The dynamics of stress p53-Mdm2 network regulated by p300 and HDAC1.

We construct a stress p53-Mdm2-p300-HDAC1 regulatory network that is activated and stabilised by two regulatory proteins, p300 and HDAC1. Different activation levels of [Formula: see text] observed due to these regulators during stress condition have been investigated using a deterministic as well as a stochastic approach to understand how the cell responds during stress conditions. We found that these regulators help in adjusting p53 to different conditions as identified by various oscillatory states, namely fixed point oscillations, damped oscillations and sustain oscillations. On assessing the impact of p300 on p53-Mdm2 network we identified three states: first stabilised or normal condition where the impact of p300 is negligible, second an interim region where p53 is activated due to interaction between p53 and p300, and finally the third regime where excess of p300 leads to cell stress condition. Similarly evaluation of HDAC1 on our model led to identification of the above three distinct states. Also we observe that noise in stochastic cellular system helps to reach each oscillatory state quicker than those in deterministic case. The constructed model validated different experimental findings qualitatively

Correction: Saoudi et al. The Role of Allium subhirsutum L. in the Attenuation of Dermal Wounds by Modulating Oxidative Stress and Inflammation in Wistar Albino Rats. Molecules 2021, 26, 4875

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Novel Polymeric Nanomaterial Based on Poly(Hydroxyethyl Methacrylate-Methacryloylamidophenylalanine) for Hypertension Treatment: Properties and Drug Release Characteristics.

In this study, a novel polymeric nanomaterial was synthesized and characterized, and it its potential usability in hypertension treatment was demonstrated. For these purposes, a poly(hydroxyethyl methacrylate-methacryloylamidophenylalanine)-based polymeric nanomaterial (p(HEMPA)) was synthesized using a mini-emulsion polymerization technique. The nanomaterials were characterized using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and zeta size analysis. The synthesized p(HEMPA) nanomaterial had a diameter of about 113 nm. Amlodipine-binding studies were optimized by changing the reaction conditions. Under optimum conditions, amlodipine’s maximum adsorption value (Qmax) of the p(HEMPA) nanopolymer was found to be 145.8 mg/g. In vitro controlled drug release rates of amlodipine, bound to the nanopolymer at the optimum conditions, were studied with the dialysis method in a simulated gastrointestinal system with pH values of 1.2, 6.8 and 7.4. It was found that 99.5% of amlodipine loaded on the nanomaterial was released at pH 7.4 and 72 h. Even after 72 h, no difference was observed in the release of AML. It can be said that the synthesized nanomaterial is suitable for oral amlodipine release. In conclusion, the synthesized nanomaterial was studied for the first time in the literature as a drug delivery system for use in the treatment of hypertension. In addition, AML–p(HEMPA) nanomaterials may enable less frequent drug uptake, have higher bioavailability, and allow for prolonged release with minimal side effects

Identification of New Mycobacterium tuberculosis Proteasome Inhibitors Using a Knowledge-Based Computational Screening Approach

Mycobacterium tuberculosis (Mtb) is a deadly tuberculosis (TB)-causing pathogen. The proteasome is vital to the survival of Mtb and is therefore validated as a potential target for anti-TB therapy. Mtb resistance to existing antibacterial agents has enhanced drastically, becoming a worldwide health issue. Therefore, new potential therapeutic agents need to be developed that can overcome the complications of TB. With this purpose, in the present study, 224,205 natural compounds from the ZINC database have been screened against the catalytic site of Mtb proteasome by the computational approach. The best scoring hits, ZINC3875469, ZINC4076131, and ZINC1883067, demonstrated robust interaction with Mtb proteasome with binding energy values of −7.19, −7.95, and −7.21 kcal/mol for the monomer (K-chain) and −8.05, −9.10, and −7.07 kcal/mol for the dimer (both K and L chains) of the beta subunit, which is relatively higher than that of reference compound HT1171 (−5.83 kcal/mol (monomer) and −5.97 kcal/mol (dimer)). In-depth molecular docking of top-scoring compounds with Mtb proteasome reveals that amino acid residues Thr1, Arg19, Ser20, Thr21, Gln22, Gly23, Asn24, Lys33, Gly47, Asp124, Ala126, Trp129, and Ala180 are crucial in binding. Furthermore, a molecular dynamics study showed steady-state interaction of hit compounds with Mtb proteasome. Computational prediction of physicochemical property assessment showed that these hits are non-toxic and possess good drug-likeness properties. This study proposed that these compounds could be utilized as potential inhibitors of Mtb proteasome to combat TB infection. However, there is a need for further bench work experiments for their validation as inhibitors of Mtb proteasome

Noise contribution on dynamics in stochastic system.

<p>The variation of as a function of time in hours in stochastic system for different values of system size,  = 1, 10, 15, 20, 25, 50 (at constant values of and ).</p

Biochemical network model of stress p53-Mdm2-p300-HDAC1.

<p>The schematic diagram of stress p53-Mdm2-p300-HDAC1 model.</p

Stability curve induced by .

<p>Plots of concentration level as a function of for different values of exposure times i.e. 10-100 (at constant value of ). The inset is the enlarged portion of the activated regime. In the curve stabilized and activated regimes are demarcated.</p

dynamics for various levels.

<p>The plots of concentration levels as a function of time in hours for various values: (a) , (b) , (c) , (d) , (e) and (f) respectively at constant value of .</p

Activation of via variation of level.

<p>Plots of concentration levels as a function of time in hours for various values 0.0002, 0.002, 0.008, 0.01, 0.02 and 0.04 respectively (at constant value of ), showing activation and stabilization of .</p