Guided by molecular networking, nine novel curvularin derivatives (1-9) and 16 known analogs (10-25) were isolated from the hydrothermal vent sediment fungus Penicillium sp. HL-50. Notably, compounds 5-7 represented a hybrid of curvularin and purine. The structures and absolute configurations of compounds 1-9 were elucidated via nuclear magnetic resonance (NMR) spectroscopy, X-ray diffraction, electronic circular dichroism (ECD) calculations, ¹³C NMR calculation, modified Mosher's method, and chemical derivatization. Investigation of anti-inflammatory activities revealed that compounds 7-9, 11, 12, 14, 15, and 18 exhibited significant suppressive effects against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in murine macrophage RAW264.7 cells, with IC₅₀ values ranging from 0.44 to 4.40 μmol·L^-1. Furthermore, these bioactive compounds were found to suppress the expression of inflammation-related proteins, including inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), NLR family pyrin domain-containing protein 3 (NLRP3), and nuclear factor kappa-B (NF-κB). Additional studies demonstrated that the novel compound 7 possessed potent anti-inflammatory activity by inhibiting the transcription of inflammation-related genes, downregulating the expression of inflammation-related proteins, and inhibiting the release of inflammatory cytokines, indicating its potential application in the treatment of inflammatory diseases.
Penicillium/chemistry* ; Mice ; Animals ; Anti-Inflammatory Agents/isolation & purification* ; RAW 264.7 Cells ; Nitric Oxide/metabolism* ; Hydrothermal Vents/microbiology* ; Macrophages/immunology* ; Molecular Structure ; Nitric Oxide Synthase Type II/immunology* ; Cyclooxygenase 2/immunology* ; Geologic Sediments/microbiology* ; NF-kappa B/immunology* ; NLR Family, Pyrin Domain-Containing 3 Protein/immunology*

Humans ; Aged ; Lung Diseases ; Pneumonia/drug therapy* ; Adrenal Cortex Hormones/therapeutic use* ; Pulmonary Disease, Chronic Obstructive/drug therapy* ; Administration, Inhalation ; Community-Acquired Infections/drug therapy*

Objective To investigate the improvement effect and mechanism of Modified Kongsheng Zhenzhong Dan medicated serum on mitochondrial function of PC12 cells injured by oxygen-glucose deprivation/reperfusion(OGD/R)based on the SIRT1/PGC-1α pathway.Methods PC12 cells were used to construct OGD/R cell model in vitro.Cell grouping:normal group(10%FBS),model group(10%FBS),10%drug-containing serum group,5%drug-containing serum group(5%drug-containing serum+5%blank serum),10%blank serum group(control group).CCK-8 method was used to detect the cell survival rate,and the appropriate oxygen glucose deprivation time(2,4,6,8 hours)was screened.MTT assay was used to detect cell activity;mitochondrial stress test(MST)was used to detect the oxygen consumption rate(OCR).Apoptosis was detected by flow cytometry(Annexin V-PE/7-AAD double staining).The protein expression levels of SIRT1 and PGC-1α in PC12 cells were detected by Western Blot.Results Compared with the normal group,the activity of PC12 cells decreased significantly after oxygen-glucose deprivation for 2,4,6 and 8 hours(P＜0.05),and 6 hours of oxygen-glucose deprivation was selected as the time of subsequent experimental modeling.Compared with the normal group,the cell activity of the model group was significantly decreased(P＜0.05).The OCR values of basic respiration value,maximum respiration value,proton leakage,ATP production and standby respiration ability were significantly decreased(P＜0.05).The apoptosis rate was significantly increased(P＜0.05).The protein expression levels of SIRT1 and PGC-1α in cells were significantly decreased(P＜0.05).Compared with the model group,the cell activity of the Modified Kongsheng Zhenzhong Dan 10%and 5%drug-containing serum groups was significantly increased(P＜0.05).The OCR values of basal respiration value,maximum respiration value,proton leakage,ATP production and spare breathing ability were significantly increased(P＜0.05).The apoptosis rate was significantly decreased(P＜0.05).The protein expression levels of SIRT1 and PGC-1α in cells were significantly increased(P＜0.05).Conclusion The Modified Kongsheng Zhenzhong Dan medicated serum can improve mitochondrial dysfunction,inhibit neuronal apoptosis and promote neuronal survival in OGD/R-injured PC12 cells.The mechanism may be related to the activation of SIRT1/PGC-1α signaling pathway.

Objective:To investigate the value of sedation in colonoscopy.Methods:A retrospective cohort study of colonoscopy procedures was performed in our institution. Inclusion criteria: (1) colonoscopy procedures were performed by well-trained gastrointestinal surgeons our institution; (2) medical records were complete and colonoscopy was documented properly by notes, videos, photographs, and traceable pathological reports. Those with incomplete records or performed in other institution were excluded. According to above criteria, clinical data of 49 057 cases of clinic and hospitalization receiving diagnostic or therapeutic colonoscopyat Department of Gastric and Colorectal Surgery, Daping Hospital from July 2007 to February 2017 were collected. Among them, there were 24 638 (50.2%) males and 24 419 females, with mean age of (50.6±14.1) (4 to 98) years. Based on the application of sedation during colonoscopy, patients were divided into the sedation group (39 412 cases, 80.3%) and the non-sedation group (9 645 cases, 19.7%). Clinical characteristics of two groups were compared.Results:The sedation rate increased from 45.6% (369/810) to 94.8% (917/967) from 2007 to 2017. As compared to non-sedation group, a higher proportion of females [51.0% (20 095/39 412) vs. 44.8% (4 324/9 645), χ 2=117.422, P<0.001] and younger median age (50.0 years vs. 51.0 years, Z=-4.774, P<0.001) were found in the sedation group, whose differences were statistically significant. In all the 9645 cases in the non-sedation group, about 5.5% (534) of them terminated the examination because of unbearable discomfort, including 244 (4.6%) males and 290 (6.7%) females (χ 2=20.522, P<0.001). Among all the screening population who were ≥50 years old, there was no significant difference in the polyp detection rate (PDR) between the sedation group and the non-sedation group [26.7% (4 737/17 753) vs. 27.4% (1 093/3 984), χ 2=0.937, P=0.330]. The cecal intubation rate (CIR) in the sedation group was significantly higher than that in the non-sedation group [(85.2% (14 422/16 933) vs. 76.1% (2 803/3 682), χ 2=180.032, P<0.001]. Five cases in the sedation group developed iatrogenic colonic perforation (ICP), with none in the non-sedation group. Conclusions:The application of sedation in colonoscopy is increasingly popular. Sedation can significantly improve CIR in colonoscopy, while it has no positive influence on PDR. Meanwhile, sedation increases the medical expense and may result in higher ICP rate.

Objective:To investigate the value of sedation in colonoscopy.Methods:A retrospective cohort study of colonoscopy procedures was performed in our institution. Inclusion criteria: (1) colonoscopy procedures were performed by well-trained gastrointestinal surgeons our institution; (2) medical records were complete and colonoscopy was documented properly by notes, videos, photographs, and traceable pathological reports. Those with incomplete records or performed in other institution were excluded. According to above criteria, clinical data of 49 057 cases of clinic and hospitalization receiving diagnostic or therapeutic colonoscopyat Department of Gastric and Colorectal Surgery, Daping Hospital from July 2007 to February 2017 were collected. Among them, there were 24 638 (50.2%) males and 24 419 females, with mean age of (50.6±14.1) (4 to 98) years. Based on the application of sedation during colonoscopy, patients were divided into the sedation group (39 412 cases, 80.3%) and the non-sedation group (9 645 cases, 19.7%). Clinical characteristics of two groups were compared.Results:The sedation rate increased from 45.6% (369/810) to 94.8% (917/967) from 2007 to 2017. As compared to non-sedation group, a higher proportion of females [51.0% (20 095/39 412) vs. 44.8% (4 324/9 645), χ 2=117.422, P<0.001] and younger median age (50.0 years vs. 51.0 years, Z=-4.774, P<0.001) were found in the sedation group, whose differences were statistically significant. In all the 9645 cases in the non-sedation group, about 5.5% (534) of them terminated the examination because of unbearable discomfort, including 244 (4.6%) males and 290 (6.7%) females (χ 2=20.522, P<0.001). Among all the screening population who were ≥50 years old, there was no significant difference in the polyp detection rate (PDR) between the sedation group and the non-sedation group [26.7% (4 737/17 753) vs. 27.4% (1 093/3 984), χ 2=0.937, P=0.330]. The cecal intubation rate (CIR) in the sedation group was significantly higher than that in the non-sedation group [(85.2% (14 422/16 933) vs. 76.1% (2 803/3 682), χ 2=180.032, P<0.001]. Five cases in the sedation group developed iatrogenic colonic perforation (ICP), with none in the non-sedation group. Conclusions:The application of sedation in colonoscopy is increasingly popular. Sedation can significantly improve CIR in colonoscopy, while it has no positive influence on PDR. Meanwhile, sedation increases the medical expense and may result in higher ICP rate.

A multicenter blinded randomized controlled trial (RCT) was conducted in accordance with international clinical trial standards to evaluate the efficacy and safety of Xuebijing injection in the treatment of severe community-acquired pneumonia (SCAP) under strict quality control condition. This article aims to illustrate key contents of the design ideas and implementation process of the RCT of Xuebijing injection in the treatment of SCAP, including the selection of research objects, design, implementation, and insights, etc., share experience with researchers of the respiratory and critical care, and provide reference for future studies in critical care.

In the original publication, the label of Fig. 2C should be read as "GFAP/lectin/DAPI" not "DMP1/GFAP/lectin/DAPI".

The blood-brain barrier (BBB) is a tight boundary formed between endothelial cells and astrocytes, which separates and protects brain from most pathogens as well as neural toxins in circulation. However, detailed molecular players involved in formation of BBB are not completely known. Dentin matrix protein 1 (DMP1)-proteoglycan (PG), which is known to be involved in mineralization of bones and dentin, is also expressed in soft tissues including brain with unknown functions. In the present study, we reported that DMP1-PG was expressed in brain astrocytes and enriched in BBB units. The only glycosylation site of DMP1 is serine89 (S89) in the N-terminal domain of the protein in mouse. Mutant mice with DMP1 point mutations changing S89 to glycine (S89G), which completely eradicated glycosylation of the protein, demonstrated severe BBB disruption. Another breed of DMP1 mutant mice, which lacked the C-terminal domain of DMP1, manifested normal BBB function. The polarity of S89G-DMP1 astrocytes was disrupted and cell-cell adhesion was loosened. Through a battery of analyses, we found that DMP1 glycosylation was critically required for astrocyte maturation both in vitro and in vivo. S89G-DMP1 mutant astrocytes failed to express aquaporin 4 and had reduced laminin and ZO1 expression, which resulted in disruption of BBB. Interestingly, overexpression of wild-type DMP1-PG in mouse brain driven by the nestin promoter elevated laminin and ZO1 expression beyond wild type levels and could effectively resisted intravenous mannitol-induced BBB reversible opening. Taken together, our study not only revealed a novel element, i.e., DMP1-PG, that regulated BBB formation, but also assigned a new function to DMP1-PG.
Animals ; Astrocytes ; cytology ; metabolism ; Blood-Brain Barrier ; cytology ; metabolism ; Cells, Cultured ; Extracellular Matrix Proteins ; genetics ; metabolism ; Female ; Glycosylation ; Male ; Mice ; Proteoglycans ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction

Aging associated cognitive decline has been linked to dampened neural stem/progenitor cells (NSC/NPCs) activities manifested by decreased proliferation, reduced propensity to produce neurons, and increased differentiation into astrocytes. While gene transcription changes objectively reveal molecular alterations of cells undergoing various biological processes, the search for molecular mechanisms underlying aging of NSC/NPCs has been confronted by the enormous heterogeneity in cellular compositions of the brain and the complex cellular microenvironment where NSC/NPCs reside. Moreover, brain NSC/NPCs themselves are not a homogenous population, making it even more difficult to uncover NSC/NPC sub-type specific aging mechanisms. Here, using both population-based and single cell transcriptome analyses of young and aged mouse forebrain ependymal and subependymal regions and comprehensive "big-data" processing, we report that NSC/NPCs reside in a rather inflammatory environment in aged brain, which likely contributes to the differentiation bias towards astrocytes versus neurons. Moreover, single cell transcriptome analyses revealed that different aged NSC/NPC subpopulations, while all have reduced cell proliferation, use different gene transcription programs to regulate age-dependent decline in cell cycle. Interestingly, changes in cell proliferation capacity are not influenced by inflammatory cytokines, but likely result from cell intrinsic mechanisms. The Erk/Mapk pathway appears to be critically involved in regulating age-dependent changes in the capacity for NSC/NPCs to undergo clonal expansion. Together this study is the first example of using population and single cell based transcriptome analyses to unveil the molecular interplay between different NSC/NPCs and their microenvironment in the context of the aging brain.
Aging ; genetics ; Animals ; Astrocytes ; cytology ; metabolism ; Brain ; cytology ; metabolism ; Cell Differentiation ; genetics ; Cell Division ; genetics ; Cell Proliferation ; genetics ; Gene Expression Regulation ; genetics ; Mice ; Neural Stem Cells ; metabolism ; Single-Cell Analysis ; Stem Cells ; cytology ; metabolism ; Transcriptome ; genetics

OBJEVTIVETo study the effect of spvB/spvC gene on Salmonella virulence and the Host immune.

METHODSSTM.211, STM.211-Delta;spvB, STM.211-Delta;spvC, STM.211-Delta;spvB.spvC and PBS were infected with 0.2 mL 10(5) CFU corresponding strain respectively by intraperitoneal. We observed the mental status, movement, diarrhea, weight, pelage changed hair of the infected mouse. Then the level of IL-10, IL-12, IFN-γ were detected by ELISA. Finally, we observe the pathological changes of liver and spleen with the general view and the microscope.

RESULTSInfection symptoms of STM.211, STM.211-Delta;spvB and STM.211-Delta;spvC were significantly worse than PBS group, but there was no significant difference between STM.211-spvB.spvC group and PBS group. The secretion of IFN-γ and IL-12 of STM.211, STM.211-Delta;spvB, STM.211-Delta;spvC group were significantly lower than those in the STM.211-Delta;spvB.spvC group (P<0.05), but IL-10 secretion was significantly higher than STM.211-Delta;spvB.spvC group (P<0.05). There were no statistical significance among the STM.211, STM.211-Delta;SpvB, STM.211-Delta;spvC groups (P>0.05).

CONCLUSIONSSalmonella virulence can be affected obviously by spvB combined with spvC gene, but not by spvB or spvC. spvB/spvC gene can inhibit the TH1 cytokines (IFN-γ and IL-12) secretion but promote the TH2 cytokines (IL-10) expression, leading immune response trend to TH2 shift. It shows that spvB/spvC gene can help the bacteria evade the host immune defenses, leading to aggravation of infection.

Animals ; Cytokines ; immunology ; Interleukin-12 ; Mice ; Salmonella ; genetics ; pathogenicity ; Salmonella Infections ; immunology ; Virulence ; Virulence Factors ; genetics