ARC Syndrome-Linked Vps33B Protein Is Required for Inflammatory Endosomal Maturation and Signal Termination.

Toll-like receptors (TLRs) and other pattern-recognition receptors (PRRs) sense microbial ligands and initiate signaling to induce inflammatory responses. Although the quality of inflammatory responses is influenced by internalization of TLRs, the role of endosomal maturation in clearing receptors and terminating inflammatory responses is not well understood. Here, we report that Drosophila and mammalian Vps33B proteins play critical roles in the maturation of phagosomes and endosomes following microbial recognition. Vps33B was necessary for clearance of endosomes containing internalized PRRs, failure of which resulted in enhanced signaling and expression of inflammatory mediators. Lack of Vps33B had no effect on trafficking of endosomes containing non-microbial cargo. These findings indicate that Vps33B function is critical for determining the fate of signaling endosomes formed following PRR activation. Exaggerated inflammatory responses dictated by persistence of receptors in aberrant endosomal compartments could therefore contribute to symptoms of ARC syndrome, a disease linked to loss of Vps33B.

Molecular Toxicology and Pathophysiology of Comorbid Alcohol Use Disorder and Post-Traumatic Stress Disorder Associated with Traumatic Brain Injury.

The increasing comorbidity of alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) associated with traumatic brain injury (TBI) is a serious medical, economic, and social issue. However, the molecular toxicology and pathophysiological mechanisms of comorbid AUD and PTSD are not well understood and the identification of the comorbidity state markers is significantly challenging. This review summarizes the main characteristics of comorbidity between AUD and PTSD (AUD/PTSD) and highlights the significance of a comprehensive understanding of the molecular toxicology and pathophysiological mechanisms of AUD/PTSD, particularly following TBI, with a focus on the role of metabolomics, inflammation, neuroendocrine, signal transduction pathways, and genetic regulation. Instead of a separate disease state, a comprehensive examination of comorbid AUD and PTSD is emphasized by considering additive and synergistic interactions between the two diseases. Finally, we propose several hypotheses of molecular mechanisms for AUD/PTSD and discuss potential future research directions that may provide new insights and translational application opportunities.

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases.

With aging, the nervous system gradually undergoes degeneration. Increased oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and cell death are considered to be common pathophysiological mechanisms of various neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), organophosphate-induced delayed neuropathy (OPIDN), and amyotrophic lateral sclerosis (ALS). Autophagy is a cellular basic metabolic process that degrades the aggregated or misfolded proteins and abnormal organelles in cells. The abnormal regulation of neuronal autophagy is accompanied by the accumulation and deposition of irregular proteins, leading to changes in neuron homeostasis and neurodegeneration. Autophagy exhibits both a protective mechanism and a damage pathway related to programmed cell death. Because of its "double-edged sword", autophagy plays an important role in neurological damage and NDDs including AD, PD, HD, OPIDN, and ALS. Melatonin is a neuroendocrine hormone mainly synthesized in the pineal gland and exhibits a wide range of biological functions, such as sleep control, regulating circadian rhythm, immune enhancement, metabolism regulation, antioxidant, anti-aging, and anti-tumor effects. It can prevent cell death, reduce inflammation, block calcium channels, etc. In this review, we briefly discuss the neuroprotective role of melatonin against various NDDs via regulating autophagy, which could be a new field for future translational research and clinical studies to discover preventive or therapeutic agents for many NDDs.

Role of Alcohol Drinking in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis.

Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), increase as the population ages around the world. Environmental factors also play an important role in most cases. Alcohol consumption exists extensively and it acts as one of the environmental factors that promotes these neurodegenerative diseases. The brain is a major target for the actions of alcohol, and heavy alcohol consumption has long been associated with brain damage. Chronic alcohol intake leads to elevated glutamate-induced excitotoxicity, oxidative stress and permanent neuronal damage associated with malnutrition. The relationship and contributing mechanisms of alcohol with these three diseases are different. Epidemiological studies have reported a reduction in the prevalence of Alzheimer's disease in individuals who drink low amounts of alcohol; low or moderate concentrations of ethanol protect against ß-amyloid (Aß) toxicity in hippocampal neurons; and excessive amounts of ethanol increase accumulation of Aß and Tau phosphorylation. Alcohol has been suggested to be either protective of, or not associated with, PD. However, experimental animal studies indicate that chronic heavy alcohol consumption may have dopamine neurotoxic effects through the induction of Cytochrome P450 2E1 (CYP2E1) and an increase in the amount of α-Synuclein (αSYN) relevant to PD. The findings on the association between alcohol consumption and ALS are inconsistent; a recent population-based study suggests that alcohol drinking seems to not influence the risk of developing ALS. Additional research is needed to clarify the potential etiological involvement of alcohol intake in causing or resulting in major neurodegenerative diseases, which will eventually lead to potential therapeutics against these alcoholic neurodegenerative diseases.

Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy.

The lack of effective and well-tolerated therapies against antibiotic-resistant bacteria is a global public health problem leading to prolonged treatment and increased mortality. To improve the efficacy of existing antibiotic compounds, we introduce a new method for strategically inducing antibiotic hypersensitivity in pathogenic bacteria. Following the systematic verification that the AcrAB-TolC efflux system is one of the major determinants of the intrinsic antibiotic resistance levels in Escherichia coli, we have developed a short antisense oligomer designed to inhibit the expression of acrA and increase antibiotic susceptibility in E. coli. By employing this strategy, we can inhibit E. coli growth using 2- to 40-fold lower antibiotic doses, depending on the antibiotic compound utilized. The sensitizing effect of the antisense oligomer is highly specific to the targeted gene's sequence, which is conserved in several bacterial genera, and the oligomer does not have any detectable toxicity against human cells. Finally, we demonstrate that antisense oligomers improve the efficacy of antibiotic combinations, allowing the combined use of even antagonistic antibiotic pairs that are typically not favored due to their reduced activities.

Contributing Roles of CYP2E1 and Other Cytochrome P450 Isoforms in Alcohol-Related Tissue Injury and Carcinogenesis.

The purpose of this review is to briefly summarize the roles of alcohol (ethanol) and related compounds in promoting cancer and inflammatory injury in many tissues. Long-term chronic heavy alcohol exposure is known to increase the chances of inflammation, oxidative DNA damage, and cancer development in many organs. The rates of alcohol-mediated organ damage and cancer risks are significantly elevated in the presence of co-morbidity factors such as poor nutrition, unhealthy diets, smoking, infection with bacteria or viruses, and exposure to pro-carcinogens. Chronic ingestion of alcohol and its metabolite acetaldehyde may initiate and/or promote the development of cancer in the liver, oral cavity, esophagus, stomach, gastrointestinal tract, pancreas, prostate, and female breast. In this chapter, we summarize the important roles of ethanol/acetaldehyde in promoting inflammatory injury and carcinogenesis in several tissues. We also review the updated roles of the ethanol-inducible cytochrome P450-2E1 (CYP2E1) and other cytochrome P450 isozymes in the metabolism of various potentially toxic substrates, and consequent toxicities, including carcinogenesis in different tissues. We also briefly describe the potential implications of endogenous ethanol produced by gut bacteria, as frequently observed in the experimental models and patients of nonalcoholic fatty liver disease, in promoting DNA mutation and cancer development in the liver and other tissues, including the gastrointestinal tract.

Population and dyadic-based seroincidence of herpes simplex virus-2 and syphilis in southern India.

OBJECTIVES: Herpes simplex virus-2 (HSV-2) and syphilis are associated with increased risk of HIV, highlighting the importance of understanding their transmission dynamics. In India, most studies of HSV-2 and syphilis incidence are in high-risk populations and may not accurately reflect infectious activity. In this study, we aim to define HSV-2/syphilis incidence and risk factors in a population sample. METHODS: We conducted a longitudinal population-based survey in Andhra Pradesh, India, in two rounds: 2004-2005 and 2010-2011. Sociodemographic and behavioural data were collected, and dried blood spots tested for HSV-2 and Treponema pallidum IgG. After calculating sexually transmitted infection (STI) incidence, associated factors were assessed using modified Poisson regression and within-couple transmission rates modelled using seroconcordance/discordance data. RESULTS: 12,617 adults participated at baseline with 8494 at follow-up. Incidence of HSV-2 and syphilis per 1000 person-years was 25.6 (95% CI 24.1 to 27.2) and 3.00 (95% CI 2.52 to 3.54). Incidence of HSV-2 was higher in women vs. men (31.1 vs. 20.2) and in rural vs urban residents (31.1 vs 19.0) (p<0.05 for both). STI seroincidence increased in a step-wise fashion with age and was associated with spousal seropositivity for both sexes (incidence rate ratio (IRR) 2.59 to 6.78). Within couples the rate of transmission per 1000 couple-years from men to women vs. women to men was higher for HSV-2 (193.3 vs. 119.0) compared with syphilis (27.6 vs. 198.8), p<0.05 for both. CONCLUSIONS: HSV-2 has higher incidence among subpopulations such as women, rural residents and older-aged individuals, suggesting a need for more generalised STI prevention approaches among populations traditionally considered low risk.

3D CT based age estimation from the pubic symphyseal surface in an Indian population using the Chen et al. method.

The pubic symphyseal surface is one of the reliable parameters used to estimate age, as it consistently shows degenerative observational variations throughout the lifespan, particularly from the 3rd decade onwards. These changes have been extensively studied to generate population-specific models for forensic age estimation. In the past, there have been many studies used to estimate age at death from the pubis symphysis using skeletal remains. However, due to dearth of contemporary skeletal repositories, and the resource intensive maceration process required for obtaining examination quality bones, studies on cadaver are difficult to conduct. Moreover, due to recent advancements in the science of medical imaging, newer radiological modalities like computed tomography (CT) can be used to visualize previously inaccessible areas such as the pubic symphysis in cadavers and the living alike, and subsequent age estimation is feasible. Recently, Chen et al. (2008, 2011) conducted a study on the cadaveric Chinese Han population in both males and females separately by using nine morphological changes and scoring them according to the changes that occurred. The present study aimed to estimate an individual's age using CT images of the pubic symphysis, by applying the scoring method for its morphological changes given by Chen et al. The present study was conducted on 263 randomly selected participants (Males = 154, Females = 109), who came for diagnostic purposes to the hospital. The CT images of these individuals were collected after obtaining ethical approval and proper consent from the study participants. Each of the morphological indicators was assessed, and appropriate scores were given according to criteria given by Chen et al. In the present study, both linear and multiple regression models to estimate age using the pubic symphyseal morphological changes were developed. From the results of the present study, it was concluded that the Chen et al. scoring method can be used to accurately estimate age from 3DCT images of the living, and the models derived in the present study could be applicable to individuals from the Indian subcontinent.

Protective effects of fecal microbiota transplantation against ischemic stroke and other neurological disorders: an update.

The bidirectional communication between the gut and brain or gut-brain axis is regulated by several gut microbes and microbial derived metabolites, such as short-chain fatty acids, trimethylamine N-oxide, and lipopolysaccharides. The Gut microbiota (GM) produce neuroactives, specifically neurotransmitters that modulates local and central neuronal brain functions. An imbalance between intestinal commensals and pathobionts leads to a disruption in the gut microbiota or dysbiosis, which affects intestinal barrier integrity and gut-immune and neuroimmune systems. Currently, fecal microbiota transplantation (FMT) is recommended for the treatment of recurrent Clostridioides difficile infection. FMT elicits its action by ameliorating inflammatory responses through the restoration of microbial composition and functionality. Thus, FMT may be a potential therapeutic option in suppressing neuroinflammation in post-stroke conditions and other neurological disorders involving the neuroimmune axis. Specifically, FMT protects against ischemic injury by decreasing IL-17, IFN-γ, Bax, and increasing Bcl-2 expression. Interestingly, FMT improves cognitive function by lowering amyloid-ß accumulation and upregulating synaptic marker (PSD-95, synapsin-1) expression in Alzheimer's disease. In Parkinson's disease, FMT was shown to inhibit the expression of TLR4 and NF-κB. In this review article, we have summarized the potential sources and methods of administration of FMT and its impact on neuroimmune and cognitive functions. We also provide a comprehensive update on the beneficial effects of FMT in various neurological disorders by undertaking a detailed interrogation of the preclinical and clinical published literature.

Drosophila acinus encodes a novel regulator of endocytic and autophagic trafficking.

Endosomal trafficking affects many cellular pathways from cell signaling to metabolism, but little is known about how these effects are coordinated. In a genetic screen for mutants affecting endosomal trafficking, we identified Drosophila acinus (dacn; hook-like). Its mammalian homolog Acinus has been implicated in RNA processing and chromatin fragmentation during apoptosis. Loss-of-function analysis of dacn revealed two distinct functions. First, dacn is required for stabilization of early endosomes, thus modulating levels of Notch and Egfr signaling. Second, loss of dacn interferes with cellular starvation responses by inhibiting autophagosome maturation. By contrast, overexpression of dacn causes lethality due to enhanced autophagy. We show that this enhanced autophagy is independent of the Tor pathway. Taken together, our data show that dacn encodes a regulator of endosomal and autophagosomal dynamics, modulating developmental signaling and the cellular response to starvation.

HIV incidence from the first population-based cohort study in India.

BACKGROUND: Understanding about who acquires new HIV infection and the determinants of why some persons get infected and others do not is fundamental to controlling HIV in the population. We assess HIV incidence and its associations in the population of a high HIV burden district in Andhra Pradesh state in southern India by a population-based longitudinal cohort study. METHODS: We re-surveyed a population-based cohort of 12,617 adults in Guntur district of Andhra Pradesh for which we had reported a baseline HIV prevalence of 1.72% (rural 1.64%, urban 1.89%) among the 15-49 years age group in 2004-2005. We conducted interviews to assess risk behaviour and performed HIV testing again in 2010-2011. We assessed the rate of new HIV infection and its associations using multiple logistic regression. RESULTS: The participation rate in the follow-up was 74.9% and 63.9% of the baseline rural and urban samples, respectively. Over a mean follow-up of 5.63 years, the incidence of HIV was 1.26 per 1000 person-years (95% CI 0.83-1.69), after adjusting for slight compositional bias in the follow-up sample. The incidence per 1000 person-years was higher among rural men (1.68) than urban men (0.85), and among rural women (1.28) than urban women (0.54). The strongest association with incidence was a HIV positive spouse in the baseline for both men (odds ratio 266, 95% CI 62-1137) and women (odds ratio 28, 95% CI 9-88). Among men the other significant associations with HIV incidence were frequent use of condom for sex over the past 6 months, non-circumcision, more than one lifetime woman sex partner or ever visited sex worker, and transport-related occupation; for women the other significant associations were having had HIV testing other than antenatal check-up, previously married but currently not, and tobacco use. CONCLUSION: These first population-based cohort incidence data from India suggest that rural areas of high HIV burden states would need more attention to prevent new HIV infections, and that spouses of HIV positive persons and some other risk groups need to be targeted more effectively by HIV prevention programmes.

Therapeutic strategies of small molecules in the microbiota-gut-brain axis for alcohol use disorder.

The microbiota-gut-brain axis (MGBA) is important in maintaining the structure and function of the central nervous system (CNS) and is regulated by the CNS environment and signals from the peripheral tissues. However, the mechanism and function of the MGBA in alcohol use disorder (AUD) are still not completely understood. In this review, we investigate the underlying mechanisms involved in the onset of AUD and/or associated neuronal deficits and create a foundation for better treatment (and prevention) strategies. We summarize recent reports focusing on the alteration of the MGBA in AUD. Importantly, we highlight the properties of small-molecule short-chain fatty acids (SCFAs), neurotransmitters, hormones, and peptides in the MGBA and discusses their usage as therapeutic agents against AUD.

A diabetic foot service established by a department of vascular surgery: an observational study.

BACKGROUND: The mechanism by which the multidisciplinary approach to diabetic foot disease reduces amputation rates is unclear. Ischemia, sepsis, and necrosis represent aspects of severe diabetic foot disease amenable to intervention. In 2006, a vascular unit introduced a rapid access service for severe foot disease, augmenting the established community provision. This study aimed to determine whether concurrent changes in amputation rates were observed, and to identify areas that may have influenced outcomes. METHODS: Unit data prospectively collected during 4 years for patients with lower-limb disease were compared with data retrieved over 2 years before the foot service. Outcome measurements were major amputations, foot surgery, vascular interventions, admissions, and length of stay. RESULTS: Major amputation rates associated with diabetes peaked in 2005 at 24.7/10,000 vs. 1.07/10,000 in 2009; (relative risk = 0.043, 95% confidence interval = 0.006-0.322). The proportion of diabetic to nondiabetic amputations decreased; foot surgery rates also dropped (53.7/10,000 in 2006 vs. 7.5/10,000 in 2009). The number of open revascularization procedures decreased, but the rates of endovascular procedures remained generally constant. Hospital admission rates decreased after initially peaking, and the length of stay was unchanged (16 vs. 15.5 days in 2004 and 2009, respectively). CONCLUSIONS: The integration of a vascular unit with community care has been associated with improved outcomes for patients with diabetic foot disease. Improvements were not related to the increased number of vascular procedures or hospitalizations, but did coincide with a greater proportion of patients attending the foot unit. The referral of patients to the unit facilitates the rapid management of severe disease, reducing delays deleterious to outcomes.

N-Docosahexaenoylethanolamide promotes development of hippocampal neurons.

DHA (docosahexaenoic acid, C22:6,n-3) has been shown to promote neurite growth and synaptogenesis in embryonic hippocampal neurons, supporting the importance of DHA known for hippocampus-related learning and memory function. In the present study, we demonstrate that DHA metabolism to DEA (N-docosahexaenoylethanolamide) is a significant mechanism for hippocampal neuronal development, contributing to synaptic function. We found that a fatty acid amide hydrolase inhibitor URB597 potentiates DHA-induced neurite growth, synaptogenesis and synaptic protein expression. Active metabolism of DHA to DEA was observed in embryonic day 18 hippocampal neuronal cultures, which was increased further by URB597. Synthetic DEA promoted hippocampal neurite growth and synaptogenesis at substantially lower concentrations in comparison with DHA. DEA-treated neurons increased the expression of synapsins and glutamate receptor subunits and exhibited enhanced glutamatergic synaptic activity, as was the case for DHA. The DEA level in mouse fetal hippocampi was altered according to the maternal dietary supply of n-3 fatty acids, suggesting that DEA formation is a relevant in vivo process responding to the DHA status. In conclusion, DHA metabolism to DEA is a significant biochemical mechanism for neurite growth, synaptogenesis and synaptic protein expression, leading to enhanced glutamatergic synaptic function. The novel DEA-dependent mechanism offers a new molecular insight into hippocampal neurodevelopment and function.

Ellagic Acid Prevents Binge Alcohol-Induced Leaky Gut and Liver Injury through Inhibiting Gut Dysbiosis and Oxidative Stress.

Alcoholic liver disease (ALD) is a major liver disease worldwide and can range from simple steatosis or inflammation to fibrosis/cirrhosis, possibly through leaky gut and systemic endotoxemia. Many patients with alcoholic steatohepatitis (ASH) die within 60 days after clinical diagnosis due to the lack of an approved drug, and thus, synthetic and/or dietary agents to prevent ASH and premature deaths are urgently needed. We recently reported that a pharmacologically high dose of pomegranate extract prevented binge alcohol-induced gut leakiness and hepatic inflammation by suppressing oxidative and nitrative stress. Herein, we investigate whether a dietary antioxidant ellagic acid (EA) contained in many fruits, including pomegranate and vegetables, can protect against binge alcohol-induced leaky gut, endotoxemia, and liver inflammation. Pretreatment with a physiologically-relevant dose of EA for 14 days significantly reduced the binge alcohol-induced gut barrier dysfunction, endotoxemia, and inflammatory liver injury in mice by inhibiting gut dysbiosis and the elevated oxidative stress and apoptosis marker proteins. Pretreatment with EA significantly prevented the decreased amounts of gut tight junction/adherent junction proteins and the elevated gut leakiness in alcohol-exposed mice. Taken together, our results suggest that EA could be used as a dietary supplement for alcoholic hepatitis patients.

Tartary buckwheat extract alleviates alcohol-induced acute and chronic liver injuries through the inhibition of oxidative stress and mitochondrial cell death pathway.

Alcohol use disorder (AUD) is an enormous public health problem that poses significant social, medical, and economic burdens. Under AUD, the liver is one of the most adversely affected organs. As current therapies and protective drugs for AUD-mediated liver injury are very limited, the prevention and therapy of alcoholic liver disease are urgently needed. The present study aims to investigate the beneficial effects of tartary buckwheat extract (TBE), the important component of Maopu tartary buckwheat liquor, on both alcoholic-induced acute and chronic liver injuries. We show that the TBE administration, similar to curcumin, significantly reduces the elevated serum aspartate aminotransferase and alanine aminotransferase levels, improves liver index, alleviates the elevated contents of hepatic malondialdehye, and restores the decreased contents of hepatic glutathione both in acute and chronic liver injuries in alcohol-exposed rats. Furthermore, histopathological analyses show that a medium dose of TBE (16.70 ml/kg body weight) alleviates hepatocyte morphology changes in both acute and chronic alcohol exposure models. We also show the protective effects of TBE on the cell death rates of alcohol-exposed primary cultured hepatocytes, HepG2 hepatoma, and Huh 7 hepatoma cells. Furthermore, we demonstrate that TBE exerts hepatoprotection partly through inhibiting the mitochondrial cell death pathway by reducing cytochrome c release, caspase-9 and -3 activities, and the number of TUNEL-positive cells. These effects of TBE were accompanied by enhanced levels of Bcl-2 and Bcl-xL and autophagic cell death pathway by reducing Beclin-1 expression, as well as through promoting its anti-oxidant capacity by suppressing reactive oxygen species production. This study demonstrates, for the first time, the protective effect of TBE against alcohol-induced acute and chronic liver injury in vivo and in vitro. Given the dietary nature of tartary buckwheat, pueraria, lycium barbarum, and hawthorn, the oral intake of TBE or liquor contained TBE, e.g., Maopu Tartary buckwheat liquor, compared with pure liquor consumption alone, may have the potential to alleviate alcoholic-induced liver injuries.

Protective Effects of Antioxidants in Huntington's Disease: an Extensive Review.

Huntington's disease (HD) is a hereditary neurodegenerative disease of the central nervous system (CNS). Onset of HD occurs between the ages of 30 and 50 years, although few cases are reported among children and elderly. HD appears to be less common in some populations such as those of Japanese, Chinese, and African descent. Clinical features of HD include motor dysfunction (involuntary movements of the face and body, abnormalities in gait, posture and balance), cognitive impairment (obsessive-compulsive disorder), and psychiatric disorders (dementia). Mutation in either of the two copies of a gene called huntingtin (HTT), which codes genetic information for a protein called "huntingtin (Htt)", precipitates the disease in an individual. Expansion of cytosine-adenine-guanine (CAG) triplet repeats in the HTT gene results in an abnormal Htt protein. Intracellular neuronal accumulation of the mutated Htt protein (mHtt) causes distinctive erratic movements associated with HD. Further, excessive accumulation of the HTT gene repeats causes abnormal production of reactive oxygen species (ROS) and the ensuing mitochondrial (MT) oxidative stress in neurons. Since there is neither a cure nor a promising strategy to delay onset or progression of HD currently available, therapeutics are mainly focusing only on symptomatic management. Several studies have shown that MT dysfunction-mediated oxidative stress is a key factor for the neurodegeneration observed in HD. Supplementation of antioxidants and nutraceuticals has been widely studied in the management of oxidative damage, an associated complication in HD. Therefore, various antioxidants are used as therapeutics for managing and/or treating HD. The present review aimed at delving into the abnormal cellular changes and energy kinetics of the neurons expressing the mHtt gene and the therapeutic roles of antioxidants in HD.

Protective effects of heat shock protein 27 in a model of ALS occur in the early stages of disease progression.

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder, characterised by progressive motor neuron degeneration and muscle paralysis. Heat shock proteins (HSPs) have significant cytoprotective properties in several models of neurodegeneration. To investigate the therapeutic potential of heat shock protein 27 (HSP27) in a mouse model of ALS, we conducted an extensive characterisation of transgenic mice generated from a cross between HSP27 overexpressing mice and mice expressing mutant superoxide dismutase (SOD1(G93A)). We report that SOD1(G93A)/HSP27 double transgenic mice showed delayed decline in motor strength, a significant improvement in the number of functional motor units and increased survival of spinal motor neurons compared to SOD1(G93A) single transgenics during the early phase of disease. However, there was no evidence of sustained neuroprotection affecting long-term survival. Marked down-regulation of HSP27 protein occurred during disease progression that was not associated with a reduction in HSP27 mRNA, indicating a translational dysfunction due to the presence of mutant SOD1 protein. This study provides further support for the therapeutic potential of HSPs in ALS and other motor neuron disorders.

Medications for alcohol use disorders: An overview.

Patients who suffer from alcohol use disorders (AUDs) usually go through various socio-behavioral and pathophysiological changes that take place in the brain and other organs. Recently, consumption of unhealthy food and excess alcohol along with a sedentary lifestyle has become a norm in both developed and developing countries. Despite the beneficial effects of moderate alcohol consumption, chronic and/or excessive alcohol intake is reported to negatively affect the brain, liver and other organs, resulting in cell death, organ damage/failure and death. The most effective therapy for alcoholism and alcohol related comorbidities is alcohol abstinence, however, chronic alcoholic patients cannot stop drinking alcohol. Therefore, targeted therapies are urgently needed to treat such populations. Patients who suffer from alcoholism and/or alcohol abuse experience harmful effects and changes that occur in the brain and other organs. Upon stopping alcohol consumption, alcoholic patients experience acute withdrawal symptoms followed by a protracted abstinence syndrome resulting in the risk of relapse to heavy drinking. For the past few decades, several drugs have been available for the treatment of AUDs. These drugs include medications to reduce or stop severe alcohol withdrawal symptoms during alcohol detoxification as well as recovery medications to reduce alcohol craving and support abstinence. However, there is no drug that completely antagonizes the adverse effects of excessive amounts of alcohol. This review summarizes the drugs which are available and approved by the FDA and their mechanisms of action as well as the medications that are under various phases of preclinical and clinical trials. In addition, the repurposing of the FDA approved drugs, such as anticonvulsants, antipsychotics, antidepressants and other medications, to prevent alcoholism and treat AUDs and their potential target mechanisms are summarized.

Extracellular vesicles as potential biomarkers for alcohol- and drug-induced liver injury and their therapeutic applications.

Extracellular vesicles (EVs) are small membranous vesicles originating from various cells and tissues, including the liver parenchymal hepatocytes and nonparenchymal cells such as Kupffer and stellate cells. Recently, the pathophysiological role of EVs, such as exosomes and microvesicles, has been increasingly recognized based on their properties of intercellular communications. These EVs travel through the circulating blood and interact with specific cells and then deliver their cargos such as nucleic acids and proteins into recipient cells. In addition, based on their stabilities, circulating EVs from body fluids such as blood, cerebrospinal fluid, urine, saliva, semen, breast milk and amniotic fluids are being studied as a valuable source of potential biomarkers for providing information about the physiological status of original cells or tissues. In addition, EVs are considered potential therapeutic agents due to their ability for intercellular communications between different cell types within the liver and between various organs through transfer of their cargos. In this review, we have briefly described recent advances in the characteristics and pathophysiological roles of EVs in alcoholic liver disease (ALD) or drug-induced liver injury (DILI) and discuss their advantages in the discovery of potential biomarkers and therapeutic agents.