Endoplasmic Reticulum Stress-Associated Lipid Droplet Formation and Type II Diabetes

Diabetes mellitus (DM), a metabolic disorder characterized by hyperglycemia, is caused by insufficient insulin production due to excessive loss of pancreatic β cells (type I diabetes) or impaired insulin signaling due to peripheral insulin resistance (type II diabetes). Pancreatic β cell is the only insulin-secreting cell type that has highly developed endoplasmic reticulum (ER) to cope with high demands of insulin synthesis and secretion. Therefore, ER homeostasis is crucial to the proper function of insulin signaling. Accumulating evidence suggests that deleterious ER stress and excessive intracellular lipids in nonadipose tissues, such as myocyte, cardiomyocyte, and hepatocyte, cause pancreatic β-cell dysfunction and peripheral insulin resistance, leading to type II diabetes. The excessive deposition of lipid droplets (LDs) in specialized cell types, such as adipocytes, hepatocytes, and macrophages, has been found as a hallmark in ER stress-associated metabolic diseases, including obesity, diabetes, fatty liver disease, and atherosclerosis. However, much work remains to be done in understanding the mechanism by which ER stress response regulates LD formation and the pathophysiologic role of ER stress-associated LD in metabolic disease. This paper briefly summarizes the recent advances in ER stress-associated LD formation and its involvement in type II diabetes

Pharmacokinetics and tissue distribution of N-3- methoxybenzyl-palmitamide in rat: A macamide derived from Lepidium meyenii

Purpose: To study the pharmacokinetics and tissue distribution of N-3-methoxybenzyl-palmitamide (MPM) derived from Lepidium meyenii (Maca)Methods: MPM and N-benzylpalmitamide (BPM, as the internal standard, IS) were prepared by one-pot synthesis method and characterized. For the analysis of MPM in rat plasma and tissue samples, a rapid ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method was developed and validated by optimizing sample preparation conditions and UPLC conditions. Finally, the pharmacokinetics and biodistribution of MPM after oral administration in rats were studied.Results: The lower limit of quantification (LLOQ) and limit of detection (LOD) of the UPLC-MS/MS method were 1.2 and 5.0 ng/mL, respectively. Good linear relationship of calibration curve (r > 0.9951) was achieved over the range of 5 – 5000 ng/mL. In pharmacokinetics, plasma concentration-time curve of MPM showed double peaks. The highest distribution of MPM after absorption was in the stomach, followed by lung. The absorption and eliminate rate of MPM were slow in rats. In fact, MPM displayed a lung targeting property.Conclusion: The developed UPLC-MS/MS method is suitable for plasma and tissue distribution studies of MPM in rats. The present study can provide guidance for the further development and utilization of Maca tuber.Keywords: Macamide, Maca tuber, Lepidium meyenii, Pharmacokinetics, Tissue distribution, UPLCMS/M

Proteomics analysis of rough endoplasmic reticulum in pancreatic beta cells

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111127/1/pmic8033.pd

Determination of esomeprazole in rabbit plasma by liquid chromatography-mass spectrometry and its application to a pharmacokinetic study

A sensitive and selective liquid chromatography-mass spectrometry (LC–MS) method for determination of esomeprazole in rabbit plasma was developed and validated. After addition of midazolam as internal standard (IS), protein precipitation by acetonitrile was used as sample preparation, and chromatography involved Agilent SB-C18 column (2.1 x 150 mm, 5.0 μm) using 0.1 % formic acid in water and acetonitrile as a mobile phase with gradient elution. Detection involved positive ion mode electrospray ionization (ESI), and selective ion monitoring (SIM) mode was used for quantification of target fragment ions m/z 198 for esomeprazole and m/z 326 for midazolam (internal standard, IS). The assay was linear over the range of 10–2000 ng/mL for esomeprazole, with a lower limit of quantitation (LLOQ) of 10 ng/mL for esomeprazole. Intra- and inter-day precisions were less than 14 % and the accuracies were in the range of 89.2-112.6 % for esomeprazole. This developed method was successfully applied for the determination of esomeprazole in rabbit plasma for pharmacokinetic study.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Biofouling characteristics in Xinghua Bay of Fujian, China

Biofouling is one of the main factors affecting the efficiency and safety of cooling water systems in coastal nuclear power plants. Understanding the population dynamics, succession rules and cumulative effects of major fouling organisms is the basis for targeted prevention and control. A 1-year simulated concrete panel test was conducted from December 2020 to November 2021 in Xinghua Bay, China. A total of 78 species of fouling organisms were recorded by combining the monthly, seasonal, semiannual, annual and monthly cumulative panels, and the community composition was dominated by nearshore warm-water species, making for a typical subtropical inner bay-type community. The fouling organisms had a peak attachment period from June to October. Significantly more attachment was observed during summer (from June to August) than during the other three seasons. The attachment amount in the second half-year (from June to November) was much higher than that in the first half-year (from December to May). The attachment thickness, density, and biomass of the bottom summer panels reached 20 cm, 105,150 ind./m2, and 19,274.50 g/m2, respectively, while those of the bottom annual panels were 40 cm, 27,300 ind./m2, and 17,762.50 g/m2, respectively. The dominant fouling organisms with calcified shells mainly included Amphibalanus reticulatus and Pernaviridis. These species had high attachment amounts,could accumulate attachments for a long time, and even might cause secondary blockage, making them the most detrimental to the safety of a cooling system. Moreover,the seasonal upward growth of hydroids and bryozoans can also significantly reduce the efficiency of cooling water intake. We suggest that targeted prevention and control should be carried out according to the larval attachment period of different dominant groups of fouling organisms during June-October, which can greatly improve the prevention and control efficiency. Strengthening the research on the biological cycle phenomenon of the main species and their main environmental impact factors, and establishing a scientific and effective early-warning model are the governance direction of formulating and implementing scientific pollution prevention and control in the future

SVIP Induces Localization of p97/VCP to the Plasma and Lysosomal Membranes and Regulates Autophagy

The small p97/VCP-interacting protein (SVIP) functions as an inhibitor of the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. Here we show that overexpression of SVIP in HeLa cells leads to localization of p97/VCP at the plasma membrane, intracellular foci and juxtanuclear vacuoles. The p97/VCP-positive vacuolar structures colocalized or associated with LC3 and lamp1, suggesting that SVIP may regulate autophagy. In support of this possibility, knockdown of SVIP diminished, whereas overexpression of SVIP enhanced LC3 lipidation. Surprisingly, knockdown of SVIP reduced the levels of p62 protein at least partially through downregulation of its mRNA, which was accompanied by a decrease in starvation-induced formation of p62 bodies. Overexpression of SVIP, on the other hand, increased the levels of p62 protein and enhanced starvation-activated autophagy as well as promoted sequestration of polyubiquitinated proteins and p62 in autophagosomes. These results suggest that SVIP plays a regulatory role in p97 subcellular localization and is a novel regulator of autophagy

Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J

Membrane-bound phosphoinositides are signalling molecules that have a key role in vesicle trafficking in eukaryotic cells(1). Proteins that bind specific phosphoinositides mediate interactions between membrane-bounded compartments whose identity is partially encoded by cytoplasmic phospholipid tags. Little is known about the localization and regulation of mammalian phosphatidylinositol-3,5-bisphosphate ( PtdIns( 3,5)P-2), a phospholipid present in small quantities that regulates membrane trafficking in the endosome - lysosome axis in yeast(2). Here we describe a multi-organ disorder with neuronal degeneration in the central nervous system, peripheral neuronopathy and diluted pigmentation in the 'pale tremor' mouse. Positional cloning identified insertion of ETn2 beta ( early transposon 2 beta)(3) into intron 18 of Fig4 (A530089I17Rik), the homologue of a yeast SAC ( suppressor of actin) domain PtdIns(3,5) P-2 5-phosphatase located in the vacuolar membrane. The abnormal concentration of PtdIns( 3,5) P2 in cultured fibroblasts from pale tremor mice demonstrates the conserved biochemical function of mammalian Fig4. The cytoplasm of fibroblasts from pale tremor mice is filled with large vacuoles that are immunoreactive for LAMP-2 (lysosomal-associated membrane protein 2), consistent with dysfunction of the late endosome - lysosome axis. Neonatal neurodegeneration in sensory and autonomic ganglia is followed by loss of neurons from layers four and five of the cortex, deep cerebellar nuclei and other localized brain regions. The sciatic nerve exhibits reduced numbers of large-diameter myelinated axons, slowed nerve conduction velocity and reduced amplitude of compound muscle action potentials. We identified pathogenic mutations of human FIG4 (KIAA0274) on chromosome 6q21 in four unrelated patients with hereditary motor and sensory neuropathy. This novel form of autosomal recessive Charcot - Marie - Tooth disorder is designated CMT4J.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62835/1/nature05876.pd

Influence factors and reasonable arrangement of corridor width of ±800 kV HVDC and 750 kV HVAC hybrid transmission lines

With the development of economy and the increased demand of power energy, it is unavoidable that high-voltage direct current (HVDC) and high-voltage alternating current (HVAC) transmission lines are in the same corridor. In order to minimise the land resource and meet the requirements of the electromagnetic environment, it is necessary to accurately predict the hybrid electric field under the hybrid transmission lines. The ±800 kV HVDC and 750 kV HVAC parallel transmission lines of parallel erection are chosen to be analysed. The corridor width with a different separation distance is calculated, and the minimum corridor width under this voltage-level combination is obtained according to the control value of the hybrid electric field recommended at home and abroad in a non-residential area. Increasing the height of DC or AC lines can reduce the corridor width. At a fixed separation distance, the minimum height of the AC line can be obtained when the height of the DC line is set at a certain value. Meanwhile the change of the corridor width is analysed with different heights of DC lines and AC lines. Based on the above analysis, the reasonable arrangement is made