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Restoring innate apoptosis and simultaneously inhibiting metastasis by a molecular drug is an effective cancer therapeutic approach. Herein, a large rigid and V-shaped NIR-II dye

By precisely controlling the waveform of ultrashort laser fields, electronic and nuclear motions in molecules can be steered on extremely short time scales, even in the attosecond regime. This new research field, termed "optochemistry", presents the light field in the time-frequency domain and opens new avenues for tailoring molecular reactions beyond photochemistry. This Perspective summarizes the ultrafast laser techniques employed in recent years for manipulating the molecular reactions based on waveform control of intense ultrashort laser pulses, where the chemical reactions can take place in isolated molecules, clusters, and various nanosystems. The underlying mechanisms for the coherent control of molecular dynamics are explicitly explored. Challenges and opportunities coexist in the field of optochemistry. Advanced technologies and theoretical modeling are still being pursued, with great prospects for controlling chemical reactions with unprecedented spatiotemporal precision.

Novel xanthenoid dyes by replacing the central oxygen atom of the xanthene dyes with less electron-rich bridging groups have been intensively sought after primarily for their long spectral wavelengths. However, the new scaffolds are likely prone to nucleophilic attack at their central methane carbon, as the result of the reduced electron density of the fluorochromic scaffolds. We envisage that the bridging group may be harnessed to sterically shield the central methane carbon from incoming nucleophiles and render high stability and synthesized xantheno-xanthene dyes. Additionally, the xantheno-bridging group can be modified via electrophilic aromatic substitution to introduce functionalities, e.g., sulfonate groups.

Ratiometric probes facilitate quantitative studies via self-calibration and are cherished for bioimaging. Often, a small probe-product spectral separation leads to crosstalk, but the rational devel...

Near-infrared (NIR) fluorophores absorbing maximally in the region beyond 800 nm, i.e., deep-NIR spectral region, are actively sought for biomedical applications. Ideal dyes are bright, nontoxic, photostable, biocompatible, and easily derivatized to introduce functionalities (e.g., for bioconjugation or aqueous solubility). The rational design of such fluorophores remains a major challenge. Silicon-substituted rhodamines have been successful for bioimaging applications in the red spectral region. The longer-wavelength silicon-substituted congeners for the deep-NIR spectral region are unknown to date. We successfully prepared four silicon-substituted bis-benzannulated rhodamine dyes (

Nitric oxide donors (NODs) are indispensable in biological research and disease treatment. NODs had been utilized to treat cardiovascular diseases in clinic and many others are under trial. Thiols are typically required for these donors to release NO. Yet, their mechanism is complex and often lead to resistance. Herein, we reported that N-nitrosated electron-deficient dyes are capable of NO release with one-electron reduction. A fluorophore is generated simultaneously, whose fluorescence is harnessed to monitor the profile of NO release. Through electrochemical and spectral studies, NOD f3 was found to exhibit good biocompatibility and high reduction efficiency and its potentials in cell-protection in oxygen and glucose deprivation (OGD) models were showcased with endothelial cells. This work aims at offering a new approach to design reduction-triggered NOD, which have therapeutic potentials in ischemia-reperfusion.

By combining a Hill-type pH probe and a pH-insensitive naphthalimide fluorophore, we synthesized a FRET-based ratiometric pH probe (PHHF), exhibiting a reduced pH transition width, representing a unique approach for development of sensitive probes for detection of biorelevant pH changes.

Social experiences during early life are thought to be critical for proper social and emotional development. Conversely, social insults during development causes long-lasting behavioral abnormalities later in life. However, how juvenile social deprivation influences social and emotional behaviors remains poorly understood. Here, we show that juvenile social isolation induces a shift in microbial ecology that negatively impacts social and emotional behaviors in adulthood. These behavioral changes, which occur during this critical period are transferable to antibiotic pre-treated mice by fecal microbiota transplant. In addition, juvenile social isolation decreases the expression of oxytocin receptor (OXTR) in the medial prefrontal cortex (mPFC), and increases the amounts of fecal propionic acid (PA), a short-chain fatty acid derived from gut micobiota. Accordingly, infusion with an OXTR antagonist (OXTR-A, l-368,899) specifically in the mPFC or supplementation of PA both can cause social deficits and anxiety-like behaviors in group housed mice. Collectively, our findings reveal that juvenile social experience regulates prefrontal cortical OXTR expression through gut microbiota-produced PA and that is essential for normal social and emotional behaviors, thus providing a cellular and molecular context to understand the consequences of juvenile social deprivation.

Fluorophores with photo-modulatory fluorescence properties are valuable for cutting-edge localization microscopy. The existing probes are either photo-activatable, or photo-switchable, but not both. We report a probe (DH-SiR), a leuco-dye obtained by reduction of Si-rhodamine, with both photo-activatable and photo-switchable fluorescence. The potential for super-resolution microscopy was showcased.

Uni-directional multi-state fluorochromic scaffolds are valuable photofunctional molecules and yet scarce. We report a general approach for their design, i.e., mechanodonor-acceptor coupling (MDAC). A photochromic molecule is a mechanodonor, due to its capability to convert photonic energy into mechanical force. Upon proper coupling, it can be used to drive a mechanochromic molecule for uni-directional multi-state fluorochromism. The embodiment of this approach is a rhodamine-dithienylethylene hydride (RDH), which has been successfully employed in super-resolution localization microscopy

The pH-responsive profile of the traditional pH probes (the HH-type pH probes) is governed by the Henderson–Hasselbalch equation. Despite their widespread use, pH probes with further enhanced pH se...

Thioxo/dithioxo-naphthalimide is a class of rarely visited fluorophore, first synthesized in 1999. Facile chemistry was devised to achieve mono or dual thionation of the two carbonyl groups of 1,8-naphthalimide. Thionation effectively shifts absorption maximum to longer spectral wavelength, significantly increase absorption coefficients, and dramatically enhances intersystem crossing efficiency with respect to their oxo-analogues. They were first explored as potent photocleavers to induce DNA strand break and novel photosensitizers for photodynamic therapies. In recent years, the unique chemistry of thioxo groups has been harnessed to achieve new applications, such as fluorescent sensors for heave metal ions. These unique photochemical and photophysical characteristics revitalize them intriguing functional molecules to investigate. In this short review, we wish to revisit their first discovery, facile synthesis, and the endeavors on the use of thioxo/dithioxo-naphthalimides for novel chemical and biomedical applications.

Ischemia-reperfusion (I/R) injuries are from the secondary radicals of ONOO

The pH-responsive profile of the traditional pH probes (the HH-type pH probes) is governed by the Henderson-Hasselbalch equation. Despite their widespread use, pH probes with further enhanced pH sensitivity, i.e., Hill-type pH probes, are sought after. As a result of positive cooperativity toward protonation, they exhibit a smaller acid-base transition width than that of a HH-type pH probe, which is 2 pH unit. As a result, the Hill-type pH probes have an improved capability to differentiate minor biorelevant pH changes. We previously devised a class of small-molecule Hill-type pH probes (

The frontier of nitric oxide biology has gradually shifted from mechanism elucidation to biomanipulation, e.g. cell-proliferation promotion, cell-apoptosis induction, and lifespan modulation. This warrants biocompatible nitric oxide (NO) donating materials, whose NO release is not only controlled by a bioorthogonal trigger, but also self-calibrated allowing real-time monitoring and hence an onset/offset of the NO release. Additionally, the dose of NO release should be facilely adjusted in a large dynamic range; flux and the dose are critical to the biological outcome of NO treatment. Via self-assembly of a PEGylated small-molecule NO donor, we developed novel NO-donating nanoparticles (PEG-NORM), which meet all the aforementioned criteria. We showcased that a low flux of NO induced cell proliferation, while a high flux induced cell oxidative stress and, ultimately, death. Notably, PEG-NORM was capable of efficiently modulating the lifespan of C. elegans. The average lifespan of C. elegans could be fine-tuned to be as short as 15.87 ± 0.29 days with a high dose of NO, or as long as 21.13 ± 0.41 days with a low dose of NO, compared to an average life-span of 18.87 ± 0.46 days. Thus, PEG-NORM has broad potential in cell manipulation and life-span modulation and could drive the advancement of NO biology and medicine., Schematic illustration of modulating the longevity of the C. elegans by PEG-NORM nanoparticles.

Fluorescent probes for nitric oxide (NO), or more frequently for its oxidized surrogate dinitrogen trioxide (N2O3), have enabled scientists to study the contributions of this signaling molecule to many physiological processes. Seeking to improve upon limitations of other probes, we have developed a family of fluorescent probes based on a 2-amino-3′-dialkylaminobiphenyl core. This core condenses with N2O3 to form benzo[c]cinnoline structures, incorporating the analyte into the newly formed fluorophore, which results in product fluorescence with virtually no background contribution from the initial probe. We varied the substituents in the core in order to optimize both the reactivity of the probes with N2O3 and their cinnoline products' fluorescence wavelengths and brightness. The top candidates were then applied to cultured cells to verify that they could respond to NO within cellular milieus, and the top performer, NO530, was compared with a “gold standard” commercial probe, DAF-FM, in a macrophage-derived cell line, RAW 264.7, stimulated to produce NO. NO530 demonstrated similar or better sensitivity and higher selectivity for NO than DAF, making it an attractive potential alternative for NO tracking in various applications., A thorough structure-property relationship study has produced much-improved fluorescence probes for nitric oxide surrogate, e.g. N2O3, compared to the original NO550.

Sensitivity is an important parameter for a molecular probe. Hill-type pH probes exhibit improved detection sensitivity compared to the traditional pH probes following the Henderson-Hasselbalch equation. Exploiting positive cooperativity, we recently devised a novel molecular scaffold (

Spiro-linked bichromophoric molecular systems are superior for triplet excited state generation. First, the two chromophores are tethered into a close proximity not accessible via alternative linkage, promoting spiro-conjugation mediated charge-transfer (CT). Second, the spiro-orthogonality inhibit FRET-type non-radiative deactivation and high rigidity largely suppresses vibronic energy dissipation. An intersystem crossing (ISC) rate constant of 1.0×10 11 s -1 was previously registered with a spiro-bis-benzophenone scaffold. We envisage that triplet generation efficiency could be further enhanced by stabilizing the spiro-CT state and rationally designed a family of spiro-compounds (SCTs), which consist of electron-rich diphenyl ether as the spiro-CT donor and electron-deficient dinaphthyl ketone as the spiro-CT acceptor. Through fine-tuning of the energy level between the CT and high energy triplet states, near-unity triplet generation quantum yield was achieved and the underlying ISC mechanism is revealed by using ultrafast spectroscopy and quantum chemical calculations. Finally, potential triplet sensitizing application was demonstrated in SCTs. Our findings suggest that spiro-bichromophoric molecular system with an enhanced spiro-charge transfer warrants efficient triplet generation and represents a powerful design strategy of heavy-atom-free triplet sensitizers with predictable ISC property.

Aspirin is a commonly used anti-inflammatory, analgesic and antithrombotic drug. It has attracted attention due to its potential antifungal therapeutic effect; however, the molecular mechanism is poorly understood. Here, the effects of aspirin on the cell wall of Saccharomyces cerevisiae were explored. We observed by scanning electron microscopy that aspirin could damage the cell wall ultrastructure. Meanwhile, a cellular surface hydrophobicity (CSH) assay showed that aspirin increased the hydrophobicity of the yeast cell surface. A drug sensitivity assay indicated that the overexpression of dolichol phosphate mannose synthase 1 (DPM1) reversed the cell wall damage and decreased the CSH induced by aspirin. Importantly, aspirin decreased the expression and enzyme activity of DPM1 in S. cerevisiae. Molecular docking results demonstrated that aspirin could directly bind to the Ser141 site of DPM1. Similarly, we found that aspirin damaged the cell wall and inhibited the expression of DPM1 in Candida albicans. These findings improve the current understanding of the action mode of aspirin and provide new strategies for antifungal drug design.

Obesity is currently one of the most important challenges to public health worldwide. Acupuncture has been widely used to treat obesity. However, whether acupuncture regulates intestinal innate immunity via intestinal microbiota against obesity remains to be elucidated. In this study, electroacupuncture (EA) effectively reduced body weight and fat accumulation in obese mice persistently fed a high-fat diet. Full-length 16S rDNA sequencing showed dysbiotic microbiota in the cecum of obese mice. The composition and function of the cecal microbiota of obese mice were markedly restored after EA treatment. After 21 d of EA intervention, the expression of defensin alpha 5 (Defa5) was restored to healthy controls, whereas fat digestion and absorption genes including fabp1 were markedly decreased in the jejunum of obese mice. The Defa5 levels were positively correlated with the family Lachnospiraceae and negatively correlated with obesity indexes. EA also reduced tissue inflammation, ameliorated misaligned glucose tolerance, and inhibited key genes for intestinal lipid absorption. In summary, EA exerted an anti-obesity effect by promoting intestinal defensins, rescuing dysbiotic cecal microbiota, and reducing lipid absorption in a synergistic mode. We present for the first time the key role of alpha defensins in the relationship between gut microbiota and disease during electroacupuncture treatment of obesity. The mucosal innate immunity seems to have a stronger ability to shape the microbiota than dietary factors.

Ample evidence indicates that maternal immune activation (MIA) during gestation is linked to an increased risk for neurodevelopmental and psychiatric disorders, such as autism spectrum disorder (ASD), anxiety and depression, in offspring. However, the underlying mechanism for such a link remains largely elusive. Here, we performed RNA sequencing (RNA-seq) to examine the transcriptional profiles changes in mice in response to MIA and identified that the expression of Scn1a gene, encoding the pore-forming α-subunit of the brain voltage-gated sodium channel type-1 (NaV1.1) primarily in fast-spiking inhibitory interneurons, was significantly decreased in the medial prefrontal cortex (mPFC) of juvenile offspring after MIA. Moreover, diminished excitatory drive onto interneurons causes reduction of spontaneous gamma-aminobutyric acid (GABA)ergic neurotransmission in the mPFC of MIA offspring, leading to hyperactivity in this brain region. Remarkably, treatment with low-dose benzodiazepines clonazepam, an agonist of GABAA receptors, completely prevented the behavioral abnormalities, including stereotypies, social deficits, anxiety- and depression-like behavior, via increasing inhibitory neurotransmission as well as decreasing neural activity in the mPFC of MIA offspring. Our results demonstrate that decreased expression of NaV1.1 in the mPFC leads to abnormalities in maternal inflammation-related behaviors and provides a potential therapeutic strategy for the abnormal behavioral phenotypes observed in the offspring exposed to MIA.

The evolution of super-resolution imaging techniques, especially single-molecule localization microscopy, demands the engineering of switchable fluorophores with labeling functionality. Yet, the switching of these fluorophores depends on the exterior conditions of UV light and enhancing buffers, which is bioincompatible for living-cell applications. Herein, to surpass these limitations, a nitroso-caging strategy is employed to cage rhodamines into leuco forms, which for the first time, is discovered to uncage highly bright zwitterions by green light. Further, clickable construction grants the specificity and versatility for labeling various components in living cells. The simultaneous photoactivation and excitation of these novel probes allow for single-laser super-resolution imaging without any harmful additives. Super-resolution imaging of microtubules in fixed cells or mitochondria and the distribution of glycans and H2B proteins in living cells are achieved at a molecular scale with robust integrity. We envision that our nitroso-caging probes would set a platform for the development of future visible-activatable probes.

DNA methylation and demethylation are the key steps in epigenetics. Emerging studies have demonstrated that these two processes play crucial roles in mammalian development and pathogenesis. Epigenetic modified cytosine and its further oxidative products, including 5-methylcytosine, 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine, are called the "new four bases of DNA". The appearance of such new epigenetic bases can complicate DNA photodamage and repairing mechanism because they could have drastically different excited-state dynamics compared to canonical DNA nucleobases. In this study, excited-state dynamics of three demethylated nucleosides in buffer solution at physiological pH were investigated by femtosecond to microsecond time-resolved spectroscopy. Distinct excited-state dynamics are found in these demethylated nucleosides. For 2'-deoxy-5-formylcytidine (5fdCyd), direct observation of ultrafast intersystem crossing to the triple state with a 69% quantum yield is presented. Meanwhile, the triplet-state energy of 5fdCyd can transfer to the ambient molecular oxygen and generate destructive singlet oxygen. On the other hand, no such observation is seen in 2'-deoxy-5-hydroxymethylcytidine (5hmdCyd) and 2'-deoxy-5-carboxycytidine (5cadCyd), and these two bases show ultrafast internal conversion similar to that in 5-methylcytidine and cytidine. These results indicate that 5fdCyd is an effective internal triplet photosensitizer in DNA, and it could act as a new hot spot in DNA photodamage.

Compact fluorophores are desired for bioconjugation because they minimally perturb the native biological functions of proteins or organelles. However, their absorption and emission wavelengths are typically short and not ideal for practical applications. For example, coumarin is one of the smallest fluorophores with excellent fluorescence properties. However, its potentials in biological applications are limited by its relatively short excitation wavelengths in the UV spectral region. It is the aim of this manuscript to develop coumarin analogs absorbing and emitting in the visible range through rational molecular engineering. We designed and synthesized C-coumarin dyes, and found that their maximal absorption wavelengths fall well within the visible region, rendering them superior for live cell imaging than O-coumarins. The other promising properties of C-coumarins include larger Stokes’ shifts, low cytotoxicity, and high chemostability.

Near infrared (NIR) absorbing and emitting dyes are sought after for their potentials in bioimaging and theranostic applications. They are typically not as stable as dyes absorbing and emitting in the visible spectral range, as the result of a reduced HOMO-LUMO band-gap. Also, they are not as efficient fluorescence emitters due to accelerated internal conversion kinetics. In addition, their large conjugative backbone render them high tendency to form aggregate and low aqueous solubility. In this tutorial, we have described a four-step approach for rational design of organic dyes with an overall high-performance to meet the rigorous requirements of biological applications. Also, some background regarding “NIR” is provided along with some recent breakthroughs of the field.

Antimicrobial resistance is a public health emergency and warrants coordinated global efforts. Challenge is that no alternative molecular platform has been identified for discovery of abundant antimicrobial hit compounds. Xanthene libraries have been screened for bioactive compounds. However, the potentially accessible chemistry space of xanthene dyes is limited by the existing xanthene synthesis. Herein we report a mild one-step synthesis, which permits late-stage introduction of a xanthene moiety onto i.e. natural products, pharmaceuticals, and bioactive compounds and construction of a focused library of rhodamine dyes exhibiting facile functional, topographical and stereochemical diversity. In vitro screening yields 37 analogs with mid-to-high bactericidal activity against WHO priority drug-resistant pathogens. These findings suggest that synthetic dye libraries exhibiting high structural diversity is a feasible chemical space combating antibacterial resistance, to complement the natural sources.

Neuropsychiatric dysfunction and reactive microglia are hallmarks of high-fat diet (HFD)-induced obesity, yet whether these reactive microglia contribute to HFD-induced obesity-related behavioral abnormalities and the underlying mechanisms remain unclear. Here, we show that HFD feeding causes social deficits and anxiety-like behaviors with impaired neuronal activity and alters the gut microbiota, particularly by depleting Lactobacillus reuteri (L. reuteri), in mice. The profiles of microbiome and metabolome in HFD-fed mice predict that specific microbial taxa and their metabolites regulate HFD-induced obesity-related behavioral abnormalities. Oral treatment with the L. reuteri reduces microglial activation and increases dendritic spine density, thus ameliorates social deficits and anxiety in HFD-fed mice. HFD-fed mice that are administered L. reuteri are also found to accumulate butyrate in their gut, sera and brain. Moreover, supplementation of butyrate improves behavioral abnormalities and modulates microglial homeostasis in HFD-fed mice. In addition, selectively removal of microglia through a pharmacologic approach can rescue dendritic spine loss and increase neuronal activity that profoundly alleviates social deficits and anxiety arising from HFD-induced obesity. Overall, this study reveals an unexpected pivotal role of gut commensal-derived butyrate in HFD-induced social deficits and anxiety-like behaviors through regulation of microglial homeostasis and identifies a potential probiotic treatment for HFD-induced obesity-related behavioral abnormalities.

Spiro conjugation has been proposed to dictate the efficiency of charge transfer, which could directly affect the spin-orbit charge transfer intersystem crossing (SOCT-ISC) process. However, this process has yet to be exemplified. Herein, we prepared three spirobis[anthracene]diones, in which two benzophenone moieties are locked in close proximity and differentially functionalized to fine-tune the charge transfer state. Its feasibility for SOCT-ISC was theoretically predicted, then experimentally evaluated. Through fine-tuning the spiro conjugation coupling and varying the solvent dielectric constants, ISC rate constants were engineered to vary in a dynamic range of three orders of magnitude, from 7.8×108 s-1 to 1.0×1011 s-1 , which is the highest ISC rate reported for SOCT-ISC system to our knowledge. Our findings substantiate the key factors for effective SOCT-ISC and offer a new avenue for the rational design of heavy atom free triplet sensitizers.

Fluorescent probes find widespread applications in chemical analysis, biosensing, and disease diagnosis and are also the cornerstones of many cutting-edge biotechnologies. Yet, the numerous probes developed thus far are actually based on a handful of probe design principles. In this article, we wish to summarize the recent progress of the field toward the use of a novel "covalent-assembly" principle for probe design.

Two new cyanine-based fluorescent probes 1 and 2 have been developed. Probe 1 bears two cyanine units in a single molecule, and probe 2 contains a bis(trifluoromethyl)benzenethiol moiety. Both are non-fluorescent. The addition of intracellular glutathione (GSH) significantly enhanced the NIR fluorescence of the two probes. Both probes were used to image varying amounts of GSH in living cells. In tumor bearing mice, the in vivo fluorescence intensity of both probes was higher in tumors, where GSH is overexpressed, than in normal tissues. These results suggest that these new fluorogenic probes have potential for GSH-targeting diagnostic imaging.