Qamre Alam

Inflammatory Process in Alzheimer’s and Parkinson's Diseases: Central Role of Cytokines

Alzheimers disease (AD) and Parkinsons disease (PD) are the two most widespread neurological disorders (NDs) characterized by degeneration of cognitive and motor functions due to malfunction and loss of neurons in the central nervous system (CNS). Numerous evidences have established the role of neuroinflammation in the AD and PD pathology. The inflammatory components such as microglia, astrocytes, complement system and cytokines are linked to neuroinflammation in the CNS. More specifically, cytokines have been found to play a central role in the neuroinflammation of AD and PD. A number of studies have demonstrated abnormally elevated levels of inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor (TNF) in AD and PD patients. Activated microglial cells have been shown to be involved in the secretion of pro-inflammatory cytokines such as IL-1, IL-6, TNF-α and transforming growth factor-β, thereby contributing towards the progress of NDs. In addition, studies on AD pathogenesis have demonstrated that microglia produce beta-amyloid protein (Aβ), which by itself is pro-inflammatory and causes activation of several inflammatory components. Similarly, chronic inflammation caused by microglial cells is the fundamental process involved in the destruction of neurons associated with dopamine (DA)-production in the brain of PD patients. Hence, there is a need to explore the key inflammatory components in AD and PD pathogenesis in order to fully understand the root cause and establish a substantial link between these two disorders. Such knowledge will help in better management and treatment of AD and PD.

A Synopsis on the Role of Tyrosine Hydroxylase in Parkinson's Disease

Parkinsons disease (PD) is a common chronic progressive neurodegenerative disorder in elderly people. A consistent neurochemical abnormality in PD is degeneration of dopaminergic neurons in substantia nigra pars compacta, leading to a reduction of striatal dopamine (DA) levels. As tyrosine hydroxylase (TH) catalyses the formation of L-dihydroxyphenylalanine (L-DOPA), the rate-limiting step in the biosynthesis of DA, the disease can be considered as a TH-deficiency syndrome of the striatum. Problems related to PD usually build up when vesicular storage of DA is altered by the presence of either α-synuclein protofibrils or oxidative stress. Phosphorylation of three physiologically-regulated specific sites of N-terminal domain of TH is vital in regulating its kinetic and protein interaction. The concept of physiological significance of TH isoforms is another interesting aspect to be explored further for a comprehensive understanding of its role in PD. Thus, a logical and efficient strategy for PD treatment is based on correcting or bypassing the enzyme deficiency by the treatment with L-DOPA, DA agonists, inhibitors of DA metabolism or brain grafts with cells expressing a high level of TH. Neurotrophic factors are also attracting the attention of neuroscientists because they provide the essential neuroprotective and neurorestorative properties to the nigrostriatal DA system. PPAR-γ, a key regulator of immune responses, is likewise a promising target for the treatment of PD, which can be achieved by the use of agonists with the potential to impact the expression of pro- and anti-inflammatory cytokines at the transcriptional level in immune cells via expression of TH. Herein, we review the primary biochemical and pathological features of PD, and describe both classical and developing approaches aimed to ameliorate disease symptoms and its progression.

Cancer chemoprevention by polyphenols and their potential application as nanomedicine.

Today cancer is a leading cause of death among the developed countries. Its highly complex nature makes it difficult to understand as it entails multiple cellular physiological systems such as cell signaling and apoptosis. The biggest challenges faced by cancer chemoprevention/chemotherapy is maintaining drug circulation and avoiding multidrug resistance. Overall there is modest evidence regarding the protective effects of nutrients from supplements against a number of cancers. Numerous scientific literatures available advocate the use of polyphenols for chemoprevention. Some groups have also suggested use of combination of nutrients in cancer prevention. However, we have yet to obtain the desired results in the line of cancer chemotherapy research. Nanotechnology can play a pivotal role in cancer treatment and prevention. Moreover, nanoparticles can be modified in various ways to prolong circulation, enhance drug localization, increase drug efficacy, and potentially decrease the chances of multidrug resistance. In this communication, we will cover the use of various polyphenols and nutrients in cancer chemoprevention. The application of nanotechnology in this regard will also be included. In view of available reports on the potential of nanoparticles, we suggest their usage along with different combination of nutrients as cancer chemotherapeutic agents.

A Possible Link of Gut Microbiota Alteration in Type 2 Diabetes and Alzheimer's Disease Pathogenicity: An Update

Imbalances in gut microbiota are associated with metabolic disorder, which are a group of obesity-related metabolic abnormalities that increase an individuals risk of developing type 2 diabetes (T2D) and Alzheimers disease (AD). Although a number of risk factors have been postulated that may trigger the development of AD, the root cause of this disease is still a matter of debate. This review further investigates the etiology of AD by accumulating the current role played by gut microbiota in human, and trying to establish an inter-link between T2D and AD pathogenesis. There is a growing body of evidence which suggests that obesity is associated with alteration in the normal gut flora, reduced bacterial diversity, metabolic pathways and altered representation of bacterial genes. Obesity and T2D are considered to be induced as a result of changes within the composition of gut microbiota. The evidence gathered so far clearly advocates the involvement of gut microbes in causing obesity, a state of chronic and low-grade inflammation. Hence, understanding the microbiota of the gut is significant in relation to inflammation, as it is a key contributor for diabetes which has a direct relation to the AD pathogenesis. Comparative analysis of gut microbiota may enable further novel insight into the complex biology of AD, which is very important in order to take preventive measure such as early diagnosis, identification of new therapeutic targets and development of novel drugs.

Candida identification: a journey from conventional to molecular methods in medical mycology

Abstract The incidence of Candida infections have increased substantially in recent years due to aggressive use of immunosuppressants among patients. Use of broad-spectrum antibiotics and intravascular catheters in the intensive care unit have also attributed with high risks of candidiasis among immunocompromised patients. Among Candida species, C. albicans accounts for the majority of superficial and systemic infections, usually associated with high morbidity and mortality often caused due to increase in antimicrobial resistance and restricted number of antifungal drugs. Therefore, early detection of candidemia and correct identification of Candida species are indispensable pre-requisites for appropriate therapeutic intervention. Since blood culture based methods lack sensitivity, and species-specific identification by conventional method is time-consuming and often leads to misdiagnosis within closely related species, hence, molecular methods may provide alternative for accurate and rapid identification of Candida species. Although, several molecular approaches have been developed for accurate identification of Candida species but the internal transcribed spacer 1 and 2 (ITS1 and ITS2) regions of the rRNA gene are being used extensively in a variety of formats. Of note, ITS sequencing and PCR–RFLP analysis of ITS region seems to be promising as a rapid, easy, and cost-effective method for identification of Candida species. Here, we review a number of existing techniques ranging from conventional to molecular approaches currently in use for the identification of Candida species. Further, advantages and limitations of these methods are also discussed with respect to their discriminatory power, reproducibility, and ease of performance.

A Brief Overview of Tyrosine Hydroxylase and α-Synuclein in the Parkinsonian Brain

Parkinsons disease (PD) is associated with neurodegeneration of the nigrostriatal tract and is accompanied with loss of tyrosine hydroxylase (TH) and dopamine (DA). Development of neuroprotective strategies targeting PD is often undermined by lack of proper understanding of processes contributing to the pathology. In this mini review we have tried to briefly outline the involvement of TH and α-synuclein in PD. Aberrant expression of α-synuclein is toxic to dopaminergic neurons. It interacts with ubiquitin-proteasomal processing system, implicated in oxidative injury and mitochondrial dysfunction which ultimately induce neurodegenration and cell death. The contributions of DJ-1 in TH regulation have also been discussed. Brain specific TH expression with the combined use of the pegylated immunoliposome (PILs) gene transfer technology and brain specific promoters as a new approach to treat PD has also been included.

Current Understanding of HSP90 as a Novel Therapeutic Target: An Emerging Approach for the Treatment of Cancer

Heat Shock Protein 90 (HSP90) is a ubiquitous molecular chaperone that is considered to be the most abundantly expressed protein in various human cancers such as breast, lung, colon, prostate, leukemia and skin. The master regulator, HSP90 plays a pivotal role in the conformational stabilization, maturation and activity of its various labile oncogenic client proteins such as p53, ErbB2, Bcr-Abl, Akt, Her-2, Cdk4, Cdk6, Raf-1 and v-Src in altered cells. Hence, making a guaranteed attempt to inhibit such a master regulator for cancer therapy appears to be a potential approach for combinatorial inhibition of numerous oncogenic signaling pathways simultaneously. Considerable efforts are being under way to develop novel molecular targets and its inhibitors that may block key signaling pathways involved in the process of tumorigenesis and metastasis. In this regards, HSP90 has acquired immense interest as a potent anticancer drug-target due to its key functional link with multiple signaling pathways involved in the process of cell proliferation and cell survival. Notably, geldanamycin and its derivatives (17-AAG, 17-DMAG) have shown quite encouraging results in inhibiting HSP90 function in several cancers and currently almost 17 drug candidates known to be target HSP90 are being under clinical trials either as single agents or combinatorial therapy. Hence, this review is an attempt to get new insight into novel drug target therapy by focusing on recent advances made in understanding HSP90 chaperone structure-function relationships, identification of new HSP90 client proteins and, more importantly, on the advancements of HSP90 targeted therapy based on various existing and emerging classical inhibitors.

DARPins Bioengineering and its Theranostic Approaches: Emerging Trends in Protein Engineering

The therapeutic significance of bioengineering proteins has increased dramatically as a new generation of pharmacological drug with a great potential in medical treatment. Protein engineering has improved the use of new non immunoglobulin affinity proteins. The designed ankyrin repeat proteins abbreviated as DARPins is a classical example. These molecules have smaller structural size, unlike immunoglobulins, but similar target affinity is of great significance. Such molecules get more binding specificity and greater thermodynamic stability. These attributes made DARPins a favorite player in diagnostics and therapeutics of cancer. How DARPins are improved into vigorous and versatile scaffold for binding protein and selected by ribosome and phage display along with related aspects is discussed in this review.

A nanotechnological approach to the management of Alzheimer disease and type 2 diabetes.

Alzheimers disease (AD) and type 2 diabetes (T2D) are both prevalent in older individuals and have gained significant attention due to alarming rates of increase. The high incidences of these diseases pose a great socioeconomic burden and cause major public health concerns worldwide. A number of studies have established potential links between AD and T2D, supporting the hypothesis that T2D is linked with an increased risk of AD and that controlling diabetes could have a positive impact on the prevention of AD. At present, both diseases lack precise diagnostic approaches for early intervention and effective cure. Further, the currently available diagnostic tools for AD screening are insufficiently sensitive and robust for preventive measures. Although several drugs are used for the treatment of both these diseases, none of these drugs offers complete remission of the disease, merely symptomatic relief. Moreover, these drugs have limited efficacy because of problems such as conventional drug delivery systems beyond the blood brain barrier, a lack of target specificity and diminished potency. From this perspective, the emerging field of nanotechnology has offered new techniques and tools to overcome these challenges. In this review, we discuss the direct and indirect limitations of existing therapies and describe alternative potential nanotechnological approaches that could be utilized to overcome these limitations. New insight in the field of nanomedicine is necessary for early diagnosis, the development of novel drug therapies, the action of drugs and prevention, as well as for gaining an in-depth understanding of the complex biology of both diseases.

Assessment of IL-18 Serum Level and Its Promoter Polymorphisms in the Saudi Coronary Artery Disease (CAD) Patients

The purpose of the current study was to find out the possible changes polymorphic site at the promoter region of IL‐18 gene in Saudi CAD patients. We have also measured serum IL‐18 level to find out, the likely association between its level and polymorphic site. The present study included total 197 subjects (98 confirmed CAD patients both men and women and 99 healthy control individuals). Serum concentration of IL‐18 was measured by enzyme linked immuno‐sorbent assay. For SNPs analysis, sanger method of DNA sequencing was followed. We observed variable numbers of SNPs at −137 C/G, −607 A/C, and −656 T/G promoter sites in our studied samples. However, the observed changes in the number of SNP hotspots were found to be non‐significant compared with control. IL‐18 level was found to be significantly (P < 0.001) elevated in CAD patients compared with control individuals. The highest rise of around 36% (P < 0.001) in IL‐18 level was recorded in unstable angina (UA) patients. Moreover, the group belonging to UA and non‐ST segment elevation myocardial infarction (NSTEMI) showed only 6% rise. On the basis of our result, inflammation seems to have a role in the pathogenesis of CAD but not leading to the significant changes at the genetic level. J. Cell. Biochem. 118: 1849–1854, 2017.