Ultrasensitive Electrochemiluminescence Biosensor with ZIF-67@MXene as an Efficient Co-Reaction Accelerator and Plasmonic Nanozyme as a Smart Signal Amplification Probe.

Exploring novel electrochemiluminescence (ECL) co-reaction accelerators to construct ultrasensitive sensing systems is a prominent focus for developing advanced ECL sensors. However, challenges still remain in finding highly efficient accelerators and understanding their promoting mechanisms. In this paper, ZIF-67@MXene nanosheet composites, with highly conductive in-plane structure and confined-stable pore/channel, are designed to act as high-efficient co-reaction accelerators and achieve a significant enhancement in the luminol-H2O2 based ECL system. Mechanism investigation suggests that hydroxyl radicals (·OH) and singlet oxygen (1O2) can be selectively and preferentially generated on ZIF-67@MXene due to the stable and efficient absorption of ·OH and 1O2, leading to a remarkable enhancement in the ECL efficiency of luminol (830%). Finally, by designing a plasmonic NH2-MIL-88@Pd nanozyme, an "on-off" switch immunosensor is constructed for the detection of prostate-specific antigen (PSA). Based on the multiple signal amplification effect, the linear detection range for PSA is expanded by three orders of magnitude. The detection limit is also improved from 1.44 × 10-11 to 9.1 × 10-13 g mL-1. This work proposes an effective method for the preparation of highly efficient co-reaction accelerators and provides a new strategy for the sensitive detection of cancer markers.

Exploring a Non-Comfort Zone: Central Chirality-Generating Macrocyclizations.

Macrocyclization reactions that are capable of stereoselectively co-creating one or more stereogenic centers have become useful strategies for the effective syntheses of structurally and functionally diverse organic molecules. This JOCSynopsis summarizes the recent progress in the field of natural product and analogue syntheses, including both bioinspired and non-bioinspired macrocyclic disconnections. Selected examples are organized on the basis of the sources of the asymmetric inductions.

Self-Assembled FeIII-TAML-Based Magnetic Nanostructures for Rapid and Sustainable Destruction of Bisphenol A.

This study focused on constructing iron(III)-tetraamidomacrocyclic ligand (FeIII-TAML)-based magnetic nanostructures via a surfactant-assisted self-assembly (SAS) method to enhance the reactivity and recoverability of FeIII-TAML activators, which have been widely employed to degrade various organic contaminants. We have fabricated FeIII-TAML-based magnetic nanomaterials (FeIII-TAML/CTAB@Fe3O4, CTAB refers to cetyltrimethylammonium bromide) by adding a mixed solution of FeIII-TAML and NH3·H2O into another mixture containing CTAB, FeCl2 and FeCl3 solutions. The as-prepared FeIII-TAML/CTAB@Fe3O4 nanocomposite showed relative reactivity compared with free FeIII-TAML as indicated by decomposition of bisphenol A (BPA). Moreover, our results demonstrated that the FeIII-TAML/CTAB@Fe3O4 composite can be separated directly from reaction solutions by magnet adsorption and reused for at least four times. Therefore, the efficiency and recyclability of self-assembled FeIII-TAML/CTAB@Fe3O4 nanostructures will enable the application of FeIII-TAML-based materials with a lowered expense for environmental implication.

New Indole Derivative Heterogeneous System for the Synergistic Reduction and Oxidation of Various Per-/Polyfluoroalkyl Substances: Insights into the Degradation/Defluorination Mechanism.

The hydrated electron (eaq-) system is typically suitable for degrading perfluoroalkyl substances (PFASs). To enhance eaq- utilization, we synthesized a new indole compound (DIHA) that forms stable nanospheres (100-200 nm) in water via a supramolecular assembly. Herein, the DIHA nanoemulsion system exhibits high degradation efficiencies toward a broad category of PFASs, regardless of the headgroup, chain length, and branching structure, under UV (254 nm) irradiation. The strong adsorption of PFAS on the DIHA surface ensures its effective degradation/defluorination. Quenching experiments further demonstrated that the reaction took place on the surface of DIHA nanospheres. This specific heterogeneous surface reaction unveiled novel PFAS degradation and defluorination mechanisms that differ from previously reported eaq- systems. First, the photogenerated surface electrons nonselectively attacked multiple C-F bonds of the -CF2- chain. This plays a dominant degrading/defluorinating role in the DIHA system. Second, abundant hydroxyl radicals (•OH) were also produced, leading to synergistic reduction (by surface electron) and oxidation (by surface •OH) in a single system. This facilitates faster and deeper defluorination of different structured PFASs through multiple pathways. The new mechanism inspires the design of innovative organo-heterogeneous eaq- systems possessing synergistic reduction and oxidation functions, thereby making them potentially effective for treating PFAS-contaminated water.

Atractylodes Processing Products Protect against Gastric Ulcers in Rats by Influencing the NF-κB-MMP-9/TIMP-1 Regulatory Mechanism and Intestinal Flora.

Atractylodes macrocephala Koidz. (AM) is a Chinese herbal medicine that is widely used for treating gastrointestinal diseases. However, little research has focused on it as a single medicine for treating gastric ulcers. Honey-bran stir-frying is a characteristic method of concocting AM, so we speculated that AM is more effective after this preparation process. Analysis by ultra-high-performance liquid chromatography-hybrid quadrupole-Orbitrap high-resolution mass spectrometry revealed changes in the chemical composition of raw Atractylodes (SG), bran-fried Atractylodes (FG), and honey-bran-fried Atractylodes (MFG). MFG was superior to SG and FG in improving the pathological structure of gastric tissue in rats with acute gastric ulcers, reducing inflammatory cell infiltration in gastric tissue, and significantly reducing malondialdehyde while increasing superoxide dismutase and glutathione peroxidase, and reducing the damage caused by free radical accumulation in the gastric mucosa. In addition, MFG reduced the expression of matrix metalloproteinase-9 (MMP-9), an inhibitor of metalloproteinase-1 (TIMP-1) and nuclear factor kappa-B (NF-κB)proteins, inhibited inflammatory response, and regulated the degradation and rebalancing of the extracellular matrix. Fecal microbiota analysis also revealed that MFG normalized the intestinal flora to some extent. Our study shows that AM had a protective effect on rats with alcohol-induced acute gastric ulcers before and after processing, and AM-processed products were more effective than raw ones. Compared with MF, MFG had a higher rate of ulcer inhibition and a stronger anti-inflammatory effect, and its mechanism of action was related to the NF-κB-MMP-9/TIMP-1 signaling pathway.

A Subtle Change in the Flexible Achiral Spacer Does Matter in Supramolecular Chirality: Two-Fold Odd-Even Effect in Polymer Assemblies.

Precise control over the chirality and morphologies of polymer assemblies, a remaining challenge for both chemists and materials scientists, is receiving ever-increasing attention in the recent years. Herein, we report the subtle manipulation of the achiral spacers from the chiral stereocenter to the azobenzene (Azo) unit, of which the chiroptical consistency or chiroptical inversion of self-assemblies could be successfully controlled and present "two-fold" odd-even effect. Furthermore, morphological transitions from 0D spherical micelles, 1D worms, and nanowires to 3D vesicles, spindle- and dumbbell-shaped vesicles were also unexpectedly found to exhibit odd-even correlations. These observations were collectively elucidated by mesomorphic properties, stacking modes, chiroptical dynamics, and stimuli-responsive behaviors. Negligible modifications to the spacer structures can enable remarkable modulation of supramolecular chirality and anisotropic topologies in polymer assemblies, which is of great significance for the design of complex chiral functional polymers.

The Fruit of Gold: Biomimicry in the Syntheses of Lankacidins.

Natural products are constructed by organisms in impressive ways through various highly selective enzyme-catalyzed chemical reactions. Over the past century, there has been considerable interest in understanding and emulating the underlying biosynthetic logic for the target molecule. The successful implementation of a biomimetic strategy usually has some uniquely valuable benefits over other abiotic routes in total synthesis by (1) corroborating the chemical feasibility of a given biogenetic hypothesis and further unraveling some insightful implications for future biosynthetic studies and (2) providing remarkably more concise access to not only the original synthetic target but also diversified biogenetically related congeners, which may result in either the structural reassignment of previously disclosed natural products or the anticipation of undiscovered natural products. However, for the devised essential biomimetic transformation, fine-tuning the optimization of the substrates and the reaction conditions can sometimes be painstakingly challenging. Turning to nature for inspiration can provide additional impetus for methodological innovations.Previously used as oral veterinary drugs, lankacidins have potential as next-generation antibiotics to tackle the problems caused by multidrug-resistant bacteria with novel modes of action (MoAs). The hypersensitive and densely functionalized lactonic core within this family of macrocyclic polyketides poses a formidable challenge for chemical total synthesis and derivatization. In this account, we summarized the evolution of a unified biomimetic approach toward 10 lankacidin antibiotics and their linear biosynthetic intermediates in the longest linear 7-12 steps from readily available starting materials. Our endeavor commenced with an intermolecular bioinspired amido sulfone-based Mannich reaction approach to assemble 2 advanced fragments under mild biphasic organocatalytic conditions. It successfully gave rise to stereodivergent access to 4 C2/C18-isomeric lankacyclinols but failed to efficiently deliver lactone-containing congeners through Stille macrocyclization. Facilitated by the thermolysis chemistry of N,O-acetal to generate the requisite N-acyl-1-azahexatriene species, we realized the projected Mannich macrocyclization and eight macrocyclic lankacidins can be produced by orchestrated desilylative manipulations. In this process, we were able to perform structural reassignments of isolankacidinol (7 to 50) and isolankacyclinol (104 to 83) and, for the first time, elucidate the natural occurrence of 2,18-bis-epi-lankacyclinol (84). Moreover, the inability of the current biomimetic route to cofurnish the reported structure of 2,18-seco-lankacidinol A (15) triggered a proposed structural revision that is rooted in reconsidered biogenesis and was confirmed by a divergent synthesis that enabled us to identify the correct isomer (116). Finally, the modular, diversity-oriented design also provided streamlined entries to acyclic 2,18-seco-lankacidinol B (120) and the biosynthetic intermediate LC-KA05 (17) together with its C7-O-deacetylated congeners in all C4/C5-stereochemical variations (18, 127-129), culminating in a need for structural revision to the six-membered lactonic segment in LC-KA05-2. The selection and execution of biomimetic strategies in lankacidin total synthesis give rise to all the previously mentioned advantages at the current stage. The modular-based, late-stage diversified complex construction offers an exceptionally high level of synthetic flexibility for future synthetic forays toward newly isolated or chemically modified congeners within the lankacidin family.

A Bridge to Alkaloid Synthesis.

The construction of a structurally rigid architecture with chiral complexity, necessary to enhance the interaction with binding sites of drug targets, has been adapted as an intriguing approach in drug development. In the past few years, we have been interested in the synthesis of biologically significant and bridged alkaloids via novel synthetic methods and strategies based on recognition of the privileged pattern. Therefore, nitroso-ene and aza-Wacker cyclizations were elevated for the first time to construct bridged alkaloids, such as hosieine A, kopsone, melinonine-E and strychnoxanthine. Mechanistic investigations, including computational calculations for nitroso-ene reaction and deuterated experiments for aza-Wacker reaction, enable us to gain more insights into the chemical reactivity and selectivity of specific functional groups in developing viable synthetic methods.

Giant cell tumor of soft tissue of the colon: a case report and review of the literature.

BACKGROUND: A giant cell tumor (GCT) is a benign neoplasm characterized by mixture of mononuclear cells and multinucleated cells. A GCT of soft tissue (GCT-ST) is developed in various extraosseous sites, but GCT-ST of the gastrointestinal tract is very rare. GCT-ST usually has a benign course, but rare cases reported malignant potential of the tumor. Therefore, complete resection is required to prevent local recurrence or distant metastasis. CASE PRESENTATION: A 53-year-old woman was admitted for follow-up colonoscopy who underwent the colorectal endoscopic submucosal dissection (ESD) of a laterally spreading tumor at the hepatic flexure 6 months ago. A colonoscopy showed a polypoid mass about 3.5 × 2.5 cm at the previous ESD site. As endoscopic finding showed a smooth multi-nodular tumor without submucosal invasion, we performed endoscopic mucosal resection. Based on pathological and immunohistochemical findings, the lesion was diagnosed as a GCT-ST in the colon. Follow-up colonoscopy performed 6 months later revealed no evidence of recurrence. CONCLUSION: This is the first report of a GCT-ST identified in the colon. Although GCT-ST generally has a benign clinical course, complete resection should be performed to prevent local recurrence and metastasis.

Potent Antibiotic Lemonomycin: A Glimpse of Its Discovery, Origin, and Chemical Synthesis.

Lemonomycin (1) was first isolated from the fermentation broth of Streptomyces candidus in 1964. The complete chemical structure was not elucidated until 2000 with extensive spectroscopic analysis. Lemonomycin is currently known as the only glycosylated tetrahydroisoquinoline antibiotic. Its potent antibacterial activity against Staphylococcus aureus and Bacillus subtilis and complex architecture make it an ideal target for total synthesis. In this short review, we summarize the research status of lemonomycin for biological activity, biosynthesis, and chemical synthesis. The unique deoxy aminosugar-lemonose was proposed to play a crucial role in biological activity, as shown in other antibiotics, such as arimetamycin A, nocathiacin I, glycothiohexide α, and thiazamycins. Given the self-resistance of the original bacterial host, the integration of biosynthesis and chemical synthesis to pursue efficient synthesis and further derivatization is in high demand for the development of novel antibiotics to combat antibiotic-resistant infections.

A High-Throughput Screening Method for the Directed Evolution of Hydroxynitrile Lyase towards Cyanohydrin Synthesis.

Chiral cyanohydrins are useful intermediates in the pharmaceutical and agricultural industries. In nature, hydroxynitrile lyases (HNLs) are a kind of elegant tool for enantioselective hydrocyanation of carbonyl compounds. However, currently available methods for demonstrating hydrocyanation are still stalled at precise, but low-throughput, GC or HPLC analyses. Herein, we report a chromogenic high-throughput screening (HTS) method that is feasible for the cyanohydrin synthesis reaction. This method was highly anti-interference and sensitive, and could be used to directly profile the substrate scope of HNLs either in cell-free extract or fermentation clear broth. This HTS method was also validated by generating new variants of PcHNL5 that presented higher catalytic efficiency and stronger acidic tolerance in variant libraries.

Stereodivergent Synthesis of Lankacyclinol and Its C2/C18-Congeners Enabled by a Bioinspired Mannich Reaction.

Lankacidin-group antibiotics are complex polyketides typically with a synthetically challenging 17-membered carbocyclic ring. Herein we evolved an alternative palladium-catalyzed coupling-based strategy for constructing this structural moiety. After assembling the two advanced fragments under basic conditions in a biphasic system, of the four possible Mannich adducts, two separable adducts bearing identical C2-stereochemistries were formed in high combined yields, and the ratio of them can be altered by changing the reaction conditions from dichloromethane and 23 °C (18R/18S, 1.5:1) to toluene and 100 °C (18R/18S, 1:3.5). Subsequent base-promoted decarboxylation at lower temperatures unexpectedly favored the formation of the 2,18-anti product, which is less accessible via the reaction carried out on known macrocyclic substrates. All four biosynthetically related C2/C18-isomeric lankacyclinols can be smoothly yielded after Stille macrocyclization, followed by global desilylation. The antimycobacterial activity of the synthetic lankacyclinols and several macrolatonic congeners were preliminarily evaluated.

Chemoselective synthesis of 5,4'-imidazolinyl spirobarbiturates via NBS-promoted cyclization of unsaturated barbiturates and amidines.

A selective cyclization of unsaturated barbiturates and amidines promoted by N-bromosuccinimide has been successfully developed to afford a vast variety of 5,4'-imidazolinyl spirobarbiturates in moderate to good yields. The present protocol features broad substrate scope, facile work-up procedure and mild reaction conditions, providing a novel strategy for the highly selective and efficient construction of structurally diverse spiroimidazolines.

Landscape of Lankacidin Biomimetic Synthesis: Structural Revisions and Biogenetic Implications.

In this report, a unified biomimetic approach to all known macrocyclic lankacidins is presented. By taking advantage of the thermolysis of N,O-acetal to generate the requisite N-acyl-1-azahexatriene species, we eventually realized the biomimetic Mannich macrocyclization, from which all of the macrocyclic lankacidins can be conquered by orchestrated desilylation. The reassignments of the reported structures of isolankacidinol (7 to 10) and the discovery of a recently isolated "lankacyclinol" found to be in fact 2,18-bis-epi-lankacyclinol (72) unraveled the previously underappreciated chemical diversity exhibited by the enzymatic macrocyclization. In addition, the facile elimination/decarboxylation/protonation process for the depletion of C1 under basic conditions resembling a physiological environment may implicate more undiscovered natural products with variable C2/C18 stereochemistries (i.e., 62, 73, and 75). The notable aspect provided by a biomimetic strategy is significantly reducing the step count compared with the two previous entries to macrocyclic lankacidins.

A highly sensitive electrochemical biosensor for protein based on a tetrahedral DNA probe, N- and P-co-doped graphene, and rolling circle amplification.

A tetrahedral DNA probe can effectively overcome the steric effects of a single-stranded probe to obtain well-controlled density and minimize nonspecific adsorption. Herein, a highly sensitive electrochemical biosensor is fabricated for determination of protein using a tetrahedral DNA probe and rolling circle amplification (RCA). N- and P-co-doped graphene (NP-rGO) is prepared, and AuNPs are then electrodeposited on it for DNA probe immobilization. Benefitting from the synergistic effects of the excellent electrical conductivity of NP-rGO, the stability of the tetrahedral DNA probe and the signal amplification of RCA, the biosensor achieves a low limit of 3.53 × 10-14 M for thrombin and a wide linear range from 1 × 10-13 to 1 × 10-7 M. This study provides a sensitive and effective method for the detection of protein in peripheral biofluids, and paves the way for future clinical diagnostics and treatment of disease. Graphical abstract.

Stereoconfining macrocyclizations in the total synthesis of natural products.

Covering: selected examples in the past three decades (up to 2018) The challenging structures and often potent biological activities of naturally occurring macrocycles have attracted much attention among the synthetic community. In a typical retrosynthetic disconnection, commonly used macrocyclization tactics, including macrolactonization, macrolactamization, ring-closing metathesis, olefination, and metal-mediated cross-coupling reactions, are invariably based on linear substrates in which all of the stereogenic centers have already been set forth. Macrocyclizations with the simultaneous installation of the requisite stereogenic centers can be advantageous with respect to a broader substrate spectrum as well as a usually higher overall synthetic efficiency. However, achieving predictably high levels of stereocontrol remains a formidable challenge. In this review, we discuss representative examples of those "nonclassic" macrocyclization strategies in the context of natural product total synthesis. Different types of macrocycle-forming methods are summarized, with a particular focus on the sense of diastereoinduction imparted through the transition-state macrocyclic ring architecture (≥12-membered) or the catalyst.

Efficacy and safety of vortioxetine for the treatment of major depressive disorder: a randomised double-blind placebo-controlled study.

Objective: This study aimed to evaluate the efficacy and adverse events of vortioxetine for Chinese patients with major depressive disorder (MDD) over 10 weeks.Methods: A total of 120 patients with MDD were randomly assigned to two groups that received vortioxetine 20 mg or placebo for 10 weeks. The outcomes were the change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HAM-A), Clinical Global Impressions-Improvement (CGI-I) scale, Sheehan Disability Scale (SDS) at Week 10, and the presence of adverse events.Results: A total of 113 patients completed the study. Vortioxetine showed greater efficacy than the placebo in improving MADRS, HAM-A, CGI-I, and SDS scores at Week 10. However, no significant differences were found between the groups for any treatment-emergent adverse events. No suicide related to vortioxetine treatment was recorded.Conclusions: In summary, the results of this study showed that 10 weeks of vortioxetine treatment was efficacious and well-tolerated in patients with MDD.

Gene Regulatory Networks for the Haploid-to-Diploid Transition of Chlamydomonas reinhardtii.

The sexual cycle of the unicellular Chlamydomonas reinhardtii culminates in the formation of diploid zygotes that differentiate into dormant spores that eventually undergo meiosis. Mating between gametes induces rapid cell wall shedding via the enzyme g-lysin; cell fusion is followed by heterodimerization of sex-specific homeobox transcription factors, GSM1 and GSP1, and initiation of zygote-specific gene expression. To investigate the genetic underpinnings of the zygote developmental pathway, we performed comparative transcriptome analysis of both pre- and post-fertilization samples. We identified 253 transcripts specifically enriched in early zygotes, 82% of which were not up-regulated in gsp1 null zygotes. We also found that the GSM1/GSP1 heterodimer negatively regulates the vegetative wall program at the posttranscriptional level, enabling prompt transition from vegetative wall to zygotic wall assembly. Annotation of the g-lysin-induced and early zygote genes reveals distinct vegetative and zygotic wall programs, supported by concerted up-regulation of genes encoding cell wall-modifying enzymes and proteins involved in nucleotide-sugar metabolism. The haploid-to-diploid transition in Chlamydomonas is masterfully controlled by the GSM1/GSP1 heterodimer, translating fertilization and gamete coalescence into a bona fide differentiation program. The fertilization-triggered integration of genes required to make related, but structurally and functionally distinct organelles-the vegetative versus zygote cell wall-presents a likely scenario for the evolution of complex developmental gene regulatory networks.

Extracellular acidity enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis via DR5 in gastric cancer cells.

The tumor microenvironment greatly influences cancer cell characteristics, and acidic extracellular pH has been implicated as an essential factor in tumor malignancy and the induction of drug resistance. Here, we examined the characteristics of gastric carcinoma (GC) cells under conditions of extracellular acidity and attempted to identify a means of enhancing treatment efficacy. Acidic conditions caused several changes in GC cells adversely affecting chemotherapeutic treatment. Extracellular acidity did inhibit GC cell growth by inducing cell cycle arrest, but did not induce cell death at pH values down to 6.2, which was consistent with down-regulated cyclin D1 and up-regulated p21 mRNA expression. Additionally, an acidic environment altered the expression of atg5, HSPA1B, collagen XIII, collagen XXAI, slug, snail, and zeb1 genes which are related to regulation of cell resistance to cytotoxicity and malignancy, and as expected, resulted in increased resistance of cells to multiple chemotherapeutic drugs including etoposide, doxorubicin, daunorubicin, cisplatin, oxaliplatin and 5-FU. Interestingly, however, acidic environment dramatically sensitized GC cells to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Consistently, the acidity at pH 6.5 increased mRNA levels of DR4 and DR5 genes, and also elevated protein expression of both death receptors as detected by immunoblotting. Gene silencing analysis showed that of these two receptors, the major role in this effect was played by DR5. Therefore, these results suggest that extracellular acidity can sensitize TRAIL-mediated apoptosis at least partially via DR5 in GCs while it confers resistance to various type of chemotherapeutic drugs.

An Enantioconvergent and Concise Synthesis of Lasonolide†A.

Efficient access to medicinally significant natural products is an essential basis for the development of pharmaceuticals. The limited availability of marine natural products impedes broad biological evaluation. Despite several elegant syntheses of (-)-lasonolide A having been reported, a practical synthesis of this potent anticancer polyketide remains elusive. Based on the application of borane as a traceless protecting group and the development of an unprecedented bissulfone reagent for Julia olefination, (-)-lasonolide A was assembled in an enantioconvergent manner through the application of stereoselective hydroboration, allylation, and oxidation. This concise route may provide a realistic solution for accessing derivatives and analogues.