Impact of Oxysterols in Age-Related Disorders and Strategies to Alleviate Adverse Effects.

Oxysterols or cholesterol oxidation products are a class of molecules with the sterol moiety, derived from oxidative reaction of cholesterol through enzymatic and non-enzymatic processes. They are widely reported in animal-origin foods and prove significant involvement in the regulation of cholesterol homeostasis, lipid transport, cellular signaling, and other physiological processes. Reports of oxysterol-mediated cytotoxicity are in abundance and thus consequently implicated in several age-related and lifestyle disorders such as cardiovascular diseases, bone disorders, pancreatic disorders, age-related macular degeneration, cataract, neurodegenerative disorders such as Alzheimer's and Parkinson's disease, and some types of cancers. In this chapter, we attempt to review a selection of physiologically relevant oxysterols, with a focus on their formation, properties, and roles in health and disease, while also delving into the potential of natural and synthetic molecules along with bacterial enzymes for mitigating oxysterol-mediated cell damage.

Structures and conformation of a benzo-12-crown-4 containing dipeptide.

Crystal structures of the dipeptide Boc-12-Crown-4-L-DOPA-Gly-OMe (chi) and Boc-12-Crown-4-D/L-DOPA-Gly-OMe (rac) were solved by single crystal X-ray diffraction. Analysis of the packing differences in the crystal reveals that the presence of a water molecule in chi enables intermolecular contacts with the solvent that result in a different conformation of the dipeptide backbone itself. An uncommon N-H…N interaction stabilizes the peptide in its solid state.

Nanomaterials-assisted photothermal therapy for breast cancer: State-of-the-art advances and future perspectives.

Breast cancer (BC) remains an enigmatic fatal modality ubiquitously prevalent in different parts of the world. Contemporary medicines face severe challenges in remediating and healing breast cancer. Due to its spatial specificity and nominal invasive therapeutic regime, photothermal therapy (PTT) has attracted much scientific attention down the lane. PTT utilizes a near-infrared (NIR) light source to irradiate the tumor target intravenously or non-invasively, which is converted into heat energy over an optical fibre. Dynamic progress in nanomaterial synthesis was achieved with specialized visual, physicochemical, biological, and pharmacological features to make up for the inadequacies and expand the horizon of PTT. Numerous nanomaterials have substantial NIR absorption and can function as efficient photothermal transducers. It is achievable to limit the wavelength range of an absorbance peak for specific nanomaterials by manipulating their synthesis, enhancing the precision and quality of PTT. Along the same lines, various nanomaterials are conjugated with a wide range of surface-modifying chemicals, including polymers and antibodies, which may modify the persistence of the nanomaterial and diminish toxicity concerns. In this article, we tend to put forth specific insights and fundamental conceptualizations on pre-existing PTT and its advances upon conjugation with different biocompatible nanomaterials working in synergy to combat breast cancer, encompassing several strategies like immunotherapy, chemotherapy, photodynamic therapy, and radiotherapy coupled with PTT. Additionally, the role or mechanisms of nanoparticles, as well as possible alternatives to PTT, are summarized as a distinctive integral aspect in this article.

Nano cellulose-laden alginate/chitosan sponge with enhanced biological and hemostatic behavior.

Present study describes about hybrid hemostat developed with alginate (Alg), chitosan (Chito) and TEMPO-oxidized nanofibrillar cellulose (TOCNF) via lyophilization. All samples were analyzed under scanning electron microscopy (SEM) to determine their microstructure, size, and distribution of pores. Cell viability and proliferation of the scaffolds tested using fibroblast type L929 cells, showed it to be an excellent medium for cell generation. Blood coagulation started in ∼7.5 min, and most of the fibrin network formation took place in the Alg-Chito-TOCNF sponge, making it a suitable hemostatic material.

Natural TEMPO oxidized cellulose nano fiber/alginate/dSECM hybrid aerogel with improved wound healing and hemostatic ability.

Natural biopolymers have attracted considerable attention in a variety of biomedical applications. Herein, tempo-oxidized-cellulose nanofibers (T) were incorporated into sodium alginate/chitosan (A/C) to reinforce the physicochemical properties and further modified with decellularized skin extracellular matrix (E). A unique ACTE aerogel was successfully prepared, and its nontoxic behavior was validated using mouse fibroblast L929 cells. In vitro hemolysis results revealed excellent platelet adhesion and fibrin network formation abilities of the obtained aerogel. A high speed of homeostasis was attained based on the quick clotting in <60 s. Skin regeneration in vivo experiments were conducted using the ACT1E0 and ACT1E10 groups. In comparison to ACT1E0 samples, ACT1E10 samples demonstrated enhanced skin wound healing with increased neo-epithelialization, increased collagen deposition, and extracellular matrix remodeling. ACT1E10 was found to be a promising aerogel for skin defect regeneration due to its improved wound-healing ability.

Porosity controlled soya protein isolate-polyethylene oxide multifunctional dual membranes as smart wound dressings.

Multifunctional membranes S7P0.7, S7P3.0, and dual membranes composed of soya protein isolate (SPI) and polyethylene oxide (PEO) were produced for wound dressing applications. The internal structure of the membranes was confirmed by scanning electron microscopy (SEM) to be homogeneous and coarser with a porous-like network. S7P3.0 showed the tensile strength of 0.78 ± 0.04 MPa. In the absence of antibiotics, the dual membrane (combination of S7P0.7 and S7P3.0) exhibited potential antibacterial activity against Escherichia coli (Gram-negative) and Staphylococcus aureus (Gram-positive) bacteria. Hemolysis quantitative data presented in the image demonstrates that all samples exhibited hemolysis levels below 5 %. Dual membrane showed 77.93 ± 9.5 % blood uptake which reflects its absorption capacity. The combination of S7P0.7 and S7P3.0 influenced the dual membrane's antibacterial, biocompatibility, and good hemolytic potentials. The dual membranes' promising histology features after implantation suggest they could be used as wound dressings.

Physico-mechanical and in-vivo evaluations of tri-layered alginate-gelatin/polycaprolactone-gelatin-ß-TCP membranes for guided bone regeneration.

Guided bone regeneration (GBR) membranes favor periodontal regrowth, but they still have certain limitations, such as improper biodegradation and poor mechanical property. To overcome these shortcomings, we have generated a unique multifunctional membrane. A polycaprolactone/gelatin/ß-TCP and alginate/gelatin trilayered construction was fabricated through electrospinning and casting technology. The prepared membranes have suitable physicomechanical and in-vitro properties to confirm the compatibility of the product in the body. Phase analysis, functional groups, surface microstructure, and contact angle were measured as basic characteristics. For a mechanical performance evaluation, the tensile strength at suturing point was measured through pullout tensile strength test, and it showed the suture capability of bi-layered membranes. Highest tensile strength for A75G25 was recorded with 2.9 ± 0.15 MPa with 105% strain. Further, the osteoblast and fibroblast-type cell toxicity results showed that the electrospun membrane offered compatible environment to cells while the alginate sheet was found to be sufficiently capable to suppress the cellular attachment while also being a nontoxic material. Post-implantation, according to the in-vivo conclusions of the tri-layered membrane, there was appreciable bone formation. Compared to an implant without membrane covering, enhanced new bone formation can be identified after 8 weeks of implantation with P1G4ß10 membranes-covered site.

Exploring the theranostic potentials of miRNA and epigenetic networks in autoimmune diseases: A comprehensive review.

BACKGROUND: Autoimmune diseases (AD) are severe pathophysiological ailments that are stimulated by an exaggerated immunogenic response towards self-antigens, which can cause systemic or site-specific organ damage. An array of complex genetic and epigenetic facets majorly contributes to the progression of AD, thus providing significant insight into the regulatory mechanism of microRNA (miRNA). miRNAs are short, non-coding RNAs that have been identified as essential contributors to the post-transcriptional regulation of host genome expression and as crucial regulators of a myriad of biological processes such as immune homeostasis, T helper cell differentiation, central and peripheral tolerance, and immune cell development. AIMS: This article tends to deliberate and conceptualize the brief pathogenesis and pertinent epigenetic regulatory mechanism as well as miRNA networks majorly affecting five different ADs namely rheumatoid arthritis (RA), type 1 diabetes, multiple sclerosis (MS), systemic lupus erythematosus (SLE) and inflammatory bowel disorder (IBD) thereby providing novel miRNA-based theranostic interventions. RESULTS & DISCUSSION: Pertaining to the differential expression of miRNA attributed in target tissues and cellular bodies of innate and adaptive immunity, a paradigm of scientific expeditions suggests an optimistic correlation between immunogenic dysfunction and miRNA alterations. CONCLUSION: Therefore, it is not astonishing that dysregulations in miRNA expression patterns are now recognized in a wide spectrum of disorders, establishing themselves as potential biomarkers and therapeutic targets. Owing to its theranostic potencies, miRNA targets have been widely utilized in the development of biosensors and other therapeutic molecules originating from the same.

Porous CDHA microspheres laden brushite-based injectable bone substitutes for improved bone regeneration.

Porous CDHA microspheres were incorporated into innovative injectable calcium phosphate cement (CPC) to enhance the rate of degradation and bioactivity of bone regeneration. With varying content of CDHA microspheres, the final setting time varied between 12 and 17 min, which is adequate for surgeons to accomplish the implantation. Compressive strength ranged between 6 and 8 MPa, until the addition of porous CDHA microsphere into CPC reached 20 vol %, but decreased dramatically after 30 vol % addition. Therefore, CPC with 20 vol % addition of porous CDHA microspheres was found appropriate for in vitro degradation and cytocompatibility studies. Histological assessment identified new bone formation around the injected bone substitute without significant inflammatory reactions. In vivo analysis of rat femoral defects revealed a threefold higher bone formation in CPC/CDHA 20 vol % than in CPC, due to the more cell migration and penetration into CPC by the existence of porous CDHA microspheres. Based on the promising results obtained, this novel injectable bone substitute may be useful in bone regeneration.

Machine learning approaches and their applications in drug discovery and design.

This review is focused on several machine learning approaches used in chemoinformatics. Machine learning approaches provide tools and algorithms to improve drug discovery. Many physicochemical properties of drugs like toxicity, absorption, drug-drug interaction, carcinogenesis, and distribution have been effectively modeled by QSAR techniques. Machine learning is a subset of artificial intelligence, and this technique has shown tremendous potential in the field of drug discovery. Techniques discussed in this review are capable of modeling non-linear datasets, as well as big data of increasing depth and complexity. Various machine learning-based approaches are being used for drug target prediction, modeling the structure of drug target, binding site prediction, ligand-based similarity searching, de novo designing of ligands with desired properties, developing scoring functions for molecular docking, building QSAR model for biological activity prediction, and prediction of pharmacokinetic and pharmacodynamic properties of ligands. In recent years, these predictive tools and models have achieved good accuracy. By the use of more related input data, relevant parameters, and appropriate algorithms, the accuracy of these predictions can be further improved.

Injectable demineralized bone matrix particles and their hydrogel bone grafts loaded with ß-tricalcium phosphate powder and granules: A comparative study.

Demineralized bone matrix (DBM), has been used as a bone-graft material because of its osteoconductivity and osteoinductivity. However, the previous research report that supports the single use of DBM is limited by its rapid resorption caused by the lack of calcium and phosphate. ß-Tricalcium phosphate (TCP) is an enriched calcium phosphate material suitable for bone healing with osteoconductive properties. In this study, we have developed injectable bone graft by the loading two kinds of TCP in DBM particles and thermo-sensitive DBM-derived hydrogel (hDBM). TCP powder (pTCP) and TCP granules (gTCP) were loaded into hDBM and DBM, respectively. The bone formation effect was investigated according to the morphological features of TCP. Residual growth factor concentrations were investigated; microstructure and morphology were characterized by SEM. In-vitro studies showed that hDBM/DBM/pTCP and hDBM/DBM/gTCP bone grafts were biocompatible and could promote osteogenesis by up-regulating the expression of Runx2 and OPN, bone-related genes. In-vivo studies using the rabbit-femur defect model revealed that the implanted hDBM/DBM/pTCP bone graft showed similar histology to that of fibrous dysplasia with the expression of CD68, whereas hDBM/DBM/gTCP showed good bone formation. Loading of gTCP in place of pTCP was noticed as an effective way to improve bone regeneration in an injectable hDBM/DBM hydrogel-based bone graft.

In-vitro and in-vivo biocompatibility of dECM-alginate as a promising candidate in cell delivery for kidney regeneration.

In this study, kidney decellularized extracellular matrix (dECM) and alginate (ALG) hybrid injectable hydrogel, with the purpose of delivering progenitor cells for tissue engineering, were prepared by using a physical crosslinking method in a CaCl2 solution with high porosity for the exchange of nutrition and waste. In addition, the physical appearance and surface morphology of the hydrogel were investigated using optical and scanning electron microscopy, respectively. The functional groups of the dECM/ALG xerogels was examined via Fourier transform infrared spectroscopy. The biocompatibility of dECM/ALG xerogels was examined in-vitro using renal progenitor cells obtained from adult rat kidney. Enhanced biocompatibility and significant hemostatic behavior was noticed. Furthermore, the in-vivo biocompatibility of dECM/ALG hydrogel with progenitor cells was determined in the deep renal cortex for 7 and 21 days, in order to assess the foreign body reaction and inflammatory response. Early-stage glomerulus-like structure and dense linear cell network-like phenomenon were noticed. Loading of progenitor cells together with hydrogel enhances the cell density obviously due to cell migration from host and form a pattern. The desired early stage in-vivo response to progenitor cell-laden dECM/ALG hydrogel plays a potential role in kidney regeneration long term.

Tailored alginate/PCL-gelatin-ß-TCP membrane for guided bone regeneration.

Membranes prepared for guided bone regeneration (GBR) signify valued resources, inhibiting fibrosis and assisting bone regenration. However, existing membranes lack bone regenerative capacity or adequate degradation profile. An alginate-casted polycaprolactone-gelatin-ß-tricalcium phosphate dual membrane was fabricated by electrospinning and casting processes to enhance new bone formation under a GBR process. Porous membranes were synthesized with suitable hydrophilicity, swelling, and degradation behavior to confirm the compatibility of the product in the body. Furthermore, osteoblast-type cell toxicity and cell adhesion results showed that the electrospun membrane offered compatible environment to cells while the alginate sheet was found capable enough to supress the cellular attachment, but was a non-toxic material. Post-implantation, thein-vivooutcomes of the dual-layered membrane, showed appreciable bone formation. Significantly, osteoid islands had fused in the membrane group by eight weeks. The infiltration of fibrous tissues was blocked by the alginate membrane, and the ingrowth of new bone was enhanced. Immunocytochemical analysis indicated that the dual membrane could direct more proteins which control mineralization and convene osteoconductive properties of tissue-engineered bone grafts.

Effect of Co-culture of mesenchymal stem cell and glomerulus endothelial cell to promote endothelialization under optimized perfusion flow rate in whole renal ECM scaffold.

In recent era, many researches on implantable bio-artificial organs has been increased owing to large gap between donors and receivers. Comprehensive organ based researches on perfusion culture for cell injury using different flow rate have not been conducted at the cellular level. The present study investigated the co-culture of rat glomerulus endothelial cell (rGEC) and rat bone marrow mesenchymal stem cells (rBMSC) to develop micro vascularization in the kidney scaffolds culturing by bioreactor system. To obtain kidney scaffold, extracted rat kidneys were decellularized by 1% sodium dodecyl sulfate (SDS), 1% triton X-100, and distilled water. Expanded rGECs were injected through decellularized kidney scaffold artery and cultured using bioreactor system. Vascular endothelial cells adhered and proliferated on the renal ECM scaffold in the bioreactor system for 3, 7 and 14 days. Static, 1 â€‹ml/min and 2 â€‹ml/min flow rates (FR) were tested and among them, 1 â€‹ml/min flow rate was selected based on cell viability, glomerulus character, inflammation/endothelialization proteins expression level. However, the flow injury was still existed on primary cell cultured at vessel in kidney scaffold. Therefore, co-culture of rGEC â€‹+ â€‹rBMSC found suitable to possibly solve this problem and resulted increased cell proliferation and micro-vascularization in the glomerulus, reducing inflammation and cell death which induced by flow injury. The optimized perfusion rate under rGEC â€‹+ â€‹rBMSC co-culture conditions resulted in enhanced endocellularization to make ECM derived implantable renal scaffold and might be useful as a way of treatment of the acute renal failure.

In silico identification and validation of triarylchromones as potential inhibitor against main protease of severe acute respiratory syndrome coronavirus 2.

The ongoing pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused COVID-19 has emerged as a severe threat to the life of human kind. The identification and designing of appropriate and reliable drug molecule for the treatment of COVID-19 patients is the pressing need of the present time. Among different drug targets, the main protease of SARS-CoV-2 is being considered as most effective target. In addition to the drug repurposing, different compounds of natural as well as synthetic origins are being investigated for their efficacy against different drug targets of SARS-CoV-2 virus. In that context, the chromone based natural flavonols have also exhibited significant antiviral properties against different targets of SARS-CoV-2. The in silico studies presented here discloses the efficacy of triarylchromones (TAC) as potential inhibitor against main protease of SARS-CoV-2. The molecular docking and ADMET study performed using 14 arylchromones which could easily be accessed through simple synthetic protocols, revealed best binding affinities in case of TAC-3 (-11.2 kcal/mol), TAC-4 (-10.5 kcal/mol), TAC-6 (-11.2 kcal/mol), TAC-7 (-10.0 kcal/mol). Additional validation studies including molecular dynamics simulation and binding energy calculation using MMGBSA for protein ligand complex for 100 ns revealed the best binding interaction of TAC-3, TAC-4, TAC-6, TAC-7 against main protease of SARS-CoV-2. Moreover, the in vitro and preclinical validation of identified compounds will help us to understand the molecular mechanisms of regulation of TACs against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Fabrication and characterization of cellulose nano crystal and soya modified injectable brushite bone cement for enhanced bone regeneration.

An inventive, cellulose nano crystal (CNC) and isolated soya flour (SPI) laden brushite-based injectable bone substitute (IBS) material has been developed in the present research. The purpose of the study was to discover the physical, mechanical, in-vitro biological, and in-vivo bone forming ability of the prepared IBS. The incomparable abilities of CNC together with SPI resulted in enhanced biocompatibility, mechanical strength, and biodegradability, which together with its exclusive properties, sort it ideal for bone restoration. The CNC/SPI laden composites showed suitable mechanical strength of ~10.5 MPa for BM23 composite. The in- vitro cytocompatibility of the prepared samples were evaluated by osteoblast type MC3T3-E1 cells via MTT assay. Protein absorption and mineralization behavior of BRCNC2.0 was around (1.7 and 2.3)-fold higher than that of BR, respectively. In vivo performance was also found appreciable with ~(31.33 ± 2.04) % BV/TV. Incorporation of SPI resulted in enhanced bone formation at the central zone of the defect, while unmodified samples resulted in bone formation only at the peripheral zone. The findings of the current study proposed that CNC/SPI laden, brushite based injectable bone substitute might be proficient for bone regeneration ability.

Arylcoumarin perturbs SARS-CoV-2 pathogenesis by targeting the S-protein/ACE2 interaction.

The vaccination drive against COVID-19 worldwide was quite successful. However, the second wave of infections was even more disastrous. There was a rapid increase in reinfections and human deaths due to the appearance of new SARS-CoV-2 variants. The viral genome mutations in the variants were acquired while passing through different human hosts that could escape antibodies in convalescent or vaccinated individuals. The treatment was based on oxygen supplements and supportive protocols due to the lack of a specific drug. In this study, we identified three lead inhibitors of arylated coumarin derivatives 4,6,8-tri(naphthalen-2-yl)-2H-chromen-2-one (NF1), 8-(4-hydroxyphenyl)-4,6-di(naphthalen-2-yl)-2H-chromen-2-one (NF12) and 8-(4-hydroxyphenyl)-3,6-di(naphthalen-2-yl)-2H-chromen-2-one (NF-13) that showed higher binding affinity towards the junction of SARS-CoV-2 spike glycoprotein (S-protein) and human angiotensin-converting enzyme 2 (ACE2) receptor. Using molecular docking analysis, we identified the putative binding sites of these potent inhibitors. Notably, molecular dynamics (MD) simulation and MM-PBSA studies confirmed that these inhibitors have the potential ability to bind Spike-protein/ACE2 protein complex with minimal energy. Further, the two major concerns are an adaptive mutation of spike proteins- N501Y and D614G which displayed strong affinity towards NF-13 in docking analysis. Additionally, in vitro and in vivo studies are required to confirm the above findings and develop the inhibitors as potential drugs against SARS-CoV-2.

An X-ray micro-fluorescence study to investigate the distribution of Al, Si, P and Ca ions in the surrounding soft tissue after implantation of a calcium phosphate-mullite ceramic composite in a rabbit animal model.

Synthetic calcium phosphates, despite their bioactivity, are brittle. Calcium phosphate- mullite composites have been suggested as potential dental and bone replacement materials which exhibit increased toughness. Aluminium, present in mullite, has however been linked to bone demineralisation and neurotoxicity: it is therefore important to characterise the materials fully in order to understand their in vivo behaviour. The present work reports the compositional mapping of the interfacial region of a calcium phosphate--20 wt% mullite biocomposite/soft tissue interface, obtained from the samples implanted into the long bones of healthy rabbits according to standard protocols (ISO-10993) for up to 12 weeks. X-ray micro-fluorescence was used to map simultaneously the distribution of Al, P, Si and Ca across the ceramic-soft tissue interface. A well defined and sharp interface region was present between the ceramic and the surrounding soft tissue for each time period examined. The concentration of Al in the surrounding tissue was found to fall by two orders of magnitude, to the background level, within ~35 µm of the implanted ceramic.

Fabrication and properties of alginate/calcium phosphate hybrid beads: A comparative study.

BACKGROUND: Microbeads for bone repair have been widely studied because they can be conveniently used in clinical applications. OBJECTIVE: This study concerns the preparation, physical properties and in vitro characterisation of different types of alginate/calcium phosphate (CaP) ceramic microbeads, which were designed for use as drug delivery systems and bone-regeneration matrices. METHODS: Hybrid microbeads were successfully prepared from sodium alginate and various CaP, namely 𝛼-tricalcium phosphate, 𝛽-tricalcium phosphate and hydroxyapatite using the liquid droplet method. RESULTS: Porosity, swelling properties and in vitro degradation of the microbeads in the aqueous environment were significantly changed by the added CaP. The compressive strength of the blocks fabricated from the beads was around 120 MPa irrespective of the type of CaP. The initial release rate of the model drug methylene blue was suppressed by the addition of CaP. CONCLUSION: The alginate-CaP composite beads hold promising potential as an encapsulation carrier of drugs and component of bone substitutes.

In-vitro and in-vivo hemostat evaluation of decellularized liver extra cellular matrix loaded chitosan/gelatin spongy scaffolds for liver injury.

Individually, Chitosan (C) and Gelatin (G) are increasingly being used for the simulation and testing of surgical procedures. In the present study, at combination of chitosan/gelatin (CG) was optimized and later enriched by the loading decellularized liver extracellular matrix powder (dLECM) prepared from porcine liver, we hypothesized CG-dLECM combination would enhance wound healing and reduce postoperative complications after liver surgery. Varying concentration of dLECM (1, 4, and 8 mg/ml) were loaded into CG, and evaluation was done to get the optimized composition. Preliminary analysis on the microstructure, in-vitro degradation, and blood clot kinetics and in-vitro cytocompatibility showed that the CG with 4 mg/ml dLECM (CG-E4) was the most suitable composition for further consideration. The prepared CG-E4 spongy scaffold enhances fast post-operative recovery with a higher blood absorption and fast clotting time (~50 s). In addition, CG-E4 spongy scaffold implanted at rat liver wound showed desired biocompatibility as evidenced by reduced wound size, earlier bioabsorption and accelerated liver regeneration. In the present study, we demonstrated that, CG with dLECM spongy scaffold as a potential hemostatic material in the prevention of excessive hemorrhage during surgeries.