Dynamic Cortical Connectivity During Propofol Sedation in Glioma Patients.

BACKGROUND: The behavioral manifestations and neurophysiological responses to sedation can assist in understanding brain function after neurological damage, and can be described by cortical functional connectivity. Glioma patients may experience neurological deficits that are not clinically detectable before sedation. We hypothesized that patients with gliomas exhibit distinct cortical connectivity patterns compared to non-neurosurgical patients during sedation. METHODS: This is a secondary analysis of a previously published prospective observational study. Patients scheduled for resection of supratentorial glioma (n=21) or a non-neurosurgical procedure (n=21) under general anesthesia were included in this study. Frontal electroencephalography (EEG) signals were recorded at different sedation levels as assessed by the Observer Assessment of Alertness/Sedation (OAA/S) score. Kernel principal component analysis and k-means clustering were used to determine possible temporal dynamics from the weighted phase lag index characteristics. RESULTS: Ten EEG connectivity states were identified by clustering (76% consistency), each with unique properties. At OAA/S 3, the median (Q1, Q3) occurrence rates of state 6 (glioma group, 0.110 [0.083, 0.155] vs. control group, 0.070 [0.030, 0.110]; P=0.008) and state 7 (glioma group, 0.105 [0.083, 0.148] vs. control group: 0.065 [0.038, 0.090]; P=0.001), which are dominated by beta connectivity, were significantly different between the 2 groups, reflecting differential conversion of the beta band between the left and right brain regions. In addition, the temporal dynamics of the brain's functional connectivity was also reflected in the transition relationships between metastable states. CONCLUSIONS: There were differences in EEG functional connectivity, which is dynamic, between the glioma and nonglioma groups during sedation.

Pyrite Characteristics in Lacustrine Shale and Implications for Organic Matter Enrichment and Shale Oil: A Case Study from the Triassic Yanchang Formation in the Ordos Basin, NW China.

Pyrite is widely distributed in lacustrine shales and has become a research focus in unconventional oil and gas exploration. Pyrite morphology is useful for identifying different types of organic matter and assessing shale oil enrichment in organic-rich shale. Abundant pyrite is developed in the source rocks from the Chang 7 Member of the Yanchang Formation in the Ordos Basin, NW China. However, the relationship between different pyrite types and the differential enrichment of shale oil still needs to be clarified. The organic geochemistry, petrology, and isotopic composition of the Chang 7 Member samples were analyzed. The significance of pyrite types and sulfur isotopic compositions as indicators of depositional environments and shale oil enrichment was emphasized. The Chang 7 shales contain three pyrite morphologies, framboidal pyrite (type A), spherulitic pyrite (type B), and euhedral and anhedral pyrite (type C), and their aggregates. The sulfur isotopic compositions of pyrite (δ34Spy) in Chang 7 shales with different pyrite types exhibited regular patterns. The δ34S values of types A, B, and C pyrites were sequentially positive overall (average values are -2.739, 2.201, and 7.487‰ in sequence), indicating that type A pyrite was formed during the syn-sedimentary to early diagenetic stage and types B and C pyrites were formed during the early to middle diagenetic stage. Types A, B, and C pyrites showed sequentially increasing kerogen type index values and kerogen carbon isotope values (mean values of -31.59, -28.70, and -26.45‰, successively), indicating that the horizons where types A, B, and C pyrites developed correspond to types I, II, and III organic matter, respectively. Strong correlations between the pyrite content and oil components reveal that pyrite indicates shale oil enrichment. Moreover, variations in pyrite type significantly influenced the enrichment behavior of shale oil. Types A and B pyrites contributing to reservoir space showed shale oil enrichment. They promoted saturated hydrocarbon enrichment at >15% pyrite content, whereas type C pyrite did not indicate shale oil enrichment. These findings provide new insights into the differential enrichment of organic matter and shale oil and valuable guidance for the large-scale exploration and development of shale oil resources.

The m6 RNA methylation regulator KIAA1429 is associated with autophagy-mediated drug resistance in lung cancer.

N6-methyladenosine (m6A) modification plays a crucial role in cancer progression. However, the role of m6A modification-mediated autophagy underlying non-small cell lung cancer (NSCLC) gefitinib resistance remains unknown. Here, we discovered that m6A methyltransferase KIAA1429 was highly expressed in NSCLC gefitinib-resistant cells (PC9-GR) as well as tissues, and KIAA1429 high expression was associated with poor survival. In addition, silent KIAA1429 repressed gefitinib resistance in NSCLC and reduced tumor growth in vivo. Mechanistically, KIAA1429 stabilized WTAP, a significant player in autophagy, by binding to the 3' untranslated regions (3'-UTR) of WTAP. In a word, our findings indicated that KIAA1429 could elevate NSCLC gefitinib resistance, which may provide a promising targeted therapy for NSCLC patients.

Amanitin-induced variable cytotoxicity in various cell lines is mediated by the different expression levels of OATP1B3.

Amanita phalloides is one of the deadliest mushrooms worldwide, causing most fatal cases of mushroom poisoning. Among the poisonous substances of Amanita phalloides, amanitins are the most lethal toxins to humans. Currently, there are no specific antidotes available for managing amanitin poisoning and treatments are lack of efficacy. Amanitin mainly causes severe injuries to specific organs, such as the liver, stomach, and kidney, whereas the lung, heart, and brain are hardly affected. However, the molecular mechanism of this phenomenon remains not understood. To explore the possible mechanism of organ specificity of amanitin-induced toxicity, eight human cell lines derived from different organs were exposed to α, ß, and γ-amanitin at concentrations ranging from 0.3 to 100 µM. We found that the cytotoxicity of amanitin differs greatly in various cell lines, among which liver-derived HepG2, stomach-derived BGC-823, and kidney-derived HEK-293 cells are most sensitive. Further mechanistic study revealed that the variable cytotoxicity is mainly dependent on the different expression levels of the organic anion transporting polypeptide 1B3 (OATP1B3), which facilitates the internalization of amanitin into cells. Besides, knockdown of OATP1B3 in HepG2 cells prevented α-amanitin-induced cytotoxicity. These results indicated that OATP1B3 may be a crucial therapeutic target against amanitin-induced organ failure.

In situ carbothermal synthesis of carbonized bacterial cellulose embedded with nano zero-valent iron for removal of Cr(VI).

Carbonized bacterial cellulose embedded with highly dispersed nano zero-valent iron (nZVI), denoted as nZVI@CBC, was prepared through one-step in situ carbothermal treatment of bacterial cellulose adsorbing iron(III) nitrate. The structure characteristics of nZVI@CBC and its performance in removing hexavalent chromium Cr(VI) were investigated. Results showed the formation of nZVI@CBC with a surface area of 409.61 m2/g at 800 °C, with nZVI particles of mean size 28.2 nm well distributed within the fibrous network of CBC. The stability of nZVI was enhanced by its carbon coating, despite some inevitable oxidation of exposed nZVI. Batch experiments demonstrated that nZVI@CBC exhibited superior removal efficiency compared to bare nZVI and CBC. Under optimal conditions, nZVI@CBC exhibited a high Cr(VI) adsorption capacity of up to 372.42 mg/g. Therefore, nZVI@CBC shows promise as an effective adsorbent for remediating Cr(VI) pollution in water.

Dual growth factor methacrylic alginate microgels combined with chitosan-based conduits facilitate peripheral nerve repair.

Treating severe peripheral nerve injuries is difficult. Nerve repair with conduit small gap tubulization is a treatment option but still needs to be improved. This study aimed to assess the use of microgels containing growth factors, along with chitosan-based conduits, for repairing nerves. Using the water-oil emulsion technique, microgels of methacrylic alginate (AlgMA) that contained vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) were prepared. The effects on rat Schwann cells (RSC96) and human umbilical vein endothelial cells (HUVECs) were evaluated. Chitosan-based conduits were fabricated and used in conjunction with microgels containing two growth factors to treat complete neurotmesis in rats. The results showed that the utilization of dual growth factor microgels improved the migration and decreased the apoptosis of RSC96 cells while promoting the growth and formation of tubes in HUVECs. The utilization of dual growth factor microgels and chitosan-based conduits resulted in notable advancements in the regeneration and myelination of nerve fibers, recovery of neurons, alleviation of muscle atrophy and recovery of neuromotor function and nerve conduction. In conclusion, the use of dual growth factor AlgMA microgels in combination with chitosan-based conduits has the potential to significantly improve the effectiveness of nerve repair.

Distribution and associations of anterior lens zonules lengths in patients with cataract.

PURPOSE: To investigate the characteristics and associations of anterior lens zonules lengths in cataract patients via ultrasound biomicroscope (UBM) measurement. METHODS: Patients with age-related cataracts and high myopic cataracts who planned to undergo cataract surgery were included in the study. After routine ophthalmic examinations, the UBM was performed on both eyes to get images of the anterior lens zonules, and Image J software was used to measure the lengths of the lens zonules. Axial length (AL), anterior chamber depth (ACD), lens thickness (LT), and white-to-white (WTW) diameter of both eyes were obtained by IOL Master 700. Univariate and multivariate regression analyses were used to assess associated factors of anterior lens zonules lengths. RESULTS: Forty-nine patients with age-related cataracts and 33 patients with high myopic cataracts were enrolled. High myopic cataract patients were younger and had longer anterior lens zonules. Multivariate regression analysis showed that anterior lens zonules lengths were associated with axial lengths (temporal location: ß = 0.036, P = 0.029; nasal location: ß = 0.034, P = 0.011; superior location: ß = 0.046, P = 0.002) and ACD (inferior location: ß = 0.305, P = 0.016) in right eyes. In left eyes, anterior lens zonules lengths were associated with axial lengths (temporal location: ß = 0.028, P = 0.017; inferior location: ß = 0.026, P = 0.016; nasal location: ß = 0.033, P < 0.001) and ACD (inferior location: ß = 0.215, P = 0.030; superior location: ß = 0.290, P = 0.011). CONCLUSIONS: High myopic cataract patients have longer anterior lens zonules. AL and ACD contributed to the lengths of anterior lens zonules. Thus, for patients with long AL and deeper ACD, lens zonules measurement was crucial. CLINICAL TRIAL REGISTRATION: www.chictr.org.cn identifier is ChiCTR2300071397.

Effects of depth of straw returning on maize yield potential and greenhouse gas emissions.

Appropriate straw incorporation has ample agronomic and environmental benefits, but most studies are limited to straw mulching or application on the soil surface. To determine the effect of depth of straw incorporation on the crop yield, soil organic carbon (SOC), total nitrogen (TN) and greenhouse gas emission, a total of 4 treatments were set up in this study, which comprised no straw returning (CK), straw returning at 15 cm (S15), straw returning at 25 cm (S25) and straw returning at 40 cm (S40). The results showed that straw incorporation significantly increased SOC, TN and C:N ratio. Compared with CK treatments, substantial increases in the grain yield (by 4.17~5.49% for S15 and 6.64~10.06% for S25) were observed under S15 and S25 treatments. S15 and S25 could significantly improve the carbon and nitrogen status of the 0-40 cm soil layer, thereby increased maize yield. The results showed that the maize yield was closely related to the soil carbon and nitrogen index of the 0-40 cm soil layer. In order to further evaluate the environmental benefits of straw returning, this study measured the global warming potential (GWP) and greenhouse gas emission intensity (GHGI). Compared with CK treatments, the GWP of S15, S25 and S40 treatments was increased by 9.35~20.37%, 4.27~7.67% and 0.72~6.14%, respectively, among which the S15 treatment contributed the most to the GWP of farmland. GHGI is an evaluation index of low-carbon agriculture at this stage, which takes into account both crop yield and global warming potential. In this study, GHGI showed a different trend from GWP. Compared with CK treatments, the S25 treatments had no significant difference in 2020, and decreased significantly in 2021 and 2022. This is due to the combined effect of maize yield and cumulative greenhouse gas emissions, indicating that the appropriate straw returning method can not only reduce the intensity of greenhouse gas emissions but also improve soil productivity and enhance the carbon sequestration effect of farmland soil, which is an ideal soil improvement and fertilization measure.

A Senescence-Associated Secretory Phenotype of Bone Marrow Mesenchymal Stem Cells Inhibits the Viability of Breast Cancer Cells.

Breast cancer, the most prevalent malignancy in women, often progresses to bone metastases, especially in older individuals. Dormancy, a critical aspect of bone-metastasized breast cancer cells (BCCs), enables them to evade treatment and recur. This dormant state is regulated by bone marrow mesenchymal stem cells (BMMSCs) through the secretion of various factors, including those associated with senescence. However, the specific mechanisms by which BMMSCs induce dormancy in BCCs remain unclear. To address this gap, a bone-specific senescence-accelerated murine model, SAMP6, was utilized to minimize confounding systemic age-related factors. Confirming senescence-accelerated osteoporosis, distinct BMMSC phenotypes were observed in SAMP6 mice compared to SAMR1 counterparts. Notably, SAMP6-BMMSCs exhibited premature senescence primarily due to telomerase activity loss and activation of the p21 signaling pathway. Furthermore, the effects of conditioned medium (CM) derived from SAMP6-BMMSCs versus SAMR1-BMMSCs on BCC proliferation were examined. Intriguingly, only CM from SAMP6-BMMSCs inhibited BCC proliferation by upregulating p21 expression in both MCF-7 and MDA-MB-231 cells. These findings suggest that the senescence-associated secretory phenotype (SASP) of BMMSCs suppresses BCC viability by inducing p21, a pivotal cell cycle inhibitor and tumor suppressor. This highlights a heightened susceptibility of BCCs to dormancy in a senescent microenvironment, potentially contributing to the increased incidence of breast cancer bone metastasis and recurrence observed with aging.

Intracellular Delivery of Therapeutic Protein via Ultrathin Layered Double Hydroxide Nanosheets.

The therapeutic application of biofunctional proteins relies on their intracellular delivery, which is hindered by poor cellular uptake and transport from endosomes to cytoplasm. Herein, we constructed a two-dimensional (2D) ultrathin layered double hydroxide (LDH) nanosheet for the intracellular delivery of a cell-impermeable protein, gelonin, towards efficient and specific cancer treatment. The LDH nanosheet was synthesized via a facile method without using exfoliation agents and showed a high loading capacity of proteins (up to 182%). Using 2D and 3D 4T1 breast cancer cell models, LDH-gelonin demonstrated significantly higher cellular uptake efficiency, favorable endosome escape ability, and deep tumor penetration performance, leading to a higher anticancer efficiency, in comparison to free gelonin. This work provides a promising strategy and a generalized nanoplatform to efficiently deliver biofunctional proteins to unlock their therapeutic potential for cancer treatment.

High-fat diet promotes prostate cancer metastasis via RPS27.

BACKGROUND: Metastasis is the leading cause of death among prostate cancer (PCa) patients. Obesity is associated with both PCa-specific and all-cause mortality. High-fat diet (HFD) is a risk factor contributing to obesity. However, the association of HFD with PCa metastasis and its underlying mechanisms are unclear. METHODS: Tumor xenografts were conducted by intrasplenic injections. The ability of migration or invasion was detected by transwell assay. The expression levels of RPS27 were detected by QRT-PCR and western blot. RESULTS: The present study verified the increase in PCa metastasis caused by HFD in mice. Bioinformatics analysis demonstrated increased RPS27 in the experimentally induced PCa in HFD mice, indicating that it is an unfavorable prognostic factor. Intrasplenic injections were used to demonstrate that RPS27 overexpression promotes, while RPS27 knockdown significantly reduces, PCa liver metastasis. Moreover, RPS27 inhibition suppresses the effects of HFD on PCa metastasis. Further mRNA sequencing analysis revealed that RPS27 promotes PCa metastasis by selectively enhancing the expression of various genes. CONCLUSION: Our findings indicate that HFD increases the risk of PCa metastasis by elevating RPS27 expression and, subsequently, the expression of genes involved in PRAD progression. Therefore, RPS27 may serve as a novel target for the diagnosis and treatment of metastatic PCa.

Influence of Lens Thickness on Accuracy of Kane, Hill-RBF 3.0, Barrett Universal II, Emmetropia Verifying Optical, and Pearl-DGS Formulas in Eyes with Nonhigh Myopia and High Myopia.

PURPOSE: To investigate the influence of lens thickness (LT) on accuracy of Kane, Hill-RBF 3.0 Barrett Universal II (BUII), Emmetropia Verifying Optical (EVO), and Pearl-DGS formulas in eyes with different axial lengths (AL). METHODS: The prospective cohort study was conducted at Eye and ENT Hospital of Fudan University. Patients who had uneventful cataract surgery between March 2021 and July 2023 were recruited. Manifest refraction was conducted two-month post-surgery. Eyes were divided into 4 groups based on AL: short (<22mm), medium (22-24.5 mm), medium long (24.5-26mm) and very long (≥26mm). In each AL group, eyes were then divided into 3 subgroups based on the LT measured with IOLmaster700: thin (<4.5 mm), medium (4.5-5.0 mm), and thick (≥ 5 mm). The influence of LT on accuracy of Kane, Hill-RBF 3.0, BUII, EVO, and Pearl-DGS formulas were investigated in each AL group. RESULTS: A total of 327 eyes from 327 patients were analyzed, with 64, 102, 73 and 88 eyes in each AL group, respectively. In eyes with AL < 24.5 mm, myopic PE was significantly associated with greater LT using all the 5 formulas (all p < 0.05). Backward stepwise multivariate regression analyses revealed that LT was an important influencing factor for PE in all 5 formulas, particularly in eyes with AL <24.5 mm. In eyes with AL <24.5 mm and LT > 5.0 mm, PE of all 5 formulas calculated with the optional parameter LT were more myopic than those calculated without LT. CONCLUSIONS: Thicker LT was associated with more myopic PE among eyes with AL <24.5 mm when using all 5 formulas. Further optimization of current formulas is necessary, especially for eyes with short AL and thick LT.

Divinyl sulfone, an oxidative metabolite of sulfur mustard, induces caspase-independent pyroptosis in hepatocytes.

Sulfur mustard (SM) is a highly toxic blister agent which has been used many times in several wars and conflicts and caused heavy casualties. Ease of production and lack of effective therapies make SM a potential threat to public health. SM intoxication causes severe damage on various target organs, such as the skin, eyes, and lungs. In addition, SM exposure can also lead to hepatotoxicity and severe liver injuries. However, despite decades of research, the molecular mechanism underlying SM-induced liver damage remains obscure. SM can be converted into various products via complex hepatic metabolism in vivo. There are some pieces of evidence that one of the oxidation products of SM, divinyl sulfone (DVS), exhibits even more significant toxicity than SM. Nevertheless, the molecular toxicology of DVS is still hardly known. In the present study, we confirmed that DVS is even more toxic than SM in the human hepatocellular carcinoma cell line HepG2. Further mechanistic study revealed that DVS exposure (200 µM) promotes pyroptosis in HepG2 cells, while SM (400 µM) mainly induces apoptosis. DVS induces gasdermin D (GSDMD) mediated pyroptosis, which is independent of caspases activation but depends on the large amounts of reactive oxygen species (ROS) and severe oxidative stress produced during DVS exposure. Our findings may provide novel insights for understanding the mechanism of SM poisoning and may be helpful to discover promising therapeutic strategies for SM intoxication.

Antioncogenic roles of USP9Y and DDX3Y in lung cancer: USP9Y stabilizes DDX3Y by preventing its degradation through deubiquitination.

In previous studies, downregulation of USP9Y and DDX3Y in lung cancer (LC) tissues was identified, while their function in LC progression remains elusive. In our current work, we intended to elucidate the effect and mechanisms of USP9Y and DDX3Y in LC. Gene downregulation has been confirmed in our LC tissues and cells. The effect of USP9Y or DDX3Y on LC cell malignancies was analyzed by functional assay. Both USP9Y and DDX3Y overexpression showed suppressive impact on LC cell malignancies. USP9Y overexpression has also been demonstrated to inhibit tumorigenesis in vivo. Based on GEPIA database, it was found that there was a positive correlation between the levels of USP9Y and DDX3Y in LC tissues. The mRNA expression of DDX3Y was not affected by USP9Y overexpression, while its protein levels were significantly up-regulated in USP9Y overexpressed LC cells. Moreover, USP9Y interacted with DDX3Y and has been demonstrated to stabilize DDX3Y expression by preventing its degradation via deubiquitination. In conclusion, USP9Y and DDX3Y exerted antioncogenic effects on the cell proliferation potential, cell cycle process, apoptosis, and tumorigenesis of LC. USP9Y binds to DDX3Y to prevent DDX3Y degradation through deubiquitination.

UTX inhibition suppresses proliferation and promotes apoptosis in patient-derived glioblastoma stem cells by modulating periostin expression.

Glioblastoma stem cells (GSCs) exert a crucial influence on glioblastoma (GBM) development, progression, resistance to therapy, and recurrence, making them an attractive target for drug discovery. UTX, a histone H3K27 demethylase, participates in regulating multiple cancer types. However, its functional role in GSCs remains insufficiently explored. This study aims to investigate the role and regulatory mechanism of UTX on GSCs. Analysis of TCGA data revealed heightened UTX expression in glioma, inversely correlating with overall survival. Inhibiting UTX suppressed GBM cell growth and induced apoptosis. Subsequently, we cultured primary GSCs from three patients, observing that UTX inhibition suppressed cell proliferation and induced apoptosis. RNA-seq was performed to analyze the gene expression changes after silencing UTX in GSCs. The results indicated that UTX-mediated genes were strongly correlated with GBM progression and regulatory tumor microenvironment. The transwell co-cultured experiment showed that silencing UTX in the transwell chamber GSCs inhibited the well plate cell proliferation. Protein-protein interaction analysis revealed that periostin (POSTN) played a role in the UTX-mediated transcriptional regulatory network. Replenishing POSTN reversed the effects of UTX inhibition on GSC proliferation and apoptosis. Our study demonstrated that UTX inhibition hindered POSTN expression by enhancing the H3K27me2/3 level, eventually resulting in inhibiting proliferation and promoting apoptosis of patient-derived GSCs. Our findings may provide a novel and effective strategy for the treatment of GBM.

Integrated network pharmacology and metabolomics reveal the action mechanisms of vincristine combined with celastrol against colon cancer.

Colon cancer is associated with a high mortality rate. Vincristine (VCR) is a commonly used chemotherapeutic drug. Celastrol (CEL) is an effective component which exerts inhibitory effects on colon cancer. Combination treatment improves resistance to chemotherapeutic drugs and enhances their efficacy. Therefore, we aimed to explore the molecular mechanisms of VCR combined with CEL in colon cancer treatment. We verified the effects of VCR combined with CEL on the proliferation, cell cycle, and apoptosis of HCT-8 cells. Non-targeted metabolomic techniques were used to analyse the changes in cellular metabolites after administration. Finally, network pharmacology technology was used to screen the potential targets and pathways. VCR combined with CEL had synergistic inhibitory effects on HCT-8 colon cancer cells. Cell metabolomics identified 12 metabolites enriched in metabolic pathways, such as the phenylalanine, tyrosine and tryptophan biosynthesis pathways. Network pharmacology revealed that MAPK1, AKT1, PIK3CB, EGFR, and VEGFA were the key targets. Western blotting revealed that VCR combined with CEL activated the P53 pathway by suppressing the PI3K/AKT signalling pathway activation and Bcl-2 expression, promoting the Bax expression. Therefore, VCR combined with CEL potentially treats colon cancer by increasing the apoptosis, improving energy metabolism, and inhibiting PI3K/AKT pathway in colon cancer cells.

Extra villous trophoblast-derived PDL1 can ameliorate macrophage inflammation and promote immune adaptation associated with preeclampsia.

INTRODUCTION: Severe preeclampsia (sPE) is a systemic syndrome that may originate from chronic inflammation. Maintaining maternal-fetal hemostasis by the co-inhibitory molecule programmed death ligand 1 (PDL1) can be favorable for ameliorating inflammation from immune cells. Apart from programmed death 1 (PD1) expression, decidual macrophages (dMs) produce inflammatory cytokines, in response to cells which express PDL1. However, strong evidence is lacking regarding whether the PDL1/PD1 interaction between trophoblasts and decidual macrophages affects inflammation during sPE development. METHODS: To determine whether the trophoblast-macrophage crosstalk via the PDL1/PD1 axis modulates the inflammatory response in sPE-like conditions, at first, maternal-fetal tissues from sPE and normal patients were collected, and the PDL1/PD1 distribution was analyzed by Western blot, immunohistochemistry/ immunofluorescence and flow cytometry. Next, a coculture system was established and flow cytometry was used to identify how PDL1 was involved in macrophage-related inflammation under hypoxic stress. Transcriptional analysis was performed to clarify the inflammation-associated pathway induced by the PDL1/PD1 interaction. Finally, the Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) mouse model was used to examine the effect of PDL1 on macrophage-related inflammation by measuring PE-like symptoms. RESULTS: In maternal-fetal tissue from sPE patients, placental extravillous trophoblasts (EVTs) and dMs had a surprisingly increase of PDL1 and PD1 expression, respectively, accompanied by a higher percentage of CD68 +CD86 + dMs. In vitro experiments showed that trophoblast-derived PDL1 under hypoxia interacted with PD1 on CD14 +CD80 +macrophages, leading to suppression of inflammation through the TNFα-p38/NFκB pathway. Accordingly, the PE-like mouse model showed a reversal of PE-like symptoms and a reduced F4/80 + CD86 + macrophage percentage in the uterus in response to recombinant PDL1 protein administration, indicating the protective effect of PDL1. DISCUSSION: Our results initially explained an immunological adaptation of trophoblasts under placental hypoxia, although this protection was insufficient. Our findings suggest the possible capacity of modulating PDL1 expression as a potential therapeutic strategy to target the inflammatory response in sPE.

Explore the pharmacological basis of ShengJiYiSui decoction in the treatment of amyotrophic lateral sclerosis based on network pharmacology and molecular docking technology.

Neurodegenerative illnesses have long been handled clinically by traditional Chinese medicine. This study is the first time to explore the pharmacological basis of application in amyotrophic lateral sclerosis (ALS) through network pharmacology and molecular docking techniques. In the present investigation, the TCMSP database and HIT2 database were examined for 9 TCM constituents of Sheng Ji Yu Sui Decoction (SJYSD), and the desired sites for the components were searched in the Drugbank database. and the Sjysd-target network was constructed. Associated targets for Amyotrophic lateral sclerosis (ALS) were then retrieved and collected in the OMIM, TTD, Genecards and DisGeNET databases. Protein-protein interaction and enrichment analysis were performed for the common targets of drugs and diseases, and molecular anchoring for the chosen core targets and related molecules was carried out. The results showed that SJYSD had 100 active compounds corresponding to 598 targets. ALS has a total of 5,325 genes. SJYSD and ALS share 163 genes, and these targets involve PI3K-AKT signaling, p53 signaling and IL-17 signaling, etc. The core components of luteolin and quercetin were discovered and may be used to treat ALS by regulating PI3K-AKT signaling pathway by HSP90AB1 protein.

Liensinine and neferine exert neuroprotective effects via the autophagy pathway in transgenic Caenorhabditis elegans.

BACKGROUND: Liensinine and neferine are the main bisbenzylisoquinoline alkaloids obtained from the seeds of Nelumbo nucifera, which commonly used as edible food and traditional medicine in Asia. It was reported that liensinine and neferine could inhibit the activities of acetylcholinesterase and cross the blood-brain barriers, suggesting their therapeutic potential for the management of Alzheimer's disease. METHODS: Here, we employed SH-SY5Y human neuroblastoma cells stably transfected with the human Swedish amyloid precursor protein (APP) mutation APP695 (APP695swe SH-SY5Y) as an in vitro model and transgenic Caenorhabditis elegans as an in vivo model to investigate the neuroprotective effects and underlying mechanism of liensinine and neferine. RESULTS: We found that liensinine and neferine could significantly improve the viability and reduce ROS levels in APP695swe SH-SY5Y cells, inhibit ß-amyloid and tau-induced toxicity, and enhance stress resistance in nematodes. Moreover, liensinine and neferine had obviously neuroprotective effects by assaying chemotaxis, 5-hydroxytryptamine sensitivity and the integrity of injured neurons in nematodes. Preliminary mechanism studies revealed that liensinine and neferine could upregulate the expression of autophagy related genes (lgg-1, unc-51, pha-4, atg-9 and ced-9) and reduce the accumulation of ß-amyloid induced autophagosomes, which suggested autophagy pathway played a key role in neuroprotective effects of these two alkaloids. CONCLUSIONS: Altogether, our findings provided a certain working foundation for the use of liensinine and neferine to treat Alzheimer's disease based on neuroprotective effects.

A randomized trial: The safety, pharmacokinetics and preliminary pharmacodynamics of ropivacaine oil delivery depot in healthy subjects.

INTRODUCTION: Ropivacaine oil delivery depot (RODD) can slowly release ropivacaine and block nerves for a long timejavascript:;. The aim of the present work was to investigate the safety, pharmacokinetics, and preliminary pharmacodynamics of RODD in subcutaneous injection among healthy subjects. METHODS: The abdomens of 3 subjects were subcutaneously administered with a single-needle RODD containing 12~30 mg of ropivacaine. The irritation, nerve blocking range and optimum dose were investigated. Forty-one subjects were divided into RODD groups containing 150, 230, 300, 350 and 400 mg of ropivacaine and a ropivacaine hydrochloride injection (RHI) 150 mg group. Multineedle subcutaneous injection of RODD or RHI was performed in the abdomens of the subjects. The primary endpoint was a safe dose or a maximum dose of ropivacaine (400 mg). Subjects' vital signs were observed; their blood was analyzed; their cardiovascular system and nervous systems were monitored, and their dermatological reactions were observed and scored. Second, the ropivacaine concentrations in plasma were determined, pharmacokinetic parameters were calculated, and the anesthetic effects of RODD were studied, including RODD onset time, duration and intensity of nerve block. RESULTS: Single-needle injection of RODD 24 mg was optimal for 3 subjects, and the range of nerve block was 42.5±20.8 mm. Multineedle subcutaneous injection of RODD in the abdomens of subjects was safe, and all adverse events were no more severe than grade II. The incidence rate of grade II adverse events, such as pain, and abnormal ST and ST-T segment changes on electrocardiography, was approximately 1%. The incidence rate of grade I adverse events, including erythema, papules, hypertriglyceridemia, and hypotension was greater than 10%. Erythema and papules were relieved after 24 h and disappeared after 72 h. Other adverse reactions disappeared after 7 days. The curve of ropivacaine concentration-time in plasma presented a bimodal profile. The results showed that ropivacaine was slowly released from the RODD. Compared with the 150 mg RHI group, Tmax was longer in the RODD groups. In particular, Tmax in the 400 mg RODD group was longer than that in the RHI group (11.8±4.6 h vs. 0.77±0.06 h). The Cmax in the 150 mg RODD group was lower than that in the 150 mg RHI group (0.35±0.09 vs. 0.58±0.13 µg·mL-1). In particular, the Cmax increased by 48% when the dose was increased by 2.6 times in the 400 mg group. Cmax, the AUC value and the intensity of the nerve block increased with increasing doses of RODD. Among them, the 400 mg RODD group presented the strongest nerve block (the percentage of level 2 and 3, 42.9%). The corresponding median onset time was 0.42 h, and the duration median was 35.7⁓47.7 h. CONCLUSIONS: RODD has a sustained release effect. Compared with the RHI group, Tmax was delayed in the RODD groups, and the duration of nerve block was long. No abnormal reaction was found in the RODD group containing 400 mg of ropivacaine after subcutaneous injection among healthy subjects, suggesting that RODD was adequately safe. TRIAL REGISTRATION: Chictr.org: CTR2200058122; Chinadrugtrials.org: CTR20192280.