Genes and primary headaches: discovering new potential therapeutic targets

Genetic studies have clearly shown that primary headaches (migraine, tension-type headache and cluster headache) are multifactorial disorders characterized by a complex interaction between different genes and environmental factors. Genetic association studies have highlighted a potential role in the etiopathogenesis of these disorders for several genes related to vascular, neuronal and neuroendocrine functions. A potential role as a therapeutic target is now emerging for some of these genes. The main purpose of this review is to describe new advances in our knowledge regarding the role of MTHFR, KCNK18, TRPV1, TRPV3 and HCRTR genes in primary headache disorders. Involvement of these genes in primary headaches, as well as their potential role in the therapy of these disorders, will be discussed

Identifying conformational changes with site-directed spin labeling reveals that the GTPase domain of HydF is a molecular switch

[FeFe]-hydrogenases catalyse the reduction of protons to hydrogen at a complex 2Fe[4Fe4S] center called H-cluster. The assembly of this active site is a multistep process involving three proteins, HydE, HydF and HydG. According to the current models, HydF has the key double role of scaffold, upon which the final H-cluster precursor is assembled, and carrier to transfer it to the target hydrogenase. The X-ray structure of HydF indicates that the protein is a homodimer with both monomers carrying two functional domains: a C-terminal FeS cluster-binding domain, where the precursor is assembled, and a N-terminal GTPase domain, whose exact contribution to cluster biogenesis and hydrogenase activation is still elusive. We previously obtained several hints suggesting that the binding of GTP to HydF could be involved in the interactions of this scaffold protein with the other maturases and with the hydrogenase itself. In this work, by means of site directed spin labeling coupled to EPR/PELDOR spectroscopy, we explored the conformational changes induced in a recombinant HydF protein by GTP binding, and provide the first clue that the HydF GTPase domain could be involved in the H-cluster assembly working as a molecular switch similarly to other known small GTPases

Lithium limits trimethyltin-induced cytotoxicity and proinflammatory response in microglia without affecting the concurrent autophagy impairment

Trimethyltin (TMT) is a highly toxic molecule present as an environmental contaminant causing neurodegeneration particularly of the limbic system both in humans and in rodents. We recently described the occurrence of impairment in the late stages of autophagy in TMT-intoxicated astrocytes. Here we show that similarly to astrocytes also in microglia, TMT induces the precocious block of autophagy indicated by the accumulation of the autophagosome marker, microtubule associated protein light chain 3. Consistent with autophagy impairment we observe in TMT-treated microglia the accumulation of p62/SQSTM1, a protein specifically degraded through this pathway. Lithium has been proved effective in limiting neurodegenerations and, in particular, in ameliorating symptoms of TMT intoxication in rodents. In our in vitro model, lithium displays a pro-survival and anti-inflammatory action reducing both cell death and the proinflammatory response of TMT-treated microglia. In particular, lithium exerts these activities without reducing TMT-induced accumulation of light chain 3 protein. In fact, the autophagic block imposed by TMT is unaffected by lithium administration. These results are of interest as defects in the execution of autophagy are frequently observed in neurodegenerative diseases and lithium is considered a promising therapeutic agent for these pathologies. Thus, it is relevant that this cation can still maintain its pro-survival and anti-inflammatory role in conditions of autophagy bloc

Expanding the knowledge related to flavors and fragrances by means of three-dimensional preparative Gas Chromatography and Molecular Spectroscopy

As universally known, gas chromatography (GC) coupled with mass spectrometry (MS) allows us to acquire spectra that can be searched in specific databases to attain qualitative information on a peak of interest. When not present in databases, structure elucidation is required before including a new component in a library: from that moment, scientists all around the world will be able to identify the new molecule with analytical confidence after GC-MS analysis. Conversely, if data are not shared in commercial databases, even if a molecule is studied and elucidated, it appears to be unknown or only identifiable on the basis of third-party data taken from the literature, which is a serious limitation. The present paper deals with a case that confirms this assumption. A component of Myrtus communis L. volatile fraction was tentatively identified based on literature data. Despite this, reliable identification could not be achieved due to the lack of a corresponding spectrum in commercial MS databases. Afterwards, the target component was isolated in a reasonable quantity and with a high degree of purity for downstream characterization by spectroscopic techniques. For this purpose, preparative (prep) GC may appear insufficient for the isolation of volatile components from highly complex samples. In this study, a prep-MDGC system was implemented for the isolation of the compound of interest from myrtle oil, consisting of three wide-bore columns of different selectivity coupled by means of Deans switch transfer devices. Based on the NMR and GC-FTIR data acquired, the unknown compound was identified as 2,2,5,5,7,7-hexamethyl-3,7-dihydro-1-benzofuran-4,6(2H,5H)-dione. Noticeably, this is a known molecule, yet its mass spectrum had never been registered into MS databases and thus was not available to the scientific community. Finally, the spectrum was included for the first time in a commercial library, namely the FFNSC 5.0 MS database. The aim of the present study was to highlight the opportunity to make analytical data quickly available in a reliable way by registering them in searchable MS databases to improve the identification means for researchers all over the worl

Wireless Sensing for the Respiratory Activity of Human Beings: Measurements and Wide-band Numerical Analysis

An electromagnetic sensing system for the measurement of the respiratory activity is presented. The aims are to demonstrate the feasibility of the proposed approach and in particular to evaluate the effect on the measured signal of the distance between the subject and the sensing apparatus. Moreover, an electromagnetic model of the system, including the monitored subject, is proposed as a tool to solve the problem of selecting working parameters for system design. The sensing system is based on the measurement of the phase variation of the reflection coefficient caused by the respiratory activity. The phase signal compared with the thorax displacement measured by a reference instrument shows a high correlation () for different subject postures (sitting, standing, and lying) and a reduction of the signal amplitude with the distance  dB/cm is reported. The numerical simulations performed on a wide-band highlight the frequencies where the method exhibits the highest sensitivity to thorax movements. The sensitivity can be further improved by reducing the antenna beamwidth. Despite the signal amplitude reduction, the proposed system makes it possible to correctly operate at distances up to 2.5 m

From micro- to nanostructured implantable device for local anesthetic delivery

Local anesthetics block the transmission of painful stimuli to the brain by acting on ion channels of nociceptor fibers, and find application in the management of acute and chronic pain. Despite the key role they play in modern medicine, their cardio and neurotoxicity (together with their short half-life) stress the need for developing implantable devices for tailored local drug release, with the aim of counterbalancing their side effects and prolonging their pharmacological activity. This review discusses the evolution of the physical forms of local anesthetic delivery systems during the past decades. Depending on the use of different biocompatible materials (degradable polyesters, thermosensitive hydrogels, and liposomes and hydrogels from natural polymers) and manufacturing processes, these systems can be classified as films or micro- or nanostructured devices. We analyze and summarize the production techniques according to this classification, focusing on their relative advantages and disadvantages. The most relevant trend reported in this work highlights the effort of moving from microstructured to nanostructured systems, with the aim of reaching a scale comparable to the biological environment. Improved intracellular penetration compared to microstructured systems, indeed, provides specific drug absorption into the targeted tissue and can lead to an enhancement of its bioavailability and retention time. Nanostructured systems are realized by the modification of existing manufacturing processes (interfacial deposition and nanoprecipitation for degradable polyester particles and high- or low-temperature homogenization for liposomes) or development of novel strategies (electrospun matrices and nanogels). The high surface-to-volume ratio that characterizes nanostructured devices often leads to a burst drug release. This drawback needs to be addressed to fully exploit the advantage of the interaction between the target tissues and the drug: possible strategies could involve specific binding between the drug and the material chosen for the device, and a multiscale approach to reach a tailored, prolonged drug release

Association between Sarcopenia and Reduced Bone Mass: Is Osteosarcopenic Obesity a New Phenotype to Consider in Weight Management Settings?

Sarcopenic obesity (SO) is a frequent phenotype in people with obesity; however, it is unclear whether this links with an impaired bone status. In this study, we aimed to investigate the association between SO and low bone mass, and to assess the prevalence of a new entity that combines excessive fat deposition, reduced muscle mass and strength, and low bone mass defined as osteosarcopenic obesity (OSO). Body composition was completed by a DXA scan in 2604 participants with obesity that were categorized as with or without SO, and with low or normal bone mineral content (BMC). Participants with both SO and low BMC were defined as OSO. Among the entire sample, 901 (34.6%) participants met the criteria for SO. This group showed a reduced mean BMC (2.56 ± 0.46 vs. 2.85 ± 0.57, p < 0.01) and displayed a higher prevalence of individuals with low BMC with respect to those without SO (47.3% vs. 25.9%, p < 0.01). Logistic regression analysis showed that the presence of SO increases the odds of having low BMC by 92% [OR = 1.92; 95% CI: (1.60–2.31), p < 0.05] after adjusting for age, body weight, and body fat percentage. Finally, 426 (16.4%) out of the total sample were affected by OSO. Our findings revealed a strong association between SO and reduced bone mass in adults with obesity, and this introduces a new phenotype that combines body fat, muscle, and bone (i.e., OSO) and appears to affect 16% of this population

Adherence to Mediterranean Diet and Its Association with Maternal and Newborn Outcomes

Background: Pregnancy is a crucial stage in a woman’s life and can be affected by epigenetic and environmental factors. Diet also plays a key role in gestation. This study aimed to evaluate how a greater or lesser adherence to the Mediterranean Diet (MD) influences specific parameters of mother and newborn. Methods: After delivery, the women participating in the study answered a questionnaire: demographic information; anthropometric data (pre-pregnancy weight, height, and gestational weight gain); dietary habits information (adherence to MD before and during pregnancy, using the validated Mediterranean Diet Adherence Screener (MEDAS), quality of protein intake); pregnancy information (onset of complications, cesarean/vaginal delivery, gestational age at birth, birth weight, birth length); and clinical practitioner for personalized dietary patterns during pregnancy. Results: A total of 501 respondents have been included in the study, and 135 were excluded for complications. Women who followed the advice of clinical nutritionists showed better adherence to MD (p = 0.02), and the baby’s birth weight was higher (p = 0.02). Significant differences in gestational weight gain (p < 0.01) between groups with dissimilar diet adherence were demonstrated. Conclusion: Our data demonstrate a significant relationship between adherence to MD and birthweight