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Bone Research May 2024Wnt/β-catenin signaling is critical for various cellular processes in multiple cell types, including osteoblast (OB) differentiation and function. Exactly how...
Wnt/β-catenin signaling is critical for various cellular processes in multiple cell types, including osteoblast (OB) differentiation and function. Exactly how Wnt/β-catenin signaling is regulated in OBs remain elusive. ATP6AP2, an accessory subunit of V-ATPase, plays important roles in multiple cell types/organs and multiple signaling pathways. However, little is known whether and how ATP6AP2 in OBs regulates Wnt/β-catenin signaling and bone formation. Here we provide evidence for ATP6AP2 in the OB-lineage cells to promote OB-mediated bone formation and bone homeostasis selectively in the trabecular bone regions. Conditionally knocking out (CKO) ATP6AP2 in the OB-lineage cells (Atp6ap2) reduced trabecular, but not cortical, bone formation and bone mass. Proteomic and cellular biochemical studies revealed that LRP6 and N-cadherin were reduced in ATP6AP2-KO BMSCs and OBs, but not osteocytes. Additional in vitro and in vivo studies revealed impaired β-catenin signaling in ATP6AP2-KO BMSCs and OBs, but not osteocytes, under both basal and Wnt stimulated conditions, although LRP5 was decreased in ATP6AP2-KO osteocytes, but not BMSCs. Further cell biological studies uncovered that osteoblastic ATP6AP2 is not required for Wnt3a suppression of β-catenin phosphorylation, but necessary for LRP6/β-catenin and N-cadherin/β-catenin protein complex distribution at the cell membrane, thus preventing their degradation. Expression of active β-catenin diminished the OB differentiation deficit in ATP6AP2-KO BMSCs. Taken together, these results support the view for ATP6AP2 as a critical regulator of both LRP6 and N-cadherin protein trafficking and stability, and thus regulating β-catenin levels, demonstrating an un-recognized function of osteoblastic ATP6AP2 in promoting Wnt/LRP6/β-catenin signaling and trabecular bone formation.
Topics: Animals; Low Density Lipoprotein Receptor-Related Protein-6; Wnt Signaling Pathway; beta Catenin; Mice, Knockout; Osteoblasts; Osteogenesis; Mice; Vacuolar Proton-Translocating ATPases; Protein Transport; Cell Differentiation; Osteocytes; Prorenin Receptor
PubMed: 38811544
DOI: 10.1038/s41413-024-00335-7 -
Psychiatry Investigation May 2024Methamphetamine use disorder (MUD) is a global health condition that impairs a person's health which may result in morbidity and mortality. Inflammation is a crucial...
OBJECTIVE
Methamphetamine use disorder (MUD) is a global health condition that impairs a person's health which may result in morbidity and mortality. Inflammation is a crucial process playing a vital role in MUD. For this reason, it is necessary to examine biochemical parameters for follow-up and treatment alternatives.
METHODS
We aimed to reveal the relationship between inflammatory response and MUD by evaluating peripheral hemogram parameters, leukocyte count, subtypes, and their ratios to each other, systemic immune inflammation index (SII), monocyte/high-density lipoprotein (HDL) ratio, and human C-reactive protein (CRP) in adult men with MUD. We included 76 adult male participants in the patient group and 70 adult male participants in the control group. We calculated the neutrophil/lymphocyte rate (NLR), monocyte/lymphocyte rate (MLR), platelet/lymphocyte rate (PLR), and basophil/lymphocyte rate (BLR). In addition, we obtained the SII and the monocyte/HDL rate.
RESULTS
The patients' leukocyte (p<0.001), platelet (p<0.001), plateletcrit (PCT) (p=0.002), neutrophil (p<0.001), monocyte (p=0.002), CRP (p<0.001), NLR (p=0.001), PLR (p=0.004), MLR (p=0.009), SII (p<0.001) and monocyte/HDL ratio (p<0.001) were higher than the control group. We observed a significant and positive relationship between the daily methamphetamine intake, and methamphetamine use duration (p=0.002), PCT (p=0.044), neutrophil (p=0.021), NLR (p=0.001), PLR (p=0.004), MLR (p=0.029), and SII (p<0.001). Daily methamphetamine intake had a significant and positive effect on SII. A one-unit increase in daily methamphetamine intake elevated SII by 165.53 units.
CONCLUSION
The results confirm the presence of peripheral subclinical inflammation and systemic immune inflammation in adult men with MUD.
PubMed: 38811000
DOI: 10.30773/pi.2023.0199 -
Journal of Research in Medical Sciences... 2024This guideline is the first Iranian guideline developed for the diagnosis, management, and treatment of hyperlipidemia in adults. The members of the guideline developing...
This guideline is the first Iranian guideline developed for the diagnosis, management, and treatment of hyperlipidemia in adults. The members of the guideline developing group (GDG) selected 9 relevant clinical questions and provided recommendations or suggestions to answer them based on the latest scientific evidence. Recommendations include the low-density lipoprotein cholesterol (LDL-C) threshold for starting drug treatment in adults lacking comorbidities was determined to be over 190 mg/dL and the triglyceride (TG) threshold had to be >500 mg/dl. In addition to perform fasting lipid profile tests at the beginning and continuation of treatment, while it was suggested to perform cardiovascular diseases (CVDs) risk assessment using valid Iranian models. Some recommendations were also provided on lifestyle modification as the first therapeutic intervention. Statins were recommended as the first line of drug treatment to reduce LDL-C, and if its level was high despite the maximum allowed or maximum tolerated drug treatment, combined treatment with ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, or bile acid sequestrants was suggested. In adults with hypertriglyceridemia, pharmacotherapy with statin or fibrate was recommended. The target of drug therapy in adults with increased LDL-C without comorbidities and risk factors was considered an LDL-C level of <130 mg/dl, and in adults with increased TG without comorbidities and risk factors, TG levels of <200 mg/dl. In this guideline, specific recommendations and suggestions were provided for the subgroups of the general population, such as those with CVD, stroke, diabetes, chronic kidney disease, elderly, and women.
PubMed: 38808220
DOI: 10.4103/jrms.jrms_318_23 -
Frontiers in Cellular and Infection... 2024The genus , which colonizes mucosal surfaces, includes both commensal and pathogenic species that are exclusive to humans. The two pathogenic species are closely... (Review)
Review
The genus , which colonizes mucosal surfaces, includes both commensal and pathogenic species that are exclusive to humans. The two pathogenic species are closely related but cause quite different diseases, meningococcal sepsis and meningitis () and sexually transmitted gonorrhea ). Although obvious differences in bacterial niches and mechanisms for transmission exists, pathogenic have high levels of conservation at the levels of nucleotide sequences, gene content and synteny. Species of express broad-spectrum -linked protein glycosylation where the glycoproteins are largely transmembrane proteins or lipoproteins localized on the cell surface or in the periplasm. There are diverse functions among the identified glycoproteins, for example type IV biogenesis proteins, proteins involved in antimicrobial resistance, as well as surface proteins that have been suggested as vaccine candidates. The most abundant glycoprotein, PilE, is the major subunit of pili which are an important colonization factor. The glycans attached can vary extensively due to phase variation of protein glycosylation ( genes and polymorphic gene content. The exact roles of glycosylation in remains to be determined, but increasing evidence suggests that glycan variability can be a strategy to evade the human immune system. In addition, pathogenic and commensal appear to have significant glycosylation differences. Here, the current knowledge and implications of protein glycosylation genes, glycan diversity, glycoproteins and immunogenicity in pathogenic are summarized and discussed.
Topics: Humans; Bacterial Proteins; Glycoproteins; Glycosylation; Neisseria gonorrhoeae; Neisseria meningitidis; Polysaccharides; Meningitis, Meningococcal; Gonorrhea
PubMed: 38808060
DOI: 10.3389/fcimb.2024.1407863 -
Caspian Journal of Internal Medicine 2024Stroke is one of the leading causes of mortality and morbidity worldwide accounting for 85% of global deaths from stroke. This study aimed to evaluate the role of...
BACKGROUND
Stroke is one of the leading causes of mortality and morbidity worldwide accounting for 85% of global deaths from stroke. This study aimed to evaluate the role of homocysteine (HCY) in modulating various stroke parameters and it's with carotid intima-media thickness (IMT).
METHODS
78 patients of radiology-confirmed acute ischemic stroke were recruited for this study and National Institutes of Health Stroke Scale (NIHSS) score was evaluated upon admission. Blood samples were tested for serum HCY, fasting blood glucose (FBG) and lipid profile. Ultrasonography of neck ascertained IMT of Common (CCA) and internal carotid artery (ICA).
RESULTS
Average age of male and female subjects was 57.88 ± 13.97 & 59.16 ± 13.62 years respectively. 71.93% of stroke patients were hyperhomocysteinemic (HHcyc) and 24.36% were hyperlipidemic. Patients with NIHSS ≥ 5 had higher low-density lipoprotein cholesterol (LDLC) than those with NIHSS < 5. HCY cutoff of ≥ 15 μmol/L had 91.7% sensitivity & 66.7% specificity for predicting. HHcyc state was associated with increased ICA IMT. HHcyc state was best predicted by ICA IMT with which it is positively correlated (P-Value = 0.012).
CONCLUSION
HHcyc state holds a good predictive value for severity of stroke. We also came to a conclusion that ICA IMT measurement may also reduce the need for a homocysteine test as it predicts higher HCY levels; this will reduce the burden on resources. We suggest that evaluating HCY and ICA IMT should be made part of the standard protocol for management of stroke.
PubMed: 38807737
DOI: 10.22088/cjim.15.2.259 -
Cell Communication and Signaling : CCS May 2024Endoplasmic reticulum (ER) stress-mediated increases in the hepatic levels of the very low-density lipoprotein (VLDL) receptor (VLDLR) promote hepatic steatosis by...
BACKGROUND
Endoplasmic reticulum (ER) stress-mediated increases in the hepatic levels of the very low-density lipoprotein (VLDL) receptor (VLDLR) promote hepatic steatosis by increasing the delivery of triglyceride-rich lipoproteins to the liver. Here, we examined whether the NAD()-dependent deacetylase sirtuin 1 (SIRT1) regulates hepatic lipid accumulation by modulating VLDLR levels and the subsequent uptake of triglyceride-rich lipoproteins.
METHODS
Rats fed with fructose in drinking water, Sirt1 mice, mice treated with the ER stressor tunicamycin with or without a SIRT1 activator, and human Huh-7 hepatoma cells transfected with siRNA or exposed to tunicamycin or different inhibitors were used.
RESULTS
Hepatic SIRT1 protein levels were reduced, while those of VLDLR were upregulated in the rat model of metabolic dysfunction-associated steatotic liver disease (MASLD) induced by fructose-drinking water. Moreover, Sirt1 mice displayed increased hepatic VLDLR levels that were not associated with ER stress, but were accompanied by an increased expression of hypoxia-inducible factor 1α (HIF-1α)-target genes. The pharmacological inhibition or gene knockdown of SIRT1 upregulated VLDLR protein levels in the human Huh-7 hepatoma cell line, with this increase abolished by the pharmacological inhibition of HIF-1α. Finally, SIRT1 activation prevented the increase in hepatic VLDLR protein levels in mice treated with the ER stressor tunicamycin.
CONCLUSIONS
Overall, these findings suggest that SIRT1 attenuates fatty liver development by modulating hepatic VLDLR levels.
Topics: Animals; Sirtuin 1; Humans; Liver; Receptors, LDL; Mice; Male; Endoplasmic Reticulum Stress; Rats; Cell Line, Tumor; Mice, Knockout; Fatty Liver; Mice, Inbred C57BL; Tunicamycin; Hypoxia-Inducible Factor 1, alpha Subunit; Rats, Sprague-Dawley
PubMed: 38807218
DOI: 10.1186/s12964-024-01666-y -
BMC Cardiovascular Disorders May 2024Autophagy, as a regulator of cell survival, plays an important role in atherosclerosis (AS). Sperm associated antigen 5 (SPAG5) is closely associated with the classical...
BACKGROUND
Autophagy, as a regulator of cell survival, plays an important role in atherosclerosis (AS). Sperm associated antigen 5 (SPAG5) is closely associated with the classical autophagy pathway, PI3K/Akt/mTOR signaling pathway. This work attempted to investigate whether SPAG5 can affect AS development by regulating autophagy.
METHODS
Human umbilical vein endothelial cells (HUVECs) were treated with oxidized-low density lipoprotein (ox-LDL) to induce cell damage. ApoE mice were fed a Western diet to establish an AS mouse model. Haematoxylin and eosin (H&E) staining and Oil Red O staining evaluated the pathological changes and in lipid deposition in aortic tissues. CCK-8 and flow cytometry detected cell proliferation and apoptosis. Immunohistochemistry, Enzyme linked immunosorbent assay, qRT-PCR and western blotting assessed the levels of mRNA and proteins.
RESULTS
Ox-LDL treatment elevated SPAG5 expression and the expression of autophagy-related proteins, LC3-I, LC3-II, Beclin-1, and p62, in HUVECs. GFP-LC3 dots were increased in ox-LDL-treated HUVECs and LPS-treated HUVECs. SPAG5 knockdown reversed both ox-LDL and LPS treatment-mediated inhibition of cell proliferation and promotion of apoptosis in HUVECs. SPAG5 silencing further elevated autophagy and repressed the expression of PI3K, p-Akt/Akt, and p-mTOR/mTOR in ox-LDL-treated HUVECs. 3-MA (autophagy inhibitor) treatment reversed SPAG5 silencing-mediated increase of cell proliferation and decrease of apoptosis in ox-LDL-treated HUVECs. In vivo, SPAG5 knockdown reduced atherosclerotic plaques in AS mice through activating autophagy and inhibiting PI3K/Akt/mTOR signaling pathway.
CONCLUSION
This work demonstrated that SPAG5 knockdown alleviated AS development through activating autophagy. Thus, SPAG5 may be a potential target for AS therapy.
Topics: Animals; Autophagy; Human Umbilical Vein Endothelial Cells; Humans; Atherosclerosis; Signal Transduction; TOR Serine-Threonine Kinases; Disease Models, Animal; Mice, Knockout, ApoE; Apoptosis; Proto-Oncogene Proteins c-akt; Plaque, Atherosclerotic; Cell Proliferation; Aortic Diseases; Mice, Inbred C57BL; Lipoproteins, LDL; Male; Cells, Cultured; Autophagy-Related Proteins; Aorta; Phosphatidylinositol 3-Kinase; Cell Cycle Proteins; Mice; Apolipoproteins E
PubMed: 38807081
DOI: 10.1186/s12872-024-03945-5 -
The Egyptian Heart Journal : (EHJ) :... May 2024Coronary artery disease (CAD) is an atherosclerotic disease of an inflammatory nature. Previous studies examining the relationship between triglycerides and high-density...
BACKGROUND
Coronary artery disease (CAD) is an atherosclerotic disease of an inflammatory nature. Previous studies examining the relationship between triglycerides and high-density lipoprotein cholesterol have highlighted the importance of plasma atherogenic index (AIP) as an important predictor of coronary heart disease. However, due to the lack of adequate information on this topic, this study aimed to investigate the relationship between AIP and coronary heart disease risk.
RESULTS
This study included 2,226 women and 1,690 men aged 35-70 years who participated in the Bandar Kong Cohort study and met the eligibility criteria. The data was collected using a checklist and questionnaires, which were designed by experienced individuals. After participants completed a registration form and gave informed consent, face-to-face interviews were conducted by trained experts. The validity and reliability of the questionnaire had been verified by the national cohort team prior to its use. The Ethics Committee of Hormozgan University of Medical Sciences (IR.HUMS.REC.1400.171) approved the study. Data from the initial cohort survey using SPSS software version 25, were analyzed to include several factors, including age, sex, smoking status, body mass index (BMI), physical activity level, socioeconomic status, AIP, systolic blood pressure, and diastolic blood pressure. The prevalence of coronary heart disease was found to be 7.5% higher in people with a BMI of 25 or higher. Also, Individuals with low physical activity had a higher prevalence. Individuals with CAD had significantly higher mean values for the AIP, age, systolic blood pressure, and diastolic blood pressure (0.46, 57.50, 128.43, and 81.10, respectively) compared to those without CAD. Furthermore, patients with CAD had lower years of education (2649.45 and 3.59) than individuals without CAD (P < 0.05). Importantly, our findings showed that AIP increased the odds ratio of coronary heart disease by 1.86 as an independent risk factor.
CONCLUSIONS
Based on our investigation, the AIP is a valuable and independent predictive risk factor for coronary artery disease. This index can be utilized effectively due to its accessibility and affordability, making it a promising tool for risk assessment in clinical settings.
PubMed: 38806969
DOI: 10.1186/s43044-024-00497-z -
Nature Communications May 2024The Crimean-Congo hemorrhagic fever virus (CCHFV) is an emerging pathogen of the Orthonairovirus genus that can cause severe and often lethal hemorrhagic diseases in...
The Crimean-Congo hemorrhagic fever virus (CCHFV) is an emerging pathogen of the Orthonairovirus genus that can cause severe and often lethal hemorrhagic diseases in humans. CCHFV has a broad tropism and can infect a variety of species and tissues. Here, by using gene silencing, blocking antibodies or soluble receptor fragments, we identify the low-density lipoprotein receptor (LDL-R) as a CCHFV entry factor. The LDL-R facilitates binding of CCHFV particles but does not allow entry of Hazara virus (HAZV), another member of the genus. In addition, we show that apolipoprotein E (apoE), an exchangeable protein that mediates LDL/LDL-R interaction, is incorporated on CCHFV particles, though not on HAZV particles, and enhances their specific infectivity by promoting an LDL-R dependent entry. Finally, we show that molecules that decrease LDL-R from the surface of target cells could inhibit CCHFV infection. Our study highlights that CCHFV takes advantage of a lipoprotein receptor and recruits its natural ligand to promote entry into cells.
Topics: Humans; Receptors, LDL; Virus Internalization; Apolipoproteins E; Hemorrhagic Fever Virus, Crimean-Congo; Animals; HEK293 Cells; Chlorocebus aethiops; Hemorrhagic Fever, Crimean; Virion; Vero Cells
PubMed: 38806525
DOI: 10.1038/s41467-024-48989-5 -
BMJ Open May 2024Adolescence is a sensitive period for cardiometabolic health. Yet, it remains unknown if adolescent health behaviours, such as alcohol use, smoking, diet and physical...
INTRODUCTION
Adolescence is a sensitive period for cardiometabolic health. Yet, it remains unknown if adolescent health behaviours, such as alcohol use, smoking, diet and physical activity, have differential effects across socioeconomic strata. Adopting a life-course perspective and a causal inference framework, we aim to assess whether the effects of adolescent health behaviours on adult cardiometabolic health differ by levels of neighbourhood deprivation, parental education and occupational class. Gaining a better understanding of these social disparities in susceptibility to health behaviours can inform policy initiatives that aim to improve population health and reduce socioeconomic inequalities in cardiometabolic health.
METHODS AND ANALYSIS
We will conduct a secondary analysis of the Young Finns Study, which is a longitudinal population-based cohort study. We will use measures of health behaviours-smoking, alcohol use, fruit and vegetable consumption, and physical activity-as exposure and parental education, occupational class and neighbourhood deprivation as effect modifiers during adolescence (ages 12-18 years). Eight biomarkers of cardiometabolic health (outcomes)-waist circumference, body mass index, blood pressure, low-density lipoprotein cholesterol, apolipoprotein B, plasma glucose and insulin resistance-will be measured when participants were aged 33-40. A descriptive analysis will investigate the clustering of health behaviours. Informed by this, we will conduct a causal analysis to estimate effects of single or clustered adolescent health behaviours on cardiometabolic health conditional on socioeconomic background. This analysis will be based on a causal model implemented via a directed acyclic graph and inverse probability-weighted marginal structural models to estimate effect modification.
ETHICS AND DISSEMINATION
The Young Finns study was conducted according to the guidelines of the Declaration of Helsinki, and the protocol was approved by ethics committees of University of Helsinki, Kuopio, Oulu, Tampere and Turku. We will disseminate findings at international conferences and a manuscript in an open-access peer-reviewed journal.
Topics: Humans; Adolescent; Health Behavior; Female; Adult; Male; Finland; Exercise; Longitudinal Studies; Child; Body Mass Index; Adolescent Behavior; Socioeconomic Factors; Smoking; Blood Pressure; Alcohol Drinking; Research Design; Waist Circumference; Cohort Studies; Blood Glucose; Diet; Insulin Resistance; Cardiovascular Diseases
PubMed: 38806419
DOI: 10.1136/bmjopen-2023-078428