Leveraging an enzyme/artificial substrate system to enhance cellular persulfides and mitigate neuroinflammation

Persulfides and polysulfides, collectively known as the sulfane sulfur pool along with hydrogen sulfide (H₂S), play a central role in cellular physiology and disease. Exogenously enhancing these species in cells is an emerging therapeutic paradigm for mitigating oxidative stress and inflammation that are associated with several diseases. In this study, we present a unique approach of using the cell''s own enzyme machinery coupled with an array of artificial substrates to enhance the cellular sulfane sulfur pool. We report the synthesis and validation of artificial/unnatural substrates specific for 3-mercaptopyruvate sulfurtransferase (3-MST), an important enzyme that contributes to sulfur trafficking in cells. We demonstrate that these artificial substrates generate persulfides in vitro as well as mediate sulfur transfer to low molecular weight thiols and to cysteine-containing proteins. A nearly 100-fold difference in the rates of H₂S production for the various substrates is observed supporting the tunability of persulfide generation by the 3-MST enzyme/artificial substrate system. Next, we show that the substrate 1a permeates cells and is selectively turned over by 3-MST to generate 3-MST-persulfide, which protects against reactive oxygen species-induced lethality. Lastly, in a mouse model, 1a is found to significantly mitigate neuroinflammation in the brain tissue. Together, the approach that we have developed allows for the on-demand generation of persulfides in vitro and in vivo using a range of shelf-stable, artificial substrates of 3-MST, while opening up possibilities of harnessing these molecules for therapeutic applications.

A persulfide/hydrogen sulfide generation strategy through artificial substrates for 3-mercaptopyruvate sulfurtransferase (3-MST) is reported, which enhances cellular persulfides, attenuates reactive oxygen species (ROS), and alleviates inflammation.     

Biocompatible Carbon Dot Decorated α-FeOOH Nanohybrid for an Effective Fluorometric Sensing of Cr (VI) in Wastewater and Living Cells

Journal of Fluorescence - This article reports the fluorometric detection of toxic hexavalent chromium Cr (VI)) in wastewater and Cr (VI) contaminated living cells using in-situ grown carbon...     

H2, B−H,and Si−H Bond Activation and Facile Protonolysis Driven by Pt-Base Metal Cooperation

We report a series of heterobimetallic Pt/Zn and Pt/Ca complexes to study the effect of proximity of a dicationic base metal on the organometallic Pt species. Varying degrees of Pt⋅⋅⋅Zn and Zn interaction with the bridging Me group are achieved, showcasing snapshots of a hypothetical process of retrotransmetalation from Pt to Zn. In contrast, only weak interactions were observed for Ca with a Pt-bound Me group. Activation of H₂, B−H and Si−H bonds leads to the formation of hydride-bridged Pt−H−Zn complexes, which is not observed in the absence of Zn, pointing out the importance of metal-metal cooperation. Reactivity of PtMe₂/M²⁺ with terminal acetylene, water and methanol is also studied, leading to facile protonation of one of the Me groups at the Pt center only when Zn is present. This study sheds light on various ways in which the presence of a 2+ metal cation significantly affects the reactivity of a common organoplatinum complex.     

Resurrection and Reactivation of Acetylcholinesterase and Butyrylcholinesterase

Organophosphorus (OP) nerve agents and pesticides present significant threats to civilian and military populations. OP compounds include the nefarious G and V chemical nerve agents, but more commonly, civilians are exposed to less toxic OP pesticides, resulting in the same negative toxicological effects and thousands of deaths on an annual basis. After decades of research, no new therapeutics have been realized since the mid-1900s. Upon phosphylation of the catalytic serine residue, a process known as inhibition, there is an accumulation of acetylcholine (ACh) in the brain synapses and neuromuscular junctions, leading to a cholinergic crisis and eventually death. Oxime nucleophiles can reactivate select OP-inhibited acetylcholinesterase (AChE). Yet, the fields of reactivation of AChE and butyrylcholinesterase encounter additional challenges as broad-spectrum reactivation of either enzyme is difficult. Additional problems include the ability to cross the blood brain barrier (BBB) and to provide therapy in the central nervous system. Yet another complication arises in a competitive reaction, known as aging, whereby OP-inhibited AChE is converted to an inactive form, which until very recently, had been impossible to reverse to an active, functional form. Evaluations of uncharged oximes and other neutral nucleophiles have been made. Non-oxime reactivators, such as aromatic general bases and Mannich bases, have been developed. The issue of aging, which generates an anionic phosphylated serine residue, has been historically recalcitrant to recovery by any therapeutic approach—that is, until earlier this year. Mannich bases not only serve as reactivators of OP-inhibited AChE, but this class of compounds can also recover activity from the aged form of AChE, a process referred to as resurrection. This review covers the modern efforts to address all of these issues and notes the complexities of therapeutic development along these different lines of research.     

Dynamic resource allocation: A flexible and tractable modeling framework

This paper presents a binary optimization framework for modeling dynamic resource allocation problems. The framework (a) allows modeling flexibility by incorporating different objective functions, alternative sets of resources and fairness controls; (b) is widely applicable in a variety of problems in transportation, services and engineering; and (c) is tractable, i.e., provides near optimal solutions fast for large-scale instances. To justify these assertions, we model and report encouraging computational results on three widely studied problems – the Air Traffic Flow Management, the Aircraft Maintenance Problems and Job Shop Scheduling. Finally, we provide several polyhedral results that offer insights on its effectiveness.     

Electronic properties of N(5)-ethyl flavinium ion

We investigated the electronic properties of N(5)-ethyl flavinium perchlorate (Et-Fl(+)) and compared them to those of its parent compound, 3-methyllumiflavin (Fl). Absorption and fluorescence spectra of Fl and Et-Fl(+) exhibit similar spectral features, but the absorption energy of Et-Fl(+) is substantially lower than that of Fl. We calculated the absorption signatures of Fl and Et-Fl(+) using time-dependent density functional theory (TD-DFT) methods and found that the main absorption bands of Fl and Et-Fl(+) are (π,π*) transitions for the S(1) and S(3) excited states. Furthermore, calculations predict that the S(2) state has (n,π*) character. Using cyclic voltammetry and a simplistic consideration of the orbital energies, we compared the HOMO/LUMO energies of Fl and Et-Fl(+). We found that both HOMO and LUMO orbitals of Et-Fl(+) are stabilized relative to those in Fl, although the stabilization of the LUMO level was more pronounced. Visible and mid-IR pump-probe experiments demonstrate that Et-Fl(+) exhibits a shorter excited-state lifetime (590 ps) relative to that of Fl (several nanoseconds), possibly due to faster thermal deactivation in Et-Fl(+), as dictated by the energy gap law. Furthermore, we observed a fast (23-30 ps) S(2) → S(0) internal conversion in transient absorption spectra of both Fl and Et-Fl(+) in experiments that utilized pump excitations with higher energy.     

Fabricating an experimental setup to investigate the performance of an automobile car radiator by using aluminum/water nanofluid

In this present work, effect of Al/water nanofluids on the rheological performance of an automobile car radiator has been investigated. Nanofluids were fabricated by two-step methods, i.e., dispersing of aluminum metal bases nanoparticles of size 75–135 nm in double-distilled water. Experiments were conducted on single-pass cross-flow compact heat exchanger by varying the various parameters such as inlet temperature, flow rate through the heat exchanger, concentration of nanoparticles and velocity of air employed for cooling purpose. It was concluded that the hot side Nusselt numbers are improved by 3.37 and 5.0877% for 0.2 and 0.3% concentrations of nanofluids, respectively, at 318.15 K inlet fluids temperature as compared to base fluids. Colburn factor was increased by 12.94 and 23.45% for 0.2 and 0.3% nanoparticles volume concentration of nanofluids, respectively, at 318.15 K inlet temperature with respect to double-distilled water. Hot fluid side friction factor was increased by 14.04 and 20.916% for 0.2 and 0.3% nanoparticles volume concentration of nanofluids with respect to base fluids, but this average value of friction factor was decreased by 2.29 and 9.1412% when temperature was increased from 318.15 to 323.15 K and 328.15 K, respectively.     

A computational study of the ground and excited state structure and absorption spectra of free-base N-confused porphine and free-base N-confused tetraphenylporphyrin

Computational investigations into the ground and singlet excited-state structures and the experimental ground-state absorption spectra of N-confused tetraphenylporphyrin tautomers 1e and 1i and N-confused porphines (NCP) 2e and 2i have been performed. Structural data for the ground state, performed at the B3LYP/6-31G(d), B3LYP/6-31+G(d)//B3LYP/6-31G(d), and B3LYP/6-311+G(d)//B3LYP/6-31G(d) levels, are consistent with those performed at lower levels of theory. Calculations of the gas-phase, ground-state absorption spectrum are qualitatively consistent with condensed phase experiments for predicting the relative intensities of the Q(0,0) and Soret bands. Inclusion of implicit solvation in the calculations substantially improves the correlation of the energy of the Soret band with experiment for both tautomers (1e, 435 nm predicted, 442 nm observed in DMAc; 1i, 435 nm predicted, 437 nm observed in CH2Cl2). The x- and y-polarized Q-band transitions were qualitatively reproduced for 1e in both the gas phase and with solvation, although the low-energy absorption band in 1i was predicted at substantially higher energy (646 nm in the gas phase and 655 nm with solvation) than observed experimentally (724 nm in CH2Cl2). Franck-Condon state and equilibrated singlet excited-state geometries were calculated for unsubstituted NCP tautomers 2e and 2i at the TD-B3LYP/SVP and TD-B3LYP/TZVP//TD-B3LYP/SVP levels. Electronic difference density plots were calculated from these geometries, thereby indicating the change of electron density in the singlet excited states. Adiabatic S1 and S2 geometries of these compounds were also calculated at the TD-B3LYP/SVP level, and the results indicate that while 2i is a more stable ground-state molecule by approximately 7.0 kcal mol-1, the energy difference for the S1 excited states is only approximately 1.0 kcal mol-1 and is 6.1 kcal mol-1 for the S2 excited states.     

Ring Expansion and 1,2‐Migration Cascade of Benzisoxazoles with Ynamides: Experimental and Theoretical Studies

Demonstrated herein is an Au^I‐catalyzed annulation of sulfonyl‐protected ynamides with substituted 1,2‐benzisoxazoles for the synthesis of E‐benzo[e][1,3]oxazine derivatives. The transformation involves the addition of benzisoxazole to the gold‐activated ynamide, ring expansion of the benzisoxazole fragment to provide an α‐imino vinylic gold intermediate, and 1,2‐migration of the sulfonamide motif to the masked carbene center to deliver the respective ring‐expanded benzo[e][1,3]oxazine of predominant E configuration. A trapping experiment justifies the participation of the α‐imino masked gold carbene. DFT computations also support the hypothesized mechanism and rationalize the product stereoselectivity.