Dysregulation of the Renin-Angiotensin-Aldosterone System (RAA) in Patients Infected with SARS-CoV-2-Possible Clinical Consequences.

SARS-CoV-2 impairs the renin-angiotensin-aledosterone system via binding ACE2 enzyme. ACE2 plays a key role in the biosynthesis of angiotensin (1-7), catalyzing the conversion of angiotensin 2 into angiotensin (1-7) and the reaction of angiotensin synthesis (1-9), from which angiotensin is (1-7) produced under the influence of ACE (Angiotensin-Converting Enzyme). Angiotensin 2 is a potent vasoconstrictor and atherogenic molecule converted by ACE2 to reducing inflammation and vasodilating in action angiotensin (1-7). Angiotensin (1-9), that is a product of angiotensin 1 metabolism and precursor of angiotensin (1-7), also exerts cell protective properties. Balance between angiotensin 2 and angiotensin (1-7) regulates blood pressure and ACE2 plays a critical role in this balance. ACE2, unlike ACE, is not inhibited by ACE inhibitors at the doses used in humans during the treatment of arterial hypertension. Membrane ACE2 is one of the receptors that allows SARS-CoV-2 to enter the host cells. ACE2 after SARS-CoV-2 binding is internalized and degraded. Hence ACE2 activity on the cell surface is reduced leading to increase the concentration of angiotensin 2 and decrease the concentration of angiotensin (1-7). Disturbed angiotensins metabolism, changes in ratio between angiotensins with distinct biological activities leading to domination of atherogenic angiotensin 2 can increase the damage to the lungs.

Up-regulation of PCSK9 gene expression and diminished level of LDL-receptor in rat liver as a potential cause of post-lipectomy hypercholesterolemia.

Studies designed to examine effects of fat mass reduction (including lipodystrophy and lipectomy) on human serum total and LDL-cholesterol concentrations are inconsistent. The purpose of this study was to examine effect of partial lipectomy in rats (as an experimental model of fat mass reduction in humans) on (1) circulating total cholesterol, LDL-cholesterol + VLDL-cholesterol and HDL-cholesterol concentrations, and (2) factors which may affect serum cholesterol concentrations such as: (a) liver LDL-receptor level, (b) expression of liver PCSK9 and (c) circulating PCSK9 concentration. Reduction of rat adipose tissue mass resulted in an increase in circulating total and LDL + VLDL-cholesterol concentrations, which was associated with (a) decrease in liver LDL-R level, (b) increase in liver PCSK9 expression, and (c) increase in circulating PCSK9 concentration as compared with sham controls. These changes were accompanied by elevated liver HNF1α (and HNF4α) mRNA levels. Silencing HNF1α in HepG2 cells by siRNA led to decrease in PCSK9 mRNA levels. This suggests that overexpression of HNF1α gene in liver of lipectomized rats can lead to overproduction of PCSK9. In conclusion, up-regulation of PCSK9, due to overexpression of HNF1α gene in liver of lipectomized rats and subsequently increase in circulating PCSK9 concentration lead to decrease in liver LDL-R level. This may contribute, at least in part, to an increase in the concentration of circulating cholesterol in rats with reduced fat mass. These findings provide a possible explanation for the molecular mechanism of hypercholesterolemia observed sometimes after reduction of fat mass in human.

Upregulation of Pnpla2 and Abhd5 and downregulation of G0s2 gene expression in mesenteric white adipose tissue as a potential reason for elevated concentration of circulating NEFA after removal of retroperitoneal, epididymal, and inguinal adipose tissue.

Elevated concentrations of circulating non-esterified fatty acids (NEFA) were reported in (a) humans with lipodystrophy, (b) humans following bariatric surgery, and (c) transgenic mice with reduced amounts of adipose tissue. Paradoxically, these findings suggest that the reduction of adipose tissue mass is associated with elevated circulating NEFA concentrations. To explain a molecular background of this phenomenon, we analyzed the effects of surgical removal of inguinal, epididymal, and retroperitoneal white adipose tissue (WAT) on (a) circulating NEFA concentrations, (b) expression of Pnpla2, a gene that encodes adipose triglyceride lipase (ATGL), genes encoding abhydrolase domain containing 5 (ABHD5) and G0/G1 switch 2 (G0S2), i.e., a coactivator and inhibitor of ATGL, respectively, and (c) expression of Lipe gene coding hormone-sensitive lipase (HSL) in mesenteric WAT. Reduction of adipose tissue mass resulted in an increase in circulating NEFA concentration, which was associated with (a) an increase in the expressions of Pnpla2 and Abhd5, (b) decrease in G0s2 expression, and (c) upregulation of Lipe expression, all measured on both mRNA and protein levels in mesenteric WAT of male rats. The rate of lipolysis in mesenteric WAT explants and isolated adipocytes from lipectomized rats was significantly higher than that from the controls. In conclusion, upregulation of Pnpla2 expression and activation of ATGL (due to an increase in ABHD5 and decrease in G0S2 levels), as well as a coordinated interplay of these genes with Lipe in mesenteric WAT, contribute, at least in part, to an increase in the concentration of circulating NEFA in rats with reduced fat mass.

Up-Regulation Mttp and Apob Gene Expression in Rat Liver is Related to Post-Lipectomy Hypertriglyceridemia.

BACKGROUND/AIMS: The aim of this study was to explain the molecular basis for elevated concentrations of circulating triglycerides (TAGs) after partial surgical removal of adipose tissue (lipectomy) in rats. METHODS: The levels of mRNA and protein: a) involved in synthesis of fatty acids and TAGs; b) participating in TAG-rich lipoproteins assembly and secretion; and c) transcription factors essential for maintaining TAG homeostasis were determined by RT-PCR and Western Blot in the livers of control and lipectomized rats. RESULTS: Partial lipectomy was associated with increase: a) in serum and liver concentration of TAGs, and b) in the liver levels of mRNA of microsomal TAG transfer protein (MTP) and apolipoprotein B-100 (ApoB- 100). These changes were tightly associated with up-regulation of Hnf1a and Hnf4a gene expression in the liver. Lipectomy was also reflected by a significant increase in the expression of genes encoding: a) fatty acid synthase (FASN), b) glycerol 3-phosphate acyltransferase 1 (GPAT1), diacylglycerol acyltransferases 1 and 2 (DGAT1 and DGAT2), c) spot 14 protein (S14) and SREBP-1 in the liver. CONCLUSION: Coordinated up-regulation of Mttp, Apob, Hnf1a, Hnf4a, Fasn, Gpam and Dgat (1 and 2) gene expressions may contribute to the increase in circulating and liver concentrations of TAGs after lipectomy in an experimental rat model.

Time-dependent changes in antioxidative enzyme expression and photosynthetic activity of Chlamydomonas reinhardtii cells under acute exposure to cadmium and anthracene.

Heavy metals (HM) and polycyclic aromatic hydrocarbons (PAHs) are present in the freshwater environment at concentrations that can be hazardous to the biota. Among HMs and PAHs, cadmium (Cd) and anthracene (ANT) are the most prevalent and toxic ones. The response of Chlamydomonas cells to Cd and ANT at concentrations that markedly reduced the growth of algal population was investigated in this study. At such concentrations, both cadmium and anthracene were recognized as oxidative stress inducers, since high concentration of H2O2 in treated cultures was observed. Therefore, as a part of the "molecular phase" of the cell response to this stress, we examined the time-dependent expression of genes encoding the main antioxidative enzymes: superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX), as well as the activity of these enzymes in cells, with special attention paid to chloroplastic and mitochondrial isoforms of SOD. To characterize the cell response at the "physiological level", we examined the photosynthetic activity of stressed cells via analysis of chlorophyll a fluorescence in vivo. In contrast to standard ecotoxicity studies in which the growth end-points are usually determined, herein we present time-dependent changes in algal cell response to Cd- and ANT-induced stress. The most significant effect(s) of the toxicants on photosynthetic activity was observed in the 6th hour, when strong depression of PI parameter value, an over 50 percent reduction of the active reaction center fraction (RC0) and a 3-fold increase in non-photochemical energy dissipation (DI0/RC) were noted. At the same time, the increase (up to 2.5-fold) in mRNA transcript of SOD and CAT genes, followed by the enhancement in the enzyme activity was observed. The high expression of the Msd 3 gene in treated Chlamydomonas cells probably complements the partial loss of chloroplast Fe-SOD and APX activity, while catalase and Mn-SOD 5 seem to be the major enzymes responsible for mitochondrion protection. The progressive increase in SOD and CAT activities seems to be involved in the recovery of photosynthesis within 12-24h after the application of the toxicants.

Cross Talk between Hydrogen Peroxide and Nitric Oxide in the Unicellular Green Algae Cell Cycle: How Does It Work?

The regulatory role of some reactive oxygen species (ROS) and reactive nitrogen species (RNS), such as hydrogen peroxide or nitric oxide, has been demonstrated in some higher plants and algae. Their involvement in regulation of the organism, tissue and single cell development can also be seen in many animals. In green cells, the redox potential is an important photosynthesis regulatory factor that may lead to an increase or decrease in growth rate. ROS and RNS are important signals involved in the regulation of photoautotrophic growth that, in turn, allow the cell to attain the commitment competence. Both hydrogen peroxide and nitric oxide are directly involved in algal cell development as the signals that regulate expression of proteins required for completing the cell cycle, such as cyclins and cyclin-dependent kinases, or histone proteins and E2F complex proteins. Such regulation seems to relate to the direct interaction of these signaling molecules with the redox-sensitive transcription factors, but also with regulation of signaling pathways including MAPK, G-protein and calmodulin-dependent pathways. In this paper, we aim to elucidate the involvement of hydrogen peroxide and nitric oxide in algal cell cycle regulation, considering the role of these molecules in higher plants. We also evaluate the commercial applicability of this knowledge. The creation of a simple tool, such as a precisely established modification of hydrogen peroxide and/or nitric oxide at the cellular level, leading to changes in the ROS-RNS cross-talk network, can be used for the optimization of the efficiency of algal cell growth and may be especially important in the context of increasing the role of algal biomass in science and industry. It could be a part of an important scientific challenge that biotechnology is currently focused on.

Increased serum resistin concentration in patients with chronic pancreatitis: possible cause of pancreatic fibrosis.

BACKGROUND: Resistin is an adipokine, which displays proinflammatory properties. Thus, it is likely that resistin can influence the course of chronic pancreatitis, and/or that chronic pancreatitis may affect the serum resistin concentration. GOALS: The aim of the present study was to determine the serum resistin concentration in patients with chronic pancreatitis and to analyze the relationship between serum resistin concentration and serum concentrations of leptin (proinflammatory adipokine) and adiponectin (anti-inflammatory adipokine). STUDY: A total of 23 male, nondiabetic patients with chronic pancreatitis of alcoholic origin and 16 healthy subjects were examined. Fasting blood samples were collected from patients in both groups. Serum resistin concentration was assayed by enzyme-linked immunosorbent assay. Serum adiponectin, leptin, and insulin concentrations were determined by radioimmunoassay. RESULTS: Serum resistin concentration was significantly higher in patients with chronic pancreatitis as compared with control subjects. In contrast, patients with chronic pancreatitis had lower serum leptin and insulin concentrations than healthy subjects. There were no statistically significant differences in serum adiponectin concentration between patients with pancreatitis and healthy subjects. CONCLUSIONS: The results presented in this paper indicate that chronic pancreatitis in human is associated with the increase in serum resistin concentration and with the decrease in serum leptin and insulin concentrations. It can be supposed that resistin, by stimulation of tumor necrosis factor-alpha synthesis in blood mononuclear cells and in macrophages, increases the concentration of tumor necrosis factor-alpha, which in turn activates stellate cells. Activated stellate cells can produce collagen, eventually resulting in the development of pancreatic fibrosis.

[Genetic basis of dyslipidemia]. / Genetyczne podloze dyslipidemii.

Genetic disorders play an important role in the ethiopathogenesis of disease processes in humans. In the present paper we have described documented genes polymorphisms associated with dyslipidemia. Some of them have been known for years, but some have been discovered quite recently. Their characteristics an impact on lipid profile are presented. Discussed are their direct relationship with atherosclerosis and cardiovascular diseases.

Exogenously applied hydrogen peroxide modifies the course of the Chlamydomonas reinhardtii cell cycle.

The interaction of NO and H2O2 in the regulation of plant development is well documented. We have recently shown that the content of NO and H2O2 changes in a characteristic way during the cell cycle of Chlamydomonas reinhardtii (Pokora et al., 2017), which implies participation of these molecules in the regulation of Chlamydomonas development. To verify this assumption, H2O2 was supplied at a concentration about 1.5 times higher than that determined in the control cells. Cells were synchronized by alternating the light/dark (10/14 h) regimen. H2O2 was added to zoospore suspensions, previously held in the dark, and cells growing for 3, 6, and 9 h in the light. The data indicate that, depending on the phase of the Chlamydomonas cell cycle, H2O2, via mild modification of redox homeostasis, may: a) accelerate or delay the duration of the cell cycle; b) increase the number of replication rounds occurring in one cell cycle; c) modify the biomass and cell volume of progeny cells and d) accelerate the liberation of daughter cells. This provides a tool to control the development of Chlamydomonas cell and thus offers the opportunity to obtain a population of cells with characteristics desired in biotechnology.

Changes in nitric oxide/hydrogen peroxide content and cell cycle progression: Study with synchronized cultures of green alga Chlamydomonas reinhardtii.

The present study aimed to evaluate the possible relationship between the changes in hydrogen peroxide (H2O2) and nitric oxide (NO) content and the course of growth and reproductive processes of the cell cycle of Chlamydomonas reinhardtii. The peak of H2O2 observed at the beginning of the cell cycle was found to originate from Fe-SOD and Mn-SODchl. activity and result from the alternation in the photosynthetic processes caused by the dark-to-light transition of daughter cells. A rapid increase in NO concentration, observed before the light-to-dark cell transition, originated from NR and NIR activity and was followed by a photosynthesis-independent, Mn-SODchl.-mediated increases in H2O2 production. This H2O2 peak overlapped the beginning of Chlamydomonas cell division, which was indicated by a profile of CYCs and CDKs characteristic of cells' passage through the G1/S and S/M checkpoints. Taken together, our results show that there is a clear relationship between the course of the Chlamydomonas cell cycle and typical changes in the H2O2/NO ratio, as well as changes in expression and activity of enzymes involved in generation and scavenging of these signaling molecules.

Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome.

Clinical studies have indicated that circulating bile acid (BA) concentrations increase following bariatric surgery, especially following malabsorptive procedures such as Roux-en-Y gastric bypasses (RYGB). Moreover, total circulating BA concentrations in patients following RYGB are positively correlated with serum glucagon-like peptide-1 concentrations and inversely correlated with postprandial glucose concentrations. Overall, these data suggest that the increased circulating BA concentrations following bariatric surgery - independently of calorie restriction and body-weight loss - could contribute, at least in part, to improvements in insulin sensitivity, incretin hormone secretion, and postprandial glycemia, leading to the remission of type-2 diabetes (T2DM). In humans, the primary and secondary BA pool size is dependent on the rate of biosynthesis and the enterohepatic circulation of BAs, as well as on the gut microbiota, which play a crucial role in BA biotransformation. Moreover, BAs and gut microbiota are closely integrated and affect each other. Thus, the alterations in bile flow that result from anatomical changes caused by bariatric surgery and changes in gut microbiome may influence circulating BA concentrations and could subsequently contribute to T2DM remission following RYGB. Research data coming largely from animal and cell culture models suggest that BAs can contribute, via nuclear farnezoid X receptor (FXR) and membrane G-protein-receptor (TGR-5), to beneficial effects on glucose metabolism. It is therefore likely that FXR, TGR-5, and BAs play a similar role in glucose metabolism following bariatric surgery in humans. The objective of this review is to discuss in detail the results of published studies that show how bariatric surgery affects glucose metabolism and subsequently T2DM remission.

[Photodynamic diagnosis and therapy of bladder cancer]. / Diagnostyka i terapia fotodynamiczna nowotworów pecherza moczowego.

High frequency of bladder cancer in polish population and relatively low sensitivity of cancer detection in early stages is a main reason for search for other, more sensitive diagnostic tests. Photodynamic diagnosis based on accumulation of photosensitizers, porphirin derived compounds emitting fluorescence in laser light is a promising tool for detecting of small or poorly differentiated neoplastic changes. On the other hand we can use photodynamic therapy when in laser light photosensitizers generate free oxygen radicals and destroy neoplastic tissue. Photodynamic therapy is a perfect tool in bladder cancer treatment especially in case of early stage or multicentric neoplastic changes that are difficult to resect in traditional endoscopic way.