Mollicellins S-U, three new depsidones from Chaetomium brasiliense SD-596 with anti-MRSA activities.

Fungi are important resources for drug development, as they have a diversity of genes, that can produce novel secondary metabolites with effective bioactivities. Here, five depsidone-based analogs were isolated from the rice media of Chaetomium brasiliense SD-596. Their structures were elucidated using NMR and mass spectrometry analysis. Five compounds, including three new depsidone analogs, mollicellin S (1), mollicellin T (2), and mollicellin U (3), and two known compounds, mollicellin D (4) and mollicellin H (5), exhibited significant inhibition against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA), with MIC values ranging from 6.25 to 12.5 µg ml-1. Herein, we identified the predicted plausible biosynthetic cluster of the compounds and discussed the structure-activity relationship. Finally, we found that the introduction of aldehyde and methoxyl groups provide marked improvement for the inhibition against MRSA.

Serum from patients with ankylosing spondylitis can increase PPARD, fra-1, MMP7, OPG and RANKL expression in MG63 cells.

OBJECTIVES: To explore the effects of serum from patients with ankylosing spondylitis on the canonical Wnt/ß-catenin pathway and to assess whether the serum has an osteogenic effect in MG63 cells. METHODS: MG63 cells were cultured with serum from 45 ankylosing spondylitis patients, 30 healthy controls, or 45 rheumatoid arthritis patients. The relative PPARD, fra-1, MMP7, OPG and RANKL mRNA levels were measured using quantitative real-time polymerase chain reaction. Associations between gene expression and patient demographics and clinical assessments were then analyzed. RESULTS: MG63 cells treated with serum from ankylosing spondylitis patients had higher PPARD, fra-1, MMP7 and OPG gene expression than did cells treated with serum from controls or rheumatoid arthritis patients (all p<0.05). RANKL expression was higher in MG63 cells treated with serum from patients with ankylosing spondylitis or rheumatoid arthritis than in those treated with serum from controls (both p<0.05). The OPG/RANKL ratio was also higher in MG63 cells treated with serum from ankylosing spondylitis patients than in those treated with serum from controls (p<0.05). No associations were found between the expression of the five genes and the patient demographics and clinical assessments (all p>0.05). CONCLUSIONS: Serum from ankylosing spondylitis patients increases PPARD, fra-1, MMP7, OPG and RANKL expression and the OPG/RANKL ratio in MG63 cells; these effects may be due to the stimulatory effect of the serum on the Wnt pathway.

Serum from patients with ankylosing spondylitis can increase PPARD, fra-1, MMP7, OPG and RANKL expression in MG63 cells

OBJECTIVES: To explore the effects of serum from patients with ankylosing spondylitis on the canonical Wnt/β-catenin pathway and to assess whether the serum has an osteogenic effect in MG63 cells. METHODS: MG63 cells were cultured with serum from 45 ankylosing spondylitis patients, 30 healthy controls, or 45 rheumatoid arthritis patients. The relative PPARD, fra-1, MMP7, OPG and RANKL mRNA levels were measured using quantitative real-time polymerase chain reaction. Associations between gene expression and patient demographics and clinical assessments were then analyzed. RESULTS: MG63 cells treated with serum from ankylosing spondylitis patients had higher PPARD, fra-1, MMP7 and OPG gene expression than did cells treated with serum from controls or rheumatoid arthritis patients (all p<0.05). RANKL expression was higher in MG63 cells treated with serum from patients with ankylosing spondylitis or rheumatoid arthritis than in those treated with serum from controls (both p<0.05). The OPG/RANKL ratio was also higher in MG63 cells treated with serum from ankylosing spondylitis patients than in those treated with serum from controls (p<0.05). No associations were found between the expression of the five genes and the patient demographics and clinical assessments (all p>0.05). CONCLUSIONS : Serum from ankylosing spondylitis patients increases PPARD, fra-1, MMP7, OPG and RANKL expression and the OPG/RANKL ratio in MG63 cells; these effects may be due to the stimulatory effect of the serum on the Wnt pathway.

Flexible Ureteroscopic Management of Horseshoe Kidney Renal Calculi.

PURPOSE: To evaluate the clinical efficacy of flexible ureteroscope (F-URS) combined with holmium laser lithotripter in treating renal calculi in horseshoe kidney. MATERIALS AND METHODS: From November 2010 to December 2013, the medical history and charts of sixteen patients (mean age 42.9 ± 11.6 years, range 26-66 years), including 13 males and 3 females were analyzed retrospectively. Mean stone burden was 29 ± 8 mm (range 17-42 mm2). Mean stone digitized surface area (DSA) was 321 ± 94 mm2 (range 180-538 mm2). Under spinal anesthesia in a modified lithotomy position with the head down, rigid ureteroscope was placed firstly into the ureter to reach the level of the pelvis, a zebra guide wire was inserted and following the removal of the rigid ureteroscope, an ureteral access sheath was positioned along the guide wire, then passed the URF P-5 flexible ureteroscope into the renal cavities over the guidewire. After locating the stones, holmium laser lithotripsy was performed. RESULTS: The average operative time was 92 ± 16 minutes (range 74-127 min.). No major complications were encountered. Ten patients obtained stone-free status with one session, four obtained stone-free status after two sessions. Single session stone-free rate was 62.5%, overall stone-free rate was 87.5%. Two patients have small residual stones in the lower pole. CONCLUSIONS: F-URS combined with holmium laser lithotripter and nitinol basket, is safe and effective in dealing with moderate stone diameter (<30 mm) in HSKs with high clearance rates and low complication rates.

Flexible Ureteroscopic Management of Horseshoe Kidney Renal Calculi

ABSTRACTPurpose:To evaluate the clinical efficacy of flexible ureteroscope (F-URS) combined with holmium laser lithotripter in treating renal calculi in horseshoe kidney.Materials and Methods:From November 2010 to December 2013, the medical history and charts of sixteen patients (mean age 42.9±11.6 years, range 26-66 years), including 13 males and 3 females were analyzed retrospectively. Mean stone burden was 29±8 mm (range 17-42 mm2). Mean stone digitized surface area (DSA) was 321±94 mm2 (range 180-538 mm2). Under spinal anesthesia in a modified lithotomy position with the head down, rigid ureteroscope was placed firstly into the ureter to reach the level of the pelvis, a zebra guide wire was inserted and following the removal of the rigid ureteroscope, an ureteral access sheath was positioned along the guide wire, then passed the URF P-5 flexible ureteroscope into the renal cavities over the guidewire. After locating the stones, holmium laser lithotripsy was performed.Results:The average operative time was 92±16 minutes (range 74-127 min.). No major complications were encountered. Ten patients obtained stone-free status with one session, four obtained stone-free status after two sessions. Single session stone-free rate was 62.5%, overall stone-free rate was 87.5%. Two patients have small residual stones in the lower pole.Conclusions:F-URS combined with holmium laser lithotripter and nitinol basket, is safe and effective in dealing with moderate stone diameter (<30 mm) in HSKs with high clearance rates and low complication rates.

Targeting STAT5 in hematologic malignancies through inhibition of the bromodomain and extra-terminal (BET) bromodomain protein BRD2.

The transcription factor signal STAT5 is constitutively activated in a wide range of leukemias and lymphomas, and drives the expression of genes necessary for proliferation, survival, and self-renewal. Thus, targeting STAT5 is an appealing therapeutic strategy for hematologic malignancies. Given the importance of bromodomain-containing proteins in transcriptional regulation, we considered the hypothesis that a pharmacologic bromodomain inhibitor could inhibit STAT5-dependent gene expression. We found that the small-molecule bromodomain and extra-terminal (BET) bromodomain inhibitor JQ1 decreases STAT5-dependent (but not STAT3-dependent) transcription of both heterologous reporter genes and endogenous STAT5 target genes. JQ1 reduces STAT5 function in leukemia and lymphoma cells with constitutive STAT5 activation, or inducibly activated by cytokine stimulation. Among the BET bromodomain subfamily of proteins, it seems that BRD2 is the critical mediator for STAT5 activity. In experimental models of acute T-cell lymphoblastic leukemias, where activated STAT5 contributes to leukemia cell survival, Brd2 knockdown or JQ1 treatment shows strong synergy with tyrosine kinase inhibitors (TKI) in inducing apoptosis in leukemia cells. In contrast, mononuclear cells isolated form umbilical cord blood, which is enriched in normal hematopoietic precursor cells, were unaffected by these combinations. These findings indicate a unique functional association between BRD2 and STAT5, and suggest that combinations of JQ1 and TKIs may be an important rational strategy for treating leukemias and lymphomas driven by constitutive STAT5 activation.