-
International Journal of Molecular... Jun 2024Vitamin D is a group of seco-steroidal fat-soluble compounds. The two basic forms, vitamin D (ergocalciferol) and vitamin D (cholecalciferol), do not have biological... (Review)
Review
Vitamin D is a group of seco-steroidal fat-soluble compounds. The two basic forms, vitamin D (ergocalciferol) and vitamin D (cholecalciferol), do not have biological activity. They are converted in the body by a two-step enzymatic hydroxylation into biologically active forms, 1α,25-dihydroxyvitamin D [ercalcitriol, 1,25(OH)D] and 1α,25-dihydroxyvitamin D [calcitriol, 1,25(OH)D], which act as classical steroid hormones. 1,25(OH)D exerts most of its physiological functions by binding to the nuclear vitamin D receptor (VDR), which is present in most body tissues to provide support to a broad range of physiological processes. Vitamin D-liganded VDR controls the expression of many genes. High levels of 1,25(OH)D cause an increase in calcium in the blood, which can lead to harmful hypercalcemia. Several analogs of 1,25(OH)D and 1,25(OH)D have been designed and synthesized with the aim of developing compounds that have a specific therapeutic function, for example, with potent anticancer activity and a reduced toxic calcemic effect. Particular structural modifications to vitamin D analogs have led to increased anticancer activity and reduced calcemic action with the prospect of extending work to provide future innovative therapies.
Topics: Humans; Receptors, Calcitriol; Antineoplastic Agents; Animals; Neoplasms; Calcitriol; Structure-Activity Relationship; Vitamin D
PubMed: 38928329
DOI: 10.3390/ijms25126624 -
International Journal of Molecular... Jun 2024Genetic variation among inhaled corticosteroid (ICS)-metabolizing enzymes may affect asthma control, but evidence is limited. This study tested the hypothesis that...
Genetic variation among inhaled corticosteroid (ICS)-metabolizing enzymes may affect asthma control, but evidence is limited. This study tested the hypothesis that single-nucleotide polymorphisms (SNPs) in Cytochrome P450 3A5 (CYP3A5) would affect asthma outcomes. Patients aged 2-18 years with persistent asthma were recruited to use the electronic AsthmaTracker (e-AT), a self-monitoring tool that records weekly asthma control, medication use, and asthma outcomes. A subset of patients provided saliva samples for SNP analysis and participated in a pharmacokinetic study. Multivariable regression analysis adjusted for age, sex, race, and ethnicity was used to evaluate the impact of CYP3A5 SNPs on asthma outcomes, including asthma control (measured using the asthma symptom tracker, a modified version of the asthma control test or ACT), exacerbations, and hospital admissions. Plasma corticosteroid and cortisol concentrations post-ICS dosing were also assayed using liquid chromatography-tandem mass spectrometry. Of the 751 patients using the e-AT, 166 (22.1%) provided saliva samples and 16 completed the PK study. The e-AT cohort was 65.1% male, and 89.6% White, 6.0% Native Hawaiian, 1.2% Black, 1.2% Native American, 1.8% of unknown race, and 15.7% Hispanic/Latino; the median age was 8.35 (IQR: 5.51-11.3) years. frequency was 75.8% in White subjects, 50% in Native Hawaiians and 76.9% in Hispanic/Latino subjects. Compared with , the genotype was associated with reduced weekly asthma control (OR: 0.98; 95% CI: 0.97-0.98; < 0.001), increased exacerbations (OR: 6.43; 95% CI: 4.56-9.07; < 0.001), and increased asthma hospitalizations (OR: 1.66; 95% CI: 1.43-1.93; < 0.001); analysis of , and separately showed an allelic copy effect. Finally, PK analysis post-ICS dosing suggested muted changes in cortisol concentrations for patients with the genotype, as opposed to an effect on ICS PK. Detection of , , and could impact inhaled steroid treatment strategies for asthma in the future.
Topics: Humans; Asthma; Child; Male; Female; Polymorphism, Single Nucleotide; Cytochrome P-450 CYP3A; Adolescent; Child, Preschool; Adrenal Cortex Hormones; Genotype; Hydrocortisone; Saliva; Treatment Outcome
PubMed: 38928254
DOI: 10.3390/ijms25126548 -
International Journal of Molecular... Jun 2024Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; = 395)... (Randomized Controlled Trial)
Randomized Controlled Trial
Molecular Long-Term Analysis of the GMMG-HD4 Trial in Multiple Myeloma-Patterns of Association of Chromosomal Aberrations with Response and Proliferation Determining Survival in Selecting Treatments in View of Limited Resources in Low- and Middle-Income Countries.
Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; = 395) randomizing VAD induction (vincristin/adriamycin/dexamthasone)/tandem-transplantation/thalidomide-maintenance vs. PAD induction (bortezomib/adriamycin/dexamethasone)/tandem transplantation/bortezomib maintenance, we discern how chromosomal aberrations determine long-term prognosis by different patterns of association with proliferation and treatment-dependent response, whether responses achieved by different regimens are equal regarding prognosis, and whether subpopulations of patients could be defined as treatable without upfront "novel agents" in cases of limited resources, e.g., in low- or middle-income countries. Serum parameters and risk factors were assessed in 395 patients. CD138-purified plasma cells were subjected to fluorescence in situ hybridization ( = 354) and gene expression profiling ( = 204). We found chromosomal aberrations to be associated in four patterns with survival, proliferation, and response: deletion (del) del17p13, del8p21, del13q14, (gain) 1q21+, and translocation t(4;14) (all adverse) associate with higher proliferation. Of these, del17p is associated with an response (pattern 1), and 1q21+, t(4;14), and del13q14 with a treatment-dependent response (pattern 2). Hyperdiploidy associates with lower proliferation without impacting response or survival (pattern 3). Translocation t(11;14) has no association with survival but a treatment-dependent adverse response (pattern 4). Significantly fewer patients reach a near-complete response or better with "conventional" (VAD) vs. bortezomib-based treatment after induction or high-dose melphalan. These patients, however, show significantly median progression-free and overall survival. Molecularly, patients responding to the two regimens differ in gene expression, indicating distinct biological properties of the responding myeloma cells. Patients with normal renal function (89.4%), low cytogenetic risk (72.5%), or low proliferation rate (37.9%) neither benefit in progression-free nor overall survival from bortezomib-based upfront treatment. We conclude that response level, the treatment by which it is achieved, and molecular background determine long-term prognosis. Chromosomal aberrations are associated in four patterns with proliferation and treatment-dependent responses. Associations with faster and deeper responses can be deceptive in the case of prognostically adverse aberrations 1q21+ and t(4;14). Far from advocating a return to "outdated" treatments, if resources do not permit state-of-the-art-treatment, normal renal function and/or molecular profiling identifies patient subpopulations doing well without upfront "novel agents".
Topics: Humans; Multiple Myeloma; Chromosome Aberrations; Female; Male; Middle Aged; Aged; Antineoplastic Combined Chemotherapy Protocols; Cell Proliferation; Prognosis; Adult; Developing Countries; Dexamethasone; Bortezomib; Thalidomide
PubMed: 38928138
DOI: 10.3390/ijms25126431 -
International Journal of Molecular... Jun 2024Age-related macular degeneration (AMD) is strictly linked to chronic oxidative stress, inflammation, loss of epithelial barrier integrity, and often with abnormal new...
Vitamin D and Sulforaphane Decrease Inflammatory Oxidative Stress and Restore the Markers of Epithelial Integrity in an In Vitro Model of Age-Related Macular Degeneration.
Age-related macular degeneration (AMD) is strictly linked to chronic oxidative stress, inflammation, loss of epithelial barrier integrity, and often with abnormal new blood vessel development. In this study, the retinal epithelial cell line ARPE-19 was treated with pro-inflammatory transforming growth factor-beta (TGF-β) to investigate the activity of vitamin D (VD) and sulforaphane (SF) in abating the consequences of oxidative stress and inflammation. The administration of VD and SF lowered reactive oxygen species (ROS) levels, and abated the related expression of the pro-inflammatory cytokines interleukin-6 and interleukin-8 induced by TGF-β. We evaluated mitochondrial respiration as a source of ROS production, and we discovered that the increased transcription of respiratory elements triggered by TGF-β was prevented by VD and SF. In this model of inflamed epithelium, the treatment with VD and SF also reduced the secretion of VEGF, a key angiogenic factor, and restored the markers of epithelial integrity. Remarkably, all the observed biological effects were potentiated by the co-stimulation with the two compounds and were not mediated by VD receptor expression but rather by the ERK 1/2 pathway. Altogether, the results of this study reveal the powerful synergistic anti-inflammatory activity of SF and VD and lay the foundation for future clinical assessment of their efficacy in AMD.
Topics: Humans; Macular Degeneration; Isothiocyanates; Oxidative Stress; Sulfoxides; Vitamin D; Reactive Oxygen Species; Cell Line; Vascular Endothelial Growth Factor A; Inflammation; Retinal Pigment Epithelium; Epithelial Cells; Transforming Growth Factor beta; Biomarkers; Interleukin-8
PubMed: 38928111
DOI: 10.3390/ijms25126404 -
Lipids in Health and Disease Jun 2024Lipids, including phospholipids and bile acids, exert various signaling effects and are thought to contribute to the development of coronary artery disease (CAD). Here,... (Observational Study)
Observational Study
BACKGROUND
Lipids, including phospholipids and bile acids, exert various signaling effects and are thought to contribute to the development of coronary artery disease (CAD). Here, we aimed to compare lipidomic and bile acid profiles in the blood of patients with and without CAD stratified by sex.
METHODS
From 2015 to 2022, 3,012 patients who underwent coronary angiography were recruited in the INTERCATH cohort. From the overall cohort, subgroups were defined using patient characteristics such as CAD vs. no CAD, 1st vs. 3rd tertile of LDL-c, and female vs. male sex. Hereafter, a matching algorithm based on age, BMI, hypertension status, diabetes mellitus status, smoking status, the Mediterranean diet score, and the intake of statins, triglycerides, HDL-c and hs-CRP in a 1:1 ratio was implemented. Lipidomic analyses of stored blood samples using the Lipidyzer platform (SCIEX) and bile acid analysis using liquid chromatography with tandem mass spectrometry (LC‒MS/MS) were carried out.
RESULTS
A total of 177 matched individuals were analyzed; the median ages were 73.5 years (25th and 75th percentile: 64.1, 78.2) and 71.9 years (65.7, 77.2) for females and males with CAD, respectively, and 67.6 years (58.3, 75.3) and 69.2 years (59.8, 76.8) for females and males without CAD, respectively. Further baseline characteristics, including cardiovascular risk factors, were balanced between the groups. Women with CAD had decreased levels of phosphatidylcholine and diacylglycerol, while no differences in bile acid profiles were detected in comparison to those of female patients without CAD. In contrast, in male patients with CAD, decreased concentrations of the secondary bile acid species glycolithocholic and lithocholic acid, as well as altered levels of specific lipids, were detected compared to those in males without CAD. Notably, male patients with low LDL-c and CAD had significantly greater concentrations of various phospholipid species, particularly plasmalogens, compared to those in high LDL-c subgroup.
CONCLUSIONS
We present hypothesis-generating data on sex-specific lipidomic patterns and bile acid profiles in CAD patients. The data suggest that altered lipid and bile acid composition might contribute to CAD development and/or progression, helping to understand the different disease trajectories of CAD in women and men.
REGISTRATION
https://clinicaltrials.gov/ct2/show/NCT04936438 , Unique identifier: NCT04936438.
Topics: Aged; Female; Humans; Male; Middle Aged; Bile Acids and Salts; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Lipidomics; Sex Characteristics; Sex Factors; Tandem Mass Spectrometry; Triglycerides; Cohort Studies
PubMed: 38926753
DOI: 10.1186/s12944-024-02184-z -
BMC Pediatrics Jun 2024Guillain‒Barre syndrome (GBS) is an acute inflammatory peripheral neuropathy caused by autoimmunity. Gangliosides and sulfatides are important components of peripheral...
BACKGROUND
Guillain‒Barre syndrome (GBS) is an acute inflammatory peripheral neuropathy caused by autoimmunity. Gangliosides and sulfatides are important components of peripheral nerves. Anti-sulfatide antibody-mediated complement is associated with acute sensorimotor peripheral neuropathy in GBS, which is characterized by pain and paresthesias.
CASE PRESENTATION
The child was a 7-year-old girl with headache and abdominal pain, followed by limb numbness and pain. Cranial imaging showed ventricular dilatation, peripheral nerve function conduction examination showed polyradiculopathy, and cerebrospinal fluid tests showed normal cell counts but elevated protein levels, all of which led to the diagnosis of GBS. After treatment with intravenous immunoglobulin (400 mg/kg × 5 days), the symptoms did not improve, and muscle strength progressively worsened, accompanied by paroxysmal complexion flushing, heart rate fluctuation, hyperhidrosis, and a progressive increase in cerebrospinal fluid protein (up to 3780.1 mg/L). On the basis of these findings combined with serum anti-sulfatide IgM positivity, anti-sulfatide antibody-related GBS was considered, and treatment with low-dose prednisolone (1 mg/kg/d) led to symptom improvement.
CONCLUSIONS
Anti-sulfatide antibody-associated GBS is associated with small fiber peripheral neuropathy. The main manifestations are pain, paresthesias and autonomic dysfunction. In addition to the dysfunction of spinal nerve root absorption caused by increased cerebrospinal fluid protein, autonomic dysfunction may be involved in pain. When the therapeutic effect of immunoglobulin is not satisfactory, a low dose and short course of corticosteroids can be considered, and the prognosis is good.
Topics: Humans; Female; Child; Guillain-Barre Syndrome; Abdominal Pain; Headache; Sulfoglycosphingolipids; Autoantibodies; Prednisolone
PubMed: 38926645
DOI: 10.1186/s12887-023-04287-5 -
BMC Pediatrics Jun 2024Kawasaki disease (KD) is an acute systemic immune vasculitis affecting multiple organs and systems in children, and is prevalent in children under 5 years of age....
BACKGROUND
Kawasaki disease (KD) is an acute systemic immune vasculitis affecting multiple organs and systems in children, and is prevalent in children under 5 years of age. Muscular weakness is a rare manifestation of KD, and only 11 pediatric patients with KD combined with muscular weakness have been reported, of which evidence of myositis was found in 2/3 of the patients, and 1/3 could not be explained by myositis, the mechanism of which is still unclear. Cases of KD combined with bladder retention are even more rare, and there has been only 1 case report of KD combined with bladder retention in a child with no previous underlying disease.
CASE PRESENTATION
We report a 22-month-old Asian child with incomplete Kawasaki disease (IKD) who initially presented with fever and progressive muscular weakness in the lower extremities, followed by the bladder and bowel retention abnormalities and rapid onset of heart failure, respiratory failure and shock. The child developed coronary artery ectasia (CAA) without the main clinical features of KD such as rash, conjunctival congestion, desquamation of the extremity endings, orofacial changes and enlarged lymph nodes in the neck. Creatine kinase and electromyography were normal. Temperature gradually normalized and muscle strength recovered slightly after intravenous immunoglobulin. The child could be helped to walk after 1 week of aspirin combined with steroid therapy.
CONCLUSIONS
We present the case of a 22-month-old child with IKD. The child began with progressive muscular weakness in the extremities, followed by the bladder and bowel retention abnormalities, and rapidly developed heart failure, respiratory failure, and shock. Despite early failure to detect the disease, the child recovered rapidly and had a favorable prognosis. KD comorbidities with muscular weakness as the main manifestation are uncommon. This is the first case report of IKD combined with both muscular weakness and bladder and bowel retention, which may provide clinicians with diagnostic and therapeutic ideas, as well as a basis for future exploration of the mechanisms of KD combined with muscular weakness or bladder and bowel retention abnormalities.
Topics: Humans; Infant; Immunoglobulins, Intravenous; Mucocutaneous Lymph Node Syndrome; Muscle Weakness; Urinary Retention
PubMed: 38926640
DOI: 10.1186/s12887-024-04874-0 -
CEN Case Reports Jun 2024Post-transplant infections constitute an important cause of morbidity and mortality in renal transplant recipients worldwide. Tuberculosis (TB) contributes significantly...
Post-transplant infections constitute an important cause of morbidity and mortality in renal transplant recipients worldwide. Tuberculosis (TB) contributes significantly to this burden in endemic countries, such as India. We report a case of renal allograft TB, 10 years post-transplantation, diagnosed during a routine outpatient visit. An asymptomatic rise in serum creatinine level and a 6 month history of immunosuppressive drug non-compliance prompted evaluation of graft dysfunction. Biopsy of the renal allograft tissue suggested chronic active antibody mediated rejection with epithelioid granulomas in the interstitium. Guided by kidney biopsy, further testing with urine acid fast bacilli and urinary GeneXpert yielded positive results for TB. Treatment of TB was further complicated by the development of anti-tubercular therapy induced hepatitis and immune reconstitution inflammatory syndrome, which were managed with the reintroduction regimen and escalation of steroid dose, respectively. Our case highlights the atypical presentation and challenges in managing patients with TB in a post-renal transplant setting.
PubMed: 38926296
DOI: 10.1007/s13730-024-00904-z -
BMJ Open Gastroenterology Jun 2024To estimate the strength of association between exposure to selected classes of prescribed medications and the risk of developing iron deficiency anaemia (IDA),...
OBJECTIVE
To estimate the strength of association between exposure to selected classes of prescribed medications and the risk of developing iron deficiency anaemia (IDA), specifically considering oral anticoagulants (OACs), antidepressants, antiplatelet agents, proton pump inhibitors (PPIs) and non-steroidal anti-inflammatories.
DESIGN
A case-control study involving the analysis of community repeat prescriptions among subjects referred with IDA, and unmatched controls referred as gastroenterology fast-tracks for other indications. Multivariable logistic regression modelling was used to calculate ORs for the association between IDA presentation and each medication class, adjusted for age, sex and coprescribing. For those classes showing significance, it was also used to calculate risk differences between those in the IDA group with or without haemorrhagic lesions on investigation.
RESULTS
A total of 1210 cases were analysed-409 in the IDA group, and 801 in the control group. Significant associations were identified between presentation with IDA and long-term exposure to PPIs (OR 3.29, 95% CI: 2.47 to 4.41, p<0.001) and to OACs (OR 2.04, 95% CI: 1.29 to 3.24, p=0.002). IDA was not associated with long-term exposure to any of the other three drug classes. In contrast to the relationship with PPIs, the association with OACs was primarily in the IDA sub-group with haemorrhagic lesions.
CONCLUSION
Long-term exposure to PPIs and OACs are independently associated with the risk of developing IDA. There are grounds for considering that these associations may be causal, though the underlying mechanisms probably differ.
Topics: Humans; Anemia, Iron-Deficiency; Case-Control Studies; Female; Male; Proton Pump Inhibitors; Middle Aged; Aged; Anticoagulants; Risk Factors; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Platelet Aggregation Inhibitors; Adult; Logistic Models; Aged, 80 and over
PubMed: 38926132
DOI: 10.1136/bmjgast-2023-001305 -
Biological & Pharmaceutical Bulletin 2024We prepared a supramolecular hydrogel composed of decanoic acid and arginine (C10/Arg gel) and evaluated its application to a transdermal formulation. C10/Arg gel...
We prepared a supramolecular hydrogel composed of decanoic acid and arginine (C10/Arg gel) and evaluated its application to a transdermal formulation. C10/Arg gel adjusted to pH 7 with 1 M NaOH aq or 1 M HCl aq provided a translucent hydrogel with a lamellar liquid crystal structure in the concentration region of decanoic acid ≥12% and arginine ≤9%. Rheological measurements showed that C10/Arg gel is a viscoelastic material with both solid and liquid properties, with elasticity being dominant over viscosity in the low shear stress region. The skin permeability of hydrocortisone (HC) and indomethacin (IM) from C10/Arg gels was investigated in vitro using hairless mouse skin and compared to control formulation drug suspensions (IM or HC) in water. The cumulative permeation amount of HC and IM from the C10/Arg gel at 10 h after application was approximately 16 and 11 times higher than that of the control, respectively. On the other hand, the flux of IM decreased with increasing arginine concentration, likely due to the acid-base interaction between Arg and IM in C10/Arg gel. Adequate drug skin permeation enhancement by C10/Arg gel requires optimizing the gel composition for each specific drug.
Topics: Animals; Arginine; Hydrogels; Mice, Hairless; Skin Absorption; Administration, Cutaneous; Skin; Indomethacin; Decanoic Acids; Hydrocortisone; Mice; Rheology; Permeability; Male
PubMed: 38925923
DOI: 10.1248/bpb.b24-00078