Microglial M1/M2 polarization and metabolic states

British Journal of Pharmacology, Journal Year: 2015, Volume and Issue: 173(4), P. 649 - 665

Published: March 20, 2015

Microglia are critical nervous system‐specific immune cells serving as tissue‐resident macrophages influencing brain development, maintenance of the neural environment, response to injury and repair. As influenced by their microglia assume a diversity phenotypes retain capability shift functions maintain tissue homeostasis. In comparison with peripheral macrophages, demonstrate similar unique features regards phenotype polarization, allowing for innate immunological functions. can be stimulated LPS or IFN ‐ γ an M 1 expression pro‐inflammatory cytokines IL‐4/IL‐13 2 resolution inflammation Increasing evidence suggests role metabolic reprogramming in regulation inflammatory response. Studies using that polarization is often accompanied from oxidative phosphorylation aerobic glycolysis energy production. More recently, link between mitochondrial metabolism has been considered microglia. Under these conditions, demands would associated functional activities cell survival thus, may serve influence contribution activation various neurodegenerative conditions. This review examines states relationship metabolism. Additional supporting experimental data provided shifts primary BV ‐2 line induced under ( M1 ) IL ‐4/ IL‐13 M2 polarization. Linked Articles article part themed section on Inflammation: maladies, models, mechanisms molecules. To view other articles this visit http://dx.doi.org/10.1111/bph.2016.173.issue-4

Language: Английский

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The contribution of astrocytes and microglia to traumatic brain injury

British Journal of Pharmacology, Journal Year: 2015, Volume and Issue: 173(4), P. 692 - 702

Published: March 5, 2015

Traumatic brain injury (TBI) represents a major cause of death and disability in developed countries. Brain injuries are highly heterogeneous can also trigger other neurological complications, including epilepsy, depression dementia. The initial often leads to the development secondary sequelae; cellular hyperexcitability, vasogenic cytotoxic oedema, hypoxia-ischaemia, oxidative stress inflammation, all which influence expansion primary lesion. It is widely known that inflammatory events following TBI contribute widespread cell chronic tissue degeneration. Neuroinflammation multifaceted response involving number types, both within CNS peripheral circulation. Astrocytes microglia, cells CNS, considered key players initiating an after injury. These capable secreting various cytokines, chemokines growth factors, undergo changes morphology. Ultimately, these local microenvironment thus determine extent damage subsequent repair. This review will focus on roles microglia astrocytes TBI, highlighting some processes, pathways mediators involved this response. Additionally, beneficial detrimental aspects responses be examined using evidence from animal models human post-mortem studies.

Language: Английский

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Movers and shakers: cell cytoskeleton in cancer metastasis

British Journal of Pharmacology, Journal Year: 2014, Volume and Issue: 171(24), P. 5507 - 5523

Published: March 26, 2014

Metastasis is responsible for the greatest number of cancer deaths. Metastatic disease, or movement cells from one site to another, a complex process requiring dramatic remodelling cell cytoskeleton. The various components cytoskeleton, actin (microfilaments), microtubules (MTs) and intermediate filaments, are highly integrated their functions well orchestrated in normal cells. In contrast, mutations abnormal expression cytoskeletal cytoskeletal-associated proteins play an important role ability resist chemotherapy metastasize. Studies on its interacting partners have highlighted key signalling pathways, such as Rho GTPases, downstream effector that, through mediate tumour migration, invasion metastasis. An emerging MTs metastasis being unravelled there increasing interest crosstalk between MT which may provide novel treatment avenues metastatic disease. Improved understanding how cytoskeleton influence migration has led development therapeutics against aggressive disease.This article part themed section Cytoskeleton, Extracellular Matrix, Cell Migration, Wound Healing Related Topics. To view other articles this visit http://dx.doi.org/10.1111/bph.2014.171.issue-24.

Language: Английский

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Are cannabidiol and Δ⁹‐tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review

British Journal of Pharmacology, Journal Year: 2014, Volume and Issue: 172(3), P. 737 - 753

Published: Sept. 26, 2014

Based upon evidence that the therapeutic properties of Cannabis preparations are not solely dependent presence Δ(9) -tetrahydrocannabinol (THC), pharmacological studies have been recently carried out with other plant cannabinoids (phytocannabinoids), particularly cannabidiol (CBD) and -tetrahydrocannabivarin (THCV). Results from some these fostered view CBD THCV modulate effects THC via direct blockade cannabinoid CB1 receptors, thus behaving like first-generation receptor inverse agonists, such as rimonabant. Here, we review in vitro ex vivo mechanistic THCV, synthesize data a meta-analysis. Synthesized regarding mechanisms then used to interpret results recent pre-clinical animal clinical trials. The indicates rimonabant-like their action appear very unlikely produce unwanted CNS effects. They exhibit markedly disparate profiles at receptors: is low-affinity ligand can nevertheless affect activity an indirect manner, while high-affinity potent antagonist yet only occasionally produces resulting antagonism. has also high affinity for CB2 receptors signals partial agonist, differing both These illustrate how do always predict pharmacology underlie necessity testing compounds before drawing any conclusion on functional given target.

Language: Английский

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Dopamine receptors – IUPHAR Review 13

British Journal of Pharmacology, Journal Year: 2014, Volume and Issue: 172(1), P. 1 - 23

Published: Oct. 17, 2014

The variety of physiological functions controlled by dopamine in the brain and periphery is mediated D1, D2, D3, D4 D5 GPCRs. Drugs acting on receptors are significant tools for management several neuropsychiatric disorders including schizophrenia, bipolar disorder, depression Parkinson's disease. Recent investigations receptor signalling have shown that receptors, apart from their canonical action cAMP-mediated signalling, can regulate a myriad cellular responses to fine-tune expression dopamine-associated behaviours functions. Such mechanisms may involve alternate G protein coupling or non-G involving ion channels, tyrosine kinases proteins such as β-arrestins classically involved GPCR desensitization. Another level complexity growing appreciation roles played heteromers. Applications new vivo techniques significantly furthered understanding receptors. Here we provide an update current knowledge regarding complex biology, physiology pharmacology

Language: Английский

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Ten things you should know about protein kinases: IUPHAR Review 14

British Journal of Pharmacology, Journal Year: 2015, Volume and Issue: 172(11), P. 2675 - 2700

Published: Jan. 29, 2015

Many human malignancies are associated with aberrant regulation of protein or lipid kinases due to mutations, chromosomal rearrangements and/or gene amplification. Protein and represent an important target class for treating disorders. This review focus on 'the 10 things you should know about their inhibitors', including a short introduction the history inhibitors ending perspective kinase drug discovery. Although '10 things' have been, certain extent, chosen arbitrarily, they cover in comprehensive way past present efforts discovery summarize status quo current as well knowledge structure binding modes. Besides describing potentials drugs, this also limitations, particularly how circumvent emerging resistance against oncological indications.

Language: Английский

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Lysophospholipid receptor nomenclature review: IUPHAR Review 8

British Journal of Pharmacology, Journal Year: 2014, Volume and Issue: 171(15), P. 3575 - 3594

Published: March 7, 2014

Lysophospholipids encompass a diverse range of small, membrane‐derived phospholipids that act as extracellular signals. The signalling properties are mediated by 7‐transmembrane GPCRs , constituent members which have continued to be identified after their initial discovery in the mid‐1990s. Here we briefly review this class receptors, with particular emphasis on protein and gene nomenclatures reflect cognate ligands. There six lysophospholipid receptors interact lysophosphatidic acid ( LPA ): names 1 – 6 italicized LPAR1‐LPAR6 (human) Lpar1‐Lpar6 (non‐human). five sphingosine 1‐phosphate (S1P) receptors: S1P ‐S1P 5 S1PR1‐S1PR5 S1pr1‐S1pr5 Recent additions receptor family resulted proposed for lysophosphatidyl inositol (LPI) name LPI LPIR1 Lpir1 (non‐human) three serine LyPS 2 3 LYPSR1‐LYPSR3 Lypsr1‐Lypsr3 along variant form does not appear exist humans is provisionally named 2L . This nomenclature incorporates previous recommendations from International U nion B asic C linical P harmacology, H uman G enome O rganization, Gene Nomenclature Committee, M ouse I nformatix.

Language: Английский

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Progressive inflammation‐mediated neurodegeneration after traumatic brain or spinal cord injury

British Journal of Pharmacology, Journal Year: 2015, Volume and Issue: 173(4), P. 681 - 691

Published: May 4, 2015

Traumatic brain injury (TBI) has been linked to dementia and chronic neurodegeneration. Described initially in boxers currently recognized across high contact sports, the association between repeated concussion (mild TBI) progressive neuropsychiatric abnormalities recently received widespread attention, termed traumatic encephalopathy. Less well appreciated are cognitive changes associated with neurodegeneration after isolated spinal cord injury. Also under-recognized is role of sustained neuroinflammation or trauma, even though this relationship known since 1950s supported by more recent preclinical clinical studies. These pathological mechanisms, manifested extensive microglial astroglial activation appropriately inflammation inflammatory encephalopathy, may be among most important causes post-traumatic terms prevalence. Importantly, emerging experimental work demonstrates that persistent can cause treatable weeks

Language: Английский

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Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre‐activation of AMPK‐dependent autophagy

British Journal of Pharmacology, Journal Year: 2014, Volume and Issue: 171(13), P. 3146 - 3157

Published: Feb. 26, 2014

Recent clinical trials report that metformin, an activator of AMP-activated protein kinase (AMPK) used to treat type 2 diabetes, significantly reduces the risk stroke by actions are independent its glucose-lowering effects. However, underlying molecular mechanisms not known. Here, we tested possibility acute metformin preconditioning confers neuroprotection pre-activation AMPK-dependent autophagy in a rat model permanent middle cerebral artery occlusion (pMCAO).Male Sprague-Dawley rats were pretreated with either vehicle, AMPK inhibitor, Compound C, or 3-methyladenine, and injected single dose (10 mg kg(-1), i.p.). Then, activity biomarkers brain assessed. At 24 h after treatment, subjected pMCAO; infarct volume, neurological deficits cell apoptosis evaluated 96 later.A activated induced brain. The enhanced autophagic was inhibited C pretreatment. Furthermore, reduced during subsequent focal ischaemia. mediated fully abolished partially 3-methyladenine.These results provide first evidence induces activation AMPK, which against This suggests well-known hypoglycaemic drug, may have practical use for prevention.

Language: Английский

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Novel lead structures and activation mechanisms for CO‐releasing molecules (CORMs)

British Journal of Pharmacology, Journal Year: 2014, Volume and Issue: 172(6), P. 1638 - 1650

Published: March 14, 2014

Carbon monoxide (CO) is an endogenous small signalling molecule in the human body, produced by action of haem oxygenase on haem. Since it very difficult to apply safely as a gas, solid storage and delivery forms for CO are now explored. Most these CO-releasing molecules (CORMs) based inactivation coordinating transition metal centre prodrug approach. After brief look at potential cellular target structures CO, overview design principles activation mechanisms release from coordination sphere given. Endogenous exogenous triggers discussed include ligand exchange reactions with medium, enzymatically-induced photoactivated liberation CO. Furthermore, attachment CORMs hard soft nanomaterials confer additional specificity such systems critically assessed. A survey analytical methods study stoichiometry kinetics release, well tracking living using fluorescent probes, concludes this review. valuable tools studying bioactivity might lead new drug candidates; however, future generations CORMs, particular attention has be paid their drug-likeness tuning peripheral 'drug sphere' specific biomedical applications. Further progress field will thus depend close interaction between synthetic chemists researchers exploring physiological effects therapeutic applications

Language: Английский

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