An Update on Vitamin D Metabolism Saponaro, Federica; Saba, Alessandro; Zucchi, Riccardo
International journal of molecular sciences,
09/2020, Volume:
21, Issue:
18
Journal Article
Peer reviewed
Open access
Vitamin D is a steroid hormone classically involved in the calcium metabolism and bone homeostasis. Recently, new and interesting aspects of vitamin D metabolism has been elucidated, namely the ...special role of the skin, the metabolic control of liver hydroxylase CYP2R1, the specificity of 1α-hydroxylase in different tissues and cell types and the genomic, non-genomic and epigenomic effects of vitamin D receptor, which will be addressed in the present review. Moreover, in the last decades, several extraskeletal effects which can be attributed to vitamin D have been shown. These beneficial effects will be here summarized, focusing on the immune system and cardiovascular system.
The importance of thyroid hormones in the regulation of development, growth, and energy metabolism is well known. Over the last decades, mass spectrometry has been extensively used to investigate ...thyroid hormone metabolism and to discover and characterize new molecules involved in thyroid hormones production, such as thyrotropin‐releasing hormone. In the earlier period, the quantification methods, usually based on gas chromatography–mass spectrometry, were complicated and time consuming. They were mainly focused on basic research, and were not suitable for clinical diagnostics on a routine basis. The development of the modern mass spectrometers, mainly coupled to liquid chromatography, enabled simpler sample preparation procedures, and the accurate quantification of thyroid hormones, of their precursors, and of their metabolites in biological fluids, tissues, and cells became feasible. Nowadays, molecules of physiological and pathological interest can be assayed also for diagnostic purposes on a routine basis, and mass spectrometry is slowly entering the clinical laboratory. This review takes stock of the advancements in the field of thyroid metabolism that were carried out with mass spectrometry, with special focus on the use of this technique for the quantification of molecules involved in thyroid diseases.
Heavy metal (HM) pollution, specifically cadmium (Cd) contamination, is a worldwide concern for its consequences for plant health and ecosystem stability. This review sheds light on the intricate ...mechanisms underlying Cd toxicity in plants and the various strategies employed by these organisms to mitigate its adverse effects. From molecular responses to physiological adaptations, plants have evolved sophisticated defense mechanisms to counteract Cd stress. We highlighted the role of phytochelatins (PCn) in plant detoxification, which chelate and sequester Cd ions to prevent their accumulation and minimize toxicity. Additionally, we explored the involvement of glutathione (GSH) in mitigating oxidative damage caused by Cd exposure and discussed the regulatory mechanisms governing GSH biosynthesis. We highlighted the role of transporter proteins, such as ATP-binding cassette transporters (ABCs) and heavy metal ATPases (HMAs), in mediating the uptake, sequestration, and detoxification of Cd in plants. Overall, this work offered valuable insights into the physiological, molecular, and biochemical mechanisms underlying plant responses to Cd stress, providing a basis for strategies to alleviate the unfavorable effects of HM pollution on plant health and ecosystem resilience.
(1) Background: In recent years, numerous studies have highlighted the beneficial effects of extra virgin olive oil (EVOO) as an active ingredient against chronic diseases. The properties of EVOO are ...due to its peculiar composition, mainly to its rich content of polyphenols. In fact, polyphenols may contribute to counteract oxidative stress, which often accompanies chronic diseases. In this work, the antioxidant effects of high-value polyphenol oleocanthal (OC) and its main metabolites, tyrosol (Tyr) and oleocanthalic acid (OA), respectively, have been investigated along with their impact on cell viability. (2) Methods: OC, Tyr, and OA have been evaluated regarding antiradical properties in term of scavenging capacity towards biologically relevant reactive species, including O
, HOCl, and ROO
, as well as their antioxidant/antiradical capacity (FRAP, DPPH
, ABTS
). Moreover, the ability to permeate the intestinal membrane was assessed by an intestinal co-culture model composed by Caco-2 and HT29-MTX cell lines. (3) Results: The capacity of OC and Tyr as radical oxygen species (ROS) scavengers, particularly regarding HOCl and O
, was clearly demonstrated. Furthermore, the ability to permeate the intestinal co-culture model was plainly proved by the good permeations (>50%) achieved by all compounds. (4) Conclusions: OC, OA, and Tyr revealed promising properties against oxidative diseases.
We took advantage of the fluorescent features of a serotonin-derived fluorophore to develop a simple and low-cost assay for copper in urine. The quenching-based fluorescence assay linearly responds ...within the concentration range of clinical interest in buffer and in artificial urine, showing very good reproducibility (CV
% = 4% and 3%) and low detection limits (16 ± 1 μg L
and 23 ± 1 μg L
). The Cu
content was also estimated in human urine samples, showing excellent analytical performances (CV
% = 1%), with a limit of detection of 59 ± 3 μg L
and a limit of quantification of 97 ± 11 μg L
, which are below the reference value for a pathological Cu
concentration. The assay was successfully validated through mass spectrometry measurements. To the best of our knowledge, this is the first example of copper ion detection exploiting the fluorescence quenching of a biopolymer, offering a potential diagnostic tool for copper-dependent diseases.
Novel interest has arisen in recent years regarding bone, which is a very complex and dynamic tissue deputed to several functions ranging from mechanical and protective support to hematopoiesis and ...calcium homeostasis maintenance. In order to address these tasks, a very refined, continuous remodeling process needs to occur involving the coordinated action of different types of bone cells: osteoblasts (OBs), which have the capacity to produce newly formed bone, and osteoclasts (OCs), which can remove old bone. Bone remodeling is a highly regulated process that requires many hormones and messenger molecules, both at the systemic and the local level. The whole picture is still not fully understood, and the role of novel actors, such as the components of the endocannabinoids system (ECS), including endogenous cannabinoid ligands (ECs), cannabinoid receptors (CBRs), and the enzymes responsible for endogenous ligand synthesis and breakdown, is extremely intriguing. This article reviews the connection between the ECS and skeletal health, supporting the potential use of cannabinoid receptor ligands for the treatment of bone diseases associated with accelerated osteoclastic bone resorption, including osteoporosis and bone metastasis.
Hypovitaminosis D has been suggested to play a possible role in coronavirus disease 2019 (COVID-19) infection.
The aim of this study is to analyze the relationship between vitamin D status and a ...biochemical panel of inflammatory markers in a cohort of patients with COVID-19. A secondary endpoint was to evaluate the correlation between 25OHD levels and the severity of the disease. Ninety-three consecutive patients with COVID-19-related pneumonia were evaluated from March to May 2020 in two hospital units in Pisa, in whom biochemical inflammatory markers, 25OHD levels, P/F ratio at nadir during hospitalization, and complete clinical data were available.
Sixty-five percent of patients presented hypovitaminosis D (25OHD ≤ 20 ng/ml) and showed significantly higher IL-6 20.8 (10.9-45.6) vs. 12.9 (8.7-21.1) pg/ml,
= 0.02, CRP 10.7 (4.2-19.2) vs. 5.9 (1.6-8.1) mg/dl,
= 0.003, TNF-α 8.9 (6.0-14.8) vs. 4.4 (1.5-10.6) pg/ml,
= 0.01, D-dimer 0.53 (0.25-0.72) vs. 0.22 (0.17-0.35) mg/l,
= 0.002, and IL-10 3.7 (1.8-6.9) vs. 2.3 (0.5-5.8) pg/ml,
= 0.03. A significant inverse correlation was found between 25OHD and all these markers, even adjusted for age and sex. Hypovitaminosis D was prevalent in patients with severe ARDS, compared with the other groups (75% vs. 68% vs. 55%,
< 0.001), and 25OHD levels were lower in non-survivor patients.
The relationship between 25OHD levels and inflammatory markers suggests that vitamin D status needs to be taken into account in the management of these patients. If vitamin D is a marker of poor prognosis or a possible risk factor with beneficial effects from supplementation, this still needs to be elucidated.
Aims/hypothesis
The glucosuria induced by sodium–glucose cotransporter 2 (SGLT2) inhibition stimulates endogenous (hepatic) glucose production (EGP), blunting the decline in HbA
1c
. We hypothesised ...that, in response to glucosuria, a renal signal is generated and stimulates EGP. To examine the effect of acute administration of SGLT2 inhibitors on EGP, we studied non-diabetic individuals who had undergone renal transplant with and without removal of native kidneys.
Methods
This was a parallel, randomised, double-blind, placebo-controlled, single-centre study, designed to evaluate the effect of a single dose of dapagliflozin or placebo on EGP determined by stable-tracer technique. We recruited non-diabetic individuals who were 30–65 years old, with a BMI of 25–35 kg/m
2
and stable body weight (±2 kg) over the preceding 3 months, and HbA
1c
<42 mmol/mol (6.0%). Participants had undergone renal transplant with and without removal of native kidneys and were on a stable dose of immunosuppressive medications. Participants received a single dose of dapagliflozin 10 mg or placebo on two separate days, at a 5- to 14-day interval, according to randomisation performed by our hospital pharmacy, which provided dapagliflozin and matching placebo, packaged in bulk bottles that were sequentially numbered. Both participants and investigators were blinded to group assignment.
Results
Twenty non-diabetic renal transplant patients (ten with residual native kidneys, ten with bilateral nephrectomy) participated in the study. Dapagliflozin induced greater glucosuria in individuals with residual native kidneys vs nephrectomised individuals (8.6 ± 1.1 vs 5.5 ± 0.5 g/6 h;
p
= 0.02; data not shown). During the 6 h study period, plasma glucose decreased only slightly and similarly in both groups, with no difference compared with placebo (data not shown). Following administration of placebo, there was a progressive time-related decline in EGP that was similar in both nephrectomised individuals and individuals with residual native kidneys. Following dapagliflozin administration, EGP declined in both groups, but the differences between the decrement in EGP with dapagliflozin and placebo in the group with bilateral nephrectomy (Δ = 1.11 ± 0.72 μmol min
−1
kg
−1
) was significantly lower (
p
= 0.03) than in the residual native kidney group (Δ = 2.56 ± 0.33 μmol min
−1
kg
−1
). In the population treated with dapagliflozin, urinary glucose excretion was correlated with EGP (
r
= 0.34,
p
< 0.05). Plasma insulin, C-peptide, glucagon, prehepatic insulin:glucagon ratio, lactate, alanine and pyruvate concentrations were similar following placebo and dapagliflozin treatment. β-Hydroxybutyrate increased with dapagliflozin treatment in the residual native kidney group, while a small increase was observed only at 360 min in the nephrectomy group. Plasma adrenaline (epinephrine) did not change after dapagliflozin and placebo treatment in either group. Following dapagliflozin administration, plasma noradrenaline (norepinephrine) increased slightly in the residual native kidney group and decreased in the nephrectomy group.
Conclusions/interpretation
In nephrectomised individuals, the hepatic compensatory response to acute SGLT2 inhibitor-induced glucosuria was attenuated, as compared with individuals with residual native kidneys, suggesting that SGLT2 inhibitor-mediated stimulation of hepatic glucose production via efferent renal nerves occurs in an attempt to compensate for the urinary glucose loss (i.e. a renal–hepatic axis).
Trial registration
ClinicalTrials.gov
NCT03168295
Funding
This protocol was supported by Qatar National Research Fund (QNRF) Award No. NPRP 8-311-3-062 and NIH grant DK024092-38.
Graphical abstract
hRPE65 is a fundamental enzyme of the retinoid visual cycle, and many missense mutations affecting its expression or function are associated with a wide range of diseases. Many hRPE65 missense ...mutations lack a clear pathogenicity classification or are labelled as VUS. In this context, we recently developed a protocol based on µs-long molecular dynamics simulations to study the potential pathogenic effect of hRPE65 missense mutations. In the present work, the structure-based protocol was integrated with a hRPE65-tailored consensus bioinformatics strategy, named ConPath, that showed high performance in predicting known pathogenic/benign hRPE65 missense mutations. The combined strategy was used to perform a multi-level evaluation of the potential pathogenicity of 13 different hRPE65 VUS, which were classified based on their likelihood of pathogenic effect. The obtained results provide information that may support the reclassification of these VUS and help clinicians evaluate the eligibility for gene therapy of patients diagnosed with such variants.
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