Gender-Specific Renoprotective Pathways in αMUPA Transgenic Mice Subjected to Acute Kidney Injury.

Acute kidney injury (AKI) is a serious health concern with high morbidity and high mortality worldwide. Recently, sexual dimorphism has become increasingly recognized as a factor influencing the severity of the disease. This study explores the gender-specific renoprotective pathways in αMUPA transgenic mice subjected to AKI. αMUPA transgenic male and female mice were subjected to ischemia-reperfusion (I/R)-AKI in the presence or absence of orchiectomy, oophorectomy, and L-NAME administration. Blood samples and kidneys were harvested 48 h following AKI for the biomarkers of kidney function, renal injury, inflammatory response and intracellular pathway sensing of or responding to AKI. Our findings show differing responses to AKI, where female αMUPA mice were remarkably protected against AKI as compared with males, as was evident by the lower SCr and BUN, normal renal histologically and attenuated expression of NGAL and KIM-1. Moreover, αMUPA females did not show a significant change in the renal inflammatory and fibrotic markers following AKI as compared with wild-type (WT) mice and αMUPA males. Interestingly, oophorectomized females eliminated the observed resistance to renal injury, highlighting the central protective role of estrogen. Correspondingly, orchiectomy in αMUPA males mitigated their sensitivity to renal damage, thereby emphasizing the devastating effects of testosterone. Additionally, treatment with L-NAME proved to have significant deleterious impacts on the renal protective mediators, thereby underscoring the involvement of eNOS. In conclusion, gender-specific differences in the response to AKI in αMUPA mice include multifaceted and keen interactions between the sex hormones and key biochemical mediators (such as estrogen, testosterone and eNOS). These novel findings shed light on the renoprotective pathways and mechanisms, which may pave the way for development of therapeutic interventions.

The Protective Pathways Activated in Kidneys of αMUPA Transgenic Mice Following Ischemia\Reperfusion-Induced Acute Kidney Injury.

Despite the high prevalence of acute kidney injury (AKI), the therapeutic approaches for AKI are disappointing. This deficiency stems from the poor understanding of the pathogenesis of AKI. Recent studies demonstrate that αMUPA, alpha murine urokinase-type plasminogen activator (uPA) transgenic mice, display a cardioprotective pathway following myocardial ischemia. We hypothesize that these mice also possess protective renal pathways. Male and female αMUPA mice and their wild type were subjected to 30 min of bilateral ischemic AKI. Blood samples and kidneys were harvested 48 h following AKI for biomarkers of kidney function, renal injury, inflammatory response, and intracellular pathways sensing or responding to AKI. αMUPA mice, especially females, exhibited attenuated renal damage in response to AKI, as was evident from lower SCr and BUN, normal renal histology, and attenuated expression of NGAL and KIM-1. Notably, αMUPA females did not show a significant change in renal inflammatory and fibrotic markers following AKI as compared with wild-type (WT) mice and αMUPA males. Moreover, αMUPA female mice exhibited the lowest levels of renal apoptotic and autophagy markers during normal conditions and following AKI. αMUPA mice, especially the females, showed remarkable expression of PGC1α and eNOS following AKI. Furthermore, MUPA mice showed a significant elevation in renal leptin expression before and following AKI. Pretreatment of αMUPA with leptin-neutralizing antibodies prior to AKI abolished their resistance to AKI. Collectively, the kidneys of αMUPA mice, especially those of females, are less susceptible to ischemic I/R injury compared to WT mice, and this is due to nephroprotective actions mediated by the upregulation of leptin, eNOS, ACE2, and PGC1α along with impaired inflammatory, fibrotic, and autophagy processes.

Effects of Angiotensin 1-7 and Mas Receptor Agonist on Renal System in a Rat Model of Heart Failure.

Congestive heart failure (CHF) is often associated with impaired kidney function. Over- activation of the renin-angiotensin-aldosterone system (RAAS) contributes to avid salt/water retention and cardiac hypertrophy in CHF. While the deleterious effects of angiotensin II (Ang II) in CHF are well established, the biological actions of angiotensin 1-7 (Ang 1-7) are not fully characterized. In this study, we assessed the acute effects of Ang 1-7 (0.3, 3, 30 and 300 ng/kg/min, IV) on urinary flow (UF), urinary Na+ excretion (UNaV), glomerular filtration rate (GFR) and renal plasma flow )RPF) in rats with CHF induced by the placement of aortocaval fistula. Additionally, the chronic effects of Ang 1-7 (24 µg/kg/h, via intra-peritoneally implanted osmotic minipumps) on kidney function, cardiac hypertrophy and neurohormonal status were studied. Acute infusion of either Ang 1-7 or its agonist, AVE 0991, into sham controls, but not CHF rats, increased UF, UNaV, GFR, RPF and urinary cGMP. In the chronic protocols, untreated CHF rats displayed lower cumulative UF and UNaV than their sham controls. Chronic administration of Ang 1-7 and AVE 0991 exerted significant diuretic, natriuretic and kaliuretic effects in CHF rats, but not in sham controls. Serum creatinine and aldosterone levels were significantly higher in vehicle-treated CHF rats as compared with controls. Treatment with Ang 1-7 and AVE 0991 reduced these parameters to comparable levels observed in sham controls. Notably, chronic administration of Ang 1-7 to CHF rats reduced cardiac hypertrophy. In conclusion, Ang 1-7 exerts beneficial renal and cardiac effects in rats with CHF. Thus, we postulate that ACE2/Ang 1-7 axis represents a compensatory response to over-activity of ACE/AngII/AT1R system characterizing CHF and suggest that Ang 1-7 may be a potential therapeutic agent in this disease state.

Effect of ArtemiC in patients with COVID-19: A Phase II prospective study.

Despite intensive efforts, there is no effective remedy for COVID-19. Moreover, vaccination efficacy declines over time and may be compromised against new SARS-CoV-2 lineages. Therefore, there remains an unmet need for simple, accessible, low-cost and effective pharmacological anti-SARS-CoV-2 agents. ArtemiC is a medical product comprising artemisinin, curcumin, frankincense and vitamin C, all of which possess anti-inflammatory and anti-oxidant properties. The present Phase II placebo-controlled, double-blinded, multi-centred, prospective study evaluated the efficacy and safety of ArtemiC in patients with COVID-19. The study included 50 hospitalized symptomatic COVID-19 patients randomized (2:1) to receive ArtemiC or placebo oral spray, twice daily on Days 1 and 2, beside standard care. A physical examination was performed, and vital signs and blood tests were monitored daily until hospital discharge (or Day 15). A PCR assessment of SARS-CoV-2 carriage was performed at screening and on last visit. ArtemiC improved NEWS2 in 91% of patients and shortened durations of abnormal SpO2 levels, oxygen supplementation and fever. No treatment-related adverse events were reported. These findings suggest that ArtemiC curbed deterioration, possibly by limiting cytokine storm of COVID-19, thus bearing great promise for COVID-19 patients, particularly those with comorbidities.

Heparanase Inhibition Prevents Liver Steatosis in E0 Mice.

BACKGROUND: Non-alcoholic fatty liver disease affects up to 30% of adults in the USA, and is associated with a higher incidence of chronic liver morbidity and mortality. Several molecular pathways are involved in the pathology of liver steatosis, including lipid uptake, lipogenesis, lipolysis, and beta-oxidation. The enzyme heparanase has been implicated in liver steatosis. Herein, we investigated the effect of heparanase inhibition on liver steatosis in E0 mice. METHODS: In vivo experiments: Male wild-type mice fed with either chow diet (n = 4) or high-fat diet (n = 6), and male E0 mice fed with chow diet (n = 8) or high-fat diet (n = 33) were included. Mice on a high-fat diet were treated for 12 weeks with PG545 at low dose (6.4 mg/kg/week, ip, n = 6) or high dose (13.3 mg/kg/week, ip, n = 7), SST0001 (1.2 mg/mouse/day, ip, n = 6), or normal saline (control, n = 14). Animals were sacrificed two days after inducing peritonitis. Serum was analyzed for biochemical parameters. Mouse peritoneal macrophages (MPMs) were harvested and analyzed for lipid content. Livers were harvested for histopathological analysis of steatosis, lipid content, and the expression of steatosis-related factors at the mRNA level. In vitro experiments: MPMs were isolated from untreated E0 mice aged 8-10 weeks and were cultured and treated with either PG545 or SST0001, both at 50 µg/mL for 24 h, followed by assessment of mRNA expression of steatosis related factors. RESULTS: Heparanase inhibition significantly attenuated the development of liver steatosis, as was evident by liver histology and lipid content. Serum analysis indicated lowering of cholesterol and triglycerides levels in mice treated with heparanase inhibitors. In liver tissue, assessment of mRNA expression of key factors in lipid uptake, lipolysis, lipogenesis, and beta-oxidation exhibited significant downregulation following PG545 treatment and to a lesser extent when SST0001 was applied. However, in vitro treatment of MPMs with PG545, but not SST0001, resulted in increased lipid content in these cells, which is opposed to their effect on MPMs of treated mice. This may indicate distinct regulatory pathways in the system or isolated macrophages following heparanase inhibition. CONCLUSION: Heparanase inhibition significantly attenuates the development of liver steatosis by decreasing tissue lipid content and by affecting the mRNA expression of key lipid metabolism regulators.

Gastric and urinary bladder pressures correlate with intra-abdominal pressure in patients with morbid obesity.

Intra-abdominal pressure (IAP) affects cardio-respiratory and hemodynamic parameters and can be measured directly or indirectly by measuring gastric or urinary bladder pressure. The aim of this study was to investigate the correlation between IAP, gastric pressure and urinary bladder pressure in patients with morbid obesity, at normal and elevated levels of IAP in two positions. As well, to examine the effects of increasing IAP and patient's position on hemodynamic and respiratory parameters. Twelve patients undergoing laparoscopic bariatric surgery were included. IAP, gastric pressure, and urinary bladder pressure were measured while patients were in the supine position and after 45° anti-Trendelenburg tilt. Mean inspiratory pressure, peak inspiratory pressure, and tidal volume were recorded and assessed. In supine position; directly measured IAP was 9.1 ± 1.8 mmHg, compared to 10 ± 3.6 and 8.9 ± 2.9 mmHg in the stomach and bladder, respectively. Increasing IAP to 15 mmHg resulted in an increased gastric pressure of 17 ± 3.8 mmHg, and urinary bladder pressure of 14.8 ± 3.9 mmHg. Gastric and urinary bladder pressures strongly correlated with IAP (R = 0.875 and 0.847, respectively). With 45° anti-Trendelenburg tilt; directly measured IAP was 9.4 ± 2.2 mmHg, and pressures of 10.8 ± 3.8 mmHg and 9.2 ± 3.8 mmHg were measured in the stomach and the bladder, respectively. Increasing IAP to 15 mmHg resulted in elevating gastric and bladder pressures to 16.6 ± 5.3 and 13.3 ± 4 mmHg, respectively. Gastric and urinary bladder pressures had good correlation with IAP (R = 0.843 and 0.819, respectively). Changing patient position from supine to 45° anti-Trendelenburg position resulted in decreased mean and peak inspiratory pressures, and increased tidal volume. Basal IAP is high in patients with morbid obesity. IAP shows positive correlation to gastric and urinary bladder pressures at both normal and elevated levels of IAP. Anti-Trendelenburg tilt of mechanically ventilated morbidly obese patients resulted in favorable effects on respiratory parameters.Trial Registration: The study was retrospectively registered in the NIH registry. Registration number is pending.

A Case of Severe COVID-19 Pneumonia Diagnosed in Bronchoscopy With Negative Repeated Nasopharyngeal Swabs.

Coronavirus disease 2019 (COVID-19) is a worldwide pandemic that had emerged in China since December 2019. The disease affects all age groups, with clinical manifestations in the spectrum from asymptomatic to rapidly lethal multi-organ failure, mainly involving the respiratory system. Diagnosis is confirmed mainly by a positive real-time polymerase chain reaction (PCR) nasopharyngeal swab. It is highly recommended to avoid performing invasive procedures in COVID-19 subjects to prevent the potential for dissemination of the pathogen. Treatment consists in particular of respiratory support and symptom relief. Dexamethasone is widely used with encouraging response. There were no cases in the literature that were diagnosed with positive reverse transcription-polymerase chain reaction (RT-PCR) testing only from fluid of involved organs, while repeated nasopharyngeal swabs returned negative for COVID-19. We here describe a case of COVID-19 that presented with moderate-severe pulmonary involvement, diagnosed by RT-PCR testing from broncho-alveolar lavage, while several nasopharyngeal swabs were consistently negative. The patient experienced no improvement under wide-spectrum antibiotics administered initially, and greatly improved after receiving systemic corticosteroids. One can realize from our case that COVID-19 could not be ruled out upon repeated negative RT-PCR nasopharyngeal swabs, and in subjects with highly suspected COVID-19, it is justified to perform invasive procedures, but still using maximal protective measures.

Heparanase as a potential player in SARS-CoV-2 infection and induced coagulopathy.

During the current formidable COVID-19 pandemic, it is appealing to address ideas that may invoke therapeutic interventions. Clotting disorders are well recognized in patients infected with severe acute respiratory syndrome (SARS) caused by a novel coronavirus (SARS-CoV-2), which lead to severe complications that worsen the prognosis in these subjects. Increasing evidence implicate Heparan sulfate proteoglycans (HSPGs) and Heparanase in various diseases and pathologies, including hypercoagulability states. Moreover, HSPGs and Heparanase are involved in several viral infections, in which they enhance cell entry and release of the viruses. Herein we discuss the molecular involvement of HSPGs and heparanase in SARS-CoV-2 infection, namely cell entry and release, and the accompanied coagulopathy complications, which assumedly could be blocked by heparanase inhibitors such as Heparin and Pixatimod.

A case of rapidly progressive upper limb ischemic necrosis in a patient with COVID-19.

BACKGROUND: For more than a year, health systems all over the world have been combating the global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease was first described in the city of Wuhan in China, presenting as an atypical infection of the lower respiratory tract. METHODS: COVID-19 is characterized by multisystemic involvement, and mortality is attributed mainly to the respiratory system involvement, which may lead to severe acute respiratory distress syndrome and respiratory failure. Several COVID-19-associated complications are being increasingly reported, including arterial and venous thromboembolic events that may lead to amputation of the affected limbs. So far, a large number of reports have described hypercoagulability crises leading to amputation of the lower limbs. However, a search of the National Library of Medicine (MEDLINE) revealed no cases of urgent upper limb amputation in COVID-19 patients. RESULTS: This article describes a novel case of upper limb ischemia in a COVID-19 patient, with rapid progression to hand necrosis, requiring urgent through-arm amputation of the upper limb. CONCLUSIONS: This case emphasizes the need for anticoagulant therapy in COVID-19 patients and to maintain a constant awareness of the possible thromboembolic COVID-19-related sequelae.

Identification, localization and expression of NHE isoforms in the alveolar epithelial cells.

Na+/H+ exchangers (NHEs), encoded by Solute Carrier 9A (SLC9A) genes in human, are ubiquitous integral membrane ion transporters that mediate the electroneutral exchange of H+ with Na+ or K+. NHEs, found in the kidney and intestine, play a major role in the process of fluid reabsorption together via Na+,K+-ATPase pump and Na+ channels. Nevertheless, the expression pattern of NHE in the lung and its role in alveolar fluid homeostasis has not been addressed. Therefore, we aimed to examine the expression of NHE specific isoforms in alveolar epithelial cells (AECs), and assess their role in congestive heart failure (CHF). Three NHE isoforms were identified in AEC and A549 cell line, at the level of protein and mRNA; NHE1, NHE2 and mainly NHE8, the latter was shown to be localized in the apical membrane of AEC. Treating A549 cells with angiotensin (Ang) II for 3, 5 and 24 hours displayed a significant reduction in NHE8 protein abundance. Moreover, the abundance of NHE8 protein was downregulated in A549 cells that were treated overnight with Ang II. NHE8 abundance in whole lung lysate was increased in rats with 1-week CHF compared to sham operated rats. However, lower abundance of NHE8 was observed in 4-week CHF group. In conclusion, we herein show for the first time, the expression of a novel NHE isoform in AEC, namely NHE8. Notably, Ang II decreased NHE8 protein levels. Moreover, NHE8 was distinctly affected in CHF rats, probably depending on the severity of the heart failure.

Dataset on mice body weights and food intake following treatment with PG545.

This data article contains analysis of data observed in E0 mice placed on high fat diet, and treated by intraperitoneal injections of either normal saline (control) or the heparanase inhibitor PG545, in two different doses. Mice body weights and food intake were measured weekly and analyzed data are presented in graphs. Data will be of value for further understanding the role of the enzyme heparanase in controlling food intake and body weight. For further interpretations, see please "Heparanase inhibition attenuates atherosclerosis progression and liver steatosis in E0 mice" (Muhammad et al. 2018).

Heparanase inhibition attenuates atherosclerosis progression and liver steatosis in E0 mice.

BACKGROUND AND AIMS: Increased oxidative stress is associated with accelerated atherosclerosis. Emerging evidence highlights the role of heparanase in atherogenesis, where heparanase inhibitor PG545 reduces oxidative stress in apolipoprotein E deficient mice (E0 mice). Herein, we studied the effects of PG545 on atherosclerosis progression in E0 mice. METHODS: Male E0 mice fed a high-fat diet (n = 20) were divided into 3 groups treated with weekly intraperitoneal injections of either low (0.2 mg/mouse) or high dose (0.4 mg/mouse)PG545 or normal saline (controls) for twelve weeks. Body weight and food intake were measured weekly. At the end of the treatment period, blood pressure was measured, animals were sacrificed and serum samples were collected and assessed for biochemical parameters and oxidative stress. Aortic vessels and livers were collected for atherosclerotic plaques and histopathological analysis, respectively. RESULTS: Blood pressure decreased in mice treated with low, but not high dose of PG545. In addition, heparanase inhibition caused a dose-dependent reduction in serum oxidative stress, total cholesterol, low-density lipoproteins, triglycerides, high-density lipoproteins, and aryl esterase activity. Although food intake was not reduced by PG545, body weight gain was significantly attenuated in PG545 treated groups. Both doses of PG545 caused a marked reduction in aortic wall thickness and atherosclerosis development, and liver steatosis. Liver enzymes and serum creatinine were not affected by PG545. CONCLUSIONS: Heparanase inhibition by PG545 caused a significant reduction in lipid profile and serum oxidative stress along with attenuation of atherosclerosis, aortic wall thickness, and liver steatosis. Moreover, PG545 attenuated weight gain without reducing food intake. Collectively, these findings suggest that heparanase blockade is highly effective in slowing atherosclerosis formation and progression, and decreasing liver steatosis.

Leucine supplementation attenuates macrophage foam-cell formation: Studies in humans, mice, and cultured macrophages.

Whereas atherogenicity of dietary lipids has been largely studied, relatively little is known about the possible contribution of dietary amino acids to macrophage foam-cell formation, a hallmark of early atherogenesis. Recently, we showed that leucine has antiatherogenic properties in the macrophage model system. In this study, an in-depth investigation of the role of leucine in macrophage lipid metabolism was conducted by supplementing humans, mice, or cultured macrophages with leucine. Macrophage incubation with serum obtained from healthy adults supplemented with leucine (5 g/d, 3 weeks) significantly decreased cellular cholesterol mass by inhibiting the rate of cholesterol biosynthesis and increasing cholesterol efflux from macrophages. Similarly, leucine supplementation to C57BL/6 mice (8 weeks) resulted in decreased cholesterol content in their harvested peritoneal macrophages (MPM) in relation with reduced cholesterol biosynthesis rate. Studies in J774A.1 murine macrophages revealed that leucine dose-dependently decreased cellular cholesterol and triglyceride mass. Macrophages treated with leucine (0.2 mM) showed attenuated uptake of very low-density lipoproteins and triglyceride biosynthesis rate, with a concurrent down-regulation of diacylglycerol acyltransferase-1, a key enzyme catalyzing triglyceride biosynthesis in macrophages. Similar effects were observed when macrophages were treated with α-ketoisocaproate, a key leucine metabolite. Finally, both in vivo and in vitro leucine supplementation significantly improved macrophage mitochondrial respiration and ATP production. The above studies, conducted in human, mice, and cultured macrophages, highlight a protective role for leucine attenuating macrophage foam-cell formation by mechanisms related to the metabolism of cholesterol, triglycerides, and energy production. © 2018 BioFactors, 44(3):245-262, 2018.

Heparanase Inhibition Reduces Glucose Levels, Blood Pressure, and Oxidative Stress in Apolipoprotein E Knockout Mice.

BACKGROUND: Atherosclerosis is a multifactorial process. Emerging evidence highlights a role of the enzyme heparanase in various disease states, including atherosclerosis formation and progression. OBJECTIVE: The aim of the study was to investigate the effect of heparanase inhibition on blood pressure, blood glucose levels, and oxidative stress in apoE-/- mice. METHODS: Male apoE-/- mice were divided into two groups: one treated by the heparanase inhibitor PG545, administered intraperitoneally weekly for seven weeks, and the other serving as control group (injected with saline). Blood pressure was measured a day before sacrificing the animals. Serum glucose levels and lipid profile were measured. Assessment of oxidative stress was performed as well. RESULTS: PG545 significantly lowered blood pressure and serum glucose levels in treated mice. It also caused significant reduction of the serum oxidative stress. For safety concerns, liver enzymes were assessed, and PG545 caused significant elevation only of alanine aminotransferase, but not of the other hepatic enzymes. CONCLUSION: Heparanase inhibition by PG545 caused marked reduction of blood pressure, serum glucose levels, and oxidative stress in apolipoprotein E deficient mice, possibly via direct favorable metabolic and hemodynamic changes caused by the inhibitor. Possible hepatotoxic and weight wasting effects are subject for future investigation.

Involvement of heparanase in the pathogenesis of acute kidney injury: nephroprotective effect of PG545.

Despite the high prevalence of acute kidney injury (AKI) and its association with increased morbidity and mortality, therapeutic approaches for AKI are disappointing. This is largely attributed to poor understanding of the pathogenesis of AKI. Heparanase, an endoglycosidase that cleaves heparan sulfate, is involved in extracellular matrix turnover, inflammation, kidney dysfunction, diabetes, fibrosis, angiogenesis and cancer progression. The current study examined the involvement of heparanase in the pathogenesis of ischemic reperfusion (I/R) AKI in a mouse model and the protective effect of PG545, a potent heparanase inhibitor. I/R induced tubular damage and elevation in serum creatinine and blood urea nitrogen to a higher extent in heparanase over-expressing transgenic mice vs. wild type mice. Moreover, TGF-ß, vimentin, fibronectin and α-smooth muscle actin, biomarkers of fibrosis, and TNFα, IL6 and endothelin-1, biomarkers of inflammation, were upregulated in I/R induced AKI, primarily in heparanase transgenic mice, suggesting an adverse role of heparanase in the pathogenesis of AKI. Remarkably, pretreatment of mice with PG545 abolished kidney dysfunction and the up-regulation of heparanase, pro-inflammatory (i.e., IL-6) and pro-fibrotic (i.e., TGF-ß) genes induced by I/R. The present study provides new insights into the involvement of heparanase in the pathogenesis of ischemic AKI.Our results demonstrate that heparanase plays a deleterious role in the development of renal injury and kidney dysfunction,attesting heparanase inhibition as a promising therapeutic approach for AKI.

Heparanase: A Potential New Factor Involved in the Renal Epithelial Mesenchymal Transition (EMT) Induced by Ischemia/Reperfusion (I/R) Injury.

BACKGROUND: Ischemia/reperfusion (I/R) is an important cause of acute renal failure and delayed graft function, and it may induce chronic renal damage by activating epithelial to mesenchymal transition (EMT) of renal tubular cells. Heparanase (HPSE), an endoglycosidase that regulates FGF-2 and TGFß-induced EMT, may have an important role. Therefore, aim of this study was to evaluate its role in the I/R-induced renal pro-fibrotic machinery by employing in vitro and in vivo models. METHODS: Wild type (WT) and HPSE-silenced renal tubular cells were subjected to hypoxia and reoxygenation in the presence or absence of SST0001, an inhibitor of HPSE. In vivo, I/R injury was induced by bilateral clamping of renal arteries for 30 min in transgenic mice over-expressing HPSE (HPA-tg) and in their WT littermates. Mice were sacrificed 48 and 72 h after I/R. Gene and protein EMT markers (α-SMA, VIM and FN) were evaluated by bio-molecular and histological methodologies. RESULTS: In vitro: hypoxia/reoxygenation (H/R) significantly increased the expression of EMT-markers in WT, but not in HPSE-silenced tubular cells. Notably, EMT was prevented in WT cells by SST0001 treatment. In vivo: I/R induced a remarkable up-regulation of EMT markers in HPA-tg mice after 48-72 h. Noteworthy, these effects were absent in WT animals. CONCLUSIONS: In conclusion, our results add new insights towards understanding the renal biological mechanisms activated by I/R and they demonstrate, for the first time, that HPSE is a pivotal factor involved in the onset and development of I/R-induced EMT. It is plausible that in future the inhibition of this endoglycosidase may represent a new therapeutic approach to minimize/prevent fibrosis and slow down chronic renal disease progression in native and transplanted kidneys.

A significant correlation between C - reactive protein levels in blood monocytes derived macrophages versus content in carotid atherosclerotic lesions.

BACKGROUND: Atherosclerosis is a complex disease involving different cell types, including macrophages that play a major role in the inflammatory events occurring in atherogenesis. C-Reactive Protein (CRP) is a sensitive systemic marker of inflammation and was identified as a biomarker of cardiovascular diseases. Histological studies demonstrate CRP presence in human atherosclerotic lesions, and we have previously shown that macrophages express CRP mRNA. CRP could be locally secreted in the atherosclerotic lesion by arterial macrophages and local regulation of CRP could affect its pro-atherogenic effects. Moreover, human blood derived macrophages (HMDM) expression of CRP could reflect atherosclerotic lesion secretion of CRP. METHODS: Ten type 2 diabetic patients and ten non-diabetic patients scheduled to undergo carotid endarterectomy were enrolled in this study, and their blood samples were used for serum CRP, lipid determination, and for preparation of HMDM further analyzed for their CRP mRNA expression and CRP content. Carotid lesions obtained from the patients were analyzed for their CRP and interleukin 6 (IL-6) content by immunohistochemistry. RESULTS: Lesions from diabetic patients showed substantially higher CRP levels by 62% (p = 0.05) than lesions from non diabetic patients, and CRP staining that co-localized with arterial macrophages. CRP carotid lesion levels positively correlated with CRP mRNA expression (r2 = 0.661) and with CRP content (r2 = 0.611) in the patient's HMDM. CONCLUSIONS: Diabetes up-regulated carotid plaques CRP levels and CRP measurements in HMDM could reflect atherosclerotic lesion macrophages secretion of CRP. Understanding the regulation of locally produced macrophage CRP in the arterial wall during atherogenesis could be of major importance in identifying the underlying mechanisms of inflammatory response pathways during atherogenesis.

Pomegranate extract (POMx) decreases the atherogenicity of serum and of human monocyte-derived macrophages (HMDM) in simvastatin-treated hypercholesterolemic patients: a double-blinded, placebo-controlled, randomized, prospective pilot study.

OBJECTIVE: To analyze pomegranate extract (POMx) effects on serum and on human HMDM atherogenicity in simvastatin - treated hypercholesterolemic patients. METHODS AND RESULTS: Patients were randomly assigned to receive either simvastatin (20 mg/day) + vegan placebo pill (n = 11), or simvastatin (20 mg/day) + POMx pill (1g/day, n = 12). Fasting blood samples were collected at baseline and after 1 and 2 months of therapy. HMDM were collected from 3 patients in each group at baseline and after 2 months of therapy, as well as from 3 healthy subjects. After 2 months of therapy, serum LDL-cholesterol levels significantly decreased, by 23%, in the simvastatin + placebo group, and by 26% in the simvastatin + POMx group. Simvastatin + POMx therapy increased serum thiols concentration by 6%. Patients' HMDM reactive oxygen species (ROS) levels were significantly increased, by 69%, vs. healthy subjects HMDM. After 2 months of therapy, HMDM ROS levels decreased by 18% in the simvastatin + placebo group, whereas in the simvastatin + POMx group it decreased by up to 30%. A novel finding was the triglycerides levels in the patients' HMDM at baseline which were significantly higher, by 71%, vs. healthy subjects HMDM. The simvastatin + POMx, but not the simvastatin + placebo therapy, significantly reduced macrophage triglycerides content by 48%, vs. baseline levels. In addition, whereas the simvastatin + placebo therapy significantly decreased the patients' HMDM cholesterol biosynthesis rate by 33%, the simvastatin + POMx therapy further decreased it, by 44%. CONCLUSION: The addition of POMx to simvastatin therapy in hypercholesterolemic patients improved oxidative stress and lipid status in the patient's serum and in their HMDM. These anti-atherogenic effects could reduce the risk for atherosclerosis development.

Chest pain unit in an internal medicine department: comparison of a year with the facility to a year without.

BACKGROUND: Chest pain is one of the most common reasons for emergency department visits and hospital admissions. Chest pain units (CPU) are being incorporated in tertiary hospitals for rapid and effective management of patients with chest pain. In Israel prior to 2010, only one chest pain unit existed in a tertiary hospital. OBJECTIVES: To report our first year experience with a CPU located in an internal medicine department as compared to the year before establishment of the CPU. METHODS: We retrospectively evaluated the medical records of consecutive patients who were admitted to our internal medicine department for the investigation of chest pain for 2 different years: a year before and a year after the establishment of the CPU in the department. We focused on the patients' characteristics and the impact of the CPU regarding the investigational modalities used and the length of in-hospital stay. RESULTS: In the year before establishment of the CPU, 258 patients were admitted to our department with chest pain, compared to 417 patients admitted to the CPU in the first year of its operation. All patients were followed for serial electrocardiographic and cardiac enzyme testing. All CPU patients (100%) underwent investigation compared to only 171 patients (66%) in the pre-CPU year. During the year pre-CPU, 164 non-invasive tests were performed (0.64 tests per patient) compared to 506 tests (1.2 tests/patient) in the CPU population. Coronary arteriography was performed in 35 patients (14%) during the pre-CPU year, mostly as the first test performed, compared to 61 patients (15%) during the CPU year, mostly as a second test, with only 5 procedures (1.1%) being the first test performed. The length of hospitalization was significantly shorter during the CPU year, 37.8 +/- 29.4 hours compared to 66.8 +/- 46 hours in the pre-CPU year. CONCLUSIONS: Establishment of a CPU in an internal medicine department significantly decreased the need for invasive coronary arteriography as the first modality for investigating patients admitted with chest pain, significantly decreased the need for invasive procedures (especially where no intervention was performed), and significantly shortened the hospitalization period. CPU is an effective facility for rapid and effective investigation of patients admitted with chest pain.

Niacin administration significantly reduces oxidative stress in patients with hypercholesterolemia and low levels of high-density lipoprotein cholesterol.

Oxidative stress has been implicated in the pathogenesis of cardiovascular disorders, including atherosclerosis. In pharmacological doses, niacin (vitamin B3) was proven to reduce total cholesterol, triglyceride, very-low-density lipoprotein, and low-density lipoprotein levels, and to increase high-density lipoprotein (HDL) levels. The aim of this study was to evaluate the effect of niacin treatment in patients with low levels of HDL cholesterol (HDL-C; <40 mg%) on their lipid profile and oxidative stress status. Seventeen patients with hypercholesterolemia and low HDL-C and 8 healthy control subjects were enrolled in the study. The patients were treated with niacin for 12 weeks. Lipid profile, oxidative stress and C-reactive protein (CRP) levels were determined at the time of enrollment, and 2 and 12 weeks after initiation of niacin treatment. Subjects with lower HDL-C levels exhibited higher oxidative stress compared with subjects with normal HDL-C levels. Niacin treatment in hypercholesterolemic patients caused a significant increase in HDL-C and apolipoprotein A1 levels, and a decrease in triglyceride levels. Niacin also significantly reduced oxidative stress, as measured by a significant decrease in the serum content of thiobarbituric acid reactive substances, lipid peroxides and paraoxonase activity, compared with the levels before treatment. Although serum CRP levels were not affected by niacin treatment, a correlation between CRP and HDL levels was obtained when computing the results. Niacin treatment in hypercholesterolemic patients with low HDL levels caused a significant decrease in their oxidative stress status. These results indicate an additional beneficial effect of niacin beyond its ability to affect the lipid profile.