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Objectives: The aim of this retrospective study was (1) to evaluate the radiographic features to differentiate arthroscopically confirmed complete and incomplete discoid lateral meniscus (DLM) (2) to determine the cutoff values for any parameter that was found to differentiate complete from incomplete DLM., Materials and Methods: We retrospectively analyzed plain knee radiographs of 130 arthroscopically proven DLM. Seventy-nine patients had complete DLM and 51 patients incomplete DLM. Knee radiographs from 52 patients with arthroscopically proven normal lateral meniscus acted as control group. Radiographic parameters measured included fibular height, lateral joint space, condylar cutoff sign, height of lateral tibial spine, obliquity of lateral tibial spine, squaring of the lateral femoral condyle, and cupping of the lateral tibial plateau., Results: Among radiographic parameters, high fibular head, widening of the lateral joint space and femoral condylar cutoff sign showed statistically significant (p<0.0001) differences between complete and incomplete DLM. At specific threshold points of fibular height<11 mm, lateral joint space>6 mm and condylar cutoff sign<0.80, the diagnosis of complete DLM revealed 87.3% sensitivity, 81.6% specificity and 78.4% positive predictive value (PPV) for the fibular height, 81.0% sensitivity, 86.6% specificity and 83.1% PPV for the lateral joint space, and 86.1% sensitivity, 83.5% specificity and 80% PPV for the condylar cutoff sign., Conclusions: Radiographic features of fibular height, lateral joint space and condylar cut off sign can be used for screening of a complete type of DLM. However, radiographs are not a reliable screening tool for an incomplete DLM., Level of Evidence: IV, Case Series., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Capsaicin has been reported to regulate blood glucose levels and to ameliorate insulin resistance in obese mice. This study demonstrates that capsaicin increases glucose uptake directly by activating AMP-activated protein kinase (AMPK) in C2C12 muscle cells, which manifested as an attenuation of glucose uptake when compound C, an AMPK inhibitor, was co-administered with capsaicin. However, the insulin signaling molecules insulin receptor substrate-1 (IRS-1) and Akt were not affected by capsaicin. Additional results showed that p38 mitogen-activated protein kinase (MAPK) is also involved in capsaicin-induced glucose transport downstream of AMPK because capsaicin increased p38 MAPK phosphorylation significantly and its specific inhibitor SB203580 inhibited capsaicin-mediated glucose uptake. Treatment with an AMPK inhibitor reduced p38 MAPK phosphorylation, but the p38 MAPK inhibitor had no effect on AMPK. Capsaicin stimulated ROS generation in C2C12 muscle cells, and when ROS were captured using the nonspecific antioxidant NAC, the increase in both capsaicin-induced AMPK phosphorylation and capsaicin-induced glucose uptake was attenuated, suggesting that ROS function as an upstream activator of AMPK. Taken together, these results suggest that capsaicin, independent of insulin, increases glucose uptake via ROS generation and consequent AMPK and p38 MAPK activations., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Our preliminary study revealed that dementia induced by β-amyloid accumulation impairs peripheral glucose homeostasis (unpublished). We therefore evaluated whether long-term oral consumption of yuzu (Citrus junos Tanaka) extract improves cognitive dysfunction and glucose homeostasis in β-amyloid-induced rats. Male rats received hippocampal CA1 infusions of β-amyloid (25-35) [plaque forming β-amyloid; Alzheimer disease (AD)] or β-amyloid (35-25) [non-plaque forming β-amyloid; C (non-Alzheimer disease control)] at a rate of 3.6 nmol/d for 14 d. AD rats were divided into 2 dietary groups that received either 3% lyophilized 70% ethanol extracts of yuzu (AD-Y) or 3% dextrin (AD-C) in high-fat diets (43% energy as fat). The AD-C group exhibited greater hippocampal β-amyloid deposition, which was not detected in the C group, and attenuated hippocampal insulin signaling. Yuzu treatment prevented β-amyloid accumulation, increased tau phosphorylation, and attenuated hippocampal insulin signaling observed in AD-C rats. Consistent with β-amyloid accumulation, the AD-C rats experienced cognitive dysfunction, which was prevented by yuzu. AD-C rats gained less weight than did C rats due to decreased feed consumption, and yuzu treatment prevented the decrease in feed consumption. Serum glucose concentrations were higher in AD-C than in C rats at 40-120 min after glucose loading during an oral-glucose-tolerance test, but not at 0-40 min. Serum insulin concentrations were highly elevated in AD-C rats but not enough to lower serum glucose to normal concentrations, indicating that rats in the AD-C group had insulin resistance and a borderline diabetic state. Although AD-C rats were profoundly insulin resistant, AD-Y rats exhibited normal first and second phases of glucose tolerance and insulin sensitivity and secretion. In conclusion, yuzu treatment prevented the cognitive dysfunction and impaired energy and glucose homeostasis induced by β-amyloid infusion.

Aims: Diabetes increases the chances of stroke and the stroke itself is thought to induce hyperglycemia and diabetes. However, this latter contention remains uncorroborated. We investigated whether ischemic hippocampal neuronal cell death induces glucose dysregulation by modulating insulin resistance, glucose-stimulated insulin secretion, and β-cell mass in Mongolian gerbils fed either a high fat or low fat diet., Main Methods: Gerbils were subjected to either an occlusion of the bilateral common carotid arteries for 8 mins to render them ischemic, or a sham operation. Ischemic gerbils were fed either an 11% fat diet (LFD) or a 40% fat diet (HFD) for 7, 14 or 28 days., Key Findings: Artery occlusion resulted in a 70% or greater initial reduction in hippocampal CA1 neurons and only HFD decreased the percentage of CA1 neurons as the ischemic periods became longer. Oral glucose tolerance test (OGTT) results revealed that ischemia induced glucose intolerance, and longer ischemic periods and HFD exacerbated this glucose intolerance in ischemic gerbils. Insulin secretion during the OGTT was lower in ischemic gerbils than sham gerbils and the decrease was greatest in the 28 day-HFD among all the groups. Insulin resistance was elevated the most in 28 day-HFD ischemic gerbils. There was a progressive loss of pancreatic β-cell mass as the post-ischemic time period increased as consequence of HFD; the decrease being caused by increased apoptosis. This increase in apoptosis was partly associated with increased serum levels of IL-1β, TNF-α and non-esterified fatty acids., Significance: Hippocampal neuronal cell death deteriorates glucose homeostasis initially through the modulation of insulin secretion and also causes a decrease in β-cell mass while HFD negatively impacts glucose regulation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

3,3'-diindolylmethane (DIM) is the major in vivo product of the acid-catalyzed oligomerization of indole-3-carbinol present in cruciferous vegetables, and it has been shown to exhibit anticancer properties. In this study, we assessed the effects of DIM on the metastasis of 4T1 mouse mammary carcinoma cells. In vitro culture studies showed that DIM dose-dependently inhibited the migration, invasion, and adhesion of 4T1 cells at concentrations of 0-10 micromol/L without attendant changes in cell viability. In an in vivo lung metastasis model, 4T1 cells (2 x 10(5) cells/mouse) were injected into the tail veins of syngeneic female BALB/c mice. Beginning on the second day, the mice were subjected to gavage with 0-10 mg DIM/(kg body weight x d) for 13 d. Oral DIM administration resulted in a marked reduction in the number of pulmonary tumor nodules. DIM treatment significantly reduced the levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and vascular cell adhesion molecule (VCAM)-1 and increased TIMP-2 levels in the sera and lungs of mice injected with 4T1 cells. Additionally, DIM treatment reduced the serum concentrations of interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)alpha. We have demonstrated that DIM profoundly inhibits the lung metastasis of 4T1 cells, which was accompanied by reduced levels of MMP, adhesion molecules, and proinflammatory cytokines. These results indicate that DIM has potential as an antimetastatic agent for the treatment of breast cancer.

A reduced life span is an outcome associated with many prevalent diseases, including diabetes, obesity, and high blood pressure. In seeking to prevent these diseases, many researchers have looked into potential therapeutic benefits of naturally occurring compounds. AMP-activated protein kinase (AMPK) is a major metabolic-sensing protein implicated in the prevention of metabolic disorders, or in minimizing the effects thereof, via the regulation of both upstream and downstream target molecules. In the field of food and nutrition, the current focus lies in the finding of components that activate AMPK. AMPK is a serine/threonine protein kinase and is activated by several natural compounds, including resveratrol, epigallocatechin gallate, berberine, and quercetin. AMPK activation can induce ATP (adenosine triphosphate) generation through pathways such as glycolysis and beta-oxidation. By contrast, ATP-consuming pathways, including fatty acid and cholesterol syntheses, and gluconeogenesis, are suppressed by AMPK activation. In this review, we will discuss how the activation of AMPK by naturally occurring compounds could help to prevent the development of numerous diseases; the potential mechanism underlying these effects will also be addressed.

Oxidative stress and inflammation contribute to the pathogenesis of cisplatin-induced nephrotoxicity. We found that genistein, a tyrosine kinase inhibitor with broad specificities, and which also has estrogen-like activity, had protective effects on cisplatin-induced renal injury in mice. Genistein significantly decreased reactive oxygen species production, the expression of intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 proteins, as well as the translocation of the p65 subunit of nuclear factor-kappaB into the nucleus and the infiltration of macrophages, all of which were increased in the kidney by cisplatin treatment. Genistein also decreased cisplatin-induced apoptosis by regulating p53 induction in kidney. Genistein significantly reduced reactive oxygen species production in cisplatin-treated normal human kidney HK-2 cells. These studies show that genistein or similar compounds might be useful in prevention of cisplatin-induced renal injury.

Inhibition of adipocyte differentiation is one approach among the anti-obesity strategies. This study demonstrates that vitisin A, a resveratrol tetramer, inhibits adipocyte differentiation most effectively of 18 stilbenes tested. Fat accumulation and PPARgamma expression were decreased by vitisin A in a dose-dependent manner. Vitisin A significantly inhibited preadipocyte proliferation and consequent differentiation within the first 2 days of treatment, indicating that the anti-adipogenic effect of vitisin A was derived from anti-proliferation. Based on cell cycle analysis, vitisin A blocked the cell cycle at the G1-S phase transition, causing cells to remain in the preadipocyte state. Vitisin A increased p21 expression, while the Rb phosphorylation level was reduced. Therefore, vitisin A seems to induce G1 arrest through p21- and consequent Rb-dependent suppression of transcription. On the other hand, ERK and Akt signaling pathways were not involved in the anti-mitotic regulation by vitisin A. Taken together, these results suggest that vitisin A inhibits adipocyte differentiation through preadipocyte cell cycle arrest.

Metabolic disorders such as obesity are major obstacles in improving the average life span. Therefore, a therapeutic approach using natural compounds has been proposed as a novel strategy for preventing metabolic disorders. Ginsenoside Rh2 is one of the ginsenosides that exert anti-diabetes, anti-inflammatory, and anti-cancer effects. However, the anti-obesity effects of Ginsenoside Rh2 remain unclear. Here, we investigated the anti-obesity ability of ginsenoside Rh2 using cell culture systems. Ginsenoside Rh2 effectively inhibited adipocyte differentiation via PPAR-gamma inhibition. Next, to find specific target molecules based on this result, we used cell culture systems to examine whether AMPK activation was involved in the anti-obesity ability of ginsenoside Rh2 since several published papers have indicated that AMPK signaling is involved in the regulation of metabolic disorders. Ginsenoside Rh2 significantly activated AMPK in 3T3-L1 adipocytes. In addition, we also examined the effect of AMPK on lipolysis molecules such as CPT-1 and UCP-2 by using an AMPK inhibitor. Ginsenoside Rh2 effectively induced CPT-1 and UCP-2 and this induction was abolished by AMPK inhibitor treatment. Moreover, we observed that ROS is an important upstream signal for AMPK activation during ginsenoside Rh2 treatment. Taken together, these results indicate that ginsenoside Rh2 is the most effective candidate for preventing metabolic disorders such as obesity and that it acts via the AMPK signaling pathway. Thus, AMPK signaling might contribute toward improving human health.

Plantainoside D (PD), was isolated from the leaves of Picrorhiza scrophulariiflora (Scrophulariaceae). The anti-oxidative activity of PD was evaluated based on scavenging effects on hydroxyl radicals and superoxide anion radicals. Adriamycin (ADR) is a potent anti-tumor drug known to cause severe cardiotoxicity. Although ADR generates free radicals, the role of free radicals in the development of cardiac toxicity has not been understood. This study was undertaken to investigate the protective effect of PD against ADR-induced apoptosis. In vitro, ADR caused dose-dependent toxicity in H9c2 cardiac muscle cells. Pre-treatment of the cardiac muscle cells with PD significantly reduced ADR-induced apoptosis of cardiac muscle cells. PD inhibited the ROS produced by ADR in the cardiac muscle cells. As well, PD increased GSH(glutathione), compared with ADR. In response to ADR, NF-kappaB was activated in H9c2 cells. However the treatment of PD reduced the activation of NF-kappaB. We also observed that the NF-kappaB inhibitor, PDTC, inhibited the cytotoxic effect on ADR-induced apoptosis in cardiac muscle cells. In parallel, IkappaBalpha-dominant negative plasmid-overexpression abrogated ADR-induced apoptosis in H9c2 cardiac muscle cells. In conclusion, these results suggest that Plantaionoside D can inhibit ADR-induced apoptosis in H9C2 cardiac muscle cells via inhibition of ROS generation and NF-kappaB activation. The pure compound PD can be a potential candidate agent which protects cardiotoxicity in ADR-exposed patients.

3,3'-Diindolylmethane (DIM) is the major in vivo product of acid-catalyzed oligomerization of indole-3-carbinol, which is a promising anticancer agent present in cruciferous vegetables and has itself been reported to have anticarcinogenic properties. This study examined DIM-mediated regulation of apoptosis in the HCT116 (wild-type p53) and HT-29 (mutant p53) human colon cancer cell lines. DIM (0-30 micromol/L) substantially decreased the number of viable cells and induced apoptosis of HCT116 and HT-29 cells in a concentration-dependent manner. Western-blot analyses of total cell lysates revealed that DIM increased the activation of caspase-3, -7, -8, and -9 and enhanced poly(ADP-ribose) polymerase cleavage in both HCT116 and HT-29 cells. In addition, DIM increased the translocation of cytochrome c and Smac/Diablo from the mitochondria to the cytoplasm. In concert with the caspase-8 activation by DIM, increased levels of Fas and truncated Bid were observed. DIM did not affect the protein levels of p53, Bcl-2, Bax, or Fas ligand (FasL) in HCT116 cells. In HT-29 cells, however, DIM decreased Bcl-2 levels, although the protein levels of Bax or FasL were not affected. The caspase-8 inhibitor Z-IETD-FMK attenuated the DIM-induced apoptosis, indicating that increased activation of this enzyme contributed to the increase in p53-independent apoptosis that was observed in colon cancer cells. We have demonstrated that DIM induces apoptosis in colon cancer cells, providing insights into the mechanisms underlying its antitumorigenic activities.

Fisetin, a natural flavonol present in edible vegetables, fruits, and wine, was reported to exert anticarcinogenic effects. The objective of the current study was to examine the effect of fisetin on the cell cycle progression of the human colon cancer cell line HT-29. HT-29 cells were cultured in serum-free medium with 0, 20, 40, or 60 micromol/L fisetin. Fisetin dose dependently inhibited both cell growth and DNA synthesis (P < 0.05), with a 79 +/- 1% decrease in cell number observed 72 h after the addition of 60 micromol/L fisetin. Perturbed cell cycle progression from the G(1) to S phase was observed at 8 h with 60 micromol/L fisetin treatment, whereas a G(2)/M phase arrest was observed after 24 h (P < 0.05). The phosphorylation state of the retinoblastoma proteins shifted from hyperphosphorylated to hypophosphorylated in cells treated with 40 micromol/L fisetin. (P < 0.05). Fisetin decreased the activities of cyclin-dependent kinases (CDK)2 and CDK4; these effects were likely attributable to decreases in the levels of cyclin E and D1 and an increase in p21(CIP1/WAF1) levels (P < 0.05). However, fisetin also inhibited CDk4 activity in a cell-free system (P < 0.05), indicating that it may directly inhibit CDk4 activity. The protein levels of cell division cycles (CDC)2 and CDC25C and the activity of CDC2 were also decreased in fisetin-treated cells (P < 0.05). These results indicate that inhibition of cell cycle progression in HT-29 cells after treatment with fisetin can be explained, at least in part, by modification of CDK activities.