SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation.

Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a mechanism by which the SARS-CoV-2 virus coopts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-ß. We reveal that the SARS-CoV-2 encoded nonstructural protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein. This interaction enhances the binding of GIGYF2 to the mRNA cap-binding protein 4EHP, thereby repressing the translation of the Ifnb1 mRNA. Depletion of GIGYF2 or 4EHP significantly enhances IFN-ß production, which inhibits SARS-CoV-2 replication. Our findings reveal a target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses.

Covalent Organic Frameworks: Opportunities for Rational Materials Design in Cancer Therapy.

Nanomedicines are extensively used in cancer therapy. Covalent organic frameworks (COFs) are crystalline organic porous materials with several benefits for cancer therapy, including porosity, design flexibility, functionalizability, and biocompatibility. This review examines the use of COFs in cancer therapy from the perspective of reticular chemistry and function-oriented materials design. First, the modification sites and functionalization methods of COFs are discussed, followed by their potential as multifunctional nanoplatforms for tumor targeting, imaging, and therapy by integrating functional components. Finally, some challenges in the clinical translation of COFs are presented with the hope of promoting the development of COF-based anticancer nanomedicines and bringing COFs closer to clinical trials.

Construction of Covalent Organic Frameworks via Multicomponent Reactions.

Multicomponent reactions (MCRs) combine at least three reactants to afford the desired product in a highly atom-economic way and are therefore viewed as efficient one-pot combinatorial synthesis tools allowing one to significantly boost molecular complexity and diversity. Nowadays, MCRs are no longer confined to organic synthesis and have found applications in materials chemistry. In particular, MCRs can be used to prepare covalent organic frameworks (COFs), which are crystalline porous materials assembled from organic monomers and exhibit a broad range of properties and applications. This synthetic approach retains the advantages of small-molecule MCRs, not only strengthening the skeletal robustness of COFs, but also providing additional driving forces for their crystallization, and has been used to prepare a series of robust COFs with diverse applications. The present perspective article provides the general background for MCRs, discusses the types of MCRs employed for COF synthesis to date, and addresses the related critical challenges and future perspectives to inspire the MCR-based design of new robust COFs and promote further progress in this emerging field.

Metalated covalent organic frameworks: from synthetic strategies to diverse applications.

Covalent organic frameworks (COFs) are a class of organic crystalline porous materials discovered in the early 21st century that have become an attractive class of emerging materials due to their high crystallinity, intrinsic porosity, structural regularity, diverse functionality, design flexibility, and outstanding stability. However, many chemical and physical properties strongly depend on the presence of metal ions in materials for advanced applications, but metal-free COFs do not have these properties and are therefore excluded from such applications. Metalated COFs formed by combining COFs with metal ions, while retaining the advantages of COFs, have additional intriguing properties and applications, and have attracted considerable attention over the past decade. This review presents all aspects of metalated COFs, from synthetic strategies to various applications, in the hope of promoting the continued development of this young field.

Spatial and temporal distribution characteristics of typical pollution loads based on SWAT model across Tuojiang River watershed located in Sichuan Province, Southwest of China.

Tuojiang River watershed is an economically developed and densely populated area in Sichuan Province (southwest of China), which is also an important tributary of the Yangtze River. Nitrogen (N) and phosphorus (P) are the main pollutants affecting water quality, but there is still lack of study on the spatial and temporal distribution characteristics of these two pollutants. In this study, the typical non-point source pollution loads in the Tuojiang River watershed are simulated by Soil and Water Assessment Tool (SWAT) model, and the spatial autocorrelation method is used to reveal the spatial and temporal distribution characteristics of the pollution loads from the annual average and water periods. Combined with redundancy analysis (RDA) and geographically weighted regression (GWR) analysis, the main driving factors affecting the typical non-point source pollution loads in the Tuojiang River watershed are discussed from the global and local perspectives. The results show that (1) from different water periods, the pollution loads of total nitrogen (TN) and total phosphorus (TP) in three water periods show obviously different, is the highest in the abundant water period, with 323.4 kg/ha and 47.9 kg/ha, followed by the normal water period, with 95.7 kg/ha and 14.1 kg/ha, and the lowest in the dry water period, with 28.4 kg/ha and 4.2 kg/ha. The annual average value of TN pollution load is higher than that of TP, with 447.5 kg/ha and 66.1 kg/ha, respectively; (2) the TN and TP pollution loads are stable on the whole, and the overall level in the middle reaches is higher. The pollution loads of Shifang City and Mianzhu City are higher in all three water periods. (3) Elevation and slope are two main driving factors affecting the TN and TP pollution loads in the Tuojiang River watershed. Therefore, the visualization and quantification of temporal and spatial distribution characteristics of typical non-point source pollution loads in the Tuojiang River watershed are helpful to provide the basis for scientific prevention and control of pollution in the Tuojiang River watershed and are of great significance to promote the sustainable, coordinated, and healthy development of water environment and economy in the watershed.

Real-Time Monitoring of Curcumin Release with a Lipid-Curcumin-Loaded Silica Colloidal Crystal Film Using Optical Interferometry.

A novel efficacious strategy for real-time monitoring of the release of hydrophobic cargo curcumin (molecule model nutraceuticals) from a lipid-curcumin-loaded silica colloidal crystal (L(Cur)-SCC) film controlled by lipase was developed. Curcumin was dispersed in a proportion of a digestible lipid complex (glycerol trioleate and glycerol tristearate) to prepare a lipid-curcumin complex and then loaded into the SCC film by a capillary to prepare an L(Cur)-SCC film. Lipase-triggered degradation of the digestible lipid complex resulted in curcumin release being tracked in real-time by ordered porous layer interferometry (OPLI). The optical thickness changes (ΔOT) of the L(Cur)-SCC film depend on the mass changes of the lipid-curcumin complex due to the migration of interference fringes caused by the lipase degradation of the digestible lipid complex. Curcumin release from the L(Cur)-SCC film was characterized and analyzed in combination with an ultraviolet-visible spectrophotometer, a nanoparticle size analyzer, and an attenuated total reflection infrared spectrometer. The introduction of a soluble dietary fiber (pectin) into the L(Cur)-SCC film delayed the release rate of curcumin. Furthermore, the real-time sustained release of curcumin from the L(Cur)-SCC film in the simulated digestive fluids was tracked. This study provides an early exploration of the real-time controlled release of lipid-soluble nutraceuticals in the gastrointestinal tract.

Glutathione S-transferase kappa 1 is positively related with sperm quality of porcine sperm.

The glutathione S-transferase (GST) superfamily members play an important role in the male reproductive tract and sperm physiology. However, the expression profiles of some members of this protein family and their effect on sperm quality remain unclear. In this study, we found that GST kappa 1 (GSTK1) encoded protein is abundant in the testes and capacitated sperm acrosome. Western blot analysis revealed that the decreased abundance of GSTK1 was observed in low motile spermatozoa; moreover, GSTK1 expression decreased in sperm stored at 17°C under a long preservation time. In vitro analyses revealed that GSTK1 had no significant effect on sperm motility, capacitation, or acrosome reaction. Notably, after capacitated sperm were incubated with 4 and 8 µg/ml anti-GSTK1 antibodies, the fertilization rate significantly decreased in vitro fertilization assay. The current study demonstrates that GSTK1 is correlated with sperm quality and is a promising marker for the assessment of sperm quality and provides a basis for understanding the potential molecular mechanism for targeting pathogenic factors in male infertility.

A Ferrocene-Functionalized Covalent Organic Framework for Enhancing Chemodynamic Therapy via Redox Dyshomeostasis.

Chemodynamic therapy (CDT), which induces cell death by decomposing high levels of H2 O2 in tumor cells into highly toxic ·OH, is recognized as a promising antineoplastic approach. However, current CDT approaches are often restricted by the highly controlled and upregulated cellular antioxidant defense. To enhance ·OH-induced cellular damage by CDT, a covalent organic framework (COF)-based, ferrocene (Fc)- and glutathione peroxidase 4 (GPX4) inhibitor-loaded nanodrug, RSL3@COF-Fc (2b), is fabricated. The obtained 2b not only promotes in situ Fenton-like reactions to trigger ·OH production in cells, but also attenuates the repair mechanisms under oxidative stress via irreversible covalent GPX4 inhibition. As a result, these two approaches synergistically result in massive lipid peroxide accumulation, subsequent cell damage, and ultimately ferroptosis, while not being limited by intracellular glutathione. It is believed that this research provides a paradigm for enhancing reactive oxygen species-mediated oncotherapy through redox dyshomeostasis and may provide new insights for developing COF-based nanomedicine.

Construction of Optical Interference Fibrin and Thrombolysis Analysis with Silica Colloidal Crystal Films.

Developing powerful real-time methods for monitoring the thrombolytic process is highly desirable for the early therapy of thrombus diseases. Herein, an optical interference fibrin was constructed, fabricated by assembling a 190 nm silica colloidal crystal on glass slides, for detecting a thrombolytic process through the shift of interference peaks caused by the variation of the thicknesses of a silica colloidal crystal film with loaded fibrin dissolution. The whole kinetic progress of thrombolysis by nattokinase and urokinase as thrombolytic drug models was recorded, and the kinetic data were calculated. Moreover, the developed method shows excellent sensitivity for the activity of nattokinase and urokinase with wide linear ranges of approximately 0.75-750 and 5-1000 units mL-1, respectively. Thus, this method can be used as a real-time, low-cost, and simple system for monitoring the thrombolytic process of drugs, demonstrating huge potential in the development of treating thromboembolic diseases and screening drugs.

[Heat shock protein 90 in male reproduction].

Heat shock protein 90 (Hsp90), as a member of the Hsp family and widely found in the gonads of humans and animals, plays an essential role in male reproduction and induces various changes in the process of reproduction. Hsp90 regulates the division of germ cells and participates in spermatogenesis, location of germ cells, formation of sperm microtubes, protection of sperm from oxidative stress, and inducement of acrosomal reaction. Studies showed significant changes in location and expression of Hsp90 in the sperm of oligospermia and asthenospermia patients. This paper presents an overview of Hsp90 in male reproduction and male infertility and a prospect of the treatment of male infertility.

Using Reflectometric Interference Spectroscopy to Real-Time Monitor Amphiphile-Induced Orientational Responses of Liquid-Crystal-Loaded Silica Colloidal Crystal Films.

An approach to optical transduction and amplification of amphiphile-triggered orientational responses of liquid crystals (LCs) based on the interference effect was developed. The sensitive substrate was obtained by lading 4'-pentyl-4-cyanobiphenyl (5CB) into three-dimensionally ordered silica colloidal crystal (SCC) films. Changes in the optical thickness (ΔOT) of the substrates, which are inverted by their Fabry-Perot fringes, depend on the changes of the refractive index caused by the differences in the orientations of LCs. The orientation changes of LCs loading into SCC films have the effect of amplifying signals. These are based on the interactions between surfactants (alkyl trimethylammonium halides (CnTABs, n = 8, 10, 12, 14, and 16) and sodium lauryl sulfonate (SLS)) and LCs, which induce a particular orientation of the LCs molecules. In this flowing system, the reversibility of the signal response for the adsorption of amphiphile was related to the length of the surfactant chain and its critical micelle concentration (CMC). A new method capable of real-time sensing adsorbate-triggered anchoring transitions based on LC-infiltrated SCC films was accomplished. These results provide basics and principles for online, label-free, and real-time analysis of molecules and their interactions in a flowing environment based on the interference effect.

Covalent Organic Frameworks (COFs) for Cancer Therapeutics.

As newly emerged crystalline porous materials, covalent organic frameworks (COFs) possess fascinating structures and some specific features such as modularity, crystallinity, porosity, stability, versatility, and biocompatibility. Besides adsorption/separation, sensing, catalysis, and energy applications, COFs have recently shown a promise in biomedical applications. This contribution provides an overview of the recent developments of COF-based medicines in cancer therapeutics, including drug delivery, photodynamic therapy (PDT), photothermal therapy (PTT), and combined therapy. Furthermore, the major challenges and developing trends in this field are also discussed. These recent developments are summarized and discussed to help encourage further contributions in this emerging and promising field.

A Glycosylated Covalent Organic Framework Equipped with BODIPY and CaCO3 for Synergistic Tumor Therapy.

Ca2+ , a ubiquitous but nuanced modulator of cellular physiology, is meticulously controlled intracellularly. However, intracellular Ca2+ regulation, such as mitochondrial Ca2+ buffering capacity, can be disrupted by 1 O2 . Thus, the intracellular Ca2+ overload, which is recognized as one of the important cell pro-death factors, can be logically achieved by the synergism of 1 O2 with exogenous Ca2+ delivery. Reported herein is a nanoscale covalent organic framework (NCOF)-based nanoagent, namely CaCO3 @COF-BODIPY-2I@GAG (4), which is embedded with CaCO3 nanoparticle (NP) and surface-decorated with BODIPY-2I as photosensitizer (PS) and glycosaminoglycan (GAG) targeting agent for CD44 receptors on digestive tract tumor cells. Under illumination, the light-triggered 1 O2 not only kills the tumor cells directly, but also leads to their mitochondrial dysfunction and Ca2+ overload. An enhanced antitumor efficiency is achieved via photodynamic therapy (PDT) and Ca2+ overload synergistic therapy.

Construction of a Liquid Crystal-Based Sensing Platform for Sensitive and Selective Detection of l-Phenylalanine Based on Alkaline Phosphatase.

The detection of l-phenylalanine (l-Phe) has become one of the most pressing issues concerning diagnosis and treatment of phenylketonuria in neonates; however, a simple and robust methodology is yet to be developed. Here, the application of novel liquid crystals (LCs)-sensing platform for sensitive, selective, and label-free detection of l-Phe was reported at the first time. We devised a strategy to fabricate the sodium monododecyl phosphate (SMP)-decorated LC sensing platform with the appearance of dark. Then, a dark to bright (D-B) optical images alteration of LCs was observed after transferring alkaline phosphatase (ALP) to the interface, owing to cleavage of SMP induced by ALP. LCs remained dark images after the SMP-decorated interface in contact with the pre-incubated ALP and l-Phe. Such optical appearance resulted from the inhibition of ALP by l-Phe, which was further verified by the isothermal titration calorimetry (ITC). The strategy was applied to sensing l-Phe, which have been proven to allow for sensitively and selectively differentiation of l-Phe from interfering compounds with similar aromatic groups, as well as seven other essential amino acids. More importantly, the detection limit of l-Phe reached 1 pg/mL in urine samples, further demonstrating its value in the practical applications. Results obtained in this study clearly demonstrated the superiority of LCs toward the l-Phe detection, which can pave a way for the development of high performance and robust probes for l-Phe detection in clinical applications.

Diiodo-Bodipy-Encapsulated Nanoscale Metal-Organic Framework for pH-Driven Selective and Mitochondria Targeted Photodynamic Therapy.

We report herein a new ZIF-90-based PDT agent which was synthesized by in situ assembly of imidazole-2-carboxaldehyde (IcaH), Zn(NO3)2, and heavy atom iodine-attached Bodipy. The obtained 2I-BodipyPhNO2@ZIF-90 (1) host-guest photosensitive system featured low cytotoxicity, good biocompatibility, pH-driven selective cancer cell uptake and release, mitochondria targeting, and highly efficient pH-triggered 1O2 generation. Therefore, it can be used as a high-performing PDT agent to selectively kill tumor cells. In comparison to free 2I-BodipyPhNO2, 1 exhibits a much higher antitumor efficacy and selectivity, which was confirmed by in vitro cell experiments.

One-Pot Synthetic Approach toward Porphyrinatozinc and Heavy-Atom Involved Zr-NMOF and Its Application in Photodynamic Therapy.

Herein, we report an iodine-attached Zn(II)-porphyrinic dicarboxylic building block (ZnDTPP-I2-2H, 1) that can be introduced into UiO-66 NMOF via one-pot synthetic approach to generate a new ZnDTPP-I2 doped UiO-66 type nano metal-organic framework (NMOF) of ZnDTPP-I2⊂UiO-66 (2). Compared to its homologous iodine-free NMOF of ZnDTPP⊂UiO-66 (4), ZnDTPP-I2⊂UiO-66 (2) with heavy iodine atoms is a more effective nanosized photosensitizer for singlet oxygen generation under physiological conditions. As expected, 2 displayed a high photodynamic therapy efficacy for treatment of liver cancer cells in vitro.

Real-time tracking of the adsorption of bovine serum albumin on lipid layer and its effect on lipolysis by optical interferometry.

The model proteins bovine serum albumin (BSA) and lipid layer were used to study the effect of proteins on lipolysis. A lipid layer with an interference effect was constructed by loading the triolein into the silica colloidal crystal (SCC) film. The ordered porous layer interferometry (OPLI) system was used to track the changes in lipid layer mass caused by lipase hydrolysis to achieve real-time lipolysis detection. The real-time tracking of the adsorption of BSA on the lipid layer by converting the migration of interference fringes caused by the change of the lipid layer into the optical thickness change (ΔOT). The effect of BSA on the early and late stages of lipolysis was studied, and lipases containing 5 mg/mL BSA degraded the lipid layer 3.4 times faster than lipases containing 0.1 mg/mL BSA in the later stages. This study deepens the understanding of protein-lipid interactions in complex digestive environments.

Mitophagy activation by rapamycin enhances mitochondrial function and cognition in 5×FAD mice.

Alzheimer's disease (AD) is the most prevalent form of dementia, characterized by severe mitochondrial dysfunction, which is an intracellular process that is significantly compromised in the early stages of AD. Mitophagy, the selective removal of damaged mitochondria, is a potential therapeutic strategy for AD. Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, augmented autophagy and mitigated cognitive impairment. Our study revealed that rapamycin enhances cognitive function by activating mitophagy, alleviating neuronal loss, and improving mitochondrial dysfunction in 5 ×FAD mice. Interestingly, the neuroprotective effect of rapamycin in AD were negated by treatment with 3-MA, a mitophagy inhibitor. Overall, our findings suggest that rapamycin ameliorates cognitive impairment in 5 ×FAD mice via mitophagy activation and its downstream PINK1-Parkin pathway, which aids in the clearance of amyloid-ß (Aß) and damaged mitochondria. This study reveals a novel mechanism involving mitophagy regulation underlying the therapeutic effect of rapamycin in AD. This study provides new insights and therapeutic targets for rapamycin in the treatment of AD. However, there are still some shortcomings in this topic; if we can further knock out the PINK1/Parkin gene in animals or use siRNA technology, we can further confirm the experimental results.

Preparation of paeoniflorin-glycyrrhizic acid complex transethosome gel and its preventive and therapeutic effects on melasma.

Paeoniflorin (PF) and glycyrrhizic acid (GL) have skin beautifying effects of anti-inflammation, anti-oxidation, inhibition of melanin formation, and reduction of skin pigmentation. To improve the transdermal permeability of PF and GL in transdermal drug delivery system (TDDS) and enhance their anti-melasma efficacy, PF-GL transethosome (PF-GL-TE) was prepared by ethanol injection method, and finally gelled with carbomer-940 to form PF-GL-TE gel. Consequently, the obtained PF-GL-TE is small and uniform, with an average particle size and a PDI value of about 167.9 nm and 0.102. PF-GL-TE gel showed sustained release behavior and high transdermal permeability in vitro release and transdermal tests. Meanwhile, PF-GL-TE gel played significant preventive effects on melasma induced by progesterone injection and ultraviolet radiation B (UVB) irradiation. According to the results of H&E staining and Masson staining of rat skin, PF-GL-TE gel can alleviate the skin inflammation of and reduce the loss of collagen fibers of back skin in the melasma model rats. Compared with the PF-GL mixture gel, PF-GL-TE gel significantly attenuated the oxidative damage of liver and skin by increasing the activity of SOD and reducing the content of MDA. The results of Western blot showed that PF-GL-TE gel might down-regulate melanin-related proteins expressions of MITF/TYR/TRP1 and TRP2 to prevent and treat melasma. These findings indicate that PF-GL-TE gel is an effective TDDS for delivering PF and GL into the skin, providing a promising preparation for effective prevention and treatment of melasma.

Kai-Xin-San ameliorates Alzheimer's disease-related neuropathology and cognitive impairment in APP/PS1 mice via the mitochondrial autophagy-NLRP3 inflammasome pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Kai-Xin-San (KXS) is a classic famous prescription that has been utilized for centuries to address dementia. New investigations have shown that the anti-dementia effect of KXS is connected with improved neuroinflammation. Nevertheless, the underlying mechanism is not well elucidated. AIM OF THE STUDY: We propose to discover the ameliorative impact of KXS on Alzheimer's disease (AD) and its regulatory role on the mitochondrial autophagy-nod-like receptor protein 3 (NLRP3) inflammasome pathway. MATERIALS AND METHODS: The Y maze, Morris water maze, and new objection recognition tests were applied to ascertain the spatial learning and memory capacities of amyloid precursor protein/presenilin 1 (APP/PS1) mice after KXS-treatment. Meanwhile, the biochemical indexes of the hippocampus were detected by reagent kits. The pathological alterations and mitochondrial autophagy in the mice' hippocampus were detected utilizing hematoxylin and eosin (H&E), immunohistochemistry, immunofluorescence staining, and transmission electron microscopy. Besides, the PTEN-induced putative kinase 1 (PINK1)/Parkin and NLRP3 inflammasome pathways protein expressions were determined employing the immunoblot analysis. RESULTS: The results of behavioral tests showed that KXS significantly enhanced the AD mice' spatial learning and memory capacities. Furthermore, KXS reversed the biochemical index levels and reduced amyloid-ß protein deposition in AD mice brains. Besides, H&E staining showed that KXS remarkably ameliorated the neuronal damage in AD mice. Concurrently, the results of transmission electron microscopy suggest that KXS ameliorated the mitochondrial damage in microglia and promoted mitochondrial autophagy. Moreover, the immunofluorescence outcomes exhibited that KXS promoted the expression of protein 1 light chain 3B (LC3B) associated with microtubule and the generation of autophagic flux. Notably, the immunofluorescence co-localization results confirmed the presence of mitochondrial autophagy in microglia. Finally, KXS promoted the protein expressions of the PINK1/Parkin pathway and reduced the activation of NLRP3 inflammasome. Most importantly, these beneficial effects of KXS were attenuated by the mitochondrial autophagy inhibitor chloroquine. CONCLUSION: KXS ameliorates AD-related neuropathology and cognitive impairment in APP/PS1 mice by enhancing the mitochondrial autophagy and suppressing the NLRP3 inflammasome pathway.