Novel mechanisms of Anshen Dingzhi prescription against PTSD: Inhibiting DCC to modulate synaptic function and inflammatory responses.

ETHNOPHARMACOLOGICAL RELEVANCE: Anshen Dingzhi prescription (ADP), documented in "Yi Xue Xin Wu", is a famous prescription for treating panic-related mental disorders such as post-traumatic stress disorder (PTSD). However, the underlying mechanism remains unclear. AIM OF THE STUDY: This study aimed to investigate the mechanisms by which ADP intervened in PTSD-like behaviors. METHODS: A mouse model of single prolonged stress (SPS) was established to evaluate the ameliorative effects and mechanisms of ADP on PTSD. Behavioral tests were used to assess PTSD-like behaviors in mice; transmission electron microscopy was used to observe changes in the ultrastructure of hippocampal synapses, and western blot, immunofluorescence, and ELISA were used to detect the expression of hippocampal deleted in colorectal cancer (DCC) and downstream Ras-related C3 botulinum toxin substrate 1 (Rac1) - P21-activated kinase 1 (PAK1) signal, as well as levels of synaptic proteins and inflammatory factors. Molecular docking technology simulated the binding of potential brain-penetrating components of ADP to DCC. RESULTS: SPS induced PTSD-like behaviors in mice and increased expression of hippocampal netrin-1 (NT-1) and DCC on the 14th day post-modeling, with concurrent elevation in serum NT-1 levels. Simultaneously, SPS also decreased p-Rac1 level and increased p-PAK1 level, the down-stream molecules of DCC. Lentiviral overexpression of DCC induced or exacerbated PTSD-like behaviors in control and SPS mice, respectively, whereas neutralization antibody against NT-1 reduced DCC activation and ameliorated PTSD-like behaviors in SPS mice. Interestingly, downstream Rac1-PAK1 signal was altered according to DCC expression. Moreover, DCC overexpression down-regulated N-methyl-d-aspartate (NMDA) receptor 2A (GluN2A) and postsynaptic density 95 (PSD95), up-regulated NMDA receptor 2B (GluN2B) and increased neuroinflammatory responses. Administration of ADP (36.8 mg/kg) improved PTSD-like behaviors in the SPS mice, suppressed hippocampal DCC, and downstream Rac1-PAK1 signal, upregulated GluN2A and PSD95, downregulated GluN2B, and reduced levels of inflammatory factors NOD-like receptor protein 3 (NLRP3), nuclear factor kappa-B (NF-κB) and interleukin-6 (IL-6). Importantly, DCC overexpression could also reduce the ameliorative effect of ADP on PTSD. Additionally, DCC demonstrated a favorable molecular docking pattern with the potential brain-penetrating components of ADP, further suggesting DCC as a potential target of ADP. CONCLUSION: Our data indicate that DCC is a key target for the regulation of synaptic function and inflammatory response in the onset of PTSD, and ADP likely reduces DCC to prevent PTSD via modulating downstream Rac1-PAK1 pathway. This study provides a novel mechanism for the onset of PTSD and warrants the clinical application of ADP.

Shenqi Yizhi prescription prevents AßO-induced memory impairment in mice by regulating the contractility of brain pericytes.

BACKGROUND: Cerebral microcirculation disturbance manifested by decrease of cerebral blood flow (CBF) is one of early features of Alzheimer's disease (AD). Shenqi Yizhi prescription (SQYZ) is widely used in the treatment of AD. However, the effect of SQYZ on the early feature of AD is not clarified. PURPOSE: To explore the effect and mechanism of SQYZ on AD-like behavior from the perspective of early pathological features of AD. METHODS: The fingerprint of SQYZ was established by ultra-high-performance liquid chromatograph. The improvement effect of SQYZ on Aß1-42 Oligomer (AßO)-induced AD-like behavior of mice was evaluated by behavioral test. The changes of CBF were detected by laser doppler meter and laser speckle imaging. The pathological changes of the hippocampus were observed by HE staining and transmission electron microscope. The expressions of intercellular communication molecules were detected by western blotting or immunofluorescence staining. The content of platelet-derived growth factor-BB (PDGF-BB) was detected by ELISA. Finally, the core components of SQYZ were docked with platelet-derived growth factor receptor beta (PDGFRß) using AutoDock Vina software. RESULTS: The similarity of the components in SQYZ extracted from different batches of medicinal materials was higher than 0.9. SQYZ administration could improve AßO-induced memory impairment and CBF reduction. Compared with the sham group, the number of neurons in the hippocampi of AßO group was significantly reduced, and the microvessels were shrunken and deformed. By contrary, SQYZ administration mitigated those pathological changes. Compared with the sham mice, the expressions of CD31, N-cadherin, PDGFRß, glial fibrillary acidic protein, phosphorylation of focal adhesion kinase, integrin ß1, and integrin α5 in the hippocampi of AßO mice were significantly increased. However, SQYZ administration significantly reduced AßO-induced expression of those proteins. Interestingly, the effect of PDGFRß inhibitor, sunitinib demonstrated a consistent modulating effect as SQYZ. Finally, the brain-entering components of SQYZ, including ginsenoside Rg5, coptisine, cryptotanshinone, dihydrotanshinone IIA, stigmasterol, and tanshinone IIA had high binding force with PDGFRß, implicating PDGFRß as a potential target for SQYZ. CONCLUSIONS: Our data indicate that SQYZ improves CBF in AßO-triggered AD-like mice through inhibiting brain pericyte contractility, indicating the treatment potential of SQYZ for AD at the early stage.

The relationship between glycemic risk and longitudinal changes in total physiological atherosclerotic burden in patients with coronary artery disease.

Background: The effects of glycemic status on coronary physiology have not been well evaluated. This study aimed to investigate changes in coronary physiology by using angiographic quantitative flow ratio (QFR), and their relationships with diabetes mellitus (DM) and glycemic control status. Methods: This retrospective cohort study included 530 patients who underwent serial coronary angiography (CAG) measurements between January 2016 and December 2021 at Tongji Hospital of Tongji University. Based on baseline and follow-up angiograms, 3-vessel QFR (3V-QFR) measurements were performed. Functional progression of coronary artery disease (CAD) was defined as a change in 3V-QFR (Δ3V-QFR = 3V-QFRfollow-up - 3V-QFRbaseline) ≤-0.05. Univariable and multivariable logistic regression analyses were applied to identify the independent predictors of coronary functional progression. Subgroup analysis according to diabetic status was performed. Results: During a median interval of 12.1 (10.6, 14.3) months between the two QFR measurements, functional progression was observed in 169 (31.9%) patients. Follow-up glycosylated hemoglobin (HbA1c) was predictive of coronary functional progression with an area under the curve (AUC) of 0.599 [95% confidence interval (CI): 0.546-0.651; P<0.001] in the entire population. Additionally, the Δ3V-QFR values were significantly lower in diabetic patients with HbA1c ≥7.0% compared to those with well-controlled HbA1c or non-diabetic patients [-0.03 (-0.09, 0) vs. -0.02 (-0.05, 0.01) vs. -0.02 (-0.05, 0.02); P=0.002]. In a fully adjusted multivariable logistics analysis, higher follow-up HbA1c levels were independently associated with progression in 3V-QFR [odds ratio (OR), 1.263; 95% CI: 1.078-1.479; P=0.004]. Furthermore, this association was particularly strong in diabetic patients (OR, 1.353; 95% CI: 1.082-1.693; P=0.008) compared to patients without DM. Conclusions: Among patients with established CAD, on-treatment HbA1c levels were independently associated with progression in physiological atherosclerotic burden, especially in patients with DM.

Automated and ultrasensitive point-of-care glycoprotein detection using boronate-affinity enhanced organic electrochemical transistor patch.

Quantifying trace glycoproteins in biofluids requires ultrasensitive components, but feedback is not available in the current portable platforms of point-of-care (POC) diagnosis technologies. A compact and ultrasensitive bioelectrochemical patch was based on boronate-affinity amplified organic electrochemical transistors (BAAOECTs) for POC use was developed to overcome this dilemma. Benefit from the cascading signal enhancement deriving from boronate-affinity targeting multiple regions of glycoprotein and OECTs' inherent signal amplification capability, the BAAOECTs achieved a detection limit of 300 aM within 25 min, displaying about 3 orders of magnitude improvement in sensitivity compared with the commercial electrochemical luminescence (ECL) kit. By using a microfluidic chip, a microcontroller module, and a wireless sensing system, the testing workflows of the above patch was automated, allowing for running the sample-to-answer pipeline even in a resource-limited environment. The reliability of such portable biosensing platform is well recognized in clinical diagnostic applications of heart failure. Overall, the remarkable enhanced sensitivity and automated workflow of BAAOECTs biosensing platform provide a prospective and generalized design policy for expanding the POC diagnosis capabilities of glycoproteins.

Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?

BACKGROUND: Accumulation of amyloid beta, tau hyperphosphorylation, and microglia activation are the three highly acknowledged pathological factors of Alzheimer's disease (AD). However, oligodendrocytes (OLs) were also widely investigated in the pathogenesis and treatment for AD. AIMS: We aimed to update the regulatory targets of the differentiation and maturation of OLs, and emphasized the key role of OLs in the occurrence and treatment of AD. METHODS: This review first concluded the targets of OL differentiation and maturation with AD pathogenesis, and then advanced the key role of OLs in the pathogenesis of AD based on both clinic and basic experiments. Later, we extensively discussed the possible application of the current progress in the diagnosis and treatment of this complex disease. RESULTS: Molecules involving in OLs' differentiation or maturation, including various transcriptional factors, cholesterol homeostasis regulators, and microRNAs could also participate in the pathogenesis of AD. Clinical data point towards the impairment of OLs in AD patients. Basic research further supports the central role of OLs in the regulation of AD pathologies. Additionally, classic drugs, including donepezil, edaravone, fluoxetine, and clemastine demonstrate their potential in remedying OL impairment in AD models, and new therapeutics from the perspective of OLs is constantly being developed. CONCLUSIONS: We believe that OL dysfunction is one important pathogenesis of AD. Factors regulating OLs might be biomarkers for early diagnosis and agents stimulating OLs warrant the development of anti-AD drugs.

Exploring the effect of Anshen Dingzhi prescription on hippocampal mitochondrial signals in single prolonged stress mouse model.

HEADINGS ETHNOPHARMACOLOGICAL RELEVANCE: Anshen Dingzhi prescription (ADP), which was first published in the masterpiece of traditional Chinese Medicine in the Qing Dynasty, "Yi Xue Xin Wu" (1732 CE), is documented to interrupt panic-related disorders. However, the mechanism of its action is still not clear. AIM OF THE STUDY: This study aims to investigate the effects of ADP on post-traumatic stress disorder (PTSD)-like behaviors and explore the mechanism from perspective of sirtuin1 (SIRT1)-peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α)-dependent mitochondrial function. MATERIALS AND METHODS: The changes of SIRT1-PGC-1α signal and mitochondrial function were evaluated in the hippocampus of mice receiving single prolonged stress (SPS). Later, the roles of this signaling pathway played in fear memory generalization and anxiety-like behavior in SPS mice was investigated using two agonists of this signaling pathway. On this basis, the effects of ADP (36.8 mg/kg) with definite therapeutic effects, on mitochondrial function were investigated and further confirmed by a SIRT1 inhibitor. Finally, the possible components of ADP targeting PGC-1α were monitored through bioinformatics. RESULTS: Compared with control mice, SIRT1-PGC-1α signal in the hippocampus was impaired in SPS mice, accompanied with dysfunction of mitochondria and abnormal expression of synaptic proteins. The agonists of SIRT1-PGC-1α signal, ZLN005, as well as resveratrol improved the behavioral changes of mice caused by SPS, reversed the decline of proteins in SIRT1-PGC-1α signal, mitochondrial dysfunction, and the abnormal expression of synaptic proteins. The fingerprint was established for the quality control of ADP. At a dose of 36.8 mg/kg, ADP could prevent fear memory generalization and anxiety-like behavior in SPS mice. Mechanically, ADP promoted SIRT1-PGC-1α signal and repaired mitochondrial function. Importantly, SIRT1 inhibitor, selisistat eliminated the ameliorative effects of ADP on behavioral and mitochondrial function. Through molecular docking simulation, the brain-entering components of ADP, including malkangunin, Rg5, fumarine, frutinone A, celabenzine, and inermin had high binding energy with PGC-1α. CONCLUSION: Dysfunction of SIRT1-PGC-1α-dependent mitochondrial function is attributed to SPS-triggered fear generalization and anxiety-like behavior, and ADP could improve PTSD-like behaviors likely through activating this signaling pathway.

Astrocytes and Memory: Implications for the Treatment of Memory-related Disorders.

Memory refers to the imprint accumulated in the brain by life experiences and represents the basis for humans to engage in advanced psychological activities such as thinking and imagination. Previously, research activities focused on memory have always targeted neurons. However, in addition to neurons, astrocytes are also involved in the encoding, consolidation, and extinction of memory. In particular, astrocytes are known to affect the recruitment and function of neurons at the level of local synapses and brain networks. Moreover, the involvement of astrocytes in memory and memory-related disorders, especially in Alzheimer's disease (AD) and post-traumatic stress disorder (PTSD), has been investigated extensively. In this review, we describe the unique contributions of astrocytes to synaptic plasticity and neuronal networks and discuss the role of astrocytes in different types of memory processing. In addition, we also explore the roles of astrocytes in the pathogenesis of memory-related disorders, such as AD, brain aging, PTSD and addiction, thus suggesting that targeting astrocytes may represent a potential strategy to treat memory-related neurological diseases. In conclusion, this review emphasizes that thinking from the perspective of astrocytes will provide new ideas for the diagnosis and therapy of memory-related neurological disorders.

Prognostic Implications of Changes in Total Physiological Atherosclerotic Burden in Patients With Coronary Artery Disease-A Serial QFR Study.

The association between coronary physiological progression and clinical outcomes has not been investigated. A total of 421 patients who underwent serial coronary angiography at least 6 months apart were included. Total physiological atherosclerotic burden was characterized by sum of quantitative flow ratio in 3 epicardial vessels (3V-QFR). The relationships of the 3V-QFR and its longitudinal change (△3V-QFR) with major adverse cardiovascular events (MACE) were explored. 3V-QFR values derived from follow-up angiograms were slightly lower compared with baseline (2.85 [2.77, 2.90] vs 2.86 [2.80, 2.90], P < .001). The median △3V-QFR value was -0.01 (-0.05, 0.02). The multivariable models demonstrated that follow-up 3V-QFR and △3V-QFR were independently associated with MACE (both P < .05). Patients with both low follow-up 3V-QFR (≤2.78) and low △3V-QFR (≤-0.05) presented 3 times higher risk of MACE than those without (hazard ratio: 2.953, 95% confidence interval 1.428-6.104, P = .003). Furthermore, adding patient-level 3V-QFR and △3V-QFR to clinical model significantly improved the predictability for MACE. In conclusion, total physiological atherosclerotic burden and its progression can provide incremental prognostic value over clinical characteristics, supporting the use of coronary physiology in the evaluation of disease progression and for the identification of vulnerable patients.

Effects of electroacupuncture on the microvascular structure and related protein expression in the hippocampus of vascular dementia rats. / ç”µé’ˆå¯¹è¡€ç®¡æ€§ç—´å‘†å¤§é¼ æµ·é©¬å¾®è¡€ç®¡ç»“æž„å’Œç›¸å ³è›‹ç™½è¡¨è¾¾çš„å½±å“.

OBJECTIVES: To explore the effect of electroacupuncture (EA) at "Baihui" (GV20) and "Shenting" (GV24) on the microvascular structure and related protein expression in the hippocampus of vascular dementia (VD) rat model, and to investigate the mechanism of EA in the treatment of VD. METHODS: A total of 24 SD rats were randomly divided into sham operation, model, EA, and oxiracetam groups, with 6 rats in each group. Multiple cerebral infarction method was used to establish VD model. In the EA group, EA was applied to GV20 and GV24 for 30 min, once daily for 14 days. Rats in the oxiracetam group were treated with oxiracetam (50 mg/kg) by intraperitoneal injection, and the course of treatment was the same as that in the EA group. Learning and memory ability were evaluated by using Morris water maze test and new object recognition experiment. The cerebral blood flow was detected by laser doppler. The microvascular structure in the hippocampus was observed by transmission electron microscopy. The expression of vascular structure related proteins of platelet-derived growth factor receptor (PDGFR)-ß, platelet endothelial cell adhesion molecule-1(CD31), neural cadherin N-Cadherin, Zonula occludens protein-1(ZO-1) in the hippocampus were measured by Western blot. RESULTS: Compared with the sham operation group, the rats in the model group had a significant increase in time of first crossing the platform, a significant decrease in the number of crossing platform and the new object preference index (P<0.05), a significant decrease in cerebral blood flow (P<0.05), and a significant increase in the brain weight (P<0.05). The structure boundary of pericyte and endothelial cells in the microvessels of the hippocampal CA1 area of model group was blurred, accompanied by obvious edema around the vessels and the reduction of tight junctions. The protein expression levels of PDGFR-ß, CD31, N-Cadherin, ZO-1 were significantly decreased in the model group compared with those in the sham operation group (P<0.05). Compared with the model group, the time of first crossing the platform of rats in the EA and oxiracetam group was shortened, the number of crossing platform were increased (P<0.05), the cerebral blood flow was increased (P<0.05), the brain weight was decreased (P<0.05), the morphology and structure of pericyte and endothelial cells in the microvessels of hippocampal CA1 area were intact, accompanied by the increase of tight junctions. Additionally, Compared with the model group, the EA group had a significant increase in the new object preference index (P<0.05), the protein expression levels of PDGFR-ß, CD31, ZO-1 in the EA group were increased (P<0.05), and the expression of PDGFR-ß, N-Cadherin, ZO-1 in the oxiracetam group were increased (P<0.05). CONCLUSIONS: EA at GV20 and GV24 can improve the learning and memory ability of VD rats, and the mechanism may be related to the repair of microvascular structures and improvement of cerebral blood flow.

Novel substituted 4-(Arylethynyl)-Pyrrolo[2,3-d]pyrimidines negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGlu5) Treat depressive disorder in mice.

In view of the fact that the G-protein-coupled receptors (GPCRs) sit at the top of the signaling pathways triggering a diverse range of signaling cascades towards a cellular event, GPCRs are regarded as central drug targets. mGlu5, a type of classical GPCRs, is highly expressed in the central nervous system (CNS) and responds to the neurotransmitter glutamate. Researches show that mGlu5 is a potential drug target for the treatment of depression. Up to now, multiple mGlu5 negative allosteric modulators (NAMs) have entered clinical trials, but no small molecule mGlu5 NAM has yet to reach market. Herein, we report the structural optimization and structure-activity relationship studies of a series of novel mGlu5 NAMs. Among them, the novel compound 10b is a high-affinity mGluR5 antagonist, with an IC50 value of 11.5 nM. Besides, we evaluated the anti-depressant effect of compound 10b using the chronic unpredictable mild stress (CUMS)-induced depression model. The data showed that the mice in CUMS group were featured by decreased level of serum 5-HT and increased level of serum CORT, and the expression of synaptic proteins were reduced, including GluA1, GluA2, p-PKA, BDNF and TrkB. However, those factors for identifying sensitivity to depression-like behaviors could be improved by compound 10b treatment. The preliminary toxicology evaluations indicated that compound 10b had a good safety profile in vivo. Collectively, the compound 10b represents a promising lead compound for the treatment of depressive disorder.

High urea induces anxiety disorders associated with chronic kidney disease by promoting abnormal proliferation of OPC in amygdala.

Chronic kidney disease (CKD) with anxiety disorder is of a great concern due to its high morbidity and mortality. Urea, as an important toxin in CKD, is not only a pathological factor for complications in patients with CKD, but also is accumulated in the brain of aging and neurodegenerative diseases. However, the pathological role and underlying regulatory mechanism of urea in CKD related mood disorders have not been well established. We previously reported a depression phenotype in mice with abnormal urea metabolism. Since patients with depression are more likely to suffer from anxiety, we speculate that high urea may be an important factor causing anxiety in CKD patients. In adenine-induced CKD mouse model and UT-B-/- mouse model, multiple behavioral studies confirmed that high urea induces anxiety-like behavior. Single-cell transcriptome revealed that down-regulation of Egr1 induced compensatory proliferation of oligodendrocyte progenitor cells (OPC). Myelin-related signaling pathways of oligodendrocytes (OL) were change significant in the urea accumulation amygdala. The study showed that high urea downregulated Egr1 with subsequent upregulation of ERK pathways in OPCs. These data indicate that the pathological role and molecular mechanism of high urea in CKD-related anxiety, and provide objective serological indicator and a potential new drug target for the prevention and treatment of anxiety in CKD patients.

Neurovascular glial unit: A target of phytotherapy for cognitive impairments.

BACKGROUND: Neurovascular glial unit (NVGU) dysfunction has been reported to be an early and critical event in the pathophysiology of Alzheimer's disease (AD) and vascular dementia (VD). Although herbal medicines, with their favorable safety profiles and low adverse effects, have been suggested to be useful for the treatment of cognitive impairment, the potential role of the NVGU as the target of the effects of herbal medicines is still unclear. PURPOSE: This review aimed to retrieve evidence from experimental studies of phytopharmaceuticals targeting the NVGU for the treatment of cognitive impairment in AD and VD, and discussed the potential of phytopharmaceuticals to improve cognitive impairment from the perspective of the NVGU. STUDY DESIGN AND METHODS: We systematically searched PubMed, Google Scholar, Web of Science, and CNKI. The keywords used for searching information on the NVGU in the treatment of cognitive impairments included "Alzheimer's disease," "Vascular dementia," "Herbal medicines," "Natural products," "Neurovascular," "Adverse reaction," and "Toxicity, etc." We selected studies on the basis of predefined eligibility criteria. RESULTS: NVGU mainly consists of endothelial cells, pericytes, astrocytes, microglia, oligodendrocytes, and neurons, and damage to these cells can induce cognitive impairment by impairing the blood-brain barrier (BBB) and cerebral blood flow (CBF) as well as neuronal function. The active components of herbal medicines, including Ginkgo biloba L., Ginseng Radix et Rhizoma, Epimedium Folium, Chuanxiong Rhizoma, Carthami flos, and Acorus tatarinowii Schott, as well as traditional Chinese medicine prescriptions have shown the potential to improve BBB function and increase CBF to prevent cognitive impairment by inhibiting astrocyte and microglia activation, protecting oligodendrocyte myelin function, reducing neuronal apoptosis, and promoting angiogenesis. CONCLUSIONS: Herbal medicines demonstrate great potential to prevent cognitive impairment. Multiple components from herbal medicines may function through different signaling pathways to target the NVGU. Future studies using novel drug-carrier or delivery systems targeting the NVGU will certainly facilitate the development of phytopharmaceuticals for AD and VD.

Phytotherapy of abnormality of fear memory: A narrative review of mechanisms.

It is generally believed that in post-traumatic stress disorder (PTSD), the high expression of fear memory is mainly determined by amygdala hyperactivity and hippocampus hypoactivity. In this review, we firstly updated the mechanisms of fear memory, and then searched the experimental evidence of phytotherapy for fear memory in the past five years. Based on the summary of those experimental studies, we further discussed the future research strategies of plant medicines, including the study of the mechanism of specific brain regions, the optimal time for the prevention and treatment of fear memory-related diseases such as PTSD, and the development of new drugs with active components of plant medicines. Accordingly, plant medicines play a clear role in improving fear memory abnormalities and have the drug development potential in the treatment of fear-related disorders.

Electroacupuncture in the treatment of IBS in rats: investigation of the mechanisms of CRH+ neurons in the paraventricular nucleus.

Electroacupuncture (EA) is well documented to treat irritable bowel syndrome (IBS). However, the mechanism of the central nervous system related to IBS and acupuncture stimulation is still not well known. In this study, a rat model of IBS was established by cold-restraint comprehensive stresses for 15 days, and it was found that the levels of corticotropin-releasing hormone (CRH), corticosterone (CORT), and adrenocorticotropic hormone (ACTH) in the peripheral serum were increased; the visceral sensitivity was enhanced; and the intestinal motility was accelerated, specifically, there was an enhancement in the discharge frequency of neurons in the paraventricular nucleus (PVN). EA treatment for 3 days, 20 min/day, alleviated the increase in the levels of CRH, CORT, and ACTH in the peripheral serum of rats, reduced the visceral sensitivity of IBS rats, and inhibited colon movement and discharge frequency of the neurons in the PVN. In addition, EA could reduce the excitability of CRH neurons and the expression of corticotropin-releasing hormone receptor 1 (CRHR1) and corticotropin-releasing hormone receptor 2 (CRHR2) in PVN. At the same time, the expression of CRH, CRHR1, and CRHR2 in the peripheral colon was decreased. Taken together, EA appears to regulate intestinal functional activity through the central CRH nervous system, revealing the central regulation mechanism of EA in IBS rats, and providing a scientific research basis for the correlation among the meridians, viscera, and brain.NEW & NOTEWORTHY The purpose of this research was to determine the central regulatory mechanism of electroacupuncture (EA) in rats with irritable bowel syndrome (IBS). Our results showed that combined with the serum changes in corticotropin-releasing hormone (CRH), corticosterone (CORT), and adrenocorticotropic hormone (ACTH), the improvement of IBS by EA was related to them. Furthermore, EA could regulate intestinal functional activity through the central CRH+ nervous system.

Screening of Potential Circulating Diagnostic Biomarkers and Molecular Mechanisms of Systemic Lupus Erythematosus-Related Myocardial Infarction by Integrative Analysis.

Background: The risk of acute myocardial infarction (AMI) is elevated in patients with systemic lupus erythematosus (SLE), and it is of great clinical value to identify potential molecular mechanisms and diagnostic markers of AMI associated with SLE by analyzing public database data and transcriptome sequencing data. Methods: AMI and SLE-related sequencing datasets GSE62646, GSE60993, GSE50772 and GSE81622 were downloaded from the Gene Expression Omnibus (GEO) database and divided into prediction and validation cohorts. To identify the key genes associated with AMI related to SLE, WGCNA and DEGs analysis were performed for the prediction and validation cohorts, respectively. The related signaling pathways were identified by GO/KEGG enrichment analysis. Peripheral blood mononuclear cells (PBMCs) from patients with AMI were collected for transcriptome sequencing to validate the expression of key genes in patients with AMI. Least absolute shrinkage and selection operator (LASSO) regression analysis was applied to screen diagnostic biomarkers. The diagnostic efficacy of biomarkers was validated by ROC analysis, and the CIBERSORTx platform was used to analyze the composition of immune cells in AMI and SLE. Results: A total of 108 genes closely related to AMI and SLE were identified in the prediction cohort, and GO/KEGG analysis showed significantly enriched signaling pathways. The results of differential analysis in validation cohort were consistent with them. By transcriptional sequencing of PBMCs from peripheral blood of AMI patients, combined with the results of prediction and validation cohort analysis, seven genes were finally screened out. LASSO analysis finally identifies DYSF, LRG1 and CSF3R as diagnostic biomarkers of SLE-related-AMI. CIBERSORTx analysis revealed that the biomarkers were highly correlated with neutrophils. Conclusion: Neutrophil degranulation and NETs formation play important roles in SLE-related AMI, and DYSF, LRG1 and CSF3R were identified as important diagnostic markers for the development and progression of SLE-related AMI.

Tenuifolin in the prevention of Alzheimer's disease-like phenotypes: Investigation of the mechanisms from the perspectives of calpain system, ferroptosis, and apoptosis.

Polygala tenuifolia was documented to calm the mind and promote wisdom. However, its underlying mechanisms are still unclear. This study aimed to investigate the mechanisms underlying the effects of tenuifolin (Ten) on Alzheimer's disease (AD)-like phenotypes. We first applied bioinformatics methods to screen the mechanisms of P. tenuifolia in the treatment of AD. Thereafter, the d-galactose combined with Aß1-42 (GCA) was applied to model AD-like behaviors and investigate the action mechanisms of Ten, one active component of P. tenuifolia. The data showed that P. tenuifolia actioned through multi-targets and multi-pathways, including regulation of synaptic plasticity, apoptosis, and calcium signaling, and so forth. Furthermore, in vitro experiments demonstrated that Ten prevented intracellular calcium overload, abnormal calpain system, and down-regulation of BDNF/TrkB signaling induced by GCA. Moreover, Ten suppressed oxidative stress and ferroptosis in HT-22 cells induced by GCA. Calpeptin and ferroptosis inhibitor prevented the decrease of cell viability induced by GCA. Interestingly, calpeptin did not interrupt GCA-induced ferroptosis in HT-22 cells but blocked the apoptosis. Animal experiments further demonstrated that Ten prevented GCA-induced memory impairment in mice and increased synaptic protein expression while reducing m-calpain expression. Ten prevents AD-like phenotypes through multiple signaling by inhibiting oxidative stress and ferroptosis, maintaining the stability of calpain system, and suppressing neuronal apoptosis.

Comprehensive analysis of atherosclerotic plaques reveals crucial genes and molecular mechanisms associated with plaque progression and rupture.

Background: Plaque rupture and acute atherothrombosis, resulting from continued progression of atherosclerotic plaques (APs), are major contributors to acute clinical events such as stroke or myocardial infarction. This article aimed to explore the gene signatures and potential molecular mechanisms in the progression and instability of APs and to identify novel biomarkers and interventional targets for AP rupture. Methods: The microarray data were downloaded from the Gene Expression Omnibus (GEO) database and grouped into discovery and validation cohorts. In the discovery cohort, Weighted Gene Co-Expression Network Analysis was performed for finding co-expression modules, and the Metascape database was used to perform functional enrichment analysis. Differential Expression Genes analysis subsequently was performed in the validation cohort for verification of the obtained results. Common genes were introduced into Metascape database for protein-protein interaction and functional enrichment analysis. We constructed the miRNAs-mRNAs network with the hub genes. Moreover, gene expression profiles of peripheral blood mononuclear cells (PBMCs) from peripheral blood of patients with plaque rupture were analyzed by high-throughput sequencing, and the diagnostic power of hub genes was verified by receiver operating characteristic (ROC) analysis. Results: In the discovery cohort, the brown module in GSE28829 and the turquoise module in GSE163154 were the most significant co-expression modules. Functional enrichment analysis of shared genes suggested that "Neutrophil degranulation" was the most significantly enriched pathway. These conclusions were also demonstrated by the validation cohort. A total of 16 hub genes were identified. The miRNA-mRNA network revealed that hsa-miR-665 and hsa-miR-512-3p might regulate the "Neutrophil degranulation" pathway through PLAU and SIRPA, which might play a significant role in AP progression and instability. Five hub genes, including PLAUR, FCER1G, PLAU, ITGB2, and SLC2A5, showed significantly increased expression in PBMCs from patients with plaque rupture compared with controls. ROC analysis finally identified three hub genes PLAUR, FCER1G, and PLAU that could effectively distinguish patients with APs rupture from controls. Conclusions: The present study demonstrated that the "neutrophil degranulation" signaling pathways and identified novel mRNA and miRNA candidates are closely associated with plaque progression and instability. The hub genes FCER1G, PLAUR, and PLAU may serve as biomarkers for the prospective prediction of AP rupture.

Ginsenoside Rg1 in neurological diseases: From bench to bedside.

Ginseng has been used in China as a superior medicinal material for thousands of years that can nourish the five internal organs, calm the mind and benefit wisdom. Due to its anti-inflammatory, antioxidant and neuroprotective activities, one of the active components of ginseng, ginsenoside Rg1, has been extensively investigated in the remedy of brain disorders, especially dementia and depression. In this review, we summarized the research progress on the action mechanisms of Rg1 ameliorating depression-like behaviors, including inhibition of hyperfunction of hypothalamic-pituitary-adrenal (HPA) axis, regulation of synaptic plasticity and gut flora. Rg1 may alleviate Alzheimer's disease in the early phase, as well as in the middle-late phases through repairing dendrite, axon and microglia- and astrocyte-related inflammations. We also proposed that Rg1 could regulate memory state (the imbalance of working and aversive memory) caused by distinct stimuli. These laboratory studies would further the clinical trials on Rg1. From the prospective of drug development, we discussed the limitations of the present investigations and proposed our ideas to increase permeability and bioavailability of Rg1. Taken together, Rg1 has the potential to treat neuropsychiatric disorders, but a future in-depth investigation of the mechanisms is still required. In addition, drug development will benefit from the clinical trials in one specific neuropsychiatric disorder.

Fear extinction induced by activation of PKA ameliorates anxiety-like behavior in PTSD mice.

Prolonged exposure (PE) therapy aiming to promote fear extinction is a useful treatment for post-traumatic stress disorder (PTSD). However, the mechanisms underlying fear extinction and effective methods used to promote fear extinction in PTSD are still lacking. In this study, we displayed dysfunctions of cyclic adenosine 3,5-monophosphate (cAMP)-protein kinase A (PKA), protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and calcium signaling in peripheral serum of PTSD patients using bioinformatics analysis. Later, we confirmed the dysfunctions of cAMP-PKA, AKT/mTOR and calcium signaling in the hippocampus of PTSD mice. Moreover, the reduction of calpain1 in the hippocampus enhanced fear memory acquisition. Single activation of PKA by systemic application of rolipram (ROL) or meglumine cyclic adenylate (M-cAMP) before re-exposure promoted fear extinction and improved anxiety-like behavior in PTSD mice. Moreover, systemic application of ROL before re-exposure improved hippocampal brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling and calpain1/AKT/mTOR signaling. Interestingly, the effects of activation of PKA could be partially blocked by TrkB antagonist, ANA-12 and mTOR inhibitor, RAPA. Finally, intranasal administration of ROL could also adjust the abnormality of fear memory and improve anxiety-like behaviors in PTSD mice. Collectively, activation of PKA could promote fear extinction, which correlated with the reduction of anxiety-like behavior. The mechanisms were related to the BDNF/TrkB and calpain1/AKT/mTOR signaling pathways. PKA activation might be a useful complementary therapy for PE in the symptom elimination of PTSD.

Curculigoside rescues hippocampal synaptic deficits elicited by PTSD through activating cAMP-PKA signaling.

Chronic traumatic stress results in various psychiatric disorders, especially posttraumatic stress disorder (PTSD). Previous study demonstrated that curculigoside (CUR) a component of Rhizoma Curculiginis prevented fear extinction and stress-induced depression-like behaviors. However, its effects on PTSD and the mechanisms are still not completely clear. In this study, we observed typical PTSD-like phenotypes, synaptic deficit, and reduction of BDNF/TrkB signaling pathway in mice receiving modified single prolonged stress and electrical stimulation (SPS&S). By contrast, systemic administration of CUR blocked PTSD-like phenotypes and synaptic deficits, including reduction of BDNF/TrkB signaling pathway, GluA1 and Arc expression. Importantly, CUR reversed the impairment of PKA signaling pathway elicited by PTSD. We further confirmed that the effects of CUR on synaptic function were through PKA signaling pathway, as H-89, an inhibitor of PKA blocked the effect of CUR on behavioral changes and BDNF/TrkB signaling pathway. Thereafter, we verified that CUR on synaptic function were through PKA pathway using direct intracerebral injection of CUR and H-89. Direct intracerebral injection of CUR activated PKA/CREB/BDNF/TrkB, which was blocked by H-89. Additionally, the docking results showed high binding energies of CUR with A2AR, AC, PRKACA, and PRKAR1A, which might indicate that CUR functions through regulating PKA signaling pathway. In conclusion, CUR prevented the behavioral changes and hippocampal synaptic deficits elicited by PTSD through activating cAMP-PKA signaling.