OBJECTIVE: To investigate the regulatory effects of two traditional mineral medicines (TMMs), Gypsum Fibrosum (Shigao, GF) and Terra Flava Usta (Zaoxintu, TFU), on gut-beneficial bacteria in mice, and preliminarily explore their mechanisms of action. METHODS: Mice were randomly divided into 3 groups (n=10 per group): the control group (standard diet), the GF group (diet supplemented with 2% GF), and the TFU group (diet supplemented with 2% TFU). After 4-week intervention, 16S rRNA gene sequencing was used to analyze the changes in the gut microbiota (GM). Scanning electron microscopy, in combination with coumarin A tetramethyl rhodamine conjugate and Hoechst stainings, was used to observe the bacteria and biofilm formation. RESULTS: Principal coordinate analysis revealed that GF and TFU significantly altered the GM composition in mice. Further analysis revealed that GF and TFU affected different types of gut bacteria, suggesting that different TMMs may selectively modulate specific bacterial populations. For certain bacteria, such as Faecalibaculum and Ileibacterium, both GF and TFU exhibited growth-promoting effects, implying that they may be sensitive to TMMs and that different TMMs can increase their abundance through their respective mechanisms. Notably, Lactobacillus reuteri, a widely recognized and used probiotic, was significantly enriched in the GF group. Random forest analysis identified Ileibacterium valens as a potential indicator bacterium for TMMs' impact on GM. Further mechanistic studies showed that gut bacteria formed biofilm structures on the TFU surface. CONCLUSIONS This study provides new insights into the interaction between TMMs and GM. As safe and effective natural clays, GF and TFU hold promise as potential candidates for prebiotic development.
Animals ; Gastrointestinal Microbiome/drug effects* ; Bacteria/growth & development* ; Mice ; Biofilms/drug effects* ; Male ; RNA, Ribosomal, 16S/genetics*

Schizophrenia (SZ) stands as a severe psychiatric disorder. This study applied diffusion tensor imaging (DTI) data in conjunction with graph neural networks to distinguish SZ patients from normal controls (NCs) and showcases the superior performance of a graph neural network integrating combined fractional anisotropy and fiber number brain network features, achieving an accuracy of 73.79% in distinguishing SZ patients from NCs. Beyond mere discrimination, our study delved deeper into the advantages of utilizing white matter brain network features for identifying SZ patients through interpretable model analysis and gene expression analysis. These analyses uncovered intricate interrelationships between brain imaging markers and genetic biomarkers, providing novel insights into the neuropathological basis of SZ. In summary, our findings underscore the potential of graph neural networks applied to multimodal DTI data for enhancing SZ detection through an integrated analysis of neuroimaging and genetic features.
Humans ; Schizophrenia/pathology* ; Diffusion Tensor Imaging/methods* ; Male ; Female ; Adult ; Brain/metabolism* ; Young Adult ; Middle Aged ; White Matter/pathology* ; Gene Expression ; Nerve Net/diagnostic imaging* ; Graph Neural Networks

Neuropathic pain, a debilitating condition caused by dysfunction of the somatosensory nervous system, remains difficult to treat due to limited understanding of its molecular mechanisms. Bioinformatics analysis identified cerebellin 2 (CBLN2) as highly enriched in human and murine proprioceptive and nociceptive neurons. We found that CBLN2 expression is persistently upregulated in dorsal root ganglia (DRG) following spinal nerve ligation (SNL) in mice. In addition, transcription factor SOX11 binds to 12 cis-regulatory elements within the Cbln2 promoter to enhance its transcription. SNL also induced SOX11 upregulation, with SOX11 and CBLN2 co-localized in nociceptive neurons. The siRNA-mediated knockdown of Sox11 or Cbln2 attenuated SNL-induced mechanical allodynia and thermal hyperalgesia. High-throughput sequencing of DRG following intrathecal injection of CBLN2 revealed widespread gene expression changes, including upregulation of numerous NF-κB downstream targets. Consistently, CBLN2 activated NF-κB signaling, and inhibition with pyrrolidine dithiocarbamate reduced CBLN2-induced pain hypersensitivity, proinflammatory cytokines and chemokines production, and neuronal hyperexcitability. Together, these findings identified the SOX11/CBLN2/NF-κB axis as a critical mediator of neuropathic pain and a promising target for therapeutic intervention.
Animals ; Neuralgia/metabolism* ; Ganglia, Spinal/metabolism* ; Up-Regulation ; Mice ; NF-kappa B/metabolism* ; SOXC Transcription Factors/genetics* ; Male ; Neuroinflammatory Diseases/metabolism* ; Mice, Inbred C57BL ; Nerve Tissue Proteins/genetics* ; Hyperalgesia/metabolism* ; Signal Transduction ; Spinal Nerves

Objective To study the bioequivalence of test and reference olmesartan tablet in Chinese healthy subjects after single dose under fasting and fed conditions.Methods A single-center,random,open,single-dose,two-preparations,double-period,crossover study was adopted.A total of 48 healthy adult male and female subjects(24 cases of fasting test and 24 cases of fed test)were included in the random crossover administration.Single oral dose 20 mg of test and reference were taken under fasting and postprandial conditions,respectively.Plasma concentration of olmesartan in plasma were determined by liquid chromatography tandem mass spectrometry.The main pharmacokinetic parameters were calculated by Phoenix WinNonlin 8.0 software.Results The main pharmacokinetic parameters of the test and reference preparations of olmesartan tablets in the fasting group were as follows:Cmax were(653.06±133.53)and(617.37±151.16)ng·mL-1,AUC0-t were(4 201.18±1 035.21)and(4 087.38±889.99)ng·mL-1·h,AUC0-∞ were(4 254.30±1 058.90)and(4 135.69±905.29)ng·mL-1·h.The main pharmacokinetic parameters of the test and reference preparations of olmesartan tablets in the postprandial group were as follows:Cmax were(574.78±177.05)and(579.98±107.74)ng·mL-1,AUC0-t were(3 288.37±866.06)and(3 181.51±801.06)ng·mL-1·h,AUC0-∞ were(3 326.11±874.26)and(3 242.01±823.09)ng·mL-1·h.Under fasting and postprandial conditions,the 90％confidence intervals of the main pharmacokinetic parameters of the test and reference preparations are both 80.00％-125.00％.Conclusion Under fasting and postprandial conditions,a single oral dose of test and reference preparations olmesartan tablets in Chinese healthy adult volunteers showed bioequivalence.

BACKGROUND: Stress cardiomyopathy (SCM) currently has a high incidence in older adults, and the theories regarding its causes include "catecholamine myocardial toxicity" and "sympathetic hyperactivation". However, the role of the central nervous system in the pathogenesis of SCM remains unknown. We investigated the role of microglia activation in the paraventricular hypothalamic nucleus (PVN) in the development of SCM. METHODS: An SCM model was created using male Sprague-Dawley (SD) rats, immobilized for 6 h every day for a week. Electrocardiogram, cardiac electrophysiology, and echocardiography examinations were performed to verify the changes in cardiac structure and function in rats with SCM. RNA sequencing was used to explore the changes in the hypothalamus during SCM. In addition, brain and heart tissues were collected to detect microglial activation and sympathetic activity. RESULTS: The main findings were as follows: (1) immobilization stress successfully induced SCM in SD rats; (2) microglia were significantly activated in the hypothalamus, as evidenced by cytosol thickening, increases in the number of microglial branches, and microglia enriched in the PVN; (3) in SCM, the microglia in the PVN exhibited increased central and peripheral cardiac sympathetic activity and increased the expression of neuroinflammatory factors; and (4) it is possible that inhibiting microglial activation could suppress the sympathetic activity of the central nervous system and heart and increase cardiac electrical stability in SCM rats. CONCLUSIONS SCM was induced in SD rats by immobilization stress, acting through the activation of the hypothalamic microglia. The activated microglia were specifically enriched in the PVN, increasing the activity of the central and peripheral sympathetic nervous systems by regulating the expression of neuro-inflammatory factors, mediating dysfunction of the left ventricle, and increasing the susceptibility to ventricular arrhythmias.

OBJECTIVE: To investigate the predictive value of blood cell ratios and inflammatory markers for adverse prognosis in patients with primary Sjögren's syndrome (PSS) combined with coronavirus disease 2019 (COVID-19). METHODS: We retrospectively collected clinical data from 80 patients with PSS and COVID-19 who visited the Rheumatology and Immunology Department of the First Affiliated Hospital of Nanchang University from December 2022 to February 2023. Inclusion criteria were (1) meeting the American College of Rheumatology (ACR) classification criteria for Sjögren's syndrome; (2) confirmed diagnosis of COVID-19 by real-time reverse transcription polymerase chain reaction or antigen testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); (3) availability of necessary clinical data; (4) age > 18 years. According to the clinical classification criteria of the "Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (trial the 10th Revised Edition)", the patients were divided into the mild and severe groups. Disease activity in primary Sjögren' s syndrome was assessed using the European League Against Rheumatism (EULAR) Sjögren' s syndrome disease activity index (ESSDAI). Platelet-lymphocyte ratio (PLR), C-reactive protein-lymphocyte ratio (CLR), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and other laboratory data were compared between the two groups within 24-72 hours post-infection. RESULTS: The mild group consisted of 66 cases with an average age of (51. 52±13. 16) years, and the severe group consisted of 14 cases with an average age of (52.64±10.20) years. Disease activity, CRP, platelets, PLR, and CLR were significantly higher in the severe group compared with the mild group (P < 0.05). Univariate analysis using age, disease activity, CRP, platelets, PLR, and CLR as independent variables indicated that disease activity, CRP, PLR, and CLR were correlated with the severity of COVID-19 (P < 0.05). Multivariate logistic regression analysis further confirmed that PLR (OR=1.016, P < 0.05) and CLR (OR=1.504, P < 0.05) were independent risk factors for the severity of COVID-19 in the critically ill patients. Receiver operator characteristic (ROC) curve analysis showed that the area under the curve (AUC) for PLR and CLR was 0.708 (95%CI: 0.588-0.828) and 0.725 (95%CI: 0.578-0.871), respectively. The sensitivity for PLR and CLR was 0.429 and 0.803, respectively, while the highest specificity was 0.714 and 0.758, respectively. The optimal cutoff values for PLR and CLR were 166.214 and 0.870, respectively. CONCLUSION PLR and CLR, particularly the latter, may serve as simple and effective indicators for predicting the prognosis of patients with PSS and COVID-19.
Humans ; Adult ; Middle Aged ; Sjogren's Syndrome/diagnosis* ; Retrospective Studies ; C-Reactive Protein ; COVID-19 ; SARS-CoV-2

ObjectiveTo investigate the risk factors and construct a predictive model for severe myelosuppression due to chemotherapy in triple negative breast cancer （TNBC）. MethodsPatients with TNBC who received anthracycline combined with cyclophosphamide sequential paclitaxel chemotherapy regimen at the Second Affiliated Hospital of Nanchang University from September 2， 2016 to September 2， 2021 were selected and assigned to severe myelosuppression group and no/mild myelosuppression group. The χ² test and binary logistic regression were used to analyze the risk factors for severe myelosuppression due to chemotherapy and to develop a prediction model. Hosmer-Lemeshow test and receiver operating characteristic （ROC） curve were used to evaluate the predictive efficiency of the regression model. Kappa consistency test was used to verify the regression model externally. ResultsA total of 207 patients who met the inclusion were enrolled and 106 patients （51%） had severe myelosuppression. Binary logistic regression multivariate analysis showed that age 40 to 60 years （OR = 3.463， 95% CI： 1.144 to 10.486， P = 0.028）， age >60 years （OR = 3.474， 95% CI： 1.004 to 12.020， P = 0.049）， body mass index （BMI） 18.5 to 24.0 （OR = 1.445， 95% CI： 0.686 to 3.087， P = 0.328）， BMI <18.5 （OR = 3.582， 95% CI： 1.260 to 10.182， P = 0.017）， tumor TNM stage Ⅱ （OR = 1.698， 95% CI： 0.831 to 3.468， P = 0.146）， tumor TNM stage Ⅲ （OR = 2.943， 95% CI： 1.199 to 7.227， P = 0.019）， previous diabetes （OR = 2.441， 95% CI： 1.076 to 5.539， P = 0.033）， low pre-treatment albumin level （OR = 2.759， 95% CI： 1.141 to 6.669， P = 0.024） and low pre-treatment lymphocytes （OR = 3.428， 95% CI： 1.689 to 6.958， P = 0.001） were independent risk factors for severe myelosuppression due to chemotherapy. The χ² value for the logistic regression model Hosmer-Lemeshow test was 11.507， P= 0.175， the area under the ROC curve was 0.763， standard error 0.033， 95% CI： 0.698-0.828， P=0.000. External validation showed that the prediction model had a specificity of 88% and a sensitivity of 80%； the kappa value was 0.679， standard error 0.081， P=0.000. conclusionThis logistic regression model had high predictive efficacy and is useful for clinicians to predict whether patients with TNBC develop severe myelosuppression.

In this study, we investigated the effects of Panax notoginseng saponins (PNS) on pulmonary vascular remodeling and ADAM10/Notch3 pathway in pulmonary arterial hypertension (PAH). PAH rat model was established, and male Sprague Dawley (SD) rats were randomly divided into control group, monocrotaline (MCT) group and MCT+PNS group, with 10 rats in each group. Rats in the control group were intraperitoneally injected with equal volume of normal saline. Rats in the MCT group was injected intraperitoneally with 60 mg/kg MCT on the first day, and then with the same volume of normal saline every day. Rats in the MCT+PNS group was injected intraperitoneally with 60 mg/kg MCT on the first day, and then with 50 mg/kg PNS every day. The modeling time of each group lasted for 21 days. After the model was established, the mean pulmonary artery pressure (mPAP) was measured by right heart catheterization technique, the right ventricular hypertrophy index (RVHI) was calculated, the microscopic morphology and changes of pulmonary vascular wall were observed by HE and Masson staining, and the expressions of ADAM10, Notch3, Hes-1, P27, PCNA, Caspase-3 proteins and mRNA in pulmonary vascular tissue of rats were detected by Western blot and qPCR. The expression and localization of Notch3 and α-SMA were detected by immunofluorescence staining. The protein expression of ADAM10 was detected by immunohistochemical staining. The results showed that compared with the control group, mPAP, RVHI, pulmonary vessels and collagen fibers in the MCT group were significantly increased, the expressions of ADAM10, Notch3, Hes-1, and PCNA protein and mRNA were significantly increased, while the expressions of P27 and Caspase-3 protein and mRNA were decreased significantly. Compared with the MCT group, mPAP and RVHI were significantly decreased, pulmonary vessels were significantly improved and collagen fibers were significantly reduced, the expressions of protein and mRNA of ADAM10, Notch3, Hes-1, and PCNA were decreased in MCT+PNS group, but the expressions of protein and mRNA of P27 and Caspase-3 were increased slightly. The results of immunofluorescence showed that Notch3 and α-SMA staining could overlap, which proved that Notch3 was expressed in smooth muscle cells. The expression of Notch3 in the MCT group was increased significantly compared with that in the control group, while PNS intervention decreased the expression of Notch3. Immunohistochemical staining showed that compared with the control group, the amount of ADAM10 in the MCT group was increased significantly, and the expression of ADAM10 in the MCT+PNS group was decreased compared with the MCT group. These results indicate that PNS can improve the PAH induced by MCT in rats by inhibiting ADAM10/Notch3 signaling pathway.
Animals ; Male ; Rats ; Caspase 3/metabolism* ; Collagen ; Disease Models, Animal ; Hypertension, Pulmonary/drug therapy* ; Monocrotaline/adverse effects* ; Panax notoginseng/chemistry* ; Proliferating Cell Nuclear Antigen/pharmacology* ; Pulmonary Arterial Hypertension ; Pulmonary Artery/metabolism* ; Rats, Sprague-Dawley ; Receptor, Notch3/genetics* ; RNA, Messenger ; Saline Solution ; Signal Transduction ; Saponins/pharmacology*

The study investigated the effects of different processed products of Polygonati Rhizoma(black bean-processed Polygonati Rhizoma, BBPR; stewed Polygonati Rhizoma, SPR) on the urinary metabolites in a rat model of Alzheimer's disease(AD). Sixty SPF-grade male SD rats were randomized into a control group, a model group, a donepezil group, a BBPR group, and a SPR group, with twelve rats in each group. Other groups except the control group were administrated with D-galactose injection(100 mg·kg~(-1)) once a day for seven weeks. The control group was administrated with an equal volume of normal saline once a day for seven consecutive weeks. After three weeks of D-galactose injection, bilateral hippocampal Aβ_(25-35) injections were performed for modeling. The rats were administrated with corresponding drugs(10 mL·kg~(-1)) by gavage since week 2, and the rats in the model and control group with an equal volume of double distilled water once a day for 35 continuous days. The memory behaviour and pathological changes in the hippocampal tissue were observed. The untargeted metabolites in the urine were detected by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry(UPLC-Q/TOF-MS). Principal component analysis(PCA) and orthogonal partial least square-discriminant analysis(OPLS-DA) were employed to characterize and screen differential metabolites and potential biomarkers, for which the metabolic pathway enrichment analysis was conducted. The results indicated that BBPR and SPR increased the new object recognition index, shortened the escape latency, and increased the times of crossing the platform of AD rats in the Morris water maze test. The results of hematoxylin-eosin(HE) staining showed that the cells in the hippocampal tissue of the drug administration groups were closely arranged. Moreover, the drugs reduced the content of interleukin-6(IL-6, P<0.01) and tumor necrosis factor-α(TNF-α) in the hippocampal tissue, which were more obvious in the BBPR group(P<0.05). After screening, 15 potential biomarkers were identified, involving two metabolic pathways: dicoumarol pathway and piroxicam pathway. BBPR and SPR may alleviate AD by regulating the metabolism of dicoumarol and piroxicam.
Rats ; Male ; Animals ; Alzheimer Disease/drug therapy* ; Chromatography, High Pressure Liquid/methods* ; Rats, Sprague-Dawley ; Dicumarol ; Galactose ; Piroxicam ; Metabolomics/methods* ; Biomarkers/urine*