The globus pallidus internus (GPi) was considered a common target for stimulation in Parkinson's disease (PD). Located deep in the brain and of small size, pinpointing it during surgery is challenging. Multi-channel microelectrode arrays (MEAs) can provide micrometer-level precision functional localization, which can maximize the surgical outcome. In this paper, a 64-channel MEA modified by platinum nanoparticles with a detection site impedance of 61.1 kΩ was designed and prepared, and multiple channels could be synchronized to cover the target brain region and its neighboring regions so that the GPi could be identified quickly and accurately. The results of the implant trajectory indicate that, compared to the control side, there is a reduction in local field potential (LFP) power in multiple subregions of the upper central thalamus on the PD-induced side, while the remaining brain regions exhibit an increasing trend. When the MEA tip was positioned at 8,700 µm deep in the brain, the various characterizations of the spike signals, combined with the electrophysiological characteristics of the ß-segmental oscillations in PD, enabled MEAs to localize the GPi at the single-cell level. More precise localization could be achieved by utilizing the distinct characteristics of the internal capsule (ic), the thalamic reticular nucleus (Rt), and the peduncular part of the lateral hypothalamus (PLH) brain regions, as well as the relative positions of these brain structures. The MEAs designed in this study provide a new detection method and tool for functional localization of PD targets and PD pathogenesis at the cellular level.
Significant variation in coding intensity among hospitals has been observed and can lead to reimbursement inequities and inadequate risk adjustment for quality measures. Reliable tools to quantify hospital coding intensity are needed. We hypothesized that coded sepsis rates among patients hospitalized with common infections may serve as a useful surrogate for coding intensity and derived a hospital-level sepsis coding intensity measure using prevalence of "sepsis" primary diagnoses among patients hospitalized with urinary tract infection, cellulitis, and pneumonia. This novel measure was well correlated with the hospital mean number of discharge diagnoses, which has historically been used to quantify hospital-level coding intensity. However, it has the advantage of inferring hospital coding intensity without the strong association with comorbidity that the mean number of discharge diagnoses has. Our measure may serve as a useful tool to compare coding intensity across institutions.
The striatum plays a crucial role in studying epilepsy, as it is involved in seizure generation and modulation of brain activity. To explore the complex interplay between the striatum and epilepsy, we engineered advanced microelectrode arrays (MEAs) specifically designed for precise monitoring of striatal electrophysiological activities in rats. These observations were made during and following seizure induction, particularly three and 7 days post-initial modeling. The modification of graphene oxide (GO)/poly (3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS)/platinu-m nanoparticles (PtNPs) demonstrated a marked reduction in impedance (10.5 ± 1.1 kΩ), and maintained exceptional stability, with impedance levels remaining consistently low (23 kΩ) even 14 days post-implantation. As seizure intensity escalated, we observed a corresponding increase in neuronal firing rates and local field potential power, with a notable shift towards higher frequency peaks and augmented inter-channel correlation. Significantly, during the grand mal seizures, theta and alpha bands became the dominant frequencies in the local field potential. Compared to the normal group, the spike firing rates on day 3 and 7 post-modeling were significantly higher, accompanied by a decreased firing interval. Power in both delta and theta bands exhibited an increasing trend, correlating with the duration of epilepsy. These findings offer valuable insights into the dynamic processes of striatal neural activity during the initial and latent phases of temporal lobe epilepsy and contribute to our understanding of the neural mechanisms underpinning epilepsy.
Many chlorophyll-a (Chl-a) remote sensing estimation algorithms have been developed for inland water, and they are proposed always based on some ideal assumptions, which are difficult to meet in complex inland waters. Based on MIE scattering theory, this study calculated the optical properties of mineral particles under different size distribution and refractive index conditions, and the Hydrolight software was employed to simulate remote sensing reflectance in the presence of different mineral particles. The findings indicated that the reflectance is significantly influenced by the slope (j) of particle size distribution function and the imaginary part (n') of the refractive index, with the real part (n) having a comparatively minor impact. Through both a simulated dataset containing 18,000 entries and an in situ measured dataset encompassing 2183 data from hundreds of lakes worldwide, the sensitivities of band ratio (BR), fluorescence baseline height (FLH), and three-band algorithms (TBA) to mineral particles were explored. It can be found that BR showed the best tolerance to mineral particles, followed by TBA. However, when the ISM concentration is less than 30â g m-3, the influence of CDOM cannot be ignored. Additionally, a dataset of over 400 entries is necessary for developing the BR algorithm to mitigate the incidental errors arising from differences in data magnitude. And if the amount of developing datasets is less than 400 but greater than 200, the TBA algorithm is more likely to obtain more stable accuracy.
In neurodegenerative disorders, neuronal firing patterns and oscillatory activity are remarkably altered in specific brain regions, which can serve as valuable biomarkers for the identification of deep brain regions. The subthalamic nucleus (STN) has been the primary target for DBS in patients with Parkinson's disease (PD). In this study, changes in the spike firing patterns and spectral power of local field potentials (LFPs) in the pre-STN (zona incerta, ZI) and post-STN (cerebral peduncle, cp) regions were investigated in PD rats, providing crucial evidence for the functional localization of the STN. Sixteen-channel microelectrode arrays (MEAs) with sites distributed at different depths and widths were utilized to record neuronal activities. The spikes in the STN exhibited higher firing rates than those in the ZI and cp. Furthermore, the LFP power in the delta band in the STN was the greatest, followed by that in the ZI, and was greater than that in the cp. Additionally, increased LFP power was observed in the beta bands in the STN. To identify the best performing classification model, we applied various convolutional neural networks (CNNs) based on transfer learning to analyze the recorded raw data, which were processed using the Gram matrix of the spikes and the fast Fourier transform of the LFPs. The best transfer learning model achieved an accuracy of 95.16%. After fusing the spike and LFP classification results, the time precision for processing the raw data reached 500 ms. The pretrained model, utilizing raw data, demonstrated the feasibility of employing transfer learning for training models on neural activity. This approach highlights the potential for functional localization within deep brain regions.
Deep Brain Stimulation , Microelectrodes , Rats, Sprague-Dawley , Subthalamic Nucleus , Subthalamic Nucleus/physiopathology , Animals , Rats , Male , Disease Models, Animal , Parkinson Disease/physiopathology , Parkinson Disease/rehabilitation , Action Potentials/physiology , Algorithms , Computer Systems , Parkinsonian Disorders/physiopathology , Parkinsonian Disorders/rehabilitation , Machine Learning
The stimulator of interferon genes (STING) plays a pivotal role in orchestrating innate immunity, and dysregulated activity of STING has been implicated in the pathogenesis of autoimmune diseases. Recent findings suggest that bacterial infection activates STING, relieving ER stress, and triggers non-canonical autophagy by spatially regulating STX17. Despite these insights, the precise mechanism governing the dynamics of autophagosome fusion elicited by STING remains unclear. In this study, we demonstrate that dynamic STING activation guides the autophagy flux, mirroring the trajectory of canonical autophagy adaptors. STING engages in a physical interaction with STX17, and agonist-induced phosphorylation or degradation alleviates STING's inhibitory effects on the assembly of the STX17-SNAP29-VAMP8 complex. Consistent with these findings, degradation-deficient mutants hinder autophagy flux by impeding STX17-mediated autophagosome-lysosome fusion. Moreover, STING mutants associated with lupus disrupt the assembly of the STX17-SNAP29-VAMP8 complex and autophagy process, which lead to persistent STING activation and elevated IFN-ß production. Our results highlight that the intracellular trajectory of STING, coupled with autophagy flux, guides the assembly and membrane fusion of the STX17-SNAP29-VAMP8 complex, ensuring the accurate regulation of innate immunity.
[This corrects the article DOI: 10.3389/fped.2022.966510.].
BACKGROUND: There are ≈5 million annual dizziness visits to US emergency departments, of which vestibular strokes account for over 250 000. The head impulse, nystagmus, and test of skew eye examination can accurately distinguish vestibular strokes from peripheral dizziness. However, the eye-movement signs are subtle, and lack of familiarity and difficulty with recognition of abnormal eye movements are significant barriers to widespread emergency department use. To break this barrier, we sought to assess the accuracy of EyePhone, our smartphone eye-tracking application, for quantifying nystagmus. METHODS AND RESULTS: We prospectively enrolled healthy volunteers and recorded the velocity of induced nystagmus using a smartphone eye-tracking application (EyePhone) and then compared the results with video oculography (VOG). Following a calibration protocol, the participants viewed optokinetic stimuli with incremental velocities (2-12 degrees/s) in 4 directions. We extracted slow phase velocities from EyePhone data in each direction and compared them with the corresponding slow phase velocities obtained by the VOG. Furthermore, we calculated the area under the receiver operating characteristic curve for nystagmus detection by EyePhone. We enrolled 10 volunteers (90% men) with an average age of 30.2±6 years. EyePhone-recorded slow phase velocities highly correlated with the VOG recordings (r=0.98 for horizontal and r=0.94 for vertical). The calibration significantly increased the slope of linear regression for horizontal and vertical slow phase velocities. Evaluating the EyePhone's performance using VOG data with a 2 degrees/s threshold showed an area under the receiver operating characteristic curve of 0.87 for horizontal and vertical nystagmus detection. CONCLUSIONS: We demonstrated that EyePhone could accurately detect and quantify optokinetic nystagmus, similar to the VOG goggles.
Nystagmus, Pathologic , Stroke , Male , Humans , Young Adult , Adult , Female , Eye-Tracking Technology , Dizziness/diagnosis , Smartphone , Nystagmus, Pathologic/diagnosis , Eye Movements , Stroke/diagnosis
The emerging contaminant nanoplastics (NPs) have received considerable attention. Due to their tiny size and unique colloidal properties, NPs could more easily enter the body and cross biological barriers with inhalation exposure. While NPs-induced hepatotoxicity has been reported, the hepatic impact of inhaled NPs was still unknown. To close this gap, a 40 nm polystyrene NPs (PS-NPs) inhalation exposure mice model was developed to explore the hepatotoxicity during acute (1 week), subacute (4 weeks), and subchronic period (12 weeks), with four exposure doses (0, 16, 40, and 100 µg/day). Results showed that inhaled PS-NPs caused a remarkable increase of ALT, AST, and ALP with a decrease of CHE, indicating liver dysfunction. Various histological abnormalities and significantly higher levels of inflammation in a dose- and time-dependent manner were observed. Moreover, after 4 weeks and 12 weeks of exposure, Masson staining and upregulated expression of TGF-ß, α-SMA, and Col1a1 identified that inhaled PS-NPs exposure triggered the progression of liver fibrosis with the exposure time prolonged. From the mechanistic perspective, transcriptome analysis revealed that ferroptosis was involved in PS-NPs-induced liver hepatotoxicity, and key features of ferroptosis were detected, including persistent oxidative stress, iron overload, increased LPO, mitochondria damage, and the expression changes of GPX4, TFRC, and Ferritin. And in vitro and in vivo recovery tests showed that ferroptosis inhibitor Fer-1 treatment alleviated liver injury and fibrosis. The above results confirmed the critical role of ferroptosis in PS-NPs-induced hepatotoxicity. Furthermore, to better conclude our findings and understand the mechanistic causality within it, an adverse outcome pathway (AOP) framework was established. In total, this present study conducted the first experimental assessment of inhalation exposure to PS-NPs on the liver, identified that continuous inhaled PS-NPs could cause liver injury and fibrosis, and PS-NPs- ferroptosis provided a novel mechanistic explanation.
Chemical and Drug Induced Liver Injury , Ferroptosis , Nanoparticles , Animals , Mice , Microplastics , Polystyrenes/toxicity , Liver Cirrhosis/chemically induced , Chemical and Drug Induced Liver Injury/etiology
Boosting the circularly polarized luminescence of small organic molecules has been a stubborn challenge because of weak structure rigidity and dynamic molecular motions. To investigate and eliminate these factors, here, we carried out the structure-property relationship studies on a newly-developed axial chiral scaffold of bidibenzo[b,d]furan. The molecular rigidity was finely tuned by gradually reducing the alkyl-chain length. The environmental factors were considered in solution, crystal, and polymer matrix at different temperatures. As a result, a significant amplification of the dissymmetry factor glum from 10-4 to 10-1 was achieved, corresponding to the situation from (R)-4C in solution to (R)-1C in polymer film at room temperature. A synergistic strategy of increasing the intramolecular rigidity and enhancing the intermolecular interaction to restrict the molecular motions was thus proposed to improve circularly polarized luminescence. The though-out demonstrated relationship will be of great importance for the development of high-performance small organic chiroptical systems in the future.
At present, the incidence and risk factors for dysphagia after extubation in elderly inpatients are still unclear, and we aimed to develop and validate a risk prediction model that prospectively identifies high-risk patients to reduce the occurrence rate of dysphagia. The 469 patients recruited were randomly divided into modeling and validation groups in a 7:3 ratio. In the modeling group, the postextubation dysphagia (PED) risk factors were analyzed, and a risk prediction model was established. In the validation group, the model was validated and evaluated. The model was constructed based on the risk factors determined by a binary logistic regression analysis. The discrimination ability of the model was evaluated by the receiver operating characteristic (ROC) curve. The calibration curve and HosmerâLemeshow test were performed to evaluate the model's calibration ability. The clinical utility of the risk prediction model was analyzed by decision curve analysis (DCA). The results showed that the incidence of PED was 15.99%, and age, duration of indwelling gastric tube, difficult endotracheal intubation, atomization after extubation, anesthesia risk level and frailty assessment were identified as important risk factors. The model was validated to have favorable discrimination, calibration ability and clinical utility. It has a certain extension value and clinical applicability, providing a feasible reference for preventing the occurrence of PED.
Deglutition Disorders , Humans , Aged , Deglutition Disorders/diagnosis , Deglutition Disorders/etiology , Cross-Sectional Studies , Anesthesia, General/adverse effects , Risk Factors , Intubation, Intratracheal/adverse effects
BACKGROUND: Peripherally inserted central catheter (PICC) is widely used in chemotherapy of children with malignant tumors because of its safe operation and long indwelling time. OBJECTIVE: To investigate the effect of intracavitary electroencephalogram (CEEG) localization technique on the success rate and complications of PICC in infants. METHODS: A total of 180 children with PICC catheterization and maintenance at Shijiazhuang People's Hospital First Hospital from January 2017 to January 2020 were selected and divided into control group (n= 90 cases) and observation group (n= 90 cases). The control group observed the tip position of the fixed catheter through X-ray film and adjusted the catheter until its tip was located in the superior vena cava. The observation group used intracavitary electrocardiogram positioning technology. Comparison of the effects of two groups on the success rate and complications of PICC puncture in infants and young children. RESULTS: The success rate of one puncture in the observation group was significantly higher than that in the control group (P< 0.05). Within one month of catheterization, 13 cases had complications, with an incidence rate of 16.00% lower than the control group's 34.00% (27/80) (P< 0.05). The screening test results showed that the specificity, sensitivity, Youden index, accuracy, kappa coefficient, positive and negative predictive value were 88.89%, 97.56%, 0.86, 96.00%, 0.86, 0.86, respectively. The measured values were 97.56% and 88.89% respectively, and the cost and time of localization were lower than those of X-ray. CONCLUSION: The technique of intracavitary electrogram can be more accurate for infants to place the tip of central venous catheter through peripheral vein, which can effectively improve the success rate of one puncture with low cost, and has high reliability, accuracy and practicability, which is safe and effective.
Catheterization, Central Venous , Central Venous Catheters , Infant , Child , Humans , Child, Preschool , Catheterization, Central Venous/adverse effects , Catheterization, Central Venous/methods , Vena Cava, Superior , Reproducibility of Results , Electrocardiography/methods
BACKGROUND: Diagnostic errors cause substantial preventable harms worldwide, but rigorous estimates for total burden are lacking. We previously estimated diagnostic error and serious harm rates for key dangerous diseases in major disease categories and validated plausible ranges using clinical experts. OBJECTIVE: We sought to estimate the annual US burden of serious misdiagnosis-related harms (permanent morbidity, mortality) by combining prior results with rigorous estimates of disease incidence. METHODS: Cross-sectional analysis of US-based nationally representative observational data. We estimated annual incident vascular events and infections from 21.5 million (M) sampled US hospital discharges (2012-2014). Annual new cancers were taken from US-based registries (2014). Years were selected for coding consistency with prior literature. Disease-specific incidences for 15 major vascular events, infections and cancers ('Big Three' categories) were multiplied by literature-based rates to derive diagnostic errors and serious harms. We calculated uncertainty estimates using Monte Carlo simulations. Validity checks included sensitivity analyses and comparison with prior published estimates. RESULTS: Annual US incidence was 6.0 M vascular events, 6.2 M infections and 1.5 M cancers. Per 'Big Three' dangerous disease case, weighted mean error and serious harm rates were 11.1% and 4.4%, respectively. Extrapolating to all diseases (including non-'Big Three' dangerous disease categories), we estimated total serious harms annually in the USA to be 795 000 (plausible range 598 000-1 023 000). Sensitivity analyses using more conservative assumptions estimated 549 000 serious harms. Results were compatible with setting-specific serious harm estimates from inpatient, emergency department and ambulatory care. The 15 dangerous diseases accounted for 50.7% of total serious harms and the top 5 (stroke, sepsis, pneumonia, venous thromboembolism and lung cancer) accounted for 38.7%. CONCLUSION: An estimated 795 000 Americans become permanently disabled or die annually across care settings because dangerous diseases are misdiagnosed. Just 15 diseases account for about half of all serious harms, so the problem may be more tractable than previously imagined.
Lung Neoplasms , Stroke , Humans , United States/epidemiology , Cross-Sectional Studies , Morbidity , Diagnostic Errors
BACKGROUND AND AIMS: This study aimed to explore the association between hyperuricemia and heart failure (HF) readmission in HF patients with preserved ejection fraction (HFpEF) because the impact of hyperuricemia on the prognosis of these patients has not been fully understood. METHODS AND RESULTS: This retrospective observational study included 538 hospitalized patients diagnosed with HFpEF. A total of 57.6 % of patients with HFpEF suffered from hyperuricemia (serum uric acid (SUA) was >7 mg/dL in men and >6 mg/dL in women). Compared to those without hyperuricemia, patients with hyperuricemia were more likely to be female (62.6 % vs. 53.9 %, p = 0.044) and older (78.0 ± 8.4 vs. 75.9 ± 9.0 years, p = 0.008). Our Cox analysis revealed that SUA level (hazard ratio (HR) = 1.158, 95 % confidence interval (CI): 1.087-1.234, p<0.001) and hyperuricemia (HR = 1.846, 95 % CI: 1.308-2.606, p<0.001) were associated with HF readmission in patients with HFpEF, respectively. Kaplan-Meier analysis showed that patients with hyperuricemia had a significantly worse prognosis (p<0.001). The receiver operating characteristic analysis revealed that the area under the ROC curve of SUA for predicting HF readmission was 0.6276 (95 % CI: 0.5763-0.6790) and a designated cut-off value of 7.53 mg/dL. CONCLUSIONS: Hyperuricemia is a common comorbidity among patients with HFpEF. Moreover, SUA level and hyperuricemia have been shown to be associated with HF readmission. Therefore, it is meaningful to monitor SUA levels in patients with HFpEF during the whole treatment period of HF. Whereas, whether intervention of hyperuricemia could benefit patients with HFpEF needs further studies.
Heart Failure , Hyperuricemia , Female , Humans , Male , China/epidemiology , Heart Failure/diagnosis , Heart Failure/epidemiology , Heart Failure/therapy , Hyperuricemia/diagnosis , Hyperuricemia/epidemiology , Patient Readmission , Stroke Volume , Uric Acid , Aged , Aged, 80 and over
BACKGROUND: Nanoplastics (NPs) could be released into environment through the degradation of plastic products, and their content in the air cannot be ignored. To date, no studies have focused on the cardiac injury effects and underlying mechanisms induced by respiratory exposure to NPs. RESULTS: Here, we systematically investigated the cardiotoxicity of 40 nm polystyrene nanoplastics (PS-NPs) in mice exposed via inhalation. Four exposure concentrations (0 µg/day, 16 µg/day, 40 µg/day and 100 µg/day) and three exposure durations (1 week, 4 weeks, 12 weeks) were set for more comprehensive information and RNA-seq was performed to reveal the potential mechanisms of cardiotoxicity after acute, subacute and subchronic exposure. PS-NPs induced cardiac injury in a dose-dependent and time-dependent manner. Acute, subacute and subchronic exposure increased the levels of injury biomarkers and inflammation and disturbed the equilibrium between oxidase and antioxidase activity. Subacute and subchronic exposure dampened the cardiac systolic function and contributed to structural and ultrastructural damage in heart. Mechanistically, violent inflammatory and immune responses were evoked after acute exposure. Moreover, disturbed energy metabolism, especially the TCA cycle, in the myocardium caused by mitochondria damage may be the latent mechanism of PS-NPs-induced cardiac injury after subacute and subchronic exposure. CONCLUSION: The present study evaluated the cardiotoxicity induced by respiratory exposure to PS-NPs from multiple dimensions, including the accumulation of PS-NPs, cardiac functional assessment, histology observation, biomarkers detection and transcriptomic study. PS-NPs resulted in cardiac injury structurally and functionally in a dose-dependent and time-dependent manner, and mitochondria damage of myocardium induced by PS-NPs may be the potential mechanism for its cardiotoxicity.
Cardiotoxicity , Nanoparticles , Animals , Mice , Polystyrenes/toxicity , Microplastics , Myocardium , Biomarkers
Based on the lumped parameter model (LPM) of the cardiovascular system, an analytic method is developed to derive its hemodynamics theoretically. As soon as the LPM (a series of differential equations) is solved, the hemodynamics would be obtained immediately. However, because of time-varying ventricular elastance and high order, it is difficult to solve analytically. Through simplifying the LPM, the original biventricular system with continuously varying elastance becomes a single ventricular system with discrete elastance which keeps constant during the systolic or diastolic phase. As a consequence, the original time-varying and high-order system becomes a time-invariant and first-order system during each phase. From the analytic solutions of the simplified system, a set of algebraic equations is carried out. Then the hemodynamics are obtained from the solutions of the algebraic equations. The nature of the algebraic equations is an integral form of the differential equations. A connection between the equations and PV loop is established. All of these equations are deduced based on the idealization of replacing the continuous elastance with the discrete elastance. However, there exist algebraic equations, that can be derived directly from volume conservation, still hold for the case of continuous elastance. As a preliminary application, the method is utilized to deduce the hemodynamics of left heart failure (LHF). The results show that the theoretical hemodynamics of LHF are coincident with simulated results. The analytic method can be generalized to investigate biventricular system. A program for developing a more general framework is presented in the last part.
Heart Failure , Hemodynamics , Humans , Heart Ventricles , Systole , Computer Simulation , Models, Cardiovascular , Ventricular Function, Left
N6-methyladenosine (m6A) methylation, the most prevalent post-transcriptional modification in eukaryotes, represents a highly dynamic and reversible process that is regulated by m6A methyltransferases, m6A demethylases and RNA-binding proteins during RNA metabolism, which affects RNA function. Notably, m6A modification is significantly enriched in the brain and exerts regulatory roles in neurogenesis and neurodevelopment through various mechanisms, further influencing the occurrence and progression of neurological disorders. This study systematically summarizes and discusses the latest findings on common m6A regulators, examining their expression, function and mechanisms in neurodevelopment and neurological diseases. Additionally, we explore the potential of m6A modification in diagnosing and treating neurological disorders, aiming to provide new insights into the molecular mechanisms and potential therapeutic strategies for neurological disorders.
Nervous System Diseases , Neurogenesis , Humans , Brain , Methyltransferases , Nervous System Diseases/genetics , RNA
Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease characterized by myofibroblast proliferation and extracellular matrix deposition that has a high mortality rate and limited therapeutic options. Flavokawain A(FKA) is the major component of chalcone in kava extract. FKA has been reported to inhibit TGF-ß1-induced cardiomyocyte fibrosis by suppressing ROS production in A7r5 cells, but the role and mechanism of FKA in pulmonary fibrosis are unknown. In this study, we evaluated the effect of FKA on pulmonary fibrosis using an animal model of bleomycin-induced pulmonary fibrosis and showed that FKA alleviated the development of pulmonary fibrosis in a dose-dependent manner and improved lung function as well as collagen deposition and extracellular matrix accumulation in mice. In vitro studies showed that FKA inhibited myofibroblast activation and lung fibrosis progression by inhibiting TGF-ß1/Smad signaling in a dose-dependent manner. In addition, we identified CXCL12 as a potential target of FKA through target prediction. Molecular docking, CETSA(cellular thermal displacement assay) and silver staining assays further demonstrated that FKA could interact with CXCL12 and that FKA could inhibit CXCL12 dimerization in vitro. Further analysis revealed that FKA could inhibit fibroblast activation and reduce extracellular matrix (ECM) production and collagen deposition by blocking CXCL12/CXCR4 signaling, and knocking down CXCR4 expression could weaken the inhibitory effect of FKA on CXCL12/CXCR4 signal transduction. In conclusion, our study showed that FKA inhibited CXCL12/CXCR4 signaling by inhibiting CXCL12 dimerization, blocked the CXCL12/CXCR4 signaling pathway and inhibited the TGF-ß1-mediated signaling pathway to ameliorate pulmonary fibrosis, and FKA is a promising therapeutic agent for pulmonary fibrosis.
Plastic pollution has become a significant global problem over the years, leading to the continuous decomposition and accumulation of micro/nanoplastics (MNPLs) in the environment. As a result, human exposure to these MNPLs is inevitable. The liver, in particular, is highly susceptible to potential MNPL toxicity. In this study, we systematically reviewed the current literature on MNPLs-induced hepatotoxicity and collected data on toxic events occurring at different biological levels. Then, to better understand the cause-mechanism causality, we developed an Adverse Outcome Pathway (AOP) framework for MNPLs-induced hepatotoxicity. The AOP framework provided insights into the mechanism of MNPL-induced hepatotoxicity and highlighted potential health risks such as liver dysfunction and inflammation, metabolism disorders and liver fibrosis. Moreover, we discussed the potential application of emerging toxicological models in the hepatotoxicity study. Liver organoids and liver-on-chips, which can simulate the structure and function of the liver in vitro, offer a promising alternative platform for toxicity testing and risk assessment. We proposed combining the AOP framework with these emerging toxicological models to improve our understanding of the hepatotoxic effects of MNPLs. Overall, this study performed a preliminary exploration of novel toxicological methodologies to assess the hepatotoxicity of MNPLs, providing a deeper understanding of environmental toxicology.
Adverse Outcome Pathways , Chemical and Drug Induced Liver Injury , Drug-Related Side Effects and Adverse Reactions , Humans , Microplastics , Chemical and Drug Induced Liver Injury/etiology
Cardiovascular diseases remain the leading cause of death worldwide; therefore, there is increasing attention to developing physiological-related in vitro cardiovascular tissue models suitable for personalized healthcare and preclinical test. Recently, more complex and powerful in vitro models have emerged for cardiac research. Human cardiac organoids (HCOs) are three-dimensional (3D) cellular constructs similar to in vivo organs. They are derived from pluripotent stem cells and can replicate the structure, function, and biogenetic information of primitive tissues. High-fidelity HCOs are closer to natural human myocardial tissue than animal and cell models to some extent, which helps to study better the development process of the heart and the occurrence of related diseases. In this review, we introduce the methods for constructing HCOs and the application of them, especially in cardiovascular disease modeling and cardiac drug screening. In addition, we propose the prospects and limitations of HCOs. In summary, we have introduced the research progress of HCOs and described their innovation and practicality of them in the biomedical field.
