Synthesis and Inhibitor Effect Novel Alkoxymethyl Derivatives of Dihetero Cycloalkanes on Carbonic Anhydrase and Acetylcholinesterase.

1,3-Diheterocycloalkanes derivatives are important starting materials in fine organic synthesis. These compounds can be widely used in various fields such as industry, medicine, biotechnology and chemical technology. The paper is focused on synthesis and study of alkoxymethyl derivatives of diheterocycloalkanes (M1-M15) and inhibition effect on carbonic anhydrase and acetylcholinesterase. The structures of compounds were confirmed by 1H and 13C NMR spectroscopy. Also, in this study alkoxymethyl derivatives of diheterocycloalkanes were assessed for their influence on various metabolic enzymes, including acetylcholinesterase (AChE) and human carbonic anhydrase isoenzymes (hCA I and hCA II). The results demonstrated that all these compounds exhibited potent inhibitory effects on all the target enzymes, surpassing the standard inhibitors, as evidenced by their IC50 and Ki values. The Ki values for the compounds concerning AChE, hCA I, and hCA II enzymes were in the ranges of 1.02±0.17-8.38±1.02, 15.30±3.15-58.14±5.17 and 24.05±3.70-312.94±27.24 nM, respectively.

Evaluation of Macular and Optic Disc Radial Peripapillary Vessel Density Using Optical Coherence Tomography Angiography in Gout Patients.

In this cross-sectional study, optical coherence tomography angiography (OCT-A) findings were compared in patients with gout (n = 30) and healthy participants (n = 32). The superficial and deep vessel density variables measured using OCT-A were compared between the groups. The superficial foveal and perifoveal vessel densities of the patient group were lower than those of the healthy participants (p = 0.014 and p = 0.045, respectively). However, all superficial and parafoveal vessel densities were similar in both groups (p = 0.469 and p = 0.284, respectively). The deep capillary plexus density measurements of the whole-zone, foveal, parafoveal, and perifoveal vessel densities using OCT-A revealed no significant differences between the groups (p = 0.251, p = 0.074, p = 0.177, and p = 0.881, respectively). A higher serum uric acid (SUA) level was found to be independently associated with a decreased superficial capillary plexus density and an increased choriocapillary flow deficit in the study population. Men were less sensitive to high SUA levels than women. These findings suggest that an elevated uric acid concentration may play a role in the development and progression of cardiovascular disease through changes in the microvasculature, as shown by the OCT-A parameters.

Optical Coherence Tomography Angiography Is a Useful Tool for Distinguishing Primary Raynaud's Phenomenon from Systemic Sclerosis and/or Very Early Disease of Systemic Sclerosis.

This cross-sectional study aimed to compare optical coherence tomography angiography (OCT-A) findings in patients with primary Raynaud's phenomenon (PRP; n = 22), very early disease of systemic sclerosis (VEDOSS; n = 19), and systemic sclerosis (SSc; 25 patients with limited cutaneous SSc (lcSSc) and 13 patients with diffuse cutaneous SSc (dcSSc)). Whole, parafoveal, and perifoveal superficial capillary plexus (SCP) vessel densities (VDs), deep capillary plexus VDs, and whole, inside, and peripapillary VDs were significantly higher in the PRP group (p < 0.001). In the lcSSc group, the FAZ perimeter was significantly higher than that in the VEDOSS group (p = 0.017). Retinal nerve fiber layer VDs were significantly lower in the lcSSc group than in the PRP and VEDOSS groups (p < 0.001). The whole and peripapillary optic disc VDs of the VEDOSS group were significantly higher than in the lcSSc group (p < 0.001). Whole SCP VDs (94.74% sensitivity, 100.00% specificity) and parafoveal SCP VDs (89.47% sensitivity, 100.00% specificity) showed the best performance in distinguishing patients with SSc from those with PRP. OCT-A seems to have potential diagnostic value in differentiating patients with PRP from patients with SSc and VEDOSS, and there is potential value in assessing prognostic roles, since findings from OCT-A images could be early indicators of retinal vascular injury long before overt SSc symptoms develop.

Measuring the Whole Wall Thickness of the Common Femoral Vein as a Distinctive Diagnostic Tool to Distinguish Behçet's Disease Presenting with Oral Ulcers from Recurrent Aphthous Stomatitis.

Recurrent oral ulcers, which are the first and most common manifestation of Behçet's disease (BD), have several etiological causes but are often idiopathic and known as recurrent aphthous stomatitis (RAS). In recent years, publications have drawn attention to the fact that whole-wall thickness (WWT) and intima-media thickness (IMT) measurements of the common femoral vein (CFV) may be useful in the diagnosis of BD, which are independent of organ involvement. In this study, the usefulness of the WWT and IMT of the CFV measured by venous Doppler ultrasound (US) was investigated in differentiating BD presenting with oral ulcers from RAS. Patients with BD (n = 84), patients with RAS (n = 85), and healthy controls (HCs) (n = 70) were the three groups included. Both the right and left WWT of the CFV were significantly higher in the BD compared with the HCs and RAS groups (p < 0.001). The diagnostic cutoff values of ≥0.58 mm for the WWT of the CFV performed well against both the patients with RAS and HCs for the discrimination of BD (sensitivity = 79.8%, specificity = 64.7%). In patients with recurrent oral ulcers, the WWT of the CFV measurement may be a distinctive new diagnostic tool for the differential diagnosis of BD and RAS.

Screening of Antiglaucoma, Antidiabetic, Anti-Alzheimer, and Antioxidant Activities of Astragalus alopecurus Pall-Analysis of Phenolics Profiles by LC-MS/MS.

Astragalus species are traditionally used for diabetes, ulcers, leukemia, wounds, stomachaches, sore throats, abdominal pain, and toothaches. Although the preventive effects of Astragalus species against diseases are known, there is no record of the therapeutic effects of Astragalus alopecurus. In this study, we aimed to evaluate the in vitro antiglaucoma, antidiabetic, anti-Alzheimer's disease, and antioxidant activities of the methanolic (MEAA) and water (WEAA) extracts of the aerial part of A. alopecurus. Additionally, its phenolic compound profiles were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). MEAA and WEAA were evaluated for their inhibition ability on α-glycosidase, α-amylase, acetylcholinesterase (AChE), and human carbonic anhydrase II (hCA II) enzymes. The phenolic compounds of MEAA were analyzed by LC-MS/MS. Furthermore, total phenolic and flavonoid contents were determined. In this context, the antioxidant activity was evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), N,N-dimethyl-p-phenylene diamine (DMPD), ferric reducing antioxidant power (FRAP), cupric ions (Cu2+) reducing antioxidant capacity (CUPRAC), ferric ions (Fe3+) reducing, and ferrous ions (Fe2+) chelating methods. MEAA and WEAA had IC50 values of 9.07 and 2.24 µg/mL for α-glycosidase, 693.15 and 346.58 µg/mL for α-amylase, 1.99 and 2.45 µg/mL for AChE, and 147.7 and 171.7 µg/mL for hCA II. While the total phenolic amounts in MEAA and WEAA were 16.00 and 18.50 µg gallic acid equivalent (GAE)/mg extract, the total flavonoid contents in both extracts were calculated as 66.23 and 33.115 µg quercetin equivalent (QE)/mg, respectively. MEAA and WEAA showed, respectively, variable activities on DPPH radical scavenging (IC50: 99.02 and 115.53 µg/mL), ABTS radical scavenging (IC50: 32.21 and 30.22 µg/mL), DMPD radical scavenging (IC50: 231.05 and 65.22 µg/mL), and Fe2+ chelating (IC50: 46.21 and 33.01 µg/mL). MEAA and WEAA reducing abilities were, respectively, Fe3+ reducing (λ700: 0.308 and 0.284), FRAP (λ593: 0.284 and 0.284), and CUPRAC (λ450: 0.163 and 0.137). A total of 35 phenolics were scanned, and 10 phenolic compounds were determined by LC-MS/MS analysis. LC-MS/MS revealed that MEAA mainly contained isorhamnetin, fumaric acid, and rosmarinic acid derivatives. This is the first report indicating that MEAA and WEAA have α-glycosidase, α-amylase, AChE, hCA II inhibition abilities, and antioxidant activities. These results demonstrate the potential of Astragalus species through antioxidant properties and enzyme inhibitor ability traditionally used in medicine. This work provides the foundation for further research into the establishment of novel therapeutics for diabetes, glaucoma, and Alzheimer's disease.

Comprehensive Metabolite Profiling of Berdav Propolis Using LC-MS/MS: Determination of Antioxidant, Anticholinergic, Antiglaucoma, and Antidiabetic Effects.

Propolis is a complex natural compound that honeybees obtain from plants and contributes to hive safety. It is rich in phenolic and flavonoid compounds, which contain antioxidant, antimicrobial, and anticancer properties. In this study, the chemical composition and antioxidant activities of propolis were investigated; ABTS•+, DPPH• and DMPD•+ were prepared using radical scavenging antioxidant methods. The phenolic and flavonoid contents of propolis were 53 mg of gallic acid equivalent (GAE)/g and 170.164 mg of quercetin equivalent (QE)/g, respectively. The ferric ion (Fe3+) reduction, CUPRAC and FRAP reduction capacities were also studied. The antioxidant and reducing capacities of propolis were compared with those of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol and Trolox reference standards. The half maximal inhibition concentration (IC50) values of propolis for ABTS•+, DPPH• and DMPD•+ scavenging activities were found to be 8.15, 20.55 and 86.64 µg/mL, respectively. Propolis extract demonstrated IC50 values of 3.7, 3.4 and 19.6 µg/mL against α-glycosidase, acetylcholinesterase (AChE) and carbonic anhydrase II (hCA II) enzyme, respectively. These enzymes' inhibition was associated with diabetes, Alzheimer's disease (AD) and glaucoma. The reducing power, antioxidant activity and enzyme inhibition capacity of propolis extract were comparable to those demonstrated by the standards. Twenty-eight phenolic compounds, including acacetin, caffeic acid, p-coumaric acid, naringenin, chrysin, quinic acid, quercetin, and ferulic acid, were determined by LC-MS/MS to be major organic compounds in propolis. The polyphenolic antioxidant-rich content of the ethanol extract of propolis appears to be a natural product that can be used in the treatment of diabetes, AD, glaucoma, epilepsy, and cancerous diseases.

Screening of Carbonic Anhydrase, Acetylcholinesterase, Butyrylcholinesterase, and α-Glycosidase Enzyme Inhibition Effects and Antioxidant Activity of Coumestrol.

Coumestrol (3,9-dihydroxy-6-benzofuran [3,2-c] chromenone) as a phytoestrogen and polyphenolic compound is a member of the Coumestans family and is quite common in plants. In this study, antiglaucoma, antidiabetic, anticholinergic, and antioxidant effects of Coumestrol were evaluated and compared with standards. To determine the antioxidant activity of coumestrol, several methods-namely N,N-dimethyl-p-phenylenediamine dihydrochloride radical (DMPD•+)-scavenging activity, 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonate) radical (ABTS•+)-scavenging activity, 1,1-diphenyl-2-picrylhydrazyl radical (DPPH•)-scavenging activity, potassium ferric cyanide reduction ability, and cupric ion (Cu2+)-reducing activity-were performed. Butylated hydroxyanisole (BHA), Trolox, α-Tocopherol, and butylated hydroxytoluene (BHT) were used as the reference antioxidants for comparison. Coumestrol scavenged the DPPH radical with an IC50 value of 25.95 µg/mL (r2: 0.9005) while BHA, BHT, Trolox, and α-Tocopherol demonstrated IC50 values of 10.10, 25.95, 7.059, and 11.31 µg/mL, respectively. When these results evaluated, Coumestrol had similar DPPH•-scavenging effect to BHT and lower better than Trolox, BHA and α-tocopherol. In addition, the inhibition effects of Coumestrol were tested against the metabolic enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carbonic anhydrase II (CA II), and α-glycosidase, which are associated with some global diseases such as Alzheimer's disease (AD), glaucoma, and diabetes. Coumestrol exhibited Ki values of 10.25 ± 1.94, 5.99 ± 1.79, 25.41 ± 1.10, and 30.56 ± 3.36 nM towards these enzymes, respectively.

Evaluation of cardiac autonomic nervous system in patients with ankylosing spondylitis using 12-lead electrocardiography and Holter monitoring.

OBJECTIVES: Ankylosing spondylitis (AS) is associated with increased risk of cardiovascular problems, including complications such as conduction defects and arrhythmias, which might lead to increased morbidity and/or mortality. The objective of the present study is to evaluate the electrocardiographic (ECG) parameters, including T-peak to T-end intervals (Tpe), Tpe/corrected QT (QTc) ratio, heart rate variability (HRV), and heart rate turbulence (HRT) in AS patients. METHODS: Seventy-six AS patients and 55 control subjects were included in the study. 12-lead ECG and 24-h Holter monitoring recordings were obtained. Tpe and Tpe/QTc were measured using the 12-lead ECG and HRV and HRT parameters were assessed using 24-h Holter ECG recordings. Subjects were assigned into three groups based on their HRT parameters (Tonset (TO) and Tslope (TS)) (HRT-0, normal TO or TS; HRT-1, abnormal TO or TS; HRT-2, abnormal TO and TS). RESULTS: Tpe was prolonged and Tpe/QTc ratio was higher in AS patients (p < 0.001 for both). Moreover, Tpe and Tpe/QTc ratio significantly correlated with disease duration. All HRV parameters (VLF, LF, HF, SDNN, SDANN, ASDNN, rMSSD, pNN50) were decreased in AS patients in comparison with those in control subjects (p < 0.05 for all parameters). Controls were significantly more likely to have normal TO and TS (82% vs 53%, p < 0.001). There was negative correlation between Holter parameters and disease duration, as well as Tpe and Tpe/QTc ratio (p < 0.05 for all parameters). CONCLUSIONS: This study demonstrated that AS patients have disrupted ventricular repolarization (increased Tpe, Tpe/QTc ratio). Results suggest a decreased cardiac impact of the parasympathetic system in AS patients. Key Points • This study demonstrated that AS patients have disrupted ventricular repolarization. • The study also finds that heart rate turbulence and heart rate variability are impaired in AS patients. • Impaired Holter and ECG parameters may be one of the high cardiovascular risk factors in AS patients.

Do Anti-TNF Agents Increase the Risk of Inflammatory Bowel Disease Evolution in Patients with Ankylosing Spondylitis? Real Life Data.

OBJECTIVE: The aim of this study was to determine whether there is any association with anti-tumor necrosis factor (TNF) agent administration and development of new-onset inflammatory bowel disease (IBD) in ankylosing spondylitis (AS) patients. METHODS: Records of the patients who met 1984 modified New York criteria for AS between 1998 and 2016 at Rheumatology Department were evaluated retrospectively and data about the patients, IBD properties and medication were obtained. RESULTS: Among 420 patients, 310 were male, the average age was 42.9 ± 1.3 years, average disease duration was 16.7 ± 10.4 years. Anti-TNF agents were in use by 154 patients, 52 patients were receiving etanercept (ETN), infliximab (INF), adalimumab (ADA), and golimumab (GO) treatments were ongoing in 50, 41, and 11 patients, respectively. New-onset IBD developed in 10 patients; 3 from the group treated with non-anti-TNF drugs (1.1%) and 7 from the group treated with anti-TNF agents (4.5%) (p = 0.042). No significant difference was detected between three anti-TNF agent forms in relation with the risk of IBD onset. In AS patients, existence of familial AS (OR 4.69 (95%CI 1.28-17.19, p = 0.020) and anti-TNF agent treatment (OR 4.17 (95%CI 1.06-16.38, p = 0.041) were independent risk factors for new-onset IBD development. CONCLUSION: Despite the increased risk of new-onset IBD development during the course of AS, paradoxical response to anti-TNF drugs must also be considered as a source that triggers onset of IBD.

Why are male patients with Behçet's disease prone to thrombosis? A rotational thromboelastographic analysis.

OBJECTIVES: To investigate whether there is a difference between male and female patients with Behçet's disease (BD) in terms of hypercoagulability by using modified rotational thromboelastograhic (ROTEM) analysis. METHODS: 126 BD patients (71 male, 55 female; mean age: 41±9 yrs) who met ISSG criteria for BD were included into the study. 23 patients with vasculitis (16 female, 7 male; mean age 49±16 yrs), and 25 healthy individuals (11 female, 14 male; mean age: 37±10 yrs) were included to the study as disease and healthy control (HC) group, respectively. Clotting time (CT), clot formation time (CFT) and maximum clot firmness (MCF) were determined by INTEM and EXTEM analyses. As a marker of vascular endothelial injury, along with inflammatory markers, vWFag levels were investigated in patients and HC group. RESULTS: Extem-CFT was shorter in only vasculitic group compared to HC group. Intem-CFT was found to be shorter in BD patients and vasculitis group compared to HC. Intem-MCF was significantly longer in male BD patients than female BD patients. Extem-CFT was found to be shorter in male BD patients compared to female BD patients. Extem-MCF was statistically longer in male BD patients. In inactive male BD patients, while Intem-CFT was shorter than HC individuals, Intem-MCF and Extem-MCF were statistically longer than HC (p<0.02, p<0.03), respectively. However, no significant differences were found between inactive female BD patients and HC in terms of all ROTEM parameters. CONCLUSIONS: These results support that male BD patients have a hypercoagulable state compared to female BD patients, which may explain why male patients are prone to thrombotic complications.

Can neck pain be an initial symptom of rheumatoid arthritis? A case report and literature review.

Although rheumatoid arthritis (RA) is most commonly associated with peripheral joints, cervical spine involvement can be seen in almost 80% of patients in the presence of long-term disease, joint erosion, and risk factors such as male sex and rheumatoid factor positivity. It is very rare to have cervical involvement in the initial period of RA. If a patient has isolated cervical spine involvement without peripheral arthritis, it is highly likely that inappropriate investigations and delayed treatment may occur. Any damage that occurs in cervical spine may cause symptoms varying from slight instability to atlantoaxial subluxation, spinal cord and brain stem compression and even death. Therefore, physician should be aware that there may be isolated cervical involvement, albeit rare, in patients with RA. In this report, we presented a case of RA presenting with cervical spine involvement without peripheral arthritis to underline the importance of this kind of involvement in clinical practice. We also briefly reviewed other cases similar to ours in light of literature.

The Long-Term Outcomes for Patients with Budd-Chiari Syndrome Caused by Behcet's Disease: A Case Series on the Results, from Cirrhosis to Death.

BACKGROUND: Budd-Chiari syndrome, which is a rare complication of Behcet's disease, carries a high mortality rate. OBJECTIVES: The aim of the study was to present our long-term follow up experience with patients suffering from Budd-Chiari syndrome due to Behcet's disease. METHODS: The records of 402 patients with Behcet's disease were evaluated retrospectively. To facilitate detection of the long-term complications caused by Budd-Chiari syndrome, the patients were evaluated via physical examinations, laboratory tests, imaging modalities, and endoscopy results. RESULTS: The data for 402 patients diagnosed with Behcet's disease, who were followed up at our hospital over 16 years, were analyzed retrospectively. Five of these 402 patients (1.2%) were diagnosed as having Budd-Chiari syndrome. The patients with Budd-Chiari syndrome were aged between 23 and 54, and all five were male. The interval between the onset of Behcet's disease and the development of Budd-Chiari syndrome ranged from 1 to 8 years. All the patients had combined venous occlusion (affecting the hepatic vein and inferior vena cava). Portal venous thrombosis was detected in only one patient (Case 1), who died 1 month after the diagnosis of Budd-Chiari syndrome. The survival time for the other four patients after the diagnosis of Budd-Chiari syndrome ranged from 4 to 16 years. During the long-term follow-up, hepatic masses were detected via radiological surveillance in Case 3 (in the form of large regenerative nodules) and Case 4 (nodular regenerative hyperplasia and cirrhosis). CONCLUSIONS: In our study, portal venous thrombosis was detected in the patient who died during the acute period only. A study including large numbers of Budd-Chiari-syndrome patients with Behcet's disease and portal venous thrombosis would be helpful to determine the prognostic significance of portal venous thrombosis in Budd-Chiari-syndrome patients with Behcet's disease. In addition, patients should be monitored regularly for the development of hepatic masses via a long-term surveillance program.