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Abstract Background Epigenetic deregulation of the cellular apoptotic mechanism is the common hallmark of cancer. Silibinin (SBN) and quercetin (QCT) are two bioflavonoids well known for their epigenetic inhibition property. The objective of the present study was to explore the preventive anti-cancer efficacy of the SBN and QCT in both in vitro as well as in vivo tumor xenograft model through regulating cellular apoptotic signaling pathway. Results SBN and QCT inhibited the growth of A549 and MDA-MB-468 cancer cells in the concentration dependent manner. The treatment caused significant (p < 0.05) reduction of the size and the number of colonies formed by the cancer cells. In vitro apoptosis assay using the fluorescence microscopy revealed that the treatment noticeably increased the percentage of apoptotic cells as compared to the untreated control. Dosing with SBN (200mg/kg), QCT (100mg/kg) alone and in combination was initiated in 3-week-old C57BL6 mice. Interestingly, the treatment prevented tumor progression significantly (p < 0.05) in adult mice without causing any toxicity. Furthermore, SBN and QCT triggered apoptosis via modulating p53 and Bcl2 gene expression and the SOD enzyme activity. Conclusion Daily oral intake of SBN and QCT alone and in combination from the very early stage of life might prevent tumor growth in adult mice through activating cellular apoptotic signaling cascade.

Abstract Background Uraria picta (Jacq.) DC is a traditional Indian herb used in the Ayurvedic system of medicine. It is an ingredient of the popular Ayurvedic formulation “Dasamoola.” It is also traditionally used as an anti-inflammatory herb in Ayurveda. The plant also has excellent antioxidant potential. Different parts of Uraria picta are useful and have diverse medicinal properties. The present investigation was done to evaluate the anticancer activity of methanolic extract of aerial parts of Uraria picta (Jacq.). Results Preliminary phytochemical screening of MEUP confirmed the presence of flavonoids, phenolics, glycosides, and tannins. Total phenolic and flavonoid contents in MEUP were found to be 14.6 gram equivalent of gallic acid and 0.735 gram equivalent of catechin, respectively. IC50 values of cisplatin and MEUP were found to be 8.75 μg/ml and 436.92 μg/ml, respectively. Induction of apoptosis was evident from DAPI staining showing a dose-dependent increase in apoptosis. Also, a reduction in intracellular ROS was evident from the DCFH-da assay, where a dose-dependent decrease in intracellular ROS (fluorescence) was observed. Significant reduction (P

Abstract Background Identifying ways to reduce the burden of prostate cancer (Pca) or benign prostatic hyperplasia (BPH) is a top research priority. It is a typical entanglement seen in men which is portrayed by trouble in micturition. It stands as a significant problem in our society. Different molecular biomarker has high potential to treat Pca or BPH but also causes serious side effects during treatment. Main text The role of calcium signalling in the alteration of different biomarkers of Pca or BPH is important. Therefore, the photoswitch drugs may hold the potential to rebalance the altered calcium signaling cascade and the biomarker levels. Thereby play a significant role in the management of Pca and BPH. Online literature searches such as PubMed, Web of Science, Scopus, and Google Scholar were carried out. The search terms used for this review were photo-pharmacology, photo-switch drug, photodynamic therapy, calcium signalling, etc. Present treatment of Pca or BPH shows absence of selectivity and explicitness which may additionally result in side effects. The new condition of the calcium flagging may offer promising outcomes in restoring the present issues related with prostate malignancy and BPH treatment. Conclusion The light-switching calcium channel blockers aim to solve this issue by incorporating photo-switchable calcium channel blockers that may control the signalling pathway related to proliferation and metastasis in prostate cancer without any side effects. Graphical abstract Schematic diagram explaining the proposed role of photo-switch therapy in curbing the side effects of active drugs in Pca (prostate cancer) and BPH (benign prostatic hyperplasia). a) Delivery of medication by ordinary strategies and irreversible phototherapy causes side effects during treatment. Utilization of photo-switch drug to control the dynamic and inert condition of the medication can cause the medication impacts as we required in prostate cancer and BPH. b) Support of harmony between the calcium signaling is essential to guarantee ordinary physiology. Increment or abatement in the dimensions of calcium signaling can result in changed physiology. c) Major factors involved in the pathogenesis of BPH; downregulation of vitamin D receptor (VDR) and histone deacetylase (HDAC) can prevent BPH. Similarly, downregulation of α-1 adrenoceptor can reduce muscle contraction, while overexpression of β-3 adrenoceptor in BPH can promote further muscle relaxation in BPH treatment therapy. Inhibition of overexpressed biomarkers in BPH TRPM2-1: transient receptor potential cation channel subfamily M member 1; TRPM2-2: transient receptor potential cation channel subfamily M member 2; Androgens; CXCL5: C-X-C motif chemokine ligand 5; TGFβ-1: transforming growth factor β-1; TXA2; thromboxane-2; NMDA: N-methyl-d-aspartate can be the potential target in BPH therapy.

Abstract Background There has been huge interest among the researchers to incorporate a medicinally active compounds in hydrogel sheets for effective treatment of wound healing. This research work involves development and evaluation of medicated hydrogel sheet incorporated with embelin which has both antimicrobial and wound healing activity. Embelin was isolated from the fruits of Embelia ribes and characterized by various physical and analytical methods like melting point, UV/VIS spectroscopy, and HPTLC. The hydrogel sheets containing polyvinyl alcohol and polyethylene glycol was prepared by freeze-thaw technique, where isolated embelin was successfully incorporated within the sheet. The prepared hydrogel sheets were further characterized by in vitro drug release study, swelling capacities, gel fraction, water vapor transmission rate (WVTR), mechanical strength, and scanning electron microscopy (SEM) study. Finally, the optimized hydrogel with embelin was evaluated for its wound healing efficacy in vivo using excision wound model on Sprague–Dawley rats. Results The optimized hydrogel sheet had a composition of 5% PEG 400 and 10% PVA. It had acceptable in physico-chemical properties with respect to swelling capacities, gel fraction, water vapor transmission rate (WVTR), and mechanical strength The release of the drug from hydrogel followed zero order kinetics with more than 80% drug release within 12 h. The in vivo studies on the Sprague–Dawley showed faster healing process with embelin loaded hydrogels as compared to the control and market formulation. Conclusions Sheet hydrogel with 0.2% embelin was found to have huge potential for moist wound healing activity.

Intranasal drug administration is receiving increased attention as a delivery method for bypassing the blood–brain barrier and rapidly targeting therapeutics to the CNS. However, rapid mucociliary clearance in the nasal cavity is a major hurdle. The purpose of this study was to evaluate the effect of mucoadhesive polymers in enhancing the delivery of nimodipine microemulsion to the brain via the intranasal route. The optimized mucoadhesive microemulsion was characterized, and the in vitro drug release and in vivo nasal absorption of drug from the new formulation were evaluated in rats. The optimized formulation consisted of Capmul MCM as oil, Labrasol as surfactant, and Transcutol P as co-surfactant, with a particle size of 250 nm and zeta potential value of −15 mV. In vitro and ex vivo permeation studies showed an initial burst of drug release at 30 min and sustained release up to 6 h, attributable to the presence of free drug entrapped in the mucoadhesive layer. In vivo pharmacokinetic studies in rats showed that the use of the mucoadhesive microemulsion enhanced brain and plasma concentrations of nimodipine. These results suggest that incorporation of a mucoadhesive agent in a microemulsion intranasal delivery system can increase the retention time of the formulation and enhance brain delivery of drugs.

A new oil-in-water microemulsion-based (ME) gel containing 1% itraconazole (ITZ) was developed for topical delivery. The solubility of ITZ in oils and surfactants was evaluated to identify potential excipients. The microemulsion existence ranges were defined through the construction of the pseudoternary phase diagrams. The optimized microemulsion was characterized for its morphology and particle size distribution. The optimized microemulsion was incorporated into polymeric gels of Lutrol F127, Xanthan gum, and Carbopol 934 for convenient application and evaluated for pH, drug content, viscosity, and spreadability. In vitro drug permeation of ME gels was determined across excised rat skins. Furthermore, in vitro antimycotic inhibitory activity of the gels was conducted using agar-cup method and Candida albicans as a test organism. The droplet size of the optimized microemulsion was found to be

Introduction: Different topical formulations of diclofenac have varying skin penetration profile. Recent advances in science and technology has led to the development of many new formulations of drugs for topical drug delivery. One such technological development has led to the innovation of Dynapar QPS, a novel, non-aqueous, quick penetrating solution (QPS) of diclofenac diethylamine. Aim: This study was aimed to measure the total exposure from the drug penetrating the skin in healthy human subjects and comparing the relative systemic bioavailability of Dynapar QPS® with diclofenac emulgel. Materials and Methods: A 200 mg of diclofenac from either Dynapar QPS® (5 ml) or emulgel (20 g) was applied on back of subject as per the randomisation schedule. Blood samples were collected up to 16 hours post drug application. Plasma concentration of diclofenac was measured by pre-validated HPLC method. Pharmacokinetic (PK) parameters like Cmax, Tmax, t 1/2, AUC0-t, AUC0-∞, and Kel, of diclofenac were determined for both the formulations. Results: Mean Cmax after administration of Dynapar QPS® and diclofenac emulgel were 175.93 and 40.04 ng/ml, respectively. Tmax of diclofenac was almost half with QPS compared to emulgel (5.24 hrs versus 9.53 hrs respectively). The mean AUC0–t and AUC0-∞ after administration of Dynapar QPS® was higher as compared to diclofenac emulgel (AUC0–t: 1224.19 versus 289.78 ng.h/ml, respectively; AUC0-∞: 1718.21 versus 513.83 ng.h/ml, respectively). None of the subject experienced any adverse event during the study. Conclusion: The results indicate an enhanced penetration and subsequent absorption of diclofenac from Dynapar QPS® as compared to diclofenac emulgel. Higher penetration is likely to translate into better pain relief in patients.

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) where the communication ability of nerve cells in the brain and spinal cord with each other gets impaired. Some current findings suggest the role of glutamate excitotoxicity in the development and progression of MS. An excess release of glutamate leads to the activation of ionotropic and metabotropic receptors, thus resulting in accumulation of toxic cytoplasmic Ca2+ and cell death. However, it has been observed that gamma-aminobutyric acid-A (GABAA) receptors located in the nerve terminals activate presynaptic Ca2+/calmodulin-dependent signaling to inhibit depolarization-evoked Ca2+ influx and glutamate release from isolated nerve terminals, which suggest a potential implication of GABAA receptor in management of MS. With this proof of concept, we tried to explore the potential of selective GABAA receptor agonists or positive allosteric modulators (diazepam and phenobarbitone sodium) and GABAA level enhancer (sodium valproate) for management of MS by screening them for their activity in experimental autoimmune encephalomyelitis (EAE) model in rats and cuprizone-induced demyelination model in mice. In this study, sodium valproate was found to show the best activity in the animal models whereas phenobarbitone sodium showed moderate activity. However, diazepam was found to be ineffective.

The efficacy of two monothiols, N-acetyl-DL-homocysteine thiolactone (NAHT) and glutathione (GSH) either alone or in combination with two vitamins, vitamin B complex and vitamin E were studied in 7 days methylmercury chloride (MMC; 1 mg kg) intoxicated male Swiss albino mice. Thirteen groups of animals, each containing 6 animals were used for the study. Three groups of animals were kept as control (treated either with vehicle, normal saline or olive oil). Rest of the ten groups were kept as treatment groups. All the animals were treated subcutaneously for 7 days with MMC and one group was sacrificed on the 8th day. The second group was kept without toxicant for another 7 days and were sacrificed on the 15th day. Two MMC pretoxicated groups were treated either with vitamin B complex (20 mg kg) or vitamin E (60 mg kg) and two other groups were treated with N-acetyl-DL-homocysteine thiolactone (40 mg kg) or glutathione (50 mg kg) for another 7 days. The rest of the four groups were treated with either N-acetyl-DL-homocysteine thiolactone or glutathione in combination with either vitamin B complex or vitamin E. All the animals were sacrificed on the 15th day, brain and spinal cord were dissected and estimated for acid phosphatase, alkaline phosphatase, succinic dehydrogenase and &agr; mannosidases. Some of the antidotes showed significant recovery of the enzymes in one tissue while some showed significant recovery in the other tissue depicting the need for treating methylmercury poisoned animals with multi-chelation therapy rather than as a monotherapy. [ABSTRACT FROM AUTHOR]