Current Landscape on Development of Phenylalanine and Toxicity of its Metabolites - A Review.

Phenylalanine, an essential amino acid, is the "building block" of protein. It has a tremendous role in different aspects of metabolic events. The tyrosine pathway is the prime one and is typically used to degrade dietary phenylalanine. Phenylalanine exceeds its limit in bodily fluids and the brain when the enzyme, phenylalanine decarboxylase, phenylalanine transaminase, phenylalanine hydroxylase (PAH) or its cofactor tetrahydrobiopterin (BH4) is deficient causes phenylketonuria, schizophrenia, attentiondeficit/ hyperactivity disorder and another neuronal effect. Tyrosine, an amino acid necessary for synthesizing the pigments in melanin, is produced by its primary metabolic pathway. Deficiency/abnormality in metabolic enzymes responsible for the catabolism pathway of Phenylalanine causes an accumulation of the active intermediate metabolite, resulting in several abnormalities, such as developmental delay, tyrosinemias, alkaptonuria, albinism, hypotension and several other undesirable conditions. Dietary restriction of the amino acid(s) can be a therapeutic approach to avoid such undesirable conditions when the level of metabolic enzyme is unpredictable. After properly identifying the enzymatic level, specific pathophysiological conditions can be managed more efficiently.

Attenuation of COX-2 enzyme by modulating H2O2-mediated NF-κB signaling pathway by monoamine oxidase inhibitor (MAOI): a further study on the reprofiling of MAOI in acute inflammation.

OBJECTIVE: This study aims to investigate the anti-inflammatory mechanism of monoamine oxidase inhibitor (MAOI) in carrageenan (CARR) induced inflammation models to reprofile their use. We also aimed to explore the role of monoamine oxidase (MAO)-mediated H2O2-NF-κB-COX-2 pathway in acute inflammation. METHODS: In vitro anti-inflammatory activity and hydrogen peroxide (H2O2) scavenging activity were performed according to the established procedure. Inflammation was induced using CARR in BALB/c mice at the foot paw and peritoneal cavity. Hourly measurement of paw swelling was performed. The level of nitric oxide (NO), myeloperoxidase (MPO), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and nuclear factor κB (NF-κB) was determined using enzyme-linked immunosorbent assay (ELISA). Peritoneal fluid was collected to investigate total count, differential count of leukocytes, and capillary permeability. RESULTS: In vitro anti-inflammatory evaluations revealed the potential role of MAOI to inhibit heat-induced protein denaturation and human red cell membrane destabilization. H2O2 inhibition activity of MAOI also proved their powerful role as an H2O2 scavenger. Treatment with MAOI in CARR-induced mice significantly reduced paw edema, leukocyte extravasation, and total and differential leukocyte count. The result of ELISA showed MAOI effectively reduce the level of COX-2, PGE2 and NF-κB in inflamed tissue. CONCLUSIONS: In short, this study demonstrates that inhibition of H2O2 by MAOI alleviates CARR-induced paw edema possibly by inhibiting the H2O2-mediated NF-κB-COX-2 pathway. The present investigation identifies MAOI might reprofile for the treatment of acute inflammation also, the MAO enzyme may use as a novel therapeutic target to design and develop new class of anti-inflammatory agents.

Repurposing monoamine oxidase inhibitors (MAOI) for the treatment of rheumatoid arthritis possibly through modulating reactive oxidative stress mediated inflammatory cytokines.

Monoamine oxidase inhibitors (MAOI) are presently used to treat depression, parkinsonian, and other psychiatric disorders. The present study was aimed to repurpose the use of MOAI in Rheumatoid Arthritis (RA). The animal model of RA was developed using collagen type II (CII) in Freund's complete adjuvant (FCA) followed by lipopolysaccharide (LPS) and a booster dose of CII in FCA. The effect of MAOI, Selegiline was evaluated whereas the indicators like paw thickness, arthritic score, and the splenic index were measured and compared with the standard drug Methotrexate. Further to explore the molecular mechanism, the expression of serum inflammatory cytokines (IL-6 and TNF-α), radiographical and histopathological study of hind paw were also checked and analyzed. Treatment with MAOI, Selegiline not only reduced the paw thickness, arthritic score, and the splenic index, but also greatly improved the inflammatory biochemical and hematologic parameters and improved the arthritis score. The serum level of IL-6 and TNF-α are considerably decreased dose dependently, however, the notable significant effect (**p < 0.01) observed at concentration of 30 mg/kg b.w. when the RA animals treated by Selegiline. Collectively, Selegiline improved the progression of RA possibly via decreased catecholamine breakdown at synovial fluid resulting decrease hydrogen peroxide (H2O2) generation and inhibition of pro-inflammatory cytokines in situ. Thus, the finding support and indicate the repurposing of MAOI for the treatment of RA meriting further studies on synovial monoamine oxidase as a new therapeutic target to design a new drug for RA.

Pharmacological studies of rhizomes of extract of Cyperus tegetum, emphasized on anticancer, anti-inflammatory and analgesic activity.

ETHNOPHARMACOLOGICAL RELEVANCE: With over 950 species, Cyperus is one of the most promising health boosting genera in the Cyperaceae family. Traditional uses of Cyperus sp. have been described for gastrointestinal blood abnormalities, menstrual irregularities, and inflammatory diseases, among others. Cyperus tegetum Roxb belonging to Cyperaceae family, is used in traditional medicine to treat skin cancers. AIM OF THE STUDY: The present study was carried out to explore the potential effect of the extract of the plant Cyperus tegetum against different pharmacological activity namely inflammatory, analgesic activity as well as skin cancer activity in mice. MATERIALS AND METHODS: Cytotoxicity of the extract was measured by MTT and Live/death assay on HeLa cell line. Skin cancer was induced by 7,12-dimethylbenz(a) anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) in mice to measure its effects. RESULT: Stigmasterol and some poly phenolic compounds are identified using HPTLC process from the methanol extract of the rhizome of the plant Cyperus tegetum (CT-II). After confirmation of the presence of different polyphenolic compound and triterpenoids in the extract, it was subject to MTT and Live/death assay on HeLa cell line. From the observation it could be concluded that the IC50 of the extract is 300 µg/ml. Thus, the CTII was evaluated further for its in vivo anticancer property. In the tumorigenesis study, the number of tumor growths, the area and weight of the tumor significantly decreases with increment in the dose of CT-II extract and some elevated enzyme release in renal (creatinine, urea) as well as hepatic (AST, ALT, ALP) enzymes are also controlled with the increased dose of the same extract. The elevated enzyme release may be due to cancer induced rupture of the plasma and cellular damage. This CT-II extract also exhibits some other pharmacological activity like anti-inflammatory and analgesic activity. CONCLUSION: As metabolic activation via carcinogens and inflammation response plays important role in development of cancer, antioxidant, anti-inflammatory and analgesic properties can be correlated with anti-cancer properties. Taken all the above studies, it was illustrated that the extract of Cyperus tegetum might be a promising compound to reduce skin cancer risk.