Tumor Necrosis Factor Alpha Deficiency Improves Endothelial Function and Cardiovascular Injury in Deoxycorticosterone Acetate/Salt-Hypertensive Mice.

It has been shown that the inflammatory cytokine tumor necrosis factor α (TNFα) plays a role in the development of hypertension and end-stage renal diseases. We hypothesize that TNFα contributes to endothelial dysfunction and cardiac and vascular injury in deoxycorticosterone acetate (DOCA)/salt-hypertensive mice. The wild-type or TNFα-deficient mice were uninephrectomized and implanted with DOCA pellet treatment for 5 weeks; the mice were given either tap water or 1% NaCl drinking water. DOCA mice developed hypertension (systolic blood pressure (SBP): 167 ± 5 vs. 110 ± 4 mmHg in control group, p < 0.05), cardiac and vascular hypertrophy, and the impairment of endothelium-dependent relaxation to acetylcholine (EDR). TNFα deficiency improved EDR and lowered cardiac and vascular hypertrophy with a mild reduction in SBP (152 ± 4 vs. 167 ± 5 mmHg in DOCA group, p < 0.05) in DOCA mice. The mRNA expressions of the inflammatory cytokines, including TNFα, interleukin 1ß (IL1ß), monocyte chemotactic protein 1 (MCP1), and monocyte/macrophage marker F4/80 were significantly increased in the aorta of DOCA-hypertensive mice; TNFα deficiency reduced these inflammatory gene expressions. DOCA-hypertensive mice also exhibited an increase in the vascular oxidative fluorescence intensities, the protein expressions of gp91phox and p22phox, and the fibrotic factors transforming growth factor ß and fibronectin. TNFα deficiency reduced oxidative stress and fibrotic protein expressions. The DOCA mice also showed a decrease in the protein expression of eNOS associated with increased miR155 expression; TNFα deficiency prevented a decrease in eNOS expression and an increase in miR155 expression in DOCA mice. These results support the idea that TNFα significantly contributes to vascular inflammation, vascular dysfunction, and injury in hypertension.

Excess salt intake promotes M1 microglia polarization via a p38/MAPK/AR-dependent pathway after cerebral ischemia in mice.

A high salt diet (HSD) is among the most important risk factors for many diseases. One mechanism by which HSD aggravates cerebral ischemic injury is independent of blood pressure changes. The direct role of HSD in inflammation after cerebral ischemia is unclear. In this research, after twenty-one days of being fed a high salt diet, permanent focal ischemia was induced in mice via operation. At 12 h and 1, 3 and 5 days postischemia, the effects of HSD on the lesion volume, microglia polarization, aldose reductase (AR) expression, and inflammatory processes were analyzed. We report that in mice, surplus dietary salt promotes inflammation and increases the activation of classical lipopolysaccharide (LPS)-induced microglia/macrophages (M1). This effect depends on the expression of the AR protein in activated microglia after permanent middle cerebral artery ligation (pMCAL) in HSD mice. The administration of either the AR inhibitor Epalrestat or a p38-neutralizing antibody blocked the polarization of microglia and alleviated stroke injury. In conclusion, HSD promotes polarization in pro-inflammatory M1 microglia by upregulating the expression of the AR protein via p38/MAPK, thereby exacerbating the development of ischemia stroke.

A Peptoid Delivers CoQ-derivative to Plant Mitochondria via Endocytosis.

Controlled delivery of molecules interfering specifically with target activities in a cell of interest can be a powerful tool for experimental manipulation, because it can be administered at a defined time point and does not require genetic transformation, which in some systems is difficult and time consuming. Peptides as versatile tools that can be tailored for binding numerous binding partners, are of special interest. However, their passage through membranes, their intracellular targeting, and their sensitivity to proteases is limiting. The use of peptoids, where cationic amino-acid side chains are linked to nitrogen (rather than to carbon) of the peptide bond, can circumvent these limitations, because they are not cleavable by proteases. In the current work, we provide a proof-of-concept that such Trojan Peptoids, the plant PeptoQ, can be used to target a functional cargo (i.e. a rhodamine-labelled peptoid and a coenzyme Q10 derivative) into mitochondria of tobacco BY-2 cells as experimental model. We show that the uptake is specific for mitochondria, rapid, dose-dependent, and requires clathrin-mediated endocytosis, as well as actin filaments, while microtubules seem to be dispensable. Viability of the treated cells is not affected, and they show better survival under salt stress, a condition that perturbs oxidative homeostasis in mitochondria. In congruence with improved homeostasis, we observe that the salt induced accumulation of superoxide is mitigated and even inverted by pretreatment with PeptoQ. Using double labelling with appropriate fluorescent markers, we show that targeting of this Trojan Peptoid to the mitochondria is not based on a passage through the plasma membrane (as thought hitherto), but on import via endocytotic vesicles and subsequent accumulation in the mitochondrial intermembrane space, from where it can enter the matrix, e.g. when the permeability of the inner membrane is increased under salt stress.

The XRCC 1 DNA repair gene modifies the environmental risk of stomach cancer: a hospital-based matched case-control study.

BACKGROUND: Previous studies have found that polymorphisms of the DNA repair gene X-ray repair cross-complementing group 1(XRCC1) and environmental factors are both associated with an increased risk of stomach cancer, but no study has reported on the potential additive effect of these factors among Thai people. The aim of this study was to investigate whether the risk of stomach cancer from XRCC1 gene polymorphisms was modified by environmental factors in the Thai population. METHODS: Hospital-based matched case-control study data were collected from 101 new stomach cancer cases and 202 controls, which were recruited from2002 to 2006 and were matched for gender and age. Genotype analysis was performed using real-time PCR-HRM. The data were analysed by the chi-square test and conditional logistic regression. RESULTS: The Arg/Arg homozygote polymorphism of the XRCC1 gene was associated with an increased risk of stomach cancer in the Thai population (OR adj, 3.7; 95%CI, 1.30-10.72) compared with Gln/Gln homozygosity. The effect of the XRCC1gene on the risk of stomach cancer was modified by both a high intake of vegetable oils and salt (p = 0.036 and p = 0.014), particularly for the Arg/Arg homozygous genotype. There were, however, no additive effects on the risk of stomach cancer between variants of the XRCC1gene and smoking,alcohol or pork oil consumption. CONCLUSIONS: The effect of the XRCC1 gene homozygosity, particularly Arg/Arg, on the risk for stomach cancer was elevated by a high intake of vegetable oils and salt.

Rhinitis and sleep disorders: The trigeminocardiac reflex link?

Rhinitis, allergic or non-allergic, is an inflammatory condition of the nose. It is associated with a wide range of sleep disorders that are generally attributed to nasal congestion and presence of inflammatory mediators like cytokines and interleukins. However, the pathophysiological mechanisms behind these sleep disorders remain unclear. On the other hand, the trigeminocardiac reflex (TCR) has recently been linked to various sleep disorders like obstructive sleep apnea, sleep bruxism and rapid eye movement (REM) sleep apnea. TCR can be incited by stimulation of the trigeminal nerve or the area innervated by its branches including the nasal mucosa. Trigeminal nasal afferents can be activated on exposure to noxious stimuli (mechanical or chemical) like ammonia vapors, carbon-dioxide, nicotine, hypertonic saline, air-puffs and smoke. In rhinitis, there is associated neuronal hyper-responsiveness of sensory nasal afferents due to inflammation (which can be suppressed by steroids). This may further lead to increased occurrence of TCR in rhinitis. Moreover, there is involvement of autonomic nervous system both in rhinitis and TCR. In TCR, parasympathetic over activity and sympathetic inhibition leads to sudden onset bradycardia, hypotension, apnea and gastric motility. Also, the autonomic imbalance reportedly plays a significant role in the pathophysiology of rhinitis. Thus, considering these facts we hypothesize that the TCR could be the link between rhinitis and sleep disorders and we believe that further research in this direction may yield significant development in our understanding of sleep disorders in rhinitis.

Effects of dry brining, liquid smoking and high-pressure treatment on the physical properties of aquacultured King salmon (Oncorhynchus tshawytscha) during refrigerated storage.

BACKGROUND: Aquacultured King salmon (Oncorhynchus tshawytscha) pieces were dry brined with a salt/brown sugar mix, dipped in liquid smoke for 3 min, vacuum packed, high hydrostatic pressure (HHP) treated at 600 or 200 MPa for 5 min and stored at 4 °C for up to 40 days. RESULTS: The surface redness (average a*) of the samples increased after dry brining, then decreased after liquid smoke treatment. HHP did not change the outside color of liquid-smoked samples. However, the inside color changed depending on pressure. HHP-treated control samples without dry brining and liquid smoking changed to a pale pink color. HHP at 600 MPa resulted in a significant increase in hardness. Compared with fresh samples, dry-brined samples had reduced water activity, while samples dipped in liquid smoke had lower pH values. CONCLUSION: Dry brining and liquid smoking protect the outside color of salmon against changes caused by HHP. The increase in hardness may counteract the softening of the smoked salmon tissue over time.

A practical and successful desensitization protocol for immediate hypersensitivity reactions to iron salts.

Orally administered iron salts (OAS) are widely used in the management of iron deficiency anemia and hypersensitivity reactions to OAS are not common. If an offending drug is the sole option or is significantly more effective than its alternatives, it can be readministered by desensitization. The oral desensitization protocols for iron published so far concern either desensitization that was completed only over a long period or did not attain the recommended therapeutic dose. We aimed to develop a more effective protocol. We report here on 2 patients who experienced hypersensitivity reactions to OAS. After confirming the diagnosis, both patients were desensitized to oral ferrous (II) glycine sulfate complex according to a 2-day desensitization protocol. A commercial suspension of oral ferrous glycine sulfate, which contains 4 mg of elemental iron in 1 ml, was preferred. We started with a dose as low as 0.1 ml from a 1/100 dilution (0.004 mg elemental iron) of the original suspension and reached the maximum effective dose in 2 days. Both patients were successfully desensitized and they went on to complete the 6-month iron treatment without any adverse effects. Although hypersensitvity reactions to iron are not common, there is no alternative for iron administration. Therefore, desensitization has to be the choice. This easy desensitization protocol seems to be a promising option.

[Post-vaccination granulomas caused by delayed-type reaction to aluminum salts]. / Impfgranulom bei Spättypallergie gegen Aluminiumsalze.

BACKGROUND: Aluminium salts are common adjuvants in all established inactivated vaccines. They are necessary to activate the humoral immune system. In the 1990s a Swedish study on an acellular vaccination against pertussis was started. Until 2013, 745 of 760,000 children with pruritic subcutaneous nodules were identified. In 77 % of these children a contact allergy to aluminium could be proven. Contact allergy to aluminium induced by vaccines causes pruritic subcutaneous nodules at the vaccination site. During infections of the upper respiratory tract the pruritus often escalates with inflammatory, erythematous and urticarial plaques. CONCLUSIONS: The use of solutions containing aluminium salts for specific immunotherapy is contraindicated in the case of contact allergy to aluminium. Intramuscular injections of inactivated vaccines can be employed to avoid granuloma formation.

The epidermal growth factor receptor is involved in angiotensin II but not aldosterone/salt-induced cardiac remodelling.

Experimental and clinical studies have shown that aldosterone/mineralocorticoid receptor (MR) activation has deleterious effects in the cardiovascular system; however, the signalling pathways involved in the pathophysiological effects of aldosterone/MR in vivo are not fully understood. Several in vitro studies suggest that Epidermal Growth Factor Receptor (EGFR) plays a role in the cardiovascular effects of aldosterone. This hypothesis remains to be demonstrated in vivo. To investigate this question, we analyzed the molecular and functional consequences of aldosterone exposure in a transgenic mouse model with constitutive cardiomyocyte-specific overexpression of a mutant EGFR acting as a dominant negative protein (DN-EGFR). As previously reported, Angiotensin II-mediated cardiac remodelling was prevented in DN-EGFR mice. However, when chronic MR activation was induced by aldosterone-salt-uninephrectomy, cardiac hypertrophy was similar between control littermates and DN-EGFR. In the same way, mRNA expression of markers of cardiac remodelling such as ANF, BNF or ß-Myosin Heavy Chain as well as Collagen 1a and 3a was similarly induced in DN-EGFR mice and their CT littermates. Our findings confirm the role of EGFR in AngII mediated cardiac hypertrophy, and highlight that EGFR is not involved in vivo in the damaging effects of aldosterone on cardiac function and remodelling.

The effect of chemical treatment on reduction of aflatoxins and ochratoxin A in black and white pepper during washing.

The effect of 18 different chemicals, which included acidic compounds (sulfuric acid, chloridric acid, phosphoric acid, benzoic acid, citric acid, acetic acid), alkaline compounds (ammonia, sodium bicarbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide), salts (acetate ammonium, sodium bisulfite, sodium hydrosulfite, sodium chloride, sodium sulfate) and oxidising agents (hydrogen peroxide, sodium hypochlorite), on the reduction of aflatoxins B(1), B(2), G(1) and G(2) and ochratoxin A (OTA) was investigated in black and white pepper. OTA and aflatoxins were determined using HPLC after immunoaffinity column clean-up. Almost all of the applied chemicals showed a significant degree of reduction on mycotoxins (p < 0.05). The lowest and highest reduction of aflatoxin B(1), which is the most dangerous aflatoxin, was 20.5% ± 2.7% using benzoic acid and 54.5% ± 2.7% using sodium hydroxide. There was no significant difference between black and white peppers (p < 0.05).

Lack of salicylic acid in Arabidopsis protects plants against moderate salt stress.

Previous studies showed that salicylic acid (SA)-deficient transgenic Arabidopsis expressing the salicylate hydroxylase gene NahG had a higher tolerance to moderate salt stress. SA may potentiate the stress response of germination and growth of Arabidopsis seedlings by inducing reactive oxygen species (ROS). However, the detailed mechanism for a better adaption of NahG plants to moderate salt stress is largely unknown. In the present study we found that a higher GSH/GSSG (glutathione/oxidized glutathione) ratio and ASA/DHA (ascorbic acid/dehydroascorbate) ratio in NahG plants during the stress may be the key reason for their stress-tolerance advantage. NahG plants actually could not produce more active antioxidant enzymes than the wild-type ones under natural conditions, but maintain higher activities of glutathione reductase (GR) and dehydroascorbate reductase (DHAR) during the stress. Hereby, the reduced glutathione and reduced ascorbic acid contents are higher in NahG plants under salt stress. However, NahG plants do not adapt better under severe salt stress. All antioxidant enzyme activities, GSH/GSSG ratio and ASA/DHA ratio declined substantively at 400 mM NaCl stress in both NahG and wild-type seedlings.

[The therapeutic effect of nanometer silver impregnated dressing on gunshot wounds after being immersed in brine and tapwater in rabbits].

OBJECTIVE: To investigate the therapeutic effect of nanometer silver impregnated dressing on gunshot wounds after being immersed in brine and tapwater in rabbits. METHODS: Rabbits were randomly divided into two groups after receiving gunshot wounds in both lower limbs. In group 1, the wounded limbs on the experimental side were immersed in brine for 5 h; in group 2, the wounded limbs on experimental side were immersed in tapwater for 5 h. All the wounds were treated with nanometer silver impregnated dressing on the experimental sides, while those of the control sides were treated with vaseline dressing. Biopsy was done after 30 min and 1, 2, 3, 4, 5 h, respectively. RESULTS: In group 1, the onset of inflammation around the wounds of the experimental sides was delayed, the inflammatory response was less serious, and the wounds were dry with less exudation compared to the controls. The mean healing time of the entry wounds on experimental and control sides was (29.4 +/- 6.6) d and (36.3 +/- 6.0) d (P < 0.01), respectively, and that of the exit wounds on experimental and control sides was (20.1 +/- 6.0) d and (27.3 +/- 5.7) d (P < 0.01), respectively. In group 2, only one of the experimental wounds showed mild inflammation, while all of the control wounds showed serious inflammation with much exudation. The mean healing time of the entry wounds on experimentsides was (13.0 +/- 1.52) d, while that on control sides was (16.0 +/- 3.10) d (P < 0.01). The mean healing time of exit wounds on experimental sides was (11.0 +/- 2.75) d, and those of the control sides was (15.6 +/- 2.85) d (P < 0.01). CONCLUSION: The nanometer silver impregnated dressing can control infection and accelerate healing in gunshot wounds in rabbits.

Human stratum corneum adsorption of nickel salts. Investigation of depth profiles by tape stripping in vivo.

Sequential adhesive tape stripping was implemented to characterize the penetration of nickel salts in human stratum corneum. Exposure areas of the salts in methanol applied open on arm and back skin in low volume were stripped 20 times to the level of the glistening layer at intervals of 30 min to 24 h post-dosing, and the strips analyzed for metal content by inductively coupled plasma-atomic emission spectroscopy. In the case of nickel chloride, sulfate, nitrate and acetate, material left on the skin surface, the depth-penetration profiles in the stratum corneum, and the dosage unaccounted for suggest the following conclusions: (a) Up to 24 h, most of the nickel dose applied remains on the skin surface or is adsorbed in the uppermost layers of the stratum corneum. (b) At higher concentrations, incomplete material recovery becomes discernible; within 24 h, nickel salts thus appear to penetrate beyond the stratum corneum to a minor degree, possibly via the skin shunts. (c) While the concentration gradients of nickel adsorbed vary with counter ion, anatomical site, dose and exposure time, for all variables tested the depth profiles converge to non-detectable levels (< 20 ppb) towards the level of the glistening layer. A notable exception is nickel as nitrate, for which levels continue at low but constant levels (1% of dose) beyond the third stratum corneum strip, indicative of intercellular diffusion. (d) Differences in material recovered suggest that the stratum corneum on the arm is more penetrable to nickel than stratum corneum on the back. (e) The counter ion in nickel salts plays a major part in their diffusion into the stratum corneum, suggestive of ion pairing. Overall, the data point to all three avenues of skin penetration by nickel: intracellular, intercellular, and transappendageal.

Human adrenomedullin gene delivery protects against cardiac hypertrophy, fibrosis, and renal damage in hypertensive dahl salt-sensitive rats.

Adrenomedullin (AM) is a potent vasodilator expressed in tissues relevant to cardiac and renal functions. Our previous study showed that delivery of the human AM gene in the form of naked DNA caused a prolonged reduction of blood pressure in genetically hypertensive rats. In this study, we evaluated potential protective effects of adenovirus-mediated AM gene delivery on salt-induced cardiorenal lesions in hypertensive Dahl saltsensitive (DSS) rats. Adenovirus carrying the human AM cDNA under the control of the cytomegalovirus promoter-enhancer (Ad.CMV-hAM) was generated by homologous recombination of E. coli. Expression of recombinant human AM was detected by a radioimmunoassay in the medium of human embryonic kidney 293 cells transfected with Ad.CMV-hAM. A single intravenous injection of Ad.CMV-hAM caused a significant reduction of systolic blood pressure for 4 weeks in DSS rats compared with control rats with or without injection of adenovirus carrying the green fluorescent protein gene. AM gene delivery significantly reduced left ventricular mass and urinary protein, increased cAMP levels, and enhanced renal function as evidenced by increases in glomerular filtration rate and renal blood flow. Morphological investigations showed that AM gene transfer reduced cardiomyocyte diameter and interstitial fibrosis in the heart as well as glomerular sclerosis, tubular disruption, and protein cast accumulation in the kidney. Expression of human AM mRNA was identified in rat heart, kidney, lung, liver, and aorta, and immunoreactive human AM levels were measured in rat plasma and urine. These results indicate that human AM gene delivery protects against salt-induced hypertension and cardiac and renal lesions in DSS rats via activation of cAMP as a second messenger. These findings provide new insights into the role of AM in salt-induced hypertension and may have implications in therapeutic applications to salt-related cardiovascular and renal diseases.

Exposure-effect relationship of platinum salt allergy in a catalyst production plant: conclusions from a 5-year prospective cohort study.

BACKGROUND: There is a high incidence of occupational asthma and rhinitis caused by platinum (Pt) salts in precious-metal refineries. OBJECTIVE: We sought to assess exposure to Pt salts and the incidence of Pt salt allergy in a catalyst production plant. METHODS: A 5-year prospective cohort study was performed in 159 catalyst production workers (94.6% of recruited), 50 craftsmen (92. 6% of recruited), and 66 control subjects (76.7% of recruited) at yearly intervals. Subjects were assigned to exposure categories of high levels of Pt (n = 115), persistently low levels of Pt (n = 51), intermittently low levels of Pt (n = 61), or no Pt (n = 48) after the initial survey according to job title and job location. Skin prick test conversion from a negative response to a 4 mm or larger wheal response with a 10(-2) mol/L hexachloroplatinic acid solution was chosen as the outcome variable. RESULTS: Exposure assessment of airborne Pt and Pt in the serum of workers demonstrated clear differences between exposure categories. The threshold limit value of 2 microg/m(3) for soluble Pt was exceeded in 3 (4%) of 78 measurements. Thirteen subjects assigned to high exposure showed skin test conversion, and new allergic symptoms were associated with exposure. Among the high-exposure category, the incidence rate of skin prick test conversion was 5.9 per 100 person-years for newly employed subjects (n = 79) and 2.1 per 100 person-years for those who had already been employed at the time of the initial survey (n = 36). A predicting factor for skin test conversion in highly exposed subjects was smoking status (relative risk, 3.9; 95% confidence interval, 1.6-9.7) but not atopy or bronchial hyperresponsiveness. CONCLUSION: Sensitization to Pt salts may develop in workers of catalyst production plants. Both the exposure to Pt salts and the incidence of Pt salt allergy were lower compared with reported data from precious-metal refineries.

Respiratory health effects of alkali dust in residents near desiccated Old Wives Lake.

Several years of drought have contributed to the desiccation of Old Wives Lake, a shallow, alkaline lake in southern Saskatchewan. The prevailing northwest wind, which blows across the 177-km2 dry lake bed, has generated airborne sodium sulfate, silt, and clay. Residents have reported nasal, eye, and respiratory irritation. A cross-sectional design that included 300 controls and 300 exposed subjects elucidated the potential adverse respiratory health effects of exposure to blowing alkali salt and dust. An increased prevalence of current cough, current wheeze, chronic cough, chronic wheeze, chronic eye irritation, and chronic nasal irritation was identified in the exposed population. Smoking-adjusted odds ratios were consistent with the prevalence ratios. Lung function did not differ between the exposed and the control populations. Rainfall during the study period reduced airborne dust levels and may have precluded demonstration of previously reported adverse effects.