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Free Radical Biology & Medicine Jun 2024Lamin A/C, essential inner nuclear membrane proteins, have been linked to progeria, a disease of accelerated aging, and many other diseases, which include cardiac...
Lamin A/C, essential inner nuclear membrane proteins, have been linked to progeria, a disease of accelerated aging, and many other diseases, which include cardiac disorder. Lamin A/C mutation and its phosphorylation are associated with altering nuclear shape and size. The role of lamin A/C in regulating normal cardiac function was reported earlier. In the present study, we hypothesized that Doxorubicin (Dox) may alter total lamin A/C expression and phosphorylation, thereby taking part in cardiac injury. An in vitro cellular injury model was generated with Dox (0.1-10.0 μM) treatment on cardiomyoblast cells (H9c2) to prove our hypothesis. Increased size and irregular (ameboid) nucleus shape were observed in H9c2 cells after Dox treatment. Similarly, we have observed a significant increase in cell death on increasing the Dox concentration. The expression of lamin A/C and its phosphorylation at serine 22 significantly decreased and increased, respectively in H9c2 cells and rat hearts after Dox exposure. Phosphorylation led to depolymerization of the lamin A/C in the inner nuclear membrane and was evidenced by their presence throughout the nucleoplasm as observed by immunocytochemistry techniques. Thinning and perforation on the walls of the nuclear membrane were observed in Dox-treated H9c2 cells. LMNA-overexpression in H9c2 protected the cells from Dox-induced cell death, reversing all changes described above. Further, improvement of lamin A/C levels was observed in Dox-treated H9c2 cells when treated with Purvalanol A, a CDK1 inhibitor and N-acetylcysteine, an antioxidant. The study provides new insight regarding Dox-induced cardiac injury with the involvement of lamin A/C and alteration of inner nuclear membrane structure.
Topics: Doxorubicin; Lamin Type A; Animals; Phosphorylation; Nuclear Envelope; Rats; Cardiotoxicity; Cell Line; Myocytes, Cardiac; Antibiotics, Antineoplastic; Male; Rats, Sprague-Dawley
PubMed: 38582228
DOI: 10.1016/j.freeradbiomed.2024.04.212 -
Aging Cell Jul 2024Searching for biomarkers of senescence remains necessary and challenging. Reliable and detectable biomarkers can indicate the senescence condition of individuals, the...
Searching for biomarkers of senescence remains necessary and challenging. Reliable and detectable biomarkers can indicate the senescence condition of individuals, the need for intervention in a population, and the effectiveness of that intervention in controlling or delaying senescence progression and senescence-associated diseases. Therefore, it is of great importance to fulfill the unmet requisites of senescence biomarkers especially when faced with the growing global senescence nowadays. Here, we established that DNA G-quadruplex (G4) in mitochondrial genome was a reliable hallmark for mesenchymal senescence. Via developing a versatile and efficient mitochondrial G4 (mtG4) probe we revealed that in multiple types of senescence, including chronologically healthy senescence, progeria, and replicative senescence, mtG4 hallmarked aged mesenchymal stem cells. Furthermore, we revealed the underlying mechanisms by which accumulated mtG4, specifically within respiratory chain complex (RCC) I and IV loci, repressed mitochondrial genome transcription, finally impairing mitochondrial respiration and causing mitochondrial dysfunction. Our findings endowed researchers with the visible senescence biomarker based on mitochondrial genome and furthermore revealed the role of mtG4 in inhibiting RCC genes transcription to induce senescence-associated mitochondrial dysfunction. These findings depicted the crucial roles of mtG4 in predicting and controlling mesenchymal senescence.
PubMed: 38955799
DOI: 10.1111/acel.14265 -
GeroScience Feb 2024Onset and rates of sarcopenia, a disease characterized by a loss of muscle mass and function with age, vary greatly between sexes. Currently, no clinical interventions...
Onset and rates of sarcopenia, a disease characterized by a loss of muscle mass and function with age, vary greatly between sexes. Currently, no clinical interventions successfully arrest age-related muscle impairments since the decline is frequently multifactorial. Previously, we found that systemic transplantation of our unique adult multipotent muscle-derived stem/progenitor cells (MDSPCs) isolated from young mice-but not old-extends the health-span in DNA damage mouse models of progeria, a disease of accelerated aging. Additionally, induced neovascularization in the muscles and brain-where no transplanted cells were detected-strongly suggests a systemic therapeutic mechanism, possibly activated through circulating secreted factors. Herein, we used ZMPSTE24-deficient mice, a lamin A defect progeria model, to investigate the ability of young MDSPCs to preserve neuromuscular tissue structure and function. We show that progeroid ZMPST24-deficient mice faithfully exhibit sarcopenia and age-related metabolic dysfunction. However, systemic transplantation of young MDSPCs into ZMPSTE24-deficient progeroid mice sustained healthy function and histopathology of muscular tissues throughout their 6-month life span in a sex-specific manner. Indeed, female-but not male-mice systemically transplanted with young MDSPCs demonstrated significant preservation of muscle endurance, muscle fiber size, mitochondrial respirometry, and neuromuscular junction morphometrics. These novel findings strongly suggest that young MDSPCs modulate the systemic environment of aged animals by secreted rejuvenating factors to maintain a healthy homeostasis in a sex-specific manner and that the female muscle microenvironment remains responsive to exogenous regenerative cues in older age. This work highlights the age- and sex-related differences in neuromuscular tissue degeneration and the future prospect of preserving health in older adults with systemic regenerative treatments.
Topics: Male; Mice; Female; Animals; Progeria; Sarcopenia; Disease Models, Animal; Adult Stem Cells; Muscles
PubMed: 37535205
DOI: 10.1007/s11357-023-00892-5 -
Cell Stress 2024In a recent issue in , Sung Min Son unveil a novel layer in the regulation of the mTORC1/autophagy axis by EP300 which can undergo nucleocytoplasmic shuttling in...
In a recent issue in , Sung Min Son unveil a novel layer in the regulation of the mTORC1/autophagy axis by EP300 which can undergo nucleocytoplasmic shuttling in response to alterations in nutrient availability. The study highlights that, in Hutchinson-Gilford progeria syndrome, overabundant cytoplasmic EP300 results in mTORC1 hyperactivation and impaired autophagy, potentially contributing to premature and accelerated aging.
PubMed: 38800095
DOI: 10.15698/cst2024.04.295 -
Clinical Genetics Oct 2023Restrictive dermopathy (RD) is a lethal condition caused by biallelic loss-of-function mutations in ZMPSTE24, whereas mutations preserving residual enzymatic activity of...
Restrictive dermopathy (RD) is a lethal condition caused by biallelic loss-of-function mutations in ZMPSTE24, whereas mutations preserving residual enzymatic activity of the ZMPSTE24 protein lead to the milder mandibuloacral dysplasia with type B lipodystrophy (MADB) phenotype. Remarkably, we identified a homozygous, presumably loss-of-function mutation in ZMPSTE24 [c.28_29insA, p.(Leu10Tyrfs*37)] in two consanguineous Pakistani families segregating MADB. To clarify how lethal consequences are prevented in affected individuals, functional analysis was performed. Expression experiments supported utilization of two alternative translation initiation sites, preventing complete loss of protein function consistent with the relatively mild phenotypic outcome in affected patients. One of these alternative start codons is newly formed at the insertion site. Our findings indicate that the creation of new potential start codons through N-terminal mutations in other disease-associated genes should generally be taken into consideration in the variant interpretation process.
Topics: Humans; Frameshift Mutation; Codon, Initiator; Metalloendopeptidases; Mutation; Codon; Membrane Proteins
PubMed: 37270786
DOI: 10.1111/cge.14381 -
European Heart Journal May 2024
Topics: Humans; Peripheral Arterial Disease; Risk Assessment; Risk Factors; Prognosis
PubMed: 38607986
DOI: 10.1093/eurheartj/ehae154 -
GeroScience Apr 2024A progeroid family was found to harbor a pathogenic variant in the CASP5 gene that encodes inflammatory caspase 5. Caspase 5-depleted fibroblasts exhibited...
A progeroid family was found to harbor a pathogenic variant in the CASP5 gene that encodes inflammatory caspase 5. Caspase 5-depleted fibroblasts exhibited hyper-activation of inflammatory cytokines in response to pro-inflammatory stimuli. Long-term intermittent hyper-inflammatory response is likely the cause of the accelerated aging phenotype comprised of earlier onset of common aging diseases, supporting inflammaging as a potential common disease mechanism of progeroid syndromes and possibly normative aging.
Topics: Humans; Progeria; Phenotype
PubMed: 37603195
DOI: 10.1007/s11357-023-00907-1 -
The Journal of Thoracic and... Nov 2023
PubMed: 37236599
DOI: 10.1016/j.jtcvs.2023.05.015 -
Problemy Endokrinologii Oct 2023Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) is an ultra-orphan disease from the group of premature aging syndromes with an autosomal recessive type of...
Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) is an ultra-orphan disease from the group of premature aging syndromes with an autosomal recessive type of inheritance associated with mutations in the POLR3A, POLR3B, and POLR3GL genes encoding RNA polymerase III. The incidence of the disease is currently unknown. We present the first clinical description in Russian Federation of a patient 7 years 6 months old with Wiedemann-Rautenstrauch syndrome (compound heterozygous mutations in POLR3A gene) with progeroid features, adentia, growth retardation (height SDS -3,41, height velocity SDS -2,47), underweight (BMI SDS -6,20), and generalized lipodystrophy. The article presents the observation of the patient for 1.5 years, the world experience of dynamic follow-up of patients with neonatal progeroid syndrome, differential diagnosis, as well as recommendations for the management of patients with this syndrome. Given the lack of specific treatment to date, patients are observed by a multidisciplinary team of physicians.
Topics: Humans; Progeria; Child; RNA Polymerase III; Male; Female; Russia; Diagnosis, Differential; Mutation; Fetal Growth Retardation
PubMed: 38796765
DOI: 10.14341/probl13369 -
Can an individual be enrolled in more than one clinical trial using exception from informed consent?Academic Emergency Medicine : Official... Mar 2024
Topics: Humans; Informed Consent; Biomedical Research
PubMed: 37634126
DOI: 10.1111/acem.14799