OBJECTIVE: To analyze the significance of total vitamin D (tVD), total procollagen type I amino-terminal propeptide (tPINP) and β-CrossLaps (β-CTx) in the staging and prognosis of patients with multiple myeloma (MM). METHODS: A total of 54 patients with newly diagnosed MM admitted to the Second Affiliated Hospital of Fujian Medical University from 2020 to 2022 were selected as the observation group (MM group), and 50 healthy persons who underwent physical examinations in our hospital were selected as the control group. The expression levels of tVD, tPINP and β-CTx in the two groups were detected by chemiluminescence method. The differences in the expression levels of tVD, tPINP and β-CTx among MM patients at different ISS stages were analyzed. The expression levels of tVD, tPINP and β-CTx in MM patients with different levels of hemoglobin (Hb), serum calcium (Ca), creatinine (Crea), albumin (ALB), β₂-microglobulin (β₂-MG) and lactate dehydrogenase (LDH) were compared. The correlations between the expression levels of tVD, tPINP, β-CTx and the aforementioned clinical parameters were analyzed, respectively. The relationship between the expression levels of tVD, tPINP, β-CTx and the progression-free survival (PFS) of MM patients was analyzed. RESULTS: The expression level of tVD in the MM group was significantly lower than that in the control group (21.73±14.45 ng/ml <i>vsi> 30.78±9.94 ng/ml, <i>Pi> =0.022). The expression level of β-CTx in the MM group was significantly higher than that in the control group (1.43±0.99 ng/ml <i>vsi> 0.53±0.29 ng/ml, <i>Pi> =0.013). The tVD level in MM patients with ISS stage I-II was significantly higher than that of MM patients with ISS stage III (29.50±14.59 ng/ml <i>vsi> 12.62±7.73 ng/ml, <i>Pi> =0.028), indicating that the higher the ISS stage, the lower the tVD level. The tPINP and β-CTx levels in MM patients with high Ca levels (>2.65 mmol/L) were significantly higher than those in patients with low Ca levels (≤2.65 mmol/L) (<i>Pi> =0.016, <i>Pi> =0.021). The tVD level of MM patients was positively correlated with the ALB level (<i>ri> =0.570), tPINP was positively correlated with Ca and β₂-MG levels (<i>ri> =0.791,<i>ri> =0.673), and β-CTx was positively correlated with tPINP level (<i>ri> =0.616). The PFS of the low tVD expression group was significantly lower than that of the high tVD expression group (<i>Pi> =0.041). CONCLUSION The expression level of tVD is decreased in MM patients, which can be used as an indicator to evaluate the disease stage and prognosis of the patients. The β-CTx expression level is increased in MM patients. tPINP and β-CTx may be correlated with clinical symptoms such as osteolytic lesions and renal function changes in MM patients.
Humans ; Multiple Myeloma/pathology* ; Procollagen/blood* ; Vitamin D/blood* ; Prognosis ; Peptide Fragments/blood* ; Collagen Type I/blood* ; Female ; Male ; Middle Aged ; Aged ; Neoplasm Staging

OBJECTIVES: To investigate the changes in blood levels of calcium and bone metabolism biochemical markers in patients with primary osteoporosis receiving treatment with denosumab. METHODS: Seventy-three patients with primary osteoporosis treated in our Department between December, 2021 and December 2023 were enrolled. All the patients were treated with calcium supplements, vitamin D and calcitriol in addition to regular denosumab treatment every 6 months. Blood calcium, parathyroid hormone (PTH), osteocalcin (OC), type I procollagen amino-terminal propeptide (PINP), and type I collagen carboxy-terminal telopeptide β special sequence (β‑CTX) data before and at 3, 6, 9, and 12 months after the first treatment were collected from each patient. RESULTS: Three months after the first denosumab treatment, the bone turnover markers (BTMs) OC, PINP, and β-CTX were significantly decreased compared to their baseline levels by 39.5% (<i>Pi><0.001), 56.2% (<i>Pi><0.001), and 81.8% (<i>Pi><0.001), respectively. At 6, 9, and 12 months of treatment, OC, PINP, and β-CTX remained significantly lower than their baseline levels (<i>Pi><0.001). Blood calcium level was decreased (<i>Pi><0.05) and PTH level increased (<i>Pi><0.05) significantly in these patients at months of denosumab treatment, but their levels were comparable to the baseline levels at 6, 9, and 12 months of the treatment (<i>Pi>>0.05). CONCLUSIONS Denosumab can suppress BTMs and has a good therapeutic effect in patients with primary osteoporosis, but reduction of blood calcium and elevation of PTH levels can occur during the first 3 months in spite of calcium supplementation. Blood calcium and PTH levels can recover the baseline levels as the treatment extended, suggesting the importance of monitoring blood calcium and PTH levels during denosumab treatment.
Humans ; Denosumab/therapeutic use* ; Calcium/blood* ; Parathyroid Hormone/blood* ; Biomarkers/blood* ; Osteoporosis/blood* ; Osteocalcin/blood* ; Procollagen/blood* ; Female ; Collagen Type I/blood* ; Peptide Fragments/blood* ; Bone Density Conservation Agents/therapeutic use* ; Bone and Bones/metabolism* ; Male ; Middle Aged ; Vitamin D ; Peptides/blood* ; Aged

OBJECTIVES: To study the level of serum vitamin K₂ (VitK₂) and its association with bone metabolism markers osteocalcin (OC), type I procollagen amino-terminal peptide (PINP), and type I collagen carboxy-terminal peptide (CTX) in children. METHODS: A prospective analysis was performed on 1 732 children who underwent routine physical examination from October 2020 to October 2021. The serum levels of VitK₂ and 25-hydroxy vitamin D [25(OH)D] were measured. According to age, they were divided into four groups: <1 year, 1-3 years group, >3-6 years group, and >6-14 years. A total of 309 children with 25(OH)D≥50 nmol/L were screened out, and serum levels of OC, PINP, and CTX were measured to investigate the correlation of the serum levels of OC, PINP, and CTX with serum VitK₂ levels in different age groups. RESULTS: The prevalence rate of serum VitK₂ deficiency was 52.31% (906/1 732). The VitK₂ deficiency group had higher prevalence rates of overweight/obesity and growth pain (≥3 years of age) than the normal VitK₂ group (<i>Pi><0.05). There were differences in the prevalence rate of serum VitK₂ deficiency (<i>Pi><0.0083) and the serum level of VitK₂ (<i>Pi><0.05) between the 1-3 years group and the >6-14 years group. The <1 year group had a higher serum level of CTX and a lower serum level of PINP than the >3-6 years group and the >6-14 years group (<i>Pi><0.05). The <1 year group had a lower serum level of OC than the >6-14 years group (<i>Pi><0.05). Serum VitK₂ level was positively correlated with OC level (<i>r_si>=0.347, <i>Pi><0.01), and CTX level was negatively correlated with PINP level (<i>r_si>=-0.317, <i>Pi><0.01). CONCLUSIONS Serum VitK₂ deficiency may be associated with overweight/obesity. Serum VitK₂ may affect the level of OC and even bone health.
Child ; Humans ; Infant ; Biomarkers/metabolism* ; Collagen Type I/metabolism* ; Obesity/complications* ; Osteocalcin/metabolism* ; Overweight/complications* ; Peptide Fragments/metabolism* ; Peptides/metabolism* ; Procollagen/metabolism* ; Vitamin K/blood* ; Child, Preschool ; Adolescent ; Bone and Bones/metabolism*

OBJECTIVE: Silicosis, caused by inhalation of silica dust, is the most serious occupational disease in China and the aim of present study was to explore the protective effect of Ang (1-7) on silicotic fibrosis and myofibroblast differentiation induced by Ang II. METHODS: HOPE-MED 8050 exposure control apparatus was used to establish the rat silicosis model. Pathological changes and collagen deposition of the lung tissue were examined by H.E. and VG staining, respectively. The localizations of ACE2 and α-smooth muscle actin (α-SMA) in the lung were detected by immunohistochemistry. Expression levels of collagen type I, α-SMA, ACE2, and Mas in the lung tissue and fibroblasts were examined by western blot. Levels of ACE2, Ang (1-7), and Ang II in serum were determined by ELISA. Co-localization of ACE2 and α-SMA in fibroblasts was detected by immunofluorescence. RESULTS: Ang (1-7) induced pathological changes and enhanced collagen deposition in vivo. Ang (1-7) decreased the expressions of collagen type I and α-SMA and increased the expressions of ACE2 and Mas in the silicotic rat lung tissue and fibroblasts stimulated by Ang II. Ang (1-7) increased the levels of ACE2 and Ang (1-7) and decreased the level of Ang II in silicotic rat serum. A779 enhanced the protective effect of Ang (1-7) in fibroblasts stimulated by Ang II. CONCLUSION Ang (1-7) exerted protective effect on silicotic fibrosis and myofibroblast differentiation induced by Ang II by regulating ACE2-Ang (1-7)-Mas axis.
Actins ; metabolism ; Angiotensin I ; blood ; pharmacology ; therapeutic use ; Angiotensin II ; blood ; Animals ; Animals, Newborn ; Cell Differentiation ; drug effects ; Cells, Cultured ; Collagen Type I ; metabolism ; Disease Models, Animal ; Lung ; metabolism ; pathology ; Myofibroblasts ; drug effects ; Peptide Fragments ; blood ; pharmacology ; therapeutic use ; Peptidyl-Dipeptidase A ; metabolism ; Rats, Wistar ; Silicosis ; metabolism ; pathology ; prevention & control

OBJECTIVETo study the effect of total flavonoids of Astmgali Radix (TFA) on liver cirrhosis induced with dimethylnitrosamine (DMN) in rats, and the effect on peroxisome proliferator-activated receptor γ (PPARγ), uncoupling protein 2 (UCP2) and farnesoid X receptor (FXR).

METHODSFifty-three Sprague-Dawley rats were randomly divided into a control group (10 rats) and a DMN group (43 rats). Rats in the DMN group were given DMN for 4 weeks and divided randomly into a model group (14 rats), a low-dosage TFA group (14 rats) and a high-dosage TFA group (15 rats) in the 3rd week. Rats were given TFA for 4 weeks at the dosage of 15 and 30 mg/kg in the low- and high-TFA groups, respectively. At the end of the experiment blood and liver samples were collected. Serum liver function and liver tissue hydroxyproline content were determined. hematoxylin-eosin (HE), Sirus red and immunohistochemical stainings of collagen I, smooth muscle actin (α-SMA) was conducted in paraffinembedded liver tissue slices. Real time polymerase chain reaction (PCR) was adopted to determine PPARγ, UCP2 and FXR mRNA levels. Western blot was adopted to determine protein levels of collagen I, α-SMA, PPARγ, UCP2 and FXR.

RESULTSCompared with the model group, TFA increased the ratio of liver/body weight (low-TFA group P<0.05, high-TFA group P<0.01), improved liver biochemical indices (P<0.01 for ALT, AST, GGT in both groups, P<0.05 for albumin and TBil in the high-TFA group) and reduced liver tissue hydroxproline content (P<0.01 in both groups) in treatment groups significantly. HE staining showed that TFA alleviated liver pathological changes markedly and Sirus red staining showed that TFA reduced collagen deposition, alleviated formation and extent of liver pseudolobule. Collagen I and α-SMA immunohistochemical staining showed that staining area and extent markedly decreased in TFA groups compared with the model group. TFA could increase PPARγ, it regulated target UCP2, and FXR levels significantly compared with the model group (in the low-TFA group all P<0.05, in the high group all P<0.01).

CONCLUSIONTFA could improve liver function, alleviate liver pathological changes, and reduce collagen deposition and formation of liver pseudolobule in rats with liver cirrhosis. The antifibrotic effect of TFA was through regulating PPARγ signal pathway and the interaction with FXR.

Actins ; metabolism ; Animals ; Blotting, Western ; Body Weight ; drug effects ; Collagen Type I ; metabolism ; Dimethylnitrosamine ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Flavonoids ; pharmacology ; therapeutic use ; Hydroxyproline ; metabolism ; Liver ; drug effects ; pathology ; Liver Cirrhosis ; blood ; drug therapy ; genetics ; pathology ; Male ; Organ Size ; drug effects ; PPAR gamma ; genetics ; metabolism ; Plant Extracts ; pharmacology ; therapeutic use ; RNA, Messenger ; genetics ; metabolism ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction ; Receptors, Cytoplasmic and Nuclear ; genetics ; metabolism ; Uncoupling Protein 2 ; genetics ; metabolism

In keloids, the mechanism underlying the excessive accumulation of extracellular matrix after injury of the skin is unclear, and there is no effective treatment because of the incomplete understanding of their pathogenesis; thus, a high recurrence rate is observed. We studied a new marker of keloids to determine a new treatment strategy. First, the keloid gene expression profile (GSE44270) was analyzed (downloaded from the Gene Expression Omnibus database) and the new keloid marker candidate, epidermal growth factor (EGF)-like repeats and discoidin I-like domains 3 (EDIL3) which were upregulated in keloid samples was identified. Knockdown of EDIL3 is known to suppresses angiogenesis by downregulating relevant inhibitory factors that can limit the supply of survival factors to tumor cells from the circulation via the vascular endothelial cells. In keloids, the mechanism of action of EDIL3 may be similar to that in tumors; the inhibition of apoptosis in tumor cells via a reduction in the apoptosis of blood vessels by upregulating an angiogenic factor. To determine whether EDIL3 is involved in keloid formation, we performed knockdown of EDIL3 in keloid fibroblasts in vitro by transfection with anti-EDIL3 small interfering RNA (via microporation). EDIL3 was upregulated in keloid fibroblasts compared with normal fibroblasts in collagen type I, II and III. Our results indicate the control of EDIL3 expression may be a new promising treatment of keloid disease also the molecular targeting of EDIL3 may improve the quality of treatment and reduce the formation of keloids.
Angiogenesis Inducing Agents ; Apoptosis ; Blood Vessels ; Cicatrix* ; Collagen ; Collagen Type I ; Endothelial Cells ; Epidermal Growth Factor* ; Extracellular Matrix ; Fibroblasts ; Gene Expression ; In Vitro Techniques ; Keloid* ; Recurrence ; RNA, Small Interfering ; Skin ; Transcriptome ; Transfection

The purpose of the present study is to explore the effect of aliskiren on the proliferation of cardiac fibroblasts (CFs) in AGT-REN double transgenic hypertensive (dTH) mice. The cultured CFs from AGT-REN dTH mice were divided into AGT-REN group (dTH) and aliskiren group (ALIS). Cultured CFs from C57B6 mice were served as control (WT). The effect of different concentration of aliskiren (1 × 10, 1 × 10, 1 × 10, 1 × 10mol/L) on CFs proliferation was determined by MTT assay. After treatment with 1 × 10mol/L aliskiren for 24 h, α-SMA, collagen I, III and NADPH oxidase (NOX) protein expression in CFs of AGT-REN dTH mice were detected by Western blot. The collagen synthesis in CFs was assessed by hydroxyproline kit. The expression of ROS was determined by DHE. Results showed that the blood pressure and plasma Ang II levels were significantly increased and CFs proliferation was significantly increased as well in AGT-REN dTH mice compared with WT group. However, aliskiren intervention decreased CFs proliferation, myofibroblast transformation, as well as the collagen I and III synthesis in CFs of AGT-REN dTH mice. Meanwhile, aliskiren inhibited ROS content and NOX2/NOX4 protein expression in CFs of AGT-REN dTH mice. These results suggest that aliskiren decreases the cell proliferation, myofibroblast transformation and collagen production in CFs of AGT-REN dTH mice, which might be through inhibition of oxidative stress response.
Amides ; Animals ; Blood Pressure ; Cell Proliferation ; Cells, Cultured ; Collagen ; Collagen Type I ; Fumarates ; Heart ; Hydroxyproline ; Hypertension ; Mice ; Mice, Transgenic ; Myocardium ; Myofibroblasts ; NADPH Oxidases

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the treatment of patients with type 2 diabetes and have proven protective effects on diabetic kidney disease (DKD). Whether DPP-4 inhibitors have renoprotective effects on insulin-deficient type 1 diabetes has not been comprehensively examined. The aim of this study was to determine whether gemigliptin, a new DPP-4 inhibitor, has renoprotective effects in streptozotocin (STZ)-induced type 1 diabetic mice. METHODS: Diabetes was induced by intraperitoneal administration of a single dose of STZ. Mice with diabetes were treated without or with gemigliptin (300 mg/kg) for 8 weeks. Morphological changes of the glomerular basement membrane (GBM) were observed by electron microscopy and periodic-acid Schiff staining. In addition, we measured blood glucose and urinary albumin excretion and evaluated fibrotic markers using immunohistochemical staining, quantitative reverse transcription polymerase chain reaction analysis, and Western blot analysis. RESULTS: Gemigliptin did not reduce the blood glucose levels of STZ-treated mice. In gemigliptin-treated mice with STZ, a significant reduction in urinary albumin excretion and GBM thickness was observed. Immunohistological examination revealed that gemigliptin attenuated renal fibrosis induced by STZ and decreased extracellular matrix protein levels, including those of type I collagen and fibronectin, and Smad3 phosphorylation. In cultured rat renal cells, gemigliptin inhibited transforming growth factor β-stimulated type I collagen and fibronectin mRNA and protein levels via down-regulation of Smad3 phosphorylation. CONCLUSION: Our data demonstrate that gemigliptin has renoprotective effects on DKD, regardless of its glucose-lowering effect, suggesting that it could be used to prevent DKD, including in patients with type 1 diabetes.
Animals ; Blood Glucose ; Blotting, Western ; Collagen Type I ; Diabetes Mellitus, Type 1 ; Diabetic Nephropathies ; Down-Regulation ; Extracellular Matrix ; Fibronectins ; Fibrosis ; Glomerular Basement Membrane ; Humans ; Mice* ; Microscopy, Electron ; Phosphorylation ; Polymerase Chain Reaction ; Rats ; Reverse Transcription ; RNA, Messenger ; Streptozocin ; Transforming Growth Factors

BACKGROUND/AIMS: The development of therapeutic strategies for the treatment of cirrhosis has become an important focus for basic and clinical researchers. Adrenergic receptor antagonists have been evaluated as antifibrotic drugs in rodent models of carbon tetrachloride (CCl4)-induced cirrhosis. The aim of the present study was to evaluate the effects of carvedilol and doxazosin on fibrosis/cirrhosis in a hamster animal model. METHODS: Cirrhotic-induced hamsters were treated by daily administration of carvedilol and doxazosin for 6 weeks. Hepatic function and histological evaluation were conducted by measuring biochemical markers, including total bilirubin, aspartate aminotransferase, alanine aminotransferase and albumin, and liver tissue slices. Additionally, transforming growth factor beta (TGF-beta) immunohistochemistry was analyzed. RESULTS: Biochemical markers revealed that hepatic function was restored after treatment with doxazosin and carvedilol. Histological evaluation showed a decrease in collagen type I deposits and TGF-beta-secreting cells. CONCLUSIONS: Taken together, these results suggest that the decrease in collagen type I following treatment with doxazosin or carvedilol is achieved by decreasing the profibrotic activities of TGF-beta via the blockage of alpha1- and beta-adrenergic receptor. Consequently, a diminution of fibrotic tissue in the CCl4-induced model of cirrhosis is achieved.
Adrenergic alpha-1 Receptor Antagonists/*pharmacology ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Bilirubin/blood ; Carbazoles/*pharmacology ; Carbon Tetrachloride ; Collagen Type I/drug effects/metabolism ; Cricetinae ; Doxazosin/*pharmacology ; Liver/metabolism/pathology ; Liver Cirrhosis/blood/chemically induced/*drug therapy ; Liver Function Tests ; Propanolamines/*pharmacology ; Serum Albumin/analysis ; Transforming Growth Factor beta/blood/*drug effects

BACKGROUND: Changes in the composition of the extracellular matrix (ECM) occur between the proliferating and involuted phases of infantile hemangiomas (IH), and are associated with angiogenic growth. We examined the composition of the ECM in proliferating and involuted IHs and assessed correlations between the composition of the ECM and whether the IH was in the proliferating or the involuted phase. METHODS: We evaluated IH samples from a cohort of patients who had five proliferating IHs and five involuted IHs. The following ECM molecules were analyzed using enzyme-linked immunosorbent assays and immunohistochemistry: laminin, fibronectin, collagen type I, collagen type II, and collagen type III. RESULTS: The involuted IHs had higher levels of deposition of collagen type III than the proliferating IHs. The median values (interquartile ranges) were 1.135 (0.946-1.486) and 1.008 (0.780-1.166) (P=0.019), respectively. The level of laminin was higher in involuted IHs than in proliferating IHs, with median values (interquartile ranges) of 3.191 (2.945-3.191) and 2.479 (1.699-3.284) (P=0.047), respectively. Abundant collagen type III staining was found in involuted IHs. Laminin alpha4 chain staining was clearly present within the basement membrane adjacent to the blood vessels, and was significantly more intense in involuted IHs than in proliferative IHs. CONCLUSIONS: Involuted hemangiomas showed extensive deposition of collagen III and laminin, suggesting that differences in the composition of the ECM reflect stages of the development of IHs. This pattern may be due to the rapid senescence of IHs.
Aging ; Basement Membrane ; Blood Vessels ; Cohort Studies ; Collagen ; Collagen Type I ; Collagen Type II ; Collagen Type III ; Enzyme-Linked Immunosorbent Assay ; Extracellular Matrix* ; Fibronectins ; Hemangioma* ; Humans ; Immunohistochemistry ; Laminin