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Recent studies have demonstrated a close interaction between neuroinflammatory responses, increased production of inflammatory mediators, and neurodegeneration. Pathological findings in neurological diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease have shown common signs of neuroinflammation and neurodegeneration. Lupeol, a natural pentacyclic triterpene, has revealed a number of pharmacological properties including an anti-inflammatory activity. This study aimed to evaluate the effect of lupeol against lipopolysaccharide (LPS)-induced neuroinflammation in the cortex and hippocampus of adult mice. Our results showed that systemic administration of LPS induced glial cell production of proinflammatory cytokines, tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS), and interleukin (IL)-1β, while co-treatment with lupeol significantly inhibited the LPS-induced activation of microglia and astrocytes, and decreased the LPS-induced generation of TNF-α, iNOS, and IL-1β. The intracellular mechanism involved in the LPS-induced activation of inflammatory responses includes phosphorylation of P38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK), which was significantly inhibited by lupeol. We further elucidated that lupeol inhibited the LPS-induced activation of the mitochondrial apoptotic pathway and reversed the LPS-induced expression of apoptotic markers such as Bax, cytochrome C, caspase-9, and caspase-3. Taken together; our results suggest that lupeol inhibits LPS-induced microglial neuroinflammation via the P38-MAPK and JNK pathways and has therapeutic potential to treat various neuroinflammatory disorders.

Neuroinflammation is a pathophysiological process present in a number of neurodegenerative disorders, such as Alzheimer's disease, Huntington's disease, Parkinson's disease, stroke, traumatic brain injury including chronic traumatic encephalopathy and other age-related CNS disorders. Although there is still much debate about the initial trigger for some of these neurodegenerative disorders, during the progression of disease, broad range anti-inflammatory drugs including cytokine suppressive anti-inflammatory drugs (CSAIDs) might be promising therapeutic options to limit neuroinflammation and improve the clinical outcome. One of the most promising CSAIDs is curcumin, which modulates the activity of several transcription factors (e.g., STAT, NF-κB, AP-1) and their pro-inflammatory molecular signaling pathways. However, normal curcumin preparations demonstrate low bioavailability in vivo. To increase bioavailability, preparations of high bioavailability curcumin have been introduced to achieve therapeutically relevant concentrations in target tissues. This literature review aims to summarize the pharmacokinetic and toxicity profile of different curcumin formulations.

The adverse effects of nanoscale-alumina (Al2O3-NPs) have been previously demonstrated in both in vitro and in vivo studies, whereas little is known about their mechanism of neurotoxicity. It is the goal of this research to determine the toxic effects of nano-alumina on human neuroblastoma SH-SY5Y and mouse hippocampal HT22 cells in vitro and on ICR female mice in vivo. Nano-alumina displayed toxic effects on SH-SY5Y cell lines in three different concentrations also increased aluminium abundance and induced oxidative stress in HT22 cells. Nano-alumina peripherally administered to ICR female mice for three weeks increased brain aluminium and ROS production, disturbing brain energy homeostasis, and led to the impairment of hippocampus-dependent memory. Most importantly, these nano-particles induced Alzheimer disease (AD) neuropathology by enhancing the amyloidogenic pathway of Amyloid Beta (Aβ) production, aggregation and implied the progression of neurodegeneration in the cortex and hippocampus of these mice. In conclusion, these data demonstrate that nano-alumina is toxic to both cells and female mice and that prolonged exposure may heighten the chances of developing a neurodegenerative disease, such as AD.

Context: One of the main targets of cyber-attacks is data exfiltration, which is the leakage of sensitive or private data to an unauthorized entity. Data exfiltration can be perpetrated by an outsider or an insider of an organization. Given the increasing number of data exfiltration incidents, a large number of data exfiltration countermeasures have been developed. These countermeasures aim to detect, prevent, or investigate exfiltration of sensitive or private data. With the growing interest in data exfiltration, it is important to review data exfiltration attack vectors and countermeasures to support future research in this field. Objective: This paper is aimed at identifying and critically analysing data exfiltration attack vectors and countermeasures for reporting the status of the art and determining gaps for future research. Method: We have followed a structured process for selecting 108 papers from seven publication databases. Thematic analysis method has been applied to analyse the extracted data from the reviewed papers. Results: We have developed a classification of (1) data exfiltration attack vectors used by external attackers and (2) the countermeasures in the face of external attacks. We have mapped the countermeasures to attack vectors. Furthermore, we have explored the applicability of various countermeasures for different states of data (i.e., in use, in transit, or at rest). Conclusion: This review has revealed that (a) most of the state of the art is focussed on preventive and detective countermeasures and significant research is required on developing investigative countermeasures that are equally important; (b) Several data exfiltration countermeasures are not able to respond in real-time, which specifies that research efforts need to be invested to enable them to respond in real-time (c) A number of data exfiltration countermeasures do not take privacy and ethical concerns into consideration, which may become an obstacle in their full adoption (d) Existing research is primarily focussed on protecting data in 'in use' state, therefore, future research needs to be directed towards securing data in 'in rest' and 'in transit' states (e) There is no standard or framework for evaluation of data exfiltration countermeasures. We assert the need for developing such an evaluation framework.

Chronic microglial activation is a prominent feature of many chronic neurodegenerative diseases, including Parkinson’s and Alzheimer’s disease. To investigate the effects of chronic microglial activation on cerebellar structure and motor function throughout the lifespan, the transgenic GFAP-IL6 mouse model was used. The aim of the study was to examine inflammatory markers and neuronal degeneration while simultaneously characterizing the motor performance of GFAP-IL6 mice at 3, 6, 14, and 24 months of age in comparison to WT (C57BL/6) mice. In respect to markers of neuroinflammation in the cerebellum, increased numbers of Iba1 + microglia were observed as early as at 3 months of age. In addition, TNF-α levels proved to be significantly higher in the GFAP-IL6 compared to WT mice at all time points. A difference in cerebellar volume between the GFAP-IL6 and WT mice was observed later in life, starting at 6 months and increasing to a loss of about 50% in aged (24 months old) GFAP-IL6 mice. Synaptic deficits were also assessed by using pre- (synaptophysin) and post-synaptic (PSD95) markers. While synaptophysin levels remained unchanged, PSD95 levels decreased in the aging GFAP-IL6 mice compared to their WT littermates from 14 months onward. To assess the effect of microglia activation and neurodegeneration on behavior, a variety of motor function tests, semi-quantitative cerebellar ataxia score, accelerod, beam walking, and open field tests were performed. An age-dependent difference between the genotypes was observed in many of the motor function tests. For example, reduced performance on the accelerod and higher ataxia scores were observed at 6 months of age, followed by the beam walking test showing differences at 14 months of age. In summary, this study constitutes a comprehensive, age-dependent examination of inflammatory, synaptic and neurodegenerative changes in the brains of GFAP-IL6 mice leading to a deterioration in motor performance. The results also indicate that early chronic microglia activation in the GFAP-IL6 mouse leads to observable cerebellar volume loss and motor deficits later in life.

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Chronic glial activation is characterized by increased numbers of activated glial cells, secreting free radicals and cytotoxic cytokines, subsequently causing neuronal damage. In order to investigate the anti-inflammatory activity of Longvida ® Optimised Curcumin (LC), we fed 500 ppm of LC to 2-monthold wild type and GFAP-IL6 mice for 6 months. LC feeding led to a significant reduction in the number of Iba-1 + microglia by 26% in the hippocampus and by 48% in the cerebellum, GFAP + astrocytes by 30%, and TSPO + cells by 24% in the hippocampus and by 31% in the cerebellum of the GFAP-IL6 mice. The morphology of the cells was assessed and LC significantly decreased the dendritic length of microglia and the convex area, convex perimeter, dendritic length, nodes and number of processes of astrocytes in the hippocampus while decreasing the soma area and perimeter in the cerebellum, in LC-fed GFAP-IL6 mice. In addition, LC feeding increased pre-and postsynaptic protein levels and improved balance measured by Rotarod. Together, these data suggest that LC is able to attenuate the inflammatory pathology and ameliorate neurodegeneration and motor deficits in GFAP-IL6 mice. For patients with neuro-inflammatory disorders, LC might potentially reverse the detrimental effects of chronic glial activation.In a healthy brain, microglia and astrocytes play a key role in the normal function of the central nervous system (CNS). The inflammatory response is mediated by the activated microglia, which is considered as the hallmark of neuroinflammation. The chronic activation of microglia leads to neuronal damage through the release of various cytotoxic molecules such as cytokines, reactive oxygen intermediates, and proteinases 1 . Microglia are involved in neural development including through phagocytosis of apoptotic cells. They also influence the function of neurons and their progenitor cells 2 . Astrocytes regulate synaptic transmission, for example through re-uptake of neurontransmitters such as glutamate, and support neurons with metabolic substrates such as gluthathione and lactate 3 .Chronic microglial activation, or neuroinflammation, has been described in many neurodegenerative diseases including chronic traumatic encephalopathy, amyotrophic lateral sclerosis, Parkinson's (PD) and Alzheimer's disease (AD) 4 . For sporadic AD, surmounting histological evidence points to chronic microglial activation as a part of the disease process 1,5 . Chronic microglial activation describes long lasting, CNS-specific, aberrant glial responses that do not reproduce the classic characteristics of inflammation although they do contribute to neurodegeneration 6 . To further support the role of neuroinflammation in AD, genome-wide association studies have identified a variety of inflammation-relevant genes that are associated with AD including clusterin (CLU), complement receptor 1 (CR1) and triggering receptor expressed on myeloid cells 2 (TREM2) 7 . The role of the microglial receptor TREM2 is to activate phagocytosis or microglial survival, an...