Upregulation of rate-limiting enzymes in cholesterol metabolism by PKCδ mediates endothelial apoptosis in diabetic wound healing.

Diabetic foot ulcer (DFU) is a prevalent complication of diabetes that poses significant challenges in terms of treatment and management. It is characterized by heightened endothelial apoptosis and impaired angiogenesis. In this study, we aimed to investigate the role of protein kinase Cδ (PKCδ) in regulating endothelial apoptosis in diabetic wounds by promoting cholesterol biosynthesis. The expression of PKCδ was increased in human umbilical vascular endothelial cells (HUVECs) cultivated in high glucose medium and skin tissue isolated from diabetic mice. High glucose-induced HUVECs apoptosis was reduced by PKCδ inhibition with siRNA or rottlerin. RNA-seq identified two enzymes, 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), as the downstream of PKCδ. PKCδ knockdown or inhibition suppressed the expression of HMGCS1 and HMGCR and lowered free cholesterol (FC) levels. Cholesterol restored high glucose-induced apoptosis in siRNA- or rottlerin-treated HUVECs. In vivo use of rosuvastatin calcium, an inhibitor of HMGCR, downregulated free cholesterol levels and accelerated the wound healing process. In conclusion, PKCδ expression in endothelial cells was activated by high glucose, which subsequently upregulates the expression of two enzymes catalyzing cholesterol biosynthesis, HMGCS1 and HMGCR. Enhanced cholesterol biosynthesis raises free cholesterol levels, promotes endothelial apoptosis, and finally delays wound healing.

Association Between Long-Term Exposure to Ambient Air Pollution and the Risk of Mild Cognitive Impairment in a Chinese Urban Area: A Case-Control Study.

Background: As a prodromal stage of dementia, significant emphasis has been placed on the identification of modifiable risks of mild cognitive impairment (MCI). Research has indicated a correlation between exposure to air pollution and cognitive function in older adults. However, few studies have examined such an association among the MCI population inChina. Objective: We aimed to explore the association between air pollution exposure and MCI risk from the Hubei Memory and Aging Cohort Study. Methods: We measured four pollutants from 2015 to 2018, 3 years before the cognitive assessment of the participants. Logistic regression models were employed to calculate odds ratios (ORs) to assess the relationship between air pollutants and MCI risk. Results: Among 4,205 older participants, the adjusted ORs of MCI risk for the highest quartile of PM2.5, PM10, O3, and SO2 were 1.90 (1.39, 2.62), 1.77 (1.28, 2.47), 0.56 (0.42, 0.75), and 1.18 (0.87, 1.61) respectively, compared with the lowest quartile. Stratified analyses indicated that such associations were found in both males and females, but were more significant in older participants. Conclusions: Our findings are consistent with the growing evidence suggesting that air pollution increases the risk of mild cognitive decline, which has considerable guiding significance for early intervention of dementia in the older population. Further studies in other populations and broader geographical areas are warranted to validate these findings.

Description and genomic characterization of Cohnella caldifontis sp. nov., isolated from hot springs in Yunnan province, south-west China.

A bacterial strain, Gram staining positive, strictly aerobic, rod-shaped, motile bacterium with flagellum and endospore-forming, designated strain YIM B05605T, was isolated from soil sampled in Hamazui hot springs, Tengchong City, Yunnan province, China. Optimum growth for the strain occurred at pH 7.0 and 45 °C. MK-7 was the main menaquinone in the strain YIM B05605T. The diagnostic diamino acid in the cell-wall peptidoglycan was meso-diaminopimelic acid. Diphosphatidylglycerol (DPG), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), phosphatidylmonomethylethanolamine (PME), unidentified glycolipid (GL), three unknown aminophospholipids (APLs) and unidentified polarlipid (PL) were part of the polar lipid profile. The major fatty acids were anteiso-C15:0 and iso-C16:0. The DNA G + C content of the type strain was 58.76%. Genome-based phylogenetic analysis confirmed that strain YIM B05605T formed a distinct phylogenetic cluster within the genus Cohnella. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values of strain YIM B05605T with the most related species C. fontinalis YT-1101T were 73.42% and 15.7%. Functional analysis by NR, Swiss-prot, Pfam, eggNOG, GO, KEGG databases revealed that strain YIM B05605T has 13 genes related to the sulfur cycle, 2 genes related to the nitrogen cycle. Based on phylogenomic and phylogenetic analyses coupled with phenotypic and chemotaxonomic characterizations, strain YIM B05605T could be classified as a novel species of the genus Cohnella, for which the name Cohnella caldifontis sp. nov., is proposed. The type strain is YIM B05605T (= CGMCC 1.60052T = KCTC 43462T = NBRC 115921T).

Safety and Efficacy of Endovascular Aortic Repair for Abdominal Aortic Aneurysms with a Hostile Neck Anatomy.

OBJECTIVE: This study aimed to investigate the safety and efficacy of endovascular aortic repair (EVAR) for the treatment of an abdominal aortic aneurysm (AAA) with a hostile neck anatomy (HNA). METHODS: From January 1, 2015 to December 31, 2019, a total of 259 patients diagnosed with an AAA who underwent EVAR were recruited into this study. Based on the morphological characteristics of the proximal neck anatomy, the patients were divided into the HNA group and the friendly neck anatomy (FNA) group. The patients were followed up for up to 4 years. RESULTS: The average follow-up time was 1056.1±535.5 days. Type I endoleak occurred in 4 patients in the HNA group, and 2 patients in the FNA group. Neither death nor intraoperative switch to open repair occurred in either group. The time of the operation was significantly longer in the HNA group (FNA vs. HNA, 99.2±51.1 min vs. 117.5±63.8 min, P=0.011). There were no significant differences in short-term clinical success rate (P=0.228) or midterm clinical success rate (P=0.889) between the two groups. The overall mortality rate was 10.4%, and Kaplan-Meier survival analysis indicated that the two groups had similar cumulative survival rates at the end of the follow-up period (P=0.889). CONCLUSION: EVAR was feasible and safe in patients with an AAA with a proximal HNA. The early and midterm results were promising; however, further studies are needed to verify the long-term effectiveness of EVAR.

Ocular manifestations and quality of life in patients after hematopoietic stem cell transplantation.

AIM: To explore the relationship between ocular and systemic conditions and the impact of ocular complications on the quality of life (QOL) in patients after allogeneic hematopoietic stem cell transplantation (ALLO-HSCT). METHODS: Forty-four patients with severe hematopoietic disease were enrolled after ALLO-HSCT at our center from July 2018 to October 2020. They completed two questionnaires: the Ocular Surface Disease Index (OSDI) and the quality-of-life scale for Chinese patients with visual impairment (SQOL-DV1). Ocular conditions and systemic conditions were also assessed. RESULTS: Eye damage was correlated with total bilirubin (P=0.005), and gamma-glutamyl transferase (GGT) (P=0.021). There was no significant correlation between the overall QOL score and OSDI (P=0.8226) or SQOL-DV1 (P=0.9526) scores. The OSDI and the overall QOL score were not correlated with ocular conditions, including best-corrected visual acuity (BCVA), intraocular pressure, Schirmer tear test II, sodium fluorescein staining, tear film breakup time, and tear meniscus height. SQOL-DV1 was correlated with BCVA (P=0.0007), sodium fluorescein staining (P=0.007), and tear film breakup time (P=0.0146). CONCLUSION: In some patients, early ocular symptoms are not evident after ALLO-HSCT, while ocular surface complications can be observed after a comprehensive ophthalmological examination. Especially for those with elevated total bilirubin or GGT, regular ophthalmic follow-up visits are essential to diagnose and treat ocular graft versus host disease (oGVHD), especially for patients with elevated total bilirubin or GGT.

A nomogram model for predicting ocular GVHD following allo-HSCT based on risk factors.

OBJECTIVE: To develop and validate a nomogram model for predicting chronic ocular graft-versus-host disease (coGVHD) in patients after allogenic haematopoietic stem cell transplantation (allo-HSCT). METHODS: This study included 61 patients who survived at least 100 days after allo-HSCT. Risk factors for coGVHD were screened using LASSO regression, then the variables selected were subjected to logistic regression. Nomogram was established to further confirm the risk factors for coGVHD. Receiver operating characteristic (ROC) curves were constructed to assess the performance of the predictive model with the training and test sets. Odds ratios and 95% confidence intervals (95% CIs) were calculated by using logistic regression analysis. RESULTS: Among the 61 patients, 38 were diagnosed with coGVHD. We selected five texture features: lymphocytes (LYM) (OR = 2.26), plasma thromboplastin antecedent (PTA) (OR = 1.19), CD3 + CD25 + cells (OR = 1.38), CD3 + HLA-DR + cells (OR = 0.95), and the ocular surface disease index (OSDI) (OR = 1.44). The areas under the ROC curve (AUCs) of the nomogram with the training and test sets were 0.979 (95% CI, 0.895-1.000) and 0.969 (95% CI, 0.846-1.000), respectively.And the Hosmer-Lemeshow test was nonsignificant with the training (p = 0.9949) and test sets (p = 0.9691). CONCLUSION: We constructed a nomogram that can assess the risk of coGVHD in patients after allo-HSCT and help minimize the irreversible loss of vision caused by the disease in high-risk populations.

Paenibacillus hamazuiensis sp. nov., a bacterium isolated from Hamazui hot spring in Yunnan province, south-west China.

A bacterial strain, Gram-positive, aerobic, rod-shaped, motile, designated YIM B00624T which was isolated from a Hamazui hot spring in Tengchong, Yunnan province, south-west China. The strain grew well on International Streptomyces Project (ISP) 2 medium and colonies were creamy yellow, flat and circular. The results of 16S rRNA gene sequence similarity analysis showed that strain YIM B00624T was closely related to the type strain of Paenibacillus filicis S4T (95.9%). The main menaquinone of strain YIM B00624T was menaquinone-7 (MK-7) and major fatty acids were anteiso-C15:0, anteiso-C17:0 and C16:0. The isolate contained meso-diaminopimelic acid as the diagnostic diamino acid and the major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylmonomethylethanolamine and four unidentified glycolipids. The DNA G+C content of strain YIM B00624T was 53.4 mol%. Based on physiological, phenotypic and chemotaxonomic data, strain YIM B00624T belongs to a novel species of the genus Paenibacillus, for which the name Paenibacillus hamazuiensis sp. nov. is proposed. The type strain is YIM B00624T (= CGMCC 1.19245T = KCTC 43365T).

A Pooled Analysis of the PCR for the Detection of Candida Auris.

BACKGROUND: Candida auris is an opportunistic pathogen with multiple drug resistance. Therefore, researchers conducted a meta-analysis to review PCR's ability to diagnose Candida auris to promote the development of accurate Candida auris diagnosis. METHODS: Researchers systematically retrieved relevant articles from PubMed, Cochrane Library, Embase, and Web of Science. Then, researchers extracted the key data required for the study from the selected articles. Meta-DiSc 1.4 was used for the statistical analysis. RevMan 5.3 was employed to assess the quality of the included literature. A funnel plot can appraise whether the included articles have publication bias. RESULTS: Five articles were included in the study. The results suggest that the pooled sensitivity and pooled specificity were 0.94 (95% CI: 0.92 - 0.95) and 0.99 (95% CI: 0.99 - 0.99), respectively. The positive and negative likelyhood ratios were 100.94 (95% CI: 47.51 - 214.47) and 0.07 (95% CI: 0.05 - 0.10), respectively. The diagnostic odds ratio was 1,814.70 (95% CI: 717.30 - 4,591.04), and the area under the SROC curve was 0.9935. Deek's funnel plot indicated that there was no publication bias. CONCLUSIONS: The results of the analysis indicate that PCR can become a valuable technique for the clinical diagnosis of Candida auris due to its excellent performance.

MMP2 and MMP9 contribute to lung ischemia-reperfusion injury via promoting pyroptosis in mice.

BACKGROUND: Lung ischemia-reperfusion injury (LIRI) is a cause of poor prognosis in several lung diseases and after lung transplantation. In LIRI, matrix metalloproteinases and pyroptosis indicators change in parallel, both of them involvement of inflammatory modulation, but it is unclear whether they are related to each other. METHODS: We analyzed the matrix metalloproteinases (MMPs) changes from RNA sequencing (RNA-Seq) data of human transplantation and rat ischemia-reperfusion lung tissues in the Group on Earth Observations (GEO) database. Then established the mouse LIRI model to validate the changes. Further, the severity of lung injury was measured after intervening the matrix metalloproteinases changes with their selective inhibitor during Lung ischemia-reperfusion. Meanwhile, lung, pyroptosis was assessed by assaying the activity of Caspase-1 and interleukin 1ß (IL-1ß) before and after intervening the matrix metalloproteinases changes. RESULTS: The RNA-Seq data revealed that matrix metallopeptidase 2 (MMP2), matrix metallopeptidase 9 (MMP9) mRNA expression was elevated both in human lung transplantation and rat lung ischemia-reperfusion tissues, consistent with the change in our mouse model. At the same time, the activity of Caspase-1 and IL-1ß were increased after LIRI. While, the lung injury was attenuated for the use of MMP2 and MMP9 selective inhibitor SB-3CT. Likewise, lung pyroptosis alleviated when treatment the mice with SB-3CT in LIRI. CONCLUSION: We conclude that MMP2 and MMP9 are involved in the process of LIRI, the mechanism of which is related to the promotion of lung pyroptosis.

Identification of Key Pathways and Genes in SARS-CoV-2 Infecting Human Intestines by Bioinformatics Analysis.

COVID-19 is a serious infectious disease that has recently swept the world, and research on its causative virus, SARS-CoV-2, remains insufficient. Therefore, this study uses bioinformatics analysis techniques to explore the human digestive tract diseases that may be caused by SARS-CoV-2 infection. The gene expression profile data set, numbered GSE149312, is from the Gene Expression Omnibus (GEO) database and is divided into a 24-h group and a 60-h group. R software is used to analyze and screen out differentially expressed genes (DEGs) and then gene ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses are performed. In KEGG, the pathway of non-alcoholic fatty liver disease exists in both the 24-h group and 60-h group. STRING is used to establish a protein-protein interaction (PPI) network, and Cytoscape is then used to visualize the PPI and define the top 12 genes of the node as the hub genes. Through verification, nine statistically significant hub genes are identified: AKT1, TIMP1, NOTCH, CCNA2, RRM2, TTK, BUB1B, KIF20A, and PLK1. In conclusion, the results of this study can provide a certain direction and basis for follow-up studies of SARS-CoV-2 infection of the human digestive tract and provide new insights for the prevention and treatment of diseases caused by SARS-CoV-2.

The Imbalance of MMP-2/TIMP-2 and MMP-9/TIMP-1 Contributes to Collagen Deposition Disorder in Diabetic Non-Injured Skin.

The importance of the early diagnosis and treatment of diabetes and its cutaneous complications has become increasingly recognized. When diabetic non-injured skin was stained with Masson's trichrome, its dermal collagen was found to be disordered, its density was variable, and it was dispersed or arranged in vague fascicles. The collagen type I sequencing results of RNA sequencing-based transcriptome analysis of three primary human skin cell types-dermal fibroblasts, dermal microvascular endothelial cells, and epidermal keratinocytes-under high glucose were analyzed. The results showed that both COL1A1 and COL1A2 mRNA expressions were reduced in human dermal fibroblasts (HDFs). The ratio of matrix metalloproteinase (MMP)-2/tissue inhibitors of metalloproteinase (TIMP)-2 and MMP-9/TIMP-1 in HDFs increased when treated with high glucose. By inhibiting MMP-2 and MMP-9 with SB-3CT, collagen deposition disorder of the skin in streptozotocin-induced diabetes mice was alleviated. The imbalance of MMP2/TIMP2 and MMP9/TIMP1 contributes to the non-injured skin disorder of collagen deposition in diabetes, suggesting a possibility for early treatment of diabetes skin complications.

Myrothins A-F from Endophytic Fungus Myrothecium sp. BS-31 Harbored in Panax notoginseng.

Endophytic fungi play important roles for host's stress tolerance including invasion by pathogenic microbes. Small molecules are common weapons in the microbe-microbe interactions. Panax notoginseng is a widely used traditional Chinese medicinal plant and harbors many endophytes, some exert functions against pathogens. Here, we report six new compounds named myrothins A-F (1-6) produced by Myrothecium sp. BS-31, an endophyte isolated from P. notoginseng, and their antifungal activities against pathogenic fungi causing host root-rot disease. Their structures were elucidated with analysis of spectroscopic data including 1D and 2D NMR, HR-ESI-MS. Myrothins B (2) and E (5) showed the weak activity against Fusarium oxysporum and Phoma herbarum, and myrothins F (6) showed weak activity against F. oxysporum.

Nocardia panacis sp. nov., a novel actinomycete with antiphytopathogen activity isolated from the rhizosphere of Panax notoginseng.

Strain YIM PH21724T was isolated from the rhizosphere of Panax notoginseng. Phylogenetic analyses based on 16S rRNA gene sequences showed that the strain exhibits close phylogenetic relatedness to Nocardia kroppenstedtii N1286T (97.70%), Nocardia farcinica NCTC 11134T (97.67%) and Nocardia puris DSM 44599T (97.40%). The menaquinones were identified as MK-9 (H4), MK-8 (H4, ω-cyclo) and MK-8 (H4), and the major fatty acids (> 10%) were identified as C16:0, C18:1 ω9c and C18:0 10-methyl. The polar lipids were found to be composed of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannosides and an unidentified lipid. The G + C content of the genomic DNA was determined to be 67.01 mol%. The phenotypic, chemotaxonomic, phylogenetic and genomic results clearly show strain YIM PH21724T should be classified in the genus Nocardia and represents a novel species, for which the name Nocardia panacis sp. nov. is proposed. The type strain is YIM PH21724T (= DSM 105904T = KCTC 49030T = CCTCC AA 2017043T).

Risk Factors and Management of Postoperative Pancreatic Fistula Following Pancreaticoduodenectomy: Single-center Experience.

Pancreatic fistula (PF) remains the most frequent complication after pancreaticoduodenectomy (PD). This study was undertaken to explore the risk factors of postoperative PF following PD and discuss the management of PF in our center. A single-center respective study, involving 241 patients who underwent PD between September 2015 and June 2018, was conducted. Differences in the demographic data, preoperative, intraoperative and postoperative variables between the group with PF [International Study Group on Pancreatic Surgery (ISGPS) grade B/C] and the group without PF (no PF and ISGPS grade BL) were evaluated. The diagnosis and grading of PF were in strict accordance with ISGPS. Risk factors were analyzed by univariate analysis and multivariate logistic regression analysis. The results showed that postoperative PF occurred in 50 (20.7%) of the patients; 25 (10.4%) patients had a PF type BL, 46 (19.1%) patients developed a PF type B and 4 (1.6%) had a PF type C. Univariate analysis showed that fasting blood glucose (P=0.02), pancreatic texture (P< 0.001) and pancreatic duct diameter (P=0.01) were correlated with PF. Multivariate logistic regression analysis identified one independent risk factor for postoperative PF: soft pancreatic texture (OR=3.251, P=0.002). Among the cases, there were three postoperative deaths, giving a 60-day hospital mortality rate of 1.2% (3/241), and the mortality related to PF was 4.0% (2/50). One of the patients died from multiple organ failure caused by postoperative abdominal hemorrhage. In conclusion, soft pancreatic texture is an independent risk factor for PF. Surgeons should be well aware of this risk factor when performing a PD.

Isolation and Characterization of New Phenazine Metabolites with Antifungal Activity against Root-Rot Pathogens of Panax notoginseng from Streptomyces.

Three new phenazine metabolites, strepphenazine A-C (1-3), along with a known compound baraphenazine E 4 were isolated from the culture broth of a Streptomyces strain YIM PH20095. The structures were elucidated based on the spectral data. Compounds 1-4 showed different antifungal activity against Fusarium oxysporum, Plectosphaerella cucumerina, Alternaria panax, and Phoma herbarum, which caused root-rot disease of Panax notoginseng with minimal inhibitory concentrations (MICs) of 16-64 µg/mL; compared with compound 4, compounds 1-3 showed better antifungal activity against some of these pathogenic fungi with MICs of 16-32 µg/mL, while compound 4 showed antifungal activity against F. oxysporum, P. cucumerina, and A. panax with the same MICs of 64 µg/mL. Thus, strain YIM PH20095 provides new sources for the development of biological control agents to prevent the infection of pathogenic fungi of P. notoginseng.

Amycolatopsis panacis sp. nov., isolated from Panax notoginseng rhizospheric soil.

A novel Gram-positive bacterium, designated strain YIM PH21725T, was isolated from a sample of rhizospheric soil of Panaxnotoginseng cultivated in Anning, Yunnan. The strain contained meso-diaminopimelic acid in the cell-wall peptidoglycan. The main fatty acids identified were C17 : 0, iso-C15 : 0, iso-C16 : 0 and C16 : 0. The main menaquinone was MK-9 (H4). The polar lipids included phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylinositol mannoside, phosphatidylinositol, phospholipids and phospholipids of an unidentified structure containing glucosamine. The G+C content of genomic DNA was 69.43 mol%. On the basis of its 16S rRNA gene sequence, strain YIM PH21725T should belong to the genus Amycolatopsis, and was closely related to Amycolatopsis sulphurea DSM 46092T (98.57 %), Amycolatopsis jejuensis JCM13280T (97.27 %), Amycolatopsis jiangsuensis KCTC 19885T (96.88 %) and Amycolatopsis ultiminotia JCM 16989T (96.8 %). The phenotypic, chemotaxonomic, phylogenetic and digital DNA-DNA hybridization results clearly indicated that strain YIM PH21725T represents a novel species of the genus Amycolatopsis, for which the name Amycolatopsispanacis sp. nov. is proposed. The type strain is YIM PH21725T (=CCTCC AA 2017044T=KCTC 49031T=DSM 105902T).

Regulation of mPGES-1 composition and cell growth via the MAPK signaling pathway in jurkat cells.

Previous studies have suggested that microsomal prostaglandin E synthase-1 (mPGES-1) is highly expressed and closely associated with mitogen-activated protein kinase (MAPK) signaling pathways in various types of malignant cells. However, their expression patterns and function with respect to T-cell acute lymphoblastic leukemia (T-ALL) remain largely unknown. The present study investigated whether mPGES-1 served a crucial role in T-ALL and aimed to identify interactions between mPGES-1 and the MAPK signaling pathway in T-ALL. The results indicated that mPGES-1 overexpression in T-ALL jurkat cells was significantly decreased by RNA silencing. Decreasing mPGES-1 on a consistent basis may inhibit cell proliferation, induce apoptosis and arrest the cell cycle in T-ALL jurkat cells. Microarray and western blot analyses revealed that c-Jun N-terminal kinase served a role in the mPGES-1/prostaglandin E2/EP4/MAPK positive feedback loops. In addition, P38 and extracellular signal-regulated kinase 1/2 exhibited negative feedback effects on mPGES-1. In conclusion, the results suggested that cross-talk between mPGES-1 and the MAPK signaling pathway was very complex. Therefore, the combined regulation of mPGES-1 and the MAPK signaling pathway may be developed into a new candidate therapy for T-ALL in the future.

Lovastatin analogues and other metabolites from soil-derived Aspergillus terreus YIM PH30711.

Eight previously undescribed metabolites including of lovastatin analogues, a pair of diastereoisomers, a cyclopentenone dimer, and three polyketides were isolated from the culture of Aspergillus terreus YIM PH30711. Two types of unprecedented skeletons, benzene-cyclopentanone complex and linear polyketide, and an unusual dimer structure were determined by spectral analysis. Compound, 3α-hydroxy-3,5-dihydromonacolin L showed moderate activity against HMG-CoA reductase, with an inhibition ratio of 34% at the concentration of 50 µM, while lovastatin and dihydromonacolin K ethyl ester presented much stronger activity against HMGR with inhibition rates of 85% and 90% at the concentration of 50 µM, respectively. Aspereusin A was active against AChE with a ratio of 62% at the concentration of 50 µM, while its stereomers did not showed obvious inhibition (<10%). The configuration at C-4 of these three diastereoisomers was crucial in the inhibition against AChE, and the ß-orientation of substituted methoxyl acrylic acid should be beneficial to the combining with AChE.

The streptazolin- and obscurolide-type metabolites from soil-derived Streptomyces alboniger YIM20533 and the mechanism of influence of γ-butyrolactone on the growth of Streptomyces by their non-enzymatic reaction biosynthesis.

Eleven new compounds with streptazolin- and obscurolide-type skeletons were isolated from soil-derived Streptomyces alboniger obtained from Tibet, China. Two types of unprecedented skeletons of obscurolide dimer and an obscurolide-type compound with an aromatic polyketide of pentanone substituted at the benzene ring were determined by spectral data analysis. Compound 11 was the first evidence of two nitrogens in streptazolin-type structures. Compound 1 indicated an inhibitory effect on nitric oxide production in LPS-activated macrophages with an inhibition ratio of 51.7% at 50 µM, and on anticoagulant activity on platelet activating factor (PAF)-induced platelet aggregation with an inhibition ratio of 26.0 ± 9.1% at 200 µg mL-1. 11 had anti-acetylcholinesterase activity with an inhibition ratio of 27.2% at a concentration of 50 µM. Mechanistic aspects of the non-enzymatic reaction as well as a more detailed picture of the biosynthetic relationships of the streptazolin- and obscurolide-type metabolites are described. Acidic and basic conditions can inhibit the growth of Streptomyces, and γ-butyrolactones were found to be hormones controlling antibiotic production in Streptomyces. In the pH fermentation tests, acylation of γ-butyrolactones was successfully used to explain the mechanism of influence on the growth of Streptomyces.

Corilagin Counteracts IL-13Rα1 Signaling Pathway in Macrophages to Mitigate Schistosome Egg-Induced Hepatic Fibrosis.

The IL-13Rα1 signaling pathway and M2 macrophages play crucial roles in schistosome egg-induced hepatic fibrosis via the expression of pro-fibrotic molecules. This study aims to investigate the inhibitory effect and mechanism of action of corilagin on schistosome egg-induced hepatic fibrosis via the IL-13Rα1 signaling pathway in M2 macrophages in vitro and in vivo. The mRNA and protein expression of IL-13Rα1, PPARγ, KLF4, SOCS1, STAT6, p-STAT6, and TGF-ß was measured in vitro with corilagin treatment after IL-13 stimulation and in vivo corilagin treatment after effectively killing the adult schistosomes in schistosome-infected mice. Histological analysis of liver tissue was assessed for the degree of hepatic fibrosis. The results revealed that corilagin significantly reduced the expression of PPARγ, KLF4, SOCS1, p-STAT6, and TGF-ß compared with model group and praziquantel administration (p < 0.01 or p < 0.05) in vivo and in vitro, which indicated a strong inhibitory effect of corilagin on IL-13Rα1 signaling pathway. As well, the inhibitory effect of corilagin showed a significant dose-dependence (p < 0.05). The area of fibrosis and distribution of M2 macrophages in mouse liver tissue were reduced significantly and dose-dependently with corilagin treatment compared to model group or praziquantel administration (p < 0.01 or p < 0.05), indicating that corilagin suppressed IL-13Rα1 signaling pathway and M2 macrophage polarization effectively in vivo. Furthermore, the anti-fibrogenic effect persisted even when IL-13Rα1 was up- or down-regulated in vitro. In conclusion, corilagin can suppress schistosome egg-induced hepatic fibrosis via inhibition of M2 macrophage polarization in the IL-13Rα1 signaling pathway.