The use of alkaline salt lands for crop production is hindered by a scarcity of knowledge and breeding efforts for plant alkaline tolerance. Through genome association analysis of sorghum, a naturally high-alkaline–tolerant crop, we detected a major locus, Alkaline Tolerance 1 ( AT1 ), specifically related to alkaline-salinity sensitivity. An at1 allele with a carboxyl-terminal truncation increased sensitivity, whereas knockout of AT1 increased tolerance to alkalinity in sorghum, millet, rice, and maize. AT1 encodes an atypical G protein γ subunit that affects the phosphorylation of aquaporins to modulate the distribution of hydrogen peroxide (H ₂ O ₂ ) _. These processes appear to protect plants against oxidative stress by alkali. Designing knockouts of AT1 homologs or selecting its natural nonfunctional alleles could improve crop productivity in sodic lands.

Inflammasomes are multi-protein complexes that trigger the activation of caspase-1 and the maturation of interleukin-1β (IL-1β), yet the regulation of these complexes remains poorly characterized. Here we show that nitric oxide (NO) inhibited the NLRP3-mediated ASC pyroptosome formation, caspase-1 activation and IL-1β secretion in myeloid cells from both mice and humans. Meanwhile, endogenous NO derived from iNOS (inducible form of NO synthase) also negatively regulated NLRP3 inflammasome activation. Depletion of iNOS resulted in increased accumulation of dysfunctional mitochondria in response to LPS and ATP, which was responsible for the increased IL-1β production and caspase-1 activation. iNOS deficiency or pharmacological inhibition of NO production enhanced NLRP3-dependent cytokine production in vivo, thus increasing mortality from LPS-induced sepsis in mice, which was prevented by NLRP3 deficiency. Our results thus identify NO as a critical negative regulator of the NLRP3 inflammasome via the stabilization of mitochondria. This study has important implications for the design of new strategies to control NLRP3-related diseases.

Apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/Ref-1, abbreviated as APE1) is a molecule with dual functions in DNA repair and redox regulation of transcription factors. Accumulated work has shown that the biological activities of APE1 are sensitive to oxidative stress; however, whether APE1 functions can be regulated by nitrosative stress remains unknown. In this investigation, we found that S-nitrosoglutathion (GSNO), a nitric oxide donor and also an S-nitrosating agent, effectively stimulated nuclear export of APE1 in a CRM1-independent manner. This nuclear-cytoplasmic translocation was dependent on S-nitrosation modification of APE1, as simultaneous mutation of S-nitrosation target sites Cys93 and Cys310 completely abrogated the cytoplasmic redistribution. The translocation process was reversal and specific, as it could be reversed by reductive reagents, but could not be mimicked by H₂O₂. In structure, the region aa.64–80 and the beta-strand aa.311–316 in proximity to Cys93 and Cys310 were important for GSNO-induced APE1 relocalization. In addition, a defect of importin-mediated nuclear import pathway was found in the NO-insulted cells, and p50 and HDAC2 were identified as APE1 nuclear export inhibitory proteins. Together, this study may provide a novel molecular mechanism, which links nitrosative stress to APE1-associated physiological and pathological processes.

Significance: The redox balance of cells provides a stable microenvironment for biological macromolecules to perform their physiological functions. As redox imbalance is closely related to the occurrence and development of a variety of diseases, antioxidant therapies are an attractive option. However, redox-based therapeutic strategies have not yet shown satisfactory results. To find the key reason is of great significance. Recent Advances: We emphasize the precise nature of redox regulation and elucidate the importance and necessity of precision redox strategies from three aspects: differences in redox status, differences in redox function, and differences in the effects of redox therapy. We then propose the “5R” principle of precision redox in antioxidant pharmacology: “Right species, Right place, Right time, Right level, and Right target.” Critical Issues: Redox status must be considered in the context of species, time, place, level, and target. The function of a biomacromolecule and its cellular signaling role are closely dependent on redox status. Accurate evaluation of redox status and specific interventions are critical for the success of redox treatments. Precision redox is the key for antioxidant pharmacology. The precise application of antioxidants as nutritional supplements is also key to the general health of the population. Future Directions: Future studies to develop more accurate methods for detecting redox status and accurately evaluating the redox state of different physiological and pathological processes are needed. Antioxidant pharmacology should consider the “5R” principle rather than continuing to apply global nonspecific antioxidant treatments. Antioxid. Redox Signal . 34, 1069–1082.

Aging is tightly associated with redox events. The free radical theory of aging indicates that redox imbalance may be an important factor in the aging process. Most studies about redox and aging focused on the static status of oxidative stress levels, there has been little research investigating differential responses to redox challenge during aging. In this study, we used Caenorhabditis elegans and human fibroblasts as models to compare differential responses to oxidative stress challenge in young and old individuals. In response to paraquat stress, young individuals generated more ROS and activated signaling pathways including p-ERK, p-AKT and p-AMPKα/β. After the initial response, young individuals then promoted NRF2 translocation and induced additional antioxidant enzymes and higher expression of phase II enzymes, including SOD, CAT, GPX, HO-1, GSTP-1and others, to maintain redox homeostasis. Moreover, young individuals also demonstrated a better ability to degrade damaged proteins by up-regulating the expression of chaperones and improving proteasome activity. Based on these data, we propose a new concept "Redox-stress Response Capacity (RRC)", which suggests cells or organisms are capable of generating dynamic redox responses to activate cellular signaling and maintain cellular homeostasis. The decay of RRC is the substantive characteristic of aging, which gives a new understand of the redox theory of aging.