A cross-sectional study of obstructive sleep apnea in patients with colorectal cancer.

Background: The association between colorectal cancer (CRC) and obstructive sleep apnoea (OSA) has been attracting increasing attention. several studies had confirmed that OSA increases the risk of CRC onset. However, the findings of studies on the morbidity of OSA in patients with CRC were unclear. Therefore, this study aimed to investigate the morbidity of OSA in patients with CRC as well as the association between the clinicopathological characteristics of OSA and CRC. Methods: A total of 414 patients with a pathological diagnosis of CRC from 1 January, 2020 to 30 December, 2020 were included in this study. Demographic characteristics, clinical information, and tumor characteristics of participants were collected; sleep was monitored using a wearable oximeter and via sleep quality questionnaire. The oxygen desaturation index (ODI) was used to classify OSA severity so that the diagnostic criteria for OSA were set based on the ODI as 0-5 (normal) and ≥5 (abnormal). After correcting for confounding factors, a logistic regression analysis was performed to calculate the odds ratio (OR) and 95% confidence interval (CI) for the factors affecting the tumor lymph node stage (N stage). Results: A total of 402 patients with CRC were included in this study, including 225 (55.97%) men and 177 (44.03%) women. The mean ODI value of participants was 3.40±8.17. The morbidity of OSA among the patients with CRC having ODI ≥5 was 16.17%. A comparison between the normal and abnormal ODI value groups revealed that the high proportion of abnormal ODI was related to higher N stage (P<0.05). Logistic regression analysis revealed a correlation of ODI values and age to the N stage. Specifically, CRC patients with an abnormal ODI had a higher risk of lymph node metastasis compared to those with normal ODI (OR =1.915, 95% CI: 1.025 to 3.579). Moreover, patients with CRC aged ≥65 years had a higher risk of lymph node metastasis compared to those aged <65 years (OR =2.190, 95% CI: 1.163 to 4.125). Conclusions: CRC patients with abnormal ODI are susceptible to OSA. Additionally, abnormal ODI and age ≥65 years are relevant factors for the N2 stage.

The Incidence of Cancer Is Increased in Hospitalized Adult Patients With Obstructive Sleep Apnea in China: A Retrospective Cohort Study.

Background: The association between obstructive sleep apnea (OSA) and the incidence and mortality of cancer remain unclear, especially in Asian populations. Thus, this study was conducted to explore the relationship between OSA and the incidence and mortality of cancer in hospitalized patients. Methods: This retrospective cohort study evaluated inpatients from Guangdong Provincial People's Hospital for suspected OSA between January 2005 and December 2015. Cancer incidence, all-cause mortality, and cancer mortality and were determined using data from the hospital information system and Centers for Disease Control. Between-group comparisons were carried out by performing a chi-square test and analysis of variance. Kaplan-Meier analysis and the Cox proportional risk model were applied to investigate the association between OSA and cancer incidence and mortality. Results: Of the 4,623 hospitalized patients included, 3,786 (81.9%) patients were diagnosed with OSA. After a median follow-up of 9.1 years (interquartile range, 9.79-11.44), the incidence of cancer was 6.6% (251/3,786), with lung cancer having the highest incidence at 1.6% (60/3,786). The mortality rate of OSA patients was higher than that of non-OSA patients (16.83% vs.12.78%, p=0.008), but the relationship between apnea-hypopnea index (AHI), oxygen saturation less than 90% (TSat90), and cancer mortality was not statistically significant (p>0.05).The mortality rate for all types of cancer was 2.8% (105/3,786), with lung cancer having the highest mortality rate at 0.8% (32/3,786). The cumulative incidence of cancer in the severe OSA group was 8.2%, which was higher than that in the normal, mild, and moderate OSA groups (P=0.010). Further, the Cox proportional risk regression model showed a progressive enhancement in the risk of cancer incidence as the AHI increased (adjusted hazard ratio [HR]: 1.009 [95% confidence interval (CI): 1.003-1.016], P=0.005). Based on subgroup analysis, the risk of cancer increased as the AHI increased in patients aged <65 years (adjusted HR: 1.019 [95% CI: 1.007-1.031], P=0.002). In addition, the cancer incidence was significantly higher in the severe OSA group than in the normal, mild, and moderate OSA groups (adjusted HR: 2.825 [95% CI: 1.358-5.878], P=0.019). Conclusion: The incidence of cancer is higher in patients with OSA than in non-OSA patients and is significantly positively associated with the severity of OSA. Particularly, for OSA patients aged <65 years, lung cancer is the main cause of death in those with new-onset cancer. Mortality was higher in OSA patients than in non-OSA patients.

Autoantibody Signatures as a Biomarker Panel for the Detection of Nasopharyngeal Carcinoma.

OBJECTIVE: The early symptoms of nasopharyngeal carcinoma (NPC) are not obvious, and it is difficult to make early diagnosis. A case-control study was conducted to identify potential biomarkers and established a diagnosis model for nasopharyngeal carcinoma. METHODS: Plasma samples of 131 cases of NPC and 132 cases of healthy individuals were incubated with the Ray Biotech Human Lung Cancer IgG Autoantibody Detection Array G1, and signal values were used to develop a risk prediction model for NPC diagnosis. RESULTS: Of the 30 autoantibodies, high expression of MAGE-A4, NY-ESO-1, HuD, Survivin, IMDH2, Ubiquilin-1, IMP1, PGP9.5, IMP3, C-Myc and low expression of Cyclin B1 were potential biomarkers for NPC diagnosis (p <0.05), among which Survivin, MAGE-A4 and IMP3 shows higher AUC of 0.674, 0.652 and 0.650 respectively, the specificity of them was 89.39% (95% CI: 82.85-94.08%), 90.15% (95% CI: 83.75-94.65%) and 88.64% (81.95-93.50%).The risk probability analysis for NPC diagnosis based on the panel of Cyclin B1, NY-ESO-1, Survivin, and IMP3 displayed the best diagnosis performance with an AUC of 0.779, p (Yi = 1) = 1/(1+EXP[8.316+1.672*CyclinB1-1.152*NY-ESO-1-2.052*Survivin-0.950*IMP3]), the specificity of that was 86.36% (95% CI: 79.31-91.71%). CONCLUSIONS: Our findings demonstrated that the panel of Cyclin B1, NY-ESO-1, Survivin, and IMP3 has a good performance in the detection of NPC, and all 11 autoantibodies may also have a certain significance for the prognosis of NPC.

High MTHFR promoter methylation levels in men confer protection against ischemic stroke.

The MTHFR gene encodes methylenetetrahydrofolate reductase required for the metabolism of homocysteine (Hcy) - a previously reported independent risk factor for ischemic stroke (IS). In this study, we first aimed to clarify the association between DNA methylation levels in the MTHFR promoter and the risk of IS, followed by the analysis of potential interactions between environmental factors and DNA methylation levels that affect IS risk. We recruited 164 patients with hypertension and IS (case group) and 345 age-matched and sex-matched patients with hypertension only (control group). Demographic and clinical information was obtained using questionnaires, and blood samples were collected for biochemical analyses. Fluorescence quantitative methylation-specific PCR (qMSP) was used to detect MTHFR promoter methylation levels. A logistic regression analysis was performed to determine the relationship between environmental factors, MTHFR promoter methylation levels, and IS risk. We finally generated a receiver operating characteristic curve to determine whether MTHFR promoter methylation levels can predict IS. The mean MTHFR methylation levels in the case group (8.10 ± 6.14) were significantly lower than those in the control group (17.44 ± 3.16; p < 0.05). MTHFR promoter methylation levels were also lower in patients with plasma Hcy levels ≥15 µmol/L (10.65 ± 4.05) than in those with Hcy levels <15 µmol/L (16.74 ± 4.26, p < 0.001). Finally, we found that MTHFR hypermethylation is a protective factor for IS, particular in men (OR in men: 0.07; 95% CI: 0.02-0.16; p < 0.001). Further, sex and MTHFR promoter methylation levels exhibited a preliminary interaction effect on IS risk. These results indicate that MTHFR promoter methylation status might have diagnostic value in IS.

Synthesis of scutellarein derivatives to increase biological activity and water solubility.

In order to improve the biological activity and water solubility of scutellarin (1), some derivatives of its main metabolite (scutellarein) were designed and synthesized. All the compounds were tested for their thrombin inhibition activity through the analyzation of thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen (FIB). Their antioxidant activities were assessed by measuring their scavenging capacities toward 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and the ability to protect PC12 cells against H2O2-induced cytotoxicity, their water solubility were also assessed by ultraviolet (UV) spectrophotometer. The results showed that compound 8b demonstrated stronger anticoagulant and antioxidant activity, better water solubility compared with scutellarein (2), which warrants it as a promising agent for the treatment of ischemic cerebrovascular disease.

Comparative Metabolomic Analysis of the Neuroprotective Effects of Scutellarin and Scutellarein against Ischemic Insult.

For more than thirty years, scutellarin (Scu) has been used in China to clinically treat acute cerebral infarction and paralysis. Scutellarein (Scue), the major Scu metabolite in vivo, exhibits heightened neuroprotective effects when compared to Scu. To explore the neuroprotective role of these compounds, we performed ultra-high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UHPLC-QTOF/MS) coupled with a pattern recognition approach to investigate metabolomic differences in a rat model of ischemia after treatment with each compound. We examined metabolites in urine, hippocampal tissue, and plasma, and we tentatively identified 23 endogenous metabolites whose levels differed significantly between sham-operated and model groups. Upon pathway analysis, we found an additional 11 metabolic pathways in urine, 14 metabolic pathways in the hippocampal tissue, and 3 metabolic pathways in plasma. These endogenous metabolites were mainly involved in sphingolipid metabolism, lysine biosynthesis, and alanine, aspartate, and glutamate metabolism. We found that metabolic changes after ischemic injury returned to near-normal levels after Scue intervention, unlike Scu treatment, further validating the heightened protective effects exerted by Scue compared to Scu. These results demonstrate that Scue is a potential drug for treatment of ischemic insult.

Investigation on the interactions of scutellarin and scutellarein with bovine serum albumin using spectroscopic and molecular docking techniques.

The binding abilities of scutellarin (Scu) and scutellarein (Scue) with bovine serum albumin (BSA) were investigated using equilibrium dialysis, high performance liquid chromatography, fluorescence spectroscopy, competitive site marker and molecular docking. The results showed that the average protein binding ratios of Scu and Scue with BSA were (79.85 ± 1.83) and (85.49 ± 1.21) % respectively. Under simulated physiological conditions, the fluorescence data indicated that Scu and Scue bound with BSA through a static mechanism. The thermodynamic parameters indicated that the interactions of Scu-BSA and Scue-BSA mainly occurred by van der Waals forces and hydrogen bonds and it was easier for Scue to bind with BSA than Scu, indicating that the glucuronic acid molecule in Scu decreased the binding affinity. Site competitive marker experiments showed that the binding sites of Scu and Scue mainly located within the sub-domain IIA of BSA. Furthermore, molecular docking studies indicated that one BSA could bind three Scue, while one BSA could carry only two Scu. All these results clearly indicated the interactions of Scu and Scue with BSA, which will lay the foundation for further research to determine the pharmacology and pharmacodynamics of Scu and Scue for treating ischemic cerebrovascular disease.

pH-responsive anionic wormlike micelle based on sodium oleate induced by NaCl.

A pH-responsive anionic surfactant wormlike micellar system induced by NaCl has been developed. In this work, the anionic surfactant, sodium oleate (NaOA) solutions, transforms from low-viscosity fluid into high-viscoelastic solution induced by NaCl of 200 mM to 350 mM concentration. According to the above, the solution reversibility has been studied via changing pH value of the solution. This pH-responsive solution can be promptly switched between gel-like solution and waterlike fluid in a narrow pH value range. Steady and dynamic rheological measurements are employed to characterize the pH-responsiveness at different pH. The transformation between wormlike micelle and spherical micelle in the various pH solutions is demonstrated by dynamic light scattering tests, cryo-TEM, and NMR measurements. The pH-responsive property of the system is attributed to the carboxylate ion contained by sodium oleate. With higher pH value, the ionized carboxylate combines with NaCl closely and thus forms wormlike micelles. On the contrary, sodium oleate converts to oleate acid when pH decreases. In this way, spherical micelles are transformed because of the weaker interaction between oleate aicd and NaCl.

Synthesis, biological evaluation and SAR analysis of O-alkylated analogs of quercetin for anticancer.

O-Alkylated quercetin analogs were synthesized and their anticancer activities were assessed by a high-throughout screening (HTS) method. The structure-activity relationships (SAR) showed that introduction of long alkyl chain such as propyl group at the C-3 OH position or short alkyl chain such as ethyl group at the C-4' OH position were very important for keeping inhibitory activities against the 16 cancer cell lines. Furthermore, when the two n-butyl groups were introduced into the C-3, C-7 or C-4', C-7 positions, the anticancer activity was enhanced.

Biological evaluation and SAR analysis of O-methylated analogs of quercetin as inhibitors of cancer cell proliferation.

Using a high-throughout screening approach, the anticancer activities of 16 O-methylated (OMe) analogs of quercetin were assessed. The structure-activity relationships showed that OMe moieties at the 4' and/or 7 positions were important for maintaining inhibitory activities against the 16 cancer cell lines. Furthermore, when the OH groups at the 3' and 4' positions were both replaced by OMe moieties, anticancer activity was enhanced.

Neuroprotective effects of scutellarin and scutellarein on repeatedly cerebral ischemia-reperfusion in rats.

Scutellarin had protective effects against neuronal injury, however, there are few studies on the protective effect of scutellarein, which is the main metabolite of scutellarin in vivo. This study investigated whether the neural injury by ischemia/reperfusion would be influenced by different doses of scutellarin and scutellarein. Male Wistar rats were orally administered with scutellarin and scutellarein at the doses of 0.09, 0.17, 0.35, 0.70, 1.40 mmol/kg, respectively; then after six consecutive days, they were subjected to global ischemia by occlusion of the bilateral common carotid arteries (BCCAO). After reperfusion for about 21 h, neurological and histological examinations were performed. The present results showed that scutellarein attenuated neuronal cell damage, reduced cerebral water content, regulated the expression of glutamic acid (Glu), aspartic acid (Asp), glycine (Gly), γ-aminobutyric acid (GABA) and taurine (Tau), and improved the Ca(2+)-ATPase and Na(+),K(+)-ATPase activity. Meanwhile, significant difference was found among various doses of scutellarin and scutellarein. Our studies indicated that scutellarin and scutellarein could improve neuronal injury, and scutellarein had better protective effect than scutellarin in rat cerebral ischemia.

Synthesis and structure-activity relationship analysis of caffeic acid amides as selective matrix metalloproteinase inhibitors.

Four series of acid amides were synthesized, and through measurement using a fluorogenic substrate assay with human recombinant MMP-1, MMP-2 and MMP-9, compound 3f showed considerable inhibitory activities against MMP-2, MMP-9 and the best selectivity over MMP-1. Preliminary structure-activity relationship analysis indicated that caffeic acid amides with electron-donating groups at para-position of amino phenyl group showed better inhibitory activities and selectivity than those with electron-withdrawing groups, and the presence of adjacent dihydroxy in the caffeoyl group was very important for the MMP-2 and MMP-9 inhibitory activities.

Design, synthesis and biological evaluation of ferulic Acid amides as selective matrix metalloproteinase inhibitors.

A series of ferulic acid amides with extended P1' groups were synthesized and tested for their inhibitory activities on matrix metalloproteinase (MMP)-1, MMP-2, and MMP-9. Preliminary structure-activity relationship analysis and docking studies indicated that ferulic acid amides with electron-donating groups at the amino phenyl ring showed better inhibitory activities and selectivity than those with electron-withdrawing groups. Compound 3e, which had a hydroxyl group at meta-position of amino phenyl ring, showed considerable inhibitory activities against MMP-2, MMP-9 and best selectivity over MMP-1. The findings of this study would provide information for the exploitation and utilization of ferulic acid as MMP inhibitor for metastatic tumor treatment.

Design, synthesis and biological evaluation of glucose-containing scutellarein derivatives as neuroprotective agents based on metabolic mechanism of scutellarin in vivo.

Based on metabolic mechanism of scutellarin in vivo that scutellarin could be hydrolyzed into scutellarein by ß-glucuronide enzyme, some glucose-containing scutellarein derivatives were designed and synthesized through the introduction of glucose moiety at C-7 position of scutellarein via a glucosidic bond. Biological activity evaluation showed that these glucose-containing scutellarein derivatives exhibited potent DPPH radical scavenging activities. Furthermore, the improvement of physicochemical properties such as anticoagulant and neuroprotective activities alongside with the water solubility was achieved by introducing glucose. These findings suggest that the introduction of the glucose moiety to scutellarein wattants further development of this kind of compounds as neuroprotective agents.

Mannich bases of scutellarein as thrombin-inhibitors: design, synthesis, biological activity and solubility.

Two series of 8-aminomethylated derivatives were prepared by Mannich reaction of scutellarein (2) with appropriate aliphatic amines, alicyclic amines and formaldehyde. All the compounds were tested for their thrombin inhibition activity through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen (FIB). The antioxidant activities of these target products were assessed by 1,1-diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) assay using 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay method and the solubility were assessed by ultraviolet (UV). The results showed that morpholinyl aminomethylene substituent derivative (3d) demonstrated stronger anticoagulant activity, better water solubility and good antioxidant activity compared with scutellarein (2), which warrants further development as a agent for ischemic cerebrovascular disease treatment.

Synthesis and protective effect of scutellarein on focal cerebral ischemia/reperfusion in rats.

Scutellarein, the main metabolite of scutellarin in vivo, has relatively better solubility, bioavailability and bio-activity than scutellarin. However, compared with scutellarin, it is very difficult to obtain scutellarein from Nature. Therefore, the present study focused on establishing an efficient route for the synthesis of scutellarein by hydrolyzing scutellarin. Neurological deficit score and cerebral infarction volume with the administration of scutellarein were then used to compare its neuroprotective effects on focal cerebral ischemia/reperfusion in rats induced by middle cerebral artery occlusion (MCAO) with those of scutellarin. The results showed that scutellarein had better protective effect on focal cerebral ischemia/reperfusion than scutellarin, which laid the foundation for further research and development of scutellarein as a promising candidate for ischemic cerebro-vascular disease.