Construction of Bi2WO6/g-C3N4 Z-Scheme Heterojunction and Its Enhanced Photocatalytic Degradation of Tetracycline with Persulfate under Solar Light.

Z-scheme heterojunction Bi2WO6/g-C3N4 was obtained by a novel hydrothermal process; its photocatalysis-persulfate (PDS) activation for tetracycline (TC) removal was explored under solar light (SL). The structure and photoelectrochemistry behavior of fabricated samples were well characterized by FT-IR, XRD, XPS, SEM-EDS, UV-vis DRS, Mott-Schottky, PL, photocurrent response, EIS and BET. The critical experimental factors in TC decomposition were investigated, including the Bi2WO6 doping ratio, catalyst dosage, TC concentration, PDS dose, pH, co-existing ion and humic acid (HA). The optimum test conditions were as follows: 0.4 g/L Bi2WO6/g-C3N4 (BC-3), 20 mg/L TC, 20 mg/L PDS and pH = 6.49, and the maximum removal efficiency of TC was 98.0% in 60 min. The decomposition rate in BC-3/SL/PDS system (0.0446 min-1) was 3.05 times higher than that of the g-C3N4/SL/PDS system (0.0146 min-1), which might be caused by the high-efficiency electron transfer inside the Z-scheme Bi2WO6/g-C3N4 heterojunction. Furthermore, the photogenerated hole (h+), superoxide (O2•-), sulfate radical (SO4•-) and singlet oxygen (1O2) were confirmed as the key oxidation factors in the BC-3/SL/PDS system for TC degradation by a free radical quenching experiment. Particularly, BC-3 possessed a wide application potential in actual antibiotic wastewater treatment for its superior catalytic performance that emerged in the experiment of co-existing components.

Co-existing inorganic anions influenced the Norrish I and Norrish II type photoaging mechanism of biodegradable microplastics.

The degradation of biodegradable plastics (BPs) in natural environments is constrained, and the mechanisms underlying their photoaging in aquatic settings remain inadequately understood. In view of this, this study systematically investigated the photoaging process of biodegradable Poly (butyleneadipate-co-terephthalate) microplastics (PBAT-MPs), which are more widely used. The investigation was carried out in the presence of common inorganic anions (Br-, Cl- and NO3-). The results of EPR, FTIR and FESEM tests, along with pseudo-first-order kinetics analyses, showed that the presence of NO3- promoted the photoaging of PBAT-MPs, while the presence of Br- and Cl- inhibited the photoaging of PBAT-MPs. In addition, the results of the Two-Dimensional Correlation Spectroscopy (2D-COS) analysis determined the order of the changes in the functional groups, revealing that the Norrish I and Norrish II reaction mechanisms are presented by PBAT-MPs during the aging process, and the process is closely related to the ion concentration and UV irradiation time. This study provides valuable insights for understanding the phototransformation process of BPs in natural aqueous environments.

Metformin promotes the normalization of abnormal blood vessels after radiofrequency ablation deficiency in hepatocellular carcinoma by microRNA-302b-3p targeting thioredoxin-interacting protein.

Metformin has shown great promise in the treatment of HCC. Radiofrequency ablation (RFA) deficiency results in recurrence and metastasis of remaining HCC tumors. Here, we aimed to investigate the role and mechanism of metformin in HCC after RFA deficiency. HCC cell line Hep-G2 was selected to simulate RFA deficiency and named HepG2-H cells. After treating cells with different concentrations of metformin (2.5, 5, 10 µM) or transfecting related plasmids, cell proliferation, migration, invasion, apoptosis and angiogenesis were detected, in vitro permeability test was performed, and an angiogenesis-related protein VEGFA was analyzed. The residual HCC model after RFA deficiency was established in mice. Metformin was administered by gavage to detect changes in tumor volume and weight, and CD31 staining was used to observe microvessels. The targeting relationship between miR-302b-3p and TXNIP was demonstrated by the bioinformatics website, dual-luciferase reporter assay, and RNA pull-down assay. The results found that metformin inhibited RFA deficiency-induced growth and angiogenesis of HCC cells in vitro. miR-302b-3p counteracted the therapeutic effect of metformin on RFA deficiency. miR-302b-3p targeted regulation of TXNIP. The up-regulation of TXNIP reversed the effects of overexpression of miR-302b-3p on RFA-deficient HCC cells. Metformin inhibited RFA-deficiency-induced HCC growth and tumor vascular abnormalities in vivo. Overall, metformin promotes the normalization of abnormal blood vessels after RFA deficiency in HCC by miR-302b-3p targeting TXNIP, which can be used to prevent the progression of HCC after RFA.

Dimethylsiloxanes in dust from nine indoor microenvironments of Henan Province: Occurrence and human exposure assessment.

Dimethylsiloxanes (MSs) are widely used in daily life and industry, with indoors being the main release site. Detecting the levels of MSs in indoor dust is essential for assessing the risks of human exposure. In this study, the content of MSs (D3-D8 and L3-L16) was quantified in indoor dust samples from nine microenvironments of Henan Province. The detection frequency of the targets ranged from 5.00 % to 100 %. The sum concentration of dimethylsiloxanes (TSi) was in a range of 463-3.32 × 104 ng·g-1 (median: 1.92 × 103 ng·g-1). The sum concentration of linear dimethylsiloxanes (TLSi) from all microenvironments was higher than the sum concentration of cyclic dimethylsiloxanes (TCSi), which was consistent with previously reported results. D7 and D8 were the main cyclic dimethylsiloxane, which had similar sources based on Spearman correlation analysis (p < 0.001). Moreover, D8 was detected with high levels in indoor dust for the first time, which warrants further exploration. L8-L16 were the main linear dimethylsiloxanes, which may have been due to their widespread use in electronic equipment and office equipment. The Spearman analysis found that total organic carbon (TOC) in indoor dust had weak effect on MSs. Additionally, relatively high MS levels were recorded in high people-flow working microenvironments. Accordingly, the exposure doses of MSs via indoor dust intake were estimated for different age groups using the model of worst-case exposure and median concentration. Toddlers had the highest EDIs (95th percentile concentration, 90.7 ng·kg-1-bw·d-1) to MSs.

Magnetic Biochar Derived from Fenton Sludge/CMC for High-Efficiency Removal of Pb(II): Synthesis, Application, and Mechanism.

Magnetic biochar composites (MBC) were developed by a simple one-step pyrolysis method using Fenton sludge waste solid and carboxymethyl cellulose sodium. Detailed morphological, chemical, and magnetic characterizations corroborate the successful fabrication of MBC. Batch adsorption experiments show that the synthesized MBC owns high-efficiency removal of Pb(II), accompanied by ease-of-separation from aqueous solution using magnetic field. The experiment shows that the equilibrium adsorption capacity of MBC for Pb(II) can reach 199.9 mg g-1, corresponding to a removal rate of 99.9%, and the maximum adsorption capacity (qm) reaches 570.7 mg g-1, which is significantly better than that of the recently reported magnetic similar materials. The adsorption of Pb(II) by MBC complies with the pseudo second-order equation and Langmuir isotherm model, and the adsorption is a spontaneous, endothermic chemical process. Investigations on the adsorption mechanism show that the combination of Pb(II) with the oxygen-containing functional groups (carboxyl, hydroxyl, etc.) on biochar with a higher specific surface area are the decisive factors. The merits of reusing solid waste resource, namely excellent selectivity, easy separation, and simple preparation make the MBC a promising candidate of Pb(II) purifier.

Astrocyte-Neuronal Communication and Its Role in Stroke.

Astrocytes are the most abundant glial cells in the central nervous system. These cells are an important hub for intercellular communication. They participate in various pathophysiological processes, including synaptogenesis, metabolic transformation, scar production, and blood-brain barrier repair. The mechanisms and functional consequences of astrocyte-neuron signaling are more complex than previously thought. Stroke is a disease associated with neurons in which astrocytes also play an important role. Astrocytes respond to the alterations in the brain microenvironment after stroke, providing required substances to neurons. However, they can also have harmful effects. In this review, we have summarized the function of astrocytes, their association with neurons, and two paradigms of the inflammatory response, which suggest that targeting astrocytes may be an effective strategy for treating stroke.

Metabolic reprogramming regulates microglial polarization and its role in cerebral ischemia reperfusion.

The brain is quite sensitive to changes in energy supply because of its high energetic demand. Even small changes in energy metabolism may be the basis of impaired brain function, leading to the occurrence and development of cerebral ischemia/reperfusion (I/R) injury. Abundant evidence supports that metabolic defects of brain energy during the post-reperfusion period, especially low glucose oxidative metabolism and elevated glycolysis levels, which play a crucial role in cerebral I/R pathophysiology. Whereas research on brain energy metabolism dysfunction under the background of cerebral I/R mainly focuses on neurons, the research on the complexity of microglia energy metabolism in cerebral I/R is just emerging. As resident immune cells of the central nervous system, microglia activate rapidly and then transform into an M1 or M2 phenotype to correspond to changes in brain homeostasis during cerebral I/R injury. M1 microglia release proinflammatory factors to promote neuroinflammation, while M2 microglia play a neuroprotective role by secreting anti-inflammatory factors. The abnormal brain microenvironment promotes the metabolic reprogramming of microglia, which further affects the polarization state of microglia and disrupts the dynamic equilibrium of M1/M2, resulting in the aggravation of cerebral I/R injury. Increasing evidence suggests that metabolic reprogramming is a key driver of microglial inflammation. For example, M1 microglia preferentially produce energy through glycolysis, while M2 microglia provide energy primarily through oxidative phosphorylation. In this review, we highlight the emerging significance of regulating microglial energy metabolism in cerebral I/R injury.

Procyanidins Alleviated Cerebral Ischemia/Reperfusion Injury by Inhibiting Ferroptosis via the Nrf2/HO-1 Signaling Pathway.

Procyanidins (PCs), which are organic antioxidants, suppress oxidative stress, exhibit anti-apoptotic properties, and chelate metal ions. The potential defense mechanism of PCs against cerebral ischemia/reperfusion injury (CIRI) was investigated in this study. Pre-administration for 7 days of a PC enhanced nerve function and decreased cerebellar infarct volume in a mouse middle cerebral artery embolization paradigm. In addition, mitochondrial ferroptosis was enhanced, exhibited by mitochondrial shrinkage and roundness, increased membrane density, and reduced or absent ridges. The level of Fe2+ and lipid peroxidation that cause ferroptosis was significantly reduced by PC administration. According to the Western blot findings, PCs altered the expression of proteins associated with ferroptosis, promoting the expression of GPX4 and SLC7A11 while reducing the expression of TFR1, hence inhibiting ferroptosis. Moreover, the treatment of PCs markedly elevated the expression of HO-1 and Nuclear-Nrf2. The PCs' ability to prevent ferroptosis due to CIRI was decreased by the Nrf2 inhibitor ML385. Our findings showed that the protective effect of PCs may be achieved via activation of the Nrf2/HO-1 pathway and inhibiting ferroptosis. This study provides a new perspective on the treatment of CIRI with PCs.

The role of mitochondrial dynamics in cerebral ischemia-reperfusion injury.

Stroke is one of the leading causes of death and long-term disability worldwide. More than 80 % of strokes are ischemic, caused by an occlusion of cerebral arteries. Without question, restoration of blood supply as soon as possible is the first therapeutic strategy. Nonetheless paradoxically, reperfusion can further aggravate the injury through a series of reactions known as cerebral ischemia-reperfusion injury (CIRI). Mitochondria play a vital role in promoting nerve survival and neurological function recovery and mitochondrial dysfunction is considered one of the characteristics of CIRI. Neurons often die due to oxidative stress and an imbalance in energy metabolism following CIRI, and there is a strong association with mitochondrial dysfunction. Altered mitochondrial dynamics is the first reaction of mitochondrial stress. Mitochondrial dynamics refers to the maintenance of the integrity, distribution, and size of mitochondria as well as their ability to resist external stimuli through a continuous cycle of mitochondrial fission and fusion. Therefore, improving mitochondrial dynamics is a vital means of treating CIRI. This review discusses the relationship between mitochondria and CIRI and emphasizes improving mitochondrial dynamics as a potential therapeutic approach to improve the prognosis of CIRI.

Ferroptosis is involved in polymyxin B-induced acute kidney injury via activation of p53.

Polymyxin B (PMB) is one of the most effective drugs for the treatment of multi-resistant and pan-resistant gram-negative infections. However, it can induce acute kidney injury (AKI), the mechanism of which has not yet been fully elucidated. In this study, RNA sequencing and in vitro and in vivo experiments demonstrated that PMB induced AKI by promoting ferroptosis. Moreover, the metallothionein-1 (MT-1) level was significantly increased in the AKI group and clinical cases revealed that iron and MT-1 levels in urine were significantly higher in patients with AKI than in those without AKI. To explore the mechanism of PMB induced ferroptosis, we silenced p53 in human kidney-2 (HK2) cells according to RNA sequencing, which showed that p53 was obviously enhanced in the PMB treated group. While PMB significantly enhanced Fe2+, lipid peroxidation, malondialdehyde (MDA), transferrin receptor protein 1 (TFR1), and arachidonate 12-lpoxygenase (ALOX12), decreased the survival rate, solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), and glutathione (GSH), downregulation of p53 reversed these effects, suggesting PMB induced ferroptosis by activating p53. Studies have shown p53 can promote ferroptosis by regulating the downstream factors SLC7A11 or TFR1. Further, we verified that silencing TFR1 expression as well as overexpression of SLC7A11 inhibited ferroptosis and significantly increased the survival rate of HK2 cells. Overall, PMB induces ferroptosis in renal tubular cells by activating p53 to reduce SLC7A11 expression and elevate TFR1, leading to AKI; MT-1 and iron levels in urine were significantly increased when PMB induced ferroptosis.

A Bifunctional BiOBr/ZIF-8/ZnO Photocatalyst with Rich Oxygen Vacancy for Enhanced Wastewater Treatment and H2O2 Generation.

Photocatalytic technology is considered an ideal approach for clean energy conversion and environmental pollution applications. In this work, a bifunctional BiOBr/ZIF-8/ZnO photocatalyst was proposed for removing phenols in wastewater and generating hydrogen peroxide. Insights from scanning electron microscopy measurements revealed the well-dispersion of ZIF-8/ZnO was on the BiOBr layer, which could effectively prevent agglomeration of ZIF-8 and facilitate the separation of carriers. In addition, the optimal H2O2 yield of the BiOBr/ZIF-8/ZnO sample could reach 116 mmol·L-1·g-1 within 2 h, much higher than that of pure BiOBr (with the value of 82 mmol·L-1·g-1). The optimal BiOBr/ZIF-8/ZnO sample could also remove 90% of the phenol or bisphenol A in 2 h, and its kinetic constants were 3.8 times and 2.3 times that of pure BiOBr, respectively. Based on the analysis of the various experimental characterizations, the photocatalytic mechanism of the S-scheme BiOBr/ZIF-8/ZnO composite for the degradation of phenolic pollutants and generation of H2O2 was proposed. The formation of the heterojunction and the oxygen vacancy work together to significantly improve its photocatalytic efficiency. In addition, the BiOBr/ZIF-8/ZnO catalyst has a certain impact on the degradation of phenol in actual wastewater, providing a way to effectively remove refractory pollutants and generate H2O2 in actual water.

The role of PI3K/AKT-related proteins in di(2-ethyl)hexylphthalate-induced BG-1 and MCF-7 cell proliferation, and inhibition by metformin.

OBJECTIVE: To investigate the molecular mechanism of the proliferation and migration of BG-1 and MCF-7cells induced by DEHP, and the antagonistic effect of metformin. METHODS: The proliferation, cell cycle progression, migration, and invasion abilities of BG-1 and MCF-7 cancer cells were examined via Cell Counting Kit-8, flow cytometry, Transwell, and scratch assays. E2F1, SKP2, cyclin D1, vimentin, E-cadherin, and GSK-3ß, all of which play key roles in cancer development via the PI3K/AKT signaling pathway, were examined by immunofluorescence and immunocytochemistry. RESULTS: Cell proliferation was significantly increased, and the wound closure and number of trans-membrane migrating cells were significantly increased, by DHEP treatment. The numbers of BG-1 and MCF-7 cells in the G0/G1 phase were significantly decreased, while those in the S phase were significantly increased. Increased E2F1, SKP2, cyclin D1, and vimentin levels and decreased E-cadherin and GSK-3ß levels were detected in BG-1 and MCF-7 cells treated with DEHP compared to that in control cells. Furthermore, DEHP-induced effects were markedly inhibited by LY294002 (a PI3K/AKT inhibitor) or metformin. CONCLUSION: We demonstrated that DEHP-induced cell proliferation and migration involves the PI3K/AKT signaling pathway and that metformin can be used to inhibit this proliferation and migration.

Upregulation of CDGSH iron sulfur domain 2 attenuates cerebral ischemia/reperfusion injury.

CDGSH iron sulfur domain 2 can inhibit ferroptosis, which has been associated with cerebral ischemia/reperfusion, in individuals with head and neck cancer. Therefore, CDGSH iron sulfur domain 2 may be implicated in cerebral ischemia/reperfusion injury. To validate this hypothesis in the present study, we established mouse models of occlusion of the middle cerebral artery and HT22 cell models of oxygen-glucose deprivation and reoxygenation to mimic cerebral ischemia/reperfusion injury in vivo and in vitro, respectively. We found remarkably decreased CDGSH iron sulfur domain 2 expression in the mouse brain tissue and HT22 cells. When we used adeno-associated virus and plasmid to up-regulate CDGSH iron sulfur domain 2 expression in the brain tissue and HT22 cell models separately, mouse neurological dysfunction was greatly improved; the cerebral infarct volume was reduced; the survival rate of HT22 cells was increased; HT22 cell injury was alleviated; the expression of ferroptosis-related glutathione peroxidase 4, cystine-glutamate antiporter, and glutathione was increased; the levels of malondialdehyde, iron ions, and the expression of transferrin receptor 1 were decreased; and the expression of nuclear-factor E2-related factor 2/heme oxygenase 1 was increased. Inhibition of CDGSH iron sulfur domain 2 upregulation via the nuclear-factor E2-related factor 2 inhibitor ML385 in oxygen-glucose deprived and reoxygenated HT22 cells blocked the neuroprotective effects of CDGSH iron sulfur domain 2 up-regulation and the activation of the nuclear-factor E2-related factor 2/heme oxygenase 1 pathway. Our data indicate that the up-regulation of CDGSH iron sulfur domain 2 can attenuate cerebral ischemia/reperfusion injury, thus providing theoretical support from the perspectives of cytology and experimental zoology for the use of this protein as a therapeutic target in patients with cerebral ischemia/reperfusion injury.

Explainable machine learning-assisted origin identification: Chemical profiling of five lotus (Nelumbo nucifera Gaertn.) parts.

Five homologous lotus parts, namely, the leaf, stamen, plumule, flower and leaf base, are all ancient nutrient sources, but their chemical differences are poorly understood. Identification of these parts of origin could contribute to determining reasonable edible and/or medicinal applications without misuse/waste risk. The present work aimed to investigate the feasibility of using metabolic profiles coupled with explainable machine learning (ML) for tracing lotus parts of origin. Assisted with molecular networking, 151 compounds were systematically annotated through an untargeted metabolomics approach. Twenty-eight representative constituents were subsequently quantified for the construction of the ML algorithm. Because most ML algorithms are data-driven black boxes with opaque inner workings, the SHaply Additive exPlanation technique was innovatively used to understand model outputs. By offering an integral analytical platform for phytochemical characterization and information interpretation, these results could serve as a basis for an explainable tool for identification of the specific lotus part of origin.

Progression of hepatocellular carcinoma after radiofrequency ablation: Current status of research.

Hepatocellular carcinoma (HCC) remains an important disease for health care systems in view of its high morbidity, mortality, and increasing incidence worldwide. Radiofrequency ablation (RFA) is preferred to surgery as a local treatment for HCC because it is safer, less traumatic, less painful, better tolerated, causes fewer adverse reactions, and allows more rapid postoperative recovery. The biggest shortcoming of RFA when used to treat HCC is the high incidence of residual tumor, which is often attributed to the vascular thermal deposition effect, the wide infiltration zone of peripheral venules, and the distance between satellite foci and the main focus of the cancer. Recurrence and progression of the residual tumor is the most important determinant of the prognosis. Therefore, it is important to be aware of the risk of recurrence and to improve the efficacy of RFA. This review summarizes the relevant literature and the possible mechanisms involved in progression of HCC after RFA. Current studies have demonstrated that multimodal treatments which RFA combined with other anti-cancer approaches can prevent progression of HCC after RFA.

Circular BANP knockdown inhibits the malignant progression of residual hepatocellular carcinoma after insufficient radiofrequency ablation.

BACKGROUND: Circular RNAs (circRNAs) are endogenous non-coding RNAs, some of which have pathological roles. The current study aimed to explore the role of circRNA BTG3-associated nuclear protein (circ-BANP) binding with let-7f-5p and its regulation of the toll-like receptor 4 (TLR4)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in residual hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA). METHODS: Circ-BANP, let-7f-5p, and TLR4 expressions in HCC samples were assessed using reverse transcription- quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Bioinformatics prediction, RNA pull-down assay, and dual luciferase reporter gene assay were used to analyze the relationships among circ-BANP, let-7f-5p, and TLR4. Huh7 cells were used to generate an in vitro model of residual HCC, defined as Huh7-H cells, which were transfected with either a plasmid or the sequence of circ-BANP, let-7f-5p, or TLR4. Expression of circ-BANP, let-7f-5p, and TLR4 mRNA was determined by RT-qPCR. TLR4, STAT3, p-STAT3, vascular endothelial growth factor A, vascular endothelial growth factor receptor-2, and epithelial-mesenchymal transformation (EMT)-related factors proteins were determined by Western blotting. Cell proliferation was determined by cell counting kit-8 and 5-Ethynyl-2'-deoxyuridine (EdU) assay and cell migration and invasion by Transwell assay. Animal studies were performed by inducing xenograft tumors in nude mice. RESULTS: Circ-BANP and TLR4 mRNAs were upregulated in HCC tissues (the fold change for circ-BANP was 1.958 and that for TLR4 was 1.736 relative to para-tumors) and expression further increased following insufficient RFA (fold change for circ- BANP was 2.407 and that of TLR4 was 2.224 relative to para-tumors). Expression of let-7f-5p showed an opposite tendency (fold change for let-7f-5p in HCC tissues was 0.491 and that in tumors after insufficient RFA was 0.300 relative to para-tumors). Competitive binding of circ-BANP to let-7f-5p was demonstrated and TLR4 was identified as a target of let-7f-5p (P < 0.01). Knockdown of circ-BANP or elevation of let-7f-5p expression inhibited the TLR4/STAT3 signaling pathway, proliferation, invasion, migration, angiogenesis, and EMT in Huh7 and Huh7-H cells (P < 0.01). The effects induced by circ-BANP knockdown were reversed by let-7f-5p inhibition. Overexpression of TLR4 reversed the impact of let-7f-5p upregulation on the cells (P < 0.01). Silencing of circ-BANP inhibited the in vivo growth of residual HCC cells after insufficient RFA (P < 0.01). CONCLUSIONS: Knockdown of circ-BANP upregulated let-7f-5p to inhibit proliferation, migration, and EMT formation in residual HCC remaining after insufficient RFA. Effects occur via regulation of the TLR4/STAT3 signaling pathway.

Arsenic trioxide inhibits angiogenesis of hepatocellular carcinoma after insufficient radiofrequency ablation via blocking paracrine angiopoietin-1 and angiopoietin-2.

OBJECTIVES: Angiogenesis occurs during tumor progression of hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA). Arsenic trioxide (ATO) shows promising therapeutic potential in advanced HCC. Whether ATO regulates angiogenesis and can be used to prevent tumor progression in HCC after insufficient RFA is still unknown. METHODS: Insufficient RFA was simulated using a water bath. MTT assay and tube formation assay were used to evaluate the effects of ATO on viability and proangiogenic abilities of SMMC7721 and HepG2 cells after insufficient RFA in vitro. The molecular changes with the treatment of ATO were evaluated through Western blot. An ectopic nude mice model was used to evaluate the effect of ATO on the tumor of SMMC7721 cells in vivo after insufficient RFA. RESULTS: In this study, HepG2 and SMMC7721 cells after insufficient RFA (named HepG2-H and SMMC7721-H, respectively) showed higher proliferation than the untreated cells and promoted tube formation of endothelial cells in a paracrine manner. ATO eliminated the difference in proliferation between untreated and RFA-treated cells and suppressed angiogenesis induced by HCC cells after insufficient RFA through the Ang-1 (angiopoietin-1)/Ang-2 (angiopoietin-2)/Tie2 pathway. Hif-1α overexpression abolished the inhibitory effect of ATO on angiogenesis in HCC after insufficient RFA. ATO inhibited tumor growth and angiogenesis in HCC after insufficient RFA. CONCLUSIONS: Our results demonstrate that ATO blocks the paracrine signaling of Ang-1 and Ang-2 by inhibiting p-Akt/Hif-1α and further suppresses the angiogenesis of HCC after insufficient RFA.

Dexmedetomidine exerts its protective effect on cerebral ischemia reperfusion injury in mice by inhibiting ferroptosis. / å³ç¾Žæ‰˜å’ªå®šé€šè¿‡æŠ‘åˆ¶é“æ­»äº¡å‘æŒ¥å¯¹å°é¼ è„‘ç¼ºè¡€å†çŒæ³¨æŸä¼¤çš„ä¿æŠ¤ä½œç”¨.

OBJECTIVES: Stroke is one of the major diseases that can threaten human life and health. The incidence of ischemic stroke accounts for more than 70% of stroke. The mechanism of ischemia reperfusion (IR) injury caused by ischemic stroke is extremely complex. In recent years, dexmedetomidine has been increasingly studied in anti-cerebral IR injury as a common clinical anesthetic adjunct, but its specific mechanism is not fully understood. Therefore, this study aims to explore the effects and mechanisms of dexmedetomidine on cerebral IR injury in mice. METHODS: The mouse middle cerebral artery occlusion (MCAO) model was prepared by modified suture method. Male ICR mice were randomly divided into a sham group, an IR group, an IR+D1 group (IR+administered 25 µg/kg dexmedetomidine), an IR+D2 group(IR+administered 50 µg/kg dexmedetomidine), an IR+D3 group (IR+administered 100 µg/kg dexmedetomidine), and an IR+D2+ML385 group (IR+administered 50 µg/kg dexmedetomidine and 30 mg/kg ML385). The neurologic behavior of mice was evaluated by Longa's five-point method. 2,3,5-triphenyltetrazolium chloride (TTC) staining was used to detect the percentage of cerebral infarct volume in mice. The protein expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), transferrin receptor 1 (TFR1), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11) in the cerebral tissues of mice were detected by Western blotting.Mitochondrial morphology was observed under the transmission electron microscope. The contents of MDA, Fe2+, and GSH in the cerebral tissues of mice were detected. RESULTS: Compared with the sham group, neurobehavioral scores, cerebral infarct volume, the contents of MDA and Fe2+, as well as the protein expression of TFR1 were significantly increased; the contents of GSH and the protein expression of SLC7A11 and GPX4 were significantly reduced (all P<0.05); mitochondria in cerebral tissue were wrinkled, cristae were reduced, and membrane density was increased in the IR group. Compared with the IR group, neurobehavioral scores, cerebral infarction volume, MDA and Fe2+ contents, as well as the protein expression of TFR1 were significantly reduced; the contents of GSH and the protein expression of SLC7A11 and GPX4 were significantly increased (all P<0.05); mitochondrial damage in cerebral tissue was significantly relieved with the pre-treatment of dexmedetomidine. Compared with the IR+D2 group, neurobehavioral scores, cerebral infarction volume, MDA and Fe2+ contents, as well as the protein expression of TFR1 were significantly increased; the contents of GSH and the protein expression of SLC7A11 and GPX4 were significantly reduced (all P<0.05);mitochondria reappeared significantly damaged with the ML385 on the basis of dexmedetomidine pre-treatment. CONCLUSIONS: The protective effect of dexmedetomidine on cerebral IR injury mice is related to its inhibition of ferroptosis, and the mechanism might be related to its regulation of Nrf2 expression.

Pannexin1 inhibits autophagy of cisplatin-resistant testicular cancer cells by mediating ATP release.

Pannexin1 (Panx-1) is a gap junction channel protein that mediates the release of intracellular ATP during autophagy, and thus plays an important role in tumor cell apoptosis and chemo-resistance. However, the role of Panx-1 in cisplatin-resistance of testicular cancer cells remains unclear. We found that cisplatin-resistant I-10 testicular cancer cell lines (I-10/CDDP) autophagy-associated proteins (p62, p-mTOR, mTOR and LC3) exhibited high levels of autophagy in their expression, while LC3-II expression was more significantly in the presence of lysosomal degradation blocked by chloroquine (CQ). Xenograft models using I-10/CDDP cells with knockdown ATG5 and ATG7 were established in mouse models and showed blockade of autophagic flux and inhibition of tumor growth. In addition, inhibition of Panx-1 by carbenoxolone (CBX) and probenecid (PBN), as well as shRNA-mediated knockdown promoted autophagy in the I-10/CDDP cells, which was accompanied by a decrease in the levels of extracellular ATP. In contrast, overexpression of Panx-1 decreased autophagy of I-10/CDDP cells and increased extracellular ATP levels. To further determine the effect of panx-1-mediated ATP release on the autophagy of I-10/CDDP cells, apyrase was used to hydrolyze the extracellular ATP. Apyrase promoted autophagy in I-10/CDDP cells city by decreasing extracellular ATP, regardless of Panx-1 expression. This study demonstrated for the first time that Panx-1-mediated ATP release inhibits autophagy of I-10/CDDP cells, which provides a potential therapeutic strategy for cisplatin-resistant testicular cancer.

Role of SPAK-NKCC1 signaling cascade in the choroid plexus blood-CSF barrier damage after stroke.

BACKGROUND: The mechanisms underlying dysfunction of choroid plexus (ChP) blood-cerebrospinal fluid (CSF) barrier and lymphocyte invasion in neuroinflammatory responses to stroke are not well understood. In this study, we investigated whether stroke damaged the blood-CSF barrier integrity due to dysregulation of major ChP ion transport system, Na+-K+-Cl- cotransporter 1 (NKCC1), and regulatory Ste20-related proline-alanine-rich kinase (SPAK). METHODS: Sham or ischemic stroke was induced in C57Bl/6J mice. Changes on the SPAK-NKCC1 complex and tight junction proteins (TJs) in the ChP were quantified by immunofluorescence staining and immunoblotting. Immune cell infiltration in the ChP was assessed by flow cytometry and immunostaining. Cultured ChP epithelium cells (CPECs) and cortical neurons were used to evaluate H2O2-mediated oxidative stress in stimulating the SPAK-NKCC1 complex and cellular damage. In vivo or in vitro pharmacological blockade of the ChP SPAK-NKCC1 cascade with SPAK inhibitor ZT-1a or NKCC1 inhibitor bumetanide were examined. RESULTS: Ischemic stroke stimulated activation of the CPECs apical membrane SPAK-NKCC1 complex, NF-κB, and MMP9, which was associated with loss of the blood-CSF barrier integrity and increased immune cell infiltration into the ChP. Oxidative stress directly activated the SPAK-NKCC1 pathway and resulted in apoptosis, neurodegeneration, and NKCC1-mediated ion influx. Pharmacological blockade of the SPAK-NKCC1 pathway protected the ChP barrier integrity, attenuated ChP immune cell infiltration or neuronal death. CONCLUSION: Stroke-induced pathological stimulation of the SPAK-NKCC1 cascade caused CPECs damage and disruption of TJs at the blood-CSF barrier. The ChP SPAK-NKCC1 complex emerged as a therapeutic target for attenuating ChP dysfunction and lymphocyte invasion after stroke.