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Stimulation of TLRs initiates intracellular signaling cascades resulting in downstream NF-B and mitogen-activated protein kinase activation and production of proinflammatory chemokines associated with mechanisms of metabolic dysfunction and cardiovascular disease progression.

Elevated fatty acids levels associated with obesity activate TLR4 signaling in fat cells and macrophages, and induce insulin resistance in murine models

BCAA supplementation was shown to delay the progression of CCl4-induced chronic liver injury in a rat model by reducing hepatic apoptosis

BCAAs promoted hepatocyte regeneration in a rat model of hepatectomy

BCAA supplementation for advanced cirrhotic patients improves nutritional status and quality of life

BCAAs activate mTOR and subsequently increase the production of eukaryotic initiation factor 4E-binding protein-1 and ribosomal protein S6 kinase, which upregulate the synthesis of albumin

BCAAs were shown to improve homeostasis model assessment scores for insulin resistance (HOMA-IR) and beta cell function (HOMA-%B) in patients with chronic liver disease, indicating that BCAAs can ameliorate insulin resistance

Several clinical trials have suggested that BCAA supplementation improves the prognosis of cirrhotic patients

A low Fischer ratio has been associated with hepatic encephalopathy

Treatment with BCAAs may therefore have a beneficial effect on patients with hepatic encephalopathy mainly by compensating decreased ratio of BCAAs to AAAs, but not by reducing serum ammonia levels

Two randomized studies also showed that BCAAs did not clearly prevent HE in patients with advanced cirrhosis, although BCAAs prevented the progression of hepatic failure

a systematic review with meta-analyses on the effect of oral BCAAs for the treatment of HE was published[66]. The review has revealed that supplementation of oral BCAAs in cirrhotic patients inhibits the manifestation of HE, especially in patients with overt HE rather than those with minimal HE, but showed no effect on the survival of those patients[66]. Thus, oral administration of BCAAs is the treatment of choice in cirrhotic patients with HE

The IL-1β-induced increase in MLCK mRNA transcription and subsequent increase in MLCK protein expression and Caco-2 TJ permeability was mediated by activation of NF-κB

In the liver, fructose bypasses the two highly regulated steps of glycolysis, catalyzed by glucokinase/hexokinase and phosphofructokinase both of which are inhibited by increasing concentrations of their byproducts. Instead, fructose enters the pathway at a level that is not regulated and is metabolized to fructose-1-phosphate primarily by fructokinase or ketohexokinase

Fructokinase has no negative feedback system, and ATP is used for the phosphorylation process. As a result, continued fructose metabolism results in intracellular phosphate depletion, activation of AMP deaminase, and uric acid generation which is harmful at the cellular level

Uric acid, a byproduct of fructose degradation,

Uric acid inhibits endothelial NO both in vivo and in vitro, [15] and directly induces adipocyte dysfunction

Serum uric acid increases rapidly after ingestion of fructose, resulting in increases as high as 2 mg/dL within 1 hour

Uncontrolled fructose metabolism leads to postprandial hypertriglyceridemia, which increases visceral adipose deposition. Visceral adiposity contributes to hepatic triglyceride accumulation, protein kinase C activation, and hepatic insulin resistance by increasing the portal delivery of free fatty acids to the liver

Several reviews have concluded that intake of both fructose and HFCS by children and adults was associated with an increased risk of obesity and metabolic syndrome

Sucrose is a disaccharide that is comprised of fructose and glucose

Figure 2

The rate of water loss can be quantified through measurement of sweat rate

Pre- and postexercise body weight measurements are the most common means to estimate overall water loss but are condition specific

It appears that 1% to 2% body weight loss is well tolerated by the exercising athlete

Dehydration, defined as greater than 2% loss of body weight, can negatively affect performance

In highly trained endurance athletes, plasma volume and sodium serum concentration were preserved despite a 5% body weight loss

In Ironman triathletes, dehydration to 5% body weight loss did not correlate with occurrence of medical complications

hydration should begin hours prior to exercise, especially if known deficits are present, and fluids should be consumed at a slow, steady rate, with 5 to 7 mL/kg taken 4 hours prior to exercise

Sodium concentration did not produce significant changes in the rate of absorption but was primarily dependent on carbohydrate concentration

Replacing 150% of body weight loss over 60 minutes has been tolerated without complications

IV treatment of severe dehydration (>7% body weight loss), exertional heat illness, nausea, emesis, or diarrhea, and in those who cannot ingest oral fluids for other reasons, is clinically indicated

A recent survey of the National Football League teams revealed that 75% (24 of 32) of the teams utilized IV infusion of fluids for prehydration in at least some otherwise healthy individuals

In the National Football League, an average of 1.5 L of normal saline was administered approximately 2.5 hours prior to competition

after 2 hours of exercise, the rectal temperature was 0.6° higher in the group not receiving IV infusion. Also, stroke volume and cardiac output were 11% to 16% lower in the control group versus the IV infusion group.

Recent evidence suggests the etiology of EAMC is related to muscle fatigue and neuronal excitability

no correlation between hydration status or electrolyte concentrations with EAMC

there may be a subset of muscle cramping that is associated with a loss of both body fluid and sodium

Glycerol is the primary agent for oral hyperhydration

elevation of plasma volume by 200 to 300 mL via dextran infusion resulted in 15% increase in stroke volume, 4% increase in VO2 max, and an increase in the exercise time to fatigue

Neither the tonicity nor mode of hydration resulted in improved speed of rehydration, greater fluid retention, or improved performance

There are beneficial anecdotal reports of EAMC treatment in elite and professional-level athletes with IV hydration during the course of an event

Plasma volume was better restored during rehydration with IV fluids at preexercise and 5 minutes of exercise. At 15 minutes, there was no difference between IV and oral rehydration

More rapid restoration of plasma volume was accomplished in the IV treatment group with no advantages over oral rehydration in physiological strain, heat tolerance, ratings of perceived effort, or thermal sensations

No difference was found in exercise time to exhaustion. IV and oral rehydration methods were equally effective. Heart rates were statistically higher in the oral rehydration group through 75 minutes of exercise, and there were higher increases in norepinephrine plasma concentrations

No significant differences between the groups were found for time to recovery, number of days with pain, number of days with stiffness, sleep disturbance, fatigue, rectal temperature, and loss of appetite

The current data suggest that IV rehydration is faster than oral

There may be physiological benefits of decreased heart rate and norepinephrine in athletes rehydrated via IV route

Postexercise blood 1 hour and 24 hours showed no differences in circulating myoglobin or creatine kinase

The use of IV fluid may be beneficial for a subset of fluid sensitive athletes

this should be reserved for high-level athletes with strong histories of symptoms in well-monitored settings.

Volume expanders may also be beneficial for some athletes

Other targets of HIF-1α include glucose transporter-1 (GLUT-1), the main transporter involved in glucose uptake [9,10]; lactate dehydrogenase V (LDHV), which is responsible for the conversion of pyruvate into lactate; pyruvate dehydrogenase kinase isozyme 1 (PDK1), which is responsible for the phosphorylation and consequent inactivation of pyruvate dehydrogenase (PDH); and carbonic anhydrase IX (CAIX), a hypoxia-related protein involved in pH regulation [11]. Alpha-methylacyl-CoA racemase (AMACR), pristanoyl-CoA oxidase (ACOX-3) and D-bifunctional protein (DBP), are also important fatty acid oxidation-related proteins in prostate cancer

the essential role played by the cross-talk between stroma and epithelium in carcinogenesis and prostate cancer progression has been increasingly recognised

strong membranous expression of MCT1 was consistently observed in cancer cells, suggesting a role for MCT1 in the transport of lactate into tumour cells from the acidic extracellular matrix, suggesting that lactate might be used as a fuel by oxidative cancer cells.

Our hypothesis is in agreement with those of Fiaschi et al.[17], who describe the metabolic reprogramming of CAFs towards the Warburg phenotype as a result of contact with prostate cancer cells

Using in vitro studies, they showed lactate production and efflux by de novo expressed MCT4 in CAFs and also demonstrated that, upon contact with CAFs, prostate cancer cells were reprogrammed towards aerobic metabolism, with an increase in lactate uptake via the lactate transporter MCT1.

pharmacological inhibition of MCT1-mediated lactate uptake dramatically affected PCa cell survival and tumour outgrowth

In this model, “energy transfer” or “metabolic coupling” between the tumour stroma and epithelial cancer cells fuels tumour growth and metastasis via oxidative mitochondrial metabolism in anabolic cancer cells

the concomitant expression of MCT1 in tumour cells and MCT4 in fibroblasts in the same tissue is clinically significant, and associated with poor prognosis.

Clinical studies of DCA have shown reduced lactate levels

It has been reported that DCA activates the PDH by inhibition of PDK in a dose-dependent manner, and results in increased delivery of pyruvate into the mitochondria

The antitumor activity of DCA on nonsmall cell lung cancer, breast cancer, glioblastomas, and endometrial and prostate cancer cells has been demonstrated

It is well known that many chemotherapeutic agents have a low therapeutic index in brain tumors.

The most common metabolic hallmark of cancer cells is their propensity to metabolize glucose to lactic acid at a high rate even in the presence of oxygen

Pyruvate dehydrogenase kinase (PDK) is a gate-keeping enzyme that regulates the flux of carbohydrates (pyruvate) into the mitochondria

In the presence of activated PDK, pyruvate dehydrogenase (PDH), a critical enzyme that converts pyruvate to acetyl-CoA instead of lactate in glycolysis, is inhibited, limiting the entry of pyruvate into the mitochondria.

the level of Hsp70 was significantly decreased

DCA can penetrate the BBB

It has been reported that DCA treatment resulted in an increase in the proportion of tumor cells in the S phase, showing a decrease in proliferation as well as the induction of apoptosis

Heat shock proteins (HSPs) are involved in protein folding, aggregation, transport, and/or stabilization by acting as a molecular chaperone, leading to the inhibition of apoptosis by both caspase-dependent and/or independent pathways

HSPs are overexpressed in a wide range of human cancers and are implicated in tumor cell proliferation, differentiation, invasion, and metastasis

Considering the fact that high expression of HSPs is essential for cancer survival, the inhibition of HSPs is an important strategy of anticancer therapy.

In addition, after 5 years of continued treatment with oral DCA at a dose of 25 mg/kg, the serum DCA levels are only slightly increased compared with the levels after the first several doses, also showing its safety for oral administration at this dose.

DCA can enter the circulation rapidly after oral administration and then generate the stimulation of PDH activity generally within minutes.

Our in vivo results in tumor tissues indicated that DCA significantly induced ROS production and decreased MMP in tumor tissues

The numbers of microvessels in the DCA treatment groups were significantly decreased, suggesting the potential antiangiogenic effect of DCA

Under hypoxic conditions, hypoxia-inducible factor (HIF-1α) is activated and induces angiogenesis

In addition, HIF-1α can also induce the expression of PDK,48 which can inhibit the activity of PDH

The inhibition effect of DCA on HIF-1α would decrease vascular endothelial growth factor and inhibit angiogenesis

the antiangiogenic effect in the 25 mg/kg treatment group was lower than that in 75 mg/kg or 125 mg/kg treatment groups

In conclusion, DCA induces the apoptosis of C6 cells through the activation of the mitochondrial pathway, arresting the cell cycle of C6 cells in S phase and down-regulating Hsp70 expression.

DCA significantly induced the ROS production and decreased the MMP in tumor tissues. Our in vivo antitumor activity results also indicated that DCA has an antiangiogenic effect