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Ischemia reperfusion injury (IRI) results from a cessation or restriction of blood supply to an organ followed by reestablishment of perfusion and reoxygenation. In the kidney, IRI due to transplantation, cardiac surgery with cardiopulmonary bypass, and other major vascular surgeries contributes to acute kidney injury (AKI), a clinical condition associated with significant morbidity and mortality in hospitalized patients. In the postischemic kidney, endothelial damage promotes inflammatory responses and leads to persistent hypoxia of the renal tubular epithelium. Like other cell types, endothelial cells respond to low oxygen tension by multiple hypoxic signaling mechanisms. Key mediators of adaptation to hypoxia are hypoxia-inducible factors (HIF)-1 and -2, transcription factors whose activity is negatively regulated by prolyl-hydroxylase domain proteins 1 to 3 (PHD1 to PHD3). The PHD/HIF axis controls several processes determining injury outcome, including ATP generation, cell survival, proliferation, and angiogenesis. Here, we discuss recent advances in our understanding of the endothelial-derived PHD/HIF signaling and its effects on postischemic AKI.

Scarless healing of injury remains a clinical challenge because of its complicated and overlapping phases of inflammation, clearing, and regeneration. Curcumin has been already established as a potential wound healing agent for normal and diabetic-impaired wounds. Herein, the question has been addressed whether a well-known antioxidant cerium oxide nanoparticle (CNP) can potentiate the activity of curcumin to promote a cellular program for scarless healing. In this study, we have developed a biocompatible poly (acrylamide) hydrogel (PAGE)-based dressing material comprising of CNP and curcumin (ACC) and tested its wound healing activity in an animal model of acute wound. Characterization of the CNP- and curcumin-entrapped hydrogel dressing (ACC) demonstrated high loading efficiency and sustained release of curcumin. In a full-thickness acute wound healing model of rat, a single application of ACC dressing demonstrated higher wound healing efficacy (78%) and negligible scarring compared to dressings containing only curcumin or CNP in 7 days. Enhanced cell proliferation, higher collagen content, advanced wound maturity, re-epithelialization, and granulation tissue formation were observed using the combination of curcumin and CNP (ACC). Study of cellular mechanisms identified MCP-1 and TGF-β as the key drivers of differential and accelerated healing observed in the ACC group. These, coupled with the upregulation of growth-related signaling pathways (HER2/ErbB2, TGF-β-Smad2/3, MAPK/ERK, AKT, and VEGF), promoted almost scarless healing in animals treated with ACC. The optimized combination of curcumin and CNP used in our study shows distinct advantage and can be a better agent for complete wound healing.

An ecofriendly and efficient method (photoinduced) has been used for green synthesis of stable gold nanoparticles (AuNPs) using aqueous extract as a reducing and stabilizing agent, derived from halotolerant microalga Dunaliella salina. Synthesis of AuNPs was confirmed by UV–Vis spectroscopy showing sharp SPR band at 560 nm after 30 min exposure of sunlight. The synthesis was optimized further as exposure(75min) to sunlight, aqueous extract of Dunaliella(AED) inoculum dose(30%) and HAuCl4.xH2O (1 mM). The presence of nearly spherical shape of AuNPs with average size of 22.4 nm and crystalline nature were confirmed by TEM, SAED and XRD analysis. The XPS analysis of AuNPs showed presence of two individual peaks at 85.17 and 88.94eV that attributed to Au 4f7/2 and Au 4f5/2 respectively. Phycochemical analysis of AED demonstrated presence of phenolics, flavonoids, tannin and proteins. AED when subjected to SDS-PAGE showed protein bands of 92 and 66 KDa. AuNPs were tested for anticancer activity on MCF7 (cancer) and MCF 10A (normal) cell lines, keeping commercial drug cisplatin as positive control. AuNPs selectively killed cancer cells and were not detrimental to the normal cell line whereas cisplatin killed normal cells also at 48 h exposure, therefore, such AuNPs may be used as an anticancer agent.

Prolonged cellular hypoxia leads to energetic failure and death. However, sublethal hypoxia can trigger an adaptive response called hypoxic preconditioning. While prolyl-hydroxylase (PHD) enzymes and hypoxia-inducible factors (HIFs) have been identified as key elements of oxygen-sensing machinery, the mechanisms by which hypoxic preconditioning protects against insults remain unclear. Here, we perform serum metabolomic profiling to assess alterations induced by two potent cytoprotective approaches, hypoxic preconditioning and pharmacologic PHD inhibition. We discover that both approaches increase serum kynurenine levels and enhance kynurenine biotransformation, leading to preservation of NAD+in the post-ischemic kidney. Furthermore, we show that indoleamine 2,3-dioxygenase 1 (Ido1) deficiency abolishes the systemic increase of kynurenine and the subsequent renoprotection generated by hypoxic preconditioning and PHD inhibition. Importantly, exogenous administration of kynurenine restores the hypoxic preconditioning in the context of Ido1deficiency. Collectively, our findings demonstrate a critical role of the IDO1-kynurenine axis in mediating hypoxic preconditioning.