RÉSUMÉ
Doxorubicin (DOX) is a broad-spectrum and highly efficient anticancer agent, but its clinical implication is limited by lethal cardiotoxicity. Growing evidences have shown that alterations in intestinal microbial composition and function, namely dysbiosis, are closely linked to the progression of DOX-induced cardiotoxicity (DIC) through regulating the gut-microbiota-heart (GMH) axis. The role of gut microbiota and its metabolites in DIC, however, is largely unelucidated. Our review will focus on the potential mechanism between gut microbiota dysbiosis and DIC, so as to provide novel insights into the pathophysiology of DIC. Furthermore, we summarize the underlying interventions of microbial-targeted therapeutics in DIC, encompassing dietary interventions, fecal microbiota transplantation (FMT), probiotics, antibiotics, and natural phytochemicals. Given the emergence of microbial investigation in DIC, finally we aim to point out a novel direction for future research and clinical intervention of DIC, which may be helpful for the DIC patients.
Sujet(s)
Cardiotoxicité , Doxorubicine , Microbiome gastro-intestinal , Microbiome gastro-intestinal/effets des médicaments et des substances chimiques , Humains , Doxorubicine/effets indésirables , Cardiotoxicité/étiologie , Animaux , Dysbiose , Transplantation de microbiote fécalRÉSUMÉ
Rationale: Vitamin D (VD) has been suggested to have antitumor effects, however, research on the role of its transporter vitamin D-binding protein (VDBP, gene name as GC) in tumors is limited. In this study, we demonstrated the mechanism underlying the inhibition of vasculogenic mimicry (VM) by VDBP in hepatocellular carcinoma (HCC) and proposed an anti-tumor strategy of combining anti-PD-1 therapy with VD. Methods: Three-dimensional cell culture models and mice with hepatocyte-specific GC deletion were utilized to study the correlation between VDBP expression and VM. A patient-derived tumor xenograft (PDX) model was further applied to validate the therapeutic efficacy of VD in combination with an anti-PD-1 drug. Results: The study revealed that VDBP expression is negatively correlated with VM in HCC patients and elevated VDBP expression is associated with a favorable prognosis. The mechanism studies suggested VDBP hindered the binding of Twist1 on the promoter of VE-cadherin by interacting with its helix-loop-helix DNA binding domain, ultimately leading to the inhibition of VM. Furthermore, VD facilitated the translocation of the vitamin D receptor (VDR) into the nucleus where VDR interacts with Yin Yang 1 (YY1), leading to the transcriptional activation of VDBP. We further demonstrated that the combination of VD and anti-PD-1 led to an improvement in the anti-tumor efficacy of an anti-PD-1 drug. Conclusion: Collectively, we identified VDBP as an important prognostic biomarker in HCC patients and uncovered it as a therapeutic target for enhancing the efficacy of immune therapy.
Sujet(s)
Carcinome hépatocellulaire , Tumeurs du foie , Humains , Souris , Animaux , Carcinome hépatocellulaire/anatomopathologie , Protéine de liaison à la vitamine D/usage thérapeutique , Tumeurs du foie/anatomopathologie , Néovascularisation pathologique/traitement médicamenteux , Néovascularisation pathologique/métabolisme , Différenciation cellulaire , Lignée cellulaire tumoraleRÉSUMÉ
Intense ultraviolet (UV) exposure can cause phototoxic reactions, such as skin inflammation, resulting in injury. UV is a direct cause of DNA damage, but the mechanisms underlying transcriptional regulation within cells after DNA damage are unclear. The bioinformatics analysis of transcriptome sequencing data from UV-irradiated and non-UV-irradiated skin showed that transcription-related proteins, such as HSF4 and COIL, mediate cellular response to UV irradiation. HSF4 and COIL can form a complex under UV irradiation, and the preference for binding target genes changed because of the presence of a large number of R-loops in cells under UV irradiation and the ability of COIL to recognize R-loops. The regulation of target genes was altered by the HSF4-COIL complex, and the expression of inflammation and ageing-related genes, such as Atg7, Tfpi, and Lims1, was enhanced. A drug screen was performed for the recognition sites of COIL and R-loop. N6-(2-hydroxyethyl)-adenosine can competitively bind COIL and inhibit the binding of COIL to the R-loop. Thus, the activation of downstream inflammation-related genes and inflammatory skin injury was inhibited.
Sujet(s)
Structures en boucle R , Peau , Régulation de l'expression des gènes , Facteurs de transcription de choc thermique/métabolisme , Inflammation/génétique , Inflammation/métabolisme , Peau/métabolisme , TranscriptomeRÉSUMÉ
Hepatocellular carcinoma (HCC) is one of the leading causes of death, which deserves further study to reveal the underlying molecular mechanisms. Studies have shown that miR-9 in associated with poor prognosis in HCC patients. However, the mechanisms of transcriptional activation regulation of miR-9 and its role in the malignant progression of HCC have been rarely investigated. Some transcriptional coactivators can form phase-separated condensates at super-enhancers that compartmentalize and concentrate the transcription apparatus to drive robust gene expression. Here, we demonstrate that Twist1 and YY1 could form a transcriptional complex with p300, creating local high-concentration phase-separated interaction hubs at the super-enhancers of miR-9 and activate its expression to promote the malignant progression of HCC by stimulating the migration and invasion of hepatocellular carcinoma cells. Twist1-YY1-p300 phase-separated condensates were disrupted by metformin (Met) and thus reduce miR-9 expression, thereby inhibiting the malignant progression of HCC. Our study demonstrates that the Twist1 transcriptional factor complex involved in the malignant progression of HCC can form phase separation condensates at super-enhancers of miR-9 to promote the expression of oncogenes in HCC cells. It provides a potential target for the therapy of HCC and offers insights into the mechanism of Met in HCC inhibition.
Sujet(s)
Carcinome hépatocellulaire , Tumeurs du foie , Metformine , microARN , Humains , Carcinome hépatocellulaire/traitement médicamenteux , Carcinome hépatocellulaire/génétique , Carcinome hépatocellulaire/métabolisme , Tumeurs du foie/traitement médicamenteux , Tumeurs du foie/génétique , Tumeurs du foie/métabolisme , Metformine/pharmacologie , Metformine/usage thérapeutique , Régulation de l'expression des gènes tumoraux , microARN/génétique , microARN/métabolisme , Lignée cellulaire tumorale , Prolifération cellulaire , Protéines nucléaires/génétique , Protéines nucléaires/métabolisme , Protéine-1 apparentée à Twist/génétique , Protéine-1 apparentée à Twist/métabolisme , Facteur de transcription YY1/génétique , Facteur de transcription YY1/métabolismeSujet(s)
Acide 3-hydroxy-butyrique/métabolisme , Carcinome hépatocellulaire/enzymologie , Histone deacetylases/métabolisme , Tumeurs du foie/enzymologie , Protéines tumorales/métabolisme , Cellules souches tumorales/enzymologie , Protéines de répression/métabolisme , Acide 3-hydroxy-butyrique/génétique , Carcinome hépatocellulaire/génétique , Histone deacetylases/génétique , Humains , Tumeurs du foie/génétique , Protéines tumorales/génétique , Protéines de répression/génétiqueRÉSUMÉ
BACKGROUND: To introduce a novel protocol to treat refractory acute primary angle closure (APAC): transscleral cyclophotocoagulation (TCP) followed by cataract surgery. METHODS: Thirteen APAC eyes (13 patients) were enrolled in this prospective case series as study group. All patients underwent emergency TCP (20 pulses of 2000 mW during 2000 ms applied to the inferior quadrant) followed by scheduled cataract surgery. They were compared to 13 age- and gender-matched patients treated with emergency phacotrabeculectomy. We recorded intraocular pressure (IOP), best corrected visual acuity (BCVA), and complications, and several ultrasound biomicroscopy (UBM) parameters before and after TCP. RESULTS: In the study group, IOP decreased from 51.5 ± 7.0 mmHg (mean ± standard deviation) before TCP to 16.4 ± 5.4 mmHg 1 day after TCP (P < 0.001). At 6 months, there was no significant difference in IOP between the study group (14.0 ± 3.4 mmHg) and control group (16.7 ± 4.3 mmHg; P = 0.090); IOP lowering medications were used by 0/13 in the study group and 2/13 patients in the control group (P = 0.48). At 6 months, there was no significant difference in BCVA between the study group and the control group (20/25 (20/200 to 20/25) and 20/30 (20/50 to 20/25), respectively; P = 1.0). The UBM parameters anterior chamber depth (P = 0.016), angle-opening distance at 500 µm (P = 0.011), and maximum ciliary body thickness (P < 0.001) increased significantly while the iris-ciliary process distance decreased significantly (P = 0.020) after TCP. CONCLUSIONS: TCP effectively lowers IOP and modifies the anterior chamber morphology in APAC; TCP followed by cataract surgery can be considered an alternative to treat refractory APAC but needs further evaluation. TRIAL REGISTRATION: This project was registered in Chinese Clinical Trial Registry (ChiCTR1800017475) at July, 31, 2018 (http://www.chictr.org.cn/edit.aspx?pid=29629&htm=4).
Sujet(s)
Corps ciliaire/chirurgie , Glaucome à angle fermé/chirurgie , Coagulation par laser/méthodes , Lasers à semiconducteur/usage thérapeutique , Phacoémulsification , Maladie aigüe , Sujet âgé , Corps ciliaire/imagerie diagnostique , Femelle , Glaucome à angle fermé/imagerie diagnostique , Glaucome à angle fermé/physiopathologie , Humains , Pression intraoculaire/physiologie , Mâle , Microscopie acoustique , Adulte d'âge moyen , Études prospectives , Sclère , Biomicroscopie , Tonométrie oculaire , Trabéculectomie , Acuité visuelle/physiologieRÉSUMÉ
Dysfunction of the ubiquitin proteasome system (UPS) has been implicated in the pathogenesis of many neurological diseases, including Alzheimer's, spinocerebellar ataxia, and several motor neuron diseases. Recent research indicates that changes in synaptic transmission may play a critical role in the progression of neurological disease; however, the mechanisms by which the UPS regulates synaptic structure and function have not been well characterized. In this report, we show that Usp14 is indispensable for synaptic development and function at neuromuscular junctions (NMJs). Usp14-deficient axJ mice display a resting tremor, a reduction in muscle mass, and notable hindlimb rigidity without any detectable loss of motor neurons. Instead, loss of Usp14 causes developmental defects at motor neuron endplates. Presynaptic defects include phosphorylated neurofilament accumulations, nerve terminal sprouting, and poor arborization of the motor nerve terminals, whereas postsynaptic acetylcholine receptors display immature plaque-like morphology. These structural changes in the NMJ correlated with ubiquitin loss in the spinal cord and sciatic nerve. Further studies demonstrated that the greatest loss of ubiquitin was found in synaptosomal fractions, suggesting that the endplate swellings may be caused by decreased protein turnover at the synapse. Transgenic restoration of Usp14 in the nervous system corrected the levels of monomeric ubiquitin in the motor neuron circuit and the defects that were observed in the motor endplates and muscles of the axJ mice. These data define a critical role for Usp14 at mammalian synapses and suggest a requirement for local ubiquitin recycling by the proteasome to control the development and function of NMJs.
Sujet(s)
Jonction neuromusculaire/enzymologie , Jonction neuromusculaire/croissance et développement , Proteasome endopeptidase complex/métabolisme , Synapses/enzymologie , Ubiquitin thiolesterase/physiologie , Ubiquitine/métabolisme , Animaux , Souris , Souris de lignée C57BL , Souris transgéniques , Jonction neuromusculaire/métabolisme , Ubiquitin thiolesterase/déficitRÉSUMÉ
Transient forebrain ischemia induces delayed, selective neuronal death in the CA1 region of the hippocampus. The underlying molecular mechanisms are as yet unclear, but it is known that activation of L-type Ca2+ channels specifically increases the expression of a group of genes required for neuronal survival. Accordingly, we examined temporal changes in L-type calcium-channel activity in CA1 and CA3 pyramidal neurons of rat hippocampus after transient forebrain ischemia by patch-clamp techniques. In vulnerable CA1 neurons, L-type Ca2+-channel activity was persistently downregulated after ischemic insult, whereas in invulnerable CA3 neurons, no change occurred. Downregulation of L-type calcium channels was partially caused by oxidation modulation in postischemic channels. Furthermore, L-type but neither N-type nor P/Q-type Ca2+-channel antagonists alone significantly inhibited the survival of cultured hippocampal neurons. In contrast, specific L-type calcium-channel agonist remarkably reduced neuronal cell death and restored the inhibited channels induced by nitric oxide donor. More importantly, L-type calcium-channel agonist applied after reoxygenation or reperfusion significantly decreased neuronal injury in in vitro oxygen-glucose deprivation ischemic model and in animals subjected to forebrain ischemia-reperfusion. Together, the present results suggest that ischemia-induced inhibition of L-type calcium currents may give rise to delayed death of neurons in the CA1 region, possibly via oxidation mechanisms. Our findings may lead to a new perspective on neuronal death after ischemic insult and suggest that a novel therapeutic approach, activation of L-type calcium channels, could be tested at late stages of reperfusion for stroke treatment.
Sujet(s)
Encéphalopathie ischémique/métabolisme , Canaux calciques de type L/métabolisme , Hippocampe/métabolisme , Dégénérescence nerveuse/métabolisme , Neurones/métabolisme , Lésion d'ischémie-reperfusion/métabolisme , Animaux , Infarctus encéphalique/métabolisme , Infarctus encéphalique/physiopathologie , Encéphalopathie ischémique/physiopathologie , Agonistes des canaux calciques/pharmacologie , Inhibiteurs des canaux calciques/pharmacologie , Canaux calciques de type L/effets des médicaments et des substances chimiques , Signalisation calcique/effets des médicaments et des substances chimiques , Signalisation calcique/physiologie , Mort cellulaire/effets des médicaments et des substances chimiques , Mort cellulaire/physiologie , Survie cellulaire/effets des médicaments et des substances chimiques , Survie cellulaire/physiologie , Régulation négative/effets des médicaments et des substances chimiques , Régulation négative/physiologie , Hippocampe/effets des médicaments et des substances chimiques , Mâle , Dégénérescence nerveuse/étiologie , Dégénérescence nerveuse/physiopathologie , Neurones/effets des médicaments et des substances chimiques , Techniques de culture d'organes , Stress oxydatif/effets des médicaments et des substances chimiques , Stress oxydatif/physiologie , Techniques de patch-clamp , Cellules pyramidales/effets des médicaments et des substances chimiques , Cellules pyramidales/métabolisme , Rats , Rat Wistar , Lésion d'ischémie-reperfusion/physiopathologie , Facteurs tempsRÉSUMÉ
An improved method is described for fast and reliable isolation of neurons from hippocampus of adult rats by a combination of mechanical and enzymatic means. The procedure allows the isolation of neurons from 500-600-d-old rats (over 300 g), preserving the proximal dendritic structure without impairing the electrical characteristics of the cells. Morphologically distinct neurons can be recognized. Using cell-attached, inside-out and whole-cell configurations of patch clamp technique, it was shown that the enzymatically isolated neurons in hippocampus from rats weighing more than 300 g exhibited voltage-gated calcium, sodium and potassium currents, outwardly rectifying chloride channel and large conductance Ca(2+)-activated potassium channel currents. Approximately, 95% of healthy cells allowed the formation of giga-ohm seals.
Sujet(s)
Séparation cellulaire/méthodes , Hippocampe/cytologie , Animaux , Ouverture et fermeture des portes des canaux ioniques/physiologie , Neurones/cytologie , Techniques de patch-clamp , Canaux potassiques calcium-dépendants/physiologie , Rats , Rat WistarRÉSUMÉ
Buyang Huanwu Decoction (BYHWD), a traditional Chinese medicine, has been developed as a drug to be used for treatment of stroke for hundreds of years. However, the underlying mechanisms remain unknown. In the present study, the effects of BYHWD on delayed neuronal death of hippocampus after transient forebrain ischemia were examined in rats. Transient forebrain ischemia in a duration of 15 min was induced with the four-vessel occlusion method. BYHWD (per 6.65 g/kg) was given orally to rats twice each day for 7 days before ischemia. In BYHWD-pretreated rats, the neuronal injury in the hippocampal CA1 region was significantly less than that of controls. Oral administration of BYHWD also markedly attenuated the number of TUNEL-positive neurons and suppressed the expression of caspase-3p20, a product of catalytically active caspase-3, in the CA1 region. Our results suggest that an inhibition of caspase-3 and apoptosis by BYHWD may partially account for its neuroprotection against ischemic injury in the hippocampal CA1 region.