Natural Radiosensitizers in Radiotherapy: Cancer Treatment by Combining Ionizing Radiation with Resveratrol.

Conventional cancer treatment is mainly based on the surgical removal of the tumor followed by radiotherapy and/or chemotherapy. When surgical removal is not possible, radiotherapy and, less often, chemotherapy is the only way to treat patients. However, despite significant progress in understanding the molecular mechanisms of carcinogenesis and developments in modern radiotherapy techniques, radiotherapy (alone or in combination) does not always guarantee treatment success. One of the main causes is the radioresistance of cancer cells. Increasing the radiosensitivity of cancer cells improves the processes leading to their elimination during radiotherapy and prolonging the survival of cancer patients. In order to enhance the effect of radiotherapy in the treatment of radioresistant neoplasms, radiosensitizers are used. In clinical practice, synthetic radiosensitizers are commonly applied, but scientists have recently focused on using natural products (phytocompounds) as adjuvants in radiotherapy. In this review article, we only discuss naturally occurring radiosensitizers currently in clinical trials (paclitaxel, curcumin, genistein, and papaverine) and those whose radiation sensitizing effects, such as resveratrol, have been repeatedly confirmed by many independent studies.

Time-space trade-offs in population protocols for the majority problem.

Population protocols are a model for distributed computing that is focused on simplicity and robustness. A system of n identical agents (finite state machines) performs a global task like electing a unique leader or determining the majority opinion when each agent has one of two opinions. Agents communicate in pairwise interactions with randomly assigned communication partners. Quality is measured in two ways: the number of interactions to complete the task and the number of states per agent. We present protocols for the majority problem that allow for a trade-off between these two measures. Compared to the only other trade-off result (Alistarh et al. in Proceedings of the 2015 ACM symposium on principles of distributed computing, Donostia-San Sebastián, 2015), we improve the number of interactions by almost a linear factor. Furthermore, our protocols can be made uniform (working correctly without any information on the population size n), yielding the first uniform majority protocols that stabilize in a subquadratic number of interactions.

Calcium-Involved Action of Phytochemicals: Carotenoids and Monoterpenes in the Brain.

BACKGROUND: Neurodegenerative and mood disorders represent growing medical and social problems, many of which are provoked by oxidative stress, disruption in the metabolism of various neurotransmitters, and disturbances in calcium homeostasis. Biologically active plant compounds have been shown to exert a positive impact on the function of calcium in the central nervous system. METHODS: The present paper reviews studies of naturally occurring terpenes and derivatives and the calcium-based aspects of their mechanisms of action, as these are known to act upon a number of targets linked to neurological prophylaxis and therapy. RESULTS: Most of the studied phytochemicals possess anticancer, antioxidative, anti-inflammatory, and neuroprotective properties, and these have been used to reduce the risk of or treat neurological diseases. CONCLUSION: The neuroprotective actions of some phytochemicals may employ mechanisms based on regulation of calcium homeostasis and should be considered as therapeutic agents.

Neuroprotective Polyphenols: A Modulatory Action on Neurotransmitter Pathways.

BACKGROUND: Balance in neurotransmission is essential for the proper functioning of the nervous system and even a small, but prolonged disturbance, can induce the negative feedback mechanisms leading to various neuropathologies. Neurodegenerative and mood disorders such as Alzheimer's, Parkinson's or affective disorders are increasing medical and social problems. Among the wide spectrum of potentially destructive events, oxidative stress and disrupted metabolism of some neurotransmitters such as acetylcholine, GABA, glutamate, serotonin or dopamine appear to play a decisive role. Biologically active plant polyphenols have been shown to exert a positive impact on the function of the central nervous system by modulation of metabolism and the action of some neurotransmitters. METHODS: Based on published research, the pharmacological activities of some naturally occurring polyphenols have been reviewed, with a focus on their potential therapeutic importance in the regulation of neurotransmitter systems. RESULTS: Phytochemicals can be classified into several groups and most of them possess anticancer, antioxidative, anti-inflammatory and neuroprotective properties. They can also modulate the metabolism or action of some neurotransmitters and/or their receptors. Based on these properties, phytochemicals have been used in traditional medicine for ages, although it was focused mainly on treating symptoms. However, growing evidence indicates that polyphenols may also prevent or slow neurological diseases. CONCLUSION: Phytochemicals seem to be less toxic than synthetic drugs and they can be a safer alternative for currently used preparations, which exert adverse side effects. The neuroprotective actions of some plant polyphenols in the regulation of neurotransmitters metabolism, functioning of neurotransmitters receptors and antioxidative defense have potential therapeutic applications in various neurodegenerative disorders.

[Biomarkers of intrauterine growth restriction].

Intrauterine growth restriction (IUGR) is a serious clinical problem affecting about 10% of all pregnancies, and even up to 15% of all monochorionic twin pregnancies. This disorder is accompanied by strongly increased perinatal mortality. IUGR has multiple causes including maternal, fetal, placental, and environmental factors. Importantly, IUGR is associated with a number of negative effects exerted just after the birth, as well as during the later years of life. Despite multiple clinical trials conducted for many years, there is no reliable algorithm to diagnose the disease at an early stage, and lack of efficient therapy increases the risk of abnormal fetus development. In this short review, we present recent progress on potential IUGR biomarkers that could be determined during pregnancy and in the umbilical blood after delivery to provide more accurate diagnosis, prophylaxis and efficient treatment.

Calcium Dyshomeostasis Alters CCL5 Signaling in Differentiated PC12 Cells.

BACKGROUND: Plasma membrane Ca2+-ATPase (PMCA) is the most sensitive cellular calcium detector. It exists in four main isoforms (PMCA1-4), among which PMCA2 and PMCA3 are considered as fast-acting neuron-specific forms. In the brain, PMCA function declines progressively during aging; thereby impaired calcium homeostasis may contribute to some neurodegenerative diseases. These destructive processes can be propagated by proinflammatory chemokines, including chemokine CCL5, which causes phospholipase C-mediated liberation of Ca2+ from endoplasmic reticulum by IP3-gated channels. METHODS: To mimic the changes in aged neurons we used stable transfected differentiated PC12 cells with downregulated PMCA2 or PMCA3 and analyzed the effect of CCL5 on calcium transients with Fluo-4 reagent. Chemokine receptors were evaluated using Western blot, and IP3 receptors expression level was assessed using qRT-PCR and Western blot. RESULTS: In PMCA-reduced cell lines, CCL5 released more Ca2+ by IP3-sensitive receptors, and the time required for Ca2+ clearance was significantly longer. Also, in these lines we detected altered expression level of CCR5 and IP3 receptors. CONCLUSION: Although modification of PMCAs composition could provide some protection against calcium overload, reduction of PMCA2 appeared to be more detrimental to the cells than deficiency of PMCA3. Under pathological conditions, including inflammatory CCL5 action and long-lasting Ca2+ dyshomeostasis, insufficient cell protection may result in progressive degeneration and death of neurons.

The Puzzling Role of Neuron-Specific PMCA Isoforms in the Aging Process.

The aging process is a physiological phenomenon associated with progressive changes in metabolism, genes expression, and cellular resistance to stress. In neurons, one of the hallmarks of senescence is a disturbance of calcium homeostasis that may have far-reaching detrimental consequences on neuronal physiology and function. Among several proteins involved in calcium handling, plasma membrane Ca2+-ATPase (PMCA) is the most sensitive calcium detector controlling calcium homeostasis. PMCA exists in four main isoforms and PMCA2 and PMCA3 are highly expressed in the brain. The overall effects of impaired calcium extrusion due to age-dependent decline of PMCA function seem to accumulate with age, increasing the susceptibility to neurotoxic insults. To analyze the PMCA role in neuronal cells, we have developed stable transfected differentiated PC12 lines with down-regulated PMCA2 or PMCA3 isoforms to mimic age-related changes. The resting Ca2+ increased in both PMCA-deficient lines affecting the expression of several Ca2+-associated proteins, i.e., sarco/endoplasmic Ca2+-ATPase (SERCA), calmodulin, calcineurin, GAP43, CCR5, IP3Rs, and certain types of voltage-gated Ca2+ channels (VGCCs). Functional studies also demonstrated profound changes in intracellular pH regulation and mitochondrial metabolism. Moreover, modification of PMCAs membrane composition triggered some adaptive processes to counterbalance calcium overload, but the reduction of PMCA2 appeared to be more detrimental to the cells than PMCA3.

Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids.

BACKGROUND: Neurosteroids form the unique group because of their dual mechanism of action. Classically, they bind to specific intracellular and/or nuclear receptors, and next modify genes transcription. Another mode of action is linked with the rapid effects induced at the plasma membrane level within seconds or milliseconds. The key molecules in neurotransmission are calcium ions, thereby we focus on the recent advances in understanding of complex signaling crosstalk between action of neurosteroids and calcium-engaged events. METHODS: Short-time effects of neurosteroids action have been reviewed for GABAA receptor complex, glycine receptor, NMDA receptor, AMPA receptor, G protein-coupled receptors and sigma-1 receptor, as well as for several membrane ion channels and plasma membrane enzymes, based on available published research. RESULTS: The physiological relevance of neurosteroids results from the fact that they can be synthesized and accumulated in the central nervous system, independently from peripheral sources. Fast action of neurosteroids is a prerequisite for genomic effects and these early events can significantly modify intracellular downstream signaling pathways. Since they may exert either positive or negative effects on calcium homeostasis, their role in monitoring of spatio-temporal Ca2+ dynamics, and subsequently, Ca2+-dependent physiological processes or initiation of pathological events, is evident. CONCLUSION: Neurosteroids and calcium appear to be the integrated elements of signaling systems in neuronal cells under physiological and pathological conditions. A better understanding of cellular and molecular mechanisms of nongenomic, calcium-engaged neurosteroids action could open new ways for therapeutic interventions aimed to restore neuronal function in many neurological and psychiatric diseases.

[Chemokine CC receptors in the nervous system]. / Receptory chemokin z motywem CC w ukladzie nerwowym.

Chemoattractant cytokines (chemokines) are traditionally known as the important mediators of inflammatory processes, however, recently, is also given to their other functions in the body. Acting through specific receptors belonging to the G proteins they regulate immune processes in the body. About 20 chemokine receptors have been identified so far, and 10 of them bind chemokines CC, i.e. having in amino-terminal domain 2 adjacent molecules of cysteins. An increasing number of data indicates that chemokines and their receptors play an important role in the nervous system by acting as trophic factors, increasing the neurons survival, neural migration and synaptic transmission. Special role chemokine receptors play primarily in the diseases of the nervous system, because due to damage of the blood-brain barrier and the blood cerebrospinal fluid barrier, infiltration of leukocytes results in development of inflammation. Chemokine CC receptors has been shown to participate in Alzheimer's disease, multiple sclerosis, dementia associated with HIV infection, stroke or some type of cancers.