Therapeutic Potential of Nitrogen-Doped Rutin-Bound Glucose Carbon Dots for Alzheimer's Disease.

The blood-brain barrier (BBB) prevents the use of many drugs for the treatment of neurological disorders. Recently, nitrogen-doped carbon dots (NCDs) have emerged as promising nanocarriers to cross BBB. The primary focus of our study was to evaluate the effectiveness of NCDs for the symptomatic treatment of Alzheimer's disease (AD). In this study, we developed and characterized NCDs bound to rutin, a flavonoid with known benefits for AD. Despite its benefits, the transportation of rutin via NCDs for AD therapy has not been explored previously. We characterized the particles using FTIR and UV-visible spectroscopy followed by atomic force microscopy. Once the design was optimized and validated, we performed in vivo testing via a hemolytic assay to optimize the dosage. Preliminary in vitro testing was performed in AlCl3-induced rat models of AD whereby a single dose of 10 mg/kg NCDs-rutin was administered intraperitoneally. Interestingly, this single dose of 10 mg/kg NCDs-rutin produced the same behavioral effects as 50 mg/kg rutin administered intraperitoneally for 1 month. Similarly, histological and biomarker profiles (SOD2 and TLR4) also presented significant protective effects of NCDs-rutin against neuronal loss, inflammation, and oxidative stress. Hence, NCDs-rutin are a promising approach for the treatment of neurological diseases.

Transcriptomic response of prostate cancer cells to carbon ion and photon irradiation with focus on androgen receptor and TP53 signaling.

BACKGROUND: Radiotherapy is essential in the treatment of prostate cancer. An alternative to conventional photon radiotherapy is the application of carbon ions, which provide a superior intratumoral dose distribution and less induced damage to adjacent healthy tissue. A common characteristic of prostate cancer cells is their dependence on androgens which is exploited therapeutically by androgen deprivation therapy in the advanced prostate cancer stage. Here, we aimed to analyze the transcriptomic response of prostate cancer cells to irradiation by photons in comparison to carbon ions, focusing on DNA damage, DNA repair and androgen receptor signaling. METHODS: Prostate cancer cell lines LNCaP (functional TP53 and androgen receptor signaling) and DU145 (dysfunctional TP53 and androgen receptor signaling) were irradiated by photons or carbon ions and the subsequent DNA damage was assessed by immuno-cytofluorescence. Furthermore, the cells were treated with an androgen-receptor agonist. The effects of irradiation and androgen treatment on the gene regulation and the transcriptome were investigated by RT-qPCR and RNA sequencing, followed by bioinformatic analysis. RESULTS: Following photon or carbon ion irradiation, both LNCaP and DU145 cells showed a dose-dependent amount of visible DNA damage that decreased over time, indicating occurring DNA repair. In terms of gene regulation, mRNAs involved in the TP53-dependent DNA damage response were significantly upregulated by photons and carbon ions in LNCaP but not in DU145 cells, which generally showed low levels of gene regulation after irradiation. Both LNCaP and DU145 cells responded to photons and carbon ions by downregulation of genes involved in DNA repair and cell cycle, partially resembling the transcriptome response to the applied androgen receptor agonist. Neither photons nor carbon ions significantly affected canonical androgen receptor-dependent gene regulation. Furthermore, certain genes that were specifically regulated by either photon or carbon ion irradiation were identified. CONCLUSION: Photon and carbon ion irradiation showed a significant congruence in terms of induced signaling pathways and transcriptomic responses. These responses were strongly impacted by the TP53 status. Nevertheless, irradiation mode-dependent distinct gene regulations with undefined implication for radiotherapy outcome were revealed. Androgen receptor signaling and irradiations shared regulation of certain genes with respect to DNA-repair and cell-cycle.

Machine Learning Tools to Assist the Synthesis of Antibacterial Carbon Dots.

Introduction: The emergence and rapid spread of multidrug-resistant bacteria (MRB) caused by the excessive use of antibiotics and the development of biofilms have been a growing threat to global public health. Nanoparticles as substitutes for antibiotics were proven to possess substantial abilities for tackling MRB infections via new antimicrobial mechanisms. Particularly, carbon dots (CDs) with unique (bio)physicochemical characteristics have been receiving considerable attention in combating MRB by damaging the bacterial wall, binding to DNA or enzymes, inducing hyperthermia locally, or forming reactive oxygen species. Methods: Herein, how the physicochemical features of various CDs affect their antimicrobial capacity is investigated with the assistance of machine learning (ML) tools. Results: The synthetic conditions and intrinsic properties of CDs from 121 samples are initially gathered to form the raw dataset, with Minimum inhibitory concentration (MIC) being the output. Four classification algorithms (KNN, SVM, RF, and XGBoost) are trained and validated with the input data. It is found that the ensemble learning methods turn out to be the best on our data. Also, ε-poly(L-lysine) CDs (PL-CDs) were developed to validate the practical application ability of the well-trained ML models in a laboratory with two ensemble models managing the prediction. Discussion: Thus, our results demonstrate that ML-based high-throughput theoretical calculation could be used to predict and decode the relationship between CD properties and the anti-bacterial effect, accelerating the development of high-performance nanoparticles and potential clinical translation.

Dopamine-Functionalized, Red Carbon Quantum Dots for In Vivo Bioimaging, Cancer Therapeutics, and Neuronal Differentiation.

One of the crucial requirements of quantum dots for biological applications is their surface modification for very specific and enhanced biological recognition and uptake. Toward this end, we present the green synthesis of bright, red-emitting carbon quantum dots derived from mango leaf extract (mQDs). These mQDs are conjugated electrostatically with dopamine to form mQDs-dopamine (mQDs:DOPA) bioconjugates. Bright-red fluorescence of mQDs was used for bioimaging and uptake in cancerous and noncancerous cell lines, tissues, and in vivo models like zebrafish. mQDs exhibited the highest uptake in brain tissue compared to the heart, kidney, and liver. mQD:DOPA conjugates killed breast cancer cells and increased uptake in epithelial RPE-1 cells and zebrafish. Additionally, mQDs:DOPA promoted neuronal differentiation of SH-SY5Y cells to differentiated neurons. Both mQDs and mQDs:DOPA exhibited the potential for higher collective cell migrations, implicating their future potential as next-generation tools for advanced biological and biomedical applications.

Poly(Lysine)-Derived Carbon Quantum Dots Conquer Enterococcus faecalis Biofilm-Induced Persistent Endodontic Infections.

Introduction: Persistent endodontic infections (PEIs) mediated by bacterial biofilm mainly cause persistent periapical inflammation, resulting in recurrent periapical abscesses and progressive bone destruction. However, conventional root canal disinfectants are highly damaging to the tooth and periodontal tissue and ineffective in treating persistent root canal infections. Antimicrobial materials that are biocompatible with apical tissues and can eliminate PEIs-associated bacteria are urgently needed. Methods: Here, ε-poly (L-lysine) derived carbon quantum dots (PL-CQDs) are fabricated using pyrolysis to remove PEIs-associated bacterial biofilms. Results: Due to their ultra-small size, high positive charge, and active reactive oxygen species (ROS) generation capacity, PL-CQDs exhibit highly effective antibacterial activity against Enterococcus faecalis (E. faecalis), which is greatly dependent on PL-CQDs concentrations. 100 µg/mL PL-CQDs could kill E. faecalis in 5 min. Importantly, PL-CQDs effectively achieved a reduction of biofilms in the isolated teeth model, disrupting the dense structure of biofilms. PL-CQDs have acceptable cytocompatibility and hemocompatibility in vitro and good biosafety in vivo. Discussion: Thus, PL-CQDs provide a new strategy for treating E. faecalis-associated PEIs.

Carbon Dot-Loaded Apoptotic Vesicles Improve the Liver Kupffer Cell-Mediated Antibacterial Effect to Synergistically Alleviate Sepsis.

Sepsis is a lethal systemic inflammatory disease against infection that lacks effective therapeutic approaches. Liver resident macrophage Kupffer cell (KC)-initiated bacterial clearance is crucial for the host to defend against infection. However, it remains unclear whether this process also governs the antibacterial therapy of sepsis that would be used to improve therapeutic outcomes. Here, we found that copper-doped carbon dots (Cu-CDs) exhibited superior antibacterial capabilities in vitro but displayed limited therapeutic effects in septic mice due to their limited ability to target the liver and restore KC antimicrobial capacity. Thus, we developed a composite nanodrug of copper-doped carbon dot-loaded apoVs (CC-apoVs) that combined the antibacterial ability of Cu-CDs and liver KC targeting features of apoV. Moreover, intravenous injection of CC-apoVs markedly alleviated the systemic infection and decreased the mortality of septic mice compared to Cu-CD and apoV infusion alone. Mechanistically, CC-apoV injection rescued impaired liver KCs during sepsis and enhanced their ability to capture and kill bloodborne bacteria. In addition, apoV-promoted macrophage killing of bacteria could be blocked by the inhibition of small GTPase Rab5. This study reveals a liver KC-targeted therapeutic strategy for sepsis and provides a nanodrug CC-apoV to improve the host antibacterial defense and amplify the therapeutic effect of the nanodrug.

White light powered antimicrobial nanoagents for triple photothermal, chemodynamic and photodynamic based sterilization.

Antibacterial nanoagents have been increasingly developed due to their favorable biocompatibility, cost-effective raw materials, and alternative chemical or optical properties. Nevertheless, there is still a pressing need for antibacterial nanoagents that exhibit outstanding bacteria-binding capabilities and high antibacterial efficiency. In this study, we constructed a multifunctional cascade bioreactor (GCDCO) as a novel antibacterial agent. This involved incorporating carbon dots (CDs), cobalt sulfide quantum dots (CoSx QDs), and glucose oxidase (GOx) to enhance bacterial inhibition under sunlight irradiation. The GCDCO demonstrated highly efficient antibacterial capabilities attributed to its favorable photothermal properties, photodynamic activity, as well as the synergistic effects of hyperthermia, glucose-augmented chemodynamic action, and additional photodynamic activity. Within this cascade bioreactor, CDs played the role of a photosensitizer for photodynamic therapy (PDT), capable of generating ˙O2- even under solar light irradiation. The CoSx QDs not only functioned as a catalytic component to decompose hydrogen peroxide (H2O2) and generate hydroxyl radicals (˙OH), but they also served as heat generators to enhance the Fenton-like catalysis process. Furthermore, GOx was incorporated into this cascade bioreactor to internally supply H2O2 by consuming glucose for a Fenton-like reaction. As a result, GCDCO could generate a substantial amount of reactive oxygen species (ROS), leading to a significant synergistic effect that greatly induced bacterial death. Furthermore, the in vitro antibacterial experiment revealed that GCDCO displayed notably enhanced antibacterial activity against E. coli (99+ %) when combined with glucose under simulated sunlight, surpassing the efficacy of the individual components. This underscores its remarkable efficiency in combating bacterial growth. Taken together, our GCDCO demonstrates significant potential for use in the routine treatment of skin infections among diabetic patients.

Hexanoic acid production and microbial community in anaerobic fermentation: Effects of inorganic carbon addition.

Carbon dioxide (CO2) plays a crucial role in carbon chain elongation with ethanol serving as an electron donor. In this study, the impacts of various carbonates on CO2 concentration, hexanoic acid production, and microbial communities during ethanol-butyric acid fermentation were explored. The results showed that the addition of MgCO3 provided sustained inorganic carbon and facilitated interspecific electron transfer, thereby increasing hexanoic acid yield by 58%. MgCO3 and NH4HCO3 inhibited the excessive ethanol oxidation and decreased the yield of acetic acid by 51% and 42%, respectively. The yields of hexanoic acid and acetic acid in the CaCO3 group increased by 19% and 15%, respectively. The NaHCO3 group exhibited high headspace CO2 concentration, promoting acetogenic bacteria enrichment while reducing the abundance of Clostridium_sensu_stricto_12. The batch addition of NaHCO3 accelerated the synthesis of hexanoic acid and increased its production by 26%. The relative abundance of Clostridium_sensus_stricto_12 was positively correlated with hexanoic acid production.

Ultrathin TiS2@N,S-Doped Carbon Hybrid Nanosheets as Highly Efficient Photoresponsive Antibacterial Agents.

Nanobactericides are employed as a promising class of nanomaterials for eradicating microbial infections, considering the rapid resistance risks of conventional antibiotics. Herein, we present a pioneering approach, reporting the synthesis of two-dimensional titanium disulfide nanosheets coated by nitrogen/sulfur-codoped carbon nanosheets (2D-TiS2@NSCLAA hybrid NSs) using a rapid l-ascorbic acid-assisted sulfurization of Ti3C2Tx-MXene to achieve efficient alternative bactericides. The as-developed materials were systematically characterized using a suite of different spectroscopy and microscopy techniques, in which the X-ray diffraction/Raman spectroscopy/X-ray photoelectron spectroscopy data confirm the existence of TiS2 and C, while the morphological investigation reveals single- to few-layered TiS2 NSs confined by N,S-doped C, suggesting the successful synthesis of the ultrathin hybrid NSs. From in vitro evaluation, the resultant product demonstrates impressive bactericidal potential against both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli bacteria, achieving a substantial decrease in the bacterial viability under a 1.2 J dose of visible-light irradiation at the lowest concentration of 5 µg·mL-1 compared to Ti3C2Tx (15 µg·mL-1), TiS2-C (10 µg·mL-1), and standard antibiotic ciprofloxacin (15 µg·mL-1), respectively. The enhanced degradation efficiency is attributed to the ultrathin TiS2 NSs encapsulated within heteroatom N,S-doped C, facilitating effective photogenerated charge-carrier separation that generates multiple reactive oxygen species (ROS) and induced physical stress as well as piercing action due to its ultrathin structure, resulting in multimechanistic cytotoxicity and damage to bacterial cells. Furthermore, the obtained results from molecular docking studies conducted via computational simulation (in silico) of the as-synthesized materials against selected proteins (ß-lactamasE. coli/DNA-GyrasE. coli) are well-consistent with the in vitro antibacterial results, providing strong and consistent validation. Thus, this sophisticated study presents a simple and effective synthesis technique for the structural engineering of metal sulfide-based hybrids as functionalized synthetic bactericides.

Nucleus-targeted carbon dots as peroxidase nanozyme for photoacoustic imaging and phototherapy of tumor.

High-purity carbon dots (CDs) with a highly π-conjugated sp2-hybridized graphite structure were prepared by the pulse electrolysis method using the graphite plate as raw material. Photoacoustic signal together with photothermal effect was found in the CDs-dispersed suspensions under near-infrared (NIR) irradiation. For the suspension with the CDs concentration of 500 µg/mL, the photothermal conversion efficiency is high up 64.3% and the solution's temperature can be increased to 82.2 °C under NIR irradiation. Moreover, CDs can be effectively endocytosed by human hepatoma (HepG2) cells with a few hours, act as peroxidase nanozyme to decompose H2O2 and facilitate the production of reactive oxygen species. Under NIR irradiation, CDs exhibit an outstanding apoptosis-inducing effect on HepG2 cells by the photothermal effect. In addition, in vivo experiments show that CDs can be used in photoacoustic imaging (PAI) and guiding the tumor treatment. As a result, the nucleus-targeted CDs with an unique combination of PAI and photothermal effect have potential in cancer diagnosis and treatment.

Copper-based carbon dots modified hydrogel with osteoimmunomodulatory and osteogenesis for bone regeneration.

Biomaterials with dual functions of osteoimmunomodulation and bone repair are very promising in the field of orthopedic materials. For this purpose, we prepared copper-based carbon dots (CuCDs) and doped them into oxychondroitin sulfate/poly-acrylamide hydrogel (OPAM) to obtain a hybrid hydrogel (CuCDs/OPAM). We evaluated its osteoimmunomodulatory and bone repair properties in vitro and in vivo. The obtained CuCDs/OPAM exhibited good rBMSCs-cytocompatibility and anti-inflammatory properties in vitro. It also could effectively promote rBMSCs differentiation and the expression of osteogenic differentiation factors from rBMSCs under an inflammatory environment. Moreover, CuCDs/OPAM could induce macrophage phenotype switching (from M1-type macrophages to M2-type macrophages) in vivo, which is beneficial for anti-inflammatory action and presents good osteoimmunomodulation capability to induce a bone immune microenvironment to promote the differentiation of rBMSCs. In conclusion, CuCDs/OPAM hydrogel has dual functions of osteoimmunomodulatory and bone repair and is a promising bone filling and repair material.

Shining light on carbon dots: Toward enhanced antibacterial activity for biofilm disruption.

In spite of tremendous efforts dedicated to addressing bacterial infections and biofilm formation, the post-antibiotic ear continues to witness a gap between the established materials and an easily accessible yet biocompatible antibacterial reagent. Here we show carbon dots (CDs) synthesized via a single hydrothermal process can afford promising antibacterial activity that can be further enhanced by exposure to light. By using citric acid and polyethyleneimine as the precursors, the photoluminescence CDs can be produced within a one-pot, one-step hydrothermal reaction in only 2 h. The CDs demonstrate robust antibacterial properties against both Gram-positive and Gram-negative bacteria and, notably, a considerable enhancement of antibacterial effect can be observed upon photo-irradiation. Mechanistic insights reveal that the CDs generate singlet oxygen (1O2) when exposed to light, leading to an augmented reactive oxygen species level. The approach for disruption of biofilms and inhibition of biofilm formation by using the CDs has also been established. Our findings present a potential solution to combat antibacterial resistance and offer a path to reduce dependence on traditional antibiotics.

Single Atom-Dispersed Silver Incorporated in ZIF-8-Derived Porous Carbon for Enhanced Photothermal Activity and Antibacterial Activities.

Purpose: Recently, Single-atom-loaded carbon-based material is a new environmentally friendly and stable photothermal antibacterial nanomaterial. It is still a great challenge to achieve single-atom loading on carbon materials. Materials and Methods: Herein, We doped single-atom Ag into ZIF-8-derived porous carbon to obtain Ag-doped ZIF-8-derived porous carbon(AgSA-ZDPC). The as-prepared samples were characterized by XRD, XPS, FESEM, EDX, TEM, and HAADF-STEM which confirmed that the single-atom Ag successfully doped into the porous carbon. Further, the photothermal properties and antimicrobial activity of AgSA-ZDPC have been tested. Results: The results showed that the temperature increased by 30 °C after near-infrared light irradiation(1 W/cm2) for 5 min which was better than ZIF-8-derived porous carbon(ZDPC). It also exhibits excellent photothermal stability after the laser was switched on and off 5 times. When the AgSA-ZDPC concentration was greater than 50 µg/mL and the near-infrared irradiation was performed for 5 min, the growth inhibition of S. aureus and E. coli was almost 100%. Conclusion: This work provides a simple method for the preparation of single-atom Ag-doped microporous carbon which has potential antibacterial application.

Biogenic carbon quantum dots from marine endophytic fungi (Aspergillus flavus) to enhance the curcumin production and growth in Curcuma longa L.

In this study, we have investigated the effect of carbon quantum dots (FM-CQDs) synthesized from marine fungal extract on Curcuma longa to improve the plant growth and curcumin production. The isolated fungus, Aspergillus flavus has produced a high amount of indole-3-acetic acid (IAA) (0.025 mg g-1), when treated with tryptophan. CQDs were synthesized from the A. flavus extract and it was characterized using ultraviolet visible spectrophotometer (UV-Vis) and high-resolution transmission electron microscopy (HR-TEM). The synthesized CQDs were excited at 365 nm in an UV-Vis and the HR-TEM analysis showed approximately 7.4 nm in size with a spherical shape. Both fungal crude extract (FCE) at 0-100 mg L-1 and FM-CQDs 0-5 mg L-1 concentrations were tested on C. longa. About 80 mg L-1 concentration FCE treated plants has shown a maximum height of 21 cm and FM-CQDs at 4 mg L-1 exhibited a maximum height of 25 cm compared to control. The FM-CQDs significantly increased the photosynthetic pigments such as total chlorophyll (1.08 mg g-1 FW) and carotenoids (17.32 mg g-1 FW) in C. longa. Further, antioxidant enzyme analysis confirmed that the optimum concentrations of both extracts did not have any toxic effects on the plants. FM-CQDs treated plants increased the curcumin content up to 0.060 mg g-1 by HPLC analysis. Semi quantitative analysis revealed that FCE and FM-CQDs significantly upregulated ClCURS1 gene expression in curcumin production.

Orange-Red-Emitting Carbon Dots for Bilirubin Detection and Its Antibacterial Activity Against Escherichia coli and Staphylococcus aureus.

In this study, orange-red-emitting carbon dots (OR-CDs) were prepared from p-phenylenediamine (p-PDA) and urea as starting precursors through the hydrothermal method. The OR-CDs exhibited bright orange-red fluorescence at 618 nm when excited at 480 nm. The obtained OR-CDs exhibited stable photophysical properties under different physiological conditions. The unique photophysical property of OR-CDs were then utilized for fluorometric determination of bilirubin. The fluorometric assay revealed that the fluorescence intensity of OR-CDs is gradually quenched upon the addition of bilirubin (1-20 µM). The mechanism of fluorescence quenching was evaluated by steady-state fluorescence analysis and time-correlated single photon counting measurements. The OR-CDs showed good selectivity and sensitivity toward bilirubin over other common interfering biomolecules. The present fluorometric assay showed a linear response toward bilirubin between 1 and 10 µM with a limit of detection of 4.80 nM. Further, a fluorescence test cotton swab-based detection probe has been successfully developed by incorporating OR-CDs for the point-of-care detection of bilirubin in biofluids. Furthermore, a light-emitting diode light that emits orange-red light was prepared by embedding the OR-CDs within the poly(vinyl alcohol) polymer matrix. Moreover, the antibacterial activity of OR-CDs was tested against Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus. The antibacterial efficacy of OR-CDs was demonstrated by various mechanisms, such as reactive oxygen species generation, destruction of cell structure, chemical binding to membrane, and surface wrapping. Interestingly, the survival assay against L929 fibroblast cells exhibits favorable biocompatibility and bioimaging.

Biofilm Inhibition on Medical Devices and Implants Using Carbon Dots: An Updated Review.

Biofilms are an intricate community of microbes that colonize solid surfaces, communicating via a quorum-sensing mechanism. These microbial aggregates secrete exopolysaccharides facilitating adhesion and conferring resistance to drugs and antimicrobial agents. The escalating global concern over biofilm-related infections on medical devices underscores the severe threat to human health. Carbon dots (CDs) have emerged as a promising substrate to combat microbes and disrupt biofilm matrices. Their numerous advantages such as facile surface functionalization and specific antimicrobial properties, position them as innovative anti-biofilm agents. Due to their minuscule size, CDs can penetrate microbial cells, inhibiting growth via cytoplasmic leakage, reactive oxygen species (ROS) generation, and genetic material fragmentation. Research has demonstrated the efficacy of CDs in inhibiting biofilms formed by key pathogenic bacteria such as Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. Consequently, the development of CD-based coatings and hydrogels holds promise for eradicating biofilm formation, thereby enhancing treatment efficacy, reducing clinical expenses, and minimizing the need for implant revision surgeries. This review provides insights into the mechanisms of biofilm formation on implants, surveys major biofilm-forming pathogens and associated infections, and specifically highlights the anti-biofilm properties of CDs emphasizing their potential as coatings on medical implants.

Selective Bacterial Growth Inactivation by pH-Sensitive Sulfanilamide Functionalized Carbon Dots.

Carbon dots (CDs) were synthesized hydrothermally by mixing citric acid (CA) and an antifolic agent, sulfanilamide (SNM), employed for pH sensing and bacterial growth inactivation. Sulfanilamide is a prodrug; aromatic hetero cyclization of the amine moiety along with other chemical modifications produces an active pharmacological compound (chloromycetin and miconazole), mostly administered for the treatment of various microbial infections. On the other hand, the efficacy of the sulfanilamide molecule as a drug for antimicrobial activity was very low. We anticipated that the binding of the sulfanilamide molecule on the carbon dot (CD) surface may form antibacterial CDs. Citric acid was hybridized with sulfanilamide during the hydrothermal preparation of the CDs. The molecular fragments of bioactivated sulfanilamide molecule play a crucial role in bacterial growth inactivation for Gram-positive and Gram-negative bacteria. The functional groups of citric acid and sulfanilamide were conserved during the CD formation, facilitating the zwitterionic behavior of CDs associated with its photophysical activity. At low concentrations of CDs, the antibacterial activity was apparent for Gram-positive bacteria only. This Gram-positive bacteria selectivity was also rationalized by zeta potential measurement.

Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis.

OBJECTIVE: Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis. DESIGN: Performance of Yaq-001 was evaluated in vitro. Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed. RESULTS: Yaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo, Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial. CONCLUSIONS: This study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation. TRIAL REGISTRATION NUMBER: NCT03202498.

Carbon dots as a novel photosensitizer for photodynamic therapy of cancer and bacterial infectious diseases: recent advances.

Carbon dots (CDs) are novel carbon-based nanomaterials that have been used as photosensitizer-mediated photodynamic therapy (PDT) in recent years due to their good photosensitizing activity. Photosensitizers (PSs) are main components of PDT that can produce large amounts of reactive oxygen species (ROS) when stimulated by light source, which have the advantages of low drug resistance and high therapeutic efficiency. CDs can generate ROS efficiently under irradiation and therefore have been extensively studied in disease local phototherapy. In tumor therapy, CDs can be used as PSs or PS carriers to participate in PDT and play an extremely important role. In bacterial infectious diseases, CDs exhibit high bactericidal activity as CDs are effective in disrupting bacterial cell membranes leading to bacterial death upon photoactivation. We focus on recent advances in the therapy of cancer and bacteria with CDs, and also briefly summarize the mechanisms and requirements for PSs in PDT of cancer, bacteria and other diseases. We also discuss the role CDs play in combination therapy and the potential for future applications against other pathogens.

Immunogenic Cell Death Induction and Oxygenation by Multifunctional Hollow Silica/Copper-Doped Carbon Dots.

The metastasis and recurrence of cancer are related to immunosuppression and hypoxia in the tumor microenvironment. Activating immune activity and improving the hypoxic environment face essential challenges. This paper reports on a multifunctional nanomaterial, HSCCMBC, that induces immunogenic cell death through powerful photodynamic therapy/chemodynamic therapy synergistic antitumor effects. The tumor microenvironment changed from the immunosuppressive type to immune type, activated the immune activity of the system, decomposed hydrogen peroxide to generate oxygen based on Fenton-like reaction, and effectively increased the level of intracellular O2 with the assistance of 3-bromopyruvate, a cell respiratory inhibitor. The structure and composition of HSCCMBC were characterized by transmission electron microscopy, X-ray photoelectron spectroscopy, X-ray diffraction, infrared spectroscopy, etc. Oxygen probe RDPP was used to investigate the oxygen level inside and outside the cell, and hydroxyl radical probe tetramethylbenzidine was used to investigate the Fenton-like reaction ability. The immunofluorescence method investigated the expression of various immune markers and hypoxia-inducing factors in vitro and in vivo after treatment. In vitro and in vivo experiments indicate that HSCCMBC is an excellent antitumor agent and is expected to be a candidate drug for antitumor immunotherapy.