Five new flavonoids and their pharmacological activities from Iris tenuifolia Pall.

Five new components including two new isoflavones, 5, 7, 2', 3'-tetrahydroxy-6-methoxyisoflavone (1), 5, 7, 2', 3'-tetrahydroxy-8-methoxyisoflavone (2), one flavonol 3, 5, 3', 4'-tetrahydroxy-7, 2'-dimethoxyflavonol (3), one flavanone (2S)-5, 7, 3'-trihydroxy-2'-methoxyflavanone (4), and one flavanonol (2R, 3R)-3, 5, 3', 4'-tetrahydroxy-7, 2'-dimethoxyflavanonol (5), along with nine known flavonoids (6-14) were isolated from under ground parts of Iris tenuifolia Pall. Their structures were elucidated by NMR and HRESIMS data and by comparison of CD spectra with compounds having similar structure. The separated compounds were evaluated for in vitro antioxidant activities by DPPH and ABTS. The α-glucosidase inhibitory activity of the compounds were evaluated with the pNPG method, the results indicated flavonoids were potential inhibitors of α-glucosidase. Moreover, in vitro anti-oxidative assay using flow cytometry indicated that compounds 1-5 showed strong oxidation resistance ability on C8D1A cells without affecting the cell viability.

Volumetric analysis of intravoxel incoherent motion diffusion-weighted imaging in preoperative assessment of non-small cell lung cancer.

PURPOSE: To evaluate the potential of intravoxel incoherent motion (IVIM) and apparent diffusion coefficient (ADC) in the prediction of tumor grade, lymph node metastasis and pleural invasion of non-small cell lung cancer (NSCLC) before surgery. MATERIALS AND METHODS: 65 patients diagnosed with NSCLC by surgery were enrolled. IVIM-DWI (10 b-values, 0-1000 s/mm2) was performed before surgery. The mean and minimum ADC (ADCmean, ADCmin) and IVIM parameters D, D* and f were independently measured and calculated by 2 radiologists by drawing regions of interest (ROIs) including the solid component of the whole tumor. Intraclass correlation coefficients (ICCs) were analysed. Spearman analysis was used to determine the correlation between IVIM parameters and tumor differentiation. Independent sample t-tests (normal distribution) or Mann-Whitney U tests (non-normal distribution) were used to compare the differences between the parameters in moderately-well and poorly differentiated groups, with and without lymph node metastasis and pleural invasion groups. Receiver operating characteristic (ROC) curves were generated. RESULTS: The ADCmean, ADCmin, D and f values were negatively correlated with the pathological grades of tumor (P < 0.05). The ADCmean and D values of patients with poor differentiation and lymph node metastasis were significantly lower than that of patients with moderately-well differentiation and without lymph node metastasis (P < 0.001-0.012). The D value was significantly lower and f value was significantly higher among patients with pleural invasion than those without (P = 0.033 and < 0.001). ROC analysis showed that the area under the ROC curve (AUC) was larger for D in predicting the degree of differentiation (0.832) and lymph node metastasis (0.806), and higher for f in predicting pleural invasion (0.832). CONCLUSIONS: IVIM is useful for predicting the tumor differentiation, lymph node metastasis and pleural invasion in NSCLC patients before surgery.

Volumetric Analysis of Intravoxel Incoherent Motion Diffusion-Weighted Imaging for Predicting the Response to Chemotherapy in Patients With Locally Advanced Non-Small Cell Lung Cancer.

OBJECTIVE: We aimed to prospectively investigate intravoxel incoherent motion parameters to predict the response to chemotherapy in locally advanced non-small cell lung cancer (NSCLC) patients. METHODS: From July 2016 to March 2018, 30 advanced NSCLC patients were enrolled and underwent chest intravoxel incoherent motion-diffusion-weighted imaging at Siemens 3T magnetic resonance imaging before and at the end of the first cycle of chemotherapy. Regions of interest were drawn including the whole tumor volume to derive the apparent diffusion coefficient value, D, D*, and f, respectively. Time-dependent receiver operating characteristic curves were generated to evaluate the cutoff values of continuous variables. A Cox proportional hazards model was used to assess the independent predictors of progression-free survival (PFS) and overall survival (OS). Kaplan-Meier curves and log-rank test were generated. RESULTS: Among the 30 patients, 28 cases (93.3%) died and 2 cases (6.7%) survived till the closeout date. Univariate Cox regression analyses revealed that the significant predictors of PFS and OS were the tumor size reduction rate, the change rates of D and apparent diffusion coefficient values, and the D value before therapy (PFS: P = 0.015, hazard ratio [HR] = 2.841; P < 0.001, HR = 5.840; P = 0.044, HR = 2.457; and P = 0.027, HR = 2.715; OS: P = 0.008, HR = 2.987; P < 0.001, HR = 4.357; P = 0.006, HR = 3.313; and P = 0.013, HR = 2.941, respectively). Multivariate Cox regression analysis suggested that △D% was identified as independent predictors of both PFS and OS (P = 0.003, HR = 9.200 and P = 0.016, HR = 4.617). In addition, the cutoff value of △D% was 21.06% calculated by receiver operating characteristic curve analysis. In the Kaplan-Meier analysis, the PFS and OS were significantly greater in the group of patients with △D% larger than 21.06% (log-rank test, χ2 = 16.453, P < 0.001; χ2 = 13.952, P < 0.001). CONCLUSIONS: Intravoxel incoherent motion-diffusion-weighted imaging was preferred for predicting the prognosis of advanced NSCLC patients treated with chemotherapy. A D increase more than 21.06% at 1 month was associated with a lower rate of disease progression and death.

B1 -Corrected T1 Mapping in Lung Cancer: Repeatability, Reproducibility, and Identification of Histological Types.

BACKGROUND: T1 mapping can potentially quantitatively assess the intrinsic properties of tumors. B1 correction can reduce the magnetic field inhomogeneity. PURPOSE: To assess the repeatability and reproducibility of B1 -corrected T1 mapping for lung cancer and the ability to identify pathological types. STUDY TYPE: Prospective reproducibility study. POPULATION: Sixty lung cancer patients (22 with emphysema) with a total of 60 lesions (adenocarcinoma [n = 23], squamous cell carcinoma [n = 19], and small-cell lung cancer [SCLC] [n = 18]). FIELD STRENGTH/SEQUENCE: A 3 T/B1 -corrected 3D variable flip angle T1 mapping and free-breathing diffusion-weighted imaging. ASSESSMENT: Intraobserver, interobserver, and test-retest reproducibility of minimum, maximum, mean, and SD of lung tumor T1 values were assessed. The correlation between mean T1 and apparent diffusion coefficient (ADC) and differences between different histological types of lung cancer were evaluated. STATISTICAL TESTS: Intraclass correlation coefficients (ICCs), within-subject coefficients of variation (WCVs), Bland-Altman plots, Pearson's correlation coefficient (r), and analysis of variance (ANOVA). A P value <0.05 was considered to be statistically significant. RESULTS: No significant differences were found in minimum, maximum, mean, and SD T1 values for repeated measurements (intraobserver and interobserver) and repeated examinations (P = 0.103-0.979). All parameters showed good intraobserver, interobserver and test-retest reproducibility (ICC, 0.780-0.978), except the maximum T1 value (ICC, 0.645-0.922). The mean T1 exhibited the best reproducibility and repeatability, with an average difference <6% for repeated measurements, <8% for repeated scans in lung cancer patients, and<10% for repeated scans in those with emphysema. The mean T1 correlated moderately with ADC (r = -0.580, -0.516, and -0.511 for observers A, B, and C). Both mean T1 and mean ADC were significantly different in SCLC patients compared with those in adenocarcinoma and squamous cell carcinoma patients. DATA CONCLUSION: The mean T1 from B1 -corrected T1 mapping is a repeatable parameter with the potential to identify histological types of lung cancer and thus may be a promising imaging biomarker for characterizing lung cancer. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Total Flavonoids of Glycyrrhiza uralensis Alleviates Irinotecan-Induced Colitis via Modification of Gut Microbiota and Fecal Metabolism.

Irinotecan (CPT-11)-induced gastrointestinal toxicity strongly limits its anticancer efficacy. Glycyrrhiza uralensis Fisch., especially flavonoids, has strong anti-inflammatory and immunomodulatory activities. Herein, we investigate the protective effect of the total flavonoids of G. uralensis (TFGU) on CPT-11-induced colitis mice from the perspective of gut microbiota and fecal metabolism. The body weight and colon length of mice were measured. Our results showed that oral administration of TFGU significantly attenuated the loss of body weight and the shortening of colon length induced by CPT-11. The elevated disease activity index and histological score of colon as well as the up-regulated mRNA and protein levels of TNF-α, IL-1ß, and IL-6 in the colonic tissue of CPT-11-treated mice were significantly decreased by TFGU. Meanwhile, TFGU restored the perturbed gut microbial structure and function in CPT-11-treated mice to near normal level. TFGU also effectively reversed the CPT-11-induced fecal metabolic disorders in mice, mainly call backing the hypoxanthine and uric acid in purine metabolism. Spearman's correlation analysis further revealed that Lactobacillus abundance negatively correlated with fecal uric acid concentration, suggesting the pivotal role of gut microbiota in CPT-11-induced colitis. Since uric acid is a ligand of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, TFGU was further validated to inhibit the activation of NLRP3 inflammasome by CPT-11. Our findings suggest TFGU can correct the overall gut microbial dysbiosis and fecal metabolic disorders in the CPT-11-induced colitis mice, underscoring the potential of using dietary G. uralensis as a chemotherapeutic adjuvant.

Chemo Proling and Simultaneous Analysis of Different Combinations of Sinomenii Caulis and Ramulus Cinnamomi Using UHPLC-Q-TOF-MS, GC-MS and HPLC Methods.

OBJECTIVE: Sinomenii Caulis (QingFengTeng) and Ramulus Cinnamomi (GuiZhi) are traditional Chinese drugs that have been used for anti-inflammation. In this study, the team plans to find out the material basis of a Chinese herb combination composed of the two herbs with different ratios. METHODS: The extracts of the herbal compound with various ratios obtained from ethanol extraction were analyzed by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) and gas chromatography coupled mass spectrometry to identify the basic chemical compounds. Simultaneously, the contents of the eight main components (sinomenine, magnoflorine, laurifoline, dauricine, coumarin, cinnamyl alcohol, cinnamic acid and cinnamaldehyde) from herb formula were determined by gradient elution by high-performance liquid chromatography. Furthermore, the content of sinomenine and cinnamaldehyde were determined by isocratic elution, respectively. RESULTS: Eighteen compounds in the herb formula were identified by UHPLC-Q-TOF-MS. The components in the GuiZhi are mostly volatile oils and the kinds of compounds isolated from the formula in the ratio of 4:1 were the most. Wherein eight compounds were identified as the main detection targets in the content determination. CONCLUSION: The extraction rate of sinomenine in QingFengTeng was related to the proportion of GuiZhi in the drug pairs. Synchronously, the addition of sinomenine in different proportions also had some influence on the extraction of cinnamaldehyde in GuiZhi. Furthermore, the series of methods was successfully applied to the simultaneous determination of chemical compounds in different samples of QingFengTeng-GuiZhi decoction.

Gardner syndrome with a giant mass in the thoracic cavity: a case report and analysis of the related complications.

Gardner syndrome (GS) is a form of familial adenomatous polyposis (FAP) and is characterized by colonic polyposis, osteomas, and soft-tissue tumors. Desmoid tumors (DT) are lesions of mesenchymal origin and are an extra-colonic manifestation of GS. Gardner-associated fibroma (GAF) is considered to be a benign soft-tissue lesion related to DT and FAP. Here we present a case of an 18-year-old female patient with a huge lump in her right thoracic cavity and another lump located in her left lumbar muscles who was diagnosed with GS through a colonoscopy and through adenomatous polyposis coli (APC) gene mutation detection. The patient underwent a surgical resection of the right thoracic tumor. Three months later, the left waist lump underwent medical treatment with tamoxifen and celecoxib and was monitored using computed tomography (CT). Subsequently, colonoscopy screening was performed annually to prevent colorectal cancer. GAF is frequent in GS, and such a huge GAP in the thorax is very rare, with few cases reported in the literature. Patients with GS must be closely monitored, and clinical and imaging examinations must be performed to detect any signs of tumors.

The value of diffusion-weighted imaging based on monoexponential and biexponential models for the diagnosis of benign and malignant lung nodules and masses.

OBJECTIVES: The objective is to compare the efficacy of diffusion-weighted imaging (DWI) parameters of mean and minimum apparent diffusion coefficient (ADCmean and ADCmin) and intravoxel incoherent motion (IVIM) in the differentiation of benign and malignant lung nodules and masses. METHODS: Lung lesions measured larger than 1.5 cm on CT were included between August 2015 and September 2018. DWI (10 b-values, 0-1000 s/mm2) scans were performed, and the data were post-processed to derive the ADCmean, ADCmin and IVIM parameters of true diffusion coefficient (D), pseudodiffusion coefficient (D*) and perfusion fraction (f). An independent sample t-test or Mann-Whitney U test was used to compare benign and malignant parameters. Receiver operating characteristic curves were generated and a Z test was used. RESULTS: 121 patients were finally enrolled, each with one lesion. Examined 121 lesions were malignant in 88 (72.7%) and benign in 33 (27.3%). The ADCmean of malignant pulmonary nodules was significantly lower than that of benign pulmonary nodules (t = 3.156, p = 0.006), whereas the other parameters revealed no significant differences (p = 0.162-0.690). Receiver operating characteristic curve analysis revealed that an ADCmean threshold value of 1.43 × 10-3 mm2/s yielded 88.57% sensitivity and 64.29% specificity. While for lung masses, the ADCmean, ADCmin, D and D* values in malignant pulmonary masses were significantly lower (P﹤0.001-0.011). Among them, the D value exhibited the best diagnostic performance when the threshold of D was 1.23 × 10-3mm2/s, which yielded a sensitivity of 90.57% and a specificity of 89.47% (Z = 2.230, 3.958, 2.877 and p = 0.026, ﹤0.001 and 0.004, respectively). CONCLUSION: ADC is the most robust parameter to differentiate benign and malignant lung nodules, whereas D is the most robust parameter to differentiate benign and malignant lung masses. ADVANCES IN KNOWLEDGE: This is the first study to compare all the quantitative parameters of DWI and IVIM mentioned in the literatures for assessing lung lesions; Second, we divided the lesions into lung nodules and lung masses with the size of 3 cm as the boundary.

A primary analysis on measuring repeatability of the maximum diameter between CT and MR imaging for lung cancers.

OBJECTIVE: To investigate the measurement reproducibility of the maximum diameter on MRI routine sequence (T1WI, T2WI, DWI) and CT in peripheral and central lung cancer, and to provide reference standard for evaluating treatment responses for lung cancer. METHODS: 53 patients with lung cancer underwent CT and 3.0T MR scanning. The maximum diameter was measured according to the RECIST1.1 standard on images of CT (lung and enhanced mediastinal window), MRI T2-BLADE, axial T1-VIBE and DWIb0, DWIb300, DWIb800, respectively. The reproducibility of the diameters was analyzed with intraclass correlation coefficient (ICC), and the distribution of measurement points with the Bland-Altman method. The difference analysis was assessed by paired samples t-test and nonparametric rank sum test, P < 0.05 is considered statistically significant. RESULTS: Reproducibility of diameters derived from routine MRI and CT was good (ICC > 0.75). For peripheral lung cancer, there was no significant difference in diameters between CT and MRI. While for central lung cancer, there was significant difference in diameters measured between using CT and each MRI sequence. However, the diameters derived from T1-VIBE and T2-BLADE were not significantly different from all DWI sequences. CONCLUSIONS: For peripheral lung cancer, the measurement on CT and routine MRI sequences can potentially replace each other after comprehensive consideration of examination purposes, but for central lung cancer, alternative use of CT and MRI in evaluating treatment responses for lung cancer should needs extra attention. The diameter measurement of lung cancer on DWI is consistent with that on T1WI and T2WI, suggesting that DWI can provide functional and morphological information.

Dual drug-loaded cubic liquid crystal gels for transdermal delivery: inner structure and percutaneous mechanism evaluations.

The goal of this paper was to develop and evaluate dual component-loaded with the hydrophilic sinomenine hydrochloride (SH) and lipophilic cinnamaldehyde (CA) cubic liquid crystal gels for transdermal delivery. The gels was prepared with a vortex method using phytantriol/water (70:30, w/w) and characterized by polarized light microscopy, small-angle X-ray scattering and rheology. The inner structure of the gels were Pn3m cubic phase and exhibited a pseudoplastic fluid behavior. Furthermore, the in vitro release profile showed that the release behavior of the two drugs from cubic liquid crystal gels conformed to Higuchi equation and were dominated by Fick's diffusion (n < 0.45). The ex vivo penetration experiment indicated that dual components-loaded liquid crystal gels can enhance and extend the skin permeation of these two drugs, especially the ratio of SH to CA is 1: 0.5. Finally, transdermal mechanisms were evaluated using laser scanning confocal microscopy and attenuated total reflectance-fourier transform infrared, hinting that hydrophilic and lipophilic drugs weaken each other's transdermal velocity at the initial stage of penetration. In short, the dual drug-loaded liquid crystal gels was a promising strategy for transdermal applications in treatment of chronic disease.

The Effect of Prescription on the Framework of Lipid Matrix and In Vitro Properties.

PURPOSE: To clarify the inner framework and relative properties in vitro of Lyotropic liquid crystal (LLC) based on various prescriptions by using hydrophilic sinomenine hydrochloride (SH) and lipophilic cinnamaldehyde (CA) as model drugs. METHODS: Phase structures were checked by polarized light microscopy (PLM) and small-angle X-ray scattering (SAXS). Rheological studies and Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) analysis were carried out to reveal their molecular interactions. In vitro release and skin permeation were conducted by Franz diffusion cell. RESULTS: PLM and SAXS showed double diamond cubic crystal. All the samples displayed characteristics of non-Newtonian fluid, and the molecular interactions increased with the reducing water. ATRFTIR showed that the strongest strength of hydrogen bond emerged in the formulation with 32% water. Released SH of S2 and S3 arrived over 80%, while S1 only reached 45%, and that of CA was about 23%. Water-rich prescription gave higher percutaneous penetration for hydrophilic drugs, whereas no significant difference existed in CA permeation. CONCLUSION: Proportion of Phytantriol to water determined the LLC assembling and affected the dissolving status of hydrophilic substance, thereby impacting on the location sites of guest molecular interactions among the substances, rheology properties, and finally the release and penetration behavior in vitro. Adjusting the basic prescription was the key to obtain satisfactory percutaneous delivery and stability for LLC carrying multi-therapeutic agents.

Novel berberine derivatives: Design, synthesis, antimicrobial effects, and molecular docking studies.

A series of berberine derivatives were synthesized by introducing substituted benzyl groups at C-9. All these synthesized compounds (4a-4m) were screened for their in vitro antibacterial activity against four Gram-positive bacteria and four Gram-negative bacteria and evaluated for their antifungal activity against three pathogenic fungal strains. All these compounds displayed good antibacterial and antifungal activities, compared to reference drugs including Ciprofloxacin and Fluconazole; Compounds 4f, 4g, and 4l showed the highest antibacterial and antifungal activities. Moreover, all the synthesized compounds were docked into topoisomerase II-DNA complex, which is a crucial drug target for the treatment of microbial infections. Docking results showed that H-bond, π-π stacked, π-cationic, and π-anionic interactions were responsible for the strong binding of the compounds with the target protein-DNA complex.

On the Structure and Transdermal Profile of Liquid Crystals Based on Phytantriol.

BACKGROUND: There has been a growing concern in transdermal drug technology over the past several decades. As a novel transdermal delivery system, Lyotropic liquid crystals (LLC) still face challenges such as drug loading, limited drug permeation and instability of systems. LLC system is so sensitive that a very subtle change in composition may induce a phase transformation or conversion of spatial configuration, and result in a diverse percutaneous delivery subsequently. OBJECTIVE: To find out the effects of hydrophilic and lipophilic components on the structure and transdermal properties of LLCs, hydrophilic sinomenine hydrochloride (SH) and lipophilic cinnamaldehyde (CA) was chosen as a model drug and a skin permeation enhancer, respectively, several formulations were prepared and compared. METHOD: The structure of LLC was evaluated by visual observation, Cross-polarizing light microscopy (CPLM) and Small angle X-ray diffraction (SAXS). The Franz diffusion cell was applied to investigate its skin penetration of SH across the rat skins. Fourier transform infrared spectroscopy (FTIR) was recorded to evaluate the intermolecular interaction between the LC samples and stratum corneum (SC). CONCLUSION: The results showed that a controlled transdermal process might be obtained by adjusting the ratios of different drugs or loading doses when LLCs with dual-components were applied.

Carboxylesterase and UDP-glucuronosyltransferases mediated metabolism of irinotecan: In vitro and in vivo insights from quantitative ultra-performance liquid chromatography-mass spectrometry analysis.

Carboxylesterase and UDP-glucuronosyltransferase-mediated metabolism of irinotecan (CPT-11) has long been proposed to be responsible for its anti-tumor activity and toxicity, like delayed-onset diarrhea. However, recent studies failed to gain more comprehensive in vivo and in vitro pharmacokinetic profiles of irinotecan. Herein, we use rat plasma, human liver microsomes and immortalized HepG2 cell as experimental subjects to describe a sensitive and versatile UHPLC-MS/MS method for simultaneously quantifying CPT-11 and its metabolites, including SN-38 and SN-38G. The method was applied to investigate the pharmacokinetic and metabolic behavior of CPT-11 in the biological samples. Calibration curves for all bio-matrices showed acceptable linearity (r2 > 0.99). The intra- and inter-day precisions (RSD, %) were within 15% and the excellent accuracy (RE) was between 2.96 and 14.12%. In addition, the specificity, matrix effect and extraction recovery all met the requirements of biological sample analysis. We successfully applied this method to investigate the pharmacokinetics of irinotecan in various biological samples, mediated by carboxylesterase and UDP-glucuronosyltransferase. This method could be employed in monitoring the metabolic status and clinical efficacy of irinotecan in the future.

Characterization and In Vitro Permeation Study of Cubic Liquid Crystal Containing Sinomenine Hydrochloride.

This study developed a new transdermal delivery system for the improved delivery of sinomenine hydrochloride (SH). The delivery system utilized the advantages of lyotropic liquid crystals (LLC) creating an adaptable system that offers a variety of options for the field of transdermal delivery. The formulation was prepared, characterized, and evaluated for its skin penetration in vitro. In the study, the appearance of samples was characterized by visual observation, and these LLC gels were colorless and transparent. Polarizing light microscopy (PLM) and small-angle X-ray diffraction (SAXS) were used to analyze the internal structures of gels, and the gels displayed a cubic double-diamond (Pn3m) internal structure with a dark field of vision. The Franze diffusion cell was used to evaluate its skin penetration. There were several factors which might influence the skin penetration of drugs, such as drug loading, water content, and the layer spacing of the LLC. In our case, drug concentration gradient played a more powerful role. The result of in vitro permeation studies demonstrated that the drug concentration was higher; the cumulative osmotic quantity of SH (Q) was greater. Therefore, the system was a promising formulation for successful percutaneous delivery of SH through the skin.

Lung Cancer: Short-Term Reproducibility of Intravoxel Incoherent Motion Parameters and Apparent Diffusion Coefficient at 3T.

PURPOSE: To prospectively evaluate the short-term reproducibility of intravoxel incoherent motion (IVIM) parameters and apparent diffusion coefficient (ADC) in lung cancer patients. MATERIALS AND METHODS: In all, 50 patients (50 lesions) underwent free-breathing diffusion-weighted imaging (DWI) (b = 0, 300, 800 s/mm2 ) and IVIM (10 b-values, 0-1000 s/mm2 ) scans twice (0.5-1-hour interval) at 3T. Regions of interests (ROIs) were drawn on ADC maps and IVIM images to derive the mean ADC value and IVIM parameters D, D*, and f. Intra- and interobserver, test-retest reproducibility were assessed with intraclass correlation coefficients (ICCs), within coefficient-of-variations (WCVs), and Bland-Altman analysis. The effects of type, size, and location of lung lesions were compared with WCVs. RESULTS: D and ADC showed good intraobserver reproducibility and interobserver agreement, while D* and f showed relatively larger variability (WCV 20.89-34.97%). The test-retest reproducibility of D and ADC were good (ICC 0.763-0.837; WCV 11.12-12.55%), while those of D* and f were relatively poor (ICC 0.604-0.842; WCV 36.54-72.62%). D and ADC had decreased reproducibility for lesions <2 cm (WCV 14.20%, 16.34%, respectively) and for lesions in the lower lung zones (WCV 16.52%, 14.78%, respectively). f had decreased reproducibility in central lung cancers (WCV 50.11%) and lesions >2 cm (WCV 42.64%). D* had even worse reproducibility in peripheral lung cancers (WCV 84.11%) and lesions in the lower lung zones (WCV 80.84%). CONCLUSION: If the change in ADC, D, D*, and f values is less than ∼31%, 34%, 170%, and 130%, respectively, it may be caused by measurement error. The type, size, and location of lung lesions have an effect on measurement errors. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2018;47:1003-1012.

Synthesis and evaluation of benzylisoquinoline derivatives for their inhibition on pancreatic lipase and preadipocyte proliferation.

The present study was designed to synthesize and evaluate a series of benzylisoquinoline derivatives. These compounds were synthesized by Bischler-Napieralski cyclization to yield 1-benzyl-3,4-dihydroisoquinolines, and the products were obtained by reductions. All these compounds were identified by MS, (1)H NMR and (13)C NMR. The inhibitory activities on pancreatic lipase and preadipocyte proliferation for the synthesized compounds and alkaloids from Nulembo nucifera were assessed in vitro. Most of the compounds showed inhibitory activities on both pancreatic lipase and preadipocyte proliferation. Particularly, compounds 7p-7u and 9d-9f exhibited significant inhibitory activity on pancreatic lipase while compounds 7c, 7d, 7f, 7g, 7i, and 7j potently inhibited the proliferation of 3T3-L1 preadipocytes. Our results provided a basis for future evaluation and development of these compounds as leads for therapeutics for human diseases.

Discovery and structural optimization of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-ones as RORc inverse agonists.

AIM: Retinoic acid receptor-related orphan nuclear receptors (RORs) are orphan nuclear receptors that show constitutive activity in the absence of ligands. Among 3 subtypes of RORs, RORc is a promising therapeutic target for the treatment of Th17-mediated autoimmune diseases. Here, we report novel RORc inverse agonists discovered through structure-based drug design. METHODS: Based on the structure of compound 8, a previously described agonist of RORa, a series of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives were designed and synthesized. The interaction between the compounds and RORc was detected at molecular level using AlphaScreen assay. The compounds were further examined in 293T cells transfected with RORc and luciferase reporter gene. Thermal stability shift assay was used to evaluate the effects of the compounds on protein stability. RESULTS: A total of 27 derivatives were designed and synthesized. Among them, the compound 22b was identified as the most potent RORc inverse agonist. Its IC50 values were 2.39 µmol/L in AlphaScreen assay, and 0.82 µmol/L in inhibition of the cell-based luciferase reporter activity. Furthermore, the compound 22b displayed a 120-fold selectivity for RORc over other nuclear receptors. Moreover, a molecular docking study showed that the structure-activity relationship was consistent with the binding mode of compound 22b in RORc. CONCLUSION: 4-(4-(Benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives are promising candidates for the treatment of Th17-mediated autoimmune diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis.

Calycosin-7-O-ß-D-glucoside regulates nitric oxide /caveolin-1/matrix metalloproteinases pathway and protects blood-brain barrier integrity in experimental cerebral ischemia-reperfusion injury.

ETHNOPHARMACOLOGY RELEVANCE: Astragali Radix (AR) has been used for thousands years to treat ischemic stroke. Calycosin and its glycoside form calycosin-7-O-ß-D-glucoside (CG) are two representative isoflavones in Astragali Radix. However, its neurological effects and related molecular mechanisms are largely unknown. The present study aims to evaluate the neuroprotective effects of CG on blood-brain barrier (BBB) integrity of ischemic brain tissue and explore the relevant signaling mechanisms. MATERIAL AND METHOD: Male adult Sprague-Daweley rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) plus 24 h or 14 days of reperfusion. CG (26.8 mg/kg) was intraperitoneally administered into the rats at 15 min before onset of ischemia. The neuroprotective effects of CG were evaluated by measuring infarct volume, histological damage and BBB permeability. Furthermore, the effects of CG on scavenging nitric oxide (NO), and modulating matrix metalloproteinases (MMPs) and caveolin-1 (cav-1) were investigated with in vitro cultured brain microvascular endothelial cells treated with NO donor or oxygen-glucose deprivation (OGD) and/or in vivo rat model of MCAO cerebral ischemia-reperfusion injury. RESULTS: CG treatment significantly reduced infarct volume, histological damage and BBB permeability in the in vivo MCAO ischemia-reperfusion rat model. CG treatment remarkably inhibited the expression and activities of MMPs, and secured the expression of cav-1 and tight junction proteins in the microvessels isolated from ischemic rat cortex. Furthermore, CG was revealed to scavenge NO, inhibit the activities of MMP-2 and MMP-9, and attenuate cell death in the in vitro cultured brain microvascular endothelial cells under OGD condition. CONCLUSION: CG could protect BBB integrity in experimental cerebral ischemia-reperfusion injury via regulating NO/cav-1/MMPs pathway.