The RNA Exosome Syncs IAV-RNAPII Transcription to Promote Viral Ribogenesis and Infectivity.

The nuclear RNA exosome is an essential multi-subunit complex that controls RNA homeostasis. Congenital mutations in RNA exosome genes are associated with neurodegenerative diseases. Little is known about the role of the RNA exosome in the cellular response to pathogens. Here, using NGS and human and mouse genetics, we show that influenza A virus (IAV) ribogenesis and growth are suppressed by impaired RNA exosome activity. Mechanistically, the nuclear RNA exosome coordinates the initial steps of viral transcription with RNAPII at host promoters. The viral polymerase complex co-opts the nuclear RNA exosome complex and cellular RNAs en route to 3' end degradation. Exosome deficiency uncouples chromatin targeting of the viral polymerase complex and the formation of cellular:viral RNA hybrids, which are essential RNA intermediates that license transcription of antisense genomic viral RNAs. Our results suggest that evolutionary arms races have shaped the cellular RNA quality control machinery.

Trained immunity in recurrent Staphylococcus aureus infection promotes bacterial persistence.

Bacterial persister cells, a sub-population of dormant phenotypic variants highly tolerant to antibiotics, present a significant challenge for infection control. Investigating the mechanisms of antibiotic persistence is crucial for developing effective treatment strategies. Here, we found a significant association between tolerance frequency and previous infection history in bovine mastitis. Previous S. aureus infection led to S. aureus tolerance to killing by rifampicin in subsequent infection in vivo and in vitro. Actually, the activation of trained immunity contributed to rifampicin persistence of S. aureus in secondary infection, where it reduced the effectiveness of antibiotic treatment and increased disease severity. Mechanically, we found that S. aureus persistence was mediated by the accumulation of fumarate provoked by trained immunity. Combination therapy with metformin and rifampicin promoted eradication of persisters and improved the severity of recurrent S. aureus infection. These findings provide mechanistic insight into the relationship between trained immunity and S. aureus persistence, while providing proof of concept that trained immunity is a therapeutic target in recurrent bacterial infections involving persistent pathogens.

Deletions of singular U1 snRNA gene significantly interfere with transcription and 3'-end mRNA formation.

Small nuclear RNAs (snRNAs) are structural and functional cores of the spliceosome. In metazoan genomes, each snRNA has multiple copies/variants, up to hundreds in mammals. However, the expressions and functions of each copy/variant in one organism have not been systematically studied. Focus on U1 snRNA genes, we investigated all five copies in Drosophila melanogaster using two series of constructed strains. Analyses of transgenic flies that each have a U1 promoter-driven gfp revealed that U1:21D is the major and ubiquitously expressed copy, and the other four copies have specificities in developmental stages and tissues. Mutant strains that each have a precisely deleted copy of U1-gene exhibited various extents of defects in fly morphology or mobility, especially deletion of U1:82Eb. Interestingly, splicing was changed at limited levels in the deletion strains, while large amounts of differentially-expressed genes and alternative polyadenylation events were identified, showing preferences in the down-regulation of genes with 1-2 introns and selection of proximal sites for 3'-end polyadenylation. In vitro assays suggested that Drosophila U1 variants pulled down fewer SmD2 proteins compared to the canonical U1. This study demonstrates that all five U1-genes in Drosophila have physiological functions in development and play regulatory roles in transcription and 3'-end formation.

Bacterial infection promotes tumorigenesis of colorectal cancer via regulating CDC42 acetylation.

Increasing evidence highlights the role of bacteria in promoting tumorigenesis. The underlying mechanisms may be diverse and remain poorly understood. Here, we report that Salmonella infection leads to extensive de/acetylation changes in host cell proteins. The acetylation of mammalian cell division cycle 42 (CDC42), a member of the Rho family of GTPases involved in many crucial signaling pathways in cancer cells, is drastically reduced after bacterial infection. CDC42 is deacetylated by SIRT2 and acetylated by p300/CBP. Non-acetylated CDC42 at lysine 153 shows an impaired binding of its downstream effector PAK4 and an attenuated phosphorylation of p38 and JNK, consequently reduces cell apoptosis. The reduction in K153 acetylation also enhances the migration and invasion ability of colon cancer cells. The low level of K153 acetylation in patients with colorectal cancer (CRC) predicts a poor prognosis. Taken together, our findings suggest a new mechanism of bacterial infection-induced promotion of colorectal tumorigenesis by modulation of the CDC42-PAK axis through manipulation of CDC42 acetylation.

Dihydroartemisinin is an inhibitor of trained immunity through Akt/mTOR/HIF1α signaling pathway.

Trained immunity is mechanistically defined as the metabolically and epigenetically mediated long-term functional adaptation of the innate immune system, characterized by a heightened response to a secondary stimulation. Given appropriate activation, trained immunity represents an attractive anti-infective therapeutic target. Nevertheless, excessive immune response and subsequent inflammatory cascades may contribute to pathological tissue damage, indicating that the negative impacts of trained immunity appear to be significant. In this study, we show that innate immune responses such as the production of extracellular traps, pro-inflammatory cytokines, and autophagy-related proteins were markedly augmented in trained BMDMs. Furthermore, heat-killed C. albicans priming promotes the activation of the AIM2 inflammasome, and AIM2-/- mice exhibit impaired memory response induced by heat-killed C. albicans. Therefore, we establish that the AIM2 inflammasome is involved in trained immunity and emerges as a promising therapeutic target for potentially deleterious effects. Dihydroartemisinin can inhibit the memory response induced by heat-killed C. albicans through modulation of mTOR signaling and the AIM2 inflammasome. The findings suggest that dihydroartemisinin can reduce the induction of trained immunity by heat-killed C. albicans in C57BL/6 mice. Dihydroartemisinin is one such therapeutic intervention that has the potential to treat of diseases characterized by excessive trained immunity.

A new era of cancer immunotherapy: combining revolutionary technologies for enhanced CAR-M therapy.

Significant advancements have been made in the application of chimeric antigen receptor (CAR)-T treatment for blood cancers during the previous ten years. However, its effectiveness in treating solid tumors is still lacking, necessitating the exploration of alternative immunotherapies that can overcome the significant challenges faced by current CAR-T cells. CAR-based immunotherapy against solid tumors shows promise with the emergence of macrophages, which possess robust phagocytic abilities, antigen-presenting functions, and the ability to modify the tumor microenvironment and stimulate adaptive responses. This paper presents a thorough examination of the latest progress in CAR-M therapy, covering both basic scientific studies and clinical trials. This study examines the primary obstacles hindering the realization of the complete potential of CAR-M therapy, as well as the potential strategies that can be employed to overcome these hurdles. With the emergence of revolutionary technologies like in situ genetic modification, synthetic biology techniques, and biomaterial-supported gene transfer, which provide a wider array of resources for manipulating tumor-associated macrophages, we suggest that combining these advanced methods will result in the creation of a new era of CAR-M therapy that demonstrates improved efficacy, safety, and availability.

GSDMD-mediated NETosis promotes the development of acute respiratory distress syndrome.

Gasdermin D (GSDMD) is a classical molecule involved in pyroptosis. It has been reported to be cleaved into N-terminal fragments to form pores in the neutrophil membrane and promote the release of neutrophil extracellular traps (NETs). However, it remains unclear if GSDMD is involved in neutrophil regulation and NET release during ARDS. The role of neutrophil GSDMD in the development of ARDS was investigated in a murine model of ARDS induced by lipopolysaccharide (LPS) using the neutrophil specific GSDMD-deficient mice. The neutrophil GSDMD cleavage and its relationship with NETosis were also explored in ARDS patients. The cleavage of GSDMD in neutrophils from ARDS patients and mice was upregulated. Inhibition of GSDMD by genetic knockout or inhibitors resulted in reduced production of NET both in vivo and in vitro, and attenuation of LPS-induced lung injury. Moreover, in vitro experiments showed that the inhibition of GSDMD attenuated endothelial injury co-cultured with neutrophils from ARDS patients, while extrinsic NETs reversed the protective effect of GSDMD inhibition. Collectively, our data suggest that the neutrophil GSDMD cleavage is crucial in NET release during ARDS. The NET release maintained by cleaved GSDMD in neutrophils may be a key event in the development of ARDS.

Whole-brain mapping of monosynaptic afferent inputs to the CRH neurons in the medial prefrontal cortex of mice.

Corticotropin-releasing hormone (CRH) neurons are densely distributed in the medial prefrontal cortex (mPFC), which plays a crucial role in integrating and processing emotional and cognitive inputs from other brain regions. Therefore, it is important to know the neural afferent patterns of mPFCCRH neurons, which are still unclear. Here, we utilized a rabies virus-based monosynaptic retrograde tracing system to map the presynaptic afferents of the mPFCCRH neurons throughout the entire brain. The results show that the mPFCCRH neurons receive inputs from three main groups of brain regions: (1) the cortex, primarily the orbital cortex, somatomotor areas, and anterior cingulate cortex; (2) the thalamus, primarily the anteromedial nucleus, mediodorsal thalamic nucleus, and central medial thalamic nucleus; and (3) other brain regions, primarily the basolateral amygdala, hippocampus, and dorsal raphe nucleus. Taken together, our results are valuable for further investigations into the roles of the mPFCCRH neurons in normal and neurological disease states. These investigations can shed light on various aspects such as cognitive processing, emotional modulation, motivation, sociability, and pain.

NAC transcription factor SlNOR-like1 plays a dual regulatory role in tomato fruit cuticle formation.

The plant cuticle is an important protective barrier on the plant surface, constructed mainly by polymerized cutin matrix and a complex wax mixture. Although the pathway of plant cuticle biosynthesis has been clarified, knowledge of the transcriptional regulation network underlying fruit cuticle formation remains limited. In the present work, we discovered that tomato fruits of the NAC transcription factor SlNOR-like1 knockout mutants (nor-like1) produced by CRISPR/Cas9 [clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9] displayed reduced cutin deposition and cuticle thickness, with a microcracking phenotype, while wax accumulation was promoted. Further research revealed that SlNOR-like1 promotes cutin deposition by binding to the promoters of glycerol-3-phosphate acyltransferase6 (SlGPAT6; a key gene for cutin monomer formation) and CUTIN DEFICIENT2 (SlCD2; a positive regulator of cutin production) to activate their expression. Meanwhile, SlNOR-like1 inhibits wax accumulation, acting as a transcriptional repressor by targeting wax biosynthesis, and transport-related genes 3-ketoacyl-CoA synthase1 (SlKCS1), ECERIFERUM 1-2 (SlCER1-2), SlWAX2, and glycosylphosphatidylinositol-anchored lipid transfer protein 1-like (SlLTPG1-like). In conclusion, SlNOR-like1 executes a dual regulatory effect on tomato fruit cuticle development. Our results provide a new model for the transcriptional regulation of fruit cuticle formation.

On-chip integrated metasystem for spin-dependent multi-channel color holography.

On-chip integrated metasurface driven by in-plane guided waves is of great interests in various light-field manipulation applications such as colorful augmented reality and holographic display. However, it remains a challenge to design colorful multichannel holography by a single on-chip metasurface. Here we present metasurfaces integrated on top of a guided-wave photonic slab that achieves multi-channel colorful holographic light display. An end-to-end scheme is used to inverse design the metasurface for projecting off-chip preset multiple patterns. Particular examples are presented for customized patterns that were encoded into the metasurface with a single-cell meta-atom, working simultaneously at RGB color channels and for several different diffractive distances, with polarization dependence. Holographic images are generated at 18 independent channels with such a single-cell metasurface. The proposed design scheme is easy to implement, and the resulting device is viable for fabrication, promising plenty of applications in nanophotonics.

The use of longitudinal CT-based radiomics and clinicopathological features predicts the pathological complete response of metastasized axillary lymph nodes in breast cancer.

BACKGROUND: Accurate assessment of axillary status after neoadjuvant therapy for breast cancer patients with axillary lymph node metastasis is important for the selection of appropriate subsequent axillary treatment decisions. Our objectives were to accurately predict whether the breast cancer patients with axillary lymph node metastases could achieve axillary pathological complete response (pCR). METHODS: We collected imaging data to extract longitudinal CT image features before and after neoadjuvant chemotherapy (NAC), analyzed the correlation between radiomics and clinicopathological features, and developed models to predict whether patients with axillary lymph node metastasis can achieve axillary pCR after NAC. The clinical utility of the models was determined via decision curve analysis (DCA). Subgroup analyses were also performed. Then, a nomogram was developed based on the model with the best predictive efficiency and clinical utility and was validated using the calibration plots. RESULTS: A total of 549 breast cancer patients with metastasized axillary lymph nodes were enrolled in this study. 42 independent radiomics features were selected from LASSO regression to construct a logistic regression model with clinicopathological features (LR radiomics-clinical combined model). The AUC of the LR radiomics-clinical combined model prediction performance was 0.861 in the training set and 0.891 in the testing set. For the HR + /HER2 - , HER2 + , and Triple negative subtype, the LR radiomics-clinical combined model yields the best prediction AUCs of 0.756, 0.812, and 0.928 in training sets, and AUCs of 0.757, 0.777 and 0.838 in testing sets, respectively. CONCLUSIONS: The combination of radiomics features and clinicopathological characteristics can effectively predict axillary pCR status in NAC breast cancer patients.

ANP promotes HTR-8/SVneo cell invasion by upregulating protein kinase N 3 via autophagy inhibition.

Preeclampsia is a gestational disease characterized by two major pathological changes-shallow trophoblast invasion and impaired spiral artery remodeling. Atrial natriuretic peptide (ANP) is a kind of peptide hormone that regulates blood pressure, while the lack of active ANP participates in preeclampsia pathogenesis. However, the underlying mechanism of how ANP modulates trophoblasts function remains unclarified. Here, we performed isobaric tags for relative and absolute quantification (iTRAQ) in ANP-treated HTR-8/SVneo cells and identified Protein Kinase 3 (PKN3) as the downstream factor of ANP, which was downregulated in preeclamptic placenta. Chromatin immunoprecipitation analysis and luciferase assays showed that NFYA was one of the transcription factors for the PKN3 promoter, which was also regulated by ANP treatment in HTR-8/SVneo cells. Transmission electron microscopy and Western Blotting in HTR-8/SVneo cells indicated that ANP inhibited autophagy via AMPK-mTORC1 signaling, while excess autophagy was observed in preeclamptic placenta. The increased expression of PKN3 and enhanced cell invasion ability in HTR-8/SVneo cells induced by ANP could be abolished by autophagy activation or transfection with PKN3 shRNA or NFYA shRNA or NPR-A shRNA via regulating the invasion-related genes and the epithelial mesenchymal transition molecules. Our results demonstrated that ANP could enhance trophoblast invasion by upregulating PKN3 via NFYA promotion through autophagy inhibition in an AMPK/mTORC1 signaling-dependent manner.

Identification and biological characteristics of Enterococcus casseliflavus TN-47 isolated from Monochamus alternatus.

With the widespread use of antibiotics, the incidence of antibiotic resistance in microorganisms has increased. Monochamus alternatus is a trunk borer of pine trees. This study aimed to investigate the in vitro antimicrobial and biological characteristics of Enterococcus casseliflavus TN-47 (PP411196), isolated from the gastrointestinal tract of M. alternatus in Jilin Province, PR China. Among 13 isolates obtained from the insects, five were preliminarily screened for antimicrobial activity. E. casseliflavus TN-47, which exhibited the strongest antimicrobial activity, was identified. E. casseliflavus TN-47 possessed antimicrobial activity against Staphylococcus aureus USA300 and Salmonella enterica serovar Pullorum ATCC 19945. Furthermore, E. casseliflavus TN-47 was sensitive to tetracyclines, penicillins (ampicillin, carbenicillin, and piperacillin), quinolones and nitrofuran antibiotics, and resistant to certain beta-lactam antibiotics (oxacillin, cefradine and cephalexin), macrolide antibiotics, sulfonamides and aminoglycosides. E. casseliflavus TN-47 could tolerate low pH and pepsin-rich conditions in the stomach and grow in the presence of bile acids. E. casseliflavus TN-47 retained its strong auto-aggregating ability and hydrophobicity. This strain did not exhibit any haemolytic activity. These results indicate that E. casseliflavus TN-47 has potential as a probiotic. This study provides a theoretical foundation for the future applications of E. casseliflavus TN-47 and its secondary metabolites in animal nutrition and feed.

STING-dependent trained immunity contributes to host defense against Clostridium perfringens infection via mTOR signaling.

Clostridium perfringens (C. perfringens) infection is recognized as one of the most challenging issues threatening food safety and perplexing agricultural development. To date, the molecular mechanisms of the interactions between C. perfringens and the host remain poorly understood. Here, we show that stimulator of interferon genes (STING)-dependent trained immunity protected against C. perfringens infection through mTOR signaling. Heat-killed Candida albicans (HKCA) training elicited elevated TNF-α and IL-6 production after LPS restimulation in mouse peritoneal macrophages (PM). Although HKCA-trained PM produced decreased levels of TNF-α and IL-6, the importance of trained immunity was demonstrated by the fact that HKCA training resulted in enhanced bacterial phagocytic ability and clearance in vivo and in vitro during C. perfringens infection. Interestingly, HKCA training resulted in the activation of STING signaling. We further demonstrate that STING agonist DMXAA is a strong inducer of trained immunity and conferred host resistance to C. perfringens infection in PM. Importantly, corresponding to higher bacterial burden, reduction in cytokine secretion, phagocytosis, and bacterial killing were shown in the absence of STING after HKCA training. Meanwhile, the high expression levels of AKT/mTOR/HIF1α were indeed accompanied by an activated STING signaling under HKCA or DMXAA training. Moreover, inhibiting mTOR signaling with rapamycin dampened the trained response to LPS and C. perfringens challenge in wild-type (WT) PM after HKCA training. Furthermore, STING­deficient PM presented decreased levels of mTOR signaling-related proteins. Altogether, these results support STING involvement in trained immunity which protects against C. perfringens infection via mTOR signaling.

Synthesis of Carboranylated Dihydropyrrolo[1,2-a]quinoxalines and Dihydroindolo[1,2-a]quinoxalines by BF3·OEt2-Catalyzed Heterocyclization of C-Formyl-o-carboranes and Investigation of Their Oxidation Stability.

A BF3·OEt2-catalyzed synthesis of carboranylated dihydropyrrolo[1,2-a]quinoxalines and dihydroindolo[1,2-a]quinoxalines in 30-99% yields is presented through the heterocyclization of various C-modified C-formyl-o-carboranes with 1-(2-aminophenyl)-pyrroles/indoles. A systematic comparative investigation of their oxidation stability in air confirmed that 4-carboranyl-4,5-dihydropyrrolo[1,2-a]quinoxaline had better stability than the 4-phenyl analogue. A cage-deboronation reaction for N-acetyl-substituted carboranylated dihydropyrrolo[1,2-a]quinoxaline produced the corresponding 7,8-nido-carborane cesium salt. A kinetic resolution was also realized to obtain an optically pure carboranylated N-heterocycle scaffold bearing a carborane cage carbon-bonded chiral stereocenter.

Group A Streptococcal meningitis in children: a short case series and systematic review.

BACKGROUND: Group A streptococcal(GAS) meningitis is a severe disease with a high case fatality rate. In the era of increasing GAS meningitis, our understanding about this disease is limited. PURPOSE: To gain a better understanding about GAS meningitis. METHODS: Five new cases with GAS meningitis were reported. GAS meningitis related literatures were searched for systematic review in PUBMED and EMBASE. Case reports and case series on paediatric cases were included. Information on demographics, risk factors, symptoms, treatments, outcomes, and emm types of GAS was summarized. RESULTS: Totally 263 cases were included. Among 100 individuals, 9.9% (8/81) had prior varicella, 11.1% (9/81) had anatomical factors, and 53.2% (42/79) had extracranial infections. Soft tissue infections were common among infants (10/29, 34.5%), while ear/sinus infections were more prevalent in children ≥ 3 years (21/42, 50.0%). The overall case fatality rate (CFR) was 16.2% (12/74). High risk of death was found in patients with shock or systemic complications, young children(< 3 years) and cases related to hematogenic spread. The predominate cause of death was shock(6/8). Among the 163 patients included in case series studies, ear/sinus infections ranged from 21.4 to 62.5%, while STSS/shock ranged from 12.5 to 35.7%, and the CFR ranged from 5.9 to 42.9%. CONCLUSIONS: A history of varicella, soft tissue infections, parameningeal infections and CSF leaks are important clinical clues to GAS in children with meningitis. Young children and hematogenic spread related cases need to be closely monitored for shock due to the high risk of death.

In Situ-Generated Hollow CoFe-LDH/Co-MOF Heterostructure Nanorod Arrays for Oxygen Evolution Reaction.

Assembling a heterostructure is an effective strategy for enhancing the electrocatalytic activity of hybrid materials. Herein, CoFe-layered double hydroxide and Co-metal-organic framework (CoFe-LDH/Co-MOF) hollow heterostructure nanorod arrays are synthesized. First, [Co(DIPL)(H3BTC)(H2O)2]n [named as Co-MOF, DIPL = 2,6-di(pyrid-4-yl)-4-phenylpyridine, H3BTC = 1,3,5-benzenetricarboxylic acid] crystalline materials with a uniform hollow structure were prepared on the nickel foam. The CoFe-LDH/Co-MOF composite perfectly inherits the original hollow nanorod array morphology after the subsequent electrodeposition process. Optimized CoFe-LDH/Co-MOF hollow heterostructure nanorod arrays display excellent performance in oxygen evolution reaction (OER) with ultralow overpotentials of 215 mV to deliver current densities of 10 mA cm-2 and maintain the electrocatalytic activity for a duration as long as 220 h, ranking it one of the non-noble metal-based electrocatalysts for OER. Density functional theory calculations validate the reduction in free energy for the rate-determining step by the synergistic effect of Co-MOF and CoFe-LDH, with the increased charge density and noticeable electron transfer at the Co-O site, which highlights the capability of Co-MOF to finely adjust the electronic structure and facilitate the creation of active sites. This work establishes an experimental and theoretical basis for promoting efficient water splitting through the design of heterostructures in catalysts.

Nupr1-mediated vascular smooth muscle cell phenotype transformation involved in methamphetamine induces pulmonary hypertension.

AIMS: Nuclear protein 1 (Nupr1) is a multifunctional stress-induced protein involved in the regulation of tumorigenesis, apoptosis, and autophagy. However, its role in pulmonary hypertension (PH) after METH exposure remains unexplored. In this study, we aimed to investigate whether METH can induce PH and describe the role and mechanism of Nupr1 in the development of PH. METHODS AND RESULTS: Mice were made to induce pulmonary hypertension (PH) upon chronic intermittent treatment with METH. Their right ventricular systolic pressure (RVSP) was measured to assess pulmonary artery pressure. Pulmonary artery morphometry was determined by H&E staining and Masson staining. Nupr1 expression and function were detected in human lungs, mice lungs exposed to METH, and cultured pulmonary arterial smooth muscle cells (PASMCs) with METH treatment. Our results showed that chronic intermittent METH treatment successfully induced PH in mice. Nupr1 expression was increased in the cultured PASMCs, pulmonary arterial media from METH-exposed mice, and METH-ingested human specimens compared with control. Elevated Nupr1 expression promoted PASMC phenotype change from contractile to synthetic, which triggered pulmonary artery remodeling and resulted in PH formation. Mechanistically, Nupr1 mediated the opening of store-operated calcium entry (SOCE) by activating the expression of STIM1, thereby promoting Ca2+ influx and inducing phenotypic conversion of PASMCs. CONCLUSIONS: Nupr1 activation could promote Ca2+ influx through STIM1-mediated SOCE opening, which promoted METH-induced pulmonary artery remodeling and led to PH formation. These results suggested that Nupr1 played an important role in METH-induced PH and might be a potential target for METH-related PH therapy.

IFI204 protects host defense against Staphylococcus aureus-induced pneumonia by promoting extracellular traps formation.

Interferon-inducible protein 204 (IFI204) is an intracellular DNA receptor that can recognize DNA viruses and intracellular bacteria. Extracellular traps (ETs) have been recognized as an indispensable antimicrobial barrier that play an indispensable role in bacterial, fungal, parasitic, and viral infections. However, how ETs form and the mechanisms by which IFI204 function in Staphylococcus aureus pneumonia are still unclear. Moreover, by in vitro experiments, we proved that IFI204 deficiency decreases the formation of ETs induced by Staphylococcus aureus in a NOX-independent manner. More importantly, Deoxyribonuclease I (DNase I) treatment significantly inhibited the formation of ETs. IFI204 contributed to ETs formation by promoting citrullination of histone H3 and the expression of PAD4 (peptidylarginine deiminase 4). Altogether, these findings highlight the potential importance of IFI204 for host defense against S. aureus USA300-TCH1516 infection.

A Tumor-Targeting Dual-Modal imaging probe for nitroreductase in vivo.

Nitroreductase (NTR) overexpression often occurs in tumors, highlighting the significance of effective NTR detection. Despite the utilization of various optical methods for this purpose, the absence of an efficient tumor-targeting optical probe for NTR detection remains a challenge. In this research, a novel tumor-targeting probe (Cy-Bio-NO2) is developed to perform dual-modal NTR detection using near-infrared fluorescence and photoacoustic techniques. This probe exhibits exceptional sensitivity and selectivity to NTR. Upon the reaction with NTR, Cy-Bio-NO2 demonstrates a distinct fluorescence "off-on" response at 800 nm, with an impressive detection limit of 12 ng/mL. Furthermore, the probe shows on-off photoacoustic signal with NTR. Cy-Bio-NO2 has been successfully employed for dual-modal NTR detection in living cells, specifically targeting biotin receptor-positive cancer cells for imaging purposes. Notably, this probe effectively detects tumor hypoxia through dual-modal imaging in tumor-bearing mice. The strategy of biotin incorporation markedly enhances the probe's tumor-targeting capability, facilitating its engagement in dual-modal imaging at tumor sites. This imaging capacity holds substantial promise as an accurate tool for cancer diagnosis.