Histology and histopathology, Vol.40, Nº12, (2025)

Ir a Estadísticas

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http://hdl.handle.net/10201/171509

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    The mechanism of dexmedetomidine regulation of the HIF-1α/FUNDC1 axis in myocardial ischemia/reperfusion injury
    (2025) Yidan Huang; Zhenfei Hu; Biología Celular e Histología
    Objective. Myocardial ischemia/reperfusion injury (MIRI) is a life-threatening event that typically follows reperfusion therapy for myocardial infarction. Regarding the effects of dexmedetomidine (Dex) in MIRI, we explored its specific mechanism. Methods. The MIRI rat model was treated with Dex, Topotecan [a hypoxia-inducible factor-1α (HIF-1α) inhibitor], and lentiviral-overexpressing FUN14 domain-containing protein 1 (Lv-oe-FUNDC1), with rat heart rate analysis. The pathological damage of rat myocardial tissue was evaluated by hematoxylin-eosin (HE) and Masson staining. Positive expression levels of PTEN-induced kinase 1 (PINK1), Parkin, microtubule-associated protein 1 light chain 3 (LC3) II/I, p62 and Beclin1 proteins, HIF-1α and FUNDC1 messenger RNA (mRNA), and HIF-1α and FUNDC1 were assessed by western blot, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and immuno-histochemical staining, respectively. HIF-1α-FUNDC1 binding sites and targeted binding relationships were predicted and verified via databases and dual-luciferase assay. HIF-1α enrichment levels in the FUNDC1 promoter region were evaluated using a ChIP assay. Results. MIRI rats exhibited myocardial injury and severe myocardial dysfunction, with elevated left ventricular diastolic pressure and p62 expression, reduced left ventricular systolic pressure, and maximum rate of change in left ventricular pressure and PINK1, Parkin, LC3 II/I ratio and Beclin-1 protein levels, which were reversed by Dex treatment. MIRI rats had increased HIF-1α and FUNDC1 expression levels, which were further boosted after Dex treatment. Dex promoted mitophagy to ameliorate myocardial injury in MIRI rats via the HIF-1α/FUNDC1 axis. Conclusion. Dex promoted mitophagy by up-regulating HIF-1α to facilitate the transcriptional expression of FUNDC1, thereby ameliorating myo-cardial injury in MIRI rats.
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    Open Access
    Differential expression of ferroptosis markers, circadian regulators, KLOTHO, and classical tumor suppressors in colorectal cancer according to tumor stage: Influence of age, anatomical location, and correlation patterns
    (2025) Cielo Garcia Montero; Oscar Fraile Martinez; Ana M. Minaya Bravo; Diego Liviu Boaru; Diego De Leon Oliva; Patricia De Castro Martinez; Majd N. Michael Alhaddadin; Silvestra Barrena Blázquez; Laura Lopez Gonzalez; Luis G. Guijarro; Natalio Garcia Honduvilla; Víctor Roberto Baena Romero; Carlos Daniel Padilla Ansala; Mar Royuela; María Del Val Toledo Lobo; Leonel Pekarek; Roberto Fernández Baillo Gallego de la Sacristana; Mauricio Hernández Fernández; Montserrat Chao Crecente; Melchor Alvarez-Mon; Raul Diaz-Pedrero; Miguel A. Ortega; Miguel A. Saez; Biología Celular e Histología
    Colorectal cancer (CRC) is a leading cause of cancer-related mortality, with an incidence projected to rise significantly worldwide. While TNM staging remains the cornerstone of prognosis and treatment decisions, additional biomarkers are needed to enhance predictive accuracy and therapeutic targeting. Ferroptosis, an iron-dependent cell death pathway, has emerged as a key regulator of CRC progression and therapy resistance. Circadian rhythms, KLOTHO, and tumor suppressors, such as p53, CDKN1A (p21), and Rb, also play crucial roles in CRC biology. Integrating TNM staging with molecular markers and patient-specific variables offers a more precise, personalized approach to CRC management. In the present work, we analyze the histopathological expression of KLOTHO, ferroptosis markers (TFRC, ALOX-5, ACSL-4, and GPX-4), circadian regulators (CLOCK, BMAL1, PER1, and PER2), and classical tumor suppressors (p53, p21, and Rb) in a cohort of 63 patients diagnosed with CRC. Besides, we have considered important clinical variables, like sex, age, and anatomical location, in our statistical analysis; correlation with the protein expression of these markers was also included for each stage (T1, T2, and T3). Our study reveals that advanced CRC stages (primarily T3) exhibit increased expression of ferroptosis markers (TFRC, ALOX5, ACSL4, and GPX4) and tumor suppressors (p53, p21, and Rb), alongside reduced histopathological detection of KLOTHO and circadian markers (BMAL1, CLOCK, PER1, and PER2) compared with earlier stages. Age, but not sex, influenced the expression of several markers. Tumor location also played a role, with right-sided CRCs showing significant stage-related differences in ferroptosis, tumor suppressor, and BMAL1, whereas left-sided tumors exhibited variations primarily in circadian markers (CLOCK, PER1, and PER2). Correlation analyses across tumor stages indicate dynamic shifts, with tumor suppressors maintaining positive associations with ferroptosis markers and anti-aging/circadian markers showing stage-dependent changes. Despite the inherent limitations of our study, these findings highlight the evolving biomarker landscape in CRC progression, although further research is needed to elucidate their clinical implications.
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    Open Access
    Developmental regulation of GABAB receptors and downstream molecules in the mouse brain
    (2025) Ana Fajardo Serrano; Rocío Alfaro Ruiz; María Llanos Martínez Poyato; Ana Esther Moreno-Martínez; Sebastián García Madrona; Alberto Roldán Sastre; Pablo Alonso-Gómez; Miriam Fernández; Ricardo Puertas-Avendaño; Ryuichi Shigemoto; Kirill A. Martemyanov; Rafael Luján; Carolina Aguado; Biología Celular e Histología
    Metabotropic GABA (GABAB) receptors have modulatory functions on neuronal excitability and neurotransmitter release. To fulfil these functions, GABAB receptors form macromolecular signaling complexes with G proteins, effectors, and other associated proteins. Here we investigated the postnatal development of GABAB receptors (GABAB1 and GABAB2 subunits) in mouse brain, focusing on potential similarities in the spatial and temporal expression pattern of their associated proteins CaV2.1, Gαo, Gβ5, and RGS7, using histoblots, immunofluorescence, and immunoelectron microscopic techniques. At all ages analyzed, histoblot showed that the six proteins were widely expressed in the brain, with mostly an overlapping pattern throughout postnatal development. In the hippocampus, immunoelectron microscopy and quantitative analysis of immunoparticles for GABAB1, GABAB2, Gαo, Gβ5, and RGS7 revealed their progressive enrichment around excitatory synapses on dendritic spines of CA1 pyramidal cells toward P15. At presynaptic sites, GABAB receptors colocalize with CaV2.1, Gαo, Gβ5, and RGS7 in the active zone and extrasynaptic membranes of axon terminals, establishing synapses on dendritic spines of CA1 pyramidal cells. In the cerebellum, double immunofluorescence at P7 and P10 revealed the colocalization of GABAB1 and CaV2.1 in the whole dendritic tree of developing Purkinje cells. Immunoelectron microscopy at P15 showed that GABAB1, GABAB2, CaV2.1, Gαo, Gβ5, and RGS7 are distributed along the dendritic surface of Purkinje cells, enriched close to excitatory synapses in spines. Altogether, these data suggest that macromolecular complexes composed of GABAB1 /GABAB2/CaV2.1/ Gαo/Gβ5/RGS7 are pre-assembled during key stages of postnatal development in hippocampal and cerebellar neurons.
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    Oroxin B prevented sepsis-evoked acute lung injury by promoting M2 macrophage polarization through the TLR4/NF-κB axis
    (2025) Jianhua Liu; Changhong Zhang; Feng Li; Nana Duan; Zhihua Zhang; Chen Li; Biología Celular e Histología
    Acute lung injury (ALI) is a frequent complication of sepsis that aggravates sepsis mortality and morbidity, which is tightly related to the inflammatory process. Oroxin B (OB), a flavonoid from Oroxylum indicum (L.) Vent, has exhibited anti-inflammatory properties in several illnesses. Nevertheless, it is still unclear how OB affects sepsis-induced ALI and how it works. RAW264.7 cells were challenged with lipopolysaccharide (LPS, 10 μg/mL), and mice received cecal ligation and puncture (CLP) to produce sepsis-evoked ALI in in vitro and in vivo models. The action of OB on sepsis-elicited ALI was probed through cell counting kit-8, pathological staining, enzyme-linked immunosorbent assay, reverse transcription-quantitative polymerase chain reaction, and western blot. The results showed that OB improved pathological damage and pulmonary fibrosis in CLP-challenged mice. OB also reduced the concentration of MPO, the protein content in BALF, and macrophage and neutrophil numbers in BALF from CLP-challenged mice. Molecularly, OB decreased the levels of IL-1β, IL-6, TNF-α, CD86, and iNOS but increased the level of Arg1 and CD206 in both LPS-evoked RAW264.7 cells and CLP-treated mice. Mechanistically, OB downregulated the level of the TLR4/NF-κB axis in both LPS-challenged RAW264.7 cells and CLP-treated mice. Overexpression of TLR4 abrogated the effect of OB on the above-mentioned indicators in LPS-elicited RAW264.7 cells. Therefore, OB improved sepsis-elicited ALI by attenuating inflammation and promoting M2 macrophage polarization through the TLR4/NF-KB signaling pathway.
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    Luteoloside ameliorates sepsis-induced acute lung injury via AMPK-ULK1 pathway-mediated autophagy
    (2025) Min Huang; Hang Qi; Cheng Liu; Hongzhou Xu; Liang Cai; Bo Xu; Biología Celular e Histología
    Background. Septic patients are at high risk of acute lung injury (ALI). Luteoloside is a flavonoid isolated from natural herbs and has many beneficial effects. This study aimed to investigate the protective role of luteoloside in sepsis-induced ALI. Methods. Sepsis was induced by cecal ligation and puncture (CLP) in C57BL/6 mice. Inflammation was induced by lipopolysaccharide (LPS) in MLE-12 cells. The survival rate over 12 days, histological changes in lung and heart, pulmonary edema, vascular leakage, hypoxemia, and inflammation were examined. Apoptosis was detected by TUNEL staining in vivo and flow cytometry in vitro. The levels of autophagy-related proteins, the AMPK/ULK1 pathway, and the NLRP3 inflammasome were evaluated by western blotting. Cell viability was estimated by MTT assays. LC3 expression was evaluated by immunofluorescence staining. Results. Luteoloside attenuated lung and cardiac injury, pulmonary edema, vascular leakage, hypoxemia, and inflammation and improved the survival of septic mice. Luteoloside (20 mg/kg) had no toxic effect on the heart, liver, spleen, and kidney in normal mice. Luteoloside enhanced autophagy to inhibit apoptosis in vivo and in vitro, and autophagy induction was responsible for the protective effect of luteoloside. Luteoloside activated AMPK/ULK1 signaling to enhance autophagy. Luteoloside also inhibited the activation of the NLRP3 inflammasome in LPS-challenged MLE-12 cells. Conclusion. Overall, luteoloside activates AMPK/ ULK1 signaling to stimulate autophagy, thereby inhibiting apoptosis and alleviating sepsis-induced ALI.