Harnessing pyroptosis for lung cancer therapy: The impact of NLRP3 inflammasome activation.

Lung cancer is still a global health challenge in terms of high incidence, morbidity, and mortality. Recent scientific studies have determined that pyroptosis, a highly inflammatory form of programmed cell death, can be identified as a potential lung cancer therapeutic target. The NLRP3 inflammasome acts as a critical mediator in this process and, upon activation, activates multiprotein complex formation as well as caspase-1 activation. This process, triggered by a release of pro-inflammatory cytokines, results in pyroptotic cell death. Also, the relationship between the NLRP3 inflammasome and lung cancer was justified by its influence on tumour growth or metastasis. The molecular pathways produce progenitive mediators and remake the tissue. Finally, targeting NLRP3 inflammasome for pyroptosis induction and inhibition of its activation appears to be a promising lung cancer treatment approach. This technique makes cancer treatment more promising and personalized. This review explores the role of NLRP3 inflammasome activation and its possibilities in lung cancer treatment.

First Total Synthesis and Pharmacological Potential of a Plant Based Hexacyclopeptide.

A new bioactive proline-rich cyclohexapeptide - diandrine C (6), previously isolated from whole plant of Drymaria diandra (Caryophyllaceae), was synthesized through coupling reactions of tetrapeptide unit Boc-Gly--Pro--Tyr--Trp-OH with dipeptide unit -Pro-Gly-OMe using N,N-diisopropylcarbodiimide (DIPC) as the coupling agent, followed by cyclization of linear hexapeptide unit under alkaline condition. Structure of cyclohexapeptide was confirmed by means of chemical, and spectroscopic analyses and also was screened for its antimicrobial and anthelmintic properties. Bioevaluation results indicated that the newly synthesized hexacyclopeptide exhibited potent antimicrobial activity against Gram-negative bacteria Pseudomonas aeruginosa, Klebsiella pneumoniae and pathogenic Candida albicans at 6 µg/mL. Moderate to good level of antihelmintic activity against three earthworm species Megascoplex konkanensis, Pontoscotex corethruses and Eudrilus eugeniae was also observed at concentration of 2 mg/mL.

Toward the Synthesis and Improved Biopotential of an N-methylated Analog of a Proline-Rich Cyclic Tetrapeptide from Marine Bacteria.

An N-methylated analog of a marine bacteria-derived natural proline-rich tetracyclopeptide was synthesized by coupling the deprotected dipeptide fragments Boc-l-prolyl-l-N-methylleucine-OH and l-prolyl-l-N-methylphenylalanine-OMe. A coupling reaction was accomplished utilizing N,N'-Dicyclohexylcarbodidimde (DCC) and 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC·HCl) as coupling agents and Triethylamine (TEA) or N-methylmorpholine (NMM) as the base in the presence of the racemization suppressing agent. This was followed by the cyclization of the linear tetrapeptide fragment under alkaline conditions. The structure of the synthesized cyclooligopeptide was confirmed using quantitative elemental analysis, FTIR (Fourier-transform infrared spectroscopy), ¹H NMR (Nuclear magnetic resonance spectroscopy), 13C NMR, and mass spectrometry. From the bioactivity results, it was clear that the newly synthesized proline-rich tetracyclopeptide exhibited better anthelmintic potential against Megascoplex konkanensis, Pontoscotex corethruses, and Eudrilus eugeniae at a concentration of 2 mg/mL as well as improved antifungal activity against pathogenic dermatophytes Trichophyton mentagrophytes and Microsporum audouinii at a concentration of 6 µg/mL, as compared to non-methylated tetracyclopeptide. Moreover, N-methylated tetracyclopeptide displayed significant activity against pathogenic Candida albicans.

Micronisation of simvastatin by the supercritical antisolvent technique: in vitro-in vivo evaluation.

Micronisation of simvastatin dissolved in acetone, dimethyl sulfoxide and ethanol with supercritical carbon dioxide as antisolvent was successfully performed using a supercritical antisolvent technique. The effect of a few process parameters such as precipitation temperature, the pressure and solute concentration in the liquid solution has been studied to evaluate their influence on morphology and size of particles. The micronised simvastatin were evaluated for drug content, particle size analysis and in vitro dissolution profiles. Fourier transform infrared spectroscopy, differential scanning calorimetry and PXRD patterns was used to study the possible changes after micronisation of simvastatin. The dissolution rate was increased after micronised compared with pure simvastatin in distilled water, pH 1.2 buffer and pH 7.0 buffer. In vivo performance of the optimised formulation was evaluated in rats using pharmacodynamic marker parameters like serum total cholesterol (CH) and triglycerides (TG) for 21 days. Pharmacodynamic studies of micronised simvastatin revealed improved reduction in CH and TG values as compared with pure simvastatin indicating improved bioavailability. In vivo pharmacokinetics in rats showed an increase in bioavailability of micronised simvastatin (3.14 times) compared with plain simvastatin.

Preparation and characterization of microemulsion of cilostazol for enhancement of oral bioavailability.

Cilostazol is a promising drug for antiplatelet combination therapy that is very important for treatment for various cardiovascular disorders. However, oral delivery of this drug is greatly impeded by the poor solubility in aqueous solutions. The aim of this study was to develop microemulsion (ME) delivery system capable of improving the drug bioavailability. In this study, Capmul MCM C8 (glycerol monocaprylate) based MEs containing Tween 20(polysorbate 20) and/or Labrafil M 1944(poly oxyglycerides) as surfactant(S) and Transcutol P(diethyl glycol monoethyl ether) as cosurfactant(CoS) were studied as potential delivery systems of cilostazol. A number of such systems were prepared containing different S:CoS ratios(1:1, 2:1 and 3:1) based on phase diagrams. Loading of cilostazol was selected as per solubilization capacity and was characterized for pH, viscosity, conductivity, particle size, zeta potential and % transmittance. The MEs systems were further investigated for chemical stability, diffusion and bioavailability. Cilostazol displayed high solubility in microemulsions with particle size up to 70 nm. It was also stable at ambient temperature up to 6 months without significant change in particle size, zeta potential, and % transmittance. Dilution up to 100 fold with aqueous medium observed a visible cloudiness having a particle size up to 104 nm. The in vitro release, and ex vivo intraduodenal diffusion, and in vivo study indicated the capacity of developed ME to improve the bioavailability (1.43 fold) via oral route administration when compared with commercially available tablets (Pletoz-50).

Preparation and characterization of methylene blue nanoparticles for Alzheimer's disease and other tauopathies.

Methylene blue (MB) has been shown to slow down the progression of the Alzheimer's disease (AD) and other tauopathies; however distribution of MB into the brain is limited due its high hydrophilicity. In this study, we aimed to prepare novel hydrophobic glutathione coated PLGA nanoparticles to improve bioavailability of MB in the brain. Glutathione coated poly-(lactide-co-glycolide) (PLGA-b-PEG) nanoparticles (NPs) were prepared and tested in two different cell culture models of AD expressing microtubule associated protein tau (tau). The NPs showed a particle size averaging 136.5±4.4nm, which is suitable for the blood brain barrier (BBB) permeation. The in vitro release profile of the NPs exhibited no initial burst release and showed sustained drug release for up to 144 hours. Interestingly, treatment of newly formulated MB-NPs showed a potent reduction in both endogenous and over expressed tau protein levels in human neuroblastoma SHSY-5Y cells expressing endogenous tau and transfected HeLa cells over-expressing tau protein, respectively. Furthermore, in vitro BBB Transwell™ study showed significantly higher permeation of MB-NP compared to the MB solution through the co culture of rat brain endothelial 4 (RBE4) and C6 astrocytoma cells (p<0.05). The proposed MB loaded nanoparticles could provide a more effective treatment option for AD and many other related disorders.

Formulation and characterization of mucoadhesive microparticles of cinnarizine hydrochloride using supercritical fluid technique.

The mucoadhesive microparticles (CHCNZ) composed of chitosan (CH) and cinnarizine (CNZ) hydrochloride were successfully prepared, in a process of solution-enhanced dispersion, by supercritical CO2 (SEDS) technique. Scanning electron microscopy was used to reveal the morphological characteristics of mucoadhesive microparticles. The average particle size of microparticles was in the range from 1.9 to 12.8 µm. In vitro and in vivo mucoadhesive tests showed that CHCNZ mucoadhesive microparticles adhered more strongly to gastric mucous layer. Thereby retaining in gastrointestinal tract for an extended period of time and exhibiting good mucoadhesive properties. The X-ray powder diffractometry and differential scanning calorimetry analysis demonstrated that the SEDS process was an efficient physical coating process to produce CHCNZ composite microparticles. It also suggests that CNZ did not undergo chemical changes during the production of microparticles. The optimized batch exhibited a high drug entrapment efficiency of 67% with particle size of 3.9 µm. A sustained pattern of drug release was obtained for more than 20 h. In vivo studies were carried out by administering orally cinnarizine HCl (CNZ) suspension and mucoadhesive microparticles to rabbits under fasted (for 12 h) conditions. The results showed that CNZ mucoadhesive microparticles had a better bioavailability than CNZ suspension due to longer retention in the gastric environment of the test animals.