The use of genes for performance enhancement: doping or therapy?

Recent biotechnological advances have permitted the manipulation of genetic sequences to treat several diseases in a process called gene therapy. However, the advance of gene therapy has opened the door to the possibility of using genetic manipulation (GM) to enhance athletic performance. In such R16;gene dopingR17;, exogenous genetic sequences are inserted into a specific tissue, altering cellular gene activity or leading to the expression of a protein product. The exogenous genes most likely to be utilized for gene doping include erythropoietin (EPO), vascular endothelial growth factor (VEGF), insulin-like growth factor type 1 (IGF-1), myostatin antagonists, and endorphin. However, many other genes could also be used, such as those involved in glucose metabolic pathways. Because gene doping would be very difficult to detect, it is inherently very attractive for those involved in sports who are prepared to cheat. Moreover, the field of gene therapy is constantly and rapidly progressing, and this is likely to generate many new possibilities for gene doping. Thus, as part of the general fight against all forms of doping, it will be necessary to develop and continually improve means of detecting exogenous gene sequences (or their products) in athletes. Nevertheless, some bioethicists have argued for a liberal approach to gene doping.

Resistance exercise improves hippocampus-dependent memory

It has been demonstrated that resistance exercise improves cognitive functions in humans. Thus, an animal model that mimics this phenomenon can be an important tool for studying the underlying neurophysiological mechanisms. Here, we tested if an animal model for resistance exercise was able to improve the performance in a hippocampus-dependent memory task. In addition, we also evaluated the level of insulin-like growth factor 1/insulin growth factor receptor (IGF-1/IGF-1R), which plays pleiotropic roles in the nervous system. Adult male Wistar rats were divided into three groups (N = 10 for each group): control, SHAM, and resistance exercise (RES). The RES group was submitted to 8 weeks of progressive resistance exercise in a vertical ladder apparatus, while the SHAM group was left in the same apparatus without exercising. Analysis of a cross-sectional area of the flexor digitorum longus muscle indicated that this training period was sufficient to cause muscle fiber hypertrophy. In a step-through passive avoidance task (PA), the RES group presented a longer latency than the other groups on the test day. We also observed an increase of 43 and 94% for systemic and hippocampal IGF-1 concentration, respectively, in the RES group compared to the others. A positive correlation was established between PA performance and systemic IGF-1 (r = 0.46, P < 0.05). Taken together, our data indicate that resistance exercise improves the hippocampus-dependent memory task with a concomitant increase of IGF-1 level in the rat model. This model can be further explored to better understand the effects of resistance exercise on brain functions.

Adipose tissue-derived stem cells promote pancreatic cancer cell proliferation and invasion

To explore the effects of adipose tissue-derived stem cells (ADSCs) on the proliferation and invasion of pancreatic cancer cells in vitroand the possible mechanism involved, ADSCs were cocultured with pancreatic cancer cells, and a cell counting kit (CCK-8) was used to detect the proliferation of pancreatic cancer cells. ELISA was used to determine the concentration of stromal cell-derived factor-1 (SDF-1) in the supernatants. RT-PCR was performed to detect the expression of the chemokine receptor CXCR4 in pancreatic cancer cells and ADSCs. An in vitro invasion assay was used to measure invasion of pancreatic cancer cells. SDF-1 was detected in the supernatants of ADSCs, but not in pancreatic cancer cells. Higher CXCR4 mRNA levels were detected in the pancreatic cancer cell lines compared with ADSCs (109.3±10.7 and 97.6±7.6 vs 18.3±1.7, respectively; P<0.01). In addition, conditioned medium from ADSCs promoted the proliferation and invasion of pancreatic cancer cells, and AMD3100, a CXCR4 antagonist, significantly downregulated these growth-promoting effects. We conclude that ADSCs can promote the proliferation and invasion of pancreatic cancer cells, which may involve the SDF-1/CXCR4 axis.

Changes in circulating endothelial progenitor cells predict responses of multiple myeloma patients to treatment with bortezomib and dexamethasone

Four cycles of chemotherapy are required to assess responses of multiple myeloma (MM) patients. We investigated whether circulating endothelial progenitor cells (cEPCs) could be a biomarker for predicting patient response in the first cycle of chemotherapy with bortezomib and dexamethasone, so patients might avoid ineffective and costly treatments and reduce exposure to unwanted side effects. We measured cEPCs and stromal cell-derived factor-1α (SDF-1α) in 46 MM patients in the first cycle of treatment with bortezomib and dexamethasone, and investigated clinical relevance based on patient response after four 21-day cycles. The mononuclear cell fraction was analyzed for cEPC by FACS analysis, and SDF-1α was analyzed by ELISA. The study population was divided into 3 groups according to the response to chemotherapy: good responders (n=16), common responders (n=12), and non-responders (n=18). There were no significant differences among these groups at baseline day 1 (P>0.05). cEPC levels decreased slightly at day 21 (8.2&#177;3.3 cEPCs/μL) vs day 1 (8.4&#177;2.9 cEPCs/μL) in good responders (P>0.05). In contrast, cEPC levels increased significantly in the other two groups (P<0.05). SDF-1α changes were closely related to changes in cEPCs. These findings indicate that change in cEPCs at day 21 in the first cycle might be considered a noninvasive biomarker for predicting a later response, and extent of change could help decide whether to continue this costly chemotherapy. cEPCs and the SDF-1α/CXCR4 axis are potential therapeutic targets for improved response and outcomes in MM patients.

Inflammation induced by increased frequency of intermittent hypoxia is attenuated by tempol administration

The levels of serum inflammatory cytokines and the activation of nuclear factor kappa B (NF-κB) and hypoxia inducible factor-1α (HIF-1α) in heart tissues in response to different frequencies of intermittent hypoxia (IH) and the antioxidant tempol were evaluated. Wistar rats (64 males, 200-220 g) were randomly divided into 6 experimental groups and 2 control groups. Four groups were exposed to IH 10, 20, 30, or 40 times/h. The other 2 experimental groups were challenged with IH (30 times/h) plus tempol, either beginning on day 0 (IH30T0) or on day 29 (IH30T29). After 6 weeks of challenge, serum levels of tumor necrosis factor (TNF)-α, intracellular adhesion molecule (ICAM)-1, and interleukin-10 were measured, and western blot analysis was used to detect NF-κB p65 and HIF-1α in myocardial tissues. Serum levels of TNF-α and ICAM-1 and myocardial expression of NF-κB p65 and HIF-1α were all significantly higher in IH rats than in controls (P<0.001). Increased IH frequency resulted in more significant changes. Administration of tempol in IH rats significantly reduced levels of TNF-α, ICAM-1, NF-κB and HIF-1α compared with the non-tempol-treated group (F=16.936, P<0.001). IH induced an inflammatory response in a frequency-dependent manner. Additionally, HIF-1α and NF-κB were increased following IH administration. Importantly, tempol treatment attenuated this effect.

Soro urêmico inibe a expressão in vitro da quimiocina SDF-1: possível impacto da toxicidade urêmica na lesão endotelial

Introdu1;ão: A disfun1;ão endotelial é importante na patogênese da doen1;a cardiovascular (DCV) relacionada à doen1;a renal crônica (DRC). Stromal cell-derived factor-1 (SDF-1) é uma quimiocina que mobiliza células endoteliais progenitoras (EPC) e em conjunto com a interleucina-8 (IL-8) podem ser usadas como marcadores de reparo e lesão tecidual. Objetivo: Neste trabalho, foi investigado o efeito do meio urêmico na expressão de SDF-1 e IL-8 in vivo e in vitro. Métodos: A inflama1;ão sistêmica foi avaliada por meio da proteína C-reativa (PCR) e interleucina-6 (IL-6). IL-8 e SDF-1 foram avaliados por ELISA como marcadores de disfun1;ão endotelial e reparo tecidual, respectivamente. Os estudos in vitro foram realizados em células endoteliais umbilicais humanas (HUVEC) expostas ao meio urêmico ou saudável. Resultados: Foram incluídos nesse estudo 26 pacientes em hemodiálise (HD) (17 &#177; 3 meses em diálise, 52 &#177; 2 anos, 38% homens e 11% diabéticos). As concentra1;ões séricas de PCR, IL-6, SDF-1 e IL-8 foram 4,9 &#177; 4,8 mg/ml, 6,7 &#177; 8,1 pg/ml, 2625,9 &#177; 1288,6 pg/ml e 128,2 &#177; 206,2 pg/ml, respectivamente. Houve correla1;ão positiva entre PCR e IL-6 (`1; = 0,57; p < 0,005) e entre SDF-1 e IL-8 (`1; = 0,45; p < 0,05). Os resultados in vitro demonstraram que a expressão de SDF-1 pelas HUVEC após 6 horas de tratamento com meio urêmico é menor comparada ao tratamento com meio saudável (p < 0,05). Após 12 horas de tratamento, ocorreu aumento de IL-8 quando as HUVECs foram expostas ao meio urêmico (p < 0,005). Conclusão: Sugerimos que SDF-1 e IL-8 nos pacientes em HD podem ser usados para mensurar a extensão do dano e consequente ativa1;ão vascular na uremia.