Soluble epoxide hydrolase inhibitor protects against blood-brain barrier dysfunction in a mouse model of type 2 diabetes via the AMPK/HO-1 pathway

Wu, Jing; Zhao, Yutong; Fan, Zhen; Chen, Qiunan; Chen, Jinliang; Sun, Yue; Jiang, Xu-shun; Xiao, Qian

doi:10.1016/j.bbrc.2020.01.085

Cited by 15 publications

(14 citation statements)

References 29 publications

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“…Soluble epoxide hydrolase inhibitors (sEHIs) have been leveraged for addressing a variety of diseases including hypertension [37][38][39], cancer [7,25,40], dyslipidemia [41], pain [42][43][44][45][46], immunological disorders [47], neurological diseases [45,[48][49][50], diabetes [51][52][53][54] and eye diseases [55,56]. Urea, carbamate and amide derivatives represent the most potent class of pharmacophores reported as sEHIs [57][58][59].…”

Section: Soluble Epoxide Hydrolase Inhibitors (Sehis)mentioning

confidence: 99%

Small Molecule Soluble Epoxide Hydrolase Inhibitors in Multitarget and Combination Therapies for Inflammation and Cancer

2020

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The enzyme soluble epoxide hydrolase (sEH) plays a central role in metabolism of bioactive lipid signaling molecules. The substrate-specific hydrolase activity of sEH converts epoxyeicosatrienoic acids (EETs) to less bioactive dihydroxyeicosatrienoic acids. EETs exhibit anti-inflammatory, analgesic, antihypertensive, cardio-protective and organ-protective properties. Accordingly, sEH inhibition is a promising therapeutic strategy for addressing a variety of diseases. In this review, we describe small molecule architectures that have been commonly deployed as sEH inhibitors with respect to angiogenesis, inflammation and cancer. We juxtapose commonly used synthetic scaffolds and natural products within the paradigm of a multitarget approach for addressing inflammation and inflammation induced carcinogenesis. Structural insights from the inhibitor complexes and novel strategies for development of sEH-based multitarget inhibitors are also presented. While sEH inhibition is likely to suppress inflammation-induced carcinogenesis, it can also lead to enhanced angiogenesis via increased EET concentrations. In this regard, sEH inhibitors in combination chemotherapy are described. Urea and amide-based architectures feature prominently across multitarget inhibition and combination chemotherapy applications of sEH inhibitors.

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Section: Soluble Epoxide Hydrolase Inhibitors (Sehis)mentioning

confidence: 99%

Small Molecule Soluble Epoxide Hydrolase Inhibitors in Multitarget and Combination Therapies for Inflammation and Cancer

2020

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“…Interestingly, several of the cellular and functional constituents of the neurogliovascular unit represent possible entry points for disease mechanisms in CSVD (Wardlaw et al, 2019). Increasing evidence is showing that AMPK activation alleviates the damage of BBB and improves endothelial functions (Zhao et al, 2014;Prasad et al, 2017;Wang et al, 2017;Wu et al, 2020), which were key factors contributing to the pathogenesis of CSVD (Wardlaw et al, 2019). As a well-recognized AMPK activator, a previous study of experimental animal models found that metformin could inhibit inflammation, thereby alleviating endothelial injury and lowering BBB permeability by an AMPK-dependent intercellular adhesion molecule-1 (ICAM-1) down-regulation (Liu et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Long-Term Use of Metformin Is Associated With Reduced Risk of Cognitive Impairment With Alleviation of Cerebral Small Vessel Disease Burden in Patients With Type 2 Diabetes

Teng

Feng

et al. 2021

Front. Aging Neurosci.

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Objective: Type 2 diabetes (T2D) is a risk factor for cognitive impairment and cerebral small vessel disease (CSVD). The relation of metformin use and cognitive impairment or CSVD is not clear. The objective of this study was to investigate the cross-sectional effects of long-term use of metformin on total CSVD burden and cognitive function in patients with T2D.Methods: A total of 234 participants with T2D from the memory clinic in Hebei General Hospital were enrolled in this retrospective study. Duration of metformin use and dosage were recorded. Along with cerebral magnetic resonance imaging (MRI) examination, Mini-Mental State Examination (MMSE) was also performed to assess their cognitive status. We determined the validated total CSVD score (ranging from 0–4) by combining four markers of CSVD that were visually rated. We used binary logistic regression analysis, ordinal logistic regression analysis and mediation analysis to assess the relation of long-term use of metformin with CSVD burden and cognitive function.Results: Binary logistic regression analysis showed long-term use of metformin was associated with reducing the risk of cognitive impairment (OR: 0.446; 95% Confidence Interval (CI): 0.249 to 0.800; P = 0.007), after adjustment of potential confounders, such as total CSVD burden score, age, HbA1c, hypertension, history of stroke, homocysteine, body mass index, TG and HDL-C. Ordinal logistic regression analysis suggested that long-term use of metformin was associated with alleviation of total CSVD burden score (OR: 0.583; 95% CI: 0.359 to 0.943; P = 0.027), after adjusting for age, HbA1c, hypertension, history of stroke, homocysteine, body mass index, TG and HDL-C. Mediation analysis showed significant mediation by the presence of severe CSVD burden score for long-term use of metformin in relation to cognitive impairment.Conclusion: Long-term use of metformin was associated with lower rates of cognitive impairment and lower total CSVD burden score in patients with T2D. A proportion of the relation between long-term use of metformin and cognitive impairment may be attributable to alleviation of CSVD burden.

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“…79 Hyperglycemia-associated BBB disruption has been blocked by glucagon-like peptide-1 (GLP-1) agonists, fibroblast growth factor 21 (FGF21) treatment, epoxide hydrolase inhibition, pitavastatin, candesartan, and metabolic carbonic anhydrase inhibitors. [80][81][82][83][84] Mfsd2a attenuates BBB disruption accompanying intracerebral hemorrhage. 85 A type IV phosphodiesterase inhibitor or antibodies to interleukin-1 beta protects the BBB after focal cerebral ischemia.…”

Section: Toward Treating the Disrupted Bbbmentioning

confidence: 99%

Transcellular routes of blood–brain barrier disruption

Erickson

Banks

2022

Exp Biol Med (Maywood)

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Disruption of the blood–brain barrier (BBB) can occur through different mechanisms and pathways. As these pathways result in increased permeability to different classes of substances, it is likely that the neurological insults that occur will also differ for these pathways. The major categories of BBB disruption are paracellular (between cells) and transcellular (across cells) with a subcategory of transcellular leakage involving vesicles (transcytotic). Older literature, as well as more recent studies, highlights the importance of the transcellular pathways in BBB disruption. Of the various transcytotic mechanisms that are thought to be active at the BBB, some are linked to receptor-mediated transcytosis, whereas others are likely involved in BBB disruption. For most capillary beds, transcytotic mechanisms are less clearly linked to permeability than are membrane spanning canaliculi and fenestrations. Disruption pathways share cellular mechanisms to some degree as exemplified by transcytotic caveolar and transcellular canaliculi formations. The discovery of some of the cellular components involved in transcellular mechanisms of BBB disruption and the ability to measure them are adding greatly to our classic knowledge, which is largely based on ultrastructural studies. Future work will likely address the conditions and diseases under which the various pathways of disruption are active, the different impacts that they have, and the cellular biology that underlies the different pathways to disruption.

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Soluble epoxide hydrolase inhibitor protects against blood-brain barrier dysfunction in a mouse model of type 2 diabetes via the AMPK/HO-1 pathway

Cited by 15 publications

References 29 publications

Small Molecule Soluble Epoxide Hydrolase Inhibitors in Multitarget and Combination Therapies for Inflammation and Cancer

Small Molecule Soluble Epoxide Hydrolase Inhibitors in Multitarget and Combination Therapies for Inflammation and Cancer

Long-Term Use of Metformin Is Associated With Reduced Risk of Cognitive Impairment With Alleviation of Cerebral Small Vessel Disease Burden in Patients With Type 2 Diabetes

Transcellular routes of blood–brain barrier disruption

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