Identification and pre-clinical investigation of 3-O-cyclohexanecarbonyl-11-keto-ß-boswellic acid as a drug for external use to treat psoriasis.

BACKGROUND AND PURPOSE: Psoriasis vulgaris is a refractory skin inflammatory disorder with 80% of the cases belonging to the mild-to-moderate type, which can be controlled by topical treatment. Nevertheless, the drugs for external use have not been upgraded for decades. We modified acetyl-11-keto-beta-boswellic acid (ABKA), a natural compound shown to treat psoriasis animal models, to improve efficacy and solubility for topical use. EXPERIMENTAL APPROACH: Eleven compounds were synthesized using AKBA as a lead compound, and their effects on Th17 cell differentiation were screened. 3-O-cyclohexanecarbonyl-11-keto-ß-boswellic acid (CKBA) potently inhibited Th17 cell differentiation. Its efficacy in a mouse model of psoriasis was assessed along with its pharmacology and safety profile when topically or systemically delivered to several animal species. KEY RESULTS: CKBA inhibited mouse and human Th17 cell differentiation with an IC50 of 3.28 and 3.61 µM, respectively, and directly targeted acetyl-CoA carboxylase 1 (ACC1). Safety evaluation and toxicity tests suggested that systemically delivered high-dose CKBA for 14 days had no dose-associated adverse effects on the CNS, haematopoietic, cardiovascular, respiratory and digestive systems of cynomolgus monkeys. CKBA ointment permeated the skin and did not irritate or sensitize intact skin. CKBA ointment mediated dose-dependent suppression of imiquimod-induced psoriasis-like skin inflammation with slow absorption and limited bioavailability (<10% in rats and <1% in minipigs). CONCLUSIONS AND IMPLICATIONS: CKBA is safe when topically or systemically delivered to animals. The beneficial effects of CKBA ointment in a mouse model of psoriasis indicate that this is a promising drug candidate for further development as a treatment for psoriasis.

Nurse and Patient Assessments of COVID-19 Care Quality in China: A Comparative Survey Study.

During the COVID-19 pandemic, the quality of nursing care was a concern due to nurses' overwhelming workload. A cross-sectional design was conducted to compare perceptions between nurses and patients about the quality of nursing care for COVID-19 patients and to explore factors associated with these perceptions. Data were collected during the COVID-19 pandemic from 17 March to 13 April 2020 in five hospitals in Wuhan, China. Perceptions of care quality were assessed among nurses and patients using the Caring Behaviors Inventory. Nurses rated the quality of caring behaviors higher than patients. Both nurses and patients rated technical caring behaviors at high levels and rated the item related to "spending time with the patient" the lowest, while patients rated it much lower than nurses. Nurses' sex, participation in ethical training organized by the hospital, professional title, being invited to Wuhan, and length of working experience in years were significantly associated with nurses' self-evaluated caring behaviors. Moreover, inpatient setting and communication mode were significantly associated with patients' self-evaluated caring behaviors.

The association between perceived hospital ethical climate and self-evaluated care quality for COVID-19 patients: the mediating role of ethical sensitivity among Chinese anti-pandemic nurses.

BACKGROUND: The COVID-19 pandemic called for a new ethical climate in the designated hospitals and imposed challenges on care quality for anti-pandemic nurses. Less was known about whether hospital ethical climate and nurses' ethical sensitivity were associated with care quality. This study examined the association between the perceived hospital ethical climate and self-evaluated quality of care for COVID-19 patients among anti-pandemic nurses, and explored the mediating role of ethical sensitivity in this relationship. METHODS: A cross-sectional study was conducted through an online survey. A total of 399 anti-pandemic nurses from ten designated hospitals in three provinces of China were recruited to fill out an online survey. Multiple linear regression analysis and a bootstrap test were used to examine the relationships between ethical climate, ethical sensitivity and care quality. RESULTS: Nurses reported mean scores of 4.43 ± 0.577 (out of 5) for hospital ethical climate, 45.00 ± 7.085 (out of 54) for ethical sensitivity, and 5.35 ± 0.661 (out of 6) for self-evaluated care quality. After controlling for covariates, perceived hospital ethical climate was positively associated with self-evaluated care quality (direct effect = 0.710, 95% confidence interval [CI] 0.628, 0.792), and was partly mediated by ethical sensitivity (indirect effect = 0.078, 95% confidence interval [CI] 0.002, 0.145). CONCLUSIONS: Chinese nurses who cared for COVID-19 patients perceived high levels of hospital ethical climate, ethical sensitivity, and self-evaluated care quality. Positive perceptions of hospital ethical climate were both directly associated with a higher level of self-evaluated care quality and indirectly associated, through the mediation effect of ethical sensitivity among anti-pandemic nurses.

Hospital ethical climate associated with the professional quality of life among nurses during the early stage of COVID-19 pandemic in Wuhan, China: A cross-sectional study.

OBJECTIVES: To describe the professional quality of life and explore its associated factors among nurses coming from other areas of China to assist with the anti-epidemic fight in Wuhan and especially examine whether the hospital ethical climate was independently associated with nurses' professional quality of life. METHODS: A cross-sectional online survey was conducted from March 2020 to April 2020. The nurses working in Wuhan from the other parts of China were the target population. The Professional Quality of Life Scale version 5, the Hospital Ethical Climate Survey, and a basic information sheet were used to collect data. Descriptive statistics, t-test, ANOVA, Pearson correlation, and multiple linear regression analysis were used to analyze the data. RESULTS: In total, 236 nurses participated in this study, and 219 valid questionnaires were analyzed. The average age of the participants was 31.2 ± 5.0 years. Most nurses were female (176/219; 80.4%) and married (145/219; 66.2%). In term of professional quality of life, nurses reported moderate (129/219; 58.9%) to high (90/219; 41.1%) levels of compassion satisfaction, low (119/219; 54.3%) to moderate (100/219; 45.7%) levels of burnout, and low (67/219; 36.0%) to high (10/219; 4.6%) levels of secondary traumatic stress. Regarding hospital ethical climate, nurses reported moderately high hospital ethical climates with an average score of 4.46. After controlling for socio-demographic characteristics, the multiple linear regression models showed that the hospital ethical climate subscale of "relationship with physicians" was independently associated with the compassion satisfaction (ß = 0.533, P < 0.01) and burnout (ß = -0.237, P < 0.05); the hospital ethical climate subscale of "relationship with peers" (ß = -0.191, P < 0.01) was independently associated with the secondary traumatic stress. CONCLUSIONS: During the early stage of the pandemic, nurses demonstrated moderate to high level of compassion satisfaction, low to moderate level of burnout, and all nurses experienced secondary traumatic stress. Nurses perceived a high level of hospital ethical climate, and the perceived hospital ethical climate played an important role in promoting nurses' professional quality of life during a life-threatening infectious disease pandemic.

Structure-activity relationship study of novel quinazoline-based 1,6-naphthyridinones as MET inhibitors with potent antitumor efficacy.

As a privileged scaffold, the quinazoline ring is widely used in the development of EGFR inhibitors, while few quinazoline-based MET inhibitors are reported. In our ongoing efforts to develop new MET-targeted anticancer drug candidates, a series of quinazoline-based 1,6-naphthyridinone derivatives were designed, synthesized, and evaluated for their biological activities. The preliminary SARs studies indicate that the quinazoline scaffold was also acceptable for the block A of class II MET inhibitors. The further pharmacokinetic studies led to the identification of the most promising compound 22a with favorable in vitro potency (MET, IC50 = 9.0 nM), human microsomal metabolic stability (t1/2 = 621.2 min) and oral bioavailability (F = 42%). Moreover, 22a displayed good in vivo antitumor efficacy (IR of 81% in 75 mg/kg) in MET-positive human glioblastoma U-87 MG xenograft model. These positive results indicated that 22a is a potential new MET-targeted antitumor drug lead, which is worthy of further development.

2,7-naphthyridinone-based MET kinase inhibitors: A promising novel scaffold for antitumor drug development.

As part of our effort to develop new molecular targeted antitumor drug, a novel 2,7-naphthyridone-based MET kinase inhibitor, 8-((4-((2-amino-3-chloropyridin-4-yl)oxy)- 3-fluorophenyl)amino)-2-(4-fluorophenyl)-2,7-naphthyridin-1(2H)-one (13f), was identified. Knowledge of the binding mode of BMS-777607 in MET led to the design of new inhibitors that utilize novel 2,7-naphthyridone scaffold to conformationally restrain the key pharmacophoric groups (block C). Detailed SAR studies resulted in the discovery of a new MET inhibitor 13f, displaying favorable in vitro potency and oral bioavailability. More importantly, 13f exhibited excellent in vivo efficacy (tumor growth inhibition/TGI of 114% and 95% in 50 mg/kg, respectively) both in the U-87 MG and HT-29 xenograft models. The favorable drug-likeness of 13f indicated that 2,7-naphthyridinone may be used a promising novel scaffold for antitumor drug development. The preclinical studies of 13f are under way.

[Self-management behaviors in patients with osteoarthritis].

Good self-management behaviors can control symptoms of the patients with osteoarthritis, improve the patients' joint function and quality of life. Patients' self-management behaviors have been impacted by disease knowledge, self-efficacy, emotional state, and social support. All the above factors should been taken into full consideration when intervening. Self-management program is an intervention mode which can improve patient self-management behaviors and promote patient health.

[Synthesis and spectral characterization of Ce(III) and Dy(III) complexes with tetraisopropylmethylenediphosphonate].

Three rare-earth complexes [CeL4] (OTf)3 x 2H2O (L = tetraisopropylmethylene -diphosphonate; OTf = triflu-oromethanesulfate), [Dy(OTf)2L2 (H2O)2](OTf)(CH3CN) and [DyL4](OTf)3 x L x 2H2O were prepared by the reaction of Ln(OTf)3 (Ln = Ce, Dy) and (iPrO)2P(O)CH2P(O)(iPrO)2 in CH3CN. Their compositions were confirmed and their properties were characterized by elemental analysis, infrared spectra, 1H and 31P NMR spectroscopy, fluorescence spectra and DTA-TGA. The data of elemental analysis of these complexes are in good agreement with the formula given above. In the infrared spectra of all these complexes, there are obvious shifts of some important absorption bands, such as the P=O or S-O bands, illustrating that the ligands L or OTf ions were coordinated to the lanthanide ions. The signals in 1H NMR spectrum at approximately 1.2, 2.4 and 4.5 have been assigned to the resonance of H atoms in the ligand L, and these signals in the spectrum of complexes are highfield shifted compared to that of free ligand due to the electron cloud of Ln-O band moving towards to P-O band. The sharp single peaks were found in the 31P NMR spectrum, and the chemical shifts are at 18.705 6 for free ligand L, 18.543 5 for complex I , 18.273 1 for complex II, and 18.489 4 for complex III. The excitation and emission signals of Ce(III) ion were in view of electric dipole transition from 4f1 5d1 to 4f7. The fluorescence spectroscopy shows that the excitation peak of [CeL4](OTf)3 x 2H2O is at 249 and 300 nm, and a strong emission peak is at 641 nm. The existence of two coordination water molecules in [Dy(OTf)2L2 (H2O)2] (OTf) (CH3CN) makes both the excitation and emission peaks weaker than that of [DyL4] (OTf)3 x L x 2H2O. The coordination model of rare-earth with diphosphonic ligand was also discussed. All of these complexes are eight-coordinated. The complexes [CeL4](OTf)3 x 2H2O and [DyL4](OTf)3 x L x 2H2O are highly-symmetrical, in which four bidentate ligands L are coordinated to Ce and Dy atoms respectively while the OTf ions and the water molecules are not coordinated. In the complex [Dy(OTf)2L2 (H2O)2] (OTf) (CH3CN), two L molecules, two water molecules and two OTf ions are coordinated to Dy atom while one OTf ion and one solvent molecule CH3 CN are not coordinated.

A concise and practical synthesis of antigenic globotriose, alpha-D-Gal-(1-->4)-beta-D-Gal-(1-->4)-beta-D-Glc.

A concise and practical synthesis of the antigenic globotriose, alpha-D-Gal-(1-->4)-beta-D-Gal-(1-->4)-beta-D-Glc (13), was achieved by coupling of a monosaccharide donor, 3-O-allyl-2-O-benzoyl-4,6-O-benzylidene-alpha-D-galactopyranosyl trichloroacetimidate (4) with a disaccharide acceptor, p-methoxyphenyl 2,3,6-tri-O-benzoyl-beta-D-galactopyranosyl-(1-->4)-2,3,6-tri-O-benzoyl-beta-D-glucopyranoside (8), followed by deprotection. In spite of the existence of a C-2-ester substituent capable of neighboring-group participation in the donor, the coupling gave exclusively the alpha-linkage in satisfactory yield. The acceptor 8 was readily obtained from selective 3-O-benzoylation of the galactosyl ring of p-methoxyphenyl 2,6-di-O-benzoyl-beta-D-galactopyranosyl-(1-->4)-2,3,6-tri-O-benzoyl-beta-D-glucopyranoside (7), which was prepared from p-methoxyphenyl beta-D-lactoside (5) via isopropylidenation, benzoylation, and deisopropylidenation. Donor 4 was obtained from p-methoxylphenyl 3-O-allyl-2,4,6-tri-O-benzoyl-beta-D-galactopyranoside (1) via selective 4,6-di-O-debenzoylation, oxidative removal of 1-O-MP, benzylidenation, and trichloroacetimidate formation.