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[This corrects the article DOI: 10.3389/fcell.2021.646575.].
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Cancer chemotherapy remains an area of concern, as many of the therapies are uncomfortable involving side effects and unpleasant experiences. These factors could further reduce patient's quality of life, and even endanger their life. Many therapeutic strategies have been tried to reduce the unpleasant side effects and increase the treatment effectiveness; however, none have shown to have promising effects. One of the main hindrances to cancer therapy is the escape strategies by tumor cells to the immune attack. Promoting inflammation in the tumor microenvironment is the cornerstone and key therapeutic target in cancer chemotherapy. High-salt diet (HSD) intake, though it has deleterious effects on human health by promoting chronic inflammation, is found to be advantageous in the tumor microenvironment. Studies identified HSD favors an increased abundance of Bifidobacterium species in the tumor environment due to gut barrier alteration, which, in turn, promotes inflammation and favors improved response to cancer chemotherapy. A review of the literature was carried out to find out the effects of an HSD on health and diseases, with special mention of its effect on cancer chemotherapy. Studies emphasized HSD would block the myeloid-derived suppressor cells which will enhance the tumor immunity. Exploration of the precise mechanism of simple HSD regime/ingestion of specific bacterial species as probiotics will be effective and essential to formulate the game-changing cancer chemotherapy. With the modern era of healthcare moving toward precision medicine where the physician can choose the treatment option suitable for the individual, HSD regime/ingestion of specific bacterial species can be considered.
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Cutaneous Leishmaniasis, an infectious disease is globally the most prevalent form of leishmaniasis accounting for approximately 1 million cases every year as per world health organization. Infected individuals develop skin lesion which has been reported to be infiltrated by immune cells and parasite with high sodium accumulation creating hypertonic environment. In our work, we tried to mimic the hypertonic environment in virtual environment to study dynamicity of SHP-1 and NFAT5 along with their interactions through molecular dynamics simulation. We validated the SHP-1 and NFAT5 dynamics in infection and HSD conditions to study the impact of hypertonicity derived NFAT5 mediated response to L.major infection. We also evaluated our therapeutic peptides for their binding to SHP-1 and to form stable complex. Membrane stability with the peptides was analyzed to understand their ability to sustain mammalian membrane. We identified PepA to be a potential candidate to interact with SHP-1. Inhibition of SHP-1 through PepA to discern IL-10 and IL-12 reciprocity may be assessed in future and furnish us with a potential therapeutic molecule. HSD mice exhibited high pro-inflammatory response to L.major infection which resulted in reduced lesion size. Contrary to observations in HSD mice, infection model exhibited low pro-inflammatory response and increased lesion size with high parasite load. Thus, increase in NFAT5 expression and reduced SHP-1 expression may result in disease resolving effect which can be further studied through incorporation of synthetic circuit using PepA to modulate IL-10 and IL-12 reciprocity.
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Leishmaniose Cutânea , Peptídeos , Proteína Tirosina Fosfatase não Receptora Tipo 6 , Animais , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Camundongos , Leishmaniose Cutânea/metabolismo , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/patologia , Peptídeos/farmacologia , Peptídeos/metabolismo , Peptídeos/química , Modelos Animais de Doenças , Simulação de Dinâmica Molecular , Interleucina-10/metabolismo , Leishmania major , Interleucina-12/metabolismo , Humanos , Camundongos Endogâmicos BALB CRESUMO
Overactive bladder (OAB) is a condition characterized by an urgency to urinate, which is associated with the urodynamic observation of detrusor overexcitation. Although the etiology of OAB is currently unclear, it has been suggested that in patients with OAB, disruption of bladder epithelial barrier integrity can disturb the normal contractile function of the detrusor. Additionally, dietary preferences have been suggested to influence the severity of OAB. Therefore, the aim of the present study was to investigate the effect of a high salt diet (HSD) on the development of OAB in a murine model. Mice were fed either a HSD or standard diet for 8 weeks, following which voiding characteristics and bladder barrier function were assessed. The present study demonstrated that a HSD in mice was associated with OAB-like symptoms such as increased urinary frequency and non-voiding bladder contractions. The HSD group demonstrated a thinner bladder mucus layer and decreased expression of bladder barrier markers, tight junction protein-1 and claudin-1, which may be potentially indicative of induced bladder damage. A HSD for 8 weeks in mice and a high salt treatment at the uroepithelium cellular (SV-HUC-1s) level resulted in increased uroepithelial oxidative stress and inflammatory cell infiltration, as indicated by increased expression levels of TNF-α and IL-1ß, as well as activation of the nucleotide-binding domain leucine-rich-containing family pyrin domain-containing 3 (NLRP3) and NF-κB signaling pathways in vivo and in vitro. Therefore, the present study indicated that a HSD could be a potentially important risk factor for the development of OAB, as it may be associated with overactivation of contractile function of the bladder by impairing the integrity of the bladder epithelial barrier and activation of the NLRP3 and NF-κB signaling pathways. Remodeling of the bladder barrier and reduction of the inflammatory response may be potential targets for the treatment of OAB in the future.
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INTRODUCTION: It is well documented that high-salt (HS) diet increases systemic and vascular oxidative stress in various animal models and in humans, leading to impairment of vascular reactivity. The present study examined the interaction of genotype and HS diet intake and the potential effects of oxidative stress - antioxidative system balance on the flow-induced dilation (FID) in pressurized carotid arteries of normotensive Tff3-/-/C57BL/6N knockout mice and their wild-type (WT) controls. METHODS: Male, ten-week-old transgenic Tff3-/-/C57BL/6N (Tff3-/-) knockout mice and WT/C57BL/6N (WT) (parental strain) healthy mice were divided in LS (0.4% NaCl in rodent chow) and HS (4% NaCl in rodent chow fed for 1 week) groups. Additionally, LS and HS groups were treated with 1 mmol/L 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL) dissolved in the drinking water. After anesthesia with ketamine chloride (100 mg/kg) and midazolam (5 mg/kg), blood pressure was measured, carotid arteries and aortas were isolated, and blood samples were collected. RESULTS: FID was decreased in WT_HS mice and restored by superoxide scavenger TEMPOL in vivo. On the other hand, attenuated FID of Tff3-/- mice was not further affected by HS diet or TEMPOL in vivo treatment. Vascular superoxide/reactive oxygen species levels were increased with HS diet in both strains and restored by TEMPOL. HS upregulated glutathione peroxidase 1 (GPx1) gene expression in WT_HS and Tff3-/-_HS mice, while GPx activity was significantly decreased only in WT_HS group. Systemic (serum) markers of oxidative stress (oxLDL and AOPP) and arterial blood pressure were similar among groups. CONCLUSION: HS diet increases vascular oxidative stress and impairs vasodilation in WT mice. Tff3 gene deficiency attenuates vasodilation per se, without further effects of HS intake. This can be attributed to vascular upregulation of antioxidative enzyme GPx1 in Tff3-/-/C57BL/6N mice conferring protection from oxidative stress.
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AIM: We aimed to test the hypothesis that a high-salt diet (HS) impairs NO signaling in kidney microvascular endothelial cells through a histone deacetylase 1 (HDAC1)-dependent mechanism. METHODS: Male Sprague Dawley rats were fed normal salt diet (NS; 0.49% NaCl) or HS (4% NaCl) for 2 weeks. NO signaling was assessed by measuring L-NAME induced vasoconstriction of the afferent arteriole using the blood perfused juxtamedullary nephron (JMN) preparation. In this preparation, kidneys were perfused with blood from a donor rat on a matching or different diet to that of the kidney donor. Kidney endothelial cells were isolated with magnetic activated cell sorting and HDAC1 activity was measured. RESULTS: We found HS-induced impaired NO signaling in the afferent arteriole. This was restored by inhibition of HDAC1 with MS-275. Consistent with these findings, HDAC1 activity was increased in kidney endothelial cells. We further found the loss of NO to be dependent upon the diet of the blood donor rather than the diet of the kidney donor and the plasma from HS-fed rats to be sufficient to induce impaired NO signaling. This indicates the presence of a humoral factor we termed plasma-derived endothelial dysfunction mediator (PDEM). Pretreatment with the antioxidants, PEG-SOD and PEG-catalase, as well as the NOS cofactor, tetrahydrobiopterin, restored NO signaling. CONCLUSION: We conclude that HS activates endothelial HDAC1 through PDEM leading to decreased NO signaling. This study provides novel insights into the molecular mechanisms by which a HS decreases renal microvascular endothelial NO signaling.
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Histona Desacetilase 1 , Rim , Óxido Nítrico , Ratos Sprague-Dawley , Transdução de Sinais , Cloreto de Sódio na Dieta , Animais , Masculino , Histona Desacetilase 1/metabolismo , Ratos , Óxido Nítrico/metabolismo , Rim/metabolismo , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Microvasos/metabolismo , Microvasos/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/efeitos dos fármacosRESUMO
Background: Recent studies reported a link between high salt diet (HSD) and clinical exacerbation in mouse models of autoimmune diseases, mainly through the induction of pathogenic Th17 cells and/or HSD-induced dysbiosis. However, the topic remains controversial and not fully understood. Purpose: In this study, we investigated the effects of HSD on the development of experimental autoimmune uveitis (EAU) in C57BL/6J mice. Methods and results: Unexpectedly, our data showed a significant attenuating effect of HSD on disease severity of native EAU, induced by direct immunization with IRBP peptide. That said, HSD had no effect on EAU disease severity induced by adoptive transfer of semi-purified auto-reactive IRBP-specific T lymphocytes. Accordingly, HSD did not affect IRBP-specific systemic afferent immune response as attested by no HSD-linked changes in T lymphocytes proliferation, cytokine production and Treg proportion. Gut microbiota analysis from cecal samples in naïve and EAU mice demonstrated that HSD affected differentially α-diversity between groups, whereas ß-diversity was significantly modified in all groups. Unknown Tannerellaceae was the only taxon associated to HSD exposure in all treatment groups. Interestingly, a significantly higher abundance of unknown Gastranaerophilales, with potential anti-inflammatory properties, appeared in HSD-fed native EAU mice, only. Discussion: In conclusion, our study suggests a possible impact of HSD on gut microbiota composition and consequently on development and clinical severity of EAU. Further studies are required to investigate the potential beneficial role of Gastranaerophilales in EAU.
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Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovial inflammation and the production of autoantibodies. Previous studies have indicated an association between high-salt diets (HSD) and an increased risk of RA, yet the underlying mechanisms remain unclear. Macrophage pyroptosis, a pro-inflammatory form of cell death, plays a pivotal role in RA. In this study, we demonstrate that HSD exacerbates the severity of arthritis in collagen-induced arthritis (CIA) mice, correlating with macrophage infiltration and inflammatory lesions. Given the significant alterations observed in macrophages from CIA mice subjected to HSD, we specifically investigate the impact of HSD on macrophage responses in the inflammatory milieu of RA. In our in vitro experiments, pretreatment with NaCl enhances LPS-induced pyroptosis in RAW.264.7 and THP-1 cells through the p38 MAPK/NF-κB signaling pathway. Subsequent experiments reveal that Slc6a12 inhibitors and SGK1 silencing inhibit sodium-induced activation of macrophage pyroptosis and the p38 MAPK/NF-κB signaling pathway, whereas overexpression of the SGK1 gene counteracts the effect of sodium on macrophages. In conclusion, our findings verified that high salt intake promotes the progression of RA and provided a detailed elucidation of the activation of macrophage pyroptosis induced by sodium transportation through the Slc6a12 channel.
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Artrite Reumatoide , Macrófagos , Proteínas Serina-Treonina Quinases , Piroptose , Animais , Camundongos , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Macrófagos/metabolismo , Piroptose/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Cloreto de Sódio/farmacologia , Células RAW 264.7 , Humanos , Masculino , Proteínas Imediatamente Precoces/metabolismo , Proteínas Imediatamente Precoces/genética , Artrite Experimental/metabolismo , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Camundongos Endogâmicos DBARESUMO
A high-salt diet (HSD) has been associated with various health issues, including hypertension and cardiovascular diseases. However, recent studies have revealed a potential link between high salt intake and cognitive impairment. This study aims to investigate the effects of high salt intake on autophagy, tau protein hyperphosphorylation, and synaptic function and their potential associations with cognitive impairment. To explore these mechanisms, 8-month-old male C57BL/6 mice were fed either a normal diet (0.4% NaCl) or an HSD (8% NaCl) for 3 months, and Neuro-2a cells were incubated with normal medium or NaCl medium (80 mM). Behavioral tests revealed learning and memory deficits in mice fed the HSD. We further discovered that the HSD decreased autophagy, as indicated by diminished levels of the autophagy-associated proteins Beclin-1 and LC3, along with an elevated p62 protein level. HSD feeding significantly decreased insulin-like growth factor-1 receptor (IGF1R) expression in the brain of C57BL/6 mice and activated mechanistic target of rapamycin (mTOR) signaling. In addition, the HSD reduced synaptophysin and postsynaptic density protein 95 (PSD95) expression in the hippocampus and caused synaptic loss in mice. We also found amyloid ß accumulation and hyperphosphorylation of tau protein at different loci both in vivo and in vitro. Overall, this study highlights the clinical significance of understanding the impact of an HSD on cognitive function. By targeting the IGF1R/mTOR/p70S6K pathway or promoting autophagy, it may be possible to mitigate the negative effects of high salt intake on cognitive function.
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Disfunção Cognitiva , Camundongos Endogâmicos C57BL , Receptor IGF Tipo 1 , Proteínas Quinases S6 Ribossômicas 70-kDa , Transdução de Sinais , Cloreto de Sódio na Dieta , Serina-Treonina Quinases TOR , Animais , Masculino , Serina-Treonina Quinases TOR/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/etiologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Cloreto de Sódio na Dieta/efeitos adversos , Receptor IGF Tipo 1/metabolismo , Proteínas tau/metabolismo , Autofagia/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacosRESUMO
Gut microbiota dysfunction is a key factor affecting chronic kidney disease (CKD) susceptibility. Puerariae lobatae Radix (PLR), a traditional Chinese medicine and food homologous herb, is known to promote the gut microbiota homeostasis; however, its role in renoprotection remains unknown. The present study aimed to investigate the efficacy and potential mechanism of PLR to alleviate CKD. An 8week 2% NaClfeeding murine model was applied to induce CKD and evaluate the therapeutic effect of PLR supplementary. After gavage for 8 weeks, The medium and high doses of PLR significantly alleviated CKDassociated creatinine, urine protein increasement and nephritic histopathological injury. Moreover, PLR protected kidney from fibrosis by reducing inflammatory response and downregulating the canonical Wnt/ßcatenin pathway. Furthermore, PLR rescued the gut microbiota dysbiosis and protected against high saltinduced gut barrier dysfunction. Enrichment of Akkermansia and Bifidobacterium was found after PLR intervention, the relative abundances of which were in positive correlation with normal maintenance of renal histology and function. Next, fecal microbiota transplantation experiment verified that the positive effect of PLR on CKD was, at least partially, exerted through gut microbiota reestablishment and downregulation of the Wnt/ßcatenin pathway. The present study provided evidence for a new function of PLR on kidney protection and put forward a potential therapeutic strategy target for CKD.
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Medicamentos de Ervas Chinesas , Microbioma Gastrointestinal , Pueraria , Insuficiência Renal Crônica , Via de Sinalização Wnt , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Camundongos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Masculino , Pueraria/química , Modelos Animais de Doenças , Disbiose/tratamento farmacológico , Regulação para Baixo/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Camundongos Endogâmicos C57BL , Transplante de Microbiota FecalRESUMO
Sodium overload during childhood impairs baroreflex sensitivity and increases arterial blood pressure and heart rate in adulthood; these effects persist even after high-salt diet (HSD) withdrawal. However, the literature lacks details on the effects of HSD during postnatal phases on cardiac ischemia/reperfusion responses in adulthood. The current study aimed to elucidate the impact of HSD during infancy adolescence on isolated heart function and cardiac ischemia/reperfusion responses in adulthood. Male 21-day-old Wistar rats were treated for 60 days with hypertonic saline solution (NaCl; 0.3M; experimental group) or tap water (control group). Subsequently, both groups were maintained on a normal sodium diet for 30 days. Subsequently, the rats were euthanized, and their hearts were isolated and perfused according to the Langendorff technique. After 30 min of the basal period, the hearts were subjected to 20 min of anoxia, followed by 20 min of reperfusion. The basal contractile function was unaffected by HSD. However, HSD elevated the left ventricular end-diastolic pressure during reperfusion (23.1 ± 5.2 mmHg vs. 11.6 ± 1.4 mmHg; p < 0.05) and increased ectopic incidence period during reperfusion (208.8 ± 32.9s vs. 75.0 ± 7.8s; p < 0.05). In conclusion, sodium overload compromises cardiac function after reperfusion events, diminishes ventricular relaxation, and increases the severity of arrhythmias, suggesting a possible arrhythmogenic effect of HSD in the postnatal phases.
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Arritmias Cardíacas , Traumatismo por Reperfusão Miocárdica , Ratos Wistar , Animais , Ratos , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/fisiopatologia , Masculino , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Diástole/fisiologia , Cloreto de Sódio na Dieta/efeitos adversos , Frequência Cardíaca/fisiologiaRESUMO
Nowadays, there is an increasing emphasis on the need to alleviate the chronic inflammatory response to effectively treat hypertension. However, there are still gaps in our understanding on how to achieve this. Therefore, research on interaction of antihypertensive drugs with the immune system is extremely interesting, since their therapeutic effect could partly result from amelioration of hypertension-related inflammation, in which macrophages seem to play a pivotal role. Thus, current comprehensive studies have investigated the impact of repeatedly administered hypotensive drugs (captopril, olmesartan, propranolol, carvedilol, amlodipine, verapamil) on macrophage functions in the innate and adaptive immunity, as well as if drug-induced effects are affected by a high-sodium diet (HSD), one of the key environmental risk factors of hypertension. Although the assayed medications increased the generation of reactive oxygen and nitrogen intermediates by macrophages from standard fed donors, they reversed HSD-induced enhancing effects on macrophage oxidative burst and secretion of pro-inflammatory cytokines. On the other hand, some drugs increased macrophage phagocytic activity and the expression of surface markers involved in antigen presentation, which translated into enhanced macrophage ability to activate B cells for antibody production. Moreover, the assayed medications augmented macrophage function and the effector phase of contact hypersensitivity reaction, but suppressed the sensitization phase of cell-mediated hypersensitivity under HSD conditions. Our current findings contribute to the recognition of mechanisms, by which excessive sodium intake affects macrophage immune activity in hypertensive individuals, and provide evidence that the assayed medications mitigate most of the HSD-induced adverse effects, suggesting their additional protective therapeutic activity.
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Anti-Hipertensivos , Macrófagos , Animais , Anti-Hipertensivos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/imunologia , Camundongos , Inflamação/tratamento farmacológico , Ativação de Macrófagos/efeitos dos fármacos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/imunologia , Masculino , Citocinas/metabolismo , Fagocitose/efeitos dos fármacos , Sódio na Dieta/efeitos adversos , Mediadores da Inflamação/metabolismoRESUMO
Excessive salt intake is a widespread health issue observed in almost every country around the world. A high salt diet (HSD) has a strong correlation with numerous diseases, including hypertension, chronic kidney disease, and autoimmune disorders. However, the mechanisms underlying HSD-promotion of inflammation and exacerbation of these diseases are not fully understood. In this study, we observed that HSD consumption reduced the abundance of the gut microbial metabolite L-fucose, leading to a more substantial inflammatory response in mice. A HSD led to increased peritonitis incidence in mice, as evidenced by the increased accumulation of inflammatory cells and elevated levels of inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and monocyte chemotactic protein-1 (MCP-1, also known as C-C motif chemokine ligand 2 or CCL2), in peritoneal lavage fluid. Following the administration of broad-spectrum antibiotics, HSD-induced inflammation was abolished, indicating that the proinflammatory effects of HSD were not due to the direct effect of sodium, but rather to HSD-induced alterations in the composition of the gut microbiota. By using untargeted metabolomics techniques, we determined that the levels of the gut microbial metabolite L-fucose were reduced by a HSD. Moreover, the administration of L-fucose or fucoidan, a compound derived from brown that is rich in L-fucose, normalized the level of inflammation in mice following HSD induction. In addition, both L-fucose and fucoidan inhibited LPS-induced macrophage activation in vitro. In summary, our research showed that reduced L-fucose levels in the gut contributed to HSD-exacerbated acute inflammation in mice; these results indicate that L-fucose and fucoidan could interfere with HSD-promotion of the inflammatory response.
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Fucose , Polissacarídeos , Cloreto de Sódio na Dieta , Camundongos , Animais , Fucose/farmacologia , Inflamação/metabolismo , DietaRESUMO
Dietary salt has been associated with cognitive impairment in mice, possibly related to damaged synapses and tau hyperphosphorylation. However, the mechanism underlying how dietary salt causes cognitive dysfunction remains unclear. In our study, either a high-salt (8%) or normal diet (0.5%) was used to feed C57BL/6 mice for three months, and N2a cells were cultured in normal medium, NaCl medium (80 mM), or NaCl (80 mM) + Liraglutide (200 nM) medium for 48 h. Cognitive function in mice was assessed using the Morris water maze and shuttle box test, while anxiety was evaluated by the open field test (OPT). Western blotting (WB), immunofluorescence, and immunohistochemistry were utilized to assess the level of Glucagon-like Peptide-1 receptor (GLP-1R) and mTOR/p70S6K pathway. Electron microscope and western blotting were used to evaluate synapse function and tau phosphorylation. Our findings revealed that a high salt diet (HSD) reduced the level of synaptophysin (SYP) and postsynaptic density 95 (PSD95), resulting in significant synaptic damage. Additionally, hyperphosphorylation of tau at different sites was detected. The C57BL/6 mice showed significant impairment in learning and memory function compared to the control group, but HSD did not cause anxiety in the mice. In addition, the level of GLP-1R and autophagy flux decreased in the HSD group, while the level of mTOR/p70S6K was upregulated. Furthermore, liraglutide reversed the autophagy inhibition of N2a treated with NaCl. In summary, our study demonstrates that dietary salt inhibits the GLP-1R/mTOR/p70S6K pathway to inhibit autophagy and induces synaptic dysfunction and tau hyperphosphorylation, eventually impairing cognitive dysfunction.
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Disfunção Cognitiva , Liraglutida , Camundongos , Animais , Liraglutida/farmacologia , Cloreto de Sódio na Dieta/efeitos adversos , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Cloreto de Sódio/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Camundongos Endogâmicos C57BL , Transdução de Sinais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Serina-Treonina Quinases TOR/metabolismo , CogniçãoRESUMO
The consumption of processed food is on the rise leading to huge intake of excess dietary salt, which strongly correlates with development of hypertension, often leading to cardiovascular diseases such as stroke and heart attack, as well as activation of the immune system. The effect of salt on macrophages is especially interesting as they are able to sense high sodium levels in tissues leading to transcriptional changes. In the skin, macrophages were shown to influence lymphatic vessel growth which, in turn, enables the transport of excess salt and thereby prevents the development of high blood pressure. Furthermore, salt storage in the skin has been linked to the onset of pro-inflammatory effector functions of macrophages in pathogen defence. However, there is only little known about the mechanisms which are involved in changing macrophage function to salt exposure. Here, we characterize the response of macrophages to excess salt both in vitro and in vivo. Our results validate and strengthen the notion that macrophages exhibit chemotactic migration in response to salt gradients in vitro. Furthermore, we demonstrate a reduction in phagocytosis and efferocytosis following acute salt challenge in vitro. While acute exposure to a high-salt diet in vivo has a less pronounced impact on macrophage core functions such as phagocytosis, our data indicate that prolonged salt challenge may exert a distinct effect on the function of macrophages. These findings suggest a potential role for excessive salt sensing by macrophages in the manifestation of diseases related to high-salt diets and explicitly highlight the need for in vivo work to decipher the physiologically relevant impact of excess salt on tissue and cell function.
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Hipertensão , Cloreto de Sódio na Dieta , Humanos , Macrófagos , Cloreto de Sódio , FagocitoseRESUMO
BACKGROUND: A high-salt diet is a leading dietary risk factor for elevated blood pressure and cardiovascular disease. Quercetin reportedly exhibits cardioprotective and antihypertensive therapeutic effects. OBJECTIVES: The objective of this study is to examine the effect of quercetin on high-salt dietinduced elevated blood pressure in Dahl salt-sensitive (SS) rats and determine the underlying molecular mechanism. MATERIALS AND METHODS: Rats of the Dahl SS and control SS-13 BN strains were separated into five groups, SS-13 BN rats fed a low-salt diet (BL group), SS-13 BN rats fed a high-salt diet (BH group), Dahl SS rats fed a low-salt diet (SL group), Dahl SS rats fed a high-salt diet (SH group), and SH rats treated with quercetin (SHQ group). Blood pressure was checked three weeks into the course of treatment, and biochemical markers in the urine and serum were examined. Additionally, western blot was done to evaluate the sirtuin 1 (SIRT1) and endothelial nitric oxide synthase (eNOS) expression levels. Immunohistochemical analysis was performed to verify SIRT1 levels. RESULTS: We demonstrated that a high-salt diet elevated blood pressure in both SS-13 BN and Dahl SS rats, and quercetin supplementation alleviated the altered blood pressure. Compared with the SH group, quercetin significantly elevated the protein expression of SIRT1 and eNOS. Immunohistochemistry results further confirmed that quercetin could improve the protein expression of SIRT1. CONCLUSION: Quercetin reduced blood pressure by enhancing the expression of SIRT1 and eNOS in Dahl SS rats fed a high-salt diet.
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Eating diets high in salt has been associated with alterations in the immune system and the potential development of neuropsychiatric disorders. This area of research shows promise, but there is currently a limited amount of research on this topic. The present study investigated whether a high salt diet (HSD) affects anhedonia and stress-coping response behaviors in young male and female Wistar rats. In this study, male and female Wistar rats were fed an HSD (8 % NaCl w/w) from weaning to post-natal day (PND) 64. From PND 60 to 64, the rats underwent a spontaneous locomotor activity test (SLA), sucrose splash test (SST), sucrose preference test (SPT), and forced swim test (FST), followed by euthanasia at PND 65. Male and female rats consuming the HSD exhibited an increase in water intake compared to the corresponding control diet (CD) groups. Male rats had lower body weight despite having similar food intakes compared to the CD group. Male rats displayed an active stress-coping behavior in the FST, characterized by increased mobility. Additionally, HSD-fed males exhibited a greater preference for sucrose solution in the SPT. However, no effect of diet and sex were detected in the SST and the SLA, and hypothalamic levels of leptin and ghrelin receptors. On the other hand, female rats were less susceptible to the experimental conditions applied in this protocol than males.
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Capacidades de Enfrentamento , Cloreto de Sódio na Dieta , Ratos , Animais , Masculino , Feminino , Ratos Wistar , Peso Corporal/fisiologia , SacaroseRESUMO
High salt diet (HSD) is a risk factor of hypertension and cardiovascular disease. Although clinical data do not clearly indicate the relationship between HSD and the prevalence of Alzheimer's disease (AD), animal experiments have shown that HSD can cause hyperphosphorylation of tau protein and cognition impairment. However, whether HSD can accelerate the progression of AD by damaging the function of neurovascular unit (NVU) in the brain is unclear. Here, we fed APP/PS1 mice (an AD model) or wild-type mice with HSD and found that the chronic HSD feeding increased the activity of enzymes related to tau phosphorylation, which led to tau hyperphosphorylation in the brain. HSD also aggravated the deposition of Aß42 in hippocampus and cortex in the APP/PS1 mice but not in the wild-type mice. Simultaneously, HSD caused the microglia proliferation, low expression of Aqp-4, and high expression of CD31 in the wild-type mice, which were accompanied with the loss of pericytes (PCs) and increase in blood brain barrier (BBB) permeability. As a result, wild-type mice fed with HSD performed poorly in Morris Water Maze and object recognition test. In the APP/PS1 mice, HSD feeding for 8 months worsen the cognition and accompanied the loss of PCs, the activation of glia, the increase in BBB permeability, and the acceleration of calcification in the brain. Our data suggested that HSD feeding induced the AD-like pathology in wild-type mice and aggravated the development of AD-like pathology in APP/PS1 mice, which implicated the tau hyperphosphorylation and NVU dysfunction.
Assuntos
Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Camundongos Transgênicos , Proteínas tau/metabolismo , Dieta , Cognição , Cloreto de Sódio na Dieta/efeitos adversos , Modelos Animais de Doenças , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismoRESUMO
The matrix glycoprotein thrombospondin-1 (THBS1) modulates nitric oxide (NO) signaling in endothelial cells. A high-salt diet induces deficiencies of NO production and bioavailability, thereby leading to endothelial dysfunction. In this study we investigated the changes of THBS1 expression and its pathological role in the dysfunction of mesenteric artery endothelial cells (MAECs) induced by a high-salt diet. Wild-type rats, and wild-type and Thbs1-/- mice were fed chow containing 8% w/w NaCl for 4 weeks. We showed that a high salt diet significantly increased THBS1 expression and secretion in plasma and MAECs, and damaged endothelium-dependent vasodilation of mesenteric resistance arteries in wild-type animals, but not in Thbs1-/- mice. In rat MAECs, we demonstrated that a high salt environment (10-40 mM) dose-dependently increased THBS1 expression accompanied by suppressed endothelial nitric oxide synthase (eNOS) and phospho-eNOS S1177 production as well as NO release. Blockade of transforming growth factor-ß1 (TGF-ß1) activity by a TGF-ß1 inhibitor SB 431542 reversed THBS1 up-regulation, rescued the eNOS decrease, enhanced phospho-eNOS S1177 expression, and inhibited Smad4 translocation to the nucleus. By conducting dual-luciferase reporter experiments in HEK293T cells, we demonstrated that Smad4, a transcription promoter, upregulated Thbs1 transcription. We conclude that THBS1 contributes to endothelial dysfunction in a high-salt environment and may be a potential target for treatment of high-salt-induced endothelium dysfunction.
Assuntos
Células Endoteliais , Cloreto de Sódio , Humanos , Ratos , Camundongos , Animais , Cloreto de Sódio/metabolismo , Células Endoteliais/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Células HEK293 , Endotélio Vascular/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Vasodilatação , Artérias Mesentéricas , Trombospondinas/metabolismo , Óxido Nítrico/metabolismoRESUMO
Salt sensitivity impacts a significant portion of the population and is an important contributor to the development of chronic kidney disease. One of the significant early predictors of salt-induced damage is albuminuria, which reflects the deterioration of the renal filtration barrier: the glomerulus. Despite significant research efforts, there is still a gap in knowledge regarding the molecular mechanisms and signaling networks contributing to instigating and/or perpetuating salt-induced glomerular injury. To address this gap, we used 8-wk-old male Dahl salt-sensitive rats fed a normal-salt diet (0.4% NaCl) or challenged with a high-salt diet (4% NaCl) for 3 wk. At the end of the protocol, a pure fraction of renal glomeruli obtained by differential sieving was used for next-generation RNA sequencing and comprehensive semi-automatic transcriptomic data analyses, which revealed 149 differentially expressed genes (107 and 42 genes were downregulated and upregulated, respectively). Furthermore, a combination of predictive gene correlation networks and computational bioinformatic analyses revealed pathways impacted by a high salt dietary challenge, including renal metabolism, mitochondrial function, apoptotic signaling and fibrosis, cell cycle, inflammatory and immune responses, circadian clock, cytoskeletal organization, G protein-coupled receptor signaling, and calcium transport. In conclusion, we report here novel transcriptomic interactions and corresponding predicted pathways affecting glomeruli under salt-induced stress.NEW & NOTEWORTHY Our study demonstrated novel pathways affecting glomeruli under stress induced by dietary salt. Predictive gene correlation networks and bioinformatic semi-automatic analysis revealed changes in the pathways relevant to mitochondrial function, inflammatory, apoptotic/fibrotic processes, and cell calcium transport.