Muhammad Imran Naseer

Neuroprotection with metformin and thymoquinone against ethanol-induced apoptotic neurodegeneration in prenatal rat cortical neurons.

BackgroundExposure to ethanol during early development triggers severe neuronal death by activating multiple stress pathways and causes neurological disorders, such as fetal alcohol effects or fetal alcohol syndrome. This study investigated the effect of ethanol on intracellular events that predispose developing neurons for apoptosis via calcium-mediated signaling. Although the underlying molecular mechanisms of ethanol neurotoxicity are not completely determined, mitochondrial dysfunction, altered calcium homeostasis and apoptosis-related proteins have been implicated in ethanol neurotoxicity. The present study was designed to evaluate the neuroprotective mechanisms of metformin (Met) and thymoquinone (TQ) during ethanol toxicity in rat prenatal cortical neurons at gestational day (GD) 17.5.ResultsWe found that Met and TQ, separately and synergistically, increased cell viability after ethanol (100 mM) exposure for 12 hours and attenuated the elevation of cytosolic free calcium [Ca2+]c. Furthermore, Met and TQ maintained normal physiological mitochondrial transmembrane potential (ΔψM), which is typically lowered by ethanol exposure. Increased cytosolic free [Ca2+]c and lowered mitochondrial transmembrane potential after ethanol exposure significantly decreased the expression of a key anti-apoptotic protein (Bcl-2), increased expression of Bax, and stimulated the release of cytochrome-c from mitochondria. Met and TQ treatment inhibited the apoptotic cascade by increasing Bcl-2 expression. These compounds also repressed the activation of caspase-9 and caspase-3 and reduced the cleavage of PARP-1. Morphological conformation of cell death was assessed by TUNEL, Fluoro-Jade-B, and PI staining. These staining methods demonstrated more cell death after ethanol treatment, while Met, TQ or Met plus TQ prevented ethanol-induced apoptotic cell death.ConclusionThese findings suggested that Met and TQ are strong protective agents against ethanol-induced neuronal apoptosis in primary rat cortical neurons. The collective data demonstrated that Met and TQ have the potential to ameliorate ethanol neurotoxicity and revealed a possible protective target mechanism for the damaging effects of ethanol during early brain development.

Molecular genetics of human primary microcephaly: an overview

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder that is characterised by microcephaly present at birth and non-progressive mental retardation. Microcephaly is the outcome of a smaller but architecturally normal brain; the cerebral cortex exhibits a significant decrease in size. MCPH is a neurogenic mitotic disorder, though affected patients demonstrate normal neuronal migration, neuronal apoptosis and neural function. Twelve MCPH loci (MCPH1-MCPH12) have been mapped to date from various populations around the world and contain the following genes: Microcephalin, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1 and CDK6. It is predicted that MCPH gene mutations may lead to the disease phenotype due to a disturbed mitotic spindle orientation, premature chromosomal condensation, signalling response as a result of damaged DNA, microtubule dynamics, transcriptional control or a few other hidden centrosomal mechanisms that can regulate the number of neurons produced by neuronal precursor cells. Additional findings have further elucidated the microcephaly aetiology and pathophysiology, which has informed the clinical management of families suffering from MCPH. The provision of molecular diagnosis and genetic counselling may help to decrease the frequency of this disorder.

Role of gut microbiota in obesity, type 2 diabetes and Alzheimer's disease.

In recent years, there is a growing interest in research to investigate the importance of gut microbiome in health and diseases. This opens a new area of research for the role of microbial flora of the human gut in inflammation, energy homeostasis, pathogenesis of obesity and other associated disorders. Recent studies propose association of the gut microbiome with development of obesity and metabolic syndromes, such as type 2 diabetes mellitus (T2DM). The T2DM is a metabolic disease that is mainly caused by obesity-linked insulin resistance. The vascular effects of obesity appears to play a role in the development of Alzheimers disease (AD) that is one of the rapidly growing diseases of a late stage of life all over the world. Studies from both humans and mice models have been demonstrated the engagement of gut microbial flora in the pathogenesis of obesity and host metabolism. The aim of this review is to discuss the current findings that may explain the cascade of gut microbial flora participation in the development of obesity, T2DM and further initiation of AD. In addition, the available data regarding the mechanisms that have been proposed to elucidate the role of gut microbiota in weight gain and possible cause of T2DM and AD have been examined.

The role of epigenetics in personalized medicine: challenges and opportunities

Epigenetic alterations are considered to be very influential in both the normal and disease states of an organism. These alterations include methylation, acetylation, phosphorylation, and ubiquitylation of DNA and histone proteins (nucleosomes) as well as chromatin remodeling. Many diseases, such as cancers and neurodegenerative disorders, are often associated with epigenetic alterations. DNA methylation is one important modification that leads to disease. Standard therapies are given to patients; however, few patients respond to these drugs, because of various molecular alterations in their cells, which may be partially due to genetic heterogeneity and epigenetic alterations. To realize the promise of personalized medicine, both genetic and epigenetic diagnostic testing will be required. This review will discuss the advances that have been made as well as the challenges for the future.

Link Between Chronic Bacterial Inflammation and Alzheimer Disease

Alzheimers disease (AD) is a degenerative disease of brain that is associated with dementia, brain atrophy, accumulation of hyperphosphorylated tau protein and amyloid-beta peptide in hippocampus and cortex region of the brain. The development of AD is a multifactorial process that may also involve infection with bacterial pathogens. Recent studies suggest that bacteria including spirochetes have the potential to initiate cascade of events, leading to inflammatory condition of the central nervous system. Bacteria and spirochetes are activators of proinflammatory cytokines, generate free radicals, nitric oxide and further induction of apoptosis. Infection with these microbes may be considered as a risk factor for pathophysiology of AD or to cognitive changes. Recent studies have revealed that exposure to these microorganisms induces Aβ accumulation and tau protein phosphorylation, and chronic infections with these pathogenic bacteria can possibly contribute to progression of AD. In this article, we update and review the role of bacteria in the pathogenesis of AD resulting from initiation of cascade events in chronic inflammations and amyloidogenesis. Controlling these chronic infections with antibacterial or anti-inflammatory drugs will allow preventing inflammation, a risk factor for AD.

Next Generation Sequencing of Acute Myeloid Leukemia: Influencing Prognosis

Acute myeloid leukemia (AML) is a clonal disorder of the blood forming cells characterized by accumulation of immature blast cells in the bone marrow and peripheral blood. Being a heterogeneous disease, AML has been the subject of numerous studies that focus on unraveling the clinical, cellular and molecular variations with the aim to better understand and treat the disease. Cytogenetic-risk stratification of AML is well established and commonly used by clinicians in therapeutic management of cases with chromosomal abnormalities. Successive inclusion of novel molecular abnormalities has substantially modified the classification and understanding of AML in the past decade. With the advent of next generation sequencing (NGS) technologies the discovery of novel molecular abnormalities has accelerated. NGS has been successfully used in several studies and has provided an unprecedented overview of molecular aberrations as well as the underlying clonal evolution in AML. The extended spectrum of abnormalities discovered by NGS is currently under extensive validation for their prognostic and therapeutic values. In this review we highlight the recent advances in the understanding of AML in the NGS era.

Apomorphine attenuates ethanol-induced neurodegeneration in the adult rat cortex.

Apomorphine, therapeutically used for Parkinsons disease, is a dopamine D1/D2 receptor agonist that has been determined to be a potent antioxidant and to prevent the reaction of free radicals in the brain. Alcohol is a neurotoxic agent that induces neurodegeneration possibly through the generation of free radicals. In this study, we investigated the antioxidant potential of apomorphine upon ethanol-induced neurodegeneration in the cortex of adult rats. Ethanol-induced apoptotic neurodegeneration was measured via the suppression of Bcl-2, the induction of Bax, the release of cytochrome C and the activation of caspase-9 and caspase-3. Moreover, ethanol-induced elevated levels of cleaved PARP-1 indicated exaggerated neuronal DNA damage. Our results demonstrated the neuroprotective effect of apomorphine by reversing the ethanol-induced apoptotic trend as observed by the increased expression of Bcl-2, down regulation of Bax, inhibition of mitochondrial cytochrome C release and inhibition of activated caspase-9 and caspase-3. Moreover, apomorphine treatment further decreased the expression of cleaved PARP-1 to reveal a reduction in ethanol-induced neuronal damage. Immunohistochemical analysis and Nissl staining also revealed neuroprotective effect of apomorphine after ethanol-induced neuronal cell death. In this study, our results indicated that apomorphine at doses of 1 and 5mg/kg has neuroprotective effects for ethanol-induced neuronal damage. Finally, we can conclude that apomorphine has effective therapeutic potential to protect the brain against ethanol-induced neurotoxicity.

Comparative Studies of Salivary and Blood Sialic Acid, Lipid Peroxidation and Antioxidative Status in Oral Squamous Cell Carcinoma (OSCC).

Objective : Oral squamous cell carcinoma (OSCC) is considered to be a serious life threatening issue for almost two decades. The objective of this study was to evaluate the over production of lipid peroxidation (LPO) byproducts and disturbances in antioxidant defense system in the pathogenesis of oral cancer. Methods : Lipid peroxidation and antioxidant status in OSCC patients were estimated and compared the sensitivity and specificity of circulating biomarkers (MDA, Sialic acid, Catalase, SOD, GSH and Neuraminidase) with β-2 microglobulin (β-2MG) at different thresholds in blood and saliva using receiver operating characteristics (ROC) curve design. R esults : Our results showed that the levels of MDA and Sialic acid were significantly increased in plasma of OSCC patients as compared to healthy subjects whereas antioxidant level was significantly decreased. Conclusion : ROC analysis indicated that MDA in saliva is a better diagnostic tool as compared to MDA in blood and β-2MG in blood is better diagnostic marker as compared to β-2MG level in saliva.

Time-dependent effect of ethanol on GnRH and GnRH receptor mRNA expression in hypothalamus and testis of adult and pubertal rats

Chronic exposure to ethanol suppresses the male reproductive activity which is primarily involved in the release of hypothalamic gonadotropin-releasing hormone (GnRH). The testicular GnRH and GnRH receptors (GnRH-R) are found in seminiferous tubules, which are predicted to act as a local regulator of spermatogenesis, although the function is not well known. In this study, we investigated the chronic ethanol effect on GnRH mRNA expression in hypothalamus and testis using in situ hybridization and RNase protection assay (RPA). The effect of ethanol on expressional changes of GnRH and GnRH-R mRNA was observed in adult and pubertal rats according to age and time from 2 weeks (short term) and 4 weeks (long term) periods. The results showed that GnRH mRNA expression in adult and pubertal rats was dramatically decreased in the testis while no significant change was observed in hypothalamus after both short and long term exposure to ethanol. The pubertal rats showed decrease in testicular GnRH and GnRH-R mRNA expression, whereas GnRH mRNA was increased significantly, while GnRH-R mRNA was further decreased after long term exposure in adults. This study suggested that chronic ethanol administration is more effective to testicular GnRH and GnRH-R mRNA expression than hypothalamus and causes a negative effect on the spermatogenesis process. Furthermore, our finding suggests that the deteriorative effects of ethanol on gonadal activity are more lethal in puberty than adults.

Bacteria from marine sponges: A source of new drugs.

BACKGROUND Sponges are rich source of bioactive natural products synthesized by the symbiotic bacteria belonging to different phyla. Due to a competition for space and nutrients the marine bacteria associated with sponges could produce more antibiotic substances. To explore the proactive potential of marine microbes extensive research has been done. These bioactive metabolites have some unique properties that are pharmaceutically important. METHODS For this review, we have performed a non-systematic search of the available literature though various online search engines. This review provides an insight that how majority of active metabolites have been identified from marine invertebrates of which sponges predominate. RESULTS Sponges harbor abundant and diverse microorganisms, which are the sources of a range of marine bioactive metabolites. From sponges and their associated microorganisms, approximately 5,300 different natural compounds are known. Current research on sponge-microbe interaction and their active metabolites has become a focal point for many researchers. Various active metabolites derived from sponges are now known to be produced by their symbiotic microflora. CONCLUSION In this review, we attempt to report the latest studies regarding capability of bacteria from sponges as producers of bioactive metabolite. Moreover, these sponge associated bacteria are an important source of different enzymes of industrial significance. In present review, we will address some novel approaches for discovering marine metabolites from bacteria that have the greatest potential to be used in clinical treatments.