Effect of tannic acid binding on the thermal degradation behavior and product toxicity of boscalid.

The effect of tannic acid (TA) binding on the thermal degradation of boscalid was studied in this work. The results revealed that TA binding has a significant impact on boscalid degradation. The degradation rate constant of bound boscalid was reduced, and its corresponding half-life was significantly prolonged compared to the free state. Four identical degradation products were detected in both states through UHPLC-Q-TOF-MS, indicating that degradation products were not affected by TA binding. Based on DFT and MS analysis, the degradation pathways of boscalid included hydroxyl substitution of chlorine atoms and cleavage of CN and CC bonds. The toxicity of B2 and B3 exceeded that of boscalid. In summary, the binding of TA and boscalid significantly affected the thermal degradation rate of boscalid while preserving the types of degradation products. This study contributed to a fundamental understanding of the degradation process of bound pesticide residues in complex food matrices.

Methylseleninic acid inhibits human glioma growth in vitro and in vivo by triggering ROS-dependent oxidative damage and apoptosis.

Selenium-containing agents showed novel anticancer activity by triggering pro-oxidative mechanism. Studies confirmed that methylseleninic acid (MeSe) displayed broad-spectrum anti-tumor activity against kinds of human cancers. However, the anticancer effects and mechanism of MeSe against human glioma growth have not been explored yet. Herein, the present study showed that MeSeA dose-dependently inhibited U251 and U87 human glioma cells growth in vitro. Flow cytometry analysis indicated that MeSe induced significant U251 cells apoptosis with a dose-dependent manner, followed by the activation of caspase-7, caspase-9 and caspase-3. Immunofluorescence staining revealed that MeSe time-dependently caused reactive oxide species (ROS) accumulation and subsequently resulted in oxidative damage, as convinced by the increased phosphorylation level of Ser428-ATR, Ser1981-ATM, Ser15-p53 and Ser139-histone. ROS inhibition by glutathione (GSH) effectively attenuated MeSe-induced ROS generation, oxidative damage, caspase-3 activation and cytotoxicity, indicating that ROS was an upstream factor involved in MeSe-mediated anticancer mechanism in glioma. Importantly, MeSe administration in nude mice significantly inhibited glioma growth in vivo by inducing apoptosis through triggering oxidative damage. Taken together, our findings validated the possibility that MeSe as a selenium-containing can act as potential tumor chemotherapy agent for therapy of human glioma.

Hexavalent Chromium Induces Neurotoxicity by Triggering Mitochondrial Dysfunction and ROS-Mediated Signals.

Hexavalent chromium (Cr (VI)), one of the most detrimental pollutants, has been ubiquitously present in the environment and causes serious toxicity to humans, such as hepatotoxicity, nephrotoxicity, pulmonary toxicity, and cardiotoxicity. However, Cr (VI)-induced neurotoxicity in primary neuron level has not been well explored yet. Herein, potassium dichromate (K2Cr2O7) was employed to examine the neurotoxicity of Cr (VI) in rat primary hippocampal neurons. MTT test was used to examine the neural viability. Mitochondrial dysfunction was assessed by the JC-1 probe and Mito-Tracker probe. DCFH-DA and Mito-SOX Red were utilized to evaluate the oxidative status. Bcl-2 family and MAPKs expression were investigated using Western blotting. The results demonstrated that Cr (VI) treatment dose- and time-dependently inhibited neural viability. Mechanism investigation found that Cr (VI) treatment causes mitochondrial dysfunction by affecting Bcl-2 family expression. Moreover, Cr (VI) treatment also induces intracellular reactive oxygen species (ROS) generation, DNA damage, and MAPKs activation in neurons. However, inhibition of ROS by glutathione (GSH) effectually balanced Bcl-2 family expression, attenuated DNA damage and the MAPKs activation, and eventually improved neural viability neurons. Collectively, these above results above suggest that Cr (VI) causes significant neurotoxicity by triggering mitochondrial dysfunction, ROS-mediated oxidative damage and MAKPs activation.

[Clinical application of percutaneous pedicle screw placement guided by ultrasound volume navigation combined with X-ray fluoroscopy: a prospective randomized controlled study].

Objective: To explore the feasibility and accuracy of ultrasound volume navigation (UVN) combined with X-ray fluoroscopy-guided percutaneous pedicle screw implantation through a prospective randomized controlled study. Methods: Patients with thoracic and lumbar vertebral fractures scheduled for percutaneous pedicle screw fixation between January 2022 and January 2023 were enrolled. Among them, 60 patients met the selection criteria and were included in the study. There were 28 males and 32 females, with an average age of 49.5 years (range, 29-60 years). The cause of injury included 20 cases of traffic accidents, 21 cases of falls, 17 cases of slips, and 2 cases of heavy object impact. The interval from injury to hospital admission ranged from 1 to 5 days (mean, 1.57 days). The fracture located at T 12 in 15 cases, L 1 in 20 cases, L 2 in 19 cases, and L 3 in 6 cases. The study used each patient as their own control, randomly guiding pedicle screw implantation using UVN combined with X-ray fluoroscopy on one side of the vertebral body and the adjacent segment (trial group), while the other side was implanted under X-ray fluoroscopy (control group). A total of 4 screws and 2 rods were implanted in each patient. The implantation time and fluoroscopy frequency during implantation of each screw, angle deviation and distance deviation between actual and preoperative planned trajectory by imaging examination, and the occurrence of zygapophysial joint invasion were recorded. Results: In terms of screw implantation time, fluoroscopy frequency, angle deviation, distance deviation, and incidence of zygapophysial joint invasion, the trial group showed superior results compared to the control group, and the differences were significant ( P<0.05). Conclusion: UVN combined with X-ray fluoroscopy-guided percutaneous pedicle screw implantation can yreduce screw implantation time, adjust dynamically, reduce operational difficulty, and reduce radiation damage.

Early screening of nasopharyngeal carcinoma.

The low positive predictive value (PPV) of early screening of nasopharyngeal carcinoma (NPC) is the problems that need to be solved urgently. The combination of cell-free DNA (cfDNA) methylation testing and Epstein-Barr virus (EBV) serological testing is the key to solve this problem. This paper reviews recent advances in early screening for NPC and cfDNA methylation, with future perspectives. Pubmed was searched for the literature related to early screening of NPC and cfDNA methylation in the past 5 years. The results of these studies were summarized. Despite these efforts, the PPV is still low (10%). Previous studies have shown that cfDNA methylation analysis has good specificity and accuracy across a variety of tumors. The combination of cfDNA methylation and EBV detection helps to improve the PPV for early screening of NPC. The combination of cfDNA methylation and EBV serological testing is key to addressing the low PPV of NPC early screening.

Vitamin B ameliorates PM2.5-induced kidney damage by reducing endoplasmic reticulum stress and oxidative stress in pregnant mice and HK-2.

As an air pollutant, particulate matters 2.5 (PM2.5) poses a severe risk to kidney and the mechanism involves oxidative stress and endoplasmic reticulum (ER) stress. As an essential nutrient for human health, Vitamin B performs anti-inflammatory and antioxidant functions. In order to study the effect of Vitamin B on PM2.5-induced kidney damage during pregnancy, the pregnant mice were divided into the four experimental groups randomly: control group, model group, treatment group and VB group. PM2.5 was sprayed on the trachea of pregnant mice once each three days for six times from pregnancy until delivery. The model group was given 30 µL PM2.5 suspension of 3.456 µg/µL and 10 mL/(kg·d) PBS. The treatment group was given 30 µL PM2.5 suspension of 3.456 µg/µL and 10 mL/(kg·d) Vitamin B. The VB group was given 10 mL/(kg·d) Vitamin B and the control group was given the same dose of PBS. Vitamin B was composed of Vitamin B6, Vitamin B12 and folic acid, with final concentrations are 1.14, 0.02 and 0.06 mg/mL, respectively. The results showed Vitamin B ameliorated PM2.5-induced kidney damage such as improving histopathological change, decreasing expressions of Bip and Chop, increasing expressions of Nrf2, HO-1 and Nqo1. In addition, HK-2 cells were used for cell experiments and were divided into the four groups, in which the dosage of PM2.5 was 75 µg/mL for 24 h and Vitamin B was 5 µL/100 µL. The results showed Vitamin B ameliorated PM2.5-induced HK-2 damage, such as decreasing expressions of Bip, Chop, P47phox and ROS, increasing expressions of Nrf2, HO-1, Nqo1 and NO. Our findings showed Vitamin B ameliorated PM2.5-induced kidney damage by reducing ER stress and oxidative stress in pregnant mice and in HK-2.

EIF4A3-induced circZFAND6 promotes breast cancer proliferation and metastasis through the miR-647/FASN axis.

AIMS: Circular RNAs (circRNAs) are important regulators in breast cancer progression. However, the underlying mechanism of circRNAs functions in breast cancer remain largely unclear. MAIN METHODS: To investigate the circRNAs expression pattern in breast cancer, high-throughput circRNA microarray assay was used. The top up-regulated circRNA, circZFAND6, was submitted to further experiments, including cell counting kit-8 (CCK-8) assay, colony formation assay, transwell assay and mouse xenograft assay. To investigate the underlying mechanism of circZFAND6 function in breast cancer progression, luciferase reporter assay and RNA immunoprecipitation (RIP) assay were conducted. KEY FINDINGS: We found a novel circRNA, circZFAND6, was up-regulated in breast cancer tissues and cell lines. Inhibition of circZFAND6 reduced proliferation and metastasis of breast cancer. Mechanically, circZFAND6 acted as a competing endogenous RNA (ceRNA) to sponge miR-647 and increase fatty acid synthase (FASN) expression. And eukaryotic translation initiation factor 4A3 (EIF4A3) was found to bind to circZFAND6 pre-mRNA transcript upstream region, leading to the high expression of circZFAND6 in breast cancer. Inhibition of EIF4A3 also suppressed proliferation and metastasis of breast cancer. SIGNIFICANCE: EIF4A3-induced circZFAND6 up-regulation promoted proliferation and metastasis of breast cancer through the miR-647/FASN axis. Our results uncovered a possible mechanism underlying breast cancer progression and might provide a breast cancer treatment target.

Metabolic engineering for the biosynthesis of bis-indolylquinone terrequinone A in Escherichia coli from L-tryptophan and prenol.

BACKGROUND: Terrequinone A is a bis-indolylquinone natural product with antitumor activity. Due to its unique asymmetric quinone core structure and multiple functional groups, biosynthesis is more efficient and environmentally friendly than traditional chemical synthesis. Currently, most bis-indolylquinones are obtained by direct extraction from fungi or by chemical synthesis. By focusing on the biosynthesis of terrequinone A, we hope to explore the way to synthesize bis-indolylquinones de novo using Escherichia coli as a cell factory. RESULTS: In this study, a terrequinone A synthesis pathway containing the tdiA-tdiE genes was constructed into Escherichia coli and activated by a phosphopantetheinyl transferase gene sfp, enabling the strain to synthesize 1.54 mg/L of terrequinone A. Subsequently, a two-step isopentenol utilization pathway was introduced to enhance the supply of endogenous dimethylallyl diphosphate (DMAPP) in E. coli, increasing the level of terrequinone A to 20.1 mg/L. By adjusting the L-tryptophan (L-Trp)/prenol ratio, the major product could be changed from ochrindole D to terrequinone A, and the content of terrequinone A reached the highest 106.3 mg/L under the optimized culture conditions. Metabolic analysis of L-Trp indicated that the conversion of large amounts of L-Trp to indole was an important factor preventing the further improvement of terrequinone A yield. CONCLUSIONS: A comprehensive approach was adopted and terrequinone A was successfully synthesized from low-cost L-Trp and prenol in E. coli. This study provides a metabolic engineering strategy for the efficient synthesis of terrequinone A and other similar bis-indolylquinones with asymmetric quinone cores. In addition, this is the first report on the de novo biosyhthesis of terrequinone A in an engineered strain.

Characterization of the interaction between boscalid and tannic acid and its effect on the antioxidant properties of tannic acid.

The binding of pesticide residues and fruit components may have a profound impact on pesticide dissipation and the functional characteristics of the corresponding components. Therefore, the interaction between boscalid and tannic acid (TA, a representative phenolic in fruit) was systematically investigated using spectroscopic, thermodynamic, and computational chemistry methods. A separable system was designed to obtain the boscalid-TA complex. Fourier transform infrared and 1 H-NMR spectroscopies indicated the formation of hydrogen bonds in the complex. Isothermal titration calorimetry showed that the complex bound spontaneously through hydrophobic interactions (ΔG < 0, ΔH > 0, ΔS > 0), with a binding constant of 6.0 × 105  M-1 at 298 K. The molecular docking results further confirmed the formation of hydrogen bonds and hydrophobic interactions in the complex at the molecular level, with a binding energy of -8.43 kcal mol-1 . In addition, the binding of boscalid to TA significantly decreased the antioxidant activity of TA. The binding of boscalid residue to TA was characterized at the molecular level, which significantly reduced the in vitro antioxidant properties of TA. PRACTICAL APPLICATION: This study provides a reference for the molecular mechanisms of the interaction between pesticide residues and food matrices, as well as a basis for regulating bound-state pesticide residues in food.

Long Non-Coding RNA LINC00052 Targets miR-548p/Notch2/Pyk2 to Modulate Tumor Budding and Metastasis of Human Breast Cancer.

Abnormal expression of long non-coding RNAs (lncRNAs) is involved in many pathological processes of cancers. However, the role of lncRNA LINC00052 in breast cancer progression is still unclear. Here, LINC00052 expression was detected by in situ hybridization and quantitative real-time PCR assays. Cell Counting Kit-8, wound healing, and transwell assays were used to investigate changes in the proliferation, migration, and invasion of breast cancer cells. MiR-548p was found associated with LINC00052 or Notch2 by RNA pull-down, dual-luciferase reporter, and qRT-PCR assays. The effect of LINC00052 on lung metastasis was explored through in vivo experiments. High LINC00052 expression was observed in breast cancer tissues and cells. LINC00052 silencing inhibited the proliferation, migration, and invasion of MCF7 cells, and LINC00052 overexpression produced the opposite results. MiR-548p, a target gene of LINC00052, partially rescued the effects of LINC00052 on proliferation, migration, and invasion of MCF7. Notch2 was the target of miR-548p and LINC00052 could promote Notch2 expression. Moreover, the phosphorylation of proline-rich tyrosine kinase 2 (Pyk2), a downstream factor of Notch2, was increased by LINC00052, and a Pyk2 mutant could inhibit the cell migration and invasion induced by LINC00052 overexpression in MDA-MB-468 cells, which was similar to the function of the miR-548p mimic. We further demonstrated that LINC00052 exacerbated the metastases of breast cancer cells in vivo. Our research demonstrated that LINC00052 is highly expressed in breast cancer and promotes breast cancer proliferation, migration, and invasion via the miR-548p/Notch2/Pyk2 axis. LINC00052 could serve as a potential therapeutic target for breast cancer.

Skimmin ameliorates cardiac function via the regulation of M2 macrophages in a myocardial infarction mouse model.

PURPOSE: Myocardial infarction (MI) is a coronary artery disorder with several complications, such as inflammation, oxidative stress, and cardiac fibrosis. The current study is aimed to explore the protective effect of skimmin (SKI) on impaired heart tissues in MI. METHODS: A mouse model of MI was induced by ligation of the left anterior descending artery. SKI was intragastric administration for 7 days after MI. Masson staining was then conducted to measure the area of fibrosis in the myocardium. The expression levels of collagen I and collagen III were analyzed using Western blot. The levels of glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), and inflammatory factor were also detected. The expression of M1 polarization markers and M2 polarization markers in mice and LPS-induced RAW264.7 cells were detected using RT-qPCR and Western blot, respectively. Finally, the migration and proliferation of vascular smooth muscle cells (VSMCs) in vitro were analyzed using transwell and EDU, respectively. RESULTS: SKI improved cardiac function and cardiac fibrosis in mice with MI. SKI also decreased collagen I and collagen III expression, and inhibited inflammatory factor TNF-α, IL-1ß, and IL-6 levels. SKI decreased the levels of MDA and increased the levels of GSH and SOD. Meanwhile, SKI could promote M2 macrophage polarization in vivo and in vitro. SKI could also repress the migration and proliferation of VSMCs. CONCLUSIONS: SKI may ameliorate inflammation, oxidative stress, and cardiac fibrosis of MI by promoting M2 polarization.

Light-Activated Gold-Selenium Core-Shell Nanocomposites with NIR-II Photoacoustic Imaging Performances for Heart-Targeted Repair.

Mitochondrial dysfunction and oxidative damage represent important pathological mechanisms of myocardial ischemia-reperfusion injury (MI/RI). Searching for potential antioxidant agents to attenuate MI/RI is of great significance in clinic. Herein, gold-selenium core-shell nanostructures (AS-I/S NCs) with good near-infrared (NIR)-II photoacoustic imaging were designed for MI/RI treatment. The AS-I/S NCs after ischemic myocardium-targeted peptide (IMTP) and mitochondrial-targeted antioxidant peptide SS31 modification achieved cardiomyocytes-targeted cellular uptake and enhanced antioxidant ability and significantly inhibited oxygen-glucose deprivation-recovery (OGD/R)-induced cardiotoxicity of H9c2 cells by inhibiting the depletion of mitochondrial membrane potential (MMP) and restoring ATP synthase activity. Furthermore, the AS-I/S NCs after SS31 modification achieved mitochondria-targeted inhibition of reactive oxygen species (ROS) and subsequently attenuated oxidative damage in OGD/R-treated H9c2 cells by inhibition of apoptosis and oxidative damage, regulation of MAPKs and PI3K/AKT pathways. The in vivo AS-I/S NCs administration dramatically improved myocardial functions and angiogenesis and inhibited myocardial fibrosis through inhibiting myocardial apoptosis and oxidative damage in MI/RI of rats. Importantly, the AS-I/S NCs showed good safety and biocompatibility in vivo. Therefore, our findings validated the rational design that mitochondria-targeted selenium-gold nanocomposites could attenuate MI/RI of rats by inhibiting ROS-mediated oxidative damage and regulating MAPKs and PI3K/AKT pathways, which could be a potential therapy for the MI/RI treatment.

NT157 inhibits cell proliferation and sensitizes glioma cells to TRAIL-induced apoptosis by up-regulating DR5 expression.

NT157, a small-molecule tyrosine kinase inhibitor, exhibits broad-spectrum anti-tumor activity. However, NT157-mediated inhibition against glioma has not been explored yet. Herein, the anticancer effects and underlying mechanism of NT157 against human giloma growth were evaluated. The results showed that NT157 alone significantly inhibited glioma cells growth in vitro by lunching cell cycle arrest through up-regulating p21 and p27, and down-regulating cell cycle-related factors. NT157 alone also induced significant glioma cells apoptosis, followed by PARP cleavage and caspase-3 activation. Our findings further revealed that NT157 triggered significant DNA damage and dysfunction of PI3K/AKT, MAPKs and EGFR-STAT3 signaling pathways. Addition of several kinases inhibitors effectively abrogated NT157-induced DR5 up-regulation, which further confirmed the significant role of DR5 pathway. Moreover, combined treatment of NT157 and TRAIL showed enhanced apoptosis against U251 and U87 cells. However, Knockdown of DR5 expression significantly attenuated combined treatment-induced PARP cleavage and caspase-3 activation. Importantly, combined administration of NT157 and TRAIL in vivo effectively inhibited glioma xenograft growth of nude mice by inhibiting cell proliferation and angiogenesis, and inducing DNA damage and apoptosis. Taken together, our findings validated the rational design that combined strategy of NT157 and TRAIL to trigger DNA damage and apoptosis by up-regulating DR5 could be a high efficient way to combat human glioma.

Step-by-Step Method Combined with Simulation-Enhanced Learner Outcomes in Minimally Invasive Breast Surgery Education.

Purpose: Traditional standardized training in ultrasound-guided minimally invasive breast surgery (UMIBS) focused on lecture-based learning (LBL) resulted in students' insufficient analysis, limited spatial visual conversion ability, and poor practical application. This study examined the effects of the step-by-step (SBS) method combined with a simulation model in UMIBS education. Subjects and Methods: A total of 84 residents participated in this study. The residents were divided into the SBS group (experience group, n=42) and the LBL group (control group, n=42), and the same teacher taught the two groups to ensure a comparable result. Based on the pork simulation model, two experts evaluated student performance scores, and the total time taken by each student was also counted. The participants were surveyed with 7 questions after the training, and each answer was assigned a score of 1, 2 or 3 to compare the participants' satisfaction. Results: The average value of the surgical skills for SBS group were significantly higher than LBS group, which was 82.8±4.4 and 72.7±4.0 (t=4.27, P<0.001), the time spend of neoplasm localization by the experience group was significantly less than the control group, which was 17.9±1.6 and 20.9±1.2 secs, (t=1.58, P<0.001), and there were significant differences in puncture accuracy and excision integrity between the two groups (P<0.05). In addition, the results of the questionnaire survey showed that learning interest, surgical ability and satisfaction were better in the SBS group than in the LBS group (P<0.05), and there were no significant differences in clinical thinking and learning pressure between the two groups. Conclusion: The SBS teaching method may help to improve the surgical skills and learning interest, as well as reduce adverse reactions and cultivate clinical thinking of the students in UMIBS training. Future studies could consider multicenter clinical research to further confirm the practicality of this teaching method and reduce the risk of deviation.

Exosomal HMGA2 protein from EBV-positive NPC cells destroys vascular endothelial barriers and induces endothelial-to-mesenchymal transition to promote metastasis.

Increased vascular permeability facilitates metastasis. Cancer-secreted exosomes are emerging mediators of cancer-host crosstalk. Epstein-Barr virus (EBV), identified as the first human tumor-associated virus, plays a crucial role in metastatic tumors, especially in nasopharyngeal carcinoma (NPC). To date, whether and how exosomes from EBV-infected NPC cells affect vascular permeability remains unclear. Here, we show that exosomes from EBV-positive NPC cells, but not exosomes from EBV-negative NPC cells, destroy endothelial cell tight junction (TJ) proteins, which are natural barriers against metastasis, and promote endothelial-to-mesenchymal transition (EndMT) in endothelial cells. Proteomic analysis revealed that the level of HMGA2 protein was higher in exosomes derived from EBV-positive NPC cells compared with that in exosomes derived from EBV-negative NPC cells. Depletion of HMGA2 in exosomes derived from EBV-positive NPC cells attenuates endothelial cell dysfunction and tumor cell metastasis. In contrast, exosomes from HMGA2 overexpressing EBV-negative NPC cells promoted these processes. Furthermore, we showed that HMGA2 upregulates the expression of Snail, which contributes to TJ proteins reduction and EndMT in endothelial cells. Moreover, the level of HMGA2 in circulating exosomes is significantly higher in NPC patients with metastasis than in those without metastasis and healthy negative controls, and the level of HMGA2 in tumor cells is associated with TJ and EndMT protein expression in endothelial cells. Collectively, our findings suggest exosomal HMGA2 from EBV-positive NPC cells promotes tumor metastasis by targeting multiple endothelial TJ and promoting EndMT, which highlights secreted HMGA2 as a potential therapeutic target and a predictive marker for NPC metastasis.

CCL18 promotes breast cancer progression by exosomal miR-760 activation of ARF6/Src/PI3K/Akt pathway.

The small GTPase ADP-ribosylation factor 6 (ARF6) mediates chemokine (C-C motif) ligand 18 (CCL18)-induced activation of breast cancer (BC) metastasis through its downstream effector AMAP1. However, the molecular mechanisms underlying CCL18 up-regulating ARF6 remain largely unclear. Here, microRNAs (miRNAs) that target ARF6 were predicted and selected in high metastatic BC cells treated with CCL18. Next, we assessed the role of exosomal miR-760 in vitro and in vivo. We further analyzed the expression of ARF6, AMAP1, and phosphorylated (p)-AMAP1 in tumor and adjacent normal tissues. We first observed that CCL18 increased the expression of ARF6 and p-AMAP1 and activated the Src/phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. ARF6 knockdown significantly impaired CCL18-induced malignant cellular behaviors and the Src/PI3K/Akt signaling pathway. Next, ARF6 was confirmed as a target gene of miR-760 in exosomes derived from CCL18-stimulated high metastatic BC cells. Moreover, recipient MCF-7 cells could effectively uptake these miR-760-rich exosomes that significantly promoted proliferation, tumor growth in vivo, migration, invasion, and chemoresistance by activating ARF6-mediated Src/PI3K/Akt signaling and the epithelial-mesenchymal transition (EMT) pathway. Together, our results support that exosomal miR-760 secreted by CCL18-stimulated high metastatic BC cells promoted the malignant behaviors in low metastatic BC cells by up-regulating the ARF6-mediated Src/PI3K/Akt signaling pathway.

Enhanced phytoremediation of selenium using genetically engineered rice plants.

Selenium (Se) is a micronutrient essential for human and animal health. However, Se is toxic at high levels because the nonspecific substitution of cysteine by selenocysteine could lead to protein malfunction. In an attempt to prevent nonspecific selenocysteine incorporation into proteins, we simultaneously overexpressed the gene encoding selenocysteine lyase from Homo sapiens (HsSL), which specifically catalyzes the decomposition of selenocysteine into elemental Se0 and alanine, and the gene encoding selenocysteine methyltransferase from Astragalus bisulcatus (AbSMT), which methylates selenocysteine into methylselenocysteine in rice. The transgenic plants showed normal growth under standard conditions. Se treatment resulted in higher levels of alanine and methylselenocysteine in transgenic plants than in wild-type plants, which indicated that this approach might have successfully redirected Se flow in the plant. Overexpression of HsSL and AbSMT in rice also endows transgenic plants with hyposensitivity to Se stress at the seed germination stage. The transgenic plants showed enhanced selenate and selenite tolerance, which was simultaneously supported by fresh weight values. Moreover, our phytoremediation assay revealed that the transgenic plants exhibited greatly improved Se elimination capabilities and accumulated about 38.5% and 128.6% more Se than wild-type plants when treated with selenate and selenite, respectively. This study offers hope that genetically modified plants could play a role in the restoration of Se-contaminated environment.

Inhibitor of glutamine metabolism V9302 promotes ROS-induced autophagic degradation of B7H3 to enhance antitumor immunity.

Despite the enormous successes of anti-PD-1/PD-L1 immunotherapy in multiple other cancer types, the overall response rates of breast cancer remain suboptimal. Therefore, exploring additional immune checkpoint molecules for potential cancer treatment is crucial. B7H3, a T-cell coinhibitory molecule, is specifically overexpressed in breast cancer compared with normal breast tissue and benign lesions, making it an attractive therapeutic target. However, the mechanism by which B7H3 contributes to the cancer phenotype is unclear. Here we show that the expression of B7H3 is negatively related to the number of CD8+ T cells in breast tumor sites. In addition, analysis of the differentially expressed B7H3 reveals that it is inversely correlated to autophagic flux both in breast cancer cell lines and clinical tumor tissues. Furthermore, block of autophagy by bafilomycin A1 (Baf A1) increases B7H3 levels and attenuates CD8+ T cell activation, while promotion of autophagy by V9302, a small-molecule inhibitor of glutamine metabolism, decreases B7H3 expression and enhances granzyme B (GzB) production of CD8+ T cells via regulation of reactive oxygen species (ROS) accumulation. We demonstrate that combined treatment with V9302 and anti-PD-1 monoclonal antibody (mAb) enhances antitumor immunity in syngeneic mouse models. Collectively, our findings unveil the beneficial effect of V9302 in boosting antitumor immune response in breast cancer and illustrate that anti-PD-1 together with V9302 treatment may provide synergistic effects in the treatment of patients insensitive to anti-PD-1 therapy.

Enhanced recovery after surgery management of perioperative period in surgical lung cancer patients: protocol for a systematic review and meta-analysis of randomised controlled trials.

INTRODUCTION: Enhanced recovery after surgery (ERAS) has been widely used in the perioperative period of lung cancer surgery. However, there remains a lack of comprehensive and systematic evidence on the effectiveness and safety of ERAS. This study aims to evaluate the efficacy and safety of ERAS in patients with lung cancer. METHODS AND ANALYSIS: Eight databases (PubMed, Web of Science, Embase, Cochrane Library, CNKI, CBM, VIP and WANFANG) will be searched from inception to November 2021. Two reviewers will independently screen studies, extract data of interest and assess the risk of bias. The revised risk of bias tool 2 will be used to assess the risk of bias in randomised controlled trials. We will use the Grading of Recommendations, Assessment, Development and Evaluations to assess the certainty of evidence. We will carry out a random-effect meta-analysis focusing on the efficacy and safety variables. All analyses will be conducted using RevMan V.5.3. ETHICS AND DISSEMINATION: Since the study will be a systematic review and will not involve direct contact with patients or make alterations to patient care, ethical approval and informed consent are not required for this study. The results of this review will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42021250761.

Epstein-Barr Virus Induces Lymphangiogenesis and Lympth Node Metastasis via Upregulation of VEGF-C in Nasopharyngeal Carcinoma.

Lymphatic metastasis is a common clinical symptom in nasopharyngeal carcinoma (NPC), the most common Epstein-Barr virus (EBV)-associated head and neck malignancy. However, the effect of EBV on NPC lymph node (LN) metastasis is still unclear. In this study, we demonstrated that EBV infection is strongly associated with advanced clinical N stage and lymphangiogenesis of NPC. We found that NPC cells infected with EBV promote LN metastasis by inducing cancer-associated lymphangiogenesis, whereas these changes were abolished upon clearance of EBV genomes. Mechanistically, EBV-induced VEGF-C contributed to lymphangiogenesis and LN metastasis, and PHLPP1, a target of miR-BART15, partially contributed to AKT/HIF1a hyperactivity and subsequent VEGF-C transcriptional activation. In addition, administration of anti-VEGF-C antibody or HIF1α inhibitors attenuated the lymphangiogenesis and LN metastasis induced by EBV. Finally, we verified the clinical significance of this prometastatic EBV/VEGF-C axis by determining the expression of PHLPP1, AKT, HIF1a, and VEGF-C in NPC specimens with and without EBV. These results uncover a reasonable mechanism for the EBV-modulated LN metastasis microenvironment in NPC, indicating that EBV is a potential therapeutic target for NPC with lymphatic metastasis. IMPLICATIONS: This research demonstrates that EBV induces lymphangiogenesis in NPC by regulating PHLPP1/p-AKT/HIF1a/VEGF-C, providing a new therapeutic target for NPC with lymphatic metastasis.