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Biochimica Et Biophysica Acta.... Feb 2023Accumulating evidences suggest that the epigenetic regulation plays a pivotal role in establishing phenotype and function of tumor associated macrophages (TAMs). KDM6B...
Accumulating evidences suggest that the epigenetic regulation plays a pivotal role in establishing phenotype and function of tumor associated macrophages (TAMs). KDM6B is an epigenetic enzyme responsible for the H3K27me3 and reported to influence macrophage polarization. However, the underlying mechanism remains to be determined. Here, we demonstrated that inhibition of KDM6B in TAMs increased M2 polarization induced by coculture of breast cancer cells. Furthermore, we identified that KDM6B downregulation activated β-catenin/c-Myc signaling, and thus promoted the M2-like phenotype. KDM6B accelerated the intranuclear ubiquitination degradation of β-catenin, which depended on its demethylase activity. Therapeutically, our data showed that activated vitamin D analog paricalcitol upregulated the expression of KDM6B and decreased the M2 polarization, consequently protected against tumor progress in the xenograft mouse model of breast cancer. Taken together, our data reveal that epigenetic regulator KDM6B prevents M2 polarization via promoting the intranuclear degradation of β-catenin. Active vitamin D analog induces KDM6B and suppresses tumor progress, suggesting a novel therapeutic potential of epigenetic modulation for the tumor treatment.
Topics: Animals; Humans; Mice; beta Catenin; Cell Line, Tumor; Epigenesis, Genetic; Jumonji Domain-Containing Histone Demethylases; Macrophages; Proto-Oncogene Proteins c-myc; Signal Transduction; Breast Neoplasms
PubMed: 36427698
DOI: 10.1016/j.bbadis.2022.166611 -
Journal of the American Society of... Sep 2020CKD leads to vitamin D deficiency. Treatment with vitamin D receptor agonists (VDRAs) may have nephroprotective and anti-inflammatory actions, but their mechanisms of...
BACKGROUND
CKD leads to vitamin D deficiency. Treatment with vitamin D receptor agonists (VDRAs) may have nephroprotective and anti-inflammatory actions, but their mechanisms of action are poorly understood.
METHODS
Modulation of the noncanonical NF-B2 pathway and its component TNF receptor-associated factor 3 (TRAF3) by the VDRA paricalcitol was studied in PBMCs from patients with ESKD, cytokine-stimulated cells, and preclinical kidney injury models.
RESULTS
In PBMCs isolated from patients with ESKD, TRAF3 protein levels were lower than in healthy controls. This finding was associated with evidence of noncanonical NF-B2 activation and a proinflammatory state. However, PBMCs from patients with ESKD treated with paricalcitol did not exhibit these features. Experiments in cultured cells confirmed the link between TRAF3 and NF-B2/inflammation. Decreased TRAF3 ubiquitination in K48-linked chains and cIAP1-TRAF3 interaction mediated the mechanisms of paricalcitol action.TRAF3 overexpression by CRISPR/Cas9 technology mimicked VDRA's effects. In a preclinical model of kidney injury, paricalcitol inhibited renal NF-B2 activation and decreased renal inflammation. In VDR knockout mice with renal injury, paricalcitol prevented TRAF3 downregulation and NF-B2-dependent gene upregulation, suggesting a VDR-independent anti-inflammatory effect of paricalcitol.
CONCLUSIONS
These data suggest the anti-inflammatory actions of paricalcitol depend on TRAF3 modulation and subsequent inhibition of the noncanonical NF-B2 pathway, identifying a novel mechanism for VDRA's effects. Circulating TRAF3 levels could be a biomarker of renal damage associated with the inflammatory state.
Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Cytokine TWEAK; Ergocalciferols; Female; Humans; Kidney Failure, Chronic; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Receptors, Calcitriol; Signal Transduction; TNF Receptor-Associated Factor 3
PubMed: 32631974
DOI: 10.1681/ASN.2019111206 -
World Journal of Diabetes Sep 2023Diabetic nephropathy (DN) is frequently seen in the development of diabetes mellitus, and its pathogenic factors are complicated. Its current treatment is controversial,...
BACKGROUND
Diabetic nephropathy (DN) is frequently seen in the development of diabetes mellitus, and its pathogenic factors are complicated. Its current treatment is controversial, and there is a lack of a relevant efficacy prediction model.
AIM
To determine the effects of paricalcitol combined with hemodiafiltration on bone-metabolism-related indexes in patients with DN and chronic renal failure (CRF), and to construct an efficacy prediction model.
METHODS
We retrospectively analyzed 422 patients with DN and CRF treated in Cangzhou Central Hospital between May 2020 and May 2022. We selected 94 patients who met the inclusion and exclusion criteria. Patients were assigned to a dialysis group ( = 45) and a joint group ( = 49) in relation to therapeutic regimen. The clinical efficacy of the two groups was compared after treatment. The changes in laboratory indexes after treatment were evaluated, and the two groups were compared for the incidence of adverse reactions. The predictive value of laboratory indexes on the clinical efficacy on patients was analyzed.
RESULTS
The dialysis group showed a notably worse improvement in clinical efficacy than the joint group ( = 0.017). After treatment, the joint group showed notably lower serum levels of serum creatinine, uric acid (UA) and blood urea nitrogen (BUN) than the dialysis group ( < 0.05). After treatment, the joint group had lower serum levels of phosphorus, procollagen type I amino-terminal propeptide (PINP) and intact parathyroid hormone than the dialysis group, but a higher calcium level ( < 0.001). Both groups had a similar incidence of adverse reactions ( > 0.05). According to least absolute shrinkage and selection operator regression analysis, UA, BUN, phosphorus and PINP were related to treatment efficacy. According to further comparison, the non-improvement group had higher risk scores than the improvement group ( < 0.0001), and the area under the curve of the risk score in efficacy prediction was 0.945.
CONCLUSION
For treatment of CRF and DN, combined paricalcitol and hemodiafiltration can deliver higher clinical efficacy and improve the bone metabolism of patients, with good safety.
PubMed: 37771325
DOI: 10.4239/wjd.v14.i9.1385 -
BMC Endocrine Disorders Oct 2020Accumulating evidence suggests that low vitamin D status may affect male gonadal structure. This study was undertaken to reveal whether vitamin D-deficient rats have...
BACKGROUND
Accumulating evidence suggests that low vitamin D status may affect male gonadal structure. This study was undertaken to reveal whether vitamin D-deficient rats have demonstrable changes in the quantitative histomorphometric properties of the testis.
METHODS
In the present investigation, adult male Sprague-Dawley rats were divided into four groups and received: group 1) conventional diet; group 2) vitamin D-deficient diet; group 3) vitamin D-deficient diet and paricalcitol and group 4) conventional diet plus paricalcitol. After 3 months, serum levels of vitamin D metabolites, Ca, P, LH, FSH, testosterone, and epididymal sperm quality were evaluated. Moreover, the morphometric characteristics of testis were assessed via stereological methods.
RESULTS
Rats fed a vitamin D-deficient diet (groups 2 and 3) were normocalcemic and had 25-hydroxyvitamin D level below 10 ng/mL. A significant reduction in serum testosterone and comparable gonadotropin levels were seen in vitamin D-deficient groups compared to controls. The concentration, morphology, and motility of sperm cells were profoundly disturbed in animals raised on the vitamin D-deficient diet. There was a significant decline in the population of different germ cells, the volume of interstitial tissue and germinal epithelium in group 2 and 3 rats, which were placed on the vitamin D-deficient diet. No appreciable difference in the estimates of the Leydig or Sertoli cell numbers were observed between groups.
CONCLUSIONS
The depletion of vitamin D stores and induction of moderate grades of vitamin D deficiency by dietary measures led to remarkable impairment of spermatogenesis and microscopic architecture of rat testis. These findings can be attributed, at least in part, to decreased androgen production.
Topics: Animals; Male; Rats; Rats, Sprague-Dawley; Testis; Vitamin D; Vitamin D Deficiency; Vitamins
PubMed: 33121469
DOI: 10.1186/s12902-020-00642-0 -
Children (Basel, Switzerland) May 2023Screening for Type 1 Diabetes (T1D, incidence 1:300) with T1D autoantibodies (T1Ab) at ages 2 and 6, while sensitive, lacks a preventive strategy. Cholecalciferol 2000...
Screening for Type 1 Diabetes (T1D, incidence 1:300) with T1D autoantibodies (T1Ab) at ages 2 and 6, while sensitive, lacks a preventive strategy. Cholecalciferol 2000 IU daily since birth reduced T1D by 80% at 1 year. T1D-associated T1Ab negativized within 0.6 years with oral calcitriol in 12 children. To further investigate secondary prevention of T1D with calcitriol and its less calcemic analog, paricalcitol, we initiated a prospective interventional non-randomized clinical trial, the PRECAL study (ISRCTN17354692). In total, 50 high-risk children were included: 44 were positive for T1Ab, and 6 had predisposing for T1D HLA genotypes. Nine T1Ab+ patients had variable impaired glucose tolerance (IGT), four had pre-T1D (3 T1Ab+, 1 HLA+), nine had T1Ab+ new-onset T1D not requiring insulin at diagnosis. T1Ab, thyroid/anti-transglutaminase Abs, glucose/calcium metabolism were determined prior and q3-6 months on calcitriol, 0.05 mcg/Kg/day, or paricalcitol 1-4 mcg × 1-3 times/day p.o. while on cholecalciferol repletion. Available data on 42 (7 dropouts, 1 follow-up < 3 months) patients included: all 26 without pre-T1D/T1D followed for 3.06 (0.5-10) years negativized T1Ab (15 +IAA, 3 IA2, 4 ICA, 2 +GAD, 1 +IAA/+GAD, 1 +ICA/+GAD) within 0.57 (0.32-1.3) years or did not develop to T1D (5 +HLA, follow-up 3 (1-4) years). From four pre-T1D cases, one negativized T1Ab (follow-up 1 year), one +HLA did not progress to T1D (follow-up 3.3 years) and two +T1Ab patients developed T1D in 6 months/3 years. Three out of nine T1D cases progressed immediately to overt disease, six underwent complete remission for 1 year (1 month-2 years). Five +T1Ab patients relapsed and negativized again after resuming therapy. Four (aged <3 years) negativized anti-TPO/TG, and two anti-transglutaminase-IgA. Eight presented mild hypercalciuria/hypercalcemia, resolving with dose titration/discontinuation. Secondary prevention of T1D with calcitriol and paricalcitol seems possible and reasonably safe, if started soon enough after seroconversion.
PubMed: 37238410
DOI: 10.3390/children10050862 -
Scientific Reports Jan 2020MicroRNA-27a/b are small non-coding RNAs which are reported to regulate inflammatory response and cell proliferation. Although some studies have demonstrated that...
MicroRNA-27a/b are small non-coding RNAs which are reported to regulate inflammatory response and cell proliferation. Although some studies have demonstrated that miR-27b is down-regulated in the oral specimens of patients suffering with oral lichen planus (OLP), the molecular mechanism of miR-27b decrease remains a large mystery, and the expression of miR-27a in OLP is not well explored. Here, we demonstrated both miR-27a and miR-27b, compared with healthy controls, were reduced in the oral biopsies, serum and saliva samples derived from OLP patients. The reductions of miR-27a/b were also confirmed in the lipopolysaccharide (LPS)- or activated CD4 T cell-treated human oral keratinocytes (HOKs). Furthermore, we found vitamin D receptor (VDR) binding sites in the promoters of miR-27a/b genes and verified this finding. We also tested miR-27a/b levels in the oral epithelium from paricalcitol-treated, vitamin D deficient or VDR knockout mice. In the rescue experiments, we confirmed vitamin D and VDR inhibited LPS- or activated CD4 T cell-induced miR-27a/b reductions in HOKs. In sum, our results show that vitamin D/VDR signaling induces miR-27a/b in oral lichen planus.
Topics: Animals; Binding Sites; Case-Control Studies; Disease Models, Animal; Down-Regulation; Epithelial Cells; Ergocalciferols; Humans; Keratinocytes; Lichen Planus, Oral; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Promoter Regions, Genetic; Receptors, Calcitriol; Signal Transduction; Vitamin D
PubMed: 31942011
DOI: 10.1038/s41598-019-57288-9 -
International Journal of Molecular... Apr 2022In our previous work, we evaluated the therapeutic effects of 1α,25-Dihydroxyvitamin D, the biologically active form of vitamin D, in the context of bleomycin-induced...
In our previous work, we evaluated the therapeutic effects of 1α,25-Dihydroxyvitamin D, the biologically active form of vitamin D, in the context of bleomycin-induced lung fibrosis. Contrary to the expected, vitamin D supplementation increased the DNA damage expression and cellular senescence in alveolar epithelial type II cells and aggravated the overall lung pathology induced in mice by bleomycin. These effects were probably due to an alteration in the cellular DNA double-strand breaks' repair capability. In the present work, we have evaluated the effects of two hypocalcemic vitamin D analogs (calcipotriol and paricalcitol) in the expression of DNA damage in the context of minilungs derived from human embryonic stem cells and in the cell line A549.
Topics: Animals; Bleomycin; DNA Damage; Human Embryonic Stem Cells; Humans; Mice; Pulmonary Fibrosis; Vitamin D
PubMed: 35563311
DOI: 10.3390/ijms23094921 -
Kidney & Blood Pressure Research 2023Restoration of podocyte autophagy is considered as a feasible strategy for the treatment of diabetic kidney disease (DKD). This study aimed at investigating the...
INTRODUCTION
Restoration of podocyte autophagy is considered as a feasible strategy for the treatment of diabetic kidney disease (DKD). This study aimed at investigating the protective effect and potential mechanism of vitamin D on podocyte injury of DKD.
METHODS
Type 2 diabetic db/db mice received intraperitoneal injections of vitamin D analog paricalcitol 400 ng/kg per day for 16 weeks. Immortalized mouse podocytes were cultured in high glucose (HG) medium with active vitamin D3 calcitriol or autophagy inhibitor 3-methyladenine. Renal function and urine albumin creatinine ratio were assessed at week 24. HE, PAS staining, and electron microscopy were used to evaluate renal histopathology and morphological changes. Immunohistochemistry, immunofluorescence, and Western blot were used to evaluate protein expression of nephrin and podocin in kidney tissue and podocytes. The expression of autophagy-related proteins (LC3, Beclin-1, Vps34) and apoptosis-related proteins (cleaved caspase-3, Bax) was determined by Western blotting. Podocyte apoptosis was further evaluated by using flow cytometer.
RESULTS
Albuminuria in a db/db mouse model was markedly attenuated after treatment with paricalcitol. This was accompanied by alleviation of mesangial matrix expansion and podocyte injury. Besides, the impaired autophagy in podocytes under diabetic conditions was also markedly enhanced after paricalcitol or calcitriol treatment, accompanied by restored decreased podocyte slit diaphragm proteins podocin and nephrin. Furthermore, the protective effect of calcitriol against HG-induced podocyte apoptosis could be abated by autophagy inhibitor 3-methyladenine.
CONCLUSION
Vitamin D ameliorates podocyte injury of DKD by enhancing podocyte autophagy activity, which may become a potential candidate autophagy activator for the therapeutic interventions for DKD.
Topics: Mice; Animals; Diabetic Nephropathies; Podocytes; Vitamin D; Calcitriol; Diabetes Mellitus, Experimental; Vitamins; Autophagy
PubMed: 37054686
DOI: 10.1159/000530403 -
Andrology Sep 2020In rodents and humans, vitamin D deficiency (VDD) is associated with altered sperm structure and function (primarily decreased motility and morphological abnormalities)...
BACKGROUND
In rodents and humans, vitamin D deficiency (VDD) is associated with altered sperm structure and function (primarily decreased motility and morphological abnormalities) that are primarily attributed to VDD-induced hypocalcemia. However, it is suspected that VDD has much more drastic effects on mammalian spermatozoa.
OBJECTIVES
The purpose of this study was to illustrate that VDD, depending on its severity and duration, can alter sperm nuclear integrity and can also lead to the loss of spermatozoa's ability to support embryonic development.
MATERIALS AND METHODS
A mouse model of induced VDD combining the action of a vitamin D-deficient diet, UV exposure limitation, and paricalcitol injections; a vitamin D2 analog that catabolizes endogenous vitamin D by increasing the expression of CYP24A, a member of the cytochrome P450 family, has been used to create different grades of VDD.
RESULTS
We show that the most significant sperm defect recorded concerns the integrity of the paternal nucleus, which is both decondensed and fragmented in moderate-to-severe VDD situations. Consistent with the known consequences of fertilization with DNA-damaged spermatozoa, we show that paternal VDD decreases the ability of spermatozoa to optimally support fertilization and embryonic development.
DISCUSSION AND CONCLUSION
Given the worldwide high prevalence of VDD in humans, and although obtained in an animal model, the data presented here suggest that subfertile/infertile males may benefit from VDD testing and that attempts to correct serum vitamin D levels could be considered prior to conception, either naturally or through ART.
Topics: Animals; Embryonic Development; Female; Fertilization; Male; Mice; Pregnancy; Spermatozoa; Vitamin D Deficiency
PubMed: 32421931
DOI: 10.1111/andr.12820 -
Frontiers in Molecular Biosciences 2023The severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has posed a significant challenge to individuals' health. Increasing evidence shows that patients with...
The severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has posed a significant challenge to individuals' health. Increasing evidence shows that patients with metabolic unhealthy obesity (MUO) and COVID-19 have severer complications and higher mortality rate. However, the molecular mechanisms underlying the association between MUO and COVID-19 are poorly understood. We sought to reveal the relationship between MUO and COVID-19 using bioinformatics and systems biology analysis approaches. Here, two datasets (GSE196822 and GSE152991) were employed to extract differentially expressed genes (DEGs) to identify common hub genes, shared pathways, transcriptional regulatory networks, gene-disease relationship and candidate drugs. Based on the identified 65 common DEGs, the complement-related pathways and neutrophil degranulation-related functions are found to be mainly affected. The hub genes, which included SPI1, CD163, C1QB, SIGLEC1, C1QA, ITGAM, CD14, FCGR1A, VSIG4 and C1QC, were identified. From the interaction network analysis, 65 transcription factors (TFs) were found to be the regulatory signals. Some infections, inflammation and liver diseases were found to be most coordinated with the hub genes. Importantly, Paricalcitol, 3,3',4,4',5-Pentachlorobiphenyl, PD 98059, Medroxyprogesterone acetate, Dexamethasone and Tretinoin HL60 UP have shown possibility as therapeutic agents against COVID-19 and MUO. This study provides new clues and references to treat both COVID-19 and MUO.
PubMed: 37877121
DOI: 10.3389/fmolb.2023.1274463