Enhanced Drug Carriage Efficiency of Curcumin-Loaded PLGA Nanoparticles in Combating Diabetic Nephropathy via Mitigation of Renal Apoptosis.

Objectives: The Curcuma-derived diferuloylmethane compound CUR, loaded on Poly (lactide-co-glycolic) acid (PLGA) nanoparticles was utilized to combat DN-induced renal apoptosis by selectively targeting and modulating Bcl2. Methods: Upon in silico molecular docking and screening study CUR was selected as the core phytocompound for nanoparticle formulation. PLGA-nano-encapsulated-curcumin (NCUR) were synthesized following standard solvent displacement method. The NCUR were characterized for shape, size and other physico-chemical properties by Atomic Force Microscopy (AFM), Dynamic Light Scattering (DLS) and Fourier-Transform Infrared (FTIR) Spectroscopy studies. For in vivo validation of nephro-protective effects, Mus musculus were pre-treated with CUR at a dose of 50 mg/kg b.w. and NCUR at a dose of 25 mg/kg b.w. (dose 1), 12.5 mg/kg b.w (dose 2) followed by alloxan administration (100 mg/kg b.w) and serum glucose levels, histopathology and immunofluorescence study were conducted. Results: The in silico study revealed a strong affinity of CUR towards Bcl2 (dock score -10.94 Kcal/mol). The synthesized NCUR were of even shape, devoid of cracks and holes with mean size of ~80 nm having -7.53 mV zeta potential. Dose 1 efficiently improved serum glucose levels, tissue-specific expression of Bcl2 and reduced glomerular space and glomerular sclerosis in comparison to hyperglycaemic group. Conclusion: This study essentially validates the potential of NCUR to inhibit DN by reducing blood glucose level and mitigating glomerular apoptosis by selectively promoting Bcl2 protein expression in kidney tissue.

Novel PLGA-encapsulated-nanopiperine promotes synergistic interaction of p53/PARP-1/Hsp90 axis to combat ALX-induced-hyperglycemia.

The present study predicts the molecular targets and druglike properties of the phyto-compound piperine (PIP) by in silico studies including molecular docking simulation, druglikeness prediction and ADME analysis for prospective therapeutic benefits against diabetic complications. PIP was encapsulated in biodegradable polymer poly-lactide-co-glycolide (PLGA) to form nanopiperine (NPIP) and their physico-chemical properties were characterized by AFM and DLS. ∼ 30 nm sized NPIP showed 86.68% encapsulation efficiency and - 6 mV zeta potential, demonstrated great interactive stability and binding with CT-DNA displaying upsurge in molar ellipticity during CD spectroscopy. NPIP lowered glucose levels in peripheral circulation by > 65 mg/dL compared to disease model and improved glucose influx in alloxan-induced in vivo and in vitro diabetes models concerted with 3-folds decrease in ROS production, ROS-induced DNA damage and 27.24% decrease in nuclear condensation. The 25% increase in % cell viability and inhibition in chromosome aberration justified the initiation of p53 and PARP DNA repairing protein expression and maintenance of Hsp90. Thus, the experimental study corroborated well with in silico predictions of modulating the p53/PARP-1/Hsp90 axis, with predicted dock score value of - 8.72, - 8.57, - 8.76 kcal/mol respectively, validated docking-based preventive approaches for unravelling the intricacies of molecular signalling and nano-drug efficacy as therapeutics for diabetics.

Morroniside interaction with poly (ADP-ribose) polymerase accentuates metabolic mitigation of alloxan-induced genotoxicity and hyperglycaemia: a molecular docking based in vitro and in vivo experimental therapeutic insight.

The present study tends to evaluate the possible potential of bio-active Morroniside (MOR), against alloxan (ALX)-induced genotoxicity and hyperglycaemia. In silico prediction revealed the interaction of MOR with Poly (ADP-ribose) polymerase (PARP) protein which corroborated well with experimental in vitro L6 cell line and in vivo mice models. Data revealed the efficacy of MOR in the selective activation of PARP protein and modulating other stress proteins NF-κB, and TNF-α to initiate protective potential against ALX-induced genotoxicity and hyperglycaemia. Further, the strong interaction of MOR with CT-DNA (calf thymus DNA) analyzed through CD spectroscopy, UV-Vis study and ITC data revealed the concerted action of bio-factors involved in inhibiting chromosomal aberration and micronucleus formation associated with DNA damage. Finally, MOR does not play any role in microbial growth inhibition which often occurs due to hyperglycemic dysbiosis. Thus, from the overall findings, we may conclude that MOR could be a potential drug candidate for the therapeutic management of induced-hyperglycaemia and genotoxicity.Communicated by Ramaswamy H. Sarma.

Exploring a new family of designer copper(II) complexes of anthracene-appended polyfunctional organic assembly displaying potential anticancer activity via cytochrome c mediated mitochondrial apoptotic pathway.

The present article describes the systematic study on design and synthesis, physicochemical properties and spectroscopic features, and potential anticancer activities of a family of novel copper(II)-based designer metal complexes [Cu2(acdp)(µ-Cl)(H2O)2] (1), [Cu2(acdp)(µ-NO3)(H2O)2] (2) and [Cu2(acdp)(µ-O2CCF3)(H2O)2] (3) of anthracene-appended polyfunctional organic assembly, H3acdp (H3acdp = N,N'-bis[anthracene-2-ylmethyl]-N,N'-bis[carboxymethyl]-1,3-diaminopropan-2-ol). Synthesis of 1-3 was accomplished under facile experimental conditions, preserving their overall integrity in solution. The incorporation of polycyclic anthracene skeleton within the backbone of organic assembly increases lipophilicity of resulting complexes, thereby dictating the degree of cellular uptake with improved biological activity. Complexes 1-3 were characterized by elemental analysis, molar conductance, FTIR, UV-Vis absorption/fluorescence emission titration spectroscopy, PXRD and TGA/DTA studies, including DFT calculations. The cellular cytotoxicity of 1-3 when studied in HepG2 cancer cell line showed substantial cytotoxic effects, whereas no such cytotoxicity was observed when exposed to normal L6 skeletal muscle cell line. Thereafter, the signaling factors involved in the process of cytotoxicity in HepG2 cancer cells were investigated. Alteration of cytochrome c and Bcl-2 protein expression levels along with modulation of mitochondrial membrane potential (MMP) in the presence of 1-3, strongly suggested the possibility of activating mitochondria-mediated apoptotic pathway involved in halting the cancer cell propagation. However, when a comparative assessment on their bio-efficacies was made, 1 showed higher cytotoxicity, nuclear condensation, DNA binding and damage, ROS generation and lower rate of cell proliferation compared to 2 and 3 in HepG2 cell line, indicating that the anticancer activity of 1 is significantly higher than that of 2 and 3.

Poly lactide-co-glycolide encapsulated nano-curcumin promoting antagonistic interactions between HSP 90 and XRCC1 proteins to prevent cypermethrin-induced toxicity: An in silico predicted in vitro and in vivo approach.

The present study describes the preparation and characterization of poly-lactide-co-glycolide encapsulated nano-curcumin (NCUR) drug, and its potential efficacy against the pesticide, such as cypermethrin-induced DNA damage and genotoxicity. Cypermethrin, the chosen pesticide, contaminates the aquatic environment after being washed off from the agricultural field to nearby water bodies leading to biomagnification-related perturbation of the ecological balance and overall environmental health by elevating adverse effects on non-target organisms producing toxic metabolites through biotransformation. The physico-chemical properties of NCUR were evaluated by employing the AFM, DLS and UV-Vis techniques. Sustainable release of NCUR, their bio-availability and ability to cross the blood-brain-barrier was assessed in the fish model. The in silico molecular docking study to identify the signalling proteins that interact with phyto-core-compound curcumin (CUR) was undertaken to predict the effectiveness of NCUR to combat pesticide-induced toxicity by modulating p53, PARP, HSP 90 and XRCC1 stress proteins, and other associated parameters in in vivo model using tilapia fish and in vitro model using L6 (mammalian skeletal muscle) cell line. Overall results revealed that negatively charged poly-lactide-co-glycolide (PLGA)-encapsulated NCUR (∼46 nm) showed hyperchromic binding with DNA and modulated the signalling cascades involved in stress and DNA repair mechanisms, corroborating well with the in silico prediction that would pave a new pathway in the arena of chemical and biological sciences to serve mankind.

A Family of [Zn6] Complexes from the Carboxylate-Bridge-Supported Assembly of [Zn2] Building Units: Synthetic, Structural, Spectroscopic, and Systematic Biological Studies.

The three discrete [Zn6] complexes [Na3Zn6(cpdp)3(µ-Bz)3(CH3OH)6][ZnCl4][ZnCl3(H2O)]·3CH3OH·1.5H2O (1), [Na3Zn6(cpdp)3(µ-p-OBz)3(CH3OH)6]·2H2O (2), and [Na3Zn6(cpdp)3(µ-p-NO2Bz)3(CH3OH)6]Cl3·2H2O (3), supported by the carboxylate-based multidentate ligand N,N'-bis[2-carboxybenzomethyl]-N,N'-bis[2-pyridylmethyl]-1,3-diaminopropan-2-ol (H3cpdp), have been successfully synthesized and fully characterized (Bz = benzoate; p-OBz = dianion of p-hydroxybenzoic acid; p-NO2Bz = p-nitrobenzoate). The complexes have been characterized by elemental analysis, FTIR, UV-vis, NMR spectroscopy, PXRD, and thermal analysis, including single-crystal X-ray crystallography of 1 and 2. The molecular architectures of 1-3 are built from the self-assembly of their corresponding [Zn2] units, which are interconnected to the central [Na3(CH3OH)6]3+ core by six endogenous benzoate groups, with each linking one Zn(II) and one Na(I) ion in a µ2:η1:η1-syn-anti bidentate fashion. The composition of the (cpdp3-)3/(Zn2+)6 complexes in 1-3 has been observed to be 1:2, on the basis of the UV-vis titration and NMR spectroscopic results, which is further supported by X-ray crystallography. Systematic biological studies performed with a mice model suggested possible antidiabetic efficacy as well as anticancer activities of the complexes. When complexes 1-3 were administered intraperitoneally in mice, 1 showed a lowering in the blood glucose level, overall maintenance of the pancreatic tissue mass, restriction of DNA damage in pancreatic cells, and retention of lipid droplet (LD) frequency, whereas 2 and 3 showed hepatic tissue mass consistency by inhibiting the DNA damage in hepatic cells, prior to the exposure to a potent diabetic inducer, alloxan (ALX). Similar trends of results were observed in inhibiting the generation of reactive oxygen species (ROS) in the pancreatic and hepatic cells, as examined by spectrofluorometric methods. Thus, 1 seems to be a better compound for overall diabetic management and control, whereas 2 and 3 seem to be promising compounds for designing chemopreventive drugs against hepatic carcinoma.

Phyto-chlorophyllin Prevents Food Additive Induced Genotoxicity and Mitochondrial Dysfunction via Cytochrome c Mediated Pathway in Mice Model.

OBJECTIVES: The issue of food-additive-toxicity causing several health hazards needs to be therapeutically managed with an immediate effect. Alloxan, a food additive, is used for whitening and shining flour. It is capable of inducing genotoxicity, diabetes, and associated mitochondrial dysfunction. Therefore, to explore a non-toxic, phyto-based compound that can delay the onset of diabetes and prevent the multitude of damage associated, Chlorophyllin (CHL) was selected for our study, having been reported to exhibit anti-cancer, anti-diabetes, and antiinflammatory responses. Therefore, the objective of the present study is to evaluate the protective role of CHL in controlling genotoxicity, glucose imbalance, and associated cytochrome c mediated mitochondrial signaling dysfunction against food-additive-induced genotoxicity, diabetic state, and its complexities in mice model in vivo. METHODS: Mice were pre-treated with CHL through oral gavage before they were exposed to alloxan. Diabetic markers, anti-oxidant enzyme profile, chromosomal study, mitochondrial functioning factors, and expression of proteins were checked against food-additive injected mice. RESULTS: The results revealed that CHL pre-treatment could delay the onset of diabetes, restrict alloxan-induced elevation of blood glucose, reduce DNA-damage and chromosomal aberration, optimize enzymatic profile (glucokinase, pyruvate, insulin), and modulates protein expression (insulin, IRS1, IRS2, GLUT2). Further, CHL-pre-treatment could stabilize mitochondrial-membrane-potential, intracellular calcium ion, ATP/ADP ratio, ATPase activity, thereby maintaining optimum functioning of cytochrome-c, bcl2, and caspase3 mitochondrial protein. CONCLUSION: Therefore, the present study reports, for the first time, the screening of phytobased bioactive CHL for preventing/limiting the extent of food-additive-induced genotoxicity and mitochondrial dysfunction and serves as an advanced therapeutic tool in the management of diabetes.