Buckwheat sprouts have been widely consumed all around world due to their great abundance of bioactive compounds. In this study, the anti-inflammatory effects of flavonoid-rich common buckwheat sprout (CBS) and tartary buckwheat sprout (TBS) extracts were evaluated in lipopolysaccharide- (LPS-) stimulated RAW 264.7 murine macrophages and primary peritoneal macrophages from male BALB/c mice. Based on the reversed-phase HPLC analysis, the major flavonoids in CBS were determined to be C-glycosylflavones (orientin, isoorientin, vitexin, and isovitexin), quercetin-3-O-robinobioside, and rutin, whereas TBS contained only high amounts of rutin. The TBS extract exhibited higher inhibitory activity as assessed by the production of proinflammatory mediators such as nitric oxide and cytokines including tumor necrosis factor-α, interleukin- (IL-) 6, and IL-12 in LPS-stimulated RAW 264.7 macrophages than CBS extract. In addition, TBS extract suppressed nuclear factor-kappa B activation by preventing inhibitor kappa B-alpha degradation and mitogen-activated protein kinase phosphorylation in LPS-stimulated RAW 264.7 macrophages. Moreover, the TBS extract markedly reduced LPS-induced cytokine production in peritoneal macrophages. Taken together, these findings suggest that TBS extract can be a potential source of anti-inflammatory agents that may influence macrophage-mediated inflammatory disorders.
Near-infrared (NIR) emissive nanomaterials are desired for bioimaging and drug delivery applications due to the high tissue penetration depth of NIR light, enabling in vitro/ex vivo/in vivo fluorescence tracking. Considering the scarcity of NIR-fluorescing biocompatible nanostructures, we have for the first-time synthesized nanometer-sized reduced graphene oxide-derived graphene quantum dots (RGQDs) with NIR (950 nm) emission highly biocompatible in vitro with no preliminary toxic response in vivo. RGQDs are obtained in a high-yield (∼90%) top-down sodium hypochlorite/ultraviolet-driven synthetic process from non-emissive micron-sized reduced graphene oxide (RGO) flakes. This oxidation of RGO yields quantum dots with an average size of 3.54 ± 0.05 nm and a highly crystalline graphitic lattice structure with distinguishable lattice fringes. RGQDs exhibit excitation-independent emission in the visible and NIR-I region with a maximum NIR quantum yield of ∼7%. Unlike their parent material, RGQDs show substantial biocompatibility with ∼75%–80% cell viability up to high (1 mg ml−1) concentrations verified via both MTT and luminescence-based cytotoxicity assays. Tracked in vitro via their NIR fluorescence, RGQDs exhibit efficient internalization in HeLa cells maximized at 12 h with further anticipated excretion. In vivo, RGQDs introduced intravenously to NCr nude mice allow for fluorescence imaging in live sedated animals without the need in sacrificing those at imaging time points. Their distribution in spleen, kidneys, liver, and intestine assessed from NIR fluorescence in live mice, is further confirmed by excised organ analysis and microscopy of organ tissue slices. This outlines the potential of novel RGQDs as NIR imaging probes suitable for tracking therapeutic delivery in live animal models. A combination of smaller size, water-solubility, bright NIR emission, simple/scalable synthesis, and high biocompatibility gives RGQDs a critical advantage over a number of existing nanomaterials-based imaging platforms.
With 18 million new cases diagnosed each year worldwide, cancer strongly impacts both science and society. Current models of cancer cell growth and therapeutic efficacy in vitro are time-dependent and often do not consider the Emax value (the maximum reduction in the growth rate), leading to inconsistencies in the obtained IC50 (concentration of the drug at half maximum effect). In this work, we introduce a new dual experimental/modeling approach to model HeLa and MCF-7 cancer cell growth and assess the efficacy of doxorubicin chemotherapeutics, whether alone or delivered by novel nitrogen-doped graphene quantum dots (N-GQDs). These biocompatible/biodegradable nanoparticles were used for the first time in this work for the delivery and fluorescence tracking of doxorubicin, ultimately decreasing its IC50 by over 1.5 and allowing for the use of up to 10 times lower doses of the drug to achieve the same therapeutic effect. Based on the experimental in vitro studies with nanomaterial-delivered chemotherapy, we also developed a method of cancer cell growth modeling that (1) includes an Emax value, which is often not characterized, and (2), most importantly, is measurement time-independent. This will allow for the more consistent assessment of the efficiency of anti-cancer drugs and nanomaterial-delivered formulations, as well as efficacy improvements of nanomaterial delivery.
Sonography offers many advantages over standard methods of diagnostic imaging due to its non-invasiveness, substantial tissue penetration depth, and low cost. The benefits of ultrasound imaging call for the development of ultrasound-trackable drug delivery vehicles that can address a variety of therapeutic targets. One disadvantage of the technique is the lack of highprecision imaging, which can be circumvented by complementing ultrasound contrast agents with visible and, especially, near-infrared (NIR) fluorophores. In this work, we, for the first time, develop a variety of lightly metal-doped (iron oxide, silver, thulium, neodymium, cerium oxide, cerium chloride, and molybdenum disulfide) nitrogen-containing graphene quantum dots (NGQDs) that demonstrate high-contrast properties in the ultrasound brightness mode and exhibit visible and/or near-infrared fluorescence imaging capabilities. NGQDs synthesized from glucosamine precursors with only a few percent metal doping do not introduce additional toxicity in vitro, yielding over 80% cell viability up to 2 mg/mL doses. Their small (<50 nm) sizes warrant effective cell internalization, while oxygen-containing surface functional groups decorating their surfaces render NGQDs water soluble and allow for the attachment of therapeutics and targeting agents. Utilizing visible and/or NIR fluorescence, we demonstrate that metal-doped NGQDs experience maximum accumulation within the HEK-293 cells 6−12 h after treatment. The successful 10-fold ultrasound signal enhancement is observed at 0.5−1.6 mg/mL for most metal-doped NGQDs in the vascular phantom, agarose gel, and animal tissue. A combination of non-invasive ultrasound imaging with capabilities of high-precision fluorescence tracking makes these metal-doped NGQDs a viable agent for a variety of theragnostic applications.
Oxidative stress damages dermal and epidermal cells and degrades extracellular matrix proteins, such as collagen, ultimately leading to skin aging. The present study evaluated the potential protective effect of the aqueous methanolic extract obtained from Lithospermum erythrorhizon (LE) against oxidative stress, induced by H2O2 and ultraviolet (UV) irradiation, on human keratinocyte (HaCaT) and human dermal fibroblast-neonatal (HDF-n) cells. Exposure of cells to H2O2 or UVB irradiation markedly increased oxidative stress and reduced cell viability. However, pretreatment of cells with the LE extract not only increased cell viability (up to 84.5%), but also significantly decreased oxidative stress. Further, the LE extract downregulated the expression of matrix metalloproteinase-1, an endopeptidase that degrades extracellular matrix collagen. In contrast, treatment with the LE extract did not affect the expression of procollagen type 1 in HDF-n cells exposed to UVA irradiation. Thirteen phenolic compounds, including derivatives of shikonin and caffeic acid, were identified by ultrahigh-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. These results suggest that LE-derived extracts may protect oxidative-stress-induced skin aging by inhibiting degradation of skin collagen, and that this protection may derive at least in part from the antioxidant phenolics present in these extracts. Further studies are warranted to determine the potential utility of LE-derived extracts in both therapeutic and cosmetic applications.
Graphene quantum dots (GQDs) are unique derivatives of graphene that show promise in multiple biomedical applications as biosensors, bioimaging agents, and drug/gene delivery vehicles. Their ease in functionalization, biocompatibility, and intrinsic fluorescence enable those modalities. However, GQDs lack deep tissue magnetic resonance imaging (MRI) capabilities desirable for diagnostics. Considering that the drawbacks of MRI contrast agent toxicity are still poorly addressed, we develop novel Mn2+ or Gd3+ doped nitrogen-containing graphene quantum dots (NGQDs) to equip the GQDs with MRI capabilities and at the same time render contrast agents biocompatible. Water-soluble biocompatible Mn-NGQDs and Gd-NGQDs synthesized via single-step microwave-assisted scalable hydrothermal reaction enable dual MRI and fluorescence modalities. These quasi-spherical 3.9–6.6 nm average-sized structures possess highly crystalline graphitic lattice structure with 0.24 and 0.53 atomic % for Mn2+ and Gd3+ doping. This structure ensures high in vitro biocompatibility of up to 1.3 mg ml−1 and 1.5 mg ml−1 for Mn-NGQDs and Gd-NGQDs, respectively, and effective internalization in HEK-293 cells traced by intrinsic NGQD fluorescence. As MRI contrast agents with considerably low Gd and Mn content, Mn-NGQDs exhibit substantial transverse/longitudinal relaxivity (r 2/r 1) ratios of 11.190, showing potential as dual-mode longitudinal or transverse relaxation time (T 1 or T 2) contrast agents, while Gd-NGQDs possess r 2/r 1 of 1.148 with high r 1 of 9.546 mM−1 s−1 compared to commercial contrast agents, suggesting their potential as T1 contrast agents. Compared to other nanoplatforms, these novel Mn2+ and Gd3+ doped NGQDs not only provide scalable biocompatible alternatives as T1/T2 and T1 contrast agents but also enable in vitro intrinsic fluorescence imaging.
Non-invasive temperature sensing is necessary to analyze biological processes occurring in the human body, including cellular enzyme activity, protein expression, and ion regulation. To probe temperature-sensitive processes at the nanoscale, novel luminescence nanothermometers are developed based on graphene quantum dots (GQDs) synthesized via top-down (RGQDs) and bottom-up (N-GQDs) approaches from reduced graphene oxide and glucosamine precursors, respectively. Because of their small 3–6 nm size, non-invasive optical sensitivity to temperature change, and high biocompatibility, GQDs enable biologically safe sub-cellular resolution sensing. Both GQD types exhibit temperature-sensitive yet photostable fluorescence in the visible and near-infrared for RGQDs, utilized as a sensing mechanism in this work. Distinctive linear and reversible fluorescence quenching by up to 19.3% is observed for the visible and near-infrared GQD emission in aqueous suspension from 25 °C to 49 °C. A more pronounced trend is observed with GQD nanothermometers internalized into the cytoplasm of HeLa cells as they are tested in vitro from 25 °C to 45 °C with over 40% quenching response. Our findings suggest that the temperature-dependent fluorescence quenching of bottom-up and top-down-synthesized GQDs studied in this work can serve as non-invasive reversible/photostable deterministic mechanisms for temperature sensing in microscopic sub-cellular biological environments.
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