Rakicidin J and K, two cytotoxic and antibacterial cyclic depsipeptides from the marine bacterium Micromonospora chalcea.

Rakicidin J (1) and rakicidin K (2), two new cyclic depsipeptides, were isolated from culture broth of Micromonospora chalcea FIM-R150103. Their structures were elucidated by extensive analysis of NMR, HR-ESI-MS, and electronic circular dichroism (ECD) data. The two compounds showed strong cytotoxic activity against human colon carcinoma HCT-8 and human pancreatic cancer PANC-1 cells under normoxic and hypoxic conditions in the range of IC50 values from 0.024 to 0.79 µg/mL. Moreover, compounds 1 and 2 also showed moderate antibacterial activity against ten Gram-positive bacterial strains with MIC values ranging from 4 to more than 32 µg/mL. Structure-activity relationship of these two compounds with a close analogue, rakicidin B1, is also discussed.

Identification of sulfamethazine degraders in swine farm-impacted river and farmland: A comparative study of aerobic and anaerobic environments.

Sulfonamides (SAs) are extensively used antibiotics in the prevention and treatment of animal diseases, leading to significant SAs pollution in surrounding environments. Microbial degradation has been proposed as a crucial mechanism for removing SAs, but the taxonomic identification of microbial functional guilds responsible for SAs degradation in nature remain largely unexplored. Here, we employed 13C-sulfamethazine (SMZ)-based DNA-stable isotope probing (SIP) and metagenomic sequencing to investigate SMZ degraders in three distinct swine farm wastewater-receiving environments within an agricultural ecosystem. These environments include the aerobic riparian wetland soil, agricultural soil, and anaerobic river sediment. SMZ mineralization activities exhibited significant variation, with the highest rate observed in aerobic riparian wetland soil. SMZ had a substantial impact on the microbial community compositions across all samples. DNA-SIP analysis demonstrated that Thiobacillus, Auicella, Sphingomonas, and Rhodobacter were dominant active SMZ degraders in the wetland soil, whereas Ellin6067, Ilumatobacter, Dongia, and Steroidobacter predominated in the agricultural soil. The genus MND1 and family Vicinamibacteraceae were identified as SMZ degrader in both soils. In contrast, anaerobic SMZ degradation in the river sediment was mainly performed by genera Microvirga, Flavobacterium, Dechlorobacter, Atopostipes, and families Nocardioidaceae, Micrococcaceae, Anaerolineaceae. Metagenomic analysis of 13C-DNA identified key SAs degradation genes (sadA and sadC), and various of dioxygenases, and aromatic hydrocarbon degradation-related functional genes, indicating their involvement in degradation of SMZ and its intermediate products. These findings highlight the variations of indigenous SAs oxidizers in complex natural habitats and emphasize the consideration of applying these naturally active degraders in future antibiotic bioremediation.

One-Step Transformations from ACQ Luminogens to DSEgens via the Boc Protection Process.

Dual-state emission luminogens (DSEgens), as a new type of luminescent materials that can effectively emit light in solution and solid state, have attracted tremendous attention due to their potential application in chemical sensing, biological imaging, organic electronic devices, etc. In this study, two new rofecoxib derivatives ROIN and ROIN-B have been synthesized, and their photophysical properties are fully investigated by experimental studies and theoretical calculations. The key intermediate ROIN, resulting from one-step conjugation of rofecoxib with an indole unit, shows the classical aggregation-caused quenching (ACQ) effect. Meanwhile, by introducing a tert-butoxycarbonyl (Boc) group on the basis of ROIN without enlarging the π conjugation system, ROIN-B was successfully developed with an obvious DSE property. In addition, both fluorescent behaviors and their transformation from ACQ to DSE were elucidated clearly by going through the analysis of their single X-ray data. Moreover, the target ROIN-B, as a new DSEgens, also displays reversible mechanofluorochromism and lipid droplet-specific imaging ability in HeLa cells. Taken together, this work proposes a precise molecular design strategy to afford a new DSEgens, which may provide guidance for the future exploration of new DSEgens.

Succession Patterns of Microbial Composition and Activity following the Diesel Spill in an Urban River.

Diesel spills in freshwater systems have adverse impacts on the water quality and the shore wetland. Microbial degradation is the major and ultimate natural mechanism that can clean the diesel from the environment. However, which, and how fast, diesel-degrading microorganisms could degrade spilled diesel has not been well-documented in river water. Using a combination of 14C-/3H--based radiotracer assays, analytical chemistry, MiSeq sequencing, and simulation-based microcosm incubation approaches, we demonstrated succession patterns of microbial diesel-degrading activities, and bacterial and fungal community compositions. The biodegradation activities of alkanes and polycyclic aromatic hydrocarbons (PAHs) were induced within 24 h after diesel addition, and reached their maximum after incubation for 7 days. Potential diesel-degrading bacteria Perlucidibaca, Acinetobacter, Pseudomonas, Acidovorax, and Aquabacterium dominated the community initially (day 3 and day 7), but later community structure (day 21) was dominated by bacteria Ralstonia and Planctomyces. The key early fungi responders were Aspergillus, Mortierella, and Phaeoacremonium by day 7, whereas Bullera and Basidiobolus dominated the fungal community at day 21. These results directly characterize the rapid response of microbial community to diesel spills, and suggest that the progression of diesel microbial degradation is performed by the cooperative system of the versatile obligate diesel-degrading and some general heterotrophic microorganisms in river diesel spills.

Facile Transformation from Rofecoxib to a New Near-Infrared Lipid Droplet Fluorescent Probe and Its Investigations on AIE Property, Solvatochromism and Mechanochromism.

Lipid-related cancers cause a large number of deaths worldwide. Therefore, development of highly efficient Lipid droplets (LDs) fluorescent imaging probes will be beneficial to our understanding of lipid-related cancers by allowing us to track the metabolic process of LDs. In this work, a LDs-specific NIR (λmax = 698 nm) probe, namely BY1, was rationally designed and synthesized via a one-step reaction by integrating triphenylamine (electron-donor group) unit into the structure of rofecoxib. This integration strategy enabled the target BY1 to form a strong Donor-Acceptor (D-A) system and endowed BY1 with obvious aggregation-induced emission (AIE) effect. Meanwhile, BY1 also showed observable solvent effect and reversible mechanochromatic luminescent property, which could be interpreted clearly via density functional theory (DFT) calculations, differential scanning calorimetry (DSC), powder X-ray diffraction (XPRD), and single crystal X-ray data analysis. More importantly, BY1 exhibited highly specific fluorescent imaging ability (Pearson's correlation = 0.97) towards lipid droplets in living HeLa cells with low cytotoxicity. These results demonstrated that BY1 is a new promising fluorescent probe for lipid droplets imaging, and it might be beneficial to facilitate biological research of lipid-related cancers.

Proteomics-based analysis of potential therapeutic targets in patients with peritoneal dialysis-associated peritonitis.

BACKGROUND: Peritoneal dialysis-associated peritonitis (PDAP) is the most common complication in peritoneal dialysis patients. We propose screening for characteristic expressed proteins in the dialysate of PDAP patients to provide clues for the diagnosis of PDAP and its therapeutic targets. METHODS: Dialysate samples were collected from patients with a first diagnosis of PDAP (n = 15) and from patients who had not experienced peritonitis (Control, n = 15). Data-independent acquisition (DIA) proteomic analysis was used to screen for differentially expressed proteins (DEPs). Co-expression networks were constructed via weighted gene co-expression network analysis (WGCNA) for detection of gene modules. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used for functional annotation of DEPs and gene modules. Hub proteins were validated using the parallel reaction monitoring (PRM) method. RESULTS: A total of 142 DEPs in the dialysate of PDAP patients were identified. 70 proteins were upregulated and 72 proteins were downregulated. GO and KEGG analysis showed that DEPs were mainly enriched in cell metabolism, glycolysis/glycogenesis and hypoxia-inducible factor-1 signaling pathway. Subsequently, a co-expression network was constructed and four gene modules were detected. Myeloperoxidase (MPO) and myeloperoxidase (HP) were the key proteins of the blue and turquoise modules, respectively. Additionally, PRM analysis showed that the expression of MPO and HP was significantly upregulated in the PDAP group compared to the non-peritonitis group, which was consistent with our proteomics data. CONCLUSION: MPO and HP were differentially expressed in the dialysate of PDAP patients and may be potential diagnostic and therapeutic targets for PDAP.

Dispersal of antibiotic resistance genes in an agricultural influenced multi-branch river network.

Rivers in agricultural regions serve as an important sink for livestock and poultry farm runoff, fertilizer runoff, and country living sewage, which could bring antibiotic resistance genes (ARGs) contaminations. However, the diversity and distribution of ARGs has not been well documented in the agricultural influenced river. Here, the diversity of ARGs, and their relationship with biochemical factors were determined in the surface water in an agricultural region of the Jialing River and its five rural branches. The 218 unique ARGs encoding resistance to eight major antibiotic classes have been detected using high-throughput quantitative PCR. The branches of the river had a remarkably higher abundance of ARGs than the mainstream. The aminoglycoside, beta_Lactamase, MLSB, and Multidrug resistance genes were significantly enriched in the branches compared to the mainstream. Compared with the mainstream, the ARGs profiles in the branches showed obvious higher spatial variability. Significant correlation between ARGs profiles and bacterial community structures were observed, and network analysis further showed that the ARGs were associated with their potential hosts, such as Ottowia and Novosphingobium. Redundancy discrimination analysis revealed that Cu content has a significant contribution to the increase of ARGs in the river. The microbial diversity index was negatively correlated with the abundance of the ARGs. These results provide evidence for the enrichment of ARGs in the agricultural influenced river and branches due to the joint influence of chemical and microbial variables.

Therapeutic targets for the anemia of predialysis chronic kidney disease: a meta-analysis of randomized, controlled trials.

Anemia is one of the major complications in predialysis patients with chronic kidney disease (CKD). A clearer cognition of the prognostic impact of hemoglobin (Hb) or hematocrit (Hct) target on the outcomes of predialysis patients with CKD is significant. This article aims to establish the suitable hemoglobin target to provide clinical guidance. MEDLINE, EmBase, the Cochrane Library and other databases were searched with both MeSH terms and keywords to gather researches that assessed all-cause mortality, stroke, treatment of renal replacement, and transfusion. The meta-analysis was accomplished via Revman 5.3 version. Totally, 13 eligible studies involving 7606 patients were included. There was a significantly lower risk of transfusion (risk ratio (RR) 0.59, 95% CI 0.52 to 0.67; p<0.00001) in the higher hemoglobin group than in the lower one. However, no significant difference was found in all-cause mortality (RR 1.10, 95% CI 0.98 to 1.23; p=0.11), stroke (RR 1.32, 95% CI 0.82 to 2.10; p=0.25) and treatment of renal replacement including hemodialysis, peritoneal dialysis and renal transplant (RR 1.08, 95% CI 0.95 to 1.22; p= 0.23) between the higher hemoglobin group and the lower one. The results favor the higher hemoglobin target. To target the higher hemoglobin when treating predialysis patients with CKD may decrease the risk of transfusion without increasing the risk of death, stoke, and treatment of renal replacement.

Hemoglobin targets for the anemia in patients with dialysis-dependent chronic kidney disease: a meta-analysis of randomized, controlled trials.

BACKGROUND: Anemia is extremely common among dialysis patients and underlies some of the symptoms associated with reduced kidney function, including fatigue, depression, reduced exercise tolerance, and dyspnea. OBJECTIVES: A clearer cognition of the prognosistic impact of hemoglobin (Hb) or hematocrit (Hct) target for the outcomes of dialysis patients is urgent. This article aims to establish the suitable hemoglobin in order to provide clinical guidance. METHODS: MEDLINE, EmBase, the Cochrane Library and other databases were searched with both MeSH terms and keywords to gather randomized controlled trials that assessed all-cause mortality, cardiovascular events, fistula thrombosis, infectious diseases and transfusion among dialysis-dependent patients using erythropoiesis-stimulating agents. The meta-analysis was accomplished via Revman 5.3 version. FINDINGS: Totally, nine eligible studies were included, with study subjects involving 3228 patients. There was a significantly higher risk of fistula thrombosis without heterogeneity (RR 1.34, 95% CI 1.15-1.55; p < 0.05) in the higher Hb target group than in the lower Hb target group in the fixed effects model. However, no significant difference was found in all-cause mortality in the fixed effects model (RR 1.09, 95% CI 0.93-1.27; p = 0.30), cardiovascular events (RR 0.77, 95% CI 0.31-1.92; p = 0.58), infectious diseases (RR 0.69, 95% CI 0.24-1.96; p = 0.49) and transfusion (RR 0.92, 95% CI 0.42-1.99; p = 0.82) in the random effects model between the higher Hb target group and the lower Hb target group. DISCUSSION: The results favor lower Hb target. To target lower Hb target when treating dialysis patients with anemia may decrease the risk of fistula thrombosis without increasing the risk of death, cardiovascular events, infectious diseases and transfusion.

Improving precision of glomerular filtration rate estimating model by ensemble learning.

BACKGROUND: Accurate assessment of kidney function is clinically important, but estimates of glomerular filtration rate (GFR) by regression are imprecise. METHODS: We hypothesized that ensemble learning could improve precision. A total of 1419 participants were enrolled, with 1002 in the development dataset and 417 in the external validation dataset. GFR was independently estimated from age, sex and serum creatinine using an artificial neural network (ANN), support vector machine (SVM), regression, and ensemble learning. GFR was measured by 99mTc-DTPA renal dynamic imaging calibrated with dual plasma sample 99mTc-DTPA GFR. RESULTS: Mean measured GFRs were 70.0 ml/min/1.73 m2 in the developmental and 53.4 ml/min/1.73 m2 in the external validation cohorts. In the external validation cohort, precision was better in the ensemble model of the ANN, SVM and regression equation (IQR = 13.5 ml/min/1.73 m2) than in the new regression model (IQR = 14.0 ml/min/1.73 m2, P < 0.001). The precision of ensemble learning was the best of the three models, but the models had similar bias and accuracy. The median difference ranged from 2.3 to 3.7 ml/min/1.73 m2, 30% accuracy ranged from 73.1 to 76.0%, and P was > 0.05 for all comparisons of the new regression equation and the other new models. CONCLUSIONS: An ensemble learning model including three variables, the average ANN, SVM, and regression equation values, was more precise than the new regression model. A more complex ensemble learning strategy may further improve GFR estimates.

The diagnostic value of serum creatinine and cystatin c in evaluating glomerular filtration rate in patients with chronic kidney disease: a systematic literature review and meta-analysis.

BACKGROUND: Serum biomarkers, such as serum creatinine (SCr) and serum cystatin C (SCysC), have been widely used to evaluate renal function in patients who have chronic kidney disease (CKD). OBJECTIVE: This article aims to assess the value of determining SCr and SCysC levels in patients that have long-term kidney disease. Approaches: MEDLINE, EmBase, the Cochrane Library and other databases were searched using both MeSH terms and text words to collect research that assessed the diagnostic value of using SCr and SCysC to evaluate Glomerular Filtration Rate (GFR) in patients with CKD. Data were converted into fourfold tables. Summary Receiver Operating Characteristic Curves and meta-analyses were accomplished via Meta-Disc version 1.4. RESULTS: In total, 21 relevant articles involving 3112 study subjects were included in our review. Results showed that the collective sensitivity for SCr and SCysC was 0.77 (95% CI: 0.69-0.84) and 0.87 (95% CI: 0.82-0.91), respectively. The pooled specificity for SCr and SCysC was 0.91 (95% CI: 0.86-0.94) and 0.87 (95% CI: 0.82-0.91), respectively. Subgroup analyses demonstrated that when GFR cut-off values are set to 60 (ml/min/1.73 m2), the pooled sensitivity is 0.94 (95% CI: 0.90-0.96) for SCysC and 0.75 (95% CI: 0.68-0.82) for SCr. CONCLUSIONS: The diagnostical accuracy for impaired kidney function favors SCysC. Confidence intervals for the pooled sensitivity and specificity for SCr and SCysC overlap. However, SCysC is more sensitive for estimating GFR than SCr when GFR cut-off values are set to 60 (ml/min/1.73 m2).

Evening versus morning dosing regimen drug therapy for chronic kidney disease patients with hypertension in blood pressure patterns: a systematic review and meta-analysis.

BACKGROUND: Evening dosing regimen drug therapy on blood pressure (BP) control is used widely, but its clinical benefits and preservation or re-establishment of the normal 24-h BP dipping pattern in chronic kidney disease (CKD) patients is not known. AIMS: To investigate the effect of an evening dosing regimen of antihypertensive drugs on BP patterns of CKD patients with hypertension. METHODS: A systematic review was conducted by searching PUBMED, EMBASE, ASN-ONLINE, the Cochrane Library and the reference lists of relevant articles of published papers. All trials designed to evaluate the effects of evening versus morning dosing regimen drug therapy for CKD patients with hypertension were included. Meta-analysis was performed using random or fixed effects models. RESULTS: Five randomised controlled trials and one comparative study, including 3732 patients, met the inclusion criteria. Compared with morning dosing regimen drug therapy, evening administration of antihypertensive medication was associated with a significant reduction of 40% in non-dipper BP patterns (risk ratio (RR), 95% CI, (0.43, 0.84)). We noted a significant decrease in nocturnal systolic blood pressure (SBP) (MD -3.17 mmHg, 95% CI (-5.41, -0.94)), a significant reduction in nocturnal diastolic blood pressure (DBP) (MD -1.37 mmHg, 95% CI (-2.05, -0.69)) and a significant increase in awake SBP (MD 1.15 mmHg, 95% CI (0.10, 2.19)) in patients assigned to the evening dosing regimen drug therapy group. Patients showed no significant differences for all-cause mortality and cardiovascular mortality. CONCLUSION: This review shows that evening dosing regimen drug therapy could reverse non-dipper BP patterns in hypertensive CKD patients.