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Cell Reports Jun 2024In contrast to most hematopoietic lineages, megakaryocytes (MKs) can derive rapidly and directly from hematopoietic stem cells (HSCs). The underlying mechanism is...
In contrast to most hematopoietic lineages, megakaryocytes (MKs) can derive rapidly and directly from hematopoietic stem cells (HSCs). The underlying mechanism is unclear, however. Here, we show that DNA damage induces MK markers in HSCs and that G2 arrest, an integral part of the DNA damage response, suffices for MK priming followed by irreversible MK differentiation in HSCs, but not in progenitors. We also show that replication stress causes DNA damage in HSCs and is at least in part due to uracil misincorporation in vitro and in vivo. Consistent with this notion, thymidine attenuated DNA damage, improved HSC maintenance, and reduced the generation of CD41 MK-committed HSCs. Replication stress and concomitant MK differentiation is therefore one of the barriers to HSC maintenance. DNA damage-induced MK priming may allow rapid generation of a lineage essential to immediate organismal survival, while also removing damaged cells from the HSC pool.
PubMed: 38935497
DOI: 10.1016/j.celrep.2024.114388 -
Human Cell Jun 2024The limited response of hepatocellular carcinoma (HCC) to chemotherapy drugs has always been a bottleneck in therapy. DNA damage repair is a major reason for...
The limited response of hepatocellular carcinoma (HCC) to chemotherapy drugs has always been a bottleneck in therapy. DNA damage repair is a major reason for chemoresistance. Previous studies have confirmed that KIN17 affects chemosensitivity. In this study, we examined the impact of KIN17 on chemotherapy response and DNA repair in HCC cells treated with oxaliplatin (L-OHP). We evaluated the expression and biological roles of KIN17 in HCC using bioinformatic analysis. The correlation between KIN17 and RAD51, particularly their nuclear expression levels, was evaluated using immunofluorescence, immunoblotting after nucleocytoplasmic separation in HCC cells, and immunohistochemistry of mouse xenograft tumors and human HCC tissues. The results indicated a significant increase in KIN17 expression in HCC tissues compared to normal tissues. The GSEA analysis revealed that upregulation of KIN17 was significantly associated with DNA damage repair. Knockdown of KIN17 led to increased DNA damage and reduced cellular survival after exposure to L-OHP. On the other hand, overexpression of KIN17 was linked to decreased DNA damage and improved cell survival following L-OHP treatment. Further experiments indicated that KIN17 affects the expression of RAD51, particularly in the nucleus. KIN17 plays a crucial role in influencing the sensitivity of HCC to chemotherapy by triggering the DNA repair response. Increased expression of KIN17 is associated with a poor prognosis for HCC patients, indicating that KIN17 could serve as a prognostic marker and therapeutic target for HCC.
PubMed: 38935235
DOI: 10.1007/s13577-024-01096-5 -
Briefings in Bioinformatics May 2024Advances in chromatin mapping have exposed the complex chromatin hierarchical organization in mammals, including topologically associating domains (TADs) and their...
Advances in chromatin mapping have exposed the complex chromatin hierarchical organization in mammals, including topologically associating domains (TADs) and their substructures, yet the functional implications of this hierarchy in gene regulation and disease progression are not fully elucidated. Our study delves into the phenomenon of shared TAD boundaries, which are pivotal in maintaining the hierarchical chromatin structure and regulating gene activity. By integrating high-resolution Hi-C data, chromatin accessibility, and DNA double-strand breaks (DSBs) data from various cell lines, we systematically explore the complex regulatory landscape at high-level TAD boundaries. Our findings indicate that these boundaries are not only key architectural elements but also vibrant hubs, enriched with functionally crucial genes and complex transcription factor binding site-clustered regions. Moreover, they exhibit a pronounced enrichment of DSBs, suggesting a nuanced interplay between transcriptional regulation and genomic stability. Our research provides novel insights into the intricate relationship between the 3D genome structure, gene regulation, and DNA repair mechanisms, highlighting the role of shared TAD boundaries in maintaining genomic integrity and resilience against perturbations. The implications of our findings extend to understanding the complexities of genomic diseases and open new avenues for therapeutic interventions targeting the structural and functional integrity of TAD boundaries.
Topics: DNA Repair; Humans; DNA Breaks, Double-Stranded; Chromatin; Gene Expression Regulation; Transcription Factors; Animals; Genomics; Genomic Instability; Chromatin Assembly and Disassembly
PubMed: 38935071
DOI: 10.1093/bib/bbae306 -
Molecular Carcinogenesis Jun 2024Cancer-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in the tumor microenvironment, which play important roles in regulating tumor...
Cancer-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in the tumor microenvironment, which play important roles in regulating tumor progression and therapy resistance by transferring exosomes to cancer cells. However, how CAFs modulate esophageal squamous cell carcinoma (ESCC) progression and radioresistance remains incompletely understood. The expression of fibroblast activation protein (FAP) in CAFs was evaluated by immunohistochemistry in 174 ESCC patients who underwent surgery and 78 pretreatment biopsy specimens of ESCC patients who underwent definitive chemoradiotherapy. We sorted CAFs according to FAP expression, and the conditioned medium (CM) was collected to culture ESCC cells. The expression levels of several lncRNAs that were considered to regulate ESCC progression and/or radioresistance were measured in exosomes derived from FAP CAFs and FAP CAFs. Subsequently, cell counting kit-8, 5-ethynyl-2'-deoxyuridine, transwell, colony formation, and xenograft assays were performed to investigate the functional differences between FAP CAFs and FAP CAFs. Finally, a series of in vitro and in vivo assays were used to evaluate the effect of AFAP1-AS1 on radiosensitivity of ESCC cells. FAP expression in stromal CAFs was positively correlated with nerve invasion, vascular invasion, depth of invasion, lymph node metastasis, lack of clinical complete response and poor survival. Culture of ESCC cells with CM/FAP CAFs significantly increased cancer proliferation, migration, invasion and radioresistance, compared with culture with CM/FAP CAFs. Importantly, FAP CAFs exert their roles by directly transferring the functional lncRNA AFAP1-AS1 to ESCC cells via exosomes. Functional studies showed that AFAP1-AS1 promoted radioresistance by enhancing DNA damage repair in ESCC cells. Clinically, high levels of plasma AFAP1-AS1 correlated with poor responses to dCRT in ESCC patients. Our findings demonstrated that FAP CAFs promoted radioresistance in ESCC cells through transferring exosomal lncRNA AFAP1-AS1; and may be a potential therapeutic target for ESCC treatment.
PubMed: 38934786
DOI: 10.1002/mc.23782 -
Journal of Microbiology and... Jun 2024The antimicrobial activity of the natural compounds from plant and food have well discovered since the interest on the beneficial effect of the natural compounds was...
The antimicrobial activity of the natural compounds from plant and food have well discovered since the interest on the beneficial effect of the natural compounds was risen. Quercetin, a flavonoid derived from vegetables, including onions, red leaf lettuces and cherries has been studied for diverse biological characteristics as anti-cancer and anti-microbial activities. The aim of current study is to investigate the specific antibacterial modes of action of quercetin against Quercetin decreased the cell viability and induced the severe damages (oxidative stress, DNA fragmentation) leading to cell death. ROS generation was observed during the process, which we confirmed that oxidative stress was the key action of antibacterial activity of quercetin exerting its influence potently. Based on the results of Annexin V and Caspace FITC-VAD-FMK assay, the oxidative damage in has led to the bacterial apoptosis-like death in . To sum up, the contribution of ROS generation exerts crucial impact in antibacterial activity of quercetin.
PubMed: 38934783
DOI: 10.4014/jmb.2403.03057 -
Journal of Food and Drug Analysis Jun 2024As cancer continues to rise globally, there is growing interest in discovering novel methods for prevention and treatment. Due to the limitations of traditional cancer... (Review)
Review
As cancer continues to rise globally, there is growing interest in discovering novel methods for prevention and treatment. Due to the limitations of traditional cancer therapies, there has been a growing emphasis on investigating herbal remedies and exploring their potential synergistic effects when combined with chemotherapy drugs. Cinnamaldehyde, derived from cinnamon, has gained significant attention for its potential role in cancer prevention and treatment. Extensive research has demonstrated that cinnamaldehyde exhibits promising anticancer properties by modulating various cellular processes involved in tumor growth and progression. However, challenges and unanswered questions remain regarding the precise mechanisms for its effective use as an anticancer agent. This article aims to explore the multifaceted effects of cinnamaldehyde on cancer cells and shed light on these existing issues. Cinnamaldehyde has diverse anti-cancer mechanisms, including inducing apoptosis by activating caspases and damaging mitochondrial function, inhibiting tumor angiogenesis, anti-proliferation, anti-inflammatory and antioxidant. In addition, cinnamaldehyde also acts as a reactive oxygen species scavenger, reducing oxidative stress and preventing DNA damage and genomic instability. This article emphasizes the promising therapeutic potential of cinnamaldehyde in cancer treatment and underscores the need for future research to unlock novel mechanisms and strategies for combating cancer. By providing valuable insights into the role and mechanism of cinnamaldehyde in cancer, this comprehensive understanding paves the way for its potential as a novel therapeutic agent. Overall, cinnamaldehyde holds great promise as an anticancer agent, and its comprehensive exploration in this article highlights its potential as a valuable addition to cancer treatment options.
Topics: Acrolein; Humans; Neoplasms; Animals; Apoptosis; Antineoplastic Agents; DNA Damage; Cell Proliferation; Reactive Oxygen Species
PubMed: 38934689
DOI: 10.38212/2224-6614.3502 -
Archivio Italiano Di Urologia,... Jun 2024Single sperm cryopreservation (SSC) is a specific technique especially used in individuals with small numbers of sperm who suffered from non-obstructive azoospermia...
Pentoxifylline treatment as a safe method for selecting viable testicular spermatozoa before cryopreservation of a small numbers of spermatozoa in azoospermia individuals.
BACKGROUND
Single sperm cryopreservation (SSC) is a specific technique especially used in individuals with small numbers of sperm who suffered from non-obstructive azoospermia (NOA). Testicular specimens possess poor motility and low population of viable spermatozoa. Therefore, sperm selection methods such as applying pentoxifylline (PTX) may improve motility in these cases. The main aim of this study was to evaluate the protective effects of PTX on testicular spermatozoa before and after performing SSC.
METHODS
Thirty testicular samples were obtained from men with azoospermia. This study was conducted in two phases. Phase 1 evaluated the effect of PTX for sperm selection before SSC. Twenty testicular samples were divided to two experimental groups: SSC without (I) and with PTX treatment (II). For PTX treatment spermatozoa were incubated with PTX at 37°C for 30 min and only motile spermatozoa were selected for SSC. In phase 2, ten testicular samples were cryopreserved with SSC and warming procedure was carried out in droplet with and without PTX. Motility and viability rates, morphology by motile sperm organelle morphology examination (MSOME), DNA fragmentation by sperm chromatin dispersion test (SCD) and mitochondrial membrane potential (MMP) were evaluated.
RESULTS
In phase 1, post warm motility rate was higher in PTX exposed group compared to the unexposed group (25.6 ± 8.13 vs. 0.85 ± 2.1) (p > 0.00). Recovery rate, viability and morphology were not significantly different between groups. DNA integrity and MMP were also similar between both groups. In phase 2 although motility increased in PTX group compared to without PTX group (29.30 ± 12.73 vs. 1.90 ± 2.64) (p > 0.00), the viability rate was not different (70.40 ± 12.12 vs. 65.30 ± 11.87). All above mentioned parameters were similar between the two SSC groups.
CONCLUSIONS
Supplementation of testicular spermatozoa with PTX before cryopreservation increases motility and did not have adverse effects on viability, morphology, DNA integrity and MMP. PTX could be used as sperm selection method before single sperm cryopreservation, but PTX could not maintain motile the most of viable testicular sperms.
Topics: Male; Humans; Pentoxifylline; Cryopreservation; Azoospermia; Spermatozoa; Sperm Motility; Semen Preservation; DNA Fragmentation; Testis; Adult; Cell Survival; Membrane Potential, Mitochondrial
PubMed: 38934523
DOI: 10.4081/aiua.2024.12525 -
The Journal of Pathology Jun 2024Chronic kidney disease (CKD) has emerged as a significant global public health concern. Recent epidemiological studies have highlighted the link between exposure to fine...
Chronic kidney disease (CKD) has emerged as a significant global public health concern. Recent epidemiological studies have highlighted the link between exposure to fine particulate matter (PM) and a decline in renal function. PM exerts harmful effects on various organs through oxidative stress and inflammation. Acute kidney injury (AKI) resulting from ischaemia-reperfusion injury (IRI) involves biological processes similar to those involved in PM toxicity and is a known risk factor for CKD. The objective of this study was to investigate the impact of PM exposure on IRI-induced AKI. Through a unique environmentally controlled setup, mice were exposed to urban PM or filtered air for 12 weeks before IRI followed by euthanasia 48 h after surgery. Animals exposed to PM and IRI exhibited reduced glomerular filtration, impaired urine concentration ability, and significant tubular damage. Further, PM aggravated local innate immune responses and mitochondrial dysfunction, as well as enhancing cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation. This increased renal senescence and suppressed the anti-ageing protein klotho, leading to early fibrotic changes. In vitro studies using proximal tubular epithelial cells exposed to PM and hypoxia/reoxygenation revealed heightened activation of the STING pathway triggered by cytoplasmic mitochondrial DNA, resulting in increased tubular damage and a pro-inflammatory phenotype. In summary, our findings imply a role for PM in sensitising proximal tubular epithelial cells to IRI-induced damage, suggesting a plausible association between PM exposure and heightened susceptibility to CKD in individuals experiencing AKI. Strategies aimed at reducing PM concentrations and implementing preventive measures may improve outcomes for AKI patients and mitigate the progression from AKI to CKD. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
PubMed: 38934262
DOI: 10.1002/path.6302 -
Intervirology Jun 2024This study aimed to investigate the differences between pregnant women with chronic hepatitis B virus (HBV) infection and intrafamilial infection and those without...
INTRODUCTION
This study aimed to investigate the differences between pregnant women with chronic hepatitis B virus (HBV) infection and intrafamilial infection and those without intrafamilial infection.
METHODS
HBV DNA was extracted from the sera of 16 pregnant women with chronic hepatitis B (CHB) and their family members for gene sequencing and phylogenetic analyses. A total of 74 pregnant women with CHB were followed up from the second trimester to three months postpartum. Viral markers and other laboratory indicators were compared between pregnant women with CHB with and without intrafamilial infection.
RESULTS
The phylogenetic tree showed that HBV lines in the mother-spread pedigree shared a node, whereas there was an unrelated genetic background for HBV lines in individuals without intrafamilial infection. From delivery to three months postpartum, compared with those without intrafamilial infection, pregnant women with intrafamilial infection were related negatively to HBV DNA (β=-0.43, 95% Confidence Interval [CI]: -0.76 to -0.12, p=0.009), HBeAg (β=-195.15, 95% CI: -366.35 to -23.96, p=0.027), and hemoglobin changes (β=-8.09, 95%CI: -15.54 to -0.64, p=0.035) and positively to changes in the levels of alanine aminotransferase (β=73.9, 95%CI:38.92-108.95, p<0.001) and albumin (β=2.73, 95% CI:0.23-5.23, p=0.033).
CONCLUSION
The mother-spread pedigree spread model differs from that of non-intrafamilial infections. Pregnant women with intra-familial HBV infection have less hepatitis flares and liver damage, but their HBV DNA and HBeAg levels rebound faster after delivery, than those without intra-familial infection by the virus.
PubMed: 38934174
DOI: 10.1159/000539994 -
Kidney Research and Clinical Practice Jun 2024Time-restricted feeding (TRF), devoid of calorie restriction, is acknowledged for promoting metabolic health and mitigating various chronic metabolic diseases. While TRF...
BACKGROUND
Time-restricted feeding (TRF), devoid of calorie restriction, is acknowledged for promoting metabolic health and mitigating various chronic metabolic diseases. While TRF exhibits widespread benefits across multiple tissues, there is limited exploration into its impact on kidney function. In this study, our aim was to investigate the potential ameliorative effects of TRF on kidney damage in a mouse model of cisplatin-induced acute kidney injury (AKI).
METHODS
Cisplatin-induced AKI was induced through intraperitoneal injection of cisplatin into C57BL/6 male mice. Mice undergoing TRF were provided unrestricted access to standard chow daily but were confined to an 8-hour feeding window during the dark cycle for 2 weeks before cisplatin injection. The mice were categorized into four groups: control, TRF, cisplatin, and TRF + cisplatin.
RESULTS
The tubular damage score and serum creatinine levels were significantly lower in the TRF + cisplatin group compared to the cisplatin group. The TRF + cisplatin group exhibited reduced expression of phosphorylated nuclear factor kappa B, inflammatory cytokines, and F4/80-positive macrophages compared to the cisplatin group. Furthermore, oxidative stress markers for DNA, protein, and lipid were markedly decreased in the TRF + cisplatin group compared to the cisplatin group. TUNEL-positive tubular cells, cleaved caspase-3 expression, and the Bax/Bcl-2 ratio in the TRF + cisplatin group were lower than those in the cisplatin group.
CONCLUSION
TRF, without calorie restriction, effectively mitigated kidney damage by suppressing inflammatory reactions, oxidative stress, and tubular apoptosis in a mouse model of cisplatin-induced AKI. TRF holds promise as a novel dietary intervention for preventing cisplatin-induced AKI.
PubMed: 38934035
DOI: 10.23876/j.krcp.23.351