scholarly journals Galactose-modified duocarmycin prodrugs as senolytics

2019 ◽  
Author(s):  
Ana Guerrero ◽  
Romain Guiho ◽  
Nicolás Herranz ◽  
Anthony Uren ◽  
Dominic J. Withers ◽  
...  
Keyword(s):  
Whole Body ◽  
Dependent Manner ◽  
Doxorubicin Treatment ◽  
Therapeutic Implications ◽  
Age Related ◽  
Wide Range ◽  
Selective Elimination ◽  
Elevated Activity ◽  
Stable Growth ◽  
Adamantinomatous Craniopharyngioma

SUMMARYSenescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells, therefore contributing to tissue homeostasis. Senescent cells accumulate during ageing and are associated with diseases, such as cancer, fibrosis and many age-related pathologies. Recent evidence suggests that the selective elimination of senescent cells can be effective on the treatment of many of these senescence-associated diseases. A universal characteristic of senescent cells is that they display elevated activity of the lysosomal β-galactosidase this has been exploited as a marker for senescence (senescence-associated β-galactosidase activity). Consequently, we hypothesised that galactose-modified cytotoxic prodrugs will be preferentially processed by senescent cells, resulting in their selective killing. Here, we show that different galactose-modified duocarmycin (GMD) derivatives preferentially kill senescent cells. GMD prodrugs induce selective apoptosis of senescent cells in a lysosomal β-galactosidase (GLB1)-dependent manner. GMD prodrugs can eliminate a broad range of senescent cells in culture, and treatment with a GMD prodrug enhances the elimination of bystander senescent cells that accumulate upon whole body irradiation or doxorubicin treatment of mice. Moreover, taking advantage of a mouse model of human adamantinomatous craniopharyngioma (ACP), we show that treatment with a GMD pro-drug result selectively reduced the number of β-catenin-positive preneoplastic senescent cells, what could have therapeutic implications. In summary, the above results show that galactose-modified duocarmycin prodrugs behave as senolytics, suggesting that they could be used to treat a wide range of senescence-related pathologies.

Age- and sex-related bone uptake of Tc-99m-HDP measured by whole-body bone scanning

2000 ◽  
Vol 39 (05) ◽  
pp. 127-132 ◽  
Author(s):  
Nicole Sieweke ◽  
K. H. Bohuslavizki ◽  
W. U. Kampen ◽  
M. Zuhayra ◽  
M. Clausen ◽  
...  
Keyword(s):  
Whole Body ◽  
Bone Lesions ◽  
Men And Women ◽  
Bone Uptake ◽  
Normal Bone ◽  
Age Related ◽  
Number Of Patients ◽  
Wide Range ◽  
Bone Scans ◽  
Body Bone

Summary Aim of this study was to validate a recently introduced new and easy-to-perform method for quantifying bone uptake of Tc-99m-labelled diphosphonate in a routine clinical setting and to establish a normal data base for bone uptake depending on age and gender. Methods: In 49 women (14-79 years) and 47 men (6-89 years) with normal bone scans as well as in 49 women (33-81 years) and 37 men (27-88 years) with metastatic bone disease whole-body bone scans were acquired at 3 min and 3-4 hours p.i. to calculate bone uptake after correction for both urinary excretion and soft tissue retention. Results: Bone uptake values of various age-related subgroups showed no significant differences between men and women (p >0.05 ). Furthermore, no differences could be proven between age-matched subgroups of normals and patients with less than 10 metastatic bone lesions, while patients with wide-spread bone metastases revealed significantly increased uptake values. In both men and women highest bone uptake was obtained (p <0.05 ) in subjects younger than 20 years with active epiphyseal growth plates. In men, bone uptake slowly decreased with age up to 60 years and then showed a tendency towards increasing uptake values. In women, the mean uptake reached a minimun in the decade 20-29 years and then slowly increased with a positive linear correlation of age and uptake in subjects older than 55 years (r = 0.57). Conclusion: Since the results proposed in this study are in good agreement with data from literature, the new method used for quantification could be validated in a large number of patients. Furthermore, age- and sexrelated normal bone uptake values of Tc-99m-HDP covering a wide range of age could be presented for this method as a basis for further studies on bone uptake.

scholarly journals Differential Dose- and Tissue-Dependent Effects of foxo on Aging, Metabolic and Proteostatic Pathways

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3577
Author(s):  
Maria S. Manola ◽  
Sentiljana Gumeni ◽  
Ioannis P. Trougakos
Keyword(s):  
Accelerated Aging ◽  
Model Organisms ◽  
Dependent Manner ◽  
Forkhead Box ◽  
Age Related ◽  
Wide Range ◽  
Transgenic Lines ◽  
Ubiquitin Proteasome ◽  
Increased Sensitivity ◽  
Proteasome Pathway

Aging is the gradual deterioration of physiological functions that culminates in death. Several studies across a wide range of model organisms have revealed the involvement of FOXO (forkhead box, class O) transcription factors in orchestrating metabolic homeostasis, as well as in regulating longevity. To study possible dose- or tissue-dependent effects of sustained foxo overexpression, we utilized two different Drosophila transgenic lines expressing high and relatively low foxo levels and overexpressed foxo, either ubiquitously or in a tissue-specific manner. We found that ubiquitous foxo overexpression (OE) accelerated aging, induced the early onset of age-related phenotypes, increased sensitivity to thermal stress, and deregulated metabolic and proteostatic pathways; these phenotypes were more intense in transgenic flies expressing high levels of foxo. Interestingly, there is a defined dosage of foxo OE in muscles and cardiomyocytes that shifts energy resources into longevity pathways and thus ameliorates not only tissue but also organismal age-related defects. Further, we found that foxo OE stimulates in an Nrf2/cncC dependent-manner, counteracting proteostatic pathways, e.g., the ubiquitin-proteasome pathway, which is central in ameliorating the aberrant foxo OE-mediated toxicity. These findings highlight the differential dose- and tissue-dependent effects of foxo on aging, metabolic and proteostatic pathways, along with the foxo-Nrf2/cncC functional crosstalk.

scholarly journals Evaluation of circulating endothelial cells in the rat after acute and fractionated whole-body gamma irradiation

Nukleonika ◽  
2014 ◽  
Vol 59 (4) ◽  
pp. 145-151 ◽  
Author(s):  
Ghassan Al-Massarani ◽  
Khaled Almohamad
Keyword(s):  
Endothelial Cells ◽  
Gamma Irradiation ◽  
Circulating Endothelial Cells ◽  
Whole Body ◽  
Dependent Manner ◽  
Wide Range ◽  
Group 3 ◽  
Group 2 ◽  
Dose Dependent ◽  
Group 1

Abstract Purpose: Damage to vascular endothelial cells is a well recognised complication of the irradiation. Our objective was to determine the gamma-irradiation effect on the rat circulating endothelial cells (CEC). Material and methods: Eight-week old rats were divided into four groups: group 1 - rats were exposed to acute whole- -body gamma irradiation with a wide range of single doses (0.5, 1, 2, 4 and 8 Gy), group 2 - rats were exposed to fractionated low doses of irradiation (0.1, 0.5 and 1 Gy) every three days for two months, group 3 as group 2, but followed by two months of rest, group 4 were control animals. CEC (CD146 positive cells) in group 1 were counted following CD146-based immuno-magnetic separation after one day and one week, as well as at the end of experiment in the other groups. Results: Quantified CEC showed that there was a dose-dependent reduction in CEC count in group 1 (one week after irradiation) and group 2. A partial re-population of CEC was observed at the end of experiment in both group 1 and group 2 compared to control group. Group 3 showed a significant increase in CEC levels as compared with group 2 without reaching the control level. Conclusion: The number of CEC (CD146 positive cells) in rats exposed to whole-body gamma irradiation was reduced in a dose-dependent manner and it partly recovered during the two-month interval after irradiation. We suggest that CEC count may be an indicator of the radiation-induced vascular damage.

scholarly journals Self DNA perpetuates IPF lung fibroblast senescence in a cGAS-dependent manner

2020 ◽  
Vol 134 (7) ◽  
pp. 889-905 ◽  
Author(s):  
Michael Schuliga ◽  
Jane Read ◽  
Kaj E.C. Blokland ◽  
David W. Waters ◽  
Janette Burgess ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Idiopathic Pulmonary Fibrosis ◽  
The Elderly ◽  
Lung Fibroblast ◽  
Lung Fibroblasts ◽  
Dependent Manner ◽  
Mitochondrial Stress ◽  
Therapeutic Implications ◽  
Age Related ◽  
P16 Expression

Abstract Senescence and mitochondrial stress are mutually reinforcing age-related processes that contribute to idiopathic pulmonary fibrosis (IPF); a lethal disease that manifests primarily in the elderly. Whilst evidence is accumulating that GMP-AMP synthase (cGAS) is crucial in perpetuating senescence by binding damaged DNA released into the cytosol, its role in IPF is not known. The present study examines the contributions of cGAS and self DNA to the senescence of lung fibroblasts from IPF patients (IPF-LFs) and age-matched controls (Ctrl-LFs). cGAS immunoreactivity was observed in regions of fibrosis associated with fibroblasts in lung tissue of IPF patients. Pharmacological inhibition of cGAS or its knockdown by silencing RNA (siRNA) diminished the escalation of IPF-LF senescence in culture over 7 days as measured by decreased p21 and p16 expression, histone 2AXγ phosphorylation and/or IL-6 production (P &lt; 0.05, n = 5–8). The targeting of cGAS also attenuated etoposide-induced senescence in Ctrl-LFs (P &lt; 0.05, n = 5–8). Levels of mitochondrial DNA (mDNA) detected by qPCR in the cytosol and medium of IPF-LFs or senescence-induced Ctrl-LFs were higher than Ctrl-LFs at baseline (P &lt; 0.05, n = 5–7). The addition of DNAse I (100 U/ml) deaccelerated IPF-LF senescence (P &lt; 0.05, n = 5), whereas ectopic mDNA or the induction of endogenous mDNA release augmented Ctrl-LF senescence in a cGAS-dependent manner (P &lt; 0.05, n = 5). In conclusion, we provide evidence that cGAS reinforces lung fibroblast senescence involving damaged self DNA. The targeting of cGAS to supress senescent-like responses may have potential important therapeutic implications in the treatment of IPF.

scholarly journals A Bacterial Tower of Babel: Quorum-Sensing Signaling Diversity and Its Evolution

2020 ◽  
Vol 74 (1) ◽  
pp. 587-606 ◽  
Author(s):  
Nitzan Aframian ◽  
Avigdor Eldar
Keyword(s):  
Quorum Sensing ◽  
Social Interactions ◽  
Signal Molecules ◽  
Allelic Polymorphism ◽  
Dependent Manner ◽  
Tower Of Babel ◽  
Cognate Receptor ◽  
Wide Range ◽  
Family Code ◽  
Bacterial Groups

Quorum sensing is a process in which bacteria secrete and sense a diffusible molecule, thereby enabling bacterial groups to coordinate their behavior in a density-dependent manner. Quorum sensing has evolved multiple times independently, utilizing different molecular pathways and signaling molecules. A common theme among many quorum-sensing families is their wide range of signaling diversity—different variants within a family code for different signal molecules with a cognate receptor specific to each variant. This pattern of vast allelic polymorphism raises several questions—How do different signaling variants interact with one another? How is this diversity maintained? And how did it come to exist in the first place? Here we argue that social interactions between signaling variants can explain the emergence and persistence of signaling diversity throughout evolution. Finally, we extend the discussion to include cases where multiple diverse systems work in concert in a single bacterium.

scholarly journals Growth Promotion or Osmotic Stress Response: How SNF1-Related Protein Kinase 2 (SnRK2) Kinases Are Activated and Manage Intracellular Signaling in Plants

Plants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1443
Author(s):  
Yoshiaki Kamiyama ◽  
Sotaro Katagiri ◽  
Taishi Umezawa
Keyword(s):  
Protein Kinase ◽  
Plant Growth ◽  
Osmotic Stress ◽  
Protein Function ◽  
Intracellular Signaling ◽  
Growth Promotion ◽  
Research Field ◽  
Dependent Manner ◽  
Related Protein ◽  
Wide Range

Reversible phosphorylation is a major mechanism for regulating protein function and controls a wide range of cellular functions including responses to external stimuli. The plant-specific SNF1-related protein kinase 2s (SnRK2s) function as central regulators of plant growth and development, as well as tolerance to multiple abiotic stresses. Although the activity of SnRK2s is tightly regulated in a phytohormone abscisic acid (ABA)-dependent manner, recent investigations have revealed that SnRK2s can be activated by group B Raf-like protein kinases independently of ABA. Furthermore, evidence is accumulating that SnRK2s modulate plant growth through regulation of target of rapamycin (TOR) signaling. Here, we summarize recent advances in knowledge of how SnRK2s mediate plant growth and osmotic stress signaling and discuss future challenges in this research field.

scholarly journals Sexuality in Later Life and Mental Health Among Older Black Gay Men

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 313-314
Author(s):  
Darlingtina Esiaka ◽  
Alice Cheng ◽  
Candidus Nwakasi
Keyword(s):  
Mental Health ◽  
Gay Men ◽  
Later Life ◽  
The United States ◽  
Mental Wellbeing ◽  
Self Identity ◽  
Sexual Identities ◽  
Age Related ◽  
Wide Range ◽  
Black Gay Men

Abstract Self-acknowledgement and integration of racial and sexual identities are significant to one’s overall sense of identity because of their implications for mental health and wellbeing. These issues are important as one ages because older people experience a wide range of factors that add layers to their ability to (re)integrate subsets of their identity into their overall self-identity such as age and age-related disabilities. This study examined the intersection of race and sexual identities on overall health status in older Black gay men, a demographic group that has historically received less attention. Data from the Social Justice Sexuality (SJS) survey of LGBTQ+ people of color which occurred over a 12-month period in the United States were analyzed. Participants (N=160), 50 years and over, responded to questions about their sexuality, social identity, family dynamics, community connection and engagement, and mental and physical health. Results show an association of mental wellbeing with racial and sexual identities. Further, results show that a strong sense of connection to other sexual minorities is positively associated with mental health in older Black gay men. We discuss the implication of findings for mental health interventions targeting this gendered population.

scholarly journals CRL4-DCAF12 Ubiquitin Ligase Controls MOV10 RNA Helicase during Spermatogenesis and T Cell Activation

2021 ◽  
Vol 22 (10) ◽  
pp. 5394
Author(s):  
Tomas Lidak ◽  
Nikol Baloghova ◽  
Vladimir Korinek ◽  
Radislav Sedlacek ◽  
Jana Balounova ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Ubiquitin Ligase ◽  
Cell Activation ◽  
Rna Helicase ◽  
Dependent Manner ◽  
Amino Acid Residues ◽  
Risc Complex ◽  
Wide Range

Multisubunit cullin-RING ubiquitin ligase 4 (CRL4)-DCAF12 recognizes the C-terminal degron containing acidic amino acid residues. However, its physiological roles and substrates are largely unknown. Purification of CRL4-DCAF12 complexes revealed a wide range of potential substrates, including MOV10, an “ancient” RNA-induced silencing complex (RISC) complex RNA helicase. We show that DCAF12 controls the MOV10 protein level via its C-terminal motif in a proteasome- and CRL-dependent manner. Next, we generated Dcaf12 knockout mice and demonstrated that the DCAF12-mediated degradation of MOV10 is conserved in mice and humans. Detailed analysis of Dcaf12-deficient mice revealed that their testes produce fewer mature sperms, phenotype accompanied by elevated MOV10 and imbalance in meiotic markers SCP3 and γ-H2AX. Additionally, the percentages of splenic CD4+ T and natural killer T (NKT) cell populations were significantly altered. In vitro, activated Dcaf12-deficient T cells displayed inappropriately stabilized MOV10 and increased levels of activated caspases. In summary, we identified MOV10 as a novel substrate of CRL4-DCAF12 and demonstrated the biological relevance of the DCAF12-MOV10 pathway in spermatogenesis and T cell activation.

scholarly journals Clinical Perspectives and Trends: Microperimetry as a trial endpoint in retinal disease

2021 ◽  
Author(s):  
Yesa Yang ◽  
Hannah Dunbar
Keyword(s):  
Clinical Trial ◽  
Retinal Disease ◽  
Age Related Macular Degeneration ◽  
Gene Therapies ◽  
Age Related ◽  
Wide Range ◽  
Trial Endpoints ◽  
Visual Acuity Loss ◽  
Psychophysical Test ◽  
Trial Endpoint

Endpoint development trials are underway across the spectrum of retinal disease. New validated endpoints are urgently required for the assessment of emerging gene therapies and in preparation for the arrival of novel therapeutics targeting early stages of common sight-threatening conditions such as age-related macular degeneration. Visual function measures are likely to be key candidates in this search. Over the last two decades, microperimetry has been used extensively to characterize functional vision in a wide range of retinal conditions, detecting subtle defects in retinal sensitivity that precede visual acuity loss and tracking disease progression over relatively short periods. Given these appealing features, microperimetry has already been adopted as an endpoint in interventional studies, including multicenter trials, on a modest scale. A review of its use to date shows a concurrent lack of consensus in test strategy and a wealth of innovative disease and treatment-specific metrics which may show promise as clinical trial endpoints. There are practical issues to consider, but these have not held back its popularity and it remains a widely used psychophysical test in research. Endpoint development trials will undoubtedly be key in understanding the validity of microperimetry as a clinical trial endpoint, but existing signs are promising.

scholarly journals Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 2. THR-687

2021 ◽  
Author(s):  
Marc Vanhove ◽  
Jean-Marc Wagner ◽  
Bernard Noppen ◽  
Bart Jonckx ◽  
Elke Vermassen ◽  
...  
Keyword(s):  
General Circulation ◽  
Pharmacokinetic Model ◽  
Systemic Exposure ◽  
Age Related Macular Degeneration ◽  
Whole Body ◽  
Pharmacological Agents ◽  
Age Related ◽  
Pharmacokinetic Properties ◽  
High Concentrations ◽  
Systemic Compartment

AbstractIntravitreal (IVT) injection remains the preferred administration route of pharmacological agents intended for the treatment of back of the eye diseases such as diabetic macular edema (DME) and neovascular age-related macular degeneration (nvAMD). The procedure enables drugs to be delivered locally at high concentrations whilst limiting whole body exposure and associated risk of systemic adverse events. Nevertheless, intravitreally-delivered drugs do enter the general circulation and achieving an accurate understanding of systemic exposure is pivotal for the evaluation and development of drugs administered in the eye. We report here the full pharmacokinetic properties of THR-687, a pan RGD integrin antagonist currently in clinical development for the treatment of DME, in both rabbit and minipig. Pharmacokinetic characterization included description of vitreal elimination, of systemic pharmacokinetics, and of systemic exposure following IVT administration. For the latter, we present a novel pharmacokinetic model that assumes clear partition between the vitreous humor compartment itself where the drug is administered and the central systemic compartment. We also propose an analytical solution to the system of differential equations that represent the pharmacokinetic model, thereby allowing data analysis with standard nonlinear regression analysis. The model accurately describes circulating levels of THR-687 following IVT administration in relevant animal models, and we suggest that this approach is relevant to a range of drugs and analysis of subsequent systemic exposure.

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