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Cells Aug 2023The liver is a complex organ with the ability to regenerate itself in response to injury. However, several factors can contribute to liver damage beyond repair. Liver... (Review)
Review
The liver is a complex organ with the ability to regenerate itself in response to injury. However, several factors can contribute to liver damage beyond repair. Liver injury can be caused by viral infections, alcoholic liver disease, non-alcoholic steatohepatitis, and drug-induced liver injury. Understanding the cellular and molecular mechanisms involved in liver injury and regeneration is critical to developing effective therapies for liver diseases. Liver regeneration is a complex process that involves the interplay of various signaling pathways, cell types, and extracellular matrix components. The activation of quiescent hepatocytes that proliferate and restore the liver mass by upregulating genes involved in cell-cycle progression, DNA repair, and mitochondrial function; the proliferation and differentiation of progenitor cells, also known as oval cells, into hepatocytes that contribute to liver regeneration; and the recruitment of immune cells to release cytokines and angiogenic factors that promote or inhibit cell proliferation are some examples of the regenerative processes. Recent advances in the fields of gene editing, tissue engineering, stem cell differentiation, small interfering RNA-based therapies, and single-cell transcriptomics have paved a roadmap for future research into liver regeneration as well as for the identification of previously unknown cell types and gene expression patterns. In summary, liver injury and regeneration is a complex and dynamic process. A better understanding of the cellular and molecular mechanisms driving this phenomenon could lead to the development of new therapies for liver diseases and improve patient outcomes.
Topics: Humans; Hepatocytes; Non-alcoholic Fatty Liver Disease; Liver Diseases, Alcoholic; Stem Cells
PubMed: 37681858
DOI: 10.3390/cells12172129 -
Nature Communications Aug 2023Cell division is the basis for the propagation of life and requires accurate duplication of all genetic information. DNA damage created during replication (replication...
Cell division is the basis for the propagation of life and requires accurate duplication of all genetic information. DNA damage created during replication (replication stress) is a major cause of cancer, premature aging and a spectrum of other human disorders. Over the years, TRAIP E3 ubiquitin ligase has been shown to play a role in various cellular processes that govern genome integrity and faultless segregation. TRAIP is essential for cell viability, and mutations in TRAIP ubiquitin ligase activity lead to primordial dwarfism in patients. Here, we have determined the mechanism of inhibition of cell proliferation in TRAIP-depleted cells. We have taken advantage of the auxin induced degron system to rapidly degrade TRAIP within cells and to dissect the importance of various functions of TRAIP in different stages of the cell cycle. We conclude that upon rapid TRAIP degradation, specifically in S-phase, cells cease to proliferate, arrest in G2 stage of the cell cycle and undergo senescence. Our findings reveal that TRAIP works in S-phase to prevent DNA damage at transcription start sites, caused by replication-transcription conflicts.
Topics: Humans; S Phase; Cell Division; Cell Proliferation; Cell Cycle; Cell Survival; Ubiquitin-Protein Ligases
PubMed: 37604812
DOI: 10.1038/s41467-023-40695-y -
Advances in Nutrition (Bethesda, Md.) Sep 2023Cellular senescence has long been considered a permanent state of cell cycle arrest occurring in proliferating cells subject to different stressors, used as a cellular... (Review)
Review
Cellular senescence has long been considered a permanent state of cell cycle arrest occurring in proliferating cells subject to different stressors, used as a cellular defense mechanism from acquiring potentially harmful genetic faults. However, recent studies highlight that senescent cells might also alter the local tissue environment and concur to chronic inflammation and cancer risk by secreting inflammatory and matrix remodeling factors, acquiring a senescence-associated secretory phenotype (SASP). Indeed, during aging and age-related diseases, senescent cells amass in mammalian tissues, likely contributing to the inevitable loss of tissue function as we age. Cellular senescence has thus become one potential target to tackle age-associated diseases as well as cancer development. One important aspect characterizing senescent cells is their telomere length. Telomeres shorten as a consequence of multiple cellular replications, gradually leading to permanent cell cycle arrest, known as replicative senescence. Interestingly, in the large majority of cancer cells, a senescence escape strategy is used and telomere length is maintained by telomerase, thus favoring cancer initiation and tumor survival. There is growing evidence showing how (poly)phenols can impact telomere maintenance through different molecular mechanisms depending on dose and cell phenotypes. Although normally, (poly)phenols maintain telomere length and support telomerase activity, in cancer cells this activity is negatively modulated, thus accelerating telomere attrition and promoting cancer cell death. Some (poly)phenols have also been shown to exert senolytic activity, thus suggesting both antiaging (directly eliminating senescent cells) and anticancer (indirectly, via SASP inhibition) potentials. In this review, we analyze selective (poly)phenol mechanisms in senescent and cancer cells to discriminate between in vitro and in vivo evidence and human applications considering (poly)phenol bioavailability, the influence of the gut microbiota, and their dose-response effects.
Topics: Animals; Humans; Telomerase; Phenols; Cell Survival; Phenol; Aging; Neoplasms; Cell Proliferation; Mammals
PubMed: 37271484
DOI: 10.1016/j.advnut.2023.05.014 -
Communications Chemistry Nov 2023The early Earth, devoid of the protective stratospheric ozone layer, must have sustained an ambient prebiotic physicochemical medium intensified by the co-existence of... (Review)
Review
The early Earth, devoid of the protective stratospheric ozone layer, must have sustained an ambient prebiotic physicochemical medium intensified by the co-existence of shortwave UV photons and very low energy electrons (vLEEs). Consequently, only intrinsically stable molecules against these two co-existing molecular destructors must have proliferated and thereby chemically evolved into the advanced molecules of life. Based on this view, we examined the stability inherent in nucleobases and their complementary pairs as resistance to the molecular damaging effects of shortwave UV photons and vLEEs. This leads to the conclusion that nucleobases could only proliferated as their complementary pairs under the unfavorable prebiotic conditions on early Earth. The complementary base pairing not only enhances but consolidates the intrinsic stability of nucleobases against short-range UV photons, vLEEs, and possibly many as-yet-unknown deleterious agents co-existed in the prebiotic conditions of the early Earth. In short, complementary base pairing is a manifestation of chemical evolution in the unfavorable prebiotic medium created by the absence of the stratospheric ozone layer.
PubMed: 38012323
DOI: 10.1038/s42004-023-01060-8 -
Cell Reports Jun 2023Glioblastoma (GBM) stem cells (GSCs) display phenotypic and molecular features reminiscent of normal neural stem cells and exhibit a spectrum of cell cycle states...
Glioblastoma (GBM) stem cells (GSCs) display phenotypic and molecular features reminiscent of normal neural stem cells and exhibit a spectrum of cell cycle states (dormant, quiescent, proliferative). However, mechanisms controlling the transition from quiescence to proliferation in both neural stem cells (NSCs) and GSCs are poorly understood. Elevated expression of the forebrain transcription factor FOXG1 is often observed in GBMs. Here, using small-molecule modulators and genetic perturbations, we identify a synergistic interaction between FOXG1 and Wnt/β-catenin signaling. Increased FOXG1 enhances Wnt-driven transcriptional targets, enabling highly efficient cell cycle re-entry from quiescence; however, neither FOXG1 nor Wnt is essential in rapidly proliferating cells. We demonstrate that FOXG1 overexpression supports gliomagenesis in vivo and that additional β-catenin induction drives accelerated tumor growth. These data indicate that elevated FOXG1 cooperates with Wnt signaling to support the transition from quiescence to proliferation in GSCs.
Topics: Humans; beta Catenin; Cell Division; Cell Proliferation; Forkhead Transcription Factors; Glioblastoma; Nerve Tissue Proteins; Neural Stem Cells; Wnt Signaling Pathway
PubMed: 37243590
DOI: 10.1016/j.celrep.2023.112561 -
BioRxiv : the Preprint Server For... Aug 2023All mammalian organs depend upon resident macrophage populations to coordinate repair processes and facilitate tissue-specific functions. Recent work has established...
All mammalian organs depend upon resident macrophage populations to coordinate repair processes and facilitate tissue-specific functions. Recent work has established that functionally distinct macrophage populations reside in discrete tissue niches and are replenished through some combination of local proliferation and monocyte recruitment. Moreover, decline in macrophage abundance and function in tissues has been shown to contribute to many age-associated pathologies, such as atherosclerosis, cancer, and neurodegeneration. Despite these advances, the cellular mechanisms that coordinate macrophage organization and replenishment within an aging tissue niche remain largely unknown. Here we show that capillary-associated macrophages (CAMs) are selectively lost over time, which contributes to impaired vascular repair and tissue perfusion in older mice. To investigate resident macrophage behavior , we have employed intravital two-photon microscopy to non-invasively image in live mice the skin capillary plexus, a spatially well-defined model of niche aging that undergoes rarefication and functional decline with age. We find that CAMs are lost with age at a rate that outpaces that of capillary loss, leading to the progressive accumulation of capillary niches without an associated macrophage in both mice and humans. Phagocytic activity of CAMs was locally required to repair obstructed capillary blood flow, leaving macrophage-less niches selectively vulnerable to both homeostatic and injury-induced loss in blood flow. Our work demonstrates that homeostatic renewal of resident macrophages is not as finely tuned as has been previously suggested. Specifically, we found that neighboring macrophages do not proliferate or reorganize sufficiently to maintain an optimal population across the skin capillary niche in the absence of additional cues from acute tissue damage or increased abundance of growth factors, such as colony stimulating factor 1 (CSF1). Such limitations in homeostatic renewal and organization of various niche-resident cell types are potentially early contributors to tissue aging, which may provide novel opportunities for future therapeutic interventions.
PubMed: 37662387
DOI: 10.1101/2023.08.25.554832 -
Molecular Cancer Apr 2024It is generally recognized that tumor cells proliferate more rapidly than normal cells. Due to such an abnormally rapid proliferation rate, cancer cells constantly... (Review)
Review
It is generally recognized that tumor cells proliferate more rapidly than normal cells. Due to such an abnormally rapid proliferation rate, cancer cells constantly encounter the limits of insufficient oxygen and nutrient supplies. To satisfy their growth needs and resist adverse environmental events, tumor cells modify the metabolic pathways to produce both extra energies and substances required for rapid growth. Realizing the metabolic characters special for tumor cells will be helpful for eliminating them during therapy. Cell death is a hot topic of long-term study and targeting cell death is one of the most effective ways to repress tumor growth. Many studies have successfully demonstrated that metabolism is inextricably linked to cell death of cancer cells. Here we summarize the recently identified metabolic characters that specifically impact on different types of cell deaths and discuss their roles in tumorigenesis.
Topics: Humans; Carcinogenesis; Cell Transformation, Neoplastic; Cell Death; Nutrients; Oxygen; Apoptosis; Neoplasms
PubMed: 38575922
DOI: 10.1186/s12943-024-01977-1 -
BMC Cancer Jul 2023A majority of prostate cancer cells are in a non-proliferating, G (quiescent) phase of the cell cycle and may lie dormant for years before activation into a...
BACKGROUND
A majority of prostate cancer cells are in a non-proliferating, G (quiescent) phase of the cell cycle and may lie dormant for years before activation into a proliferative, rapidly progressing, disease phase. Many mechanisms which influence proliferation and quiescence choices remain to be elucidated, including the role of non-coding RNAs. In this study, we investigated the role of a long non-coding RNA (lncRNA), SNHG1, on cell proliferation, quiescence, and sensitivity to docetaxel as a potential factor important in prostate cancer biology.
METHODS
Publically available, anonymous, clinical data was obtained from cBioPortal for analysis. RNAi and prostate cancer cell lines were utilized to investigate SNHG1 in vitro. We measured G cells, DNA synthesis, and cell cycle distribution by flow cytometry. Western blotting was used to assess G arrest and apoptosis. These parameters were also investigated following docetaxel treatment.
RESULTS
We discovered that in prostate cancer patients from The Cancer Genome Atlas (TCGA) data set, high SNHG1 expression in localized tumors correlated with reduced progression-free survival, and in a data set of both primary and metastatic tumors, high SNHG1 expression was associated with metastatic tumors. In vitro analysis of prostate cancer cell lines showed SNHG1 expression correlated with a quiescent versus proliferative phenotype. Knockdown of SNHG1 by RNAi in PC3 and C4-2B cells resulted in an accumulation of cells in the G phase. After knockdown, 60.0% of PC3 cells were in G, while control cultures had 13.2% G. There were reciprocal decreases in G phase, but little impact on the proportion of cells in S and G/M phases, depending on cell line. DNA synthesis and proliferation were largely halted- decreasing by 75% and 81% in C4-2B and PC3 cells, respectively. When cells were treated with docetaxel, SNHG1-depleted C4-2B and PC3 cells were resistant to G arrest, and displayed reduced apoptosis, as indicated by reduced cyclin B1 and cleaved caspase 3, suggesting SNHG1 levels may modulate drug response.
CONCLUSIONS
Overall, these results indicate SNHG1 has complex roles in prostate cancer, as it stimulates cell cycle entry and disease progression, but sensitizes cells to docetaxel treatment.
Topics: Humans; Male; Docetaxel; Cell Division; Cell Proliferation; Prostatic Neoplasms; Apoptosis; Cell Line, Tumor; DNA; RNA, Long Noncoding
PubMed: 37464317
DOI: 10.1186/s12885-023-11006-x -
Diagnostics (Basel, Switzerland) Mar 2024Intravascular lymphomas are rare disease conditions that exhibit neoplastic lymphoid cells that are confined mainly to the lumens of small capillaries and medium-sized... (Review)
Review
Intravascular lymphomas are rare disease conditions that exhibit neoplastic lymphoid cells that are confined mainly to the lumens of small capillaries and medium-sized vessels. The majority of the intravascular lymphomas are of B-cell origin, but they can include NK/T-cell and CD30+ immunophenotypes. In the histologic differential diagnosis are benign proliferations such as intralymphatic histiocytosis and intravascular atypical CD30+ T-cell proliferation. In this review, we discuss the clinical, histopathologic, and molecular findings of intravascular B-cell lymphoma, intravascular NK/T-cell lymphoma, intralymphatic histiocytosis, and benign atypical intravascular CD30+ T-cell proliferation.
PubMed: 38611591
DOI: 10.3390/diagnostics14070679