Apoptosis mechanisms related to the increased sensitivity of Jurkat T-cells vs A431 epidermoid cells to photodynamic therapy with the phthalocyanine Pc 4

To examine the clinical applicability of Pc 4, a promising second-generation photosensitizer, for the photodynamic treatment of lymphocyte-mediated skin diseases, we studied the A431 and Jurkat cell lines, commonly used as surrogates for human keratinocyte-derived carcinomas and lymphocytes, respectively. As revealed by ethyl acetate extraction and absorption spectrophotometry, uptake of Pc 4 into the two cell lines was linear with Pc 4 concentration and similar on a per cell basis but greater in Jurkat cells on a per mass basis. Flow cytometry showed that uptake was linear at low doses; variations in the dose-response for uptake measured by fluorescence supported differential aggregation of Pc 4 in the two cell types. As detected by confocal microscopy, Pc 4 localized to mitochondria and endoplasmic reticulum in both cell lines. Jurkat cells were much more sensitive to the lethal effects of phthalocyanine photodynamic therapy (Pc 4-PDT) than were A431 cells, as measured by a tetrazolium dye reduction assay, and more readily underwent morphological apoptosis. In a search for molecular factors to explain the greater photosensitivity of Jurkat cells, the fate of important Bcl-2 family members was monitored. Jurkat cells were more sensitive to the induction of immediate photodamage to Bcl-2, but the difference was insufficient to account fully for their greater sensitivity. The antiapoptotic protein Mcl-1 was extensively cleaved in a dose- and caspase-dependent manner in Jurkat, but not in A431, cells exposed to Pc 4-PDT. Thus, the greater killing by Pc 4-PDT in Jurkat compared with A431 cells correlated with greater Bcl-2 photodamage and more strongly to the more extensive Mcl-1 degradation. Pc 4-PDT may offer therapeutic advantages in targeting inflammatory cells over normal keratinocytes in the treatment of T-cell-mediated skin diseases, such as cutaneous lymphomas, dermatitis, lichenoid tissue reactions and psoriasis, and it will be instructive to evaluate the role of Bcl-2 family proteins, especially Mcl-1, in the therapeutic response.     

Superlattice formation in binary mixtures of block copolymer micelles

Two distinct diblock copolymers, poly(styrene-b-isoprene) (SI) and poly(styrene-b-dimethylsiloxane) (SD), were codissolved at various concentrations in the polystyrene selective solvent diethyl phthalate. Two SI diblocks, with block molar masses of 12,000-33,000 and 30,000-33,000, and two SD diblocks, with block molar masses of 19,000-6000 and 16,000-9000, were employed. The size ratio of the smaller SD micelles (S) to the larger SI micelles (L) varied from approximately 0.5 to 0.6, based on hydrodynamic radii determined by dynamic light scattering on dilute solutions containing only one polymer component. Due to incompatibility between the polyisoprene and polydimethylsiloxane blocks, a binary mixture of distinct SI and SD micelles was formed in each mixed solution, as confirmed by cryogenic transmission electron microscopy. When the total concentration of polymer was increased to 20-30%, the micelles adopted a superlattice structure. Small angle X-ray scattering revealed the lattice to be the full LS13 superlattice (space group Fm3c) in all cases, with unit cell dimensions in excess of 145 nm. A coexistent face-centered cubic phase composed of SD micelles was also observed when the number ratio of S to L micelles was large.     

Environment-induced surface dynamics of a biomimetic ionomer studied using in situ second harmonic generation

The environmental-induced surface dynamics of the biomimetic phosphoryl choline (PC)-functionalized poly(trimethylene carbonate) ionomer has been studied and compared to its unfunctionalized counterpart using in situ second harmonic generation measurements. Whereas the nonpolar liquid n-hexane did not induce any surface dynamic processes in the ionomer under study, the presence of water initiated a Debye-type dynamic reaction at the surface of the PC ionomer, which had no equivalent in the unfunctionalized material. This first-order reaction was attributed to a surface enrichment process of the functionalized ionomer in the hydrophilic environment involving movement of the PC endgroups from aggregates in the bulk to the surface. The time constant of the process was found to be about 6 min, and the corresponding activation energy was 0.4 eV. The dehydration process of the PC-functionalized ionomer in nitrogen gas atmosphere could be described by two time constants, one slightly below 1 min and the other one just above 13 min. The results presented in this work show that SHG measurements are well suited for the study of polymer surface restructuring dynamics in response to environmental changes. Such information is very important for the successful design and implementation of biomimetic polymers intended for biomedical applications.     

Novel Ferrocenyl Linked Pyrazoline Analogs as Potent Antiamoebic Agents

Some novel ferrocenyl linked pyrazoline analogs were synthesized, well characterized, and evaluated for in vitro antiamoebic activity against HM1 : IMSS strain of Entamoeba histolytica. Most of the compounds exhibited higher antiamoebic activity with the IC₅₀ value in the range of 0.12–1.20 μM, than the reference drug metronidazole, (IC₅₀ value of 1.78 μM). Compound 9 showed the most promising antiamoebic activity (IC₅₀ = 0.12 μM), concluding that these compounds hold immense potential to be employed as new antiamoebic agents. Also, being novel, they can be a solution to the increasing resistance that has posed a major problem globally.     

Plant-Based Indole Alkaloids: A Comprehensive Overview from a Pharmacological Perspective

Plant-based indole alkaloids are very rich in pharmacological activities, and the indole nucleus is considered to contribute greatly to these activities. This review’s fundamental objective is to summarize the pharmacological potential of indole alkaloids that have been derived from plants and provide a detailed evaluation of their established pharmacological activities, which may contribute to identifying new lead compounds. The study was performed by searching various scientific databases, including Springer, Elsevier, ACS Publications, Taylor and Francis, Thieme, Wiley Online Library, ProQuest, MDPI, and online scientific books. A total of 100 indole compounds were identified and reviewed. The most active compounds possessed a variety of pharmacological activities, including anticancer, antibacterial, antiviral, antimalarial, antifungal, anti-inflammatory, antidepressant, analgesic, hypotensive, anticholinesterase, antiplatelet, antidiarrheal, spasmolytic, antileishmanial, lipid-lowering, antimycobacterial, and antidiabetic activities. Although some compounds have potent activity, some only have mild-to-moderate activity. The pharmacokinetic profiles of some of the identified compounds, such as brucine, mitragynine, 7-hydroxymitragynine, vindoline, and harmane, were also reviewed. Most of these compounds showed promising pharmacological activity. An in-depth pharmacological evaluation of these compounds should be performed to determine whether any of these indoles may serve as new leads.     

Biocomputational Screening of Natural Compounds against Acetylcholinesterase

Alzheimer’s disease (AD) is the most common form of dementia and is characterized by irreversible and progressive neurodegeneration. Cholinergic dysfunction has been reported in AD, and several cholinesterase inhibitors, including natural compounds and synthetic analogs, have been developed to treat the disease. However, there is currently no treatment for AD, as most drug-like compounds have failed in clinical trials. Acetylcholinesterase (AChE) is the target of most drugs used commercially to treat AD. This work focused on screening natural compounds obtained from the ZINC database (224, 205 compounds) against AChE to identify those possibly capable of enabling the management of AD. Indirubin and dehydroevodiamine were the best potential AChE inhibitors with free binding energies of −10.03 and −9.00 kcal/mol, respectively. The key residue (His⁴⁴⁷) of the active site of AChE was found to participate in complex interactions with these two molecules. Six H-bonds were involved in the ‘indirubin–AChE’ interaction and three H-bonds in the ‘dehydroevodiamine–AChE’ interaction. These compounds were predicted to cross the blood–brain barrier (BBB) and to exhibit high levels of intestinal absorption. Furthermore, ‘indirubin–AChE’ and ‘dehydroevodiamine–AChE’ complexes were found to be stable, as determined by root mean square deviation (RMSD) during a 50 ns molecular dynamics simulation study. Based on the free binding energies and stabilities obtained by simulation studies, we recommend that experimental studies be undertaken on indirubin and dehydroevodiamine with a view towards their potential use as treatments for AD.     

Sustainable Development of Chitosan/Calotropis procera-Based Hydrogels to Stimulate Formation of Granulation Tissue and Angiogenesis in Wound Healing Applications

The formation of new scaffolds to enhance healing magnitude is necessarily required in biomedical applications. Granulation tissue formation is a crucial stage of wound healing in which granulation tissue grows on the surface of a wound by the formation of connective tissue and blood vessels. In the present study, porous hydrogels were synthesized using chitosan incorporating latex of the Calotropis procera plant by using a freeze–thaw cycle to stimulate the formation of granulation tissue and angiogenesis in wound healing applications. Structural analysis through Fourier transform infrared (FTIR) spectroscopy confirmed the interaction between chitosan and Calotropis procera. Latex extract containing hydrogel showed slightly higher absorption than the control during water absorption analysis. Thermogravimetric analysis showed high thermal stability of the 60:40 combination of chitosan (CS) and Calotropis procera as compared to all other treatments and controls. A fabricated scaffold application on a chick chorioallantoic membrane (CAM) showed that all hydrogels containing latex extract resulted in a significant formation of blood vessels and regeneration of cells. Overall, the formation of connective tissues and blood capillaries and healing magnitude decreased in ascending order of concentration of extract.     

New alkaloids from Phoebe scortechinii

The leaves of the Phoebe scortechinii (Gamb.) Kochummen Comb. Nov. (Lauraceae), afforded one new proaporphine-tryptamine dimer; (-)-phoebescortechiniine (1), along with two known ones; phoebegrandine A and phoebegrandine B. The proaporphine, tetrahydropronuciferine (2), was isolated for the first time as a natural product. The alkaloids were elucidated primarily by means of high field NMR and HRMS.     

De novo design of chiral organotin cancer drug candidates: validation of enantiopreferential binding to molecular target DNA and 5'-GMP by UV-visible, fluorescence, (1)H and (31)P NMR

N,N-bis[(R-/S-)-1-benzyl-2-ethoxyethane] tin (IV) complexes were synthesized by applying de novo design strategy by the condensation reaction of (R-/S-)2-amino-2-phenylethanol and dibromoethane in presence of dimethyltin dichloride and thoroughly characterized by elemental analysis, conductivity measurements, IR, ESI-MS, (1)H, (13)C and (119)Sn, multinuclear NMR spectroscopy and XRD study. Enantioselective and specific binding profile of R-enantiomer 1 in comparison to S-enantiomer 2 with ultimate molecular target CT-DNA was validated by UV-visible, fluorescence, circular dichroism, (1)H and (31)P NMR techniques. This was further corroborated well by interaction of 1 and 2 with 5'-GMP.