Background Age-related loss of muscle mass and function is a major component of frailty. Nutrition supplementation with exercise is an effective strategy to decrease frailty by preventing sarcopenia, but the effect of protein alone is controversial. Objective The present study was performed to investigate a dose-dependent effect of protein supplementation on muscle mass and frailty in prefrail or frail malnourished elderly people. Design A 12-wk double-blind randomized controlled trial was conducted in elderly subjects aged 70–85 y with ≥1 of the Cardiovascular Health Study frailty criteria and a Mini Nutritional Assessment score ≤23.5 (n = 120). Participants were randomly assigned to 1 of 3 groups: 0.8, 1.2, or 1.5 g protein · kg–1 · d–1, with concealed allocation and intention-to-treat analysis. Primary outcomes were appendicular skeletal muscle mass (ASM) and skeletal muscle mass index (SMI) measured by dual-energy X-ray absorptiometry. Results After the 12-wk intervention, the 1.5-g protein · kg–1 · d–1 group had higher ASM (mean ± SD: 0.52 ± 0.64 compared with 0.08 ± 0.68 kg, P = 0.036) and SMI (ASM/weight: 0.87% ± 0.69% compared with 0.15% ± 0.89%, P = 0.039; ASM/BMI: 0.02 ± 0.03 compared with 0.00 ± 0.04, P = 0.033; ASM:fat ratio: 0.04 ± 0.11 compared with −0.02 ± 0.10, P = 0.025) than the 0.8-g protein · kg–1 · d–1 group. In addition, gait speed was improved in the 1.5-g protein · kg–1 · d–1 group compared with the 0.8-g protein · kg–1 · d–1 group (0.09 ± 0.07 compared with 0.04 ± 0.07 m/s, P = 0.039). There were no significant differences between the 1.2- and 0.8-g protein · kg–1 · d–1 groups in muscle mass and physical performance. No harmful adverse effects were observed. Conclusions The present study indicates that protein intake of 1.5 g · kg–1 · d–1 has the most beneficial effects in regard to preventing sarcopenia and frailty compared with protein intakes of 0.8 and 1.2 g · kg–1 · d–1 in prefrail or frail elderly subjects at risk of malnutrition. This trial was registered at cris.nih.go.kr as KCT0001923.
Ethyl pyruvate (EP), a stable lipophilic pyruvate derivative, has been shown to exert anti-inflammatory activities through inhibiting the expression of various pro-inflammatory mediators as well as circulating levels of high mobility group box protein 1 (HMGB1) in a variety of in vitro and in vivo model systems. Necrotic cell death triggers an inflammatory response through release of HMGB1 in the extracellular space due to the membrane rupture. In an effort to better understand the pharmacological action mechanism that could explain the anti-inflammatory properties of EP, we examined the effects of EP on necrotic cell death in A549 lung adenocarcinoma cells in response to glucose deprivation (GD), a common characteristic of the tumor microenvironment. Here we show that EP prevented GD-induced necrosis and HMGB1 release and switched the cell death mode to apoptosis through inhibiting GD-induced CuZn superoxide dismutase release and ROS production. These results suggest that the necrosisto-apoptosis switch activity of EP may contribute to its anti-inflammatory action and that EP may suppress tumor development possibly through its activity to induce the cell death mode switch from tumor promoting necrotic cell death to tumor suppressive apoptotic cell death.
Hepatocellular carcinoma (HCC) is resistant to chemotherapy. Recently, however, several oxaliplatin-based combinatorial treatments have shown a promising anti-tumor activity in patients with HCC. Presently, we demonstrate that oxaliplatin triggers necrosis more than apoptosis in HepG2, SK-Hep1, SNU-423 and Hep3B HCC cells, while mainly inducing apoptosis in HCT116 and HT29 colon cancer cells. Interestingly, ursodeoxycholic acid (UDCA), a less hydrophobic bile acid that can suppress carcinogenesis, shifted oxaliplatin-induced necrosis to apoptosis in HepG2 cells. The same effect was produced by hydrophilic bile acids (tauroursodeoxycholic acid and taurohyodeoxycholic acid), but not by highly hydrophobic bile acids (deoxycholic acid and chenodeoxycholic acid). UDCA also triggered the necrosis-to-apoptosis switch when cotreated with other platinum-based chemotherapeutic drugs including cisplatin and carboplatin, suggesting that the cell death mode switching effect of UDCA is a general phenomenon when combined with platinum drugs. Oxaliplatin produced high level of reactive oxygen species (ROS) in HepG2 cells and UDCA significantly reduced oxaliplatin-induced ROS generation. In addition, N-acetyl-L-cysteine and the superoxide scavengers butylated hydroxyanisole and dihydroxybenzene-3,5-disulfonic acid attenuated necrosis, indicating a critical role(s) of ROS in occurrence of necrotic death. Apoptosis induced by combined treatment appeared to be mediated by p53-caspase 8-caspase 3 pathway. In conclusion, UDCA switches oxaliplatin-induced necrosis to apoptosis via inhibition of ROS production and activation of the p53-caspase 8 pathway in HepG2 cells. As necrosis and subsequent inflammation are implicated in tumor progression and malignancy, our results imply a potential improved efficacy of UDCA-combined chemotherapy in HCC by reducing inflammatory responses that may be triggered by oxaliplatin.Hepatocellular carcinoma (HCC) is one of the most common malignancies and the leading causes of cancer-related mortality, and it generally represents highly resistant features to chemotherapy.1-3 Surgical resection and liver transplantation might be the most effective way to cure the cancer, but these approaches have limited applicability and advanced tumors frequently recur even after complete surgical resection. 4,5 Hence, chemotherapy remains an important option to treat HCC and developments of new chemotherapeutic strategies are necessary.Oxaliplatin, a third generation platinum-based chemotherapeutic agent, displays a broader spectrum of antitumor activity than cisplatin and carboplatin and no cross-resistance against some cisplatin-and carboplatin-resistant tumors. [6][7][8][9] Currently, it is widely used as a basis of combination regimens for various cancers including gastric, colorectal and advanced nasopharyngeal carcinoma. [10][11][12] In addition, several oxaliplatin-combined regimens have been used for patients with advanced HCC and these have shown a moderate but promising anti-tumor effect. 13,14
Ursodeoxycholic acid (UDCA) is known as a suppressor of cholestatic liver diseases and colorectal cancer development. Here, we demonstrate that UDCA induces apoptosis without necrotic features in SNU601, SNU638, SNU1 and SNU216 human gastric cancer cells, implying its possible use as an effective chemotherapeutic agent in treatment of gastric cancer. UDCA-induced apoptosis was dominantly mediated by an extrinsic pathway dependent on caspase-8, -6 and -3. UDCA increased expression of death receptor 5 [(DR5), also known as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2], and this DR appeared to be responsible for UDCA-induced apoptosis, as evidenced by DR5 knockdown. UDCA triggered formation of lipid rafts that played crucial roles in UDCA-induced apoptotic actions. Lipid rafts were required not only for provision of a proper site for DR5 action but also for mediation of DR5 expression. In addition, reactive oxygen species (ROS) and protein kinase C (PKC) δ appeared to be implicated in UDCA-induced raft-dependent DR5 expression. Our results indicate that UDCA-induced apoptosis is mediated by DR5 expression, which is regulated by the raft formation/ROS production/PKCδ activation pathway and DR5 localization into lipid rafts in gastric cancer cells. Tumor-suppressive activity of UDCA was confirmed in an in vivo system: UDCA (120 mg/kg/day) significantly decreased tumor growth in gastric cancer xenograft mice. Taken together, our results demonstrate that UDCA can be used as a potent chemotherapeutic agent for treatment of gastric cancer.
To assess the clinical efficacy of short-course doxycycline in the treatment of scrub typhus, we compared conventional 7-day tetracycline therapy with 3-day doxycycline therapy in 116 patients. Patients were randomized to receive either tetracycline (500 mg four times daily; n = 50) or doxycycline (100 mg twice daily; n = 66) and were followed for 4 weeks after the completion of treatment. The cure rate was 100% in the tetracycline group and 93.9% in the doxycycline group (P > .05). The two groups did not differ significantly in terms of the interval required for defervescence or for the alleviation of symptoms. There were no relapses in either group. These data suggest that 3-day doxycycline therapy is as effective as conventional 7-day tetracycline therapy for the cure of scrub typhus and the prevention of relapses.
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