Wide Range Of Pathophysiological Conditions Research Articles

Arthrospira platensis prevents oxidative stress and suppresses IL-1β expression in the ileum of rats fed a hypercaloric diet

Obesity is characterized by an energy imbalance caused by caloric intake and expenditure, being a risk factor associated with a wide range of pathophysiological conditions including gastrointestinal diseases. In recent years, it has been shown that overexpression of oxidative stress and pro-inflammatory cytokines is a mechanistic link between obesity and cellular functions in animals and humans. Some natural products are reported to be effective in counteracting the adverse effects of oxidative stress. Thus, Arthorpira platensis (AP) stands out, an alga with anti-inflammatory and antioxidant activities. Thus, the objective is to evaluate the preventive effects of AP supplementation on oxidative stress and interleukin-1β (IL-1β) levels in the ileum of rats fed a hypercaloric diet. The rats were divided into a group fed a standard diet (SD), a hypercaloric diet (HCD) and/or fed a hypercaloric diet and supplemented simultaneously with AP 25 mg/Kg (HCD + AP25), after 8 weeks of treatment the ileum was collected for The analyses. It was observed that in the DHC group there was underproduction of antioxidant enzymes as well as overexpression of oxidative stress in the ileum of rats, interestingly this damage was prevented by the alga. Furthermore, the DHC group showed high levels of IL-1β (940.6 ± 34.5) such an increase was prevented in the HCD + AP25 group (597.2 ± 33.3). It is evident, therefore, that AP prevents the increase in oxidative stress and the inflammatory profile in the ileum of obese rats, making it a promising therapeutic alternative in the treatment of inflammatory bowel diseases aggravated by obesity.

The Effects of Antioxidant Nutraceuticals on Cellular Sulfur Metabolism and Signaling.

Significance: Nutraceuticals are ingested for health benefits, in addition to their general nutritional value. These dietary supplements have become increasingly popular since the late 20th century and they are a rapidly expanding global industry approaching a half-trillion U.S. dollars annually. Many nutraceuticals are promulgated as potent antioxidants. Recent Advances: Experimental support for the efficacy of nutraceuticals has lagged behind anecdotal exuberance. However, accumulating epidemiological evidence and recent, well-controlled clinical trials are beginning to support earlier animal and in vitro studies. Although still somewhat limited, encouraging results have been suggested in essentially all organ systems and against a wide range of pathophysiological conditions. Critical Issues: Health benefits of "antioxidant" nutraceuticals are largely attributed to their ability to scavenge oxidants. This has been criticized based on several factors, including limited bioavailability, short tissue retention time, and the preponderance of endogenous antioxidants. Recent attention has turned to nutraceutical activation of downstream antioxidant systems, especially the Keap1/Nrf2 (Kelch like ECH associated protein 1/nuclear factor erythroid 2-related factor 2) axis. The question now becomes, how do nutraceuticals activate this axis? Future Directions: Reactive sulfur species (RSS), including hydrogen sulfide (H2S) and its metabolites, are potent activators of the Keap1/Nrf2 axis and avid scavengers of reactive oxygen species. Evidence is beginning to accumulate that a variety of nutraceuticals increase cellular RSS by directly providing RSS in the diet, or through a number of catalytic mechanisms that increase endogenous RSS production. We propose that nutraceutical-specific targeting of RSS metabolism will lead to the design and development of even more efficacious antioxidant therapeutic strategies. Antioxid. Redox Signal. 38, 68-94.

Wearable microneedle array-based sensor for transdermal monitoring of pH levels in interstitial fluid

Microneedle-based wearable sensors offer an alternative approach to traditional invasive blood-based health monitoring and disease diagnostics techniques. Instead of blood, microneedle-based sensors target the skin interstitial fluid (ISF), in which the biomarker type and concentration profile resemble the one found in the blood. However, unlike blood, interstitial fluid does not have the same pH-buffering capacity causing deviation of pH levels from the physiological range. Information about the skin ISF pH levels can be used as a biomarker for a wide range of pathophysiological conditions and as a marker for the calibration of a wearable sensor. The ISF pH can significantly affect the detection accuracy of other biomarkers as it influences enzyme activity, aptamer affinity, and antibody-antigen interaction. Herein, we report the fabrication of a high-density polymeric microneedle array-based (PMNA) sensing patch and its optimization for the potentiometric transdermal monitoring of pH levels in ISF. The wearable sensor utilizes a polyaniline-coated PMNA having a density of ∼10,000 microneedles per cm2, containing individual microneedles with a height of ∼250 μm, and a tip diameter of ∼2 μm. To prevent interference from other body fluids like sweat, an insulating layer is deposited at the base of the PMNA. The wearable pH sensor operates from pH 4.0 to 8.6 with a sensitivity of 62.9 mV per pH unit and an accuracy of ±0.036 pH units. Furthermore, testing on a mouse demonstrates the ability of the PMNA to provide a real-time reading of the transdermal pH values. This microneedle-based system will significantly contribute to advancing transdermal wearable sensors technology, simplifying the fabrication process, and improving the cost-effectiveness of such devices.

Snake Venoms in Drug Discovery: Valuable Therapeutic Tools for Life Saving.

Animal venoms are used as defense mechanisms or to immobilize and digest prey. In fact, venoms are complex mixtures of enzymatic and non-enzymatic components with specific pathophysiological functions. Peptide toxins isolated from animal venoms target mainly ion channels, membrane receptors and components of the hemostatic system with high selectivity and affinity. The present review shows an up-to-date survey on the pharmacology of snake-venom bioactive components and evaluates their therapeutic perspectives against a wide range of pathophysiological conditions. Snake venoms have also been used as medical tools for thousands of years especially in tradition Chinese medicine. Consequently, snake venoms can be considered as mini-drug libraries in which each drug is pharmacologically active. However, less than 0.01% of these toxins have been identified and characterized. For instance, Captopril® (Enalapril), Integrilin® (Eptifibatide) and Aggrastat® (Tirofiban) are drugs based on snake venoms, which have been approved by the FDA. In addition to these approved drugs, many other snake venom components are now involved in preclinical or clinical trials for a variety of therapeutic applications. These examples show that snake venoms can be a valuable source of new principle components in drug discovery.

The Current Status of O-Heterocycles: A Synthetic and Medicinal Overview.

O-Heterocycles have been explored in the field of medicinal chemistry for a long time, but their significance has not been duly recognised and they are often shunned in favour of N-heterocycles. The design of bioactive molecules for nearly every pathophysiological condition is primarily focused on novel N-heterocycles. The main reasons for such bias include the ease of synthesis and possible mimicking of physiological molecules by N-heterocycles. But considering only this criterion rarely provides breakthrough molecules for a given disease condition, and instead the risks of toxicity or side effects are increased with such molecules. On the other hand, owing to improved synthetic feasibility, O-heterocycles have established themselves as equally potent lead molecules for a wide range of pathophysiological conditions. In the last decade there have been hundreds of reports validating the fact that equally potent molecules can be designed and developed by using O-heterocycles, and these are also expected to have comparably low toxicity. Even so, researchers tend to remain biased toward the use of N-heterocycles over O-heterocycles. Thus, this review provides a critical analysis of the synthesis and medicinal attributes of O-heterocycles, such as pyrones, oxazolones, furanones, oxetanes, oxazolidinones, and dioxolonones, and others, reported in the last five years, underlining the need for and the advantages guiding researchers toward them.

Inflammatory Mediators in Ovarian Follicles: The Possible Role of Platelet-Activating Factor and its Metabolic Enzyme

Abstract: Platelet-activating factor (PAF) is a potent proinflammatory negotiator that shows a distinct spectrum of biological and pharmacological effects and participates in a wide range of pathophysiological conditions. In the reproductive system, PAF has been shown to have an important role in initiating ovulation, progesterone production and chemokine production. The purpose of this article was to review the roles of PAF, a well-known family of messenger phospholipids, in the reproductive process, especially in ovulation. This review highlights the interesting parallels between PAF's mechanism in ovulation and inflammatory process.

Platelet activating factor: A potential biomarker in acute coronary syndrome?

Platelet activating factor (PAF) is a potent pro-inflammatory negotiator that shows distinct spectrum of biological and pharmacological effects. Importantly, it participates in a wide range of pathophysiological conditions. In cardiovascular system, PAF has been shown to have an important role in platelet and neutrophil aggregation, vascular permeability, microvascular leakage, thrombus formation, leukocyte adhesion to the endothelial cells, and initiation and progression of atherosclerosis. The purpose of this article was to review the PAF, a family of lipids that is associated with the pathology of coronary artery diseases due to their association with leading etiological mechanisms such as inflammation, endothelial dysfunction, oxidative and nitrosative stress, and platelet reactivity. This review further provides information about PAF and its potential role as a key contributor to the pathogenesis of cardiovascular disorders.

Autophagy in Pulmonary Diseases.

The pathogenesis of pulmonary diseases is often complex and characterized by multiple cellular events, including inflammation, cell death, and cell proliferation. The mechanisms by which these events are regulated in pulmonary diseases remain poorly understood. Autophagy is an essential process for cellular homeostasis and stress adaptation in eukaryotic cells. This highly conserved cellular process involves the sequestration of cytoplasmic components in double-membrane autophagosomes, which are delivered to lysosomes for degradation. The critical roles of autophagy have been demonstrated in a wide range of pathophysiological conditions. Emerging studies have identified that autophagy plays important roles in the pathogenesis of various lung diseases. In addition, autophagy has been shown to selectively degrade subcellular targets, including proteins, organelles, and pathogens. Here, we highlight the recent advances in the molecular regulation and function of autophagy in lung diseases.

Fully automated multidimensional reversed-phase liquid chromatography with tandem anion/cation exchange columns for simultaneous global endogenous tyrosine nitration detection, integral membrane protein characterization, and quantitative proteomics mapping in cerebral infarcts.

Protein tyrosine nitration (PTN) is a signature hallmark of radical-induced nitrative stress in a wide range of pathophysiological conditions, with naturally occurring abundances at substoichiometric levels. In this present study, a fully automated four-dimensional platform, consisting of high-/low-pH reversed-phase dimensions with two additional complementary, strong anion (SAX) and cation exchange (SCX), chromatographic separation stages inserted in tandem, was implemented for the simultaneous mapping of endogenous nitrated tyrosine-containing peptides within the global proteomic context of a Macaca fascicularis cerebral ischemic stroke model. This integrated RP-SA(C)X-RP platform was initially benchmarked through proteomic analyses of Saccharomyces cerevisiae, revealing extended proteome and protein coverage. A total of 27 144 unique peptides from 3684 nonredundant proteins [1% global false discovery rate (FDR)] were identified from M. fascicularis cerebral cortex tissue. The inclusion of the S(A/C)X columns contributed to the increased detection of acidic, hydrophilic, and hydrophobic peptide populations; these separation features enabled the concomitant identification of 127 endogenous nitrated peptides and 137 transmembrane domain-containing peptides corresponding to integral membrane proteins, without the need for specific targeted enrichment strategies. The enhanced diversity of the peptide inventory obtained from the RP-SA(C)X-RP platform also improved analytical confidence in isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analyses.

Determinants of myocardial conduction velocity: implications for arrhythmogenesis

Slowed myocardial conduction velocity (θ) is associated with an increased risk of re-entrant excitation, predisposing to cardiac arrhythmia. θ is determined by the ion channel and physical properties of cardiac myocytes and by their interconnections. Thus, θ is closely related to the maximum rate of action potential (AP) depolarization [(dV/dt)max], as determined by the fast Na+ current (INa); the axial resistance (ra) to local circuit current flow between cells; their membrane capacitances (cm); and to the geometrical relationship between successive myocytes within cardiac tissue. These determinants are altered by a wide range of pathophysiological conditions. Firstly, INa is reduced by the impaired Na+ channel function that arises clinically during heart failure, ischemia, tachycardia, and following treatment with class I antiarrhythmic drugs. Such reductions also arise as a consequence of mutations in SCN5A such as those occurring in Lenègre disease, Brugada syndrome (BrS), sick sinus syndrome, and atrial fibrillation (AF). Secondly, ra, may be increased due to gap junction decoupling following ischemia, ventricular hypertrophy, and heart failure, or as a result of mutations in CJA5 found in idiopathic AF and atrial standstill. Finally, either ra or cm could potentially be altered by fibrotic change through the resultant decoupling of myocyte–myocyte connections and coupling of myocytes with fibroblasts. Such changes are observed in myocardial infarction and cardiomyopathy or following mutations in MHC403 and SCN5A resulting in hypertrophic cardiomyopathy (HCM) or Lenègre disease, respectively. This review defines and quantifies the determinants of θ and summarizes experimental evidence that links changes in these determinants with reduced myocardial θ and arrhythmogenesis. It thereby identifies the diverse pathophysiological conditions in which abnormal θ may contribute to arrhythmia.

NMR structure and dynamics of a designed water-soluble transmembrane domain of nicotinic acetylcholine receptor

The nicotinic acetylcholine receptor (nAChR) is an important therapeutic target for a wide range of pathophysiological conditions, for which rational drug designs often require receptor structures at atomic resolution. Recent proof-of-concept studies demonstrated a water-solubilization approach to structure determination of membrane proteins by NMR (Slovic et al., PNAS, 101: 1828–1833, 2004; Ma et al., PNAS, 105: 16537–42, 2008). We report here the computational design and experimental characterization of WSA, a water-soluble protein with ~83% sequence identity to the transmembrane (TM) domain of the nAChR α1 subunit. Although the design was based on a low-resolution structural template, the resulting high-resolution NMR structure agrees remarkably well with the recent crystal structure of the TM domains of the bacterial Gloeobacter violaceus pentameric ligand-gated ion channel (GLIC), demonstrating the robustness and general applicability of the approach. NMR T2 dispersion measurements showed that the TM2 domain of the designed protein was dynamic, undergoing conformational exchange on the NMR timescale. Photoaffinity labeling with isoflurane and propofol photolabels identified a common binding site in the immediate proximity of the anesthetic binding site found in the crystal structure of the anesthetic-GLIC complex. Our results illustrate the usefulness of high-resolution NMR analyses of water-solubilized channel proteins for the discovery of potential drug binding sites.

Spider-Venom Peptides as Therapeutics

Spiders are the most successful venomous animals and the most abundant terrestrial predators. Their remarkable success is due in large part to their ingenious exploitation of silk and the evolution of pharmacologically complex venoms that ensure rapid subjugation of prey. Most spider venoms are dominated by disulfide-rich peptides that typically have high affinity and specificity for particular subtypes of ion channels and receptors. Spider venoms are conservatively predicted to contain more than 10 million bioactive peptides, making them a valuable resource for drug discovery. Here we review the structure and pharmacology of spider-venom peptides that are being used as leads for the development of therapeutics against a wide range of pathophysiological conditions including cardiovascular disorders, chronic pain, inflammation, and erectile dysfunction.

Reciprocal regulation of metabolic and signaling pathways

BackgroundBy studying genome-wide expression patterns in healthy and diseased tissues across a wide range of pathophysiological conditions, DNA microarrays have revealed unique insights into complex diseases. However, the high-dimensionality of microarray data makes interpretation of heterogeneous gene expression studies inherently difficult.ResultsUsing a large-scale analysis of more than 40 microarray studies encompassing ~2400 mammalian tissue samples, we identified a common theme across heterogeneous microarray studies evident by a robust genome-wide inverse regulation of metabolic and cell signaling pathways: We found that upregulation of cell signaling pathways was invariably accompanied by downregulation of cell metabolic transcriptional activity (and vice versa). Several findings suggest that this characteristic gene expression pattern represents a new principle of mammalian transcriptional regulation. First, this coordinated transcriptional pattern occurred in a wide variety of physiological and pathophysiological conditions and was identified across all 20 human and animal tissue types examined. Second, the differences in metabolic gene expression predicted the magnitude of differences for signaling and all other pathways, i.e. tissue samples with similar expression levels of metabolic transcripts did not show any differences in gene expression for all other pathways. Third, this transcriptional pattern predicted a profound effect on the proteome, evident by differences in structure, stability and post-translational modifications of proteins belonging to signaling and metabolic pathways, respectively.ConclusionsOur data suggest that in a wide range of physiological and pathophysiological conditions, gene expression changes exhibit a recurring pattern along a transcriptional axis, characterized by an inverse regulation of major metabolic and cell signaling pathways. Given its widespread occurrence and its predicted effects on protein structure, protein stability and post-translational modifications, we propose a new principle for transcriptional regulation in mammalian biology.

Intensified Doxorubicin-Based Regimen Efficacy in Residual Non-Hodgkin's Lymphoma Disease: Towards a Computationally Supported Treatment Improvement

Despite recent advances, treatment of patients with aggressive Non-Hodgkin's lymphoma (NHL 2 ) has yet to be optimally designed. Notwithstanding the contribution of molecular treatments, intensiflcation of chemotherapeutic regimens may still be beneflcial. Hoping to aid in the design of intensifled chemotherapy, we put forward a mathematical and computational model that analyses the efiect of Doxorubicin on NHL over a wide range of patho-physiological conditions. The model represents tumour growth both in difiusion-limited settings, that is, in small avascular tumours and tumour cords, and in perfusion-limited settings, e.g. in well-vascularized tumours. Model simulations indicated the presence of a critical regimen intensity below which treatment will fall short of tumour elimination. Taking this critical intensity into account, we compared two regimen intensiflcation strategies: Dose escalation and regimen densiflcation, i.e. reducing the inter-dosing interval. In the difiusion-limited setting, dose escalation was somewhat more e-cient than regimen densiflcation. In the perfusion-limited setting, both intensiflcation strategies yielded similar results. The present study coupled with a realistic myelotoxicity model may add insight on the optimisation of NHL intensifled chemotherapy design.

Effect of penicillin G-induced epileptic seizures on hemorheological parameters in rats

Normally, cerebral blood flow (CBF) is quantitatively coupled to cerebral metabolic rate like other tissues and maintained basically by altering vascular geometry and appropriate perfusion pressure. However, the rheological properties of the blood are important factors for effective tissue perfusion. Although a lot of studies have reported that hemorheological parameters are affected by a wide range of pathophysiological conditions, to our knowledge no research related to the effects of epileptic seizures on hemorheological parameters has been carried out. Thus, the aim of this study was to explore possible changes in rheological parameters including red blood cell (RBC) deformability, rigidity and aggregation, whole blood and plasma viscosity during epileptic seizures induced by penicillin G in rats. Eighteen female albino rats were divided into three groups that included sham operated controls (Group S), epileptic group (Group E), intraperitoneal penicillin group (Group IPP). Epilepsy was induced by intracortical injections of penicillin G. Hemorheological studies had been carried out 3 h after the induction of epilepsy. Among the studied hemorheological parameters, only RBC deformability was found to be different in the E group compared to S group. Epileptic seizures led to an increase in RBC deformability in the E group. In conclusion, these results suggest that in addition to an increase in CBF, RBC deformability may also improve to better match brain metabolic demands during seizures.

Nitrosative Stress in the ER: A New Role for S-Nitrosylation in Neurodegenerative Diseases

S-Nitrosylation, the covalent addition of a nitrogen monoxide group to a cysteine thiol, has been shown to modify the function of a broad spectrum of mammalian, plant, and microbial proteins and thereby to convey the ubiquitous influence of nitric oxide on cellular signal transduction and host defense. Accumulating evidence indicates that dysregulated, diminished, or excessive S-nitrosylation may be implicated in a wide range of pathophysiological conditions. A recent study establishes a functional relationship between inhibitory S-nitrosylation of the redox enzyme protein disulfide isomerase (PDI), defects in regulation of protein folding within the endoplasmic reticulum (ER), and neurodegeneration. Further, an examination of human brains afflicted with Parkinson's or Alzheimer's disease supports a causal role for the S-nitrosylation of PDI and consequent ER stress in these prevalent neurodegenerative disorders.

Physiological variation in plasma total homocysteine concentrations in rats

Hyperhomocysteinemia was initially related to cardiovascular diseases; but homocysteine (Hcy) metabolism disturbances have more recently associated with a wide range of pathophysiological conditions including age-related diseases, disrupted circadian rhythms and gynaecological disorders. Since in many cases we do not know to what extent animal models are physiologically similar to human ones, this study aimed to track spontaneous variations in rat plasma Hcy concentrations during different physiological processes such as life cycle, 24 hours and estrous cycle. Plasma total Hcy concentrations were accessed by HPLC. Plasma Hcy concentration varied with age and newborns had the lowest values (2.94 ± 0.47 μmol/L). Rats aged 10 days presented concentration similar to 3 month old animals (6.87 ± 0.67 and 8.29 ± 1.55 μmol/L respectively). Values decreased to 6.42 ± 1.65 μmol/L at 6 months and 4.87 ± 0.81 μmol/L at 28 months. Concerning circadian variations in Hcy concentration cosinor analysis showed acrophase in young rats at 1:09 pm, but no plasma Hcy circadian variations in aged rats. Female rats showed changes in Hcy concentration during the estrous cycle with higher values during the diestrous I (10.61 ± 1.81 μmol/L) compared with the estrous (8.47 ± 1.86 μmol/L) and diestrous II (7.68 ± 1.58 μmol/L) phases. In conclusion, plasma Hcy concentration varied spontaneously with ontogenic development and during the estrous cycle and presented a circadian rhythm variation in young rats.

Magnetic Source Imaging

MAGNETIC SOURCE IMAGING (MSI) is a new, noninvasive technique for defining the relationship between brain function and structure on a patient-to-patient basis. It achieves this by combining detailed neurophysiological data derived from magnetoencephalography with high-quality neuroanatomical data derived via magnetic resonance imaging. By the use of mathematical models, the spatial locations of those neurons that generate neuromagnetic signals of interest are estimated and subsequently marked on spatially aligned magnetic resonance images. There are three prominent types of clinical MSI examinations. These are: 1) functional mapping examinations in which sensory and motor functions are localized; 2) examinations of interictal epileptiform activity; and 3) examinations of abnormal low-frequency magnetic activity, which has been found to be present in a wide range of pathophysiological conditions. Functional mapping provides useful information regarding the relationship between the cortical representation of eloquent function and the location of pathological lesions that may be surgically resectable. This application is of particular utility in cases of intracortical masses that distort and obscure the local neuroanatomy. By defining the primary sites of interictal epileptiform activity, MSI examinations are useful in the surgical planning for the implantation of depth electrodes and the planning of partial lobectomies. Abnormal low-frequency magnetic activity appears to be a neurophysiological correlate of ischemic penumbra associated with stroke, neoplasms, and vascular malformations. Abnormal low-frequency magnetic activity has also been found to be present in several other conditions, including head trauma and psychiatric dysfunction, although the exact pathophysiological mechanisms are presently unclear. Additional applications of MSI are forthcoming, but even in their absence, the demonstrated utility of MSI with respect to the applications outlined here is sufficient to secure its position in both basic and applied research and as a clinically useful tool for the neurosurgeon.

Analysis of overall pathophysiological relationships between serum levels of TSH and thyroid hormones using a large laboratory database.

Factors associated with the basal level of serum thyrotropin (TSH) were analyzed over a wide range of pathophysiological conditions by means of a large laboratory database on thyroid function. When data were analyzed two-dimensionally, serum TSH showed significant inverse correlations with total triiodothyronine (T3), free T3 index (FT3I), total thyroxin (TT4) and free T4 index (FT4I) in the order of increasing intensity. The three-dimensional analysis, however, revealed that 1) total hormone levels were actually unrelated to serum TSH when the levels of free hormone indices were held constant, 2) the relation between FT3I and TSH became obscure when the influence of FT4I was similarly removed. On the other hand, 3) the relation of FT4I with TSH was unaffected by the level of FT3I. These results suggest that free T4 is the main determinant of the serum TSH level. This study also implies that it is possible to use large amounts of laboratory data to elucidate the overall profile of a given patho-physiological system, whose structure is only partially revealed by conventional clinical or animal studies.