HIV-Associated Hypertension: Risks, Mechanisms, and Knowledge Gaps.

HIV type 1 (HIV-1) is the causative agent of AIDS. Since the start of the epidemic, HIV/AIDS has been responsible for ≈40 million deaths. Additionally, an estimated 39 million people are currently infected with the virus. HIV-1 primarily infects immune cells, such as CD4+ (cluster of differentiation 4+) T lymphocytes (T cells), and as a consequence, the number of CD4+ T cells progressively declines in people living with HIV. Within a span of ≈10 years, HIV-1 infection leads to the systemic failure of the immune system and progression to AIDS. Fortunately, potent antiviral therapy effectively controls HIV-1 infection and prevents AIDS-related deaths. The efficacy of the current antiviral therapy regimens has transformed the outcome of HIV/AIDS from a death sentence to a chronic disease with a prolonged lifespan of people living with HIV. However, antiviral therapy is not curative, is challenged by virus resistance, can be toxic, and, most importantly, requires lifelong adherence. Furthermore, the improved lifespan has resulted in an increased incidence of non-AIDS-related morbidities in people living with HIV including cardiovascular diseases, renal disease, liver disease, bone disease, cancer, and neurological conditions. In this review, we summarize the current state of knowledge of the cardiovascular comorbidities associated with HIV-1 infection, with a particular focus on hypertension. We also discuss the potential mechanisms known to drive HIV-1-associated hypertension and the knowledge gaps in our understanding of this comorbid condition. Finally, we suggest several directions of future research to better understand the factors, pathways, and mechanisms underlying HIV-1-associated hypertension in the post-antiviral therapy era.

On the identification of hyperhydrated sodium chloride hydrates, stable at icy moon conditions.

Sodium chloride is expected to be found on many of the surfaces of icy moons like Europa and Ganymede. However, spectral identification remains elusive as the known NaCl-bearing phases cannot match current observations, which require higher number of water of hydration. Working at relevant conditions for icy worlds, we report the characterization of three "hyperhydrated" sodium chloride (SC) hydrates, and refined two crystal structures [2NaCl·17H2O (SC8.5); NaCl·13H2O (SC13)]. We found that the dissociation of Na+ and Cl- ions within these crystal lattices allows for the high incorporation of water molecules and thus explain their hyperhydration. This finding suggests that a great diversity of hyperhydrated crystalline phases of common salts might be found at similar conditions. Thermodynamic constraints indicate that SC8.5 is stable at room pressure below 235 K, and it could be the most abundant NaCl hydrate on icy moon surfaces like Europa, Titan, Ganymede, Callisto, Enceladus, or Ceres. The finding of these hyperhydrated structures represents a major update to the H2O-NaCl phase diagram. These hyperhydrated structures provide an explanation for the mismatch between the remote observations of the surface of Europa and Ganymede and previously available data on NaCl solids. It also underlines the urgent need for mineralogical exploration and spectral data on hyperhydrates at relevant conditions to help future icy world exploration by space missions.

Early Low-Grade Inflammation Induced by High-Salt Diet in Sprague Dawley Rats Involves Th17/Treg Axis Dysregulation, Vascular Wall Remodeling, and a Shift in the Fatty Acid Profile.

BACKGROUND/AIMS: Unrestricted increased table salt (NaCl) intake is associated with oxidative stress and inflammation, leading to endothelial dysfunction and atherosclerosis. However, data on salt-induced immunomodulatory effects in the earliest phase of salt loading are scarce. METHODS: In the present study, an animal model of short-term salt loading was employed, including male Sprague Dawley rats consuming a high-salt diet (HSD; 4% NaCl) or standard laboratory chow (low-salt; LSD; 0.4% NaCl) during a 7-day period. The contribution of angiotensin II (ANGII) suppression was tested by adding a group of rats on a high-salt diet receiving ANGII infusions. Samples of peripheral blood/mesenteric lymph node leukocytes, brain blood vessels, and serum samples were processed for flow cytometry, quantitative real-time PCR, total proteome analysis, and multiplex immunoassay. RESULTS: Data analysis revealed the up-regulation of Il 6 gene in the microcirculation of high-salt-fed rats, accompanied by an increased serum level of TNF-alpha cytokine. The high-salt diet resulted in increased proportion of serum mono-unsaturated fatty acids and saturated fatty acids, reduced levels of linoleic (C18:2 ω-6) and α-linolenic (C18:3 ω-3) acid, and increased levels of palmitoleic acid (C16:1 ω-7). The high-salt diet had distinct, lymphoid compartment-specific effects on leukocyte subpopulations, which could be attributed to the increased expression of salt-sensitive SGK-1 kinase. Complete proteome analysis revealed high-salt-diet-induced vascular tissue remodeling and perturbations in energy metabolism. Interestingly, many of the observed effects were reversed by ANGII supplementation. CONCLUSION: Low-grade systemic inflammation induced by a HSD could be related to suppressed ANGII levels. The effects of HSD involved changes in Th17 and Treg cell distribution, vascular wall remodeling, and a shift in lipid and arachidonic acid metabolism.

The sodium-chloride difference: A marker of prognosis in patients with acute myocardial infarction.

BACKGROUND: The difference between serum sodium and chloride ion concentrations (SCD) may be considered as a surrogate of a strong ion difference and may help to identify patients with a worse prognosis. We aimed to assess SCD as an early prognostic marker among patients with myocardial infarction. METHODS: Data of 594 consecutive patients with acute myocardial infarction treated with PCI (44.9% STEMI patients; 70.7% males) was analysed for SCD in relation to their 30-day mortality. A restricted cubic spline regression model was used to study the relationship between mortality and SCD. Cox regression models were used to assess the association between SCD and the mortality risk. RESULTS: Patients with Killip class ≥3 had lower SCD values in comparison to patients with Killip class ≤2: (32.0 [30.0-34.0] vs. 33.0 [31.0-36.0], p = .006). The overall 30-day mortality was 7.7% (n = 46). There was a significant difference in SCD values between survivors and non-survivors groups of patients (median (IQR): (33.0 [31.0-36.0] vs. 31.5 [28.0-34.0] (mmol/L), p = .002). The restricted cubic splines model confirmed a non-linear association between SCD and mortality. Patients with SCD <30 mmol/L (in comparison to SCD ≥30 mmol/L) had an increased mortality risk (unadjusted HR 2.92, 95% CI 1.59-5.36, p = .001; and an adjusted HR 2.30, 95% CI 1.02-5.19, p = .04). CONCLUSIONS: Low SCD on admission is associated with an increased risk of 30-day mortality in patients with acute myocardial infarction treated with PCI and may serve as a useful prognostic marker for these patients.

The IFNγ-PDL1 Pathway Enhances CD8T-DCT Interaction to Promote Hypertension.

BACKGROUND: Renal T cells contribute importantly to hypertension, but the underlying mechanism is incompletely understood. We reported that CD8Ts directly stimulate distal convoluted tubule cells (DCTs) to increase NCC (sodium chloride co-transporter) expression and salt reabsorption. However, the mechanistic basis of this pathogenic pathway that promotes hypertension remains to be elucidated. METHODS: We used mouse models of DOCA+salt (DOCA) treatment and adoptive transfer of CD8+ T cells (CD8T) from hypertensive animals to normotensive animals in in vivo studies. Co-culture of mouse DCTs and CD8Ts was used as in vitro model to test the effect of CD8T activation in promoting NCC-mediated sodium retention and to identify critical molecular players contributing to the CD8T-DCT interaction. Interferon (IFNγ)-KO mice and mice receiving renal tubule-specific knockdown of PDL1 were used to verify in vitro findings. Blood pressure was continuously monitored via radio-biotelemetry, and kidney samples were saved at experimental end points for analysis. RESULTS: We identified critical molecular players and demonstrated their roles in augmenting the CD8T-DCT interaction leading to salt-sensitive hypertension. We found that activated CD8Ts exhibit enhanced interaction with DCTs via IFN-γ-induced upregulation of MHC-I and PDL1 in DCTs, thereby stimulating higher expression of NCC in DCTs to cause excessive salt retention and progressive elevation of blood pressure. Eliminating IFN-γ or renal tubule-specific knockdown of PDL1 prevented T cell homing into the kidney, thereby attenuating hypertension in 2 different mouse models. CONCLUSIONS: Our results identified the role of activated CD8Ts in contributing to increased sodium retention in DCTS through the IFNγ-PDL1 pathway. These findings provide a new mechanism for T cell involvement in the pathogenesis of hypertension and reveal novel therapeutic targets.

Adding salt to food at table as an indicator of gastric cancer risk among adults: a prospective study.

BACKGROUND: While dietary salt intake has been linked with gastric cancer risk in Asian studies, findings from Western populations are sparse and limited to case-control studies. Our aim was to evaluate the frequency of adding salt to food at table in relation to gastric cancer risk among UK adults. METHODS: We evaluated associations between the frequency of adding salt to food and the risk of gastric cancer in the UK Biobank (N = 471,144) using multivariable Cox regression. Frequency of adding salt to food was obtained from a touchscreen questionnaire completed at baseline (2006-2010). 24-h urinary sodium excretion was estimated using INTERSALT formulae. Cancer incidence was obtained by linkage to national cancer registries. RESULTS: During a median follow-up period of 10.9 years, 640 gastric cancer cases were recorded. In multivariable models, the gastric cancer risk among participants reporting adding salt to food at table "always" compared to those who responded "never/rarely" was HR = 1.41 (95% CI: 1.04, 1.90). There was a positive linear association between estimated 24-h urinary sodium levels and the frequency of adding salt to food (p-trend <0 .001). However, no significant association between estimated 24-h urinary sodium with gastric cancer was observed (HR = 1.19 (95% CI: 0.87, 1.61)). CONCLUSIONS: "Always adding salt to food" at table was associated with a higher gastric cancer risk in a large sample of UK adults. High frequency of adding salt to food at table can potentially serve as a useful indicator of salt intake for surveillance purposes and a basis for devising easy-to-understand public health messages.

Effect of transporting Oreochromis niloticus in water with and without sodium chloride on skin morphology and some immunity-related genes expression.

The aim of this study was to examine the effects of salt addition on the skin gene expression of Mucin, Antimicrobial peptides, cortisol, and glucose in Oreochromis niloticus after 5-hour transportation in water. Three groups were compared: Control, post-transport without salt (PT-S), and post-transport with 5 g salt-1(PT + S), with a stocking density of 28.6 gL-1, 20 fish for each experimental group. The results showed that the PT-S group had more significant changes in gene expression than the PT + S group, suggesting that salt alleviated the stress and immune responses of O. niloticus. The PT-S group had higher expression of mucin- 2(MUC + 2) (7.58 folds) and mucin-5AC (MUC5-AC) (6.29 folds) than the PT + S group (3.30 folds and 4.16 folds, respectively). The PT-S group also had lower expression of ß-defensin-1 (Dß1) (0.42 folds), ß-defensin-2 (Dß2) (0.29 folds), and Cath1 (0.16 folds) than the PT + S group (0.82 folds, 0.69 folds, and 0.75 folds, respectively). The skin morphology of the PT-S group revealed some white patches with no goblet cell openings, while the PT + S group had better preservation of skin features with some goblet cell openings and slight white patches. This study indicates that O. niloticus can benefit from sodium chloride during transportation, as it helps to reduce stress and inflammation, balance mineral levels, enhance health and immunity, and regulate mucous secretion.

The potential for current sodium and potassium production to support a global switch to the use of potassium-enriched salt: a desktop research study.

OBJECTIVE: Switching regular salt (sodium chloride) to salt enriched with potassium chloride (25 % potassium chloride, 75 % sodium chloride) has been shown to reduce blood pressure and the risk of cardiovascular diseases. We sought to define the potential for the current production of sodium chloride and potassium chloride to support a global switch to the use of potassium-enriched salt. DESIGN: We summarised data from geological surveys, government reports and trade organisations describing the global production and supply of sodium chloride and potash (the primary source of potassium chloride) and compared this to potential requirements for potassium-enriched salt. SETTING: Global. PARTICIPANTS: Not applicable. RESULTS: Approximately 280 million tonnes of sodium chloride were produced in 2020 with China and the USA the main producers. Global production of potash from which potassium chloride is extracted was about forty-four million tonnes with Canada, Belarus, Russia and China providing 77 % of the world's supply. There were forty-eight countries in which potassium-enriched salt is currently marketed with seventy-nine different brands identified. Allowing for loss of salt between manufacture and consumption, a full global switch from regular salt to potassium-enriched salt would require about 9·7 million tonnes of sodium chloride to be replaced with 9·7 million tonnes of potassium chloride annually. CONCLUSIONS: Significant upscaling of the production of potassium chloride and the capacity of companies able to manufacture potassium-enriched salt, as well as a robust business case for the switch to potassium chloride, would be required.

Effects of Balanced Versus Saline-based Solutions on Acute Kidney Injury in Off-pump Coronary Artery Bypass Surgery: A Randomized Controlled Trial.

OBJECTIVES: To determine whether balanced solutions can reduce the incidence of acute kidney injury after off-pump coronary artery bypass surgery compared with saline. DESIGN: Randomized controlled trial. SETTING: Single tertiary care center. PARTICIPANTS: Patients who underwent off-pump coronary artery bypass surgery between June 2014 and July 2020. INTERVENTIONS: Balanced solution-based chloride-restrictive intravenous fluid strategy. MEASUREMENTS AND MAIN RESULTS: The primary outcome was acute kidney injury within 7 postoperative days, as defined by the 2012 Kidney Disease: Improving Global Outcomes Clinical Practice Guideline. The incidence of acute kidney injury was 4.4% (8/180) in the balanced group and 7.3% (13/178) in the saline group. The difference was not statistically significant (risk difference, -2.86%; 95% confidence interval [CI], -7.72% to 2.01%; risk ratio, 0.61, 95% CI, 0.26 to 1.43; p = 0.35). Compared with the balanced group, the saline group had higher levels of intraoperative serum chloride and lower base excess, which resulted in a lower pH. CONCLUSIONS: In patients undergoing off-pump bypass surgery with a normal estimated glomerular filtration rate, the intraoperative balanced solution-based chloride-restrictive intravenous fluid administration strategy did not decrease the rate of postoperative acute kidney injury compared with the saline-based chloride-liberal intravenous fluid administration strategy.

Vitamin D is involved in the regulation of Cl- uptake in zebrafish (Danio rerio).

Cl- is a major anion in the bodily fluids of vertebrates, and maintaining its homeostasis is essential for normal physiological functions. Fishes inhabiting freshwater (FW) passively lose body fluid ions, including Cl-, to the external environment because of the electrochemical gradient of ions across the body surface. Therefore, FW fishes have to actively absorb Cl- from the surroundings to maintain ion homeostasis in their bodily fluids. Hormonal control is vital for modulating ion uptake in fish. Vitamin D is involved in the regulation of Ca2+ uptake and acid secretion in fish. In the present study, we found that the levels of bioactive vitamin D, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), significantly increased in zebrafish embryos and adults after exposure to water containing low levels of Cl-. Moreover, the administration of 1α,25(OH)2D3 treatment (20 µg/L) in zebrafish embryos, and intraperitoneal (i.p.) injection of 1α,25(OH)2D3 (5 µg/kg body mass) in zebrafish adults, resulting the increased Cl- content in bodily fluid in zebrafish. Na+-Cl- cotransporter 2b (NCC2b) and Cl- channel 2c (CLC2c) are specifically expressed during Cl- uptake by ionocytes in zebrafish. Our results indicated that the mRNA and protein expression of NCC2b and CLC2c considerably increased in the zebrafish with exogenous 1α,25(OH)2D3 treatment. Additionally, exogenous 1α,25(OH)2D3 administration increased the number of NCC2b- and CLC2c-expressing cells in yolk skins of zebrafish embryos and the gill filaments of zebrafish adults. Transcript signals of vitamin D receptors (VDRs) were identified in NCC2b-expressing cells. Knockdown of VDRa and VDRb significantly reduced the expression of NCC2b and CLC2c and the number of NCC2b- and CLC2c-expressing cells. These results indicate that vitamin D can affect Cl- uptake in zebrafish and extend our knowledge of the role of vitamin D in fish physiology.

Effect of Temperature and Salinity on Survival of Protoscoleces of Hydatid Cyst in Liver In Vitro.

Hydatid cyst is the metacestode stage of Echinococcus granulosus that occurs in herbivores and humans as intermediate hosts by consuming parasite eggs through forage and vegetables. Carnivores, as definitive hosts, become infected by consuming infected vesicles of herbivores. The most effective treatment for a hydatid cyst is surgical operation. Inactivating E. granulosus protoscoleces through heating, cooling, or chemicals such as sodium chloride can be considered an effective method for controlling hydatidosis in both humans and animals. The main objective of this study was to evaluate the effect of different temperatures and salinity conditions on the survival of Echinococcus granulosus protoscoleces. For this purpose, 50 g of infected liver (in triplicate) was separately treated with different temperatures (+10°C, +50°C, +60°C, +72°C, and -20°C) and concentrations of sodium chloride (5%, 10%, 15%, and 20%) for 3, 6, 12, 24, 48, and 72 h. Additionally, 50 g of infected liver was stored separately in the refrigerator (+4°C) as a control group. The survival rate of the protoscoleces was evaluated by staining with 1% eosin under a light microscope. The results showed that the protoscoleces were significantly affected, with 100% mortality at -20°C after 0.5 h, and complete death at +72°C, +60°C, +50°C, and +10°C after 1, 1.5, 3, and 24 h, respectively (p < 0.005). Similarly, the protoscoleces in the liver mass survived at 5% NaCl after 3 h but died at 10% after 24 h, at 15% after 12 h, and at 20% after 6 h. It is concluded that exposing the liver infected with protoscoleces hydatid cyst to a temperature of -20°C and a sodium chloride concentration of 10% for 24 h is suitable for inactivating the protoscoleces.

Spatial, temporal, and biological factors influencing plant responses to deicing salt in roadside bioinfiltration basins.

Plants are arguably the most visible components of stormwater bioretention basins and play key roles in stabilizing soils and removing water through transpiration. In regions with cold winters, bioretention basins along roadways can receive considerable quantities of deicing salt, much of which migrates out of the systems prior to the onset of plant growth but the rest remains in the soil. The resulting effects on plants presumably vary with time (due to annual weather patterns), space (because stormwater exposure is location-dependent), and biology (because plant taxa differ in their salt tolerance). The goal of this study was to investigate the magnitude of deicing salt's effects on bioretention plants and how it varies with spatial, temporal, and biological factors. The study took place in a set of five bioretention basins in Philadelphia, USA that receive runoff from a major highway. Over a five-year period, the electrical conductivity (EC) of influent stormwater frequently exceeded 1 mS cm-1 in winter, and occasionally surpassed that of seawater (∼50 mS cm-1). In both of the years when soil EC was measured as well, it remained elevated through all spring months, especially near basin inlets and centers. Mortality of nine plant taxa ranged widely after three years (0-90%), with rankings largely corresponding to salt tolerances. Moreover, leaf areas and/or crown volumes were strongly reduced in proportion to stormwater exposure in seven of these taxa. In the three taxa evaluated for tissue concentrations of 14 potentially toxic elements (Hemerocallis 'Happy Returns', Iris 'Caesar's Brother', and Cornus sericea 'Cardinal'), only sodium consistently exceeded the toxicity limit for salt intolerant plants (500 mg kg-1). However, exceedance of the sodium toxicity limit was associated with plants' topographic positions, with median concentrations greatest in the bottom of basins and least on basin rims. This study demonstrates that deicing salts can have detrimental effects on plants in bioretention basins, with the strongest effects likely to occur in years with the greatest snowfall (and therefore deicing salt use), in portions of basins with greatest stormwater exposure (typically around inlets and centers), and in plants with minimal salinity tolerance. Our results therefore underscore the value of installing salt-tolerant taxa in basins likely to experience any frequency of deicing salt exposure.

Effect of processing (cutter versus continuous emulsifier) and sodium reduction on the physicochemical properties of bologna sausages.

BACKGROUND: Overcoming the impact of sodium reduction in the properties of emulsified sausages is a current challenge in the production of healthier meat products. Because the emulsifying process play a key role in the stability of sausages, the present study aimed to evaluate the effects of two mechanical emulsifying systems (cutter versus continuous emulsifier) and two levels of sodium chloride (2.50 and 1.25%) on the physicochemical characteristics of bologna sausages. RESULTS: A reduction of sodium increased the L* value and reduced the a* value, and also decreased the protein extraction yield in sausages produced in the cutter system. Moreover, the emulsion stability of reduced sodium batter was increased by cutter emulsification (F50C). On the other hand, the continuous emulsifier process did not decrease the extraction of myofibrillar proteins in F50E (sodium reduced treatment), resulting in minimal impact on emulsion stability and an increase in hardness in reduced-sodium sausages. CONCLUSION: Therefore, to produce low-sodium sausages, the continuous emulsifier was more effective producing batters with increased extracted myofibrillar proteins, improving the structure and functionality of myofibrillar proteins compared to the cutter process. © 2023 Society of Chemical Industry.

Effects of pH and salt concentration on freeze-thaw fractionation of soymilk protein.

BACKGROUND: The two major storage proteins of soymilk are the globulins 7S and 11S. Freeze-thaw fractionation is a simple method for separating these proteins in raw soymilk. In this study, we assessed the freeze-thaw fractionation ability of raw soymilk under various pH (4.3-11.6) conditions and added salt (sodium chloride) concentrations (0.00-0.67 mol L-1). RESULTS: We successfully achieved fractionation within a pH range of 5.8-6.7 and when the salt concentration was 0.22 mol L-1 or lower. Analysis of particle size distribution and microscopic examination of soymilk revealed no direct correlation between particle size and freeze-thaw fractionation ability. Interestingly, it was confirmed that the ranges of zeta potential values associated with successful freeze-thaw fractionation in raw soymilk remained consistent across different pH and salt concentration conditions. These ranges were between -23 and -28 mV at pH levels ranging from 5.8 to 6.7 and between -18 and -29 mV at added salt concentrations ranging from 0 to 0.22 mol L-1. CONCLUSION: The pH and salt concentration in raw soymilk markedly influence the freeze-thaw fractionation process. We confirmed that the range of zeta potential values where fractionation was possible remained consistent under various pH and salt concentration conditions. These findings suggest that the zeta potential value might serve as an indicator for evaluating the freeze-thaw fractionation ability of raw soymilk. © 2024 Society of Chemical Industry.

Comparative analysis of tracer studies in the determination of longitudinal dispersion coefficient.

The research presented in this paper is to determine the best tracer studies that will give acceptable estimates of longitudinal dispersion coefficient for Orashi river using rhodamine WT dye and sodium chloride as water tracer. Estimated results obtained for longitudinal dispersion coefficient for the case of rhodamine WT experiment ranges between 71 and 104.4 m2s-1 while that of sodium chloride experiment ranges between 20.1 and 34.71 m2s-1. These results revealed lower dispersion coefficient using sodium chloride as water tracer (WT) indicating that for larger rivers, sodium chloride should not be used as water tracer. The usage of sodium chloride as water tracer in the estimation of longitudinal dispersion coefficient is recommended in smaller streams as NaCl is relatively conservative. The established equations for both cases of investigation are proving satisfactory upon validation as degree of accuracy of 100.0% was obtained using discrepancy ratio (Dr). Standard error (SE), normal mean error (NME) and mean multiplication error (MME) of the developed equations is better when compared with other existing equations. However, Equation (17) is satisfactorily recommended.

Characterizing the Stability of Angiotensin II in 0.9% Sodium Chloride Using High Performance Liquid Chromatography and Liquid Chromatography Tandem Mass Spectrometry.

Purpose: The purpose of this study was to evaluate the stability of angiotensin II in 0.9% sodium chloride for up to 5 days. Methods: We prepared angiotensin II dilutions, by aseptically diluting 2.5 mg (1 mL) in 249 mL 0.9% sodium chloride creating a solution of 10 000 ng/mL. Admixtures were stored under refrigeration (5 ± 3°C). Stability of the dilution was assessed by: preservation of clarity, consistency of pH, and retention of concentration. Solutions were sampled at times 0, 24, 48, 72, 96, 120 hours. Solutions were analyzed via High-Performance Liquid Chromatography (HPLC-UV) and Liquid Chromatography Mass Spectrometry (LC-MS/MS). Retention of concentration was set a priori at > 90% of initial concentration. Results: Clarity, color, and pH at all sample time points remained constant. Both methods of analysis confirmed similar results. When stored under refrigeration, the concentration of angiotensin II solution remained above 90% of initial concentration throughout the entire sampling period. Conclusions: Angiotensin II in 0.9% sodium chloride stored in infusion bags under refrigeration (5 ± 3°C) maintained at least 90% of their original concentrations for up to 5 days. Stability was also demonstrated based on turbidity, color, and pH assessment.

Salt-Induced Hepatic Inflammatory Memory Contributes to Cardiovascular Damage Through Epigenetic Modulation of SIRT3.

BACKGROUND: High salt intake is the leading dietary risk factor for cardiovascular diseases. Although clinical evidence suggests that high salt intake is associated with nonalcoholic fatty liver disease, which is an independent risk factor for cardiovascular diseases, it remains elusive whether salt-induced hepatic damage leads to the development of cardiovascular diseases. METHODS: Mice were fed with normal or high-salt diet for 8 weeks to determine the effect of salt loading on liver histological changes and blood pressure, and salt withdrawal and metformin treatment were also conducted on some high-salt diet-fed mice. Adeno-associated virus 8, global knockout, or tissue-specific knockout mice were used to manipulate the expression of some target genes in vivo, including SIRT3 (sirtuin 3), NRF2 (NF-E2-related factor 2), and AMPK (AMP-activated protein kinase). RESULTS: Mice fed with a high-salt diet displayed obvious hepatic steatosis and inflammation, accompanied with hypertension and cardiac dysfunction. All these pathological changes persisted after salt withdrawal, displaying a memory phenomenon. Gene expression analysis and phenotypes of SIRT3 knockout mice revealed that reduced expression of SIRT3 was a chief culprit responsible for the persistent inflammation in the liver, and recovering SIRT3 expression in the liver effectively inhibits the sustained hepatic inflammation and cardiovascular damage. Mechanistical studies reveal that high salt increases acetylated histone 3 lysine 27 (H3K27ac) on SIRT3 promoter in hepatocytes, thus inhibiting the binding of NRF2, and results in the sustained inhibition of SIRT3 expression. Treatment with metformin activated AMPK, which inhibited salt-induced hepatic inflammatory memory and cardiovascular damage by lowering the H3K27ac level on SIRT3 promoter, and increased NRF2 binding ability to activate SIRT3 expression. CONCLUSIONS: This study demonstrates that SIRT3 inhibition caused by histone modification is the key factor for the persistent hepatic steatosis and inflammation that contributes to cardiovascular damage under high salt loading. Avoidance of excessive salt intake and active intervention of epigenetic modification may help to stave off the persistent inflammatory status that underlies high-salt-induced cardiovascular damage in clinical practice.

Asparagine Uptake: a Cellular Strategy of Methylocystis to Combat Severe Salt Stress.

Methylocystis spp. are known to have a low salt tolerance (≤1.0% NaCl). Therefore, we tested various amino acids and other well-known osmolytes for their potential to act as an osmoprotectant under otherwise growth-inhibiting NaCl conditions. Adjustment of the medium to 10 mM asparagine had the greatest osmoprotective effect under severe salinity (1.50% NaCl), leading to partial growth recovery of strain SC2. The intracellular concentration of asparagine increased to 264 ± 57 mM, with a certain portion hydrolyzed to aspartate (4.20 ± 1.41 mM). In addition to general and oxidative stress responses, the uptake of asparagine specifically induced major proteome rearrangements related to the KEGG level 3 categories of "methane metabolism," "pyruvate metabolism," "amino acid turnover," and "cell division." In particular, various proteins involved in cell division (e.g., ChpT, CtrA, PleC, FtsA, FtsH1) and peptidoglycan synthesis showed a positive expression response. Asparagine-derived 13C-carbon was incorporated into nearly all amino acids. Both the exometabolome and the 13C-labeling pattern suggest that in addition to aspartate, the amino acids glutamate, glycine, serine, and alanine, but also pyruvate and malate, were most crucially involved in the osmoprotective effect of asparagine, with glutamate being a major hub between the central carbon and amino acid pathways. In summary, asparagine induced significant proteome rearrangements, leading to major changes in central metabolic pathway activity and the sizes of free amino acid pools. In consequence, asparagine acted, in part, as a carbon source for the growth recovery of strain SC2 under severe salinity. IMPORTANCE Methylocystis spp. play a major role in reducing methane emissions into the atmosphere from methanogenic wetlands. In addition, they contribute to atmospheric methane oxidation in upland soils. Although these bacteria are typical soil inhabitants, Methylocystis spp. are thought to have limited capacity to acclimate to salt stress. This called for a thorough study into potential osmoprotectants, which revealed asparagine as the most promising candidate. Intriguingly, asparagine was taken up quantitatively and acted, at least in part, as an intracellular carbon source under severe salt stress. The effect of asparagine as an osmoprotectant for Methylocystis spp. is an unexpected finding. It may provide Methylocystis spp. with an ecological advantage in wetlands, where these methanotrophs colonize the roots of submerged vascular plants. Collectively, our study offers a new avenue into research on compounds that may increase the resilience of Methylocystis spp. to environmental change.

Short-term high-salt consumption does not influence resting or exercising heart rate variability but increases MCP-1 concentration in healthy young adults.

High salt consumption increases blood pressure (BP) and cardiovascular disease risk by altering autonomic function and increasing inflammation. However, it is unclear whether salt manipulation alters resting and exercising heart rate variability (HRV), a noninvasive measure of autonomic function, in healthy young adults. The purpose of this investigation was to determine whether short-term high-salt intake 1) alters HRV at rest, during exercise, or exercise recovery and 2) increases the circulating concentration of the inflammatory biomarker monocyte chemoattractant protein 1 (MCP-1). With the use of a randomized, placebo-controlled, crossover study, 20 participants (8 females; 24 ± 4 yr old, 110 ± 10/64 ± 8 mmHg) consumed salt (3,900 mg sodium) or placebo capsules for 10 days each separated by ≥2 wk. We assessed HRV during 10 min of baseline rest, 50 min of cycling (60% V̇o2peak), and recovery. We quantified HRV using the standard deviation of normal-to-normal RR intervals, the root mean square of successive differences (RMSSD), and additional time and frequency domain metrics of HRV. Plasma samples were collected to assess MCP-1 concentration. No main effect of high salt or condition × time interaction was observed for HRV metrics. However, acute exercise reduced HRV (e.g., RMSSD time: P < 0.001, condition: P = 0.877, interaction: P = 0.422). High salt elevated plasma MCP-1 (72.4 ± 12.5 vs. 78.14 ± 14.7 pg/mL; P = 0.010). Irrespective of condition, MCP-1 was moderately associated (P values < 0.05) with systolic (r = 0.32) and mean BP (r = 0.33). Short-term high-salt consumption does not affect HRV; however, it increases circulating MCP-1, which may influence BP in young adults.

Oral Exposure to Sodium Chloride without Subsequent Consumption Does Not Alter Salt Taste Function in Adults: A Cross-Over Intervention Study.

BACKGROUND: Reduction in dietary sodium increases salt taste sensitivity; however, non-oral sodium supplementation does not, suggesting that oral exposure is more important for modulating taste perception than consumption without tasting. OBJECTIVE: Using psychophysical methods, we assessed the effect of a two-week intervention involving oral exposure to a tastant without consumption on modulating taste function. METHODS: In a cross-over intervention study, n = 42 adults (age, mean ± SD: 29.7 ± 8.0 years) completed 4 intervention treatments requiring participants to rinse their mouths with 30 mL of a tastant, 3 times daily for 2 weeks. Treatments included oral exposure to 400 mM sodium chloride (NaCl), monosodium glutamate (MSG), monopotassium glutamate, and sucrose. Participants' taste function for salty, umami, and sweet [detection threshold (DT), recognition threshold (RT), and suprathreshold (ST)], and the glutamate-sodium discrimination status was evaluated before and after the tastant treatments. Effects of the interventions on taste function were assessed by using linear mixed models including treatment, time, and treatment x time interactions as fixed effects; significance was set at P > 0.05. RESULTS: There was no treatment × time interaction on DT and RT for all tastes assessed (P > 0.05). The only change in ST was following the NaCl intervention, participants' salt ST decreased at the highest concentration (400 mM) compared with the pre-NaCl treatment taste assessment (mean difference (MD): -0.052 [95% CI: -0.093, -0.010] labeled magnitude scale, P = 0.016). Compared with the pre-MSG treatment taste assessment, participants improved their ability to perform the glutamate-sodium discrimination task after the MSG intervention (MD:1.64 [95% CI: 0.395, 2.878] correct discrimination tasks, P = 0.010). CONCLUSION: Saltiness of an adult's free-living diet is unlikely to influence salt taste function, as oral exposure without consumption to a salt concentration greater than normally found in food, only attenuated taste responses to highly salty stimuli. This provides preliminary evidence that regulating salt taste function may require a coordinated response between oral activation and consumption of sodium.