Semi-Synthesis of Flavonoid Glycosides and Their Anti-Inflammatory and Antitumor Activities towards Triple Negative Breast Cancer.

BACKGROUND: Flavonoid glycosides are known to possess diverse bioactivities including antitumor and anti-inflammatory properties. Hesperetin is abundant in nature and can be used to synthesize bioactive flavonoids. This has the advantages of low cost, short synthetic steps, simple operation, and good yields. OBJECTIVE: In this study, we aimed to synthesize bioactive flavonoids and flavonoid glycosides from hesperetin and evaluate the antitumor and anti-inflammatory activities of these compounds. METHODS: A series of flavonoids and their derivatives were synthesized by methoxylation, oxidative dehydrogenation, benzylation, debenzylation, and deacetylation as well as using a modified peroxyacetone method and a glycoside condensation reaction. Their anti-inflammatory activities were evaluated for their inhibitory effects on nitric oxide (NO), tumor necrosis factor (TNF-α), and interleukin-6 (IL-6) production in LPS-induced RAW264.7 mouse macrophages. Their structures were characterized by HRMS, 1 H-NMR, and 13 C-NMR, and their cytotoxicity on the human triple-negative breast cancer cell (TNBC) line, SUM 149, was tested by using the MST assay. RESULTS: Most of the compounds markedly reduced NO production in LPS-stimulated murine macrophages at the tested concentrations in a dose-dependent manner. Among these, compounds 1, 7, 9, and 17 showed significant anti-inflammatory activities against NO production in LPS-induced RAW264.7 mouse macrophages. In addition, they could also reduce the release of TNF-α and IL-6 in a concentration-dependent manner. Most of the tested compounds showed remarkable anti-human TNBC activities. Compounds 1b-1m, 1, and 3 showed a certain degree of growth inhibition effect on the human TNBC cell lines and their IC50 values were all below 16.61 µM. In addition, compound 1l was the most cytotoxic with IC50 values of 1.38±0.31 µM, while the other compounds were inactive with inhibition rates <50 % at the highest concentration tested (20 µM). CONCLUSIONS: A novel series of flavonoids were synthesized from the natural flavonoid, hesperetin, including 17 new compounds. Screening tests indicated that most of these compounds reduced NO production in LPS-stimulated murine macrophages at concentrations of 15 to 60 µM, and the inhibition generally increased in a dose-dependent manner. Some compounds showed different degrees of cytotoxicity on the human TBNC cell lines, SUM 149.

Erectile dysfunction in nonmuscle-invasive bladder cancer patients before and after transurethral resection (TUR) of bladder tumor in China.

The aim of this study was to investigate the incidence of erectile dysfunction (ED) in nonmuscle-invasive bladder cancer (NMIBC) patients before and after transurethral resection (TUR) in China. Clinical data from 165 male patients with NMIBC who received adjuvant intravesical chemotherapy after TUR in Neijiang First People's Hospital (Neijiang, China) between January 2010 and June 2019 were retrospectively reviewed. The sexual function of these patients was evaluated before and 1.5 years after initial TUR by the International Index of Erectile Function-5 (IIEF-5). An age-specific subanalysis was performed among the patients: <45 years old (Group 1, n = 19) and ≥45 years old (Group 2, n = 146). Before and 1.5 years after TUR, the incidence rates of ED in Group 1 were 15.8% and 52.6%, and those in Group 2 were 54.1% and 61.0%, respectively. The difference between groups was statistically significant at the preoperative stage (15.8% vs 54.1%, P = 0.002) but not at the postoperative stage (52.6% vs 61.0%, P = 0.562). Compared with the preoperative stage, the incidence of ED at the postoperative stage was increased significantly in Group 1 (15.8% vs 52.6%, P = 0.017) but not in Group 2 (54.1% vs 61.0%, P = 0.345). In conclusion, the incidence of ED increased in male NMIBC patients under the age of 45 years after TUR in China. These patients should be offered professional counseling during the follow-up period.

Antitarget Selectivity and Tolerability of Novel Pyrrolo[2,3-d]pyrimidine RET Inhibitors.

The selective inhibition of RET kinase as a treatment for relevant cancer types including lung adenocarcinoma has garnered considerable interest in recent years and prompted a variety of efforts toward the discovery of small-molecule therapeutics. Hits uncovered via the analysis of archival kinase data ultimately led to the identification of a promising pyrrolo[2,3-d]pyrimidine scaffold. The optimization of this pyrrolo[2,3-d]pyrimidine core resulted in compound 1, which demonstrated potent in vitro RET kinase inhibition and robust in vivo efficacy in RET-driven tumor xenografts upon multiday dosing in mice. The administration of 1 was well-tolerated at established efficacious doses (10 and 30 mg/kg, po, qd), and plasma exposure levels indicated a minimal risk of KDR or hERG inhibition in vivo, as evaluated by Miles assay and free plasma concentrations, respectively.

Lanostane-type triterpenoids from Ganoderma applanatum and their inhibitory activities on NO production in LPS-induced BV-2 cells.

Five previously undescribed lanostane-type triterpenoids, including two triterpenoids with a rearranged side chain (applanoic acids E and F), one C21 nortriterpenoid (16,17-dehydroapplanone E), as well as two highly oxygenated lanostane triterpenoids (methyl applaniate B and applanoic acid G), were isolated from the fruiting bodies of Ganoderma applanatum (Pers.) Pat. Their structures were elucidated on the basis of spectroscopic analysis, X-ray crystallography and ECD data. Applanoic acid E, 16,17-dehydroapplanone E, and methyl applaniate B showed inhibitory effects on the release of NO by LPS-induced BV-2 cells.

Efficacy and Tolerability of Pyrazolo[1,5-a]pyrimidine RET Kinase Inhibitors for the Treatment of Lung Adenocarcinoma.

RET (REarranged during Transfection) kinase gain-of-function aberrancies have been identified as potential oncogenic drivers in lung adenocarcinoma, along with several other cancer types, prompting the discovery and assessment of selective inhibitors. Internal mining and analysis of relevant kinase data informed the decision to investigate a pyrazolo[1,5-a]pyrimidine scaffold, where subsequent optimization led to the identification of compound WF-47-JS03 (1), a potent RET kinase inhibitor with >500-fold selectivity against KDR (Kinase insert Domain Receptor) in cellular assays. In subsequent mouse in vivo studies, compound 1 demonstrated effective brain penetration and was found to induce strong regression of RET-driven tumor xenografts at a well-tolerated dose (10 mg/kg, po, qd). Higher doses of 1, however, were poorly tolerated in mice, similar to other pyrazolo[1,5-a]pyrimidine compounds at or near the efficacious dose, and indicative of the narrow therapeutic windows seen with this scaffold.

Accumulation of steroid hormones in soil and its adjacent aquatic environment from a typical intensive vegetable cultivation of North China.

Steroid hormones released from manure agricultural application are a matter of global concern. The residual levels of steroid hormones were studied in a typical intensive vegetable cultivation area in northeast China, with a long history of heavy manure application. Seven steroids (estrone, 17α-estradiol, 17ß-estradiol, estriol, testosterone, androstendione and progesterone) were analyzed from soil sampled from vegetable greenhouses, from sediments and water from the adjacent drainage ditch and from the groundwater. The results showed that target steroids were detected in the soil samples, with detection frequencies varying from 3.13 to 100%. The steroid concentrations varied substantially in soils, ranging from below the detection limit to 109.7µg·kg(-1). Three steroids-progesterone, androstendione and estrone-were found to have relatively high residue concentrations in soil, with maximum concentrations of 109.7, 9.83 and 13.30µg·kg(-1), respectively. In adjacent groundwater, all the steroids, with the exception of estrone, were detected in one or more of the 13 groundwater samples. The concentrations of steroids in groundwater ranged from below the method detection limit to 2.38ng·L(-1). Six of the seven (excluding androstendione) were detected in drainage ditch water samples, with concentrations ranging from below the detection limit to 14ng·L(-1). Progesterone, androstendione and estrone accumulated relatively easily in soils; their concentrations in groundwater were lower than those of other steroids. The concentrations of testosterone and estriol were relatively low in soil, while in groundwater were higher than those of other steroids. The residual levels of steroids in soil and groundwater showed a clear spatial variation in the study area. The residual levels of steroid hormones in soil varied substantially between differently planted greenhouses.

Investigation of residual fluoroquinolones in a soil-vegetable system in an intensive vegetable cultivation area in Northern China.

One of the largest vegetable cultivation field sites in Northeast China was selected to investigate the occurrence and distribution pattern of fluoroquinolones (FQs) in the soil-vegetable system. A total of 100 surface soil samples and 68 vegetable samples were collected from this study area. The antibiotic concentration was analyzed using high-performance liquid chromatography tandem mass spectrometry. Results indicated the presence of FQs in all soil samples. Ciprofloxacin (CIP) had the highest mean concentration, at 104.4 µg · kg(-1) in the soil, a level that represents a relatively high risk to the environment and to human health. However, in the vegetable samples, norfloxacin (NOR) was significantly higher than CIP and enrofloxacin (ENR), ranging from 18.2 to 658.3 µg · kg(-1). The transfer ability of NOR in soil-vegetables is greater than that of CIP and ENR. Moreover, we found that the solanaceous fruits had a higher antibiotic accumulation ability than the leafy vegetables. Taken together, these data indicate that greater attention should be paid to the region in which vegetables with higher accumulation ability are grown.

Spatial estimation of antibiotic residues in surface soils in a typical intensive vegetable cultivation area in China.

Antibiotic residues in surface soils can lead to serious health risks and ecological hazards. Spatial mean concentration of antibiotic residues in the soil is the most important indicator of a region's environmental risk to antibiotic residues. Considerable estimation error would lead to an inefficient strategy of pollution control that happens when sample size is small and the estimation model does not match the spatial features of the object to be surveyed. On the basis of the available datasets, it was found that the distribution of antibiotics residue in soil follows a spatial stratification pattern. Accordingly, we used a new spatial estimation method called Mean of Surface with Non-homogeneity (MSN) to estimate antibiotic concentrations in surface soil of the Shandong Province, an important vegetable growing region in China. The standard error of the mean estimates obtained by MSN was significantly smaller (by about 1.02-6.82 µg/kg) than the estimation errors produced by three mainstream methods, simple arithmetic estimation (2.9-11.8 µg/kg), stratified estimation (2.5-10.6 µg/kg) and ordinary kriging estimation (2.2-8.2 µg/kg).

[Analysis of urinary storage symptoms following transurethral resection of the prostate].

OBJECTIVE: To explore the lower urinary tract symptoms (LUTS), especially those in the urinary storage phase, following transurethral resection of the prostate (TURP), and to improve the postoperative management and patients' quality of life after TURP. METHODS: A total of 86 patients with benign prostate hyperplasia (BPH) underwent TURP, and were interviewed on urinary symptoms at 1, 3, 7, 15 and 30 days after removal of the catheter. The patients were divided into two groups according to whether they had preoperative detrusor instability and/or compliance of the bladder (Group A) or not (Group B), and observed for the changes in IPSS scores and urinary storage symptoms after removal of the catheter. RESULTS: Complete follow-ups were achieved in 71 cases, 28 with detrusor instability and/or compliance of the bladder and the other 43 without. Their IPSS scores on the 1st, 3rd, 7th, 15th and 30th day after removal of the catheter were 8.1 +/- 2.5, 7.2 +/- 3.1, 6.3 +/- 3.8, 5.3 +/- 4.2 and 2.4 +/- 3.4, respectively, with statistically significant differences between the 7th and the 1st as well as the 30th and the 15th day (P < 0.05), but not between the 1st and the3rd nor the 15th and the 7th day (P > 0.05). On the 1st day, the cardinal symptoms in the urinary storage phase were urinary frequency, urgency and incontinence; the scores on IPSS and urinary storage symptoms were 10.4 +/- 3.3 and 9.3 +/- 3.8 in Group A and 6.2 +/- 2.8 and 5.2 +/- 2.7 in Group B, with significant differences between the two groups (P < 0.05). After treatment with tolterodine and alpha-adrenoreceptor inhibitor, neither IPSS scores nor the scores on urinary storage symptoms showed any significant differences between Groups A and B on the 15th and 30th day (P > 0.05). CONCLUSION: The lower urinary tract symptoms following TURP, especially those in the urinary storage phase, are correlated with preoperative bladder function, and getting improved gradually after surgery.

Identification of novel series of human CCR1 antagonists.

A hit-to-lead optimization process was carried out on the high throughput screening hit compound 1 resulting in the identification of several potent and selective CCR1 receptor antagonists. Compound 37 shows the best overall profile with IC(50) values of <100 nM in binding and functional assays.

[The impact of Yishenqinghuo recipe on alveolar bone reconstruction of rats with experimental periodontitis].

PURPOSE: To evaluate the impact of Yishenqinghuo recipe on alveolar bone reconstruction of rats with experimental periodontitis. METHODS: 12-months old Spague-Dawley rats were selected for the study. All rats were randomly divided into 4 groups. Group A: control group (with no periodontitis model, fed with the same dosage of saline as Group D); Group B: model group (with periodontitis model, fed with the same dosage of saline as Group D); Group C: high-dosage group (with periodontitis model, fed with doubling dosage of medicine as Group D); Group D: equivalent-dosage group (with periodontitis model, fed with clinical equivalent effective dosage of medicine). After being gavaged with medicine/saline for 3 months, the alveolar bone were collected to make undecalcified histological slices and evaluate the changes of alveolar bone histomorphometric parameters. All the results were analyzed by ANOVA, with the use of SAS 6.04 software package. RESULTS: Compared with group B, the formation of osteoid were increased and had less free ending trabecular in group C and D. The percent age of trabecular area (%Tb.Ar) and node-terminus ratio (NTR) of alveolar bone for this 4 groups were 75.24+/-3.82/1.49+/-0.12, 45.78+/-6.70/0.48+/-0.08, 73.33+/-4.20/1.33+/-0.06 and 67.69+/-2.83/1.26+/-0.10,respectively. This two parameters of group B were much lower than that in other three groups (P<0.01). At the same time, the NTR in group D was significantly lower than that in group A (P<0.01). The osteoid area (Os.Ar) of different groups were (88.44+/-7.52) microm(2), (145.37+/-13.91) microm(2), (211.10+/-22.96) microm(2) and (201.22+/-24.75) microm(2) (transformation variables), respectively. The Os.Ar of group A was lowest, and that in group B was lower than group C and D, there were significant differences(P<0.01). CONCLUSIONS: From this study, we conclude that Yishenqinghuo recipe is in favor of enhancing alveolar bone quantity, improving bone structure and reconstructing bone loss of rats with experimental periodontitis. Supported by National Key Technologies R&D Program (Grant No.2004BA726) and Natural Science Foundation of Shanghai Municipality (Grant No.03ZR14081).

Structure-activity relationships of novel, highly potent, selective, and orally active CCR1 antagonists.

Design and synthesis of a series of 3-amino-4-(2-(2-(4-benzylpiperazin-1-yl)-2-oxoethoxy)phenylamino)cyclobutenedione derivatives as novel CCR1 antagonists are described. Structure-activity relationship studies led to the identification of compound 22, which demonstrated potent binding activity, functional antagonism of CCR1 as well as good species cross-reactivity. In addition, compound 22 also showed desirable pharmacokinetic profiles and was selected for in vivo studies in the mouse collagen-induced arthritis model.

[A study on the state of periodontal health of 400 professional adults by random sampling in Shanghai].

PURPOSE: To investigate and analyze the state of periodontal health of 400 adults at their post and risk factors in Shanghai. METHODS: 400 subjects (249 male, 151 female), aged from 25 to 59, were requested to fill a questionnaire. The probing depth (PD), clinical attachment level (CAL), tooth mobility (TM) and bleeding on probing(BOP) on 6 sites of each indicated tooth were measured and recorded. SAS 6.12 software package was used for statistical analysis. RESULTS: OHI-S of Shanghai adults at their post was 2.16 +/- 0.99 and GI = 1.2227, indicating moderate gingivitis. The difference of periodontal disease among the adults at varied occupations in Shanghai municipality was significant. Periodontal destruction of the clerk group was the lightest The difference of periodontal disease among the adults at varied age groups in Shanghai municipality was also significant. Periodontal destruction of the elder group was heavier than of the lower age group. 146 subjects suffered from initial to moderate periodontitis. 140 subjects suffered from advanced periodontitis. 79, 317 and 4 subjects had received college education, high school education and postgraduate school education respectively. There was no relationship between the severity of periodontitis and educational level. 330 out of 400 (82.5%) subjects had never been treated, 70 out of 400 (12.5%) had scaling,and only 3.25% of subjects had received regular periodontal treatment. CONCLUSION: It is very important to develop an education program on oral health for people in Shanghai. Supported by National "Tenth Five-Year" Key Project (Grant No.2004BA720A26), Research Fund of the Science and Technology Committee of Shanghai Municipality (Grant No.0352nm126) and Shanghai Leading Academic Discipline Project(Grant No.94-III-008).

Design of 2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylaminopyrazolo[1,5-a]pyrimidine (NBI 30775/R121919) and structure--activity relationships of a series of potent and orally active corticotropin-releasing factor receptor antagonists.

We have previously shown that 3-phenylpyrazolo[1,5-a]pyrimidines exemplified by 8 were potent antagonists of the human corticotropin-releasing factor-1 receptor. A series of 3-pyridylpyrazolo[1,5-a]pyrimidines 15, 25-30, 34, and 35 containing a weakly basic pyridine ring at the 3-position of the bicyclic nucleus was designed to reduce lipophilicity from the initial leads such as 7. Here, we showed that these 3-pyridyl compounds exhibited potent antagonists at the human CRF(1) receptor. Moreover, the hydrophilic and weakly basic pyridine moiety increased the water solubility of some analogues. Compound 26 h exhibited good binding affinity at the human CRF(1) receptor with a K(i) value of 3.5 nM. As a functional antagonist, it dose-dependently inhibited CRF-stimulated cAMP production in cells expressing the CRF(1) receptor (IC(50) = 50 nM), and CRF-stimulated ACTH release from cultured rat pituitary cells (IC(50) = 20 nM). 26 h had a log P value of 4.9 and water solubility of greater than 10 mg/mL. Pharmacokinetic studies in rats showed that 26 h was orally bioavailable and able to penetrate into the brain. 26 h has been demonstrated in vivo efficacy in animal behavioral models that measure anxiolytic activity. These results suggest that analogues from this series were potent CRF(1) receptor antagonists with proper physicochemical properties and good pharmacokinetic profiles. 26 h was developed into a clinical compound and exhibited efficacy in patients with major depression.

Synthesis and SAR of 8-arylquinolines as potent corticotropin-releasing factor1 (CRF1) receptor antagonists.

A series of 4-substituted 8-aryl-2-methylquinolines 4 was designed and synthesized as highly potent antagonists for the human CRF(1) receptor. This series of compounds displayed parallel SAR to other bicyclic systems such as pyrazolo[1,5-a]pyrimidines, with several compounds possessing low nanomolar binding affinity. In addition to the high potency, the basicity of this 4-aminoquinoline core may offer CRF(1) antagonists with lower lipophilicity.

[Expression of estrogen and progesterone receptors in the gingival tissues of female patients with moderate and advanced periodontitis].

OBJECTIVE: The purpose of this study was to compare the difference of sexual hormone receptors' expression and distribution in the gingival tissues between periodontitis patients and normal females and to provide the theoretical facts for the clarification of periodontitis's pathogenesis. METHODS: The test group was 34 samples and normal control group was 30 samples. The test group and the normal control group were divided into 3 subgroups separately according to age. All specimens were studied for ER and PR proteins' expression using immunohistochemical techniques (Envision) uniformly, and observed by light microscope. RESULTS: ER and PR proteins located in cytoplasm or nuclear. ER and PR proteins' stainings occurred in the epithelium, the distribution of them had no regularity and staining intensity varied. The positive rates of ER and PR in the gingival tissues of normal female were low. The positive rate of ER in the gingival tissues of female with periodontitis soared apparently (P<0.01), but the positive rate of PR changed little (P>0.05). CONCLUSION: The expression of ER in the gingival tissues might have relation to periodontitis of females. Besides acting indirectly on the gingival tissues, estrogen could affect the gingival tissues directly by ER; progesterone might have indirect effects on gingival tissues.