Inhibition of DDR1 promotes ferroptosis and overcomes gefitinib resistance in non-small cell lung cancer.

Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), which serves the critical pillar for the treatment of non-small cell lung cancer (NSCLC). However, the acquired resistance remains a challenge for its clinical application, for which, practical strategies to reverse gefitinib resistance in NSCLC are necessary. Ferroptosis, a programmed cell death driven by ferritin-dependent lipid peroxidation, involves in NSCLC progression and related chemoresistance. In our previous work, the self-synthesised EGFR inhibitor Yfq07 (N4, N6-disubstituted pyrimidine-4,6-diamine derivatives) displayed a considerable inhibitory effect on NSCLC both in vitro and in vivo. Herein, we observed that Yfq07 suppressed the proliferation of PC-9GR and HCC827GR cells, two gefitinib resistance NSCLC cell lines. Mechanically, Yfq07 inhibited the phosphorylation of the Discoidin Domain Receptor 1 (DDR1), a receptor tyrosine kinase (RTK) highly expressed in multiple cancers, accompanied by downregulated miR-3648 and upregulated SOCS2. Inhibition or knockdown of DDR1 suppressed the proliferation, migration, and invasion of gefitinib-resistant NSCLC cells, and on the other hand, also downregulated miR-3648 and promoted SOCS2 expression. More specifically, miR-3648 targeted the 3'UTR segment of SOCS2 mRNA and thus affecting the P-ERK signalling pathway to regulate the malignant behaviors of gefitinib-resistant NSCLC cells. Furthermore, Yfq07 also indirectly induced the ferroptosis of gefitinib-resistant NSCLC cells via SOCS2 triggered inhibition of xCT-GPX4 pathway. In conclusion, our study indicates that DDR1 inhibitor Yfq07 promotes ferroptosis and reverses gefitinib-resistance of NSCLC through DDR1-miR-3648-SOCS2 signalling pathway, which provides insights for targeted therapy of gefitinib-resistant NSCLC and drug developments targeting ferroptosis.

Discovery of a prominent dual-target DDR1/EGFR inhibitor aimed DDR1/EGFR-positive NSCLC.

This study aimed to develop the first dual-target small molecule inhibitor concurrently targeting Discoidin domain receptor 1 (DDR1) and Epidermal growth factor receptor (EGFR), which play a crucial interdependent roles in non-small cell lung cancer (NSCLC), demonstrating a synergistic inhibitory effect. A series of innovative dual-target inhibitors for DDR1 and EGFR were discovered. These compounds were designed and synthesized using structural optimization strategies based on the lead compound BZF02, employing 4,6-pyrimidine diamine as the core scaffold, followed by an investigation of their biological activities. Among these compounds, D06 was selected and showed micromolar enzymatic potencies against DDR1 and EGFR. Subsequently, compound D06 was observed to inhibit NSCLC cell proliferation and invasion. Demonstrating acceptable pharmacokinetic performance, compound D06 exhibited its anti-tumor activity in NSCLC PC-9/GR xenograft models without apparent toxicity or significant weight loss. These collective results showcase the successful synthesis of a potent dual-targeted inhibitor, suggesting the potential therapeutic efficacy of co-targeting DDR1 and EGFR for DDR1/EGFR-positive NSCLC.

Synthesis and biological evaluation of novel benzothiazole derivatives as potential anticancer and antiinflammatory agents.

Introduction: Cancer, a significant global health concern, necessitates innovative treatments. The pivotal role of chronic inflammation in cancer development underscores the urgency for novel therapeutic strategies. Benzothiazole derivatives exhibit promise due to their distinctive structures and broad spectrum of biological effects. This study aims to explore new anti-tumor small molecule drugs that simultaneously anti-inflammatory and anticancer based on the advantages of benzothiazole frameworks. Methods: The compounds were characterized by nuclear magnetic resonance (NMR), liquid chromatograph-mass spectrometer (LC-MS) and high performance liquid chromatography (HPLC) for structure as well as purity and other related physicochemical properties. The effects of the compounds on the proliferation of human epidermoid carcinoma cell line (A431) and human non-small cell lung cancer cell lines (A549, H1299) were evaluated by MTT method. The effect of compounds on the expression levels of inflammatory factors IL-6 and TNF-α in mouse monocyte macrophages (RAW264.7) was assessed using enzyme-linked immunosorbent assay (ELISA). The effect of compounds on apoptosis and cell cycle of A431 and A549 cells was evaluated by flow cytometry. The effect of compounds on A431 and A549 cell migration was evaluated by scratch wound healing assay. The effect of compounds on protein expression levels in A431 and A549 cells was assessed by Western Blot assay. The physicochemical parameters, pharmacokinetic properties, toxicity and drug similarity of the active compound were predicted using Swiss ADME and admetSAR web servers. Results: Twenty-five novel benzothiazole compounds were designed and synthesized, with their structures confirmed through spectrogram verification. The active compound 6-chloro-N-(4-nitrobenzyl) benzo[d] thiazol-2-amine (compound B7) was screened through a series of bioactivity assessments, which significantly inhibited the proliferation of A431, A549 and H1299 cancer cells, decreased the activity of IL-6 and TNF-α, and hindered cell migration. In addition, at concentrations of 1, 2, and 4 µM, B7 exhibited apoptosis-promoting and cell cycle-arresting effects similar to those of the lead compound 7-chloro-N-(2, 6-dichlorophenyl) benzo[d] thiazole-2-amine (compound 4i). Western blot analysis confirmed that B7 inhibited both AKT and ERK signaling pathways in A431 and A549 cells. The prediction results of ADMET indicated that B7 had good drug properties. Discussion: This study has innovatively developed a series of benzothiazole derivatives, with a focus on compound B7 due to its notable dual anticancer and anti-inflammatory activities. B7 stands out for its ability to significantly reduce cancer cell proliferation in A431, A549, and H1299 cell lines and lower the levels of inflammatory cytokines IL-6 and TNF-α. These results position B7B7 as a promising candidate for dual-action cancer therapy. The study's mechanistic exploration, highlighting B7's simultaneous inhibition of the AKT and ERK pathways, offers a novel strategy for addressing both the survival mechanisms of tumor cells and the inflammatory milieu facilitating cancer progression.

Aging induces region-specific dysregulation of hormone synthesis in the primate adrenal gland.

Adrenal glands, vital for steroid secretion and the regulation of metabolism, stress responses and immune activation, experience age-related decline, impacting systemic health. However, the regulatory mechanisms underlying adrenal aging remain largely uninvestigated. Here we established a single-nucleus transcriptomic atlas of both young and aged primate suprarenal glands, identifying lipid metabolism and steroidogenic pathways as core processes impacted by aging. We found dysregulation in centripetal adrenocortical differentiation in aged adrenal tissues and cells in the zona reticularis region, responsible for producing dehydroepiandrosterone sulfate (DHEA-S), were highly susceptible to aging, reflected by senescence, exhaustion and disturbed hormone production. Remarkably, LDLR was downregulated in all cell types of the outer cortex, and its targeted inactivation in human adrenal cells compromised cholesterol uptake and secretion of dehydroepiandrosterone sulfate, as observed in aged primate adrenal glands. Our study provides crucial insights into endocrine physiology, holding therapeutic promise for addressing aging-related adrenal insufficiency and delaying systemic aging.

Identification of FOXO1 as a geroprotector in human synovium through single-nucleus transcriptomic profiling.

The synovium, a thin layer of tissue that adjacent to the joints and secretes synovial fluid, undergoes changes in aging that contribute to intense shoulder pain and other joint diseases. However, the mechanism underlying human synovial aging remains poorly characterized. Here, we generated a comprehensive profile of synovial cell types present in subacromial synovium from young and aged individuals. By delineating aging-related transcriptomic changes across cell types and their associated regulatory networks, we identified two subsets of mesenchymal stromal cell (MSC) in human synovium, which are lining and sublining MSCs, and found that angiogenesis and fibrosis-associated genes were upregulated whereas genes associated with cell adhesion and cartilage development were downregulated during aging. Moreover, the specific cell-cell communications in aged synovium mirrors that of aging-related inflammation and tissue remodeling, including vascular hyperplasia and tissue fibrosis. In particular, we identified Forkhead box O1 (FOXO1) as one of the major regulons for aging DEGs of synovium MSCs, and validated its downregulation in both lining and sublining MSC populations of the aged synovium. In human FOXO1-depleted MSCs derived from human embryonic stem cells, we recapitulated the senescent phenotype observed in the subacromial synovium of aged donors. These data indicate the important role for FOXO1 in the regulation of human synovial aging. Overall, our study improves upon our understanding of synovial aging during joint degeneration, thereby informing development of new treatments aimed at rejuvenating the aged joint.

CHIT1-positive microglia drive motor neuron ageing in the primate spinal cord.

Ageing is a critical factor in spinal-cord-associated disorders1, yet the ageing-specific mechanisms underlying this relationship remain poorly understood. Here, to address this knowledge gap, we combined single-nucleus RNA-sequencing analysis with behavioural and neurophysiological analysis in non-human primates (NHPs). We identified motor neuron senescence and neuroinflammation with microglial hyperactivation as intertwined hallmarks of spinal cord ageing. As an underlying mechanism, we identified a neurotoxic microglial state demarcated by elevated expression of CHIT1 (a secreted mammalian chitinase) specific to the aged spinal cords in NHP and human biopsies. In the aged spinal cord, CHIT1-positive microglia preferentially localize around motor neurons, and they have the ability to trigger senescence, partly by activating SMAD signalling. We further validated the driving role of secreted CHIT1 on MN senescence using multimodal experiments both in vivo, using the NHP spinal cord as a model, and in vitro, using a sophisticated system modelling the human motor-neuron-microenvironment interplay. Moreover, we demonstrated that ascorbic acid, a geroprotective compound, counteracted the pro-senescent effect of CHIT1 and mitigated motor neuron senescence in aged monkeys. Our findings provide the single-cell resolution cellular and molecular landscape of the aged primate spinal cord and identify a new biomarker and intervention target for spinal cord degeneration.

A single-cell transcriptomic atlas of exercise-induced anti-inflammatory and geroprotective effects across the body.

Exercise benefits the whole organism, yet, how tissues across the body orchestrally respond to exercise remains enigmatic. Here, in young and old mice, with or without exercise, and exposed to infectious injury, we characterized the phenotypic and molecular adaptations to a 12-month exercise across 14 tissues/organs at single-cell resolution. Overall, exercise protects tissues from infectious injury, although more effectively in young animals, and benefits aged individuals in terms of inflammaging suppression and tissue rejuvenation, with structural improvement in the central nervous system and systemic vasculature being the most prominent. In vascular endothelial cells, we found that readjusting the rhythmic machinery via the core circadian clock protein BMAL1 delayed senescence and facilitated recovery from infectious damage, recapitulating the beneficial effects of exercise. Our study underscores the effect of exercise in reconstituting the youthful circadian clock network and provides a foundation for further investigating the interplay between exercise, aging, and immune challenges across the whole organism.

The activation of spliced X-box binding protein 1 by isorhynchophylline therapy improves diabetic encephalopathy.

The primary symptom of diabetic encephalopathy (DE), a kind of central diabetic neuropathy caused by diabetes mellitus (DM), is cognitive impairment. In addition, the tetracyclic oxindole alkaloid isorhynchophylline (IRN) helps lessen cognitive impairment. However, it is still unclear how IRN affects DM and DE and what mechanisms are involved. The effectiveness of IRN on brain insulin resistance was carefully examined in this work, both in vitro and in vivo. We found that IRN accelerates spliced form of X-box binding protein 1 (sXBP1) translocation into the nucleus under high glucose conditions in vitro. IRN also facilitates the nuclear association of pCREB with sXBP1 and the binding of regulatory subunits of phosphatidylinositol 3-kinase (PI3K) p85α or p85ß with XBP1 to restore high glucose impairment. Also, IRN treatment improves high glucose-mediated impairment of insulin signaling, endoplasmic reticulum stress, and pyroptosis/apoptosis by depending on sXBP1 in vitro. In vivo studies suggested that IRN attenuates cognitive impairment, ameliorating peripheral insulin resistance, activating insulin signaling, inactivating activating transcription factor 6 (ATF6) and C/EBP homology protein (CHOP), and mitigating pyroptosis/apoptosis by stimulation of sXBP1 nuclear translocation in the brain. In summary, these data indicate that IRN contributes to maintaining insulin homeostasis by activating sXBP1 in the brain. Thus, IRN is a potent antidiabetic agent as well as an sXBP1 activator that has promising potential for the prevention or treatment of DE.

Discovery of 4-methoxy-N-(1-naphthyl)benzenesulfonamide derivatives as small molecule dual-target inhibitors of tubulin and signal transducer and activator of transcription 3 (STAT3) based on ABT-751.

Overexpressed tubulin and continuously activated STAT3 play important roles in the development of many cancers and are potential therapeutic targets. A series of 4-methoxy-N -(1-naphthalene) benzenesulfonamide derivatives were designed and optimized based on ß-tubulin inhibitor ABT-751 to verify whether STAT3 and tubulin dual target inhibitors have better antitumor effects. Compound DL14 showed strong inhibitory activity against A549, MDA-MB-231 and HCT-116 cells in vitro with IC50 values of 1.35 µM, 2.85 µM and 3.04 µM, respectively. Further experiments showed that DL14 not only competitively bound to colchicine binding site to inhibit tubulin polymerization with IC50 values 0.83 µM, but also directly bound to STAT3 protein to inhibit STAT3 phosphorylation with IC50 value of 6.84 µM. Three other compounds (TG03, DL15, and DL16) also inhibit this phosphorylation. In terms of single target inhibition, DL14 is slightly inferior to positive drugs, but it shows a good anti-tumor effect in vivo, and can inhibit >80% of xenograft tumor growth. This study describes a novel 4-methoxy-N-(1-naphthyl) benzenesulfonamide skeleton as an effective double-targeted anticancer agent targeting STAT3 and tubulin.

Discovery of N-substituted sulfamoylbenzamide derivatives as novel inhibitors of STAT3 signaling pathway based on Niclosamide.

Signal transducer and activator of transcription 3 (STAT3) has been confirmed as an attractive therapeutic target for cancer therapy. Herein, we designed and synthesized a series of N-substituted Sulfamoylbenzamide STAT3 inhibitors based on small-molecule STAT3 inhibitor Niclosamide. Compound B12, the best active compound of this series, was identified as an inhibitor of IL-6/STAT3 signaling with an IC50 of 0.61-1.11 µM in MDA-MB-231, HCT-116 and SW480 tumor cell lines with STAT3 overexpression, by inhibiting the phosphorylation of STAT3 of Tyr705 residue and the expression of STAT3 downstream genes, inducing apoptosis and inhibiting the migration of cancer cells. Furthermore, in vivo study revealed that compound B12 suppressed the MDA-MB-231 xenograft tumor growth in nude mice at the dose of 30 mg/kg (i.g.), which has better antitumor activity than the positive control Niclosamide. More importantly, B12 is an orally bioavailable anticancer agent as a promising candidate for further development.

Hydrogen sulphide ameliorates dopamine-induced astrocytic inflammation and neurodegeneration in minimal hepatic encephalopathy.

It has been demonstrated that the action of dopamine (DA) could enhance the production of tumour necrosis factor-α (TNF-α) by astrocytes and potentiate neuronal apoptosis in minimal hepatic encephalopathy (MHE). Recently, sodium hydrosulfide (NaHS) has been found to have neuroprotective properties. Our study addressed whether NaHS could rescue DA-challenged inflammation and apoptosis in neurons to ameliorate memory impairment in MHE rats and in the neuron and astrocyte coculture system. We found that NaHS suppressed DA-induced p65 acetylation, resulting in reduced TNF-α production in astrocytes both in vitro and in vivo. Furthermore, decreased apoptosis was observed in neurons exposed to conditioned medium from DA + NaHS-challenged astrocytes, which was similar to the results obtained in the neurons exposed to TNF-α + NaHS, suggesting a therapeutic effect of NaHS on the suppression of neuronal apoptosis via the reduction of TNF-α level. DA triggered the inactivation of p70 S6 ribosomal kinase (S6K1) and dephosphorylation of Bad, resulting in the disaggregation of Bclxl and Bak and the release of cytochrome c (Cyt. c), and this process could be reversed by NaHS administration. Our work demonstrated that NaHS attenuated DA-induced astrocytic TNF-α release and ameliorated inflammation-induced neuronal apoptosis in MHE. Further research into this approach may uncover future potential therapeutic strategies for MHE.

Discovery of 4,6-pyrimidinediamine derivatives as novel dual EGFR/FGFR inhibitors aimed EGFR/FGFR1-positive NSCLC.

FGF2-FGFR1 autocrine pathway activation reduces the sensitivity of non-small cell lung cancer (NSCLC) cells to EGFR inhibitors like Gefitinib. Therefore, dual-specific drugs targeting EGFR and FGFR with high selectivity and activity are required. Through structure analysis of excellent EGFR inhibitors and FGFR inhibitors, we designed and synthesized 33 4,6-pyrimidinediamine derivatives as dual EGFR and FGFR inhibitors and selected BZF 2 as a potential EGFR and FGFR inhibitor after initial cell screening. Then, through kinase testing and western blot analysis, BZF 2 was defined as a dual EGFR and FGFR inhibitor with high selectivity 1and activity. Biological evaluation of NSCLC cell lines with the FGF2-FGFR1 autocrine loop indicated that BZF 2 significantly inhibited cell proliferation (IC50 values for H226 and HCC827 GR were 2.11 µM, and 0.93 µM, respectively), cell migration, and induced cell apoptosis and cell cycle arrest. Anti-tumor activity test in vivo showed that BZF 2 obviously shrank tumor size. Therefore, BZF 2 is a highly selective and potent dual EGFR/FGFR compound with promising therapeutic effects against EGFR/FGFR1-positive NSCLC.

Design, synthesis and activity of novel 2,6-disubstituted purine derivatives, potential small molecule inhibitors of signal transducer and activator of transcription 3.

Sustained activation of STAT3 is closely related to the cancer development, but the inhibitors for STAT3 overexpression are still in the clinical research stage. In this study, a series of 2,6-disubstituted purine derivatives were designed and synthesized, and their biological activities, as small molecule inhibitors of STAT3, were assessed. Compound PD26-TL07 exhibited remarkable antiproliferative activity against three cancer cell lines (IC50 values for HCT-116, SW480 and MDA-MB-231 were 1.77 ±â€¯0.35, 1.51 ±â€¯0.19, and 1.25 ±â€¯0.38 µM, respectively). Moreover, detailed biological assays revealed that PD26-TL07 could effectively inhibited STAT3 phosphorylation, and had little inhibition to others'. The newly discovered PD26-TL07 displayed an expecting anticancer effect both in vitro and in vivo. The molecular docking models revealed that PD26-TL07 could bind to the SH2 domain of STAT3. Three additional compounds (PD26-BZ01, PD26-TL03 and PD26-AS06) were also able to inhibit this phosphorylation. This study described novel 2,6-disubstituted purine derivatives as potent anticancer agents targeting STAT3.

Radar Emitter Recognition Based on the Energy Cumulant of Short Time Fourier Transform and Reinforced Deep Belief Network.

To cope with the complex electromagnetic environment and varied signal styles, a novel method based on the energy cumulant of short time Fourier transform and reinforced deep belief network is proposed to gain a higher correct recognition rate for radar emitter intra-pulse signals at a low signal-to-noise ratio. The energy cumulant of short time Fourier transform is attained by calculating the accumulations of each frequency sample value with the different time samples. Before this procedure, the time frequency distribution via short time Fourier transform is processed by base noise reduction. The reinforced deep belief network is proposed to employ the input feature vectors for training to achieve the radar emitter recognition and classification. Simulation results manifest that the proposed method is feasible and robust in radar emitter recognition even at a low SNR.

Design, synthesis and biological evaluation of 4-bromo-N-(3,5-dimethoxyphenyl)benzamide derivatives as novel FGFR1 inhibitors for treatment of non-small cell lung cancer.

A series of 4-bromo-N-(3,5-dimethoxyphenyl)benzamide derivatives were designed and synthesised as novel fibroblast growth factor receptor-1 (FGFR1) inhibitors. We found that one of the most promising compounds, C9, inhibited five non-small cell lung cancer (NSCLC) cell lines with FGFR1 amplification, including NCI-H520, NCI-H1581, NCI-H226, NCI-H460 and NCI-H1703. Moreover, the IC50 values for the compound C9 were 1.36 ± 0.27 µM, 1.25 ± 0. 23 µM, 2.31 ± 0.41 µM, 2.14 ± 0.36 µM and 1.85 ± 0.32 µM, respectively. The compound C9 arrested the cell cycle at the G2 phase in NSCLC cell lines. The compound C9 also induced cellular apoptosis and inhibited the phosphorylation of FGFR1, PLCγ1 and ERK in a dose-dependent manner. In addition, molecular docking experiments showed that compound C9 binds to FGFR1 to form six hydrogen bonds. Taken together, our data suggested that the compound C9 represented a promising lead compound-targeting FGFR1.

Design, synthesis and ability of non-gold complexed substituted purine derivatives to inhibit LPS-induced inflammatory response.

In order to study the anti-inflammatory activity of novel 6-substituted and 6,9-disubstituted purine derivatives, 20 compounds, L1-10 and W1-10, derived from purine and lacking a gold complex were designed, synthesized and their anti-inflammatory activity was screened. LPS-induced TNF-α, IL-1ß, IL-6, PGE2, NO, COX-2 and iNOS mRNA were evaluated, and western blot and NF-κB p65 translocation assay were performed in RAW 264.7 macrophages. Furthermore, carrageenan-induced hind paw edema experiments were performed in mice. Compound L1, L4, W2, and W4 markedly exerted a dose-dependent inhibition of TNF-α, IL-1ß, IL-6 and PGE2 release induced by LPS in RAW 264.7 macrophages. Moreover, these compounds strongly inhibited LPS-induced NO, COX-2 and iNOS mRNA in the same cells. Anti-inflammatory activity tests in vivo showed that L1 and L4 were more effective than Au(L3)(PPh3), a known anti-inflammatory agent, at 2-5 h, and W4 was the most effective at 3-5 h after dosing. Thus, W2, W4, and L1, L4, could effectively inhibit LPS-induced inflammatory response in vitro and in vivo suggesting a promising role as anti-inflammatory agents.

Baicalin reverses the impairment of synaptogenesis induced by dopamine burden via the stimulation of GABAAR-TrkB interaction in minimal hepatic encephalopathy.

BACKGROUND: It has been reported that D1 receptor (D1R) activation reduces GABAA receptor (GABAAR) current, and baicalin (BAI) displays therapeutic efficacy in diseases involving cognitive impairment. METHODS: We investigated the mechanisms by which BAI could improve DA-induced minimal hepatic encephalopathy (MHE) using immunoblotting, immunofluorescence, and co-immunoprecipitation. RESULTS: BAI did not induce toxicity on the primary cultured neurons. And no obvious toxicity of BAI to the brain was found in rats. DA activated D1R/dopamine and adenosine 3'5'-monophosphate-regulated phospho-protein (DARPP32) to reduce the GABAAR current; BAI treatment did not change the D1R/DARPP32 levels but blocked DA-induced reduction of GABAAR levels in primary cultured neurons. DA decreased the interaction of GABAAR with TrkB and the expression of downstream AKT, which was blocked by BAI treatment. Moreover, BAI reversed the decrease in the expression of GABAAR/TrkB/AKT and prevented the impairment of synaptogenesis and memory deficits in MHE rats. CONCLUSIONS: These results suggest that BAI has neuroprotective and synaptoprotective effects on MHE which are not related to upstream D1R/DARPP32 signaling, but to the targeting of downstream GABAAR signaling to TrkB.

Dopamine induces glutamate accumulation in astrocytes to disrupt neuronal function leading to pathogenesis of minimal hepatic encephalopathy.

Minimal hepatic encephalopathy (MHE) is induced by elevated intracranial dopamine (DA). Glutamate (Glu) toxicity is known to be involved in many neurological disorders. In this study, we investigated whether DA increased Glu levels and collaborated with Glu to impair memory. We found that DA upregulated TAAR1, leading to reduced EAAT2 expression and Glu clearance in primary cortical astrocytes (PCAs). High DA increased TAAR1 expression, and high Glu increased AMPAR expression, inducing the activation of CaN/NFAT signaling and a decrease in the production of BDNF (Brain Derived Nerve Growth Factor)/NT3 (neurotrophin-3) in primary cortical neurons (PCNs). DA activated TAAR1 to downregulate EAAT2 and increase extracellular Glu levels in MHE. Additionally, DA together with Glu caused decreased production of neuronal BDNF/NT3 and memory impairment through the activation of CaN/NFAT signaling in MHE. From these findings, we conclude that DA increases Glu levels via interaction with TAAR1 and disruption of EAAT2 signaling in astrocytes, and DA interacting with TAAR1 and Glu interacting with AMPAR synergistically decreased the production of BDNF by activation of CaN/NFAT signaling to impair memory in MHE rats.

DA Negatively Regulates IGF-I Actions Implicated in Cognitive Function via Interaction of PSD95 and nNOS in Minimal Hepatic Encephalopathy.

Insulin-like growth factor I (IGF-I) has been positively correlated with cognitive ability. Cognitive decline in minimal hepatic encephalopathy (MHE) was shown to be induced by elevated intracranial dopamine (DA). The beneficial effect of IGF-I signaling in MHE remains unknown. In this study, we found that IGF-I content was reduced in MHE rats and that IGF-I administration mitigated cognitive decline of MHE rats. A protective effect of IGF-I on the DA-induced interaction between postsynaptic density protein 95 (PSD95) and neuronal nitric oxide synthase (nNOS) was found in neurons. Ribosomal S6 protein kinase (RSK) phosphorylated nNOS in response to IGF-I by recruiting extracellular signal-regulated kinase (ERK1/2). In turn, DA inactivated the ERK1/2/RSK pathway and stimulated the PSD95-nNOS interaction by downregulating IGF-I. Inhibition of the interaction between PSD95 and nNOS ameliorated DA-induced memory impairment. As DA induced deficits in the ERK1/2/RSK pathway and the interaction between PSD95 and nNOS in MHE brains, IGF-I administration exerted a protective effect via interruption of the interaction between PSD95 and nNOS. These results suggest that IGF-I antagonizes DA-induced cognitive loss by disrupting PSD95-nNOS interactions in MHE.