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Bioorganic Chemistry Jun 2024In recent years, Varicocele (VC) has been recognized as a common cause of male infertility that can be treated by surgery or drugs. How to reduce the damage of VC to...
Chlorogenic acid can improve spermatogenic dysfunction in rats with varicocele by regulating mitochondrial homeostasis and inhibiting the activation of NLRP3 inflammasomes by oxidative mitochondrial DNA and cGAS/STING pathway.
In recent years, Varicocele (VC) has been recognized as a common cause of male infertility that can be treated by surgery or drugs. How to reduce the damage of VC to testicular spermatogenic function has attracted extensive attention in recent years. Among them, overexpressed ROS and high levels of inflammation may play a key role in VC-induced testicular damage. As the key mediated innate immune pathways, cGAS-STING shaft under pathological conditions, such as in cell and tissue damage stress can be cytoplasmic DNA activation, induce the activation of NLRP3 inflammatory corpuscle, triggering downstream of the inflammatory cascade reaction. Chlorogenic acid (CGA), as a natural compound from a wide range of sources, has strong anti-inflammatory and antioxidant activities, and is a potential effective drug for the treatment of varicocele infertility. The aim of this study is to investigate the role of CGA in the spermatogenic dysfunction of the rat testis induced by VC and the potential mechanisms. The results of this study have shown that CGA gavage treatment ameliorated the pathological damage of seminiferous tubules, increased the number of sperm in the lumen, and increased the expression levels of Occludin and ZO-1, which indicated the therapeutic effect of CGA on spermatogenic dysfunction in the testis of VC rats. Meanwhile, the damage of mitochondrial structure was alleviated and the expression levels of ROS, NLRP3 and pro-inflammatory cytokines (IL-1β, IL-6, IL-18) were significantly reduced in the testicular tissues of model rats after CGA treatment. In addition, we demonstrated for the first time the high expression status of cGAS and STING in testicular tissues of VC model rats, and this was ameliorated to varying degrees after CGA treatment. In conclusion, this study suggests that CGA can improve the spermatogenic function of the testis by reducing mitochondrial damage and inhibiting the activation of the cGAS-STING axis, inhibiting the activation of the NLRP3 inflammasome, and improving the inflammatory damage of the testis, highlighting the potential of CGA as a therapeutic agent for varicocele infertility.
PubMed: 38936048
DOI: 10.1016/j.bioorg.2024.107571 -
Proceedings of the National Academy of... Jul 2024In 1967, in this journal, Evelyn Witkin proposed the existence of a coordinated DNA damage response in , which later came to be called the "SOS response." We revisited...
In 1967, in this journal, Evelyn Witkin proposed the existence of a coordinated DNA damage response in , which later came to be called the "SOS response." We revisited this response using the replication inhibitor azidothymidine (AZT) and RNA-Seq analysis and identified several features. We confirm the induction of classic Save our ship (SOS) loci and identify several genes, including many of the pyrimidine pathway, that have not been previously demonstrated to be DNA damage-inducible. Despite a strong dependence on LexA, these genes lack LexA boxes and their regulation by LexA is likely to be indirect via unknown factors. We show that the transcription factor "stringent starvation protein" SspA is as important as LexA in the regulation of AZT-induced genes and that the genes activated by SspA change dramatically after AZT exposure. Our experiments identify additional LexA-independent DNA damage inducible genes, including 22 small RNA genes, some of which appear to activated by SspA. Motility and chemotaxis genes are strongly down-regulated by AZT, possibly as a result of one of more of the small RNAs or other transcription factors such as AppY and GadE, whose expression is elevated by AZT. Genes controlling the iron siderophore, enterobactin, and iron homeostasis are also strongly induced, independent of LexA. We confirm that IraD antiadaptor protein is induced independent of LexA and that a second antiadaptor, IraM is likewise strongly AZT-inducible, independent of LexA, suggesting that RpoS stabilization via these antiadaptor proteins is an integral part of replication stress tolerance.
Topics: Escherichia coli; DNA Damage; Gene Expression Regulation, Bacterial; Escherichia coli Proteins; DNA Replication; SOS Response, Genetics; Bacterial Proteins; Serine Endopeptidases
PubMed: 38935560
DOI: 10.1073/pnas.2407832121 -
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