Engineering magnetic nanosystem for TRPV1 and TRPV4 channel activation.

Recently, physical tools for remotely stimulating mechanical force-sensitive and temperature-sensitive proteins to regulate intracellular pathways have opened up novel and exciting avenues for basic research and clinical applications. Among the numerous modes of physical stimulation, magnetic stimulation is significantly attractive for biological applications due to the advantages of depth penetration and spatial-temporally controlled transduction. Herein, the physicochemical parameters (e.g., shape, size, composition) that influence the magnetic properties of magnetic nanosystems as well as the characteristics of transient receptor potential vanilloid-1 (TRPV1) and transient receptor potential vanilloid-4 (TRPV4) channels are systematically summarized, which offer opportunities for magnetic manipulation of cell fate in a precise and effective manner. In addition, representative regulatory applications involving magnetic nanosystem-based TRPV1 and TRPV4 channel activation are highlighted, both at the cellular level and in animal models. Furthermore, perspectives on the further development of this magnetic stimulation mode are commented on, with emphasis on scientific limitations and possible directions for exploitation. This article is categorized under: Diagnostic Tools > Biosensing Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

Photodynamic therapy with NIR-II probes: review on state-of-the-art tools and strategies.

In 2022 10% of the world's population was aged 65+, and by 2100 this segment is expected to hit 25%. These demographic changes place considerable pressure over healthcare systems worldwide, which results in an urgent need for accurate, inexpensive and non-invasive ways to treat cancers, a family of diseases correlated with age. Among the therapeutic tools that gained important attention in this context, photodynamic therapies (PDT), which use photosensitizers to produce cytotoxic substances for selectively destroying tumor cells and tissues under light irradiation, profile as important players for next-generation nanomedicine. However, the development of clinical applications is progressing at slow pace, due to still pending bottlenecks, such as the limited tissue penetration of the excitation light, and insufficient targeting performance of the therapeutic probes to fully avoid damage to normal cells and tissues. The penetration depth of long-wavelength near infrared (NIR) light is significantly higher than that of short-wavelength UV and visible light, and thus NIR light in the second window (NIR-II) is acknowledged as the preferred phototherapeutic means for eliminating deep-seated tumors, given the higher maximum permissible exposure, reduced phototoxicity and low autofluorescence, among others. Upon collective multidisciplinary efforts of experts in materials science, medicine and biology, multifunctional NIR-II inorganic or organic photosensitizers have been widely developed. This review overviews the current state-of-the art on NIR-II-activated photosensitizers and their applications for the treatment of deep tumors. We also place focus on recent efforts that combine NIR-II activated PDT with other complementary therapeutic routes such as photothermal therapy, chemotherapy, immunotherapy, starvation, and gas therapies. Finally, we discuss still pending challenges and problems of PDT and provide a series of perspectives that we find useful for further extending the state-of-the art on NIR-II-triggered PDT.

Zinc Doping Engineering in ZnxFe3-xO4 Heterostructures for Enhancing Photodynamic Therapy in the Near-Infrared-II Region.

Currently, photodynamic therapy (PDT) is restricted by the laser penetration depth. Except for PDT at 1064 nm wavelength excitation, the development of other NIR-II-activated nanomaterials with a higher response depth is still hindered and rarely reported in the literature. To overcome these problems, we fabricated a nanoplatform with heterostructures that generate reactive oxygen species (ROS) and ferrite nanoparticles under a high concentration of zinc doping (ZnxFe3-xO4 NPs), which can achieve oxidative damage of tumor cells under near-infrared (NIR) illumination. The recombination of photoelectrons and holes has been markedly inhibited due to the formation of heterostructures in the interfaces, thus greatly enhancing the capability for ROS and oxygen production by modulating the single-component doping content. The efficiency of PDT was verified by in vivo and in vitro assays under NIR light. Our results revealed that NIR-II (1208 nm) light irradiation of ZnxFe3-xO4 NPs exerted a remarkable antitumor activity, superior to NIR-I light (808 nm). More importantly, the reported ZnxFe3-xO4 NPs strategy provides an opportunity for the success of comparison with light in the first and second near-infrared regions.

Causal relationships between gut microbiota, gut metabolites, and diabetic neuropathy: A mendelian randomization study.

BACKGROUND: Previous studies have shown a strong correlation between gut microbiota and diabetes and its associated complications. We aimed to evaluate the causal relationships between the gut microbiota, gut metabolites, and diabetic neuropathy. METHODS: Summary statistics of 211 gut microbiota and 12 gut-related metabolites (ß-hydroxybutyric acid, betaine, trimethylamine-N-oxide, carnitine, choline, glutamate, kynurenine, phenylalanine, propionic acid, serotonin, tryptophan, and tyrosine) were obtained from previous genome-wide association studies (GWAS). A two-sample Mendelian randomization (MR) design was used to estimate the effects of gut microbiota and gut metabolites on the risk of diabetic neuropathy based on FinnGen GWAS. RESULTS: Higher levels of Acidaminococcaceae (OR = 0.62; 95%CI = 0.46 to 0.84; P = 0.002), Peptococcaceae (OR = 0.70; 95%CI = 0.54 to 0.90; P = 0.006), and Eubacterium coprostanoligenes group (OR = 0.68; 95%CI = 0.50 to 0.93; P = 0.016) are genetically determined to provide protection against diabetic neuropathy. Conversely, the presence of Alistipes (OR = 1.65; 95%CI = 1.18 to 2.31; P = 0.003), ChristensenellaceaeR7 group (OR = 1.52; 95%CI = 1.03 to 2.23; P = 0.033), Eggerthella (OR = 1.28; 95%CI = 1.05 to 1.55; P = 0.014), RuminococcaceaeUCG013 (OR = 1.35; 95%CI = 1.01 to 1.82; P = 0.046), and Firmicutes (OR = 1.42; 95%CI = 1.05 to 1.93; P = 0.023) increases the risk of diabetic neuropathy. Moreover, a correlation has been identified between diabetic neuropathy and two gut metabolites: betaine (OR = 0.95; 95%CI = 0.90 to 1.00; P = 0.033) and tyrosine (OR = 1.03; 95%CI = 1.01 to 1.06; P = 0.019). Sensitivity analysis indicated robust results with no sign of heterogeneity or pleiotropy. CONCLUSION: The present study elucidated the impact of specific gut microbiota and gut metabolites on the susceptibility to diabetic neuropathy. Interventions targeting the improvement of the gut microbiota diversity and composition hold considerable promise as a potential strategy.

Recent applications and prospects of omega-3 fatty acids: A bibliometric study and visualization analysis in 2014-2023.

Omega-3 fatty acids are indispensable and crucial nutrients that are pivotal in promoting cardiovascular well-being, enhancing cognitive function, and regulating the body's inflammatory response. This study employed bibliometric analysis to investigate the progression of omega-3 fatty acids research. We used the Web of Science Core Collection (WoSCC) to find articles about omega-3 fatty acids published from January 1, 2014, to December 31, 2023. The bibliometric analysis and visualization were conducted using VOSviewer and CiteSpace. This analysis contained a total of 18,764 articles that were focused on omega-3 fatty acids. Among these articles, the nations with the highest number of publications were the United States, China, and Spain. The United States held the greatest influence. The journal Nutrients had the most publications related to this search. Upon analyzing the highly referenced literature, we discovered there is ongoing debate on the potential benefits of Omega-3 fatty acids for illnesses. Moreover, the time-overlapping network analysis of keywords finds investigating the impact of omega-3 fatty acids dietary supplementation on gut microbiota is a promising area of future research. Ultimately, bibliometrics could help researchers comprehend the trajectory of development, noticeable topics, and scholarly impact within omega-3 fatty acids linked domains, thereby offering substantial backing for future investigations of greater depth.

Identification of Drug Targets and Agents Associated with Ferroptosis-related Osteoporosis through Integrated Network Pharmacology and Molecular Docking Technology.

BACKGROUND: Osteoporosis is a systemic bone disease characterized by progressive reduction of bone mineral density and degradation of trabecular bone microstructure. Iron metabolism plays an important role in bone; its imbalance leads to abnormal lipid oxidation in cells, hence ferroptosis. In osteoporosis, however, the exact mechanism of ferroptosis has not been fully elucidated. OBJECTIVE: The main objective of this project was to identify potential drug target proteins and agents for the treatment of ferroptosis-related osteoporosis. METHODS: In the current study, we investigated the differences in gene expression of bone marrow mesenchymal stem cells between osteoporosis patients and normal individuals using bioinformatics methods to obtain ferroptosis-related genes. We could predict their protein structure based on the artificial intelligence database of AlphaFold, and their target drugs and binding sites with the network pharmacology and molecular docking technology. RESULTS: We identified five genes that were highly associated with osteoporosis, such as TP53, EGFR, TGFB1, SOX2 and MAPK14, which, we believe, can be taken as the potential markers and targets for the diagnosis and treatment of osteoporosis. Furthermore, we observed that these five genes were highly targeted by resveratrol to exert a therapeutic effect on ferroptosis-related osteoporosis. CONCLUSION: We examined the relationship between ferroptosis and osteoporosis based on bioinformatics and network pharmacology, presenting a promising direction to the pursuit of the exact molecular mechanism of osteoporosis so that a new target can be discovered for the treatment of osteoporosis.

Quantification and biological evaluation of ZnxFe3-xO4 nanoparticle stiffness in a drug delivery system of MCF-7 cancer cells.

The delivery of nanoparticles (NPs) to tumors remains challenging despite significant advancements in drug delivery technologies. Addressing this issue requires the establishment of quantitative and reliable criteria to evaluate the cellular absorption of NPs. The mechanical characteristics of NPs and their interaction with cells play a crucial role in cellular drug delivery by influencing cellular internalization. In particular, NPs' stiffness has emerged as a key factor affecting cellular uptake and viability. In this study, we synthesized ZnxFe3-xO4 NPs with varying Zn doping concentrations and conducted an extensive measurement process to investigate the impact of NP stiffness on cellular uptake and the viability of cancerous cells. Initially, the stiffness of the NPs was measured using two methods: single-molecule force spectrometry of atomic force microscopy (SMFS-AFM) and cation distribution as chemical structure analysis. The influence of NP stiffness on intracellular behavior was examined by assessing cellular uptake and viability at different time points during the incubation period. The results obtained from both stiffness measurement methods exhibited consistent trends. NPs with higher stiffness exhibited enhanced cellular uptake but exhibited reduced cellular viability compared to the lower-stiffness NPs. Our findings provide valuable insights into the influence of Zn doping concentration on the mechanical properties of ZnxFe3-xO4 NPs and their consequential impacts on cellular internalization. This study contributes to an improved comprehension of the mechanisms underlying cellular uptake and facilitates advancements in the field of drug transport, thereby enhancing the efficiency of NP-based drug delivery.

Percutaneous Coronary Intervention in Acute Coronary Syndrome with Mild-to-Moderate Thrombocytopenia.

BACKGROUND: Baseline thrombocytopenia is commonly observed in patients with acute coronary syndrome (ACS) requiring percutaneous coronary intervention (PCI). AIM: The purpose of this analysis was to investigate safety and effectiveness of PCI in ACS patients with baseline mild-to-moderate thrombocytopenia. METHODS: The data were collected from the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome project. A total of 50,009 ACS patients were recruited between July 2017 and December 2019. Among them, there were 6,413 patients with mild-to-moderate thrombocytopenia, defined as a platelet count of ≥50 × 109/L and <150 × 109/L on admission. The primary outcome was in-hospital net adverse clinical events (NACE), consisting of major adverse cardiac events (MACE) and major bleeding events. The associations between PCI and in-hospital outcomes were analyzed by inverse probability treatment weighting (IPTW) method. RESULTS: PCI was performed in 4,023 of 6,413 patients (62.7%). The IPTW analysis showed that PCI was significantly associated with a reduced risk of in-hospital MACE (odd ratio [OR]: 0.45; 95% confidence interval [CI]: 0.31-0.67; p < 0.01) and NACE (OR: 0.59; 95% CI: 0.42-0.83; p < 0.01). PCI was also associated with an increased risk of any bleeding (OR: 1.56; 95% CI: 1.09-2.22; p = 0.01) and minor bleeding (OR: 1.52; 95% CI: 1.00-2.30; p = 0.05), but not major bleeding (OR: 1.51; 95% CI: 0.76-2.98; p = 0.24). CONCLUSION: Compared with medical therapy alone, PCI is associated with better in-hospital outcomes in ACS patients with mild-to-moderate thrombocytopenia. Further studies with long-term prognosis are needed.

Biodegradable hollow mesoporous bimetallic nanoreactors to boost chemodynamic therapy.

As an endogenous catalytic treatment, chemodynamic therapy (CDT) was attracting considerable attention, but the weak catalytic efficiency of Fenton agents and the non-degradation of nanocarriers severely limited its development. In this work, a biodegradable bimetallic nanoreactor was developed for boosting CDT, in which Fe-doped hollow mesoporous manganese dioxide (HMnO2) was selected as nanocarrier, and the Fe/HMnO2@DOX-GOD@HA nanoprobe was constructed by loading doxorubicin (DOX) and modifying glucose oxidase (GOD) and hyaluronic acid (HA). The glutathione (GSH) responsive degradation of HMnO2 promoted the release of DOX, by which the release rate significantly increased to 96.6%. Moreover, by the GSH depletion, the reduction of Mn2+/Fe2+ achieved strong bimetallic Fenton efficiency, and the hydroxyl radicals (·OH) generation was further enhanced using the self-supplying H2O2 of GOD. Through the active targeting recognition of HA, the bimetallic nanoreactor significantly enriched the tumor accumulation, by which the enhanced antitumor efficacy was realized. Thus, this work developed biodegradable bimetallic nanoreactor by consuming GSH and self-supplying H2O2, and provided a new paradigm for enhancing CDT.

Inter-hospital transfer in patients with acute myocardial infarction in China: Findings from the improving care for cardiovascular disease in China-acute coronary syndrome project.

Background: Little is known about the current scenario of inter-hospital transfer for patients with acute myocardial infarction (AMI) in China. Methods: From November 2014 to December 2019, 94,623 AMI patients were enrolled from 241 hospitals in 30 provinces in China. We analyzed the pattern of inter-hospital transfer, and compared in-hospital treatments and outcomes between transferred patients and directly admitted patients. Results: Of these patients, 40,970 (43.3%) were transferred from hospitals that did not provide percutaneous coronary intervention (PCI). The proportion of patients who were transferred from non-PCI hospital was 46.3% and 11.9% (P < 0.001) in tertiary hospitals and secondary hospitals, respectively; 56.2% and 37.3% (P < 0.001) in hospitals locating in low-economic regions and affluent areas, respectively. Compared with directly admitted patients, transferred patients had lower rates of reperfusion for STEMI (57.8% vs. 65.2%, P < 0.001) and timely PCI for NSTEMI (34.7%vs. 41.1%, P < 0.001). The delay for STEMI patients were long, with 6.5h vs. 4.5h from symptom onset to PCI for transferred and directly admitted patients, respectively. The median time-point was 9 days for in-hospital outcomes. Compared with direct admission, the hazard ratios and 95% confidence intervals associated with inter-hospital transfer were 0.87 (0.75-1.01) and 0.87 (0.73-1.03) for major adverse cardiovascular events and total mortality, respectively, in inverse probability of treatment weighting models in patients with STEMI, and 1.02 (0.71-1.48) and 0.98 (0.70-1.35), respectively, in patients with NSTEMI. Conclusion: More than 40% of the hospitalized AMI patients were transferred from non-PCI-capable hospitals in China. Further strategies are needed to enhance the capability of revascularization and reduce the inequality in management of AMI.

Prevalence, awareness, treatment, and control rates of hypertension in patients hospitalized with atrial fibrillation in China: Findings from the CCC-AF project.

Background: The status of hypertension in patients with atrial fibrillation (AF) remains unknown in China. Methods: This study used data from patients hospitalized with AF recruited by the Improving Care for Cardiovascular Disease in China-AF (CCC-AF) project from 236 hospitals enrolled by geographic-economic level in China from 2015 to 2019. The prevalence, awareness, treatment, and control rates of hypertension in patients hospitalized with AF were estimated. Multivariable logistic regression was used to analyze the factors associated with uncontrolled hypertension. Results: Among 60,390 patients hospitalized with AF, the prevalence of hypertension according to the 2018 Chinese hypertension guidelines was 66.1%. The awareness, treatment, and control rates of hypertension were 80.3, 55.8, and 39.9%, respectively. Among patients treated for hypertension, the treatment control rate was 46.2%. These rates varied according to patient clinical characteristics and geographic regions. The young (18-44 and 45-54 years old), rural insurance, alcohol drinking, history of heart failure, valvular AF, first diagnosed AF, and permanent AF, were associated with uncontrolled hypertension. Under the 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guidelines, the prevalence of hypertension was 79.3%, and the control and treatment control rates dropped to 16.7 and 21.2%, respectively. Conclusion: Hypertension is common in patients hospitalized with AF in China. Although most patients were aware of their hypertensive status, the treatment and control rates of hypertension were still low. The management of hypertension in patients with AF needs to be further improved.

Pre-hospital delay in patients with acute myocardial infarction in China: findings from the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome (CCC-ACS) project.

OBJECTIVE: To describe the duration of the pre-hospital delay time and identify factors associated with prolonged pre-hospital delay in patients with acute myocardial infarction (AMI) in China. METHODS: Data were collected from November 2014 to December 2019 as part of the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome (CCC-ACS) project. A total of 33,386 patients with AMI admitted to the index hospitals were included in this study. Two-level logistic regression was conducted to explore the factors associated with the pre-hospital delay and the associations between different pre-hospital delay and in-hospital outcomes. RESULTS: Of the 33,386 patients with AMI, 70.7% of patients arrived at hospital ≥ 2 h after symptom onset. Old age, female, rural medical insurance, symptom onset at early dawn, and non-use of an ambulance predicted a prolonged pre-hospital delay (all P < 0.05). Hypertension and heart failure at admission were only significant in predicting a longer delay in patients with ST-segment elevation myocardial infarction (STEMI) (all P < 0.05). A pre-hospital delay of ≥ 2 h was associated with an increased risk of mortality [odds ratio (OR) = 1.36, 95% CI: 1.09-1.69, P = 0.006] and major adverse cardiovascular events (OR = 1.22, 95% CI: 1.02-1.47, P = 0.033) in patients with STEMI compared with a pre-hospital delay of < 2 h. CONCLUSIONS: Prolonged pre-hospital delay is associated with adverse in-hospital outcomes in patients with STEMI in China. Our study identifies that patient characteristics, symptom onset time, and type of transportation are associated with pre-hospital delay time, and provides focuses for quality improvement.

Practice of reperfusion in patients with ST-segment elevation myocardial infarction in China: findings from the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome project.

BACKGROUND: Reperfusion therapy is fundamental for ST-segment elevation myocardial infarction (STEMI). However, the details of contemporary practice and factors associated with reperfusion therapy in China are largely unknown. Therefore, this study aimed to explore reperfusion practice and its associated factors among hospitalized patients with STEMI in China. METHODS: Patients with STEMI who were admitted to 159 tertiary hospitals from 30 provinces in China were included in the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome project from November 2014 to December 2019. The associations of the characteristics of patients and hospitals with reperfusion were examined using hierarchical logistic regression. The associations between therapies and in-hospital major adverse cardiovascular events were examined with a mixed effects Cox regression model. RESULTS: Among the 59,447 patients, 37,485 (63.1%) underwent reperfusion, including 4556 (7.7%) receiving fibrinolysis and 32,929 (55.4%) receiving primary percutaneous coronary intervention (PCI). The reperfusion rate varied across geographical regions (48.0%-73.5%). The overall rate increased from 60.0% to 69.7% from 2014 to 2019, mainly due to an increase in primary PCI within 12 h of symptom onset. Timely PCI, but not fibrinolysis alone, was associated with a decreased risk of in-hospital major adverse cardiovascular events compared with no reperfusion, with an adjusted hazard ratio (95% confidence interval) of 0.64 (0.54,0.76) for primary PCI at <12 h, 0.53 (0.37,0.74) for primary PCI at 12 to 24 h, 0.46 (0.25,0.82) for the pharmaco-invasive strategy, and 0.79 (0.54,1.15) for fibrinolysis alone. CONCLUSIONS: Nationwide quality improvement initiatives should be strengthened to increase the reperfusion rate and reduce inequality in China. TRIAL REGISTRATION: www.ClinicalTrials.gov , NCT02306616.

An Automatic Personalized Internal Fixation Plate Modeling Framework for Minimally Invasive Curved Bone Fracture Surgery Based on Preregistration With Capsule Projection Model.

OBJECTIVE: In this paper, a framework to visualize and model internal fixation plates is presented for computer-aided personalized and minimally invasive curved bone fracture surgery. METHODS: We focus on personalized reverse reconstruction of the bone fracture plate based on three-dimensional (3-D) mesh models obtained from a 3-D optical scanner. The steps of the method are as follows. First, principal component analysis and the K-means method are used to reconstruct a Bezier curve (ridge line) of broken bones. Second, based on the geometric shape of the curved broken bones, a capsule projection model of the broken bones is proposed to obtain the feature information of the broken bone sections. Third, the ordering points to identify the clustering structure (OPTICS) method is utilized for preregistration (rough registration). Fourth, a regional self-growth strategy is designed to extract the cross-section points. Fifth, the iterative closest point method is applied for the accurate registration of the fracture surface models. Finally, a personalized internal fixation plate model is reconstructed based on several user points. RESULTS: The internal fixation plate model can be reconstructed according to the patient's bone parameters. CONCLUSION: Clinicians can use this framework to obtain personalized and accurate internal fixation plate models that effectively represent the broken bones of patients. Via X-ray navigation, the personalized forged plate can be fixed on the target area through a small incision. SIGNIFICANCE: This framework provides a reasonable and practicable technical approach for computer-aided minimally invasive curved bone fracture surgery.