Metabolism and signaling of cytokinins was first established in plants, followed by cytokinin discoveries in all kingdoms of life. However, understanding of their role in mammalian cells is still scarce. Kinetin is a cytokinin that mitigates the effects of oxidative stress in mammalian cells. The effective concentrations of exogenously applied kinetin in invoking various cellular responses are not well standardized. Likewise, the metabolism of kinetin and its cellular targets within the mammalian cells are still not well studied. Applying vitality tests as well as comet assays under normal and hyper-oxidative states, our analysis suggests that kinetin concentrations of 500 nM and above cause cytotoxicity as well as genotoxicity in various cell types. However, concentrations below 100 nM do not cause any toxicity, rather in this range kinetin counteracts oxidative burst and cytotoxicity. We focus here on these effects. To get insights into the cellular targets of kinetin mediating these pro-survival functions and protective effects we applied structural and computational approaches on two previously testified targets for these effects. Our analysis deciphers vital residues in adenine phosphoribosyltransferase (APRT) and adenosine receptor (A2A-R) that facilitate the binding of kinetin to these two important human cellular proteins. We finally discuss how the therapeutic potential of kinetin against oxidative stress helps in various pathophysiological conditions. The small-molecule adenosine N 6-furfuryladenine (N6FFA: kinetin) is commonly used by the plant community as a low-priced proxy for the natural cytokinins (CKs) in plant tissue-culture experiments 1. CKs are a group of phytohormones influencing the entire bauplan of plants; ranging from seed germination, cell division, flowering, organogenesis, immunity, and communication until senescence of the plant 1,2. In plants, kinetin binds to almost all known CKs canonical pathway receptors and invokes analogous physiological responses as many more specific CK-types 2. The naturally occurring CKs in plants are isoprenoid-type CKs, for instance, isopentenyl adenine (iP), trans-zeatin (tZ), cis-zeatin (cZ), and dihydrozeatin (DZ) are the most common forms 3. The majority of naturally occurring CKs exist as free (active forms) bases. Cytokinins conjugate with sugars or amino acid residues and thus form inactive forms 4,5. Previously, CKs were assumed to be exclusively present in the kingdom Plantae; however, their discovery in all forms of life except Archaea, have changed the former notion 6. Likewise, land plants are considered to be the only eukaryotes that harbor two-components system (TCS) that senses and transduces the signal of CKs 7. No such CKs-sensing circuitry has ever been reported for mammalian cells. More intriguingly, many human pathogens such as Mycobacterium tuberculosis 8 and rodent malarial parasites such as apicomplexan

The present study was undertaken to investigate the anti-inflammatory effect of piperine against adjuvant-induced arthritis in rats, an experimental model for rheumatoid arthritis and compared it with that of the non-steroidal anti-inflammatory drug indomethacin. Administration of heat-killed Mycobacterium tuberculosis (0. 1 ml) intradermally into the right hind paw of rats resulted in increased paw volume, lysosomal enzymes, glycoproteins and tissue marker enzymes and decreased body weight. However, these changes were reverted to near normal levels upon piperine (30 mg/kg body weight, i.p.) treatment. Histopathological analysis of joints also revealed that synovial hyperplasia and mononuclear infiltration observed in arthritic rats were alleviated by piperine. Thus, the present study clearly indicated that piperine possesses promising anti-inflammatory effect against adjuvant-induced arthritis by suppressing inflammation and cartilage destruction.

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