Natural tyrosinase enzyme inhibitors: A path from melanin to melanoma and its reported pharmacological activities.

The skin containing melanin pigment acts as a protective barrier and counteracts the UVR and other environmental stressors to maintain or restore disrupted cutaneous homeostasis. The production of melanin pigment is dependent on tyrosine levels. L-tyrosine and L-dihydroxyphenylalanine (L-DOPA) can serve both as a substrates and intermediates of melanin synthetic pathway and as inducers and positive regulators of melanogenesis. The biosynthesis of melanin is stimulated upon exposure to UVR, which can also stimulate local production of hormonal factors, which can stimulate melanoma development by altering the chemical properties of eu- and pheomelanin. The process of melanogenesis can be altered by several pathways. One involves activation of POMC, with the production of POMC peptides including MSH and ACTH, which increase intracellular cAMP levels, which activates the MITF, and helps to stimulate tyrosinase (TYR) expression and activity. Defects in OCA1 to 4 affects melanogenic activity via posttranslational modifications resulting in proteasomal degradation and reducing pigmentation. Further, altering, the MITF factor, helps to regulate the expression of MRGE in melanoma, and helps to increase the TYR glycosylation in ER. CRH stimulates POMC peptides that regulate melanogenesis and also by itself can stimulate melanogenesis. The POMC, P53, ACTH, MSH, MC1R, MITF, and 6-BH4 are found to be important regulators for pigmentation. Melanogenesis can affect melanoma behaviour and inhibit immune responses. Therefore, we reviewed natural products that would alter melanin production. Our special focus was on targeting melanin synthesis and TYR enzyme activity to inhibit melanogenesis as an adjuvant therapy of melanotic melanoma. Furthermore, this review also outlines the current updated pharmacological studies targeting the TYR enzyme from natural sources and its consequential effects on melanin production.

Identification of (2R,3R)-2-(3,4-dihydroxyphenyl)chroman-3-yl-3,4,5-trihydroxy benzoate as multiple inhibitors of SARS-CoV-2 targets; a systematic molecular modelling approach.

Coronavirus disease of 2019 (COVID-19) is a zoonotic disease caused by a new severe acute respiratory syndrome (SARS-CoV-2) which has quickly resulted in a pandemic. Recent anti-COVID-19 drug discoveries are leaning towards repurposing phytochemicals which have been previously reported for SARS and MERS-CoV outbreaks. However, they have been either virtually screened or tested so far against mono targets and the potent derivatives of virtually sorted lead molecules remain elusive. We aimed to identify the phytochemicals having potentials to inhibit SARS CoV-2 infection via multiple targets. The selected 132 phytochemicals were virtually screened using a structure based in silico technique against main protease (Mpro) which is a potential target of SARS CoV-2. Six compounds were selected based on the LibDock scores and further subjected to induced fit docking using the CDOCKER module of DS. Two compounds namely cinnamtannin-B and gallocatechin gallate were identified as top HITS against main protease (Mpro). Based on the Lipinski rule of five (L-ROF) and synthetic feasibility, gallocatechin gallate was taken for our further studies. Six analogues of gallocatechin gallate were screened against the next important targets such as RNA-dependent RNA polymerase (RdRp), angiotensin converting enzyme-2 (ACE2), transmembrane protease serine -2 (TMPRSS2) and interleukin-6 (IL-6) along with main protease (Mpro). Our molecular docking results reveal that a gallocatechin analogue (GC-2) namely (2R,3R)-2-(3,4-dihydroxyphenyl)chroman-3-yl-3,4,5-trihydroxy benzoate has shown potential to inhibit multiple targets of SARS CoV-2. Further, the molecular dynamics study was carried out to ascertain the stability of the GC-2 and RdRp complex.

Minutes of PPAR-γ agonism and neuroprotection.

Peroxisome proliferator-activated receptor gamma (PPAR-γ) is one of the ligand-activated transcription factors which regulates a number of central events and considered as a promising target for various neurodegenerative disease conditions. Numerous reports implicate that PPAR-γ agonists have shown neuroprotective effects by regulating genes transcription associated with the pathogenesis of neurodegeneration. In regards, this review critically appraises the recent knowledge of PPAR-γ receptors in neuroprotection in order to hypothesize potential neuroprotective mechanism of PPAR-γ agonism in chronic neurological conditions. Of note, the PPAR-γ's interaction dynamics with PPAR-γ coactivator-1α (PGC-1α) has gained significant attention for neuroprotection. Likewise, a plethora of studies suggest that the PPAR-γ pathway can be actuated by the endogenous ligands present in the CNS and thus identification and development of novel agonist for the PPAR-γ receptor holds a vow to prevent neurodegeneration. Together, the critical insights of this review enlighten the translational possibilities of developing novel neuroprotective therapeutics targeting PPAR-γ for various neurodegenerative disease conditions.

Targeting obesity with plant-derived pancreatic lipase inhibitors: A comprehensive review.

The prevalence of obesity is alarmingly increasing in the last few decades and leading to many serious public health concerns worldwide. The dysregulated lipid homeostasis due to various genetic, environmental and lifestyle factors is considered one of the critical putative pathways mediating obesity. Nonetheless, the scientific advancements unleashing the molecular dynamics of lipid metabolism have provided deeper insights on the emerging roles of lipid hydrolysing enzymes, including pancreatic lipase. It is hypothesized that inhibiting pancreatic lipase would prevent the breakdown of triglyceride and delays the absorption of fatty acids into the systemic circulation and adipocytes. Whilst, orlistat is the only conventional pancreatic lipase enzyme inhibitor available in clinics, identifying the safe clinical alternatives from plants to inhibit pancreatic lipase has been considered a significant advancement. Consequently, plants which have shown significant potential to combat obesity are now revisited for its abilities to inhibit pancreatic lipase. In this regard, our review surveyed the potential of medicinal plants and its phytoconstituents to inhibit pancreatic lipase and to elicit anti-obesity effects. Thus, the review collate and critically appraise the potential of medicinal plants and phyto-molecules inhibiting pancreatic lipase enzyme and consequently modulating triglyceride absorption in gut, and discuss its implications in the development of novel therapeutic strategies to combat obesity.

Cytosolic lipid excess-induced mitochondrial dysfunction is the cause or effect of high fat diet-induced skeletal muscle insulin resistance: a molecular insight.

Mitochondria play a central role in the energy homeostasis in eukaryotic cells by generating ATP via oxidative metabolism of nutrients. Excess lipid accumulation and impairments in mitochondrial function have been considered as putative mechanisms for the pathogenesis of skeletal muscle insulin resistance. Accumulation of lipids in tissues occurs due to either excessive fatty acid uptake, decreased fatty acid utilization or both. Consequently, elevated levels cytosolic lipid metabolites, triglycerides, diacylglycerol and ceramides have been demonstrated to adversely affect glucose homeostasis. Several recent studies indicate that reduced insulin-stimulated ATP synthesis and reduced expression of mitochondrial enzymes and PPAR-γ coactivator, in high fat feeding (lipid overload) are associated with insulin resistance. Despite the fact, few notable studies suggest mitochondrial dysfunction is prevalent in type 2 diabetes mellitus; it is still not clear whether the defects in mitochondrial function are the cause of insulin resistance or the consequential effects of insulin resistance itself. Thus, there is a growing interest in understanding the intricacies of mitochondrial function and its association with cytosolic lipid excess. This review therefore critically examines the molecular cascades linking cytosolic lipid excess and mitochondrial dysfunction in the pathogenesis of high fat diet-induced insulin resistance in skeletal muscle. The sequential processes following the excess intake of high fat diet in skeletal muscle includes, accumulation of cytosolic fatty acids, increased production of reactive oxygen species, mutations and ageing, and decreased mitochondrial biogenesis. The consequent mitochondrial dysfunction is then leading to decreased ß-oxidation, respiratory functions and glycolysis and increased glucolipotoxicity. These events collectively induce the insulin resistance in skeletal muscle.

Data on the Lignosus rhinocerotis water soluble sclerotial extract affecting intracellular calcium level in rat dorsal root ganglion cells.

The data in this article contain supporting evidence for the research manuscript entitled "Bronchodilator effects of Lignosus rhinocerotis extract on rat isolated airways is linked to the blockage of calcium entry" by Lee et al. (2018) [1]. The data were obtained by calcium imaging technique with fluorescent calcium indicator dyes, Fura 2-AM, to visualize calcium ion movement in the rat dorsal ganglion (DRG) cells. The effects of L. rhinocerotis cold water extract (CWE1) on intracellular calcium levels in the DRG cells were presented.

Bronchodilator effects of Lignosus rhinocerotis extract on rat isolated airways is linked to the blockage of calcium entry.

BACKGROUND: Lignosus rhinocerotis (Cooke) Ryvarden is a popular medicinal mushroom used for centuries in Southeast Asia to treat asthma and chronic cough. The present study aimed to investigate the effect of this mushroom on airways patency. MATERIALS AND METHODS: The composition of L. rhinocerotis TM02 cultivar was analyzed. Organ bath experiment was employed to study the bronchodilator effect of Lignosus rhinocerotis cold water extract (CWE) on rat isolated airways. Trachea and bronchus were removed from male Sprague-Dawley rats, cut into rings of 2 mm, pre-contracted with carbachol before adding CWE into the bath in increasing concentrations. To investigate the influence of incubation time, tissues were exposed to intervals of 5, 15 and 30 min between CWE concentrations after pre-contraction with carbachol in subsequent protocol. Next, tissues were pre-incubated with CWE before the addition of different contractile agents, carbachol and 5-hydroxytrptamine (5-HT). The bronchodilator effect of CWE was compared with salmeterol and ipratropium. In order to uncover the mechanism of action of CWE, the role of beta-adrenoceptor, potassium and calcium channels was investigated. RESULTS: Composition analysis of TM02 cultivar revealed the presence of ß-glucans and derivatives of adenosine. The extract fully relaxed the trachea at 3.75 mg/ml (p < 0.0001) and bronchus at 2.5 mg/ml (p < 0.0001). It was observed that lower concentrations of CWE were able to fully relax both trachea and bronchus but at a longer incubation interval between concentrations. CWE pre-incubation significantly reduced the maximum responses of carbachol-induced contractions (in both trachea, p = 0.0012 and bronchus, p = 0.001), and 5-HT-induced contractions (in trachea, p = 0.0048 and bronchus, p = 0.0014). Ipratropium has demonstrated a significant relaxation effect in both trachea (p = 0.0004) and bronchus (p = 0.0031), whereas salmeterol has only affected the bronchus (p = 0.0104). The involvement of ß2-adrenoceptor and potassium channel in CWE-mediated airway relaxation is ruled out, but the bronchodilator effect was unequivocally affected by influx of calcium. CONCLUSIONS: The bronchodilator effect of L. rhinocerotis on airways is mediated by calcium signalling pathway downstream of Gαq-coupled protein receptors. The airway relaxation effect is both concentration- and incubation time-dependent. Our findings provide unequivocal evidence to support its traditional use to relieve asthma and cough.

Khat (Catha edulis) and Obesity: A Scoping Review of Animal and Human Studies.

BACKGROUND: Khat (Catha edulis) is a plant that is deeply rooted in the cultural life of East African and Southwestern Arabian populations. Prevalent traditional beliefs about khat are that the plant has an effect on appetite and body weight. SUMMARY: This review assesses the accumulated evidences on the mutual influence of monoamines, hormones and neuropeptides that are linked to obesity. A few anti-obesity drugs that exert their mechanisms of action through monoamines are briefly discussed to support the notion of monoamines being a critical target of drug discovery for new anti-obesity drugs. Subsequently, the review provides a comprehensive overview of central dopamine and serotonin changes that are associated with the use of khat or its alkaloids. Then, all the studies on khat that describe physical, biochemical and hormonal changes are summarised and discussed in depth. CONCLUSION: The reviewed studies provide relatively acceptable evidence that different khat extracts or cathinone produces changes in terms of weight, fat mass, appetite, lipid biochemistry and hormonal levels. These changes are more pronounced at higher doses and long durations of intervention. The most suggested mechanism of these changes is the central action that produces changes in the physiology of dopamine and serotonin. Nonetheless, there are a number of variations in the study design, including species, doses and durations of intervention, which makes it difficult to arrive at a final conclusion about khat regarding obesity, and further studies are necessary in the future to overcome these limitations.