Some factors affecting the response of muscle to insulin.
Ontology highlight
ABSTRACT:
SUBMITTER: Manchester KL
PROVIDER: S-EPMC1264912 | biostudies-other | 1966 Mar
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Glioblastoma (GBM) is a highly invasive primary brain tumor in adults with a 5-year survival rate of less than 10%. Conventional radiotherapy with photons, along with concurrent and adjuvant temozolomide, is the mainstay for treatment of GBM although no significant improvement in survival rates has been observed over the last 20 years. Inherent factors such as tumor hypoxia, radioresistant GBM stem cells, and upregulated DNA damage response mechanisms are well established as contributing to treatment resistance and tumor recurrence. While it is understandable that efforts have focused on targeting these factors to overcome this phenotype, there have also been striking advances in precision radiotherapy techniques, including proton beam therapy and carbon ion radiotherapy (CIRT). These enable higher doses of radiation to be delivered precisely to the tumor, while minimizing doses to surrounding normal tissues and organs at risk. These alternative radiotherapy techniques also benefit from increased biological effectiveness, particularly in the case of CIRT. Although not researched extensively to date, combining these new radiation modalities with radio-enhancing agents may be particularly effective in improving outcomes for patients with GBM.
| S-EPMC9617255 | biostudies-literature
Project description:Introductionβ-blockers are among the most widely prescribed of all drugs, used for treatment of a large number of cardiovascular diseases. Herein we evaluate literature pertaining to pharmacogenetics of β-blocker therapy, provide insight into the robustness of the genetic associations, and determine the appropriateness for translating these genetic associations into clinical practice.Areas coveredA literature search was conducted using PubMed to collate evidence on associations between CYP2D6, ADRB1, ADRB2, and GRK5 genetic variation and drug-response outcomes in the presence of β-blocker exposure. Pharmacokinetic, pharmacodynamic, and clinical outcomes studies were included if genotype data and β-blocker exposure were documented.Expert opinionSubstantial data suggest that specific ADRB1 and GRK5 genotypes are associated with improved β-blocker efficacy and have potential for use to guide therapy decisions in the clinical setting. While the data do not justify ordering a CYP2D6 pharmacogenetic test, if CYP2D6 genotype is available in the electronic health record, there may be clinical utility for understanding dosing of β-blockers.
| S-EPMC7606773 | biostudies-literature
Project description:Aspirin and clopidogrel are the mainstay oral antiplatelet regimens, yet a substantial number of major adverse cardiac events (MACE) still occur. Herein, we investigated genetic and nongenetic factors associated with clopidogrel response in Egyptians. In all, 190 Egyptians with acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI), treated with clopidogrel (75 mg/day) for at least a month, were genotyped for CYP2C19 *2, *3, *6, *8, *10, and *17, CES1 G143E and ABCB1*6 and *8. These variants along with nongenetic factors were tested for association with the risk of having MACE in clopidogrel-treated patients. CYP2C19 loss-of-function (LOF) alleles carriers had increased risk of MACE vs. noncarriers (odds ratio 2.52; 95% confidence interval 1.23-5.15, P = 0.011). In a logistic regression, CYP2C19 LOF variants (P = 0.011), age (P = 0.032), and body mass index (BMI, P = 0.039) were significantly associated with the incidence of MACE in patients taking clopidogrel. CYP2C19 genetic variants, age, and BMI are potential predictors associated with variability to clopidogrel response in Egyptians.
| S-EPMC4760893 | biostudies-literature
Project description:Asthma is a frequent disease, mainly characterized by airway inflammation, in which drug therapy is crucial in its management. The potential of pharmacogenomics testing in asthma therapy has been, to date, little explored. In this review, we discuss pharmacogenetic factors affecting asthma treatment, both related to drugs used as controller medications for regular maintenance, such as inhaled corticosteroids, anti-leukotriene agents, long-acting beta-agonists, and the new biologic agents used to treat severe persistent asthma. In addition, we discuss current pharmacogenomics knowledge for rescue medications provided to all patients for as-needed relief, such as short-acting beta-agonists. Evidence for genetic variations as a factor related to drugs response has been provided for the following genes and groups of drugs: Inhaled corticosteroids: FCER2; anti-leukotriene agents: ABCC1, and LTC4S; beta-agonists: ADRB2. However, the following genes require further studies confirming or rejecting association with the response to asthma therapy: ADCY9, ALOX5, ARG1, ARG2, CRHR1, CRHR2, CYP3A4, CYP3A5, CYSLTR1, CYSLTR2, GLCCI1, IL4RA, LTA4H, ORMDL3, SLCO2B1, SPATS2L, STIP1, T, TBX21, THRA, THRB, and VEGFA. Although only a minority of these genes are, at present, listed as associated with drugs used in asthma therapy, in the Clinical Pharmacogenomics Implementation Consortium gene-drug pair list, this review reveals that sufficient evidence to start testing the potential of clinical pharmacogenomics in asthma therapy already exists. This evidence supports the inclusion in pilot pharmacogenetics tests of at least four genes. Hopefully these tests, if proven useful, will increase the efficiency and the safety of asthma therapy.
| S-EPMC6537658 | biostudies-literature
Project description:BackgroundTissue-engineered muscles ("myobundles") offer a promising platform for developing a human in vitro model of healthy and diseased muscle for drug development and testing. Compared to traditional monolayer cultures, myobundles better model the three-dimensional structure of native skeletal muscle and are amenable to diverse functional measures to monitor the muscle health and drug response. Characterizing the metabolic function of human myobundles is of particular interest to enable their utilization in mechanistic studies of human metabolic diseases, identification of related drug targets, and systematic studies of drug safety and efficacy.MethodsTo this end, we studied glucose uptake and insulin responsiveness in human tissue-engineered skeletal muscle myobundles in the basal state and in response to drug treatments.ResultsIn the human skeletal muscle myobundle system, insulin stimulates a 50% increase in 2-deoxyglucose (2-DG) uptake with a compiled EC50 of 0.27 ± 0.03 nM. Treatment of myobundles with 400 µM metformin increased basal 2-DG uptake 1.7-fold and caused a significant drop in twitch and tetanus contractile force along with decreased fatigue resistance. Treatment with the histone deacetylase inhibitor 4-phenylbutyrate (4-PBA) increased the magnitude of insulin response from a 1.2-fold increase in glucose uptake in the untreated state to a 1.4-fold increase after 4-PBA treatment. 4-PBA treated myobundles also exhibited increased fatigue resistance and increased twitch half-relaxation time.ConclusionAlthough tissue-engineered human myobundles exhibit a modest increase in glucose uptake in response to insulin, they recapitulate key features of in vivo insulin sensitivity and exhibit relevant drug-mediated perturbations in contractile function and glucose metabolism.
| S-EPMC7710786 | biostudies-literature
Project description:Insulin-like growth factor (IGF) is a potent stimulus of muscle growth. Myoferlin is a membrane-associated protein important for muscle development and regeneration. Myoferlin-null mice have smaller muscles and defective myoblast fusion. To understand the mechanism by which myoferlin loss retards muscle growth, we found that myoferlin-null muscle does not respond to IGF1. In vivo after IGF1 infusion, control muscle increased myofiber diameter by 25%, but myoferlin-null muscle was unresponsive. Myoblasts cultured from myoferlin-null muscle and treated with IGF1 also failed to show the expected increase in fusion to multinucleate myotubes. The IGF1 receptor colocalized with myoferlin at sites of myoblast fusion. The lack of IGF1 responsiveness in myoferlin-null myoblasts was linked directly to IGF1 receptor mistrafficking as well as decreased IGF1 signaling. In myoferlin-null myoblasts, the IGF1 receptor accumulated into large vesicular structures. These vesicles colocalized with a marker of late endosomes/lysosomes, LAMP2, specifying redirection from a recycling to a degradative pathway. Furthermore, ultrastructural analysis showed a marked increase in vacuoles in myoferlin-null muscle. These data demonstrate that IGF1 receptor recycling is required for normal myogenesis and that myoferlin is a critical mediator of postnatal muscle growth mediated by IGF1.-Demonbreun, A. R., Posey, A. D., Heretis, K., Swaggart, K. A., Earley, J. U., Pytel, P., McNally, E. M. Myoferlin is required for insulin-like growth factor response and muscle growth.
| S-EPMC2845429 | biostudies-literature
Project description:ContextThere is limited research on what factors are most salient to implementation of evidence-based practices (EBPs) among public health agencies in public health emergency preparedness and response (PHPR) and under what conditions EBP implementation will occur.ObjectiveThis study assessed the conditions, barriers, and enablers affecting EBP implementation among the PHPR practice community and identified opportunities to support EBP implementation.DesignA Web-based survey gathered information from public health agencies. Data obtained from 228 participating agencies were analyzed.SettingState, local, and territorial public health agencies across the United States.ParticipantsPreparedness program officials from 228 public health agencies in the United States, including Public Health Emergency Preparedness (PHEP) cooperative agreement awardees (PHEP awardees) and a random sample of local health departments (LHDs).ResultsRespondents indicated that EBP is necessary and improves PHPR functions and tasks and that staff are interested in improving skills for EBP implementation. Top system-level barriers to EBP implementation were insufficient funding, lack of EBP, and lack of clarity regarding which practices are evidence based. PHEP awardees were significantly more likely to report a lack of EBP in the field, whereas LHDs were significantly more likely to report a lack of incentives. The top organizational-level barrier was insufficient staff. Most respondents indicated their agency culture supports EBP; however, LHDs were significantly more likely to report a lack of support from supervisors and leadership. Few respondents reported individual barriers to EBP implementation.ConclusionsFindings indicate an opportunity to improve dissemination strategies, communication efforts, and incentives to support EBP implementation in PHPR. Potential strategies include improving awareness of and accessibility to EBPs through targeted dissemination efforts; building organizational capacity to support EBP implementation, particularly staff capacity, knowledge, and skills; and identifying funding and incentives to promote EBP uptake and sustainment.
| S-EPMC7523532 | biostudies-literature
Project description:Insulin-like growth factors (Igfs) are key regulators of key biological processes such as embryonic development, growth, and tissue repair and regeneration. The role of Igf in myogenesis is well documented and, in zebrafish, promotes fin and heart regeneration. However, the mechanism of action of Igf in muscle repair and regeneration is not well understood. Using adult zebrafish extraocular muscle (EOM) regeneration as an experimental model, we show that Igf1 receptor blockage using either chemical inhibitors (BMS754807 and NVP-AEW541) or translation-blocking morpholino oligonucleotides (MOs) reduced EOM regeneration. Zebrafish EOMs regeneration depends on myocyte dedifferentiation, which is driven by early epigenetic reprogramming and requires autophagy activation and cell cycle reentry. Inhibition of Igf signaling had no effect on either autophagy activation or cell proliferation, indicating that Igf signaling was not involved in the early reprogramming steps of regeneration. Instead, blocking Igf signaling produced hypercellularity of regenerating EOMs and diminished myosin expression, resulting in lack of mature differentiated muscle fibers even many days after injury, indicating that Igf was involved in late re-differentiation steps. Although it is considered the main mediator of myogenic Igf actions, Akt activation decreased in regenerating EOMs, suggesting that alternative signaling pathways mediate Igf activity in muscle regeneration. In conclusion, Igf signaling is critical for re-differentiation of reprogrammed myoblasts during late steps of zebrafish EOM regeneration, suggesting a regulatory mechanism for determining regenerated muscle size and timing of differentiation, and a potential target for regenerative therapy.
| S-EPMC5802911 | biostudies-literature
Project description:Obesity is characterized by adipose tissue expansion as well as macrophage infiltration of adipose tissue. This results in an increase in circulating inflammatory cytokines and nonesterified fatty acids, factors that cause skeletal muscle insulin resistance. Whether obesity also results in skeletal muscle inflammation is not known. In this study, we quantified macrophages immunohistochemically in vastus lateralis biopsies from eight obese and eight lean subjects. Our study demonstrates that macrophages infiltrate skeletal muscle in obesity, and we developed an in vitro system to study this mechanistically. Myoblasts were isolated from vastus lateralis biopsies and differentiated in culture. Coculture of differentiated human myotubes with macrophages in the presence of palmitic acid, to mimic an obese environment, revealed that macrophages in the presence of palmitic acid synergistically augment cytokine and chemokine expression in myotubes, decrease IkappaB-alpha protein expression, increase phosphorylated JNK, decrease phosphorylated Akt, and increase markers of muscle atrophy. These results suggest that macrophages alter the inflammatory state of muscle cells in an obese milieu, inhibiting insulin signaling. Thus in obesity both adipose tissue and skeletal muscle inflammation may contribute to insulin resistance.
| S-EPMC2692398 | biostudies-literature
Project description:ObjectivesThe primary goal of this study was to characterize the clinical presentation of feline cutaneous lymphoma. The secondary aims included determining if treatment or initial response to treatment affected the overall survival of patients, and understanding if disease characteristics such as immunophenotype, cell size or the presence of epitheliotropism influenced response to treatment.MethodsVeterinary medical oncologists at four academic veterinary teaching hospitals submitted cases of feline patients with cutaneous lymphoma diagnosed by histopathology or cytology. Signalment, feline leukemia virus (FeLV)/feline immunodeficiency virus (FIV) status, physical examination findings, clinical signs, diagnostic tests, therapy, response and outcome, and necropsy findings, when available, were recorded.ResultsForty-one patients were identified and described. The majority of patients were domestic shorthair cats (n = 29). The median age at diagnosis was 12.3 years. Males were over-represented in the population (n = 30). In the majority of patients (n = 33), the FIV/FeLV status was unknown. Twenty patients were fully staged. Thirty-four patients were treated with a variety of modalities, including surgery, radiation, single-agent or combination chemotherapy, or prednisolone only. In multiple patients, surgery or radiation was combined with a systemic therapy. Of 34 patients treated with some form of therapy, 20 responded (achieving either a partial response or complete remission).Conclusions and relevanceClinical signs and physical examination findings varied among patients. Response to therapy appeared to be associated with survival (P = 0.0025); however, this population was highly censored. Immunophenotype, cell size and the presence of epitheliotropism did not influence treatment response. Results were limited by small numbers of patients, heterogeneous disease manifestations and treatment protocols. Further studies are necessary to evaluate the effect of specific treatment modalities and disease subtype on prognosis.
| S-EPMC10812239 | biostudies-literature