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The draining of brain interstitial fluid (ISF) to cerebrospinal fluid (CSF) and the subsequent draining of CSF to meningeal lymphatics is well‐known. Nonetheless, its role in the development of glioma is a remarkable finding that has to be extensively understood. The glymphatic system (GS) collects CSF from the subarachnoid space and brain ISF through aquaporin‐4 (AQP4) water channels. The glial limiting membrane and the perivascular astrocyte‐end‐feet membrane both have elevated levels of AQP4. CSF is thought to drain through the nerve sheaths of the olfactory and other cranial nerves as well as spinal meningeal lymphatics via dorsal or basal lymphatic vessels. Meningeal lymphatic vessels (MLVs) exist below the skull in the dorsal and basal regions. In this view, MLVs offer a pathway to drain macromolecules and traffic immunological cells from the CNS into cervical lymph nodes (CLNs), and thus can be used as a candidate curing strategy against glioma and other associated complications, such as neuro‐inflammation. Taken together, the lymphatic drainage system could provide a route or approach for drug targeting of glioma and other neurological conditions. Nevertheless, its pathophysiological role in glioma remains elusive, which needs extensive research. The current review aims to explore the lymphatic drainage system, its role in glioma progression, and possible therapeutic techniques that target MLVs in the CNS. [ABSTRACT FROM AUTHOR]

[Display omitted] • ATP1A3 was significantly associated with immune features in GBM samples and immunotherapy process. • ATP1A3 demonstrated substantial expression differences in different immunophenotypes and molecular types. • The scoring model generated by nine genes could be used as an independent prognostic factor. The ATP1A3 gene is associated with the development and progression of neurological diseases. However, the pathological function and therapeutic value of ATP1A3 in glioblastoma (GBM) remains unknown. In this study, we tried to explore the correlation between the ATP1A3 gene expression and immune features in GBM samples. We found that ATP1A3 gene expression levels showed significant negative correlation with immune checkpoints such as PD-L1, CTLA-4 and IDO1. Next, ATP1A3 gene expression levels showed significant negative correlation with the anti-cancer immune cell process, the immune score and stromal score. By grouping ATP1A3 expression levels, we found that that immunomodulator-related genes and tumor-associated immune cell effector gene expression levels were associated with lower ATP1A3 expression. In addition, immunotherapy prediction pathway activity and a majority of the anti-cancer immune cell process activity levels were also showed to be correlated with lower ATP1A3 gene expression. Further, nine prognostic factors were identified by prognostic analysis, and a GBM prognostic model (risk score) was established. We applied the model to the TCGA GBM training set sample and the GSE4412 validation set sample and found that patients in the high risk score subgroup had significantly shorter survival time, demonstrating the prognostic value and prognostic efficacy of the risk score. Furthermore, ATP1A3 overexpression has also been found to sensitize cancer cells to anti-PD-1 therapy. In conclusion, we showed that ATP1A3 is a highly promising treatment target in GBM and the risk score is an independent prognostic factor for cancer and can be used to help guide the prediction of survival time in patients with GBM. [ABSTRACT FROM AUTHOR]

Aquaporin 4 (AQP4) is a primary water channel found on astrocytes in the central nervous system (CNS). Besides its function in water and ion homeostasis, AQP4 has also been documented to be involved in a myriad of acute and chronic cerebral pathologies, including autoimmune neurodegenerative diseases. AQP4 has been postulated to be associated with the incidence of a progressive neurodegenerative disorder known as amyotrophic lateral sclerosis (ALS), a disease that targets the motor neurons, causing muscle weakness and eventually paralysis. Raised AQP4 levels were noted in association with vessels surrounded with swollen astrocytic processes as well as in the brainstem, cortex, and gray matter in patients with terminal ALS. AQP4 depolarization may lead to motor neuron degeneration in ALS via GLT-1. Besides, alterations in AQP4 expression in ALS may result in the loss of blood-brain barrier (BBB) integrity. Changes in AQP4 function may also disrupt K+ homeostasis and cause connexin dysregulation, the latter of which is associated to ALS disease progression. Furthermore, AQP4 suppression augments recovery in motor function in ALS, a phenomenon thought to be associated to NGF. No therapeutic drug targeting AQP4 has been developed to date. Nevertheless, the plethora of suggestive experimental results underscores the significance of further exploration into this area. [ABSTRACT FROM AUTHOR]

Bufalin (BF) is a cardiotonic steroid that has recently been found to have substantial anticancer activity; however, more efforts should be directed toward clarifying the detailed molecular mechanisms underlying this activity. BF could exert its anticancer effect by inducing apoptosis in various human cancer cells and thus triggering autophagic cancer cell death. The anti-inflammatory activities of BF are potentially important for its anticancer functions. Notably, some promising synthetic BF derivatives, including poly (ethylene glycol)-based polymeric prodrug of BF and BF211, have shown potent anticancer activity. Additionally, clinical trials regarding the use of BF-related agents in patients have supported the positive effect of BF as an anticancer treatment. Currently, large-scale randomized, double-blind, placebo or positive drug parallel controlled studies are required to confirm the anticancer potential of BF in various cancer types in the clinical setting. The present review will evaluate the potential mechanisms mediated by BF in intracellular signaling events in cancer cells and various promising BF derivatives that may have greater anticancer activity, thereby clarifying BF-mediated anticancer effects. The experimental and clinical results reviewed strongly emphasize the importance of this topic in future investigations. [ABSTRACT FROM AUTHOR]

Objective: Traumatic brain injury (TBI) is a significant cause of death and long-term deficits in motor and cognitive functions for which there are currently no effective chemotherapeutic drugs. Bazedoxifene (BZA) is a third-generation selective estrogen receptor modulator (SERM) and has been investigated as a treatment for postmenopausal osteoporosis. It is generally safe and well tolerated, with favorable endometrial and breast safety profiles. Recent findings have shown that SERMs may have therapeutic benefits; however, the role of BZA in the treatment of TBI and its molecular and cellular mechanisms remain poorly understood. The aim of the present study was to examine the neuroprotective effects of BZA on early TBI in rats and to explore the underlying mechanisms of these effects.Materials and methods: TBI was induced using a modified weight-drop method. Neurological deficits were evaluated according to the neurological severity score (NSS). Morris water maze and open-field behavioral tests were used to test cognitive functions. Brain edema was measured by brain water content, and impairments in the blood-brain barrier (BBB) were evaluated by expression analysis of tight junction-associated proteins, such as occludin and zonula occludens-1 (ZO-1). Neuronal injury was assessed by hematoxylin and eosin (H&E) staining. LC-MS/MS analysis was performed to determine the ability of BZA to cross the BBB.Results: Our results indicated that BZA attenuated the impaired cognitive functions and the increased BBB permeability of rats subjected to TBI through activation of inflammatory cascades. In vivo experiments further revealed that BZA provided this neuroprotection by suppressing TBI-induced activation of the MAPK/NF-κB signaling pathway. Thus, mechanically, the anti-inflammatory effects of BZA in TBI may be partially mediated by blocking the MAPK signaling pathway.Conclusions: These findings suggest that BZA might attenuate neurological deficits and BBB damage to protect against TBI by blocking the MAPK/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Background/Aims:Uncaria rhynchophylla, known as “Gou-teng”, is a traditional Chinese medicine (TCM) used to extinguish wind, clear heat, arrest convulsions, and pacify the liver. Although U. rhynchophylla has a long history of being often used to treat central nervous system (CNS) diseases, its efficacy and potential mechanism are still uncertain. This study investigated neuroprotective effect and the underlying mechanism of U. rhynchophylla extract (URE) in MPP+-induced SH-SY5Y cells and MPTP-induced mice. Methods: MPP+-induced SH-SY5Y cells and MPTP-induced mice were used to established Parkinson’s disease (PD) models. Quantitative proteomics and bioinformatics were used to uncover proteomics changes of URE. Western blotting was used to validate main differentially expressed proteins and test HSP90 client proteins (apoptosis-related, autophagy-related, MAPKs, PI3K, and AKT proteins). Flow cytometry and JC-1 staining assay were further used to confirm the effect of URE on MPP+-induced apoptosis in SH-SY5Y cells. Gait analysis was used to detect the behavioral changes in MPTP-induced mice. The levels of dopamine (DA) and their metabolites were examined in striatum (STR) by HPLC-EC. The positive expression of tyrosine hydroxylase (TH) was detected by immunohischemical staining and Western blotting. Results: URE dose-dependently increased the cell viability in MPP+-induced SH-SY5Y cells. Quantitative proteomics and bioinformatics results confirmed that HSP90 was an important differentially expressed protein of URE. URE inhibited the expression of HSP90, which further reversed MPP+-induced cell apoptosis and autophagy by increasing the expressions of Bcl-2, Cyclin D1, p-ERK, p-PI3K p85, PI3K p110α, p-AKT, and LC3-I and decreasing cleaved caspase 3, Bax, p-JNK, p-p38, and LC3-II. URE also markedly decreased the apoptotic ratio and elevated mitochondrial transmembrane potential (DΨm). Furthermore, URE treatment ameliorated behavioral impairments, increased the contents of DA and its metabolites and elevated the positive expressions of TH in SN and STR as well as the TH protein. Conclusions: URE possessed the neuroprotective effect in vivo and in vitro, regulated MAPK and PI3K-AKT signal pathways, and inhibited the expression of HSP90. U. rhynchophylla has potentials as therapeutic agent in PD treatment. [ABSTRACT FROM AUTHOR]

Chansu is a traditional Chinese medicine that is generally recognized as a specific inhibitor of Na + /K + -ATPase. Bufalin, an active component of Chansu, is an endogenous steroid hormone with great potential as a cancer treatment. However, the mechanism by which it exerts its antitumor activity requires further research. Currently, the α1 subunit of Na + /K + -ATPase (ATP1A1) is known to exert important roles in tumorigenesis, and the precise mechanisms underlying the effect of Bufalin on the Na + /K + -ATPase α1 subunit was therefore investigated in this study to determine its role in glioblastoma treatments. The effect of ATP1A1 on the sensitivity of glioblastoma cells to Bufalin was investigated using MTT assays, RT-PCR and siRNA. Western blot was also used to explore the important roles of the ubiquitin-proteasome pathway in the Bufalin-mediated inhibition of ATP1A1. Xenografted mice were used to examine the anti-tumor activity of Bufalin in vivo . LC–MS/MS analysis was performed to determine the ability of Bufalin to traverse the blood-brain barrier (BBB). The results indicated that Bufalin inhibited the expression of ATP1A1 in glioblastoma by promoting the activation of proteasomes and the subsequent protein degradation of ATP1A1, while Bufalin had no effect on ATP1A1 protein synthesis. Bufalin also inhibited the expression of ATP1A1 in xenografted mice and significantly suppressed tumor growth. These data should contribute to future basic and clinical investigations of Bufalin. In conclusion, Bufalin significantly inhibited the expression of ATP1A1 in glioblastoma cells by activating the ubiquitin-proteasome signaling pathway. Bufalin may therefore have the potential to be an effective anti-glioma drug for human glioblastoma in the future. [ABSTRACT FROM AUTHOR]

Abstract: Malignant glioma is one of the most challenging central nervous system diseases to treat and has high rates of recurrence and mortality. Current therapies often fail to control tumor progression or improve patient survival. Marinobufagenin (MBG) is an endogenous mammalian cardiotonic steroid involved in sodium pump inhibition. Currently, various studies have indicated the potential of MBG in cancer treatments; however, the precise mechanisms are poorly understood. The functions of MBG were examined using colony formation, migration, cell cycle, and apoptosis assays in glioma cells. A mitochondrial membrane potential assay was performed to determine the mitochondrial transmembrane potential change, and cytochrome c release from mitochondria was assayed by fluorescence microscopy. An immunofluorescence assay was performed, and the nuclear translocation of NF‐κB in glioma cells was confirmed by confocal microscopy. Western blotting and RT‐qPCR were used to detect the protein and gene expression levels, respectively. In addition, transfection experiment of ATP1A1‐siRNA was further carried out to confirm the role of sodium pump α1 subunit in the anticancer effect of MBG in human glioma. The apoptosis‐promoting and anti‐inflammatory effects of MBG were further investigated, and the sodium pump α1 subunit and the ERK signaling pathway were found to be involved in the anticancer effect of MBG. The in vivo anticancer efficacy of MBG was also tested in xenografts in nude mice. Thus, therapies targeting the ERK signaling‐mediated mitochondrial apoptotic pathways regulated by MBG might represent potential treatments for human glioma, and this study could accelerate the finding of newer therapeutic approaches for malignant glioma treatment. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by memory loss and cognitive dysfunction. Aquaporin-4 (AQP4), which is primarily expressed in astrocytes, is the major water channel expressed in the central nervous system (CNS). This protein plays an important role in water and ion homeostasis in the normal brain and in various brain pathological conditions. Emerging evidence suggests that AQP4 deficiency impairs learning and memory and that this may be related to the expression of glutamate transporter-1 (GLT-1). Moreover, the colocalization of AQP4 and GLT-1 has long been studied in brain tissue; however, far less is known about the potential influence that the AQP4/GLT-1 complex may have on AD. Research on the functional interaction of AQP4 and GLT-1 has been demonstrated to be of great significance in the study of AD. Here, we review the interaction of AQP4 and GLT-1 in astrocytes, which might play a pivotal role in the regulation of distinct cellular responses that involve neuroprotection against AD. The association of AQP4 and GLT-1 could greatly supplement previous research regarding neuroprotection against AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and disordered cognition. Women have a higher AD incidence than men, indicating that the declining estrogen levels during menopause may influence AD pathogenesis. However, the mechanism underlying estrogen's neuroprotective effect is not fully clarified and is complicated by the presence of several distinct estrogen receptor (ER) types and the identification of a growing number of ER splice variants. Thus, a deeper analysis of ERs could elucidate the role of estrogen in age-related cognitive changes. Intracellular calcium signaling cascades play a pivotal role in ERα neuroprotection against AD. The ERα-mediated inhibition of Death domain-associated protein (Daxx) translocation and the combination of membrane ERα and caveolin in caveolae may protect against AD. Moreover, the voltage-dependent anion channel (VDAC)/ERα association may be important for maintaining channel inactivation and may be relevant in neuronal preservation against Aβ injury. Additionally, ERα may prevent glutamate excitotoxic injury by Aβ through estrogen signaling mechanisms. ERα and IGF-IR co-activation may mediate neuroprotection, and many other growth factors and intracellular signaling responses triggered by ERα may also play important roles in this process. Furthermore, details regarding the genes and mRNA variants of ERα that are expressed in different parts of the human organs have been clarified recently. Therefore, here we review the literature to clarify the neuroprotective role of ERα. This review focuses on the potential mechanisms mediated by ERα in the intracellular signaling events in nervous system cells, thereby clarifying ERα-mediated protection against AD. [ABSTRACT FROM AUTHOR]

Glutamate is the most abundant excitatory brain neurotransmitter that has important functional significance with respect to neurodegenerative conditions. Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease (AD) has been gradually becoming elucidated recently. Excessive release of glutamate induces an increase in intracellular Ca levels, thus triggers a cascade of cellular responses, ultimately leading to neuronal cell death. This type of neuronal damage induced by over-excitation has been proposed to be involved in a number of neuropathological conditions, ranging from acute insults to chronic neurodegenerative disorders. Estrogen could be effective in modulating glutamate-induced neurotoxicity and the protective responsivenesses are mostly estrogen receptors (ERs)-dependent. However, the mechanism underlying estrogen's neuroprotective effect is not fully clarified and is complicated by the presence of several distinct ER types. So a deeper research into the neuroprotection of ERs might be informative about the positive effect that estrogen might have on ageing-related cognitive changes. Extensive studies have indicated the neuroprotective effects of ERs against glutamate-induced neurotoxicity. The purpose of this review is to elucidate ERs' neuroprotective effects against glutamate-induced cytotoxicity and explore new ways to prevent and cure neurotoxicity-associated neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

RNA modification is an important form of regulation in cancer biology, that is capable of affecting cell proliferation, migration, other genetic characteristics of tumors, and protein expression. Recent research has shown that dysregulation of RNA modification plays an important role in glioma pathogenesis. A key form of RNA post-transcriptional modification, alternative polyadenylation (APA), may represent a mechanism by which genes escape miRNA-mediated inhibition of cancer. Global shortening of 3' untranslated region (3'-UTR)-mediated APA events have become a potential novel marker of cancer progression. Current treatments in which a single gene or pathway is targeted do not have significant therapeutic benefits for glioma patients, while strategies that are less targeted, in which inhibitors of major regulatory hubs such as APA regulators are utilized, may have superior therapeutic effects. However, the precise mechanisms by which untranslated region-alternative polyadenylation (UTR-APA) regulates glioma are poorly understood. In the present review, we will discuss the important roles of UTR-APA in glioma. In addition to the role of APA in the progression of glioma, we will also explore potential treatment options that target these processes to improve the prognosis of glioma patients. [Display omitted] • UTR-APA exerts various important effects on the regulation of glioma progression. • Various factors could regulate APA and 3'UTR length in the brain. • UTR-APA exerts important effects on various oncogenes during glioma tumorigenesis. • UTR-APA plays important roles in drug resistance in glioma treatment. [ABSTRACT FROM AUTHOR]

Objectives: Temozolomide (TMZ) is one of the most commonly used clinical drugs for glioblastoma (GBM) treatment, but its drug sensitivity needs to be improved. Gamabufotalin (CS‐6), the primary component of the traditional Chinese medicine "ChanSu," was shown to have strong anti‐cancer activity. However, more efforts should be directed towards reducing its toxicity or effective treatment doses. Methods: Target fishing experiment, Western blotting, PCR, confocal immunofluorescence and molecular cloning techniques were performed to search for possible downstream signalling pathways. In addition, GBM xenografts were used to further determine the potential molecular mechanisms of the synergistic effects of CS‐6 and TMZ in vivo. Results: Mechanistic research revealed a negative feedback loop between ATP1A3 and AQP4 through which CS‐6 inhibited GBM growth and mediated the synergistic treatment effect of CS‐6 and TMZ. In addition, by mutating potential amino acid residues of ATP1A3, which were predicted by modelling and docking to interact with CS‐6, we demonstrated that abrogating hydrogen bonding of the amino acid Thr794 interferes with the activation of ATP1A3 by CS‐6 and that the Thr794Ala mutation directly affects the synergistic treatment efficacy of CS‐6 and TMZ. Conclusions: As the main potential target of CS‐6, ATP1A3 activation critically depends on the hydrogen bonding of Thr794 with CS‐6. The combination of CS‐6 and TMZ could significantly reduce the therapeutic doses and promote the anti‐cancer efficacy of CS‐6/TMZ monotherapy. [ABSTRACT FROM AUTHOR]

Isoalantolactone (IATL), a sesquiterpene lactone compound, possesses many pharmacological and biological activities, but its role in glioblastoma (GBM) treatment is still unknown. The aim of the current study was to investigate the antiglioma effects of IATL and to explore the underlying molecular mechanisms. In the current study, the biological functions of IATL were examined by MTT, cell migration, colony formation, and cell apoptosis assays. Confocal immunofluorescence techniques, chromatin immunoprecipitation, and pull‐down assays were used to explore the precise underlying molecular mechanisms. To examine IATL activity and the molecular mechanisms by which it inhibits glioma growth in vivo, we used a xenograft tumor mouse model. Furthermore, Western blotting was used to confirm the changes in protein expression after IATL treatment. According to the results, IATL inhibited IKKβ phosphorylation, thus inhibiting both the binding of NF‐κB to the cyclooxygenase 2 (COX‐2) promoter and the recruitment of p300 and eventually inhibiting COX‐2 expression. In addition, IATL induced glioma cell apoptosis by promoting the conversion of F‐actin to G‐actin, which in turn activates the cytochrome c (Cyt c) and caspase‐dependent apoptotic pathways. In the animal experiments, IATL reduced the size and weight of glioma tumors in xenograft mice and inhibited the expression of COX‐2 and phosphorylated NF‐κB p65 in the transplanted tumors. In conclusion, the current study indicated that IATL inhibited the expression of COX‐2 through the NF‐κB signaling pathway and induced the apoptosis of glioma cells by increasing actin transformation. These results suggested that IATL could be greatly effective in GBM treatment. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the clinical efficacy of bladder hydrodistention and intravesical sodium hyaluronate in the treatment of interstitial cystitis (IC).Materials and Methods: Twenty-one patients with IC received intravesical sodium hyaluronate therapy under nerve block or intravenous anesthesia. Bladders were perfused with 100 cmH2O perfusion pressure and expanded for 10 min and were later injected with 40 mg/50 mL sodium hyaluronate through the catheter. After 1 h, the perfusion fluid was released. Perfusion was applied once per week, 4 to 6 times as a course of treatment.Results: Under anesthesia, the average bladder capacity was 191.62 ± 88.67 mL, and after bladder expansion, the bladder capacity reached 425.33 ± 79.83 mL (P = .000). There were 2 suspected bladder ruptures after bladder expansion at 6.5 min and 7.2 min. After 10 min of bladder expansion, there were 19 cases of significantly gross hematuria. After treatment, the catheters of 17 patients were removed at 24 h; for the 2 cases of hematuria, catheters were removed at 72 h and for the 2 cases of suspected bladder rupture, catheters were removed after 4 days. After catheter removal, the pain threshold significantly decreased, and the maximum urinary output increased slightly. Compared with values before treatment, the day before the second injection of sodium hyaluronate, the frequency of urination decreased significantly (32.8 vs. 18.5 times/24 h), the maximum urinary output increased significantly (86.7 vs. 151.9 mL), the pain decreased significantly (8.7 vs. 3.0), and the O'Leary-Sant IC score and quality of life score were significantly decreased (30.0 vs. 17.0 and 5.9 vs. 2.4, respectively) (P = .000).Conclusion: Bladder hydrodistention under anesthesia for patients with severe intractable IC produces immediate effectiveness; sodium hyaluronic infusion can alleviate frequent urination and pain, and the efficacy was positively correlated with the duration of treatment. [ABSTRACT FROM AUTHOR]