Curcumin regulates colon cancer by inhibiting p-glycoprotein in in-situ cancerous colon perfusion rat model

STUDY BACKGROUND: Studies on p-glycoprotein was carried out world vide with cell lines like Caco2, MDR1-LLC-PK1 and MDR1-MDCK in-vitro, but most of the results were failed to produce similar results in-vivo. In the present study curcumin inhibitory action on p-glycoprotein increased permeability of irinotecan, so in the colon cancer it would be beneficial if curcumin used as add on therapy. METHODS: Intra-rectal administered of N-Nitroso N-methyl urea (2 mg/Kg) induced colon cancer. Single pass whole length of colon in-situ perfusion was carried out in rats with irinotecan to study the influence of p-glycoprotein modulators like verapamil and curcumin. The rats were divided in to 5 groups (n=6), Group I served as control perfused with 30 μg/ml of irinotecan, propronolol and phenol red. Group II was cancerous group, induced by N-methyl N-nitroso urea. Group III was perfused with irinotican in cancerous rats. Group IV, perfused with irinotican in presence of verapamil and group V was pre-treated with curcumin and then perfused with irinotican and was estimated by HPLC-UV to effective permeability coefficient. RESULTS: Our qRT-PCR and Western blot results confirmed that about 15-fold decreases in the expression of p-glycoprotein (P-gp) in curcumin treated colon cancer cells. Irinotecan was increased to 0.00066 cm/s and about 11-fold increase in verapamil-coperfused group, where curcumin pre-treated group irinotecan was increases 0.00006 cm/s to 0.00042 cm/s that is about 7-fold increase p-glycoprotein inhibitory activity by verapamil and curcumin found to be significantly enhanced the cancerous colon permeability of irinotecan. CONCLUSIONS: Any safe suitable p-glycoprotein inhibitors along with irinotecan will enhance the therapeutic benefit in the treatment of the colon cancer

Corrigendum: Topical Ophthalmic Formulation of Trichostatin A and SurR9-C84A for Quick Recovery Post-alkali Burn of Corneal Haze

Alkali burn injury is a true ocular emergency of the conjunctiva and cornea that requires immediate precision. Lack of an immediate therapy can lead to a substantial damage in the ocular surface and anterior segment further causing visual impairment and disfigurement. We explored the regenerative capability of dominant negative survivin protein (SurR9-C84A) and histone deacetylase inhibitor trichostatin-A (TSA) in vivo, in a rat alkali burn model. A topical insult in rat eyes with NaOH led to degradation of the conjunctival and corneal epithelium. The integrity of the conjunctival and corneal tissue was increased by TSA and SurR9-C84A by improving the clathrin and claudin expressions. Wound healing was initiated by an increase in TGF-beta-1 and, increased endogenous survivin which inhibited apoptosis post-TSA and SurR9-C84A treatments. Protein expressions of fibronectin and alpha-integrin 5 were found to increase promoting corneal integrity. The cytokine analysis confirmed increased expressions of IL-1beta, IL-6, IL-12, IL-13, IFN-gamma, TNF-alpha, GMCSF, Rantes, and MMP-2 in injured cornea, which were found to be significantly downregulated by the combined treatment of SurR9-C84A and TSA. The ocular and systemic pharmacokinetic (PK) parameters were measured post-topical ocular administration of TSA and SurR9-C84A. The SurR9-C84A and TSA sustained relatively longer in the cornea, conjunctiva, and aqueous humor than in the tear fluid and plasma. Our results confirmed that a combination of TSA with SurR9-C8A worked in synergy and showed a promising healing and anti-inflammatory effect in a very short time against alkali burn. Therefore, a combination of TSA and SurR9-C84A can fulfill the need for an immediate response to wound healing in alkali burnt cornea. We also synthesized ultra-small chitosan nanoparticles (USC-NPs) targeted with alpha-SMA antibodies that can be used for delivery of TSA and SurR9-C84A specifically to the ocular burn site

Quercetin nanoparticles attenuates scopolamine induced spatial memory deficits and pathological damages in rats

Quercetin is a well-known flavonoid, has low bioavailability. Quercetin nanoparticles (NQC) enhance its bioavailability. NQC were not explored for their potential therapeutic activities in Alzheimer’s disease (AD). Hence, the present study was performed to evaluate the protective effect of NQC in comparison to free quercetin against scopolamine induced spatial memory impairments. NQC prepared by anti solvent precipitation method. Quercetin, NQC (30 mg/kg p.o.) and rivastigmine (2 mg/kg i.p.) as a reference drug were administered for 8 consecutive days. At the end of the treatment period memory impairments were induced by a single injection of scopolamine (20 mg/kg; i.p.). Conditioned avoidance and rectangular-maze tests were conducted 30 min thereafter then rats were sacrificed and brain homogenates were used for the estimation of glutathione (GSH), catalase and malondialdehyde (MDA) contents together with acetyl cholinesterase (AchE) activity. In addition, histopathologic studies were also performed. The size of NQC was observed below 300 nm. NQC significantly reduced the transfer latency and conditioned avoidance response compared to scopolamine treated group (p < 0.05). Pretreatment with NQC showed a significant (p < 0.05) decrease in MDA, AchE levels and increase in brain catalase and GSH levels to be similar to that observed in the rivastigmine group. In all the behavioral, biochemical and histological experiments, the rats treated with NQC showed additional distinguished results compared to quercetin group indicating that a preventive strategy against the progression of AD. This approach of quercetin nanoparticles provides the potential therapeutic application in human neurodegenerative disease in future

A new steroidal derivative from the skin of Indian Toad (Bufo melanostictus) as a hypolipidemic and CYP 3A inhibitor

Purpose: To investigate the inhibitory effect of a novel steroidal derivative (NSD) on CYP3A in Wistar rats. Methods: Column chromatography and thin-layer chromatography (TLC) were used for the isolation and identification of NSD, while its structure was elucidated using, Infrared (IR) 13Carbon Nuclear Magnetic Resonance (13C NMR), Proton nuclear magnetic resonance (1H-NMR), and liquid chromatography with tandem mass spectrometry (LC-MS). Toxicity studies were conducted in female Wistar rats according to Organisation for Economic Co-operation and Development (OECD) 423 guidelines. Hyperlipidemia was induced in the rats with high-fat diet (HFD). In vitro cytochrome P-450 (CYP) 3A studies were carried out by erythromycin demethylation assay (EMD), while pharmacokinetic studies were undertaken after treatment for eight days with NSD. Plasma drug concentrations were assessed using high-performance liquid chromatography (HPLC), while pharmacokinetic parameters were computed using WinNonlin 8.2 software. Lipid profile was evaluated by Cholestech LDX analyzer; furthermore, hematoxylin-and eosin-stained histological sections of the arch of the aorta were examined by microscopy. Results: The lethal dose-50 (LD50) was 200 mg/kg. In vitro studies shown CYP activity in liver microsomes (551.41 ± 107.70 to 136.11 ± 2.978) and in intestine microsomes (496.71 ± 20.23 to 146.20 ± 23.7), compared to control (p ˂ 0.001). Pharmacokinetic studies Cmax, increased from 55.26 ± 5.16 to 387.8 ± 40.95 ng/mL; and area under the curve (AUC) from 547.588 ± 20.150 to 2730.548 ± 27.19. The volume of distribution (Vd), mean residual time (MRT), time to maximum concentration (Tmax) were decreased. NSD significantly reduced serum cholesterol (SC) from 254.5 ± 27.5 to 88.6 ± 8.8 mg/dL, and other lipids as well. Conclusion: NSD inhibits CYP3A-mediated ATV drug metabolism and is also a potent hypolipidemic agent in vitro and in vivo studies. Co-administration of ATV and NSD may expedite oral bioavailability

Brain targeted PLGA nanocarriers alleviating amyloid-Β expression and preserving basal survivin in degenerating mice model

The chronic systemic administration of d-Galactose in C57BL/6J mice showed a relatively high oxidative stress, amyloid-&beta; expression and neuronal cell death. Enhanced expression of pyknotic nuclei, caspase-3 and reduced expression of neuronal integrity markers further confirmed the aforesaid insults. However, concomitant treatment with the recombinant protein (SurR9-C84A) and the anti-transferrin receptor antibody conjugated SurR9-C84A (SurR9+TFN) nanocarriers showed a significant improvement in the disease status and neuronal health. The beauty of this study is that the biodegradable Food and Drug Administration (FDA) approved poly(lactic-co-glycolic acid) (PLGA) nanocarriers enhanced the biological half-life and the efficacy of the treatments. The nanocarriers were effective in lowering the amyloid-&beta; expression, enhancing the neuronal integrity markers and maintaining the basal levels of endogenous survivin that is essential for evading the caspase activation and apoptosis. The current study herein reports for the first time that the brain targeted SurR9-C84A nanocarriers alleviated the d-Galactose induced neuronal insults and has potential for future brain targeted nanomedicine application

Targeted multimodal liposomes for nano-delivery and imaging: An avenger for drug resistance and cancer

Understanding the cellular target structure and thereby proposing the best delivery system to achieve sustained release of drugs has always been a significant area of focus in biomedical research for translational benefits. Specific targeting of the receptors expressed on the target cell represents an effective strategy for increasing the pharmacological efficacy of the administered drug. Liposomes offer enhanced conveyance as a potential carrier of biomacromolecules such as anti-cancer proteins, drugs and siRNA for targeting tumour cell death. Commonly used liposomal constructs for various therapies are Doxil, Myocet, DepoCyt and Abraxanes. However, recent strategy of using multifunctional liposomes for the sustained release of drugs with increased plasma residence time and monoclonal antibody-based targeting of tumours coupled with imaging modalities have attracted enormous scientific attention. The ability of liposomes coated with specific ligands such as Apo-E derived RGD R9 and Tat peptide, to reverse the conceptualisation of drug resistance and cross the blood brain barrier, provides promising future for their use as an efficient drug delivery system. By outlining the recent advancements and innovations in the established concept of liposomal drug delivery, this review will focus on the multifunctional liposomes as an emerging novel lipid based drug delivery system

Targeting VEGF with LNA-stabilized G-rich oligonucleotide for efficient breast cancer inhibition

In this study, we investigated the efficacy of an LNA (locked nucleic acid)-modified DNA aptamer named RNV66 targeting VEGF against various breast cancer cell lines. Our results demonstrate that RNV66 efficiently inhibits breast cancer cell proliferation both in vitro and in vivo. Introduction of LNA nucleotides were crucial for higher efficacy. Furthermore, the binding interaction of RNV66 with VEGF was investigated using molecular dynamic simulations leading to the first computational model of the LNA aptamer-VEGF complex blocking its interaction with VEGF-receptor