Variability of urinary albumin to creatinine ratio and eGFR are independently associated with eGFR slope in Japanese with type 2 diabetes: a three-year, single-center, retrospective cohort study.

BACKGROUND: To evaluate the seasonal variability of urinary albumin to creatinine ratio (UACR) and eGFR and these effects on three-year eGFR slope in persons with type 2 diabetes (T2D). METHODS: A total of 1135 persons with T2D were analyzed in this single-center, retrospective cohort study in Japan. The standard deviation (SD) of UACR (SD [UACR]) and SD of eGFR (SD [eGFR]) were calculated for each person's 10-point data during the three years, and a multiple linear regression analysis was performed to evaluate associations with eGFR slope. A sensitivity analysis was performed in a group with no medication changes (n = 801). RESULTS: UACR exhibited seasonal variability, being higher in winter and lower in spring, early summer, and autumn especially in the UACR ≥ 30 mg/g subgroup, while eGFR showed no seasonal variability. The eGFR slope was significantly associated with SD (eGFR) (regression coefficient -0.170 [95% CI -0.189--0.151]) and SD (UACR) (0.000 [-0.001-0.000]). SGLT-2 inhibitors, baseline eGFR, and baseline systolic blood pressure (SBP) were also significantly associated. These associated factors, except baseline SBP, were still significant in the sensitivity analysis. CONCLUSIONS: The UACR showed clear seasonal variability. Moreover, SD (UACR) and SD (eGFR) were independently associated with a three-year eGFR slope in persons with T2D. TRIAL REGISTRATION: This study was not registered for clinical trial registration because it was a retrospective observational study.

Plantainoside B in Bacopa monniera Binds to Aß Aggregates Attenuating Neuronal Damage and Memory Deficits Induced by Aß.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by dementia. The most characteristic pathological changes in AD brain include extracellular amyloid-ß (Aß) accumulation and neuronal loss. Particularly, cholinergic neurons in the nucleus basalis of Meynert are some of the first neuronal groups to degenerate; accumulating evidence suggests that Aß oligomers are the primary form of neurotoxicity. Bacopa monniera is a traditional Indian memory enhancer whose extract has shown neuroprotective and Aß-reducing effects. In this study, we explored the low molecular weight compounds from B. monniera extracts with an affinity to Aß aggregates, including its oligomers, using Aß oligomer-conjugated beads and identified plantainoside B. Plantainoside B exhibited evident neuroprotective effects by preventing Aß attachment on the cell surface of human induced pluripotent stem cell (hiPSC)-derived cholinergic neurons. Moreover, it attenuated memory impairment in mice that received intrahippocampal Aß injections. Furthermore, radioisotope experiments revealed that plantainoside B has affinity to Aß aggregates including its oligomers and brain tissue from a mouse model of Aß pathology. In addition, plantainoside B could delay the Aß aggregation rate. Accordingly, plantainoside B may exert neuroprotective effects by binding to Aß oligomers, thus interrupting the binding of Aß oligomers to the cell surface. This suggests its potential application as a theranostics in AD, simultaneously diagnostic and therapeutic drugs.

Genetic and Functional Analyses of Patients with Marked Hypo-High-Density Lipoprotein Cholesterolemia.

AIM: This study aimed to analyze two cases of marked hypo-high-density lipoprotein (HDL) cholesterolemia to identify mutations in ATP-binding cassette transporter A1 (ABCA1) and elucidate the molecular mechanism by which these novel pathological mutations contribute to hypo-HDL cholesterolemia in Tangier disease. METHODS: Wild type and mutant expression plasmids containing a FLAG tag inserted at the C-terminus of the human ABCA1 gene were generated and transfected into HEK293T cells. ABCA1 protein expression and cholesterol efflux were evaluated via Western blotting and efflux assay. The difference in the rate of change in protein expression was evaluated when proteolytic and protein-producing systems were inhibited. RESULTS: In case 1, a 20-year-old woman presented with a chief complaint of gait disturbance. Her HDL-C level was only 6.2 mg/dL. Tangier disease was suspected because of muscle weakness, decreased nerve conduction velocity, and splenomegaly. Whole-exome analysis showed compound heterozygosity for a W484* nonsense mutation and S1343I missense mutation, which confirmed Tangier disease. Cholesterol efflux decreased by a mixture of W484* and S1343I mutations. The S1343I mutation decreased the protein production rate but increased the degradation rate, decreasing the protein levels. This patient also had Krabbe disease. The endogenous ABCA1 protein level of macrophage cell decreased by knocking down its internal galactocerebrosidase.Case 2, a 51-year-old woman who underwent tonsillectomy presented with peripheral neuropathy, corneal opacity, and HDL-C of 3.4 mg/dL. Whole-exome analysis revealed compound heterozygosity for R579* and R1572* nonsense mutations, which confirmed Tangier disease. CONCLUSION: Case 1 is a new ABCA1 mutation with complex pathogenicity, namely, a W484*/S1343I compound heterozygote with marked hypo-HDL cholesterolemia. Analyses of the compound heterozygous mutations indicated that decreases in ABCA1 protein levels and cholesterol efflux activity caused by the novel S1343I mutation combined with loss of W484* protein activity could lead to marked hypo-HDL cholesterolemia. Galactocerebrosidase dysfunction could also be a potential confounding factor for ABCA1 protein function.

Identification of key microRNAs regulating ELOVL6 and glioblastoma tumorigenesis.

ELOVL fatty acid elongase 6 (ELOVL6) controls cellular fatty acid (FA) composition by catalyzing the elongation of palmitate (C16:0) to stearate (C18:0) and palmitoleate (C16:1n-7) to vaccinate (C18:1n-7). Although the transcriptional regulation of ELOVL6 has been well studied, the post-transcriptional regulation of ELOVL6 is not fully understood. Therefore, this study aims to evaluate the role of microRNAs (miRNAs) in regulating human ELOVL6. Bioinformatic analysis identified five putative miRNAs: miR-135b-5p, miR-135a-5p, miR-125a-5p, miR-125b-5p, and miR-22-3p, which potentially bind ELOVL6 3'-untranslated region (UTR). Results from dual-luciferase assays revealed that these miRNAs downregulate ELOVL6 by directly interacting with the 3'-UTR of ELOVL6 mRNA. Moreover, miR-135b-5p and miR-135a-5p suppress cell proliferation and migration in glioblastoma multiforme cells by inhibiting ELOVL6 at the mRNA and protein levels. Taken together, our results provide novel regulatory mechanisms for ELOVL6 at the post-transcriptional level and identify potential candidates for the treatment of patients with glioblastoma multiforme.

A Rare Coexistence of Pheochromocytoma and Parkinson's Disease With Diagnostic Challenges.

We herein report a case of pheochromocytoma occurring in the course of Parkinson's disease. The coexistence of these two disease is extremely rare, with only four cases hitherto reported across the public databases. It is also noteworthy that biochemical tests, which are critical for the diagnosis of pheochromocytoma, are severely confounded by dopaminergic medications for Parkinson's disease, highlighting the importance of image-based modalities in this setting. We further attempted to gain insight into the potential molecular mechanisms, proposing that hypoxia-inducible factor signaling could make these two diseases mutually exclusive, while excessive reactive oxygen species could enable their coexistence.