Nanocatalysts for modulating antitumor immunity: fabrication, mechanisms and applications.

Immunotherapy harnesses the inherent immune system in the body to generate systemic antitumor immunity, offering a promising modality for defending against cancer. However, tumor immunosuppression and evasion seriously restrict the immune response rates in clinical settings. Catalytic nanomedicines can transform tumoral substances/metabolites into therapeutic products in situ, offering unique advantages in antitumor immunotherapy. Through catalytic reactions, both tumor eradication and immune regulation can be simultaneously achieved, favoring the development of systemic antitumor immunity. In recent years, with advancements in catalytic chemistry and nanotechnology, catalytic nanomedicines based on nanozymes, photocatalysts, sonocatalysts, Fenton catalysts, electrocatalysts, piezocatalysts, thermocatalysts and radiocatalysts have been rapidly developed with vast applications in cancer immunotherapy. This review provides an introduction to the fabrication of catalytic nanomedicines with an emphasis on their structures and engineering strategies. Furthermore, the catalytic substrates and state-of-the-art applications of nanocatalysts in cancer immunotherapy have also been outlined and discussed. The relationships between nanostructures and immune regulating performance of catalytic nanomedicines are highlighted to provide a deep understanding of their working mechanisms in the tumor microenvironment. Finally, the challenges and development trends are revealed, aiming to provide new insights for the future development of nanocatalysts in catalytic immunotherapy.

Effects of the motor cortical theta-burst transcranial-focused ultrasound stimulation on the contralateral motor cortex.

Theta-burst transcranial ultrasound stimulation (tbTUS) increases primary motor cortex (M1) excitability for at least 30 min. However, the remote effects of focal M1 tbTUS on the excitability of other cortical areas are unknown. Here, we examined the effects of left M1 tbTUS on right M1 excitability. An 80 s train of active or sham tbTUS was delivered to the left M1 in 20 healthy subjects. Before and after the tbTUS, we measured: (1) corticospinal excitability using motor-evoked potential (MEP) amplitudes from single-pulse transcranial magnetic stimulation (TMS) of left and right M1; (2) interhemispheric inhibition (IHI) from left to right M1 and from right to left M1 using a dual-site paired-pulse TMS paradigm; and (3) intracortical circuits of the right M1 with short-interval intracortical inhibition and intracortical facilitation (ICF) using paired-pulse TMS. Left M1 tbTUS decreased right M1 excitability as shown by decreased MEP amplitudes, increased right M1 ICF and decreased short-interval IHI from left to right hemisphere at interstimulus interval (ISI) of 10 ms but not long-interval IHI at interstimulus interval of 40 ms. The study showed that left M1 tbTUS can change the excitability of remote cortical areas with decreased right M1 excitability and interhemispheric inhibition. The remote effects of tbTUS should be considered when it is used in neuroscience research and as a potential neuromodulation treatment for brain disorders. KEY POINTS: Transcranial ultrasound stimulation (TUS) is a novel non-invasive brain stimulation technique for neuromodulation with the advantages of being able to achieve high spatial resolution and target deep brain structures. A repetitive TUS protocol, with an 80 s train of theta burst patterned TUS (tbTUS), has been shown to increase primary motor cortex (M1) excitability, as well as increase alpha and beta movement-related spectral power in distinct brain regions. In this study, we examined on the effects of the motor cortical tbTUS on the excitability of contralateral M1 measured with MEPs elicited by transcranial magnetic stimulation. We showed that left M1 tbTUS decreased right M1 excitability and left-to-right M1 interhemispheric inhibition, and increased intracortical facilitation of right M1. These results lead to better understand the effects of tbTUS and can help the development of tbTUS for the treatment of neurological and psychiatric disorders and in neuroscience research.

Chemoproteomic strategy identifies PfUCHL3 as the target of halofuginone.

The human malaria parasite Plasmodium falciparum (P. falciparum) continues to pose a significant public health challenge, leading to millions of fatalities globally. Halofuginone (HF) has shown a significant anti-P. falciparum effect, suggesting its potential as a therapeutic agent for malaria treatment. In this study, we synthesized a photoaffinity labeling probe of HF to identify its direct target in P. falciparum. Our results reveal that ubiquitin carboxyl-terminal hydrolase 3 (PfUCHL3) acts as a crucial target protein of HF, which modulates parasite growth in the intraerythrocytic cycle. In particular, we discovered that HF potentially forms hydrogen bonds with the Leu10, Glu11, and Arg217 sites of PfUCHL3, thereby inducing an allosteric effect by promoting the embedding of the helix 6' region on the protein surface. Furthermore, HF disrupts the expression of multiple functional proteins mediated by PfUCHL3, specifically those that play crucial roles in amino acid biosynthesis and metabolism in P. falciparum. Taken together, this study highlights PfUCHL3 as a previously undisclosed druggable target of HF, which contributes to the development of novel anti-malarial agents in the future.

Molecular cloning and functional analyses of C-C motif chemokine ligand 3 (CCL3) in mandarin fish Siniperca chuatsi.

Chemokines are critical molecules involved in immune reaction and immune system homeostasis, and some chemokines play a role in antiviral immunity. It is not known if the C-C motif chemokine ligand 3 (CCL3), a member of the CC chemokine family, possesses antiviral properties in fish. In this study, a ccl3 was cloned from the mandarin fish (Siniperca chuatsi), and it has an open reading frame (ORF) of 276 base pairs, which are predicted to encode a 91-amino acid peptide. Mandarin fish CCL3 revealed conserved sequence features with four cysteine residues and closely relationships with the CCL3s from other vertebrates based on the sequence alignment and phylogenetic analysis. The transcripts of ccl3 were notably enriched in immune-related organs, such as spleen and gills in healthy mandarin fish, and the ccl3 was induced in the isolated mandarin fish brain (MFB) cells following infection with infectious spleen and kidney necrosis virus (ISKNV). Moreover, in MFB cells, overexpression of CCL3 induced immune factors, such as IL1ß, TNFα, MX, IRF1 and IFNh, and exhibited antiviral activity against ISKNV. This study sheds light on the immune role of CCL3 in immune response of mandarin fish, and its antiviral defense mechanism is of interest for further investigation.

Effect of WeChat-Based Medication Guidance on Symptoms and Serological Parameters in Children with Mycoplasma Pneumoniae.

Objective: The aim of this study was to assess the effect of microsoft-based medication guidance on the level of symptoms and serological indicators in children receiving budesonide nebulisation combined with terbutaline for the treatment of Mycoplasma pneumoniae pneumoniae (MPP). Methods: A total of 109 children with MPP treated in The First Affiliated Hospital of Ningbo University of China between October 2022 and April 2023 were divided into the conventional group (n=54, with medication guidance by telephone follow-up) and the WeChat group (n=55, with medication guidance based on the WeChat platform) using a randomized number table. The time to resolution of symptoms, serological index levels, incidence of adverse drug events, medication adherence scores and satisfaction rate of family guidance were compared between the two groups. Results: The disappearance time of symptoms such as wheezing and cough in the WeChat group was shorter than that in the conventional group (P < .05). After treatment, the C-reactive protein (CRP), interleukin-6 (IL-6) and calcitoninogen (PCT) levels and the incidence of adverse drug events were lower in the WeChat group than in the conventional group (P < .05). After treatment, the levels of forceful spirometry (FVC), 1st-second expiratory volume (FEV1), peak expiratory flow rate (PEF), medication compliance score and family guidance satisfaction rate were higher in the WeChat group than in the conventional group (P < .05). Conclusion: WeChat-based medication guidance can optimize the therapeutic effect of MPP, improve children's medication compliance and satisfaction rate of family guidance, and reduce the occurrence of adverse drug events.

Inherent Capability of Self-Assembling Nanostructures in Specific Proteasome Activation for Cancer Cell Pyroptosis.

Understanding the direct interaction of nanostructures per se with biological systems is important for biomedical applications. However, whether nanostructures regulate biological systems by targeting specific cellular proteins remains largely unknown. In the present work, self-assembling nanomicelles are constructed using small-molecule oleanolic acid (OA) as a molecular template. Unexpectedly, without modifications by functional ligands, OA nanomicelles significantly activate cellular proteasome function by directly binding to 20S proteasome subunit alpha 6 (PSMA6). Mechanism study reveals that OA nanomicelles interact with PSMA6 to dynamically modulate its N-terminal domain conformation change, thereby controlling the entry of proteins into 20S proteasome. Subsequently, OA nanomicelles accelerate the degradation of several crucial proteins, thus potently driving cancer cell pyroptosis. For translational medicine, OA nanomicelles exhibit a significant anticancer potential in tumor-bearing mouse models and stimulate immune cell infiltration. Collectively, this proof-of-concept study advances the mechanical understanding of nanostructure-guided biological effects via their inherent capacity to activate proteasome.

Induction of Human Motor Cortex Plasticity by Theta Burst Transcranial Ultrasound Stimulation.

OBJECTIVE: Transcranial ultrasound stimulation (TUS) is a promising noninvasive brain stimulation technique with advantages of high spatial precision and ability to target deep brain regions. This study aimed to develop a TUS protocol to effectively induce brain plasticity in human subjects. METHODS: An 80-second train of theta burst patterned TUS (tbTUS), regularly patterned TUS (rTUS) with the same sonication duration, and sham tbTUS was delivered to the motor cortex in healthy subjects. Transcranial magnetic stimulation (TMS) was used to examine changes in corticospinal excitability, intracortical inhibition and facilitation, and the site of plasticity induction. The effects of motor cortical tbTUS on a visuomotor task and the effects of occipital cortex tbTUS on motor cortical excitability were also tested. RESULTS: The tbTUS produced consistent increase in corticospinal excitability for at least 30 minutes, whereas rTUS and sham tbTUS produced no significant change. tbTUS decreased short-interval intracortical inhibition and increased intracortical facilitation. The effects of TMS in different current directions suggested that the site of the plastic changes was within the motor cortex. tbTUS to the occipital cortex did not change motor cortical excitability. Motor cortical tbTUS shortened movement time in a visuomotor task. INTERPRETATION: tbTUS is a novel and efficient paradigm to induce cortical plasticity in humans. It has the potential to be developed for neuromodulation treatment for neurological and psychiatric disorders, and to advance neuroscience research. ANN NEUROL 2022;91:238-252.

Allogeneic cord blood regulatory T cells can resolve lung inflammation.

BACKGROUND AIMS: CD4+CD25+CD127lo regulatory T cells (Tregs) are responsible for maintaining immune homeostasis. Tregs can be rendered defective and deficient as a result of the immune imbalance seen in lung injury, and such dysfunction can play a major role in continued tissue inflammation. The authors hypothesized that adoptive therapy with healthy allogeneic umbilical cord blood (UCB)-derived Tregs may be able to resolve inflammation. RESULTS: Ex vivo-expanded UCB Tregs exhibited a unique phenotype with co-expression of CD45RA+CD45RO+ >80% and lung homing markers, including CD49d. UCB Tregs did not turn pathogenic when exposed to IL-6. Co-culture with increasing doses of dexamethasone led to a synergistic increase in UCB Treg-induced apoptosis of conventional T cells (Tcons), which translated into significantly higher suppression of proliferating Tcons, especially at a lower Treg:Tcon ratio. Multiple injections of UCB Tregs led to their preferential accumulation in lung tissue in an immune injury xenogenic model. A significant decrease in lung resident cytotoxic CD8+ T cells (P = 0.0218) correlated with a sustained decrease in their systemic distribution compared with controls (P < 0.0001) (n = 7 per arm) as well as a decrease in circulating human soluble CD40 ligand level (P = 0.031). Tissue architecture was preserved in the treatment arm, and a significant decrease in CD3+ and CD8+ burden was evident in immunohistochemistry analysis. CONCLUSIONS: UCB Treg adoptive therapy is a promising therapeutic strategy for treatment of lung injury.

Accelerated Transcranial Ultrasound Neuromodulation in Parkinson's Disease: A Pilot Study.

OBJECTIVE: Low-intensity transcranial focused ultrasound (TUS) is a novel method for neuromodulation. We aimed to study the feasibility of stimulating the bilateral primary motor cortices (M1) with accelerated theta-burst TUS (a-tbTUS) on neurophysiologic and clinical outcomes in Parkinson's disease (PD). METHODS: Patients were randomly assigned to receive active or sham a-tbTUS for the first visit and the alternate condition on the second visit, at least 10 days apart. a-tbTUS was administered in three consecutive sonications at 30-minute intervals. We used an accelerated protocol to produce an additive effect of stimulation. Patients were studied in the OFF-medication state. Transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs) were used to assess motor cortical excitability before and after TUS. Clinical outcomes after a-tbTUS administration were assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS)-III. RESULTS: A total of 20 visits were conducted in 10 PD patients. Compared to the baseline, TMS-elicited MEP amplitudes significantly increased following active but not sham sonication (P = 0.0057). MEP amplitudes were also higher following a-tbTUS than sham sonication (P = 0.0064). There were no statistically significant changes in MDS-UPDRS-III scores with active or sham a-tbTUS. CONCLUSIONS: a-tbTUS increases motor cortex excitability and is a feasible non-invasive neuromodulation strategy in PD. Future studies should determine optimal dosing parameters and the durability of neurophysiologic and clinical outcomes in PD patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Long-Term Recording of Subthalamic Aperiodic Activities and Beta Bursts in Parkinson's Disease.

BACKGROUND: Local field potentials (LFPs) represent the summation of periodic (oscillations) and aperiodic (fractal) signals. Although previous studies showed changes in beta band oscillations and burst characteristics of the subthalamic nucleus (STN) in Parkinson's disease (PD), how aperiodic activity in the STN is related to PD pathophysiology is unknown. OBJECTIVES: The study aimed to characterize the long-term effects of STN-deep brain stimulation (DBS) and dopaminergic medications on aperiodic activities and beta bursts. METHODS: A total of 10 patients with PD participated in this longitudinal study. Simultaneous bilateral STN-LFP recordings were conducted in six separate visits during a period of 18 months using the Activa PC + S device in the off and on dopaminergic medication states. We used irregular-resampling auto-spectral analysis to separate oscillations and aperiodic components (exponent and offset) in the power spectrum of STN-LFP signals in beta band. RESULTS: Our results revealed a systematic increase in both the exponent and the offset of the aperiodic spectrum over 18 months following the DBS implantation, independent of the dopaminergic medication state of patients with PD. In contrast, beta burst durations and amplitudes were stable over time and were suppressed by dopaminergic medications. CONCLUSIONS: These findings indicate that oscillations and aperiodic activities reflect at least partially distinct yet complementary neural mechanisms, which should be considered in the design of robust biomarkers to optimize adaptive DBS. Given the link between increased gamma-aminobutyric acidergic (GABAergic) transmission and higher aperiodic activity, our findings suggest that long-term STN-DBS may relate to increased inhibition in the basal ganglia. © 2022 International Parkinson and Movement Disorder Society.

Improve the Crosslinking Reactivity of Nitrile: Design of Nitrile-Functionalized Pyrazine and its Hydrogen Bond-Assisted Nucleophilic Enhancement Study.

In this study, molecular engineering and biomimetic principles are utilized to prepare highly effective nitrile-functionalized pyrazine crosslinking units by exploiting pyrazine's unique nucleophilic strengthening mechanism and proton bonding ability. The curing behaviors of pyrazine-2,3-dicarbonitrile and phthalonitrile are investigated through model curing systems and molecular simulation. The results indicate that pyrazine-2,3-dicarbonitrile exhibits higher reactivity than phthalonitrile, promoted by amine. The cured products of pyrazine-2,3-dicarbonitrile predominantly comprise thermally stable azaisoindoline and azaphthalocyanine. This novel type of highly effective crosslinking unit, and the comprehended mechanism of action of pyrazine at the molecular level, significantly expand the application of pyrazine in materials science.

Drug resistance and influencing factors of biofilm bacteria in upper urinary calculi patients with double J stent indwelling.

OBJECTIVE: To analyze the distribution and drug resistance of biofilm bacteria infected with upper urinary calculi patients with double J stent indwelling, and to explore the influencing factors of Biofilm Bacteria Infections. METHODS: A total of 400 patients with upper urinary calculi who adopted double J stent inserting in our hospital from January 2019 to January 2022 were included. Urine and double J stent samples were collected, pathogen cultures were performed, and then drug sensitivity test analysis was carried out for isolates. Univariate and multivariate logistic regression analyzes were used to analyze the influencing factors of patients with double J stent associated biofilm bacteria infections. RESULTS: A total of 13 strains (3.2%) of biofilm bacteria were detected in urine samples and 168 strains (42%) in double J stent samples (P < 0.05), 95 strains (23.7%) of pathogenic bacteria were separated from urine samples and 117 strains (29.2%) from double J-stent samples (P > 0.05). Escherichia coli were the most common bacteria. There was significantly higher drug resistance observed in biofilm bacteria versus urine-cultured pathogens (P < 0.05). Advanced age, long-term catheterization, inadequate water intake, hypoproteinemia, abnormal renal function, and diabetes mellitus were independent risk factors for biofilm bacteria infection associated with double J stent(P < 0.05). CONCLUSION: Among the upper urinary calculi patients with double J stent indwelling, the positive rate and drug resistance of biofilm bacteria obtained from double J stent were significantly higher than that from urine. More attention should be paid to the factors that influence biofilm bacteria infections.

Transurethral en bloc resection of a bladder perivascular epithelioid cell tumor (PEComa): a case report.

BACKGROUND: Perivascular epithelioid cell tumor (PEComa) is a mesenchymal tumor with distinct histologic and immunologic features. PEComas that originate in the bladder are extremely rare clinically, with only 35 cases reported in the English literature thus far. Here, we report a case of bladder PEComa resection by transurethral en bloc resection of bladder tumor (ERBT). CASE PRESENTATION: A 66-year-old female with a history of poorly controlled type 2 diabetes with associated complications of frequent urinary tract infections presented to our hospital for a routine physical examination. Outpatient ultrasound examination revealed a strong echogenic mass of approximately 1.5 × 1.3 × 1.3 cm in size on the posterior wall of the bladder. The enhanced computed tomography and enhanced magnetic resonance imaging after admission both suggested a well-defined isolated nodular mass on the posterior wall of the bladder with significant enhancement on the enhanced scan. The tumor was successfully and completely resected by ERBT. Postoperative pathological examination and immunohistochemical results confirmed the mass was a bladder PEComa. No tumor recurrence was observed in the six-month postoperative follow-up. CONCLUSION: Bladder PEComa is an extremely rare mesenchymal tumor of the urinary system. When imaging and cystoscopy reveal a nodular mass with an abundant blood supply in the bladder, PEComa should be included in the differential diagnosis of bladder tumors. Surgical resection is currently the primary option for the treatment of bladder PEComa. For a solitary, pedunculated, narrow-based, small-sized bladder PEComa, resection of the tumor by ERBT was a safe and feasible approach in our patient and may be considered for similar cases in the future.

Calycosin protects against oxidative stress-induced cardiomyocyte apoptosis by activating aldehyde dehydrogenase 2.

Myocardial infarction (MI) is the leading cause of death worldwide, and oxidative stress is part of the process that causes MI. Calycosin, a naturally occurring substance with cardioprotective properties, is one of the major active constituents in Radix Astragali. In this study, effect of Calycosin was investigated in vivo and in vitro to determine whether it could alleviate oxidative stress and oxidative stress-induced cardiac apoptosis in neonatal cardiomyocytes (NCMs) via activation of aldehyde dehydrogenase 2 (ALDH2). Calycosin protected against oxidative stress and oxidative stress-induced apoptosis in NCMs. Molecular docking revealed that the ALDH2-Calycosin complex had a binding energy of -9.885 kcal/mol. In addition, molecular docking simulations demonstrated that the ALDH2-Calycosin complex was stable. Using BLI assays, we confirmed that Calycosin could interact with ALDH2 (KD  = 1.9 × 10-4 M). Furthermore, an ALDH2 kinase activity test revealed that Calycosin increased ALDH2 activity, exhibiting an EC50 of 91.79 µM. Pre-incubation with ALDH2 inhibitor (CVT-10216 or disulfiram) reduced the cardio-protective properties Calycosin. In mice with MI, Calycosin therapy substantially reduced myocardial apoptosis, oxidative stress, and activated ALDH2. Collectively, our findings clearly suggest that Calycosin reduces oxidative stress and oxidative stress-induced apoptosis via the regulation of ALDH2 signaling, which supports potential therapeutic use in MI.

Effects of interpretation bias modification on hostile attribution bias and reactive cyber-aggression in Chinese adolescents: a randomized controlled trial.

Highly aggressive individuals tend to interpret others' motives and intentions as hostile in both offline and online social situations. The current study examined whether hostile interpretation bias can be modified to influence cyber-aggression in Chinese middle school students using an interpretation bias modification program. Gender differences and the heterogeneity of cyber-aggression were also investigated since previous studies suggest that they play important roles in determining the intervention effect. One hundred and twenty-one middle school students were randomized to receive either an eight-session interpretation bias modification task (CBM-I; n = 61) or an eight-session placebo control task (PCT; n = 60) over four weeks. Measures of hostile attribution bias and cyber-aggression were administered at baseline, post-training, and at one week follow-up. Results showed that compared to PCT, participants in CBM-I showed a significant reduction in reactive cyber-aggression. However, contrary to our expectation, there was no significant difference between the two groups in the reduction of hostile attribution bias after training. The moderated mediation analysis revealed that the effect of CBM-I on hostile attribution bias and the mediating role of hostile attribution bias in the relationship between CBM-I condition and reactive cyber-aggression was only observed among females, but not among males. These findings provide initial evidence for the potential of CBM-I in reducing hostile attribution bias and cyber-aggression. However, for male students, CBM-I might not be effective enough as expected. Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-023-04433-3.

[Anti-infectious pneumonia target discovery and molecular mechanism study of Jingfang Granules].

This study aimed to identify the direct pharmacological targets of Jingfang Granules in treating infectious pneumonia via "target fishing" strategy. Moreover, the molecular mechanism of Jingfang Granules in treating infectious pneumonia was also investigated based on target-related pharmacological signaling pathways. First, the Jingfang Granules extract-bound magnetic nanoparticles were prepared, which were incubated with lipopolysaccharide(LPS)-induced mouse pneumonia tissue lysates. The captured proteins were analyzed by high-resolution mass spectrometry(HRMS), and the target groups with specific binding to the Jingfang Granules extract were screened out. Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis was used to identify the target protein-associated signaling pathways. On this basis, the LPS-induced mouse model of infectious pneumonia was established. The possible biological functions of target proteins were verified by hematoxylin-eosin(HE) staining and immunohistochemical assay. A total of 186 Jingfang Granules-specific binding proteins were identified from lung tissues. KEGG pathway enrichment analysis showed that the target protein-associated signaling pathways mainly included Salmonella infection, vascular and pulmonary epithelial adherens junction, ribosomal viral replication, viral endocytosis, and fatty acid degradation. The target functions of Jingfang Granules were related to pulmonary inflammation and immunity, pulmonary energy metabolism, pulmonary microcirculation, and viral infection. Based on the in vivo inflammation model, Jingfang Granules significantly improved the alveolar structure of the LPS-induced mouse model of infectious pneumonia and down-regulated the expressions of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6). Meanwhile, Jingfang Gra-nules significantly up-regulated the expressions of key proteins of mitochondrial function COX Ⅳ and ATP, microcirculation-related proteins CD31 and Occludin, and proteins associated with viral infection DDX21 and DDX3. These results suggest that Jingfang Gra-nules can inhibit lung inflammation, improve lung energy metabolism and pulmonary microcirculation, resist virus infection, thus playing a protective role in the lung. This study systematically explains the molecular mechanism of Jingfang Granules in the treatment of respiratory inflammation from the perspective of target-signaling pathway-pharmacological efficacy, thereby providing key information for clinical rational use of Jingfang Granules and expanding potential pharmacological application.

[Anti-depression targets and mechanism study of Kaixin San].

This study identified the anti-depression targets of Kaixin San(KXS) in the brain tissue with "target fishing" strategy, and explored the target-associated pharmacological signaling pathways to reveal the anti-depression molecular mechanism of KXS. The Balb/c mouse model of depression was established by chronic unpredictable mild stress(CUMS) and the anti-depression effect of KXS was evaluated by forced swimming test and sucrose preference test. KXS active components were bonded to the benzophenone-modified magnetic nanoparticles by photocrosslinking reaction for capturing target proteins from cortex, thalamus and hippocampus of depressive mice. The target proteins were identified by liquid chromatography-mass spectrometry/mass spectrometry(LC-MS/MS). The enrichment analysis on signaling pathways was performed by Cytoscape. The potential biological functions of targets were verified by immunohistochemistry and Western blot assay. The results showed that KXS significantly improved the behavioral indexes. There were 64, 91, and 44 potential targets of KXS identified in cortex, thalamus, and hippocampus, respectively, according to the target identification experiment. The functions of these targets were mainly associated with vasopressin-regulated water reabsorption, salmonella infection, thyroid hormone synthesis, and other signaling pathways. Besides, the results of immunohistochemistry and Western blot showed that KXS up-regulated the expressions of argipressine(AVP) in the cortex, heat shock protein 60(HSP60), cytochrome C oxidase 4(COX4), and thyrotropin-releasing hormone(TRH) in the thalamus, and down-regulated the expressions of tumor necrosis factor-α(TNF-α) and nuclear factor kappa B(NF-κB) p65 in the thalamus. Therefore, KXS may exert anti-depression effect through regulating vasopressin signaling pathway in the cortex and inflammation, energy metabolism, and thyroid hormone signaling pathways in the thalamus, and the effect of KXS on hippocampus is not significant.

When High-Temperature Cesium Chemistry Meets Self-Templating: Metal Acetates as Building Blocks of Unusual Highly Porous Carbons.

Self-templating is a facile strategy for synthesizing porous carbons by direct pyrolysis of organic metal salts. However, the method typically suffers from low yields (<4%) and limited specific surface areas (SSA<2000 m2 g-1 ) originating from low activity of metal cations (e.g., K+ or Na+ ) in promoting construction and activation of carbon frameworks. Here we use cesium acetate as the only precursor of oxo-carbons with large SSA of the order of 3000 m2 g-1 , pore volume approaching 2 cm3 g-1 , tunable oxygen contents, and yields of up to 15 %. We unravel the role of Cs+ as an efficient promoter of framework formation, templating and etching agent, while acetates act as carbon/oxygen sources of carbonaceous frameworks. The oxo-carbons show record-high CO2 uptake of 8.71 mmol g-1 and an ultimate specific capacitance of 313 F g-1 in the supercapacitor. This study helps to understand and rationally tailor the materials design by a still rare organic solid-state chemistry.

Gold Nanoparticle-Based Photo-Cross-Linking Strategy for Cellular Target Identification of Supercomplex Molecular Systems.

Cellular target identification plays an essential role in innovative drug development and pharmacological mechanism elucidation. However, very few practical experimental methodologies have been developed for identifying target proteins for supercomplex molecular systems such as biologically active phytochemicals or pharmaceutical compositions. To overcome this limitation, we synthesized gold nanoparticles (AuNPs) as solid scaffolds, which were bound with 4,4'-dihydroxybenzophenone (DHBP) as a photo-cross-linking group on the surface. Then, DHBP-modified AuNPs cross-linked various organic compounds from phytochemicals under ultraviolet radiation via carbene reactions, H-C bond insertion, for catalytic C-C bond formation. We next used the phytochemical-cross-linked AuNPs (phytoAuNPs) to pull down potential binding proteins from brain tissue lysate and identified 13 neuroprotective targets by mass spectrometry analysis. As an exemplary study, we selected Hsp60 as a crucial cellular target to further screen 14 target-binding compounds from phytochemicals through surface plasmon resonance (SPR) analysis, followed by Hsp60 activity detection and neuroprotective effect assay in cells. Collectively, this gold nanoparticle-based photo-cross-linking strategy can serve as a useful platform for discovering novel cellular targets for supercomplex molecular systems and help to explore pharmacological mechanisms and active substances.

Photoaffinity Labeling-Based Chemoproteomic Strategy Reveals RBBP4 as a Cellular Target of Protopanaxadiol against Colorectal Cancer Cells.

Protopanaxadiol (PPD), a main ginseng metabolite, exerts powerful anticancer effects against multiple types of cancer; however, its cellular targets remain elusive. Here, we synthesized a cell-permeable PPD probe via introducing a bifunctional alkyne-containing diazirine photo-crosslinker and performed a photoaffinity labeling-based chemoproteomic study. We identified retinoblastoma binding protein 4 (RBBP4), a chromatin remodeling factor, as an essential cellular target of PPD in HCT116 colorectal cancer cells. PPD significantly decreased RBBP4-dependent trimethylation at lysine 27 of histone H3 (H3K27me3), a crucial epigenetic marker that correlates with histologic signs of colorectal cancer aggressiveness, and PPD inhibition of proliferation and migration of HCT116 cells was antagonized by RBBP4 RNA silencing. Collectively, our study highlights a previously undisclosed anti-colorectal cancer cellular target of the ginseng metabolite and advances the fundamental understanding of RBBP4 functions via a chemical biology strategy.