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Physiological Reports Jul 2024The central role of natriuretic peptides (NPs) in the complex cardio-renal integrated physiology and organ failure has been revealed over the last four decades. Atrial... (Review)
Review
The central role of natriuretic peptides (NPs) in the complex cardio-renal integrated physiology and organ failure has been revealed over the last four decades. Atrial natriuretic peptide (ANP), the oldest representative of the NPs family, is produced through conversion of proANP to the mature peptide by corin, a trans-membrane protease localized to the cardiac myocyte membrane. Similarly, brain natriuretic peptide (BNP) is generated by furin, which cleaves proBNP to BNP in myocytes. Though the components of NPs system, their synthesis and target organs are well established, understanding their role in the interplay between the heart and the kidney is steadily evolving. In this context, Feldman et al. (New England Journal of Medicine, 389, 1685) recently described patients with hypertension, cardiomyopathy, atrial arrhythmia and left atrial fibrosis, associated with a homozygous loss-of-function variant of the gene encoding corin (Cor). Notably, reduced baseline urinary electrolyte and creatinine excretion have been observed in one of the studied patients. This renal excretory functional impairment could be attributed to the lack of cardiac-derived ANP in these patients, as implied by Feldman et al. Yet, in this mini-review we suggest that this aberrant renal manifestation may principally stem from lack of local ANP production at renal tissue, as corin is normally expressed in proximal tubules, Henle's loop and collecting ducts, with locally produced ANP provoking Na and water exertion. Collectively, it seems that beside the classic well-established cardio-renal axis, the renal NPs system functions as local endocrine machinery in the regulation of sodium excretion.
Topics: Humans; Animals; Kidney; Serine Endopeptidases; Atrial Natriuretic Factor; Heart
PubMed: 38942727
DOI: 10.14814/phy2.16105 -
RMD Open Jun 2024To investigate the efficacy, safety, pharmacokinetics and pharmacodynamics of nipocalimab in participants with moderate to severe active rheumatoid arthritis (RA) and... (Randomized Controlled Trial)
Randomized Controlled Trial
Nipocalimab, an anti-FcRn monoclonal antibody, in participants with moderate to severe active rheumatoid arthritis and inadequate response or intolerance to anti-TNF therapy: results from the phase 2a IRIS-RA study.
OBJECTIVES
To investigate the efficacy, safety, pharmacokinetics and pharmacodynamics of nipocalimab in participants with moderate to severe active rheumatoid arthritis (RA) and inadequate response or intolerance to ≥1 antitumour necrosis factor agent.
METHODS
In this phase 2a study, participants with RA seropositive for anticitrullinated protein antibodies (ACPA) or rheumatoid factors were randomised 3:2 to nipocalimab (15 mg/kg intravenously every 2 weeks) or placebo from Weeks 0 to 10. Efficacy endpoints (primary endpoint: change from baseline in Disease Activity Score 28 using C reactive protein (DAS28-CRP) at Week 12) and patient-reported outcomes (PROs) were assessed through Week 12. Safety, pharmacokinetics and pharmacodynamics were assessed through Week 18.
RESULTS
53 participants were enrolled (nipocalimab/placebo, n=33/20). Although the primary endpoint did not reach statistical significance for nipocalimab versus placebo, a numerically higher change from baseline in DAS28-CRP at Week 12 was observed (least squares mean (95% CI): -1.03 (-1.66 to -0.40) vs -0.58 (-1.24 to 0.07)), with numerically higher improvements in all secondary efficacy outcomes and PROs. Serious adverse events were reported in three participants (burn infection, infusion-related reaction and deep vein thrombosis). Nipocalimab significantly and reversibly reduced serum immunoglobulin G, ACPA and circulating immune complex levels but not serum inflammatory markers, including CRP. ACPA reduction was associated with DAS28-CRP remission and 50% response rate in American College of Rheumatology (ACR) criteria; participants with a higher baseline ACPA had greater clinical improvement.
CONCLUSIONS
Despite not achieving statistical significance in the primary endpoint, nipocalimab showed consistent, numerical efficacy benefits in participants with moderate to severe active RA, with greater benefit observed for participants with a higher baseline ACPA.
TRIAL REGISTRATION NUMBER
NCT04991753.
Topics: Humans; Arthritis, Rheumatoid; Male; Female; Middle Aged; Treatment Outcome; Antirheumatic Agents; Severity of Illness Index; Antibodies, Monoclonal, Humanized; Aged; Adult; Tumor Necrosis Factor-alpha; Double-Blind Method; Patient Reported Outcome Measures; Anti-Citrullinated Protein Antibodies
PubMed: 38942592
DOI: 10.1136/rmdopen-2024-004278 -
International Journal of Pharmaceutics Jun 2024We have recently witnessed that considerable progresses have been made in the rapid detection and appropriate treatments of COVID-19, but still this virus remains one of...
We have recently witnessed that considerable progresses have been made in the rapid detection and appropriate treatments of COVID-19, but still this virus remains one of the main targets of world research. Based on the knowledge of the complex mechanism of viral infection we designed peptide-dendrimer inhibitors of SARS-CoV-2with the aim to block cell infection through interfering with the host-pathogen interactions. We used two different strategies: i) the first one aims at hindering the virus anchorage to the human cell; ii) the second -strategy points to interfere with the mechanism of virus-cell membrane fusion. We propose the use of different nanosized carriers, formed by several carbosilane dendritic wedges to deliver two different peptides designed to inhibit host interaction or virus entry. The antiviral activity of the peptide-dendrimers, as well as of free peptides and free dendrimers was evaluated through the use of SARS-CoV-2 pseudotyped lentivirus. The results obtained show that peptides designed to block host-pathogen interaction represent a valuable strategy for viral inhibition.
PubMed: 38942185
DOI: 10.1016/j.ijpharm.2024.124389 -
Stem Cell Research Jun 2024Cardiovascular disease remains a global health concern. Stem cell therapy utilizing human cardiac progenitor cells (hCPCs) shows promise in treating cardiac vascular...
Cardiovascular disease remains a global health concern. Stem cell therapy utilizing human cardiac progenitor cells (hCPCs) shows promise in treating cardiac vascular disease. However, limited availability and senescence of hCPCs hinder their widespread use. To address these challenges, researchers are exploring innovative approaches. In this study, a bioengineered cell culture plate was developed to mimic the natural cardiac tissue microenvironment. It was coated with a combination of extracellular matrix (ECM) peptide motifs and mussel adhesive protein (MAP). The selected ECM peptide motifs, derived from fibronectin and vitronectin, play crucial roles in hCPCs. Results revealed that the Fibro-P and Vitro-P coated plates significantly improved hCPC adhesion, proliferation, migration, and differentiation compared to uncoated plates. Additionally, long-term culture on the coated plates delayed cellular senescence and maintained hCPC stemness. These enhancements were attributed to the activation of integrin downstream signaling pathways. The findings suggest that the engineered ECM peptide motif-MAP-coated plates hold potential for enhancing the therapeutic efficacy of stem cell-based therapies in cardiac tissue engineering and regenerative medicine.
PubMed: 38941882
DOI: 10.1016/j.scr.2024.103476 -
Journal of Magnetic Resonance (San... Jun 2024Hyperpolarized water in dissolution dynamic nuclear polarization (dDNP) experiments has emerged as a promising method for enhancing nuclear magnetic resonance (NMR)...
Hyperpolarized water in dissolution dynamic nuclear polarization (dDNP) experiments has emerged as a promising method for enhancing nuclear magnetic resonance (NMR) signals, particularly in studies of proteins and peptides. Herein, we focus on the application of "proton exchange-doubly relayed" nuclear Overhauser effects (NOE) from hyperpolarized water to achieve positive signal enhancement of methyl groups in the side chain of an alanine-glycine peptide. In particular, we show a cascade hyperpolarization transfer. Initial proton exchange between solvent and amide introduces hyperpolarization into the peptide. Subsequently, intermolecular NOE relays the hyperpolarization first to Ala-H and then in a second step to the Ala-CH moiety. Both NOEs have negative signs. Hence, the twice-relayed NOE pathway leads to a positive signal enhancement of the methyl group with respect to the thermal equilibrium magnetization. This effect might indicate a way towards hyperpolarized water-based signal enhancement for methyl groups, which are often used for NMR studies of large proteins in solution.
PubMed: 38941676
DOI: 10.1016/j.jmr.2024.107727 -
Science Advances Jun 2024The formation of vascular niche is pivotal during the early stage of peripheral nerve regeneration. Nevertheless, the mechanisms of vascular niche in the regulation of...
The formation of vascular niche is pivotal during the early stage of peripheral nerve regeneration. Nevertheless, the mechanisms of vascular niche in the regulation of peripheral nerve repair remain unclear. Netrin-1 (NTN1) was found up-regulated in nerve stump after peripheral nerve injury (PNI). Herein, we demonstrated that NTN1-high endothelial cells (NTN1+ECs) were the critical component of vascular niche, fostering angiogenesis, axon regeneration, and repair-related phenotypes. We also found that NTN1+EC-derived exosomes (NTN1 EC-EXO) were involved in the formation of vascular niche as a critical role. Multi-omics analysis further verified that NTN1 EC-EXO carried a low-level expression of let7a-5p and activated key pathways associated with niche formation including focal adhesion, axon guidance, phosphatidylinositol 3-kinase-AKT, and mammalian target of rapamycin signaling pathway. Together, our study suggested that the construction of a pre-regenerative niche induced by NTN1 EC-EXO could establish a beneficial microenvironment for nerve repair and facilitate functional recovery after PNI.
Topics: Netrin-1; Exosomes; Nerve Regeneration; Animals; Endothelial Cells; Peripheral Nerve Injuries; Mice; Neovascularization, Physiologic; Signal Transduction; Humans; Peripheral Nerves
PubMed: 38941462
DOI: 10.1126/sciadv.adm8454 -
Science Advances Jun 2024Decades of research have uncovered how plants respond to two environmental variables that change across latitudes and over seasons: photoperiod and temperature. However,...
Decades of research have uncovered how plants respond to two environmental variables that change across latitudes and over seasons: photoperiod and temperature. However, a third such variable, twilight length, has so far gone unstudied. Here, using controlled growth setups, we show that the duration of twilight affects growth and flowering time via the clock genes in the model plant Arabidopsis. Using a series of progressively truncated no-twilight photoperiods, we also found that plants are more sensitive to twilight length compared to equivalent changes in solely photoperiods. Transcriptome and proteome analyses showed that twilight length affects reactive oxygen species metabolism, photosynthesis, and carbon metabolism. Genetic analyses suggested a twilight sensing pathway from the photoreceptors , , , and through to flowering modulation through the pathway. Overall, our findings call for more nuanced models of day-length perception in plants and posit that twilight is an important determinant of plant growth and development.
Topics: Arabidopsis; Flowers; Arabidopsis Proteins; Photoperiod; Gene Expression Regulation, Plant; Transcription Factors; Reactive Oxygen Species; Photosynthesis; Cryptochromes
PubMed: 38941453
DOI: 10.1126/sciadv.adl3199 -
Medicine Jun 2024To investigate causal associations between diabetes, insulin treatment and osteoporosis using LDSC analysis with a 2-way Mendelian randomization study. (Observational Study)
Observational Study
OBJECTIVE
To investigate causal associations between diabetes, insulin treatment and osteoporosis using LDSC analysis with a 2-way Mendelian randomization study.
METHODS
LDSC analysis was used to estimate the likelihood-scale heritability of the genome-wide association study used with genetic correlation between the 2 genome-wide association study used. Then a 2-sample Mendelian randomization study was performed using 3 methods including inverse variance weighted, MR Egger, and weighted median.
RESULTS
The genetic correlation between diabetes, insulin treatment (h2_Z = 3.70, P = 2.16e-4), osteoporosis (h2_Z = 4.93, h2_p = 8.13e-7) and genes was significant. There was a significant genetic correlation (rg = 0.122, P = 0.0211). There was a causal association between diabetes, insulin treatment and osteoporosis [P = 0.003754, OR (95%CI) = 0.998876 (0.998116-0.999636)], while no causal association existed between osteoporosis and insulin use (P = 0.998116-0.999636) causal association existed (P = 0.333244).
CONCLUSION
There was a strong genetic correlation between diabetes, insulin treatment and osteoporosis, a causal association between diabetes, insulin treatment and osteoporosis, and no causal association between osteoporosis and diabetes, insulin treatment.
Topics: Humans; Mendelian Randomization Analysis; Insulin; Osteoporosis; Genome-Wide Association Study; Diabetes Mellitus; Polymorphism, Single Nucleotide
PubMed: 38941431
DOI: 10.1097/MD.0000000000038535 -
Medicine Jun 2024This study investigates the correlation between thyroid hormone levels and metabolic dysfunction in patients with type 2 diabetes mellitus (T2DM) who exhibit normal...
BACKGROUND
This study investigates the correlation between thyroid hormone levels and metabolic dysfunction in patients with type 2 diabetes mellitus (T2DM) who exhibit normal thyroid function and metabolic dysfunction associated with steatotic liver disease (MASLD).
OBJECTIVE
The objective is to identify a scientific basis for the management of T2DM complicated by MASLD, aiming to refine clinical strategies and enhance patient well-being.
METHODS
Statistical analysis was conducted using SPSS 26.0, employing independent sample t-tests for normally distributed data and logarithmic transformations for non-normal data to meet analysis prerequisites. Multifactorial logistic regression analysis elucidated the impact of various factors on the risk of MASLD in T2DM patients.
RESULTS
Elevated levels of FT3 may be associated with an increased risk of nonalcoholic fatty liver disease. Additionally, the FT3/FT4 ratio has been validated as an effective serological marker for predicting the risk of MASLD. In patients with DM2 and normal thyroid function, changes in thyroid hormone levels are closely related to the occurrence of MASLD. Elevated levels of FT3, total triiodothyronine (TT3), and thyroid-stimulating hormone are associated with an increased risk of MASLD.
CONCLUSION
FT3, TT3, and thyroid-stimulating hormone have important clinical value in the diagnosis of patients with T2DM complicated with MASLD.
Topics: Humans; Diabetes Mellitus, Type 2; Male; Female; Middle Aged; Triiodothyronine; Thyroid Hormones; Aged; Non-alcoholic Fatty Liver Disease; Thyrotropin; Biomarkers; Risk Factors; Thyroid Function Tests; Adult
PubMed: 38941427
DOI: 10.1097/MD.0000000000038643 -
Medicine Jun 2024Surgical site infection (SSI) after posterior open lumbar fusion (POLF) is a major concern for both surgeons and patients. We sought to explore whether local application... (Observational Study)
Observational Study
Surgical site infection (SSI) after posterior open lumbar fusion (POLF) is a major concern for both surgeons and patients. We sought to explore whether local application of vancomycin could decrease the rate of SSI. We reviewed the clinical data of patients who underwent POLF between June 2015 and June 2022 at 3 spinal centers. Patients were divided into those who received local vancomycin (vancomycin group) and those who did not (non-vancomycin group). The SSI rates at 12 months postoperatively were compared between the 2 groups. Although a trend toward a lower infection rate was observed in the vancomycin group than in the non-vancomycin group; the difference was not statistically significant (3.6% vs 5.5%, P = .121). However, we found that the postoperative SSI rate was significantly lower in the vancomycin group than in the non-vancomycin group (4.9% vs 11.4%, P = .041) in patients ≥ 2 fused segments, while there was no significant difference in postoperative SSI rate in patients with single fusion segment (3.1% vs 3.6%, P = .706). The logistic regression analysis indicated that the SSI rate in the non-vancomycin group was approximately 2.498 times higher than that in the vancomycin group (P = .048, odds ratio: 2.498, 95% confidence interval: 1.011-6.617) in patients with ≥2 fused segments. In SSI patients with confirmed pathogens, the SSI rate of Gram-negative bacteria in the vancomycin group was significantly higher than that in the non-vancomycin group (10/14 [71.4%] vs 5/22 [31.8%]), whereas the SSI rate of Gram-positive bacteria in the vancomycin group was significantly lower than that in the non-vancomycin group (4/14 [28.6%] vs 15/22 [68.2%]). Local administration of vancomycin is recommended in patients with ≥2 fused segments as it may facilitate to reduce the postoperative rate of SSI after POLF. Additionally, the local use of vancomycin can decrease the Gram-positive bacterial infections but is not effective against Gram-negative infections, which indirectly leads to an increase in the proportion of Gram-negative infections in SSI patients with confirmed pathogens.
Topics: Humans; Vancomycin; Surgical Wound Infection; Spinal Fusion; Retrospective Studies; Male; Female; Middle Aged; Anti-Bacterial Agents; Aged; Lumbar Vertebrae; Adult
PubMed: 38941406
DOI: 10.1097/MD.0000000000038664