In terms of mental illnesses, depression has an enormous influence in society. Major symptoms of depression are a "depressed mood" and "loss of interest and joy." Despite recent advances in the knowledge related to brain development and function, the mechanisms underlying the pathogenesis of depression remain unclear.The endoplasmic reticulum is a principal site for protein synthesis, folding, and calcium signaling.1) It is highly sensitive to alterations in calcium homeostasis and perturbations in its environment. A condition that impaired the function of the endoplasmic reticulum, collectively designated "endoplasmic reticulum stress," can lead to an accumulation of unfolded proteins in the endoplasmic reticulum lumen.2) In response to endoplasmic reticulum stress, cells have developed a self-protective signal pathway termed the unfolded protein response (UPR), leading to induction of molecular chaperones such as 78 kDa glucose-regulated protein (GRP78) and 94 kDa glucose-regulated protein (GRP94), translational attenuation, and endoplasmic reticulum associated degradation.3) However, if the damage is excessive, the UPR ultimately activates an apoptotic pathway such as CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP) activation. 4)Recently, GRP78 and GRP94 have been found in the temporal cortex of subjects with major depressive disorder who died by suicide.5) Furthermore, in a rodent depression model, endoplasmic reticulum stress-related proteins were increased and these were attenuated by an antidepressant.6) Recently, we have reported that restraint stress increases in the expression of endoplasmic reticulum stress-related genes in the mouse brain.7) These findings indicate that endoplasmic reticulum stress may have some roles in the pathogenesis of depression.Luteolin is a common flavonoid that exists in many types of plants such as Apium graveolens L. var. dulce, 8)Petroselium crispum, 9) and Capsicum annuum L. var.'grossum.' 10) It has various pharmacological activities such as antioxidant, 11) anticancer action, 12) memory-improving, 13) and anxiolytic 14) activities, suggesting that luteolin could penetrate easily into the brain. 15) In this study, we investigated the antidepressant effects of luteolin from the green pepper leaf, as well as its mechanism, using cell death assay induced by endoplasmic reticulum stress in human neuroblastoma (SH-SY5Y) cells and animal models of depression. MATERIALS AND METHODS Purification of LuteolinLuteolin aglycon (luteolin) was provided by Theravalues (Tokyo, Japan). The purity of luteolin was 80%. In the experiments, it was dissolved in phosphate buffered saline contained 1% dimethyl sulfoxide (DMSO) or suspended in the 0.5% carboxymethylcellulose (Wako, Osaka, Japan).Cell Culture SH-SY5Y cells were purchased from the European Collection of Cell Culture (Wiltshire, U.K.) and maintained in Dulbecco's modified Eagle's medium (SigmaAldrich, St. Louis, MO, U.S.A.) containing 10% fetal bovine serum (VALEANT, Costa Mesa, CA, U.S.A.), 100 units/ml of penici...
A randomized double‑blind placebo‑controlled clinical study was conducted to evaluate the chondroprotective action of glucosamine on healthy subjects (soccer players) without joint disorders. Collegiate soccer players (n=43) without joint disorders were randomly assigned to receive a glucosamine (2 g/day)‑containing supplement (n=22, glucosamine group) or a placebo (n=21, placebo group) for 16 weeks, and cartilage metabolism was evaluated by analyzing markers for type II collagen degradation urine C‑terminal telopeptide‑II (CTX‑II) and serum collagen type II cleavage (C2C) and synthesis urine C-terminal type II procollagen peptide (CPII). In the initial analysis of all subjects, urine CTX‑II level substantially decreased in the glucosamine group, but not in the placebo group after the intervention for 16 weeks (P=0.05). Moreover, CTX‑II level in the glucosamine group was also significantly lower than that in the placebo group at week 16 during the intervention. In the second analysis, to make the effect of the test supplement more clear, 41 subjects with less variation of exercise loading were evaluated. The results revealed that urine CTX‑II level significantly decreased in the glucosamine group (n=21), but not in the placebo group (n=20) after the intervention (P<0.05). Moreover, CTX‑II levels in the glucosamine group significantly decreased compared with the placebo group after the intervention (P<0.05). Both in the initial and second analyses, serum C2C level significantly decreased in the glucosamine group, but not in the placebo group after the intervention (P<0.05). In contrast, urine CPII level was not significantly changed even after the intervention in both the placebo and glucosamine groups. Importantly, no test supplement‑related adverse events were observed. These observations suggest that oral administration of glucosamine (2 g/day for 16 weeks) exerts a chondroprotective action on healthy subjects (soccer players) without joint disorders. This effect was achieved by improving cartilage metabolism (suppressing type II collagen degradation but maintaining type II collagen synthesis), without causing apparent adverse effects.
In this study, to evaluate cartilage and bone metabolism in athletes, the levels of type II collagen degradation marker CTX-II and synthesis marker CPII, and type I collagen degradation marker NTx were measured using urine samples of collegiate athletes belonging to various sports clubs (soccer, tennis, triathlon, squash, swimming, volleyball, kendo, judo, gymnastics, basketball, handball, baseball, long-distance, throwing-event, jumping, sprint and futsal) and compared with those of non-athlete controls (5-11 subjects in each group). NTx levels were significantly increased in soccer, volleyball, basketball and handball players compared with non-athletes. Similarly, CTX-II levels were significantly increased in soccer, volleyball and handball players compared with non-athletes. In contrast, CPII levels were significantly increased in squash players and long-distance runners compared with non-athletes. Moreover, CTX-II/CPII ratios were increased in soccer, volleyball, basketball and handball players compared with non-athlete control, suggesting that type II collagen degradation is relatively increased compared with type II collagen synthesis in these players. Together these observations indicate that cartilage and bone metabolism (type II and type I collagen degradation) is enhanced in players of ball games associated with jumping action, such as soccer, volleyball, basketball and handball.
Abstract. In the present study, to investigate the effect of glucosamine, a component of glycosaminoglycans with a chondroprotective action, on articular cartilage in athletes, we looked at soccer players, who expose their joints to excessive motion and loading, and compared the levels of biomarkers for type II collagen degradation (CTX-II) and type II collagen synthesis (CPII) between soccer players and non-athlete controls, and in soccer players before and after glucosamine-administration. CTX-II (P<0.01) and CPII (P=0.08) levels were substantially elevated in soccer players compared with those in controls, indicating that cartilage metabolism (type II collagen degradation and synthesis) is increased in soccer players. Of note, glucosamine administration (1.5 g and 3 g/day for 3 months) significantly decreased the CTX-II level (P<0.05); however, the effect disappeared after withdrawal of administration. In contrast, glucosamine administration did not essentially affect the increased level of CPII. Furthermore, cartilage damage was evaluated by using the ratio of type II collagen breakdown to synthesis (CTX-II/CPII). The ratio in soccer players was significantly higher than that in controls (P<0.05), suggesting that type II collagen degradation is relatively enhanced compared with type II collagen synthesis in soccer players than in control students. Of importance, the ratio was reduced by glucosamine administration but returned to the pre-administration level after withdrawal of administration. Together these observations suggest that glucosamine is expected to exert a chondroprotective action in athletes (soccer players) by preventing type II collagen degradation but maintaining type II collagen synthesis, although the effect is transient and disappears after withdrawal of administration.
Cartilage and bone metabolism (type II collagen degradation) is increased by endurance exercise with intense joint loading. Interestingly, glucosamine-containing diet exhibits a chondroprotective action on osteoarthritis by inhibiting type II collagen degradation and improves the symptoms. Thus, in the present study, we evaluated the effect of glucosamine on cartilage metabolism in collegiate soccer players and professional rugby players with intense joint loading. In soccer and rugby players, the urine level of type II collagen degradation maker CTX-II was significantly increased compared with non-athlete control, indicating that cartilage metabolism (type II collagen degradation) is increased in these athletes. In contrast, the urine level of type II collagen synthesis maker CPII was almost the same as in non-athletes. Based on these findings, the CTX-II/CPII ratios were higher in soccer and rugby players than non-athletes, suggesting that type II collagen degradation is relatively increased compared with type II collagen synthesis in these athletes. Importantly, the administration of glucosamine significantly decreased the CTX-II levels in soccer and rugby players; however, the CTX-II level returned to almost the pre-administration level after withdrawal of glucosamine administration. In contrast, the CPII level was not essentially changed during the test period. Based on these findings, the CTX-II/CPII ratios were reduced by glucosamine administration, and returned to the pre-administration level after withdrawal of glucosamine. Together these observations suggest that glucosamine exhibits a chondroprotective action on endurance athletes, such as soccer and rugby players by preventing type II collagen degradation but maintaining type II collagen synthesis. However, the effect is transient and disappears after withdrawal of the administration.
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