Development of an mRNA-based therapeutic vaccine mHTV-03E2 for high-risk HPV-related malignancies.

Human Papillomavirus (HPV) 16 and 18 infections are related to many human cancers. Despite several preventative vaccines for high-risk (hr) HPVs, there is still an urgent need to develop therapeutic HPV vaccines for targeting pre-existing hrHPV infections and lesions. In this study, we developed a lipid nanoparticle (LNP)-formulated mRNA-based HPV therapeutic vaccine (mHTV)-03E2, simultaneously targeting the E2/E6/E7 of both HPV16 and HPV18. mHTV-03E2 dramatically induced antigen-specific cellular immune responses, leading to significant CD8+ T cell infiltration and cytotoxicity in TC-1 tumors derived from primary lung epithelial cells of C57BL/6 mice expressing HPV E6/E7 antigens, mediated significant tumor regression, and prolonged animal survival, in a dose-dependent manner. We further demonstrated significant T cell immunity against HPV16/18 E6/E7 antigens for up to 4 months post-vaccination in immunological and distant tumor rechallenging experiments, suggesting robust memory T cell immunity against relapse. Finally, mHTV-03E2 synergized with immune checkpoint blockade to inhibit tumor growth and extend animal survival, indicating the potential in combination therapy. We conclude that mHTV-03E2 is an excellent candidate therapeutic mRNA vaccine for treating malignancies caused by HPV16 or HPV18 infections.

Self-Amplified pH/ROS Dual-Responsive Co-Delivery Nano-System with Chemo-Photodynamic Combination Therapy in Hepatic Carcinoma Treatment.

Background: Chemo-photodynamic combination therapy has demonstrated significant potential in the treatment of cancer. Triptolide (TPL), a naturally derived anticancer agent, when combined with the photosensitizer Chlorin e6 (Ce6), has shown to provide enhanced anti-tumor benefits. However, the development of stimuli-responsive nanovehicles for the co-delivery of TPL and Ce6 could further enhance the efficacy of this combination therapy. Methods: In this study, we synthesized a pH/ROS dual-responsive mPEG-TK-PBAE copolymer, which contains a pH-sensitive PBAE moiety and a ROS-sensitive thioketal (TK) linkage. Through a self-assembly process, TPL and Ce6 were successfully co-loaded into mPEG-TK-PBAE nanoparticles, hereafter referred to as TPL/Ce6 NPs. We evaluated the pH- and ROS-sensitive drug release and particle size changes. Furthermore, we investigated both the in vitro suppression of cellular proliferation and induction of apoptosis in HepG2 cells, as well as the in vivo anti-tumor efficacy of TPL/Ce6 NPs in H22 xenograft nude mice. Results: The mPEG-TK-PBAE copolymer was synthesized through a one-pot Michael-addition reaction and successfully co-encapsulated both TPL and Ce6 by self-assembly. Upon exposure to acid pH values and high ROS levels, the payloads in TPL/Ce6 NPs were rapidly released. Notably, the abundant ROS generated by the released Ce6 under laser irradiation further accelerated the degradation of the nanosystem, thereby amplifying the tumor microenvironment-responsive drug release and enhancing anticancer efficacy. Consequently, TPL/Ce6 NPs significantly increased PDT-induced oxidative stress and augmented TPL-induced apoptosis in HepG2 cells, leading to synergistic anticancer effects in vitro. Moreover, administering TPL/Ce6 NPs (containing 0.3 mg/kg of TPL and 4 mg/kg of Ce6) seven times, accompanied by 650 nm laser irradiation, efficiently inhibited tumor growth in H22 tumor-bearing mice, while exhibiting lower systemic toxicity. Conclusion: Overall, we have developed a tumor microenvironment-responsive nanosystem for the co-delivery of TPL and Ce6, demonstrating amplified synergistic effects of chemo-photodynamic therapy (chemo-PDT) for hepatocellular carcinoma (HCC) treatment.

Environmental-friendly, flexible silk fibroin-based film as dual-responsive shape memory material.

Bio-based shape memory materials have attracted wide attention due to their biocompatibility, degradability and safety. However, designing and manufacturing wearable bio-based shape memory films with excellent flexibility and toughness is still a challenge. In this work, silk fibroin substrate with a ß-sheet structure was combined with a tri-block shape memory copolymer to prepare a transparent composited shape memory film. The silk fibroin-based film showed a dual-responsive shape memory function, which can respond to both temperature and water stimuli. This film has a sensitive water-responsive shape memory, which starts deforming after exposure to water for 3 s and fully recovers in 30 s. In addition, the composite film shows highly stretchable (>300 %) and could maintain its high tensile properties after 5 cycles of regeneration. The films also exhibited rapid degradation ability. This study provides new insights for the design of dual-responsive shape memory materials by combining biocompatible matrix and multi-block SMP to simultaneously enhance the mechanical properties, which can be used for intelligent packaging, medical supplies, soft actuators and wearable devices.

Manipulating Crystal Growth and Secondary Phase PbI2 to Enable Efficient and Stable Perovskite Solar Cells with Natural Additives.

In perovskite solar cells (PSCs), the inherent defects of perovskite film and the random distribution of excess lead iodide (PbI2) prevent the improvement of efficiency and stability. Herein, natural cellulose is used as the raw material to design a series of cellulose derivatives for perovskite crystallization engineering. The cationic cellulose derivative C-Im-CN with cyano-imidazolium (Im-CN) cation and chloride anion prominently promotes the crystallization process, grain growth, and directional orientation of perovskite. Meanwhile, excess PbI2 is transferred to the surface of perovskite grains or formed plate-like crystallites in local domains. These effects result in suppressing defect formation, decreasing grain boundaries, enhancing carrier extraction, inhibiting non-radiative recombination, and dramatically prolonging carrier lifetimes. Thus, the PSCs exhibit a high power conversion efficiency of 24.71%. Moreover, C-Im-CN has multiple interaction sites and polymer skeleton, so the unencapsulated PSCs maintain above 91.3% of their initial efficiencies after 3000 h of continuous operation in a conventional air atmosphere and have good stability under high humidity conditions. The utilization of biopolymers with excellent structure-designability to manage the perovskite opens a state-of-the-art avenue for manufacturing and improving PSCs.

Quantitative phase imaging by gradient retardance optical microscopy.

Quantitative phase imaging (QPI) has become a vital tool in bioimaging, offering precise measurements of wavefront distortion and, thus, of key cellular metabolism metrics, such as dry mass and density. However, only a few QPI applications have been demonstrated in optically thick specimens, where scattering increases background and reduces contrast. Building upon the concept of structured illumination interferometry, we introduce Gradient Retardance Optical Microscopy (GROM) for QPI of both thin and thick samples. GROM transforms any standard Differential Interference Contrast (DIC) microscope into a QPI platform by incorporating a liquid crystal retarder into the illumination path, enabling independent phase-shifting of the DIC microscope's sheared beams. GROM greatly simplifies related configurations, reduces costs, and eradicates energy losses in parallel imaging modalities, such as fluorescence. We successfully tested GROM on a diverse range of specimens, from microbes and red blood cells to optically thick (~ 300 µm) plant roots without fixation or clearing.

Polystyrene microplastics induce pulmonary fibrosis by promoting alveolar epithelial cell ferroptosis through cGAS/STING signaling.

Polystyrene microplastics (PS-MPs) are new types of environmental pollutant that have garnered significant attention in recent years since they were found to cause damage to the human respiratory system when they are inhaled. The pulmonary fibrosis is one of the serious consequences of PS-MPs inhalation. However, the impact and underlying mechanisms of PS-MPs on pulmonary fibrosis are not clear. In this study, we studied the potential lung toxicity and PS-MPs-developed pulmonary fibrosis by long-term intranasal inhalation of PS-MPs. The results showed that after exposing to the PS-MPs, the lungs of model mouse had different levels of damage and fibrosis. Meanwhile, exposing to the PS-MPs resulted in a markedly decrease in glutathione (GSH), an increase in malondialdehyde (MDA), and iron overload in the lung tissue of mice and alveolar epithelial cells (AECs). These findings suggested the occurrence of PS-MP-induced ferroptosis. Inhibitor of ferroptosis (Fer-1) had alleviated the PS-MPs-induced ferroptosis. Mechanically, PS-MPs triggered cell ferroptosis and promoted the development of pulmonary fibrosis via activating the cGAS/STING signaling pathway. Inhibition of cGAS/STING with G150/H151 attenuated pulmonary fibrosis after PS-MPs exposure. Together, these data provided novel mechanistic insights of PS-MPs-induced pulmonary fibrosis and a potential therapeutic paradigm.

A comparison study of dynamic [18F]Alfatide II imaging and [11C]MET in orthotopic rat models of glioblastoma.

PURPOSE: To investigate and compare the dynamic positron emission tomography (PET) imaging with [18F]Alfatide II Imaging and [11C]Methionine ([11C]MET) in orthotopic rat models of glioblastoma multiforme (GBM), and to assess the utility of [18F]Alfatide II in detecting and evaluating neoangiogenesis in GBM. METHODS: [18F]Alfatide II and [11C]MET were injected into the orthotopic GBM rat models (n = 20, C6 glioma cells), followed by dynamic PET/MR scans 21 days after surgery of tumor implantation. On the PET image with both radiotracers, the MRI-based volume-of-interest (VOI) was manually delineated encompassing glioblastoma. Time-activity curves were expressed as tumor-to-normal brain ratio (TNR) parameters and PET pharmacokinetic modeling (PKM) performed using 2-tissue-compartment models (2TCM). Immunofluorescent staining (IFS), western blotting and blocking experiment of tumor tissue were performed for the validation. RESULTS: Compared to 11C-MET, [18F]Alfatide II presented a persistent accumulation in the tumor, albeit with a slightly lower SUVmean of 0.79 ± 0.25, and a reduced uptake in the contralateral normal brain tissue, respectively. This resulted in a markedly higher tumor-to-normal brain ratio (TNR) of 18.22 ± 1.91. The time-activity curve (TACs) showed a significant increase in radioactive uptake in tumor tissue, followed by a plateau phase up to 60 min for [18F]Alfatide II (time to peak:255 s) and 40 min for [11C]MET (time to peak:135 s) post injection. PKM confirmed significantly higher K1 (0.23/0.07) and K3 (0.26/0.09) in the tumor region compared to the normal brain with [18F]Alfatide II. Compared to [11C]MET imaging, PKM confirmed both significantly higher K1/K2 (1.24 ± 0.79/1.05 ± 0.39) and K3/K4 (11.93 ± 4.28/3.89 ± 1.29) in the tumor region with [18F]Alfatide II. IFS confirmed significant expression of integrin and tumor vascularization in tumor region. CONCLUSION: [18F]Alfatide II demonstrates potential in imaging tumor-associated neovascularization in the context of glioblastoma multiforme (GBM), suggesting its utility as a tool for further exploration in neovascular characterization.

Differentiation of Native Vertebral Osteomyelitis: A Comprehensive Review of Imaging Techniques and Future Applications.

Native vertebral osteomyelitis, also termed spondylodiscitis, is an antibiotic-resistant disease that requires long-term treatment. Without proper treatment, NVO can lead to severe nerve damage or even death. Therefore, it is important to accurately diagnose the cause of NVO, especially in spontaneous cases. Infectious NVO is characterized by the involvement of 2 adjacent vertebrae and intervertebral discs, and common infectious agents include Staphylococcus aureus, Mycobacterium tuberculosis, Brucella abortus, and fungi. Clinical symptoms are generally nonspecific, and early diagnosis and appropriate treatment can prevent irreversible sequelae. Advances in pathologic histologic imaging have led physicians to look more forward to being able to differentiate between tuberculous and septic spinal discitis. Therefore, research in identifying and differentiating the imaging features of these 4 common NVOs is essential. Due to the diagnostic difficulties, clinical and radiologic diagnosis is the mainstay of provisional diagnosis. With the advent of the big data era and the emergence of convolutional neural network algorithms for deep learning, the application of artificial intelligence (AI) technology in orthopedic imaging diagnosis has gradually increased. AI can assist physicians in imaging review, effectively reduce the workload of physicians, and improve diagnostic accuracy. Therefore, it is necessary to present the latest clinical research on NVO and the outlook for future AI applications.

Tetrandrine alleviates pulmonary fibrosis by inhibiting alveolar epithelial cell senescence through PINK1/Parkin-mediated mitophagy.

Idiopathic pulmonary fibrosis (IPF) is a fatal and insidious interstitial lung disease. So far, there are no effective drugs for preventing the disease process. Cellular senescence plays a critical role in the development of IPF, with the senescence and insufficient mitophagy of alveolar epithelial cells being implicated in its pathogenesis. Tetrandrine is a natural alkaloid which is now produced synthetically. It was known that the tetrandrine has anti-fibrotic effects, but the efficacy and mechanisms are still not well evaluated. Here, we reveal the roles of tetrandrine on AECs senescence and the antifibrotic effects by using a bleomycin challenged mouse model of pulmonary fibrosis and a bleomycin-stimulated mouse alveolar epithelial cell line (MLE-12). We performed the ß-galactosidase staining, immunohistochemistry and fluorescence to assess senescence in MLE-12 cells. The mitophagy levels were detected by co-localization of LC3 and COVIX. Our findings indicate that tetrandrine suppressed bleomycin-induced fibroblast activation and ultimately blocked the increase of collagen deposition in mouse model lung tissue. It has significantly inhibited the bleomycin-induced senescence and senescence-associated secretory phenotype (SASP) in alveolar epithelial cells (AECs). Mechanistically, tetrandrine suppressed the decrease of mitochondrial autophagy-related protein expression to rescue the bleomycin-stimulated impaired mitophagy in MLE-12 cells. We revealed that knockdown the putative kinase 1 (PINK1) gene by a short interfering RNA (siRNA) could abolish the ability of tetrandrine and reverse the MLE-12 cells senescence, which indicated the mitophagy of MLE-12 cells is PINK1 dependent. Our data suggest the tetrandrine could be a novel and effective drug candidate for lung fibrosis and senescence-related fibrotic diseases.

Experimental Study on the Erosion-Corrosion Characteristics of Desulfurization Slurry on Stainless Steel Pipe Materials.

The recovery of low-grade waste heat from power plants greatly benefits energy conservation and emission reduction during electricity generation, while the waste heat utilization directly from desulfurization slurry is a significantly promising method to deeply recover such low-grade energy and has been developed in practical application. However, the pipe materials are subjected to erosion and corrosion challenges due to the high level of solid compositions and the presence of harmful ions, such as Cl-1, which requires further evaluation under the condition of slurry heat exchange. The present study aimed at an experimental study on the erosion-corrosion characteristics of desulfurization slurry on three types of stainless steel, including type 304, 316L, and 2205. Both mass loss and micromorphology features were analyzed with possible mechanisms elucidated. The erosion-corrosion rate is weak at low temperatures, while the increase in the slurry temperature clearly promotes its rate. The influence of the temperature on the corrosion resistance of 304 is much greater than that of 2205. With an increase in duration time, the weight loss rate of stainless steel in the desulfurization slurry declines, and the changing trend of metal mass slightly slows down. The present study offers a better understanding of the erosion-corrosion behaviors of three types of stainless steel under flow and heat transfer conditions of a desulfurization slurry.

Effect and Safety of Herbal Medicine Foot Baths in Patients with Diabetic Peripheral Neuropathy: A Multicenter Double-Blind Randomized Controlled Trial.

OBJECTIVE: To evaluate the effect and safety of foot baths with Tangbi Waixi Decoction (TW) in treating patients with diabetic peripheral neuropathy (DPN). METHODS: It is a multicenter double-blinded randomized controlled trial. Participants with DPN were recruited between November 18, 2016 and May 30, 2018 from 8 hospitals in China. All patients received basic treatments for glycemic management. Patients received foot baths with TW herbal granules either 66.9 g (intervention group) or 6.69 g (control group) for 30 min once a day for 2 weeks and followed by a 2-week rest, as a therapeutic course. If the Toronto Clinical Scoring System total score (TCSS-TS) ⩾6 points, the patients received a total of 3 therapeutic courses (for 12 weeks) and were followed up for 12 weeks. The primary outcome was change in TCSS-TS score at 12 and 24 weeks. Secondary outcomes included changes in bilateral motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV) of the median and common peroneal nerve. Safety was also assessed. RESULTS: Totally 632 patients were enrolled, and 317 and 315 were randomized to the intervention and control groups, respectively. After the 12-week intervention, patients in both groups showed significant declines in TCSSTS scores, and significant increases in MNCV and SNCV of the median and common peroneal nerves compared with pre-treatment (P<0.05). The reduction of TCSS-TS score at 12 weeks and the increase of SNCV of median nerve at 24 weeks in the control group were greater than those in the intervention group (P<0.05). The number of adverse events did not differ significantly between groups (P>0.05), and no serious adverse event was related with treatment. CONCLUSION: Treatment of TW foot baths was safe and significantly benefitted patients with DPN. A low dose of TW appeared to be more effective than a high dose. (Registry No. ChiCTR-IOR-16009331).

Anti-metastatic effects of AGS-30 on breast cancer through the inhibition of M2-like macrophage polarization.

AGS-30, a new andrographolide derivative, showed significant anticancer and anti-angiogenic characteristics. However, its role in controlling macrophage polarization and tumor immune response is unknown. Thus, the main goals of this study are to investigate how AGS-30 regulates macrophage polarization and how it suppresses breast cancer metastasis. AGS-30 inhibited IL-4 and IL-13-induced RAW 264.7 and THP-1 macrophages into M2-like phenotype. However, AGS-30 did not affect the LPS and IFN-γ-induced polarization of M1-like macrophages. AGS-30 reduced the mRNA expressions of CD206, Arg-1, Fizz-1, Ym-1, VEGF, IL-10, MMP2, and MMP9 in M2-like macrophages in a concentration-dependent manner. In contrast, andrographolide treatment at 5 µM did not affect M1-like and M2-like macrophage polarization. The conditioned medium from M2-like macrophages increased 4T1 breast cancer cell migration and invasion, whereas AGS-30 inhibited these effects. In the 4T1 breast tumor xenograft mice, the tumor volume and weight were reduced without affecting body weight after receiving AGS-30. AGS-30 treatment also reduced lung and liver metastasis, with reduced STAT6, CD31, VEGF, and Ki67 protein expressions. Moreover, the tumors had considerably fewer M2-like macrophages and Arg-1 expression, but the proportion of M1-like macrophages and iNOS expression increased after AGS-30 treatment. Same results were found in the tail vein metastasis model. In conclusion, this study shows that AGS-30 inhibits breast cancer growth and metastasis, probably through inhibiting M2-like macrophage polarization. Our findings suggest that AGS-30 may be a potential immunotherapeutic alternative for metastatic breast cancer.

The role and mechanism of esketamine in preventing and treating remifentanil-induced hyperalgesia based on the NMDA receptor-CaMKII pathway.

Remifentanil-induced hyperalgesia (RIH) is a common clinical phenomenon that limits the use of opioids in pain management. Esketamine, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to prevent and treat RIH. However, the underlying effect mechanism of esketamine on RIH remains unclear. This study aimed to investigate the role and mechanism of esketamine in preventing and treating RIH based on the NMDA receptor-CaMKIIα pathway. In this study, an experimental animal model was used to determine the therapeutic effect of esketamine on pain elimination. Moreover, the mRNA transcription and protein expression levels of CaMKII and GluN2B were investigated to offer evidence of the protective capability of esketamine in ameliorating RIH. The results demonstrated that esketamine attenuated RIH by inhibiting CaMKII phosphorylation and downstream signaling pathways mediated by the NMDA receptor. Furthermore, ketamine reversed the upregulation of spinal CaMKII induced by remifentanil. These findings suggest that the NMDA receptor-CaMKII pathway plays a critical role in the development of RIH, and ketamine's effect on this pathway may provide a new therapeutic approach for the prevention and treatment of RIH.

Phase-Transition of Mo2 C Induced by Tungsten Doping as Heterointerface-Rich Electrocatalyst for Optimizing Hydrogen Evolution Activity.

Electrochemical hydrogen evolution reaction (HER) from water splitting driven by renewable energy is considered a promising method for large-scale hydrogen production, and as an alternative to noble-metal electrocatalysts, molybdenum carbide (Mo2 C) has exhibited effective HER performance. However, the strong bonding strength of intermediate adsorbed H (Hads ) with Mo active site slows down the HER kinetics of Mo2 C. Herein, using phase-transition strategy, hexagonal ß-Mo2 C could be easily transferred to cubic δ-Mo2 C through electron injection triggered by tungsten (W) doping, and heterointerface-rich Mo2 C-based composites, including ß-Mo2 C, δ-Mo2 C, and MoO2 , are presented. Experimental results and density functional theory calculations reveal that W doping mainly contributes to the phase-transition process, and the generated heterointerfaces are the dominant factor in inducing remarkable electron accumulation around Mo active sites, thus weakening the Mo─H coupling. Wherein, the ß-Mo2 C/MoO2 interface plays an important role in optimizing the electronic structure of Mo 3d orbital and hydrogen adsorption Gibbs free energy (ΔGH* ), enabling these Mo2 C-based composites to have excellent intrinsic catalytic activity like low overpotential (η10 = 99.8 mV), small Tafel slope (60.16 dec-1 ), and good stability in 1 m KOH. This work sheds light on phase-transition engineering and offers a convenient route to construct heterointerfaces for large-scale HER production.

Regulation Dipole Moments of N-Doped Graphene Coordinated with FePc Toward Highly Efficient Microwave Absorption Performance in C Band.

The development of composites with highly efficient microwave absorption (MA) performance deeply depends on polarization loss, which can be induced by charge redistribution. Considering the fact that polarization centers can be easily obtained in graphene, herein, iron phthalocyanine (FePc) is used as polarization site to coordinate with nitrogen-doped graphene (FePc/N-rGO) to optimize MA performance comprehensively. The factors influencing MA properties focus on the interaction between FePc and N-rGO, and the change of dipole moments. The density functional theory (DFT) results demonstrated that FePc has strong interaction with N defect sites in graphene. The charge loss for FePc and charge accumulation for N-rGO occurred, leading to great increase of dipole moment, and the increased dipole moment can be acted as a descriptor to evaluate the enhanced polarization loss. Due to high charge redistribution capacity of N defect sites and FePc polarization centers, the FePc/N-rGO showed excellent MA properties in C band, and the minimum reflection loss value can reach -49.3 dB at 5.4 GHz with thickness of 3.8 mm. In addition, the fabric loaded with FePc/N-rGO showed good heat dissipation property. This work opens the door to the development of MA performance bound to polarization site with dipole moment.

Real-world effects of Yishen Tongbi decoction for rheumatoid arthritis: protocol for a prospective, observational, multicenter cohort study with validation against double-blind, randomized, controlled trial.

Introduction: Rheumatoid arthritis (RA) is a globally challenging and refractory autoimmune disease, constituting a serious menace to human health. RA is characterized by recurrent pain and is difficult to resolve, necessitating prolonged medication for control. Yishen Tongbi decoction is a traditional Chinese herbal compound prescribed for treating RA. We have completed a 3-year RCT study that confirmed the clinical efficacy of Yishen Tongbi decoction for RA. Notably, we observed a faster clinical remission rate compared to MTX by week 4 of treatment. In our forthcoming study, we intend to conduct a comprehensive assessment of the efficacy and safety of Yishen Tongbi decoction in the real-world treatment of RA through a prospective study. Methods and analysis: This prospective, multicenter, real-world observational study will be conducted at two designated centers in China from October 2023 to August 2025. The study will include 324 patients with active rheumatoid arthritis. One group will receive Yishen Tongbi decoction combined with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). The other group will receive standard treatment. Standard treatment can be further divided into subgroups: csDMARDs, targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), and biologic disease-modifying antirheumatic drugs (bDMARDs). In each group, the number of tender joints, number of swollen joints, pain score, patient global assessment, physician global assessment, disease activity index (DAS28-ESR or DAS28-CRP), clinical disease activity index (cDAI), simplified disease activity index (sDAI) and relevant laboratory data will be compared. Clinical indicators and disease activity of the patients will be assessed at baseline, week 4 and week 12 after the initiation of treatment. The primary outcome will be the American College of Rheumatology 20% improvement criteria (ACR20) attainment rate among patients at week 12 after treatment. Every adverse event will be reported. Ethics and dissemination: This study has been approved by the Ethics Committee of the first affiliated Hospital of Guangzhou University of traditional Chinese Medicine (NO.K-2023-009). The results of the study will be published in national and international peer-reviewed journals and at scientific conferences. The researchers will inform participants and other RA patients of the results through health education. Clinical Trial Registration: https://www.chictr.org.cn/index.html, identifier ChiCTR2300076073.

Inhibition of cannabinoid degradation enhances hippocampal contextual fear memory and exhibits anxiolytic effects.

Recent studies have demonstrated the pivotal involvement of endocannabinoids in regulating learning and memory, but the conclusions obtained from different paradigms or contexts are somewhat controversial, and the underlying mechanisms remain largely elusive. Here, we show that JZL195, a dual inhibitor of fatty acid amide hydrolase and monoacylglycerol lipase, can enhance the performance of mice in a contextual fear conditioning task and increase the time spent in open arms in the elevated zero maze (EZM). Although the effect of JZL195 on fear memory could not be inhibited by antagonists of cannabinoid receptors, the effect on the EZM seems to be mediated by CB1R. Simultaneously, hippocampal neurons are hyperactive, and theta oscillation power is significantly increased during the critical period of memory consolidation upon treatment with JZL195. These results suggest the feasibility of targeting the endocannabinoid system for the treatment of various mental disorders.

Tumor Microenvironment ROS/pH Cascade-Responsive Supramolecular Nanoplatform with ROS Regeneration Property for Enhanced Hepatocellular Carcinoma Therapy.

The low targeted drug delivery efficiency, including poor tumor accumulation and penetration and uncontrolled drug release, leads to the failure of cancer therapy. Herein, a multifunctional supramolecular nanoplatform loading triptolide (TPL/PBAETK@GA NPs) was fabricated via the host-guest interaction between glycyrrhetinic-acid-modified poly(ethylene glycol)-adamantanecarboxylic acid moiety and reactive oxygen species (ROS)/pH cascade-responsive copolymer poly(ß-amino esters)-thioketal (TK)-ß-cyclodextrin. TPL/PBAETK@GA NPs could accumulate in hepatocellular carcinoma (HCC) tissue effectively, mediated by nanoscale advantage and GA' recognition to specific receptors. The elevated concentration of ROS in tumor microenvironment (TME) quickly breaks the TK linkages, causing the detachment of shell (cyclodextrin) CD layer. Then, the accompanying negative-to-positive charge-reversal of NPs was realized via the PBAE moiety protonation under the slightly acidic TME, significantly enhancing the NPs' cellular internalization. Remarkably, the pH-responsive endo/lysosome escape of PBAE core triggered intracellular TPL burst release, promoting the cancer cell apoptosis, autophagy, and intracellular ROS generation, leading to the self-amplification of ROS in TME. Afterward, the ROS positive-feedback loop was generated to further promote size-shrinkage and charge-reversal of NPs. Both in vitro and in vivo tests verified that TPL/PBAETK@GA NPs produced a satisfactory anti-HCC therapy outcome. Collectively, this study offers a potential appealing paradigm to enhance TPL-based HCC therapy outcomes via multifunctionalized supramolecular nanodrugs.

Up-to-date quality survey and evaluation of neonatal screening programs in China.

AIMS: To thoroughly evaluate the quality of the entire process of neonatal screening (NBS) in China. METHODS: We collected survey questionnaires from 54.4% (135/248) of NBS institutions in China and conducted on-site visits to 20 of these facilities to validate the data. The quality performance of the institutions was evaluated, and differences across various factors were analysed. RESULTS: Merely 62.5% of the provinces had acceptable performance in neonatal screening. Institutions with limited staff were more prone to organizational management shortcomings. Institutions in provinces with a per capita GDP below 10,000 USD exhibited lower quality control levels than those with a per capita GDP between 10,000 and 15,000 USD. Obstetrics departments have a lower awareness of quality control compared to other blood collection facilities. CONCLUSIONS: A nationwide, comprehensive quality control system for continuous enhancements in quality management, screening, diagnosis, and treatment is imperative to ensure prompt diagnosis and intervention.

Effects of 12-week aerobic exercise with different frequencies on executive function in preschool children: a cluster randomized controlled trial.

OBJECTIVE: To explore the effects of a 12-week aerobic exercise program with different frequencies on executive functions (EFs) in preschool children. METHOD: Four kindergartens, comprising 126 preschool children in Shanghai, were enrolled in this 12-week cluster randomized controlled trial with a 12-week follow-up period. Kindergartens were allocated to high-frequency (three times a week) or low-frequency (once a week) exercise groups using stratified block randomization. Three core sub-EFs, including inhibition, working memory, and cognitive flexibility, were assessed at baseline, post-intervention, and the 12-week follow-up. RESULTS: Compared to baseline, both groups showed significant improvements in inhibition and working memory after the intervention and at the 12-week follow-up. However, only the high-frequency exercise group demonstrated a significant improvement in cognitive flexibility after the follow-up period. Nonetheless, there were no significant differences in the core sub-functions of EFs between the two groups at the end of the intervention or the follow-up periods. CONCLUSION: A 12-week aerobic exercise of three times a week was insufficient to significantly improve EFs in preschool children compared to once a week. Future studies are needed to examine the dose-response relationship of aerobic exercise on EFs and to verify the effects of different exercise modalities on EFs in preschool children.