Parkinson's disease: autoimmunity and neuroinflammation

Parkinson's disease is a neurodegenerative disease that causes the death of dopaminergic neurons in the substantia nigra. The resulting dopamine deficiency in the basal ganglia leads to a movement disorder that is characterized by classical parkinsonian motor symptoms. Parkinson's disease is recognized as the most common neurodegenerative disorder after Alzheimer's disease. PD ethiopathogenesis remains to be elucidated and has been connected to genetic, environmental and immunologic conditions. The past decade has provided evidence for a significant role of the immune system in PD pathogenesis, either through inflammation or an autoimmune response. Several autoantibodies directed at antigens associated with PD pathogenesis have been identified in PD patients. This immune activation may be the cause of, rather than a response to, the observed neuronal loss. Parkinsonian motor symptoms include bradykinesia, muscular rigidity and resting tremor. The non-motor features include olfactory dysfunction, cognitive impairment, psychiatric symptoms and autonomic dysfunction. Microscopically, the specific degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies, which are brain deposits containing a substantial amount of α-synuclein, have been recognized. The progression of Parkinson's disease is characterized by a worsening of motor features; however, as the disease progresses, there is an emergence of complications related to long-term symptomatic treatment. The available therapies for Parkinson's disease only treat the symptoms of the disease. A major goal of Parkinson's disease research is the development of disease-modifying drugs that slow or stop the neurodegenerative process. Drugs that enhance the intracerebral dopamine concentrations or stimulate dopamine receptors remain the mainstay treatment for motor symptoms. Immunomodulatory therapeutic strategies aiming to attenuate PD neurodegeneration have become an attractive option and warrant further investigation

CELL WILTING AND BLOSSOMING FOR ENERGY EFFICIENCY

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In vivo longitudinal study of rodent skeletal muscle atrophy using ultrasonography

Muscle atrophy is a widespread ill condition occurring in many diseases, which can reduce quality of life and increase morbidity and mortality. We developed a new method using non-invasive ultrasonography to measure soleus and gastrocnemius lateralis muscle atrophy in the hindlimb-unloaded rat, a well-Accepted model of muscle disuse. Soleus and gastrocnemius volumes were calculated using the conventional truncated-cone method and a newly-designed sinusoidal method. For Soleus muscle, the ultrasonographic volume determined in vivo with either method was linearly correlated to the volume determined ex-vivo from excised muscles as muscle weight-To-density ratio. For both soleus and gastrocnemius muscles, a strong linear correlation was obtained between the ultrasonographic volume and the muscle fiber cross-sectional area determined ex-vivo on muscle cryosections. Thus ultrasonography allowed the longitudinal in vivo evaluation of muscle atrophy progression during hindlimb unloading. This study validates ultrasonography as a powerful method for the evaluation of rodent muscle atrophy in vivo, which would prove useful in disease models and therapeutic trials

Forskolin sensitizes human acute myeloid leukemia cells to H3K27me2/3 demethylases GSKJ4 inhibitor via Protein Kinase A

Acute myeloid leukemia (AML) is an aggressive hematological malignancy occurring very often in older adults, with poor prognosis depending on both rapid disease progression and drug resistance occurrence. Therefore, new therapeutic approaches are demanded. Epigenetic marks play a relevant role in AML. GSKJ4 is a novel inhibitor of the histone demethylases JMJD3 and UTX. To note GSKJ4 has been recently shown to act as a potent small molecule inhibitor of the proliferation in many cancer cell types. On the other hand, forskolin, a natural cAMP raising compound, used for a long time in traditional medicine and considered safe also in recent studies, is emerging as a very interesting molecule for possible use in cancer therapy. Here, we investigate the effects of forskolin on the sensitivity of human leukemia U937 cells to GSKJ4 through flow cytometry-based assays (cell-cycle progression and cell death), cell number counting, and immunoblotting experiments. We provide evidence that forskolin markedly potentiates GSKJ4-induced antiproliferative effects by apoptotic cell death induction, accompanied by a dramatic BCL2 protein down-regulation as well as caspase 3 activation and PARP protein cleavage. Comparable effects are observed with the phosphodiesterase inhibitor IBMX and 8-Br-cAMP analogous, but not by using 8-pCPT-2'-O-Me-cAMP Epac activator. Moreover, the forskolin-induced enhancement of sensitivity to GSKJ4 is counteracted by pre-treatment with Protein Kinase A (PKA) inhibitors. Altogether, our data strongly suggest that forskolin sensitizes U937 cells to GSKJ4 inhibitor via a cAMP/PKA-mediated mechanism. Our findings provide initial evidence of anticancer activity induced by forskolin/GSKJ4 combination in leukemia cells and underline the potential for use of forskolin and GSKJ4 in the development of innovative and effective therapeutic approaches for AML treatment

Calcium homeostasis is altered in skeletal muscle of spontaneously hypertensive rats cytofluorimetric and gene expression analysis

Hypertension is often associated with skeletal muscle pathological conditions related to function and metabolism. The mechanisms underlying the development of these pathological conditions remain undefined. Because calcium homeostasis is a biomarker of muscle function, we assessed whether it is altered in hypertensive muscles. We measured resting intracellular calcium and store-operated calcium entry (SOCE) in fast- and slow-twitch muscle fibers from normotensive Wistar-Kyoto rats and spontaneously hypertensive rats (SHRs) by cytofluorimetric technique and determined the expression of SOCE gene machinery by real-time PCR. Hypertension caused a phenotype-dependent dysregulation of calcium homeostasis; the resting intracellular calcium of extensor digitorum longus and soleus muscles of SHRs were differently altered with respect to the related muscle of normotensive animals. In addition, soleus muscles of SHR showed reduced activity of the sarcoplasmic reticulum and decreased sarcolemmal calcium permeability at rest and after SOCE activation. Accordingly, we found an alteration of the expression levels of some SOCE components, such as stromal interaction molecule 1, calcium release-activated calcium modulator 1, and transient receptor potential canonical 1. The hypertension-induced alterations of calcium homeostasis in the soleus muscle of SHRs occurred with changes of some functional outcomes as excitability and resting chloride conductance. We provide suitable targets for therapeutic interventions aimed at counterbalancing muscle performance decline in hypertension, and propose the reported calcium-dependent parameters as indexes to predict how the antihypertensive drugs could influence muscle function

Patient-reported outcome measures in drugs for neurological conditions approved by European Medicines Agency 2017-2022

BackgroundRegulatory agencies have been responsive to public demand for inclusion of the patient experience in evaluating and approving therapies. Over the years, patient-reported outcome measures (PROMs) have become increasingly prevalent in clinical trial protocols; however, their influence on regulators, payers, clinicians, and patients' decision-making is not always clear. We recently conducted a cross-sectional study aimed at investigating the use of PROMs in new regulatory approvals of drugs for neurological conditions between 2017 and 2022 in Europe.MethodsWe reviewed European Public Assessment Reports (EPARs) and recorded on a predefined data extraction form whether they considered PROMs, their characteristics (e.g., primary/secondary endpoint, generic/specific instrument) and other relevant information (e.g., therapeutic area, generic/biosimilar, orphan status). Results were tabulated and summarized by means of descriptive statistics.ResultsOf the 500 EPARs related to authorized medicines between January 2017 and December 2022, 42 (8%) concerned neurological indications. Among the EPARs of these products, 24 (57%) reported any use of PROMs, typically considered as secondary (38%) endpoints. In total, 100 PROMs were identified, of which the most common were the EQ-5D (9%), the SF-36 (6%), or its shorter adaptation SF-12, the PedsQL (4%).ConclusionsCompared to other disease areas, neurology is one where the use of patient-reported outcomes evidence is inherently part of the clinical evaluation and for which core outcome sets exist. Better harmonization of the instruments recommended for use would facilitate the consideration of PROMs at all stages in the drug development process

Pazopanib-Induced Heart Failure In A Metastastic Sarcoma Patient: Between Reversible Side Effect and Efficacy

Introduction: Pazopanib, a multi-target tyrosine-kinase inhibitor (TKI), is a relatively novel anticancer agent registered for advanced renal cell carcinoma recently emerged in the setting of advanced soft-tissue sarcoma (STS). In the early clinical trials pazopanib has been very marginally linked to left ventricular ejection fraction (LVEF) dysfunction as, on contrary, reported for other anti-angiogenesis TKIs, such as Sunitinib and Sorafenib. Presentation of Case: We here present a case of severe, but reversible, congestive cardiac failure in a 37-year old Caucasian man affected by soft-tissue sarcoma during an efficacious treatment with pazopanib. Conclusion: Cardiac damage from novel TKI treatments is still an underestimated phenomenon. In our patient, pazopanib was the only treatment ensuring stability of disease and its discontinuation meant disease progression. Post-approval monitoring of novel TKIs should be taken into account by clinicians including a careful monitoring of LVEF and all symptoms suggestive of cardiac dysfunction, in particular for drugs potentially capable to change the natural history of still uncurable cancer

The KDM inhibitor GSKJ4 triggers CREB down-regulation via a protein kinase A and proteasome dependent mechanism in human acute myeloid leukemia cells

Acute myeloid leukemia (AML) is a progressive hematopoietic-derived cancer arising from stepwise genetic mutations of the myeloid lineage. CREB is a nuclear transcription factor, which plays a key-role in the multistep process of leukemogenesis, thus emerging as an attractive potential drug target for AML treatment. Since epigenetic dysregulations, such as DNA methylation, histone modifications as well as chromatin remodelling, are a frequent occurrence in AML, an increasing and selective number of epi-drugs are emerging as encouraging therapeutic agents. Here, we demonstrate that the histone lysine demethylases (KDM) JMJD3/UTX inhibitor GSKJ4 results in both proliferation decrease and CREB protein down-regulation in AML cells. We found that GSKJ4 clearly decreases CREB protein, but not CREB mRNA levels. By cycloheximide assay we provide evidence that GSKJ4 reduces CREB protein stability; moreover, proteasome inhibition largely counteracts the GSKJ4-induced CREB down-regulation. Very interestingly, a rapid CREB phosphorylation at the Ser133 residue precedes CREB protein decrease in response to GSKJ4 treatment. In addition, PKA inhibition, but not ERK1/2 inhibition, almost completely prevents both GSKJ4-induced p-Ser133-CREB phosphorylation and CREB protein down-regulation. Overall, our study enforces the evidence regarding CREB as a potential druggable target, identifies the small epigenetic molecule GSKJ4 as an "inhibitor" of CREB, and encourages the design of future GSKJ4-based studies for the development of innovative approaches for AML therapy

Pazopanib-Induced Heart Failure in a Metastatic Sarcoma Patient: between Reversible Side Effect and Efficacy

 Introduction: Pazopanib, a multi-target tyrosine-kinase inhibitor (TKI), is a relatively novel anticancer agent registered for advanced renal cell carcinoma recently emerged in the setting of advanced soft-tissue sarcoma (STS). In the early clinical trials pazopanib has been very marginally linked to left ventricular ejection fraction (LVEF) dysfunction as, on contrary, reported for other anti-angiogenesis TKIs, such as Sunitinib and Sorafenib. Presentation of Case: We here present a case of severe, but reversible, congestive cardiac failure in a 37-year old Caucasian man affected by soft-tissue sarcoma during an efficacious treatment with pazopanib. Conclusion: Cardiac damage from novel TKI treatments is still an underestimated phenomenon. In our patient, pazopanib was the only treatment ensuring stability of disease and its discontinuation meant disease progression. Post-approval monitoring of novel TKIs should be taken into account by clinicians including a careful monitoring of LVEF and all symptoms suggestive of cardiac dysfunction, in particular for drugs potentially capable to change the natural history of still uncurable cancer.

Feminismo camponês e popular: uma história de construções coletivas

ABSTRACT. The following article describes and analyses the process of construction of the Peasant Popular Feminism in the Peasant Women's Movement (MMC), a new subject of academic studies. The methodology used is participatory action research, given the direct immersion of the authors in said movement for more than fifteen years. As part of the results of this immersion, we have three Master's dissertations (Conte, 2011; Cinelli, 2012; Santos, 2012) and two Doctorate's theses (Conte, 2014; Cinelli, 2016). Furthermore, the authors were involved in the process of debating the Peasant Popular Feminism in MMC for the past three years. We highlight the relevance of the fact that the Peasant Popular Feminism is fruit of the collective identity of the fighting MMC women. Above all, it is constructed in dialogue with other peasant's organizations of working women and feminists, in the defense of agroecology and freedom/liberation, and hoping to build a fair and solidary, that is to say, socialist society.ABSTRACT. The following article describes and analyses the process of construction of the Peasant Popular Feminism in the Peasant Women's Movement (MMC), a new subject of academic studies. The methodology used is participatory action research, given the direct immersion of the authors in said movement for more than fifteen years. As part of the results of this immersion, we have three Master's dissertations (Conte, 2011; Cinelli, 2012; Santos, 2012) and two Doctorate's theses (Conte, 2014; Cinelli, 2016). Furthermore, the authors were involved in the process of debating the Peasant Popular Feminism in MMC for the past three years. We highlight the relevance of the fact that the Peasant Popular Feminism is fruit of the collective identity of the fighting MMC women. Above all, it is constructed in dialogue with other peasant's organizations of working women and feminists, in the defense of agroecology and freedom/liberation, and hoping to build a fair and solidary, that is to say, socialist society.RESUMEN. El presente artículo describe y analiza el proceso de construcción del Feminismo Campesino y Popular en el Movimiento de Mujeres Campesinas (MMC), siendo este un tema nuevo en los estudios académicos. La metodología utilizada es la investigación participante y la investigación-acción debido a la inserción directa de las autoras en ese movimiento desde hace más de quince años. Como parte de los resultados de esta inserción, tenemos tres disertaciones de maestría (Conte, 2011; Cinelli, 2012; Santos, 2012) y dos tesis de doctorado (Conte, 2014; Cinelli, 2016). Además, hubo la participación de las autoras en el proceso de debate sobre el Feminismo Campesino y Popular en lo MMC en los últimos tres años. Destacamos como aspecto relevante el hecho de que el Feminismo Campesino y Popular es fruto de la identidad colectiva de las mujeres del MMC en lucha. Sobre todo, se construye en la articulación con otras organizaciones campesinas de mujeres y feministas, ancladas en el universo de trabajo, en la defensa de la agroecología y en la libertad / liberación, buscando la construcción de una sociedad justa y solidaria, o sea, socialista.O artigo descreve e analisa o processo de construção do Feminismo Camponês e Popular no Movimento de Mulheres Camponesas (MMC), sendo esse um assunto novo nos estudos acadêmicos. A metodologia utilizada é a pesquisa participante e a pesquisa-ação devido à inserção direta das autoras nesse movimento há mais de quinze anos. Como parte dos resultados dessa inserção, temos três dissertações de mestrado (Conte, 2011; Cinelli, 2012; Santos, 2012) e duas teses de doutorado (Conte, 2014; Cinelli, 2016). Além disso, houve a participação das autoras no processo de debate sobre o Feminismo Camponês e Popular no MMC nos últimos três anos. Destacamos como aspecto relevante o fato de que o Feminismo Camponês e Popular é fruto da identidade coletiva das mulheres do MMC em luta. Sobretudo, ele é construído na articulação com outras organizações camponesas de mulheres e feministas, ancoradas no universo de trabalho, na defesa da agroecologia e na liberdade/libertação, almejando a construção de uma sociedade justa e solidária, ou seja, socialista. Palavras-chave: Feminismo Camponês e Popular; Movimento de Mulheres Camponesas; Lutas.   Peasant and popular feminism: a history of collective constructions                                          ABSTRACT. The following article describes and analyses the process of construction of the Peasant Popular Feminism in the Peasant Women's Movement (MMC), a new subject of academic studies. The methodology used is participatory action research, given the direct immersion of the authors in said movement for more than fifteen years. As part of the results of this immersion, we have three Master's dissertations (Conte, 2011; Cinelli, 2012; Santos, 2012) and two Doctorate's theses (Conte, 2014; Cinelli, 2016). Furthermore, the authors were involved in the process of debating the Peasant Popular Feminism in MMC for the past three years. We highlight the relevance of the fact that the Peasant Popular Feminism is fruit of the collective identity of the fighting MMC women. Above all, it is constructed in dialogue with other peasant's organizations of working women and feminists, in the defense of agroecology and freedom/liberation, and hoping to build a fair and solidary, that is to say, socialist society. keywords: Peasant Popular Feminism; Peasant Women's Movement; Fights.     Feminismo campesino y popular: una historia de construcciones colectivas RESUMEN. El presente artículo describe y analiza el proceso de construcción del Feminismo Campesino y Popular en el Movimiento de Mujeres Campesinas (MMC), siendo este un tema nuevo en los estudios académicos. La metodología utilizada es la investigación participante y la investigación-acción debido a la inserción directa de las autoras en ese movimiento desde hace más de quince años. Como parte de los resultados de esta inserción, tenemos tres disertaciones de maestría (Conte, 2011; Cinelli, 2012; Santos, 2012) y dos tesis de doctorado (Conte, 2014; Cinelli, 2016). Además, hubo la participación de las autoras en el proceso de debate sobre el Feminismo Campesino y Popular en lo MMC en los últimos tres años. Destacamos como aspecto relevante el hecho de que el Feminismo Campesino y Popular es fruto de la identidad colectiva de las mujeres del MMC en lucha. Sobre todo, se construye en la articulación con otras organizaciones campesinas de mujeres y feministas, ancladas en el universo de trabajo, en la defensa de la agroecología y en la libertad / liberación, buscando la construcción de una sociedad justa y solidaria, o sea, socialista. Palabras clave: Feminismo Campesino y Popular; Movimiento de Mujeres Campesinas; Luchas