Metabolic brain disease最新文献

{"title":"Unraveling the role of Nrf2 in dopaminergic neurons: a review of oxidative stress and mitochondrial dysfunction in Parkinson's disease.","authors":"Manpreet Kaur, Khadga Raj Aran","doi":"10.1007/s11011-025-01552-7","DOIUrl":"10.1007/s11011-025-01552-7","url":null,"abstract":"<p><p>Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential transcriptional factor, involved in the regulation of countenance of various anti-oxidant enzymes and cytoprotective genes that respond to mitochondrial dysfunctions, oxidative stress, and neuroinflammation, thus potentially contributing to several neurodegenerative diseases (NDDs), including Parkison's disease (PD). PD is the second most prevalent progressive NDD, characterized by gradual neuronal death in substantia nigra pars compacta (SNpc), depletion of dopamine level, and a wide range of motor symptoms, including bradykinesia, tremor, tingling, and muscle fatigue. The etiopathology of PD is caused by multifactorial intertwined with the onset and progression of the disease. In this context, Nrf2 exhibits neuroprotective action by preserving dopaminergic neurons in the striatum and retarding the disease progression; thus, Nrf2 activation plays a crucial role in PD. Additionally, Nrf2 binds with the antioxidant response element, which is located in the promoter region of most of the genes that are responsible for coding antioxidant enzymes. Moreover, protein kinase C (PKC) mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K) are also involved in the regulation of Keap1 pathway-mediated Nrf2 activation. As Nrf2 revealed its defensive and protective role in the central nervous system (CNS), it is gaining enough interest in treating PD. The treatments that are currently available are intended to alleviate the symptoms of PD; however, they are unable to halt the progression and severity of the disease. Therefore, in this review we delve deeper into various molecular mechanisms associated with oxidative stress, mitochondrial dysfunction, and neuroinflammation in PD. Additionally, we elaborated on the substantial role that NRF2 plays in mitigating these adverse effects and its potential as a therapeutic target.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 2","pages":"123"},"PeriodicalIF":3.2,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiota-derived short chain fatty acids act as mediators of the gut-liver-brain axis.","authors":"Cunyin Li, Jingtong Yao, Chang Yang, Shengnan Yu, Zizhen Yang, Lijing Wang, Shangyong Li, Ningning He","doi":"10.1007/s11011-025-01554-5","DOIUrl":"10.1007/s11011-025-01554-5","url":null,"abstract":"<p><p>The gut microbiota plays a crucial role in the communication between the gut, liver, and brain through the production of short chain fatty acids (SCFAs). SCFAs serve as key mediators in the Gut-Liver-Brain Axis, influencing various physiological processes and contributing to overall health. SCFAs are produced by bacterial fermentation of dietary fiber in the gut, and they exert systemic effects by signaling through various pathways. In the Gut-Liver axis, SCFAs regulate liver metabolism through peroxisome proliferator-activated receptor-γ (PPAR-γ), AMP-activated protein kinase (AMPK) and other pathways, promotes fat oxidation, modulate inflammation through mTOR pathway, and impact metabolic health. In the Gut-Brain axis, SCFAs influence brain function, behavior, and may have implications for neurological disorders, in which G-protein coupled receptors (GPCRs) play an essential role, along with other pathways such as hypothalamic-pituitary-adrenal (HPA) pathway. Understanding the mechanisms by which SCFAs mediate communication between the gut, liver, and brain is crucial for elucidating the complex interplay of the Gut-Liver-Brain Axis. This review aims to provide insight into the role of gut microbiota-derived SCFAs as mediators of the Gut-Liver-Brain Axis and their potential therapeutic implications. Further research in this area will be instrumental in developing novel strategies to target the Gut-Liver-Brain Axis for the prevention and treatment of various health conditions.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 2","pages":"122"},"PeriodicalIF":3.2,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glutamate/GABA/glutamine ratios in intact and ischemia reperfusion challenged rat brain subregions, the effect of ischemic preconditioning.","authors":"Eva Baranovicova, Dagmar Kalenska, Jan Lehotsky","doi":"10.1007/s11011-024-01511-8","DOIUrl":"10.1007/s11011-024-01511-8","url":null,"abstract":"<p><p>The proper function of the brain is entirely dependent on intact neurotransmission, where glutamate (Glu) and γ-aminobutyric acid (GABA) are the two most present neurotransmitters. Maintenance of these neurotransmitters pools is strictly relying on the de novo synthesis of glutamine in astrocytes. Cerebral ischemic events disrupt the balance in uptake and re-synthesis, altering Glu, GABA, and glutamine (Gln) levels. We focused on the determining of the ratios of glutamate, GABA and glutamine in the brain of rats in the intact state, the early changes and temporal development of changes towards the recovery after disruption of balance by global cerebral ischemia. Animals underwent 15 min of global cerebral ischemia, and changes in Glu/GABA/Gln ratios in the hippocampus, cortex, and cerebellum were assessed at 3 h, 24 h, and 72 h post-reperfusion using high-resolution NMR. Ischemic preconditioning was also used to induce tolerance. In an intact rat brain, glutamate level was about twice that of glutamine in all substructures, about sevenfold compared to GABA in the hippocampus and cortex, and almost eightfold compared to GABA in the cerebellum. There were three to four times as much glutamine compared to GABA. After severe cerebral ischemia, Glu/Gln as well as GABA/Gln ratios extensively dropped in early reperfusion (3 h) and gradually increased in 72 h reperfusion time, however, only the Glu/Gln ratio recovered to the level of controls. Glu/GABA ratio remained in all three reperfusion times over the level of control animals. We observed a decrease in glutathione NMR peak in brain tissue homogenates after ischemia. The obtained data suggest the accelerated accumulation of intraparenchymal glutamate after ischemia, which was even more pronounced in the preconditioned animals three days after an ischemic event. The postischemic GABA level restoration did not achieve the level before ischemia in 72 h reperfusion, which could be one of the limiting factors in the complete postischemic GABA transmission recovery. Presented data may be of advantage not only when comparing glutamate and GABA homeostasis and neurotransmission, but also for glutamine reserve display as neurotransmitter precursor and ammonia transfer buffer in glutamate/GABA/glutamine cycle within the intact brain substructures as well after ischemic insult in rats.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 2","pages":"121"},"PeriodicalIF":3.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11805880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sodium butyrate ameliorates mitochondrial oxidative stress and alterations in membrane-bound enzyme activities in pentylenetetrazole-induced kindling rat model.","authors":"Olusegun Lateef Adebayo, Gbemileke Emmanuel Luro, Ifewunmi Deborah Akeju, Chiamaka Favour Onu, Moyonuoluwa Esther Fawehinmi, Victoria Adejumoke Aderemi, Adeleke Kazeem Atunnise","doi":"10.1007/s11011-025-01550-9","DOIUrl":"10.1007/s11011-025-01550-9","url":null,"abstract":"<p><p>Epilepsy is a chronic neurological disorder manifested through repeatedly recurrent unprovoked seizures. It is a debilitating neurological illness arising from exacerbated hypersynchronous neuronal firing in the brain. Among various factors, oxidative stress has been implicated in the initiation of epileptogenesis and the progression of epileptic seizures. This study investigates the neuroprotective effect of sodium butyrate in a pentylenetetrazole (PTZ)-induced kindling rat model. Male and female Wistar rats were randomly assigned into four groups for each sex. The PTZ groups were administered 40 mg/kg b.w.t intraperitoneally on alternate days for 30 days and a final single dose on the 40th day, while the sodium butyrate groups were administered along with the rat's drinking water (4 g/L). The seizure score, oxidative stress parameter, acetylcholinesterase (AChE), Na⁺-K⁺-ATPase, Ca²⁺ + Mg²⁺-ATPase, and Ca²⁺-ATPase activities were evaluated. The results showed that seizure score was significantly increased in the PTZ group, but the score was attenuated with sodium butyrate treatment. Also, mitochondrial lipid peroxidation and oxidized glutathione were elevated, while the reduction in redox potential, GSH levels, and SOD activity were detected. In addition, a decrease in AChE, Na⁺-K⁺-ATPase, Ca²⁺ + Mg²⁺-ATPase, and Ca²⁺-ATPase activities and altered hippocampal and cortical architecture were observed. The administration of sodium butyrate enhanced the antioxidant status and membrane-bound enzymes and restored the histological architecture, as shown in the study, which signifies improved neurological functions. Hence, due to its antioxidant capacity, sodium butyrate may be a possible agent for inhibiting the progression and management of epilepsy in Wistar rats.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 2","pages":"120"},"PeriodicalIF":3.2,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of neuroinflammation on brain glutamate and dopamine signalling in schizophrenia: an update.","authors":"Usha Nayak, Jyothsna Manikkath, Devinder Arora, Jayesh Mudgal","doi":"10.1007/s11011-025-01548-3","DOIUrl":"10.1007/s11011-025-01548-3","url":null,"abstract":"<p><p>Schizophrenia is one of the most severe and chronic psychiatric disorders. Over the years, numerous treatment options have been introduced for schizophrenia. Although they are relatively successful in managing the positive symptoms of schizophrenia, most of the current treatments have a negligible effect on the negative and cognitive symptoms. Thus, none of them could prevent the relapse of psychotic episodes. Among the numerous hypotheses explaining the development and progression of schizophrenia, the cytokine hypothesis explains the role of inflammatory markers as a significant culprit in the development of schizophrenia. Elevated cytokines are reported in animal models and schizophrenic patients. The cytokine hypothesis is based on how increased inflammatory markers can cause changes in the dopaminergic, glutamate, and tryptophan metabolism pathways, like that observed in schizophrenic patients. Reasons, such as autoimmune disease, maternal immune activation, infection, etc., can pave the way for the development of schizophrenia and are associated with the negative, positive and cognitive symptoms of schizophrenia. Thus, there is a need to focus on the significance of anti-inflammatory drugs against these symptoms. The development of new treatment strategies in the management of schizophrenia can provide better therapeutic outcomes in terms of the severity of symptoms and treatment of drug-resistant schizophrenia. This review attempts to explain the association between elevated inflammatory markers and various neurotransmitters, and the possible use of medications like nonsteroidal anti-inflammatory drugs, monoclonal antibodies, statins, and estrogens as adjuvant therapy. Over the years, these hypotheses have been the basis for drug discovery for the treatment of schizophrenia.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 2","pages":"119"},"PeriodicalIF":3.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered gut microbiome and serum metabolome profiles associated with essential tremor.","authors":"Zhenzhen Yan, Zhilin Zheng, Lanxiao Cao, Zeyu Zhu, Chen Zhou, Qiying Sun, Beisha Tang, Guohua Zhao","doi":"10.1007/s11011-025-01549-2","DOIUrl":"10.1007/s11011-025-01549-2","url":null,"abstract":"<p><p>The genetic predisposition and environmental factors both trigger the complex neurological dyskinesia of essential tremor (ET). Gut dysbiosis may facilitate the occurrence and development of neurological diseases. Therefore, it is worth exploring the inner connections between gut microbiota and ET. First, the gut microbiota of 19 ET patients and 21 healthy controls (HCs) were analysed with metagenomics approach. Second, the potential linkages between gut microbiome and serum metabolome profiles were explored by integrative analysis. The gut microbiota disorders were present in ET patients. The LEfSe method showed a significant decrease in Bacteroides. The functional analysis revealed that there were differences in gut microbial apoptosis, retinol metabolism, and steroid hormone biosynthesis pathways. The levels of various lipids and lipid-like molecules alter in serum of ET patients, which correlated with altered gut microbial abundance, indicating the alterations in lipid metabolism involved in apoptosis pathway in ET. All of these data point to the gut dysbiosis in ET, and some changed gut microbial species were linked to abnormalities in blood lipid metabolism, which open up new avenues for investigation into the pathophysiology of ET.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 2","pages":"118"},"PeriodicalIF":3.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TIPS and hepatic encephalopathy in patients with cirrhosis.","authors":"Pauline Bozon-Rivière, Marika Rudler, Nicolas Weiss, Dominique Thabut","doi":"10.1007/s11011-025-01541-w","DOIUrl":"10.1007/s11011-025-01541-w","url":null,"abstract":"<p><p>Despite a better understanding in its prognosis and pathogenesis, hepatic encephalopathy (HE) remains one of the major complications of Transjugular Intrahepatic Portosystemic Shunt (TIPS) with a prevalence ranging from 35 to 50%. Its epidemiology differs according to the indication for TIPS (salvage/rescue TIPS, preemptive (pTIPS) or elective TIPS). In salvage/rescue TIPS, the prognosis is linked to that of bleeding, and HE should not be a contraindication to TIPS, especially as bleeding is a common precipitating factor of HE. In pTIPS, i.e. TIPS performed within the 72 h after stabilization of acute variceal bleeding in high-risk patients, the risk rebleeding and HE is reduced, when compared to endoscopic and drugs treatment. As a consequence, the Baveno VII recommendations state that HE at admission should not be considered as a contraindication to pTIPS placement. In elective situations, such as refractory (intractable ascites (intolerance to diuretics) or resistant ascites (i.e. despite optimal diuretic treatment (spironolactone 400 mg/d and Furosemide 160 mg/d combined with low-salt treatment (< 5.2 g/day) or recurrent ascites (the need for at least 3 paracenteses per year) and secondary prophylaxis of variceal bleeding, it is recommended to systematically look for risk factors for HE, and chronic or refractory HE remain not recommended to TIPS in most centers. Chronic HE involves persistent neurological symptoms with fluctuating acute episodes. Recurrent HE refers to repeated episodes occurring within 6 months, while refractory HE is resistant to standard treatments, often requiring more aggressive management (Vilstrup et al. 2014). A careful selection of patients is mandatory before elective TIPS decision. Risk factors must be identified and corrected if possible before any TIPS decision is made. Management of HE after TIPS is based on identification of precipitating factors, curative treatment with lactulose as first-line therapy and rifaximin as second-line therapy, and nutritional management. In elective TIPS, prophylactic administration of rifaximin is recommended in order to decrease the risk of further HE development in selected patients (not in everyone, at least according to Baveno VII). Liver transplantation (LT) should be discussed with a multidisciplinary team as an alternative option to TIPS in case of high-risk of post-TIPS HE, and in case of refractory HE after TIPS.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 2","pages":"117"},"PeriodicalIF":3.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effects of ursodeoxycholic acid on Parkinson's disease, a mechanistic review of the recent evidence.","authors":"Seyed Mehrad Razavi, Niusha Esmaealzadeh, Mazyar Ataei, Nadia Afshari, Moloud Saleh, Yasaman Amini, Sadaf Hasrati, Fatemeh Ghazizadeh Hashemi, Abolghasem Mortazavi, Leila Mohaghegh Shalmani, Amir Hossein Abdolghaffari","doi":"10.1007/s11011-025-01542-9","DOIUrl":"10.1007/s11011-025-01542-9","url":null,"abstract":"<p><strong>Introduction: </strong>Parkinson`s disease stands as the second-most widespread neurodegenerative disorder. Parkinson`s disease is relentless in progression and irreversible in nature, for which there is no cure. Therapies are only used to attenuate motor symptoms. As Parkinson`s disease is primarily defined by degeneration of dopaminergic neurons in the substantia nigra, and considering that neuroinflammation and mitochondrial dysfunction in these neurons are key factors contributing to disease progression, alternative therapies should aim to preserve healthy mitochondria. Method. Eligible studies on the effect of Ursodeoxycholic acid (UDCA) on Parkinson`s disease were collected from PubMed, Google Scholar, Scopus, Web of Science and Cochrane library for clinical, in-vivo, and in-vitro studies. Result. UDCA and its taurine conjugate (TUDCA), which are endogenous bile acids, have exhibited neuroprotective potential in various neurological conditions, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, in both animal experimental models and clinical investigations. This is attributed to three significant properties, in addition to their capability to cross the blood-brain barrier. First, their anti-inflammatory properties are manifested through the reduction of significant inflammatory factors such as tumor necrosis factor-α, interleukin 1β and other related elements. Second, their antioxidant property is marked by an increase in the expression of superoxide dismuthase, glutathione peroxidase and other antioxidant enzymes. The third property is the antiapoptotic activity, characterized by decreased caspase-3 activity and lower expression of pro-apoptotic Bax in the striatum. Conclusion. Based on this comprehensive review, UDCA and TUDCA have the potential to be considered as a therapeutic agent in the management of the Parkinson's disease.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 2","pages":"115"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain interleukins and Alzheimer's disease.","authors":"Heba G Abdelhamed, Arwa A Hassan, Alaa A Sakraan, Radwa T Al-Deeb, Dalia M Mousa, Heba S Aboul Ezz, Neveen A Noor, Yasser A Khadrawy, Nasr M Radwan","doi":"10.1007/s11011-025-01538-5","DOIUrl":"10.1007/s11011-025-01538-5","url":null,"abstract":"<p><p>The central nervous system (CNS) is immune-privileged by several immuno-modulators as interleukins (ILs). ILs are cytokines secreted by immune cells for cell-cell signaling communications and affect the functions of the CNS. ILs were reported to orchestrate different molecular and cellular mechanisms of both physiological and pathological events, through overproduction or over-expression of their receptors. They interact with numerous receptors mediating pro-inflammatory and/or anti-inflammatory actions. Interleukins have been implicated to participate in neurodegenerative diseases. They play a critical role in Alzheimer's disease (AD) pathology which is characterized by the over-production of pro-inflammatory ILs. These may aggravate neurodegeneration, in addition to their contribution to detrimental mechanisms as oxidative stress, and excitotoxicity. However, recent research on the relation between ILs and AD revealed major discrepancies. Most of the major ILs were shown to play both pro- and anti-inflammatory roles in different experimental settings and models. The interactions between different ILs through shared pathways also add to the difficulty of drawing solid conclusions. In addition, targeting the different ILs has not yielded consistent results. The repeated failures of therapeutic drugs in treating AD necessitate the search for novel agents targeting multiple mechanisms of the disease pathology. In this context, the understanding of interleukins and their roles throughout the disease progression and interaction with other systems in the brain may provide promising therapeutic targets for the prevention or treatment of AD.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 2","pages":"116"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11787210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione protects against MPP⁺-induced neurotoxicity by ameliorating oxidative stress, apoptosis and autophagy in SH-SY5Y cells.","authors":"Kechen Du, Ying Su, Qiong Song, Shuai Chen, Ribao Wu, Xiahong Teng, Renbin Huang, Lihui Wang, Chunlin Zou","doi":"10.1007/s11011-025-01544-7","DOIUrl":"10.1007/s11011-025-01544-7","url":null,"abstract":"<p><p>2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) is a cyclohexanedione compound extracted from the roots of Averrhoa carambola L. Several studies have documented its beneficial effects on diabetes, Alzheimer's disease, and cancer. However, its potential neuroprotective effects on Parkinson's disease (PD) have not yet been explored. The present study aimed to investigate the protective effects and underlying mechanisms of DMDD in a cellular model of PD. In this study, SH-SY5Y cells were incubated with or without DMDD following intoxication with the parkinsonian neurotoxin 1-methyl-4-phenylpyridine (MPP⁺). Cell viability and apoptosis were evaluated using 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium (MTS) assay and Hoechst 33,342 staining, respectively. The mitochondrial membrane potential (Δψm) was assessed through the JC-10 assay. The activities of superoxide dismutase (SOD) and the levels of reactive oxygen species (ROS) were measured using WST-8 and DCFH-DA assays. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore significant biological processes and pathways influenced by DMDD. Molecular docking was employed to predict the domains of potential protein targets interacting with DMDD. Western blotting was subsequently conducted to determine the protein expression levels of TH, Nrf2, Bax, Bcl-2, Caspase-3, Beclin-1, PARP, LC3-II, LC3-I, p-PI3K, PI3K, p-mTOR and mTOR. Our study showed that DMDD treatment significantly increased cell viability and reduced apoptosis in MPP⁺-treated SH-SY5Y cells. In addition, DMDD treatment reversed the loss of TH expression and Δψm in MPP⁺-exposed SH-SY5Y cells. Moreover, DMDD treatment reduced MPP+-induced ROS production by promoting SOD activity. Additionally, compared with those in the MPP⁺ group, the protein expression levels of Beclin-1, Caspase-3, and PARP and the LC3II/I ratio were significantly decreased, whereas the protein expression levels of Nrf2 and the Bcl-2/Bax, p-PI3K/PI3K, and p-mTOR/mTOR ratios were significantly increased in the DMDD-treated group. In conclusion, DMDD protects against MPP⁺-induced cytotoxicity by mitigating oxidative stress, apoptosis, and autophagy. PI3K/mTOR signaling at least partly mediates the cytoprotective effect of DMDD.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 1","pages":"113"},"PeriodicalIF":3.2,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}