-
Journal of the Endocrine Society May 2024Empagliflozin increases sodium levels in patients with a chronic syndrome of inappropriate antidiuresis (SIAD), and dapagliflozin increases apelin levels in patients...
BACKGROUND
Empagliflozin increases sodium levels in patients with a chronic syndrome of inappropriate antidiuresis (SIAD), and dapagliflozin increases apelin levels in patients with diabetes mellitus. Exogenous apelin increases sodium levels in rats with SIAD. We aimed to investigate whether an increase in plasma apelin concentration may contribute to the efficacy of empagliflozin in SIAD.
METHODS
Post hoc secondary analysis of a double-blind, crossover, placebo-controlled trial performed from December 2017 to August 2021 at the University Hospital Basel, Switzerland, investigating the effect of 4-week treatment with empagliflozin 25 mg/day as compared to placebo in 14 outpatients with chronic SIAD (NCT03202667). The objective was to investigate the effect of empagliflozin on plasma apelin and copeptin concentrations and their ratio.
RESULTS
Fourteen patients, 50% female, with a median [interquartile range] age of 72 years [65-77] were analyzed. Median apelin concentration was 956 pmol/L [853, 1038] at baseline. Median [interquartile range] apelin relative changes were +11% [0.7, 21] and +8% [-5, 25] ( = .672) at the end of the placebo and empagliflozin phases, respectively. Median copeptin concentration was 2.6 [2.2, 4.5] pmol/L at baseline and had a relative change of +5 [-2. 11]% and +25% [10, 28] ( = .047) over the placebo and empagliflozin phases, respectively.
CONCLUSION
Empagliflozin did not lead to significant changes in apelin or the apelin/copeptin ratio in patients with chronic SIAD but led to an increase in copeptin. This suggests that the efficacy of empagliflozin in SIAD is independent of apelin and is not blunted by the adaptative increase in copeptin.
PubMed: 38872994
DOI: 10.1210/jendso/bvae106 -
Genomics Jul 2024Spinal cord injury (SCI) is a devastating neurological and pathological condition. Exosomal tsRNAs have reported to be promising biomarkers for cancer diagnosis and...
BACKGROUND
Spinal cord injury (SCI) is a devastating neurological and pathological condition. Exosomal tsRNAs have reported to be promising biomarkers for cancer diagnosis and therapy. This study aimed to investigate the roles of SCI-associated exosomes, and related tsRNA mechanisms in SCI.
METHODS
The serum of healthy controls and SCI patients at the acute stage were collected for exosomes isolation, and the two different exosomes were used to treat human astrocytes (HA). The cell viability, apoptosis, and cycle were determined, and the expression of the related proteins were detected by western blot. Then, the two different exosomes were sent for tsRNA sequencing, and four significant known differentially expressed tsRNAs (DE-tsRNAs) were selected for RT-qPCR validation. Finally, tRT-41 was chosen to further explore its roles and related mechanisms in SCI.
RESULTS
After sequencing, 21 DE-tsRNAs were identified, which were significantly enriched in pathways of Apelin, AMPK, Hippo, MAPK, Ras, calcium, PI3K-Akt, and Rap1. RT-qPCR showed that tRF-41 had higher levels in the SCI-associated exosomes. Compared with the control HA, healthy exosomes did not significantly affect the growth of HA cells, but SCI-associated exosomes inhibited viability of HA cells, while promoted their apoptosis and increased the HA cells in G2/M phase; but tRF-41 inhibitor reversed the actions of SCI-associated exosomes. Additionally, SCI-associated exosomes, similar with tRF-41 mimics, down-regulated IGF-1, NGF, Wnt3a, and β-catenin, while up-regulated IL-1β and IL-6; but tRF-41 inhibitor had the opposite actions, and reversed the effects induced by SCI-associated exosomes.
CONCLUSIONS
SCI-associated exosomes delivered tRF-41 may inhibit the growth of HA through regulating Wnt/ β-catenin pathway and inflammation response, thereby facilitating the progression of SCI.
Topics: Exosomes; Humans; Spinal Cord Injuries; Apoptosis; Astrocytes; Male; RNA, Long Noncoding; Female; Disease Progression; Cells, Cultured; Midkine; Adult; Cell Proliferation; Middle Aged
PubMed: 38866256
DOI: 10.1016/j.ygeno.2024.110885 -
Frontiers in Cardiovascular Medicine 2024ACE2 is the earliest receptor discovered to mediate the entry of SARS-CoV-2. In addition to the receptor, it also participates in complex pathological and physiological... (Review)
Review
ACE2 is the earliest receptor discovered to mediate the entry of SARS-CoV-2. In addition to the receptor, it also participates in complex pathological and physiological processes, including regulating the RAS system, apelin, KKS system, and immune system. In addition to affecting the respiratory system, viral infections also interact with cardiovascular diseases. SARS-CoV-2 can directly invade the cardiovascular system through ACE2; Similarly, cardiovascular diseases such as hypertension and coronary heart disease can affect ACE2 levels and exacerbate the disease, and ACE2 dysregulation may also be a potential mechanism for long-term acute sequelae of COVID-19. Since the SARS CoV-2 epidemic, many large population studies have tried to clarify the current focus of debate, that is, whether we should give COVID-19 patients ACEI and ARB drug treatment, but there is still no conclusive conclusion. We also discussed potential disease treatment options for ACE2 at present. Finally, we discussed the researchers' latest findings on ACE2 and their prospects for future research.
PubMed: 38863899
DOI: 10.3389/fcvm.2024.1409723 -
Journal For Immunotherapy of Cancer Jun 2024A combination of axitinib and immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in the treatment of advanced renal cell carcinoma (RCC). This study...
BACKGROUND
A combination of axitinib and immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in the treatment of advanced renal cell carcinoma (RCC). This study aims to prospectively evaluate the safety, efficacy, and biomarkers of neoadjuvant toripalimab plus axitinib in non-metastatic clear cell RCC.
METHODS
This is a single-institution, single-arm phase II clinical trial. Patients with non-metastatic biopsy-proven clear cell RCC (T2-T3N0-1M0) are enrolled. Patients will receive axitinib 5 mg twice daily combined with toripalimab 240 mg every 3 weeks (three cycles) for up to 12 weeks. Patients then will receive partial (PN) or radical nephrectomy (RN) after neoadjuvant therapy. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease-free survival, safety, and perioperative complication rate. Predictive biomarkers are involved in exploratory analysis.
RESULTS
A total of 20 patients were enrolled in the study, with 19 of them undergoing surgery. One patient declined surgery. The primary endpoint ORR was 45%. The posterior distribution of πORR had a mean of 0.44 (95% credible intervals: 0.24-0.64), meeting the predefined primary endpoint with an ORR of 32%. Tumor shrinkage was observed in 95% of patients prior to nephrectomy. Furthermore, four patients achieved a pathological complete response. Grade ≥3 adverse events occurred in 25% of patients, including hypertension, hyperglycemia, glutamic pyruvic transaminase/glutamic oxaloacetic transaminase (ALT/AST) increase, and proteinuria. Postoperatively, one grade 4a and eight grade 1-2 complications were noted. In comparison to patients with stable disease, responders exhibited significant differences in immune factors such as Arginase 1(ARG1), Melanoma antigen (MAGEs), Dendritic Cell (DC), TNF Superfamily Member 13 (TNFSF13), Apelin Receptor (APLNR), and C-C Motif Chemokine Ligand 3 Like 1 (CCL3-L1). The limitation of this trial was the small sample size.
CONCLUSION
Neoadjuvant toripalimab combined with axitinib shows encouraging activity and acceptable toxicity in locally advanced clear cell RCC and warrants further study.
TRIAL REGISTRATION NUMBER
clinicaltrials.gov, NCT04118855.
Topics: Humans; Carcinoma, Renal Cell; Axitinib; Male; Female; Kidney Neoplasms; Middle Aged; Neoadjuvant Therapy; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Adult; Prospective Studies; Nephrectomy
PubMed: 38862251
DOI: 10.1136/jitc-2023-008475 -
Neurobiology of Disease Aug 2024Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease leading to demyelination and axonal loss. Current treatments are immunomodulatory or...
Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease leading to demyelination and axonal loss. Current treatments are immunomodulatory or immunosuppressive drugs acting on the inflammatory component. However, these treatments do not adequately address the crucial aspect of neuroprotection. Recently, an association between an altered balance of adipokines and MS has been proposed as both a risk factor for developing MS and a chronic disease aggravating factor. Specifically, a decrease of apelin plasma levels in MS patients compared to controls correlates with the number of relapses and disease severity. Here we report a dramatic downregulation of apelin levels in the CNS of EAE mice which is also detected in MS patients brain samples compared to controls. Exploiting innovative design and synthesis techniques, we engineered a novel fluorinated apelin-13 peptide characterized by enhanced plasmatic stability compared to its native counterpart. With this peptide, we assessed the potential therapeutic benefits of apelin preventive supplementation in the EAE mouse model. We show that the fluorinated Apelin-13 peptide ameliorates EAE clinical score and preserves myelin content in the EAE MOG model recapitulating the progressive form of disease. These results combined with ex-vivo experiments in brain organotypic slices and in vitro studies in neurons and primary microglia and macrophages suggest that apelin has neuroprotective effects and influences the microglia/macrophages function.
Topics: Animals; Neuroprotective Agents; Encephalomyelitis, Autoimmune, Experimental; Mice; Multiple Sclerosis; Mice, Inbred C57BL; Female; Humans; Intercellular Signaling Peptides and Proteins; Brain; Disease Models, Animal; Microglia; Apelin
PubMed: 38844244
DOI: 10.1016/j.nbd.2024.106552 -
BMC Genomics Jun 2024Indigenous Chinese cattle have abundant genetic diversity and a long history of artificial selection, giving local breeds advantages in adaptability, forage tolerance...
BACKGROUND
Indigenous Chinese cattle have abundant genetic diversity and a long history of artificial selection, giving local breeds advantages in adaptability, forage tolerance and resistance. The detection of selective sweeps and comparative genome analysis of selected breeds and ancestral populations provide a basis for understanding differences among breeds and for the identification and utilization of candidate genes. We investigated genetic diversity, population structure, and signatures of selection using genome-wide sequencing data for a new breed of Qinchuan cattle (QNC, n = 21), ancestral Qinchuan cattle (QCC, n = 20), and Zaosheng cattle (ZSC, n = 19).
RESULTS
A population structure analysis showed that the ancestry components of QNC and ZSC were similar. In addition, the QNC and ZSC groups showed higher proportions of European taurine ancestry than that of QCC, and this may explain the larger body size of QNC, approaching that of European cattle under long-term domestication and selection. A neighbor-joining tree revealed that QCC individuals were closely related, whereas QNC formed a distinct group. To search for signatures of selection in the QNC genome, we evaluated nucleotide diversity (θπ), the fixation index (F) and Tajima's D. Overlapping selective sweeps were enriched for one KEGG pathway, the apelin signaling pathway, and included five candidate genes (MEF2A, SMAD2, CAMK4, RPS6, and PIK3CG). We performed a comprehensive review of genomic variants in QNC, QCC, and ZSC using whole-genome sequencing data. QCC was rich in novel genetic diversity, while diversity in QNC and ZSC cattle was reduced due to strong artificial selection, with divergence from the original cattle.
CONCLUSIONS
We identified candidate genes associated with production traits. These results support the success of selective breeding and can guide further breeding and resource conservation of Qinchuan cattle.
Topics: Animals; Cattle; Selection, Genetic; Genetic Variation; Genomics; Polymorphism, Single Nucleotide; Genetics, Population; Genome-Wide Association Study; Genome; Breeding
PubMed: 38834950
DOI: 10.1186/s12864-024-10482-0 -
PloS One 2024Studies of the interplay between metabolism and immunity, known as immunometabolism, is steadily transforming immunological research into new understandings of how...
Studies of the interplay between metabolism and immunity, known as immunometabolism, is steadily transforming immunological research into new understandings of how environmental cues like diet are affecting innate and adaptive immune responses. The aim of this study was to explore antiviral transcriptomic responses under various levels of polyunsaturated fatty acid. Atlantic salmon kidney cells (ASK cell line) were incubated for one week in different levels of the unsaturated n-3 eicosapentaneoic acid (EPA) resulting in cellular levels ranging from 2-20% of total fatty acid. These cells were then stimulated with the viral mimic and interferon inducer poly I:C (30 ug/ml) for 24 hours before total RNA was isolated and sequenced for transcriptomic analyses. Up to 200 uM EPA had no detrimental effects on cell viability and induced very few transcriptional changes in these cells. However, in combination with poly I:C, our results shows that the level of EPA in the cellular membranes exert profound dose dependent effects of the transcriptional profiles induced by this treatment. Metabolic pathways like autophagy, apelin and VEGF signaling were attenuated by EPA whereas transcripts related to fatty acid metabolism, ferroptosis and the PPAR signaling pathways were upregulated. These results suggests that innate antiviral responses are heavily influenced by the fatty acid profile of salmonid cells and constitute another example of the strong linkage between general metabolic pathways and inflammatory responses.
Topics: Animals; Salmo salar; Immunity, Innate; Eicosapentaenoic Acid; Cell Line; Poly I-C; Kidney; Transcriptome; Signal Transduction; Cell Survival; Gene Expression Profiling
PubMed: 38805503
DOI: 10.1371/journal.pone.0302286 -
Frontiers in Neuroscience 2024Glioblastoma multiforme (GBM) is one of the most common and lethal forms of brain cancer, carrying a very poor prognosis (median survival of ~15 months...
Glioblastoma multiforme (GBM) is one of the most common and lethal forms of brain cancer, carrying a very poor prognosis (median survival of ~15 months post-diagnosis). Treatment typically involves invasive surgical resection of the tumour mass, followed by radiotherapy and adjuvant chemotherapy using the alkylating agent temozolomide, but over half of patients do not respond to this drug and considerable resistance is observed. Tumour heterogeneity is the main cause of therapeutic failure, where diverse progenitor glioblastoma stem cell (GSC) lineages in the microenvironment drive tumour recurrence and therapeutic resistance. The apelin receptor is a class A GPCR that binds two endogenous peptide ligands, apelin and ELA, and plays a role in the proliferation and survival of cancer cells. Here, we used quantitative whole slide immunofluorescent imaging of human GBM samples to characterise expression of the apelin receptor and both its ligands in the distinct GSC lineages, namely neural-progenitor-like cells (NPCs), oligodendrocyte-progenitor-like cells (OPCs), and mesenchymal-like cells (MES), as well as reactive astrocytic cells. The data confirm the presence of the apelin receptor as a tractable drug target that is common across the key cell populations driving tumour growth and maintenance, offering a potential novel therapeutic approach for patients with GBM.
PubMed: 38803685
DOI: 10.3389/fnins.2024.1379658 -
Brain Sciences May 2024The discovery of novel diagnostic methods and therapies for Alzheimer's disease (AD) faces significant challenges. Previous research has shed light on the...
BACKGROUND
The discovery of novel diagnostic methods and therapies for Alzheimer's disease (AD) faces significant challenges. Previous research has shed light on the neuroprotective properties of Apelin-13 in neurodegenerative disorders. However, elucidating the mechanism underlying its efficacy in combating AD-related nerve injury is imperative. In this study, we aimed to investigate Apelin-13's mechanism of action in an in vivo model of AD induced by streptozocin (STZ).
METHODS
We utilized an STZ-induced nerve injury model of AD in mice to investigate the effects of Apelin-13 administration. Apelin-13 was administered intranasally, and cognitive impairment was assessed using standardized behavioral tests, primarily, behavioral assessment, histological analysis, and biochemical assays, in order to evaluate synaptic plasticity and oxidative stress signaling pathways.
RESULTS
Our findings indicate that intranasal administration of Apelin-13 ameliorated cognitive impairment in the STZ-induced AD model. Furthermore, we observed that this effect was potentially mediated by the enhancement of synaptic plasticity and the attenuation of oxidative stress signaling pathways.
CONCLUSIONS
The results of this study suggest that intranasal administration of Apelin-13 holds promise as a therapeutic strategy for preventing neurodegenerative diseases such as AD. By improving synaptic plasticity and mitigating oxidative stress, Apelin-13 may offer a novel approach to neuroprotection in AD and related conditions.
PubMed: 38790466
DOI: 10.3390/brainsci14050488 -
BMC Genomics May 2024The peri-implantation period is a critical time during pregnancy that mostly defines the overall litter size. Most authors agree that the highest percentage of embryo...
BACKGROUND
The peri-implantation period is a critical time during pregnancy that mostly defines the overall litter size. Most authors agree that the highest percentage of embryo mortality occurs during this time. Despite the brevity of the peri-implantation period, it is the most dynamic part of pregnancy in which the sequential and uninterrupted course of several processes is essential to the animal's reproductive success. Also then, the maternal uterine tissues undergo an intensive remodelling process, and their energy demand dramatically increases. It is believed that apelin, a member of the adipokine family, is involved in the control of female reproductive functions in response to the current metabolic state. The verified herein hypothesis assumed the modulatory effect of apelin on the endometrial tissue transcriptome on days 15 to 16 of gestation (beginning of implantation).
RESULTS
The analysis of data obtained during RNA-seq (Illumina HiSeq2500) of endometrial slices treated and untreated with apelin (n = 4 per group) revealed changes in the expression of 68 genes (39 up-regulated and 29 down-regulated in the presence of apelin), assigned to 240 gene ontology terms. We also revealed changes in the frequency of alternative splicing events (397 cases), as well as single nucleotide variants (1,818 cases) in the presence of the adipokine. The identified genes were associated, among others, with the composition of the extracellular matrix, apoptosis, and angiogenesis.
CONCLUSIONS
The obtained results indicate a potential role of apelin in the regulation of uterine tissue remodelling during the peri-implantation period.
Topics: Animals; Female; Endometrium; Embryo Implantation; Transcriptome; Pregnancy; Swine; Intercellular Signaling Peptides and Proteins; Gene Expression Profiling; Apelin; Alternative Splicing
PubMed: 38773369
DOI: 10.1186/s12864-024-10417-9