Liver acts as a metabolic gate for the traumatic brain injury pathology: Protective action of thyroid hormone.

Clinical evidence indicates that injury to the brain elicits systemic metabolic disturbances that contributes to the brain pathology. Since dietary fructose is metabolized in the liver, we explored mechanisms by which traumatic brain injury (TBI) and dietary fructose influence liver function and their possible repercussions to brain. Consumption of fructose contributed to the detrimental effects of TBI on liver operation, in terms of glucose and lipid metabolism, de novo lipogenesis, lipid peroxidation. Thyroid hormone (T4) is metabolized in the liver and found that T4 supply improved lipid metabolism by reducing de novo lipogenesis, lipid accumulation, lipogenic enzymes (ACC, AceCS1, FAS), lipid peroxidation in liver in response to fructose and fructose-TBI. T4 supply also helped to normalize glucose metabolism and improve insulin sensitivity. Furthermore, T4 counteracted elevations of the pro-inflammatory cytokines, Tnfα and Mcp-1 after TBI and/or fructose intake in liver and circulation. T4 also exerted an effect on isolated primary hepatocytes by potentiating phosphorylation of AMPKα and AKT substrate, AS160, leading to increased glucose uptake. In addition, T4 restored the metabolism of DHA in the liver disrupted by TBI and fructose, adding important information to optimize the action of DHA in therapeutics. The overall evidence seems to indicate that the liver works as a gate for the regulation of the effects of brain injury and foods on brain pathologies.

AdipoRon induces AMPK activation and ameliorates Alzheimer's like pathologies and associated cognitive impairment in APP/PS1 mice.

Alzheimer's disease (AD) is a progressive devastating neurodegenerative disorder characterized by extracellular amyloid beta (Aß42) plaque formation, hyperphosphorylation of tau protein leading to intracellular neurofibrillary tangle formation. Recently discovered hallmark features responsible for AD pathogenesis are neuronal insulin resistance, dysregulation in adiponectin and AMPK signaling. The presence of adiponectin and its receptor in the brain with its unique anti-diabetic effects and association with neurodegenerative diseases has raised our interest in exploring orally active small molecule adiponectin receptor agonist, AdipoRon. To date, all the available drugs for the treatment of AD provides symptomatic relief and do not stall the progression of the disease. Indeed, it is becoming increasingly apparent to find appropriate targets. Here, we attempt to shed lights on adiponectin receptor agonist, AdipoRon and its downstream molecular targets in reducing disease pathogenesis and insulin resistance. In brain, AdipoRon induced AMPK activation, increased insulin sensitivity, reduced amyloid beta plaque deposition and improved cognitive impairment. Levels of BACE were also downregulated while LDLR, APOE and neprilysin were upregulated promoting amyloid beta clearance from brain. AdipoRon further reduced the chronic inflammatory marker, GFAP and improved synaptic markers PSD-95 and synaptophysin in APP/PS1 mice. Our in-vitro studies further confirmed the potential role of AdipoRon in improving insulin sensitivity by increasing GLUT 4 translocation, glucose uptake and insulin signaling under hyperinsulinemic condition. Our findings suggest that AdipoRon could be a promising lead in the future treatment strategies in the development of effective AD treatment.

Gamma radiation improves AD pathogenesis in APP/PS1 mouse model by potentiating insulin sensitivity.

Alzheimer's disease (AD) is the largest unmet medical complication. The devastation caused by the disease can be assumed from the disease symptoms like speech impairment, loss of self-awareness, acute memory loss etc. The individuals suffering from AD completely depend on caregivers and have to bear the high cost of treatment which increases the socio-economic burden on the society. Recent studies have shown that radiation exposure can have therapeutic effects when given in suitable amount for a specific time period. Therefore, we investigated the role of gamma irradiation in AD pathogenesis. The effect of radiation on amelioration of disease progression was studied in AD transgenic mice model (APP/PS1). Our in-vivo studies using APP/PS1 mice demonstrated that a single dose of 4.0 Gy gamma irradiation improves AD associated behavioral impairment. Radiation exposure also increased the level of anti-oxidant enzymes and reduced the astrocyte activation in the brain of APP/PS1 mice. A significant reduction was observed in AD associated proteins (APP, pTau, BACE) and neurofibrillary tangle formations (NFTs). Exposure to a single dose of 4 Gy gamma radiation also increased glucose metabolic functionality in AD transgenic mouse model. The kinases involved in insulin signaling such as GSK, ERK and JNK were also found to be modulated. However, an increased level of GSK3ß (ser 9) was observed, which could be responsible for downregulating ERK and JNK phosphorylation. This resulted in a decrease in neurofibrillary tangle formations and amyloid deposition. The reduced hyperphosphorylation of Tau can be attributed to the increased level of GSK3ß (ser 9) downregulating ERK and JNK phosphorylation. Thus, a single dose of 4 Gy gamma irradiation was found to have therapeutic benefits in treating AD via potentiating insulin signaling in APP/PS1 transgenic mice.

Development and characterization of supramolecular calcitonin assembly and assessment of its interactions with the bone remodelling process.

Osteoporosis is the most common metabolic bone disease, which poses an immense socio-economic burden on the society. Human calcitonin, though safe, is not considered as a therapeutic option because of its high tendency to self-associate to form amyloid fibrils thereby affecting its potency. To circumvent this issue we harnessed the inherent capacity of aggregation and developed an assemblage of human calcitonin monomers, [Supramolecular Calcitonin Assembly (SCAI)], which releases biologically active calcitonin monomers in a sustained manner for a period of at least three weeks. AFM and FT-IR analysis showed that SCA-I is amorphous aggregates of calcitonin monomers. Both SCA-I and monomer released from it demonstrated superior anti-osteoclast activity and proteolytic stability in-vitro. SCA-I upon single injection significantly improved bone formation markers and reduced bone resorption markers in ovariectomized (OVX) rat model of postmenopausal osteoporosis. Micro-CT analysis revealed that calcitonin released from SCA-I exhibits its beneficial effect on cortical bone more profoundly compared to trabecular bone. This study demonstrates that SCA-I is more effective compared to the human calcitonin monomers on osteoclasts and has site-specific effect on bone in a model of post-menopausal osteoporosis. This approach opens up an innovative way to use and study the function of human calcitonin.

Homocysteine alters the osteoprotegerin/RANKL system in the osteoblast to promote bone loss: pivotal role of the redox regulator forkhead O1.

In this study we determined the molecular mechanisms of how homocysteine differentially affects receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) synthesis in the bone. The results showed that oxidative stress induced by homocysteine deranges insulin-sensitive FOXO1 and MAP kinase signaling cascades to decrease OPG and increase RANKL synthesis in osteoblast cultures. We observed that downregulation of insulin/FOXO1 and p38 MAP kinase signaling mechanisms due to phosphorylation of protein phosphatase 2A (PP2A) was the key event that inhibited OPG synthesis in homocysteine-treated osteoblast cultures. siRNA knockdown experiments confirmed that FOXO1 is integral to OPG and p38 synthesis. Conversely homocysteine increased RANKL synthesis in osteoblasts through c-Jun/JNK MAP kinase signaling mechanisms independent of FOXO1. In the rat bone milieu, high-methionine diet-induced hyperhomocysteinemia lowered FOXO1 and OPG expression and increased synthesis of proresorptive and inflammatory cytokines such as RANKL, M-CSF, IL-1α, IL-1ß, G-CSF, GM-CSF, MIP-1α, IFN-γ, IL-17, and TNF-α. Such pathophysiological conditions were exacerbated by ovariectomy. Lowering the serum homocysteine level by a simultaneous supplementation with N-acetylcysteine improved OPG and FOXO1 expression and partially antagonized RANKL and proresorptive cytokine synthesis in the bone milieu. These results emphasize that hyperhomocysteinemia alters the redox regulatory mechanism in the osteoblast by activating PP2A and deranging FOXO1 and MAPK signaling cascades, eventually shifting the OPG:RANKL ratio toward increased osteoclast activity and decreased bone quality.