Liver fibrosis is a fundamental pathological alteration observed in individuals with Wilson disease. Quercetin (Que) has shown potential in inhibiting fibrosis in various diseases. However, the precise mechanism by which Que alleviates liver fibrosis in Wilson disease remains unclear. The present study aimed to investigate the potential role of Que in liver fibrosis of Wilson disease using male Toxic Milk (TX) mice and Cu2+-induced hepatoblastoma cells (HepG2 cells). In TX mice, Analyses using Histopathology, Immunohistochemical staining, Enzyme-linked immunosorbent assay (ELISA), and Western blot, revealed that Que treatment facilitated the efflux of Cu2+ from the liver, improvement of liver function indicators and pathological damage of liver tissue, and significantly inhibited Hedghog (Hh) signaling pathway, leading to significant downregulation of key proteins and genes involved in this pathway, including Gli1, Ptch1, Smo, and Shh. Moreover, Que can reverse epithelial-mesenchymal transition (EMT), and we have also investigated key proteins and genes of EMT and the specific transcription factors controlling E-cadherin expression at the transcriptional level (Slug, Snail, ZEB-1, and Twist) and found that Que can regulatory their expression levels. In Cu2+-induced HepG2 cells, we using Hh Signaling pathway Inhibitor: GDC-0449, found blocking Hh Signaling pathway can reverse the EMT and consistent with in vivo results. Therefore, Que may have the potential to ameliorate liver fibrosis in Wilson disease and EMT by suppressing the Hh signaling pathway.

Acute myeloid leukemia (AML) is a prevalent hematological tumor associated with a high morbidity and mortality rate. CDK9, functioning as a pivotal transcriptional regulator, facilitates transcriptional elongation through phosphorylation of RNA polymerase II, which further governs the protein levels of Mcl-1 and c-Myc. Therefore, CDK9 has been considered as a promising therapeutic target for AML treatment. Here, we present the design, synthesis, and evaluation of CDK9 inhibitors bearing a flavonoid scaffold. Among them, compound 21a emerged as a highly selective CDK9 inhibitor (IC50 = 6.7 nM), exhibiting over 80-fold selectivity towards most other CDK family members and high kinase selectivity. In Mv4-11 cells, 21a effectively hindered cell proliferation (IC50 = 60 nM) and induced apoptosis by down-regulating Mcl-1 and c-Myc. Notably, 21a demonstrated significant inhibition of tumor growth in the Mv4-11 xenograft tumor model. These findings indicate that compound 21a holds promise as a potential candidate for treating AML.

Carbon nanotubes (CNTs) have become far and wide used in a number of technical and merchant applications as a result of substantial advances in nanotechnology, therein single-walled carbon nanotubes (SWCNT) are one of the most promising nanoparticles. Inhaling CNTs has been linked to a variety of health problems, including lung fibrosis. Glycyrrhetinic acid 3-O-mono-β-D-glucuronide (GAMG), a natural sweetener, has anti-inflammatory and antioxidant capacities. The purpose of this study was to evaluate the potential for GAMG to alleviate SWCNT-induced lung inflammation and fibrosis. During days 3–28 after SWCNT intratracheal administration, we observed a remarkable increase of IL-1β, IL-6 and TNF-α in bronchoalveolar lavage fluid (BALF) on day 3 and collagen deposition on day 28. GAMG treatment remarkably ameliorated SWCNT-induced pulmonary fibrosis and attenuated SWCNT-induced inflammation and collagen deposition, and suppressed the activation of PI3K/AKT/NF-κB signaling pathway in the lungs. Therefore, GAMG has a therapeutic potential for the treatment of SWCNT-induced pulmonary fibrosis. Targeting PI3K/AKT/NF-κB signaling pathway may be a potential therapeutic approach to treat pulmonary fibrosis in mice with SWCNT.

Novel benzothiazole‒urea hybrids were designed, synthesized and evaluated their anti-bacterial activity. They only exhibited anti-bacterial activity against Gram-positive bacteria, including clinical methicillin-resistant S. aureus (MRSA), compounds 5f, 5i, 8e, 8k and 8l exhibited potent activity (MIC = 0.39 and 0.39/0.78 μM against SA and MRSA, respectively). Crystal violet assay showed that compounds 5f, 8e and 8l not only inhibited the formation of biofilms but also eradicated preformed biofilms. Compound 8l had membrane disruption, little propensity to induce resistance, benign safety and in vivo anti-MRSA efficacy in a mouse model of abdominal infection. Therefore, our data demonstrated the potential to advance benzothiazole‒urea hybrids as a new class of antibiotics.

Objectives: The aim of this study was to explore the antibiofilm and antivirulence efficacy of benzylaniline 4k against MRSA. Methods: The clinical MRSA strains were identified and used to evaluate their potential to form biofilm using crystal violet assay. The minimal inhibitory concentration (MIC) was determined using broth microdilution method. The expression of genes was detected using quantitative real-time PCR (qRT-PCR). Rabbit blood he-molytic assay was used to observe the inhibitory ability of alpha-hemolysin (Hla). Results: Compound 4k showed potent antibacterial activity against 16 clinical MRSA with an MIC50 of 1.25 mg/L and MIC90 of 2.25 mg/L. The value of minimum biofilm eradication concentration (MBEC) against MRSA2858 biofilm was of 1.5 mg/L, close to its MIC, superior to those of vancomycin and erythromycin. Compound 4k eradicated the formation of biofilm through inhibiting the gene expression of branched-chain fatty acid syn-thesis, down-regulating the expression of quorum-sensing (QS) regulatory genes (norA, agrA, icaA, hla), decreasing the level of hemolysis in a dose-dependent manner, and inhibiting rabbit blood hemolysis by 86.9% at a concentration of 1.25 mg/L. In a mouse model of abdominal infection, compound 4k was more effective than vancomycin in reducing bacterial load. Conclusions: These results suggested that compound 4k could be developed as promising an anti-MRSA agent through affecting quorum-sensing system.

Cannabidiol (CBD) and rivastigmine have been launched as drugs for treating dementia and cholinesterases (ChEs) are ideal drug targets. This study focused on developing novel ChE inhibitors as drug leads against dementia through molecular modeling and fragment reassembly approaches. A potent carbamate fragment binding to active site gorge of BuChE was found via a docking-based structural splicing approach, thus, 17 novel compounds were designed by structural reassembly. Compound C16 was identified as a highly selective potent BuChE inhibitor (IC50 = 5.3 nM, SI > 4000), superior to CBD (IC50 = 0.67 mu M). C16 possessed BBB penetrating ability, benign safety, neuroprotection, antioxidant and pseudo-irreversible BuChE inhibition (K-d = 13 nM, k(2) = 0.26 min(-1)), showing good drug-like properties. In vivo studies confirmed that C16 significantly ameliorated the scopolamine-induced cognition impairment, almost entirely recovered the A beta(1-42) (icv)-impaired cognitive function to the normal level, showed better behavioral performance than donepezil and good anti-amyloidogenic effect. Hence, the potential BuChE inhibitor C16 can be developed as a promising disease-modifying treatment of AD. (C) 2021 Elsevier Masson SAS. All rights reserved.

Carbonyl cyanide m-chlorophenylhydrazone (CCCP), as a protonophore, in combination with antibiotics exhibited potentiating antibacterial activity. To improve CCCP's potency and toxicity, a series of aromatic hydrazones were synthesized and their antimicrobial activity was evaluated; amongst them, compounds 2e and 2j with a strong para-electron-withdrawing substituent (-NO2 and -CF3) at the phenyl ring had the lowest MICs against both S. aureus and methicillin resistant Staphylococcus aureus (1.56 and 1.56 μM, respectively). Some compounds in combination with antibiotics exhibited potentiate Gram-positive antibacterial activity; compound 2e was found to display unaided or synergistic efficacy against MRSA. In particular, when compound 2e is combined with ofloxacin, it has a good synergistic effect against MRSA. Moreover, electron microscopy revealed that compound 2e inhibits biofilm formation and effectively eradicates preformed biofilm. MTT assay showed that compound 2e displays as low toxicity as CCCP. Overall, our data showed that the aromatic hydrazone is a promising scaffold for anti-staphylococcal drug development.

Background: : Inflammation is a biological response of body tissues to harmful stimuli, so it is desirable to search for novel anti-inflammatory agents with improved pharmaceutical profiles and reduced adverse effects. Objective: : This study was to explore natural anti-inflammatory agents and improve therapeutic application of glycyrrhetic acid (GA) through molecular hybridization with active aromatics. Methods: : Fourteen novel GA-aromatic hybrids were synthesized and evaluated for their antiinflammatory activities by inhibiting LPS-induced nitric oxide (NO) release in RAW264.7 cells. The synthesized compounds were characterized by single-crystal X-ray diffraction, 1H NMR, 13C NMR and HRMS. Result: : The structure-activity relationship (SAR) study indicated that compounds with styryl displayed better NO inhibitory activity. Among them, compounds 2a and 3c exhibited the most promising activity with IC50 values of 9.93 μM and 12.25 μM, respectively. In addition, X-ray singlecrystal diffraction data for compounds 2e and 3c showed that the absolute configuration of GA skeleton was consistent with that of natural 18 β-glycyrrhetic acid. Conclusion: : The results showed that GA-aromatic hybrids were a new class of anti-inflammatory agents and this study provided useful information on further optimization.

利用水热法制备出新型方糖状介孔羟基磷灰石(CaCO3@HA)颗粒并评价了其生物学性能,结果表明:该方糖状介孔CaCO3@HA内核是方解石型CaCO3,外壳为HA,其相成分比例可以通过水热时间进行调控.水热反应1 h制备的样品比表面积(SBET)高达117.046 m2·g-1,介孔孔径约为3.83 nm,对阿霉素盐酸盐(DOX)的装载能力高达95％.这种材料还具有良好的pH响应特性,可以控制释放DOX抑制肿瘤细胞的增殖.该方糖状介孔CaCO3@HA颗粒是一种良好的药物控释载体,具有广泛的应用前景.

目的 研究小户型家具产品的创新设计.方法 根据小户型居住空间的特点和人在小户型空间下的行为模式和心理特征,从创新原则、创新方式两个方面设计小户型家具产品.结论 在可以预见的将来,家具概念因为家具与家用产品的一体化设计,以及人工智能的运用,而全面模糊化.

To develop novel antibacterial agents, 2-sulfoether-4-quinolone scaffolds were synthesized by a free radical process and evaluated for their antibacterial abilities. Excellent activities against Gram-positive bacteria were observed, among which compounds 3m, 3n, 3p and 3t possessed the lowest MICs against both S. aureus and B. cereus (0.8 μM and 1.61 μM, respectively). The structure-activity relationship (SAR) showed that: (i) the antibacterial activity was related to the substituent, such as 2-SCH3 = 2-SCH2CH3 > 2-S(=O)CH3 > 2-OH, 8-Br > 7-Br > 6-Br; (ii) -CF3 increased the antibacterial activity; (iii) the di-substituted group performed the better activity. The DNA supercoiling inhibitory analysis confirmed their fluoroquinolone characters. The docking showed that compound 3n was nicely bound into the DNA-gryase complex via extensive interactions, including conventional hydrogen bonds, halogen bonds and hydrophobic interactions. The microscopy analysis of compound 3n against S. aureus exhibited the damages on the cell wall construction, which may facilitate the penetration into Gram-positive bacteria.

Based on the structural analysis of tricyclic scaffolds as butyrylcholinesterase (BuChE) inhibitors, a series of pyrazolo[1,5-c][1,3]benzoxazin-5(5H)-one derivatives were designed, synthesized and evaluated for their acetylcholinesterase (AChE) and BuChE inhibitory activity. Compounds with 5-carbonyl and 7- or/and 9-halogen substitutions showed potential BuChE inhibitory activity, among which compounds 6a, 6c and 6g showed the best BuChE inhibition (IC50 = 1.06, 1.63 and 1.63 mu M, respectively). The structure-activity relationship showed that the 5-carbonyl and halogen substituents significantly influenced BuChE activity. Compounds 6a and 6g were found nontoxic, lipophilic and exhibited remarkable neuroprotective activity and mixed-type inhibition against BuChE (K-i=7.46 and 3.09 mu M, respectively). Docking studies revealed that compound 6a can be accommodated into BuChE via five hydrogen bonds, one Pi-Sigma interaction and three Pi-Alkyl interactions.

To identify the natural antifungal agents, the antifungal activities of Melaleuca leucadendra (L.) L. essential oil (ML-EO) from Fujian Province of China were assayed. Treatment of ML-EO in combination with the front-line using antibiotics against Candida led to synergistic effects. Electron microscopy analysis on the oil treated C. albicans cells revealed the formation of mesosome-like structures, suggesting well the membrane damage caused by the essential oil. The Griess assay by monitoring NO production in LPS-stimulated RAW264.7 cells indicated the potent anti-inflammatory activity of ML-EO. In comparison with the marked essential oil of Melaleuca alternifolia EO, ML-EO had almost the same chemical components. In general, the antifungal activity of ML-EO and its synergistic interactions with conventional antibiotics were able to lead the development of new treatment strategies on Candida infection.

Based on the SAR analysis of glycyrrhizin, 18α-glycyrrhetinic acid monoglucuronide (18α-GAMG) with strong inhibition against LPS-induced NO and IL-6 production in RAW264.7 cells was discovered. Western blotting and immunofluorescence results showed that 18α-GAMG reduced the expression of iNOS, COX-2, and MAPKs, as well as activation of NF-κB in the LPS-stimulated RAW264.7 cells. Further in vivo results showed that 18α-GAMG could significantly improve the pathological changes of CCl4-induced hepatic fibrosis.

After rationalized design of structure and surface modification for magnetic microspheres,they show unique physical and chemical properties and have wide application in medical imaging,in vitro detection,drug carriers and bacteria/cell screening and other biomedical fields.In this paper,the current research progress in the development of multifunctional magnetic microspheres was reviewed and the typical structure,preparation methods and biomedical application of magnetic microspheres were mainly introduced.A systematic reference for the design and biomedical application of magnetic microspheres was provided as well.

Objective To detect serum brucellosis in high risk population,three methods were used and their advantages and disadvantages was compared.Methods In accordance with the "surveillance standard for brucello-sis"(GB 16885 -1997)and "brucellosis diagnostic criteria"(WS269 -2007)in the prescribed method,rose -bengal plate agglutination test (RBPT),standard -tube agglutination test (SAT)and enzyme linked immunoassay assay (ELISA)were used to detect brucellosis and analysis of its diagnostic significance in the high risk population of sheep farm of Guoyang county in Anhui province.Results The positive rates of RBPT,SAT and ELISA were 19.1%,12.1% and 16.3% in 257 blood samples,respectively.Compared to SAT,the sensitivity,specificity,accura-cy and the area under the ROC curve of RBPT were 88.5%,91.8%,91.4%,0.81,respectively,which of ELISA were 93.9%,95.1%,94.9%,0.88.Conclusion The sensitivity,specificity,accuracy and the area under the ROC curve of ELISA were higher than those of other methods.Proper method,early surveillance and effective technology can help to control the occurrence and epidemic of brucellosis in the actual test work promotion.