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Abstract Glioblastoma (GBM), a primary brain tumor, exhibits remarkable invasiveness and is characterized by its intricate location, infiltrative behavior, the presence of both the blood–brain barrier (BBB) and the blood–brain tumor barrier (BBTB), phenotypic diversity, an immunosuppressive microenvironment with limited development yet rich vascularity, as well as the resistant nature of glioblastoma stem cells (GSCs) towards traditional chemotherapy and radiotherapy. These formidable factors present substantial obstacles in the quest for effective GBM treatments. Following extensive research spanning three decades, the hepatocellular receptor A2 (EphA2) receptor tyrosine kinase has emerged as a promising molecular target with translational potential in the realm of cancer therapy. Numerous compounds aimed at targeting EphA2 have undergone rigorous evaluation and clinical investigation. This article provides a comprehensive account of the distinctive roles played by canonical and non-canonical EphA2 signaling in various contexts, while also exploring the involvement of the EphA2-ephrin A1 signaling axis in GBM pathogenesis. Additionally, the review offers an overview of completed clinical trials targeting EphA2 for GBM treatment, shedding light on both the prospects and challenges associated with EphA2-directed interventions in the domain of cancer therapeutics.

Abstract Diabetic cardiomyopathy (DCM) represents a unique myocardial disease originating from diabetic metabolic disturbances that is characterized by myocardial fibrosis and diastolic dysfunction. While recent research regarding the pathogenesis and treatment of DCM has focused primarily on myocardial cells, nonmyocardial cells—including fibroblasts, vascular smooth muscle cells (VSMCs), endothelial cells (ECs), and immune cells—also contribute significantly to the pathogenesis of DCM. Among various therapeutic targets, fibroblast growth factor 21 (FGF21) has been identified as a promising agent because of its cardioprotective effects that extend to nonmyocardial cells. In this review, we aim to elucidate the role of nonmyocardial cells in DCM and underscore the potential of FGF21 as a therapeutic strategy for these cells.

Abstract Aims The endoscopic treatment of esophagogastric varices is challenging, and the nationwide application of endoscopic therapies for various types of esophagogastric varices and different clinical scenarios remains unclear. This study investigated the use of endoscopic therapy for portal hypertension in China. Methods This study used a questionnaire survey initiated by the Liver Health Consortium in China to investigate the use of endoscopic therapies for portal hypertension. Questionnaires were released online from January 30, 2023 to February 28, 2023 and filled out by chief physicians or senior instructors responsible for endoscopic therapies in participating hospitals across 31 provinces (autonomous regions and municipalities) in China. Comparisons of guideline adherence between primary and referral medical centers were performed using the chi‐square test or Fisher's exact test. Results In total, 836 hospitals participated in the survey. For primary and secondary prophylaxis of esophagogastric variceal bleeding (EGVB), adherence to the national guidelines was 72.5% (606/836) and 39.2% (328/836), respectively. Significant differences were observed in the rate of adherence between the primary and referral centers for primary (79.9% [111/139] vs. 71.0% [495/697], p = 0.033) and secondary prophylaxis (27.3% [38/139] vs. 41.6% [290/697], p = 0.002). Of the hospitals, 78.2% (654/836) preferred endoscopic therapies for acute EGVB, and the timing of endoscopy was usually within 12 h (48.5%, 317/654) and 12–24 h (36.9%, 241/654) after bleeding. Endoscopic therapy was more likely to be the first choice of treatment for acute EGVB in referral centers than in primary centers (82.6% [576/697] vs. 56.1% [78/139], p

Chemotherapy remains the first choice of treatment for colon cancer despite the inevitable adverse effects. Curcumin (CU) possesses antitumor activity but has poor aqueous solubility, low bioavailability, and weak activity. To address this, nine novel monocarbonyl CU analogues were designed, synthesized, and evaluated in the present study. Among them, CA8 exhibited the highest water solubility, which was approximately 2.37 × 106 times that of CU. In addition, compared with CU, its cytotoxicity on Caco-2 cells (19.2 times/48 h) was stronger. Of note, CA8 arrestedthe cell cycle of Caco-2 cells at the G2/M phase and induced apoptosis. Meanwhile, acute toxicity experiments indicated that KM mice tolerated CA8 for up to 300 mg/kg CA8 (oral administration) and 50 mg/kg CA8 (intraperitoneal injection). The oral administration of CA8 to Sprague Dawley rats exhibited higher AUC (0-t) (6.23-fold) and longer MRT (0-t) (3.35-fold) than that of CU. CA8 also inhibited the proliferation and angiogenesis of tumor cells more than CU and tegafur. Finally, CA8 may exert anti-tumor effects through the activation of JNK pathway and inhibition of AKT pathway. These results suggest that CA8 is a safe and highly effective new drug for colon cancer treatment.

IntroductionThe surgery of clival chordoma remains one of the most formidable challenges for neurosurgeons because of its location at great depth in the cranium and proximity to critical neurovascular structures. Here, we describe the technique and feasibility of the purely endoscopic far-lateral supracerebellar infratentorial approach (EF-SCITA) for resection of an intradural clival chordoma.Case descriptionA 68-year-old women presented with sudden ptosis on the left side for two weeks. Imaging examinations revealed an upper-middle clival lesion that transgressed dural confines towards the posterior fossa, which was separated from the sphenoid cavity by an intact thin layer of membrane structure in front. For surgery, the EF-SCITA approach via suboccipital craniotomy was attempted for protecting surrounding neurovascular tissue and the membrane barrier under direct vision. The patients were placed in a “head-up” lateral park-bench position. With the endoscopic holder, endoscopic procedures were performed using standard two-hand microsurgical techniques by one surgeon. Tentorium incision allowed a working corridor toward the clival bulge through the crural cistern, without brain traction seen in traditional retrosigmoid approach. Efficient tumor debulking facilitated the exposure of surrounding critical structures, including ipsilateral CN III and superior cerebellar artery above, the brainstem and basilar artery posteriorly, as well as ipsilateral CN VI displaced laterally, and subsequent tumor separation from them. Step-wise tumor resection was performed within dural and bone confines. After significant tumor removal, the pituitary stalk could be visualized anteriorly, together with contralateral internal carotid artery and CN III. Postoperative MRI depicted gross total excision of the lesion. The patient on follow-up at one year had complete recovery of cranial nerve functions, without signs of cerebrospinal fluid rhinorrhea.DiscussionThis technique combines advantages of the posterolateral approach and endoscopy, allowing access to the upper-middle clivus with seemingly low risks of postoperative morbidity. It would be a safe and effective alternative for resection of this rare entity.

Background: G protein-coupled receptor 68 (GPR68), an orphan receptor, has emerged as a promising therapeutic target for mitigating neuronal inflammation and oxidative damage. This study explores the protective mechanisms of GPR68 in cerebral ischemia-reperfusion injury (CIRI). Methods: An in vivo middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model was established. Mice received intraperitoneal injections of Ogerin, a selective GPR68 agonist. In vitro, GPR68 was overexpressed in SH-SY5Y and HMC3 cells, and the effects of oxygen-glucose deprivation/reperfusion (OGD/R) on cell viability were assessed using real-time quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and flow cytometry. Results: The expression of GPR68 was suppressed in cells subjected to OGD/R treatment, whereas its upregulation conferred protection to SH-SY5Y and HMC3 cells. In vivo, levels of GPR68 were reduced in brain tissues affected by MCAO/R, correlating with oxidative stress, inflammation, and neurological damage. Treatment with a GPR68 agonist decreased brain infarction, apoptosis, and dysregulated gene expression induced by MCAO/R. Mechanistically, GPR68 agonist treatment may inhibit the activation of the NF-κB/Hif-1α pathway, thereby reducing oxidative and inflammatory responses and enhancing protection against CIRI. Conclusions: This study confirms that the GPR68/NF-κB/Hif-1α axis modulates apoptosis, inflammation, and oxidative stress in CIRI, indicating that GPR68 is a potential therapeutic target for CIRI.

ObjectiveThis study aims to investigate the inhibitory effect of Polydatin (PD) on endoplasmic reticulum (ER) stress following subarachnoid hemorrhage (SAH) and to elucidate the underlying mechanisms.MethodsA standard intravascular puncture model was established to mimic SAH in mice. Neurological functions were assessed using neurological scoring, Grip test, and Morris water maze. Brain edema and Evans blue extravasation were measured to evaluate blood-brain barrier permeability. Western blot and quantitative real-time polymerase chain reaction (PCR) analyses were performed to examine protein and mRNA expressions related to ER stress. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining was used to detect cell apoptosis, and transmission electron microscopy was used to observe the ultrastructure of the endoplasmic reticulum.ResultsThe results indicated that PD significantly reduced brain edema and Evans blue extravasation after SAH, improving neurological function. Compared to the SAH group, the expression levels of ER stress-related proteins including glucose-regulated protein 78 (GRP78), phosphorylated protein kinase R-like endoplasmic reticulum kinase (p-PERK), phosphorylated eukaryotic initiation factor 2α (p-eIF2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP), were significantly lower in the PD-treated group. Moreover, PD significantly enhances the protein expression of Sirtuin 1 (SIRT1). Validation with sh-SIRT1 confirmed the critical role of SIRT1 in ER stress, with PD’s inhibitory effect on ER stress being dependent on SIRT1 expression. Additionally, PD attenuated ER stress-mediated neuronal apoptosis and SAH-induced ferroptosis through upregulation of SIRT1.ConclusionPD alleviates ER stress following SAH by upregulating SIRT1 expression, thereby mitigating early brain injury. The protective effects of PD are mediated through SIRT1, which inhibits ER stress and reduces neuronal apoptosis and ferroptosis.

Gliomas are primary tumors that originate in the central nervous system. The conventional treatment options for gliomas typically encompass surgical resection and temozolomide (TMZ) chemotherapy. However, despite aggressive interventions, the median survival for glioma patients is merely about 14.6 months. Consequently, there is an urgent necessity to explore innovative therapeutic strategies for treating glioma. The foundational study of regulated cell death (RCD) can be traced back to Karl Vogt’s seminal observations of cellular demise in toads, which were documented in 1842. In the past decade, the Nomenclature Committee on Cell Death (NCCD) has systematically classified and delineated various forms and mechanisms of cell death, synthesizing morphological, biochemical, and functional characteristics. Cell death primarily manifests in two forms: accidental cell death (ACD), which is caused by external factors such as physical, chemical, or mechanical disruptions; and RCD, a gene-directed intrinsic process that coordinates an orderly cellular demise in response to both physiological and pathological cues. Advancements in our understanding of RCD have shed light on the manipulation of cell death modulation - either through induction or suppression - as a potentially groundbreaking approach in oncology, holding significant promise. However, obstacles persist at the interface of research and clinical application, with significant impediments encountered in translating to therapeutic modalities. It is increasingly apparent that an integrative examination of the molecular underpinnings of cell death is imperative for advancing the field, particularly within the framework of inter-pathway functional synergy. In this review, we provide an overview of various forms of RCD, including autophagy-dependent cell death, anoikis, ferroptosis, cuproptosis, pyroptosis and immunogenic cell death. We summarize the latest advancements in understanding the molecular mechanisms that regulate RCD in glioma and explore the interconnections between different cell death processes. By comprehending these connections and developing targeted strategies, we have the potential to enhance glioma therapy through manipulation of RCD.

Abstract NOAA Daily Optimum Interpolation Sea Surface Temperature (DOISST) and other similar sea surface temperature (SST) products indicate that the globally averaged SST set a new daily record in March 2023. The record‐high SST in March was immediately broken in April, and new daily records were set again in July and August 2023. The SST anomaly (SSTA) persisted at a record high from mid‐March to the remainder of 2023. Our analysis indicates that the record‐high SSTs, and associated marine heatwaves (MHWs) and even super‐MHWs, are attributed to three factors: (a) a long‐term warming trend, (b) a shift to the warm phase of the multi‐decadal Pacific‐Atlantic‐Arctic (PAA) mode, and (c) the transition from the triple‐dip succession of La Niña events to the 2023–24 El Niño event.

Aims: To provide a comprehensive bibliometric overview of drug resistance in bladder cancer (BC) from 1999 to 2022, aiming to illuminate its historical progression and guide future investigative avenues. Methods: Literature on BC drug resistance between 1999 and 2022 was sourced from the Web of Science. Visual analyses were executed using Vosviewer and Citespace software, focusing on contributions by countries, institutions, journals, authors, references, and keywords. Results: From 2727 publications, a marked growth in BC drug resistance studies was discerned over the two decades. Prominent among all institutions is the University of Texas System. The majority of top-ranked journals were American. In authorship significance, McConkey DJ led in publications, while Bellmunt J dominated in citations. Research topics predominantly spanned cancer demographics, drug efficacy evaluations, molecular features, oncology subtypes, and individualized treatment strategies, with a notable contemporary emphasis on molecular mechanisms behind drug resistance and nuances of ICIs. Conclusions: Our bibliometric analysis charts the landscape of BC drug resistance research from 1999 to 2022. While the study of resistance mechanisms has been robust, there's an evident need for deeper exploration into the molecular intricacies and the potential of ICIs and targeted therapeutic strategies.

BackgroundFalcotentorial meningiomas (FM) are surgical challenges for protecting sinus, and the technique notes on the management of superior sagittal or transverse sinus are required for good results.MethodsWe improved the technique notes on the management of superior sagittal or transverse sinus in three FM patients with signs of increased intracranial pressure or chronic headache.ResultsAll patients underwent surgeries in the prone position, and occipital/sup-occipital/sub-occipital craniotomy was performed. In one patient, the skull was removed traditionally with exposure of the confluence of sinuses, superior sagittal, and transverse sinus, while the longitudinal skull bridge was left to suspend the dura for protecting the superior sagittal sinus in one patient, and the transverse skull bridge was left to suspend the dura for protecting the transverse sinus in one patient. The dura was opened infratentorially or supratentorially to spare the sinus and then the “skull bridge” was suspended. The tumor was then removed completely without brain swelling or significant venous bleeding. Complete tumor resection was confirmed by early postoperative imaging, and all patients recovered well without postoperative morbidity.ConclusionThe authors recommend the “skull bridge” to suspend the dura for optimal control of the venous sinuses during FM surgery (less venous bleeding).

Abstract Due to their atomically dispersed active centers, single‐atom nanozymes (SAzymes) have unparalleled advantages in cancer catalytic therapy. Here, loaded with chlorin e6 (Ce6), a hydrothermally mass‐produced bimetallic silicate‐based nanoplatforms with atomically dispersed manganese/gadolinium (Mn/Gd) dual sites and oxygen vacancies (OVs) (PMnSAGMSNs‐V@Ce6) is constructed for tumor glutathione (GSH)‐triggered chemodynamic therapy (CDT) and O2‐alleviated photodynamic therapy. The band gaps of silica are significantly reduced from 2.78 to 1.88 eV by doping with metal ions, which enables it to be excited by a 650 nm laser to produce electron‐hole pairs, thereby facilitating the generation of reactive oxygen species. The Gd sites can modulate the local electrons of the atom‐catalyzed Mn sites, which contribute to the generation of superoxide and hydroxyl radicals (•OH). Tumor GSH‐triggered Mn2+ release can convert endogenous H2O2 to •OH and realize GSH‐depletion‐enhanced CDT. Significantly, the hydrothermally generated OVs can not only capture Mn and Gd atoms to form atomic sites but also can elongate and weaken the O‐O bonds of H2O2, thereby improving the efficacy of Fenton reactions. The degraded Mn2+/Gd3+ ions can be used as tumor‐specific magnetic resonance imaging contrast agents. All the experimental results demonstrate the great potential of PMnSAGMSNs‐V@Ce6 as cancer theranostic agent.

Verticillium wilt, caused by Verticillium dahliae, seriously restricts the yield and quality improvement of cotton. Previous studies have revealed the involvement of WRKY members in plant defense against V. dahliae, but the underlying mechanisms involved need to be further elucidated. Here, we demonstrated that Gossypium hirsutum WRKY DNA-binding protein 33 (GhWRKY33) functions as a negative regulator in plant defense against V. dahliae. GhWRKY33 expression is induced rapidly by V. dahliae and methyl jasmonate, and overexpression of GhWRKY33 reduces plant tolerance to V. dahliae in Arabidopsis. Quantitative RT-PCR analysis revealed that expression of several JA-associated genes was significantly repressed in GhWRKY33 overexpressing transgenic plants. Yeast one-hybrid analysis revealed that GhWRKY33 may repress the transcription of both AtERF1 and GhERF2 through its binding to their promoters. Protein–protein interaction analysis suggested that GhWRKY33 interacts with G. hirsutum JASMONATE ZIM-domain protein 3 (GhJAZ3). Similarly, overexpression of GhJAZ3 also decreases plant tolerance to V. dahliae. Furthermore, GhJAZ3 acts synergistically with GhWRKY33 to suppress both AtERF1 and GhERF2 expression. Our results imply that GhWRKY33 may negatively regulate plant tolerance to V. dahliae via the JA-mediated signaling pathway.

Abstract Purpose Glioma patients have varying degrees of psychiatric symptoms, which severely affect the quality of life of patients and their families. The present study investigated the correlation between preoperative psychiatric symptoms and local cerebral perfusion parameters of in glioma patients. Patients and methods The depression, anxiety, and cognitive impairment (CI) scores of 39 patients were assessed separately, and all of the patients underwent a preoperative perfusion computed tomography scan. Results This study found that: (1) The incidence of preoperative symptoms of depression, anxiety, and CI was 46.15%, 48.72%, and 25.64%, respectively. (2) Cerebral blood volume (CBV) (lesion‐sided [LS] occipital lobe white matter [WM] and parietal lobe WM and normal‐sided temporal lobe WM), permeability surface (PS) (LS temporal lobe gray matter [GM] and parietal lobe WM) in the depression group were significantly decreased (p

Abstract. Meningiomas are the most common primary intracranial neoplasm with diverse pathological types and complicated clinical manifestations. The fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5), published in 2021, introduces major changes that advance the role of molecular diagnostics in meningiomas. To follow the revision of WHO CNS5, this expert consensus statement was formed jointly by the Group of Neuro-Oncology, Society of Neurosurgery, Chinese Medical Association together with neuropathologists and evidence-based experts. The consensus provides reference points to integrate key biomarkers into stratification and clinical decision making for meningioma patients. Registration:. Practice guideline REgistration for transPAREncy (PREPARE), IPGRP-2022CN234

Abstract The current study aimed to investigate the effects associated with SNAI2 on the proliferation of glioma stem cells (GSCs) to elucidate its underlying molecular mechanism in the development of glioma. The expression of Snail family transcriptional repressor 2 (SNAI2) in glioma tissues was initially predicted via bioinformatics analysis and subsequently confirmed by reverse transcription quantitative polymerase chain reaction (RT-qPCR), which revealed that SNAI2 was highly expressed in glioma tissues as well as GSCs, with an inverse correlation with overall glioma patient survival detected. Loss- and gain- of-function assays were performed to determine the roles of SNAI2 and pleckstrin homology domain and leucine rich repeat protein phosphatase 2 (PHLPP2) on GSC viability, proliferation and apoptosis. Data were obtained indicating that SNAI2 promoted the proliferation of GSCs, while overexpressed PHLPP2 brought about a contrasting trend. As detected by chromatin immunoprecipitation, RT-qPCR and agarose gel electrophoresis, SNAI2 bound to the promoter region of PHLPP2 and repressed the transcription of PHLPP2 while SNAI2 was found to inhibit PHLPP2 resulting in activation of the Akt pathway. Finally, the roles of SNAI2 and PHLPP2 were verified in glioma growth in nude mice xenografted with tumor. Taken together, the key findings of the present study suggest that SNAI2 may promote the proliferation of GSCs through activation of the Akt pathway by downregulating PHLPP2.

The integration of a microfluidic chip into terahertz time-domain attenuated total reflection (THz TD-ATR) spectroscopy is highly demanded for the accurate measurement of aqueous samples. Hitherto, however little work has been reported on this regard. Here, we demonstrate a strategy of fabricating a polydimethylsiloxane microfluidic chip (M-chip) suitable for the measurement of aqueous samples, and investigate the effects of its configuration, particularly the cavity depth of the M-chip on THz spectra. By measuring pure water, we find that the Fresnel formulae of two-interface model should be applied to analyze the THz spectral data when the depth is smaller than 210 μm, but the Fresnel formula of one-interface model can be applied when the depth is no less than 210 μm. We further validate this by measuring physiological solution and protein solution. This work can help promote the application of THz TD-ATR spectroscopy in the study of aqueous biological samples.

Abstract Long non-coding RNAs (lncRNAs) have been manifested to manipulate diverse biological processes, including tumor-induced immune tolerance. Thus, we aimed in this study to identify the expression pattern of lncRNA homeobox A cluster antisense RNA 2 (HOXA-AS2) in glioma and decipher its role in immune tolerance and glioma progression. We found aberrant upregulation of lncRNA HOXA-AS2, lysine demethylase 2A (KDM2A), and jagged 1 (JAG1) and a downregulation of microRNA-302a (miR-302a) in glioma specimens. Next, RNA immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter gene assay demonstrated that lncRNA HOXA-AS2 upregulated KDM2A expression by preventing miR-302a from binding to its 3′untranslated region. The functional experiments suggested that lncRNA HOXA-AS2 could promote regulatory T (Treg) cell proliferation and immune tolerance, which might be achieved through inhibition of miR-302a and activation of KDM2A/JAG1 axis. These findings were validated in a tumor xenograft mouse model. To conclude, lncRNA HOXA-AS2 facilitates KDM2A/JAG1 expression to promote Treg cell proliferation and immune tolerance in glioma by binding to miR-302a. These findings may aid in the development of novel antitumor targets.

The phytochrome B mediated light signaling integrates with various phytohormone signalings to control plant immune response. However, it is still unclear whether phyB-mediated light signaling has an effect on the biosynthesis of jasmonate during plant defense response against Botrytis cinerea. In this study, we demonstrated that phyB-mediated light signaling has a role in this process. Initially, we confirmed that phyb plants were obviously less resistant to B. cinerea while phyB overexpressing plants showed significantly enhanced resistance. We also found that the expression of numerous JA biosynthesis genes was promoted upon treatment with red or white light when compared to that of darkness, and that this promotion is dependent on phyB. Consistent with the gene expression results, phyb plants accumulated reduced pool of JA-Ile, indicating that phyB-mediated light signaling indeed increased JA biosynthesis. Further genetic analysis showed that light-mediated JAZ9 degradation and phyB-enhanced resistance were dependent on the receptor COI1, and that pif1/3/4/5 (pifq) can largely rescue the severe symptom of phyb. Taken together, our study demonstrates that phyB may participate in plant defense against B. cinerea through the modulation of the biosynthesis of JA.

Abstract Background The aim of this study was to investigate the relationship between tumor biology and values of cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), time to peak (TTP), permeability surface (PS) of tumor in patients with glioma. Methods Forty-six patients with glioma were involved in the study. Histopathologic and molecular pathology diagnoses were obtained by tumor resection, and all patients accepted perfusion computed tomography (PCT) before operation. Regions of interests were placed manually at tumor and contralateral normal-appearing thalamus. The parameters of tumor were divided by those of contralateral normal-appearing thalamus to normalize at tumor (relative [r] CBV, rCBF, rMTT, rTTP, rPS). The relationships of the parameters, world health organization (WHO) grade, molecular pathological findings were analysed. Results The rCBV, rMTT and rPS of patients are positively related to the pathological classification (P

WRKY transcription factors play essential roles during leaf senescence. However, the mechanisms by which they regulate this process remains largely unknown. Here, we identified the transcription factor WRKY75 as a positive regulator during leaf senescence. Mutations of WRKY75 caused a delay in age-triggered leaf senescence, whereas overexpression of WRKY75 markedly accelerated this process. Expression of senescence-associated genes (SAGs) was suppressed in WRKY75 mutants but increased in WRKY75-overexpressing plants. Further analysis demonstrated that WRKY75 directly associates with the promoters of SAG12 and SAG29, to activate their expression. Conversely, GAI and RGL1, two DELLA proteins, can suppress the WRKY75-mediated activation, thereby attenuating SAG expression during leaf senescence. Genetic analyses showed that GAI gain-of-function or RGL1 overexpression can partially rescue the accelerated senescence phenotype caused by WRKY75 overexpression. Furthermore, WRKY75 can positively regulate WRKY45 expression during leaf senescence. Our data thus imply that WRKY75 may positively modulate age-triggered leaf senescence through the gibberellin-mediated signaling pathway.

Abstract Glioblastoma angiogenesis is critical for tumor growth, making it an appealing target for treatment development. BAY1143269 is a novel inhibitor of mitogen‐activated protein kinase interacting serine/threonine‐protein kinase 1 (MKN1) and has potent anti‐cancer activity. We identified BAY1143269 as an angiogenesis inhibitor, by in vitro and in vivo glioblastoma angiogenesis models. BAY1143269 inhibited the capillary network formation of glioblastoma microvascular endothelial cells (GMECs), particularly the early stage of tubular structure formation. It also inhibited migration and proliferation, and induced apoptosis of GMECs isolated from glioblastoma patients. We found that BAY1143269 acted on GMECs by suppressing the eukaryotic translation initiation factor 4E (eIF4E) and eIF4E‐mediated expression of oncogenic proteins, including those involved in cell cycle, epithelial‐mesenchymal transition (EMT), and pro‐survival. In addition, BAY1143269 suppressed eIF4E phosphorylation, inhibited proliferation, and induced apoptosis of glioblastoma cells. Interestingly, it reduced vascular endothelial growth factor (VEGF) level in tumor cells and culturing medium, demonstrating the inhibitory effect of BAY1143269 on tumor proangiogenic microenvironment. We finally challenged BAY1143269 on the glioblastoma xenograft mice model and observed a significant tumor growth reduction without toxicity in mice receiving oral BAY1143269. Immunoblotting analysis demonstrated significantly less phosphorylated‐eIF4E (p‐eIF4E), cluster of differentiation 31 (CD31) (microvascular endothelial cell marker), and VEGF in tumors from drug‐treated mice. In summary, the inhibition of glioblastoma angiogenesis with BAY1143269 may provide an alternative approach for anti‐glioblastoma therapy.

Background: Glioma has a high incidence in young and middle-aged adults and a poor prognosis. Because of late diagnosis and uncontrollable recurrence of the primary tumor after failure of existing treatments, glioma patients tend to have a poor prognosis. Recent advances in research have revealed that gliomas exhibit unique genetic features. Mitogen-activated protein kinase 9 (MAPK9) is significantly upregulated in mesenchymal glioma spheres and may be a new target for glioma diagnosis. This study aimed to investigate the potential diagnostic significance and predictive value of MAPK9 in glioma. Methods: Paraffin-embedded tumor tissues and paracancerous tissues were collected from 150 glioma patients seen at the General Hospital of Northern Theater Command. Immunohistochemistry and western blot assays were used to detect the expression levels of MAPK9. Prognosis and survival analyses were performed using SPSS 26 software for univariate/multivariate analysis and log-rank analysis. Cellular models were used to assess the effect of MAPK9 overexpression and knockdown in vitro. Results: MAPK9 expression was higher in glioma tissues than in paraneoplastic tissues. Prognostic and survival analyses revealed that the MAPK9 expression level is an independent prognostic factor in glioma patients. In addition, overexpression of MAPK9 significantly promoted the proliferation and migration of primary glioma cells, possibly via the Wnt/β-catenin-regulated EMT pathway. Conclusions: MAPK9 is an independent prognostic factor in glioma and is involved in tumor progression.

SERRATE (SE) plays critical roles in RNA metabolism and plant growth regulation. However, its function in stress–response processes remains largely unknown. Here, we examined the regulatory role of SE using the se-1 mutant and its complementation line under saline conditions. The expression of SE was repressed by salt treatment at both mRNA and protein levels. After treatment with different NaCl concentrations, the se-1 mutants showed increased sensitivity to salinity. This heightened sensitivity was evidenced by decreased germination, reduced root growth, more serious chlorosis, and increased conductivity of the mutants compared with the wild type. Further analysis revealed that SE regulates the pre-mRNA splicing of several well-characterized marker genes associated with salt stress tolerance. Our data thus imply that SE may function as a key component in plant response to salt stress by modulating the splicing of salt stress-associated genes.

Nonlinear evolution equation is a research hot spot in the field of science and engineering. Recently, searching for breather and rogue wave solutions to nonlinear evolution equations has become a popular topic in nonlinear mathematical physics. In this paper, with the help of symbolic calculation, breather and rogue wave solutions to the two generalized (3+1)-dimensional Jimbo-Miwa equation are investigated, respectively. Those analytic solutions are presented, and the influences of the corresponding parameters on breathers and rogue waves are analyzed. Their dynamic properties are discussed based on graphical presentation. Amplitude of breathers and rogue waves are adjusted. Results of this study are helpful to the generation of breather and rogue waves in applied mechanics and physics.

Compared with the traditional rigid mechanism, the flexible mechanism has more advantages, which play an important role in critical situations such as microsurgery, IC (integrated circuit) fabrication/detection, and some precision operating environment. Especially, there is an increasing need for 3-DOF (degrees-of-freedom) compliant translational micro-platform (CTMP) providing good performance characteristics with large motion range, low cross coupling, and high spatial density. Decoupled topology design of the CTMP can easily realize these merits without increasing the difficulty of controlling. This paper proposes a new three DOF compliant hybrid micromanipulator which have large range of motion up to 100 μm × 100 μm × 100 μm in the direction in the dimension of 90 mm × 90 mm × 50 mm, smaller cross-axis coupling (the max coupling only 2.5%) than the initial XY compliant platform in XY axial.

Ischemic stroke is one of the leading causes of death and disability among adults. Despite the economic burden of the disease, available treatment options are still very limited. With the exception of anti-thrombolytics and hypothermia, current therapies fail to reduce neuronal injury, neurological deficits and mortality rates, suggesting that the development of novel and more effective therapies against ischemic stroke is urgent. In the present study, we found that artemether, which has been used in the clinic as an anti-malarial drug, was able to improve the neurological deficits, attenuate the infarction volume and the brain water content in a middle cerebral artery occlusion (MCAO) animal model. Furthermore, artemether treatment significantly suppressed cell apoptosis, stimulated cell proliferation and promoted the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), P90rsk and cAMP responsive element-binding protein (CREB). Artemether protective effect was attenuated by PD98059, an ERK1/2 inhibitor, administration. Similarly, in oxygen-glucose deprivation/reperfusion (OGD/RP) cell models, artemether pre-treatment induced the suppression of the intracellular ROS, the down-regulation of LDH activity, the reduction of caspase 3 activity and of the apoptosis cell rate and reversed the decrease of mitochondrial membrane potential. As with MCAO animal model, artemether promoted the activation of Erk1/2-P90rsk-CREB signaling pathway. This effect was blocked by the inhibition or knock-down of ERK1/2. The present study provides evidences of the neuroprotective effect of artemether unravelling its potential as a new therapeutic candidate for the prevention and treatment of stroke.

Gliomas are the most prevalent form of primary malignant brain tumor, which currently have no effective treatments. Evidence from human studies has indicated that oral microbiota is closely related to cancers; however, whether oral microbiota plays a role in glioma malignancy remains unclear. The present study aimed to investigate the association between oral microbiota and grade of glioma and examine the relationship between malignancy-related oral microbial features and the isocitrate dehydrogenase 1 (IDH1) mutation in glioma. High-grade glioma (HGG; n=23) patients, low-grade glioma (LGG; n=12) patients, and healthy control (HCs; n=24) participants were recruited for this case-control study. Saliva samples were collected and analyzed for 16S ribosomal RNA (rRNA) sequencing. We found that the shift in oral microbiota β-diversity was associated with high-grade glioma (p=0.01). The phylum Patescibacteria was inversely associated with glioma grade (LGG and HC: p=0.035; HGG and HC: p

Purpose: Tumors derived from the neuroepithelium are collectively termed gliomas and are the most common malignant primary brain tumor. Epilepsy is a common clinical symptom in patients with glioma, which can impair neurocognitive function and quality of life. Currently, the pathogenesis of glioma-related epilepsy is not fully described. Therefore, it is necessary to further understand the mechanism of seizures in patients with glioma. In this study, a comprehensive meta-analysis was conducted to investigate the relationship between five commonly used tumor molecular markers and the incidence of perioperative epilepsy in patients with glioma.Methods: PubMed, EMBASE, and Cochrane Library databases were searched for related research studies. Odds ratio and the corresponding 95% confidence interval were used as the main indicators to evaluate the correlation between tumor molecular markers and the incidence of perioperative epilepsy in patients with glioma.Results: A total of 12 studies were included in this meta-analysis. The results showed that isocitrate dehydrogenase 1 (IDH1) mutation was significantly correlated with the incidence of perioperative epilepsy. A subgroup analysis showed that IDH1 was significantly correlated with the incidence of preoperative epilepsy, but not with intraoperative and postoperative epilepsy. There was no correlation between O6-methylguanine-DNA methyltransferase methylation and 1p/19q deletion and the incidence of perioperative epilepsy. Tumor protein p53 and epidermal growth factor receptor could not be analyzed because of the limited availability of relevant literature. There was no significant heterogeneity or publication bias observed among the included studies.Conclusion: The present meta-analysis confirms the relationship between tumor molecular markers and the incidence of perioperative epilepsy in patients with glioma. The present results provide more comprehensive evidence for the study of the pathogenesis of glioma-related epilepsy. Our research may offer a new method for the treatment of perioperative seizures in patients with glioma.

Background: The occurrence of microthrombosis contributes to not only delayed cerebral ischemia (DCI), but also early brain injury (EBI) after SAH. However, the underlying mechanism is not completely investigated. In the current study, we explored the underlying mechanism of microthrombosis in EBI stage after SAH in ApoE-deficient mice.Methods: Experimental SAH was established by endovascular perforation in apolipoprotein E (ApoE)-deficient mice and wild type (WT) mice. Neurobehavioral, molecular biological and histopathological methods were used to assess the relationship between pericytes loss, neurobehavioral performance, and microthrombosis.Results: We found that the number of microthrombi was significantly increased and peaked 48 h after SAH in WT mice. The increased microthrombosis was related to the decreased effective microcirculation perfusion area and EBI severity. ApoE-deficient mice showed more extensive microthrombosis than that of WT mice 48 h after SAH, which was thereby associated with greater neurobehavioral deficits. Immunohistochemical staining showed that microthrombi were predominantly located in microvessels where pericytes coverage was absent. Mechanistically, ApoE deficiency caused more extensive CypA-NF-κB-MMP-9 pathway activation than that observed in WT mice, which thereby led to more degradation of N-cadherin, and subsequently more pericytes loss. Thereafter, the major adhesion molecule that promoting microthrombi formation in microvessels, P-selectin, was considerably increased in WT mice and increased to a greater extent in the ApoE-deficient mice.Conclusion: Taken together, these data suggest that pericytes loss is associated with EBI after SAH through promoting microthrombosis. Therapies that target ApoE to reduce microthrombosis may be a promising strategy for SAH treatment.

Abstract Glioma is regarded as an aggressive lethal primary brain tumor. Jumonji domain containing 1C (JMJD1C) is a H3K9 demethylase which participates in the progression of various tumors, but its specific function and underlying mechanism in glioma development remain undefined, which is the purpose of our work. We initially assessed JMJD1C expression in glioma tissues and cells using the assays of RT‐qPCR and immunohistochemistry. Meanwhile, the H3K9 level at the microRNA (miR)‐302a promoter region was measured by chromatin immunoprecipitation assay, while luciferase‐based reporter assay was performed for validation of the binding affinity between miR‐302a and methyltransferase‐like 3 (METTL3). The effect of METTL3 on suppressor of cytokine signaling 2 (SOCS2) was subsequently analyzed by MeRIP‐RT‐qPCR. Finally, a xenograft tumor model was established in nude mice, followed by measurement of tumor‐associated macrophages using flow cytometry. JMJD1C was poorly expressed in glioma tissues. Furthermore, JMJD1C increased miR‐302a expression through promoting H3K9me1 demethylation at the miR‐302a promoter region. miR‐302a was identified to target METTL3, which could inhibit SOCS2 expression via m6A modification. JMJD1C promoted M1 macrophage polarization and suppressed the growth of glioma xenografts through the miR‐302a/METTL3/SOCS2 axis both in vivo and in vitro. In conclusion, JMJD1C could enhance M1 macrophage polarization to inhibit the onset of glioma, bringing a new insight into the contribution of JMJD1C to the pathobiology of glioma, with possible implications for targeted therapeutic method.

Near-infrared-excited upconversion nanoparticles (UCNPs) have multicolor emissions, a low auto-fluorescence background, a high chemical stability, and a long fluorescence lifetime. The fluorescent probes based on UCNPs have achieved great success in the analysis of different samples. Here, we presented the research results of UCNPs probes utilized in analytical applications including environment, biology, food and medicine in the last five years; we also introduced the design and construction of upconversion optical sensing platforms. Future trends and challenges of the UCNPs used in the analytical field have also been discussed with particular emphasis.

Hydrodesulfurization of 4, 6-dimethyldibenzothiophene is of great significance for emission reduction and environmental protection. Herein, the effects of Mg addition on CoMo/Al2O3 were systematically studied for the hydrodesulfurization of 4, 6-dimethyldibenzothiophene. The CoMo/Mg-Al2O3 was formed by incorporating Mg in the alumina lattice and showed excellent hydrodesulfurization performance compared to CoMo/Mg/Al2O3 formed after deposition of Mg on the alumina surface and to CoMo/Al2O3 without introducing Mg. Experimental characterization and theoretical calculations showed that the introduction of Mg is beneficial to the formation of β-CoMoO4, which significantly promoted the production of CoMoS active sites. Meanwhile, the introduction of Mg mainly improved the medium-strong surface basic sites.

WRKY transcription factors play critical roles in the modulation of transcriptional changes during leaf senescence, but the underlying mechanisms controlled by them in this progress still remain enigmatic. In this study, Gossypium hirsutum WRKY DNA-binding protein 33 (GhWRKY33) was characterized as a negative regulator of both ageing and JA-mediated leaf senescence. The overexpression of GhWRKY33 in Arabidopsis greatly delayed leaf senescence, as determined by elevated chlorophyll content, lower H2O2 content, and reduced expression of several senescence-associated genes (SAGs). An electrophoretic mobility shift assay (EMSA) and transient dual–luciferase reporter assay revealed that GhWRKY33 could bind to the promoters of both AtSAG12 and Ghcysp and suppress their expression. Yeast two-hybrid (Y2H) and firefly luciferase complementation imaging (LUC) assays showed that GhWRKY33 could interact with GhTIFY10A. Similarly, the overexpression of GhTIFY10A in Arabidopsis also dramatically delayed leaf senescence. Furthermore, both GhWRKY33 and GhTIFY10A negatively regulate JA-mediated leaf senescence. In addition, a transientdual-luciferase reporter assay indicated that GhWRKY33 and GhTIFY10A could function synergistically to inhibit the expression of both AtSAG12 and Ghcysp. Thus, our work suggested that GhWRKY33 may function as a negative regulator to modulate both ageing and JA-mediated leaf senescence and also contributes to a basis for further functional studies on cotton leaf senescence.

Female genital tuberculosis (FGTB) is an infection caused by Mycobacterium tuberculosis and usually occurs secondary to pulmonary tuberculosis (TB) through the blood circulation, lymph circulation, or direct spreading from abdominal TB. FGTB is an uncommon type of TB that can destroy genital organs, and lead to menstrual disorders and infertility. The diagnosis of FGTB is often made by detection of acid-fast bacilli under microscopy, culture with endometrial biopsy, or histopathological examination of epithelioid granuloma on a biopsy. A multidrug anti-TB regimen is the major management of FGTB, including rifampicin, isoniazid, pyrazinamide, and ethambutol, while surgery is proposed in more deteriorated cases. However, the conception rate in infertile women with FGTB is still low, even after multidrug anti-TB therapy. Additionally, the risk of complications, such as ectopic pregnancy or miscarriage, remains high. In this review, we summarize the characteristics of FGTB, present current epidemiological data, and focus on its early diagnosis and effective management.

Glioblastoma (GBM), the primary malignant brain tumor, is typically associated with a poor prognosis and poor quality of life, mainly due to the lack of early diagnostic biomarkers and therapeutic targets. However, gene sequencing technologies and bioinformatics analysis are currently being actively utilized to explore potential targets for the diagnosis and management of malignancy. Herein, based on a variety of bioinformatics tools for the reverse prediction of target genes associated with the prognosis of GBM, a ceRNA network of AGAP2-AS1-miR-9-5p-MMP2/MMP9 was constructed, and a potential therapeutic target for GBM was identified. Enrichment analysis predicted that the ceRNA regulatory network participates in the processes of cell proliferation, differentiation, and migration.

Glioblastoma accounts for 45.2% of central nervous system tumors. Despite the availability of multiple treatments (e.g., surgery, radiotherapy, chemotherapy, biological therapy, immunotherapy, and electric field therapy), glioblastoma has a poor prognosis, with a 5-year survival rate of approximately 5%. The pathogenesis and prognostic markers of this cancer are currently unclear. To this end, this study aimed to explore the pathogenesis of glioblastoma and identify potential prognostic markers. We used data from the GEO and TCGA databases and identified five genes (ITGA5, MMP9, PTPRN, PTX3, and STX1A) that could affect the survival rate of glioblastoma patients and that were differentially expressed between glioblastoma patients and non-tumors groups. Based on a variety of bioinformatics tools for reverse prediction of target genes associated with the prognosis of GBM, a ceRNA network of messenger RNA (STX1A, PTX3, MMP9)-microRNA (miR-9-5p)-long non-coding RNA (CRNDE) was constructed. Finally, we identified five potential therapeutic drugs (bacitracin, hecogenin, clemizole, chrysin, and gibberellic acid) that may be effective treatments for glioblastoma.

Subarachnoid hemorrhage (SAH) is a devastating form of stroke, which poses a series of intractable challenges to clinical practice. Imbalance of mitochondrial homeostasis has been thought to be the crucial pathomechanism in early brain injury (EBI) cascade after SAH. Irisin, a protein related to metabolism and mitochondrial homeostasis, has been reported to play pivotal roles in post-stroke neuroprotection. However, whether this myokine can exert neuroprotection effects after SAH remains unknown. In the present study, we explored the protective effects of irisin and the underlying mechanisms related to mitochondrial biogenesis in a SAH animal model. Endovascular perforation was used to induce SAH, and recombinant irisin was administered intracerebroventricularly. Neurobehavioral assessments, TdT-UTP nick end labeling (TUNEL) staining, dihydroethidium (DHE) staining, immunofluorescence, western blot, and transmission electron microscopy (TEM) were performed for post-SAH assessments. We demonstrated that irisin treatment improved neurobehavioral scores, reduced neuronal apoptosis, and alleviated oxidative stress in EBI after SAH. More importantly, the administration of exogenous irisin conserved the mitochondrial morphology and promoted mitochondrial biogenesis. The protective effects of irisin were partially reversed by the mitochondrial uncoupling protein-2 (UCP-2) inhibitor. Taken together, irisin may have neuroprotective effects against SAH via improving the mitochondrial biogenesis, at least in part, through UCP-2 related targets.

Background: Therapeutic hypothermia may need prolonged duration for the patients with severe traumatic brain injury (sTBI). Methods: The Long-Term Hypothermia trial was a prospective, multicenter, randomized, controlled clinical trial to examine the safety and efficacy in adults with sTBI. Eligible patients were 18–65, Glasgow Coma Scale score at 4 to 8, and initial intracranial pressure (ICP) ≥ 25 mm Hg, randomly assigned to the long-term mild hypothermia group (34–35 °C for 5 days) or normothermia group at 37 °C. The primary outcome was the Glasgow outcome scale (GOS) at 6 months. Secondary outcomes included ICP control, complications and laboratory findings, the length of ICU and hospital stay, and GOS at 6 months in patients with initial ICP ≥ 30 mm Hg. This trial is registered with ClinicalTrials.gov, NCT01886222. Findings: 302 patients were enrolled from June 25, 2013, to December 31, 2018, with 6 months follow-up in 14 hospitals, 156 in hypothermia group and 146 in normothermia group. There was no difference in favorable outcome (OR 1·55, 95%CI 0·91–2·64; P = 0·105) and in mortality (P = 0·111) between groups. In patients with an initial ICP ≥ 30 mm Hg, hypothermic treatment significantly increased favorable outcome over normothermia group (60·82%, 42·71%, respectively; OR 1·861, 95%CI 1·031–3·361; P = 0·039). Long-term mild hypothermia did not increase the incidences of complications. Interpretation: Long-term mild hypothermia did not improve the neurological outcomes. However, it may be a potential option in sTBI patients with initial ICP ≥ 30 mm Hg. Funding: : Shanghai municipal government and Shanghai Jiao Tong University/School of Medicine.

Female genital tuberculosis is an important cause of infertility in developing countries where tuberculosis is endemic. However, the true incidence of genital tuberculosis is unknown because symptoms and signs are usually minimal, making its detection difficult. We herein report a case of subfertility due to endometrial tuberculosis. The patient had primary infertility and planned to utilize assisted reproductive technology because of bilateral fallopian tube obstruction. She underwent hysteroscopy and endometrial biopsy. The biopsy revealed epithelioid cells and multinuclear giant cells in the interstitium, and tuberculosis of the endometrium could not be excluded. Chest computed tomography showed secondary pulmonary tuberculosis in the upper left lung. A tuberculin test was positive, and a sputum culture of Mycobacterium tuberculosis was negative. The clinical diagnosis was secondary pulmonary tuberculosis. Considering the above findings in combination with the endometrial biopsy results, we concluded that the patient had endometrial tuberculosis. She underwent antituberculosis treatment for 6 months, after which the endometrial tuberculosis resolved and she achieved pregnancy by in vitro fertilization.

Abstract Purpose Behavioral symptoms, including depression, anxiety, and cognitive impairment, are common clinical symptoms of patients with glioma. However, the mechanisms underlying the behavioral symptoms of glioma patients remain unclear. In this study, we explore the correlation between markers of systemic inflammation and preoperational behavioral symptoms in glioma patients. Patients and Methods Patients (n = 71) who had recently undertaken imaging (i.e., CT, MRI) for suspected glioma had a face‐to‐face interview, completed self‐report scales, and provided blood samples. Furthermore, we tested blood samples by a protein chip to select differential inflammatory cytokines and further confirm such differences using liquid‐phase chip technology. Results The prevalence of depression, anxiety, and cognitive impairment in glioma patients prior to surgery in this study was 53.5%, 70.4%, and 32.4%, respectively. The increased levels of IFN‐γ were positively correlated with clinical symptoms of depression in the glioma patients. Moreover, increased IL‐2 levels were negatively associated with anxiety symptoms (p = .00) and positively correlated with cognitive impairment in glioma patients. Conclusion This study suggests that systemic inflammation is associated with behavioral symptoms in glioma patients. This provides further evidence of the contribution of inflammatory markers to psychological symptoms in the context of physical conditions and lays the foundation for the development of further treatments of the behavioral symptoms in glioma patients.

Most patients with primary central system lymphoma (PCNSL) have immune dysfunction. PCNSL without immune dysfunction is rare and extremely challenging to diagnose. Here, we report the case of a 52-year-old woman without immune dysfunction who presented with PCNSL. The patient died a few months after diagnosis and during treatment. A review of this PCNSL patient’s case highlighted that poor interpretation of imaging features and the poor correlation of laboratory test results with clinical findings led to a difficulty in making a diagnosis and administering the best treatment. For an accurate diagnosis of early stage PCNSL, positron-emission tomography computed tomography and corticosteroids should be used cautiously before stereotactic biopsy.

Abstract Background LIM and SH3 protein 1 (LASP1) is upregulated in several types of human cancer and implicated in cancer progression. However, the expression and intrinsic function of LASP1 in glioblastoma (GBM) remains unclear. Method Oncomine and The Cancer Genome Atlas (TCGA) database was analyzed for the expression and clinical significance of LASP1 in GBM. LASP1 mRNA and protein level were measured by qRT-PCR and western blotting. The effect of LASP1 on GBM proliferation was examined by MTT assay and colony formation assay, the effect of LASP1 on sensitivity of Temozolomide was measured by flow cytometry and subcutaneous tumor model. The association between LASP1 and PI3K/AKT signaling was assessed by western blotting. Results Oncomine GBM dataset analysis indicated LASP1 is significantly upregulated in GBM tissues compared to normal tissues. GBM dataset from The Cancer Genome Atlas (TCGA) revealed that high LASP1 expression is related to poor overall survival. LASP1 mRNA and protein in clinical specimens and tumor cell lines are frequently overexpressed. LASP1 knockdown dramatically suppressed U87 and U251 cell proliferation. Silencing LASP1 potentiated cell chemosensitivity to temozolomide in vitro, LASP1 knockdown inhibited tumor growth and enhanced the therapeutic effect of temozolomide in vivo. TCGA dataset analysis indicated LASP1 was correlated with PI3K/AKT signaling pathway, and LASP1 deletion inhibited this pathway. Combination treatment with PI3K/AKT pathway inhibitor LY294002 dramatically accelerated the suppression effect of temozolomide. Conclusion LASP1 may function as an oncogene in GBM and regulate cell proliferation and chemosensitivity in a PI3K/AKT-dependent mechanism. Thus, the LASP1/PI3K/AKT axis is a promising target and therapeutic strategy for GBM treatment.

Purpose: This study investigated the underlying mechanism of LIM and SH3 protein 1 (LASP1)-induced malignant glioma growth and invasion. Materials and methods: We compared the expression of LASP1 in malignant glioma tumor tissues and low-grade glioma tissues by immunohistochemistry. We also compared LASP1 overexpression and LASP1 knockout glioma cell proliferation and invasion in vitro and in vivo. We detected activation of the PI3K/AKT signaling pathway and epithelial-mesenchymal transition (EMT) process in tumor cells by western blotting or immunofluorescence. Glioma-bearing mice were used to investigate the anticancer effects of PI3K/AKT inhibitors in combination with temozolomide. Results: We observed the enhanced expression of LASP1 in malignant glioma tumor tissues compared to low-grade glioma tissues, and LASP1 overexpression in glioma cells revealed an elevated capability of proliferation and invasion in vitro and in vivo. LASP1 overexpression also facilitated PI3K/AKT signaling and the EMT process through the downstream transcription factor Snail, which resulted in the intensive invasion of cancer cells. We combined PI3K/AKT inhibitors and temozolomide to block the LASP1/PI3K/AKT/Snail signaling pathway, which dramatically enhanced tumor suppression and provides an innovative approach for clinical glioma treatment. Conclusion: LASP1 is upregulated in malignant glioma and facilitates glioma cell proliferation and invasion by activation the PI3K/AKT/Snail signaling pathway. Blockade of the PI3K/AKT signal efficiently enhanced the anticancer effects of chemotherapeutic agents, which provides an innovative target in glioma treatment.

Acquired brain ischemia-and reperfusion-injury (IRI), including both Ischemic stroke (IS) and Traumatic Brain injury (TBI), is one of the most common causes of disability and death in adults and represents a major burden in both western and developing countries worldwide. China’s clinical neurological therapeutic experience in the use of traditional Chinese medicines (TCMs), including TCM-derived active compounds, Chinese herbs, TCM formulations and decoction, in brain IRI diseases indicated a trend of significant improvement in patients’ neurological deficits, calling for blind, placebo-controlled and randomized clinical trials with careful meta-analysis evaluation. There are many TCMs in use for brain IRI therapy in China with significant therapeutic effects in preclinical studies using different brain IRI-animal. The basic hypothesis in this field claims that in order to avoid the toxicity and side effects of the complex TCM formulas, individual isolated and identified compounds that exhibited neuroprotective properties could be used as lead compounds for the development of novel drugs. China’s efforts in promoting TCMs have contributed to an explosive growth of the preclinical research dedicated to the isolation and identification of TCM-derived neuroprotective lead compounds. Tanshinone, is a typical example of TCM-derived lead compounds conferring neuroprotection toward IRI in animals with brain middle cerebral artery occlusion (MCAO) or TBI models. Recent reports show the significance of the inflammatory response accompanying brain IRI. This response appears to contribute to both primary and secondary ischemic pathology, and therefore anti-inflammatory strategies have become popular by targeting pro-inflammatory and anti-inflammatory cytokines, other inflammatory mediators, reactive oxygen species, nitric oxide, and several transcriptional factors. Here, we review recent selected studies and discuss further considerations for critical reevaluation of the neuroprotection hypothesis of TCMs in IRI therapy. Moreover, we will emphasize several TCM’s mechanisms of action and attempt to address the most promising compounds and the obstacles to be overcome before they will enter the clinic for IRI therapy. We hope that this review will further help in investigations of neuroprotective effects of novel molecular entities isolated from Chinese herbal medicines and will stimulate performance of clinical trials of Chinese herbal medicine-derived drugs in IRI patients.

White matter injury (WMI) is associated with motor deficits and cognitive dysfunctions in subarachnoid hemorrhage (SAH) patients. Therapeutic strategy targeting WMI would likely improve the neurological outcomes after SAH. Low-density lipoprotein receptor-related protein-1 (LRP1), a scavenger receptor of apolipoprotein E (apoE), is able to modulate microglia polarization towards anti-inflammatory M2 phenotypes during inflammatory and oxidative insult. In the present study, we investigated the effects of LRP1 activation on WMI and underlying mechanisms of M2 microglial polarization in a rat model of SAH. Two hundred and seventeen male Sprague Dawley rats (weight 280–330 g) were used. SAH was induced by endovascular perforation. LPR1 ligand, apoE-mimic peptide COG1410 was administered intraperitoneally. Microglial depletion kit liposomal clodronate (CLP), LPR1 siRNA or PI3K inhibitor were administered intracerebroventricularly. Post-SAH assessments included neurobehavioral tests, brain water content, immunohistochemistry, Golgi staining, western blot and co-immunoprecipitation. SAH induced WMI shown as the accumulation of amyloid precursor protein and neurofilament heavy polypeptide as well as myelin loss. Microglial depletion by CLP significantly suppressed WMI after SAH. COG1410 reduced brain water content, increased the anti-inflammatory M2 microglial phenotypes, attenuated WMI and improved neurological function after SAH. LRP1 was bound with endogenous apoE and intracellular adaptor protein Shc1. The benefits of COG1410 were reversed by LPR1 siRNA or PI3K inhibitor. LRP1 activation attenuated WMI and improved neurological function by modulating M2 microglial polarization at least in part through Shc1/PI3K/Akt signaling in a rat model of SAH. The apoE-mimic peptide COG1410 may serve as a promising treatment in the management of SAH patients. Keywords: Subarachnoid hemorrhage, White matter injury, apoE, LRP1, Microglia

Subarachnoid hemorrhage (SAH) is a major cause of high morbidity, disability, and mortality in the field of neurovascular disease. Most previous SAH studies have focused on improving cerebral blood flow, reducing cerebral vasospasm, reducing neuronal calcium overload, and other treatments. While these studies showed exciting findings in basic science, therapeutic strategies based on the findings have not significantly improved neurological outcomes in patients with SAH. Currently, the only drug proven to effectively reduce the neurological defects of SAH patients is nimodipine. Current advances in imaging technologies in the field of stroke have confirmed that white matter injury (WMI) plays an important role in the prognosis of types of stroke, and suggests that WMI protection is essential for functional recovery and poststroke rehabilitation. However, WMI injury in relation to SAH has remained obscure until recently. An increasing number of studies suggest that the current limitations for SAH treatment are probably linked to overlooked WMI in previous studies that focused only on neurons and gray matter. In this review, we discuss the biology and functions of white matter in the normal brain, and discuss the potential pathophysiology and mechanisms of early brain injury after SAH. Our review demonstrates that WMI encompasses multiple substrates, and, therefore, more than one pharmacological approach is necessary to preserve WMI and prevent neurobehavioral impairment after SAH. Strategies targeting both neuronal injury and WMI may potentially provide a novel future for SAH knowledge and treatment.