Protective effect of 13-methylberberine against mouse enteritis caused by MRSA.

ETHNOPHARMACOLOGICAL RELEVANCE: The emergence and spread of antibiotic resistance bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), urgently need to develop alternative strategies or novel antibacterial drugs. Coptis chinensis Franch., one ancient Chinese herb, has been widely used for the treatment of intestine disease, such as diarrhea. Alkaloids are the major active compounds of Coptis chinensis Franch., and has anti-inflammatory, antioxidant, and antimicrobial effects. AIM OF THE STUDY: The aim of the study was tried to investigate the potential antibacterial effects of the alkaloids from Coptis chinensis Franch. and explore the mechanism. MATERIALS AND METHODS: A checkerboard assay, time-killing analysis, membrane functions assay, transcriptome analysis, and inducible resistance test showed the antibacterial effects and mechanisms of alkaloids from Coptis chinensis Franch. Hemolytic assay and MRSA-infected RAW264.7 cells were used to evaluate anti-virulence and anti-inflammatory activities of 13-methylberberine (13-MB). MRSA-infected Vero cells and mouse enteritis models were used to evaluate the anti-infectious effect of 13-MB against MRSA both in vitro and in vivo. RESULTS: 13-methylberberine (13-MB) displayed high bactericidal efficiency against methicillin-resistant S. aureus (MRSA). Mechanistic studies showed that 13-MB rapidly killed MRSA by interfering with the proton motive force, ROS generation and membrane fluidity via direct interaction with membrane phospholipids. 13-MB suppressed the virulence of MRSA, modulated the host immune response, and effectively eliminated MRSA in Vero cells. Importantly, 13-MB suppressed weight loss, inflammatory response, bacterial colonization and intestinal lesion in mouse enteritis caused by 13-MB susceptible and resistant S. aureus. CONCLUSION: These results supported the 13-MB has promising potential to be developed as natural drug with antibacterial activity, anti-virulence activity, and host modulation activity for the treatment of enteritis caused by MRSA.

Tanshinone IIA protected against lipopolysaccharide-induced brain injury through the protective effect of the blood-brain barrier and the suppression of oxidant stress and inflammatory response.

Brain microvascular endothelial cells are essential components of the blood-brain barrier (BBB) that acts as a selective physical barrier and plays protective roles in maintaining brain homeostasis. Tanshinone IIA (Tan IIA), isolated from Salvia miltiorrhiza Bunge, exhibited healthy effects such as antioxidant effects, anti-inflammatory effects, and cardiovascular protective effects. Here, we tried to investigate the positive effect and the potential mechanism of Tan IIA on the lipopolysaccharide (LPS)-induced brain injury in mice and brain microvascular endothelial cells in vitro. In vivo, Tan IIA inhibited the brain injury, and the enhancement of blood-brain barrier permeability in the LPS-induced brain injury in mice. Moreover, Tan IIA suppressed inflammatory response and oxidant response in LPS-treated mice evidenced by low levels of serum TNF-α and IL-1ß, high superoxide dismutase (SOD) activity and low malondialdehyde (MDA) in the brain. In vitro, Tan IIA suppressed the generation of reactive oxygen species (ROS) and MDA, and promoted SOD activity in LPS-stimulated brain microvascular endothelial cells. Moreover, Tan IIA promoted the expression of Claudin5, ZO-1, Nrf2, HO-1 and NQO1 in LPS-stimulated brain microvascular endothelial cells. In conclusion, Tan IIA protected against the LPS-induced brain injury via the suppression of oxidant stress and inflammatory response and protective effect of the BBB through activating Nrf2 signaling pathways and rescue of the tight junction proteins in microvascular endothelial cells, supporting the application of Tan IIA and Salvia miltiorrhiza Bunge as food supplements for the treatment of brain disease.

Natural Antibacterial and Antivirulence Alkaloids From Macleaya cordata Against Methicillin-Resistant Staphylococcus aureus.

The emergence and spread of antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), underly the urgent need to develop novel antibacterial drugs. Macleaya cordata, a traditional medicinal plant, has been widely used in livestock animals, plants, and humans. Alkaloids are the primary bioactive compounds of Macleaya cordata and exhibit antibacterial, antiinflammatory, and antioxidant activities. Nevertheless, the antibacterial compounds and mode of action of Macleaya cordata remain unclear. In the present study, we investigated the antibacterial activity and mode of action of alkaloids from Macleaya cordata. Sanguinarine, 6-ethoxysanguinarine (6-ES), 6-methoxydihydrosanguinarine (6-MS), chelerythrine (CH), and dihydrochelerythrine (DICH) exhibited good antibacterial activity against Gram-positive bacteria, including MRSA. 6-ES rapidly killed MRSA, possibly by interfering with membrane and metabolic functions including ROS production by targeting the membrane and FtsZ in S. aureus. Additionally, 6-ES directly suppressed the hemolytic activity of α-hemolysin, alleviated inflammatory responses, and eliminated intracellular MRSA, as well as displayed low development of drug resistance, in vitro. Finally, a 6-ES-loaded thermosensitive hydrogel promoted wound healing in mice infected with MRSA. These results supported 6-ES as a novel potential candidate or leading compound with antibacterial, antivirulence, and host immunomodulatory activities in fighting against bacterial infections.

Health Benefits of Silybum marianum: Phytochemistry, Pharmacology, and Applications.

Silybum marianum (SM), a well-known plant used as both a medicine and a food, has been widely used to treat various diseases, especially hepatic diseases. The seeds and fruits of SM contain a flavonolignan complex called silymarin, the active compounds of which include silybin, isosilybin, silychristin, dihydrosilybin, silydianin, and so on. In this review, we thoroughly summarize high-quality publications related to the pharmacological effects and underlying mechanisms of SM. SM has antimicrobial, anticancer, hepatoprotective, cardiovascular-protective, neuroprotective, skin-protective, antidiabetic, and other effects. Importantly, SM also counteracts the toxicities of antibiotics, metals, and pesticides. The diverse pharmacological activities of SM provide scientific evidence supporting its use in both humans and animals. Multiple signaling pathways associated with oxidative stress and inflammation are the common molecular targets of SM. Moreover, the flavonolignans of SM are potential agonists of PPARγ and ABCA1, PTP1B inhibitors, and metal chelators. At the end of the review, the potential and perspectives of SM are discussed, and these insights are expected to facilitate the application of SM and the discovery and development of new drugs. We conclude that SM is an interesting dietary medicine for health enhancement and drug discovery and warrants further investigation.

Natural Flavones from Morus alba against Methicillin-Resistant Staphylococcus aureus via Targeting the Proton Motive Force and Membrane Permeability.

The emergence and rapid spread of methicillin-resistant Staphylococcus aureus (MRSA) critically requires alternative therapeutic options. New antibacterial drugs and strategies are urgently needed to combat MRSA-associated infections. Here, we investigated the antibacterial activity of flavones from Morus alba and the potential mode of action against MRSA. Kuwanon G, kuwanon H, mulberrin, and morusin displayed high efficiency in killing diverse MRSA isolates. On the basis of structure-activity analysis, the cyclohexene-phenyl ketones and isopentenyl groups were critical to increase the membrane permeability and to dissipate the proton motive force. Meanwhile, mechanistic studies further showed that kuwanon G displayed rapid bactericidal activity in vitrowith difficulty in developing drug resistance. Kuwanon G targeted phosphatidylglycerol and cardiolipin in the cytoplasmic membrane through the formation of hydrogen bonds and electrostatic interactions. Additionally, kuwanon G promoted wound healing in a mouse model of MRSA skin infection. In summary, these results indicate that flavones are promising lead compounds to treat MRSA-associated infections through disrupting the proton motive force and membrane permeability.

Baicalin protects mice against Salmonella typhimurium infection via the modulation of both bacterial virulence and host response.

BACKGROUND: The worsening problems of antibiotic resistance prompt the need for alternative strategies. Baicalin, which is isolated from Scutellaria baicalensisi, has been demonstrated to exhibit anti-inflammatory, anti-virulence and antimicrobial effects. Salmonella typhimurium is an important foodborne pathogenic bacteriaum that causes gastrointestinal disease in humans and many animals. PURPOSE: The aim of this study was to investigate the effects of baicalin on S. typhimurium infection in mice and its possible mechanism in vitro. STUDY DESIGN: To evaluate the effect of baicalin in vivo, mice were orally administered of baicalin, and then were infected by an intragastric administration of S. typhimurium. The minimal inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of baicalin, baicalein, and oroxylin A against S. typhimurium were detected under the guides of the Clinical and Laboratory Standards Institute. In vitro, Caco-2 cells were infected with S. typhimurium in the presence or absence of baicalin, baicalein, and oroxylin A at sub-MICs. METHODS: In the in vivo experiment, the body weight loss, the serum levels of TNFα,  IL-6, and lactic dehydrogenase (LDH), the pathological changes of the caecum and the caecum bacterial burdens were examined. The MICs and MBCs of baicalin, baicalein, and oroxylin A against S. typhimurium were detected by two-fold serial dilutions. In vitro, Caco-2 cells were infected with S. typhimurium, and the invasion capacity, TNFα, nitrate, and LDH were analysed. The transcription levels of Salmonella pathogenicity island 1 virulence associated genes (sopB, sopE, sopE2) of S. typhimurium in the presence of baicalin, baicalein, and oroxylin A were detected by qRT-PCR. RESULTS: Our results showed that baicalin significantly decreased the body weight loss, the serum levels of TNFα,  IL-6, and LDH, and the caecum bacterial burdens of mice challenged with S. typhimurium. Histological examination showed that baicalin decreased the lesion in the caecum of S. typhimurium-infected mice. MICs and MBCs of baicalin, and oroxylin A. against S. typhimurium were > 128 µg/ml. MICs and MBCs of baicalein against S. typhimurium were 64 µg/ml, and > 128 µg/ml, respectively. Pretreatment of Caco-2 cells or S. typhimurium with baicalin, baicalein, and oroxylin A significantly inhibited the invasion of Caco-2 cells by S. typhimurium in a dose-dependent manner. Sub-MICs of baicalin, baicalein, and oroxylin A also significantly decreased the levels of TNFα, nitrate, and LDH from S. typhimurium-infected Caco-2 cells. Moreover, the transcription levels of sopB, sopE, and sopE2 were significantly suppressed by baicalin, baicalein, and oroxylin A. CONCLUSIONS: These results demonstrated that baicalin is a promising agent for the prevention of S. typhimurium infection via the modulation of both bacterial virulence and host response.

Xiang-Qi-Tang and its active components exhibit anti-inflammatory and anticoagulant properties by inhibiting MAPK and NF-κB signaling pathways in LPS-treated rat cardiac microvascular endothelial cells.

Xiang-Qi-Tang (XQT) is a Chinese herbal formula containing Cyperus rotundus, Astragalus membranaceus and Andrographis paniculata. Alpha-Cyperone (CYP), astragaloside IV (AS-IV) and andrographolide (AND) are the three major active components in this formula. XQT may modulate the inflammatory or coagulant responses. We therefore assessed the effects of XQT on lipopolysaccharide (LPS)-induced inflammatory model of rat cardiac microvascular endothelial cells (RCMECs). XQT, CYP, AS-IV and AND inhibited the production of tumor necrosis factor alpha (TNF-α), intercellular cell adhesion molecule-1 (ICAM-1) and plasminogen activator inhibitor-1 (PAI-1), and up-regulated the mRNA expression of Kruppel-like factor 2 (KLF2). XQT and CYP inhibited the secretion of tissue factor (TF). To further explore the mechanism, we found that XQT, or its active components CYP, AS-IV and AND significantly inhibited extracellular signal-regulated kinase (ERK), c-jun NH2-terminal kinase (JNK) and p38 phosphorylation protein expression as well as decreased the phosphorylation levels of nuclear factor κB (NF-κB) p65 proteins in LPS-stimulated RCMECs. These results suggested that XQT and its active components inhibited the expression of inflammatory and coagulant mediators via mitogen-activated protein kinase (MAPKs) and NF-κB signaling pathways. These findings may contribute to future research on the action mechanisms of this formula, as well as therapy for inflammation- or coagulation-related diseases.

Xiang-qi-tang increases avian pathogenic Escherichia coli-induced survival rate and regulates serum levels of tumor necrosis factor alpha, interleukin-1 and soluble endothelial protein C receptor in chicken.

Xiang-qi-tang (XQT) is a Chinese herbal formula containing rhizoma Cyperi, Andrographis paniculata and Astragalus membranaceus. The present study investigated the effects of XQT on the mortality and inflammatory mediators in a chicken model challenged with avian pathogenic Escherichia coli (APEC). To detect the effect of XQT, the chickens were pretreated with the formula 12 h before being challenged with 10(8) colony forming unit (CFU) of APEC. The results showed that 0.6 g/kg XQT significantly elevated the survival rate of infected chickens. To further investigate the mechanism of decreasing mortality of XQT, we examined plasma inflammatory mediator levels. The levels of tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1) and soluble endothelial protein C receptor (sEPCR) were significantly increased in chickens challenged with APEC alone, whereas chickens pretreated with 0.6 g/kg XQT showed marked decrease of these inflammatory mediator levels during the death peak. Taken together, this study demonstrates that XQT has protective effects in APEC-treated chickens. The action mechanisms of XQT involve anti-inflammation and antithrombotic activity. These findings may contribute to future research on the action mechanisms of this formula, as well as prevention of or therapy for avian colibacillosis.