Search Results (63)

Beyond gas transport, red blood cells (RBCs) have emerging roles regarding innate immunity, regulating blood flow, and participating in nutrient transport, which can be engineered as drug delivery systems since they contribute to maintaining water homeostasis. Following extensive thermoanalytical studies of human blood plasma, our working group investigated the properties of RBCs, examining their role in healthy and in different disease states by using differential scanning calorimetry (DSC) and the deconvolution of the resulting thermal curve. In the first study, guinea pigs were treated with intraperitoneal chemotherapy. Cyclophosphamide treatment showed a dose-dependent difference between the thermal parameters of control and treated samples, indicating that DSC can be used in this area. Following deconvolution of the DSC studies, the changes can be attributed to the damaged compounds. In the second part of our study, a method for the thermal analysis and deconvolution of RBCs in patients with lower limb ischemia during a three-month cilostazol treatment was developed. The control DSC curve showed 5–6 distinct thermal domains, and in contrast to other drug treatments, this remained stable throughout the entire study period. No effects of stiffness or compact were caused by the anticancer drug cyclophosphamide were observed in the structure of RBCs. These preliminary results highlight the uniqueness of thermodynamic studies of RBCs and provide a fingerprint-like identification of a given individual or disease state. Full article

Background: This study investigated the renoprotective potential of Nano-Cilostazol against cisplatin (CIS)-induced renal injury in male rats and explored its molecular mechanisms. Our results showed that Nano-Cilostazol has a favorable physicochemical characteristic, including a mean particle size of approximately 101 nm, narrow polydispersity, and high stability. FTIR analysis indicated successful drug entrapment, preserving functional groups and enhancing hydrogen bonding. Docking analysis showed that cilostazol had stronger binding affinities than disulfiram against seven acute kidney injury-related targets. Interaction profiling confirmed stable binding through hydrogen bonding, hydrophobic, and π-interactions with BAX, ASC, GSDMD, KIM-1, JAK2, NLRP3, and miRNA-155. In vivo, CIS administration led to marked renal dysfunction, showing up as significant elevations in serum urea, creatinine, cystatin-C, CRP, and NGAL which indicated by severe histopathological damage. Co-treatment with Nano-Cilostazol significantly lessened renal functional impairment biochemically and histopatologically. Nano-Cilostazol markedly reduced lipid peroxidation and oxidized glutathione while also restoring antioxidant defenses like superoxide dismutase and catalase, with total and reduced glutathione. Additionally, Nano-Cilostazol attenuated renal inflammation, inhibiting NF-κB activation, lowering pro-inflammatory cytokines (TNF-α and IL-1β), and downregulating inflammatory and injury-related genes. CIS-triggered apoptotic signaling was also mitigated, shown by increased caspase-3 and BAX expression with downregulation of BCL-2. Nano-Cilostazol significantly inhibited apoptosis and pyroptosis (NLRP3, ASC, GSDMD)-related pathways, modulated JAK2/STAT3 signaling, and downregulated miRNA-155 expression. In conclusion, Nano-Cilostazol offers potent protection against cisplatin-induced nephrotoxicity. Full article

Background: Restenosis after coronary stent implantation remains a major clinical challenge, especially in patients with diabetes, long lesions, or multiple stents. Standard therapy with aspirin and P2Y12 inhibitors does not reliably prevent this complication. Objectives: We reviewed experimental and clinical evidence on cilostazol, a selective phosphodiesterase-3 inhibitor, as a strategy to reduce restenosis after percutaneous coronary intervention (PCI). Methods: Preclinical and clinical studies were critically appraised, focusing on the effects of cilostazol on vascular smooth muscle and endothelial cells, platelet aggregation, lipid metabolism, and restenosis rates. Results: Experimental models show that cilostazol inhibits smooth muscle proliferation and intimal hyperplasia after arterial injury. Clinical trials demonstrate reduced restenosis after balloon angioplasty and stent implantation compared with aspirin, ticlopidine, or clopidogrel. Although approved by the FDA for intermittent claudication, cilostazol remains underused in the prevention of coronary restenosis. Conclusions: Current evidence supports cilostazol as an effective adjunctive therapy to reduce restenosis following PCI. Wider adoption and further large-scale trials are warranted to better define its role in contemporary interventional practice. Full article

Kidney disease (KD) is a major health challenge, affecting millions of people worldwide, highlighting the need for improved prevention and management strategies. The pathophysiological mechanisms converged on a common pathway characterized by inflammation, oxidative stress, fibrosis, nephron loss and failure. Curcumin, the active compound derived from turmeric (Curcuma longa), attracts considerable interest as a potential therapy for KD due to its anti-inflammatory, antioxidant and anti-fibrotic properties. Despite the benefits of curcumin, co-administration with kidney medications may cause drug interactions. Here, we systematically reviewed the efficacy of curcumin in alleviating KD and its safety when used with conventional treatments. Search terms included: curcumin AND (“diabetic nephropathy” OR “renal disease” OR “kidney disease”). Data on mechanisms of action, redox status, clinical benefits, side effects, and drug interactions were extracted and analyzed. Curcumin reduces oxidative stress, inflammation, apoptosis, fibrosis, ER stress, and lipid and glucose metabolism. Curcumin has multifaceted nephroprotective effects, while it is safe and well-tolerated. The curcumin–drug interactions reviewed were: -piperine, -epigallocatechin gallate, -losartan, -ginkgolide B, -rosuvastatin, -insulin, -cilostazol, and -ginger. These interactions improve curcumin bioavailability, and synergistic anti-inflammatory/antioxidant/antifibrotic and renoprotective effects. Future research should prioritize large-scale clinical trials to evaluate the efficacy and safety of curcumin in diverse KD populations. Full article

Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are neurodevelopmental disorders marked by deficits in communication and social interaction, often accompanied by anxiety, seizures, and intellectual disability. FXS, the most common monogenic cause of ASD, results from silencing of the FMR1 gene and consequent loss of FMRP, a regulator of synaptic protein synthesis. Disruptions in cyclic nucleotide (cAMP and cGMP) signaling underlie both ASD and FXS contributing to impaired neurodevelopment, synaptic plasticity, learning, and memory. Notably, reduced cAMP levels have been observed in platelets, lymphoblastoid cell lines and neural cells from FXS patients as well as Fmr1 KO and dfmr1 Drosophila models, linking FMRP deficiency to impaired cAMP regulation. Phosphodiesterase (PDE) inhibitors, which prevent the breakdown of cAMP and cGMP, have emerged as promising therapeutic candidates due to their ability to modulate neuronal signaling. Several PDE isoforms—including PDE2A, PDE4D, and PDE10A—have been implicated in ASD, and FXS, as they regulate pathways involved in synaptic plasticity, cognition, and social behavior. Preclinical and clinical studies show that PDE inhibition modulates neuroplasticity, neurogenesis, and neuroinflammation, thereby ameliorating autism-related behaviors. BPN14770 (a PDE4 inhibitor) has shown promising efficacy in FXS patients while cilostazol, pentoxifylline, resveratrol, and luteolin have showed improvements in children with ASD. However, challenges such as isoform-specific targeting, optimal therapeutic window, and timing of intervention remain. Collectively, these findings highlight PDE inhibition as a novel therapeutic avenue with the potential to restore cognitive and socio-behavioral functions in ASD and FXS, for which effective targeted treatments remain unavailable. Full article

Background: While anticoagulant and antiplatelet therapies are commonly combined in clinical settings, this combination increases the risk of hemorrhage. However, comparative data on the bleeding risks of different drug combinations remain limited. This study assesses hemorrhage risk associated with various anticoagulant–antiplatelet combinations using data from the USFDA Adverse Event Reporting System (AERS). Methods: Hemorrhage-related reports were extracted from the AERS database (March 2004–June 2024). Anticoagulants analyzed included warfarin, rivaroxaban, dabigatran, apixaban, edoxaban, betrixaban, and acenocoumarol; antiplatelets included aspirin, clopidogrel, ticagrelor, cilostazol, prasugrel, and dipyridamole. Disproportionality analysis using frequentist and Bayesian approaches was conducted to detect hemorrhage signals. Results: Out of 160,715 hemorrhage reports, rivaroxaban, warfarin, and apixaban were the most frequently reported anticoagulants, while aspirin and clopidogrel were the top antiplatelets. Apixaban had the lowest reporting odds ratio for hemorrhage. The rivaroxaban-aspirin combination showed the highest hemorrhage risk, while combinations with cilostazol were the lowest. Apixaban, alone and in combination, was associated with reduced hemorrhage and mortality risks. Conclusions: Combining anticoagulants with antiplatelets increases hemorrhage and mortality risk. While our findings highlight potential safety signals related to hemorrhage with antithrombotic drug combinations, they remain hypothesis-generating and should not be interpreted as causal associations. Instead, they provide an initial basis for further validation in well-designed clinical cohorts where comorbidities can be adequately accounted for. Full article

Background/Objectives: Drug discovery is a lengthy and expensive process, taking an average of 10 years and more than USD 2 billion from target discovery to drug approval. It is even more challenging in complex diseases due to disease heterogeneity and limited knowledge about the underlying mechanisms. We present a novel computational framework that integrates network analysis, statistical mediation, and deep learning to identify causal target genes and repurposable small-molecule candidates. Methods: We applied weighted gene co-expression network analysis (WGCNA) and bidirectional mediation analysis (causal WGCNA) to transcriptomic data from idiopathic pulmonary fibrosis (IPF) patients to identify genes causally linked to the disease phenotype. These genes were used as a phenotypic signature for deep learning-based compound screening using the DeepCE model. Results: Using RNA-seq data from 103 IPF patients and 103 controls, we identified seven significantly correlated modules and 145 causal genes. Five of these genes (ITM2C, PRTFDC1, CRABP2, CPNE7, and NMNAT2) were predictive of disease severity in IPF. Our compound screening identified several promising candidates, such as Telaglenastat (GLS1 inhibitor), Merestinib (MET kinase inhibitor), and Cilostazol (PDE3 inhibitor), with significant inverse correlation with the IPF-specific gene signature. Conclusions: This study demonstrates the utility of combining causal inference and deep learning for drug discovery. Our framework identified novel gene targets and therapeutic candidates for IPF, offering a scalable strategy for phenotype-driven drug discovery and repurposing. Full article

Objective: Several strategies have been described for stroke prevention, and the most commonly used medication is aspirin. Cilostazol, which is a substance with a pleiotropic effect, is still not well investigated. In this study, we aimed to delineate the effects of mono- and combinatorial pre-treatment upon neurological status and biomarkers, namely protein S100b, GFAP, procalcitonin, and galectin-3, following stroke. Methods: Twelve-week-old Sprague–Dawley rats were randomly assigned to four groups, each containing six rats: control group (normal saline), cilostazol group (30 mg/kg/daily), aspirin group (10 mg/kg/daily), and aspirin/cilostazol group. Each substance was administered by gavage for four weeks. All animals were subjected to cerebral ischemia for 2 h using intraluminal middle cerebral artery occlusion. A neurological examination was performed, serum concentrations of biomarkers were determined, and the animals were then sacrificed. Results: All treatment groups exhibited variations in the severity of immediate neurological presentation. Unlike the control group, where all rats presented with severe focal neurology or mortality, most rats in the treatment groups displayed no to moderate focal neurology. Moreover, the aspirin/cilostazol group consistently exhibited significantly lower levels in the studied biomarkers compared to other groups. Conclusions: Co-administration of cilostazol and aspirin significantly ameliorates the immediate expression of the studied biomarkers. Further large-scale studies are needed to investigate the effect of combined therapy for primary and secondary prevention of stroke, using not only serum biomarkers but other specific clinical and laboratory endpoints. Full article

Introduction: Intermittent claudication, an early symptom of peripheral artery disease, can be treated by cilostazol to alleviate symptoms and improve walking distance. Our previous investigation focused on cilostazol-induced alterations in the thermodynamic properties of plasma, utilizing differential scanning calorimetry (DSC) as a potential monitoring tool. The current proof-of-concept study aimed to enhance the interpretation of DSC data through deconvolution techniques, specifically examining protein transitions within the plasma proteome during cilostazol therapy. Results: Notable differences in thermal unfolding profiles were found between cilostazol-treated patients and healthy controls. The fibrinogen-associated transition exhibited a downward shift in denaturation temperature and decreased enthalpy by the third month. The albumin-related transition shifted to higher temperatures, accompanied by lower enthalpy. Transitions associated with globulins showed changes in thermal stability, while the transferrin-related peak demonstrated increased structural rigidity in treated patients compared to controls. Discussion: These observations suggest that cilostazol induces systemic changes in the thermodynamic behavior of plasma proteins. DSC, when combined with deconvolution methods, presents a promising approach for detecting subtle, therapy-related alterations in plasma protein stability. Materials and methods: Ten patients (median age: 58.6 years) received 100 milligrams of cilostazol twice daily. Blood samples were collected at the baseline and after 2 weeks, 1 month, 2 months, and 3 months of therapy. Walking distances were also assessed. The DSC curves were retrieved from the thermal analysis investigated by deconvolution mathematical methods. Conclusions: Although the exact functional consequences remain unclear, the observed biophysical changes may reflect broader molecular adaptations involving protein–protein interactions, post-translational modifications, or acute phase response elements. Full article

Background: Since clazosentan was approved for insurance coverage in Japan, the postoperative management of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) has changed as each facility gains experience. Here, we investigate the prevention, treatment, and management of DCI after SAH throughout Japan in 2023. Methods: In 2024, we conducted an anonymous questionnaire survey—emailed to certified neurosurgeons in hospitals across Japan—regarding management for preventing DCI after aneurysmal SAH. Of them, 78 hospitals responded and were included in this study. These results were compared with the findings of a survey conducted prior to the approval of clazosentan in Japan (2022). Results: The proportion of institutions with a standardized protocol for DCI after aneurysmal SAH at a level of ≥50% was 93.0%. For both craniotomy and endovascular surgery, clazosentan was used most frequently, followed by cilostazol, fasudil, and statins. The most common drug for both direct and endovascular procedures was clazosentan. The predominant reason for discontinuing clazosentan was respiratory complications—such as pulmonary edema—followed by cardiac complications. However, 62.1% of facilities felt that the number of cases wherein clazosentan was discontinued was deceasing. While 77.5% of respondents felt that clazosentan was effective for preventing DCI after aneurysmal SAH, only 49.3% felt that it improved outcomes. Conclusions: Since its approval, clazosentan has been the most common treatment for DCI prevention after aneurysmal SAH. The impression of the effectiveness in preventing DCI and the outcomes of clazosentan have been mixed. As data accumulate, clazosentan use and management protocols will be refined and developed. Full article

Background/Objectives: Aneurysmal subarachnoid hemorrhage (aSAH) remains a life-threatening cerebrovascular event with high rates of mortality and long-term morbidity. Among its complications, delayed cerebral ischemia (DCI) is a major contributor to poor clinical outcomes. Although cerebral vasospasm has traditionally been considered the primary mechanism underlying DCI, recent studies have revealed the multifactorial nature of this condition. This review aims to provide a comprehensive overview of the pathophysiology, preventive strategies, and current treatment options for DCI following aSAH. Methods: A narrative literature review was conducted using the PubMed database to identify peer-reviewed articles relevant to the prevention and treatment of DCI following aSAH. The search strategy employed the following terms: (“Subarachnoid Hemorrhage” [MeSH]) AND “Delayed Cerebral Ischemia” AND (“Prevention and Control” [Subheading] OR “Secondary Prevention” [MeSH]). This search strategy was designed to capture studies addressing both pharmacological and non-pharmacological preventive measures for DCI. Results: A comprehensive PubMed search identified a total of 113 relevant articles. Among these, 40 publications primarily addressed pharmacological interventions, while 22 focused on neuromonitoring techniques. An additional 20 articles explored the pathophysiological mechanisms underlying DCI, and 15 involved preclinical studies utilizing animal models. The remaining 16 articles encompassed diverse topics, including prophylactic endovascular therapies, newly proposed definitions of DCI, treatment algorithm development, functional outcome analyses, and entries in clinical trial registries. Emerging evidence highlights that vasospasm alone does not account for all cases of DCI. Pharmacological approaches such as nimodipine, clazosentan, and fasudil have shown varying degrees of efficacy. Circulatory management and removal of subarachnoid hematoma via CSF drainage or thrombolytics may reduce DCI risk, although their impact on long-term neurological outcomes remains controversial. Endovascular therapy and adjunctive agents such as cilostazol or anticoagulants have demonstrated potential but require further validation through large-scale trials. Conclusions: Effective DCI prevention and treatment require a multimodal approach targeting diverse pathological mechanisms beyond vasospasm. Improved risk stratification, early detection, and individualized therapy are essential for advancing the management of patients with aSAH. Full article

Background/Objective: Cyclosporine A and other calcineurin inhibitors have been identified as prospective treatments for preventing Alzheimer’s disease. We previously found that calcineurin inhibitors elicit a unique behavioral profile in zebrafish larvae, characterized by increased activity, acoustic hyperexcitability, and reduced visually guided behaviors. Screening a large library of FDA-approved compounds using Z-LaP Tracker revealed that some heart medications produce a similar behavioral profile, suggesting these drugs may exert calcineurin-inhibitor-like effects relevant to prevent-ing or ameliorating Alzheimer’s disease. Methods: Screening a large library of FDA-approved drugs using Z-LaP Tracker, a neural network model, revealed a cluster of 65 drugs demonstrating a cyclosporine A-like behavioral profile. Fourteen of these drugs were heart medications, including angiotensin receptor blockers, beta blockers, al-pha-adrenergic receptor antagonists, and a statin. Results: Dual administration of the heart medications with cyclosporine A in Z-LaP Tracker revealed synergistic effects: lower doses of each heart medication could be delivered in conjunction with a lower dose of cyclosporine A to evoke a similar or larger behavioral effect than higher doses of each drug independently. Other studies have shown that many of these heart medica-tions drugs directly or indirectly inhibit the calcineurin–NFAT pathway, like cyclo-sporine A, providing a potential mechanism. Conclusions: Co-administering a low dose of cyclosporine A with select cardiac drugs could be a potentially effective treatment strategy for preventing Alzheimer’s disease occurrence and simultaneously treating cardiovascular dysfunction, while mitigating the side effects associated with higher doses of cyclosporine A. Given that heart disease precedes Alzheimer’s disease in many patients, physicians may be able to create a treatment regimen that addresses both con-ditions. Our results suggest that a calcineurin inhibitor combined with simvastatin, irbesartan, cilostazol, doxazosin, or nebivolol is the most promising candidate for future exploration. Full article

Objective: The contralateral hippocampus, a critical region for cognitive function, is often overlooked in everyday clinical practice and stroke research. This study aimed to evaluate the effect of specific antiplatelet agents on the hippocampus (ipsilateral and contralateral) during the hyperacute phase of stroke. Materials and Methods: Twelve-week-old rats were randomly assigned to four groups, each containing six rats: a cilostazol group, an aspirin group, an aspirin plus cilostazol group, and a control group. Each substance was administered for four weeks. Permanent brain ischemia was induced over 2 h using intraluminal middle cerebral artery occlusion. A neurologic examination was conducted, followed by euthanasia and histological examination of the CA1 hippocampal region. The hematoxylin and eosin stain was used to assess the total number of intact neuronal cell bodies and pyknotic nuclei, an indicator of early irreversible neuronal injury. Results: In the ipsilateral hippocampus, monotherapy with either aspirin or cilostazol significantly reduced pyknotic nuclei compared with the control group (p = 0.0016 and p = 0.0165, respectively). However, combination therapy showed no significant difference from the controls (p = 0.2375). In the contralateral hippocampus, cilostazol monotherapy demonstrated significantly reduced pyknotic nuclei (p = 0.0098), whereas aspirin monotherapy and combination therapy did not (p = 0.1009 and p = 0.9999, respectively). A cumulative analysis of both hemispheres revealed that monotherapy with aspirin or cilostazol markedly reduced injury markers (p = 0.0002 and p = 0.0001, respectively), whereas combined therapy revealed no significant benefit (p = 0.1984). A neurological assessment indicated that the most severe deficits were in the combination therapy group. Conclusions: To the best of our knowledge, this is the first study to compare acute histopathological changes in the affected and unaffected hippocampus after a stroke in a rat model. Dual antiplatelet therapy resulted in worse outcomes (histopathological and neurological) than monotherapy. Full article

Background/Objectives: The outcome for aneurysmal subarachnoid hemorrhage (SAH) remains poor, particularly for patients presenting with World Federation of Neurological Surgeons (WFNS) grades IV–V. This study was designed to identify independent prognostic factors in this group of patients with poor-grade SAH. Methods: We prospectively analyzed 357 SAH patients with admission WFNS grades IV–V enrolled in nine primary stroke centers in Mie prefecture, Japan, from 2013 to 2022. This study compared clinical variables, including treatments for angiographic vasospasm and delayed cerebral ischemia (DCI), between patients with favorable (modified Rankin Scale [mRS] scores 0–2) and unfavorable (mRS scores 3–6) outcomes at 90 days post-onset. Multivariate analyses were then performed to identify independent determinants of favorable 90-day outcomes, followed by propensity score matching analyses. Results: The median age was 68 years, and 53.5% of patients had admission WFNS grade V. DCI occurred in 12.9% of patients, and 66.9% had unfavorable outcomes. Independent variables related to unfavorable outcomes were older age, admission WFNS grade V, ventricular drainage, edaravone administration, and delayed cerebral infarction, while those for favorable outcomes were spinal drainage (adjusted odds ratio [aOR] 6.118, 95% confidence interval [CI] 2.687–13.927, p < 0.001), modified Fisher grade 3 (aOR 2.929, 95% CI 1.668–5.143, p < 0.001), and triple prophylactic anti-DCI medication consisting of cilostazol, fasudil hydrochloride and eicosapentaenoic acid (aOR 1.869, 95% CI 1.065–3.279, p = 0.029). Nimodipine is not approved in Japan, and statin and cerebral vasospasm did not influence outcomes. As spinal drainage and the triple prophylactic anti-DCI medication were intervenable variables, propensity score matchings were performed, and they confirmed that both spinal drainage and the triple prophylactic anti-DCI medication were useful to achieve favorable outcomes. Conclusions: In poor-grade SAH, spinal drainage and the triple prophylactic anti-DCI medication may be effective in improving outcomes, possibly by suppressing DCI pathologies other than cerebral vasospasm. Full article

Background and Objectives: Hip surgery is increasingly performed among elderly patients. Oral antithrombotics, which are taken for patients’ underlying diseases, are a main concern regarding perioperative bleeding. Postoperative venous thromboembolism (VTE) is a leading cause of mortality after hip surgery. Therefore, administration of preoperative oral antithrombotics is a double-edged sword in hip surgery. In this study, we examined the correlation between the occurrence of postoperative VTE and the type of oral antithrombotics administered preoperatively. Materials and Methods: We analyzed the medical records of 601 patients aged 19 and over who underwent hip surgery from January 2021 to June 2023. The patients were assigned to two groups as follows: Groups VTE+ (patients who developed postoperative VTE) and VTE- (patients who did not develop postoperative VTE), respectively. Results: Of the 139 patients who had been taking oral antithrombotics for 6 months or more, 24 were allocated to group VTE+ and 115 to group VTE-, respectively. The number of patients who took clopidogrel and cilostazol was significantly higher in groups VTE- and VTE+, respectively (12.5 vs. 33.9%, p = 0.038, odds ratio (OR) = 0.278, 95% confidence interval (CI) = 0.078–0.991; 20.8 vs. 5.2%, p = 0.010, 95% CI = 1.325–17.245; group VTE+ vs. group VTE-). Preoperative albumin levels were significantly lower in group VTE+ (3.4 ± 0.6 g/dL vs. 3.7 ± 0.4 g/dL, p = 0.004, OR = 0.285, 95% CI = 0.115–0.702). In multivariate regression analysis, the results were statistically significant for clopidogrel, cilostazol, and preoperative albumin levels (p = 0.035, OR = 0.237, 95% CI = 0.062–0.901; p = 0.011, OR = 6.479, 95% CI = 1.542–27.226; p = 0.002, OR = 0.211, 95% CI = 0.080–0.558). Conclusions: Among the patients who had been taking oral antithrombotics for ≥6 months, clopidogrel had a prophylactic effect, but cilostazol showed an aggravating effect on postoperative VTE in hip surgery. Preoperative hypoalbuminemia increases the risk of postoperative VTE in hip surgery. Full article