Pharmaceutical Crops: An Overview

Pharmaceutical crops is an ambiguous term used by biologists and chemists for different categories of plants. We define pharmaceutical crops as those cultivated species that are used for extraction or preparation of therapeutic substances such as active pharmaceutical ingredients (APIs), excipients used in pharmaceutical formulations, vaccines and antibodies, as well as other therapeutic proteins. Based on the type of pharmaceutical product, these crops can be classified into three distinct yet sometimes overlapping categories: crops for the production of small therapeutic molecules (STMs), large therapeutic molecules (LMTs), or standard therapeutic extracts (STEs). This review briefly discusses the relationships of pharmaceutical crops with traditional food crops, medicinal plants, medicinal crops, and invasive species. It also addresses the importance, advantages, problems, and challenges of research and development of pharmaceutical crops. This article references the plant specimen Nyssaceae, Camptotheca lowreyana, currently found in the lab of the National Center for Pharmaceutical Crops

Chemical composition and product quality control of turmeric (Curcuma longa L.)

Chemical constituents of various tissues of turmeric (Curcuma longa L.) have been extensively investigated. To date, at least 235 compounds, primarily phenolic compounds and terpenoids have been identified from the species, including 22 diarylheptanoids and diarylpentanoids, eight phenylpropene and other phenolic compounds, 68 monoterpenes, 109 sesquiterpenes, five diterpenes, three triterpenoids, four sterols, two alkaloids, and 14 other compounds. Curcuminoids (diarylheptanoids) and essential oils are major bioactive ingredients showing various bioactivities in in vitro and in vivo bioassays. Curcuminoids in turmeric are primarily accumulated in rhizomes. The essential oils from leaves and flowers are usually dominated by monoterpenes while those from roots and rhizomes primarily contained sesquiterpenes. The contents of curcuminoids in turmeric rhizomes vary often with varieties, locations, sources, and cultivation conditions, while there are significant variations in composition of essential oils of turmeric rhizomes with varieties and geographical locations. Further, both curcuminoids and essential oils vary in contents with different extraction methods and are unstable with extraction and storage processes. As a result, the quality of commercial turmeric products can be markedly varied. While curcumin (1), demethoxycurcumin (2), and bisdemethoxycurcumin (5) have been used as marker compounds for the quality control of rhizomes, powders, and extract (“curcumin”) products, Ar-turmerone (99), -turmerone (100), and -turmerone (101) may be used to control the product quality of turmeric oil and oleoresin products. Authentication of turmeric products can be achieved by chromatographic and NMR techniques, DNA markers, with morphological and anatomic data as well as GAP and other information available

Antagonizing Arachidonic Acid-Derived Eicosanoids Reduces Inflammatory Th17 and Th1 Cell-Mediated Inflammation and Colitis Severity

During colitis, activation of two inflammatory T cell subsets, Th17 and Th1 cells, promotes ongoing intestinal inflammatory responses. n-6 polyunsaturated fatty acid- (PUFA-) derived eicosanoids, such as prostaglandin E2 (PGE2), promote Th17 cell-mediated inflammation, while n-3 PUFA antagonize both Th17 and Th1 cells and suppress PGE2 levels. We utilized two genetic mouse models, which differentially antagonize PGE2 levels, to examine the effect on Th17 cells and disease outcomes in trinitrobenzene sulfonic acid- (TNBS-) induced colitis. Fat-1 mice contain the ω3 desaturase gene from C. elegans and synthesize n-3 PUFA de novo, thereby reducing the biosynthesis of n-6 PUFA-derived eicosanoids. In contrast, Fads1 Null mice contain a disrupted Δ5 desaturase gene and produce lower levels of n-6 PUFA-derived eicosanoids. Compared to Wt littermates, Fat-1 and Fads1 Null mice exhibited a similar colitic phenotype characterized by reduced colonic mucosal inflammatory eicosanoid levels and mRNA expression of Th17 cell markers (IL-17A, RORγτ, and IL-23), decreased percentages of Th17 cells and, improved colon injury scores (P≤0.05). Thus, during colitis, similar outcomes were obtained in two genetically distinct models, both of which antagonize PGE2 levels via different mechanisms. Our data highlight the critical impact of n-6 PUFA-derived eicosanoids in the promotion of Th17 cell-mediated colonic inflammation

A Role for Cardiac Glycosides in GBM Therapy

There is a pressing need for new effective therapeutic strategies to treat glioblastoma (GBM). Cardiac glycoside compounds consisting of both cardenolides and bufadienolides have been shown to possess potent activity against GBM cell lines and in vivo GBM tumors. In addition, recent research has shown that certain cardiac glycoside compounds contribute to an additive and even synergistic manner with the standard of care GBM treatments such as radiotherapy and chemotherapy. Finally, the finding that cardiac glycosides may offer a unique role in the control of GBM stem cells offers hope for better therapeutic outcomes in treating this deadly form of brain cancer

Differential Effects of Pravastatin and Simvastatin on the Growth of Tumor Cells From Different Organ Sites

3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, commonly known as statins, may possess cancer preventive and therapeutic properties. Statins are effective suppressors of cholesterol synthesis with a well-established risk-benefit ratio in cardiovascular disease prevention. Mechanistically, targeting HMGCR activity primarily influences cholesterol biosynthesis and prenylation of signaling proteins. Pravastatin is a hydrophilic statin that is selectively taken up by a sodium-independent organic anion transporter protein-1B1 (OATP1B1) exclusively expressed in liver. Simvastatin is a hydrophobic statin that enters cells by other mechanisms. Poorly-differentiated and well-differentiated cancer cell lines were selected from various tissues and examined for their response to these two statins. Simvastatin inhibited the growth of most tumor cell lines more effectively than pravastatin in a dose dependent manner. Poorly-differentiated cancer cells were generally more responsive to simvastatin than well-differentiated cancer cells, and the levels of HMGCR expression did not consistently correlate with response to statin treatment. Pravastatin had a significant effect on normal hepatocytes due to facilitated uptake and a lesser effect on prostate PC3 and colon Caco-2 cancer cells since the OATP1B1 mRNA and protein were only found in the normal liver and hepatocytes. The inhibition of cell growth was accompanied by distinct alterations in mitochondrial networks and dramatic changes in cellular morphology related to cofilin regulation and loss of p-caveolin. Both statins, hydrophilic pravastatin and hypdrophobic simvastatin caused redistribution of OATP1B1 and HMGCR to perinuclear sites. In conclusion, the specific chemical properties of different classes of statins dictate mechanistic properties which may be relevant when evaluating biological responses to statins

A Combination of Sulindac and Antimicrobial Eradication of H. pylori Prevents Progression of Gastric Cancer in Hypergastrinemic INS-GAS Mice

Author Manuscript: 2010 October 15Helicobacter pylori infection causes severe dysplasia manifested as gastrointestinal intraepithelial neoplasia (GIN) after 28 weeks post–H. pylori infection (WPI) in cancer-prone, hypergastrinemic male INS-GAS mice. We examined the efficacy of the nonsteroidal anti-inflammatory drug sulindac (400 ppm in drinking water) alone, the CCK2/gastrin receptor antagonist YM022 (45 mg/kg/wk) alone, and sulindac or YM022 combined with H. pylori eradication therapy to prevent H. pylori–associated gastric cancer in male INS-GAS mice. Treatments started at 22 WPI, and mice were euthanized at 28 WPI. In uninfected mice, all treatments significantly delayed development of spontaneous GIN (P < 0.05). In H. pylori–infected mice, sulindac alone or YM022 alone had no protective effect on H. pylori–associated GIN. Importantly, sulindac exacerbated the severity of H. pylori–associated gastritis despite decreased gastric prostaglandin E2 levels. However, sulindac combined with H. pylori antimicrobial eradication reduced the incidence of GIN (P < 0.05), whereas YM022 combined with antimicrobial eradication did not reduce GIN. In infected mice, sulindac or YM022 treatment did not alter gastric expression of the proinflammatory cytokines Ifn-γ and Tnf-α and mucosal cell proliferation. Sulindac or YM022 combined with antimicrobial eradication down-regulated mRNA levels of Ifn-γ and Tnf-α and mucosal cell proliferation (P < 0.05). We conclude that sulindac enhances H. pylori gastritis and may promote inflammation-mediated gastric carcinogenesis. The combination of sulindac and antimicrobial H. pylori eradication was beneficial for reducing proinflammatory cytokine mRNA in the stomach and preventing progression from severe dysplasia to gastric cancer in H. pylori–infected INS-GAS mice. [Cancer Res 2009;69(20):8166–74]National Institutes of Health (U.S.) (Grant R01AI37750)National Institutes of Health (U.S.) (Grant P01CA26731)National Institutes of Health (U.S.) (Grant P30ES02109)National Institutes of Health (U.S.) (Grant R01CA093405-07A1

CD24-p53 axis suppresses diethylnitrosamine-induced hepatocellular carcinogenesis by sustaining intrahepatic macrophages

It is generally assumed that inflammation following diethylnitrosamine (DEN) treatment promotes development of hepatocellular carcinoma (HCC) through the activity of intrahepatic macrophages. However, the tumor-promoting function of macrophages in the model has not been confirmed by either macrophage depletion or selective gene depletion in macrophages. Here we show that targeted mutation of Cd24 dramatically increased HCC burden while reducing intrahepatic macrophages and DEN-induced hepatocyte apoptosis. Depletion of macrophages also increased HCC burden and reduced hepatocyte apoptosis, thus establishing macrophages as an innate effector recognizing DEN-induced damaged hepatocytes. Mechanistically, Cd24 deficiency increased the levels of p53 in macrophages, resulting in their depletion in Cd24 -/- mice following DEN treatment. These data demonstrate that the Cd24-p53 axis maintains intrahepatic macrophages, which can remove hepatocytes with DNA damage. Our data establish a critical role for macrophages in suppressing HCC development and call for an appraisal of the current dogma that intrahepatic macrophages promote HCC development

Antagonizing Arachidonic Acid-Derived Eicosanoids Reduces Inflammatory Th17 and Th1 Cell-Mediated Inflammation and Colitis Severity

During colitis, activation of two inflammatory T cell subsets, Th17 and Th1 cells, promotes ongoing intestinal inflammatory responses. n-6 polyunsaturated fatty acid- (PUFA-) derived eicosanoids, such as prostaglandin E2 (PGE2), promote Th17 cell-mediated inflammation, while n-3 PUFA antagonize both Th17 and Th1 cells and suppress PGE2 levels. We utilized two genetic mouse models, which differentially antagonize PGE2 levels, to examine the effect on Th17 cells and disease outcomes in trinitrobenzene sulfonic acid- (TNBS-) induced colitis. Fat-1 mice contain the ω3 desaturase gene from C. elegans and synthesize n-3 PUFA de novo, thereby reducing the biosynthesis of n-6 PUFA-derived eicosanoids. In contrast, Fads1 Null mice contain a disrupted Δ5 desaturase gene and produce lower levels of n-6 PUFA-derived eicosanoids. Compared to Wt littermates, Fat-1 and Fads1 Null mice exhibited a similar colitic phenotype characterized by reduced colonic mucosal inflammatory eicosanoid levels and mRNA expression of Th17 cell markers (IL-17A, RORγτ, and IL-23), decreased percentages of Th17 cells and, improved colon injury scores (P≤0.05). Thus, during colitis, similar outcomes were obtained in two genetically distinct models, both of which antagonize PGE2 levels via different mechanisms. Our data highlight the critical impact of n-6 PUFA-derived eicosanoids in the promotion of Th17 cell-mediated colonic inflammation