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5-Lipoxygenase (LO) catalyzes the first steps in the formation of pro-inflammatory leukotrienes (LT) that are pivotal lipid mediators contributing to allergic reactions and inflammatory disorders. Based on its key role in LT biosynthesis, 5-LO is an attractive drug target, demanding for effective and selective inhibitors with efficacy in vivo, which however, are still rare. Encouraged by the recent identification of the catechol 4-(3,4-dihydroxyphenyl)dibenzofuran 1 as 5-LO inhibitor, simple structural modifications were made to yield even more effective and selective catechol derivatives. Within this new series, the two most potent compounds 3,4-dihydroxy-3'-phenoxybiphenyl (6b) and 2-(3,4-dihydroxyphenyl)benzo[b]thiophene (6d) potently inhibited human 5-LO in cell-free (IC

Oxidative stress and inflammation are two conditions that coexist in many multifactorial diseases and the discovery of antioxidants is an attractive approach that can simultaneously tackle two or more therapeutic targets of the arachidonic acid cascade. We report that the simple structural variations on the 4-aryl-benzene-1,2-diol side-arm of the scaffold significantly influence the selectivity against 5-LOX vs 12- and 15-LOX. Derivatives 4 a-l were evaluated for their antioxidant activity, using the DPPH, and ferric ion reducing antioxidant power (FRAP) methods. Docking simulations proposed concrete binding of the catechol series to 5-LO. Selected active compound 4-(3,4-dihydroxyphenyl)dibenzofuran (4l) was also tested in different in vivo mouse models of inflammation. 4l (0.1 mg/kg; i.p.) impaired (I) bronchoconstriction in ovalbumin-sensitized mice challenged with acetylcholine, (II) exudate formation in carrageenan-induced paw edema, and (III) zymosan-induced leukocyte infiltration in air pouches. These results pave the way for investigating the therapeutic potential of 4-aryl-benzene-1,2-diol, as novel multitarget therapeutic drugs, able to regulate the complex inflammatory cascade mechanisms. © 2022

Nephropathic subjects with impaired immune responses show dramatically high infection rates of coronavirus disease 2019 (COVID-19). This work evaluated the ability to acquire and maintain protective antibodies over time in 26 hemodialysis patients and 21 kidney transplant recipients. The subjects were followed-up through quantitative determination of circulating SARS-CoV-2 S1/S2 IgG and neutralizing antibodies in the 6-month period after clinical and laboratory recovery. A group of 143 healthcare workers with no underlying chronic pathologies or renal diseases recovered from COVID was also evaluated. In both dialysis and transplanted patients, antibody titers reached a zenith around the 3rd month, and then a decline occurred on average between the 270th and 300th day. Immunocompromised patients who lost antibodies around the 6th month were more common than non-renal subjects, although the difference was not significant (38.5% vs. 26.6%). Considering the decay of antibody levels below the positivity threshold (15 AU/mL) as “failure”, a progressive loss of immunisation was found in the overall population starting 6 months after recovery. A longer overall antibody persistence was observed in severe forms of COVID-19 (p = 0.0183), but within each group, given the small number of patients, the difference was not significant (dialysis: p = 0.0702, transplant: p = 0.1899). These data suggest that immunocompromised renal patients recovered from COVID-19 have weakened and heterogeneous humoral responses that tend to decay over time. Despite interindividual variability, an association emerged between antibody persistence and clinical severity, similar to the subjects with preserved immune function.

Background/Aims: The coronavirus disease 2019 (CO­VID-19) pandemic is the major current health emergency worldwide, adding a significant burden also to the community of nephrologists for the management of their patients. Here, we analyzed the impact of COVID-19 infection in renal patients to assess the time to viral clearance, together with the production and persistence of IgG and IgM antibody response, in consideration of the altered immune capacity of this fragile population. Methods: Viral clearance and antibody kinetics were investigated in 49 renal patients recovered from COVID-19 infection: 7 of them with chronic decompensated renal failure, 31 under dialysis treatment, and 11 kidney transplant recipients. Results: The time span between the diagnosis of infection and recovery based on laboratory testing (2 negative nasopharyngeal swabs in consecutive days) was 31.7 ± 13.3 days. Three new positive cases were detected from 8 to 13 days following recovery. At the first serological determination after swab negativization, all the patients developed IgG and IgM antibodies. The semiquantitative analysis showed a progressive increase in IgG and a slow reduction in IgM. Discussion/Conclusion: In subjects with decompensated chronic kidney disease, under dialysis and in transplant recipients, viral clearance is lengthened compared to the general population. However, in spite of their common status of immunodepression, all of them were able to produce specific antibodies. These data might provide useful insights for monitoring and planning health-care activities in the weak category of patients with compromised renal function recovered from COVID-19.

Background: In hemodialysis patients, a tunneled-cuffed permanent catheter is mandatory when the arteriovenous fistula is not feasible. The major risks of the use of tunneled-cuffed permanent catheter are bloodstream infections. The aim of this study is to analyze bloodstream infections from tunneled-cuffed permanent catheter in hemodialysis patients. Methods: An observational prospective study was carried out and 79 hemodialysis patients with tunneled-cuffed permanent catheter were enrolled. Patients were divided into those with bloodstream infections from tunneled-cuffed permanent catheter and those without. Their clinical and laboratory characteristics were compared. An original tunneled-cuffed permanent catheter lock therapy sequence was carried out combined with systemic antibiotic therapy. In case of antibiotic resistance, the tunneled-cuffed permanent catheter was removed. Results: The patients affected by bloodstream infections from tunneled-cuffed permanent catheter were 16/79 (20.3%). The bloodstream infection from tunneled-cuffed permanent catheter’s incidence rate was 0.52 per 1000 catheter days. Twenty-three bloodstream infections from tunneled-cuffed permanent catheter were found in 16/79 patients who used tunneled-cuffed permanent catheter. Staphylococcus aureus was the cause of bloodstream infection from tunneled-cuffed permanent catheter in 35% of the cases and Staphylococcus epidermidis in 30% of the cases. Risk factors were infection located in other organs and the presence of peripheral obstructive arterial disease. Conclusion: The enrolled cohort showed a reduced bloodstream infection from tunneled-cuffed permanent catheter incidence rate in comparison with the reference value (1 per 1000 catheter days). To reduce the number of bloodstream infections from tunneled-cuffed permanent catheter, hand hygiene and asepsis management of the tunneled-cuffed permanent catheter during the connection to the extracorporeal circuit and an original tunneled-cuffed permanent catheter lock therapy sequence seem to be the most efficient measures. Infections of other organs and the presence of peripheral obstructive arterial disease are the most important risk factors for bloodstream infections from tunneled-cuffed permanent catheter.

Introduction: Renal allograft biopsy is the gold standard for the detection of histological lesions of chronic allograft dysfunction. The identification of a noninvasive routine test would be desirable. Elastosonography is used to assess tissue stiffness according to viscosity, and no data are available on the use of point quantification shear-wave elastography (ElastPQ) for the evaluation of renal chronic lesions. Research Question: To evaluate the feasibility of ElastPQ to assess cortical allograft stiffness and to determine the correlation of clinical, biological, and pathological factors with the diagnostic accuracy of kidney stiffness values in patients with histological lesions. Design: Forty-two patients underwent kidney transplant biopsy and 10 valid measurements of ElastPQ, blindly performed by 2 operators. The interobserver reproducibility was assessed according to intraclass correlation coefficient. The ElastPQ measurements and the clinical data were compared using the Spearman correlation analysis. Results: 97.6% reliable measurements were obtained using ElastPQ, with an excellent interobserver agreement. The kidney stiffness was significantly higher in the patients with a time since transplantation >12 months and was correlated with chronic lesions (interstitial fibrosis, tubular atrophy transplant glomerulopathy, and mesangial matrix), with the interstitial fibrosis/tubular atrophy, score and with the sum of the scores of the chronic lesions. Mesangial matrix increase is the only independent determinant of kidney stiffness. Discussion: ElastPQ is a noninvasive, reproducible, and sensitive diagnostic tool able to detect moderate/severe chronic lesions. Its routine use during follow-up can identify patients eligible for biopsy, which remains the gold standard exam for detecting chronic allograft dysfunction.

Stilbenes with well-known antioxidant and antiradical properties are beneficial in different pathologies including cardiovascular diseases. The present research was performed to investigate the potential protective effect of resveratrol (1) and piceatannol (2), against hypoxia-induced oxidative stress in the H9c2 cardiomyoblast cell line, and the underlying mechanisms. Compounds 1 and 2 significantly inhibited the release of peroxynitrite and thiobarbituric acid levels at na no- or submicromolar concentrations, and this effect was more evident in piceatannol-treated cells, that significantly increased MnSOD protein level in a concentration dependent manner. Furthermore, since piceatannol, which is far less abundant in natural sources, displayed a higher bioactivity than the parent compound, we hereby report on a very fast synthesis and detailed structure-based design of a focused stilbene library. Finally, taking into account that hypoxia-induced ROS accumulation also increases expression and activity of 5-lipoxygenase (5-LOX) with production of leukotrienes, we have disclosed structural key factors crucial for 5-LOX activity. Among the synthesized analogues ( 3-7), compound 7 was the most effective in improving cardiomyocytes viability and in 5-LOX inhibition. In conclusion, modeling and experimental studies provided the basis for further optimization of stilbene analogues as multi-target inhibitors of the inflammatory and oxidative pathway. (C) 2019 Elsevier Masson SAS. All rights reserved.

The release of pro-inflammatory mediators, such as prostaglandines (PGs) and leukotrienes (LTs), arising from the arachidonic acid (AA) cascade, play a crucial role in initiating, maintaining, and regulating inflammatory processes. New dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E-2 synthase-1 (mPGES-1), that block, at the same time, the formation of PGE(2) and LTs, are currently emerged as a highly interesting drug candidates for better pharmacotherapie of inflammation-related disorders. Following our previous studies, we here performed a detailed structure-based design of benzo[g]indol-3-carboxylate derivatives, disclosing several new key factors that affect both enzyme activity. Ethyl 2-(3,4-dichlorobenzy1)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (4b, RAF-01) and ethyl 2-(3,4-dichlorophenyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (7h, RAF-02) emerged as the most active compounds of the series. Additionally, together with selected structure based analogues, both derivatives displayed significant in vivo anti-inflammatory properties.In conclusion, modeling and experimental studies lead to the discovery of new candidate compounds prone to further developments as multi-target inhibitors of the inflammatory pathway. (C) 2018 Elsevier Masson SAS. All rights reserved.

5-Lipoxygenase (5-LO), an enzyme that catalyzes the initial steps in the biosynthesis of pro-inflammatory leukotrienes, is an attractive drug target for the pharmacotherapy of inflammatory and allergic diseases. Here, we present the design, synthesis and biological evaluation of novel series of ethyl 5-hydroxyindole- 3-carboxylate derivatives that efficiently inhibit human 5-LO. SAR analysis revealed that the potency of compounds is closely related to the positioning of the substituents at the phenylthiomethyl ring. The introduction of methyl or chlorine groups in ortho- and ortho/para-position of thiophenol represent the most favorable modifications. Among all tested compounds, ethyl 5-hydroxy-2-(mesitylthiomethyl)-1- methyl-1H-indole-3-carboxylate (19) is the most potent derivative which blocks 5-LO activity in cellfree assays with IC50 ¼ 0.7 mM, and suppressed 5-LO product synthesis in polymorphonuclear leukocytes with IC50 = 0.23 mM.

The products of 5-lipoxygenase are synthesized and released in the airway when an asthmatic reaction occurs. 5-lipoxygenase via arachidonic acid metabolism produces leukotrienes that mediate bronchoconstriction and inflammatory modifications essential in the pathophysiology of asthma. Until to now, only one approved 5-LO inhibitor, zileuton, can be found as a potential therapy for asthma. With the increasing number of indications for anti-leukotriene (anti-LT) drugs, the development of 5-LO inhibitor agents becomes increasingly important. The present MiniReview reports an update on 5-LO inhibitors currently under clinical investigation. In addition, the latest advances focused on the development of new 5-lipoxygenase inhibitors as asthma anti-inflammatory agents are also discussed. The products of 5-lipoxygenase are synthesized and released in the airway when an asthmatic reaction occurs. 5-lipoxygenase via arachidonic acid metabolism produces leukotrienes that mediate bronchoconstriction and inflammatory modifications essential in the pathophysiology of asthma. Until to now, only one approved 5-LO inhibitor, zileuton, can be found as a potential therapy for asthma. With the increasing number of indications for anti-leukotriene (anti-LT) drugs, the development of 5-LO inhibitor agents becomes increasingly important. The present MiniReview reports an update on 5-LO inhibitors currently under clinical investigation. In addition, the latest advances focused on the development of new 5-lipoxygenase inhibitors as asthma anti-inflammatory agents are also discussed.

5-Lipoxygenase (5-LO) is a potential target for pharmacological intervention with various inflammatory and allergic diseases. Starting from the natural dual 5-LO/microsomal prostaglandin E2 synthase (mPGES)-1 inhibitor embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone, 2) that suppresses 5-LO activity in human primary leukocytes with IC50 Combining double low line 0.8-21/4M, we synthesized 48 systematically modified derivatives of 2. We modified the 1,4-quinone to 1,2-quinone, mono- or bimethylated the hydroxyl groups, and varied the C11-n-alkyl residue (C4- to C16-n-alkyl or prenyl) of 2. Biological evaluation yields potent analogues being superior over 2 and obvious structure-activity relationships (SAR) for inhibition of 5-LO. Interestingly, conversion to 1,2-benzoquinone and bimethylation of the hydroxyl moieties strongly improves 5-LO inhibition in polymorphonuclear leukocytes versus 2 up to 60-fold, exemplified by the C12-n-alkyl derivative 22c (4,5-dimethoxy-3-dodecyl-1,2-benzoquinone) with IC50 Combining double low line 29 nM. Regarding inhibition of mPGES-1, none of the novel benzoquinones could outperform the parental compound 2 (IC50 Combining double low line 0.21 1/4M), and only modest suppressive effects on 12- and 15-LOs were evident. Together, our detailed SAR study reveals 22c as highly potent 5-LO-selective lead compound in intact cells that warrants further preclinical evaluation as anti-inflammatory agent. © 2015 Published by Elsevier Masson SAS.

In this paper, a recombinant catalase-peroxidase HPI from Escherichia coli was prepared, purified, and used in enzymatic polymerization reactions for the production of several oligomeric products. We tested the enzyme on four different substrates, chosen as representative of phenols and anilines: phenol, 3-methoxyphenol, catechol, and aniline. The polymerization reactions were followed by SEC-HPLC analysis, and except for aniline, all the other substrates were completely converted into one or more polymerization products. Results showed that reactions performed with phenol and 3-methoxyphenol allowed the isolation of some oligomers of different weight: a 27-monomeric unit oligomer and a 23-U oligomer are the heaviest ones. Experiments performed with catechol showed the formation of oligomers of 7 U in the reaction with HPI. HPI polymerization reactions performed with aniline allowed the identification of two different oligomers, one of 4 U and one of 10 U. All the substrates have been also used in reactions catalyzed by HRP in the same reaction conditions. Several products were common to the two enzymes. This work suggests the use of HPI as an alternative enzyme in peroxidatic reactions for the production of different oligomers from phenols and other compounds. © 2013 Springer-Verlag Berlin Heidelberg.