“D-cell hypothesis of schizophrenia”: Background theory of Novel non-D2 receptor medicinal chemistry

The latest psychopharmacological study showed effectiveness of a novel non-D2-receptor-binding drug, SEP-363856, for the treatment of schizophrenia. Characteristic receptor profile of the compound is shown to be trace amine-associated receptor 1 (TAAR1) full agonist and 5-hydroxytryptamin 1A (5-HT 1A) receptor partial agonist. I found the TAAR1 ligand neuron, D-neuron, in the striatum and nucleus accumbens (Acc), an antipsychotic acting site, of human brain, though failed to find in the homologous area of monkey. To study human D-neuron functions, total of 154 post-mortem brains, and a modified immunohistochemical method using high qualified antibodies against monoamine-related substances, was applied. Number of D-neurons in the caudate nucleus, putamen, and Acc was reduced in post-mortem brains with schizophrenia. The reduction was significant (p<0.05) in Acc. “D-cell hypothesis of schizophrenia”, which I proposed based on this post-mortem brain study, that NSC dysfunction-induced D-neuron reduction as cellular and molecular basis of mesolimbic dopamine (DA) hyperactivity, showing progressive pathophysiology of schizophrenia, has been proved to be a predictive hypothesis for TAAR1 medicinal chemistry.

Peripheral blood CD4+CCR6+ compartment differentiates HIV-1 infected or seropositive elite controllers from long-term successfully treated individuals

HIV-1 infection induces a chronic inflammatory environment not restored by suppressive antiretroviral therapy (ART). As of today, the effect of viral suppression and immune reconstitution in people living with HIV-1 (PLWH) on long-term suppressive ART (PLWHART) is not well-described. Herein, we show how PLWH who naturally control the virus (PLWHEC) have a reduced proportion of CD4+CCR6+ cells compared to PLWHART and HIV-1 negative controls. Specifically, the CD4+CCR6+/CCR6- cells exhibited a uniqe proteomic profile with a modulated energy metabolism in PLWHEC compared to PLWHART independent of CCR6 status. Furthermore, the CD4+CCR6+ cells were enriched in proteins involved in apoptosis and p53 signalling in PLWHEC compared to PLWHART, indicative of increased sensitivity towards cell death mechanisms. Collectively, this data shows how PLWHEC have a unique chemokine receptor profile that may aid in facilitating natural control of HIV-1 infection.

Clinical features of labor and morphological aspects of the myometrium receptor profile in obese women

BACKGROUND: Obesity is currently considered as one of the most significant social chronic diseases. It has been proven that obese pregnant women are more likely than women with normal body weight to experience complications of pregnancy and labor. The most frequent complications of labor in obese women are weakness and discoordination, which are probably associated with a decrease in the sensitivity of the myometrium to oxytocin, due to suppression of oxytocin receptor expression. AIM: The aim of this study was to explore the clinical features of labor and morphological aspects of the myometrium receptor apparatus in obese women. MATERIALS AND METHODS: We performed a prospective assessment of labor activity in women with obesity, with a combination of obesity and gestational diabetes mellitus and in healthy women. We also conducted a morphological study of myometrium biopsies obtained during cesarean section. RESULTS: Obese patients are more likely to experience various complications of pregnancy and labor, which is the reason for the higher frequency of operative delivery. Patients with obesity showed lower expression of oxytocin receptors in the lower segment of the uterus, which, apparently, is the cause of abnormal contractility of the myometrium during labor and the lack of effect from drug correction of this condition. CONCLUSIONS: The presence of obesity in women before pregnancy contributes to frequent complications of pregnancy and labor, abnormal uterine contractility related to the decreased oxytocin receptor expression, and a high incidence of surgical delivery.

Pro- and anti-inflammatory macrophages express a sub-type specific purinergic receptor profile

Extracellular nucleotides act as danger signals that orchestrate inflammation by purinergic receptor activation. The expression pattern of different purinergic receptors may correlate with a pro- or anti-inflammatory phenotype. Macrophages function as pro-inflammatory M1 macrophages (M1) or anti-inflammatory M2 macrophages (M2). The present study found that murine bone marrow-derived macrophages express a unique purinergic receptor profile during in vitro polarization. As assessed by real-time polymerase chain reaction (PCR), Gαs-coupled P1 receptors A2A and A2B are upregulated in M1 and M2 compared to M0, but A2A 15 times higher in M1. The ionotropic P2 receptor P2X5 is selectively upregulated in M1- and M2-polarized macrophages. P2X7 is temporarily expressed in M1 macrophages. Metabotropic P2Y receptors showed a distinct expression profile in M1 and M2-polarized macrophages: Gαq coupled P2Y1 and P2Y6 are exclusively upregulated in M2, whereas Gαi P2Y13 and P2Y14 are overexpressed in M1. This consequently leads to functional differences between M1 and M2 in response to adenosine di-phosphate stimulation (ADP): In contrast to M1, M2 showed increased cytoplasmatic calcium after ADP stimulation. In the present study we show that bone marrow-derived macrophages express a unique repertoire of purinergic receptors. We show for the first time that the repertoire of purinergic receptors is highly flexible and quickly adapts upon pro- and anti-inflammatory macrophage differentiation with functional consequences to nucleotide stimulation.

Novel case of Parkinson’s disease and schizophrenia: challenges in the management

Coexistence of idiopathic Parkinson’s disease (iPD) and schizophrenia can pose great diagnostic and therapeutic challenges because of their pathophysiology. Our case highlights such challenges in management. We present a case of 73-year-old man who had parkinsonism for last several years and was also diagnosed with schizophrenia. Due to lack of collateral information about the onset of symptoms and clinical course, it was difficult to distinguish iPD from neuroleptic-induced parkinsonism. Even though, certain clinical findings may help to differentiate between the two conditions, single positron emission computerized tomography/DatScan was used to confirm the diagnosis of iPD. Treatment of coexisting iPD and schizophrenia can be challenging, and a delicate pharmacologic balance must be maintained to ensure adequate symptomatic control. Current evidence suggests that clozapine is a better choice for managing psychosis in these patients due to its unique receptor profile and better safety data.

Apocrine Breast Carcinoma - Pathohistological And Immunohistochemical Analysis, Prognosis and Complex Treatment

Apocrine breast cancer (ABC) is a rarely diagnosed pathomorphological subtype of invasive ductal carcinoma of the breast. We present a clinical case of apocrine breast cancer in a 36-year-old woman. A left-sided breast-preserving surgery (quadrantectomy am blok with underlying muscle fascia) and axillary lymph dissection at all three levels were performed. The complex treatment is continued with adjuvant chemotherapy, followed by radiotherapy of the left mammary gland. The pathomorphological and immunohistochemical characteristics of apocrine breast cancer, the prognosis and the necessary complex treatment are discussed. Immunohistochemical (IHC) analysis of apocrine carcinoma cells reported a characteristic steroid receptor profile with negative IHC expression for estrogen and progesterone receptors and positive for androgen receptors. ABC is prognostically similar to invasive ductal carcinoma / NOS. Apocrine breast cancer needs to be classified as a separate nosological unit, due to growing evidence of a different hormonal profile with different clinical behavior following androgen deprivation therapy.