No abstract

No abstract

Resveratrol has been clinically shown to possess a number of human health benefits. As a result, many attempts have been made to engineer resveratrol production in major cereal grains but have been largely unsuccessful. In this study, we report the creation of a transgenic rice plant that accumulates 1.9 µg resveratrol/g in its grain, surpassing the previously reported anti-metabolic syndrome activity of resveratrol through a synergistic interaction between the transgenic resveratrol and the endogenous properties of the rice. Consumption of our transgenic resveratrol-enriched rice significantly improved all aspects of metabolic syndrome and related diseases in animals fed a high-fat diet. Compared with the control animals, the resveratrol-enriched rice reduced body weight, blood glucose, triglycerides, total cholesterol, and LDL-cholesterol by 24.7%, 22%, 37.4%, 27%, and 59.6%, respectively. The resveratrol-enriched rice from our study may thus provide a safe and convenient means of preventing metabolic syndrome and related diseases without major lifestyle changes or the need for daily medications. These results also suggest that future transgenic plants could be improved if the synergistic interactions of the transgene with endogenous traits of the plant are considered in the experimental design.

No abstract

The signaling axis of glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) has been an important component in overcoming diabetes, and recent reports have uncovered novel beneficial roles of this signaling axis in central nervous system (CNS) disorders, such as Alzheimer's disease, Parkinson's disease, and cerebral ischemia, accelerating processes for exendin-4 repositioning. Here, we studied whether multiple sclerosis (MS) could be a complement to the CNS disorders that are associated with the GLP-1/GLP-1R signaling axis. Both components of the signaling axis, GLP-1 and GLP-1R proteins, are expressed in neurons, astrocytes, and microglia in the spinal cord of normal mice. In particular, they are abundant in Iba1-positive microglia. Upon challenge by experimental autoimmune encephalomyelitis (EAE), an animal model of MS, the mRNA expression of both GLP-1 and GLP-1R was markedly downregulated in EAE-symptomatic spinal cords, indicating attenuated activity of GLP-1/GLP-1R signaling in EAE. Such a downregulation obviously occurred in LPS-stimulated rat primary microglia, a main cell type to express both GLP-1 and GLP-1R, further indicating attenuated activity of GLP-1/GLP-1R signaling in activated microglia. To investigate whether increased activity of GLP-1R has a therapeutic benefit, exendin-4 (5 μg/kg, i.p.), a GLP-1R agonist, was administered daily to EAE-symptomatic mice. Exendin-4 administration to symptomatic EAE mice significantly improved the clinical signs of the disease, along with the reversal of histopathological sequelae such as cell accumulation, demyelination, astrogliosis, microglial activation, and morphological transformation of activated microglia in the injured spinal cord. Such an improvement by exendin-4 was comparable to that by FTY720 (3 mg/kg, i.p.), a drug for MS. The neuroprotective effects of exendin-4 against EAE were also associated with decreased mRNA expression of proinflammatory cytokines, such as interleukin (IL)-17, IL-1β, IL-6, and tumor necrosis factor (TNF)-α, all of which are usually upregulated in injured sites of the EAE spinal cord. Interestingly, exendin-4 exposure similarly reduced mRNA levels of IL-1β and TNF-α in LPS-stimulated microglia. Furthermore, exendin-4 administration significantly attenuated activation of NF-κB signaling in EAE spinal cord and LPS-stimulated microglia. Collectively, the current study demonstrates the therapeutic potential of exendin-4 for MS by reducing immune responses in the CNS, highlighting the importance of the GLP-1/GLP-1R signaling axis in the development of a novel therapeutic strategy for MS.

No abstract

Initial and recurrent stroke produces central nervous system (CNS) damage, involving neuroinflammation. Receptor-mediated S1P signaling can influence neuroinflammation and has been implicated in cerebral ischemia through effects on the immune system. However, S1P-mediated events also occur within the brain itself where its roles during stroke have been less well studied. Here we investigated the involvement of S1P signaling in initial and recurrent stroke by using a transient middle cerebral artery occlusion/reperfusion (M/R) model combined with analyses of S1P signaling. Gene expression for S1P receptors and involved enzymes was altered during M/R, supporting changes in S1P signaling. Direct S1P microinjection into the normal CNS induced neuroglial activation, implicating S1P-initiated neuroinflammatory responses that resembled CNS changes seen during initial M/R challenge. Moreover, S1P microinjection combined with M/R potentiated brain damage, approximating a model for recurrent stroke dependent on S1P and suggesting that reduction in S1P signaling could ameliorate stroke damage. Delivery of FTY720 that removes S1P signaling with chronic exposure reduced damage in both initial and S1P-potentiated M/R-challenged brain, while reducing stroke markers like TNF-α. These results implicate direct S1P CNS signaling in the etiology of initial and recurrent stroke that can be therapeutically accessed by S1P modulators acting within the brain.

The increasing prevalence of diabetes heightens concerns over diabetic complications such as neuropathy. Diabetic neuropathy is one of the most debilitating complications of type 1 and type 2 diabetes.1) The histopathology of the condition is characterized by axonal degeneration, demyelination, and atrophy in association with failed axonal regeneration, remyelination, and impaired synaptogenesis. 2)Previous reports have suggested that reduced availability of nerve growth factor (NGF) plays a significant role in the pathogenesis of diabetic polyneuropathy.3) Retrograde axonal transport of NGF is impaired in animals with diabetes mellitus (DM), 4) and its transcription in neuronal target tissues is reduced.5) NGF itself has been considered an option for the treatment of diabetic peripheral neuropathy. Although systemic administration of exogenous recombinant human NGF was found to prevent neuropathy in a phase II clinical trial, 6) unfortunately efficacy of NGF was not demonstrated in a completed phase III trial due to its limited delivery to the nervous system and adverse effects after subcutaneous injection.7) An alternative therapeutic approach is the use of small molecules to induce or enhance neurotropic factor production. Saito and colleagues reported that the orally active small molecule MCC-257, a sialic acid derivative, elevated NGF levels in the sciatic nerve and improved nerve conduction velocity in a diabetic rodent model. 8) Also, retinoic acid can revert functional and ultrastructural changes and induce neural regeneration after the establishment of diabetic neuropathy, possibly because of increased NGF concentrations in nerve terminals. 9)Our study focused on diosgenin (DG), a major steroidal sapogenin isolated from Dioscoreaceae. DG is the primary spirostane-type sapogenin found in several plants, including fenugreek, Costus speciosus, and the Dioscorea species. 10) DG has been shown to be useful in maintaining healthy blood cholesterol levels, 11) and is a precursor for several hormones such as dehydroepiandrosterone.12)The present study examined the neuroprotective effect of DG on diabetic peripheral neuropathy through increasing NGF levels in a diabetic rodent model. MATERIALS AND METHODS Isolation of Diosgenin from Dioscorea nipponicaRhizomes of Dioscorea nipponica (DN) MAKINO (Dioscoreaceae), referred to as Cheonsangyong in China and as Buchema in Korea, were obtained from the Kyungdong Herb Market in Seoul, Korea. They were identified by Dr. C. S. Yook, Department of Pharmacy, Kyung Hee University. Dried DN rhizomes (1 kg) were extracted 3 times using 85% methanol under ultrasonic apparatus for each 2 h and evaporated to dryness. Such an extraction process was repeated twice. The residue (147 g) was then partitioned between water-saturated n-butanol and water, and the n-butanol layer was separated, which was repeated 5 times, and evaporated to dryness. The yield was 3.4%. The residue was subsequently taken up into 2.5 N HCl for 4 h at 94°C, extracted using CHCl 3 , filtered, and evaporated to...