Comparison of supercritical CO2 extraction and pressurized fluid extraction for isolation of alkaloids from Anacardium occidentale with the study of its anti-inflammatory activity.

In recent years, there has been a growing interest in the therapeutic potential of natural compounds, particularly of plant origin, owing to their demonstrated anti-inflammatory properties. Among these, Anacardium occidentale, commonly known as cashew, has garnered significant attention due to its reputed health benefits. This study aim to establish a correlation between the bioactive compounds contained in the extracts of Anacardium occidentale and its anti-inflammatory activity. Dried Anacardium occidentale leaves powder was used as the extraction matrix. Extraction techniques are maceration, pressurized fluid extraction (PFE), and supercritical fluid extraction (SFE). The preliminary analysis of extracts was made by LC-MS/MS. The Response Surface Methodology (RSM), Principal Component Analysis (PCA), and heat maps were employed to model the influence of experimental conditions on extraction yield and peak area of specific compounds from the plant. To evaluate anti-inflammatory activity, RAW 264.7 cells were cultured, activated with LPS, and treated with varying concentrations of the plant extracts. Cell proliferation was assessed using the XTT assay. Indeed, Anacardium occidentale extracts contain anacardic acids, cardanols, and cardol, with distinct profiles yielded by SFE and ethanol-based methods. RSM shows that temperature and ethanol, as additives to CO2, significantly affect extraction efficiency in both PFE and SFE. Moreover, this composition with SFE demonstrate higher selectivity for specific group of compounds. The extracts exhibit anti-inflammatory properties without cytotoxicity in macrophages, reducing levels of pro-inflammatory proteins COX-2, COX-1, and TLR4 in activated cells. This suggests their potential as anti-inflammatory agents without adverse effects on cell viability or pro-inflammatory protein levels in non-activated cells. Overall, these findings underscore the promising therapeutic potential of Anacardium occidentale extracts in mitigating inflammation, while also providing crucial insights into optimizing the extraction process for targeted compound isolation. Thus, this makes a good prospect for the development of anti-inflammatory drugs from this plant.

Therapeutic role of eicosapentaenoic and arachidonic acid in benzo(a) pyrene-induced toxicity in HUVEC endothelial cells.

Endothelial cells are characterized by intense metabolic activity and control of homeostasis. Exposure to benzo(a)pyrene (BaP) plays an important role in the etiology of atherosclerosis. The study aimed to determine the effect of arachidonic (ARA), and eicosapentaenoic acid (EPA) on pro-inflammatory gene and protein levels in human umbilical vein endothelial cells (HUVEC) exposed to BaP. Cyclooxygenase-2 (COX-2), aryl hydrocarbon receptor (AHR), and glutathione S transferase Mu1 (GSTM1) proteins expression were analyzed by Western blot. Prostaglandin synthase 2 (PTGS2), AHR, GSTM1, phospholipase A2 (PLA2G4A), cytochrome P450 CYP1A1, intercellular adhesion molecule-1 (ICAM-1), endothelial nitric-oxide synthase (NOS3), and vascular adhesion molecule-1 gene expression (VCAM-1) was analyzed in Real time-qPCR. Phospholipase A2 activity was measured using the ELISA technique, and CYP1A1 activity was analyzed in luminescence assay. The highest amount of COX-2, the most increased activity of CYP1A1 and cPLA2, and overexpression of GSTM1, CYP1A1, ICAM-1, and VCAM-1 gene was observed in HUVEC cells treated with BaP. After co-treatment with BaP and ARA or EPA, an increase of GSTM1 level was observed. Incubation of endothelial cells with ARA or EPA and BaP resulted in lower CYP1A1 and cPLA2 activities and lower expression of VCAM-1 and ICAM-1 genes. Significant overexpression of AHR, GSTM1, CYP1A1, PTGS2, PLA2G4A, and NOS3 genes was noted in cells treated with EPA and BaP. Our data suggest a beneficial effect of EPA and ARA on endothelial function. Thus, it justifies further research on the participation of fatty acids in the regulation of physiological and pathological processes in endothelial cells.

Effect of Eicosapentaenoic Acid Supplementation on Murine Preadipocytes 3T3-L1 Cells Activated with Lipopolysaccharide and/or Tumor Necrosis Factor-α.

The beneficial effect of n-3 fatty acids can be related to anti-inflammatory properties. The aim of the study was to analyzed the effect of eicosapentaenoic acid (EPA) on 3T3-L1 cells (murine embryonic fibroblasts‒preadipocytes) activated with inflammatory factors (IF). Cells were incubated with 50 µmol of EPA for 48 h, and then activated with lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α). The level of cycloxygenase-2 (Prostaglandin-Endoperoxide Synthase 2, PTGS2, COX-2), cytosolic prostaglandin synthase E2 (cPGES), fatty acid binding protein 4 (FABP4), toll-like receptor 4 (TLR4), glucose receptor type 4 (GLUT-4), and cannabinoid receptor 2 (CB2) was determined using Western blot analysis. The phospholipase A2 (Pla2g4a), and prostaglandin-Endoperoxide Synthase 2 (Ptgs2) gene expression was analyzed by real-time qPCR. After EPA and IF activation, a significant decrease in the COX-2, cPGES, and TRL4 protein levels was observed. Incubation of cells with EPA and IF resulted in a decrease in Ptgs2 and an increase in the Pla2g4a gene. A significant increase in the CB2 protein was observed in adipocytes co-treated with EPA and IF. The results indicated an anti-inflammatory properties of EPA. Interestingly, the activation of the GLUT4 receptor by EPA suggests an unique role of this FA in the regulation of the adipocyte metabolism and prevention of insulin resistance.

Clostridium difficile caused changes in fatty acids profile and resolvin D1 content in plasma of infected patients.

OBJECTIVES: Clostridium difficile infection (CDI) is an acute gastrointestinal infection caused by anaerobic, toxin-producing bacteria. During the course of CDI, there is a general inflammatory state. In order to gain a deeper understanding of the role of fatty acids (FAs) in the pathogenesis of acute infection we analyzed their plasma content in both patients with CDI and controls. METHODS: The study groups included 40 patients with CDI and 40 healthy volunteers. Plasma FA content was analyzed by gas chromatography, resolvin D1 (RvD1) level using ELISA assay, and we assessed the white blood cell (WBC) count, neutrophil count and C-reactive protein (CRP) level. RESULTS: Patients with CDI were characterized by significantly higher values of WBC, neutrophils, platelets and CRP compared with the control group. The saturated FA index was statistically higher and total n-3 FA was significantly decreased in the plasma of CDI patients as compared with the control group. RvD1 content was significantly higher in the control group as compared with patients with CDI. CONCLUSION: In patients with good outcomes, we probably observed the effective resolution of inflammation, as reflected in n-3 FA metabolism and their significant decrease in plasma. This may indicate the therapeutic role of n-3 FA in CDI infection.

Fatty acids and selected endocannabinoids content in cerebrospinal fluids from patients with neuroinfections.

Neuroinfections are a significant medical problem and can have serious health consequences for patients. Their outcome, if not fatal, can be associated with permanent residual deficits. Cerebrospinal fluid (CSF) examination is commonly used for meningitis confirmation. Fatty acids (FA) are precursors of lipid mediators with pharmacological activity. They actively modulate inflammation as well as contribute to its resolution. Therefore the aim of this study was to determine the FA and selected endocannabinoids (ECB) content in the CSF obtained from patients with bacterial (BM) and viral meningitis (VM) using chromatographic techniques. A significantly lower level of saturated FA was found in patients with BM and VM as compared to controls. There was a significantly higher concentration of long-chain monounsaturated FA and polyunsaturated n-6 FA in the CSF obtained from patients with neuroinfection. Moreover, a significant reduction of n-3 FA in CSF obtained from patients with BM and VM was demonstrated. The highest amount of ECB was detected in the CSF of patients with VM: eicosapentaenoyl ethanolamide (1.65 pg/mL), docosahexaenoyl ethanolamide (655.5 pg/mL) and nervonoyl ethanolamide (3.09 ng/mL). Results indicate the participation of long-chain monounsaturated and polyunsaturated FA and their derivatives in the inflammatory process and likely in the process of resolution of inflammation during neuroinfection. It seems that the determination of the FA and ECB profile in CSF may be a valuable biomarker of health and may allow the development of new pharmacological strategies, therapeutic goals and fatty acids supplementation necessary in the fight against inflammation of the central nervous system.

Differential effect of nanoparticle and standard forms of ZnO on serum zinc and magnesium levels in rats.

This study examined the effect of chronic (2 weeks) administration of zinc oxide nanoparticles (NPs-ZnO) and standard zinc oxide (S-ZnO) on the levels of zinc (Zn), magnesium (Mg) and calcium (Ca) in rat serum. S-ZnO and NPs-ZnO were administered either per os (p.o.) or intraperitoneally (i.p.) at doses of 7 mg/kg or 14 mg/kg. Neither form of ZnO administered p.o. altered serum zinc concentration. However, different effects dependent upon either S-ZnO or NPs-ZnO forms were noticed after i.p. administration. Namely, while S-ZnO increased serum zinc concentration (by 136%) only at the higher dose (14 mg/kg), both doses of NPs-ZnO increased zinc concentration (by 97% at 7 mg/kg and by 564% at 14 mg/kg). The form-dependence of the ZnO effect was also demonstrated in the effect on the serum magnesium level. Only the S-ZnO form (at the dose of 14 mg/kg) reduced serum magnesium concentration (by 14% p.o., 6% i.p.). No influence of NPs-ZnO on the serum calcium level was observed. The present study demonstrated effects on the serum Zn and Mg levels, which differed between the standard and nanoparticle forms of ZnO. This may contribute to the different functional effects of these ZnO forms shown previously.

Effect of selected drugs on zinc accumulation in teeth of laboratory animals.

BACKGROUND: Zinc (Zn) is a micronutrient and essential element of life and its deficiency causes severe disorders of numerous body systems, such as immune, reproductive and central nervous system. Zinc supplementation affects wound healing and sexual development. The interactions between drugs administration and Zn level in tissues are not fully understood. The aim of the study was to demonstrate differences in Zn content in teeth of laboratory animals that have undergone pharmacological tests. METHODS: The teeth were extracted from laboratory animals after chronic administration of a non-steroidal anti-inflammatory drug (8-[4-[4-(4-chlorophenyl) piperazine-1-sulfonylphenyl]]-1-propylxanthine), a steroid anti-inflammatory drug (deoxycorticosterone) and an anti-cancer drug (oxaliplatin used acutely). The method of flame atomic absorption spectrometry was used to determine the Zn content in the teeth of the laboratory animals. RESULTS: Based on the studies conducted, the administration of the anti-inflammatory drug PSB-603 and deoxycorticosterone results in an increase in Zn accumulation in the teeth of laboratory animals, which may be indicative of the effect of anti-inflammatory drugs on the metabolism of this bioelement. Oxaliplatin has the opposite effect, after which the level of the measured bioelement in the teeth of mice depended on the administered dose. This level was on average 21.0-28.1% lower than the Zn level in the teeth of the control group. Anti-cancer drugs may interfere with Zn accumulation in the teeth and cause the removal of this metal from bone tissue. CONCLUSION: It can be assumed that the Zn content in teeth can be markedly affected by the drugs that were administrated to animals.

Comparison of the Psychopharmacological Effects of Tiletamine and Ketamine in Rodents.

The glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine (KET) produces rapid and sustained antidepressant effects in patients. Tiletamine (TIL; 2-ethylamino-2-thiophen-2-yl-cyclohexan-1-one) is another uncompetitive NMDA receptor antagonist, used in a medical (veterinary) setting as an anesthetic tranquilizer. Here, we compared the behavioral actions of KET and TIL in a variety of tests, focusing on antidepressant-like and dissociative-like effects in mice and rats. The minimum effective doses of KET and TIL were 10 mg/kg to reduce mouse forced swim test immobility and 15 mg/kg to reduce marble-burying behavior. However, at similar doses, both compounds diminished locomotor activity and disturbed learning processes in the mouse passive avoidance test and the rat novel object recognition test. KET and TIL also reduced social behavior and accompanying 50-kHz "happy" ultrasonic vocalizations (USVs) in rats. TIL (5-15 mg/kg) displayed additional anxiolytic-like effects in the four-plate test. Neither KET nor TIL affected pain response in the hot plate test. Examination of the "side effects" revealed that only at the highest doses investigated did both compounds produce motor deficits in the rotarod test in mice. While KET produced behavioral effects at doses comparable between species, in the rats, TIL was ~10 times more potent than in the mice. In summary, antidepressant-like properties of both KET and TIL are similar, as are their adverse effect liabilities. We suggest that TIL could be an alternative to KET as an antidepressant with an additional anxiolytic-like profile.

Evaluation of anti-inflammatory and ulcerogenic potential of zinc-ibuprofen and zinc-naproxen complexes in rats.

Because of numerous indications and high availability, non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed and used medicines in the world. However, long-term therapy with and improper use of NSAIDs may lead to gastrointestinal damage. Therefore, improving the therapeutic index of the existing drugs has become a priority over the past decades. Considerable attention in the field has been concentrated on metal complexes of non-steroidal anti-inflammatory drugs. The aim of this study is to evaluate the effect of complexation with zinc on the anti-inflammatory and ulcerogenic effects of ibuprofen and naproxen after single and triple intragastric administration to rats. The anti-inflammatory effect was assessed in carrageenan-induced inflammatory edema in the hind paw of male albino Wistar rats. The mucosal lesions were inspected and evaluated for gross pathology. Single administration of both the investigated complexes, namely zinc-ibuprofen and zinc-naproxen (20 mg/kg equivalent to ibuprofen and naproxen, respectively) and their parent drugs and physical mixtures with zinc hydroaspartate (ZHA doses: 16.05 and 14.37 mg/kg), caused a significant reduction of the edema after the same time from the carrageenan injection in comparison to the control groups. However, no statistically significant differences between the investigated drugs were observed after their single administration. The mean ulceration score for the mixture of ibuprofen and ZHA was statistically lower than the mean score achieved in rats after treatment with ibuprofen alone. On the other hand, triple intragastric administration of the ZHA-ibuprofen and ZHA-naproxen combination showed substantial enhancement of the anti-inflammatory activity against control groups, as well as against the parent NSAIDs. The most potent anti-inflammatory activity was demonstrated after 2 h from the carrageenan injection in animals receiving ZHA together with naproxen. The edema growth was reduced in these animals by 80.9% as compared to the control group. This result was significantly higher than the results achieved in animals receiving zinc-naproxen (50.2%) or naproxen alone (47.9%). Both NSAID complexes with zinc and mixtures with ZHA alleviated ulcerations caused by parent NSAIDs; however, the mixtures of both ibuprofen and naproxen with ZHA after triple administration were the least damaging. In view of the above results, zinc supplementation during NSAID therapy may have a beneficial effect on ulcer prevention and healing by reducing the effective dose of the parent drug and increasing its potency.

Beneficial effect of nanoparticles over standard form of zinc oxide in enhancing the anti-inflammatory activity of ketoprofen in rats.

BACKGROUND: Zinc is known as an anti-inflammatory agent. Recent studies demonstrated the usage of zinc ions for enhancing the anti-inflammatory effect of Non-Steroidal Anti-inflammatory Drugs (NSAIDs). METHODS: This study compares the influence of chronic administration of zinc oxide nanoparticles (ZnO-NPs) and zinc oxide standard form (ZnO-S) on the anti-inflammatory and gastric activity of ketoprofen in rats. Both ZnO-S and ZnO-NPs were administered at doses of 7 or 14mg/kg (intraperitoneally (ip) and per os (po)) for 2 weeks followed by single po ketoprofen administration (in three doses: 5, 10, and 20mg/kg). RESULTS: The ZnO-NPs (but not ZnO-S) at a dose of 14mg/kg ip reduced the carrageenan-induced paw edema at the second hour after carrageenan administration and enhanced the ketoprofen anti-inflammatory activity at second and third hour after carrageenan administration. A dose of 7mg/kg of both forms administered ip was ineffective in these measures. ZnO-NPs and ZnO-S administered po did not affect the carrageenan-induced paw edema or ketoprofen anti-inflammatory activity. ZnO-S and ZnO-NPs administered po and ip at both doses (7 and 14mg/kg) protected the gastric mucosa from ketoprofen-induced gastric ulcer. CONCLUSION: Zinc oxide nanoparticles demonstrated beneficial effects over standard form in enhancing the anti-inflammatory activity of ketoprofen.

Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling.

Zinc is a nutritionally fundamental trace element, essential to the structure and function of numerous macromolecules, including enzymes regulating cellular processes and cellular signaling pathways. The mineral modulates immune response and exhibits antioxidant and anti-inflammatory activity. Zinc retards oxidative processes on a long-term basis by inducing the expression of metallothioneins. These metal-binding cysteine-rich proteins are responsible for maintaining zinc-related cell homeostasis and act as potent electrophilic scavengers and cytoprotective agents. Furthermore, zinc increases the activation of antioxidant proteins and enzymes, such as glutathione and catalase. On the other hand, zinc exerts its antioxidant effect via two acute mechanisms, one of which is the stabilization of protein sulfhydryls against oxidation. The second mechanism consists in antagonizing transition metal-catalyzed reactions. Zinc can exchange redox active metals, such as copper and iron, in certain binding sites and attenuate cellular site-specific oxidative injury. Studies have demonstrated that physiological reconstitution of zinc restrains immune activation, whereas zinc deficiency, in the setting of severe infection, provokes a systemic increase in NF-κB activation. In vitro studies have shown that zinc decreases NF-κB activation and its target genes, such as TNF-α and IL-1ß, and increases the gene expression of A20 and PPAR-α, the two zinc finger proteins with anti-inflammatory properties. Alternative NF-κB inhibitory mechanism is initiated by the inhibition of cyclic nucleotide phosphodiesterase, whereas another presumed mechanism consists in inhibition of IκB kinase in response to infection by zinc ions that have been imported into cells by ZIP8.

Combined micro-XRF and TXRF methodology for quantitative elemental imaging of tissue samples.

Local differences in structural properties of biological specimens pose a major limitation to quantitative X-ray fluorescence imaging. This is because both the various tissue compartments of different density and variation in the sample thickness upon frequently used freeze-drying come up with the different values of the sample mass per unit area to be taken into account. Even though several solutions to tackle this problem based on the home-made standards for quantification in terms of thickness- and density-independent elemental mass fractions have been proposed, this issue is not addressed enough due to the samples' heterogeneity. In our recent study, we propose a calculation scheme based on combined external-standard micro X-ray fluorescence (micro-XRF) imaging and internal-standard total reflection X-ray fluorescence (TXRF) analysis to determine the corrected elemental mass fraction distributions in commonly analysed rat tissues: kidney, liver and spleen. The results of TXRF analysis of digested large tissue sections together with the mean values of elemental masses per unit area obtained with micro-XRF were employed to determine the average masses per unit area of the samples. The correction for variation of the tissue thickness and density was done through with the use of Compton intensities. Importantly, by its versatility, our novel approach can be used to produce elemental contrast in a variety of biological specimens where local variations in either the sample density or thickness are no longer the issue.

Assessing gastric toxicity of xanthone derivatives of anti-inflammatory activity using simulation and experimental approaches.

Xanthones are tricyclic compounds of natural or synthetic origin exhibiting a broad spectrum of therapeutic activities. Three synthetic xanthone derivatives (KS1, KS2, and KS3) with properties typical for nonsteroidal anti-inflammatory drugs (NSAID) were objects of the presented model study. NSAIDs are in common use however; several of them exhibit gastric toxicity predominantly resulting from their direct interactions with the outermost lipid layer of the gastric mucosa that impair its hydrophobic barrier property. Among the studied xanthones, gastric toxicity of only KS2 has been determined in previous pharmacological studies, and it is low. In this study, carried out using X-ray diffraction and computer simulation, a palmitoyloleoylphosphatidylcholine-cholesterol bilayer (POPC-Chol) was used as a model of a hydrophobic layer of lipids protecting gastric mucosa as POPC and Chol are the main lipids in human mucus. X-ray diffraction data were used to validate the computer model. The aim of the study was to assess potential gastric toxicity of the xanthones by analysing their atomic level interactions with lipids, ions, and water in the lipid bilayer and their effect on the bilayer physicochemical properties. The results show that xanthones have small effect on the bilayer properties except for its rigidity whereas their interactions with water, ions, and lipids depend on their protonation state and for a given state, are similar for all the xanthones. As gastric toxicity of KS2 is low, based on MD simulations one can predict that toxicity of KS1 and KS3 is also low.

Complementary pharmacological and toxicological characterization data on the pharmacological profile of N-(2,6-dichlorophenyl)-2-(4-methyl-1-piperidinyl) acetamide.

This text presents complementary data corresponding to pharmacological and toxicological characterization of N-(2,6-dichlorophenyl)-2-(4-methyl-1-piperidinyl)acetamide (LIA) compound. These data support our research article entitled "Pharmacological profile of N-(2,6-dichlorophenyl)-2-(4-methyl-1-piperidinyl)acetamide, a novel analog of lidocaine" Déciga-Campos M., Navarrete-Vázquez G., López-Muñoz F.J., Librowski T., Sánchez-Recillas A., Yañez-Pérez V., Ortiz-Andrade R. (2016) [1]. Toxicity was predicted through the ACD/ToxSuite software and evaluated in vivo using brine shrimp larvae (Artemia salina L.) and mice. Also, we used the micronucleus assay to determine genotoxicity. We used the platform admetSAR to predict absorption properties of LIA and lidocaine.

Resolvin D1 down-regulates CYP1A1 and PTGS2 gene in the HUVEC cells treated with benzo(a)pyrene.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) can interact with lipids and their derivatives and have been known to induce atherosclerosis. The aim of this study was to evaluate the impact of Resolvin D1 (RvD1) on inflammatory-state realted proteins and genes in the human primary umbilical vein endothelial HUVEC cells exposed to benzo(a)pyrene (BaP). METHODS: We analyzed the influence of RvD1 and/or BaP on cyclooxygenase-2 (COX-2), cytosolic prostaglandine E2 synthase (cPGES), glutathione S transferase (GSTM1) and aryl hydrocarbon receptor (AhR) protein expression by Western blot. Additionaly, phospholipase A2 (cPLA2) and cytochrome P450 (CYP1A1) activity, as well as AhR, CYP1A1, phospholipase A2 (PLA2G4A) and prostaglandin synthase 2 (PTGS2) gene expression by qRT-PCR was studied. RESULTS: RvD1 down-regulates cytochrome P450 (CYP1A1) and prostaglandin synthase 2 (PTGS2) gene expression in HUVEC cells exposed to BaP. Repressesion of COX-2, cPGES and overexpressesion of GSTM1 protein was noted after co-treatment with RvD1 and BaP. After incubation with RvD1 an increase of cPLA2 and a decrease of CYP1A1 activity was observed when compared to BaP treated alone endothelial cells. CONCLUSIONS: Our data suggests that RvD1 can significantly contributes on vascular function and alleviates the harmful effects caused by BaP, which might potentially aid in the repair of the injured endothelium.

Pharmacological profile of N-(2,6-dichlorophenyl)-2-(4-methyl-1-piperidinyl)acetamide, a novel analogue of lidocaine.

AIM: N-(2,6-Dichlorophenyl)-2-(4-methyl-1-piperidinyl)acetamide (LIA), a lidocaine analogue, has potential applications in treating neuropathic pain. The aim of this work was to characterize the pharmacological activity of LIA related with central nervous system and cardiovascular activity. METHODS: Anesthetic effect was tested in guinea pigs and mice. Ambulatory activity, anti-anxiety effect, sodium pentobarbital (PB)-induced hypnosis and pentylenetetrazol (PTZ)-induced seizures test were evaluated in mice to determine the possible central nervous system activity. The cardiovascular activities in vivo and ex vivo were analyzed in rats. KEY FINDINGS: LIA (2%) presents, similar to lidocaine (2%), anesthetic activity on the corneal reflex, infiltration anesthesia and tail immersion test. LIA (1-100mg/kg, i.p.), similar to lidocaine (1-100mg/kg, i.p.), presents a dose-dependent sedative-hypnotic effect in mice. Both compounds did not produce anti-anxiety activity in mice. LIA did not prevent PTZ-induced seizures. However, LIA itself did not produce seizures at high doses in mice, as lidocaine does. LIA is a vasorelaxant compound for smooth muscle cells and presents hypotensive effect in vivo without increments to the heart rate significantly. SIGNIFICANCE: High doses of lidocaine produce seizures and vasoconstriction. In this study, we found that LIA shares a similar pharmacological profile as lidocaine's but without the primary adverse effects of seizures and vasoconstriction.

Does titanium in ionic form display a tissue-specific distribution?

Most studies have focused on the biodistribution of titanium(IV) oxide as nanoparticles or crystals in organism. But several reports suggested that titanium is released from implant in ionic form. Therefore, gaining insight into toxicokinetics of Ti ions will give valuable information, which may be useful when assessing the health risks of long-term exposure to titanium alloy implants in patients. A micro synchrotron radiation-induced X-ray fluorescence (µ-SRXRF) was utilized to investigate the titanium distribution in the liver, spleen and kidneys of rats following single intravenous or 30-days oral administration of metal (6 mg Ti/b.w.) in ionic form. Titanium was mainly retained in kidneys after both intravenous and oral dosing, and also its compartmentalization in this organ was observed. Titanium in the liver was non-uniformly distributed-metal accumulated in single aggregates, and some of them were also enriched in calcium. Correlation analysis showed that metal did not displace essential elements, and in liver titanium strongly correlated with calcium. Two-dimensional maps of Ti distribution show that the location of the element is characteristic for the route of administration and time of exposure. We demonstrated that µ-SRXRF can provide information on the distribution of titanium in internal structures of whole organs, which helps in enhancing our understanding of the mechanism of ionic titanium accumulation in the body. This is significant due to the popularity of titanium implants and the potential release of metal ions from them to the organism.

Effect of pregabalin on contextual memory deficits and inflammatory state-related protein expression in streptozotocin-induced diabetic mice.

Diabetes mellitus is a metabolic disease characterized by hyperglycemia due to defects in insulin secretion or its action. Complications from long-term diabetes consist of numerous biochemical, molecular, and functional tissue alterations, including inflammation, oxidative stress, and neuropathic pain. There is also a link between diabetes mellitus and vascular dementia or Alzheimer's disease. Hence, it is important to treat diabetic complications using drugs which do not aggravate symptoms induced by the disease itself. Pregabalin is widely used for the treatment of diabetic neuropathic pain, but little is known about its impact on cognition or inflammation-related proteins in diabetic patients. Thus, this study aimed to evaluate the effect of intraperitoneal (ip) pregabalin on contextual memory and the expression of inflammatory state-related proteins in the brains of diabetic, streptozotocin (STZ)-treated mice. STZ (200 mg/kg, ip) was used to induce diabetes mellitus. To assess the impact of pregabalin (10 mg/kg) on contextual memory, a passive avoidance task was applied. Locomotor and exploratory activities in pregabalin-treated diabetic mice were assessed by using activity cages. Using Western blot analysis, the expression of cyclooxygenase-2 (COX-2), cytosolic prostaglandin E synthase (cPGES), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), nuclear factor-ĸB (NF-ĸB) p50 and p65, aryl hydrocarbon receptor (AhR), as well as glucose transporter type-4 (GLUT4) was assessed in mouse brains after pregabalin treatment. Pregabalin did not aggravate STZ-induced learning deficits in vivo or influence animals' locomotor activity. We observed significantly lower expression of COX-2, cPGES, and NF-κB p50 subunit, and higher expression of AhR and Nrf2 in the brains of pregabalin-treated mice in comparison to STZ-treated controls, which suggested immunomodulatory and anti-inflammatory effects of pregabalin. Antioxidant properties of pregabalin in the brains of diabetic animals were also demonstrated. Pregabalin does not potentiate STZ-induced cognitive decline, and it has antioxidant, immunomodulatory, and anti-inflammatory properties in mice. These results confirm the validity of its use in diabetic patients. Graphical abstract Effect of pregabalin on fear-motivated memory and markers of brain tissue inflammation in diabetic mice.

Toxicokinetics and tissue distribution of titanium in ionic form after intravenous and oral administration.

Titanium is widely used both in food and cosmetics, as well as in surgery and industry. Contrary to most studies, the present work focused on the determination of the toxicokinetic parameters of titanium in ionic form, as well as on its tissue biodistribution in rats. The animals were administered either a single intravenous dose of 6 mg Ti/kg b.w., or received the same dose orally every day for 30 days. The concentration of titanium in the serum and organs was measured by a graphite furnace atomic absorption spectrometry. Metal rapidly distributed from the circulation to the investigated organs after both routes of administration, and kidney was identified as the main target tissue, followed by liver and spleen. One month of oral exposure to Ti led to the increase of its concentration in liver, kidneys, spleen, and heart. In the intravenous study, both the highest area under concentration-time curves and the longest elimination half-life time were recorded in the kidney followed by serum, spleen and liver. The present study contributes to the knowledge of the toxicokinetics of titanium in ionic form, which may be especially useful when assessing the health risks of long-term exposure to titanium alloy implants in patients.

n-3 Fatty acids regulate the inflammatory-state related genes in the lung epithelial cells exposed to polycyclic aromatic hydrocarbons.

BACKGROUND: Chronic airway inflammation is coordinated by a complex of inflammatory mediators, including eicosanoids. The aim of this study was to evaluate the impact of polycyclic aromatic hydrocarbons (PAHs) on the human lung epithelial carcinoma A549 cells supplemented with docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids. METHODS: We analyzed the influence of DHA, EPA and/or benzo(a)pyrene (BaP), chrysene (Chr), fluoranthene (Flu) and benzo(a)anthracene (Baa) treatment on the fatty acids (FAs) profile and the formation of isoprostanes. We studied the cyclooxygenase-2, FP-receptor, peroxisome proliferator-activated receptors PPARδ and PPARγ, transcription factor NF-кB p50 and p65 expression by Western blot, phospholipase A2 (cPLA2) activity, as well as aryl hydrocarbon receptor (AHR), cytochrome P450 (CYP1A1), phospholipase A2 (PLA2G4A) and prostaglandin synthase 2 (PTGS2) gene expression by qRT-PCR. RESULTS: DHA or EPA supplementation and BaP or Baa treatment resulted in a higher level of PGF3α. COX-2 expression was decreased while PPARδ expression and cPLA2 activity was increased after fatty acid supplementation and PAHs treatment. DHA and EPA up-regulated AHR and PLA2G4A genes. CONCLUSIONS: Supplementation with n-3 FAs resulted in changes of inflammatory-state related genes in the lung epithelial cells exposed to PAHs. The altered profile of lipid mediators from n-3 FA as well as repression of the COX-2 protein by n-3 PUFAs in A549 cells incubated with PAHs suggests anti-inflammatory and pro-resolving properties of DHA and EPA. It remains to be shown whether these pleiotropic and protective actions of n-3 FAs contribute to fish oil's therapeutic effect in asthma.