Marrubium vulgare ethanolic extract induces proliferation block, apoptosis, and cytoprotective autophagy in cancer cells in vitro.

Marrubium vulgare is a European medicinal plant with numerous beneficial effects on human health. The aim of the study was to isolate the plant ethanolic extract (MVE) and to investigate its anti-melanoma and anti-glioma effects. MVE was prepared by the modified pharmacopoeial percolation method and characterized by UHPLC-LTQ OrbiTrap MS. MVE dose-dependently reduced viability of melanoma (B16) and glioma (U251) cells, but not peripheral blood mononuclear cells. It arrested cell cycle in S+G2/M phase, which was associated with the activation of MAP kinase p38 and up-regulation of antiproliferative genes p53, p21 and p27. MVE induced oxidative stress, while antioxidants abrogated its antitumor effect. Furthermore, MVE induced mitochondrial depolarization, activation of caspase-9 and -3, Parp cleavage, phosphatidylserine exposure and DNA fragmentation. The mitochondrial apoptotic pathway was associated with the up-regulation of proapoptotic genes Pten, Bak1, Apaf1, and Puma and down-regulation of antiapoptotic genes survivin and Xiap. MVE also stimulated the expression of autophagy-related genes Atg5, Atg7, Atg12, Beclin-1, Gabarab and Sqstm1, as well as LC3-I conversion to the autophagosome associated LC3-II, while autophagy inhibitors exacerbated its cytotoxicity. Finally, the most abundant phenolic components of MVE, ferulic, p-hydroxybenzoic, caffeic and chlorogenic acids, did not exert a profound effect on viability of tumor cells, suggesting that other components individually or in concert are the mediators of the extracts' cytotoxicity. By demonstrating the ability of MVE to inhibit proliferation, induce apoptosis and cytoprotective autophagy, our results suggest that MVE, alone or combined with autophagy inhibitors, could be a good candidate for anti-melanoma and anti-glioma therapy.

Signalling, inflammation and arthritis: Crossed signals: the role of interleukin-15 and -18 in autoimmunity.

Several cytokines are involved in the complex processes ultimately leading to autoimmune diseases. In a preceding review, we have already discussed the role of the IL-12 and -17 families of cytokines. This review is focused on IL-15 and -18. Both these molecules have pro-inflammatory activity and act on many cell types and because of their broad spectrum of activity they play an important role in autoimmunity and disease pathogenesis. Their biological activity is ultimately regulated by the signalling cascades set into motion within their target cells. In this second review, we will, once again, describe the signal transduction pathways activated by these two cytokines and focus on how this relates to the pathogenesis of autoimmune diseases. We will also describe some of the therapeutic approaches that are being investigated to curtail the pro-inflammatory activities of these two molecules.

Signalling, inflammation and arthritis: crossed signals: the role of interleukin (IL)-12, -17, -23 and -27 in autoimmunity.

Autoimmune diseases such as rheumatoid arthritis are the consequence of a persistent imbalance between pro- and anti-inflammatory immune mechanisms leading to chronic inflammation. The action of several cytokines is at the basis of this complex process. This review is focused on the signalling events triggered by two major groups of cytokines, namely the IL-12 and IL-17 families, which in the past few years have been shown to have a prominent role in the pathogenesis of such diseases. In particular, we will focus on the signalling cascades set in motion by such cytokines and how this may relate to the pathogenesis of human immune and inflammatory disorders as knowledge of such cascades may help in the development of novel therapeutic approaches for such diseases.

Schizophrenia and polymorphic CAG repeats array of calcium-activated potassium channel (KCNN3) gene in Serbian population.

KCNN3 might be a candidate gene for schizophrenia. The KCNN3 cDNA sequence contains two stretches of CAG trinucleotide repeats encoding two separate polyglutamine segments near the N-terminus of this channel protein. The second CAG repeat is highly polymorphic in the Caucasian population from both Europe and United States. The authors carried out a study to compare the allelic frequency distribution of the CAG repeat in KCNN3 gene in 55 Serbian schizophrenic patients and 46 controls. The data indicate a significant association between longer CAG repeats in second polymorphic KCNN3 region and schizophrenia in the Serbian population.

Efficacy of usual antidepressant dosing regimens of fluoxetine in panic disorder: randomised, placebo-controlled trial.

BACKGROUND: Although serotonin reuptake inhibitors are effective in panic disorder, questions concerning whether doses associated with antidepressant efficacy are also effective for panic disorder remain. AIMS: To assess the efficacy of the usual antidepressant dose of fluoxetine in treating full panic attacks. METHOD: Patients with panic disorder were randomised to placebo or to fluoxetine initiated at 10 mg daily for 1 week and then increased to 20 mg daily. The trial lasted 12 weeks, but after 6 weeks patients who had failed to achieve a satisfactory response were eligible for dose escalation to a maximum of 60 mg of fluoxetine daily. RESULTS: Fluoxetine was associated with a statistically significantly greater proportion of panic-free patients compared with placebo after 6 weeks and at end-point. CONCLUSIONS: Fluoxetine at a dose of 20 mg daily is safe and efficacious in reducing symptoms of panic disorder. Patients who fail to obtain a satisfactory response at 20 mg daily may benefit from further dose increases.

Reasoning under uncertainty in deluded schizophrenic patients: a longitudinal study.

Several current hypotheses consider the process of attribution of importance to stimuli and the integration of actually perceived reality with experience as a cognitive base for the genesis of delusions. We tested these models by a comparison of deluded schizophrenics, healthy controls, and anxious patients on reasoning under uncertainty. Reasoning under uncertainty was examined in currently deluded schizophrenics (n = 29), in 16 of them also in remission, in normal control groups (n = 35), and in anxious patients (n = 31) using a probabilistic inference task. Acutely psychotic schizophrenics were less ready than normal subjects, anxious patients, and schizophrenics, in remission to modify their judgement in probabilistic situation confronted with potentially disconfirmatory data. They were also less prone than anxious patients and schizophrenics in remission to correct their estimate confronted with confirmatory data. The data support the hypothesis of a weaker influence of incoming stimuli on reasoning under uncertainty as a cognitive base of the maintenance of delusions.

[The concept of motivation--an analysis of the concept and metatheoretical considerations]. / Koncept motivacije--analiza pojma i metateorijska razmatranja.

In this paper we analysed the concept of motivation pointing to the two broader conceptual frames that can comprise it and enable us to understand its theoretical meaning. Two paradigms of scientific reasoning--the dynamic conceptualization of the world and the theory of evolution--have been used in the explanation of human behavior since the very beginning of the scientific dealing with the problem. The difference between these two metatheoretical positions is rich in consequences. The object of research of the same problem--the reason (cause) of human behavior--in the two metatheoretical conceptualizations is situated at adjacent but completely different strata of reality. The object of research of motivation as a dynamic explanation of behavior is contained in the psychic layer of reality. On the other hand, the conception of behavior as an adaptation to the biological heritage understands investigations of the objects situated at the organic or biological stratum. We also pointed to a complementary relation of the two research approaches to human behavior.

[Thyrotropin-releasing hormone in psychiatry: marker, predictor and therapeutical tool]. / Oslobadjajuci hormon tireotropina u psihijatriji: dijagnosticke mogcnosti i primena u farmakoterapiji.

In this article the up-to-date knowledge about the neuroanatomy, physiology and pathophysiology of TRH is reviewed. The dysfunction of hypothalamo-pituitary-thyroid axis is evident in depression, alcoholism and schizophrenia. The majority of depressed patients are euthyroid with elevated plasma levels of reverse T3. On the other hand, a great number of rapid cycling bipolar patients display hypothyroidism. About 25-30 percent of patients with endogenous depression show blunted TSH response after TRH administration (TRH test). In the majority of cases the abnormal TRH test was normalized during remission. There is an associated appearance of blunted TRH test and the missing suppression of cortisol after administration of dexamethasone in patients with endogenous depression. Many factors which are not in connection with mental disorders may modify the result of TRH test. After administration of TRH to patients with endogenous depression, there is also a diminished prolactin response and a paradoxical secretion of the growth hormone. The TRH test may be valid in differentiation of endogenous depression from other depressive states, prediction of pharmacotherapeutic outcome of endogenous depression and differential diagnosis of bipolar disorder and schizophrenia. The alcoholics also show blunted TSH and prolactin response after stimulation with TRH, while paranoid schizophrenics may display hyperthyroxinaemia.

[Clinical-psychiatric and social-psychologic study of suicidal attempts]. / Klinicko-psihijatrijska i socialno-psiholoska studija o pokusaju samouubistva.

The study concerned 148 patients attempting suicide over the period from 1980 to 1990. The patients were hospitalized or examined for suicidal attempts in the Institute of psychiatry, University Clinical Centre, Belgrade. The analysis included statements of the patients, information obtained from witnesses and accompanying persons, objective medical and clinical findings noted on admission, psychiatric and psychologic findings. The phenomenologic statistical study greatly confirmed data reported in the up-to-date referential literature. The background data, clinical-psychiatric and psychologic personality analysies were observed and classified according to suicidal motives. The classification defined three basic types of suicidal reaction: escape, attack and cry for help. Within them some of the basic motives were found in each of the suicidal personalities. In our series only 53.5% of patients endangered their lives severely or seriously; in them the suicidal attempts would result in either fatal outcome or major disability during the absence of appropriate care in a of health service. In the authors' opinion this article evaluates the degree of actual risk to which suicidal individuals are exposed, refusing the old, strictly medical model which took into account only the objectively estimated vital risk without any detailed elaboration of personality analysis or analysis of social motives.

The side-effects of clozapine: a four year follow-up study.

Clozapine, as the model agent for the atypical antipsychotic drugs, is currently recommended as effective regarding negative symptoms of schizophrenia and treatment-resistant schizophrenic patients. This study focuses on the clozapine-induced side-effects in 100 hospitalized schizophrenic patients (negative and therapy-resistant forms), followed-up for a four year period. Clinically relevant side-effects occurred in 73% of all patients. Tachycardia (67%), the increase of liver enzymes (36%), hypotension (29%) and sedation (27%) were most frequent. Tachycardia, hypotension and sedation disappeared during the initial phase of treatment (i.e. 4-6 weeks), as tolerance developed with continuation of therapy. The increase of liver enzymes appeared to be dose related, since the reduction of daily clozapine dose led to the normalization of transaminases values. The other side-effects (constipation, nausea and vertigo) were rare and transient. Leucopenia was not registered in any patient during the follow-up period. Therefore, clozapine is efficient and, with some precautions concerning hepatotoxicity, is safe for in- and outpatient long-term treatment in appropriately selected patients.

[Biologic stress: possible role in the pathogenesis of depression]. / Biologija stresa: moguca uloga u patogenezi depresije.

This paper presents a review of biologic mechanisms of stress and analyzes their role in the pathogenesis of depressive disorder. Recent investigations point to the fact that apart from hereditary predisposition in the pathogenesis of depression different biologic mechanisms, included into the regulation of organism response to stress, have an important role. These findings are in harmony with the well known fact from the clinical practice, that exposure to stressor may lead to depression in persons who do not normally react depressively. The newest findings point out the significance of biologic mechanisms of stress which exert influence on a person at the early neonatal period, even before that, during the embryonal development. However, on the other hand in humans it is very probable that mechanisms, included into the regulation of response of the organism to stress, are important for the homeostasis of emotions and willing--instinctive dynamisms, and indirectly for the cognitive functions, as well as for maintaining harmony among these dimensions of psychic existence and demands of the external--physical, biologic and social--environment.

Neuroleptic actions on the thyroid axis: different effects of clozapine and haloperidol.

Twenty-six in-patients treated for schizophrenia, were divided in two groups. The first group received haloperidol, 20-40 mg p.d., and the second, clozapine, 150-250 mg p.d. TRH-TSH test was performed by injecting 0.2 mg TRH. Four drug-free schizophrenic patients gave normal TSH response to TRH, as well as the group of patients treated with haloperidol. Contrary to that, the clozapine-treated group showed a blunted TSH response. The results obtained are discussed in terms of the different pharmacological profiles of haloperidol and clozapine, especially regarding their dopaminergic actions, alpha-adrenergic and serotonergic control upon thyroid axis.

The development of dependence to an octapeptide somatostatin analog: contribution to the study of somatostatin analgesia.

This paper reports the phenomenon of dependence to a somatostatin octapeptide analog used for the treatment of acromegaly and severe headache. The mechanism of this dependence is still unknown, but could be based on the interaction of the somatostatin analog with opioid receptors. Analgesia may be at least partially supported by the opioid modulation of pain transmission, but also by general "appetitive" behavioral activation due to the effect of somatostatin on its receptors.

[Obsessional syndrome after organic cerebral involvement]. / Syndrome obsessionnel au décours d'une atteinte cérébrale organique.

The obsessive syndrome after an organic brain damage. The evolution of an obsessive syndrome which appeared after a vascular insult in the anterior parts of dominant hemisphere has been followed-up. The conclusion was that the disturbed cingular-dominant frontal connections might play an important role in the genesis of obsession.

Effects of mesencephalic central gray and raphe nuclei lesions on hypothalamically induced escape.

Central gray (CG) lesions, in particular those located in its anterior part, provoked in about half of the lesioned rats a decrease in switch-off responses (SOR) induced by medial hypothalamic stimulation. Such a decrease in performance, followed by a partial or even total recovery, occurred only when the stimulation site was located in the postero-medial part of the medial hypothalamus. Occurrence and duration of the decrease in SOR did not depend on a possible severance of noradrenergic fibers that ascend from the locus coeruleus and course along the CG, since bilateral destruction of the locus coeruleus did not alter SOR. On the other hand, a lasting facilitation of SOR was observed in those rats in which the CG lesion extended more caudalle fully explained by an interruption of serotonergic fibers ascending from the raphé nuclei since lesions limited to the dorsal nucleus as well as combined lesions of the dorsal and medial raphé nuclei induced only a transient facilitation, whereas a lasting one was provoked both by raphé lesions that encroached upon the ventro-medial tegmentum and by CG lesions that only partially destroyed the dorsal raphé nucleus.

[Topography of stimulation sites with aversive effects in the rat's medial hypothalamus (author's transl)]. / Topographie des points de stimulation à effets "aversifs" dans l'hypothalamus médian du Rat

The intensity of the aversive effects induced by an electrical stimulation of various sites in the rat's medial hypothalamus was evaluated through analysing the relation between stimulation intensity and the induced switch-off responses. Series of "hot points" were found in both the ventro-medial and the dorso-medial nuclei. Stimulation sites with less marked aversive effects were found in a periventricular region.