■ Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: ( a) Zymogen gene transcription is regulated; ( b) antiapoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and ( c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.

Mammalian caspases: structure ,a ctivation ,s ubstrates, and functions during apoptosis

Occurrence, Biogenesis, and Synthesis of Biologically Active Carbazole Alkaloids

Flavonoids and their glycosides, including anthocyanins

Inflammation, although first characterized by Cornelius Celsus, a physician in first Century Rome, it was Rudolf Virchow, a German physician in nineteenth century who suggested a link between inflammation and cancer, cardiovascular diseases, diabetes, pulmonary diseases, neurological diseases and other chronic diseases. Extensive research within last three decades has confirmed these observations and identified the molecular basis for most chronic diseases and for the associated inflammation. The transcription factor, Nuclear Factor-kappaB (NF-kappaB) that controls over 500 different gene products, has emerged as major mediator of inflammation. Thus agents that can inhibit NF-kappaB and diminish chronic inflammation have potential to prevent or delay the onset of the chronic diseases and further even treat them. In an attempt to identify novel anti-inflammatory agents which are safe and effective, in contrast to high throughput screen, we have turned to "reverse pharmacology" or "bed to benchside" approach. We found that Ayurveda, a science of long life, almost 6,000 years old, can serve as a "goldmine" for novel anti-inflammatory agents used for centuries to treat chronic diseases. The current review is an attempt to provide description of various Ayurvedic plants currently used for treatment, their active chemical components, and the inflammatory pathways that they inhibit.

Identification of Novel Anti-inflammatory Agents from Ayurvedic Medicine for Prevention of Chronic Diseases: “Reverse Pharmacology” and “Bedside to Bench” Approach

Excerpt Essentially all the hydroxyproline in the tissues of vertebrates is found in collagen, and, except for the small amount of hydroxyproline in elastin, no other animal protein contains signif...

Relationship of Hydroxyproline Excretion in Urine to Collagen Metabolism

Considerable attention has been focused on plants which are sources of natural anti-oxidant compounds, because most of them have a modulatory role on physiological functions and biotransformation reactions involved in the detoxification process. Such compounds are likely to afford protection from cytotoxic, genotoxic and metabolic actions of environmental toxicant thereby reducing the risk for cancer. The present study reports the anticarcinogenic activity of Swertia chirata Buch.Ham, an Indian medicinal plant. All the four detoxification enzymes studied viz, GST, GPx, SOD and CAT were found to be activated in different degrees following treatment with infusion of Swertia chirata, its crude extract and a purified 'Amarogentin' rich extract. The activation of the enzymes was accompanied by significant reduction in lipid peroxidation and inhibition of incidence as well as multiplicity of Dimethylbenz(a)anthracene (DMBA) induced papillomas. The effect of S.chirata on apoptosis and cell proliferation was also studied in mice skin exposed to DMBA. Both the crude and purified extracts significantly inhibited cell proliferation and induced apoptosis. This is the fi rst report of its kind and the observation suggests the chemopreventive potential of Swertia chirata.

Evaluation of the anticarcinogenic activity of Swertia chirata Buch.Ham, an Indian medicinal plant, on DMBA-induced mouse skin carcinogenesis model.

Antidiarrhoeal activity of carbazole alkaloids from Murraya koenigii Spreng (Rutaceae) seeds

Mean individual fatty acid concentration among differentspecies of the family Cruciferae are not similar because of the presence ofdifferent kind of significant relationship among the individual fatty acids.Brassica napus L., Sinapis alba L.,Raphanus caudatus L.f. Raphanus sativusL. and B. nigra (L.) Koch arecomparatively low erucic acid (<40%) containing species. Crambeabyssinica Hochst. ex. R. E. Fries collections gave as high as 60%erucic acid. Low erucic acid concentration was found associated with thepresence of high level of palmitic and oleic acid concentrations. Erucic acidconcentrations were found varied within the range of 42 to 57% among thecollections of Brassica rapa L. and B.carinata A. Braun. All the collections ofB. nigra (L.) Koch were found to havehigher proportion of linoleic acid than the corresponding oleic acidconcentration. Linolenic acid concentrations of B.nigra (L.) Koch was also higher in comparison to otherspecies of the Cruciferae. Raphanus collections were foundto contain higher levels of total saturated fatty acids as well as eicosenoicacid. Oil content of the total collections under present study did not show anysignificant relationship either with linolenic acid or with erucic acidconcentration. But significant positive relationship was observed between totaloil and erucic acid level within the collections of B.juncea Czern. & Coss. Similarly significant negativecorrelation was observed between total oil and linolenic acid content inBrassica rapa L. ssp. trilocularis (Roxb.) Hanelt, yellow sarson.

Correlation studies on oil content and fatty acid profile of some Cruciferous species

Amarogentin, a secoiridoid glycoside, is an active component of the medicinal plant Swertia chirata. In this study, chemopreventive and chemotherapeutic actions of amarogentin were evaluated in a carbon tetrachloride (CCl(4))/N-nitrosodiethylamine (NDEA)-induced liver carcinogenesis mouse model system during continuous and posttreatment schedule. Better survival, no toxicity and increased body weight were noted in amarogentin-treated mice. Reduction in proliferation and increase in apoptosis frequency were evident in amarogentin-treated groups. In carcinogen control group moderate dysplasia, severe dysplasia and hepatocellular carcinoma were evident at 10th, 20th and 30th week, respectively. Amarogentin was found to prevent progression of liver carcinogenesis at mild dysplastic stage. Exposure to CCl(4)/NDEA resulted in upregulation of ppRb807/811, cyclinD1 and cdc25A at 10th week and additional activation of cMyc and mdm2 along with downregulation of LIMD1, p53 and p21 at 20th week. This was followed by activation of ppRb567 and downregulation of Rbsp3 at 30th week. Prevention of carcinogenesis by amarogentin in both groups might be due to cumulative upregulation of LIMD1, RBSP3, p16 and downregulation of cdc25A at 10th week along with activation of p53 and p21 and downregulation of ppRb807/811 and ppRb567 at 20th week, followed by downregulation of cyclinD1, cMyc and mdm2 at 30th week. During carcinogenesis reduction of apoptosis was evident since 20th week. However, amarogentin treatment could significantly induce apoptosis through upregulation of the Bax-Bcl2 ratio, activation of caspase-3 and poly ADP ribose polymerase cleavage. This is the first report of chemopreventive/therapeutic role of amarogentin during liver carcinogenesis through modulation of cell cycle and apoptosis.

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Suvra Mandal

Papers

Evaluation of the anticarcinogenic activity of Swertia chirata Buch.Ham, an Indian medicinal plant, on DMBA-induced mouse skin carcinogenesis model.

Antidiarrhoeal activity of carbazole alkaloids from Murraya koenigii Spreng (Rutaceae) seeds

Correlation studies on oil content and fatty acid profile of some Cruciferous species

Prevention of liver carcinogenesis by amarogentin through modulation of G1/S cell cycle check point and induction of apoptosis.

Amarogentin can reduce hyperproliferation by downregulation of Cox-II and upregulation of apoptosis in mouse skin carcinogenesis model