BACKGROUND Hepatic fibrosis is a serious condition,and the development of hepatic fibrosis can lead to a series of complications.However,the pathogenesis of hepatic fibrosis remains unclear,and effective therapy optio...BACKGROUND Hepatic fibrosis is a serious condition,and the development of hepatic fibrosis can lead to a series of complications.However,the pathogenesis of hepatic fibrosis remains unclear,and effective therapy options are still lacking.Our group identified hepatitis C virus nonstructural protein 3-transactivated protein 1(NS3TP1) by suppressive subtractive hybridization and bioinformatics analysis,but its role in diseases including hepatic fibrosis remains undefined.Therefore,additional studies on the function of NS3TP1 in hepatic fibrosis are urgently needed to provide new targets for treatment.AIM To elucidate the mechanism of NS3TP1 in hepatic fibrosis and the regulatory effects of calcitriol on NS3TP1.METHODS Twenty-four male C57BL/6 mice were randomized and separated into three groups,comprising the normal,fibrosis,and calcitriol treatment groups,and liver fibrosis was modeled by carbon tetrachloride(CCl4).To evaluate the level of hepatic fibrosis in every group,serological and pathological examinations of the liver were conducted.TGF-β1 was administered to boost the in vitro cultivation of LX-2 cells.NS3TP1,α-smooth muscle actin(α-SMA),collagen I,and collagen Ⅲ in every group were examined using a Western blot and real-time quantitative polymerase chain reaction.The activity of the transforming growth factor beta 1(TGFβ1)/Smad3 and NF-κB signaling pathways in each group of cells transfected with pcDNA-NS3TP1 or siRNA-NS3TP1 was detected.The statistical analysis of the data was performed using the Student’s t test.RESULTS NS3TP1 promoted the activation,proliferation,and differentiation of hepatic stellate cells(HSCs)and enhanced hepatic fibrosis via the TGFβ1/Smad3 and NF-κB signaling pathways,as evidenced by the presence of α-SMA,collagen I,collagen Ⅲ,p-smad3,and p-p65 in LX-2 cells,which were upregulated after NS3TP1 overexpression and downregulated after NS3TP1 interference.The proliferation of HSCs was lowered after NS3TP1 interference and elevated after NS3TP1 overexpression,as shown by the luciferase assay.NS3TP1 inhibited the apoptosis of HSCs.Moreover,both Smad3 and p65 could bind to NS3TP1,and p65 increased the promoter activity of NS3TP1,while NS3TP1 increased the promoter activity of TGFβ1 receptor I,as indicated by coimmunoprecipitation and luciferase assay results.Both in vivo and in vitro,treatment with calcitriol dramatically reduced the expression of NS3TP1.Calcitriol therapy-controlled HSCs activation,proliferation,and differentiation and substantially suppressed CCl4-induced hepatic fibrosis in mice.Furthermore,calcitriol modulated the activities of the above signaling pathways via downregulation of NS3TP1.CONCLUSION Our results suggest that calcitriol may be employed as an adjuvant therapy for hepatic fibrosis and that NS3TP1 is a unique,prospective therapeutic target in hepatic fibrosis.展开更多
Background:Capacitation is a set of physiological changes sperms undergo to acquire fertilizing capacity.In vivo,this process is directly associated with high calcium levels in sperm cytoplasm.Calcitriol,the vitamin D...Background:Capacitation is a set of physiological changes sperms undergo to acquire fertilizing capacity.In vivo,this process is directly associated with high calcium levels in sperm cytoplasm.Calcitriol,the vitamin D hypercalcemic metabolite,is related to human sperm motility,capacitation,and acrosome reaction.This work aimed to study the effect of calcitriol on bull sperm quality parameters and capacitation.Methods:One million freezethawed spermatozoa were obtained from different bulls and treated with 20 nM of calcitriol for 30 min.Untreated cells(negative control)and treated ones with calcitriol or heparin(100μg/mL,positive capacitation control)were evaluated for motility,viability,and functional parameters.Menadione(70μM,30 min)treatment was included as a reactive oxygen species(ROS)positive sperm agent.Results:The results elucidated that sperm exposed to 20 nM calcitriol showed higher viability,vigor,and capacitation than their positive and negative controls.The percentage of sperm with intact plasma and acrosome membranes,mitochondrial membrane potential(ΔΨm),and phosphatidylserine externalization was similar in all the conditions evaluated,while ROS production was higher with heparin and menadione-treated groups than the calcitriol group or negative control.Conclusion:Our results indicate that calcitriol induces the capacitation of thawed bull spermatozoa and maintains acceptable values of progressive motility,viability,and vigor without altering key biological parameters such as redox status,ΔΨm,and cell death.展开更多
BACKGROUND Calcitriol-induced hypercalcemia has been rarely reported in cases of lung cancer;however,it is frequently reported in cases of lymphoid malignancy and granulomatous disease.We present a rare case of hyperc...BACKGROUND Calcitriol-induced hypercalcemia has been rarely reported in cases of lung cancer;however,it is frequently reported in cases of lymphoid malignancy and granulomatous disease.We present a rare case of hypercalcemia associated with squamous cell cancer of the lung with elevated calcitriol level.CASE SUMMARY A 61-year-old Caucasian female with severe hypercalcemia of 15 mg/dL,which led to a new diagnosis of metastatic lung cancer.Since the parathyroid hormonerelated peptide(PTHrP)level was minimally elevated at 2.1 pmol/L,we believe excessive calcitriol production by tumor cells was the underlying mechanism for hypercalcemia.Calcitriol was significantly elevated at 130 pg/mL with a low 25-hydroxyvitamin D level of 25.9 ng/mL and suppressed PTH level of 8 pg/mL.Corticosteroids are generally used to treat calcitriol-induced hypercalcemia,but we successfully treated our patient with bisphosphonate,highlighting the further utility of bisphosphonates in hypercalcemia treatment.CONCLUSION We believe that the underlying cause of hypercalcemia,in this case of metastatic squamous cell lung carcinoma,was elevated calcitriol,which was likely produced by the tumor cells.In addition to PTHrP,calcitriol levels should be included in the workup for hypercalcemia in cases of lung cancer.However,the pathophysiology and prognostic significance of dysregulated calcitriol production in solid tumors remain unclear and warrant further research.Bisphosphonate may be used as a steroid-sparing therapy even in cases of calcitriol-induced hypercalcemia and warrants further investigation.展开更多
Solid dispersion of calcitriol with lipophilic surfactants and triglycerides was developed by melt-mixing method to modify the release and enhance stability of the drug.The solid dispersions were characterized by diff...Solid dispersion of calcitriol with lipophilic surfactants and triglycerides was developed by melt-mixing method to modify the release and enhance stability of the drug.The solid dispersions were characterized by differential scanning calorimetry(DSC),hot stage polarized optical microscopy(HSPM),infrared spectroscopy(FTIR)and stability studies.The solid dispersion significantly enhanced the stability of calcitriol,which could be attributed to the high antioxidant activity of the solid lipid dispersion.The rapid dissolution rate from the solid dispersion was attributed to the amorphous or solid solution state of drug with improved specific surface area and wettability than the drug crystals.Therefore,solid dispersion of calcitriol with D-a-tocopheryl polyethylene glycol 1000 succinate(TPGS)offers a good approach to modify the release and enhance stability of calcitriol.The influence of lipophilic solid dispersion on drug bioavailability needs further investigation.展开更多
Back ground: There are no published clinical data in hemodialysis (HD) patients with mineral bone disorder (CKD-MBD) regarding the effect of sevelamer hydrochloride on the absorption of the oral calcitriol. Objectives...Back ground: There are no published clinical data in hemodialysis (HD) patients with mineral bone disorder (CKD-MBD) regarding the effect of sevelamer hydrochloride on the absorption of the oral calcitriol. Objectives: The aim of the present study was to determine the association of the sevelamer hydrochloride and serum 1-25(OH)2D concentration during oral calcitriol therapy. Methods: This was a before-and-after study in HD patients. Forty-six patients co-administered with phosphate-binder and calcitriol for CKD-MBD therapy took lanthanum carbonate (LC) and sevelamer hydrochloride (SH) for 4 weeks, respectively with calcitriol. The serum 1-25(OH)2D concentration was assessed after each period. Results: Serum 1-25(OH)2D concentration was significantly reduced with co-administration of SH compared to LH (mean, calcitriol with LC→SH: 19.9 pg/ml → 14.2 pg/ml, p 2D concentrations after oral calcitriol administration compared to LH in HD patients. When we use SH as a phosphate binder with calcitriol for HD patients with CKD-MBD, we should consider the inhibitory effect of SH on oral calcitriol absorption.展开更多
Objective:To investigate calcitriol, cinacalcet plus comprehensive intervention on maintenance hemodialysis (MHD) patients with secondary hyperparathyroidism (SHPT) calcium (Ca), phosphorus (P) metabolism and parathyr...Objective:To investigate calcitriol, cinacalcet plus comprehensive intervention on maintenance hemodialysis (MHD) patients with secondary hyperparathyroidism (SHPT) calcium (Ca), phosphorus (P) metabolism and parathyroid hormone (PTH) effect.Methods: A total of 80 cases of patients with SHPT from January 2014 to January 2016 in our hospital were randomly divided into observation group and control group, control group to eat the whole piece of cinacalcet hydrochloride oral tablets, the initial dose of 25 mg/d, every 2 to 4 weeks, according to Ca×P, parathyroid hormone (iPTH) test results adjust the dose, the maximum dose of not more than 75 mg/d, the observation group in the control group on the basis of oral administration of Calcitriol Soft Capsules 0.25 g/d, 3 times/week, 2 groups were given comprehensive intervention measures, to evaluate the curative effect after 3 months of treatment. The 2 groups before and after treatment collected fasting peripheral venous blood, the determination of Ca, P and alkaline phosphatase by colorimetric method (ALP), Ca, P product calculation (Ca×P), to detect the level of iPTH before and after treatment by ELISA method;TY-6858-HI type ultrasound instrument, measuring length, width and thickness of the parathyroid glands, and calculate the parathyroid gland volume.Results:in the observation group after treatment, Ca, Ca×P increased degree, P, ALP, iPTH lower than the control group, the size of the parathyroid gland was better than the control group.Conclusion:calcitriol, cinacalcet combined intervention therapy has good clinical effect in patients with MHD SHPT, Ca, P can effectively improve the metabolism, reduce the level of iPTH, reduce the parathyroid gland volume is worthy of promotion.展开更多
AIM: To investigate the effects of ZK1916784, a low calcemic analog of calcitriol on intestinal inflammation. METHODS: Acute and chronic colitis was induced by dextran sodium sulfate (DSS) according to standard proced...AIM: To investigate the effects of ZK1916784, a low calcemic analog of calcitriol on intestinal inflammation. METHODS: Acute and chronic colitis was induced by dextran sodium sulfate (DSS) according to standard procedures. Mice were treated intraperitoneally with ZK1916784 or placebo and colonic inflammation was evaluated. Cytokine production by mesenterial lymph node (MLN) cells was measured by ELISA. Immunohistochemistry was performed to detect intestinal dendritic cells (DCs) within the colonic tissue, and the effect of the calcitriol analog on DCs was investigated. RESULTS: Treatment with ZK191784 resulted in significant amelioration of disease with a reduced histological score in acute and chronic intestinal inflammation. In animals with acute DSS colitis, down- regulation of colonic inflammation was associated with a dramatic reduction in the secretion of the proinflammatory cytokine interferon (IFN)-γ and a significant increase in intereleukin (IL)-10 by MLN cells. Similarly, in chronic colitis, IL-10 expression in colonic tissue increased 1.4-fold when mice were treated with ZK191784, whereas expression of the Th1-specific transcription factor T-beta decreased by 81.6%. Lower numbers of infiltrating activated CD11c+ DCs were found in the colon in ZK191784-treated mice with acute DSScolitis, and secretion of proinflammatory cytokines by primary mucosal DCs was inhibited in the presence of the calcitriol analog. CONCLUSION: The calcitriol analog ZK191784 demonstrated significant anti-inflammatory properties in experimental colitis that were at least partially mediated by the immunosuppressive effects of the derivate on mucosal DCs.展开更多
An 86-year-old man, diagnosed as having mycosis fungoides in May 2008 and treated with repeated radiation therapy, was admitted to our hospital for initiation of hemodialysis due to end-stage renal disease(ESRD) in Ap...An 86-year-old man, diagnosed as having mycosis fungoides in May 2008 and treated with repeated radiation therapy, was admitted to our hospital for initiation of hemodialysis due to end-stage renal disease(ESRD) in April 2012. On admission, his corrected serum calcium level was 9.3 mg/d L, and his intact parathyroid hormone level was 121.9 pg/mL(normal range 13.9-78.5pg/mL), indicating secondary hyperparathyroidism due to ESRD. After starting hemodialysis, urinary volume diminished rapidly. The serum calcium level increased(12.7 mg/dL), and the intact parathyroid hormone level was suppressed(< 5 pg/m L), while the 1,25-dihy-droxyvitamin D3(calcitriol) level increased(114 pg/mL, normal range: 20.0-60.0 pg/m L) in June 2012. The possibilities of sarcoidosis and tuberculosis were ruled out. Skin biopsies from tumorous lesions revealed a diagnosis of granulomatous mycosis fungoides. The serum soluble interleukin-2 receptor levels and the degrees of skin lesions went in parallel with the increased serum calcium and calcitriol levels. Therefore, the patient was diagnosed as having calcitriol-induced hypercalcemia possibly associated with granulomatous mycosis fungoides. Granulomatous mycosis fungoides is rare, and its association with calcitriol-induced hypercalcemia has not been reported. Careful attention to calcium metabolism is needed in patients with granulomatous mycosis fungoides, especially in patients with ESRD.展开更多
Background:Colorectal cancer(CRC)is one of the most malignant tumorswith high incidence,yet its molecular mechanism is not fully understood,hindering the development of targeted therapy.Metabolic abnormalities are a h...Background:Colorectal cancer(CRC)is one of the most malignant tumorswith high incidence,yet its molecular mechanism is not fully understood,hindering the development of targeted therapy.Metabolic abnormalities are a hallmark of cancer.Targeting dysregulated metabolic features has become an important direction for modern anticancer therapy.In this study,we aimed to identify a new metabolic enzyme that promotes proliferation of CRC and to examine the related molecular mechanisms.Methods:We performed RNA sequencing and tissue microarray analyses of human CRC samples to identify new genes involved in CRC.Squalene epoxidase(SQLE)was identified to be highly upregulated in CRC patients.The regulatory function of SQLE in CRC progression and the therapeutic effect of SQLE inhibitors were determined by measuring CRC cell viability,colony and organoid formation,intracellular cholesterol concentration and xenograft tumor growth.Themolecularmechanism of SQLE functionwas explored by combining transcriptome and untargeted metabolomics analysis.Western blotting and realtime PCR were used to assess MAPK signaling activation by SQLE.Results:SQLE-related control of cholesterol biosynthesis was highly upregulated in CRC patients and associated with poor prognosis.SQLE promoted CRC growth in vitro and in vivo.Inhibition of SQLE reduced the levels of calcitriol(active form of vitamin D3)and CYP24A1,followed by an increase in intracellular Ca2+concentration.Subsequently,MAPK signaling was suppressed,resulting in the inhibition of CRC cell growth.Consistently,terbinafine,an SQLE inhibitor,suppressed CRC cell proliferation and organoid and xenograft tumor growth.Conclusions:Our findings demonstrate that SQLE promotes CRC through the accumulation of calcitriol and stimulation of CYP24A1-mediated MAPK signaling,highlighting SQLE as a potential therapeutic target for CRC treatment.展开更多
基金the National Key Research and Development Program of China,No.2017YFC0908104National Science and Technology Projects,No.2017ZX10203201,No.2017ZX10201201,and No.2017ZX10202202.
文摘BACKGROUND Hepatic fibrosis is a serious condition,and the development of hepatic fibrosis can lead to a series of complications.However,the pathogenesis of hepatic fibrosis remains unclear,and effective therapy options are still lacking.Our group identified hepatitis C virus nonstructural protein 3-transactivated protein 1(NS3TP1) by suppressive subtractive hybridization and bioinformatics analysis,but its role in diseases including hepatic fibrosis remains undefined.Therefore,additional studies on the function of NS3TP1 in hepatic fibrosis are urgently needed to provide new targets for treatment.AIM To elucidate the mechanism of NS3TP1 in hepatic fibrosis and the regulatory effects of calcitriol on NS3TP1.METHODS Twenty-four male C57BL/6 mice were randomized and separated into three groups,comprising the normal,fibrosis,and calcitriol treatment groups,and liver fibrosis was modeled by carbon tetrachloride(CCl4).To evaluate the level of hepatic fibrosis in every group,serological and pathological examinations of the liver were conducted.TGF-β1 was administered to boost the in vitro cultivation of LX-2 cells.NS3TP1,α-smooth muscle actin(α-SMA),collagen I,and collagen Ⅲ in every group were examined using a Western blot and real-time quantitative polymerase chain reaction.The activity of the transforming growth factor beta 1(TGFβ1)/Smad3 and NF-κB signaling pathways in each group of cells transfected with pcDNA-NS3TP1 or siRNA-NS3TP1 was detected.The statistical analysis of the data was performed using the Student’s t test.RESULTS NS3TP1 promoted the activation,proliferation,and differentiation of hepatic stellate cells(HSCs)and enhanced hepatic fibrosis via the TGFβ1/Smad3 and NF-κB signaling pathways,as evidenced by the presence of α-SMA,collagen I,collagen Ⅲ,p-smad3,and p-p65 in LX-2 cells,which were upregulated after NS3TP1 overexpression and downregulated after NS3TP1 interference.The proliferation of HSCs was lowered after NS3TP1 interference and elevated after NS3TP1 overexpression,as shown by the luciferase assay.NS3TP1 inhibited the apoptosis of HSCs.Moreover,both Smad3 and p65 could bind to NS3TP1,and p65 increased the promoter activity of NS3TP1,while NS3TP1 increased the promoter activity of TGFβ1 receptor I,as indicated by coimmunoprecipitation and luciferase assay results.Both in vivo and in vitro,treatment with calcitriol dramatically reduced the expression of NS3TP1.Calcitriol therapy-controlled HSCs activation,proliferation,and differentiation and substantially suppressed CCl4-induced hepatic fibrosis in mice.Furthermore,calcitriol modulated the activities of the above signaling pathways via downregulation of NS3TP1.CONCLUSION Our results suggest that calcitriol may be employed as an adjuvant therapy for hepatic fibrosis and that NS3TP1 is a unique,prospective therapeutic target in hepatic fibrosis.
基金Research was funded by grants from National University of Río Cuarto(UNRC)through the Secretary of Science and Technology(SECYT,PPI 2020-2022,Res 083).
文摘Background:Capacitation is a set of physiological changes sperms undergo to acquire fertilizing capacity.In vivo,this process is directly associated with high calcium levels in sperm cytoplasm.Calcitriol,the vitamin D hypercalcemic metabolite,is related to human sperm motility,capacitation,and acrosome reaction.This work aimed to study the effect of calcitriol on bull sperm quality parameters and capacitation.Methods:One million freezethawed spermatozoa were obtained from different bulls and treated with 20 nM of calcitriol for 30 min.Untreated cells(negative control)and treated ones with calcitriol or heparin(100μg/mL,positive capacitation control)were evaluated for motility,viability,and functional parameters.Menadione(70μM,30 min)treatment was included as a reactive oxygen species(ROS)positive sperm agent.Results:The results elucidated that sperm exposed to 20 nM calcitriol showed higher viability,vigor,and capacitation than their positive and negative controls.The percentage of sperm with intact plasma and acrosome membranes,mitochondrial membrane potential(ΔΨm),and phosphatidylserine externalization was similar in all the conditions evaluated,while ROS production was higher with heparin and menadione-treated groups than the calcitriol group or negative control.Conclusion:Our results indicate that calcitriol induces the capacitation of thawed bull spermatozoa and maintains acceptable values of progressive motility,viability,and vigor without altering key biological parameters such as redox status,ΔΨm,and cell death.
文摘BACKGROUND Calcitriol-induced hypercalcemia has been rarely reported in cases of lung cancer;however,it is frequently reported in cases of lymphoid malignancy and granulomatous disease.We present a rare case of hypercalcemia associated with squamous cell cancer of the lung with elevated calcitriol level.CASE SUMMARY A 61-year-old Caucasian female with severe hypercalcemia of 15 mg/dL,which led to a new diagnosis of metastatic lung cancer.Since the parathyroid hormonerelated peptide(PTHrP)level was minimally elevated at 2.1 pmol/L,we believe excessive calcitriol production by tumor cells was the underlying mechanism for hypercalcemia.Calcitriol was significantly elevated at 130 pg/mL with a low 25-hydroxyvitamin D level of 25.9 ng/mL and suppressed PTH level of 8 pg/mL.Corticosteroids are generally used to treat calcitriol-induced hypercalcemia,but we successfully treated our patient with bisphosphonate,highlighting the further utility of bisphosphonates in hypercalcemia treatment.CONCLUSION We believe that the underlying cause of hypercalcemia,in this case of metastatic squamous cell lung carcinoma,was elevated calcitriol,which was likely produced by the tumor cells.In addition to PTHrP,calcitriol levels should be included in the workup for hypercalcemia in cases of lung cancer.However,the pathophysiology and prognostic significance of dysregulated calcitriol production in solid tumors remain unclear and warrant further research.Bisphosphonate may be used as a steroid-sparing therapy even in cases of calcitriol-induced hypercalcemia and warrants further investigation.
基金The work was supported by the National Natural Science Foundation of China(No 81173002)National Science and Technology Support Program(No 2012BAI35B02)International Science and Technology Cooperation and Exchange Projects(No 2008DFA31080).
文摘Solid dispersion of calcitriol with lipophilic surfactants and triglycerides was developed by melt-mixing method to modify the release and enhance stability of the drug.The solid dispersions were characterized by differential scanning calorimetry(DSC),hot stage polarized optical microscopy(HSPM),infrared spectroscopy(FTIR)and stability studies.The solid dispersion significantly enhanced the stability of calcitriol,which could be attributed to the high antioxidant activity of the solid lipid dispersion.The rapid dissolution rate from the solid dispersion was attributed to the amorphous or solid solution state of drug with improved specific surface area and wettability than the drug crystals.Therefore,solid dispersion of calcitriol with D-a-tocopheryl polyethylene glycol 1000 succinate(TPGS)offers a good approach to modify the release and enhance stability of calcitriol.The influence of lipophilic solid dispersion on drug bioavailability needs further investigation.
文摘Back ground: There are no published clinical data in hemodialysis (HD) patients with mineral bone disorder (CKD-MBD) regarding the effect of sevelamer hydrochloride on the absorption of the oral calcitriol. Objectives: The aim of the present study was to determine the association of the sevelamer hydrochloride and serum 1-25(OH)2D concentration during oral calcitriol therapy. Methods: This was a before-and-after study in HD patients. Forty-six patients co-administered with phosphate-binder and calcitriol for CKD-MBD therapy took lanthanum carbonate (LC) and sevelamer hydrochloride (SH) for 4 weeks, respectively with calcitriol. The serum 1-25(OH)2D concentration was assessed after each period. Results: Serum 1-25(OH)2D concentration was significantly reduced with co-administration of SH compared to LH (mean, calcitriol with LC→SH: 19.9 pg/ml → 14.2 pg/ml, p 2D concentrations after oral calcitriol administration compared to LH in HD patients. When we use SH as a phosphate binder with calcitriol for HD patients with CKD-MBD, we should consider the inhibitory effect of SH on oral calcitriol absorption.
文摘Objective:To investigate calcitriol, cinacalcet plus comprehensive intervention on maintenance hemodialysis (MHD) patients with secondary hyperparathyroidism (SHPT) calcium (Ca), phosphorus (P) metabolism and parathyroid hormone (PTH) effect.Methods: A total of 80 cases of patients with SHPT from January 2014 to January 2016 in our hospital were randomly divided into observation group and control group, control group to eat the whole piece of cinacalcet hydrochloride oral tablets, the initial dose of 25 mg/d, every 2 to 4 weeks, according to Ca×P, parathyroid hormone (iPTH) test results adjust the dose, the maximum dose of not more than 75 mg/d, the observation group in the control group on the basis of oral administration of Calcitriol Soft Capsules 0.25 g/d, 3 times/week, 2 groups were given comprehensive intervention measures, to evaluate the curative effect after 3 months of treatment. The 2 groups before and after treatment collected fasting peripheral venous blood, the determination of Ca, P and alkaline phosphatase by colorimetric method (ALP), Ca, P product calculation (Ca×P), to detect the level of iPTH before and after treatment by ELISA method;TY-6858-HI type ultrasound instrument, measuring length, width and thickness of the parathyroid glands, and calculate the parathyroid gland volume.Results:in the observation group after treatment, Ca, Ca×P increased degree, P, ALP, iPTH lower than the control group, the size of the parathyroid gland was better than the control group.Conclusion:calcitriol, cinacalcet combined intervention therapy has good clinical effect in patients with MHD SHPT, Ca, P can effectively improve the metabolism, reduce the level of iPTH, reduce the parathyroid gland volume is worthy of promotion.
基金Supported by Grants from the German Research Foundation DFG (UGS, HCR)as well as research grants from the University of Regensburg, Germany, as part of the ReForM-program (UGS, FO)
文摘AIM: To investigate the effects of ZK1916784, a low calcemic analog of calcitriol on intestinal inflammation. METHODS: Acute and chronic colitis was induced by dextran sodium sulfate (DSS) according to standard procedures. Mice were treated intraperitoneally with ZK1916784 or placebo and colonic inflammation was evaluated. Cytokine production by mesenterial lymph node (MLN) cells was measured by ELISA. Immunohistochemistry was performed to detect intestinal dendritic cells (DCs) within the colonic tissue, and the effect of the calcitriol analog on DCs was investigated. RESULTS: Treatment with ZK191784 resulted in significant amelioration of disease with a reduced histological score in acute and chronic intestinal inflammation. In animals with acute DSS colitis, down- regulation of colonic inflammation was associated with a dramatic reduction in the secretion of the proinflammatory cytokine interferon (IFN)-γ and a significant increase in intereleukin (IL)-10 by MLN cells. Similarly, in chronic colitis, IL-10 expression in colonic tissue increased 1.4-fold when mice were treated with ZK191784, whereas expression of the Th1-specific transcription factor T-beta decreased by 81.6%. Lower numbers of infiltrating activated CD11c+ DCs were found in the colon in ZK191784-treated mice with acute DSScolitis, and secretion of proinflammatory cytokines by primary mucosal DCs was inhibited in the presence of the calcitriol analog. CONCLUSION: The calcitriol analog ZK191784 demonstrated significant anti-inflammatory properties in experimental colitis that were at least partially mediated by the immunosuppressive effects of the derivate on mucosal DCs.
文摘An 86-year-old man, diagnosed as having mycosis fungoides in May 2008 and treated with repeated radiation therapy, was admitted to our hospital for initiation of hemodialysis due to end-stage renal disease(ESRD) in April 2012. On admission, his corrected serum calcium level was 9.3 mg/d L, and his intact parathyroid hormone level was 121.9 pg/mL(normal range 13.9-78.5pg/mL), indicating secondary hyperparathyroidism due to ESRD. After starting hemodialysis, urinary volume diminished rapidly. The serum calcium level increased(12.7 mg/dL), and the intact parathyroid hormone level was suppressed(< 5 pg/m L), while the 1,25-dihy-droxyvitamin D3(calcitriol) level increased(114 pg/mL, normal range: 20.0-60.0 pg/m L) in June 2012. The possibilities of sarcoidosis and tuberculosis were ruled out. Skin biopsies from tumorous lesions revealed a diagnosis of granulomatous mycosis fungoides. The serum soluble interleukin-2 receptor levels and the degrees of skin lesions went in parallel with the increased serum calcium and calcitriol levels. Therefore, the patient was diagnosed as having calcitriol-induced hypercalcemia possibly associated with granulomatous mycosis fungoides. Granulomatous mycosis fungoides is rare, and its association with calcitriol-induced hypercalcemia has not been reported. Careful attention to calcium metabolism is needed in patients with granulomatous mycosis fungoides, especially in patients with ESRD.
基金National Natural Science Foundation of China,Grant/Award Numbers:31630047,81874201,81725014Natural Science Foundation of Shanghai,Grant/AwardNumber:20ZR1452300+1 种基金Shanghai Municipal Health Bureau,Grant/Award Number:201840359The National Key Research and Development Program of China,Grant/Award Numbers:2020YFA0509000,2017YFA0503600。
文摘Background:Colorectal cancer(CRC)is one of the most malignant tumorswith high incidence,yet its molecular mechanism is not fully understood,hindering the development of targeted therapy.Metabolic abnormalities are a hallmark of cancer.Targeting dysregulated metabolic features has become an important direction for modern anticancer therapy.In this study,we aimed to identify a new metabolic enzyme that promotes proliferation of CRC and to examine the related molecular mechanisms.Methods:We performed RNA sequencing and tissue microarray analyses of human CRC samples to identify new genes involved in CRC.Squalene epoxidase(SQLE)was identified to be highly upregulated in CRC patients.The regulatory function of SQLE in CRC progression and the therapeutic effect of SQLE inhibitors were determined by measuring CRC cell viability,colony and organoid formation,intracellular cholesterol concentration and xenograft tumor growth.Themolecularmechanism of SQLE functionwas explored by combining transcriptome and untargeted metabolomics analysis.Western blotting and realtime PCR were used to assess MAPK signaling activation by SQLE.Results:SQLE-related control of cholesterol biosynthesis was highly upregulated in CRC patients and associated with poor prognosis.SQLE promoted CRC growth in vitro and in vivo.Inhibition of SQLE reduced the levels of calcitriol(active form of vitamin D3)and CYP24A1,followed by an increase in intracellular Ca2+concentration.Subsequently,MAPK signaling was suppressed,resulting in the inhibition of CRC cell growth.Consistently,terbinafine,an SQLE inhibitor,suppressed CRC cell proliferation and organoid and xenograft tumor growth.Conclusions:Our findings demonstrate that SQLE promotes CRC through the accumulation of calcitriol and stimulation of CYP24A1-mediated MAPK signaling,highlighting SQLE as a potential therapeutic target for CRC treatment.
