Revisiting edible insects as sources of therapeutics and drug delivery systems for cancer therapy.

Cancer has been medicine's most formidable foe for long, and the rising incidence of the disease globally has made effective cancer therapy a significant challenge. Drug discovery is targeted at identifying efficacious compounds with minimal side effects and developments in nanotechnology and immunotherapy have shown promise in the fight against this complicated illness. Since ancient times, insects and insect-derived products have played a significant role in traditional medicine across several communities worldwide. The aim of this study was to inspect the traditional use of edible insects in various cultures and to explore their modern use in cancer therapy. Edible insects are sources of nutrients and a variety of beneficial substances with anticancer and immunomodulatory potential. Recently, insect derived bioactive-components have also been used as nanoparticles either in combination with chemotherapeutics or as a nano-cargo for the enhanced delivery of chemotherapeutic drugs due to their high biocompatibility, low bio-toxicity, and their antioxidant and anticancer effects. The crude extracts of different edible insects and their active components such as sericin, cecropin, solenopsin, melittin, antimicrobial peptides and fibroin produce anti-cancer and immunomodulatory effects by various mechanisms which have been discussed in this review.

Protective Effects of Pelargonidin against DMBA-Induced Mammary Tumorigenesis in BALB/c Mice through Reduced Oxidative Stress and Lipid Anomalies.

Among luminal types of breast cancers, ER + breast cancer is the most frequently diagnosed cancer globally. ER + breast cancer is commonly treated with SERM drugs that block ER to prevent ER-mediated cancerous growth. Our previous computational screening found pelargonidin (PG) can inhibit ER-signaling with potent bioactivity and satisfactory toxicological features. The present study explored the anti-tumoral prospect of PG against DMBA-induced ER + murine mammary carcinogenesis. The female BALB/c mice were divided into control (A) and DMBA-exposed groups. Following tumor appearance, the DMBA-exposed group was divided into five groups: tumor control, PG-treated (Groups P25, P50, and P100), and tamoxifen-treated (TAM). The results indicated that PG-treatment dose-dependently reduced the mean tumor volume, reinstated body weight loss, and enhanced the percentage survival of tumor-bearing mice. In addition, we recorded a significant reduction in LPO, total cholesterol, and triglycerides and a surge in the activity of antioxidases and phase II detoxifying enzymes in PG-treated animals. PG also dose-dependently increased the serum level of unbound estradiol, an indicator of competitive ER binding by an ER agonist/antagonist. These data suggest that pelargonidin has potent anticancer potential against the animal model of ER + breast cancer that matches the efficiency of tamoxifen with conceivably fewer side effects.

Low level of BRCA2 in peripheral blood lymphocytes is associated with an increased risk for head and neck squamous cell carcinoma (HNSCC) in a population of North-East India: a case-control study.

Background: We investigated the role of DNA repair proteins breast cancer susceptibility 2 (BRCA2), xeroderma pigmentosum group D (XPD) and apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) in determining the risk for head and neck squamous cell cancer (HNSCC) in a case-control study from North-East India. Methods: Expression of BRCA2, XPD and APE1 genes in the matched tumour, normal adjacent tissue (NAT) and blood of 12 HNSCC patients and blood of 8 age- and gender-matched controls was determined by quantitative real-time PCR. Results were validated by expression analysis of the corresponding proteins in the peripheral blood lymphocytes (PBLs) of 228 subjects (106 patients and 122 controls) by a slot-blot immunoassay. Findings: Expression of the BRCA2 and XPD genes in tumour tissue of HNSCC patients declined progressively as the cancer stage advanced, was reverse that of the NAT, but was mirrored by the expression in the blood. BRCA2 and XPD proteins were significantly (p < 0.0001) downregulated in the PBL of HNSCC patients to 71% and 77% the levels in controls, showing significant negative correlation with HNSCC stage (Spearman correlation coefficient (r s) of -0.9060, p < 0.0001 for BRCA2; r s of -0.8008, p < 0.01 for XPD). On the contrary, APE1 was significantly upregulated in PBL of HNSCC patients to 1.47 fold the level in controls, showing significant positive correlation with HNSCC stage (r s of 0.7023, p < 0.01). Classification and regression tree analyses predicted low levels of BRCA2 protein in PBL as the single most important risk factor for HNSCC, independent of gender. Smokers above 36 years of age with low level of BRCA2 appeared to exhibit a 1.78-fold increased risk for HNSCC (with a 1.78-fold increased risk for HNSCC (OR = 1.78, 95% confidence interval (CI) = 0.33-9.52) though this risk was not significant statistically. Similarly, low levels of BRCA2 appeared to indicate a moderate, but non-significant risk for HNSCC in non-smokers aged between 36 and 56 years (OR = 1.15, 95% CI = 0.21-6.37). Conclusions: Low level of BRCA2 protein in the peripheral blood indicates increased risk for HNSCC.

In silico assessment of DNA damage response gene variants associated with head and neck cancer.

Head and neck cancer (HNC), the sixth most common cancer globally, stands first in India, especially Northeast India, where tobacco usage is predominant, which introduces various carcinogens leading to malignancies by accumulating DNA damages. Consequently, the present work aimed to predict the impact of significant germline variants in DNA repair and Tumour Suppressor genes on HNC development. WES in Ion ProtonTM platform on 'discovery set' (n = 15), followed by recurrence assessment of the observed variants on 'confirmation set' (n = 40) using Sanger Sequencing was performed on the HNC-prevalent NE Indian populations. Initially, 53 variants were identified, of which seven HNC-linked DNA damage response gene variants were frequent in the studied populations. Different tools ascertained the biological consequences of these variants, of which the non-coding variants viz. EXO1_rs4150018, RAD52_rs6413436, CHD5_rs2746066, HACE1_rs6918700 showed risk, while FLT3_rs2491227 and BMPR1A_rs7074064 conferred protection against HNC by affecting transcriptional regulation and splicing mechanism. Molecular Dynamics Simulation of the full-length p53 model predicted that the observed coding TP53_rs1042522 variant conferred HNC-risk by altering the structural dynamics of the protein, which displayed difficulty in the transition between active and inactive conformations due to high-energy barrier. Subsequent pathway and gene ontology analysis revealed that EXO1, RAD52 and TP53 variants affected the Double-Strand Break Repair pathway, whereas CHD5 and HACE1 variants inactivated DNA repair cascade, facilitating uncontrolled cell proliferation, impaired apoptosis and malignant transformation. Conversely, FLT3 and BMPR1A variants protected against HNC by controlling tumorigenesis, which requires experimental validation. These findings may serve as prognostic markers for developing preventive measures against HNC.

Studies on antimicrobial stress with reference to biofilm formation of faecal microbial communities from Apatani tribe of Arunachal Pradesh.

PURPOSE: Antibiotic resistant bacteria have created serious health conditions worldwide, disseminating various infections to people and community along with direct clinical implications in therapeutic options. METHODS: The present study analysed 20 samples from human faeces of Apatani tribe, Arunachal Pradesh, India. Biofilm assay, antimicrobial susceptibility tests and antimicrobial profiling were performed along with phylogenetic analysis. RESULTS: Phenotypic screening indicated the presence of 21 aerobic isolates comprising Escherichia sp 42.8% (n â€‹= â€‹9), Citrobacter sp 9.52% (n â€‹= â€‹2), Klebsiella sp 23.8% (n â€‹= â€‹5) and Enterococcus sp 23.8% (n â€‹= â€‹5). Tetracycline, ciprofloxacin, ceftadizime, gentamicine, vancomycin and erythromycin were observed to highly dominate the biofilm producing bacteria. Antimicrobial activity of Escherichia sp, Citrobacter sp, Klebsiella sp, and Enterococcus sp inhibited the growth of at least one of the tested pathogens. Phylogenetic analysis revealed that antibiotic resistant Klebsiella sp belonged to Klebsiella pneumonia; Escherichia sp belonged to Escherichia fergusonii and Escherichia coli; Enterococcus sp belonged to Enterococcus faecium while Citrobacter sp belonged to Citrobacter freundii. CONCLUSION: The present work shows that antibiotic resistant bacteria-Klebsiella sp, Enterococcus sp, Escherichia sp and Citrobacter sp were highly prevalent in the faecal microbial communities of Apatani tribe from Arunachal Pradesh. Presence of such antibiotic resistance and biofilm formation in faecal microbiota poses serious concerns regarding health and therapeutic options as this tribe mostly resides in remote vicinities of Arunachal Pradesh. Thus, exploring the mechanisms for dissemination of antibiotic resistance in this tribe helped us to identify key factors pertaining to the health of this tribe as well as their environment.

The antidiabetic drug pioglitazone ameliorates betel-nut-induced carcinogenesis in mice by restoring normal lipid metabolism, reducing oxidative stress, and inducing apoptosis.

CONTEXT: Oral administration (2 mg mL-1) of aqueous extract of betel nut (AEBN) for 24 weeks induced oncogenic alterations in the liver of female Swiss Albino mice concomitant with aberrant lipid metabolism, overactivation of Akt/mTOR signaling, and loss of apoptosis. AIM: This study was designed to investigate the potential of repurposing the antidiabetic drug pioglitazone for alleviating AEBN-induced carcinogenesis. METHODS: Sera of animals were evaluated for lipid profile and free fatty acid levels. Liver tissues were investigated for oxidative stress, histopathology, and expression of proteins involved in lipid metabolism and oncogenesis by western blotting. Apoptosis was determined using TUNEL assay. RESULTS: Coadministration of pioglitazone (10 mg kg-1 b.w) with AEBN for 8 weeks restored normal lipid profile and AMPK/ACC signaling, reduced FASN and HMGCR expressions and oxidative stress, and actively induced Akt/mTOR-mediated apoptosis in the liver. CONCLUSIONS: Pioglitazone can effectively alleviate AEBN-induced carcinogenesis in mice.

Elucidating the gut microbiome alterations of tribal community of Arunachal Pradesh: perspectives on their lifestyle or food habits.

Gut microbiota studies of ethnic populations reveal gut microbial biomarkers for therapeutic options and detection of the disease state. The present study aimed to analyze the gut microbiome signatures in thirty individuals from the Adi, Apatani and Nyshi tribes of Arunachal Pradesh (ten in each cohort) by sequencing the V3 and V4 regions of 16S rRNA on the Illumina MiSeq Platform. The gut microbiome was highly predominated by Firmicutes, Actinobacteria, Proteobacteria, and Bacteroidates in the three studied tribal groups. At the genus level, significant abundance of Bifidobacterium, Collinsella, Bacteroides, Prevotella, Lactobacillus, Streptococcus, Clostridium, Coprococcus, Dorea, Lachnospira, Roseburia, Ruminococcus, Faecalibacterium, Catenibacterium, Eubacterium, Citrobacter and Enterobacter were observed amongst the three tribes. The tribal communities residing in remote areas and following traditional lifestyle had higher gut microbiome diversity with a high prevalence of Prevotella and Collinsella in the Adi and Nyshi tribes, and Bifidobacterium and Catenibacterium in the Apatani tribe. Elucidating the gut microbiome of the tribal community of Arunachal Pradesh will add to the knowledge on relationships between microbial communities, dietary food factors, and the overall state of health of humans worldwide.

Circular RNAs are Potential Prognostic Markers of Head and Neck Squamous Cell Carcinoma: Findings of a Meta-Analysis Study.

Background: Several studies have reported the role of circRNAs in the pathogenesis, diagnosis and prognosis of different cancers. This meta-analysis study aimed to evaluate the potential of using circRNAs as prognostic biomarkers of head and neck squamous cell carcinoma (HNSCC). Methods: 816 relevant articles were retrieved from PubMed and Science Direct databases, out of which 17 met the inclusion criteria. These 17 studies were assessed for quality by the Newcastle-Ottawa Scale (NOS) system, and 9 high quality studies (NOS>7) were included in the meta-analysis. Cochran Q test and the I square (I 2) metric were calculated to detect potential heterogeneity among studies. Sensitivity analysis was performed to validate the credibility of outcomes, and publication bias was determined using Begg's funnel plot and Egger's test. Hazard ratio (HR) and 95% Confidence Intervals (CIs) were used to evaluate overall survival (OS) of HNSCC patients by univariate and multivariate analyses. Results: The dysregulated levels of 9 circRNAs (circPVT1, circCORO1C, circ_0000199, circCUX1, circPARD3, circMYC, circ_0102272, circ_0092125 and circ_00072387) were inversely related to OS of HNSCC patients [upregulated circRNA (univariate analysis: HR = 3.40, 95% CI: 2.66-4.36, p < 0.0001, I 2 = 0%; multivariate analysis: HR = 3.33, 95% CI: 2.54-4.38, p < 0.0001, I 2 = 0%), downregulated circRNA (univariate analysis: HR = 2.83, 95% CI: 1.73-4.65, p < 0.0001, I2 = 57.8%; multivariate analysis: HR = 2.35, 95% CI: 1.42-3.89, p = 0.0009, I2 = 0%)]. The individual HR for these 9 circRNAs indicated inverse relation to OS, validating the overall HR. The dyregulated levels of these circRNAs were also associated with poor clinicopathological outcomes such as primary tumor size, lymph node metastasis, distant metastasis and poor tumor (T), nodes (N), metastases (M); i.e TNM staging, and six of these circRNAs regulated diverse micro RNAs, revealing their role in tumorigenesis and cancer progression. Conclusion: Nine different circRNAs dysregulated in HNSCC tumors may serve as potential prognostic markers of HNSCC. These markers are associated with reduced OS and poor clinicopathological outcomes of HNSCC patients. They are also involved in the pathogenesis and progression of HNSCC through diverse mechanisms.

Whole exome sequencing identifies the potential role of genes involved in p53 pathway in Nasopharyngeal Carcinoma from Northeast India.

Nasopharyngeal Carcinoma (NPC) found to be dependent on geographical and racial variation and is more prevalent in Northeast (NE) India. WES-based study was conducted in three states (tribes); Nagaland (Naga), Mizoram (Mizo) and Manipur (Manipuri), which provided an overview of germline variants involved inthemajor signaling pathways. Validation and recurrence assessment of WES data confirmed the risk effect of STEAP3_rs138941861 and JAG1_rs2273059, and the protective role of PARP4_rs17080653 and TGFBR1_rs11568778 variants, where STEAP3_rs138941861conferring Arg290His substitution was the only exonic non-synonymous variant and to be located in proximity to the linking region between the transmembrane and oxidoreductasedomainsof STEAP3 protein, andaffectedits structural and functional dynamics by altering the Electrostatic Potential around this connecting region. Moreover, these significantly associated variants having deleterious effect were observed to have interactions in p53 signaling pathway which emphasizes the importance of this pathway in the causation of NPC.

The impact of prehistoric human dispersals on the presence of tobacco-related oral cancer in Northeast India.

BACKGROUND: Northeast (NE) India is a subject of debate for predicting its involvement in prehistoric anatomically modern human (AMH) dispersal. The unique lifestyle and genetic characteristics of native ethnic groups in this region are believed to be responsible for their susceptibility to tobacco-related oral cancer (TrOC). The present study assessed mitochondrial macro-haplogroup (mHG) diversity and TrOC susceptibility autosomal loci to evaluate the impact of prehistoric AMH dispersal on the present day's high TrOC prevalence in major NE Indian ethnics. METHODS: We considered 175 unrelated individuals from 35 ethnic groups and previously published 374 sequences for sequencing-based assessment of mtDNA-based marker by subsequent analyses like haplogroup diversity, phylogenetic, genetic structure by AMOVA, and MDS, descriptive statistics of demographic parameters, and migration analysis. Besides, we selected prolonged tobacco-chewing 124 case-control individuals from similar ethnic backgrounds for genotyping 115 autosomal loci in Sequenom iPLEX MassARRAY™ platform and mined 1000genome data (n = 398) for consequent global admixture and ancestry-specific allele frequencies-based analyses. RESULTS: Our mtDNA-based findings suggested that NE populations were distinct from other Indian populations, owing to the first wave of migration from ancient southern China (∼54kya) and two successive spatial expansion events at âˆ¼45kya and âˆ¼43kya. Consequently, it probably acted as another source for prehistoric AMH dispersal in N/NE Asia. Besides, the second wave of back-migration from SE Asia (∼40kya) probably replaced the mitochondrial footprints of survivors from the first migrants and introduced the TrOC susceptibility traits in this region. Afterward, the autosomal marker-based observations on the transition of the disease-associated admixture component 'K6' from SE Asia reconfirmed these results. Moreover, we also observed that the mitochondrial mHG 'R' is significantly associated with the risk of TrOC (OR > 9.5) in NE India. Furthermore, the possible onset of the phenotypic expression of those traits was predicted at âˆ¼4kya, thus, contributing to present-day's TrOC prevalence. CONCLUSIONS: This study reflects its uniqueness by revealing an updated AMH dispersal route for the peopling in and out of NE India, which probably introduced the disease-causing traits in the ancestral NE Indian population. Those traits were then imprinted in their genome to get transferred through their respective generations, forming the present-day's TrOC-prevalent NE Indian population.

Oral Nicotine Induces Oxidative Stress and Inflammation but Does Not Subvert Tumor Suppressor and DNA Repair Responses in Mice.

Nicotine, responsible for the addictive properties of tobacco, is widely used in nicotine replacement therapy for tobacco use cessation. We investigated the time-dependent effect of treatment with nicotine on the tumor suppressor, DNA repair and immune responses. Swiss Albino mice (laca strain) of both sexes received nicotine dissolved at a dose of 100 µg/ml in 2% sucrose for 24 weeks, by oral gavage, while age- and gender-matched controls received only 2% sucrose for the same period. Nicotine-treated and control mice were sacrificed 6, 16 and 24 weeks post-treatment, and their tissues evaluated for alterations in histology, oxidative stress, TNF-α levels, nitric oxide (NO) and myeloperoxidase (MPO) release, tumor suppressor response and DNA repair response. Statistical significance of results was determined using Students' t test. The tissues of nicotine treated mice exhibited a large number of multinucleated and binucleated cells, enlarged nuclei and non-uniform distribution of cells, significant increase in expression of TNF-α gene and serum TNF-α, and time-dependent significant increase in lipid peroxidation, protein carbonylation, NO and MPO release when compared to age-and gender-matched controls. The mRNA expression of the tumor suppressor gene p53, its primary regulator Mdm2, and the DNA repair genes Brca2 and Ape1 were significantly elevated, but the corresponding protein levels remained largely unaltered. In conclusion, treatment with nicotine caused oxidative stress and inflammation which can cause widespread cellular damage from the very onset of treatment, without subverting the tumor suppressor and DNA repair responses.

Silencing lung cancer genes using miRNAs identified by 7mer-seed matching.

Lung cancer (LC) is the main cause of cancer-associated deaths in both men and women globally with a very high mortality rate. The microRNAs (miRNAs) are a class of noncoding RNAs consisting of 18-25 nucleotides. They inhibit translation of protein through binding to complementary target mRNAs. The non-coding miRNAs are recognized as potent biomarkers for detection, development and treatment of malignancy. In this study, we screened a set of 12 genes over expressed in small cell lung cancer, non small cell lung cancer and the genes involved in both categories and their binding sites for human miRNAs as no work was reported yet. Screening of human miRNAs revealed that a few genes showed numerous miRNA binding sites. Free energy values of mRNA sequences revealed that they might acquire compact folded structure causing complexity for miRNAs to interact. GC content in the target site was relatively higher than that of their flanks. It was observed through analysis of cosine similarity metric and compAI parameters that the genes related to lung cancer were encoded with non optimal codons and thus might be translationally less efficient for producing polypeptides. Gene ontology analysis was carried out to understand the diverse functions of these 12 genes.

Rhizodegradation of Pyrene by a Non-pathogenic Klebsiella pneumoniae Isolate Applied With Tagetes erecta L. and Changes in the Rhizobacterial Community.

The non-clinical Klebsiella pneumoniae variants, isolated from different environments, are now well acknowledged for their role in plant-growth promotion and biodegradation of pollutants. In the present study, a non-clinical environmental isolate K. pneumoniae AWD5 is being described for rhizoremediation of pyrene, applied through the rhizosphere of an ornamental plant, Tagetes erecta L (marigold). The non-pathogenic nature of AWD5 was established using an in vivo mouse model experiment, where AWD5 was unable to cause lung infection in tested mice. Degradation of pyrene, in the presence of succinate as co-substrate, was observed to be 87.5% by AWD5, after 21 days of incubation in minimal (Bushnell-Hass) medium in vitro conditions. Consequently, the bacterial inoculation through the rhizosphere of T. erecta L. plants resulted in 68.61% degradation of pyrene, which was significantly higher than control soil. Inoculation of AWD5 also improved plant growth and exhibited an increase in root length (14.64%), dry root weight (80.56%), shoot length (3.26%), and dry shoot weight (45.35%) after 60 days of incubation. T. erecta L., an ornamental plant, was also found to be suitable for bioremediation of pyrene. The effect of AWD5 application, and rhizoremediation process, on rhizosphere bacterial diversity and community structure has been studied using the metagenomic analysis of the 16S (V3-V4) region of rRNA. 37 bacterial phyla constituted the core microbiome, which was dominated by Proteobacteria followed by Actinobacteria, Actinobacteria, and Planctomycetes for all the treatments. AWD5 inoculation enhanced the relative abundance of Firmicutes and Acidobacteria as compared with other treatments. Genus Kaistobacter and Verrucomicrobia were found to be an abundant indigenous population in pyrene-spiked soils. Bacterial richness and diversity were analyzed using the Shannon-Wiener (H) index. A lower diversity index was observed in pyrene-spiked soils. Canonical correspondence analysis (CCA) showed a possible linkage with plant growth attributes and available nitrogen content that influences diversity and abundance of the bacterial community.

Phylogeny, Biofilm Production, and Antimicrobial Properties of Fecal Microbial Communities of Adi Tribes of Arunachal Pradesh, India.

The fecal flora consists of trillions of bacteria influencing human health and several host factors. Such population-based fecal flora studies are critical to uplift the health status of ethnic tribes from Arunachal Pradesh. This study aimed to analyze the ethnic tribe's biofilm producing antibiotic resistant bacteria and their phyllogenetic analysis in 15 stool samples collected from Adi tribes of Arunachal Pradesh. Of the analyzed samples, 42.85% were Escherichia, 20% lactic acid bacteria, 20% Salmonella, and 17.14% Enterococcus. Escherichia coli, lactic acid bacteria, and Enterococcus sp. emerged as strong biofilm producers; however, Salmonella declined to exhibit characters for a strong biofilm producer. Tetracycline resistance dominated in all the gut bacterial profiles. The 16SrRNA amplified PCR product was used for sequencing, and a phylogenetic tree was constructed exhibiting the relationship between the isolates. The test sequences were compared with the non-redundant Gene bank collection of the database with the Basic Local Alignment Search Tool.

Vildagliptin, a dipeptidyl peptidase-4 inhibitor, reduces betel-nut induced carcinogenesis in female mice.

AIM: Betel-nut, a popular masticatory among Southeast Asian populations is a class I carcinogen, previously associated with dyslipidemia and aberrant lipid metabolism, and is reported to be used more frequently by females, than males. This study investigates the potential of repurposing the anti-diabetic drug, vildagliptin, a dipeptidyl peptidase-4 inhibitor, for alleviating the oncogenic condition in female Swiss Albino mice administered an aqueous extract of betel-nut (AEBN) orally (2 mg ml-1) for 24 weeks. MAIN METHODS: Tissues were investigated by histopathological, immunohistochemical and apoptosis assays. Biochemical analyses of oxidative stress markers and lipid profile were performed using different tissues and sera. The expressions of different proteins involved in lipid metabolism and oncogenic pathways were evaluated by Western blotting. KEY FINDINGS: AEBN induced carcinogenesis primarily in the liver by significantly impairing AMPK signaling, inducing oxidative stress, activating Akt/mTOR signaling, increasing Ki-67 immunoreactivity and cyclin D1 expression, and significantly diminishing apoptosis. Co-administration of AEBN with vildagliptin (10 mg kg-1 body weight) for 8 weeks reduced liver dysplasia, and significantly decreased free palmitic acid, increased free oleic acid, normalized lipid profile, decreased oxidative stress, cyclin D1 expression, Ki-67 immunoreactivity, and Bcl2 expression, and increased the ratio of apoptotic/non-apoptotic cells. Mechanistically, vildagliptin elicited these physiological and molecular alterations by restoring normal AMPK signaling and reducing the cellular expressions of FASN and HMGCR, restoring AMPK-dependent phosphorylation of p53 at Ser-15 and reducing Akt/mTOR signaling. SIGNIFICANCE: These results indicate that vildagliptin may alleviate betel-nut induced carcinogenesis in the liver of female mice.

A Crosstalk on Codon Usage in Genes Associated with Leukemia.

Leukemia is the outcome of aggregation of damaged white blood cells. Several genes were reported to be associated with the pathogenesis of leukemia. These genes were computationally analyzed to decipher their codon usage bias (CUB) and to identify the prime factors influencing the codon usage profile as no work was reported yet. The mean values of synonymous codon usage order (SCUO) parameter indicated low CUB of the genes. Significant positive association of SCUO with overall GC and positional GCs might signal the presence of mutational pressure. However, neutrality plot suggested the dominant role of natural selection across the genes. Along with natural selection, the role of mutation pressure was also prominent and that might be responsible for lower CUB (SCUO = 0.19) of genes. Low translational speed might permit accuracy in the process. A strong inverse relationship of translational rate was observed with CUB of genes and folding energy.

Synonymous codon usage and context analysis of genes associated with pancreatic cancer.

Pancreatic cancer is a fatal disorder which originates in pancreas. Its mortality rate is increasing with time. Some studies also reported that pancreatic cancer would be ranked 2nd by the year 2030. Codon usage bias (CUB) arises when synonymous codons for each amino acid are not used randomly in the coding sequences of genes. We used bioinformatic methods to analyze the compositional properties, codon context and codon usage trend of the genes associated with pancreatic cancer as no work was reported yet. From the base composition analysis, the pancreatic cancer genes were found to be GC-rich and at the 3rd codon position the G/C ending codons were more preferred to A/T ending ones. The CUB was low in genes associated with pancreatic cancer. Correspondence analysis proposed that other than base constraints, CUB might also be affected by some other factors such as natural selection. Moreover, results of correlation analysis indicated that CUB and various GC contents i.e. GC, GC1, GC2, GC3 played important role in the release of free energy by transcripts of the genes associated with pancreatic cancer. The low compAI values of coding sequences suggested a low translation rate of the genes.

Pleiotropic effects of anti-diabetic drugs: A comprehensive review.

Diabetes mellitus characterized by hyperglycaemia presents an array of comorbidities such as cardiovascular and renal failure, dyslipidemia, and cognitive impairments. Populations above the age of 60 are in an urgent need of effective therapies to deal with the complications associated with diabetes mellitus. Widely used anti-diabetic drugs have good safety profiles and multiple reports indicate their pleiotropic effects in diabetic patients or models. This review has been written with the objective of identifying the widely-marketed anti-diabetic drugs which can be efficiently repurposed for the treatment of other diseases or disorders. It is an updated, comprehensive review, describing the protective role of various classes of anti-diabetic drugs in mitigating the macro and micro vascular complications of diabetes mellitus, and differentiating these drugs on the basis of their mode of action. Notably, metformin, the anti-diabetic drug most commonly explored for cancer therapy, has also exhibited some antimicrobial effects. Unlike class specific effects, few instances of drug specific effects in managing cardiovascular complications have also been reported. A major drawback is that the pleiotropic effects of anti-diabetic drugs have been mostly investigated only in diabetic patients. Thus, for effective repurposing, more clinical trials devoted to analyse the effects of anti-diabetic drugs in patients irrespective of their diabetic condition, are required.

Codon usage trend in genes associated with obesity.

Obesity is not only a social menace but also an economic burden as it reduces productivity and increases health care cost. We used bioinformatic tools to analyze the CUB of obesity associated genes and compared with housekeeping genes (control) to explore the similarities and differences between two data sets as no work was reported yet. The mean effective number of codons (ENC) in genes associated with obesity and housekeeping gene was 50.45 and 52.03 respectively, indicating low CUB. The relative synonymous codon usage (RSCU) suggested that codons namely CTG and GTG were over-represented in both obesity and housekeeping genes while under-represented codons were TCG, TTA, CTA, CCG, CAA, CGT, ATA, ACG, GTA and GCG in obesity genes and TCG, TTA, CCG, ATA, ACG, GTA, and GCG in housekeeping genes. t test analysis suggested that 11 codons namely TTA (Leu), TTG (Leu), CCG (Pro), CAC (His), CAA (Gln), CAG (Gln), CGT (Arg), AGA (Arg), ATA (Ile), ATT (Ile) and GCG (Ala) were significantly differed (p < 0.05 or p < 0.01) between obesity and housekeeping genes. Highly significant correlation was observed between GC12 and GC3 in obesity and housekeeping genes i.e. r = 0.580** and r = 0.498** (p < 0.01) respectively indicating the effect of directional mutation pressure present in all codon positions.

Treatment with the anti-diabetic drug metformin ameliorates betel-nut induced carcinogenesis in a murine model.

BACKGROUND: Metformin, a widely used anti-diabetic drug has gained enormous attention as an anticancer agent. This study seeks to investigate the efficacy of metformin in ameliorating aqueous extract of betel-nut (AEBN) and arecoline induced carcinogenesis in a murine model. METHODS: Swiss albino mice were exposed to AEBN (2 mg ml-1) and arecoline (10 µg ml-1) in drinking water for 16 weeks followed by co-administration of metformin (75 mg kg-1 or 150 mg kg-1) for 4 or 8 weeks. Histological changes and oxidative stress were assessed by haematoxylin and eosin staining, TBARS assay and protein carbonylation assay respectively. Lipid profile was determined using an automated analyzer. Expression of total and phosphorylated AMPK, ACC and p53 were determined by immunoblotting. RESULTS: AEBN and arecoline induced dyslipidemia by downregulating AMPK (Thr-172) and activating ACC (Ser-79); they also downregulated tumor suppressor p53 (Ser-15). Metformin treatment induced AMPK-dependent alleviation of dyslipidemia in a dose and time dependent manner, upregulated p53 (Ser-15), restored tissue architecture and reduced oxidative stress in tissues of AEBN and arecoline treated mice. CONCLUSION: This study establishes that betel nut induces dyslipidemia through its alkaloid, arecoline by inhibition of AMPK (Thr-172) and activation of ACC (Ser-79) and highlights the therapeutic potential of metformin for treatment of betel-nut induced carcinogenesis, indicating the repurposing of the old drug in a new avenue.