Activation of endogenous TRPV1 fails to induce overstimulation-based cytotoxicity in breast and prostate cancer cells but not in pain-sensing neurons

Vanilloids including capsaicin and resiniferatoxin are potent transient receptor potential vanilloid type 1 (TRPV1) agonists. TRPV1 overstimulation selectively ablates capsaicin-sensitive sensory neurons in animal models in vivo. The cytotoxic mechanisms are based on strong Na⁺ and Ca2 + influx via TRPV1 channels, which leads to mitochondrial Ca2 + accumulation and necrotic cell swelling. Increased TRPV1 expression levels are also observed in breast and prostate cancer and derived cell lines. Here, we examined whether potent agonist- induced overstimulation mediated by TRPV1 might represent a means for the eradication of prostate carcinoma (PC-3, Du 145, LNCaP) and breast cancer (MCF7, MDA-MB-231, BT-474) cells in vitro. While rat sensory neurons were highly vanilloid- sensitive, normal rat prostate epithelial cells were resistant in vivo. We found TRPV1 to be expressed in all cancer cell lines at mRNA and protein levels, yet protein expression levels were significantly lower compared to sensory neurons. Treatment of all human carcinoma cell lines with capsaicin didn't lead to overstimulation cytotoxicity in vitro. We assume that the low vanilloid-sensitivity of prostate and breast cancer cells is associated with low expression levels of TRPV1, since ectopic TRPV1 expression rendered them susceptible to the cytotoxic effect of vanilloids evidenced by plateau- type Ca2 + signals, mitochondrial Ca2 + accumulation and Na⁺- and Ca2 +-dependent membrane disorganization. Moreover, long- term monitoring revealed that merely the ectopic expression of TRPV1 stopped cell proliferation and often induced apoptotic processes via strong activation of caspase-3 activity. Our results indicate that specific targeting of TRPV1 function remains a putative strategy for cancer treatment

The effect of psychiatric comorbidities and stress-coping strategies on perceived quality of life in migraine

Migraine is one of the most disabling primary headache conditions. We aimed to detect hidden symptoms of anxiety and depression and to survey stress-coping mechanisms and related quality of life in a large migraine population without any known psychiatric comorbidity.123 migraine patients (MG) and 66 healthy subjects (HC) completed the Beck Depression Inventory-II (BDI-II), the State and Trait Anxiety Inventory (S-STAI and T-STAI), the Stress and Coping Inventory (SCI) and the 36-Item Short Form Health Survey (SF-36).MG patients reached significantly higher scores on the BDI-II and the T-STAI yielding previously undetected anxiety and depression symptoms. Significant differences were present on the SCI: higher stress scores and lower coping levels suggested impaired stress-coping strategies in migraine. MG patients achieved significantly lower scores on most of SF-36 subscales indicating lower perceived quality of life. Significant correlations were found between BDI-II, T-STAI, SCI scores and subscales of the SF-36.Unrecognized symptoms of anxiety and depression, as well as less effective stress-coping strategies might be related to the lower perceived quality of life in migraine. The screening of these symptoms might lead to more focused and efficient therapeutic strategies. Addressing stress management techniques could improve quality of life on the long-term

Folyóirat-referátumok; Beszámolók

Folyóirat-referátumok: Atherosclerosis: 1. E.A. Brinton: Az etanolfogyasztás hatása a lipoproteinekre és az atherosclerosisra = Effects of Ethanol Intake on Lipoproteins and Atherosclerosis Kardiológia: 1. V. Parakh [et al.]: Meszes gyűrű a pitvar-kamrai barázdában = Calcification Ring in the Atrioventricular Groove Neurológia: 1. Murakami H. [et al.]: Megváltozott fájdalomérzékelés szkizofréniában = Altered Pain Perception in Schizophrenia Onkológia: 1. L. Junquera [et al.]: Fültőmirigy kétoldali bazálsejtes adenomája: nem gyakori esetismertetés és irodalmi áttekintés = Bilateral Parotid Basal Cell Adenoma: An Unusual Case Report and Review of the Literature Szemészet: 1. F. Bazari - M. Hind - Y.E. Ong: Horner-tünetcsoport - érdemes vele foglalkozni = Horner’s Syndrome – Not to be Sneezed At Szív- és érbetegségek: 1. M. Borjesson - Luc Vanhees [et al.]: Cardiovascularis szűrés a középkorú és idős egyéneknek a szabadidős sportolásuk előtt: az Európai Cardiovascularis Megelőzési és Rehabilitációs Társaság állásfoglalása = Cardiovascular Evaluation of Middle-Eged/Senior Individuals Engaged in Leisure-Time Sport Activities: Position Stand from the Sections of Exercise Physiology and Sports Cardiology of the European Association of Cardiovascular Prevention and Rehabilitation 2. M. Böhm - K. Swedberg - M. Komajda [et al.]: A nyugalmi szívfrekvencia rizikótényező krónikus szívelégtelenségben (SHIFT): a nyugalmi szívfrekvencia és a végpontok alakulása közötti összefüggés idült pangásos szívelégtelenségben = Heart Rate as a Risk Factor in Chronic Heart Failure (SHIFT): The Association Between Heart Rate and Outcomes in a Randomised Placebo-Controlled Trial Szülészet-nőgyógyászat: 1. M. Stukan: Óriási petefészek-fibroma = A Giant Ovarian Fibroma Beszámolók: 1. Orvostörténeti Gyűjtemény Debrecenbe

Kynurenines and PACAP in migraine: medicinal chemistry and pathogenetic aspects

BACKGROUND: Migraine is a highly disabling neurovascular primary headache disorder, with its exact pathomechanism being still unrevealed. The current leading hypotheses are based on the sensitization and activation of the trigeminovascular system. OBJECTIVE: To review the literature with focus on the effects of kynurenines (L-kynurenine and kynurenic acid) and pituitary adenylate cyclase-activating polypeptide on the regulation of the trigeminovascular system. METHOD: A literature search was conducted to identify preclinical and clinical publications (198 references) by using the keywords 'kynurenines', 'pituitary adenylate cyclase-activating polypeptide', and 'migraine' in the database of MEDLINE/PubMed up to 10 September 2016for topical review. Additional filters used included 'review', 'systematic review', 'original article', and 'English language'. RESULTS: L-kynurenine and kynurenic acid act on the glutamatergic system at the level of the second-order nociceptive neurons in the trigeminal nucleus caudalis. Pituitary adenylate cyclase-activating polypeptide is released from the peripheral nerve endings of the trigeminal pseudounipolar neurons and causes vasodilation and mast cell degranulation, leading to consequent peripheral sensitization of the dural nociceptors. Centrally released pituitary adenylate cyclase-activating polypeptide in the trigeminal nucleus caudalis results in the central sensitization of the second-order neurons. The sensitization process leads to the characteristic features of migraine. CONCLUSION: L-kynurenine, kynurenic acid, and pituitary adenylate cyclase-activating polypeptide may have fundamental roles in the initiation of migraine headache attacks

Comparative Protein Composition of the Brains of PACAP-Deficient Mice Using Mass Spectrometry-Based Proteomic Analysis

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a widespread neuropeptide acting as a neurotransmitter, neuromodulator, or neurotrophic factor. The diverse biological actions provide the background for the variety of deficits observed in mice lacking endogenous PACAP. PACAP-deficient mice display several abnormalities, such as sudden infant death syndrome (SIDS)-like phenotype, decreased cell protection, and increased risk of Parkinson's disease. However, the molecular and proteomic background is still unclear. Therefore, our aim was to investigate the differences in peptide and protein composition in the brains of PACAP-deficient and wild-type mice using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectrometric (MS)-based proteomic analysis. Brains from PACAP-deficient mice were removed, and different brain areas (cortex, hippocampus, diencephalon, mesencephalon, brainstem, and cerebellum) were separated. Brain pieces were weighed, homogenized, and further processed for electrophoretic analysis. Our results revealed several differences in diencephalon and mesencephalon. The protein bands of interest were cut from the gel, samples were digested with trypsin, and the tryptic peptides were measured by matrix-assisted laser desorption ionization time of flight (MALDI TOF) MS. Results were analyzed by MASCOT Search Engine. Among the altered proteins, several are involved in metabolic processes, energy homeostasis, and structural integrity. ATP-synthase and tubulin beta-2A were expressed more strongly in PACAP-knockout mice. In contrast, the expression of more peptides/proteins markedly decreased in knockout mice, like pyruvate kinase, fructose biphosphate aldolase-A, glutathione S-transferase, peptidyl propyl cis-trans isomerase-A, gamma enolase, and aspartate amino transferase. The altered expression of these enzymes might partially account for the decreased antioxidant and detoxifying capacity of PACAP-deficient mice accompanying the increased vulnerability of these animals. Our results provide novel insight into the altered biochemical processes in mice lacking endogenous PACAP

Pécs az egyháztörténet tükrében : Tanulmányok

A Pécsi Egyházmegye millenniuma tiszteletére, 2009 szeptemberében szervezett konferencia előadásai