Synergistic action and mechanism of scoparone, a key bioactive component of Artemisia capillaris, and spirodiclofen against spider mites.

BACKGROUND: Plants have numerous defensive secondary metabolites to withstand insect attacks. Scoparone, which is extracted from the medicinal plant Artemisia capillaris, has potent acaricidal effects on Tetranychus cinnabarinus. Spirodiclofen, derived from a tetronic acid derivative, is a potent commercial acaricide that is extensively used globally. However, whether scoparone has synergistic effects when used in conjunction with spirodiclofen and the underlying synergistic mechanism remains unclear. RESULTS: Scoparone exhibited a potent synergistic effect when it was combined with spirodiclofen at a 1:9 ratio. Subsequently, cytochrome P450 monooxygenase (P450) activity, RNA-Seq and qPCR assays indicated that the enzyme activity of P450 and the expression of one P450 gene from T. cinnabarinus, TcCYP388A1, were significantly inhibited by scoparone and spirodiclofen + scoparone; conversely, P450 was activated in spirodiclofen-exposed mites. Importantly, RNAi-mediated silencing of the TcCYP388A1 gene markedly increased the susceptibility of spider mites to spirodiclofen, scoparone and spirodiclofen + scoparone, and in vitro, the recombinant TcCYP388A1 protein could metabolize spirodiclofen. Molecular docking and functional analyses further indicated that R117, which is highly conserved in Arachnoidea species, may be a vital specific binding site for scoparone in the mite TcCYP388A1 protein. This binding site was subsequently confirmed using mutagenesis data, which revealed that this binding site was the sole site selected by scoparone in spider mites over mammalian or fly CYP388A1. CONCLUSIONS: These results indicate that the synergistic effects of scoparone and spirodiclofen on mites occurs through the inhibition of P450 activity, thus reducing spirodiclofen metabolism. The synergistic effect of this potent natural product on the detoxification enzyme-targeted activity of commercial acaricides may offer a sustainable strategy for pest mite resistance management. © 2024 Society of Chemical Industry.

The safety and effectiveness of prophylactic hyperthermic intraperitoneal chemotherapy in patients with pathological T3-4 locally advanced colon cancer.

INTRODUCTION: The safety and effectiveness of prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) in pathological T3-4 locally advanced (pT3N + M0 and pT4NxM0) colon cancer (CC) patients with radical resection need further study. METHODS: Clinical and pathological information of pT3-4 locally advanced CC patients who received radical surgery in our hospital from January 2018 to December 2020 were analyzed. The prognosis of patients was estimated using Cox proportional hazards regression analysis and Kaplan-Meier method. RESULTS: Among 927 patients, 10.4% (96/927) received prophylactic HIPEC based on 5-FU, 4.6% (43/927) received prophylactic HIPEC based on lobaplatin, 85.0% (788/927) received conventional therapy. The incidence of metachronous peritoneal carcinomatosis (mPC) was 9.4%. Complications occurred in 32 patients (4.1%) in the conventional therapy group, 6 patients (6.3%) in the prophylactic HIPEC group based on 5-FU and 3 patients (7.0%) in the prophylactic HIPEC group based on lobaplatin within 30 days after surgery (5-FU vs. conventional therapy group, p = 0.464; Lobaplatin vs. conventional therapy group, p = 0.591). Multivariate Cox regression analysis revealed that prophylactic HIPEC based on either 5-FU or lobaplatin regimen could not effectively improve mPC-free survival (5-FU: p = 0.020, HR = 1.927, 95% CI, 1.111-3.343; Lobaplatin: p = 0.167, HR = 0.247, 95% CI, 0.034-1.796), overall survival (5-FU: p = 0.361, HR = 1.360, 95% CI, 0.703-2.634; Lobaplatin: p = 0.780, HR = 0.816, 95% CI, 0.195-3.416) and disease-free survival (5-FU: p = 0.525, HR = 1.149, 95% CI, 0.749-1.760; Lobaplatin: p = 0.117, HR = 0.488, 95% CI, 0.199-1.198). CONCLUSION: Early prophylactic HIPEC based on 5-FU or lobaplatin subsequent to radical resection for patients with pT3-4 locally advanced CC is safe, but not effective in reducing the risk for mPC.

Fatty Acid Oxidation Promotes Apoptotic Resistance and Proinflammatory Phenotype of CD4+ Tissue-resident Memory T cells in Crohn's Disease.

BACKGROUND & AIMS: As the most abundant memory T cells and major source of tumor necrosis factor α in the intestinal mucosa of Crohn's disease (CD) patients, CD4+ tissue-resident memory T (TRM) cells play a critical role in CD pathogenesis. We investigated the role of metabolic reprogramming in the regulation of proinflammatory and apoptosis-resistant phenotype for CD4+ TRM cells. METHODS: CD4+ TRM cells were collected from intestinal resection tissues from control and CD patients. Transcriptomic and metabolomic analysis were performed to identify metabolic characteristics of CD4+ TRM cells. Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction experiments were used to assess cytokines level in CD4+ TRM cells; activation-induced cell apoptosis rate was evaluated by flow cytometry. Transwell assay and wound healing assay were performed to detect the effect of CD4+ TRM cells on the migration of normal intestinal epithelial cells. RESULTS: Transcriptomic data combined with unbiased metabolomic analysis revealed an increased fatty acid oxidation (FAO) phenotype existed in CD4+ TRM cells from CD patients. The lipidomic data and stable isotope tracer experiments demonstrated that CD4+ TRM cells up-regulated their lipid lipolysis and fatty acid uptake to fuel FAO in CD patients. Mechanistically, the activated nuclear factor kappa B signaling increased transcription of genes involved in lipid lipolysis, fatty acid uptake, and oxidation in CD4+ TRM cells from CD patients. Targeting FAO of CD4+ TRM cells reversed their apoptosis-resistant and proinflammatory phenotype in CD patients. CONCLUSIONS: CD4+ TRM cells process an accelerated FAO mediated by activated nuclear factor kappa B signaling in CD patients; targeting FAO could reverse their apoptosis-resistant and proinflammatory phenotype. These findings shed a new light on the pathogenic mechanism investigation and novel therapy development in CD patients.

Combining pathological risk factors and T, N staging to optimize the assessment for risk stratification and prognostication in low-risk stage III colon cancer.

BACKGROUND: This study aimed to investigate the combined pathological risk factors (PRFs) to stratify low-risk (pT1-3N1) stage III colon cancer (CC), providing a basis for individualized treatment in the future. PATIENTS AND METHODS: PRFs for low-risk stage III CC were identified using COX model. Low-risk stage III CC was risk-grouped combining with PRFs, and survival analysis were performed using Kaplan-Meier. The Surveillance, Epidemiology, and End Results (SEER) databases was used for external validation. RESULTS: Nine hundred sixty-two stage III CC patients were included with 634 (65.9%) as low risk and 328 (34.1%) as high risk. Poor differentiation (OS: P = 0.048; DFS: P = 0.011), perineural invasion (OS: P = 0.003; DFS: P < 0.001) and tumor deposits (OS: P = 0.012; DFS: P = 0.003) were identified as PRFs. The prognosis of low-risk CC combined with 2 PRFs (OS: HR = 3.871, 95%CI, 2.004-7.479, P < 0.001; DFS: HR = 3.479, 95%CI, 2.158-5.610, P < 0.001) or 3 PRFs (OS: HR = 5.915, 95%CI, 1.953-17.420, P = 0.002; DFS: HR = 5.915, 95%CI, 2.623-13.335, P < 0.001) was similar to that of high-risk CC (OS: HR = 3.927, 95%CI, 2.317-6.656, P < 0.001; DFS: HR = 4.132, 95%CI, 2.858-5.974, P < 0.001). In the SEER database, 18,547 CC patients were enrolled with 10,023 (54.0%) as low risk and 8524 (46.0%) as high risk. Low-risk CC combined with 2 PRFs (OS: HR = 1.857, 95%CI, 1.613-2.139, P < 0.001) was similar to that of high-risk CC without PRFs (HR = 1.876, 95%CI, 1.731-2.033, P < 0.001). CONCLUSION: Combined PRFs improved the risk stratification of low-risk stage III CC, which could reduce the incidence of undertreatment and guide adjuvant chemotherapy.

Construction and Validation of a Novel Prognosis Model in Colon Cancer Based on Cuproptosis-Related Long Non-Coding RNAs.

Colon cancer (CC) is one of the most common (6%) malignancies and leading cause of cancer-associated death (more than 0.5 million) worldwide, which demands reliable prognostic biomarkers. Cuproptosis is a novel modality of regulated cell death triggered by the accumulation of intracellular copper. LncRNAs have been reported as prognostic signatures in different types of tumors. However, the correlation between cuproptosis-related lncRNAs (CRLs) and CC remains unclear. Data of CC patients were downloaded from public databases. The prognosis-associated CRLs were identified by co-expression analysis and univariate Cox. Least absolute shrinkage and selection operator were utilized to construct the CRLs-based prognostic signature in silico for CC patients. CRLs level was validated in human CC cell lines and patient tissues. ROC curve and Kaplan-Meier curve results revealed that high CRLs-risk score was associated with poor prognosis in CC patients. Moreover, the nomogram revealed that this model possessed a steady prognostic prediction capability with C-index as 0.68. More importantly, CC patients with high CRLs-risk score were more sensitive to eight targeted therapy drugs. The prognostic prediction power of the CRLs-risk score was further confirmed by cell lines, tissues and two independent CC cohorts. This study constructed a novel ten-CRLs-based prognosis model for CC patients. The CRLs-risk score is expected to serve as a promising prognostic biomarker and predict targeted therapy response in CC patients.

Prognostic Implications of Endoscopic Obstruction in Patients with Pathological Stage II Colon Cancers: a Single-Center Retrospective Cohort Study.

BACKGROUND: The prognostic effect of endoscopic obstruction (eOB) on the survival of stage II colon cancer patients and the role of eOB in guiding postoperative adjuvant chemotherapy of stage II colon cancer are little known. METHODS: In this retrospective, single-center cohort study, patients who had undergone curative surgery and preoperative colonoscope for stage II colon carcinoma were included. The eOB was defined as severe luminal colon obstruction that prevented the standard colonoscope from passing beyond the tumor. The association between eOB and stage II colon cancer survival and the predictive role of eOB for adjuvant chemotherapy were evaluated using multivariate Cox regression analysis. RESULTS: Of 1102 included patients, 616 (55.9%) had eOB and 486 (44.1%) had no eOB. The median follow-up was 49 months (interquartile range, 38-68 months). Kaplan-Meier curves showed that patients with eOB had poor 5-year overall survival (OS; 85.3% vs. 95.3%, p < 0.001) compared to patients without eOB. Five-year disease-free survival (DFS; 78.5% vs. 87.6%, p = 0.004) was also poor in these patients. Multivariate analysis demonstrated eOB was a significant prognostic factor for poor OS (hazard ratio [HR] = 2.531, p < 0.001), but not for DFS (p = 0.081). Even when patients with clinical colonic obstruction were excluded from the population with eOB, the worse OS (HR = 2.262, p = 0.001) was observed. The OS and DFS of eOB patients improved slightly after adjuvant chemotherapy, but there was no statistical significance. CONCLUSIONS: Stage II colon cancer patients with eOB have a poor prognosis. However, whether eOB can guide adjuvant chemotherapy still needs further study.

A Novel m7G-Related Gene Signature Predicts the Prognosis of Colon Cancer.

Colon cancer (CC), one of the most common malignancies worldwide, lacks an effective prognostic prediction biomarker. N7-methylguanosine (m7G) methylation is a common RNA modification type and has been proven to influence tumorigenesis. However, the correlation between m7G-related genes and CC remains unclear. The gene expression levels and clinical information of CC patients were downloaded from public databases. Twenty-nine m7G-related genes were obtained from the published literature. Via unsupervised clustering based on the expression levels of m7G-related genes, CC patients were divided into three m7G clusters. Based on differentially expressed genes (DEGs) from the above three groups, CC patients were further divided into three gene clusters. The m7G score, a prognostic model, was established using principal component analysis (PCA) based on 15 prognosis-associated m7G genes. KM curve analysis demonstrated that the overall survival rate was remarkably higher in the high-m7G score group, which was much more significant in advanced CC patients as confirmed by subgroup analysis. Correlation analysis indicated that the m7G score was associated with tumor mutational burden (TMB), PD-L1 expression, immune infiltration, and drug sensitivity. The expression level of prognosis-related m7G genes was further confirmed in human CC cell lines and samples. This study established an m7G gene-based prognostic model (m7G score), which demonstrated the important roles of m7G-related genes during CC initiation and progression. The m7G score could be a practical biomarker to predict immunotherapy response and prognosis in CC patients.

Elevated preoperative CA125 is associated with poor survival in patients with metastatic colorectal cancer undergoing primary tumor resection: a retrospective cohort study.

Background: The impact of the preoperative carbohydrate antigen 125 (CA125) level on the survival of metastatic colorectal cancer (CRC) patients undergoing primary tumor resection (PTR) remains uncertain. The aim of this study was to assess the prognostic value in overall survival (OS) and cancer-specific survival (CSS) between patients with and without an elevated preoperative CA125 level. Methods: All metastatic CRC patients receiving PTR between 2007 and 2017 at the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) were retrospectively included. OS and CSS rates were compared between patients with and without elevated preoperative CA125 levels. Results: Among 326 patients examined, 46 (14.1%) exhibited elevated preoperative CA125 levels and the remaining 280 (85.9%) had normal preoperative CA125 levels. Patients with elevated preoperative CA125 levels had lower body mass index, lower preoperative albumin level, lower proportion of preoperative chemotherapy, higher carcinoembryonic antigen and carbohydrate antigen 19-9 (CA19-9) levels, poorer differentiation, and more malignant histopathological type than patients with normal preoperative CA125 levels. In addition, patients with elevated preoperative CA125 levels exhibited more advanced pathological T and N stages, more peritoneal metastasis, and more vessel invasion than patients with normal preoperative CA125 levels. Moreover, the primary tumor was more likely to be located at the colon rather than at the rectum in patients with elevated CA125 levels. Both OS and CSS rates in patients with elevated preoperative CA125 levels were significantly lower than those in patients with normal preoperative CA125 levels. Multivariate Cox regression analysis revealed that an elevated preoperative CA125 level was significantly associated with poor prognosis in metastatic CRC patients undergoing PTR. The hazard ratio (HR) in OS was 2.36 (95% confidence interval [CI], 1.67-3.33, P < 0.001) and the HR in CSS was 2.50 (95% CI, 1.77-3.55, P < 0.001). The survival analysis stratified by peritoneal metastasis also demonstrated that patients with elevated preoperative CA125 levels had lower OS and CSS rates regardless of peritoneal metastasis. Conclusion: Based on an analysis of metastatic CRC patients undergoing PTR, an elevated preoperative CA125 level was associated with poor prognosis, which should be taken into consideration in clinical practice.

Risk factors for metachronous peritoneal carcinomatosis after radical resection for patients with nonmetastatic pT3-4 colon cancer.

BACKGROUND: Patients with nonmetastatic pT3-4 colon cancers are prone to develop metachronous peritoneal carcinomatosis (mPC). Risk factors for mPC and the influence of mutant kirsten rat sarcoma viral oncogene (KRAS)/neuroblastoma rat sarcoma (NRAS)/v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and DNA mismatch repair (MMR) status on mPC remain to be described in these patients. METHOD: All enrolled patients were identified from the prospectively collected colorectal cancer database of a tertiary referral hospital between 2013 and 2018. Multivariate analysis was used to identify risk factors associated with mPC. RESULTS: Of the 1689 patients with nonmetastatic pT3-4 colon carcinoma, 8.4% (142/1689) progressed to mPC. Endoscopic obstruction (HR = 3.044, p < 0.001), elevated CA125 (HR = 1.795, p = 0.009), pT (T4a vs. T3, HR = 2.745, p < 0.001; T4b vs. T3, HR = 3.167, p = 0.001), pN (N1 vs. N0, HR = 2.592, p < 0.001; N2 vs. N0, HR = 4.049, p < 0.001), less than 12 lymph nodes harvested (HR = 2.588, p < 0.001), mucinous or signet ring cell carcinoma (HR = 1.648, p = 0.038), perineural invasion (HR = 1.984, p < 0.001), and adjuvant chemotherapy (HR = 1.522, p = 0.039) were strongly related to mPC but that mutant KRAS/NRAS/BRAF and MMR status was not associated with mPC. CONCLUSION: This study identified the high-risk factors for mPC in patients with nonmetastatic pT3-4 colon carcinoma, and these factors should be considered in selective preventive therapy and close follow-up for patients subsequently deemed to have high risk for mPC.

Split stoma with delayed anastomosis may be preferred for 2-stage surgical resection in high-risk patients with Crohn's disease.

BACKGROUND: Fecal diversion after bowel resection is a safe and effective procedure in high-risk patients with Crohn's disease, but the better approach between primary anastomosis with protective stoma and split stoma with delayed anastomosis has not yet been investigated. This study aimed to compare the outcomes of these approaches in high-risk patients with Crohn's disease. METHODS: A retrospective investigation on consecutive high-risk patients with Crohn's disease was conducted at a tertiary referral hospital from August 2009 to March 2019. The primary outcomes were the overall early postoperative complications and overall anastomosis-related adverse events in an intention-to-treat approach. RESULTS: A total of 118 consecutive patients who underwent 121 surgeries (35 procedures with a protective stoma and 86 procedures with a split stoma) were enrolled. After a median follow-up period of 659 days and 728 days, respectively, 25 patients underwent a stoma-reversal procedure in the protective-stoma group, and 54 patients underwent delayed anastomosis in the split stoma group. Overall, early 30-day surgical morbidity and anastomosis-related adverse events were observed in more patients in the protective-stoma group than in the split-stoma group (51.4% [18/35] vs 30.2% [26/86]; P = .028 and 37.1% [13/35] vs 2.3% [2/86]; P < .001, respectively; intention-to-treat analysis). Similar results were found in the per-protocol analysis (44.0% [11/25] vs 20.4% [11/54]; P = .029 and 36.0% [12/25] vs 3.7% [2/54]; P < .001, respectively.) CONCLUSION: Split stoma with delayed anastomosis is associated with a reduction in anastomotic adverse events and overall early surgical complications and thus may be a better surgical option for high-risk patients with Crohn's disease.

Microbial spectrum and drug resistance of pathogens cultured from gallbladder bile specimens of patients with cholelithiasis: A single-center retrospective study.

BACKGROUND: Bacterial infection is an important cause of cholelithiasis or gallstones and interferes with its treatment. There is no consensus on bile microbial culture profiles in previous studies, and identified microbial spectrum and drug resistance is helpful for targeted preventive and therapeutic drugs in the perioperative period. AIM: To analyze the bile microbial spectrum of patients with cholelithiasis and the drug susceptibility patterns in order to establish an empirical antibiotic treatment for cholelithiasis-associated infection. METHODS: A retrospective single-center study was conducted on patients diagnosed with cholelithiasis between May 2013 and December 2018. RESULTS: This study included 185 patients, of whom 163 (88.1%) were diagnosed with gallstones and 22 (11.9%) were diagnosed with gallstones and common bile duct stones (CBDSs). Bile culture in 38 cases (20.5%) was positive. The presence of CBDSs (OR = 5.4, 95%CI: 1.3-21.9, P = 0.03) and longer operation time (> 80 min) (OR = 4.3, 95%CI: 1.4-13.1, P = 0.01) were identified as independent risk factors for positive bile culture. Gram-negative bacteria were detected in 28 positive bile specimens, and Escherichia coli (E. coli) (19/28) and Klebsiella pneumoniae (5/28) were the most frequently identified species. Gram-positive bacteria were present in 10 specimens. The resistance rate to cephalosporin in E. coli was above 42% and varied across generations. All the isolated E. coli strains were sensitive to carbapenems, with the exception of one imipenem-resistant strain. K. pneumoniae showed a similar resistance spectrum to E. coli. Enterococcus spp. was largely sensitive to glycopeptides and penicillin, except for a few strains of E. faecium. CONCLUSION: The presence of common bile duct stones and longer operation time were identified as independent risk factors for positive bile culture in patients with cholelithiasis. The most commonly detected bacterium was E. coli. The combination of ß-lactam antibiotics and ß-lactamase inhibitors prescribed perioperatively appears to be effective against bile pathogens and is recommended. Additionally, regular monitoring of emerging resistance patterns is required in the future.

Risk factors for metachronous adenoma in patients with stage I/II colorectal cancer after radical surgery.

BACKGROUND: It is important to implement a preventive strategy for early detection and endoscopic removal of metachronous adenoma in patients with colorectal cancer (CRC). Here, we retrospectively explored the associated factors of metachronous adenoma in these patients. METHODS: This study recruited 551 patients with stage I and II CRC who underwent radical surgery between January 1, 2012 and July 1, 2017 with postoperative colonoscopic surveillance. Data on clinicopathological characteristics and surveillance colonoscopies were obtained from medical records. Univariate analysis by Kaplan-Meier method and multivariate analysis by Cox proportional hazards model were used to identify the factors associated with metachronous adenoma. RESULTS: Metachronous adenoma was detected in 110 (20.0%) patients. In these patients, 94.5% (104/110) had metachronous adenoma within 3 years postoperatively. Age, synchronous adenoma, hypertension, tumor stage, and surgical resection were correlated with metachronous adenoma in patients with stage I-II CRC after radical resection (log rank test, P<0.05). Multivariate analyses showed that synchronous adenoma (HR =2.515, 95% CI: 1.691-3.742, P<0.01); stage II (HR =2.066, 95% CI: 1.329-3.210, P<0.01); and left-side colorectal resection (HR =2.207, 95% CI: 1.292-3.772, P<0.01) were independent risk factors. CONCLUSIONS: Synchronous adenoma, left-side colorectal resection, and stage II cancer are independent risk factors of metachronous adenoma in patients with previous stage I and II CRC. In patients with risk factors, an enhanced colonoscopic strategy might be needed for early detection and timely endoscopic removal of metachronous adenoma.

Optimization of Laccase from Ganoderma lucidum Decolorizing Remazol Brilliant Blue R and Glac1 as Main Laccase-Contributing Gene.

Many dyes and pigments are used in textile and printing industries, and their wastewater has been classed as a top source of pollution. Biodegradation of dyes by fungal laccase has great potential. In this work, the influence of reaction time, pH, temperature, dye concentration, metal ions, and mediators on laccase-catalyzed Remazol Brilliant Blue R dye (RBBR) decolorization were investigated in vitro using crude laccase from the white-rot fungus Ganoderma lucidum. The optimal decolorization percentage (50.3%) was achieved at 35 °C, pH 4.0, and 200 ppm RBBR in 30 min. The mediator effects from syringaldehyde, 1-hydroxybenzotriazole, and vanillin were compared, and 0.1 mM vanillin was found to obviously increase the decolorization percentage of RBBR to 98.7%. Laccase-mediated decolorization percentages significantly increased in the presence of 5 mM Na+ and Cu2+, and decolorization percentages reached 62.4% and 62.2%, respectively. Real-time fluorescence-quantitative PCR (RT-PCR) and protein mass spectrometry results showed that among the 15 laccase isoenzyme genes, Glac1 was the main laccase-contributing gene, contributing the most to the laccase enzyme activity and decolorization process. These results also indicate that under optimal conditions, G. lucidum laccases, especially Glac1, have a strong potential to remove RBBR from reactive dye effluent.