROUND: Sarcocephalus latifolius is used as a traditional medicine for curing many diseases in Sudan. The main objective of the current study was to determine the antioxidant activity and acetylcholinesterase inhibition (AChEI) of S. latifolius, and to estimate its total phenolic and flavonoid contents. METHODS: Antioxidant activity of the tested plant extracts was carried out by determining their ability to scavenge the 2,2-diphenyl-1-picryl hydrazyl (DPPH) free radical. On the other hand, AChE inhibitory activity was determined spectrophotometrically using the Ellman's colorimetric method. The levels of total phenols and flavonoids were determined quantitatively using spectrophotometric methods. MTT assay was consumed to assess the cytotoxic effect of the most active fractions. These fractions were subjected to phytochemical analysis using GC-MS techniques to determine thier chemical composition. RESULTS: Hexane and chloroform fractions exhibited the highest antioxidant activity with IC50 values of (0.098 ± 0.08 and 0.099 ± 0.029 mg/ml) respectively. Standard propyl gallate had the lowest IC50 value of 0.0414 ± 0.11 mg/ml. The ethanolic crude extract showed low AChEI activity with 40.2 ± 0.10%. High concentrations of phenolic and flavonoid contents were observed. GCMS revealed the presence of well-known antioxidants compounds e.g. Vitamin E and caffeic acid. CONCLUSION: The ethanolic extract of bark of S. latifolius showed potent antioxidant effects and low AChEI activity, high phenolic and flavonoid contents and presence of pharmacologically active compounds. These findings explain its wide usages in traditional medicine.