Artemisinin protects against sepsis-associated encephalopathy by activating the AMPK axis in the microglia

Abstract Background and purpose: Artemisinin has been in use as an anti-malarial drug for almost half a century in the world. There is growing evidence that artemisinin also possesses potent anti-inflammatory and immunoregulatory properties. However, the efficacy of artemisinin treatment in sepsis-associated encephalopathy (SAE) remains unknown. Here, we evaluate the possible protective effects and explore the underlying mechanism of action of artemisinin on SAE. Methods: Male C57BL/6mice were pretreated with either vehicle or artemisinin, and then injected with LPS to establish an animal model of SAE. The cognitive function was then assessed using the Morris water maze. Neuronal damage and neuroinflammation in the hippocampus were evaluated by immunohistochemical analysis. Additionally, the protective mechanism of artemisinin was determined in vitro. Results: The results showed that artemisinin preconditioning attenuated LPS-induced cognitive impairment, neural damage, and microglial activation in the mouse brain. Luminex liquid chip revealed that artemisinin could inhibit the pro-inflammatory cytokines and chemokines induced by LPS in the BV2 microglia cells. Meanwhile, artemisinin suppressed the migratory ability of BV2 cells. Western blot demonstrated that artemisinin promoted adenosine monophosphate-activated protein kinaseα1 (AMPKα1) expression and suppressed nuclear translocation of NF-κB. Furthermore, knock-down of AMPKα1 markedly abolished the anti-inflammatory effects of artemisinin when exposed to LPS. Conclusion: Artemisinin is a potential therapeutic agent for SAE, and its effect was probably mediated by the activation of AMPKα1signalling pathway in microglia.

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Artemisinin improves neurocognitive deficits associated with sepsis by activating the AMPK axis in the microglia.

10.21203/rs.2.17969/v2 ◽

2020 ◽

Author(s):

Shao-Peng Lin ◽

Jue-Xian Wei ◽

Shan Ye ◽

Jiasong Hu ◽

Jingyi Bu ◽

...

Keyword(s):

Cognitive Impairment ◽

Inflammatory Cytokines ◽

Nuclear Translocation ◽

Neuronal Damage ◽

Protective Mechanism ◽

Protective Effects ◽

Neurocognitive Deficits ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Abstract Background and purpose: Artemisinin has been in use as an anti-malarial drug for almost half a century in the world. There is growing evidence that artemisinin also possesses potent anti-inflammatory and immunoregulatory properties. However, the efficacy of artemisinin treatment in neurocognitive deficits associated with sepsis remains unknown. Here, we evaluate the possible protective effects and explore the underlying mechanism of artemisinin on cognitive impairment resulting from sepsis.Methods: Male C57BL/6 mice were pretreated with either vehicle or artemisinin, and then injected with LPS to establish an animal model of sepsis. The cognitive function was then assessed using the Morris water maze. Neuronal damage and neuroinflammation in the hippocampus were evaluated by immunohistochemical and ELISA analysis. Additionally, the protective mechanism of artemisinin was determined in vitro.Results: The results showed that artemisinin preconditioning attenuated LPS-induced cognitive impairment, neural damage, and microglial activation in the mouse brain. The in vitro experiment revealed that artemisinin could reduce the production of pro-inflammatory cytokines and suppress the microglial migration in the BV2 microglia cells. Meanwhile, western blot demonstrated that artemisinin suppressed nuclear translocation of nuclear factor kappa-B and the expression of pro-inflammatory cytokines (i.e. tumor necrosis factor alpha, interleukin-6) by activating adenosine monophosphate-activated protein kinaseα1 (AMPKα1) pathway. Furthermore, knock-down of AMPKα1 markedly abolished the anti-inflammatory effects of artemisinin.Conclusion: Artemisinin is a potential therapeutic agent for sepsis-associated neuroinflammation and cognitive impairment, and its effect was probably mediated by the activation of AMPKα1 signalling pathway in microglia.

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Vitexin regulates EPAC and NLRP3 and ameliorates chronic cerebral hypoperfusion injury

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2021-0034 ◽

2021 ◽

Author(s):

Qilong Zhang ◽

Zhijia Fan ◽

wei xue ◽

Fanfan Sun ◽

Huaqing Zhu ◽

...

Keyword(s):

Neuronal Damage ◽

Critical Factor ◽

Underlying Mechanism ◽

Cerebrovascular Diseases ◽

Artery Occlusion ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion ◽

Protective Effects ◽

Ht22 Cells

Chronic cerebral hypoperfusion (CCH), as a critical factor of chronic cerebrovascular diseases, has greatly influenced the health of patients with vascular dementia (VD). The putative protective effects of vitexin on the CCH need further investigations. In the current study, the role of vitexin and its underlying mechanism were investigated with permanent bilateral common carotid artery occlusion (2VO) in rats as well as HT22 cells with OGD/R injury model. The results demonstrated that vitexin improved cognitive dysfunction as well as alleviated pathological neuronal damage in HE and TUNEL results. The decreased levels of Epac1, Epac2, Rap1 and p-ERK were reversed by vitexin in rats with CCH. Furthermore, this study indicated that vitexin alleviated CCH-induced inflammation injuries by reducing the expression of NLRP3, Caspase-1, IL-1β, IL-6, and cleaved Caspase-3. In vitro, vitexin increased the expression of Epac1 and Epac2, decreased the activation of the NLRP3-mediated inflammation, and improved cell viability. Taken together, our findings suggest that vitexin can reduce the degree of the progressing pathological damage in the cortex and hippocampus and inhibit further deterioration of cognitive function in rats with CCH. Epac and NLRP3 can be regulated by vitexin, which provides enlightenment for the protection of CCH injury.

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Targeting Connexin43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling

10.21203/rs.3.rs-35961/v1 ◽

2020 ◽

Author(s):

Hailong Yu ◽

Xiang Cao ◽

Wei Li ◽

Pinyi Liu ◽

Yuanyuan Zhao ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Nuclear Translocation ◽

Treatment Strategies ◽

Neurological Deficits ◽

Proximity Ligation Assay ◽

Protective Effects ◽

Cx43 Expression ◽

Anti Inflammatory

Abstract Background: In the central nervous system(CNS),Connexin43 (Cx43) is mainly expressed in astrocytes and regulates astrocytic network homeostasis. Like Cx43 overexpression,abnormal excessive opening of Cx43 hemichannels (Cx43Hcs) on reactive astrocytes aggravates the inflammatory response and cell death in CNS pathologies.However, the role of excessive Cx43Hc opening in intracerebral hemorrhage (ICH) injury is not clear.Methods: Hemin stimulation in primary cells and collagenase IV injection in C57BL/6J (B6) mice were used as ICH modals in vitro and vivo.Cx43 mimetic peptide Gap19 was treated after ICH injury. Ethidium bromide (EtBr) uptake assays was used to measure the opening of Hcs. Western blot and immunofluorescence were used to measure the expression of protein. qRT-PCR and ELISA were used to determine the level of cytokines. Co-immunoprecipitation(Co-IP) and Duolink in situ proximity ligation assay (PLA) were applied to measure the association between proteins.Results: In this study,Cx43 expression was upregulated, and excessive Cx43Hc opening was observed in mice after ICH injury. Delayed treatment with Gap19significantly alleviated hematoma volume and neurological deficits after ICH injury. In addition,Gap19 decreased inflammatory cytokine levels in the tissue surrounding the hematoma and decreased reactive astrogliosis after ICH injury in vitro and in vivo, as determined by GFAP staining. Intriguingly, Cx43 transcriptional activity and expression in astrocytes were significantly increased after hemin stimulation in culture.However,Gap19 treatment downregulated astrocytic Cx43 expression through the ubiquitin-proteasome pathway without affecting Cx43 transcription. Additionally, our data showed that Gap19 increased YAP nuclear translocation, which upregulated SOCS1 and SOCS3 expression, and then inhibited the TLR4-NFκB and JAK2-STAT3 pathways in hemin-stimulated astrocytes. Finally, the YAP inhibitor verteporfin (VP) reversed the anti-inflammatory effect of Gap19 in vitro and almost completely blocked its protective effects in vivo after ICH injury.Conclusions: This study provides new insight into potential treatment strategies for ICH injury involving astroglial Cx43 and Cx43Hcs.Suppression of abnormal astroglial Cx43 expression and Cx43Hc opening by Gap19 plays anti-inflammatory and neuroprotective roles after ICH injury.

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Attenuation of Inflammatory Symptoms by Icariside B2 in Carrageenan and LPS-Induced Inflammation Models via Regulation of MAPK/NF-κB Signaling Cascades

Biomolecules ◽

10.3390/biom10071037 ◽

2020 ◽

Vol 10 (7) ◽

pp. 1037

Author(s):

Md Badrul Alam ◽

Yoon-Gyung Kwon ◽

Shakina Yesmin Simu ◽

Sk Abrar Shahriyar ◽

Sang Han Lee

Keyword(s):

Nuclear Translocation ◽

Inflammatory Responses ◽

Binding Energies ◽

Inhibitory Protein ◽

Expression Levels ◽

Bv2 Cells ◽

Tnf Α ◽

Cox 2 ◽

Anti Inflammatory

Prolonged inflammatory responses can lead to the development of several chronic diseases, such as autoimmune disorders and the development of natural therapeutic agents is required. A murine model was used to assess the anti-inflammatory effects of the megastigmane glucoside, icariside B2 (ICSB), and the assessment was carried out in vitro, and in vivo. The in vitro anti-inflammatory effects of ICSB were tested using LPS-stimulated BV2 cells, and the protein expression levels of inflammatory genes and cytokines were assessed. Mice were subcutaneously injected with 1% carrageenan (CA) to induce acute phase inflammation in the paw. Inflammation was assessed by measuring paw volumes hourly; subsequently, the mice were euthanized and the right hind paw skin was expunged and processed for reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analyses. ICSB inhibits LPS-stimulated nitric oxide (NO) and prostaglandin E2 (PGE2) generation by reducing the expression of inducible NO synthase (iNOS) and cyclooxygenase 2 (COX-2). ICSB also inhibits the COX-2 enzyme with an IC50 value of 7.80 ± 0.26 µM. Molecular docking analysis revealed that ICSB had a strong binding affinity with both murine and human COX-2 proteins with binding energies of −8 kcal/mol and −7.4 kcal/mol, respectively. ICSB also reduces the manifestation of pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, at their transcriptional and translational level. ICSB hinders inhibitory protein κBα (IκBα) phosphorylation, thereby terminating the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) nuclear translocation. ICSB also represses the mitogen-activated protein kinases (MAPKs) signaling pathways. ICSB (50 mg/kg) showed an anti-edema effect in CA-induced mice and suppressed the CA-induced increases in iNOS and COX-2 protein levels. ICSB attenuated inflammatory responses by downregulating NF-κB expression through interference with extracellular signal-regulated kinase (ERK) and p38 phosphorylation, and by modulating the expression levels of iNOS, COX-2, TNF-α, IL-1β, and IL-6.

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The impact of indole-3-lactic acid on immature intestinal innate immunity and development: a transcriptomic analysis

Scientific Reports ◽

10.1038/s41598-021-87353-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Wuyang Huang ◽

Ky Young Cho ◽

Di Meng ◽

W. Allan Walker

Keyword(s):

Lactic Acid ◽

Mechanistic Model ◽

Transcriptomic Analysis ◽

Dependent Manner ◽

Protective Effects ◽

Very Preterm Infants ◽

Anti Inflammatory ◽

The Impact

AbstractAn excessive intestinal inflammatory response may have a role in the pathogenesis of necrotizing enterocolitis (NEC) in very preterm infants. Indole-3-lactic acid (ILA) of breastmilk tryptophan was identified as the anti-inflammatory metabolite involved in probiotic conditioned media from Bifidobacteria longum subsp infantis. This study aimed to explore the molecular endocytic pathways involved in the protective ILA effect against inflammation. H4 cells, Caco-2 cells, C57BL/6 pup and adult mice were used to compare the anti-inflammatory mechanisms between immature and mature enterocytes in vitro and in vivo. The results show that ILA has pleiotropic protective effects on immature enterocytes including anti-inflammatory, anti-viral, and developmental regulatory potentials in a region-dependent and an age-dependent manner. Quantitative transcriptomic analysis revealed a new mechanistic model in which STAT1 pathways play an important role in IL-1β-induced inflammation and ILA has a regulatory effect on STAT1 pathways. These studies were validated by real-time RT-qPCR and STAT1 inhibitor experiments. Different protective reactions of ILA between immature and mature enterocytes indicated that ILA’s effects are developmentally regulated. These findings may be helpful in preventing NEC for premature infants.

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Isoquinolinequinone Derivatives from a Marine Sponge (Haliclona sp.) Regulate Inflammation in In Vitro System of Intestine

Marine Drugs ◽

10.3390/md19020090 ◽

2021 ◽

Vol 19 (2) ◽

pp. 90

Author(s):

Yun Kim ◽

Yeong Ji ◽

Na-Hyun Kim ◽

Nguyen Van Tu ◽

Jung-Rae Rho ◽

...

Keyword(s):

Nitric Oxide ◽

Marine Sponge ◽

Nuclear Translocation ◽

Hydroxyl Group ◽

Subsequent Increase ◽

Inflammatory Bowel ◽

Anti Inflammatory ◽

Key Functional Groups ◽

Oxide Synthase

Using bio-guided fractionation and based on the inhibitory activities of nitric oxide (NO) and prostaglandin E2 (PGE2), eight isoquinolinequinone derivatives (1–8) were isolated from the marine sponge Haliclona sp. Among these, methyl O-demethylrenierate (1) is a noble ester, whereas compounds 2 and 3 are new O-demethyl derivatives of known isoquinolinequinones. Compound 8 was assigned as a new 21-dehydroxyrenieramycin F. Anti-inflammatory activities of the isolated compounds were tested in a co-culture system of human epithelial Caco-2 and THP-1 macrophages. The isolated derivatives showed variable activities. O-demethyl renierone (5) showed the highest activity, while 3 and 7 showed moderate activities. These bioactive isoquinolinequinones inhibited lipopolysaccharide and interferon gamma-induced production of NO and PGE2. Expression of inducible nitric oxide synthase, cyclooxygenase-2, and the phosphorylation of MAPKs were down-regulated in response to the inhibition of NF-κB nuclear translocation. In addition, nuclear translocation was markedly promoted with a subsequent increase in the expression of HO-1. Structure-activity relationship studies showed that the hydroxyl group in 3 and 5, and the N-formyl group in 7 may be key functional groups responsible for their anti-inflammatory activities. These findings suggest the potential use of Haliclona sp. and its metabolites as pharmaceuticals treating inflammation-related diseases including inflammatory bowel disease.

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Dangguijakyak-San Protects against 1-Methyl-4-phenyl-1,2,3,6,-tetrahydropyridine-Induced Neuronal Damage via Anti-Inflammatory Action

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/976270 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Deok-Sang Hwang ◽

Hyo Geun Kim ◽

Jun-Bock Jang ◽

Myung Sook Oh

Keyword(s):

Neuronal Damage ◽

Cell Damage ◽

Substantia Nigra Pars Compacta ◽

Inflammatory Factors ◽

Dopaminergic Cell ◽

Therapeutic Implications ◽

Anti Inflammatory ◽

Inflammatory Action

Dangguijakyak-san (DJS), a famous traditional Korean multiherbal medicine, has been used to treat gynecological and neuro-associated disease. Recent studies demonstrated that DJS has multiple bioactivities including neuroprotection. In the present study, we were to investigate the effect of DJS and its mechanism in anin vitroandin vivomodel of Parkinson’s disease (PD). In primary mesencephalic culture system, DJS attenuated the dopaminergic cell damage induced by 1-methyl-4-phenylpyridine toxicity, and it inhibited production of inflammatory factors such as tumor necrosis factorα(TNF-α), nitric oxide (NO), and activation of microglial cells. Then, we confirmed the effect of DJS in a mouse PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the pole test, DJS at 50 mg/kg/day for 5 days showed increase of motor activity showing shortened time to turn and locomotor activity compared with the MPTP only treated mice. In addition, DJS significantly protected nigrostriatal dopaminergic neuron from MPTP stress. Moreover, DJS showed inhibition of gliosis in the substantia nigra pars compacta. These results have therapeutic implications for DJS in the treatment of PD via anti-inflammatory effects.

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Suppression of LPS-Induced Inflammation by Chalcone Flavokawain A through Activation of Nrf2/ARE-Mediated Antioxidant Genes and Inhibition of ROS/NFκB Signaling Pathways in Primary Splenocytes

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/3476212 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

Hsin-Ling Yang ◽

Ting-Yu Yang ◽

Yugandhar Vudhya Gowrisankar ◽

Chun-Huei Liao ◽

Jiunn-Wang Liao ◽

...

Keyword(s):

Proinflammatory Cytokine ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Ex Vivo ◽

Root Extract ◽

Piper Methysticum ◽

Serum Lipase ◽

Antioxidant Genes ◽

Anti Inflammatory

Oxidative stress is an important contributing factor for inflammation. Piper methysticum, also known as Kava-kava, is a shrub whose root extract has been consumed as a drink by the pacific islanders for a long time. Flavokawain A (FKA) is a novel chalcone derived from the kava plant that is known to have medicinal properties. This study was aimed at demonstrating the antioxidant molecular mechanisms mediated by FKA on lipopolysaccharide- (LPS-) induced inflammation in BALB/c mouse-derived primary splenocytes. In vitro data show that the nontoxic concentrations of FKA (2-30 μM) significantly suppressed the proinflammatory cytokine (TNF-α, IL-1β, and IL-6) release but induced the secretion of interleukin-10 (IL-10), an anti-inflammatory cytokine. It was also shown that FKA pretreatment significantly downregulated the LPS-induced ROS production and blocked the activation of the NFκB (p65) pathway leading to the significant suppression of iNOS, COX-2, TNF-α, and IL-1β protein expressions. Notably, FKA favored the nuclear translocation of Nrf2 leading to the downstream expression of antioxidant proteins HO-1, NQO-1, and γ-GCLC via the Nrf2/ARE signaling pathway signifying the FKA’s potent antioxidant mechanism in these cells. Supporting the in vitro data, the ex vivo data obtained from primary splenocytes derived from the FKA-preadministered BALB/c mice (orally) show that FKA significantly suppressed the proinflammatory cytokine (TNF-α, IL-1β, and IL-6) secretion in control-, LPS-, or Concanavalin A- (Con A-) stimulated cells. A significant decrease in the ratios of pro- and anti-inflammatory cytokines (IL-6/IL-10; TNF-α/IL-10) showed that FKA possesses strong anti-inflammatory properties. Furthermore, BALB/c mice induced with experimental pancreatitis using cholecystokinin- (CCK-) 8 showed decreased serum lipase levels due to FKA pretreatment. We conclude that with its potent antioxidant and anti-inflammatory properties, chalcone flavokawain A could be a novel therapeutic agent in the treatment of inflammation-associated diseases.

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Resveratrol Promotes Mitochondrial Biogenesis and Protects against Seizure-Induced Neuronal Cell Damage in the Hippocampus Following Status Epilepticus by Activation of the PGC-1α Signaling Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms20040998 ◽

2019 ◽

Vol 20 (4) ◽

pp. 998 ◽

Cited By ~ 11

Author(s):

Yao-Chung Chuang ◽

Shang-Der Chen ◽

Chung-Yao Hsu ◽

Shu-Fang Chen ◽

Nai-Ching Chen ◽

...

Keyword(s):

Status Epilepticus ◽

Signaling Pathway ◽

Mitochondrial Biogenesis ◽

Neuronal Damage ◽

Cell Damage ◽

Neuroprotective Effect ◽

Neuronal Cell ◽

Protective Mechanism ◽

Protective Effects ◽

Prolonged Seizure

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is known to regulate mitochondrial biogenesis. Resveratrol is present in a variety of plants, including the skin of grapes, blueberries, raspberries, mulberries, and peanuts. It has been shown to offer protective effects against a number of cardiovascular and neurodegenerative diseases, stroke, and epilepsy. This study examined the neuroprotective effect of resveratrol on mitochondrial biogenesis in the hippocampus following experimental status epilepticus. Kainic acid was microinjected into left hippocampal CA3 in Sprague Dawley rats to induce bilateral prolonged seizure activity. PGC-1α expression and related mitochondrial biogenesis were investigated. Amounts of nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (Tfam), cytochrome c oxidase 1 (COX1), and mitochondrial DNA (mtDNA) were measured to evaluate the extent of mitochondrial biogenesis. Increased PGC-1α and mitochondrial biogenesis machinery after prolonged seizure were found in CA3. Resveratrol increased expression of PGC-1α, NRF1, and Tfam, NRF1 binding activity, COX1 level, and mtDNA amount. In addition, resveratrol reduced activated caspase-3 activity and attenuated neuronal cell damage in the hippocampus following status epilepticus. These results suggest that resveratrol plays a pivotal role in the mitochondrial biogenesis machinery that may provide a protective mechanism counteracting seizure-induced neuronal damage by activation of the PGC-1α signaling pathway.

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Isoflurane protects against renal ischemia and reperfusion injury and modulates leukocyte infiltration in mice

AJP Renal Physiology ◽

10.1152/ajprenal.00161.2007 ◽

2007 ◽

Vol 293 (3) ◽

pp. F713-F722 ◽

Cited By ~ 70

Author(s):

H. Thomas Lee ◽

Mihwa Kim ◽

Minjae Kim ◽

NaLa Kim ◽

Frederic T. Billings ◽

...

Keyword(s):

Nuclear Translocation ◽

Ischemia Reperfusion ◽

Volatile Anesthetics ◽

Renal Ischemia ◽

Renal Protection ◽

Ischemia And Reperfusion Injury ◽

Pentobarbital Anesthesia ◽

Isoflurane Anesthesia ◽

Anti Inflammatory

Inflammation after renal ischemia-reperfusion (IR) injury is a major contributor to renal cell death. We previously demonstrated that several volatile anesthetics protect against renal IR injury and necrosis in rats in vivo. We subsequently showed that volatile anesthetics produced direct anti-inflammatory and anti-necrotic effects in cultured proximal tubule cells in vitro. In this study, we wanted to determine whether the volatile anesthetic isoflurane protects against renal IR injury by producing anti-inflammatory effects in mice. C57BL/6 mice subjected to renal IR under isoflurane anesthesia demonstrated improved renal function and reduced necrosis compared with mice subjected to renal IR under pentobarbital anesthesia. Mice subjected to renal IR under isoflurane anesthesia also showed a reduction in inflammation evidenced by a reduced renal influx of neutrophils and macrophages, reduced ICAM-1 expression, less upregulation of proinflammatory mRNAs (TNF-α, ICAM-1, KC, and IL-1β) as well as reduced nuclear translocation of NF-κB 24 h after renal IR injury. Analysis of specific lymphocyte subset trafficking to the kidney using flow cytometry demonstrated that isoflurane anesthesia reduced intrarenal influx of CD3+, CD4+, CD8+, and NK1.1+ lymphocytes at 3 h after renal ischemia compared with pentobarbital anesthesia. However, only the differential reduction of NK1.1+ lymphocytes persisted 24 h after renal ischemia. Therefore, we conclude that isoflurane anesthesia significantly attenuated renal IR injury in mice by reducing inflammation and modulating leukocyte influx. In particular, neutrophil, macrophage, and NK1.1+ lymphocyte cell modulation may play a significant role in renal protection by isoflurane anesthesia.

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