Prasenjit Manna

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.

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.

Therapeutic potentials of Houttuynia cordata Thunb. against inflammation and oxidative stress: A Review

Abstract Ethnopharmacological relevance Houttuynia cordata Thunb. (Family: Saururaceae) is an herbaceous perennial plant that grows in moist and shady places. The plant is well known among the people of diverse cultures across Japan, Korea, China and North-East India for its medicinal properties. Traditionally the plant is used for its various beneficial properties against inflammation, pneumonia, severe acute respiratory syndrome, muscular sprain, stomach ulcer etc. Oxidative stress and inflammation were found to be linked with most of the diseases in recent times. Many ancient texts from Chinese Traditional Medicine, Ayurveda and Siddha, and Japanese Traditional medicine have documented the efficacy of H. cordata against oxidative stress and inflammation. Aim of the study This review aims to provide up-to-date and comprehensive information on the efficacy of H. cordata extracts as well as its bioactive compounds both in vitro and in vivo, against oxidative stress and inflammation Materials and methods Relevant information on H. cordata against oxidative stress and inflammation were collected from the established scientific databases such as NCBI, Web of Science, ScienceDirect, Elsevier, and Springer. Additionally, a few books and magazines were also consulted to get the important information. Results Herbal medicines or plant products were traditionally being used for treating the oxidative stress and inflammation related diseases in diverse communities across the world. Scientifically, H. cordata has shown to target several signaling pathways and found to effectively reduce the oxidative stress and inflammation. Phyto-constituents such as afzelin, hyperoside and quercitrin have shown to reduce inflammation both in vitro and in vivo models. These molecules were also shown to have strong antioxidant properties both in vivo and in vitro models. Conclusions H. cordata extracts and its bioactive molecules were shown to have both anti-inflammatory and anti-oxidative properties. As both in vitro and in vivo studies were shown that H. cordata did not have any toxicity on the various model systems used, future clinical studies will hopefully make an impact on the future direction of treating inflammation-related diseases.

Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets

Abstract Diabetic neuropathy is regarded as one of the most debilitating outcomes of diabetes mellitus and may cause pain, decreased motility, and even amputation. Diabetic neuropathy includes multiple forms, ranging from discomfort to death. Prognosis of diabetic neuropathy is an uphill task as it remains silent for several years after the onset of diabetes. Hyperglycemia, apart from inducing oxidative stress in neurons, also leads to activation of multiple biochemical pathways which constitute the major source of damage and are potential therapeutic targets in diabetic neuropathy. A vast array of molecular pathways, including polyol pathway, hexosamine pathway, PKCs signaling, oxidative stress, AGEs pathway, PARP pathway, MAPK pathway, NF‐&kgr;B signaling, hedgehog pathways, TNF‐&agr; signaling, cyclooxygenase pathway, interleukins, lipoxygenase pathway, nerve growth factor, Wnt pathway, autophagy, and GSK3 signaling may be accounted for the pathogenesis and progression of diabetic neuropathy. Although symptomatic treatment is available for diabetic neuropathy, few treatment options are available to eliminate the root cause. The immense physical, psychological, and economic burden of diabetic neuropathy highlights the need for cost effective and targeted therapies. The main aim of this review is to highlight the putative role of various mechanisms and pathways involved in the development of diabetic neuropathy and to impart an in‐depth insight on new therapeutic approaches aimed at delaying or reversing various modalities of diabetic neuropathy.

Efflux pump inhibition by 11H-pyrido[2,1-b]quinazolin-11-one analogues in mycobacteria

Mycobacterium tuberculosis infection causes 1.8 million deaths worldwide, of which half a million has been diagnosed with resistant tuberculosis (TB). Emergence of multi drug resistant and extensive drug resistant strains has made all the existing anti-TB therapy futile. The major involvement of efflux pump in drug resistance has made it a direct approach for therapeutic exploration against resistant M. tuberculosis. This study demarcates the role of 11H-pyrido[2,1-b]quinazolin-11-one (quinazolinone) analogues as efflux pump inhibitor in Mycobacterium smegmatis. Sixteen quinazolinone analogues were synthesized by treating 2-aminopyridine and 2-fluorobenzonitrile with KtOBu. Analogues were tested, and 3a, 3b, 3c, 3g, 3j, 3l, 3m, and 3p were found to modulate EtBr MIC by >4 whereas 3a, 3g, 3i and 3o showed >4 modulation on norfloxacin MIC. 3l and 3o in addition to their very low toxicity they showed high EtBr and norfloxacin accumulation respectively. Time kill curve showed effective log reduction in colony forming unit in presence of these analogues, thus confirming their role as efflux pump inhibitor. Through docking and alignment studies, we have also shown that the LfrA amino acid residues that the analogues are interacting with are present in Rv2333c and Rv2846c of M. tuberculosis. This study have shown for the first time the possibility of developing the 11H-pyrido[2,1-b]quinazolin-11-one analogues as efflux pump inhibitors for M. smegmatis and hence unbolts the scope to advance this study against resistant M. tuberculosis as well.