Tag Archives: RG7388

There is also increasing evidence that the proliferation

There is also increasing evidence that the proliferation and dendricity of melanocytes is controlled by Mitf, which is regulated by MAPK signaling and stress-activated kinase p38 signaling. Therefore, it is possible that the signaling pathway of keratinocyte-derived factors through MK or p38 regulates Mitf in melanocytes and consequently controls the proliferation of mammalian epidermal melanocytes. Thus, melanocytes and keratinocytes form well-organized units in the RG7388 and hair follicles through cell-to-cell interaction.


Funding source

Recently, many topical depigmenting agents have been developed and widely applied for the amelioration of pigmentary dermatoses. Depigmenting formulations can be classified as either pharmacological agents or cosmetic agents. Hydroquinone (HQ) is a main component of topical pharmacological agents, which exhibits great efficacy, but has a relatively high rate of adverse side effect. For this reason, most of these formulations require a doctor\’s prescription. By contrast, cosmetic agents place more importance on safety, and therefore reduce adverse reactions by using nonirritant ingredients or using lower concentrations of irritant ingredients. Although these cosmetic agents can be used safely without a prescription, they are generally less effective than HQ-based pharmacological agents. The present article reviews current clinical usage of pharmacological and cosmetic depigmenting agents, as well as the current status of emerging depigmenting ingredients. In addition, we present laboratory data on the efficacy and safety of HQ and other cosmetic ingredients.

Pharmacological depigmenting agents

Cosmetic depigmenting agents

Comparative laboratory study of HQ and cosmetic ingredients

New approaches to developing depigmenting agents
The data described herein indicate that HQ is not a safe tyrosinase inhibitor and that it is necessary to develop novel topical agents for the treatment of pigmentary disorders. 4-n-Butylresorcinol may be used to produce a safe cosmetic agent, with the clinical efficacy required of a pharmacological agent. Furthermore, a multitarget approach is necessary because the combined use of two agents with different mechanisms of action can produce more powerful, additive effects. For example, 4-n-butylresorcinol acts mainly by inhibition of tyrosinase activity and has no effect on MITF. However, when combined with hinokitiol, an additive effect is produced which reduces MITF expression. The combination of two agents with different mechanisms may therefore be another useful strategy for increasing the efficacy of these agents.


This study was supported by a grant (HI10C0174, A100179) from the Good Health R&D Project, Ministry of Health and Welfare, Republic of Korea.

Skin color is an important social and cultural characteristic, which explains why the parents of children with any deviations from normal pigmentation are concerned about this problem. Troubles in skin color may raise considerable concern in black and Asian communities. Normal constitutive pigmentation is under the control of myriad genes, but recent studies in humans have attributed a major part of pigmentation variation across races to a limited number of genes. The human equivalent of the mutant golden zebrafish SLC24A5/NCKX5 explains a major part of the shift observed from Negroid to Caucasian phenotypes, and has recently been related to oculocutaneous albinism type 6. Other important human genes include MATP/SLC45A2, which when mutated is responsible for oculocutaneous albinism type 4, and the MRC-1 gene, several loss of function variants of which have been described to be associated with pale skin and red hair, indicating a skewing of melanin production toward that of pheomelanin. Although recreational sun exposure is contraindicated in babies, examination at birth may be misleading for congenital anomalies, because modifications of pigmentation are frequently revealed after the first outdoor exposures. Normal skin has essentially all its melanin in the epidermis and hairs. The color that one perceives when viewing the skin depends on several factors, especially the depth of pigment deposits. If melanin pigment is present in the dermis, the integument takes on a blue–gray hue that looks bluer as the pigment is deposited deeper. Melanin is not the only natural skin pigment. Diet carotenoids deposit in the epidermis and dermis, and contribute in a minimal way to the yellowish tint of the skin. However, a pronounced yellowing of the integument is common in babies on high carotenoid diets. Red and blue hues are the product of oxyhemoglobin and reduced hemoglobin in capillaries, arteries, and veins in the dermis. They may mix in some areas with abnormalities of the pigmentary system, such as in phakomatosis pigmentovascularis (Figure 1), and variations may depend on the maturation of the skin and its thickness.

Plants are excellent sources of

Plants are excellent sources of food, chemicals and herbal medicines. Many important drugs have been derived from these (Khalid et al., 2011). M. nigra is one of the most important species of the genus Morus, the fruits containing substantial levels of phenolics, flavonoids, and ascorbic RG7388 (Kostic et al., 2013). It has recently been reported to exhibit biological properties, such as antidiabetic, antioxidative, anti-inflammatory and antihyperlipidemic activities. These biological activities are due to the polyphenol components, including anthocyanins, present in some varieties (Kutlu et al., 2011; Kamiloglu et al., 2013). Various studies have investigated in vitro antiproliferative and proapoptotic characteristics of different Morus species in the recent years (Fathy et al., 2013; Eo et al., 2014), but studies involving the in vitro cytotoxic effect of M. nigra extract are very limited (Qadir et al., 2014). No previous studies have investigated the cytotoxic effect of M. nigra extract on prostate cancer. Sforcin and Bankova reported that in vitro methods are useful for preliminary investigation of the possible beneficial biological effects of a natural product. If positive results are obtained from in vitro studies, then in vivo or clinical trials are recommended (Sforcin and Bankova, 2011). The PC-3 cell line is an androgen receptor negative prostate cancer cell line with high metastatic potential frequently in cancer research for in vitro prostate cancer models (Shahneh et al., 2014; Huo et al., 2015). We therefore planned this study on the prostate cancer cell line (PC-3) under in vitro conditions.
Many methods are available for extraction of active components from plant materials. Maceration is one such technique. In this method, many solvents, such as water, ethanol, methanol, ethyl acetate, dimethyl sulfoxide, hexane or acetone, are used to extract the components from plant materials directly without compromising the structure (Dai and Mumper, 2010). The DMSO extract of M. nigra was prepared using the maceration technique in this study.
Various in vitro assays can be used to determine antioxidant activity of herbal extracts, and the use of at least two different methods is recommended (Nuutila et al., 2003). The TPC and FRAP methods were employed for the determination of antioxidant activity of DEM in this study. TPC and FRAP values of M. nigra extract were 20.7±0.3mg gallic acid equivalents and 48.8±1.6mg trolox equivalents per g sample, respectively. The TPC values of various extracts of M. nigra fruit from different regions range between 1.69 and 22.37mg gallic acid equivalents/g sample (Kostic et al., 2013), while the FRAP value of 75% aqueous-methanol extract of M. nigra fruit from Turkey has been reported at 3.8mg trolox equivalents/g sample (Kamiloglu et al., 2013). Our results were broadly similar to those of other studies. Any differences may have been due to the type of extraction method and solvent, environmental factors, soil, geographic region, harvest season, post-harvesting conditions and the maturity level of the fruits.
Several reports have described the use of HPLC with a diode array detector (DAD) for the characterization and quantification of phenolic composition (Boligon and Athayde, 2014). We used the HPLC-DAD spectra system for phytochemical analysis. Seven phenolic compounds (ascorbic acid, gallic acid, 3,4-dihydroxy benzoic acid, protocatechuic acid, chlorogenic acid, p-coumaric acid and rutin hydrate) were determined in the DEM. These results agree with previous research showing that the genus Morus is rich in polyphenolic compounds such as cyanidin-3-glucoside, kaempferol-3-O-rutinoside, rutin, quercetin, catechin, quercetin-3-O-glucoside, quercetin-3-O-rutinoside, taxifolin, chlorogenic acid, p-coumaric acid, vanillic acid, gallic acid, ferulic acid, caffeic acid, and syringic acid (Hassimotto et al., 2007; Gundogdu et al., 2011; Kostic et al., 2013).
An effective and acceptable chemopreventive or anticancer agent has to meet various criteria, including having no harmful effects on normal cells (Galati and O’Brien, 2004). We therefore performed cytotoxicity experiments in PC-3 cells coupled with human normal foreskin fibroblast cells. DEM exhibited reasonable selective toxicity against PC-3 cells compared to normal fibroblast cells via MTT assay, a nonradioactive, quick, and affordable method widely used in cytotoxicity studies (Russo et al., 2004). Qadir et al. demonstrated that M. nigra leaf extract exhibited cytotoxic effect on a human cervical cancer (HeLa) cell line (Qadir et al., 2014). Shi et al. isolate numerous flavonoids with isoprenoid groups from Morus mongolica and demonstrate selective cytotoxic activity in two human oral cancer cell lines (HSC-2 and HSG) against normal human gingival fibroblasts (Shi et al., 2001). In another study, Fathy et al. reported that M. alba extract exhibits cytotoxic effect on the hepatocellular cell line (Fathy et al., 2013), while Kofujita et al. demonstrated that prenylated flavanone separated from M. alba root shows cytotoxic effect against rat hepatoma cells (Kofujita et al., 2004). Additionally, Dat et al. isolated 11 flavonoids from the leaves of the white mulberry and evaluated their cytotoxic effect on three human cancer cell lines (HeLa, MCF-7 and Hep3B). Morusin was identified as the most potent cytotoxic compound against HeLa cells (Dat et al., 2010).

Results br Discussion N sativa seeds


N. sativa seeds have been used as a food additive and medicinal herb for many years [3,4]. Black seeds, which have shown galactagogue effect, have been used in traditional medicine for the treatment of several health problems [5,7].
The results of the acute toxicity test demonstrated that LD50 values of compounds vary depending on the species and ways of administration. The aqueous and ethanolic extracts of N. sativa (0.5, 2, 8, 16, and 32 g/kg, orally) did not cause any mortality. The i.p. LD50 values of N. sativa aqueous and ethanolic extracts in mice were 4.23 and 4.9 g/kg, respectively. According to the toxicity classification, compounds with an LD50 value in the range of 1–5 g/kg are considered slightly toxic and those with an LD50 value of more than 5.0 g/kg may be considered practically nontoxic [29]. According to the LD50 values ( g/kg, oral route), the present study indicates that N. sativa is practically nontoxic in acute oral administration. The i.p. LD50 values of both extracts were in the range of 1–5 g/kg; thus, N. sativa should be considered slightly toxic in acute intraperitoneal route, and data showed that the toxicity of aqueous extract is more than that of ethanolic extract.
Determination of the milk yield in animals is difficult. Milk production measurement for rats from the weight of pups and their weight gains has been applied in some reports [2,30–32]. According to data, production of milk in the animals treated with N. sativa was significantly more than in the control group from Day 8. Also, the milk yield increased considerably about 23 hours after treatment with both extracts, and the pup growth level was improved. In some study, it was indicated that several plants influenced milk production in animals through the stimulation of lactogenic hormone (prolactin) [1,33]. Fennel (Foeniculum vulgare) and anise (Pimpinella anisum), which contain estrogenic constituents such as anethole, increase milk secretion, promote menstruation, and facilitate birth. Structurally, anethole is similar to dopamine and exerts a competitive antagonism at the dopamine receptor site. Thus, it may stimulate RG7388 release and increase milk production [34].
One of the various constituents of N. sativa seeds, t-anethole (1–4%) [35], accounts for the lactogenic activity of this plant. In addition, the growth and weight gain of pups in treated groups could be related to increase of milk production and milk components. In this study, it was shown that the milk production and milk yield increased considerably from about Day 8 after treatment with both the extracts of N. sativa. With regard to the fact that the pups can take a feed from Days 10–12 [36], the growth and weight gain of pups might be also due to the effect of this plant on their nutrition and feeding. Therefore, evaluation of milk component, and microscopic examinations of mammary glands and pituitary prolactin contents are needed to clarify the exact mechanism of the lactogenic activity of this plant.
The results of this study showed that the beneficial effect of N. sativa aqueous extract on milk production was observed in lower dose (0.5 g/kg), whereas that of the ethanolic extract was observed in high dose (1 g/kg). Regarding the LD50 value of these extracts, the toxicity of aqueous extract is more than that of ethanolic extract. The aqueous extract may induce chronic toxic effect and muscle relaxant effect at high dose [37,38]. Thus, the beneficial effect of aqueous extract was demonstrated at a lower dose.
It is concluded that aqueous and ethanolic extracts of N. sativa stimulates milk production. This research confirms the traditional use of N. sativa seeds as a lactogenic agent.


Noninsulin-dependent diabetes mellitus (NIDDM) is a common disease of the endocrine system caused by the decreased secretion of insulin by the pancreatic Langerhans β cell or by the lowering of insulin resistance due to excessive absorption of glucose [1]. A number of pharmacological approaches are used to control diabetes by different modes of action such as stimulation of insulin release, increase in the number of glucose transporters, inhibition of gluconeogenesis, and reducing absorption of glucose from the intestine [2]. Diabetes is a multifactorial disease leading to several complications and, therefore, it demands multiple therapeutic approaches. In the prediabetic state of insulin resistance, glycemic control can be achieved using oral agents that either interfere with the absorption of glucose (α-glycosidase and/or pancreatic α-amylase inhibitors) or facilitate glucose disposal in peripheral tissues (insulin-sensitizing agents). One of the most beneficial therapies for NIDDM is said to be the control of postprandial hyperglycemia after a meal [3]. In patients with diabetes, postprandial hyperglycemia is most pronounced following a meal due to the absorption of glucose from the gastrointestinal tract. Inhibiting glucose uptake in the intestines and/or promoting glucose disposal in the tissues may be beneficial for these patients to control the blood glucose level in the postprandial state.

Unfortunately histologic evaluation of glomeruli using routine hematoxylin

Unfortunately, histologic evaluation of glomeruli using routine hematoxylin and eosin staining is often insufficient for the correct diagnosis of either category. Additional staining techniques such as Periodic RG7388 Schiff, Masson\’s trichrome, Congo red and Jones methenamine silver can be used to highlight various features of glomerular disease (Table 2). Importantly, all histochemical techniques (with the exception of the Congo red method) should be performed on well-fixed tissues sectioned at 3 µm thickness. Thin sections enable identification of hypercellularity and remodeling of the GBM. The section used for the Congo red method should be 8–10 µm thick, in order to detect small amounts of amyloid. Even with the appropriate panel of stains, the histopathologic diagnosis can be difficult. In fact, 25% of the 501 renal biopsy specimens from proteinuric dogs submitted to the IVRPS required TEM for a final diagnosis (Schneider et al., 2013). Examples of renal biopsies that required IF and TEM for the final diagnosis are shown in Figs. 2 and 3.
Immunofluorescence is performed on unfixed tissue and allows identification of immune complex deposits in glomeruli. Samples for IF need to be placed in Michel\’s transport media and should be washed, embedded in optimal cutting temperature (OCT) and frozen within 5 days. If the transport media is unavailable, samples can be placed in saline but they need to be embedded in OCT within 1 day. Direct IF for the detection of immunoglobulins and complement components is performed on frozen sections. At the IVRPS, fluorescent antibodies directed against canine IgG, IgM, IgA and C3 are routinely used. Fluorescent antibodies against human C1q, kappa light chain and lambda light chain cross react with canine tissue and can provide robust labeling of immunoglobulins. Evaluation of IF staining requires sufficient training (Walker, 2009) because the pattern of staining is often more important than the intensity. For example granular staining indicates immune complexes, whereas splotchy staining is usually non-specific (Fig. 2, panel f).
TEM is performed on well-fixed tissue. Ideally, samples are submitted in glutaraldehyde; however, if glutaraldehyde is unavailable, small cores/cubes placed in formalin can be post-fixed in glutaraldehyde once they arrive in the renal biopsy laboratory. Samples should be small (1–2 mm3) in order to ensure adequate fixation by either fixative. Oftentimes one to three glomeruli are evaluated ultrastructurally (Fig. 2, panel e). This study is used to detect electron dense deposits, which can be located between the GBM and podocytes (subepithelial), within the GBM (intramembranous), between the GBM and endothelial cells (subendothelial), within the mesangial matrix (mesangial) or along the GBM that encircles the mesangium (paramesangial). In many cases there are deposits in more than one location. An interesting correlation between ultrastructure and histology is that deposits located in subendothelial zones often activate the complement pathway near the capillary lumen, thereby attracting inflammatory cells to the glomerular tuft to result in endocapillary hypercellularity. Similarly, mesangial deposits can induce mesangial cells to become activated and replicate, leading to mesangial hypercellularity. Therefore, when mesangial and subendothelial deposits are present, the histologic pattern tends to be ‘membranoproliferative’. In contrast, when deposits are subepithelial (as opposed to subendothelial), the histologic pattern usually lacks hypercellularity and is called ‘membranous’ (Nangaku and Couser, 2005; Nangaku et al., 2005). Similar relationships between deposit location and histologic pattern occur in human renal biopsies (Jennette et al., 2007). There are exceptions to the rule, however, wherein deposits can be identified in all of the above locations and have either a membranous or membranoproliferative histologic pattern. In the end, it is still unknown whether the histologic pattern or the ultrastructural pattern is more important with respect to the clinical prognosis.

In this work we first analyse

In this work, we first, analyse the human power of discriminating colours at the computational and algorithmic levels by invoking the theory of fuzzy sets. Then, we implement the formulated algorithm by using chemical systems consisting of either three or four or five photochromic compounds among those depicted in Fig. 1. Such systems, RG7388 which we have termed Biologically Inspired Photochromic Fuzzy Logic (BIPFUL) systems, have been determined to extend the human ability to discriminate frequencies of the electromagnetic spectrum from the visible into the UV region.
Finally, we identify the best BIPFUL systems for discriminating between the three main regions of the ultraviolet spectrum, i.e. UV-A, UV-B and UV-C, by transforming their RG7388 spectra in colour coordinates and determining the Colourability and the Eucledian distance between pairs of vectors in the CIE L*a*b* space.
This work shows how systems of properly chosen photochromic compounds have the computing power of discriminating UV frequencies. It demonstrates that Systems Chemistry [6] may be really useful for the development of Chemical Artificial Intelligence [3].
2. Experimental
2.1. Materials and facilities
The spectrophotometric measurements were carried out by using a Hewlett-Packard 8453 diode array spectrophotometer. The photochromic species were dissolved in acetonitrile (from Fluka, ≥99.8%) in concentrations ranging from 10?5 to 10?3 mol dm?3, without experiencing any solubility limit.
A 125 W Xe lamp, filtered by a Jobin-Yvon H10 UV monochromator and focused on the sample through a 0.6 cm diameter silica optical fibre, was used as the irradiation source. A mercury lamp (Mineralight Compact 4-Watt UV lamp) was used to irradiate at 254 nm. The irradiation intensity was determined by potassium ferrioxalate actinometry and by performing spectro-radiometric measurements. For the latter measurements, we used an irradiance-calibrated AvaSpec-2048-2 spectrometer (Avantes, NL) provided with a 200 μm diameter optical fibre (FC-UVIR200-2ME, Avantes) and an 8 mm active area cosine corrector (CC-UV- VIS/NIR, Avantes). The spectroradiometer operated in the 171-1100 nm range (300 lines per mm grating) and was equipped with an AvaBench-75 optical bench, a 25 μm slit which produced 1.2 nm FWHM (Full Width at Half Maximum) spectral resolution and a 2048 pixel CCD detector.
The profiles of UV-A, UV-B and UV-C radiations used to study the response of the BIPFUL systems are depicted in Fig. 2, below. The UV-A and UV-B are the output of the 125 W Xe lamp, whereas UV-C is the output of the Mineralight Compact 4-Watt UV lamp. Regarding the UV-C, we considered only radiation having wavelength longer than 250 nm.
Fig. 2. Spectral profiles of the UV-A, UV-B and UV-C radiation used to study the responses of the BIPFUL systems.Figure optionsDownload full-size imageDownload as PowerPoint slide
2.2. Computational methods
In Equation (1), xˉ,yˉ,zˉ are the colour-matching functions whereby the CIE (Commision Internationale de l’;Éclairage) standardized the sensitivity of human eye in 1964; D(λ) is the energy distribution of the CIE normalized illuminant D65 (which closely matches that of normal daylight); T(λ) is the transmittance spectrum, and k is a normalization factor defined in such a way that a sample with a uniform transmittance T(λ) = 1 for λ∈[360?800]λ∈[360?800] gives a luminance component Y = 1:equation(2)k=∫360800D(λ)yˉ(λ)dλ
From Equation (6), it derives that x + y + z = 1. The values of the chromaticity coordinates were used to estimate the Colourability formulated from the definition of Shannon\’s Information, according to Equation (7):equation(7)C=ICol?IUn=xCollog2(xCol)?xUnlog2(xUn)+yCollog2(yCol)?yUnlog2(yUn)+zCollog2(zCol)?zUnlog2(zUn)wherein xUn, yUn, zUn and xCol, yCol, zCol are the values of the chromaticity coordinates for the uncoloured (Un) and coloured forms (Col), respectively (see reference [8] and the text below, for more information). Since the chromaticity coordinates of the solutions before irradiation assumed the values of a white hue (for example, xUn = 0.3187, yUn = 0.3403, zUn = 0.3410), when the solutions under irradiation gave rise to grey hues, the resulting C was low.