Month: September 2020

The exact mechanism of acute kidney injury remains elusive, but it is believed that uric acid serves as an antioxidant, and in states of hypouricaemia this protective role is lost. Kaneko et al. demonstrated in a 15 year old girl with idiopathic renal hypouricaemia an oxidative imbalance soon after exercise with a predisposition to exercise-induced acute renal failure. In contrast, some patients may present with more minor renal features including nephrolithiasis or hematuria. In 2002, Enomoto et al. established that URAT1 transporter was responsible for tubular reabsorption of urate. SLC22A12 encodes the protein URAT1 and loss of function mutations are responsible for majority of patients with idiopathic renal hypouricaemia. The W258X variant of URAT1 is a typical mutation found in Japanese and Korean populations. R428 allele frequency of W258X in the general population in Japan was found to be as high as 1.9%. Heterozygous carriers of URAT1 mutations are usually asymptomatic but they may develop nephrolithiasis. Prevalence of hypouricaemia in Japan varies between 0.15% and 0.23% from the analysis of serum urate levels in 1730 school children. In Korea, the prevalence of hypouricaemia in healthy adults is 3.3%. Therefore, school-age children who plan to performing competitive sporting activities are advised to have their serum uric acid level checked. Loss of function mutations affecting URAT1 have not been previously reported in a Caucasian population. However, single case reports from European patients presenting with clinical and biochemical features of hereditary renal hypouricaemia exist. Tzovaras et al. tested nine Greek subjects with primary renal hypouricaemia. All had serum uric acid levels,2.5 mg/dl, associated with a FEurate.10% and no other known cause of hypouricaemia. No definite pathogenic mutations were detected in this series and just one silent polymorphism in exon 2 of the SLC22A12 gene was noted. It is questionable why hereditary renal hypouricaemia is apparently so rare in Caucasian populations. Either the prevalence of URAT1 mutations is indeed low in this population, or a decreased awareness of this disease and its presentation outside of the Far East allows cases to go undetected. Even in Japan, there are patients who have clinical features of renal hypouricaemia but no SLC22A12 mutations. Very recently, a genome-wide association study was performed in 6890 African Americans and 21708 European participants in order to try and identify risk alleles for elevated serum urate, associated with gout. A novel URAT1 variant was identified and was associated with a reduction in serum urate of around 1.2 mg/dl per copy of the minor allele. Urate transport studies demonstrated a reduction in the urate transport for the G65W URAT1 variant. This study validates heterozygous changes within URAT1 as a determinate of reduced serum urate levels. In this study the variant allele provided a protective affect against gout, but one may postulate that this may also be an at-risk allele for the hypouricaemia. Both biochemically and clinically, a single heterozygous change in URAT1 may be significant. Cheong et al. reported a W258X homozygous mutation in a 7 year old child.

In conclusion, we have identified Macedonian and British patients with hypouricaemia, who presented with symptoms including renal stone disease and haematuria. We have identified missense mutations in VE-821 1232410-49-9 SLC22A12 encoding URAT1. This data highlights the importance of renal urate transporters in determining serum urate concentrations and the of clinical phenotypes that should lead the clinician to suspect an inherited form of renal hypouricaemia. Cancer is caused by an accumulation of mutations, often in a subset of genes that confer survival and growth advantage. The protein kinase gene family, which controls key signaling pathways associated with cell growth and survival, is one of the most overrepresented families of oncogenes. Targeted sequencing of 518 protein kinase exons encoded in the human genome has revealed hundreds of mutations in the protein kinase domain. Although these mutations are currently catalogued in various databases, identification and experimental characterization of key cancer-causing mutations is essential for developing new therapies for cancer. Experimental characterization of cancer mutations, however, requires that one first formulate the right hypotheses based on analysis of existing data. In particular, analysis of mutation data in light of other forms of data available on protein kinases such as sequence, structure, function and pathway is necessary to develop and test new hypotheses regarding the functional impact of cancer mutations. Integrative analysis of protein kinase data, however, is a challenge because of the disparate nature of protein kinase data sources and formats. For example, a researcher interested in the structural location of a cancer mutation, or distribution of kinase mutations in various cancer types, has to go through the time-consuming and error prone process of collecting and parsing data from disparate sources, often in different data formats. Although several kinase-specific resources such as KinBase, KING, PKR and KinMutBase have been developed, these resources largely focus on one, or few types, of protein kinase data, leaving aside the challenge of data integration. Ontologies have emerged as a powerful tool for integrative and quantitative analysis of biological data. By capturing domain knowledge in the form of concepts and relationships, ontologies provide a conceptual representation of data in a way that computers can read and humans can understand. For example, for an automated and informed response to the query “kinase mutations associated with cancer types”, the computer needs to understand the concepts, “kinase mutations” and “cancer types”, and the relationships between the concepts, namely, “associated with”. It is this conceptual representation of knowledge that distinguishes ontologies from relational databases, and enables efficient integration and mining of diverse data sets. Indeed, several ontologies have been developed to capture and mine the wealth of information on genes, sequence, pathways, protein modification and others. Focused ontologies on selected protein families such as the protein phosphatase family and transporter family have also been developed. However, up until now, a focused ontology capturing the state of knowledge on the protein kinase family has not been reported.

mTOR is also among the effectors of the Wnt signaling pathway, Accelerated hepatic lipogenesis is commonly observed in a number of metabolic disorders, including insulin resistance, metabolic syndrome and T2D. The increase in lipogenesis is another mechanism by which HFD consumption leads to obesity and diabetes. ChREBP and SREBP-1c are two key transcription factors for genes that encode lipogenic enzymes. Very little is known about the effect of curcumin on hepatic lipogenesis, although a recent study showed that in adipocytes curcumin inhibits fatty acid synthase. We found that curcumin reduced liver weight and intra-hepatic lipid content. More importantly, dietary curcumin was shown to repress SREBP-1c and ChREBP expression. This, along with the repression of L-PK by curcumin and the in vitro ChREBP LUC reporter analysis, suggest that inhibition of ChREBP expression and function are among the mechanisms by which this dietary component prevents obesity and its associated metabolic defects. It should also be pointed out that curcumin can block cardiac hypertrophy and the implicated underlying mechanism was the repression of p300-HAT activity and hence the inhibition of p300 acetylation of certain transcription factors. ChREBP was found to require p300 or CBP as a co-factor in stimulating the expression of TxNIP. We found here that TxNIP protein and mRNA expression in curcumin fed mice was also reduced. It remains to be determined whether p300 inhibition is among the mechanisms by which curcumin reduces the expression of L-PK and other targets of ChREBP. Together, our observations confirm that curcumin improves insulin signaling, glucose disposal, and blocks obesity during HFD consumption. Our data confirm that in this chronic HFD feeding model, the function of curcumin is mediated via increasing the capability of the animals in anti-oxidative stress and attenuating inflammatory response in adipocytes. Furthermore, in mature adipocytes, this appears occur independent of Wnt activation as curcumin did not activate Wnt pathway components or Wnt downstream target genes. Finally, we revealed the repressive effect of curcumin on hepatic lipogeneis, associated with the inhibition of ChREBP and SREBP-1c expression. Further investigation is required to determine whether the repressive property of curcumin on p300/CBP is additionally involved in reducing hepatic lipogenesis. Thus, the development of curcumin as a therapy for obesity, insulin CHIR-99021 GSK-3 inhibitor resistance and T2D is supported. The elderly population forms a precarious group characterized by multimorbidity, frailty and polypharmacy, leading to more complex care. Studies have shown that elderly patients do not receive the care that is known to be appropriate for them. It is postulated that there is much room for improvement of the quality of care for this group. Efforts have been made to explore where, when and for which conditions quality deficiencies exist in order to know where improvements are needed. Measurement sets like HEDIS, with 75 measures across eight domains of care, have been developed to assist in assessing the quality of care. In addition criteria such as the Beers criteria were suggested to map the use of inappropriate medication for the elderly. The Assessing Care of Vulnerable Elders quality indicator set was developed in the year 2000 by Rand Healthcare.

Since some ApoE4 carriers do not develop AD even at a great age, other factors, such as amylin, may interact with ApoE4 to influence AD development. High plasma levels of amylin were associated with obesity and type 2 diabetes, as well as with other biomarkers of metabolic syndrome and cerebrovascular disease including low HDL levels, high creatinine levels, and non-linear increased levels of cholesterol and LDL. These data suggest a relationship between amylin Nutlin-3 resistance, obesity, and type 2 diabetes, which is consistent with findings in other studies . Amylin was independently associated with Ab even after adjusting for these biomarkers of metabolic syndrome. Since amylin is cleared by the kidney, the relationship between plasma amylin and Ab, especially Ab1-40, was influenced by adding creatinine to the models. Amylin’s major role in the brain is to reduce food intake thereby controlling body weight and regulating glucose metabolism. Administering exogenous amylin, either peripherally or intracerebroventricularly, results in reduced appetite and food intake. Pramlintide, an amylin analog differing by three amino acids, is an effective and well-tolerated drug in clinical use for the treatment of diabetes . Given the effectiveness of the amylin class of peptides in reducing amyloid pathology in the brain in the preclinical study and the relationship between amylin and Ab in the context of ApoE allele seen in this human study, pramlintide may have potential as a treatment in AD. A clinical trial of pramlintide in AD, an off-label use, may be warranted. Limitations of our study are its cross-sectional design and lack of brain imaging. Longitudinal studies are needed to confirm the causal relationship between high levels of plasma amylin and decreased Abdeposition in the brain. There were no diagnoses of AD and mild cognitive impairment for this population based study. Future studies are necessary to examine the concentrations of amylin and its relationship to Ab in specific diagnostic groups. Gastric cancer is the second most frequent cause of death from cancer in the world. Thus far, few tumor suppressor genes and tumor-related genes have been reported in GC. Although extensive studies have been performed to identify genetic pathways and mechanisms involved in cancer development, few improvements on the early diagnosis of cancer have been made. MicroRNAs are endogenous small noncoding RNAs that have been identified as posttranscriptional regulators of gene expression. Previous studies have indicated that miRNAs exert their functions through imperfect base-pairing with the 39untranslated region of target mRNAs and miRNAs have been extensively studied in the context of cell cycle regulation, differentiation, development and apoptosis. Accumulated evidence indicates that miRNAs are deregulated in various diseases, especially in cancer. For example, miR-216b is markedly down-regulated in nasopharyngeal carcinoma; miR340 is deregulated in breast cancer and can inhibit breast cancer cell migration and invasion.

However, none of the reference genes discovered thus far is consistently expressed in a universal and invariant way under various experimental conditions, and recent reference gene selection studies indicate that a single reference gene is generally insufficient to normalize the expression data of all target genes. In insect, the reference genes have been validated at least in the desert locust Schistocerca gregaria, the oriental fruit fly Bactrocera dorsalis, the fruit fly Drosophila melanogaster emerald ash borer Agrilus planipennis, the diamondback moth Plutella xylostella, the tobacco whitefly Bemisia tabaci, and the red imported fire ant, Solenopsis invicta under a diverse set of biotic and abiotic conditions. However, no one single universal reference was identified, either. Therefore, it is not surprising that no single universal reference is available for four different lepidopteran insect species. In this context, reliable reference genes for gene expression analysis based on different experimental conditions should be selected. The tobacco whitefly, B. tabaci, is an invasive insect pest of agriculture and horticulture worldwide. Because of the application of chemical insecticides has been the MK-4827 primary strategy for the control of B. tabaci, this pest has developed different levels of resistance to a wide range of insecticides. It has been well documented that insecticide resistance in B. tabaci usually is associated with enhanced detoxification by oxidative and hydrolytic pathways. Therefore, increasing numbers of studies are using the RT-qPCR techniques to detect the changes of mRNA expression of detoxifying enzymes genes in resistant populations and tried to provide new insights into insecticides resistance mechanisms. Though the suitable references genes has been documented in bacterially challenged bees, in Tribolium beetles infected with fungus, in plant virus infected B. tabaci and in Bt toxin treated P. xylostella, this kind of information is lacking for insects stressed by different types of chemical insecticides. In this study, a set of reliable reference genes for gene expression analysis in the B. tabaci biotype Q, one of the most invasive and destructive pest in the world, after exposure to eight commonly used insecticides was selected and then valuated with two target genes, a P450 gene and glutathione S-transferase gene. Over expression of the P450 has been proved to be responsible for neonicotinoid insecticides resistance in B. tabaci while this is not the case for GST. The objective of this work is to provide a set of universal reliable reference genes for research of genes with toxicological function in B. tabaci. There exists no doubt that the qRT-PCR technology has made the quantitative determination of gene expression more convenient than ever before. However, extreme care must be taken for the selection of internal reference genes before their application of qRT-PCR. It has been documented that the selection of suitable reference genes is very important to obtain reliable and accurate data.