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Journal of Inflammation Research 2024Apelin is the native ligand for the G protein-coupled receptor APJ. Numerous studies have demonstrated that the Apelin/APJ system has positive inotropic,... (Review)
Review
Apelin is the native ligand for the G protein-coupled receptor APJ. Numerous studies have demonstrated that the Apelin/APJ system has positive inotropic, anti-inflammatory, and anti-apoptotic effects and regulates fluid homeostasis. The Apelin/APJ system has been demonstrated to play a protective role in sepsis and may serve as a promising therapeutic target for the treatment of sepsis. Better understanding of the mechanisms of the effects of the Apelin/APJ system will aid in the development of novel drugs for the treatment of sepsis. In this review, we provide a brief overview of the physiological role of the Apelin/APJ system and its role in sepsis.
PubMed: 38250143
DOI: 10.2147/JIR.S436169 -
Frontiers in Molecular Neuroscience 2023The initiation and progression of neurodegenerative diseases (NDs), distinguished by compromised nervous system integrity, profoundly disrupt the quality of life of... (Review)
Review
The initiation and progression of neurodegenerative diseases (NDs), distinguished by compromised nervous system integrity, profoundly disrupt the quality of life of patients, concurrently exerting a considerable strain on both the economy and the social healthcare infrastructure. Exercise has demonstrated its potential as both an effective preventive intervention and a rehabilitation approach among the emerging therapeutics targeting NDs. As the largest secretory organ, skeletal muscle possesses the capacity to secrete myokines, and these myokines can partially improve the prognosis of NDs by mediating the muscle-brain axis. Besides the well-studied exerkines, which are secreted by skeletal muscle during exercise that pivotally exert their beneficial function, the physiological function of novel exerkines, e.g., apelin, kynurenic acid (KYNA), and lactate have been underappreciated previously. Herein, this review discusses the roles of these novel exerkines and their mechanisms in regulating the progression and improvement of NDs, especially the significance of their functions in improving NDs' prognoses through exercise. Furthermore, several myokines with potential implications in ameliorating ND progression are proposed as the future direction for investigation. Elucidation of the function of exerkines secreted by skeletal muscle in the regulation of NDs advances the understanding of its pathogenesis and facilitates the development of therapeutics that intervene in these processes to cure NDs.
PubMed: 38249295
DOI: 10.3389/fnmol.2023.1305208 -
Frontiers in Endocrinology 2023Bone and skeletal muscle work in coordination to maintain the function of the musculoskeletal system, in which skeletal muscle contraction drives the movement of the... (Review)
Review
Bone and skeletal muscle work in coordination to maintain the function of the musculoskeletal system, in which skeletal muscle contraction drives the movement of the bone lever system while bone provides insert sites for skeletal muscle through the bone-muscle junction. Existing evidence suggests that factors secreted by skeletal muscle and bone mediate the interaction between the two tissues. Herein, we focused on the relationship between skeletal muscle and bone and the underlying mechanism of the interaction. Exercise can promote bone strength and secrete osteocalcin and insulin-like growth factor I into the blood, thus improving muscle quality. In addition, exercise can also promote myostatin, interleukin-6, Irisin, and apelin in muscles to enter the blood so that they can act on bones to maintain the balance between bone absorption and bone formation. There is a special regulatory axis interleukin-6/osteocalcin between myokines and osteokines, which is mainly influenced by exercise. Therefore, we pay attention to the important factors in the bone-muscle intersection that are affected by exercise, which were found or their functions were expanded, which strengthened the connection between organs of the whole body, highlighting the importance of exercise and contributing to the diagnosis, prevention, and treatment of osteoporosis and sarcopenia in the clinic.
Topics: Bone and Bones; Exercise; Interleukin-6; Muscle, Skeletal; Osteocalcin
PubMed: 38239981
DOI: 10.3389/fendo.2023.1287972 -
Cell Communication and Signaling : CCS Jan 2024Conventional therapies for metastatic cancers have limited efficacy. Recently, cancer therapies targeting noncancerous cells in tumor microenvironments have shown... (Review)
Review
Conventional therapies for metastatic cancers have limited efficacy. Recently, cancer therapies targeting noncancerous cells in tumor microenvironments have shown improved clinical outcomes in patients. However, further advances in our understanding of the metastatic tumor microenvironment are required to improve treatment outcomes. Adipocytes are distributed throughout the body, and as a part of the metastatic tumor microenvironment, they interact with cancer cells in almost all organs. Adipocytes secrete various factors that are reported to exert clinical effects on cancer progression, including engraftment, survival, and expansion at the metastatic sites. However, only a few studies have comprehensively examined their impact on cancer cells. In this review, we examined the impact of adipocytes on cancer by describing the adipocyte-secreted factors that are involved in controlling metastatic cancer, focusing on adipokines, such as adiponectin, leptin, visfatin, chemerin, resistin, apelin, and omentin. Adipocyte-secreted factors promote cancer metastasis and contribute to various biological functions of cancer cells, including migration, invasion, proliferation, immune evasion, and drug resistance at the metastatic sites. We propose the establishment and expansion of "adipo-oncology" as a research field to enhance the comprehensive understanding of the role of adipocytes in metastatic cancers and the development of more robust metastatic cancer treatments.
Topics: Humans; Adipocytes; Adipokines; Neoplasms; Adiponectin; Tumor Microenvironment
PubMed: 38238841
DOI: 10.1186/s12964-024-01474-4 -
Epigenetics Dec 2024Long noncoding RNAs (lncRNAs) regulate the progression of type 2 diabetes mellitus complicated with obstructive sleep apnoea (T2DM-OSA). However, the role of the lncRNA...
LncRNA NEAT1 aggravates human microvascular endothelial cell injury by inhibiting the Apelin/Nrf2/HO-1 signalling pathway in type 2 diabetes mellitus with obstructive sleep apnoea.
Long noncoding RNAs (lncRNAs) regulate the progression of type 2 diabetes mellitus complicated with obstructive sleep apnoea (T2DM-OSA). However, the role of the lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) in T2DM-OSA remains unknown. This study aimed to reveal the function of NEAT1 in T2DM-OSA and the underlying mechanism. KKAy mice were exposed to intermittent hypoxia (IH) or intermittent normoxia to generate a T2DM-OSA mouse model. HMEC-1 cells were treated with high glucose (HG) and IH to construct a T2DM-OSA cell model. RNA expression was detected by qRT-PCR. The protein expression of Apelin, NF-E2-related factor 2 (Nrf2), haem oxygenase-1 (HO-1), and up-frameshift suppressor 1 (UPF1) was assessed using western blot. Cell injury was evaluated using flow cytometry, enzyme-linked immunosorbent assay, and oxidative stress kit assays. RIP, RNA pull-down, and actinomycin D assays were performed to determine the associations between NEAT1, UPF1, and Apelin. NEAT1 expression was upregulated in the aortic vascular tissues of mice with T2DM exposed to IH and HMEC-1 cells stimulated with HG and IH, whereas Apelin expression was downregulated. The absence of NEAT1 protected HMEC-1 cells from HG- and IH-induced damage. Furthermore, NEAT1 destabilized Apelin mRNA by recruiting UPF1. Apelin overexpression decreased HG- and IH-induced injury to HMEC-1 cells by activating the Nrf2/HO-1 pathway. Moreover, NEAT1 knockdown reduced HG- and IH-induced injury to HMEC-1 cells through Apelin. NEAT1 silencing reduced HMEC-1 cell injury through the Apelin/Nrf2/HO-1 signalling pathway in T2DM-OSA. LncRNAs, long non-coding RNAs; T2DM, type 2 diabetes mellitus; OSA, obstructive sleep apnoea; NEAT1, nuclear paraspeckle assembly transcript 1; IH, intermittent hypoxia; HMEC-1, human microvascular endothelial cells; HG, high glucose; Nrf2, NF-E2-related factor 2; UPF1, up-frameshift suppressor 1; HO-1, haem oxygenase-1; qRT-PCR, quantitative real-time polymerase chain reaction; ELISA, enzyme-linked immunosorbent assay; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; TNF-α, tumour necrosis factor-α; CCK-8, Cell Counting Kit-8; IL-1β, interleukin-1β; ROS, reactive oxygen species; MDA, malondialdehyde; SOD, superoxide dismutase; RIP, RNA immunoprecipitation; SD, standard deviations; GSH, glutathione; AIS, acute ischaemic stroke; HMGB1, high mobility group box-1 protein; TLR4, toll-like receptor 4.
Topics: Animals; Humans; Mice; Apelin; Brain Ischemia; Diabetes Mellitus, Type 2; DNA Methylation; Endothelial Cells; Glucose; Heme Oxygenase (Decyclizing); Hypoxia; NF-E2-Related Factor 2; RNA Helicases; RNA, Long Noncoding; Sleep Apnea, Obstructive; Stroke; Trans-Activators; Tumor Necrosis Factor-alpha
PubMed: 38232183
DOI: 10.1080/15592294.2023.2293409 -
Cell Death & Disease Jan 2024Intrahepatic cholangiocarcinoma (ICC) is the second most common malignancy among primary liver cancers, with an increasing overall incidence and poor prognosis. The...
Intrahepatic cholangiocarcinoma (ICC) is the second most common malignancy among primary liver cancers, with an increasing overall incidence and poor prognosis. The intertumoral and intratumoral heterogeneity of ICC makes it difficult to find efficient drug therapies. Therefore, it is essential to identify tumor suppressor genes and oncogenes that induce ICC formation and progression. Here, we performed CRISPR/Cas9-mediated genome-wide screening in a liver-specific Smad4/Pten knockout mouse model (Smad4;Pten;Alb-Cre, abbreviated as SPC), which normally generates ICC after 6 months, and detected that mutations in Trp53, Fbxw7, Inppl1, Tgfbr2, or Cul3 markedly accelerated ICC formation. To illustrate the potential mechanisms, we conducted transcriptome sequencing and found that multiple receptor tyrosine kinases were activated, which mainly upregulated the PI3K pathway to induce cell proliferation. Remarkably, the Cul3 mutation stimulated cancer progression mainly by altering the immune microenvironment, whereas other mutations promoted the cell cycle. Moreover, Fbxw7, Inppl1, Tgfbr2, and Trp53 also affect inflammatory responses, apelin signaling, mitotic spindles, ribosome biogenesis, and nucleocytoplasmic transport pathways, respectively. We further examined FDA-approved drugs for the treatment of liver cancer and performed high-throughput drug screening of the gene-mutant organoids. Different drug responses and promising drug therapies, including chemotherapy and targeted drugs, have been discovered for ICC.
Topics: Mice; Animals; Receptor, Transforming Growth Factor-beta Type II; F-Box-WD Repeat-Containing Protein 7; Phosphatidylinositol 3-Kinases; Cholangiocarcinoma; Mutation; Signal Transduction; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Tumor Microenvironment
PubMed: 38212325
DOI: 10.1038/s41419-023-06406-7 -
Heliyon Jan 2024Hypertension has become a part of the lives of many people worldwide. With the development, an increasing number of people have begun to control their hypertension...
Antihypertensive effect and mechanism of the traditional recipe of medicine food homology (Buyang Huanwu Decoction) in China: Meta analysis and network pharmacological exploration.
BACKGROUND
Hypertension has become a part of the lives of many people worldwide. With the development, an increasing number of people have begun to control their hypertension through products of medicine food homology, such as Buyang Huanwu Decoction (BYHWD). However, there has been no objective review of the regulation of hypertension by BYHWD.
METHODS
As of 9 October 2023, this review made a detailed search of nine databases to look for random controlled trials (RCTs) focused on the use of BYHWD for treating hypertension. This was followed by network pharmacological analysis, and molecular docking assessment using AutoDockTools to explore the mode of action.
RESULTS
BYHWD was effective in reducing SBP (MD: 0.767; 95 % CI: 0.629, 0.905; = 0.000), DBP (MD: 0.427; 95 % CI: 0.292, 0.561; = 0.000), 24h SBP (MD: 0.665; 95 % CI: 0.368, 0.962; = 0.000), 24h DBP (MD: 0.547; 95 % CI: 0.318, 0.777; = 0.000), dSBP (MD: 0.625; 95 % CI: 0.395, 0.855; = 0.000), dDBP (MD: 0.632; 95 % CI: 0.401, 0.862; = 0.000), nSBP (MD: 0.859; 95 % CI: 0.340, 1.377; = 0.001), nDBP (MD: 0.704; 95 % CI: 0.297, 1.112; = 0.001), pv (MD: 1.311; 95 % CI: 0.363, 2.259; = 0.007) and NIHSS (MD: 1.149; 95 % CI: 0.100, 2.199; = 0.032), and elevating CER (OR = 2.848; 95 % CI: 1.388, 5.843; = 0.004). However, BYHWD did not significantly reduce HCY, and there was no significant difference in the incidence of AE. In terms of the mechanism of action, the main active ingredient of BYHWD is quercetin, and the core targets are AKT1, MMP9, and others. Molecular docking also showed that quercetin mainly interacts with the amino acid residue CYS-28 of MMP2. Second, the KEGG analysis showed that BYHWD mainly act on HIF-1, Apelin, and cGMP-PKG signalling pathways, and GO analysis showed that it related to the apical part of the cell, circulatory system processes, and nuclear receptor activity. BYHWD can lowered blood pressure, reduced plasma viscosity, and restored neurological function with good tolerability, and had no significant effect on HCY levels. This study further demonstrated that quercetin is the main active ingredient of BYHWD that acts via the AKT1 and HIF-1 signalling pathways. These results provide new guidance for people's dietary choices by the general public.
PubMed: 38205319
DOI: 10.1016/j.heliyon.2023.e23474 -
International Journal of Molecular... Dec 2023Gestational diabetes mellitus (GDM) is one of the most common medical disorders in pregnancy. Adipokines, predominantly secreted by adipose tissue, are involved in...
Gestational diabetes mellitus (GDM) is one of the most common medical disorders in pregnancy. Adipokines, predominantly secreted by adipose tissue, are involved in numerous metabolic processes. The exact role of adipokines in the pathogenesis of GDM is still not well known, and numerous adipokines have been analysed throughout pregnancy and proposed as biomarkers of GDM. This study aimed to evaluate serum adiponectin, chemerin, lipocalin and apelin levels in GDM and non-GDM women, to assess them as clinically useful biomarkers of the occurrence of GDM and to demonstrate the correlation between the levels of the above adipokines in the blood serum and the increased risk of the development of GDM. The role of these adipokines in the pathogenesis of GDM was also analysed. The statistically significant differences between the levels of adiponectin (7234.6 vs. 9837.5 ng/mL, < 0.0001), chemerin (264.0 vs. 206.7 ng/mL, < 0.0001) and lipocalin (39.5 vs. 19.4 ng/mL, < 0.0001) were observed between pregnant women with GDM and healthy ones. The diagnostic usefulness of the tested adipokines in detecting GDM was also assessed. The research results confirm the hypothesis on the significance of adiponectin, chemerin, lipocalin and apelin in the pathophysiological mechanisms of GDM. We speculate that these adipokines could potentially be established as novel biomarkers for the prediction and early diagnosis of GDM.
Topics: Pregnancy; Female; Humans; Adipokines; Adiponectin; Apelin; Diabetes, Gestational; Lipocalins; Biomarkers
PubMed: 38203346
DOI: 10.3390/ijms25010175 -
AIMS Neuroscience 2023Post-translational modifications (PTMs) are protein modifications that occur after protein biosynthesis, playing a crucial role in regulating protein function. They are...
Post-translational modifications (PTMs) are protein modifications that occur after protein biosynthesis, playing a crucial role in regulating protein function. They are involved in the functional expression of G-protein-coupled receptors (GPCRs), as well as intracellular and secretory protein signaling. Here, we aimed to investigate the PTMs of the apelin receptor (APLNR), a GPCR and their potential influence on the receptor's function. In an in vitro experiment using HEK cells, we only observed glycosylation as a PTM of the APLNR and ineffective receptor signaling by the agonist, (Pyr)-apelin-13. In contrast, when analyzing mouse spinal cord, we detected glycosylation and other PTMs, excluding isopeptidation. This suggests that additional PTMs are involved in the functional expression of the APLNR in vitro. In summary, these findings suggest that the APLNR in vivo requires multiple PTMs for functional expression. To comprehensively understand the pharmacological effects of the APLNR, it is essential to establish an in vitro system that adequately replicates the receptor's PTM profile. Nonetheless, it is crucial to overcome the challenge of heat-sensitive proteolysis in APLNR studies. By elucidating the regulation of PTMs, further research has the potential to advance the analysis and pharmacological studies of both the apelin/APLNR system and GPCR signal modulation.
PubMed: 38188005
DOI: 10.3934/Neuroscience.2023022 -
BMC Endocrine Disorders Jan 2024Diabetic nephropathy and hepatopathy are health problems described by specific renal and hepatic structure and function disturbances. The protective effects of the stem...
Effects of conditioned media derived from human Wharton's jelly mesenchymal stem cells on diabetic nephropathy and hepatopathy via modulating TGF-β and apelin signaling pathways in male rats.
BACKGROUND
Diabetic nephropathy and hepatopathy are health problems described by specific renal and hepatic structure and function disturbances. The protective effects of the stem cell secretome have been shown in several kidney and liver diseases. The current study aims to evaluate the capability of conditioned media derived from human Wharton's jelly mesenchymal stem cells (hWJ-MSCs-CM) to alleviate diabetic complications.
METHODS
Twenty Sprague Dawley rats were made diabetic through injection of STZ (60 mg/kg, i.p.). At week 8, diabetic rats were divided into two groups: treated [DM + hWJ-MSCs-CM (500 µl/rat for three weeks, i.p.)] and not treated (DM). At the 11th week, three groups (control, DM, and DM + hWJ-MSCs-CM) were kept in metabolic cages, and urine was collected for 24 h. The serum samples were maintained for measuring fasting blood glucose (FBG) and kidney and liver functional analysis. The left kidney and liver parts were kept at -80 °C to assess apelin and transforming growth factor-beta (TGF-β) expression. The right kidney, pancreas, and liver parts were used for histopathologic evaluation.
RESULTS
DM was detected by higher FBG, microalbuminuria, increased albumin/creatinine ratio, and pancreas, renal, and hepatic structural disturbances. Diabetic hepatopathy was determined by increasing liver enzymes and decreasing total bilirubin. The TGF-β gene expression was significantly upregulated in the diabetic kidney and liver tissues. Apelin gene expression was significantly downregulated in the diabetic liver tissue but did not change in kidney tissue. Administration of hWJ-MSCs-CM improved renal and hepatic functional and structural disturbances. Moreover, CM therapy significantly decreased TGF-β expression and enhanced apelin expression in the kidney and liver tissues.
CONCLUSION
Human WJ-MSCs-CM may have protective effects on diabetic renal and hepatic complications. These effects may happen through the regulation of TGF-β and apelin signaling pathways.
Topics: Animals; Humans; Male; Rats; Apelin; Culture Media, Conditioned; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Liver Diseases; Mesenchymal Stem Cells; Rats, Sprague-Dawley; Signal Transduction; Transforming Growth Factor beta; Wharton Jelly
PubMed: 38178017
DOI: 10.1186/s12902-023-01535-8