Production and Stability Evaluation of Modified-Release Microparticles for the Delivery of Drug Combinations

Production and evaluation of novel formulations of tizanidine and tramadol microparticles was the chief purpose of this project. Microparticles of both drugs were prepared separately via temperature change method. To extend the release of formulations, ethyl cellulose was employed. Higuchi, zero-order, first-order, and Korsmeyer–Peppas kinetic models were applied to appraise the mechanism and mode of drugs release. Higuichi model was found to be best for all release profiles. Stability of microparticles at 40°C/75% RH over a 3-month duration was determined by Fourier transform infrared (FTIR), X-ray diffractometry (XRD), and drugs assay. Microparticles were compatible and stable as no significant differences were observed when subjected to drug assay, FTIR, and XRD during accelerated stability studies.     

Mutations in the Alpha 1,2-Mannosidase Gene, MAN1B1, Cause Autosomal-Recessive Intellectual Disability

We have used genome-wide genotyping to identify an overlapping homozygosity-by-descent locus on chromosome 9q34.3 (MRT15) in four consanguineous families affected by nonsyndromic autosomal-recessive intellectual disability (NS-ARID) and one in which the patients show additional clinical features. Four of the families are from Pakistan, and one is from Iran. Using a combination of next-generation sequencing and Sanger sequencing, we have identified mutations in the gene MAN1B1, encoding a mannosyl oligosaccharide, alpha 1,2-mannosidase. In one Pakistani family, MR43, a homozygous nonsense mutation (RefSeq number {"type":"entrez-nucleotide","attrs":{"text":"NM_016219.3","term_id":"218749882","term_text":"NM_016219.3"}}NM_016219.3: c.1418G>A [p.Trp473^∗]), segregated with intellectual disability and additional dysmorphic features. We also identified the missense mutation c. 1189G>A (p.Glu397Lys; RefSeq number {"type":"entrez-nucleotide","attrs":{"text":"NM_016219.3","term_id":"218749882","term_text":"NM_016219.3"}}NM_016219.3), which segregates with NS-ARID in three families who come from the same village and probably have shared inheritance. In the Iranian family, the missense mutation c.1000C>T (p.Arg334Cys; RefSeq number {"type":"entrez-nucleotide","attrs":{"text":"NM_016219.3","term_id":"218749882","term_text":"NM_016219.3"}}NM_016219.3) also segregates with NS-ARID. Both missense mutations are at amino acid residues that are conserved across the animal kingdom, and they either reduce k_cat by ∼1300-fold or disrupt stable protein expression in mammalian cells. MAN1B1 is one of the few NS-ARID genes with an elevated mutation frequency in patients with NS-ARID from different populations.     

Ultraviolet-C mediated physiological and ultrastructural alterations in <Emphasis Type="Italic">Juncus effusus</Emphasis> L. shoots

Increased ultraviolet radiations intruding on the earth pose a serious threat to the unadapted plants. Due to the ecological and economic significance of mat rush (Juncus effusus L.), an in vitro experiment was conducted to unveil the toxic effects of ultraviolet radiation (UV-C) on its physiology and ultrastructure. The basal culm segments of plant were used for in vitro treatments of UV-C with different exposure times (15, 30 and 45 min). The treated segments were first transferred to 1/2 strength MS media and then shifted to soil-perlite mixture for further growth. With increasing exposure time to UV-C, there was significant reduction in plant growth and biomass, and increased activities of antioxidant enzymes. Physiological and ultrastructural alterations were observed in the shoots of UV-treated plants. These plants exhibited significant reduction in chlorophyll contents and noticeable modifications at the ultra-cellular levels. Cell and chloroplast size reduced greatly, and there was appearance of higher amounts of plastoglobuli in chloroplasts resulting in disruption of thylakoid integrity. The functional and ultrastructural alterations in the stressed plants suggest a potential hazard of UV-C radiation on this aquatic flora and thus the ecosystem. The study further explores that UV-C radiations trigger these modifications mainly by damaging the chloroplast.     

Effect of a dianthin G analogue in the differentiation of rat bone marrow mesenchymal stem cells into cardiomyocytes

Molecular and Cellular Biochemistry - Polo-like kinase 1 (Plk1) is a mitotic serine/threonine kinase implicated in spindle formation and cytokinesis in mammalian cells. Here, purified Plk1 was...     

Pathoadaptive Mutations in Salmonella enterica Isolated after Serial Passage in Mice

How pathogenic bacteria adapt and evolve in the complex and variable environment of the host remains a largely unresolved question. Here we have used whole genome sequencing of Salmonella enterica serovar Typhimurium LT2 populations serially passaged in mice to identify mutations that adapt bacteria to systemic growth in mice. We found unique pathoadaptive mutations in two global regulators, phoQ and stpA, which increase the competitive indexes of the bacteria 3- to 5-fold. Also, all mouse-adapted lineages had changed the orientation of the hin invertable element, resulting in production of a FliC type of flagellum. Competition experiments in mice with locked flagellum mutants showed that strains expressing the FliC type of flagellum had a 5-fold increase in competitive index as compared to those expressing FljB type flagellum. Combination of the flagellum cassette inversion with the stpA mutation increased competitive indexes up to 20-fold. These experiments show that Salmonella can rapidly adapt to a mouse environment by acquiring a few mutations of moderate individual effect that when combined confer substantial increases in growth.     

Synthesis of 2′,3′-Dideoxyribavirin

Abstract

A synthesis of 1-(2,3-dideoxy-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (2′,3′-dideoxyribavirin, ddR) is described. Glycosylation of the sodium salt of 1,2,4-triazole-3-carbonitrile (5) with 1-chloro-2-deoxy-3,5-di-0-p-toluoyl-α-D-erythro-pentofuranose (1) gave exclusively the corresponding N-1 glycosyl derivative with β-anomeric configuration (6), which on ammonolysis provided a convenient synthesis of 2′-deoxyribavirin (7). Similar glycosylation of the sodium salt of methyl 1,2,4-triazole-3-carboxylate (2) with 1 gave a mixture of corresponding N-1 and N-2 glycosyl derivatives (3) and (4), respectively. Ammonolysis of 3 furnished yet another route to 7. A four-step deoxygenation procedure using imidazolylthiocarbonylation of the 3′-hydroxy group of 5′-0-toluoyl derivative (9a) gave ddR (11). The structure of 11 was proven by single crystal X-ray studies. In a preliminary in vitro study ddR was found to be inactive against HIV retrovirus.     

Role of Salicylic Acid in Promoting Salt Stress Tolerance and Enhanced Artemisinin Production in Artemisia annua L.

In the present investigation, the role of salicylic acid (SA) in inducing salinity tolerance was studied in Artemisia annua L., which is a major source of the antimalarial drug artemisinin. SA, when applied at 1.00 mM, provided considerable protection against salt stress imposed by adding 50, 100, or 200 mM NaCl to soil. Salt stress negatively affected plant growth as assessed by length and dry weight of shoots and roots. Salinity also reduced the values of photosynthetic attributes and total chlorophyll content and inhibited the activities of nitrate reductase and carbonic anhydrase. Furthermore, salt stress significantly increased electrolyte leakage and proline content. Salt stress also induced oxidative stress as indicated by the elevated levels of lipid peroxidation compared to the control. A foliar spray of SA at 1.00 mM promoted the growth of plants, independent of salinity level. The activity of antioxidant enzymes, namely, catalase, peroxidase, and superoxide dismutase, was upregulated by salt stress and was further enhanced by SA treatment. Artemisinin content increased at 50 and 100 mM NaCl but decreased at 200 mM NaCl. The application of SA further enhanced artemisinin content when applied with 50 and 100 mM NaCl by 18.3 and 52.4%, respectively. These results indicate that moderate saline conditions can be exploited to obtain higher artemisinin content in A. annua plants, whereas the application of SA can be used to protect plant growth and induce its antioxidant defense system under salt stress.     

Defective Protein Folding and Aggregation as the Basis of Neurodegenerative Diseases: The Darker Aspect of Proteins

Abstract  

The ability of a polypeptide to fold into a unique, functional, and three-dimensional structure depends on the intrinsic properties of the amino acid sequence, function of the molecular chaperones, proteins, and enzymes. Every polypeptide has a finite tendency to misfold and this forms the darker side of the protein world. Partially folded and misfolded proteins that escape the cellular quality control mechanism have the high tendency to form inter-molecular hydrogen bonding between the same protein molecules resulting in aggregation. This review summarizes the underlying and universal mechanism of protein folding. It also deals with the factors responsible for protein misfolding and aggregation. This article describes some of the consequences of such behavior particularly in the context of neurodegenerative conformational diseases such as Alzheimer’s, Parkinson’s, Huntington’s, amyotrophic lateral sclerosis and other non-neurodegenerative conformational diseases such as cancer and cystic fibrosis etc. This will encourage a more proactive approach to the early diagnosis of conformational diseases and nutritional counseling for patients.