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1.
Glia ; 71(1): 71-90, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36222019

RESUMEN

Microglia, the innate immune cells of the central nervous system (CNS), execute their sentinel, housekeeping and defense functions through a panoply of genes, receptors and released cytokines, chemokines and neurotrophic factors. Moreover, microglia functions are closely linked to the constant communication with other cell types, among them neurons. Depending on the signaling pathway and type of stimuli involved, the outcome of microglia operation can be neuroprotective or neurodegenerative. Accordingly, microglia are increasingly becoming considered cellular targets for therapeutic intervention. Among signals controlling microglia activity, the endocannabinoid (EC) system has been shown to exert a neuroprotective role in many neurological diseases. Like neurons, microglia express functional EC receptors and can produce and degrade ECs. Interestingly, boosting EC signaling leads to an anti-inflammatory and neuroprotective microglia phenotype. Nonetheless, little evidence is available on the microglia-mediated therapeutic effects of EC compounds. This review focuses on the EC signals acting on the CNS microglia in physiological and pathological conditions, namely on the CB1R, CB2R and TRPV1-mediated regulation of microglia properties. It also provides new evidence, which strengthens the understanding of mechanisms underlying the control of microglia functions by ECs. Given the broad expression of the EC system in glial and neuronal cells, the resulting picture is the need for in vivo studies in transgenic mouse models to dissect the contribution of EC microglia signaling in the neuroprotective effects of EC-derived compounds.


Asunto(s)
Microglía , Fármacos Neuroprotectores , Animales , Ratones , Microglía/metabolismo , Endocannabinoides/farmacología , Endocannabinoides/metabolismo , Transducción de Señal , Ratones Transgénicos , Fármacos Neuroprotectores/farmacología
2.
Int J Mol Sci ; 24(10)2023 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-37239933

RESUMEN

The present editorial intends to comment on the contributions published in the second edition of the Special Issue (SI) "The Multiple Mechanisms Underlying Neuropathic Pain" [...].


Asunto(s)
Neuralgia , Humanos
3.
Int J Mol Sci ; 24(10)2023 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-37239924

RESUMEN

Neuropathic pain (NeuP) is still an intractable form of highly debilitating chronic pain, resulting from a lesion or disease of the somatosensory nervous system [...].


Asunto(s)
Dolor Crónico , Neuralgia , Neuroesteroides , Humanos , Factores Sexuales , Neuralgia/tratamiento farmacológico , Neuralgia/patología
4.
Int J Mol Sci ; 24(3)2023 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-36769236

RESUMEN

Traumatic brain injury (TBI) represents one of the most common worldwide causes of death and disability. Clinical and animal model studies have evidenced that TBI is characterized by the loss of both gray and white matter, resulting in brain atrophy and in a decrease in neurological function. Nowadays, no effective treatments to counteract TBI-induced neurological damage are available. Due to its complex and multifactorial pathophysiology (neuro-inflammation, cytotoxicity and astroglial scar formation), cell regeneration and survival in injured brain areas are strongly hampered. Recently, it has been proposed that adult neurogenesis may represent a new approach to counteract the post-traumatic neurodegeneration. In our laboratory, we have recently shown that physical exercise induces the long-lasting enhancement of subventricular (SVZ) adult neurogenesis in a p21 (negative regulator of neural progenitor proliferation)-null mice model, with a concomitant improvement of olfactory behavioral paradigms that are strictly dependent on SVZ neurogenesis. On the basis of this evidence, we have investigated the effect of running on SVZ neurogenesis and neurorepair processes in p21 knock-out mice that were subject to TBI at the end of a 12-day session of running. Our data indicate that runner p21 ko mice show an improvement in numerous post-trauma neuro-regenerative processes, including the following: (i) an increase in neuroblasts in the SVZ; (ii) an increase in the migration stream of new neurons from the SVZ to the damaged cortical region; (iii) an enhancement of new differentiating neurons in the peri-lesioned area; (iv) an improvement in functional recovery at various times following TBI. All together, these results suggest that a running-dependent increase in subventricular neural stem cells could represent a promising tool to improve the endogenous neuro-regenerative responses following brain trauma.


Asunto(s)
Lesiones Traumáticas del Encéfalo , Células-Madre Neurales , Carrera , Animales , Ratones , Ratones Noqueados , Lesiones Traumáticas del Encéfalo/genética , Lesiones Traumáticas del Encéfalo/terapia , Neuronas , Neurogénesis , Proliferación Celular
5.
Int J Mol Sci ; 23(23)2022 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-36498830

RESUMEN

As a widely prescribed anti-diabetic drug, metformin has been receiving novel attention for its analgesic potential. In the study of the complex etiology of neuropathic pain (NeP), male and female individuals exhibit quite different responses characterized by higher pain sensitivity and greater NeP incidence in women. This "gender gap" in our knowledge of sex differences in pain processing strongly limits the sex-oriented treatment of patients suffering from NeP. Besides, the current investigation of the analgesic potential of metformin has not addressed the "gender gap" problem. Hence, this study focuses on metformin and sex-dependent analgesia in a murine model of NeP induced by chronic constriction injury of the sciatic nerve. We investigated sexual dimorphism in signaling pathways involved by 7 days of metformin administration, such as changes in AMP-activated protein kinase and the positive regulation of autophagy machinery, discovering that metformin affected in a sexually dimorphic manner the immunological and inflammatory response to nerve lesion. These effects were complemented by morphological and adaptive changes occurring after peripheral nerve injury. Altogether these data can contribute to explaining a number of potential mechanisms responsible for the complete recovery from NeP found in male mice, as opposed to the failure of long-lasting recovery in female animals.


Asunto(s)
Analgésicos , Metformina , Neuralgia , Neuropatía Ciática , Caracteres Sexuales , Animales , Femenino , Masculino , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Analgésicos/farmacología , Hiperalgesia/metabolismo , Metformina/farmacología , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Nervio Ciático/metabolismo , Neuropatía Ciática/tratamiento farmacológico
6.
Neurobiol Dis ; 160: 105538, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34743985

RESUMEN

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by depletion of motor neurons (MNs), for which effective medical treatments are still required. Previous transcriptomic analysis revealed the up-regulation of C-X-C motif chemokine receptor 2 (CXCR2)-mRNA in a subset of sporadic ALS patients and SOD1G93A mice. Here, we confirmed the increase of CXCR2 in human ALS cortex, and showed that CXCR2 is mainly localized in cell bodies and axons of cortical neurons. We also investigated the effects of reparixin, an allosteric inhibitor of CXCR2, in degenerating human iPSC-derived MNs and SOD1G93A mice. In vitro, reparixin rescued MNs from apoptotic cell death, preserving neuronal morphology, mitochondrial membrane potential and cytoplasmic membrane integrity, whereas in vivo it improved neuromuscular function of SOD1G93A mice. Altogether, these data suggest a role for CXCR2 in ALS pathology and support its pharmacological inhibition as a candidate therapeutic strategy against ALS at least in a specific subgroup of patients.


Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Degeneración Nerviosa/metabolismo , Unión Neuromuscular/metabolismo , Neuronas/metabolismo , Receptores de Interleucina-8B/metabolismo , Esclerosis Amiotrófica Lateral/genética , Animales , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Ratones , Ratones Transgénicos , Degeneración Nerviosa/genética , Unión Neuromuscular/genética , Receptores de Interleucina-8B/genética , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo
7.
Acta Neuropathol ; 142(3): 537-564, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34302498

RESUMEN

Medulloblastoma (MB) is a childhood malignant brain tumour comprising four main subgroups characterized by different genetic alterations and rate of mortality. Among MB subgroups, patients with enhanced levels of the c-MYC oncogene (MBGroup3) have the poorest prognosis. Here we identify a previously unrecognized role of the pro-autophagy factor AMBRA1 in regulating MB. We demonstrate that AMBRA1 expression depends on c-MYC levels and correlates with Group 3 patient poor prognosis; also, knockdown of AMBRA1 reduces MB stem potential, growth and migration of MBGroup3 stem cells. At a molecular level, AMBRA1 mediates these effects by suppressing SOCS3, an inhibitor of STAT3 activation. Importantly, pharmacological inhibition of autophagy profoundly affects both stem and invasion potential of MBGroup3 stem cells, and a combined anti-autophagy and anti-STAT3 approach impacts the MBGroup3 outcome. Taken together, our data support the c-MYC/AMBRA1/STAT3 axis as a strong oncogenic signalling pathway with significance for both patient stratification strategies and targeted treatments of MBGroup3.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Autofagia/efectos de los fármacos , Neoplasias Cerebelosas/tratamiento farmacológico , Meduloblastoma/tratamiento farmacológico , Factor de Transcripción STAT3/genética , Transducción de Señal/efectos de los fármacos , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Niño , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Ratones Endogámicos C57BL , Células Madre Neoplásicas , Pronóstico , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Proteínas Proto-Oncogénicas c-myc/genética , Proteína 3 Supresora de la Señalización de Citocinas/antagonistas & inhibidores
8.
Int J Mol Sci ; 22(9)2021 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-33922372

RESUMEN

Neuropathic pain (NeP) in humans is often a life-long condition with no effective therapy available. The higher incidence of female gender in NeP onset is worldwide reported, and although the cause is generally attributed to sex hormones, the actual mechanisms and the players involved are still unclear. Glial and immune cells take part in NeP development, and orchestrate the neuroimmune and inflammatory response, releasing pro-inflammatory factors with chemoattractant properties that activate resident immune cells and recruit immune cells from circulation. The neuro-immune crosstalk is a key contributor to pain hypersensitivity following peripheral nervous system injury. Our previous works showed that in spite of the fact that female mice had an earlier analgesic response than males following nerve lesion, the recovery from NeP was never complete, suggesting that this difference could occur in the very early stages after injury. To further investigate gender differences in immune and neuroimmune responses to NeP, we studied the main immune cells and mediators elicited both in plasma and sciatic nerves by peripheral nerve lesion. After injury, we found a different pattern of distribution of immune cell populations showing either a higher infiltration of T cells in nerves from females or a higher infiltration of macrophages in nerves from males. Moreover, in comparison to male mice, the levels of cytokines and chemokines were differently up- and down-regulated in blood and nerve lysates from female mice. Our study provides some novel insights for the understanding of gender-associated differences in the generation and perseveration of NeP as well as for the isolation of specific neurodegenerative mechanisms underlying NeP. The identification of gender-associated inflammatory profiles in neuropathy is of key importance for the development of differential biomarkers and gender-specific personalized medicine.


Asunto(s)
Gliosis/patología , Hiperalgesia/patología , Inflamación/patología , Macrófagos/patología , Neuralgia/patología , Traumatismos de los Nervios Periféricos/complicaciones , Nervio Ciático/patología , Animales , Citocinas , Femenino , Gliosis/etiología , Hiperalgesia/etiología , Inflamación/etiología , Masculino , Ratones , Neuralgia/etiología , Factores Sexuales
9.
Future Oncol ; 14(29): 3049-3058, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30091371

RESUMEN

AIM: This multicenter field-practice study evaluates outcomes of long-term sorafenib in hepatocellular carcinoma (HCC) patients. METHODS: Consecutive HCC patients on sorafenib were enrolled. We evaluated those receiving sorafenib for ≥12 months. RESULTS: Out of 800 patients on sorafenib, 81 (10%) received long-term treatment. Median duration of treatment was 22.7 months (range: 12.3-92.6). Only 21 (26%) reported grade 3/4 adverse events. Complete response was reported in 11 patients (14%). Median overall survival was 34.8 months (95% CI: 29.9-44.3). Only baseline Child-Pugh class was associated with survival. CONCLUSION: Sorafenib could result in long-term control of HCC in a relevant proportion of patients. Given the availability of regorafenib in the second-line setting, an earlier introduction of systemic therapy may be considered according to clinical indications.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Cuidados a Largo Plazo/métodos , Sorafenib/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidad , Femenino , Humanos , Italia/epidemiología , Estimación de Kaplan-Meier , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
10.
Hepatology ; 63(3): 827-38, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26599351

RESUMEN

UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of metabolic syndrome and may evolve into hepatocellular carcinoma (HCC). Only scanty clinical information is available on HCC in NAFLD. The aim of this multicenter observational prospective study was to assess the clinical features of patients with NAFLD-related HCC (NAFLD-HCC) and to compare them to those of hepatitis C virus (HCV)-related HCC. A total of 756 patients with either NAFLD (145) or HCV-related chronic liver disease (611) were enrolled in secondary care Italian centers. Survival was modeled according to clinical parameters, lead-time bias, and propensity analysis. Compared to HCV, HCC in NAFLD patients had a larger volume, showed more often an infiltrative pattern, and was detected outside specific surveillance. Cirrhosis was present in only about 50% of NAFLD-HCC patients, in contrast to the near totality of HCV-HCC. Regardless of tumor stage, survival was significantly shorter (P = 0.017) in patients with NAFLD-HCC, 25.5 months (95% confidence interval 21.9-29.1), than in those with HCV-HCC, 33.7 months (95% confidence interval 31.9-35.4). To eliminate possible confounders, a propensity score analysis was performed, which showed no more significant difference between the two groups. Additionally, analysis of patients within Milan criteria submitted to curative treatments did not show any difference in survival between NAFLD-HCC and HCV-HCC (respectively, 38.6 versus 41.0 months, P = nonsignificant) CONCLUSIONS: NAFLD-HCC is more often detected at a later tumor stage and could arise also in the absence of cirrhosis, but after patient matching, it has a similar survival rate compared to HCV infection; a future challenge will be to identify patients with NAFLD who require more stringent surveillance in order to offer the most timely and effective treatment.


Asunto(s)
Carcinoma Hepatocelular/virología , Hepatitis C Crónica/complicaciones , Neoplasias Hepáticas/virología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/mortalidad , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Estudios Prospectivos
11.
Liver Int ; 35(3): 1036-47, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24750853

RESUMEN

BACKGROUND & AIMS: Sorafenib and transarterial (90) Y-radioembolization (TARE) are possible treatments for Barcelona Clinic Liver Cancer (BCLC) intermediate-advanced stage hepatocellular carcinoma (HCC). No study directly comparing sorafenib and TARE is currently available. This single-centre retrospective study compares the outcomes achieved with sorafenib and TARE in HCC patients potentially amenable to either therapy. METHODS: Seventy-four sorafenib (71 ± 10 years, male 87%, BCLC B/C 53%/47%) and 63 TARE HCC patients (66 ± 9 years, male 79%, BCLC B/C 41%/59%) were included based on the following criteria: Child-Pugh class A/B, performance status ≤1, HCC unfit for other effective therapies, no metastases and no previous systemic chemotherapy. RESULTS: Median overall survivals of the two groups were comparable, being 14.4 months (95% CI: 4.3-24.5) in sorafenib and 13.2 months (95% CI: 6.1-20.2) in TARE patients, with 1-, 2- and 3-year survival rates of 52.1%, 29.3% and 14.7% vs 51.8%, 27.8% and 21.6% respectively. Two TARE patients underwent liver transplantation after successful down-staging. To minimize the impact of confounding factors on survival analysis, propensity model matched 32 patients of each group for median age, tumour gross pathology and the independent prognostic factors (portal vein thrombosis, performance status, Model for End Liver Disease). Even after matching, the median survival did not differ between sorafenib (13.1 months; 95% CI: 1.2-25.9) and TARE patients (11.2 months; 95% CI: 6.7-15.7), with comparable 1-, 2- and 3-year survival rates. CONCLUSIONS: In cirrhotic patients with intermediate-advanced or not-otherwise-treatable HCC, sorafenib and TARE provide similar survivals. Down-staging allowing liver transplantation only occurred after TARE.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/terapia , Embolización Terapéutica , Neoplasias Hepáticas/terapia , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Radioisótopos de Itrio/uso terapéutico , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/mortalidad , Estudios de Casos y Controles , Causas de Muerte , Femenino , Humanos , Italia/epidemiología , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Niacinamida/uso terapéutico , Puntaje de Propensión , Estudios Retrospectivos , Sorafenib
12.
J Cell Physiol ; 229(6): 783-90, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24166293

RESUMEN

The peripheral application of the M2 cholinergic agonist arecaidine on sensory nerve endings shows anti-nociceptive properties. In this work, we analyze in vitro, the mechanisms downstream M2 receptor activation causing the analgesic effects, and in vivo the effects produced by M2 agonist arecaidine administration on nociceptive responses in a murine model of nerve growth factor (NGF)-induced pain. Cultured DRG neurons treated with arecaidine showed a decreased level of VR1 and SP transcripts. Conversely, we found an increased expression of VR1 and SP transcripts in DRG from M2/M4(-/-) mice compared to WT and M1(-/-) mice, confirming the inhibitory effect in particular of M2 receptors on SP and VR1 expression. Patch-clamp experiments in the whole-cell configuration showed that arecaidine treatment caused a reduction of the fraction of capsaicin-responsive cells, without altering the mean capsaicin-activated current in responsive cells. We also demonstrated that arecaidine prevents PKCϵ translocation to the plasma membrane after inflammatory agent stimulation, mainly in medium-small sensory neurons. Finally, in mice, we have observed that intraperitoneal injection of arecaidine reduces VR1 expression blocking hyperalgesia and allodynia caused by NGF intraplantar administration. In conclusion, our data demonstrate that in vivo M2 receptor activation induces desensitization to mechanical and heat stimuli by a down-regulation of VR1 expression and by the inhibition of PKCϵ activity hindering its translocation to the plasma membrane, as suggested by in vitro experiments.


Asunto(s)
Receptor Muscarínico M2/metabolismo , Células Receptoras Sensoriales/fisiología , Canales Catiónicos TRPV/metabolismo , Animales , Arecolina/administración & dosificación , Arecolina/análogos & derivados , Arecolina/farmacología , Células Cultivadas , Agonistas Colinérgicos/administración & dosificación , Agonistas Colinérgicos/farmacología , Regulación de la Expresión Génica/fisiología , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Inyecciones Intraperitoneales , Masculino , Ratones , Ratones Noqueados , Factor de Crecimiento Nervioso , Técnicas de Placa-Clamp , Proteína Quinasa C-epsilon/metabolismo , Ratas , Ratas Wistar , Receptor Muscarínico M2/agonistas , Receptor Muscarínico M2/genética , Células Receptoras Sensoriales/clasificación , Células Receptoras Sensoriales/efectos de los fármacos , Canales Catiónicos TRPV/genética
13.
Int J Cancer ; 135(5): 1247-56, 2014 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-24510746

RESUMEN

Although new treatment modalities changed the global approach to hepatocellular carcinoma (HCC), this disease still represents a medical challenge. Currently, the therapeutic stronghold is sorafenib, a tyrosine kinase inhibitor (TKI) directed against the vascular endothelial growth factor (VEGF) family. Previous observations suggested that polymorphisms of VEGF and its receptor (VEGFR) genes may regulate angiogenesis and lymphangiogenesis and thus tumour growth control. The aim of our study was to evaluate the role of VEGF and VEGFR polymorphisms in determining the clinical outcome of HCC patients receiving sorafenib. From a multicentre experience 148 samples (tumour or blood samples) of HCC patients receiving sorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients' progression-free survival (PFS) and overall survival (OS) were analysed. At univariate analysis VEGF-A alleles C of rs25648, T of rs833061, C of rs699947, C of rs2010963, VEGF-C alleles T of rs4604006, G of rs664393, VEGFR-2 alleles C of rs2071559, C of rs2305948 were significant predictors of PFS and OS. At multivariate analysis rs2010963, rs4604006 and BCLC (Barcelona Clinic Liver Cancer) stage resulted to be independent factors influencing PFS and OS. Once prospectively validated, the analysis of VEGF and VEGFR SNPs may represent a clinical tool to better identify HCC patients more likely to benefit from sorafenib. On the other hand, the availability of more accurate predictive factors could help avoiding unnecessary toxicities to potentially resistant patients who may be optimal candidates for different treatments interfering with other tumour molecular pathways.


Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Adulto , Anciano , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/mortalidad , Proliferación Celular/efectos de los fármacos , Supervivencia sin Enfermedad , Femenino , Genotipo , Humanos , Neoplasias Hepáticas/mortalidad , Linfangiogénesis/efectos de los fármacos , Masculino , Persona de Mediana Edad , Neovascularización Patológica/tratamiento farmacológico , Niacinamida/uso terapéutico , Polimorfismo de Nucleótido Simple , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos , Sorafenib , Resultado del Tratamiento , Factor C de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 3 de Factores de Crecimiento Endotelial Vascular/genética
14.
BMC Cancer ; 14: 403, 2014 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-24902850

RESUMEN

BACKGROUND: Development of escape pathways from antiangiogenic treatments was reported to be associated with enhanced tumor aggressiveness and rebound effect was suggested after treatment stop. Aim of the study was to evaluate tumor response simulating different conditions of administration of antiangiogenic treatment (transient or definitive treatment stop) in a mouse model of hepatocellular carcinoma. METHODS: Subcutaneous tumors were created by inoculating 5 × 10(6) Huh7 cells into the right flank of 14 nude mice. When tumor size reached 5-10 mm, mice were divided in 3 groups: group 1 was treated with placebo, group 2 was treated with sorafenib (62 mg/kg via gavage) but temporarily suspended from day +5 to +9, whereas in group 3 sorafenib was definitively stopped at day +5. At day +13 all mice were sacrificed, collecting masses for Western-Blot analyses. Volume was calculated with B-mode ultrasonography at day 0, +5, +9, +11 and +13. VEGFR2-targeted contrast-enhanced ultrasound using BR55 (Bracco Imaging) was performed at day +5 and +13 and elastonosography (Esaote) at day +9 and +11 to assess tumor stiffness. RESULTS: Median growth percentage delta at day +13 versus day 0 was 197% (115-329) in group 1, 81% (48-144) in group 2 and 111% (27-167) in group 3. Median growth delta at day +13 with respect to day +5 was 79% (48-127), 37% (-14128) and 81% (15-87) in groups 1, 2 and 3, respectively. Quantification of targeted-CEUS at day +13 showed higher values in group 3 (509 Arbitrary Units AI, range 293-652) than group 1 (275 AI, range 191-494) and group 2 (181 AI, range 63-318) (p=0.033). Western-Blot analysis demonstrated higher VEGFR2 expression in group 3 with respect to group 1 and 2. CONCLUSIONS: A transient interruption of antiangiogenic treatment does not impede restoration of tumor response, while a definitive interruption tends to stimulate a rebound of angiogenesis to higher level than without treatment.


Asunto(s)
Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/tratamiento farmacológico , Inhibidores de la Angiogénesis/administración & dosificación , Animales , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Neoplasias Hepáticas/patología , Ratones , Neovascularización Patológica/tratamiento farmacológico , Niacinamida/administración & dosificación , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Sorafenib , Ultrasonografía , Receptor 2 de Factores de Crecimiento Endotelial Vascular/química
15.
J Psychosoc Oncol ; 32(5): 517-34, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24988462

RESUMEN

Security of attachment is described as an inner resource that may also facilitate the adaptation of individuals during critical life adversity, even when facing end-stage illness and death. This study assessed the relation between attachment styles, patient-caregiver reciprocal empathy, and patient-physician working alliance, in the terminal phase of an oncological disease. We hypothesized that the attachment security of patients, as measured by the Relationship Questionnaire (RQ), is related to the reciprocal empathy with the caregiver, as measured by the Perception of Partner Empathy (PPE) questionnaire, and to the working alliance with the physician, as measured by the Working Alliance Inventory-Short Form (WAI-S). Thirty-seven end-stage cancer patients, their caregivers, and physicians participated in the study. The PPE and WAI-S were administered twice: immediately after the hospice recovery and a week later. Results showed a significant improvement in patient-caregiver empathy and in patient-physician alliance after a week at the hospice. Findings indicated that the patients' attachment style influenced their perception of reciprocal empathy with the caregiver and the working alliance with the physician. Patients with a secure attachment had a greater capacity to show empathic closeness with their caregivers and enjoyed a better working alliance with their physicians. Caregivers' attachment security, otherwise, did not show the same influence on empathy and alliance. Findings support the hypothesis that patients' attachment security plays a crucial role in the relation with their own caregiver and with the physician, even at the terminal phase. Theoretical and clinical implications of these findings are explored in the discussion.


Asunto(s)
Cuidadores/psicología , Empatía , Cuidados Paliativos al Final de la Vida , Neoplasias/terapia , Apego a Objetos , Relaciones Médico-Paciente , Adulto , Anciano , Cuidadores/estadística & datos numéricos , Femenino , Cuidados Paliativos al Final de la Vida/psicología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/psicología , Teoría Psicológica
16.
Stem Cell Res Ther ; 15(1): 197, 2024 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-38971774

RESUMEN

BACKGROUND: Traumatic Brain Injury (TBI) represents one of the main causes of brain damage in young people and the elderly population with a very high rate of psycho-physical disability and death. TBI is characterized by extensive cell death, tissue damage and neuro-inflammation with a symptomatology that varies depending on the severity of the trauma from memory loss to a state of irreversible coma and death. Recently, preclinical studies on mouse models have demonstrated that the post-traumatic adult Neural Stem/Progenitor cells response could represent an excellent model to shed light on the neuro-reparative role of adult neurogenesis following damage. The cyclin-dependent kinase inhibitor p21Waf1/Cip1 plays a pivotal role in modulating the quiescence/activation balance of adult Neural Stem Cells (aNSCs) and in restraining the proliferation progression of progenitor cells. Based on these considerations, the aim of this work is to evaluate how the conditional ablation of p21Waf1/Cip1 in the aNSCS can alter the adult hippocampal neurogenesis in physiological and post-traumatic conditions. METHODS: We designed a novel conditional p21Waf1/Cip1 knock-out mouse model, in which the deletion of p21Waf1/Cip1 (referred as p21) is temporally controlled and occurs in Nestin-positive aNSCs, following administration of Tamoxifen. This mouse model (referred as p21 cKO mice) was subjected to Controlled Cortical Impact to analyze how the deletion of p21 could influence the post-traumatic neurogenic response within the hippocampal niche. RESULTS: The data demonstrates that the conditional deletion of p21 in the aNSCs induces a strong increase in activation of aNSCs as well as proliferation and differentiation of neural progenitors in the adult dentate gyrus of the hippocampus, resulting in an enhancement of neurogenesis and the hippocampal-dependent working memory. However, following traumatic brain injury, the increased neurogenic response of aNSCs in p21 cKO mice leads to a fast depletion of the aNSCs pool, followed by declined neurogenesis and impaired hippocampal functionality. CONCLUSIONS: These data demonstrate for the first time a fundamental role of p21 in modulating the post-traumatic hippocampal neurogenic response, by the regulation of the proliferative and differentiative steps of aNSCs/progenitor populations after brain damage.


Asunto(s)
Lesiones Traumáticas del Encéfalo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Hipocampo , Ratones Noqueados , Células-Madre Neurales , Neurogénesis , Animales , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Células-Madre Neurales/metabolismo , Ratones , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/genética , Hipocampo/metabolismo , Hipocampo/patología , Modelos Animales de Enfermedad , Masculino , Proliferación Celular , Ratones Endogámicos C57BL
17.
Brain Behav Immun ; 32: 40-50, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23402794

RESUMEN

The use of botulinum neurotoxin type A (BoNT/A) against pain, with emphasis for its possible use in alleviating chronic pain, still represents an outstanding challenge for experimental research. In this study, we examined the effects of BoNT/A on morphine-induced tolerance during chronic morphine treatment in neuropathic CD1 mice subjected to sciatic nerve lesion according to the Chronic Constriction Injury (CCI) model of neuropathic pain. We measured the effects of BoNT/A on CCI-induced allodynia and hyperalgesia and on the expression of glial fibrillary acidic protein (GFAP, marker of astrocytes), complement receptor 3/cluster of differentiation 11b (CD11b, marker of microglia), and neuronal nuclei (NeuN) at the spinal cord level. We also analyzed the colocalized expression of GFAP, CD11b and NeuN with phosphorylated p-38 mitogen-activated protein kinase and with µ-opioid receptor (MOR). A single intraplantar injection of BoNT/A (15 pg/paw) into the injured hindpaw, the day before the beginning of chronic morphine treatment (9 days of twice daily injections of 40 mg/kg morphine), was able to counteract allodynia and enhancement of astrocytes expression/activation induced by CCI. In addition, BoNT/A increased the analgesic effect of morphine and countered morphine-induced tolerance during chronic morphine treatment. These effects were accompanied, in neurons, by re-expression of MORs that had been reduced by repeated morphine administration. The combinatory effects of BoNT/A and morphine could have relevant therapeutic implications for sufferers of chronic pain who could benefit of pain relief reducing tolerance due to repeated treatment with opiates.


Asunto(s)
Analgésicos Opioides/uso terapéutico , Toxinas Botulínicas Tipo A/uso terapéutico , Tolerancia a Medicamentos/fisiología , Activación de Macrófagos/fisiología , Morfina/uso terapéutico , Neuroglía/efectos de los fármacos , Fármacos Neuromusculares/uso terapéutico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Receptores Opioides mu/biosíntesis , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Antígeno CD11b/metabolismo , Dolor Crónico/tratamiento farmacológico , Sinergismo Farmacológico , Proteína Ácida Fibrilar de la Glía/metabolismo , Calor , Hiperalgesia/tratamiento farmacológico , Inmunohistoquímica , Masculino , Ratones , Microscopía Confocal , Enfermedades del Sistema Nervioso Periférico/inmunología , Enfermedades del Sistema Nervioso Periférico/psicología , Estimulación Física , Receptores Opioides mu/genética , Médula Espinal/patología
18.
Liver Int ; 33(5): 771-9, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23445369

RESUMEN

AIM: Primary aim was to validate the percentage of intrahepatic cholangiocarcinomas (ICC) which have a contrast vascular pattern at contrast enhanced ultrasound (CEUS) at risk of misdiagnosis with hepatocellular carcinoma (HCC) and, secondary aim, to verify if any characteristics in the CEUS pattern helps to identify ICC. METHODS: All ICC on cirrhosis seen in three Italian centres (Bologna, Milan and Pavia) between 2003 and 2011, in which CEUS and at least another imaging technique (CT or MRI) had been performed, were retrospectively identified. Those patients with ICC size comparable to the early HCC stage (Milan criteria, considered as small ICC) were enrolled for this study. The enhancement pattern at CEUS was analysed and compared with CT or MRI. RESULTS: A total of 25 small ICC made this study group. CEUS was at risk of misdiagnosis of ICC for HCC in a significantly higher number of cases than in CT (performed in 24 ICC) (52% vs. 4.2%, P = 0.009) and MRI (11 ICC) (52% vs. 9.1%, P = 0.02). A different contrast pattern among all techniques was found in 6 of 10 ICC lesions submitted to the three imaging methods. In the arterial phase, ICC lacked global hyperenhacement in approximately 50% of cases at CEUS and the degree of intensity of wash-out in the late phase was marked in 24% of nodules. CONCLUSIONS: CEUS misdiagnosed as HCC a significantly higher number of ICC lesions in cirrhotic patients than CT and MRI. However, some CEUS contrast features can help suspect ICC, especially in some cases with inconclusive CT or MRI.


Asunto(s)
Carcinoma Hepatocelular/diagnóstico por imagen , Colangiocarcinoma/diagnóstico por imagen , Colangiocarcinoma/patología , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/diagnóstico por imagen , Anciano , Neoplasias de los Conductos Biliares , Conductos Biliares Intrahepáticos , Colangiocarcinoma/etiología , Diagnóstico Diferencial , Femenino , Humanos , Italia , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Estadísticas no Paramétricas , Tomografía Computarizada por Rayos X , Ultrasonografía
19.
Toxins (Basel) ; 15(4)2023 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-37104185

RESUMEN

Xeomin® is a commercial formulation of botulinum neurotoxin type A (BoNT/A) clinically authorized for treating neurological disorders, such as blepharospasm, cervical dystonia, limb spasticity, and sialorrhea. We have previously demonstrated that spinal injection of laboratory purified 150 kDa BoNT/A in paraplegic mice, after undergoing traumatic spinal cord injury (SCI), was able to reduce excitotoxic phenomena, glial scar, inflammation, and the development of neuropathic pain and facilitate regeneration and motor recovery. In the present study, as proof of concept in view of a possible clinical application, we studied the efficacy of Xeomin® in the same preclinical SCI model in which we highlighted the positive effects of lab-purified BoNT/A. Data comparison shows that Xeomin® induces similar pharmacological and therapeutic effects, albeit with less efficacy, to lab-purified BoNT/A. This difference, which can be improved by adjusting the dose, can be attributable to the different formulation and pharmacodynamics. Although the mechanism by which Xeomin® and laboratory purified BoNT/A induce functional improvement in paraplegic mice is still far from being understood, these results open a possible new scenario in treatment of SCI and are a stimulus for further research.


Asunto(s)
Blefaroespasmo , Toxinas Botulínicas Tipo A , Enfermedades del Sistema Nervioso , Traumatismos de la Médula Espinal , Animales , Ratones , Toxinas Botulínicas Tipo A/farmacología , Toxinas Botulínicas Tipo A/uso terapéutico , Blefaroespasmo/tratamiento farmacológico , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Traumatismos de la Médula Espinal/tratamiento farmacológico
20.
iScience ; 26(10): 107914, 2023 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-37817933

RESUMEN

Epidemiological data and research highlight increased neuropathy and chronic pain prevalence among females, spanning metabolic and normometabolic contexts, including murine models. Prior findings demonstrated diverse immune and neuroimmune responses between genders in neuropathic pain (NeP), alongside distinct protein expression in sciatic nerves. This study unveils adipose tissue's (AT) role in sex-specific NeP responses after peripheral nerve injury. Metabolic assessments, metabolomics, energy expenditure evaluations, AT proteomic analyses, and adipokine mobilization depict distinct AT reactions to nerve damage. Females exhibit altered lipolysis, fatty acid oxidation, heightened energy expenditure, and augmented steroids secretion affecting glucose and insulin metabolism. Conversely, male neuropathy prompts glycolysis, reduced energy expenditure, and lowered unsaturated fatty acid levels. Males' AT promotes regenerative molecules, oxidative stress defense, and stimulates peroxisome proliferator-activated receptors (PPAR-γ) and adiponectin. This study underscores AT's pivotal role in regulating gender-specific inflammatory and metabolic responses to nerve injuries, shedding light on female NeP susceptibility determinants.

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