Comparative salivary proteomics analysis of children with and without early childhood caries using the DIA approach: A pilot study.

OBJECTIVE: To screen differentially expressed proteins (DEPs) in the saliva of Early childhood caries (ECC) with different degrees of severity. METHODS: The proteomic profiles of salivary of children with ECC of varying severity by data independent acquisition data independent acquisition (DIA) technique. A total of 12 preschool children aged 3-5 years were included in this study. RESULTS: In this study, a total of 15,083 peptides and 1944 proteins were quantified; The results of DEPs screening showed that 34 DEPs were identified between the group H and the group LC, including 18 up-regulated proteins and 16 down-regulated proteins; 34 DEPs were screened between the group H and the group HC, including 17 up-regulated proteins and 17 down-regulated proteins; 42 DEPs were screened between the group LC and the group HC, including 18 up-regulated proteins and 24 down-regulated proteins. Among these DEPs, we screened several key proteins that may play a role in ECC, such as MK, histone H4, TGFß3, ZG16B, MUC20, and SMR-3B. CONCLUSION: Salivary proteins, as important host factors of caries, are differentially expressed between the saliva of ECC children and healthy children. Specific DEPs are expected to become potential biomarkers for the diagnosis of ECC.

Enantioselective Assembly of Ferrocenes with Axial and Planar Chiralities via Palladium/Chiral Norbornene Cooperative Catalysis.

The preparation of ferrocenes with both axial and planar chiralities poses a considerable challenge. Herein, we report a strategy for the construction of both axial and planar chiralities in a ferrocene system via palladium/chiral norbornene (Pd/NBE*) cooperative catalysis. In this domino reaction, the first established axial chirality is dictated by Pd/NBE* cooperative catalysis, while the latter planar chirality is controlled by the preinstalled axial chirality through a unique axial-to-planar diastereoinduction process. This method exploits readily available ortho-ferrocene-tethered aryl iodides (16 examples) and the bulky 2,6-disubstituted aryl bromides (14 examples) as the starting materials. Five- to seven-membered benzo-fused ferrocenes with both axial and planar chiralities (32 examples) are obtained in one step with constantly high enantioselectivities (>99% e.e.) and diastereoselectivities (>19:1 d.r.).

An Analytical and Experimental Study on Cutting Characteristics and Transient Cutting Force Modeling in Feed Directional Ultrasonic Vibration-Assisted Cutting of High Strength Alloys.

Ultrasonic vibration-assisted cutting (UVC) is progressively being used in machining as it can significantly promote the fabrication process. However, the ultrasonic vibration affecting the cutting process is still controversial. The full-transient cutting process is proposed in this study to analyze the affecting mechanism induced by ultrasonic vibration in the cutting process. This novel model is the first developed based on the fact that ultrasonic vibration would change mechanical behaviors and the cutting process. For example, the reduction of shear flowing stress in the primary shear zone and alteration of the shear angle in the UVC process. Then, considering those coupled effects, a novel model is proposed to determine the average and transient cutting forces. Here, insight and understanding into the physical phenomenon in UVC are provided. The effectiveness of the proposed model is verified by comparison with experimental results and analytical models available in the literature, with cutting parameters varying from macro to micro-scale. The results show that the ultrasonic vibration affects the cutting process in a complicated way, which is determined by transient characteristics, acoustic softening, thermal softening, plowing, and friction. Those effects on cutting performances in the UVC process under various cutting scenarios are investigated and discussed systematically. The average deviation of cutting forces between experiments and values predicted by the proposed model for Ti6Al4V, AISI 1045, and Al6063 is about 7%, 10.2%, and 11%, respectively. The deviation decreases with the increase of cutting speed in the machining of Ti6Al4V, which is different from the machining of other materials. This is contributed by the varied effect of ultrasonic vibration on the cutting process.

Effects of grape seed proanthocyanidins on the expression of inflammatory mediators in gingival epithelial cells.

OBJECTIVES: This study aims to determine the effect of grape seed proanthocyanidin (GSP) pretreatment on lipopolysaccharide (LPS)-induced inflammation of human gingival epithelial cells (HGECs). METHODS: HGECs were cultivated with different concentrations of GSPs (0, 1, 5, 10, 20, 40, 60, 80, 100 µg·mL-1) for 6, 12, 24, and 48 h. CCK-8 was used to detect the proliferation activity of HGECs. HGECs were treated with different concentrations of GSPs (0, 10, 20, and 40 µg·mL-1) for 24 h and then cultured with 1.0 µg·mL-1 LPS. Enzyme-linked immunosorbent assay (ELISA) was used to detect the expression levels of pro-inflammatory cytokine tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6 and anti-inflammatory cytokines IL-4, IL-10, and transforming growth factor-ß (TGF-ß). Quantitative real-time polymerase chain reaction (QRT-PCR) was used to detect the mRNA expression levels of TNF-α, IL-1ß, IL-6, IL-4, IL-10, and TGF-ß. RESULTS: When the GSP concentration was 0-40 µg·mL-1, the cell proliferation had no significant difference. When the action time reached 24 h, the cell proliferation was the highest. The results of ELISA and QRT-PCR showed that 10, 20, and 40 µg·mL-1 GSPS decreased the expression levels of TNF-α, IL-1ß, and IL-6 (P<0.05) and increased the expression levels of IL-4, IL-10, and TGF-ß compared with 0 µg·mL-1 GSPS (P<0.05). CONCLUSIONS: GSPS (0-40 µg·mL-1) has no significant effect on the proliferation activity of HGECs. Pretreatment with GSPS can inhibit the expression of pro-inflammatory factors and enhance the expression of anti-inflammatory factors. Hence, GSPS has a certain preventive effect on the resistance of HGECs to the stimulation of endotoxin.

Recent progress in sono-photodynamic cancer therapy: From developed new sensitizers to nanotechnology-based efficacy-enhancing strategies.

Many sensitizers have not only photodynamic effects, but also sonodynamic effects. Therefore, the combination of sonodynamic therapy (SDT) and photodynamic therapy (PDT) using sensitizers for sono-photodynamic therapy (SPDT) provides alternative opportunities for clinical cancer therapy. Although significant advances have been made in synthesizing new sensitizers for SPDT, few of them are successfully applied in clinical settings. The anti-tumor effects of the sensitizers are restricted by the lack of tumor-targeting specificity, incapability in deep intratumoral delivery, and the deteriorating tumor microenvironment. The application of nanotechnology-based drug delivery systems (NDDSs) can solve the above shortcomings, thereby improving the SPDT efficacy. This review summarizes various sensitizers as sono/photosensitizers that can be further used in SPDT, and describes different strategies for enhancing tumor treatment by NDDSs, such as overcoming biological barriers, improving tumor-targeted delivery and intratumoral delivery, providing stimuli-responsive controlled-release characteristics, stimulating anti-tumor immunity, increasing oxygen supply, employing different therapeutic modalities, and combining diagnosis and treatment. The challenges and prospects for further development of intelligent sensitizers and translational NDDSs for SPDT are also discussed.

Catalytic Synthesis of Atropisomeric o-Terphenyls with 1,2-Diaxes via Axial-to-Axial Diastereoinduction.

Herein, we report a modular and convergent strategy for the assembly of atropisomeric o-terphenyls with 1,2-diaxes via palladium/chiral norbornene cooperative catalysis and axial-to-axial diastereoinduction. Readily available aryl iodides, 2,6-substituted aryl bromides, and potassium aryl trifluoroborates are used as the building blocks, laying the foundation for diversity-oriented synthesis of these scaffolds (46 examples). Other features include the unique axial-to-axial diastereoinduction mode, construction of two axes in a single operation, and step economy. DFT calculations are performed to rationalize the axial-to-axial diastereoinduction process. Synthetic utilities of this method in preparation of atropisomeric oligophenyls, chiral catalysts, and ligands are demonstrated.

Isochromanoindolenines suppress triple-negative breast cancer cell proliferation partially via inhibiting Akt activation.

As the most malignant subtype of breast cancers, triple-negative breast cancer (TNBC) lacks effective targeted therapeutics clinically to date. In this study, one lead compound FZU-0025-065 with isochromanoindolenine scaffold was identified by a cell-based screening. Among nine breast cancer cell lines tested, TNBC are the most sensitive cell lines to FZU-0025-065. FZU-0025-065 inhibits TNBC cell growth in a time- and dosage-dependent manner. FZU-0025-065 suppresses the expression of cell cycle dependent kinase 4 (CDK4), Cyclin D1 and Cyclin B1; meanwhile, elevates the expression of cell cycle dependent kinase inhibitor p21 and p27. Importantly, we found that FZU-0025-065 suppresses AKT activation in a time- and dosage-dependent manner. Over-expression of constitutive active AKT partially rescues FZU-0025-065 induced cell growth inhibition in MDA-MB-468 cells, indicating FZU-0025-065 suppresses TNBC cell growth partially via inhibiting AKT activation. Finally, FZU-0025-065 suppresses TNBC cell growth in a xenograft mouse model. Taken together, our findings suggested that isochromanoindolenine derivative FZU-0025-065 inhibits TNBC via suppressing the AKT signaling and that FZU-0025-065 may be useful for TNBC treatment.

Pyrrolo [3,4-b]-quinolin-9-amine compound FZU-0038-056 suppresses triple-negative breast cancer partially through inhibiting the expression of Bcl-2.

Triple-negative breast cancer (TNBC) has a poorer prognosis than other subtypes of breast cancer; however, it lacks effective targeted therapies clinically. In this study, we found FZU-0038-056, a novel compound derived from last-stage functionalization of tetrahydro-ß-carboline scaffold, showed the most potent anti-cancer activity against TNBC cells among the 42 synthesized derivatives. We found FZU-0038-056 significantly induces apoptosis in HCC1806 and HCC1937 TNBC cells. FZU-0038-056 reduces the expression levels of several anti-apoptosis proteins, including Bcl-2, Mcl-1 and XIAP. Furthermore, we found FZU-0038-056 induces apoptosis partially through inhibiting the expression of Bcl-2. Finally, we found FZU-0038-056 significantly suppresses HCC1806 xenograft tumor growth in nude mice without affecting their body weight. Therefore, FZU-0038-056 has the potential to be a new anticancer agent for treating human TNBC.

Near-infrared/pH dual-responsive nanocomplexes for targeted imaging and chemo/gene/photothermal tri-therapies of non-small cell lung cancer.

Combination therapy offers promising opportunities for treating advanced non-small cell lung cancer (NSCLC). Here, we established a chitosan-based nanocomplex CE7Q/CQ/S to deliver molecular-targeted drug erlotinib (Er), Survivin shRNA-expressing plasmid (SV), and photothermal agent heptamethine cyanine dye (Cy7) in one platform for simultaneous near-infrared (NIR) fluorescence imaging and triple-combination therapy of NSCLC bearing epidermal growth factor receptor (EGFR) mutations. The obtained CE7Q/CQ/S exhibited favorable photothermal effects, good DNA binding ability, and pH/NIR dual-responsive release behaviors. The conjugated Er could mediate specific delivery of Cy7 to EGFR-mutated NSCLC cells to enable targeted NIR fluorescence imaging and photothermal therapy (PTT). The in vitro and in vivo results showed that downregulation of Survivin expression and the photothermal effects could act synergistically with Er to induce satisfactory anticancer effects in either Er-sensitive or Er-resistant EGFR-mutated NSCLC cells. By integrating chemo/gene/photothermal therapies into one theranostic nanoplatform, CE7Q/CQ/S could significantly suppress EGFR-mutated NSCLC, indicating its potential use in treating NSCLC. STATEMENT OF SIGNIFICANCE: The development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has improved overall survival in patients with NSCLC driven by EGFR mutations. Unfortunately, the emergence of acquired resistance of EGFR-TKIs is almost inevitable after treatment. Here, we constructed a NIR/pH dual-responsive nanocomplex CE7Q/CQ/S based on chitosan which could integrate targeted near-infrared fluorescence imaging and chemo/gene/phototheramal tri-therapies together. We found that CE7Q/CQ/S possessed a promising outcome in fighting against EGFR-mutated NSCLC. The inhibition of Survivin expression and the application of photothermal therapy could act synergistically with erlotinib and reverse erlotinib resistance. The results of this work suggested that this chitosan-based combination therapeutic nanoplatform could be a promising candidate for NSCLC treatment.

Construction of Bisindolines via Oxidative Coupling Cyclization.

Herein, we report a general approach for the efficient construction of three-dimensional bisindolines via oxidative coupling cyclization in an intermolecular manner. This reaction is featured by its operational simplicity, metal-free conditions, lack of protecting group, and high selectivity. Notably, a wide range of anilines are suitable in this intermolecular cyclization, furnishing corresponding bisindolines in up to 98% yield.

Facile access to evodiakine enabled by aerobic copper-catalyzed oxidative rearrangement.

Oxidation as a fundamentally important method for the synthesis of complex structures is difficult to achieve in a selective manner. Evodiakine, a complex natural product possessing an unprecedented ring system (6/5/5/7/6), has a high oxidation state without a practical solution. Herein, we report the first synthesis of evodiakine via aerobic copper-catalyzed late-stage functionalization of evodiamine.

Stabilization of Transient 3-Chloroindolenines Enables Diverse Functionalization.

Transient intermediates as highly reactive species are difficult to manipulate due to their poor stability. Stabilization of unstable intermediates for functionalization is an attractive approach, but the practical applications are still rare. Herein, we explore a strategy that could effectively stabilize labile 3-chloroindolenines and significantly improve the lifetime from seconds to weeks. This chemistry was utilized to enable the synthesis of 55 diverse compounds which are unable to be achieved by traditional approach.

Modular Dual-Tasked C-H Methylation via the Catellani Strategy.

We report a dual-tasked methylation that is based on cooperative palladium/norbornene catalysis. Readily available (hetero)aryl halides (39 iodides and 4 bromides) and inexpensive MeOTs or trimethylphosphate are utilized as the substrates and methylating reagent, respectively. Six types of "ipso" terminations can modularly couple with this "ortho" C-H methylation to constitute a versatile methylation toolbox for preparing diversified methylated arenes. This toolbox features inexpensive methyl sources, excellent functional-group tolerance, simple reaction procedures, and scalability. Importantly, it can be uneventfully extended to isotope-labeled methylation by switching to the corresponding reagents CD3OTs or 13CH3OTs. Moreover, this toolbox can be applied to late-stage modification of biorelevant substrates with complete stereoretention. We believe these salient and practical features of our dual-tasked methylation toolbox will be welcomed by academic and industrial researchers.

Manipulation of Water for Diversified Functionalization of Tetrahydro-ß-carbolines (THßCs) with Indoles.

Water plays a crucial role in organic synthesis. However, diversified functionalization manipulated by water is still rare and remains unexplored. Herein, we report the first water-manipulated protocol to achieve the diversified functionalization of tetrahydro-ß-carbolines (THßCs) in an open flask at room temperature that exhibit a broad functional-group tolerance. More water leads to monoarylation, while less water leads to diarylation. Further one-step transformation afforded oxidized bis(indolyl)methanes, eudistomin U, and the related derivatives in satisfactory yields.

Biomimetic Oxidative Coupling Cyclization Enabling Rapid Construction of Isochromanoindolenines.

Herein, we report a biomimetic oxidative coupling cyclization strategy for the highly efficient functionalization of tetrahydrocarbolines (THCs). This process enables rapid access to complex isochromanoindolenine scaffolds in moderate to excellent yields. The reaction proceeds smoothly and rapidly (complete within minutes) in an open flask. This operationally simple protocol is scalable and compatible with a wide range of functional groups. Late-stage functionalization of a pharmacologically relevant molecule is also demonstrated.

Discovery of novel mifepristone derivatives via suppressing KLF5 expression for the treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is one of the most malignant breast cancers currently with a lack of targeted therapeutic drugs. Accumulating evidence supports that KLF5 represents a novel therapeutic target for the treatment of basal TNBC. Our previous studies revealed that mifepristone is capable of suppressing TNBC cell proliferation and promoting cancer cell apoptosis by inhibiting KLF5 expression. Nevertheless, its anticancer efficacy is only modest with high dose. Moreover, its main metabolite N-desmethyl mifepristone with the removal of one methyl moiety results in a significant loss of antiproliferative activity, indicating an important pharmacophore domain around this methyl moiety. To improve the pharmacokinetic properties including metabolic stability and enhance the anticancer activities, a focused compound library by altering this sensitive metabolic region of mifepristone has been designed and synthesized for scaffold repurposing and structural optimization. Compound 17 (FZU-00,004) has been identified with an attractive anticancer profile against TNBC via suppressing KLF5 expression.

Oxidative Rearrangement Coupling Reaction for the Functionalization of Tetrahydro-ß-carbolines with Aromatic Amines.

The observation of an unexpected oxidative rearrangement coupling reaction led to the development of a novel method for the efficient functionalization of tetrahydro-ß-carbolines (THßCs). The treatment of THßCs with photogenerated singlet oxygen (1 O2 ) afforded unstable dioxetanes, which underwent further transformation to form new bonds in the presence of trifluoroacetic acid. This operationally simple protocol exhibits broad functional-group tolerance and is suitable for the late-stage functionalization of complex druglike molecules.