Possible therapeutics for Pseudomyxoma peritonei: a rare, lethal, and the least investigated disease

Pseudomyxoma peritonei (PMP) refers to a growth disorder characterized by glycoprotein neoplasm in the peritoneum, where mucin oversecretion occurs. The tumors of the appendix region are well associated with PMP; however, ovarian, colon, stomach, pancreas, and urachus tumors have also been linked to PMP. Other mucinous tumors in the pelvis, paracolic gutters, greater omentum, retrohepatic space, and Treitz ligament can be the reason for PMP. Despite being rare and having a slow growth rate, PMP can be lethal without treatment. It is treated with neoadjuvant chemotherapy with the option of cytoreductive surgery and intraperitoneal chemotherapy. In the current study, we hypothesize that there may be novel gentle ways to inhibit or eliminate the mucin. Dr. David Morris has used mucolytics - such as bromelain and N-acetyl cysteine to solubilize mucin. In the present review, we aimed to study the regulation of mucin expression by promoter methylation, and drugs that can inhibit mucin, such as boldine, amiloride, naltrexone, dexamethasone, and retinoid acid receptors antagonist. This review also explored some possible pathways, such as inhibition of Na + , Ca2+ channels and induction of DNA methyltransferase along with inhibition of ten-eleven translocation enzymes, which can be good targets to control mucin. Mucins are strong adhesive molecules that play great roles in clinging to cells or cell to cell. Besides, they have been greatly involved in metastasis and also act as disease markers for cancers. Diagnostic markers may have exclusive roles in disease initiation and progression. Therefore, the present review explores various drugs to control and target mucin in various diseases, specifically cancers. (AU)

Improved drug carriage and protective potential against Cisplatin-induced toxicity using Boldine-loaded PLGA nanoparticles

Background: Cisplatin is a widely-used potent anti-cancer drug having severe side-effects precluding itssustained use.Objectives: Poly (lactide-co-glycolide) (PLGA)-nanoparticles loaded Boldine, an antioxidant ingredient ofethanolic extract of Boldo plant (Peumus boldus) was tested in cancer mice model, Mus musculus toexamine if it could reduce unwanted Cisplatin-induced toxicity in normal tissue.Material and methods: Nano-encapsulation of Boldine was done by following the standardized solventdisplacement method. Physico-chemical characterization of PLGA-encapsulated nano-Boldine (NBol) wasaccomplished through analyses of various spectroscopic techniques. Status of major antioxidant enzymes, functional markers, and lipid peroxidation (LPO) was also determined in certain tissue and serumsamples. Percentage of cells undergoing cytotoxic death, Reactive oxygen species (ROS) accumulationand mitochondrial functioning were analyzed in both normal and cancer mice. Nanoscale changes inchromatin organization were assessed by Transmission electron microscopy (TEM). mRNA and proteinexpressions of Top II, Bax, Bcl-2, Cyt c, caspase 3 were studied by RT-PCR, immunoblot andimmunofluorescence.Results: NBol had faster mobility, site-specific action and ability of sustained particle release. NBol readilyentered cells, prevented Cisplatin to intercalate with dsDNA resulting in reduction of chromatincondensation, with corresponding changes in ROS levels, mitochondrial functioning and antioxidantenzyme activities, leading to reduction in Deoxyribose nucleic acid (DNA) damage and cytotoxic celldeath. Expression pattern of apoptotic genes like Top II, p53, Bax, Bcl-2, cytochrome c and caspase-3suggested greater cytoprotective potentials of NBol in normal tissues.Conclusions: Compared to Boldine (Bol), NBol had better ability of drug carriage and protective potentials(29.00% approximately) against Cisplatin-induced toxicity. Combinational therapeutic use of PLGA-NBolcan reduce unwanted Cisplatin-induced cellular toxicity facilitating use of Cisplatin.© 2018 Transdisciplinary University, Bangalore and World Ayurveda Foundation. Publishing Services byElsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Simultaneous Determination of Four Alkaloid Components in Xiangbin Decoction by UPLC-QqQ-MS/MS / 中国实验方剂学杂志

Objective: To establish a quantitative method for the simultaneous determination of arecaine,arecoline,norisoboldine and boldine in Xiangbin decoction by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-QqQ-MS/MS), and compare the variation of their contents between single and mixed decoctions. Method: The separation was carried on a Waters ACQUITY UPLC BEH Shield RP18(2.1 mm×150 mm,1.7 μm)column, with 0.1%formic acid solution-acetonitrile as mobile phase for gradient elution. The flow rate was 0.2 mL·min-1, and the column temperature was 30℃. The quantitative MRM transitions of the four components were m/z 142.10/44.11 for arecaine,m/z 156.20/44.07 for arecoline,m/z 314.29/265.12 for norisoboldine and m/z 328.13/265.10 for boldine. The determination was performed in multiple reaction monitoring (MRM) mode by mass spectrometry with electrospray ionization (ESI) source under positive mode. Result: The linear ranges of arecaine,arecoline,norisoboldine and boldine were 0.479 0-57.48,0.976 0-78.08,0.812 0-64.96, 0.091 2-18.24 μg·L-1,respectively. The average recoveries of the above compounds ranged from 93.73%to 104.34%, with RSD (n=6) of less than 5%. The contents of arecoline,arecoline,norbibeldine and boltinine in Xiangbin decoction were (90.07±1.26),(445.27±12.39),(742.35±38.39),(38.50±3.33) μg·g-1,which were significantly lower than the contents in Linderae Radix and Arecae Semen. Conclusion: The method is rapid,sensitive,accurate and reproducible,and suitable for the simultaneous determination of multiple components in Xiangbin decoction,so as to provide a basis for the quality control of Xiangbin decoction. The compatibility of Xiangbin decoction has a significant effect on the dissolution contents of arecaine,arecoline,norisoboldine and boldine.

Boldina disminuye la apoptosis miocárdica post isquemia reperfusión en la rata / Boldine decrease myocardial apoptosis post ischemic reperfusion in rats

Antecedentes: En la isquemia/reperfusión (IR) miocárdica es relevante la pérdida de cardiomiocitos por apoptosis. En estos, los hemicanales (HC) permiten el ingreso de sustancias proapoptóticas durante la IR. Boldina (B), compuesto extraído del Peumus boldus, ha demostrado ser antioxidante y bloquear los HC. Objetivo: Determinar el efecto de boldina sobre la apoptosis de cardiomiocitos de ratas sometidas a IR. Métodos: Ratas macho de 200 g de peso se sometieron a ligadura reversible de la arteria coronaria izquierda por 30 minutos (I) y posterior reperfusión (R) por 24 horas post I. Un subgrupo de estos animales recibió una dosis de boldina intraventricular (IR+B, 40 mg/Kg) y luego dos dosis vía gavage (75 mg/Kg) a los 30 y 60 minutos post-R. Como controles se usaron ratas sham con operación ficticia, que recibieron igual tratamiento. Se determinaron las masas corporal (MC) y cardiaca relativa (MCR) y presión arterial sistólica (PAS). Porcentaje de cardiomiocitos apoptóticos (CMAP), otras células apoptóticas (OCAP) y total de células apoptóticas (TCAP) se determinó por TUNEL. La activación de metaloproteinasas (MMPs) 2 y 9 se determinó por zimografía y el mRNA de MCP-1 por RT-PCR. Resultados: La boldina no modificó la MC y la MCR. Sin embargo, disminuyó significativamente la PAS así como el por cientoCMAP y el por cientoTCAP en el grupo IR+B versus IR (CMAP 69 +/- 1,5 vs 44 ± 0,4, p=0,016, TCAP 71 +/- 2,4 vs 57 +/- 1,5, p=0,016). No se encontraron diferencias en el OCAP, actividad de MMPs y en los niveles de mRNA de MCP-1. Conclusiones: Boldina disminuyó la PAS y la apoptosis de cardiomiocitos post IR. Su efecto no es mediado por modificaciones en la actividad de MMPs y expresión génica de MCP-1.

Background: Ischemia / reperfusion (IR) is relevant in the myocardial loss of cardiomyocytes through apoptosis. During IR, hemi channels (HC) allow the entry of proapoptotic substances to the cell. Boldine, a compound extracted from Peumus boldus, has proven to be antioxidant and to block HC. Objective: To determine the effect of boldine on cardiomyocyte apoptosis in rats subjected to IR. Methods: Male rats, body weight (BW) 200 g, were subjected to reversible ligation of the left coronary artery for 30 minutes (I) and subsequent reperfusion (R) for 24 hours. A subset of these animals (IR+B) received an intraventricular dose of boldine (40mg/kg) and then two doses via gavage (75 mg/kg) at 30 and 60 minutes post-R. Sham operated rats (S) receiving the same treatment were used as controls. We determined body weight (BW), relative heart mass (RHM) and systolic blood pressure (SBP). Percentage of apoptotic cardiomyocytes (CMAP), other apoptotic cells (OCAP) and total apoptotic cells (TCAP) were determined by TUNEL. Activation of metalloproteinases (MMPs) 2 and 9 was determined by zymography and MCP-1 mRNA levels by RT-PCR. Results: Compared to IR alone, IR+Boldine did not change BW or RCM, but significantly decreased PAS, TCAP (71 +/- 2.4 vs 57 +/- 1.5, p=0.016) and CMAP (69 +/- 1.5 vs 44 +/- 0.4, p=0.016). No difference was observed in the OCAP, MMPs activity and MCP-1 mRNA levels. Conclusions: Boldine decreased SBP and post-IR cardiomyocyte apoptosis without effect on other cells. This effect was not mediated by MMPs activity or MCP-1 gene expression.

Farmacologia e Toxicologia de Peumus boldus e Baccharis genistelloides / Pharmacology and toxicology of Peumus boldus and Baccharis genistelloides

Um grande número de espécies com uso medicinal tradicional ainda continua sem comprovação da eficácia e da segurança de seu uso. Este artigo apresenta uma pequena revisão sobre os trabalhos publicados com boldo (Peumus boldus) e carqueja (Baccharis genistelloides). Os estudos farmacológicos realizados com P. boldus e B. genistelloides comprovam várias das atividades atribuídas popularmente a esses chás, além de correlacionarem esses efeitos a compostos puros, isolados a partir desses extratos. Já os estudos toxicológicos sugerem que o chá de boldo deve ser consumido com moderação e cuidado, principalmente no primeiro trimestre da gravidez (indícios de teratogenia) e no uso por tempo prolongado (indícios de hepatotoxicidade), enquanto o consumo do chá de carqueja deve ser proibido para gestantes (risco comprovado de aborto) e para pacientes que utilizam drogas para tratamento de problemas pressóricos (ação hipotensora). Estes relatos reforçam a necessidade de um maior conhecimento sobre as plantas medicinais utilizadas popularmente, não apenas para a confirmação das atividades descritas pelo uso tradicional, mas também para que o uso seguro seja estabelecido.

There are a great number of medicinal plants without any scientific confirmation about their efficacy and safety. This paper is a short review about two medicinal plants, "boldo do chile" (Peumus boldus) and "carqueja" (Baccharis genistelloides). Pharmacological studies have confirmed several popular indications for P. boldus and B. genistelloides, besides have established a relationship between isolated compounds from these extracts and the pharmacological effects observed. On the other hand, toxicological researches have pointed out that P. boldus tea should not be consumed during a long period (potential hepatotoxicity) and by pregnant, especially during the first three months. Moreover, B. genistelloides tea must be prohibited for pregnant because of confirmed abortive action, and for patients using medicines for blood pressure disorders. These studies point out the continuous necessity of more studies about medicinal plants; only with this knowledge it will be possible a safe and efficient use.