Spindle epithelial tumor with thymus-like element (SETTLE)-Report of a rare thyroid carcinoma.

Spindle epithelial tumor with thymus-like element should be included in the differential diagnosis of thyroid gland cancers, particularly in medullary carcinoma, younger patients and indolent clinical presentation, because it may influence treatment and prognosis.

Unveiling the role of taxonomic sufficiency for enhanced ecosystem monitoring.

The use of Artificial substrates (AS) as sampling devices addresses challenges in macrofaunal quantitative sampling. While effectively capturing biodiversity patterns, the time-intensitive identification process at the species level remains a substantial challenge. The Taxonomic Sufficiency approach (TS), where only taxa above species level are identified, arises as a potential solution to be tested across different environmental monitoring scenarios. In this paper, we analyzed three AS macrobenthic datasets to evaluate the odds of TS in improving the cost-effective ratio in AS monitoring studies and establish the highest resolution level to detect assemblage changes under different environmental factors. Results indicated that the family level emerged as a pragmatic compromise, balancing precision and taxonomic effort. Cost/benefit analysis supported TS efficiency, maintaining correlation stability until the family level. Results also showed that reducing resolution to family does not entail a significant Loss of Information. This study contributes to the discourse on TS applicability, highlighting its practicality in monitoring scenarios, including spatial-temporal studies, and rapid biodiversity assessments. Additionally, it highlights the "second best approach" of family-level practicality depending on the specific monitoring scenario and recognizes the importance of the species-level "best approach" before applying TS in monitoring studies.

Enhancing Dental Pulp Stem Cell Proliferation and Odontogenic Differentiation with Protein Phosphatase 1-Disrupting Peptide: An In Vitro Study.

The reparative and regenerative capabilities of dental pulp stem cells (DPSCs) are crucial for responding to pulp injuries, with protein phosphatase 1 (PP1) playing a significant role in regulating cellular functions pertinent to tissue healing. Accordingly, this study aimed to explore the effects of a novel cell-penetrating peptide Modified Sperm Stop 1-MSS1, that disrupts PP1, on the proliferation and odontogenic differentiation of DPSCs. Employing MSS1 as a bioportide, DPSCs were cultured and characterized for metabolic activity, cell proliferation, and cell morphology alongside the odontogenic differentiation through gene expression and alkaline phosphatase (ALP) activity analysis. MSS1 exposure induced early DPSC proliferation, upregulated genes related to odontogenic differentiation, and increased ALP activity. Markers associated with early differentiation events were induced at early culture time points and those associated with matrix mineralization were upregulated at mid-culture stages. This investigation is the first to document the potential of a PP1-disrupting bioportide in modulating DPSC functionality, suggesting a promising avenue for enhancing dental tissue regeneration and repair.

Impact of HIV-Related Immune Impairment of Yellow Fever Vaccine Immunogenicity in People Living with HIV-ANRS 12403.

The yellow fever (YF) vaccine is one of the safest and most effective vaccines currently available. Still, its administration in people living with HIV (PLWH) is limited due to safety concerns and a lack of consensus regarding decreased immunogenicity and long-lasting protection for this population. The mechanisms associated with impaired YF vaccine immunogenicity in PLWH are not fully understood, but the general immune deregulation during HIV infection may play an important role. To assess if HIV infection impacts YF vaccine immunogenicity and if markers of immune deregulation could predict lower immunogenicity, we evaluated the association of YF neutralization antibody (NAb) titers with the pre-vaccination frequency of activated and exhausted T cells, levels of pro-inflammatory cytokines, and frequency of T cells, B cells, and monocyte subsets in PLWH and HIV-negative controls. We observed impaired YF vaccine immunogenicity in PLWH with lower titers of YF-NAbs 30 days after vaccination, mainly in individuals with CD4 count <350 cells/mm3. At the baseline, those individuals were characterized by having a higher frequency of activated and exhausted T cells and tissue-like memory B cells. Elevated levels of those markers were also observed in individuals with CD4 count between 500 and 350 cells/mm3. We observed a negative correlation between the pre-vaccination level of CD8+ T cell exhaustion and CD4+ T cell activation with YF-NAb titers at D365 and the pre-vaccination level of IP-10 with YF-NAb titers at D30 and D365. Our results emphasize the impact of immune activation, exhaustion, and inflammation in YF vaccine immunogenicity in PLWH.

Does the use of bisphosphonates during pregnancy affect fetal outcomes? A systematic review.

PURPOSE: This systematic review aimed to determine the effects of maternal exposure to bisphosphonates (BPs) during pregnancy on neonatal outcomes. It aimed to disclosfe the impact of BPs on neonates and identify aspects that require further investigation. METHODS: A comprehensive search of PubMed, Science Direct, LILACS, EMBASE, and Web of Science was conducted until August 2022, with no time restrictions. The selection criteria included studies published in English that evaluated pregnant women who were exposed to BPs. RESULTS: From an initial pool of 2169 studies, 13 met the inclusion criteria for this systematic review. These studies collectively included 106 women (108 pregnancies) who were exposed to BPs either before orduring pregnancy. A summary of the key characteristics of the selected studies and the risk of bias assessment are provided. Exposure to BPs occurs at various stages of pregnancy, with different indications for BP treatment. The most frequently reported neonatal outcomes were spontaneous abortion, congenital malformations, hypocalcemia, preterm birth, and low birth weight. CONCLUSION: Although previous reports have linked BPs before or during pregnancy with adverse neonatal outcomes, these associations should be interpreted with caution. Given the complexity of these findings, further research is necessary to provide more definitive insights to guide clinical decisions regarding the use of BPs in pregnant women.

Hyperbaric oxygen therapy in malignant otitis externa: a retrospective analysis.

PURPOSE: Malignant otitis externa (MOE) is a rare form of invasive osteomyelitis of the external ear canal. It is typically caused by Pseudomonas aeruginosa in immunocompromised patients. The diagnosis is clinical, and the initial treatment involves systemic antibiotics or antifungal therapy. Surgery is usually only considered when medical treatment has failed. Although hyperbaric oxygen therapy (HBOT) is recommended for refractory osteomyelitis, there are no specific guidelines for MOE. METHODS: This is a retrospective study that evaluates clinical data, treatment, and results obtained in patients diagnosed with MOE treated with HBOT at the Pedro Hispano Hospital between 2007 and 2022. RESULTS: During the study period, fifteen patients diagnosed with MOE were admitted for treatment with HBOT. All patients received antibiotic and/or antifungal therapy, and three required surgical intervention before starting HBOT. The pathology was successfully managed on all patients. CONCLUSIONS: HBOT may be an effective adjuvant treatment option in patients with MOE but it lacks robust scientific evidence. However, its therapeutic value should not be underestimated due to the good results and few adverse effects reported in recent retrospective studies and case reports.

Hidden in the depths, discovery of a new spiny sucker eel of the genus Lipogenys Goode and Bean 1895 (Teleostei, Notacanthiformes, Notacanthidae) in the eastern North Atlantic Ocean.

This study describes Lipogenys hyalinumvelum, a new species of the genus Lipogenys found on the Portuguese coast on the northeastern Atlantic during a crustacean survey. Information on the classification history and known distribution of the genus Lipogenys is provided. Dichotomous keys to the genera of Notacanthidae and the species of Lipogenys, based on morphology, are provided. The specimens were analysed using both morphological and molecular methods, including DNA sequencing of the COI and 16S genes. The distinct genetic characteristics support the recognition of the present specimens as a new species. The hyaline color of the flap at the posterior edge of the operculum is a characteristic that differentiates L. hyalinumvelum from Lipogenys gillii and provides the etymology of the species name.

Incorporation of abandoned and lost fishing gear into the structure of Dendrophyllia ramea in the Atlantic coast of Portugal.

Plastic pollution poses global and societal concerns, especially from discarded fishing gear, threatening seabed environments like coral reefs. This study examines the incorporation of lost and/or abandoned fishing gear - specifically synthetic lines, and filaments - into the structure of orange tree coral, Dendrophyllia ramea along the coast of Portugal, in the North-East Atlantic Ocean. The specimens were inadvertently captured by local fishers (Sines and Cascais), with 6 % showing filaments inside their structure, raising questions about their potential impact on coral health. We discuss the implications of understanding the interactions between plastics, fishing gear, and corals, which is important for developing conservation strategies. We address the need for improved of measures aimed at reducing the impact of fishing gear on corals, emphasizing the importance of endorsing biodegradable fishing materials and supporting lost gear retrieval initiatives. Furthermore, we emphasize the urgent need to communicate these issues to both fishers and stakeholders.

Cross-Cultural Validation of the Portuguese Version of the Quality of Oncology Nursing Care Scale.

BACKGROUND: Quality assessment in oncology nursing care has been a growing topic in the literature, gaining relevance as oncological nursing care becomes more complex as the science progresses. However, there are no instruments that assess the perception of the quality of oncology nursing care from the point of view of patients for the Portuguese population. Thus, the cross-cultural translation and validation of the Quality of Oncology Nursing Care Scale (QONCS) was performed for the Portuguese context. This instrument allows nurses to assess patients' self-perception of the quality of nursing care provided in an oncological setting. It also allows researchers to compare the results obtained internationally with the application of this scale. METHODS: This is a methodological study, with two distinct phases: the first corresponded to the translation and cultural adaptation of the scale to the Portuguese context, and the second consisted of the psychometric validation of the QONCS, which included factor analysis and the evaluation of the psychometric properties of the instrument. We obtained responses from 402 patients from a Portuguese oncology hospital. RESULTS: The Portuguese version of the Quality of Oncology Nursing Care Scale (QONCS_PT) consists of 34 items inserted into a tetra-factorial model, which explains a total variance of the instrument of 69.8%. A Cronbach's alpha of 0.93 was obtained for the complete instrument. CONCLUSIONS: QONCS_PT has a competent and reliable structure. The scale's validity was assured and can be used in the Portuguese population, as it is useful for direct care provision but also for researchers and managers.

Blended intensive programme's implementation in dental education: post-pandemic evolution of learning.

Blended Intensive Programmes (BIP's) represent a valuable tool for gathering knowledge and summarising the latest trends in medicine and dentistry. Blended education has been found, even before the COVID-19 pandemic, to increase the level of education and stimulate effective learning for postgraduate healthcare professionals. Interprofessional education is critical for preparing students to enter the health workforce, where teamwork and collaboration are important competencies. This article outlines the key points of the Blended Intensive Programme's implementation in dental education organised by Wroclaw Medical University in Poland. BIP involved professors from 12 universities or research institutions from Europe and South America and 28 participants from 8 countries. The course was taught remotely and in person. In addition, it included a visit to the university and practical classes with artificial simulation and practice in dentistry. A structured questionnaire enabled measuring the evaluation of students' perception of the COVID-19 education before and after the pandemic. The European Region Action Scheme for the Mobility of University Students (ERASMUS) was fundamental to carrying out the BIP with the participation of several countries, allowing the exchange of knowledge, assessing the impact of the pandemic on dental universities, and strengthening international collaborations and the future project of research, education and clinical assistance. We conclude that hybrid teaching programmes broaden the learning spectrum in dental studies by allowing transnational and interdisciplinary approaches that make students aware of the importance of their work within the framework of the general health approach, as this differs from country to country.

Is There an Over-Indication for Elective Tracheostomy in Patients With Oral Cavity Cancer?

OBJECTIVES: Temporary tracheostomies (TT) are often used in oral oncologic surgery to secure the postoperative airway. Our primary objective was to determine if there was an over-indication for elective tracheostomy in our population. If so, our secondary objective was to ascertain which patients could have possibly avoided TT. MATERIALS AND METHODS: We performed a retrospective study of patients with oral and oropharyngeal squamous cell carcinoma in which resection with curative intent and TT were performed. Variables collected included demographics, comorbidities, and complications. Additionally, we retrospectively applied the Cameron and TRACHY tracheostomy scoring systems to evaluate overall tracheostomy recommendations. RESULTS: A total of 116 elective tracheostomies were performed between January 2019 and December 2020. According to the Cameron and TRACHY scoring systems, recommendations for tracheostomy coincided in only 54.3% and 45.7%, respectively. Tumor anatomy and type of reconstruction were associated with less time until decannulation. Additionally, in patients without TT recommendation determined by both scores with tumor anatomy and location, as well as T and N stages were also associated with less time until decannulation. CONCLUSION: There appears to be an over-indication for elective tracheostomy in our patients with oral cavity and oropharyngeal cancer. The patients that could have potentially avoided elective TT were those with lateral anatomy, without flap or with fasciocutaneous flap, location in the mandibular alveolus or anterior tongue, as well as N0/N1 and T1/T2 patients.

Effect of Blueberry Supplementation on a Diet-Induced Rat Model of Prediabetes-Focus on Hepatic Lipid Deposition, Endoplasmic Stress Response and Autophagy.

Blueberries, red fruits enriched in polyphenols and fibers, are envisaged as a promising nutraceutical intervention in a plethora of metabolic diseases. Prediabetes, an intermediate state between normal glucose tolerance and type 2 diabetes, fuels the development of complications, including hepatic steatosis. In previous work, we have demonstrated that blueberry juice (BJ) supplementation benefits glycemic control and lipid profile, which was accompanied by an amelioration of hepatic mitochondrial bioenergetics. The purpose of this study is to clarify the impact of long-term BJ nutraceutical intervention on cellular mechanisms that govern hepatic lipid homeostasis, namely autophagy and endoplasmic reticulum (ER) stress, in a rat model of prediabetes. Two groups of male Wistar rats, 8-weeks old, were fed a prediabetes-inducing high-fat diet (HFD) and one group was fed a control diet (CD). From the timepoint where the prediabetic phenotype was achieved (week 16) until the end of the study (week 24), one of the HFD-fed groups was daily orally supplemented with 25 g/kg body weight (BW) of BJ (HFD + BJ). BW, caloric intake, glucose tolerance and insulin sensitivity were monitored throughout the study. The serum and hepatic lipid contents were quantified. Liver and interscapular brown and epidydimal white adipose tissue depots (iBAT and eWAT) were collected for histological analysis and to assess thermogenesis, ER stress and autophagy markers. The gut microbiota composition and the short-chain fatty acids (SCFAs) content were determined in colon fecal samples. BJ supplementation positively impacted glycemic control but was unable to prevent obesity and adiposity. BJ-treated animals presented a reduction in fecal SCFAs, increased markers of arrested iBAT thermogenesis and energy expenditure, together with an aggravation of HFD-induced lipotoxicity and hepatic steatosis, which were accompanied by the inhibition of autophagy and ER stress responses in the liver. In conclusion, despite the improvement of glucose tolerance, BJ supplementation promoted a major impact on lipid management mechanisms at liver and AT levels in prediabetic animals, which might affect disease course.

Clinical and molecular profiling of human visceral adipose tissue reveals impairment of vascular architecture and remodeling as an early hallmark of dysfunction.

Adipose tissue dysfunction is more related to insulin resistance than body mass index itself and an alteration in adipose tissue function is thought to underlie the shift from metabolically healthy to unhealthy obesity. Herein, we performed a clustering analysis that revealed distinct visceral adipose tissue gene expression patterns in patients with obesity at distinct stages of metabolic dysregulation. We have built a cross-sectional cohort that aims at reflecting the evolution of the metabolic sequelae of obesity with the main objective to map the sequential events that play a role in adipose tissue dysfunction from the metabolically healthy (insulin-sensitive) state to several incremental degrees of metabolic dysregulation, encompassing insulin resistance establishment, pre-diabetes, and type 2 diabetes. We found that insulin resistance is mainly marked by the downregulation of adipose tissue vasculature remodeling-associated gene expression, suggesting that processes like angiogenesis and adaptative expansion/retraction ability suffer early dysregulation. Prediabetes was characterized by compensatory growth factor-dependent signaling and increased response to hypoxia, while type 2 diabetes was associated with loss of cellular response to insulin and hypoxia and concomitant upregulation of inflammatory markers. Our findings suggest a putative sequence of dysregulation of biological processes that is not linear and has multiple distinct phases across the metabolic dysregulation process, ultimately culminating in the climax of adipose tissue dysfunction in type 2 diabetes. Several studies have addressed the transcriptomic changes in adipose tissue of patients with obesity. However, to the best of our knowledge, this is the first study unraveling the potential molecular mechanisms associated with the multi-step evolution of adipose tissue dysfunction along the metabolic sequelae of obesity.

Reviewing particulate delivery systems loaded with repurposed tetracyclines - From micro to nanoparticles.

Tetracyclines (TCs) are a class of broad-spectrum antibacterial agents recognized for their multifaceted properties, including anti-inflammatory, angiogenic and osteogenic effects. This versatility positions them as suitable candidates for drug repurposing, benefitting from well-characterized safety and pharmacological profiles. In the attempt to explore both their antibacterial and pleiotropic effects locally, innovative therapeutic strategies were set on engineering tetracycline-loaded micro and nanoparticles to tackle a vast number of clinical applications. Moreover, the conjoined drug carrier can function as an active component of the therapeutic approach, reducing off-target effects and accumulation, synergizing to an improvement of the therapeutic efficacy. In this comprehensive review we will critically evaluate recent advances involving the use of tetracyclines loaded onto micro- or nanoparticles, intended for biomedical applications, and discuss emerging approaches and current limitations associated with these drug carriers. Owing to their distinctive physical, chemical, and biological properties, these novel carriers have the potential to become a platform technology in personalized regenerative medicine and other therapeutic applications.

Osteoinductive activity of photobiomodulation in an organotypic bone model.

Photobiomodulation (PBM) is a technique that harnesses non-ionizing light at specific wavelengths, triggering the modulation of metabolic pathways, engendering favourable biological outcomes that reduce inflammation and foster enhanced tissue healing and regeneration. PBM holds significant promise for bone tissue applications due to its non-invasive nature and ability to stimulate cellular activity and vascularization within the healing framework. Notwithstanding, the impact of PBM on bone functionality remains largely undisclosed, particularly in the absence of influencing factors such as pathologies or regenerative therapies. This study aims to investigate the potential effects of PBM using red (660 nm) (RED) and near-infrared (808 nm) (NIR) wavelengths within an ex vivo bone culture system - the organotypic embryonic chicken femur model. A continuous irradiation mode was used, administering a total energy dose of 1.0 J, at an intensity of 100 mW for 10 s, which was repeated four times over the course of the 11-day culture period. The primary focus is on characterizing the expression of pivotal osteoblastic genes, the maturation and deposition of collagen, and the formation of bone mineral. Exposing femora to both RED and NIR wavelengths led to a notable increase in the expression of osteochondrogenic transcription factors (i.e., SOX9 and RUNX2), correlating with enhanced mineralization. Notably, NIR irradiation further elevated the expression of bone matrix-related genes and fostered enhanced deposition and maturation of fibrillar collagen. This study demonstrates that PBM has the potential to enhance osteogenic functionality within a translational organotypic bone culture system, with the NIR wavelength showing remarkable capabilities in augmenting the formation and maturation of the collagenous matrix.

Assessing the Seasonal and Spatial Dynamics of Zooplankton through DNA Metabarcoding in a Temperate Estuary.

Zooplankton are key components of estuarine trophic networks. However, routine monitoring is hindered by the difficulty of morphology-based identification. DNA-based methods allow us to circumvent some of these hurdles, providing precise species identifications regardless of the taxonomic expertise of the investigator or the developmental stage of the specimens. However, the process is dependent on the completeness of the reference libraries. In this study, we sought to evaluate the potential of DNA metabarcoding to assess the seasonal (summer, autumn, and early spring) and spatial dynamics of zooplankton (four locations spanning ca. 6 km) in the Lima estuary (NW Portugal). Two genetic markers were used: the cytochrome c oxidase subunit I and the V4 hypervariable region of the ribosomal 18S rRNA genes. Overall, 327 species were recovered, and both markers displayed minute overlap (7% were detected with both markers). Species richness, composition, and taxonomic distinctness were majorly influenced by the season, with a declining tendency from summer (highest number of exclusive species, n = 74) to spring. Second to season, the taxa composition was influenced by spatial variation where the most downstream site displayed the highest number of exclusive species, n = 53. A total of 16 non-indigenous species were detected using metabarcoding, but only one (Austrominus modestus) has been documented out in the estuary. In conclusion, both the seasonal and spatial gradients influenced the recovered richness, composition, and taxonomic distinctness, confirming the great aptitude of DNA metabarcoding for providing higher density monitoring and shedding new light on the composition and dynamics of complex zooplankton communities.

Influence of the Anatomical Site on Adipose Tissue-Derived Stromal Cells' Biological Profile and Osteogenic Potential in Companion Animals.

Adipose tissue-derived stromal cells (ADSCs) have generated considerable interest in the field of veterinary medicine, particularly for their potential in therapeutic strategies focused on bone regeneration. These cells possess unique biological characteristics, including their regenerative capacity and their ability to produce bioactive molecules. However, it is crucial to recognize that the characteristics of ADSCs can vary depending on the animal species and the site from which they are derived, such as the subcutaneous and visceral regions (SCAT and VAT, respectively). Thus, the present work aimed to comprehensively review the different traits of ADSCs isolated from diverse anatomical sites in companion animals, i.e., dogs, cats, and horses, in terms of immunophenotype, morphology, proliferation, and osteogenic differentiation potential. The findings indicate that the immunophenotype, proliferation, and osteogenic potential of ADSCs differ according to tissue origin and species. Generally, the proliferation rate is higher in VAT-derived ADSCs in dogs and horses, whereas in cats, the proliferation rate appears to be similar in both cells isolated from SCAT and VAT regions. In terms of osteogenic differentiation potential, VAT-derived ADSCs demonstrate the highest capability in cats, whereas SCAT-derived ADSCs exhibit superior potential in horses. Interestingly, in dogs, VAT-derived cells appear to have greater potential than those isolated from SCAT. Within the VAT, ADSCs derived from the falciform ligament and omentum show increased osteogenic potential, compared to cells isolated from other anatomical locations. Consequently, considering these disparities, optimizing isolation protocols becomes pivotal, tailoring them to the specific target species and therapeutic aims, and judiciously selecting the anatomical site for ADSC isolation. This approach holds promise to enhance the efficacy of ADSCs-based bone regenerative therapies.

Differential gene expression of cytokines, receptors, and miRNAs in individuals living with HIV-1 and vaccinated against yellow fever.

Between 2016 and 2018, Brazil faced a yellow fever (YF) outbreak, which led to an expansion of vaccination coverage. The coexistence of the YF outbreak and the HIV-1 epidemic in Brazil raised concerns regarding the immune response and vaccine effectiveness in individuals living with HIV (PLWH). The aim of this study was to investigate the immune response to YF vaccination in PLWH and HIV-uninfected individuals as controls. Transcript levels of immunomodulatory molecules, including IL-6, IL-10, IL-21, TGF-ß, CD19, CD163, miR-21, miR-146, and miR-155, were measured using RTqPCR. TCD4+ cells were evaluated by cytometry, and neutralizing antibody (Nab) titers were detected by a micro plaque-reduction neutralization test. The findings of our study revealed several noteworthy observations. First, there was a notable reduction in the circulation of TCD4+ cells postvaccination. Among people living with HIV (PLWH), we observed an increase in the expression of IL-10 following vaccination, while IL-6 expression was diminished in PLWH with lower TCD4+ counts. Furthermore, we identified the downregulation of CD19 and TGF-ß, along with the upregulation of IL-21 and CD163. Notably, we observed positive correlations between the levels of IL-10/IL-21, IL-10/CD163, and IL-6/CD19. Additionally, there was a positive correlation between miRNAs 146 and 155. It is important to emphasize that all participants exhibited robust neutralizing antibody responses after receiving 17DD YF vaccination. In this context, the gene expression data presented can be useful for biomarker studies of protective antibodies induced by YF vaccination. This study sheds light on immune mechanisms in individuals living with HIV and YF vaccination.

Lactococcus lactis CNCM I-5388 versus NCDO2118 by its GABA hyperproduction ability, counteracts faster stress-induced intestinal hypersensitivity in rats.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by its main symptom, visceral hypersensitivity (VH), which is aggravated by stress. Gut-brain interactions and gut bacteria may alleviate IBS symptoms, including VH. γ-amino butyric acid (GABA), produced notably by lactic acid bacteria (LAB), shows promising result in IBS symptoms treatment. In bacteria, GABA is generated through glutamate decarboxylase (GAD) metabolism of L-glutamic acid, maintaining intracellular pH. In mammals, GABA acts as an inhibitory neurotransmitter, modulating pain, stress, and anxiety. Therefore, utilizing GABA-producing LAB as a therapeutic approach might be beneficial. Our previous work showed that a GABA-producing Lactococcus lactis strain, NCDO2118, reduced VH induced by acute stress in rats after a 10-day oral treatment. Here, we identified the strain CNCM I-5388, with a four-fold higher GABA production rate under the same conditions as NCDO2118. Both strains shared 99.1% identical GAD amino acid sequences and in vitro analyses revealed the same optimal pH for GAD activity; however, CNCM I-5388 exhibited 17 times higher intracellular GAD activity and increased resistance to acidic pH. Additionally, in vivo experiments have demonstrated that CNCM I-5388 has faster anti-VH properties in rats compared with NCDO2118, starting from the fifth day of treatment. Finally, CNCM I-5388 anti-VH effects partially persisted after 5-day treatment interruption and after a single oral treatment. These findings highlight CNCM I-5388 as a potential therapeutic agent for managing VH in IBS patients.

Structural Optimization of Antimycobacterial Azaaurones Towards Improved Solubility and Metabolic Stability.

While N-acetyl azaaurones have already been disclosed for their potential against tuberculosis (TB), their low metabolic stability remains an unaddressed liability. We now report a study designed to improve the metabolic stability and solubility of the azaaurone scaffold and to identify the structural requirements for antimycobacterial activity. Replacing the N-acetyl moiety for a N-carbamoyl group led to analogues with sub- and nanomolar potencies against M. tuberculosis H37Rv, as well as equipotent against drug-susceptible and drug-resistant M. tuberculosis isolates. The new N-carbamoyl azaaurones exhibited improved microsomal stability, compared to their N-acetylated counterparts, with several compounds displaying moderate to high kinetic solubility. The frequency of spontaneous resistance to azaaurones was observed to be in the range of 10-8 , a value that is comparable to current TB drugs in the market. Overall, these results reveal that azaaurones are amenable to structural modifications to improve metabolic and solubility liabilities, and highlight their potential as antimycobacterial agents.