Polycaprolactone/graphene oxide/acellular matrix nanofibrous scaffolds with antioxidant and promyelinating features for the treatment of peripheral demyelinating diseases.

Peripheral demyelinating diseases entail damage to axons and Schwann cells in the peripheral nervous system. Because of poor prognosis and lack of a cure, this group of diseases has a global impact. The primary underlying cause of these diseases involves the inability of Schwann cells to remyelinate the damaged insulating myelin around axons, resulting in neuronal death over time. In the past decade, extensive research has been directed in the direction of Schwann cells focusing on their physiological and neuroprotective effects on the neurons in the peripheral nervous system. One cause of dysregulation in the remyelinating function of Schwann cells has been associated with oxidative stress. Tissue-engineered biodegradable scaffolds that can stimulate remyelination response in Schwann cells have been proposed as a potential treatment strategy for peripheral demyelinating diseases. However, strategies developed to date primarily focussed on either remyelination or oxidative stress in isolation. Here, we have developed a multifunctional nanofibrous scaffold with material and biochemical cues to tackle both remyelination and oxidative stress in one matrix. We developed a nanofibrous scaffold using polycaprolactone (PCL) as a foundation loaded with antioxidant graphene oxide (GO) and coated this bioscaffold with Schwann cell acellular matrix. In vitro studies revealed both antioxidant and remyelination properties of the developed bioscaffold. Based on the results, the developed multifunctional bioscaffold approach can be a promising biomaterial approach for treating demyelinating diseases.

Schwann cell-matrix coated PCL-MWCNT multifunctional nanofibrous scaffolds for neural regeneration.

Nerve tissue engineering aims to create scaffolds that promote nerve regeneration in the damaged peripheral nervous system. However, there remain some challenges in the construction of scaffolds in terms of mechanical properties and cellular behaviour. The present work aims to develop multifunctional implantable nanofibrous scaffolds for nerve regeneration. Using electrospinning, nanofibrous neat polycaprolactone (PCL) and PCL/multiwalled carbon nanotubes (PCL-MWCNT) composite scaffolds were prepared in random and aligned morphology. Schwann cells and their secreted biochemical factors are responsible for neuronal survival in the peripheral nervous system. Therefore, the acellular matrix of Schwann cells was spin-coated on the PCL-MWCNT scaffolds to aid nerve regeneration. Physicochemical and mechanical properties, and the in vitro cellular response of the developed nanofibrous were investigated. We observed no significant change in fibre diameter between neat PCL and PCL-MWCNT scaffolds regardless of the morphology. However, the inclusion of MWCNT reduced the mechanical strength of nanocomposite scaffolds compared to neat PCL. In vitro study revealed biocompatibility of the developed scaffolds both with and without an acellular matrix. Gene expression study revealed a significant increase in peripheral myelin protein (PMP22) expression on acellular matrix-coated PCL-MWCNT scaffolds compared to neat PCL counterparts. Overall, the results suggested Schwann cell matrix-coated PCL-MWCNT nanofibers as a promising conduit for peripheral nerve regeneration.

Molecular modeling piloted analysis for semicarbazone derivative of curcumin as a potent Abl-kinase inhibitor targeting colon cancer.

The human Abl kinases comprise a family of proteins that are known to be key stimulus drivers in the signaling pathways modulating cell growth, cell survival, cell adhesion, and apoptosis. Recent collative studies have indicated the role of activation of Abl and Abl-related genes in solid tumors; further terming the Abl kinases as molecular switches which promote proliferation, tumorigenesis, and metastasis. The up-regulated Abl-kinase expression in colorectal cancer (CRC) and the role of Abl tyrosine kinase activity in the Matrigel invasion of CRC cells have cemented its significance in CRC advancement. Therefore, the requisite of identifying small molecules which serve as Abl selective inhibitors and designing anti-Abl therapies, particularly for CRC tumors, has driven this study. Curcumin has been touted as an effective inhibitor of cancer cells; however, it is limited by its physicochemical inadequacies. Hence, we have studied the behavior of heterocyclic derivatives of curcumin via computational tools such as pharmacophore-based virtual screening, molecular docking, free-energy binding, and ADME profiling. The most actively docked molecule, 3,5-bis(4-hydroxy-3-methylstyryl)-1H-pyrazole-1-carboxamide, was comparatively evaluated against Curcumin via molecular dynamics simulation using Desmond, Schrödinger. The study exhibited the improved stability of the derivative as compared to Curcumin in the tested protein pocket and displayed the interaction bonds with the contacted key amino acids. To further establish the claim, the derivatives were synthesized via the mechanism of cyclization of Curcumin and screened in vitro using SRB assay against human CRC cell line, HCT 116. The active derivative indicated an IC50 value of 5.85 µM, which was sevenfold lower as compared to Curcumin's IC50 of 35.40 µM. Hence, the results base the potential role of the curcumin derivative in modulating Abl-kinase activity and in turn may have potential therapeutic value as a lead for CRC therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-021-03051-9.

The potency of heterocyclic curcumin analogues: An evidence-based review.

Curcumin, a potent phytochemical, has been a significant lead compound and has been extensively investigated for its multiple bioactivities. Owing to its natural origin, non-toxic, safe, and pleiotropic behavior, it has been extensively explored. However, several limitations such as its poor stability, bioavailability, and fast metabolism prove to be a constraint to achieve its full therapeutic potential. Many approaches have been adopted to improve its profile, amongst which, structural modifications have indicated promising results. Its symmetric structure and simple chemistry have prompted organic and medicinal chemists to manipulate its arrangement and study its implications on the corresponding activity. One such recurring and favorable modification is at the diketo moiety with the aim to achieve isoxazole and pyrazole analogues of curcumin. A modification at this site is not only simple to achieve, but also has indicated a superior activity consistently. This review is a comprehensive and wide-ranged report of the different methods adopted to achieve several cyclized curcumin analogues along with the improvement in the efficacy of the corresponding activities observed.

Developments in the anticancer activity of structurally modified curcumin: An up-to-date review.

Curcumin is a pharmacologically active polyphenol derived from the popular spice element-Turmeric. The therapeutic activity of curcumin has been extensively investigated over the last few decades and reports suggest the role of curcumin in a large number of biological activities, particularly its prominent anticancer activity. Curcumin, being a pleiotropic molecule, is a regulator of multiple molecular targets which play crucial roles in various cell signaling pathways. It is known to suppress transformation, inhibit proliferation as well as induce apoptosis. However, despite all these benefits, the efficacy of curcumin remains limited due to its poor bioavailability, poor absorption within the systemic circulation and rapid elimination from the body. To overcome these limiting factors, researchers all around the world are working towards designing a synthetic and superior curcuminoid by making suitable structural modifications to the parent skeleton. These curcuminoids, mainly analogues and derivatives, will not only improve the physicochemical properties but also enhance the efficacy simultaneously. The present review will provide a comprehensive account of the analogues and derivatives of curcumin that have been reported since 2014 which have indicated a better anticancer activity than curcumin.

Crosslinking Biopolymers for Advanced Drug Delivery and Tissue Engineering Applications.

A popular approach to attaining controlled drug delivery from polymer based systems involves the use of cross-linkers. In order to improve the properties of polymers specific to their applications, they can be modified by either physical cross-linkers (high pressure, irradiation) or chemical cross-linkers (glutaraldehyde, genipin). This chapter provides an insight into the different types and mechanisms of cross-linking. It reviews the existing drug delivery systems to understand the effects of cross-linking in them. The recent applications of cross-linked polymeric drug delivery and tissue engineering systems are also discussed.

Gelatin-based emulsion gels for diffusion-controlled release applications.

Emulsion gels are now emerging as a new class of biomaterials for controlled-release applications. Novel food-grade emulsion gels consisting of indomethacin-loaded vegetable oil droplets dispersed within genipin-cross-linked gelatin-based hydrogels were characterized for their physical and drug-release properties. Varying the weight ratio of the aqueous and oil phases between 5:1 and 5:5 was used to modulate construct swelling and drug release. The dispersed oil droplets generally became larger, more polydispersed and aggregated with an increase in oil fraction. Cross-linking with genipin increased the puncture strength of the gels vs. their uncross-linked counterparts and was necessary to prevent breakdown. Swelling of the emulsion gels demonstrated Fickian behaviour at all gelatin: oil ratios. Indomethacin release followed Fickian diffusion at higher oil fractions only, demonstrating coupled Fickian and super-Case-II transport at lower oil ratios (5:1, 5:2 and 5:3). Overall, the introduction of a dispersed oil phase within a hydrogel was exploited for the release of hydrophobic bioactive compounds, with tailoring of composition used to significantly alter release kinetics.

Characterization and scanning electron microscopic investigation of crosslinked freeze dried gelatin matrices for study of drug diffusivity and release kinetics.

Drug delivery is a promising technique to enhance the therapeutic efficacy of the drug. However, properties of carrier materials require intense improvement for effective transport of drug molecules. In the current study, attempts have been made to develop freeze dried gelatin matrices cross linked with genipin at various temperatures (5°C, 15°C and 25°C) prior to freeze-drying (-80°C). The freeze dried matrices thus obtained at the said temperatures are characterized for crosslinking density, compression strength, swelling behaviors. The matrix crosslinked at 25°C showed highest Flory-Rehner crosslinking density (467 ± 46) (p<0.05), highest compressive strength (12.36 ± 0.12) (p<0.05) and lowest equilibrium water content. In this context, scanning electron microscopy (SEM) was performed to study the surface morphology (size and shape of pores) of the crosslinked matrices. These images were further processed for quantitative analysis of morphological features, viz., areas, radius, ferret diameter, length of major and minor axis and eccentricity using MATLAB toolboxes. These quantitative analyses correlate transport and the release kinetics of model anti-inflammatory drug (indomethacin) from crosslinked matrices in vitro to tune as a controllable delivery system. The diffusional exponent (n) for all constructs ranging from 0.61 to 0.69 (p<0.05) (0.45

Crosslinking of gelatin-based drug carriers by genipin induces changes in drug kinetic profiles in vitro.

Hydrogels are extensively studied as carrier matrices for the controlled release of bioactive molecules. The aim of this study was to design gelatin-based hydrogels crosslinked with genipin and study the impact of crosslinking temperature (5, 15 or 25°C) on gel strength, microstructure, cytocompatibility, swelling and drug release. Gels crosslinked at 25°C exhibited the highest Flory-Rehner crosslink density, lowest swelling ratio and the slowest release of indomethacin (Idn, model anti-inflammatory drug). Diffusional exponents (n) indicated non-Fickian swelling kinetics while drug transport was anomalous. Hydrogel biocompatibility, in vitro cell viability, cell cycle experiments with AH-927 and HaCaT cell lines indicated normal cell proliferation without any effect on cell cycle. Overall, these results substantiated the use of genipin-crosslinked hydrogels as a viable carrier matrix for drug release applications.

Effect of flaxseed gum on reduction of blood glucose and cholesterol in type 2 diabetic patients.

The effects of ingestion of flaxseed gum on blood glucose and cholesterol, particularly low-density lipoprotein cholesterol, in type 2 diabetes were evaluated. Flaxseed gum was incorporated in wheat flour chapattis. Sixty patients of type 2 diabetes were fed a daily diet for 3 months, along with six wheat flour chapattis containing flaxseed gum (5 g), as per the recommendations of the American Diabetic Association. The control group (60 individuals) consumed an identical diet but the chapattis were without gum. The blood biochemistry profiles monitored before starting the study and at monthly intervals showed fasting blood sugar in the experimental group decreased from 154 ± 8 mg/dl to 136 ± 7 mg/dl (P=0.03) while the total cholesterol reduced from 182 ± 11 mg/dl to 163 ± 9 mg/dl (P=0.03). Results showed a decrease in low-density lipoprotein cholesterol from 110 ± 8 mg/dl to 92 ± 9 mg/dl (P=0.02). The study demonstrated the efficacy of flax gum in the blood biochemistry profiles of type 2 diabetes.

Long-term effects of a carbohydrate-rich diet on fasting blood sugar, lipid profile, and serum insulin values in rural Bengalis.

BACKGROUND: The prevalence of Type 2 diabetes is increasing in rural areas of India, where there is also often a lack of health infrastructure. Thus, a proper dietary study with the view of combating diabetes is essential. The aim of the present study was to determine the long-term effect of a carbohydrate-rich diet in rural Bengal. METHODS: Volunteers (n = 320) were selected from three villages in Kharagpur and were randomly divided into a control and experimental group (n = 160 in each). The design of the study was such that non-significant differences in any of the dependent variables were maintainted prior to the application of control or treatment modes. In the control group, volunteers consumed <70% carbohydrate as part of their diet, whereas in the experimental group carbohydrate consumption was >70%. Blood samples from both groups were collected on yearly basis for 5 years and fasting blood sugar (FBS), lipid profile and serum insulin values were analyzed. RESULTS: The blood biochemistry profiles were monitored before the start and at the end of the study. The results indicate that increased intake of carbohydrate causes significant increases in FBS (P < 0.05) and serum insulin (P < 0.05), as well as changes in the lipid profile, particularly triglycerides (P < 0.05) and very low-density lipoprotein-cholesterol (VLDL-C; P < 0.05). CONCLUSIONS: The effects of increased carbohydrate on FBS, serum insulin, triglycerides and VLDL-C indicate that a proper nutritional policy needs to be implemented for this population of rural, low-income Bengalis.