The development of chiral metal-organic frameworks for enantioseparation of racemates.

MIL-101(Cr), an achiral metal-organic framework, made up of a terephthalic acid ligand and a metal chromium ion was selected as a template. Its structural features are unsaturated Lewis acid sites that can be easily activated and it has an extremely high specific surface area, big pore size, and good thermal/chemical/water stability. This achiral framework was modified to introduce chirality within the structure to develop chiral metal-organic frameworks (CMOFs). Here, natural chiral ligands, amino acids (l-proline, l-thioproline and l-tyrosine), were selected for post synthetic modification (PSM) of MIL-101(Cr). This is a very simple, clean and facile methodology with respect to the reactants and reaction conditions. CMOFs 1-3 abbreviated as MIL-101-l-proline (CMOF-1), MIL-101-l-thioproline (CMOF-2) and MIL-101-l-tyrosine (CMOF-3) were prepared by introducing l-proline, l-thioproline and l-tyrosine as chiral moieties within the framework of (Cr). These CMOFs were characterized by FTIR, PXRD, SEM, and thermo gravimetric analysis. Chirality within these CMOFs 1-3 was established by circular dichroism (CD) and polarimetric methods. These three CMOFs 1-3 showed enantioselectivity towards RS-ibuprofen, RS-mandelic acid and RS-1-phenylethanol to varying extents. Their enantioselectivity towards racemates was studied by chiral HPLC and polarimetry.

Novel Small-Molecule Inhibitor of NLRP3 Inflammasome Reverses Cognitive Impairment in an Alzheimer's Disease Model.

Aberrant activation of the Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays an essential role in multiple diseases, including Alzheimer's disease (AD) and psoriasis. We report a novel small-molecule inhibitor, NLRP3-inhibitory compound 7 (NIC7), and its derivative, which inhibit NLRP3-mediated activation of caspase 1 along with the secretion of interleukin (IL)-1ß, IL-18, and lactate dehydrogenase. We examined the therapeutic potential of NIC7 in a disease model of AD by analyzing its effect on cognitive impairment as well as the expression of dopamine receptors and neuronal markers. NIC7 significantly reversed the associated disease symptoms in the mice model. On the other hand, NIC7 did not reverse the disease symptoms in the imiquimod (IMQ)-induced disease model of psoriasis. This indicates that IMQ-based psoriasis is independent of NLRP3. Overall, NIC7 and its derivative have therapeutic prospects to treat AD or NLRP3-mediated diseases.

A Rational Insight into the Effect of Dimethyl Sulfoxide on TNF-α Activity.

Direct inhibition of tumor necrosis factor-alpha (TNF-α) action is considered a promising way to prevent or treat TNF-α-associated diseases. The trimeric form of TNF-α binds to its receptor (TNFR) and activates the downstream signaling pathway. The interaction of TNF-α with molecular-grade dimethyl sulfoxide (DMSO) in an equal volumetric ratio renders TNF-α inert, in this state, TNF-α fails to activate TNFR. Here, we aimed to examine the inhibition of TNF-α function by various concentrations of DMSO. Its higher concentration led to stronger attenuation of TNF-α-induced cytokine secretion by fibroblasts, and of their death. We found that this inhibition was mediated by a perturbation in the formation of the functional TNF-α trimer. Molecular dynamics simulations revealed a transient interaction between DMSO molecules and the central hydrophobic cavity of the TNF-α homodimer, indicating that a brief interaction of DMSO with the TNF-α homodimer may disrupt the formation of the functional homotrimer. We also found that the sensitizing effect of actinomycin D on TNF-α-induced cell death depends upon the timing of these treatments and on the cell type. This study will help to select an appropriate concentration of DMSO as a working solvent for the screening of water-insoluble TNF-α inhibitors.

Therapeutic Interventions into Innate Immune Diseases by Means of Aptamers.

The immune system plays a crucial role in the body's defense system against various pathogens, such as bacteria, viruses, and parasites, as well as recognizes non-self- and self-molecules. The innate immune system is composed of special receptors known as pattern recognition receptors, which play a crucial role in the identification of pathogen-associated molecular patterns from diverse microorganisms. Any disequilibrium in the activation of a particular pattern recognition receptor leads to various inflammatory, autoimmune, or immunodeficiency diseases. Aptamers are short single-stranded deoxyribonucleic acid or ribonucleic acid molecules, also termed "chemical antibodies," which have tremendous specificity and affinity for their target molecules. Their features, such as stability, low immunogenicity, ease of manufacturing, and facile screening against a target, make them preferable as therapeutics. Immune-system-targeting aptamers have a great potential as a targeted therapeutic strategy against immune diseases. This review summarizes components of the innate immune system, aptamer production, pharmacokinetic characteristics of aptamers, and aptamers related to innate-immune-system diseases.

Toll-Like Receptors and Relevant Emerging Therapeutics with Reference to Delivery Methods.

The built-in innate immunity in the human body combats various diseases and their causative agents. One of the components of this system is Toll-like receptors (TLRs), which recognize structurally conserved molecules derived from microbes and/or endogenous molecules. Nonetheless, under certain conditions, these TLRs become hypofunctional or hyperfunctional, thus leading to a disease-like condition because their normal activity is compromised. In this regard, various small-molecule drugs and recombinant therapeutic proteins have been developed to treat the relevant diseases, such as rheumatoid arthritis, psoriatic arthritis, Crohn's disease, systemic lupus erythematosus, and allergy. Some drugs for these diseases have been clinically approved; however, their efficacy can be enhanced by conventional or targeted drug delivery systems. Certain delivery vehicles such as liposomes, hydrogels, nanoparticles, dendrimers, or cyclodextrins can be employed to enhance the targeted drug delivery. This review summarizes the TLR signaling pathway, associated diseases and their treatments, and the ways to efficiently deliver the drugs to a target site.

The crosslinking of polysaccharides with polyamines and dextran-polyallylamine antibacterial hydrogels.

A facile modular approach to rapidly prepare pH-responsive hydrogels by crosslinking polysaccharides with polyamines is demonstrated. Hydrogels are prepared by first reacting the less reactive polysaccharides with the cross-linker epichlorohydrin and completed by the addition of polyamines. The crosslinking of polysaccharides with polyamines provides a facile method for incorporating functionality into polysaccharide based hydrogels. This process is demonstrated with the polysaccharides dextran, pullulan and carboxymethyl cellulose and with the polyamines polyallylamine and polyethylene imine. The hydrogels were characterized by FTIR and swelling studies, which showed pH-dependent swelling due to the presence of the polyamine. The hydrogels can also be tailored by varying the mass ratio between the polysaccharide and polyamine. Absorption studies of organic analytes showed the polyamine content affecting the uptake of a charged substrate (methylene blue) and no effect on a neutral substrate (6-methyl coumarin). This synthetic method was also used to prepare hydrogels with antibacterial activity against E. coli and S. aureus by utilizing an amphiphilic polyallylamine.

Reference range of zinc in adult population (20-29 years) of Lahore, Pakistan.

OBJECTIVE: To determine the reference range of zinc in adult population (age range 20 to 29 years) of Lahore. METHODS: It was a descriptive cross sectional study which was carried out from Jan- August 2012 in Chemical Pathology Department of University of Health Sciences, Lahore. Serum zinc concentration was measured by flame atomic absorption spectrometry in randomly selected 450 healthy adults aged 20 to 29 years. After application of exclusion criteria reference values were determined in apparently healthy subjects according to guidelines of International Federation of Clinical Chemistry. The data was entered & analyzed using SPSS version 20.0. Serum Zn levels was expressed as Mean ± SD. RESULTS: A total of 450 healthy subjects were included in this study. Out of these, 234 were females. Mean age was 25±0.13years. The mean concentration of zinc in serum of healthy individual was 24.02±7.03 µmol/L (range11.47-36.72). The mean±SD for males subjects were 22.33±6.42 µmol/L(range11.93-32.4). Similarly the mean±SD for females were 21.72±7.34 µmol/L (range9.94-36.87). CONCLUSION: This study presents reference range for serum zinc concentration in adult population of Lahore. The results showed that there is significant difference in serum level of zinc among different countries. This study will help us in establishing reference ranges of trace elements on larger population in future.