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Simonetta Baldi,1 Gian Domenico Pinna,2 Claudio Bruschi,1 Fabrizio Caldara,3 Roberto Maestri,2 Elena Dacosto,1 Antonella Rezzani,1 Ermanno Popovich,1 Ezio Bellinzona,1 Paola Crotti,1 Silvia Montemartini,1 Claudio Fracchia1 1Department of Pneumology, 2Department of Biomedical Engineering, Scientific Institute of Montescano, Salvatore Maugeri Foundation, Istituto Di Ricovero e Cura a Carattere Scientifico, Montescano (Pavia), 3Center of Thermal Studies Pietro d’Abano, AbanoTerme, Padua, Italy Background: Inspiratory resistive breathing (IRB) challenges affect respiratory muscle endurance in healthy individuals, which is considered to be an interleukin 6 (IL-6)–dependent mechanism. Whether nonpharmacological thermal therapies promote the endurance of loaded inspiratory muscles in chronic obstructive pulmonary disease (COPD) is unclear. The objectives of this study were to compare the effects of two thermal interventions on endurance time (ET) and plasma IL-6 concentration following an IRB challenge.Methods: This study was a randomized, parallel-group, unblinded clinical trial in a single-center setting. Forty-two patients (aged 42–76 years) suffering from mild to severe COPD participated in this study. Both groups completed 12 sessions of the mud bath therapy (MBT) (n=22) or leisure thermal activity (LTA) (n=19) in a thermal spa center in Italy. Pre- and postintervention spirometry, maximum inspiratory pressure, and plasma mediators were obtained and ET and endurance oxygen expenditure (VO2Endur) were measured following IRB challenge at 40% of maximum inspiratory pressure.Results: There was no difference in ΔIL-6 between the intervention groups. But, IRB challenge increased cytokine IL-6 plasma levels systematically. The effect size was small. A statistically significant treatment by IRB challenge effect existed in ET, which significantly increased in the MBT group (P=0.003). In analysis of covariance treatment by IRB challenge analysis with LnVO2Endur as the dependent variable, ΔIL-6 after intervention predicted LnVO2Endur in the MBT group, but not in the LTA group. Adverse events occurred in two individuals in the MBT group, but they were mainly transient. One patient in the LTA group dropped out.Conclusion: MBT model improves ET upon a moderate IRB challenge, indicating the occurrence of a training effect. The LnVO2Endur/ΔIL-6 suggests a physiologic adaptive mechanism in respiratory muscles of COPD patients allocated to treatment. Both thermal interventions are safe. Keywords: hydrotherapy, cytokine IL-6, inspiratory resistive breathing, balneotherapy, pulmonary rehabilitation

Simonetta Baldi,1 Paul E Jose,2 Claudio Bruschi,1 Gian Domenico Pinna,3 Roberto Maestri,3 Antonella Rezzani,1 Ezio Bellinzona,1 Claudio Fracchia,1 Elena Dacosto,1 Paola Crotti,1 Silvia Montemartini1 1Department of Pneumology, Scientific Institute of Montescano, Salvatore Maugeri Foundation IRCCS, Montescano, Pavia, Italy; 2School of Psychology, Victoria University, Wellington, New Zealand; 3Department of Biomedical Engineering, Scientific Institute of Montescano, Salvatore Maugeri Foundation IRCCS, Montescano, Pavia, ItalyObjectives: To explore the mediating role of protein interleukin-6 (IL-6) on the relationship between forced expiratory volume in 1 second (FEV1) and 6-minute walk distance (6MWD) and, further, to determine whether status variables (such as age, sex, and body mass index [BMI]) operate as moderators of this mediation relationship.Design: Moderated mediation model.Setting: An inpatient pulmonary rehabilitation center in Italy.Participants: All 153 patients involved in the screening of a randomized controlled clinical trial (ClinicalTrials.gov identifier: NCT01253941) were included in this study. All patients were Global initiative for chronic Obstructive Lung Disease (GOLD) stages I–IV and were aged 70.1±9.1 years.Measurements: At run-in phase of the protocol, clinical and functional screening included BMI, fasting plasma levels of protein (IL-6), spirometry, and standardized 6-minute walking test, measured at the start of the respiratory rehabilitation program.Methods: The size of the indirect effect of the initial variable (FEV1) upon the outcome variable (6MWD) through the intervening variable (IL-6) was computed and tested for statistical significance. Moderated mediation analyses were subsequently conducted with age, sex, and BMI.Results: FEV1 averaged 53.4%±21.2%, and 6MWD 66.4%±41.3% of predicted. Median protein IL-6 was 6.68 pg/mL (interquartile range: 5.96). A bootstrapped mediation test supported the predicted indirect pathway (P=0.003). The indirect effect through IL-6 log units accounted for 17% of the total effect between FEV1 and 6MWD. Age functioned as a significant moderator of the mediational pattern. For individuals aged 70 years it was not significant (0.04, 95% CI: –0.010 to 0.142, P=0.10).Conclusion: This moderated mediation result based on concurrent data suggests, but does not prove, a causal role of systemic inflammatory syndrome on progression from functional impairment to “frailty” status and substantial disability in aging chronic obstructive pulmonary disease. Keywords: COPD, chronic airflow obstruction, aging, mediation analysis

Buccal fat pads are biconvex adipose tissue bags that are uniquely found on both sides of the human face along the anterior border of the masseter muscles. Buccal fat pads are important determinants of facial appearance, facilitating gliding movements of facial masticatory and mimetic muscles. Buccal fad pad flaps are used for the repair of oral defects and as a rich and easily accessible source of mesenchymal stem cells. Here, we introduce the buccal fat pad anatomy and morphology and report its functions and applications for oral reconstructive surgery and for harvesting mesenchymal stem cells for clinical use. Future frontiers of buccal fat pad research are discussed. It is concluded that many biological and molecular aspects still need to be elucidated for the optimal application of buccal fat pad tissue in regenerative medicine.

Atherosclerosis represents one of the main risk factors for the development of cardiovascular diseases. Their etiologies have been studied in recent years in order to better define therapeutic targets for intervention and to identify diagnostic methods. Two different subtypes of macrophages, M1 and M2, have been described in physiological conditions. They can also be found in the atherosclerotic process, where they both have opposite roles in disease progression. Perivascular brown adipose tissue is also involved in inflammation and endothelial damage. In this work, we provide insights into the protective role of melatonin in the atherosclerotic process by morphological and 18F-FDG-PET/CT analyses. In particular, we examined the effects of melatonin on pathways that are linked to atherosclerosis development. We showed that melatonin, by suppressing M1 activity, reduced inflammation and directed macrophage polarization toward the M2 macrophage subtype. Moreover, melatonin preserved the activity of perivascular brown adipose tissue. In addition, 18F-FDG uptake is very high in mice treated with melatonin, confirming that other factors may alter 18F-FDG distribution. In conclusion, we showed that melatonin affects inflammatory pathways that have been linked to atherosclerosis, assessed the relationships of the 18F-FDG PET/CT parameters with macrophage markers and the production of their cytokines, which that have been defined by morphological evaluations.

Robot abuse encompasses a range of actions enacted by users against robots that resemble aggressive actions enacted by humans against each other. Research in this area faces numerous challenges due to ethical concerns and methodological limitations. Despite preliminary indications of robot abuse, most people are still not personally familiar with robots but hold collective imaginaries promoted by science fiction. Little is known about how abuse will manifest in practice, and research is in dire need of operational and theoretical definitions. As a response, this paper applies theory-driven speculative design to collect imaginaries of robot abuse with a sample of university students (N = 69). The inductive analysis revealed four behavioural patterns (Outburst, Clash, Oppression, and Rebellion) that were then operationalised in the orthogonal space defined by the Function of Aggression (reactive vs. proactive) and Robot Identity (object vs. subject). We ground the Space of Robot Abuse on the General Aggression Model and a sociotechnical definition of robots, provide a method for designing storyboards and evaluate them. We conclude by advancing a sociotechnical definition of robot abuse, which could interest researchers and designers alike. [ABSTRACT FROM AUTHOR]

Respiratory infections, including tuberculosis, constitute a major global health challenge. Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains one of the leading causes of mortality worldwide. The disease's complexity is attributed to Mtb's capacity to persist in latent states, evade host immune defenses, and develop resistance to antimicrobial treatments, posing significant challenges for diagnosis and therapy. Traditional models, such as animal studies and two-dimensional (2D) in vitro systems, often fail to accurately recapitulate human-specific immune processes, particularly the formation of granulomas—a defining feature of tubercular infection. These limitations underscore the need for more physiologically relevant models to study TB pathogenesis. Emerging three-dimensional (3D) in vitro systems, including organoids and lung-on-chip platforms, offer innovative approaches to mimic the structural and functional complexity of the human lung. These models enable the recreation of key aspects of the tubercular granulomas, such as cellular interactions, oxygen gradients, and nutrient limitations, thereby providing deeper insights into Mtb pathogenesis. This review aims to elucidate the advantages of 3D in vitro systems in bridging the translational gap between traditional experimental approaches and clinical applications. Particular emphasis is placed on their potential to address challenges related to genetic variability in both the host and pathogen, thereby advancing tubercular research and therapeutic development. [ABSTRACT FROM AUTHOR]

Orofacial pain represents one of the most common health problems that negatively affects the activities of daily living. However, the mechanisms underlying these conditions are still unclear, and their comprehensive management is often lacking. Moreover, even if pain is a common symptom in dentistry, differential diagnostic procedures are needed to exclude other pain origins. Misinterpretation of the pain origin, in fact, can lead to misdiagnosis and to subsequent mismanagement. Pain in the orofacial area is the most common reason for patients to visit the dentist, but this area is complex, and the pain could be associated with the hard and soft tissues of the head, face, oral cavity, or to a dysfunction of the nervous system. Considering that the origins of orofacial pain can be many and varied, a thorough assessment of the situation is necessary to enable the most appropriate diagnostic pathway to be followed to achieve optimal clinical and therapeutic management.

Autism spectrum disorders (ASDs) are a pool of neurodevelopment disorders in which social impairment is the main symptom. Presently, there are no definitive medications to cure the symptoms but the therapeutic strategies that are taken ameliorate them. The purpose of this study was to investigate the effects of melatonin (MLT) in treating ASDs using an autistic mouse model BTBR T+Itpr3tf/J (BTBR). We evaluated the hepatic cytoarchitecture and some markers of autophagy, ferritinophagy/ferroptosis, in BTBR mice treated and not-treated with MLT. The hepatic morphology and the autophagy and ferritinophagy/ferroptosis pathways were analyzed by histological, immunohistochemical, and Western blotting techniques. We studied p62 and microtubule-associated protein 1 light chain 3 B (LC3B) for evaluating the autophagy; nuclear receptor co-activator 4 (NCOA4) and long-chain-coenzyme synthase (ACSL4) for monitoring ferritinophagy/ferroptosis. The liver of BTBR mice revealed that the hepatocytes showed many cytoplasmic inclusions recognized as Mallory–Denk bodies (MDBs); the expression and levels of p62 and LC3B were downregulated, whereas ACSL4 and NCOA4 were upregulated, as compared to control animals. MLT administration to BTBR mice ameliorated liver damage and reduced the impairment of autophagy and ferritinophagy/ferroptosis. In conclusion, we observed that MLT alleviates liver damage in BTBR mice by improving the degradation of intracellular MDBs, promoting autophagy, and suppressing ferritinophagy/ferroptosis. [ABSTRACT FROM AUTHOR]

Microbial exopolymers are gaining attention as sources for the development of biodegradable materials. Milk kefir, a fermented dairy product produced by a symbiotic community of microorganisms, generates milk kefir grains as a by-product, consisting of the polysaccharide kefiran and proteins. This study develops two materials, one from whole milk kefir grains and another from purified kefiran. Film-forming dispersions were subjected to ultrasonic homogenisation and thermal treatment, yielding homogeneous dispersions. Kefiran dispersion exhibited lower pseudoplastic behaviour and higher viscous consistency, with minimal effects from glycerol. Both films exhibited continuous and homogeneous microstructures, with kefiran films being transparent and milk kefir films displaying a yellowish tint. Analysis revealed that milk kefir films comprised approximately 30% proteins and 70% kefiran. Kefiran films demonstrated stronger interpolymeric interactions, as evidenced using thermogravimetric and mechanical tests. Glycerol increased hydration while decreasing thermal stability, glass transition temperature, elastic modulus, and tensile strength in both films. However, in kefiran films, elongation at the break and water vapour permeability decreased at low glycerol content, followed by an increase at higher plasticiser contents. This suggests an unusual interaction between glycerol and kefiran in the absence of proteins. These findings underscore differences between materials derived from the whole by-product and purified kefiran, offering insights into their potential applications. [ABSTRACT FROM AUTHOR]

Buccal fat pads are biconvex adipose tissue bags that are uniquely found on both sides of the human face along the anterior border of the masseter muscles. Buccal fat pads are important determinants of facial appearance, facilitating gliding movements of facial masticatory and mimetic muscles. Buccal fad pad flaps are used for the repair of oral defects and as a rich and easily accessible source of mesenchymal stem cells. Here, we introduce the buccal fat pad anatomy and morphology and report its functions and applications for oral reconstructive surgery and for harvesting mesenchymal stem cells for clinical use. Future frontiers of buccal fat pad research are discussed. It is concluded that many biological and molecular aspects still need to be elucidated for the optimal application of buccal fat pad tissue in regenerative medicine. [ABSTRACT FROM AUTHOR]

Bone regenerative medicine is a clinical approach combining live osteoblast progenitors, such as mesenchymal stromal cells (MSCs), with a biocompatible scaffold that can integrate into host bone tissue and restore its structural integrity. Over the last few years, many tissue engineering strategies have been developed and thoroughly investigated; however, limited approaches have been translated to clinical application. Consequently, the development and clinical validation of regenerative approaches remain a centerpiece of investigational efforts towards the clinical translation of advanced bioengineered scaffolds. The aim of this review was to identify the latest clinical trials related to the use of scaffolds with or without MSCs to regenerate bone defects. A revision of the literature was performed in PubMed, Embase, and Clinicaltrials.gov from 2018 up to 2023. Nine clinical trials were analyzed according to the inclusion criteria: six presented in the literature and three reported in Clinicaltrials.gov. Data were extracted covering background trial information. Six of the clinical trials added cells to scaffolds, while three used scaffolds alone. The majority of scaffolds were composed of calcium phosphate ceramic alone, such as β-tricalcium phosphate (TCP) (two clinical trials), biphasic calcium phosphate bioceramic granules (three clinical trials), and anorganic bovine bone (two clinical trials), while bone marrow was the primary source of the MSCs (five clinical trials). The MSC expansion was performed in GMP facilities, using human platelet lysate (PL) as a supplement without osteogenic factors. Only one trial reported minor adverse events. Overall, these findings highlight the importance and efficacy of cell–scaffold constructs in regenerative medicine under different conditions. Despite the encouraging clinical results obtained, further studies are needed to assess their clinical efficacy in treating bone diseases to optimize their application.

Aging is characterized by a progressive deterioration in physiological functions and metabolic processes. The loss of cells during aging in vital tissues and organs is related to several factors including oxidative stress and inflammation. Skeletal muscle degeneration is common in elderly people; in fact, this tissue is particularly vulnerable to oxidative stress since it requires large amounts of oxygen, and thus, oxidative damage is abundant and accumulates with increasing age. Melatonin (N-acetyl-5-methoxytryptamine) is a highly efficient scavenger of reactive oxygen species and it also exhibits beneficial anti-inflammatory and anti-aging effects. This study investigated the susceptibility of rat L6 skeletal muscle cells to an induced oxidative stress following their exposure to hydrogen peroxide (50 μM) and evaluating the potential protective effects of pre-treatment with melatonin (10 nM) compared to the known beneficial effect of alpha-lipoic acid (300 μM). Hydrogen peroxide-induced obvious oxidative stress; it increased the expression of tumour necrosis factor-alpha and in turn promoted nuclear factor kappa-B and overrode the endogenous defence mechanisms. Conversely, pre-treatment of the hydrogen peroxide-exposed cells to melatonin or alpha-lipoic acid increased endogenous antioxidant enzymes, including superoxide dismutase-2 and heme oxygenase-1; moreover, they ameliorated significantly oxidative stress damage and partially reduced alterations in the muscle cells, which are typical of aging. In conclusion, melatonin was equally effective as alpha-lipoic acid; it exhibited marked antioxidant and anti-aging effects at the level of skeletal muscle in vitro even when it was given in a much lower dose than alpha-lipoic acid.

The skin is considered the most important organ system in mammals, and as the population ages, it is important to consider skin aging and anti-aging therapeutic strategies. Exposure of the skin to various insults induces significant changes throughout our lives, differentiating the skin of a young adult from that of an older adult. These changes are caused by a combination of intrinsic and extrinsic aging. We report the interactions between skin aging and its metabolism, showing that the network is due to several factors. For example, iron is an important nutrient for humans, but its level increases with aging, inducing deleterious effects on cellular functions. Recently, it was discovered that ferroptosis, or iron-dependent cell death, is linked to aging and skin diseases. The pursuit of new molecular targets for ferroptosis has recently attracted attention. Prevention of ferroptosis is an effective therapeutic strategy for the treatment of diseases, especially in old age. However, the pathological and biological mechanisms underlying ferroptosis are still not fully understood, especially in skin diseases such as melanoma and autoimmune diseases. Only a few basic studies on regulated cell death exist, and the challenge is to turn the studies into clinical applications. [ABSTRACT FROM AUTHOR]

Objective: NOV/CCN3 is an adipocytokine recently linked to obesity, insulin resistance, and cardiometabolic dysfunction. NOV is manufactured and secreted from adipose tissue, with blood levels highly correlated with BMI. NOV levels are increased in obesity and a myriad of inflammatory diseases. Elevated NOV levels cause oxidative stress by increasing free radicals, decreasing antioxidants, and decreasing heme oxygenase (HO-1) levels, resulting in decreased vascular function. Silencing NOV in NOV knockout mice improved insulin sensitivity. We wanted to study how suppressing NOV expression in an obese animal model affected pathways and processes related to obesity, inflammation, and cardiometabolic function. This is the first study to investigate the interaction of adipose tissue-specific NOV/CCN3 and cardiometabolic function. Methods: We constructed a lentivirus containing the adiponectin-promoter-driven shNOV to examine the effect of NOV inhibition (shNOV) in adipose tissue on the heart of mice fed a high-fat diet. Mice were randomly divided into three groups (five per group): (1) lean (normal diet), (2) high-fat diet (HFD)+ sham virus, and (3) HFD + shNOV lentivirus. Blood pressure, tissue inflammation, and oxygen consumption were measured. Metabolic and mitochondrial markers were studied in fat and heart tissues. Results: Mice fed an HFD developed adipocyte hypertrophy, fibrosis, inflammation, and decreased mitochondrial respiration. Inhibiting NOV expression in the adipose tissue of obese mice by shNOV increased mitochondrial markers for biogenesis (PGC-1α, the nuclear co-activator of HO-1) and functional integrity (FIS1) and insulin signaling (AKT). The upregulation of metabolic and mitochondrial markers was also evident in the hearts of the shNOV mice with the activation of mitophagy. Using RNA arrays, we identified a subgroup of genes that highly correlated with increased adipocyte mitochondrial autophagy in shNOV-treated mice. A heat map analysis in obese mice confirmed that the suppression of NOV overrides the genetic susceptibility of adiposity and the associated detrimental metabolic changes and correlates with the restoration of anti-inflammatory, thermogenic, and mitochondrial genes. Conclusion: Our novel findings demonstrate that inhibiting NOV expression improves adipose tissue function in a positive way in cardiometabolic function by inducing mitophagy and improving mitochondrial function by the upregulation of PGC-1α, the insulin sensitivity signaling protein. Inhibiting NOV expression increases PGC-1, a key component of cardiac bioenergetics, as well as key signaling components of metabolic change, resulting in improved glucose tolerance, improved mitochondrial function, and decreased inflammation. These metabolic changes resulted in increased oxygen consumption, decreased adipocyte size, and improved cardiac metabolism and vascular function at the structural level. The crosstalk of the adipose tissue-specific deletion of NOV/CCN3 improved cardiovascular function, representing a novel therapeutic strategy for obesity-related cardiometabolic dysfunction.

The involvement of platelets in immune and inflammatory processes is generally recognized; nevertheless, in psoriasis, their role is not clearly understood. We studied the in vitro growth factor release from a platelet-rich plasma preparation, the concentrated growth factors (CGF), in a case of a psoriasis subject three days before the onset of the papule. The CGF clots were incubated in a cell culture medium without growth supplements for 5 h and 1, 3, 6, 7, and 8 days, and the release kinetics of PDGF-AB, VEGF, TNF-α, and TGF-β1 were evaluated. The data, based on the results obtained during the case study, report a general increase in growth factor release in the psoriasis subject with respect to the healthy control, indicating an imbalance of growth factor production from blood cells. Although the results should be validated in the future, they show new aspects of this dermatological pathology, opening new possibilities both as the method of study, using CGF, and the involvement of platelets and growth factors in its development and maintenance.

The collection of studies in this Special Issue, “The Role of Antioxidant Molecules and Melatonin in Cellular Protection”, published in Antioxidants (accessed on 30 April 2021; https://www [...]

During implant restorative dentistry, common and crippling postoperative complications are pain and swelling of perioral soft tissues which engraving on patient quality of life. Concentrated growth factors (CGF), a novel generation of autologous platelet concentrate, and melatonin, endogenous indoleamine with also bone regenerative properties, may be useful for reconstruction of bony defects as well as in prosthetic and esthetic rehabilitation. We report a clinical case in which guided bone regeneration was performed combining CGF, melatonin and heterologous biomaterial. Great postoperative recovery without any complications was reported. In conclusion, in restorative dentistry the combined use of CGF and melatonin may have important roles in restoring bone defect, in improving implant osteointegration and, not less important, in preventing postoperative complications.

The juxtaoral organ was first described 1885 as a rudimentary structure that developed and disappeared in the embryonic period. Since then, it has been studied further and is now known to be a permanent anatomical structure of considerable importance in clinical, surgical and pathological fields. However, there are no precise and uniform descriptions about its anatomical localization and functional significance. Precise and in-depth anatomical knowledge is crucial to reducing the risk of incorrect identification of the juxtaoral organ, due to fact that this anatomical structure can be misinterpreted as a carcinoma, leading to unnecessary treatments. Therefore, the purpose of this review is to summarize the actual knowledge on the gross and microscopic anatomy of the juxtaoral organ and outline its clinical relevance in order to prevent unnecessary investigations/treatments of this anatomical pitfall. We believe that further studies are still needed to add new perspectives in relation to the juxtaoral organ.

Obesity is a worldwide epidemic disease that induces important structural and functional changes to the heart and predisposes a patient to devastating cardiac complications. Sirtuin1 (SIRT1) has been found to have roles in regulating cardiac function, but whether it can help in cardioprotection is not clear. The aim of the present study was to determine whether melatonin, by modulating SIRT1 and in turn mitochondria signaling, may alleviate obesity-induced cardiac injuries. We investigated 10 lean control mice and 10 leptin-deficient obese mice (ob/ob) orally supplemented with melatonin for 8 weeks, as well as equal numbers of age-matched lean and ob/ob mice that did not receive melatonin. Hearts were evaluated using multiple parameters, including biometric values, morphology, SIRT1 activity and expression of markers of mitochondria biogenesis, oxidative stress, and inflammation. We observed that ob/ob mice experienced significant heart hypertrophy, infiltration by inflammatory cells, reduced SIRT1 activity, altered mitochondrial signaling and oxidative balance, and overexpression of inflammatory markers. Notably, melatonin supplementation in ob/ob mice reverted these obesogenic heart alterations. Melatonin prevented heart remodeling caused by obesity through SIRT1 activation, which, together with mitochondrial pathways, reduced oxidative stress and inflammation. [ABSTRACT FROM AUTHOR]