Jatin Kalita

Predictive and prognostic biomarkers in colorectal cancer: A systematic review of recent advances and challenges

BACKGROUND Colorectal cancer (CRC) is one of the leading cause of cancer deaths worldwide. Since CRC is largely asymptomatic until alarm features develop to advanced stages, the implementation of the screening programme is very much essential to reduce cancer incidence and mortality rates. CRC occurs predominantly from accumulation of genetic and epigenetic changes in colon epithelial cells, which later gets transformed into adenocarcinomas. SCOPE OF REVIEW The current challenges of screening paradigm and diagnostic ranges are from semi-invasive methods like colonoscopy to non-invasive stool-based test, have resulted in over-diagnosis and over-treatment of CRC. Hence, new screening initiatives and deep studies are required for early diagnosis of CRC. In this regard, we not only summarise current predictive and prognostic biomarkers with their potential for diagnostic and therapeutic applications, but also describe current limitations, future perspectives and challenges associated with the progression of CRC. MAJOR CONCLUSIONS Currently many potential biomarkers have already been successfully translated into clinical practice eg. Fecal haemoglobin, Carcinoembryonic antigen (CEA) and CA19.9, although these are not highly promising diagnostic target for personalized medicine. So there is a critical need for reliable, minimally invasive, highly sensitive and specific genetic markers of an individualised and optimised patient treatment at the earliest disease stage possible. GENERAL SIGNIFICANCE Identification of a new biomarker, or a set of biomarkers to the development of a valid, and clinical sensible assay that can be served as an alternative tool for early diagnosis of CRC and open up promising new targets in therapeutic intervention strategies.

Complete genome sequence analysis of Pseudomonas aeruginosa N002 reveals its genetic adaptation for crude oil degradation.

The present research work reports the whole genome sequence analysis of Pseudomonas aeruginosa strain N002 isolated from crude oil contaminated soil of Assam, India having high crude oil degradation ability. The whole genome of the strain N002 was sequenced by shotgun sequencing using Ion Torrent method and complete genome sequence analysis was done. It was found that the strain N002 revealed versatility for degradation, emulsification and metabolizing of crude oil. Analysis of cluster of orthologous group (COG) revealed that N002 has significantly higher gene abundance for cell motility, lipid transport and metabolism, intracellular trafficking, secretion and vesicular transport, secondary metabolite biosynthesis, transport and catabolism, signal transduction mechanism and transcription than average levels found in other genome sequences of the same bacterial species. However, lower gene abundance for carbohydrate transport and metabolism, replication, recombination and repair, translation, ribosomal structure, biogenesis was observed in N002 than average levels of other bacterial species.

Taraxerol, a pentacyclic triterpenoid, from Abroma augusta leaf attenuates diabetic nephropathy in type 2 diabetic rats

Persistent hyperglycaemia coupled with inflammation plays an important role in the pathogenesis of diabetic nephropathy (DN). Present study examined the therapeutic potential of taraxerol isolated from the methanol extract of Abroma augusta leaf against DN using rodent model of type 2 diabetes (T2D). T2D was experimentally induced by high fat diet and a single low-single dose of streptozotocin (35mg/kg, i.p.). Accumulation of serum creatinine, urea, and uric acid, activation of lactate dehydrogenase and creatinin kinase, and release of urinary albumin represented the glomerular damage and the progression of nephropathy in T2D rats. Taraxerol (20mg/kg, p.o.) treatment significantly reinstated the aforementioned changes in biochemical parameters near to normalcy. Molecular mechanism studies demonstrated an impaired signaling cascade, IRS1/PI3K/Akt/AMPK/GLUT4/GSK3β, of glucose metabolism in the skeletal muscle and increase in serum levels of pro-inflammatory cytokines, CRP and MCP1 in T2D rats. Activation of polyol pathway, enhanced production of AGEs, up-regulation of NF-κB/PKCs/PARP signaling, and renal fibrosis was also observed in T2D rats. Taraxerol (20mg/kg, p.o.) treatment stimulated glucose metabolism in skeletal muscle, regulated blood glycaemic status and lipid profile in the sera, reduced the secretion of pro-inflammatory cytokines, and restored the renal physiology in T2D rats. Histological assessments were also in agreement with the above findings. Molecular docking study again supported the probable interactions of taraxerol with PKCβ, PKCδ, NF-κB, PARP, PI3K, IRS, Akt and AMPK. In silico ADME study predicted the drug-likeness character of taraxerol. Results suggest a possibility of taraxerol to be a new therapeutic agent for DN in future.

Antioxidant Potential of Vespa affinis L., a Traditional Edible Insect Species of North East India

Introduction Elevated oxidative stress plays an important role in the pathogenesis of health disorders, like arthritis. Traditionally, Vespa affinis L., a common edible insect among many tribes in North-East India, is believed to have a beneficial role in extenuating health disorders, such as arthritis. The present study investigated the molecular mechanism underlying medicinal benefit of the Aqueous Extract of Vespa affinis L. (AEVA) against oxidative stress pathophysiology. Methods The free radical scavenging activities of AEVA were examined against DPPH, hydroxyl, and superoxide radicals and the effect on the activities of antioxidant enzyme (GST and CAT) was determined using both recombinant proteins and human plasma. The antioxidant potential of AEVA was again investigated using THP-1 monocytes. Results AEVA possesses a significant free radical scavenging activity as evident from the DPPH, superoxide, and hydroxyl radical scavenging assay. Incubation of AEVA (2.5, 5, 7.5, and 10 μg/μL) with the recombinant antioxidant enzymes, rGST and rCAT significantly increased the enzyme activities compared to those observed in corresponding enzyme alone or AEVA itself. AEVA supplementation (5, 7.5, and 10 μg/μL) also stimulates the activities of GST and CAT when incubated with human plasma. A cell culture study also confirmed the beneficial role of AEVA (0.8 and 1.2 μg/μL) which enhances the activities of GST and CAT, and also reduces the intercellular ROS production in monocytes treated with or without H2O2 and the effects are at par with what is observed in N-acetyl cysteine-treated cells. Conclusion The antioxidant potential of the aqueous extract of Vespa affinis L. may mediate its therapeutic activities in oxidative stress-associated health disorders.

Vitamin K1 inversely correlates with glycemia and insulin resistance in patients with type 2 diabetes (T2D) and positively regulates SIRT1/AMPK pathway of glucose metabolism in liver of T2D mice and hepatocytes cultured in high glucose

There is no previous study in the literature that has examined the relationship between circulating vitamin K1 (VK1) with glycemic status in type 2 diabetes (T2D). Moreover, scientific explanation for the beneficial role of VK1 supplementation in lowering glycemia in diabetes is yet to be determined. This study for the first time demonstrated that circulating VK1 was significantly lower in T2D patients compared to age-matched control subjects, and VK1 levels in T2D were significantly and inversely associated with fasting glucose and insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)], which suggest that boosting plasma VK1 may reduce the fasting glucose and insulin resistance in T2D patients. Using high-fat-diet-fed T2D animal model, this study further investigated the positive effect of VK1 supplementation on glucose metabolism and examined the underlying molecular mechanism. Results showed that VK1 supplementation [1, 3, 5 μg/kg body weight (BW), 8 weeks] dose dependently improved the glucose tolerance; decreased BW gain, fasting glucose and insulin, glycated hemoglobin, HOMA-IR and cytokine secretion (monocyte chemoattractant protein-1 and interleukin-6); and regulated the signaling pathway of hepatic glucose metabolism [sirtuin 1 (SIRT1)/AMP-activated protein kinase (AMPK)/phosphoinositide 3-kinase/phosphatase and tensin homolog/glucose transporter 2/glucokinase/glucose 6 phosphatase], lipid oxidation (peroxisome proliferator-activated receptor alpha/carnitine palmitoyltransferase 1A) and inflammation (nuclear factor kappa B) in T2D mice. Comparative signal silencing studies also depicted the role of SIRT1/AMPK in mediating the effect of VK1 on glucose metabolism, lipid oxidation and inflammation in high-glucose-treated cultured hepatocytes. In conclusion, this study demonstrates that circulating VK1 has a positive effect on lowering fasting glucose and insulin resistance in T2D via regulating SIRT1/AMPK signaling pathway.

Implication of a novel Gla-containing protein, Gas6 in the pathogenesis of insulin resistance, impaired glucose homeostasis, and inflammation: A review

Growth arrest specific 6 (Gas6), a vitamin K-dependent protein plays a significant role in the regulation of cellular homeostasis via binding with TAM-receptor tyrosine kinases. Several studies reported the role of Gas6 in cancer, glomerular injury, obesity, and inflammation, however, very little is known about its role in insulin resistance (IR) and impaired glucose metabolism. Majority of the studies reported an inverse correlation of Gas6 protein levels or gene polymorphism with plasma glucose, HbA1c, IR, and inflammatory cytokines among type 2 diabetes (T2D) and obese subjects. However, few studies reported a positive correlation of Gas6 protein levels or gene polymorphism with IR and inflammation among obese subjects. This review for the first time provides an overview of the association of Gas6 protein levels or gene polymorphism with IR, glucose intolerance, and inflammation among T2D and obese subjects. This review also depicts the probable mechanism underlying the association of Gas6 with glucose intolerance and inflammation. The outcome of this review will increase the understanding about the role of Gas6 in the pathogenesis of IR, glucose intolerance and inflammation and that should in turn lead to the design of clinical interventions to improve glucose metabolism and the lives of the T2D patients.

Carnosic Acid, a Natural Diterpene, Attenuates Arsenic-Induced Hepatotoxicity via Reducing Oxidative Stress, MAPK Activation, and Apoptotic Cell Death Pathway

The present studies have been executed to explore the protective mechanism of carnosic acid (CA) against NaAsO2-induced hepatic injury. CA exhibited a concentration dependent (1–4 μM) increase in cell viability against NaAsO2 (12 μM) in murine hepatocytes. NaAsO2 treatment significantly enhanced the ROS-mediated oxidative stress in the hepatic cells both in in vitro and in vivo systems. Significant activation of MAPK, NF-κB, p53, and intrinsic and extrinsic apoptotic signaling was observed in NaAsO2-exposed hepatic cells. CA could significantly counteract with redox stress and ROS-mediated signaling and thereby attenuated NaAsO2-mediated hepatotoxicity. NaAsO2 (10 mg/kg) treatment caused significant increment in the As bioaccumulation, cytosolic ATP level, DNA fragmentation, and oxidation in the liver of experimental mice (n = 6). The serum biochemical and haematological parameters were significantly altered in the NaAsO2-exposed mice (n = 6). Simultaneous treatment with CA (10 and 20 mg/kg) could significantly reinstate the NaAsO2-mediated toxicological effects in the liver. Molecular docking and dynamics predicted the possible interaction patterns and the stability of interactions between CA and signal proteins. ADME prediction anticipated the drug-likeness characteristics of CA. Hence, there would be an option to employ CA as a new therapeutic agent against As-mediated toxic manifestations in future.

Implication of a novel vitamin K dependent protein, GRP/Ucma in the pathophysiological conditions associated with vascular and soft tissue calcification, osteoarthritis, inflammation, and carcinoma

Gla-rich protein (GRP) or unique cartilage matrix-associated protein (Ucma), the newest member of vitamin K dependent proteins, carries exceptionally high number of γ-carboxyglutamic acid (Gla) residues which contributes to its outstanding capacity of binding with calcium in the extracellular environment indicating its potential role as a global calcium modulator. Recent studies demonstrated a critical function of GRP in the regulation of different pathophysiological conditions associated with vascular and soft tissue calcification including cardiovascular diseases, osteoarthritis, inflammation, and skin and breast carcinomas. These findings established an important relationship between γ-carboxylation of GRP and calcification associated disease pathology suggesting a critical role of vitamin K in the pathophysiological features of various health disorders. This review for the first time summarizes all of the updated findings related to the functional activities of GRP in the pathogenesis of several diseases associated with vascular and soft tissue mineralization, osteoarthritis, inflammation, and carcinoma. The outcome of this review will improve the understanding about the role of GRP in the pathogenesis of tissue calcification and its associated health disorders, which should in turn lead to the design of clinical interventions to improve the condition of patients associated with these health disorders.

Circulatory heavy metals (cadmium, lead, mercury, and chromium) inversely correlate with plasma GST activity and GSH level in COPD patients and impair NOX4/Nrf2/GCLC/GST signaling pathway in cultured monocytes

This study aims to examine the hypothesis that circulatory heavy metals may be associated with lung function decline and lower plasma GST activity and GSH level in COPD patients via activating monocytes mediated by impairing the NOX4/Nrf2/GCLC/GST signaling pathway. Results showed that the blood levels of heavy metals (cadmium, lead, mercury, and chromium) were significantly higher in COPD patients of coal mine site compared to the healthy controls. The levels of heavy metals in COPD patients were significantly and negatively correlated with lung function, GST activity, and GSH level. Using flowcytometry, fluorescence spectroscopy, and immunoblotting studies we have further demonstrated that treatment with individual heavy metals dose-dependently increased the NOX4 protein expression, intracellular ROS production, and decreased the Nrf2, GCLC, and GST protein expression, GST activity, and GSH level in THP-1 monocytes. None of the treatment caused any change in cell viability compared to control. In conclusion, this study suggests that circulatory heavy metals in COPD patients of coal mine site weakened the lung function, decreased the plasma GST activity and GSH level via impairing the NOX4/Nrf2/GCLC/GST signaling pathway in monocytes, which may cause monocyte activation and initiate the COPD pathophysiology.

Hexane-Isopropanolic Extract of Tungrymbai, a North-East Indian fermented soybean food prevents hepatic steatosis via regulating AMPK-mediated SREBP/FAS/ACC/HMGCR and PPARα/CPT1A/UCP2 pathways

This study for the first time examined the prophylactic role of Tungrymbai, a well-known fermented soybean food of North-East India, against hepatic steatosis. Treatment with hexane-isopropanolic (2:1, HIET) but not hydro-alcoholic (70% ethanol, HAET) extract dose-dependently (0.1, 0.2, or 0.3 µg/mL) reduced the intracellular lipid accumulation as shown by lower triglyceride levels and both Oil Red O and Nile Red staining in palmitate (PA, 0.75 mM)-treated hepatocytes. Immunobloting, mRNA expression, and knock-down studies demonstrated the role of AMPK-mediated SREBP/FAS/ACC/HMGCR and PPARα/CPT1A/UCP2 signaling pathways in facilitating the beneficial role of HIET against lipid accumulation in PA-treated hepatocytes. Animal studies further showed a positive effect of HIET (20 µg/kg BW, 8 weeks, daily) in regulating AMPK/SREBP/PPARα signaling pathways and reducing body weight gain, plasma lipid levels, and hepatic steatosis in high fat diet (HFD)-fed mice. Histological analyses also revealed the beneficial effect of HIET in reducing hepatic fat accumulation in HFD mice. Chemical profiling (HRMS, IR, and HPLC) demonstrated the presence of menaquinone-7 (vitamin K2) as one of the bio-active principle(s) in HIET. Combining all, this study demonstrates the positive effect of HIET on reducing hepatic steatosis via regulating AMPK/SREBP/PPARα signaling pathway.