Construction of Benzoxazine-linked One-Dimensional Covalent Organic Frameworks Using the Mannich Reaction.

Covalent polymerization of organic molecules into crystalline one-dimensional (1D) polymers is effective for achieving desired thermal, optical, and electrical properties, yet it remains a persistent synthetic challenge for their inherent tendency to adopt amorphous or semicrystalline phases. Here we report a strategy to synthesize crystalline 1D covalent organic frameworks (COFs) composing quasi-conjugated chains with benzoxazine linkages via the one-pot Mannich reaction. Through [4+2] and [2+2] type Mannich condensation reactions, we fabricated stoichiometric and sub-stoichiometric 1D covalent polymeric chains, respectively, using doubly and singly linked benzoxazine rings. The validity of their crystal structures has been directly visualized through state-of-the-art cryogenic low-dose electron microscopy techniques. Post-synthetic functionalizations of them with a chiral MacMillan catalyst produce crystalline organic photocatalysts that demonstrated excellent catalytic and recyclable performance in light-driven asymmetric alkylation of aldehydes, affording up to 94 % enantiomeric excess.

Examining the relationship between the Short Warwick-Edinburgh Mental Well-being Scale (SWEMWBS) and EQ-5D-5L and comparing their psychometric properties.

BACKGROUND: The purpose of this study is to examine the relationship between the Short Warwick-Edinburgh Mental Well-being Scale (SWEMWBS) and EQ-5D-5L and compare their psychometric properties in 4 chronic conditions in China. METHODS: Participants were invited to complete the online survey. Spearman's rank correlation was used to evaluate the correlation between SWEMWBS and EQ-5D-5L; exploratory factor analysis was used to ascertain the number of unique underlying latent factors measured by SWEMWBS and EQ-5D-5L. Next, we assessed the psychometric properties of SWEMWBS and EQ-5D-5L by reporting distributions and examining their known-group validity and convergent validity. RESULTS: In total, 500 individuals participated the online survey. Spearman's rank correlation showed that EQ-5D-5L dimensions, except for the anxiety/depression dimension, were weakly correlated with all dimensions of SWEMWBS. The two-factor solution for exploratory factor analysis found that all of SWEMWBS dimensions loaded onto one factor, four EQ-5D-5L dimensions (mobility, self-care, usual activities and pain/discomfort) onto another, and the EQ-5D-5L item of anxiety/depression item loaded moderately onto both factors. Patients of four disease groups had different distributions of responses for both SWEMWBS and EQ-5D-5L. In terms of known-group validity, both the F statistic and AUROC value of EQ-5D-5L utility scores were significantly higher than SWEMWBS scores in all four pair-wised comparisons. The Pearson correlation coefficient between EQ-5D-5L utility scores, SWEMWBS scores and EQ-VAS was 0.44 (P < 0.01) and 0.65 (P < 0.01), respectively. CONCLUSIONS: SWEMWBS and EQ-5D-5L measure different constructs and can be seen as complementary measures. Both measures demonstrated good convergent validity and known-group validity with EQ-5D-5L being a more sensitive measure, even for mental conditions.

SESLA suppresses the activation of macrophages and dendritic cells after Gram-positive bacterial challenge.

BACKGROUND: Secoeudesma sesquiterpenes lactone A (SESLA) is a sesquiterpene derived from Inula japonica Thunb. and is known to possess many pharmacological properties, e.g. anti-tumor and anti-inflammatory activities. However, the immunomodulatory role of SESLA in gram-positive (G+) bacterial infection is not clear. MATERIALS AND METHODS: To set up a G+ bacterial infection model in vitro, we carried out a bacterial mimic (PGN or Pam3CSK4) or Methicillin-resistant Staphylococcus aureus (MRSA) stimulated experiment using macrophages or dendritic cells (DCs). ELISA and qPCR were performed to measure the expression of inflammatory cytokines. Flow cytometry was used to detect the expression of MHC II and co-stimulatory molecules on the surface of DCs. The network pharmacology was used to identify the molecular mechanism and potential targets of SESLA that are predicted to be involved in the MRSA-elicited inflammation. Western blot and dual luciferase reporter assay were adopted to certify possible molecular mechanism of SESLA. RESULTS: This study demonstrated that SESLA treatment significantly reduced the levels of inflammatory cytokines stimulated by PGN, Pam3CSK4 or even MRSA in vitro, and it also reduced PGN-induced expression of MHC II and co-stimulatory molecules on the surface of DCs. Mechanistically, the inhibition of IκBα phosphorylation and the suppression of T cells activation could account for its anti-inflammatory activity. CONCLUSION: The present study validated the notable anti-inflammatory activity of SESLA and discovered its previously uncharacterized immunoregulatory role and the underlying mechanism in G+ bacterial infections. Overall, SESLA has a potential to be an antibiotic adjuvant for the treatment of G+ bacterial infections.

Laparoendoscopic Single-Site Technique Contrasted with Conventional Laparoscopy in Cystectomy for Benign Ovarian Cysts.

Objective: To compare the laparoendoscopic single-site (LESS) technique with conventional laparoscopy in cystectomy for benign ovarian cysts. Materials and methods: A retrospective analysis was performed at Yixing People's Hospital from April 2020 until December 2021. Results: Thirty-seven patients using the LESS technique were compared with a control group of 45 patients who underwent a traditional laparoscopic ovarian cystectomy. There was no statistically significant difference in the perioperative hemoglobin level changes, cyst rupture rate, postoperative recovery of exhausting time, or pain score at 24 hours after surgery between the 2 groups (P > 0.05). The mean operating time was significantly longer in the LESS group than that of the control group (88.38 ± 30.57 minutes vs 59.44 ± 24.22 minutes; P = 0.001). However, the length of postoperative hospital stay was significantly shorter in the LESS group (3.70 ± 0.57 days vs 4.38 ± 0.86 days; P = 0.001). In addition, total hospitalization expenses were higher in the LESS group (14,709.78 ± 1618.63 yuan vs 12,676.73 ± 1411.78 yuan; P = .001) and the satisfaction score was also significantly higher in the LESS group (z = -2.272; P = 0.023). After a follow-up time of 12 to 24 months, no patient in either group showed wound infection, umbilical hernia, or recurrent cysts. Conclusions: The LESS technique for benign ovarian cystectomy is safe, feasible, and equally effective compared with the multiport laparoscopic oophorocystectomy. Although it currently costs more, patients with benign ovarian cysts are highly satisfied with the LESS technique.

MCL Plays an Anti-Inflammatory Role in Mycobacterium tuberculosis-Induced Immune Response by Inhibiting NF-κB and NLRP3 Inflammasome Activation.

Mycobacterium tuberculosis (Mtb) remains a significant menace to global health as it induces granulomatous lung lesions and systemic inflammatory responses during active tuberculosis (TB). Micheliolide (MCL), a sesquiterpene lactone, was recently reported to have a function of relieving LPS-induced inflammatory response, but the regulative role of MCL on the immunopathology of TB still remains unknown. In this experiment, we examined the inhibitory effect of MCL on Mtb-induced inflammatory response in mouse macrophage-like cell line Raw264.7 by downregulating the activation of nuclear factor kappa B (NF-κB) and NLRP3 inflammasome. Evidences showed that MCL decreased the secretion of Mtb-induced inflammatory cytokines (IL-1ß and TNF-α) in a dose-dependent manner. Meanwhile, MCL dramatically suppressed Mtb-induced activation of iNOS and COX2 as well as subsequent production of NO. Furthermore, MCL inhibited Mtb-induced phosphorylation of Akt (Ser 473) in Raw264.7. According to our results, MCL plays an important role in modulating Mtb-induced inflammatory response through PI3K/Akt/NF-κB pathway and subsequently downregulating the activation of NLRP3 inflammasome. Therefore, MCL may represent as a potential drug candidate in the adjuvant treatment of TB by regulating host immune response.

Cyclovirobuxine D inhibits hepatocellular carcinoma growth by inducing ferroptosis of hepatocellular carcinoma cells.

OBJECTIVE: Hepatocellular carcinoma (HCC) is one cancer with high death rates. Nowadays, there are no effective drugs to treat it. Cyclovirobuxine D (CVB-D) is the primary ingredient of the traditional Chinese medicine (TCM) Buxus microphylla. Here, we try to explore the impacts of CVB-D on human HCC cells and explain the potential mechanisms. METHODS: HepG2 and Huh-7 cells were used for our experiments. The cell viability and half inhibitory concentration (IC50) were detected by MTT assays. The apoptosis ratio was examined by Annexin V-FITC/7AAD staining and flow cytometry (FCM). The Fe2+ content was examined by ferrous ion content assays. The malondialdehyde (MDA) content was evaluated by lipid peroxidation MDA assays. The reactive oxygen species (ROS) level was examined by the DCFH-DA probe. The expression of apoptotic markers (Bax and Bcl-2) and ferroptosis-related proteins (GPX4 and FSP1) was detected by western blotting. The in vivo curative effect of CVB was explored using xenograft models established in C-NKG mice. RESULTS: The cell viability could be inhibited by CVB-D in HepG2 and Huh-7 cells. The IC50 value of CVB-D on HepG2 and Huh-7 cells are 91.19 and 96.29 µM at 48 h, and 65.60 and 72.80 µM at 72 h. FCM showed that the apoptosis rate was increased by CVB-D in HepG2 and Huh-7 cells. Next, ferrous ion content assays showed that the level of Fe2+ was increased by CVB-D in HepG2 and Huh-7 cells. Then, we found the level of MDA and ROS was increased by CVB-D. And the Fe2+ promotion by CVB-D could be reversed by Fer-1. Additionally, western blotting assays showed that the expression of GPX4 and FSP1 was inhibited by CVB-D in HepG2 and Huh-7 cells. Moreover, in vivo, CVB-D displayed excellent anticancer effects in HCC tumor-bearing C-NKG mice. CONCLUSION: CVB-D suppresses the growth in HCC cells through ferroptosis.

Ginkgolide C inhibits ROS-mediated activation of NLRP3 inflammasome in chondrocytes to ameliorate osteoarthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba, as the most widely available medicinal plant worldwide, has been frequently utilized for treat cardiovascular, cerebrovascular, diabetic and other diseases. Due to its distinct pharmacological effects, it has been broadly applications in pharmaceuticals, health products, dietary supplements, and so on. Ginkgolide C (GC), a prominent extract of Ginkgo biloba, possesses potential in anti-inflammatory and anti-oxidant efficacy. AIMS OF THE STUDY: To determine whether GC mitigated the progressive degeneration of articular cartilage in a Monosodium Iodoacetate (MIA)-induced osteoarthritis (OA) rat model by inhibiting the activation of the NLRP3 inflammasome, and the specific underlying mechanisms. MATERIALS AND METHODS: In vivo, an OA rat model was established by intra-articular injection of MIA. The protective effect of GC (10 mg/kg) on articular cartilage was evaluated. Application of ATDC5 cells to elucidate the mechanism of the protective effect of GC on articular cartilage. Specifically, the expression levels of molecules associated with cartilage ECM degrading enzymes, OS, ERS, and NLRP3 inflammasome activation were analyzed. RESULTS: In vivo, GC ameliorated MIA-induced OA rat joint pain, and exhibited remarkable anti-inflammatory and anti- ECM degradation effects via inhibition of the activation of NLRP3 inflammasome, the release of inflammatory factors, and the expression of matrix-degrading enzymes in cartilage. Mechanically, GC inhibited the activation of NLRP3 inflammasome by restraining ROS-mediated p-IRE1α and activating Nrf2/NQO1 signal path, thereby alleviating OA. The ROS scavenger NAC was as effective as GC in reducing ROS production and inhibiting the activation of NLRP3 inflammasome. CONCLUSIONS: GC have exerted chondroprotective effects by inhibiting the activation of NLRP3 inflammasome.

Research on acupuncture and glial cells: A bibliometric analysis.

BACKGROUND: There are a growing number of studies on the effect of acupuncture on glial cells in the central nervous system; however, there are few related bibliometric analyses in this area. Therefore, the purpose of this bibliometric study was to visualize the literature on acupuncture-regulated glial cells. METHODS: On November 23, 2022, regular and review articles on acupuncture and glial cell-related research were retrieved from the Web of Science Core Collection database. The R package "bibliometrix" was used to summarize the main findings, count the occurrences of the top keywords, visualize the international collaboration network, and generate a 3-field plot. The VOSviewer software was used to conduct both co-authorship and co-occurrence analyses. CiteSpace was used to identify the best references and keywords with the highest citation rates. RESULTS: Overall, 348 publications on acupuncture and glial cells were included. The publications were primarily from China, Korea, and the United States of America. The majority of publications were found in relevant journals. Apart from "acupuncture" and "glial cells," the most frequently used keywords were "neuroinflammation," "hyperalgesia," and "pain." CONCLUSION: This bibliometric study mapped a fundamental knowledge structure comprising countries, institutions, authors, journals, and articles in the research fields of acupuncture and glial cells over the last 3 decades. These results provide a comprehensive perspective on the wider landscape of this research area.

Irisflorentin promotes bacterial phagocytosis and inhibits inflammatory responses in macrophages during bacterial infection.

Bacterial infection remains a big concern in the patients of ICU, which is the main cause of life-threatening organ dysfunction, or even sepsis. The poor control of bacterial infection caused by antibiotic resistance, etc. or the overwhelming immune response are the most important patho genic factors in intensive care unit (ICU) patients. As main pathogens, antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), impose serious challenges during sepsis and require alternative therapeutic options. Irisflorentin (IFL) is one of the major bioactive compounds isolated from the roots of Belamcanda chinensis (Shegan). In this study, IFL could suppress inflammatory response induced by MRSA or a synthetic mimic of bacterial lipoprotein (Pam3CSK4). IFL treatment enhanced the ability of macrophages to phagocytose bacteria likely through up-regulating the expression of phagocytic receptors SR-A1 and FcγR2a. Furthermore, IFL inhibited Pam3CSK4-induced production of pro-inflammatory cytokines, including IL-6 and TNF-α in Raw 264.7 cells, mouse primary macrophages or dendritic cells. IFL treatment also inhibited heat-killed MRSA-induced secretion of IL-6 and TNF-α in mouse bone marrow-derived macrophages. Moreover, IFL attenuated M1 polarization of macrophages as indicated by the down-regulated expression of its polarization markers CD86 and iNOS. Mechanistically, IFL markedly decreased the Pam3CSK4-induced activation of ERK, JNK or p38 MAPK pathways in macrophages. Taken together, IFL may serve as a promising compound for the therapy of bacterial infection, particularly those caused by antibiotic-resistant bacteria, such as MRSA.

Characterization techniques for tobacco and its derivatives: a systematic review.

Biomass and its derivatives have broad applications in the fields of bio-catalysis, energy storage, environmental remediation. The structure and components of biomass, which are vital parameters affecting corresponding performances of derived products, need to be fully understood for further regulating the biomass and its derivatives. Herein, tobacco is taken as an example of biomass to introduce the typical characterization techniques in unraveling the structural information, chemical components, and properties of biomass and its derivatives. Firstly, the structural information, chemical components and application for biomass are summarized. Then the characterization techniques together with the resultant structural information and chemical components are introduced. Finally, to promote a wide and deep study in this field, the perspectives and challenges concerning structure and composition charaterization in biomass and its derivatives are put forward.

Microbiologically induced calcite precipitation for in situ stabilization of heavy metals contributes to land application of sewage sludge.

Microbiologically induced calcite precipitation (MICP) has shed new light on solving the problem of in situ stabilization of heavy metals (HMs) in sewage sludge before land disposal. In this study, we examined whether MICP treatment can be integrated into a sewage sludge anaerobic digestion-land application process. Our results showed that MICP treatment not only prevented the transfer of ionic-state Cd from the sludge to the supernatant (98.46 % immobilization efficiency) but also reduced the soluble exchangeable Pb and Cd fractions by up to 100 % and 48.54 % and increased the residual fractions by 22.54 % and 81.77 %, respectively. In addition, the analysis of the stability of HMs in MICP-treated sludge revealed maximum reductions of 100 % and 89.56 % for TCLP-extractable Pb and Cd, respectively. Three-dimensional fluorescence, scanning electron microscopy-energy-dispersive X-ray spectroscopy, X-ray diffraction, and Fourier-transform infrared spectroscopy analyses confirmed the excellent performance of the ureolytic bacteria Sporosarcina ureilytica ML-2 in the sludge system. High-throughput sequencing showed that the relative abundance of Sporosarcina sp. reached 53.18 % in MICP-treated sludge, and the urease metabolism functional genes unit increased by a maximum of 239.3 %. The MICP technology may be a feasible method for permanently stabilizing HMs in sewage sludge before land disposal.

Dietary and Sexual Correlates of Gut Microbiota in the Japanese Gecko, Gekko japonicus (Schlegel, 1836).

Numerous studies have demonstrated that multiple intrinsic and extrinsic factors shape the structure and composition of gut microbiota in a host. The disorder of the gut microbiota may trigger various host diseases. Here, we collected fecal samples from wild-caught Japanese geckos (Gekko japonicus) and captive conspecifics fed with mealworms (mealworm-fed geckos) and fruit flies (fly-fed geckos), aiming to examine the dietary and sexual correlates of the gut microbiota. We used 16S rRNA gene sequencing technology to determine the composition of the gut microbiota. The dominant phyla with a mean relative abundance higher than 10% were Verrucomicrobiota, Bacteroidota, and Firmicutes. Gut microbial community richness and diversity were higher in mealworm-fed geckos than in wild geckos. Neither community evenness nor beta diversity of gut microbiota differed among wild, mealworm-fed, and fly-fed geckos. The beta rather than alpha diversity of gut microbiota was sex dependent. Based on the relative abundance of gut bacteria and their gene functions, we concluded that gut microbiota contributed more significantly to the host's metabolic and immune functions. A higher diversity of gut microbiota in mealworm-fed geckos could result from higher chitin content in insects of the order Coleoptera. This study not only provides basic information about the gut microbiota of G. japonicus but also shows that gut microbiota correlates with dietary habits and sex in the species.

Cytokine Storm in Acute Viral Respiratory Injury: Role of Qing-Fei-Pai-Du Decoction in Inhibiting the Infiltration of Neutrophils and Macrophages through TAK1/IKK/NF-[Formula: see text]B Pathway.

COVID-19 has posed unprecedented challenges to global public health since its outbreak. The Qing-Fei-Pai-Du decoction (QFPDD), a Chinese herbal formula, is widely used in China to treat COVID-19. It exerts an impressive therapeutic effect by inhibiting the progression from mild to critical disease in the clinic. However, the underlying mechanisms remain obscure. Both SARS-CoV-2 and influenza viruses elicit similar pathological processes. Their severe manifestations, such as acute respiratory distress syndrome (ARDS), multiple organ failure (MOF), and viral sepsis, are correlated with the cytokine storm. During flu infection, QFPDD reduced the lung indexes and downregulated the expressions of MCP-1, TNF-[Formula: see text], IL-6, and IL-1[Formula: see text] in broncho-alveolar lavage fluid (BALF), lungs, or serum samples. The infiltration of neutrophils and inflammatory monocytes in lungs was decreased dramatically, and lung injury was ameliorated in QFPDD-treated flu mice. In addition, QFPDD also inhibited the polarization of M1 macrophages and downregulated the expressions of IL-6, TNF-[Formula: see text], MIP-2, MCP-1, and IP-10, while also upregulating the IL-10 expression. The phosphorylated TAK1, IKK[Formula: see text]/[Formula: see text], and I[Formula: see text]B[Formula: see text] and the subsequent translocation of phosphorylated p65 into the nuclei were decreased by QFPDD. These findings indicated that QFPDD reduces the intensity of the cytokine storm by inhibiting the NF-[Formula: see text]B signaling pathway during severe viral infections, thereby providing theoretical and experimental support for its clinical application in respiratory viral infections.

Study on anaerobic co-digestion of municipal sewage sludge and fruit and vegetable wastes: Methane production, microbial community and three-dimension fluorescence excitation-emission matrix analysis.

Constantly increased sewage sludge (SS) and fruit and vegetable wastes (FVW) are becoming the major organic solid wastes in human society. Thus, anaerobic digestion is employed as a low carbon energy strategy to reduce their environmental pollution risk. Anaerobic co-digestion system was developed based on the carbon to nitrogen ratio strategy. Results showed that the daily biogas production was higher in co-digester, and the volumetric biogas production rate (VBPR) significantly enhanced for 1.3 âˆ¼ 3 folds, and the highest VBPR was 2.04 L/L • day with optimal OLR of 2.083 Kg L-1 d-1. Analytic results indicated that co-digestion could improve the biodegradable of feedstocks, which transforming to more VFAs and biogas. Compared with mono SS digester, mixed substrates relieved ammonia nitrogen inhibition and enhanced the hydrolytic acidification and methanogenesis. Meanwhile, the excessive humification of organics was suppressed. This study supported the concepts of improving carbon recovery from SS and FVW.

Improvement of sewage sludge anaerobic digestion through synergistic effect combined trace elements enhancer with enzyme pretreatment and microbial community response.

In this study, a double E strategy (enzymes and enhancer) characterized by high efficiency for enhancing sewage sludge anaerobic digestion (AD) is proposed. This strategy combines addition of trace elements (TEs) enhancer and enzyme pretreatment, inducing a synergistic effect on AD, and it is more effective and economical compared with TEs addition or enzyme pretreatment in isolation. When adding 400 U/g cocktail enzymes and 1.24% trance elements enhancers, the cumulative methane production and the maximum daily methane increased yield by 45.29% and 84.7%, respectively. According to microbial community analysis, the double E strategy significantly motivate the growth of acetogens and protein fermenting bacterium. The relative abundance of Fermentimonas and Lutispora increased by 6.15% and 5.4%, respectively. Archaeal community analysis and changes in the mcrA gene abundance demonstrate enrichment of hydrogenotrophic methanogens, with the methanogens exhibiting high vitalities and stress resistance. The double E strategy could be a promising way to improve industrial sewage sludge AD efficiency.

Analyses of deodorization performance of mixotrophic biotrickling filter reactor using different industrial and agricultural wastes as packing material.

In this study, to efficiently remove malodorous gas and reduce secondary pollution under mixotrophic conditions, pine bark, coal cinder, straw and mobile bed biofilm reactor (MBBR) fillers were used as packing materials in a biological trickling filter (BTF) to simultaneously treat high-concentration H2S and NH3. The results showed that the removal rate of BTF-A filled with pine bark was the highest, which was 86.31% and 94.06% under the H2S and NH3 loading rates of 53.59 g/m³·h while the empty bed residence time (EBRT) was 40.5 s. The theoretical maximum load was obtained by fitting the kinetic curve, and the value were 90.09 g H2S m-³·h-1 and 172.41 g NH3 m-³·h-1. Meanwhile, after treating with 720 ppm of NH3, the average concentration of NO3- in the BTF circulating fluid was only 127.58 mg/L, indicating the better performance of secondary pollutants control. Microbiological analysis showed that Dokdonella, Micropruina, Candidatus_Alysiosphaera, Nakamurella and Thiobacillus possessed high abundance at the genus level, and their entire percentage in four BTF reactors were 62.87%, 46.32%, 47.98%, and 57.35% respectively. It is worthwhile that the genera Comamonas and Trichococcus with heterotrophic nitrification and aerobic denitrification capabilities and proportion of 3.66%, 1.45%, 5.43%, and 3.23% were observed in four reactors.

Secoeudesma sesquiterpenes lactone A alleviates inflammation and offers adjuvant protection in severe infection of carbapenem-resistant Klebsiella pneumoniae.

ETHNOPHARMACOLOGICAL RELEVANCE: Secoeudesma sesquiterpenes lactone A (SESLA) is a sesquiterpene compound isolated from Inula japonica Thunb. (I. japonica). It is an herb widely distributed in Asian countries often used for the treatment of various conditions including tumors, bronchitis and bacterial and viral infections. It has been reported that SESLA could significantly inhibit the production of nitric oxide (NO) by lipopolysaccharide (LPS) in Raw264.7 cells. However, the mechanism responsible for this anti-inflammatory role and its role in the treatment of antibiotic-resistant bacterial infection, e.g., carbapenem-resistant Klebsiella pneumoniae (CRKP), remain to be investigated. AIM OF THE STUDY: This study was carried out to investigate the protective anti-inflammatory role and the underlying molecular mechanisms of SESLA in LPS or CRKP evoked inflammation. MATERIALS AND METHODS: ELISA and PCR were utilized to detect the expression of inflammatory mediators in LPS or heat-killed CRKP (HK CRKP)-stimulated immune cells containing different concentrations of SESLA. The protective role of SESLA was observed in mice challenged with a lethal dose of CRKP. Mice were intraperitoneally injected with CRKP to create a septic mouse model to evaluate the protective role of SESLA in vivo. Phosphorylated proteins, which represented the activation of signaling pathways, were examined by Western blot. RESULTS: SESLA was showed to inhibit the expression of inflammatory mediators in various macrophages and dendritic cells upon stimulation of LPS or HK CRKP. It also facilitated phagocytosis of bacteria by Raw264.7 cells. The combined use of SELSA and the ineffective antibiotic, meropenem, increased the survival rate of CRKP infected mice from 25% to 50%. ERK, NF-κB and PI3K/Akt pathways accounted for the anti-inflammatory role of SESLA with the stimulation of LPS. CONCLUSION: According to the notable anti-inflammatory effect in vitro and its joint protective effects on a septic mouse model, SESLA might act as an adjuvant drug candidate for sepsis, even those caused by antibiotic-resistant bacteria, e.g., CRKP.

Baicalin protects mice from infection with methicillin-resistant Staphylococcus aureus via alleviating inflammatory response.

Sepsis was redefined as life-threatening organ dysfunction caused by a dysregulated host response to infection in 2016. One of its most common causes is Staphylococcus aureus, especially methicillin-resistant Staphylococcus aureus (MRSA), which leads to a significant increase in morbidity and mortality. Therefore, innovative and effective approaches to combat MRSA infection are urgently needed. Recently, host-directed therapy (HDT) has become a new strategy in the treatment of infectious diseases, especially those caused by antibiotic-resistant bacteria. Baicalin (BAI) is the predominant flavonoid and bioactive compound isolated from the roots of Radix Scutellariae (Huang Qin), a kind of traditional Chinese medicine. It has been reported that BAI exhibits multiple biological properties such as anti-oxidant, antitumor, and anti-inflammatory activities. However, the therapeutic role of BAI in MRSA infection is still unknown. In this study, it is found that BAI treatment inhibited the production of IL-6, TNF-α, and other cytokines from MRSA- or bacterial mimics-stimulated Mϕs and dendritic cells (DCs). BAI played an anti-inflammatory role by inhibiting the activation of ERK, JNK MAPK, and NF-κB pathways. Moreover, the serum level of TNF-α was decreased, whereas IL-10 was increased, in mice injected with MRSA. Furthermore, the bacterial load in livers and kidneys were further decreased by the combination of BAI and vancomycin (VAN), which might account for the amelioration of tissue damage. BAI reduced the high mortality rate caused by MRSA infection. Collectively, the results suggested that BAI may be a viable candidate of HDT strategy against severe sepsis caused by antibiotic-resistant bacteria such as MRSA.

Xuebijing Injection Alleviates Pam3CSK4-Induced Inflammatory Response and Protects Mice From Sepsis Caused by Methicillin-Resistant Staphylococcus aureus.

A leading cause of death worldwide is sepsis that develops as a dysregulated immune response to infection. Serious infection caused by methicillin-resistant Staphylococcus aureus (MRSA) increases the difficulty of treatment in septic patients. Host-directed therapy (HDT) is an emerging approach to bacterial infections. Xuebijing injection (XBJ), a commercialized injectable prescription from traditional Chinese medicine, has been used as adjuvant therapy for sepsis with a history of 15 years. Whether it plays a protective role in severe infection caused by antibiotic-resistant bacteria is still unknown. In this study, XBJ significantly improved the survival of MRSA-induced sepsis mice. In MRSA-infected mouse model, XBJ down-regulated the expression of inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, MCP-1, MIP-2, and IL-10 in sera. Besides that, it decreased the bacterial load in spleens, livers, and alleviated tissue damage of lung, liver, and kidney. The combination of XBJ with vancomycin or dexamethasone exhibited a better down-regulatory role of the inflammatory response. Then, the protective mechanism of XBJ was further investigated. XBJ inhibited heat-killed MRSA-induced IL-6 and TNF-α production in mouse macrophages. XBJ also decreased Pam3CSK4 (a synthetic tripalmitoylated lipopeptide mimicking bacterial lipoproteins)-stimulated expression of IL-6, TNF-α, IL-1ß, IL-12, etc. in mouse macrophages. Furthermore, XBJ down-regulated the activation of NF-κB, MAPK, and PI3K/Akt pathways in Pam3CSK4-stimulated mouse macrophages. In conclusion, our findings demonstrated that XBJ played a protective role in MRSA-challenged mice and down-regulated the inflammatory response and the activation of signaling pathways initiated by Pam3CSK4. It enlarged the clinical application of XBJ in the treatment of severe bacterial infection, e.g. caused by MRSA.

Ephedrine hydrochloride protects mice from staphylococcus aureus-induced peritonitis.

Staphylococcus aureus is a Gram-positive (G+) bacterium that causes a wide range of diseases in humans and livestock. Therefore, the development of innovative and effective therapies is essential for the treatment of S. aureus-induced severe infections. Ephedrine hydrochloride (EH) is a compound derived from ephedrine and is widely used for the management of cardiovascular diseases and hypotension. The results of our previous studies demonstrated that EH has anti-inflammatory activity in macrophages and protects against endotoxic shock. However, whether EH regulates the function of dendritic cells (DCs) and the immune response in S. aureus-induced infection is unknown. In this study, the anti-inflammatory and regulatory activity of EH on DCs was evaluated. EH increased the production of anti-inflammatory cytokine IL-10 and decreased the production of proinflammatory cytokines TNF-α and IL-12 in DCs stimulated with peptidoglycan (PGN), the main cell wall component in G+ bacteria. The PI3K/Akt and p38 MAPK signaling pathways controlled EH-induced IL-10 expression and EH-inhibited TNF-α expression, respectively. The PGN-induced expression of co-stimulatory molecules CD40, CD80, CD86, and MHC class II molecule Iab was down-regulated in DCs by EH. Furthermore, EH protected the liver and kidney and increased the survival rate of mice with S. aureus-induced peritonitis. In conclusion, EH helps to keep immune homeostasis and alleviate organ damage during S. aureus-induced peritonitis. Therefore, EH may be a promising drug candidate in the treatment of S. aureus-induced severe infections and other invasive G+ bacterial infections.