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Mitochondrial DNA (mtDNA) copy number (CN) is a biomarker of mitochondrial function and has been reported associated with kidney disease. However, its association with IgA nephropathy (IgAN), the most common cause of glomerulonephritis (GN), has not been evaluated. We included 664 patients with biopsy-proven IgAN and measured mtDNA-CN in peripheral blood by multiplexed real-time quantitative polymerase chain reaction (RT-qPCR). We examined the associations between mtDNA-CN and clinical variables and found that patients with higher mtDNA-CN had higher estimated glomerular filtration rate (eGFR) (r = 0.1009, p =.0092) and lower serum creatinine (SCr), blood urea nitrogen (BUN), and uric acid (UA) (r=−0.1101, −0.1023, −0.07806, respectively, all p values <.05). In terms of pathological injury, mtDNA-CN was higher in patients with less mesangial hypercellularity (p =.0385, M0 vs. M1 score by Oxford classification). Multivariable logistic regression analyses also showed that mtDNA-CN was lower for patients with moderate to severe renal impairment (defined as eGFR < 60 mL/min/1.73 m2) vs. mild renal impairment, with the odds ratio of 0.757 (95% confidence interval: 0.579–0.990, p =.042). In conclusion, mtDNA-CN was correlated with better renal function and less pathological injury in patients with IgAN, proposing that systemic mitochondrial dysfunction may be involved in or reflect the development of IgAN. [ABSTRACT FROM AUTHOR]

Inflammation is a defense mechanism that the immune system uses in response to harmful stimuli such as pathogens, damaged cells, toxic compounds, or irradiation. These stimuli may induce inflammatory response and potentially tissue damage in respiratory, cardiovascular, digestive, nervous, endocrine, urinary, or reproductive systems. Inflammatory diseases include a broad array of disorders and conditions that are characterized by inflammation, ranging from autoimmune disease, atopic dermatitis, asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, glomerulonephritis, hepatitis, reperfusion injury, transplant rejection, diabetes, cancer, Parkinson’s disease, multiple sclerosis, to depression. Epigenetic mechanisms play crucial roles in many biological processes by regulating transcriptional activation or repression. Histone post-translational modifications have emerged as prospective therapeutic targets. Methylation of histone 3 at lysine 9 is one of the most highly conserved epigenetic marks that correlate well with gene silencing. The methylation status of H3K9 modulates immune cell differentiation and immune responses and therefore influences the outcome of cancer, infection, and other inflammatory diseases. Here, we review the high impact and innovate discoveries in this field, highlight the critical role of the H3K9 methylation/de-methylation in human inflammatory diseases, discuss potential new therapeutic strategies based on a better understanding of the biology of H3K9 methylation modifications. Abbreviations: 2OG: 2-oxoglutarate; AOL: Amine oxidase-like; ChIP: Chromatin immunoprecipitation; CNS2: conserved noncoding sequence 2; COPD: Chronic obstructive pulmonary disease; CoREST: Corepressor of RE1 silencing transcription factor; CPP: Cell-permeant protein; CTLA4: Cytotoxic T-lymphocyte antigen 4; DCs: Dendritic cells; DN: Diabetic nephropathy; ESRD: End-stage renal disease; ETDB: SET domain bifurcated histone lysine methyltransferase; FAD: Flavin adenine dinucleotide; FEV1%: The percentage of forced expiratory volume in one second; FEV1/FVC: Forced expiratory volume in one second (FEV1)/Forced vital capacity (FVC) value; FOXP3: forkhead/winged helix transcription factor 3; GLP: G9a like protein; GZMB: Granzyme B; H3K27me3: Trimethylation of lysine 27 on histone H3; H3K4me3: Trimethylation of lysine 4 on histone H3; H3K9: Histone 3 Lysine 9; HG: Hyperglycemia; HDAC3: Histone deacetylase 3; HP1: Heterochromatin protein 1; I/R: Ischemia/Reperfusion; IBD: Inflammatory bowel disease; IFN-: Interferon-; IFNG: Interferon Gamma; IL-2: Interleukin-2; ILC2s: Group 2 innate lymphoid cells; JMJD: Jumonji domain-containing protein; iTreg: inducible Treg; KDM: Lysine-specific demethylase; LPS: Lipopolysaccharide; LSD: Lys-specific demethylase; MCP-1: Monocyte chemoattractant protein-1; MCSF: Macrophage colony-stimulating factor; MIP-1: Macrophage inflammatory protein-1; MS: Metabolic syndrome; NAFLD: Non-alcoholic fatty liver disease; NKRF: NF-kappaB repressing factor; NOR: Norisoboldine; NuRD: Nucleosome remodeling and deacetylase; OxLDL: Oxidized low-density lipoprotein; PBMCs: Peripheral blood monocytes; PHD: Plant homology domain; Poly I:C: Polyinosinic:polycytidylic acid; PPARγ: Peroxisome proliferator-activated receptor gamma; PTMs: Post-translational modifications; SUV3-9: Suppressor of variegation3-9; T1D: Type 1 diabetes; TLRs: Toll like receptors; TSDR: TGF-β sensitive region and Treg cell specific demethylated region; Treg: Regulatory T cell; VSMCs: Vascular smooth muscle cells. [ABSTRACT FROM AUTHOR]

Context: Danshen tablets (DST), an effective traditional Chinese multi-herbal formula, are often combined with atorvastatin calcium (AC) for treating coronary heart disease in the clinic. Objective: This study investigated the effects of DST on the pharmacokinetics of AC and the potential mechanism. Materials and methods: The pharmacokinetics of AC (1 mg/kg) with or without pretreatment of DST (100 mg/kg) were investigated using LC-MS/MS. The effects of DST (50 μg/mL) on the metabolic stability of AC were also investigated using rat liver microsome incubation systems. Results: The results indicated that Cmax (23.87 ± 4.27 vs. 38.94 ± 5.32 ng/mL), AUC(0-t) (41.01 ± 11.32 vs. 77.28 ± 12.92 ng h/mL), and t1/2 (1.91 ± 0.18 vs. 2.74 ± 0.23 h) decreased significantly (p < 0.05) when DST and AC were co-administered, which suggested that DST might influence the pharmacokinetic behavior of AC when they are co-administered. The metabolic stability (t1/2) of AC was also decreased (25.7 ± 5.2 vs. 42.5 ± 6.1) with the pretreatment of DST. Discussion and conclusions: This study indicated that the main components in DST could accelerate the metabolism of AC in rat liver microsomes and change the pharmacokinetic behaviors of AC. So these results showed that the herb-drug interaction between DST and AC might occur when they were co-administered. Therefore, the clinical dose of AC should be adjusted when DST and AC are co-administered. [ABSTRACT FROM AUTHOR]

Peritoneal fibrosis caused by long-term peritoneal dialysis (PD) is the main reason why patients withdraw from PD treatment. Lipid accumulation in the peritoneum was shown to participate in fibrosis, and klotho is a molecule involved in lipid metabolism. GSK343 (enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitor) has been verified to inhibit epithelial mesenchymal transdifferentiation (EMT) and peritoneal fibrosis, but its related mechanism remains unclear. This study aimed to investigate whether lipid accumulation was involved in the effect of GSK343 and its related mechanism. First, the expression of EZH2, klotho and EMT indices in human peritoneal mesothelial cells (HMrSV5) incubated with high glucose (HG) levels was detected. After EZH2 was inhibited by GSK343, Western blot (WB), wound healing and Transwell assays were used to explore the effect of GSK343. EZH2 and klotho expression was also detected. Oil red O and Nile red staining and triglyceride (TG) detection kits were used to detect lipid accumulation. A rescue experiment with small interfering RNA specific for klotho (si-klotho) on the basis of GSK343 was also conducted to verify that GSK343 exerted its effect via klotho. In in vivo experiments, rats were administered GSK343, and the related index was assessed. In our study, we revealed that the expression of EZH2 was significantly upregulated and klotho was significantly downregulated in HMrSV5 cells induced by high glucose. With the aid of GSK343, we found that lipid deposition caused by HG was significantly decreased. In addition, EMT and fibrosis were also significantly alleviated. Moreover, GSK343 could also restore the downregulation of klotho. To further verify whether klotho mediated the effect of EZH2, a rescue experiment with si-klotho was also conducted. The results showed that si-klotho could counteract the protective effect of GSK343 on high glucose-induced lipid accumulation and fibrosis. In vivo experiments also revealed that GSK343 could relieve peritoneal fibrosis, lipid deposition and EMT by mitigating EZH2 and restoring klotho expression. Combining these findings, we found that EZH2 regulated lipid deposition, peritoneal fibrosis, and EMT mediated by klotho. To our knowledge, this is the first study to demonstrate the effect of the EZH2-klotho interaction on peritoneal fibrosis. Hence, EZH2 and klotho could act as potential targets for the treatment of peritoneal fibrosis. [ABSTRACT FROM AUTHOR]

Eucommia ulmoidesis a small tree that has evolved strong pest resistance. This study investigated the mechanism of this resistance by evaluating pest damage and antifeedant activity of the secondary metabolite gutta-percha. In the field,E. ulmoidesdisplayed an average plant resistance of 93.3%, with most damage confined to leaves. We assessed the effects of gutta-percha as a feeding deterrent againstHyphantria cuneaandAnoplophora glabripennislarvae by mixing it into or daubing it onto the surface of artificial diets. Diets containing more than 6% gutta-percha significantly reduced the amount of feeding byA. glabripennislarvae and the body length ofH. cunealarvae. In addition, approximately 95% of the artificial diet was not consumed compared to the control without gutta-percha. The content, distribution, properties, and dynamics of gutta-percha inE. ulmoidesindicate that gutta-percha may function as a physical-chemical barrier against insect pests. [ABSTRACT FROM AUTHOR]

Chlorophorus caragana(Coleoptera: Cerambycidae) is a trunk borer that feeds onCaraganashrubs in the desert. There are five species ofCaraganaplant in the distribution area ofCh. caragana. We investigated damagedCaraganaplants in the field. Olfactory responses of femaleCh. caraganato plants and identified volatile compounds fromCaraganaplants were further evaluated.Caragana davazamciiwas severely damaged in the field, followed byCaragana microphylla. No damage was found to the other three species. Behavioral experiments showed thatC. davazamcii, C. microphylla, andCaragana korshinskiiwere attractive to female insects.Caragana ordosicacould repel and avoid female insects.Caragana brachypodahad no effect on the orientation behavior of female insects. Seventy volatile components were identified from theCaraganaplants, and (Z)-β-ocimene, 1,3-pentadiene, (Z)-3-hexenyl acetate, perillene, chrysanthenone, and limonene were the most abundant volatiles identified from theCaraganaplants. The volatiles were categorized into three groups. Those most attractive toCh. caraganaconsisted of chrysanthenone, 1,3-pentadiene, and (Z)-β-ocimene. Those repellingCh. caraganaconsisted of perillene, dibutyl phthalate, nonanal, and pentadecane, and those irrelevant to each other consisted of (Z)-3-hexenyl acetate, 1-octene, nonene, decanal, (Z)-3-hexenol, and α-pinene. [ABSTRACT FROM AUTHOR]

The amino acid, protein, carbohydrate, and mineral element contents and composition of the xylem, phloem, and leaves of healthy and insect-damaged Caragana korshinskii plants were analyzed to evaluate the changes in the nutrient content of C. korshinskii after damage by Chlorophorus caragana. The amino acid content decreased in the leaf and phloem but increased in the xylem in response to damage, while the protein content did not change in the leaf, increased in the xylem, and decreased in the phloem. The carbohydrate content increased slightly in the leaf but decreased in the xylem and phloem. The six mineral elements analyzed, namely, phosphorous, potassium, magnesium, zinc, manganese, and iron decreased in the xylem, phloem, and leaf. The present results may provide a basis for understanding the mechanisms underlying the effect of C. caragana on the loss of viability of C. korshinskii. [ABSTRACT FROM AUTHOR]

Ginseng black spot, caused by Alternaria panax, is one of the most common diseases of Panax ginseng, which usually causes serious yield loss of ginseng plants. However, the pathogenic mechanism of A. panax has not been clarified clearly. Mycotoxins produced by phytopathogens play an important role in the process of infection. Previous study reported that dibutyl phthalate (DBP) identified from the metabolites of A. panax is a potent mycotoxin against P. ginseng. However, more evidence suggests that DBP is one of the constituents of plasticisers. To identify mycotoxins from A. panax and evaluate their phytotoxicity on the leaves of P. ginseng, different chromatographic, spectral and bioassay-guided methods were used together in this report. As a result, tyrosol (1), 3-hydroxy-3-(4-methoxyphenyl) propanoic acid (2), and 3-benzylpiperazine-2,5-dione (3) were isolated and characterised from the extract of A. panax, in which compounds 1 and 2 showed phytotoxic activity on ginseng leaves. Furthermore, DBP was confirmed to come from the residue of ethyl acetate through UPLC-MS/MS analysis, and displayed no phytotoxicity on ginseng leaves based on biological experiments. The results in this report first revealed that tyrosol (1), and 3-hydroxy-3-(4-methoxyphenyl) propanoic acid (2) not DBP were the potent mycotoxins of A. panax. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a syndrome characterized by an accelerating decrease in renal function in a short time. Thymol is one of the main components of thyme species and has a variety of pharmacological effects. Here, we investigated whether thymol could ameliorate rhabdomyolysis (RM)-induced AKI and its related mechanism. Glycerol was used to induce RM-associated AKI in rats. Rats received thymol (20 mg/kg/day or 40 mg/kg/day) gavage 24 h before glycerol injection until 72 h after injection daily. Kidney injury was identified by measuring serum creatinine (Scr) and urea levels and by H&E and PAS staining and immunohistochemistry (the expression of proliferating cell nuclear antigen (PCNA)). Renal superoxide dismutase (SOD), malondialdehyde (MDA), and oxidative stress-related Nrf2/HO-1 signaling pathways were measured. The expression of the inflammatory markers TNF-α, IL-6, MCP-1, and NF-κB was assessed by ELISA and western blotting. Finally, the expression of the PI3K/Akt signaling pathway was detected by western blotting. Glycerol administration induced obvious renal histologic damage and increased Scr, urea, and PCNA expression. Notably, thymol treatment attenuated these structural and functional changes and prevented renal oxidative stress, inflammatory damage and PI3K/Akt pathway downregulation associated with glycerol-induced AKI. In conclusion, thymol might have potential applications in the amelioration of AKI via its antioxidant and anti-inflammatory effects and upregulation of the PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

The aims of the study were to explore the potential associations between plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) and coagulation indexes in patients with primary membranous nephropathy (PMN). A total of 87 patients diagnosed with PMN were enrolled in our study. 30 healthy participants were recruited to match PMN participants. Plasma PCSK9 concentrations were tested by enzyme-linked immunosorbent assay (ELISA). Correlations between PCSK9 and coagulation abnormalities in patients with PMN were analyzed using univariate and multiple linear regression analysis. Plasma PCSK9 levels in patients with PMN were significantly higher than that in healthy controls [232.0 (143.5, 359.5) ng/mL vs. 166.8 (129.7, 199.7) ng/mL; p = 0.001]. Plasma levels of PCSK9 were positively correlated with factor VIII, factor IX, factor XI, log-transformed tissue factor, protein C and protein S (r = 0.267, p = 0.013; r = 0.496, p < 0.001; r = 0.217, p = 0.045; r = 0.584, p < 0.001; r = 0.372, p = 0.001; r = 0.282, p = 0.011). In multiple linear regression analysis, PCSK9 concentration was independently and positively correlated with factor VIII, factor IX, and tissue factor (β = 0.186, p = 0.047; β = 0.325, p = 0.001; β = 0.531, p < 0.001; respectively). PCSK9 concentration was independently and negatively correlated with PT (β= −0.343, p = 0.011). Plasma PCSK9 levels had good positive correlations with procoagulant clotting factors and negative correlations with PT in PMN, which might provide novel information with regard to PCSK9 and hypercoagulability in PMN. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor-associated acute kidney injury (ICI-AKI) is the most common renal complication and has attracted increasing amounts of attention. However, studies on this topic in Chinese cancer patients are very limited. Therefore, we conducted a retrospective study on the incidence, risk factors, clinical features and renal recovery of ICI-AKI in all patients with malignancies treated with ICIs in Shandong Provincial Hospital Affiliated to Shandong First Medical University. In this single-center retrospective cohort study, the data of 904 patients who received immune checkpoint inhibitors (ICIs) treatment were retrospectively analyzed. Multivariable logistic regression was used to identify the predictors of ICI-AKI. A total of 46 of 904 patients receiving ICIs developed ICI-AKI, and the incidence of ICI-AKI was 5.1%. Patients developed ICI-AKI at a median of 9 weeks (IQR 3–23) after ICIs initiation. A lower baseline estimated glomerular filtration rate (eGFR) and use of antibiotics were associated with a higher risk of ICI-AKI. Renal recovery occurred in 17 patients (46%) at a median of 4 weeks (IQR 2–8) after ICI-AKI, including 16 (43%) with complete recovery and 1 (3%) with partial recovery. Of the 14 rechallenged patients, only one developed recurrent ICI-AKI. Patients with ICI-AKI were more likely to have impaired renal function at baseline and after treatment with antibiotics. Approximately half of the patients achieved renal recovery. [ABSTRACT FROM AUTHOR]

Predicting future urban land-use scenarios and assessing their encroachment on ecological land is important for sustainability policy formulation. This study develops a new Futureland model using cellular automata with user-defined transformation rules, graphical neighborhood configuration and matrixed transformation cost to simulate multiple land-use changes. Compared with existing models, Futureland applies different factors to different land-use types in a single simulation experiment. Futureland was developed using Geospatial Data Abstraction Library and parallel computing, which significantly improve the implementation efficiency. The case study of Shanghai 2010–2020 illustrates an overall accuracy of 86.6% and a Kappa simulation of 0.79. The land-use scenarios for 2020–2035 were projected under greenspace planning constraints using Futureland. The results indicate that Shanghai's urban sprawl will gradually slow down by 2030, and the increased urban areas will be mainly in the urban fringes and suburban regions. Futureland can help decision-makers to manage future land-use and optimize urban planning policies. [ABSTRACT FROM AUTHOR]

To investigate the clinical manifestations, pathological features, pathogenesis, treatment, and prognosis of anti-glomerular basement membrane (anti-GBM) disease with membranous nephropathy (MN). Seven patients with anti-GBM disease and concurrent MN were enrolled in this study. Control subjects included 13 patients with anti-GBM glomerulonephritis (GN) and 6 with anti-GBM disease and concurrent anti-neutrophil cytoplasmic antibodies-associated disease (anti-GBM + ANCA). Laboratory tests and pathological information were analyzed before immunosuppressive therapy or plasmapheresis administration. Prognosis was assessed in continuous follow-up. In the anti-GBM + MN group, 28.57% of patients exhibited acute kidney disease, lower than that in the anti-GBM GN group (84.62%, p =.022). None of the anti-GBM + MN or + ANCA patients exhibited hemoptysis, but 15.4% of anti-GBM GN patients did, with no significant difference (p =.720). Only 14.3% of anti-GBM + MN patients had crescentic GN. The proportion of necrosis averaged 29.0% in the anti-GBM + MN group. Survival curve analysis revealed that renal outcomes in the anti-GBM + MN group were better than those in the anti-GBM GN group (p =.019). Patients with both anti-GBM disease and MN showed atypical anti-GBM GN. They had a lower proportion of glomerular crescents and a better renal function prognosis than patients with classical anti-GBM GN. To improve renal recovery, early identification and treatment of anti-GBM disease associated with MN is needed. [ABSTRACT FROM AUTHOR]

The aims of the study were to identify whether left renal vein (LRV) entrapment was more prevalent in IgA nephropathy (IgAN) and Henoch–Schönlein purpura nephritis (HSPN) compared with other types of renal diseases, and the association of LRV entrapment with glomerular incidental IgA and galactose-deficient-IgA1 (Gd-IgA1) deposition. A total of 797 patients with biopsy-proven kidney diseases have been screened for LRV entrapment by color Doppler ultrasound, and the prevalence of LRV entrapment in different types of renal diseases were then analyzed. Propensity score matching analysis was used to adjust for age, gender, and body mass index. Immunostaining of Gd-IgA1 with KM55 was performed in paraffin-embedded sections of renal biopsy specimens. LRV entrapment was diagnosed in 47 patients (6%) with several kinds of renal diseases in our cohort. A total of 32 (68%) LRV entrapments were combined with expanded IgAN (idiopathic IgAN and HSPN). The prevalence of LRV entrapment in expanded IgAN was significantly higher than that in non-expanded IgAN (17 vs. 2%, p < 0.001), even after adjustment for age, gender, and body mass index by propensity score matching analysis (13 vs. 2%, p < 0.001). Removing expanded IgAN and LN, glomerular incidental IgA deposition was observed to be significantly more common in patients with LRV entrapment compared with patients without it (43 vs. 9%, p < 0.001). Furthermore, in glomerular diseases with incidental IgA deposits, significantly much larger proportion of patients with LRV entrapment were positive for glomerular Gd-IgA1 in contrast to patients without LRV entrapment (5/5 vs. 5/17, p = 0.01). LRV entrapment coexisted with several kinds of renal diseases, with a significantly higher prevalence in patients with idiopathic IgAN and HSPN. In patients of LN and IgAN-unrelated disease with LRV entrapment, glomerular IgA and Gd-IgA1 deposition was more common compared with patients without LRV entrapment. [ABSTRACT FROM AUTHOR]

Primary membranous nephropathy (PMN) is associated with the highest risk for developing venous thrombosis compared with other nephrotic diseases. The aim of the study was to assess the predictive value of the pathognomonic anti-phospholipase A2 receptor (PLA2R) antibody with regard to incidence of venous thrombosis in PMN. A total of 365 in-hospital patients diagnosed with PMN were enrolled in the study. Anti-PLA2R antibody was detected by commercial enzyme-linked immunosorbent assay. Multivariate logistic regression was used to detect the independent risk factors for venous thrombosis. Thirty-seven patients (10.14%) had venous thrombosis. Patients with venous thrombosis had higher levels of cholesterol (CHOL), low-density lipoprotein (LDL), and D-dimer than those without venous thrombosis (p <.05). Patients with venous thrombosis had significantly lower levels of albumin (23.95 ± 5.53 vs. 26.18 ± 6.59 g/L, p =.049). No significant differences were found in proteinuria, serum creatinine, estimated glomerular filtration rate, platelets, and fibrinogen between patients with and without thrombosis. Anti-PLA2R antibody levels in patients with venous thrombosis were significantly higher than in patients without it (p =.002). In the univariate logistic regression, Ln anti-PLA2R antibody (OR: 1.340; p =.004), albumin (OR: 0.945; p =.050), CHOL (OR: 1.191; p =.006), and LDL (OR: 1.271, p =.006) were associated with venous thrombosis. Ln anti-PLA2R antibody (OR = 1.269; 95%CI: 1.032–1.561), and LDL (OR = 1.213; 95%CI: 1.017–1.448) were the independent risk factors for venous thrombosis (p <.05) in multivariate analysis. Anti-PLA2R antibody was the independent risk factor for venous thrombosis in PMN. Larger prospective studies were warranted to verify the results in future. [ABSTRACT FROM AUTHOR]

Smart structures have the advantages of high system integrity and diverse sensing capabilities. However, the labor-intensive and time-consuming fabrication process hinders the large-scale adoption of smart structures. Despite recent attempts to develop sensor-embedded structures using 3D printing technologies, the reported smart structures generally suffer from the complex fabrication process, constrained part size, and limited sensing modality. Herein, we propose a workflow to design and fabricate novel smart structures via multimaterial fused deposition modeling (FDM)-based 3D printing. More specifically, conductive filaments with tailorable mechanical and electrical properties, e.g. piezoresistive effects, were developed. Additionally, the printing process was optimized for processing soft filaments with Young's modulus around 2 MPa, resolving the issue of filament buckling. Furthermore, the potential applications of the proposed workflow were showcased using three design cases, i.e. biaxial strain sensor, smart tire, and cable-driven soft finger with multiple sensing capabilities. This workflow provides a cost-effective and rapid solution for developing novel smart structures with soft materials. [ABSTRACT FROM AUTHOR]

A significant decrease in red blood cell (RBC) survival has been observed in patients with renal failure, which is supposed to contribute to renal anemia. The aim of this observational study was to determine RBC survival in hemodialysis (HD) patients treated with roxadustat or recombinant human erythropoietin (rhuEPO) compared with healthy persons. RBC lifespan was measured by Levitt's CO breath test with newly developed automatic instrument ELS Tester. A total of 102 patients receiving long-term HD from two independent dialysis centers enrolled in the study, of whom 62 were treated with rhuEPO and 40 were on roxadustat therapy. A total of 25 healthy participants were recruited to match HD participants according to age and sex. Median RBC survival times in rhuEPO, roxadustat, and control groups were 65.0 (25th–75th percentile, 49.5–77.3), 75.5 (25th–75th percentile, 57.3–99.3), and 108.0 (25th–75th percentile, 89.0–141.5) d, respectively. Patients treated with roxadustat had significantly longer RBC survival time than patients treated with rhuEPO (p <.05). In multivariate analysis of factors affecting RBC lifespan in the whole HD patients, anemia treatment drugs (rhuEPO/roxadustat) and levels of hemoglobin were the significantly independent factors. RBC survival was not found to correlate with either weekly rhuEPO dosage (r = –0.087, p =.500) or weekly roxadustat dosage (r = −0.267, p =.110) in our cohort. HD patients treated with roxadustat had significantly longer RBC survival time than patients treated with rhuEPO, large prospective studies with long-term follow-up are warranted to verify the results in future. Abbreviations RBC: red blood cell; HD: hemodialysis; rhu EPO: recombinant human erythropoietin; ESRD: end-stage renal disease; EPO: erythropoietin; ROS: reactive oxygen species; CKD: chronic kideny disease; ESAs: erythropoiesis-stimulating agents; HIF-PHD: hypoxia-inducible factor prolyl hydroxylase; CO: carbon monoxide; Hb: hemoglobin [ABSTRACT FROM AUTHOR]

Nifedipine is completely absorbed by the gastrointestinal tract and its pharmacokinetics and metabolism may be influenced by microorganisms. If gut microbes are involved in the metabolism of nifedipine, plateau hypoxia may regulate the bioavailability and the therapeutic effect of nifedipine by altering the metabolic activity of the gut microbiota. We herein demonstrated for the first time that gut flora is involved in the metabolism of nifedipine by in vitro experiments. In addition, based on the results of 16S rRNA analysis of feces in rats after acute plateau, we first confirmed that the plateau environment could cause changes in the number and composition of intestinal microbes. More importantly, these changes in flora could lead to a slower metabolic activity of nifedipine in the body after an acute plateau, resulting in increased bioavailability and therapeutic efficacy of nifedipine. Our research will provide basis and new ideas for changes in the fecal flora of human acutely entering the plateau, and contribute to rational drug use of nifedipine. [ABSTRACT FROM AUTHOR]

Nifedipine is completely absorbed by the gastrointestinal tract and its pharmacokinetics and metabolism may be influenced by microorganisms. If gut microbes are involved in the metabolism of nifedipine, plateau hypoxia may regulate the bioavailability and the therapeutic effect of nifedipine by altering the metabolic activity of the gut microbiota. We herein demonstrated for the first time that gut flora is involved in the metabolism of nifedipine by in vitro experiments. In addition, based on the results of 16S rRNA analysis of feces in rats after acute plateau, we first confirmed that the plateau environment could cause changes in the number and composition of intestinal microbes. More importantly, these changes in flora could lead to a slower metabolic activity of nifedipine in the body after an acute plateau, resulting in increased bioavailability and therapeutic efficacy of nifedipine. Our research will provide basis and new ideas for changes in the fecal flora of human acutely entering the plateau, and contribute to rational drug use of nifedipine. [ABSTRACT FROM AUTHOR]

Context: Development of a reliable and selective anti-inflammatory agent of cyclooxygenase-2 (COX-2), induced or up-regulated by inflammatory/injury stimulus such as IL-1β, TNF-α and LPS in the various types of organs, tissues and cells, with low side effects is a long-standing medicinal chemistry problem with significant social implications. Objective: To target druggable enzymome COX-2 by exploiting NSAIDs and genipin (GEP) in anti-inflammatory infection. Materials and methods: The compound aspirin GEP ester (AGE) was designed by computer-assisted screening, synthesized in the esterification of the acylate derivative and the methylate derivative with Et3N, and evaluated with 20, 40 and 60 mg/kg from days 18 to 24 after immunization in collagen-induced arthritis (CIA) rats by the sequential enzymatic experiments, western-blot analysis and pathological observation methods. Results: AGE exhibited higher binding affinity with COX-1 and displayed the lowest estimated free energy with COX-2 than other ligands built by hanging NSAIDs with GEP, and was characterized by1H NMR,13C NMR and HRMS. AGE was competed against COX-2 with molecule-dependent potencies and selectivity (IC50: 0.36 mM; selectivity index: 275) in the sequential enzymatic experiments and decreased the expression of COX-2 in peripheral blood lymphocytes of CIA rats. AGE (40 and 60 mg/kg) could significantly relieve the secondary hind paw swelling and arthritis index, along with observing AGE attenuated histopathological changes of fibroblast like synovial tissue (FLST) and mesenteric lymph node lymphocytes (MLNL) in CIA rats. Discussion and conclusion: AGE pharmacophore reported herein may be an effective strategy to develop a novel anti-inflammatory agent and potential inhibitor of COX-2. [ABSTRACT FROM AUTHOR]

We propose a novel two-step procedure to combine epidemiological data obtained from diverse sources with the aim to quantify risk factors affecting the probability that an individual develops certain disease such as cancer. In the first step, we derive all possible unbiased estimating functions based on a group of cases and a group of controls each time. In the second step, we combine these estimating functions efficiently to make full use of the information contained in data. Our approach is computationally simple and flexible. We illustrate its efficacy through simulation and apply it to investigate pancreatic cancer risks based on data obtained from the Connecticut Tumor Registry, a population-based case–control study, and the Behavioral Risk Factor Surveillance System which is a state-based system of health surveys. Supplementary materials for this article are available online. [ABSTRACT FROM AUTHOR]

Meat batters were made with lean pork and back fat in a vacuum bowl chopper. The integrated light scattering analysis showed that the droplet/particle size distribution in the batters was bimodal for 3, 5, and 7 min of chopping. The distance between the two peaks in a distribution curve was gradually reduced with shearing time. Back fat was sheared into various sizes and shapes of droplets/particles in meat batters. The results showed that regardless of raw meat batter or meat-batter gel, fat globules, particles, and clusters were all surrounded with smooth protein films and entrapped in a rigid protein matrix. The sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis showed that the protein films consisted of C-protein, actin, α-actinin, troponin T, tropomyosin, and other proteins besides myosin. The results could help us to better understand the emulsion mechanism for meat batters. [ABSTRACT FROM PUBLISHER]

Individuals carrying a germ line mutation of the breast cancer susceptibility gene BRCA2 are predisposed to breast, ovarian, and other types of cancer. The BRCA2 protein has been proposed to function in the repair of DNA double-strand breaks. Using an immunopurification-mass spectrometry approach to identify novel proteins that associate with the BRCA2 gene product, we found that a deubiquitinating enzyme, USP11, formed specific complexes with BRCA2. Moreover, BRCA2 was constitutively ubiquitinated in vivo in the absence of detectable proteasomal degradation. Mitomycin C (MMC) led to decreased BRCA2 protein levels associated with increased ubiquitination, consistent with proteasome-dependent degradation. While BRCA2 could be deubiquitinated by USP11 in transient overexpression assays, a catalytically inactive USP11 mutant had no effect on BRCA2 ubiquitination or protein levels. Antagonism of USP11 function either through expression of this mutant or through RNA interference increased cellular sensitivity to MMC in a BRCA2-dependent manner. All of these results imply that BRCA2 expression levels are regulated by ubiquitination in the cellular response to MMC-induced DNA damage and that USP11 participates in DNA damage repair functions within the BRCA2 pathway independently of BRCA2 deubiquitination. [ABSTRACT FROM AUTHOR]