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The molecular modification of chlorogenic acid (1) through γ-irradiation resulted in the formation of five new products: chlorogenosins A (2), B (3), C (4), D (5), and E (6) along with known compounds rosmarinosin B (7), protocatechuic acid (8), and protocatechuic aldehyde (9). The structures of the new compounds were elucidated using spectroscopic methods, including one-dimensional and two-dimensional nuclear magnetic resonance, high-resolution electrospray ionization mass spectroscopy, and circular dichroism spectroscopy. The potential anti-inflammatory activities of all the isolated compounds were determined by evaluating their inhibitory effects on the nitric oxide production in lipopolysaccharide-induced RAW 264.7 macrophages. Notably, compounds 2 and 3, which contained two hydroxymethyl functionalities instead of the trans-olefinic moiety present in the original chlorogenic acid, exhibited stronger inhibitory effects on NO production than that of the original compound. These findings suggest that the predominant chemical changes induced in chlorogenic acid by γ-irradiation may enhance its anti-inflammatory properties.

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The modulation of macrophage polarization is a promising strategy for maintaining homeostasis and improving innate and adaptive immunity. Low-dose ionizing radiation has been implicated in macrophage immunomodulatory responses. However, studies on the relationship between exosomes and regulation of macrophage polarization induced by ionizing radiation are limited. Therefore, this study investigated the alterations in macrophages and exosomes induced by gamma irradiation and elucidated the underlying mechanisms. We used the mouse macrophage cell line RAW 264.7 to generate macrophages and performed western blot, quantitative reverse transcription-PCR, and gene ontology analyses to elucidate the molecular profiles of macrophage-derived exosomes under varying treatment conditions, including 10 Gy gamma irradiation. Exosomes isolated from gamma-irradiated M1 macrophages exhibited an enhanced M1 phenotype. Irradiation induced the activation of NF-κB and NLRP3 signaling in M1 macrophages, thereby promoting the expression of pro-inflammatory cytokines. Cytokine expression was also upregulated in gamma-irradiated M1 macrophage-released exosomes. Therefore, gamma irradiation has a remarkable effect on the immunomodulatory mechanisms and cytokine profiles of gamma-irradiated M1 macrophage-derived exosomes, and represents a potential immunotherapeutic modality.

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The huge diversity of secondary bioactive metabolites, such as antibiotic and anticancer compounds produced by Micromonospora sp., makes it an attractive target for study. Here, we explored the anti-proliferative activities of Micromonospora sp. M2 extract (MBE) in relation to its pro-oxidative activities in A549 and MCF7 cell lines. Anti-proliferative effects were assessed by treating cells with MBE. We found that treatment with MBE decreased cell proliferation and increased intracellular reactive oxygen species, and that these observations were facilitated by the suppression of the PI3K-AKT pathway, alterations to the Bcl/Bad ratio, and increased caspase activity. These observations also demonstrated that MBE induced apoptotic cell death in cell lines. In addition, the phosphorylation of P38 and c-Jun N-terminal kinase (JNK) were upregulated following MBE treatment in both cell lines. Collectively, these results indicate that MBE acts as an anticancer agent via oxidative stress and JNK/mitogen-activated protein kinase pathway activation, enhancing apoptotic cell death in cell lines.

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Nialamide is a non-selective monoamine oxidase inhibitor that was widely used as an antidepressant. However, it has been prohibited for decades in the depressive medicine market due to the adverse hepatotoxic side effects. The re-use of drugs that have been withdrawn from the market represents a promising approach for the development of novel incrementally modified drugs and, in this context, ionizing radiation can serve as a powerful tool for producing new drug candidates. The present study exposed nialamide to γ radiation at 50 kGy to obtain the novel cyclized benzylamide, nialaminosin (compound 2), along with five known compounds, 3-amino-N-benzylpropanamide (compound 3), 3-methoxy-N-benzylpropanamide (compound 4), 3-hydroxy-N-benzylpropanamide (HBPA; compound 5), N-benzylpropanamide (compound 6) and isonicotinamide (compound 7). Among the isolated compounds, HBPA was established to inhibit the lipopolysaccharide-induced overproduction of pro-inflammatory mediators, including nitric oxide (NO) and prostaglandin E2 and cytokines including TNF-α, IL-6 and IL-10, without causing cytotoxicity to both RAW 264.7 and DH82 cells. Furthermore, HBPA was found to reduce the protein expression of inducible NO synthase and cyclooxygenase-2 in macrophages and compared with nialamide, it was established to have more potent radical scavenging activity. The present study therefore suggested the application of HBPA for the improvement of anti-inflammatory properties using ionizing radiation technology on the withdrawn drug nialamide.

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Human fibroblast growth factor 7 (hFGF7) is a member of the paracrine-acting FGF family and mediates various reactions such as wound healing, tissue homeostasis, and liver regeneration. These activities make it a plausible candidate for pharmaceutical applications as a drug. However, the low expression level and stability of the recombinant hFGF7 were known to be major hurdles for further applications. Here, the expression level and stability of hFGF7 were attempted to improve by changing the order of amino acids through circular permutation (CP), thereby expecting an alternative fate according to the N-end rule. CP-hFGF7 variants were constructed systematically by using putative amino acid residues in the loop region that avoided the disruption of the structural integrity especially in the functional motif. Among them, cp-hFGF7115-114 revealed a relatively higher expression level in the soluble fraction than the wild-type hFGF7 and was efficiently purified (7 mg L-1) to apparent homogeneity. The activity and stability of the purified variant cp-hFGF7115-114 were comparable or superior to that of the wild-type hFGF7, thereby strongly suggesting that CP could be an alternative tool for the functional expression of hFGF7 in Escherichia coli.

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Baicalin, a glucuronic flavone, is the major active component in the medicinal plant Scutellaria baicalensis. Herein, baicalin was irradiated by γ-rays to afford four unusual flavanones, baicalinols A (2), B (3), and C (4) and peroxybaicaleinol (5), and two known flavones, oroxylin A (6) and baicalein (7). The structures of the hydroxymethylated products were elucidated using nuclear magnetic resonance spectroscopy and mass spectrometry, and their absolute configuration was established using electronic circular dichroism spectroscopy. Novel hydroxymethylated flavanones 2 and 3 suppressed both nitric oxide (NO) production and the expression of inducible NO synthase and showed significantly higher anti-inflammatory activities in lipopolysaccharide-stimulated macrophages than the parent compound. These newly generated hydroxymethylated flavanones can be potentially used for treating inflammatory diseases.

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Radiation molecularly transforms naturally occurring products by inducing the methoxylation, hydroxylation, and alkylation of parent compounds, thereby affecting the anti-inflammatory capacities of those compounds. Minaprine (1) modified by ionizing radiation generated the novel hydroxymethylation hydropyridazine (2), and its chemical structure was determined based on NMR and HRESIMS spectra. Compared to the original minaprine, the novel generated product showed a highly enhanced anti-inflammatory capacity inhibited nitric oxide (NO) and prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 and DH82 macrophage cells. In addition, minaprinol (2) effectively inhibited cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) at the protein level and pro-inflammatory cytokine (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-10) production in macrophages.

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Rotenone, isolated from Derris, Lonchocarpus, and Tephrosia from the family Fabaceae, has been shown to have a variety of biological properties and is used in various agricultural industries as a potent biopesticide. However, recent reports have demonstrated that rotenone has the potential to cause several adverse effects such as a neurodegenerative disease. This study aimed to induce thermolysis of the biopesticide rotenone and enhance the functionality of the degraded products. Rotenone (1) was degraded after autoclaving for 12 h, and the thermolytic reactants showed enhanced anti-inflammatory capacity against nitric oxide (NO) production. The structures of the newly modified products were spectroscopically determined. The thermal reaction products included various isoflavonoid derivatives 2-6, whose structures were characterized as being produced via chemical reactions in rotenone at the C-12 positions. Among the degraded products, (-)-tubaic acid (6) exhibited significantly improved anti-inflammatory effects compared to the original rotenone. Quantitative LC-MS analysis of the major thermolysis products generated in Derris extract containing rotenone was performed using isolate 2-5 purified from autoclaved rotenone. These results suggest that the thermal transformation of rotenone can improve the functionality of anti-inflammatory agents.

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Asthma is a common airway inflammatory disorder, characterized by increased infiltration of leukocytes and bronchoconstriction. Dexamethasone (DEX) has been widely used in the treatment of allergic asthma. However, long-term and frequent use of DEX has side effects. We therefore reasoned that if drug carriers have intrinsic anti-inflammatory and anti-asthmatic activity and synergize with drug payloads, a low dose of DEX could exert sufficient therapeutic effects. In this study, we developed DEX-loaded H2O2-activatable boronate maltodextrin (DEX-BM) nanoparticles. DEX-BM nanoparticles released DEX in a H2O2-triggered manner and remarkably suppressed the expression of pro-inflammatory cytokines in activated macrophages and lung epithelial cells. In the studies of a murine allergic asthma model, DEX-BM nanoparticles (5 mg/kg) effectively inhibited the inflammatory cell infiltration and airway inflammation than equivalent DEX and BM nanoparticles without noticeable side effects. We anticipate that DEX-BM nanoparticles hold great potential as therapeutic agents for various airway inflammatory diseases.

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Combination therapy, a treatment regimen that combines more than two therapeutic agents to diseased tissues has recently gained increasing attentions in anticancer therapy. As cancer cells are more vulnerable to oxidative stress and heat compared to normal cells, we developed hyperthermia- and oxidative stress-inducing maltodextrin (HTOM) nanoparticles as a platform of combinational photothermal/oxidative anticancer therapy. HTOM was designed to incorporate cinnamaldehyde as an oxidative stress inducer through acid-labile acetal linkage and IR780 as a photoabsorber. HTOM nanoparticles could generate excess reactive oxygen species (ROS) to kill cancer cells effectively. When exposed to near infrared (NIR) laser irradiation (808 nm), HTOM nanoparticles also increased temperature to destroy cancer cells. The combination of NIR laser irradiation with HTOM nanoparticles exhibited significantly higher anticancer activity than HTOM nanoparticles alone and NIR lasers irradiation alone. When combined with NIR laser irradiation on the tumor site, intravenously administrated HTOM nanoparticles effectively eradicated tumors in mouse xenograft models. Our strategy for combination of oxidative stress and photothermal heating may offer a new combinational treatment modality for cancer.

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There has been increasing interest in the development of pathological stimulus-activatable nanoplatforms with theranostic functions. Here, we report ketalized maltodextrin (KMD) nanoparticles which are able to deliver therapeutic and imaging functions to the acidic conditions simultaneously, as may be found in the site of inflammation. KMD was synthesized as a platform of the theranostic nanoparticles by conjugating acid-cleavable hydrophobic moieties to maltodextrin through carbonate bonds. KMD nanoparticles could undergo acid-triggered hydrolytic degradation to generate carbon dioxide (CO2) bubbles, amplifying the ultrasound signal. The potential of KMD nanoparticles as a drug carrier was evaluated using silymarin as a model drug. KMD nanoparticles displayed significantly enhanced ultrasound contrast at acidic pH and released drug payloads in acid-triggered manners. The translational potential of silymarin-loaded KMD (s-KMD) nanoparticles as ultrasound contrast agents and therapeutic agents was thoroughly evaluated using cell culture models and mouse models of acetaminophen (APAP)-induced acute liver failure. s-KMD nanoparticles exhibited significantly enhanced ultrasound contrast in the APAP-intoxicated liver and also remarkably suppressed the hepatic damages by inhibiting the expression of pro-inflammatory cytokines. These results suggest that KMD nanoparticles hold tremendous potential as theranostic agents for various inflammatory diseases.

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