Herein, we provide the enhancement of SDT effect through elaborate strategies including the design and modification of sonosensitizers, the combination other therapy modalities, and molecular imaging-guided SDT for precise treatment.

Glucose-stimulated insulin secretion is biphasic, with a rapid first phase and a slowly developing sustained second phase; both are disturbed in type 2 diabetes (T2D). Biphasic secretion results from vastly different release probabilities of individual insulin granules, but the morphological and molecular basis for this is unclear. Here, we show that human insulin secretion and exocytosis critically depend on the availability of membrane-docked granules and that T2D is associated with a strong reduction in granule docking. Glucose accelerated granule docking, and this effect was absent in T2D. Newly docked granules only slowly acquired release competence; this was regulated by major signaling pathways, but not glucose. Gene expression analysis indicated that key proteins involved in granule docking are downregulated in T2D, and overexpression of these proteins increased granule docking. The findings establish granule docking as an important glucose-dependent step in human insulin secretion that is dysregulated in T2D.

Loss of first-phase insulin secretion is an early sign of developing type 2 diabetes (T2D). Ca2+ entry through voltage-gated L-type Ca2+ channels triggers exocytosis of insulin-containing granules in pancreatic β cells and is required for the postprandial spike in insulin secretion. Using high-resolution microscopy, we have identified a subset of docked insulin granules in human β cells and rat-derived clonal insulin 1 (INS1) cells for which localized Ca2+ influx triggers exocytosis with high probability and minimal latency. This immediately releasable pool (IRP) of granules, identified both structurally and functionally, was absent in β cells from human T2D donors and in INS1 cells cultured in fatty acids that mimic the diabetic state. Upon arrival at the plasma membrane, IRP granules slowly associated with 15 to 20 L-type channels. We determined that recruitment depended on a direct interaction with the synaptic protein Munc13, because expression of the II–III loop of the channel, the C2 domain of Munc13-1, or of Munc13-1 with a mutated C2 domain all disrupted L-type channel clustering at granules and ablated fast exocytosis. Thus, rapid insulin secretion requires Munc13-mediated recruitment of L-type Ca2+ channels in close proximity to insulin granules. Loss of this organization underlies disturbed insulin secretion kinetics in T2D.

MnO 2 nanomaterials have aroused widespread attention because of their nanozyme activity, redox properties, good biocompatibility, and therapy-related activities. However, not many reports on self-luminescent MnO 2 materials have been concerned to date, which greatly hampered their further development in various fields. In this paper, luminescent MnO 2 quantum dots (MnO 2 QDs) have been first prepared via a facile one-step ultrasonic method. With the assistance of bovine serum albumin (BSA) or cysteine (Cys), the synthesized MnO 2 QDs (BSA-MnO 2 QDs or Cys-MnO 2 QDs) display strongly enhanced fluorescence (FL). The prepared BSA-MnO 2 QDs with a particle size of about 1 to 2 nm show the maximum excitation and emission peaks at 320 and 410 nm with excellent salt stability, anti-photobleaching ability, and time stability. It is confirmed that BSA plays a dual function as the exfoliating agent to promote the exfoliation of bulk MnO 2 nanosheets and as the capping agent to provide a friendly microenvironment for MnO 2 QDs. Ag ions can destroy the microenvironment of BSA-MnO 2 QDs owing to the in situ formation of Ag nanoparticles (Ag NPs) mediated by BSA on the surface of the QDs. Then, these Ag NPs can quench the FL intensity of the QDs by fluorescence resonance energy transfer. However, the FL strength of the BSA-MnO 2 QDs is recovered after adding H 2 O 2 and NaHS since they may react with Ag NPs to produce Ag + and Ag 2 S, which further confirmed the role of BSA. This work not only opens up a facile and universal avenue to synthesize luminescent MnO 2 QDs with enhanced FL but also provides a possible sensing platform through tuning the microenvironment of the MnO 2 QDs. The MnO 2 QDs with outstanding performance may show great potential as fluorescent probes in the fields of biological imaging, optical sensing, drug delivery, and therapy.

A fluorescent probe (N-(4-methyl-2-oxo-2H-chromen-7-yl)-2,4-dinitrobenzenesulfonamide), which exhibits high selectivity to glutathione and cysteine among amino acids including sulphur-containing methionine and metal ions, was synthesized. The experiments demonstrate that the fluorescent probe is a reliable and specific probe for glutathione and cysteine in living cells.

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Due to the harsh reaction conditions, high energy consumption, and numerous carbon emissions of the traditional Haber–Bosch method, the fixation of nitrogen under environmentally friendly and milder conditions is of great importance. Recently, photoelectrochemical (PEC) strategies have attracted extensive attention, where the catalysts with the advantages of cost-effectiveness and improved efficiency are critical for the nitrogen reduction reaction (NRR). Herein, we synthesized nitrogen vacancies that contained g-C3N5 (NV-g-C3N5) and combined with BiOBr to construct the p–n heterostructure NV-g-C3N5/BiOBr, in which the double-electron transfer mechanism was constructed. In one side, the nitrogen vacancies store the electrons coming from the g-C3N5 and provide for the nitrogen activation when needed; in addition, NV-g-C3N5/BiOBr further separates photoinduced electrons and holes because of the matched “Z”-shaped energy band structure. The double-electron transfer mechanism effectively retards the recombination of charge carriers and ensures the support of high-quality electrons, which results in excellent PEC NRR performance without the addition of noble metals. Although yields and durability are insufficient, the described double-electron transfer mechanism manifests the potential of the non-noble metal material in the PEC NRR, providing a foundation for the design of a more affordable and efficient photocathode in nitrogen reduction.

Fluorescent proteins (FPs) have proven to be valuable tools for high-resolution imaging studies of vesicle transport processes, including exo- and endocytosis. Since the pH of the vesicle lumen changes between acidic and neutral during these events, pH-sensitive FPs with near neutral pKa, such as pHluorin, are particularly useful. FPs with pKa>6 are readily available in the green spectrum, while red-emitting pH-sensitive FPs are rare and often not well characterized as reporters of exo- or endocytosis. Here we tested a panel of ten orange/red and two green FPs in fusions with neuropeptide Y (NPY) for use as secreted vesicle marker and reporter of dense core granule exocytosis and release. We report relative brightness, bleaching rate, targeting accuracy, sensitivity to vesicle pH, and their performance in detecting exocytosis in live cells. Tandem dimer (td)-mOrange2 was identified as well-targeted, bright, slowly bleaching and pH-sensitive FP that performed similar to EGFP. Single exocytosis events were readily observed, which allowed measurements of fusion pore lifetime and the dynamics of the exocytosis protein syntaxin at the release site during membrane fusion and cargo release.