"One-Pot" In Situ Tandem Reaction─Dy(III) Coordination-Catalyzed Multicomponent Condensation of Salicylaldehyde Derivatives to Obtain Ketals.

It is difficult to subject simple reaction starting materials to a "one-pot" in situ tandem reaction without post-treatment under mild reaction conditions to obtain multimers with complex structural linkages. In organic synthesis, acetal reactions are often used to protect derivatives containing carbonyl functional groups. Therefore, acetal products tend to have very low stability, and performing multi-step condensation to obtain complex multimeric products is difficult. Herein, we achieved the first efficient multiple condensation of o-vanillin derivatives using Dy(OAc)3·6H2O undergoing a "one-pot" in situ tandem reaction under mild solvothermal conditions to obtain a series of dimers (I and II, clusters 1 and 2) and trimers (I and II, clusters 3 and 4). When methanol or ethanol is used as the solvent, the alcoholic solvent participates in acetal and dehydration reactions to obtain dimers (I and II). Surprisingly, when using acetonitrile as the reaction solvent, the o-vanillin derivatives undergo acetal and dehydration reactions to obtain trimers (I and II). In addition, clusters 1-4 all showed distinct single-molecule magnetic behaviors under zero-field conditions. To the best of our knowledge, this is the first time that multiple acetal reactions catalyzed by coordination-directed catalysis under "one-pot" conditions have been realized, opening a new horizon for the development of fast, facile, green, and efficient synthetic methods for complex compounds.

Aggregation-Induced Emission via the Restriction of the Intramolecular Vibration Mechanism of Pinacol Lanthanide Complexes.

Pinacol lanthanide complexes PyraLn (Ln = Dy and Tb) with the restriction of intramolecular vibration were obtained for the first time via an in situ solvothermal coordination-catalyzed tandem reaction using cheap and simple starting materials, thereby avoiding complex, time-consuming, and expensive conventional organic synthesis strategies. A high-resolution electrospray ionization mass spectrometry (HRESI-MS) analysis confirmed the stability of PyraLn in an organic solution. The formation process of PyraLn was monitored in detail using time-dependent HRESI-MS, which allowed for proposing a mechanism for the formation of pinacol complexes via in situ tandem reactions under one-pot coordination-catalyzed conditions. The PyraLn complexes constructed using a pinacol ligand with a butterfly configuration exhibited distinct aggregation-induced emission (AIE) behavior, with the αAIE value as high as 60.42 according to the AIE titration curve. In addition, the PyraLn complexes in the aggregated state exhibit a rapid photoresponse to various 3d metal ions with low detection limits. These findings provide fast, facile, and high-yield access to dynamic, smart lanthanide complex emissions with bright emission and facilitate the rational construction of molecular machines for artificial intelligence.

Giant Crown-Shaped Dy34 Nanocluster with High Acid-Base Stability Assembled by an out-to-in Growth Mechanism.

Lanthanoid metal ions have large ionic radii, complex coordination modes, and easy distortion of coordination spheres, but the design and synthesis of high-nucleation lanthanoid clusters with high stability in solution (especially aqueous solution) are challenging. Herein, a diacylhydrazone ligand (H2L1) with multidentate chelating coordination sites was used to react with Dy(OAc)3·4H2O under solvothermal conditions to obtain an example of a 34-nucleus crown-shaped dysprosium cluster [Dy34(L)8(µ2-OH)(µ3-OH)21(µ3-O)14(OAc)31(OCH3)2(H2O)15](OAc)3 (1). Structural analysis showed that the bisacylhydrazone ligand H2L1 with polydentate chelate coordination sites could rapidly capture DyIII ions, thereby forming 34-nucleus crown-shaped dysprosium cluster 1 following the out-to-in growth mechanism. Cluster 1 remained stable after immersion in solutions with different pH values (3-14) for 24 h. To the best of the authors' knowledge, high-nucleation lanthanoid clusters with excellent strong acid and base stability and water stability are very rare. Meanwhile, high-resolution electrospray mass spectrometry molecular ion peaks produced by cluster 1 were captured, which proved to be stable also in organic solvents. Magnetic research showed that cluster 1 exhibited frequency-dependent behavior. This work provides a new idea for designing and synthesizing high-nucleation lanthanoid clusters with high stability.

Manipulating Solvothermal Coordination-Catalyzed In Situ Tandem Reactions to Construct Dysprosium-Based Complexes with Different Shapes and Zero-Field SMM Behaviors.

By changing the coordination anions (OAc- and Cl-), reaction temperature, solvent, and ligand substituents, four Dy(III)-based complexes were obtained by directed synthesis, which are [Dy4(L1)2(L2)2(OAc)4]·4C2H5OH·3H2O (1, L1 = 1,3,4-thiadiazole-2,5-diamine, H4L2 = 6,6'-(((1,3,4-thiadiazole-2,5-diyl)bis(azanediyl))bis(((3-ethoxy-2-hydroxybenzyl)oxy)methylene))bis(2-ethoxyphen), [Dy4(L3)4(OAc)4]·C2H5OH·H2O (2, H3L3 = 2-(((5-amino-1,3,4-thiadiazol-2-yl)amino)((3-ethoxy-2-hydroxybenzyl)oxy)methyl)-6-ethoxyphenol)), [Dy6(L4)4(L5)2(µ3-OH)4(CH3O)4Cl4]Cl2 (3, H2L4 = 2-hydroxy-3-methoxybenzaldehyde, H2L5 = 2-(((5-amino-1,3,4-thiadiazol-2-yl)amino)(hydroxy)methyl)-6-methoxyphenol), and [Dy6(L6)4(L7)2(µ3-OH)4(CH3O)4Cl4]Cl2·2H3O (4, H2L6 = 2-hydroxy-3-ethoxybenzaldehyde, H2L7 = 2-(((5-amino-1,3,4-thiadiazol-2-yl)amino)(hydroxy)methyl)-6-ethoxyphenol). A series of acetal products (H4L2, H3L3, H2L5, and H2L7) were obtained through dehydration in situ tandem reactions. Magnetic studies show that complexes 1-4 exhibited different single-molecule magnet behavior under zero-field conditions. The best fitting results showed that under zero DC field, the effective energy barriers (Ueff) and magnetic relaxation times (τ0) of complexes 1-4 are Ueff = 117.0 (2.1) K and τ0 = 6.07 × 10-7 s; Ueff = 83.91 (1.5) K and τ0 = 4.28 × 10-7 s; Ueff = 1.28 (0.2) K and τ0 = 0.73 s, and Ueff = 104.43 (13.3) K and τ0 = 8.25 × 10-8 s, respectively.

Anion-Manipulated Hydrolysis Process Assembles of Giant High-Nucleation Lanthanide-Oxo Cluster.

Widespread concern has been raised over the synthesis of highly nucleated lanthanide clusters with special shapes and/or specific linkages. Construction of lanthanide clusters with specific shapes and/or linkages can be achieved by carefully regulating the hydrolysis of lanthanide metal ions and the resulting hydrolysis products. However, studies on the manipulation of lanthanide-ion hydrolysis to obtain giant lanthanide-oxo clusters have been few. In this study, we obtained a tetraicosa lanthanide cluster (3) by manipulating the hydrolysis of Dy(III) ions using an anion (OAc-). As far as we know, cluster 3 has the highest nucleation among all lanthanide-oxo clusters reported. In 3, two triangular Dy3O4 are oriented in opposite directions to form the central connecting axis Dy6(OH)8, which is in turn connected to six Dy3O4 that are oriented in different directions. Meanwhile, a sample of a chiral trinuclear dysprosium cluster (1) was obtained in a mixed CH3OH and CH3CN solvent and by replacing the anion in the reaction to Cl- ions. In this cluster, 1,3,4-thiadiazole-2,5-diamine (L2) is free on one side through π···π interactions and is parallel to the o-vanillin (L1)- ligand, thus resulting in a triangular arrangement. The arrangement of L2 affects the end group coordination in the cluster 1 structure through hydrogen bonding and induces the cluster to exhibit chirality. When the reaction solvent was changed to CH3OH, a sample of cluster 2, composed of two independent triangular Dy3 that have different end group arrangements, was obtained. Magnetic analysis showed that clusters 1 and 3 both exhibit distinctive single-molecule magnetic properties under zero-magnetic-field conditions. This study thus provides a method for the creation of chiral high-nucleation clusters from achiral ligands and potentially paves the way for the synthesis of high-nucleation lanthanide clusters with unique forms.

A Series of High-Nuclear Gadolinium Cluster Aggregates with a Magnetocaloric Effect Constructed through Two-Component Manipulation.

The serialized expansion of high-nuclear clusters usually includes the controlled variable method and changes only a single variable. However, changing both variables will greatly increase the complexity of the reaction simultaneously. Therefore, the use of a two-component regulation reaction is rare. Herein, we used a diacylhydrazone ligand (H4L1) with multidentate chelating coordination sites for the reaction with Gd(NO3)3·6H2O under solvothermal conditions to obtain an example of 16-nucleus disc-shaped cluster 1 with a brucite structure. The overall structure of cluster 1 can be regarded as an equilateral triangle, which is formed by three (L1)4- ions that can be regarded as "sides" and wrap the four-layer metal center Gd(III) ions. Notably, upon simultaneous regulation of the substituent of the ligand and the coordination anion, heptanuclear gadolinium cluster 2 was obtained. Cluster 2 can be regarded as a butterfly structure, which was formed by connecting two Gd3L2 molecules that were not in the same plane and through the central Gd(III) ion as an intersection. Moreover, hexanuclear gadolinium cluster 3 was obtained by changing the ligand substituent and adding an auxiliary ligand. Cluster 3 can be regarded as a chair structure, which was composed of two molecules of diacylhydrazone ligand (L2)4- wrapping vacant cubane shared by four vertices. This study was the first to construct a series of high-nuclear gadolinium clusters through two-component regulation manipulation. The study of the magnetocaloric effect showed that the maximum values of -ΔSm for clusters 1-3 were 34.05, 29.04, and 24.32 J kg-1 K-1, respectively, when T = 2 K and ΔH = 7 T.

An Investigation into the Interaction between Double Hydroxide-Based Antioxidant Benzophenone Derivatives and Cyclooxygenase 2.

Cyclooxygenases 2 (COX2) is a therapeutic target for many inflammation and oxidative stress associated diseases. A high-throughput technique, biolayer interferometry, was performed to primarily screen the potential COX2 binding activities of twelve newly synthesized double hydroxide-based benzophenone derivatives. Binding confirmation was achieved by molecular docking and multi-spectroscopy studies. Such a combined method provided a comprehensive understanding of binding mechanism and conformational changes. Compounds DB2, SC2 and YB2 showed effective COX2 binding activity and underlined the benefits of three phenolic hydroxyl groups adjacent to each other on the B ring. The twelve tested derivatives were further evaluated for antioxidant activity, wherein compound SC2 showed the highest activity. Its concentration for the 50% of maximal effect (EC50) value was approximately 1000 times greater than that of the positive controls. SC2 treatment effectively improved biochemical indicators caused by oxidative stress. Overall, compound SC2 could serve as a promising candidate for further development of a new potent COX2 inhibitor.

Antiviral mechanism of carvacrol on HSV-2 infectivity through inhibition of RIP3-mediated programmed cell necrosis pathway and ubiquitin-proteasome system in BSC-1 cells.

BACKGROUND: Carvacrol, as the major components of aromatic plants used for treating human skin diseases including origanum, Satureja, thymus, and coridothymus species, presented a kind of antiviral activity. To explore the mechanisms of carvacrol against herpes simplex virus (HSV) in vitro. METHOD: The BSC-1 cells model of HSV infection was established, and from the two aspects of viral replication level and cell death pathway, the antiviral effects of carvacrol on HSV infected cells were also evaluated by plaque assay under the three modes including prevention, treatment, and direct inactivation. RESULTS: In the three ways, the half-maximal effective concentration (EC50) of 2% true carvacrol solution on HSV-2 infected cells were severally 0.43, 0.19 and 0.51 mmol/L, and the corresponding therapeutic index (TI) were 4.02, 9.11 and 3.39, respectively. It's the opposite of the increased levels caused by HSV-2 infection, that both the expressions at the transcription genes and protein levels of virus own replication key factors (including ICP4, ICP27, VP16, gB, and UL30) and cytokines (including RIP3, TNF-α, and MLKL) of infected cells treated with carvacrol were dose-dependently inhibited. Besides, HSV-2 infection can cause the decrease of intracellular protein ubiquitination level, and carvacrol can reverse the ubiquitination decrease level caused by HSV-2 infection. CONCLUSION: Carvacrol exhibits significant antiviral activity by inhibiting the HSV-2 proliferation process and HSV-2-induced TNF-α increasing levels, decreasing RIP3 and MLKL protein expressions through the intracellular RIP3-mediated programmed cell necrosis pathway. In addition, carvacrol also may exhibit anti-HSV-2 activity by reversing the ubiquitination decrease level caused by HSV-2 infection on the ubiquitin-proteasome system, which provides insights into the molecular mechanism.

Protective Antioxidant Effects of Amentoflavone and Total Flavonoids from Hedyotis diffusa on H2 O2 -Induced HL-O2 Cells through ASK1/p38 MAPK Pathway.

In this study, total flavonoids and total triterpenoid acid were extracted with ethyl acetate from Hedyotis diffusa Willd, and hepatoprotective activities of them and five compounds from total flavonoids against H2 O2 induced hepatocyte damage on HL-02 cells were determined. In particular, amentoflavone and total flavonoids had influence on the leakage of ALT, AST, LDH, the activities of SOD and the content of MDA. They effectively reduced the loss of MMP, the release of Cyt C, and then inhibited activation of caspase-3/caspase-9 cascade in hepatotoxic cells. The contents of ROS were significantly reduced to inhibit p38 in amentoflavone and flavonoids groups which decreased ASK1 and p-p38 levels through increasing thioredoxin Trx1 and reductase TrxR1. These results suggesting that the antioxidant protection of amentoflavone and flavonoids might be reducing ROS to inhibit the H2 O2 -induced upstream of pathway via increasing levels of Trx1 and TrxR1, which were pivotal in blocking the down streaming effectors of ASK1/p38 MAPK pathway and alleviating hepatotoxicity.

[Antiviral activity of nano-realgar against herpes simplex virus Type II in vitro].

OBJECTIVE: To explore the antiviral activity of nano-realgar against herpes simplex virus Type II (HSV-2) in vitro.
 Methods: Acyclovir (ACV) as a positive control, the cytotoxicity of nano-realgar at different concentrations (including 200.00, 150.00, 100.00, 50.00, 25.00, 12.50, 6.25, 3.13, 1.54, 0.78, 0.39 and 0 mg/L) on normal Vero cells were determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. HSV-2 virus titer was determined by plaque assay, and the Vero cells model of HSV-2 infection was established. Subsequently, the antiviral effects of nano-realgar at different concentrations (including 20.00, 10.00, 5.00, 2.50, 1.25, 0.63, 0.31, 0.15, 0.08, 0.04 and 0 mg/L) on infected cells model were evaluated by the observation of cytopathic effect (CPE) and MTT method under the 3 modes including pre-treatment, treatment and direct inactivation.
 Results: The 50% cytotoxic concentration (CC50) of nano-realgar on Vero cells was 37.15 mg/L. The titer of HSV-2 was 7.30 log PFUs/mL. In the 3 modes, the half-maximal effective concentration (EC50) of nano-realgar on HSV-2 infected Vero cells were 0.13, 1.80 and 0.52 mg/L, and the corresponding therapeutic index (TI) were 285.77, 20.64, 71.44, respectively. The TI value of nano-realgar on pre-treatment mode was higher than that of nano-realgar on treatment and direct inactivation modes.
 Conclusion: Nano-realgar can play a good anti-HSV-2 activity in the 3 modes (pre-treatment, treatment and direct inactivation), and the anti-HSV-2 efficacy of nano-realgar on pre-treatment mode is better than that of nano-realagr on other 2 modes.

Effect of Dibutyltin Dilaurate on Triglyceride Metabolism through the Inhibition of the mTOR Pathway in Human HL7702 Liver Cells.

Dibutyltin dilaurate (DBTD) has multiple applications in daily life. However, DBTD is easily deposited in the liver and affects liver functions. This study was designed to explore the effects of DBTD on triglyceride metabolism in human normal hepatocyte HL7702 cells. Our results showed that the intracellular fat contents were dose-dependently decreased by DBTD. The expression of lipolysis genes and proteins were elevated while the lipogenesis genes and proteins were diminished by DBTD. The phosphorylation levels of ribosomal S6 kinase 1 were reduced by both rapamycin and DBTD, indicating that the mTOR pathway was suppressed possibly. The decreased sterol regulatory element-binding protein 1C (SREBP1C) transcription levels, as well as the increased peroxisome proliferator-activated receptor alpha (PPARα) transcription levels, caused by rapamycin and DBTD corresponded to the inactive mTOR pathway. In conclusion, it was possible that DBTD reduced the intracellular triglyceride through depressing the mTOR pathway and affecting its downstream transcription factors.

Proteomics Analysis Reveals an Important Role for the PPAR Signaling Pathway in DBDCT-Induced Hepatotoxicity Mechanisms.

A patented organotin di-n-butyl-di-(4-chlorobenzohydroxamato)tin (DBDCT) with high a antitumor activity was designed, however, its antitumor and toxic mechanisms have not yet been clearly illustrated. Hepatic proteins of DBDCT-treated rats were identified and analyzed using LC-MS/MS with label-free quantitative technology. In total, 149 differentially expressed proteins were successfully identified. Five protein and mRNA expressions were involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, including a scavenger receptor (CD36), adipocyte fatty acid binding protein 4 (FABP4), enoyl-CoA hydratase (EHHADH), acetyl-CoA acyltransferase 1 (ACAA1), and phosphoenolpyruvate carboxykinase (PEPCK) in DBDCT-treated Rat Liver (BRL) cells. PPAR-α and PPAR-λ were also significantly decreased at both protein and mRNA levels. Furthermore, compared with the DBDCT treatment group, a special blocking agent of PPAR-λ T0070907 was used to evaluate the relationship between PPAR-λ and its downstream genes. Our studies indicated that DBDCT may serve as a modulator of PPAR-λ, further up-regulating CD36, FABP4 and EHHADH on the PPAR signal pathway.

Different anion (NO3- and OAc-)-controlled construction of dysprosium clusters with different shapes.

The complex hydrolysis process and strong uncertainty of self-assembly rules have led to the precise synthesis of lanthanide clusters still being in the "blind-box" stage and simplifying the self-assembly process and developing reliable regulation strategies have attracted widespread attention. Herein, different anions are used to induce the construction of a series of dysprosium clusters with different shapes and connections. When the selected anion is NO3-, it blocks the coordination of metal sites around the cluster through the terminal group coordination mode, thereby controlling the growth of the cluster. When NO3- was changed to OAc-, OAc- adopted a bridging mode to induce modular units to build dysprosium clusters through an annular growth mechanism. Specifically, we selected 2-amino-6-methoxybenzoic acid, 2-hydroxybenzaldehyde, and Dy(NO3)3·6H2O to react under solvothermal conditions to obtain a pentanuclear dysprosium cluster (1). The five Dy(III) ions in 1 are distributed in upper and lower planes and are formed by the tight connection of nitrogen and oxygen atoms, and µ3-OH- bridges on the ligand. Next, octa-nuclear dysprosium cluster (2) were obtained by only regulating ligand substituents. The eight Dy(III) ions in 2 are tightly connected through ligand oxygen atoms, µ2-OH-, and µ3-OH- bridges, forming an elliptical {Dy/O} cluster core. Furthermore, only by changing NO3- to OAc-, a wheel-shaped tetradeca-nuclear dysprosium cluster (3) was obtained. Cluster 3 is composed of OAc- bridged multiple template Dy3L3 units and pulling of these template units connected by an annular growth mechanism forms a wheel-shaped cluster. The angle of the coordination site on NO3- is ∠ONO = 115°, which leads to the further extension of the metal sites on the periphery of clusters 1 and 2 through the terminal group coordination mode, thereby regulating the structural connection of the clusters. However, the angle of the coordination site on OAc- is ∠OCO = 128°, and a slightly increased angle leads to the formation of a ring-shaped cluster 3 by connecting the template units through bridging. This is a rare example of the controllable construction of lanthanide clusters with different shapes induced by the regulation of different anions, which provides a new method for the precise construction of lanthanide clusters with special shapes.

Aggregation induced emission dynamic chiral europium(III) complexes with excellent circularly polarized luminescence and smart sensors.

The synthesis of dynamic chiral lanthanide complex emitters has always been difficult. Herein, we report three pairs of dynamic chiral EuIII complex emitters (R/S-Eu-R-1, R = Et/Me; R/S-Eu-Et-2) with aggregation-induced emission. In the molecular state, these EuIII complexes have almost no obvious emission, while in the aggregate state, they greatly enhance the EuIII emission through restriction of intramolecular rotation and restriction of intramolecular vibration. The asymmetry factor and the circularly polarized luminescence brightness are as high as 0.64 (5D0 → 7F1) and 2429 M-1cm-1 of R-Eu-Et-1, achieving a rare double improvement. R-Eu-Et-1/2 exhibit excellent sensing properties for low concentrations of CuII ions, and their detection limits are as low as 2.55 and 4.44 nM, respectively. Dynamic EuIII complexes are constructed by using chiral ligands with rotor structures or vibration units, an approach that opens a door for the construction of dynamic chiral luminescent materials.

Organotin benzohydroxamate derivatives (OTBH) target colchicine-binding site exerting potent antitumor activity both in vitro and vivo revealed by quantitative proteomic analysis.

The activity of four typical organotin benzohydroxamate compounds (OTBH) with the different electronegativity of fluorine and chlorine atoms was assessed both in vitro and in vivo, revealing that they all exhibited notable antitumor effects. Furthermore, it was discovered that the biochemical capacity against cancer was influenced by their substituents' electronegativity and structural symmetry. For instance, benzohydroxamate derivatives with single chlorine at the fourth site on the benzene ring, two normal­butyl organic ligands, a symmetrical structure, and so on ([n-Bu2Sn[{4-ClC6H4C(O)NHO}2] (OTBH-1)) had stronger antitumor activity than others. Furthermore, the quantitative proteomic analysis discovered 203 proteins in HepG2 cells and 146 proteins in rat liver tissues that were differently identified before and after administration. Simultaneously, bioinformatics analysis of differentially expressed proteins demonstrated that the antiproliferative effects involved in the microtubule-based process, tight junction and its downstream apoptosis pathways. As predicted analytically, molecular docking indicated that ''-O-'' were the target docking atoms for the colchicine-binding site; meanwhile, this site was additionally verified by the EBI competition experiment and the microtubule assembly inhibition test. In conclusion, these derivatives promising for developing microtubule-targeting agents (MTAs) were shown to target the colchicine-binding site, impair cancer cell microtubule networks, and then halt mitosis and trigger apoptosis.

SIRT1-dependent mitochondrial biogenesis supports therapeutic effects of 4-butyl-polyhydroxybenzophenone compounds against NAFLD.

The mitochondria have been identified as key targets in nonalcoholic fatty liver disease (NAFLD), one of the most prevalent chronic liver damage diseases globally. Meanwhile, the biological information analysis in this study revealed that SIRT1, PPARG, PPARA, and PPARGC1A (mitochondrial biogenesis-related proteins) were NAFLD therapeutic targets. Therefore, the design and synthesis of targeted drugs that promote mitochondrial biogenesis and improve mitochondrial function are particularly important for NAFLD treatment. Recently, we introduced butyls, hydroxyls, and halogens to benzophenone and synthesized a series of NAFLD-related 4-butylpolyhydroxybenzophenone compounds, aiming at investigating the hepatoprotective activity from the aspect of mitochondrial biogenesis. The structure-activity relationship demonstrated that hydroxyl and ketone groups were active groups interacting with mitochondrial biogenesis proteins (SIRT1 and PGC1α), and the activity was stronger when the o-hydroxyl group was present on the benzene ring. In contrast, the activity was little affected by the presence of the p-hydroxyl group, m-hydroxyl group, butyl group type, or halogen. In addition, in vitro studies confirmed that these compounds could directly bind to SIRT1 and PGC1α, markedly promote their interaction, significantly increase the expression of proteins and genes related to mitochondrial biogenesis (SIRT1, PGC1α, NRF1, TFAM, COX1, and ND6) and subsequently ameliorate mitochondria dysfunction, which was evidenced by the decreased ROS, upregulated ATP production, increased MMP, and enhanced mitochondrial number. According to the outcomes of our in vitro and in vivo experiments, 4-butyl-polyhydroxybenzophenone compounds could also effectively reduce the formation of lipid droplets and liver injury index (ALT, AST, LDH, AKP, γ-GT, and GDH) and improve the level of antioxidant enzymes (GSH and SOD). Particularly, the treatment of these compounds after a high-fat diet could significantly reduce body weight, decrease liver coefficient, attenuate liver damage, and ameliorate lipid accumulation in rat liver, demonstrating their therapeutic effects on NAFLD. Mechanistically, 4-butyl-polyhydroxybenzophenone compounds promoted mitochondrial biogenesis and eventually prevented NAFLD liver injury by activating the PGC1α signaling pathway in a SIRT1-dependent manner, which was strongly supported by SIRT1 inhibitor EX527.

A cyanoacrylate/triethyl citrate/nanosilica-based closure glue with wet-adhesion capability for treatment of superficial varicose veins.

Varicose veins in legs are common in clinics. Currently, medical adhesive-based, minimally invasive endovenous occlusion is used to treat them. However, the most common cyanoacrylate medical adhesives do not perform well when used under blood/wet conditions. In particular, poor adhesion, short curing time, and high heat release greatly limit their clinical use. In this paper, we demonstrate the use of a composite system composed of butyl-cyanoacrylate, triethyl citrate, and nanosilica that exhibits a blood/wet-adhesion capability to serve as a new sealing glue. Hydrophobic triethyl citrate groups displace boundary waters while also protecting cyanoacrylate monomers from undergoing rapid polymerization. Nanosilica increases viscosity, which contributes to in situ extrusion molding and retention. An optimal formulation, FAL-006, exhibited good physical and chemical properties in vitro. The performed additional safety assays indicated that FAL-006 has good biocompatibility. The closure efficiency of FAL-006 in vivo was evaluated in both a rat abdominal aortic closure model and in a sheep lower limb venous closure model. Taken together, these results indicate that FAL-006 exhibits promising potential for use in clinical applications. Furthermore, this study provides a new strategy for designing underwater adhesive agents for additional clinical applications, and a strategy for constructing other biomaterials needed for use under wet conditions.

A contact-polymerizable hemostatic powder for rapid hemostasis.

The immediate control of a hemorrhage is crucial for reducing fatalities in critical situations such as battlefields, traffic accidents, natural disasters, etc. Most existing commercial hemostatic powders have weak adhesion capability and poor biodegradability, restricting their clinical use. In this paper, a new poly(ethylene glycol)-di(cyanoacrylate) (CA-PEG-CA)-based hemostatic powder with tissue-contact-triggered strong adhesion and controlled fast degradation is proposed. The monomers quickly underwent crosslinking polymerization while in contact with tissue or blood, forming an in situ gel on the wound. The hemostatic mechanism was demonstrated to depend on both adhesive-based sealing and the aggregation of platelets and erythrocytes. The powder showed excellent hemostatic effects both in vitro and in vivo, even in a rat model with a weakened native hemostatic capacity. In addition, the poly-CA-PEG-CA gel could be rapidly biodegraded by ester bond hydrolysis. Notably, a cysteamine (CS)-containing solution could accelerate the degradation rate, endowing the gel with an on-demand removal property. This hemostatic powder not only can be used to efficiently control bleeding in emergency scenarios, but it can also allow nontraumatic re-exposure of wounds during subsequent surgical care. These properties make the CA-PEG-CA powder a promising candidate to act as a multifunctional wound care agent for first aid.

Highly Accessible Computational Prediction and In Vivo/In Vitro Experimental Validation: Novel Synthetic Phenyl Ketone Derivatives as Promising Agents against NAFLD via Modulating Oxidoreductase Activity.

Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions with no pharmacological treatment approved. Several highly accessible computational tools were employed to predict the activities of twelve novel compounds prior to actual chemical synthesis. We began our work by designing two or three hydroxyl groups appended to the phenyl ketone core, followed by prediction of drug-likeness and targets. Most predicted targets for each compound overlapped with NAFLD targets (≥80%). Enrichment analysis showed that these compounds might regulate oxidoreductase activity. Then, these compounds were synthesized and confirmed by IR, MS, 1H, and 13C NMR. Their cell viability demonstrated that twelve compounds exhibited appreciable potencies against NAFLD (EC50 values ≤ 13.5 µM). Furthermore, the most potent compound 5f effectively prevented NAFLD progression as evidenced by the change in histological features. 5f significantly reduced total cholesterol and triglyceride levels in vitro/in vivo, and the effects of 5f were significantly stronger than those of the control drug. The proteomic data showed that oxidoreductase activity was the most significantly enriched, and this finding was consistent with docking results. In summary, this validated presynthesis prediction approach was cost-saving and worthy of popularization. The novel synthetic phenyl ketone derivative 5f holds great therapeutic potential by modulating oxidoreductase activity to counter NAFLD.

Inhibition of cytochrome P450 3A in rat liver by the Diorganotin (IV) compound di-n-Butyl-di-(4-chlorobenzo-hydroxamato)tin (IV) and Its Probable Mechanism.

The specific aims of this study were to evaluate the inhibition effect on CYP3A of di-n-butyl-di-(4-chlorobenzohydroxamato)tin (IV) (DBDCT), a tin-based complex with high antitumor activity, and the probable mechanism(s) of this action. Adult male SD rats were treated separately with natural saline (NS), lipopolysaccharide (LPS, 5 mg/kg), DBDCT (1.25, 2.5 and 5.0 mg/kg) intraperitoneally for 2 days after induction of CYP3A with dexamethasone (DEX, 100 mg/kg) for 4 days. Western blot analysis and fluorescent quantitation PCR (FQ-PCR) were conducted to determine the changes in expression of CYP3A, PXR, CAR and RXR. The biological accumulation of DBDCT and total Sn were determined by high-performance liquid chromatography (HPLC) and atomic fluorescence spectrometry (AFS). CYP450 content and CYP3A activities were significantly inhibited (p < 0.05) in DBDCT-treated rats compared with the control group, as was the expression of CYP3A (p < 0.05) at both protein and mRNA levels. In DBDCT-treated groups, the expression of PXR protein and mRNA increased, while the expression of CAR decreased. The biological accumulation of DBDCT and Sn in rat livers treated with DBDCT was high. The accumulation of DBDCT and Sn due to the inhibition of CYP3A may be involved in the mechanism of toxicity of DBDCT in rat liver.