In life science, water is the ubiquitous solvent, sometimes even called the “matrix of life”. There is increasing experimental and theoretical evidence that solvation water is not a passive spectator ...in biomolecular processes. New experimental techniques can quantify how water interacts with biomolecules and, in doing so, differs from “bulk” water. Terahertz (THz) absorption spectroscopy has turned out to be a powerful tool to study (bio)molecular hydration. The main concepts that have been developed in the recent years to describe the underlying solute-induced sub-picosecond dynamics of the hydration shell are discussed herein. Moreover, we highlight recent findings that show the significance of hydrogen bond dynamics for the function of antifreeze proteins and for molecular recognition. In all of these examples, a gradient of water motion toward functional sites of proteins is observed, the so-called “hydration funnel”. By means of molecular dynamics simulations, we provide new evidence for a specific water–protein coupling as the cause of the observed dynamical heterogeneity. The efficiency of the coupling at THz frequencies is explained in terms of a two-tier (short- and long-range) solute–solvent interaction.
Hydration free energies are dictated by a subtle balance of hydrophobic and hydrophilic interactions. We present here a spectroscopic approach, which gives direct access to the two main ...contributions: Using THz‐spectroscopy to probe the frequency range of the intermolecular stretch (150–200 cm−1) and the hindered rotations (450–600 cm−1), the local contributions due to cavity formation and hydrophilic interactions can be traced back. We show that via THz calorimetry these fingerprints can be correlated 1 : 1 with the group specific solvation entropy and enthalpy. This allows to deduce separately the hydrophobic (i.e. cavity formation) and hydrophilic contributions to thermodynamics, as shown for hydrated alcohols as a case study. Accompanying molecular dynamics simulations quantitatively support our experimental results. In the future our approach will allow to dissect hydration contributions in inhomogeneous mixtures and under non‐equilibrium conditions.
Dissecting hydration entropy and enthalpy into hydrophobic and hydrophilic contributions from “wrap” and “bound” spectroscopic fingerprints in the low frequency THz range is reported. In the future, this THz‐calorimetry decomposition method could be broadly applied to uncover local hydration thermodynamics, e.g. in molecular recognition.
Oxidative stress is generally considered as the consequence of an imbalance between pro- and antioxidants species, which often results into indiscriminate and global damage at the organismal level. ...Elderly people are more susceptible to oxidative stress and this depends, almost in part, from a decreased performance of their endogenous antioxidant system. As many studies reported an inverse correlation between systemic levels of antioxidants and several diseases, primarily cardiovascular diseases, but also diabetes and neurological disorders, antioxidant supplementation has been foreseen as an effective preventive and therapeutic intervention for aging-associated pathologies. However, the expectations of this therapeutic approach have often been partially disappointed by clinical trials. The interplay of both endogenous and exogenous antioxidants with the systemic redox system is very complex and represents an issue that is still under debate. In this review a selection of recent clinical studies concerning antioxidants supplementation and the evaluation of their influence in aging-related diseases is analyzed. The controversial outcomes of antioxidants supplementation therapies, which might partially depend from an underestimation of the patient specific metabolic demand and genetic background, are presented.
The main focus of enzymology is on the enzyme rates, substrate structures, and reactivity, whereas the role of solvent dynamics in mediating the biological reaction is often left aside owing to its ...complex molecular behavior. We used integrated X-ray– and terahertz- based time-resolved spectroscopic tools to study protein–water dynamics during proteolysis of collagen-like substrates by a matrix metalloproteinase. We show equilibration of structural kinetic transitions in the millisecond timescale during degradation of the two model substrates collagen and gelatin, which have different supersecondary structure and flexibility. Unexpectedly, the detected changes in collective enzyme–substrate–water-coupled motions persisted well beyond steady state for both substrates while displaying substrate-specific behaviors. Molecular dynamics simulations further showed that a hydration funnel (i.e., a gradient in retardation of hydrogen bond (HB) dynamics toward the active site) is substrate-dependent, exhibiting a steeper gradient for the more complex enzyme–collagen system. The long-lasting changes in protein–water dynamics reflect a collection of local energetic equilibrium states specifically formed during substrate conversion. Thus, the observed long-lasting water dynamics contribute to the net enzyme reactivity, impacting substrate binding, positional catalysis, and product release.
Significance The solvent in biological reactions plays an active role in protein function; however, correlating solvation dynamics with specific biological scenarios remains a scientific challenge. Here, we followed time-dependent changes in solvation dynamics using terahertz absorption spectroscopy during proteolysis of collagen substrates by a metalloproteinase. Unexpectedly, we revealed that solvation dynamics do not follow the traditional enzymatic steady-state kinetic theory but generate long-lasting protein–water-coupled motions that last longer than a single catalytic cycle and are substrate-specific. These prolonged solvation dynamics contribute to the net enzyme reactivity impacting substrate binding, positional catalysis, and product release.
Estrogen deficiency is a major cause of loss of postmenopausal bone mineral density (BMD). This study aimed to evaluate the effects of equol and resveratrol on bone turnover biomarkers in ...postmenopausal women. Sixty healthy postmenopausal women were randomly assigned to receive 200 mg fermented soy containing 10 mg equol and 25 mg resveratrol or a placebo for 12 months. Whole-body BMD and bone turnover biomarkers, such as deoxypyridinoline (DPD), tartrate-resistant acid phosphatase 5b (TRACP-5b), osteocalcin, and bone-specific alkaline phosphatase (BAP), were measured at baseline and after 12 months of treatment. At the end of treatment, DPD, osteocalcin, and BAP significantly improved in the active group (
< 0.0001 for all) compared to the placebo group. Conversely, TRACP-5b levels were unaffected by supplementation (
= 0.051). Statistically significant changes in the concentrations of DPD (
< 0.0001), osteocalcin (
= 0.0001), and BAP (
< 0.0001) compared to baseline were also identified. Overall, the intervention significantly increased BMD measured in the whole body (
= 0.0220) compared with the placebo. These data indicate that the combination of equol and resveratrol may positively modulate bone turnover biomarkers and BMD, representing a potential approach to prevent age-related bone loss in postmenopausal women.
PD-L1 Dysregulation in COVID-19 Patients Sabbatino, Francesco; Conti, Valeria; Franci, Gianluigi ...
Frontiers in immunology,
06/2021, Letnik:
12
Journal Article
Recenzirano
Odprti dostop
The COVID-19 pandemic has reached direct and indirect medical and social consequences with a subset of patients who rapidly worsen and die from severe-critical manifestations. As a result, there is ...still an urgent need to identify prognostic biomarkers and effective therapeutic approaches. Severe-critical manifestations of COVID-19 are caused by a dysregulated immune response. Immune checkpoint molecules such as Programmed death-1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) play an important role in regulating the host immune response and several lines of evidence underly the role of PD-1 modulation in COVID-19. Here, by analyzing blood sample collection from both hospitalized COVID-19 patients and healthy donors, as well as levels of PD-L1 RNA expression in a variety of model systems of SARS-CoV-2, including
in vitro
tissue cultures, ex-vivo infections of primary epithelial cells and biological samples obtained from tissue biopsies and blood sample collection of COVID-19 and healthy individuals, we demonstrate that serum levels of PD-L1 have a prognostic role in COVID-19 patients and that PD-L1 dysregulation is associated to COVID-19 pathogenesis. Specifically, PD-L1 upregulation is induced by SARS-CoV-2 in infected epithelial cells and is dysregulated in several types of immune cells of COVID-19 patients including monocytes, neutrophils, gamma delta T cells and CD4+ T cells. These results have clinical significance since highlighted the potential role of PD-1/PD-L1 axis in COVID-19, suggest a prognostic role of PD-L1 and provide a further rationale to implement novel clinical studies in COVID-19 patients with PD-1/PD-L1 inhibitors.
Monitoring the occurrence of microplastic contamination in the Antarctic area is the key to implement policy measures for waste regulations in the research stations. Antarctic fish Trematomus ...bernachii is a suitable species for establishing microplastic contamination and for investigating changes over time in the concentration and type of microplastics in the Antarctic region. In this paper a total of 78 fish, caught during the 37th Italian Antarctic expedition (2021–2022) in the Ross Sea (Antarctica) were analysed. Different microfibers and dyes were identified by Raman spectroscopy and the results were compared with those obtained for fish sampled in 1998. Differences in polymer type emerged with a predominance of synthetic fibers with respect to natural ones. These changes appear to be related to the increased human activities in the Antarctica over the last twenty years and highlights the need to improve the environmental sustainability of the numerous research stations operating throughout that area.
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•Anthropogenic microparticles were found in Trematomus bernacchii specimens from Antarctica.•Polyester (PES) was the main polymer found (52 %).•Indigo was the main industrial dye found (56 %).•The polymers found are compatible with most of the clothing used by research personnel in MZS.
Hydropinotherapy is a salus per aquam (Spa) treatment suitable as a complementary approach to treat several diseases, which strongly affect the quality of life (QoL). Hydropinotherapy with sulphurous ...mineral water exerts benefits thanks to components, such as hydrogen sulphide, which is considered mainly responsible for antioxidant and hypoglycaemic effects. Such properties, linked from each other, could favour an improvement in patients’ QoL. However, data on humans are scarce. This study aimed to investigate whether a cycle of sulphurous hydropinotherapy was able to modify plasma levels of glucose and reactive oxygen metabolites (ROMs) and improve QoL in patients suffering from several chronic disorders. A prospective, observational study involved patients with gastrointestinal diseases who received a prescription of a cycle of sulphurous hydropinotherapy (S-HT). Age- and sex-matched control group was enrolled (No S-HT). Glycaemia and plasma concentration of ROMs were measured in all subjects. The impact of spa treatment on the QoL was assessed using the Short Form 36 Health Status Survey questionnaire (SF-36). All parameters were measured at baseline and at the end of a 2-week treatment. Between the groups, no differences were found in glycaemia and ROMs at baseline. In the S-HT group, a reduction in glycaemia and ROMs, both in respect to baseline (p = 0.005 and p = 0.031, respectively) and to control group, as shown by the delta value calculated, as the difference between the values at 2 weeks and baseline (p = 0.0009 and p = 0.0001, respectively). In the S-HT, delta ROMs was the best predictor of delta glycaemia with a direct linear correlation (beta = 0.559, 95% CI 0.471 to 0.647, p < 0.0001). In the S-HT, the SF-36 total score was improved both when compared with baseline (p = 0.002) and with No S-HT (p = 0.001). Sulphurous hydropinotherapy induces a decrease in glycaemia and ROM levels, also ameliorating the patients’ QoL. Therefore, it could be considered a useful complementary therapeutic approach.
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