MicroRNAs (miRNAs) are small, highly conserved, non-coding RNA that alter protein expression and regulate multiple intracellular processes, including those involved in the response to cellular ...stress. Alterations in miRNA expression may occur following exposure to several stress-inducing anticancer agents including ionizing radiation, etoposide, and hydrogen peroxide (H(2)O(2)).
Normal human fibroblasts were exposed to radiation, H(2)O(2), or etoposide at doses determined by clonogenic cell survival curves. Total RNA was extracted and miRNA expression was determined by microarray. Time course and radiation dose responses were determined using RT-PCR for individual miRNA species. Changes in miRNA expression were observed for 17 miRNA species following exposure to radiation, 23 after H(2)O(2) treatment, and 45 after etoposide treatment. Substantial overlap between the miRNA expression changes between agents was observed suggesting a signature miRNA response to cell stress. Changes in the expression of selected miRNA species varied in response to radiation dose and time. Finally, production of reactive oxygen species (ROS) increased with increasing doses of radiation and pre-treatment with the thiol antioxidant cysteine decreased both ROS production and the miRNA response to radiation.
These results demonstrate a common miRNA expression signature in response to exogenous genotoxic agents including radiation, H(2)O(2), and etoposide. Additionally, pre-treatment with cysteine prevented radiation-induced alterations in miRNA expression which suggests that miRNAs are responsive to oxidative stress. Taken together, these results imply that miRNAs play a role in cellular defense against exogenous stress and are involved in the generalized cellular response to genotoxic oxidative stress.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The chemistry and biology of nitroxide compounds Soule, Benjamin P.; Hyodo, Fuminori; Matsumoto, Ken-ichiro ...
Free radical biology & medicine,
06/2007, Letnik:
42, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Cyclic nitroxides are a diverse group of stable free radicals that have unique antioxidant properties. Because of their ability to interact with free radicals, they have been used for many years as ...biophysical tools. During the past 15–20 years, however, many interesting biochemical interactions have been discovered and harnessed for therapeutic applications. Biologically relevant effects of nitroxides have been described, including their ability to degrade superoxide and peroxide, inhibit Fenton reactions, and undergo radical–radical recombination. Cellular studies defined the activity of nitroxides in vitro. By modifying oxidative stress and altering the redox status of tissues, nitroxides have been found to interact with and alter many metabolic processes. These interactions can be exploited for therapeutic and research use, including protection against ionizing radiation, as probes in functional magnetic resonance imaging, cancer prevention and treatment, control of hypertension and weight, and protection from damage resulting from ischemia/reperfusion injury. Although much remains to be done, many applications have been well studied and some are currently being tested in clinical trials. The therapeutic and research uses of nitroxide compounds are reviewed here with a focus on the progress from initial development to modern trials.
Genotoxic stressors, such as radiation, induce cellular damage that activates pre-programmed repair pathways, some of which involve microRNAs (miRNA) that alter gene expression. The let-7 family of ...miRNA regulates multiple cellular processes including cell division and DNA repair pathways. However, the role and mechanism underlying regulation of let-7 genes in response to stress have yet to be elucidated. In this study we demonstrate that let-7a and let-7b expression decreases significantly following exposure to agents that induce stress including ionizing radiation. This decrease in expression is dependent on p53 and ATM in vitro and is not observed in a p53(-/-) colon cancer cell line (HCT116) or ATM(-/-) human fibroblasts. Chromatin Immunoprecipitation (ChIP) analysis showed p53 binding to a region upstream of the let-7 gene following radiation exposure. Luciferase transient transfections demonstrated that this p53 binding site is necessary for radiation-induced decreases in let-7 expression. A radiation-induced decrease in let-7a and let-7b expression is also observed in radiation-sensitive tissues in vivo and correlates with altered expression of proteins in p53-regulated pro-apoptotic signaling pathways. In contrast, this decreased expression is not observed in p53 knock-out mice suggesting that p53 directly repress let-7 expression. Exogenous expression of let-7a and let-7b increased radiation-induced cytotoxicity in HCT116 p53(+/+) cells but not HCT116 p53(-/-) cells. These results are the first demonstration of a mechanistic connection between the radiation-induced stress response and the regulation of miRNA and radiation-induced cytotoxicity and suggest that this process may be a molecular target for anticancer agents.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
SEPRA, a 2-year, ongoing, open-label, randomized, pragmatic study (NCT03596450) compares the effects of once-weekly SC semaglutide (sema) with physician's choice SOC when added to ≤2 oral ...antidiabetic medications for treatment intensification in US health-insured adults with T2D. The objective is to generate real-world evidence to support routine clinical decision making and complement clinical trial data. The primary endpoint is the proportion of patients who achieve HbA1c <7% at 1 year. Patients (N=1278) were randomized to receive sema according to label (n=644) or SOC excluding sema (n=634). All other treatment was per routine clinical care. Baseline characteristics were comparable (Table 1). Most common SOC medications were other GLP-1RAs (71.3%) and SGLT2is (15.5%). Sema dosing at 1 year was 26.6% at 0.25 mg, 30.4% at 0.5 mg and 24.4% at 1 mg (10.6% ended study and 7.6% not on sema at year 1). Use of sema resulted in a significantly greater proportion of patients achieving HbA1c <7% and body weight reduction vs SOC at 1 year (Table 1). A lower proportion of sema patients required additional treatment intensification in year 1 of the study vs SOC. No new safety concerns were identified. SEPRA demonstrates the superior effect of sema vs physician's choice SOC and that sema is an efficacious, durable treatment option in routine clinical practice.
Disclosure
J.B.Buse: Consultant; Alkahest, Anji Pharmaceuticals, AstraZeneca, Bayer Inc., Biomea Fusion, Inc., Boehringer Ingelheim International GmbH, CeQur SA, Cirius Therapeutics, Inc., Corcept Therapeutics, Eli Lilly and Company, GentiBio, Glycadia, Glyscend Inc., Janssen Pharmaceuticals, Inc., Mellitus Health, Pendulum Therapeutics, Praetego, LLC, Stability Health, Terns, Inc, Valo, Other Relationship; Novo Nordisk, Research Support; Dexcom, Inc., Novo Nordisk, vTv Therapeutics, Stock/Shareholder; Glyscend Inc., Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Praetego, LLC, Stability Health. B.P.Soule: Employee; Novo Nordisk. B.J.Harty: Research Support; Novo Nordisk. H.N.Christensen: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk A/S. M.J.Cziraky: Other Relationship; Novo Nordisk. V.Willey: Other Relationship; Novo Nordisk A/S. S.Skibsted: Employee; Novo Nordisk A/S.
Funding
Novo Nordisk
Survival in chronic granulomatous disease is related to the level of NADPH oxidase activity, which correlates with the altered site on the mutated gene. Assessed NADPH oxidase activity is a more ...powerful prognostic factor than reported clinical features of the disease.
Chronic granulomatous disease, first described in the 1950s,
1
is a rare genetic disease (approximately 1 case in 200,000 people) without ethnic preference. The risk of death among persons with chronic granulomatous disease is 1 to 5% per year, and the extent of risk has been thought to depend on whether inheritance is an autosomal recessive trait or an X-linked trait.
2
Chronic granulomatous disease is caused by defects in any one of five subunits of phagocyte-derived NADPH oxidase, including gp91phox (
CYBB
cytochrome b-245, beta polypeptide, in approximately 65% of patients), p22phox (
CYBA
cytochrome b-245, alpha polypeptide, <5%), p47phox ( . . .
SEPRA (NCT03596450) is a 2-yr, multicenter, open-label, randomized pragmatic clinical trial comparing the long-term effects of once-weekly subcutaneous semaglutide vs. standard of care (both added to ...≤2 oral antidiabetic medications) in US health-insured adults with T2D and physician-determined inadequate glycemic control. SEPRA will assess glycemic control, weight loss, healthcare utilization, and patient-reported outcomes by collecting individual-level data from routine clinical practice and health insurance claims. The primary endpoint is the proportion of patients achieving HbA1c <7.0% at yr 1. The study design was evaluated using the Pragmatic Explanatory Continuum Indicator Summary (PRECIS) -2 assessment; it scored 4-5 in all 9 domains, suggesting a highly pragmatic study. Of 1,278 patients enrolled, 54% were male with mean (± SD) age 57.4 ± 11.1 yrs, BMI 35.7± 8.0 kg/m2, diabetes duration 7.4 ± 6.0 yrs, HbA1c 8.48 ± 1.6%, and mean individualized HbA1c target 6.66 ± 0.5%. Of note, 86.9% of patients had HbA1c >7.0% and most required sizeable reductions in HbA1c to reach the clinician-assigned individualized target. SEPRA will provide real-world evidence on the long-term effectiveness of semaglutide in a population with a broad range of HbA1c levels and other clinical characteristics when used as intensification early on in usual T2D care practice settings.
Disclosure
V.Willey: Employee; HealthCore Inc. J.B.Buse: Consultant; Alkahest, Anji, AstraZeneca, Boehringer Ingelheim International GmbH, Cirius Therapeutics, Inc., Eli Lilly and Company, Fortress biotech, GentiBio, Glycadia, Glyscend, Janssen Pharmaceuticals, Inc., Mellitus Health, Moderna, Inc., Pendulum Therapeutics, Praetego, LLC, Stability Health, Valo, Zealand Pharma A/S, Other Relationship; Adocia, AstraZeneca, Eli Lilly and Company, Intarcia Therapeutics, Inc., MannKind Corporation, Novo Nordisk, Sanofi, Senseonics, vTv Therapeutics, Research Support; AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, vTv Therapeutics, Stock/Shareholder; Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Praetego, LLC, Stability Health. B.Harty: None. J.L.Mitchell: None. B.P.Soule: Employee; Bristol-Myers Squibb Company, Novo Nordisk. H.N.Christensen: Employee; Novo Nordisk. M.J.Cziraky: None. S.Skibsted: Employee; Novo Nordisk.
Funding
Funded by Novo Nordisk Inc
Highlights • microRNA's affected by diet are reviewed. • microRNA families most dysregulated are discussed. • The same families role in disease is illustrated. • Diet therefore, may be used to treat ...disease.
Nitroxide compounds have been used for many years as biophysical tools, but only during the past 15-20 years have the many interesting biochemical interactions been discovered and harnessed for ...therapeutic applications. By modifying oxidative stress and altering the redox status of tissues, nitroxides have the ability to interact with and alter many metabolic processes. This interaction can be exploited for therapeutic and research use, including protection against ionizing radiation, as probes in functional magnetic resonance imaging, cancer prevention and treatment, control of hypertension and weight, and protection from damage resulting from ischemia/reperfusion injury. Although much remains to be done, many applications have been well studied, and some are presently being tested in clinical trials. The therapeutic and research uses of nitroxides are reviewed here, with a focus on the progress from initial development to modern, state-of-the art trials.
IntroductionOnce-weekly subcutaneous semaglutide, a glucagon-like peptide-1 analog, is approved in the USA as an adjunct to diet and exercise for adults with inadequately controlled type 2 diabetes ...(T2D) to improve glycemic control and reduce the risk of major adverse cardiovascular events in people with T2D and established cardiovascular disease. The Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) phase III clinical trial program demonstrated the efficacy and safety of once-weekly subcutaneous semaglutide; however, determining its effectiveness in a real-world setting could support decision-making by clinicians, payers and policy makers in routine clinical practice.Research design and methodsSEmaglutide PRAgmatic (SEPRA) is an ongoing open-label, randomized, pragmatic clinical trial designed to compare the effects of once-weekly subcutaneous semaglutide versus standard of care in US health-insured adults with T2D and physician-determined inadequate glycemic control. The primary end point is the proportion of participants achieving glycated hemoglobin (HbA1c) <7.0% at year 1; other key outcomes include glycemic control, weight loss, healthcare utilization, and patient-reported outcomes. Individual-level data will be collected from routine clinical practice and health insurance claims. The last patient last visit is expected by June 2023.ResultsBetween July 2018 and March 2021, 1278 participants were enrolled from 138 study sites across the USA. At baseline, 54% were male with mean±SD age 57.4±11.1 years and body mass index 35.7±8.0 kg/m2. Mean diabetes duration was 7.4±6.0 years and mean HbA1c was 8.5±1.6%. At baseline, concomitant antidiabetes medications included metformin, sulfonylureas, sodium-glucose co-transporter-2 inhibitors, and dipeptidyl peptidase-4 inhibitors. The majority of participants had hypertension and dyslipidemia. The trial design was self-assessed using the PRagmatic Explanatory Continuum Indicator Summary-2 tool by the study steering group and was scored 4–5 in all domains suggesting a highly pragmatic study.ConclusionsSEPRA, a highly pragmatic ongoing study, will provide data on the effects of once-weekly subcutaneous semaglutide in a real-world setting when used during routine management of T2D.Trial registration numberNCT03596450.Trial registration number
Introduction
One target of rheumatoid arthritis (RA) treatment is to achieve early sustained remission; over the long term, patients in sustained remission have less structural joint damage and ...physical disability. We evaluated Simplified Disease Activity Index (SDAI) remission with abatacept + methotrexate versus abatacept placebo + methotrexate and impact of de-escalation (DE) in anti-citrullinated protein antibody (ACPA)-positive patients with early RA.
Methods
The phase IIIb, randomized, AVERT-2 two-stage study (NCT02504268) evaluated weekly abatacept + methotrexate versus abatacept placebo + methotrexate. Primary endpoint: SDAI remission (≤ 3.3) at week 24. Pre-planned exploratory endpoint: maintenance of remission in patients with sustained remission (weeks 40 and 52) who, from week 56 for 48 weeks (DE period), (1) continued combination abatacept + methotrexate, (2) tapered abatacept to every other week (EOW) + methotrexate for 24 weeks with subsequent abatacept withdrawal (abatacept placebo + methotrexate), or (3) withdrew methotrexate (abatacept monotherapy).
Results
Primary study endpoint was not met: 21.3% (48/225) of patients in the combination and 16.0% (24/150) in the abatacept placebo + methotrexate arm achieved SDAI remission at week 24 (
p
= 0.2359). There were numerical differences favoring combination therapy in clinical assessments, patient-reported outcomes (PROs) and week 52 radiographic non-progression. After week 56, 147 patients in sustained remission with abatacept + methotrexate were randomized (combination,
n
= 50; DE/withdrawal,
n
= 50; abatacept monotherapy,
n
= 47) and entered DE. At DE week 48, SDAI remission (74%) and PRO improvements were mostly maintained with continued combination therapy; lower remission rates were observed with abatacept placebo + methotrexate (48.0%) and with abatacept monotherapy (57.4%). Before withdrawal, de-escalating to abatacept EOW + methotrexate preserved remission.
Conclusions
The stringent primary endpoint was not met. However, in patients achieving sustained SDAI remission, numerically more maintained remission with continued abatacept + methotrexate versus abatacept monotherapy or withdrawal.
Trial Registration
ClinicalTrials.gov identifier, NCT02504268.
6DHXqidsCNRrz-f8FYdsgJ
Video abstract (MP4 62241 KB)
Plain Language Summary
Patients with rheumatoid arthritis (RA) experience inflamed and damaged joints. RA is an autoimmune disease in which proteins called autoantibodies, particularly anti-citrullinated protein autoantibodies, target the patient’s own joint tissue and organs by mistake, leading to symptomatic inflammation. Successful treatment can decrease the disease’s activity to a state known as remission. Patients in remission may experience little or no symptoms and it may be possible for some to then be able to decrease their treatment. Here, we report the results of a large, international study that looked at two treatments, abatacept and methotrexate, in patients with RA and anti-citrullinated protein autoantibodies. The study had two parts. Firstly, to see how many patients had success (remission) with weekly abatacept and/or methotrexate treatment, and secondly, to see if remission was maintained when treatment was either continued or decreased and stopped. The study showed that the number of patients in remission 6 months after treatment started was not greatly different between patients treated with both abatacept and methotrexate and those treated with just methotrexate. Those taking abatacept and methotrexate together had better remission rates 1 year later. More patients also stayed in remission when they continued to receive both abatacept and methotrexate compared with those who were just treated with abatacept or when their abatacept treatment was decreased and stopped. More patients stayed in remission when abatacept was decreased than when it was stopped. The results from this study may help determine possible future treatment reduction and/or withdrawal plans for some patients with RA.
PDF
