Calbindin 2 (CALB2) regulates 5-fluorouracil sensitivity in colorectal cancer by modulating the intrinsic apoptotic pathway

The role of the calcium binding protein, Calbindin 2 (CALB2), in regulating the response of colorectal cancer (CRC) cells to 5-Fluorouracil (5-FU) was investigated. Real-time RT-PCR and Western blot analysis revealed that CALB2 mRNA and protein expression were down-regulated in p53 wild-type and p53 null isogenic HCT116 CRC cell lines following 48 h and 72 h 5-FU treatment. Moreover, 5-FU-induced apoptosis was significantly reduced in HCT116 and LS174T CRC cell lines in which CALB2 expression had been silenced. Further investigation revealed that CALB2 translocated to the mitochondria following 5-FU treatment and that 5-FU-induced loss of mitochondrial membrane potential (Δψ(m)) was abrogated in CALB2-silenced cells. Furthermore, CALB2 silencing decreased 5-FU-induced cytochrome c and smac release from the mitochondria and also decreased 5-FU-induced activation of caspases 9 and 3/7. Of note, co-silencing of XIAP overcame 5-FU resistance in CALB2-silenced cells. Collectively, these results suggest that following 5-FU treatment in CRC cell lines, CALB2 is involved in apoptosis induction through the intrinsic mitochondrial pathway. This indicates that CALB2 may be an important mediator of 5-FU-induced cell death. Moreover, down-regulation of CALB2 in response to 5-FU may represent an intrinsic mechanism of resistance to this anti-cancer drug.     

Peroxisomal protein PEX13 functions in selective autophagy

PEX13 is an integral membrane protein on the peroxisome that regulates peroxisomal matrix protein import during peroxisome biogenesis. Mutations in PEX13 and other peroxin proteins are associated with Zellweger syndrome spectrum (ZSS) disorders, a subtype of peroxisome biogenesis disorder characterized by prominent neurological, hepatic, and renal abnormalities leading to neonatal death. The lack of functional peroxisomes in ZSS patients is widely accepted as the underlying cause of disease; however, our understanding of disease pathogenesis is still incomplete. Here, we demonstrate that PEX13 is required for selective autophagy of Sindbis virus (virophagy) and of damaged mitochondria (mitophagy) and that disease‐associated PEX13 mutants I326T and W313G are defective in mitophagy. The mitophagy function of PEX13 is shared with another peroxin family member PEX3, but not with two other peroxins, PEX14 and PEX19, which are required for general autophagy. Together, our results demonstrate that PEX13 is required for selective autophagy, and suggest that dysregulation of PEX13‐mediated mitophagy may contribute to ZSS pathogenesis.     

Heterogeneity in response to serological exposure markers of recent Plasmodium vivax infections in contrasting epidemiological contexts

BackgroundAntibody responses as serological markers of Plasmodium vivax infection have been shown to correlate with exposure, but little is known about the other factors that affect antibody responses in naturally infected people from endemic settings. To address this question, we studied IgG responses to novel serological exposure markers (SEMs) of P. vivax in three settings with different transmission intensity.MethodologyWe validated a panel of 34 SEMs in a Peruvian cohort with up to three years’ longitudinal follow-up using a multiplex platform and compared results to data from cohorts in Thailand and Brazil. Linear regression models were used to characterize the association between antibody responses and age, the number of detected blood-stage infections during follow-up, and time since previous infection. Receiver Operating Characteristic (ROC) analysis was used to test the performance of SEMs to identify P. vivax infections in the previous 9 months.Principal findingsAntibody titers were associated with age, the number of blood-stage infections, and time since previous P. vivax infection in all three study sites. The association between antibody titers and time since previous P. vivax infection was stronger in the low transmission settings of Thailand and Brazil compared to the higher transmission setting in Peru. Of the SEMs tested, antibody responses to RBP2b had the highest performance for classifying recent exposure in all sites, with area under the ROC curve (AUC) = 0.83 in Thailand, AUC = 0.79 in Brazil, and AUC = 0.68 in Peru.ConclusionsIn low transmission settings, P. vivax SEMs can accurately identify individuals with recent blood-stage infections. In higher transmission settings, the accuracy of this approach diminishes substantially. We recommend using P. vivax SEMs in low transmission settings pursuing malaria elimination, but they are likely to be less effective in high transmission settings focused on malaria control.     

A comparison of linear and daily undulating periodized programs with equated volume and intensity for local muscular endurance

The purpose of this study was to compare linear periodization (LP), daily undulating periodization (DUP), and reverse linear periodization (RLP) for gains in local muscular endurance and strength. Sixty subjects (30 men, 30 women) were randomly assigned to LP, DUP, or RLP groups. Maximal repetitions at 50% of the subject's body weight were recorded for leg extensions as a pretest, midtest, and posttest. Training involved 3 sets (leg extensions) 2 days per week. The LP group performed sets of 25 repetition maximum (RM), 20RM, and 15RM changing every 5 weeks. The RLP group progressed in reverse order (15RM, 20RM, 25RM), changing every 5 weeks. The DUP group adjusted training variables between each workout (25RM, 20RM, 15RM repeated for the 15 weeks). Volume and intensity were equated for each training program. No significant differences were measured in endurance gains between groups (RLP = 73%, LP = 56%, DUP = 55%; p = 0.58). But effect sizes (ES) demonstrated that the RLP treatment (ES = 0.27) was more effective than the LP treatment (control) and the DUP treatment (ES = -0.02) at increasing muscular endurance. Therefore, it was concluded that making gradual increases in volume and gradual decreases in intensity was the most effective program for increasing muscular endurance.     

Mitochondrial function and toxicity: role of B vitamins on the one-carbon transfer pathways

The B vitamins are water-soluble vitamins that are required as coenzymes for reactions essential for cellular function. This review focuses on the essential role of vitamins in maintaining the one-carbon transfer cycles. Folate and choline are believed to be central methyl donors required for mitochondrial protein and nucleic acid synthesis through their active forms, 5-methyltetrahydrofolate and betaine, respectively. Cobalamin (B12) may assist methyltetrahydrofolate in the synthesis of methionine, a cysteine source for glutathione biosynthesis. Pyridoxal, pyridoxine and pyridoxamine (B6) seem to be involved in the regeneration of tetrahydrofolate into the active methyl-bearing form and in glutathione biosynthesis from homocysteine. Other roles of these vitamins that are relevant to mitochondrial functions will also be discussed. However these roles for B vitamins in cell function are mostly theoretically based and still require verification at the cellular level. For instance it is still not known what B vitamins are depleted by xenobiotic toxins or which cellular targets, metabolic pathways or molecular toxic mechanisms are prevented by B vitamins. This review covers the current state of knowledge and suggests where this research field is heading so as to better understand the role vitamin Bs play in cellular function and intermediary metabolism as well as molecular, cellular and clinical consequences of vitamin deficiency. The current experimental and clinical evidence that supplementation alleviates deficiency symptoms as well as the effectiveness of vitamins as antioxidants will also be reviewed.     

Running-specific, periodized strength training attenuates loss of stride length during intense endurance running

The purpose of this study was to determine the effects of a running-specific, periodized strength training program (performed over the specific period [8 weeks] of a 16-week macrocycle) on endurance-trained runners' capacity to maintain stride length during running bouts at competitive speeds. Eighteen well-trained middle-distance runners completed the study (personal bests for 1500 and 5000 m of 3 minutes 57 seconds +/- 12 seconds and 15 minutes 24 seconds +/- 36 seconds). They were randomly assigned to each of the following groups (6 per group): periodized strength group, performing a periodized strength training program over the 8-week specific (intervention) period (2 sessions per week); nonperiodized strength group, performing the same strength training exercises as the periodized group over the specific period but with no week-to-week variations; and a control group, performing no strength training at all during the specific period. The percentage of loss in the stride length (cm)/speed (m.s) (SLS) ratio was measured by comparing the mean SLS during the first and third (last) group of the total repetitions, respectively, included in each of the interval training sessions performed at race speeds during the competition period that followed the specific period. Significant differences (p < 0.05) were found in mean percentage of SLS loss between the 3 study groups, with the periodized strength group showing no significant SLS change (0.36 +/- 0.95%) and the 2 other groups showing a moderate or high SLS loss (-1.22 +/- 1.5% and -3.05 +/- 1.2% for the nonperiodized strength and control groups, respectively). In conclusion, periodized, running-specific strength training minimizes the loss of stride length that typically occurs in endurance runners during fatiguing running bouts.     

Noncompatibility of power and endurance training among college baseball players

Exercise professionals seeking to develop evidence-based training programs rely on several training principles demonstrated through research and professional experience. In an effort to further research examining these principles, an investigation was designed and completed to evaluate the compatibility of cardiovascular endurance and neuromuscular power training. Sixteen Division-I collegiate baseball players were divided into two training groups with lower body power measured before and after their college playing season. The two groups differed in training in that one group performed moderate- to high-intense cardiovascular endurance training 3-4 days per week throughout the season, while the other group participated in speed/speed endurance training. A significant difference between groups (P < .05) was identified in the change in lower body power during the baseball season. During the season, the endurance training group decreased an average of 39.50 +/- 128.03 watts while the speed group improved an average of 210.63 +/- 168.96 watts. These data demonstrate that moderate- to high-intense cardiovascular endurance and neuromuscular power training do not appear to be compatible when performed simultaneously. For baseball players, athletes who rely heavily on power and speed, conventional baseball conditioning involving significant amounts of cardiovascular endurance training should be altered to include more speed/power interval training.