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OBJECTIVES: Frontotemporal Degeneration (FTD) is a common cause of early onset dementia with symptoms often presenting before 65 years of age and adding tremendous burden on caregivers. FTD caregiving research describes patient behavioral symptoms such as apathy and disinhibition as primary sources of poor caregiver psychological health; however, little attention has been paid to other common patient behaviors, such as loss of empathy. To better understand the relationship between empathy loss and FTD caregiver outcomes, this integrative review aimed to address the question: How does the loss of empathy in a person living with FTD (PLwFTD) impact the caregiver? METHOD: Quantitative and qualitative articles were found in PubMed, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Scopus and were assessed for quality using the Crowe Critical Appraisal Tool (CCAT). Through constant comparative analysis, articles were assessed to abstract common themes in the literature. RESULTS: From 333 citations, 8 qualitative and 8 quantitative studies published between 2010 and 2022 were included. Three main themes were uncovered: 1) caregiver emotional reactions to the PLwFTD; 2) caregiver psychological distress; 3) changes in the relationship. CONCLUSION: This review emphasizes the detrimental impact of empathy loss on FTD caregivers. Understanding these underexplored consequences is critical in understanding the well-being of caregivers and promoting ways to support caregivers.
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Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by cytochrome P450 epoxygenation of arachidonic acid, which are metabolized by EPHX2 (epoxide hydrolase 2, alias soluble epoxide hydrolase or sEH). EETs have pleiotropic effects, including anti-inflammatory activity. Using a Connectivity Map (CMAP) approach, we identified an inverse-correlation between an exemplar EPHX2 inhibitor (EPHX2i) compound response and an inflammatory bowel disease patient-derived signature. To validate the gene-disease link, we tested a pre-clinical tool EPHX2i (GSK1910364) in a mouse disease model, where it showed improved outcomes comparable to or better than the positive control Cyclosporin A. Up-regulation of cytoprotective genes and down-regulation of proinflammatory cytokine production were observed in colon samples obtained from EPHX2i-treated mice. Follow-up immunohistochemistry analysis verified the presence of EPHX2 protein in infiltrated immune cells from Crohn's patient tissue biopsies. We further demonstrated that GSK2256294, a clinical EPHX2i, reduced the production of IL2, IL12p70, IL10 and TNFα in both ulcerative colitis and Crohn's disease patient-derived explant cultures. Interestingly, GSK2256294 reduced IL4 and IFNγ in ulcerative colitis, and IL1ß in Crohn's disease specifically, suggesting potential differential effects of GSK2256294 in these two diseases. Taken together, these findings suggest a novel therapeutic use of EPHX2 inhibition for IBD.
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Colitis/tratamiento farmacológico , Ciclohexilaminas/farmacología , Evaluación Preclínica de Medicamentos/métodos , Epóxido Hidrolasas/antagonistas & inhibidores , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Triazinas/farmacología , Animales , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Citocinas/metabolismo , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Ratones , Ratones Endogámicos C57BLRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease with large unmet need. Non-alcoholic steatohepatitis (NASH), a progressive variant of NAFLD, can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. To identify potential new therapeutics for NASH, we used a computational approach based on Connectivity Map (CMAP) analysis, which pointed us to bromodomain and extra-terminal motif (BET) inhibitors for treating NASH. To experimentally validate this hypothesis, we tested a small-molecule inhibitor of the BET family of proteins, GSK1210151A (I-BET151), in the STAM mouse NASH model at two different dosing timepoints (onset of NASH and progression to fibrosis). I-BET151 decreased the non-alcoholic fatty liver disease activity score (NAS), a clinical endpoint for assessing the severity of NASH, as well as progression of liver fibrosis and interferon-γ expression. Transcriptional characterization of these mice through RNA-sequencing was consistent with predictions from the CMAP analysis of a human NASH signature and pointed to alterations in molecular mechanisms related to interferon signaling and cholesterol biosynthesis, as well as reversal of gene expression patterns linked to fibrotic markers. Altogether, these results suggest that inhibition of BET proteins may present a novel therapeutic opportunity in the treatment of NASH and liver fibrosis.
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Biología Computacional/métodos , Redes Reguladoras de Genes/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Cirrosis Hepática/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Animales , Colesterol/biosíntesis , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Interferón gamma/metabolismo , Cirrosis Hepática/genética , Cirrosis Hepática/inmunología , Ratones , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/inmunología , Análisis de Secuencia de ARN , Índice de Severidad de la EnfermedadRESUMEN
In addition to classic functions of facilitating hepatobiliary secretion and intestinal absorption of lipophilic nutrients, bile acids (BA) are also endocrine factors and regulate glucose and lipid metabolism. Recent data indicate that antiobesity bariatric procedures e.g. Roux-en-Y gastric bypass surgery (RYGB), which also remit diabetes, increase plasma BAs in humans, leading to the hypothesis that BAs may play a role in diabetes resolution following surgery. To investigate the effect of RYGB on BA physiology and its relationship with glucose homeostasis, we undertook RYGB and SHAM surgery in Zucker diabetic fatty (ZDF) and normoglycemic Sprague Dawley (SD) rats and measured plasma and fecal BA levels, as well as plasma glucose, insulin, Glucagon like peptide 1 (GLP-1) and Peptide YY (PYY), 2 days before and 3, 7, 14 and 28 days after surgery. RYGB decreased body weight and increased plasma GLP-1 in both SD and ZDF rats while decreasing plasma insulin and glucose in ZDF rats starting from the first week. Compared to SHAM groups, both SD-RYGB and ZDF-RYGB groups started to have increases in plasma total BAs in the second week, which might not contribute to early post-surgery metabolic changes. While there was no significant difference in fecal BA excretion between SD-RYGB and SD-SHAM groups, the ZDF-RYGB group had a transient 4.2-fold increase (P<0.001) in 24-hour fecal BA excretion on post-operative day 3 compared to ZDF-SHAM, which paralleled a significant increase in plasma PYY. Ratios of plasma and fecal cholic acid/chenodeoxycholic acid derived BAs were decreased in RYGB groups. In addition, tissue mRNA expression analysis suggested early intestinal BA reabsorption and potentially reduced hepatic cholic acid production in RYGB groups. In summary, we present novel data on RYGB-mediated changes in BA metabolism to further understand the role of BAs in RYGB-induced metabolic effects in humans.
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Ácidos y Sales Biliares/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/cirugía , Derivación Gástrica , Animales , Glucemia , Peso Corporal , Diabetes Mellitus Experimental/genética , Modelos Animales de Enfermedad , Derivación Gástrica/métodos , Polipéptido Inhibidor Gástrico/sangre , Perfilación de la Expresión Génica , Péptido 1 Similar al Glucagón/sangre , Insulina/sangre , Especificidad de Órganos/genética , Péptido YY/sangre , RatasRESUMEN
Pharmacotherapy for obesity remains a key challenge, and gastrointestinal weight-loss surgery remains a preferred option to help reduce excess body weight along with resolution of several comorbidities associated with obesity. This offers a unique opportunity to study the underlying mechanisms of gastro-intestinal weight-loss surgery to develop effective and less invasive long-term therapeutic interventions potentially mimicking the benefits of gastrointestinal weight-loss surgery. Here, we present an integrative analysis of currently available human transcriptomics data sets pre- and post-surgery and propose a computational biology strategy for selecting putative drug targets. We anticipate that approaches similar to the one that we outline here, would help elucidate underlying mechanisms that result in metabolic improvements and provide guidance on pharmaceutical targets to develop effective and less invasive therapies for obesity and related comorbidities.
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Fármacos Antiobesidad/farmacología , Cirugía Bariátrica , Descubrimiento de Drogas , Terapia Molecular Dirigida , Obesidad/tratamiento farmacológico , Obesidad/cirugía , Pérdida de Peso/efectos de los fármacos , Animales , Fármacos Antiobesidad/química , Biología Computacional , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Metabolómica , Obesidad/genética , Obesidad/metabolismo , Fenotipo , Proteómica , Transducción de Señal/efectos de los fármacos , Resultado del TratamientoRESUMEN
Organic anion transporters (OATs) play a pivotal role in the clearance of small organic anions by the kidney, yet little is known about how their activity is regulated. A yeast two-hybrid assay was used to identify putative OAT3-associated proteins in the kidney. Atypical protein kinase Czeta (PKCzeta) was shown to bind to OAT3. Binding was confirmed in immunoprecipitation assays. The OAT3/PKCzeta interaction was investigated in rodent renal cortical slices from fasted animals. Insulin, an upstream activator of PKCzeta, increased both OAT3-mediated uptake of estrone sulfate (ES) and PKCzeta activity. Both effects were abolished by a PKCzeta-specific pseudosubstrate inhibitor. Increased ES transport was not observed in renal slices from OAT3-null mice. Transport of the shared OAT1/OAT3 substrate, rho-aminohippurate, behaved similarly, except that stimulation was reduced, not abolished, in the OAT3-null mice. This suggested that OAT1 activity was also modified by PKCzeta, subsequently confirmed using an OAT1-specific substrate, adefovir. Inhibition of PKCzeta also blocked the increase in ES uptake seen in response to epidermal growth factor and to activation of protein kinase A. Thus, PKCzeta acted downstream of the epidermal growth factor to protein kinase A signaling pathway. Activation of transport was accompanied by an increase in V(max) and was blocked by microtubule disruption, indicating that activation may result from trafficking of OAT3 into the plasma membrane. These data demonstrate that PKCzeta activation up-regulates OAT1 and OAT3 function, and that protein-protein interactions play a central role controlling these two important renal drug transporters.
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Proteína 1 de Transporte de Anión Orgánico/fisiología , Transportadores de Anión Orgánico Sodio-Independiente/fisiología , Proteína Quinasa C/metabolismo , Animales , Transporte Biológico , Activación Enzimática , Técnicas In Vitro , Ratones , Ratones Noqueados , Proteína 1 de Transporte de Anión Orgánico/genética , Transportadores de Anión Orgánico Sodio-Independiente/genética , Ratas , Ratas Sprague-DawleyRESUMEN
Organic anion transporters (OATs) play a critical role in the handling of endogenous and exogenous organic anions by excretory and barrier tissues. Little is known about the OAT three-dimensional structure or substrate/protein interactions involved in transport. In this investigation, a theoretical three-dimensional model was generated for human OAT1 (hOAT1) based on fold recognition to the crystal structure of the glycerol 3-phosphate transporter (GlpT) from Escherichia coli. GlpT and hOAT1 share several sequence motifs as major facilitator superfamily members. The structural hOAT1 model shows that helices 5, 7, 8, 10, and 11 surround an electronegative putative active site ( approximately 830A(3)). The site opens to the cytoplasm and is surrounded by three residues not previously examined for function (Tyr(230) (domain 5) and Lys(431) and Phe(438) (domain 10)). Effects of these residues on p-aminohippurate (PAH) and cidofovir transport were assessed by point mutations in a Xenopus oocyte expression system. Membrane protein expression was severely limited for the Y230A mutant. For the K431A and F438A mutants, [(3)H]PAH uptake was less than 30% of wild-type hOAT1 uptake after protein expression correction. Reduced V(max) values for the F438A mutant confirmed lower protein expression. In addition, the F438A mutant exhibited an increased affinity for cidofovir but was not significantly different for PAH. Differences in handling of PAH and cidofovir were also observed for the Y230F mutant. Little uptake was determined for cidofovir, whereas PAH uptake was similar to wild-type hOAT1. Therefore, the hOAT1 structural model has identified two new residues, Tyr(230) and Phe(438), which are important for substrate/protein interactions.
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Proteína 1 de Transporte de Anión Orgánico/química , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Aminoácidos Aromáticos/química , Animales , Secuencia de Bases , Sitios de Unión/genética , Cartilla de ADN/genética , Femenino , Humanos , Técnicas In Vitro , Cinética , Modelos Moleculares , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Oocitos/metabolismo , Proteína 1 de Transporte de Anión Orgánico/genética , Proteína 1 de Transporte de Anión Orgánico/metabolismo , Conformación Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homología de Secuencia de Aminoácido , Electricidad Estática , Xenopus laevisRESUMEN
The 26S proteasome degrades denatured proteins and other proteins targeted for destruction by covalent modification. Here we show that impaired proteasome function influences the transcription of numerous yeast genes. Of 6144 genes present on the macroarray filters used in this study, approximately 5% showed measurable mRNA decreases and 2% showed mRNA increases following 30 min of proteasome inhibition. Northern blot hybridization shows that this response is time- and dose-dependent and occurs with either pharmacological or genetic impairment of the proteasome. A number of splicing factors possess the PEST motif found in certain proteasome substrates. However, mRNA levels drop with proteasome inhibition without obvious increases in intron-bearing pre-mRNA, indicating that splicing is not generally impaired when proteome activity is blocked. Chimeric gene constructs, nuclear run-on experiments, and transcriptional inhibition studies show that for members of three functional groups (i.e., ribosomal protein genes, histone genes, and heat shock protein genes) changes in mRNA levels occur largely by transcriptional modulation. In addition, these studies reveal a possible new means of modulating kinetochore levels through CEP3 expression. Together these data strongly support the view that proteasome activity plays a significant role in the regulation of eukaryotic gene expression.