Ginseng polysaccharides alter the gut microbiota and kynurenine/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) immunotherapy.

OBJECTIVE: Programmed death 1 and its ligand 1 (PD-1/PD-L1) immunotherapy is promising for late-stage lung cancer treatment, however, the response rate needs to be improved. Gut microbiota plays a crucial role in immunotherapy sensitisation and Panax ginseng has been shown to possess immunomodulatory potential. In this study, we aimed to investigate whether the combination treatment of ginseng polysaccharides (GPs) and αPD-1 monoclonal antibody (mAb) could sensitise the response by modulating gut microbiota. DESIGN: Syngeneic mouse models were administered GPs and αPD-1 mAb, the sensitising antitumour effects of the combination therapy on gut microbiota were assessed by faecal microbiota transplantation (FMT) and 16S PacBio single-molecule real-time (SMRT) sequencing. To assess the immune-related metabolites, metabolomics analysis of the plasma samples was performed. RESULTS: We found GPs increased the antitumour response to αPD-1 mAb by increasing the microbial metabolites valeric acid and decreasing L-kynurenine, as well as the ratio of Kyn/Trp, which contributed to the suppression of regulatory T cells and induction of Teff cells after combination treatment. Besides, the microbial analysis indicated that the abundance of Parabacteroides distasonis and Bacteroides vulgatus was higher in responders to anti-PD-1 blockade than non-responders in the clinic. Furthermore, the combination therapy sensitised the response to PD-1 inhibitor in the mice receiving microbes by FMT from six non-responders by reshaping the gut microbiota from non-responders towards that of responders. CONCLUSION: Our results demonstrate that GPs combined with αPD-1 mAb may be a new strategy to sensitise non-small cell lung cancer patients to anti-PD-1 immunotherapy. The gut microbiota can be used as a novel biomarker to predict the response to anti-PD-1 immunotherapy.

S-Propargyl-Cysteine Remodels the Gut Microbiota to Alleviate Rheumatoid Arthritis by Regulating Bile Acid Metabolism.

Background: Rheumatoid arthritis (RA) is a long-term autoimmune disorder characterized by chronic inflammation that results in swollen and painful joints and even cartilage and bone damage. The gut microbiota, a novel anti-inflammatory target, is considered an important environmental factor in the development of RA. S-propargyl-cysteine (SPRC), an amino acid analogue, exerts anti-inflammatory, cardioprotective effects, and neuroprotective effects on various diseases. In recent studies, an SPRC treatment exerted anti-inflammatory effects on RA. Meanwhile, gut microbiome dysbiosis in individuals with RA has also been reported by many researchers. However, the relationship between SPRC and gut microbiota in individuals with RA remains unclear. Methods: Thirty male Sprague-Dawley (SD) rats were randomly divided into three groups of 10 each, including the Control, Model, and SPRC groups. Adjuvant-induced arthritis (AIA) rats in SPRC group were treated with SPRC. Measurement of paw volume and serum tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) levels were applied to evaluate the inflammatory status. Fecal samples were collected on the 14th day and 28th day. Gut microbiota were analyzed using 16S ribosomal RNA (rRNA) gene amplicon sequencing. Untargeted metabolomics on plasma samples was applied to investigate the metabolic changes induced by the altered gut microbiota by using derivatization-UHPLC-Q-TOF/MS. Findings: Using 16S rRNA amplicon sequencing, we found that SPRC significantly altered the gut microbiota structure in AIA rats. In particular, Bifidobacterium, a genus of BSH (Bile Salt Hydrolase)-producing microbes, was overrepresented in SPRC-treated AIA rats. Additionally, a subsequent metabolomics analysis indicated that bile acid metabolism was also altered by SPRC treatment. Interestingly, glycochenodeoxycholic acid (GCDCA) and glycocholic acid (GCA), which are formed with the participation of BSH-producing microbes in the intestine, were identified as crucial biomarkers responding to SPRC treatment with significantly lowered levels. Interpretation: A mechanistic link between the gut microbiota and plasma metabolites was revealed in this study, which provides insights into the mechanism of SPRC treatment for RA from the perspective of the gut microbiota.

A novel dendritic mesoporous silica based sustained hydrogen sulfide donor for the alleviation of adjuvant-induced inflammation in rats.

PURPOSE: S-propargyl-cysteine (SPRC), an excellent endogenous hydrogen sulfide (H2S) donor, could elevate H2S levels via the cystathionine γ-lyase (CSE)/H2S pathway both in vitro and in vivo. However, the immediate release of H2S in vivo and daily administration of SPRC potentially limited its clinical use. METHODS: To solve the fore-mentioned problem, in this study, the dendritic mesoporous silica nanoparticles (DMSN) was firstly prepared, and a sustained H2S delivery system consisted of SPRC and DMSN (SPRC@DMSN) was then constructed. Their release profiles, both in vitro and in vivo, were investigated, and their therapeutical effect toward adjuvant-induced arthritis (AIA) rats was also studied. RESULTS: The spherical morphology of DMSN could be observed under scanning Electron Microscope (SEM), and the transmission electron microscope (TEM) images showed a central-radiational pore channel structure of DMSN. DMSN showed excellent SPRC loading capacity and attaining a sustained releasing ability than SPRC both in vitro and in vivo, and the prolonged SPRC releasing could further promote the release of H2S in a sustained manner through CSE/H2S pathway both in vitro and in vivo. Importantly, the SPRC@DMSN showed promising anti-inflammation effect against AIA in rats was also observed. CONCLUSIONS: A sustained H2S releasing donor consisting of SPRC and DMSN was constructed in this study, and this sustained H2S releasing donor might be of good use for the treatment of AIA.

An effective treatment of experimental osteomyelitis using the antimicrobial titanium/silver-containing nHP66 (nano-hydroxyapatite/polyamide-66) nanoscaffold biomaterials.

Effective treatment of osteomyelitis remains a formidable clinical challenge. The rapid emergence of multidrug-resistant bacteria has renewed interest in developing antimicrobial biomaterials using antiseptic silver ions to treat osteomyelitis. However, inadequate local retention and severe cytotoxic effects have limited the clinical use of ionic silver for bone grafts. We recently developed novel porous nano-hydroxyapatite/polyamide 66 (nHP66)-based nanoscaffold materials containing varied concentrations of silver ions (Ag+) (TA-nHAPA66) and oxidized titanium (TiO2), which was added as a second binary element to enhance antibacterial activity and biocompatibility. In this study, we establish a large cohort of rabbit model of experimental osteomyelitis and investigate the in vivo antimicrobial and therapeutic effects of TA-nHP66 biomaterials and their in vivo silver release kinetics. We find the TA-nHP66 scaffolds exhibit potent antibacterial activities against E. coli and S. aureus, support cell adhesion and cell proliferation of pre-osteoblasts, and stimulate osteogenic regulator/marker expression. Moreover, the TA2-nHP66 scaffold exerts potent antibacterial/anti-inflammation effects in vivo and promotes bone formation at the lesion site of osteomyelitis. We further demonstrate that TA2-nHP66 exhibits excellent biosafety profile without apparent systemic toxicities. Therefore, the TA-nHP66 scaffold biomaterials may be further explored as an effective adjuvant therapy for infected bone defects and/or osteomyelitis debridement.

Biodegradable drug-eluting poly[lactic-co-glycol acid] nanofibers for the sustainable delivery of vancomycin to brain tissue: in vitro and in vivo studies.

Successful treatment of a brain infection requires aspiration of the pus or excision of the abscess, followed by long-term (usually 4-8 weeks) parenteral antibiotic treatment. Local antibiotic delivery using biodegradable drug-impregnated carriers is effective in treating postoperative infections, thereby reducing the toxicity associated with parenteral antibiotic treatment and the expense involved with long-term hospitalization. We have developed vancomycin-loaded, biodegradable poly[lactic-co-glycol acid] nanofibrous membranes for the sustainable delivery of vancomycin to the brain tissue of rats by using the electrospinning technique. A high-performance liquid chromatography assay was employed to characterize the in vitro and in vivo release behaviors of pharmaceuticals from the membranes. The experimental results suggested that the biodegradable nanofibers can release high concentrations of vancomycin for more than 8 weeks in the cerebral cavity of rats. Furthermore, the membranes can cover the wall of the cavity after the removal of abscess more completely and achieve better drug delivery without inducing adverse mass effects in the brain. Histological examination also showed no inflammation reaction of the brain tissues. By adopting the biodegradable, nanofibrous drug-eluting membranes, we will be able to achieve long-term deliveries of various antibiotics in the cerebral cavity to enhance the therapeutic efficacy of cerebral infections.

Preclinical experiments on the release behavior of biodegradable nanofibrous multipharmaceutical membranes in a model of four-wall intrabony defect.

Guided tissue regeneration (GTR) therapy has been widely used to regenerate lost periodontium from periodontal disease. However, in terms of regenerative periodontal therapy, a multidrug-loaded biodegradable carrier can be even more promising in dealing with periodontal disease. In the current study, we fabricated biodegradable nanofibrous collagen membranes that were loaded with amoxicillin, metronidazole, and lidocaine by an electrospinning technique. The in vitro release behavior and the cytotoxicity of the membranes were investigated. A four-wall intrabony defect was created in rabbits for in vivo release analysis. The bioactivity of the released antibiotics was also examined. The experimental results showed that the drug-loaded collagen membranes could provide sustainable release of effective amoxicillin, metronidazole, and lidocaine for 28, 56, and 8 days, respectively, in vivo. Furthermore, the bioactivity of the released antibiotics remained high, with average bioactivities of 50.5% for amoxicillin against Staphylococcus aureus and 58.6% for metronidazole against Escherichia coli. The biodegradable nanofibrous multipharmaceutical membranes developed in this study may provide a promising solution for regenerative periodontal therapy.