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Tackling cutaneous herpes simplex virus disease with topical immunomodulators—a call to action
(American Society for Microbiology, 2025-03-13)
DUARTE PEÑALOZA, LUISA FERNANDA
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Javier Carbone-Schellman
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Susan M. Bueno
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Alexis M. Kalergis
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Claudia A. Riedel
Antivirals play important roles in restricting viral diseases. Nevertheless, they act on a relatively limited number of viruses and occasionally display partial effectiveness in some tissues or against escape variants. Although vaccination remains the most cost-effective approach for preventing microbial diseases, developing prophylactic or therapeutic solutions for pathogens, such as herpes simplex viruses (HSVs), that effectively reduce their clinical manifestations in the skin has proven exceptionally challenging despite extensive research. Alternatively, a less explored approach for tackling HSV skin infection involves using topical immunomodulatory molecules to potentiate the host’s innate antiviral immune responses. When applied directly to herpetic skin lesions where viral antigen is present, this strategy has the potential to elicit virus-specific adaptive immunity. Based on currently available data, we foresee substantial potential for this approach in addressing HSV skin infections, along with additional prospects to advance understanding of skin biology and apply relevant new findings to other dermatological conditions. However, due to the limited number of case studies evaluating this method and its safety profile, particularly in immunocompromised individuals and pregnant women, further research is crucial, especially to assess the effects of immunomodulators in these vulnerable populations. Here, we revisit and discuss the use of immunomodulatory molecules for potentiating the host immune response against HSV skin infection and call for action for increased research and clinical trials regarding the possible benefits of this latter strategy for treating HSV cutaneous disease and recurrences. We also revisit and discuss antivirals and vaccine candidates against HSVs.
Scopus© Citations 2 7
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Gut Microbiota‐Derived Extracellular Vesicles Influence Alcohol Intake Preferences in Rats
(Wiley, 2025-03)
Macarena Díaz‐Ubilla
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Aliosha I. Figueroa‐Valdés
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Hugo E. Tobar
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María Elena Quintanilla
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Eugenio Díaz
<jats:title>ABSTRACT</jats:title><jats:p>Growing preclinical and clinical evidence suggests a link between gut microbiota dysbiosis and problematic alcohol consumption. Extracellular vesicles (EVs) are key mediators involved in bacteria‐to‐host communication. However, their potential role in mediating addictive behaviour remains unexplored. This study investigates the role of gut microbiota‐derived bacterial extracellular vesicles (bEVs) in driving high alcohol consumption. bEVs were isolated from the gut microbiota of a high alcohol‐drinking rat strain (UChB rats), either ethanol‐naïve or following chronic alcohol consumption and administered intraperitoneally or orally to alcohol‐rejecting male and female Wistar rats. Both types of UChB‐derived bEVs increased Wistar's voluntary alcohol consumption (three bottle choice test) up to 10‐fold (<jats:italic>p</jats:italic> < 0.0001), indicating that bEVs are able and sufficient to transmit drinking behaviour across different rat strains. Molecular analysis revealed that bEVs administration did not induce systemic or brain inflammation in the recipient animals, suggesting that the increased alcohol intake triggered by UChB‐derived bEVs operates through an inflammation‐independent mechanism. Furthermore, we demonstrate that the vagus nerve mediates the bEV‐induced increase in alcohol consumption, as bilateral vagotomy completely abolished the high drinking behaviour induced by both intraperitoneally injected and orally administered bEVs. Thus, this study identifies bEVs as a novel mechanism underlying gut microbiota‐induced high alcohol intake in a vagus nerve‐dependent manner.</jats:p>
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Molecular Interplay Between Non-Coding RNAs and Connexins and Its Possible Role in Cancer
(MDPI AG, 2025-03-12)
Pablo Pérez-Moreno
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Juan P. Muñoz
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RETAMAL LUCERO, MAURICIO ANTONIO
Non-coding RNAs (ncRNAs) are sequences that do not encode for proteins and play key roles in different cellular processes, including cell proliferation and differentiation. On the other hand, connexins (Cxs) are transmembrane proteins that principally allow intercellular communication. In pathological conditions such as cancer, there is a deregulation in the expression and/or function of ncRNAs and Cxs, which in turn leads to an enhancement in the aggressive phenotype, such as a greater proliferative and invasive capacity. This suggests a plausible interplay between ncRNAs and Cxs. Based on that, this review aims to summarize the current knowledge regarding this relationship and to analyze how it may influence the development of aggressive traits in cancer cells and the clinicopathological features of cancer patients. Finally, we discuss the potential of ncRNAs and Cxs as promising clinical biomarkers for cancer diagnosis, prognosis, and therapeutic targeting.
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Paw Skin as a Translational Model for Investigating Fibrotic and Inflammatory Wound Healing Defects in Recessive Dystrophic Epidermolysis Bullosa
(MDPI AG, 2025-04-30)
DE GREGORIO CONCHA, CRISTIAN ALEJANDRO
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Giselle Ramos-Gonzalez
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Bernardo Morales-Catalán
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EZQUER, EDUARDO FERNANDO
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EZQUER, EDUARDO MARCELO
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genetic disease caused by COL7A1 mutations. It leads to skin fragility, chronic inflammation, and impaired wound healing. The condition often results in fibrotic scarring, pseudosyndactyly, and cutaneous squamous cell carcinoma (SCC). However, current animal models fail to fully replicate chronic RDEB wounds. In this study, we used Collagen VII-hypomorphic mice (Col7a1flNeo/flNeo) and created full-thickness wounds on their paw skin, an area prone to fibrosis due to mechanical stress. We analyzed the healing process using histology, immunofluorescence, and electron microscopy. The RDEB mice showed delayed wound closure, increased inflammation, and poor granulation tissue formation. At 30 days post-injury, we observed persistent fibrosis, with elevated levels of Collagen I, α-SMA+ myofibroblasts, and tenascin-C. These mice also had fewer intraepidermal nerve fibers, which may help explain the neuropathic pain associated with RDEB. Our model reproduces the main features of chronic RDEB wounds. It offers a useful tool for evaluating therapies aimed at reducing inflammation, fibrosis, and tumor risk in these patients.
Scopus© Citations 3 4
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The Unexplored Role of Connexin Hemichannels in Promoting Facioscapulohumeral Muscular Dystrophy Progression
(MDPI AG, 2025-01-04)
Macarena Díaz-Ubilla
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RETAMAL LUCERO, MAURICIO ANTONIO
<jats:p>DUX4 is typically a repressed transcription factor, but its aberrant activation in Facioscapulohumeral Muscular Dystrophy (FSHD) leads to cell death by disrupting muscle homeostasis. This disruption affects crucial processes such as myogenesis, sarcolemma integrity, gene regulation, oxidative stress, immune response, and many other biological pathways. Notably, these disrupted processes have been associated, in other pathological contexts, with the presence of connexin (Cx) hemichannels—transmembrane structures that mediate communication between the intracellular and extracellular environments. Thus, hemichannels have been implicated in skeletal muscle atrophy, as observed in human biopsies and animal models of Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Dysferlinopathies, suggesting a potentially shared mechanism of muscle atrophy that has not yet been explored in FSHD. Despite various therapeutic strategies proposed to manage FSHD, no treatment or cure is currently available. This review summarizes the current understanding of the mechanisms underlying FSHD progression, with a focus on hormones, inflammation, reactive oxygen species (ROS), and mitochondrial function. Additionally, it explores the potential of targeting hemichannels as a therapeutic strategy to slow disease progression by preventing the spread of pathogenic factors between muscle cells.</jats:p>
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Maraviroc/cisplatin combination inhibits gastric cancer tumoroid growth and improves mice survival
(Springer Science and Business Media LLC, 2025-01-18)
Bárbara Mora-Lagos
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María Elena Reyes
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LOBOS GONZALEZ, LORENA DE LOURDES
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Matías del Campo
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Kurt Buchegger
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Gastric cancer (GC) is a significant cancer-related cause of death worldwide. GC’s most used chemotherapeutic regimen is based on platinum drugs such as cisplatin (CDDP). However, CDDP chemoresistance reduces the survival rate of advanced GC. The immune C-C chemokine receptor type 5 (CCR5) have been proposed as a pivotal factor in cancer progression since its blockade has been linked with antineoplastic effects on tumor cell proliferation; nevertheless, its role in the chemoresistance of GC has not been elucidated. This study aimed to determine the effects induced by the CCR5 using Maraviroc (MVC), a highly selective CCR5 antagonist, on CDDP-resistant AGS cells (AGS R-CDDP), tumoroids (<jats:italic>3D</jats:italic> tumor spheroids), and animal models.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>The combined CDDP and MVC treatment reduced cell viability and inhibited tumoroid formation in AGS R-CDDP cells. The effects of the MVC/CDDP combination on apoptosis and cell cycle progression were correlated with the increase in CDDP (dose-dependent). The mRNA levels of C-C Motif Chemokine Ligand 5 (CCL5), the main ligand for CCR5, decreased significantly in cells treated with the MVC/CDDP combination. MVC in the MVC/CDDP combination improved the survival rate and biochemical parameters of CDDP-treated mice by reducing the side effects of CDDP alone.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>This finding suggests that MVC/CDDP combination could be a potential complementary therapy for GC.</jats:p> </jats:sec>
3Scopus© Citations 4
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Hosts and vectors of scrub typhus in Chile: epidemiological study and molecular analyses of Orientia infection in rodents and rodent-associated mites
(Springer Science and Business Media LLC, 2024-12-18)
Constanza Martínez-Valdebenito
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Gerardo Acosta-Jamett
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Rayitray Abello
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Ju Jiang
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Allen L. Richards
<jats:title>Abstract</jats:title><jats:p><jats:italic>Candidatus</jats:italic> Orientia chiloensis causes scrub typhus over a wide geographical range in southern Chile. The life cycle, including vectors and reservoirs of this novel rickettsial pathogen, is incompletely understood. We analyzed rodent tissue and rodent-associated mite samples collected during a field study in six localities on Chiloé Island, where human scrub typhus cases have occurred. Using molecular methods, we detected <jats:italic>Orientia</jats:italic> DNA in 24.8% of rodents, belonging to five of seven captured species. <jats:italic>Orientia</jats:italic>-infection rates showed geographical variations, but were not influenced by rodent species, sex, age, and mite infestation. Phylogenetic analysis showed that <jats:italic>Orientia</jats:italic> sequences from trombiculid mites (<jats:italic>Proschoengastia eloisae</jats:italic>) were identical to those from scrub typhus patients from the same region. The results suggest that these rodent-associated mites serve as vectors and play an important role in the ecology of scrub typhus in southern Chile. Further studies are required to determine whether <jats:italic>Orientia</jats:italic>-infected rodents can also serve as reservoir of <jats:italic>Orientia</jats:italic> in Chile.</jats:p> <jats:p><jats:bold>Graphical Abstract</jats:bold></jats:p>
1Scopus© Citations 8
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The role of astrocytes in depression, its prevention, and treatment by targeting astroglial gliotransmitter release
(2024)
Yorley Duarte
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Daisy Quintana-Donoso
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Rodrigo Moraga-Amaro
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Ivanka Dinamarca
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Yordan Lemunao
<jats:p>The role of ventral hippocampus (vHipp) astroglial gliotransmission in depression was studied using chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) rodent models. CRS increased Cx43 hemichannel activity and extracellular glutamate levels in the vHipp and blocking astroglial Cx43 hemichannel-dependent gliotransmission during CRS prevented the development of depression and glutamate buildup. Moreover, the acute blockade of Cx43 hemichannels induced antidepressant effects in rats previously subjected to CRS or CUMS. This antidepressant effect was prevented by coinjection of glutamate and D-serine. Furthermore, Cx43 hemichannel blockade decreased postsynaptic NMDAR currents in vHipp slices in a glutamate and D-serine-dependent manner. Notably, chronic microinfusion of glutamate and D-serine, L-serine, or the NMDAR agonist NMDA, into the vHipp induced depressive-like symptoms in nonstressed rats. We also identified a small molecule, cacotheline, which blocks Cx43 hemichannels and its systemic administration induced rapid antidepressant effects, preventing stress-induced increases in astroglial Cx43 hemichannel activity and extracellular glutamate in the vHipp, without sedative or locomotor side effects. In conclusion, chronic stress increases Cx43 hemichannel-dependent release of glutamate and D-/L-serine from astrocytes in the vHipp, overactivating postsynaptic NMDARs and triggering depressive-like symptoms. This study highlights the critical role of astroglial gliotransmitter release in chronic stress-induced depression and suggests it can be used as a target for the prevention and treatment of depression.</jats:p>
Scopus© Citations 5 8
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Morphine self-administration is inhibited by the antioxidant N‐acetylcysteine and the anti-inflammatory ibudilast; an effect enhanced by their co-administration
(2024)
María Elena Quintanilla
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Paola Morales
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Daniela Santapau
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Javiera Gallardo
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Rocío Rebolledo
<jats:sec id="sec001"> <jats:title>Background</jats:title> <jats:p>The treatment of opioid addiction mainly involves the medical administration of methadone or other opioids, aimed at gradually reducing dependence and, consequently, the need for illicit opioid procurement. Thus, initiating opioid maintenance therapy with a lower level of dependence would be advantageous. There is compelling evidence indicating that opioids induce brain oxidative stress and associated glial activation, resulting in the dysregulation of glutamatergic homeostasis, which perpetuates drug intake. The present study aimed to determine whether inhibiting oxidative stress and/or neuroinflammation reduces morphine self-administration in an animal model of opioid dependence.</jats:p> </jats:sec> <jats:sec id="sec002"> <jats:title>Methods</jats:title> <jats:p>Morphine dependence, assessed as voluntary morphine self-administration, was evaluated in Wistar-derived UChB rats. Following an extended period of morphine self-administration, animals were administered either the antioxidant N-acetylcysteine (NAC; 40 mg/kg/day), the anti-inflammatory ibudilast (7.5 mg/kg/day) or the combination of both agents. Oxidative stress and neuroinflammation were evaluated in the hippocampus, a region involved in drug recall that feeds into the nucleus accumbens, where the levels of the glutamate transporters GLT-1 and xCT were further assessed.</jats:p> </jats:sec> <jats:sec id="sec003"> <jats:title>Results</jats:title> <jats:p>Daily administration of either NAC or ibudilast led to a mild reduction in voluntary morphine intake, while the co-administration of both therapeutic agents resulted in a marked inhibition (-57%) of morphine self-administration. The administration of NAC or ibudilast markedly reduced both the oxidative stress induced by chronic morphine intake and the activation of microglia and astrocytes in the hippocampus. However, only the combined administration of NAC + ibudilast was able to restore the normal levels of the glutamate transporter GLT-1 in the nucleus accumbens.</jats:p> </jats:sec> <jats:sec id="sec004"> <jats:title>Conclusion</jats:title> <jats:p>Separate or joint administration of an antioxidant and anti-inflammatory agent reduced voluntary opioid intake, which could have translational value for the treatment of opioid use disorders, particularly in settings where the continued maintenance of oral opioids is a therapeutic option.</jats:p> </jats:sec>
1Scopus© Citations 3
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Kinin Receptors B1 and B2 Mediate Breast Cancer Cell Migration and Invasion by Activating the FAK-Src Axis
(2024)
Felipe González-Turén
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Lorena Lobos-González
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Alexander Riquelme-Herrera
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Andrés Ibacache
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Luis Meza Ulloa
Kinin receptors B1 and B2 are involved in migration and invasion in gastric, glioma, and cervical cancer cells, among others. However, the role of kinin receptors in breast cancer cells has been poorly studied. We aimed to reveal the impact of B1 and B2 receptors on migration and invasion in breast cancer cells and demonstrate their capacity to modulate in vivo tumor growth. MDA-MB-231, MCF-7, and T47D cells treated with Lys-des[Arg9]bradykinin (LDBK) or bradykinin (BK) were used to evaluate migration and invasion. Des-[Arg9]-Leu8-BK and HOE-140 were used as antagonists for the B1 and B2 receptors. MDA-MB-231 cells incubated or not with antagonists were subcutaneously inoculated in BALBc NOD/SCID mice to evaluate tumor growth. LDBK and BK treatment significantly increased migration and invasion in breast cancer cells, effects that were negated when antagonists were used. The use of antagonists in vivo inhibited tumor growth. Moreover, the migration and invasion induced by kinins in breast cancer cells were inhibited when focal adhesion kinase (FAK) and Src inhibitors were used. The novelty revealed in our work is that B1 and B2 receptors activated by LDBK and BK induce migration and invasion in breast cancer cells via a mechanism that involves the FAK–Src signaling pathway, and the antagonism of both receptors in vivo impairs breast tumor growth.
3Scopus© Citations 3

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