High Protein Research Articles

Conserved sequence features in intracellular domains of viral spike proteins

Viral spike proteins mutate frequently, but conserved features within these proteins often have functional importance and can inform development of anti-viral therapies which circumvent the effects of viral sequence mutations. Through analysis of large numbers of viral spike protein sequences from several viral families, we found highly (>99%) conserved patterns within their intracellular domains. The patterns generally consist of one or more basic amino acids (arginine or lysine) adjacent to a cysteine, many of which are known to undergo acylation. These patterns were not enriched in cellular proteins in general. Molecular dynamics simulations show direct electrostatic and hydrophobic interactions between these conserved residues in hemagglutinin (HA) from influenza A and B and the phosphoinositide PIP2. Super-resolution microscopy shows nanoscale colocalization of PIP2 and several of the same viral proteins. We propose the hypothesis that these conserved viral spike protein features can interact with phosphoinositides such as PIP2.

Prion protein gene (PRNP) variation in German and Danish cervids

The structure of cellular prion proteins encoded by the prion protein gene (PRNP) impacts susceptibility to transmissible spongiform encephalopathies, including chronic wasting disease (CWD) in deer. The recent emergence of CWD in Northern European reindeer (Rangifer tarandus), moose (Alces alces alces) and red deer (Cervus elaphus), in parallel with the outbreak in North America, gives reason to investigate PRNP variation in European deer, to implement risk assessments and adjust CWD management for deer populations under threat. We here report PRNP-sequence data from 911 samples of German red, roe (Capreolus capreolus), sika (Cervus nippon) and fallow deer (Dama dama) as well as additional data from 26 Danish red deer close to the German border and four zoo species not native to Germany. No PRNP sequence variation was observed in roe and fallow deer, as previously described for populations across Europe. In contrast, a broad PRNP variation was detected in red deer, with non-synonymous polymorphisms at codons 98, 226 and 247 as well as synonymous mutations at codons 21, 78, 136 and 185. Moreover, a novel 24 bp deletion within the octapeptide repeat was detected. In summary, 14 genotypes were seen in red deer with significant differences in their geographical distribution and frequencies, including geographical clustering of certain genotypes, suggesting “PRNP-linages” in this species. Based on data from North American CWD and the genotyping results of the European CWD cases, we would predict that large proportions of wild cervids in Europe might be susceptible to CWD once introduced to naive populations.

Endothelial Cell Transcription Modulation in Cerebral Aneurysms After Endovascular Flow Diversion.

Flow diverting stents (FDS) are used to treat cerebral aneurysms, by promoting thrombosis and occlusion of the aneurysm sac. However, retreatment is required in some cases, and the biologic basis behind treatment outcome is not known. The goal of this study was to understand how changes in hemodynamic flow after FDS placement affect aneurysmal endothelial cell (EC) activity. Three-dimensional models of patient-specific aneurysms were created to quantify the EC response to FDS placement. Computational fluid dynamic simulations were used to determine the hemodynamic impact of FDS. Two identical models were created for each patient; into one a FDS was inserted. Each model was then populated with human carotid ECs and subjected to patient-specific pulsatile flow for 24 h. ECs were isolated from aneurysm dome from each model and bulk RNA sequencing was performed. Paired untreated and treated models were created for four patients. Aneurysm dome EC analysis revealed 366 (2.6%) significant gene changes between the untreated and FDS conditions, out of 13909 total expressed genes. Gene set enrichment analysis of the untreated models demonstrated enriched gene ontology terms related to cell adhesion, growth/tensile activity, cytoskeletal organization, and calcium ion binding. In the FDS models, enriched terms were related to cellular proliferation, ribosomal activity, RNA splicing, and protein folding. Treatment of cerebral aneurysms with FDS induces significant EC gene transcription changes related to aneurysm hemodynamics in patient-specific in vitro 3D-printed models subjected to pulsatile flow. Further investigation is needed into the relationship between transcriptional change and treatment outcome.

Immune response of Rhinogobio ventralis to Ichthyophthirius multifiliis infection: Insights from histopathological and real-time gene expression analyses

Ichthyophthirius multifiliis is a parasite that poses a considerable threat to aquaculture and the ornamental fish industry, but with limited effective treatment options available. This study employed RT-qPCR to detect and analyze the expression changes of partial toll-like receptor (TLR) genes (TLR1 and TLR21), adapter protein and signal transduction molecule genes (MyD88, TRIF, NF-κB, IRAK4, and IRF3), and cytokines (IL-6, IL-8, IL-13, CXC-α and CXCR1), as well as complement C3, in the skin, gill, fin, liver, head kidney and spleen of Rhinogobio ventralis under different infection conditions. Additionally, tissue sections and scanning electron microscopy were utilized to observe the pathological changes in the gills and fins of R. ventralis after infection with I. multifiliis. The expression patterns of TLR-related DEGs (differentially expressed genes) in diseased wild fish were analyzed, revealing upregulation of TLR1, TLR21, MyD88, NF-κB, IRAK4, TRIF, IRF3, IL-6, IL-8, IL-13, CXC-α, CXCR1, and C3 genes in various tissues, indicating that these genes may be involved in the immune response of R. ventralis to I. multifiliis infection. To further analyze the gene expression of sampled from the field, an artificial infection model of R. ventralis was established under laboratory conditions, with additional sampling from the skin and fins. These genes continued to show varying degrees of upregulation, but the results were not entirely consistent with those from Wudongde samples, which may be due to the more complex environment in the wild or differences in the degree of I. multifiliis infection in wild fish. The infection of I. multifiliis caused severe damage to the gills and fins of R. ventralis, characterized by extensive secretions on the gill and fin surfaces, with the presence of attached I. multifiliis trophonts, including damage and loss of gill filaments, swollen gill lamellae, and deformed gill plates, as well as cell proliferation and necrosis of gill epithelial cells. This study sheds light on the role of the TLR signaling pathway in resisting I. multifiliis infection and its associated histopathological changes in R. ventralis, providing valuable insights for the prevention and treatment of I. multifiliis infection in R. ventralis.

Computational studies on the catalytic potential of the double active site for enzyme engineering

Proteins possessing double active sites have the potential to revolutionise enzyme design strategies. This study extensively explored an enzyme that contains both a natural active site (NAS) and an engineered active site (EAS), focusing on understanding its structural and functional properties. Metadynamics simulations were employed to investigate how substrates interacted with their respective active sites. The results revealed that both the NAS and EAS exhibited similar minimum energy states, indicating comparable binding affinities. However, it became apparent that the EAS had a weaker binding site for the substrate due to its smaller pocket and constrained conformation. Interestingly, the EAS also displayed dynamic behaviour, with the substrate observed to move outside the pocket, suggesting the possibility of substrate translocation. To gain further insights, steered molecular dynamics (SMD) simulations were conducted to study the conformational changes of the substrate and its interactions with catalytic residues. Notably, the substrate adopted distinct conformations, including near-attack conformations, in both the EAS and NAS. Nevertheless, the NAS demonstrated superior binding minima for the substrate compared to the EAS, reinforcing the observation that the engineered active site was less favourable for substrate binding due to its limitations. The QM/MM (Quantum mechanics and molecular mechanics) analyses highlight the energy disparity between NAS and EAS. Specifically, EAS exhibited elevated energy levels due to its engineered active site being located on the surface. This positioning exposes the substrate to solvents and water molecules, adding to the energy challenge. Consequently, the engineered enzyme did not provide a significant advantage in substrate binding over the single active site protein. Further, the investigation of internal channels and tunnels within the protein shed light on the pathways facilitating transport between the two active sites. By unravelling the complex dynamics and functional characteristics of this double-active site protein, this study offers valuable insights into novel strategies of enzyme engineering. These findings establish a solid foundation for future research endeavours aimed at harnessing the potential of double-active site proteins in diverse biotechnological applications.

Effects of higher dietary acid load: a narrative review with special emphasis in children.

Metabolic effects of high diet acid load (DAL) have been studied for years in adults, although only recently in children. Contemporary diets, especially those of Western societies, owe their acidogenic effect to high animal-origin protein content and low contribution of base-forming elements, such as fruits and vegetables. This imbalance, where dietary acid precursors exceed the body's buffering capacity, results in an acid-retaining state known by terms such as "eubicarbonatemic metabolic acidosis," "low-grade metabolic acidosis," "subclinical acidosis," or "acid stress". Its consequences have been linked to chronic systemic inflammation, contributing to various noncommunicable diseases traditionally considered more common in adulthood, but now have been recognized to originate at much earlier ages. In children, effects of high DAL are not limited to growth impairment caused by alterations of bone and muscle metabolism, but also represent a risk factor for conditions such as obesity, insulin resistance, diabetes, hypertension, urolithiasis, and chronic kidney disease (CKD). The possibility that high DAL may be a cause of chronic acid-retaining states in children with growth impairment should alert pediatricians and pediatric nephrologists, since its causes have been attributed traditionally to inborn errors of metabolism and renal pathologies such as CKD and renal tubular acidosis. The interplay between DAL, overall diet quality, and its cascading effects on children's health necessitates comprehensive nutritional assessments and interventions. This narrative review explores the clinical relevance of diet-induced acid retention in children and highlights the potential for prevention through dietary modifications, particularly by increasing fruit and vegetable intake alongside appropriate protein consumption.

Ferulic acid improved the yogurt stability through interaction with milk protein

Our previous study suggested that bound phenolic acids of rice bran were converted into free phenolic acids during fermentation and these free phenolic acids improved the yogurt stability. Thus, this work investigated the effect of adding ferulic acid, the major phenolic acid of rice bran, on the yogurt stability. It was observed that the syneresis of yogurt was reduced by adding 100 μg/mL ferulic acid before fermentation, which suggested that ferulic acid increased the yogurt stability. Accordingly, adding ferulic acid made the yogurt gel more compact. However, 100 μg/mL ferulic acid had no significant impact on the pH, viscosity, and viscoelasticity of yogurt. Thus, the interaction between ferulic acid and milk protein was investigated. It was observed that ferulic acid interacted with milk protein through the hydrogen bond and van der Waals force. Therefore, it was speculated that ferulic acid interacted with milk protein molecules and induced the more compact structure of yogurt, thus improving the yogurt stability. However, adding ferulic acid after fermentation had no significant impact on the yogurt stability, because the gelation of milk protein caused by fermentation hindered the interaction between ferulic acid and milk protein.

Single and Combined Serum Proteins Expressed in TB Infection are Candidates for Point-of-care Diagnostic Testing of Active TB Patients in Lambaréné, Gabon.

Point-of-care testing using nonsputum samples like serum or plasma proteins can improve tuberculosis (TB) patients access to a definitive diagnosis, especially in resource-constrained and remote areas. Recently, approximately 400 proteins were identified as playing a role in the pathogenesis of TB, offering a translational clinical research repository for TB. In a previous manuscript, we proved the potential use of these proteins for point-of-care testing for active TB diagnosis. The present work aims to confirm the performance of single and combination proteins to select the best candidate biomarkers for further development as a diagnostic testing tool for active TB. Seventy-four participants were assessed on the diagnostic performance of 17 single proteins and combinations of 2 to 4 proteins to diagnose active TB. The selection criteria included differential expression of the proteins between active TB and community-acquired pneumonia (CAP) and a performance rate ≥70% for active TB. SULT4A1, WASPF3, SPTLC1, FAM107B, SORCS2, and CYTOb561 were differentially expressed in TB compared to CAP patients. Two single proteins, SULT4A1 and WASPF3, performed ≥70% to discriminate active TB from CAP patients. The diagnostic performance of 3 protein-based combinations of active TB was 81% after leave-one-out cross-validation. Single proteins and 3 protein-based combinations are candidate biomarkers for diagnosing active TB disease. A large and prospective study will confirm their performance as complementary diagnostic tools to rapid diagnostic methods for detecting active TB.

Evolutionary analysis of ZAP and its cofactors identifies intrinsically disordered regions as central elements in host-pathogen interactions

The zinc-finger antiviral protein (ZAP) is an innate immunity sensor of non-self nucleic acids. Its antiviral activity is exerted through the physical interaction with different cofactors, including TRIM25, Riplet and KHNYN. Cellular proteins that interact with infectious agents are expected to be engaged in genetic conflicts that often result in their rapid evolution. To test this possibility and to identify the regions most strongly targeted by natural selection, we applied in silico molecular evolution tools to analyze the evolutionary history of ZAP and cofactors in four mammalian groups. We report evidence of positive selection in all genes and in most mammalian groups. On average, the intrinsically disordered regions (IDRs) embedded in the four proteins evolve significantly faster than folded domains and most positively selected sites fall within IDRs. In ZAP, the PARP domain also shows abundant signals of selection, and independent evolution in different mammalian groups suggests modulation of its ADP-ribose binding ability. Detailed analyses of the biophysical properties of IDRs revealed that chain compaction and conformational entropy are conserved across mammals. The IDRs in ZAP and KHNYN are particularly compact, indicating that they may promote phase separation (PS). In line with this hypothesis, we predicted several PS-promoting regions in ZAP and KHNYN, as well as in TRIM25. Positively selected sites are abundant in these regions, suggesting that PS may be important for the antiviral functions of these proteins and the evolutionary arms race with viruses. Our data shed light into the evolution of ZAP and cofactors and indicate that IDRs represent central elements in host-pathogen interactions.

Protein modification in neurodegenerative diseases.

Posttranslational modifications play a crucial role in governing cellular functions and protein behavior. Researchers have implicated dysregulated posttranslational modifications in protein misfolding, which results in cytotoxicity, particularly in neurodegenerative diseases such as Alzheimer disease, Parkinson disease, and Huntington disease. These aberrant posttranslational modifications cause proteins to gather in certain parts of the brain that are linked to the development of the diseases. This leads to neuronal dysfunction and the start of neurodegenerative disease symptoms. Cognitive decline and neurological impairments commonly manifest in neurodegenerative disease patients, underscoring the urgency of comprehending the posttranslational modifications' impact on protein function for targeted therapeutic interventions. This review elucidates the critical link between neurodegenerative diseases and specific posttranslational modifications, focusing on Tau, APP, α-synuclein, Huntingtin protein, Parkin, DJ-1, and Drp1. By delineating the prominent aberrant posttranslational modifications within Alzheimer disease, Parkinson disease, and Huntington disease, the review underscores the significance of understanding the interplay among these modifications. Emphasizing 10 key abnormal posttranslational modifications, this study aims to provide a comprehensive framework for investigating neurodegenerative diseases holistically. The insights presented herein shed light on potential therapeutic avenues aimed at modulating posttranslational modifications to mitigate protein aggregation and retard neurodegenerative disease progression.

Impact of protein and small molecule interactions on kinase conformations.

Protein kinases act as central molecular switches in the control of cellular functions. Alterations in the regulation and function of protein kinases may provoke diseases including cancer. In this study we investigate the conformational states of such disease-associated kinases using the high sensitivity of the kinase conformation (KinCon) reporter system. We first track BRAF kinase activity conformational changes upon melanoma drug binding. Second, we also use the KinCon reporter technology to examine the impact of regulatory protein interactions on LKB1 kinase tumor suppressor functions. Third, we explore the conformational dynamics of RIP kinases in response to TNF pathway activation and small molecule interactions. Finally, we show that CDK4/6 interactions with regulatory proteins alter conformations which remain unaffected in the presence of clinically applied inhibitors. Apart from its predictive value, the KinCon technology helps to identify cellular factors that impact drug efficacies. The understanding of the structural dynamics of full-length protein kinases when interacting with small molecule inhibitors or regulatory proteins is crucial for designing more effective therapeutic strategies.

Impact of protein and small molecule interactions on kinase conformations

Protein kinases act as central molecular switches in the control of cellular functions. Alterations in the regulation and function of protein kinases may provoke diseases including cancer. In this study we investigate the conformational states of such disease-associated kinases using the high sensitivity of the kinase conformation (KinCon) reporter system. We first track BRAF kinase activity conformational changes upon melanoma drug binding. Second, we also use the KinCon reporter technology to examine the impact of regulatory protein interactions on LKB1 kinase tumor suppressor functions. Third, we explore the conformational dynamics of RIP kinases in response to TNF pathway activation and small molecule interactions. Finally, we show that CDK4/6 interactions with regulatory proteins alter conformations which remain unaffected in the presence of clinically applied inhibitors. Apart from its predictive value, the KinCon technology helps to identify cellular factors that impact drug efficacies. The understanding of the structural dynamics of full-length protein kinases when interacting with small molecule inhibitors or regulatory proteins is crucial for designing more effective therapeutic strategies.

GmIRT1.1 from soybean (Glycine max L.) is involved in transporting Fe, Mn and Cd

Soybean is one of the most important crops for producing high quality oil and protein. Mineral nutrient deficiencies are frequently observed in soybeans. However, there are few studies to understand the absorption process of mineral nutrients in soybeans. Here, we investigated the functions of soybean (Glycine max L.) IRT1.1 (IRON-REGULATED TRANSPORTER 1.1) in the transportation of mineral elements. Heterologous expression of GmIRT1.1 in yeast mutants revealed that GmIRT1.1 compensated for the growth defects of Δfet3fet4 and Δsmf1 mutants under iron (Fe) and manganese (Mn) deficiency conditions, respectively, and enhanced the sensitivity of the Δycf1 mutant to cadmium (Cd) toxicity. Expression analysis revealed that GmIRT1.1 was only significantly induced by Fe deficiency and was primarily expressed in roots. Furthermore, the GmIRT1.1 overexpression lines enhanced Arabidopsis tolerance to Fe deficiency, leading to increased accumulation of Fe in the roots and shoots. Additionally, the transgenic lines increased the sensitivity to Mn and Cd toxicity. Subcellular localization analysis revealed that GmIRT1.1 was localized on the plasma membrane. Moreover, the results obtained from the soybean hairy roots system indicated that the localization of GmIRT1.1 was dependent on the regulation of Fe homeostasis in plant. Consequently, these results suggested that GmIRT1.1 was responsible for the transportation of Fe, Mn and Cd.

Autophagy in drusen biogenesis secondary to age-related macular degeneration.

Age-related macular degeneration (AMD) is an emerging cause of blindness in aged people worldwide. One of the key signs of AMD is the degeneration of the retinal pigment epithelium (RPE), which is indispensable for the maintenance of the adjacent photoreceptors. Because of impaired energy metabolism resulting from constant light exposure, hypoxia, and oxidative stress, accumulation of drusen in AMD-affected eyes is observed. Drusen contain damaged cellular proteins, lipoprotein particles, lipids and carbohydrates and they are related to impaired protein clearance, inflammation, and extracellular matrix modification. When autophagy, a major cellular proteostasis pathway, is impaired, the accumulations of intracellular lipofuscin and extracellular drusen are detected. As these aggregates grow over time, they finally cause the disorganisation and destruction of the RPE and photoreceptors leading to visual loss. In this review, the role of autophagy in drusen biogenesis is discussed since impairment in removing cellular waste in RPE cells plays a key role in AMD progression. In the future, means which improve intracellular clearance might be of use in AMD therapy to slow the progression of drusen formation.

Human eRF1 Translation Regulation

Eukaryotic translation release factor eRF1 is an important cellular protein that plays a key role in translation termination, nonsense-mediated mRNA decay (NMD), and readthrough of stop codons. The amount of eRF1 in the cell influences all these processes. The mechanism of regulation of eRF1 translation through an autoregulatory NMD-dependent expression circuit has been described for plants and fungi, but the mechanisms of regulation of human eRF1 translation have not yet been studied. Using reporter constructs, we studied the effect of eRF1 mRNA elements on its translation in cell-free translation systems and HEK293 cell culture. Our data indicate the absence of an NMD-dependent autoregulatory circuit for human eRF1 expression. We found that the translation of the eRF1 coding sequence is most strongly influenced by the 5′ untranslated region of eRF1 mRNA and the start codon of the upstream open reading frame. According to the transcription start database, eRF1 mRNA is characterized by high heterogeneity of the transcription start and a variable 5' untranslated region in length. In addition, the start codon of the CDS in eRF1 mRNA is located within the known translational regulator of short 5' untranslated regions (TISU), which also stimulates mRNA transcription of genes with high transcription start heterogeneity. We hypothesize that regulation of human eRF1 synthesis occurs at both the transcriptional and translational levels. At the transcription level, the length of the eRF1 5' untranslated region and the number of the upstream open reading frames in it are regulated. This regulation in turn, regulates the production of eRF1 at the translation level.

Polyamidoamine dendrimer-modified polyvinylidene fluoride microporous membranes for protein separation

The separation efficiency of pressure-driven filtration membranes is primarily dictated by the membrane pore size. Membranes with larger pores typically demonstrate high flux but low or zero rejection when it comes to separating small molecules. In protein separation, ultrafiltration (UF) membranes with pore sizes smaller than the molecular dimensions of target proteins are commonly used for size rejection. Taking inspiration from the separation mechanism of nanofiltration (NF) membranes, we hypothesize that introducing charged groups into membranes of appropriate pore sizes could significantly enhance the electrical interaction between membrane charges and protein charges. This enhancement, occurring at the nanoscale distance when protein molecules approach or pass through charged nanoscale membrane channels, may enable the rejection of proteins substantially smaller than the pore size. Using membranes with relatively large pore sizes could lead to an increase in flux. To test this hypothesis, we conducted experiments involving the modification of polyvinylidene fluoride (PVDF) membranes with suitable pore sizes, using polyamidoamine (PAMAM) dendrimers to introduce negative charges to the membranes. The performance of the PVDF membranes and the modified membranes were investigated in the separation of whey proteins. To evaluate the contribution of steric and electrical hindrance to the solute separation, filtration experiments were performed using polyethylene oxide (PEO) and polyacrylic acid (PAA). The membranes were characterized using techniques such as Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR), X-ray Photoelectron Spectroscopy (XPS), and Scanning Electron Microscopy (SEM). The results indicate that the modification enhances the rejection efficiency of whey proteins. The whey protein rejection and permeate flux for PVDF membranes were 58.9% and 15.3 LMH, respectively. Following alkaline treatment or PAMAM-G3.5 dendrimer modification, the whey protein rejection increased to 97.3% and 98.8%, respectively. However, alkaline treatment and PAMAM-G3.5 dendrimer modification resulted in a reduction of permeate flux to 5.6 LMH and 2.3 LMH, respectively. This suggests that increasing membrane charge effectively enhances the separation ability of filtration membranes in charged macromolecule separation.

Effect of mild subcritical fluid treatment on meat quality of farmed large yellow croakers

Farmed large yellow croaker fish have stronger fishy smell and less tender texture than wild-caught ones, mostly caused by the high fat accumulation from aquaculture feeding patterns. To improve the commercial value of fillets, this study investigated a mild subcritical fluid treatment with subcritical butane (SBE) and dimethyl ether (SDME). Changes in the chemical compositions, volatile flavor compounds (VFCs) and protein denaturation were determined for 1-5h treatments. The results showed 24% and 44% defatting levels under SBE and SDME treatment, respectively. GC-MS showed that SDME could induce a significant reduction of total VFC content, especially for the dominant aldehydes. There was less n-nonanal (14.65-40.13mg/kg) and octanal content (1.67-7.21mg/kg), no detection of trans, trans-2,4-decadienal in the SDME treated samples in comparison to those treated with SBE. The results showed that SDME treatment for 3h had the best defatting effect, good deodorization effect and less degradation of fish protein.

Understanding protein adsorption on silica mesoporous materials through thermodynamic simulations

This work presents a molecular thermodynamic theory to study protein interactions within a charge-regulating silica-like nanopore structure. The theory accounts for electrostatic interactions, steric repulsions, finite-size entropic effects, and protonation equilibrium of silanol groups on silica and protein residue side-chains. Coarse-grained representations of proteins based on their 3D crystallographic structures are employed. We evaluate the influence of pH, salt concentration, and pore size on the adsorption of selected proteins (cytochrome c, lysozyme, and myoglobin) in both single- and binary-protein solutions. The surface charge density on the nanopore walls is more negative than on the adjacent planar surface, primarily influenced by pH and salt concentration. Adsorption within the nanopore from single protein solutions exhibits a non-monotonic behavior with pH, increasing with decreasing salt concentration and diminishing pore size. Analysis of the effective interactions between proteins and silica surfaces indicates that adsorption is enhanced when the protein size matches that of the nanopore. Evaluation of various adsorption pathways indicates minimized free energy when the protein enters the nanopore through its edge and contacts its cylindrical walls. In binary solutions, the presence of another protein significantly alters the affinity of a protein for the silica surfaces, potentially preventing its adsorption, and affects its organization on these surfaces upon adsorption.

The role of osteopontin and osteocyte-derived factors in secondary hyperparathyroidism-induced myopathy.

Muscle weakness is a common symptom in CKD patients, and the pathway by which secondary hyperparathyroidism (SHPT) affects muscle function is unknown. Osteopontin (OPN), a bone matrix protein stimulated by PTH and phosphate, has been associated with inflammatory muscle diseases. In this observational and prospective cohort study, we evaluated 30 patients with severe SHPT (39 ± 12yr; 18 women), before and 6mo after parathyroidectomy (PTx). We examined the relationships among CKD-mineral and bone disorder parameters; myokine and inflammatory cytokine levels; and changes in resting energy expenditure (REE), muscle function, BMD, and muscle-related proteins. At baseline, the patients showed low gene expression of muscle turnover markers and irisin, as well as high protein expression of OPN, transforming growth factor beta (TGF-β), and fibroblast growth factor 21. Six months after PTx, REE and muscle mass had not changed, but physical performance, muscle strength, and bone mass improved, more so in patients undergoing total PTx. Also, there were reductions in the protein expression of OPN (11 vs 3%, p=.01) and TGF-β (21 vs 7%, p=.002) in muscle, together with a significant increase in irisin muscular levels (30 vs 35pg/mg, p=.02). The gain in bone mass and the increase in irisin levels correlated with a reduction in PTH. The levels of interleukin (IL)-1β, tumor necrosis factor alpha, and IL-17 (markers of myositis) were also lower after PTx. Our data suggest that SHPT plays a role in CKD-induced muscle dysfunction, indirectly, via release of bone-specific proteins, which is partially reverted with PTx.

Protein Intake and Mortality in Older Adults With Chronic Kidney Disease.

Avoiding high protein intake in older adults with chronic kidney disease (CKD) may reduce the risk of kidney function decline, but whether it can be suboptimal for survival is not well known. To estimate the associations of total, animal, and plant protein intake with all-cause mortality in older adults with mild or moderate CKD and compare the results to those of older persons without CKD. Data from 3 cohorts (Study on Cardiovascular Health, Nutrition and Frailty in Older Adults in Spain 1 and 2 and the Swedish National Study on Aging and Care in Kungsholmen [in Sweden]) composed of community-dwelling adults 60 years or older were used. Participants were recruited between March 2001 and June 2017 and followed up for mortality from December 2021 to January 2024. Those with no information on diet or mortality, with CKD stages 4 or 5, or undergoing kidney replacement therapy and kidney transplant recipients were excluded. Data were originally analyzed from June 2023 to February 2024 and reanalyzed in May 2024. Cumulative protein intake, estimated via validated dietary histories and food frequency questionnaires. The study outcome was 10-year all-cause mortality, ascertained with national death registers. Chronic kidney disease was ascertained according to estimated glomerular filtration rates, urine albumin excretion, and diagnoses from medical records. The study sample consisted of 8543 participants and 14 399 observations. Of the 4789 observations with CKD stages 1 to 3, 2726 (56.9%) corresponded to female sex, and mean (SD) age was 78.0 (7.2) years. During the follow-up period, 1468 deaths were recorded. Higher total protein intake was associated with lower mortality among participants with CKD; adjusted hazard ratio (HR) for 1.00 vs 0.80 g/kg/d was 0.88 (95% CI, 0.79-0.98); for 1.20 vs 0.80 g/kg/d, 0.79 (95% CI, 0.66-0.95); and for 1.40 vs 0.80 g/kg/d, 0.73 (95% CI, 0.57-0.92). Associations with mortality were comparable for plant and animal protein (HRs, 0.80 [95% CI, 0.65-0.98] and 0.88 [95% CI, 0.81-0.95] per 0.20-g/kg/d increment, respectively) and for total protein intake in participants younger than 75 years vs 75 years or older (HRs, 0.94 [95% CI, 0.85-1.04] and 0.91 [95% CI, 0.85-0.98] per 0.20-g/kg/d increment in total protein intake, respectively). However, the hazards were lower among participants without CKD than in those with CKD (HRs, 0.85 [95% CI, 0.79-0.92] and 0.92 [95% CI, 0.86-0.98] per 0.20-g/kg/d increment, respectively; P = .02 for interaction). In this multicohort study of older adults, higher intake of total, animal, and plant protein was associated with lower mortality in participants with CKD. Associations were stronger in those without CKD, suggesting that the benefits of proteins may outweigh the downsides in older adults with mild or moderate CKD.