Research Progress on the Mechanism of the Antitumor Effects of Cannabidiol.

Cannabidiol (CBD), a non-psychoactive ingredient extracted from the hemp plant, has shown therapeutic effects in a variety of diseases, including anxiety, nervous system disorders, inflammation, and tumors. CBD can exert its antitumor effect by regulating the cell cycle, inducing tumor cell apoptosis and autophagy, and inhibiting tumor cell invasion, migration, and angiogenesis. This article reviews the proposed antitumor mechanisms of CBD, aiming to provide references for the clinical treatment of tumor diseases and the rational use of CBD.

Understanding Chromium Slag Recycling with Sintering-Ironmaking Processes: Influence of Cr2O3 on the Sinter Microstructure and Mechanical Properties of the Silico-Ferrite of Calcium and Aluminum (SFCA).

Chromium slag is a solid waste of chromium salt production, which contains highly toxic Cr(VI) and significant amounts of valuable metals, such as Fe and Cr. Recycling chromium slag as a raw sintering material in sintering-ironmaking processes can simultaneously reduce toxic Cr(VI) and recover valuable metals. A micro-sintering experiment, compressive strength test, microhardness test, and first-principles calculation are performed to investigate the influence of Cr2O3 on the sintering microstructure and mechanical properties of the silico-ferrite of calcium and aluminum (SFCA) in order to understand the basis of the sintering process with chromium slag addition. The results show that the microstructure of SFCA changes from blocky to interwoven, with further increasing Cr2O3 content from 0 wt% to 3 wt%, and transforms to blocky with Cr2O3 content increasing to 5 wt%. Cr2O3 reacts with Fe2O3 to form (Fe1-xCrx)2O3 (0 ≤ x ≤ 1), which participates in forming SFCA. With the increase in Cr doping concentrations, the hardness of SFCA first decreases and then increases, and the toughness increases. When Cr2O3 content increases from 0 wt% to 3 wt%, the SFCA microhardness decreases and the compressive strength of the sintered sample increases. Further increasing Cr2O3 contents to 5 wt%, the SFCA microhardness increases, and the compressive strength of sintered sample decreases.

Lymphatic plastic bronchitis and primary chylothorax: A study based on computed tomography lymphangiography.

BACKGROUND: This study presents an evaluation of the computed tomography lymphangiography (CTL) features of lymphatic plastic bronchitis (PB) and primary chylothorax to improve the diagnostic accuracy for these two diseases. AIM: To improve the diagnosis of lymphatic PB or primary chylothorax, a retrospective analysis of the clinical features and CTL characteristics of 71 patients diagnosed with lymphatic PB or primary chylothorax was performed. METHODS: The clinical and CTL data of 71 patients (20 with lymphatic PB, 41 with primary chylothorax, and 10 with lymphatic PB with primary chylothorax) were collected retrospectively. CTL was performed in all patients. The clinical manifestations, CTL findings, and conventional chest CT findings of the three groups of patients were compared. The chi-square test or Fisher's exact test was used to compare the differences among the three groups. A difference was considered to be statistically significant when P < 0.05. RESULTS: (1) The percentages of abnormal contrast medium deposits on CTL in the three groups were as follows: Thoracic duct outlet in 14 (70.0%), 33 (80.5%) and 8 (80.0%) patients; peritracheal region in 18 (90.0%), 15 (36.6%) and 8 (80.0%) patients; pleura in 6 (30.0%), 33 (80.5%) and 9 (90.0%) patients; pericardium in 6 (30.0%), 6 (14.6%) and 4 (40.0%) patients; and hilum in 16 (80.0%), 11 (26.8%) and 7 (70.0%) patients; and (2) the abnormalities on conventional chest CT in the three groups were as follows: Ground-glass opacity in 19 (95.0%), 18 (43.9%) and 8 (80.0%) patients; atelectasis in 4 (20.0%), 26 (63.4%) and 7 (70.0%) patients; interlobular septal thickening in 12 (60.0%), 11 (26.8%) and 3 (30.0%) patients; bronchovascular bundle thickening in 14 (70.0%), 6 (14.6%) and 4 (40.0%) patients; localized mediastinal changes in 14 (70.0%), 14 (34.1%), and 7 (70.0%) patients; diffuse mediastinal changes in 6 (30.0%), 5 (12.2%), and 3 (30.0%) patients; cystic lesions in the axilla in 2 (10.0%), 6 (14.6%), and 2 (20.0%) patients; and cystic lesions in the chest wall in 0 (0%), 2 (4.9%), and 2 (4.9%) patients. CONCLUSION: CTL is well suited to clarify the characteristics of lymphatic PB and primary chylothorax. This method is an excellent tool for diagnosing these two diseases.

The value of the dermal rim sign on nonenhanced magnetic resonance imaging for predicting dermal backflow in patients with primary lower extremity lymphedema.

PURPOSE: The dermal rim sign (DRS) on nonenhanced magnetic resonance imaging has been shown to predict dermal backflow (DBF) in patients with secondary upper limb lymphedema. However, whether the DRS has the same effects on primary lower extremity lymphedema (PLEL) has not been clearly reported. Therefore, this study aimed to explore whether the DRS can be used to diagnose DBF on lymphoscintigraphy in patients with PLEL. METHODS: A total of 94 patients who were diagnosed with PLEL were recruited for this retrospective study from January 2022 to December 2023. All the patients were divided into two groups according to the lymphoscintigraphy findings: no DBF and DBF. The magnetic resonance imaging data of the two groups were recorded and statistically compared for the following indicators: range of lymphedema involvement (left, right, whole lower limbs, only thigh, only calf and ankle), signs of lymphedema (notable thickening of skin, parallel line sign, grid sign, honeycomb sign, band sign, lymph lake sign, crescent sign, DRS), and lymphedema measurement (skin thickness, band width). The DRS is characterized by notable thickening of the skin plus the grid sign and/or honeycomb sign, plus the band sign. RESULTS: The following statistically significant differences in the following indicators were found between the two groups (P < .05): notable skin thickening, parallel line sign, grid sign, honeycomb sign, band sign, DRS, skin thickness, and band width. The sensitivity, specificity, and accuracy for predicting for DBF with the DRS was 82%, 64%, and 77%, respectively. CONCLUSIONS: This study confirmed good consistency between the DRS and DBF from the perspective of imaging. This tool is suitable for children, adolescents, and patients with contraindications to lymphoscintigraphy. The DRS has important value in assessing the severity of PLEL. The DRS is suggested for the clinical use of combined surgical treatment of PLEL.

NLRP3 knockout in mice provided protection against Serratia marcescens-induced acute pneumonia by decreasing PD-L1 and PD-1 expression in macrophages.

Antibiotic-resistant Serratia marcescens (Sm) is known to cause bloodstream infections, pneumonia, etc. The nod-like receptor family, pyrin domain-containing 3 (NLRP3), has been implicated in various lung infections. Yet, its role in Sm-induced pneumonia was not well understood. In our study, we discovered that deletion of Nlrp3 in mice significantly improved Sm-induced survival rates, reduced bacterial loads in the lungs, bronchoalveolar lavage fluid (BALF), and bloodstream, and mitigated the severity of acute lung injury (ALI) compared to wild-type (WT) mice. Mechanistically, we observed that 24 h post-Sm infection, NLRP3 inflammasome activation occurred, leading to gasdermin D NH2-terminal (GSDMD-NT)-induced pyroptosis in macrophages and IL-1ß secretion. The NLRP3 or NLRP3 inflammasome influenced the expression PD-L1 and PD-1, as well as the count of PD-L1 or PD-1-expressing macrophages, alveolar macrophages, interstitial macrophages, PD-L1-expressing neutrophils, and the count of macrophage receptors with collagenous structure (MARCO)-expressing macrophages, particularly MARCO+ alveolar macrophages. The frequency of MARCO+ alveolar macrophages, PD-1 expression, particularly PD-1+ interstitial macrophages were negatively or positively correlated with the Sm load, respectively. Additionally, IL-1ß levels in BALF correlated with three features of acute lung injury: histologic score, protein concentration and neutrophil count in BALF. Consequently, our findings suggest that Nlrp3 deletion offers protection agaisnt acute Sm pneumonia in mice by inhibiting inflammasome activation and reducing Sm infection-induced PD-L1/PD-1 or MARCO expression, particularly in macrophages. This highlights potential therapeutic targets for Sm and other gram-negative bacteria-induced acute pneumonia.

Value of the short time inversion recovery sequence of magnetic resonance imaging in the staging of Klippel-Trenaunay syndrome complicated with lymphedema.

OBJECTIVE: Currently, the focus on limb lymphedema (LE) is on classification and staging. However, few scholars have conducted staging for Klippel-Trenaunay syndrome complicated LE (KTS-LE). This study aimed to investigate the value of the short time inversion recovery sequence of magnetic resonance imaging (MRI) in the staging of KTS-LE. METHODS: Forty-six patients who were diagnosed with KTS-LE were recruited for this retrospective study from July 2011 to November 2022. Referring to the clinical staging standard of lower extremity LE of the International Society of Lymphology in 2020, all patients were divided into three groups: stages I, II, and III. The MRI indicators of the three groups were recorded and statistically compared: LE range (unilateral bilateral, lower limbs, only thighs, only calves and ankles), abnormal parts (skin thickening, abnormal subcutaneous fat signal, abnormal muscle signal, muscle hypertrophy or contraction, abnormal bone signal, hyperostosis), and subcutaneous soft tissue signs (parallel line sign, grid sign, band sign, honeycomb sign, lymph lake sign, crescent sign, and nebula sign). RESULTS: There was a significant difference in the honeycomb sign among the three periods (P = .028). There was a significant difference between stage II and stage I disease (P < .05). There was a significant difference between stage II and stage III disease (P < .05). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the honeycomb sign in diagnosing KTS-LE of stage II were 87.5%, 63.2%, 33.3%, 96.0%, and 67.4%, respectively. In contrast, the other signs were not statistically significant among the three periods. CONCLUSIONS: The short time inversion recovery sequence of MRI is of great value in KTS-LE. The honeycomb sign is an important imaging indicator for the diagnosis of stage II disease. It is necessary to evaluate the severity of edema with MRI for KTS-LE, which is very important for therapeutic options.

MRI-based volume measurement methods for staging primary lower extremity lymphedema: a single-center study of asymmetric volume difference-a diagnostic study.

BACKGROUND: Lower extremity lymphedema (LEL) staging is mainly assessed by systems that solely depend on physical examinations and lack quantitative assessment based on modern imaging. OBJECTIVE: To explore the value of MRI-based asymmetric volume measurements in the clinical staging of primary LEL. METHODS: 92 patients with unilateral primary LEL underwent MRI examinations to determine the volume of the mid-calf (Vcl) calculated using the clinical dermatome method as well as the total volume (Vmri), musculoskeletal volume (VM), and subcutaneous volume (VS) volume of the middle calves. The difference between Vmri (DVmri) and VS (DVS) of the affected and unaffected calves was obtained and defined as the asymmetric volume difference. Meanwhile, the volume of the mid-calf (Vcl) and the difference in volume (DVcl) were calculated using the clinical circumferential method. The relationship between the asymmetric volume difference and clinical staging was then evaluated. Interobserver consistency was assessed through the intraclass correlation coefficient (ICC). Volume comparisons between the three groups were performed using the one-way analysis of variance (ANOVA) or the Kruskal-Wallis test. Spearman's correlation was used to assess volume and clinical stage correlation. The receiver operating characteristic (ROC) curve was used to evaluate the value of asymmetric volume difference for clinical staging. RESULTS: The asymmetric volume difference was statistically significant in stage I compared to stages II and III (p < 0.05). The asymmetric volume difference (DVmri: r = 0.753; DVS: r = 0.759) correlated more with the clinical stage than the affected Vcl (r = 0.581), Vmri (r = 0.628), VS (r = 0.743), and DVcl (r = 0.718). The area under the ROC curve (AUC) for identifying the clinical stage by the asymmetric volume difference was greater than that for the affected Vcl, Vmri, VS, and DVcl, with DVS (AUC = 0.951) having the largest area under the curve to distinguish between stages I and II. CONCLUSION: MRI-based asymmetric volume difference is an adjunctive measure for LEL clinical staging with good reproducibility. DVS could be the best indicator for differentiating between stages I and II of primary LEL.

Quantitative evaluation of primary lower extremity lymphedema staging using MRI: a preliminary study.

Background: The staging of primary lower extremity lymphedema (LEL) is difficult yet vital in clinical work, and magnetic resonance imaging (MRI) can be used for quantitative assessment of primary LEL due to its high resolution for soft tissues. In this study, we evaluated the value of MRI-based soft tissue area measurements for staging primary LEL. Methods: A total of 90 consecutive patients with clinically diagnosed primary lower limb lymphoedema from January 2017 to December 2019 in Beijing Shijitan Hospital were enrolled retrospectively. Short time inversion recovery (STIR) sequence was applied to measure the total, muscle, bone, and subcutaneous areas in the upper 1/3 level of the bilateral lower calf. The difference between the affected and unaffected calf regarding the subcutaneous area was obtained, and (subcutaneous area)/(bone area) and (subcutaneous area)/(muscle area) were calculated. According to the International Society of Lymphology (ISL) clinical staging standard established in 2020, all patients were divided into stages I, II, and III, accordingly. Statistical analysis was performed to determine the validity of MRI measurements in staging LEL. Results: There were 33 patients classified as stage I clinically, 44 patients as stage II, and 13 patients as stage III. There were significant differences in total, subcutaneous, the difference in subcutaneous area of limbs, subcutaneous/bone (S/B), and subcutaneous/muscle (S/M) between stage I and II as well as between stage I and III (P<0.001), but not between stage II and III (P=0.706, 0.329, and 0.229, respectively). A positive correlation was detected between the clinical stage and difference in subcutaneous area of limbs (rho =0.752, P<0.001), S/B (rho =0.747, P<0.001), S/M (rho =0.709, P<0.001), and subcutaneous (rho =0.723, P<0.001). For staging primary LEL, receiver operating characteristic (ROC) curves indicated that the difference in subcutaneous area of limbs had the best discrimination ability among parameters [area under the ROC curve (AUC) =0.950; 95% confidence interval (CI): 0.875-0.987; sensitivity: 95.45%; specificity: 84.85%], followed by S/B (AUC =0.930; 95% CI: 0.848-0.975; sensitivity: 77.27%; specificity: 93.94%) and S/M (AUC =0.895; 95% CI: 0.804-0.953; sensitivity: 77.27%; specificity: 90.91%). The ROC curves indicated that subcutaneous area (AUC =0.927; 95% CI: 0.844-0.974; sensitivity: 84.09%, specificity: 90.91%) and total (AUC =0.852; 95% CI: 0.753-0.923; sensitivity: 70.45%; specificity: 90.91%) also had discrimination ability between stage I and II. Conclusions: The measurement of the soft tissue area of the calf may be used as an auxiliary method for staging primary LEL. For patients with unilateral primary LEL, the difference in subcutaneous area of limbs could be a specific indicator to distinguish clinical stage I from II.

Singapore grouper iridovirus VP122 targets grouper STING to evade the interferon immune response.

Singapore grouper iridovirus (SGIV) is a highly pathogenic Iridoviridae that causes hemorrhage and spleen enlargement in grouper. Despite previous genome annotation efforts, many open reading frames (ORFs) in SGIV remain uncharacterized, with largely unknown functions. In this study, we identified the protein encoded by SGIV ORF122, now referred to as VP122. Notably, overexpression of VP122 promoted SGIV replication. Moreover, VP122 exhibited antagonistic effects on the natural antiviral immune response through the cGAS-STING signaling pathway. It specifically inhibited the cGAS-STING-triggered transcription of various immune-related genes, including IFN1, IFN2, ISG15, ISG56, PKR, and TNF-α in GS cells. Additionally, VP122 significantly inhibited the activation of the ISRE promoter mediated by EccGAS and EcSTING but had no effect on EccGAS or EcSTING alone. Immunoprecipitation and Western blotting experiments revealed that VP122 specifically interacts with EcSTING but not EccGAS. Notably, this interaction between VP122 and EcSTING was independent of any specific domain of EcSTING. Furthermore, VP122 inhibited the self-interaction of EcSTING. Interestingly, VP122 did not affect the recruitment of EcTBK1 and EcIRF3 to the EcSTING complex. Collectively, our results demonstrate that SGIV VP122 targets EcSTING to evade the type I interferon immune response, revealing a crucial role for VP122 in modulating the host-virus interaction.

Case Report: Molecular and microenvironment change upon midostaurin treatment in mast cell leukemia at single-cell level.

Mast cell leukemia is a rare and aggressive disease, predominantly with KIT D816V mutation. With poor response to conventional poly-chemotherapy, mast cell leukemia responded to the midostaurin treatment with a 50% overall response rate (ORR), but complete remission rate is approximately 0%. Therefore, the potential mechanisms of midostaurin resistance and the exact impacts of midostaurin on both gene expression profile and mast cell leukemia microenvironment in vivo are essential for design tailored combination therapy targeting both the tumor cells and the tumor microenvironment. Here we report a 59-year-old male mast cell leukemia patient with KIT F522C mutation treated with midostaurin. Single-cell sequencing of peripheral blood and whole exome sequencing (WES) of bone marrow were performed before and 10 months after midostaurin treatment. In accordance with the clinical response, compared to the pretreatment aberration, the decline of mast cells and increase of T-, NK, B-cells in peripheral blood, and the decrease of the KIT F522C mutation burden in bone marrow were observed. Meanwhile, the emergence of RUNX1 mutation, upregulations of genes expression (RPS27A, RPS6, UBA52, RACK1) on tumor cells, and increased frequencies of T and NK cells with TIGIT, CTLA4, and LAG3 expression were observed after midostaurin treatment, predicting the disease progression of this patient. As far as we know, this is the first case reporting the clinical, immunological, and molecular changes in mast cell leukemia patients before and after midostaurin treatment, illustrating the in vivo mechanisms of midostaurin resistance in mast cell leukemia, providing important clues to develop a sequential option to circumvent tumor progression after targeting oncogene addiction and prolong patients' survival.

α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure.

The sarcomeric interaction of α-myosin heavy chain (α-MHC) with Titin is vital for cardiac structure and contraction. However, the mechanism regulating this interaction in normal and failing hearts remains unknown. Lactate is a crucial energy substrate of the heart. Here, we identify that α-MHC undergoes lactylation on lysine 1897 to regulate the interaction of α-MHC with Titin. We observed a reduction of α-MHC K1897 lactylation in mice and patients with heart failure. Loss of K1897 lactylation in α-MHC K1897R knock-in mice reduces α-MHC-Titin interaction and leads to impaired cardiac structure and function. Furthermore, we identified that p300 and Sirtuin 1 act as the acyltransferase and delactylase of α-MHC, respectively. Decreasing lactate production by chemical or genetic manipulation reduces α-MHC lactylation, impairs α-MHC-Titin interaction and worsens heart failure. By contrast, upregulation of the lactate concentration by administering sodium lactate or inhibiting the pivotal lactate transporter in cardiomyocytes can promote α-MHC K1897 lactylation and α-MHC-Titin interaction, thereby alleviating heart failure. In conclusion, α-MHC lactylation is dynamically regulated and an important determinant of overall cardiac structure and function. Excessive lactate efflux and consumption by cardiomyocytes may decrease the intracellular lactate level, which is the main cause of reduced α-MHC K1897 lactylation during myocardial injury. Our study reveals that cardiac metabolism directly modulates the sarcomeric structure and function through lactate-dependent modification of α-MHC.

A mesoporous Al2O3 zincophilic sieve enables ultra-long lifespan of Zn-ion batteries.

The Zn dendrite growth and side reactions hinder the practical application of aqueous Zn-ion batteries. Here, a lactic acid-induced mesoporous Al2O3 (LA-MA) zincophilic sieve was constructed on a Zn anode to resolve these issues. The LA-MA layer with abundant mesoporous ion channels of 3.0 nm can regulate the solvation structure from [Zn2+(H2O)6]SO42- to more highly coordinated [Zn2+(H2O)5OSO32-] and restrain water-induced side reactions. Furthermore, the electrostatic attraction with zincophilic groups (CO, C-O) in the LA-MA layer has a positive effect on reducing the Zn2+ desolvation barrier and accelerating the Zn2+ diffusion. Under the synergism, the LA-MA@Zn symmetric cell exhibits over 5100 h at 0.25 mA cm-2. Impressively, an excellent capacity retention of 94.2% is achieved after 3500 cycles for the CNT/MnO2 cathode.

Down-regulation of WWP2 aggravates Type 2 diabetes mellitus-induced vascular endothelial injury through modulating ubiquitination and degradation of DDX3X.

BACKGROUND: Endothelial injury caused by Type 2 diabetes mellitus (T2DM) is considered as a mainstay in the pathophysiology of diabetic vascular complications (DVCs). However, the molecular mechanism of T2DM-induced endothelial injury remains largely unknown. Here, we found that endothelial WW domain-containing E3 ubiquitin protein ligase 2 (WWP2) act as a novel regulator for T2DM-induced vascular endothelial injury through modulating ubiquitination and degradation of DEAD-box helicase 3 X-linked (DDX3X). METHODS: Single-cell transcriptome analysis was used to evaluate WWP2 expression in vascular endothelial cells of T2DM patients and healthy controls. Endothelial-specific Wwp2 knockout mice were used to investigate the effect of WWP2 on T2DM-induced vascular endothelial injury. In vitro loss- and gain-of-function studies were performed to assess the function of WWP2 on cell proliferation and apoptosis of human umbilical vein endothelial cells. The substrate protein of WWP2 was verified using mass spectrometry, coimmunoprecipitation assays and immunofluorescence assays. The mechanism of WWP2 regulation on substrate protein was investigated by pulse-chase assay and ubiquitination assay. RESULTS: The expression of WWP2 was significantly down-regulated in vascular endothelial cells during T2DM. Endothelial-specific Wwp2 knockout in mice significantly aggravated T2DM-induced vascular endothelial injury and vascular remodeling after endothelial injury. Our in vitro experiments showed that WWP2 protected against endothelial injury by promoting cell proliferation and inhibiting apoptosis in ECs. Mechanically, we found that WWP2 is down-regulated in high glucose and palmitic acid (HG/PA)-induced ECs due to c-Jun N-terminal kinase (JNK) activation, and uncovered that WWP2 suppresses HG/PA-induced endothelial injury by catalyzing K63-linked polyubiquitination of DDX3X and targeting it for proteasomal degradation. CONCLUSION: Our studies revealed the key role of endothelial WWP2 and the fundamental importance of the JNK-WWP2-DDX3X regulatory axis in T2DM-induced vascular endothelial injury, suggesting that WWP2 may serve as a new therapeutic target for DVCs.

Spleen tyrosine kinase (SYK) signals are implicated in cardio-cerebrovascular diseases.

Post-translational modifications regulate numerous biochemical reactions and functions through covalent attachment to proteins. Phosphorylation, acetylation and ubiquitination account for over 90% of all reported post-translational modifications. As one of the tyrosine protein kinases, spleen tyrosine kinase (SYK) plays crucial roles in many pathophysiological processes and affects the pathogenesis and progression of various diseases. SYK is expressed in tissues outside the hematopoietic system, especially the heart, and is involved in the progression of various cardio-cerebrovascular diseases, such as atherosclerosis, heart failure, diabetic cardiomyopathy, stroke and others. Knowledge on the role of SYK in the progress of cardio-cerebrovascular diseases is accumulating, and many related mechanisms have been discovered and validated. This review summarizes the role of SYK in the progression of various cardio-cerebrovascular diseases, and aims to provide a theoretical basis for future experimental and clinical research targeting SYK as a therapeutic option for these diseases.

A novel mechanism of 6-methoxydihydroavicine in suppressing ovarian carcinoma by disrupting mitochondrial homeostasis and triggering ROS/ MAPK mediated apoptosis.

Introduction: Alkaloids derived from M. cordata (Papaveraceae family), have been found to display antineoplastic activity in several types of cancer. However, the antitumor effects and mechanisms of a new alkaloid extracted from the fruits of M. cordata, named 6-Methoxydihydroavicine (6-ME), remains unclear in the case of ovarian cancer (OC). Methods: CCK-8 assay was employed to analyze the cell viabilities of OC cells. RTCA, and colony-formation assays were performed to measure OC cell growth. Alterations in apoptosis and ROS levels were detected by flow cytometry in accordance with the instructions of corresponding assay kits. A Seahorse XFe96 was executed conducted to confirm the effects of 6-ME on cellular bioenergetics. Western blot and q-RT-PCR were conducted to detect alterations in target proteins. The subcutaneous xenografted tumor model of OC was used to further validate the anti-tumor activity of 6-ME in vivo. Results: Here, we reported for the first time that 6-ME inhibits OC cells growth in vitro and in vivo. Meanwhile, we found that 6-ME showed great antineoplastic activities by disrupting mitochondria homeostasis and promoting apoptosis in OC cells. Further investigation of the upstream signaling of apoptosis revealed that 6-ME-triggered apoptosis was induced by reactive oxygen species (ROS)-mediated mitogen-activated protein kinase (MAPK) activation and mitochondria dysfunction in OC cells. Furthermore, we found oxaloacetic acid (OAA), a crucial metabolite has been proved to be related to NADPH production, can block the cytotoxicity and accumulation of ROS caused by 6-ME in OC cells. Discussion: In summary, our data show that 6-ME exhibits cytotoxicity to OC cells in a ROS-dependent manner by interrupting mitochondrial respiration homeostasis and inducing MAPK-mediated apoptosis. This evidence suggests that 6-ME is a promising remedy for OC intervention.

Creating a Nanoscale Lateral Junction in a Semiconductor Monolayer with a Large Built-in Potential.

The ability to engineer atomically thin nanoscale lateral junctions is critical to lay the foundation for future two-dimensional (2D) device technology. However, the traditional approach to creating a heterojunction by direct growth of a heterostructure of two different materials constrains the available band offsets, and it is still unclear if large built-in potentials are attainable for 2D materials. The electronic properties of atomically thin semiconducting transition metal dichalcogenides (TMDs) are not static, and their exciton binding energy and quasiparticle band gap depend strongly on the proximal environment. Recent studies have shown that this effect can be harnessed to engineer the lateral band profile of a monolayer TMD to create a lateral electronic junction. Here we demonstrate the synthesis of a nanoscale lateral junction in monolayer MoSe2 by intercalating Se at the interface of an hBN/Ru(0001) substrate. The Se intercalation creates a spatially abrupt modulation of the local hBN/Ru work function, which is imprinted directly onto an overlying MoSe2 monolayer to create a lateral junction with a large built-in potential of 0.83 ± 0.06 eV. We spatially resolve the MoSe2 band profile and work function using scanning tunneling spectroscopy to map out the nanoscale depletion region. The Se intercalation also modifies the dielectric environment, influencing the local band gap renormalization and increasing the MoSe2 band gap by ∼0.26 ± 0.1 eV. This work illustrates that environmental proximity engineering provides a robust method to indirectly manipulate the band profile of 2D materials outside the limits of their intrinsic properties.

A novel mechanism of cannabidiol in suppressing ovarian cancer through LAIR-1 mediated mitochondrial dysfunction and apoptosis.

Cannabidiol (CBD) is a nonpsychoactive cannabinoid compound. It has been shown that CBD can inhibit the proliferation of ovarian cancer cells, but the underlying specific mechanism is unclear. We previously presented the first evidence for the expression of leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), a member of the immunosuppressive receptor family, in ovarian cancer cells. In the present study, we investigated the mechanism by which CBD inhibits the growth of SKOV3 and CAOV3 ovarian cancer cells, and we sought to understand the concurrent role of LAIR-1. In addition to inducing ovarian cancer cell cycle arrest and promoting cell apoptosis, CBD treatment significantly affected the expression of LAIR-1 and inhibited the PI3K/AKT/mTOR signaling axis and mitochondrial respiration in ovarian cancer cells. These changes were accompanied by an increase in ROS, loss of mitochondrial membrane potential, and suppression of mitochondrial respiration and aerobic glycolysis, thereby inducing abnormal or disturbed metabolism and reducing ATP production. A combined treatment with N-acetyl-l-cysteine and CBD indicated that a reduction in ROS production would restore PI3K/AKT/mTOR pathway signaling and ovarian cancer cell proliferation. We subsequently confirmed that the inhibitory effect of CBD on the PI3K/AKT/mTOR signal axis and mitochondrial bioenergy metabolism was attenuated by knockdown of LAIR-1. Our animal studies further support the in vivo anti-tumor activity of CBD and suggest its mechanism of action. In summary, the present findings confirm that CBD inhibits ovarian cancer cell growth by disrupting the LAIR-1-mediated interference with mitochondrial bioenergy metabolism and the PI3K/AKT/mTOR pathway. These results provide a new experimental basis for research into ovarian cancer treatment based on targeting LAIR-1 with CBD.

Detection of ß-amyloid peptide aggregates by quartz crystal microbalance based on dual-aptamer assisted signal amplification.

ß-amyloid peptide (Aß) aggregates are regarded as a typical neuropathology hallmark for the diagnosis of Alzheimer's disease (AD). Aß40 aggregates include soluble oligomers (Aß40O) and insoluble fibrils (Aß40F). Both of them can simultaneously bind to two different kinds of its aptamer (Apt1 and Apt2). As a mass-sensitive sensing platform, quartz crystal microbalance (QCM) converts changes in mass on the Au chip surface into frequency shift. Here, a dual-aptamer assisted Aß40 aggregates assay was developed. Taking Aß40O detection as an example, Apt2 was modified on the surface of Au chip by Au-S bond. Subsequently, the solution consisted of Aß40O and gold nanoparticles-Apt1 (AuNPs-Apt1) were injected into the QCM chamber. As a result, Aß40O was specifically recognized and captured by Apt2. AuNPs-Apt1 were also combined on the surface of the Au chip because Aß40O can simultaneously bind to Apt1. Then, a significant frequency shift occurred because of the large weight of AuNPs. Similarly, this procedure can be used to detect Aß40F. This QCM biosensor was able to detect Aß40O with a range of 0.2-10 pM with a detection limit of 0.11 pM, while the linear range for Aß40F was 0.1-10 pM with a detection limit of 0.02 pM. This QCM biosensor was simple and highly sensitive, which provided a new method for Aß40 aggregates detection.

Multilayered Ceramic Membrane with Ion Conducting Thin Layer Induced by Interface Reaction for Stable Hydrogen Production.

Conventional methods for fabricating multilayered ceramic membranes with ion conducting dense thin layers are often cumbersome, costly, and limited by poor adhesion between layers. Inspired by the architectural structure of the rooted grasses in soil, here, we report an interface-reaction-induced reassembly approach for the direct fabrication of Ce0.9 Gd0.1 O2-δ (CGO) thin layers rooted in the parent multilayered ceramic membranes by only one firing step. The CGO dense layers are very thin, and adhered strongly to the parent support layer, ensuring low ionic transport resistance and structural integrity of the multilayered membranes. When using as an oxygen permeable membrane for upgrading fossil-fuel-derived hydrogen, it shows very long durability in harsh conditions containing H2 O, CH4 , H2 , CO2 and H2 S. Furthermore, our approach is highly scalable and applicable to a wide variety of ion conducting thin layers, including Y0.08 Zr0.92 O2-δ , Ce0.9 Sm0.1 O2-δ and Ce0.9 Pr0.1 O2-δ .

Elevated serum IL-13 level is associated with increased Treg cells in tumor microenvironment and disease progression of diffuse large B-cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common aggressive lymphoid malignancy, with an immunosuppressive microenvironment affecting clinical outcome. Interleukin (IL)-13 overexpression is observed in multiple solid tumors and contributes to tumor progression. This study aims to investigate pretreatment serum IL-13 levels and their relationship with the prognosis of DLBCL patients. One hundred and sixty-six patients with newly diagnosed DLBCL from June 2015 to July 2017 were included. Patients with elevated pretreatment serum IL-13 levels (IL-13≥1.63 pg/ml) were classified into the high IL-13 group and they had significantly lower complete remission rate (60% vs. 74%, p = 0.0059), higher progression rate (43% vs. 23%, p = 0.0051), and poor progression-free survival (2-year PFS, 63% vs. 78%, p = 0.0078) and overall survival (2-year OS, 75% vs. 92%, p = 0.0027), when compared to those in the low IL-13 group (IL-13<1.63 pg/ml). Meanwhile, increased Treg cell ratio in peripheral blood (p = 0.0147) and elevated serum IL-2 levels (p = 0.0272) were observed in the high IL-13 group. Moreover, RNA sequencing data showed that patients in the high IL-13 group had significantly elevated expression of chemokines and chemokine receptors (CCR4, CCL19, CCL21, CXCL2) related to Treg activation and recruitment. Consistent with the chemokine profile, tumor immunophenotyping analysis revealed that higher Treg cells recruitment in the high IL-13 group than the low IL-13 group (p = 0.0116). In vitro, when lymphoma cells co-cultured with peripheral blood monocytes of healthy controls, metformin down-regulated both IL-13 level and Treg cell ratio, in consistent with the decreased serum IL-13 levels of patients after 6 months of metformin maintenance therapy in the high IL-13 group. Taken together, pretreatment serum IL-13 level is related to the immunosuppressive microenvironment and poor clinical outcome of DLBCL patients and could be targeted by metformin, thus providing a new therapeutic strategy in treating DLBCL with high serum IL-13 levels.