N-Phenyl-2-Pyridone-Derived Endoperoxide Suppressing both Lung Cancer and Idiopathic Pulmonary Fibrosis Progression by Three-Pronged Action.

We report an endoperoxide compound (E5) which can deliver three therapeutic components by a thermal cycloreversion, namely, singlet oxygen, triplet oxygen and 3-methyl-N-phenyl-2-pyridone, thus targeting multiple mechanisms for treating non-small cell lung cancer and idiopathic pulmonary fibrosis. In aqueous environment, E5 undergoes clean reaction to afford three therapeutic components with a half-life of 8.3 hours without the generation of other by-products, which not only achieves good cytotoxicity toward lung cancer cells and decreases the levels of HIF-1α protein, but also inhibits the TGF-ß1 induced fibrosis in vitro. In vivo experiments also demonstrated the efficacy of E5 in inhibiting tumor growth and relieving idiopathic pulmonary fibrosis, while exhibiting good biocompatibility. Many lines of evidence reveal the therapeutic efficacy of singlet oxygen and 3-methyl-N-phenyl-2-pyridone, and triplet oxygen could downregulate HIF-1α and relieve tumor hypoxia which is a critical issue in conventional PDT. Unlike other combination therapies, in which multiple therapeutic agents are given in independent formulations, our work demonstrates single molecule endoperoxide prodrugs could be developed as new platforms for treatment of cancers and related diseases.

Targeted Endoperoxides Delivering Singlet Oxygen to Cancer Cell Mitochondria: Exploration of the Therapeutic Potential.

The clinical practice of photodynamic therapy of cancer (PDT) is mostly limited to superficial types of skin cancer. The major reason behind this limited applicability is the need for light in the photogeneration of ROS, and in particular singlet oxygen. In order to circumvent this major roadblock, we designed and synthesized naphthalene-derived endoperoxides with mitochondria targeting triphenylphosphonium moieties. Here, we show that these compounds release singlet oxygen by thermal cycloreversion, and initiate cell death with IC50 < 10 µM in cancer cell cultures. The mouse 4T1 breast tumor model study, where the endoperoxide compound was introduced intraperitoneally, also showed highly promising results, with negligible systemic toxicity. Targeted delivery of singlet oxygen to cancer cell mitochondria could be the breakthrough needed to transform Photodynamic Therapy into a broadly applicable methodology for cancer treatment by keeping the central tenet and discarding problematic dependencies on oxygen or external light.

Discovery of Disubstituted Carboranes as Inhibitors of Heat Shock Protein 90-Heat Shock Factor 1 Interaction.

Efficient synthesis of disubstituted para- and ortho-carboranes (2 and 3, respectively) was achieved. Among the compounds synthesized, 3e showed potent suppression of hypoxia-inducible factor 1 (HIF-1) transcriptional activity under hypoxia by a cell-based reporter gene assay. Detailed mechanism-of-action studies revealed that 3e reduced the stability of heat shock protein (HSP) 90 client proteins such as CDK4, AKT, and cyclin D1 by inhibiting HSP90 chaperone activity but did not induce a heat shock response (HSR), which may cause drug resistance. Furthermore, 3e inhibited the interaction between HSP90 and heat shock factor 1 (HSF1), resulting in reducing HSF1 protein stability and thereby suppressing the transcription of heat shock proteins.

Review on active components and mechanism of natural product polysaccharides against gastric carcinoma.

One of the malignant tumors with a high occurrence rate worldwide is gastric carcinoma, which is an epithelial malignant tumor emerging from the stomach. Natural product polysaccharides are a kind of natural macromolecular polymers, which have the functions of regulating immunity, anti-oxidation, anti-fatigue, hypoglycemia, etc. Natural polysaccharides have remarkable effectiveness in preventing the onset, according to studies, and development of gastric cancer at both cellular and animal levels. This paper summarizes the inhibitory mechanisms and therapeutic significance of plant polysaccharides, fungi polysaccharides, and algal polysaccharides in natural product polysaccharides on the occurrence and development of gastric cancer in recent years, providing a theoretical basis for the research, development, and medicinal value of polysaccharides.

Spatiotemporal Controllable Sono-Nanovaccines Driven by Free-Field Based Whole-Body Ultrasound for Personalized Cancer Therapy.

Therapeutic cancer vaccines fail to produce satisfactory outcomes against solid tumors since vaccine-induced anti-tumor immunity is significantly hampered by immunosuppression. Generating an in situ cancer vaccine targeting immunological cold tumor microenvironment (TME) appears attractive. Here, a type of free-field based whole-body ultrasound (US)-driven nanovaccines are constructed, named G5-CHC-R, by conjugating the sonosensitizer, Chenghai chlorin (CHC) and the immunomodulator, resiquimod (R848) on top of a super small-sized dendrimeric nanoscaffold. Once entering tumors, R848 can be cleaved from a hypoxia-sensitive linker, thus modifying the TME via converting macrophage phenotypes. The animals bearing orthotopic pancreatic cancer with intestinal metastasis and breast cancer with lung metastasis are treated with G5-CHC-R under a free-field based whole-body US system. Benefit from the deep penetration capacity and highly spatiotemporal selectiveness, G5-CHC-R triggered by US represented a superior alternative for noninvasive irradiation of deep-seated tumors and magnification of local immune responses via driving mass release of tumor antigens and "cold-warm-hot" three-state transformation of TME. In addition to irradiating primary tumors, a robust adaptive anti-tumor immunity is potentiated, leading to successful induction of systemic tumor suppression. The sono-nanovaccines with good biocompatibility posed wide applicability to a broad spectrum of tumors, revealing immeasurable potential for translational research in oncology.

An AIE Metal Iridium Complex: Photophysical Properties and Singlet Oxygen Generation Capacity.

Photodynamic therapy (PDT) has garnered significant attention in the fields of cancer treatment and drug-resistant bacteria eradication due to its non-invasive nature and spatiotemporal controllability. Iridium complexes have captivated researchers owing to their tunable structure, exceptional optical properties, and substantial Stokes displacement. However, most of these complexes suffer from aggregation-induced quenching, leading to diminished luminous efficiency. In contrast to conventional photosensitizers, photosensitizers exhibiting aggregation-induced luminescence (AIE) properties retain the ability to generate a large number of reactive oxygen species when aggregated. To overcome these limitations, we designed and synthesized a novel iridium complex named Ir-TPA in this study. It incorporates quinoline triphenylamine cyclomethylated ligands that confer AIE characteristics for Ir-TPA. We systematically investigated the photophysical properties, AIE behavior, spectral features, and reactive oxygen generation capacity of Ir-TPA. The results demonstrate that Ir-TPA exhibits excellent optical properties with pronounced AIE phenomenon and robust capability for producing singlet oxygen species. This work not only introduces a new class of metal iridium complex photosensitizer with AIE attributes but also holds promise for achieving remarkable photodynamic therapeutic effects in future cellular experiments and biological studies.

Ethnic, Botanic, Phytochemistry and Pharmacology of the Acorus L. Genus: A Review.

The genus Acorus, a perennial monocotyledonous-class herb and part of the Acoraceae family, is widely distributed in the temperate and subtropical zones of the Northern and Southern Hemispheres. Acorus is rich in biological activities and can be used to treat various diseases of the nervous system, cardiovascular system, and digestive system, including Alzheimer's disease, depression, epilepsy, hyperlipidemia, and indigestion. Recently, it has been widely used to improve eutrophic water and control heavy-metal-polluted water. Thus far, only three species of Acorus have been reported in terms of chemical components and pharmacological activities. Previously published reviews have not further distinguished or comprehensively expounded the chemical components and pharmacological activities of Acorus plants. By carrying out a literature search, we collected documents closely related to Acorus published from 1956 to 2022. We then performed a comprehensive and systematic review of the genus Acorus from different perspectives, including botanical aspects, ethnic applications, phytochemistry aspects, and pharmacological aspects. Our aim was to provide a basis for further research and the development of new concepts.

Biological interactions of polystyrene nanoplastics: Their cytotoxic and immunotoxic effects on the hepatic and enteric systems.

As emerging pollutants in the environment, nanoplastics (NPs) can cross biological barriers and be enriched in organisms, posing a greatest threat to the health of livestock and humans. However, the size-dependent toxic effects of NPs in higher mammals remain largely unknown. To determine the size-dependent potential toxicities of NPs, we exposed mouse (AML-12) and human (L02) liver cell lines in vitro, and 6-week-old C57BL/6 mice (well-known preclinical model) in vivo to five different sizes of polystyrene NPs (PS-NPs) (20, 50, 100, 200 and 500 nm). We found that ultra-small NPs (20 nm) induced the highest cytotoxicity in mouse and human liver cell lines, causing oxidative stress and mitochondrial membrane potential loss on AML-12 cells. Unexpectedly in vivo, after long-term oral exposure to PS-NPs (75 mg/kg), medium NPs (200 nm) and large NPs (500 nm) induced significant hepatotoxicity, evidenced by increased oxidative stress, liver dysfunction, and lipid metabolism disorders. Most importantly, medium or large NPs generated local immunotoxic effects via recruiting and activating more numbers of neutrophils and monocytes in the liver or intestine, which potentially resulted in increased proinflammatory cytokine secretion and the tissue damage. The discrepancy in in vitro-in vivo toxic results might be attributed to the different properties of biodistribution and tissue accumulation of different sized NPs in vivo. Our study provides new insights regarding the hepatotoxicity and immunotoxicity of NPs on human and livestock health, warranting us to take immense measures to prevent these NPs-associated health damage.

Immunomodulatory activity of semen Ziziphi Spinosae protein: a potential plant protein functional food raw material.

Semen Ziziphi Spinosae protein (SZSP) is a new plant protein resource with good food functional properties and health care function. However, the biological activity of SZSP has not been further studied, which greatly limits the development and utilization of SZSP in the food industry. The aim of this study was to investigate the protective effect of SZSP on immunosuppressed mice and its inhibitory effect on immune-stimulated RAW264.7 cells. The results demonstrated that SZSP remarkably improved the immunomodulatory secretion in serum (interleukin-2, tumor necrosis factor-α [TNF-α], interferon-γ, immunoglobulin-A, immunoglobulin-G, immunoglobulin-M) and primary macrophages (nitric oxide, interleukin-1ß, TNF-α) and promoted the NK-cell killing activity of primary splenocytes in CTX-induced immunosuppression mice. Immunohistochemical analysis results indicated that the secretion of CD4+ and CD8+ in the spleen and thymus can be regulated by SZSP, leading to inhibition of the damage induced by cyclophosphamide in mice. Meanwhile, in order to clarify the immunomodulatory mechanism of SZSP, we showed that SZSP significantly inhibited the secretion of NO, interleukin-6, and TNF-α and reduced the phosphorylation expression of p-ERK, p-JNK, and p-IκBα in lipopolysaccharide-stimulated RAW264.7 cells. Therefore, the immunomodulatory effect of SZSP may be related to the activation of MAPKs and NF-κB signaling pathways. Based on the above studies, the preliminary purification of SZSP was continued, and S1F2G1 with immunomodulatory activity was obtained. Taken together, SZSP has an immunoregulatory effect in vivo and in vitro and may be a favorable candidate of functional food raw material for regulating immune responses.

Synthesis and biological evaluation of oleanolic acid derivatives with electrophilic warheads as antitumor agents.

Aim: The oleanolic acid derivatives containing electrophilic warheads were synthesized, and their antitumor activities were investigated. Materials & methods: The cytotoxicity of compounds against tumor cells were determined by the MTT method. The antitumor effects of compounds 27a, Y03 and Y04 were evaluated in vitro through a wound-healing assay, apoptosis and cell circle analysis, and cellular reactive oxide species determination. The levels of related proteins in MCF-7 cells treated with Y03 was determined through Western blot analysis. Results & conclusion: Compounds 27a, Y03 and Y04 displayed high cytotoxicity against breast cancer cells and inhibited cell migration, induced apoptosis, arrest cell circle at G0/G1 and promoted cellular reactive oxide species generation. The antitumor mechanism involved inhibition of Akt/mTOR and induction of ferroptosis.

Yuhong ointment ameliorates inflammatory responses and wound healing in scalded mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Yuhong ointment (YHO) is famous for its efficacy in clearing away heat and dampness, reducing swelling and relieving pain, and it has been used for more than 600 years. Scalding damages the skin's defense function, resulting in a large number of necrotic tissues and cells on the wound surface, which favors bacterial growth and inflammation. If the inflammation reaction is not controlled on time, it may lead to reduced immunity and cause complications such as infection. Yuhong ointment can promote wound healing in scalded mice, but its potential pharmacological mechanism is still unclear. AIM OF THE STUDY: This study focused on identifying the active ingredients of YHO and on investigating the performance of YHO in terms of anti-inflammatory activity and scald wound healing activity. MATERIALS AND METHODS: High-performance liquid chromatography (HPLC) and high-performance liquid chromatography-mass spectrometry (HPLC-MS) were performed to identify the active ingredients of YHO. The performance of transdermal delivery of YHO was studied via HPLC for analyzing the ingredients of the exposed skin liquid of mice. Enzyme-linked immunosorbent assay (ELISA) analysis, immunohistochemistry, and real-time fluorescence quantitative PCR (qRT-PCR) were used to investigate the anti-inflammatory and scald wound healing activity of YHO. RESULTS: A total of 41 components of YHO were identified via HPLC and HPLC-MS for the first time. In the transdermal delivery experiment, the cumulative amounts of chlorogenic acid, sesamol, ferulic acid, and L-shikonin were calculated to be 342.28, 567.89, 384.54, and 528.67 µg/cm2, respectively. Pharmacological activity experiments indicated that these four kinds of drugs exhibited different degrees of therapeutic effects on scald. Specifically, YHO high-dose (YHO-H) group showed better therapeutic ability (P < 0.01) than FN and MB group. Furthermore, the immune function of the YHO group was enhanced due to the continuous increment of the levels of Hydroxyproline (HYP), Immunoglobulin G (IgG), and vascular endothelial growth factor (VEGF) and simultaneous decrement of the levels of TNF-α, TNF-ß, IL-10, and IL-6 in the skin wound. Histological results showed that the thickening of skin tissue was alleviated after treatment with YHO. Moreover, the expression of substance P (SP), calcitonin gene related peptide (CGRP) and transient receptor potential vanilloid-1 (TRPV1) was inhibited, and the expression of VEGF was promoted by YHO (P < 0.01). The qRT-PCR test results indicated that the YHO group exhibited better inhibitory effect on interleukin 6 (IL-6), interleukin 10 (IL-10), transforming growth factor-beta (TGF-ß), and Smad-3 mRNA expression levels than the other groups. CONCLUSIONS: In this work, the active ingredients of YHO were identified via HPLC and HPLC-MS analysis. Importantly, YHO showed great advantages in transdermal delivery and scald wound healing, which can be attributed to the both anti-inflammatory and tissue regeneration mechanisms. Therefore, this work not only identified the active ingredients of YHO but also revealed the potential pharmacological mechanism of YHO for the healing of scald.

Self-assembled nanoparticles based on cationic mono-/AIE tetra-nuclear Ir(III) complexes: long wavelength absorption/near-infrared emission photosensitizers for photodynamic therapy.

Cyclometalated Ir(III) complexes as photosensitizers (PSs) have attracted widespread attention because of their good photostability and efficient 1O2 production ability. However, their strong absorption in the UV-vis region severely limits their applications in photodynamic therapy (PDT) because the short wavelength illuminating light can be easily absorbed by the skin and subcutaneous adipose tissue causing damage to the patient's normal tissue. Herein, mono- and tetra-nuclear Ir(III) complex-porphyrin conjugates are rationally designed and synthesized, especially [TPP-4Ir]4+ exhibits obvious aggregation-induced emission (AIE) characteristics. PSs comprising Ir(III) complex-porphyrin conjugates self-assembled as nanoparticles (NPs) are successfully achieved. The obtained [TPP-Ir]+ NPs and [TPP-4Ir]4+ NPs exhibit long wavelength absorption (500-700 nm) and near-infrared emission (635-750 nm), successfully overcoming the inherent defects of short wavelength absorption of traditional Ir(III) complexes. Moreover, [TPP-4Ir]4+ NPs exhibit good biocompatibility, high 1O2 generation ability, low half-maximal inhibitory concentration (IC50) (0.47 × 10-6 M), potent cytotoxicity toward cancer cells and superior cellular uptake under white light irradiation. This work extends the scope for transition metal complex PSs with promising clinical applications.

Neuroprotective effect of Ziziphi Spinosae Semen on rats with p-chlorophenylalanine-induced insomnia via activation of GABAA receptor.

Ziziphus jujuba var. spinosa (Bunge) Hu ex H.F.Chow [Rhamnaceae; Ziziphi Spinosae Semen (ZSS)] has attracted extensive attention as the first choice of traditional Chinese medicine in the treatment of insomnia. However, recent studies on the sleep-improving mechanism of ZSS have mainly focused on the role of single components. Thus, to further reveal the potential mechanism of ZSS, an assessment of its multiple constituents is necessary. In this study, ZSS extract (ZSSE) was obtained from ZSS via detailed modern extraction, separation, and purification technologies. The chemical constituents of ZSSE were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS). For in vivo experiments, a rat model of insomnia induced by p-chlorophenylalanine (PCPA) was established to investigate the potential effect and corresponding mechanism of ZSSE on improving sleep. Hematoxylin-eosin staining (HE) results revealed that the drug group showed prominent advantages over the model group in improving sleep. Moreover, the brain levels of γ-aminobutyric acid (GABA), glutamic acid (Glu), 5-hydroxytryptamine (5-HT), and dopamine (DA) were monitored via enzyme-linked immunosorbent assay (ELISA) to further study the sleep-improving mechanism of ZSSE. We found that sleep was effectively improved via upregulation of GABA and 5-HT and downregulation of Glu and DA. In addition, molecular mechanisms of ZSSE in improving sleep were studied by immunohistochemical analysis. The results showed that sleep was improved by regulating the expression levels of GABA receptor subunit alpha-1 (GABAARα1) and GABA acid receptor subunit gamma-2 (GABAARγ2) receptors in the hypothalamus and hippocampus tissue sections. Therefore, this work not only identified the active ingredients of ZSSE but also revealed the potential pharmacological mechanism of ZSSE for improving sleep, which may greatly stimulate the prospective development and application of ZSSE.

AIE-active Ir(III) complexes functionalised with a cationic Schiff base ligand: synthesis, photophysical properties and applications in photodynamic therapy.

Photodynamic therapy (PDT) is a promising cancer treatment method. Traditional small-molecule photosensitizers (PSs) suffer from low intersystem crossing (ISC) ability and aggregation-caused quenching (ACQ), which adversely affects the luminous efficiency and singlet oxygen (1O2) yield of PSs in the aggregated state. Ir(III) complexes are promising PSs with long excited-state lifetime, good photophysical and photochemical properties and large Stokes shifts. Aggregation-induced emission (AIE) characteristics could reduce the nonradiative recombination and improve the ISC ability of excited states through the restriction of the intramolecular motions in aggregated states. Accordingly, two AIE-active Ir(III) complexes Ir-1-N+ and Ir-2-N+ were successfully designed and obtained based on Schiff base ligands. Experimental results showed that Ir-1-N+ and Ir-2-N+ have good photophysical properties and the corresponding nanoparticles (NPs) have good water solubility and 1O2 generation ability. Notably, Ir-2-N+ NPs can be efficiently taken up by mouse breast cancer cells (4T1 cells) with good biocompatibility, low dark toxicity and excellent phototoxicity. This work demonstrates a versatile strategy for exploiting efficient transition metal PSs with a cationic ligand in PDT.

Targeted Singlet Oxygen Delivery: A Bioorthogonal Metabolic Shunt Linking Hypoxia to Fast Singlet Oxygen Release.

Singlet oxygen can be generated by thermal cycloreversion of aromatic endoperoxides. However, for any practical potential of chemically generated singlet oxygen within a therapeutic context, the time and place of the release of this cytotoxic species must be tightly regulated. We now show that using a bimodular design with a hypoxia responsive unit and fluoride-triggered endoperoxide unit, a bioorthogonal metabolic shunt can be established, where an enzymatically generated submicromolar fluoride signal plays a crucial role. Thus, cellular nitroreductase is repurposed in a bioorthogonal enzymatic activity, where it releases fluoride ions upon the reduction of a targeted compound. The fluoride ions released in the initial reaction remove the silyl stopper, yielding a highly accelerated release of singlet oxygen. The result is a remarkable difference in cytotoxicity between hypoxic and normoxic conditions as evidenced by microscopy, viability assays and the use of control compounds.

AIE-active iridium(III) complex integrated with upconversion nanoparticles for NIR-irradiated photodynamic therapy.

The integration of an aggregation induced emission (AIE)-active Ir(III) complex and upconversion nanoparticles (UCNPs) has achieved a NIR-irradiated photosensitizer (PS), UCNPs@Ir-2-N. This PS has satisfactory biocompatibility, excellent phototoxicity, good accumulation in cells and high 1O2 generation ability, thereby effectively killing 4T1 mouse cancer cells in vitro. This work has potential for future photodynamic therapy (PDT) applications.

Physico-chemical properties, antioxidant activity, and ACE inhibitory activity of protein hydrolysates from wild jujube seed.

Wild jujube seed protein (WJSP) as one kind of functional food material has attracted much attention due to its highly nutritive and medicinal value in anti-inflammatory and improving immunomodulatory ability. However, owing to its large molecular weight and complex structure, biological activities of WJSP were greatly limited and cannot be fully utilized by the human body. Therefore, how to improve the bioavailability of WJSP and develop promising WJSP nutritious materials is a great challenge. In this work, wild jujube seed protein hydrolysates (WJSPHs) were prepared from WJSP via enzymatic hydrolysis method, and their physico-chemical properties, antioxidant activity, and angiotensin converting enzyme (ACE) inhibitory activity in vitro have been investigated for the first time. SDS-PAGE electrophoresis and size-exclusion chromatographic results indicate that WJSPHs have lower molecular weight distribution (< 5,000 Da) than WJSP. Circular dichroism (CD) spectroscopy and Fourier transform infrared spectroscopy (FTIR) results illustrated that random coil is the main secondary structure of WJSPHs. Antioxidant experiments indicate that WJSPHs exhibit high radicals-scavenging ability of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals (94.60%), 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulfonate) (ABTS+ ) radicals (90.84%), superoxide radicals (44.77%), and hydroxyl radicals (47.77%). In vitro, WJSPHs can significantly decrease the accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA), and increase the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in HepG2 cells. Moreover, ACE activity was found that can be significantly inhibited by WJSPHs (73.02%). Therefore, all previously mentioned results suggest that WJSPHs may be a promising antioxidant food to prevent oxidative-related diseases in future. PRACTICAL APPLICATION: This study shows that WJSPHs exhibit high antioxidant activity and ACE inhibitory activity in vitro, which provide potential application value as antioxidant peptides to prevent oxidative-related diseases.

Salmonella Induces the cGAS-STING-Dependent Type I Interferon Response in Murine Macrophages by Triggering mtDNA Release.

Salmonella enterica serovar Typhimurium (S. Typhimurium) elicited strong innate immune responses in macrophages. To activate innate immunity, pattern recognition receptors (PRRs) in host cells can recognize highly conserved pathogen-associated molecular patterns (PAMPs). Here, we showed that S. Typhimurium induced a robust type I interferon (IFN) response in murine macrophages. Exposure of macrophages to S. Typhimurium activated a Toll-like receptor 4 (TLR4)-dependent type I IFN response. Next, we showed that type I IFN and IFN-stimulated genes (ISGs) were elicited in a TBK1-IFN-dependent manner. Furthermore, cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) and immune adaptor protein stimulator of interferon genes (STING) were also required for the induction of type I IFN response during infection. Intriguingly, S. Typhimurium infection triggered mitochondrial DNA (mtDNA) release into the cytosol to activate the type I IFN response. In addition, we also showed that bacterial DNA was enriched in cGAS during infection, which may contribute to cGAS activation. Finally, we showed that cGAS and STING deficient mice and cells were more susceptible to S. Typhimurium infection, signifying the critical role of the cGAS-STING pathway in host defense against S. Typhimurium infection. In conclusion, in addition to TLR4-dependent innate immune response, we demonstrated that S. Typhimurium induced the type I IFN response in a cGAS-STING-dependent manner and the S. Typhimurium-induced mtDNA release was important for the induction of type I IFN. This study elucidated a new mechanism by which bacterial pathogen activated the cGAS-STING pathway and also characterized the important role of cGAS-STING during S. Typhimurium infection. IMPORTANCE As one of the most common foodborne transmitted zoonotic pathogens, S. Typhimurium infection causes diarrheal disease in humans and animals. S. Typhimurium infection has been implicated as an inducer for the type I interferon (IFN) response in macrophages, but the mechanisms are not fully understood. In this study, we reported that in addition to TLR4-dependent response, the cytosolic surveillance pathway (CSP) cGAS-STING is also required for the activation of type I IFN response during S. Typhimurium infection. We further showed that the infection of S. Typhimurium triggered mtDNA release into the cytosol, which induces the type I IFN response. In addition, physical interactions between cGAS and S. Typhimurium DNA have been identified in the context of infection. Importantly, we also provided convincing in vivo and in vitro evidence that the cGAS-STING pathway was potently implicated in the host defense against S. Typhimurium infection. Together, we uncovered a mechanism by which type I IFN response is elicited during S. Typhimurium infection in murine macrophages in an mtDNA-cGAS-STING-dependent manner.

Taming of Singlet Oxygen: Towards Artificial Oxygen Carriers Based on 1,4-Dialkylnaphthalenes.

Naphthalene endoperoxides are known as convenient sources of singlet oxygen (O2 , 1 Δg ), which is the major product of endoperoxide cycloreversion reaction. However, their potential as carriers of ground-state molecular oxygen (O2 , 3 Σg ) similar to artificial oxygen carriers remains largely unexplored. This is due to the extreme reactivity and cytotoxic effects of the released singlet oxygen. We now report that a compound with a bimodular design, which incorporates an endoperoxide and an efficient physical quencher of singlet oxygen, 1,4-diazabicyclo[2.2.2]octane (DABCO), produces exclusively ground-state molecular oxygen. This result, coupled with the fact that oxygen release rates from endoperoxides are highly amenable to fine-tuning in a very broad range, and open to targeting by ligand attachment, raises the potential of these compounds far above any comparable chemical, or even biochemical sources. In cell culture experiments, we showed that the addition of the endoperoxide-quencher conjugate can enhance and sustain cell proliferation.

Novel Water-Soluble Chlorin-Based Photosensitizer for Low-Fluence Photodynamic Therapy.

Photodynamic therapy (PDT), performed with low-fluence rates, can improve antitumor responses and prevent adverse effects. However, photosensitizers (PSs) for low-fluence PDT treatment are rarely reported. Herein, we exploited an amphiphilic chlorin-based PS, named DYSP-C34, which has a variety of beneficial biological properties, such as improved water solubility, better cellular permeability, specific localization and enhanced phototoxicity under low light dose irradiation. In addition, DYSP-C34 could effectively accumulate in a mouse subcutaneous xenograft tumor and exhibit substantial tumor regression after irradiation with an extremely low light fluence (6 J/cm2). Meanwhile, the excellent phototoxicity could stimulate the host immune system and lead to a strong inhibition of tumor growth synergistically. These results indicated the potential value of DYSP-C34 as a chlorin-type PS for low-fluence PDT application.