Myostatin, a member of the transforming growth factor-β (TGF-β) superfamily, has been shown to be a negative regulator of myogenesis. Here we show that myostatin functions by controlling the proliferation of muscle precursor cells. When C2C12 myoblasts were incubated with myostatin, proliferation of myoblasts decreased with increasing levels of myostatin. Fluorescence-activated cell sorting analysis revealed that myostatin prevented the progression of myoblasts from the G1- to S-phase of the cell cycle. Western analysis indicated that myostatin specifically up-regulated p21Waf1, Cip1, a cyclin-dependent kinase inhibitor, and decreased the levels and activity of Cdk2 protein in myoblasts. Furthermore, we also observed that in myoblasts treated with myostatin protein, Rb was predominately present in the hypophosphorylated form. These results suggests that, in response to myostatin signaling, there is an increase in p21 expression and a decrease in Cdk2 protein and activity thus resulting in an accumulation of hypophosphorylated Rb protein. This, in turn, leads to the arrest of myoblasts in G1-phase of cell cycle. Thus, we propose that the generalized muscular hyperplasia phenotype observed in animals that lack functional myostatin could be as a result of deregulated myoblast proliferation.

Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation.

Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this second of 5 sections of the guidelines of care for psoriasis, we give an overview of psoriatic arthritis including its cardinal clinical features, pathogenesis, prognosis, classification, assessment tools used to evaluate psoriatic arthritis, and the approach to treatment. Although patients with mild to moderate psoriatic arthritis may be treated with nonsteroidal anti-inflammatory drugs and/or intra-articular steroid injections, the use of disease-modifying antirheumatic drugs, particularly methotrexate, along with the biologic agents, are considered the standard of care in patients with more significant psoriatic arthritis. We will discuss the use of disease-modifying antirheumatic drugs and the biologic therapies in the treatment of patients with moderate to severe psoriatic arthritis.

https://www.jaad.org/article/S0190-9622(09)00012-7/pdf

Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: Overview and guidelines of care for treatment with an emphasis on the biologics

One of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders is achieving sufficient blood-brain barrier (BBB) penetration. Research in the past few decades has revealed that the BBB is not only a substantial barrier for drug delivery to the CNS but also a complex, dynamic interface that adapts to the needs of the CNS, responds to physiological changes, and is affected by and can even promote disease. This complexity confounds simple strategies for drug delivery to the CNS, but provides a wealth of opportunities and approaches for drug development. Here, I review some of the most important areas that have recently redefined the BBB and discuss how they can be applied to the development of CNS therapeutics.

From blood–brain barrier to blood–brain interface: new opportunities for CNS drug delivery

This work was supported by the Foundation for Science and Technology (FCT), Portugal (projects PTDC/QUI-QUI/113687/2009 and PEst-C/QUI/UI0081/2013). A.G. (SFRH/BD/43531/2008) and M.J.M. (SFRH/BD/61262/2009) thank FCT for grants.

/pdf/chromone-a-valid-scaffold-in-medicinal-chemistry-4qd4v5m5z2.pdf

Chromone: A Valid Scaffold in Medicinal Chemistry

Since cancer is the most common cause of death in the world population, the possibility that readily available natural substances from plants, vegetables, herbs, and spices may be beneficial in the prevention of cancer warrants closer examination. Saffron in filaments is the dried, dark red stigmata of Crocus sativus L. flowers and it is used as a spice, food colorant, and a drug in medicine. A growing body of research has demonstrated that saffron extract itself and its main constituents, the carotenoids, possess chemopreventive properties against cancer. This review discusses recent literature data and our results on the cancer chemopreventive activities of saffron and its main ingredients.

Cancer chemopreventive and tumoricidal properties of saffron (Crocus sativus L.).

Earlier we reported that a 308-nm xenon chloride (XeCl) UVB laser is highly effective for treating psoriasis. As ultraviolet B light seems to cause T cell apoptosis, in the present study we studied the ability of the XeCl laser to induce T-cell apoptosis in vitro, and then compared the apoptosis-inducing capacities of narrow-band UVB (NB-UVB) light and the XeCl laser. The role of laser impulse frequency and intensity in the therapeutical and apoptosis-inducing efficacy of XeCl laser was also investigated. Both XeCl laser and NB-UVB induced T cell apoptosis, but quantitative induction was greater with XeCl laser. Changes in the frequency and intensity of impulses of XeCl laser did not influence its therapeutic and T cell apoptosis-inducing efficacy. These results suggest that the more effective induction of T cell apoptosis can be responsible for the greater clinical efficacy of XeCl laser compared to NB-UVB. Additionally, the optical properties of the XeCl laser (a monochromatic, coherent, pulse-mode laser; easier precise dosimetry, there are no ‘contaminating’ wavelengths) can make this laser light an ideal tool for studies of the mode of action of UVB light.

Xenon chloride ultraviolet B laser is more effective in treating psoriasis and in inducing T cell apoptosis than narrow-band ultraviolet B

In the present work a systematic study was initiated with crocine, ginsenoside and cannabinoid derivatives on multidrug resistant mouse lymphoma cells, viral tumor antigen expression and some human leukocyte functions. Among saffron derivatives, crocin and picrocrocin, triglucosyl and diglucosyl crocetin were ineffective on the reversal of multidrug resistance of lymphoma cells. Ginsenoside increased drug accumulation and tumor antigen expression at 2.0-20.0 micrograms/mL. Some cannabinoid derivatives such as cannabinol, cannabispirol and cannabidiol increased drug accumulation, while cannabidiolic acid, delta-9-THC and tetrahydro-cannabidiolic acid reduced drug accumulation of the human mdr1-gene transfected mouse lymphoma cells. The reversal of multidrug resistance is the result of the inhibition of the efflux pump function in the tumor cells. Crocetin esters were less potent than crocin itself in the inhibition of EBV early antigen expression. However crocin and diglucosylcrocetin inhibited early tumor antigen expression of adenovirus infected cells, but triglucosylcrocetin was less effective at 0.01-1.0 microgram/mL. The crocin had no antiviral effect [on HSV-2 infected vero cells] up to 25 micrograms/mL concentration. Ginsenosides had a moderate inhibitory effect except ginsenoside Rb1 (was the less effective) on the drug efflux pump. Among the cannabinoid derivatives the cannabinol and cannabispirol increased drug accumulation, while cannabidiolic acid and delta-8-THC, delta-9-THC and tetrahydro-cannabinol reduced drug accumulation in multidrug resistant mouse lymphoma cells. It is interesting that ginsenosides had a chemical structure-dependent immunomodulating effect by enhancing the activity of NK-cells and ADCC activities.

Membrane associated antitumor effects of crocine-, ginsenoside- and cannabinoid derivates.

The aim of the present study was to investigate the anticancer properties of five alkaloids isolated from Amaryllidaceae, including the inhibitory effect on P-glycoprotein (P-gp) and the apoptosis-inducing capacity. The tested alkaloids were evaluated for their multidrug resistance (MDR)-reversing activity on human MDR1-gene- transfected L5178 mouse lymphoma cells, using the rhodamine-123 (Rh-123) assay. Trisphaeridine and pretazettine increased the intracellular Rh-123 concentration 30- and 50-fold, respectively, as compared to the non-treated cells, and 2-O-acetyllycorine and trisphaeridine were demonstrated by means of the checkerboard method to enhance the antiproliferative activity of doxorubicin on L5178 MDR mouse lymphoma cells. The MTT assay revealed that pretazettine, trisphaeridine and 2-O-acetyllycorine displayed excellent antiproliferative effects on both the human and the mouse cell lines. The apoptosis-inducing activities of selected agents (2-O-acetyllycorine and trisphaeridine) were measured via acridine orange and ethidium bromide dual staining and flow cytometry of the subG1 population. One of the most serious problems in the treatment of cancerous diseases is the development of multidrug resistance (MDR) during the therapy. This can occur for a variety of reasons, e.g. the activation or the up-regulation of the ATP-binding cassette (ABC) proteins, leading to a decreased sensitivity of the cancer cells to cytostatic agents (1). To date, 49 members of the ABC family have been discovered in the human genome, with similar sequences and structural elements (2); on the basis of their structural features, they are classified into 7 subfamilies (from ABCA to ABCG). Three of the human ABC proteins (ABCB1, ABCC1 and ABCG2) are generally accepted as transporters responsible for the development of MDR during the chemotherapy of cancers. ABCB1 (also known as P-glycoprotein or P-gp) was first recognized and is currently the most widely studied member of this transporter family. Antitumor agents can exert their cytostatic effects in many

Imre Ocsovszki

Papers

Xenon chloride ultraviolet B laser is more effective in treating psoriasis and in inducing T cell apoptosis than narrow-band ultraviolet B

Membrane associated antitumor effects of crocine-, ginsenoside- and cannabinoid derivates.

Antitumor activity of alkaloids derived from Amaryllidaceae species.

Synthesis and investigation of the anticancer effects of estrone-16-oxime ethers in vitro

Chemical composition, antioxidant and anticancer activity of licorice from Fruska Gora locality