Diabetic foot ulcer (DFU) is a severe diabetes complication characterized by chronic inflammation and impaired wound healing. This study aimed to investigated Danggui Sini decoction's (DSD) mechanisms through network pharmacology, molecular docking, and molecular dynamics simulations. We identified143 common targets, with AKT1, IL6, and TNF are core targets involved in inflammation, and angiogenesis. Key active compounds, including quercetin, naringenin, and kaempferol, showed strong AKT1 binding affinities (-9.1, -8.7, and -8.2 kcal/mol, respectively). MD simulations showed that the binding of quercetin and naringenin increased AKT1 C-terminal flexibility, potentially modulating downstream signaling. These findings reveal the potential multi-target mechanisms of DSD for DFU treatment.

Background:Hepatic encephalopathy (HE) requires objective biomarkers for early diagnosis and mechanistic clarification. This study first integrates the Morphometric Inverse Divergence (MIND) network with graph theory to explore cerebral cortical morphological similarity and topological abnormalities in HE, cirrhotic non-HE (NHE), and healthy control (HC) groups. Methods:A total of 31 HE, 30 NHE patients and 30 HCs were enrolled for 3.0T magnetic resonance imaging (MRI) 3D-T1WI scanning. FreeSurfer was used for image preprocessing, and 5 cortical morphological features were extracted based on the Schaefer-400 atlas. MIND networks were constructed via symmetric Kullback-Leibler divergence, graph theory was applied to extract topological properties, and intergroup differences were analyzed by general linear model (GLM). Results:Compared with HCs, HE patients exhibited significantly elevated mean MIND values across multiple functional subnetworks, including the visual (VIS; t = 3.629, p = 0.004), default mode (DMN; t = 3.115, p = 0.009), limbic (LMB; t = 2.969, p = 0.009), frontoparietal (FPN; t = 2.917, p = 0.009), and ventral attention (VAN; t = 2.212, p = 0.043) networks. Graph theoretical analysis revealed increased global efficiency (Eglob, t = 2.681, p = 0.0100) and local efficiency (Eloc, t = 2.683, p = 0.010). NHE patients showed mild DMN connectivity enhancement in edge analysis, but no significant differences in subnetwork mean MIND and nodal metrics (all p > 0.05), exhibiting a non-significant transitional trend in efficiency indices between HE and HC groups. Conclusion:HE causes abnormal whole-brain cortical morphological covariance networks with enhanced connectivity and efficiency, and NHE has early-stage network alterations. MIND network indices are potential imaging biomarkers for HE diagnosis and monitoring, supplementing the neuropathological mechanism of HE and making up for the limitations of traditional structural covariance network research in HE.

Acute kidney injury (AKI) is driven by maladaptive tubular responses, yet upstream regulators remain incompletely understood. Here, we identify phosphatidylinositol 4-kinase alpha (Pi4ka) as a critical determinant of proximal tubule cell (PTC) homeostasis and injury progression. PI4KA expression was reduced in human diseased kidneys and negatively correlated with renal function. Single-cell RNA sequencing in mouse models revealed that Pi4ka deficiency preferentially perturbs specific PTC states, including Slc34a1+Ccn1+, and Slc34a1+Apob+ populations, which diverge along distinct maladaptive trajectories. From these trajectories we derived a 40-gene injury signature enriched for lysosome-associated pathways, and functional assays showed that lysosomal dysfunction is an early event linking Pi4ka loss to ER stress, impaired autophagy, and proteostasis disruption. Transcriptional network analysis identified Creb3l2 as a central regulator of lysosomal activation. Notably, Creb3l2 perturbation suppressed stress and cell-death programs while promoting transcriptional programs associated with repair and phospholipid metabolism. Ligand-receptor inference further indicated that Pi4ka-deficient PTCs shape a pro-inflammatory immune microenvironment via immunomodulatory gene activation, an effect abolished by Creb3l2 deletion. Collectively, these findings define a Pi4ka-lysosome-Creb3l2 axis that coordinates tubular injury, maladaptive remodeling, and immune activation, highlighting potential therapeutic targets to limit AKI progression.

[This corrects the article DOI: 10.3389/fneur.2025.1634369.].

Diabetic neuropathic pain (DNP) is a common and intractable complication of diabetes mellitus that is relatively poorly managed by current pharmacotherapies. The ventral posterolateral nucleus (VPL) is a key thalamic subnucleus involved in nociceptive transmission, but the role of VPL astrocytes in DNP remains unclear. In this study, we observed a significant increase in VPL astrocyte activity 14 days after injections of streptozotocin in male rats. Short-term inhibition of VPL astrocytes with designer receptors exclusively activated by designer drugs (DREADDs) alleviated mechanical allodynia in DNP model rats, whereas astrocyte activation induced mechanical allodynia in control rats. To further explore the therapeutic potential of the modulation of VPL astrocyte activity, we examined the effects of koumine (KM), an alkaloid derived from Gelsemium. Notably, KM administration not only alleviated mechanical allodynia but also attenuated VPL astrocyte hyperactivity in DNP model rats. Moreover, prolonged activation of VPL astrocytes via DREADDs induced chronic pain-like behaviours in control rats, while subsequent KM administration reversed mechanical allodynia. Importantly, compared with DREADD-induced inhibition alone, prolonged inhibition of VPL astrocytes via DREADDs combined with KM administration induced great antiallodynic effects in DNP model rats. Collectively, these findings demonstrate that VPL astrocyte activation leads to neuropathic pain, providing a novel strategy for DNP intervention, and support the use of KM as a potential clinical therapy for DNP.

Objective:Hepatic encephalopathy (HE) is linked to widespread gray matter abnormalities, but it remains unclear whether these changes follow the organizing principles of large-scale brain networks. This study examined the spatial distribution of gray matter abnormalities in HE and their relationships with brain network hubs, neighborhood connectivity, and disease epicenters. Methods:In this cross-sectional study, 45 patients with HE and 45 healthy controls underwent high-resolution T1-weighted MRI. Cortical thickness was extracted from 308 cortical regions using the Desikan-Killiany atlas, and volumes were measured from 14 subcortical structures. Group differences were analyzed controlling for age, sex, and total intracranial volume. Connectome-based analyses were based on normative functional and structural connectomes from the Human Connectome Project and assessed hub-related vulnerability, network-neighborhood effects, disease epicenters, and individual-level network patterns. Results:Patients with HE showed widespread gray matter abnormalities in the prefrontal, motor, temporal, and limbic cortices, as well as basal ganglia and thalamus, without significant alignment with normative functional or structural hubs. Structural neighborhood abnormalities were positively correlated with cortical changes (r = 0.58, P spin = 0.004), whereas functional neighborhoods were not. Functional-connectome epicenters were concentrated in the left inferior frontal gyrus, orbitofrontal cortex, and striatum, while structural-connectome epicenters centered on the bilateral superior frontal gyri and left inferior frontal gyrus. Individual analyses revealed heterogeneous epicenter patterns, with prefrontal-related regions repeatedly implicated. Conclusion:These findings suggest that gray matter abnormalities in HE are non-randomly organized, constrained by structural connectivity, and associated with prefrontal-centered disease epicenter networks, providing connectome-based insights into gray matter abnormalities in HE.

Purpose: This study aimed to evaluate the predictive value of inflammatory markers, particularly the neutrophil-to-platelet ratio (NPR), combined with clinical parameters for early mortality following mechanical thrombectomy (MT) in patients with large artery occlusive acute ischemic stroke (LAO-AIS), to guide timely clinical interventions. Patients and methods: This retrospective study analyzed 320 LAO-AIS patients who underwent MT between January 2023 and January 2025. Missing data (< 15%) were imputed. Boruta feature selection identified variables for multiple logistic regression. The dataset was randomly divided into training and test sets (7:3). A nomogram was constructed, and four machine learning algorithms-Decision Tree (DT), Extreme Gradient Boosting (XGBoost), Support Vector Machine (SVM), and Naive Bayes (NB)-were developed and validated. Results: Early mortality occurred in 67 cases. Multivariate analysis identified six independent predictors: standardized NPR (NPR_std; OR = 4.51, P < 0.001), age (OR = 1.10, P < 0.001), decompressive craniectomy (DC; OR = 0.19, P < 0.001), responsible artery location (OR = 0.34, P = 0.006), lymphocyte count (LYM; OR = 2.14, P = 0.008), and prothrombin time (PT; OR = 1.31, P = 0.011). The nomogram showed high reliability. XGBoost achieved superior predictive performance, with SHapley Additive exPlanations (SHAP) analysis confirming NPR_std as the most important predictor. Conclusion: The neutrophil-to-platelet ratio (NPR) is an independent predictor of early mortality after MT in LAO-AIS patients. The predictive model provides valuable guidance for clinicians to adjust treatment strategies early.

This study developed and externally validated a multicenter machine learning framework to predict 6-month poor functional outcome (modified Rankin Scale score ≥2) in patients with traumatic cerebral venous sinus thrombosis (tCVST) complicating moderate-to-severe traumatic brain injury. A retrospective cohort (n = 165, 2015-2020) and a prospective cohort (n = 78, 2020-2024) were assembled from three tertiary centers. Thirty-one admission variables underwent recursive feature elimination and LASSO regression, yielding nine key predictors. Five machine learning algorithms-support vector machine, logistic regression, random forest, extreme gradient boosting, and light gradient boosting machine (LightGBM)-were trained and optimized using nested five-fold cross-validation, with Borderline-Synthetic Minority Oversampling Technique applied to address class imbalance. Model performance was further assessed in the prospective cohort, and bootstrap resampling (2,000 iterations) was used to estimate confidence intervals. Among the evaluated models, LightGBM showed the best predictive performance, with an internal mean area under the receiver operating characteristic (ROC) curve of 0.91 ± 0.03 and an external validation area under the curve (AUC) of 0.86 (95% CI, 0.76-0.94), together with a sensitivity of 0.74, specificity of 0.86, and F1 score of 0.81. SHapley Additive exPlanations analysis was used to improve interpretability and quantify the contribution of individual predictors. In addition, an online risk calculator was developed to facilitate individualized risk estimation. These findings suggest that an explainable machine learning framework may provide useful support for early prognostic stratification in tCVST and may assist clinical decision-making in this complex neurotrauma population.

Chat Generative Pretrained Transformer (ChatGPT), a large language model developed by OpenAI, has shown potential in healthcare communication and patient education. However, its performance in specialized medical domains, such as pituitary adenomas (PAs), remains unclear. Therefore, this study aimed to evaluate the reliability and consistency of ChatGPT in answering PA-related questions. We hypothesized that ChatGPT would demonstrate high reliability in responding to general patient-oriented queries but lower reliability for specialized clinical questions. A total of 256 PA-related questions were collected from patients and families, clinical practice guidelines, and medical question banks. Each question was input into ChatGPT (GPT-4, March 2025 version), and the generated responses were independently reviewed by 2 senior neurosurgeons. Any discrepancies in their assessments were resolved by a third neurosurgeon with over 30 years of clinical experience. Responses were categorized as completely correct, partially correct but usable, partially correct, or incorrect. Responses rated as completely correct or partially correct but usable were considered reliable. Consistency was assessed based on the stability of response quality across similar question types. Comparisons were made by question type (general vs professional) and source using univariate analysis. Among the 256 responses, 143 (55.8%) were completely correct, 68 (26.6%) were partially correct but usable, 19 (7.4%) were partially correct, and 26 (10.2%) were incorrect. Overall, 82.4% of the responses were considered reliable, and 68.4% demonstrated consistency. Reliability was significantly higher for general questions than for professional ones (95.0% vs 78.6%, OR = 5.182, 95% CI: 1.545–17.378, P = .003), and for guideline-derived questions compared to question bank-derived ones (100.0% vs 75.7%, OR = 1.321, 95% CI: 1.214–1.437, P = .017). Differences in consistency across subgroups were not statistically significant. ChatGPT exhibits high reliability and moderate consistency in answering PA-related questions, especially for general and guideline-based content. It may serve as a supplementary source of patient information but should not replace professional medical consultation, particularly in complex or surgical contexts. As this study was conducted in an artificial testing environment without validation in real patient consultations, the generalizability of the findings remains limited.

Pituitary adenomas (PAs) are common intracranial tumours with heterogeneous behaviour. Accurate risk stratification is critical for predicting recurrence/progression and for guiding management. The pituitary adenoma nomenclature 3 (PANOMEN 3) classification, introduced in 2024, integrates clinical, radiological, and pathological factors; however, its prognostic utility and histopathological criteria remain uncertain. This multicentre retrospective cohort study included 804 patients with PAs surgically treated between January 2010 and December 2023. Patients were classified using the original PANOMEN 3 system and a modified system incorporating silent corticotroph adenomas (SCAs) as high-risk subtypes, revised proliferative activity criteria (Ki-67 ≥ 3

Sleep-onset insomnia, characterized by difficulty falling asleep, is linked to increased health risks. Previous studies have shown that the central amygdala (CeA) plays a crucial role in stress regulation, with the somatostatin neurons in the CeA (CeASST+) involved in adaptive stress responses. However, the role of CeASST+ neurons in stress-induced sleep-onset insomnia remains unclear. In this study, we found that the activity of CeASST+ neurons is closely associated with stressful events using fiber photometry in mice. Acute optogenetic activation of CeASST+ neurons induced a rapid transition from non-rapid eye movement (NREM) sleep to wakefulness. Semi-chronic optogenetic and chemogenetic activation of CeASST+ neurons led to prolonged sleep-onset latency and increased wakefulness. Chemogenetic inhibition of these neurons ameliorated sleep-onset insomnia induced by stressful stimuli, but did not affect sleep-wake behavior under physiological conditions. Collectively, our results suggested that CeASST+ neurons are a key neural substrate for modulating stress-induced sleep-onset insomnia, without influencing physiological sleep. These findings highlight CeASST+ neurons as a promising target for treating stress-related sleep-onset insomnia in clinical practice.

Background:In cerebrovascular diseases (CVD), the management strategies for ischemic stroke (IS) and cerebral venous thrombosis (CVT) have significant differences, but the underlying inflammation-driven mechanisms in these two conditions have not been fully translated into individualized intervention criteria. Methods:We searched PubMed, Embase, Web of Science and Cochrane Library through February 1, 2025, and included 18 eligible studies in a Bayesian network meta-analysis following PRISMA-NMA. The data were processed using Revman (version 5.4.1) and R (version 4.3.3). The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method was used to assess the quality of evidence. This study was registered in PROSPERO (CRD42024539498). Results:In total, 18 studies were included in the review. The results showed that acute-phase inflammatory markers were significantly elevated in both CVT and IS. CVT was associated with a relatively stronger systemic inflammatory response, while lymphocyte counts were reduced in both, suggesting a immunosuppressive phenomenon in cerebral thrombotic disease. This network Meta-Analysis showed that CRP (MD = 7.58, 95% CI: 2.48-14.09) and IL-6 (MD = 6.98, 95% CI: 2.75-11.44) were more significantly elevated in the acute phase in CVT patients than in IS patients, suggesting they could serve as key inflammatory markers for differentiating the two conditions. Conclusion:Inflammatory markers exhibit both specific differences and shared characteristics in CVT and IS. CRP and IL-6 were higher in CVT than in IS in Bayesian NMA, suggesting potential adjunctive markers for differential diagnosis; however, these findings are hypothesis-generating and require prospective validation, and neuroimaging remains the diagnostic gold standard. Systematic review registration:https://www.crd.york.ac.uk/PROSPERO/view/CRD42024539498, CRD42024539498.

Background Diabetic neuropathic pain (DNP) is a severe and clinically common form of neuropathic pain. Ventral posterolateral nucleus (VPL) glutamatergic neurones are reportedly involved in the development of neuropathic pain. However, the roles and mechanism of VPL GABAergic neurones and neural circuits in DNP remain unclear. Methods After constructing a streptozotocin (STZ)-induced DNP model in male rats, we assessed VPL neuronal activity by immunofluorescence staining and von Frey test. Moreover, the roles of VPL GABAergic neurones and that projected to the forelimb primary somatosensory cortex (S1FL) were investigated using optogenetic and chemogenetic approaches, viral tracing, and behavioural tests. Results Optogenetic (F2,18=376.155, P<0.001) and chemogenetic (F2,16=226.340, P<0.001) activation of VPL GABAergic neurones relieved mechanical allodynia in male DNP model rats, which revealed that VPL GABAergic neurones mediated antinociceptive effects. We identified a GABAergic thalamocortical circuit in the VPL that projected to the S1FL and revealed that the thalamocortical circuit mediated antinociceptive effects (optogenetic: F2,20=303.807, P<0.001; chemogenetic: F2,15=62.008, P<0.001) in the context of DNP. Conclusions These findings identify a GABAergic neuronal thalamocortical circuit associated with pain processing, reveal the mechanism of diabetic neuropathic pain pathogenesis and the role of thalamocortical pain circuits in analgesia, and provide new insights for the development of analgesics.

BACKGROUND:Glutamatergic neurons in the supramammillary nucleus (SuM) have been recently identified as a key node in arousal system, yet their role in regulating general anesthesia remains unclear. The aim of the current study is to examine the role of the glutamatergic supramammillary neurons and their projections to the medial septum in mediating the effects of isoflurane anesthesia. METHODS:Fiber photometry recording was used to determine the changes in calcium signals of glutamatergic neurons in the SuM during isoflurane anesthesia. Optogenetic and chemogenetic approaches were employed to manipulate SuM glutamatergic neuron activity, and the effects on cortical activity, behavioral responses, and physiologic parameters-including pupil diameter, respiratory rate, and blood pressure-were examined in anesthetized mice. Both male and female mice were used in this study. RESULTS:The activities of SuM glutamatergic neurons decreased during isoflurane anesthesia and recovered after the emergence. Optogenetic activation of these neurons enhanced cortical activity, decreasing electroencephalogram delta power (mean ± SD, prestimulation vs . stimulation: 51.35 ± 7.26% vs . 32.08 ± 10.48%, n = 8, P = 0.002) and burst suppression ratio (81.82 ± 7.83% vs . 44.53 ± 28.62%, n = 8, P = 0.002). Furthermore, optogenetic activation altered physiologic parameters including enlarged pupil diameter (prestimulation vs. stimulation: 1.05 ± 0.08% vs. 1.95 ± 0.46%, n = 8, P < 0.001), increased respiratory rate (0.98 ± 0.08% vs. 1.57 ± 0.39%, n = 10, P < 0.001) and elevated blood pressure and induced behavioral responses including increased arousal scores and accelerated emergence (light off vs . light on, 171.40 ± 56.39 s to 59.88 ± 27.18 s, n = 8, P = 0.007). Moreover, chemogenetic activation produced similar effects, whereas inhibition led to opposite effects. Finally, optogenetically activating SuM glutamatergic terminals projecting to the medial septum mimicked the effects of activating SuM glutamatergic soma and increased the activity of medial septum glutamatergic neurons. CONCLUSIONS:This study identifies glutamatergic neurons of the SuM as key neural substrates regulating isoflurane anesthesia and facilitating emergence through their projections to the medial septum.

Background:Recent evidence indicates that general anesthesia and sleep-wake behavior share some overlapping neural substrates. gamma-Aminobutyric acid-mediated (GABAergic) neurons in the central amygdala have a high firing rate during wakefulness and play a role in regulating arousal-related behaviors. The objective of this study was to investigate whether central amygdala GABAergic neurons participate in the regulation of isoflurane general anesthesia and uncover the underlying neural circuitry.Methods:Fiber photometry recording was used to determine the changes in calcium signals of central amygdala GABAergic neurons during isoflurane anesthesia in Vgat-Cre mice. Chemogenetic and optogenetic approaches were used to manipulate the activity of central amygdala GABAergic neurons, and a righting reflex test was used to determine the induction and emergence from isoflurane anesthesia. Cortical electroencephalogram (EEG) recording was used to assess the changes in EEG spectral power and burst-suppression ratio during 0.8% and 1.4% isoflurane anesthesia, respectively. Both male and female mice were used in this study.Results:The calcium signals of central amygdala GABAergic neurons decreased during the induction of isoflurane anesthesia and were restored during the emergence. Chemogenetic activation of central amygdala GABAergic neurons delayed induction time (mean +/- SD, vehicle vs. clozapine-N-oxide: 58.75 +/- 5.42 s vs. 67.63 +/- 5.01 s; n = 8; P = 0.0017) and shortened emergence time (385.50 +/- 66.26 s vs. 214.60 +/- 40.21 s; n = 8; P = 0.0017) from isoflurane anesthesia. Optogenetic activation of central amygdala GABAergic neurons produced a similar effect. Furthermore, optogenetic activation decreased EEG delta power (prestimulation vs. stimulation: 46.63 +/- 4.40% vs. 34.16 +/- 6.47%; n = 8; P = 0.0195) and burst-suppression ratio (83.39 +/- 5.15% vs. 52.60 +/- 12.98%; n = 8; P = 0.0003). Moreover, optogenetic stimulation of terminals of central amygdala GABAergic neurons in the basal forebrain also promoted cortical activation and accelerated behavioral emergence from isoflurane anesthesia.Conclusions:The results suggest that central amygdala GABAergic neurons play a role in general anesthesia regulation, which facilitates behavioral and cortical emergence from isoflurane anesthesia through the GABAergic central amygdala-basal forebrain pathway.

BACKGROUND:Spontaneous pain is commonly reported in patients with nerve injuries, posing a great challenge to physicians. However, the mechanisms underlying spontaneous pain remain largely unknown in comparison to evoked pain (e.g. allodynia and hyperalgesia). Cortical processing is vital in coding nociception, and dysfunction of anterior cingulate cortex might facilitate pain hypersensitivity. This indicates a distinct pattern of ensemble activity during spontaneous pain-like behaviour. METHODS:Combining in vivo calcium imaging and ex vivo electrophysiological recording, we explored the maladaptive changes of cortical neurones at individual and population levels induced by several models of neuropathic pain in mice. We also examined the role of the anterior cingulate cortex in the regulation of spontaneous pain-like behaviour using optogenetic methods. RESULTS:We identified a common status of cortical hyperactivity in pyramidal neurones and neural ensembles recorded in the anterior cingulate cortex. Optogenetic inhibition of the anterior cingulate cortex inhibited spontaneous pain-like behaviour, while optogenetic activation restored it. In addition, the cortical representation of spontaneous behaviour was inhibited by nerve injury, which conversely was restored with pain relief. In freely moving animals, we further demonstrated a stable mode of cortical integration in response to spontaneous grooming episodes, independent of the presence of pain, with a dynamic reconfiguration mechanism. CONCLUSIONS:Our data reveal an essential role of the anterior cingulate cortex in the processing and modulation of non-evoked reflex in distinct preclinical models of neuropathic pain in mice.

Recent evidence highlights the importance of glutamatergic neurons in the basal forebrain (BF) in promoting cortical activity; however, whether BF glutamatergic neurons are involved in regulating general anesthesia and the underlying neural circuits remains unclear. Here, we showed that the activity of BF glutamatergic neurons decreased during the induction of isoflurane anesthesia and restored during the emergence in mice. Optogenetic activation of these neurons significantly enhanced cortical activation, accelerated behavioral emergence, and improved physiological indicators in both male and female mice under isoflurane anesthesia. Specifically, activation of BF glutamatergic neurons shortened emergence time from isoflurane anesthesia, decreased isoflurane sensitivity, and increased arousal scores of mice. Moreover, optogenetic activation of BF glutamatergic neurons decreased EEG delta power and burst suppression ratio, while increasing pupil size and respiration rate in mice during isoflurane anesthesia. Similar results were observed during the optogenetic activation of BF glutamatergic terminals in the ventral tegmental area (VTA). Additionally, we found that the activity of BF glutamatergic neurons and VTA glutamatergic neurons synchronously fluctuated during isoflurane anesthesia, and optogenetic activation of BF glutamatergic terminals in the VTA potently increased the calcium signals in VTA glutamatergic neurons during isoflurane anesthesia. Collectively, these findings demonstrate that BF glutamatergic neurons promote emergence from isoflurane anesthesia by activating VTA glutamatergic neurons.

BACKGROUND:Perimenopausal women often experience physiological and psychological decline due to the effects of oestrogen fluctuations and the decline of ovarian function, leading to significantly increased depression rates, decreases in the quality of life and mental health issues. Studies have shown that the gut microbiota exerts anti-perimenopausal depression (PMD) effects via the microbiota-gut-brain (MGB) axis, the mechanisms of which may be related to inflammation. In this review, we discuss the effects and mechanisms of gut microbiota in PMD and provide new insights for future PMD treatment. METHODS:This review elaborates on the role of MGB axis in PMD from different aspects of inflammation, including gut microbiota metabolites, inflammatory signaling pathways, and clinical applications. RESULTS:Disorders of gut microbiota and decreased levels of gut microbiota metabolites (short-chain fatty acids, monoamine neurotransmitters) may cause PMD. The mechanism of intestinal microbiota-mediated inflammation may be related to TLR4/NF-κB pathway, NOD-like receptor protein 3 (NLRP3) inflammasome pathway and JAK-STAT pathway. At the same time, it was found that gut microbiota (probiotics, prebiotics, etc.) had good therapeutic potential in the treatment of PMD. CONCLUSIONS:MGB axis mediated inflammation may play an important role in PMD. The application of gut microbiota in the treatment of PMD patients has profound clinical transformation value, but a lot of efforts are still needed.

Purpose:Dysregulation of the microbiota-gut-brain (MGB) axis and activation of the NOD-like receptor protein 3 (NLRP3) inflammasome are implicated in estrogen deficiency induced depression and anxiety disorders. This study aims to investigate the effects of the probiotic Bifico on neuroinflammation and behaviors in ovariectomized (OVX) rats. Methods:After OVX rats were treated with Bifico for 6 weeks, depression- and anxiety-like behaviors were evaluated using the sucrose preference test, forced swimming test, open field test and elevated plus maze. Furthermore, 16S rRNA sequencing was used to analyze changes in gut microbiota. Hematoxylin-eosin (HE) staining was used to observe the changes in tissue structure (intestinal tissue and hippocampus). Enzyme-linked immunosorbent assay (ELISA) was used to detect inflammatory factors. Western blot was used to detect tissue protein levels. Results:The treatment of Bifico for 6 weeks can ameliorate depression- and anxiety-like behaviors induced by estrogen deficiency. In addition, Bifico increased the abundance of gut microbiota, especially Lactobacillus sp. and Desulfovibrio, and significantly ameliorated histological injuries in the ileum, colon and hippocampus. Bifico up-regulated the expression of tight-junction proteins zona occludens 1 (ZO-1) and Occludin in the colon and hippocampus, and down-regulated the expression of NLRP3 inflammasome signaling pathway-related proteins, including NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), Caspase-1, interleukin (IL)-1β, IL-18, toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), phosphorylated (P)-P65 and P65. Meanwhile, Bifico also reduced the levels of IL-6 and tumor necrosis factor (TNF)-α in serum and hippocampus. Conclusion:Our findings suggest that probiotics ameliorate the depression- and anxiety-like behaviors in OVX rats by alleviating gut microbiota dysbiosis and reduce gut inflammation, thereby dampening neuroinflammation via inhibition of the NLRP3 inflammasome signaling pathway in the hippocampus. Therefore, NLRP3 inflammasome activation mediated by the MGB axis may be a potential therapeutic target for estrogen deficiency-induced affective disorders.

Diabetic neuropathic pain (DNP) is a common chronic complication of diabetes mellitus and a clinically common form of neuropathic pain. The thalamus is an important center for the conduction and modulation of nociceptive signals. The paraventricular thalamic nucleus (PVT) is an important midline nucleus of the thalamus involved in sensory processing, but the specific role of PVT astrocytes and GABAergic neurons in DNP remains unclear. Here, we examined the activity of PVT astrocytes and neurons at various time points during the development of DNP by fluorescence immunohistochemistry and found that the activity of PVT astrocytes was significantly increased while that of PVT neurons was significantly decreased 14 d after streptozotocin injection in male rats. The inhibition of PVT astrocytes by chemogenetic manipulation relieved mechanical allodynia in male DNP model rats, whereas the activation of PVT astrocytes induced mechanical allodynia in normal male rats. Interestingly, chemogenetic activation of GABAergic neurons in the PVT alleviated mechanical allodynia in male DNP model rats, whereas chemogenetic inhibition of GABAergic neurons in the PVT induced mechanical allodynia in normal male rats. These data demonstrate the distinct roles of PVT astrocytes and GABAergic neurons in modulating DNP, revealing the mechanism of DNP pathogenesis and the role of the PVT in pain modulation.