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.     

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.     

Regional variation in hospitalisation and mortality in heart failure: comparison of England and Lombardy using multistate modelling

Heart failure (HF) is a common, serious chronic condition with high morbidity, hospitalisation and mortality. The healthcare systems of England and the northern Italian region of Lombardy share important similarities and have comprehensive hospital administrative databases linked to the death register. We used them to compare admission for HF and mortality for patients between 2006 and 2012 (n = 37,185 for Lombardy, 234,719 for England) with multistate models. Despite close similarities in age, sex and common comorbidities of the two sets of patients, in Lombardy, HF admissions were longer and more frequent per patient than in England, but short- and medium-term mortality was much lower. English patients had more very short stays, but their very elderly also had longer stays than their Lombardy counterparts. Using a three-state model, the predicted total time spent in hospital showed large differences between the countries: women in England spent an average of 24 days if aged 65 at first admission and 19 days if aged 85; in Lombardy these figures were 68 and 27 days respectively. Eight-state models suggested disease progression that appeared similar in each country. Differences by region within England were modest, with London patients spending more time in hospital and having lower mortality than the rest of England. Whilst clinical practice differences plausibly explain these patterns, we cannot confidently disentangle the impact of alternatives such as coding, casemix, and the availability and use of non-hospital settings. We need to better understand the links between rehospitalisation frequency and mortality.     

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.     

N-hydroxy-pyrroline modification of verapamil exhibits antioxidant protection of the heart against ischemia/reperfusion-induced cardiac dysfunction without compromising its calcium antagonistic activity

Any clinical intervention (e.g., coronary angioplasty, thrombolysis) used to reintroduce blood flow to an ischemic region of the myocardium is accompanied by a complex enzymatic cascade of reactions resulting in severe injury to the heart, termed myocardial ischemia/reperfusion (I/R) injury. In this study, we evaluated the ability of H-3010 (1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (2-(3,4-dimethoxyphenyl)-5-([2-(3,4-dimethoxyphenyl)ethyl]-methylamino)-2-isopropylpentyl)-amide), a pyrroline modification of verapamil (2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethylmethyl-amino]-2-(1-methylethyl)pentanenitrile), to protect the heart against I/R-mediated injury. Isolated perfused rat hearts pretreated with verapamil and H-3010 were subjected to 30 min of global no-flow ischemia followed by 45 min of reperfusion. The recovery (expressed as a percentage of preischemic baseline) in contractile function (left ventricular developed pressure) of hearts subjected to I/R was significantly higher in hearts treated with H-3010 at 5 microM (51.0 +/- 6.4%) as well as at 50 microM (75.1 +/- 7.4%) as compared with verapamil at 5 microM (32.2 +/- 3.7%) or untreated control hearts (18.1 +/- 2.8%). Creatine kinase release was significantly attenuated in hearts treated with H-3010 (45.7 +/- 4.5 U/liter) as compared with untreated controls (131.5 +/- 6.4 U/liter). Similar trends were also observed for lactate dehydrogenase release as well. A marked reduction in percent area of infarction was observed in the H-3010 group (11.7 +/- 1.6%) compared with verapamil (25.1 +/- 2.9%) and control (41.3 +/- 1.9%) groups. Additional in vitro studies showed a marked decrease in reactive oxygen species generation with H-3010. In conclusion, our data clearly demonstrated that the verapamil derivative, H-3010, significantly decreased I/R-induced cardiac dysfunction. This can be attributed to the combined benefits of the pyrroline moiety (antioxidant) and the parent verapamil component (antiarrhythmic) in the protection of the heart from I/R-induced injury.     

Cardioprotection by sulfaphenazole, a cytochrome p450 inhibitor: mitigation of ischemia-reperfusion injury by scavenging of reactive oxygen species

Cytochrome P450 (P450) enzymes play a significant role in promoting myocardial ischemia-reperfusion (I/R) injury. CYP2C9, an isoform of P450, is known to generate superoxide radicals in the reperfused heart. Sulfaphenazole (SPZ), a CYP2C9 inhibitor, has been shown to decrease I/R injury; however, the mechanism of cardioprotection by SPZ is not well elucidated. The objective of this study was to test whether SPZ mitigates myocardial I/R injury by scavenging reactive oxygen species (ROS). Isolated rat hearts were subjected to 30 min of global ischemia followed by 45 min of reperfusion. Hearts were perfused with SPZ and/or N(omega)-nitro-L-arginine methylester (L-NAME). Coronary flow (CF), left-ventricular developed pressure (LVDP), and rate-pressure product (RPP) were monitored. Superoxide and nitric oxide (NO) generation in the reperfused tissue was determined using fluorescence methods. Myocardial infarct size was measured using triphenyltetrazolium chloride staining. The SPZ-treated group showed a significant recovery of cardiac function compared with the untreated I/R group (CF, 53 versus 45%; LVDP, 48 versus 22%; RPP, 51 versus 20%). The infarct size was significantly reduced in the SPZ-treated group (15%) compared with the I/R control (42%). Coadministration of L-NAME with SPZ significantly attenuated the beneficial effects of SPZ. In addition, SPZ treatment showed significantly decreased superoxide levels and enhanced NO bioavailability in the reperfused heart. In conclusion, the protective effect of SPZ against I/R-mediated myocardial damage appears to be due to a reduction in the superoxide level caused by its inhibition of CYP2C9, as well as scavenging of oxygen free radicals generated in the reperfused heart.     

Molecular aspects on the interaction of protoberberine, benzophenanthridine, and aristolochia group of alkaloids with nucleic acid structures and biological perspectives

Alkaloids occupy an important position in chemistry and pharmacology. Among the various alkaloids, berberine and coralyne of the protoberberine group, sanguinarine of the benzophenanthridine group, and aristololactam-beta-d-glucoside of the aristolochia group have potential to form molecular complexes with nucleic acid structures and have attracted recent attention for their prospective clinical and pharmacological utility. This review highlights (i) the physicochemical properties of these alkaloids under various environmental conditions, (ii) the structure and functional aspects of various forms of deoxyribonucleic acid (DNA) (B-form, Z-form, H(L)-form, protonated form, and triple helical form) and ribonucleic acid (RNA) (A-form, protonated form, and triple helical form), and (iii) the interaction of these alkaloids with various polymorphic DNA and RNA structures reported by several research groups employing various analytical techniques like absorbance, fluorescence, circular dichroism, and NMR spectroscopy; electrospray ionization mass spectrometry, thermal melting, viscosity, and DNase footprinting as well as molecular modeling and thermodynamic studies to provide detailed binding mechanism at the molecular level for structure-activity relationship. Nucleic acids binding properties of these alkaloids are interpreted in relation to their biological activity.