Covalent Organic Frameworks: Linkage Chemistry and Its Critical Role in The Evolution of π Electronic Structures and Functions.

Covalent organic frameworks (COFs) provide a molecular platform for designing a novel class of functional materials with well-defined structures. A crucial structural parameter is the linkage, which dictates how knot and linker units are connected to form two-dimensional polymers and layer frameworks, shaping ordered π-array and porous architectures. However, the roles of linkage in the development of ordered π electronic structures and functions remain fundamental yet unresolved issues. Here we report the designed synthesis of COFs featuring four representative linkages: hydrazone, imine, azine, and C=C bonds, to elucidate their impacts on the evolution of π electronic structures and functions. Our observations revealed that the hydrazone linkage provides a non-conjugated connection, while imine and azine allow partial π conjugation, and the C=C bond permits full π-conjugation. Importantly, the linkage profoundly influences the control of π electronic structures and functions, unraveling its pivotal role in determining key electronic properties such as band gap, frontier energy levels, light absorption, luminescence, carrier density and mobility, and magnetic permeability. These findings highlight the significance of linkage chemistry in COFs and offer a general and transformative guidance for designing framework materials to achieve electronic functions.

Photoresponsive Covalent Organic Frameworks: Visible-Light Controlled Conversion of Porous Structures and Its Impacts.

Covalent organic frameworks are a novel class of crystalline porous polymers that enable molecular design of extended polygonal skeletons to attain well-defined porous structures. However, construction of a framework that allows remote control of pores remains a challenge. Here we report a strategy that merges covalent, noncovalent, and photo chemistries to design photoresponsive frameworks with reversibly and remotely controllable pores. We developed a topology-guided multicomponent polycondensation system that integrates protruded tetrafluoroazobenzene units as photoresponsive sites on pore walls at predesigned densities, so that a series of crystalline porous frameworks with the same backbone can be constructed to develop a broad spectrum of pores ranging from mesopores to micropores. Distinct from conventional azobenzene-based systems, the tetrafluoroazobenzene frameworks are highly sensitive to visible lights to undergo high-rate isomerization. The photoisomerization exerts profound effects on pore size, shape, number, and environment, as well as molecular uptake and release, rendering the system able to convert and switch pores reversibly and remotely with visible lights. Our results open a way to a novel class of smart porous materials with pore structures and functions that are convertible and manageable with visible lights.

8-Br-cGMP activates HSPB6 and increases the antineoplastic activity of quinidine in prostate cancer.

Heat shock protein family B [small] member 6 (HSPB6), widely found in various muscles, has been recently identified as a tumor suppressor gene. However, its role in prostate cancer remains unexplored. Herein, we investigated the expression of HSPB6 in prostate cancer and its association with prognosis. Our findings revealed that HSPB6 downregulation in prostate cancer correlated with a poor prognosis. Moreover, we discovered that HSPB6 can be phosphorylated and activated by 8-Br-cGMP, leading to apoptosis in prostate cancer cells by activating Cofilin. Additionally, we demonstrated that knocking down E2F1 by quinidine administration enhances the transcriptional level of HSPB6. Furthermore, we evaluated the combination of quinidine and 8-Br-cGMP as a potential therapeutic strategy for prostate cancer. Our results revealed that the combined treatment was more effective than either treatment alone in inhibiting the growth of prostate cancer through the HSPB6 pathway, both in vitro and in vivo. Overall, our study provides compelling evidence that HSPB6 suppresses malignant behavior in prostate cancer by inducing apoptosis. The combination of quinidine and 8-Br-cGMP emerges as a promising approach for the treatment of prostate cancer.

PDE3B regulates KRT6B and increases the sensitivity of bladder cancer cells to copper ionophores.

Cuproptosis is a new Cu-dependent programmed cell death manner that has shown regulatory functions in many tumor types, however, its mechanism in bladder cancer remains unclear. Here, we reveal that Phosphodiesterase 3B (PDE3B), a cuproptosis-associated gene, could reduce the invasion and migration of bladder cancer. PDE3B is downregulated in bladder cancer tissues, which is correlated with better prognosis. Conversely, overexpression of PDE3B in bladder cancer cell could significantly resist invasion and migration, which is consistent with the TCGA database results. Future study demonstrate the anti-cancer effect of PDE3B is mediated by Keratin 6B (KRT6B) which leads to the keratinization. Therefore, PDE3B can reduce KRT6B expression and inhibit the invasion and migration of bladder cancer. Meanwhile, increased expression of PDE3B was able to enhance the sensitivity of Cuproptosis drug thiram. This study show that PDE3B/KRT6B is a potential cancer therapeutic target and PDE3B activation is able to increase the sensitivity of bladder cancer cells to copper ionophores.

TrkA promotes MDM2-mediated AGPS ubiquitination and degradation to trigger prostate cancer progression.

BACKGROUND: As a novel necrosis manner, ferroptosis has been increasingly reported to play a role in tumor progression and treatment, however, the specific mechanisms underlying its development in prostate cancer remain unclear. Growing evidence showed that peroxisome plays a key role in ferroptosis. Herein, we identified a novel mechanism for the involvement of ferroptosis in prostate cancer progression, which may provide a new strategy for clinical treatment of prostate cancer. METHODS: Label-Free Mass spectrometry was used to screen and identify candidate proteins after ferroptosis inducer-ML210 treatment. Immunohistochemistry was undertaken to explore the protein expression of AGPS in prostate cancer tissues compared with normal tissues. Co-immunoprecipitation and GST pull-down were used to identify the directly binding of AGPS to MDM2 in vivo and in vitro. CCK8 assay and colony formation assay were used to illustrate the key role of AGPS in the progression of prostate cancer in vitro. The xenograft model was established to verify the key role of AGPS in the progression of prostate cancer in vivo. RESULTS: AGPS protein expression was downregulated in prostate cancer tissues compared with normal tissues from the first affiliated hospital of Zhengzhou University dataset. Lower expression was correlated with poorer overall survival of patients compared to those with high expression of AGPS. In addition, AGPS can promote ferroptosis by modulating the function of peroxisome-resulting in the lower survival of prostate cancer cells. Furthermore, it was shown that AGPS can be ubiquitinated and degraded by the E3 ligase-MDM2 through the proteasomal pathway. Meanwhile, kinase TrkA can promote the combination of AGPS and MDM2 by phosphorylating AGPS at Y451 site. It was verified that kinase TrkA inhibitor-Larotrectinib can increase the susceptibility of prostate cancer cells to ferroptosis, which leads to the inhibition of prostate cancer proliferation to a great extent in vitro and in vivo. CONCLUSION: Based on these findings, we proposed the combination of ferroptosis inducer and TrkA inhibitor to synergistically exert anti-tumor effects, which may provide a new strategy for the clinical treatment of prostate cancer.

Crystalline, Porous Helicene Covalent Organic Frameworks.

Helicenes are a class of fascinating chiral helical molecules with rich chemistry developed continuously over the past 100 years. Their helical, conjugated, and twisted structures make them attractive for constructing molecular systems. However, studies over the past century are mainly focused on synthesizing helicenes with increased numbers of aromatic rings and complex heterostructures, while research on inorganic, organic, and polymeric helicene materials is still embryonic. Herein, we report the first examples of helicene covalent organic frameworks, i.e., [7]Helicene sp2 c-COF-1, by condensing [7]Helicene dialdehyde with trimethyl triazine via the C=C bond formation reaction under solvothermal conditions. The resultant [7]Helicene sp2 c-COF-1 exhibits prominent X-ray diffraction peaks and assumes a highly ordered 2D lattice structure originated from the twisted configuration of [7]Helicene unit. The C=C linked [7]Helicene sp2 c-COF-1 materials exhibited extended π conjugation and broadly tuned their absorption, emission, redox activity, photoconductivity, and light-emitting activity, demonstrating rich multifunctionalities and great potentials in developing various applications. This work opens a way to a new family of COFs as well as helicene materials, enabling the exploration of unprecedented π architectures and properties.

Covalent Organic Frameworks: Reversible 3D Coalesce via Interlocked Skeleton-Pore Actions and Impacts on π Electronic Structures.

Covalent organic frameworks (COFs) create extended two-dimensional (2D) skeletons and aligned one-dimensional (1D) channels, constituting a class of novel π architectures with predesignable structural ordering. A distinct feature is that stacks of π building units in skeletons shape the pore walls, onto which a diversity of different units can be assembled to form various pore interfaces, opening a great potential to trigger a strong structural correlation between the skeleton and the pore. However, such a possibility has not yet been explored. Herein, we report reversible three-dimensional (3D) coalescence and interlocked actions between the skeleton and pore in COFs by controlling hydrogen-bonding networks in the pores. Introducing carboxylic acid units to the pore walls develops COFs that can confine water molecular networks, which are locked by the surface carboxylic acid units on the pore walls via multipoint, multichain, and multidirectional hydrogen-bonding interactions. As a result, the skeleton undergoes an interlocked action with pores to shrink over the x-y plane and to stack closer along the z direction upon water uptake. Remarkably, this interlocked action between the skeleton and pore is reversibly driven by water adsorption and desorption and triggers profound effects on π electronic structures and functions, including band gap, light absorption, and emission.

A Case of Toxic Epidermal Necrolysis Caused by Lamotrigine Combined With Valproic Acid and Literature Review.

After suffering from frequent symptomatic seizures secondary to cerebral hemorrhage, a 58-year-old male patient was prescribed a one-time 50 mg dose of lamotrigine, which he took for a week. However, the patient's seizure symptoms were not controlled until a dosage of 500 mg of sodium valproate tablets was taken twice daily, which ultimately resolved his seizures. Unfortunately, about two weeks after the combination, the patient developed a rash. Nine days later, the patient developed new blisters, necrotizing epidermal desquamation, and lesions over 80% of their body surface area. This was diagnosed as toxic epidermal necrolysis (TEN) resulting from the combination of lamotrigine and sodium valproate. The sodium valproate and lamotrigine were discontinued and treated symptomatically for about one month. The patient's condition improved as the fatal rash gradually subsided. However, after the onset of TEN, unexpected psychiatric symptoms such as poor sleep, less than four hours of sleep, irritability, paranoia, crying, fear of rash recurrence, and suspicious hallucinations and delusions emerged in the patient. Surprisingly, after discontinuation of lamotrigine and sodium valproate due to the rash, the patient did not experience any further seizures.

An Ir(III) cyclometalate-functionalized molecularly imprinted polymer: photophysics, photochemistry and chemosensory applications.

A luminescent trimethylamine (TMA) sensor, PTMA-Ir, has been designed and synthesized through immobilizing a phosphorescent iridium(III) complex on a TMA-imprinted polymer. Detailed study shows that the quenching of phosphorescence of PTMA-Ir can serve as a reporter for the binding of TMA on the imprinting sites, thus providing a sensitive, selective, and rapid detection of TMA in both aqueous solutions and gaseous states. Loading PTMA-Ir on filter paper produced a deposition T-Ir, the phosphorescence of which is quenched within 5 s upon exposure to TMA vapor with detection limits of 9.0 ± 0.1 ppm under argon and 15.0 ± 0.1 ppm in an air atmosphere. This work provided an effective method for establishing an imprinting polymer-immobilized luminescent amine sensor.

Bottom-Up Design of Photoactive Chiral Covalent Organic Frameworks for Visible-Light-Driven Asymmetric Catalysis.

The development of chiral covalentorganic framework catalysts (CCOFs) to synthesize enantiopure organic compounds is crucial and highly desirable in synthetic chemistry. Photocatalytic asymmetric reactions based on CCOFs are eco-friendly and sustainable while they are still elaborate. In this work, we report a general bottom-up strategy to successfully synthesize several photoactive CCOFX (X = 1-5 and 1-Boc). The photoactive porphyrin building blocks are selected as knots and various secondary-amine-based chiral catalytic centers are immobilized on the pore walls of CCOFX through a rational design of benzoimidazole linkers. The porphyrin units act as light-harvesting antennae to generate photo-induced charge carriers for the activation of bromide during the photocatalytic asymmetric alkylation of aldehydes. Meanwhile, various aldehydes are activated by the chiral secondary amine to form the target products with a high yield (up to 97%) and ee value (up to 93%). The results significantly expand the scope to predesign CCOF photocatalysts for visible-light-driven asymmetric catalysis.

ANXA13 promotes cell proliferation and invasion and attenuates apoptosis in renal cell carcinoma.

Purpose: Emerging evidences have demonstrated that annexin A13 (ANXA13) is closely related to the occurrence and development of malignant tumors. However, the functions and underlying molecular mechanisms of ANXA13 in Clear cell renal cell carcinoma (ccRCC) have not been defined. Therefore, this study aimed to clarify the potential role of ANXA13 in regulating the proliferation, migration, invasion, cell cycle, and apoptosis of ccRCC cells. Patients and methods: The quantitative real-time PCR (qRT-PCR) and western blotting was performed for detecting the ANXA13 expression in ccRCC tissues at the mRNA and protein levels, respectively. The GEPIA2 databases were used to derive data for analyzing the ANXA13 expression in pan-cancer and ccRCC clinical features. Cell Counting and colony formation assays, as well as flow cytometry, were used to detect cell proliferation, apoptosis, or cell cycle. The wound healing assay was used to evaluate the migration ability of cells, and the Trans-well assay was conducted to determine the cell invasiveness. Results: ANXA13 was upregulated in ccRCC cells and human ccRCC tissues. Furthermore, siANXA13 inhibited ccRCC cell proliferation, migration, invasion and induced cell apoptosis. Conclusion: ANXA13 was upregulated in ccRCC. ANXA13 promotes tumorigenic traits of ccRCC cell lines in vitro. ANXA13 is a potential novel biomarker and a potential therapeutic target in ccRCC.

Porphyrin-Based Covalent Organic Frameworks Anchoring Au Single Atoms for Photocatalytic Nitrogen Fixation.

The development of efficient photocatalysts for N2 fixation to produce NH3 under ambient conditions remains a great challenge. Since covalent organic frameworks (COFs) possess predesignable chemical structures, good crystallinity, and high porosity, it is highly significant to explore their potential for photocatalytic nitrogen conversion. Herein, we report a series of isostructural porphyrin-based COFs loaded with Au single atoms (COFX-Au, X = 1-5) for photocatalytic N2 fixation. The porphyrin building blocks act as the docking sites to immobilize Au single atoms as well as light-harvesting antennae. The microenvironment of the Au catalytic center is precisely tuned by controlling the functional groups at the proximal and distal positions of porphyrin units. As a result, COF1-Au decorated with strong electron-withdrawing groups exhibits a high activity toward NH3 production with rates of 333.0 ± 22.4 µmol g-1 h-1 and 37.0 ± 2.5 mmol gAu-1 h-1, which are 2.8- and 171-fold higher than that of COF4-Au decorated with electron-donating functional groups and a porphyrin-Au molecular catalyst, respectively. The NH3 production rates could be further increased to 427.9 ± 18.7 µmol g-1 h-1 and 61.1 ± 2.7 mmol gAu-1 h-1 under the catalysis of COF5-Au featuring two different kinds of strong electron-withdrawing groups. The structure-activity relationship analysis reveals that the introduction of electron-withdrawing groups facilitates the separation and transportation of photogenerated electrons within the entire framework. This work manifests that the structures and optoelectronic properties of COF-based photocatalysts can be finely tuned through a rational predesign at the molecular level, thus leading to superior NH3 evolution.

Molecularly Imprinted Polymer-Based Luminescent Chemosensors.

Molecularly imprinted polymer (MIP)-based luminescent chemosensors combine the advantages of the highly specific molecular recognition of the imprinting sites and the high sensitivity with the luminescence detection. These advantages have drawn great attention during the past two decades. Luminescent molecularly imprinted polymers (luminescent MIPs) towards different targeted analytes are constructed with different strategies, such as the incorporation of luminescent functional monomers, physical entrapment, covalent attachment of luminescent signaling elements on the MIPs, and surface-imprinting polymerization on the luminescent nanomaterials. In this review, we will discuss the design strategies and sensing approaches of luminescent MIP-based chemosensors, as well as their selected applications in biosensing, bioimaging, food safety, and clinical diagnosis. The limitations and prospects for the future development of MIP-based luminescent chemosensors will also be discussed.

Integrated interfacial design of covalent organic framework photocatalysts to promote hydrogen evolution from water.

Attempts to develop photocatalysts for hydrogen production from water usually result in low efficiency. Here we report the finding of photocatalysts by integrated interfacial design of stable covalent organic frameworks. We predesigned and constructed different molecular interfaces by fabricating ordered or amorphous π skeletons, installing ligating or non-ligating walls and engineering hydrophobic or hydrophilic pores. This systematic interfacial control over electron transfer, active site immobilisation and water transport enables to identify their distinct roles in the photocatalytic process. The frameworks, combined ordered π skeletons, ligating walls and hydrophilic channels, work under 300-1000 nm with non-noble metal co-catalyst and achieve a hydrogen evolution rate over 11 mmol g-1 h-1, a quantum yield of 3.6% at 600 nm and a three-order-of-magnitude-increased turnover frequency of 18.8 h-1 compared to those obtained with hydrophobic networks. This integrated interfacial design approach is a step towards designing solar-to-chemical energy conversion systems.

Identification of the immunosuppressive effect of γδ T cells correlated to bone morphogenetic protein 2 in acute myeloid leukemia.

Description of immune landscapes in malignant microenvironment is critical to the improvement of therapeutic strategies for various tumors. Acute myeloid leukemia (AML) remains a severe life-threatening malignancy and often confronts treatment dilemma in clinic. Although γδ T cells exhibit independent and potent cytotoxicity against leukemic cells in vitro and in the mouse models, efficacy of γδ T cell-based immunotherapy on AML patients has seemed unsatisfying so far. How the anti-AML capacity of γδ T cells is suppressed in vivo remains elusive. Herein, we found an aberrant γδ T cells subset expressing CD25+CD127lowVδ2+ in the bone marrows of patients with newly diagnosed AML. The emergence of this subset was significantly associated with disease status and risk stratification as well as with the abnormally increased bone morphogenetic protein 2 (BMP2). Mechanistically, BMP2 could directly induce CD25+CD127lowVδ2+ γδ T cells (named as Reg-Vδ2) in vitro. The immunosuppressive features of Reg-Vδ2 cells were identified by combining immunophenotypical and functional data. Furthermore, inhibition of BMP2 pathway significantly blocked the emergence of Reg-Vδ2 cells and enhanced the anti-AML immunity in humanized mice. These findings not only provide a novel insight into the mechanisms of immunosuppression in the context of leukemia, but also suggest potential targets for the treatment of AML and other hematopoietic malignancies.

SOX15 transcriptionally increases the function of AOC1 to modulate ferroptosis and progression in prostate cancer.

Amine oxidase copper-containing 1 (AOC1) is considered an oncogene in many types of tumors. Nevertheless, there have been no investigations of AOC1 and its regulatory mechanism in prostate cancer. Here, we reveal a novel action of AOC1 and a tumor suppressor mechanism in prostate cancer. AOC1 is downregulated in prostate cancer. Abatement of AOC1 in prostate cancer tissue is positively correlated with the tumor size, lymph node metastasis, and Gleason score for prostate cancer. Conversely, high expression of AOC1 is significantly associated with reduced proliferation and migration in prostate cancer both in vitro and in vivo. We show that the anticancer effect of AOC1 is mediated by its action on spermidine which leads to the activation of reactive oxygen species and ferroptosis. AOC1 expression in prostate cancer is positively regulated by the transcription factor SOX15. Therefore, SOX15 can transcriptionally promote AOC1 expression and strengthen this effect. Targeting AOC1 and SOX15 may be promising for the treatment of prostate cancer.

Distinct activities of Vδ1+ T-cells upon different cytomegalovirus reactivation status after haematopoietic transplantation.

Cytomegalovirus (CMV) reactivation is the most frequent viral infectious complication correlating to non-relapse mortality after allogeneic haematopoietic cell transplantation (alloHCT). The intrinsic anti-CMV immunity has not been completely elucidated. γδ T-cells have drawn increasing attentions due to their distinct biological features and potential ability against viral infections. Previous studies reported a general association of γδ T-cells or Vδ2-negative γδ T-cells with CMV reactivation. Whereas researches for the direct responses and specific functions of γδ T subsets remain limited, especially in the scenario of alloHCT. Herein, we initially demonstrated that Vδ1+ T-cells directly and independently recognized cell-free CMV and CMV-infected target cells, and inhibited CMV replication in vitro. The anti-CMV effect of Vδ1+ T-cells was partially through TCRγδ, TLR2 and NKG2D receptor pathways. Further investigation about the anti-CMV characteristics of Vδ1+ T-cells was performed in a clinical cohort with different CMV reactivation status after alloHCT. We found that occasional CMV reactivation remarkably increased the recovery levels and stimulated the functional activity of Vδ1+ T-cells. Whereas disability of Vδ1+ T-cells was observed upon refractory CMV reactivation indicating the differential responses of Vδ1+ T-cells under different CMV reactivation status. CXCL10 and IFN-ß that were dramatically induced by occasional CMV reactivation could re-activate the deficient Vδ1+ T-cells from recipients with refractory CMV reactivation. These findings unveiled the distinct activities of Vδ1+ T-cells in anti-CMV immunity after alloHCT and may help develop novel strategies for the treatment of CMV infectious diseases.

Improvement of pneumonia by curcumin-loaded bionanosystems based on platycodon grandiflorum polysaccharides via calming cytokine storm.

Pneumonia can lead to high morbidity and mortality secondary to uncontrolled inflammation of the lung tissue. Blocking cytokine storm storms may be the key to saving the life of patients with severe pneumonia. According to the medicinal guide theory of Traditional Chinese Medicine (TCM) and the inherent affinity with macrophages for the site of inflammation, we constructed the drug delivery platform (MNPs) derived from macrophage-membrane encapsulated reaction oxygen species (ROS)-responsive Platycodon grandiflorum polysaccharides (PGP) nanoparticles (PNPs) to calm the cytokine storm and improve lung inflammation. By loading the anti-inflammatory agent Curcumin (Cur), we demonstrated that MNPs@Cur significantly attenuated inflammation and cytokine storm syndrome in acute lung injury (ALI) mice by suppressing pro-inflammatory factor production and inflammatory cell infiltration. Interestingly, we observed that the PNPs also have potent pulmonary targeting ability compared to other polysaccharide carriers, which is in line with the medicinal guide theory of TCM. Our study revealed the rational design of drug delivery platforms to improve the treatment of lung injury, which inherits and develops the important theories of TCM through the perfect combination of guide theory and biomimetic nanotechnology and provides the experimental scientific basis for the clinical application of channel ushering drugs.

γδ T Cells May Aggravate Acute Graft-Versus-Host Disease Through CXCR4 Signaling After Allogeneic Hematopoietic Transplantation.

Graft-versus-host disease (GVHD) is a pathology in which chemokines and their receptors play essential roles in directing the migration of alloreactive donor T cells into GVHD organs, thereby leading to further target tissue damage. Currently, acute GVHD (aGVHD) remains a major cause of high morbidity and mortality in patients who underwent allogeneic hematopoietic cell transplantation (alloHCT). The identification of immune cells that correlate with aGVHD is important and intriguing. To date, the involvement of innate-like γδ T cells in the pathogenesis of aGVHD is unclear. Herein, we found that primary human γδ T cells did not directly trigger allogeneic reactions. Instead, we revealed that γδ T cells facilitated the migration of CD4 T cells via the SDF-1-CXCR4 axis. These results indicate indirect regulation of γδ T cells in the development of aGVHD rather than a direct mechanism. Furthermore, we showed that the expression of CXCR4 was significantly elevated in γδ T cells and CD4 and CD8 T cells in recipients who experienced grades II-IV aGVHD after alloHCT. Consistently, CXCR4-expressing γδ T cells and CD4 T cells were induced in the target organs of mice suffering aGVHD. The depletion of γδ T cells in transplant grafts and treatment with AMD3100, an inhibitor of CXCR4 signaling, delayed the onset of aGVHD and prolonged survival in mice. Taken together, these findings suggest a role for γδ T cells in recruiting alloreactive CD4 T cells to target tissues through the expression of CXCR4. Our findings may help in understanding the mechanism of aGVHD and provide novel therapeutic targets.