Structure-Guided Discovery of Diverse Cytotoxic Dimeric Xanthones/Chromanones from Penicillium chrysogenum C-7-2-1 and Their Interconversion Properties.

Xanthone-chromanone homo- or heterodimers are regarded as a novel class of topoisomerase (Topo) inhibitors; however, limited information about these compounds is currently available. Here, 14 new (1-14) and 6 known tetrahydroxanthone chromanone homo- and heterodimers (15-20) are reported as isolated from Penicillium chrysogenum C-7-2-1. Their structures and absolute configurations were unambiguously demonstrated by a combination of spectroscopic data, single-crystal X-ray diffraction, modified Mosher's method, and electronic circular dichroism analyses. Plausible biosynthetic pathways are proposed. For the first time, it was discovered that tetrahydroxanthones can convert to chromanones in water, whereas chromone dimerization does not show this property. Among them, compounds 5, 7, 8, and 16 exhibited significant cytotoxicity against H23 cell line with IC50 values of 6.9, 6.4, 3.9, and 2.6 µM, respectively.

Effects of Germination on the Structure, Functional Properties, and In Vitro Digestibility of a Black Bean (Glycine max (L.) Merr.) Protein Isolate.

The utilization of black beans as a protein-rich ingredient presents remarkable prospects in the protein food industry. The objective of this study was to assess the impact of germination treatment on the physicochemical, structural, and functional characteristics of a black bean protein isolate. The findings indicate that germination resulted in an increase in both the total and soluble protein contents of black beans, while SDS-PAGE demonstrated an increase in the proportion of 11S and 7S globulin subunits. After germination, the particle size of the black bean protein isolate decreased in the solution, while the absolute value of the zeta potential increased. The above results show that the stability of the solution was improved. The contents of ß-sheet and ß-turn gradually decreased, while the content of α-helix increased, and the fluorescence spectrum of the black bean protein isolate showed a red shift phenomenon, indicating that the structure of the protein isolate and its polypeptide chain were prolonged, and the foaming property, emulsification property and in vitro digestibility were significantly improved after germination. Therefore, germination not only improves functional properties, but also nutritional content.

Mechanism of Yiqi Yangying Heluo Formula in the Treatment of IgA Nephropathy by Affecting Gd-IgA1 Based on BAFF Molecular Level and T Lymphocyte Immunity.

Background: Galactose-deficient IgA1 (Gd-IgA1) is a critical initiating factor in the pathogenesis of IgA nephropathy (IgAN), which plays an important role in the diagnosis and evaluation of this disease. Moreover, the whole pathogenesis process has an intimate association with the immune response of T and B lymphocytes and their inflammatory factors. There is no specific therapy for IgAN at present. Yiqi Yangyin Formula can significantly reduce urinary protein and hematuria in patients with IgAN. Yiqi Yangying Heluo Formula (YYHF) is optimized on the basis of the above prescription, but its specific mechanism remains to be further studied. Methods: The effect of YYHF on urinary protein and urinary red blood cell count in patients with IgAN was observed by a self-controlled clinical study before and after treatment. On this basis, flow cytometry was used to detect the proportion of T lymphocyte subsets in peripheral blood of patients with IgAN before and after treatment and healthy controls. Meanwhile, the levels of Gd-IgA1, B cell activation factor (BAFF), and their cytokines (IL-4, IL-6, and IL-17) in peripheral blood were detected by enzyme-linked immunosorbent assay. The changes in mechanism-related indicators of the two groups were observed and subject to correlation analysis. Results: (1) Compared with the levels before treatment, 24-hour urinary protein content decreased by 47.7% and urinary red blood cell number decreased by 67% in patients with IgAN intervened by YYHF after 48 weeks of follow-up. (2) Compared with the healthy control group, patients with IgAN showed a significantly increased proportion of Th1 cells, Th17 cells, Th1/Th2, Th1/Treg, Th2/Treg, and Th17/Treg, obviously reduced proportion of Th2 cells and Treg cells, and evidently elevated levels of Gd-IgA1, BAFF, and their cytokines (IL-4, IL-6, and IL-17) in the peripheral blood. (3) Following 48 weeks of follow-up after intervention treatment with YYHF, the levels of Gd-IgA1, BAFF, IL-6, and IL-17 were significantly lower, but the level of IL-4 was higher in peripheral blood of patients with IgAN than those before treatment and after 24 weeks of treatment; simultaneously, the proportion of Th1 cells, Th17 cells, Th1/Th2, Th1/Treg, Th2/Treg, and Th17/Treg decreased while that of Th2 cells and Treg cells increased after 48 weeks of follow-up compared with that before treatment in peripheral blood of patients with IgAN. (4) The results of correlation analysis revealed that the level of Gd-IgA1 in peripheral blood of patients with IgAN was positively correlated with the level of BAFF, as well as the proportion of Th1 cells, Th17 cells, Th1/Th2, IL-6, and IL-17 levels, and negatively correlated with the proportion of Treg cells. In addition, the level of Gd-IgA1 in peripheral blood was positively correlated with proteinuria, yet without correlation with hematuria. Conclusion: YYHF can reduce the quantitative level of 24 h urinary protein and urinary red blood cell count in patients with IgAN. Patients with IgAN have obvious T cell immune imbalance. YYHF can significantly reduce the level of Gd-IgA1 in patients with IgAN, and its mechanism may be explained by the reduced level of BAFF in peripheral blood and improved immune balance of T cells.

Thiolated Mesoporous Silica Nanoparticles as an Immunoadjuvant to Enhance Efficacy of Intravesical Chemotherapy for Bladder Cancer.

The characteristics of global prevalence and high recurrence of bladder cancer has led numerous efforts to develop new treatments. The spontaneous voiding and degradation of the chemodrug hamper the efficacy and effectiveness of intravesical chemotherapy following tumor resection. Herein, the externally thiolated hollow mesoporous silica nanoparticles (MSN-SH(E)) is fabricated to serve as a platform for improved bladder intravesical therapy. Enhanced mucoadhesive effect of the thiolated nanovector is confirmed with porcine bladder. The permeation-enhancing effect is also verified, and a fragmented distribution pattern of a tight junction protein, claudin-4, indicates the opening of tight junction. Moreover, MSN-SH(E)-associated reprogramming of M2 macrophages to M1-like phenotype is observed in vitro. The antitumor activity of the mitomycin C (MMC)-loaded nanovector (MMC@MSN-SH(E)) is more effective than that of MMC alone in both in vitro and in vivo. In addition, IHC staining is used to analyze IFN-γ, TGF-ß1, and TNF-α. These observations substantiated the significance of MMC@MSN-SH(E) in promoting anticancer activity, holding the great potential for being used in intravesical therapy for non-muscle invasive bladder cancer (NMIBC) due to its mucoadhesivity, enhanced permeation, immunomodulation, and prolonged and very efficient drug exposure.

Shengxuening versus Oral Iron Supplementation for the Treatment of Renal Anemia: A Systematic Review.

Shengxuening (SXN), as an effective supplement to heme-like iron, has been widely used in China to treat renal anemia. However, proof of its use for improving inflammation is scarce in the past decades. This work aimed to evaluate the effectiveness of SXN with inflammatory factors as primary endpoints. By searching PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Biology Medicine disc (CBM), VIP Information/ China Science and Technology Journal Database, and WANFANG Database, we identified previous studies that met the inclusion criteria and included them in the systematic review. Analyses were performed using STATA. Nine randomized controlled trials were included in this systematic review. The results revealed that, when compared with oral iron supplementation, SXN can reduce the level of inflammatory factors, including hs-CRP (WMD -1.93 mg/L; 95% CI -2.14 to -1.72), IL-6 (P< 0.05), and TNF-α (P< 0.05), and significantly enhance the level of Hb (WMD 13.40 g/L; 95% CI 12.95 to 13.84), TSAT (WMD 6.88%; 95% CI 6.50 to 7.26), and SF (WMD 38.46 µg/L; 95% CI 23.26 to 53.67). Moreover, SXN exhibits a superior security than oral iron supplementation with less gastrointestinal adverse reactions (RR 0.14; 95% CI 0.06 to 0.32). In patients with renal anemia, SXN is more efective and safer than oral iron supplementation, especially in reducing the level of inflammation.

Efficacy of Traditional Chinese Medicine Regimen Jian Pi Qu Shi Formula for Refractory Patients with Idiopathic Membranous Nephropathy: A Retrospective Case-Series Study.

BACKGROUND: The treatment of adult refractory idiopathic membranous nephropathy with steroid and other immunosuppressant-resistant nephrotic syndromes can be a significant challenge. We evaluated the efficacy and safety of the traditional Chinese medicine Jian Pi Qu Shi Formula (JPQSF) as a promising regimen. METHODS: We analyzed 15 consecutive patients with biopsy-proven idiopathic membranous nephropathy who failed immunosuppressive therapy from October 2013 to January 2017. JPQSF was administered orally two times per day, respectively, in the morning and at night for 6 months. All patients had at least 1 year of follow-up. The primary endpoints included complete or partial remission. Secondary endpoints included change of clinical parameters and adverse events after 12 months of treatment. RESULTS: After 12 months, complete remission was achieved in 13.3% of patients and partial remission in 66.7%, yielding a response rate of 80%. Proteinuria, serum albumin, and cholesterol were improved significantly (P<0.001, P<0.001, and P<0.05, respectively). After 1 year of treatment, proteinuria (mean ± SD) decreased from 5.93 ± 2.54 g per 24 h to 1.99 ± 1.17 g per 24 h (P<0.001). No serious adverse events occurred during the observation. CONCLUSIONS: JPQSF may be an alternative therapeutic option for steroid and general immunosuppressant-resistant membranous nephrotic syndrome patients, with a favorable safety profile. Larger and longer follow-up studies evaluating this regimen are warranted.

A novel scoring model for predicting mortality risk in patients with cirrhosis and hepatorenal syndrome.

BACKGROUND AND AIMS: This study aimed to create a risk scoring model for death from cirrhosis and hepatorenal syndrome, improve the detection rate of high-risk groups, and provide clinical evidence for early intervention treatment. PATIENTS AND METHODS: We retrospectively recruited 196 patients with cirrhosis and hepatorenal syndrome between 1 January 2013 and 31 July 2014 at Beijing Ditan Hospital, Capital Medical University, China. The clinical information, biochemical values, age, and sex of the patients were included in the multivariate logistic regression model for screening independent risk factors. The model was validated in 56 patients with cirrhosis and hepatorenal syndrome between 1 August 2014 and 31 December 2014 at Beijing Ditan Hospital, Capital Medical University, China. RESULTS: The death risk prediction scoring model included the following four independent risk factors: liver cancer, neutrophil above 70%, alanine aminotransferase higher than 40 U/l, and creatinine higher than 127 mmol/l. The sum death risk score ranged from 0 to 5: 0-2 identified patients with a lower risk of death (mortality rates: 12-41.4%), whereas 3-5 identified patients with a higher risk of death (mortality rates: 48.8-80%). Receiver-operating characteristic curves were constructed for the scoring model and the areas under the curves (AUC) were compared using the z-test. The AUC of the scoring model was 0.843. In addition, the AUC of validated model in 56 patients was 0.742. CONCLUSION: The scoring model can accurately predict mortality risk in patients with hepatorenal syndrome.

Chondrogenic differentiation of ChM-I gene transfected rat bone marrow-derived mesenchymal stem cells on 3-dimensional poly (L-lactic acid) scaffold for cartilage engineering.

We have explored the role of Chondromodulin-I (ChM-I) in chondrogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) in 3-dimensional (3D) scaffold for cartilage tissue engineering. BMSCs of Sprague Dawley (SD) rats were cultured on poly-(L-lactic acid) [PLLA] scaffolds with different pore sizes (80-200 µm, 200-450 µm) with or without surface modification by chitosan. Cell viability, proliferation, and morphology were measured using confocal microscope and the CCK-8 method. Untransfected BMSCs, BMSCs expressing pcDNA3.1(+), BMSCs expressing plasmid pcDNA3.1 (+)/ChM-I were cultured on 3D scaffolds in standard growth medium or transforming growth factor-ß1 (TGF-ß1) supplemented chondrogenic induction medium in vitro for 3 weeks and the expression of collagen type II was determined. Cell-scaffolds constructs were implanted subcutaneously for 3 months in vivo. BMSCs had a higher viability and proliferation in PLLA scaffolds of pore size 200-450 µm than that of 80-200 µm, and surface modification with chitosan did not enhance cell attachment. The ChM-I gene enhanced chondrogenesis and increased collagen type II synthesis. Immunohistochemistry from in vivo study showed enhanced cartilage regeneration in BMSCs expressing pcDNA3.1 (+)/ChM-I on 3D PLLA scaffolds. It also demonstrated that TGF-ß1 might promote chondrogenesis of rat BMSCs by synergizing with the ChM-I gene. ChM-I could be beneficial to future applications in cartilage repair.

Targeting 11q23 positive acute leukemia cells with high molecular weight-melanoma associated antigen-specific monoclonal antibodies.

BACKGROUND: Acute leukemia with 11q23 aberrations is associated with a poor outcome with therapy. The lack of efficacy of conventional therapy has stimulated interest in developing novel strategies. Recent studies have shown that 11q23-positive acute leukemia cells express the high molecular weight-melanoma associated antigen (HMW-MAA). This tumor antigen represents a useful target to control growth of human melanoma tumors in patients and in severe combined immunodeficient (SCID) mice, utilizing antibody-based immunotherapy. This effect appears to be mediated by inhibition of the HMW-MAA function such as triggering of the focal adhesion kinase/proline-rich tyrosine kinase 2 (Pyk2) pathways. Therefore, in this study we tested whether HMW-MAA-specific monoclonal antibodies (mAb) could inhibit growth of 11q23-positive leukemia cells in SCID mice. METHODS: HMW-MAA-specific mAb were tested for their ability to inhibit the in vitro proliferation of an 11q23-positive acute myeloid leukemia (AML) cell line and blasts from four patients with 11q23 aberrations and their in vivo growth in subcutaneous and disseminated xenograft models. RESULTS: The HMW-MAA-specific mAb did not affect in vitro proliferation although they down-regulated phosphorylated (P) Pyk2 expression. Furthermore, the mAb enhanced the in vitro anti-proliferative effect of cytarabine. In vivo the mAb inhibited the growth of leukemic cells in a dose-dependent fashion. However, the difference did not reach statistical significance. No effect was detected on P-Pyk2 expression. Furthermore, HMW-MAA-specific mAb in combination with cytarabine did not improve tumor inhibition. Lastly, the combination of two mAb which recognize distinct HMW-MAA determinants had no detectable effect on survival in a disseminated xenograft model. CONCLUSIONS: HMW-MAA-specific mAb down-regulated P-Pyk2 expression and enhanced the anti-proliferative effect of cytarabine in vitro, but had no detectable effect on survival or growth of leukemia cells in vivo. Whether the HMW-MAA-specific mAb can be used as carriers of toxins or chemotherapeutic agents against 11q23-acute leukemia remains to be determined.