Iodinated curcumin bearing dermal cream augmented drug delivery,antimicrobial and antioxidant activities

Objectives: Curcumin (Cur) exhibits weak microbicidal activity owing to high lipophilicity and low cell permeability. Therefore, in the present investigation, Cur was iodinated using elemental iodine (I₂) to synthesise Cur–I₂ powder that was later formulated as Cur–I₂ dermal cream and characterised in vitro for antimicrobial and antioxidant activities.

Methods and results: Electrophilic addition of I₂ saturated the olefinic bonds of Cur, as confirmed by UV/visible spectroscopy, FT-IR, ¹H NMR and DSC techniques. In addition, in vitro skin permeation and retention analysis indicated that Cur–I₂ cream followed the first order and Higuchi model for drug release through the rat skin. The minimum inhibitory concentration (MIC) of Cur–I₂ powder was measured to be 60 and 90?µg/ml significantly (p?Staphylococcus aureus and Escherichia coli, respectively. Moreover, Cur–I₂ also exhibited strong antioxidant potential.

Conclusions: Cur–I₂ cream warrants further in vivo study to scale up the technology for clinical translation.     

Development and Characterization of Gastroretentive High-Density Pellets Lodged With Zero Valent Iron Nanoparticles

The objective of the present study is to improve iron bioavailability using high-density gastroretentive pellets of zero valent iron nanoparticles (ZVINPs). ZVINPs were prepared by the chemical reduction method and were characterized for surface morphology, surface charge, and thermal properties. High-density gastroretentive pellets of iron nanoparticles were prepared using spheronization technique. Pellets were characterized for its micromeritic properties, in vitro drug release, and ex vivo permeability. The pharmacokinetic parameters, organ distribution, and toxicity of the optimized pellets were investigated in Wistar rats. In vivo results revealed more than 2-fold increases in oral bioavailability of iron by pellets compared to plane ferrous sulfate. Toxicological studies of the carriers indicated no evidence of liver damage in acute treatment; however, few complications were observed in chronic treatment groups. These results indicated that ZVINPs pellets successfully improve the oral iron bioavailability but need to obtain more information on repeated dose toxicity to initiate the clinical evaluation of investigational products.     

Mitigation of Oxidation in Therapeutic Antibody Formulations: a Biochemical Efficacy and Safety Evaluation of <Emphasis Type="Italic">N</Emphasis>-Acetyl-Tryptophan and L-Methionine

Purpose

Biotherapeutics can be susceptible to oxidation during manufacturing and storage. Free L-methionine is known to protect methionine residues in proteins from oxidation. Similarly, free tryptophan and other indole derivatives have been shown to protect tryptophan residues from oxidation. N-acetyl-DL-tryptophan was previously identified as a potentially superior antioxidant to tryptophan as it has a lower oxidation potential and produces less peroxide upon light exposure. This study sought to confirm the antioxidant efficacy and safety of N-acetyl-DL-tryptophan and L-methionine as formulation components for biotherapeutic drugs.

Methods

Antibodies were subjected to AAPH and light exposure in the presence of N-acetyl-DL-tryptophan and L-methionine. Oxidation in relevant CDR and Fc residues was quantified by peptide map. In silico, in vitro, and in vivo studies were performed to evaluate the safety of N-acetyl-DL-tryptophan and L-methionine.

Results

Peptide mapping demonstrated that N-acetyl-DL-tryptophan was effective at protecting tryptophans from AAPH stress, and that the combination of N-acetyl-DL-tryptophan and L-methionine protected both tryptophan and methionine from AAPH stress. The safety assessment suggested an acceptable safety profile for both excipients.

Conclusions

N-acetyl-tryptophan and L-methionine effectively reduce the oxidation of susceptible tryptophan and methionine residues in antibodies and are safe for use in parenteral biotherapeutic formulations.

     

DNA interaction,anti-proliferative effect of copper oxide nanocolloids prepared from metallosurfactant based microemulsions acting as precursor,template and reducing agent

In the present study, we have synthesized mixed cuprous/copper oxide nanosuspensions by metallosurfactant based microemulsion technique. Three metallosurfactants were synthesized which includes two non-ionic double chained metallosurfactants with C₁₂, C₁₆ chains with coordinated copper i.e. Cudda and Cuhexa, respectively. Another cationic double chained metallosurfactant with loosely bound metal (Cuctac) was also prepared. The prepared metallocomplexes were characterized using FTIR, elemental analysis, and NMR. The effect of the position of metallosurfactant in microemulsion on the fabrication and properties of nanosuspensions was elucidated. In this method, no external reducing agent and capping agent were added and tween 80 acted both as reducing and stabilizing agent for the nanoparticles. The synthesized nanoparticles were characterized and it was observed that mixed copper and cuprous oxide particles are present in colloidal suspension for all the three studied metallosurfactants. The kinetics of formation of mixed copper/cuprous oxide nanosuspensions (Ns) and their stability was estimated using Uv-visible spectroscopy. Further, the binding and interactions of copper nanosuspensions with calf Thymus DNA (CT-DNA) were assessed using Uv–vis spectroscopy, circular dichroism and gel electrophoresis. Additionally, the antioxidant activity of the Cu Ns was checked using DPPH assay. The role of positive charge on nanoparticles as evaluated from Zeta potential was responsible for DNA affinity. The DNA conformational changes in the presence of nanosuspensions and relevant scavengers were investigated. Further, the anti-proliferative activity of copper Ns was assessed using HeLa cells and Cuhexa derived Ns were proved to be active with highest activity at a low concentration and were nontoxic towards normal cell lines. In summary, this work demonstrates a softer approach for the synthesis of copper nanosuspensions with a size range of 2–5?nm and evaluated the role of type and structure of metallosurfactant on size, stability of particles and anti-proliferative activity.     

Singular value based characterization and analysis of thermal patches for early breast abnormality detection

The purpose of this study is to develop a novel breast abnormality detection system by utilizing the potential of infrared breast thermography (IBT) in early breast abnormality detection. Since the temperature distributions are different in normal and abnormal thermograms and hot thermal patches are visible in abnormal thermograms, the abnormal thermograms possess more complex information than the normal thermograms. Here, the proposed method exploits the presence of hot thermal patches and vascular changes by using the power law transformation for pre-processing and singular value decomposition to characterize the thermal patches. The extracted singular values are found to be statistically significant (p?<?0.001) in breast abnormality detection. The discriminability of the singular values is evaluated by using seven different classifiers incorporating tenfold cross-validations, where the thermograms of the Department of Biotechnology-Tripura University-Jadavpur University (DBT-TU-JU) and Database of Mastology Research (DMR) databases are used. In DMR database, the highest classification accuracy of 98.00% with the area under the ROC curve (AUC) of 0.9862 is achieved with the support vector machine using polynomial kernel. The same for the DBT-TU-JU database is 92.50% with AUC of 0.9680 using the same classifier. The comparison of the proposed method with the other reported methods concludes that the proposed method outperforms the other existing methods as well as other traditional feature sets used in IBT based breast abnormality detection. Moreover, by using Rank1 and Rank2 singular values, a breast abnormality grading (BAG) index has also been developed for grading the thermograms based on their degree of abnormality.     

Protective effect of MOTILIPERM in varicocele-induced oxidative injury in rat testis by activating phosphorylated inositol requiring kinase 1α (p-IRE1α) and phosphorylated c-Jun N-terminal kinase (p-JNK) pathways

Context: MOTILIPERM was prepared as a mixture of extracts of three medicinal herbs [roots of Morinda officinalis How (Rubiaceae), outer scales of Allium cepa L. (Liliaceae) and seeds of Cuscuta chinensis Lamark (Convolvulaceae)].

Objective: To investigate the role of reactive oxygen species (ROS)-based endoplasmic reticulum (ER) stress in a rat model of varicocele and the therapeutic efficacy of MOTILIPERM in this model.

Materials and methods: Sixty male rats were divided into five experimental groups: a normal control group (CTR?+?vehicle), a control group administered MOTILIPERM 200?mg/kg (CTR?+?M 200), a varicocele-induced control group (VC?+?vehicle) and two varicocele-induced groups administered MOTILIPERM 100 (VC?+?M 100) or 200 (VC?+?M 200) mg/kg for 4 weeks. Testis weights were recorded and serums were assayed for hormone concentrations. Tissues were subjected to semen analysis, histopathology, analyses of ER response protein expression levels and oxidative stress were assessed by measuring ROS, reactive nitrogen species (RNS), malondialdehyde (MDA) level and ratios of total glutathione (GSH)/oxidized GSH (GSSG).

Results: MOTILIPERM treatment of varicocele-induced groups significantly increased left testis weight, testosterone level, sperm motility, count and spermatogenic cell density. ER-response protein expression levels were dose-dependently decreased in VC?+?M 200 group compared with VC?+?vehicle group. MOTILIPERM treatment also decreased MDA and ROS/RNS level but increased GSH/GSSG ratio.

Discussion and conclusions: This study suggests that ROS-related ER stress may play a major role in varicocele-induced infertility and MOTILIPERM, a novel compound targeting ROS-based ER stress, may be therapeutically useful in treatment of varicocele, or as a supplement for the treatment of infertility.     

Therapeutic targets for altering mitochondrial dysfunction associated with diabetic retinopathy

Introduction: Retinopathy remains as one of the most feared blinding complications of diabetes, and with the prevalence of this life-long disease escalating at an alarming rate, the incidence of retinopathy is also climbing. Although the cutting edge research has identified many molecular mechanisms associated with its development, the exact mechanism how diabetes damages the retina remains obscure, limiting therapeutic options for this devastating disease.

Areas covered: This review focuses on the central role of mitochondrial dysfunction/damage in the pathogenesis of diabetic retinopathy, and how damaged mitochondria initiates a self-perpetuating vicious cycles of free radicals. We have also reviewed how mitochondria could serve as a therapeutic target, and the challenges associated with the complex double mitochondrial membranes and a well-defined blood-retinal barrier for optimal pharmacologic/molecular approach to improve mitochondrial function.

Expert opinion: Mitochondrial dysfunction provides many therapeutic targets for ameliorating the development of diabetic retinopathy including their biogenesis, DNA damage and epigenetic modifications. New technology to enhance pharmaceuticals uptake inside the mitochondria, nanotechnology to deliver drugs to the retina, and maintenance of mitochondrial homeostasis via lifestyle changes and novel therapeutics to prevent epigenetic modifications, could serve as some of the welcoming avenues for a diabetic patient to target this sight-threatening disease.