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Bufalin is the primary component of the traditional Chinese medicine "Chan Su," which has been widely used for cancer treatment at oncology clinics in certain countries. Evidence suggests that this compound possesses potent antitumor activities, although the exact molecular mechanism(s) require further elucidation. Therefore, this study aimed to further clarify the in vitro and in vivo antiglioma effects of bufalin and the molecular mechanism underlying the regulation of drug sensitivity. The anticancer effects of bufalin were determined by colony formation assays, apoptosis assays, and cellular redox state tests of glioma cells. Confocal microscopy was performed to determine the expression changes of the DNA damage biomarker γ-H2AX and the nuclear translocation of p53 in glioma cells. Western blotting and RT-PCR were used to detect the protein and gene expression levels, respectively. Here, we report that bufalin induced glioblastoma cell apoptosis and oxidative stress and triggered DNA damage. The critical roles of the sodium pump α1 subunit (ATP1A1) in mediating the XPO1-targeted anticancer effect of bufalin in human glioma were further confirmed. Mechanistic studies confirmed the important roles of Src and p53 signaling in mediating bufalin-induced apoptosis. Importantly, bufalin also inhibited the growth of glioma xenografts. In conclusion, our study indicated that therapies targeting the ATP1A1 and p53 signaling-mediated mitochondrial apoptotic pathways regulated by bufalin might be potential treatments for human glioma, and these findings will provide molecular bases for developing bufalin into a drug candidate for the treatment of malignant glioma. [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]

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]

Various studies have confirmed the important roles of endogenous hormones in the development of gliomas, while the roles of exogenous hormones remain controversial. Based on case-control studies and cohort studies, a meta-analysis was exerted to explore the effect of two exogenous hormones use (HRT: hormone replacement therapy; OC: oral contraceptives) on glioma risk. 16 eligible studies, including 11 case-control studies and 5 cohort studies, containing 8055027 women, were included in our study. All included studies have reported the relative risks (RRs) or odds ratios (ORs), and 95% confidence intervals (CIs). We use the fixed-effects model to calculate the estimated overall risk. In case-control studies, the risk of glioma was lower in women who had ever been treated with an exogenous hormone than in the control group (HRT: OR 0.91, 95% CI 0.84-0.99; OC: OR 0.99, 95% CI 0.91-1.07). In research of cohort studies, similar results have been obtained (HRT: RR 0.95, 95% CI 0.83-1.08; OC: RR 0.75, 95% CI 0.66-0.84). Our study further confirmed that the use of exogenous hormones has an important impact on the risk of glioma in women. However, more prospective studies are needed to further confirm this conclusion. [ABSTRACT FROM AUTHOR]

Aquaporin 4 (AQP4) is the major water channel expressed in the central nervous system (CNS), and it is primarily expressed in astrocytes. It has been studied in various brain pathological conditions. However, the potential for AQP4 to influence Alzheimer's disease (AD) is still unclear. Research regarding AQP4 functions related to AD can be traced back several years and has gradually progressed toward a better understanding of the potential mechanisms. Currently, it has been suggested that AQP4 influences synaptic plasticity, and AQP4 deficiency may impair learning and memory, in part, through glutamate transporter-1 (GLT-1). AQP4 may mediate the clearance of amyloid beta peptides (Aβ). In addition, AQP4 may influence potassium (K) and calcium (Ca) ion transport, which could play decisive roles in the pathogenesis of AD. Furthermore, AQP4 knockout is involved in neuroinflammation and interferes with AD. To date, no specific therapeutic agents have been developed to inhibit or enhance AQP4. However, experimental results strongly emphasize the importance of this topic for future investigations. [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]