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The osteoclast is a giant cell that resorbs calcified matrix by secreting acids and collagenolytic enzymes. The molecular mechanisms underlying metabolic adaptation to the increased biomass and energetic demands of osteoclastic bone resorption remain elusive. Here we show that during osteoclastogenesis the expression of both glucose transporter 1 (Glut1) and glycolytic genes is increased, whereas the knockdown of hypoxia-inducible factor 1-alpha (Hif1), as well as glucose deprivation, inhibits the bone-resorbing function of osteoclasts, along with a suppression of Glut1 and glycolytic gene expression. Furthermore, the expression of the glutamine transporter solute carrier family 1 (neutral amino acid transporter), member 5 (Slc1a5) and glutaminase 1 was increased early in differentiation, and a depletion of L-glutamine or pharmacological inhibition of the Slc1a5 transporter suppressed osteoclast differentiation and function. Inhibition of c-Myc function abrogated osteoclast differentiation and function, along with a suppression of Slc1a5 and glutaminase 1 gene expression. Genetic and pharmacological inhibition of mammalian target of rapamycin (mTOR), as well as the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), inhibited osteoclastogenesis. Thus, the uptake of glucose and glutamine and utilization of the carbon sources derived from them, coordinated by HIF1 and c-Myc, are essential for osteoclast development and bone-resorbing activity through a balanced regulation of the nutrient and energy sensors, mTOR and AMPK.

Method: This was a case - control study. Case was 50 Indonesian origin children with ADHD and without any other mental disorders and metal retardation. Control is Indonesian origin children without ADHD, other mental disorders and mental retardation. ADHD diagnosis was taken after doing the psychiatric interview and observation based on the DSM-IV TR diagnostic criteria for ADHD at the Child and Adolescent Psychiatry Out-patient Clinic, Dr. Cipto Mangunkusumo National Referral Hospital - Faculty of Medicine Universitas Indonesia. DNA isolation, DNA purity and concentration were measured. PCR was done by using a primer based on Homo sapiens solute carrier family 6 (neurotransmitter transporter), member 3 (SLC6A3), RefSeq Gene on chromosome 5 with accession number NG_015885.1. To identify the serial of repeated allele, we used the sequencing technique.

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As a hydrophilic base existing at physiological pH as a cationic species (> 99.9%), the effectiveness of metformin pharmacokinetics depends on the function of the transporters involved [8]. One of the major transporters known to play an important role in metformin pharmacokinetics to date is Organic Cation Transporter 1 (OCT1), a protein mainly expressed in liver sinusoidal cells, renal basolateral membrane [9], and apical membrane of tubule cells [10], which transports metformin to hepatocytes as the target of its antihyperglycemic action as well as plays a part in the elimination and reabsorption in the renal tubules. Variations in SLC22A1 gene have led to changes in the function of OCT1 protein, which results in varied plasma concentrations of metformin and decreased amount of metformin in the receptors, making the therapeutic response to metformin decline. Such genetic variations can take the form of methionine deletion at codon 420 located in the ninth transmembrane domain of SLC22A1, which is the highest functional variant in the gene. Several studies have found that SLC22A1 gene variants cause variability in both steady-state concentrations of metformin and glycemic response [11], [12], [13], [14]. Also, recent research showed that genetic variations in the gene are related to the level of gastrointestinal intolerance due to the use of metformin [15], [16].

Despite being performed only on experimental animal models, there were no differences in the expression of OCT1 in renal cells based on gender [25], [26]. Therefore, the difference in sex-type proportions in a pharmacogenomics study involving OCT1 transporters can be ignored, or no matching technique is needed in the data analysis for this patient-factor.

Several studies have been conducted to analyse the association of genetic variation in the SLC22A1 gene with its effects, such as the variability of expression, disposition, and therapeutic response of a drug. A study of liver tissue samples from subjects of the Caucasian population identified the genetic variation as a critical factor of OCT1 hepatic expression [27]. This could lead to changes in the function of OCT1 as a protein transporter for several drugs that have liver as the action target, such as metformin. Expert studies of OCT1 distribution showed that such protein is found in the stomach, small intestine, kidney, and skeletal muscles in human, and is mainly expressed through the liver [28], [29]. Although early studies reported that OCT1 is found in the basolateral membrane [30], some other studies reported that the apical surface of intestinal epithelial cells also becomes the location of OCT1 [31], [32], [33]. To date, studies of the reduced function of OCT1 transporter in the intestine has been more associated with the level of gastrointestinal intolerance of metformin use because of the possibly higher effect on increasing local concentrations of metformin in the intestine (lumen and enterocytes) when compared to the level of metformin transported to the blood [15]. Thus, genetic variation in SLC22A1 as an OCT1 encoding gene affects not only the absorption of metformin but also the function of OCT1 involved during the distribution to hepatocytes as the primary action target of such antidiabetic drug as well as during the reabsorption in the renal tubules. This analysis has been justified in several studies that found the effects of polymorphism on the pharmacokinetic and pharmacodynamic variability of metformin.

Methionine deletion at codon 420 (Met420del) located in the ninth transmembrane region of the SLC22A1 gene, the polymorphism target of this research, has been the most commonly studied functional variant. In contrast to the majority of other functional SLC22A1 variants that are population specific, the Met420 deletion can be found in some populations in different regions in the world [34], [35], [36], [37]. Such polymorphism causes a decrease in the activity of metformin transporter, leading to a reduced antihyperglycemic response [38]. This is also proven by a study of 20 healthy subjects receiving metformin as much as 1850 mg/day that indicates the presence of polymorphism, one of which is Met420del, causing the variant allele group to have higher AUC of plasma metformin concentration but lower volume of distribution in oral administration compared to the wild-type group [39]. Therefore, the metformin concentration transported to the hepatocytes as its action target is reduced, resulting in a decreased antihyperglycemic response [24]. Also, a study of 108 Iranian patients newly diagnosed T2DM and using metformin for 12 weeks also showed that the Met420del variant causes lower FBG reduction compared to the wild-type group [20]. Other studies also found a variation in the scores of metformin clearance in the kidney and the metformin uptake to the liver which will eventually affect blood glucose levels followed by an effect on the appropriate dose to administer to T2DM patients [37], [40]. In contrast, the research involving 1531 patients in GoDART study revealed that 420del does not affect A1C reduction in T2DM patients receiving metformin [41]. These contradictory differences require further research using more improved methods.

Also, although contradictory findings remain to appear, particularly related to the effect of Met420del polymorphism in SLC22A1 gene on the glycemic response to metformin and gastrointestinal intolerance, the high frequency of mutant alleles in Javanese-Indonesian population requires further research. This is in line with the minimum involvement of the Indonesian population in the development of new drugs. Additionally, OCT1 is also an important transporter for several other drugs. Therefore, further studies of pharmacokinetic variability and therapeutic response to the use of other drugs that also require OCT1 in their pharmacokinetics, such as oxaliplatin, sorafenib, and lamivudine, are recommended [27], [45].

DHL Express has expanded its electric fleet in Indonesia with 24 electric transporter vans. The new electric delivery vans will be used in the capital Jakarta and in Bandung. The delivery fleet is also to be electrified beyond this.

One of the causes of zinc deficiency is decreased zinc intake or impaired absorption of zinc which causes zinc bioavailability to decrease in the blood. Phytate is one of the compounds found in food that can interfere with zinc absorption in the human digestive system. The formation of a zinc complex with phytate affects zinc absorption through the human ZiP transporter (hZiP). Sea cucumber has also long been used as a dietary supplement in the East Asian region which helps maintain body health. However, there has not been much research on the potential of sea cucumber metabolites as phytate inhibitors that inhibit zinc absorption in the digestive system. The result obtained from molecular docking is that sea cucumber metabolite has the potential to inhibit the binding of phytates in ZiP2 and ZiP4 membrane proteins that act as zinc transporters from extracellular to intracellular. The metabolites in sea cucumber that have the potential as phytate inhibitors in the ZiP2 membrane protein are Holothurin, Arguside, Miliariside, Nobiliside, and Virescenoside. In the smoldering protein ZiP4, the six compounds also have the potential to inhibit phytate. Based on the molecular docking analysis, holothurin has potency as a phytate inhibitor, evidenced by binding energy and conformation in the binding site. Visualization analysis described that the holothurin precisely binds in phytate binding site in protein receptor. In addition, literature reported, that holothurin has potency as antiviral, antibacterial, and anticancer. The sea cucumber with active metabolites is one of the important marine commodities for maintaining human health and supplementation nutrition. e24fc04721