Selective GSK3ß Inhibition Mediates an Nrf2-Independent Anti-inflammatory Microglial Response.

Glycogen synthase kinase 3 (GSK3) is associated with the proinflammatory phenotype of microglia and has been shown to act in concert with nuclear factor kappa B (NF-κB). GSK3 is also a suppressor of nuclear factor erythroid 2-related factor 2 (Nrf2), the principal regulator of redox homeostasis. Agreeing with the oxidative paradigm of aging, Nrf2 is often deregulated in parainflammatory and neurodegenerative diseases. In this study, we aimed to explore a multimodal disease-modifying utility of GSK3 inhibition, beyond neuronal proteopathologies. Furthermore, we aimed to underscore the difference in therapeutic value between the two GSK3 paralogs by isoform-selective chemical inhibition. The anti-inflammatory effects of paralog-selective GSK3 inhibitors were evaluated as a function of the reductive capacity of each to mitigate LPS-induced activation of SIM-A9 microglia. The Griess method was employed to detect the nitrate-lowering capacity of selective GSK3 inhibition. Real-time PCR was used to assess post-treatment expression levels of pro-inflammatory markers and antioxidant genes; pro-inflammatory cytokines were assayed by ELISA. Nuclear lysates of treated cells were examined for Nrf2 and NF-κB accumulation by immunoblotting. Finally, to infer whether the counter-inflammatory activity of GSK3 inhibition was Nrf2-dependent, DsiRNA-mediated knockdown of Nrf2 was attempted. Results from our experiments reveal a superior anti-inflammatory and anti-oxidative efficacy for GSK3ß-selective inhibition, compared to GSK3α-selective and non-selective pan-inhibition; hence, use of selective GSK3ß inhibitors is likely to be more propitious than non-selective dual inhibitors administered at comparable doses. Moreover, our results suggest that the anti-inflammatory effects of GSK3 inhibition are not Nrf2 dependent.

The Anti-Inflammatory Properties of Phytochemicals and Their Effects on Epigenetic Mechanisms Involved in TLR4/NF-κB-Mediated Inflammation.

Innate immune response induces positive inflammatory transducers and regulators in order to attack pathogens, while simultaneously negative signaling regulators are transcribed to maintain innate immune homeostasis and to avoid persistent inflammatory immune responses. The gene expression of many of these regulators is controlled by different epigenetic modifications. The remarkable impact of epigenetic changes in inducing or suppressing inflammatory signaling is being increasingly recognized. Several studies have highlighted the interplay of histone modification, DNA methylation, and post-transcriptional miRNA-mediated modifications in inflammatory diseases, and inflammation-mediated tumorigenesis. Targeting these epigenetic alterations affords the opportunity of attenuating different inflammatory dysregulations. In this regard, many studies have identified the significant anti-inflammatory properties of distinct naturally-derived phytochemicals, and revealed their regulatory capacity. In the current review, we demonstrate the signaling cascade during the immune response and the epigenetic modifications that take place during inflammation. Moreover, we also provide an updated overview of phytochemicals that target these mechanisms in macrophages and other experimental models, and go on to illustrate the effects of these phytochemicals in regulating epigenetic mechanisms and attenuating aberrant inflammation.

Mercury and Alzheimer's disease: a look at the links and evidence.

This review paper investigates a specific environmental-disease interaction between mercury exposure and Alzheimer's disease hallmarks. Alzheimer's disease is a neurodegenerative disorder affecting predominantly the memory of the affected individual. It prevails mostly in the elderly, rendering many factors as possible causative agents, which potentially contribute to the disease pathogenicity cumulatively. Alzheimer's disease affects nearly 50 million people worldwide and is considered one the most devastating diseases not only for the patient, but also for their families and caregivers. Mercury is a common environmental toxin, found in the atmosphere mostly due to human activity, such as coal burning for heating and cooking. Natural release of mercury into the atmosphere occurs by volcanic eruptions, in the form of vapor, or weathering rocks. The most toxic form of mercury to humans is methylmercury, to which humans are exposed to by ingestion of fish. Methylmercury was found to exert its toxic effects on different parts of the human body, with predominance on the brain. There is no safe concentration for mercury in the atmosphere, even trace amounts can elicit harm to humans in the long term. Mercury's effect on Alzheimer's disease hallmarks formation, extracellular senile plaques and intracellular neurofibrillary tangles, has been widely studied. This review demonstrates the involvement of mercury, in its different forms, in the pathway of amyloid beta deposition and tau tangles formation. It aims to understand the link between mercury exposure and Alzheimer's disease so that, in the future, prevention strategies can be applied to halt the progression of this disease.

Hepigenetics: A Review of Epigenetic Modulators and Potential Therapies in Hepatocellular Carcinoma.

Hepatocellular carcinoma is the fifth most common cancer worldwide and the second most lethal, following lung cancer. Currently applied therapeutic practices rely on surgical resection, chemotherapy and radiotherapy, or a combination thereof. These treatment options are associated with extreme adversities, and risk/benefit ratios do not always work in patients' favor. Anomalies of the epigenome lie at the epicenter of aberrant molecular mechanisms by which the disease develops and progresses. Modulation of these anomalous events poses a promising prospect for alternative treatment options, with an abundance of felicitous results reported in recent years. Herein, the most recent epigenetic modulators in hepatocellular carcinoma are recapitulated on.

Delineation of radiometric anomalies and conductive zones using gamma-ray spectrometric and electromagnetic methods, east Gabal El-Urf area, Northern Eastern Desert, Egypt.

Ground gamma-ray spectrometric (GRS) and horizontal-loop electromagnetic (HLEM) surveys were carried out to determine the radioactive anomalous zones and to follow their lateral and vertical extensions in east Gabal (G.) El-Urf area, Northern Eastern Desert, Egypt. This area and its surroundings are mainly covered by basement rocks of Late Precambrian age, represented by quartz diorites and granite porphyry, which are intruded by pegmatites, quartz veins, and basic dykes. These rocks are traversed by dry wadis (dry valleys), which are filled by Quaternary sediments. The ground gamma-ray spectrometric data revealed that the study area possesses a wide range of radioelement concentrations, oscillating from 37 to 2164 µR/h, 0.9-170 ppm, 0.1-312 ppm, and 0.2%-7.8% for total count (TC), equivalent uranium (eU), equivalent thorium (eTh), and potassium (K), respectively. The eU composite image showed that high radioactive parts are mainly associated with the pegmatite rocks. Ground HLEM survey was performed at four frequencies (7040 Hz, 1760 Hz, 440 Hz, and 110 Hz) in the study area. The interpretation of the HLEM data indicated the presence of various conductive zones, mainly associated with pegmatite bodies. The parameters of source causative bodies, such as location, dip angle, width, and conductivity thickness were estimated for three conductive bodies. The calculated depths to the selected HLEM anomalies appear to be shallow, varying from 10 m to 22 m. All the anomalous bodies have dips ranging between 60° and 80° toward the south and west. The widths of the anomalous bodies range from medium conductors (13 m) to broad conductors (40 m or more). The conductivity thicknesses showed a wide range (1.14-72.7 Siemens), with the highest value associated with the highest eU anomaly.