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Abstract Accumulating evidence suggests that caspase-3 plays critical roles beyond apoptosis, serving pro-survival functions in malignant transformation and tumorigenesis. However, the mechanism of non-apoptotic action of caspase-3 in oncogenic transformation remains unclear. In the present study, we show that caspase-3 is consistently activated in malignant transformation induced by exogenous expression of oncogenic cocktail (c-Myc, p53DD, Oct-4, and H-Ras) in vitro as well as in the mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT) mouse model of breast cancer. Genetic ablation of caspase-3 significantly attenuated oncogene-induced transformation of mammalian cells and delayed breast cancer progression in MMTV-PyMT transgenic mice. Mechanistically, active caspase-3 triggers the translocation of endonuclease G (EndoG) from mitochondria, which migrates to the nucleus, thereby induces phosphorylation of Src-STAT3 signaling pathway to facilitate oncogenic transformation. Taken together, our data suggest that caspase-3 plays pivotal role in facilitating rather than suppressing oncogene-induced malignant transformation of mammalian cells.

Cancer is the leading cause of mortality in human health, with the highest mortality rate among all diseases. Unfortunately, most of the current cancer treatments inevitably come with certain side effects. Therefore, a significant amount of research is focused on the development of safe and effective anticancer drugs. Sulforaphane is one of the most bioactive natural compounds isolated from cruciferous plants. Numerous studies show its anti-cancer, antioxidant, and antiviral properties, as well as its anticancer mechanisms. Sulforaphane can inhibit the growth of cancer cells by regulating the cell cycle, inhibiting cell migration and invasion, and inhibiting the expression of apoptosis related proteins. It can also inhibit the occurrence and development of cancer cells through anti-inflammatory and antioxidant measures. Some reports also indicate that sulforaphane can impede the development of cancer cells through its anti-inflammatory and antioxidant effects. Compared to most traditional cancer treatment methods, sulforaphane is much safer and more reliable. It is also more readily available and has great anticancer potential. This paper review the anticancer mechanisms of sulforaphane over the past two years and provide the corresponding theoretical basis for further research on the anticancer effects of sulforaphane.

Abstract High intraocular pressure (IOP) is one of the early complications after pars plana vitrectomy (PPV), which may cause glaucoma and poor visual prognosis secondary to surgery. Proliferative vitreoretinopathy (PVR) is one of the complications of retinal detachment (RD) and is the main reason for the poor prognosis, which is related to different kinds of cytokines. It’s essential for the basic mechanism to analyze the relative aqueous humor cytokine profiles with IOP after PPV for RD. In this study, we have collected the aqueous humor of 16 patients and qualified 27 cytokines using Luminex and compared biomarkers with the high IOP group and the normal group. As a result, the concentrations of VEGF, IL-6, FGF2, and G-CSF upregulated significantly (P

Abstract Background The incidence of postoperative sore throat (POST) after tracheal intubation using double-lumen endobronchial tubes (DLTs) is higher in patients with prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection than in the general population. This prospective trial was conducted to determine whether thermal softening of DLTs could decrease the incidence of POST or other airway injuries in patients with prior SARS-CoV-2 infection. Methods A total of 120 patients with prior SARS-CoV-2 infection undergoing thoracoscopic surgery were randomly assigned to two groups (n = 60 each). In the thermal softening group, the distal portion of the DLT was placed in thermostatic saline (50 °C) for 10 min before endotracheal intubation. In the control group, the distal portion of the DLT was placed in room temperature saline for 10 min before endotracheal intubation. The incidence and severity of POST and hoarseness were assessed at 1, 6 and 24 h postoperatively. The primary outcomes were the incidence and severity of POST at 6 h postoperatively. The secondary outcomes were the incidence and severity of hoarseness, vocal cord and tracheal injuries, and hemodynamic changes in patients at intubation. Results The incidence of POST at 6 h postoperatively was greater in the control group than in the thermal softening group [41 (68%) vs. 22 (37%), P = 0.001]. The overall incidence of POST at 24 h postoperatively was greater in the control group than in the thermal softening group [46 (76%) vs. 24 (40%), P

The high penetration of distributed photovoltaics (PV) in distribution networks (DNs) results in voltage violations, imbalances, and flickers, leading to significant disruptions in DN stability. To address this issue, this paper proposes a multi-timescale voltage regulation approach that involves the coordinated control of a step voltage regulator (SVR), switched capacitor (SC), battery energy storage system (BESS), and electric vehicle (EV) across different timescales. During the day-ahead stage, the proposed method utilizes artificial hummingbird algorithm optimization-based least squares support vector machine (AHA-LSSVM) forecasting to predict the PV output, enabling the formulation of a day-ahead schedule for SVR and SC adjustments to maintain the voltage and voltage unbalance factor (VUF) within the limits. In the intra-day stage, a novel floating voltage threshold band (FVTB) control strategy is introduced to refine the day-ahead schedule, enhancing the voltage quality while reducing the erratic operation of SVR and SC under dead band control. For real-time operation, the African vulture optimization algorithm (AVOA) is employed to optimize the BESS output for precise voltage regulation. Additionally, a novel smoothing fluctuation threshold band (SFTB) control strategy and an initiate charging and discharging strategy (ICD) for the BESS are proposed to effectively smooth voltage fluctuations and expand the BESS capacity. To enhance user-side participation and optimize the BESS capacity curtailment, some BESSs are replaced by EVs for voltage regulation. Finally, a simulation conducted on a modified IEEE 33 system validates the efficacy of the proposed voltage regulation strategy.

Abstract Introduction We estimated the safety and efficacy of ultrasound-guided multipoint fascial plane block, including serratus anterior plane block (SAPB) and bilateral transversus abdominis plane block (TAPB) in elderly patients who underwent combined thoracoscopic–laparoscopic esophagectomy (TLE). Methods The authors enrolled 80 patients in this prospective study after patient selection using the inclusion and exclusion criteria who were scheduled for elective TLE from May 2020 to May 2021. Patients were randomly assigned to the treated group (group N) or the control group (group C) (n = 40 per group) using the sealed-envelope method. Multipoint fascial plane blocks, including serratus anterior plane block (SAPB) and bilateral TAPB, were performed on patients undergoing TLE using a solution of 60 mL 0.375% ropivacaine plus 2.5 mg dexamethasone by 3 injections of 20 mL each (group N) or no interventions (group C). Results Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) at T incision and 30 min after T incision were significantly higher in group C than in group N, and also significantly higher than at baseline (P

In recent decades, antiangiogenic therapy, which blocks the supply of oxygen and nutrition to tumor cells, has become a promising clinical strategy for the treatment of patients with tumors. However, recent studies revealed that vasculogenic mimicry (VM), which is the process by which vascular morphological structures are formed by highly invasive tumor cells, has been considered a potential factor for the failure of antiangiogenic therapy in patients with tumors. Thus, inhibition of VM formation might be a potential target for improving the outcome of antiangiogenic strategies. However, the mechanism underlying VM formation is still incompletely elucidated. Herein, we report that L1CAM might be a critical regulator of VM formation in glioma, and might be associated with the resistance of glioma to antiangiogenic therapy. We found that the tumor‐invasion and tube‐formation capabilities of L1CAM‐overexpressing cells were significantly enhanced in vitro and in vivo. In addition, the results indicated that miR‐143‐3p, which might directly target the 3'UTR of the hexokinase 2 (HK2) gene to regulate its protein expression, was subsequently involved in L1CAM‐mediated VM formation by glioma cells. Further study revealed that the regulation of MMP2, MMP9, and VEGFA expression was involved in this process. Moreover, we identified that activation of the downstream PI3K/AKT signaling pathway of the L1CAM/HK2 cascade is critical for VM formation by glioma cells. Furthermore, we found that the combined treatment of anti‐L1CAM neutralizing monoclonal antibody and bevacizumab increases efficacy beyond that of bevacizumab alone, and suppresses glioma growth in vivo, indicating that the inhibition of L1CAM‐mediated VM formation might efficiently improve the effect of antiangiogenic treatment for glioma patients. Together, our findings demonstrated a critical role of L1CAM in regulating VM formation in glioma, and that L1CAM might be a potential target for ameliorating tumor resistance to antiangiogenic therapy in glioma patients.

Due to the unsatisfactory therapeutic efficacy and inexorable side effects of small molecule antineoplastic agents, extensive efforts have been devoted to the development of more potent macromolecular agents with high specificity. Gelonin is a plant-derived protein toxin that exhibits robust antitumor effect via inactivating ribosomes and inhibiting protein synthesis. Nonetheless, its poor internalization ability to tumor cells has compromised the therapeutic promise of gelonin. In this study, a tumor acidity-responsive intracellular protein delivery system ─ functional gelonin (Trx-pHLIP-Gelonin, TpG) composed of a thioredoxin (Trx) tag, a pH low insertion peptide (pHLIP) and gelonin, was designed and obtained by genetic recombination technique for the first time. TpG could effectively enter into tumor cells under weakly acidic conditions and markedly suppress tumor cell proliferation via triggering cell apoptosis and inhibiting protein synthesis. Most importantly, treatment by intravenous injection into subcutaneous SKOV3 solid tumors in a mouse model showed that TpG was much more effective than gelonin in curtailing tumor growth rates with negligible toxicity. Collectively, our present work suggests that the tumor acidity-targeted delivery manner endowed by pHLIP offers a new avenue for efficient delivery of other bioactive substances to acidic diseased tissues.

BackgroundNeuropathic pain is caused by a neurological injury or disease and can have a significant impact on people’s daily lives. Studies have shown that neuropathic pain is commonly associated with neurodegenerative diseases. In recent years, there has been a lot of literature on the relationship between neuropathic pain and neurodegenerative diseases. However, bibliometrics is rarely used in analyzing the general aspects of studies on neuropathic pain in neurodegenerative diseases.MethodsThe bibliometric analysis software CiteSpace and VOSviewer were used to analyze the knowledge graph of 387 studies in the Science Citation Index Expanded of the Web of Science Core Collection Database.ResultsWe obtained 2,036 documents through the search, leaving 387 documents after culling. 387 documents were used for the data analysis. The data analysis showed that 330 papers related to neuropathic pain in neurodegenerative diseases were published from 2007–2022, accounting for 85.27% of all published literature. In terms of contributions to the scientific study of neuropathic pain, the United States is in the top tier, with the highest number of publications, citations, and H-indexes.ConclusionThe findings in our study may provide researchers with useful information about research trends, frontiers, and cooperative institutions. Multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease are the three most studied neurodegenerative diseases. Among the pathological basis of neurodegenerative diseases, microglia-regulated neuroinflammation is a hot research topic. Deep brain stimulation and gamma knife radiosurgery are two popular treatments.

Abstract This study examines the 22-year development of the Shanghai Biennale from a localized contemporary art exhibition to an internationally renowned art biennale. Through the lens of organizational legitimacy, this research examines how the Shanghai Biennale negotiated changing external pressures to establish within China and grow into the international art world. Using a mix-methods approach, we first create a unique database of participant nationality and then examine artist and curatorial statements, media reports, and interviews with organizers and curators of the Shanghai Biennale from 1996 to 2018. Our study delineates three periods of the Shanghai Biennale’s development: incipient (1996–1998), internationalization (2000–2010), and expanding period (2012–2018). Through these periods we examine the different pathways by which the Shanghai Biennale attained legitimacy first within the local and national Chinese context and then within the Biennale’s expansion into the international art scene. We find at the beginning stage of the Shanghai Biennale, establishing local legitimacy was the foremost concern. When the Shanghai Biennale started to diffuse into the global art world in 2000, focus shifted towards remaking the Shanghai Biennale to comply with international perceptions. That said, our research finds both local and international legitimacy requirements remained salient simultaneously, with the importance of maintaining a good relationship with the Chinese State as a critical basis for internationalization and development. In the most recent editions, more local and non-Western features are included in the Shanghai Biennale, signaling the Biennale’s efforts of distinguishing itself in the global biennale scene. This research contributes to organizational study by closely examining a cultural organization’s ability to negotiate legitimacy requirements in different contexts, but also empirically responds to recent calls for studies on the global development of non-Western biennales.

ObjectiveNeuropathic pain (NP) is a common disease that manifests with pathological changes in the somatosensory system. In recent years, the interactions of NP with the epigenetic mechanism have been increasingly elucidated. However, only a few studies have used bibliometric tools to systematically analyze knowledge in this field. The objective of this study is to visually analyze the trends, hotspots, and frontiers in epigenetics and NP research by using a bibliometric method.MethodsStudies related to epigenetics and NP were searched from the Science Citation Index-Expanded of the Web of Science Core Collection database. Search time is from inception to November 30, 2022. No restrictions were placed on language. Only articles and reviews were included as document types. Data on institutions, countries, authors, journal distribution, and keywords were imported into CiteSpace software for visual analysis.ResultsA total of 867 publications met the inclusion criteria, which spanned the period from 2000 to 2022. Over the years, the number of publications and the frequency of citations exhibited a clear upward trend in general, reaching a peak in 2021. The major contributing countries in terms of the number of publications were China, the United States, and Japan. The top three institutions were Rutgers State University, Xuzhou Medical University, and Nanjing Medical University. Molecular Pain, Pain, and Journal of Neuroinflammation contributed significantly to the volume of issues. Among the top 10 authors in terms of the number of publications, Tao Yuan-Xiang contributed 30 entries, followed by Zhang Yi with 24 and Wu Shao-Gen with 20. On the basis of the burst and clusters of keywords, “DNA methylation,” “Circular RNA,” “acetylation,” “long non-coding RNA,” and “microglia” are global hotspots in the field.ConclusionThe bibliometric analysis indicates that the number of publications related to epigenetics and NP is exhibiting a rapid increase. Keyword analysis shows that “DNA methylation,” “Circular RNA,” “acetylation,” “long non-coding RNA” and “microglia” are the most interesting terms for researchers in the field. More rigorous clinical trials and additional studies that explore relevant mechanisms are required in the future.

Summary: Cyclic GMP-AMP synthase (cGAS) senses cytosolic incoming DNA and consequently activates stimulator of interferon response cGAMP interactor 1 (STING) to mount immune response. Here, we show nuclear cGAS could regulate VEGF-A-mediated angiogenesis in an immune-independent manner. We found VEGF-A stimulation induces cGAS nuclear translocation via importin-β pathway. Moreover, nuclear cGAS subsequently regulates miR-212-5p-ARPC3 cascade to modulate VEGF-A-mediated angiogenesis through affecting cytoskeletal dynamics and VEGFR2 trafficking from trans-Golgi network (TGN) to plasma membrane via a regulatory feedback loop. In contrast, cGAS deficiency remarkably impairs VEGF-A-mediated angiogenesis in vivo and in vitro. Furthermore, we found strong association between the expression of nuclear cGAS and VEGF-A, and the malignancy and prognosis in malignant glioma, suggesting that nuclear cGAS might play important roles in human pathology. Collectively, our findings illustrated the function of cGAS in angiogenesis other than immune surveillance, which might be a potential therapeutic target for pathological angiogenesis-related diseases.

Abstract Cytotoxic chemotherapy is a primary treatment modality for many patients with advanced cancer. Increasing preclinical and clinical observations indicate that chemotherapy can exacerbate tumor metastasis. However, the underlying mechanism remains unclear. Here, it is attempted to identify the mechanisms underlying chemotherapy‐induced cancer recurrence and metastasis. It is revealed that a small subpopulation of “near‐death cells” (NDCs) with compromised plasma membranes can reverse the death process to enhance survival and repopulation after exposure to lethal doses of cytotoxins. Moreover, these NDCs acquire enhanced tumorigenic and metastatic capabilities, but maintain chemosensitivity in multiple models. Mechanistically, cytotoxin exposure induces activating transcription factor 4 (ATF4)‐dependent nonclassical NF‐κB signaling activation; ultimately, this results in nuclear translocation of p52 and RelB in NDCs. Deletion of ATF4 in parental cancer cells significantly reduces colony formation and metastasis of NDCs, whereas overexpression of ATF4 activates the nonclassical NF‐κB signaling pathway to promote chemotherapy‐induced metastasis of NDCs. Overall, these results provide novel mechanistic insights into the chemotherapy‐induced metastasis and indicate the pivotal role of NDCs in mediating tumor relapse after cytotoxic therapy. This study also suggests that targeting ATF4 may be an effective approach in improving the efficacy of chemotherapy.

Assessing the relationships between ecosystem services supply and demand is crucial to support sustainable planning and human well-being. In the present study, we analyzed the ecosystem services supply and demand, synergies and trade-offs among services, as well as the spatial relationships between supply and demand, for four services in a desert steppe of Inner Mongolia. In terms of the balance between supply and demand, the grass production and carbon stock supply exceeded the demand, whereas the demand of water yield and windbreak and sand fixation services surpassed the supply. The degree of demand in windbreak and sand fixation service was met increased from 14.7% in 2000 to 20.6% in 2017, versus a decrease from 18.0% to 8.2% in water yield. The spatial distributions of the water yield and carbon stock demand were similar, and there was a significant synergy between them. The grass production supply and demand were not spatially matched, with higher supply in the eastern part of the study area and higher demand in the western part. Areas with high demand for the windbreak and sand fixation service also had a high supply. The water supply and demand in the low-coverage grassland were relatively balanced, and the deficiency of carbon stock supply was mainly found in construction land. In summary, for the sustainable development of animal husbandry and to reduce wind erosion, each county should establish an appropriate livestock density standard based on local constraints. Furthermore, it is also crucial for policymakers to develop water-saving industries to improve water utilization efficiency, and to set targets for CO2 emissions to reduce the impact on climate change.

Alternative splicing generates RNA isoforms that contribute to phenotypic diversity. Here the authors perform single-molecule full-length RNA sequencing to identify disease-associated variant transcript isoforms.

Liandan Xiaoyan Formula (LXF), a classic Traditional Chinese medicine (TCM) formula, is composed of two Chinese herbal medicines for treating bowel disease under the TCM theory. This study aimed to develop a rapid, stable, sensitive, and reliable method based on ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to simultaneously determine four major bioactive components of LXF (andrographolide, dehydroandrographolide, 1-methoxicabony-β-carboline, 4-methoxy-5-hydroxy-canthin-6-one) in rat serum and evaluate the pharmacokinetic characteristics of LXF in ulcerative colitis (UC) and control rats. After pretreating by protein precipitation with methanol, separation was performed on a UPLC C18 column using gradient elution with a mobile phase consisting of acetonitrile and 0.1% formic acid at a flowing rate of 0.4 ml/min. Detection was performed on Triple-TOF™ 5600 mass spectrometry set at the positive ionization and multiple reaction monitoring (MRM) mode. The validated method showed good linearity (R2 ≥ 0.9970), the intra- and inter-day accuracy were within ±11.58%, whereas the intra- and inter-day precision were less than 13.79%. This method was validated and applied to compare the pharmacokinetic profiles of the analytes in serum of UC induced by dextran sulphate sodium (DSS) and control rats after oral administration of LXF. The results showed that four major bioactive components of LXF were quickly absorbed after oral administration in both groups, with higher exposure levels in the UC group. This relationship between the active ingredients’ pharmacokinetic properties provided essential scientific information for applying LXF in clinical.

Rabdosia serra (Maxim.) Hara (R. serra), one of the source plants of “Xihuangcao”, has been widely used as a Chinese folk herb with the concomitant function of both medicine and foodstuff for the prevention and treatment of liver disease. Diterpenoids were considered as the major bioactive components in R. serra, responsible for their effect on hepatoprotection in previous phytochemical and pharmacological studies, while few comparative pharmacokinetic studies have been conducted under the physiological and pathological conditions. To reveal the difference in the pharmacokinetics process of R. serra extract (RSE) in normal and Con A-induced liver injury rats, a rapid ultra-high-pressure liquid chromatography–tandem mass spectrometry method (total running time: 5 min) was established to simultaneously determine three bioactive diterpenoids (enmein, epinodosin, and isodocarpin) in rat plasma. The results showed significant differences in the pharmacokinetic properties of three analytes between the physiological and pathological states. Compared with normal rats, the AUC of the three analytes was remarkably higher in liver injury rats, while the Tmax, T1/2, and MRT were shortened. It indicated that RSE has higher exposure and quicker elimination in liver injury rats than that in normal rats. Our results suggested that the pharmacokinetics of hepatoprotective medications was affected by liver injury, which prospected to provide essential information for guiding the healthcare and clinical application of R. serra in pathological states.

Abstract Background Ovarian clear cell carcinoma (OCCC) is a special pathological type of epithelial ovarian carcinoma (EOC). We conducted this research to investigate the clinical characteristics and outcomes of OCCC and to provide additional supporting evidence to aid in the clinical diagnosis and management. Methods This was a retrospective study investigating the clinical characteristics and survival outcomes of 86 patients with OCCC treated at our center between January 2010 and March 2020. Survival analysis was also performed on 179 patients with OCCC obtained from the Surveillance, Epidemiology and End Results (SEER) cancer registry database. Results The median age of participants was 49.21 ± 9.91 years old, and 74.42% of them were diagnosed at early stage. The median CA125 level was 601.48 IU/mL, while 19.77% of the patients had normal CA125 levels. Sixteen patients (18.60%) had co-existing endometriosis and 8 patients (9.3%) developed venous thromboembolism (VTE). There were 5 patients received suboptimal cytoreduction. Sixty-six patients (76.74%) underwent lymphadenectomy, and only 3 (4.55%) patients had positive lymph nodes. Patients diagnosed at an early stage had higher 3-year overall survival (OS) and progression-free survival (PFS) rates than those with advanced stage OCCC. CA19–9 (P = 0.025) and ascites (P = 0.001) were significantly associated with OS, while HE4 (P = 0.027) and ascites (P = 0.001) were significantly associated with PFS. Analysis of data from the SEER database showed that positive lymph nodes is also an independent prognostic factor for OS (P = 0.001). Conclusions OCCC often presents at an early stage and young age with a mildly elevated CA125. CA19–9, HE4, massive ascites, and positive lymph node are independent prognostic factors.

Abstract Background Grazing is an important land use in northern China. In general, different grazing intensities had a different impact on the morphological and physiological traits of plants, and especially their photosynthetic capacity. We investigated the responses of Leymus chinensis to light, medium, and heavy grazing intensities in comparison with a grazing exclusion control. Results With light grazing, L. chinensis showed decreased photosynthetic capacity. The low chlorophyll and carotenoid contents constrained light energy transformation and dissipation, and Rubisco activity was also low, restricting the carboxylation efficiency. In addition, the damaged photosynthetic apparatus accumulated reactive oxygen species (ROS). With medium grazing, more energy was used for thermal dissipation, with high carotene content and high non-photochemical quenching, whereas photosynthetic electron transport was lowest. Significantly decreased photosynthesis decreased leaf C contents. Plants decreased the risk caused by ROS through increased energy dissipation. With high grazing intensity, plants changed their strategy to improve survival through photosynthetic compensation. More energy was allocated to photosynthetic electron transport. Though heavy grazing damaged the chloroplast ultrastructure, adjustment of internal mechanisms increased compensatory photosynthesis, and an increased tiller number facilitated regrowth after grazing. Conclusions Overall, the plants adopted different strategies by adjusting their metabolism and growth in response to their changing environment.

Background: Immune checkpoint inhibitors have been successfully used in a variety of tumors, however, the efficacy of immune checkpoint blockade therapy for patients with glioma is limited. In this study, we tried to clarify gene expression signatures related to the prognosis of gliomas and construct a signature to predict the survival of patients with gliomas.Methods: Calcium-related differential expressed genes (DEGs) between gliomas and normal brain tissues were comprehensively analyzed in two independent databases. Univariate, multivariate Cox regression analysis and proportional hazards model were used to identify the prognostic of calcium-related risk score signature. The CIBERSORT algorithm and association analysis were carried out to evaluate the relationship between calcium-related signature and characteristic clinical features, tumor-infiltrating immune cell signatures as well as immune checkpoint molecules in glioma. A nomogram model was developed for predicting the overall survival for patients with gliomas.Results: We found the intersection of 415 DEGs between gliomas and normal brain tissues, and identified that an eighteen calcium-related gene panel was significantly enriched in these DEGs. A calcium-related signature derived risk score was developed to divide patients into high- and low-risk groups. Low levels of calcium-related gene expression in high-risk score cases were accompanied with worse outcomes of patients. Calcium-related risk scores were significantly associated with characteristic clinical features, immune infiltrating signatures of tumor microenvironment, and exhausted T cell markers including programmed cell death 1 (PD-1), lymphocyte activating 3 (LAG3), and T cell membrane protein 3 (TIM-3), which contribute to an adverse therapeutic effect of immunotherapy. Calcium-related signature risk score was considered as an independent prognostic parameter to predict the of overall survival of patients with gliomas in nomogram model.Conclusion: Our study demonstrated that calcium signaling pathway is highly associated with immunosuppression of gliomas and overall survival of patients. Targeting the calcium signaling pathway might be a new strategy to reverse the immunosuppressive microenvironment of gliomas and improve the efficacy of glioma immunotherapy.

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial pulmonary disease with a poor prognosis. The extract of Nervilia fordii (NFE) has shown remarkable benefit in the treatment of acute lung injury, lung cancer, and severe acute respiratory syndrome (SARS). However, the potential mechanism and efficacy of NFE in the treatment of IPF remain unknown. In this study, a systematic network pharmacology analysis was used to predict the mechanism and efficacy of NFE in the treatment of IPF, based on the major components of NFE elucidated by UPLC-TOF-MS/MS. The potential molecular interactions between the compounds and potential targets were predicted using molecular docking. In vivo, rats with pulmonary fibrosis induced by a single intratracheal injection of bleomycin (BLM) were orally administered NFE for 14 days. Lung index and biochemical levels were determined, and histopathological analysis using hematoxylin and eosin (H&E) and Masson staining was performed. The effects of NFE on fibroblast proliferation in Lipopolysaccharide (LPS) and TGF-β1-induced mouse 3T6 fibroblasts were evaluated in vitro. In total, 20 components were identified in NFE, and 102 potential targets for IPF treatment were predicted. These targets potentially participate in processes regulated by transmembrane receptor protein tyrosine kinase, ERBB2, and et al. Molecular docking results predicted high affinity interactions between three components (rhamnazin, rhamnetin, and rhamnocitrin) and the potential targets, suggesting that TGF-β is the most important potential target of NFE in the treatment of pulmonary fibrosis. NFE significantly decreased the lung index and alleviated BLM-induced pulmonary fibrosis in rats. Histopathological observation of lung tissues showed that NFE alleviated inflammation and collagen deposition in BLM-induced rats. NFE inhibited the migration of LPS- and TGF-β1-induced 3T6 fibroblasts, reduced the contents of hydroxyproline and collagen, and contributed to anti-inflammation and anti-oxidation. With the intervention of NFE, the protein and RNA expression of TGF-β1, a-SMA, Smad3/4, p-Smad3/4, CTGF, and p-ERK1/2 were significantly downregulated, while Smad7 and ERK1/2 were upregulated significantly in vivo and in vitro. These findings indicated that NFE may exert therapeutic effects on pulmonary fibrosis by alleviating inflammation, oxidation, and collagen deposition. The mechanism related to the inhibition of the TGF-β/Smad signaling pathway.

This research aimed to excavate compounds with activity reducing hepatocytes lipid accumulation from Delphinium brunonianum. Four novel diterpenoid alkaloids, brunodelphinine B–E, were isolated from D. brunonianum together with eleven known diterpenoid alkaloids through a phytochemical investigation. Their structures were elucidated by comprehensive spectroscopy methods including HR-ESI-MS, NMR, IR, UV, CD, and single-crystal X-ray diffraction analysis. The inhibitory effects of a total of 15 diterpenoid alkaloids on hepatocytes lipid accumulation were evaluated using 0.5 mM FFA (oleate/palmitate 2:1 ratio) to induce buffalo rat liver (BRL) cells by measuring the levels of triglyceride (TG), total cholesterol (TC), alanine transaminase (ALT), aspartate transaminase (AST), and the staining of oil red O. The results show that five diterpenoid alkaloids—brunodelphinine E (4), delbruline (5), lycoctonine (7), delbrunine (8), and sharwuphinine A (12)—exhibited significant inhibitory effects on lipid accumulation in a dose-dependent manner and without cytotoxicity. Among them, sharwuphinine A (12) displayed the strongest inhibition of hepatocytes lipid accumulation in vitro. Our research increased the understanding on the chemical composition of D. brunonianum and provided experimental and theoretical evidence for the active ingredients screened from this herbal medicine in the treatment of the diseases related to lipid accumulation, such as non-alcoholic fatty liver disease and hyperlipidemia.

This case report describes a 43-year-old female initially diagnosed with gestational trophoblastic neoplasia that then experienced metastasis to the liver and then subsequently to the pancreas nearly 4 years after the primary diagnosis. After resection of the body and tail of the pancreas, the postoperative histopathological examination confirmed a placental site trophoblastic tumour that had developed after several cycles of chemotherapy for the original primary tumour and the liver metastases. This type of sequential recurrence of gestational trophoblastic neoplasia in the primary site or metastatic sites, such as the liver or pancreas, can be cured by a comprehensive treatment strategy involving surgery and/or salvage chemotherapy and continuous follow-up over a long period, especially for patients with a high-risk status.

The data presented here are related to a research article entitled âDevelopment of a phosphorylated Momordica charantia protein system for inhibiting susceptible dose-dependent C. albicans to available antimycotics: An allosteric regulation of proteinâ (Qiao et al., 2017) [1]. The data set includes three portions: (1) a relationship between reaction velocities of protein phosphorylation as a function of the substrate concentrations, determined in enzymatic reactions in aid of protein kinases; (2) a result of antifungal susceptibility testing of C. albicans after it is selected in antimycotics; and (3) a comparison of protein expression in the susceptible dose-dependent fungus relative to the wild C. albicans. In the first portion, the relationship of reaction velocities and substrate concentrations is expressed as an output from the inverse variation model. All data and analyses are made publicly available and citied in the research article using a style for the Data in Brief. Keywords: in vitro phosphorylation, Momordica charantia protein, Protein kinase catalysis, Antifungal susceptibility testing, C. albicans

Aims and Hypothesis: NEDD9 is highly expressed in gastric cancer and has a significant involvement in its pathogenesis. However, the mechanism behind hypoxia-promoted cancer cell migration and its regulation because of NEDD9 is still unknown. The aim of this study is to investigate the involvement of NEDD9 in gastric cancer cell migration under hypoxia and explore the underlying potential molecular mechanisms.MethodsCell motility was measured by wound healing and transwell assay. NEDD9 and MICAL1 expressions were examined by western blot analysis. Interaction between NEDD9 and MICAL1 was assessed by immunohistochemistry and co-immunoprecipitation assay, respectively. Cells were transfected with plasmids or siRNA to upregulate or downregulate the expression of NEDD9 and MICAL1. Rac1, Cdc42, and RhoA activation was assessed by pulldown assay.ResultsThe mRNA and protein level of NEDD9 increased as a result of hypoxia in gastric cancer cell lines BGC-823 and SGC-7901 while decreased levels of NEDD9 caused reduced cell migratory potential in response to hypoxia. Hypoxia also caused the enhancement of MICAL1 expression. Furthermore, it was revealed that there is a positive correlation between NEDD9 and MICAL1 protein while hypoxia played role in increasing their interaction. Under hypoxic conditions, silencing of NEDD9 caused reduction in the stability of MICAL1 protein, while depletion of MICAL1 also inhibited the migration of NEDD9-overexpressing gastric cancer cells. In addition, silencing of NEDD9 or MICAL1 expression reversed the increased GTP forms of Rac1 and Cdc42 in hypoxic cells. However, only the upregulation of Rac1-GTP level was observed in gastric cancer cells that were already overexpressed by MICAL1.ConclusionIn all, it is concluded that MICAL1 is regulated by NEDD9 that facilitates hypoxia-induced gastric cancer cell migration via Rac1-dependent manner.

H3K36 methylation by Set2 targets Rpd3S histone deacetylase to transcribed mRNA genes, repressing internal cryptic promoters and modulating elongation. Here, the authors provide evidence that the Set2-Rpd3S pathway also regulates dynamic expression of mRNAs and lncRNAs.

The histone variant H2A.Z is a hallmark of nucleosomes flanking promoters of protein-coding genes and is often found in nucleosomes that carry lysine 56-acetylated histone H3 (H3-K56Ac), a mark that promotes replication-independent nucleosome turnover. Here, we find that H3-K56Ac promotes RNA polymerase II occupancy at many protein-coding and noncoding loci, yet neither H3-K56Ac nor H2A.Z has a significant impact on steady-state mRNA levels in yeast. Instead, broad effects of H3-K56Ac or H2A.Z on RNA levels are revealed only in the absence of the nuclear RNA exosome. H2A.Z is also necessary for the expression of divergent, promoter-proximal noncoding RNAs (ncRNAs) in mouse embryonic stem cells. Finally, we show that H2A.Z functions with H3-K56Ac to facilitate formation of chromosome interaction domains (CIDs). Our study suggests that H2A.Z and H3-K56Ac work in concert with the RNA exosome to control mRNA and ncRNA expression, perhaps in part by regulating higher-order chromatin structures.

OBJECTIVES:The aim of this study was to elucidate the molecular mechanisms by which food-derived casein glycomacropeptide (CGMP) maintains internal homeostasis in the intestinal mucosa and to investigate the effects of CGMP on the intestinal mucosal immunological barrier and related signal transduction pathways. METHODS:In this study, a famoxadone (OXZ)-induced mouse experimental ulcerative colitis (UC) model was built. The experimental UC mice were intragastrically administered milk-derived CGMP for four consecutive days. The molecular mechanisms by which milk-derived CGMP improved and restored the inflammatory status in UC symptoms were elucidated by H&E staining, immunohistochemical staining and western blotting. RESULTS:The results indicated that CGMP (50 mg/(kg bw·d)) could significantly improve morphological injury to intestinal mucosa in OXZ-induced UC mice to the same extent that did sulfasalazine (SASP, 40 mg/(kg bw·d)), a medicine used to treat UC, in the control group. The study found that CGMP could significantly reduce the expression of Human mucosal addressin cell adhesion molecule-1 (MAdCAM-1), Cluster of differentiation 4 (CD4) and Cluster of differentiation 8 (CD8) in the lamina propria of the intestinal mucosa and significantly stimulate the secretion of sIgA to increase intestinal immunity. Furthermore, CGMP was found to be directly involved in inhibiting the MAPK pathway and activating the TGF-β1/Smad signal transduction cascade, which could maintain immunological regulation of the intestinal mucosa and protect the functions of the intestinal mucosal barrier. CONCLUSIONS:This study elucidated the molecular mechanisms by which CGMP maintained homeostasis of the intestinal mucosa and further confirmed its pharmaceutical value as a food-derived functional component with promising potential for further exploration/utilization.

Yeast Npl3 is a highly abundant, nuclear-cytoplasmic shuttling, RNA-binding protein, related to metazoan SR proteins. Reported functions of Npl3 include transcription elongation, splicing and RNA 3' end processing. We used UV crosslinking and analysis of cDNA (CRAC) to map precise RNA binding sites, and strand-specific tiling arrays to look at the effects of loss of Npl3 on all transcripts across the genome. We found that Npl3 binds diverse RNA species, both coding and non-coding, at sites indicative of roles in both early pre-mRNA processing and 3' end formation. Tiling arrays and RNAPII mapping data revealed 3' extended RNAPII-transcribed RNAs in the absence of Npl3, suggesting that defects in pre-mRNA packaging events result in termination readthrough. Transcription readthrough was widespread and frequently resulted in down-regulation of neighboring genes. We conclude that the absence of Npl3 results in widespread 3' extension of transcripts with pervasive effects on gene expression.

A high-sensitivity mechano-luminescent sensor was fabricated on the basis of piezoelectric/electroluminescent composites. The working principle of this mechano-luminescent sensor was elucidated by analyzing the relationship between the piezoelectric-induced charges and the electroluminescent effects. When a stress is applied on the piezoelectric layer, electrical charges will be induced at both the top and bottom sides of the piezoelectric layer. The induced electrical charges will lead to a light output from the electroluminescent layer, thus producing a mechano-luminescence effect. By increasing the vibration strength or frequency applied, the mechano-luminescence output can be obviously enhanced. Mechano-luminescence sensors have potential in smart stress-to-light devices, such as foot-stress-distribution-diagnosis systems and dynamic-load-monitors for bridge hanging cables.

The objective of this study was to evaluate the hepatoprotective and metabolic effects of rosmarinic acid (RA) in rats. RA [100 mg/kg body weight (BW)] was intragastrically (i.g.) administered to Sprague-Dawley (SD) rats once a day for seven consecutive days. The rats were then i.g. administered α-naphthylisothiocyanate (ANIT) (80 mg/kg once on the 5th day) to induce acute intrahepatic cholestasis after the last administration of RA. Blood samples were collected at different time points (0.083 h, 0.17 h, 0.33 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, 20 h) after administration, and the levels of RA were estimated by HPLC. Plasma and bile biochemical analysis, bile flow rate, and liver histopathology were measured to evaluate the hepatoprotective effect of RA. The PK-PD curves showed obviously clockwise (AST and ALT) or anticlockwise (TBA, TBIL). Pretreatment with RA at different doses significantly restrained ANIT-induced pathological changes in bile rate, TBA, TBIL, ALT, AST (p < 0.05 or p < 0.01). The relationship between RA concentration and its hepatoprotective effects on acute cholestasis responses was assessed by PK-PD modeling.

The quantitative analysis of multiple components with a single marker (QAMS) method was firstly established for simultaneous determination of 18 active components in Ilex kudingcha C. J. Tseng by HPLC. Using rutin, isochlorogenic acid A and kudinoside A as internal refererence substances (IRS), compatibility results showed that the relative correction factors (RCFs) of all compounds showed good reproducibility under different chromatographic conditions. On the basis of previous studies, the accuracy of the QAMS method was systematically evaluated by investigating the influences of curve intercept, analytes and IRS concentration. The results showed that the concentration (especially at low level) of analytes and curve intercept were the major influencing parameters for the LRG-QAMS method (LRG = linear regression), whereas the influence of IRS concentration seemed more apparent in terms of the AVG-QAMS method (AVG = average). The two approaches were complementary with each other. In addition, hierarchical clustering analysis (HCA), principal components analysis (PCA) and similarity analysis (SA) were performed to differentiate and classify the samples based on the contents of 18 marker compounds. The results of the different chemometric analyses were completely consistent with each other, and could be supported by the quantification results.

Nature Communications 7: Article number: 13534 (2016); Published 28 November 2016; Updated 29 November 2017 The ArrayExpress accession code is incorrect in this Article. The correct accession code is E-MTAB-4268.

In contrast to the extensively reported therapeutic activities, far less attention has been paid to the intestinal absorption of the total saponins from Radix Ilicis Pubescentis (in Chinese Mao-Dong-Qing, MDQ). This study aimed to investigate the intestinal absorption characteristics of ilexgenin A (C1), ilexsaponin A1 (C2), ilexsaponin B1 (C3), ilexsaponin B2 (C4), ilexsaponin B3 (DC1), and ilexoside O (DC2) when administrated with the total saponins from MDQ (MDQ-TS). An UPLC method for simultaneous determination of C1, C2, C3, C4, DC1, and DC2 in intestinal outflow perfusate was developed and validated. The absorption characteristics of MDQ-TS were investigated by evaluating the effects of intestinal segments, drug concentration, P-glycoprotein (P-gp) inhibitor (verapomil), endocytosis inhibitor (amantadine) and ethylene diamine tetraacetic acid (EDTA, tight junction modulator) on the intestinal transportation of MDQ-TS by using a single-pass intestinal perfusion (SPIP) rat model, and the influence of co-existing components on the intestinal transport of the six saponins was discussed. The results showed that effective apparent permeability (Papp) of C1, C2, C3, C4, and DC2 administrated in MDQ-TS form had no segment-dependent changes at low and middle dosage levels. C1, C2, C3, D4, DC1, and DC2 administrated in MDQ-TS form all exhibited excellent transmembrane permeability with Papp > 0.12 × 10−2 cm·min−1. Meanwhile, Papp and effective absorption rate constant (Ka) values for the most saponins showed concentration dependence and saturation characteristics. After combining with P-gp inhibitor of verapamil, Papp of C2, C3, and DC1 in MDQ-TS group was significantly increased up to about 2.3-fold, 1.4-fold, and 3.4-fold, respectively in comparison to that of non-verapamil added group. Verapamil was found to improve the absorption of C2, C3, and DC1, indicating the involvement of an active transport mechanism in the absorption process. Compared with the non-amantadine added group, the absorption of C1, C2, C4, DC1, and DC2 were decreased by 40%, 71%, 31%, 53%, and 100%, respectively. Papp for the six target compounds increased up to about 1.2–2.1-fold in comparison with the non-EDTA added, respectively. The gastrointestinal transport of MDQ-TS could be greatly promoted by EDTA, and inhibited by amantadine, implying that the intestinal absorption of MDQ-TS was by passive diffusion and endocytosis process. Compared with monomer administration group, the intestinal absorption of C3, C4, DC1, and DC2 was significantly improved by co-existing components in MDQ-TS, and the non-absorbable saponins of C4, DC1, and DC2 unexpectedly showed sufficient intestinal permeability with Papp > 0.12 × 10−2 cm·min−1. This suggested that compounds orally administrated in TCM extract forms displayed unique intestinal absorption characteristics different from those of monomers, and the enhancing intestinal absorption of MDQ-TS reflected a holistic and specific view of traditional Chinese medicines (TCMs).

Unraveling the molecular processes that lead from genotype to phenotype is crucial for the understanding and effective treatment of genetic diseases. Knowledge of the causative genetic defect most often does not enable treatment; therefore, causal intermediates between genotype and phenotype constitute valuable candidates for molecular intervention points that can be therapeutically targeted. Mapping genetic determinants of gene expression levels (also known as expression quantitative trait loci or eQTL studies) is frequently used for this purpose, yet distinguishing causation from correlation remains a significant challenge. Here, we address this challenge using extensive, multi-environment gene expression and fitness profiling of hundreds of genetically diverse yeast strains, in order to identify truly causal intermediate genes that condition fitness in a given environment. Using functional genomics assays, we show that the predictive power of eQTL studies for inferring causal intermediate genes is poor unless performed across multiple environments. Surprisingly, although the effects of genotype on fitness depended strongly on environment, causal intermediates could be most reliably predicted from genetic effects on expression present in all environments. Our results indicate a mechanism explaining this apparent paradox, whereby immediate molecular consequences of genetic variation are shared across environments, and environment-dependent phenotypic effects result from downstream integration of environmental signals. We developed a statistical model to predict causal intermediates that leverages this insight, yielding over 400 transcripts, for the majority of which we experimentally validated their role in conditioning fitness. Our findings have implications for the design and analysis of clinical omics studies aimed at discovering personalized targets for molecular intervention, suggesting that inferring causation in a single cellular context can benefit from molecular profiling in multiple contexts.