Renoprotective effects of apocynin and/or umbelliferone against acrylamide-induced acute kidney injury in rats: role of the NLRP3 inflammasome and Nrf-2/HO-1 signaling pathways.

Acrylamide (ACR) is a toxic, probably carcinogenic compound commonly found in fried foods and used in the production of many industrial consumer products. ACR-induced acute kidney injury is mediated through several signals. In this research, we investigated, for the first time, the therapeutic effects of phytochemicals apocynin (APO) and/or umbelliferone (UMB) against ACR-induced nephrotoxicity in rats and emphasized the underlying molecular mechanism. To achieve this goal, five groups of rats were randomly assigned: the control group received vehicle (0.5% CMC; 1 ml/rat), ACR (40 mg/kg, i.p.), ACR + APO (100 mg/kg, P.O.), ACR + UMB (50 mg/kg, P.O.), and combination group for 10 days. In ACR-intoxicated rats, there was a significant reduction in weight gain while the levels of blood urea, uric acid, creatinine, and Kim-1 were elevated, indicating renal injury. Histopathological injury was also observed in the kidneys of ACR-intoxicated rats, confirming the biochemical data. Moreover, MDA, TNF-α, and IL-1ß levels were raised; and GSH and SOD levels were decreased. In contrast, treatment with APO, UMB, and their combination significantly reduced the kidney function biomarkers, prevented tissue damage, and decreased inflammatory cytokines and MDA. Mechanistically, it suppressed the expression of NLRP-3, ASC, GSDMD, caspase-1, and IL-1ß, while it upregulated Nrf-2 and HO-1 in the kidneys of ACR-intoxicated rats. In conclusion, APO, UMB, and their combination prevented ACR-induced nephrotoxicity in rats by attenuating oxidative injury and inflammation, suppressing NLRP-3 inflammasome signaling, enhancing antioxidants, and upregulating Nrf-2 and HO-1 in the kidneys of ACR-induced rats.

Edaravone and obeticholic acid protect against cisplatin-induced heart toxicity by suppressing oxidative stress and inflammation and modulating Nrf2, TLR4/p38MAPK, and JAK1/STAT3/NF-κB signals.

Cardiotoxicity is a significant adverse effect of cisplatin (CIS) that necessitates extensive medical care. The current study examines the cardioprotective effects of edaravone (EDV), obeticholic acid (OCA), and their combinations on CIS-induced cardiac damage. Rats were allocated into five groups: the normal control group, the remaining four groups received CIS (7.5 mg/kg, i.p.) as a single dose on the fifth day and were assigned to CIS, OCA (10 mg/kg/day) + CIS, EDV (20 mg/kg/day) + CIS, and the (EDV + OCA) + CIS group. Compared to the CIS-treated group, co-treating rats with EDV, OCA, or their combinations significantly decreased ALP, AST, LDH, CK-MB, and troponin-I serum levels and alleviated histopathological heart abnormalities. Biochemically, EDV, OCA, and EDV plus OCA administration mitigated cardiac oxidative stress as indicated by a marked decrease in heart MDA content with a rise in cardiac antioxidants SOD and GSH associated with upregulating Nrf2, PPARγ, and SIRT1 expression. Besides, it dampened inflammation by decreasing cardiac levels of TNF-α, IL-1ß, and IL-6, mediated by suppressing NF-κB, JAK1/STAT3, and TLR4/p38MAPK signal activation. Notably, rats co-administered with EDV plus OCA showed noticeable protection that exceeded that of EDV and OCA alone. In conclusion, our study provided that EDV, OCA, and their combinations effectively attenuated CIS-induced cardiac intoxication by activating Nrf2, PPARγ, and SIRT1 signals and downregulating NF-κB, JAK1/STAT3, and TLR4/p38MAPK signals.

Discovery of new 5-substituted-indole-2-carboxamides as dual epidermal growth factor receptor (EGFR)/cyclin dependent kinase-2 (CDK2) inhibitors with potent antiproliferative action.

A new series of 5-substituted-3-ethylindole-2-carboxamides 5a-k and 6a-c was designed and synthesised in an attempt to develop a dual targeted antiproliferative agent. Various spectroscopic methods of analysis were used to confirm the structures of the new compounds. The antiproliferative effect of compounds 5a-k and 6a-c against four cancer cell lines was investigated. Compounds 5a-k and 6a-c had significant antiproliferative activity against the four cancer cell lines tested, with mean GI50 values ranging from 37 nM to 193 nM. The most powerful derivatives were compounds 5g, 5i, and 5j, with GI50 values of 55 nM, 49 nM, and 37 nM, respectively, in comparison to the reference erlotinib, which had a GI50 of 33 nM. The four most potent compounds, 5c, 5g, 5i, and 5j, were then investigated for their efficacy as EGFR inhibitors, and the findings showed that the tested compounds inhibited EGFR with IC50 values ranging from 85 nM to 124 nM when compared to the reference erlotinib (IC50 = 80 nM). Moreover, compounds 5c and 5g inhibited CDK2 with IC50 values of 46 ± 05 nM and 33 ± 04 nM, respectively. The EGFR and CDK2 assays revealed that compounds 5i and 5j displayed potent antiproliferative activity and can be considered as potential dual EGFR and CDK2 inhibitors.

Acetovanillone augmented the cardioprotective effect of carvedilol against cadmium-induced heart injury via suppression of oxidative stress and inflammation signaling pathways.

Cardiac toxicity is a public health issue that can be caused by both environmental and occupational exposures. The current study aimed to investigate the effectiveness of carvedilol (CV), Acetovanillone (ACET), and their combination for ameliorating cadmium (Cd)-induced oxidative stress, inflammation, and necroptosis. Rats were assigned to; the normal group, Cd group (2 mg/kg; i.p., single dose), and the other three groups received orally CV (10 mg/kg), ACET (25 mg/kg), and CV plus ACET, respectively and a single dose of Cd. Oral administration of CV, ACET, and their combination significantly dampens cardiac oxidative injury by increasing antioxidants GSH and SOD levels, while it decreases MDA and NADPH oxidase levels mediated by decreasing cardiac abundance of Nrf2, HO-1, and SIRT1 and downregulating KEAP-1 and FOXO-3 levels. Also, they significantly attenuated inflammatory response as indicated by reducing MPO and NOx as well as proinflammatory cytokines TNF-α and IL-6 mediated by downregulating TLR4, iNOS, and NF-κB proteins expression as well as IκB upregulation. Moreover, they potently counteracted cardiac necroptosis by downregulating RIPK1, RIPK3, MLKL, and caspase-8 proteins expression. Of note, the combination of CV and ACET have marked protection that exceeded each drug alone. Conclusively, CV ad ACET potently mitigated Cd-induced cardiac intoxication by regulating NADPH oxidase, KEAP-1/Nrf2/HO-1, SIRT1/FOXO-3, TLR4/NF-κB/iNOS, and RIPK1/RIPK3/MLKL signals.

Therapeutic interventions of acute and chronic liver disorders: A comprehensive review.

Liver disorders are one of the most common pathological problems worldwide. It affects more than 1.5 billion worldwide. Many types of hepatic cells have been reported to be involved in the initiation and propagation of both acute and chronic liver diseases, including hepatocytes, Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells (HSCs). In addition, oxidative stress, cytokines, fibrogenic factors, microRNAs, and autophagy are also involved. Understanding the molecular mechanisms of liver diseases leads to discovering new therapeutic interventions that can be used in clinics. Recently, antioxidant, anti-inflammatory, anti-HSCs therapy, gene therapy, cell therapy, gut microbiota, and nanoparticles have great potential for preventing and treating liver diseases. Here, we explored the recent possible molecular mechanisms involved in the pathogenesis of acute and chronic liver diseases. Besides, we overviewed the recent therapeutic interventions that targeted liver diseases and summarized the recent studies concerning liver disorders therapy.

COVID-19 and hepatic injury: cellular and molecular mechanisms in diverse liver cells.

The coronavirus disease 2019 (COVID-19) represents a global health and economic challenge. Hepatic injuries have been approved to be associated with severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection. The viral tropism pattern of SARS-CoV-2 can induce hepatic injuries either by itself or by worsening the conditions of patients with hepatic diseases. Besides, other factors have been reported to play a crucial role in the pathological forms of hepatic injuries induced by SARS-CoV-2, including cytokine storm, hypoxia, endothelial cells, and even some treatments for COVID-19. On the other hand, several groups of people could be at risk of hepatic COVID-19 complications, such as pregnant women and neonates. The present review outlines and discusses the interplay between SARS-CoV-2 infection and hepatic injury, hepatic illness comorbidity, and risk factors. Besides, it is focused on the vaccination process and the role of developed vaccines in preventing hepatic injuries due to SARS-CoV-2 infection.

Combined apocynin and carvedilol protect against cadmium-induced testicular damage via modulation of inflammatory response and redox-sensitive pathways.

Testicular damage is considered a severe complication of cadmium (Cd) exposure which is associated with tissue oxidative stress damage, inflammation, and apoptosis. The present study investigated the antioxidant, anti-inflammatory, and anti-apoptotic activities of apocynin (APO) and carvedilol (CVD) against Cd-induced acute testicular damage. Rats were allocated into five groups as follows: normal control (received vehicle), Cd control group (2 mg/kg, i.p), APO-treated group (25 mg/kg, P.O.), CVD-treated group (10 mg/kg, P.O.), and combination group (APO + CVD). Blood, serum, and tissue samples were withdrawn for hematological, biochemical, molecular, and histological analyses. The present results confirmed testicular damage after cd exposure as indicated by alteration of serum hormonal levels, hematological defects, histopathological changes, and loss of steroidogenic functions. Besides, Cd injection-induced up-regulation of NADPH oxidase, MDA, NF-κB, IRF3, MPO, pro-inflammatory cytokines, Bax, and cleaved caspase-3 expression concomitant with down-regulation of Nrf2, GSH, SOD, and Bcl2 expression. Interestingly, pretreatment with APO and/or CVD significantly relieved Cd-induced testicular damage at cellular and molecular levels. Notably, the combined protective effect of APO plus CVD was higher than the protective effect of each drug alone. Overall, combined APO and CVD could serve as a good candidate for protection against Cd-induced testicular damage via suppression of inflammatory response and modulation of the redox-sensitive pathway.

Ursodeoxycholic acid abrogates gentamicin-induced hepatotoxicity in rats: Role of NF-κB-p65/TNF-α, Bax/Bcl-xl/Caspase-3, and eNOS/iNOS pathways.

AIM: The present study focused on the possible underlying protective mechanisms of UDCA against GNT-induced hepatic injury. METHODS: For achieving this goal, adult male rats were allocated into 4 groups: normal control (received vehicle), GNT (100 mg/kg, i.p. for 8 days), UDCA (60 mg/kg, P.O. for 15 days), and GNT + UDCA (received UDCA for 15 days and GNT started from the 7th day and lasted for 8 days). RESULTS: The results revealed that UDCA significantly improved GNT-induced hepatic injury, oxidative stress, apoptosis, and inflammatory response. Interestingly, UDCA inhibited apoptosis by marked down-regulation of the Bax gene, Caspase-3, and cleaved Caspase-3 protein expressions while the level of Bcl-xL gene significantly increased. Moreover, UDCA strongly inhibited the inflammatory response through the down-regulation of both NF-κB-p65 and TNF-α accompanied by IL-10 elevation. Furthermore, the obtained results ended with the restored of mitochondria function that confirmed by electron microscopy. Histological analysis showed that UDCA remarkably ameliorated the histopathological changes induced by GNT. SIGNIFICANCE: UDCA may be a promising agent that can be used to prevent hepatotoxicity observed in GNT treatment. This effect could be attributed to, at least in part, the ability of UDCA to modulate NF-κB-p65/TNF-α, Bax/Bcl-xl/Caspase-3, and eNOS/iNOS signaling pathways.

Diosmin enhances the anti-angiogenic activity of sildenafil and pentoxifylline against hepatopulmonary syndrome via regulation of TNF-α/VEGF, IGF-1/PI3K/AKT, and FGF-1/ANG-2 signaling pathways.

Hepatopulmonary syndrome (HPS) is a severe complication of hepatic cirrhosis, which is characterized by hypoxia, intrapulmonary vasodilation, inflammation, and angiogenesis. In this study, we aimed to investigate the regulatory effects of diosmin (DS) on selected phosphodiesterase inhibitors against chronic bile duct ligation (CBDL)-induced HPS. Experimentally, Wistar Albino rats were used and HPS was induced by CBDL for 28 days. DS (100 mg/kg, daily, P.O.), sildenafil (Sild; 10 mg/kg, twice daily, P.O.), and pentoxifylline (PTX; 50 mg/kg, daily, P.O.) were evaluated either alone or in combinations for their anti-angiogenic activity. CBDL significantly altered oxidative stress biomarkers and up-regulated pulmonary mRNA expressions of VEGF, IGF-1, ET-1, iNOS, eNOS, and ANG-2 as well as the protein expressions of vWF, FGF-1, PI3K, AKT, p-AKT, TGF-ß, HYP, MPO activity and circulating TNF-α. Treatment with DS, Sild, PTX, and their combinations significantly attenuated molecular and cellular changes due to CBDL. Improvement of histopathological changes was also observed after drug treatment which further supported our results. Furthermore, DS combination with Sild or PTX exhibited an improvement in HPS in comparison to each drug alone. Collectively, DS can augment the anti-angiogenic activity of Sild and PTX during HPS through regulation of TNF-α/VEGF, IGF-1/PI3K/AKT, and FGF-1/ANG-2 signaling pathways.

Reproductive and Productive Efficiency of Maghrebi Dairy She-Camels Fed Diets Supplemented with Zinc-Methionine.

This study is aimed at evaluating the effect of dietary zinc-methionine (Zn-Met) supplementation during 3 months prepartum up to 9 months postpartum on reproductive performance, blood biochemical, and milk production of lactating she-camels besides growth performance of their calves. Twenty pregnant Maghrebi she-camels (439.49 ± 11.57 kg; 3-5 parties) were divided into four similar groups. Animals were fed the basal diet (G1) or the basal diet supplemented with Zn-Met at levels of 30 mg (G2), 40 mg (G3), and 50 mg (G4)/kg diet. Results revealed that IgA, IgM, and IgG concentrations in colostrum, monthly milk yield, and lactation period were significantly increased in Zn-Met-supplemented groups. Milk contents of fat, ash, and total solids improved (P < 0.05) in G4 as compared with other groups. Pre- and postpartum Zn, T3, T4, P4, and E2 concentrations in plasma and milk Zn level were higher (P < 0.05) in all Zn-Met-supplemented groups. Postpartum first estrus interval, number of services/conception, days open, pregnancy rate, duration of placental drop, and calving interval improved (P < 0.05) in G4. Weaning weight and average daily gain of calves were enhanced all in Zn-Met-supplemented groups. Conclusively, the inclusion of Zn-Met especially at a level of 50 mg/kg diet, 3 months prepartum up to 9 months postpartum, led to better productive and reproductive performance, immunity of she-camels, and growth performance of their offspring.

Perindopril mitigates LPS-induced cardiopulmonary oxidative and inflammatory damage via inhibition of renin angiotensin system, inflammation and oxidative stress.

Aim: Renin-angiotensin system (RAS) is thought to have a noticeable effect in the pathophysiological injury in multiple organs by inducing different cellular and molecular reactions. The objective of the current study is to investigate the possible protective effects of perindopril against lipopolysaccharide (LPS)-induced cardiopulmonary oxidative and inflammatory damage in rats. Methods: To achieve this goal, animals were randomly divided into six groups: normal group, LPS group (3 mg/kg, i.p., single dose), perindopril-LPS treated group (1 mg/kg/day, i.p.), perindopril-LPS treated group (2 mg/kg/day, i.p.), and two perindopril negative groups (perindopril 1 or 2 mg/kg/day, i.p.) alone for seven days. Lungs and hearts tissue angiotensin II (Ang-II), angiotensin-1-7 (Ang-1-7), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were assessed using ELISA. Nuclear factor kappa-B-p65 (NF-κB-p65) was assessed using real time PCR, while protein kinase B (Akt) was evaluated by Western blot analysis. Furthermore, oxidative stress biomarkers and myeloperoxidase (MPO) enzyme were evaluated spectrophotometrically. Tissues inducible and endothelial nitric oxide synthases (iNOS and eNOS) were assessed immunohistochemically. Histopathological study was carried out to confirm our results. Results: LPS-intoxicated rats significantly elevated Ang-II, NF-κB-p65, Akt, and iNOS levels, coupled with significant down-regulation of Ang-1-7 and eNOS levels and corrected the oxidative stress biomarkers. Perindopril administration significantly attenuated the disturbances induced by LPS in a dose-dependent manner. Conclusion: Perindopril mitigates LPS-induced heart and lung damage through modulation of RAS, iNOS/eNOS, Akt, and NF-κB-p65 signaling pathways.

Screening for BK Viremia/Viruria and the Impact of Management of BK Virus Nephropathy in Renal Transplant Recipients.

OBJECTIVES: The prevalence of BK-induced nephritis in renal transplant recipients is estimated to be 1% to 10%; the rate of graft loss within 1 year is 30% to 65%. We conducted this study to evaluate screening of BK virus in blood and/or urine among renal transplant recipients and to assess the effects of different therapeutic modalities in renal transplant recipients with BK nephropathy. MATERIALS AND METHODS: Kidney transplant recipients were screened at the time of transplant and then at 1, 2, 3, 6, 9, 12, 18, and 24 months posttransplant. Fiftynine patients were diagnosed with BK virus viremia. Patients were divided into 2 groups according to treatment: group 1 (n = 29) received an active treatment and group 2 (n = 30) received minimized immunosuppression. RESULTS: Most patients required graft biopsies to confirm diagnosis (86.2% in group 1 vs 50% in group 2; P = .03). Both groups were comparable regarding demographic data. Initial posttransplant graft function was significantly better in group 1 (P = .017); ultimately, there was no significant difference between both groups regarding graft survival (P= .51). Fifty percent of patients had biopsy-proven acute T-cell-mediated rejection before BK virus-associated nephropathy diagnosis (significantly higher in group 1). Serum creatinine levels were significantly better in group 2 at 3, 4, and 5 years after BK nephropathy (P = .001, .017, and .003, respectively). CONCLUSIONS: The prevalence of BK nephropathy in our renal transplant recipients was 5.9% with a rate of graft loss ranging from 43% to 51%. Regular screening, less intensive immunosuppressive therapy, and early intervention by reduction of immunosuppressive medications are advisable to obtain early diagnosis and to have better outcomes of BK virus-associated nephropathy with antiviral agents.

Hepatoprotective effects of diosmin and/or sildenafil against cholestatic liver cirrhosis: The role of Keap-1/Nrf-2 and P38-MAPK/NF-κB/iNOS signaling pathway.

The present study was designed to investigate the potential protective effects of diosmin (DS) and/or sildenafil against bile duct ligation (BDL). In order to achieve this goal, BDL was performed to induce liver cirrhosis, DS (100 mg/kg/day, p.o.) and sildenafil (10 mg/kg, twice daily, p.o.) were administrated alone or in combination 24 h after the surgical operation and lasted for 4 weeks. Liver function biomarkers, fibrotic markers, oxidative stress markers, mRNA expression of NF-κB-p65, P38-MAPK, Nrf-2, and Keap-1, as well as protein expression of cytoglobin, NF-κB-p65, Nrf-2, iNOS and eNOS were investigated concomitantly with histopathological study. The results revealed that, 4 weeks of BDL induced a significant alteration in liver functions, fibrotic and oxidative stress markers. Furthermore, up-regulation of NF-κB-p65, P38-MAPK, Keap-1 and iNOS concomitantly with down-regulation of Nrf-2, cytoglobin and eNOS expressions were observed after BDL. DS and/or sildenafil treatment significantly alleviated the disturbance induced by BDL. These findings were further supported by the improvement in histopathological features. Additionally, co-administration of DS and sildenafil were found to significantly improved liver defects due to BDL as compared to the individual drugs. It can be concluded that, DS and sildenafil exhibit hepatoprotective effects through modulation of Keap-1/Nrf-2 and P38-MAPK/NF-κB/iNOS pathway.

Targeting Keap-1/Nrf-2 pathway and cytoglobin as a potential protective mechanism of diosmin and pentoxifylline against cholestatic liver cirrhosis.

AIM: The effects of diosmin (DS), pentoxifylline (PTX) and their combination on inflammatory response, oxidant/antioxidant balance, cytoglobin and cirrhotic reaction during bile duct ligation (BDL) were investigated and explored. MAIN METHODS: Fifty adult male Wistar albino rats were randomly allocated to five groups as following, sham: received vehicle only, BDL: subjected to common BDL without treatment, BDL plus DS: received 100 mg/kg/day orally, BDL plus PTX: received 50 mg/kg/day orally, BDL plus DS plus PTX: received DS and PTX in the same manner. The test period lasted 28 days, liver tissues and blood samples were collected to investigate biochemical markers (liver function biomarkers, oxidative stress markers, and antifibrotic markers), mRNA expression of Nrf-2, Keap-1, NF-κB-p65 and p38-MAPK by real-time PCR, protein expression of cytoglobin and NF-κB-p65 by western blot and iNOS and eNOS by immunohistochemistry. Histopathological study was performed to confirm our results. KEY FINDINGS: Chronic BDL induced a significant alteration in liver functions, oxidative stress and fibrotic markers. Furthermore, unfavorable effects on gene and protein expression were observed after BDL. Histopathological findings of this group showed parallel effects. DS, PTX and their combination treatment significantly ameliorated the disturbance that occurred due to BDL. Similar findings were observed in liver histopathology. SIGNIFICANCE: DS and PTX could mitigate liver cirrhosis through modulation of Keap-1/Nrf-2/GSH and NF-κB-p65/p38-MAPK signaling pathways. In addition, we demonstrated that the hepatoprotective effect of DS and PTX is mediated by up-regulation of cytoglobin with inhibition of fibrotic reaction.

Protective effects of phloridzin against methotrexate-induced liver toxicity in rats.

BACKGROUND: Liver is the largest internal organ concerning with metabolism, hormonal balance and clarifying of the toxins. One of the main complications of methotrexate (MTX) therapy was the hepatic injury. OBJECTIVE: This study was conducted to elucidate the possible protective effects of phloridzin (PHL) against MTX-induced hepatotoxicity as compared to standard agent N-acetylcysteine (NAC). MATERIALS AND METHODS: Rats were randomly divided into a normal control group, a respective group (PHL 40mg/kg/day orally (p.o.) for 10 consecutive days), a hepatotoxicity control group (MTX 20mg/kg, i.p., once), and three treated groups received NAC (150mg/kg/day; a reference standard), PHL (40mg/kg/day) and PHL (80mg/kg/day) p.o. for 10 consecutive days, at the end of the day 3 of the experiment rats were administered MTX. Assessed biomarkers included serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) as liver function parameters, serum tumor necrosis factor-α (TNF-α) and cyclooxygenase-II (COX-II), as inflammatory biomarkers, hepatic total antioxidant capacity (TAC), thiobarbituric acid reactive substances (TBARS), glutathione reduced (GSH), nitrite (NO2-), catalase (CAT), glutathione-S-transferase (GST) and superoxide dismutase (SOD) as oxidative stress biomarkers. Furthermore, hepatic caspase-3 expression was assessed. Biochemical and molecular estimations reinforced by histopathological findings. RESULTS: Rats pre-treated with PHL significantly reduced hepatic injury, evidenced by significant reductions in ALT, AST and LDH, TNF-α and COX-II levels, significant reductions in hepatic NO2- and TBARS levels, and significant elevations in hepatic TAC, GSH, GST, CAT and SOD levels. Additionally, downregulation of hepatic caspase-3 expression. Finally, histopathological results consistent with our previous findings. CONCLUSION: PHL protects against hepatic injury in rats mainly through mitigation of oxidative stress, inflammation and apoptosis in hepatic tissues and may be promising to alleviate and early treatment of MTX-induced hepatoxicity in man.

Patients with non-obstructive coronary artery disease admitted with acute myocardial infarction carry a better outcome compared to those with obstructive coronary artery disease.

BACKGROUND: The characterization of patients who have acute myocardial infarction (AMI) and insignificant coronary stenosis is unclear. AIM: The present study aimed to investigate the clinical profile, in-hospital and 3-month outcome of AMI patients with insignificant coronary stenosis in comparison with those with significant disease. METHODS: This prospective observational study included 200 consecutive patients admitted with AMI. Group I (100 patients) included patients with insignificant CAD (all lesions <50% stenosis). Group II (100 patients) included patients with one or more lesions >70% stenosis. Patients with previous CABG were excluded. Patients with significant CAD had successful total revascularization. RESULTS: Patients with insignificant CAD were significantly younger (61 vs. 67 years, p < 0.001), more likely to be females (41% vs. 23%, p = 0.006), less likely to smoke (p = 0.006), less likely to have diabetes mellitus (p < 0.001), and less likely to have history of CAD (p = 0.042) or prior PCI (p = 0.037). They were also less likely to have typical anginal pain at presentation (61% vs 91%, p < 0.001), less likely to have heart failure at presentation (9% vs 30%, p < 0.001), less likely to have ischemic ST-segment changes on presentation (10% vs 46%, p < 0.001), lower peak troponin (p < 0.001) and CK-MB levels (p < 0.001), with lower LDL-C (p = 0.006), and higher HDL-C level (p = 0.020). They were less likely to be treated with b-blockers (p = 0.002), ACEI/ARBS (p = 0.007), and higher rates of calcium channel blocker therapy (p < 0.001). They had lower prevalence of major adverse clinical events at follow-up (readmission for ACS (p = 0.009), need for revascularization (p = 0.035), recurrent chest pain (p = 0.009), and cardiogenic shock (p = 0.029). CONCLUSION: Patients with AMI and insignificant CAD have different clinical profile and outcome compared to those with significant disease.

Effects of carbon monoxide-releasing molecules on pulmonary vasoreactivity in isolated perfused lungs.

In addition to its renowned poisonous effects, carbon monoxide (CO) is being recognized for its beneficial actions on inflammatory and vasoregulatory pathways, particularly when applied at low concentrations via CO-releasing molecules (CO-RMs). In the lung, CO gas and CO-RMs are suggested to decrease pulmonary vascular tone and hypoxic pulmonary vasoconstriction (HPV). However, the direct effect of CO-RMs on the pulmonary vasoreactivity in isolated lungs has not yet been investigated. We assessed the effect of CORM-2 and CORM-3 on the pulmonary vasculature during normoxia and acute hypoxia (1% oxygen for 10 min) in isolated ventilated and perfused mouse lungs. The effects were compared with those of inhaled CO gas (10%). The interaction of CORM-2 or CO with cytochrome P-450 (CYP) was measured simultaneously by tissue spectrophotometry. Inhaled CO decreased HPV and vasoconstriction induced by the thromboxane mimetic U-46619 but did not alter KCl-induced vasoconstriction. In contrast, concentrations of CORM-2 and CORM-3 used to elicit beneficial effects on the systemic circulation did not affect pulmonary vascular tone. High concentration of CO-RMs or long-term application induced a continuous increase in normoxic pressure. Inhaled CO showed spectral alterations correlating with the inhibition of CYP. In contrast, during application of CORM-2 spectrophotometric signs of interaction with CYP could not be detected. Application of CO-RMs in therapeutic doses in isolated lungs neither decreases pulmonary vascular tone and HPV nor does it induce spectral alterations that are characteristic of CO-inhibited CYP. High doses, however, may cause pulmonary vasoconstriction.

Effects of dimethylarginine dimethylaminohydrolase-1 overexpression on the response of the pulmonary vasculature to hypoxia.

Acute and sustained hypoxic pulmonary vasoconstriction (HPV), as well as chronic pulmonary hypertension (PH), is modulated by nitric oxide (NO). NO synthesis can be decreased by asymmetric dimethylarginine (ADMA), which is degraded by dimethylarginine dimethylaminohydrolase-1 (DDAH1). We investigated the effects of DDAH1 overexpression (DDAH1(tg)) on HPV and chronic hypoxia-induced PH. HPV was measured during acute (10 min) and sustained (3 h) hypoxia in isolated mouse lungs. Chronic PH was induced by the exposure of mice to 4 weeks of hypoxia. ADMA and cyclic 3',5'-guanosine monophosphate (cGMP) were determined by ELISA, and NO generation was determined by chemiluminescence. DDAH1 overexpression exerted no effects on acute HPV. However, DDAH1(tg) mice showed decreased sustained HPV compared with wild-type (WT) mice. Concomitantly, ADMA was decreased, and concentrations of NO and cGMP were significantly increased in DDAH1(tg). The administration of either Nω-nitro-l-arginine or 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one potentiated sustained HPV and partly abolished the differences in sustained HPV between WT and DDAH1(tg) mice. The overexpression of DDAH1 exerted no effect on the development of chronic hypoxia-induced PH. DDAH1 overexpression selectively decreased the sustained phase of HPV, partly via activation of the NO-cGMP pathway. Thus, increased ADMA concentrations modulate sustained HPV, but not acute HPV or chronic hypoxia-induced PH.

Mitochondrial hyperpolarization in pulmonary vascular remodeling. Mitochondrial uncoupling protein deficiency as disease model.

Alterations of mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and mitochondrial respiration are possible triggers of pulmonary vascular remodeling in pulmonary hypertension (PH). We investigated the role of MMP in PH and hypothesized that deletion of the mitochondrial uncoupling protein 2 (UCP2) increases MMP, thus promoting pulmonary vascular remodeling and PH. MMP was measured by JC-1 in isolated pulmonary arterial smooth muscle cells (PASMCs) of patients with PH and animals with PH induced by exposure to monocrotaline (MCT) or chronic hypoxia. PH was quantified in vivo in UCP2-deficient (UCP2(-/-)) mice by hemodynamics, morphometry, and echocardiography. ROS were measured by electron spin resonance spectroscopy and proliferation by thymidine incorporation. Mitochondrial respiration was investigated by high-resolution respirometry. MMP was increased in PASMCs of patients and in animal models of PH. UCP2(-/-) mice exhibited pulmonary vascular remodeling and mild PH compared with wild-type (WT) mice. PASMCs of UCP2(-/-) mice showed increased proliferation, MMP, and ROS release. Increased proliferation of UCP2(-/-) PASMCs could be attenuated by ROS inhibitors and inhibited by carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, which decreased MMP to the level of WT mice. Mitochondrial respiration was altered in PASMCs from MCT rats and PASMCs exposed to hypoxia but not in isolated pulmonary mitochondria of UCP2(-/-) mice or PASMCs after treatment with small interfering RNA for UCP2. Our data suggest that increased MMP causes vascular remodeling in UCP2(-/-) mice partially via increased ROS. In chronic hypoxia and MCT-induced PH, additional pathomechanisms such as decreased respiration may play a role.

The Senior-Loken syndrome: Two cases from the State of Qatar.

We are describing two sisters with the rare Senior-Loken syndrome, which is a combination of familial juvenile nephronophthisis and retinal dystrophy. The earliest presenting features include an impaired urinary concentrating ability, leading to polyuria and polydipsia and these are associated with visual impairment. The two patients had blindness shortly after their births. They presented to us with evidence of chronic kidney disease (CKD) in their teens, that required the initiation of the renal replacement therapy. We are reporting these two cases, as this was the first occurrence of this condition in the State of Qatar.