Cucurbitacin E Alleviates Colonic Barrier Function Impairment and Inflammation Response and Improves Microbial Composition on Experimental Colitis Models.

Purpose: Cucurbitacins, which are found in a variety of medicinal plants, vegetables and fruits, were known for their diverse pharmacological and biological activities, including anticancer, anti-oxidative and anti-inflammatory effects. Cucurbitacin E, one of the major cucurbitacins, was recently proved to inhibit inflammatory response. Methods: To explore the therapeutic effects of cucurbitacin E on colitis and the underlying mechanisms, male mice drunk water containing 2.5% dextran sulfate sodium (DSS) to establish colitis model and administrated with cucurbitacin E during and after DSS treatment. The disease activity index was scored and colonic histological damage was observed. Intestinal tight junction and inflammatory response were determined. 16S rRNA and transcriptome sequencing were performed to analyze gut microbiota composition and gene expression, respectively. Results: We found that cucurbitacin E alleviated DSS-induced body weight loss and impaired colonic morphology. Cucurbitacin E decreased the expression of inflammatory cytokines and cell apoptosis, and maintained barrier function. Additionally, cucurbitacin E retrieved DSS-induced alterations in the bacterial community composition. Furthermore, a variety of differentially expressed genes (DEGs) caused by cucurbitacin E were enriched in several pathways including the NFκB and TNF signaling pathways as well as in Th17 cell differentiation. There was a close relationship between DEGs and bacteria such as Escherichia-Shigella and Muribaculaceae. Conclusion: Our results revealed that cucurbitacin E may exert protective effects on colitis via modulating inflammatory response, microbiota composition and host gene expression. Our study supports the therapeutic potential of cucurbitacin E in colitis and indicates that gut microbes are potentially therapeutic targets.

Antiproliferative and immunomodulative potential of Citrullus colocynthis and its bioactive compounds in human lymphocytes and lung cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Citrullus colocynthis (L.) Schrad is a member of the Cucurbitaceae plant family which has been used in traditional medicine for the treatment of lung diseases such as asthma and bronchitis. AIM OF THE STUDY: The study was conducted to investigate antiproliferative and immunomodulating effects of C. colocynthis and isolated cucurbitacins on human T lymphocytes and lung epithelial cells in order to evaluate their potential in the treatment of airway diseases. MATERIALS AND METHODS: Different concentrations of an ethanolic extract of C. colocynthis fruits and cucurbitacins B (CuB), E (CuE) and E-glucopyranoside (CuE-Glu) were analysed for their cytotoxicity and immunomodulatory potential on Peripheral Blood Mononuclear Cells (PBMCs) of healthy donors and on the epithelial lung cancer cell line A549. Viability and proliferation were tested using WST1 and CFSE assays. Flow cytometric analysis of AnnexinV/PI staining was used to investigate cell death through apoptosis/necrosis. Effects on regulatory mechanisms of T lymphocytes, such as CD69 and CD25 marker activation, cytokine production of the cytokines interleukin 2 (IL2), tumor necrosis factor α (TNFα) and interferon γ (IFNy) were also analysed via flow cytometry. Influences on the activator protein 1 (AP1), nuclear factor of activated T-cells (NFAT) or nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFκB) pathways were analysed in the Jurkat reporter cell line. Cytokine secretion in A549 cells stimulated with virus-like particles was analysed using the bead-based Legendplex™ assay. RESULTS: Non-toxic concentrations of C. colocynthis and CuE-Glu showed dose-dependent effects on viability and proliferation in both T lymphocytes and A549 cells. The extracts inhibited lymphocyte activation and suppressed T cell effector functions, which was also shown by lower production of cytokines IL2, TNFα and IFNy. A dose dependent inhibition of the pathways NFκB, NFAT and AP1 in Jurkat cells could be observed. In A549 cells, especially CuE and CuE-Glu showed inhibitory effects on cytokine production following a simulated viral infection. Unglycosylated cucurbitacins were more effective in suppressing the immune function in lymphocytes than glycosylated cucurbitacins, however this activity is limited to cytotoxic concentrations. CONCLUSION: In our study we could confirm the immunmodulating effect of C. colocynthis and cucurbitacins B, E and E-glucopyranoside in vitro by suppression of different pathways of inflammation and T cell proliferation. Activity in a lung cell model using a virus-like stimulation shows promise for further research regarding cucurbitacins in airway diseases.

Total cucurbitacins from Herpetospermum pedunculosum pericarp do better than Hu-lu-su-pian (HLSP) in its safety and hepatoprotective efficacy.

The pericarp of Herpetospermum pedunculosum (HPP) has traditionally been used for treating jaundice and hepatitis. However, the specific hepatoprotective components and their safety/efficacy profiles remain unclear. This study aimed to characterize the total cucurbitacins (TCs) extracted from HPP and evaluate their hepatoprotective potential. As a reference, Hu-lu-su-pian (HLSP), a known hepatoprotective drug containing cucurbitacins, was used for comparison of chemical composition, effects, and safety. Molecular networking based on UHPLC-MS/MS identified cucurbitacin B, isocucurbitacin B, and cucurbitacin E as the major components in TCs, comprising 70.3%, 26.1%, and 3.6% as determined by RP-HPLC, respectively. TCs treatment significantly reversed CCl4-induced metabolic changes associated with liver damage in a dose-dependent manner, impacting pathways including energy metabolism, oxidative stress and phenylalanine metabolism, and showed superior efficacy to HLSP. Safety evaluation also showed that TCs were safe, with higher LD50 and no observable adverse effect level (NOAEL) values than HLSP. The median lethal dose (LD50) and NOAEL values of TCs were 36.21 and 15 mg/kg body weight (BW), respectively, while the LD50 of HLSP was 14 mg/kg BW. In summary, TCs extracted from HPP demonstrated promising potential as a natural hepatoprotective agent, warranting further investigation into synergistic effects of individual cucurbitacin components.

Molecular interactions of cucurbitacins A and B with anaplastic lymphoma kinase for lung cancer treatment.

Lung cancer is a major global public health issue and the leading cause of cancer-related deaths. Several medications are commonly used to treat lung cancer, either alone or in combination with other treatments. The anaplastic lymphoma kinase (ALK) protein is one of several target proteins that are thought to be potential therapeutic targets in the context of lung cancer. Several ALK inhibitors have been identified, but many of these have been associated with side effects and toxicity concerns. In this study, we intend to computationally predict the binding potential of cucurbitacins (CBNs), A and B to the active pockets of ALK, in order to estimate their potential ALK inhibitors. Compared to CBN-A, which has a binding energy of -7.9 kcal/mol, CBN B exhibits significantly better binding efficacy with a binding energy of -8.1 kcal/mol. This is closely comparable to the binding energy of Crizotinib, which is -8.2 kcal/mol. The results of the molecular dynamics simulation indicated that the docked complexes remained stable for the duration of the 100 ns simulation period. CBN inhibited the proliferation of both non-small cell lung cancer cell lines, H1299 and A549, in a dose-dependent manner. CBN-B inhibited the proliferation of lung cancer cells, showing IC50 values of 0.08 µM for H1299 cells and 0.10 µM for A549 cells. The computational analyses provide strong evidence that CBN-B has the potential to act as a potent natural inhibitor against ALK, and could prove to be a valuable treatment option for lung cancer.Communicated by Ramaswamy H. Sarma.

Mass Spectrometric Analysis of Cucurbitacins and Dihydrocucurbitacins from the Tuber of Citrullus naudinianus.

The vast pool of structurally and functionally distinct secondary metabolites (i.e., natural products (NPs)) is constantly being expanded, a process also driven by the rapid progress in the development of analytical techniques. Such NPs often show potent biological activities and are therefore prime candidates for drug development and medical applications. The ethyl acetate extract of the tuber of Citrullus naudinianus (C. naudinianus), an African melon with edible fruits and seeds, shows in vitro immunomodulatory activity presumably elicited by cucurbitacins that are known major constituents of this plant. Further potentially immunomodulatory cucurbitacins or cucurbitacin derivatives were assumed to be in the tuber. Given the typically high content of cucurbitacins with similar physicochemical features but often distinct bioactivities, an efficient and reliable separation process is a prerequisite for their detailed characterization and assessment in terms of bioactivity. We therefore developed a detection method to screen and differentiate cucurbitacins via high-performance liquid chromatography/quadrupole-time-of-flight tandem mass spectrometry (HPLC-QTOF-MS/MS). In order to confirm the identification, the fragmentation patterns of two cucurbitacins and one 23,24-dihydrocucurbitacin were also investigated. Six characteristic fragments were identified and three of them were employed for the identification of cucurbitacins and 23,24-dihydrocucurbitacins in the extract. As a result, in addition to eight previously reported cucurbitacins from this plant four distinct 23,24-dihydrocucurbitacins (B, D, E, and I) were putatively identified and newly found in the ethyl acetate extract of the tuber of C. naudinianus. The established methodology enables rapid and efficient LC-MS-based analysis and identification of cucurbitacins and 23,24-dihydrocucurbitacins in plant extracts.

Site-directed mutagenesis identified the key active site residues of 2,3-oxidosqualene cyclase HcOSC6 responsible for cucurbitacins biosynthesis in Hemsleya chinensis.

Hemsleya chinensis is a Chinese traditional medicinal plant, containing cucurbitacin IIa (CuIIa) and cucurbitacin IIb (CuIIb), both of which have a wide range of pharmacological effects, including antiallergic, anti-inflammatory, and anticancer properties. However, few studies have been explored on the key enzymes that are involved in cucurbitacins biosynthesis in H. chinensis. Oxidosqualene cyclase (OSC) is a vital enzyme for cyclizing 2,3-oxidosqualene and its analogues. Here, a gene encoding the oxidosqualene cyclase of H. chinensis (HcOSC6), catalyzing to produce cucurbitadienol, was used as a template of mutagenesis. With the assistance of AlphaFold2 and molecular docking, we have proposed for the first time to our knowledge the 3D structure of HcOSC6 and its binding features to 2,3-oxidosqualene. Mutagenesis experiments on HcOSC6 generated seventeen different single-point mutants, showing that single-residue changes could affect its activity. Three key amino acid residues of HcOSC6, E246, M261 and D490, were identified as a prominent role in controlling cyclization ability. Our findings not only comprehensively characterize three key residues that are potentially useful for producing cucurbitacins, but also provide insights into the significant role they could play in metabolic engineering.

Apoptotic and antimetastatic effect of cucurbitacins in cancer: recent trends and advancement.

The Cucurbitaceae family produces a class of secondary metabolites known as cucurbitacins. The eight cucurbitacin subunits are cucurbitacin B, D, E, I, IIa, L glucoside, Q, and R with the most significant anticancer activity. They are reported to inhibit cell proliferation, invasion, and migration; induce apoptosis; and encourage cell cycle arrest, as some of their modes of action. The JAK-STAT3, Wnt, PI3K/Akt, and MAPK signaling pathways, which are essential for the survival and apoptosis of cancer cells, have also been shown to be suppressed by cucurbitacins. The goal of the current study is to summarize potential molecular targets that cucurbitacins could inhibit in order to suppress various malignant processes. The review is noteworthy since it presents all putative molecular targets for cucurbitacins in cancer on a single podium.

Heterodimers with a cucurbitane-type triterpenoid skeleton from the branches of Elaeocarpus dubius.

Four undescribed and two known cucurbitane-type triterpenoids, including two heterodimers, elaeocarpudubins A and B, were isolated from the branches of Elaeocarpus dubius (Elaeocarpaceae). The chemical structures of these undescribed isolates were determined by analyses of 1D and 2D NMR and MS data, electronic circular dichroism (ECD) calculations, and chemical transformation. Biogenetically, elaeocarpudubins A and B might be derived from cucurbitacin F through Michael addition with vitamin C and (-)-catechin, respectively. These six isolates were evaluated for their cytotoxic activities against human leukemia HL-60, human lung adenocarcinoma A549, human hepatoma SMMC-7721, human breast cancer MCF-7, human colon cancer SW480, and paclitaxel-resistant A549 (A549/Taxol) cell lines, for their antioxidant properties using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, and for their differentiation effects on nerve growth factor (NGF)-mediated neurite outgrowth in rat pheochromocytoma PC12 cells. Cucurbitacins F (IC50 of 4.98-38.11 µM) and D (IC50 of 0.03-4.40 µM) showed growth-inhibitory activities against these six cancer cell lines. Elaeocarpudubin B (IC50 of 61.04 µM) and elaeocarpudoside B (IC50 of 6.93 µM) showed antioxidant activities. Elaeocarpudubin B and elaeocarpudoside B also showed neurite outgrowth-promoting activities in PC12 cells at a concentration of 10 µM.

Cucurbitacins as potential anticancer agents: new insights on molecular mechanisms.

Since ancient times, plants have been an extensive reservoir of bioactive compounds with therapeutic interest for new drug development and clinical application. Cucurbitacins are a compelling example of these drug leads, primarily present in the plant kingdom, especially in the Cucurbitaceae family. However, these natural compounds are also known in several genera within other plant families. Beyond the Cucurbitaceae family, they are also present in other plant families, as well as in some fungi and one shell-less marine mollusc. Despite the natural abundance of cucurbitacins in different natural species, their obtaining and isolation is limited, as a result, an increase in their chemical synthesis has been developed by researchers. Data on cucurbitacins and their anticancer activities were collected from databases such as PubMed/MedLine, TRIP database, Web of Science, Google Scholar, and ScienceDirect and the information was arranged sequentially for a better understanding of the antitumor potential. The results of the studies showed that cucurbitacins have significant biological activities, such as anti-inflammatory, antioxidant, antimalarial, antimicrobial, hepatoprotective and antitumor potential. In conclusion, there are several studies, both in vitro and in vivo reporting this important anticancer/chemopreventive potential; hence a comprehensive review on this topic is recommended for future clinical research.

Pharmacokinetics and Biological Activity of Cucurbitacins.

Cucurbitacins are a class of secondary metabolites initially isolated from the Cucurbitaceae family. They are important for their analgesic, anti-inflammatory, antimicrobial, antiviral, and anticancer biological actions. This review addresses pharmacokinetic parameters recently reported, including absorption, metabolism, distribution, and elimination phases of cucurbitacins. It includes recent studies of the molecular mechanisms of the biological activity of the most studied cucurbitacins and some derivatives, especially their anticancer capacity, to propose the integration of the pharmacokinetic profiles of cucurbitacins and the possibilities of their use. The main botanical genera and species of American origin that have been studied, and others whose chemo taxonomy makes them essential sources for the extraction of these metabolites, are summarized.

Bitter bottle gourd poisoning: A case report and review of literature.

Bottle gourd juice is considered a panacea in traditional Indian medicine and used in various chronic diseases. Increased levels of Cucurbitacin can turn it bitter causing toxic effects in gastrointestinal system. We report the case of an elderly female who presented with shock in few hours after consumption of bitter bottle gourd juice. After proper evaluation we considered the possibility of bottle gourd poisoning as a probable diagnosis due to the Naranjo adverse drug reactions probability scale. Since there is no specific antidote available, management is mostly supportive with intravenous fluids, control of bleeding and management of shock.

In Vitro Sprouted Plantlets of Citrullus colocynthis (L.) Schrad Shown to Possess Interesting Levels of Cucurbitacins and Other Bioactives against Pathogenic Fungi.

Cucurbitacins, structurally different triterpenes mainly found in the members of Cucurbitaceae, possess a vast pharmacological potential. Genus Cucurbita, Cucumis, and Citrullus are affluent in these bioactive compounds, and, amongst them, Citrullus colocynthis (L.) Schrad. is widely exploited in folk medicine, since a huge number of diseases are successfully treated with organic and aqueous extracts obtained from different organs and tissues of the plant. The well-known pharmacological activities of such species have been attributed to its peculiar composition, which includes cucurbitacins and other bioactive molecules; thus, owing to its high importance as a valuable natural resource for pharmaceuticals and nutraceuticals, C. colocynthis propagation and multiplication protocols are considered significant, but the exploitation of its phytochemical potential is limited by the restricted cultivation conditions and the low rate of seed germination in the natural environment; in fact, the assessment of accumulation rate of specific phytochemicals under controlled conditions is still missing. Axenically sprouted plantlets obtained without the use of culture media or the addition of hormones have been evaluated here for the production of bioactive compounds and relevant bioactive features. Our results proved that derived organic extracts contain cucurbitacins and other bioactives, show antioxidant potential, and exert activity against some pathogenic fungi (Candida krusei, C. albicans, C. parapsilosis, C. glabrata, and Aspergillus flavus), supporting the feasibility of a methodology intended to scale-up cultivation of this species as a source of pharmaceutically interesting compounds, achievable from plantlets cultivated under laboratory conditions.

Anti-Cancer Effect of Sesquiterpene and Triterpenoids from Agarwood of Aquilaria sinensis.

Two new guaiane sesquiterpenes, aquisinenoids A and B (1 and 2), two new eudesmane-type sesquiterpenoids, aquisinenoids C and D (3 and 4), one new cucurbitacin, aquisinenoid E (5), and five known cucurbitacins (6-10) were isolated from agarwood of Aquilaria sinensis. The structures of these new compounds, including their absolute configurations, were characterized by spectroscopic and computational methods. The biological evaluation showed that compounds 3 and 9 had an anti-cancer effect on most of the cancer cells at 5 µM, especially in human breast cancer cells. Interestingly, the new compound 3 exhibited more sensitivity on cancer cells than normal cells, highlighting its potential as a novel anti-cancer agent. Mechanically, compound 3 treatment increased the ROS generation and triggered apoptosis of human breast cancer cells.

Xuedan Sustained Release Pellets Ameliorate Dextran Sulfate Sodium-Induced Ulcerative Colitis in Rats by Targeting Gut Microbiota and MAPK Signaling Pathways.

Cucurbitacins have a variety of bioactivities, such as anticancer, anti-inflammatory, antidepressant-like, and antiviral effects, but their pharmacological effect in ulcerative colitis (UC) has not been reported until now. Thus, this study aims to investigate the preventive effects of Xuedan sustained release pellets (XSPs) on UC rats and the underlying mechanisms. XSPs were prepared by extracting cucurbitacins from Hemsleya. Experimental UC rats were induced by the intake of 4% dextran sulfate sodium (DSS) for a week and treated with different doses of XSP (0.95, 1.90, and 3.8 mg/kg). The body weight, colon length, disease activity index (DAI), and histological changes of colonic tissue were measured. In addition, the expressions of pro-inflammatory cytokines were detected by using the enzyme-linked immunosorbent assay. Pathways involved in the intestinal inflammation were targeted by RNA-sequencing. Moreover, the changes of gut microbial diversity and composition were analyzed by the 16SrNA analysis and the contents of short-chain fatty acids (SCFAs) were detected by GC-MS. The results revealed that XSP intervention greatly restored the weight loss and colonic shortening (p < 0.05) and reduced the raised DAI scores, myeloperoxidase, and nitric oxide activities in UC in rats (p < 0.05). XSP administration also downregulated the protein levels of pro-inflammatory factors IL-1ß, IL-6, and TNF-α. Notably, it was found that XSP considerably suppressed the activation of the MAPK signaling pathway. In addition, XSP treatment improved the balance of gut microbiota that was disturbed by DSS. The beneficial bacteria Lachnospiraceae_NK4A136 group and Lactobacillus at the genus level significantly increased in the XSP group, which had decreased with the use of DSS (p < 0.05). Pathogenic bacteria including Escherichia-Shigella and Bacteroides in UC in rats were reduced by XSP intervention. Furthermore, XSP significantly elevated the production of SCFAs in UC in rats (p < 0.05). These alterations in inflammatory status were accompanied with changes in gut microbiota diversity and SCFA production. In conclusion, XSP exhibited protective effects against DSS-induced UC in rats. XSP treatment decreased inflammation via modulation of gut microbiota composition and SCFA production.

Ecology and Evolutionary History of Diabrotica Beetles-Overview and Update.

An overview is given on several aspects of evolutionary history, ecology, host plant use, and pharmacophagy of Diabrotica spp. with a focus on the evolution of host plant breadth and effects of plant compounds on natural enemies used for biocontrol of pest species in the group. Recent studies on each aspect are discussed, latest publications on taxonomic grouping of Diabrotica spp., and new findings on variations in the susceptibility of corn varieties to root feeding beetle larvae are presented. The further need for in-depth research on biology and ecology of the large number of non-pest species in the genus is pointed out.

Cucurbitacins and the Immune System: Update in Research on Anti- inflammatory, Antioxidant, and Immunomodulatory Mechanisms.

Cucurbitacins are a wide group of natural products found in several plant families, especially in the Cucurbitaceae family. In the last decade, there has been a significant increase in studies aimed at identifying new biological activities of cucurbitacins and describing their mechanisms of action. The most researched pharmacological activities are antineoplastic and anti-inflammatory activity, the first being recently reviewed. The present review explains the anti-inflammatory, antioxidant, and immunomodulatory potential of cucurbitacins, identifying the most studied compounds in this area and exploring their mechanisms of action already studied. A brief report was made about the main structural characteristics of cucurbitacins, in addition to an update on the biological activities attributed to this class in the last 5 years. Cucurbitacin B and cucurbitacin E have been identified as the most investigated when it comes to the immune response, playing roles in both innate and adaptive immunity. The most cited mechanisms were inhibition of COX-2 and NOS, reduction of oxidative stress, suppression of proinflammatory cytokines and modulation of acquired immunity proteins. It was found that cucurbitacins are promising molecules in the search for therapeutic innovation and have wide versatility in the immune response.

Pentacyclic and hexacyclic cucurbitacins from Elaeocarpuspetiolatus.

Four undescribed cucurbitacins, designated as petiolaticins A-D, and four known cucurbitacins were isolated from the bark and leaves of Elaeocarpus petiolatus (Jack) Wall. Their chemical structures were elucidated based on detailed analyses of the NMR and MS data. The absolute configuration of petiolaticin A was also determined by X-ray diffraction analysis. Petiolaticin A represents a cucurbitacin derivative incorporating a 3,4-epoxyfuranyl-bearing side chain, while petiolaticin B possesses a furopyranyl unit fused to the tetracyclic cucurbitane core structure. Petiolaticins A, B, and D were evaluated in vitro against a panel of human breast, pancreatic, and colorectal cancer cell lines. Petiolaticin A exhibited the greatest cytotoxicity against the MDA-MB-468, MDA-MB-231, MCF-7, and SW48 cell lines (IC50 7.4, 9.2, 9.3, and 4.6 µM, respectively). Additionally, petiolaticin D, 16α,23α-epoxy-3ß,20ß-dihydroxy-10αH,23ßH-cucurbit-5,24-dien-11-one, and 16α,23α-epoxy-3ß,20ß-dihydroxy-10αH,23ßH-cucurbit-5,24-dien-11-one 3-O-ß-D-glucopyranoside were tested for their ability to inhibit cell entry of a pseudotyped virus bearing the hemagglutinin envelope protein of a highly pathogenic avian influenza virus. Petiolaticin D showed the highest inhibition (44.3%), followed by 16α,23α-epoxy-3ß,20ß-dihydroxy-10αH,23ßH-cucurbit-5,24-dien-11-one (21.0%), and 16α,23α-epoxy-3ß,20ß-dihydroxy-10αH,23ßH-cucurbit-5,24-dien-11-one 3-O-ß-D-glucopyranoside showed limited inhibition (9.0%). These preliminary biological assays have demonstrated that petiolaticins A and D possess anticancer and antiviral properties, respectively, which warrant for further investigations.

The effect of squash domestication on a belowground tritrophic interaction.

The domestication of plants has commonly resulted in the loss of plant defense metabolites, with important consequences for the plants' interactions with herbivores and their natural enemies. Squash domestication started 10'000 years ago and has led to the loss of cucurbitacins, which are highly toxic triterpenes. The banded cucumber beetle (Diabrotica balteata), a generalist herbivore, is adapted to feed on plants from the Cucurbitaceae and is known to sequester cucurbitacins, supposedly for its own defense. However, the evidence for this is inconclusive. In this study we tested the impact of squash domestication on the chemical protection of D. balteata larvae against a predatory rove beetle (Dalotia coriaria). We found that cucurbitacins do not defend the larvae against this common soil dwelling predator. In fact, D. balteata larvae were less attacked when they fed on cucurbitacin-free roots of domesticated varieties compared to high-cucurbitacin roots of wild plants. This study appears to be the first to look at the consequences of plant domestication on belowground tritrophic interactions. Our results challenge the generalized assumption that sequestered cucurbitacins protect this herbivore against natural enemies, and instead reveals an opposite effect that may be due to a tradeoff between coping with cucurbitacins and avoiding predation.

Cucurbitacins as Potent Chemo-Preventive Agents: Mechanistic Insight and Recent Trends.

Cucurbitacins constitute a group of cucumber-derived dietary lipids, highly oxidized tetracyclic triterpenoids, with potential medical uses. These compounds are known to interact with a variety of recognized cellular targets to impede the growth of cancer cells. Accumulating evidence has suggested that inhibition of tumor cell growth via induction of apoptosis, cell-cycle arrest, anti-metastasis and anti-angiogenesis are major promising chemo-preventive actions of cucurbitacins. Cucurbitacins may be a potential choice for investigations of synergism with other drugs to reverse cancer cells' treatment resistance. The detailed molecular mechanisms underlying these effects include interactions between cucurbitacins and numerous cellular targets (Bcl-2/Bax, caspases, STAT3, cyclins, NF-κB, COX-2, MMP-9, VEGF/R, etc.) as well as control of a variety of intracellular signal transduction pathways. The current study is focused on the efforts undertaken to find possible molecular targets for cucurbitacins in suppressing diverse malignant processes. The review is distinctive since it presents all potential molecular targets of cucurbitacins in cancer on one common podium.

Contrasting Metabolic Fingerprints and Seed Protein Profiles of Cucurbita foetidissima and C. radicans Fruits from Feral Plants Sampled in Central Mexico.

Cucurbita foetidissima and C. radicans are scarcely studied wild pumpkin species that grow in arid and semi-arid areas of Mexico and the United States. This study describes the morphological, proximal composition, metabolic finger-prints and seed protein profiles of C. foetidissima and C. radicans fruits collected in the wild during a one-year period in different locations of central-western Mexico. The results obtained complement the limited information concerning the fruit composition of C. foetidissima and greatly expand information in this respect regarding C. radicans. Morphology and proximal composition of their fruits varied significantly. Different metabolic fingerprints and seed protein profiles were detected between them and also with the chemical composition of domesticated Cucurbita fruits. The neutral lipids in seed, pulp and peels were rich in wax content and in unsaturated compounds, probably carotenoids and tocopherols, in addition to tri-, di- and mono-acylglycerols. The tri- and diacylglycerol profiles of their seed oils were different from commercial seed oils and between each other. They also showed unusual fatty acid compositions. Evidence of a possible alkaloid in the pulp and peel of both species was obtained in addition to several putative cucurbitacins. An abundance of phenolic acids was found in all fruit parts, whereas flavonoids were only detected in the peels. Unlike most cucurbits, globulins were not the main protein fraction in the seeds of C. radicans, whereas the non-structural carbohydrate and raffinose oligosaccharide content in their fruit parts was lower than in other wild cucurbit species. These results emphasize the significantly different chemical composition of these two marginally studied Cucurbita species, which was more discrepant in C. radicans, despite the notion regarding C. foetidissima as an aberrant species with no affinity to any other Cucurbita species.