Predictive performance of [18F]F-fibroblast activation protein inhibitor (FAPI)-42 positron emission tomography/computed tomography (PET/CT) in evaluating response of recurrent or metastatic gastrointestinal stromal tumors: complementary or alternative to [18F]fluorodeoxyglucose (FDG) PET/CT?

Background: Accurately and promptly predicting the response of gastrointestinal stromal tumors (GISTs) to targeted therapy is essential for optimizing treatment strategies. However, some fractions of recurrent or metastatic GISTs present as non-FDG-avid lesions, limiting the value of [18F]fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) in treatment evaluation. This study evaluated the efficacy of [18F]F-fibroblast activation protein inhibitor (FAPI)-42 [18F]FAPI-42) PET/CT for assessing the treatment response in recurrent or metastatic GISTs, in comparison to [18F]FDG PET/CT and explores a model integrating PET/CT imaging and clinical parameters to optimize the clinical use of these diagnostic tools. Methods: Our retrospective analysis included 27 patients with recurrent or metastatic GISTs who underwent [18F]FAPI-42 PET/CT and [18F]FDG PET/CT at baseline before switching targeted therapy. Treatment response status was divided into a progression group (PG) and a non-progression group (NPG) based on the Response Criteria in Solid Tumors (RECIST) 1.1, according to the contrast-enhanced computed tomography (CT) scan at six months. [18F]FAPI-42 and [18F]FDG PET/CT parameters including the mean standardized uptake value (SUVmean), the standard uptake value corrected for lean body mass (SULpeak), the maximum standardized uptake value (SUVmax), tumor-to-blood pool SUV ratio (TBR), tumor-to-liver SUV ratio (TLR), metabolic tumor volume (MTV)/FAPI-positive tumor volume (GTV-FAPI), total lesion glycolysis (TLG)/FAPI-positive total lesion accumulation (TLF) were correlated with the response status to identify indicative of treatment response. The predictive performance of them was quantified by generating receiver operating characteristic curves (ROC), calibration curves, and cross-validation. Results: A total of 110 lesions were identified in 27 patients. Compared with PG, NPG was associated with lower levels of TBR and SUVmean in FDG PET/CT (TBR-FDG, SUVmean-FDG; P=0.033 and P=0.038, respectively), with higher SULpeak and TLF in FAPI PET/CT (SULpeak-FAPI, TLF-FAPI; P=0.10 and P=0.049, respectively). The predictive power of a composite-parameter model, including TBR-FDG, SULpeak-FAPI, gene mutation, and type of targeted therapy [area under the curve (AUC) =0.865], was superior to the few-parameter models incorporating TBR-FDG (AUC =0.637, P<0.001), SULpeak-FAPI (AUC =0.665, P<0.001) or both (AUC =0.721, P<0.001). Conclusions: Both [18F]FAPI-42 PET/CT and [18F]FDG PET/CT have value in predicting the treatment response of recurrent or metastatic GISTs. And [18F]FAPI-42 PET/CT offers synergistic value when used in combination with [18F]FDG PET/CT. Notably, the nomogram generated from the model incorporating [18F]FAPI-42 PET/CT, [18F]FDG PET/CT parameters, gene mutation, and type of targeted therapy could yield more precise predictions of the response of recurrent metastatic GISTs.

Size and morphology control over MOF-74 crystals.

Precise control of the size and morphology of metal-organic framework (MOF) crystals is challenging yet critical for the expansion of the application potential of MOF materials. This work presents a detailed investigation of the impact of various synthetic conditions such as reactant ratio, acidity, capping agent, reaction solution (H2O, ethanol and DMF) etc. on the size and morphology of Mg-MOF-74, a classical MOF with record high CO2 uptake capacity. By varying these fabrication parameters and modulators, the morphology and size of crystals can be precisely tuned in the nanometer to micrometer range. Particularly, the nanosized flaky Mg-MOF-74 crystals with an aspect ratio of ∼0.5 were synthesized for the first time by varying the amount of water. The MOF-74 crystals with different size and morphologies are good candidates for more advanced applications favored by crystal size and morphology control.

A Lego-Like Reconfigurable Microfluidic Stabilizer System with Tunable Fluidic RC Constants and Stabilization Ratios.

In microfluidic systems, it is important to maintain flow stability to execute various functions, such as chemical reactions, cell transportation, and liquid injection. However, traditional flow sources, often bulky and prone to unpredictable fluctuations, limit the portability and broader application of these systems. Existing fluidic stabilizers, typically designed for specific flow sources, lack reconfigurability and adaptability in terms of the stabilization ratios. To address these limitations, a modular and standardized stabilizer system with tunable stabilization ratios is required. In this work, we present a Lego-like modular microfluidic stabilizer system, which is fabricated using 3D printing and offers multi-level stabilization combinations and customizable stabilization ratios through the control of fluidic RC constants, making it adaptable to various microfluidic systems. A simplified three-element circuit model is used to characterize the system by straightforwardly extracting the RC constant without intricate calculations of the fluidic resistance and capacitance. By utilizing a simplified three-element model, the stabilizer yields two well-fitted operational curves, demonstrating an R-square of 0.95, and provides an optimal stabilization ratio below 1%. To evaluate the system's effectiveness, unstable input flow at different working frequencies is stabilized, and droplet generation experiments are conducted and discussed. The results show that the microfluidic stabilizer system significantly reduces flow fluctuations and enhances droplet uniformity. This system provides a new avenue for microfluidic stabilization with a tunable stabilization ratio, and its plug-and-play design can be effectively applied across diverse applications to finely tune fluid flow behaviors in microfluidic devices.

Effect of different physical activities on erectile dysfunction in adult men not receiving phosphodiesterase-5 inhibitors therapy: A systematic review and meta-analysis.

BACKGROUND: Erectile dysfunction (ED) is prevalent not only among older males but also in younger. The physical activity has been considered a potential protective factor against ED. However, there is a lack of comprehensive research on the impact of exercise interventions specifically on ED patients. OBJECTIVES: This study aimed to assess the effectiveness of the physical activity in addressing ED symptoms among adult males, without the use of the phosphodiesterase-5 inhibitors (PDE5i) therapy. Additionally, subgroup analysis was performed to evaluate the effects of different exercise modes. METHODS: Employing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a systematic literature search. A registered protocol is available at PROSPERO (CRD42023441717). Our search spanned PubMed, Web of Science, Embase, and Cochrane Library, with data collection ending on 11 April 2024. The Cochrane Risk of Bias tool was applied by two independent authors to assess randomized controlled trial (RCT) quality. The primary endpoint was determined as the International Index of Erectile Function (IIEF) scores. RESULTS: A total of seven RCTs were included. Utilizing a random-effects model, the estimated standardized mean difference (SMD) was 0.69 (95% confidence interval [CI] 0.37 to 1.02, p < 0.0001) for the overall impact of the physical activity. Subgroup analysis revealed SMDs of 0.81 (95% CI 0.56 to 1.06; p < 0.00001) for aerobic training alone. However, no significant improvement was observed with pelvic floor muscle training (PFMT) (SMD 0.03; 95% CI -0.68 to 0.75; p = 0.93) and a combination of aerobic and resistance training (SMD 0.84; 95% CI -0.41 to 2.09; p = 0.19) CONCLUSION: The findings of this study highlight a significant improvement in the erectile function following exercise interventions for adult men with ED, who are not receiving the PDE5i therapy, especially in conducting aerobic training alone. However, PFMT and a combination of aerobic and resistance training did not show significant improvements in erectile function from this study.

Identifying therapeutic targets for breast cancer: insights from systematic Mendelian randomization analysis.

Background: Breast cancer (BC) exhibits a high incidence rate, imposing a substantial burden on healthcare systems. Novel drug targets are urgently needed for BC. Mendelian randomization (MR) has gained widespread application for identifying fresh therapeutic targets. Our endeavor was to pinpoint circulatory proteins causally linked to BC risk and proffer potential treatment targets for BC. Methods: Through amalgamating protein quantitative trait loci from 2,004 circulating proteins and comprehensive genome-wide association study data from the Breast Cancer Association Consortium, we conducted MR analyses. Employing Steiger filtering, bidirectional MR, Bayesian colocalization, phenotype scanning, and replication analyses, we further solidified MR study outcomes. Additionally, protein-protein interaction (PPI) network was harnessed to unveil latent associations between proteins and prevailing breast cancer medications. The phenome-wide MR (Phe-MR) was employed to assess potential side effects and indications for the druggable proteins of BC. Finally, we further affirmed the drugability of potential drug targets through mRNA expression analysis and molecular docking. Results: Through comprehensive analysis, we identified five potential drug targets, comprising four (TLR1, A4GALT, SNUPN, and CTSF) for BC and one (TLR1) for BC_estrogen receptor positive. None of these five potential drug targets displayed reverse causation. Bayesian colocalization suggested that these five latent drug targets shared variability with breast cancer. All drug targets were replicated within the deCODE cohort. TLR1 exhibited PPI with current breast cancer therapeutic targets. Furthermore, Phe-MR unveiled certain adverse effects solely for TLR1 and SNUPN. Conclusion: Our study uncovers five prospective drug targets for BC and its subtypes, warranting further clinical exploration.

Synthesis and biological evaluation of multimodal monoaminergic arylpiperazine derivatives with potential antidepressant profile.

Depression is a common psychiatric disorder with an estimated global prevalence of 4.4 %. Here, we designed a series of new multimodal monoaminergic arylpiperazine derivatives using a pharmacophore hybrid approach and synthesized them for the treatment of depression. Molecular docking was employed to elucidate the differences in activity and selectivity of the corresponding compounds on SERT, NET, and DAT. In vitro experiments demonstrated that compound A3 has a relatively balanced multi-target activity profile with SERT reuptake inhibition (IC50 = 12 nM), NET reuptake inhibition (IC50 = 78 nM), DAT reuptake inhibition (IC50 = 135 nM), and 5-HT1AR agonism (EC50 = 34 nM). Pharmacokinetic experiments revealed that A3 exhibited excellent bioavailability and low clearance in mice. Subsequent behavioral experiments further confirmed its significant antidepressant effects. These results further highlight the rationality of our design strategy.

BMI mediates the association of serum uric acid with bone health: a cross-sectional study of the National Health and Nutrition Examination Survey (NHANES).

BACKGROUND: The associations between serum uric acid and osteoporosis or osteopenia remain controversial, and few studies have explored whether BMI acts as a mediators in the association between the SUA and OP/ osteopenia. OBJECTIVE: To explore the relationship between serum uric acid and osteoporosis or osteopenia among US adults. METHODS: A cross-sectional study was conducted to examine the association between serum uric acid and osteoporosis or osteopenia from four cycles of NHANES. Binary logistic regression models and restricted cubic spline models were used to evaluate the association between serum uric acid and osteoporosis or osteopenia, and interaction analysis was used to test the differences between subgroups. Mediation analysis was utilized to investigate whether BMI acts as a mediator in the association between SUA and OP/ osteopenia. RESULTS: 12581 participants aged ≥ 18 years were included. A U-shape nonlinear relationship between SUA and osteoporosis or osteopenia in all people was found (P < 0.0001, P for nonlinear = 0.0287). There were significant interactions in age subgroups (P for interaction = 0.044), sex subgroups (P for interaction = 0.005), and BMI subgroups (P for interaction = 0.017). We further assessed the subgroups and found the optimal range of serum uric acid levels with a lower risk of osteoporosis or osteopenia was 357-535 µmol/L in males, 327-417 µmol/L in people aged ≥ 50 years, above 309 µmol/L in people aged < 50 years, 344-445 µmol/L in people with BMI ≥ 30, and above 308 µmol/L in people with BMI < 30. BMI fully mediated the association of SUA and OP/osteopenia, with a value of -0.0024(-0.0026--0.0021). These results were robust in sensitivity analyses. CONCLUSIONS: A complicated relationship between SUA and bone health in different populations was observed. Maintaining SUA within a specific range may be beneficial to bone health. In addition, BMI may play an important role in the association between SUA and bone health, but considering the limitations of this study, further prospective research is required.

The antidepressant-like effect and proposed mechanism of action of TPN672MA, a novel serotonin-dopamine receptor modulator for the treatment of schizophrenia.

TPN672MA, an innovative antipsychotic drug candidate currently in clinical trials, acts as a dopamine D2/D3 receptor partial agonist, serotonin 5-HT1A receptor agonist, and serotonin 5-HT2A receptor antagonist. Preclinical investigations have demonstrated its potential in treating the core symptoms of schizophrenia. The present study highlights TPN672MA's significant antidepressant-like effects in classical behavioral models, such as the chronic social defeat stress paradigm. The pronounced 5-HT1A receptor agonism and D2/D3 receptor partial agonism of TPN672MA likely contribute to its therapeutic effects in depression. Additionally, TPN672MA's antidepressant-like efficacy may be linked to its ability to enhance the expression levels of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein-95 (PSD95) in the hippocampus. Furthermore, TPN672MA displayed a more rapid onset of antidepressant-like action. In conclusion, TPN672MA represents a promising new drug candidate for the treatment of symptoms of schizophrenia and depression.

Mg-ZIF nanozyme regulates the switch between osteogenic and lipogenic differentiation in BMSCs via lipid metabolism.

The accumulation of reactive oxygen species (ROS) within the bone marrow microenvironment leads to diminished osteogenic differentiation and heightened lipogenic differentiation of mesenchymal stem cells residing in the bone marrow, ultimately playing a role in the development of osteoporosis (OP). Mitigating ROS levels is a promising approach to counteracting OP. In this study, a nanozyme composed of magnesium-based zeolitic imidazolate frameworks (Mg-ZIF) was engineered to effectively scavenge ROS and alleviate OP. The results of this study indicate that Mg-ZIF exhibits significant potential in scavenging ROS and effectively promoting osteogenic differentiation of bone mesenchymal stem cells (BMSCs). Additionally, Mg-ZIF was found to inhibit the differentiation of BMSCs into adipose cells. In vivo experiments further confirmed the ability of Mg-ZIF to mitigate OP by reducing ROS levels. Mechanistically, Mg-ZIF enhances the differentiation of BMSCs into osteoblasts by upregulating lipid metabolic pathways through ROS scavenging. The results indicate that Mg-ZIF has potential as an effective therapeutic approach for the treatment of osteoporosis.

Cannabidiol exhibits anxiolytic-like effects and antipsychotic-like effects in mice models.

Cannabidiol (CBD), a non-psychoactive compound derived from the cannabis plant, has been confirmed to induce anxiolytic-like and antipsychotic-like effects. However, the exact mechanisms remain unclear. This study substantiated CBD's interaction with the 5-HT1A receptor (5-HT1AR) in vitro (CHO cells expressing human 5-HT1AR) and in vivo (rat lower lip retraction test, LLR test). We then assessed the impact of CBD in mice using the stress-induced hyperthermia (SIH) model and the phencyclidine (PCP)-induced negative symptoms of schizophrenia model, respectively. Concurrently, we investigated whether WAY-100635, a typical 5-HT1AR antagonist, could attenuate these effects. Furthermore, the neurotransmitter changes through high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) were studied. Results revealed that CBD exhibits selective 5-HT1AR agonists-mediated effects in the rat lower lip retraction test, aligning with the robust agonistic (EC50 = 1.75 µM) profile observed in CHO cells. CBD at 3 mg/kg significantly reduced SIH (ΔT), a response that WAY-100635 abolished. Chronic administration of CBD at 100 mg/kg mitigated the increase in PCP-induced immobility time in the forced swim test (FST) and tail suspension test (TST). Moreover, it induced significant alterations in gamma-aminobutyric acid (GABA) and norepinephrine (NE) levels within the hippocampus (HPC). Thus, we concluded that the 5-HT1AR mediates CBD's anxiolytic-like effects. Additionally, CBD's effects on the negative symptoms of schizophrenia may be linked to changes in GABA and NE levels in the hippocampus. These findings offer novel insights for advancing the exploration of CBD's anxiolytic-like and antipsychotic-like effects.

Biomimetic "Gemini nanoimmunoregulators" orchestrated for boosted photoimmunotherapy by spatiotemporally modulating PD-L1 and tumor-associated macrophages.

A novel strategy of not only stimulating the immune cycle but also modulating the immunosuppressive tumor microenvironment is of vital importance to efficient cancer immunotherapy. Here, a new type of spatiotemporal biomimetic "Gemini nanoimmunoregulators" was engineered to activate robust systemic photoimmunotherapy by integrating the triple-punch of amplified immunogenic cell death (ICD), tumor-associated macrophages (TAMs) phenotype reprogramming and programmed cell death ligand 1 (PD-L1) degradation. The "Gemini nanoimmunoregulators" PM@RM-T7 and PR@RM-M2 were constructed by taking the biocompatible mesoporous polydopamine (mPDA) as nanovectors to deliver metformin (Met) and toll-like receptor 7/8 agonist resiquimod (R848) to cancer cells and TAMs by specific biorecognition via wrapping of red blood cell membrane (RM) inlaid with T7 or M2 peptides. mPDA/Met@RM-T7 (abbreviated as PM@RM-T7) was constructed to elicit an amplified in situ ICD effect through the targeted PTT and effectively stimulated the anticancer immunity. Meanwhile, PD-L1 on the remaining cancer cells was degraded by the burst metformin to prevent immune evasion. Subsequently, mPDA/R848@RM-M2 (abbreviated as PR@RM-M2) specifically recognized TAMs and reset the phenotype from M2 to M1 state, thus disrupting the immunosuppressive microenvironment and further boosting the function of cytotoxic T lymphocytes. This pair of sister nanoimmunoregulators cooperatively orchestrated the comprehensive anticancer activity, which remarkably inhibited the growth of primary and distant 4T1 tumors and prevented malignant metastasis. This study highlights the spatiotemporal cooperative modalities using multiple nanomedicines and provides a new paradigm for efficient cancer immunotherapy against metastatic-prone tumors.

TREM2 gene induces differentiation of induced pluripotent stem cells into dopaminergic neurons and promotes neuronal repair via TGF-ß activation in 6-OHDA-lesioned mouse model of Parkinson's disease.

OBJECTIVE: Induced pluripotent stem cells (iPSCs) hold a promising potential for rescuing dopaminergic neurons in therapy for Parkinson's disease (PD). This study clarifies a TREM2-dependent mechanism explaining the function of iPSC differentiation in neuronal repair of PD. METHODS: PD-related differentially expressed genes were screened by bioinformatics analyses and their expression was verified using RT-qPCR in nigral tissues of 6-OHDA-lesioned mice. Following ectopic expression and depletion experiments in iPSCs, cell differentiation into dopaminergic neurons as well as the expression of dopaminergic neuronal markers TH and DAT was measured. Stereotaxic injection of 6-OHDA was used to develop a mouse model of PD, which was injected with iPSC suspension overexpressing TREM2 to verify the effect of TREM2 on neuronal repair. RESULTS: TREM2 was poorly expressed in the nigral tissues of 6-OHDA-lesioned mice. In the presence of TREM2 overexpression, the iPSCs showed increased expression of dopaminergic neuronal markers TH and DAT, which facilitated the differentiation of iPSCs into dopaminergic neurons. Mechanistic investigations indicated that TREM2 activated the TGF-ß pathway and induced iPSC differentiation into dopaminergic neurons. In vivo data showed that iPSCs overexpressing TREM2 enhanced neuronal repair in 6-OHDA-lesioned mice. CONCLUSION: This work identifies a mechanistic insight for TREM2-mediated TGF-ß activation in the regulation of neuronal repair in PD and suggests novel strategies for neurodegenerative disorders.

Discovery of a CB2 and 5-HT1A receptor dual agonist for the treatment of depression and anxiety.

Cannabinoid CB2R agonists have gained considerable attention as potential novel therapies for psychiatric disorders due to their non-psychoactive nature, in contrast to CB1R agonists. In this study, we employed molecular docking to design and synthesize 23 derivatives of cannabidiol (CBD) with the aim of discovering potent CB2R agonists rather than CB2R antagonists or inverse agonists. Structure-activity relationship (SAR) investigations highlighted the critical importance of the amide group at the C-3' site and the cycloalkyl group at the C-4' site for CB2R activation. Interestingly, three CBD derivatives, namely 2o, 6g, and 6h, exhibited substantial partial agonistic activity towards the CB2 receptor, in contrast to the inverse agonistic property of CBD. Among these, 2o acted as a CB2R and 5-HT1AR dual agonist, albeit with some undesired antagonist activity for CB1R. It demonstrated significant CB2R partial agonism while maintaining a level of 5-HT1AR agonistic and CB1R antagonistic activity similar to CBD. Pharmacokinetic experiments confirmed that 2o possesses favorable pharmacokinetic properties. Behavioral studies further revealed that 2o elicits significant antidepressant-like and anxiolytic-like effects while maintaining a good safety profile.

Silk nanofibrils-MOF composite membranes for pollutant removal from water.

Membrane separation technology is considered an effective strategy to remove pollutants in sewage. However, it remains a significant challenge to fabricate inexpensive membranes with high purification efficiency. Therefore, the present study proposes the integration of silk nanofibrils (SNFs) and polydopamine⊂metal-organic framework (PDA⊂MOF) nanoparticles to prepare self-supporting membranes, which can effectively intercept nanoparticle pollutants through the size exclusion effect and can strongly adsorb organic dyes and metal ions by SNF. In addition, PDA⊂MOF enables these membranes to adsorb small molecules and heavy metal ions during the filtration process, thereby effectively removing various pollutants from sewage. The integration of size-exclusion and adsorption capabilities enables the SNF/PDA⊂MOF membrane to remove nanoparticles, small-molecule dyes, heavy metal ions, and radioactive elements. This work provides a rational approach for the design and development of the next generation of water treatment membranes and is expected to be used in environmental, food-related, and biomedical fields.

Biomimetic Nano-Immunoactivator via Ionic Metabolic Modulation for Strengthened NIR-II Photothermal Immunotherapy.

Reprogramming the immunologically "cold" environment of solid tumors is currently becoming the mainstream strategy to elicit powerful and systemic anticancer immunity. Here, a facile and biomimetic nano-immunnoactivator (CuS/Z@M4T1 ) is detailed by engineering a Zn2+ -bonded zeolitic imidazolate framework-8 (ZIF-8) with CuS nanodots (NDs) and cancer cell membrane for amplified near-infrared-II (NIR-II) photothermal immunotherapy via Zn2+ metabolic modulation. Taking advantage of the NIR-II photothermal effect of CuS NDs and the acidic responsiveness of ZIF-8, CuS/Z@M4T1 rapidly causes intracellular Zn2+ pool overload and disturbs the metabolic flux of 4T1 cells, which effectively hamper the production of heat shock proteins and relieve the resistance of photothermal therapy (PTT). Thus, amplified immunogenic cell death is evoked and initiates the immune cascade both in vivo and in vitro as demonstrated by dendritic cells maturation and T-cell infiltration. Further combination with antiprogrammed death 1 (aPD-1) achieves escalated antitumor efficacy which eliminates the primary, distant tumor and avidly inhibits lung metastasis due to cooperation of enhanced photothermal stimulation and empowerment of cytotoxic T lymphocytes by aPD-1. Collectively, this work provides the first report of using the intrinsic modulation property of meta-organometallic ZIF-8 for enhanced cancer photoimmunotherapy together with aPD-1, thereby inspiring a novel combined paradigm of ion-rich nanomaterials for cancer treatment.

Porous Mo3 P/Mo Nanorods as Efficient Mott-Schottky Cathode Catalysts for Low Polarization Li-CO2 Battery.

Li-CO2 battery with high energy density has aroused great interest recently, large-scale applications are hindered by the limited cathode catalysis performance and execrably cycle performance. Herein, Mo3 P/Mo Mott-Schottky heterojunction nanorod electrocatalyst with abundant porous structure is fabricated and served as cathodes for Li-CO2 batteries. The Mo3 P/Mo cathodes exhibit ultra-high discharge specific capacity of 10 577 mAh g-1 , low polarization voltage of 0.15 V, and high energy efficiency of up to 94.7%. Mott-Schottky heterojunction formed by Mo and Mo3 P drives electron transfer and optimizes the surface electronic structure, which is beneficial to accelerate the interface reaction kinetics. Distinctively, during the discharge process, the C2 O4 2- intermediates combine with Mo atoms to form a stable Mo-O coupling bridge on the catalyst surface, which effectively facilitate the formation and stabilization of Li2 C2 O4 products. In addition, the construction of the Mo-O coupling bridge between the Mott-Schottky heterojunction and Li2 C2 O4 promotes the reversible formation and decomposition of discharge products and optimizes the polarization performance of the Li-CO2 battery. This work provides another pathway for the development of heterostructure engineering electrocatalysts for high-performance Li-CO2 batteries.

Function of BrSOC1b gene in flowering regulation of Chinese cabbage and its protein interaction.

MAIN CONCLUSION: BrSOC1b may promote early flowering of Chinese cabbage by acting on BrAGL9 a, BrAGL9 b, BrAGL2 and BrAGL8 proteins. SOC1 is a flowering signal integrator that acts as a key regulator in controlling plant flowering time. This study focuses on the cloning of the open reading frame of SOC1b (BrSOC1b, Gene ID: Bra000393) gene, and analyzes its structure and phylogenetic relationships. Additionally, various techniques such as vector construction, transgenic technology, virus-induced gene silencing technology, and protein interaction technology were employed to investigate the function of the BrSOC1b gene and its interactions with other proteins. The results indicate that BrSOC1b consists of 642 bp and encodes 213 amino acids. It contains conserved domains such as the MADS domain, K (keratin-like) domain, and SOC1 box. The phylogenetic analysis reveals that BrSOC1b shares the closest homology with BjSOC1 from Brassica juncea. Tissue localization analysis demonstrates that BrSOC1b exhibits the highest expression in the stem during the seedling stage and the highest expression in flowers during the early stage of pod formation. Sub-cellular localization analysis reveals that BrSOC1b is localized in the nucleus and plasma membrane. Furthermore, through genetic transformation of the BrSOC1b gene, it was observed that Arabidopsis thaliana plants expressing BrSOC1b flowered earlier and bolted earlier than wild-type plants. Conversely, Chinese cabbage plants with silenced BrSOC1b exhibited delayed bolting and flowering compared to the control plants. These findings indicate that BrSOC1b promotes early flowering in Chinese cabbage. Yeast two-hybrid and quantitative real-time PCR (qRT-PCR) analyses suggest that BrSOC1b may participate in the regulation of flowering by interacting with BrAGL9a, BrAGL9b, BrAGL2, and BrAGL8 proteins. Overall, this research holds significant implications for the analysis of key genes involved in regulating bolting and flowering in Chinese cabbage, as well as for enhancing germplasm innovation in Chinese cabbage breeding.

NIR/pH-triggered aptamer-functionalized DNA origami nanovehicle for imaging-guided chemo-phototherapy.

Targeted chemo-phototherapy has received widespread attention in cancer treatment for its advantages in reducing the side effects of chemotherapeutics and improving therapeutic effects. However, safe and efficient targeted-delivery of therapeutic agents remains a major obstacle. Herein, we successfully constructed an AS1411-functionalized triangle DNA origami (TOA) to codeliver chemotherapeutic drug (doxorubicin, DOX) and a photosensitizer (indocyanine green, ICG), denoted as TOADI (DOX/ICG-loaded TOA), for targeted synergistic chemo-phototherapy. In vitro studies show that AS1411 as an aptamer of nucleolin efficiently enhances the nanocarrier's endocytosis more than 3 times by tumor cells highly expressing nucleolin. Subsequently, TOADI controllably releases the DOX into the nucleus through the photothermal effect of ICG triggered by near-infrared (NIR) laser irradiation, and the acidic environment of lysosomes/endosomes facilitates the release. The downregulated Bcl-2 and upregulated Bax, Cyt c, and cleaved caspase-3 indicate that the synergistic chemo-phototherapeutic effect of TOADI induces the apoptosis of 4T1 cells, causing ~ 80% cell death. In 4T1 tumor-bearing mice, TOADI exhibits 2.5-fold targeted accumulation in tumor region than TODI without AS1411, and 4-fold higher than free ICG, demonstrating its excellent tumor targeting ability in vivo. With the synergetic treatment of DOX and ICG, TOADI shows a significant therapeutic effect of ~ 90% inhibition of tumor growth with negligible systemic toxicity. In addition, TOADI presents outstanding superiority in fluorescence and photothermal imaging. Taken together, this multifunctional DNA origami-based nanosystem with the advantages of specific tumor targeting and controllable drug release provides a new strategy for enhanced cancer therapy.

Stimulus-Detonated Biomimetic "Nanobomb" with Controlled Release of HSP90 Inhibitor to Disrupt Mitochondrial Function for Synergistic Gas and Photothermal Therapy.

Photothermal therapy (PTT) is considered a promising treatment for tumors; however, its efficacy is restricted by heat shock proteins (HSPs). Herein, a stimuli-responsive theranostic nanoplatform (M/D@P/E-P) is designed for synergistic gas therapy and PTT. This nanoplatform is fabricated by a load of manganese carbonyl (MnCO, CO donor) in dendritic mesoporous silicon (DMS), followed by the coating with polydopamine (PDA) and loading of epigallocatechin gallate (EGCG, HSP90 inhibitor). Upon near-infrared (NIR) irradiation, the photothermal effect of PDA can kill tumor cells and allow for the controlled drug release of MnCO and EGCG. Moreover, the acidity and H2 O2 -rich tumor microenvironment enable the decomposition of the released MnCO, accompanied by the production of CO. CO-initiated gas therapy can realize to disrupt the mitochondrial function, which will accelerate cell apoptosis and down-regulate HSP90 expression by decreasing intracellular ATP. The combination of EGCG and MnCO can significantly minimize the thermo-resistance of tumors and improve PTT sensitivity. In addition, the released Mn2+ enables T1 -weighted magnetic imaging of tumors. The therapeutic efficacy of the nanoplatform is methodically appraised and validated both in vitro and in vivo. Taken together, this study affords a prime paradigm for applying this strategy for enhanced PTT via mitochondrial dysfunction.

A tumor-specific ROS self-supply enhanced cascade-responsive prodrug activation nanosystem for amplified chemotherapy against multidrug-resistant tumors.

Chemotherapy remains the mainstay of cancer treatment, and doxorubicin (DOX) is recommended as a first-line chemotherapy drug against cancer. However, systemic adverse drug reactions and multidrug resistance limit its clinical applications. Here, a tumor-specific reactive oxygen species (ROS) self-supply enhanced cascade responsive prodrug activation nanosystem (denoted as PPHI@B/L) was developed to optimize multidrug resistance tumor chemotherapy efficacy while minimizing the side effects. PPHI@B/L was constructed by encapsulating the ROS-generating agent ß-lapachone (Lap) and the ROS-responsive doxorubicin prodrug (BDOX) in acidic pH-sensitive heterogeneous nanomicelles. PPHI@B/L exhibited particle size decrease and charge increase when it reached the tumor microenvironment due to acid-triggered PEG detachment, to favor its endocytosis efficiency and deep tumor penetration. Furthermore, after PPHI@B/L internalization, rapidly released Lap was catalyzed by the overexpressed quinone oxidoreductase-1 (NQO1) enzyme NAD(P)H in tumor cells to selectively raise intracellular ROS levels. Subsequently, ROS generation further promoted the specific cascade activation of the prodrug BDOX to exert the chemotherapy effects. Simultaneously, Lap-induced ATP depletion reduced drug efflux, synergizing with increased intracellular DOX concentrations to assist in overcoming multidrug resistance. This tumor microenvironment-triggered cascade responsive prodrug activation nanosystem potentiates antitumor effects with satisfactory biosafety, breaking the chemotherapy limitation of multidrug resistance and significantly improving therapy efficiency. STATEMENT OF SIGNIFICANCE: Chemotherapy remains the mainstay of cancer treatment, and doxorubicin (DOX) is recommended as a first-line chemotherapy drug against cancer. However, systemic adverse drug reactions and multidrug resistance limit its clinical applications. Here, a tumor-specific reactive oxygen species (ROS) self-supply enhanced cascade responsive prodrug activation nanosystem (denoted as PPHI@B/L) was developed to optimize multidrug resistance tumor chemotherapy efficacy while minimizing the side effects. The work provides a new sight for simultaneously addressing the molecular mechanisms and physio-pathological disorders to overcome MDR in cancer treatment.