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Turkish Journal of Chemistry 2023ABC-type triblock copolymers, namely poly[(ethylene glycol)methyl ether]--poly(-butyl methacrylate)--poly[2(diisopropylamino)ethyl methacrylate] (MPEG--PBuMA--PDPA),...
ABC-type triblock copolymers, namely poly[(ethylene glycol)methyl ether]--poly(-butyl methacrylate)--poly[2(diisopropylamino)ethyl methacrylate] (MPEG--PBuMA--PDPA), were first synthesized and then the middle blocks were successfully converted into poly(methacrylic acid) to obtain MPEG--PMAA--PDPA zwitterionic triblock copolymers. These block copolymers were soluble in water and formed micellar aggregates with complex cores via hydrogen bonding interactions between MPEG and PMAA blocks below pH 4.0. When the pH was between 5.0 and 7.0, due to charge compensation between partially protonated PDPA and partially ionized PMAA blocks, micelles with polyion complex cores were observed. If the solution pH was above 8.0, deprotonation of tertiary amine groups provided a hydrophobic character to the PDPA block, which resulted in the formation of PDPA-core micelles while MPEG/anionic PMAA hybrid blocks formed hydrated coronas. Intermediary layer cross-linked (ILCL) micelles from PDPA-core micelles were also prepared by cross-linking the inner PMAA shell. The hydrophobic drug dipyridamole (DIP) was used to investigate the release profile of ILCL micelles. DIP can be loaded to the PDPA cores of the micelles in basic aqueous media. An increase in the degree of cross-linking causes slower release for the model drug. It was concluded that the more complex matrix formation in the intermediary layer of the micelles via cross-linking retards the drug release from the core.
PubMed: 38173758
DOI: 10.55730/1300-0527.3597 -
ACS Applied Materials & Interfaces Jan 2024Adenosine metabolism through adenosine receptors plays a critical role in lung cancer biology. Although recent studies showed the potential of targeting adenosine...
Adenosine metabolism through adenosine receptors plays a critical role in lung cancer biology. Although recent studies showed the potential of targeting adenosine receptors as drug targets for lung cancer treatment, conventional methods for investigating receptor activities often suffer from various drawbacks, including low sensitivity and slow analysis speed. In this study, adenosine receptor activities in nonsmall cell lung cancer (NSCLC) cells were monitored in real time with high sensitivity through a carbon nanotube field-effect transistor (CNT-FET). In this method, we hybridized a CNT-FET with NSCLC cells expressing A and A adenosine receptors to construct a hybrid platform. This platform could detect adenosine, an endogenous ligand of adenosine receptors, down to 1 fM in real time and sensitively discriminate adenosine among other nucleosides. Furthermore, we could also utilize the platform to detect adenosine in complicated environments, such as human serum. Notably, our hybrid platform allowed us to monitor pharmacological effects between adenosine and other drugs, including dipyridamole and theophylline, even in human serum samples. These results indicate that the NSCLC cell-hybridized CNT-FET can be a practical tool for biomedical applications, such as the evaluation and screening of drug-candidate substances.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Nanotubes, Carbon; Lung Neoplasms; Receptors, Purinergic P1; Adenosine
PubMed: 38166368
DOI: 10.1021/acsami.3c14492 -
Journal of Cardiovascular Echography 2023The Italian Society of Echography and Cardiovascular Imaging (SIECVI) conducted a national survey to understand the volumes of activity, modalities and stressors used...
BACKGROUND
The Italian Society of Echography and Cardiovascular Imaging (SIECVI) conducted a national survey to understand the volumes of activity, modalities and stressors used during stress echocardiography (SE) in Italy.
METHODS
We analyzed echocardiography laboratory activities over a month (November 2022). Data were retrieved through an electronic survey based on a structured questionnaire, uploaded on the SIECVI website.
RESULTS
Data were obtained from 228 echocardiographic laboratories, and SE examinations were performed in 179 centers (80.6%): 87 centers (47.5%) were in the northern regions of Italy, 33 centers (18.4%) were in the central regions, and 61 (34.1%) in the southern regions. We annotated a total of 4057 SE. We divided the SE centers into three groups, according to the numbers of SE performed: <10 SE (low-volume activity, 40 centers), between 10 and 39 SE (moderate volume activity, 102 centers) and ≥40 SE (high volume activity, 37 centers). Dipyridamole was used in 139 centers (77.6%); exercise in 120 centers (67.0%); dobutamine in 153 centers (85.4%); pacing in 37 centers (21.1%); and adenosine in 7 centers (4.0%). We found a significant difference between the stressors used and volume of activity of the centers, with a progressive increase in the prevalence of number of stressors from low to high volume activity ( = 0.033). The traditional evaluation of regional wall motion of the left ventricle was performed in all centers, with combined assessment of coronary flow velocity reserve (CFVR) in 90 centers (50.3%): there was a significant difference in the centers with different volume of SE activity: the incidence of analysis of CFVR was significantly higher in high volume centers compared to low - moderate - volume (32.5%, 41.0% and 73.0%, respectively, < 0.001). The lung ultrasound (LUS) was assessed in 67 centers (37.4%). Furthermore for LUS, we found a significant difference in the centers with different volume of SE activity: significantly higher in high volume centers compared to low - moderate - volume (25.0%, 35.3% and 56.8%, respectively, < 0.001).
CONCLUSIONS
This nationwide survey demonstrated that SE was significantly widespread and practiced throughout Italy. In addition to the traditional indication to coronary artery disease based on regional wall motion analysis, other indications are emerging with an increase in the use of LUS and CFVR, especially in high-volume centers.
PubMed: 38161775
DOI: 10.4103/jcecho.jcecho_48_23 -
Colloids and Surfaces. B, Biointerfaces Feb 2024The recent "cell-based theory" of coagulation suggests that platelets serve as the site of coagulation factor reactions, making platelets an effective target for...
The recent "cell-based theory" of coagulation suggests that platelets serve as the site of coagulation factor reactions, making platelets an effective target for inhibiting membrane thrombosis. Unfortunately, there is limited research on how blood purification membranes affect platelet intracellular signaling. In this study, we modified polyethersulfone (PES) membranes with the platelet phosphodiesterase (PDE) inhibitor dipyridamole (DIP) and investigated the effects of the DIP/PES (DP) membranes on platelet adhesion, activation, aggregation, and secretion, as well as the role of the PDE-cyclic adenosine monophosphate (cAMP) intracellular signaling pathway. Additionally, we evaluated the hemocompatibility and preliminary in vivo safety of DP membranes. Our results demonstrate that the modified DP membranes effectively inhibited platelet adhesion, membrane CD62P expression, and plasma soluble P-selectin activation levels. Furthermore, we confirmed that DP membranes achieved platelet aggregation inhibition and reduced platelet factor 4 and β-thromoglobulin secretion levels by inhibiting platelet intracellular PDE-cAMP signaling. Moreover, the modified DP membranes exhibited good anticoagulant and red blood cell membrane stability and complement resistance and demonstrated preliminary biocompatibility in mouse experiments. Collectively, these findings highlight the potential application of DP dialysis membranes in blood purification for critically ill patients.
Topics: Humans; Mice; Animals; Phosphodiesterase Inhibitors; Renal Dialysis; Platelet Aggregation Inhibitors; Dipyridamole; Blood Platelets; Platelet Aggregation
PubMed: 38157764
DOI: 10.1016/j.colsurfb.2023.113725 -
Journal of Cancer Research and... Dec 2023This study investigated the antitumor efficacy of programmed cell death protein-1 (PD-1) antibody and DBDx, a triple-drug combination of dipyridamole, bestatin, and...
OBJECTIVE
This study investigated the antitumor efficacy of programmed cell death protein-1 (PD-1) antibody and DBDx, a triple-drug combination of dipyridamole, bestatin, and dexamethasone, and their related immunomodulation.
MATERIALS AND METHODS
Mouse melanoma B16, mouse Lewis lung carcinoma, and mouse breast carcinoma 4T1 were used for evaluating the in vivo therapeutic efficacy of DBDx, PD-1 antibody, and their combination. The peripheral blood and tumor tissues of 4T1 tumor-bearing mice were collected to analyze regulatory T cells and measured using flow cytometry.
RESULTS
The combination of PD-1 antibody and DBDx enhanced the therapeutic efficacy against B16 melanoma. The suppression of tumor growth by PD-1 antibody and DBDx was more significant than that by anti-PD-1 monotherapy. The tumor growth inhibition rates of PD-1 antibody, DBDx, and their combination were 54.0%, 72.4%, and 83.1%, respectively, suggesting a synergistic effect as determined by the coefficient of drug interaction. No significant changes were found in the body weights in all the above groups, indicating that the treated mice tolerated the applied drug doses. Similarly, enhanced therapeutic efficacy of the PD-1 antibody and DBDx combination was observed in murine Lewis lung carcinoma and 4T1 breast cancer models. In 4T1 breast cancer-bearing mice, the immunotherapy-related changes in lymphocytes in peripheral blood and tumor microenvironment were evaluated with flow cytometry. Compared with anti-PD-1 monotherapy, peripheral blood and tumor-infiltrating lymphocytes were found a lower ratio of regulatory T cell (Treg) subset cells and a higher ratio of CD8+/Treg cells.
CONCLUSIONS
The combination of PD-1 antibody and DBDx could achieve enhanced therapeutic antitumor efficacy than anti-PD-1 monotherapy, suggesting potential for using the triple-drug combination DBDx in cancer immunotherapy.
Topics: Animals; Mice; T-Lymphocytes, Regulatory; Carcinoma, Lewis Lung; Programmed Cell Death 1 Receptor; Cell Line, Tumor; CD8-Positive T-Lymphocytes; Drug Combinations; Tumor Microenvironment
PubMed: 38156928
DOI: 10.4103/jcrt.jcrt_350_23 -
ACS Applied Materials & Interfaces Jan 2024Tumor-associated platelets can bind to tumor cells and protect circulating tumor cells from NK-mediated immune surveillance. Tumor-associated platelets secrete cytokines...
Tumor-associated platelets can bind to tumor cells and protect circulating tumor cells from NK-mediated immune surveillance. Tumor-associated platelets secrete cytokines to induce the epithelial-mesenchymal transition (EMT) in tumor cells, which promotes tumor metastasis. Combining chemotherapeutic agents with antiplatelet drugs can reduce the occurrence of metastasis, but the systemic application of chemotherapeutic agents and antiplatelet drugs is prone to causing serious side effects. Therefore, delivering drugs to the tumor microthrombus site for long-lasting inhibition is a problem that needs to be addressed. Here, we show that small molecule peptide nanoparticles containing the Cys-Arg-Glu-Lys-Ala (CREKA) peptide can deliver the platelet inhibitor dipyridamole (DIP) and the chemotherapeutic drug paclitaxel (PTX) to tumor tissues, thereby inhibiting tumor-associated platelet function while killing tumor cells. The drug-loaded nanoparticles PD/Pep1 inhibited platelet-tumor cell interactions, were effectively taken up by tumor cells, and underwent morphological transformation induced by alkaline phosphatase (ALP) to prolong the retention time of the drugs. After intravenous injection, PD/Pep1 can target tumors and inhibit tumor metastasis. Thus, this small molecule peptide nanoformulation provides a simple strategy for efficient drug delivery and shows promise as a novel cancer therapy platform.
Topics: Humans; Paclitaxel; Platelet Aggregation Inhibitors; Dipyridamole; Peptides; Neoplastic Cells, Circulating; Nanoparticles; Cell Line, Tumor
PubMed: 38143309
DOI: 10.1021/acsami.3c13855 -
Neurochemical Research Mar 2024White matter lesions (WMLs) resulting from chronic cerebral hypoperfusion (CCH) are the leading cause of vascular dementia (VaD). This study aimed to investigate whether...
White matter lesions (WMLs) resulting from chronic cerebral hypoperfusion (CCH) are the leading cause of vascular dementia (VaD). This study aimed to investigate whether dipyridamole could alleviate WMLs by regulating the phenotype of disease-associated microglia (DAM) through equilibrative nucleoside transporter 2 (ENT2) and adenosine A2A receptor (Adora2a) and to clarify the underlying molecular mechanisms. CCH rat models were constructed to mimic VaD. Morris water maze and Luxol Fast Blue staining were employed to assess cognitive function and quantify the severity of WMLs, respectively. Immunofluorescent staining was performed to analyze the activation of glial cells and the phenotypic transformation of DAM. Additionally, levels of ENT2, proteins in the NF-κB and ERK1/2 pathways and inflammatory cytokines were detected. The results indicated that dipyridamole diminished the activation and proliferation of microglia and astrocytes, increased the expression of myelin basic protein and ameliorated WMLs and cognitive decline in CCH rats. Further study revealed that dipyridamole decreased the expression of ENT2 and inhibited the activation of ERK1/2 and NF-κB signaling pathways, which ultimately converted DAM to anti-inflammatory phenotype and suppressed the levels of TNF-α, IL-1β, IL-6 in WMLs. However, Adora2a inhibitor (SCH58261) attenuated above effects. Our study demonstrates that dipyridamole facilitates the conversion of DAM to the anti-inflammatory phenotype through ENT2/Adora2a pathway and inhibits the activation of ERK1/2 and NF-κB signaling pathways, thereby alleviating neuroinflammation in WMLs. The current findings establish the basis for using dipyridamole to treat VaD.
Topics: Rats; Animals; Microglia; NF-kappa B; White Matter; Dipyridamole; Brain Ischemia; Nervous System Diseases; Anti-Inflammatory Agents; Disease Models, Animal
PubMed: 38102341
DOI: 10.1007/s11064-023-04066-9 -
Polish Journal of Veterinary Sciences Dec 2023Cyclosporine is an immunosuppressive drug that is used to prevent tissue rejection in organ transplants and to treat autoimmune diseases such as psoriasis and rheumatoid...
Cyclosporine is an immunosuppressive drug that is used to prevent tissue rejection in organ transplants and to treat autoimmune diseases such as psoriasis and rheumatoid arthritis. It has important toxic effects in many organs such as the liver and kidney. The aim of this study was to determine and compare the effectiveness of the single and combined treatment of dipyridamole, which is a vasodilator and has an antioxidant effect, ketotifen which is toll-like receptor-4 inhibitory and has an antioxidant effect, quercetin which is an antioxidant and has an anti-inflammatory effect in cyclosporine-induced hepatorenal toxicity. Forty-eight Wistar Albino rats were divided into 7 groups. The research period was 21 days. The cyclosporine increased serum ALT and AST levels, in contrast to their increased levels prevented by all the treatments. The serum creatinine level decreased significantly with ketotifen and combined treatment, while cyclosporine partially increased serum creatinine and urea levels. The urine microalbumin and protein levels were increased significantly by cyclosporine, whereas they decreased with dipyridamole treatment. The protein levels decreased by quercetin and combined treatments. The kidney injury molecule- 1 and retinol-binding protein levels were increased by the cyclosporine, while ketotifen treatment partially decreased them. In conclusion, ketotifen and dipyridamole can prevent cyclosporine- induced hepatorenal toxicity and quercetin can increase the effectiveness of this treatment.
Topics: Rats; Animals; Quercetin; Antioxidants; Cyclosporine; Ketotifen; Dipyridamole; Creatinine; Kidney; Rats, Wistar; Liver; Oxidative Stress
PubMed: 38088299
DOI: 10.24425/pjvs.2023.148275 -
Frontiers in Cardiovascular Medicine 2023Patients with heart failure (HF) with reduced left ventricular (LV) ejection fraction (EF) have a heterogeneous prognosis, and assessment of coronary physiology with...
BACKGROUND AND AIMS
Patients with heart failure (HF) with reduced left ventricular (LV) ejection fraction (EF) have a heterogeneous prognosis, and assessment of coronary physiology with coronary flow velocity (CFV) and coronary flow velocity reserve (CFVR) may complement established predictors based on wall motion and EF.
METHODS AND RESULTS
In a prospective multicenter study design, we enrolled 1,408 HF patients (age 66 ± 12 years, 1,035 men), with EF <50%, 743 (53%) with coronary artery disease, and 665 (47%) with normal coronary arteries. Recruitment (years 2004-2022) involved 8 accredited laboratories, with inter-observer variability <10% for CFV measurement. Baseline CFV (abnormal value >31 cm/s) was obtained by pulsed-wave Doppler in mid-distal LAD. CFVR (abnormal value ≤2.0) was assessed with exercise ( = 99), dobutamine ( = 100), and vasodilator stress (dipyridamole in 1,149, adenosine in 60). Inducible myocardial ischemia was identified with wall motion score index (WMSI) stress > rest (cut-off Δ ≥ 0.12). LV contractile reserve (CR) was identified with WMSI stress < rest (cutoff Δ ≥ 0.25). Test response ranged from score 0 (EF > 30%, CFV ≥ 32 cm/s, CFVR > 2.0, LVCR present, ischemia absent) to score 5 (all steps abnormal). All-cause death was the only endpoint. Results. During a median follow-up of 990 days, 253 patients died. Independent predictors of death were EF (HR: 0.956, 95% CI: 0.943-0.968, < 0.0001), CFV (HR: 2.407, 95% CI: 1.871-3.096, < 0.001), CFVR (HR: 3.908, 95% CI: 2.903-5.260, < 0.001), stress-induced ischemia (HR: 2.223, 95% CI: 1.642-3.009, < 0.001), and LVCR (HR: 0.524, 95% CI: 0.324-.647, = 0.008). The annual mortality rate was lowest (1.2%) in patients with a score of 0 (= 61) and highest (31.9%) in patients with a score of 5 ( = 15, < 0.001).
CONCLUSION
High resting CFV is associated with worse survival in ischemic and nonischemic HF with reduced EF. The value is independent and additive to resting EF, CFVR, LVCR, and inducible ischemia.
PubMed: 38075970
DOI: 10.3389/fcvm.2023.1290366 -
International Journal of Molecular... Nov 2023The purinergic system has a dual role: the maintenance of energy balance and signaling within cells. Adenosine and adenosine triphosphate (ATP) are essential for... (Review)
Review
The purinergic system has a dual role: the maintenance of energy balance and signaling within cells. Adenosine and adenosine triphosphate (ATP) are essential for maintaining these functions. Sarcopenia is characterized by alterations in the control of energy and signaling in favor of catabolic pathways. This review details the association between the purinergic system and muscle and adipose tissue homeostasis, discussing recent findings in the involvement of purinergic receptors in muscle wasting and advances in the use of the purinergic system as a novel therapeutic target in the management of sarcopenia.
Topics: Humans; Sarcopenia; Adenosine Triphosphate; Adenosine; Receptors, Purinergic; Signal Transduction
PubMed: 38069224
DOI: 10.3390/ijms242316904