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The direct construction of bioisosteric compounds enriched in Csp3 content represents an attractive and dependable approach to imbuing biologically active molecules with enhanced three-dimensional characteristics, finding wide utility across the synthetic and medicinal chemistry community. Despite recent advancements in the synthesis of (aza)-bicyclo[3.1.1]heptanes (BCHeps and aza-BCHeps), which serve as meta-substituted (aza)-arene bioisosteres, the enantioselective assembly of chiral 3-aza-BCHeps remains a coveted goal yet to be achieved. Here, we disclose an unprecedented copper-catalyzed asymmetric formal [4π+2σ] cycloaddition of bicyclo[1.1.0]butanes (BCBs) and azomethine ylides, furnishing a diverse array of enantioenriched 3-aza-BCHeps with exceptional levels of diastereo- and enantioselectivites (51 examples, all >20:1 dr, mostly 97-99% ee). Both mono- and disubstituted BCBs are well compatible with this protocol, offering an enticing route for the efficient synthesis of challenging tetrasubstituted bicyclic products bearing two quaternary centers. The synthetic significance of this methodology is further demonstrated by the successful preparation of several piperidine drug analogues.
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Chiral eight-membered heterocycles comprise a diverse array of natural products and bioactive compounds, yet accessing them poses significant challenges. Here we report a gold-catalyzed stereoselective (4 + 4) cycloaddition as a reliable and divergent strategy, enabling readily accessible precursors (anthranils and ortho-quinone methides) to be intercepted by in situ generated gold-furyl 1,4-dipoles, delivering previously inaccessible chiral furan/pyrrole-containing eight-membered heterocycles with good results (56 examples, all >20 : 1 dr, up to 99% ee). Moreover, we achieve a remarkably efficient kinetic resolution (KR) process (s factor up to 747). The scale-up synthesis and diversified transformations of cycloadducts highlight the synthetic potential of this protocol. Computational calculations provide an in-depth understanding of the stereoselective cycloaddition process.
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ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese herb Panax notoginseng (PN) tonifies blood, and its main active ingredient is saponin. PN is processed by different methods, resulting in different compositions and effects. AIM OF THE STUDY: To investigate changes in the microstructure and composition of fresh PN processed by different techniques and the anti-anemia effects on tumor-bearing BALB/c mice after chemotherapy with cyclophosphamide (CTX). MATERIALS AND METHODS: Fresh PN was processed by hot-air drying (raw PN, RPN), steamed at 120 °C for 5 h (steamed PN, SPN), or fried at 130 °C, 160 °C, or 200 °C for 8 min (fried PN, FPN1, FPN2, or FPN3, respectively); then, the microstructures were compared with 3D optical microscopy, quasi-targeted metabolites were detected by liquid chromatography tandem mass spectrometry (LCâMS/MS), and saponins were detected by high-performance liquid chromatography (HPLC). An anemic mouse model was established by subcutaneous H22 cell injection and treatment with CTX. The antianemia effects of PN after processing via three methods were investigated by measuring peripheral blood parameters, performing HE staining and measuring cell proliferation via immunofluorescence. RESULTS: 3D optical profiling revealed that the surface roughness of the SPN and FPN was greater than that of the other materials. Quasi-targeted metabolomics revealed that SPN and FPN had more differentially abundant metabolites whose abundance increased, while SPN had greater amounts of terpenoids and flavones. Analysis of the composition and content of the targeted saponins revealed that the contents of rare saponins (ginsenoside Rh1, 20(S)-Rg3, 20(R)-Rg3, Rh4, Rk3, Rg5) were greater in the SPN. In animal experiments, the RBC, WBC, HGB and HCT levels in peripheral blood were increased by SPN and FPN. HE staining and immunofluorescence showed that H-SPN and M-FPN promoted bone marrow and spleen cell proliferation. CONCLUSION: The microstructure and components of fresh PN differed after processing via different methods. SPN and FPN ameliorated CTX-induced anemia in mice, but the effects of PN processed by these two methods did not differ.
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Anemia , Ciclofosfamida , Ratones Endogámicos BALB C , Panax notoginseng , Saponinas , Animales , Ciclofosfamida/toxicidad , Panax notoginseng/química , Ratones , Saponinas/farmacología , Anemia/inducido químicamente , Anemia/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Masculino , Línea Celular Tumoral , FemeninoRESUMEN
Limb ischemia is a refractory disease characterized by persistent inflammation, insufficient angiogenesis, and tissue necrosis. Although mesenchymal stem cells (MSCs) have shown potential for treating limb ischemia, their therapeutic effects are limited by low engraftment rates. Therefore, developing an optimal MSC delivery system that enhances cell viability is imperative. Selenium, known for its cytoprotective properties in various cell types, offers a potential strategy to enhance therapeutic effect of MSCs. In this study, we evaluated the cytoprotective effects of selenium on MSCs, and developed an injectable thermosensitive selenium-containing hydrogel based on PLGA-PEG-PLGA triblock copolymer, as a cell carrier to improve MSC viability after engraftment. The biocompatibility, biodegradability, and cytoprotective capabilities of selenium-containing hydrogels were assessed. Furthermore, the therapeutic potential of MSCs encapsulated within a thermosensitive selenium-containing hydrogel in limb ischemia was evaluated using cellular and animal experiments. Selenium protects MSCs from oxidative damage by upregulating GPX4 through a transcriptional mechanism. The injectable thermosensitive selenium-containing hydrogel exhibited favorable biocompatibility, biodegradability, and antioxidant properties. It can be easily injected into the target area in liquid form at room temperature and undergoes gelation at body temperature, thereby preventing the diffusion of selenium and promoting the cytoprotection of MSCs. Furthermore, MSCs encapsulated within the selenium-containing hydrogel effectively inhibited macrophage M1 polarization while promoting macrophage M2 polarization, thus accelerating angiogenesis and restoring blood perfusion in ischemic limbs. This study demonstrated the potential of an injectable thermosensitive selenium-containing hydrogel as a promising method for MSC delivery. By addressing the challenge of low retention rate, which is a major obstacle in MSC application, this strategy effectively improves limb ischemia.
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Hematopoietic stem cells (HSC) are primarily dormant in a cell-cycle quiescence state to preserve their self-renewal capacity and long-term maintenance. How HSC maintain the balance between activation and quiescence remains largely unknown. Herein, we found that phosphatase, Mg2+/Mn2+ dependent 1B (Ppm1b) is required for the expansion of phenotypic HSC in vitro. By using a conditional knockout mouse model in which Ppm1b was specifically depleted in hematopoietic cells, we demonstrated that loss of Ppm1b impaired the HSC homeostasis and hematopoietic reconstitution. Ppm1b deficiency mice also exhibited B-cell leukocytopenia, which is due to the compromised commitment and proliferation of B-biased lymphoid progenitor cells from common lymphoid progenitors. With the aid of a small molecular inhibitor, we confirmed the roles of Ppm1b in adult hematopoiesis that phenocopied the effects with loss of Ppm1b. Furthermore, transcriptome profiling of Ppm1b-deficient HSC revealed the disruptive quiescence of HSC. Mechanistically, Ppm1b interacted with ß-catenin and mediated its dephosphorylation. Loss of Ppm1b led to the decrease in the active ß-catenin (non-phosphorylated) that interrupted the Wnt/ß-catenin signaling in HSC, which consequently suppressed HSC expansion. Together, our study identified an indispensable role for Ppm1b in regulating HSC homeostasis via the Wnt/ß-catenin pathway.
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Células Madre Hematopoyéticas , Homeostasis , Ratones Noqueados , Proteína Fosfatasa 2C , Vía de Señalización Wnt , Animales , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/citología , Ratones , Proteína Fosfatasa 2C/metabolismo , Proteína Fosfatasa 2C/genética , beta Catenina/metabolismo , HematopoyesisRESUMEN
The enantioselective functionalization and transformation of readily available cyclopropyl compounds are synthetically appealing yet challenging topics in organic synthesis. Here we report an asymmetric ß-arylation of cyclopropanols with aryl bromides enabled by photoredox and nickel dual catalysis. This dual catalytic transformation features a broad substrate scope and good functional group tolerance at room temperature, providing facile access to a wide array of enantioenriched ß-aryl ketones bearing a primary alcohol moiety in good yields with satisfactory enantioselectivities (39 examples, up to 83% yield and 90% ee). The synthetic value of this protocol was illustrated by the concise asymmetric construction of natural product calyxolane B analogues.
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Idiopathic pulmonary fibrosis (IPF), a lethal respiratory disease with few treatment options, occurs due to repetitive microinjuries to alveolar epithelial cells (AECs) and progresses with an overwhelming deposition of extracellular matrix (ECM), ultimately resulting in fibrotic scars and destroyed the alveolar architecture. Here, an inhaled ribosomal protein-based mRNA nanoformulation is reported for clearing the intrapulmonary ECM and re-epithelializing the disrupted alveolar epithelium, thereby reversing established fibrotic foci in IPF. The nanoformulation is sequentially assembled by a ribosomal protein-condensed mRNA core, a bifunctional peptide-modified corona and keratinocyte growth factor (KGF) with a PEGylated shielding shell. When inhaled via a nebulizer, the nanoformulations carried by microdrops are deposited in the alveoli, and penetrate into fibrotic foci, where the outer KGFs are detached after matrix metalloproteinase 2 (MMP2) triggering. The RGD motif-grafted cores then expose and specifically target the integrin-elevated cells for the intracellular delivery of mRNA. Notably, repeated inhalation of the nanoformulations accelerates the clearance of locoregional collagen by boosting the intralesional expression of MMP13 and alveolar re-epithelialization mediated by KGFs, which synergistically ameliorates the lung function of a bleomycin-induced murine model. Therefore, this work provides an alternative mRNA-inhalation delivery strategy, which shows great potential for the treatment of IPF.
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Bleomicina , Fibrosis Pulmonar Idiopática , Animales , Bleomicina/farmacología , Modelos Animales de Enfermedad , Fibrosis Pulmonar Idiopática/inducido químicamente , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/genética , Metaloproteinasa 2 de la Matriz/genética , Ratones , ARN Mensajero , Proteínas RibosómicasRESUMEN
Background: Bone metastasis is a frequent symptom of breast cancer and current targeted therapy has limited efficacy. Osteoclasts play critical roles to drive osteolysis and metastatic outgrowth of tumor cells in bone. Previously we identified CST6 as a secretory protein significantly downregulated in bone-metastatic breast cancer cells. Functional analysis showed that CST6 suppresses breast-to-bone metastasis in animal models. However, the functional mechanism and therapeutic potential of CST6 in bone metastasis is unknown. Methods: Using in vitro osteoclastogenesis and in vivo metastasis assays, we studied the effect and mechanism of extracellular CST6 protein in suppressing osteoclastic niches and bone metastasis of breast cancer. A number of peptides containing the functional domain of CST6 were screened to inhibit bone metastasis. The efficacy, stability and toxicity of CST6 recombinant protein and peptides were evaluated in preclinical metastasis models. Results: We show here that CST6 inhibits osteolytic bone metastasis by inhibiting osteoclastogenesis. Cancer cell-derived CST6 enters osteoclasts by endocytosis and suppresses the cysteine protease CTSB, leading to up-regulation of the CTSB hydrolytic substrate SPHK1. SPHK1 suppresses osteoclast maturation by inhibiting the RANKL-induced p38 activation. Importantly, recombinant CST6 protein effectively suppresses bone metastasis in vitro and in vivo. We further identified several peptides mimicking the function of CST6 to suppress cancer cell-induced osteoclastogenesis and bone metastasis. Pre-clinical analyses of CTS6 recombinant protein and peptides demonstrated their potentials in treatment of breast cancer bone metastasis. Conclusion: These findings reveal the CST6-CTSB-SPHK1 signaling axis in osteoclast differentiation and provide a promising approach to treat bone diseases with CST6-based peptides.
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Catepsina B/metabolismo , Cistatina M/metabolismo , Animales , Neoplasias Óseas/secundario , Huesos/metabolismo , Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Catepsina B/efectos de los fármacos , Catepsinas/metabolismo , Línea Celular Tumoral , Cistatina M/genética , Femenino , Humanos , Macrófagos/metabolismo , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Metástasis de la Neoplasia/patología , Osteoclastos/efectos de los fármacos , Osteogénesis/fisiología , Osteólisis/patología , Transducción de Señal/efectos de los fármacosRESUMEN
We analytically and numerically study the different types of solitary wave in the two-component helicoidal spin-orbit coupled Bose-Einstein condensates (BECs). Adopting the multiscale perturbation method, we derive the analytical bright and dark solitary wave solutions of the system, and the stationary and moving bright (dark) solitary waves are obtained. The effects of spin-orbit coupling, the helicoidal gauge potential, the momentum, the Zeeman splitting, and the atomic interactions on the solitary wave types are discussed, and it is found that the coupling of these physical parameters can manipulate different types of solitary waves in the system. The results indicate that the helicoidal gauge potential breaks the symmetric properties of the energy band of the system and adjusts the energy band structure, thus further effecting the solitary wave properties, i.e., stationary or moving solitary wave, bright, or dark solitary wave. Correspondingly, the analytical predictions for exciting stationary or moving bright (dark) solitary wave in parameter space are obtained. In particular, the helicoidal gauge potential changes the solitary wave types drastically for the weak spin-orbit coupling, i.e., in the absence of the helicoidal gauge potential, only dark (bright) solitary wave solutions exist in the system with repulsive (attractive) atomic interaction; however, in the presence of the helicoidal gauge potential, both dark and bright solitary waves can exist in the system regardless of whether the atomic interaction is repulsive or attractive. In addition, we investigate the stability of solitary waves and obtain the stability regions of different types of solitary waves by applying the linear stability analysis. The dynamic evolution results of the solitary waves by the direct numerical simulation not only validate the linear stability analysis but also confirm the analytical prediction of the solitary waves. Finally, the collision effects between solitary waves are also presented by the numerical simulation. It is shown that the interactions between solitary waves in the system have both elastic and inelastic collisions, which are closely related to the position of solitary wave states in the linear energy band. Our results provide a potential way to adjust the types of solitary waves in BECs with helicoidal gauge potential.
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Benzofuran-derived azadienes (BDAs) have been widely used as four-atom synthons in transition-metal-mediated cycloaddition reactions, while the exploitation of their reactivity as a two-atom unit to construct spirocycles is still underdeveloped. Herein, we reported the first palladium(0)-catalyzed diastereo- and enantioselective [3 + 2] annulation of vinylcyclopropanes (VCPs) and BDAs. This transformation is featured with a broad substrate scope (31 examples), allowing for facile access to a variety of enantioenriched spirocycles bearing a quaternary stereogenic center in good yields with excellent regio-, diastereo-, and enantioselectivities (up to 93% yield, >20:1 dr, and mostly >99% ee) under mild reaction conditions. Moreover, the spirocyclic products could be efficiently converted to structurally complex tricyclo[8.3.0.01,5]-azatridecane and tricyclo[7.3.0.01,5]-azadodecane skeletons.
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c-Jun N-Terminal Kinases (JNKs), members of the Mitogen-Activated Protein Kinase (MAPK) signaling pathway, play a key role in the pathogenesis of many diseases including cancer, inflammation, Parkinson's disease, Alzheimer's disease, cardiovascular disease, obesity, and diabetes. Therefore, JNKs represent new and excellent target by therapeutic agents. Many JNK inhibitors based on different molecular scaffolds have been discovered in the past decade. However, only a few of them have advanced to clinical trials. The major obstacle for the development of JNK inhibitors as therapeutic agents is the JNKisoform selectivity. In this review, we describe the recent development of JNK inhibitors, including ATP competitive and ATP non-competitive (allosteric) inhibitors, bidentatebinding inhibitors and dual inhibitors, the challenges, and the future direction of JNK inhibitors as potential therapeutic agents.
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Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacosRESUMEN
In this review, transition metal-catalyzed methodologies and applications that exploit C-C bond cleavage of vinylcyclopropanes (VCPs) are summarized with a focus on cycloaddition and related addition reactions. Transition metals, including palladium, nickel, iron, ruthenium, rhodium, cobalt, and iridium, can catalyze the cleavage of C-C bonds in activated or nonactivated VCPs. Additionally, these bond-breaking reactions can occur as intra- or intermolecular processes. The properties of activated and nonactivated VCPs are discussed in the Introduction. Various transition metal-catalyzed cycloaddition and addition reactions involving the cleavage of C-C bonds in activated VCPs are then discussed in the next chapter. The transition metal-catalyzed cycloadditions involving the cleavage of C-C in nonactivated VCPs are summarized in the following chapter. Finally, challenges and potential opportunities are outlined in the last chapter.
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Cancer stem-like cells (CSCs) are the tumorigenic cell subpopulation and contribute to cancer recurrence and metastasis. However, the understanding of CSC regulatory mechanisms remains incomplete. By transcriptomic analysis, we identify a scaffold protein SH3RF3 (also named POSH2) that is upregulated in CSCs of breast cancer clinical tumors and cancer cell lines, and enhances the CSC properties of breast cancer cells. Mechanically, SH3RF3 interacts with the c-Jun N-terminal kinase (JNK) in a JNK-interacting protein (JIP)-dependent manner, leading to enhanced phosphorylation of JNK and activation of the JNK-JUN pathway. Further the JNK-JUN signaling expands CSC subpopulation by transcriptionally activating the expression of Pentraxin 3 (PTX3). The functional role of SH3RF3 in CSCs is validated with patient-derived organoid culture, and supported by clinical cohort analyses. In conclusion, our work elucidates the role and molecular mechanism of SH3RF3 in CSCs of breast cancer, and might provide opportunities for CSC-targeting therapy.
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Neoplasias de la Mama/genética , Proteína C-Reactiva/genética , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Células Madre Neoplásicas/metabolismo , Componente Amiloide P Sérico/genética , Ubiquitina-Proteína Ligasas/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proteína C-Reactiva/metabolismo , Línea Celular , Línea Celular Tumoral , Activación Enzimática , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Sistema de Señalización de MAP Quinasas/genética , Fosforilación , Componente Amiloide P Sérico/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Regulación hacia ArribaRESUMEN
x-membered lactams were synthesized via either an amidation of sp3 C-H bonds or an electrophilic substitution of arenes via Ir-nitrene intermediates. With the employment of a readily available iridium catalyst in dichloromethane or hexafluoro-2-propanol, a wide range of lactams were synthesized in good to excellent yields with high selectivity.
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Tumor-initiating cells (TICs) are considered the culprits of cancer development and progression. Dysregulation of metastasis suppressor protein 1 (MTSS1) has been widely observed in tumor metastasis, but its functional contribution and mechanism in cancer is poorly understood. Here we report a role of MTSS1 in suppressing TICs in breast cancer. Mtss1 knockout (KO) enhances the mammary epithelial TIC subpopulation in both luminal and basal-like breast cancer mouse models. MTSS1 also suppresses tumorsphere formation in breast cancer cells. Mechanistically, MTSS1 interacts with the E3 ligase RanBP2-type and C3HC4-type zinc finger containing 1 (RBCK1) to facilitate RBCK1-mediated p65 ubiquitination and degradation, thus suppressing the NF-κB signaling pathway and tumorigenesis. In addition, actin beta-like 2 (ACTBL2) competes with RBCK1 for MTSS1 binding, leading to p65 stabilization. Importantly, MTSS1 silencing promotes patient-derived organoid formation and xenograft growth. MTSS1 downregulation in clinical tumors is also linked to worse prognosis. Overall our data reveal a new paradigm of NF-κB regulation and may have important implications in therapeutics targeting TICs.
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Neoplasias de la Mama , FN-kappa B , Animales , Neoplasias de la Mama/genética , Femenino , Humanos , Ratones , Proteínas de Microfilamentos/genética , FN-kappa B/metabolismo , Proteínas de Neoplasias/genética , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/genética , UbiquitinaciónRESUMEN
Solution processing is widely used for preparing quantum dot (QD) films for fabricating QD light-emitting diode display (QLED) devices. However, current approaches suffer from either the coffee-ring effect or a large amount of wasted solution, leading to low performance and high cost. Here, a facile approach guided by a fibrous liquid bridge is developed for the continuous and controllable transfer of QD solution into ultrasmooth films by using a taut fiber with its two ends placed into capillary tubes. Guided along the fiber, a liquid bridge is formed between the horizontal fiber and the substrate, with a large mass of liquid steadily being held within the vertically placed tubes. Directionally moving the liquid bridge generates a high-quality QD film on the substrate. Particularly, the liquid consumption is quantitative, namely, in proportion to the area of the as-prepared film. Moreover, multilayered ultrasmooth red/green/blue QD films are prepared by multiple transfers of liquid onto the same targeted area in sequence. The as-prepared white QLEDs show a rather high performance with a maximum luminance of 57 190 cd m-2 and a maximum current efficiency of 15.868 cd A-1 . It is envisioned that this strategy offers new perspectives for the low-cost fabrication of high-performance QLED devices.
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We theoretically study the modulation instability (MI) of the two-component helicoidal spin-orbit coupled Bose-Einstein condensates (BECs). The effects of spin-orbit coupling, the helicoidal gauge potential, and atomic interactions on MI are investigated. The results indicate that the presence of the helicoidal gauge potential breaks the symmetric properties of MI, strongly modifies the distribution of the MI region and the MI gain in parameters space, and the MI can be excited even when the miscibility condition for the atomic interactions is satisfied. Furthermore, the effect of the helicoidal gauge potential on MI is strongly coupled with the intra and intercomponent atomic interactions. Particularly, with the increase of the helical gauge potential, the MI gain increases for the repulsive atomic interaction case, however, the MI gain decreases for the attractive atomic interaction case. The direct numerical simulations are performed to support the analytical predictions, and a good agreement is found. Our results provide a potential way to manipulate the MI in BECs with helicoidal gauge potential.
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Precisely patterning large-area quantum dot (QD) nanoparticles is an essential technique for enhancing high-resolution and high-performance in the next-generation display-QLEDs. However, conventional solution-based assembly techniques suffer from trade-offs between large-scale and spatial precision. As such, large nondefect areas and ordered stacking of QD assembly architectures are difficult to achieve, and both are essential to fabricating a high-performance device. Herein, we demonstrate a facile method for assembling the QD nanoparticles into a microstructure using an asymmetric wettability template to regulate the dewetting process. The wettability difference of the interface induces the continuous liquid film to recede into individual liquid bridges, which enabled unidirectional dewetting and regulated the QD solution mass transport. In addition, because of the asymmetric wettability between the substrate and template, large-scale, ultrafine (1 µm), and highly flat microwire QD arrays with the precise position and strict alignment are easily assembled and transferred onto the target substrate. The method has been further introduced into the fabrication of high-resolution patterned QLED devices, with maximum electroluminescence values of 73 490, 4357, and 950 cd/m2 for green, red, and blue, respectively. This research provides a novel and facile perspective for manufacturing high-resolution and high-performance patterned QLED devices.
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of low density lipoprotein receptor (LDLR). Anti-PCSK9 agents have been approved for the treatment of hypercholesterolemia. We recently discovered a series of small-molecule PCSK9 modulators that contains a relatively small pharmacophore of 2,3'-diindolylmethane with molecular weights around only 250. These molecules can significantly lower the amount of PCSK9 protein in a cell-based phenotypic assay. Our SAR studies yielded compound 16 with a IC50-value of 200â¯nM. No obvious cytotoxicity was observed at concentrations below 50⯵M.