Protective effect of sucrose esters from cape gooseberry (Physalis peruviana L.) in TNBS-induced colitis.

Phytotherapy is an attractive strategy to treat inflammatory bowel disease (IBD) that could be especially useful in developing countries. We previously demonstrated the intestinal anti-inflammatory effect of the total ethereal extract from the Physalis peruviana (Cape gooseberry) calyces in TNBS-induced colitis. This work investigates the therapeutic potential of Peruviose A and B, two sucrose esters that constitute the major metabolites of its calyces. The effect of the Peruvioses A and B mixture on TNBS-induced colitis was studied after 3 (preventive) and 15-days (therapy set-up) of colitis induction in rats. Colonic inflammation was assessed by measuring macroscopic/histologic damage, MPO activity, and biochemical changes. Additionally, LPS-stimulated RAW 264.7 macrophages were treated with test compounds to determine the effect on cytokine imbalance in these cells. Peruvioses mixture ameliorated TNBS-induced colitis in acute (preventive) or established (therapeutic) settings. Although 3-day treatment with compounds did not produce a potent effect, it was sufficient to significantly reduce the extent/severity of tissue damage and the microscopic disturbances. Beneficial effects in the therapy set-up were substantially higher and involved the inhibition of pro-inflammatory enzymes (iNOS, COX-2), cytokines (TNF-α, IL-1ß, and IL-6), as well as epithelial regeneration with restoration of goblet cells numbers and expression of MUC-2 and TFF-3. Consistently, LPS-induced RAW 264.7 cells produced less NO, PGE2, TNF-α, IL-6, and MCP-1. These effects might be related to the inhibition of the NF-κB signaling pathway. Our results suggest that sucrose esters from P. peruviana calyces, non-edible waste from fruit production, might be useful as an alternative IBD treatment.

Transcriptome Changes in Colorectal Cancer Cells upon Treatment with Avicequinone B.

Purpose: Naphtho[2,3-b]furan-4,9-dione (Avicequinone B), a natural naphthoquinone isolated from the mangrove tree Avicennia alba , is recognized as a valuable synthetic precursor with anti-proliferative effect. However, the molecular mechanism involved in its bioactivity has not been investigated. This study aimed to determine the selectivity of avicequinone B against cancer cells and the transcriptomic changes induced in colorectal cancer (CRC). Methods: The cytotoxic effect against adenocarcinoma-derived cells or fibroblasts was evaluated using MTT assay. In addition, CRC cells were treated with avicequinone B in different settings to evaluate colony-forming ability, cell cycle progression, apoptosis/necrosis induction, and transcriptome response by RNA-seq. Results: Avicequinone B effectively reduced the viability of breast, colorectal, and lung adenocarcinoma cells with IC50 lower than 10 µM, while fibroblasts were less affected. The induction of G2/M arrest and necrosis-like cell death were observed in avicequinone B-treated HT-29 cells. Furthermore, RNA-seq revealed 490 differentially expressed genes, highlighting the reduction of interferon stimulated genes and proliferative signaling pathways (JAK-STAT, MAPK, and PI3K-AKT), as well as the induction of ferroptosis and miR-21 expression. Conclusion: In short, these results demonstrated the therapeutic potential of avicequinone B and paved the foundation for elucidating its mechanisms in the context of CRC.

Physalis angulata Calyces Modulate Macrophage Polarization and Alleviate Chemically Induced Intestinal Inflammation in Mice.

As part of the search for new bioactive plants from the Colombian Caribbean, the dichloromethane fraction of the calyces of Physalis angulata L. (PADF) was selected for its anti-inflammatory activity. In this work, we investigated the immunomodulatory effect of PADF in activated macrophages and during dextran sulfate sodium (DSS)-induced colitis. PADF displayed a low content of withanolides or phenolic compounds, and a higher content of sucrose esters, representative anti-inflammatory metabolites of the Physalis genus. The PADF fraction at 12.5 µg/mL prevented the induction of interleukin (IL)-1ß, tumor necrosis factor (TNF-α), IL-6, IL-12, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) by lipopolysaccharide (LPS), while increased the levels of arginase (ARG1), IL-10, and mannose receptor C (MRC1). The polarization towards an anti-inflammatory profile was also observed in resting macrophages, without promoting the typical gene profile induced by IL-4, suggesting that PADF promotes a shift to a regulatory status rather than to an alternative one. In vivo, the administration of PADF to mice with chronic DSS-colitis reduced disease signs (i.e., body weight loss and colon shortening), and improved the histology score by diminishing the levels of pro-inflammatory cytokines and increasing the production of IL-10. Overall, results suggest that the regulatory effect on PADF towards macrophages might contribute to the therapeutic activity observed in the murine model of inflammatory bowel disease.

A screening of plants used in Colombian traditional medicine revealed the anti-inflammatory potential of Physalis angulata calyces.

The use of natural products by communities from the Colombian Caribbean region to treat health issues, together with biodiversity and geographical features, constitute a great scenery to develop new therapies based on ethnopharmacological heritage. Here, we investigated the anti-inflammatory potential of 10 commonly used plants in Colombian folk medicine, evaluating their effect on nitric oxide (NO) production by LPS-stimulated RAW 264.7 macrophages. The most active plant was evaluated in vivo using 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced mouse ear edema, along with its effect on the production of pro-inflammatory mediators in vitro. The extract of Physalis angulata L. calyces showed the highest activity. This extract was fractionated and its dichloromethane fraction (DF) was the most active in vitro, inhibiting the production of NO, prostaglandin E2 (PGE2), interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α and monocyte chemotactic protein (MCP)-1 (CCL2). In vivo, DF showed a significant inhibition of ear edema and myeloperoxidase (MPO) activity, with evident reduction of the leukocyte infiltration into tissue. Our results support the ethnopharmacological use of the selected plants in folk medicine. P. angulata dichloromethane fraction represents a promising source of pharmacological compounds with great potential therapeutic use to treat inflammatory illness.

In vivo and in vitro anti-inflammatory activity of Cryptostegia grandiflora Roxb. ex R. Br. leaves.

BACKGROUND: Despite Cryptostegia grandiflora Roxb. ex R. Br. (Apocynaceae) leaves are widely used in folk Caribbean Colombian medicine for their anti-inflammatory effects, there are no studies that support this traditional use. Therefore, this work aimed to evaluate the effect of the total extract and primary fractions obtained from Cryptostegia grandiflora leaves, using in vivo and in vitro models of inflammation, and further get new insights on the mechanisms involved in this activity. RESULTS: Ethanolic extract of Cryptostegia grandiflora leaves, and its corresponding ether and dichloromethane fractions, significantly reduced inflammation and myeloperoxidase activity (MPO) in ear tissue of mice treated with 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Histological analysis revealed a reduction of edema and leukocyte infiltration. Complementarily, we demonstrated that extract and fractions reduced nitric oxide (NO•) and prostaglandin E2 (PGE2) production in LPS-stimulated RAW 264.7 macrophages, as well as scavenging activity on DPPH and ABTS radicals. CONCLUSIONS: Our results demonstrated for the first time the anti-inflammatory activity of Cryptostegia grandiflora leaves, supporting its traditional use. This activity was related to inhibition of MPO activity, and PGE2 and NO• production. These mechanisms and its antioxidant activity could contribute, at least in part, to the anti-inflammatory effect showed by this plant.

In vivo and in vitro anti-inflammatory activity of Cryptostegia grandiflora Roxb. ex R. Br. leaves

BACKGROUND: Despite Cryptostegia grandiflora Roxb. ex R. Br. (Apocynaceae) leaves are widely used in folk Caribbean Colombian medicine for their anti-inflammatory effects, there are no studies that support this traditional use. Therefore, this work aimed to evaluate the effect of the total extract and primary fractions obtained from Cryptostegia grandiflora leaves, using in vivo and in vitromodels of inflammation, and further get new insights on the mechanisms involved in this activity. RESULTS: Ethanolic extract of Cryptostegia grandiflora leaves, and its corresponding ether and dichloromethane fractions, significantly reduced inflammation and myeloperoxidase activity (MPO) in ear tissue of mice treated with 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Histological analysis revealed a reduction of edema and leukocyte infiltration. Complementarily, we demonstrated that extract and fractions reduced nitric oxide (NO•) and prostaglandin E2 (PGE2) production in LPS-stimulated RAW 264.7 macrophages, as well as scavenging activity on DPPH and ABTS radicals. CONCLUSIONS: Our results demonstrated for the first time the anti-inflammatory activity of Cryptostegia grandiflora leaves, supporting its traditional use. This activity was related to inhibition of MPO activity, and PGE2 and NO• production. These mechanisms and its antioxidant activity could contribute, at least in part, to the anti-inflammatory effect showed by this plant.

Pazopanib as second-line treatment after sunitinib or bevacizumab in patients with advanced renal cell carcinoma: a Sarah Cannon Oncology Research Consortium Phase II Trial.

BACKGROUND: This phase II trial examined the activity and toxicity of second-line treatment with pazopanib after failure of first-line single-agent treatment with sunitinib or bevacizumab in patients with advanced clear cell renal carcinoma. PATIENTS AND METHODS: Fifty-five patients with metastatic clear cell renal carcinoma who had previously received first-line treatment with sunitinib (39 patients) or bevacizumab (16 patients) were enrolled. Patients received pazopanib 800 mg orally daily and were evaluated for response after 8 weeks of treatment. Responses were measured using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, and confirmed with repeated scans after 8 weeks. Patients with objective response or stable disease continued treatment until disease progression or unacceptable toxicity occurred. RESULTS: Fifteen of 55 patients (27%) had objective response to pazopanib. An additional 27 patients (49%) had stable disease, for a disease control rate of 76%. After a median follow-up of 16.7 months, the median progression-free survival for the entire group was 7.5 months (95% confidence interval, 5.4-9.4 months). Similar progression-free survival was observed regardless of whether previous treatment was with sunitinib or bevacizumab. The estimated overall survival rate for the entire group at 24 months was 43%. CONCLUSION: Pazopanib is an active agent for the treatment of advanced clear cell renal carcinoma, even after failure of sunitinib or bevacizumab. Treatment with pazopanib should be considered early in the sequence of therapy for patients with advanced renal cell carcinoma.

Brief-duration rituximab/chemotherapy followed by maintenance rituximab in patients with diffuse large B-cell lymphoma who are poor candidates for R-CHOP chemotherapy: a phase II trial of the Sarah Cannon Oncology Research Consortium.

INTRODUCTION: Patients with diffuse large B-cell lymphoma (DLBCL) who are very elderly or have poor performance status are difficult to treat with a full course of R-CHOP (rituximab plus cyclophosphamide/doxorubicin/vincristine/ prednisone) therapy. In this phase II trial, we treated this group of patients with a novel regimen containing 3 courses of rituximab/chemotherapy followed by maintenance rituximab. PATIENTS AND METHODS: Patients with newly diagnosed stage II-IV DLBCL were eligible if they were considered poor candidates for 6-8 cycles of R-CHOP therapy. Patients who were eligible for anthracycline therapy received 3 cycles of rituximab plus cyclophosphamide/ mitoxantrone/vincristine/prednisone (CNOP); the remainder of patients received R-CVP (rituximab plus cyclophosphamide/ vincristine/prednisone). Patients without progression after completion of 3 cycles received 4 courses of maintenance rituximab (375 mg/m2 weekly x 4, repeated every 6 months) for 24 months. RESULTS: Between May 2003 and July 2007, 51 patients were enrolled. The median age was 78 years, and 43% of patients were > 80 years of age. Nineteen patients (37%) had Eastern Cooperative Oncology Group performance status of 2, and 72% had high-intermediate or high-risk International Prognostic Index scores. After a median follow-up of 48 months, the 2-, 3-, and 4-year progression-free survival rates are 71%, 65%, and 56%, respectively. The 2-, 3-, and 4-year overall survival rates are 72%, 67%, and 67%, respectively. Treatment was well tolerated, with few severe toxicities and no treatment-related deaths. CONCLUSION: This abbreviated course of rituximab/chemotherapy, followed by maintenance rituximab, was active and well tolerated in these very elderly patients. Brief-duration rituximab/chemotherapy as well as maintenance rituximab merit further evaluation in this setting.

[Antiinflammatory activity of extracts and fractions obtained from Physalis peruviana L. calyces]. / Actividad antinflamatoria de extractos y fracciones obtenidas de cálices de Physalis peruviana L.

INTRODUCTION: Cape gooseberry calyces (Physalis peruviana) have been used in folk medicine for their medicinal properties including anticancer, antimycobacterial, antipyretic, diuretic, immunomodulatory and antiinflammatory properties. OBJECTIVE: The antiinflammatory effect was evaluated for extracts and fractions obtained from Physalis peruviana calyces in a mice model of acute inflammation. The fractions responsible for antiinflammatory activity were extracted for possible identification. MATERIALS AND METHODS: The Physalis peruviana calyces were extracted by percolation with organic solvents. The primary hydroalcoholic fraction was purified by column chromatography. The antiinflammatory effect of extracts and fractions was evaluated using the 12-O-tetradecanoylphorbol-13-acetate-induced mouse model of ear edema. RESULTS: Thirty-eight secondary fractions were obtained by column chromatography of primary hydroalcoholic fraction. Six fractions, evaluated in 12-O-tetradecanoylphorbol-13-acetate-induced inflammation assay, showed significant antiinflammatory activity (p<0.05). The major fraction, Pp-D28-LF, showed a significant dose-dependent response at doses over 250 microg/ear. CONCLUSION: The antiinflammatory activity attributed to Physalis peruviana calyces was confirmed and validated its use in folk medicine. Fractions responsible for the antiinflammatory action were identified and seem promising for phytomedicinal development. Further studies are needed to isolate and identify the active constituents of these fractions as well as to ascertain the mechanisms involved in the antiinflammatory effect.

Bronquiolitis en el lactante pequeño: evolución y factores de riesgo durante su internación / Bronchiolitis in infant under four months: evolution and risk factors during hospitalization

Objetivos: Conocer las características clinicoepidemiologicas y los factores de riesgo de la bronquiolitis aguda en los lactantes menores de cuatro meses hospitalizados durante un brote estacional. Materiales y Métodos: Estudio retrospectivo de 49 historias clínicas de lactantes menores de cuatro meses ingresados en el hospital escuela del litoral de Paysandú (Uruguay) durante el período comprendido entre los meses de julio a setiembre de 1995. Resultados: El análisis de los factores de riesgo al ingreso solo mostró una relación estadísticamente significativa (p<0.05) de la hipoxia y el grado de sindrome funcional respiratorio al ingreso con una peor evolución, valorada por las necesidades de oxígeno y la persistencia de hiperactividad en los dos meses subsiguientes. Ninguno de los restantes factores de riesgo analizados (edad, prematuridad, antecedentes familiares o personales y consolidación en la radiografía de tórax) se asoció estadísticamente a un peor pronóstico, si bien se detectaron diferencias entre los grupos no estadísticamente significativas. Se administraron antibióticos en un 32,5 por ciento (n= 17) de los pacientes y broncodilatadores en un 69,3 por ciento (n=34) de los casos. Recibieron corticoides un 40,8 por ciento de pacientes (n=20), a pesar de que este tratamiento es controvertido en la entidad. Más de la mitad de los lactantes sometidos a exámen radiológico mostraron imágenes de consolidación en la radiografía de torax. Precisaron internación en unidad de cuidados intensivos 3 pacientes (6,1 por ciento) requiriendo ventilación mecánica solamente uno de ellos. No se produjo ningún exitus en nuestra serie. Conclusiones: La bronquiolitis aguda en el lactante pequeño presenta unas características especiales que marcan su evolución y tratamiento. Se halla una relación clara entre la dificultad respiratoria a su ingreso y su evolución posterior, no detectándose esta relación con otros factores de riesgo debido, probablemente al pequeño tamaño de muestra. Creemos conveniente la realización rutinaria de estudios radiográficos a todo lactante menor de cuatro meses ingresado por esta patología