Aims/hypothesis
Beta cell death triggered by pro-inflammatory cytokines plays a central role in the pathogenesis of type 1 diabetes and loss of transplanted islets. The nuclear factor κB (NF-κB) ...signalling pathway is a key regulator of beta cell stress response, survival and apoptosis. Withaferin A (WA), a steroidal lactone derived from
Withania somnifera
, has been demonstrated to be a potent, safe, anti-inflammatory molecule that can inhibit NF-κB signalling. Therefore, we evaluated the ability of WA to protect mouse and human islets from the damaging effects of pro-inflammatory cytokines in vitro and following intraportal transplantation.
Methods
Mouse and human islets were treated with a cytokine cocktail, and NF-κB activation was measured by immunoblots, p65 nuclear translocation and chromatin immunoprecipitation of p65-bound DNA. Intraportal transplantation of a marginal mass of syngeneic mouse islets was performed to evaluate the in vivo protective effect of WA.
Results
Treatment with WA substantially improved islet engraftment of syngeneic islets (83% for infusion with 200 islets + WA; 0% for 200 islets + vehicle) in a mouse model of diabetes, compared with marginal graft controls with superior islet function in WA-treated mice confirmed by glucose tolerance test. Treatment of human and mouse islets with WA prevented cytokine-induced cell death, inhibited inflammatory cytokine secretion and protected islet potency.
Conclusions
WA was shown to be a strong inhibitor of the inflammatory response in islets, protecting against cytokine-induced cell damage while improving survival of transplanted islets. These results suggest that WA could be incorporated as an adjunctive treatment to improve islet transplant outcome.
A metal-free pyrazine dye exhibited vapoluminescence when exposed to benzene vapour. Single-crystal X-ray analysis revealed that its flexible bulky groups and weak interactions involving halogens ...play an essential role in the occurrence of the observed vapoluminescence.
To investigate whether the direct application of vibratory stimuli inhibits spasticity in the hemiplegic upper limbs of post-stroke patients.
A randomized controlled study.
Thirty-six post-stroke ...patients.
Patients were randomly allocated to the "Rest group", "Stretch group", or "Direct application of vibratory stimuli group". After relaxing in a supine posture for 30 min, subjects received the interventions for 5 min. The Modified Ashworth Scale scores and F-wave parameters were recorded before, immediately after and 30 min after each intervention.
The Rest group showed no significant changes in F-wave parameters and Modified Ashworth Scale scores. The Stretch group showed a tendency to decrease in F-wave amplitude and F/M ratio immediately after the intervention, but not 30 min later. The Direct application of vibratory stimuli group showed significant improvements in F-wave parameters and Modified Ashworth Scale scores immediately after the intervention, which remained 30 minutes later. The changes in F-wave parameters and Modified Ashworth Scale scores observed in the Direct application of vibratory stimuli group significantly differed from those in the Rest group and the Stretch group.
The direct application of vibratory stimuli has anti-spastic effects in the hemiplegic upper limbs of post-stroke patients.
A linkage map of Chinese cabbage (Brassica rapa) was constructed to localize the clubroot resistance (CR) gene, Crr3. Quantitative trait loci analysis using an F₃ population revealed a sharp peak in ...the logarithm of odds score around the sequence-tagged site (STS) marker, OPC11-2S. Therefore, this region contained Crr3. Nucleotide sequences of OPC11-2S and its proximal markers showed homology to sequences in the top arm of Arabidopsis chromosome 3, suggesting a synteny between the two species. For fine mapping of Crr3, a number of STS markers were developed based on genomic information from Arabidopsis. We obtained polymorphisms in 23 Arabidopsis-derived STS markers, 11 of which were closely linked to Crr3. The precise position of Crr3 was determined using a population of 888 F₂ plants. Eighty plants showing recombination around Crr3 locus were selected and used for the mapping. A fine map of 4.74 cM was obtained, in which two markers (BrSTS-41 and BrSTS-44) and three markers (OPC11-2S, BrSTS-54 and BrSTS-61) were cosegregated. Marker genotypes of the 21 selected F₂ families and CR tests of their progenies strongly suggested that the Crr3 gene is located in a 0.35 cM segment between the two markers, BrSTS-33 and BrSTS-78.
Abstract Glycated albumin (GA) is used alongside glycated hemoglobin (HbA1C ) as an indicator of glycemic control. Although serum GA levels are affected mainly by plasma glucose, they are also ...influenced by serum albumin metabolism. Thyroid hormone is known to promote albumin catabolism, and it is thus thought to affect serum GA levels. In the present study, the effects of thyroid hormone on serum GA measurements were investigated in patients with thyroid dysfunction. Six patients with untreated hypothyroidism and 17 patients with untreated thyrotoxicosis were investigated. Patients who had anemia or diabetes were excluded. A total of 25 non-diabetic, euthyroid individuals were enrolled as controls. HbA1C , serum GA, thyroid-stimulating hormone (TSH), free triiodothyronine (T3 ), and free thyroxine (T4 ) levels were measured in all these subjects, and their relationships were examined. Although no intergroup differences were observed for HbA1C , serum GA was significantly higher among patients with hypothyroidism than controls, and significantly lower among patients with thyrotoxicosis. Serum GA had a significant positive correlation with serum TSH and significant inverse correlations with free T3 and free T4. Thyroid hormone levels are inversely associated with serum GA levels. Cautions are necessary when evaluating serum GA levels in patients with thyroid dysfunction.
Magnesium supplementation has been reported to have a nephroprotective effect on cisplatin-induced renal dysfunction, but little evidence exists regarding the effect of magnesium preloading before ...cisplatin administration. We started to include magnesium preloading (8 mEq) in cisplatin-containing treatment regimens in January 2011. The aim of the present study was to evaluate whether magnesium preloading reduces cisplatin-induced nephrotoxicity.
We retrospectively reviewed 496 thoracic malignancy patients treated with cisplatin (≥60 mg/m²)-containing regimens as a first-time chemotherapy between January 2009 and December 2011. We compared the incidence of Grade ≥2 serum creatinine elevation according to the Common Terminology Criteria for Adverse Events, version 4.0, between magnesium preloading group (n = 161 32%) and non-magnesium preloading group (n = 335 68%) during the first cycle and all cycles.
The median number of administered cycles was four in both groups. The incidence of Grade ≥2 serum creatinine elevation in magnesium preloading group was significantly lower during both the first cycle and all cycles than in the non-magnesium preloading group (4.9 versus 19.1% during the first cycle, and 14.2 versus 39.7% during all the cycles). A multivariate analysis indicated that magnesium preloading significantly reduced cisplatin-induced nephrotoxicity throughout the entire period from after the first administration (odds ratio: 0.262, 95% confidence interval: 0.106-0.596 during the first cycle, and odds ratio: 0.234, 95% confidence interval: 0.129-0.414 during all cycles).
Magnesium preloading before cisplatin administration significantly reduced cisplatin-induced nephrotoxicity.
Interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signals play key roles in the pathogenesis of inflammatory bowel disease (IBD). We previously described that both ...intact cells and a cell wall-derived polysaccharide-peptidoglycan complex (PSPG) in a strain of lactobacillus Lactobacillus casei Shirota (LcS) inhibited IL-6 production in lipopolysaccharide (LPS)-stimulated lamina propria mononuclear cells (LPMCs) isolated from murine IBD. Diets with LcS improve murine IBD by suppression of IL-6 synthesis in LPMCs. Moreover, LcS supplementation with fermented milk ameliorates disease activity in patients with active ulcerative colitis. Here, we focused on the specific roles of PSPG in LcS concerning their anti-inflammatory actions. PSPG derived from LcS, and no other strain of lactobacilli, inhibited IL-6 production in LPS-stimulated murine IBD LPMCs. Purified PSPG-I from LcS inhibited IL-6 synthesis in LPS-stimulated murine IBD LPMCs through the inhibition of nuclear factor-κB. The anti-IL-6 action of LcS PSPG was abrogated by masking with monoclonal anti-PSPG-I. Furthermore, PSPG-I-negative L. casei strains (PSPG-I-negative mutant LcS: LCΔPSPG⁻I, L. casei ATCC 334) did not inhibit IL-6 production. Finally, we confirmed the effects of PSPG-I on LcS in the models of both IBD and colitis-associated cancer (CAC). In the IBD model, ingestion of LcS improved ileitis and inhibited activation of IL-6/STAT3 signaling, while ingestion of the LCΔPSPG⁻I strain did not. In the CAC model, treatment with LcS, but not the LCΔPSPG⁻I strain, showed tumour-suppressive effects with an inhibition of IL-6 production in the colonic mucosa. These results suggested that a specific polysaccharide component in an L. casei strain plays a crucial role in its anti-inflammatory actions in chronic intestinal inflammatory disorders.
Summary
Background
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder causing multiple hamartomas. Treatment of TSC lesions with mammalian target of rapamycin inhibitors is effective. ...Recently, several reports have shown the efficacy of topical rapamycin (sirolimus) for angiofibromas. However, almost all studies have been case studies and the 0·1% solution caused skin irritation. A comparative study of topical rapamycin and a vehicle has not yet been reported.
Objectives
To compare the efficacy of topical rapamycin formulation with that of vehicle for angiofibromas.
Methods
A left–right comparative study between rapamycin 0·2% topical formulation and vehicle was conducted in 11 patients with TSC. Two formulations, an ointment and a gel, were prepared and in vitro percutaneous absorption of rapamycin was determined.
Results
In vitro percutaneous absorption of rapamycin was significantly greater with the gel compared with the ointment. In the clinical study, the rapamycin‐treated cheek showed significant improvements relative to the vehicle‐treated cheek in all outcome measures after 12 weeks of treatment. The improvement was particularly remarkable in children aged ≤ 10 years. No side‐effects were noted, and rapamycin was not detected in the blood of the patients.
Conclusions
Topical rapamycin was significantly effective against angiofibromas. Both formulations used were effective and safe. The 0·2% gel is especially useful because of its better skin penetration and low irritancy. Initiation of topical rapamycin therapy in early childhood would be beneficial for patients with TSC.
What's already known about this topic?
Case studies indicate that 0·1–1% rapamycin ointment, 1% cream and 0·1% solution are effective against angiofibromas in tuberous sclerosis complex (TSC).
The 0·1% solution causes skin irritation.
What does this study add?
This left–right comparative study confirmed that rapamycin 0·2% ointment and gel are effective in TSC compared with vehicle.
In vitro percutaneous absorption is significantly better with the gel than the ointment.
Significantly greater effects are observed in younger children.
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