Current Medicinal Chemistry (v.23, #7)

Meet Our Editorial Board Member by Krzysztof W. Pankiewicz (635-635).

Antineoplastic Effects of PPAR? Agonists, with a Special Focus on Thyroid Cancer by Silvia Martina Ferrari, Gabriele Materazzi, Enke Baldini, Salvatore Ulisse, Paolo Miccoli, Alessandro Antonelli, Poupak Fallahi (636-649).
Peroxisome Proliferator-Activated Receptor-? (PPAR?) is a ligand-activated nuclear hormone receptor that functions as transcription factor and plays an important role in lipid metabolism and insulin sensitization. Recent studies have shown that PPAR? is overexpressed in many tumor types, including cancers of breast, lung, pancreas, colon, glioblastoma, prostate and thyroid differentiated/anaplastic cancers. These data suggest a role of PPAR? in tumor development and/or progression. PPAR? is emerging as a growth-limiting and differentiation-promoting factor, and it exerts a tumor suppressor role.
Moreover, naturally-occurring and synthetic PPAR? agonists promote growth inhibition and apoptosis. Thiazolidinediones (TZDs) are synthetic agonists of PPAR? that were developed to treat type II diabetes. These compounds also display anticancer effects which appear mainly to be independent of their PPAR? agonist activity. Various preclinical and clinical studies strongly suggest a role for TZDs both alone and in combination with existing chemotherapeutic agents, for the treatment of cancer.
Differentiation therapy involves the use of agents with the ability to induce differentiation in cells that have lost this ability, i.e. cancer cells, targeting pathways capable of re-activating blocked terminal differentiation programs. PPAR? agonists have been shown to induce differentiation in solid tumors such as thyroid differentiated/ anaplastic cancers and sarcomas.
However, emerging data suggest that chronic use of TZDs is associated with increased risk of adverse cardiovascular events. The exploration of newer PPAR? agonists can help in unveiling the underlying mechanisms of these drugs, providing new molecules that are able to treat cancer, without increasing the cardiovascular risk of neoplastic patients.


Eosinophils in Cancer: Favourable or Unfavourable? by Samy Sakkal, Sarah Miller, Vasso Apostolopoulos, Kulmira Nurgali (650-666).
Eosinophils are granulocytic leukocytes residing in blood and tissues in the lung, breast, gastrointestinal and reproductive systems. Eosinophilia is uncommon in healthy individuals, however, it is associated with allergies, helminth infections and some inflammatory states. Eosinophilia has also been observed in cancer, including colorectal, breast, ovarian, cervical, oral squamous, Hodgkin's lymphoma and prostate cancer. Whether an increase in eosinophils leading to a favourable or unfavourable prognosis still remains controversial and depends on many factors including the type of cancer. Eosinophil infiltration is considered unfavourable in Hodgkin's lymphoma, conversely it has also been linked to a favourable prognosis in colorectal, breast and prostate cancers. Eosinophils secrete a variety of cytokines and factors including eosinophil cationic protein, eosinophil-derived neurotoxin, peroxidase and major basic protein which have either anti-tumor effects or stimulate tumor progression. Herein, we discuss the role of eosinophils in tumor immunity and propose mechanisms accounting for their functional differences in tumorigenesis.

Role of Tyrosine Isomers in Acute and Chronic Diseases Leading to Oxidative Stress - A Review by Gerg| A. Molnár, Szilárd Kun, Eszter Sélley, Melinda Kertész, Lívia Szélig, Csaba Csontos, Katalin Böddi, Lajos Bogár, Attila Miseta, István Wittmann (667-685).
Oxidative stress plays a major role in the pathogenesis of a variety of acute and chronic diseases. Measurement of the oxidative stress-related end products may be performed, e.g. that of structural isomers of the physiological para-tyrosine, namely meta- and ortho-tyrosine, that are oxidized derivatives of phenylalanine. Recent data suggest that in sepsis, serum level of meta-tyrosine increases, which peaks on the 2nd and 3rd days (p<0.05 vs. controls), and the kinetics follows the intensity of the systemic inflammation correlating with serum procalcitonin levels. In a similar study subset, urinary meta-tyrosine excretion correlated with both need of daily insulin dose and the insulin-glucose product in non-diabetic septic cases (p<0.01 for both). Using linear regression model, meta-tyrosine excretion, urinary meta-tyrosine/para-tyrosine, urinary ortho-tyrosine/para-tyrosine and urinary (meta- + orthotyrosine)/ para-tyrosine proved to be markers of carbohydrate homeostasis.
In a chronic rodent model, we tried to compensate the abnormal tyrosine isomers using para-tyrosine, the physiological amino acid. Rats were fed a standard high cholesterol-diet, and were given para-tyrosine or vehicle orally. High-cholesterol feeding lead to a significant increase in aortic wall meta-tyrosine content and a decreased vasorelaxation of the aorta to insulin and the glucagon-like peptide-1 analogue, liraglutide, that both could be prevented by administration of para-tyrosine.
Concluding, these data suggest that meta- and ortho-tyrosine are potential markers of oxidative stress in acute diseases related to oxidative stress, and may also interfere with insulin action in septic humans. Competition of meta- and ortho-tyrosine by supplementation of para-tyrosine may exert a protective role in oxidative stress-related diseases.


Astrocytes are the most abundant neuron-supporting glial cells in the central nervous system. The neuroprotective role of astrocytes has been demonstrated in various neurological disorders such as amyotrophic lateral sclerosis, spinal cord injury, stroke and Parkinson's disease (PD). Astrocyte dysfunction or loss-of-astrocytes increases the susceptibility of neurons to cell death, while astrocyte transplantation in animal studies has therapeutic advantage. We reported recently that stimulation of serotonin 1A (5-HT1A) receptors on astrocytes promoted astrocyte proliferation and upregulated antioxidative molecules to act as a neuroprotectant in parkinsonian mice. PD is a progressive neurodegenerative disease with motor symptoms such as tremor, bradykinesia, rigidity and postural instability, that are based on selective loss of nigrostriatal dopaminergic neurons, and with non-motor symptoms such as orthostatic hypotension and constipation based on peripheral neurodegeneration. Although dopaminergic therapy for managing the motor disability associated with PD is being assessed at present, the main challenge remains the development of neuroprotective or disease- modifying treatments. Therefore, it is desirable to find treatments that can reduce the progression of dopaminergic cell death. In this article, we summarize first the neuroprotective properties of astrocytes targeting certain molecules related to PD. Next, we review neuroprotective effects induced by stimulation of 5-HT1A receptors on astrocytes. The review discusses new promising therapeutic strategies based on neuroprotection against oxidative stress and prevention of dopaminergic neurodegeneration.

Effective Delivery of Male Contraceptives Behind the Blood-Testis Barrier (BTB) - Lesson from Adjudin by Haiqi Chen, Dolores D. Mruk, Weiliang Xia, Michele Bonanomi, Bruno Silvestrini, Chuen-Yan Cheng (701-713).
The blood-testis barrier (BTB) is one of the tightest blood-tissue barriers in the mammalian body. It divides the seminiferous epithelium of the seminiferous tubule, the functional unit of the testis, where spermatogenesis takes place, into the basal and the adluminal (apical) compartments. Functionally, the BTB provides a unique microenvironment for meiosis I/II and post-meiotic spermatid development which take place exclusively in the apical compartment, away from the host immune system, and it contributes to the immune privilege status of testis. However, the BTB also poses major obstacles in developing male contraceptives (e.g., adjudin) that exert their effects on germ cells in the apical compartment, such as by disrupting spermatid adhesion to the Sertoli cell, causing germ cell exfoliation from the testis. Besides the tight junction (TJ) between adjacent Sertoli cells at the BTB that restricts the entry of contraceptives from the microvessels in the interstitium to the adluminal compartment, drug transporters, such as P-glycoprotein and multidrug resistance-associated protein 1 (MRP1), are also present that actively pump drugs out of the testis, limiting drug bioavailability. Recent advances in drug formulations, such as drug particle micronization (<50 ?m) and co-grinding of drug particles with Β-cyclodextrin have improved bioavailability of contraceptives via considerable increase in solubility. Herein, we discuss development in drug formulations using adjudin as an example. We also put emphasis on the possible use of nanotechnology to deliver adjudin to the apical compartment with multidrug magnetic mesoporous silica nanoparticles. These advances in technology will significantly enhance our ability to develop effective non-hormonal male contraceptives for men.

Protein post-translational modification (PTM) occurs following their biosynthesis and is a key cellular event that defines their ultimate functional properties. It is an important control mechanism for display of biological functions of proteins often in a profound manner. It may switch on or off a protein's function. Several studies have been conducted to understand their mechanisms, physiological pathways and functional properties. PTMs have been shown to alter structural, conformational and physicochemical properties of proteins. So far a variety of protein modifications have been detected in physiological systems. These involve covalent modifications of amino acids via their side chains, backbone peptide bonds and terminal moieties. Following PTM, proteins may become (a) pathologically toxic, (b) biologically active or inactive, (c) more or less susceptible to proteolytic processing, (d) increasingly/decreasingly bound to its partner protein/s, or (e) modified with altered protease activities. These changes may affect pathways linked to cell signaling/transduction, trafficking, storing, expression, binding and/or affinity. Any of these events may be linked to metabolic, growth and/or chronic dysfunctions with serious health consequences that may include cancer, cardiovascular disease, stroke, viral/bacterial/parasite infections, inflammation, thrombosis, diabetes; central nervous system related conditions. Some of the modifications are more prevalent physiologically and widely studied. However, in recent years additional PTMs have been described that are less common. These include glypiation, neddylayion, siderophorylation, sumoylation, AMPylation, Cholesteroylation and others which are also important. This manuscript provides a comprehensive review of these rare and unconventional types of protein modifications and their functional implications to health, metabolism and disease conditions.