Linking energy sensing to suppression of JAK-STAT signalling: A potential route for repurposing AMPK activators?

Exaggerated Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling is key to the pathogenesis of pro-inflammatory disorders, such as rheumatoid arthritis and cardiovascular diseases. Mutational activation of JAKs is also responsible for several haematological malignancies, including myeloproliferative neoplasms and acute lymphoblastic leukaemia. Accumulating evidence links adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), an energy sensor and regulator of organismal and cellular metabolism, with the suppression of immune and inflammatory processes. Recent studies have shown that activation of AMPK can limit JAK-STAT-dependent signalling pathways via several mechanisms. These novel findings support AMPK activation as a strategy for management of an array of disorders characterised by hyper-activation of the JAK-STAT pathway. This review discusses the pivotal role of JAK-STAT signalling in a range of disorders and how both established clinically used and novel AMPK activators might be used to treat these conditions.

Regulation of the nitric oxide oxidase activity of myeloperoxidase by pharmacological agents.

The leukocyte-derived heme enzyme myeloperoxidase (MPO) is released extracellularly during inflammation and impairs nitric oxide (NO) bioavailability by directly oxidizing NO or producing NO-consuming substrate radicals. Here, structurally diverse pharmacological agents with activities as MPO substrates/inhibitors or antioxidants were screened for their effects on MPO NO oxidase activity in human plasma and physiological model systems containing endogenous MPO substrates/antioxidants (tyrosine, urate, ascorbate). Hydrazide-based irreversible/reversible MPO inhibitors (4-ABAH, isoniazid) or the sickle cell anaemia drug, hydroxyurea, all promoted MPO NO oxidase activity. This involved the capacity of NO to antagonize MPO inhibition by hydrazide-derived radicals and/or the ability of drug-derived radicals to stimulate MPO turnover thereby increasing NO consumption by MPO redox intermediates or NO-consuming radicals. In contrast, the mechanism-based irreversible MPO inhibitor 2-thioxanthine, potently inhibited MPO turnover and NO consumption. Although the phenolics acetaminophen and resveratrol initially increased MPO turnover and NO consumption, they limited the overall extent of NO loss by rapidly depleting H2O2 and promoting the formation of ascorbyl radicals, which inefficiently consume NO. The vitamin E analogue trolox inhibited MPO NO oxidase activity in ascorbate-depleted fluids by scavenging NO-consuming tyrosyl and urate radicals. Tempol and related nitroxides decreased NO consumption in ascorbate-replete fluids by scavenging MPO-derived ascorbyl radicals. Indoles or apocynin yielded marginal effects. Kinetic analyses rationalized differences in drug activities and identified criteria for the improved inhibition of MPO NO oxidase activity. This study reveals that widely used agents have important implications for MPO NO oxidase activity under physiological conditions, highlighting new pharmacological strategies for preserving NO bioavailability during inflammation.

Effect of bajijiasu isolated from Morinda officinalis F. C. how on sexual function in male mice and its antioxidant protection of human sperm.

ETHNOPHARMACOLOGICAL RELEVANCE: In recent years, the physiological aspects of human fertility have been seriously influenced by the interactions of genetic and environmental factors. Almost one in 20 males has been affected by male infertility, providing a great challenge and an opportunity to use natural compounds as alternatives to chemical drugs with comprehensive adverse effects. However, ample evidences are scanty to support the physiological mechanisms of natural compounds used to treat male infertility. In traditional Chinese medicine, Morinda officinalis F. C. How is widely used as a herb that invigorates the kidneys and supports yang, the original energy in the human body, to resist diseases and in treating male infertility. In this study, we evaluated whether bajijiasu isolated from the roots of M. officinalis F.C. How is a potential agent for the treatment of male infertility. MATERIALS AND METHOD: In this study, both normal and kidney-yang-deficient mice were administered bajijiasu orally at different concentrations. To determine the pharmacological mechanism of bajijiasu, we observed the sexual behavior and genital organ coefficients, determined their serum hormone levels, analyzed their sperm quality parameters, and examined histopathological sections from them. We also used enzymatic assays to determine the effects of bajijiasu on superoxide dismutase, glutathione peroxidase, and malondialdehyde. Confocal micro-Raman spectroscopy was used to investigate the changes in the DNA of H2O2-damaged human sperm after treatment with bajijiasu in vitro. RESULTS: Our results showed that bajijiasu enhanced the sexual behavior of both normal and kidney-yang-deficient mice. It also markedly increased the testosterone concentrations, reduced the levels of cortisol, improved the quality of the sperm, and counteracted the histopathological impairment induced by hydroxyurea in the kidney-yang-deficient mice. The enzymatic assay and Raman spectra showed that bajijiasu protects the DNA of sperm from damage by H2O2. CONCLUSION: Bajijiasu is a potential androgen-like drug that modulates hormone levels to some extent without producing reproductive-organ lesions, enhances the sexual function of male mice, and protects the DNA of human sperm from H2O2 damage. Thus, bajijiasu is an active ingredient of M. officinalis F.C. How that improves the human reproductive capacity.