Activatable molecular probes hold great promise for targeted cancer imaging. However, the hydrophobic nature of most conventional probes makes them generate precipitated agglomerate in aqueous media, thereby annihilating their responsiveness to analytes and precluding their practical applications for bioimaging. This study reports the development of two small molecular probes with unprecedented aggregation enhanced responsiveness to H 2 S for in vivo imaging of H 2 S-rich cancers. The subtle modulation of the equilibrium between hydrophilicity and lipophilicity by N-methylpyridinium endows these designed probes with the capability of spontaneously self-assembling into nanoprobes under physiological conditions. Such probes in an aggregated state, rather than a molecular dissolved state, show NIR fluorescence light up and photoacoustic signals turn on upon H 2 S specific activation, allowing in vivo visualization and differentiation of cancers based on differences in H 2 S content. Thus, our study presents an effective design strategy which should pave the way to molecular design of optimized probes for precision cancer diagnostics.

NOD-like receptor protein 3 (NLRP3) detects microbial infections or endogenous danger signals and activates the NLRP3 inflammasome, which has important functions in host defense and contributes to the pathogenesis of inflammatory diseases, and thereby needs to be tightly controlled. Deubiquitination of NLRP3 is considered a key step in NLRP3 inflammasome activation. However, the mechanisms by which deubiquitination controls NLRP3 inflammasome activation are unclear. Here, we show that the UAF1/USP1 deubiquitinase complex selectively removes K48-linked polyubiquitination of NLRP3 and suppresses its ubiquitination-mediated degradation, enhancing cellular NLRP3 levels, which are indispensable for subsequent NLRP3 inflammasome assembly and activation. In addition, the UAF1/USP12 and UAF1/USP46 complexes promote NF-κB activation, enhance the transcription of NLRP3 and proinflammatory cytokines (including pro-IL-1β, TNF, and IL-6) by inhibiting ubiquitination-mediated degradation of p65. Consequently, Uaf1 deficiency attenuates NLRP3 inflammasome activation and IL-1β secretion both in vitro and in vivo. Our study reveals that the UAF1 deubiquitinase complexes enhance NLRP3 and pro-IL-1β expression by targeting NLRP3 and p65 and licensing NLRP3 inflammasome activation.

Patients with subarachnoid hemorrhage (SAH) often suffer from cognitive function impairments even when they have received proper treatment, such as the clipping or coiling of aneurysms, and this causes problems with returning to work and burdens the family. Increasing attention has been paid to mesenchymal stem cell (MSC)-derived extracellular vesicle (MSC-EV) as promising therapeutic vesicles for stroke management. In this study, we explored the potential role of MSC-EV in a rat model of SAH. We observed that MSC-EV ameliorated early brain injury (EBI) after SAH by reducing the apoptosis of neurons and that SAH induced an increase in the expression level of miR-21 in the prefrontal cortex and hippocampus. In addition, using miRNA profiling and CSF sequencing data from the exRNA Atlas, we demonstrated that EV-derived miR-21 protected neurons from apoptosis and alleviated SAH-induced cognitive dysfunction. The neuroprotective role of MSC-EV was abrogated by miR-21 knockdown or the administration of MK2206, a PTEN/Akt inhibitor. Overall, our results suggest that MSC-EV promotes neuronal survival and alleviates EBI after SAH through transferring miR-21 to recipient neurons.

A hybrid thia‐norhexaphyrin comprising a directly linked N‐confused pyrrole and thiophene unit (1) revealed unique macrocycle transformations to afford multiply inner‐annulated aromatic macrocycles. Oxidation with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone triggered a cleavage of the C−S bond of the thiophene unit, accompanied with skeletal rearrangement to afford unique π‐conjugated products: a thiopyrrolo‐pentaphyrin embedded with a pyrrolo[1,2]isothiazole (2), a sulfur‐free pentaphyrin incorporating an indolizine moiety (3), and a thiopyranyltriphyrinoid containing a 2H‐thiopyran unit (4). Furthermore, 2 underwent desulfurization reactions to afford a fused pentaphyrin containing a pyrrolizine moiety (5) under mild conditions. Using expanded porphyrin scaffolds, oxidative thiophene cleavage and desulfurization of the hitherto unknown N‐confused core‐modified macrocycles would be a practical approach for developing unique polypyrrolic aromatic macrocycles.

Expanded porphyrins have been attracting increasing attention owing to their unique optical and electrochemical properties as well as switchable aromaticity. Toward material applications, regioselective functionalization of the expanded porphyrins at their periphery is indeed challenging due to the presence of multiple reactive sites. Herein, a set of regioselective halogenated isomers (L5-Br-A/B/C) of neo-confused isosmaragdyrin (L5) are synthesized by a combination of the halogenation reaction of L5 and sequential macrocycle-to-macrocycle transformation reactions of its halogenated isomers. On this basis, the regioselectively functionalized isosmaragdyrins are utilized as building blocks for constructing multichromophoric porphyrinoids, specifically, heterodyads L5-ZnP-A/B/C, in which a common zinc porphyrin is linked at three different pyrrolic positions of isosmaragdyrins, respectively, by Sonogashira coupling reactions. The highly efficient energy cascade from porphyrin to isosmaragdyrin is elucidated using steady-state/time-resolved spectroscopies and theoretical calculations. Notably, the energy transfer processes from the porphyrin to the isosmaragdyrin moieties as well as the excitation energy transfer rates in L5-ZnP-A/B/C are highly dependent on the linking sites by through-bond and Förster-type resonance energy transfer mechanisms. The site-selective functionalization and subsequent construction of a set of heterodyads of the expanded porphyrinoid would provide opportunities for developing new materials for optoelectronic applications.

An N‐confused phlorin isomer bearing a dipyrrin moiety at the α‐position of the confused pyrrole ring (1) was synthesized. PdII and BIII coordination at the peripheral prodigiosin‐like moiety of 1 afforded the corresponding complexes 2 and 3. Reflux of 2 in triethylamine (TEA) converted the meso‐phenyl into the PdII‐coordinating phenoxy group to afford 4. Under the same reaction conditions, TEA was linked to the α‐position of the dipyrrin unit in 3 as an N,N‐diethylaminovinyl group to afford 5. Furthermore, peripheral coordination of BIII in 3 and 5 improved the planarity of the phlorin macrocycle and thus facilitated the coordination of AgIII at the inner cavity to afford 3‐Ag and 5‐Ag, respectively. These results provide an effective approach for developing unique porphyrinoids through peripheral coordination.

Directly linked porphyrin dimers have attracted considerable attention because of their intriguing electronic features. Most emphasis has been placed on either dimers with large dihedral angles between the constituent planar monomeric subunits or those with overall planarity, referred to as “Planar-Twisted-Planar” and “Planar-Planar-Planar”, respectively. Herein, we report a “Twisted-Planar-Twisted” framework, the hexaphyrin dimer D that exists in a trans configuration. Treatment of D with MeOH affords two isomeric dimers, MD1 and MD2, both of which incorporate a methoxy moiety and exist in cis orientations with respect to the tethering linkage. The methanol-promoted conversion is accompanied by a readily discernible color change from green to brown and is not induced to an appreciable level by other alcohols. Dimer D thus acts as a rudimentary, albeit highly selective, reaction-based methanol indicator. This work provides a promising approach for constructing reaction-based chemosensors using porphyrinoid dimers of nonplanar subunits with biased reactivity.

A tripyrrin-armed isosmaragdyrin containing a β,β-linked bipyrrole moiety has been synthesized from a linear octapyrrole, and the succeeding metallation afforded an enantiomer pair of mononuclear NiII- and heterodinuclear NiII/CuII-complexes that exhibit P- and M-helices.