Molecular insights into the interactions of theaflavin and epicatechin with different lipid bilayer membranes by molecular dynamics simulation.

At present, consumers increasingly favored the natural food preservatives with fewer side-effects on health. The green tea catechins and black tea theaflavins attracted considerable interest, and their antibacterial effects were extensively reported in the literature. Epicatechin (EC), a green tea catechin without a gallate moiety, showed no bactericidal activity, whereas the theaflavin (TF), also lacking a gallate moiety, exhibited potent bactericidal activity, and the antibacterial effects of green tea catechins and black tea theaflavins were closely correlated with their abilities to disrupt the bacterial cell membrane. In our present study, the mechanisms of membrane interaction modes and behaviors of TF and EC were explored by molecular dynamics simulations. It was demonstrated that TF exhibited markedly stronger affinity for the POPG bilayer compared to EC. Additionally, the hydrophobic interactions of tropolone/catechol rings with the acyl chain part could significantly contribute to the penetration of TF into the POPG bilayer. It was also found that the resorcinol/pyran rings were the key functional groups in TF for forming hydrogen bonds with the POPG bilayer. We believed that the findings from our current study could offer useful insights to better understand the stronger antibacterial effects of TF compared to EC.

A novel nomogram for predicting prolonged mechanical ventilation in lung transplantation patients using extracorporeal membrane oxygenation.

Prolonged mechanical ventilation (PMV) is commonly associated with increased post-operative complications and mortality. Nevertheless, the predictive factors of PMV after lung transplantation (LTx) using extracorporeal membrane oxygenation (ECMO) as a bridge remain unclear. The present study aimed to develop a novel nomogram for PMV prediction in patients using ECMO as a bridge to LTx. A total of 173 patients who used ECMO as a bridge following LTx from January 2022 to June 2023 were divided into the training (122) and validation sets (52). A mechanical ventilation density plot of patients after LTx was then performed. The training set was divided in two groups, namely PMV (95) and non-prolonged ventilation (NPMV) (27). For the survival analysis, the effect of PMV was assessed using the log-rank test. Univariate and multivariate logistic regression analyses were performed to assess factors associated with PMV. A risk nomogram was established based on the multivariate analysis, and model performance was further assessed in terms of calibration, discrimination, and clinical usefulness. Internal validation was additionally conducted. The difference in survival curves in PMV and NPMV groups was statistically significant (P < 0.001). The multivariate analysis and risk factors in the nomogram revealed four factors to be significantly associated with PMV, namely the body mass index (BMI), operation time, lactic acid at T0 (Lac), and driving pressure (DP) at T0. These four factors were used to develop a nomogram, with an area under the curve (AUC) of 0.852 and good calibration. After internal validation, AUC was 0.789 with good calibration. Furthermore, goodness-of-fit test and decision-curve analysis (DCA) indicated satisfactory performance in the training and internal validation sets. The proposed nomogram can reliably and accurately predict the risk of patients to develop PMV after LTx using ECMO as a bridge. Four modifiable factors including BMI, operation time, Lac, and DP were optimized, which may guide preventative measures and improve prognosis.

Ginsenoside compound K plays an anti-inflammatory effect without inducing glucose metabolism disorder in adjuvant-induced arthritis rats.

Ginsenoside compound K (GCK) possesses a glucocorticoid (GC)-like structure and functions as an agonist of the glucocorticoid receptor (GR), thereby exerting anti-inflammatory effects through GR activation. However, it remains unclear whether GCK leads to hyperglycemia, which is a known adverse reaction associated with classical GCs. In this study, we have successfully demonstrated that GCK exerts its anti-inflammatory effects in a rat model of adjuvant arthritis without impacting gluconeogenesis and pentose phosphate pathways, thus avoiding any glucose metabolism disorders. By employing the GR mutant plasmid, we have identified the binding site between GCK and GR as GRM560T, which differs from the binding site shared by dexamethasone (DEX) and GR. Notably, compared to DEX, GCK induces distinct levels of phosphorylation at S211 on GR upon binding to activate steroid receptor coactivator 1 (SRC1)-a co-factor responsible for mediating anti-inflammatory effects-while not engaging peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)-an associated coactivator involved in gluconeogenesis.

Longitudinal study on the trajectory and influencing factors of cognitive dysfunction in lung transplantation patients.

INTRODUCTION: Lung transplantation is an effective method for treating end-stage lung disease. It prolongs the survival time of patients, improves the quality of life, and prevents the degree of mental disability. In particular, postoperative cognitive dysfunction (POCD) is one of the complications after lung transplantation. Despite this, longitudinal studies on the identification and heterogeneity of cognitive dysfunction subgroup trajectories in transplant patients are lacking. Therefore, our study aimed to evaluate the factors that influence POCD in lung transplant patients. METHODS: This prospective longitudinal study included patients who underwent lung transplantation at the transplant center of Wuxi People's Hospital from September 2022 to September 2023. Patients with lung transplants were evaluated at 8 days (T1), 1 month (T2), 3 months (T3), and 6 months (T4) after the operation. The general information questionnaire evaluated cognitive functions using the Montreal Cognitive Assessment (MoCA) numerical rating scale (NRS) and the digital pain assessment to obtain the POCD values. Latent category growth model (LCGM) analysis was used to identify heterogeneous POCD subgroups in the four observation periods. Univariate and logistic regression analyses were used to identify factors affecting POCD classification and independent risk factors. RESULTS: Based on clinical outcomes, 79 patients completed all four surveys, of whom 16 were lost during the follow-up period (loss rate, 16.8%). The cognitive function by MoCA NRS score was 14.18 ± 5.32 points on day 8 (T1), 22.51 ± 5.13 points at 1 month (T2), 25.44 ± 3.61 at 3 months (T3), and 27.04 ± 3.03 points at 6 months (T4) after lung transplantation, showing an increasing trend. The LCGM, used to fit the trajectory of MoCA scores, observed a heterogeneous trajectory of changes in lung transplant patients. Based on this analysis, patients could be divided into two categories: those with high risk (25,32%) and those with low risk (54,68%). The single-factor analysis identified that POCD values were affected by early postoperative rehabilitation exercise, degree of pain, intensive care unit (ICU) stay time, and donor lung cold ischemia time (all P < 0.05). Using the low-risk group as the reference class, logistic regression analysis showed that the model could correctly classify the subjects. CONCLUSION: Our 6-month observation of lung transplant patients showed that the degree of cognitive dysfunction had an overall downward trend and that patients could be divided into two trajectories of high and low risk for POCD. Early postoperative rehabilitation exercise, degree of pain, ICU stay time, and donor lung cold ischemia time were all influencing factors for POCD in lung transplant patients.

Successful bilateral lung transplantation in a five-year-old child with pulmonary interstitial fibrosis caused by an ABCA3 gene mutation.

The ATP-binding cassette subfamily A member 3 (ABCA3) protein plays a fundamental role in surfactant homeostasis. Most children with ABCA3 gene mutations develop pulmonary interstitial fibrosis leading to the development of interstitial lung disease. Since traditional medicine does not offer effective therapy, the best option is lung transplantations, especially bilateral lung transplantations. We are reporting the case of a successful bilateral lung transplantation in a five-year-old child with pulmonary interstitial fibrosis caused by ABCA3 gene mutations. This successful transplantation enabled the patient to get rid of chronic cough and tachypnea.

Bioinspired Mechanochromic Liquid Crystal Materials: from Fundamentals to Functionalities and Applications.

Inspired by intriguing color changeable ability of natural animals, the design and fabrication of artificial mechanochromic materials capable of changing colors upon stretching or pressing have attracted intense scientific interest. Liquid crystal (LC) is a self-organized soft matter with anisotropic molecular alignment. Due to the sensitivity to various external stimulations, LC has been considered as an emerging and appealing responsive building block to construct intelligent materials and advanced devices. Recently, mechanochromic LC materials have becoming a hot topic in multi fields from flexible artificial skins to visualized sensors and smart biomimetic devices. In this review, the recent progress of mechanochromic LCs is comprehensively summarized. Firstly, the mechanism and functionalities of mechanochromic LC is introduced, followed by preparation of various functional materials based on mechanochromic LCs. Then the applications of mechanochromic LCs are provided. Finally, the conclusion and outlooks of this field is given. This overview is hoped to provide inspiration in fabrication of advanced functional soft materials for scientists and engineers from multidisciplines including materials science, elastomers, chemistry and physical science. This article is protected by copyright. All rights reserved.

Research progress of green antisolvent for perovskite solar cells.

Conventional antisolvents such as chlorobenzene and benzotrifluoride are highly toxic and volatile, and therefore not preferred for large-scale fabrication. As such, green antisolvents are favored for the eco-friendly fabrication of perovskite films. This review primarily discusses the impact of various green antisolvents on the fabrication of thin perovskite films and analyzes the main chemical characteristics of these green antisolvents. It also interprets the impact of green antisolvent treatment on crystal growth and nucleation crystallization mechanisms. It introduces the effective fabrication of large-area devices using green antisolvents and analyzes the mechanisms by which green antisolvents enhance device stability. Subsequently, several green antisolvents capable of preparing highly stable and efficient devices are listed. Finally, we outline the key challenges and future prospects of antisolvent treatment. This review paves the way for green fabrication of industrial perovskite solar cells.

Lung transplantation, case anecdotes reconstruction for inadequate left atrial cuff on the donor side by aortic arch: A feasible case report.

Abnormalities in pulmonary vasculature or technical issues during lung procurement can lead to an insufficient left atrial (LA) cuff in donors. However, surgeons frequently need to reconfigure these less-than-ideal lungs for transplantation. This case report introduces a novel technique for such reconstruction. The patient was a 35-year-old male diagnosed with pneumoconiosis for over a year. Due to progressive worsening dyspnoea leading to respiratory failure on multiple occasions, he was deemed a candidate for lung transplantation. While obtaining the donor's lung, an inadvertent short cut of the LA cuff around the left inferior pulmonary vein orifice resulted in the residual vein retracting into the pulmonary hilum. To overcome this, we employed the aortic arch for reconstruction, enabling the successful completion of the lung transplantation. On post-transplantation day 2, extracorporeal membrane oxygenation was no longer required. Mechanical ventilation ceased after 13 days, with the subsequent removal of a tracheostomy. The patient spent 35 days in the intensive care unit and 58 days in the hospital. Post-transplantation complications included primary graft dysfunction, acute kidney failure, pneumothorax in the transplanted lung, the clots in the inferior vena cava, and pneumonia. Remarkably, over a year of follow-up (19 months after lung transplantation), the patient reported no adverse events and had successfully returned to work. In this case, the aortic arch is an alternative for reconstructing an insufficient LA cuff.

Hspb1 and Lgals3 in spinal neurons are closely associated with autophagy following excitotoxicity based on machine learning algorithms.

Excitotoxicity represents the primary cause of neuronal death following spinal cord injury (SCI). While autophagy plays a critical and intricate role in SCI, the specific mechanism underlying the relationship between excitotoxicity and autophagy in SCI has been largely overlooked. In this study, we isolated primary spinal cord neurons from neonatal rats and induced excitotoxic neuronal injury by high concentrations of glutamic acid, mimicking an excitotoxic injury model. Subsequently, we performed transcriptome sequencing. Leveraging machine learning algorithms, including weighted correlation network analysis (WGCNA), random forest analysis (RF), and least absolute shrinkage and selection operator analysis (LASSO), we conducted a comprehensive investigation into key genes associated with spinal cord neuron injury. We also utilized protein-protein interaction network (PPI) analysis to identify pivotal proteins regulating key gene expression and analyzed key genes from public datasets (GSE2599, GSE20907, GSE45006, and GSE174549). Our findings revealed that six genes-Anxa2, S100a10, Ccng1, Timp1, Hspb1, and Lgals3-were significantly upregulated not only in vitro in neurons subjected to excitotoxic injury but also in rats with subacute SCI. Furthermore, Hspb1 and Lgals3 were closely linked to neuronal autophagy induced by excitotoxicity. Our findings contribute to a better understanding of excitotoxicity and autophagy, offering potential targets and a theoretical foundation for SCI diagnosis and treatment.

Correlation between desynchrony of hippocampal neural activity and hyperlocomotion in the model mice of schizophrenia and therapeutic effects of aripiprazole.

AIMS: The hippocampus has been reported to be morphologically and neurochemically altered in schizophrenia (SZ). Hyperlocomotion is a characteristic SZ-associated behavioral phenotype, which is associated with dysregulated dopamine system function induced by hippocampal hyperactivity. However, the neural mechanism of hippocampus underlying hyperlocomotion remains largely unclear. METHODS: Mouse pups were injected with N-methyl-D-aspartate receptor antagonist (MK-801) or vehicle twice daily on postnatal days (PND) 7-11. In the adulthood phase, one cohort of mice underwent electrode implantation in field CA1 of the hippocampus for the recording local field potentials and spike activity. A separate cohort of mice underwent surgery to allow for calcium imaging of the hippocampus while monitoring the locomotion. Lastly, the effects of atypical antipsychotic (aripiprazole, ARI) were evaluated on hippocampal neural activity. RESULTS: We found that the hippocampal theta oscillations were enhanced in MK-801-treated mice, but the correlation coefficient between the hippocampal spiking activity and theta oscillation was reduced. Consistently, although the rate and amplitude of calcium transients of hippocampal neurons were increased, their synchrony and correlation to locomotion speed were disrupted. ARI ameliorated perturbations produced by the postnatal MK-801 treatment. CONCLUSIONS: These results suggest that the disruption of neural coordination may underly the neuropathological mechanism for hyperlocomotion of SZ.

Clot removAl with or without decompRessive craniectomy under ICP monitoring for supratentorial IntraCerebral Hemorrhage (CARICH): a randomized controlled trial.

BACKGROUND: Decompressive craniectomy, a surgery to remove part of the skull and open the dura mater, maybe an effective treatment for controlling intracranial hypertension. It remains great interest to elucidate whether decompressive craniectomy is beneficial to intracerebral hemorrhage patients who warrant clot removal to prevent intracranial hypertension. METHODS: The trial was a prospective, pragmatic, controlled trial involving adult patients with intracerebral hemorrhage who were undergoing removal of hematoma. Intracerebral hemorrhage patients were randomly assigned at a 1:1 ratioto undergo clot removal with or without decompressive craniectomy under the monitoring of intracranial pressure. The primary outcome was the proportion of unfavorable functional outcome (modified Rankin Scale 3-6) at 3 months. Secondary outcomes included the mortality at 3 months and the occurrence of re-operation. RESULTS: A total of 102 patients were assigned to the clot removal with decompressive craniectomy group and 102 to the clot removal group. Median hematoma volume was 54.0 mL (range 30-80 mL) and median preoperative Glasgow Coma Scale was 10 (range 5-15). At 3 months, 94 patients (92.2%) in clot removal with decompressive craniectomy group and 83 patients (81.4%) in the clot removal group had unfavorable functional outcome (P=0.023). Fourteen patients (13.7%) in the clot removal with decompressive craniectomy group died versus five patients (4.9%) in the clot removal group (P=0.030). The number of patients with re-operation was similar between the clot removal with decompressive craniectomy group and clot removal group (5.9% vs. 3.9%; P=0.517). Postoperative intracranial pressure values were not significantly different between two groups and the mean values were less than 20 mmHg. CONCLUSIONS: Clot removal without decompressive craniectomy decreased the rate of modified Rankin Scale score of 3-6 and mortality in patients with intracerebral hemorrhage, compared with clot removal with decompressive craniectomy.

The Impact of SARS-CoV-2 Infection on the Length of Stay in the Neuro-ICU:A Prospective Multicenter Cohort Study in Eight Neuro-ICU, China Between February and April 2023.

Purpose: The SARS-CoV-2 infection cases are increasing rapidly in neuro-intensive care units (neuro-ICUs) at the beginning of 2023 in China. We aimed to characterize the prevalence, risk factors, and prognosis of critically ill patients treated in neuro-ICUs. Materials and Methods: In the prospective, multicenter, observational registry study, critically ill patients with intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), and traumatic brain injury (TBI) admitted to eight Chinese neuro-ICUs between Feb 16, 2023, to Apr 30, 2023 were enrolled for the study. Mortality and ICU stay day were used as the primary outcomes. Results: 131 patients were finally included and analyzed (mean age 60.36 years [SD 13.81], 64.12% male, 39.69% SARS-CoV-2 infected). The mortality is higher in the SARS-CoV-2 infection group without statistical signification (7.69% vs 5.06%, p>0.05). The length of stay (LOS) in neuro-ICUs was significantly longer among the SARS-CoV-2 infection patients (7(1-12) vs 4(1-8), p<0.01), with increased viral pneumonia occurrence (58.54% vs 7.32%, p<0.01). SARS-CoV-2 infection, surgery, and low GCS scores were independent risk factors for prolonged LOS, and respiratory/renal failure were independent risk factors for death. Conclusion: Based on the present neuro-ICU cohort, SARS-CoV-2 infection was a significant risk for the prolonged LOS of neuro-critically ill patients. Trial Registration: Registered with Chictr.org.cn (ChiCTR2300068355) at 16 February 2023, Prospective registration. https://www.chictr.org.cn/showproj.html?proj=188252.

The novel molecular mechanism of pulmonary fibrosis: insight into lipid metabolism from reanalysis of single-cell RNA-seq databases.

Pulmonary fibrosis (PF) is a severe pulmonary disease with limited available therapeutic choices. Recent evidence increasingly points to abnormal lipid metabolism as a critical factor in PF pathogenesis. Our latest research identifies the dysregulation of low-density lipoprotein (LDL) is a new risk factor for PF, contributing to alveolar epithelial and endothelial cell damage, and fibroblast activation. In this study, we first integrative summarize the published literature about lipid metabolite changes found in PF, including phospholipids, glycolipids, steroids, fatty acids, triglycerides, and lipoproteins. We then reanalyze two single-cell RNA-sequencing (scRNA-seq) datasets of PF, and the corresponding lipid metabolomic genes responsible for these lipids' biosynthesis, catabolism, transport, and modification processes are uncovered. Intriguingly, we found that macrophage is the most active cell type in lipid metabolism, with almost all lipid metabolic genes being altered in macrophages of PF. In type 2 alveolar epithelial cells, lipid metabolic differentially expressed genes (DEGs) are primarily associated with the cytidine diphosphate diacylglycerol pathway, cholesterol metabolism, and triglyceride synthesis. Endothelial cells are partly responsible for sphingomyelin, phosphatidylcholine, and phosphatidylethanolamines reprogramming as their metabolic genes are dysregulated in PF. Fibroblasts may contribute to abnormal cholesterol, phosphatidylcholine, and phosphatidylethanolamine metabolism in PF. Therefore, the reprogrammed lipid profiles in PF may be attributed to the aberrant expression of lipid metabolic genes in different cell types. Taken together, these insights underscore the potential of targeting lipid metabolism in developing innovative therapeutic strategies, potentially leading to extended overall survival in individuals affected by PF.

Flexible vanillin-polyacrylate/chitosan/mesoporous nanosilica-MXene composite film with self-healing ability towards dual-mode sensors.

Manufacturing flexible sensors with prominent mechanical properties, multifunctional sensing abilities, and remarkable self-healing capabilities remains a difficult task. In this study, a novel vanillin-modified polyacrylate (VPA), which is capable of forming green dynamic covalent crosslinking with chitosan (CS), was synthesized. The synthesized VPA was combined with mesoporous silica-modified MXene (AMS-MXene) and covalently cross-linked simultaneously with CS, resulting in the formation of a flexible composite conductive film designed for dual-mode sensors. Due to the multidimensional structure formed by the mesoporous silica and MXene layers, the resulting composite film is not only suitable for strain sensing but also excels in gas response sensing. Most importantly, the composite films demonstrate a remarkable self-healing capability through reversible dynamic covalent bonds, specifically Schiff base bonds, coupled with multiple hydrogen bonding interactions with AMS-MXene. This robust self-repair functionality remains effective even at a low temperature of 30 °C. Additionally, the synergistic antibacterial effect exerted by vanillin and CS in the film can endow the composite sensor with excellent antimicrobial properties. This multifunctional composite film holds tremendous potential for applications in green flexible wearable sensors. Furthermore, it can show diverse applications in a wide variety of fields, driving advances in wearable technology and human health monitoring.

EV-COMM: A database of interspecies and intercellular interactions mediated by extracellular vesicles.

Intra- and inter-organismal interactions play a crucial role in the maintenance and function of individuals, as well as communities. Extracellular vesicles (EVs) have been identified as effective mediators for the communication both within and between species. They can carry and transport molecular cargoes to transmit biological messages. Several databases (ExoBCD, ExoCarta, EVpedia, EV-TRACK, Vesiclepedia) complied the cargoes information including DNA, RNA, protein, lipid and metabolite associated with EVs. Databases that refer to the complete records on both donor and recipient information are warranted to facilitate the understanding of the interaction across cells and species. In this study, we developed a database that compiled the records equipped with a structured process of EV-mediated interaction. The sources of donor and recipient were classified by cell type, tissues/organs and species, thus providing an extended knowledge of cell-cell, species-species interaction. The isolation and identification methods were presented for assessing the quality of EVs. Information on functional cargoes was included, where microRNA was linked to a prediction server to broaden its potential effects. Physiological and pathological context was marked to show the environment where EVs functioned. At present, a total of 1481 data records in our database, including 971 cell-cell interactions belonging to more than 40 different tissues/organs, and 510 cross-species records. The database provides a web interface to browse, search, visualize and download the interaction records. Users can search for interactions by selecting the context of interest or specific cells/species types, as well as functional cargoes. To the best of our knowledge, the database is the first comprehensive database focusing on interactions between donor and recipient cells or species mediated by EVs, serving as a convenient tool to explore and validate interactions. The Database, shorten as EV-COMM (EV mediated communication) is freely available at http://sdc.iue.ac.cn/evs/list/ and will be continuously updated.

A Preliminary Study on the Application of Contrast-Enhanced Ultrasonography in Children With Peripheral Neuroblastic Tumors.

The purpose of this study was to retrospectively analyze the characteristics of contrast-enhanced ultrasound (CEUS) images and quantitative parameters of time-intensity curves (TICs) in children's peripheral neuroblastic tumors (pNTs). By comparing the imaging features and quantitative parameters of the TICs of neuroblastoma (NB) and ganglioneuroblastoma (GNB) patients, we attempted to identify the distinguishing points between NB and GNB. A total of 35 patients confirmed to have pNTs by pathologic examination were included in this study. Each child underwent CEUS with complete imaging data (including still images and at least 3 min of video files). Twenty-four patients were confirmed to have NB, and 11 were considered to have GNB according to differentiation. The CEUS image features and quantitative parameters of the TICs of all lesions were analyzed to determine whether there were CEUS-related differences between the two types of pNT. There was a significant difference in the enhancement patterns of the CEUS features (χ2 = 5.303, p < 0.05), with more "peripheral-central" enhancement in the NB group and more "central-peripheral" enhancement in the GNB group. In the TIC, the rise time and time to peak were significantly different (p < 0.05). The receiver operating characteristic curve showed that the probability of ganglion cell NB increased significantly after RT > 15.29, with a sensitivity of 0.636 and a specificity of 0.958. When the peak time was greater than 16.155, the probability of NB increased significantly, with a sensitivity of 0.636 and a specificity of 0.958. The CEUS features of NB and GNB patients are very similar, and it is difficult to distinguish them. Rise time and time to peak may be useful in identifying GNB and NB, but the sample size of this study was small, and the investigation was only preliminary; a larger sample size is needed to support these conclusions.

Lercanidipine's Antioxidative Effect Prevents Noise-Induced Hearing Loss.

Noise-induced hearing loss (NIHL) is a prevalent form of adult hearing impairment, characterized by oxidative damage to auditory sensory hair cells. Although certain dihydropyridines, the L-type calcium channel blockers, exhibit protective properties against such damage, the ability of third-generation dihydropryidines like lercanidipine to mitigate NIHL remains unclear.We utilized glucose oxidase (GO)-treated OC1 cell lines and cochlear explants to evaluate the protective influence of lercanidipine on hair cells. To further investigate its effectiveness, we exposed noise-stimulated mice in vivo and analyzed their hearing thresholds. Additionally, we assessed the antioxidative capabilities of lercanidipine by examining oxidation-related enzyme expression and levels of oxidative stress markers, including 3-nitrotyrosine (3NT) and 4-hydroxynonenal (4HNE). Our findings demonstrate that lercanidipine significantly reduces the adverse impacts of GO on both OC-1 cell viability (0.3 to 2.5 µM) and outer hair cell (OHC) survival in basal turn cochlear explants (7 µM). These results are associated with increased mRNA expression of antioxidant enzyme genes (HO-1, SOD1/2, and Txnrd1), along with decreased expression of oxidase genes (COX-2, iNOS). Crucially, lercanidipine administration prior to, and following, noise exposure effectively ameliorates NIHL, as evidenced by lowered hearing thresholds and preserved OHC populations in the basal turn, 14 days post-noise stimulation at 110 dB SPL. Moreover, our observations indicate that lercanidipine's antioxidative action persists even three days after simultaneous drug and noise treatments, based on 3-nitrotyrosine and 4-hydroxynonenal immunostaining in the basal turn. Based on these findings, we propose that lercanidipine has the capacity to alleviate NIHL and safeguard OHC survival in the basal turn, potentially via its antioxidative mechanism. These results suggest that lercanidipine holds promise as a clinically viable option for preventing NIHL in affected individuals.

Identification of key immune cells infiltrated in lung adenocarcinoma microenvironment and their related long noncoding RNA.

LncRNA associated with immune cell infiltration in tumor microenvironment (TME) may be a potential therapeutic target for lung adenocarcinoma. We established a machine learning (ML) model based on 3896 samples characterized by the degree of immune cell infiltration, and further screened the key lncRNA. In vitro experiments were applied to validate the prediction. Treg is the key immune cell in the TME of lung adenocarcinoma, and the degree of infiltration is negatively correlated with the prognosis. PCBP1-AS1 may affect the infiltration of Tregs by regulating the TGF-ß pathway, which is a potential predictor of clinical response to immunotherapy. PCBP1-AS1 regulates cell proliferation, cell cycle, invasion, migration, and apoptosis in lung adenocarcinoma. The results of clinical sample staining and in vitro experiments showed that PCBP1-AS1 was negatively correlated with Treg infiltration and TGF-ß expression. Tregs and related lncRNA PCBP1-AS1 can be used as targets for the diagnosis and treatment of lung adenocarcinoma.

HLA-class II restricted TCR targeting human papillomavirus type 18 E7 induces solid tumor remission in mice.

T cell receptor (TCR)-engineered T cell therapy is a promising potential treatment for solid tumors, with preliminary efficacy demonstrated in clinical trials. However, obtaining clinically effective TCR molecules remains a major challenge. We have developed a strategy for cloning tumor-specific TCRs from long-term surviving patients who have responded to immunotherapy. Here, we report the identification of a TCR (10F04), which is human leukocyte antigen (HLA)-DRA/DRB1*09:01 restricted and human papillomavirus type 18 (HPV18) E784-98 specific, from a multiple antigens stimulating cellular therapy (MASCT) benefited metastatic cervical cancer patient. Upon transduction into human T cells, the 10F04 TCR demonstrated robust antitumor activity in both in vitro and in vivo models. Notably, the TCR effectively redirected both CD4+ and CD8+ T cells to specifically recognize tumor cells and induced multiple cytokine secretion along with durable antitumor activity and outstanding safety profiles. As a result, this TCR is currently being investigated in a phase I clinical trial for treating HPV18-positive cancers. This study provides an approach for developing safe and effective TCR-T therapies, while underscoring the potential of HLA class II-restricted TCR-T therapy as a cancer treatment.

Mitochondrial DNA leakage triggers inflammation in age-related cardiovascular diseases.

Mitochondrial dysfunction is one of the hallmarks of cardiovascular aging. The leakage of mitochondrial DNA (mtDNA) is increased in senescent cells, which are resistant to programmed cell death such as apoptosis. Due to its similarity to prokaryotic DNA, mtDNA could be recognized by cellular DNA sensors and trigger innate immune responses, resulting in chronic inflammatory conditions during aging. The mechanisms include cGAS-STING signaling, TLR-9 and inflammasomes activation. Mitochondrial quality controls such as mitophagy could prevent mitochondria from triggering harmful inflammatory responses, but when this homeostasis is out of balance, mtDNA-induced inflammation could become pathogenic and contribute to age-related cardiovascular diseases. Here, we summarize recent studies on mechanisms by which mtDNA promotes inflammation and aging-related cardiovascular diseases, and discuss the potential value of mtDNA in early screening and as therapeutic targets.