Conjugating AIE-featured AuAg nanoclusters with highly luminescent carbon dots for improved visible-light-driven antibacterial activity.

Metal nanoclusters (NCs) have emerged as novel antibacterial agents featuring broad-spectrum antibacterial activity without drug resistance for bacteria, but suffer from fast antibacterial invalidation due to their consumption by bacteria. Herein we report the design of a visible-light-driven photodynamic antibacterial agent based on conjugating aggregation-induced emission (AIE)-featured AuAg NCs with highly luminescent carbon dots (CDs). The conjugation of CDs with AuAg NCs could not only enhance the visible-light harvest, but also promote charge carrier generation/separation via charge/energy transfer, leading to the production of abundant reactive oxygen species (ROS) for bacterial killing under visible-light irradiation. Consequently, the as-obtained CDs@AuAg NCs display excellent photodynamic antibacterial activity against both Gram-positive and Gram-negative bacteria with 4-5 orders of magnitude reduction in colony forming units, which is different from the conventional metal NC-based analogue relying on self-consumption for bacterial killing. In addition, the CDs@AuAg NCs are found to be free of cytotoxicity; the ROS capture experiments indicate that the photoproduced H2O2 by CDs@AuAg NCs is the main active species for bacterial killing, accounting for nearly 48% of the total antibacterial efficacy. This study provides a paradigm for the design of metal NC-based photodynamic antibacterial agents for diverse bactericidal applications.

Marrying luminescent Au nanoclusters to TiO2 for visible-light-driven antibacterial application.

Long-lasting yet visible-light-driven bacterial inhibition is highly desired for environmental protection and public health maintenance. However, conventional semiconductors such as titanium dioxide (TiO2) are impotent for such antibacterial application due to their low utilization rate for visible light. Herein we report the design of a long-lasting yet visible-light-driven antibacterial agent based on marrying luminescent Au nanoclusters (Au NCs for short) to TiO2 (TiO2-NH2@Au NCs). The as-obtained TiO2-NH2@Au NC antibacterial agent not only possesses superior utilization for visible light due to the participation of Au NCs as a good photosensitizer, but also has excellent separation efficacy of photogenerated carriers, thereby efficiently enhancing the generation of reactive oxygen species (ROS) for killing bacteria. Consequently, the TiO2-NH2@Au NCs display excellent antibacterial activity with good durability against both Gram-positive and Gram-negative bacteria such as Staphylococcus aureus (99.37%) and Escherichia coli (99.92%) under visible-light irradiation (λ ≥ 400 nm). This study is interesting because it provides a paradigm change in the design of long-lasting yet visible-light-driven NC-based antibacterial agents for diversified bactericidal applications.

Mechanistic insights into the two-phase synthesis of heteroleptic Au nanoclusters.

A mechanistic study on the two-phase synthesis of heteroleptic Au nanoclusters (NCs) is reported here. First, the effects of binary ligands on controlling the size of Au NCs were examined: (1) the binary ligands could exhibit an eclectic effect on the size control of Au NCs if the binding affinities of such hetero-ligands with Au are comparable and (2) the binary ligands could exhibit a competitive effect on the size control of Au NCs, and the size of the Au NCs could be determined by the ligand with stronger binding affinity to Au. This finding is interesting and can shed some light on the design of new functional metal NCs. Secondly, the formation mechanism of the heteroleptic Au NCs that originated from the complex precursors was unprecedentedly studied. The complex precursors of the heteroleptic Au NCs were identified to be the predominant hybridized ligand#1-Au(i)-ligand#2 species, which is helpful for understanding the synthetic mechanisms in depth. Moreover, the growth processes of the heteroleptic Au NCs were also monitored, and some fundamental perceptions about the growth pathway and the structures of the Au NCs were obtained.

From understanding the roles of tetraoctylammonium bromide in the two-phase Brust-Schiffrin method to tuning the size of gold nanoclusters.

The two-phase Brust-Schiffrin (B-S) method has been widely used for synthesizing small-sized Au nanoparticles (NPs) of size 2-6 nm, as well as Au nanoclusters (NCs) of size <2 nm. However, size tuning of Au NCs at the atomic level by this method is challenging probably due to a lack of in-depth understanding of its mechanism. Herein, we report the identification of two roles of tetraoctylammonium bromide (TOAB) in the two-phase B-S method: TOAB not only transfers Au(iii) precursors but also transfers the reducing agent NaBH4 from the aqueous to the organic phase. On this basis, we developed a novel two-phase synthetic strategy by decoupling the roles of the TOAB: (1) using the hydrophobic selenolate ligand to transfer Au(iii) precursors from the aqueous to the organic phase via the formation of selenolate-Au(i) complexes and (2) deploying a small amount of TOAB as "shuttles" to transfer NaBH4 into the organic phase for controlled reduction of selenolate-Au(i) complexes in organic phase. Using this strategy, size tuning of Au NCs at the atomic level could be achieved by simply varying the amount of TOAB. The high yields of Au NCs (≥76%) together with the short synthetic time (≤3 h) and size-tuning capability further illustrate the attractiveness of this synthetic strategy. These advantages also present the classical B-S method with greater strength and flexibility towards NC synthesis.

Effect of subtle changes of isomeric ligands on the synthesis of atomically precise water-soluble gold nanoclusters.

The subtle structural change of hydrophilic ligands on the size control of metal nanoclusters (NCs) is unclear but critically important for fundamental understanding. Herein, we report our findings that subtle changes of isomeric ligands lead to a dramatic difference in the size of water-soluble Au NCs. By using isomeric para-mercaptobenzoic acid (p-MBA), m-MBA, and o-MBA as model ligands, it was found that both the steric hindrance and the electronic effect of isomeric ligands significantly influences the size of Au NCs, resulting in the formation of different sized Au44(p-MBA)26 NCs, Au25(m-MBA)18 NCs, and Au37/43(o-MBA)22/26 NCs. Besides this, by collocating any two of the isomeric MBAs as ligand pairs to compare their protecting capability for Au NCs, the protecting abilities of such ligands were found to follow the trend: m-MBA > o-MBA > p-MBA. In addition, the growth process of Au44(p-/o-MBA)26 NCs from Au(i)-MBA complexes in the NaBH4 reduction system was also monitored by real-time UV-vis absorption spectroscopy and ESI mass spectrometry, which complies with the 2e- hopping growth principle, indicating the universal applicability of this principle in the synthesis of thiolated metal NCs. This study provides a fundamental understanding of the effect of ligands' steric hindrance and electronic factors on the size control of water-soluble metal NCs and sheds light on the formation of metal NCs in the NaBH4 reduction system.

Combined treatment of sodium ferulate, n-butylidenephthalide, and ADSCs rehabilitates neurovascular unit in rats after photothrombotic stroke.

The remodelling of structural and functional neurovascular unit (NVU) becomes a central therapeutic strategy after cerebral ischaemic stroke. In the present study, we investigated the effect of combined therapy of sodium ferulate (SF), n-butylidenephthalide (BP) and adipose-derived stromal cells (ADSCs) to ameliorate the injured NVU in the photochemically induced thrombotic stroke in rats. After solely or combined treatment, the neovascularization, activation of astrocytes, neurogenesis, expressions of vascular endothelial growth factor (VEGF) and claudin-5 were assessed by immunohistochemical or immunofluorescence staining. In order to uncover the underlying mechanism of therapeutic effect, signalling of protein kinase B/mammalian target of rapamycin (AKT/mTOR), extracellular signal-regulated kinase 1/2 (ERK1/2), and Notch1 in infarct zone were analysed by western blot. 18 F-2-deoxy-glucose/positron emission tomography, magnetic resonance imaging, Evans blue staining were employed to evaluate the glucose metabolism, cerebral blood flow (CBF), and brain-blood barrier (BBB) permeability, respectively. The results showed that combined treatment increased the neovascularization, neurogenesis, and VEGF secretion, modulated the astrocyte activation, enhanced the regional CBF, and glucose metabolism, as well as reduced BBB permeability and promoted claudin-5 expression, indicating the restoration of structure and function of NVU. The activation of ERK1/2 and Notch1 pathways and inhibition of AKT/mTOR pathway might be involved in the therapeutic mechanism. In summary, we have demonstrated that combined ADSCs with SF and BP, targeting the NVU remodelling, is a potential treatment for ischaemic stroke. These results may provide valuable information for developing future combined cellular and pharmacological therapeutic strategy for ischaemic stroke.

Radicals and Sulfur Dioxide: A Versatile Combination for the Construction of Sulfonyl-Containing Molecules.

Molecules containing a sulfonyl functionality, such as sulfones, sulfonyl chlorides or sulfonamides play an important role in organic chemistry and have found widespread application, especially in the construction of biologically active compounds. Recently, methods for the synthesis of the sulfonyl moiety utilizing sulfur dioxide as a key building block have received considerable attention. In this context, radical-based transformations with sulfur dioxide have emerged as a new and attractive approach for the construction of the sulfonyl functional group. This short review highlights recent advances in the use of sulfur dioxide in radical reactions and covers the historical background, which forms the basis for these current progresses. Limitations of the existing methods and potential further developments will be discussed.

Visible-Light Photoredox/Nickel Dual Catalysis for the Cross-Coupling of Sulfinic Acid Salts with Aryl Iodides.

An efficient cross-coupling of sodium or lithium sulfinates with aryl iodides, using a combination of nickel and photoredox catalysis, is described. The dual catalyst system enables a versatile synthesis of aryl sulfones at room temperature in good yields and displays a broad functional group compatibility. The potential utility of this method in the late-stage diversification of complex molecules and in the conversion of organolithium reagents and sulfur dioxide into sulfones is demonstrated.

Synthesis of sulfones via selective C-H-functionalization.

The synthesis of sulfones via a selective functionalization of C-H-bonds represents a powerful alternative to classical methods for the preparation of this important compound class. Within the last decade, significant progress has been made in this field. This review highlights recent advances in the area of metal-catalyzed as well as metal-free transformations for the direct sulfonylation of C(sp2)-H and C(sp3)-H bonds.

Bone Marrow Stromal Cells Combined With Sodium Ferulate and n-Butylidenephthalide Promote the Effect of Therapeutic Angiogenesis via Advancing Astrocyte-Derived Trophic Factors After Ischemic Stroke.

Being a potential candidate for stroke treatment, bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) have been demonstrated to be able to enhance angiogenesis and proliferation of reactive astrocytes, which subsequently leads to the amelioration of neurological injury. Increasing evidence further indicates that combining BM-MSCs with certain agents, such as simvastatin, may improve therapeutic effects. Sodium ferulate (SF) and n-butylidenephthalide (BP), two main components of Radix Angelica Sinensis, are proven to be important regulators of stem cells in cell migration, differentiation, and pluripotency maintenance. This study aimed to investigate whether combining BM-MSCs with SF and BP had better therapeutic effect in the treatment of stroke, and the underlying molecular basis for the therapeutic effects was also investigated. The results showed that combination treatment notably reduced neurological injury after stroke and increased the expression of astrocyte-derived vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and von Willebrand factor-positive vascular density in the ischemic boundary zone as evaluated by immunofluorescence staining. After treatment with BM-MSCs plus SF and BP, astrocytes showed increased expression of VEGF and BDNF by upregulating protein kinase B/mammalian target of rapamycin (AKT/mTOR) expression in an oxygen- and glucose-deprived (OGD) environment. Human umbilical vein endothelial cells (HUVECs) incubated with the conditioned medium (CM) derived from OGD astrocytes treated with BM-MSCs plus SF and BP showed significantly increased migration and tube formation compared with those incubated with the CM derived from OGD astrocytes treated with BM-MSCs alone. These results demonstrate that combination treatment enhances the expression of astrocyte-derived VEGF and BDNF, which contribute to angiogenesis after cerebral ischemia, and the underlying mechanism is associated with activation of the astrocytic AKT/mTOR signaling pathway. Our study provides a potential therapeutic approach for ischemic stroke.

Evolutional Characterization of Photochemically Induced Stroke in Rats: a Multimodality Imaging and Molecular Biological Study.

Photochemically induced cerebral ischemia is an easy-manipulated, reproducible, relatively noninvasive, and lesion controllable model for translational study of ischemic stroke. In order to longitudinally investigate the characterization of the model, magnetic resonance imaging, 18F-2-deoxy-glucose positron emission tomography, fluorescence, and bioluminescence imaging system were performed in correlation with triphenyl tetrazolium chloride (TTC), hematoxylin-eosin staining, and immunohistochemistry examinations of glial fibrillary acidic protein, CD68, NeuN, von willebrand factor, and α-smooth muscle actin in the infarct zone. The results suggested that the number of inflammatory cells, astrocytes, and neovascularization significantly elevated in peri-infarct region from day 7 and a belt of macrophage/microglial and astrocytes was formed surrounding infarct lesion at day 14. Both vasogenic and cytotoxic edema, as well as blood brain-barrier leakage, occurred since day 1 after stroke induction and gradually attenuated with time. Numerous cells other than neuronal cells infiltrated into infarct lesion, which resulted in no visible TTC negative regional existence at day 14. Furthermore, recovery of cerebral blood flow and glucose utilization in peri-infarct zone were noted and more remarkably than that in infarct core following the stroke progression. In conclusion, these characterizations may be highly beneficial to the development of therapeutic strategies for ischemic stroke.

Sodium ferulate and n-butylidenephthalate combined with bone marrow stromal cells (BMSCs) improve the therapeutic effects of angiogenesis and neurogenesis after rat focal cerebral ischemia.

BACKGROUND: Studies have indicated that bone marrow stromal cell (BMSC) administration is a promising approach for stroke treatment. For our study, we chose sodium ferulate (SF) and n-butylidenephthalide (BP) combined with BMSC, and observed if the combination treatment possessed more significant effects on angiogenesis and neurogenesis post-stroke. METHODS: We established rat permanent middle cerebral artery occlusion (MCAo) model and evaluated ischemic volumes of MCAo, BMSC, SF + BP, Simvastatin + BMSC and SF + BP + BMSC groups with TTC staining on the 7th day after ischemia. Immunofluorescence staining of vascular endothelial growth factor (VEGF) and brain derived neurotrophic factor (BDNF), as well as immunohistochemistry staining of von Willebrand factor (vWF) and neuronal class III ß-tubulin (Tuj1) were performed in ischemic boundary zone (IBZ), furthermore, to understand the mechanism, western blot was used to investigate AKT/mammalian target of rapamycin (mTOR) signal pathway in ischemic cortex. We also tested BMSC derived-VEGF and BDNF expressions by western blot assay in vitro. RESULTS: SF + BP + BMSC group obviously decreased infarction zone, and elevated the expression of VEGF and the density and perimeter of vWF-vessels as same as Simvastatin + BMSC administration; moreover, its effects on BDNF and Tuj1 expressions were superior to Simvastatin + BMSC treatment in IBZ. Meanwhile, it showed that SF and BP combined with BMSC treatment notably up-regulated AKT/mTOR signal pathway compared with SF + BP group and BMSC alone post-stroke. Western blot results showed that SF and BP treatment could promote BMSCs to synthesize VEGF and BDNF in vitro. CONCLUSIONS: We firstly demonstrate that SF and BP combined with BMSC can significantly improve angiogenesis and neurogenesis in IBZ following stroke. The therapeutic effects are associated with the enhancement of VEGF and BDNF expressions via activation of AKT/mTOR signal pathway. Furthermore, triggering BMSC paracrine function of SF and BP might contribute to amplifying the synergic effects of the combination treatment.

Synthesis of bromo-, boryl-, and stannyl-functionalized 1,2-bis(trimethylsilyl)benzenes via Diels-Alder or C-H activation reactions.

1,2-Bis(trimethylsilyl)benzenes are key starting materials for the synthesis of benzyne precursors, Lewis acid catalysts, and certain luminophores. We have developed efficient, high-yield routes to functionalized 4-R-1,2-bis(trimethylsilyl)benzenes, starting from either 1,2-bis(trimethylsilyl)acetylene/5-bromopyran-2-one (2) or 1,2-bis(trimethylsilyl)benzene (1)/bis(pinacolato)diborane. In the first reaction, 5 (R = Br) is obtained through a cobalt-catalyzed Diels-Alder cycloaddition. The second reaction proceeds via iridium-mediated C-H activation and provides 8 (R = Bpin). Besides its use as a Suzuki reagent, compound 8 can be converted into 5 with CuBr(2) in i-PrOH/MeOH/H(2)O. Lithium-bromine exchange on 5, followed by the addition of Me(3)SnCl, gives 10 (R = SnMe(3)), which we have applied for Stille coupling reactions. A Pd-catalyzed C-C coupling reaction between 5 and 8 leads to the corresponding tetrasilylbiphenyl derivative. The bromo derivative 5 cleanly undergoes Suzuki reactions with electron-rich as well as electron-poor phenylboronic acids.

Effect of Yinian Jiangya Yin on primary hypertension in early stage--a clinical observation on 40 patients.

OBJECTIVE: To observe the effect of Yinian Jiangya Yin (Decoction for lowering blood pressure to prolong life) on patients with early hypertension and its mechanism on the function of vascular endotheliocytes. METHODS: The 79 patients with early primary hypertension belonging to the TCM syndrome of stagnation of phlegm and blood stasis in meridians and hyperactivity of the liver-yang were randomly divided into a treatment group of 40 patients treated with Yinian Jiangya Yin and a control group of 39 patients treated with Tianma Gouteng Yin (Decoction of Gastrodia and Uncaria). The changes in score of TCM syndrome and in blood pressure before and after treatment were observed in the two groups. The contents of nitrogen monoxide (NO) and endothelin (ET) in serum after treatment were determined. RESULTS: There was a statistical difference (P < 0.05) in score of TCM syndrome, effect of lowering blood pressure, and the contents of ET and NO in serum after treatment between the two groups. CONCLUSION: The effect of Yinian Jiangya Yin on improving TCM syndrome of patients with primary hypertension in early stage and on lowering blood pressure may be related to its regulating the imbalanced condition between ET and NO for restoring the function of endothelium-dependent vasodilation.

[Effects of yinian jiangya decoction contained serum on endothelial cell proliferation and PPAR gamma mRNA expression in spontaneously hypertensive rat].

OBJECTIVE: To observe the effects of Yinian Jiangya (YNJY) Decoction contained serum on cell proliferation of primary cultured endothelial cells of spontaneously hypertensive rat (SHR) and the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) mRNA expression in the cells. METHODS: SD rats were fed with high-lipid diet and different doses (high, medium and low, containing crude drug of 5.2 g/mL, 2.6 g/mL, 1.3 g/mL respectively) of YNJY respectively and the serum contained different doses of YNJY (S-YNJY) was prepared by collecting the rats' serum after 20 days of feeding. The serum obtained from SD rats fed with normal diet, i.e. drug free serum (S-free) was taken for control. Primary cultured endothelial cells of SHR were treated respectively with S-YNJY in different doses (treated groups) and S-free (control group), the cell activity and the mRNA expression of PPAR-gamma in cells of all groups were detected by MTT and RT-PCR respectively at different time points: 2, 4, 8, 16 and 24 h after treatment. RESULTS: MTT test showed that at time points of 4 and 8 h, the OD value raised in the treated groups with insignificant difference among them (P>0.05), but was higher than that in the control group (P<0.05); at 16 h, it increased but showed a smaller increment in the medium-dose treated group (P<0.05); at 24 h, it decreased in all groups, but the decrement in the high- and medium-dose treated groups was more remarkable (P<0.05); at 48 h, it decreased continuously, with the decrement more significant in the high-dose group than in the control group (P<0.05). RT-PCR detection showed that at 4 h, the expression of PPAR-gamma mRNA was not changed significantly in all groups (P>0.05); at 8 h, it was remarkably lower in high-dose group than in others (P<0.05); at 16 h, it was higher in the three treated groups than in the control group (P<0.05), with a highest level shown in the high-dose treated group (P<0.01); at 24 h, the expression decreased in all groups, but the level in the low-dose treated group was still higher than that in the control group (P<0.05). CONCLUSIONS: YNJY Decoction shows a two-way regulation on endothelial cells proliferation, and which is negatively dose-dependent in the late stage. The regulation is perhaps relevant to the regulating of the PPAR-gamma mRNA expressions. The PPAR-gamma mRNA expression up-regulating and maintaining effects of YNJY Decoction may be one of the mechanisms for its vascular endothelial cell protection and blood pressure suppressing.