Alcohol Dependence Modulates Amygdalar mTORC2 and PKCε Expression in a Rodent Model.

Multiple alcohol use disorder (AUD)-related behavioral alterations are governed by protein kinase C epsilon (PKCε), particularly in the amygdala. Protein kinase C (PKC) is readily phosphorylated at Ser729 before activation by the mTORC2 protein complex. In keeping with this, the current study was conducted to assess the variations in mTORC2 and PKCε during different ethanol exposure stages. The following groups of rats were employed: control, acute, chronic, ethanol withdrawal (EW), and EW + ethanol (EtOH). Ethanol-containing and non-ethanol-containing modified liquid diets (MLDs) were administered for 27 days. On day 28, either saline or ethanol (2.5 g/kg, 20% v/v) was intraperitoneally administered, followed by bilateral amygdala extraction. PKCε mRNA levels were noticeably increased in the amygdala of the EW + EtOH and EW groups. Following chronic ethanol consumption, the stress-activated map kinase-interacting protein 1 (Sin1) gene expression was markedly decreased. In the EW, EW + EtOH, and chronic ethanol groups, there was a profound increase in the protein expression of mTOR, Sin1, PKCε, and phosphorylated PKCε (Ser729). The PKCε gene and protein expressions showed a statistically significant moderate association, according to a correlation analysis. Our results suggest that an elevated PKCε protein expression in the amygdala during EW and EW + EtOH occurred at the transcriptional level. However, an elevation in the PKCε protein expression, but not its mRNA, after chronic ethanol intake warrants further investigation to fully understand the signaling pathways during different episodes of AUD.

Alzheimer's Disease: An Update and Insights Into Pathophysiology.

Alzheimer's disease (AD) is an irreversible brain disorder associated with slow, progressive loss of brain functions mostly in older people. The disease processes start years before the symptoms are manifested at which point most therapies may not be as effective. In the hippocampus, the key proteins involved in the JAK2/STAT3 signaling pathway, such as p-JAK2-Tyr1007 and p-STAT3-Tyr705 were found to be elevated in various models of AD. In addition to neurons, glial cells such as astrocytes also play a crucial role in the progression of AD. Without having a significant effect on tau and amyloid pathologies, the JAK2/STAT3 pathway in reactive astrocytes exhibits a behavioral impact in the experimental models of AD. Cholinergic atrophy in AD has been traced to a trophic failure in the NGF metabolic pathway, which is essential for the survival and maintenance of basal forebrain cholinergic neurons (BFCN). In AD, there is an alteration in the conversion of the proNGF to mature NGF (mNGF), in addition to an increase in degradation of the biologically active mNGF. Thus, the application of exogenous mNGF in experimental studies was shown to improve the recovery of atrophic BFCN. Furthermore, it is now coming to light that the FGF7/FGFR2/PI3K/Akt signaling pathway mediated by microRNA-107 is also involved in AD pathogenesis. Vascular dysfunction has long been associated with cognitive decline and increased risk of AD. Vascular risk factors are associated with higher tau and cerebral beta-amyloid (Aß) burden, while synergistically acting with Aß to induce cognitive decline. The apolipoprotein E4 polymorphism is not just one of the vascular risk factors, but also the most prevalent genetic risk factor of AD. More recently, the research focus on AD shifted toward metabolisms of various neurotransmitters, major and minor nutrients, thus giving rise to metabolomics, the most important "omics" tool for the diagnosis and prognosis of neurodegenerative diseases based on an individual's metabolome. This review will therefore proffer a better understanding of novel signaling pathways associated with neural and glial mechanisms involved in AD, elaborate potential links between vascular dysfunction and AD, and recent developments in "omics"-based biomarkers in AD.

Physicochemical and Medicinal Properties of Tualang, Gelam and Kelulut Honeys: A Comprehensive Review.

Tualang, Gelam and Kelulut honeys are tropical rainforest honeys reported to have various medicinal properties. Studies related to the medicinal properties and physicochemical characteristics of these honeys are growing extensively and receiving increased attention. This review incorporated and analysed the findings on the biological and physicochemical properties of these honeys. Tualang, Gelam and Kelulut honeys were found to possess a wide variety of biological effects attributed to their physicochemical characteristics. Findings revealed that these honeys have anti-diabetic, anti-obesity, anti-cancer, anti-oxidative, anti-microbial, anti-inflammatory and wound-healing properties and effects on the cardiovascular system, nervous system and reproductive system. The physicochemical properties of these honeys were compared and discussed and results showed that they have high-quality contents and excellent antioxidant sources.

Alcohol, Aggression, and Violence: From Public Health to Neuroscience.

Alcohol has been associated with violent crimes and domestic violence across many nations. Various etiological factors were linked to chronic alcohol use and violence including psychiatric comorbidities of perpetrators such as personality disorders, mood disorders, and intermittent explosive disorders. Aggression is the precursor of violence and individuals prone to aggressive behaviors are more likely to commit impulsive violent crimes, especially under the influence of alcohol. Findings from brain studies indicate long-term alcohol consumption induced morphological changes in brain regions involved in self-control, decision-making, and emotional processing. In line with this, the inherent dopaminergic and serotonergic anomalies seen in aggressive individuals increase their susceptibility to commit violent crimes when alcohol present in their system. In relation to this, this article intends to investigate the influence of alcohol on aggression with sociopsychological and neuroscientific perspectives by looking into comorbidity of personality or mood disorders, state of the mind during alcohol consumption, types of beverages, environmental trigger, neurochemical changes, and gender differences that influence individual responses to alcohol intake and susceptibility to intoxicated aggression.

Pathophysiological Perspective of Osteoarthritis.

Osteoarthritis (OA) is the most well-known degenerative disease among the geriatric and is a main cause of significant disability in daily living. It has a multifactorial etiology and is characterized by pathological changes in the knee joint structure including cartilage erosion, synovial inflammation, and subchondral sclerosis with osteophyte formation. To date, no efficient treatment is capable of altering the pathological progression of OA, and current therapy is broadly divided into pharmacological and nonpharmacological measures prior to surgical intervention. In this review, the significant risk factors and mediators, such as cytokines, proteolytic enzymes, and nitric oxide, that trigger the loss of the normal homeostasis and structural changes in the articular cartilage during the progression of OA are described. As the understanding of the mechanisms underlying OA improves, treatments are being developed that target specific mediators thought to promote the cartilage destruction that results from imbalanced catabolic and anabolic activity in the joint.

Alcohol Use Disorder, Neurodegeneration, Alzheimer's and Parkinson's Disease: Interplay Between Oxidative Stress, Neuroimmune Response and Excitotoxicity.

Alcohol use disorder (AUD) has been associated with neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Prolonged excessive alcohol intake contributes to increased production of reactive oxygen species that triggers neuroimmune response and cellular apoptosis and necrosis via lipid peroxidation, mitochondrial, protein or DNA damage. Long term binge alcohol consumption also upregulates glutamate receptors, glucocorticoids and reduces reuptake of glutamate in the central nervous system, resulting in glutamate excitotoxicity, and eventually mitochondrial injury and cell death. In this review, we delineate the following principles in alcohol-induced neurodegeneration: (1) alcohol-induced oxidative stress, (2) neuroimmune response toward increased oxidants and lipopolysaccharide, (3) glutamate excitotoxicity and cell injury, and (4) interplay between oxidative stress, neuroimmune response and excitotoxicity leading to neurodegeneration and (5) potential chronic alcohol intake-induced development of neurodegenerative diseases, including Alzheimer's and Parkinson's disease.

Effect of Nigella sativa and its bioactive compound on type 2 epithelial to mesenchymal transition: a systematic review.

BACKGROUND: Nigella sativa or commonly known as black seed or black cumin is one of the most ubiquitous complementary medicine. Epithelial to mesenchymal transition (EMT) of type 2 is defined by the balance between wound healing and tissue fibrosis, which is dependent to the state of inflammation. This systematic review is conducted to provide an overview regarding the reported effect of Nigella sativa and its bioactive compound on the type 2 EMT. METHODS: A search was done in EBSCOHOST, OVID and SCOPUS database to obtain potentially relevant articles that were published between 1823 and August 2019. This review includes studies that focus on the effect of Nigella sativa and its bioactive compound on the events related to type 2 EMT. RESULTS: A total of 1393 research articles were found to be potentially related to the effect of Nigella sativa and its bioactive compound, thymoquinone on Type 2 EMT. After screening was done, 22 research articles met inclusion criteria and were included in this review. Majority of the studies, reported better wound healing rate or significant prevention of tissue inflammation and organ fibrosis following Nigella sativa or thymoquinone treatments. In terms of wound healing, studies included reported progression of EMT related pathological changes after treatment with Nigella sativa or thymoquinone. Alternatively, in terms of fibrosis and inflammation, studies included reported reversal of pathological changes related to EMT after treatment with Nigella sativa or thymoquinone. CONCLUSION: Through this review, Nigella sativa and thymoquinone have been associated with events in Type 2 EMT. They have been shown to promote wound healing, attenuate tissue inflammation, and prevent organ fibrosis via regulation of the EMT process.