Author: Li, Zhao ; Li, Lin ; Tang, Shuang ; Wang, Yingwen ; Yan, Jin ; Tang, Wei ; Yang, Xiaomin ; Zhang, Zhaosi ; Zhou, Chao ; Wang, Lin ; Chen, Hong ; Yu, Shenghui ; Sun, Xiaochuan ; Gu, Nina ; Huang, Zhijian

AbstractBackgroundWhite matter injury (WMI) is an important pathological process after traumatic brain injury (TBI). The correlation between white matter functions and the myeloid cells expressing triggering receptor‐2 (TREM2) has been convincingly demonstrated. Moreover, a recent study revealed that microglial sterol metabolism is crucial for early remyelination after demyelinating diseases. However, the potential roles of TREM2 expression and microglial sterol metabolism in WMI after TBI have not yet been explored.MethodsControlled cortical injury was induced in both wild‐type (WT) and TREM2 depletion (TREM2 KO) mice to simulate clinical TBI. COG1410 was used to upregulate TREM2, while PLX5622 and GSK2033 were used to deplete microglia and inhibit the liver X receptor (LXR), respectively. Immunofluorescence, Luxol fast blue staining, magnetic resonance imaging, transmission electron microscopy, and oil red O staining were employed to assess WMI after TBI. Neurological behaviour tests and electrophysiological recordings were utilized to evaluate cognitive functions following TBI. Microglial cell sorting and transcriptomic sequencing were utilized to identify alterations in microglial sterol metabolism‐related genes, while western blot was conducted to validate the findings.ResultsTREM2 expressed highest at 3 days post‐TBI and was predominantly localized to microglial cells within the white matter. Depletion of TREM2 worsened aberrant neurological behaviours, and this phenomenon was mediated by the exacerbation of WMI, reduced renewal of oligodendrocytes, and impaired phagocytosis ability of microglia after TBI. Subsequently, the upregulation of TREM2 alleviated WMI, promoted oligodendrocyte regeneration, and ultimately facilitated the recovery of neurological behaviours after TBI. Finally, the expression of DHCR24 increased in TREM2 KO mice after TBI. Interestingly, TREM2 inhibited DHCR24 and upregulated members of the LXR pathway. Moreover, LXR inhibition could partially reverse the effects of TREM2 upregulation on electrophysiological activities.ConclusionsWe demonstrate that TREM2 has the potential to alleviate WMI following TBI, possibly through the DHCR24/LXR pathway in microglia.

01 Feb 2024·Inflammation Research

Activation of LXRs alleviates neuropathic pain-induced cognitive dysfunction by modulation of microglia polarization and synaptic plasticity via PI3K/AKT pathway

Article

Author: Yuan, Xiaoman ; Han, Siyi ; Gao, Feng ; Wang, Jie ; Zhao, Fengtian ; Manyande, Anne ; Zhang, Wen ; Tian, Xuebi

OBJECTIVECognitive dysfunction is a common comorbidity in patients with chronic pain. Activation of Liver X receptors (LXRs) plays a potential role in improving cognitive disorders in central nervous diseases. In this study, we investigated the role of LXRs in cognitive deficits induced by neuropathic pain.METHODSWe established the spared nerve injury (SNI) model to investigate pain-induced memory dysfunction. Pharmacological activation of LXRs with T0901317 or inhibition with GSK2033 was applied. PI3K inhibitor LY294002 was administered to explore the underlying mechanism of LXRs. Changes in neuroinflammation, microglia polarization, and synaptic plasticity were assessed using biochemical technologies.RESULTSWe found that SNI-induced cognitive impairment was associated with reduced LXRβ expression, increased M1-phenotype microglia, decreased synaptic proteins, and inhibition of PI3K/AKT signaling pathway in the hippocampus. Activation of LXRs using T0901317 effectively alleviated SNI-induced cognitive impairment. Additionally, T0901317 promoted the polarization of microglia from M1 to M2, reduced pro-inflammatory cytokines, and upregulated synaptic proteins in the hippocampus. However, administration of GSK2033 or LY294002 abolished these protective effects of T0901317 in SNI mice.CONCLUSIONSLXRs activation alleviates neuropathic pain-induced cognitive impairment by modulating microglia polarization, neuroinflammation, and synaptic plasticity, at least partly via activation of PI3K/AKT signaling in the hippocampus. LXRs may be promising targets for addressing pain-related cognitive deficits.

05 Dec 2023·Journal of ethnopharmacology

Shenlian extract protected ox-LDL-loaded macrophages against ER stress by promoting LAL-LXRα mediated cholesterol flux.

Article

Author: Nie, Chun-Xia ; Cai, Wei-Yan ; Yang, Qing ; Zhu, Xiao-Xin ; Li, Man-Jing ; Du, Xin-Ke ; Dong, Yu ; Weng, Xiao-Gang ; Liu, Li ; Yang, Li-Na ; Chen, Ying ; Li, Qi

ETHNOPHARMACOLOGICAL RELEVANCEShenlian (SL) extract is consisted of extracts from Salvia miltiorrhiza Bunge and Andrographis paniculata (Burm.f.) Nees, two herbs commonly used in Chinese clinical formula to treat atherosclerosis by removing blood stasis and clearing away heat. Pharmacologically, the anti-atherosclerotic effects of these two herbs are related to unresolved inflammation and the macrophage anergy or apoptosis in lesions led by the lipid flux blockage and ER stress. However, the deeper understanding of SL extract in protecting macrophage in plaques remains unknown.AIM OF THE STUDYThis study aimed to investigate the underlying mechanism of SL extract in protecting ER-stressed macrophages from apoptosis in atherosclerosis.METHODSThe ApoE^-/- atherosclerotic mice model and ox-LDL loaded macrophages model were established to assess the effect of SL extract on ER stress in vivo and in vitro. Key markers related to ER stress in plaque were determined by immunohistochemical staining. Proteins involved in apoptosis and ER stress in macrophages loaded by ox-LDL were assessed by Western blot. ER morphology was observed by electron microscope. Lipid flux was temporally and quantitatively depicted by Oil red staining. The LAL and LXRα were blocked by lalistat and Gsk 2033 respectively to investigate whether SL extract protected the function of macrophages by the activation of LAL-LXRα axis.RESULTSOur study reported that, in ApoE-/- atherosclerotic mice, SL extract effectively relieved ER stress of carotid artery plaque. In lipid-overloaded macrophage models, SL extract significantly alleviated ER stress by promoting cholesterol degradation and efflux, which finally prevented apoptosis of foam cells induced by ox-LDL. Blockage of ER stress by 4-Phenylbutyric acid (4-PBA), an inhibitor of Endoplasmic Reticulum (ER) stress, largely attenuated the protective effects of SL extract on macrophage. By utilizing the selective antagonists against both LAL and LXRα, this study further revealed that the beneficial effects of SL extract in macrophages was dependent on the proper functionalization of LAL-LXRα axis.CONCLUSIONSBy highlighting the therapeutic significance of macrophage protection in resolving atherosclerosis inflammation, our study pharmacologically provided convincing mechanistic evidence of SL extract in the activation LAL-LXRα axis and revealed its promising potential in the promotion of cholesterol turnover and prevention of ER stress induced apoptosis in lipid-loaded macrophages.

100 Deals associated with GSK-2033

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Indication	Highest Phase	Country/Location	Organization	Date
Metabolic dysfunction-associated steatotic liver disease	Preclinical	US	Saint Louis University School of Medicine	-
Cardiovascular Diseases	Discovery	US	GlaxoSmithKline, Inc.	-

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