Is MG53 a potential therapeutic target for cancer?

Cancer treatment still encounters challenges, such as side effects and drug resistance. The tripartite-motif (TRIM) protein family is widely involved in regulation of the occurrence, development, and drug resistance of tumors. MG53, a member of the TRIM protein family, shows strong potential in cancer therapy, primarily due to its E3 ubiquitin ligase properties. The classic membrane repair function and anti-inflammatory capacity of MG53 may also be beneficial for cancer prevention and treatment. However, MG53 appears to be a key regulatory factor in impaired glucose metabolism and a negative regulatory mechanism in muscle regeneration that may have a negative effect on cancer treatment. Developing MG53 mutants that balance the pros and cons may be the key to solving the problem. This article aims to summarize the role and mechanism of MG53 in the occurrence, progression, and invasion of cancer, focusing on the potential impact of the biological function of MG53 on cancer therapy.

Supplementation with food-derived oligopeptides promotes lipid metabolism in young male cyclists: a randomized controlled crossover trial.

BACKGROUND: Accumulation of body fat and dyslipidemia are associated with the development of obesity and cardiometabolic diseases. Moreover, the degree to which lipids can be metabolized has been cited as a determinant of cardiometabolic health and prolonged endurance capacity. In the backdrop of increasing obesity and cardiometabolic diseases, lipid metabolism and its modulation by physical activity, dietary adjustments, and supplementation play a significant role in maintaining health and endurance. Food-derived oligopeptides, such as rice and soybean peptides, have been shown to directly regulate abnormal lipid metabolism or promote hypolipidemia and fat oxidation in cell culture models, animal models, and human studies. However, whether supplementation with oligopeptides derived from multiple food sources can promote lipid degradation and fat oxidation in athletes remains unclear. Therefore, in a randomized controlled crossover trial, we investigated the impact of food-derived oligopeptide supplementation before and during exercise on lipid metabolism in young male cyclists. METHODS: Sixteen young male cyclists (age: 17.0 ± 1.0 years; height: 178.4 ± 6.9 cm; body mass: 68.7 ± 12.7 kg, body mass index: 21.5 ± 3.4 kg/m2; maximum oxygen uptake: 56.3 ± 5.8 mL/min/kg) participated in this randomized controlled crossover trial. Each participant drank two beverages, one containing a blend of three food-derived oligopeptides (treatment, 0.5 g/kg body weight in total) and the other without (control), with a 2-week washout period between two experiments. The cyclists completed a one-day pattern protocol that consisted of intraday fasting, 30 min of sitting still, 85 min of prolonged exercise plus a 5-min sprint (PE), a short recovery period of 60 min, a 20-min time trial (TT), and recovery till next morning. Blood samples were collected for biochemical analyses of serum lipids and other biomarkers. We analyzed plasma triglyceride species (TGs), free amino acids (FAAs), and tricarboxylic acid (TCA) cycle intermediates using omics methods. In addition, exhaled gas was collected to assess the fat oxidation rate. RESULTS: Five of 20 plasma FAAs were elevated pre-exercise (pre-Ex) only 20 min after oligopeptide ingestion, and most FAAs were markedly increased post PE and TT. Serum levels of TG and non-esterified fatty acids were lower in the experimental condition than in the control condition at the post PE and TT assessments, respectively. Further, the omics analysis of plasma TGs for the experimental condition demonstrated that most TGs were lower post PE and at the next fasting when compared with control levels. Simultaneously, the fat oxidation rate began to increase only 20 min after ingestion and during the preceding 85 min of PE. Levels of TCA cycle intermediates did not differ between the conditions. CONCLUSIONS: The study noted that continuous ingestion of food-derived oligopeptides accelerated total body triglyceride breakdown, non-esterified fatty acid uptake, and fat oxidation during both sedentary and exercise states. Elevated circulating and intracellular FAA flux may modulate the selection of substrates for metabolic pathways in conjunction with the release of neuroendocrinological factors that slow down carbohydrate metabolism via acetyl coenzyme A feedback inhibition. This may increase the availability of fatty acids for energy production, with FAAs supplying more substrates for the TCA cycle. The findings of this study provide novel insight into strategies for promoting lipid metabolism in populations with dyslipidemia-related metabolic disorders such as obesity and for improving physiological functioning during endurance training. However, the absence of a non-exercising control group and verification of long-term supplementation effects was a limitation. Future studies will emphasize the impacts of whole protein supplementation as a control and of combined food-derived peptides or oligopeptides with probiotics and healthy food components on lipid metabolism in individuals who exercise.

Graphene oxide quantum dot exposure induces abnormalities in locomotor activities and mechanisms in zebrafish (Danio rerio).

Graphene oxide quantum dots (GOQDs) have broad applications such as bioimaging and drug delivery, among others, even expanding into the aquatic environment. However, reports on the adverse effects of GOQDs on fish development are limited. In this study, we exposed zebrafish embryos to GOQDs for 7 days after fertilization and found that GOQDs exposure at low concentrations (12.5, 25, 50 or 100 µg/L) decreased the total distance and the mean velocity of larvae movement. Additionally, the GOQDs significantly reduced the enzyme activity related to energy supply and locomotor capacity, including Ca2+ -ATPase in the 12.5, 25, 50 and 100 µg/L GOQDs groups and Na+ /K+ -ATPase in the 25 and 50 µg/L GOQDs groups. Moreover, GOQD exposure altered the mRNA expression of genes involved in energy supply and calcium transport. The levels of the atp2a2b, atp2a1, and cacna1sb genes were significantly downregulated in the 25, 50 and 100 µg/L GOQDs groups, and ryr3 expression was significantly reduced in the 25 and 50 µg/L GOQDs groups. The expression level of cacna1c was significantly upregulated in the 50 and 100 µg/L GOQDs groups. In summary, GOQD exposure induced a decrease in locomotor capacity in zebrafish, which may be due to the reduction of Ca2+ -ATPase and Na+ /K+ -ATPase activity levels, and dysregulated expression of the genes involved in energy metabolism and calcium transport. Our study provides novel insight into the effects of GOQDs on the embryonic development of fish, which will be useful for the development of environment-friendly GOQDs that reduce the potential hazard to aquatic species.

Effects of vitamin D3 supplementation on serum 25(OH)D concentration and strength in athletes: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The purpose of this systematic review and meta-analysis is to investigate the effects of vitamin D3 supplementation on skeletal muscle strength in athletes. Vitamin D3 supplements or vitamin D3 fortified foods always have claims for bringing people health benefits including bone and muscle health. An up-to-date rigorous systematic review and meta-analysis is important to better understand the effect of vitamin D3 supplementation on muscle strength. METHODS: English written randomized controlled trials (RCTs) that looked at effects of vitamin D3 supplementation on muscle strength in healthy athletes were searched using three databases (PubMed, Embase and Cochrane Library). Serum 25(OH)D above 30 ng/mL is considered to be sufficient in this systematic review and meta-analysis. RESULTS: Five RCTs with 163 athletes (vitamin D3 n = 86, placebo n = 77) met inclusion criteria. Fourteen athletes were lost to follow-up and 149 athletes (vitamin D3 n = 80, placebo n = 69) were documented with complete result. Among athletes with baseline serum 25(OH)D values suggesting insufficiency, vitamin D3 daily dosage at 5000 IU for over 4 weeks led to a serum 25(OH)D concentration of 31.7 ng/mL. Athletes with sufficient serum 25(OH)D level at baseline were recruited in only one study, and the participants of which were assigned to either vitamin D3 at a daily dosage of 3570 IU or placebo for 12 weeks, their serum 25(OH)D sufficiency (VD: 37.2 ± 7.6 vs. 45.6 ± 7.6; PL: 38 ± 6.8 vs. 32 ± 8.4) was well maintained above the cut-off boundary. One repetition maximum Bench Press (1-RM BP) was not improved significantly (SMD 0.07, 95% CI: - 0.32 to 0.47, P = 0.72) and there was no significant increase in maximal quadriceps contraction (SMD -2.14, 95% CI: - 4.87 to 0.59, P = 0.12). Furthermore, there was no significant overall effect of vitamin D3 intervention on muscle strength in this meta-analysis (SMD -0.75, 95% CI: - 1.82 to 0.32, P = 0.17). CONCLUSION: Although, serum 25(OH)D concentrations after supplementation reached sufficiency was observed, muscle strength did not significantly improve at this point of current meta-analysis. Additional well-designed RCTs with large number of participants examined for the effect of vitamin D3 supplementation on serum 25(OH)D concentrations, muscle strength in a variety of sports, latitudes and diverse multicultural populations are needed.

Effects of Three Commercially Available Sports Drinks on Substrate Metabolism and Subsequent Endurance Performance in a Postprandial State.

Purpose: To examine the effects of commercially available sports beverages with various components on substrate metabolism and subsequent performance. Methods: Two studies were conducted in a double-blinded, counterbalanced manner. Study I was designed to determine the glycemic index, while study II determined the utilization of substrates and subsequent exercise performance. Ten healthy male participants (age 21.70 ± 2.41 years, height 176.60 ± 5.23 cm, weight 66.58 ± 5.38 kg, V̇O2max 48.1 ± 8.4 mL/kg/min) participated in both study I and study II. Three types of commercially available sports beverage powders were used. The powders consisted primarily of oligosaccharides (low molecular weight carbohydrates, L-CHO), hydrolyzed starch (high molecular weight CHO, H-CHO), and whey protein powder with carbohydrate (CHO-PRO). They were dissolved in purified water with identical CHO concentration of 8% (w/v). In study I, each participant underwent two oral glucose tolerance tests (OGTT) and one glycemic response test for each sports drink. In study II, participants cycled for 60 min at 70% V̇O2max, one hour after consuming a standardized breakfast. One of four prescribed beverages (L-CHO, H-CHO, CHO-PRO, and Placebo control, PLA) was served at 0, 15, 30, 45 min during the exercise. Six hours after the first exercise session, participants came back for a "time to exhaustion test" (TTE). Blood samples were drawn at 0, 30, and 60 min in the first exercise session, while arterial blood gas analysis was conducted at 0, 30, and 60 min in both sessions. Subjective feelings (rating of perceived exertion and abdominal discomfort) were also evaluated every 30 min during exercise. Results: Compared to the reference standardized glucose solution, the glycemic index of the L-CHO beverage was 117.70 ± 14.25, while H-CHO was 105.50 ± 12.82, and CHO-PRO was 67.23 ± 5.88. During the exercise test, the insulin level at 30 and 60 min was significantly lower than baseline following the treatment of L-CHO, H-CHO, and PLA (p < 0.05). The CHO oxidation rate at 60 min in the first exercise session was significantly higher than that at 60 min in the second exercise session following the L-CHO treatment (p < 0.05). Time to exhaustion was not significantly different (p > 0.05). Conclusion: The CHO sports beverage with additional PRO maintains insulin production during endurance cycling at 70% V̇O2max in the postprandial state. L-CHO sports beverage suppresses fat utilization during the subsequent exercise performance test. The subsequent exercise performance (as evaluated by TTE) was not influenced by the type of CHO or the addition of PRO in the commercially available sports beverages used in the present study.

The effect of almond consumption on elements of endurance exercise performance in trained athletes.

BACKGROUND: Almonds are a healthy tree nut food with high nutrient density. Their consumption has been shown to ameliorate oxidative stress, inflammation, etc. The objective of the study was to examine the effect of almonds on elements of endurance exercise performance in trained athletes. METHODS: A 10-week crossover, placebo controlled study was conducted. Eight trained male cyclists and two triathletes were randomly assigned to consume 75 g/d whole almonds (ALM) or isocaloric cookies (COK) with equal subject number. They consumed the assigned food for 4 wks and then the alternate food for another 4 wks. They underwent 3 performance tests including 125-min steady status exercise (SS) and 20-min time trial (TT) on an indoor stationary trainer at the start of the study (BL) and at the end of each intervention phase. Venous blood was collected in the morning prior to the performance test for biochemical measurements and finger blood during the test for glucose determination. Carbohydrate and fat oxidation, energy expenditure, and oxygen use were calculated using respiratory gas analysis. RESULTS: ALM increased cycling distance during TT by 1.7 km as compared BL (21.9 vs. 20.2 km, P = 0.053) and COK increased 0.6 km (20.8 vs. 20.2 km, P > 0.05). ALM, but not COK, led to higher CHO and lower fat oxidation and less oxygen consumption during TT than BL (P < 0.05), whereas there was no significant difference in heart rate among BL, ALM and COK. ALM maintained higher blood glucose level after TT than COK (P < 0.05). ALM had higher vitamin E and haemoglobin and lower serum free fatty acid (P < 0.05), slightly elevated serum arginine and nitric oxide and plasma insulin (P > 0.05) than BL, and a higher total antioxidant capacity than COK (P < 0.05). CONCLUSIONS: Whole almonds improved cycling distance and the elements related to endurance performance more than isocaloric cookies in trained athletes as some nutrients in almonds may contribute to CHO reservation and utilization and effective oxygen utilization. The results suggest that almonds can be incorporated into diets of those who undertake exercise training for performance improvement.

[Advances in mechanisms of health benefits of exercise and nutrition].

Adequate physical activity/exercise and nutrition are the footstone for health, and primary components of healthy life style and prevention and treatment of life style-related diseases. Here we briefly review the recent advances in mechanisms of health benefits of regular physical activity/exercise and adequate nutrition, mitochondrial nutrients, and so on.

Switch from ER-mitochondrial to SR-mitochondrial calcium coupling during muscle differentiation.

Emerging evidence indicates that mitochondria are locally coupled to endoplasmic reticulum (ER) Ca2+ release in myoblasts and to sarcoplasmic reticulum (SR) Ca2+ release in differentiated muscle fibers in order to regulate cytoplasmic calcium dynamics and match metabolism with cell activity. However, the mechanism of the developmental transition from ER to SR coupling remains unclear. We have studied mitochondrial sensing of IP3 receptor (IP3R)- and ryanodine receptor (RyR)-mediated Ca2+ signals in H9c2 myoblasts and differentiating myotubes, as well as the attendant changes in mitochondrial morphology. Mitochondria in myoblasts were largely elongated, luminally connected and relatively few in number, whereas the myotubes were densely packed with globular mitochondria that displayed limited luminal continuity. Vasopressin, an IP3-linked agonist, evoked a large cytoplasmic Ca2+ ([Ca2+]c) increase in myoblasts, whereas it elicited a smaller response in myotubes. Conversely, RyR-mediated Ca2+ release induced by caffeine, was not observed in myoblasts, but triggered a large [Ca2+]c signal in myotubes. Both the IP3R and the RyR-mediated [Ca2+]c rise was closely associated with a mitochondrial matrix Ca2+ ([Ca2+]m) signal. Every myotube that showed a [Ca2+]c spike also displayed a [Ca2+]m response. Addition of IP3 to permeabilized myoblasts and caffeine to permeabilized myotubes also resulted in a rapid [Ca2+]m rise, indicating that Ca2+ was delivered via local coupling of the ER/SR and mitochondria. Thus, as RyRs are expressed during muscle differentiation, the local connection between RyR and mitochondrial Ca2+ uptake sites also appears. When RyR1 was exogenously introduced to myoblasts by overexpression, the [Ca2+]m signal appeared together with the [Ca2+]c signal, however the mitochondrial morphology remained unchanged. Thus, RyR expression alone is sufficient to induce the steps essential for their alignment with mitochondrial Ca2+ uptake sites, whereas the mitochondrial proliferation and reshaping utilize either downstream or alternative pathways.

Calcium signalling and mitochondrial motility.

Intracellular Ca2+ is able to control numerous cellular responses through complex spatial and temporal organization. For the effective handling of intracellular Ca2+, endoplasmic reticulum (ER) Ca2+ mobilization and plasma membrane Ca2+ entry have to be complemented by strategic and dynamic positioning of an energy source that is usually provided by mitochondrial ATP production. Mitochondria also participate in the transport of Ca2+. Mitochondria are dynamically distributed in cells and utilize cytoskeletal tracks and motor proteins for their movements. Recent studies have reported that Ca2+ inhibits mitochondrial motility providing a mechanism to retain mitochondria at Ca2+ signalling sites. Here we discuss the control of the mitochondrial distribution by cell signalling mechanisms, the spatial relationship among individual mitochondria and ER domains, and the possible implications of mitochondrial movements in the Ca(2+)-dependent cell survival and cell death mechanisms.

Mitochondrial calcium signalling and cell death: approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosis.

Local Ca(2+) transfer between adjoining domains of the sarcoendoplasmic reticulum (ER/SR) and mitochondria allows ER/SR Ca(2+) release to activate mitochondrial Ca(2+) uptake and to evoke a matrix [Ca(2+)] ([Ca(2+)](m)) rise. [Ca(2+)](m) exerts control on several steps of energy metabolism to synchronize ATP generation with cell function. However, calcium signal propagation to the mitochondria may also ignite a cell death program through opening of the permeability transition pore (PTP). This occurs when the Ca(2+) release from the ER/SR is enhanced or is coincident with sensitization of the PTP. Recent studies have shown that several pro-apoptotic factors, including members of the Bcl-2 family proteins and reactive oxygen species (ROS) regulate the Ca(2+) sensitivity of both the Ca(2+) release channels in the ER and the PTP in the mitochondria. To test the relevance of the mitochondrial Ca(2+) accumulation in various apoptotic paradigms, methods are available for buffering of [Ca(2+)], for dissipation of the driving force of the mitochondrial Ca(2+) uptake and for inhibition of the mitochondrial Ca(2+) transport mechanisms. However, in intact cells, the efficacy and the specificity of these approaches have to be established. Here we discuss mechanisms that recruit the mitochondrial calcium signal to a pro-apoptotic cascade and the approaches available for assessment of the relevance of the mitochondrial Ca(2+) handling in apoptosis. We also present a systematic evaluation of the effect of ruthenium red and Ru360, two inhibitors of mitochondrial Ca(2+) uptake on cytosolic [Ca(2+)] and [Ca(2+)](m) in intact cultured cells.

Control of mitochondrial motility and distribution by the calcium signal: a homeostatic circuit.

Mitochondria are dynamic organelles in cells. The control of mitochondrial motility by signaling mechanisms and the significance of rapid changes in motility remains elusive. In cardiac myoblasts, mitochondria were observed close to the microtubular array and displayed both short- and long-range movements along microtubules. By clamping cytoplasmic [Ca2+] ([Ca2+]c) at various levels, mitochondrial motility was found to be regulated by Ca2+ in the physiological range. Maximal movement was obtained at resting [Ca2+]c with complete arrest at 1-2 microM. Movement was fully recovered by returning to resting [Ca2+]c, and inhibition could be repeated with no apparent desensitization. The inositol 1,4,5-trisphosphate- or ryanodine receptor-mediated [Ca2+]c signal also induced a decrease in mitochondrial motility. This decrease followed the spatial and temporal pattern of the [Ca2+]c signal. Diminished mitochondrial motility in the region of the [Ca2+]c rise promotes recruitment of mitochondria to enhance local Ca2+ buffering and energy supply. This mechanism may provide a novel homeostatic circuit in calcium signaling.