A review on the application of chitosan-based polymers in liver tissue engineering.

Chitosan-based polymers have enormous structural tendencies to build bioactive materials with novel characteristics, functions, and various applications, mainly in liver tissue engineering (LTE). The specific physicochemical, biological, mechanical, and biodegradation properties give the effective ways to blend these biopolymers with synthetic and natural polymers to fabricate scaffolds matrixes, sponges, and complexes. A variety of natural and synthetic biomaterials, including chitosan (CS), alginate (Alg), collagen (CN), gelatin (GL), hyaluronic acid (HA), hydroxyapatite (HAp), polyethylene glycol (PEG), polycaprolactone (PCL), poly(lactic-co-glycolic) acid (PGLA), polylactic acid (PLA), and silk fibroin gained considerable attention due to their structure-properties relationship. The incorporation of CS within the polymer matrix results in increased mechanical strength and also imparts biological behavior to the designed PU formulations. The significant and growing interest in the LTE sector, this review aims to be a detailed exploration of CS-based polymers biomaterials for LTE. A brief explanation of the sources and extraction, properties, structure, and scope of CS is described in the introduction. After that, a full overview of the liver, its anatomy, issues, hepatocyte transplantation, LTE, and CS LTE applications are discussed.

Exploring Citrus sinensis Phytochemicals as Potential Inhibitors for Breast Cancer Genes BRCA1 and BRCA2 Using Pharmacophore Modeling, Molecular Docking, MD Simulations, and DFT Analysis.

BACKGROUND: Structure-activity relationship (SAR) is considered to be an effective in silico approach when discovering potential antagonists for breast cancer due to gene mutation. Major challenges are faced by conventional SAR in predicting novel antagonists due to the discovery of diverse antagonistic compounds. Methodologyand Results: In predicting breast cancer antagonists, a multistep screening of phytochemicals isolated from the seeds of the Citrus sinensis plant was applied using feasible complementary methodologies. A three-dimensional quantitative structure-activity relationship (3D-QSAR) model was developed through the Flare project, in which conformational analysis, pharmacophore generation, and compound alignment were done. Ten hit compounds were obtained through the development of the 3D-QSAR model. For exploring the mechanism of action of active compounds against cocrystal inhibitors, molecular docking analysis was done through Molegro software (MVD) to identify lead compounds. Three new proteins, namely, 1T15, 3EU7, and 1T29, displayed the best Moldock scores. The quality of the docking study was assessed by a molecular dynamics simulation. Based on binding affinities to the receptor in the docking studies, three lead compounds (stigmasterol P8, epoxybergamottin P28, and nobiletin P29) were obtained, and they passed through absorption, distribution, metabolism, and excretion (ADME) studies via the SwissADME online service, which proved that P28 and P29 were the most active allosteric inhibitors with the lowest toxicity level against breast cancer. Then, density functional theory (DFT) studies were performed to measure the active compound's reactivity, hardness, and softness with the help of Gaussian 09 software. CONCLUSIONS: This multistep screening of phytochemicals revealed high-reliability antagonists of breast cancer by 3D-QSAR using flare, docking analysis, and DFT studies. The present study helps in providing a proper guideline for the development of novel inhibitors of BRCA1 and BRCA2.

Applications of guar gum polysaccharide for pharmaceutical drug delivery: A review.

Bio-based materials are rapidly replacing synthetic materials owing to their significant biomedical applications, easy availability, nontoxicity, biodegradability and biocompatibility. Guar gum (GG) is a plant-derived biocompatible and biodegradable polymeric compound found abundantly in nature. It is a non-ionic, hydrophilic carbohydrate and is a cost-effective hydrocolloid polysaccharide considered as a wonderful representative of the new generation of plant gums. Various composites of guar gum with other polymers have been reported in last few decades and they are extensively used in different industries like food, textile, mining, petrochemical, paper and explosives etc. Easy availability, non-toxicity, eco-friendly and biodegradable nature of GG has made it ideal candidate for for drug delivery (DD) applications. GG based hydrogels, films, scaffolds and nanoparticles have been explored widely for their DD applications. These non-toxic DD carriers can be used for targeted drug delivery. This review article directs the current efforts and improvements on GG and GG-based materials to be used in DD.

Integration of virtual screening of phytoecdysteroids as androgen receptor inhibitors by 3D-QSAR Model, CoMFA, molecular docking and ADMET analysis: An extensive and interactive machine learning.

Ecdysteroids, a class of naturally isolated polyhydroxylated sterols, stands at a very good place in the pharmaceutical industry from their medicinal point of views like anti-inflammatory, neuroprotective, anti-microbial, anti-diabetic, antioxidant, and anti-tumor effects. Due to their excellent antioxidant and anti-microbial potential, ecdysteroids have extensive use in skin products, especially derma creams. To monitor the best anti-acne phytoecdysteroids, here made use of different computational approaches, by using the rapid, easy, cost-effective and high throughput method to screen and identify ecdysteroids as androgen receptor inhibitors. 3D-QSAR study was carried out on a dataset of ecdysteroids by using comparative molecular field analysis (CoMFA) to determine the factors responsible for the activity of compounds. Statistically a cross-validated (q2) 0.1457 and regression coefficient (r2) 0.9713 indicated the best model. Contour map results showed the influence of steric effect to enhance activity. A molecular docking analysis was done to further find out the binding sites and their anti-acne potential against three crystal structured macromolecules (PDB ID: 2REQ, 2BAC, 4EM0). Docking results were further evaluated by prime MM-GBSA analysis and findings confirmed the accuracy. Toxicity by ADMET assessment was carried out and M2 was found as lead druglike with best anti-acne activity against Propionium acnes GehA lipase bacteria after passing all filters. This research study is novel because it is representing first effort to explore ecdysteroids class for their high therapeutic output as androgen receptor inhibitor by using computational tools and expectedly led to novel scaffold for androgen receptor inhibitor. This is a novel and new approach to investigate the ecdysteroids for first time for their practical applications.

Exploration of phenolic acid derivatives as inhibitors of SARS-CoV-2 main protease and receptor binding domain: potential candidates for anti-SARS-CoV-2 therapy.

Severe acute respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) is the etiological virus of Coronavirus Disease 2019 (COVID-19) which has been a public health concern due to its high morbidity and high mortality. Hence, the search for drugs that incapacitate the virus via inhibition of vital proteins in its life cycle is ongoing due to the paucity of drugs in clinical use against the virus. Consequently, this study was aimed at evaluating the potentials of natural phenolics against the Main protease (Mpro) and the receptor binding domain (RBD) using molecular modeling techniques including molecular docking, molecular dynamics (MD) simulation, and density functional theory (DFT) calculations. To this end, thirty-five naturally occurring phenolics were identified and subjected to molecular docking simulation against the proteins. The results showed the compounds including rosmarinic acid, cynarine, and chlorogenic acid among many others possessed high binding affinities for both proteins as evident from their docking scores, with some possessing lower docking scores compared to the standard compound (Remdesivir). Further subjection of the hit compounds to drug-likeness, pharmacokinetics, and toxicity profiling revealed chlorogenic acid, rosmarinic acid, and chicoric acid as the compounds with desirable profiles and toxicity properties, while the study of their electronic properties via density functional theory calculations revealed rosmarinic acid as the most reactive and least stable among the sets of lead compounds that were identified in the study. Molecular dynamics simulation of the complexes formed after docking revealed the stability of the complexes. Ultimately, further experimental procedures are needed to validate the findings of this study.

Angiogenic potential and wound healing efficacy of chitosan derived hydrogels at varied concentrations of APTES in chick and mouse models.

Chitosan (Cs) based biomaterials seem to be indispensable for neovasculogenesis and angiogenesis that ensure accelerated wound healing. Cs/poly (vinyl alcohol) (PVA) bio-constructs were cross-linked and investigated with varying concentrations of aminopropyltriethoxysilane (APTES). This study comprised of three phases: fabrication of hydrogels, characterization, assessment of angiogenic potential along with toxico-pathological effects, wound healing efficacy in chick and mice, respectively. The hydrogels were characterized by FTIR, SEM and TGA and the swelling response was examined in different solvents. The hydrogels swelling ratio was decreased with increasing amount of APTES, showed the highest swelling at acidic and basic pH while low swelling at neutral pH. Chorioallantoic membranes (CAM) assay was performed to study in-vivo angiogenesis, toxicological, morphological, biochemical and histological analyses in developing chicks. The results showed remarkably improved angiogenesis with little deviations in morphological, histological features and liver enzymes of chick embryos at higher concentrations of APTES. Besides, full thickness wounds were excised on mice dorsolateral skin to assess the wound healing. The rate of wound size reduction was significantly higher after topical application of hydrogels with elevated levels of crosslinker. Hence, the hydrogels showed enhanced angiogenesis, accelerated wound healing with little or no observable in-vivo toxicity.

In vitro modulatory effects of functionalized pyrimidines and piperidine derivatives on Aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR) activities.

The development of biologically active molecules based on molecular recognition is an attractive and challenging task in medicinal chemistry and the molecules that can activate/deactivate certain receptors are of great medical interest. In this contribution, selected pyrimidine/piperidine derivatives were synthesized and tested for the ability to activate/deactivate Aryl hydrocarbon receptor (AhR) and Glucocorticoid receptor (GR). Tested compounds are shown to activate the receptors but to much lesser extent than positive controls, dioxin and dexamethasone for Ahr and GR, respectively. However, some of them antagonized the positive controls action. Although further in vivo studies are needed to fully characterize the bioactivities of these compounds, the reported in vitro evidences demonstrate that they might be used as the modulators of AhR and GR activities.

Organocatalyzed Novel Synthetic Methodology for Highly Functionalized Piperidines as Potent α-Glucosidase Inhibitors.

An efficient atom-economic one-pot synthesis of highly functionalized piperidines was achieved by catalytic multicomponent reaction. A wide range of heterogeneous and homogenous catalysts were explored; however, promising results were achieved when a ß-keto-ester was reacted with selected aromatic aldehydes and anilines by using N-acetyl glycine (NAG) as catalyst. The implication of this methodology is straightforward since the products were precipitated out from the reaction solution, eliminating the need of column chromatography purifications. The synthesized piperidines were screened against α-glucosidase inhibition, which revealed that these compounds were very active inhibitors, and some of the compounds showed even better inhibition than the reference compound, at low micromolar concentrations. In silico molecular modeling was also performed to investigate the binding modes of the compounds into the active sites of the target protein.

Novel meloxicam releasing electrospun polymer/ceramic reinforced biodegradable membranes for periodontal regeneration applications.

Periodontal disease is associated with the destruction of periodontal tissues, along with other disorders/problems including inflammation of tissues and severe pain. This paper reports the synthesis of meloxicam (MX) immobilized biodegradable chitosan (CS)/poly(vinyl alcohol) (PVA)/hydroxyapatite (HA) based electrospun (e-spun) fibers and films. Electrospinning was employed to produce drug loaded fibrous mats, whereas films were generated by solvent casting method. In-vitro drug release from materials containing varying concentrations of MX revealed that the scaffolds containing higher amount of drug showed comparatively faster release. During initial first few hours fast release was noted from membranes and films; however after around 5h sustained release was achieved. The hydrogels showed good swelling property, which is highly desired for soft tissue engineered implants. To investigate the biocompatibility of our synthesized materials, VERO cells (epithelial cells) were selected and cell culture results showed that these all materials were non-cytotoxic and also these cells were very well proliferated on these synthesized scaffolds. These properties along with the anti-inflammatory potential of our fabricated materials suggest their effective utilization in periodontital treatments.

Synthesis of piroxicam loaded novel electrospun biodegradable nanocomposite scaffolds for periodontal regeneration.

Development of biodegradable composites having the ability to suppress or eliminate the pathogenic micro-biota or modulate the inflammatory response has attracted great interest in order to limit/repair periodontal tissue destruction. The present report includes the development of non-steroidal anti-inflammatory drug encapsulated novel biodegradable chitosan (CS)/poly(vinyl alcohol) (PVA)/hydroxyapatite (HA) electro-spun (e-spun) composite nanofibrous mats and films and study of the effect of heat treatment on fibers and films morphology. It also describes comparative in-vitro drug release profiles from heat treated and control (non-heat treated) nanofibrous mats and films containing varying concentrations of piroxicam (PX). Electrospinning was used to obtain drug loaded ultrafine fibrous mats. The physical/chemical interactions were evaluated by Fourier Transform Infrared (FT-IR) spectroscopy. The morphology, structure and pore size of the materials were investigated by scanning electron microscopy (SEM). The thermal behavior of the materials was investigated by thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC). Control (not heat treated) and heat treated e-spun fibers mats and films were tested for in vitro drug release studies at physiological pH7.4 and initially, as per requirement burst release patterns were observed from both fibers and films and later sustained release profiles were noted. In vitro cytocompatibility was performed using VERO cell line of epithelial cells and all the synthesized materials were found to be non-cytotoxic. The current observations suggested that these materials are potential candidates for periodontal regeneration.

Synthesis and DPPH scavenging assay of reserpine analogues, computational studies and in silico docking studies in AChE and BChE responsible for Alzheimer's disease

Alzheimer's disease (AD) is a fast growing neurodegenerative disorder of the central nervous system and anti-oxidants can be used to help suppress the oxidative stress caused by the free radicals that are responsible for AD. A series of selected synthetic indole derivatives were biologically evaluated to identify potent new antioxidants. Most of the evaluated compounds showed significant to modest antioxidant properties (IC50 value 399.07 140.0±50 µM). Density Functional Theory (DFT) studies were carried out on the compounds and their corresponding free radicals. Differences in the energy of the parent compounds and their corresponding free radicals provided a good justification for the trend found in their IC50 values. In silico, docking of compounds into the proteins acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which are well known for contributing in AD disease, was also performed to predict anti-AD potential.

A doença de Alzheimer (DA) é uma doença neurodegenerativado sistema nervoso central, em rápido crescimento, e antioxidantes ajudam a suprimir o estresse oxidativo causado por radicais livres, responsávies pela DA. Avaliou-se, biologicamente, série de derivados sintéticos de indol selecionados para identificar novos antioxidantes. A maioria dos compostos avaliados apresentou de significativa a boa propriedade antioxidante (valor de IC50 399,07140.0 ± 50 µM). Eftuaram-se estudos de Teoria do Funcional de Densidade (DFT) com os compostos e os seus correspondentes radicais livres. As diferenças de energia entre os compostos protótipos e os radicais livres correspondentes proporcionaram boa justificativa para a tendência encontrada nos seus valores de IC50. O ancoramento in silico dos compostos com a acetilcolinesterase (AChE) e com a butirilcolinesterase (BChE), que contribuem para a DA, foi, também, realizado para prever o seu potencial anti-DA.

Chemical constituents of Citrus sinensis var. Shukri from Pakistan.

The variety 'Shukri' is a new hybrid of Citrus sinensis and is frequently grown for its sweet edible fruits in the southern part of Pakistan. The leaves of this hybrid variety have been investigated in search of secondary metabolites for the first time. As a result of chromatographic analysis of the methanolic extract, a new ceramide along with a flavonone glycoside and two steroids has been isolated, which were spectroscopically characterized as (E)-N-(1,3,4,5-tetrahydroxyhexadecan-2-yl)dec-4-enamide (1), atripliside B (2), beta-sitosterol (3), and beta-sitosterol-3-O-beta-D-glucopyranoside (4), respectively. Compound 1 was found to be a new addition in the list of natural products, whereas, to the best of our knowledge, compounds 2-4 have been isolated for the first time from this source.