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Endocrine Practice : Official Journal... Apr 2024To evaluate the association of serum 25-hydroxyvitamin D (25(OH) D) levels with bone mineral density (BMD), fracture risk, and bone metabolism.
OBJECTIVE
To evaluate the association of serum 25-hydroxyvitamin D (25(OH) D) levels with bone mineral density (BMD), fracture risk, and bone metabolism.
METHODS
This multicenter cross-sectional study recruited menopausal females and males greater than or equal to 50 year old with osteoporosis/fractures between September 2016 and September 2021. Assessment included clinical data, 25(OH)D, intact parathyroid hormone (iPTH), procollagen type 1 amino-terminal propeptide (P1NP), carboxy-terminal collagen crosslinks (CTX), lateral thoracolumbar spine x-rays, and BMD.
RESULTS
A total of 3003 individuals were stratified by 25(OH) D levels: 720 individuals (24%) <20 ng/mL, 1338 individuals (44.5%) 20 to 29 ng/mL, and 945 individuals (31.5%) ≥30 ng/mL. In unadjusted and multivariable models, BMD T-score, except spine, was significantly and positively associated with 25(OH)D levels. 25(OH) D levels were inversely associated with Fracture Risk Assessment Tool scores. Patients with 25(OH)D <20 ng/mL had significantly higher iPTH and bone turnover markers (P1NP and CTX) than patients with 25(OH)D ≧20 ng/mL in all models. When analyzing bone-related markers and BMD, total hip and femoral neck BMD T-scores were positively correlated with 25(OH)D concentrations and BMI but negatively correlated with iPTH, P1NP, CTX, and age. In multivariate models with all bone-related markers, only 25(OH)D levels were significantly associated with total hip and femoral neck BMD.
CONCLUSION
Vitamin D deficiency is significantly associated with decreased total hip and femoral neck BMD and increased fracture risk as assessed by Fracture Risk Assessment Tool. In those with osteoporosis/fractures, vitamin D is implicated in the causal relationship between bone remodeling and BMD. Assessing vitamin D status is imperative for those at risk for osteoporosis/fractures.
PubMed: 38692490
DOI: 10.1016/j.eprac.2024.04.013 -
Particle and Fibre Toxicology Apr 2024Plastic accumulation in the environment is rapidly increasing, and nanoplastics (NP), byproducts of environmental weathering of bulk plastic waste, pose a significant...
Plastic accumulation in the environment is rapidly increasing, and nanoplastics (NP), byproducts of environmental weathering of bulk plastic waste, pose a significant public health risk. Particles may enter the human body through many possible routes such as ingestion, inhalation, and skin absorption. However, studies on NP penetration and accumulation in human skin are limited. Loss or reduction of the keratinized skin barrier may enhance the skin penetration of NPs. The present study investigated the entry of NPs into a human skin system modeling skin with compromised barrier functions and cellular responses to the intracellular accumulations of NPs. Two in vitro models were employed to simulate human skin lacking keratinized barriers. The first model was an ex vivo human skin culture with the keratinized dermal layer (stratum corneum) removed. The second model was a 3D keratinocyte/dermal fibroblast cell co-culture model with stratified keratinocytes on the top and a monolayer of skin fibroblast cells co-cultured at the bottom. The penetration and accumulation of the NPs in different cell types were observed using fluorescent microscopy, confocal microscopy, and cryogenic electron microscopy (cryo-EM). The cellular responses of keratinocytes and dermal fibroblast cells to stress induced by NPs stress were measured. The genetic regulatory pathway of keratinocytes to the intracellular NPs was identified using transcript analyses and KEGG pathway analysis. The cellular uptake of NPs by skin cells was confirmed by imaging analyses. Transepidermal transport and penetration of NPs through the skin epidermis were observed. According to the gene expression and pathway analyses, an IL-17 signaling pathway was identified as the trigger for cellular responses to internal NP accumulation in the keratinocytes. The transepidermal NPs were also found in co-cultured dermal fibroblast cells and resulted in a large-scale transition from fibroblast cells to myofibroblast cells with enhanced production of α-smooth muscle actin and pro-Collagen Ia. The upregulation of inflammatory factors and cell activation may result in skin inflammation and ultimately trigger immune responses.
Topics: Keratinocytes; Humans; Coculture Techniques; Fibroblasts; Nanoparticles; Skin Absorption; Skin; Microplastics; Cells, Cultured; Particle Size
PubMed: 38685063
DOI: 10.1186/s12989-024-00583-9 -
Frontiers in Bioscience (Landmark... Apr 2024The extracellular matrix (ECM) modeling induced by the metalloproteinases is a vital characteristic for tumor progression. Previous studies mainly focus on the functions...
Multi-Omics Pan-Cancer Analysis of Procollagen N-Propeptidase Gene Family of ADAMTS as Novel Biomarkers to Associate with Prognosis, Tumor Immune Microenvironment, Signaling Pathways, and Drug Sensitivities.
BACKGROUND
The extracellular matrix (ECM) modeling induced by the metalloproteinases is a vital characteristic for tumor progression. Previous studies mainly focus on the functions of two subgroups of metalloproteinases: matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs) in tumors. The roles of another important group: the ADAMs with thrombospondin motifs (ADAMTS) remain unclear. This study aimed to perform a pan-cancer analysis of procollagen N-propeptidase subgroup of ADAMTS (PNPSA).
METHODS
We systematically analyzed expression landscape, genomic variations, prognostic value, and cell expression clusters of PNPSA in pan-cancer based on the multiple integrated open databases. Besides, we also analyzed the impacts of expressions and genomic variations of PNPSA members on tumor immune microenvironment (TIME) and immune-related molecules in pan-cancer based on the immune-related open databases. The Gene Set Variation Analysis (GSVA) was performed to evaluate the associations of the whole PNPSA with prognosis, tumor indicators, TIME, and drug sensitivities. Meanwhile, the Kyoto Encyclopedia of Genes and Genomes (KEGG) was performed to reveal related signaling pathways. Finally, immunohistochemical staining was used to validate the differential analysis results.
RESULTS
We found a dual prognostic role of PNPSA members in pan-cancer and they were significantly correlated with TIME and immune-related molecules. Interestingly, the copy number variations (CNVs) of all PNPSA members were revealed to be negatively correlated with NK cell infiltration in most cancers. Single-cell sequencing analysis reveals expressions of PNPSA gene family members on some specific tumor and immune cells in addition to the fibroblasts. The GSVA score was found to have some predictive value for survival status in Brain Lower Grade Glioma (LGG), Mesothelioma (MESO), and Uveal Melanoma (UVM) and to be significantly correlated with tumorigenesis-related pathways such as PI3K-Akt, AGE-RAGE, etc. The GSVA score also shows some predictive value for chemotherapy and immunotherapy efficacy in some tumors.
CONCLUSIONS
PNPSA was correlated with tumor development and might be potential tumor biomarker and therapeutic target.
Topics: Humans; Tumor Microenvironment; Signal Transduction; Prognosis; Neoplasms; Biomarkers, Tumor; ADAMTS Proteins; Gene Expression Regulation, Neoplastic; Multiomics
PubMed: 38682182
DOI: 10.31083/j.fbl2904151 -
Antioxidants (Basel, Switzerland) Apr 2024Osteoporosis is a bone-debilitating disease, demonstrating a higher prevalence in post-menopausal women due to estrogen deprivation. One of the main mechanisms...
Osteoporosis is a bone-debilitating disease, demonstrating a higher prevalence in post-menopausal women due to estrogen deprivation. One of the main mechanisms underlying menopause-related bone loss is oxidative stress. -allylmercapto--acetylcysteine (ASSNAC) is a nuclear factor erythroid 2-related factor 2 (Nrf2) activator and cysteine supplier, previously shown to have anti-oxidation protective effects in cultured cells and animal models. Here, we studied the therapeutic potential of ASSNAC with and without Alendronate in ovariectomized (OVX) female mice. The experimental outcome included (i) femur and L3 lumbar vertebra morphometry via Micro-Computed Tomography (μCT); (ii) bone remodeling (formation vs. resorption); and (iii) oxidative stress markers in bone marrow (BM) cells. Four weeks after OVX, there was a significant bone loss that remained evident after 8 weeks, as demonstrated via µCT in the femur (cortical and trabecular bone compartments) and vertebra (trabecular bone). ASSNAC at a dose of 50 mg/Kg/day prevented bone loss after the four-week treatment but had no significant effect after 8 weeks, while ASSNAC at a dose of 20 mg/Kg/day significantly protected against bone loss after 8 weeks of treatment. Alendronate prevented ovariectomy-induced bone loss, and combining it with ASSNAC further augmented this effect. OVX mice demonstrated high serum levels of both C-terminal cross-linked telopeptides of type I collagen (CTX) (bone resorption) and procollagen I N-terminal propeptide (P1NP) (bone formation) after 2 weeks, and these returned to control levels after 8 weeks. Alendronate, ASSNAC and their combination decreased CTX and increased P1NP. Alendronate induced oxidative stress as reflected by decreased glutathione and increased malondialdehyde (MDA) levels, and combining it with ASSNAC partially attenuated these changes. These results portray the therapeutic potential of ASSNAC for the management of post-menopausal osteoporosis. Furthermore, ASSNAC ameliorates the Alendronate-associated oxidative stress, suggesting its potential to prevent Alendronate side effects as well as improve its bone-protective effect.
PubMed: 38671921
DOI: 10.3390/antiox13040474 -
Journal of Ethnopharmacology Aug 2024Hai-Honghua medicinal liquor (HHML), an external Chinese herbal formula preparation, is often applied to treat freshly closed tibia/fibular fractures, ankle fractures,... (Randomized Controlled Trial)
Randomized Controlled Trial
ETHNOPHARMACOLOGICAL RELEVANCE
Hai-Honghua medicinal liquor (HHML), an external Chinese herbal formula preparation, is often applied to treat freshly closed tibia/fibular fractures, ankle fractures, and other bone-related disorders, but the related molecular mechanism is unclear.
AIM OF THE STUDY
To evaluate the therapeutic effect of HHML in patients with tibial/fibular and ankle fractures, and to explore its related possible mechanism.
METHODS AND MATERIALS
A total of 182 patients with tibia/fibular fractures and 183 patients with ankle fractures were enrolled in this study. A randomized, controlled, unblinded clinical trial was designed to evaluate the therapeutic effect of HHML on tibial/fibular and ankle fractures. The chemical compositions of HHML were analyzed by the HPLC-Q-Extractive MS/MS. Furthermore, a rat tibial fracture model was established to evaluate the therapeutic effects of HHML in promoting fracture healing, and the mouse embryonic osteoblasts cell line of MC3T3-E1 was further carried out to explore the mechanisms of HHML on osteoblast differentiation.
RESULTS
In the clinical evaluation, HHML treatment significantly shortened the time for pain and swelling in patients with tibial/fibular fractures (P < 0.01) and ankle fractures (P < 0.01), and the incidence of complications was significantly reduced as well. Subsequently, 116 constituents were identified from HHML via HPLC-Q-TOF-MS/MS analysis. In vivo, no obvious changes in weight were observed in HHML-treated rats. Moreover, the levels of bone formation markers (including osteocalcin (OCN), N-terminal propeptide of type I procollagen (PINP), alkaline phosphatase (ALP), calcium (Ca) and substance P) in rat serum were significantly increased in HHML-treated rats compared with model rats (P < 0.05). Micro-CT analysis showed bone mineral density (BMD), bone volume fraction (BV/TV), trabecular thickness (Tb.Th) of the HHML-treated rats were significantly increased (P < 0.05, vs. Model) while trabecular separation (Tb.Sp) and structure model index (SMI) values were significantly reduced (P < 0.05, vs. Model). Histological analysis showed that HHML treatment promoted the healing of fractures and cartilage repair, and increased the osteoblasts and collagen fibers. Furthermore, our results also revealed HHML could promote MC3T3-E1 cells proliferation and osteoblast differentiation via regulation of the runt-related transcription factor 2 (RUNX2), bone alkaline phosphatase (BALP), and OCN by activating phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, which confirmed by adding PI3K chemical inhibitor of LY294002.
CONCLUSION
HHML treatment is a reliable remedy for fractures in tibial and ankle by promotion of osteogenic differentiation via activation of PI3K/Akt pathway.
Topics: Animals; Drugs, Chinese Herbal; Proto-Oncogene Proteins c-akt; Male; Osteogenesis; Humans; Mice; Rats, Sprague-Dawley; Cell Differentiation; Female; Middle Aged; Adult; Rats; Osteoblasts; Signal Transduction; Fracture Healing; Phosphatidylinositol 3-Kinases; Fractures, Bone; Aged; Young Adult; Disease Models, Animal
PubMed: 38670404
DOI: 10.1016/j.jep.2024.118234 -
Journal of Osteoporosis 2024Osteoporosis treatment plays a crucial role in preventing fractures, particularly in bedridden patients. We conducted a questionnaire survey presenting hypothetical...
Osteoporosis treatment plays a crucial role in preventing fractures, particularly in bedridden patients. We conducted a questionnaire survey presenting hypothetical clinical cases in 2015 and 2020 to investigate trends over a 5-year period. The target population included physicians working in clinics and hospitals within our neighbourhood. The cases were presented, and the questionnaire was administered in a confidential format. The orthopaedic surgeons were matched for age and practice, resulting in 74 cases being included in the analysis. Comparing the 2015 and 2020 results, we observed a notable increase in physicians who would perform "bone mineral density measurements of the lumbar spine and hip." Furthermore, there was a significant rise in the percentage of respondents willing to test for bone metabolic markers, such as serum type I collagen cross-linked N-telopeptide (NTX), procollagen I N-terminal propeptide (P1NP), and tartrate-resistant acid phosphatase 5b (TRACP-5b). Regarding therapeutic agents, bisphosphonates decreased in usage, whereas parathyroid hormone and romosozumab witnessed an increase. In conclusion, the percentage of physicians requesting bone mineral density measurements of the lumbar spine and hip increased over the five-year period. In addition, more physicians chose to utilise bone metabolic markers due to their ease of measurement through blood tests and reduced diurnal variation. Finally, there was a marked trend towards the administration of drugs capable of rapidly and effectively increasing bone mineral density at an early stage of treatment.
PubMed: 38659619
DOI: 10.1155/2024/9629891 -
BMC Endocrine Disorders Apr 2024Sodium glucose cotransporter 2 (SGLT2) inhibitors are widely used in type 2 diabetes mellitus (T2DM) therapy. The impact of SGLT2 inhibitors on bone metabolism has been... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Sodium glucose cotransporter 2 (SGLT2) inhibitors are widely used in type 2 diabetes mellitus (T2DM) therapy. The impact of SGLT2 inhibitors on bone metabolism has been widely taken into consideration. But there are controversial results in the study on the effect of SGLT2 inhibitors on bone metabolism in patients with T2DM. Therefore, we aimed to examine whether and to what extent SGLT2 inhibitors affect bone metabolism in patients with T2DM.
METHODS
A literature search of randomized controlled trials (RCTs) was conducted through PubMed, Web of Science, Embase, Cochrane databases, and Scopus from inception until 15 April 2023. Eligible RCTs compared the effects of SGLT2 inhibitors versus placebo on bone mineral density and bone metabolism in patients with T2DM. To evaluate the differences between groups, a meta-analysis was conducted using the random effects inverse-variance model by utilizing standardized mean differences (SMD).
RESULTS
Through screening, 25 articles were finally included, covering 22,828 patients. The results showed that, compared with placebo, SGLT2 inhibitors significantly increased parathyroid hormone (PTH, SMD = 0.13; 95%CI: 0.06, 0.20), and cross-linked C-terminal telopeptides of type I collagen (CTX, SMD = 0.11; 95%CI: 0.01, 0.21) in patients with T2DM, decreased serum alkaline phosphatase levels (ALP, SMD = -0.06; 95%CI: -0.10, -0.03), and had no significant effect on bone mineral density (BMD), procollagen type 1 N-terminal propeptide (P1NP), 25-hydroxy vitamin D, tartrate resistant acid phosphatase-5b (TRACP-5b) and osteocalcin.
CONCLUSIONS
SGLT2 inhibitors may negatively affect bone metabolism by increasing serum PTH, CTX, and decreasing serum ALP. This conclusion needs to be verified by more studies due to the limited number and quality of included studies.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO, identifier CRD42023410701.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Bone Density; Bone and Bones; Randomized Controlled Trials as Topic
PubMed: 38658986
DOI: 10.1186/s12902-024-01575-8 -
International Journal of General... 2024To investigate the risk factors for the development of portal hypertension in patients with decompensated cirrhosis and analyze their prognosis.
OBJECTIVE
To investigate the risk factors for the development of portal hypertension in patients with decompensated cirrhosis and analyze their prognosis.
METHODS
Patients with decompensated cirrhosis who were admitted to our hospital and Qu fu People's Hospital from June 2022 to June 2023 were included in this study. Among them, there were 45 male and 15 female patients, with a median age of 56 (range: 35-77) years. A comparative analysis was performed between Group A (hepatic venous pressure gradient, HVPG <16 mmHg) and Group B (HVPG ≥16 mmHg) patients, along with various clinical outcomes. Multivariate analysis was conducted to explore the risk factors influencing the occurrence of portal hypertension and adverse prognosis in patients with cirrhosis.
RESULTS
In Group A patients with portal hypertension, we observed lower levels of aspartate aminotransferase, laminin, serum hyaluronic acid, type III procollagen N-terminal peptide, total bile acids, and cholylglycine acid compared to Group B. On the other hand, levels of alanine aminotransferase, white blood cells, and serum albumin were higher in Group A than in Group B. These differences between the groups were statistically significant (P < 0.05). Multivariate analysis of the aforementioned risk factors indicated that low white blood cell count, high cholylglycine acid levels, and high serum hyaluronic acid levels were identified as independent risk factors for the occurrence of difficult-to-control complications in decompensated portal hypertension among patients with liver cirrhosis (P < 0.05).
CONCLUSION
Liver cirrhosis patients with portal hypertension and multiple risk factors like low white blood cell count and high liver transaminase levels should be cautious regarding the progression of portal hypertension when combined with splenomegaly, liver fibrosis, and bile stasis, as it often indicates a poor prognosis.
PubMed: 38655006
DOI: 10.2147/IJGM.S453107 -
Oncogene Jun 2024Mammalian target of rapamycin (mTOR) kinase functions as a central regulator of cell growth and metabolism, and its complexes mTORC1 and mTORC2 phosphorylate distinct...
Mammalian target of rapamycin (mTOR) kinase functions as a central regulator of cell growth and metabolism, and its complexes mTORC1 and mTORC2 phosphorylate distinct substrates. Dysregulation of mTOR signaling is commonly implicated in human diseases, including cancer. Despite three decades of active research in mTOR, much remains to be determined. Here, we demonstrate that prolyl 4-hydroxylase alpha-2 (P4HA2) binds directly to mTOR and hydroxylates one highly conserved proline 2341 (P2341) within a kinase domain of mTOR, thereby activating mTOR kinase and downstream effector proteins (e.g. S6K and AKT). Moreover, the hydroxylation of P2341 strengthens mTOR stability and allows mTOR to accurately recognize its substrates such as S6K and AKT. The growth of lung adenocarcinoma cells overexpressing mTOR is significantly reduced when compared with that of cells overexpressing mTOR. Interestingly, in vivo cell growth assays show that targeting P4HA2-mTOR significantly suppresses lung adenocarcinoma cell growth. In summary, our study reveals an undiscovered hydroxylation-regulatory mechanism by which P4HA2 directly activates mTOR kinase, providing insights for therapeutically targeting mTOR kinase-driven cancers.
Topics: Humans; Hydroxylation; TOR Serine-Threonine Kinases; Adenocarcinoma of Lung; Lung Neoplasms; Cell Proliferation; Animals; Mice; Cell Line, Tumor; Signal Transduction; Procollagen-Proline Dioxygenase
PubMed: 38654109
DOI: 10.1038/s41388-024-03032-1 -
Acta Dermatovenerologica Croatica : ADC Dec 2023Platelet-rich plasma (PRP) is used in medicine as a source of autologous growth factors in different indications. At present, PRP is applied increasingly frequently in...
Platelet-rich plasma (PRP) is used in medicine as a source of autologous growth factors in different indications. At present, PRP is applied increasingly frequently in aesthetic medicine with the aim of skin revitalization. Until now, the mechanisms of PRP effects in healthy human skin treated with aesthetic goals have not been identified in detail. This study aimed to examine PRP effects on the synthesis of procollagen type I in human skin. This study was a prospective, single-center, single-dose, open-label, non-randomized controlled clinical study. The study was conducted on a group of 10 volunteers in whom forearm skin was injected with PRP, while the placebo control group received injections of 0.9% NaCl. Expression of procollagen type I was examined after 21 days using immunohistochemistry. The study demonstrated that skin fragments subjected therapy using PRP demonstrated a significantly higher expression of procollagen than that which was observed in placebo controls. The study demonstrated that PRP stimulated collagen expression in healthy human skin.
Topics: Humans; Platelet-Rich Plasma; Collagen Type I; Female; Adult; Prospective Studies; Male; Skin; Middle Aged; Immunohistochemistry
PubMed: 38651842
DOI: No ID Found