Mohammad Alam Jafri

Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies

Telomeres maintain genomic integrity in normal cells, and their progressive shortening during successive cell divisions induces chromosomal instability. In the large majority of cancer cells, telomere length is maintained by telomerase. Thus, telomere length and telomerase activity are crucial for cancer initiation and the survival of tumors. Several pathways that regulate telomere length have been identified, and genome-scale studies have helped in mapping genes that are involved in telomere length control. Additionally, genomic screening for recurrent human telomerase gene hTERT promoter mutations and mutations in genes involved in the alternative lengthening of telomeres pathway, such as ATRX and DAXX, has elucidated how these genomic changes contribute to the activation of telomere maintenance mechanisms in cancer cells. Attempts have also been made to develop telomere length- and telomerase-based diagnostic tools and anticancer therapeutics. Recent efforts have revealed key aspects of telomerase assembly, intracellular trafficking and recruitment to telomeres for completing DNA synthesis, which may provide novel targets for the development of anticancer agents. Here, we summarize telomere organization and function and its role in oncogenesis. We also highlight genomic mutations that lead to reactivation of telomerase, and mechanisms of telomerase reconstitution and trafficking that shed light on its function in cancer initiation and tumor development. Additionally, recent advances in the clinical development of telomerase inhibitors, as well as potential novel targets, will be summarized.

Role of miRNAs in human cancer metastasis: Implications for therapeutic intervention

Metastasis is the spread and growth of localized cancer to new locations in the body and is considered the main cause of cancer-related deaths. Metastatic cancer cells display distinct genomic and epigenomic profiles and almost universally an aggressive pathophysiology. A better understanding of the molecular mechanisms and regulation of metastasis, including how metastatic tumors grow and survive in the nascent niche and the interactions of the emergent metastatic cancer cells within the local microenvironment may provide tools to design strategies to restrict metastatic dissemination. Aberrant microRNAs (miRNA) expression has been reported in metastatic cancer cells. MicroRNAs are known to regulate divergent and/or convergent metastatic gene pathways including activation of reprogramming switches during metastasis. An in-depth understanding of role of miRNAs in the metastatic cascade may lead to the identification of novel targets for anti-metastatic therapeutics as well as potential candidate miRNAs for cancer treatment. This review primarily focuses on the role of miRNAs in the mechanisms of cancer metastasis as well as implications for metastatic cancer treatment.

Protective Effect of Solanum nigrum Leaves Extract on Immobilization Stress Induced Changes in Rat’s Brain

The prophylactic or curative antioxidant efficacy of crude extract and the active constituent of S. nigrum leaves were evaluated in modulating inherent antioxidant system altered due to immobilization stress in rat brain tissues, in terms of measurement of glutathione (GSH), lipid peroxidation (thiobarbituric acid reactive substances, TBARS), and free radical scavenging enzymes activities. Rats were treated with single dose of crude extract of S. nigrum prior to and after 6 h of immobilization stress exposure. Exposure to immobilization stress resulted in a decrease in the brain levels of glutathione, SOD, GST, and catalase, with an increase in thiobarbituric acid reactive substances (TBARS) levels. Treatment of S. nigrum extract and its active constituents to both pre- and poststressed rats resulted in significant modulation in the above mentioned parameters towards their control values with a relative dominance by the latter. Brain is vulnerable to stress induced prooxidant insult due to high levels of fat content. Thus, as a safe herbal medication the S. nigrum leaves extract or its isolated constituents can be used as nutritional supplement for scavenging free radicals generated in the brain due to physical or psychological stress or any neuronal diseases per se.

MicroRNAs as potential drug targets for therapeutic intervention in colorectal cancer

Introduction: MicroRNAs (miRNAs) are small (19 – 22 nucleotide), non-protein-coding RNA segments that function as master regulators of hundreds of genes simultaneously in both normal and malignant cells. In colorectal cancer (CRC) miRNAs are deregulated and have critical roles in initiation and progression of CRC by interacting with various oncogenes and tumor suppressor genes including APC, KRAS and p53, or by modulating downstream signal transduction pathways. Numerous promising miRNAs have emerged as potential drug targets for therapeutic intervention and possible candidates for replacement therapy in CRC. Areas covered: In this review the authors summarize the available information on miRNAs and their role in CRC. The authors point out specific miRNAs as potential drug targets and those having a significant role in gene activation and gene silencing during the process of CRC development, to highlight their importance as possible therapeutic candidates for the treatment of CRC. Expert opinion: Targeting miRNAs provides an emerging opportunity to develop effective miRNA-based replacement therapy or antagonists to alter expression in colon cancer patient tumors. However, the biggest challenge is to overcome obstacles associated with pharmacokinetics, delivery and toxicity in order to translate the potential of miRNAs into efficacious anticancer drugs.

Role of Nanodiamonds in Drug Delivery and Stem Cell Therapy

Context The use of nanotechnology in medicine and more specifically drug delivery is set to spread rapidly. Currently many substances are under investigation for drug delivery and more specifically for cancer therapy. Evidence Acquisition Nanodiamonds (NDs) have contributed significantly in the development of highly efficient and successful drug delivery systems, and in stem cell therapy. Drug delivery through NDs is an intricate and complex process that deserves special attention to unravel underlying molecular mechanisms in order to overcome certain bottlenecks associated with it. It has already been established that NDs based drug delivery systems have excellent biocompatibility, nontoxicity, photostability and facile surface functionalization properties. Results There is mounting evidence that suggests that such conjugated delivery systems well retain the properties of nanoparticles like small size, large surface area to volume ratio that provide greater biocatalytic activity to the attached drug in terms of selectivity, loading and stability. Conclusions NDs based drug delivery systems may form the basis for the development of effective novel drug delivery vehicles with salient features that may facilitate their utility in fluorescence imaging, target specificity and sustainedrelease.

Reno-protective effect of garlic extract against immobilization stress induced changes in rats

ABSTRACT Objective To examine immobilization stress-induced antioxidant defense alterations in rat kidney and the antioxidant effects of aqueous garlic extract in pre and post stress extract treatments. Methods Albino rats were treated with aqueous extract of garlic both before and 6 h of immobilization stress. Pro-oxidant eminence of rat kidney was assessed by determining the levels of glutathione, thiobarbituric acid reactive substances, aspartate aminotransferase, alanine aminotransferase, glucose, uric acid, alkaline phosphatase and antioxidant enzymes activities. Results In response to 6 h of immobilization stress, a significant rise in the level of kidney enzymes was recorded. However, antioxidant enzyme activities showed a sharp decline. Conclusions The extract treatment before and after the stress reverted the activities of above mentioned enzymes towards their control values. Hence, garlic extract can be given as nutritional supplement for scavenging the free radicals generated in rat kidney.

Antibacterial activity of iron oxide nanoparticles synthesized by co-precipitation technology against Bacillus cereus and Klebsiella pneumoniae

Abstract The present study investigates the synthesis and characterization of iron oxide nanoparticles (Fe3O4-NPs) for their antibacterial potential against Bacillus cereus and Klebsiella pneumonia by modified disc diffusion and broth agar dilution methods. DLS and XRD results revealed the average size of synthesized Fe3O4-NPs as 24 nm while XPS measurement exhibited the spin-orbit peak of Fe 2p3/2 binding energy at 511 eV. Fe3O4-NPs inhibited the growth of K. pneumoniae and B. cereus in both liquid and soild agar media, and displayed 26 mm and 22 mm zone of inhibitions, respectively. MIC of Fe3O4-NPs was found to be 5 μg/mL against these strains. However, MBC for these strains was observed at 40 μg/mL concentration of Fe3O4-NPs for exhibiting 40–50% loss in viable bacterial cells and 80 μg/mL concentration of Fe3O4-NPs acted as bactericidal for causing 90–99% loss in viability. Hence, these nanoparticles can be explored for their additional antimicrobial and biomedical applications.

Role of Glutaraldehyde in Imparting Stability to Immobilized β-Galactosidase Systems

This review article highlights the role of glutaraldehyde as a matrix activator/stabilizer in imparting higher operational and thermal stability to β-galactosidase (βG) for biotechnological applications. Glutaraldehyde has been used extensively as a crosslinking agent as well as for functionalization of matrices to immobilize βgalactosidase. Immobilized β-galactosidase systems (IβGS) obtained as a result of glutaraldehyde treatment has been employed to hydrolyze whey and milk lactose in batch reactors, continuous packed-bed and fluidized bed reactors under various operational conditions. Moreover, these IβGS have also been utilized for the production of galactooligosaccharides in food, dairy and fermentation industries. It was observed that glutaraldehyde provided remarkable stability to immobilize βG against various physical/chemical denaturants, thus enhancing thermal/operational stability and rendering it more suitable for repeated utilization in industrial scale operations.

UTILITY OF FUNCTIONALIZED AGAROSE NANOPARTICLES IN HYDROLYZING LACTOSE IN BATCH REACTORS FOR DAIRY INDUSTRIES

Shakeel Ahmed Ansaria,*, Syed Ismail Ahmadb, Mohammad Alam Jafria, Muhammad Imran Naseera and Rukhsana Satarc Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah-21589, Kingdom of Saudi Arabia Physics Division, Department of Basic Sciences, Ibn Sina National College for Medical Studies, Jeddah-21418, Kingdom of Saudi Arabia Department of Biochemistry, Ibn Sina National College for Medical Sciences, Jeddah-21418, Kingdom of Saudi Arabia

A novel homozygous mutation in SZT2 gene in Saudi family with developmental delay, macrocephaly and epilepsy

Epileptic encephalopathies are genetically heterogeneous disorders which leads to epilepsy and cause neurological disorders. Seizure threshold 2 (SZT2) gene located on chromosome 1p34.2 encodes protein mainly expressed predominantly in the parietal and frontal cortex and dorsal root ganglia in the brain. Previous studies in mice showed that mutation in this gene can confers low seizure threshold, enhance epileptogenesis and in human may leads to facial dysmorphism, intellectual disability, seizure and macrocephaly. Objective of this study was to find out novel gene or novel mutation related to the gene phenotype. We have identified a large consanguineous Saudi family segregating developmental delay, intellectual disability, epilepsy, high forehead and macrocephaly. Exome sequencing was performed in affected siblings of the family to study the novel mutation. Whole exome sequencing data analysis, confirmed by subsequent Sanger sequencing validation study. Our results showed a novel homozygous mutation (c.9368G>A) in a substitution of a conserved glycine residue into a glutamic acid in the exon 67 of SZT2 gene. The mutation was ruled out in 100 unrelated healthy controls. The missense variant has not yet been reported as pathogenic in literature or variant databases. In conclusion, the here detected homozygous SZT2 variant might be the causative mutation that further explain epilepsy and developmental delay in this Saudi family.