RESUMEN
Lactate transport is an important means of communication between astrocytes and neurons and is implicated in a variety of neurobiological processes. However, the connection between astrocyte-neuron lactate transport and nociceptive modulation has not been well established. Here, we found that Complete Freund's adjuvant (CFA)-induced inflammation pain leads to a significant increase in extracellular lactate levels in the anterior cingulate cortex (ACC). Inhibition of glycogenolysis and lactate release in the ACC disrupted the persistent, but not acute, inflammation pain induced by CFA, and this effect was reversed by exogenous L-lactate administration. Knocking down the expression of lactate transporters (MCT1, MCT4, or MCT2) also disrupted the long lasting inflammation pain induced by CFA. Moreover, glycogenolysis in the ACC is critical for the induction of molecular changes related to neuronal plasticity, including the induction of phospho- (p-) ERK, p-CREB, and Fos. Taken together, our findings indicate that astrocyte-neuron lactate transport in the ACC is critical for the occurrence of persistent inflammation pain, suggesting a novel mechanism underlying chronic pain.
Asunto(s)
Arabinosa/farmacología , Comunicación Celular/inmunología , Dolor Crónico/inmunología , Giro del Cíngulo/patología , Iminofuranosas/farmacología , Ácido Láctico/metabolismo , Alcoholes del Azúcar/farmacología , Animales , Arabinosa/uso terapéutico , Astrocitos/metabolismo , Comunicación Celular/efectos de los fármacos , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/patología , Modelos Animales de Enfermedad , Adyuvante de Freund/administración & dosificación , Adyuvante de Freund/inmunología , Glucogenólisis/efectos de los fármacos , Glucogenólisis/inmunología , Giro del Cíngulo/citología , Giro del Cíngulo/efectos de los fármacos , Giro del Cíngulo/inmunología , Humanos , Iminofuranosas/uso terapéutico , Masculino , Ratones , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/inmunología , Neuronas/metabolismo , Alcoholes del Azúcar/uso terapéuticoRESUMEN
Aberrant regulation of BCL-2 family members enables evasion of apoptosis and tumor resistance to chemotherapy. BCL-2 and functionally redundant counterpart, MCL-1, are frequently over-expressed in high-risk diffuse large B-cell lymphoma (DLBCL). While clinical inhibition of BCL-2 has been achieved with the BH3 mimetic venetoclax, anti-tumor efficacy is limited by compensatory induction of MCL-1. Voruciclib, an orally bioavailable clinical stage CDK-selective inhibitor, potently blocks CDK9, the transcriptional regulator of MCL-1. Here, we demonstrate that voruciclib represses MCL-1 protein expression in preclinical models of DLBCL. When combined with venetoclax in vivo, voruciclib leads to model-dependent tumor cell apoptosis and tumor growth inhibition. Strongest responses were observed in two models representing high-risk activated B-cell (ABC) DLBCL, while no response was observed in a third ABC model, and intermediate responses were observed in two models of germinal center B-cell like (GCB) DLBCL. Given the range of responses, we show that CIVO, a multiplexed tumor micro-dosing technology, represents a viable functional precision medicine approach for differentiating responders from non-responders to BCL-2/MCL-1 targeted therapy. These findings suggest that the combination of voruciclib and venetoclax holds promise as a novel, exclusively oral combination therapy for a subset of high-risk DLBCL patients.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzopiranos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Iminofuranosas/farmacología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Animales , Antineoplásicos/uso terapéutico , Benzopiranos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Línea Celular Tumoral , Sinergismo Farmacológico , Humanos , Iminofuranosas/uso terapéutico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Ratones , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Sulfonamidas/farmacología , Sulfonamidas/uso terapéuticoRESUMEN
PURPOSE OF REVIEW: To update recent developments in medications targeting hyperuricemia, but not including medications recently labelled in the European Union and the United States. RECENT FINDINGS: A new xanthine oxidase inhibitor, Topiloric (Fujiyakuhin Co., Ltd. Japan) Uriadec (Sanwa Kagaku Kenkyusho Co., Ltd. Japan), has been developed and labelled in Japan. An inhibitor of purine nucleoside phosphorylase, Ulodesine, is in development in combination with allopurinol. The rest of the medications in the pipeline for hyperuricemia are targeting renal transporters of uric acid, mainly URAT1 and OAT4, acting as uricosuric agents. Most of them, such as lesinurad and arhalofenate, are being tested in trials in combination with allopurinol and febuxostat. The most potent RDEA3170 is being tested in monotherapy, but also associated with febuxostat. Recently, medications showing dual activity, inhibiting both xanthine oxidoreductase and URAT1, have been communicated or started exploratory clinical trials. There is no report of medications targeting other transporters such as Glut9 or ABCG2. SUMMARY: There are a number of medications in the pipeline targeting hyperuricemia, mostly uricosurics in combination with xanthine oxidase inhibitors, but some targeting both xanthine oxidoreductase and URAT1. Increasing the number of available medications will ensure proper control of hyperuricemia to target serum urate levels in the near future for most, if not all, patients with hyperuricemia.
Asunto(s)
Supresores de la Gota/uso terapéutico , Gota/tratamiento farmacológico , Hiperuricemia/tratamiento farmacológico , Acetamidas/uso terapéutico , Diseño de Fármacos , Humanos , Iminofuranosas/uso terapéutico , Terapia Molecular Dirigida/métodos , Fenilacetatos/uso terapéutico , Pirimidinonas/uso terapéutico , Tioglicolatos/uso terapéutico , Triazoles/uso terapéutico , Uricosúricos/uso terapéuticoRESUMEN
Over the past decade much has been learned about the mechanisms of crystal-induced inflammation and renal excretion of uric acid, which has led to more specific targeting of gout therapies and a more potent approach to future management of gout. This article outlines agents being developed for more aggressive lowering of urate and more specific anti-inflammatory activity. The emerging urate-lowering therapies include lesinurad, arhalofenate, ulodesine, and levotofisopam. Novel gout-specific anti-inflammatories include the interleukin-1ß inhibitors anakinra, canakinumab, and rilonacept, the melanocortins, and caspase inhibitors. The historic shortcomings of current gout treatment may, in part, be overcome by these novel approaches.