Anxiety disorder is a major symptom of autism spectrum disorder (ASD) with a comorbidity rate of ~40%. However, the neural mechanisms of the emergence of anxiety in ASD remain unclear. In our study, we found that hyperactivity of basolateral amygdala (BLA) pyramidal neurons (PNs) in Shank3 InsG3680 knock-in (InsG3680^+/+) mice is involved in the development of anxiety. Electrophysiological results also showed increased excitatory input and decreased inhibitory input in BLA PNs. Chemogenetic inhibition of the excitability of PNs in the BLA rescued the anxiety phenotype of InsG3680^+/+ mice. Further study found that the diminished control of the BLA by medial prefrontal cortex (mPFC) and optogenetic activation of the mPFC-BLA pathway also had a rescue effect, which increased the feedforward inhibition of the BLA. Taken together, our results suggest that hyperactivity of the BLA and alteration of the mPFC-BLA circuitry are involved in anxiety in InsG3680^+/+ mice.
Animals ; Prefrontal Cortex/metabolism* ; Basolateral Nuclear Complex/metabolism* ; Mice ; Anxiety/metabolism* ; Nerve Tissue Proteins/genetics* ; Male ; Gene Knock-In Techniques ; Pyramidal Cells/physiology* ; Mice, Transgenic ; Neural Pathways/physiopathology* ; Mice, Inbred C57BL ; Microfilament Proteins

Chronic pain, frequently comorbid with neuropsychiatric disorders, significantly impairs patients' quality of life and functional capacity. Accumulating evidence implicates the chemokine CCL2 and its receptor CCR2 as key players in chronic pain pathogenesis. This review examines the regulatory mechanisms of the CCL2/CCR2 axis in chronic pain processing at three hierarchical levels: (1) Peripheral Sensitization: CCL2/CCR2 modulates TRPV1, Nav1.8, and HCN2 channels to increase neuronal excitability and CGRP signaling and calcium-dependent exocytosis in peripheral nociceptors to transmit pain. (2) Spinal Cord Central Sensitization: CCL2/CCR2 contributes to NMDAR-dependent plasticity, glial activation, GABAergic disinhibition, and opioid receptor desensitization. (3) Supraspinal Central Networks: CCL2/CCR2 signaling axis mediates the comorbidity mechanisms of pain with anxiety and cognitive impairment within brain regions, including the ACC, CeA, NAc, and hippocampus, and it also increases pain sensitization through the descending facilitation system. Current CCL2/CCR2-targeted therapeutic strategies and their development status are discussed, highlighting novel avenues for chronic pain management.
Humans ; Chronic Pain/physiopathology* ; Animals ; Neuroglia/metabolism* ; Chemokine CCL2/metabolism* ; Receptors, CCR2/metabolism*

Peroxisome proliferator activated receptor-α (PPAR-α) is significantly expressed in various tissues such as the liver, kidney, myocardium, and skeletal muscle, which plays a central role in the development of various diseases by regulating key physiological processes such as energy homeostasis, redox balance, inflammatory response, and ferroptosis. As an important metabolic and excretory organ of the body, renal dysfunction can lead to water and electrolyte imbalance, toxin accumulation, and multiple system complications. The causes of kidney injury are complex and diverse, including acute injury factors (such as ischemia/reperfusion, nephrotoxic drugs, septic shock, and immune glomerulopathy), as well as chronic progressive causes [such as metabolic disease-related nephropathy, hypertensive nephropathy (HN)], and risk factors such as alcohol abuse, obesity, and aging. This review briefly describes the structure, function, and activity regulation mechanism of PPAR-α, systematically elucidates the molecular regulatory network of PPAR-α in the pathological process of kidney injury including acute kidney injury (AKI) such as renal ischemia/reperfusion injury (IRI), drug-induced AKI, sepsis-associated acute kidney injury (SA-AKI), glomerulonephritis, chronic kidney disease (CKD) such as diabetic nephropathy (DN), HN, and other kidney injury, and summarizes the mechanisms related to PPAR-α regulation of kidney injury, including regulation of metabolism, antioxidation, anti-inflammation, anti-fibrosis, and anti-ferroptosis. This review also evaluates PPAR-α's medical value as a novel therapeutic target, and aims to provide theoretical basis for the development of kidney protection strategies based on PPAR-α targeted intervention.
Humans ; PPAR alpha/metabolism* ; Acute Kidney Injury/therapy* ; Animals ; Kidney/metabolism*

The contents, application progress, application effect and optimization strategy of group pregnancy health care model were reviewed, in order to provide reference for the establishment of standardized intervention and health management practice strategies of rural women′s pregnancy care in line with China′s national conditions.

The interaction of gut microbiota and its metabolites with the host not only plays an important role in maintaining gut homeostasis and host health, but also is a key link in responding to pathogen infections. A thorough understanding of the changes in gut microbiota and its metabolites during infection, as well as their role and mechanism in host defense against infection, is helpful to guide anti-infection treatment. This review focuses on the role of gut microbiota and their metabolites in host defense against bacterial, fungal, and viral infections, and reveals that they can exert anti-infection effects through resistance mechanisms (inducing antimicrobial substances, training immunity, inhibiting pathogen respiration, directly neutralizing pathogens, immune regulation) and tolerance mechanisms (altering energy metabolism patterns of microbiota, cell proliferation and tissue damage repair, maintaining physiological signal transduction in extraintestinal organs, inflammation regulation, maintaining the integrity of the intestinal barrier), and also summarizes measures to regulate gut microbiota against pathogen infections, in order to provide more ideas for novel anti-infection prevention and treatment strategies targeting gut microbiota and its metabolites.

BackgroundNarrative exposure therapy （NET）， an integration of narrative therapy and exposure therapy， has been shown to be effective in relieving the symptoms of post-traumatic stress disorder （PTSD）， which can help patients gain a deeper understanding of their trauma and is also considered to be quite safe. PTSD is highly prevalent in children and adolescents， while the effectiveness of NET intervention varies among the subjects. ObjectiveTo systematically evaluate the effectiveness of NET for PTSD in children and adolescents， so as to provide references for the clinical application of NET. MethodsOn August 1， 2022， the Cochrane Library， PubMed， Web of Science， CINAHL， China National Knowledge Infrastructure （CNKI）， SinoMed， VIP and Wanfang database were searched from their inception to June 2022. Search was conducted with the use of a combination of medical subject heading and free text terms， and randomized controlled trials relevant to NET for PTSD in children and adolescents were collected. Then the quality of the controlled trials was evaluated according to the Cochrane Collaboration's tool for assessing risk of bias （2011）， and Meta-analysis was performed using RevMan 5.4 software. ResultsNine randomized controlled trials involving 394 children and adolescents with PTSD were included. Meta-analysis showed that NET and relaxation therapy reported comparable symptom relief in PTSD patients within 1 to 3 months after intervention （SMD=0.22， 95% CI： -0.84~1.28） and at 6 months after intervention （SMD=0.21， 95% CI： -0.75~1.17）， while NET provided greater PTSD symptom relief than routine therapy both within 1 to 3 months after intervention （SMD=-0.66， 95% CI： -1.04~-0.27） and at 6 months after intervention （SMD=-0.77， 95% CI： -1.36~-0.19）， with statistically significant differences. Regarding the alleviation of depressive symptoms， the effect was similar between NET and routine therapy within 1 to 3 months after intervention （SMD=-0.39， 95% CI： -0.98~0.21） and at 6 months after intervention （SMD=-0.74， 95% CI： -2.23~0.75）. No statistical difference was demonstrated between NET and routine therapy in relieving psychological distress （SMD=-0.54， 95% CI： -2.14~1.07） and suppressing hyperorexia （SMD=-0.17， 95% CI： -0.54~0.19） 1 to 3 months after intervention. ConclusionNET yields a better outcome and a medium- and long-term effectiveness in alleviating symptoms of PTSD in children and adolescents compared with routine therapy， while it does not offer any significant advantages in improving depression symptoms， psychological distress and hyperorexia.

Objective:To investigate the predictive value of differential distribution of peripheral lymphocyte subsets before and after the first 131I treatment on the therapeutic response to 131I treatment in patients with papillary thyroid cancer (PTC). Methods:A retrospective study was conducted on 46 PTC patients (16 males, 30 females, age 20-77 years) who underwent total thyroidectomy and received 131I treatment between January 2021 and August 2021 in First Hospital of Shanxi Medical University. Peripheral blood lymphocyte subsets (T, B, CD4 + T, CD8 + T, natural killer (NK), helper T (Th)1, Th2, Th17, and regulatory T (Treg) cells) were measured 1-2 d before and 30 d after 131I treatment. Based on serological and imaging evidence, therapeutic response at 6-12 months post- 131I therapy was categorized as either excellent response (ER) or non-excellent response (NER). Differences of preablative stimulated thyroglobulin (psTg) and clinical baseline characteristics between two groups were assessed by using independent-sample t test, paired t test, or Mann-Whitney U test. Predictive value of lymphocyte subsets before and after 131I treatment for therapeutic response was assessed through logistic regression analysis, ROC curve analysis, and decision curve analysis (DCA). Results:In ER group ( n=33) and NER group ( n=13), most lymphocyte subsets showed different degrees of reduction 30 d after 131I treatment compared to before 131I treatment, such as T, B, CD4 + T and Th1 cells in ER group, as well as T, B, CD4 + T, Th1, Th2, Th17, and Treg cells in NER group ( t values: 2.41-9.57, all P<0.05). Before 131I treatment, NER group had significantly higher levels of psTg, Th2, Th17, and Treg cells compared to the ER group ( t values: from -3.32 to -2.48, U=29.00, all P<0.05). After 131I treatment, most of lymphocyte subsets in NER group (T, B, CD4 + T, CD8 + T, Th1 and Treg cells) showed higher trend than those in ER group but without statistical significances ( t values: from -1.12 to -0.06, all P>0.05). Th2 cells before 131I treatment (odds ratio ( OR)=25.00, 95% CI: 1.36-459.10, P=0.030) was identified as a risk factor for NER. ROC curve analysis indicated that AUCs of psTg and Th2 cells for predicting therapeutic response were 0.932 and 0.790, respectively, which was 0.958 for the combined psTg and Th2 cells. DCA showed that within the threshold probability range of 10%-60%, the curves for psTg, Th2 cells, and the combined psTg and Th2 cells were all higher than the extreme curve, suggesting good effect. Conclusions:Most lymphocyte subsets decrease to varying degrees, and NER group shows a significant decrease 30 d after 131I treatment. Th2 cells may be a risk factor for poor response to 131I treatment, providing a certain value in predicting the therapeutic response to 131I treatment.

Objective:To explore the expression pattern of aryl hydrocarbon receptor (AhR) in mice peritoneal macrophages (PMs) after major trauma and analyze the effects of enhanced AhR expression on the inflammatory cytokine level and bactericidal ability after trauma.Methods:The experimental study method was used. Forty 6-8-week-old male C57BL/6J mice (the same mouse age, sex, and strain below) were divided into control group, post trauma hour (PTH) 2 group, PTH 6 group, and PTH 12 group according to the random number table (the same grouping method below), with 10 mice in each group. Mice in the latter 3 groups were constructed as severe trauma model with fracture+blood loss, while mice in control group were left untreated. The primary PMs (the same cells below) were extracted from the mice in control group, PTH 2 group, PTH 6 group, and PTH 12 group when uninjured or at PTH 2, 6, and 12, respectively. Then the protein and mRNA expressions of AhR were detected by Western blotting and real-time fluorescence quantitative reverse transcription polymerase chain reaction, respectively, and the gene expressions of AhR signaling pathway related molecules were analyzed by transcriptome sequencing. Twenty mice were divided into control group and PTH 6 group, with 10 mice in each group, and the PMs were extracted. The level of ubiquitin of AhR was detected by immunoprecipitation. Twelve mice were divided into dimethyl sulfoxide (DMSO) alone group, PTH 6+DMSO group, MG-132 alone group, and PTH 6+MG-132 group, with 3 mice in each group. After the corresponding treatment, PMs were extracted, and the protein expression of AhR was detected by Western blotting. Twenty mice were constructed as PTH 6 model. Then, the PMs were extracted and divided into empty negative control adenovirus (Ad-NC) group and AhR overexpression adenovirus (Ad-AhR) group. The protein expression of AhR was detected by Western blotting at 36 h after some PMs were transfected with the corresponding adenovirus. The rest cells in Ad-NC group were divided into Ad-NC alone group and Ad-NC+endotoxin/lipopolysaccharide (LPS) group, and the rest cells in Ad-AhR group were divided into Ad-AhR alone group and Ad-AhR+LPS group. The expressions of interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) in the cell supernatant were detected by enzyme-linked immunosorbent assay at 12 h after the corresponding treatment ( n=6). Twenty mice were obtained to extract PMs. The cells were divided into control+Ad-NC group, PTH 6+Ad-NC group, control+Ad-AhR group, and PTH 6+Ad-AhR group, and the intracellular bacterial load was detected by plate spread method after the corresponding treatment ( n=6). Data were statistically analyzed with one-way analysis of variance, least significant difference test, analysis of variance for factorial design, and independent sample t test. Results:Compared with 1.16±0.28 of control group, the protein expressions of AhR in PMs in PTH 2 group (0.59±0.14), PTH 6 group (0.72±0.16), and PTH 12 group (0.71±0.17) were all significantly decreased ( P<0.05). The overall comparison of the difference of AhR mRNA expression in PMs among control group, PTH 2 group, PTH 6 group, and PTH 12 group showed no statistical significance ( P>0.05). The AhR signaling pathway related molecules included AhR, AhR inhibitor, cytochrome P450 family member 1b1, cytochrome P450 family member 11a1, heat shock protein 90, aryl hydrocarbon receptor-interaction protein, and heat shock protein 70 interaction protein. The heat shock protein 90 expression of PMs in PTH 2 group was higher than that in control group, while the expressions of other molecules did not change significantly after trauma. Compared with that in control group, the level of ubiquitin of AhR in PMs in PTH 6 group was increased. Compared with that in DMSO alone group, the protein expression of AhR in PMs in PTH 6+DMSO group was decreased, while that in PMs in MG-132 alone group had no significant change. Compared with that in PTH 6+DMSO group, the protein expression of AhR in PMs in PTH 6+MG-132 group was up-regulated. At transfection hour 36, compared with that in Ad-NC group, the protein expression of AhR in PMs in Ad-AhR group was increased. At treatment hour 12, compared with those in Ad-NC+LPS group, the expressions of IL-6 and TNF-α in PM supernatant of Ad-AhR+LPS group were significantly decreased (with t values of 4.80 and 3.82, respectively, P<0.05). The number of intracellular bacteria of 1×10 6 PMs in control+Ad-NC group, PTH 6+Ad-NC group, control+Ad-AhR group, and PTH 6+Ad-AhR group was (3.0±1.8), (41.8±10.2), (1.8±1.2), and (24.2±6.3) colony forming unit, respectively. Compared with that in PTH 6+Ad-NC group, the number of intracellular bacteria of PMs in PTH 6+Ad-AhR group was significantly decreased ( t=3.61, P<0.05). Conclusions:Ubiquitin degradation of AhR in PMs of mice after major trauma results in decreased protein expression of AhR. Increasing the expression of AhR in post-traumatic macrophages can reduce the expressions of LPS-induced inflammatory cytokines IL-6 and TNF-α, and improve the bactericidal ability of macrophages after trauma.

PiT2 is an inorganic phosphate (Pi) transporter whose mutations are linked to primary familial brain calcification (PFBC). PiT2 mainly consists of two ProDom (PD) domains and a large intracellular loop region (loop7). The PD domains are crucial for the Pi transport, but the role of PiT2-loop7 remains unclear. In PFBC patients, mutations in PiT2-loop7 are mainly nonsense or frameshift mutations that probably cause PFBC due to C-PD1131 deletion. To date, six missense mutations have been identified in PiT2-loop7; however, the mechanisms by which these mutations cause PFBC are poorly understood. Here, we found that the p.T390A and p.S434W mutations in PiT2-loop7 decreased the Pi transport activity and cell surface levels of PiT2. Furthermore, we showed that these two mutations attenuated its membrane localization by affecting adenosine monophosphate-activated protein kinase (AMPK)- or protein kinase B (AKT)-mediated PiT2 phosphorylation. In contrast, the p.S121C and p.S601W mutations in the PD domains did not affect PiT2 phosphorylation but rather impaired its substrate-binding abilities. These results suggested that missense mutations in PiT2-loop7 can cause Pi dyshomeostasis by affecting the phosphorylation-regulated cell-surface localization of PiT2. This study helps understand the pathogenesis of PFBC caused by PiT2-loop7 missense mutations and indicates that increasing the phosphorylation levels of PiT2-loop7 could be a promising strategy for developing PFBC therapies.
Humans ; Cell Membrane ; Mutation, Missense ; Phosphates/metabolism* ; Sodium-Phosphate Cotransporter Proteins, Type III/genetics*

Objective To study the mechanism of Chaihu Guizhi Decoction(CGD)in the treatment of influenza and staphylococcus aureus co-infection.Methods The co-infection model of influenza and staphylococcus aureus was established and CGD was used to intervene.The chemical components of CGD were qualitatively analyzed by UPLC-Q-Exactive/MS technology.The potential action targets of chemical components in CGD and the related targets of influenza Staphylococcus aureus co-infection were mined by network pharmacology method.The"component target disease"network was constructed.Core targets were selected according to degree ranking.Core action pathways were enriched by KEGG analysis and GO annotation analysis.The core target was verified by RT-qPCR,and the interaction between the core component and the key target was verified by molecular docking.Results CGD could significantly improve the decrease of body weight and thymus index(P<0.05)caused by co-infection.The lung index(P<0.05),relative amount of MmRNA expression(P<0.05)and bacterial load(P<0.05)were decreased,and the survival rate was improved.51 chemical constituents were identified from CGD.Through network pharmacological analysis,107 related targets corresponding to CGD treatment of bacterial pneumonia secondary to influenza were excavated.TNF,AKT1,ALB,VEGFA,MAPK3,PTGS2,STAT3,EGFR and other targets with strong correlation,mainly involved Fc epsilon RI signal pathway,GnRH signal pathway,NF-κB signal path,etc.Molecular docking study showed that the main active component of CGD,including oroxyloside,baicalein and wogonin have strong affinity with TNF,PTGS2 and EGFR targets.Compared with co-infection model group,in CGD group TNF-α、EGFR and PTGS2 increased significantly(P<0.05).Conclusion The main active ingredient of CGD is oroxyloside,baicalein and wogonin.TNF-α,PTGS2,EGFR and other targets to played a role in the treatment of influenza staphylococcus aureus co-infection.