Gas therapy potentiates aggregation-induced emission luminogen-based photoimmunotherapy of poorly immunogenic tumors through cGAS-STING pathway activation.

The immunologically "cold" microenvironment of triple negative breast cancer results in resistance to current immunotherapy. Here, we reveal the immunoadjuvant property of gas therapy with cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation to augment aggregation-induced emission (AIE)-active luminogen (AIEgen)-based photoimmunotherapy. A virus-mimicking hollow mesoporous tetrasulfide-doped organosilica is developed for co-encapsulation of AIEgen and manganese carbonyl to fabricate gas nanoadjuvant. As tetra-sulfide bonds are responsive to intratumoral glutathione, the gas nanoadjuvant achieves tumor-specific drug release, promotes photodynamic therapy, and produces hydrogen sulfide (H2S). Upon near-infrared laser irradiation, the AIEgen-mediated phototherapy triggers the burst of carbon monoxide (CO)/Mn2+. Both H2S and CO can destroy mitochondrial integrity to induce leakage of mitochondrial DNA into the cytoplasm, serving as gas immunoadjuvants to activate cGAS-STING pathway. Meanwhile, Mn2+ can sensitize cGAS to augment STING-mediated type I interferon production. Consequently, the gas nanoadjuvant potentiates photoimmunotherapy of poorly immunogenic breast tumors in female mice.

A polydopamine coated nanoscale FeS theranostic platform for the elimination of drug-resistant bacteria via photothermal-enhanced Fenton reaction.

Infections caused by drug-resistant bacteria pose a great threat to human health. Non-antibiotic-dependent antibacterial strategies have become the focus of research. Among them, chemical dynamic treatment-based (CDT) therapeutic systems, which catalyze the production of hydroxyl radicals by enzymes, have achieved tremendous success for antibacterial purposes. However, limited kinetics of the Fenton reaction, poor permeability, and short half-life of hydroxyl radicals compromise the antibacterial effects of CDT. In addition, difficulties in the early diagnosis of infection lead to drug abuse and delayed treatment. Herein, a polydopamine coated ferrous sulfide theranostic platform adsorbing a hypochlorite responsive probe with photothermal treatment (PTT) enhanced CDT was synthesized. The probe component was used for the early diagnosis of infection. PTT not only inactivated bacteria by hyperthermia but also accelerated the Fenton reaction to produce more ·OH. In vitro antibacterial experiments demonstrated that the multifunctional theranostic platform has a broad antibacterial spectrum, including methicillin-resistant Staphylococcus aureus (MRSA), drug-resistant Escherichia coli (DR E. coli), and Pseudomonas aeruginosa (P. aeruginosa). In addition, in vivo antibacterial experiments demonstrated that nanoparticles could effectively rescue S. aureus-infected full-thickness skin defects with negligible cytotoxicity. This study proposes an efficient and multifunctional theranostic platform for bacterial infection, providing an effective synergistic antibacterial strategy for the treatment of antibiotic resistance. STATEMENT OF SIGNIFICANCE: An infection responsive theranostic platform (ClO- probe@FeS@PDA) is prepared. ·CDT is enhanced prominently by PTT at a relative low temperature. · FeS@PDA exhibits good antibacterial performance against drug resistant bacteria in vitro and in vivo.

The inhibition of subchondral bone lesions significantly reversed the weight-bearing deficit and the overexpression of CGRP in DRG neurons, GFAP and Iba-1 in the spinal dorsal horn in the monosodium iodoacetate induced model of osteoarthritis pain.

BACKGROUND: Chronic pain is the most prominent and disabling symptom of osteoarthritis (OA). Clinical data suggest that subchondral bone lesions contribute to the occurrence of joint pain. The present study investigated the effect of the inhibition of subchondral bone lesions on joint pain. METHODS: Osteoarthritic pain was induced by an injection of monosodium iodoacetate (MIA) into the rat knee joint. Zoledronic acid (ZOL), a third generation of bisphosphonate, was used to inhibit subchondral bone lesions. Joint histomorphology was evaluated using X-ray micro computed tomography scanning and hematoxylin-eosin staining. The activity of osteoclast in subchondral bone was evaluated using tartrate-resistant acid phosphatase staining. Joint pain was evaluated using weight-bearing asymmetry, the expression of calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DRG), and spinal glial activation status using glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) immunofluorescence. Afferent neurons in the DRGs that innervated the joints were identified using retrograde fluorogold labeling. RESULTS: MIA injections induced significant histomorphological alterations and joint pain. The inhibition of subchondral bone lesions by ZOL significantly reduced the MIA-induced weight-bearing deficit and overexpression of CGRP in DRG neurons, GFAP and Iba-1 in the spinal dorsal horn at 3 and 6 weeks after MIA injection; however, joint swelling and synovial reaction were unaffected. CONCLUSIONS: The inhibition of subchondral bone lesions alleviated joint pain. Subchondral bone lesions should be a key target in the management of osteoarthritic joint pain.

Analysis of immunological enhancement of immunosuppressed chickens by Chinese herbal extracts.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix astragali, Radix codonopis, Herba epimedii and Radix glycyrrizae are 4 plants commonly used in Chinese traditional medicine or veterinary medicine to improve immune functions against chronic diseases in humans and animals. AIM OF THE STUDY: We compared immunological enhancement by 4 herbal extracts in clinical healthy chickens or immunosuppressed chickens singly and in combination. MATERIALS AND METHODS: Water extracts of 4 herbs individually and in different combinations were supplemented in drinking water. Hemagglutination inhibition (HI) antibody titers against Newcastle disease virus (NDV) and H5 avian influenza virus (H5-AIV) after vaccination were measured as indicators to evaluate immunological stimulation across groups supplemented with different herbal extracts. The experiments were conducted in both clinically healthy chickens and chickens with immunosuppression induced by reticuloendotheliosis virus (REV) infection. RESULTS: In clinically healthy chickens HI antibody titers against NDV and H5-AIV after vaccination were not influenced by supplementation with the herbal extracts of Radix astragali, Radix codonopis, Herba epimedii and Radix glycyrrizae in drinking water. In chicks with REV-induced immunosuppression, however, supplementation of some herbal extracts significantly increased HI antibody titers to NDV and H5-AIV when compared to the immunosuppressed control group (P<0.01), but the titers were still lower than those in chicks not infected by REV. The 4 herbal mixtures produced the best enhancement among various combinations. The components of the herbal extract were water soluble and treatment by ether had no influence on immunological enhancement. The molecular weights of the active components of the herbal extracts were in the range of 10,000-100,000 Da. CONCLUSION: Our results show that the herbal extract supplementation in drinking water can induce an immune stimulation response in immunosuppressed chickens. It suggests that chickens with REV infection-induced immunosuppression could be used as an experiment model for determination of immunological enhancement effects of some herbal components.