Umesh Sai Jonnalagadda

BACKGROUND: Vascular calcification is a detrimental aging pathology markedly accelerated in patients with chronic kidney disease. PLA (prelamin A) is a biomarker of vascular smooth muscle cell aging that accelerates calcification however the mechanisms remain undefined. METHODS: Vascular smooth muscle cells were transduced with PLA using an adenoviral vector and epigenetic modifications were monitored using immunofluorescence and targeted polymerase chain reaction array. Epigenetic findings were verified in vivo using immunohistochemistry in human vessels, in a mouse model of inducible prelamin A expression, and in a rat model of chronic kidney disease–induced calcification. Transcriptomic and chromatin immunoprecipitation followed by sequencing analyses were used to identify gene targets impacted by changes in the epigenetic landscape. Molecular tools and antibody arrays were used to monitor the effects of mineral dysregulation on heterochromatin, inflammation, aging, and calcification. RESULTS: Here, we report that depletion of the repressive heterochromatin marks, H3K9me3 (histone H3, lysine 9, trimethylation) and H3K27me3 (histone H3, lysine 27,trimethylation), is an early hallmark of vascular aging induced by both nuclear lamina dysfunction and dysregulated mineral metabolism, which act to modulate the expression of key epigenetic writers and erasers. Global analysis of H3K9me3 and H3K27me3 marks and pathway analysis revealed deregulation of insulin signaling and autophagy pathways as well as cross-talking DNA damage and NF-κB (nuclear factor κB) inflammatory pathways consistent with early activation of the senescence-associated secretory phenotype. Expression of PLA in vivo induced loss of heterochromatin and promoted inflammation and osteogenic differentiation which preceded aging indices, such as DNA damage and senescence. Vessels from children on dialysis and rats with chronic kidney disease showed prelamin A accumulation and accelerated loss of heterochromatin before the onset of calcification. CONCLUSIONS: Dysregulated mineral metabolism drives changes in the epigenetic landscape and nuclear lamina dysfunction that together promote early induction of inflammaging pathways priming the vasculature for downstream pathological change.

Sonochemistry has shown potential to facilitate chemical conversion under near-ambient conditions in water without any chemical additive or other external stimulus. With the help of catalytic cavitation agents, the generation of radicals from ultrasound-induced inertial cavitation can be enhanced and utilized more efficiently for selective chemical transformations. In this study, multicavity CuO (MC-CuO) microparticles were prepared and employed as catalytic cavitation agents to promote spatially selective cavitation and simultaneously catalyze sonochemical oxidation of glucose. Accordingly, the rate of production of OH radicals by sonolysis of water, inferred from titration, was directly related to the cavitation energy, which was determined by analyzing the acoustic signal during pulsed irradiation of 500 kHz ultrasound. Two reaction pathways for glucose oxidation were identified. First, the generation of OH radicals and possibly other reactive oxygen species in the bulk aqueous phase resulted in the formation of gluconic acid, together with other byproducts of C–C bond cleavage and ring opening. Second, the generation of OH radicals in close proximity to CuO resulted in the formation of glucuronic acid with the six membered ring preserved. The present study demonstrates that by appropriately controlling the acoustic parameters (e.g. duty cycle, peak negative pressure and irradiation time) and reaction conditions (e.g. gas atmosphere and the addition of catalytic cavitation agent), it is possible to steer the selectivity of sono-oxidation of glucose towards glucuronic acid, the most value-added product, whilst minimizing the energy input to drive the sonochemical oxidation reaction.

Hollow titanium dioxide supported iridium oxygen evolution reaction catalysts exhibit high activity and durability for the half cell and membrane electrode assembly testing protocols.

Novel catalytic chemistry of demethylenation of benzyl alcohol to phenol is presented here using the synergy between an earth-abundant transition metal oxide (CuO) catalyst and high frequency ultrasound.

Catalytic nanomaterials have been demonstrated to enhance sonochemical processing through interactions with inertial cavitation events. Typically, sonochemistry generates inertial cavitation events directly from the solvent, which results in spatially uncontrolled cavitation events with limited interaction with the catalytic active site. These high intensity acoustic fields also result in thermal effects and side reactions, which may further influence chemical yields and selectivity. Herein, we report on ultrasound‐responsive structured AuPd/TiO₂ open nanoshells (TONs) to surface‐stabilize gas bubbles for promoting cavitation events in the vicinity of catalytic active site. These exogenous bubbles trapped on catalytic active sites readily cavitate to produce free radicals for chemical reactions. Our findings indicate a positive trend between cavitation and benzaldehyde production in the presence of our AuPd/TONs. In contrast, nanostructures without gas‐stabilization demonstrate reduced sonochemical conversion, suggesting the catalytic potential of nanostructuring photocatalytic materials to function as both cavitation agents and photo‐oxidative catalysts, or photocatalytic nanostructure (PCN).

We report a serendipitously discovered initiator-free photohydrogelation of linear poly(ethylene glycols) (PEGs) containing coumarin and methacrylate end groups. The mechanistic studies by NMR spectroscopic reaction monitoring with various control experiments and by real-time UV curing rheology reveal that hydrogelation occurs via a 3-reaction, 1-step process, involving two [2 + 2]-cycloadditions between coumarin and coumarin and coumarin and methacrylate groups and an initiator-free radical polymerization of the methacrylate. We also elucidate the important role of PEGs in this initiator-free UV-induced gelation. Coumarin groups are shown to rheologically impact the network strength and flexibility of hydrogels through [2 + 2]-cycloaddition spacing elongation. Using this methodology, coumarin-containing PEG methacrylates of various molecular weights afford a range of hydrogels G1–G8 with good yields after purification and drying. Interestingly, the same chemistry can be applied to react a dicoumarin containing PEG with a PEG dimethacrylate at various weight ratios (G9–G11). The gels could be partially broken down under several types of ultrasound triggers. In polymer solution, coumarin photodimers (CPDs) are shown to return partially to the coumarin state in response to 30 kHz ultrasound. In gel states, the breakdowns triggered by 30 kHz sonication and by 1.1 MHz high-intensity focused ultrasound are observed at PEG chains without any conversion of CPDs into coumarin. Our methodology may be applicable to the development of a controlled delivery system for hydrophobic actives where a conventional photohydrogelation with the use of a photoinitiator and the subsequent presence of its byproduct can cause migration and toxicity concerns to the surrounding environment.

Sonogelation by supramolecular gelators is highlighted as a paradigm shift for their potential applications in material and biomedical sciences. Yet, these materials require organic solvents and low‐frequency ultrasound, limiting their utility. Here, a comb‐like polymethacrylate copolymer is synthesized with 2,6‐bis(1‐methylbenzimidazolyl)‐4‐oxypyridine tridentate ligand randomly distributed on poly(ethylene glycol) side chains. Upon addition of zinc perchlorate salt, this copolymer rapidly forms a hydrogel after exposure to either mechanical (i.e., ultrasound) or thermal stimuli. Spectroscopic analysis, to elucidate the mechanism, indicates metal ion coordination to ligand as well as the carbonyl and ethylene glycol units; interestingly, ¹H‐NMR suggests that the coordination between tridentate ligand moiety and Zn²⁺ is unexpectedly weaker in water than in acetonitrile. Investigations by dynamic light scattering indicates that the copolymer forms nanodispersions in excess salt, which coalesces to form a hydrogel by either heating or high intensity focused ultrasound (HIFU). Rheological quantification of these gels suggests stronger crosslinking by HIFU compared to heating.