Arsenic album 30C exhibits crystalline nano structure of arsenic trioxide and modulates innate immune markers in murine macrophage cell lines.

Macrophages are associated with innate immune response and M1-polarized macrophages exhibit pro-inflammatory functions. Nanoparticles of natural or synthetic compounds are potential triggers of innate immunity. As2O3 is the major component of the homeopathic drug, Arsenic album 30C.This has been claimed to have immune-boosting activities, however, has not been validated experimentally. Here we elucidated the underlying mechanism of Ars. alb 30C-mediated immune priming in murine macrophage cell line. Transmission Electron Microscopy (TEM) and X-ray diffraction (XRD) used for the structural analysis of the drug reveals the presence of crystalline As2O3 nanoparticles of cubic structure. Similarly, signatures of M1-macrophage polarization were observed by surface enhanced Raman scattering (SERS) in RAW 264.7 cells with concomitant over expression of M1 cell surface marker, CD80 and transcription factor, NF-κB, respectively. We also observed a significant increase in pro-inflammatory cytokines like iNOS, TNF-α, IL-6, and COX-2 expression with unaltered ROS and apoptosis in drug-treated cells. Enhanced expression of Toll-like receptors 3 and 7 were observed both in transcriptional and translational levels after the drug treatment. In sum, our findings for the first time indicated the presence of crystalline As2O3 cubic nanostructure in Ars. alb 30C which facilitates modulation of innate immunity by activating macrophage polarization.

Epigenomic interplay in tumor heterogeneity: Potential of epidrugs as adjunct therapy.

"Heterogeneity" in tumor mass has immense importance in cancer progression and therapy. The impact of tumor heterogeneity is an emerging field and not yet fully explored. Tumor heterogeneity is mainly considered as intra-tumor heterogeneity and inter-tumor heterogeneity based on their origin. Intra-tumor heterogeneity refers to the discrepancy within the same cancer mass while inter-tumor heterogeneity refers to the discrepancy between different patients having the same tumor type. Both of these heterogeneity types lead to variation in the histopathological as well as clinical properties of the cancer mass which drives disease resistance towards therapeutic approaches. Cancer stem cells (CSCs) act as pinnacle progenitors for heterogeneity development along with various other genetic and epigenetic parameters that are regulating this process. In recent times epigenetic factors are one of the most studied parameters that drive oxidative stress pathways essential during cancer progression. These epigenetic changes are modulated by various epidrugs and have an impact on tumor heterogeneity. The present review summarizes various aspects of epigenetic regulation in the tumor microenvironment, oxidative stress, and progression towards tumor heterogeneity that creates complications during cancer treatment. This review also explores the possible role of epidrugs in regulating tumor heterogeneity and personalized therapy against drug resistance.

Epigenetic signature in neural plasticity: the journey so far and journey ahead.

Neural plasticity is a remarkable characteristic of the brain which allows neurons to rewire their structure in response to internal and external stimuli. Many external stimuli collectively referred to as 'epigenetic factors' strongly influence structural and functional reorganization of the brain, thereby acting as a potential driver of neural plasticity. DNA methylation and demethylation, histone acetylation, and deacetylation are some of the frontline epigenetic mechanisms behind neural plasticity. Epigenetic signature molecules (mostly proteins) play a pivotal role in epigenetic reprogramming. Though neuro-epigenetics is an incredibly important field of emerging research, the critical role of signature proteins associated with epigenetic alteration and their involvement in neural plasticity needs further attention. This study gives an integrated and systematic overview of the current state of knowledge with a clear idea of types of neural plasticity and the context-dependent role of epigenetic signature molecules and their modulation by some natural bioactive compounds.

The benzene metabolite p-benzoquinone inhibits the catalytic activity of bovine liver catalase: A biophysical study.

The current communication reports the inhibitory effect of para-benzoquinone (p-BQ) on the structure and function of bovine liver catalase (BLC), a vital antioxidant enzyme. Both BLC and p-BQ were dissolved in respective buffers and the biophysical interaction was studied at physiological concentrations. For the first time our data reveals an enthalpy-driven interaction between BLC and p-BQ which is due to hydrogen bonding and van der Waals interactions. The binding affinity of p-BQ with BLC is nearly 2.5 folds stronger in MOPS buffer than Phosphate buffer. Importantly, the binding affinity between BLC and p-BQ was weak in HEPES buffer as compared to other buffers being the strongest in Tris buffer. Molecular docking studies reveal that binding affinity of p-BQ with BLC differ depending upon the nature of buffers rather than on the participating amino acid residues of BLC. This is further supported by the differential changes in secondary structures of BLC. The p-BQ-induced conformational change in BLC was evident from the reduced BLC activity in presence of different buffers in the following order, Phosphate>MOPS>Tris>HEPES. The absorbance peak of BLC was gradually increased and fluorescence spectra of BLC were drastically decreased when BLC to p-BQ molar ratio was incrementally enhanced from 0 to 10,000 times in presence of all buffers. Nevertheless, the declined activity of BLC was positively correlated with the reduced fluorescence and negatively correlated with the enhanced absorbance. Electrochemical study with cyclic voltammeter also suggests a direct binding of p-BQ with BLC in presence of different buffers. Thus, p-BQ-mediated altered secondary structure in BLC results into compromised activity of BLC.

A human epidermal growth factor-curcumin bandage bioconjugate loaded with mesenchymal stem cell for in vivo diabetic wound healing.

Bone-marrow-derived mesenchymal stem cells (MSCs) are of growing interest for the treatment of diabetic wound healing. However, they are often associated with poor proliferation and viability at the wounded site. Here, it is reported the use of human epidermal growth factor -curcumin bandage bioconjugate (EGF-Cur B) loaded with MSCs (MSCs-EGF-Cur B) at the wounded site for diabetic wound healing. Conjugation efficiency of EGF was determined by FTIR and XPS, surface morphology was analyzed by SEM and AFM and hydrophilicity by contact angle. Chemical integrity of curcumin with the polymeric matrix was studied by FTIR and, antiinflamatory and biocompatibility of EGF-Cur B were determined by TNF α ELISA and MTT study respectively. The culture of MSCs over EGF-Cur B enhanced MSC viability and expression of transcription factors associated with the maintenance of pluripotency and self-renewal (OCT¾, SOX2, and Nanog) as compared to MSCs grown in standard conditions. Its therapeutic effect was examined on diabetic full-thickness excisional wound model in terms of size and histological examination. Synergetic combinational approach especially when treated with MSCs-EGF-Cur B significantly enhanced wound closure by increasing granulation tissue formation, collagen deposition, and angiogenesis as compared to other groups. In conclusion, biocompatible therapeutic MSCs-EGF-Cur B might have great application for diabetic wound healing in the near future.

Protective efficacy of crocetin and its nanoformulation against cyclosporine A-mediated toxicity in human embryonic kidney cells.

AIM: This study is aimed to formulate crocetin-loaded lipid Nanoparticles (NPs) and to evaluate its antioxidant properties in a cyclosporine A-mediated toxicity in Human Embryonic Kidney (HEK-293) cells in vitro. MAIN METHODS: Crocetin-loaded NPs were prepared followed by physicochemical characterization. In vitro protective efficacy of crocetin and crocetin loaded NPs was investigated in cyclosporine A-mediated toxicity in HEK-293 cells by assessing free radical scavenging, DNA Nicking, cytotoxicity, intracellular Reactive oxygen species (ROS) inhibition, Mitochondrial membrane potential (MMPs) loss and evaluating the activity and expression of antioxidant enzymes and non-enzyme level. Further, we have studied the mechanism of protective activity of crocetin either native or in NPs by studying the expression of phase II detoxifying proteins (HO-1) via Nrf2 mediated regulation. KEY FINDINGS: Our results showed that pretreatment with crocetin and crocetin-loaded NPs attenuated the cyclosporine A-mediated toxicity, ROS production and exhibited enhance free radical scavenging ability and cytoprotective activity. Further, the treatment prevented MMPs loss by directly scavenging the ROS and restored the antioxidant enzyme network with normalization of heme oxygenase-1 (HO-1) expression by inhibiting nuclear translocation of Nrf2. SIGNIFICANCE: Pretreatment of crocetin and crocetin-loaded NPs provided pronounce protective effect against cyclosporine A-mediated toxicity in HEK-293 cells by nullifying the ROS formation and restored antioxidant network through inhibition of Nrf2 translocation and followed by expression of HO-1. Such an approach may be anticipated to be beneficial for antioxidant therapy.

Curcumin restores hepatic epigenetic changes in propylthiouracil(PTU)Induced hypothyroid male rats: A study on DNMTs, MBDs, GADD45a, C/EBP-ß and PCNA.

6-n-propyl-2-thiouracil (PTU), a thioamide drug, is used as an effective anti-thyroid agent to treat hyperthyroidism and Graves' disease. However, acute liver oxidative damage is an important side effect of the drug. In the present study, we report that PTU administration to rat induces hepatic epigenetic changes by upregulating expression of DNMT1, DNMT3a, DNMT3b, MBD4, MeCP2, p53 and Gadd45a and down-regulation of PCNA and C/EBP-ß. This is accompanied by decrease in the cell population and augmentation of cellular lipid peroxidation, an index of oxidative stress, in liver. On the other hand, co-administration of curcumin, a polyphenol extract from the rhizome of Curcuma longa L, along with PTU ameliorates PTU- induced oxidative stress and epigenetic parameters except for the expression of MBD4. Also, co-administration of curcumin with PTU resulted in restoration of hepatic cell population and histoarchitecture. The protective effect of curcumin to PTU-induced hepatotoxicity is attributed to its antioxidative properties.

Host plant-derived allelochemicals and metal components are associated with oxidative predominance and antioxidant plasticity in the larval tissues of silkworm, Antheraea mylitta: Further evidence of joint effects hypothesis.

Tasar silkworm, Antheraea mylitta is a polyphagous insect that primarily feeds on Terminalia arjuna, Terminalia tomentosa and Shorea robusta. However, larval rearing on S. robusta results in poor performance for the reasons unexplored. Oxidative burden imposed by host plants is presumed to be a determining factor for larval fitness. With this hypothesis we have analyzed the foliar constituents of the respective host plants, the levels of oxidative stress and antioxidant protection in the larval tissues in response to their altered feeding on different host plants for different durations (2 and 10 days). Results indicate that S. robusta leaves contain the highest amount of tannin and redox active metals compared to those of other host plants. Consequently, hemolymph and midgut tissues of the larvae shifted to S. robusta exhibited oxidative predominance. Increased activities of superoxide dismutase, catalase and glutathione S-transferase in the larval tissues indicated an adaptive response to host plant driven oxidative assault. Our in vitro study also strongly supplements the in vivo findings indicating S. robusta foliages as a strong inducer of lipid peroxidation (LPx). Copper and Iron were found to be more potent in inducing LPx in the midgut tissues of the larvae compared to Zinc and Manganese. This study for the first time demonstrates the combined implications of host plant derived allelochemicals and elements on oxidative stress and antioxidant plasticity in this insect. The overall findings also brace up the newly emerging concept on joint effects hypothesis (organic and elemental defence) for enhanced plant defence.