Orofacial pain represents a multidisciplinary biomedical challenge involving basic and clinical research for which no satisfactory solution has been found. In this regard, trigeminal pain is ...described as one of the worst pains perceived, leaving the patient with no hope for the future. The aim of this review is to evaluate the latest discoveries on the involvement of neurotrophins in orofacial nociception, describing their role and expression in peripheral tissues, trigeminal ganglion, and trigeminal nucleus considering their double nature as "supporters" of the nervous system and as "promoters" of nociceptive transmission. In order to scan recent literature (last ten years), three independent researchers referred to databases PubMed, Embase, Google Scholar, Scopus, and Web of Science to find original research articles and clinical trials. The researchers selected 33 papers: 29 original research articles and 4 clinical trials. The results obtained by the screening of the selected articles show an interesting trend, in which the precise modulation of neurotrophin signaling could switch neurotrophins from being a "promoter" of pain to their beneficial neurotrophic role of supporting the nerves in their recovery, especially when a structural alteration is present, as in neuropathic pain. In conclusion, neurotrophins could be interesting targets for orofacial pain modulation but more studies are necessary to clarify their role for future application in clinical practice.
Pain is a very important problem of our existence, and the attempt to understand it is one the oldest challenges in the history of medicine. In this review, we summarize what has been known about ...pain, its pathophysiology, and neuronal transmission. We focus on orofacial pain and its classification and features, knowing that is sometimes purely subjective and not well defined. We consider the physiology of orofacial pain, evaluating the findings on the main neurotransmitters; in particular, we describe the roles of glutamate as approximately 30–80% of total peripheric neurons associated with the trigeminal ganglia are glutamatergic. Moreover, we describe the important role of oxidative stress and its association with inflammation in the etiogenesis and modulation of pain in orofacial regions. We also explore the warning and protective function of orofacial pain and the possible action of antioxidant molecules, such as melatonin, and the potential influence of nutrition and diet on its pathophysiology. Hopefully, this will provide a solid background for future studies that would allow better treatment of noxious stimuli and for opening new avenues in the management of pain.
The role of the microbiome in hair follicle (HF) growth represents a growing field of research. Here, we studied the bacterial population in the scalp hair follicles of subjects with alopecia areata ...(AA). Two Healthy and two AA subjects, respectively (20−60 years old), were enrolled and studied regarding the microbial community in the subepidermal scalp compartments by means of a 4-mm biopsy punch. Samples were examined by 16S sequencing, histochemical staining (Gram’s method), and transmission electron microscopy (TEM). Bacterial foci were observed in the AA subjects’ follicles with both the two adopted complementary approaches (electron microscopy and Gram staining). Significant (p < 0.05) differences were also found in the three-layer biopsy samples (p < 0.05) regarding the bacterial population. In particular, in the deep epidermis and dermis levels, a significant (p < 0.05) lower abundance of Firmicutes and a higher abundance of Proteobacteria were found in AA samples compared to the healthy control. Firmicutes also showed a significant (p < 0.05) lower abundance in hypodermis in AA subjects. In addition, Enterobacteriaceae and the genera Streptococcus, Gemella, Porphyromonas, and Granulicatella were relatively more abundant in AA groups at the deep epidermis level. The Staphylococcus and Flavobacterium genera were significantly less abundant in AA samples than in controls in all three-layer biopsy samples (p < 0.05). In contrast, Veillonella and Neisseriaceae were relatively more abundant in the healthy control group compared to the AA sample. Therefore, higher alpha diversity was observed in all three-layer biopsy samples of AA patients compared to the control. In conclusion, our data suggest that tAA could be defined as a “hair disease associated with dysregulated microbiome-immunity axis of hair follicles”.
Chronic neuroinflammation plays a crucial role in the progression of several neurodegenerative diseases (NDDs), including Parkinson's disease (PD) and Alzheimer's disease (AD). Intriguingly, in the ...last decade, leucine-rich repeat kinase-2 (
), a gene mutated in familial and sporadic PD, was revealed as a key mediator of neuroinflammation. Therefore, the anti-inflammatory properties of LRRK2 inhibitors have started to be considered as a disease-modifying treatment for PD; however, to date, there is little evidence on the beneficial effects of targeting LRRK2-related neuroinflammation in preclinical models. In this study, we further validated LRRK2 kinase modulation as a pharmacological intervention in preclinical models of AD- and PD-related neuroinflammation. Specifically, we reported that LRRK2 kinase inhibition with MLi2 and PF-06447475 (PF) molecules attenuated neuroinflammation, gliosis and cytotoxicity in mice with intracerebral injection of Aβ
fibrils or α-syn preformed fibrils (pffs). Moreover, for the first time in vivo, we showed that LRRK2 kinase activity participates in AD-related neuroinflammation and therefore might contribute to AD pathogenesis. Overall, our findings added evidence on the anti-inflammatory effects of LRRK2 kinase inhibition in preclinical models and indicate that targeting LRRK2 activity could be a disease-modifying treatment for NDDs with an inflammatory component.
Intracerebral accumulation of amyloid-β in the extracellular plaques of Alzheimer’s disease (AD) brains represents the main cause of reactive astrogliosis and neuroinflammatory response. Of ...relevance, leucine-rich repeat kinase 2 (LRRK2), a kinase linked to genetic and sporadic Parkinson’s disease (PD), has been identified as a positive mediator of neuroinflammation upon different inflammatory stimuli, however its pathogenicity in AD remains mainly unexplored. In this study, by using pharmacological inhibition of LRRK2 and murine primary astrocytes, we explored whether LRRK2 regulates astrocytic activation in response to amyloid-β1-42 (Aβ1-42). Our results showed that murine primary astrocytes become reactive and recruit serine 935 phosphorylated LRRK2 upon Aβ1-42 fibril exposure. Moreover, we found that pharmacological inhibition of LRRK2, with two different kinase inhibitors, can attenuate Aβ1-42-mediated inflammation and favor the clearance of Aβ1-42 fibrils in astrocytes. Overall, our findings report that LRRK2 kinase activity modulates astrocytic reactivity and functions in the presence of Aβ1-42 deposits and indicate that PD-linked LRRK2 might contribute to AD-related neuroinflammation and pathogenesis.
Several pathological conditions, including hypertension, atherosclerosis, diabetes, ischemia/reperfusion injury and nicotine-induced vasculopathy, are associated with vascular endothelial dysfunction ...characterized by altered secretory output of endothelial cells. Therefore there is a search for molecules and interventions that could restore endothelial function, in particular augmenting NO production, reducing the generation of free radicals and vasoconstrictors and preventing undesired inflammation. The pineal hormone melatonin exhibits several endothelium protective properties: it scavenges free radicals, activates antioxidant defence enzymes, normalizes lipid and blood pressure profile and increases NO bioavailability. Melatonin improved vascular function in experimental hypertension, reducing intimal infiltration and restoring NO production. Melatonin improved the NO pathway also in animal models for the study of diabetes and prevented NO down-regulation and adhesive molecules up-regulation in nicotine-induced vasculopathy. The protection against endothelial damage, vasoconstriction, platelet aggregation and leukocyte infiltration might contribute to the beneficial effects against ischemia-reperfusion injury by melatonin. Therefore, melatonin administration has endothelium-protective potential in several pathological conditions. Nevertheless, it still needs to be established, whether melatonin is able to revert already established endothelial dysfunction in these conditions.
Abstract The increasing incidence of obesity, leading to metabolic complications, is now recognized as a major public health problem. The adipocytes are not merely energy-storing cells, but they play ...crucial roles in the development of the so-called metabolic syndrome due to the adipocyte-derived bioactive factors such as adipokines, cytokines, and growth factors. The dysregulated production and secretion of adipokines seen in obesity is linked to the pathogenesis of the metabolic disease processes. In this study, we hypothesized that dietary melatonin administration would support an anti-inflammatory response and play an important role in energy metabolism in subcutaneous and visceral adipose tissues of obese mice and so may counteract some of the disruptive effects of obesity. Lean and obese mice ( ob/ob ) received melatonin or vehicle in drinking water for 8 weeks. Thereafter, they were evaluated for morphologic alteration, inflammatory cell infiltration, and the adipokine patterns in visceral and subcutaneous white fat depots. In obese mice treated with vehicle, we observed a significant increase in fat depots, inflammation, and a dysregulation of the adipokine network. In particular, we measured a significant reduction of adiponectin and an increase of tumor necrosis factor α, resistin, and visfatin in adipose tissue deposits. These changes were partially reversed when melatonin was supplemented to obese mice. Melatonin supplementation by regulating inflammatory infiltration ameliorates obesity-induced adipokine alteration, whereas melatonin administration in lean mice was unaffected. Thus, it is likely that melatonin would be provided in supplement form to control some of the disruptive effects on the basis of obesity pathogenic process.
The main neuropathological features of Parkinson's disease are dopaminergic nigrostriatal neuron degeneration, and intraneuronal and intraneuritic proteinaceous inclusions named Lewy bodies and Lewy ...neurites, respectively, which mainly contain α-synuclein (α-syn, also known as SNCA). The neuronal phosphoprotein synapsin III (also known as SYN3), is a pivotal regulator of dopamine neuron synaptic function. Here, we show that α-syn interacts with and modulates synapsin III. The absence of α-syn causes a selective increase and redistribution of synapsin III, and changes the organization of synaptic vesicle pools in dopamine neurons. In α-syn-null mice, the alterations of synapsin III induce an increased locomotor response to the stimulation of synapsin-dependent dopamine overflow, despite this, these mice show decreased basal and depolarization-dependent striatal dopamine release. Of note, synapsin III seems to be involved in α-syn aggregation, which also coaxes its increase and redistribution. Furthermore, synapsin III accumulates in the caudate and putamen of individuals with Parkinson's disease. These findings support a reciprocal modulatory interaction of α-syn and synapsin III in the regulation of dopamine neuron synaptic function.
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