The Role of Mitochondrial Energetics and Inflammasome NLRP3 in Diabetic Cardiomyopathy

Diabetic Cardiomyopathy is the worldwide leading cause of lethal heart disorders burdening the healthcare systems. Mitochondrion is the key regulator of myocardial metabolism. It fuels the cardiocytes and regulates the pumping activity of heart. People living with diabetes have defected myocardial metabolism which may likely to cause ventricular dysfunction or other heart disorders due to mitochondrial DNA (mtDNA) mutation. Furthermore, the inflammatory injury due to inflammasome activation is a potent contributor to the cardiac injuries. Though the mechanism of inflammation is still poorly known. This review highlights the association of altered mitochondrial energetics and inflammasome activation with cardiomyopathies.

Susceptibility of the Formate Hydrogenlyase Reaction to the Protonophore CCCP Depends on the Total Hydrogenase Composition

Fermentative hydrogen production by enterobacteria derives from the activity of the formate hydrogenlyase (FHL) complex, which couples formate oxidation to H2 production. The molybdenum-containing formate dehydrogenase and type-4 [NiFe]-hydrogenase together with three iron-sulfur proteins form the soluble domain, which is attached to the membrane by two integral membrane subunits. The FHL complex is phylogenetically related to respiratory complex I, and it is suspected that it has a role in energy conservation similar to the proton-pumping activity of complex I. We monitored the H2-producing activity of FHL in the presence of different concentrations of the protonophore CCCP. We found an inhibition with an apparent EC50 of 31 µM CCCP in the presence of glucose, a higher tolerance towards CCCP when only the oxidizing hydrogenase Hyd-1 was present, but a higher sensitivity when only Hyd-2 was present. The presence of 200 mM monovalent cations reduced the FHL activity by more than 20%. The Na+/H+ antiporter inhibitor 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) combined with CCCP completely inhibited H2 production. These results indicate a coupling not only between Na+ transport activity and H2 production activity, but also between the FHL reaction, proton import and cation export.

Depth and turbidity affect in situ pumping activity of the Mediterranean sponge Chondrosia reniformis (Nardo, 1847)

Effects of depth and turbidity on the in situ pumping activity of the Mediterranean sponge Chondrosia reniformis (Nardo, 1847) were characterized by measuring osculum diameter, oscular outflow velocity, osculum density per sponge and sponge surface area at different locations around the Bodrum peninsula (Turkey). Outflow velocity was measured using a new method based on video analysis of neutrally buoyant particles moving in the exhalant stream of sponge oscula, which yielded results that were in good comparison to other studies. Using the new method, it was shown that for C. reniformis, oscular outflow had a location-dependent, in most cases positive relationship with oscular size: bigger oscules process more water per cm2 of osculum surface. Turbidity and depth both affected sponge pumping in a negative way, but for the locations tested, the effect of depth was more profound than the effect of turbidity. Depth affected all parameters investigated except sponge size, whereas turbidity only affected specific pumping rates normalized to sponge surface area. Deep water sponges had clearly smaller oscula than shallow water sponges, but partially compensated for this lower pumping potential by showing a higher osculum density. Both increasing turbidity and increasing depth considerably decreased volumetric pumping rates of C. reniformis. These findings have important implications for selecting sites for mariculture of this species.

Roles of sarcoplasmic reticulum Ca2+ ATPase pump in the impairments of lymphatic contractile activity in a metabolic syndrome rat model

The intrinsic lymphatic contractile activity is necessary for proper lymph transport. Mesenteric lymphatic vessels from high-fructose diet-induced metabolic syndrome (MetSyn) rats exhibited impairments in its intrinsic phasic contractile activity; however, the molecular mechanisms responsible for the weaker lymphatic pumping activity in MetSyn conditions are unknown. Several metabolic disease models have shown that dysregulation of sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump is one of the key determinants of the phenotypes seen in various muscle tissues. Hence, we hypothesized that a decrease in SERCA pump expression and/or activity in lymphatic muscle influences the diminished lymphatic vessel contractions in MetSyn animals. Results demonstrated that SERCA inhibitor, thapsigargin, significantly reduced lymphatic phasic contractile frequency and amplitude in control vessels, whereas, the reduced MetSyn lymphatic contractile activity was not further diminished by thapsigargin. While SERCA2a expression was significantly decreased in MetSyn lymphatic vessels, myosin light chain 20, MLC20 phosphorylation was increased in these vessels. Additionally, insulin resistant lymphatic muscle cells exhibited elevated intracellular calcium and decreased SERCA2a expression and activity. The SERCA activator, CDN 1163 increased phasic contractile frequency in the vessels from MetSyn, thereby, partially restored lymph flow. Thus, our data provide the first evidence that SERCA2a modulates the lymphatic pumping activity by regulating phasic contractile amplitude and frequency, but not the lymphatic tone. Diminished lymphatic contractile activity in the vessels from the MetSyn animal is associated with the decreased SERCA2a expression and impaired SERCA2 activity in lymphatic muscle.

Populus euphratica WRKY1 binds the promoter of H+-ATPase gene to enhance gene expression and salt tolerance

Plasma membrane proton pumps play a crucial role in maintaining ionic homeostasis in salt-resistant Populus euphratica under saline conditions. High levels of NaCl (200 mM) induced PeHA1 expression in P. euphratica roots and leaves. We isolated a 2022 bp promoter fragment upstream of the translational start of PeHA1 from P. euphratica. The promoter–reporter construct PeHA1-pro::GUS was transferred to tobacco plants, demonstrating that β-glucuronidase activities increased in root, leaf, and stem tissues under salt stress. DNA affinity purification sequencing revealed that PeWRKY1 protein targeted the PeHA1 gene. We assessed the salt-induced transcriptional response of PeWRKY1 and its interaction with PeHA1 in P. euphratica. PeWRKY1 binding to the PeHA1 W-box in the promoter region was verified by a yeast one-hybrid assay, EMSA, luciferase reporter assay, and virus-induced gene silencing. Transgenic tobacco plants overexpressing PeWRKY1 had improved expression of NtHA4, which has a cis-acting W-box in the regulatory region, and improved H+ pumping activity in both in vivo and in vitro assays. We conclude that salt stress up-regulated PeHA1 transcription due to the binding of PeWRKY1 to the W-box in the promoter region of PeHA1. Thus, we conclude that enhanced H+ pumping activity enabled salt-stressed plants to retain Na+ homeostasis.

Comparison of cardiac time intervals between echocardiography and impedance cardiography at various heart rates

The non-invasively measured initial systolic time interval (ISTI) reflects a time difference between the electrical and pumping activity of the heart and depends on cardiac preload, afterload, autonomic nervous control and training level. However, the duration of the ISTI has not yet been compared to other time markers of the heart cycle. The present study gauges the duration of the ISTI by comparing the end point of this interval, the C-point, with heart cycle markers obtained by echocardiography. The heart rate of 16 healthy subjects was varied by means of an exercise stimulus. It was found that the C-point, and therefore the end point of ISTI, occurred around the moment of the maximum diameter of the aortic arch in all subjects and at all heart rates. However, while the time difference between the opening of the aortic valves and the maximum diameter of the aortic arch decreased significantly with decreasing RR-interval, the time difference with respect to the moment of the C-point remained constant within the subjects. This means that the shortening of the ISTI with increasing heart rate in response to an exercise stimulus was caused by a shortening of the pre-ejection period (PEP). It is concluded that the ISTI can be used as a non-invasive parameter indicating the time difference between the electrical and mechanical pumping activity of the heart, both inside and outside the clinic.

PgpRules: a decision tree based prediction server for P-glycoprotein substrates and inhibitors

Summary P-glycoprotein (P-gp) is a member of ABC transporter family that actively pumps xenobiotics out of cells to protect organisms from toxic compounds. P-gp substrates can be easily pumped out of the cells to reduce their absorption; conversely P-gp inhibitors can reduce such pumping activity. Hence, it is crucial to know if a drug is a P-gp substrate or inhibitor in view of pharmacokinetics. Here we present PgpRules, an online P-gp substrate and P-gp inhibitor prediction server with ruled-sets. The two models were built using classification and regression tree algorithm. For each compound uploaded, PgpRules not only predicts whether the compound is a P-gp substrate or a P-gp inhibitor, but also provides the rules containing chemical structural features for further structural optimization. Availability and implementation PgpRules is freely accessible at https://pgprules.cmdm.tw/. Supplementary information Supplementary data are available at Bioinformatics online.

Eisosomes are metabolically regulated storage compartments for APC-type nutrient transporters

Eisosomes are lipid domains of the yeast plasma membrane that share similarities to caveolae of higher eukaryotes. Eisosomes harbor APC-type nutrient transporters for reasons that are poorly understood. Our analyses support the model that eisosomes function as storage compartments, keeping APC transporters in a stable, inactive state. By regulating eisosomes, yeast is able to balance the number of proton-driven APC transporters with the proton-pumping activity of Pma1, thereby maintaining the plasma membrane proton gradient. Environmental or metabolic changes that disrupt the proton gradient cause the rapid restructuring of eisosomes and results in the removal of the APC transporters from the cell surface. Furthermore, we show evidence that eisosomes require the presence of APC transporters, suggesting that regulating activity of nutrient transporters is a major function of eisosomes.