Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Despite scepticism concerning its bioavailability, a growing body of in vivo evidence indicates that resveratrol has protective effects in rodent models of stress and disease. Here, we provide a comprehensive and critical review of the in vivo data on resveratrol, and consider its potential as a therapeutic for humans.

Therapeutic potential of resveratrol: the in vivo evidence.

Phenolics and polyphenolics in foods, beverages and spices: Antioxidant activity and health effects – A review

Dietary phenolics: chemistry, bioavailability and effects on health.

There is great geographical variation in the distribution of hepatocellular carcinoma (HCC), with the majority of all cases worldwide found in the Asia–Pacific region, where HCC is one of the leading public health problems. Since the “Toward Revision of the Asian Pacific Association for the Study of the Liver (APASL) HCC Guidelines” meeting held at the 25th annual conference of the APASL in Tokyo, the newest guidelines for the treatment of HCC published by the APASL has been discussed. This latest guidelines recommend evidence-based management of HCC and are considered suitable for universal use in the Asia–Pacific region, which has a diversity of medical environments.

/pdf/asia-pacific-clinical-practice-guidelines-on-the-management-3qdf1cp1jm.pdf

Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.

/pdf/role-of-resveratrol-in-prevention-and-therapy-of-cancer-tq57uztzep.pdf

Role of Resveratrol in Prevention and Therapy of Cancer: Preclinical and Clinical Studies

Purine and pyrimidine nucleotides are major energy carriers, subunits of nucleic acids and precursors for the synthesis of nucleotide cofactors such as NAD and SAM. Despite the obvious importance of these molecules, we still have much to learn about how these nucleotides are synthesized and metabolized by plants. Moreover, of the research that has been done in this area relatively little has used genetic analysis to evaluate the function(s) of specific enzymes.

The pathways for the synthesis of nucleotides in plant cells are similar to those found in animals and microorganisms. This conclusion is based primarily on the results of studies using in vivo radiotracers, specific inhibitors of nucleotide synthesis and on analyses of the kinetic parameters of purified enzymes involved in nucleotide synthesis that are unlikely to have similar demands for purine and pyrimidine nucleotides have been used in this research. A more comprehensive understanding of the role(s) of specific nucleotide biosynthetic enzymes throughout plant development and factors that regulate their activity/expression is still lacking. Ultimately this information will explain how the requirements of different plants are met, such as those of ureide-producing legumes (Schubert and Boland, 1990) or those synthesizing caffeine (Suzuki et al., 1992; Ashihara and Crozier, 1999).

There are two principal routes for the synthesis of nucleotides: the de novo and the salvage pathways (Figures 1 and ​and2,2, Figures 3 and ​and4,4, respectively). Using 5-phosphoribosyl-1-pyrophosphate (PRPP), the de novo pathway enzymes build purine and pyrimidine nucleotides from “scratch” using simple molecules such as CO2, amino acids and tetrahydrofolate. This route of nucleotide synthesis has a high requirement for energy as compared that of the salvage pathway. For example, five of the 12 steps of de novo purine synthesis require hydrolysis of ATP or GTP but only one salvage cycle reaction uses ATP. The enzymes of both of these biosynthetic routes are classified as “housekeeping” enzymes because they perform basic, cellular activities and are assumed to be present in low, constitutive levels in all cells. Whereas the de novo pathway is thought to reside in plastids, salvage cycle enzymes may be localized in more than one compartment.




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Figure 1.


De novo biosynthetic pathway of purine nucleotides in plants. Enzymes shown are: amido phosphoribosyltransferase, (2) GAR synthetase, (3) GAR formyl transferase, (4) FGAM synthetase, (5) AIR synthetase, (6) AIR carboxylase, (7) SAICAR synthetase, (8) adenylosuccinate lyase, (9) AICAR formyl transferase, (10) IMP cyclohydrolase, (11) SAMP synthetase, (12) adenylosuccinase, (13) IMP dehydrogenase, (14) GMP synthetase.

https://bioone.org/journals/The-Arabidopsis-Book/volume-2002/issue-1/tab.0018/Purine-and-Pyrimidine-Nucleotide-Synthesis-and-Metabolism/10.1199/tab.0018.pdf

Purine and Pyrimidine Nucleotide Synthesis and Metabolism

https://www.cell.com/trends/plant-science/pdf/S1360-1385(01)02055-6.pdf

Caffeine: a well known but little mentioned compound in plant science

Caffeine synthase is an enzyme that catalyses the final two steps in the caffeine biosynthesis pathway. We have cloned the gene encoding caffeine synthase from young leaves of tea (Camellia sinensis), opening up the possibility of creating tea and coffee (Coffea arabica) plants that are naturally deficient in caffeine. Consumers concerned about the possible adverse effects of caffeine consumption will welcome this development towards caffeine-free drinks that retain their flavour.

/pdf/caffeine-synthase-gene-from-tea-leaves-4221j3zxiq.pdf

Caffeine synthase gene from tea leaves

A large amount of gamma-aminobutyric acid (GABA) was found to accumulate in tomato (Solanum lycopersicum) fruits before the breaker stage. Shortly thereafter, GABA was rapidly catabolized after the breaker stage. We screened the GABA-rich tomato cultivar 'DG03-9' which did not show rapid GABA catabolism after the breaker stage. Although GABA hyperaccumulation and rapid catabolism in fruits is well known, the mechanisms are not clearly understood. In order to clarify these mechanisms, we performed comparative studies of 'Micro-Tom' and 'DG03-9' fruits for the analysis of gene expression levels, protein levels and enzymatic activity levels of GABA biosynthesis- and catabolism-related enzymes. During GABA accumulation, we found positive correlations among GABA contents and expression levels of SlGAD2 and SlGAD3. Both of these genes encode glutamate decarboxylase (GAD) which is a key enzyme of GABA biosynthesis. During GABA catabolism, we found a strong correlation between GABA contents and enzyme activity of alpha-ketoglutarate-dependent GABA transaminase (GABA-TK). The contents of glutamate and aspartate, which are synthesized from GABA and glutamate, respectively, increased with elevation of GABA-TK enzymatic activity. GABA-TK is the major GABA transaminase form in animals and appears to be a minor form in plants. In 'DG03-9' fruits, GAD enzymatic activity was prolonged until the ripening stage, and GABA-TK activity was significantly low. Taken together, our results suggest that GAD and GABA-TK play crucial roles in GABA accumulation and catabolism, respectively, in tomato fruits.

Biochemical mechanism on GABA accumulation during fruit development in tomato.

Publisher Summary This chapter discusses the biosynthesis and metabolism of caffeine and related purine alkaloids in plants. Caffeine and other purine alkaloids, including theobromine and theophylline, have played a major role in the long-standing popularity of non-alcoholic beverages and foods such as coffee, tea, cocoa, mate, chocolate and a wide range of soft drinks. This chapter begins by summarizing those aspects of general purine metabolism in plants that are related to purine alkaloid metabolism, and then provides an up-to-date account of the biosynthesis of caffeine and theobromine in a variety of plant species. Recent information on the properties and isolation of key enzymes, such as the caffeine synthase, are presented. Physiological studies on caffeine biosynthesis in tea and coffee plants including the authors' own work are also introduced. Catabolism of caffeine via demethylation to xanthine and degradation via the purine catabolism pathway in higher plants is then reviewed. The diversity of caffeine catabolism between species and between tissues of different age is considered. In young tea leaves, theophylline, a catabolite of caffeine, is reutilized for caffeine synthesis, but in aged Coffea arabica leaves 7-methylxanthine accumulates.

Hiroshi Ashihara

Papers

Purine and Pyrimidine Nucleotide Synthesis and Metabolism

Caffeine: a well known but little mentioned compound in plant science

Caffeine synthase gene from tea leaves

Biochemical mechanism on GABA accumulation during fruit development in tomato.

Biosynthesis and Metabolism of Caffeine and Related Purine Alkaloids in Plants