-
International Journal of Molecular... Jun 2024Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in the world, which begins with liver lipid accumulation and is associated with...
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in the world, which begins with liver lipid accumulation and is associated with metabolic syndrome. Also, the name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). We performed focused drug screening and found that Cilostazol effectively ameliorated hepatic steatosis and might offer potential for NAFLD treatment. Our aim was to investigate the therapeutic effects of Cilostazol on the glycolipid metabolism and intestinal flora in NAFLD mice and explore the specific mechanism. In this study, 7-week-old male C57BL/6J mice were fed a high-fat diet (HFD) for 8 weeks to induce NAFLD, and then treated with intragastric administration for 12 weeks. The results showed that Cilostazol inhibited liver lipid de novo synthesis by regulating the AMPK-ACC1/SCD1 pathway and inhibited liver gluconeogenesis by the AMPK-PGC1α-G6P/PEPCK pathway. Cilostazol improved the intestinal flora diversity and intestinal microbial composition in the NAFLD mice, and specifically regulated Desulfovibrio and Akkermansia. In addition, Cilostazol increased the level of short-chain fatty acids in the NAFLD mice to a level similar to that in the blank Control group. Cilostazol reduces liver lipid accumulation in NAFLD mice by improving glucose and lipid metabolism disorders and intestinal dysfunction, thereby achieving the purpose of treating NAFLD.
Topics: Animals; Cilostazol; Non-alcoholic Fatty Liver Disease; Mice; Male; Mice, Inbred C57BL; Gastrointestinal Microbiome; Lipid Metabolism; Liver; Diet, High-Fat; Intestinal Diseases; Disease Models, Animal
PubMed: 38892467
DOI: 10.3390/ijms25116280 -
International Journal of Molecular... May 2024This review article focuses on the role of adenosine in coronary artery disease (CAD) diagnosis and treatment. Adenosine, an endogenous purine nucleoside, plays crucial... (Review)
Review
This review article focuses on the role of adenosine in coronary artery disease (CAD) diagnosis and treatment. Adenosine, an endogenous purine nucleoside, plays crucial roles in cardiovascular physiology and pathology. Its release and effects, mediated by specific receptors, influence vasomotor function, blood pressure regulation, heart rate, and platelet activity. Adenosine therapeutic effects include treatment of the no-reflow phenomenon and paroxysmal supraventricular tachycardia. The production of adenosine involves complex cellular pathways, with extracellular and intracellular synthesis mechanisms. Adenosine's rapid metabolism underscores its short half-life and physiological turnover. Furthermore, adenosine's involvement in side effects of antiplatelet therapy, particularly ticagrelor and cangrelor, highlights its clinical significance. Moreover, adenosine serves as a valuable tool in CAD diagnosis, aiding stress testing modalities and guiding intracoronary physiological assessments. Its use in assessing epicardial stenosis and microvascular dysfunction is pivotal for treatment decisions. Overall, understanding adenosine's mechanisms and clinical implications is essential for optimizing CAD management strategies, encompassing both therapeutic interventions and diagnostic approaches.
Topics: Humans; Adenosine; Coronary Artery Disease; Animals; Adenosine Monophosphate; Platelet Aggregation Inhibitors
PubMed: 38892037
DOI: 10.3390/ijms25115852 -
International Journal of Molecular... May 2024One aspect of ovarian tumorigenesis which is still poorly understood is the tumor-stroma interaction, which plays a major role in chemoresistance and tumor progression....
One aspect of ovarian tumorigenesis which is still poorly understood is the tumor-stroma interaction, which plays a major role in chemoresistance and tumor progression. Cancer-associated fibroblasts (CAFs), the most abundant stromal cell type in the tumor microenvironment, influence tumor growth, metabolism, metastasis, and response to therapy, making them attractive targets for anti-cancer treatment. Unraveling the mechanisms involved in CAFs activation and maintenance is therefore crucial for the improvement of therapy efficacy. Here, we report that CAFs phenoconversion relies on the glucose-dependent inhibition of autophagy. We show that ovarian cancer cell-conditioning medium induces a metabolic reprogramming towards the CAF-phenotype that requires the autophagy-dependent glycolytic shift. In fact, 2-deoxy-D-glucose (2DG) strongly hampers such phenoconversion and, most importantly, induces the phenoreversion of CAFs into quiescent fibroblasts. Moreover, pharmacological inhibition (by proline) or autophagy gene knockdown (by siBECN1 or siATG7) promotes, while autophagy induction (by either 2DG or rapamycin) counteracts, the metabolic rewiring induced by the ovarian cancer cell secretome. Notably, the nutraceutical resveratrol (RV), known to inhibit glucose metabolism and to induce autophagy, promotes the phenoreversion of CAFs into normal fibroblasts even in the presence of ovarian cancer cell-conditioning medium. Overall, our data support the view of testing autophagy inducers for targeting the tumor-promoting stroma as an adjuvant strategy to improve therapy success rates, especially for tumors with a highly desmoplastic stroma, like ovarian cancer.
Topics: Humans; Female; Autophagy; Cancer-Associated Fibroblasts; Ovarian Neoplasms; Glucose; Cell Line, Tumor; Tumor Microenvironment; Resveratrol; Culture Media, Conditioned; Deoxyglucose; Glycolysis
PubMed: 38891879
DOI: 10.3390/ijms25115691 -
International Journal of Molecular... May 2024Infants and young animals often suffer from intestinal damage caused by oxidative stress, which may adversely affect their overall health. Hydroxytyrosol, a plant...
Infants and young animals often suffer from intestinal damage caused by oxidative stress, which may adversely affect their overall health. Hydroxytyrosol, a plant polyphenol, has shown potential in decreasing intestinal oxidative stress, but its application and mechanism of action in infants and young animals are still inadequately documented. This study selected piglets as a model to investigate the alleviating effects of hydroxytyrosol on intestinal oxidative stress induced by diquat and its potential mechanism. Hydroxytyrosol improved intestinal morphology, characterized by higher villus height and villus height/crypt depth. Meanwhile, hydroxytyrosol led to higher expression of Occludin, MUC2, Nrf2, and its downstream genes, and lower expression of cytokines IL-1β, IL-6, and TNF-α. Both oxidative stress and hydroxytyrosol resulted in a higher abundance of , and a lower abundance of and , without a significant effect on short-chain fatty acids levels. Oxidative stress also led to disorders in bile acid (BA) metabolism, such as the lower levels of primary BAs, hyocholic acid, hyodeoxycholic acid, and tauroursodeoxycholic acid, which were partially restored by hydroxytyrosol. Correlation analysis revealed a positive correlation between these BA levels and the expression of Nrf2 and its downstream genes. Collectively, hydroxytyrosol may reduce oxidative stress-induced intestinal damage by regulating BA metabolism.
Topics: Animals; Oxidative Stress; Phenylethyl Alcohol; Swine; Bile Acids and Salts; Intestinal Mucosa; Intestines; Disease Models, Animal; Gastrointestinal Microbiome; NF-E2-Related Factor 2
PubMed: 38891778
DOI: 10.3390/ijms25115590 -
AAPS PharmSciTech Jun 2024Unexpected cross-contamination by foreign components during the manufacturing and quality control of pharmaceutical products poses a serious threat to the stable supply...
Unexpected cross-contamination by foreign components during the manufacturing and quality control of pharmaceutical products poses a serious threat to the stable supply of drugs and the safety of customers. In Japan, in 2020, a mix-up containing a sleeping drug went undetected by liquid chromatography during the final quality test because the test focused only on the main active pharmaceutical ingredient (API) and known impurities. In this study, we assessed the ability of a powder rheometer to analyze powder characteristics in detail to determine whether it can detect the influence of foreign APIs on powder flow. Aspirin, which was used as the host API, was combined with the guest APIs (acetaminophen from two manufacturers and albumin tannate) and subsequently subjected to shear and stability tests. The influence of known lubricants (magnesium stearate and leucine) on powder flow was also evaluated for standardized comparison. Using microscopic morphological analysis, the surface of the powder was observed to confirm physical interactions between the host and guest APIs. In most cases, the guest APIs were statistically detected due to characteristics such as their powder diameter, pre-milling, and cohesion properties. Furthermore, we evaluated the flowability of a formulation incorporating guest APIs for direct compression method along with additives such as microcrystalline cellulose, potato starch, and lactose. Even in the presence of several additives, the influence of the added guest APIs was successfully detected. In conclusion, powder rheometry is a promising method for ensuring stable product quality and reducing the risk of unforeseen cross-contamination by foreign APIs.
Topics: Powders; Rheology; Drug Contamination; Excipients; Acetaminophen; Cellulose; Pharmaceutical Preparations; Quality Control; Aspirin; Chemistry, Pharmaceutical; Lactose; Drug Compounding; Lubricants; Bulk Drugs
PubMed: 38890193
DOI: 10.1208/s12249-024-02856-0 -
Open Heart Jun 2024For high bleeding-risk patients (HBR) undergoing percutaneous coronary intervention (PCI), the LEADERS FREE (LF) and LEADERS FREE II (LF II) trials established the... (Comparative Study)
Comparative Study
BACKGROUND
For high bleeding-risk patients (HBR) undergoing percutaneous coronary intervention (PCI), the LEADERS FREE (LF) and LEADERS FREE II (LF II) trials established the safety and efficacy of a stainless steel polymer-free biolimus-coated stent (SS-BCS) with 30 days of dual antiplatelet treatment (DAPT). The LEADERS FREE III (LF III) trial investigated clinical outcomes after PCI with the next-generation cobalt-chromium thin-strut polymer-free biolimus-coated stent (CoCr-BCS) in HBR patients.
AIMS
To report the final 3-year results of the LF III trial and compare them to LF II.
METHODS
LF III was a prospective, multicentre, open-label single-arm study to evaluate the safety and efficacy of the CoCr-BCS stent. The primary safety endpoint was the composite of cardiac death (CD), myocardial infarction(MI) or definite/probable stent thrombosis (ST). The primary efficacy endpoint was clinically driven target lesion revascularisation (cd-TLR). We performed a propensity-matched comparison to the 3-year outcomes of LF II.
RESULTS
After 3 years, CD/MI/ST had occurred in 57 patients (15%, 95% CI 11.8% to 19%) and cd-TLR in 23 (6.2%, 95% CI 4.1% to 9.2%) patients. In a propensity-matched comparison of patients treated with the CoCr-BCS versus the SS-BCS, there were similar rates of CD (6.6% vs 7.8%, p=0.50), MI (7.1% vs 8.3%, p=0.47) and definite/probable ST (1.1% vs 2%, HR 0.56, 95% CI 0.16 to 1.93, p=0.35). The rates of cd-TLR were 5.3% with CoCr-BCS versus 9.8% with SS-BCS (HR 0.54, 95% CI 0.31 to 0.96, p=0.03).
CONCLUSION
LF III confirms the long-term safety and efficacy of the CoCr-BCS in HBR patients treated with 1 month of DAPT.
TRIAL REGISTRATION NUMBER
NCT02843633, NCT03118895.
Topics: Humans; Drug-Eluting Stents; Male; Prospective Studies; Female; Percutaneous Coronary Intervention; Prosthesis Design; Sirolimus; Treatment Outcome; Coronary Artery Disease; Aged; Time Factors; Middle Aged; Follow-Up Studies; Platelet Aggregation Inhibitors; Risk Factors
PubMed: 38890129
DOI: 10.1136/openhrt-2024-002679 -
Acta Neurochirurgica Jun 2024This comprehensive review delves into the evolving field of neurointervention for intracranial aneurysms, exploring the critical adjunct of Dual Antiplatelet Therapy... (Review)
Review
Variability patterns in dual antiplatelet therapy following endovascular repair of intracranial aneurysms: Insight into regimen heterogeneity and the need for a consensus.
This comprehensive review delves into the evolving field of neurointervention for intracranial aneurysms, exploring the critical adjunct of Dual Antiplatelet Therapy (DAPT) to endovascular coiling, stent-assisted coiling (SAC), flow-diversion stents, and flow-disruption (intrasaccular) devices. Despite growing evidence supporting the success of DAPT in reducing thromboembolic events, the lack of consensus on optimal regimens, doses, and duration is evident. Factors contributing to this variability include genetic polymorphisms affecting treatment response and ongoing debates regarding the clinical significance of hemorrhagic complications associated with DAPT. This review analyzes pre- and post-procedural antiplatelet usage across various interventions. The imperative lies in ongoing research to define optimal DAPT durations, ensuring a nuanced approach to the delicate balance between thrombosis and hemorrhage in intracranial aneurysm management.
Topics: Humans; Intracranial Aneurysm; Endovascular Procedures; Platelet Aggregation Inhibitors; Dual Anti-Platelet Therapy; Consensus; Stents
PubMed: 38888678
DOI: 10.1007/s00701-024-06137-4 -
Bulletin of Experimental Biology and... Apr 2024In in vitro model of short-term therapeutic inhalation of Xe/O mixture, xenon in millimolar concentrations led to a pronounced decrease in induced platelet aggregation...
In in vitro model of short-term therapeutic inhalation of Xe/O mixture, xenon in millimolar concentrations led to a pronounced decrease in induced platelet aggregation in the platelet-enriched blood plasma. The maximum and statistically significant decrease occurred in response to induction by collagen (by ≈30%, p≤0.01) and ADP (by ≈25%, p≤0.01). A slightly weaker but statistically significant reduction in aggregation appeared in response to ristocetin (by ≈12%, p≤0.01) and epinephrine (by ≈9%, p≤0.01). It should be noted that the spontaneous aggregation exceeded the reference values in the control group. Nevertheless, even at minimal absolute values, spontaneous platelet aggregation decreased by 2 times in response to xenon (p≤0.01). The reasons for the decrease of spontaneous and induced aggregation are xenon accumulation in the lipid bilayer of the membrane with subsequent nonspecific (mechanical) disassociation of membrane platelet structures and specific block of its distinct from neuronal NMDA receptor.
Topics: Xenon; Platelet Aggregation; Humans; Blood Platelets; Adenosine Diphosphate; Platelet Aggregation Inhibitors; Platelet-Rich Plasma; Epinephrine; Collagen
PubMed: 38888651
DOI: 10.1007/s10517-024-06101-3 -
EuroIntervention : Journal of EuroPCR... Jun 2024
Topics: Humans; Platelet Aggregation Inhibitors; Clopidogrel; Percutaneous Coronary Intervention; Treatment Outcome
PubMed: 38887879
DOI: 10.4244/EIJ-E-24-00009 -
Analytical Chemistry Jul 2024This study investigated the added value of combining both near-infrared (NIR) and Raman spectroscopy into a single NIRaman Combi Fiber Probe for in-line blend potency...
This study investigated the added value of combining both near-infrared (NIR) and Raman spectroscopy into a single NIRaman Combi Fiber Probe for in-line blend potency determination in the feed frame of a rotary tablet press. A five-component platform formulation was used, containing acetylsalicylic acid as the Active Pharmaceutical Ingredient (API). Calibration models for the determination of 1 and 5% label claim tablets were developed using NIR and Raman spectra of powder blends ranging from 0.75 to 1.25% and 3.75 to 6.25% API, respectively. Step-change experiments with deliberate 10% deviation steps from the label claims were performed, from which the collected spectra were used for model validation. For model development and validation, low-level data fusion was explored through concatenation of preprocessed NIR and Raman spectra. Mid-level data fusion was also evaluated, based on extracted features of the preprocessed data. Herewith, score vectors were extracted by transforming preprocessed spectra through Principal Component Analysis, followed by critical feature selection through Elastic Net Regression. Partial Least Squares regression was applied to regress singular, low-level or mid-level fused data versus blend potency. It could be concluded that irrespective of the data fusion technique, an increase in Step-Change Sensitivity (SCS) and decrease in Root Mean Squared Error (RMSE) was observed when predicting the 5% step-change experiment. For the prediction of the 1% step-change experiment, no added benefit with regard to SCS and RMSE was observed due to the addition of the noisy NIR spectra.
Topics: Spectrum Analysis, Raman; Tablets; Spectroscopy, Near-Infrared; Aspirin; Principal Component Analysis; Calibration
PubMed: 38887018
DOI: 10.1021/acs.analchem.4c01134