Synthesis of oxidative metabolites of CRA13 and their analogs: Identification of CRA13 active metabolites and analogs thereof with selective CB2R affinity

CRA13; a peripheral dual CB₁R/CB₂R agonist with clinically proven analgesic properties, infiltrates into CNS producing adverse effects due to central CB₁R agonism. Such adverse effects might be circumvented by less lipophilic compounds with attenuated CB₁R affinity. Metabolism produces less lipophilic metabolites that might be active metabolites. Some CRA13 oxidative metabolites and their analogues were synthesized as less lipophilic CRA13 analogues. Probing their CB₁R and CB₂R activity revealed the alcohol metabolite 8c as a more potent and more effective CB₂R ligand with attenuated CB₁R affinity relative to CRA13. Also, the alcohol analogue 8b and methyl ester 12a possessed enhanced CB₂R affinity and reduced CB₁R affinity. The CB₂R binding affinity of alcohol analogue 8b was similar to CRA13 while that of methyl ester 12a was more potent. In silico study provided insights into the possible molecular interactions that might explain the difference in the elicited biological activity of these compounds.     

Neuroprotective effect of polysaccharide separated from Perilla frutescens Britton var. acuta Kudo against H2O2-induced oxidative stress in HT22 hippocampus cells

This study was carried out to evaluate the neuroprotective activity of polysaccharide extracts isolated from Perilla frutescens (PEPF) in H₂O₂-treated HT22 hippocampus cells. The PEPF treatment was found to increase the anti-oxidant activities of HT22 hippocampus cells. PEPF treatment resulted in a significant protection of HT22 hippocampus cells against H₂O₂-induced neurotoxicity, this protection ultimately occurred through an inhibition of ROS-mediated intracellular Ca²⁺ levels leading to MAPKs and NF-κB, as well as the accumulation of PI3K/AKT and Nrf2-mediated HO-1/NQO1 pathways. Furthermore, PEPF not only decreased the expression of Bax, cytochrome c, and cleaved caspases-3, -8, and -9, but also increased the expression of PARP and Bcl-2 in the H₂O₂-treated HT22 hippocampus cells, which overall contributed to the neuroprotective action. PEPF retains its mitochondrial membrane potential and reduces the elevated levels of sub-G1 phase and apoptotic morphological features induced by H₂O₂. It also reduces the malondialdehyde levels and enhances the intracellular SOD activity.     

Anti‐cancer therapy with TNFα and IFNγ: A comprehensive review

Tumour necrosis factor alpha (TNFα) and interferon gamma (IFNγ) were originally found to be produced by inflammatory cells and play important roles in the immune system and surveillance of tumour growth. By activating distinct signalling pathways of nuclear factor‐κB (NF‐κB), mitogen‐activated protein kinase (MAPK), and JAK/STAT, TNFα and IFNγ were reported to effectively trigger cell death and perform powerful anti‐cancer effects. In this review, we will discuss the new advancements of TNFα and IFNγ in anti‐cancer therapy.     

Chlorination caused a shift in marine biofilm niches on microfiltration/ultrafiltration and reverse osmosis membranes and UV irradiation effectively inactivated a chlorine-resistant bacterium

Applied Microbiology and Biotechnology - The effect of chlorine disinfection on marine biofilm populations and communities formed on membrane surfaces was investigated under two feedwater...     

Post‐GWAS in Psychiatric Genetics: A Developmental Perspective on the “Other” Next Steps

As psychiatric genetics enters an era where gene identification is finally yielding robust, replicable genetic associations and polygenic risk scores, it is important to consider next steps and delineate how that knowledge will be applied to ultimately ameliorate suffering associated with substance use and psychiatric disorders. Much of the post‐genome‐wide association study discussion has focused on the potential of genetic information to elucidate the underlying biology and use this information for the development of more effective pharmaceutical treatments. In this review we focus on additional areas of research that should follow gene identification. By taking genetic findings into longitudinal, developmental studies, we can map the pathways by which genetic risk manifests across development, elucidating the early behavioral manifestations of risk, and studying how various environments and interventions moderate that risk across developmental stages. The delineation of risk across development will advance our understanding of mechanism, sex differences and risk and resilience processes in different racial/ethnic groups. Here, we review how the extant twin study literature can be used to guide these efforts. Together, these new lines of research will enable us to develop more informed, tailored prevention and intervention efforts.     

Deficiency of aminopeptidase P1 causes behavioral hyperactivity,cognitive deficits,and hippocampal neurodegeneration

Metabolic diseases affect various organs including the brain. Accumulation or depletion of substrates frequently leads to brain injury and dysfunction. Deficiency of aminopeptidase P1, a cytosolic proline‐specific peptidase encoded by the Xpnpep1 gene, causes an inborn error of metabolism (IEM) characterized by peptiduria in humans. We previously reported that knockout of aminopeptidase P1 in mice causes neurodevelopmental disorders and peptiduria. However, little is known about the pathophysiological role of aminopeptidase P1 in the brain. Here, we show that loss of aminopeptidase P1 causes behavioral and neurological deficits in mice. Mice deficient in aminopeptidase P1 (Xpnpep1^?/?) display abnormally enhanced locomotor activities in both the home cage and open‐field box. The aminopeptidase P1 deficiency in mice also resulted in severe impairments in novel‐object recognition, the Morris water maze task, and contextual, but not cued, fear memory. These behavioral dysfunctions were accompanied by epileptiform electroencephalogram activity and neurodegeneration in the hippocampus. However, mice with a heterozygous mutation for aminopeptidase P1 (Xpnpep1^+/?) exhibited normal behaviors and brain structure. These results suggest that loss of aminopeptidase P1 leads to behavioral, cognitive and neurological deficits. This study may provide insight into new pathogenic mechanisms for brain dysfunction related to IEMs.     

Modulation of gut microbiome in nonalcoholic fatty liver disease: pro-, pre-, syn-, and antibiotics

Nonalcoholic fatty liver disease (NAFLD) is one of the most common types of liver diseases worldwide and its incidence continues to increase. NAFLD occurs when the body can no longer effectively store excess energy in the adipose tissue. Despite the increasing prevalence of NAFLD, making lifestyle changes, including increased exercise, is often an elusive goal for patients with NAFLD. The liver directly connects to the gut-gastrointestinal milieu via the portal vein, which are all part of the gut-liver axis. Therefore, the gut-microbiome and microbial products have been actively studied as likely key factors in NAFLD pathophysiology. Hence, dysbiosis of the gut microbiome and therapeutic manipulation of the gut-liver axis are being investigated. Novel therapeutic approaches for modulating gut microbiota through the administration of probiotics, prebiotics, synbiotics, and antibiotics have been proposed with numerous promising initial reports on the effectiveness and clinical applications of these approaches. This review delves into the current evidence on novel therapies that modulate gut microbiota and discusses ongoing clinical trials targeting the gut-liver axis for the management and prevention of NAFLD.     

The effect of multi-frequency whole-body vibration on night-shifted mouse model

The circadian rhythm controls several biological activities; therefore, a disorganized circadian rhythm may cause fatal health problems. The aim of this study was to assess the effects of circadian rhythm disturbances induced by simulated night shift activities on the abdominal adipose tissue, bone microstructures and muscle volume in the tibiae of mice. Moreover, we evaluated the effects of multi-frequency whole-body vibration as a countermeasure against the consequences of circadian rhythm disturbances. Twenty-four 5-week-old C57BL/6J male mice were equally assigned to three groups: the normal group (Nor), night shift group (NS), and night shift with multi-frequency whole-body vibration group (NS + V). The NS and NS + V groups were exposed to circadian rhythm disturbances for 4 weeks with 3-day intervals by changing the day and night cycle based on 7 o’clock. After 4 weeks, morphological changes in the adipose tissue, bone microstructures and muscle volume in the tibiae were evaluated from three-dimensional images using in vivo micro-computed tomography. As a result, the volume of the abdominal adipose tissue was significantly higher in the NS than in the Nor and NS + V groups. Also, the microstructures of the tibia were more enhanced in the NS + V than the NS group. The volume of tibial muscle was increased in all groups, while there were no significant changes in muscle volume. From these results, we can conclude that circadian rhythm disturbances induced by night shift activities may reduce bone condition and increase the accumulation of abdominal adipose tissue and these negative effects may be prevented or improved through applying multi-frequency whole-body vibration.