TNAP: A New Multitask Enzyme in Energy Metabolism

Tissue-nonspecific alkaline phosphatase (TNAP) is mainly known for its necessary role in skeletal and dental mineralization, which relies on the hydrolysis of the mineralization inhibitor inorganic pyrophosphate (PPi). Mutations in the gene encoding TNAP leading to severe hypophosphatasia result in strongly reduced mineralization and perinatal death. Fortunately, the relatively recent development of a recombinant TNAP with a bone anchor has allowed to correct the bone defects and prolong the life of affected babies and children. Researches on TNAP must however not be slowed down, because accumulating evidence indicates that TNAP activation in individuals with metabolic syndrome (MetS) is associated with enhanced cardiovascular mortality, presumably in relation with cardiovascular calcification. On the other hand, TNAP appears to be necessary to prevent the development of steatohepatitis in mice, suggesting that TNAP plays protective roles. The aim of the present review is to highlight the known or suspected functions of TNAP in energy metabolism that may be associated with the development of MetS. The location of TNAP in liver and its function in bile excretion, lipopolysaccharide (LPS) detoxification and fatty acid transport will be presented. The expression and function of TNAP in adipocyte differentiation and thermogenesis will also be discussed. Given that TNAP is a tissue- and substrate-nonspecific phosphatase, we believe that it exerts several crucial pathophysiological functions that are just beginning to be discovered.

The Role of Gut Microbial β-Glucuronidase in Estrogen Reactivation and Breast Cancer

Over the past decade, the gut microbiota has received considerable attention for its interactions with the host. Microbial β-glucuronidase generated by this community has hence aroused concern for its biotransformation activity to a wide range of exogenous (foreign) and endogenous compounds. Lately, the role of gut microbial β-glucuronidase in the pathogenesis of breast cancer has been proposed for its estrogen reactivation activity. This is plausible considering that estrogen glucuronides are the primary products of estrogens’ hepatic phase II metabolism and are subject to β-glucuronidase-catalyzed hydrolysis in the gut via bile excretion. However, research in this field is still at its very preliminary stage. This review outlines the biology of microbial β-glucuronidase in the gastrointestinal tract and elaborates on the clues to the existence of microbial β-glucuronidase–estrogen metabolism–breast cancer axis. The research gaps in this field will be discussed and possible strategies to address these challenges are suggested.

The effect of cranioskeletal trauma complicated by blood loss on the functional state of the liver in the early period of traumatic disease in rats with different resistance to hypoxia and their correction

Introduction. Traumatic events are considered to be one of the current problems in modern urban society. Beyond being the immediate cause of the death of the injured, the development of multiple organ failure syndrome is a perilous complication of severe multiple and combined trauma. An experimental cranioskeletal trauma is known to be accompanied by internal organ dysfunction. Nonetheless, the development of organ dysfunction in terms of hypoxia resistance in the presence of cranioskeletal trauma remains insufficiently studied.The objective of research: to establish the dynamics of the functional state of the liver in the presence of cranioskeletal trauma, complicated by blood loss in rats with different hypoxia resistance in the early period of traumatic disease and evaluate the efficacy of Thiocetam in the correction of identified abnormalities.Material and methods: The experimental studies were conducted on 196 white non-linear male rats weighing 180-200g. Initially, an individual resistance to hypoxia of the rats was estimated, and the animals demonstrated high- and low- resistance value to hypoxia (HR and LR, respectively) were selected for the further study. The HR- and LR-rats were separately divided into 4 groups: control and three experimental once. In the first experimental groups the HR-and LR-animals were induced the cranioskeletal trauma under thiopental sodium anesthesia (40 mg·kg-1); the animals of the second experimental groups were inflicted the acute blood loss of 20-22% of circulating blood volume; in the third experimental groups, the HR and LR animals were subjected to an acute blood loss following the cranioskeletal trauma and administered the intraperitoneal injection of the Thiocetam at a dose of 250 mg·кg-1 of body weight once a day for correction. The bile excretion function of the liver was analyzed in the controls and experimental groups of animals 1, 3 and 7 days after trauma.The results and discussion. The conducted studies indicated the higher rate of bile excretion in the control group of LR-rats compared to the control of HR-rats. The rate of bile excretion was occurred decreased in both HR- and LR-rats under the influence of the cranioskeletal trauma. However, the degree of decrease in the studied parameter of the LR-rats was considerably greater than the corresponding value of the HR-rats. An additional blood loss model resulted in more marked abnormalities, particularly in the experimental group of LR-rats. The 7-day administration of Thiocetam led to the significant decrease in the abnormal bile excretion rate in the experimental groups of HR- and LR-rats compared to the animals without corrective medication. The analysis of deviation degree of the studied parameter in the animals administered Thiocetam in relation to the animals without correction evidenced better efficacy of the medication in the experimental group consisted of LR-rats compared to the group of HR-rats, especially under the conditions of additional acute blood loss model. Consequently, Thiocetam is able to compensate less-developed defense mechanisms of LR-rats compared to the HR-rats, which should be taken into consideration in real-life clinical practice settings in the comprehensive treatment of the injured with cranioskeletal trauma complicated by blood loss considering the possibility to determine their resistance to hypoxia.Conclusions. The rate of bile excretion as a basic indicator of the functional state of the liver in the intact LR-rats is found to be substantially higher than in HR-rats. The degree of decrease in the rate of bile excretion is significantly greater in LR-rats after 7 days of the post-traumatic period under the influence of cranioskeletal trauma complicated by acute blood loss. The administration of Thiocetam is accompanied by a marked positive effect on the rate of bile excretion in the HR- and LR-rats, but the degree of increase in the studied parameter is considerably greater in the experimental group of LR-rats.

Nifedipine Oral Disintegration Tablet: Design, Optimization, Invivo-pharmacokinetic and Stability Studies

Nifedipine has a bioavailability of 45-56 percent and a 2-hour elimination half-life. It has a 50 percent kidney excretion rate and a 5-15 percent bile excretion rate. The intention of this research is to invent and evaluate Nifedipine loaded ODT and to prove the enhancement of bioavailability. The 23 factorial optimization design exposed about the outcome of independent variable on dependent variable throughout the formulation of Nifedipine ODT. From the records, it was accomplished that there was a good correlation between Disintegration time, Dissolution rate and super disintegration concentration. The formulation F4 (Nifedipine ODT) has achieve the goal of ODT drug delivery with desired release characteristics, cost-effective, decreased dose, effective administration and hence improved patient compliance. The invivo pharmacokinetic studies reveals that increase in AUC0-∞; decrease in Tmax; increase in Cmax in Nifedipine ODT shows better bioavailability and faster duration of therapeutic action than marketed Nifilat® dosage form. Nifedipine ODT was stable at various temperature, humidity conditions and there was no drastic change in evaluation parameters. That it was concluded that Oral dispersible tablet (ODT) was a suitable dosage form to enhance the solubility at the same time the bioavailability of BCS class II drugs like Nifedipine.

Frozen Autoclaved Sorghum Enhanced Colonic Fermentation and Lower Visceral Fat Accumulation in Rats

As raw sorghum is not able to influence considerable colonic fermentation despite its higher resistant starch (RS) content, our study aimed to investigate the effects of frozen autoclaved sorghum on colonic fermentation. Fischer 344 rats were fed frozen cooked refined (S-Rf) and whole (S-Wh) sorghum diets and were compared against α-corn starch (CON) and high amylose starch (HAS) fed rats for zoometric parameters, cecal biochemical and microbiological parameters. Sorghum fed rats exhibited significantly lower feed intake and visceral adipose tissue mass compared to CON. Bacterial alpha diversity was significantly higher in the sorghum fed rats compared to HAS and the two sorghum fed groups clustered together, separately from HAS and CON in the beta diversity plot. Serum non-High Density Lipoprotein cholesterol and total cholesterol in S-Rf group were significantly lower compared to CON, while total fecal bile excretion was also significantly higher in the two sorghum fed groups. Lower visceral adiposity was correlated with lower feed intake, RS content ingested and cecal short chain fatty acid (SCFA) contents. Thus, higher RS inflow to the colon via frozen autoclaved sorghum might have influenced colonic fermentation of RS and the resultant SCFA might have influenced lower adiposity as manifested by the lower body weight gain.

INFLUENCE OF TWO-HOUR TOURNIQUETS ISCHEMIA OF LIMB AND ACUTE BLOOD LOSS ON SYSTEMIC DISORDERS OF THE BODY IN THE REPERFUSION PERIOD (EXPERIMENTAL STUDY)

The aim: to find out the effect of a two-hour tourniquets ischemia of the limb and acute blood loss on systemic disorders of the body in the postperfusion period. Materials and methods: The experiments were performed on 96 nonlinear male rats weighing 200-220 g. All experiments were performed under sodium thiopental anesthesia. In the first experimental group, two-hour tourniquets limb ischemia was simulated. In the second experimental group, acute blood loss was modeled. In the third experimental group, these lesions were combined. In 1 and 2 hours, as well as in 1, 7 and 14 days, the biliary function of the liver was determined in the experimental animals. Results: Two-hour tourniquets ischemia of the limb in the reperfusion period compared with the control was accompanied by a significant decrease in the rate of bile excretion, which reached a minimum value in 3 h – 1 day of the experiment and returned to the control level in 14 days. After the simulation of acute blood loss, the rate disturbance of bile excretion became significantly greater in all observation periods. The complication of acute ischemia-limb reperfusion caused a greater decrease in the rate of bile excretion with a maximum in 1 day of the experiment. Under these conditions, at 1, 7, and 14 days, the indicator was statistically significantly lower than in the other study groups. Conclusions: In the case of acute blood loss, complicated by two-hour tourniquets ischemia of the limb, the reperfusion period is accompanied by a summation of the negative impact of blood loss, ischemia and reperfusion of the limb on the functional state of the liver, which is a significant decrease in the rate of bile excretion with a maximum in 1 day, which further increases, but up to 14 days does not reach the level of control.