Institut d'Investigació Biomédica de Bellvitge

Hepatocyte growth factor (HGF)/hepatocyte growth factor receptor (MET) signaling plays a critical role during liver regeneration upon acute and chronic damage, and is therefore an interesting target for therapeutic intervention. Nevertheless, the molecular mechanisms underlying the pro-regenerative effects of HGF/MET signaling are not fully elucidated, particularly during cholestatic injury. Our aim was to analyze the impact of moderately enhanced MET on the hepatic response to cholestatic injury, and uncover the mechanisms behind it. For that, Alb-R26Met mice expressing a wild-type Met transgene in albumin-positive liver cells were fed with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-supplemented diet, used as a model simulating human primary sclerosing cholangitis. Results indicate that increased MET expression diminished liver damage in DDC-fed mice, evidenced by lower serum levels of bilirubin and alkaline phosphatase, and decreased cell apoptosis. However, decreased ductular expansion was observed, which together with enhanced hepatocyte proliferation suggests that hepatocytes act as the main cellular defense. Both invivo and in vitro studies using Alb-R26Met liver-derived hepatocytes under cholestasis-simulated in vitro conditions demonstrated an enhanced upregulation of nuclear factor erythroid 2-related factor 2 (NRF2; encoded by the Nfe2l2 gene), parallel to an upregulation of glutathione biosynthesis enzymes, increased levels of glutathione, and decreased reactive oxygen species, along with decreased activation of transforming growth factor beta (TGF-β)-induced signaling. Consistently, MET transgenic hepatocytes were protected against TGF-β-induced oxidative stress and apoptosis in vitro. In conclusion, our work evidences that moderate upregulation of wild-typeMET in hepatocytes is sufficient to promote a strong antioxidant response in the liver that efficiently protects against chronic cholestasis, thus allowing optimal liver regeneration.

ObjectivesRadiation-induced dermatitis (RID) is a common side effect of radiotherapy, and some medicinal herbs may affect its development or severity. This clinical trial aimed to evaluate the protective effects of a topical herbal ointment containing Plantago major, mallow, and honey in patients with breast cancer.MethodsThis randomized double-blind clinical trial included patients with breast cancer who were candidates for adjuvant radiotherapy. The patients were randomized into the intervention (n = 42) and placebo (n = 42) groups. Dermatitis grade and related symptoms (itching, burning, pain) were assessed on days 7, 14, and 21 of radiotherapy and two weeks and three months post-treatment using standardized scoring scales.ResultsTopical application of the herbal ointment significantly reduced the severity of radiation-induced dermatitis compared with placebo, with lower itching scores on days 14 (0.71 vs. 2.93; P < 0.01) and 21 (1.26 vs. 4.26; P < 0.01), and fewer cases of grade ≥2 dermatitis (26.2% vs. 61.9%). Three months after treatment, subacute pigmentation was also significantly lower in the intervention group (P = 0.001).ConclusionTopical application of an ointment containing Plantago major, mallow, and honey significantly reduced the severity and duration of RID, as well as associated symptoms such as itching and burning, suggesting its potential as a safe complementary treatment.

The hypothalamic-pituitary-gonadal axis (HPG) controls pubertal development, sexual maturation, and fertility. We identified a role of hypothalamic microglia in controlling the HPG axis through receptor activator of nuclear factor κβ (Rank) signaling. Whole-body and microglia Rank depletion led to hypogonadotropic hypogonadism (HH) resulting from an alteration in gonadotropin-releasing hormone (GnRH) neuron function. In addition, we identified rare gene variants of RANK in patients with HH. Transcriptional profiling upon Rank loss revealed defective microglia activation and morphological alterations in the median eminence, decreasing the contacts and engulfment of GnRH terminal projections and impairing GnRH neuronal responses to kisspeptin. Overall, our data uncover the microglia as regulator of GnRH neuronal function through Rank signaling, with potential implications for reproductive maturation and fertility.

Nephrolithiasis is a major global health challenge, with oxidative stress and mitochondrial dysfunction emerging as key drivers of renal injury and stone formation. l-ergothioneine (l-Erg), a naturally occurring antioxidant transported by OCTN1, has shown promising effects in cystinuria models, preventing stone formation. Despite evidence supporting an indirect mechanism of action, key mechanistic aspects have yet to be fully clarified. This study aimed to evaluate whether l-Erg can prevent stone progression in cystinuria and in other types of lithiasis, such as calcium oxalate nephrolithiasis, and to further elucidate its mechanistic basis. Using mouse models, l-Erg significantly reduced cystine stone growth and renal inflammation, and its combination with d-penicillamine enhanced stone dissolution and mitigated drug-related toxicity. In calcium oxalate nephrolithiasis, l-Erg decreased crystal deposition, preserved renal architecture, normalized glutathione levels, and restored mitochondrial respiration. Transcriptomic analysis revealed downregulation of immune pathways and activation of cell cycle genes, suggesting attenuation of inflammation and promotion of tubular repair. This study is the first to demonstrate that l-Erg exerts renoprotective effects through combined antioxidant and mitochondrial mechanisms in two major forms of nephrolithiasis and introduces a dual therapeutic approach combining an antioxidant with a cystine-solubilizing agent. By targeting oxidative stress and mitochondrial dysfunction, l-Erg represents a promising therapeutic strategy for nephrolithiasis, either alone or as an adjunct to current treatments. Antioxid. Redox Signal. 44, 878-891.

Recurrence patterns in OPC differ by HPV status and smoking history. HPV-positive heavy smokers represent a distinct high-risk subgroup characterized by increased distant metastasis and inferior survival, warranting refined stratification beyond p16 status alone.

Hippocampal mossy fiber (hMF) to CA3 pyramidal cell synapses are thought to support the formation of working memory through presynaptic short-term facilitation (STF) and post-tetanic potentiation (PTP). However, the molecular mechanisms underlying these transient forms of synaptic enhancement are unclear. We show here that Munc13-1-mediated priming of synaptic vesicles at active zones controls hMF STF and PTP in response to Ca2+-phospholipid and Ca2+-calmodulin signaling. Knockin mice expressing Munc13-1 variants insensitive to either signaling pathway exhibit pronounced deficits in STF and PTP, and the PTP induction threshold is markedly increased upon blockade of Ca2+-phospholipid-Munc13-1 signaling. Since these synaptic defects are accompanied by working memory deficits, especially in mice expressing the Ca2+-phospholipid-insensitive Munc13-1 variant, we conclude that the Ca2+-dependent regulation of Munc13-1-mediated SV priming co-determines hMF short-term plasticity and working memory formation.