Targeting Inflammation and Downstream Protein Metabolism in Sarcopenia: A Brief Up-Dated Description of Concurrent Exercise and Leucine-Based Multimodal Intervention.

Sarcopenia is defined as the progressive loss of muscle mass with age, and poses a serious threat to the physiological and psychological health of the elderly population with consequential economic and social burdens. Chronic low-grade inflammation plays a central role in the development of sarcopenia such that it alters cellular protein metabolism to favor proteolysis over synthesis, and thereby accelerates muscular atrophy. The purpose of this review is to highlight how exercise and nutrition intervention strategies can attenuate or treat sarcopenia. Resistance exercise increases not only muscle mass but also muscle strength, while aerobic exercise is able to ameliorate the age-related metabolic disorders. Concurrent exercise training integrates the advantages of both aerobic and resistance exercise, and may exert a significant synergistic effect in the aging organism. Higher protein intakes rich in the amino acid leucine appear to restore skeletal muscle protein metabolism balance by rescuing protein synthesis in older adults. There is good reason to believe that a multimodal treatment, a combination of exercise and increased leucine consumption in the diet, can combat some of the muscle loss associated with aging. Future research is needed to consolidate these findings to humans, and to further clarify to what extent and by which mechanisms protein metabolism might be directly involved in sarcopenia pathogenesis and the multimodal treatment responses.

Hypertrophy-Promoting Effects of Leucine Supplementation and Moderate Intensity Aerobic Exercise in Pre-Senescent Mice.

Several studies have indicated a positive influence of leucine supplementation and aerobic training on the aging skeletal muscle signaling pathways that control muscle protein balance and muscle remodeling. However, the effect of a combined intervention requires further clarification. Thirteen month old CD-1(®) mice were subjected to moderate aerobic exercise (45 min swimming per day with 3% body weight workload) and fed a chow diet with 5% leucine or 3.4% alanine for 8 weeks. Serum and plasma were prepared for glucose, urea nitrogen, insulin and amino acid profile analysis. The white gastrocnemius muscles were used for determination of muscle size and signaling proteins involved in protein synthesis and degradation. The results show that both 8 weeks of leucine supplementation and aerobic training elevated the activity of mTOR (mammalian target of rapamycin) and its downstream target p70S6K and 4E-BP1, inhibited the ubiquitin-proteasome system, and increased fiber cross-sectional area (CSA) in white gastrocnemius muscle. Moreover, leucine supplementation in combination with exercise demonstrated more significant effects, such as greater CSA, protein content and altered phosphorylation (suggestive of increased activity) of protein synthesis signaling proteins, in addition to lower expression of proteins involved in protein degradation compared to leucine or exercise alone. The current study shows moderate aerobic training combined with 5% leucine supplementation has the potential to increase muscle size in fast-twitch skeletal muscle during aging, potentially through increased protein synthesis and decreased protein breakdown.

FOXM1 expression correlates with tumor invasion and a poor prognosis of colorectal cancer.

FOXM1, a member of the Forkhead Box (Fox) family of transcription factors, plays a critical role in tumor development and metastasis. The aim of this study was to elucidate its role in colorectal cancer (CRC), particularly prognosis and metastasis. Semi-quantitative RT-PCR and Western blot assays were used to measure the expression levels of FOXM1 mRNA and protein in 15 CRC and adjacent normal mucosa tissues. Immunohistochemical assay was performed to detect FOXM1 protein expression in 112 CRC tissues and further determine its clinicopathological and prognostic significance. RNA interference (RNAi) was used to knockdown endogenous FOXM1 expression in CRC cell lines and to analyze the effects of FOXM1 knockdown on migration and invasion of CRC cells. The relative expression levels of FOXM1 mRNA and protein were significantly higher in CRC tissues than in adjacent normal mucosa tissues (P<0.01). In addition, the immunostaining of FOXM1 protein was stronger in CRC tissues than in adjacent normal mucosa tissues. By statistical analysis, we showed that high FOXM1 expression was closely correlated with the presence of lymph node metastasis, incidence of liver metastasis, and advanced TNM stage. Moreover, the cumulative 5-year survival rate of CRC patients with high FOXM1 expression was lower than that of those with low FOXM1 expression (P=0.0047). Multivariate analysis showed that the status of FOXM1 expression was an independent prognostic factor for CRC patients (P=0.025). Furthermore, RNAi-mediated FOXM1 knockdown could significantly inhibit growth, migration and invasion of CRC cells. Our results showed that FOXM1 over-expression is a molecular marker predicting increased invasive/metastatic potential of CRC and a poorer prognosis.

Overexpression of survivin is correlated with increased invasion and metastasis of colorectal cancer.

BACKGROUND: The aim of this study was to investigate the association of survivin expression with metastasis of colorectal cancer (CRC). METHODS: RT-PCR and Western blot assays were performed to detect survivin expression in CRC cells and normal intestinal epithelial cell. The expression of survivin gene was also detected in 15 CRC tissues, surrounding and adjacent colon tissues. Moreover, survivin expression in 48 CRC tissues with or without lymph node metastasis was analyzed. Multivariate analysis for lymph node metastasis was performed using logistic regression model. RNA interference was used to inhibit survivin expression in CRC cells and analyze its effect on invasion and metastasis of CRC cells. RESULTS: The expression levels of survivin mRNA and protein were higher in CRC cells than in normal intestinal epithelial cell line. The average levels of survivin mRNA and protein were higher in CRC tissues than surrounding or adjacent colon tissues (P < 0.05). High survivin expression was an independent factor for predicting lymph node metastasis of CRC (P = 0.043). RNAi-mediated survivin knockdown could significantly inhibit in vitro invasion and in vivo metastasis of CRC cells, which might be inactivation of matrix metalloproteinases. CONCLUSION: Targeting survivin will be a potential strategy to suppress metastasis of CRC.

Synchronous Gastric Carcinoma and Nodal Malignant Lymphoma: A Rare Case Report and Literature Review.

Synchronous double malignancies of gastric carcinoma (GC) and malignant lymphoma (ML) are rare and very difficult to treat. We report a case of synchronous GC and nodal ML, regarding which clinical and pathological features and treatment are discussed. A 68-year-old woman with a history of inguinal hernia was admitted for abdominal pain and high fever and subsequently underwent herniorrhaphy, but the fever remained. Computerized tomography showed a stomach mass and multiple enlarged lymph nodes in the abdominal cavity and inguinal regions. Gastric adenocarcinoma coexistent with advanced in situ follicular lymphoma was confirmed by endoscopy, biopsy of inguinal lymph nodes and bone marrow examination. Two chemotherapy regimens, R-CHOP (rituximab, cyclophosphamide, perarubicin, vincristine and prednisone) and systemic therapy (5-fluorouracil and calcium folinate) combined with regional perfusion (oxaliplatin and etoposide) through the left gastric artery were performed at intervals against ML and GC, respectively. Partial remission in both tumors was achieved after 4 courses of treatment, but the patient finally died of heart failure. Scrupulous biopsy of non-draining lymph nodes in patients with gastrointestinal carcinomas is supposed to improve the diagnostic rate of simultaneous nodal ML. The interval chemotherapy strategy with two independent regimens is beneficial for such patients, especially for those unable to tolerate major surgery.

Rapid Remission in Peripheral T-Cell Lymphoma of the Nasal Type by the Bortezomib plus CHOP Therapy.

Peripheral T-cell lymphoma (PTCL) is rare and difficult to treat for its high relapse rate. The authors report a case of PTCL of the skin, regarding which clinical and pathological features, treatment, and prognosis were discussed. A 66-year-old woman was admitted with complaints of enlarging erythematous noduloplaques on the right anterior tibial skin for one year and similar lesions on the left for 6 months. Surgical resection of right leg lesion and biopsy of enlarged inguinal lymph nodes histologically indicated a PTCL of the nasal type. The patient was treated by CHOP plus bortezomib, reached complete remission just after two courses of chemotherapy and then received another two as consolidation. The patient remained in remission for 11 months until local relapse. As for cutaneous lesions, detailed lymph node examination and prompt tissue biopsy are judicious choices prior to any medical management. The chemotherapy consisting of bortezomib and CHOP is safe and efficient in PTCL of the skin.

Effects of allicin supplementation on plasma markers of exercise-induced muscle damage, IL-6 and antioxidant capacity.

To investigate the effects of allicin supplementation on exercise-induced muscle damage (EIMD), interleukin-6 (IL-6), and antioxidative capacity, a double-blinded, placebo-controlled study was conducted in well-trained athletes. Subjects were randomly assigned to an allicin supplementation group (AS group) and a control group, and received either allicin or placebo for 14 days before and 2 days after a downhill treadmill run. Plasma creatine kinase (CK), muscle-specific creatine kinase (CK-MM), lactate dehydrogenase (LDH), IL-6, superoxide dismutase (SOD), total antioxidative capacity (TAC), and perceived muscle soreness were measured pre and post exercise. AS group had significantly lower plasma levels of CK, CK-MM and IL-6, and reduced perceived muscle soreness after exercise, when compared with the control group. AS group also demonstrated a trend toward reducing plasma concentration of LDH after exercise (P = 0.08), although not statistically significant. Allicin supplementation induced a higher value of TAC at rest, and this higher value was maintained 48 h after exercise, however, there was no difference in SOD values after exercise between the two groups. The results suggested that allicin might be a potential agent to reduce EIMD. Further studies concerning anti-inflammatory and anti-oxidative effects of allicin on EIMD are needed.

Autoimmune responses induced by Helicobacter pylori improve the prognosis of gastric carcinoma.

Gastric carcinoma (GC) remains one of most serious malignant tumors worldwide, with Helicobacter pylori being the definite carcinogen. The H. pylori components, cytotoxin-associated gene A (CagA), vacuolating toxin A (VacA) and blood-group antigen-binding adhesin gene (BabA), can mimic and bind to specific receptors or surface molecules both on gastric epithelial cells and platelets, in which CagA and VacA may also be directly involved in loosening of tight junctions in monolayers of polarized gastric epithelial cells. It has been shown that a history of H. pylori infection is found in the majority of patients with GC, and that anti-CagA, anti-VacA and anti-BabA antibodies targeting both H. pylori components and host mimic molecules can be detected in them with increased levels. Patients with GC who are positive for H. pylori prospectively have a better outlook than those negative. The stimulation of mentioned autoantibodies in antigen processing and presentation and subsequent T-cell activation and proliferation improves host immune status. On the other hand, in an autoimmune response, autoantibodies can induce the cross-reaction against those localized or circulating GC cells, which are characterized by mimic or absorbed H. pylori antigens, and lead to the killing and even suppressing of metastasis of cancer cells. Therefore, we here hypothesize that autoimmune responses induced by H. pylori components may play a key role in improving the prognosis of patients with gastric carcinoma.