Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases.

O-GlcNAc is a common modification found on nuclear and cytoplasmic proteins. Determining the catalytic mechanism of the enzyme O-GlcNAcase (OGA), which removes O-GlcNAc from proteins, enabled the creation of potent and selective inhibitors of this regulatory enzyme. Such inhibitors have served as important tools in helping to uncover the cellular and organismal physiological roles of this modification. In addition, OGA inhibitors have been important for defining the augmentation of O-GlcNAc as a promising disease-modifying approach to combat several neurodegenerative diseases including both Alzheimer's disease and Parkinson's disease. These studies have led to development and optimization of OGA inhibitors for clinical application. These compounds have been shown to be well tolerated in early clinical studies and are steadily advancing into the clinic. Despite these advances, the mechanisms by which O-GlcNAc protects against these various types of neurodegeneration are a topic of continuing interest since improved insight may enable the creation of more targeted strategies to modulate O-GlcNAc for therapeutic benefit. Relevant pathways on which O-GlcNAc has been found to exert beneficial effects include autophagy, necroptosis, and processing of the amyloid precursor protein. More recently, the development and application of chemical methods enabling the synthesis of homogenous proteins have clarified the biochemical effects of O-GlcNAc on protein aggregation and uncovered new roles for O-GlcNAc in heat shock response. Here, we discuss the features of O-GlcNAc in neurodegenerative diseases, the application of inhibitors to identify the roles of this modification, and the biochemical effects of O-GlcNAc on proteins and pathways associated with neurodegeneration.

The Evolving Role of Calcium Channel Blockers in Hypertension Management: Pharmacological and Clinical Considerations.

Worldwide, hypertension is the leading risk factor for cardiovascular disease and death. An estimated 122 million people, per the American Heart Association in 2023, have been diagnosed with this common condition. It is generally agreed that the primary goal in the treatment of hypertension is to reduce overall blood pressure to below 140/90 mmHg, with a more optimal goal of 130/80 mmHg. Common medications for treating hypertension include calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and diuretics. CCBs are one of the most widely studied agents and are generally recommended as first-line therapy alone and in combination therapies. This is largely based on the vast knowledge of CCB mechanisms and their minimal side effect profile. CCBs can be separated into two classes: dihydropyridine and non-dihydropyridine. Non-dihydropyridine CCBs act on voltage-dependent L-type calcium channels of cardiac and smooth muscle to decrease muscle contractility. Dihydropyridine CCBs act by vasodilating the peripheral vasculature. For many patients with only mild increases in systolic and diastolic blood pressure (e.g., stage 1 hypertension), the medical literature indicates that CCB monotherapy can be sufficient to control hypertension. In this regard, CCB monotherapy in those with stage 1 hypertension reduced renal and cardiovascular complications compared to other drug classes. Combination therapy with CCBs and angiotensin receptor blockers or angiotensin-converting enzyme inhibitors has been shown to be an effective dual therapy based on recent meta-analyses. This article is a review of calcium channel blockers and their use in treating hypertension with some updated and recent information on studies that have re-examined their use. As for new information, we tried to include some information from recent studies on hypertensive treatment involving calcium channel blockers.

Role of antihypertensive medicines in prostate cancer: a systematic review.

BACKGROUND: Hypertension is associated with the risk of prostate cancer (PCa) and its progression, however, it remains unclear whether antihypertensive medicines alter PCa risk or prognosis. This systematic review evaluated the role of calcium channel blockers (CCBs) and renin-angiotensin system (RAS) inhibitors in the risk and prognosis of PCa. This review was performed in line with PRISMA 2020 guidelines. METHODS: Eligible studies comprised peer-reviewed observational studies which reported the role of CCBs and RAS inhibitors in PCa, had accessible full texts, and were written in English. Using a combination of keywords, 5 electronic bibliographic databases which included Web of Science, EMBASE, PubMed, Google Scholar and Scopus were searched. RESULTS: A total of 1,346 studies were retrieved and 18 met the inclusion criteria. Thirteen studies reported reduced or no associated risk, improved prognosis, and survival with the use of RAS inhibitors. Studies on CCBs showed evidence of associated risk of PCa. Data extraction from retrieved studies focused on included study characteristics, setting, authors, year, outcomes of interest, and risk ratios. The quality assessment of included studies by the National Heart, Lung, and Blood Institute study assessment tools, showed that all studies had good quality. CONCLUSIONS: The use of RAS inhibitors was mostly associated with lower risks or improved prognosis of PCa. CCBs may also be associated with risks of PCa. This suggests that high-risk patients managed with CCBs should be actively monitored for PCa. However, there is need for further evidence from large-scale prospective, controlled cohort studies to determine any influence of CCBs on PCa.

Exploring the Impact of Protein Chain Selection in Binding Energy Calculations with DFT.

Calculation of binding free energies between a protein and a ligand are highly desired for computer-aided drug design. Here we approximate the binding energies of ABL1, an enzyme which is the target for drugs used in the treatment of chronic myeloid leukaemia, with minimal models and density functional theory (DFT). Starting from the crystal structures of protein-drug complexes, we estimated the binding free energies having used all available individual molecules (protein chains) within each structure, not only a single one as commonly used, in order to see if the choice of the protein chain is important in such calculations. Differences were observed between chains in the same file. Energy decomposition analysis (EDA) revealed that the most important factors for binding were exchange, repulsion and electrostatics. The desolvation term varied dramatically between the inhibitors (between 4.2 and 92.3 kcal/mol). All functionals showed similar patterns in the EDA and in discriminating between the ligands. Non-covalent interactions (NCI) analysis was used to further explain the differences between protein chains and functionals. Overall, it is shown that small minimal models of a drug binding site can be useful to infer on the suitability of an initial crystal structure for further analysis such as EDA.

Synthesis and kinetic evaluation of phosphomimetic inhibitors targeting type B ribose-5-phosphate isomerase from Mycobacterium tuberculosis.

Because tuberculosis is still a major health threat worldwide, identification of new drug targets is urgently needed. In this study, we considered type B ribose-5-phosphate isomerase from Mycobacterium tuberculosis as a potential target, and addressed known problems of previous inhibitors in terms of their sensitivity to hydrolysis catalyzed by phosphatase enzymes, which impaired their potential use as drugs. To this end, we synthesized six novel phosphomimetic compounds designed to be hydrolytically stable analogs of the substrate ribose 5-phosphate and the best known inhibitor 5-phospho-d-ribonate. The phosphate function was replaced by phosphonomethyl, sulfate, sulfonomethyl, or malonate groups. Inhibition was evaluated on type A and type B ribose-5-phosphate isomerases, and stability towards hydrolysis using alkaline phosphatase and veal serum was assessed. One of the phosphomimetic analogs, 5-deoxy-5-phosphonomethyl-d-ribonate, emerged as the first strong and specific inhibitor of the M. tuberculosis enzyme that is resistant to hydrolysis.

Are Sodium-Glucose Cotransporter-2 Inhibitors the Cherry on Top of Cardio-Oncology Care?

The increasing aging of the population combined with improvements in cancer detection and care has significantly improved the survival and quality of life of cancer patients. These benefits are hampered by the increase of cardiovascular diseases being heart failure the most frequent manifestation of cardiotoxicity and becoming the major cause of morbidity and mortality among cancer survivor. Current strategies to prevent cardiotoxicity involves different approaches such as optimal management of CV risk factors, use of statins and/or neurohormonal medications, and, in some cases, even the use of chelating agents. As a class, SGLT2-i have revolutionized the therapeutic horizon of HF patients independently of their ejection fraction or glycemic status. There is an abundance of data from translational and observational clinical studies supporting a potential beneficial role of SGLT2-i in mitigating the cardiotoxic effects of cancer patients receiving anthracyclines. These findings underscore the need for more robust clinical trials to investigate the effect on cardiovascular outcomes of the prophylactic SGLT2-i treatment in patients undergoing cancer treatment.

Use of drugs for hypertension or heart failure and the risk of death in COVID-19: association with loop-diuretics.

PURPOSE: To study the association between the use of drugs for hypertension or heart failure, particularly diuretics, and risk of death in COVID-19. METHODS: We conducted a cohort study, based on record linked individual-based data from national registers, of all Swedish inhabitants 50 years and older (n = 3,909,321) at the start of the first SARS-CoV-2 wave in Sweden. The association between use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), thiazides, loop diuretics, aldosterone antagonists, beta blocking agents and calcium channel blockers at the index date 6 March 2020, and death in COVID-19 during 7 March to 31 July 2020, was analysed using Cox-proportional hazards regression, adjusted for a wide range of possible confounders. RESULTS: Use of loop diuretics was associated with higher risk [adjusted hazard ratio (HR) 1.26; 95% confidence interval (95% CI) 1.17-1.35] and thiazides with reduced risk (0.78; 0.69-0.88) of death in COVID-19. In addition, lower risk was observed for ACEI and higher risk for beta-blocking agents, although both associations were weak. For ARB, aldosterone antagonists and calcium channel blockers no significant associations were found. CONCLUSION: In this nationwide cohort of nearly 4 million persons 50 years and older, the use of loop diuretics was associated with increased risk of death in COVID-19 during the first SARS-CoV-2 wave in Sweden. This contrasted to the decreased risk observed for thiazides. As treatment with loop diuretics is common, particularly in the elderly, the group most affected by severe COVID-19, this finding merit further investigation.

Cardiovascular medications used for comorbid diseases in patients with atrial fibrillation. The JoFib study.

PURPOSE: Many atrial fibrillation (AF) patients use cardiovascular medications for indications other than AF. These medications can affect morbidity and mortality. We aim to investigate the characteristics of AF patients who use different medication classes and their clinical course. METHODS: We collected data from the prospective, multicenter registry, JoFib study. We identified classes of non-AF medications (medications not used for rate control, rhythm control, or anticoagulation), described demographic and clinical characteristics, and investigated AF-related outcomes according to these medication classes. RESULTS: From a total of 2020 patients, five classes of cardiovascular non-AF medications were identified, aspirin, P2Y12 inhibitors, ACE inhibitors/ARBs, statins, and diuretics. The most commonly used non-AF medications were diuretics and ACE inhibitors/ARBs (39.2%, and 39%, respectively). 51% of AF patients took more than one non-AF medication. Multivariable Cox regression analysis demonstrated that ACE inhibitor/ARB therapy independently reduced the risks of all-cause mortality and cardiovascular mortality (aHR 0.50, 95%CI 0.37-0.68; aHR 0.51, 95%CI 0.34-0.75, respectively) and that statin therapy reduced the risk of cardiovascular mortality (aHR 0.68, 95%CI 0.48-0.98) in AF patients. Multivariable logistic regression analysis demonstrated a protective effect of statin therapy against the secondary outcome, clinically relevant non-major bleeding (CRNMB) (adjusted OR 0.62 95%CI 0.42-0.94). CONCLUSION: Our findings suggest a protective effect of ACE inhibitors/ARBs against all-cause and cardiovascular mortality, statins against cardiovascular mortality, and CRNMB in patients with AF. Accordingly, these medications should be encouraged in patients with AF when indicated. Additionally, future research should explore whether these medications should be offered to AF patients more routinely. The study was registered with Clinicaltrials.gov (unique identifier number: NCT03917992, Registration date:14/4/2019).

Insights into nucleoside hydrolase from Leishmania donovani inhibition: A new bioaffinity chromatography-based screening assay and docking studies.

Leishmaniasis, a group of neglected infectious diseases, encompasses a serious health concern, particularly with visceral leishmaniasis exhibiting potentially fatal outcomes. Nucleoside hydrolase (NH) has a fundamental role in the purine salvage pathway, crucial for Leishmania donovani survival, and presents a promising target for developing new drugs for visceral leishmaniasis treatment. In this study, LdNH was immobilized into fused silica capillaries, resulting in immobilized enzyme reactors (IMERs). The LdNH-IMER activity was monitored on-flow in a multidimensional liquid chromatography system, with the IMER in the first dimension. A C18 analytical column in the second dimension furnished the rapid separation of the substrate (inosine) and product (hypoxanthine), enabling direct enzyme activity monitoring through product quantification. LdNH-IMER exhibited high stability and was characterized by determining the Michaelis-Menten constant. A known inhibitor (1-(ß-d-Ribofuranosyl)-4-quinolone derivative) was used as a model to validate the established method in inhibitor recognition. Screening of three additional derivatives of 1-(ß-d-Ribofuranosyl)-4-quinolone led to the discovery of novel inhibitors, with compound 2a exhibiting superior inhibitory activity (Ki = 23.37 ± 3.64 µmol/L) compared to the employed model inhibitor. Docking and Molecular Dynamics studies provided crucial insights into inhibitor interactions at the enzyme active site, offering valuable information for developing new LdNH inhibitors. Therefore, this study presents a novel screening assay and contributes to the development of potent LdNH inhibitors.

The transmembrane domain of Frey1 harbors a transplantable inhibitory motif for intramembrane proteases.

Although aspartic intramembrane-cleaving proteases (I-CLIPs) are crucial switches of multiple signaling pathways and involved in several devastating diseases, little is known about their physiological regulation. We have recently identified Frey regulator of sperm-oocyte fusion 1 (Frey1) as an inhibitory protein of Signal Peptide Peptidase-like 2c (SPPL2c), a member of this protease family. Employing structure modeling along with cell-based inhibition and interaction studies, we identify a short motif within the Frey1 transmembrane domain essential for inhibition of SPPL2c. Intriguingly, this motif can be transplanted to the SPPL2c substrate PLN, thereby transforming it into an inhibitor of this enzyme. It can be adopted for the generation of Notch1-based γ-Secretase inhibitors demonstrating its versatile use among aspartic I-CLIPs. In summary, we describe a mechanism of aspartic I-CLIP inhibition which allows the targeted generation of specific inhibitors of these enzymes and might enable the identification of endogenous negative regulators of these enzymes.

The association of withholding or continuing angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers on acute kidney injury after non-cardiac surgery.

BACKGROUND: Withholding or continuing angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers peri-operatively in non-cardiac surgery remains controversial as they may result in intra-operative hypotension and postoperative organ damage. METHODS: We included patients prescribed angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers who underwent surgical procedures > 1 h duration under general or spinal anaesthesia from January 2012 to June 2022 in a single centre. We categorised patients by whether these drugs were withheld for 24 h before surgery. We evaluated the association of withholding these drugs before non-cardiac surgery with creatinine concentrations that increased ≥ 26.4 µmol.l-1 in the first 48 postoperative hours (acute kidney injury). We also analysed changes in creatinine concentrations and estimated glomerular filtration rates. RESULTS: Angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers were withheld in 24,285 of 32,933 (74%) patients and continued in 8648 (26%) patients. We used propensity scores for drug discontinuation to match 8631 patient pairs who did or did not continue these drugs: acute kidney injury was recorded for 1791 (21%) patients who continued these drugs vs. 1587 (18%) who did not (OR (95%CI) 1.16 (1.08-1.25), p < 0.001). Intra-operative hypotension was recorded for 3892 (45%) patients who continued drugs vs. 3373 (39%) patients who did not (OR (95%CI) 1.28 (1.21-1.36), p < 0.001). Continuing drugs was independently associated with a mean increase in creatinine of 2.2 µmol.l-1 (p < 0.001) and a mean decrease in estimated glomerular filtration rate of 1.4 ml.min.1.73 m-2 (p < 0.001). CONCLUSIONS: Continuing angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers 24 h before non-cardiac surgery was associated with intra-operative hypotension and postoperative acute kidney injury.

Predictors of overall mortality after endovascular abdominal aortic repair - A single centre study.

OBJECTIVES: A current and ongoing challenge is to reduce patient mortality after endovascular abdominal aortic repair (EVAR). This study aimed to assess the predictors of all-cause mortality after EVAR. METHODS: Data regarding the demographic characteristics, comorbidities, laboratory values, selected anatomical factors, post-EVAR treatment, surveillance and complications of patients who underwent elective EVAR for non-ruptured abdominal aortic aneurysm (AAA) between January 2010 and January 2021 were evaluated. Mortality was assessed until 10 October 2023. Multivariate analyses were performed after adjusting for age, hypertension, diabetes mellitus, dyslipidaemia, sex, smoking, number of lumbar arteries, patency of inferior mesenteric artery (IMA), IMA diameter and reinterventions. RESULTS: This study included 196 patients (183 men and 13 women) with a mean age of 72.4 ± 7.67 years. The overall mortality rate during a mean follow-up period of 5.75 ± 3.1 years was 50.0% (N = 98). The 2-, 5- and 10-year mortality rates were 9.7%, 32.0% and 66.6%, respectively. The mortality rates decreased by 59% in patients with reinterventions (hazard ratio [HR]: 0.41; 95% confidence interval [CI]: 0.23-0.73; p = .002) and by 59% in patients treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) (HR: 0.41; 95% CI: 0.26-0.66; p < .001). Chronic anticoagulation was associated with 2.09-fold higher mortality (HR: 2.09; 95% CI: 1.19-3.67; p = .010), and coronary artery disease (CAD) was associated with 1.74-fold higher mortality (HR: 1.74; 95% CI: 1.09-2.78; p = .021). Pre-EVAR AAA diameter and 1-year post-EVAR sac diameter were positively associated with mortality (HR: 1.05; 95% CI: 1.03-1.08; p < .001, and HR: 1.05; 95% CI: 1.03-1.07; p < .001, respectively), that is, an increase of pre-EVAR and/or 1-year post-EVAR AAA diameter by 1 mm was associated with a 5% higher risk of all-cause mortality. CONCLUSIONS: Reinterventions and treatment with ACE inhibitors or ARBs may be associated with decreased post-EVAR mortality. A greater pre-EVAR, a post-EVAR AAA diameter, CAD and chronic anticoagulation were associated with higher all-cause mortality post-EVAR.

Assessing the Chemical Composition, Antioxidant and enzyme Inhibitory Effects of Pentapleura subulifera and Cyclotrichium glabrescens Extracts.

The Lamiaceae family, encompassing diverse plant species, holds significant value in food, medicine, and cosmetics. Within this family, Pentapleura subulifera and Cyclotrichium glabrescens, relatively unexplored species, were investigated for their chemical composition, antioxidant capacity, and enzyme-inhibiting effects. The chemical composition of hexane, methanolic, and aqueous extracts from P. subulifera and C. glabrescens were analyzed using LC-ESI-MS/MS and the non-polar hexane fraction was investigated via GC-MS. The antioxidant potential of the extracts was determined through radical scavenging, reducing power and metal chelating assays. Additionally, inhibitory activity against six enzymes - acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase, amylase, and glucosidase - was examined. The aqueous extract of P. subulifera and the methanolic extract of C. glabrescens exhibited elevated phenolic content at 129.47 mg gallic acid equivalent (GAE)/g and 55.97 mg GAE/g, respectively. Chemical profiling of the constituents of the two plant species resulted in the identification of a total of twenty compounds. The majority of which belonged to flavonoids and quinic acid derivatives, primarily concentrated in the methanol and aqueous extracts. Among all antioxidant assays, the aqueous extracts of P. subulifera demonstrated superior antioxidant activity, with the highest recorded activity of 404.93 mg trolox equivalent (TE)/g in the cupric reducing antioxidant capacity (CUPRAC) test. Meanwhile, the hexane extract of C. glabrescens exhibited the highest AChE inhibitory activity at 2.71 mg galanthamine equivalent (GALAE)/g, followed by the methanol extract of P. subulifera at 2.41 mg GALAE/g. These findings unequivocally establish the notable antioxidant and enzyme inhibitory activity of P. subulifera and C. glabrescens extracts, underscoring their potential as a source of valuable natural antioxidants.

Imidazole-thiadiazole hybrids: A multitarget de novo drug design approach, in vitro evaluation, ADME/T, and in silico studies.

A library of imidazole-thiadiazole compounds (1-24) was synthesized to explore their therapeutic applications. The compounds were subjected to meticulous in vitro evaluation against α-glucosidase, α-amylase, acetylcholinesterase (AChE), and butylcholinesterase (BChE) enzymes. Compounds were also investigated for antioxidant activities using cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays. Derivatives 5-7, 9-11, 18, and 19 displayed potent inhibitory activities with IC50 values of 1.4 ± 0.01 to 13.6 ± 0.01 and 0.9 ± 0.01 to 12.8 ± 0.02 µM against α-glucosidase, and α-amylase enzymes, respectively, compared to the standard acarbose (IC50 = 14.8 ± 0.01 µM). Compounds 11-13, 16, 20, and 21 exhibited potent activity IC50 = 8.6 ± 0.02 to 34.7 ± 0.03 µM against AChE enzyme, compared to donepezil chloride (IC50 = 39.2 ± 0.05 µM). Compound 21 demonstrated comparable inhibition IC50 = 45.1 ± 0.09 µM against BChE, compared to donepezil chloride (IC50 = 44.2 ± 0.05 µM). All compounds also demonstrated excellent antioxidant activities via CUPRAC, FRAP, and DPPH methods. Complementing the experimental studies, extensive kinetics, ADME/T, and molecular docking analysis were also conducted to unravel the pharmacokinetics and safety profiles of the designed compounds. These studies supported the experimental findings and facilitated the prioritization of hit candidates for subsequent stages of drug development.

On the hunt for metalloenzyme inhibitors: Investigating the presence of metal-coordinating compounds in screening libraries and chemical spaces.

Metalloenzymes play vital roles in various biological processes, requiring the search for inhibitors to develop treatment options for diverse diseases. While compound library screening is a conventional approach, the exploration of virtual chemical spaces housing trillions of compounds has emerged as an alternative strategy. In this study, we investigated the suitability of selected screening libraries and chemical spaces for discovering inhibitors of metalloenzymes featuring common ions (Mg2+, Mn2+, and Zn2+). First, metal-coordinating groups from ligands interacting with ions in the Protein Data Bank were extracted. Subsequently, the prevalence of these groups in two focused screening libraries (Life Chemicals' chelator library, comprising 6,428 compounds, and Otava's chelator fragment library, with 1,784 fragments) as well as two chemical spaces (GalaXi and REAL space, containing billions of virtual products) was investigated. In total, 1,223 metal-coordinating groups were identified, with about a quarter of these groups found within the examined libraries and spaces. Our results indicate that these can serve as valuable starting points for drug discovery targeting metalloenzymes. In addition, this study suggests ways to improve libraries and spaces for better success in finding potential inhibitors for metalloenzymes.

Association of ACEI/ARB therapy with total and cardiovascular death in coronary artery disease patients with advanced chronic kidney disease: a large multi-center longitudinal study.

INTRODUCTION: Advanced chronic kidney disease (CKD) is common among patients with coronary artery disease (CAD), and angiotensin­converting enzyme inhibitors (ACEI) or angiotensin­receptor blockers (ARB) can improve cardiac and renal function, but whether ACEI/ARB therapy improves long-term prognosis remains unclear among these high-risk patients. Therefore, this research aimed to investigate the relationship between ACEI/ARB therapy and long-term prognosis among CAD patients with advanced CKD. METHODS: CAD patients with advanced CKD were included in five hospitals. Advanced CKD was defined as estimated glomerular filtration rate (eGFR)<30 ml/min per 1.73 m2. Cox regression models and competing risk Fine and Gray models were used to examine the relationship between ACEI/ARB therapy and all-cause and cardiovascular death, respectively. RESULTS: Of 2527 patients, 47.6% population of our cohort was discharged on ACEI/ARB. The overall all-cause and cardiovascular mortality were 38.6% and 24.7%, respectively. Multivariate Cox regression analyses indicated that ACEI/ARB therapy was found to be associated with lower rates of both all-cause mortality (hazard ratio (HR)=0.836, 95% confidence interval (CI): 0.738-0.948, p = 0.005) and cardiovascular mortality (HR = 0.817, 95%CI: 0.699-0.956, p = 0.011). In the propensity-matched cohort, the survival benefit was consistent, and significantly better survival was observed for all-cause mortality (HR = 0.856, 95%CI: 0.752-0.974, p = 0.019) and cardiovascular mortality (HR = 0.830, 95%CI: 0.707-0.974, p = 0.023) among patients treated with ACEI/ARB. CONCLUSION: ACEI/ARB therapy showed a better survival benefit among high-risk CAD patients with advanced CKD at long-term follow-up, which manifested that strategies to maintain ACEI/ARB treatment may improve clinical outcomes among these high-risk populations.

What is the current knowledge on the topic? Advanced CKD is highly prevalent and strongly associated with higher mortality risk and worse outcomes among CAD patients, and patients with advanced CKD have often been excluded from randomized controlled trials, creating an evidence gap for these high-risk CAD patients. ACEI/ARB are beneficial for greater survival among CAD patients, but the effect of ACEI/ARB therapy on long-term prognosis is unclear among CAD patients with advanced CKD.What does this study add to our knowledge? ACEI/ARB treatment showed a better survival benefit among high-risk CAD patients with advanced CKD at long-term follow-up.How might this change clinical pharmacology or translational science? CAD patients with advanced CKD are not only have worse outcomes but also limited in their choice of therapy strategies. Our study may prompt an important reference for the subsequent improvement of long-term prognosis among these high-risk populations.

An Insight into Fluorinated Imines and Hydrazones as Antibacterial Agents.

Fluorinated imines (Schiff bases) and fluorinated hydrazones are of particular interest in medicinal chemistry due to their potential usefulness in treating opportunistic strains of bacteria that are resistant to commonly used antibacterial agents. The present review paper is focused on these fluorinated molecules revealing strong, moderate or weak in vitro antibacterial activities, which have been reported in the scientific papers during the last fifteen years. Fluorinated building blocks and reaction conditions used for the synthesis of imines and hydrazones are mentioned. The structural modifications, which have an influence on the antibacterial activity in all the reported classes of fluorinated small molecules, are highlighted, focusing mainly on the importance of specific substitutions. Advanced research techniques and innovations for the synthesis, design and development of fluorinated imines and hydrazones are also summarized.

Potential of Tryptamine Derivatives as Multi-Target Directed Ligands for Alzheimer's Disease: AChE, MAO-B, and COX-2 as Molecular Targets.

Extensive research has been dedicated to develop compounds that can target multiple aspects of Alzheimer's disease (AD) treatment due to a growing understanding of AD's complex multifaceted nature and various interconnected pathological pathways. In the present study, a series of biological assays were performed to evaluate the potential of the tryptamine analogues synthesized earlier in our lab as multi-target-directed ligands (MTDLs) for AD. To assess the inhibitory effects of the compounds, various in vitro assays were employed. Three compounds, SR42, SR25, and SR10, displayed significant AChE inhibitory activity, with IC50 values of 0.70 µM, 0.17 µM, and 1.00 µM, respectively. These values superseded the standard drug donepezil (1.96 µM). In the MAO-B inhibition assay, SR42 (IC50 = 43.21 µM) demonstrated superior inhibitory effects as compared to tryptamine and other derivatives. Moreover, SR22 (84.08%), SR24 (79.30%), and SR42 (75.16%) exhibited notable percent inhibition against the COX-2 enzyme at a tested concentration of 100 µM. To gain insights into their binding mode and to validate the biological results, molecular docking studies were conducted. Overall, the results suggest that SR42, a 4,5 nitro-benzoyl derivative of tryptamine, exhibited significant potential as a MTDL and warrants further investigation for the development of anti-Alzheimer agents.

Establishing a link between the chemical composition and biological activities of Gladiolus italicus Mill. from the Turkish flora utilizing in vitro, in silico and network pharmacological methodologies.

OBJECTIVES: Five solvent extracts (n-hexane, ethyl acetate, ethanol, ethanol/water (70%), and water) of Gladiolus italicus Mill. from Turkey were evaluated for chemical and biological properties. METHODS: Antioxidant activities, inhibitory properties against key enzymes involved in the etiology of chronic diseases were tested, as well as cytotoxic effects on different cell lines. Chemical characterization was also carried out to determine the most abundant compounds of each extract. RESULTS: The highest total phenolic content (TPC) was observed in the water extract while highest TFC in ethanol/water extract. The most abundant compounds in the extracts were hyperoside (69041.06 mg kg-1), isoquercitrin (46239.49 mg kg-1), delphindin-3,5-diglucoside (42043.81 mg kg-1), myricetin (21486.61 mg kg-1), and kaempferol-3-glucoside (21199.76 mg kg-1). Molecular dynamic (MD) simulations confirmed the structural stability and dynamic conformational integrity of these complexes over a period of 100 ns. In network pharmacology, A total of 657 unique target genes were screened: 52 associated with programmed cell death-1 (PD-1), 85 with vascular endothelial growth factor receptor-2 (VEGFR2), and 130 with fibroblast growth factor receptor-2 (FGFR2), identifying crucial gene interactions for these proteins. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted, revealing significant interactions and pathways such as the advanced glycation end products (AGE) and their receptors (RAGE) signaling pathway in diabetic complications and T- helper 17 (Th17) cell differentiation, among others. This elucidation of complex networks involving key genes like AKT Serine/Threonine Kinase 1 (AKT1), MYC proto-oncogene (MYC), tumor protein 53 (TP53), Interleukin 6 (IL6), and tumor necrosis factor (TNF) provides a promising foundation for the development of targeted therapies in the treatment of non-communicable diseases. CONCLUSION: These results show that G. italicus could be a natural source of potent antioxidants and enzyme inhibitors which need to be further explored for the development of biopharmaceuticals.

Hyponatremia in geriatric patients.

Hyponatremia is the most frequent electrolyte imbalance in geriatric medicine. Causes of hyponatremia were retrospectively analyzed in all in-patients treated in 2016 (N = 2267, 1564 women, 703 men, mean age ± standard deviation 81.9 ± 7.6 years). Any form of hyponatremia on admission, during the stay or on discharge was noted in 308 patients (13.6%, 231 women, 77 men; mean age ± standard deviation 83.1 ± 7.3 years, p = 0.009 vs. age of all patients). Women had a higher probability of developing hyponatremia compared to men (p = 0.019), 131 patients were hypovolemic, and dyspnea as an indicator of hypervolemia was noted in 71 patients.Only 12 patients suffering from hyponatremia (3.9%) did not receive any of the potentially sodium-lowering drugs assessed (diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, antidepressants, neuroleptics, nonsteroidal antirheumatics, carbamazepine, oxcarbazepine). The median number of drugs per patient potentially lowering the plasma sodium level was 3 and the maximum number was 7.Hypovolemic hyponatremia and the syndrome of inadequate antidiuretic hormone secretion were the most important causes of hyponatremia. Adverse drug effects were the main origins of both conditions. In patients with hyponatremia the drug load influencing plasma sodium level should be minimized, thiazide diuretics should be avoided and older individuals should receive a diet with sufficient salt content.