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Developing biomimetic nanoparticles without loss of the integrity of proteins remains a major challenge in cancer chemotherapy. Here, we develop a biocompatible tumor-cell-exocytosed exosome-biomimetic porous silicon nanoparticles (PSiNPs) as drug carrier for targeted cancer chemotherapy. Exosome-sheathed doxorubicin-loaded PSiNPs (DOX@E-PSiNPs), generated by exocytosis of the endocytosed DOX-loaded PSiNPs from tumor cells, exhibit enhanced tumor accumulation, extravasation from blood vessels and penetration into deep tumor parenchyma following intravenous administration. In addition, DOX@E-PSiNPs, regardless of their origin, possess significant cellular uptake and cytotoxicity in both bulk cancer cells and cancer stem cells (CSCs). These properties endow DOX@E-PSiNPs with great in vivo enrichment in total tumor cells and side population cells with features of CSCs, resulting in anticancer activity and CSCs reduction in subcutaneous, orthotopic and metastatic tumor models. These results provide a proof-of-concept for the use of exosome-biomimetic nanoparticles exocytosed from tumor cells as a promising drug carrier for efficient cancer chemotherapy. The generation of biomimetic nanoparticles that retain the integrity of proteins has been a challenge. Here, the authors generate biomimetic nanoparticles that are exocytosed from tumour cells and show their therapeutic potential in targeting tumours and cancer stem cells in multiple mouse models.

Effective charge separation and migration pose a critical challenge in the field of solar-driven hydrogen production. In this work, a Z-scheme structured CuInS2/ZnIn2S4 heterojunction was successfully fabricated through a two-step hydrothermal synthesis method to significantly enhance the efficiency of solar-to-hydrogen energy conversion. Structural characterization revealed that the lattice-matched CuInS2/ZnIn2S4 heterojunction exhibits an enlarged interfacial contact area, which facilitates the transfer and separation of photogenerated charges. Microscopic analysis indicated that the CuInS2/ZnIn2S4 composite material has a tightly interwoven interface and a morphology resembling small sugar cubes. Photoelectrochemical spectroscopy analysis demonstrated that the heterojunction structure effectively enhances visible light absorption and charge separation efficiency, leading to an improvement in photocatalytic activity. Hydrogen production experimental data indicated that the CuInS2/ZnIn2S4 heterojunction photocatalyst prepared with a CuInS2 content of 20 wt% exhibits the highest hydrogen evolution rate, reaching 284.9 μmol·g−1·h−1. Moreover, this photocatalyst maintains robust photocatalytic stability even after three consecutive usage cycles. This study demonstrated that the Z-scheme CuInS2/ZnIn2S4 heterojunction photocatalyst exhibits enhanced hydrogen evolution efficiency, offering an effective structural design for harnessing solar energy to obtain hydrogen fuel. Therefore, this heterojunction photocatalyst is a promising candidate for practical applications in solar hydrogen production.

This study aimed to investigate self-determination, explore the mediating role of professional identity between role models and self-determination, and detect how role models and professional identity contribute to the development of self-determination among medical students. A multicenter cross-sectional descriptive study involving 289 medical students in China was conducted. The Self-Determination Scale (SDS), Professional Identity Scale (PIS), and Sense of Admiration Scale (SAS) were employed to collect data. The bootstrapping method was used to analyze the mediating effect of professional identity between role models and self-determination. The average score on the SDS was 71.21 (SD = 11.72), while the mean score on the PIS was 69.49 (SD = 11.57), and the mean score on the SAS was 61.48 (SD = 10.41). A high level of role model perception had a significant direct effect (40.54%) on the degree of self-determination among medical students. Furthermore, professional identity had a significant positive mediating effect (54.83%) on the relationship between role models and self-determination. Medical educators should focus on creating positive role models and enhancing their perceptions of these role models to foster self-determination among medical students. Additionally, strengthening professional identity could indirectly enhance the self-determination of medical students.

This study focuses on the development of heterojunction photocatalysts for the efficient utilization of solar energy to address the energy crisis and reduce environmental pollution. Cadmium sulfide (CdS)/graphite-type carbon nitride (g-C3N4) nanocomposites were synthesized using a hydrothermal method, and their photoelectrochemical properties and photocatalytic performance for hydrogen evolution reaction (HER) were characterized. Scanning electron microscope images showed the intimate interface and caviar-like nanoheterojunction of the CdS nanoparticles on g-C3N4 nanospheres, suggesting their potential involvement in the photocatalytic process. Electrochemical and spectroscopic analyses were conducted to confirm the roles of CdS in the nanoheterojunction. The results showed that 10 wt% CdS/g-C3N4 nanospheres exhibited higher photocatalytic activity than pure g-C3N4 under visible light irradiation. A HER rate of 655.5 μmol/g/h was achieved after three photocatalytic cycles, signifying good photocatalytic stability. The synergistic effect of the Z-scheme heterojunction formed by g-C3N4 and CdS was identified as the main factor responsible for the enhanced photocatalytic performance and stability. The interface engineering effect of CdS/g-C3N4 facilitated the separation of photogenerated electrons and holes. This study provides insights into the design and fabrication of efficient HER photocatalysts.

Crystallization selectivity is an important principle in polymorph control. Ribavirin Form I, Form II, DMSO solvate, and amorphous ribavirin are prepared, and the short-range order similarities between these solid forms and ribavirin aqueous solution and DMSO solution are compared via mid-frequency Raman difference spectra (MFRDS). The crystallization process from amorphous ribavirin to Form I and from solution to amorphous phase is explained. Reasons for the difficulty in preparing the DMSO solvate are proposed. The rationale provided for the crystallization selectivity provides a foundation for the synthesis of metastable phases with a robust and convenient method.

Herein, we reported a octahedral Cd 3 (C 3 N 3 S 3 ) 2 coordination polymer as a new noble metal-free photocatalyst for robust photocatalytic H 2 O 2 production from methanol/water solution. The coordination polymer can give an unprecedented H 2 O 2 yield of ca. 110.0 mmol • L −1  • g −1 at pH = 2.8 under visible light illumination. The characterization results clearly revealed that the photocatalytic H 2 O 2 production proceeds by a pathway of two-electron reduction of O 2 on the catalyst surface. This work showed the potential perspective of M x (C 3 N 3 S 3 ) y (M = transitional metals) coordination polymers as a series of new materials for solar energy storage and conversion.

Brain endothelial cells (BECs) are involved in the pathogenesis of ischemic stroke. Recently, several microRNAs (miRNAs) in BECs were reported to regulate the endothelial function in ischemic brain. Therefore, modulation of miRNAs in BECs by a therapeutic oligonucleotide to inhibit miRNA (antimiR) could be a useful strategy for treating ischemic stroke. However, few attempts have been made to achieve this strategy via systemic route due to lack of efficient delivery-method toward BECs. Here, we have developed a new technology for delivering an antimiR into BECs and silencing miRNAs in BECs, using a mouse ischemic stroke model. We designed a heteroduplex oligonucleotide, comprising an antimiR against miRNA-126 (miR-126) known as the endothelial-specific miRNA and its complementary RNA, conjugated to α-tocopherol as a delivery ligand (Toc-HDO targeting miR-126). Intravenous administration of Toc-HDO targeting miR-126 remarkably suppressed miR-126 expression in ischemic brain of the model mice. In addition, we showed that Toc-HDO targeting miR-126 was delivered into BECs more efficiently than the parent antimiR in ischemic brain, and that it was delivered more effectively in ischemic brain than non-ischemic brain of this model mice. Our study highlights the potential of this technology as a new clinical therapeutic option for ischemic stroke.

Collateral growth after acute occlusion of an intracranial artery is triggered by increasing shear stress in preexisting collateral pathways. Recently, sphingosine-1-phosphate receptor-1 (S1PR1) on endothelial cells was reported to be essential in sensing fluid shear stress. Here, we evaluated the expression of S1PR1 in the hypoperfused mouse brain and investigated the effect of a selective S1PR1 agonist on leptomeningeal collateral growth and subsequent ischemic damage after focal ischemia. In C57Bl/6 mice (n = 133) subjected to unilateral common carotid occlusion (CCAO) and sham surgery. The first series examined the time course of collateral growth, cell proliferation, and S1PR1 expression in the leptomeningeal arteries after CCAO. The second series examined the relationship between pharmacological regulation of S1PR1 and collateral growth of leptomeningeal anastomoses. Animals were randomly assigned to one of the following groups: LtCCAO and daily intraperitoneal (i.p.) injection for 7 days of an S1PR1 selective agonist (SEW2871, 5 mg/kg/day); sham surgery and daily i.p. injection for 7 days of SEW2871 after surgery; LtCCAO and daily i.p. injection for 7 days of SEW2871 and an S1PR1 inverse agonist (VPC23019, 0.5 mg/kg); LtCCAO and daily i.p. injection of DMSO for 7 days after surgery; and sham surgery and daily i.p. injection of DMSO for 7 days. Leptomeningeal anastomoses were visualized 14 days after LtCCAO by latex perfusion method, and a set of animals underwent subsequent permanent middle cerebral artery occlusion (pMCAO) 7 days after the treatment termination. Neurological functions 1 hour, 1, 4, and 7 days and infarction volume 7 days after pMCAO were evaluated. In parallel with the increase in S1PR1 mRNA levels, S1PR1 expression colocalized with endothelial cell markers in the leptomeningeal arteries, increased markedly on the side of the CCAO, and peaked 7 days after CCAO. Mitotic cell numbers in the leptomeningeal arteries increased after CCAO. Administration of the S1PR1 selective agonist significantly increased cerebral blood flow (CBF) and the diameter of leptomeningeal collateral vessels (42.9 ± 2.6 μm) compared with the controls (27.6 ± 5.7 μm; P < 0.01). S1PR1 inverse agonist administration diminished the effect of the S1PR1 agonist (P < 0.001). After pMCAO, S1PR1 agonist pretreated animals showed significantly smaller infarct volume (17.5% ± 4.0% vs. 7.7% ± 4.0%, P < 0.01) and better functional recovery than vehicle-treated controls. These results suggest that S1PR1 is one of the principal regulators of leptomeningeal collateral recruitment at the site of increased shear stress and provide evidence that an S1PR1 selective agonist has a role in promoting collateral growth and preventing of ischemic damage and neurological dysfunction after subsequent stroke in patients with intracranial major artery stenosis or occlusion.

Epidemiology research has demonstrated that magnesium (Mg) deficiency is associated with a high incidence of Parkinson's disease (PD). It is known that the systemic administration of MgSO is not able to elevate the Mg concentration in cerebrospinal fluid (CSF). This study aims to verify the protective effect of magnesium-L-threonate (MgT) in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) mouse model. C57BL/6J mice were orally administered MgT or MgSO for 4 weeks, and received MPTP in the third week. After analysis of open-field and rotarod tests on the last day, tyrosine hydroxylase (TH) immunopositive cells and protein levels were quantified in the substantia nigra pars compacta (SNpc) and striatum. The expression of inducible nitric oxide synthase (iNOS) level was evaluated. Mg concentration in serum and CSF was measured after oral administration of MgSO or MgT in normal mice. Mg concentration in the CSF was increased in the mice treated with MgT but not MgSO . The total distance and mean speed in open-field tests, and the time spent on rotarod in the MgT group were increased, compared with MPTP group. The MgT treatment but not MgSO dose-dependently attenuated the loss of TH-positive neurons, and the reduction of the TH expression in the SNpc. The MgT treatment also inhibited the expression of iNOS as measured by immunohistochemistry and Western blots. Double-immunofluorescence staining of TH and iNOS showed iNOS-positive cells were collocalized for TH-positive cells. The treatment with MgT is associated with an increase of Mg in the CSF. MgT, rather than MgSO4, can significantly attenuate MPTP-induced motor deficits and dopamine (DA) neuron loss.

The design of enantiopure stereoisomers of N-2-phenylcyclopropylmethyl-substituted ortho-c oxide-bridged phenylmorphans, the E and Z isomers of an N-cinnamyl moiety, and N-propyl enantiomers were based on combining the most potent oxide-bridged phenylmorphan (the ortho-c isomer) with the most potent N-substituent that we previously found with a 5-(3-hydroxy)phenylmorphan (i.e., N-2-phenylcyclopropyl methyl moieties, N-cinnamyl, and N-propyl substituents). The synthesis of the eight enantiopure N-2-phenylcyclopropylmethyl ortho-c oxide-bridged phenylmorphans and six additional enantiomers of the N-substituted ortho-c oxide-bridged phenylmorphans (N-E and Z-cinnamyl compounds, and N-propyl compounds) was accomplished. The synthesis started from common intermediates (3R,6aS,11aS)-10-methoxy-1,3,4,5,6,11a-hexahydro-2H-3,6a-methano-benzofuro[2,3-c]azocine (+)-6 and its enantiomer, (3S, 6aR, 11aR)-(-)-6, respectively. The enantiomers of ±-6 were obtained through salt formation with (S)-(+)- and (R)-(-)-p-methylmandelic acid, and the absolute configuration of the (R)-(-)-p-methylmandelate salt of (3S, 6aR, 11aR)-(-)-6 was determined by single-crystal X-ray analysis. The enantiomeric secondary amines were reacted with N-(2-phenylcyclopropyl)methyl derivatives, 2-(E)-cinnamyl bromide, and (Z)-3-phenylacrylic acid. These products led to all of the desired N-derivatives of the ortho-c oxide-bridged phenylmorphans. Their opioid receptor binding affinity was measured. The compounds with MOR affinity < 50 nM were examined for their functional activity in the forskolin-induced cAMP accumulation assay. Only the enantiomer of the N-phenethyl ortho-c oxide-bridged phenylmorphan ((-)-1), and only the (3S,6aR,11aR)-2-(((1S,2S)-2-phenylcyclopropyl)methyl)-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol isomer ((+)-17), and the N-phenylpropyl derivative ((-)-25) had opioid binding affinity < 50 nM. Both (-)-1 and (-)-25 were partial agonists in the cAMP assay, with the former showing high potency and low efficacy, and the latter with lower potency and less efficacy. Most interesting was the N-2-phenylcyclopropylmethyl (3S,6aR,11aR)-2-(1S,2S)-enantiomer ((+)-17). That compound had good MOR binding affinity (Ki = 11.9 nM) and was found to have naltrexone-like potency as a MOR antagonist (IC50 = 6.92 nM).