|
1
|
Xu Y, Chen J, Zhou L, Zhao Y, He N, Xu Q, Zhao J, Liu Y. GASTRODIN PROTECTS AGAINST SEPSIS-ASSOCIATED ENCEPHALOPATHY BY SUPPRESSING FERROPTOSIS. Shock 2025; 63:628-637. [PMID: 39749958 DOI: 10.1097/shk.0000000000002542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
ABSTRACT Background: Sepsis-associated encephalopathy (SAE) represents a severe complication of sepsis, substantially elevating both mortality and healthcare costs for patients. Gastrodin (GAS), a principal bioactive constituent of Gastrodia elata Blume, is neuroprotective in various neurological disorders, including ischemic stroke, epilepsy, Alzheimer's disease, and neuropathic pain. In this study, we sought to investigate whether GAS could serve as a protective agent against SAE. Methods: Mice were subjected to cecal ligation and puncture (CLP) or the murine brain microvascular endothelial cell bEnd.3 was exposed to lipopolysaccharide (LPS) and subsequently treated with GAS. We assessed neurological deficits, blood-brain barrier (BBB) integrity, neuroinflammation, and the state of ferroptosis to evaluate the regulation of GAS on SAE. Mechanistically, we utilized glutathione peroxidase 4 (GPX4) knockout mice to delineate the crucial role of GPX4 and examined the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway to uncover the upstream signaling of GPX4. Results: GAS mitigated neurological deficits in SAE mice and reduced BBB disruption and neuroinflammation both in vivo and in vitro . Functionally, the neuroprotective effects of GAS were realized through the inhibition of ferroptosis. Furthermore, we demonstrated that GPX4 played a pivotal role in this process. Lastly, we found that the COX-2/PGE2 pathway was activated following GAS treatment in SAE mice, thereby increasing the expression level of GPX4. Conclusions: Our study elucidated that GAS offers protection against SAE by suppressing ferroptosis through the activation of the COX-2/PGE2/GPX4 axis. This research validates the therapeutic potential of GAS and provides novel insights into potential therapeutic strategies for the management of SAE.
Collapse
Affiliation(s)
| | - Jing Chen
- Department of Pathology and Pathophysiology, Faculty of Basic Medical Science, Kunming Medical University, Kunming, Yunnan, China
| | | | | | | | | | | | | |
Collapse
|
|
2
|
Polat Ö, Orhun G, Anakli I, Yilmaz V, Koral G, Ulusoy C, Canbaz M, Ozcan PE, Tüzün E, Esen F. Renal Expression Levels of C5a Receptor and Autophagy-related Beclin-1 and LC3A/B Are Simultaneously Enhanced Under Immunoglobulin Treatment in a Rat Model of Sepsis. In Vivo 2025; 39:810-818. [PMID: 40010959 PMCID: PMC11884498 DOI: 10.21873/invivo.13883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/07/2024] [Accepted: 12/09/2024] [Indexed: 02/28/2025]
Abstract
BACKGROUND/AIM Sepsis-induced acute kidney injury is a fatal, potentially reversible clinical condition. C5a receptor (C5aR) has been implied to play pivotal roles in both autophagy and sepsis-induced organ dysfunction. The aim of this study was to demonstrate the effects of intravenous immunoglobulin preparations on the expression of autophagy markers and investigate possible association between C5aR expression and autophagy in the kidney tissue of septic rats. MATERIALS AND METHODS Sepsis was induced by cecal ligation perforation (CLP) in rats, which were divided into control, sham, CLP+saline, CLP+IgG (250 mg/kg, iv), and CLP+immunoglobulins enriched with immunoglobulin M (IgGAM) (250 mg/kg, iv) groups. Kidney samples were obtained in two sets of experiments to examine the early (1 day) and late (10 days) effects of treatment. Renal expression levels of C5aR, LC3A/B, and beclin-1 were measured using immunoblotting. RESULTS CLP did not enhance the renal expression of autophagy markers or C5aR. Contrariwise, IgG, and IgGAM administration reduced mortality caused by the CLP procedure and significantly increased C5aR, beclin-1, and LC3A/B expression levels in kidney samples of septic rats. Surviving rats had higher renal expression levels of C5aR, beclin-1, and LC3A/B than deceased rats. Expression levels of C5aR, beclin-1, and LC3A/B showed a strong correlation during the early stage of CLP-induced sepsis but not in the late stage. CONCLUSION Human-derived immunoglobulin preparations may ameliorate sepsis-related organ dysfunction partially through autophagy-related mechanisms. In the early stage of treatment, enhancement of autophagy in the kidney appears to be associated with C5aR expression.
Collapse
Affiliation(s)
- Özlem Polat
- Department of Anesthesiology and Reanimation, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkiye;
| | - Gunseli Orhun
- Department of Anesthesiology and Reanimation, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkiye
| | - Ilkay Anakli
- Department of Anesthesiology and Reanimation, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkiye
| | - Vuslat Yilmaz
- Department of Neuroscience, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkiye
| | - Gizem Koral
- Department of Neuroscience, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkiye
| | - Canan Ulusoy
- Department of Neuroscience, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkiye
| | - Mert Canbaz
- Department of Anesthesiology and Reanimation, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkiye
| | - Perihan Ergin Ozcan
- Department of Anesthesiology and Reanimation, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkiye
| | - Erdem Tüzün
- Department of Neuroscience, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkiye
| | - Figen Esen
- Department of Anesthesiology and Reanimation, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkiye
| |
Collapse
|
|
3
|
Kan Y, Wang H, Lin H, Li Y, Pei S, Cui Y, Xie K, Chen H, Yu Y. Transcript and Lipid Profile Alterations in Astrocyte-Neuron Mitochondrial Transfer Under Lipopolysaccharide Exposure: An In Vitro Study. J Neurochem 2025; 169:e70003. [PMID: 39902645 PMCID: PMC11791887 DOI: 10.1111/jnc.70003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 01/05/2025] [Accepted: 01/09/2025] [Indexed: 02/06/2025]
Abstract
Sepsis-associated encephalopathy (SAE) is a brain dysfunction for which no effective therapy currently exists. Recent studies suggest that transferring mitochondria from astrocytes to neurons may benefit SAE patients, though the underlying mechanism remains unclear. We cultured astrocytes and neurons from mice in vitro. Astrocytes were stimulated with lipopolysaccharide (LPS) for 24 h, and the astrocyte-conditioned medium (ACM) was collected. Neuronal cultures were then treated with ACM or mitochondria-depleted ACM (mdACM) for further analysis. Mitochondrial transfer was examined under a fluorescence microscope. Western blotting analyzed the protein expression of genes related to apoptosis and mitochondrial metabolism. RNA sequencing and mass spectrometry were employed to investigate the mechanisms underlying mitochondrial transfer. Astrocyte-derived mitochondria migrated toward and connected with LPS-exposed neurons. The addition of ACM significantly attenuated LPS-induced alterations in the proteins linked to apoptosis and mitochondrial dynamics. RNA sequencing revealed notable alterations in the transcript profile of neurons upon ACM treatment, highlighting the involvement of mitochondria metabolism, inflammation, and apoptosis-related factors. Additionally, mitochondrial transfer modified the lipid composition of neurons, increasing phosphatidylserine levels, which correlated with neuroinflammation and enriched pathways related to cytokine and MAPK signaling. Our findings suggest that astrocyte-neuron mitochondrial transfer holds therapeutic potential for alleviating SAE, possibly through the anti-inflammatory effects of lipids, particularly phosphatidylserine.
Collapse
Affiliation(s)
- Yufei Kan
- Department of AnesthesiologyTianjin Institute of Anesthesiology, Tianjin Medical University General HospitalTianjinPR China
| | - Hong Wang
- Department of AnesthesiologyShanxi Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical SciencesTaiyuanShanxi ProvincePR China
| | - Huaying Lin
- Department of AnesthesiologyChongqing University Cancer HospitalChongqingPR China
| | - Yongfa Li
- Department of AnesthesiologyTianjin Institute of Anesthesiology, Tianjin Medical University General HospitalTianjinPR China
| | - Shuaijie Pei
- Department of AnesthesiologyTianjin Institute of Anesthesiology, Tianjin Medical University General HospitalTianjinPR China
- Department of Critical Care MedicineTianjin Medical University General HospitalTianjinPR China
| | - Yan Cui
- Department of Pathogen BiologySchool of Basic Medical Sciences, Tianjin Medical UniversityTianjinPR China
| | - Keliang Xie
- Department of AnesthesiologyTianjin Institute of Anesthesiology, Tianjin Medical University General HospitalTianjinPR China
- Department of Critical Care MedicineTianjin Medical University General HospitalTianjinPR China
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong ProvinceSchool of Anesthesiology, Shandong Second Medical UniversityWeifangShandongPR China
| | - Hongguang Chen
- Department of AnesthesiologyTianjin Institute of Anesthesiology, Tianjin Medical University General HospitalTianjinPR China
| | - Yonghao Yu
- Department of AnesthesiologyTianjin Institute of Anesthesiology, Tianjin Medical University General HospitalTianjinPR China
| |
Collapse
|
|
4
|
Aguiar-Geraldo JM, Canever L, Marino DP, Coan C, Possamai-Della T, Pescador B, Quevedo J, Dal-Pizzol F, Valvassori SS, Zugno AI. Exploring the Different Impacts of Ketamine on Neurotrophic Factors and Inflammatory Parameters in a Cecal Ligation and Puncture-Induced Sepsis Model. Neurotox Res 2025; 43:5. [PMID: 39833594 DOI: 10.1007/s12640-024-00727-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 12/26/2024] [Accepted: 12/27/2024] [Indexed: 01/22/2025]
Abstract
Given ketamine's conflicting impacts on the central nervous system, investigating its effects within an inflammatory context becomes crucial. This study aimed to assess the impact of varying ketamine doses on neurotrophin and inflammatory cytokine levels within the brains of rats submitted to the sepsis model. Wistar rats were submitted to the cecal ligation and puncture (CLP) model of sepsis. Intraperitoneal ketamine injections (5, 15, or 25 mg/kg) or saline were administered daily for seven days, thirty days post-CLP. Rats were euthanized thirty minutes following the last injection for analysis of IL-1β, IL-6, IL-10, TNF-α, BDNF, NGF, NT-3, and GDNF levels in the frontal cortex, hippocampus, and striatum. CLP-induced elevated IL-1𝛽, IL-6, IL-10, and TNF-α levels in the frontal cortex and hippocampus of rats, with reduced BDNF levels across all structures examined. Furthermore, reduced NGF and GDNF levels were observed solely in the hippocampus. Ketamine at 5 mg/kg normalized CLP-induced alterations and, in Sham animals, increased BDNF and NGF levels in the frontal cortex and/or hippocampus. At 15 mg/kg, ketamine elevated BDNF and NGF levels in Sham animals, while at 25 mg/kg, it exacerbated the inflammatory response initiated by CLP. These findings suggest variable effects of ketamine within a context of systemic inflammation, emphasizing the importance of considering individual inflammatory backgrounds when utilizing ketamine.
Collapse
Affiliation(s)
- Jorge M Aguiar-Geraldo
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, Universidade do Extremo Sul Catarinense (UNESC), Criciúma, SC, Brazil
| | - Lara Canever
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, Universidade do Extremo Sul Catarinense (UNESC), Criciúma, SC, Brazil
| | - Debora P Marino
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, Universidade do Extremo Sul Catarinense (UNESC), Criciúma, SC, Brazil
| | - Camila Coan
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, Universidade do Extremo Sul Catarinense (UNESC), Criciúma, SC, Brazil
| | - Taise Possamai-Della
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, Universidade do Extremo Sul Catarinense (UNESC), Criciúma, SC, Brazil
| | - Bruna Pescador
- Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, Universidade do Extremo Sul Catarinense (UNESC), Criciúma, Brazil
| | - João Quevedo
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, Universidade do Extremo Sul Catarinense (UNESC), Criciúma, SC, Brazil
- Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
- Center of Excellence on Mood Disorders, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
- Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Felipe Dal-Pizzol
- Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, Universidade do Extremo Sul Catarinense (UNESC), Criciúma, Brazil
| | - Samira S Valvassori
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, Universidade do Extremo Sul Catarinense (UNESC), Criciúma, SC, Brazil
| | - Alexandra Ioppi Zugno
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, Universidade do Extremo Sul Catarinense (UNESC), Criciúma, SC, Brazil.
| |
Collapse
|
|
5
|
Gad ES, Aldossary SA, El-Ansary MR, Abd El-Galil MM, Abd-El-Hamid AH, El-Ansary AR, Hassan NF. Cilostazol counteracts mitochondrial dysfunction in hepatic encephalopathy rat model: Insights into the role of cAMP/AMPK/SIRT1/ PINK-1/parkin hub and p-CREB /BDNF/ TrkB neuroprotective trajectory. Eur J Pharmacol 2025; 987:177194. [PMID: 39667427 DOI: 10.1016/j.ejphar.2024.177194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 11/17/2024] [Accepted: 12/09/2024] [Indexed: 12/14/2024]
Abstract
A devasting stage of chronic hepatic dysfunction is strictly correlated with neurological impairment, signifying hepatic encephalopathy (HE). HE is a multifactorial condition; therefore, hyperammonemia, oxidative stress, neuroinflammation, and mitochondrial dysfunction interplay in HE's progressive development. Cilostazol (Cilo) has shown promising neuroprotective and hepatoprotective effectiveness in different neuronal and hepatic disorders; however, its efficiency against HE hasn't yet been explored. This study aimed to investigate the protective role of Cilo against thioacetamide (TAA)-induced HE in rats targeting mitochondrial dysfunction via modulation of Adenosine monophosphate-activated protein kinase (AMPK)/Silent information regulator 1 (SIRT1) dependent pathways. Rats were allocated into three groups: the normal control group, the TAA group received (100 mg/kg, three times per week, for six weeks) to induce HE, and the Cilo group received (Cilo 100 mg/kg/day for six weeks, oral gavage) concurrently with TAA. Cilo counteracted HE indicated in the enhancement of cognitive impairment and the motor performance of rats (P < 0.0001), modulation AMPK/SIRT1signaling pathway causing reduction of NF-kB p65 (P < 0.0001) evoked inflammation along with histopathological alterations and glial fibrillary acidic protein (GFAP) immunoreactivity (P < 0.0001), restoration nuclear factor E2-related factor 2 (Nrf2) (P < 0.0001) antioxidant effects, reduction of Bax and elevation of Bcl2 immunoreactivity (P < 0.0001) in addition to boosting mitochondrial biogenesis by upregulation of PTEN-induced kinase-1 (PINK-1)/Parkin (P < 0.0001)and restoration of Brain-derived neurotrophic factor (BDNF) (P = 0.0002)/tropomyosin-related kinase B (TrkB) (P < 0.0001)/cAMP response element-binding (CREB) (P < 0.0001) neuroprotective axis. Collectively, Cilo activates the SIRT1 trajectory to abridge mitochondrial dysfunction invigorated in the HE rat model via restoration of mitochondrial hemostasis.
Collapse
Affiliation(s)
- Enas S Gad
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, AL Ahsa, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University, Kantara Branch, Ismailia, Egypt
| | - Sara A Aldossary
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, AL Ahsa, Saudi Arabia
| | - Mona R El-Ansary
- Department of Biochemistry, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Mona M Abd El-Galil
- Department of Histology and Cell Biology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Asmaa Hassan Abd-El-Hamid
- Department of Histology and Cell Biology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Amira R El-Ansary
- Department of Internal Medicine, Faculty of Medicine, Misr University for Science and Technology, Cairo, Egypt
| | - Noha F Hassan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt.
| |
Collapse
|
|
6
|
Zhang X, Li R, Chen MY, Ye WQ, Liang JZ, Yang WJ, Yang F, Ji HM. Investigating the potential mechanism of Pioglitazone in Sepsis-Related brain injury through transcriptomics. Gene 2024; 931:148892. [PMID: 39187138 DOI: 10.1016/j.gene.2024.148892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 08/06/2024] [Accepted: 08/23/2024] [Indexed: 08/28/2024]
Abstract
Sepsis-related brain injury (SRBI) refers to brain dysfunction and structural damage caused by sepsis, which is characterized by inflammation, oxidative stress, and destruction of the blood-brain barrier. Pioglitazone is a PPAR-γ agonist in which PPAR-γ acts as an inflammatory modulator, determining the relationship between PPAR-γ and SRBI and inflammatory state is critical for the disease. This study aimed to construct a drug-target-disease network for SRBI and Pioglitazone based on network pharmacology, and to investigate the therapeutic effect and potential mechanism of Pioglitazone in SRBI induced by lipopolysaccharide (LPS) in rats through transcriptomics. To establish a rat Model of SRBI by intraperitoneal injection of LPS (10 mg/kg): SD rats were divided into Control, Model (LPS), Pioglitazone, (LPS + Pioglitazone) and GW9662 group (LPS+GW9662). The effects and potential mechanisms of Pioglitazone in the treatment of SRBI were studied using biochemical indexes, pathological changes and transcriptome-sequencing (RNA-seq). RNA-seq results showed 620 DEGs between the Model and the Pioglitazone groups. Enrichment analysis involved multiple inflammatory response processes and chemokine receptor binding functions. TLR4 and CXCL10 in the Toll signaling pathway may play an important role in SRBI as important targets. Pioglitazone may ameliorate SRBI through the PPAR-γ/TLR4/CXCL10 pathway.
Collapse
Affiliation(s)
- Xuan Zhang
- The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan 030001, China; Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030001, China.
| | - Rui Li
- School of Pharmacy, Shanxi Medical University, Taiyuan 030001, China; Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China; Shanxi Provincial Key Laboratory of Drug Synthesis and Novel Pharmaceutical Preparation Technology, Shanxi Medical University, Taiyuan 030001, China.
| | - Ming-Yuan Chen
- School of Pharmacy, Shanxi Medical University, Taiyuan 030001, China; Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China; Shanxi Provincial Key Laboratory of Drug Synthesis and Novel Pharmaceutical Preparation Technology, Shanxi Medical University, Taiyuan 030001, China.
| | - Wen-Qian Ye
- School of Pharmacy, Shanxi Medical University, Taiyuan 030001, China; Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China; Shanxi Provincial Key Laboratory of Drug Synthesis and Novel Pharmaceutical Preparation Technology, Shanxi Medical University, Taiyuan 030001, China.
| | - Jing-Zhen Liang
- School of Pharmacy, Shanxi Medical University, Taiyuan 030001, China; Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China; Shanxi Provincial Key Laboratory of Drug Synthesis and Novel Pharmaceutical Preparation Technology, Shanxi Medical University, Taiyuan 030001, China.
| | - Wen-Jing Yang
- School of Pharmacy, Shanxi Medical University, Taiyuan 030001, China; Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China; Shanxi Provincial Key Laboratory of Drug Synthesis and Novel Pharmaceutical Preparation Technology, Shanxi Medical University, Taiyuan 030001, China.
| | - Fan Yang
- School of Pharmacy, Shanxi Medical University, Taiyuan 030001, China; Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China; Shanxi Provincial Key Laboratory of Drug Synthesis and Novel Pharmaceutical Preparation Technology, Shanxi Medical University, Taiyuan 030001, China.
| | - Hong-Ming Ji
- The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan 030001, China; Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030001, China.
| |
Collapse
|
|
7
|
Li X, Xu X, Zhang J, Wang X, Zhao C, Liu Q, Fan K. Review of the therapeutic effects of traditional Chinese medicine in sepsis-associated encephalopathy. JOURNAL OF ETHNOPHARMACOLOGY 2024; 334:118588. [PMID: 39029543 DOI: 10.1016/j.jep.2024.118588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 07/08/2024] [Accepted: 07/15/2024] [Indexed: 07/21/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Sepsis-associated encephalopathy (SAE) is a common and serious complication during the acute phase of and after recovery from sepsis that seriously affects the quality of life of patients. Traditional Chinese medicine (TCM) has been widely used in modern medicine for neurological anomalies and has become a therapeutic tool for the treatment of SAE due to its multitargeting effects and low toxicity and side effects. AIMS OF THE STUDY This review provides insights into the pathogenesis and treatments of SAE, focusing on the clinical and experimental impacts of TCM formulations and their single components. METHODS Several known databases such as PubMed, Web of Science, Google Scholar, China National Knowledge Infrastructure (CNKI), and others were extensively explored with keywords and phrases such as "sepsis-associated encephalopathy", "traditional Chinese medicine", "herbs", "SAE", "sepsis", "cerebral" or other relevant terms to obtain literature between 2018 and 2024. RESULTS Extensive evidence indicated that TCM could decrease mortality and normalize neurological function in patients with sepsis; these effects might be associated with factors such as reduced oxidative stress and downregulated expression of inflammatory factors. CONCLUSIONS TCM shows notable efficacy in treating SAE, warranting deeper mechanistic studies to optimize its clinical application.
Collapse
Affiliation(s)
- Xingyao Li
- College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China.
| | - Xiaolong Xu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, China.
| | - Jun Zhang
- Intensive Care Unit, Wuhan Hospital of Traditional Chinese Medicine, Wu Han, 430014, China.
| | - Xuerui Wang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, China.
| | - Chunming Zhao
- Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Qingquan Liu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, China.
| | - Kai Fan
- College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China.
| |
Collapse
|
|
8
|
Guo J, Kong D, Luo J, Xiong T, Wang F, Deng M, Kong Z, Yang S, Da J, Chen C, Lan J, Chu L, Han G, Liu J, Tan Y, Zhang J. Orexin-A Attenuates the Inflammatory Response in Sepsis-Associated Encephalopathy by Modulating Oxidative Stress and Inhibiting the ERK/NF-κB Signaling Pathway in Microglia and Astrocytes. CNS Neurosci Ther 2024; 30:e70096. [PMID: 39508266 PMCID: PMC11541240 DOI: 10.1111/cns.70096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 09/30/2024] [Accepted: 10/09/2024] [Indexed: 11/15/2024] Open
Abstract
BACKGROUND Oxidative stress-induced inflammation is a major pathogenic mechanism in sepsis-associated encephalopathy (SAE). We hypothesized that regulation of reactive oxygen species (ROS) by the neuropeptide orexin-A could prevent SAE-induced oxidative stress and inflammation. Therefore, the aim of this study was to investigate the effects of orexin-A on oxidative stress and inflammation in SAE in mice. METHODS Adult male mice were treated with orexin-A (250 μg/kg, intranasal administration) to establish a cecal ligation perforation (CLP) model. We performed behavioral tests, observed neuronal damage in the hippocampal region, measured the levels of ROS, NOX2, and observed the structure of mitochondria by transmission electron microscopy. We then examined the inflammatory factors TNF-α and IL-1β, the activation of microglia and astrocytes, the expression of ERK/NF-κB, C3, and S100A10, and the presence of A1 type astrocytes and A2 type astrocytes. RESULTS Orexin-A treatment improved cognitive performance in CLP-induced SAE mice, attenuated neuronal apoptosis in the hippocampal region, ameliorated ROS levels and the extent of mitochondrial damage, and reduced protein expression of NOX2 in hippocampal tissue. In addition, orexin-A treatment significantly reduced microglia and astrocyte activation, inhibited the levels of P-ERK and NF-κB, and reduced the release of IL-1β and TNF-α, which were significantly increased after CLP. Finally, Orexin-A treatment significantly decreased the number of C3/glial fibrillary acidic protein (GFAP)-positive cells and increased the number of S100A10/GFAP-positive cells. CONCLUSION Our data suggest that orexin-A reduces ROS expression by inhibiting CLP-induced NOX2 production, thereby attenuating mitochondrial damage and neuronal apoptosis. Its inhibition of microglial and A1-type astrocyte activation and inflammation was associated with the ERK/NF-κB pathway. These suggest that orexin-A may reduce cognitive impairment in SAE by reducing oxidative stress-induced inflammation.
Collapse
Affiliation(s)
- Jing Guo
- GuiZhou University Medical CollegeGuiyangGuizhouChina
| | | | - Junchi Luo
- Department of NeurosurgeryGuizhou Provincial People's HospitalGuiyangChina
| | - Tao Xiong
- Department of NeurosurgeryGuizhou Provincial People's HospitalGuiyangChina
| | - Fang Wang
- GuiZhou University Medical CollegeGuiyangGuizhouChina
| | - Mei Deng
- Department of NeurosurgeryGuizhou Provincial People's HospitalGuiyangChina
| | - Zhuo Kong
- Department of NeurosurgeryGuizhou Provincial People's HospitalGuiyangChina
| | - Sha Yang
- GuiZhou University Medical CollegeGuiyangGuizhouChina
| | - Jingjing Da
- Department of NephrologyGuizhou Provincial People's HospitalGuiyangChina
| | - Chaofei Chen
- Institute of Pediatrics, Guangzhou Women and Children's Medical CenterGuangzhou Medical UniversityGuangzhouChina
| | - Jinhai Lan
- Department of the Second SurgeryZiyun People's HospitalAnshunChina
| | - Liangzhao Chu
- Department of NeurosurgeryThe Affiliated Hospital of Guizhou Medical UniversityGuiyangChina
| | - Guoqiang Han
- Department of NeurosurgeryGuizhou Provincial People's HospitalGuiyangChina
| | - Jian Liu
- Department of NeurosurgeryGuizhou Provincial People's HospitalGuiyangChina
| | - Ying Tan
- Department of NeurosurgeryGuizhou Provincial People's HospitalGuiyangChina
| | - Jiqin Zhang
- Department of AnesthesiologyGuizhou Provincial People's HospitalGuiyangChina
| |
Collapse
|
|
9
|
Hassan NF, El-Ansary MR, El-Ansary AR, El-Saied MA, Zaki OS. Unveiling the protective potential of mirabegron against thioacetamide-induced hepatic encephalopathy in rats: Insights into cAMP/PPAR-γ/p-ERK1/2/p S536 NF-κB p 65 and p-CREB/BDNF/TrkB in parallel with oxidative and apoptotic trajectories. Biochem Pharmacol 2024; 229:116504. [PMID: 39179118 DOI: 10.1016/j.bcp.2024.116504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 08/12/2024] [Accepted: 08/20/2024] [Indexed: 08/26/2024]
Abstract
Hepatic encephalopathy (HE) is one of the most prevalent and severe hepatic and brain disorders in which escalation of the oxidative, inflammatory and apoptotic trajectories pathologically connects acute liver injury with neurological impairment. Mirabegron (Mira) is a beta3 adrenergic receptor agonist with proven antioxidant and anti-inflammatory activities. The current research pointed to exploring Mira's hepato-and neuroprotective impacts against thioacetamide (TAA)-induced HE in rats. Rats were distributed into three experimental groups: the normal control group, the TAA group, received TAA (200 mg/kg/day for three consecutive days) and the Mira-treated group received Mira (10 mg/kg/day; oral gavage) for 15 consecutive days and intoxicated with TAA from the 13th to the 15th day of the experimental period. Mira counteracted hyperammonemia, enhanced rats' locomotor capability and motor coordination. It attenuated hepatic/neurological injuries by its antioxidant, anti-apoptotic as well as anti-inflammatory potentials. Mira predominantly targeted cyclic adenosine monophosphate (cAMP)/phosphorylated extracellular signal-regulated kinase (p-Erk1/2)/peroxisome proliferator-activated receptor gamma (PPARγ) dependent pathways via downregulation of p S536-nuclear factor kappa B p65 (p S536 NF-κB p 65)/tumor necrosis alpha (TNF-α) axis. Meanwhile, it attenuated nuclear factor erythroid 2-related factor (Nrf2) depletion in parallel with restoring of the neuroprotective defensive pathway by upregulation of cerebral cAMP/PPAR-γ/p-ERK1/2 and p-CREB/BDNF/TrkB besides reduction of GFAP immunoreactivity. Mira showed anti-apoptotic activity through inhibition of Bax immunoreactivity and elevation of Bcl2. To summarize, Mira exhibited a hepato-and neuroprotective effect against TAA-induced HE in rats via shielding antioxidant defense and mitigation of the pathological inflammatory and apoptotic axis besides upregulation of neuroprotective signaling pathways.
Collapse
Affiliation(s)
- Noha F Hassan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Mona R El-Ansary
- Department of Biochemistry, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Amira R El-Ansary
- Department of Internal Medicine, Faculty of Medicine, Misr University for Science and Technology, Giza, Egypt
| | - Mohamed A El-Saied
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Omnia S Zaki
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt.
| |
Collapse
|
|
10
|
Zhao P, Zhang W, Zhou X, Zhao Y, Li A, Sun Y. Gypenoside XLIX alleviates sepsis-associated encephalopathy by targeting PPAR-α. Exp Neurol 2024; 383:115027. [PMID: 39490624 DOI: 10.1016/j.expneurol.2024.115027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/15/2024] [Accepted: 10/23/2024] [Indexed: 11/05/2024]
Abstract
Sepsis-related systemic inflammation is a deadly condition with high rates of morbidity and mortality. There is evidence that sepsis affects the brain, and the most frequent organ dysfunction linked to sepsis is sepsis-associated encephalopathy. Sepsis-related brain damage can drastically reduce a patient's chances of survival. However, a specific treatment for sepsis-associated encephalopathy is not currently available. Consequently, to treat the brain damage caused by sepsis, investigating novel therapeutic strategies is imperative. After establishing the CLP-induced mouse SAE model, we treated the mice with Gyp-XLIX and evaluated apoptosis, neuroinflammation, brain damage, and oxidative stress in the brain tissue of each group of mice. Furthermore, the protective effects of Gyp-XLIX on LPS-treated BV-2 cells were assessed. We discovered that Gyp-XLIX treatment increased the survival rate of CLP-treated mice, alleviated SAE-related cerebral nerve abnormalities, and decreased blood-brain barrier breakdown, all of which could better preserve brain tissue in vivo. Furthermore, we identified associated proteins and found that Gyp-XLIX may reduce oxidative stress, cell apoptosis, and inflammation in the brain tissues of SAE mice. This observation was further validated in vitro. We established that Gyp-XLIX alleviates SAE by targeting PPAR-α. These findings may be important for the clinical applicability of Gyp-XLIX in SAE treatment. We found that Gyp-XLIX can alleviate brain injury in SAE by targeting PPAR-α and is a potential protective agent for SAE.
Collapse
Affiliation(s)
- Panpan Zhao
- Department of Neurosurgery, Institute of Neuroscience, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang Clinical College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang 222000, China
| | - Wei Zhang
- Department of Neurosurgery, Institute of Neuroscience, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang Clinical College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang 222000, China; Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Xinyu Zhou
- Department of Neurology, The First Affiliated Hospital of Kangda College of Nanjing Medical University, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang 222000, China
| | - Yikun Zhao
- Department of Neurosurgery, Institute of Neuroscience, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang Clinical College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang 222000, China
| | - Aimin Li
- Department of Neurosurgery, Institute of Neuroscience, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang Clinical College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang 222000, China.
| | - Yong Sun
- Department of Neurosurgery, Institute of Neuroscience, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang Clinical College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang 222000, China.
| |
Collapse
|
|
11
|
Zhou G, Xie RF, Li SN, Chen SX, Feng YM, Xiang N, Tan ZY, Zhou X. Synergic effects and possible mechanism of emodin and stilbene glycosides on colorectal cancer. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 132:155821. [PMID: 39004030 DOI: 10.1016/j.phymed.2024.155821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 05/25/2024] [Accepted: 06/11/2024] [Indexed: 07/16/2024]
Abstract
BACKGROUND Polygonum multiflorum (PM) is a core herb that enhances immunity. It can also detoxify, reduce swelling, and intercept malaria. Its main components, emodin (EMD) and 2,3,5,4'-Tetrahydroxy stilbene-2-O-β-D-glucoside (stilbene glycoside, TSG), have good anti-cancer potential. PURPOSE The study aims to investigate synergic effects of EMD and TSG on CRC and its possible mechanism. METHODS Network pharmacology and bioinformatics were used to identify targets. HPLC was used to analyze the effective ingredients in PM and to determine the content of the main ingredients. HT-29 cells were used for in vitro experiments. Cell Counting Kit-8 (CCK8) and scratch test were used to detect the effects of various chemical components of PM on the proliferation and migration of HT-29 cells, and Western Bolt (WB) test was used to evaluate the effects of EMD and TSG on P53 pathway. In vivo experiments, the effects of EMD and TSG were evaluated by measuring tumor weight and tumor volume in CRC mice model and histological analysis were carried out with HE staining. The expressions of HSP90, P53, COX2, and ROS were detected by quantitative reverse transcription polymerase chain reaction (PCR), and IL-1β, IL-4, IL-6, IL-10, TGF-β and IFN-γ were detected by enzyme linked immunosorbent assay (ELISA). WB and Immunohistochemistry (IHC) were used to detect the expression of P53 related proteins. RESULTS Network pharmacology showed PM closely related to colorectal cancer pathway and the core targets included STAT3 and P53; bioinformatics indicated P53 played an important role in the development and prognosis of CRC; chemical analysis showed identified and quantified gallic acid (GA), cis-TSG, trans-TSG, Emodin glucoside(EMDG), physcion glucoside (PHYG), EMD in PM; EMD induced apoptosis and TSG inhibited migration of HT-29 cells; EMD and TSG could coordinately shrink tumor size of CRC mice, elevate expressions of F4/80, decrease the content of IL-6 and TGF-β, promote tumor oxidized and reduce expression of P53 and STAT3 in the tumor. CONCLUSIONS In vitro experiments showed that TSG inhibited cancer cell migration and EMD induced apoptosis. EMD and TSG had synergic effects on CRC, whose possible mechanism might be to regulate the expression of cytokines and inhibit P53 pathway.
Collapse
Affiliation(s)
- Gui Zhou
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Rui-Fang Xie
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Shan-Ni Li
- Shanghai Nanyang Model Private High School, Shanghai, China
| | - Shi-Xiu Chen
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Yi-Ming Feng
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Nan Xiang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Ze-Ye Tan
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Xin Zhou
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
| |
Collapse
|
|
12
|
Zhu L, Zhang H, Zhang X, Xia L. RNA m6A methylation regulators in sepsis. Mol Cell Biochem 2024; 479:2165-2180. [PMID: 37659034 DOI: 10.1007/s11010-023-04841-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 08/16/2023] [Indexed: 09/05/2023]
Abstract
N6-methyladenosine (m6A) modification is a class of epitope modifications that has received significant attention in recent years, particularly in relation to its role in various diseases, including sepsis. Epigenetic research has increasingly focused on m6A modifications, which is influenced by the dynamic regulation of three protein types: ‟Writers" (such as METTL3/METTL14/WTAP)-responsible for m6A modification; ‟Erasers" (FTO and ALKBH5)-involved in m6A de-modification; and ‟Readers" (YTHDC1/2, YTHDF1/2/3)-responsible for m6A recognition. Sepsis, a severe and fatal infectious disease, has garnered attention regarding the crucial effect of m6A modifications on its development. In this review, we attempted to summarize the recent studies on the involvement of m6A and its regulators in sepsis, as well as the significance of m6A modifications and their regulators in the development of novel drugs and clinical treatment. The potential value of m6A modifications and modulators in the diagnosis, treatment, and prognosis of sepsis has also been discussed.
Collapse
Affiliation(s)
- Lin Zhu
- School of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Hairong Zhang
- Department of Obstetrics and Gynecology, Shandong Provincial Third Hospital, Jinan, 250031, People's Republic of China.
| | - Xiaoyu Zhang
- School of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Lei Xia
- Department of Pathology, Shandong University of Traditional Chinese Medicine, Jinan, 250355, People's Republic of China.
| |
Collapse
|
|
13
|
Bai G, Ling J, Lu J, Fang M, Yu S. Adiponectin receptor agonist AdipoRon alleviates memory impairment in the hippocampus of septic mice. Behav Brain Res 2024; 472:115174. [PMID: 39098398 DOI: 10.1016/j.bbr.2024.115174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 07/20/2024] [Accepted: 08/01/2024] [Indexed: 08/06/2024]
Abstract
Sepsis-associated encephalopathy (SAE) is a common and severe clinical feature of sepsis; however, therapeutic approaches are limited because of the unclear pathogenesis. Adiponectin receptor agonist (AdipoRon) is a small-molecule agonist of the adiponectin receptor that exhibits anti-inflammatory and memory-improving effects in various diseases. In the present study, we established lipopolysaccharide (LPS)-induced mice models of SAE and found that Adiponectin receptor 1 (AdipoR1) was significantly decreased in the hippocampus. Administration of AdipoRon improves memory impairment, mitigates synaptic damage, and alleviates neuronal death. Furthermore, AdipoRon reduces the number of microglia. More importantly, AdipoRon promotes the phosphorylation of adenosine 5 '-monophosphate activated protein kinase (pAMPK). In conclusion, AdipoRon is protective against SAE-induced memory decline and brain injury in the SAE models via activating the hippocampal adenosine 5 '-monophosphate activated protein kinase (AMPK).
Collapse
Affiliation(s)
- Guangyang Bai
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Jianmin Ling
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Jun Lu
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Minghao Fang
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
| | - Shanshan Yu
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
| |
Collapse
|
|
14
|
Chen M, Ji T, Liu YY, Liu WL, Yan XT, Jiang HX, Zhang ZZ, He XH. Emodin alleviates intestinal ischemia/reperfusion-induced lung injury by upregulating HO-1 expression via PI3K/AkT pathway. Surgery 2024; 176:499-510. [PMID: 38811326 DOI: 10.1016/j.surg.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 03/16/2024] [Accepted: 04/06/2024] [Indexed: 05/31/2024]
Abstract
BACKGROUND Emodin, a natural anthraquinone derivative found in various Chinese medicinal herbs, has been proved to be an effective therapeutic agent in the treatment of many diseases. However, its effect on lung injury after intestinal ischemia/reperfusion injury remains unknown. This research was designed to investigate whether emodin protects against intestinal ischemia/reperfusion-induced lung injury and to elucidate the underlying molecular mechanisms in vivo and in vitro. METHODS Intestinal ischemia/reperfusion injury was induced by occluding the superior mesenteric artery in mice, and mouse lung epithelial-12 cells were subjected to oxygen-glucose deprivation and reoxygenation to establish an in vitro model. RESULTS Our data indicated that emodin treatment reduced intestinal ischemia/reperfusion-induced oxidative stress, inflammation and apoptosis in lung tissues and alleviated lung injury. However, the protective effects of emodin on intestinal ischemia/reperfusion-induced lung injury were reversed by the protein kinase B inhibitor triciribine or the heme oxygenase-1 inhibitor tin protoporphyrin IX. The protein kinase inhibitor triciribine also downregulated the expression of heme oxygenase-1. CONCLUSION In conclusion, our data suggest that emodin treatment protects against intestinal ischemia/reperfusion-induced lung injury by enhancing heme oxygenase-1 expression via activation of the PI3K/protein kinase pathway. Emodin may act as a potential therapeutic agent for the prevention and treatment of lung injury induced by intestinal ischemia/reperfusion.
Collapse
Affiliation(s)
- Meng Chen
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Hubei, China; Department of Anesthesiology, Maternal and Child Health Hospital of Hubei Province, Wuhan, Hubei, China
| | - Tuo Ji
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Hubei, China; Department of Anesthesiology, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China
| | - Yin-Yin Liu
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Hubei, China
| | - Wan-Li Liu
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Hubei, China
| | - Xue-Tao Yan
- Department of Anesthesiology, Shenzhen Bao'an Maternity and Child Health Hospital, China
| | - Hai-Xing Jiang
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Hubei, China
| | - Zong-Ze Zhang
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Hubei, China
| | - Xiang-Hu He
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Hubei, China.
| |
Collapse
|
|
15
|
Liu QQ, Wu GH, Wang XC, Xiong XW, Rui-Wang, Yao BL. The role of Foxo3a in neuron-mediated cognitive impairment. Front Mol Neurosci 2024; 17:1424561. [PMID: 38962803 PMCID: PMC11220205 DOI: 10.3389/fnmol.2024.1424561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 06/06/2024] [Indexed: 07/05/2024] Open
Abstract
Cognitive impairment (COI) is a prevalent complication across a spectrum of brain disorders, underpinned by intricate mechanisms yet to be fully elucidated. Neurons, the principal cell population of the nervous system, orchestrate cognitive processes and govern cognitive balance. Extensive inquiry has spotlighted the involvement of Foxo3a in COI. The regulatory cascade of Foxo3a transactivation implicates multiple downstream signaling pathways encompassing mitochondrial function, oxidative stress, autophagy, and apoptosis, collectively affecting neuronal activity. Notably, the expression and activity profile of neuronal Foxo3a are subject to modulation via various modalities, including methylation of promoter, phosphorylation and acetylation of protein. Furthermore, upstream pathways such as PI3K/AKT, the SIRT family, and diverse micro-RNAs intricately interface with Foxo3a, engendering alterations in neuronal function. Through several downstream routes, Foxo3a regulates neuronal dynamics, thereby modulating the onset or amelioration of COI in Alzheimer's disease, stroke, ischemic brain injury, Parkinson's disease, and traumatic brain injury. Foxo3a is a potential therapeutic cognitive target, and clinical drugs or multiple small molecules have been preliminarily shown to have cognitive-enhancing effects that indirectly affect Foxo3a. Particularly noteworthy are multiple randomized, controlled, placebo clinical trials illustrating the significant cognitive enhancement achievable through autophagy modulation. Here, we discussed the role of Foxo3a in neuron-mediated COI and common cognitively impaired diseases.
Collapse
Affiliation(s)
| | | | | | | | | | - Bao-Le Yao
- Department of Rehabilitation Medicine, Ganzhou People’s Hospital, Ganzhou, China
| |
Collapse
|
|
16
|
Mu X, Ma ZB, Chen H, Liang R, Li Z, Guo XX, Xu TR, Xiang C. Therapeutic potential of CB 1R activation by Qingyangshen glycoside M1 for seizure relief. JOURNAL OF ETHNOPHARMACOLOGY 2024; 327:117982. [PMID: 38423411 DOI: 10.1016/j.jep.2024.117982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 02/23/2024] [Accepted: 02/24/2024] [Indexed: 03/02/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Cynanchum otophyllum C.K.Schneid.PI.Wilson, commonly referred as ''Qingyangshen'' (QYS), is a traditional folk medicine from Yunnan, renowned for its efficacy in neurological and psychiatric disorders. Glycosides isolated from QYS have shown promise in alleviating epilepsy, however, mechanisms of action and specific molecular targets remain to be elucidated. AIM OF THE STUDY The study aimed to evaluate the anticonvulsant effects of Qingyangshen glycosides M1 (M1), a C21 steroidal glycoside from QYS, on pentylenetetrazol (PTZ)-induced convulsions in zebrafish (Danio rerio), and its neuroprotective effect on Glutamate (Glu)-induced damage to PC12 cells, and importantly to identify its potential molecular targets. MATERIALS AND METHODS To evaluate anticonvulsant activity of M1, 7 days-post-fertilization (7-dpf) animals were pretreated (by immersion) and then exposed to PTZ (10 mM) solution. Furthermore, Glu-induced PC12 cell damage was employed to investigate the neuroprotective and anti-apoptotic capacity. Cells were pretreated with various concentrations of M1 (0-10 μM) for 12 h and then co-treated with Glu (15 mM) for an additional 24 h. The cell viability, apoptosis rate and apoptosis-related proteins (p-PI3K, PI3K, Akt, p-Akt, CREB, p-CREB, BDNF, Bax and Bcl-2) were measured using CCK-8, annexin V/PI and Western blot assays. To model the expected interaction between M1 and candidate cannabinoid receptor type 1 (CB1R), ERK phosphorylation, molecular docking, and drug affinity responsive target stability (DARTS) techniques were employed. Finally, CB1R antagonist Rimonabant (Rim) was validated by co-administration in both zebrafish and cells to confirm the requirement of CB1R for M1 efficacy. RESULTS At a concentration of 400 μM, M1 dramatically reversed PTZ-induced convulsive-like behaviors in zebrafish, as evidenced by a significant reduction in locomotor activity. In the context of Glu-induced cytotoxicity, M1 (10 μM) demonstrated a notable increase in cell viability and suppressed apoptosis through modulation of the Bax/Bcl-2 ratio and activation of the PI3K/Akt/CREB/BDNF signaling axis. These effects were facilitated through CB1R activation. In contrast, Rim dampened the beneficial activities of M1 as a cannabinoid agonist. CONCLUSIONS These results demonstrated that M1 as a potential CB1R activator, exhibiting anticonvulsive effects in a PTZ-induced zebrafish model and neuroprotective properties via the PI3K/Akt/CREB/BDNF signaling axis in a Glu-induced PC12 cell injury model. Notably, the observed seizure relief attenuated by CB1R chemical antagonism.
Collapse
Affiliation(s)
- Xi Mu
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, 650500, PR China
| | - Zhao-Bin Ma
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, 650500, PR China
| | - Hao Chen
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, 650500, PR China
| | - Rui Liang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, 650500, PR China
| | - Zhao Li
- Laboratory Animal Center, Yunnan University, Kunming, Yunnan, 650500, PR China
| | - Xiao-Xi Guo
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, 650500, PR China
| | - Tian-Rui Xu
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, 650500, PR China.
| | - Cheng Xiang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, 650500, PR China.
| |
Collapse
|
|
17
|
Sun J, Fleishman JS, Liu X, Wang H, Huo L. Targeting novel regulated cell death：Ferroptosis, pyroptosis, and autophagy in sepsis-associated encephalopathy. Biomed Pharmacother 2024; 174:116453. [PMID: 38513593 DOI: 10.1016/j.biopha.2024.116453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 03/04/2024] [Accepted: 03/15/2024] [Indexed: 03/23/2024] Open
Abstract
Sepsis-associated encephalopathy (SAE), a common neurological complication of sepsis, is a heterogenous complex clinical syndrome caused by the dysfunctional response of a host to infection. This dysfunctional response leads to excess mortality and morbidity worldwide. Despite clinical relevance with high incidence, there is a lack of understanding for its both its acute/chronic pathogenesis and therapeutic management. A better understanding of the molecular mechanisms behind SAE may provide tools to better enhance therapeutic efficacy. Mounting evidence indicates that some types of non-apoptotic regulated cell death (RCD), such as ferroptosis, pyroptosis, and autophagy, contribute to SAE. Targeting these types of RCD may provide meaningful targets for future treatments against SAE. This review summarizes the core mechanism by which non-apoptotic RCD leads to the pathogenesis of SAE. We focus on the emerging types of therapeutic compounds that can inhibit RCD and delineate their beneficial pharmacological effects against SAE. Within this review we suggest that pharmacological inhibition of non-apoptotic RCD may serve as a potential therapeutic strategy against SAE.
Collapse
Affiliation(s)
- Jingjing Sun
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 11004, China
| | - Joshua S Fleishman
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Xueyan Liu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 11004, China
| | - Hongquan Wang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, 300060, China
| | - Liang Huo
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 11004, China.
| |
Collapse
|
|
18
|
Wu P, Xiao Y, Qing L, Mi Y, Tang J, Cao Z, Huang C. Emodin activates autophagy to suppress oxidative stress and pyroptosis via mTOR-ULK1 signaling pathway and promotes multi-territory perforator flap survival. Biochem Biophys Res Commun 2024; 704:149688. [PMID: 38387327 DOI: 10.1016/j.bbrc.2024.149688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 02/01/2024] [Accepted: 02/13/2024] [Indexed: 02/24/2024]
Abstract
BACKGROUND Multi-territory perforator flap reconstruction has been proven effective in treating large skin and soft tissue defects in clinical settings. However, in view of that the multi-territory perforator flap is prone to partial postoperative necrosis, increasing its survival is the key to the success of reconstruction. In this study, we aimed to clarify the effect of emodin on multi-territory perforator flap survival. METHODS Flap survival was assessed by viability area analysis, infrared laser imaging detector, HE staining, immunohistochemistry, and angiography. Western blotting, immunofluorescence assays, and real-time fluorescent quantitative PCR were performed to detect the indicators of oxidative stress, pyroptosis and autophagy. RESULTS After emodin treatment, the multi-territory perforator flap showed a significantly increased survival rate, which was shown to be closely related to the inhibition of oxidative stress and pyroptosis and enhanced autophagy. Meanwhile, the use of autophagy inhibitor 3 MA was found to reverse the inhibitory effects of emodin on oxidative stress and pyroptosis and weaken the improving effect of emodin on flap survival, suggesting that autophagy plays a critical role in emodin-treated flaps. Interestingly, our mechanistic investigations revealed that the positive effect of emodin on multi-territory perforator flap was attributed to the mTOR-ULK1 signaling pathway activation. CONCLUSIONS Emodin can inhibit oxidative stress and pyroptosis by activating autophagy via the mTOR-ULK1 pathway, thereby improving the multi-territory perforator flap survival.
Collapse
Affiliation(s)
- Panfeng Wu
- Department of Orthopedics, Hand and Microsurgery, National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yu Xiao
- Department of Orthopedics, Hand and Microsurgery, National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Liming Qing
- Department of Orthopedics, Hand and Microsurgery, National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yanan Mi
- Department of Orthopedics, Hand and Microsurgery, National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Juyu Tang
- Department of Orthopedics, Hand and Microsurgery, National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zheming Cao
- Department of Orthopedics, Hand and Microsurgery, National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
| | - Chengxiong Huang
- Department of Orthopedics, Hand and Microsurgery, National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
| |
Collapse
|
|
19
|
Nikpour F, Salimi A, Saghazadeh A, Rezaei N. Blood and CSF levels of brain-derived neurotrophic factor in patients with encephalopathy/encephalitis: a systematic review and meta-analysis. Acta Neurol Belg 2024; 124:533-542. [PMID: 38267724 DOI: 10.1007/s13760-023-02442-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 11/20/2023] [Indexed: 01/26/2024]
Abstract
BACKGROUND Brain-derived neurotrophic factor (BDNF) is critical for enhancing the survival and growth of neurons and modulating the synaptic plasticity. BDNF levels have been demonstrated to be changed in plasma and cerebrospinal fluid (CSF) following brain insults such as inflammation or ischemia or infection in several studies. Currently, there is no systematic review regarding BDNF levels in encephalitis or encephalopathy patients. Considering inconsistency between studies, we aimed to pool the data from existing studies to determine whether blood or CSF levels of BDNF are different in patients with encephalopathy/encephalitis. METHODS We comprehensively searched Web of Science, PubMed, Scopus, and Embase databases to identify eligible studies. The last search occurred in December 2022. RESULTS 12 studies met our inclusion criteria and ten studies including 283 patients and 323 healthy controls were enrolled in this meta-analysis. In comparison to controls, patients with encephalitis/encephalopathy had higher levels of BDNF in their CSF [standardized mean difference (SMD) = 1.48, 95% CI 0.18-2.77; P = 0.03)], while their blood levels of BDNF did not differ significantly [standardized mean difference (SMD) = 0.27, 95% CI = - 0.71 to 1.25; P = 0.58)]. Moreover, regarding the heterogeneity among studies reporting BDNF blood levels, we performed two subgroup analyses based on the disease etiology and the specimen (plasma and serum); none of them indicated statistically significant difference in BDNF levels between the subgroups (P = 0.41 and 0.20, respectively). CONCLUSION Meta-analysis provides evidence that patients with encephalopathy/encephalitis have higher CSF levels of BDNF compared to controls.
Collapse
Affiliation(s)
- Fatemeh Nikpour
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Amir Salimi
- Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amene Saghazadeh
- Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Research Center for Immunodeficiencies, Children's Medical Center Hospital, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center Hospital, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, Iran.
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
| |
Collapse
|
|
20
|
Mayer MG, Fischer T. Microglia at the blood brain barrier in health and disease. Front Cell Neurosci 2024; 18:1360195. [PMID: 38550920 PMCID: PMC10976855 DOI: 10.3389/fncel.2024.1360195] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 02/23/2024] [Indexed: 01/24/2025] Open
Abstract
The blood brain barrier (BBB) plays a crucial role in maintaining brain homeostasis by selectively preventing the entry of substances from the peripheral blood into the central nervous system (CNS). Comprised of endothelial cells, pericytes, and astrocytes, this highly regulated barrier encompasses the majority of the brain's vasculature. In addition to its protective function, the BBB also engages in significant crosstalk with perivascular macrophages (MΦ) and microglia, the resident MΦ of the brain. These interactions play a pivotal role in modulating the activation state of cells comprising the BBB, as well as MΦs and microglia, themselves. Alterations in systemic metabolic and inflammatory states can promote endothelial cell dysfunction, reducing the integrity of the BBB and potentially allowing peripheral blood factors to leak into the CNS compartment. This may mediate activation of perivascular MΦs, microglia, and astrocytes, and initiate further immune responses within the brain parenchyma, suggesting neuroinflammation can be triggered by signaling from the periphery, without primary injury or disease originating within the CNS. The intricate interplay between the periphery and the CNS through the BBB highlights the importance of understanding the role of microglia in mediating responses to systemic challenges. Despite recent advancements, our understanding of the interactions between microglia and the BBB is still in its early stages, leaving a significant gap in knowledge. However, emerging research is shedding light on the involvement of microglia at the BBB in various conditions, including systemic infections, diabetes, and ischemic stroke. This review aims to provide a comprehensive overview of the current research investigating the intricate relationship between microglia and the BBB in health and disease. By exploring these connections, we hope to advance our understanding of the role of brain immune responses to systemic challenges and their impact on CNS health and pathology. Uncovering these interactions may hold promise for the development of novel therapeutic strategies for neurological conditions that involve immune and vascular mechanisms.
Collapse
Affiliation(s)
- Meredith G. Mayer
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA, United States
| | - Tracy Fischer
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA, United States
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, United States
| |
Collapse
|
|
21
|
Lei M, Feng T, Zhang M, Chang F, Liu J, Sun B, Chen M, Li Y, Zhang L, Tang P, Yin P. CHRONIC CRITICAL ILLNESS-INDUCED MUSCLE ATROPHY: INSIGHTS FROM A TRAUMA MOUSE MODEL AND POTENTIAL MECHANISM MEDIATED VIA SERUM AMYLOID A. Shock 2024; 61:465-476. [PMID: 38517246 DOI: 10.1097/shk.0000000000002322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2024]
Abstract
ABSTRACT Background: Chronic critical illness (CCI), which was characterized by persistent inflammation, immunosuppression, and catabolism syndrome (PICS), often leads to muscle atrophy. Serum amyloid A (SAA), a protein upregulated in critical illness myopathy, may play a crucial role in these processes. However, the effects of SAA on muscle atrophy in PICS require further investigation. This study aims to develop a mouse model of PICS combined with bone trauma to investigate the mechanisms underlying muscle weakness, with a focus on SAA. Methods: Mice were used to examine the effects of PICS after bone trauma on immune response, muscle atrophy, and bone healing. The mice were divided into two groups: a bone trauma group and a bone trauma with cecal ligation and puncture group. Tibia fracture surgery was performed on all mice, and PICS was induced through cecal ligation and puncture surgery in the PICS group. Various assessments were conducted, including weight change analysis, cytokine analysis, hematological analysis, grip strength analysis, histochemical staining, and immunofluorescence staining for SAA. In vitro experiments using C2C12 cells (myoblasts) were also conducted to investigate the role of SAA in muscle atrophy. The effects of inhibiting receptor for advanced glycation endproducts (RAGE) or JAK2 on SAA-induced muscle atrophy were examined. Bioinformatic analysis was conducted using a dataset from the GEO database to identify differentially expressed genes and construct a coexpression network. Results: Bioinformatic analysis confirmed that SAA was significantly upregulated in muscle tissue of patients with intensive care unit-induced muscle atrophy. The PICS animal models exhibited significant weight loss, spleen enlargement, elevated levels of proinflammatory cytokines, and altered hematological profiles. Evaluation of muscle atrophy in the animal models demonstrated decreased muscle mass, grip strength loss, decreased diameter of muscle fibers, and significantly increased expression of SAA. In vitro experiment demonstrated that SAA decreased myotube formation, reduced myotube diameter, and increased the expression of muscle atrophy-related genes. Furthermore, SAA expression was associated with activation of the FOXO signaling pathway, and inhibition of RAGE or JAK2/STAT3-FOXO signaling partially reversed SAA-induced muscle atrophy. Conclusions: This study successfully develops a mouse model that mimics PICS in CCI patients with bone trauma. Serum amyloid A plays a crucial role in muscle atrophy through the JAK2/STAT3-FOXO signaling pathway, and targeting RAGE or JAK2 may hold therapeutic potential in mitigating SAA-induced muscle atrophy.
Collapse
|
|
22
|
Esmaeili A, Ebrahimpour S, Hefshejani KF, Esmaeili A. Molecular mechanisms underlying the effect of tooth shortening on memory dysfunction in Wistar male rat. Arch Oral Biol 2024; 159:105878. [PMID: 38171058 DOI: 10.1016/j.archoralbio.2023.105878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 12/15/2023] [Accepted: 12/27/2023] [Indexed: 01/05/2024]
Abstract
OBJECTIVE We investigated the effects of molar tooth shortening on the mRNA expression of the AβPP/BACE1, BDNF/TrkB, and Bax/Bcl-2 signaling pathways in the Wistar male rat hippocampal regions. DESIGN Four groups (n = 5 per group) of male Wistar rats (control, SRM (shortened right molar), SLM (shortened left molar), and SBM (shortened bilateral molar)) were used. RNA was isolated from the hippocampus and transformed into cDNA. Real-time quantitative PCR was used to evaluate the mRNA expression levels of AβPP, BACE1, Bax, Bcl-2, BDNF, and TrkB. RESULTS Differential mRNA expression was observed in rat groups. SBM significantly upregulated the AβPP, BACE1, and Bax mRNA expressions, whereas the expression levels of Bcl-2, BDNF, and TrkB were decreased. SRM and SLM approximately had the same effect on the expression enhancement of AβPP, BACE1, and Bax; however, SRM was more effective than SLM in increasing the expression of these genes. CONCLUSIONS Symmetrical molar teeth shortening affected the mRNA expression of AβPP and BACE1, which is related to learning and memory dysfunction.
Collapse
Affiliation(s)
- Ali Esmaeili
- Dental Materials Research Center, Dental Research Institute, School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shiva Ebrahimpour
- Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | | | - Abolghasem Esmaeili
- Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
| |
Collapse
|
|
23
|
Wang CM, Zhang Y, Yang YS, Lin S, He HF. Effect of esketamine pretreatment on acute sepsis-associated encephalopathy. Exp Neurol 2024; 372:114646. [PMID: 38070725 DOI: 10.1016/j.expneurol.2023.114646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 11/12/2023] [Accepted: 12/03/2023] [Indexed: 12/17/2023]
Abstract
PURPOSE Esketamine, the S(+) enantiomer of ketamine, exhibits good anesthetic efficacy and controllability; however, its potential clinical applications, particularly in sepsis-associated encephalopathy (SAE), remain underexplored. SAE involves the development of diffuse brain dysfunction after sepsis, leading to markedly increased sepsis-related disability and mortality. In this study, we investigated the effects of esketamine pretreatment on acute SAE. METHODS Mice were randomly divided into four groups: control (C, n = 22), acute SAE (L, n = 22), esketamine pretreatment + acute SAE (EL, n = 22), and nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor (ML385) + esketamine pretreatment + acute SAE (N + EL, n = 22). Acute SAE was established using intraperitoneal (i.p.) injection of lipopolysaccharide (LPS; 10 mg/kg), while controls received equal amounts of saline. The EL group received daily i.p. injections of esketamine (10 mg/kg) for 5 consecutive days, followed by LPS on day 6. The N + EL group received i.p. injections of ML385 (30 mg/kg) 1 h before esketamine pretreatment. The remainder of treatment followed the same protocol as the EL group. Behavioral tests were performed 24 h post-LPS injection, and whole blood and brain tissues were collected for further analysis. RESULTS Esketamine improved sepsis symptoms, 7-day survival, and spatial cognitive impairment, without altering locomotor activity. Moreover, esketamine reversed the LPS-induced increase in serum S100 calcium-binding protein β and neuron-specific enolase levels and reduced hippocampal neuroinflammation, oxidative stress, and neuronal apoptosis in the EL group. However, these neuroprotective effects of esketamine were reversed by ML385. CONCLUSION The results of our study suggest that esketamine pretreatment mitigates acute SAE, highlighting the involvement of the Nrf2/heme oxygenase-1 pathway in mediating its neuroprotective effects.
Collapse
Affiliation(s)
- Cong-Mei Wang
- Department of Anesthesiology, Shishi General Hospital, Fujian Province, China
| | - Yan Zhang
- Department of Anesthesiology, Zhuzhou Central Hospital, Hunan Province, China
| | - Yu-Shen Yang
- Department of Anesthesiology, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Shu Lin
- Department of Anesthesiology, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China; Group of Neuroendocrinology, Garvan Institute of Medical Research, 384 Victoria St, Sydney, Australia; Center of Neurological and Metabolic Research, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - He-Fan He
- Department of Anesthesiology, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China.
| |
Collapse
|
|
24
|
Liao HH, Livneh H, Huang HL, Hung JY, Lu MC, Guo HR, Tsai TY. Reduced risk of dementia in patients with type 2 diabetes mellitus using Chinese herbal medicine: A nested case-control study. World J Diabetes 2023; 14:1632-1642. [DOI: 10.4239/wjd.v14.i11.1632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/14/2023] [Accepted: 10/25/2023] [Indexed: 11/14/2023] Open
Abstract
BACKGROUND Dementia is a prevalent condition in type 2 diabetes mellitus (T2DM) patients. While Chinese herbal medicine (CHM) is often employed as complementary therapy for glycemic control, its effect in controlling likelihood of dementia has not yet been fully elucidated.
AIM To compare the risk of dementia between T2DM patients with and without CHM treatment.
METHODS We undertook a nested case-control study and obtained data on patients 20-70 years of age who received medical care for T2DM between 2001 and 2010 from the National Health Insurance Research database in Taiwan. Cases, defined as those with dementia that occurred at least one year after the diagnosis of T2DM, were randomly matched to controls without dementia from the study cohort at a 1:1 ratio. We applied conditional logistic regression to explore the associations between CHM treatment and dementia.
RESULTS A total of 11699 dementia cases were matched to 11699 non-dementia controls. We found that adding CHM to conventional care was related to a lower risk of dementia [adjusted odds ratio (OR) = 0.51], and high-intensity CHM treatment was associated with an adjusted OR of 0.22.
CONCLUSION This study shows that the cumulative CHM exposure was inversely associated with dementia risk in an exposure-response manner, implying that CHM treatment may be embraced as a disease management approach for diabetic patients to prevent dementia.
Collapse
Affiliation(s)
- Hou-Hsun Liao
- Department of Chinese Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi 62247, Taiwan
- Graduate Institute of Chinese Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404333, Taiwan
- Department of Nursing, Tzu Chi University of Science and Technology, Hualien 62247, Taiwan
| | - Hanoch Livneh
- Department of Special and Counselor Education, Portland State University, Portland, OR 97207, United States
| | - Hua-Lung Huang
- Department of Rehabilitation, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi 62247, Taiwan
| | - Jui-Yu Hung
- Department of Nursing, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi 62247, Taiwan
| | - Ming-Chi Lu
- Division of Allergy, Immunology and Rheumatology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi 62247, Taiwan
| | - How-Ran Guo
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan
- Department of Occupational and Environmental Medicine, National Cheng Kung University Hospital, Tainan 70428, Taiwan
- Occupational Safety, Health, and Medicine Research Center, National Cheng Kung University, Tainan 70428, Taiwan
| | - Tzung-Yi Tsai
- Department of Nursing, Tzu Chi University of Science and Technology, Hualien 62247, Taiwan
- Department of Medical Research, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi 62247, Taiwan
| |
Collapse
|
|
25
|
Li HH, Livneh H, Huang HL, Wang YH, Lu MC, Chen WJ, Tsai TY. Integrating Chinese Herbal Medicine into Conventional Care Was Related to Lower Risk of Sarcopenia Among Rheumatid Arthritis Patients: A Retrospective, Population-Based Study. J Multidiscip Healthc 2023; 16:3117-3127. [PMID: 37901596 PMCID: PMC10612505 DOI: 10.2147/jmdh.s428948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/28/2023] [Indexed: 10/31/2023] Open
Abstract
Objective Sarcopenia is a frequently observed comorbidity of rheumatoid arthritis (RA) due to the chronic activation of the innate immune system. Accumulating evidence has indicated that Chinese herbal medicine (CHM) safely suppresses proinflammatory pathways and controls inflammation-associated disease, but its effect in reducing the risk of developing sarcopenia among RA subjects has not been established. We conducted a population-level cohort study to compare the sarcopenia risk in patients with RA who use or do not use CHM. Methods Using claims from a nationwide insurance database, we recruited patients with newly diagnosed RA and without sarcopenia between 2002 and 2010. Propensity score matching was applied to randomly select sets of CHM users and non-CHM users to compare the sarcopenia risk until the end of 2013. The risk of new-onset sarcopenia was assessed using the Cox proportional hazards model. Results As compared to non-CHM users, those receiving CHM treatment had a lower incidence of sarcopenia (7.69 vs 9.83 per 1000 person-years). CHM was correlated with a decreased chance of sarcopenia after controlling for potential covariates. Notably, use of CHM for more than two years may diminish the risk of getting sarcopenia by about 47% when taken as prescribed. Prescriptions of several herbal formulae may benefit the reduction of sarcopenia risk, such as Yan-Hu-Suo, Bei-Mu, Da-Huang, Huang Qin, Ping-Wei-San (PWS), Shu-Jing-Huo-Xue-Tang (SJHXT) and Chuan-Xiong-Cha-Tiao-San (CXCTS). Conclusion This study produced new evidence as it is the first to show that the longer duration of CHM use was correlated to reduced risk of sarcopenia in a dose-dependent manner, implying that CHM treatment could be embraced as a routine care strategy for preventing sarcopenia.
Collapse
Affiliation(s)
- Hsin-Hua Li
- Department of Chinese Medicine, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, 62247, Taiwan
| | - Hanoch Livneh
- Rehabilitation Counseling Program, Portland State University, Portland, OR, 97207-0751, USA
| | - Hua-Lung Huang
- Department of Rehabilitation, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Yu-Han Wang
- Center of Sports Medicine, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, 62247, Taiwan
| | - Ming-Chi Lu
- Division of Allergy, Immunology and Rheumatology, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, 62247, Taiwan
- School of Medicine, Tzu Chi University, Hualien, 97004, Taiwan
| | - Wei-Jen Chen
- Department of Chinese Medicine, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, 62247, Taiwan
- Center of Sports Medicine, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, 62247, Taiwan
- School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, 97004, Taiwan
- Graduate Institute of Sports Science, National Taiwan Sport University, Taoyuan, 33301, Taiwan
| | - Tzung-Yi Tsai
- Department of Medical Research, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, 62247, Taiwan
- Department of Nursing, Tzu Chi University of Science and Technology, Hualien, 97004, Taiwan
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, 70428, Taiwan
| |
Collapse
|
|
26
|
Du L, Wu Y, Jia Q, Li J, Li Y, Ma H, Fan Z, Guo X, Li L, Peng Y, Li J, Fang Z, Zhang X. Autophagy Suppresses Ferroptosis by Degrading TFR1 to Alleviate Cognitive Dysfunction in Mice with SAE. Cell Mol Neurobiol 2023; 43:3605-3622. [PMID: 37341832 PMCID: PMC11410008 DOI: 10.1007/s10571-023-01370-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 05/30/2023] [Indexed: 06/22/2023]
Abstract
Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis that is characterized by long-term cognitive impairment, which imposes a heavy burden on families and society. However, its pathological mechanism has not been elucidated. Ferroptosis is a novel form of programmed cell death that is involved in multiple neurodegenerative diseases. In the current study, we found that ferroptosis also participated in the pathological process of cognitive dysfunction in SAE, while Liproxstatin-1 (Lip-1) effectively inhibited ferroptosis and alleviated cognitive impairment. Additionally, since an increasing number of studies have suggested the crosstalk between autophagy and ferroptosis, we further proved the essential role of autophagy in this process and demonstrated the key molecular mechanism of the autophagy-ferroptosis interaction. Currently, we showed that autophagy in the hippocampus was downregulated within 3 days of lipopolysaccharide injection into the lateral ventricle. Moreover, enhancing autophagy ameliorated cognitive dysfunction. Importantly, we found that autophagy suppressed ferroptosis by downregulating transferrin receptor 1 (TFR1) in the hippocampus, thereby alleviating cognitive impairment in mice with SAE. In conclusion, our findings indicated that hippocampal neuronal ferroptosis is associated with cognitive impairment. In addition, enhancing autophagy can inhibit ferroptosis via degradation of TFR1 to ameliorate cognitive impairment in SAE, which shed new light on the prevention and therapy for SAE.
Collapse
Affiliation(s)
- Lixia Du
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
- College of Life Sciences, Northwest University, Xi'an, 710069, Shaanxi, China
| | - You Wu
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Qi Jia
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Jin Li
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Yi Li
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Hongwei Ma
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Zhongmin Fan
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Xiaofeng Guo
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Ling Li
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Yuliang Peng
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Jing Li
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Zongping Fang
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
- Translational Research Institute of Brain and Brain-Like Intelligence, School of Medicine, Shanghai Fourth People's Hospital, Tongji University, Shanghai, 200434, China.
| | - Xijing Zhang
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
| |
Collapse
|
|
27
|
Su J, Zhou F, Wu S, Tong Z. Research Progress on Natural Small-Molecule Compounds for the Prevention and Treatment of Sepsis. Int J Mol Sci 2023; 24:12732. [PMID: 37628912 PMCID: PMC10454676 DOI: 10.3390/ijms241612732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 08/02/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
Sepsis is a serious disease with high mortality and has been a hot research topic in medical research in recent years. With the continuous reporting of in-depth research on the pathological mechanisms of sepsis, various compounds have been developed to prevent and treat sepsis. Natural small-molecule compounds play vital roles in the prevention and treatment of sepsis; for example, compounds such as resveratrol, emodin, salidroside, ginsenoside, and others can modulate signaling through the NF-κB, STAT3, STAT1, PI3K, and other pathways to relieve the inflammatory response, immunosuppression, and organ failure caused by sepsis. Here, we discuss the functions and mechanisms of natural small-molecule compounds in preventing and treating sepsis. This review will lay the theoretical foundation for discovering new natural small-molecule compounds that can potentially prevent and treat sepsis.
Collapse
|
|
28
|
Chu J, Li H, Yuan Z, Zhou W, Yu Y, Yu Y. Acetaminophen impairs ferroptosis in the hippocampus of septic mice by regulating glutathione peroxidase 4 and ferroptosis suppressor protein 1 pathways. Brain Behav 2023; 13:e3145. [PMID: 37443407 PMCID: PMC10454284 DOI: 10.1002/brb3.3145] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 06/02/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
BACKGROUND Neuronal ferroptosis is a major cause of cognitive impairment and mortality in patients with sepsis-associated encephalopathy (SAE). A low dose of acetaminophen (APAP) in septic mice can prevent ferroptosis in the hippocampal tissue; however, the underlying mechanism is unknown. This study aimed to investigate the mechanism by which APAP reduces ferroptosis in the hippocampal tissues of septic mice. METHODS A mouse model of SAE was established, and the ferroptosis pathway inhibitors RSL3 and iFSP1+RSL3 were used in addition to APAP for the interventions, respectively. The 7-day survival rate of the mice was recorded, and cognitive function was examined using the Morris water maze test. Hematoxylin and eosin staining was performed to observe hippocampal tissue damage. Hippocampal iron and malondialdehyde (MDA) were measured using chemical colorimetric methods. Immunofluorescence was used to detect the reactive oxygen species (ROS) content in hippocampal tissues. RESULTS RSL3 reversed the efficacy of APAP on improving cognitive dysfunction in septic mice but did not obviously reverse the survival rate of mice enhanced by APAP. RSL3 aggravated APAP-induced hippocampal tissue damage in mice attenuated by APAP. RSL3 inhibited glutathione peroxidase 4 (GPX4) expression and increased ferroptosis suppressor protein 1 (FSP1) and 4-hydroxy-2-nonenal (4-HNE) expression. RSL3 also reversed the effects of APAP in reducing iron, MDA, and ROS levels in the hippocampal tissues of septic mice. iFSP1+RSL3 further reversed the effect of APAP on ameliorating cognitive dysfunction in septic mice and successfully reversed the survival rate of mice enhanced by APAP. iFSP1+RSL3 aggravated APAP-induced cerebral hippocampal damage. iFSP1+RSL3 inhibited both GPX4 and FSP1, further reversing the effect of APAP on the reduction in iron, 4-HNE, ROS, and MDA levels in the cerebral hippocampus of mice with sepsis. CONCLUSION These data suggest that APAP inhibits ferroptosis in the cerebral hippocampus of septic mice through the GPX4 and FSP1 pathways.
Collapse
Affiliation(s)
- Jing Chu
- Department of AnesthesiologyCharacteristic Medical Center of Chinese People's Armed Police Force (PAP)TianjinChina
- Department of AnesthesiologyTianjin Medical University General HospitalTianjinChina
- Tianjin Institute of AnesthesiologyTianjinChina
| | - Hong Li
- Department of AnesthesiologyCharacteristic Medical Center of Chinese People's Armed Police Force (PAP)TianjinChina
| | - Zhihao Yuan
- Department of AnesthesiologyTianjin Children's HospitalTianjinChina
| | - Wenyu Zhou
- Department of AnesthesiologyCharacteristic Medical Center of Chinese People's Armed Police Force (PAP)TianjinChina
| | - Yang Yu
- Department of AnesthesiologyTianjin Medical University General HospitalTianjinChina
- Tianjin Institute of AnesthesiologyTianjinChina
| | - Yonghao Yu
- Department of AnesthesiologyTianjin Medical University General HospitalTianjinChina
- Tianjin Institute of AnesthesiologyTianjinChina
| |
Collapse
|
|
29
|
Cui YR, Bu ZQ, Yu HY, Yan LL, Feng J. Emodin attenuates inflammation and demyelination in experimental autoimmune encephalomyelitis. Neural Regen Res 2023; 18:1535-1541. [PMID: 36571359 PMCID: PMC10075100 DOI: 10.4103/1673-5374.358612] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Emodin, a substance extracted from herbs such as rhubarb, has a protective effect on the central nervous system. However, the potential therapeutic effect of emodin in the context of multiple sclerosis remains unknown. In this study, a rat model of experimental autoimmune encephalomyelitis was established by immune induction to simulate multiple sclerosis, and the rats were intraperitoneally injected with emodin (20 mg/kg/d) from the day of immune induction until they were sacrificed. In this model, the nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and the microglia exacerbated neuroinflammation, playing an important role in the development of multiple sclerosis. In addition, silent information regulator of transcription 1 (SIRT1)/peroxisome proliferator-activated receptor-alpha coactivator (PGC-1α) was found to inhibit activation of the NLRP3 inflammasome, and SIRT1 activation reduced disease severity in experimental autoimmune encephalomyelitis. Furthermore, treatment with emodin decreased body weight loss and neurobehavioral deficits, alleviated inflammatory cell infiltration and demyelination, reduced the expression of inflammatory cytokines, inhibited microglial aggregation and activation, decreased the levels of NLRP3 signaling pathway molecules, and increased the expression of SIRT1 and PGC-1α. These findings suggest that emodin improves the symptoms of experimental autoimmune encephalomyelitis, possibly through regulating the SIRT1/PGC-1α/NLRP3 signaling pathway and inhibiting microglial inflammation. These findings provide experimental evidence for treatment of multiple sclerosis with emodin, enlarging the scope of clinical application for emodin.
Collapse
Affiliation(s)
- Yue-Ran Cui
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Zhong-Qi Bu
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Hai-Yang Yu
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Li-Li Yan
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Juan Feng
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| |
Collapse
|
|
30
|
Jin C, Wang T, Yang Y, Zhou P, Li J, Wu W, Lv X, Ma G, Wang A. Rational targeting of autophagy in colorectal cancer therapy: From molecular interactions to pharmacological compounds. ENVIRONMENTAL RESEARCH 2023; 227:115721. [PMID: 36965788 DOI: 10.1016/j.envres.2023.115721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 03/13/2023] [Accepted: 03/18/2023] [Indexed: 05/08/2023]
Abstract
The abnormal progression of tumors has been a problem for treatment of cancer and therapeutic should be directed towards targeting main mechanisms involved in tumorigenesis in tumors. The genomic mutations can result in changes in biological mechanisms in human cancers. Colorectal cancer is one of the most malignant tumors of gastrointestinal tract and its treatment has been faced some difficulties due to development of resistance in tumor cells and also, their malignant behavior. Hence, new therapeutic modalities for colorectal cancer are being investigated. Autophagy is a "self-digestion" mechanism that is responsible for homeostasis preserving in cells and its aberrant activation/inhibition can lead to tumorigenesis. The current review focuses on the role of autophagy mechanism in colorectal cancer. Autophagy may be associated with increase/decrease in progression of colorectal cancer due to mutual function of this molecular mechanism. Pro-survival autophagy inhibits apoptosis to increase proliferation and survival rate of colorectal tumor cells and it is also involved in cancer metastasis maybe due to EMT induction. In contrast, pro-death autophagy decreases growth and invasion of colorectal tumor cells. The status of autophagy (upregulation and down-regulation) is a determining factor for therapy response in colorectal tumor cells. Therefore, targeting autophagy can increase sensitivity of colorectal tumor cells to chemotherapy and radiotherapy. Interestingly, nanoparticles can be employed for targeting autophagy in cancer therapy and they can both induce/suppress autophagy in tumor cells. Furthermore, autophagy modulators can be embedded in nanostructures in improving tumor suppression and providing cancer immunotherapy.
Collapse
Affiliation(s)
- Canhui Jin
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Tianbao Wang
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Yanhui Yang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, 471003, China
| | - Pin Zhou
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Juncheng Li
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Wenhao Wu
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Xin Lv
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Guoqing Ma
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Aihong Wang
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China.
| |
Collapse
|
|
31
|
Lu H, Xie D, Qu B, Li M, He Y, Liu W. Emodin prevents renal ischemia-reperfusion injury via suppression of p53-mediated cell apoptosis based on network pharmacology. Heliyon 2023; 9:e15682. [PMID: 37215853 PMCID: PMC10195913 DOI: 10.1016/j.heliyon.2023.e15682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 04/16/2023] [Accepted: 04/18/2023] [Indexed: 05/24/2023] Open
Abstract
Background Previous evidence indicated that emodin has significant advantages for preventing acute kidney injury (AKI). However, the mechanisms responsible for these effects of emodin have yet to be elucidated. Methods We first used network pharmacology and molecular docking to identify the core targets of emodin for AKI and performed a range of experiments to validate this result. Pretreatment with emodin for 7 days, the rats were treated with bilateral renal artery clipping for 45 min to identify the prevention effect. Hypoxia/reoxygenation (H/R), and vancomycin - induced renal tubular epithelial cells (HK-2 cells) were treated with emodin to explore the related molecular mechanism. Results Network pharmacology and molecular docking showed that anti-apoptosis might be the core mechanism responsible for the action of emodin on AKI; this anti-apoptotic effect appears to because by regulation p53-related signaling pathway. Our data showed that pretreatment with emodin significantly improved renal function and renal tubular injury in renal I/R model rats (P < 0.05. The prevention effect of emodin was proved to be related to anti - apoptosis of HK-2 cells, possibly by downregulating the levels of p53, cleaved-caspase-3, pro-caspase-9, and upregulated the levels of Bcl-2. The efficacy and mechanism of emodin on anti - apoptosis was also confirmed in vancomycin - induced HK-2 cells. Meanwhile, the data also showed that emodin promoted angiogenesis in I/R damaged kidneys and H/R-induced HK-2 cells, which was associated with decreasing HIF-1α levels and increasing VEGF levels. Conclusions Our findings indicated that the preventive effect of emodin on AKI is probably attributable to anti-apoptosis response and promoting angiogenesis effect.
Collapse
Affiliation(s)
- Hongmei Lu
- Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100700, China
- Department of Clinical Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610072, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Beijing, 100700, China
| | - Dengpiao Xie
- Department of Clinical Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610072, China
| | - Bo Qu
- Department of Clinical Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610072, China
| | - Mingquan Li
- Department of Clinical Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610072, China
| | - Yuhua He
- Department of Clinical Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610072, China
| | - Weijing Liu
- Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100700, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Beijing, 100700, China
| |
Collapse
|
|
32
|
Chen CJ, Livneh H, Chen WJ, Wang YH, Lu MC, Yeh CC, Yen CT, Tsai TY. The Prescription of Chinese Herbal Medicine and Risk of Endometriosis in Women with Rheumatoid Arthritis: A Population-Based Cohort Study. Int J Womens Health 2022; 14:1603-1612. [PMID: 36411747 PMCID: PMC9675347 DOI: 10.2147/ijwh.s386134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 10/13/2022] [Indexed: 11/16/2022] Open
Abstract
Purpose The systemic inflammation is believed to provide an outline of the association between rheumatoid arthritis (RA) and endometriosis. This retrospective cohort study aimed to explore the association of Chinese herbal medicine (CHM) use with the prevention of endometriosis onset in women diagnosed with RA. Methods We utilized the claims data from the National Health Insurance of Taiwan from 2000 to 2009 and excluded individuals diagnosed with endometriosis before being diagnosed with RA, using age at clinical diagnosis. After selection and propensity-score matching, a total of 5992 females aged ≧20 years old and with newly diagnosed RA but without endometriosis at baseline were included, which contained 2996 CHM users and 2996 non-CHM users. All of them were followed until the end of 2013 to measure the incidence of endometriosis. Results During the study period, we noticed that CHM users had a substantially lower incidence of endometriosis compared to non-CHM users (2.54 vs 5.19 per 1000 person-years). Use of CHM correlated significantly with a lower endometriosis likelihood even after adjusting for potential covariates, with the adjusted hazard ratio of 0.47 (95% confidence interval, 0.35–0.65). A longer duration of CHM use was associated with a reduction in endometriosis risk, especially in those using CHM for more than 730 days. Uses of several herbal products may be associated with a lower risk of endometriosis, like Ge-Gen, Da-Huang, Huang-Qin, Ye-Jiao-Teng, Chuan-Niu-Xi, Shu-Jing-Huo-Xue-Tang, Du-Huo-Ji-Sheng-Tang, Ge-Gen-Tang, Shao-Yao-Gan-Cao-Tang, Ping-Wei-San, Gan-Lu-Yin, and Dang-Gui-Nian-Tong-Tang. Conclusion Taken together, adding CHM to conventional therapy may reduce the incidence of endometriosis in women with RA. The therapeutic mechanisms and safety of these natural products may be a direction for future clinical studies.
Collapse
Affiliation(s)
- Chia-Jung Chen
- Department of Chinese Medicine, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Hanoch Livneh
- Rehabilitation Counseling Program, Portland State University, Portland, OR, USA
| | - Wei-Jen Chen
- Department of Chinese Medicine, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
- Graduate Institute of Sports Science, National Taiwan Sport University, Taoyuan, Taiwan
- School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan
- Center of Sports Medicine, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Yu-Han Wang
- Center of Sports Medicine, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Ming-Chi Lu
- Division of Allergy, Immunology and Rheumatology, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Chia-Chou Yeh
- Department of Chinese Medicine, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
- School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan
| | - Chieh-Tsung Yen
- Department of Neurology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
- Correspondence: Chieh-Tsung Yen; Tzung-Yi Tsai, Tel +886-5-2648000-5003; +886-5-2648000-3209, Fax +886-5-2648006, Email ;
| | - Tzung-Yi Tsai
- Department of Nursing, Tzu Chi University of Science and Technology, Hualien, Taiwan
- Department of Medical Research, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| |
Collapse
|
|
33
|
Liu YX, Yu Y, Liu JP, Liu WJ, Cao Y, Yan RM, Yao YM. Neuroimmune Regulation in Sepsis-Associated Encephalopathy: The Interaction Between the Brain and Peripheral Immunity. Front Neurol 2022; 13:892480. [PMID: 35832175 PMCID: PMC9271799 DOI: 10.3389/fneur.2022.892480] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 05/27/2022] [Indexed: 11/15/2022] Open
Abstract
Sepsis-associated encephalopathy (SAE), the most popular cause of coma in the intensive care unit (ICU), is the diffuse cerebral damage caused by the septic challenge. SAE is closely related to high mortality and extended cognitive impairment in patients in septic shock. At present, many studies have demonstrated that SAE might be mainly associated with blood–brain barrier damage, abnormal neurotransmitter secretion, oxidative stress, and neuroimmune dysfunction. Nevertheless, the precise mechanism which initiates SAE and contributes to the long-term cognitive impairment remains largely unknown. Recently, a growing body of evidence has indicated that there is close crosstalk between SAE and peripheral immunity. The excessive migration of peripheral immune cells to the brain, the activation of glia, and resulting dysfunction of the central immune system are the main causes of septic nerve damage. This study reviews the update on the pathogenesis of septic encephalopathy, focusing on the over-activation of immune cells in the central nervous system (CNS) and the “neurocentral–endocrine–immune” networks in the development of SAE, aiming to further understand the potential mechanism of SAE and provide new targets for diagnosis and management of septic complications.
Collapse
Affiliation(s)
- Yu-xiao Liu
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, Beijing, China
- Department of Neurosurgery, The Chinese PLA General Hospital, Beijing, China
| | - Yang Yu
- Department of Traditional Chinese Medical Science, Sixth Medical Center of the Chinese PLA General Hospital, Beijing, China
| | - Jing-peng Liu
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, Beijing, China
- Department of Traditional Chinese Medical Science, Sixth Medical Center of the Chinese PLA General Hospital, Beijing, China
| | - Wen-jia Liu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
| | - Yang Cao
- Department of Neurosurgery, The Chinese PLA General Hospital, Beijing, China
| | - Run-min Yan
- Department of Neurosurgery, The Chinese PLA General Hospital, Beijing, China
- *Correspondence: Yong-ming Yao
| | - Yong-ming Yao
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, Beijing, China
- Run-min Yan
| |
Collapse
|
|
34
|
Effects of Anthraquinones on Immune Responses and Inflammatory Diseases. Molecules 2022; 27:molecules27123831. [PMID: 35744949 PMCID: PMC9230691 DOI: 10.3390/molecules27123831] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 06/03/2022] [Accepted: 06/09/2022] [Indexed: 12/12/2022] Open
Abstract
The anthraquinones (AQs) and derivatives are widely distributed in nature, including plants, fungi, and insects, with effects of anti-inflammation and anti-oxidation, antibacterial and antiviral, anti-osteoporosis, anti-tumor, etc. Inflammation, including acute and chronic, is a comprehensive response to foreign pathogens under a variety of physiological and pathological processes. AQs could attenuate symptoms and tissue damages through anti-inflammatory or immuno-modulatory effects. The review aims to provide a scientific summary of AQs on immune responses under different pathological conditions, such as digestive diseases, respiratory diseases, central nervous system diseases, etc. It is hoped that the present paper will provide ideas for future studies of the immuno-regulatory effect of AQs and the therapeutic potential for drug development and clinical use of AQs and derivatives.
Collapse
|