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1.
Role of ACE2-Ang (1-7)-Mas axis in post-COVID-19 complications and its dietary modulation.
Sahu, S, Patil, CR, Kumar, S, Apparsundaram, S, Goyal, RK
Molecular and cellular biochemistry. 2022;(1):225-240
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Abstract
Severe acute respiratory syndrome-coronavirus-2 (COVID-19) virus uses Angiotensin-Converting Enzyme 2 (ACE2) as a gateway for their entry into the human body. The ACE2 with cleaved products have emerged as major contributing factors to multiple physiological functions and pathogenic complications leading to the clinical consequences of the COVID-19 infection Decreased ACE2 expression restricts the viral entry into the human cells and reduces the viral load. COVID-19 infection reduces the ACE2 expression and induces post-COVID-19 complications like pneumonia and lung injury. The modulation of the ACE2-Ang (1-7)-Mas (AAM) axis is also being explored as a modality to treat post-COVID-19 complications. Evidence indicates that specific food components may modulate the AAM axis. The variations in the susceptibility to COVID-19 infection and the post-COVID its complications are being correlated with varied dietary habits. Some of the food substances have emerged to have supportive roles in treating post-COVID-19 complications and are being considered as adjuvants to the COVID-19 therapy. It is possible that some of their active ingredients may emerge as the direct treatment for the COVID-19.
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Glycomacropeptide: long-term use and impact on blood phenylalanine, growth and nutritional status in children with PKU.
Daly, A, Evans, S, Chahal, S, Santra, S, Pinto, A, Jackson, R, Gingell, C, Rocha, J, Van Spronsen, FJ, MacDonald, A
Orphanet journal of rare diseases. 2019;(1):44
Abstract
UNLABELLED In phenylketonuria, casein glycomacropeptide (CGMP) requires modification with the addition of some essential and semi essential amino acids to ensure suitability as a protein substitute. The optimal amount and ratio of additional amino acids is undefined. AIM: A longitudinal, parallel, controlled study over 12 months evaluating a CGMP (CGMP-AA2) formulation compared with phenylalanine-free L-amino acid supplements (L-AA) on blood Phe, Tyr, Phe:Tyr ratio, biochemical nutritional status and growth in children with PKU. The CGMP-AA2 contained 36 mg Phe per 20 g protein equivalent. METHODS Children with PKU, with a median age of 9.2 y (5-16y) were divided into 2 groups: 29 were given CGMP-AA2, 19 remained on Phe-free L-AA. The CGMP-AA2 formula gradually replaced L-AA, providing blood Phe concentrations were maintained within target range. Median blood Phe, Tyr, Phe:Tyr ratio and anthropometry, were compared within and between the two groups at baseline, 26 and 52 weeks. Nutritional biochemistry was studied at baseline and 26 weeks only. RESULTS At the end of 52 weeks only 48% of subjects were able to completely use CGMP-AA2 as their single source of protein substitute. At 52 weeks CGMP-AA2 provided a median of 75% (30-100) of the total protein substitute with the remainder being given as L-AA. Within the CGMP-AA2 group, blood Phe increased significantly between baseline and 52 weeks: [baseline to 26 weeks; baseline Phe 270 μmol/L (170-430); 26 weeks, Phe 300 μmol/L (125-485) p = 0.06; baseline to 52 weeks: baseline, Phe 270 μmol/L (170-430), 52 weeks Phe 300 μmol/L (200-490), p < 0.001)]. However, there were no differences between the CGMP-AA2 and L-AA group for Phe, Tyr, Phe:Tyr ratio or anthropometry at any of the three measured time points. Within the CGMP-AA2 group only weight (p = 0.0001) and BMI z scores (p = 0.0001) increased significantly between baseline to 52 weeks. Whole blood and plasma selenium were significantly higher (whole blood selenium [p = 0.0002]; plasma selenium [p = 0.0007]) at 26 weeks in the CGMP-AA2 group compared L-AA. No differences were observed within the L-AA group for any of the nutritional markers. CONCLUSIONS CGMP-AA increases blood Phe concentrations and so it can only be used partly to contribute to protein substitute in some children with PKU. CGMP-AA should be carefully introduced in children with PKU and close monitoring of blood Phe control is essential.
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Ghrelin, CCK, GLP-1, and PYY(3-36): Secretory Controls and Physiological Roles in Eating and Glycemia in Health, Obesity, and After RYGB.
Steinert, RE, Feinle-Bisset, C, Asarian, L, Horowitz, M, Beglinger, C, Geary, N
Physiological reviews. 2017;(1):411-463
Abstract
The efficacy of Roux-en-Y gastric-bypass (RYGB) and other bariatric surgeries in the management of obesity and type 2 diabetes mellitus and novel developments in gastrointestinal (GI) endocrinology have renewed interest in the roles of GI hormones in the control of eating, meal-related glycemia, and obesity. Here we review the nutrient-sensing mechanisms that control the secretion of four of these hormones, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide tyrosine tyrosine [PYY(3-36)], and their contributions to the controls of GI motor function, food intake, and meal-related increases in glycemia in healthy-weight and obese persons, as well as in RYGB patients. Their physiological roles as classical endocrine and as locally acting signals are discussed. Gastric emptying, the detection of specific digestive products by small intestinal enteroendocrine cells, and synergistic interactions among different GI loci all contribute to the secretion of ghrelin, CCK, GLP-1, and PYY(3-36). While CCK has been fully established as an endogenous endocrine control of eating in healthy-weight persons, the roles of all four hormones in eating in obese persons and following RYGB are uncertain. Similarly, only GLP-1 clearly contributes to the endocrine control of meal-related glycemia. It is likely that local signaling is involved in these hormones' actions, but methods to determine the physiological status of local signaling effects are lacking. Further research and fresh approaches are required to better understand ghrelin, CCK, GLP-1, and PYY(3-36) physiology; their roles in obesity and bariatric surgery; and their therapeutic potentials.
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Accuracy of Presepsin in Sepsis Diagnosis: A Systematic Review and Meta-Analysis.
Wu, J, Hu, L, Zhang, G, Wu, F, He, T
PloS one. 2015;(7):e0133057
Abstract
OBJECTIVE It's difficult to differentiate sepsis from non-sepsis, especially non-infectious SIRS, because no good standard exists for proof of infection. Soluble CD14 subtype (sCD14-ST), recently re-named presepsin, was identified as a new marker for the diagnosis of sepsis in several reports. However, the findings were based on the results of individual clinical trials, rather than a comprehensive and overall estimation. Thus, we conducted this systematic review and meta-analysis to estimate the pooled accuracy of presepsin in patients with sepsis suspect. METHODS A comprehensive electronic search was performed via internet retrieval system up to 15 December 2014. Methodological quality assessment was applied by using the QUADAS2 tool. The diagnostic value of presepsin in sepsis was evaluated by using the pooled estimate of sensitivity, specificity, likelihood ratio, and diagnostic odds ratio, as well as summary receiver operating characteristics curve. RESULTS Nine studies with 10 trials and 2159 cases were included in the study. Only two trials had low concerns regarding applicability, whereas all trials were deemed to be at high risk of bias. Heterogeneity existed in the non-threshold effect, but not in the threshold effect. The pooled sensitivity of presepsin for sepsis was 0.78 (0.76-0.80), pooled specificity was 0.83 (0.80-0.85), pooled positive likelihood ratio was 4.63 (3.27-6.55), pooled negative likelihood ratio was 0.22 (0.16-0.30), and pooled diagnostic odds ratio was 21.73 (12.81-36.86). The area under curve of summary receiver operating characteristics curve was 0.89 (95%CI: 0.84 to 0.94) and Q* index was 0.82 (95%CI: 0.77 to 0.87). CONCLUSION This meta-analysis demonstrates that presepsin had some superiority in the management of patients, and may be a helpful and valuable biomarker in early diagnosis of sepsis. However, presepsin showed a moderate diagnostic accuracy in differentiating sepsis from non-sepsis which prevented it from being recommended as a definitive test for diagnosing sepsis in isolation, but the results should be interpreted cautiously.
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Utility of traditional circulating and imaging-based cardiac biomarkers in patients with predialysis CKD.
Colbert, G, Jain, N, de Lemos, JA, Hedayati, SS
Clinical journal of the American Society of Nephrology : CJASN. 2015;(3):515-29
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Abstract
Cardiac biomarkers, such as cardiac troponin T (cTnT), brain natriuretic peptide (BNP), and N-terminal-pro-BNP (NT-pro-BNP), are commonly used to diagnose acute coronary syndrome and congestive heart failure exacerbation in symptomatic patients. Levels of these biomarkers are frequently chronically elevated in asymptomatic patients with ESRD who are receiving maintenance dialysis. Other imaging biomarkers commonly encountered in nephrologists' clinical practice, such as coronary artery calcium measured by computed tomography, left ventricular hypertrophy, and carotid intima-media thickness, are also frequently abnormal in asymptomatic patients with ESRD. This article critically reviews the limited observational data on associations between cTnT, BNP, NT-pro-BNP, coronary artery calcium, left ventricular hypertrophy, and carotid intima-media thickness with cardiovascular events and death in non-dialysis-dependent patients with CKD. Although sufficient evidence suggests that these biomarkers may be used for prognostication, the diagnostic utility of cTnT, BNP, and NT-pro-BNP remain challenging in patients with CKD. Decreased renal clearance may affect the plasma levels of these biomarkers, and upper reference limits were originally derived in patients without CKD. Until better data are available, higher cutoffs, or a rise in level compared with previous values, have been proposed to help distinguish acute myocardial infarction from chronic elevations of cTnT in symptomatic patients with CKD. Additionally, it is not known whether these biomarkers are modifiable and amenable to interventions that could change hard clinical outcomes in patients with CKD not yet undergoing long-term dialysis.
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Cerebrospinal fluid β-amyloid1-42 levels in the differential diagnosis of Alzheimer's disease--systematic review and meta-analysis.
Mo, JA, Lim, JH, Sul, AR, Lee, M, Youn, YC, Kim, HJ
PloS one. 2015;(2):e0116802
Abstract
OBJECTIVES The purpose of this study was to carry out systematic review of the literature and meta-analysis to evaluate the diagnostic utility of cerebrospinal fluid (CSF) levels of the 42 amino acid form of amyloid-beta (Aβ1-42) as a biomarker for differentiating Alzheimer's disease (AD) from non-AD dementia. METHODS Design. Systematic literature review was used to evaluate the effectiveness of the Aβ for the diagnosis of AD. The Scottish Intercollegiate Guidelines Network (SIGN) tool was used to evaluate independently the quality of the studies. Data sources. The literature review covered from January 1, 2004, to October 22, 2013, and searched eight domestic databases including Korea Med and international databases including Ovid-MEDLINE, EMBASE, and Cochrane Library. Data Extraction and Synthesis. Primary criteria for inclusion were valid studies on (i) patients with mild cognitive impairment with confirmed or suspected AD and non-AD dementia, and (ii) assessment of Aβ1-42 levels using appropriate comparative tests. RESULTS A total of 17 diagnostic evaluation studies were identified in which levels of CSF Aβ1-42 were assessed. Meta-analysis was performed on 11 robust studies that compared confirmed AD (n = 2211) with healthy individuals (n = 1030), 10 studies that compared AD with non-AD dementias (n = 627), and 5 studies that compared amnestic mild cognitive impairment (n = 1133) with non-amnestic type subjects (n = 1276). Overall, the CSF Aβ1-42 levels were reduced in AD compared to controls or non-AD dementia. The effectiveness of test was evaluated for diagnostic accuracy (pooled sensitivity, 0.80 (95% CI 0.78-0.82); pooled specificity, 0.76 (95% CI 0.74-0.78). CONCLUSIONS Reduced CSF Aβ1-42 levels are of potential utility in the differential diagnosis of AD versus non-AD dementias and controls. Diagnostic accuracy was high in AD versus healthy controls. However, differential diagnosis for MCI or non-AD might be evaluated by other biomarkers.
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Observing the translocation of a mitochondria-penetrating peptide with solid-state NMR.
Marbella, LE, Cho, HS, Spence, MM
Biochimica et biophysica acta. 2013;(8):1674-82
Abstract
A new class of penetrating peptides that can target the mitochondria with high specificity was recently discovered. In this work, we developed a model inner mitochondrial membrane, equipped with a transmembrane gradient, suitable for solid-state NMR experiments. Using solid-state NMR, we observed a mitochondria-penetrating peptide interacting with the model inner mitochondrial membrane to gain insight into the mechanism of translocation. The paramagnetic relaxation effect due to Mn(2+) ions on (13)C magic angle spinning NMR was used to measure the insertion depth of the peptide and its distribution in each monolayer of the membrane. We found that at low peptide concentration the peptide binds to the outer leaflet and at high concentration, it crosses the hydrophobic bilayer core and is distributed in both leaflets. In both concentration regimes, the peptide binds at the C2 position on the lipid acyl chain. The mitochondria-penetrating peptide crossed to the inner leaflet of the model membranes without disrupting the lamellarity. These results provide evidence that supports the electroporation model of translocation. We estimated the energy associated with crossing the inner mitochondrial membrane. We found that the transmembrane potential provides sufficient energy for the peptide to cross the hydrophobic core, which is the most unfavorable step in translocation.
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Development of click peptide: stimuli-responsive precursor producing Alzheimer's disease-related amyloid beta peptide.
Taniguchi, A
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan. 2009;(10):1227-32
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Abstract
In a pathological mechanism of Alzheimer's disease (AD), amyloid beta peptide (Abeta) 1-42 plays a crucial role. However, the detailed pathological mechanism remains unclear. This elucidation is hampered by handling difficulties of Abeta1-42 due to its poor water-solubility and uncontrollable aggregation. These properties prevent reproducing neurotoxicity-related assembly events of Abeta1-42 in the experiments, leading to discrepant study outcomes. Namely, such properties of Abeta1-42 are serious obstacles to establish an experiment system that clarifies the pathological mechanism of Abeta1-42 in AD. To solve these problems, we developed "click peptide" of Abeta1-42 based on the "Omicron-acyl isopeptide method". The click peptide, which contains an Omicron-acyl instead of N-acyl residue at Gly(25)-Ser(26) of Abeta1-42, is converted to Abeta1-42 via an Omicron-to-N intramolecular acyl migration upon being triggered by pH-change (pH-click) or photo-irradiation (photo-click). The click peptide was 100-fold more water-soluble than Abeta1-42 and clearly adopted a monomeric random coil structure due to the Omicron-acyl moiety in the peptide backbone. The click peptide was quickly converted to monomer Abeta1-42 with a random coil structure under physiological conditions upon an action (click). The obtained Abeta1-42 underwent both self-assembly and conformational changes with time. Because the in situ production of intact Abeta1-42 from the water-soluble and non-aggregative precursor could overcome the handling problems of Abeta1-42, this click peptide strategy would provide a reliable experiment system to investigate the pathological functions of Abeta1-42 in AD.
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Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease.
De Strooper, B
EMBO reports. 2007;(2):141-6
Abstract
Presenilin mutations are the main cause of familial Alzheimer disease. From a genetic point of view, these mutations seem to result in a gain of toxic function; however, biochemically, they result in a partial loss of function in the gamma-secretase complex, which affects several downstream signalling pathways. Consequently, the current genetic terminology is misleading. In fact, the available data indicate that several clinical presenilin mutations also lead to a decrease in amyloid precursor protein-derived amyloid beta-peptide generation, further implying that presenilin mutations are indeed loss-of-function mutations. The loss of function of presenilin causes incomplete digestion of the amyloid beta-peptide and might contribute to an increased vulnerability of the brain, thereby explaining the early onset of the inherited form of Alzheimer disease. In this review, I evaluate the implications of this model for the amyloid-cascade hypothesis and for the efficacy of presenilin/gamma-secretase as a drug target.
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[A case of bladder tumor producing granulocyte-colony stimulation factor and parathyroid hormone-related protein].
Tsuchiya, F, Ikeda, I, Kanda, F, Fukuoka, H
Hinyokika kiyo. Acta urologica Japonica. 2001;(12):873-6
Abstract
A 68-year-old woman presented with urinary pain and frequency. Cystoscopy, intravenous pyelography and magnetic resonance imaging showed a huge bladder mass and hydronephrosis of the left kidney. Transurethral resection of bladder tumor (TUR-Bt) was done. Histopathological findings of TUR-biopsy was high grade transitional cell carcinoma. Post operatively, the laboratory examination showed marked leukocytosis with a maximum of 99,600/mm3 in the peripheral blood and a high level of granulocyte colony stimulating factor (G-CSF), 70 pg/ml in the serum (normal: less than 9.8 pg/ml). Serum calcium level increased gradually and parathyroid hormone-related protein (PTH-rP) revealed high, 8.4 pMol/l (normal: less than 0.6 pMol/l). The tumor cells were positive for G-CSF and PTH-rP immunohistochemical staining. She died of the disease 46 days after the operation. This is the third case of G-CSF and PTH-rP producing bladder tumor in the literature.