Establishment of a mortality risk nomogram for predicting in-hospital mortality of sepsis: cohort study from a Chinese single center.

Objective: To establish a mortality risk nomogram for predicting in-hospital mortality of sepsis patients in the Chinese population. Methods: Data were obtained from the medical records of sepsis patients enrolled at the Affiliated Huadu Hospital, Southern Medical University, between 2019 and 2021. A total of 696 sepsis patients were initially included in our research, and 582 cases were finally enrolled after screening and divided into the survival group (n = 400) and the non-survival group (n = 182) according to the incidence of mortality during hospitalization. Twenty-eight potential sepsis-related risk factors for mortality were identified. Least absolute shrinkage and selection operator (LASSO) regression was used to optimize variable selection by running cyclic coordinate descent with k-fold (tenfold in this case) cross-validation. We used binary logistic regression to build a model for predicting mortality from the variables based on LASSO regression selection. Binary logistic regression was used to establish a nomogram based on independent mortality risk factors. To validate the prediction accuracy of the nomogram, receiver operating characteristic curve (ROC) analysis, decision curve analysis (DCA) and restricted cubic spline (RCS) analysis were employed. Eventually, the Hosmer-Lemeshow test and calibration curve were used for nomogram calibration. Results: LASSO regression identified a total of ten factors, namely, chronic heart disease (CHD), lymphocyte count (LYMP), neutrophil-lymphocyte ratio (NLR), red blood cell distribution width (RDW), C reactive protein (CRP), Procalcitonin (PCT), lactic acid, prothrombin time (PT), alanine aminotransferase (ALT), total bilirubin (Tbil), interleukin-6 (IL6), that were incorporated into the multivariable analysis. Finally, a nomogram including CHD, LYMP, NLR, RDW, lactic acid, PT, CRP, PCT, Tbil, ALT, and IL6 was established by multivariable logistic regression. The ROC curves of the nomogram in the training and validation sets were 0.9836 and 0.9502, respectively. DCA showed that the nomogram could be applied clinically if the risk threshold was between 29.52 and 99.61% in the training set and between 31.32 and 98.49% in the testing set. RCS showed that when the value of independent risk factors from the predicted model exceeded the median, the mortality hazard ratio increased sharply. The results of the Hosmer-Lemeshow test (χ2 = 0.1901, df = 2, p = 0.9091) and the calibration curves of the training and validation sets showed good agreement with the actual results, which indicated good stability of the model. Conclusion: Our nomogram, including CHD, LYMP, NLR, RDW, lactic acid, PT, CRP, PCT, Tbil, ALT, and IL6, exhibits good performance for predicting mortality risk in adult sepsis patients.

Identification of a novel hypoglycemic small molecule, trans-2, 4-dimethoxystilbene by rectifying gut microbiota and activating hepatic AMPKα-PPARγ pathway through gut-liver axis.

With the increasing prevalence of metabolic disorders, hyperglycemia has become a common risk factor that endangers people's lives and the need for new drug solutions is burgeoning. Trans-2, 4-dimethoxystilbene (TDMS), a synthetic stilbene, has been found as a novel hypoglycemic small molecule from glucose consumption test. Normal C57BL/6 J mice, mouse models of type 1 diabetes mellitus and diet-induced obesity subjected to TDMS gavage were found with lower glycemic levels and better glycemic control. TDMS significantly improved the symptoms of polydipsia and wasting in type 1 diabetic mice, and could rise their body temperature at the same time. It was found that TDMS could promote the expression of key genes of glucose metabolism in HepG2, as do in TDMS-treated liver, while it could improve the intestinal flora and relieve intestinal metabolic dysbiosis in hyperglycemic models, which in turn affected its function in the liver, forming the gut-liver axis. We further fished PPARγ by virtual screening that could be promoted by TDMS both in-vitro and in-vivo, which was regulated by upstream signaling of AMPKα phosphorylation. As a novel hypoglycemic small molecule, TDMS was proven to be promising with its glycemic improvements and amelioration of diabetes symptoms. It promoted glucose absorption and utilization by the liver and improved the intestinal flora of diabetic mice. Therefore, TDMS is expected to become a new hypoglycemic drug that acts through gut-liver axis via AMPKα-PPARγ signaling pathway in improving glycemic metabolism, bringing new hope to patients with diabetes and glucose metabolism disorders.

Predictive value of the neutrophil-to-lymphocyte ratio in the prognosis and risk of death for adult sepsis patients: a meta-analysis.

Background: The neutrophil-to-lymphocyte ratio (NLR) is a commonly used biomarker for acute inflammation that often rises during sepsis, making it a valuable diagnostic indicator for clinical practice. However, no consensus has been reached on the prognostic value of NLR for predicting the prognosis and mortality risk in adult sepsis patients. In light of this controversy, we conducted a meta-analysis to clarify the prognostic significance of NLR in adult sepsis patients. The meta-analysis was registered in the PROSPERO database (registration number CRD42023433143). Methods: We performed a comprehensive literature search in PubMed, Cochrane Library, Ovid, and Springer databases, using retrieval terms "sepsis" or "septic shock" and "prognosis" or "mortality" for studies published between January 1, 2000, and May 31, 2023. Children and neonates with sepsis were excluded from our research. Two independent researchers conducted the literature search and data extraction. Consensus was reached when discrepancies occurred, and in case of persistent discrepancies, the final decision was made by the research supervisor. The hazard ratio (HR) and its corresponding 95% confidence interval (95% CI) were extracted from each study included in the analysis. A random-effects model was used to synthesize all HRs and their 95% CIs. Sensitivity analysis was performed to investigate heterogeneity. Sensitivity analysis was conducted to identify studies that had a significant impact on the overall results of the meta-analysis. Subgroup analysis and meta-regression were performed to explore sources of heterogeneity. Egger's test was also used to investigate publication bias in this meta-analysis. Results: After a comprehensive literature search and screening, we included 12 studies comprising 10,811 patients for the meta-analysis. The pooled results indicated that patients with a higher NLR level were associated with a poor prognosis (Random-effects model, HR: 1.6273, 95% CI: 1.3951-1.8981). Heterogeneity testing showed significant heterogeneity (I2 = 87.2%, 95% CI: 79.5-92, p<0.0001). Sensitivity analysis was performed to investigate the sources of heterogeneity, which revealed that the omission of one highly sensitive study significantly reduced the I2 value. After removing this study, a strong association was found between a higher NLR level and poor prognosis and risk of death in adult sepsis patients (Random-effects model, HR: 1.6884, 95% CI: 1.4338-1.9882). Both subgroup analysis and meta-regression indicated that the study design and testing time of NLR were sources of heterogeneity. Egger's test showed no obvious publication bias in this meta-analysis. Conclusion: NLR is a reliable and valuable biomarker for predicting prognosis and the risk of death in adult sepsis patients. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023433143] PROSPERO, identifier [CRD42023433143].

Exploring the therapeutic potential of cannabidiol for sleep deprivation-induced hyperalgesia.

Hyperalgesia resulting from sleep deprivation (SD) poses a significant a global public health challenge with limited treatment options. The nucleus accumbens (NAc) plays a crucial role in the modulation of pain and sleep, with its activity regulated by two distinct types of medium spiny neurons (MSNs) expressing dopamine 1 or dopamine 2 (D1-or D2) receptors (referred to as D1-MSNs and D2-MSNs, respectively). However, the specific involvement of the NAc in SD-induced hyperalgesia remains uncertain. Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has demonstrated analgesic effects in clinical and preclinical studies. Nevertheless, its potency in addressing this particular issue remains to be determined. Here, we report that SD induced a pronounced pronociceptive effect attributed to the heightened intrinsic excitability of D2-MSNs within the NAc in Male C57BL/6N mice. CBD (30 mg/kg, i.p.) exhibited an anti-hyperalgesic effect. CBD significantly improved the thresholds for thermal and mechanical pain and increased wakefulness by reducing delta power. Additionally, CBD inhibited the intrinsic excitability of D2-MSNs both in vitro and in vivo. Bilateral microinjection of the selective D2 receptor antagonist raclopride into the NAc partially reversed the antinociceptive effect of CBD. Thus, these findings strongly suggested that SD activates NAc D2-MSNs, contributing heightened to pain sensitivity. CBD exhibits antinociceptive effects by activating D2R, thereby inhibiting the excitability of D2-MSNs and promoting wakefulness under SD conditions.

Immune effector dysfunction signatures predict outcomes in patients with colorectal cancer.

BACKGROUND: Immune effector dysfunction (IED) is mainly manifested as immune exhaustion and senescence, which are the primary obstacles to the success of cancer immunotherapy. In the current study, we characterized the prognostic relevance of IED signatures in patients with colorectal cancer (CRC). METHODS: Immunohistochemistry (IHC) data of CRC tissue samples from 41 newly diagnosed patients in our clinical center (HDPH cohort) were used to investigate the prognostic importance of IED signatures. The results were validated by the RNA sequencing data of 372 CRC patients from the Cancer Genome Atlas (TCGA) database. RESULTS: In the HDPH cohorts, high Natural Killer (NK) and CD8+ tumor-infiltrating lymphocytes (TILs) were associated with poor overall survival (OS) and relapse-free survival (RFS) in CRC patients. Optimal IED signatures, including high expression of CCR9, ISG20, and low expression of ICOS, and CACNA2D2, predicted poor OS and RFS. Moreover, high-risk scores estimated by a weighted combination of these four IED genes were associated with poor OS and RFS. Notably, risk stratification was constructed by combining risk score and tumor node metastasis (TNM) stage better than TNM stage alone in predicting OS and RFS for CRC patients. The above results were confirmed in the TCGA cohort. CONCLUSION: CCR9, ISG20, ICOS, and CACNA2D2 were optimal IED signatures for predicting the outcomes of CRC patients, which might be a potential biomarker for prognostic stratification and designing novel CRC therapy.

Progress of studies on natural products for glioblastoma therapy.

Glioblastoma (GBM) is the most common, malignant, and lethal primary brain tumor in adults. Up to now, the chemotherapy approaches for GBM are limited. Therefore, more studies on identifying and exploring new chemotherapy drugs or strategies overcome the GBM are essential. Natural products are an important source of drugs against various human diseases including cancers. With the better understanding of the molecular etiology of GBM, the development of new anti-GBM drugs has been increasing. Here, we summarized recent researches of natural products for the GBM therapy and their potential mechanisms in details, which will provide new ideas for the research on natural products and promote developing drugs from nature products for GBM therapy.

Synthesis of Novel Acetyl-11-keto-ß-boswellic Acid Derivatives as Potential Anti-GBM Agents.

Acetyl-11-keto-ß-boswellic acid (AKBA) is known to inhibit the growth of glioblastoma (GBM) cells and subcutaneous GBM. A series of acetyl-11-keto-ß-boswellic acid (AKBA) derivatives containing the oxime-ester functionality or amide side chains were synthesized, and their anti-GBM activities were evaluated. Some of these compounds exhibited significant inhibitory activity against cell proliferation in U87 and U251 GBM cell lines, with IC50 values in the micromolar concentration range. Cellular thermal shift analysis showed that A-01 and A-10 improved the thermal stability of FOXM1, indicating that these highly active compounds may directly bind to FOXM1 in cells. Docking studies of the two most active compounds, A-01 and A-10, revealed key interactions between these compounds and the active site of FOXM1, in which the amide moiety at the C-24 position was essential for improving the activity. These results suggested that A-10 is a suitable lead molecule for the development of FOXM1 inhibitors. Thus, the rational design of AKBA derivatives with amide side chains holds significant potential for discovering of a new class of triterpenoids capable of inhibiting GBM cell proliferation.

A nomogram for predicting in-hospital overall survival of hypertriglyceridemia-induced severe acute pancreatitis: A single center, cross-sectional study.

Background: Hypertriglyceridemia-induced severe acute pancreatitis (HTG-SAP) is a type of pancreatitis characterized by an abnormal elevation of plasma triglyceride. HTG-SAP has been associated with various complications and a high mortality rate. In this study, we established a nomogram for predicting the overall survival (OS) of HTG-SAP patients during hospitalization. Methods: 128 HTG-SAP cases hospitalized at the Affiliated Huadu Hospital, Southern Medical University, from 2019 to 2022 were analyzed retrospectively. A nomogram including prognostic factors correlated with OS during hospitalization was established by multivariate Cox regression analysis. We internally validated the nomogram using time-dependent (at 1-, 2-, and 3- months) survival receiver operating characteristic (SROC) and calibration curve with 500 iterations of bootstrap resampling. Time-dependent decision curve analysis (DCA) was employed to validate the clinical value of the nomogram. Results: Multivariate Cox regression indicated that serum triglyceride, red blood cell distribution width (RDW), lactic acid, and interleukin-6 (IL6) were independent prognostic factors for OS of HTG-SAP patients during hospitalization and were used to construct a nomogram. The time-dependent area under the curve (AUC) values at 1-, 2-, and 3- months were 0.946, 0.913, and 0.929, respectively, and the Concordance index (C-index) of the nomogram was 0.916 (95%CI 0.871-0.961). The time-dependent calibration curves indicated good consistency between the observed and predicted outcomes. The time-dependent DCAs also revealed that the nomogram yielded a high clinical net benefit. After stratifying the included cases into two risk groups based on the risk score obtained from the nomogram, the high-risk group exhibited a significantly inferior overall survival (OS) compared to the low-risk group (p < 0.0001). Conclusions: Our nomogram exhibited good performance in predicting the overall survival of HTG-SAP patients during hospitalization.

Application of temperature-sensitive liquid embolic agent loaded with oxaliplatin in the TACE procedure for rabbit VX2 gastric cancer.

As a promising drug delivery system, the temperature-sensitive liquid embolic agent (TempSLE) has yet to be reported in animal experiments in treating gastric cancer. We observed and compared computed tomography (CT) imaging changes, tumor volume, HE staining, and immunohistochemistry after transcatheter arterial chemoembolization (TACE) treatment in rabbit VX2 gastric cancer models to clarify the effectiveness of TempSLE loaded with oxaliplatin (TempSLE/Oxa) in treating gastric cancer. One milliliter TempSLE can be loaded with 20 mg oxaliplatin. The accumulative drug release rate at 30 min was 38.76%, and after 24 h, it reached more than 90%. CT examination 1 week after TACE revealed that the TempSLE/Oxa group presents unenhanced hypodense necrotic foci, the iodinated oil loaded with oxaliplatin (Ioil/Oxa) group presents shrinking tumors but still visible speckled foci of enhancement, and the normal saline (NS) group presents heterogeneous enhancement with larger tumors than before. In the postoperative autopsy of TACE, the tumor volumes of TempSLE/Oxa, Ioil/Oxa, and NS groups were 0.15 ± 0.06 cm3, 0.37 ± 0.11 cm3, and 1.19 ± 0.16 cm3, respectively, all of which were statistically different. The positive vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (PCNA) expression percentages in the TempSLE/Oxa, Ioil/Oxa, and NS groups were statistically different and lowest in the TempSLE/Oxa group. In conclusion, the TempSLE can load a high dose of oxaliplatin to meet the demand of clinical applications. TempSLE/Oxa could effectively inhibit tumor cell proliferation and angiogenesis. This study provides experimental evidence for the further clinical application of the TempSLE/Oxa.

ß-acetoxyisovalerylalkannin suppresses proliferation and induces ROS-based mitochondria-mediated apoptosis in human melanoma cells.

ß-acetoxyisovalerylalkannin (ß-AIVA) is one of shikonin/alkannin derivative, which were mainly extracted from Boraginaceae family. The effects of ß-AIVA on human melanoma A375 cells and U918 cells were investigated in vitro. The CCK-8 assay showed that ß-AIVA inhibited proliferation of cells. Results from flow cytometry, ROS assay and JC-1 assay showed that ß-AIVA increased late apoptosis rate, induced the production of ROS and promoted mitochondrial depolarization in cells. ß-AIVA regulated expressions of BAX and Bcl-2 proteins, and increased the expression of cleaved caspase-9 and cleaved caspase-3. These findings suggest that ß-AIVA may be a potential therapeutic drug for treating melanoma.

Diverse terpenoid glycosides with in vitro cytotoxicity from Glechoma longituba.

Terpenoids are the largest class of all known natural products, possessing structural diversity and numerous biological activities. Ten previously undescribed terpenoid glycosides, glechlongsides A-J (1-10), were isolated from the ethanol extract of the whole plant of Glechoma longituba, including diterpenoid glycoside and pentacyclic triterpenoid saponin. The structures of these compounds were characterized by extensive analysis of 1D and 2D NMR as well as HRESIMS spectra. In addition, glechlongsides F-I (6-9) exhibited weak cytotoxicity against human cancer cell lines BGC-823, Be1, HCT-8, A2780, and A549 with IC50 values ranging from 3.77 to 30.95 µM, respectively.

Comparison of the safety profile, conversion rate and hospitalization duration between early and delayed laparoscopic cholecystectomy for acute cholecystitis: a systematic review and meta-analysis.

Background: Although the past decade has witnessed unprecedented medical progress, no consensus has been reached on the optimal approach for patients with acute cholecystitis. Herein, we conducted a systematic review and meta-analysis to assess the differences in patient outcomes between Early Laparoscopic Cholecystectomy (ELC) and Delayed Laparoscopic Cholecystectomy (DLC) in the treatment of acute cholecystitis. Our protocol was registered in the PROSPERO database (registration number: CRD42023389238). Objectives: We sought to investigate the differences in efficacy, safety, and potential benefits between ELC and DLC in acute cholecystitis patients by conducting a systematic review and meta-analysis. Methods: The online databases PubMed, Springer, and the Cochrane Library were searched for randomized controlled trials (RCTs) and retrospective studies published between Jan 1, 1999 and Jan 1, 2022. Results: 21 RCTs and 13 retrospective studies with a total of 7,601 cases were included in this research. After a fixed-effects model was applied, the pooled analysis showed that DLC was associated with a significantly high conversion rate (OR: 0.6247; 95%CI: 0.5115-0.7630; z = -4.61, p < 0.0001) and incidence of postoperative complications (OR: 0.7548; 95%CI: 0.6197-0.9192; z = -2.80, p = 0.0051). However, after applying a random-effects model, ELC was associated with significantly shorter total hospitalization duration than DLC (MD: -4.0657; 95%CI: -5.0747 to -3.0566; z = -7.90, p < 0.0001). Conclusion: ELC represents a safe and feasible approach for acute cholecystitis patients since it shortens hospitalization duration and decreases the incidence of postoperative complications of laparoscopic cholecystectomy. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=389238, identifier (CRD42023389238).

O-H bond activation of ß,γ-unsaturated oximes via hydrogen atom transfer (HAT) and photoredox dual catalysis.

Hydrogen atom transfer (HAT) and photoredox dual catalysis provides a unique opportunity in organic synthesis, enabling the direct activation of C/Si/S-H bonds. However, the activation of O-H bonds of ß,γ-unsaturated oximes poses a challenge due to their relatively high redox potential, which exceeds the oxidizing capacity of most currently developed photocatalysts. We here demonstrate that the combination of HAT and photoredox catalysis allows the activation of O-H bond of ß,γ-unsaturated oximes. The strategy effectively addresses the oxime's high redox potential and offers a universal pathway for iminoxyl radical formation. Leveraging the versatility of this approach, a diverse array of valuable heterocycles have been synthesized with the use of different radical acceptors. Mechanistic studies confirm a HAT process for the O-H bond activation.

High Expression of Ten Eleven Translocation 1 Is Associated with Poor Prognosis in Hepatocellular Carcinoma.

Background: DNA methylation patterns have been found to be distinct between tumor and normal patients. However, the effect of DNA demethylation enzymes, ten eleven translocation (TET) proteins, has not been comprehensively characterized in liver cancer. In this research, we sought to unravel the linkage of TET proteins with prognosis, immune characteristics and biological pathways in hepatocellular carcinoma (HCC). Materials and Methods: Four independent datasets with gene expression data and clinical data of HCC samples were downloaded from public databases. CIBERSORT, single sample Gene Set Enrichment Analysis (ssGSEA), MCP-counter, and TIMER were implemented to evaluate immune cell infiltration. limma was employed to screen differentially expressed genes (DEGs) between two groups. The demethylation-related risk model was established by using univariate Cox regression analysis, the least absolute shrinkage and selection operator (LASSO), and stepwise Akaike information criterion (stepAIC). Results: TET1 was significantly higher expressed in tumor samples than that in normal samples. HCC patients with advanced stages (III+IV) and grades (G3+G4) had higher TET1 expression compared to early stages (I+II) and grades (G1+G2). HCC samples with high TET1 expression had worse prognosis than that with low expression. High and low TET1 expression groups had distinct immune cell infiltration and response to immunotherapy and chemotherapy. We identified 90 DEGs related to DNA demethylation in high vs. low TET1 expression groups. Furthermore, we established a risk model based on 90 DEGs containing seven key prognostic genes (SERPINH1, CDC20, HACD2, SPHK1, UGT2B15, SLC1A5, and CYP2C9) with effectiveness and robustness in predicting HCC prognosis. Conclusions: Our study suggested TET1 as a potential indicator in HCC progression. TET1 was closely involved in immune infiltration and activation of oncogenic pathways. The DNA demethylation-related risk model was potential to be applied for predicting HCC prognosis in clinics.

Establishment of a 7-gene prognostic signature based on oxidative stress genes for predicting chemotherapy resistance in pancreatic cancer.

Background: Oxidative stress is involved in regulating various biological processes in human cancers. However, the effect of oxidative stress on pancreatic adenocarcinoma (PAAD) remained unclear. Methods: Pancreatic cancer expression profiles from TCGA were downloaded. Consensus ClusterPlus helped classify molecular subtypes based on PAAD prognosis-associated oxidative stress genes. Limma package filtered differentially expressed genes (DEGs) between subtypes. A multi-gene risk model was developed using Lease absolute shrinkage and selection operator (Lasso)-Cox analysis. A nomogram was built based on risk score and distinct clinical features. Results: Consistent clustering identified 3 stable molecular subtypes (C1, C2, C3) based on oxidative stress-associated genes. Particularly, C3 had the optimal prognosis with the greatest mutation frequency, activate cell cycle pathway in an immunosuppressed status. Lasso and univariate cox regression analysis selected 7 oxidative stress phenotype-associated key genes, based on which we constructed a robust prognostic risk model independent of clinicopathological features with stable predictive performance in independent datasets. High-risk group was found to be more sensitive to small molecule chemotherapeutic drugs including Gemcitabine, Cisplatin, Erlotinib and Dasatinib. The 6 of 7 genes expressions were significantly associated with methylation. Survival prediction and prognostic model was further improved through a decision tree model by combining clinicopathological features with RiskScore. Conclusion: The risk model containing seven oxidative stress-related genes may have a greater potential to assist clinical treatment decision-making and prognosis determination.

Bioinformatics-based construction of prognosis-related methylation prediction model for pancreatic cancer patients and its application value.

Objective: Pancreatic adenocarcinoma (PAAD) is a highly malignant gastrointestinal tumor with almost similar morbidity and mortality. In this study, based on bioinformatics, we investigated the role of gene methylation in PAAD, evaluated relevant factors affecting patient prognosis, screened potential anti-cancer small molecule drugs, and constructed a prediction model to assess the prognosis of PAAD. Methods: Clinical and genomic data of PAAD were collected from the Tumor Genome Atlas Project (TCGA) database and gene expression profiles were obtained from the GTEX database. Analysis of differentially methylated genes (DMGs) and significantly differentially expressed genes (DEGs) was performed on tumorous samples with KRAS wild-type and normal samples using the "limma" package and combined analysis. We selected factors significantly associated with survival from the significantly differentially methylated and expressed genes (DMEGs), and their fitting into a relatively streamlined prognostic model was validated separately from the internal training and test sets and the external ICGC database to show the robustness of the model. Results: In the TCGA database, 2,630 DMGs were identified, with the largest gap between DMGs in the gene body and TSS200 region. 318 DEGs were screened, and the enrichment analysis of DMGs and DEGs was taken to intersect DMEGs, showing that the DMEGs were mainly related to Olfactory transduction, natural killer cell mediated cytotoxicity pathway, and Cytokine -cytokine receptor interaction. DMEGs were able to distinguish well between PAAD and paraneoplastic tissues. Through techniques such as drug database and molecular docking, we screened a total of 10 potential oncogenic small molecule compounds, among which felbamate was the most likely target drug for PAAD. We constructed a risk model through combining three DMEGs (S100P, LY6D, and WFDC13) with clinical factors significantly associated with prognosis, and confirmed the model robustness using external and internal validation. Conclusion: The classification model based on DMEGs was able to accurately separate normal samples from tumor samples and find potential anti-PAAD drugs by performing gene-drug interactions on DrugBank.

Uncovering the effect and mechanism of Panax notoginseng saponins on metabolic syndrome by network pharmacology strategy.

ETHNOPHARMACOLOGICAL RELEVANCE: Metabolic syndrome (MetS) is a cluster of disease centered on obesity, which is the result of stagnation of liver qi according to traditional Chinese medicine. Panax notoginseng is a traditional Chinese herbal medicine, entering liver and stomach meridians and dissipating blood stasis, in which panax notoginseng saponins (PNS) are the main active components. However, its effects and mechanism on metabolic syndrome has not been revealed yet. AIM OF STUDY: To evaluate the anti-MetS effect of PNS, including body weight and adiposity, glucose metabolism and non-alcoholic fatty liver disease (NAFLD), as well as to explore the mechanism and signaling pathway of PNS on MetS effect. MATERIALS AND METHODS: HPLC was utilized to affirm the percentages of saponins in PNS. In vivo, normal C57BL/6J mice and high-fat diet (HFD)-induced MetS mice were used to evaluate anti-MetS effect of PNS. Body weight, food and water intake were recorded. NMR imager was used for NMR imaging and lipid-water analysis. Blood glucose detection, glucose and insulin tolerance test were performed to evaluate glucose metabolism. Biochemical indexes analysis and histopathological staining were used to evaluate the effect on NAFLD. The expressions of mRNA and proteins related to thermogenesis in adipose tissue were determined using real-time PCR and Western blot. In silico, network pharmacology was utilized to predict potential mechanism. In vitro, matured 3T3-L1 adipocyte was used as subject to confirm the signaling pathway by Western blot. RESULTS: We determined the content of PNS component by HPLC. In vivo, PNS could improve metabolic syndrome with weight loss, reduction of adiposity, improvement of adipose distribution, correction of glucose metabolism disorder and attenuation of NAFLD. Mechanismly, PNS boosted energy exhaustion and dramatically enhanced thermogenesis in brown adipose tissue (BAT), induced white adipose tissue (WAT) browning. In silico, utilizing network pharmacology strategy, we identified 307 candidate targets which were enriched in MAPK signaling pathway specifically in liver tissue and adipocyte. In vitro validation confirmed ERK and p38MAPK mediated anti-MetS effects of PNS, not JNK signaling pathway. CONCLUSION: PNS exerted protective effect on metabolic syndrome through MAPK-mediated adipose thermogenic activation, which may serve as a prospective therapeutic drug for metabolic syndrome.

Diagnostic value of RDW for the prediction of mortality in adult sepsis patients: A systematic review and meta-analysis.

Background: Red blood cell distribution width (RDW) is a common biomarker of bacterial infections, and it can be easily obtained from a routine blood test. We investigate the diagnostic value of RDW for the prediction of mortality in adult sepsis patients through a review and meta-analysis. We registered this review in PROSPERO (Registration Number: CRD42022357712), and the details of the registration are included in Appendix 1. Methods: We searched PubMed, Cochrane Library, Springer, and Embase between Jan. 1, 2000, and May 30, 2022, for primary studies about this research. We collected articles that investigated RDW for varying degrees of sepsis patients-those who suffered from sepsis, severe sepsis, or sepsis shock. Studies of healthy people and sepsis of children and neonates were excluded from our research. The definition of study characteristics and data extraction were finished by two independent researchers and discrepancies resolved by consensus. The combined sensitivities and specificities were calculated by meta-analysis using STATA14.0. The sensitivity of the included studies was analyzed by excluding studies that had potential heterogeneity. A summary operating characteristic curve was made to evaluate the diagnostic value for the prediction of mortality in adult sepsis patients. The Fagan test was used to explore likelihood ratios and posttest probabilities. Finally, we investigated the source of heterogeneity using meta-regression. Results: Twenty-four studies, including 40,763 cases altogether, were included in this analysis. Bivariate analysis indicated a combined sensitivity of 0.81 (95% CI 0.73-0.86) and specificity of 0.65 (95% CI 0.54-0.75). The area under the summary receiver operating characteristic curve was 0.81 (95% CI 0.77-0.84). Substantial heterogeneity resided in the studies (I2 = 96.68, 95% CI 95.95-97.4). Meta-regression showed that the reference description, prospective design, and blinded interpretation of the included studies could be responsible for the heterogeneity. Conclusions: RWD is an available and valuable biomarker for prediction of mortality in adult sepsis patients. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022357712.

A sensitive LC-MS method for the determination of Sinomenine derivative SWX and its application to pharmacokinetic research in rats.

The goal of this work was to develop a sensitive and accurate method based on high performance liquid chromatography with tandem mass spectrometry (LC-MS) detection for determining the concentration of the Sinomenine derivative SWX in plasma and tissue of rat. Chromatographic separation was achieved on an Agilent SB-C18 (2.1*50 mm, 2.7 µm) column. The mobile phase consisted of acetonitrile (solvent A) and 0.2 % formic acid in water (solvent B) with gradient elution as follows: 0-3 min, 50-90 % A, 3 min-3.01 min, 90-50 % A, 90 % A in 3.01 min-10 min. The flow rate was set to 0.3 mL/min. The column temperature was 40 °C, and the sample injection volume was 10 µL. The calibration curve had good linearity in the range of 10 ng/mL to 600 ng/mL. Biological samples were prepared by protein precipitation with acetonitrile. The area under the curve (AUC) and the peak drug concentration (Cmax) were linearly related to SWX dose. After oral administration of 25, 50 and 100 mg/kg SWX and intravenous administration of 0.5 mg/kg SWX, respectively, the absolute bioavailability of SWX was estimated as 12.4 %, 12.2 % and 10.6 %. SWX was widely distributed in heart, liver, spleen, lung, kidney, brain, breast, and fat, especially in lung, liver, and spleen. Distribution of SWX in brain suggested that it can pass the blood-brain barrier. The method established in this study has the advantages of high recovery and good reproducibility, and was suitable for the determination of the content of Sinomenine derivatives, providing a reliable scientific tool for carrying out pharmacokinetics research, providing a reliable scientific resource.

Constructing a Novel Prognostic Signature Based on TGF-ß Signaling for Personalized Treatment in Pancreatic Adenocarcinoma.

Background: Pancreatic adenocarcinoma (PAAD) shows significantly high mortality. Transforming growth factor-beta (TGF-ß) signaling plays an important role in tumorigenesis and development. A prognostic model was conducted using transforming growth factor-beta (TGF-ß) signaling for predicting PAAD prognosis and guiding personalized therapies. Methods: Datasets were grouped into test and training sets. Univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) were applied and introduced for identifying prognostic genes associated with TGF-ß. Risk score of each sample was calculated by the prognostic model. The difference in survival, clinical information, mutations, pathways, and chemotherapy and immunotherapy sensitivities between high-risk and low-risk groups was analyzed. Results: Based on TGF-ß signaling, this work built a 7-gene prognostic model showing robustness in sample classification into low-risk and high-risk groups with differential prognoses. Oncogenic pathways like glycolysis, Notch signaling, and hypoxia were noticeably enriched in the group with high risk. Interferon and STAT1 were positively associated with risk score. Importantly, the low-risk group may develop a more favorable response to both chemotherapy and immunotherapy. The current work highlighted the significant function of TGF-ß signaling in PAAD development and described the potential cross-links with other oncogenic pathways. Conclusion: Notably, the prognostic signature can act as a predictor of prognosis, but as a biomarker for optimizing personalized therapies in clinical practice.