Tuberculosis is an ongoing threat to global health, especially with the emergence of multi drug-resistant (MDR) and extremely drug-resistant strains that are motivating the search for new treatment ...strategies. One potential strategy is immunotherapy using Innate Defence Regulator (IDR) peptides that selectively modulate innate immunity, enhancing chemokine induction and cell recruitment while suppressing potentially harmful inflammatory responses. IDR peptides possess only modest antimicrobial activity but have profound immunomodulatory functions that appear to be influential in resolving animal model infections. The IDR peptides HH2, 1018 and 1002 were tested for their activity against two M. tuberculosis strains, one drug-sensitive and the other MDR in both in vitro and in vivo models. All peptides showed no cytotoxic activity and only modest direct antimicrobial activity versus M. tuberculosis (MIC of 15-30 µg/ml). Nevertheless peptides HH2 and 1018 reduced bacillary loads in animal models with both the virulent drug susceptible H37Rv strain and an MDR isolate and, especially 1018 led to a considerable reduction in lung inflammation as revealed by decreased pneumonia. These results indicate that IDR peptides have potential as a novel immunotherapy against TB.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A role for the nucleotide‐binding oligomerization domain 2 (NOD2) receptor in pulmonary innate immune responses has recently been explored. In the present study, we investigated the role that NOD2 ...plays in human alveolar macrophage innate responses and determined its involvement in the response to infection with virulent Mycobacterium tuberculosis. Our results showed that NOD2 was expressed in human alveolar macrophages, and significant amounts of IL‐1β, IL‐6, and TNF‐α were produced upon ligand recognition with muramyldipeptide (MDP). NOD2 ligation induced the transcription and protein expression of the antimicrobial peptide LL37 and the autophagy enzyme IRGM in alveolar macrophages, demonstrating a novel function for this receptor in these cells. MDP treatment of alveolar macrophages improved the intracellular growth control of virulent M. tuberculosis; this was associated with a significant release of TNF‐α and IL‐6 and overexpression of bactericidal LL37. In addition, the autophagy proteins IRGM, LC3 and ATG16L1 were recruited to the bacteria‐containing autophagosome after treatment with MDP. In conclusion, our results suggest that NOD2 can modulate the innate immune response of alveolar macrophages and play a role in the initial control of respiratory M. tuberculosis infections.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Tuberculosis (TB) is a major worldwide health problem in part due to the lack of development of new treatments and the emergence of new strains such as multidrug-resistant (MDR) and extensively ...drug-resistant strains that are threatening and impairing the control of this disease. In this study, the efficacy of natural and synthetic cationic antimicrobial (host defence) peptides that have been shown often to possess broad-spectrum antimicrobial activity was tested. The natural antimicrobial peptides human LL-37 and mouse CRAMP as well as synthetic peptides E2, E6 and CP26 were tested for their activity against Mycobacterium tuberculosis both in in vitro and in vivo models. The peptides had moderate antimicrobial activities, with minimum inhibitory concentrations ranging from 2μg/mL to 10μg/mL. In a virulent model of M. tuberculosis lung infection, intratracheal therapeutic application of these peptides three times a week at doses of ca. 1mg/kg led to significant 3–10-fold reductions in lung bacilli after 28–30 days of treatment. The treatments worked both against the drug-sensitive H37Rv strain and a MDR strain. These results indicate that antimicrobial peptides might constitute a novel therapy against TB.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Hyperpolarization-activated cationic HCN channels comprise four members (HCN1-4) that control dendritic integration, synaptic transmission and action potential firing. In the kidney, HCN1, HCN2 and ...HCN3 are differentially expressed and contribute to the transport of sodium, potassium (K
) and ammonium into the nephrons. HCN3 is regulated by K
diets in the kidney. In this work we performed a proteomic analysis of HCN3 expressed in human embryonic kidney cells (HEK293 cells). More than 50% of the interacting proteins belonged to mitochondria. Therefore, we explored the presence of HCN channels in kidney mitochondria. By immunoblotting and immunogold electron microscopy HCN3 protein expression was found in rat kidney mitochondria; it was also confirmed in human kidney. Patch-clamp recordings of renal mitochondria and mitochondria from HEK293 cells overexpressing HCN1, HCN2 and HCN3 channels, stained with MitoTracker Green FM, indicated that only HCN3 could produce inwardly K
currents that were inhibited by ZD7288, a specific blocker of HCN channels. Furthermore, ZD7288 caused inhibition of the oxygen consumption coupled to ATP synthesis and hyperpolarization of the inner mitochondrial membrane. In conclusion, we show for the first time that pacemaker HCN channels contribute to K
transport in mitochondria facilitating the activity of the respiratory chain and ATP synthesis by controlling the inner mitochondrial membrane potential.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Identification of alternative attenuation targets of
(
) is pivotal for designing new candidates for live attenuated anti-tuberculosis (TB) vaccines. In this context, the CtpF P-type ATPase of
is an ...interesting target; specifically, this plasma membrane enzyme is involved in calcium transporting and response to oxidative stress. We found that a mutant of
H37Rv lacking
expression (
Δ
) displayed impaired proliferation in mouse alveolar macrophages (MH-S) during in vitro infection. Further, the levels of tumor necrosis factor and interferon-gamma in MH-S cells infected with
Δ
were similar to those of cells infected with the parental strain, suggesting preservation of the immunogenic capacity. In addition, BALB/c mice infected with
∆
showed median survival times of 84 days, while mice infected with
H37Rv survived 59 days, suggesting reduced virulence of the mutant strain. Interestingly, the expression levels of
in a mouse model of latent TB were significantly higher than in a mouse model of progressive TB, indicating that
is involved in
persistence in the dormancy state. Finally, the possibility of complementary mechanisms that counteract deficiencies in Ca
transport mediated by P-type ATPases is suggested. Altogether, our results demonstrate that CtpF could be a potential target for
attenuation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Curcumin exhibits several therapeutic properties. Potassium dichromate (K2Cr2O7)-induced nephropathy is associated with oxidative stress. Reactive oxygen species production affects renal oxygenation ...that may participate in the progression of renal damage. The aim of the present work was to elucidate whether K2Cr2O7-induced nephropathy is associated to partial O2 pressure (pO2) impairment and if curcumin is able to prevent it. Four groups of rats were studied: control group; K2Cr2O7 group (12.5 mg/kg, s.c.); curcumin + K2Cr2O7 group, in which animals were treated with curcumin (400 mg/kg/day, p.o.) for 10 days before K2Cr2O7 injection; and curcumin group. All animals were sacrificed 48 h after the end of the treatments. K2Cr2O7 administration increased renal function markers and decreased glomerular filtration rate, pO2 and renal perfusion. Concerning hemodynamic parameters, K2Cr2O7 increased mean arterial pressure and renal vascular resistance and reduced renal blood flow. The hemodynamic changes were attributed to decreased availability of nitric oxide and increased 3-nitrotyrosine levels. Moreover, increased superoxide anion production and vascular endothelial growth factor levels were observed after K2Cr2O7 administration. Curcumin attenuated all the above-described alterations. Our results suggest that the protective effects of curcumin in K2Cr2O7-induced nephropathy are associated with its ability to prevent O2 supply reduction.
•Curcumin prevented the reduction of renal oxygenation maintaining oxygen supply through renal blood flow.•Nitric oxide plays a central role in the maintenance of renal oxygenation, but K2Cr2O7 abated its levels.•Curcumin prevented K2Cr2O7-induced nitrosative stress.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Agroindustrial activities generate various residues or byproducts which are inefficiently utilized, impacting the environment and increasing production costs. These byproducts contain significant ...amounts of bioactive compounds, including dietary fiber with associated phenolic compounds, known as antioxidant dietary fiber (ADF). Phenolic compounds are related to the prevention of diseases related to oxidative stress, such as neurodegenerative and cardiovascular diseases. The mechanism of ADF depends on its chemical structure and the interactions between the dietary fiber and associated phenolic compounds. This work describes ADF, the main byproducts considered sources of ADF, its mechanisms of action, and its potential use in the formulation of foods destined for human consumption. ADF responds to the demand for low-cost, functional ingredients with great health benefits. A higher intake of antioxidant dietary fiber contributes to reducing the risk of diseases such as type II diabetes, colon cancer, obesity, and kidney stones, and has bile-acid retention-excretion, gastrointestinal laxative, hypoglycemic, hypocholesterolemic, prebiotic, and cardioprotective effects. ADF is a functional, sustainable, and profitable ingredient with different applications in agroindustry; its use can improve the technofunctional and nutritional properties of food, helping to close the cycle following the premise of the circular economy.
Summary
Phenolics bound to dietary fibres (DF‐PCs) represent a valuable source of antioxidants that are often wasted. DF‐PCs can be obtained as residues from conventional extraction processes of PCs ...derived from agro‐industrial by‐products. This study aimed to characterise DF‐PCs generated after the PC extraction process from the avocado peel (AP), mango peel (MP) and husk mango seed (testa) (MT), with a focus on solid residue or concentrated fibre (APFT: avocado peel fibre; MPFT: mango peel fibre; MTFT: mango testa fibre). The by‐products were evaluated under both non‐defatted and defatted conditions before simulating the PC extraction process. PCs were quantified (TPC) and identified (HPLC‐IDA‐EPI‐MS). Their antioxidant activity (AA) was determined (ABTS+, DPPH* and FRAP). Among the evaluated fibres, non‐defatted AP and defatted MP and MT exhibited the highest TPC content (22.64 ± 0.3, 37.31 ± 1.78 and 6.07 ± 0.08 mg GAE/g), respectively. Using the DPPH* assay, all fibre concentrates showed lower AA compared to the by‐products. Using FRAP assay, defatting gave the largest activity for mango samples. HPLC‐IDA‐EPI‐MS analysis of PC profiles resulted in the presence of 62 PC compounds in the fibre concentrates. These DF‐PCs, with a significant content of PCs, may be relevant as functional ingredients for food production.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The kidney controls body fluids, electrolyte and acid–base balance. Previously, we demonstrated that hyperpolarization-activated and cyclic nucleotide-gated (HCN) cation channels participate in ...ammonium excretion in the rat kidney. Since acid–base balance is closely linked to potassium metabolism, in the present work we aim to determine the effect of chronic metabolic acidosis (CMA) and hyperkalemia (HK) on protein abundance and localization of HCN3 in the rat kidney. CMA increased HCN3 protein level only in the outer medulla (2.74 ± 0.31) according to immunoblot analysis. However, immunofluorescence assays showed that HCN3 augmented in cortical proximal tubules (1.45 ± 0.11) and medullary thick ascending limb of Henle’s loop (4.48 ± 0.45) from the inner stripe of outer medulla. HCN3 was detected in brush border membranes (BBM) and mitochondria of the proximal tubule by immunogold electron and confocal microscopy in control conditions. Acidosis did not alter HCN3 levels in BBM and mitochondria but augmented them in lysosomes. HCN3 was also immuno-detected in mitoautophagosomes. In the distal nephron, HCN3 was expressed in principal and intercalated cells from cortical to medullary collecting ducts. CMA did not change HCN3 abundance in these nephron segments. In contrast, HK doubled HCN3 level in cortical collecting ducts and favored its basolateral localization in principal cells from the inner medullary collecting ducts. These findings further support HCN channels contribution to renal acid–base and potassium balance.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
10.
Fundus autofluorescence in premature infants Salcedo-Villanueva, Guillermo; Lopez-Contreras, Yurico; Gonzalez-H Leon, Ana ...
Scientific reports,
04/2021, Volume:
11, Issue:
1
Journal Article
Peer reviewed
Open access
To describe fundus autofluorescence (FAF) patterns in premature infants and to determine whether FAF increases gradually with increasing post-gestational age. This was a cross-sectional, ...observational and descriptive case series. FAF images were obtained from patients screened for Retinopathy of Prematurity. The presence of the following hypo-autofluorescence areas/structures was graded and ranked: macular pigment (foveal centre), optic nerve head, peripapillary vessels/vascular arcade (PP/VA), and equatorial vessels (EqV). Ranks were attributed to the number of structures visualized from the posterior pole towards the periphery. The rank of FAF could then be analysed by Spearman's correlation against age. Additionally, patients were divided by age into group 1 (< 40 weeks of corrected gestational age (WCGA)) and group 2 (> 40 WCGA). Differences between groups were tested with the Mann-Whitney U test. Thirteen patients were analysed. The mean WCGA at examination was 47.85 weeks. Spearman's correlation showed a strong positive correlation (r = 0.714) (P = 0.006) of FAF and WCGA. The Mann-Whitney U test revealed that the PP/VA and EqV were significantly more visible at > 40 WCGA than at < 40 WCGA (8.0 P = 0.016 and 7.5 P = 0.03, respectively). Patterns of FAF are described for the first time in premature infants. FAF increases gradually with age and centrifugally from the posterior pole towards the equator in premature infants.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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