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Nitric oxide (NO) is a gaseous signal molecule with multiple physiological functions, and it also plays a key role in cancer therapy. However, the production of NO which depends on O2 or H2O2 is limited within the tumor microenvironment, leading to unsatisfactory anticancer effect. Herein, we report a NO‐based phototherapeutic strategy mediated by photogenerated holes for hypoxic tumors, which is achieved by irradiation of the poly‐L‐arginine modified carbon‐dots‐doped graphitic carbon nitride nanomaterial (ArgCCN). Upon red light irradiation, the photogenerated holes on ArgCCN oxidized water into H2O2 which subsequently oxidized the arginine residues to produce NO. In vitro and in vivo experiments showed that the high concentration of NO produced by ArgCCN could induce cancer cell apoptosis. The presented phototherapeutic strategy is based on microenvironment‐independent photogenerated holes mediated oxidation reaction, paving the way for the development of NO therapeutic strategy. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is a gaseous signal molecule with multiple physiological functions, and it also plays a key role in cancer therapy. However, the production of NO which depends on O2 or H2O2 is limited within the tumor microenvironment, leading to unsatisfactory anticancer effect. Herein, we report a NO‐based phototherapeutic strategy mediated by photogenerated holes for hypoxic tumors, which is achieved by irradiation of the poly‐L‐arginine modified carbon‐dots‐doped graphitic carbon nitride nanomaterial (ArgCCN). Upon red light irradiation, the photogenerated holes on ArgCCN oxidized water into H2O2 which subsequently oxidized the arginine residues to produce NO. In vitro and in vivo experiments showed that the high concentration of NO produced by ArgCCN could induce cancer cell apoptosis. The presented phototherapeutic strategy is based on microenvironment‐independent photogenerated holes mediated oxidation reaction, paving the way for the development of NO therapeutic strategy. [ABSTRACT FROM AUTHOR]

Oxidative stress can induce neuronal apoptosis via the production of superoxide and hydroxyl radicals. This process is as a major pathogenic mechanism in neurodegenerative disorders. In this study, we aimed to clarify whether theaflavins protect PC12 cells from oxidative stress damage induced by HO. A cell model of PC12 cells undergoing oxidative stress was created by exposing cells to 200 μM HO in the presence or absence of varying concentrations of theaflavins (5, 10, and 20 μM). Cell viability was monitored using the MTT assay and Hoechst 33258 staining, showing that 10 μM theaflavins enhanced cell survival following 200 μM HO induced toxicity and increased cell viability by approximately 40 %. Additionally, we measured levels of intracellular reactive oxygen species (ROS) and antioxidant enzyme activity. This suggested that the neuroprotective effect of theaflavins against oxidative stress in PC12 cells is derived from suppression of oxidant enzyme activity. Furthermore, Western blot analyses indicated that theaflavins downregulated the ratio of pro-apoptosis/anti-apoptosis proteins Bax/Bcl-2. Theaflavins also downregulated the expression of caspase-3 compared with a HO-treated group that had not been treated with theaflavins. Interestingly, this is the first study to report that the four main components of theaflavins found in black tea can protect neural cells (PC12) from apoptosis induced by HO. These findings provide the foundations for a new field of using theaflavins or its source, black tea, in the treatment of neurodegenerative diseases caused by oxidative stress. [ABSTRACT FROM AUTHOR]

Herein, a signal magnification electrochemical aptasensor for the detection of breast cancer cell via free-running DNA walker is constructed. Theoretically, just one DNA walker, released by target cell-responsive reaction, can automatically cleave all D-RNA (a chimeric DNA/RNA oligonucleotide with a cleavage point rArU) anchored on electrode into shorter produces, giving rise to considerably detectable signal finally. Under the optimal conditions, the electrochemical signal decreased linearly with the concentration of MCF-7 cell. The linear range is from 0 to 500 cells mL −1 with a detection limit of 47 cells mL −1 . In a word, this approach may have advantages over traditional reported DNA machines for bioassay, particularly in terms of ease of operation, cost efficiency, free of labeling and of complex track design, which may hold great potential for wide application. [ABSTRACT FROM AUTHOR]

Background: Lipofuscin (LF) is formed during lipid peroxidation and sugar glycosylation by carbonyl-amino crosslinks with biomacrolecules, and accumulates slowly within postmitotic cells. The environmental pollution, modern dietary culture and lifestyle changes have been found to be the major sources of reactive carbonyl compounds in vivo. Irreversible carbonyl-amino crosslinks induced by carbonyl stress are essentially toxiferous for aging-related functional losses in modern society. Results show that (-)-epigallocatechin gallate (EGCG), the main polyphenol in green tea, can neutralize the carbonyl-amino cross-linking reaction and inhibit LF formation, but the underlying mechanism is unknown. Methods and Results: We explored the mechanism of the neutralization process from protein, cell, and animal levels using spectrofluorometry, infrared spectroscopy, conformation antibodies, and electron microscopy. LF demonstrated an amyloidogenic β-sheet-rich with antiparallel structure, which accelerated the carbonyl-amino crosslinks formation and disrupted proteolysis in both PC12 cells and D-galactose (D-gal)-induced brain aging mice models. Additionally, EGCG effectively inhibited the formation of the amyloidogenic β-sheet-rich structure of LF, and prevented its conversion into toxic and on-pathway aggregation intermediates, thereby cutting off the carbonyl-amino crosslinks. Conclusions: Our study indicated that the amyloidogenic β-sheet structure of LF may be the core driving force for carbonyl-amino crosslinks further formation, which mediates the formation of amyloid fibrils from native state of biomacrolecules. That EGCG exhibits anti-amyloidogenic β-sheet-rich structure properties to prevent the LF formation represents a novel strategy to impede the development of degenerative processes caused by ageing or stress-induced premature senescence in modern environments. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common type of malignant tumor in women. Recently, it has been shown that detection of breast cancer tumor cells outside the primitive tumor is an effective early diagnosis with great prognostic and clinical utility. For this purpose, we developed a signal-on fluorescence aptasensor for label-free, facile and sensitive detection of MCF-7 breast cancer cells. Due to target–aptamer specific recognition and single-stranded DNA-sensitized luminescence of terbium (III), the proposed aptasensor exhibits excellent sensitivity with detection limit as low as 70 cells mL − 1 . Compared with common organic dyes and the emerging nano-technological probes, the combination of terbium (III) and single-stranded DNA signal probe (Tb 3+ –SP) serves as a more powerful bio-probe because of its stable optical property, good biocompatibility and free from complex synthesis. The feasibility investigations have illustrated the potential applicability of this aptasensor for selective and sensitive detection of MCF-7 breast cancer cells. Moreover, this proposed aptasensor can be also extended for the determination of other tumor cancers or bio-molecules by altering corresponding aptamers. Taken together, this easy-to-perform aptasensor may represent a promising way for early screening and detection of tumor cancers or other bio-molecules in clinical diagnosis. [ABSTRACT FROM AUTHOR]

Background: Renal accumulation of reactive carbonyl compounds (RCCs) has been linked to the progression of diabetic nephropathy. We previously demonstrated that carbonyl stress induces the formation of amino-carbonyl cross-links and sharply increases the content of β-sheet-rich structures, which is the seed of insoluble aggregates formation, and tea catechin (-)-epigallocatechin 3-gallate (EGCG) can reverse this process in vitro and in vivo. In this study, methylated derivative (-)-epigallocatechin-3-O-(3-O-methyl)-gallate (EGCG3”Me) was hypothesized to neutralize carbonyl stress mediating the formation of insoluble ubiquitinated protein (IUP) aggregates, and reduce the early development of diabetic nephropathy. Methods and results: Diabetes was induced in mice by intraperitoneally injecting alloxan monohydrate (200 mg/kg/d) twice and administering EGCG3”Me by gavage for 15 d. Reagent case and western blot results showed that, in diabetic kidneys, the carbonyl proteins in the serum increased; and in insoluble protein fraction, 4-hydroxynonenal-modified proteins, IUP aggregates and p62 accumulated; FT-IR study demonstrated that the lipid content, anti-parallel β-sheet structure and aggregates increased. EGCG3”Me treatment could effectively reverse this process, even better than the negative control treatment. Conclusions: EGCG3”Me exhibiting anti-β-sheet-rich IUP aggregate properties, maybe represents a new strategy to impede the progression of diabetic nephropathy and other diabetic complications. [ABSTRACT FROM AUTHOR]

This study introduces a novel approach for synthesizing Benzoxazine‐centered Polychiral Polyheterocycles (BPCPHCs) via an innovative asymmetric carbene‐alkyne metathesis‐triggered cascade. Overcoming challenges associated with intricate stereochemistry and multiple chiral centers, the catalytic asymmetric Carbene Alkyne Metathesis‐mediated Cascade (CAMC) is employed using dirhodium catalyst/Brønsted acid co‐catalysis, ensuring precise stereo control as validated by X‐ray crystallography. Systematic substrate scope evaluation establishes exceptional diastereo‐ and enantioselectivities, creating a unique library of BPCPHCs. Pharmacological exploration identifies twelve BPCPHCs as potent Nav ion channel blockers, notably compound 8 g. In vivo studies demonstrate that intrathecal injection of 8 g effectively reverses mechanical hyperalgesia associated with chemotherapy‐induced peripheral neuropathy (CIPN), suggesting a promising therapeutic avenue. Electrophysiological investigations unveil the inhibitory effects of 8 g on Nav1.7 currents. Molecular docking, dynamics simulations and surface plasmon resonance (SPR) assay provide insights into the stable complex formation and favorable binding free energy of 8 g with C5aR1. This research represents a significant advancement in asymmetric CAMC for BPCPHCs and unveils BPCPHC 8 g as a promising, uniquely acting pain blocker, establishing a C5aR1‐Nav1.7 connection in the context of CIPN. [ABSTRACT FROM AUTHOR]

This study introduces a novel approach for synthesizing Benzoxazine‐centered Polychiral Polyheterocycles (BPCPHCs) via an innovative asymmetric carbene‐alkyne metathesis‐triggered cascade. Overcoming challenges associated with intricate stereochemistry and multiple chiral centers, the catalytic asymmetric Carbene Alkyne Metathesis‐mediated Cascade (CAMC) is employed using dirhodium catalyst/Brønsted acid co‐catalysis, ensuring precise stereo control as validated by X‐ray crystallography. Systematic substrate scope evaluation establishes exceptional diastereo‐ and enantioselectivities, creating a unique library of BPCPHCs. Pharmacological exploration identifies twelve BPCPHCs as potent Nav ion channel blockers, notably compound 8 g. In vivo studies demonstrate that intrathecal injection of 8 g effectively reverses mechanical hyperalgesia associated with chemotherapy‐induced peripheral neuropathy (CIPN), suggesting a promising therapeutic avenue. Electrophysiological investigations unveil the inhibitory effects of 8 g on Nav1.7 currents. Molecular docking, dynamics simulations and surface plasmon resonance (SPR) assay provide insights into the stable complex formation and favorable binding free energy of 8 g with C5aR1. This research represents a significant advancement in asymmetric CAMC for BPCPHCs and unveils BPCPHC 8 g as a promising, uniquely acting pain blocker, establishing a C5aR1‐Nav1.7 connection in the context of CIPN. [ABSTRACT FROM AUTHOR]

Neuropathic pain is a refractory chronic disease affecting millions of people worldwide. Given that present painkillers have poor efficacy or severe side effects, developing novel analgesics is badly needed. The multiplex structure of active ingredients isolated from natural products provides a new source for phytochemical compound synthesis. Here, we identified a natural product, Narirutin, a flavonoid compound isolated from the Citrus unshiu, showing antinociceptive effects in rodent models of neuropathic pain. Using calcium imaging, whole-cell electrophysiology, western blotting, and immunofluorescence, we uncovered a molecular target for Narirutin's antinociceptive actions. We found that Narirutin (i) inhibits Veratridine-triggered nociceptor activities in L4-L6 rat dorsal root ganglion (DRG) neurons, (ii) blocks voltage-gated sodium (NaV) channels subtype 1.7 in both small-diameter DRG nociceptive neurons and human embryonic kidney (HEK) 293 cell line, (iii) does not affect tetrodotoxin-resistant (TTX-R) NaV channels, and (iv) blunts the upregulation of Nav1.7 in calcitonin gene-related peptide (CGRP)-labeled DRG sensory neurons after spared nerve injury (SNI) surgery. Identifying Nav1.7 as a molecular target of Narirutin may further clarify the analgesic mechanism of natural flavonoid compounds and provide an optimal idea to produce novel selective and efficient analgesic drugs. [ABSTRACT FROM AUTHOR]

The new acridone derivative 5, 7-dinitro-2-sulfo-acridone (DSA) with excellent electrochemical activity was synthesized and reported for the first time in this paper. Then an electrochemical biosensor was fabricated for the signal amplified detection of microRNA (miRNA) via applying home-made DSA as signal unit. The p19 protein-functionalized magnetic beads (PFMBs) for specific recognition and enrichment of miRNA. Then DSA is combined with the long DNA concatamers, which functions as a signal enhancement platform to facilitate the high selectivity and sensitivity determination of miRNA. The usage of this novel electrochemical activity made a contribution to the performance of the approach, such as achieving a detection limit of 6 aM. To the best of our knowledge, this is the first attempt to apply DSA, PFMBs and long DNA concatamers for the fabrication of the electrochemical biosensors, which may represent a promising path toward early diagnosis of cancer at the point of care. [ABSTRACT FROM AUTHOR]

Abstract: The selective detection of ultratrace amounts of ochratoxin A (OTA) is extremely important for food safety since it is one of the most toxic and widespread mycotoxin. Here we develop a signal-on fluorescent biosensor for detection of OTA based on fluorescent DNA-scaffolded silver-nanocluster (AgNCs), structure-switching of anti-OTA aptamer (Ap) and magnetic beads (MBs), and demonstrate its feasibility in the application of detecting OTA in real samples of wheat. The method exhibits superior sensitivity with a detection limit as low as 2pg/mL OTA with high specificity. To the best of our knowledge, this is the first attempt to detect OTA based on DNA-scaffolded AgNCs, which possesses relatively high fluorescence quantum yield and photostability with regard to traditional organic dyes and quantum dots. Moreover, combined with the merits of MBs and aptamer, the proposed sensor has many advantages such as fabrication easiness, operation convenience, low cost, and being fast and portable, which may represent a promising path toward routine OTA control. [Copyright &y& Elsevier]

Abstract: A new acridone derivative 10-methyl-3-nitro-acridone (MNA) with excellent electrochemical activity was synthesized in this paper. Using it as an electrochemical indicator, a signal-on and label-free electrochemical biosensor was developed for picomolar determination of nuclear factor kappa B (NF-κB) in serum. Initially, linear double-stranded DNA (dsDNA) probes, which contain a protein-binding site specific to NF-κB, were self-assembled on the surface of a glass carbon electrode (GCE). If the NF-κB was absent, the dsDNA probes were cut into ss-DNA fragments by the digestion of ExoIII, resulting in a low electrochemical signal of MNA due to the weak binding affinity of MNA to ss-DNA. On the contrary, in the presence of NF-κB, it could bind with the dsDNA probes at the specific site and hinder the digestion of ExoIII, resulting in a significant increase of electrochemical response due to the intercalation of MNA into the dsDNA probes. By employing the above strategy, this sensor could detect as low as 40pM NF-κB with high specificity. To the best of our knowledge, the proposed sensor is the first attempt to use acridone derivative as an electrochemical indicator for NF-κB detection, which may represent a promising path toward clinical diagnosis and drug developments. [Copyright &y& Elsevier]

l -Theanine (LTA; γ-glutamylethylamide), a peculiar non-protein-derived amino acid isolated from tea, is widely used as a functional ingredient and dietary supplement. l -Theanine has been confirmed to have hepatoprotective effects, but the underlying mechanism remains unknown. This study investigated the protective effect of l -Theanine-in vivo, using an enterotoxigenic Escherichia coli (ETEC)-infected mouse model. l -Theanine significantly decreased the elevated serum activities of both aspartate aminotransferase (AST) and alanine aminotransferase (ALT), two biomarkers of hepatic impairment. This was consistent with histopathological images from the microscopic observation of liver tissue. In addition, l -theanine significantly increased the mRNA and protein expression of Bcl-2 and decreased the expression of Bax, anti- and pro-apoptotic molecules, respectively, compared with levels in the ETEC control group. The expression of cleaved caspase-3 protein in the group pre-treated with l -theanine was significantly lower than that in the ETEC group. Additionally, decreases in extracellular signal-regulated kinase (ERK1/2) and c-Jun NH 2 -terminal kinase(JNK1/2) MAPK phosphorylation were observed in the l -theanine pre-treated group. Our study demonstrates that l -theanine possesses anti-apoptotic activity, which can be attributed to suppression of the intrinsic mitochondria-mediated apoptosis and MAPK phosphorylation signaling pathways. [ABSTRACT FROM AUTHOR]

In this paper, we describe a novel label-free fluorescence method for microRNA-21 (miR-21) detection based on terbium (Tb3+) and duplex-specific nuclease (DSN) assisted target recycling. Capture probes (Cps), containing a target-binding part and a signal-output part, are immobilized on magnetic beads (MBs). In the presence of the target miR-21, it hybridizes with the target-binding part of a Cp to form a DNA–RNA heteroduplex. Due to the considerable cleavage preference for DNA in DNA–RNA hybrids, DSN hydrolyzes the target-binding part of the Cp while liberating the intact target miR-21 to hybridize with a new Cp and initiate the second cycle of hydrolysis. Eventually, through magnetic separation, only the signal-output part of the Cp could remain in solution and function as a signalling flare to increase the fluorescence intensity of Tb3+ dramatically. By employing the above strategy, this approach can gain an amplified fluorescent signal and detect as low as 8 fM miR-21 under the optimized conditions. Moreover, due to the high selectivity of DSN, the method shows little cross-hybridization among the closely related miRNA family members even at the single-base-mismatched level. Successful attempts were made in applying the approach to detect miR-21 in human cell lysate samples of breast cancer patients. [ABSTRACT FROM AUTHOR]

Non-invasive early diagnosis of liver cancer is the most effective way to improve the survival rate. In this paper, we developed a label-free and enzyme-free fluorescent biosensor based on target recycling and Thioflavin T (ThT) induced G-quadruplex formation for MXR7 (liver cancer related short gene) detection in human serum. The proposed sensor can detect the target DNA in the concentration range of 0–350 fM with the detection limit as low as 10 fM. Due to the outstanding structural selectivity of ThT for G-quadruplex, this sensor possesses better discrimination ability and higher sensitivity. Furthermore, this enzyme-free and label-free fluorescence sensor has demonstrated to be capable of detecting target DNA in human serum samples because of its high selectivity and sensitivity. The mechanism employed in this study represents a promising path toward directing liver cancer detection in human serum. In addition, this strategy may be extended to detect other cancer related genes by choosing a rational DNA probe according to different sequences of targets. [ABSTRACT FROM AUTHOR]

Locked nucleic acid (LNA) is applied in toehold-mediated strand displacement reaction (TMSDR) to develop a junction-probe electrochemiluminescence (ECL) biosensor for single-nucleotide polymorphism (SNP) detection in the BRCA1 gene related to breast cancer. More than 65-fold signal difference can be observed with perfectly matched target sequence to single-base mismatched sequence under the same conditions, indicating good selectivity of the ECL biosensor. [ABSTRACT FROM AUTHOR]

Highlights: [•] The biosensor was based on target recycling and Thioflavin T-induced quadruplex. [•] Thioflavin T was first used as a fluorescent indicator for biosensor fabrication. [•] This sensor can detect as low as 20fM DNA with ultra-high discrimination ability. [Copyright &y& Elsevier]

Keratinocytes are rich in lipids and are the main sensitive cells to ultraviolet (UV) rays. Theaflavins are the core functional components of black tea and are known as the "soft gold" in tea. In this study, ultraviolet-B (UVB) irradiation caused apoptosis and necrosis of human epidermal keratinocytes (HaCaT). EGCG and the four theaflavins had anti-UVB damage activity, among which theaflavin-3′-gallate (TF3'G) had the best activity. The results of biophysical and molecular biology experiments showed that TF3'G has anti-damage effects on UVB-irradiated HaCaT cells through the dual effects of photoprotection and maintenance of cell homeostasis. That is, TF3'G preincubation could absorb UV rays, reduce the accumulation of aging-related heterochromatin (SAHF) formation, increase mitochondrial membrane potential, downregulate NF-κB inflammation pathways, inhibit the formation of cytotoxic aggregates, and protect biological macromolecules Structure, etc. The accumulation of conjugated π bonds and the balance benzoquinone are the core functional structure of TF3'G with high efficiency and low toxicity. The study indicates that TF3'G has the potential to inhibit the photoaging and intrinsic aging of skin cells. [Display omitted] • EGCG and the four theaflavins had anti-UVB damage activity, among which theaflavin-3′-gallate (TF3'G) had the best activity. • TF3'G inhibited the apoptosis and necrosis of HaCaT cells caused by UVB irradiation, and had a photoprotective effect. • TF3'G maintained cell homeostasis and had the potential to inhibit photoaging and intrinsic aging of skin cells. [ABSTRACT FROM AUTHOR]