Search Results (6)

The gut-brain axis (GBA) represents an operant acting in a two-direction communication system between the gastrointestinal tract and the central nervous system, mediated by the enteric nervous system (ENS), vagus nerve, immune pathways, and endocrine signaling. In recent years, evidence has highlighted the pivotal role of the gut microbiota in modulating this axis, forming the microbiota-gut-brain axis (MGBA). Our review synthesizes current knowledge on the anatomical and functional substrates of gut-brain communication, focusing on interoceptive signaling, the roles of intrinsic primary afferent neurons (IPANs) and enteroendocrine cells (EECs) and the influence of microbial metabolites, including short-chain fatty acids (SCFAs), bile acids, and indoles. These agents modulate neurotransmission, epithelial barrier function, and neuroimmune interactions. The vagus nerve serves as a primary pathway for afferent sensory signaling from the gut influenced indirectly by the ENS and microbiota. Dysbiosis has been associated with altered gut-brain signaling and implicated in the pathophysiology of disorders ranging from irritable bowel syndrome to mood disorders and neurodegeneration. Microbial modulation of host gene expression via epigenetic mechanisms, including microRNAs, adds another layer of complexity. The gut has a crucial role as an active sensory and signaling organ capable of influencing higher-order brain functions. Understanding the MGBA has significant implications for new therapeutic interventions targeting the microbiome to manage neurogastroenterological and even neuropsychiatric conditions. Full article

The expanded newborn screening (NBS) program in the Russian Federation was initiated in 2023, among which severe combined immunodeficiency (SCID) is screened using TREC/KREC assays. Here, we report a rare case of a TP63-associated disease identified through this NBS program. Dried blood spots from newborns were initially screened for TREC/KREC levels, and those with values below the cut-off underwent confirmatory testing and further genetic analysis, including whole-exome sequencing (WES). A male newborn was identified with significantly reduced TREC values, indicative of T cell lymphopenia. Genetic analysis revealed a heterozygous NM_003722.5:c.1027C>T variant in TP63, leading to the p.(Arg343Trp) substitution within the DNA binding domain. This mutation has been previously associated with Ectrodactyly–Ectodermal Dysplasia–Cleft lip/palate syndrome (EEC) syndrome and shown to reduce the transactivation activity of TP63 in a dominant-negative manner. This case represents one of the few instances of immune system involvement in a patient with a TP63 mutation, highlighting the need for further investigation into the immunological aspects of TP63-associated disorders. Our findings suggest that comprehensive immunological evaluation should be considered for patients with TP63 mutations to better understand and manage potential immune dysfunctions. Full article

Background/Aims: The Ectrodactyly-Ectodermal dysplasia-Clefting (EEC) and Ankyloblepharon–ectodermal defect–cleft lip/palate (AEC) syndromes are rare autosomal dominant diseases caused by heterozygous mutations in the p63 gene. Patients are characterized by abnormalities of the skin, teeth, and hair and have limb defects, orofacial clefting and ectodermal dysplasia. In addition, they often show ocular surface alterations, leading to progressive corneal clouding and eventually blindness. Here, we present 8 cases describing patients affected by EEC (n = 6, with 5 sporadic and 1 familial cases) and AEC (n = 2, both sporadic cases) syndromes. We attempt to provide a description of the ocular disease progression over the years. Methods: Clinical examinations and monitoring of ocular parameters for the assessment of limbal stem cell deficiency were constantly performed on patients between 2009 and 2023. Quantitative data and comparison with existing cases described in the literature are reported. Results: The therapies supplied to patients were essential for the management of the symptoms, but unfortunately did not halt the progression of the pathology. Conclusions: A constant monitoring of the patients would help avoid the sudden worsening of symptoms. If the progression of the disease slows down, it would allow for the development of newer therapeutic strategies aimed at correcting the genetic defect. Full article

Ectrodactyly-Ectodermal dysplasia-Clefting (EEC) syndrome is caused by heterozygous missense point mutations in the p63 gene, an important transcription factor during embryogenesis and for stem cell differentiation in stratified epithelia. Most of the cases are sporadic, related to de novo mutations arising during early-stage development. Familial cases show an autosomic dominant inheritance. The major cause of visual morbidity is limbal stem cell failure, which develops in the second to third decade of life. Patients often show ocular surface alterations, such as recurrent blepharitis and conjunctivitis, superficial microlesions of the cornea, and spontaneous corneal perforation and ulceration, leading to progressive corneal clouding and eventually visual loss. No definitive cures are currently available, and treatments to alleviate symptoms are only palliative. In this review, we will discuss the proposed therapeutic strategies that have been tested or are under development for the management of the ocular defects in patients affected by EEC syndrome: (i) gene therapy-based approaches by means of Allele-Specific (AS) siRNAs to correct the p63 mutations; (ii) cell therapy-based approaches to replenish the pool of limbal stem cells; and (iii) drug therapy to correct/bypass the genetic defect. However, as the number of patients with EEC syndrome is too limited, further studies are still necessary to prove the effectiveness (and safety) of these innovative therapeutic approaches to counteract the premature differentiation of limbal stem cells. Full article

The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the DNA binding domain cause Ectrodactyly, Ectodermal Dysplasia, characterized by limb deformation, cleft lip/palate, and ectodermal dysplasia while mutations in in the C-terminal domain of the α-isoform cause Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility, severe, long-lasting skin erosions, and cleft lip/palate. The molecular disease mechanisms of these syndromes have recently become elucidated and have enhanced our understanding of the role of p63 in epidermal development. Here we review the molecular cause and functional consequences of these p63-mutations for skin development and discuss the consequences of p63 mutations for female fertility. Full article

Influenza virus infections can lead to viral pneumonia and acute respiratory distress syndrome in severe cases, causing significant morbidity and mortality and posing a great threat to human health. Because of the diversity of influenza virus strains and drug resistance to the current direct antiviral agents, there have been no effective drugs as yet to cure all patients infected by influenza viruses. Natural products from plants contain compounds with diverse structures that have the potential to interact with multiple host and virus factors. In this study, we identified the ethanol extract of Caesalpinia decapetala (Roth) Alston (EEC) as an inhibitor against the replication of a panel of influenza A and B viruses both on human pulmonary epithelial A549 and human monocytic U937 cells. The animal study revealed that EEC administration reduces the weight loss and improves the survival rate of mice infected with lethal influenza virus. Also, EEC treatment attenuated lung injury and reduced virus titer significantly. In conclusion, we showed that EEC has antiviral activity both in vitro and in vivo, suggesting that the plant C. decapetala has the potential to be further developed as a resource of new anti-influenza drugs. Full article