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The last decade has seen multiple research work on the use of LoRaWAN technology in smart agriculture. In open field storage, monitoring is crucial for increasing the logistics efficiency and improving crop quality. As battery maintenance is expensive in such areas, LoRa is a suitable technology that allows for low-power communications. Within the framework of the research, a prototype has been built for tracking goods in open field storage. The battery lifetime has been analysed through calculations and measurements using LoRa communications. Our findings indicate that although sleeping current has the smallest percentage, it has the greatest effect on increasing the battery life, for longer battery life LoRa node must have a low self-discharge battery, and finally, sensors are the main battery depleting factor on the LoRa node.

Background and Purpose: Leukotrienes (LTs) are inflammatory mediators produced via the 5‐lipoxygenase (5‐LOX) pathway and are linked to diverse disorders, including asthma, allergic rhinitis and cardiovascular diseases. We recently identified the benzimidazole derivative BRP‐7 as chemotype for anti‐LT agents by virtual screening targeting 5‐LOX‐activating protein (FLAP). Here, we aimed to reveal the in vitro and in vivo pharmacology of BRP‐7 as an inhibitor of LT biosynthesis. Experimental Approach: We analysed LT formation and performed mechanistic studies in human neutrophils and monocytes, in human whole blood (HWB) and in cell‐free assays. The effectiveness of BRP‐7 in vivo was evaluated in rat carrageenan‐induced pleurisy and mouse zymosan‐induced peritonitis. Key Results: BRP‐7 potently suppressed LT formation in neutrophils and monocytes and this was accompanied by impaired 5‐LOX co‐localization with FLAP. Neither the cellular viability nor the activity of 5‐LOX in cell‐free assays was affected by BRP‐7, indicating that a functional FLAP is needed for BRP‐7 to inhibit LTs, and FLAP bound to BRP‐7 linked to a solid matrix. Compared with the FLAP inhibitor MK‐886, BRP‐7 did not significantly inhibit COX‐1 or microsomal prostaglandin E2 synthase‐1, implying the selectivity of BRP‐7 for FLAP. Finally, BRP‐7 was effective in HWB and impaired inflammation in vivo, in rat pleurisy and mouse peritonitis, along with reducing LT levels. Conclusions and Implications: BRP‐7 potently suppresses LT biosynthesis by interacting with FLAP and exhibits anti‐inflammatory effectiveness in vivo, with promising potential for further development. [ABSTRACT FROM AUTHOR]

Introduction The crossmatch test is essential prior to kidney transplantation (tx) to confirm compatibility between the donor and the recipient. However, its results can be misleading due to “undetectable antibodies” in the recipient's serum. To establish if undetectable autoantibodies are responsible for a positive result, an auto-crossmatch test can be performed. In this study, we aim to determine the long-term prognostic value of auto-flow cytometric auto-crossmatch (FCXM) test on kidney survival in kidney tx recipients. Materials and Methods The primary outcome variable was reduced renal function. Secondary endpoints were incidence of biopsy-confirmed chronic antibody-mediated rejection (CAMR) and recurrent glomerulonephritis (GN). Results There were no differences regarding initial serum creatinine levels between the study and control groups ( P = .441). Patients who had positive auto-B FCXM had a significantly reduced renal function compared with the control group ( P = .016). Four patients developed biopsy-confirmed CAMR in the study group and 1 patient in the control group ( P = .047). Five patients had biopsy-confirmed recurrent GN in the GN study group, and only 1 patient had recurrent GN in the GN control group ( P = .026). Discussion Kidney transplant recipients with positive auto-FCXM test had significantly reduced renal function and a higher incidence of recurrent GN and CAMR compared with the control group. The findings of this study suggest a potential role of auto-antibody causing positive auto-FCXM test result, meanwhile increasing the risk of CAMR, recurrent GN, and new-onset diabetes after tx. [ABSTRACT FROM AUTHOR]

Background: Effective pain management is vital in critical care settings, particularly post-surgery. Clinicians should maintain objective and efficient standards to assess pain in a patient-centered manner, in order to effectively manage this complex issue. A newer technology, the nociception level (NOL) index, shows promise in achieving this task through its multi-parameter evaluation., Methods: This study was a prospective, controlled, randomized trial involving two groups of patients (n=30 each) in a diverse intensive care unit. Participants were over 18 years old with American Society of Anesthesiology scores ranging from I to III and were scheduled for critical care follow-up after general anesthesia. All subjects followed a standard analgesia protocol that included rescue analgesia. Drug administration was guided by a numeric rating scale and the critical care pain observation tool in the Control Group, while it was guided by nociception level index monitoring in the NOL Group., Results: Pain scores between the two groups did not significantly differ. However, within the NOL Group, pain scores and noci-ception values displayed a strong positive correlation. Notably, total analgesic consumption was significantly lower in the NOL Group (p=0.036)., Conclusion: Monitoring pain using the nociception level index is an effective method for detecting pain compared to standard pain scores utilized in critical care. Its guidance facilitates personalized analgesic titration. Additionally, the potential of nociception level index guidance to reduce the duration of intensive care and hospital stays may be linked to its effects on delirium, a connection that awaits further exploration in future studies.

Selective inhibition of microsomal prostaglandin E 2 synthase-1 (mPGES-1) is implicated as a new therapeutic modality for the development of new-generation anti-inflammatory drugs. Here, we present the discovery of new and potent inhibitors of human mPGES-1, i.e., compounds 13, 15-25, 29-30 with IC 50 values in the range of 5.6-82.3 nM in a cell-free assay of prostaglandin (PG)E 2 formation. We also demonstrate that 20 (TG554, IC 50  = 5.6 nM) suppresses leukotriene (LT) biosynthesis at low µM concentrations, providing a benchmark compound that dually intervenes with inflammatory PGE 2 and LT biosynthesis. Comprehensive lipid mediator (LM) metabololipidomics with activated human monocyte-derived macrophages showed that TG554 selectively inhibits inflammatory PGE 2 formation over all cyclooxygenase (COX)-derived prostanoids, does not cause substrate shunting towards 5-lipoxygenase (5-LOX) pathway, and does not interfere with the biosynthesis of the specialized pro-resolving mediators as observed with COX inhibitors, providing a new chemotype for effective and safer anti-inflammatory drug development., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Erden Banoglu reports financial support was provided by Scientific and Technological Research Council of Turkey. Oliver Werz reports financial support was provided by German Research Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: This study aims to evaluate the ABCA4 variants in patients diagnosed with Stargardt disease., Methods: This is a retrospective study designed to investigate variants in the ABCA4 in Stargardt disease and the clinical findings of the cases. Sex, age, age of onset of symptoms, best-corrected visual acuity, color fundus photography, optical coherence tomography, and visual field test of the patients were recorded. Genetic analyses were screened, and patients with at least two variants in the ABCA4 were included in this study., Results: Twenty-seven patients diagnosed with Stargardt disease with the ABCA4 variants were included in this study. Twelve of them (44.4%) were female and fifteen (55.5%) were male. The mean age of the cases was 27.44 years (ranging from 8 to 56 years). Thirty different variants were detected in 54 ABCA4 alleles of 27 patients. The two most common pathogenic variants were c.5882 G>A p.(Gly1961Glu) and c.52C>T p.(Arg18Trp) in this cohort. Two novel variants were identified (c.3855_3856dup, c.1554 + 3_1554 + 4del) and the patient with the c.1554 + 3_1554 + 4del variant additionally had a different ABCA4 variant in trans. The other novel variant was homozygous., Conclusions: In this study, two novel variants were described in a Turkish cohort with Stargardt disease. The variant c.52C>T p.(Arg18Trp) was the most common disease-causing variant besides the c.5882 G>A p.(Gly1961Glu) which was identified frequently in the previous studies. A larger sample size is necessary for describing different pathogenic variants and understanding the phenotype-genotype correlations.

Background: This study explored the change of anesthesia management for emergent cesarean sections in our tertiary care hospital in the first year of pandemic. We searched primarily for the changes in spinal to general anesthesia rate and secondarily for presented adult and neonatal intensive care needs in comparison to the year before the pandemic. We also presented the postoperative PCR tests of the emergent cesarean sections as a tertiary outcome., Methods: We retrospectively analyzed clinical data such as anesthetic technique, need for postoperative intensive care, duration of hospital stays, postoperative PCR result, and newborn status., Results: The rate of spinal anesthesia changed remarkably from 44.1% to 72.1% after the pandemic (p=0.001). The comparison of the median duration of hospital stays of the pre-pandemic group and post-pandemic group was found significantly longer than that of the before COVID-19 group (p=0.001). The rate of need for postoperative intensive care in the after COVID-19 group was higher (p=0.058). The rate of postoperative intensive care of the newborns in the after COVID-19 group was significantly higher than that of the before COVID-19 group (p=0.001)., Conclusion: The spinal anesthesia rate for emergent cesarean sections increased significantly during the peak of the COVID-19 pandemic in tertiary care hospitals. Total health care services after the pandemic were enhanced as seen with elevated numbers of hospital stays, postoperative need of adult and neonatal intensive care.

Inhibition of soluble epoxide hydrolase (sEH) is indicated as a new therapeutic modality against a variety of inflammatory diseases, including metabolic, renal, and cardiovascular disorders. In our ongoing research on sEH inhibitors, we synthesized novel benzoxazolone-5-urea analogues with highly potent sEH inhibitory properties inspired by the crystallographic fragment scaffolds incorporating a single H-bond donor/acceptor pair. The tractable SAR results indicated that the aryl or benzyl fragments flanking the benzoxazolone-urea scaffold conferred potent sEH inhibition, and compounds 31-39 inhibited the sEH activity with IC 50 values in the range of 0.39-570 nM. Docking studies and molecular dynamics simulations with the most potent analogue 33 provided valuable insights into potential binding interactions of the inhibitor in the sEH binding region. In conclusion, benzoxazolone-5-ureas furnished with benzyl groups on the urea function can be regarded as novel lead structures, which allow the development of advanced analogues with enhanced properties against sEH., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Glaucoma is a neuropathy disorder and is generally treated by drugs. Allergic conjunctivitis is a common ophthalmologic disease. Paraoxonase 1 (PON1) is an organophosphate hydrolyzer and antiatherogenic enzyme. PON1 is known for preventing atherosclerosis through lipid-modifying features, as well as which has decisive actions of antiapoptosis, anti-inflammatory, antithrombosis, and antiadhesion antioxidant activity properties. Thus, reducing the enzyme levels in hyperthyroidism, chronic renal failure, glaucoma, diabetes mellitus, and cardiovascular diseases is a significant risk. This study was tested some ophthalmic drugs used to treat the diseases, such as glaucoma and allergic conjunctivitis, mentioned above, travoprost, latanoprost, ketotifen, emedastine, and olopatadine, for their inhibition activities against PON1. These drugs displayed the potent inhibition effect with IC 50 values ranging between 14.95 ± 0.15 and 299.60 ± 4.07 μM and K I constants ranging from 9.71 ± 2.63 to 261.50 ± 59.98 μM. Besides, the molecular docking analyses of the competitive inhibitors, travoprost, emedastine, and olopatadine, were performed to understand the binding interactions on the enzyme's binding site. According to both in vitro and in silico analysis results, travoprost had the most potent effect on PON1 enzyme activity., (© 2021 International Union of Biochemistry and Molecular Biology, Inc.)

Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs), which are endowed with beneficial biological activities as they reduce inflammation, regulate endothelial tone, improve mitochondrial function, and decrease oxidative stress. Therefore, inhibition of sEH for maintaining high EET levels is implicated as a new therapeutic modality with broad clinical applications for metabolic, renal, and cardiovascular disorders. In our search for new sEH inhibitors, we designed and synthesized novel amide analogues of the quinazolinone-7-carboxylic acid derivative 5 , a previously discovered 5-lipoxygenase-activating protein (FLAP) inhibitor, to evaluate their potential for inhibiting sEH. As a result, we identified new quinazolinone-7-carboxamides that demonstrated selective sEH inhibition with decreased FLAP inhibitor properties. The tractable SAR results indicated that the amide and thiobenzyl fragments flanking the quinazolinone nucleus are critical features governing the potent sEH inhibition, and compounds 34 , 35 , 37 , and 43 inhibited the sEH activity with IC 50 values of 0.30-0.66 μM. Compound 34 also inhibited the FLAP-mediated leukotriene biosynthesis (IC 50 = 2.91 μM). In conclusion, quinazolinone-7-carboxamides can be regarded as novel lead structures, and newer analogues with improved efficiency against sEH along with or without FLAP inhibition can be generated., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

The vicinal diaryl heterocyclic framework has been widely used for the development of compounds with significant bioactivities. In this study, a series of diaryl heterocycles were designed and synthesized based on an in-house diaryl isoxazole derivative ( 9 ), and most of the newly synthesized derivatives demonstrated moderate to good antiproliferative activities against a panel of hepatocellular carcinoma and breast cancer cells, exemplified with the diaryl isoxazole 11 and the diaryl pyrazole 85 with IC 50 values in the range of 0.7-9.5 μM. Treatments with both 11 and 85 induced apoptosis in these tumor cells, and they displayed antitumor activity in vivo in the Mahlavu hepatocellular carcinoma and the MDA-MB-231 breast cancer xenograft models, indicating that these compounds could be considered as leads for further development of antitumor agents. Important structural features of this compound class for the antitumor activity have also been proposed, which warrant further exploration to guide the design of new and more potent diaryl heterocycles., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

A series of novel piperazine urea derivatives with thiadiazole moieties were designed, synthesized, and investigated for their inhibition potential against human fatty acid amide hydrolase (hFAAH). The urea derivatives possessing p-chlorophenylthiadiazole and benzylpiperazine fragments (19-22) were effective inhibitors of hFAAH. Notably, compounds with 4-chlorobenzyl (19) and 4-fluorobenzyl (20) tails at the piperazine side were identified as the most active inhibitors with IC 50 values of 0.13 and 0.22 µM, respectively. The preincubation test of 19 was in agreement with the irreversible binding mechanism. Molecular docking was performed to explore the potential binding interactions with key amino acid residues at the FAAH active site. These newly identified inhibitors could serve as leads for the further development of potent and selective FAAH inhibitors for FAAH-associated diseases., (© 2022 Deutsche Pharmazeutische Gesellschaft.)

Soluble epoxide hydrolase (sEH) is implicated as a potential therapeutic target for inflammation-related pathologies in the context of cardiovascular, central nervous system and metabolic diseases. In our search for novel sEH inhibitors, we designed and synthesized novel analogs of the piperazine urea derivative 4, a previously discovered dual microsomal prostaglandin E 2 synthase-1 (mPGES-1)/soluble epoxide hydrolase (sEH) inhibitor, to evaluate their potential as sEH inhibitors. We identified two 1,3,4-oxadiazol-5-one and -thione congeners (compounds 19 and 20), which demonstrated selective sEH inhibition with IC 50 values in the two-digit nanomolar range (42 and 56 nM, respectively). These results suggest that the installation of terminal 1,3,4-oxadiazol-5-one/thione functions to the benzyl end can be regarded as a promising secondary pharmacophore in addition to the urea group for sEH inhibition, and compound 19 can be regarded as novel lead structure for further optimization of improved sEH inhibitors., (© 2022 Wiley-VCH GmbH.)

In this study, we report 3 cases of ultrasound-guided rectus sheath block used for anaesthetic management of simple periumbilical surgery. We selected 3 patients based on the American Society of Anaesthesiology I-II and defect sizes known to be smaller than 4 cm without peritoneal involvement. We applied a rectus sheath block with 10 mL of 0.5% bupivacaine and 5 mL of 2% lidocaine bilaterally deposited in the space between rectus abdominis and posterior rectus sheath under real-time ultrasonography. Two of our patients tolerated surgery well with minimal sedoanalgesia; however, one of our patients needed dissociative anaesthesia to be compatible because the surgeon found out that the defect was bigger and adjacent to the peritoneum. Rectus sheath block is an underused technique that has the potential to be used as a sole anaesthetic technique in selected cases. So it would be wise to improve and consider rectus sheath block as a valuable tool when there is no better.

Microsomal prostaglandin E 2 synthase-1 (mPGES-1) is recognized as a promising therapeutic target for next-generation anti-inflammatory drugs to treat inflammatory diseases. In this study, we report the identification of new, potent and selective inhibitors of human mPGES-1 such as compounds 10, 31 and 49 with IC 50 of 0.03-0.09 μM in a cell-free assay of PGE 2 production. Compound 10 and 49 also inhibited leukotriene C 4 synthase (LTC 4 S) at sub-μM concentrations (IC 50  = 0.7 and 0.4 μM, respectively), affording compounds dually targeting inflammatory PGE 2 and cysteinyl leukotriene (cys-LT) biosynthesis. However, compound 31 showed substantial selectivity towards mPGES-1 (IC 50  = 0.03 μM) with a decreased inhibitory activity on LTC 4 S (IC 50  = 2.8 μM), and also on other related targets such as FLAP and 5-LO. These oxadiazole thione-benzimidazole derivatives warrant further exploration of new and alternative analogs that may lead to the identification of novel derivatives with potent anti-inflammatory properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Oxidative stress is to upregulate the pentose phosphate pathway (PPP). The PPP consists of two functional branches, glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconaste dehydrogenase (6PGD). Glutathione reductase (GR) has a significant role in catalyzing an oxidized glutathione form into a reduced form. The purpose of this study is to investigate the effects of brimonidine and proparacaine on the activity of 6PGD, G6PD, and GR enzymes purified from human erythrocytes. Brimonidine displayed considerable inhibition profile against G6PD with IC 50 value and K I constant of 29.93 ± 3.56 and 48.46 ± 0.66 μM, respectively. On the other hand, proparacaine had no inhibitory effect against G6PD. K I values were found to be 66.06 ± 0.78 and 811.50 ± 11.13 μM for brimonidine and proparacaine, respectively, for 6PGD. K I values were found to be 144.10 ± 2.01 and 1,654.00 ± 26.29 μM for brimonidine and proparacaine, respectively, for GR. Herein, also in silico molecular docking studies were performed between drugs and enzymes., (© 2021 International Union of Biochemistry and Molecular Biology, Inc.)

Pseudoexfoliation syndrome (PEX) represents an age-related systemic disease that is characterized by the accumulation of extracellular matrix material in ocular tissues and visceral organs. Abnormal matrix remodeling is thought to be one of the important factors in the etiopathogenesis of the disease. Prolidase represents an enzyme, which takes a significant part in collagen biosynthesis and remodeling of the extracellular matrix. The purpose of the current research was to assess the prolidase enzyme activity in the aqueous and serum samples of subjects with PEX. The study population consisted of 66 subjects, involving 33 subjects with age-related cataract among patients with PEX and 33 subjects with age-related cataract without PEX. The prolidase activity measurement was performed using the modified Chinard's method. Significantly increased aqueous prolidase activity was detected in the group with PEX (p < 0.01). Despite about a three times higher increase in the serum prolidase activity of the group with PEX in comparison with the control group, the two groups did not differ statistically significantly (p > 0.05). The high prolidase enzyme activity in the aqueous samples of subjects with PEX suggests that the collagen cycle and the remodeling of the extracellular matrix are accelerated. These results can be a guide for understanding the formation mechanisms of PEX., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In our effort for the development of novel anticancer therapeutics, a series of isoxazole-piperazine analogues were prepared, and primarily screened for their antiproliferative potential against hepatocellular carcinoma (HCC; Huh7/Mahlavu) and breast (MCF-7) cancer cells. All compounds demonstrated potent to moderate cytotoxicity on all cell lines with IC 50 values in the range of 0.09-11.7 μM. Further biological studies with 6a and 13d in HCC cells have shown that both compounds induced G1 or G2/M arrests resulting in apoptotic cell death. Subsequent analysis of proteins involved in cell cycle progression as well as proliferation of HCC cells revealed that 6a and 13d may affect cellular survival pathways differently depending on the mutation profiles of cells (p53 and PTEN), epidermal/mesenchymal characteristics, and activation of cell mechanisms through p53 dependent/independent pathways. Lastly, we have demonstrated the potential anti-stemness properties of these compounds in which the proportion of liver CSCs in Huh7 cells (CD133+/EpCAM+) were significantly reduced by 6a and 13d. Furthermore, both compounds caused a significant reduction in expression of stemness markers, NANOG or OCT4 proteins, in Mahlavu and Huh7 cells, as well as resulted in a decreased sphere formation capacity in Huh7 cells. Together, these novel isoxazole-piperazine derivatives may possess potential as leads for development of effective anti-cancer drugs against HCC cells with stem cell-like properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Coronavirus disease 2019 (COVID-19) is caused by the SARS-CoV-2 virus and has been affecting the world since the end of 2019. The disease led to significant mortality and morbidity in Turkey, since the first case was reported on March 11th, 2020. Studies suggest a positive association between air pollution and SARS-CoV-2 infection. The aim of the present study was to investigate the role of ambient particulate matters (PM), as potential carriers for SARS-CoV-2. Ambient PM samples in various size ranges were collected from 13 sites including urban and urban-background locations and hospital gardens in 10 cities across Turkey between 13th of May and 14th of June 2020 to investigate the possible presence of SARS-CoV-2 RNA on ambient PM. A total of 203 daily samples (TSP, n = 80; PM 2.5 , n = 33; PM 2.5 - 10 , n = 23; PM 10 μm, n = 19; and 6 size segregated PM, n = 48) were collected using various samplers. The N1 gene and RdRP gene expressions were analyzed for the presence of SARS-CoV-2, as suggested by the Centers for Disease Control and Prevention (CDC). According to real time (RT)-PCR and three-dimensional (3D) digital (d) PCR analysis, dual RdRP and N1 gene positivity were detected in 20 (9.8%) samples. Ambient PM-bound SARS-CoV-2 was analyzed quantitatively and the air concentrations of the virus ranged from 0.1 copies/m 3 to 23 copies/m 3 . The highest percentages of virus detection on PM samples were from hospital gardens in Tekirdağ, Zonguldak, and Istanbul, especially in PM 2.5 mode. Findings of this study have suggested that SARS-CoV-2 may be transported by ambient particles, especially at sites close to the infection hot-spots. However, whether this has an impact on the spread of the virus infection remains to be determined., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Critical care ultrasound has earned its place not just as a further investigation step but as a bedside physical assessment and monitoring tool. Its potential to become the twenty-first-century stethoscope has proved its accuracy by many protocols so far.

Microsomal prostaglandin E 2 synthase-1 (mPGES-1), 5-lipoxygenase (5-LO) and 5- lipoxygenase-activating protein (FLAP) are key for biosynthesis of proinflammatory lipid mediators and pharmacologically relevant drug targets. In the present study, we made an attempt to explore the role of small heteroaromatic fragments on the 4,5-diarylisoxazol-3-carboxylic acid scaffold, which are selected to interact with focused regions in the active sites of mPGES-1, 5-LO and FLAP. We report that the simple structural variations on the benzyloxyaryl side-arm of the scaffold significantly influence the selectivity against mPGES-1, 5-LO and FLAP, enabling to produce multi-target inhibitors of these protein targets, exemplified by compound 18 (IC 50 mPGES-1 = 0.16 µM; IC 50 5-LO = 0.39 µM) with in vivo efficacy in animal model of inflammation. The computationally modeled binding structures of these new inhibitors for three targets provide clues for rational design of modified structures as multi-target inhibitors. In conclusion, the simple synthetic procedure, and the possibility of enhancing the potency of this class of inhibitors through structural modifications pave the way for further development of new multi-target inhibitors against mPGES-1, 5-LO and FLAP, with potential application as anti-inflammatory agents., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: In cancer treatment, it is important to prevent or slow down metastasis as well as preventing the proliferation of cancer cells. In this study, we aimed to find pyrazole compounds with antimigratory properties., Methods: The 'PASSonline' programme was used to determine the possible pharmacological activities of the pyrazole compounds selected from the library, and two pyrazole derivatives were identified as a transcription factor STAT inhibitor with a high probability. There are studies known that JAK/STAT pathway is related to cancer cell migration, thus the possible antimigratory effects of these two synthesized pyrazole compounds were examined in A549 cancer cells., Key Findings: Our data demonstrated that compound-2 at different concentrations significantly inhibited cell migration in A549 cells. Then, the effects of these compounds on STAT activation were evaluated. We reported that 10 µM compound-2 induced a significant phosphorylation of STAT1 suggesting that STAT1 activation may be responsible for the antimigratory effect of compound-2., Conclusions: Taken together, the compound-2 is a promising compound with the antimigratory activity for cancer treatment, and further studies are needed to synthesize more active derivatives by evaluating the structure-activity relationship of leading compound-2., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We describe the synthesis of a series of 2-arylbenzimidazole derivatives bearing sulfonamide functionality (4a-d, 7a-c and 10) as well as hydroxamic acid (15a-b), carboxylic acid (16a-b), carboxamide (17a-b) and boronic acid (22a-b and 26) functionalities, which act as human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors. The newly synthesized benzimidazole derivatives were evaluated against 4 physiologically relevant CA isoforms (hCA I, II, IX, and XII), and especially the sulfonamide-containing benzimidazoles demonstrated intriguing inhibitory activity against tumor associated CA IX and XII with K I values in the range of 5.2-29.3 nM and 9.9-41.7 nM, respectively. Notably, compound 4c was the most potent and selective CA IX (K I  = 6.6 nM) and XII (K I  = 9.9 nM) inhibitor with a significant selectivity ratio over cytosolic CA I and II isoforms in the range of 3.4-25.2. In addition, compounds having hydroxamic acid (15a-b) or carboxylic acid (16a-b) functionalities resulted in greater selectivity ratios for CA IX/XII over CAI/II in the range of 4.1-121.5 although with K I values in lower micromolar potency (K I s = 0.36-0.85 μM for CA IX/XII)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Allogeneic hematopoietic stem cell transplant is a life-saving treatment, but donor numbers in Turkey do not meet the increasing demand for this procedure. Here, our objectives were (1) to assess the frequency of HLA-matched related donors in the Turkish population and (2) to identify the HLA antigens and haplotypes that are most frequent in Turkey., Materials and Methods: The HLA genotypes of 841 consecutive recipients and 3071 family members were retrospectively reviewed., Results: Matched related donors were identified for 368/841 recipients (44%). Extended family donor searches were performed for 111/181 pediatric recipients (61%), with nonsibling matched related donors found for 23 patients (21%). Matched related donors were found for a significantly higher proportion of pediatric patients (52%) than adult patients (41%) (odds ratio of 2.5; 95% confidence interval, 1.9-4.1; P = .02). The percentage of pediatric versus adult patients with 3 or more siblings was 13% versus 46% (odds ratio of 5.6; 95% confidence interval, 3.6-8.5; P = .001). The most frequent HLA class I antigens at each locus were HLA-A*02 (20.2%), HLA-B*35 (19.5%), and HLA-C*07 (19.8%). The most frequent HLA class II antigens at each locus were HLA-DRB1*11 (21.6%) and HLA-DQB1*03 (40.2%). The most common 3-locus haplotypes were HLA-A*24 B*35 DRB1*11 (F:0.020) and HLA-A*01 B*08 DRB1*03 (F:0.015). When adult and pediatric groups were combined, the most common locus haplotypes were found in 43/345 sibling donors (12%) and in 7/23 nonsibling pediatric donors (30%) (odds ratio of 2.7; 95% confidence interval, 1.2-6.4; P = .02)., Conclusions: The results indicate that, in Turkey, it can be beneficial to revise donor search algorithms to include an extended family donor search before an unrelated donor search. This type of search can be effective because of the HLA haplotype diversity in Turkey, the frequency of consanguinity, and the country's limited donor pool.

Microsomal prostaglandin E 2 synthase-1 (mPGES-1) is a potential therapeutic target for the treatment of inflammatory diseases and certain types of cancer. To identify novel scaffolds for mPGES-1 inhibition, we applied a virtual screening (VS) protocol that comprises molecular docking, fingerprints-based clustering with diversity-based selection, protein-ligand interactions fingerprints, and molecular dynamics (MD) simulations with molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations. The hits identified were carefully analyzed to ensure the selection of novel scaffolds that establish stable interactions with key residues in the mPGES-1 binding pocket and inhibit the catalytic activity of the enzyme. As a result, we discovered two promising chemotypes, 4-(2-chlorophenyl)-N-[(2-{[(propan-2-yl)sulfamoyl]methyl}phenyl)methyl]piperazine-1-carboxamide (6) and N-(4-methoxy-3-{[4-(6-methyl-1,3-benzothiazol-2-yl)phenyl]sulfamoyl}phenyl)acetamide (8), as non-acidic mPGES-1 inhibitors with IC 50 values of 1.2 and 1.3 μm, respectively. Minimal structural optimization of 8 resulted in three more compounds with promising improvements in inhibitory activity (IC 50 : 0.3-0.6 μm). The unprecedented chemical structures of 6 and 8, which are amenable to further derivatization, reveal a new and attractive approach for the development of mPGES-1 inhibitors with potential anti-inflammatory and anticancer properties., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In our endeavour towards the development of effective anticancer therapeutics, a novel series of isoxazole-piperazine hybrids were synthesized and evaluated for their cytotoxic activities against human liver (Huh7 and Mahlavu) and breast (MCF-7) cancer cell lines. Within series, compounds 5l-o showed the most potent cytotoxicity on all cell lines with IC 50 values in the range of 0.3-3.7 μM. To explore the mechanistic aspects fundamental to the observed activity, further biological studies with 5m and 5o in liver cancer cells were carried out. We have demonstrated that 5m and 5o induce oxidative stress in PTEN adequate Huh7 and PTEN deficient Mahlavu human liver cancer cells leading to apoptosis and cell cycle arrest at different phases. Further analysis of the proteins involved in apoptosis and cell cycle revealed that 5m and 5o caused an inhibition of cell survival pathway through Akt hyperphosphorylation and apoptosis and cell cycle arrest through p53 protein activation.

Leukotrienes are proinflammatory lipid mediators associated with diverse chronic inflammatory diseases such as asthma, COPD, IBD, arthritis, atherosclerosis, dermatitis and cancer. Cellular leukotrienes are produced from arachidonic acid via the 5-lipoxygenase pathway in which the 5-lipoxygenase activating protein, also named as FLAP, plays a critical role by operating as a regulatory protein for efficient transfer of arachidonic acid to 5-lipoxygenase. By blocking leukotriene production, FLAP inhibitors may behave as broad-spectrum leukotriene modulators, which might be of therapeutic use for chronic inflammatory diseases requiring anti-leukotriene therapy. The early development of FLAP inhibitors (i.e. MK-886, MK-591, BAY-X-1005) mostly concentrated on asthma cure, and resulted in promising readouts in preclinical and clinical studies with asthma patients. Following the recent elucidation of the 3D-structure of FLAP, development of new inhibitor chemotypes is highly accelerated, eventually leading to the evolution of many un-drug-like structures into more drug-like entities such as AZD6642 and BI665915 as development candidates. The most clinically advanced FLAP inhibitor to date is GSK2190918 (formerly AM803) that has successfully completed phase II clinical trials in asthmatics. Concluding, although there are no FLAP inhibitors reached to the drug approval phase yet, due to the rising number of indications for anti-LT therapy such as atherosclerosis, FLAP inhibitor development remains a significant research field. FLAP inhibitors reviewed herein are classified into four sub-classes as the first-generation FLAP inhibitors (indole and quinoline derivatives), the second-generation FLAP inhibitors (diaryl-alkanes and biaryl amino-heteroarenes), the benzimidazole-containing FLAP inhibitors and other FLAP inhibitors with polypharmacology for easiness of the reader. Hence, we meticulously summarize how FLAP inhibitors historically developed from scratch to their current advanced state, and leave the reader with a positive view that a FLAP inhibitor might soon reach to the need of patients who may require anti-LT therapy., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Leukotrienes (LTs) and prostaglandin (PG)E 2 are enzymatically produced from arachidonic acid and represent highly bioactive lipid mediators with pro-inflammatory functions. Here, we report on novel multi-target inhibitors that potently and dually interfere with 5-lipoxygenase-activating protein (FLAP) and microsomal prostaglandin E 2 synthase (mPGES)-1 in LT and PGE 2 biosynthesis, based on the previously identified selective FLAP inhibitor BRP-7 (8, IC 50  = 0.31 μM). C (5)-substitution of the benzimidazole ring of BRP-7 by carboxylic acid and its bioisosteres provided compounds, exemplified by 57 that potently suppress LT formation (IC 50  = 0.05 μM) by targeting FLAP along with inhibition of mPGES-1 (IC 50  = 0.42 μM). Besides FLAP, also 5-lipoxygenase (5-LO) and LTC 4 synthase activities were inhibited by 57, albeit with lower potency (IC 50  = 0.6 and 6.2 μM) than FLAP. Docking studies and molecular dynamic simulations with FLAP, mPGES-1 and 5-LO provide valuable insights into potential binding interactions of the inhibitors with their targets. Together, these novel benzimidazole derivatives may possess potential as leads for development of effective anti-inflammatory drugs with multi-target properties for dually inhibiting LT and PGE 2 production., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The pro-inflammatory leukotrienes (LTs) are formed from arachidonic acid (AA) in activated leukocytes, where 5-lipoxygenase (5-LO) translocates to the nuclear envelope to assemble a functional complex with the integral nuclear membrane protein 5-LO-activating protein (FLAP). FLAP, a MAPEG family member, facilitates AA transfer to 5-LO for efficient conversion, and LT biosynthesis critically depends on FLAP. Here we show that the novel LT biosynthesis inhibitor BRP-187 prevents the 5-LO/FLAP interaction at the nuclear envelope of human leukocytes without blocking 5-LO nuclear redistribution. BRP-187 inhibited 5-LO product formation in human monocytes and polymorphonuclear leukocytes stimulated by lipopolysaccharide plus N-formyl-methionyl-leucyl-phenylalanine (IC 50 =7-10nM), and upon activation by ionophore A23187 (IC 50 =10-60nM). Excess of exogenous AA markedly impaired the potency of BRP-187. Direct 5-LO inhibition in cell-free assays was evident only at >35-fold higher concentrations, which was reversible and not improved under reducing conditions. BRP-187 prevented A23187-induced 5-LO/FLAP complex assembly in leukocytes but failed to block 5-LO nuclear translocation, features that were shared with the FLAP inhibitor MK886. Whereas AA release, cyclooxygenases and related LOs were unaffected, BRP-187 also potently inhibited microsomal prostaglandin E 2 synthase-1 (IC 50 =0.2μM), another MAPEG member. In vivo, BRP-187 (10mg/kg) exhibited significant effectiveness in zymosan-induced murine peritonitis, suppressing LT levels in peritoneal exudates as well as vascular permeability and neutrophil infiltration. Together, BRP-187 potently inhibits LT biosynthesis in vitro and in vivo, which seemingly is caused by preventing the 5-LO/FLAP complex assembly and warrants further preclinical evaluation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Pharmacological intervention with 5-lipoxygenase (5-LO) pathway leading to suppression of leukotriene (LT) biosynthesis is a clinically validated strategy for treatment of respiratory and cardiovascular diseases such as asthma and atherosclerosis. Here we describe the synthesis of a series of C(5)-substituted analogues of the previously described 5-LO-activating protein (FLAP) inhibitor BRP-7 (IC50 = 0.31 μM) to explore the effects of substitution at the C(5)-benzimidazole (BI) ring as a strategy to increase the potency against FLAP-mediated 5-LO product formation. Incorporation of polar substituents on the C(5) position of the BI core, exemplified by compound 11 with a C(5)-nitrile substituent, significantly enhances the potency for suppression of 5-LO product synthesis in human neutrophils (IC50 = 0.07 μM) and monocytes (IC50 = 0.026 μM)., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

In this article, we report novel leukotriene (LT) biosynthesis inhibitors that may target 5-lipoxygenase-activating protein (FLAP) based on the previously identified isoxazole derivative (8). The design and synthesis was directed towards a subset of 4,5-diaryl-isoxazole-3-carboxylic acid derivatives as LT biosynthesis inhibitors. Biological evaluation disclosed a new skeleton of potential anti-inflammatory agents, exemplified by 39 and 40, which potently inhibit cellular 5-LO product synthesis (IC50 = 0.24 μM, each) seemingly by targeting FLAP with weak inhibition on 5-LO (IC50 ≥ 8 μM). Docking studies and molecular dynamic simulations with 5-LO and FLAP provide valuable insights into potential binding modes of the inhibitors. Together, these diaryl-isoxazol-3-carboxylic acids may possess potential as leads for development of effective anti-inflammatory drugs through inhibition of LT biosynthesis., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: Henoch-Schönlein Purpura (HSP) is a systemic hypersensitivity disease of unknown cause that is characterized by a purpuric rash and systemic manifestations, such as colicky abdominal pain, polyarthralgia, and acute glomerulonephritis. Common complications of HSP that lead to surgical intervention include intussusception, perforation, necrosis, and massive gastrointestinal bleeding. Unusual clinical manifestations of HSP may include edema of the scrotum and eyes. Lumbar swelling is rarely seen as a complication of HSP., Case Report: A four-year-old boy was admitted to our emergency room with a 7 day history of increasing abdominal pain. Within 48 hours of admission, erythematous macules and palpable purpuric lesions developed on the lower extremities. On the third day of hospitalization, sudden onset of severe back pain, swelling on the lumbar region and refusal to walk were seen. On the fifth day, lumbosacral edema and pain resolved but facial edema developed. He was diagnosed clinically with HSP., Conclusion: To the best of our knowledge, only a few cases of HSP with lumbar edema have been reported so far. If the first clinical symptoms of HSP are atypical, clinical progress can be atypical, too.

Purpose: Necrotizing enterocolitis (NEC) is a severe disease of mostly premature infants with high morbidity and mortality rates. There is no reliable biomarker for detecting newborns at risk for NEC development. We aimed to investigate small intestinal lactoferrin (LF) and calprotectin (CAL) levels as predictors and indicators of disease severity in an experimental newborn rat model., Materials and Methods: Newborn pups were randomly divided into two groups, NEC and control. The NEC group pups were decapitated on the second, third and fourth days of the experiment for an assessment of the different stages of NEC. In the study group, hypoxia-reoxygenation model used to induce NEC. As biochemical parameters, small intestinal LF and CAL levels were measured with an enzyme-linked immunosorbent assay technique and intestinal injury scoring was evaluated as a pathologic parameter., Results: Small intestinal levels of both LF and CAL increased in the second and the third day groups, but began to decrease by the fourth day. The first, second and third day levels of LF and CAL were higher than controls. The intestinal injury scores of all NEC groups were significantly higher than the control group., Conclusion: Small intestinal lactoferrin and calprotectin were good markers for demonstrating NEC. However, instead of spot testing, monitoring the levels of these markers may be more informative., (Copyright © 2015 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Infectious diseases are the leading cause of FUO. A case of prolonged fever with hepatic and pulmonary tuberculosis as a final diagnosis is herein presented. A 4-year-old, otherwise healthy boy presented with an axillary temperature of up to 39.5ºC for the previous 3 weeks. His medical history revealed an occasional increase in body temperature up to 38.5ºC for the last 6 months. Physical examination revealed coarse breath sounds on the basal lung area. Chest X-ray showed mediastinal lymphadenomegaly and computed tomography revealed paratracheal conglomerated lymph nodes and a groundglass appearance on the right lung. There were multiple contrast-enhanced, hypoechoic nodules with central necrosis in the liver parenchyma on abdominal magnetic resonance imaging. Open liver biopsy yielded chronic granulomatous inflammation compatible with pathological findings of tuberculosis infection. The culture specimen was positive for Mycobacterium tuberculosis. The patient improved rapidly after antituberculous therapy was initiated. Tuberculosis, especially in its disseminated form, poses a distinct diagnostic challenge in cases of prolonged fever with unproven etiology, and thus persistence should be exercised in disclosing the cause of such fevers.

We synthesized a series of novel amide derivatives of 5-(p-tolyl)-1-(quinolin-2-yl)pyrazole-3-carboxylic acid and assessed their antiproliferative activities against three human cancer cell lines (Huh7, human liver; MCF7, breast and HCT116, colon carcinoma cell lines) with the sulforhodamine B assay. Compound 4j with 2-chloro-4-pyridinyl group in the amide part exhibited promising cytotoxic activity against all cell lines with IC50 values of 1.6 μM, 3.3 μM and 1.1 μM for Huh7, MCF7 and HCT116 cells, respectively, and produced dramatic cell cycle arrest at SubG1/G1 phase as an indicator of apoptotic cell death induction. On the basis of their high potency in cellular environment, these straightforward pyrazole-3-carboxamide derivatives may possess potential in the design of more potent compounds for intervention with cancer cell proliferation., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Antiplatelet drugs are promising therapeutics to intervene with platelet aggregation in arterial thrombosis, most prominently in myocardial infarction and ischemic stroke. Here, we describe the synthesis and structure-activity relationships of potent inhibitors of platelet aggregation based on the 1,5-diarylpyrazol-3-carboxamide scaffold. Analogs from this series demonstrated potent anti-aggregatory activities against arachidonic acid-induced platelet aggregation, as measured by turbidimetric method of Born. 1,5-Diarylpyrazole-3-carboxamides obtained with small-basic amines (7, 8, 50, 51, 61, 62) displayed the strongest activity with IC50 values in low nanomolar range (5.7-83 nM). On the basis of their high potency in cellular environment, these straightforward pyrazole derivatives may possess potential in the design of more potent compounds for intervention with cardiovascular diseases., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)