In the biosynthesis sterols an enzyme-catalyzed demethylation is achieved via a stepwise oxidative transformation of alcohols to olefins. The overall demethylation proceeds through two sequential ...monooxygenation reactions and a subsequent dehydroformylative saturation. To mimic the desaturation processes observed in nature, we have successfully integrated photoredox proton-coupled electron transfer (PCET) and cobaloxime chemistry for the acceptorless dehydrogenation of alcohols. The state-of-the-art remote and precise desaturation of ketones proceeds efficiently through the activation of cyclic alcohols using bond-dissociation free energy (BDFE) as thermodynamic driving force. The resulting transient alkoxyl radical allows C-C bond scission to generate the carbon-centered radical remote to the carbonyl moiety. This key intermediate is subsequently combined with cobaloxime photochemistry to furnish the alkene. Moreover, the mild protocol can be extended to desaturation of linear alcohols as well as aromatic hydrocarbons. Application to bioactive molecules and natural product derivatives is also presented.
The first metal-free ring opening/trifluoromethylthiolation of cycloalkanols for the formation of remote C(sp3)–SCF3 bonds has been developed. A variety of trifluoromethylthiolated carbonyl ...compounds that are otherwise difficult to achieve were prepared in good yields under mild reaction conditions. The reaction is assumed to proceed via C–C bond cleavage of the alkoxyl radical species generated via a photoredox-enabled intramolecular proton-coupled electron transfer process, followed by trifluoromethylthiolation of the resulting C-centered radical with the N-(trifluoromethylthio)phthalimide reagent.
Perineural invasion (PNI) is considered to be a main reason for the poor prognosis of pancreatic cancer. In the present study, we analyzed the roles of substance P (SP)/neurokinin-1 receptor (NK-1R) ...and lncRNA LOC389641 in pancreatic cancer PNI. Pancreatic cancer cell lines BxPC-3 and MIAPaCa-2 were cocultured with SH-SY5Y cells and then stimulated with SP to simulate the in vivo influence of ganglia on pancreatic cancer. The BxPC-3 and MIAPaCa-2 cells were transfected with a neurokinin-1 receptor (NK-1R) overexpression vector, NK-1R silencing vector, LOC389641 overexpression vector, or LOC389641 silencing vector, respectively. The proliferative abilities of BxPC-3 and MIAPaCa-2 cells were assessed using the cell counting kit-8 and 5-ethynyl-2′-deoxyuridine (EdU) assays. Wound-healing and Transwell assays were performed to determine the migration and invasion abilities of the cells. When SP was added to the coculture system, it positively regulated cancer cell proliferation, migration, and PNI and significantly activated the NK-1R/Akt/NF-κB signaling pathway. Incubation with 100 nmol/L SP for 24 h was selected as the optimal condition for treatment. The activated NK-1R positively regulated the proliferation, migration, and invasion of pancreatic cancer cells. However, the levels of lncRNA LOC389641 and tumor necrosis factor receptor SF10A (TNFRSF10A) mRNA in BxPC-3 and MIAPaCa-2 cells were not affected by SP treatment. Overexpression or silencing of LOC389641 changed the effect of SP stimulation on pancreatic cancer PNI. When taken together, these results revealed that SP/NK-1R and LOC389641 promoted the progression of pancreatic cancer PNI. Moreover, we found that pancreatic cancer PNI promoted by the SP/NK-1R axis could be blocked by the TNFRSF10A/NF-κB pathway mediated by LOC389641.
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.
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.
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.
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.
Glioblastoma multiforme (GBM) in the central nervous system is the most lethal advanced glioma and currently there is no effective treatment for it. Studies of sinomenine, an alkaloid from the ...Chinese medicinal plant, Sinomenium acutum, showed that it had inhibitory effects on several kinds of cancer. Here, we synthesized a sinomenine derivative, sino-wcj-33 (SW33), tested it for antitumor activity on GBM and explored the underlying mechanism. SW33 significantly inhibited proliferation and colony formation of GBM and reduced migration and invasion of U87 and U251 cells. It also arrested the cell cycle at G2/M phase and induced mitochondria-dependent apoptosis. Differential gene enrichment analysis and pathway validation showed that SW33 exerted anti-GBM effects by regulating PI3K/AKT and AMPK signaling pathways and significantly suppressed tumorigenicity with no obvious adverse effects on the body. SW33 also induced autophagy through the PI3K/AKT/mTOR and AMPK/mTOR pathways. Thus, SW33 appears to be a promising drug for treating GBM effectively and safely.
Sinomenine ester derivative SW33 significantly inhibited glioblastoma multiforme (GBM) by arresting cell cycle at G2/M phase, promoting apoptosis in mitochondria-dependent manner and inducing autophagy via PI3K/AKT/mTOR and AMPK/mTOR pathways with a good safety profile in vivo and in vitro. Display omitted
Nymphaea candida was used to treat hepatitis in Ugyhur medicine, and nicotiflorin (kaempferol 3-O-β-rutinoside) is the main characteristic component in this plant ....
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 (
I
2 =
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.
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).
We performed a comprehensive literature search in PubMed, Cochrane Library, Ovid, and Springer databases, using retrieval terms "
" or "
" and "
" or "
" 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.
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 (I
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 I
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.
NLR is a reliable and valuable biomarker for predicting prognosis and the risk of death in adult sepsis patients.
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023433143 PROSPERO, identifier CRD42023433143.
Oxidative stress is involved in regulating various biological processes in human cancers. However, the effect of oxidative stress on pancreatic adenocarcinoma (PAAD) remained unclear.
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.
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.
The risk model containing seven oxidative stress-related genes may have a greater potential to assist clinical treatment decision-making and prognosis determination.
PDF
