Novel SCN5A and GPD1L Variants Identified in Two Unrelated Han-Chinese Patients With Clinically Suspected Brugada Syndrome

Brugada syndrome (BrS) is a complexly genetically patterned, rare, malignant, life-threatening arrhythmia disorder. It is autosomal dominant in most cases and characterized by identifiable electrocardiographic patterns, recurrent syncope, nocturnal agonal respiration, and other symptoms, including sudden cardiac death. Over the last 2 decades, a great number of variants have been identified in more than 36 pathogenic or susceptibility genes associated with BrS. The present study used the combined method of whole exome sequencing and Sanger sequencing to identify pathogenic variants in two unrelated Han-Chinese patients with clinically suspected BrS. Minigene splicing assay was used to evaluate the effects of the splicing variant. A novel heterozygous splicing variant c.2437-2A>C in the sodium voltage-gated channel alpha subunit 5 gene (SCN5A) and a novel heterozygous missense variant c.161A>T [p.(Asp54Val)] in the glycerol-3-phosphate dehydrogenase 1 like gene (GPD1L) were identified in these two patients with BrS-1 and possible BrS-2, respectively. Minigene splicing assay indicated the deletion of 15 and 141 nucleotides in exon 16, resulting in critical amino acid deletions. These findings expand the variant spectrum of SCN5A and GPD1L, which can be beneficial to genetic counseling and prenatal diagnosis.

Metabolomic and Proteomic Analyses of Persistent Valvular Atrial Fibrillation and Non-Valvular Atrial Fibrillation

Atrial fibrillation (AF) is an abnormal heart rhythm related to an increased risk of heart failure, dementia, and stroke. The distinction between valvular and non-valvular AF remains a debate. In this study, proteomics and metabolomics were integrated to describe the dysregulated metabolites and proteins of AF patients relative to sinus rhythm (SR) patients. Totally 47 up-regulated and 41 down-regulated proteins in valvular AF, and 59 up-regulated and 149 down-regulated proteins in non-valvular AF were recognized in comparison to SR patients. Moreover, 58 up-regulated and 49 significantly down-regulated metabolites in valvular AF, and 47 up-regulated and 122 down-regulated metabolites in persistent non-valvular AF patients were identified in comparison to SR patients. Based on analysis of differential levels of metabolites and proteins, 15 up-regulated and 22 down-regulated proteins, and 13 up-regulated and 122 down-regulated metabolites in persistent non-valvular AF were identified relative to valvular AF. KEGG pathway enrichment analysis showed the altered proteins and metabolites were significantly related to multiple metabolic pathways, such as Glycolysis/Gluconeogenesis. Interestingly, the enrichment pathways related to non-valvular AF were obviously different from those in valvular AF. For example, valvular AF was significantly related to Glycolysis/Gluconeogenesis, but non-valvular AF was more related to Citrate cycle (TCA cycle). Correlation analysis between the differentially expressed proteins and metabolites was also performed. Several hub proteins with metabolites were identified in valvular AF and non-valvular AF. For example, Taurine, D-Threitol, L-Rhamnose, and DL-lactate played crucial roles in valvular AF, while Glycerol-3-phosphate dehydrogenase, Inorganic pyrophosphatase 2, Hydroxymethylglutaryl-CoAlyase, and Deoxyuridine 5-triphosphate nucleotidohydrolase were crucial in non-valvular AF. Then two hub networks were recognized as potential biomarkers, which can effectively distinguish valvular AF and non-valvular persistent AF from SR samples, with areas under curve of 0.75 and 0.707, respectively. Hence, these metabolites and proteins can be used as potential clinical molecular markers to discriminate two types of AF from SR samples. In summary, this study provides novel insights to understanding the mechanisms of AF progression and identifying novel biomarkers for prognosis of non-valvular AF and valvular AF by using metabolomics and proteomics analyses.

Differential expression of glycerol-3-phosphate dehydrogenase 1 in cancers of the breast.

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding glycerol-3-phosphate dehydrogenase 1, GPD1, when comparing primary tumors of the breast to the tissue of origin, the normal breast. GPD1 mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of GPD1 in primary tumors of the breast was correlated with recurrence-free survival in patients with normal-like subtype cancer, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by PAM50 molecular subtype. GPD1 may be of relevance to initiation, maintenance or progression of cancers of the female breast.

Differential expression of GPD1L in cancer of the vulva.

In these brief notes we document work using published microarray data (1, 2) to pioneer integrative transcriptome analysis comparing vulvar carcinoma to its tissue of origin, the vulva. We report the differential expression of glycerol-3-phosphate dehydrogenase 1-like, encoded by GPD1L, in cancer of the vulva. GPD1L may be of pertinence to understanding transformation and disease progression in vulvar cancer (3).

Decreased serum levels of glycerol-3- phosphate dehydrogenase 1 and monoacylglycerol lipase act as diagnostic biomarkers for breast cancer

BACKGROUND: Breast cancer (BC) is one of the most life-threatening cancer types among women. Despite major developments in medical sciences and technologies, the incidence and mortality rates of BC cases are still increasing. One of the reasons for this increase is the absence of an easy to perform early-diagnostic tool. Although there are defined BC biomarkers routinely used for diagnostic and prognostic purposes, none of these biomarkers is useful for early diagnosis. Therefore, early diagnosis of BC remains an important challenge and there is a great need for the early-diagnostic biomarker(s). OBJECTIVE: In this study, we aimed to evaluate the diagnostic and prognostic values of glycerol-3-phosphate dehydrogenase (GPD1) and monoacylglycerol lipase (MAGL) proteins as non-invasive serum biomarkers. METHODS: GPD1 and MAGL serum levels were determined by ELISA for BC patients (n= 100) from five different subtypes, and healthy controls (n= 20), and a comparative analysis was performed to determine statistically significant expression differences among the groups. RESULTS: The results provided evidence that GPD1 acted as a diagnostic biomarker in distinguishing triple-negative breast cancer (TNBC) patients from other subtypes, and MAGL acted as a diagnostic biomarker in distinguishing healthy individuals from BC patients. CONCLUSION: GPD1 and MAGL might be proposed as non-invasive diagnostic biomarkers for BC with high sensitivity and specificity.

Antileishmanial Potential of Berberine Alkaloids From Berberis glaucocarpa Roots: Molecular Docking Suggests Relevant Leishmania Protein Targets

Leishmaniases are a spectrum of poverty-linked neglected parasitic diseases that are endemic in 88 countries around the globe and affect millions of people every year. Currently available chemotherapeutic options are inadequate due to side effects, high cost, prolonged treatment, and parasite resistance. Thus, there is an existing need to develop new potent and safer leishmanicidal drugs. Considering the folkloric antiulcer and leishmanicidal use of the genus Berberis and its alkaloids, 5 reported alkaloids, namely berberine (1), palmatine (2), columbamine (3), 8-trichloromethyldihydroberberine (4), and jatrorrhizine (5), were isolated from the roots of Berberis glaucocarpa using classical (column and preparative chromatography) and modern isolation techniques (Sephadex LH-20). Their structures were elucidated and established from 1D and 2D spectroscopic data. The isolated alkaloids displayed excellent antileishmanial potential with IC50 values ranging from 1.50 to 2.56 µM: 1 (1.50 ± 0.53 µM), 2 (2.31 ± 0.37 µM), 3 (2.56 ± 0.48 µM), 4 (1.40 ± 0.90 µM), 5 (2.44 ± 1.34 µM). While the IC50 value for the standard drug (Amphotericin-B) was found to be 1.08 ± 0.95 µM. All of the isolated alkaloids displayed excellent antileishmanial potential as well as minimal cytotoxicity against THP-1 monocytic cells. Molecular docking analysis has revealed Leishmania N-myristoyl transferase, methionyl-tRNA synthetase, pteridine reductase 1, oligopeptidase B, tyrosyl-tRNA synthetase, and/or glycerol-3-phosphate dehydrogenase to be potential protein targets for the alkaloids.

Chemical and biological investigations of Limonium axillare reveal mechanistic evidence for its antidiabetic activity

Root and bark of Limonium axillare (Forssk) Kuntze are used as antidiabetic remedies in parts of East Africa, but this activity has never been fully investigated. To validate its ethnobotanical use, we compared the chemical and pharmacological profiles of the ethanolic extracts of L. axillare root (REE) and aerial parts (AEE). Administration of REE (500 mg kg-1) reduced streptozotocin-induced hyperglycemia by 44%, restored serum insulin levels, reestablished Glut2 and Glut4 expression and ameliorated pancreatic tissue damage in diabetic rats. In vitro studies revealed a strong radical scavenging effect, α-glucosidase, and α-amylase inhibition activity of REE at IC50 at 25.2, 44.8 and 89.1μg/mL, respectively. HPLC analysis identified ten phenolic compounds in REE with umbelliferone as the major constituents at 10 ± 0.081 mg/g of extract. Additionally, six compounds were isolated from REE including, β-sitosterol-3-palmitate, β-sitosterol, myricetin and gallic acids with two new tetrahydrofuran monoterpenes; 2-isopropyl- 3,4,4, trimethyl-tetrahydrofuran (3), and 2-isopropyl-4-methyl-tetrahydrofuran-3,4 dicarboxylic acid (4), the latter was revealed by molecular docking to be a good ligand to glycerol-3-phosphate dehydrogenase a key enzyme in glycolysis.

Effect of Sake Lees on the Inhibition of Lipid Accumulation in Adipocytes

Recent lifestyle changes, such as the Westernization of diets and the rise in the prevalence of obesity, with an associated increase in the number of patients with lifestyle-related diseases, have become a social issue. Fermented food has attracted attention as a solution to problems caused by obesity. Sake lees, a byproduct of sake brewing, represent one such food that is expected to have health benefits. In this study, we investigated the effects of sake lees components on preadipocytes (3T3-L1). We cultured preadipocytes in a medium with indigestible sake lees components (ISLCs) to investigate lipid accumulation, analyzed the glycerol 3-phosphate dehydrogenase (GPDH) and LPL activities of those cells, and performed a real-time PCR analysis of the IL6 expression in the cells. The results show that lipid accumulation and GPDH activity were significantly decreased in adipocytes treated with 1.0 mg/mL ISLCs compared to untreated cells. Furthermore, the expression of IL6 in adipocytes treated with 1.0 mg/mL ISLCs was significantly decreased and the lipase activity was significantly increased in adipocytes treated with ISLCs after differentiation. IL6 is known to have multiple functions in adipose tissue. In conclusion, ISLCs were associated with reduced lipid accumulation in adipocytes, with effects on IL6 expression and LPL activity observed throughout the differentiation period.

Effects of Baccharin Isolated from Brazilian Green Propolis on Adipocyte Differentiation and Hyperglycemia in ob/ob Diabetic Mice

Propolis is a honeybee product with various biological activities, including antidiabetic effects. We previously reported that artepillin C, a prenylated cinnamic acid derivative isolated from Brazilian green propolis, acts as a peroxisome proliferator-activated receptor γ (PPARγ) ligand and promotes adipocyte differentiation. In this study, we examined the effect of baccharin, another major component of Brazilian green propolis, on adipocyte differentiation. The treatment of mouse 3T3-L1 preadipocytes with baccharin resulted in increased lipid accumulation, cellular triglyceride levels, glycerol-3-phosphate dehydrogenase activity, and glucose uptake. The mRNA expression levels of PPARγ and its target genes were also increased by baccharin treatment. Furthermore, baccharin enhanced PPARγ-dependent luciferase activity, suggesting that baccharin promotes adipocyte differentiation via PPARγ activation. In diabetic ob/ob mice, intraperitoneal administration of 50 mg/kg baccharin significantly improved blood glucose levels. Our results suggest that baccharin has a hypoglycemic effect on glucose metabolic disorders, such as type 2 diabetes mellitus.