Adverse reactions associated with nivolumab and small molecule antiangiogenic drugs: A pharmacovigilance analysis.

AIMS: Immune checkpoint inhibitors, such as nivolumab, combined with small molecule antiangiogenic receptor tyrosine kinase inhibitors (TKIs), present a promising strategy for future immunotherapy. However, combination therapy can lead to specific adverse drug reactions (ADRs) in various clinical settings. Current research on the ADRs associated with combination therapy is limited. Our study aims to assess the safety of combination therapy. METHODS: We extracted ADR reports on combination therapy from the Food and Drug Administration (FDA) Adverse Event Reporting System database, covering the period from the first quarter of 2012 to the third quarter of 2023, and conducted a large-scale retrospective study. We evaluated ADR risk signals using the reporting odds ratio (ROR) and calculated the Ro/e ratio to compare the differences in the risk of fatal ADRs among various tumour types. RESULTS: We comprehensively reported the occurrence of ADRs in pan-cancer patients undergoing combination therapy. The combination therapy significantly increased the risk of sensitive skin (ROR: 231.43, 95% CI: 55.01-973.72, P < .05), metastatic renal cell carcinoma (ROR: 220.71, 95% CI: 28.99-1695.41, P < .05) and renal cell carcinoma (ROR: 188.22, 95% CI: 44.24-800.85, P < .05). We also compared the differences in ADRs resulting from different small molecule drug combinations, as well as the differences in ADRs among patients with different types of tumours under combination therapy. Furthermore, we analysed the characteristics of patients prone to experiencing fatal ADRs. CONCLUSION: These results can help enhance understanding of the ADRs commonly associated with combination therapy and assist oncologists in formulating screening protocols.

Clinical Implications of Interleukin-4 and C-reactive Protein in Atopic Dermatitis and Their Changes Before and after Dupilumab Treatment.

Objective: To analyze the clinical implications of C-reactive protein (C-reactive protein) and interleukin-4 (IL-4) in atopic dermatitis and their correlations with the therapeutic effect of Dupilumab (DU). Methods: Seventy-four cases of atopic dermatitis (intervention group) were admitted to Xingtai Third Hospital between May 2021 and January 2023, and 55 concurrent healthy controls (control group) were selected as research participants. Atopic dermatitis patients were treated with a DU injection of 600 mg for the first time after diagnosis. Peripheral blood IL-4 and C-reactive protein levels before and after treatment in the intervention group and their levels at admission in the control group were comparatively analyzed, and their predictive value for the occurrence, clinical efficacy, and adverse reactions of atopic dermatitis were determined. Additionally, alterations in C-reactive protein and IL-4 levels before and after treatment in the intervention group and their relationship with the Scoring Atopic Dermatitis (SCORAD) index were discussed. Results: The intervention group exhibited higher C-reactive protein and IL-4 levels than the control group. The diagnostic sensitivity and specificity of C-reactive protein + IL-4 detection for atopic dermatitis were 74.32% and 94.55%, respectively (P < .05). The post-treatment C-reactive protein and IL-4 were lower in the intervention group, and the test results were positively correlated with SCORAD before and after treatment (P < .05). In addition, C-reactive protein + IL-4 detection showed excellent predictive effects on the therapeutic efficacy of DU and adverse reactions. Conclusions: IL-4 and C-reactive protein are closely related to atopic dermatitis, which can be used as the evaluation indexes for disease development of atopic dermatitis and therapeutic effects of DU in the future.

Thrombocytopenia and In-hospital outcomes in patients with acute ischemic stroke undergoing intravenous thrombolysis: Findings from a nationwide registry study in China.

BACKGROUND AND OBJECTIVE: Our study aimed to evaluate the associations between platelet count (PC) and in-hospital outcomes for patients with stroke after rt-PA intravenous thrombolysis. METHODS: We identified patients who had been hospitalized with a primary diagnosis of stroke and had received rt-PA intravenous thrombolysis from June 2015 to July 2019 at participating hospitals in the Chinese Stroke Center Alliance. PC measured before intravenous thrombolysis was categorized into the following four groups: severe thrombocytopenia (PC < 100 × 109/L), mild thrombocytopenia (100 ≤ PC < 150 × 109/L), normal PC (150 ≤ PC ≤ 450 × 109/L), and thrombocythemia (PC > 450 × 109/L). Outcomes were determined from clinical data collected during hospitalization. The primary clinical outcome was symptomatic intracranial hemorrhage (sICH). Secondary outcomes were mortality, bleeding events, gastrointestinal (GI) hemorrhage, and in-hospital stroke recurrence. We used multivariate logistic regression models to evaluate the associations between PC and outcomes. RESULTS: We included 44,882 individuals with a median age of 66 years, of whom 34.7 % were female, 951 (2.1 %) had severe thrombocytopenia, 7218 (16.1 %) had mild thrombocytopenia, 36,522 (81.4 %) had a normal PC, and 191 (0.4 %) had thrombocythemia. Both severe and mild thrombocytopenia groups had higher risks of bleeding events (adjusted OR 1.30; 95 % CI,1.01-1.67; p = 0.045; adjusted OR 1.32; 95 % CI,1.19-1.46; p < 0.001) and sICH (adjusted OR 1.48;95 % CI,1.13-1.94; p = 0.005; adjusted OR 1.43;95 % CI,1.27-1.60; p < 0.001) than the normal PC group. Patients with 100 ≤ PC < 150 × 109/L also had a higher risk of in-hospital stroke recurrence (adjusted OR 1.12; 95 % CI,1.02-1.22; p = 0.02). CONCLUSIONS: Intravenous thrombolysis brings a high risk of sICH given PC < 150 × 109/L, especially PC < 100 × 109/L. It indicated that PC < 100 × 109/L is a reasonable contraindication to thrombolysis.

Influence of endotracheal tube and laryngeal mask airway for general anesthesia on perioperative adverse events in patients undergoing laparoscopic hysterectomy: A propensity score-matched analysis.

Background: To compare perioperative adverse events between general anesthesia with endotracheal tube (ETT) and general anesthesia with laryngeal mask airway (LMA) in patients undergoing laparoscopic hysterectomy. Materials and Methods: This was a large sample retrospective, propensity score-matched (PSM) study. We collected the data of 6739 female patients who underwent laparoscopic hysterectomy between January 2016 and June 2021 in our hospital, China. Patients were divided into two groups (ETT group and LMA group) according to different airway management modes. Data on all perioperative adverse events were collected. PSM analysis was performed to control confounding factors and differences in baseline values between the two groups. Finally, 4150 female patients were recruited after PSM. Results: The total number of patients taking intraoperative vasoactive drugs during surgery was higher in the ETT group than in the LMA group (P = 0.04). The LMA group had a higher incidence of vomiting (51 [2.46%]) and somnolence (165 [7.95]) in the postanesthesia care unit (PACU) than the ETT group (71 [3.42%] and 102 [4.92%], respectively) (P = 0.02 and P < 0.001). Hypothermia was significantly higher in the LMA group (183 [10.36%]) than in the ETT group (173 [8.34%]) in the PACU (P = 0.03). The number of patients with sore throat was significantly higher in the ETT group (434 [20.02%]) than in the LMA group (299 [14.41%]) in the ward (P < 0.001). Other variables such as hypoxemia, moderate to severe pain, abdominal distension, diarrhea, sleep disorders, wound bleeding, and skin itch were not significantly different between the two groups (P > 0.05). Conclusion: The ETT group had more incidences of vomiting, sore throat, and cough complications and needed more drug treatment than the LMA group. LMA is a better airway management mode and LMA general anesthesia can be safely used in patients undergoing laparoscopic nonemergency hysterectomy.

Inhibition of endoplasmic reticulum stress and the downstream pathways protects CD4+ T cells against apoptosis and immune dysregulation in sepsis.

Immunosuppression mediated by CD4+ T cell apoptosis and dysfunction is a key factor in promoting the progression of sepsis. Endoplasmic reticulum (ER) stress participates in the apoptosis and dysfunction of immune cells. We aimed to investigate the role of ER stress inhibition in CD4+ T cells in both in vitro and in vivo models of sepsis. In vitro model of sepsis was established with lipopolysaccharide (LPS) and the rat model of sepsis was established using cecal ligation and puncture (CLP). After the LPS treatment or CLP, ER stress inhibitors including 4-PBA, SNJ-1945, and SP600125 were used to treat cells or rats, and the CD4+ T cells were obtained by magnetic bead sorting. The effects of ER stress inhibitors on apoptosis and the function of CD4+ T cells were evaluated. After the LPS stimulation or CLP, the levels of ER stress and downstream markers (PERK, eIF2α, IRE-1α, ATF6, ATF4, XBP-1 s, GRP78, CHOP, and p-JNK) were increased in CD4+ T cells at the beginning of sepsis. Meanwhile, the number of apoptotic CD4+ T cells markedly increased. In addition, sepsis impaired the function of CD4+ T cells, manifested by the increased population of Th1, Th2, Th17, and Treg, as well as the production of TNF-α, interleukin (IL)-6, IL-4, and IL-10. However, inhibitors of ER stress, JNK, and calpain all decreased the induction of Th1 and Th17, enhanced the increase of Th2 and Treg, decreased the production of TNF-α and IL-6, and enhanced the production of IL-4 and IL-10. Our findings indicate that ER stress inhibitors may play a protective role by reducing CD4+ T cell apoptosis and maintaining CD4+ T cell function, which may be useful for enhancing the immune function and poor prognosis of patients with sepsis.

Association between haemoglobin A1c and cerebral microbleeds in community-based stroke-free individuals: A cross-sectional study.

AIMS: The association between haemoglobin A1c (HbA1c) and cerebral microbleeds (CMBs) remains unclear. We aimed to investigate the association between HbA1c and CMBs in community-based individuals without stroke or transient ischaemic attack (TIA) and whether the association differs between individuals with and without diabetes mellitus (DM). MATERIALS AND METHODS: All individuals were recruited from a community in Beijing, China, from January 2015 to September 2019. All individuals completed a questionnaire and underwent blood tests and brain magnetic resonance imaging. A susceptibility-weighted imaging sequence was acquired to detect CMBs, which were defined as small, round and low-signal lesions with <10 mm diameter. The association between HbA1c and CMBs was analysed using multivariable logistic regression adjusted for demographics, medical history and blood sample test results. Subgroup analyses stratified by history of DM were performed. RESULTS: Of 544 recruited individuals, 119 (21.88%) had CMBs. HbA1c was independently associated with CMBs (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.03-2.22). In 87 individuals with DM, multivariable logistic analysis showed that HbA1c was significantly associated with CMBs (OR, 1.67; 95% CI, 1.04-2.69), whereas in individuals without DM, no significant association was observed between HbA1c and CMBs (OR, 1.07; 95% CI, 0.50-2.30). CONCLUSIONS: HbA1c was associated with CMBs in individuals without stroke or TIA, particularly in individuals with DM, suggesting that the status of glycaemic control warrants attention for the prevention of CMBs. It would be beneficial to manage HbA1c specifically to control the risk of CMBs, especially in individuals with DM.

Spheroidization of ultrasonic degraded corn silk polysaccharide to enhance bioactivity by the anti-solvent precipitation method.

BACKGROUND: Corn silk is a very important by-product of corn production with medicinal value. Corn silk polysaccharide (CSP) is the main active ingredient. In the present study, ultrasound and spheroidization by anti-solvent were applied to improve the biological activity of CSP. RESULTS: The results showed that ultrasonic degradation improved the α-glucosidase inhibitory activity of CSP by changing its physicochemical characteristics. As the anti-solvent ratio increased, the particle size of the nanoparticles (NPs) from the spheroidization of ultrasonic-degraded corn silk polysaccharide (UCSP) gradually increased, and NP-1 exhibited the highest inhibitory effect of α-glucosidase. Isothermal titration calorimetry (ITC) results indicated that the enhanced activity might be due to more α-glucosidase binding sites with NP-1 compared with no spheroidization. Western blotting results showed that NP-1 could improve the 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) uptake in the L6 cells by regulating the phosphatidylinositol 3-kinase (PI3K)/Akt signal pathway and the translocation of glucose transporter 4 (GLUT4). NP-1 also exhibited excellent stability in different environments. CONCLUSION: The study revealed that ultrasonic treatment and spheroidization processing showed potential applications for improving the biological activity of polysaccharides. © 2021 Society of Chemical Industry.

Increased Levels of Glycated Hemoglobin A1c and Iron Deficiency Anemia: A Review.

Worldwide, the prevalence of diabetes remains high. Studies have shown that iron deficiency anemia (IDA) is associated with increased levels of glycated hemoglobin A1c (HbA1c), but the mechanism remains unclear. Hematological changes, iron metabolism, study methodology, and other factors could affect the results of diagnostic investigations, leading to false results. Red blood cell turnover in the bone marrow and the quality and heterogeneity of erythrocytes may influence the rate of hemoglobin glycation. By changing the structure of hemoglobin and inducing peroxidation, iron deficiency accelerates glycation. This review aims to discuss the possible causes of the association between increased levels of HbA1c and IDA.

Tumor necrosis factor superfamily 15 promotes lymphatic metastasis via upregulation of vascular endothelial growth factor-C in a mouse model of lung cancer.

Lymphatic metastasis is facilitated by lymphangiogenic growth factor vascular endothelial growth factor-C (VEGFC) that is secreted by some primary tumors. We previously identified tumor necrosis factor superfamily 15 (TNFSF15), a blood vascular endothelium-derived cytokine, in lymphatic endothelial cells, as a key molecular modulator during lymphangiogenesis. However, the effect of TNFSF15 on tumor lymphatic metastasis and the underlying molecular mechanisms remain unclear. We report here that TNFSF15, which is known to inhibit primary tumor growth by suppressing angiogenesis, can promote lymphatic metastasis through facilitating lymphangiogenesis in tumors. Mice bearing tumors induced by A549 cells stably overexpressing TNFSF15 exhibited a significant increase in densities of lymphatic vessels and a marked enhancement of A549 tumor cells in newly formed lymphatic vessels in the primary tumors as well as in lymph nodes. Treatment of A549 cells with TNFSF15 results in upregulation of VEGFC expression, which can be inhibited by siRNA gene silencing of death domain-containing receptor-3 (DR3), a cell surface receptor for TNFSF15. In addition, TNFSF15/DR3 signaling pathways in A549 cells include activation of NF-κB during tumor lymphangiogenesis. Our data indicate that TNFSF15, a cytokine mainly produced by blood endothelial cells, facilitates tumor lymphangiogenesis by upregulating VEGFC expression in A549 cells, contributing to lymphatic metastasis in tumor-bearing mice. This finding also suggests that TNFSF15 may have potential as an indicator for prognosis evaluation.

Prognostic and predictive value of plasma D-dimer levels in patients with small-cell lung cancer.

BACKGROUND: To investigate the predictive value of plasma D-dimer levels for short-term therapeutic effect and progression-free survival (PFS) in patients with small-cell lung cancer (SCLC); and to analyze the correlation between baseline plasma D-dimer levels and other clinicopathological features. The aim of the study was to investigate whether the levels of plasma D-dimer could serve as a predictive and prognostic factor in patients with SCLC. METHODS: A retrospective review of the clinicopathological data of 160 patients with pathologically confirmed SCLC, who were treated at the Department of Thoracic Oncology of Tianjin Medical University Tumor Institute and Hospital between June 2011 and June 2016, was performed. At the same time, we collected 100 patients with benign pulmonary diseases as a control group. The correlations between baseline plasma D-dimer levels and other clinical features, therapeutic effect and PFS were analyzed statistically. RESULTS: The level of plasma D-dimer in patients with SCLC was significantly higher than that of patients with benign pulmonary diseases (P = 0.001). The PFS of patients with elevated D-dimer levels before therapy were significantly shorter than that of patients with normal D-dimer levels (6.0 versus 7.5 months, P = 0.013). The patients whose plasma D-dimer level always (before and after treatment) in the normal range have the best prognosis, and continuously elevated D-dimer carried out a poor prognosis (8.0 versus 5.0 months). According to multivariate analysis, elevated D-dimer level was confirmed to be an independent prognostic factor for worse survival (P = 0.029). The level of D-dimer was associated with tumor stage, the level of neuron-specific enolase, the presence of distant metastasis, hyponatremia, and the Karnofsky performance status score; and levels decreased when therapy was effective, but increased when the disease progressed. CONCLUSIONS: High levels of baseline plasma D-dimer may indicate advanced disease stage and poor prognosis. Therefore, plasma D-dimer levels could serve as a predictive and prognostic factor in patients with SCLC.

Oxyresveratrol, a Stilbene Compound from Morus alba L. Twig Extract Active Against Trichophyton rubrum.

Morus alba L. (mulberry) twig is known to have an inhibitory effect on pathogens in traditional Chinese medicine. In the present study, the dermophytic fungus, Trichophyton rubrum, was used to evaluate the inhibitory effect of total M. alba twig extract and extracts obtained using solvents with different polarities by the method of 96-well MTT colorimetry. The main active substance was isolated and identified by tracking its activity. In addition, the inhibitory effects of active extracts and a single active substance were investigated in combination with miconazole nitrate. Our data indicated that ethyl acetate extracts of mulberry twig (TEE) exhibited a desired inhibitory activity on T. rubrum with the minimum inhibitory concentration (MIC) of 1.000 mg/mL. With activity tracking, the main substance showing antimicrobial activity was oxyresveratrol (OXY), which was isolated from TEE. Its MIC for inhibiting the growth of T. rubrum was 0.500 mg/mL. The combined use of miconazole nitrate and OXY showed a synergistic inhibitory effect, as shown by a significant decrease in the MIC of both components. Based on the OXY content in TEE, the contribution rate of OXY to the inhibitory effect of TEE on T. rubrum was 80.52%, so it was determined to be the main antimicrobial substance in M. alba twig. Copyright © 2017 John Wiley & Sons, Ltd.

The Pharmacological Mechanisms Underlying the Protective Effect of Ginsenoside Rg3 against Heart Failure.

Background: Heart failure represents the terminal stage of various cardiovascular diseases. This study aims to explore the pharmacological mechanisms underlying the protective effect of Ginsenoside Rg3 against heart failure. Methods: Potential targets of Ginsenoside Rg3 were identified using SwissTargetPrediction and the Comparative Toxicogenomics Database, while heart failure-related genes were retrieved from the Comparative Toxicogenomics Database, Therapeutic Target Database, DisGeNET, and PharmGKB. Overlapping of Ginsenoside Rg3 targets with heart failure-related genes identified drug-disease interaction genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted on the drug-disease interaction genes to elucidate their biological functions. A protein-protein interaction network was constructed using the drug-disease interaction genes, and the hub genes were identified by topological analysis. Additionally, we validate the expression of IL-6 and TNF by real-time PCR. Results: The intersection of Ginsenoside Rg3 targets and heart failure-related genes yielded 15 drug-disease interaction genes. Enrichment analysis highlighted the involvement of inflammation-related GO terms and KEGG pathways, such as positive regulation of interleukin-8 and -6 production, regulation of immune effector process, cytokine receptor binding, cytokine activity, adipocytokine signaling pathway, and IL-17 signaling pathway, which are implicated in the cardioprotective effect. Topological analysis revealed four hub genes: STAT3, CASP3, TNF, and IL-6. The application of Ginsenoside Rg3 significantly reversed the elevated levels of IL-6 and TNF in the isoproterenol-treated H9c2 cell line. Conclusions: Our findings suggest that the cardioprotective effect of Ginsenoside Rg3 may be mediated through its anti-inflammation properties. Further research is required to elucidate and validate the detailed cardioprotective mechanisms of Ginsenoside Rg3.

Impaired neural circuitry of hippocampus in Pax2 nervous system-specific knockout mice leads to restricted repetitive behaviors.

INTRODUCTION: Restricted repetitive behaviors (RRBs), which are associated with many different neurological and mental disorders, such as obsessive-compulsive disorder (OCD) and autism, are patterns of behavior with little variation and little obvious function. Paired Box 2 (Pax2) is a transcription factor that is expressed in many systems, including the kidney and the central nervous system. The protein that is encoded by Pax2 has been implicated in the development of the nervous system and neurodevelopmental disorders. In our previous study, Pax2 heterozygous gene knockout mice (Pax2+/- mice) showed abnormally increased self-grooming and impaired learning and memory abilities. However, it remains unclear which cell type is involved in this process. In this study, we deleted Pax2 only in the nervous system to determine the regulatory mechanism of Pax2 in RRBs. METHODS: In this study, Pax2 nervous system-specific knockout mice (Nestin-Pax2 mice) aged 6-8 weeks and Pax2 flox mice of the same age were recruited as the experimental group. Tamoxifen and vehicle were administered via intraperitoneal injection to induce Pax2 knockout after gene identification. Western blotting was used to detect Pax2 expression. After that, we assessed the general health of these two groups of mice. The self-grooming test, marble burying test and T-maze acquisition and reversal learning test were used to observe the lower-order and higher-order RRBs. The three-chamber test, Y-maze, and elevated plus-maze were used to assess social ability, spatial memory ability, and anxiety. Neural circuitry tracing and transcriptome sequencing (RNA-seq) were used to observe the abnormal neural circuitry, differentially expressed genes (DEGs) and signaling pathways affected by Pax2 gene knockout in the nervous system and the putative molecular mechanism. RESULTS: (1) The Nestin-Pax2 mouse model was successfully constructed, and the Nestin-Pax2 mice showed decreased expression of Pax2. (2) Nestin-Pax2 mice showed increased self-grooming behavior and impaired T-maze reversal behavior compared with Pax2 flox mice. (3) An increased number of projection fibers can be found in the mPFC projecting to the CA1 and BLA, and a reduction in IGFBP2 can be found in the hippocampus of Nestin-Pax2 mice. CONCLUSION: The results demonstrated that loss of Pax2 in the nervous system leads to restricted repetitive behaviors. The mechanism may be associated with impaired neural circuitry and a reduction in IGFBP2.

[Effect of Land Use on the Stability of Soil Organic Carbon in a Karst Region].

The composition of soil organic carbon and its stability mechanism are the key to understanding the terrestrial carbon sink capacity. The stability of soil organic carbon in a karst ecosystem greatly affects the soil carbon fixation capacity. In order to understand the impact of human activities on the stability of soil organic carbon in karst areas, the karst valley area of Zhongliang Mountain in Chongqing was selected as an example, and soil samples of four typical land use modes (mixed forest, bamboo forest, grassland, and cultivated land) were collected in layers to analyze the total organic carbon (TOC) and heavy fraction organic carbon (HFOC). The distribution characteristics of light fraction organic carbon (LFOC), labile organic carbon (LOC), and recalcitrant organic carbon (ROC) were analyzed quantitatively by using a structural equation model to provide basic data for soil carbon sink assessment and soil quality protection in karst areas. The results showed that the organic carbon components under different land use patterns in karst areas had obvious surface accumulation, and the content of organic carbon components in the surface layer was 1.2 times that in the bottom layer. Except for LFOC, the content of other organic carbon components was the highest in the mixed forest, followed by that in the bamboo forest and wasteland, with the lowest in cultivated land. Mixed forest ω(TOC) content was the highest, 42.5 g·kg-1, followed by that of bamboo forest (36.6 g·kg-1) and grassland (18.7 g·kg-1), and cultivated land content was the lowest, 13.4 g·kg-1. The soil organic carbon content of cultivated land was 68.5%, 63.5%, and 28.3% lower than that of mixed forest, bamboo forest, and grassland, respectively. Mixed forest had the highest content of ω(HFOC), 21 g·kg-1, followed by those of bamboo forest (20.9 g·kg-1), grassland (18.2 g·kg-1), and cultivated land (13.5 g·kg-1). The mixed forest ω(LOC) content was the highest, 16.3 g·kg-1, followed by those of bamboo forest (14.9 g·kg-1), grassland (11.5 g·kg-1), and cultivated land (5.3 g·kg-1). Mixed forest ω (ROC) content was the highest, 25.7 g·kg-1, followed by those of bamboo forest (21.6 g·kg-1), grassland (15.9 g·kg-1), and cultivated land (10.3 g·kg-1). The bamboo forest land ω(LFOC) content was 15.9 g·kg-1, followed by those of mixed forest (13.9 g·kg-1), grassland (7.3 g·kg-1), and cultivated land (4.9 g·kg-1). The recalcitrant organic carbon index (ROCI) was used to indicate the stability of soil organic carbon. The variation range of ROCI was 33.9%-64.5%, of which the highest was mixed forest (64.5%-66.3%), and the lowest was cultivated land (33.8%-39.6%). The ROCI of mixed forest, bamboo forest, and grassland were 1.8 times, 1.6 times, and 1.4 times that of cultivated land, respectively. Karst area ω (inert organic carbon) content and ROCI showed that human agricultural activities caused the reduction in soil organic carbon content and the destruction of soil physical structure, resulting in the accelerated decomposition and turnover rate of soil organic matter. The most important factor affecting soil stability in karst areas was soil pH. Tillage activities caused soil pH to rise, reduced soil microbial activity, and were not conducive to the accumulation of the inert organic carbon and soil organic carbon pool in the soil.

[Effects of Land Use Change on Soil Aggregate Stability and Soil Aggregate Organic Carbon in Karst Area of Southwest China].

Investigating the relationship of soil aggregate stability with the organic carbon in the aggregate and its response to land use change is conducive to the estimation of soil carbon sink potential, improvement of rocky desertification, and rational land use in karst areas of Southwest China. In order to explore the effects of land use change on the composition and stability of soil aggregate stability as well as the content of aggregate organic carbon, the soil (0-30 cm) of five land use types (secondary forest, pomelo forest, paddy field, pepper forest, and dry land) was selected as the research object. The characteristics and correlation of soil aggregate components and organic carbon under different land use patterns were obtained, and the contribution of soil aggregates to the change in organic carbon after land use change was calculated. The results showed that the macroaggregates in the surface soil (0-15 cm) of the secondary forest, pomelo forest, and paddy field were 63.32%, 52.38%, and 47.77%, respectively, which were significantly higher than that of dry land (23.70%), as was also seen in the lower layer (15-30 cm). The geometric mean diameter (GMD) and mean weight diameter (MWD) of soil aggregates in the secondary forest, pomelo forest, and paddy field were significantly higher than those in dry land. In the surface soil, the organic carbon of the secondary forest and paddy field was significantly higher than that of other land use patterns. By contrast, in the lower soil layer, only the organic carbon of the paddy field was significantly higher than that of the others. Under different land use patterns, the organic carbon content of aggregates followed the same order of macroaggregates > microaggregates > silt and clay, indicating that macroaggregates allowed soil organic carbon to accumulate, whereas silt and clay did the opposite. According to correlation analysis, the content of soil macroaggregates was significantly positively correlated with GMD, MWD, and soil aggregate organic carbon, suggesting that the increase in soil macroaggregates could improve the stability of soil aggregates and store more soil organic carbon. Further, as land use change may have significantly affected the soil aggregate, moderate development of forestry and paddy cultivation is suggested to improve the soil carbon sequestration potential in the karst area of Southwest China.

Individualized management of immunosuppressants in liver transplant recipients by using a novel immune score system.

BACKGROUND: There is no reliable means to evaluate the immune status of liver transplant recipients. We proposed a novel score model, namely Mingdao immune cell analysis and Mingdao immune score system, to quantify the immunity. METHODS: Data from those who underwent a single liver transplant between January 2017 and June 2020 at Beijing Chaoyang Hospital, were collected. In addition, healthy volunteers were also enrolled. The score model was based on the immune cell populations determined by flow cytometry. RESULTS: There were a total of 376 healthy controls with 376 tests and 148 liver transplant recipients with 284 tests in this study. Evaluated by Mingdao immune cell analysis and Mingdao immune score system, the mean scores of healthy controls were near zero suggesting a balanced immune system. In contrast, the mean scores of liver transplant recipients were negative both before and after surgery indicating a compromised immune system. When liver transplant recipients were given a reduced or routine first dose according to their preoperative score, they had similar recovery of liver function. Moreover, liver transplant recipients with increased scores ≥ 5 were associated with elevated aspartate transaminase and alanine amiotransferase. Finally, on multivariate analysis the score model was the only significant independent risk factor for clinical acute rejection (P = 0.021; Odds ratio, 0.913; 95% confidence interval, 0.845-0.987). CONCLUSION: The novel score model could be used as an indicator to reflect immunity and to regulate immunosuppressants in liver transplant recipients after surgery.

Impact of metabolic dysfunction-associated fatty liver disease on liver transplant recipients with hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease was proposed by international consensus to redefine the metabolic abnormal condition. However, its impact on liver transplant recipients with hepatitis B virus-related hepatocellular carcinoma has not been explored. METHODS: A two-center retrospective cohort study on liver transplant recipients with hepatitis B virus-related hepatocellular carcinoma was performed to analyze the impact of metabolic dysfunction-associated fatty liver disease on the clinicopathologic parameters and prognosis. RESULTS: There were 201 liver transplant recipients enrolled from two hospitals in our study. The pre- and post-transplant prevalences of metabolic dysfunction-associated fatty liver disease were 9.95% and 28.86%, respectively. The clinicopathological parameters revealed a similarity between patients with and without pre-transplant metabolic dysfunction-associated fatty liver disease. In contrast, the group with post-transplant metabolic dysfunction-associated fatty liver disease was linked with older age, a higher hepatitis recurrence rate and incidence of cardiovascular disease, usage of calcineurin inhibitors, a greater body mass index and waist circumference, lower albumin and high-density lipoprotein cholesterol levels, and poorer tumor-free survival and overall survival. The multivariate analysis showed the largest tumor size >4 cm (95% confidence intervals: 0.06~0.63, p = 0.006), microvascular invasion (95% confidence intervals: 1.61~14.92, p = 0.005), post-transplant metabolic dysfunction-associated fatty liver disease (95% confidence intervals: 1.40~10.60, p = 0.009), and calcineurin inhibitors-based regimen (95% confidence intervals: 0.33~0.96, p = 0.036) were the independent risk factors for recurrent hepatocellular carcinoma. CONCLUSIONS: Our study suggests that post-transplant metabolic dysfunction-associated fatty liver disease is more closely to metabolic abnormalities and that it can help identify liver transplant recipients at high risk of recurrent hepatocellular carcinoma.

Studies on the key constituents and the related mechanisms of Clerodendranthus spicatus in the treatment of diabetes based on network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Clerodendranthus spicatus is a traditional Chinese medicine and has been used to treat diabetes and some kidney diseases for a long history. AIM OF THE STUDY: The research aimed to study the active constituents, the potential targets and the related mechanisms of C. spicatus in the treatment of diabetes through network pharmacology method and verify the antidiabetic activity by molecular biology experiments. MATERIALS AND METHODS: A comprehensive network pharmacology strategy was used to predict the key active constituents, the key targets and the related mechanisms and pathways of C. spicatus in the treatment of diabetes. The strategy mainly included screening and predicting potential active constituents and targets by network construction, GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis. Based on the predicted results, C. spicatus was extracted by ultrasonic method with 50% ethanol and enriched by using macroporous resin. The compounds with potential antidiabetic effects were separated through silica-gel column chromatography and HPLC (high performance liquid chromatography), and then identified by MS (mass spectrum) and NMR (nuclear magnetic resonance). The C. spicatus extract and isolated compounds were tested by in-vitro and cell experiments to verify their antidiabetic activities, including antioxidant activities, inhibition activities on α-glucosidase and α-amylase, the influence on glucose uptake in cell experiments and the Western blot of PI3K and Akt expression levels. RESULTS: A total of 18 active constituents and 16 key targets of C. spicatus in the treatment of diabetes were screened out through network pharmacology method. Phenolic acids might be the main target compounds for the next research. After extraction, enrichment and separation, the phenolic acids-enriched fraction of C. spicatus and four phenolic acid compounds (helisterculin C, salvianolic acid B, orthosiphoic acid E and ethyl caffeate) were obtained. Among them, salvianolic acid B was isolated from C. spicatus for the first time and orthosiphoic acid E was isolated from natural products for the first time. In experiment verification, the crude extract of C. spicatus, the phenolic acids-enriched fraction and the four compounds all showed antidiabetic potentials. The phenolic acids in C. spicatus had antioxidant activities, inhibitory activities on α-amylase and α-glucosidase and promoted glucose uptake in L6 cells through PI3K/Akt signaling pathway. CONCLUSIONS: This study showed that C. spicatus had antidiabetic activities with the mechanism of the mode of multi-compounds acting on multi-targets and multi-pathways. The main active phenolic acid compounds were also identified. It provided theoretical basis for further development and utilization of C. spicatus.

Gut microbiome-mediated glucose and lipid metabolism mechanism of star apple leaf polyphenol-enriched fraction on metabolic syndrome in diabetic mice.

BACKGROUND: Diabetes is a kind of metabolic syndrome (MetS) that seriously threatens human health globally. The leaf of star apple (Chrysophyllum cainito L.) is an incompletely explored folk medicine on diabetes. And, the effects and mechanisms on diabetes complicated glycolipid metabolism disorders are unknown till now. PURPOSE: This study aimed to investigate the constituents of star apple leaf polyphenol enriched-fraction (SAP), and elucidate their treatment effects and mechanism on diabetes and accompanied other MetS. METHODS: The components of SAP were tentatively identified by HPLC-Q-TOF-MS/MS. The antioxidant activity was determined by the scavenging of free radicals and hypoglycemic activities by inhibition of α-glucosidase in vitro. HepG2 cells were used for evaluating the alleviation effects of SAP on lipid accumulation. Streptozotocin and high-fat diet induced diabetic mice were grouped to evaluate the effects of different dosages of SAP. 16S rRNA was conducted to analysis gut microbiome-mediated glucose and lipid metabolism mechanism. RESULTS: It showed that myricitrin was one of the main active constituents of SAP. SAP not only showed low IC50 on -glucosidase (24.427± 0.626 µg/mL), OH·(3.680± 0.054 µg/mL) and ABTS· (9.155±0.234 µg/mL), but significantly induced the lipid accumulation in HepG2 cells (p < 0.05). SAP at 200 mg/kg·day significantly decreased the blood glucose, insulin and oral glucose tolerance test value (p < 0.05). The insulin resistance indexes and oxidative stress were alleviated after administration. SAP not only attenuated hepatic lipid deposition, but also reversed the hepatic glycogen storage. 16S rRNA sequencing results revealed that the interaction between SAP and gut microbiota led to the positive regulation of beneficial bacteria including Akkermansia, Unspecified S24_7, Alistipes and Unspecified_Ruminococcaceae, which might be one of the mechanisms of SAP on MetS. CONCLUSION: For the first time, this study explored the regulation effect of star apple leaf polyphenols on the hepatic glycolipid metabolism and studied the underlying mechanism from the view of gut microbiota. These findings indicated that SAP possesses great potential to serve as a complementary medicine for diabetes and associated MetS. It provided scientific evidence for folk complementary medicine on the treatment of diabetes-complicated multiple metabolic disorders.

Risk factors and clinical outcomes of basilar artery occlusion presenting with paroxysmal sympathetic hyperactivity as the initial manifestation: a prospective study.

BACKGROUND: Paroxysmal sympathetic hyperactivity (PSH) has been linked to a worse clinical prognosis in patients with traumatic brain injury. We aimed to identify the risk factors and clinical features associated with basilar artery occlusion (BAO) presenting with PSH as the first clinical presentation. METHODS: This study recruited patients with acute BAO who received endovascular therapy (EVT) at two stroke centers in China. PSH Assessment Measure ≥8 was included in the PSH+ group, while those with a score below 8 were classified as the PSH- group. Clinical data and radiological findings were compared between the two groups. A binary logistic regression model was employed to identify independent risk factors for PSH. RESULTS: 101 participants were enrolled, of whom 19 (18.8%) presented with PSH as the initial manifestation of BAO. Worse prognosis (modified Rankin Scale score of 4-6) at day 90 occurred in 14 (73.7%) of the PSH+ patients and 42 (51.2%) of the PSH- patients (P=0.076). The 90-day mortality rate was higher in the PSH+ group with 12 (63.2%) participants, compared with 31 (37.8%) participants in the PSH- group (P=0.044). A significantly increased risk of PSH was found in patients with midbrain involvement (OR 6.53, 95% CI 1.56 to 27.30, P=0.01) and a high baseline National Institutes of Health Stroke Scale (NIHSS) score (OR 1.15, 95% CI 1.01 to 1.31, P=0.037). CONCLUSIONS: Patients with BAO presenting with PSH as the initial clinical manifestation experience a higher risk of 90-day mortality, despite undergoing EVT. Midbrain infarction and baseline NIHSS score may be significant risk factors for PSH following BAO.