The biphasic role of Hspb1 on ferroptotic cell death in Parkinson's disease.

Rationale: Ferroptosis-driven loss of dopaminergic neurons plays a pivotal role in the pathogenesis of Parkinson's disease (PD). In PD patients, Hspb1 is commonly observed at abnormally high levels in the substantia nigra. The precise consequences of Hspb1 overexpression in PD, however, have yet to be fully elucidated. Methods: We used human iPSC-derived dopaminergic neurons and Coniferaldehyde (CFA)-an Nrf2 agonist known for its ability to cross the blood-brain barrier-to investigate the role of Hspb1 in PD. We examined the correlation between Hspb1 overexpression and Nrf2 activation and explored the transcriptional regulation of Hspb1 by Nrf2. Gene deletion techniques were employed to determine the necessity of Nrf2 and Hspb1 for CFA's neuroprotective effects. Results: Our research demonstrated that Nrf2 can upregulate the transcription of Hspb1 by directly binding to its promoter. Deletion of either Nrf2 or Hspb1 gene abolished the neuroprotective effects of CFA. The Nrf2-Hspb1 pathway, newly identified as a defense mechanism against ferroptosis, was shown to be essential for preventing neurodegeneration progression. Additionally, we discovered that prolonged overexpression of Hspb1 leads to neuronal death and that Hspb1 released from ruptured cells can trigger secondary cell death in neighboring cells, exacerbating neuroinflammatory responses. Conclusions: These findings highlight a biphasic role of Hspb1 in PD, where it initially provides neuroprotection through the Nrf2-Hspb1 pathway but ultimately contributes to neurodegeneration and inflammation when overexpressed. Understanding this dual role is crucial for developing therapeutic strategies targeting Hspb1 and Nrf2 in PD.

Dihydromyricetin Alleviates Ischemic Brain Injury by Antagonizing Pyroptosis in Rats.

Ischemic stroke is a worldwide disease that seriously threatens human health, and there are few effective drugs to treat it. Dihydromyricetin (DHM) has anti-inflammatory, antioxidant, and antiapoptotic functions. We identified pyroptosis following ischemic stroke. Here, we investigated the effect of DHM on ischemic stroke and pyroptosis. In the first part of the experiment, Sprague-Dawley rats were randomly divided into the sham group and MCAO group. The MCAO model was established by occlusion of the middle cerebral artery for 90 min using a silica gel suture. The ischemic penumbra was used for mRNA sequencing 1 day after reperfusion. In the second part, rats were divided into the sham group, MCAO group, and DHM group. DHM was injected intraperitoneally at the same time as reperfusion starting 90 min after embolization for 7 consecutive days. The changes in pyroptosis were observed by morphological and molecular methods. The transcriptomics results suggested the presence of NLRP3-mediated pyroptotic death pathway activation after modeling. The Longa score was increased after MCAO and decreased after DHM treatment. 2,3,5-Triphenyltetrazolium chloride (TTC) staining showed that DHM could reduce the infarct volume induced by MCAO. Nissl staining showed disordered neuronal arrangement and few Nissl bodies in the MCAO group, but this effect was reversed by DHM treatment. Analysis of pyroptosis-related molecules showed that the MCAO group had serious pyroptosis, and DHM effectively reduced pyroptosis. Our results demonstrate that DHM has a neuroprotective effect on ischemic stroke that is at least partly achieved by reducing pyroptosis.

Integrated multiomics analysis reveals changes in liver physiological function in Aqp9 gene knockout mice.

Aquaporin 9 (AQP9) is the main channel by which blood glycerol enters the liver, where it plays key roles in osmotic pressure regulation and energy metabolism. Previous studies have shown that AQP9 is involved in the pathogenesis of many liver diseases. In this study, we aimed to clarify the role of AQP9 in maintaining the physiological environment of the liver using Aqp9-/- mice. We constructed Aqp9 knockout mice and used comprehensive multiomics analysis to elucidate the potential molecular effects of AQP9 expression on liver tissue. Knockout of Aqp9 reduced mouse body weight by affecting glycerol metabolism and led to hepatocyte death and inflammatory cell infiltration, which was confirmed by transcriptomics, proteomics and metabolomics. Moreover, knockout of Aqp9 triggered immune and inflammatory responses, leading to scattered and mild liver cell pyroptosis and compensatory liver cell proliferation.

Untargeted metabolomics reveals the role of AQP9 in nonalcoholic fatty liver disease in a mice model.

Previous studies have shown that AQP9 plays an important role in energy metabolism in nonalcoholic fatty liver disease (NAFLD). Recently, metabolomic analyses were used to determine the slight changes in metabolic profiles and helped to understand the disease progression, therapeutic intervention of NAFLD. A mouse model of NAFLD was established with a high-fat diet (HFD), and Aqp9 knockout mice were constructed. Untargeted metabolomics techniques were used to evaluate the potential mechanism of the effect of AQP9 in NAFLD. The results indicated that AQP9 plays a regulatory role in the occurrence of NAFLD. Moreover, a total of 220 candidate biomarkers were screened and identified. Cluster analysis and enrichment analysis of differential metabolites indicated that fatty acid biosynthesis was mainly disturbed when compared against the control group, which was mitigated by knockout of Aqp9. These results show that untargeted metabolomics help to understand the effects of AQP9 in NAFLD.

High-Altitude Hypoxia Exposure Induces Iron Overload and Ferroptosis in Adipose Tissue.

High altitude (HA) has become one of the most challenging environments featuring hypobaric hypoxia, which seriously threatens public health, hence its gradual attraction of public attention over the past decade. The purpose of this study is to investigate the effect of HA hypoxia on iron levels, redox state, inflammation, and ferroptosis in adipose tissue. Here, 40 mice were randomly divided into two groups: the sea-level group and HA hypoxia group (altitude of 5000 m, treatment for 4 weeks). Total iron contents, ferrous iron contents, ROS generation, lipid peroxidation, the oxidative enzyme system, proinflammatory factor secretion, and ferroptosis-related biomarkers were examined, respectively. According to the results, HA exposure increases total iron and ferrous iron levels in both WAT and BAT. Meanwhile, ROS release, MDA, 4-HNE elevation, GSH depletion, as well as the decrease in SOD, CAT, and GSH-Px activities further evidenced a phenotype of redox imbalance in adipose tissue during HA exposure. Additionally, the secretion of inflammatory factors was also significantly enhanced in HA mice. Moreover, the remarkably changed expression of ferroptosis-related markers suggested that HA exposure increased ferroptosis sensitivity in adipose tissue. Overall, this study reveals that HA exposure is capable of inducing adipose tissue redox imbalance, inflammatory response, and ferroptosis, driven in part by changes in iron overload, which is expected to provide novel preventive targets for HA-related illness.

Evolution of associating liver partition and portal vein ligation for staged hepatectomy from 2012 to 2021: A bibliometric analysis. Review.

BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has become increasingly popular during the past few decades, and its indications have extended from patients with normal liver to post-chemotherapy patients and even patients with cirrhosis. However, few studies have assessed the publications in relation to ALPPS. METHODS: Web of Science was searched to identify studies related to ALPPS published from 2012 to 2021. The analysis was performed using the bibliometric package (Version 3.1.0) in R software. RESULTS: In total, 486 publications were found. These articles were published in 159 journals and authored by 2157 researchers from 694 organizations. The most prolific journal was Annals of Surgery (24 articles and 1170 citations). The most frequently cited article was published in Annals of Surgery (average citations, 72.7; total citations, 727). China was the most productive country for ALPPS publications but had comparatively less interaction with other countries. Both thematic evolution and co-occurrence network analysis showed low numbers of topics such as failure, resection, and safety among the publications but large numbers of highly cited papers on outcomes, prediction, mechanisms, multicenter analysis, and novel procedures such as liver venous deprivation. A total of 196 studies focused the clinical application of ALPPS, and most studies were IDEAL Stages I and II. The specific mechanism of ALPPS liver regeneration remains unclear. CONCLUSIONS: This is the first bibliometric analysis offering an overview of the development of ALPPS research publications. Our findings identified prominent studies, countries, institutions, journals, and authors to indicate the future direction of ALPPS research. The role of ALPPS in liver regeneration and the long-term results of ALPPS need further study. Future research directions include comparison of ALPPS with portal vein embolization, liver venous deprivation, and other two-stage hepatectomies as well as patients' quality of life after ALPPS.

CircSV2b participates in oxidative stress regulation through miR-5107-5p-Foxk1-Akt1 axis in Parkinson's disease.

As a novel type of non-coding RNAs, covalently closed circular RNAs (circRNAs) are ubiquitously expressed in eukaryotes. Emerging studies have indicated that dysregulation of circRNAs was related to neurological diseases. However, the biogenesis, regulation, function, and mechanism of circRNAs in Parkinson's disease (PD) remain largely unclear. In this study, thirty-three differentially expressed circRNAs (DECs) were detected by RNA-sequencing between the MPTP-induced PD mice model and the wild-type mice. Quantitative real-time PCR was used to determine the RNA level of DECs in the striatum (STR), substantia nigra pars compacta (SNpc), and serum exosomes, and it was found that circSV2b was downregulated in PD mice. Then, functional experiments in vivo were employed to explore the effect of circSV2b in PD. For the mechanism study, dual-luciferase reporter, fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP), RNA pull-down, gene editing, and CUT & Tag were performed in vitro to confirm that circSV2b directly sponged miR-5107-5p and alleviated the suppression of the expression of the target gene Foxk1, and then positively regulated Akt1 transcription. In vivo, the mechanistic analysis demonstrated that circSV2b overexpression resisted oxidative stress damage through the ceRNA-Akt1 axis in PD models. Taken together, these findings suggested that the miR-5107-5p-Foxk1-Akt1 axis might serve as a key target of circSV2b overexpression in PD treatment, and highlighted the significant change of circSV2b in serum exosomes. Therefore, circSV2b might be a novel biomarker for the diagnosis and treatment of PD.

The Role of Autophagy in the Pathogenesis of Ischemic Stroke.

Autophagy is a strictly regulated process that degrades and recycles long-lived or misfolded proteins and damaged organelles for the maintenance of energy and function homeostasis of cells. Insufficient oxygen and glucose supply caused by cerebral ischemia lead to a higher ratio of AMP/ATP, which will activate the AMPK pathway to initiate the process of autophagy. Accumulating evidence shows that autophagy participates in the pathogenesis of ischemic stroke as a double- edged sword. However, the exact role of autophagy in the pathogenesis of ischemic stroke is controversial and yet to be elucidated. In this review, the autophagy pathway, both in physiological conditions and in ischemic stroke, is expounded. The focus was also on discussing the doubleedged sword effect of autophagy in brain ischemia and its underlying mechanisms. In addition, potential therapeutic strategies for ischemic stroke targeting autophagy pathway were also reviewed.

A Preliminary Study on the Effect of Hydrogen Gas on Alleviating Early CCl4-Induced Chronic Liver Injury in Rats.

As a small-molecule reductant substance, hydrogen gas has an obvious antioxidant function. It can selectively neutralize hydroxyl radicals (•OH) and peroxynitrite (ONOO•) in cells, reducing oxidative stress damage. The purpose of this study was to investigate the effect of hydrogen gas (3%) on early chronic liver injury (CLI) induced by CCl4 and to preliminarily explore the protective mechanism of hydrogen gas on hepatocytes by observing the expression of uncoupling protein 2 (UCP2) in liver tissue. Here, 32 rats were divided into four groups: the control group, CCl4 group, H2 (hydrogen gas) group, and CCl4 + H2 group. The effect of hydrogen gas on early CLI was observed by serological tests, ELISA, hematoxylin and eosin staining, and oil red O staining. Immunohistochemical staining and Western blotting were used to observe the expression of UCP2 in liver tissues. We found that CCl4 can induce significant steatosis in hepatocytes. When the hydrogen gas was inhaled, hepatocyte steatosis was reduced, and the UCP2 expression level in liver tissue was increased. These results suggest that hydrogen gas might upregulate UCP2 expression levels, reduce the generation of intracellular oxygen free radicals, affect lipid metabolism in liver cells, and play a protective role in liver cells.

Aquaporin 9 Represents a Novel Target of Chronic Liver Injury That May Antagonize Its Progression by Reducing Lipotoxicity.

In recent years, chronic liver injury has become a common disease that harms human health. Its clinical manifestations are hepatic steatosis and secondary chronic steatohepatitis, which can quickly transform into liver fibrosis and cirrhosis if not treated in time. Therefore, this study is aimed at searching for new therapeutic targets of chronic liver injury and clarifying the molecular mechanisms of the new targets involved in chronic liver injury. After aquaporin 9 was identified as a target by proteomics, Aqp9-/- mice were constructed using the CRISPR/Cas9 system. Biochemical and morphological tests were used to verify the effect of Aqp9 knockout on early chronic liver injury. Proteomics, molecular biology, and morphology experiments were used to screen and verify the effects of Aqp9 knockout on its downstream pathway. Through the above experiments, we demonstrated that aquaporin 9 could be used as an intervention target for antagonizing the development of early chronic liver injury and its gene knockout affected downstream inflammation, oxidative stress, apoptosis, and pyroptosis by alleviating hepatic lipotoxicity.

Effect of Methylene Blue on White Matter Injury after Ischemic Stroke.

Methylene blue, the FDA-grandfathered drug was proved to be neuroprotective in ischemic stroke in rat. However, the mechanism of the protective effect was unknown. In this study, we used different animal models to investigate the effect of MB administration given within and beyond the therapeutic time window on behavioral deficits and infarct volume and related mechanism about the white matter protection. Middle cerebral artery occlusion and reperfusion (MCAO) and photothrombotic middle cerebral artery occlusion (PT-MCAO) models were used. Behavioral deficits and infarct volume were measured by foot fault test, Garcia neurological score, and TTC staining. Black gold staining and western blot were used to evaluate the brain white matter injury. We found that intraperitoneal administration of MB immediately or 24 h after the MCAO or PT-MCAO surgery reduced infarct volume, improved the neurological deficits, and reduced the white matter injury via myelin basic protein (BMP) protection. These findings suggested that MB relieved the white matter injury besides neuronal protection and has potential therapeutic effects on ischemic stroke.

Dihydromyricetin ameliorates chronic liver injury by reducing pyroptosis.

BACKGROUND: Chronic liver injury (CLI) is now a worldwide disease. However, there is no effective treatment. Pyroptosis plays an essential role in CLI. Dihydromyricetin (DHM) resists oxidation and protects the liver. We hypothesize that the beneficial effect of DHM on CLI is related to its effect on the expression of pyroptosis-related molecules. Therefore, we studied the influence of DHM on CLI and pyroptosis. AIM: To study the role of pyroptosis in the pathogenesis of CLI and the therapeutic mechanism of DHM. METHODS: Thirty-two mice were randomly divided into four groups: The control group was injected with olive oil, the carbon tetrachloride (CCl4) group was injected with CCl4, the vehicle group was injected with hydroxypropyl-ß-cyclodextrin while injecting CCl4 and the DHM group was injected with DHM while injecting CCl4. After four weeks of treatment, liver tissues from the mice were stained with hematoxylin and eosin, and oil red O. Blood was collected from the angular vein for serological analysis. The severity of CLI was estimated. Some liver tissue was sampled for immunohistochemistry, Western blotting and quantitative reverse transcription PCR to observe the changes in pyroptosis-related molecules. RESULTS: Serum total cholesterol, low density lipoprotein, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the CCl4 group were higher than those in the control group, and serum total cholesterol, low density lipoprotein, AST and ALT in the DHM group were lower than those in the vehicle group. Hematoxylin and eosin and oil red O staining showed that there were more lipid droplets in the CCl4 group than in the control group, and there were fewer lipid droplets in the DHM group than in the vehicle group. Western blotting showed that the expression of the pyroptosis-related molecules caspase-1, NOD-, LRR- and pyrin domain-containing 3 (NLRP3) and gasdermin D (GSDMD)-N in the CCl4 group was higher than that in the control group, while expression of these proteins in the DHM group was lower than that in the vehicle group. Quantitative reverse transcription PCR results showed that the expression of the pyroptosis-related genes caspase-1, NLRP3, GSDMD and interleukin-1ß (IL-1ß) in the CCl4 group was higher than that in the control group, while there was no significant change in NLRP3 and caspase-1 expression in the DHM group compared with that in the vehicle group, and the expression of GSDMD and IL-1ß was decreased. CONCLUSION: DHM improves CCl4-induced CLI and regulates the pyroptosis pathway in hepatocytes. DHM may be a potential therapeutic agent for CLI.