Biology subjects

Moura-Alves, P.

Publications and source records attributed to Moura-Alves, P..

4 recordsLinked to original sources

bioRxiv2025

Lactucopicrin: A sesquiterpene lactone with anti-inflammatory activity modulates the crosstalk between NF-kB and AHR pathways

Chronic inflammatory diseases, including inflammatory bowel diseases and cardiovascular diseases, share inflammation as a central pathological feature. The transcription factors NF-kB and AHR are key regulators of inflammatory responses, yet their interplay remains underexplored in the context of natural anti-inflammatory compounds. This study investigates the anti-inflammatory properties of sesquiterpene lactones derived from Cichorium intybus L. (chicory), focusing on their modulation of NF-kB and AHR signaling pathways. Using a TNF-induced inflammation model in macrophages, endothelial, and intestinal epithelial cells, we identified lactucopicrin as a potent NF-kB antagonist. Notably, in silico docking and functional assays revealed lactucopicrin as a novel AHR modulator. Crucially, silencing AHR expression attenuated lactucopicrin-mediated NF-kB inhibition, uncovering a previously unrecognized AHR-NF-kB crosstalk mechanism. These findings not only position lactucopicrin as a dual-pathway modulator but also highlight the therapeutic potential of chicory-derived sesquiterpene lactones in treating inflammation-driven diseases and opening new avenues for leveraging natural products in targeted anti-inflammatory strategies.

molecular biology↗

bioRxiv2023

Loss of MC1R signaling implicates TBX3 in pheomelanogenesis and melanoma predisposition

The human Red Hair Color (RHC) trait is caused by increased pheomelanin (red-yellow) and reduced eumelanin (black-brown) pigment in skin and hair due to diminished melanocortin 1 receptor (MC1R) function. In addition, individuals harboring the RHC trait are predisposed to melanoma development. While MC1R variants have been established as causative of RHC and are a well-defined risk factor for melanoma, it remains unclear mechanistically why decreased MC1R signaling alters pigmentation and increases melanoma susceptibility. Here, we use single-cell RNA-sequencing (scRNA-seq) of melanocytes isolated from RHC mouse models to reveal a Pheomelanin Gene Signature (PGS) comprising genes implicated in melanogenesis and oncogenic transformation. We show that TBX3, a well-known anti-senescence transcription factor implicated in melanoma progression, is part of the PGS and binds both E-box and T-box elements to regulate genes associated with melanogenesis and senescence bypass. Our results provide key insights into mechanisms by which MC1R signaling regulates pigmentation and how individuals with the RHC phenotype are predisposed to melanoma.

genetics↗

bioRxiv2019

Inhibition of host Lactate dehydrogenase A by a small-molecule limits Mycobacterium tuberculosis growth and potentiates bactericidal activity of isoniazid

Lactate dehydrogenase A (LDHA) mediates interconversion of pyruvate and lactate. Increased lactate turnover is shared by malignant and immune cells. Hypoxic lung granuloma in Mycobacterium tuberculosis-infected animals present elevated levels of Ldha and lactate. Such alteration in metabolic milieu could influence the outcome of interactions between M. tuberculosis and its infected immune cells. Given the central role of LDHA for tumorigenicity, targeting lactate metabolism is a promising approach for cancer therapy. Here, we sought to determine the importance of LDHA for Tuberculosis (TB) disease progression and its potential as a host-directed therapeutic target. To this end, we administered FX11, a small-molecule NADH-competitive LDHA inhibitor, to M. tuberculosis infected C57BL/6J mice and Nos2-/- mice with hypoxic necrotizing lung TB lesions mimicking human pathology more closely. FX11 did not inhibit M. tuberculosis growth in aerobic/hypoxic liquid culture, but modestly reduced the pulmonary bacterial burden in C57BL/6J mice. Intriguingly, FX11 administration limited M. tuberculosis replication and onset of necrotic lesions in Nos2-/- mice. In this model, Isoniazid (INH) monotherapy has been known to exhibit biphasic killing kinetics owing to the probable selection of an INH-tolerant subpopulation. This adverse effect was corrected by adjunct FX11 treatment and augmented the INH-derived bactericidal effect against M. tuberculosis. Our findings therefore support LDHA as a potential target for host-directed adjunctive TB therapy and encourage further investigations into the underlying mechanism.\n\nIMPORTANCETuberculosis (TB) continues to be a global health threat of critical dimension. Standard TB drug treatment is prolonged and cumbersome. Inappropriate treatment or non-compliance results in emergence of drug-resistant Mycobacterium tuberculosis strains (MDR-TB) that render current treatment options ineffective. Targeting the host immune system as adjunct therapy to augment bacterial clearance is attractive as it is also expected to be effective against MDR-TB. Here, we provide evidence that pharmaceutical blockade of host lactate dehydrogenase A (LDHA) by a small-molecule limits M. tuberculosis growth and reduces pathology. Notably, LDHA inhibition potentiates the effect of Isoniazid, a first-line anti-TB drug. Hence, its implications of our findings for short-term TB treatment are profound. In sum, our findings establish murine LDHA as a potential target for host-directed TB therapy.

microbiology↗

bioRxiv2018

The Aryl Hydrocarbon Receptor senses the Henna pigment Lawsone and mediates Yin-Yang effects on skin homeostasis

As a first host barrier, the skin is constantly exposed to environmental insults that perturb its integrity. Tight regulation of skin homeostasis is largely controlled by the aryl hydrocarbon receptor (AhR). Here, we demonstrate that Henna and its major pigment, the naphthoquinone Lawsone activate AhR, both in vitro and in vivo. In human keratinocytes and epidermis equivalents, Lawsone exposure enhances the production of late epidermal proteins, impacts keratinocyte differentiation and proliferation, and regulates skin inflammation. To determine the potential use of Lawsone for therapeutic application, we harnessed human, murine and zebrafish models. In skin regeneration models, Lawsone interferes with physiological tissue regeneration and inhibits wound healing. Conversely, in a human acute dermatitis model, topical application of a Lawsone-containing cream ameliorates skin irritation. Altogether, our study reveals how a widely used natural plant pigment is sensed by the host receptor AhR, and how the physiopathological context determines beneficial and detrimental outcomes.

cell biology↗