Intratumoral inorganic phosphate deprivation: A new anticancer strategy?

Tumor epidemiology, as well as tumor microenvironments and cancer cell signaling study, has been presented with statistical relevance of inorganic phosphate (Pi) to tumorigenesis. Although serum Pi is still not acknowledged as a clinical tumor biomarker, abnormally high Pi concentration in serum or tumor lesions is gradually recognized as a characteristic of malignancy. On the other hand, phosphate binder (e.g. La2 (CO3)3, Fosrenols) has been clinically approved to treat hyperphosphatemia, a metabolic disease characterized by a high serum phosphate level. We hypothesize that, if reducing phosphate burden comes to benefit tumor therapy, could systemic or intratumoral administration of phosphate binder effectively deprive tumor Pi concentration, and then inhibit tumor growth and metastases? From the past clinical and preclinical outcomes, we'd conclude that Pi is not only a metabolite during tumor growth but also a force to trigger tumor progression and metastases. Two types of cancer models were developed to initiate this study. Firstly, a patient-derived xenograft mouse model of colorectal cancer was designed, where mice were administered systemically or intratumorally with lanthanum acetate (a molecular phosphate binder), and the serum or intratumoral Pi concentration levels were found to a dropdown. Secondly, a rabbit VX2 liver tumor was set up for the local-regional therapy model, where lanthanum acetate was intratumorally administered by the standard transcatheter arterial chemoembolization procedure, and it significantly reduced intratumoral Pi concentration. Therefore, Pi deprivation by phosphate binder might be a new anticancer strategy if reducing phosphate burden could effectively arrest tumor growth and delay metastatic progression.

Sustained release of arsenic trioxide benefits interventional therapy on rabbit VX2 liver tumor.

The benefit of chemotherapy as a constituent of transcatheter arterial chemoembolization (TACE) is still in debate. Recently we have developed arsenic trioxide nanoparticle prodrug (ATONP) as a new anticancer drug, but its systemic toxicity is a big issue. In this preclinical TACE study, ATONP emulsified in lipiodol behaved as drug-eluting bead manner. Sustained release of arsenic from ATONP within occluded tumor caused very low arsenic level in plasma, avoiding the "rushing out" effect as ATO did. Correspondingly, intratumoral arsenic accumulation and inorganic phosphate deprivation were simultaneously observed, and arsenic concentration was much higher as ATONP was transarterially administered than ATO, or intravenously injected. Tumor necrosis and apoptosis were remarkably more severe in ATONP group than ATO, but no significant hepatic and renal toxicity was perceived. In brief, ATONP alleviated arsenic toxicity and boosted the therapeutic effect of TACE via Pi-activated drug sustainable release.

Encapsulation of omega-3 fatty acids in nanoemulsions and microgels: Impact of delivery system type and protein addition on gastrointestinal fate.

Carefully designed delivery systems are required to encapsulate and protect omega-3 fatty acids in commercial food and beverage products, but then release them at the required site-of-action within the human gastrointestinal tract (GIT). Previously, we showed that the oxidative stability of flaxseed oil (a plant-based source of omega-3 fatty acids) encapsulated in nanoemulsion droplets or calcium alginate microgels (hydrogel beads) was improved using caseinate as a natural antioxidant. In this study, the impact of caseinate on the digestion of flaxseed oil encapsulated in these delivery systems was investigated using a simulated GIT. The flaxseed oil was incorporated into four delivery systems: nanoemulsions (NE); nanoemulsions mixed with caseinate (NE+C); hydrogel beads (HB); and, hydrogel beads containing caseinate (HB+C). The gastrointestinal fate of the flaxseed oil droplets depended on delivery system type and the presence of protein. The flaxseed oil in the nanoemulsions (NE and NE+C) was rapidly hydrolyzed within the simulated small intestine, with over 76% and 65% of free fatty acids (FFAs) being released in the first 5 minutes, respectively. Conversely, the flaxseed oil in the hydrogel beads (HB and HB+C) was digested much more slowly, with only around 37% and 22% being released in the same period. This knowledge may be useful for designing delivery systems to protect omega-3 fatty acids from oxidation in functional foods, while still allowing them to be released in the GIT.

[The effects of methionine and choline on the expression levels of CaMKII and CREB mRNA and proteins in rats exposed to lead].

OBJECTIVE: To study the effects of methionine and choline on the expression levels of CaMKII and CREB mRNA and proteins in hippocampus of rats exposed to lead. METHODS: Male SD rats were divided into five groups. (1) control group, (2) group exposed to lead+2 by drinking water with 0.40 g/L lead acetate, (3) group exposed to methionine and choline (1:1, 400 mg/kg), (4) group exposed to 0.40 g/L lead acetate plus methionine and choline (1:1, 100 mg/kg), (5) group exposed to 0.40 g/L lead acetate plus methionine and choline (1:1, 400 mg/kg). In 8 weeks after exposure, all rats were killed. Then CREB mRNA and CaMK II mRNA expression levels in hippocampus were detected by real-time PCR, CREB and CaMK II protein expression levels in hippocampus were measured by western blot assay. RESULTS: The expression levels (0.743 ± 0.185 and 0.729 ± 0.199) of CaMKII mRNA and CREB mRNA in the hippocampus of lead group were significantly lower than those (0.950 ± 0.238 and 0.901 ± 0.232) of control group (P < 0.05), also the expression levels (0.271 ± 0.045 and 0.212 ± 0.058) of CREB protein and pCREB protein in the hippocampus of lead group were significantly lower than those (0.319 ± 0.058 and 0.506 ± 0.125) of control group (P < 0.05). The expression levels (1.014 ± 0.210 and 1.126 ± 0.379) of CaMKII mRNA and the expression levels (1.029 ± 0.335 and 0.932 ± 0.251) of CREB mRNA in the hippocampus of 2 groups exposed to lead acetate plus methionine and choline were significantly higher than those of lead group (P < 0.05). The expression levels (0.407 ± 0.951 and 0.563 ± 0.178) of CREB protein and pCREB protein in the hippocampus of group exposed to lead acetate plus 400 mg/kg methionine and choline were significantly higher than those of lead group (P < 0.05). CONCLUSION: Methionine and choline could decrease the inhibition effects of lead on the expression of CaMKII and CREB mRNA or CREB and pCREB proteins in the hippocampus of rats.

[Study on mental workload of teachers in primary schools].

OBJECTIVE: To investigate the distribution characteristics and influencing factors of mental workload of teachers in primary schools. METHODS: National Aeronautics and Space Administration-Task Load Index (NASA-TLX) was used to assess the mental workload levels for 397 teachers of primary schools in a city. RESULTS: The mental workload (64.34+10.56) of female teachers was significantly higher than that (61.73+ 9.77) of male teachers (P<0.05). The mental workload (65.66+10.42) of "-35" years old group was the highest. When age of teachers was younger than 35 years old, there was a positive correlation between the mental workload and age (r=0.146, P<0.05). When age of teachers was older than 35 years old, there was a negative correlation between the mental workload and age (r=-0.190, P<0.05). The teachers with higher education level felt higher mental workload (unstandardized coefficients B=1.524, standardized coefficients /=0.111, P<0.05). There was a positive correlation between the mental workload and working hours per day (unstandardized coefficients B =4.659, standardized coefficients/3 =0.223, P<0.001). CONCLUSION: Mental workload of the teachers in primary schools is closely related to age, educational level and work hours per day. Work hours per day is an important risk factor for mental workload. Reducing work hours per day (8 hours) is an effective measure of alleviating the mental workload of teachers in primary schools.