High-frequency magnetic stimulation attenuates beta-amyloid protein 1-42 neurotoxicity in organotypic hippocampal slices

Repetitive transcranial magnetic stimulation （rTMS） has been utilized as a therapeutic tool for neurodegenerative disorders including Alzheimer＇s disease. However, the precise mechanisms of its clinical effects remain unknown. β-amyloid （Aβ） exhibits direct neurotoxic effects and is closely related to neuronal degeneration in Alzheimer＇s disease. Therefore, it has been hypothesized that the neuroprotective effects of rTMS are related to the mechanisms of protection against Aβ neurotoxicity. Organotypic hippocampal slices were prepared from 8-day old, Sprague Dawley rats. The tissue slices were exposed to 100 μmol/L Al3142 since day 12 in vitro with and without high-frequency （20 Hz） magnetic stimulation. Magnetic stimulation efficacy was evaluated by measuring neuronal nuclei （NeuN） protein expression and by observing cultures following propidium iodide fluorescence staining and bromodeoxyuridine （BrdU） immunohistochemistry. Lactate dehydrogenase activity was detected in the culture media to evaluate hippocampal neuronal damage. Our results demonstrated that high-frequency magnetic stimulation significantly reversed the reduction of NeuN protein expression because of Aβ1-42 exposure （P 〈 0.05） and significantly reduced the number of damaged cells in the hippocampal slices （P 〈 0.05）. However, lactate dehydrogenase levels and anti-BrdU staining results did not reveal any statistical differences These findings indicate that high-frequency magnetic stimulation might have protective effect on hippocampal neurons from Aβ1-42 neurotoxicity.

Therapeutic strategy targeting host lipolysis limits infection by SARS-CoV-2 and influenza A virus

The biosynthesis of host lipids and/or lipid droplets(LDs)has been studied extensively as a putative therapeutic target in diverse viral infections.However,directly targeting the LD lipolytic catabolism in virus-infected cells has not been widely investigated.Here,we show the linkage of the LD-associated lipase activation to the breakdown of LDs for the generation of free fatty acids(FFAs)at the late stage of diverse RNA viral infections,which represents a broad-spectrum antiviral target.Dysfunction of membrane transporter systems due to virus-induced cell injury results in intracellular malnutrition at the late stage of infection,thereby making the virus more dependent on the FFAs generated from LD storage for viral morphogenesis and as a source of energy.The replication of SARS-CoV-2 and influenza A virus(IAV),which is suppressed by the treatment with LD-associated lipases inhibitors,is rescued by supplementation with FFAs.The administration of lipase inhibitors,either individually or in a combination with virus-targeting drugs,protects mice from lethal IAV infection and mitigates severe lung lesions in SARS-CoV-2-infected hamsters.Moreover,the lipase inhibitors significantly reduce proinflammatory cytokine levels in the lungs of SARS-CoV-2-and IAV-challenged animals,a cause of a cytokine storm important for the critical infection or mortality of COVID-19 and IAV patients.In conclusion,the results reveal that lipase-mediated intracellular LD lipolysis is commonly exploited to facilitate RNA virus replication and furthermore suggest that pharmacological inhibitors of LD-associated lipases could be used to curb current COVID-19-and future pandemic outbreaks of potentially troublesome RNA virus infection in humans.

Emerging role of the orphan nuclear receptor estrogen-related receptor gamma in liver metabolic diseases

Estrogen-related receptor gamma(ERRg)is one of three members of the ERR family and remains an orphan,as there are no known natural ligands.ERRg is an inducible transcription factor,and its ligandindependent transcriptional activity is regulated by co-regulator interactions and post-transcriptional modifications.Recent findings from animal models show that ERRg,as a downstream mediator of multiple extracellular signals,plays a key role in coordinating endocrine and metabolic signals,resulting in changes in glucose,alcohol,lipid,and iron metabolism in the liver.Therefore,dysregulation of this receptor contributes to the pathogenesis of metabolic diseases such as hyperglycemia,insulin resistance,and alcoholic liver injury.Interestingly,ERRg is also involved in responses to bacterial infection.These findings establish the importance of ERRg in the endocrine and metabolic control of liver metabolism,and suggest that ERRg may be a promising therapeutic target for metabolic diseases of the liver.