Search

During cardiac differentiation, numerous factors contribute to the development of the heart. Understanding the molecular mechanisms underlying cardiac development will help combat cardiovascular disorders, among the leading causes of morbidity and mortality worldwide. Among the main mechanisms, we indeed find Cripto. Cripto is found in both the syncytiotrophoblast of ampullary pregnancies and the inner cell mass along the primitive streak as the second epithelial-mesenchymal transformation event occurs to form the mesoderm and the developing myocardium. At the same time, it is now known that cardiac signaling pathways are intimately intertwined with the expression of myomiRNAs, including miR-1. This miR-1 is one of the muscle-specific miRs; aberrant expression of miR-1 plays an essential role in cardiac diseases. Given this scenario, our study aimed to evaluate the inverse correlation between Cripto and miR-1 during heart development. We used in vitro models of the heart, represented by embryoid bodies (EBs) and embryonic carcinoma cell lines derived from an embryo-derived teratocarcinoma in mice (P19 cells), respectively. First, through a luciferase assay, we demonstrated that Cripto is a target of miR-1. Following this result, we observed that as the days of differentiation increased, the Cripto gene expression decreased, while the level of miR-1 increased; furthermore, after silencing miR-1 in P19 cells, there was an increase in Cripto expression. Moreover, inducing damage with a cobra cardiotoxin (CTX) in post-differentiation cells, we noted a decreased miR-1 expression and increased Cripto. Finally, in mouse cardiac biopsies, we observed by monitoring gene expression the distribution of Cripto and miR-1 in the right and left ventricles. These results allowed us to detect an inverse correlation between miR-1 and Cripto that could represent a new pharmacological target for identifying new therapies.

Background: Childhood obesity (CO) is a serious medical condition affecting approximately 120 million children and adolescents worldwide. It is characterized by a persistent inflammatory state with inflammatory markers overexpressed, which in turn leads to a higher cardiovascular risk. It is well known that physical exercise reduces the inflammatory state in obese children. In the present study, we evaluated various biochemical parameters in obese children performing physical exercise compared to a group of obese sedentary children. Hence, the objective is to identify a panel of biomarkers to prevent numerous obesity-related complications. Methods: We examined two populations: 44 sedentary obese children (OSe), recruited on 5 November 2018 from Santobono−Pausilipon Children’s Hospital, Naples (Italy) of age = 11 ± 3.3 and 30 obese children who practice sport (OSp) of age = 10 ± 2.5. We observed a significant variation in some biochemical parameters such as white blood cells, C-reactive protein (CRP), glycemia and insulinemia. Moreover, we determined the levels of interleukins, chemokines and defensins by ELISA assay. Results: Our results showed a reduction in serum level of glycemia (p-value < 0.001), neutrophils (p-value < 0.05) and CRP (p-value < 0.05), whereas no relevant variations have been reported in insulin levels. Moreover, we found a decrease in serum levels of PDGF-β (p-value < 0.05), IL-9 (p-value < 0.01), IL-6 (p-value < 0.0001), IL-8 (p-value < 0.0001), IP-10 (p-value < 0.01), Eotaxin (p-value < 0.0001) and GM-CSF (p-value < 0.01) in OSp population in comparison to OSe. At the same time, we did not observe any significant variation in serum levels of IL-1ra and IL-17 between the two populations. On the other hand, we found an increase in HNP-1 (p-value < 0.0001) and HBD1 (p-value < 0.01) in OSp if compared to OSe. Conclusions: This study shed light on the role of physical exercise on CO, demonstrating in our population that an early evaluation of some biochemical parameters could be an assumption to prescribe physical exercise in order to monitor and prevent childhood obesity and related disorders.

Preeclampsia is a leading cause of perinatal maternal-foetal mortality and morbidity. This study aims to identify the key microRNAs (miRNA) in preeclampsia and uncover their potential functions. We downloaded the miRNA expression profile of GSE119799 for plasma and GSE177049 for the placenta. Each dataset consisted of five patients (PE) and five controls (N). From a technical point of view, we analysed the counts per million (CPM) for both datasets, highlighting 358 miRNAs in common, 78 unique for plasma and 298 unique for placenta. At the same time, we performed an expression differential analysis (|logFC| ≥ 1|and FDR ≤ 0.05) to evaluate the biological impact of the miRNAs. This approach allowed us to highlight 321 miRNAs in common between plasma and placenta, within which four were upregulated in plasma. Furthermore, the same analysis revealed five miRNAs expressed exclusively in plasma; these were also upregulated. In conclusion, the in-depth bioinformatics analysis conducted during our study will allow us, on the one hand, to verify the targets of each of the nine identified miRNAs; on the other hand, to use them both as new non-invasive biomarkers and as therapeutic targets for the development of personalised treatments.

Pregnancy is characterized by significant immunological changes and a cytokine profile, as well as vitamin deficiencies that can cause problems for the correct development of a fetus. Defensins are small antimicrobial peptides that are part of the innate immune system and are involved in several biological activities. Following that, this study aims to compare the levels of various cytokines and to investigate the role of defensins between pregnant women with confirmed COVID-19 infection and pregnant women without any defined risk factor. TNF-α, TGF-β, IL-2 and IL-10, β-defensins, have been evaluated by gene expression in our population. At the same time, by ELISA assay IL-6, IL-8, defensin alpha 1, defensin beta 1 and defensin beta 4 have been measured. The data obtained show that mothers affected by COVID-19 have an increase in pro-inflammatory factors (TNF-α, TGF-β, IL-2, IL-6, IL-8) compared to controls; this increase could generate a sort of "protection of the fetus" from virus attacks. Contemporarily, we have an increase in the anti-inflammatory cytokine IL-10 and an increase in AMPs, which highlights how the mother's body is responding to the viral attack. These results allow us to hypothesize a mechanism of "trafficking" of antimicrobial peptides from the mother to the fetus that would help the fetus to protect itself from the infection in progress.

Aberrant signaling in myeloproliferative neoplasms may arise from alterations in genes coding for signal transduction proteins or epigenetic regulators. Both mutated and normal cells cooperate, altering fragile balances in bone marrow niches and fueling persistent inflammation through paracrine or systemic signals. Despite the hopes placed in targeted therapies, myeloid proliferative neoplasms remain incurable diseases in patients not eligible for stem cell transplantation. Due to the emergence of drug resistance, patient management is often very difficult in the long term. Unexpected connections among signal transduction pathways highlighted in neoplastic cells suggest new strategies to overcome neoplastic cell adaptation.

Physical activity, combined with adequate nutrition, is considered a protective factor against cardiovascular disease, musculoskeletal disorders, and intestinal dysbiosis. Achieving optimal performance requires a significantly high energy expenditure, which must be correctly supplied to avoid the occurrence of diseases such as muscle injuries, oxidative stress, and heart pathologies, and a decrease in physical performance during competition. Moreover, in sports activities, the replenishment of water, vitamins, and minerals consumed during training is essential for safeguarding athletes' health. In this scenario, vitamins play a pivotal role in numerous metabolic reactions and some muscle biochemical adaptation processes induced by sports activity. Vitamins are introduced to the diet because the human body is unable to produce these micronutrients. The aim of this review is to highlight the fundamental role of vitamin supplementation in physical activity. Above all, we focus on the roles of vitamins A, B6, D, E, and K in the prevention and treatment of cardiovascular disorders, muscle injuries, and regulation of the microbiome.

Background: Treatment of myocardial ischemia/reperfusion (IR) injury is still an unmet clinical need. A large variability of remote ischemic conditioning (RIC) protection has been reported; however, no studies have considered the temperature of the ischemic limb. We analyzed the effects of temperature on RIC protection., Methods: Left hind-limbs of anesthetized male mice were immersed in warm (40 °C, warm-RIC) or cold (20 °C, cold-RIC) water and subjected to a RIC protocol (4 × 5 min limb ischemia/reperfusion). In the control groups (warm-CTR or cold-CTR), the limbs underwent thermic conditions only. Isolated hearts underwent 30 min ischemia and 60 min reperfusion. A PI3K-inhibitor, LY294002 (5 µM), was infused in warm-RIC hearts before the IR protocol (warm-RIC LY). Infarct size was evaluated by nitro blue tetrazolium staining and expressed as the percent of risk area., Results: While cold-RIC did not reduce the infarct size compared to cold-CTR (51 ± 1.62% vs. 54 ± 1.07% of risk area, p =NS), warm-RIC (44 ± 1.13%) significantly reduced the infarct size with respect to either cold-RIC ( p <0.001) or warm-CTR (58 ± 1.41%, p <0.0001). LY294002 infusion revealed the PI3K/Akt involvement in the warm-RIC protection. Infarct size reduction was abrogated by LY294002 pretreatment (warm-RIC: 44 ± 1.13% vs. warm-CTR 58 ± 1.41% p <0.0001; vs. warm-RIC LY 54 ± 1.69% p =0.0002)., Conclusion: our study shows a remarkable difference between warm-RIC and cold-RIC in terms of infarct size reduction, supporting a pivotal role for limb temperature in RIC-induced cardioprotection.

Coronaviruses (CoVs) are a large family of respiratory viruses that can cause mild to moderate illness. The new variant COVID-19 has started to spread rapidly since December 2019, posing a new threat to global health. To counter the spread of the virus, the Italian government forced the population to close all activities starting from 9 March 2020 to 4 May 2020. In this scenario, we conducted a cross-sectional study on a heterogeneous sample (average age of 28 ± 12 years, 62.6% females) of the University of Naples Federico II (Italy). The aim of the study was to describe the lifestyle change in the university population during quarantine for the COVID 19 pandemic. Participants compiled an online survey consisting of 3 sections: socio-demographic data, dietary behaviours, physical activity habits and psychological aspects. The different results by gender are: 90.8% of females continued to work from home (81.9% were students); 34.8% increased their physical activity; and, only 0.8% prefer ready meals. Whereas, the same percentage of men continued to work from home (90%), but only 72.1% were students ( p < 0.001 vs. females), only 23.9% increased physical activity ( p < 0.001) and 1.7% favous ready meals. Our data shows that the male population was more affected by isolation and quarantine reporting more unfavourable behavioural changes.

Coronaviruses (CoVs) represent a large family of RNA viruses that can infect different living species, posing a global threat to human health. CoVs can evade the immune response, replicate within the host, and cause a rapid immune compromise culminating in severe acute respiratory syndrome. In humans, the immune system functions are influenced by physical activity, nutrition, and the absence of respiratory or cardiovascular diseases. This review provides an in-depth study between the interactions of the immune system and coronaviruses in the host to defend against CoVs disease.

The loss of muscle mass and force characterizes muscle atrophy in several different conditions, which share the expression of atrogenes and the activation of their transcriptional regulators. However, attempts to antagonize muscle atrophy development in different experimental contexts by targeting contributors to the atrogene pathway showed partial effects in most cases. Other master regulators might independently contribute to muscle atrophy, as suggested by our recent evidence about the co-requirement of the muscle-specific chaperone protein melusin to inhibit unloading muscle atrophy development. Furthermore, melusin and other muscle mass regulators, such as nNOS, belong to costameres, the macromolecular complexes that connect sarcolemma to myofibrils and to the extracellular matrix, in correspondence with specific sarcomeric sites. Costameres sense a mechanical load and transduce it both as lateral force and biochemical signals. Recent evidence further broadens this classic view, by revealing the crucial participation of costameres in a sarcolemmal "signaling hub" integrating mechanical and humoral stimuli, where mechanical signals are coupled with insulin and/or insulin-like growth factor stimulation to regulate muscle mass. Therefore, this review aims to enucleate available evidence concerning the early involvement of costamere components and additional putative master regulators in the development of major types of muscle atrophy.

Moderate exercise combined with proper nutrition are considered protective factors against cardiovascular disease and musculoskeletal disorders. However, physical activity is known not only to have positive effects. In fact, the achievement of a good performance requires a very high oxygen consumption, which leads to the formation of oxygen free radicals, responsible for premature cell aging and diseases such as heart failure and muscle injury. In this scenario, a primary role is played by antioxidants, in particular by natural antioxidants that can be taken through the diet. Natural antioxidants are molecules capable of counteracting oxygen free radicals without causing cellular cytotoxicity. In recent years, therefore, research has conducted numerous studies on the identification of natural micronutrients, in order to prevent or mitigate oxidative stress induced by physical activity by helping to support conventional drug therapies against heart failure and muscle damage. The aim of this review is to have an overview of how controlled physical activity and a diet rich in antioxidants can represent a "natural cure" to prevent imbalances caused by free oxygen radicals in diseases such as heart failure and muscle damage. In particular, we will focus on sulfur-containing compounds that have the ability to protect the body from oxidative stress. We will mainly focus on six natural antioxidants: glutathione, taurine, lipoic acid, sulforaphane, garlic and methylsulfonylmethane.

Acute or intense exercise is sometimes related to infections of the urinary tract. It can also lead to incorrect hydration as well as incorrect glomerular filtration due to the presence of high-molecular-weight proteins that cause damage to the kidneys. In this context, our study lays the foundations for the use of a urine test in a team of twelve male basketball players as a means of monitoring numerous biochemical parameters, including pH, specific weight, color, appearance, presence of bacterial cells, presence of squamous cells, leukocytes, erythrocytes, proteins, glucose, ketones, bilirubin, hemoglobin, nitrite, and leukocyte esterase, to prevent and/or treat the onset of pathologies, prescribe personalized treatments for each athlete, and monitor the athletes' health status.

Tumor suppressors play an important role in cancer pathogenesis and in the modulation of resistance to treatments. Loss of function of the proteins encoded by tumor suppressors, through genomic inactivation of the gene, disable all the controls that balance growth, survival, and apoptosis, promoting cancer transformation. Parallel to genetic impairments, tumor suppressor products may also be functionally inactivated in the absence of mutations/deletions upon post-transcriptional and post-translational modifications. Because restoring tumor suppressor functions remains the most effective and selective approach to induce apoptosis in cancer, the dissection of mechanisms of tumor suppressor inactivation is advisable in order to further augment targeted strategies. This review will summarize the role of tumor suppressors in chronic lymphocytic leukemia and attempt to describe how tumor suppressors can represent new hopes in our arsenal against chronic lymphocytic leukemia (CLL).

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancer types world-wide. Its high mortality is related to the difficulty in the diagnosis, which often occurs when the disease is already advanced. As of today, no early diagnostic tests are available, while only a limited number of prognostic tests have reached clinical practice. The main reason is the lack of reliable biomarkers that are able to capture the early development or the progression of the disease. Hence, the discovery of biomarkers for early diagnosis or prognosis of PDAC remains, de facto, an unmet need. An increasing number of studies has shown that cell-free DNA (cfDNA) methylation analysis represents a promising non-invasive approach for the discovery of biomarkers with diagnostic or prognostic potential. In particular, cfDNA methylation could be utilized for the identification of disease-specific signatures in pre-neoplastic lesions or chronic pancreatitis (CP), representing a sensitive and non-invasive method of early diagnosis of PDAC. In this review, we will discuss the advantages and pitfalls of cfDNA methylation studies. Further, we will present the current advances in the discovery of pancreatic cancer biomarkers with early diagnostic or prognostic potential, focusing on pancreas-specific (e.g., CUX2 or REG1A ) or abnormal (e.g., ADAMTS1 or BNC1 ) cfDNA methylation signatures in high risk pre-neoplastic conditions and PDAC.

Gamma-glutamyl transpeptidase (GGT) is a cell surface enzyme involved in glutathione metabolism and maintenance of redox homeostasis. High expression of GGT on tumor cells is associated with an increase of cell proliferation and resistance against chemotherapy. GGT inhibitors that have been evaluated in clinical trials are too toxic for human use. We have previously identified ovothiols, 5(Nπ)-methyl-thiohistidines of marine origin, as non-competitive-like inhibitors of GGT that are more potent than the known GGT inhibitor, 6-diazo-5-oxo-l-norleucine (DON), and are not toxic for human embryonic cells. We extended these studies to the desmethylated form of ovothiol, 5-thiohistidine, and confirmed that this ovothiol derivative also acts as a non-competitive-like GGT inhibitor, with a potency comparable to ovothiol. We also found that both 5-thiohistidine derivatives act as reversible GGT inhibitors compared to the irreversible DON. Finally, we probed the interactions of 5-thiohistidines with GGT by docking analysis and compared them with the 2-thiohistidine ergothioneine, the physiological substrate glutathione, and the DON inhibitor. Overall, our results provide new insight for further development of 5-thiohistidine derivatives as therapeutics for GGT-positive tumors., Competing Interests: The authors declare no conflict of interest.

Liver fibrosis is a pathophysiologic process involving the accumulation of extracellular matrix proteins as collagen deposition. Advanced liver fibrosis can evolve in cirrhosis, portal hypertension and often requires liver transplantation. At the cellular level, hepatic fibrosis involves the activation of hepatic stellate cells and their transdifferentiation into myofibroblasts. Numerous pro-fibrogenic mediators including the transforming growth factor-β1, the platelet-derived growth factor, endothelin-1, toll-like receptor 4, and reactive oxygen species are key players in this process. Knowledge of the cellular and molecular mechanisms underlying hepatic fibrosis development need to be extended to find novel therapeutic strategies. Antifibrotic therapies aim to inhibit the accumulation of fibrogenic cells and/or prevent the deposition of extracellular matrix proteins. Natural products from terrestrial and marine sources, including sulfur-containing compounds, exhibit promising activities for the treatment of fibrotic pathology. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans are largely unknown. This review aims to provide a reference collection on experimentally tested natural anti-fibrotic compounds, with particular attention on sulfur-containing molecules. Their chemical structure, sources, mode of action, molecular targets, and pharmacological activity in the treatment of liver disease will be discussed., Competing Interests: The authors declare no conflict of interest.

The gut microbiota is significantly involved in the preservation of the immune system of the host, protecting it against the pathogenic bacteria of the stomach. The correlation between gut microbiota and the host response supports human gastric homeostasis. Gut microbes may be shifted in Helicobacter pylori ( Hp )-infected individuals to advance gastric inflammation and distinguished diseases. Particularly interesting is the establishment of cooperation between gut microbiota and antimicrobial peptides (AMPs) of the host in the gastrointestinal tract. AMPs have great importance in the innate immune reactions to Hp and participate in conservative co-evolution with an intricate microbiome. β-Defensins, a class of short, cationic, arginine-rich proteins belonging to the AMP group, are produced by epithelial and immunological cells. Their expression is enhanced during Hp infection. In this review, we discuss the impact of the gut microbiome on the host response, with particular regard to β-defensins in Hp -associated infections. In microbial infections, mostly in precancerous lesions induced by Hp infection, these modifications could lead to different outcomes., Competing Interests: The authors declare no conflict of interest.

The past twenty years have witnessed the most remarkable breakthroughs in our understanding of the molecular and cellular mechanisms that underpin circadian (approximately one day) time-keeping. Across model organisms in diverse taxa: cyanobacteria ( Synecho c occ us ), fungi ( Neurospora ), higher plants ( Arabidopsis ), insects ( Drosophila ) and mammals (mouse and humans), a common mechanistic motif of delayed negative feedback has emerged as the Deus ex machina for the cellular definition of ca. 24 h cycles. This review will consider, briefly, comparative circadian clock biology and will then focus on the mammalian circadian system, considering its molecular genetic basis, the properties of the suprachiasmatic nucleus (SCN) as the principal circadian clock in mammals and its role in synchronising a distributed peripheral circadian clock network. Finally, it will consider new directions in analysing the cell-autonomous and circuit-level SCN clockwork and will highlight the surprising discovery of a central role for SCN astrocytes as well as SCN neurons in controlling circadian behaviour., Competing Interests: The authors declare no conflict of interest.