Abstract
Objectives
Chamomile has long been used as a medicinal plant due to its antioxidative and anti-inflammatory activity. Apigenin-7-O-glucoside (AG) is one of the major ethanol extract ...components from chamomile; however, the underlying mechanism remains unclear.
Methods
In this study, the antioxidant potential and the anti-inflammatory activities of AG were analysed and compared with those of trolox. We demonstrate the protective effects of AG on free radical-induced oxidative damage of DNA, proteins and erythrocytes. Flow cytometry assay was used to detect ROS production. Additionally, the expression of anti-oxidation-related and inflammation-related factors was detected by ELISA and Western blotting, respectively.
Key findings
AG and trolox showed different efficiency as antioxidant in different experimental systems. AG had similar effect as trolox to inhibit H2O2-induced ROS production in RAW264.7 cells, while exerted stronger inhibition against free radical-induced oxidative damage on erythrocytes than trolox. Interestingly, compared with trolox, AG also had stronger inhibitory effect on LPS-induced NF-κB/NLRP3/caspase-1 signalling in RAW246.7 cells.
Conclusions
These results suggest the potential of AG as a pharmaceutical drug for anti-oxidation and anti-inflammation, and the combined usage of AG and trolox might promote its efficacy. Our findings will provide new insights into the development of new drugs with antioxidative and anti-inflammatory functions.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A systemic treatment strategy is urgently demanded to suppress the rapid growth and easy metastasis characteristics of breast cancer. In this work, a chimeric peptide‐engineered self‐delivery ...nanomedicine (designated as ChiP‐CeR) for photodynamic‐triggered breast cancer immunotherapy by macrophage polarization. Among these, ChiP‐CeR is composed of the photosensitizer of chlorine e6 (Ce6) and the TLR7/8 agonist of lmiquimod (R837), which is further modified with tumor matrix targeting peptide (Fmoc‐K(Fmoc)‐PEG8‐CREKA. ChiP‐CeR is preferred to actively accumulate at the tumor site via specific recognition of fibronectin, which can eradicate primary tumor growth through photodynamic therapy (PDT). Meanwhile, the destruction of primary tumors would trigger immunogenic cell death (ICD) effects to release high‐mobility group box‐1(HMGB1) and expose calreticulin (CRT). Moreover, ChiP‐CeR can also polarize M2‐type tumor‐associated macrophages (TAMs) into M1‐type TAMs, which can activate T cell antitumor immunity in combination with ICD. Overall, ChiP‐CeR possesses superior antitumor effects against primary and lung metastatic tumors, which provide an applicable nanomedicine and a feasible strategy for the systemic management of metastatic breast cancer.
A chimeric peptide‐engineered self‐delivery nanomedicine (designated as ChiP‐CeR) based on matrix tumor‐targeting peptide (designated as ChiP), photosensitizer (Ce6), and immune adjuvant (R837) is developed for photodynamic therapy and immunotherapy. ChiP‐CeR possess superior antitumor effects against primary and lung metastatic tumor, which provide an applicable nanomedicine and a feasible strategy for the systemic management of metastatic breast cancer.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Tigecycline is one of the last-resort antibiotics to treat complicated infections caused by both multidrug-resistant Gram-negative and Gram-positive bacteria
. Tigecycline resistance has sporadically ...occurred in recent years, primarily due to chromosome-encoding mechanisms, such as overexpression of efflux pumps and ribosome protection
. Here, we report the emergence of the plasmid-mediated mobile tigecycline resistance mechanism Tet(X4) in Escherichia coli isolates from China, which is capable of degrading all tetracyclines, including tigecycline and the US FDA newly approved eravacycline. The tet(X4)-harbouring IncQ1 plasmid is highly transferable, and can be successfully mobilized and stabilized in recipient clinical and laboratory strains of Enterobacteriaceae bacteria. It is noteworthy that tet(X4)-positive E. coli strains, including isolates co-harbouring mcr-1, have been widely detected in pigs, chickens, soil and dust samples in China. In vivo murine models demonstrated that the presence of Tet(X4) led to tigecycline treatment failure. Consequently, the emergence of plasmid-mediated Tet(X4) challenges the clinical efficacy of the entire family of tetracycline antibiotics. Importantly, our study raises concern that the plasmid-mediated tigecycline resistance may further spread into various ecological niches and into clinical high-risk pathogens. Collective efforts are in urgent need to preserve the potency of these essential antibiotics.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A series of thioether pleuromutilin derivatives containing 1,2,4‐triazole on the side chain of C14 were designed and synthesized. The in vitro antibacterial activities experiments of the synthesized ...derivatives showed that compounds 72 and 73 displayed superior in vitro antibacterial effect against MRSA minimal inhibitory concentration (MIC = 0.0625 μg/mL) than tiamulin (MIC = 0.5 μg/mL). The results of time‐kill study and postantibiotic effect study indicated that compound 72 could inhibit the growth of MRSA quickly (−2.16 log10 CFU/mL) and showed certain postantibiotic effect (PAE) time (exposure to 2 × MIC and 4 × MIC for 2 h, the PAE was 1.30 and 1.35 h) against MRSA. Furthermore, the binding mode between compound 72 and 50S ribosome of MRSA was explored by molecular docking and five hydrogen bonds were formed between compound 72 and 50S ribosome.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A series of pleuromutilin derivatives containing benzimidazole were designed, synthesized, and evaluated for their antibacterial activities against Methicillin-resistant Staphylococcus aureus (MRSA) ...in this study. The in vitro antibacterial activities of the synthesized derivatives against four strains of S. aureus (MRSA ATCC 43300, S. aureus ATCC 29213, S. aureus 144, and S. aureus AD3) were determined by the broth dilution method. Among these derivatives, compound 58 exhibited superior in vitro antibacterial effect against MRSA (minimal inhibitory concentration MIC = 0.0625 μg/mL) than tiamulin (MIC = 0.5 μg/mL). Compound 58 possessed a faster bactericidal kinetic and a longer post-antibiotic effect time against MRSA than tiamulin. Meanwhile, at 8 μg/mL concentration, compound 58 did not display obviously cytotoxic effect on the RAW 264.7 cells. In addition, compound 58 (-2.04 log
CFU/mL) displayed superior in vivo antibacterial efficacy than tiamulin (-1.02 log
CFU/mL) in reducing MRSA load in mice thigh infection model. In molecular docking study, compound 58 can successfully attach to the 50S ribosomal active site (the binding free energy is -8.11 kcal/mol). Therefore, compound 58 was a potential antibacterial candidate for combating MRSA infections.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A seize of pleuromutilin derivatives containing amide side chains were designed and synthesized as potential antibiotics against Methicillin‐resistant Staphylococcus aureus (MRSA). Among all target ...compounds (compounds 11–30), compound 25 was found to have the strongest antibacterial activity against MRSA (minimum inhibitory concentration = 0.5 μg/ml). The result of the time‐kill curves indicated that compound 25 could repress the growth of MRSA in vitro obviously (−3.72 log10CFU/ml reduction). Furthermore, molecular docking studies demonstrated that compound 25 was localized in the binding pocket of 50S ribosomal subunit (ΔGb = −8.99 kcal/mol). Besides, compound 25 displayed low cytotoxicity to RAW 264.7 cells. The results suggested that compound 25 might be further developed into a novel antimicrobial agent against MRSA.
Synthesis of novel pleuromutilin derivatives bearing amide side chains. Compound 25 exhibited superior in vitro efficacy against MRSA (minimum inhibitory concentration = 0.5 μg/ml). Compound 25 possessed a certain affinity with the 50S ribosome.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Flavonoids, which contain a benzo‐γ‐pyrone (C6–C3–C6) skeleton, have been reported to exhibit effective antioxidant ability. This study aimed to compare the antioxidant activities of ...7,8‐dihydroxyflavone (7,8‐DHF) and 7‐hydroxyflavone (7‐HF) in H2O2, lipopolysaccharide (LPS), or tert‐butyl hydroperoxide (t‐BHP)‐induced RAW264.7 cells, respectively. The antioxidant capacities of 7,8‐DHF and 7‐HF were firstly evaluated by 2,2‐azinobis‐3‐ethyl‐benzothiazoline‐6‐sulphonic acid (ABTS), 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays. Then, reactive oxygen species (ROS), super oxide dismutase (SOD), and malondialdehyde (MDA) productions in H2O2, LPS, or t‐BHP‐induced RAW264.7 cells were tested and compared, respectively. Finally, the antioxidant mechanisms of 7‐HF and 7,8‐DHF were initially investigated by western blot. Our results showed that 7,8‐DHF possessed stronger free‐radical scavenging capacity than 7‐HF. Both 7,8‐DHF and 7‐HF suppressed MDA production and ROS accumulation, improved the activity of SOD in H2O2, LPS, or t‐BHP‐induced RAW264.7 cells, respectively. And 7,8‐DHF exerted a better antioxidant effect than 7‐HF, especially in t‐BHP‐induced oxidative stress. Mechanically, 7,8‐DHF prevented the activation of poly ADP‐ribosepolymerase and caspase‐3, meanwhile markedly upregulated the expression of HO‐1 protein in t‐BHP‐induced oxidative stress. These results suggested that 7,8‐DHF might serve as a potential pharmaceutical drug against oxidative stress injury.
7,8‐dihydroxyflavone exhibited potent antioxidative activity in different experimental systems, and 7,8‐dihydroxyflavone displayed antioxidant effect through activating Heme oxygenase‐1 (HO‐1) expression and inhibiting caspase‐3/poly ADP‐ribosepolymerase activation in RAW264.7 cells.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Two series of pleuromutilin derivatives were designed and synthesized as inhibitors against Staphylococcus aureus (S. aureus). 6-chloro-4-amino-1-R-1H-pyrazolo3,4-dpyrimidine or ...4-(6-chloro-1-R-1H-pyrazolo3,4-dpyrimidine-4-yl)amino-phenylthiol were connected to pleuromutilin. A diverse array of substituents was introduced at the N-1 position of the pyrazole ring. The in vitro antibacterial activities of these semisynthetic derivatives were evaluated against two standard strains, Methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300, Staphylococcus aureus (S. aureus), ATCC 29213 and two clinical S. aureus strains (144, AD3) using the broth dilution method. Compounds 12c, 19c and 22c (MIC = 0.25 μg/mL) manifested good in vitro antibacterial ability against MRSA which was similar to that of tiamulin (MIC = 0.5 μg/mL). Among them, compound 22c killed MRSA in a time-dependent manner and performed faster bactericidal kinetics than tiamulin in time–kill curves. In addition, compound 22c exhibited longer PAE than tiamulin, and showed no significant inhibition on the cell viability of RAW 264.7, Caco-2 and 16-HBE cells at high doses (≤8 μg/mL). The neutropenic murine thigh infection model study revealed that compound 22c displayed more effective in vivo bactericidal activity than tiamulin in reducing MRSA load. The molecular docking studies indicated that compound 22c was successfully localized inside the binding pocket of 50S ribosomal, and four hydrogen bonds played important roles in the binding of them.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A series of novel pleuromutilin derivatives containing nitrogen groups on the side chain of C14 were synthesized under mild conditions. Most of the synthesized derivatives displayed potent ...antibacterial activities. Compound
was found to be the most active antibacterial derivative against MRSA (MIC = 0.06 μg/mL). Furthermore, the result of time-kill curves showed that compound
had a certain inhibitory effect against MRSA in vitro. Moreover, according to a surface plasmon resonance (SPR) study, compound
(K
= 1.77 × 10
M) showed stronger affinity to the 50S ribosome than tiamulin (K
= 2.50 × 10
M). The antibacterial activity of compound
was further evaluated in an MRSA-infected murine thigh model. Compared to the negative control group, tiamulin reduced MRSA load (~0.7 log
CFU/mL), and compound
performed a treatment effect (~1.3 log
CFU/mL). In addition, compound
was evaluated in CYP450 inhibition assay and showed only moderate in vitro CYP3A4 inhibition (IC
= 2.92 μg/mL).
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A series of pleuromutilin analogs containing substituted benzoxazole were designed, synthesised, and assessed for their antibacterial activity both
and
. The MIC of the synthesised derivatives was ...initially assessed using the broth dilution method against four strains of
(MRSA ATCC 43300,
ATCC 29213, clinical isolation of
AD3 and
144). Most of the synthesised derivatives displayed prominent
activity (MIC ≤ 0.5 µg/mL). Compounds
and
exhibited the most effective antibacterial effect against MRSA (MIC = 0.125 µg/mL). Furthermore, the time-kill curves showed that compounds
and
had a certain inhibitory effect against MRSA
. The
antibacterial activity of compound
was evaluated further using a murine thigh model infected with MRSA (-1.24 log
CFU/mL). Compound
exhibited superior antibacterial efficacy to tiamulin. It was also found that compound
did not display significant inhibitory effect on the proliferation of RAW 264.7 cells. Molecular docking study revealed that compound
can effectively bind to the active site of the 50S ribosome (the binding free energy -7.50 kcal/mol).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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