Anti-Trypanosoma cruzi activity of 10 medicinal plants used in northeast Mexico

The aim of this study was to screen the trypanocidal activity of plants used in traditional Mexican medicine for the treatment of various diseases related to parasitic infections. Cultured Trypanosoma cruzi epimastigotes were incubated for 96 h with different concentrations of methanolic extracts obtained from Artemisia mexicana, Castela texana, Cymbopogon citratus, Eryngium heterophyllum, Haematoxylum brasiletto, Lippia graveolens, Marrubium vulgare, Persea americana, Ruta chalepensis and Schinus molle. The inhibitory concentration (IC₅₀) was determined for each extract via a colorimetric method. Among the evaluated species, the methanolic extracts of E. heterophyllum, H. brasiletto, M. vulgare and S. molle exhibited the highest trypanocidal activity, showing percentages of growth inhibition between 88 and 100% at a concentration of 150 μg/ml. These medicinal plants may represent a valuable source of new bioactive compounds for the therapeutic treatment of trypanosomiasis.     

TSH/cAMP up-regulate sarco/endoplasmic reticulum Ca2+-ATPases expression and activity in PC Cl3 thyroid cells

OBJECTIVE: We recently reported that the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) 2b is the SERCA form preferentially expressed in rat thyroid. Moreover, SERCA2b expression dramatically decreases in virally transformed, highly tumorigenic, PC Cl3 thyroid cells. These results suggest that, in the thyroid, SERCA2b, in addition to its housekeeping role, is linked to differentiation and is a regulated gene. We therefore sought to study the effect of TSH, the main regulator of thyroid function, on SERCA2b expression and activity. METHODS: PC Cl3 cells were hormone starved in low-serum medium and stimulated for long (48 h) or short (1, 2 and 4 h) times. SERCA2b expression and activity were evaluated by Northern and Western blots, Ca2+-ATPase activity and Ca2+ store content. RESULTS: In PC Cl3 cells, SERCA2b mRNA and protein were induced twofold by a 48-h long treatment with TSH. Long-term elevation (48 h) of intracellular cAMP levels, by forskolin or 8-Br-cAMP, had similar effects on SERCA2b mRNA and protein. We also measured Ca2+-ATPase activity and Ca2+ store content. Both long (48 h) and short (0.5-1 h) treatments with TSH, forskolin or 8-Br-cAMP induced a marked increase of SERCA2b activity. This effect was completely abolished by H89, a specific inhibitor of cAMP-dependent protein kinase A (PKA). TSH and 8-Br-cAMP increased Ca2+ store content after both long (48 h) and short (1-2 h) treatments. CONCLUSIONS: These data suggested that TSH/cAMP acts as an important regulator of both SERCA2b expression and activity in the thyroid system, through PKA activation.     

Ixazomib for the treatment of multiple myeloma

Introduction: Proteasome inhibition is a mainstay in the treatment of multiple myeloma (MM). Bortezomib, the first proteasome inhibitor (PI) approved for MM therapy, has shown efficacy in relapsed/refractory patients and in the front-line setting. Among second-generation PIs, MLN9708 (ixazomib) is the first oral compound to be evaluated in MM treatment and has shown improvement in pharmacokinetic and pharmacodynamic parameters compared with bortezomib with a similar efficacy in the control of myeloma growth and in the prevention of bone loss.

Areas covered: In this review, the authors discuss the rationale for use of PIs. They then summarize the clinical development of ixazomib in MM, from initial Phase I to Phase II studies as a monotherapy and in combination with other chemotherapeutics.

Expert opinion: Preliminary data of Phase I/II trials showed that ixazomib had a good safety profile and exerted anti-myeloma activity as a single agent in relapsed/refractory patients. Furthermore, ixazomib also had efficacy in patients who were refractory to bortezomib. Its use in combination with lenalidomide and dexamethasone was shown to be an effective and well-tolerated regimen in up-front treatment leading to minimal residual disease negativity in a significant number of patients. Results of Phase III trials, evaluating ixazomib in induction or maintenance therapy, are awaited.     

Smoldering multiple myeloma: to treat or not to treat

Introduction: Smoldering multiple myeloma (SMM) is an asymptomatic disorder characterized by the presence of ≥ 30 g/l serum M-protein and/or ≥ 10% bone marrow plasma cell infiltration. The progression risk to active multiple myeloma (MM) is not uniform, and several prognostic parameters are useful for identifying patients at high risk of progression. A watch-and-wait approach has been the standard of care up to now. However, recently, it has been demonstrated that a subset of high-risk cases can benefit from early treatment with new drugs.

Areas covered: In this editorial, we focus on SMM and evaluate the diagnostic work-up and the prognostic factors predicting progression to symptomatic MM. We also review the studies in which the role of early treatment has been evaluated for patients with SMM.

Expert opinion: After the update performed by the International Myeloma Working Group regarding MM diagnosis, it is now time to change the therapeutic paradigm for this disease. While “ultra high-risk” myeloma should now be considered as active MM, for low-risk patients the “watch-and-wait” strategy is still recommended. More caution is needed for the high-risk group: physicians should continue monitoring patients using every tool now available while waiting for results from ongoing trials that will establish if this group will benefit from an early intervention.     

Ipilimumab for the treatment of metastatic prostate cancer

Introduction: Immunotherapy with checkpoint inhibitors is beginning to be recognized as a valid weapon for the treatment of metastatic prostate cancer (PCa) when chemotherapy fails. Ipilimumab (ipi) is a fully humanized monoclonal antibody that blocks the activity of CTLA4. It also has a molecular weight of 148 kDa and is water-soluble at physiological pH. Ipi was first approved by the FDA for the treatment of malignant melanoma and is currently being studied in metastatic castration-resistant prostate cancer, with promising early results.

Areas covered: The aim of this review is to collate the most significant preclinical and clinical studies available that look at ipi to propose new strategies for the future.

Expert opinion: Additional studies are required to reduce toxicity and increase the activity of ipi in PCa. A possible strategy is to combine ipi with standard anti-cancer therapeutics such as vaccines, PDL1 inhibitors, antiandrogen drugs, and chemotherapy agents. Several initial results have suggested that combination strategies are useful to increase the activity in mCRPC, even if the toxicity of the treatment can increase. The activity of combined treatments is still not predictable, but considering the ongoing studies, we believe that they have good potential that will lead to the discovery of an optimal therapeutic strategy.     

Direct visualization of intestinal villi by high-resolution magnifying upper endoscopy: a validation study

BACKGROUND: New generation videoendoscopes potentially may visualize duodenal villi. This study compared endoscopic findings with this type of instrument to the histopathologic evaluation of duodenal villi. METHODS: A total of 191 patients underwent upper endoscopy for the purpose of obtaining duodenal biopsy specimens. The findings were assessed independently by 3 experienced observers by using a commercially available, high-resolution, high-magnifying (x2) videoendoscope. The duodenal villous profile was determined by endoscopic magnification and by endoscopic magnification after filling the duodenum with water. With both endoscopic magnification and endoscopic magnification after filling the duodenum with water, villous patterns were scored as the following: definitely present, partially present, or definitely absent. Villous patterns also were histopathologically scored as the following: normal, partial villous pattern, or total villous atrophy. RESULTS: Interobserver variability was excellent (kappa = 0.93). The concordance between either endoscopic magnification or endoscopic magnification after filling the duodenum with water and histology was 100% for presence/absence of villi. The sensitivity, the specificity, and the positive and negative predictive values of endoscopic magnification for detection of any villous abnormality were 95%, 99%, 95%, and 99%, respectively; the respective values of endoscopic magnification after filling the duodenum with water were 95%, 98%, 92%, and 99%. CONCLUSIONS: High-resolution magnifying upper endoscopy can reliably predict the presence or the absence of duodenal villi.