Efficacy of Allopurinol in Improving Endothelial Dysfunction: A Systematic Review and Meta-Analysis.

INTRODUCTION: Endothelial dysfunction has been implicated in various cardiovascular disorders as the initial pathology. Allopurinol has been shown to improve endothelial dysfunction in patients with gout, but its effect on cardiovascular patients is unclear. AIMS: We aim to assess allopurinol efficacy in improving endothelial dysfunction overall and in different disease states including but not limited to heart failure, chronic kidney disease, ischemic heart disease METHODS: We conducted a literature search of PubMed, Cochrane's Central Library, and Scopus until December 2022, including randomized controlled trials and double-arm observational studies. The primary outcome measure was endothelial function assessed by change in flow mediated dilation (FMD) RESULTS: Our meta-analysis included 22 studies with a total of 1472 patients. Our pooled analysis shows that allopurinol significantly improved FMD (WMD = 1.46%, 95% CI [0.70, 2.22], p < 0.01) compared to control. However, there was no significant difference between allopurinol and control for endothelial-independent vasodilation measured by forearm blood flow (WMD = 0.10%, 95% CI [- 0.89, 0.69], p = 0.80). Subgroup analysis indicated that the effect of allopurinol on FMD was more significant in diabetic and congestive heart failure patients. CONCLUSION: While allopurinol may improve endothelial function in various patient populations, further high-quality randomized controlled trials are needed to determine its efficacy in preventing cardiovascular disease exacerbation.

Comprehensive multi-level expression profiling of key biomarkers in breast cancer patients.

OBJECTIVES: In this comprehensive breast cancer (BC) study, we aimed to identify, validate, and characterize key biomarkers with significant implications in BC diagnosis, prognosis, and as therapeutic targets. METHODS: Our research strategy involved a multi-level methodology, combining bioinformatic analysis with experimental validation. RESULTS: Initially, we conducted an extensive literature search to identify BC biomarkers, selecting those with reported accuracies exceeding 20% in specificity and sensitivity. This yielded nine candidate biomarkers, which we subsequently analyzed using Cytoscape to identify a few key biomarkers. Based on the degree method, we denoted four key biomarkers, including progesterone receptor (PGR), epidermal growth factor receptor (EGFR), estrogen receptor 1 (ESR1), and Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2). Expression analysis using The Cancer Genome Atlas (TCGA) dataset revealed that PGR and EGFR exhibited significant (p-value < 0.05) down-regulation in BC samples when compared to controls, while ESR1 and ERBB2 showed up-regulation. To strengthen our findings, we collected clinical BC tissue samples from Pakistani patients and performed expression verification using real-time quantitative polymerase chain reaction (RT-qPCR). The results aligned with our initial TCGA dataset analysis, further validating the differential expression of these key biomarkers in BC. Furthermore, we utilized receiver operating characteristic (ROC) curves to demonstrate the diagnostic use of these biomarkers. Our analysis underscored their accuracy and sensitivity as diagnostic markers for BC. Survival analysis using the Kaplan-Meier Plotter tool revealed a prognostic significance of PGR, ESR1, EGFR, and ERBB2. Their expression levels were associated with poor overall survival (OS) of BC patients, shedding light on their roles as prognostic indicators in BC. Lastly, we explored DrugBank to identify drugs that may reverse the expression patterns , and estradiol, decitabine, and carbamazepine were singled out. CONCLUSION: Our study gives valuable insight into BC biomarkers, for diagnosis and prognosis. These findings have implications for BC management using personalized and targeted therapeutic approaches for BC patients.

A Rare Case of Huge Schistosomiasis-Associated Cecal Polyp Mimicking Colon Carcinoma.

Schistosomiasis is a parasitic infection caused by Schistosoma species, commonly found in tropical and subtropical regions. It affects millions of people worldwide and can lead to different clinical presentations like abdominal pain, weight loss, anemia, and chronic colonic schistosomiasis. In rare cases, chronic infection can result in the development of polyps, which can mimic colon carcinoma, posing a diagnostic challenge. Here, we present a rare case of a huge Schistosomiasis-associated cecal polyp in a patient initially suspected to have colon cancer. The patient's clinical history and the histopathological analysis confirmed the diagnosis, emphasizing the importance of considering parasitic infections in the differential diagnosis of gastrointestinal polyps in Schistosomiasis-endemic areas. This case report highlights the need for increased awareness among healthcare professionals of the potential for Schistosomiasis-associated polyps and the importance of multidisciplinary management in such cases.

Ultrasensitive and Selective Copper(II) Detection: Introducing a Bioinspired and Robust Sensor.

A nanopore-based CuII -sensing system is reported that allows for an ultrasensitive and selective detection of CuII with the possibility for a broad range of applications, for example in medical diagnostics. A fluorescent ATCUN-like peptide 5/6-FAM-Dap-ß-Ala-His is employed to selectively bind CuII ions in the presence of NiII and ZnII and was crafted into ion track-etched nanopores. Upon CuII binding the fluorescence of the peptide sensor is quenched, permitting the detection of CuII in solution. The ion transport characteristics of peptide-modified nanopore are shown to be extremely sensitive and selective towards CuII allowing to sense femtomolar CuII concentrations in human urine mimics. Washing with EDTA fully restores the CuII -binding properties of the sensor, enabling multiple repetitive measurements. The robustness of the system clearly has the potential to be further developed into an easy-to-use, lab-on-chip CuII -sensing device, which will be of great importance for bedside diagnosis and monitor of CuII levels in patients with copper-dysfunctional homeostasis.

Label-Free Pyrophosphate Recognition with Functionalized Asymmetric Nanopores.

The label-free detection of pyrophosphate (PPi) anions with a nanofluidic sensing device based on asymmetric nanopores is demonstrated. The pore surface is functionalized with zinc complexes based on two di(2-picolyl)amine [bis(DPA)] moieties using carbodiimide coupling chemistry. The complexation of zinc (Zn(2+) ) ion is achieved by exposing the modified pore to a solution of zinc chloride to form bis(Zn(2+) -DPA) complexes. The chemical functionalization is demonstrated by recording the changes in the observed current-voltage (I-V) curves before and after pore modification. The bis(Zn(2+) -DPA) complexes on the pore walls serve as recognition sites for pyrophosphate anion. The experimental results show that the proposed nanofluidic sensor has the ability to sense picomolar concentrations of PPi anion in the surrounding environment. On the contrary, it does not respond to other phosphate anions, including monohydrogen phosphate, dihydrogen phosphate, adenosine monophosphate, adenosine diphosphate, and adenosine triphosphate. The experimental results are described theoretically by using a model based on the Poisson-Nernst-Planck equations.

Metal ion affinity-based biomolecular recognition and conjugation inside synthetic polymer nanopores modified with iron-terpyridine complexes.

Here we demonstrate a novel biosensing platform for the detection of lactoferrin (LFN) via metal-organic frameworks, in which the metal ions have accessible free coordination sites for binding, inside the single conical nanopores fabricated in polymeric membrane. First, monolayer of amine-terminated terpyridine (metal-chelating ligand) is covalently immobilized on the inner walls of the nanopore via carbodiimide coupling chemistry. Second, iron-terpyridine (iron-terPy) complexes are obtained by treating the terpyridine modified-nanopores with ferrous sulfate solution. The immobilized iron-terPy complexes can be used as recognition elements to fabricate biosensing nanodevice. The working principle of the proposed biosensor is based on specific noncovalent interactions between LFN and chelated metal ions in the immobilized terpyridine monolayer, leading to the selective detection of analyte protein. In addition, control experiments proved that the designed biosensor exhibits excellent biospecificity and nonfouling properties. Furthermore, complementary experiments are conducted with multipore membranes containing an array of cylindrical nanopores. We demonstrate that in the presence of LFN in the feed solution, permeation of methyl viologen (MV(2+)) and 1,5-naphthalenedisulphate (NDS(2-)) is drastically suppressed across the iron-terPy modified membranes. On the basis of these findings, we envision that apart from conventional ligand-receptor interactions, the designing and immobilization of alternative functional ligands inside the synthetic nanopores would extend this method for the construction of new metal ion affinity-based biomimetic systems for the specific binding and recognition of other biomolecules.

ATP-modulated ionic transport through synthetic nanochannels.

Here, we demonstrate an anion controlled molecular gate based on synthetic ion channels modified with polyethyleneimine. For single conical nanochannels, addition of ATP leads to significant decrease in the rectified ion flux, representing the closure of the ionic gate. Complementary experiments performed with nanoporous membranes show that the flux of charged dye (NDS(2-)) through a cylindrical nanochannel array diminishes by the co-addition of ATP in the analyte solution.

Proton-regulated rectified ionic transport through solid-state conical nanopores modified with phosphate-bearing polymer brushes.

We describe the use of polyprotic polymer brushes to construct robust signal-responsive chemical devices mimicking the transport properties of proton regulated biological channels.

Development and in vitro cytotoxic evaluation of parenteral docetaxel lipid nanoemulsions for application in cancer treatment.

The aim of the present study was to develop stable lipid nanoemulsions (LNEs) for delivery of docetaxel for treatment of cancer. The LNEs of docetaxel were prepared by using olive oil and egg lecithin by hot homogenization followed by ultrasonication. The influence of formulation variables such as change in proportion of charge inducers, that is, oleic acid (negative) and stearyl amine (positive), was studied. Stable LNEs of docetaxel having the mean size range of 190-230 nm and zeta potential of -19.2 to -31 mV in the case of oleic acid emulsions and 49.5 to 50.5 mV in the case of stearyl amine emulsions were developed. There was considerable increase in zeta potential value on increasing concentration of oleic acid, whereas no such effect was observed on increasing stearyl amine concentration. During in vitro studies the cumulative amount of docetaxel released from LNE (control emulsion), LNE-O1, LNE-O2, LNE-O3, LNE-S1, LNE-S2, and LNE-S3 was determined. The results indicated that there was no significant effect in varying the concentration of charge inducers on size and in vitro cumulative release of prepared LNEs at 12 h. The optimized formulations were identified as LNE-O3 and LNE-S3 based on relative stabilities during centrifugal stress, dilution stress, and in storage at room temperature. The total drug content and entrapment efficiency of LNE-O3 were found to be 0.96 ± 0.02 mg/mL and 96.35 ± 1.21%, respectively, whereas for LNE-S3 the total drug content and entrapment efficiency were 0.97 ± 0.01 mg/mL and 97.07 ± 0.82%, respectively. During in vitro studies on cancer cell lines both of the optimized formulations, LNE-O3 and LNE-S3, showed similar values of IC50 (half maximal inhibitory concentration) in comparison to docetaxel solution. Based on this, it was concluded that the optimized LNEs were efficacious for the delivery of docetaxel and could act as alternative delivery systems to overcome the poor solubility, hydrolytic instability, and drug-induced and vehicle-related side effects of docetaxel.

Logic gates using nanofluidic diodes based on conical nanopores functionalized with polyprotic acid chains.

Single-track conical nanopores functionalized with polyprotic acid chains have pH-sensitive fixed charge groups and show three levels of conductance that allow integrating several functions on a single nanofluidic diode. Nanometer-scaled pores have previously been employed in separation and sensing but not in logic devices, despite the fact that biological ion channels with pH-dependent fixed charges are known to be responsible for information processing in biophysical structures. As a preliminary application, we propose a logic gate scheme where binary and multivalued logical functions are implemented.