Bioactive compounds from Huashi Baidu decoction possess both antiviral and anti-inflammatory effects against COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health concern, and effective antiviral reagents are urgently needed. Traditional Chinese medicine theory-driven natural drug research and development (TCMT-NDRD) is a feasible method to address this issue as the traditional Chinese medicine formulae have been shown effective in the treatment of COVID-19. Huashi Baidu decoction (Q-14) is a clinically approved formula for COVID-19 therapy with antiviral and anti-inflammatory effects. Here, an integrative pharmacological strategy was applied to identify the antiviral and anti-inflammatory bioactive compounds from Q-14. Overall, a total of 343 chemical compounds were initially characterized, and 60 prototype compounds in Q-14 were subsequently traced in plasma using ultrahigh-performance liquid chromatography with quadrupole time-of-flight mass spectrometry. Among the 60 compounds, six compounds (magnolol, glycyrrhisoflavone, licoisoflavone A, emodin, echinatin, and quercetin) were identified showing a dose-dependent inhibition effect on the SARS-CoV-2 infection, including two inhibitors (echinatin and quercetin) of the main protease (Mpro), as well as two inhibitors (glycyrrhisoflavone and licoisoflavone A) of the RNA-dependent RNA polymerase (RdRp). Meanwhile, three anti-inflammatory components, including licochalcone B, echinatin, and glycyrrhisoflavone, were identified in a SARS-CoV-2-infected inflammatory cell model. In addition, glycyrrhisoflavone and licoisoflavone A also displayed strong inhibitory activities against cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4). Crystal structures of PDE4 in complex with glycyrrhisoflavone or licoisoflavone A were determined at resolutions of 1.54 Å and 1.65 Å, respectively, and both compounds bind in the active site of PDE4 with similar interactions. These findings will greatly stimulate the study of TCMT-NDRD against COVID-19.

DrugAI: a multi-view deep learning model for predicting drug-target activating/inhibiting mechanisms.

Understanding the mechanisms of candidate drugs play an important role in drug discovery. The activating/inhibiting mechanisms between drugs and targets are major types of mechanisms of drugs. Owing to the complexity of drug-target (DT) mechanisms and data scarcity, modelling this problem based on deep learning methods to accurately predict DT activating/inhibiting mechanisms remains a considerable challenge. Here, by considering network pharmacology, we propose a multi-view deep learning model, DrugAI, which combines four modules, i.e. a graph neural network for drugs, a convolutional neural network for targets, a network embedding module for drugs and targets and a deep neural network for predicting activating/inhibiting mechanisms between drugs and targets. Computational experiments show that DrugAI performs better than state-of-the-art methods and has good robustness and generalization. To demonstrate the reliability of the predictive results of DrugAI, bioassay experiments are conducted to validate two drugs (notopterol and alpha-asarone) predicted to activate TRPV1. Moreover, external validation bears out 61 pairs of mechanism relationships between natural products and their targets predicted by DrugAI based on independent literatures and PubChem bioassays. DrugAI, for the first time, provides a powerful multi-view deep learning framework for robust prediction of DT activating/inhibiting mechanisms.

Metagenomic next-generation sequencing for pulmonary infections diagnosis in patients with diabetes.

BACKGROUND: Diabetes mellitus is a major cause of high mortality and poor prognosis in patients with pulmonary infections. However, limited data on the application of metagenomic next-generation sequencing (mNGS) are available for diabetic patients. This study aimed to evaluate the diagnostic performance of mNGS in diabetic patients with pulmonary infections. METHODS: We retrospectively reviewed 184 hospitalized patients with pulmonary infections at Guizhou Provincial People's Hospital between January 2020 to October 2021. All patients were subjected to both mNGS analysis of bronchoalveolar lavage fluid (BALF) and conventional testing. Positive rate by mNGS and the consistency between mNGS and conventional testing results were evaluated for diabetic and non-diabetic patients. RESULTS: A total of 184 patients with pulmonary infections were enrolled, including 43 diabetic patients and 141 non-diabetic patients. For diabetic patients, the microbial positive rate by mNGS was significantly higher than that detected by conventional testing methods, primarily driven by bacterial detection (microbes: 95.3% vs. 67.4%, P = 0.001; bacteria: 72.1% vs. 37.2%, P = 0.001). mNGS and traditional tests had similar positive rates with regard to fungal and viral detection in diabetic patients. Klebsiella pneumoniae was the most common pathogen identified by mNGS in patients with diabetes. Moreover, mNGS identified pathogens in 92.9% (13/14) of diabetic patients who were reported negative by conventional testing. No significant difference was found in the consistency of the two tests between diabetic and non-diabetic groups. CONCLUSIONS: mNGS is superior to conventional microbiological tests for bacterial detection in diabetic patients with pulmonary infections. mNGS is a valuable tool for etiological diagnosis of pulmonary infections in diabetic patients.

Effects of orthodontic treatment on masticatory muscles activity: a meta-analysis.

Context: A comprehensive meta-analysis was carried out to investigate the impact of orthodontics on masticatory muscles.Methods: A thorough search of various databases, including CNKI, Wan Fang, VIP, CBM, MEDLINE, PubMed, Cochrane Library, EMBASE, Web of Science, and Google Scholar, was performed to identify relevant studies on patients undergoing orthodontics or functional corrections. Six case-control studies were finally included in this analysis, which specifically examined the effect of orthodontic treatment on masticatory muscle function.Results: The results revealed that the mean masticatory muscle voltage in patients treated with orthodontics was found to be higher after treatment compared to before treatment [odds ratio (OR)=1.57, 95% confidence interval (CI) (0.57, 2.57), p = 0.002], which could potentially have an impact on masticatory muscle function, particularly in individuals with Class II Division 1 malocclusion.Conclusion: These findings contribute to our understanding of the effects of orthodontic interventions on masticatory muscles, further highlighting the importance of orthodontics in optimising masticatory function.

Effects of iron on the growth, biofilm formation and virulence of Klebsiella pneumoniae causing liver abscess.

BACKGROUND: Klebsiella pneumoniae is considered the most clinically relevant species of Enterobacteriaceae, known to cause severe infections including liver abscesses. To the best of our knowledge, a large proportion of iron in the human body is accumulated and stored in the liver. We hypothesize that increased iron availability is an important factor driving liver abscess formation and we therefore aim to understand the effects of iron on K. pneumoniae causing liver abscesses. RESULTS: All tested K. pneumoniae clinical isolates, including those isolated from liver abscesses and other abdominal invasive infection sites, grew optimally when cultured in LB broth supplemented with 50 µM iron and exhibited the strongest biofilm formation ability under those conditions. Decreased growth and biofilm formation ability were observed in all tested strains when cultured with an iron chelator (P < 0.05). The infection model of G. mellonella larvae indicated the virulence of liver abscess-causing K. pneumoniae (2/3) cultured in LB broth with additional iron was significantly higher than those under iron-restricted conditions (P < 0.05). The relative expression levels of the four siderophore genes (iucB, iroB, irp1, entB) in K. pneumoniae strains isolated from liver abscesses cultured with additional iron were lower than those under iron-restricted conditions (P < 0.05). CONCLUSIONS: It is suggested by our research that iron in the environment can promote growth, biofilm formation and enhance virulence of K. pneumoniae causing liver abscesses. A lower expression of siderophore genes correlates with increased virulence of liver abscess-causing K. pneumoniae. Further deeper evaluation of these phenomena is warranted.

Clinical characteristics of 134 convalescent patients with COVID-19 in Guizhou, China.

BACKGROUND: Previous studies have focused on the clinical characteristics of hospitalized patients with the novel 2019 coronavirus disease (COVID-19). Limited data are available for convalescent patients. This study aimed to evaluate the clinical characteristics of discharged COVID-19 patients. METHODS: In this retrospective study, we extracted data for 134 convalescent patients with COVID-19 in Guizhou Provincial Staff Hospital from February 15 to March 31, 2020. Cases were analyzed on the basis of demographic, clinical, and laboratory data as well as radiological features. RESULTS: Of 134 convalescent patients with COVID-19, 19 (14.2%) were severe cases, while 115 (85.8%) were non-severe cases. The median patient age was 33 years (IQR, 21.8 to 46.3), and the cohort included 69 men and 65 women. Compared with non-severe cases, severe patients were older and had more chronic comorbidities, especially hypertension, diabetes, and thyroid disease (P < 0.05). Leukopenia was present in 32.1% of the convalescent patients and lymphocytopenia was present in 6.7%, both of which were more common in severe patients. 48 (35.8%) of discharged patients had elevated levels of alanine aminotransferase, which was more common in adults than in children (40.2% vs 13.6%, P = 0.018). A normal chest CT was found in 61 (45.5%) patients during rehabilitation. Severe patients had more ground-glass opacity, bilateral patchy shadowing, and fibrosis. No significant differences were observed in the positive rate of IgG and/or IgM antibodies between severe and non-severe patients. CONCLUSION: Leukopenia, lymphopenia, ground-glass opacity, and fibrosis are common in discharged severe COVID-19 patients, and liver injury is common in discharged adult patients. We suggest physicians develop follow-up treatment plans based on the different clinical characteristics of convalescent patients.

Evolution of resistance mechanisms and biological characteristics of rifampicin-resistant Staphylococcus aureus strains selected in vitro.

BACKGROUND: We aimed to determine the evolutionary pathways of rifampicin resistance in Staphylococcus aureus, and the impact of resistance mutations in the rpoB gene on fitness. METHODS: Three clinical strains and one reference strain were used to select for rifampicin-resistant S. aureus variants. The mutations responsible for rifampicin resistance in all of the selected isolates in vitro were investigated by polymerase chain reaction (PCR) and DNA sequencing. To compare the fitness cost of rpoB mutations against their corresponding original isolates, we performed bacterial growth curve assays, static biofilm assays, in vitro competition experiments and an infection model of Galleria mellonella larvae. RESULTS: We obtained four rifampicin-resistant S. aureus isolates that showed high levels of resistance to rifampicin with a minimal inhibitory concentration (MIC) of 128 mg/L, and all isolates had a mutation at position 481 (H481F/Y) in RpoB. A broth microdilution assay indicated that mutation of H481F/Y did not affect susceptibility to common antibacterial drugs but slightly increased the vancomycin MIC. To identify the pathways involved in the development of rifampicin resistance, 32 variants (eight mutants for each strain) and four original isolates were selected for gene sequencing. Different generations of isolates were found to harbor various mutations sites. Compared with the corresponding original isolates, an in vitro fitness assay of the variant isolates showed that growth and virulence were reduced, with a statistically significantly decreased fitness, whereas the capacity for biofilm formation was elevated. CONCLUSIONS: Our findings suggested that the acquisition of rifampicin resistance in S. aureus was dynamic and was associated with a significant fitness cost.

[Quality Assessment of Euglycemic Glucose Clamp Test].

OBJECTIVE: To explorethe quality of euglycemic glucose clamptest performed in the West China Hospital from 2014 to 2017 and to evaluate whether the quality control indexes are suitable for the quality assessment of the clamp test. METHODS: The data collected from 80 euglycemic glucose clamp tests performed between 2014 and2017 were divided into 4 groups according to the coefficient of variation of the blood glucose concentrations (CVBG): group A (CVBG≤4.5%), group B (4.5% < CVBG≤5.0%), group C (5.0% < CVBG≤5.5%) and group D(CVBG > 5.5%).The differences in percentage of glucose excursion from target range (GEFTR), the duration of GEFTR, the area under curve (AUC) of GEFTR, the mean value of excursion from target glucose (GEFT) and the AUC of GEFT were calculated and compared. RESULTS: In group A, the mean value of CVBG was 3.75%. In group B, the mean value of CVBG was 4.76%. In group C, the mean value of CVBG was 5.28%. The median value of CVBG in group D was 6.07%. The percentage of GEFTR, the duration of GEFTR, the AUC of GEFTR, the mean value of GEFT and the AUC of GEFT in group A were all less than those of other groups (P < 0.05).For the same indexes, there were no significant differences between group B and C, while they were higher in group D compared with the other three groups. CVBG was positively correlated with other quality control indexes (correlation coefficient r was 0.770-0.805). Based on the cut-off point 5% of CVBG, the cut-off points of the percentage of GEFTR, the duration of GEFTR, the AUC of GEFTR, the mean value of GEFT and the AUC of GEFT were 5.8%, 14.6 min, 22.82 mg/dL×min, 3.23 mg/dL, 216.25 mg/dL×min/h respectively, with the sensitivity range from 79.3% to 100% and the specificity range from 74.5% to 89.7%.Combined with these indexes, 8.11% of euglycemic clamps were found to havepoor quality in group A, while 66.67% of euglycemic clamps showed acceptable quality in group C. CONCLUSIONS: The investigators should provide an estimation of the quality of the clamps when reporting the results of the insulin analogues' PK/PD characteristics using euglycemic clamps. CVBG less than 4.5% indicates a good quality, and the above-mentioned quality control indexes especially the AUC of GEFT(cut-off point: 216.25 mg·/dL×min/h) should be evaluated when CVBG is more than 4.5%.False high quality and false low quality euglycemic clamps will be detected and a more precise estimation of quality assessment should be made by the combination of these indexes.

Preoperative Cardiac, Pulmonary and Digestive Comorbidities of Morbidly Obese Patients Undergoing Bariatric Surgery: Morbidity, Assessment and Management.

BACKGROUND/AIMS: To investigate a proper preoperative assessment and management of preoperative cardiac, pulmonary and digestive comorbidities in morbidly obese patients undergoing bariatric surgery. METHODOLOGY: A general description of comorbidities in bariatric patients was reviewed and a clinical practice path in assessment and management of comorbidities was summarized. RESULTS: Morbidly obese patients frequently carried serious comorbidities in cardiovascular, pulmonary and digestive systems. The most common abnormalities included hypertension, left ventricular wall hypertrophy, ST and T wave abnormalities, obstructive sleep apnea, ventilatory dysfunction, and nonalcoholic fatty liver disease. A routine specialized preoperative evaluation could find the potential abnormality and screen the appropriate patients. Prophylactic treatments obviously reduced the morbidity of peri-operative complications CONCLUSION: Comprehensive preoperative evaluation and proper management is essential to appropriately select and prepare bariatric patients, and minimize surgical risk.

Soat2 inhibitor avasimibe alleviates acute pancreatitis by suppressing acinar cell ferroptosis.

Ferroptosis, characterized by lipid peroxidation, plays a significant role in the pathogenesis of acute pancreatitis (AP). While sterol O-acyltransferase 2 (Soat2) is known for its crucial regulatory role in cholesterol homeostasis, its involvement in the development of AP remains unreported. We conducted this study to identify the pivotal role of Soat2 in AP using transcriptomic databases. Subsequently, we confirmed its alterations through both in vitro and in vivo experimental models. Furthermore, we performed intervention with the Soat2 inhibitor avasimibe to evaluate pancreatic tissue pathology and serum enzymatic levels and observe inflammatory cell infiltration through immunohistochemistry. Additionally, changes in indicators related to ferroptosis were also observed. The results showed that in the AP mouse model, the protein and mRNA levels of Soat2 were significantly increased. Following avasimibe administration, there was a decrease in serum amylase levels, reduction in pancreatic tissue pathological damage, and attenuation of inflammatory cell infiltration. Furthermore, avasimibe administration resulted in downregulation of ferroptosis-related indicators. In conclusion, our findings suggest that the Soat2 inhibitor avasimibe protects against AP in mice through inhibition of the ferroptosis.

LncRNA XIST protects podocyte from high glucose-induced cell injury in diabetic nephropathy by sponging miR-30 and regulating AVEN expression.

Diabetic nephropathy (DN) is one of the most important complications of diabetes mellitus. Thus, it is urgent to develop a novel diagnosis or therapeutic strategy that could suspend DN progression. Moreover, there is increasing evidence demonstrating that long non-coding RNA (lncRNA) acts as critical players in regulating autophagy and are involved in DN. We demonstrated that lncRNA X-inactive specific transcript (XIST) was downregulated in high glucose (HG) treated podocytes, accompanied by increased apoptosis of podocytes. Overexpression of XIST significantly reduced the apoptosis and promoted the number of viable cells of podocyte under HG treatment. Prediction by Targets can and dual-luciferase reporter assay revealed the interaction between miR-30 and XIST and AVEN. Further WB (Western Blot), MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), and flow cytometry confirmed that XIST could reverse the expression of AVEN and ameliorate HG-induced apoptosis. In conclusion, our research revealed that XIST plays a protective effect on podocyte injury induced by HG through miR-30/AVEN axis.

The prognostic value and immunological role of CD44 in pan-cancer study.

To investigate the correlation between cluster of differentiation-44 (CD44) expression and immunotherapy response and identify its possible predictive value in pan-cancer. Datasets of 33 cancer types from The Cancer Genome Atlas (TCGA) database were applied to investigate the relationship of CD44 expression with prognosis, tumor mutational burden (TMB), and microsatellite instability (MSI), and determine its potential prognostic value in pan-cancer. Patients were split into high-risk and low-risk cancer groups based on the survival outcomes of various cancer types. Additionally, the underlying mechanisms of CD44 in the tumor microenvironment (TME) were analyzed using ESTIMATE and CIBERSORT algorithms and Gene Set Enrichment Analysis (GSEA). Subsequently, the biological role of CD44 at single-cell level was investigated using CancerSEA database. Variable expression levels of CD44 between tumor and adjacent normal tissues were identified in pan-cancer datasets, further survival analysis revealed that CD44 expression was associated with multiple clinical annotations and survival indicators. Besides, the expression of CD44 was significantly associated with TMB and MSI in 10 types and 6 types of cancer, respectively, indicating it could be exploited as a potential biomarker predicting immunotherapy outcomes. Meanwhile, CD44 could influence several crucial immune cell-related pathways. and the results revealed by CancerSEA database denoted the correlation of CD44 with malignant phenotype and functional states, further indicating it can serve as a potential therapeutic target in cancer management. Our study demonstrated that CD44 shows great promise as a prognostic biomarker in numerous cancers, which will assist in developing new strategies in cancer management.

Genetic and Phenotypic Characterization of Multidrug-Resistant Klebsiella pneumoniae from Liver Abscess.

Cooccurrence of multidrug resistant (MDR) and hypervirulence phenotypes in liver abscess-causing Klebsiella pneumoniae (LAKp) would pose a major threat to public health. However, relatively little information is available on the genomic and phenotypic characteristics of this pathogen. This study aimed to investigate the virulence and resistance phenotype and genotype of MDR LAKp strains from 2016 to 2020. We collected 18 MDR LAKp strains from 395 liver abscess samples and characterized these strains using antimicrobial susceptibility test, string test, mucoviscosity assay, biofilm formation assay, Galleria mellonella killing assay, and whole-genome sequencing. Besides, phylogenetic and comparative genomic analyses were performed on these MDR LAKp, along with 94 LAKp genomes from global sources. Most of these MDR LAKp strains exhibited resistance to cephalosporins, quinolones, and chloramphenicol. Virulence assays revealed that only half of MDR LAKp strains exhibited higher virulence than classical MDR strain K. pneumoniae MGH78578. Importantly, we identified three ST11 KL64 hypervirulence carbapenem-resistant strains carrying blaKPC-2 and one colistin-resistant strain carrying mcr-1. Phylogenetic analysis revealed that 112 LAKp genomes were divided into two clades, and most of MDR LAKp strains in this study belonged to clade 1 (83.33%, 15/18). We also detected the loss of mucoviscosity mediated by mutations and ISKpn14 insertion in rmpA, and the latter representing a novel mechanism by which bacteria regulate RmpA system. This study provides novel insights into MDR LAKp and highlights the necessity for measures to prevent further spread of such organisms in hospital settings and the community. IMPORTANCE Pyogenic liver abscess is a potentially life-threatening suppurative infection of hepatic parenchyma. K. pneumoniae has emerged as a predominant pathogen of pyogenic liver abscess. Liver abscess-causing K. pneumoniae is generally considered hypervirulent K. pneumoniae and is susceptible to most antibiotics. Recently, convergence of multidrug resistant and hypervirulence phenotypes in liver abscess-causing K. pneumoniae was emerging and poses a major threat to public health. However, relatively little information is available on liver abscess-causing multidrug-resistant hypervirulent K. pneumoniae. In this study, we characterized phenotype and genotype of virulence and resistance of 18 multidrug-resistant hypervirulent liver abscess-causing K. pneumoniae strains collected from 395 pyogenic liver abscess cases in a tertiary teaching hospital over a 5-year period to enable in-depth understanding of this pathogen.

Role of Fibrinogen in Type-2 Diabetes Mellitus with Diabetic Neuropathy and its Preliminary Mechanism.

INTRODUCTION: Diabetic peripheral neuropathy (DN) is the most common complication of type 2 diabetes mellitus (T2DM). OBJECTIVE: This study aimed to explore the role of fibrinogen (FIB) in T2DM neuropathy and its preliminary mechanism. METHODS: Ten male Sprague-Dawley rats were divided into a normal control group (NC group) and a T2DM neuropathy model group (DN group). The DN group was given a high-energy diet and streptozotocin, while the NC group was given a normal diet and a citric acid buffer. The expression levels of related proteins were analysed. RESULTS: Electrophysiology: Compared with the NC group, the conduction latency of the somatosensory-evoked potential and nerve conduction velocity was prolonged in the DN group, while the motor nerve action potential was decreased. As seen under a light microscope, the peripheral nerve fibres in the DN group were swollen, and the nerve fibres in the posterior funiculus of the spinal cord were loose or missing. Moreover, as seen under an electron microscope, the peripheral nerve demyelination of the DN group was severe, with microvascular blood coagulation, luminal stenosis, and collapse. Compared with the NC group, in the DN group, the expression of FIB was positively correlated with the expression of both ionised calcium-binding adaptor molecule-1 and glial fibrillary acidic protein. Compared with the NC group, in the DN group, the expression of platelet/endothelial cell adhesion molecule-1 and B-cell lymphoma 2 was negatively correlated. CONCLUSION: The increased concentration of FIB may be the cause of neuropathy, and its mechanism may be related to its promotion of inflammatory response, blood coagulation, and vascular stenosis.

Fast Segmentation of Vertebrae CT Image Based on the SNIC Algorithm.

Automatic image segmentation plays an important role in the fields of medical image processing so that these fields constantly put forward higher requirements for the accuracy and speed of segmentation. In order to improve the speed and performance of the segmentation algorithm of medical images, we propose a medical image segmentation algorithm based on simple non-iterative clustering (SNIC). Firstly, obtain the feature map of the image by extracting the texture information of it with feature extraction algorithm; Secondly, reduce the image to a quarter of the original image size by downscaling; Then, the SNIC super-pixel algorithm with texture information and adaptive parameters which used to segment the downscaling image to obtain the superpixel mark map; Finally, restore the superpixel labeled image to the original size through the idea of the nearest neighbor algorithm. Experimental results show that the algorithm uses an improved superpixel segmentation method on downscaling images, which can increase the segmentation speed when segmenting medical images, while ensuring excellent segmentation accuracy.

In vitro activity of imipenem-relebactam alone and in combination with fosfomycin against carbapenem-resistant gram-negative pathogens.

The aim of this study was to investigate in vitro activity of imipenem-relebactam alone and in combination with fosfomycin against carbapenem-resistant Gram-negative pathogens. A total of 100 Gram-negative bacteria resistant to carbapenem were collected. Among collected 25 carbapenem-resistant Klebsiella pneumoniae strains, 24 (96%) were KPC producers and none of them displayed NDM-1, NDM-5, and IMP carbapenemase. Among 25 carbapenem-resistant Escherichia coli strains, 3(12%), 1(4%), 17(68%), 25(100%) and 20(80%) harbored KPC, NDM-1, NDM-5, ESBLs, and membrane porin OmpC or OmpF mutations, respectively. Among all the carbapenem-resistant strains, 40% (40/100) were resistant to imipenem-relebactam. The FICI revealed the synergistic (60%, 6/10) and additive (40%, 4/10) effects of imipenem-relebactam in combination with fosfomycin, wherein synergistic activity was found against all tested Klebsiella pneumoniae and Acinetobacter baumannii. Imipenem-relebactam may be a new alternative for carbapenem-resistant Gram-negative pathogens infections and the combination of imipenem-relebactam and fosfomycin warrants further exploration.

Polysaccharides from Laminaria japonica protect memory abilities and neurogenesis in mice after cranial irradiation through ameliorating neuroinflammation and collagen IV degradation.

BACKGROUND: Radiation-induced brain injury (RIBI) is one of the most common long-term complications for patients with malignant brain tumors after radiotherapy. At present, there is no effective treatment for RIBI. Recent studies have also confirmed that polysaccharides from laminaria japonica (LJP) display potential neuroprotective function. However, its mechanisms of neuroprotection remain unclear. AIM: In this study, we aimed to explore the effect and underlying mechanism of LJP on neurogenesis in radiation-induced brain injury mice. METHODS: SPF two-month-old male mice were randomly divided into control group (Con), LJP treatment group (LJP), irradiation group (IR), and irradiation with LJP treatment group (IR + LJP). LJP (40 mg/kg/day) was intraperitoneally injected at one day before radiation for seven consecutive days (once daily). The mice were exposed to 10 Gy × 2 fractionated doses, once every other day, with a total dose of 20 Gy. Changes in cognitive function of mice following radiation were evaluated by the Morris water maze test. Furthermore, body weight and general status of mice were measured throughout the experiment. Immunohistochemical staining for neural proliferating cells (Ki67+ cells) and immature neurons (DCX + cells) was utilized to assay changes of neurogenesis in hippocampus. Microglial activation and collagen IV deposition within the neurogenic microenvironment were observed respectively by immunohistochemical staining for Iba-1 and Collagen IV in the hippocampus. Levels of pro-inflammatory cytokines (TNF-α and IL-1ß) in the hippocampus were detected by ELISA kits post-radiation. RESULTS: Morris water maze test showed that LJP therapy markedly reduced the escape latency and increased the times of crossing platform and percent time of the target quadrant in the radiated mice. In addition, the decrease of the neural proliferating cells (Ki67+ cells) and immature neurons (DCX + cells) in the hippocampus of mice following irradiation was significantly mitigated by the LJP treatment, suggesting that LJP could prevent from neurogenesis damage after irradiation. LJP injection significantly attenuated degradation of collagen IV, activation of microglia, and increase of pro-inflammatory cytokines (TNF-α and IL-1ß) levels in the neurogenic microenvironment of the hippocampus after radiation. CONCLUSION: These findings suggest that LJP early treatment may mitigate radiation-induced cognitive impairments and that its mechanism may relate to its protection of neurogenesis by alleviating neuroinflammation and collagen IV degradation within the neurogenic microenvironment.

Association of a Novel Prognosis Model with Tumor Mutation Burden and Tumor-Infiltrating Immune Cells in Thyroid Carcinoma.

Although immunotherapy has recently demonstrated a substantial promise in treating advanced thyroid carcinoma (THCA), it is not appropriate for all THCA patients. As a result, this study aims to identify biomarkers for predicting immunotherapy efficacy and prognosis in THCA patients based on a constructed prognostic model. The transcriptomic and corresponding clinical data of THCA patients were obtained from the Cancer Genome Atlas (TCGA) database. We identified differentially expressed genes (DEGs) between THCA and normal samples and performed an intersection analysis of DEGs with immune-related genes (IRGs) downloaded from the ImmPort database. Functional enrichment analysis was performed on the chosen immune-related DEGs. Subsequently, Cox and LASSO regression analyses were conducted to obtain three hub immune-related DEGs, including PPBP, SEMA6B, and GCGR. Following that, a prognostic risk model was established and validated based on PPBP, SEMA6B, and GCGR genes to predict immunotherapy efficacy and THCA prognosis. Finally, we investigated the association between the constructed risk model and tumor mutational burden (TMB), abundance of tumor-infiltrating immune cells (TICs) as well as immunotherapeutic targets (PDL-1, PD-1, and CTLA4) in THCA. THCA patients in the high-risk score (RS) group showed higher TMB levels and worse prognosis than the low RS group. Patients in the high-RS group had higher proportions of monocytes, M2 macrophages, and activated dendritic cells, whereas those in the low-RS group exhibited higher numbers of M1 macrophages and dendritic resting cells. Our data implied that the constructed THCA prognostic model was sound and we concluded that the THCA patients having high TMB and low PD-L1 expression levels might respond poorly to immunotherapy. Taken together, we constructed a novel prognostic model for THCA patients to predict their prognosis and immunotherapy efficacy, providing a viable option for the future management of THCA patients in the clinic.

Deciphering the Pharmacological Mechanisms of Guizhi-Fuling Capsule on Primary Dysmenorrhea Through Network Pharmacology.

Guizhi-Fuling capsule (GZFLC), originated from a classical traditional Chinese herbal formula Guizhi-Fuling Wan, has been clinically used for primary dysmenorrhea in China. Nonetheless, the underlying pharmacological mechanisms of GZFLC remain unclear. The integration of computational and experimental methods of network pharmacology might be a promising way to decipher the mechanisms. In this study, the target profiles of 51 representative compounds of GZFLC were first predicted by a high-accuracy algorithm, drugCIPHER-CS, and the network target of GZFLC was identified. Then, potential functional modules of GZFLC on primary dysmenorrhea were investigated using functional enrichment analysis. Potential bioactive compounds were recognized by hierarchical clustering analysis of GZFLC compounds and first-line anti-dysmenorrhea drugs. Furthermore, the potential anti-dysmenorrhea mechanisms of GZFLC were verified through enzyme activity assays and immunofluorescence tests. Moreover, effects of GZFLC on primary dysmenorrhea were evaluated in oxytocin-induced dysmenorrhea murine model. In the network target analysis, GZFLC may act on five functional modules of pain, inflammation, endocrine, blood circulation and energy metabolism. Integrating computational and experimental approaches, we found that GZFLC significantly inhibited the writhing response and reduced the degree of uterine lesions in oxytocin-induced dysmenorrhea murine model. Furthermore, GZFLC may partially alleviate primary dysmenorrhea by inhibiting cyclooxygenase 2 (COX2) and downregulating MAPK signaling pathway. Consequently, GZFLC presented pain relief and sustained benefits for primary dysmenorrhea. This study could provide a scientific approach for deciphering pharmacological mechanisms of herbal formulae through network pharmacology.

Artesunate Combined With Metformin Ameliorate on Diabetes-Induced Xerostomia by Mitigating Superior Salivatory Nucleus and Salivary Glands Injury in Type 2 Diabetic Rats via the PI3K/AKT Pathway.

Polydipsia and xerostomia are the most common complications that seriously affect oral health in patients with diabetes. However, to date, there is no effective treatment for diabetic xerostomia. Recent studies have reported that artesunate (ART) and metformin (Met) improve salivary gland (SG) hypofunction in murine Sjögren's syndrome. Therefore, aim of this study was to investigate the effect and underlying mechanism of artesunate (ART) alone and in combination with metformin (Met) on hyposalivation in type 2 diabetes mellitus (T2DM) rats. T2DM rats were induced using a high-fat diet and streptozotocin. SPF male Sprague-Dawley rats were divided into the following five groups: normal control group, untreated diabetic group, ART-treated diabetic group (50 mg/kg), Met-treated diabetic group (150 mg/kg), and ART/Met co-treated diabetic group (50 mg/kg ART and 150 mg/kg Met). ART and Met were intragastrically administered daily for 4 weeks. The general conditions, diabetes parameters and serum lipids were evaluated after drug treatment. Furthermore, we observed changes in the central superior salivatory nucleus (SSN) and SG, and changes in the AQP5 expression, parasympathetic innervation (AChE and BDNF expression), and PI3K/AKT pathway- (p-AKT, and p-PI3K), apoptosis- (Bax, Bcl-2, and Caspase3), and autophagy- (LC3 and P62) related markers expression in T2DM rats after treatment. Our results showed that ART or Met alone and ART/Met combination attenuated a range of diabetic symptoms, including weight loss, urine volume increase, water consumption increase, hyperglycemia, insulin resistance, glucose intolerance and dyslipidemia. More importantly, we found that these three treatments, especially ART/Met combination, mitigated hyposalivation in the T2DM rats via improving the central SSN and SGs damage in hyperglycemia. Our data also indicated that ART/Met attenuated SG damage though regulating the PI3K/Akt pathway to inhibit apoptosis and autophagy of SGs in the T2DM rats. Moreover, ART/Met preserved parasympathetic innervation (AChE and BDNF expression) in SGs to alleviate diabetes-induced hyposalivation likely through rescuing central SSN damage. Taken together, these findings might provide a novel rationale and treatment strategy for future treatment of diabetes-induced xerostomia in the clinic.