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ACS Omega Apr 2023COVID-19, the disease caused by SARS-CoV-2, has been disrupting our lives for more than two years now. SARS-CoV-2 interacts with human proteins to pave its way into the...
COVID-19, the disease caused by SARS-CoV-2, has been disrupting our lives for more than two years now. SARS-CoV-2 interacts with human proteins to pave its way into the human body, thereby wreaking havoc. Moreover, the mutating variants of the virus that take place in the SARS-CoV-2 genome are also a cause of concern among the masses. Thus, it is very important to understand human-spike protein-protein interactions (PPIs) in order to predict new PPIs and consequently propose drugs for the human proteins in order to fight the virus and its different mutated variants, with the mutations occurring in the spike protein. This fact motivated us to develop a complete pipeline where PPIs and drug-protein interactions can be predicted for human-SARS-CoV-2 interactions. In this regard, initially interacting data sets are collected from the literature, and noninteracting data sets are subsequently created for human-SARS-CoV-2 by considering only spike glycoprotein. On the other hand, for drug-protein interactions both interacting and noninteracting data sets are considered from DrugBank and ChEMBL databases. Thereafter, a model based on a sequence-based feature is used to code the protein sequences of human and spike proteins using the well-known Moran autocorrelation technique, while the drugs are coded using another well-known technique, viz., PaDEL descriptors, to predict new human-spike PPIs and eventually new drug-protein interactions for the top 20 predicted human proteins interacting with the original spike protein and its different mutated variants like Alpha, Beta, Delta, Gamma, and Omicron. Such predictions are carried out by random forest as it is found to perform better than other predictors, providing an accuracy of 90.53% for human-spike PPI and 96.15% for drug-protein interactions. Finally, 40 unique drugs like eicosapentaenoic acid, doxercalciferol, ciclesonide, dexamethasone, methylprednisolone, etc. are identified that target 32 human proteins like ACACA, DST, DYNC1H1, etc.
PubMed: 37163139
DOI: 10.1021/acsomega.3c00030 -
Antimicrobial Agents and Chemotherapy Jan 2018Vitamin D analogs were identified as compounds that induced lysis of planktonic cultures of in a high-throughput screen of FDA-approved drugs. Previous studies have...
Vitamin D analogs were identified as compounds that induced lysis of planktonic cultures of in a high-throughput screen of FDA-approved drugs. Previous studies have demonstrated that certain derivatives of vitamin D possess lytic activity against other bacteria, though the mechanism has not yet been established. Through the use of a combinatorial approach, the vitamin D derivative doxercalciferol was shown to act synergistically with bacitracin, a polypeptide-type drug that is known to interfere with cell wall synthesis, suggesting that doxercalciferol may act in a bacitracin-related pathway. Innate resistance to bacitracin is attributed to efflux by a conserved ABC-type transporter, which in is encoded by the operon. possesses two characterized mechanisms of resistance to bacitracin, the ABC transporter, bacitracin resistance (Mbr) cassette, consisting of MbrABCD, and the rhamnose-glucose polysaccharide (Rgp) system, RgpABCDEFGHI. Loss of function of the transporter in and mutants exacerbated the effect of the combination of doxercalciferol and bacitracin. Despite conservation of a transporter homologous to , the combination of doxercalciferol and bacitracin appeared to be synergistic only in streptococcal species. We conclude that vitamin D derivatives possess lytic activity against and act through a mechanism dependent on the bacitracin resistance mechanism of MbrABCD.
Topics: ATP-Binding Cassette Transporters; Anti-Bacterial Agents; Bacitracin; Bacterial Proteins; Drug Resistance, Bacterial; Drug Synergism; Ergocalciferols; Gene Expression Regulation, Bacterial; High-Throughput Screening Assays; Microbial Sensitivity Tests; Streptococcus mutans; Vitamin D; Vitamins
PubMed: 29061743
DOI: 10.1128/AAC.01675-17 -
Clinical Journal of the American... Mar 2020In the United States, intravenous vitamin D analogs are the first-line therapy for management of secondary hyperparathyroidism in hemodialysis patients. Outside the...
BACKGROUND AND OBJECTIVES
In the United States, intravenous vitamin D analogs are the first-line therapy for management of secondary hyperparathyroidism in hemodialysis patients. Outside the United States, oral calcitriol (1,25-dihydroxyvitamin D) is routinely used. We examined standard laboratory parameters of patients on in-center hemodialysis receiving intravenous vitamin D who switched to oral calcitriol.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
We conducted a retrospective cohort study of adult patients treated within Fresenius Kidney Care clinics. During a 6-month period (December 2013 to May 2014), we identified patients on an intravenous vitamin D analog (doxercalciferol or paricalcitol) who switched to oral calcitriol and matched them to patients receiving an intravenous vitamin D analog. Mean serum calcium, phosphate, and intact parathyroid hormone (iPTH) concentrations were examined for up to 12 months of follow-up. We used Poisson and Cox proportional hazards regression models to examine hospitalization and survival rates. The primary analysis was conducted as intention-to-treat; secondary analyses included an as-treated evaluation.
RESULTS
A total of 2280 patients who switched to oral calcitriol were matched to 2280 patients receiving intravenous vitamin D. Compared with patients on intravenous vitamin D, mean calcium and phosphate levels in the oral calcitriol group were lower after the change to oral calcitriol. In contrast, iPTH levels were higher in the oral calcitriol group. At 12 months, the percentage of patients with composite laboratories in target range (calcium <10 mg/dl, phosphate 3.0-5.5 mg/dl, and iPTH 150-600 pg/ml) were comparable between groups (45% versus 45%; =0.96). Hospital admissions, length of hospital stay, and survival were comparable between groups. An as-treated analysis and excluding those receiving cinacalcet did not reveal significant between-group differences.
CONCLUSIONS
Among patients receiving in-center hemodialysis who were switched to oral calcitriol versus those on an intravenous vitamin D analog, the aggregate of all mineral and bone laboratory parameters in range was largely similar between groups.
Topics: Administration, Intravenous; Administration, Oral; Aged; Biomarkers; Calcitriol; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Drug Substitution; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Phosphates; Renal Dialysis; Retrospective Studies; Time Factors; Treatment Outcome; United States; Vitamins
PubMed: 32111702
DOI: 10.2215/CJN.07960719 -
International Journal of Molecular... Dec 2017Alzheimer's disease (AD) is characterized by extracellular plaques in the brain, mainly consisting of amyloid-β (Aβ), as derived from sequential cleavage of the...
Alzheimer's disease (AD) is characterized by extracellular plaques in the brain, mainly consisting of amyloid-β (Aβ), as derived from sequential cleavage of the amyloid precursor protein. Epidemiological studies suggest a tight link between hypovitaminosis of the secosteroid vitamin D and AD. Besides decreased vitamin D level in AD patients, an effect of vitamin D on Aβ-homeostasis is discussed. However, the exact underlying mechanisms remain to be elucidated and nothing is known about the potential effect of vitamin D analogues. Here we systematically investigate the effect of vitamin D and therapeutically used analogues (maxacalcitol, calcipotriol, alfacalcidol, paricalcitol, doxercalciferol) on AD-relevant mechanisms. D₂ and D₃ analogues decreased Aβ-production and increased Aβ-degradation in neuroblastoma cells or vitamin D deficient mouse brains. Effects were mediated by affecting the Aβ-producing enzymes BACE1 and γ-secretase. A reduced secretase activity was accompanied by a decreased BACE1 protein level and nicastrin expression, an essential component of the γ-secretase. Vitamin D and analogues decreased β-secretase activity, not only in mouse brains with mild vitamin D hypovitaminosis, but also in non-deficient mouse brains. Our results further strengthen the link between AD and vitamin D, suggesting that supplementation of vitamin D or vitamin D analogues might have beneficial effects in AD prevention.
Topics: Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Animals; Brain; Cell Line, Tumor; Female; Humans; Mice; Mice, Inbred C57BL; Plaque, Amyloid; Proteolysis; Vitamin D; Vitamins
PubMed: 29257109
DOI: 10.3390/ijms18122764 -
Peritoneal Dialysis International :... 2015Limited well-controlled research exists examining the impact of different formulations of oral vitamin D on clinical outcomes in dialysis patients, specifically those on... (Comparative Study)
Comparative Study
BACKGROUND
Limited well-controlled research exists examining the impact of different formulations of oral vitamin D on clinical outcomes in dialysis patients, specifically those on peritoneal dialysis. For this retrospective mortality analysis, we compared mortality rates of patients on 3 of the most commonly prescribed vitamin D agents.
METHODS
We examined 2 years (7/1/2008 to 6/30/2010) of oral medication records of peritoneal dialysis patients from a large US dialysis organization. Patients were identified whose physicians prescribed a single form of vitamin D (calcitriol, paricalcitol, or doxercalciferol) for ≥ 90% of all patient-months. We excluded incident patients (< 90 days on dialysis) and patients whose physicians treated < 5 peritoneal dialysis patients at a dialysis facility, and we assessed mortality.
RESULTS
The analysis inclusion criteria identified 1,707 patients. The subset in this analysis included 12.6% of all prevalent peritoneal dialysis patients and 11.8% of prevalent patient-months. Patients with physicians who predominately prescribed calcitriol had a lower mortality rate: 9.33 (confidence interval (CI) 7.06, 11.60) deaths per 100 patient-years than the doxercalciferol, 12.20 (CI 9.34, 15.06) or paricalcitol, 12.27 (CI 9.27, 15.28) groups. However, these differences were not statistically significant. A Cox proportional hazards model, adjusting for differences in age, vintage, gender, race, body mass index, and comorbidities also showed no significant differences.
CONCLUSIONS
For this peritoneal dialysis population, instrumental variable analyses showed no significant difference in mortality in patients taking the most common oral vitamin D formulations (calcitriol, doxercalciferol, paricalcitol).
Topics: Adult; Aged; Calcitriol; Cause of Death; Cohort Studies; Confidence Intervals; Dietary Supplements; Drug Administration Schedule; Ergocalciferols; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Prognosis; Proportional Hazards Models; Reference Values; Retrospective Studies; Risk Assessment; Survival Analysis; Treatment Outcome; Vitamin D
PubMed: 24584595
DOI: 10.3747/pdi.2012.00324 -
British Journal of Pharmacology Aug 2017Pathological growth of ocular vasculature networks can underpin visual impairment in neovascular age-related macular degeneration, proliferative diabetic retinopathy and...
BACKGROUND AND PURPOSE
Pathological growth of ocular vasculature networks can underpin visual impairment in neovascular age-related macular degeneration, proliferative diabetic retinopathy and retinopathy of prematurity. Our aim was to uncover novel pharmacological regulators of ocular angiogenesis by phenotype-based screening in zebrafish.
EXPERIMENTAL APPROACH
A bioactive chemical library of 465 drugs was screened to identify small molecule inhibitors of ocular hyaloid vasculature (HV) angiogenesis in zebrafish larvae. Selectivity was assessed by evaluation of non-ocular intersegmental vasculature development. Safety pharmacology examined visual behaviour and retinal histology in larvae. Molecular mechanisms of action were scrutinized using expression profiling of target mRNAs and miRNAs in larval eyes.
KEY RESULTS
Library screening identified 10 compounds which significantly inhibited HV developmental angiogenesis. The validated hit calcitriol selectively demonstrated dose-dependent attenuation of HV development. In agreement, vitamin D receptor (VDR) agonists paricalcitol, doxercalciferol, maxacalcitol, calcipotriol, seocalcitol, calcifediol and tacalcitol significantly and selectively attenuated HV development. VDR agonists induced minor ocular morphology abnormalities and affected normal visual function. Calcitriol induced a three to sevenfold increase in ocular dre-miR-21 expression. Consistently, all-trans-retinoic acid attenuated HV development and increased ocular dre-miR-21 expression. Interestingly, zebrafish ocular vegfaa and vegfab expression was significantly increased while, vegfc, flt1 and kdrl expression was unchanged by calcitriol.
CONCLUSION AND IMPLICATIONS
These studies identified VDR agonists as significant and selective anti-angiogenics in the developing vertebrate eye and miR21 as a key downstream regulated miRNA. These targets should be further evaluated as molecular hallmarks of, and therapeutic targets for pathological ocular neovascularization.
Topics: Angiogenesis Inhibitors; Animals; Animals, Genetically Modified; Calcitriol; Eye; Larva; MicroRNAs; Neovascularization, Physiologic; Receptors, Calcitriol; Tretinoin; Vascular Endothelial Growth Factor A; Zebrafish; Zebrafish Proteins
PubMed: 28547797
DOI: 10.1111/bph.13875 -
Bone Oct 2019Impaired osteoblast and osteocyte maturation contribute to mineralization defects and excess FGF23 expression in CKD bone. Vitamin D sterols decrease osteoid...
Impaired osteoblast and osteocyte maturation contribute to mineralization defects and excess FGF23 expression in CKD bone. Vitamin D sterols decrease osteoid accumulation and increase FGF23 expression; these agents also increase osteoblast maturation in vitro but a link between changes in bone cell maturation, bone mineralization, and FGF23 expression in response to vitamin D sterols has not been established. We evaluated unmineralized osteoid accumulation, osteocyte maturity markers (FGF23: early osteocytes; sclerostin: late osteocytes), and osteocyte apoptosis in iliac crest of 11 pediatric dialysis patients before and after 8 months of doxercalciferol therapy. We then evaluated the effect of 1,25(OH)vitamin D on in vitro maturation and mineralization of primary osteoblasts from dialysis patients. Unmineralized osteoid accumulation decreased while numbers of early (FGF23-expressing) increased in response to doxercalciferol. Osteocyte apoptosis was low but increased with doxercalciferol. Bone FGF23 expression correlated with numbers of early, FGF23-expressing, osteocytes (r = 0.83, p < 0.001). In vitro, 1,25(OH)vitamin D increased expression of the mature osteoblast marker osteocalcin (BGLAP) but only very high (100 nM) concentrations affected in vitro osteoblast mineralization. High doses (10 and 100 nM) of 1,25(OH)vitamin D also increased the ratio of RANKL/OPG expression in CKD osteoblasts. Vitamin D sterols directly stimulate osteoblast maturation. They also increase osteocyte turnover and increase osteoblast expression of osteoclast differentiation factors, thus likely modulating osteoblast/osteoclast/osteocyte coupling. By increasing numbers of early osteocytes, vitamin D sterols increase FGF23 expression in CKD bone.
Topics: Adolescent; Apoptosis; Bone and Bones; Calcification, Physiologic; Cell Count; Cell Differentiation; Cells, Cultured; Ergocalciferols; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Male; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Renal Insufficiency, Chronic; Sterols; Vitamin D
PubMed: 31377240
DOI: 10.1016/j.bone.2019.07.026 -
The Journal of Steroid Biochemistry and... Mar 2019Standard therapy for Acute Myeloid Leukemia (AML) is rarely curative, and several suggested improvements have had little success so far. We have reported that in an in...
Standard therapy for Acute Myeloid Leukemia (AML) is rarely curative, and several suggested improvements have had little success so far. We have reported that in an in vitro model of a potential therapeutic regimen for AML, the activity of cytarabine (AraC) is enhanced by a sequential treatment with a combination of the vitamin D2 analog Doxercalciferol (D2) and the plant-derived antioxidant carnosic acid (CA). Importantly, the enhancement occurred selectively in patient-derived AML blasts, but not in the normal bone marrow cells. We now demonstrate that TXNIP, previously known as Vitamin D up-regulated protein 1 (VDUP1) [PMID 808674] plays a part in signaling cell death (CD) in this regimen. This is shown by the reduced CD when TXNIP protein levels are decreased by the CRISPR/CAS9 or RNAi technology. Further, we show that direct activation of ASK1 kinase by TXNIP is required for the optimal transmission of the CD signal to apoptotic machinery, regulated by JNK and BIM. These studies provide a rationale for a projected clinical trial of this vitamin D-based new therapeutic regimen for AML.
Topics: Abietanes; Antineoplastic Agents; Antioxidants; Carrier Proteins; Cell Line, Tumor; Cell Survival; Cytarabine; Ergocalciferols; Humans; Leukemia, Myeloid, Acute; MAP Kinase Kinase Kinase 5; Mitogen-Activated Protein Kinase 8; Signal Transduction; Vitamins
PubMed: 30508644
DOI: 10.1016/j.jsbmb.2018.11.015 -
The Journal of Steroid Biochemistry and... Mar 2018Numerous clinical studies of vitamin D, its derivatives or analogs, have failed to clearly demonstrate sustained benefits when used for the treatment of human malignant...
Numerous clinical studies of vitamin D, its derivatives or analogs, have failed to clearly demonstrate sustained benefits when used for the treatment of human malignant diseases. However, given the strong preclinical evidence of anti-neoplastic activity and the epidemiological associations suggesting that vitamin D compounds may have a place in cancer therapy, attempts are continuing to devise new approaches to their therapeutic use. This laboratory has developed a strategy to enhance the effectiveness of the currently standard therapy of Acute Myeloid Leukemia (AML) by the immediate addition of the vitamin D2 analog Doxercalciferol combined with the plant polyphenol-derived Carnosic acid to AML cells previously treated with Cytarabine (AraC). Enhancement of AML cell death was noted to be dependent on VDR and BRAF kinase. Here we document that the stress-related kinase JNK is an important additional component of cell death enhancement in this protocol. Either the Knock-down or the inhibition of JNK activity reduced the enhancement of AraC-induced cell death, and we show that JNK signaling to the apoptosis regulator BIM and Caspase executioners of cell death are downstream of VDR and BRAF. A clear understanding of the molecular basis for the increased efficacy of AraC in the therapy of AML is expected to bring this regimen to a clinical trial.
Topics: Antimetabolites, Antineoplastic; Cell Death; Cytarabine; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinase 9; Proto-Oncogene Proteins B-raf; RNA, Messenger; RNA, Small Interfering; Receptors, Calcitriol; Signal Transduction
PubMed: 28765039
DOI: 10.1016/j.jsbmb.2017.07.005 -
The Journal of Steroid Biochemistry and... Mar 2020Hepatocellular carcinoma (HCC) is the most common form of liver cancer and it is the third leading cause of global cancer mortality. Sorafenib (Sf) is the first oral...
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and it is the third leading cause of global cancer mortality. Sorafenib (Sf) is the first oral multi-kinase inhibitor approved for systemic treatment of advanced HCC, and can prolong survival, although only for three months longer than placebo treated patients. Preclinical studies showed that active forms of vitamin D can induce cell differentiation and regulate cell survival in several cell types, and epidemiological data link vitamin D insufficiency to an increased risk of neoplastic diseases, suggesting a potentially important role of vitamin D in cancer therapy. Other studies showed that the effect of vitamin D analogs on human neoplastic cells is potentiated by carnosic acid (CA), a plant polyphenol with anti-oxidant properties. Here we tested if the addition of the vitamin D2 analog Doxercalciferol (D2) together with CA can enhance the cytotoxic effect of Sf on HCC cell lines Huh7 (Sf-sensitive) and HCO2 (Sf-resistant). Indeed, this combination increased HCC cell death in cell lines, enhancing autophagy as well as apoptosis. Autophagy was confirmed by increased cytoplasmic vacuolation, perinuclear aggregation of LC3, and elevated protein levels of autophagy markers Beclin1, Atg3, and LC3. These results suggest that a regimen which combines a vitamin D2 analog/CA mixture with Sf can be a novel and promising therapeutic option for the treatment of HCC.
Topics: Abietanes; Antineoplastic Agents; Antioxidants; Apoptosis; Autophagy; Bone Density Conservation Agents; Carcinoma, Hepatocellular; Cell Proliferation; Drug Synergism; Drug Therapy, Combination; Ergocalciferols; Humans; Liver Neoplasms; Signal Transduction; Sorafenib; Tumor Cells, Cultured
PubMed: 31704246
DOI: 10.1016/j.jsbmb.2019.105524