Selective Vulnerability of GABAergic Inhibitory Interneurons to Bilirubin Neurotoxicity in the Neonatal Brain.

Hyperbilirubinemia (HB) is a key risk factor for hearing loss in neonates, particularly premature infants. Here we report that bilirubin (BIL)-dependent cell death in auditory brainstem of neonatal mice of both sexes is significantly attenuated by ZD7288, a blocker for hyperpolarization-activated cyclic nucleotide-gated (HCN) channel mediated current (Ih), or by genetic deletion of HCN1. GABAergic inhibitory interneurons predominantly express HCN1, on which BIL selectively acts to increase their intrinsic excitability and mortality by enhancing HCN1 activity and Ca2+-dependent membrane targeting. Chronic BIL elevation in neonatal mice in vivo increases the fraction of spontaneously active interneurons and their firing frequency, Ih and death, compromising audition at young adult stage in HCN1+/+, but not in HCN1-/- genotype. We conclude that HB preferentially targets HCN1 to injure inhibitory interneurons, fueling a feedforward loop in which lessening inhibition cascades hyperexcitability, Ca2+ overload, neuronal death and auditory impairments. These findings rationalize HCN1 as a potential target for managing HB encephalopathy.Significance Statement This study demonstrated that bilirubin preferentially targets GABAergic interneurons where it facilitates not only gating of HCN1 channels but also targeting of intracellular HCN1 to plasma membrane in calcium-dependent manner, resulting in neuronal hyperexcitability, injury and sensory dysfunction. These findings implicate HCN1 channel not only as a potential driver for auditory abnormalities in neonatal patients with bilirubin encephalopathy, but also potential intervention target for clinical management of neurological impairments associated with severe jaundice. Selective vulnerability of interneurons to neurotoxicity may be of general significance for understanding other forms of brain injury.

[Retracted] miR­218 functions as a tumor suppressor gene in cervical cancer.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that, concerning the Transwell cell migration and invasion assays shown in Fig. 4Ba and 4Ca on p. 215, quite a large number of the data panels contained overlapping sections, such that data panels which were intended to show the results from differently performed experiments had been derived from a smaller number of original sources. After having considered this matter, in view of the number of overlapping data panels that were identified, the Editor of Molecular Medicine Reports has decided that this paper should be retracted from the Journal on account of a lack of confidence in the presented data. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 21: 209-219, 2020; DOI: 10.3892/mmr.2019.10809].

The relationship between anesthesia, surgery and postoperative immune function in cancer patients: a review.

This review comprehensively examines the impact of anesthesia and surgical interventions on the immune function of cancer patients postoperatively. Recent studies have shown that surgery and its accompanying anesthesia management can significantly influence immune function in cancer patients, potentially affecting their prognosis. This review synthesizes clinical studies and basic research to summarize the specific effects of anesthesia methods, drugs, postoperative analgesia, intraoperative transfusion, surgical techniques, and trauma extent on the immune function of cancer patients post-surgery. Additionally, this review discusses optimization strategies based on current research, aiming to refine anesthesia and surgical management to maximize the preservation and enhancement of postoperative immune function in cancer patients, with the potential to improve clinical outcomes.

Angiopoietin-like 4 is a potential biomarker for diabetic kidney disease in type 2 diabetes patients.

AIMS/INTRODUCTION: The association between serum angiopoietin-like 4 (ANGPTL4) levels and the severity of diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus remains unclear. METHODS: A total of 1,115 type 2 diabetes mellitus patients were analyzed in this cross-sectional study. DKD index included DKD stages defined by estimated glomerular filtration rate, the albuminuria grades and DKD risk management grades. Serum levels of ANGPTL4 and other biomarkers were detected. Multivariable-adjusted linear and logistic analyses were used to study the association between ANGPTL4 and DKD. The protein levels of ANGPTL4 were assessed in the kidney. Renal tubular cells were stimulated with glucose to study ANGPTL4 expression. RESULTS: Compared with the participants in the third or fourth quantile of ANGPTL4, those in the first or second quantile of ANGPTL4 were younger, with lower glycated hemoglobin, triglycerides and urinary albumin creatinine ratio (all P < 0.05). There was a negative nonlinear relationship between ANGPTL4 and estimated glomerular filtration rate in type 2 diabetes mellitus patients. One standard deviation increased serum ANGPTL4 levels, the odds ratio of having DKD was 1.40 (95% confidence interval 1.08-1.80). The mediation analysis showed that triglycerides did not mediate the association between ANGPTL4 and DKD. Furthermore, ANGPTL4 could be the strongest among multiple panels of biomarkers in its association of DKD. Compared with mice at 8 weeks-of-age, db/db mice at 18 weeks-of-age had increased ANGPTL4 expression in glomeruli and tubular segments. In vitro, glucose could stimulate ANGPTL4 expression in tubular cells in a dose-dependent manner. CONCLUSIONS: ANGPTL4 could be a potential marker and therapeutic target for DKD treatment.

Moxibustion pre-treatment attenuates seizure severity during status epilepticus and counteracts the proconvulsant function of the purinergic P2X7 receptor.

Moxibustion, traditional Chinese medicine treatment, involves the warming of specific acupuncture points of the body using ignited herbal materials. Evidence suggests beneficial effects of moxibustion in several brain diseases including epilepsy, however, whether moxibustion pretreatment impacts on seizures and what are the underlying mechanisms remains to be established. Evidence has suggested the purinergic ATP-gated P2X7 receptor (P2X7R) to be involved in the actions of moxibustion. Moreover, P2X7R signalling is now well established to contribute to long-lasting brain hyperexcitability underlying epilepsy development. Whether P2X7R signalling is involved in the seizure-reducing actions of moxibustion has not been investigated to date. For our studies we used C57BL/6 male mice that received moxibustion pre-treatments at the acupoints Zusanli (ST36) and Dazhui (GV14) once daily for either 7, 14, or 21 days. This was followed by an intraperitoneal injection of kainic acid (KA, 30 mg/kg) to induce status epilepticus. Behavioral changes during KA-induced status epilepticus were analyzed according to the Racine scale. Changes in electrographic seizures were analyzed via cortical implanted electroencephalogram (EEG) electrodes. While no effect on seizure severity was observed following 7 days of moxibustion pre-treatment, moxibustion pre-treatment at both ST36 and GV14 for 14 or 21 days significantly reduced KA-induced behavior seizures at a similar rate. Cortical EEG recordings showed that 14 days of moxibustion pre-treatments also reduced electrographic seizures, confirming the anticonvulsant actions of moxibustion pre-treatment. To determine whether moxibustion impacts the pro-convulsant actions of P2X7R signaling, mice were treated with the P2X7R agonist BzATP or P2X7R antagonist A438079. While treatment with the P2X7R agonist BzATP exacerbated seizure severity, treatment with the P2X7R antagonist reduced seizure severity. We further found that moxibustion pre-treatment attenuated epileptic seizures by counteracting the effects of BzATP. These results suggest that moxibustion pre-treatment at the acupoints ST36 and GV14 for 14 days has anti-epileptic effects, which may counteract the proconvulsant functions of the P2X7R.

[Growth characteristic of statolith of Todarodes pacificus in the East China Sea in the La Niña year]. / 拉尼娜发生期东海太平洋褶柔鱼耳石生长特征.

To investigate the differences on morphological growth patterns of statolith of Todarodes pacificus in the East China Sea during La Niña and normal years, we analyzed the samples of T. pacificus collected in the East China Sea by Chinese light purse seine fishery fleets from February to April in 2020 (a normal year) and 2021 (a La Niña year). The results showed that total statolith length (TSL), lateral dome length (LDL), wing length (WL), and maximum width (MW) could be used as characterization parameters to representing the morphological growth of statolith. The characterization parameters of statolith in T. pacificus differed significantly between different climate years and between different genders. The values of those characterization parameters of statolith were greater in normal year than those in La Niña year, which in both years were larger in females, except for TSL in males in La Niña year. The statolith growth of males were faster than that of females in different climate years. TSL, LDL, and WL increased faster in normal year, while MW increased faster in La Niña year. The relative size of statolith gradually slowed down with the growth of individuals.

High-throughput arousing interconnected interfaces for excellent sodium storage chemistry.

Heterostructures endow electrochemical hybrids with promising energy storage properties owing to synergistic effects and interfacial interaction. However, developing a facile but effective approach to maximize interface effects is crucial but challenging. Herein, a bimetallic sulfide/carbon heterostructure is realized in a confined carbon network via a high-throughput template-assisted strategy to induce highly active and stable electrode architecture. The designed heterostructures not only yield abundant interconnected Co9S8/MoS2/N-doped carbon (Co9S8/MoS2/NC) heterojunctions with continuous channels for ion/electron transfer but maintain excellent conversion reversibility. Serving as anode for sodium storage, the Co9S8/MoS2/NC framework displayed excellent sodium storage properties (reversible capacity of 480 mAh/g after 100 cycles at 0.2 A/g and 286.2 mAh/g after 500 cycles at 2 A/g). Given this, this study can guide future design protocols for interface engineering by forming dynamic channels of conversion reaction kinetics for potential applications in high-performance electrodes.

Combination Therapy Consisting of Transarterial Chemoembolization, Lenvatinib, and Programmed Cell Death Protein 1 Blockade for Hepatocellular Carcinoma with Inferior Vena Cava Tumor Thrombus: A Case Series Study and Literature Review.

INTRODUCTION: Patients with hepatocellular carcinoma (HCC) and inferior vena cava tumor thrombus (IVCTT) have poor prognosis. Combination therapy involving the blockade of programmed cell death protein 1 (PD-1) and tyrosine kinase inhibitors is an efficient treatment strategy for advanced HCC. However, surgical treatment after a combination of systemic therapy and transarterial chemoembolization (TACE) for HCC with IVCTT has not been widely reported, and the efficacy and safety of this treatment have not been studied. METHODS: In the 21 cases reported herein, the patients were treated with TACE, lenvatinib, and PD-1 blockade. The treatment responses, progression-free survival (PFS), overall survival (OS), disease control rate, and toxicities were evaluated, and the related literature was reviewed. RESULTS: The overall response and disease control rates were 66.7% and 85.7%, respectively. The median PFS time was 16.0 months, with a 1-year PFS rate of 55.60%. The median OS was not reached, with a 1-year OS rate of 66.70%. Four patients underwent hepatectomy without serious complications and survived for 29.1, 24.7, 14.2, and 13.8 months. Three patients survived tumor-free, and 1 patient experienced intrahepatic recurrence. Pathological complete response and major pathological responses were observed in 1 and 3 patients, respectively. Treatment-related adverse events of any grade occurred in 8/9 patients (88.9%), and grade 3 treatment-related adverse events occurred in 1 patient. CONCLUSION: The combination of TACE, lenvatinib, and PD-1 is effective for HCC with IVCTT and has acceptable adverse effects.

Myocardial ischemia-reperfusion injury: The balance mechanism between mitophagy and NLRP3 inflammasome.

Myocardial ischemia-reperfusion injury (MIRI) is an injury to cardiomyocytes due to restoration of blood flow after myocardial infarction (MI). It has recently gained much attention in clinical research with special emphasis on the roles of mitochondrial autophagy and inflammation. A mild inflammatory response promotes recovery of post-ischemic cardiomyocyte function and vascular regeneration, but a severe inflammatory response can cause irreversible and substantial cellular damage. Similarly, moderate mitochondrial autophagy can help inhibit excessive inflammation and protect cardiomyocytes. However, MIRI is aggravated when mitochondrial function is disrupted, such as inadequate clearance of damaged mitochondria or excessive activation of mitophagy. How to moderately control mitochondrial autophagy while promoting its balance with nucleotide-binding oligomerization structural domain receptor protein 3 (NLRP3) inflammasome activation is critical. In this paper, we reviewed the molecular mechanisms of mitochondrial autophagy and NLRP3 inflammasome, described the interaction between NLRP3 inflammasome and mitochondrial autophagy, and the effects of different signaling pathways and molecular proteins on MIRI, to provide a reference for future research.

Clinical drug interactions between linezolid and other antibiotics: For adverse drug event monitoring.

Detailed data on safety associated with drug-drug interactions (DDIs) between Linezolid (LZD) and other antibiotics are limited. The aim of this study was to investigate the safety signals related to these DDIs and to provide a reference for clinically related adverse drug event monitoring. Adverse event (AE) information from 1 January 2004 to 16 June 2022 of the target antibiotics including LZD using alone or in combination with LZD was extracted from the OpenVigil FDA data platform for safety signal analysis. The combined risk ratio model, reporting ratio method, Ω shrinkage measure model, and chi-square statistics model were used to analyze the safety signals related to DDIs. Meanwhile, we evaluated the correlation and the influence of sex and age between the drug(s) and the target AE detected. There were 18991 AEs related to LZD. There were 2293, 1726, 4449, 821, 2431, 1053, and 463 AE reports when LZD was combined with amikacin, voriconazole, meropenem, clarithromycin, levofloxacin, piperacillin-tazobactam, and azithromycin, respectively. Except for azithromycin, there were positive safety signals related to DDIs between LZD and these antibiotics. These DDIs might influence the incidence of 13, 16, 7, 7, 6, and 15 types of AEs, respectively, and is associated with higher reporting rates of AEs compared with use alone. Moreover, sex and age might influence the occurrence of AEs. We found that the combinations of LZD and other antibiotics are related to multiple AEs, such as hepatotoxicity, drug resistance and electrocardiogram QT prolonged, but further research is still required to investigate their underlying mechanisms. This study can provide a new reference for the safety monitoring of LZD combined with other antibiotics in clinical practice.

Aberrant neural oscillations in poststroke aphasia.

Neural oscillations are electrophysiological indicators of synchronous neuronal activity in the brain. Recent work suggests aberrant patterns of neuronal activity in patients with poststroke aphasia. Yet, there is a lack of systematic explorations of neural oscillations in poststroke aphasia. Investigating changes in the dynamics of neuronal activity after stroke may be helpful to identify neural markers of aphasia and language recovery and increase the current understanding of successful language rehabilitation. This review summarizes research on neural oscillations in poststroke aphasia and evaluates their potential as biomarkers for specific linguistic processes. We searched the literature through PubMed, Web of Science, and EBSCO, and selected 31 studies that met the inclusion criteria. Our analyses focused on neural oscillation activity in each frequency band, brain connectivity, and therapy-induced changes during language recovery. Our review highlights potential neurophysiological markers; however, the literature remains confounded, casting doubt on the reliability of these findings. Future research must address these confounds to confirm the robustness of cross-study findings on neural oscillations in poststroke aphasia.

Elucidating CTLA-4's role in tumor immunity: a comprehensive overview of targeted antibody therapies and clinical developments.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) emerges as a key single-chain transmembrane glycoprotein predominantly expressed in effector T cells and regulatory T cells. It plays a crucial role in tumor immunity by modulating T cell responses. Specifically, CTLA-4 dampens T cell activation and proliferation while bolstering the survival of regulatory T cell through its competitive interaction with B7 family molecules, thereby aiding tumor cells in eluding immune detection. Given CTLA-4's significant influence on tumor immune dynamics, an array of anti-CTLA-4 antibody therapeutics have been clinically developed to combat various malignancies, including melanoma, renal cell carcinoma, colorectal carcinoma, hepatocellular carcinoma, non-small cell lung carcinoma, and pleural mesothelioma, demonstrating notable clinical therapeutic effects. This paper aims to delve into CTLA-4's integral role in tumor immunity and to encapsulate the latest advancements in the clinical research of anti-CTLA-4 antibody.

Benzo(a)pyrene promotes the malignant progression of malignant-transformed BEAS-2B cells by regulating YTH N6-methyladenosine RNA binding protein 1 to inhibit ferroptosis.

Benzo[a]pyrene (BaP) is associated with the development of lung cancer, but the underlying mechanism has not been completely clarified. Here, we used 10 µM BaP to induce malignant transformation of human bronchial epithelial BEAS-2B cells, named BEAS-2B-T. Results indicated that BaP (6.25, 12.5 and 25 µM) treatment significantly promoted the migration and invasion of BEAS-2B-T cells. Meanwhile, BaP exposure inhibited ferroptosis in BEAS-2B-T, ferroptosis-related indexes Fe2+, malondialdehyde (MDA), lipid peroxidation (LPO) and reactive oxygen species (ROS) decreased significantly. The protein level of ferroptosis-related molecule transferrin receptor (TFRC) decreased significantly, while solute carrier family 7 membrane 11 (SLC7A11), ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4) increased significantly. The intervention of ferroptosis dramatically effected the migration and invasion of BEAS-2B-T induced by BaP. Furthermore, the expression of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) was markedly increased after BaP exposure. YTHDF1 knockdown inhibited BEAS-2B-T migration and invasion by promoting ferroptosis. In the meantime, the contents of Fe2+, MDA, LPO and ROS increased significantly, TFRC was markedly increased, and SLC7A11, FTH1, and GPX4 were markedly decreased. Moreover, overexpression of YTHDF1 promoted BEAS-2B-T migration and invasion by inhibiting ferroptosis. Importantly, knockdown of YTHDF1 promoted ferroptosis and reduced BEAS-2B-T migration and invasion during BaP exposure, and overexpression of YTHDF1 increased migration and invasion of BEAS-2B-T by inhibiting ferroptosis during BaP exposure. RNA immunoprecipitation assays indicated that the binding of YTHDF1 to SLC7A11 and FTH1 markedly increased after YTHDF1 overexpression. Therefore, we concluded that BaP promotes the malignant progression of BEAS-2B-T cells through YTHDF1 upregulating SLC7A11 and FTH1 to inhibit ferroptosis. This study reveals new epigenetic and ferroptosis markers for preventing and treating lung cancer induced by environmental carcinogens.

Development of implantable electrode based on bioresorbable Mg alloy for tissue welding application.

An implantable electrode based on bioresorbable Mg-Nd-Zn-Zr alloy was developed for next-generation radiofrequency (RF) tissue welding application, aiming to reduce thermal damage and enhance anastomotic strength. The Mg alloy electrode was designed with different structural features of cylindrical surface (CS) and continuous long ring (LR) in the welding area, and the electrothermal simulations were studied by finite element analysis (FEA). Meanwhile, the temperature variation during tissue welding was monitored and the anastomotic strength of welded tissue was assessed by measuring the avulsion force and burst pressure. FEA results showed that the mean temperature in the welding area and the proportion of necrotic tissue were significantly reduced when applying an alternating current of 110 V for 10 s to the LR electrode. In the experiment of tissue welding ex vivo, the maximum and mean temperatures of tissues welded by the LR electrode were also significantly reduced and the anastomotic strength of welded tissue could be obviously improved. Overall, an ideal welding temperature and anastomotic strength which meet the clinical requirement can be obtained after applying the LR electrode, suggesting that Mg-Nd-Zn-Zr alloy with optimal structure design shows great potential to develop implantable electrode for next-generation RF tissue welding application.

Integrated cell wall and transcriptomic analysis revealed the mechanism underlying zinc-induced alleviation of cadmium toxicity in Cosmos bipinnatus.

Plant growth is severely harmed by cadmium (Cd) contamination, while the addition of zinc (Zn) can reduce the toxic effects of Cd. However, the interaction between Cd and Zn on the molecular mechanism and cell wall of Cosmosbipinnatus is unclear. In this study, a transcriptome was constructed using RNA-sequencing. In C. bipinnatus root transcriptome data, the expression of 996, 2765, and 3023 unigenes were significantly affected by Cd, Zn, and Cd + Zn treatments, respectively, indicating different expression patterns of some metal transporters among the Cd, Zn, and Cd + Zn treatments. With the addition of Zn, the damage to the cell wall was reduced, both the proportion and content of polysaccharides in the cell wall were changed, and Cd accumulation was decreased by 32.34%. In addition, we found that Cd and Zn mainly accumulated in pectins, the content of which increased by 30.79% and 61.4% compared to the CK treatment. Thus, Zn could alleviate the toxicity of Cd to C. bipinnatus. This study revealed the interaction between Cd and Zn at the physiological and molecular levels, broadening our understanding of the mechanisms of tolerance to Cd and Zn stress in cosmos.

Comprehensive analysis of the clinical significance and molecular mechanism of T-box transcription factor 3 in osteosarcoma.

Background: T-box transcription factor 3 (TBX3) has been implicated in various malignant tumors, while its exact involvement in osteosarcoma (OS) remains unknown. Methods: Utilizing microarray data and bulk and single-cell RNA-seq data and qRT-PCR, we compared TBX3 mRNA expression levels in different stages of OS. Diagnostic ability testing and prognosis analysis were conducted to better understand the clinical importance of TBX3. Enrichment analysis was performed using gene groups with biological functions similar to TBX3 in different stages of OS to investigate the potential role of TBX3 in OS progression. In addition, we predicted medications targeted at TBX3 and identified downstream target genes to gain a comprehensive understanding of its therapeutic direction and regulatory mechanism. Results: TBX3 expression was highly upregulated in OS and was predominantly expressed in osteoblastic OS cells, with higher expression levels in metastatic tissues. TBX3 expression appeared somewhat suitable for discriminating between OS and normal samples, as well as different stages of OS. We found that TBX3 increased the malignant development of OS by altering cell cycle and cell adhesion molecules; exisulind and tacrolimus, which are targeted small-molecule medicines, were anticipated to counteract this dysregulation. The expression of CCNA2 could potentially be regulated by TBX3, contributing to OS advancement. Conclusion: TBX3 emerges as a potential biomarker for OS. In-depth research into its underlying molecular processes may offer new perspectives on treating OS.

Mitochondrial RelA empowers mtDNA G-quadruplex formation for hypoxia adaptation in cancer cells.

Mitochondrial DNA (mtDNA) G-quadruplexes (G4s) have important regulatory roles in energy metabolism, yet their specific functions and underlying regulatory mechanisms have not been delineated. Using a chemical-genetic screening strategy, we demonstrated that the JAK/STAT3 pathway is the primary regulatory mechanism governing mtDNA G4 dynamics in hypoxic cancer cells. Further proteomic analysis showed that activation of the JAK/STAT3 pathway facilitates the translocation of RelA, a member of the NF-κB family, to the mitochondria, where RelA binds to mtDNA G4s and promotes their folding, resulting in increased mtDNA instability, inhibited mtDNA transcription, and subsequent mitochondrial dysfunction. This binding event disrupts the equilibrium of energy metabolism, catalyzing a metabolic shift favoring glycolysis. Collectively, the results provide insights into a strategy employed by cancer cells to adapt to hypoxia through metabolic reprogramming.

Copper-Catalyzed [4+1+1] Annulation of Ammonium Salts and Anthranils: Synthesis of 2,3-Diaroylquinolines.

A copper(I)-catalyzed protocol is developed for the synthesis of various 2,3-diaroylquinolines starting from achiral ammonium salts and anthranils through [4+1+1] annulation. Using copper(I) chloride as the sole catalyst, this reaction is featured with easily available starting materials, broad substrate scope, good yields and simple reaction conditions.