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Proteasomes are protein complexes responsible for degrading unneeded or damaged proteins through proteolysis and play critical roles in regulating plant development and response to environmental stresses. However, it is still unclear whether proteasomes regulate fruit development and ripening. In this study, we investigated the function of a core proteasome subunit, SlPBB2, in tomato fruit. We found that silencing the SlPPB2 gene through virus-induced gene silencing resulted in tomato seedling death, while SlPPB2 RNA interference (RNAi- SlPBB2 ) plants driven by a fruit-specific promoter PP2C present normal development. Further observation reveals that silencing SlPBB2 in fruits impaired the chloroplast development and chlorophyll metabolism of fruits, increased the fruit size, and delayed fruit ripening. These findings provide novel insights into the role of proteasomes in regulating fruit development and ripening.

We report herein that three facile rearrangements of epoxy ketones can be employed for the efficient and practical synthesis of cephalotaxine, the parent member of the family of Cephalotaxus alkaloids. The Meinwald rearrangement of epoxy ketone (90%) was used for the preparation of the dense functional groups in the cyclopentane ring of cephalotaxine. A novel acid-catalyzed umpolung S N 2' rearrangement and the Wharton transposition reaction of epoxy ketones were also developed to synthesize the Mori intermediate via the key azaspiro allylic alcohols in a stereodivergent manner.

1,2,4-Oxadiazole derivatives, a class of Nrf2-ARE activators, exert an extensive therapeutic effect on inflammation, cancer, neurodegeneration, and microbial infection. Among these analogues, DDO-7263 is the most potent Nrf2 activator and used as the core structure for bioactive probes to explore the precise mechanism. In this work, we obtained compound 7 , a mimic of DDO-7263 , and biotin-labeled and fluorescein-based probes, which exhibited homologous biological activities to DDO-7263 , including activating Nrf2 and its downstream target genes, anti-oxidative stress, and anti-inflammatory effects. Affinity chromatography and mass analysis techniques revealed Rpn6 as the potential target protein regulating the Nrf2 signaling pathway. In vitro affinity experiments further confirmed that DDO-7263 upregulated Nrf2 through binding to Rpn6 to block the assembly of 26S proteasome and the subsequent degradation of ubiquitinated Nrf2. These results indicated that Rpn6 is a promising candidate target to activate the Nrf2 pathway for protecting cells and tissues from oxidative, electrophilic, and exogenous microbial stimulation.

Unprecedented copper-catalyzed regiodivergent hydrosilylation reactions of substituted 1,3-dienes with hydrosilanes have been developed. The 1,2- and 1,4-hydrosilylations of 1-(hetero)aryl-substituted 1,3-dienes were highly selectively controlled via variation of the catalytic systems. Meanwhile, the 1,4-hydrosilylation reaction of 2-aryl-substituted 1,3-dienes with diphenylsilane was also successfully realized for the first time. These methods provide convenient and efficient approaches for the synthesis of structurally diverse allylsilanes.

A new Lewis acid-catalyzed [2 + 2] cycloaddition/retroelectrocyclization (CA-RE)/1,6-addition relay of aurone-derived 1-azadienes and 1-alkynylnaphthalen-2-ols has been reported, leading to the regio- and diastereoselective synthesis of 1,2-dihydrobenzofuro[3,2- b ]pyridine with a chiral carbon center and an axial chirality in good yields. This protocol enables the C-C double-bond scission/recombination to rapidly construct aza-heterocyclic architectures and features 100% atom utilization, a wide substrate scope, good compatibility with substituents, and excellent diastereoselectivity.

The NLRP3 inflammasome is a critical component of innate immunity, which defends internal and external threats. However, inappropriate activation of the NLRP3 inflammasome induces various human diseases. In this study, we discovered and synthesized a series of tetrahydroquinoline inhibitors of NLRP3 inflammasome. Among these analogues, compound 6 exhibited optimal NLRP3 inhibitory activity. In vitro studies indicated that compound 6 directly bound to the NACHT domain of NLRP3 but not to protein pyrin domain (PYD) or LRR domain, inhibited NLRP3 ATPase activity, and blocked ASC oligomerization, thereby inhibiting NLRP3 inflammasome assembly and activation. Compound 6 specifically inhibited the NLRP3 inflammasome activation, but had no effect on the activation of NLRC4 or AIM2 inflammasomes. Furthermore, in the dextran sulfate sodium (DSS)-induced colitis mouse model, compound 6 exhibited significant anti-inflammatory activity through inhibiting NLRP3 inflammasome in vivo . Therefore, our study provides a potent NLRP3 inflammasome inhibitor, which deserves further structural optimization as a novel therapeutic candidate for NLRP3-driven diseases.

A copper-catalyzed anti -Markovnikov hydrosilylation of alkynes with PhSiH 3 was reported. This reaction represents a notable and efficient example on copper-catalyzed hydrosilylatioin of alkynes, which shows excellent recognition between the terminal and internal triple bonds. Various (hetero)aromatic and aliphatic substituted terminal alkynes underwent this reaction to afford the ( E )-vinylsilanes in high yields and with excellent regioselectivity.

In this work, a series of water-soluble propofol prodrugs were synthesized, and their propofol release rate and pharmacodynamic characteristics were measured. We found that inserting glycolic acid as a linker between propofol and the cyclic amino acid accelerated the release of propofol from prodrugs into the plasma while preserving its safety. In animal experiments, prodrugs ( 3e , 3g , and 3j ) were significantly better than fospropofol (the only water-soluble propofol prodrug that has been used clinically) in terms of safety, onset, and duration time of anesthesia. Their molar dose, onset time, and anesthesia duration time were comparable to those of propofol, helping to maintain the clinical benefits of propofol. The experimental results showed the potential of such compounds as water-soluble prodrugs of propofol.

Direct conversion of the readily available alkyl bromides and alcohols to value-added epoxides using dimethyl sulfoxide (DMSO) under mild reaction conditions has been developed. Benzyl and allyl bromides, and activated and unactivated alcohols all proceeded smoothly to give epoxides in high to excellent yield. Dimethyl sulfide, generated by DMSO oxidations, was in situ elaborated to form the substituted dimethyl sulfonium ylide species that participates in the Corey-Chaykovsky epoxidation in a domino and one-pot fashion, respectively.

A copper-catalyzed highly regio- and stereoselective silaboration of alkynes was developed. In this work, direct cis-difunctionalization of alkynes was realized with silaboronate reagent and copper catalyst in aprotic solvents. The regiodivergent silaborations were controlled by tuning the copper catalysts and phosphine ligands used in reactions. This protocol provides an efficient and practical method to synthesize the multisubstituted functionalized alkenes with specific stereoselectivity.

The excretion, tissue distribution, and metabolic profile of astilbin in rat were studied by HPLC and UPLC-QTOF-MS. Astilbin underwent isomerization in the small intestine, and its four isomers were found in feces. Besides, taxifolin, the aglycone of astilbin, and its further metabolites by gut microbes through hydrogenation, dehydration, and ring-fission were found. The total feces excretion of astilbin was about 14.4% of administration. The forming of zein-caseinate nanoparticles can significantly delay and reduce the feces excretion of astilbin. Astilbin and its isomers were absorbed in their intact form. The main metabolites found in plasma and tissues were the methylated products. Astilbin was rapidly distributed in various tissues including brain and maintained relatively high concentration in heart. Compared with other tissues, significantly higher concentration and longer duration of astilbin were found in the gastrointestinal tract. Astilbin and its isomers were excreted in their intact and methylated form in urine.

Constant pressure simulations were carried out to construct a new rigid nonpolarizable seven-site water model (TIP7P), which is an effective and efficient version of flexible seven-fluctuating-charge water model. In this model, the positive charges are located on three nuclei and the negative charges disperse on two bond sites at the geometric center of each OH bond and two lone-pair sites along the tetrahedral direction away from the oxygen atom. Our new model performs better than other models in properties, such as radial distribution function, liquid density, thermal expansion coefficient, isothermal compressibility, vaporization enthalpy, isobaric heat capacity, static dielectric constant, self-diffusion coefficient, critical temperature, and density. This model reproduces liquid density and static dielectric constant over the temperatures from 253 to 373 K at 1 atm with the standard deviation of 0.0010 g/cm 3 and 1.37 to the experimental data, respectively. The maximum density is 1.0006 g/cm 3 at 277 K. The calculated isobaric compressibility presents a minimum at about 310 K close to the experimental value of 319 K. The self-diffusion coefficient agrees the experimental data with the standard deviation of 0.55 × 10 -5 cm 2 /s, although it is not the target property for parameterization. Liquid-vapor phase equilibrium was examined in slab simulations. The evaluated critical temperature and density are 633 K and 0.337 g/cm 3 close to the experimental values of 647.096 K and 0.322 g/cm 3 . This model also presents reasonable vaporization enthalpy and isobaric heat capacity. Based upon good performances mentioned, our new model is a good choice for more accurate investigation to large molecular systems.

A palladium-catalyzed dialkylation of 1,3-dien-5-ynes was developed using alkenyl double bonds as the initiator and terminator for the synthesis of functionalized indene derivatives. The reactions were performed under mild reaction conditions, affording the corresponding multi-substituted indene derivatives in high efficiency via unprecedented 5- endo cyclization and alkylation processes. It was found that the substituent location at the alkenyl double bond was essential for the chemoselective synthesis of the indene and naphthalene derivatives, respectively.

Asymmetric synthesis of the pentacyclic alkaloid (-)-cephalotaxine was accomplished via palladium-catalyzed enantioselective Tsuji allylation for construction of the aza-containing tetrasubstituted stereogenic center (95% yield, 93% ee). The allyl enol carbonate precursor was prepared from Hanaoka's ketone intermediate, which was formed by a novel formic acid promoted ring-expansion reaction.

Chitinase ChiEn1 did not hydrolyze insoluble chitin but showed hydrolysis and transglycosylation activities toward chitin-oligosaccharides. Interestingly, the addition of ChiEn1 increased the amount of reducing sugars released from chitin powder by endochitinase ChiIII by 105.0%, and among the released reducing sugars the amount of (GlcNAc) 2 was increased by 149.5%, whereas the amount of GlcNAc was decreased by 10.3%. The percentage of GlcNAc in the products of chitin powder with the combined ChiIII and ChiEn1 was close to that in the products of chitin-oligosaccharides with ChiEn1, rather than that with ChiIII. These results indicate that chitin polymers are first degraded into chitin oligosaccharides by ChiIII and the latter are further degraded to monomers and dimers by ChiEn1, and the synergistic action of ChiEn1 and ChiIII is involved in the efficient degradation of chitin in cell walls during pileus autolysis. The structure modeling explores the molecular base of ChiEn1 action.

A putative class III endochitinase (ChiIII) was reported previously to be expressed dominantly in fruiting bodies of Coprinopsis cinerea, and its expression levels increased with the maturation of the fruiting bodies. This paper further reports that ChiIII is a novel chitinase with exo- and endoactivities. When the substrate was (GlcNAc)3-5, ChiIII exhibited exoactivity, releasing GlcNAc processively from the reducing end of (GlcNAc)3-5; when the substrate was (GlcNAc)6-7, the activity of ChiIII shifted to an endoacting enzyme, randomly splitting chitin oligosaccharides to various shorter oligosaccharides. This shift in the mode of action of ChiIII may be related to its stronger hydrolytic capacity to degrade chitin in fungal cell walls. The predicted structure of ChiIII shows that it lacks the α+β domain insertion; however, its substrate binding cleft seems to be deeper than that of common endochitinases but shallower and more open than that of common exochitinases, which may be related to its exo- and endohydrolytic activities.

Upconversion nanoparticles (UCNPs) possess several unique features, but they suffer from surface quenching effects caused by the interaction between the UCNPs and fluorophore. Thus, the use of UCNPs for target-induced emission changes for biosensing and bioimaging has been challenging. In this work, fluorophore and UCNPs are effectively separated by a silica transition layer with a thickness of about 4 nm to diminish the surface quenching effect of the UCNPs, allowing a universal and efficient luminescence resonance energy transfer (LRET) ratiometric upconversion luminescence nanoplatform for biosensing applications. A pH-sensitive fluorescein derivative and Hg(2+)-sensitive rhodamine B were chosen as fluoroionphores to construct the LRET nanoprobes. Both showed satisfactory target-triggered ratiometric upconversion luminescence responses in both solution and live cells, indicating that this strategy may find wide applications in the design of nanoprobes for various biorelated targets.

Pyrene excimer possesses a large Stokes shift and long fluorescence lifetime and has been widely applied in developing time-resolved biosensing systems to solve the autofluorescence interference problems in biological samples. However, only a few of pyrene excimer-based small molecular probes have been reported so far. Ratiometric probes, on the other hand, can eliminate interferences from environmental factors such as instrumental efficiency and environmental conditions by a built-in correction of the dual emission bands but are ineffective for endogenous autofluorescence in biosystems. In this work, by combining the advantages of time-resolved fluorescence technique with ratiometric probe, we reported a bispyrene-fluorescein hybrid FRET cassette (PF) as a novel ratiometric time-resolved sensing platform for bioanalytical applications, with pH chosen as a biorelated target. The probe PF showed a fast, highly selective, and reversible ratiometric fluorescence response to pH in a wide range from 3.0 to 10.0 in buffered solution. By employing time-resolved fluorescence technique, the pH-induced fluorescence signal of probe PF can be well-discriminated from biological autofluorescence background, which enables us to detect pH in a range of 4.0-8.0 in cell media within a few seconds. It has also been preliminarily applied for ratiometric quantitative monitoring of pH changes in living cells with satisfying results. Since many fluorescein-based fluorescence probes have been developed, our strategy might find wide applications in design ratiometric time-resolved probes for detection of various biorelated targets.

A formal synthesis of cephalotaxine, the parent member of the Cephalotaxus alkaloids, was achieved. It features a practical four-step assembly of the benzazepine-bearing pentacyclic ring system through two alkylation reactions, acidic hydrolysis, and aldolization.

Fluorescence resonance energy transfer (FRET) strategy has been widely applied in designing ratiometric probes for bioimaging applications. Unfortunately, for FRET systems, sufficiently large spectral overlap is necessary between the donor emission and the acceptor absorption, which would limit the resolution of double-channel images. The through-bond energy transfer (TBET) system does not need spectral overlap between donor and acceptor and could afford large wavelength difference between the two emissions with improved imaging resolution and higher energy transfer efficiency than that of the classical FRET system. It seems to be more favorable for designing ratiometric probes for bioimaging applications. In this paper, we have designed and synthesized a coumarin-rhodamine (CR) TBET system and demonstrated that TBET is a convenient strategy to design an efficient ratiometric fluorescent bioimaging probe for metal ions. Such TBET strategy is also universal, since no spectral overlap between the donor and the acceptor is necessary, and many more dye pairs than that of FRET could be chosen for probe design. As a proof-of-concept, Hg(2+) was chosen as a model metal ion. By combining TBET strategy with dual-switch design, the proposed sensing platform shows two well-separated emission peaks with a wavelength difference of 110 nm, high energy transfer efficiency, and a large signal-to-background ratio, which affords a high sensitivity for the probe with a detection limit of 7 nM for Hg(2+). Moreover, by employing an Hg(2+)-promoted desulfurization reaction as recognition unit, the probe also shows a high selectivity to Hg(2+). All these unique features make it particularly favorable for ratiometric Hg(2+) sensing and bioimaging applications. It has been preliminarily used for a ratiometric image of Hg(2+) in living cells and practical detection of Hg(2+) in river water samples with satisfying results.

We present in this report the development of a convergent and highly stereocontrolled cycloaddition strategy toward the synthesis of C-1, C-6, and C-14 tris-oxygenated eudesmane sesquiterpenoids. This approach was demonstrated in the first total synthesis of (±)-6β,14-epoxyeudesm-4(15)-en-1β-ol (1), a structurally unique ethereal eudesmane sesquiterpenoid, via an effective Diels-Alder construction of a compact functionalized tricycle intermediate from readily available N-benzylfurfurylamine (2) and homoprenyl maleic anhydride (3) as the C(5) and C(10) building blocks, respectively.

On the basis of the n-acenes (n = 1, 2, 3 and 4), the α-Li@n-acenes and β-Li@n-acenes salts were selected to investigate how increasing the number n of conjugated benzenoid rings affects the linear and nonlinear optical responses. The α-Li@n-acenes and β-Li@n-acenes salts are obtained by a lithium atom substituting the α-H and β-H, respectively. In the present work, both ab initio (HF and MP2) and DFT (B3LYP, BhandHLYP, M05-2X, and CAM-B3LYP) methods are adopted to calculate the polarizability (α(0)) and first hyperpolarizability (β(tot)) of the α-Li@n-acenes and β-Li@n-acenes salts. MP2 results show that the α(0) values of both classes of lithium salts increase with increasing number n of conjugated benzenoid rings. Interestingly, we found that the β(tot) values of α-Li@n-acenes and β-Li@n-acenes salts take on opposite trends: the β(tot) values of α-Li@n-acenes are decreasing slowly (2187 for α-Li@benzene > 1978 for α-Li@naphthalene > 1898 for α-Li@anthrecene > 1830 au for α-Li@tetracene) and inceasing remarkably (2738 for β-Li@naphthalene < 3186 for β-Li@anthrecene < 3314 au for β-Li@tetracene) for β-Li@n-acenes. Furthermore, we found that the β(tot) values (2738-3314 au) of the β-Li@n-acenes are larger than those of the α-Li@n-acenes (1830-2187 au). On the other hand, comparing the results of different methods, the β(tot) values obtained by the M05-2X and CAM-B3LYP methods reproduce the polarizability and first hyperpolarizability of the α-Li@n-acenes and β-Li@n-acenes salts well, which test and verify the results of the MP2 method. Our present work may be beneficial to development of high-performance organic NLO optical materials.

In a continuing study on discovery of more potent derivatives of sinomenine (1), a clinically available alkaloid for rheumatoid arthritis (RA) treatment, oxidation of sinomenine provided two unique stereoisomers, disinomenines 2 and 3. The structure of 3 was determined by MS, NMR, and X-ray analysis. The formation of 2 and 3 via oxidation of sinomenine by potassium permanganate (KMnO4) exhibited a pH-dependent stereoselectivity. The bioassay results using human synovial sarcoma cells (SW982) showed that 2 inhibited, while 3 stimulated, IL-6 production.