MOMP: A critical event in cell death regulation and anticancer treatment

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2025, Volume and Issue: unknown, P. 189280 - 189280

Published: Feb. 1, 2025

Language: Английский

---

Cellular Senescence as a Key Player in Chronic Heart Failure Pathogenesis: Unraveling Mechanisms and Therapeutic Opportunities

Progress in Biophysics and Molecular Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

---

Mitochondrially Transcribed dsRNA Mediates Manganese-induced Neuroinflammation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Abstract Manganese (Mn) is an essential trace element required for various biological functions, but excessive Mn levels are neurotoxic and lead to significant health concerns. The mechanisms underlying Mn-induced neurotoxicity remain poorly understood. Neuropathological studies of affected brain regions reveal astrogliosis, neuronal loss, along with evidence neuroinflammation. Here, we present a novel Mn-dependent mechanism linking mitochondrial dysfunction We found that disrupts transcriptome processing, resulting in the accumulation complementary RNAs form double-stranded RNA (dsRNA). This dsRNA released cytoplasm, where it activates cytosolic sensor pathways, triggering type I interferon responses inflammatory cytokine production. 100-day human cerebral organoids, observed predominantly mature astrocytes. Similar effects were vivo mouse model carrying mutations SLC30A10 gene, which results accumulation. These findings highlight previously unrecognized role neuroinflammation provide insights into molecular basis manganism. propose this dsRNA-induced pathway has broad implications neurodegenerative diseases caused by environmental or genetic insults.

Language: Английский

---

Demonstration of the Feasibility of Mainstream Aging Theories and Intervention

Published: Jan. 1, 2025

Language: Английский

---

The composition of human sperm sncRNAome: a cross-country small RNA profiling

Reproductive Biology and Endocrinology, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 6, 2025

Over the last decade, numerous studies have implicated sperm-borne small non-coding RNAs (sncRNAs) in fertility and transgenerational inheritance. Spermatozoa contain a variety of RNAs; however, inter-individual inter-population variations human sperm sncRNA content (sncRNAome) not yet been ascertained. We performed sequencing 54 normozoospermic proven fertile Indian donors. also obtained second semen sample from 13 donors third eight repeated sequencing. To better understand sncRNAome similarities variations, data for eligible Chinese (n = 87), US 14), Spanish 2) (fertile or presumptive fertile) samples were downloaded analyzed uniform manner. compared within across populations to identify differences. In samples, rsRNAs (13.71-78.76%), YsRNAs (0.64-76.53%) tsRNAs (5.63-35.16%) constituted major fraction miRNAs, piRNAs, mt-tsRNAs, other sncRNAs minor fraction. Across three populations, (11-80%) (10-60%) fraction, (0.62-4.28%), miRNAs (0.41-7.37%), piRNAs (1.37-4.36%), mt-tsRNAs (0.14-4.33%), Only 47 consistent only 17 four populations. Interestingly, all detected derived chromosome 15 piRNA cluster, which predominantly present tRNA-Gly-GCC contributed approximately 50% tsRNA pool The originated majorly one mt-tRNA that differed Among rsRNAs, maximum number reads belonged 28S, followed by 18S, 5S, 5.8S, 45S decreasing order. Y4sRNAs most abundant YsRNAs, while common contributor has 'core component' shows 'peripheral significant individuals availability normal would help delineate biologically meaningful sample-to-sample natural/random variations.

Language: Английский

---

Cytosolic nucleic acid sensing as driver of critical illness: mechanisms and advances in therapy

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 19, 2025

Abstract Nucleic acids from both self- and non-self-sources act as vital danger signals that trigger immune responses. Critical illnesses such acute respiratory distress syndrome, sepsis, trauma ischemia lead to the aberrant cytosolic accumulation massive release of nucleic are detected by antiviral innate receptors in endosome or cytosol. Activation for deoxyribonucleic ribonucleic triggers inflammation, a major contributor morbidity mortality critically ill patients. In past decade, there has been growing recognition therapeutic potential targeting acid sensing critical care. This review summarizes current knowledge ischemia. Given extensive research on common pathological conditions like cancer, autoimmune disorders, metabolic disorders aging, we provide comprehensive summary beyond illness offer insights may inform its role conditions. Additionally, discuss strategies specifically target sensing. By examining sources, sensor activation function, well impact regulating these pathways across various diseases, highlight driving illness.

Language: Английский

---

Oncogene-induced senescence mitochondrial metabolism and bioenergetics drive the secretory phenotype: further characterization and comparison with other senescence-inducing stimuli

Redox Biology, Journal Year: 2025, Volume and Issue: unknown, P. 103606 - 103606

Published: March 1, 2025

Cellular senescence is characterized by proliferation arrest and a senescence-associated secretory phenotype (SASP), that plays role in aging the progression of various age-related diseases. Although metabolic alterations have been reported, no consensus exists regarding mitochondrial bioenergetics. Here we compared metabolism human fibroblasts after inducing with different stimuli: oxidant hydrogen peroxide (H2O2), genotoxic doxorubicin, serial passage, or expression H-RASG12V oncogene (RAS). In induced H2O2, doxorubicin passage decrease respiratory control ratio (RCR) coupling efficiency was noted, relation to cells. On contrary, oncogene-induced senescent cells had an overall increase respiration rates, RCR, spare capacity efficiency. (OIS) rates accompanied fatty acid catabolism, AMPK activation, persistent DNA damage response (DDR), were not present either H2O2 doxorubicin. Inhibition reduced oxygen consumption secretion proinflammatory cytokines OIS. Assessment enzymes involved acetyl-CoA OIS showed 3- 7.5-fold pyruvate dehydrogenase complex (PDH), 40% inhibition aconitase, increased phosphorylation activation ATP-citrate lyase (ACLY), carboxylase (ACC). There also significant nuclear levels deacetylase sirtuin 6 (SIRT6). These changes can influence sub-cellular distribution modulate protein acetylation reactions cytoplasm nuclei. fact, ACLY histone 3 (H3K9Ac) SASP components. summary, our data show marked heterogeneity energy cells, depending on stimulus, reveal new features identify as potential targets for modulation.

Language: Английский

---

Taurine can restrict mtdsRNA mediated pyroptosis by enhancing mitophagy in nucleus pulposus cells

Published: April 15, 2025

Mitochondrial double-stranded RNA (mtdsRNA), a long-stranded molecule generated by bidirectional transcription of the circular mitochondrial genome, can trigger type 1 interferon response activating pattern recognition receptors in cytoplasm during dysfunction. However, its regulatory and pathogenic mechanisms intervertebral disc degeneration are poorly understood. Here, we showed that mtdsRNA was abnormally elevated degenerative nucleus pulposus tissues. Furthermore, found leakage into could cause MAVS oligomerization binding to RLRs, oligomerized then promote cell pyroptosis NLRP3. To further elucidate upstream mechanism mtdsRNA, performed untargeted metabolomics analysis, which revealed downregulation taurine under external stimuli drive an imbalance homeostasis. RNA-seq exogenous supplementation with protected cells from mtdsRNA-induced increasing mitophagy. In conclusion, our study links metabolism, nucleic acids suggests is important causative potential therapeutic target degeneration.

Language: Английский

---

Emerging insights in senescence: pathways from preclinical models to therapeutic innovations

npj Aging, Journal Year: 2024, Volume and Issue: 10(1)

Published: Nov. 22, 2024

Abstract Senescence is a crucial hallmark of ageing and significant contributor to the pathology age-related disorders. As committee members young International Cell Association (yICSA), we aim synthesise recent advancements in identification, characterisation, therapeutic targeting senescence for clinical translation. We explore novel molecular techniques that have enhanced our understanding senescent cell heterogeneity their roles tissue regeneration pathology. Additionally, delve into vivo models senescence, both non-mammalian mammalian, highlight tools available advancing contextual senescence. Furthermore, discuss innovative diagnostic senotherapeutic approaches, emphasising potential application. Future directions research are explored, underscoring need precise, context-specific classification integration advanced technologies such as machine learning, long-read sequencing, multifunctional senoprobes senolytics. The dual role promoting homoeostasis contributing chronic diseases highlights complexity these cells improved outcomes.

Language: Английский

---

HRK downregulation and augmented BCL-xL binding to BAK confer apoptotic protection to therapy-induced senescent melanoma cells

Cell Death and Differentiation, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 3, 2024

Abstract Senescent cells are commonly detected in tumors after chemo and radiotherapy, leading to a characteristic cellular phenotype that resists apoptotic cell death. In this study, we used multiple melanoma lines, molecular markers, therapies investigate the key role of BCL-2 family proteins survival senescent cells. We first BH3 profiling assess changes priming upon senescence induction. Unexpectedly, not all types analyzed showed decrease priming, BIM was downregulated, there variability BAX expression BAK remained constant or increased. Therefore, clear pattern for pro-survival adaptation. Many studies have been devoted find ways eliminate cells, one most studied senolytic agents: navitoclax, promiscuous mimetic inhibits BCL-2, BCL-xL BCL-W. While it is known upregulated complexity network has fully explored. Interestingly, found distinct protein always mediated adaptation, as assessed by profiling. When analyzing potential therapeutic strategies, observed stronger activity these lines when specifically targeting using A-1331852, navitoclax PROTAC degrader DT2216. sensitizer HRK systematically downregulated induced, an increased availability BCL-xL. Furthermore, identified main inhibition shaped binding increase prevented mitochondrial permeabilization apoptosis. To our knowledge, time basis anti-apoptotic adaptation described, paving way development new molecules either prevent downregulation displace be senolytics.

Language: Английский

---