Derivatization of Rosmarinic Acid Enhances its in vitro Antitumor, Antimicrobial and Antiprotozoal Properties.

On its own, rosmarinic acid possesses multiple biological activities such as anti-inflammatory, antimicrobial, cardioprotective and antitumor properties, and these are the consequence of its ROS scavenging and inhibitory effect on inflammation. In this study, two quaternary phosphonium salts of rosmarinic acid were prepared for the purpose of increasing its penetration into biological systems with the aim of improving its antimicrobial, antifungal, antiprotozoal and antitumor activity. The synthetized molecules, the triphenylphosphonium and tricyclohexylphosphonium salts of rosmarinic acid, exhibited significantly stronger inhibitory effects on the growth of HCT116 cells with IC50 values of 7.28 or 8.13 µM in comparison to the initial substance, rosmarinic acid (>300 µM). For the synthesized derivatives, we detected a greater than three-fold increase of activity against Acanthamoeba quina, and a greater than eight-fold increase of activity against A. lugdunensis in comparison to rosmarinic acid. Furthermore, we recorded significantly higher antimicrobial activity of the synthetized derivatives when compared to rosmarinic acid itself. Both synthetized quaternary phosphonium salts of rosmarinic acid appear to be promising antitumor and antimicrobial agents, as well as impressive molecules for further research.

Some quantitative EEG features in default mode resting state network under general anaesthesia.

OBJECTIVES: The default mode resting state network (DMRSN) constitutes a circuit which is active in conditions when the subject is at rest. We tested the hypothesis that its function will be altered during unconsciousness. METHODS: Changes in the mean squared coherences in five conventional frequency bands (delta to gamma) in DMRSN during general anaesthesia (GA) were investigated in 39 patients. They were compared with the normal EEG of 86 alert subjects, severely abnormal EEG of 112 patients with dementia and/or encephalopathy, and the mathematical model of brain death. RESULTS: Anaesthetised patients showed significant decrease in the gamma coherence in the posterior area of the DMRSN compared to both the control group and the patients with dementia and/or encephalopathy. Among the anaesthetized patients 21 had a clear burst suppression pattern with prolonged epochs of suppression in EEG. In suppressed EEG segment the differences between the connections of the anterior to posterior parts and connections between the posterior parts of the DMRSN were almost lost. However, they still showed highly significant differences in most items when compared with coherences in the mathematical model of brain death. CONCLUSION: The functional connectivity in the DMRSN could be a reliable and robust method for assessing the depth of anaesthesia and maybe also disorders of consciousness in general. The mean squared coherences in the gamma frequency band indicated the highest sensitivity for the depth of unconsciousness. The measure is not dependent on the diffused slowing in dementia or encephalopathy patients as long as they remain in a full consciousness.

Prefrontal left--dominant hemisphere--gamma and delta oscillators in general anaesthesia with volatile anaesthetics during open thoracic surgery.

OBJECTIVES: The main objective was to indicate sufficient general anaesthesia (GA) inhibition for negative experience rejection in GA. PATIENTS AND METHODS: We investigated the group of patients (n = 17, mean age 63.59 years, 9 male--65.78 years, 8 female - 61.13 years) during GA in open thorax surgery and analyzed EEG signal by power spectrum (pEEG) delta (DR), and gamma rhythms (GR). EEG was performed: OPO - the day before surgery and in surgery phases OP1-OP5 during GA. Particular GA phases: OP1 = after pre- medication, OP2 = surgery onset, OP3 = surgery with one-side lung ventilation, OP4 = end of surgery, both sides ventilation, OP5 = end of GA. pEEG registering in the left frontal region Fp1-A1 montage in 17 right handed persons. RESULTS: Mean DR power in OP2 phase is significantly higher than in phase OP5 and mean DR power in OP3 is higher than in OP5. One-lung ventilation did not change minimal alveolar concentration and gases should not accelerate decrease in mean DR power. Higher mean value of GR power in OPO than in OP3 was statistically significant. Mean GR power in OP3 is statistically significantly lower than in OP4 correlating with the same gases concentration in OP3 and OP4. CONCLUSION: Our results showed DR power decreased since OP2 till the end of GA it means inhibition represented by power DR fluently decreasing is sufficient for GA depth. GR power decay near the working memory could reduce conscious cognition and unpleasant explicit experience in GA.

Overexpression of the YAP1, PDE2, and STB3 genes enhances the tolerance of yeast to oxidative stress induced by 7-chlorotetrazolo[5,1-c]benzo[1,2,4]triazine.

7-chlorotetrazolo[5,1-c]benzo[1,2,4]triazine (CTBT) is an antifungal agent that induces oxidative stress and enhances the activity of other antifungals with different modes of action. A genome-wide screening of Saccharomyces cerevisiae genomic library in the high-copy-number plasmid revealed three genes, YAP1, PDE2, and STB3, which increased the CTBT tolerance of the parental strain. The YAP1 gene is known to activate many genes in response to oxidants. The PDE2 and STB3 genes encode the high-affinity cAMP phosphodiesterase and the transcription factor recognizing the ribosomal RNA processing element in promoter sequences, respectively. The protective effects of their overexpression against CTBT toxicity was observed in the absence of certain proteins involved in stress responses, cell wall integrity signaling, and chromatin remodeling. The enhanced CTBT tolerance of the YAP1, PDE2, and STB3 transformants was a consequence of their high antioxidant enzyme activities at the beginning of CTBT treatment in comparison with that of the parental strain, for that they inactivated the CTBT-induced reactive oxygen species. These results point to the complex interplay among the oxidant sensing, cAMP-protein kinase A signaling, and transcription reprogramming of yeast cells, leading to their better adaptation to the stress imposed by CTBT.

Acute consciousness disorders in intensive care medicine - value of its grading for prognostic conclusion.

OBJECTIVES: To understand consciousness we have to understand the mechanism of its function, which is to effectively organize sensory inputs from our environment. Consciousness is the basic, essential outcome of the process of organizing these sensory inputs, resulting in cognitive, mental, emotional, executive, instinctual or other marginally aware states. This reciprocal process of the CNS implies that organization is an act, which precedes consciousness, i.e. preconscious function. Most scientific explanations portray consciousness as an "emergent property" of classical computer-like activities in the brains neural networks. Doctors at ICU work daily with patients with altered human consciousness. Therefore, they must recognize and manage it skilfully and use adequate approaches for definite solutions. MATERIAL AND METHODS: We observed a series of patients with traumatic and non traumatic brain injuries admitted to the ICU. The quality of life of these patients during the course of intensive care was very elementary and the final outcome GCS (oGCS) for future life was defined as a comatose state or apallic state, very rarely was it restored to premorbid condition as far as lucidity, attention, cognition, and executive functions. RESULTS: We found that a significant oGCS increase in relation to condition at admission or intake GCS (iGCS) in the group with 184 patients total (p<0.00001), in cardio-pulmonary resuscitation (CPR), traumatic brain injury (TBI) subgroups (p<0.00001) and in spontaneous haemorrhage (SH) (p<0.05) represents the only basic prerequisite for further improvement. It is not easy to find good therapeutic approaches after traumatic and non traumatic brain injury. A statistically significant oGCS increase in relation to iGCS due to quite intense medical care and keeping disclosed the state of unconsciousness with further probable evolution through the following possible ways: death in fluent comatose state, delirium and awakening, delirium ending in death, direct awakening from comatose state. Therefore significantly increased oGCS is the only basic prerequisite for pragmatically optimal "quality of life" in the course of later life. CONCLUSION: We raise general questions for both scientists and clinicians that will assist in their efforts to understand the basic endogenous conscious biological processes, their pathological changes and the links between them.

Serum neuron specific enolase and malondialdehyde in patients after out-of-hospital cardiac arrest.

BACKGROUND: Sudden cardiac arrest (CA) is a leading cause of death in Europe. The victims of CA need immediate cardiopulmonary resuscitation (CPR). Patients resuscitated due to CA have high mortality rate. Prognostic evaluation based on clinical observation is uncertain and would benefit from the use of biochemical markers of hypoxic brain damage. Multiple factors of brain origin can be measured in blood. OBJECTIVE: The purpose of this study was to validate the use of the serum neuron-specific enolase (NSE) and malondialdehyde (MDA) concentrations for predicting in-hospital death, after resuscitation from out-of-hospital CA. Neuronal damage and impairment of the blood-brain-barrier integrity can be detected by the release of NSE into cerebrospinal fluid and eventually into the blood. MDA represents a product of lipid peroxide decomposition reactions. METHODS: In a prospective study of 35 consecutive survivors of out-of-hospital CA, serum samples were obtained within 24, 72 and 168 h after the CA. NSE and MDA concentrations were measured, relationship between concentration in group of in-hospital death and survived patients were examined. Results There was a significant difference in NSE concentration between survivors and dead group on 1st day of measurement, marginally significant difference on 3rd day and no statistically significant difference in NSE on 7th day of measurement. There was marginally significant difference in MDA levels in both groups in all days of measurements. CONCLUSION: Estimation serum concentrations of NSE but not MDA seems to be a predictor of fate of patients after CA. The exact nature of oxidative stress can only be resolved by further studies.

Loss-of-function pdr3 mutations convert the Pdr3p transcription activator to a protein suppressing multidrug resistance in Saccharomyces cerevisiae.

The PDR1 and PDR3 genes encode the main transcription activators involved in the control of multidrug resistance in Saccharomyces cerevisiae. To identify the amino acids essential for Pdr3p function, the loss-of-function pdr3 mutants were isolated and characterized. Two plasmid-borne pdr3 alleles, pdr3-E902Ter and pdr3-D853Y, which failed to complement drug hypersensitivity in the Deltapdr1Deltapdr3 mutant strain, were isolated. The E902Ter mutation resulted in a truncated protein lacking the C-terminal activation domain. The D853Y mutation allowed the expression of entire Pdr3p, but its transactivation function was lost. When overexpressed from the P(GAL1) promoter, the two mutant alleles increased the sensitivity of wild-type cells to cycloheximide and fluconazole and suppressed drug resistance in gain-of-function pdr1 and pdr3 mutant strains. The drug-sensitizing effect of overexpressed loss-of-function pdr3 mutant alleles correlated with their ability to suppress PDR5 transcription and rhodamine 6G accumulation in transformants of the wild-type and Deltapdr1 mutant strains. These results demonstrate that amino acid residue Asp853 is essential for Pdr3p function, and indicate that specific loss-of-function pdr3 mutations can convert the Pdr3p transcription activator to a multicopy suppressor of multidrug resistance.