Pallaval Veera Bramhachari

Hypoxia inducible factor-1α: Its role in colorectal carcinogenesis and metastasis

Tumor growth creates a hypoxic microenvironment, which promotes angiogenesis and aggressive tumor growth and invasion. HIF1α is a central molecule involved in mediating these effects of hypoxia. In colorectal cancer (CRC), hypoxia stabilizes the transcription factor HIF1α, leading to the expression of genes that are involved in tumor vascularization, metastasis/migration, cell survival and chemo-resistance. Therefore, HIF1α is a rational target for the development of new therapeutics for CRC. This article reviews the central role of HIF1α in CRC angiogenesis, metastasis, and progression as well as the strategies to target HIF1α stabilization.

Manganese-superoxide dismutase (Mn-SOD) overexpression is a common event in colorectal cancers with mitochondrial microsatellite instability.

Mitochondrial displacement loop (D-loop) is a hot spot for mitochondrial DNA (mtDNA) alterations that effects cellular reactive oxygen species (ROS) generation. Manganese-superoxide dismutase (Mn-SOD) is a major antioxidant enzyme that protects cells from ROS-mediated damage. In the present study, we investigated the relationship between sequence alterations of mitochondrial D-loop and Mn-SOD expression in colorectal cancer (CRC). Genotyping of entire mitochondrial D-loop (1124xa0bp) was carried out on mtDNA of analogous tumor and normal tissues from 35 CRC patients of south Indian origin by PCR-sequencing analysis. Tumor-specific large-scale mtDNA deletions and Mn-SOD expression was analyzed by PCR and Western blot analysis, respectively. We identified 87 polymorphisms in the D-loop region of tumor and/or control tissues. Polymorphisms were predominantly located in hypervariable region I (67.9xa0%) than in II (32.1xa0%) of D-loop. Significantly increased mtDNA microsatellite instability (mtMSI) [310‘C’ insertion (Pu2009=u20090.00001) and T16189C (Pu2009=u20090.0007)] and elevated Mn-SOD expression was observed in tumor tissues compared with controls. Interestingly, mtMSI was significantly high in tumors with Mn-SOD overexpression. Tumor-specific large-scale mtDNA deletions were not observed in CRC tissues. In conclusion, mtMSI and Mn-SOD overexpression are a common event in CRC. The analysis of mtMSI and/or Mn-SOD expression might help to identify patients at high risk for disease outcome, thereby helping to refine therapeutic decisions in CRC.

Role of hypoxia-inducible factors (HIF) in the maintenance of stemness and malignancy of colorectal cancer

Hypoxia is a condition of insufficient tissue oxygenation, which is observed during normal development as well as tumorigenesis and its response at the cellular level is primarily mediated through hypoxia inducible factors (HIFs). HIFs have a significant role in the maintenance of stemness in both stem cells as well as in cancer stem cells (CSC) by acting as transcription factors. The CSCs are proposed to be the driving force of colon tumorigenesis and malignancy. These HIFs play a significant role in a wide range of diseases including colon cancer. HIFs signaling functions with stemness, and maintaining Wnt/β-catenin signaling pathways. Due to HIFs functional significance in stemness maintenance in malignancy, targeting HIFs might provide a new approach for development of new therapy for colon cancer. In this review, we will be briefing on the colon and its stem cells, various molecular signaling pathways involved in stemness preservation, and the role hypoxia and its HIFs in the maintenance of stemness in colon stem cells and colon cancer stem cells.

Extracellular Polysaccharide Production by Bacteria as a Mechanism of Toxic Heavy Metal Biosorption and Biosequestration in the Marine Environment

Marine environments are one of the most diverse environments owing to their vast natural resource of imperative functional molecules. Interestingly, marine bacteria offer a great diversity of polysaccharides which could play an important role in biotechnology and industry. Among the various bioactive compounds, marine exopolymers are attracting major interest and attention due to their structural and functional diversity. Bacterial exopolysaccharides (EPSs) contain ionizable functional groups, which enable them to bind and sequestrate toxic heavy metal ions. Due to their biodegradability and safety of the environment, biosorption of heavy metals by these biopolymers has attracted considerable attention as promising alternatives capable to compete with expensive, inefficient and conventional technologies, including chemical precipitation, adsorption on activated carbon, membrane separations, ion exchange and solvent extraction methods. This review particularly emphasizes on utilization of marine bacteria in the field of bioremediation and understanding the mechanism behind acquiring the characteristic feature of adaptive responses. Fundamental insights regarding metals in relation to metal-binding proteins/peptides for immobilization, information regarding genetic engineering for enzymes involved in metal transformation and strategies that can be employed to overcome the bottlenecks associated with microbial-based remediation are highlighted in this review. The important engineering properties based on structural characteristics such as adsorption, biodegradability and hydrophilicity/hydrophobicity of EPS matrix are also discussed. A thorough understanding of microbes that produce exopolysaccharides for metal biosequestration and biosorption would solve several problems in bioremediation process.

Molecular interplay of pro-inflammatory transcription factors and non-coding RNAs in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma is the sixth most common cancer in the developing world. The aggressive nature of esophageal squamous cell carcinoma, its tendency for relapse, and the poor survival prospects of patients diagnosed at advanced stages, represent a pressing need for the development of new therapies for this disease. Chronic inflammation is known to have a causal link to cancer pre-disposition. Nuclear factor kappa B and signal transducer and activator of transcription 3 are transcription factors which regulate immunity and inflammation and are emerging as key regulators of tumor initiation, progression, and metastasis. Although these pro-inflammatory factors in esophageal squamous cell carcinoma have been well-characterized with reference to protein-coding targets, their functional interactions with non-coding RNAs have only recently been gaining attention. Non-coding RNAs, especially microRNAs and long non-coding RNAs demonstrate potential as biomarkers and alternative therapeutic targets. In this review, we summarize the recent literature and concepts on non-coding RNAs that are regulated by/regulate nuclear factor kappa B and signal transducer and activator of transcription 3 in esophageal cancer progression. We also discuss how these recent discoveries can pave way for future therapeutic options to treat esophageal squamous cell carcinoma.

Adiponectin: Its role in obesity-associated colon and prostate cancers

Adipose tissue synthesizes many proteins and hormones collectively called adipokines, which are linked to a number of diseases, including cancer. Low levels of adiponectin are reported to be a risk factor for obesity-related cancers including colorectal and prostate cancers. Accordingly, obesity/lifestyle-related diseases, including certain cancers, may be treated by developing drugs that act specifically on adiponectin levels in circulation. Adiponectin may also serve as a clinical biomarker in obesity-related diseases. Adiponectin-based therapies are known to inhibit cancer advancement and thus may provide a therapeutic approach to delay cancer progression. Better understanding of the function of adiponectin is of great significance in the fight against cancer. This timely review is concentrated on the role of adiponectin and the impact of obesity on the development of cancers, especially colorectal and prostate cancers.

Small molecule tyrosine kinase inhibitors and pancreatic cancer—Trials and troubles

Pancreatic cancer (PC) is an aggressive carcinoma and the fourth cause of cancer deaths in Western countries. Although surgery is the most effective therapeutic option for PC, the management of unresectable, locally advanced disease is highly challenging. Our improved understanding of pancreatic tumor biology and associated pathways has led to the development of various treatment modalities that can control the metastatic spread of PC. This review intends to present trials of small molecule tyrosine kinase inhibitors (TKIs) in PC management and the troubles encountered due to inevitable acquired resistance to TKIs.

Current Perspectives on Rhizobacterial-EPS interactions in Alleviation of Stress Responses: Novel Strategies for Sustainable Agricultural Productivity

Rhizobacterial exopolysaccharides (EPSs) are the active constituents of soil organic matter which possess numerous biological functions, viz., biofilm development and survival, host colonization, and bacterial autoaggregation, including host specificity, quorum sensing, participation in early stages of host plant infection, signaling molecule during plant development, and most importantly protection from environmental stresses. These adverse conditions lead to negative environmental impacts and socioeconomic consequences such as reduction of crop productivity and soil fertility. However, environmental concerns related to these stresses motivate the scientists to find out environment-friendly approaches for sustainable agriculture. Interestingly the plant growth-promoting rhizobacteria (PGPR) have evolved with several biochemical mechanisms to cope with the environmental biotic and abiotic stressors, viz., plant pathogen defenses, metal, salt, and drought. This review presents the recent advances and applications made hitherto in understanding the biochemical mechanisms of rhizobacterial-EPS interactions alleviate stress responses and their role in major processes involved in phytoremediation, such as heavy metal detoxification, biocomplexation, bioaggregation, biosorption, and biosequestration. Interestingly these EPSs have rapidly emerged as a new and industrially important source of polymeric materials, which are gradually becoming economically competitive for crop productivity. Nevertheless future progress in understanding of PGPR, mechanisms of plant-microbe-EPS interactions, could facilitate their development as the reliable components in management of sustainable agricultural systems.

Detection and Expression of Biosynthetic Gene Clusters in Actinobacteria

Abstract Actinobacteria, one of the largest taxonomic groups in the bacterial domain, exhibit diverse physiological and metabolic properties, producing a wealth of structurally diverse secondary metabolites that possess remarkable biological functions. Many of these secondary metabolites are potently antibacterial, antifungal, anticancer, antiviral, antiparasitic, and immunosuppressant. Structurally they belong to macrolides, polyethers, aminoglycosides, streptothricins, actinomycins cyclopolylactones, quinoxaline peptides, glycopeptides, and orthosomycins. Advances in genomics have revealed the fact that many microorganisms have greater potential than that which we have discovered till now through bioactivity screenings. Recent improvements in sequencing whole genomes discovered the presence of more than one biosynthetic gene cluster (BGC), which are not yet explored. In order to express this unexplored potential, several methods have been adapted, of which heterologous expression was successful to some extent in expressing silent biosynthetic gene clusters producing novel secondary metabolites. In this book chapter, we discuss the various existing methods used to detect and identify the BGCs from whole genome sequencing, along with the strategies currently available for cloning large DNA fragments and their heterologous expression.

Novel Perspectives of Biotic and Abiotic Stress Tolerance Mechanism in Actinobacteria

Abstract Actinobacteria continue to be important sources for discovery of secondary metabolites for application in medicine and agriculture. Interestingly, the genus actinobacteria exhibits plant growth promoting (PGP) properties, biocontrol, biopesticide agents, antifungal compounds, and biocorrosion and agroactive compounds. Actinobacteria encounter different environmental stresses, and adaptation to these stresses causes extended tolerance to lethal stressors. Like other microbes, Actinobacteria compete for nutrients, and they have developed sophisticated ways to adapt to different environmental biotic and abiotic stresses. Some of the known genetic-based mechanisms contributing to genomic rearrangements are considered to be the means for bacterial cells evolving within the constraints of environmental stressors. Changes in gene expression constitute the main component of bacterial response to stress and environmental changes, and involve a myriad of different mechanisms to alleviate the stress responses. In this review an attempt is made to cover model systems, with a broad overview of the stress-responsive regulatory systems in agriculturally important actinobacteria, where elucidation of certain aspects of these systems could lead to significant biotechnological applications in industry and agriculture.