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Gut Microbes 2024Intratumoral bacteria flexibly contribute to cellular and molecular tumor heterogeneity for supporting cancer recurrence through poorly understood mechanisms. Using...
Intratumoral bacteria flexibly contribute to cellular and molecular tumor heterogeneity for supporting cancer recurrence through poorly understood mechanisms. Using spatial metabolomic profiling technologies and 16SrRNA sequencing, we herein report that right-sided colorectal tumors are predominantly populated with Colibactin-producing (CoPEC) that are locally establishing a high-glycerophospholipid microenvironment with lowered immunogenicity. It coincided with a reduced infiltration of CD8 T lymphocytes that produce the cytotoxic cytokines IFN-γ where invading bacteria have been geolocated. Mechanistically, the accumulation of lipid droplets in infected cancer cells relied on the production of colibactin as a measure to limit genotoxic stress to some extent. Such heightened phosphatidylcholine remodeling by the enzyme of the Land's cycle supplied CoPEC-infected cancer cells with sufficient energy for sustaining cell survival in response to chemotherapies. This accords with the lowered overall survival of colorectal patients at stage III-IV who were colonized by CoPEC when compared to patients at stage I-II. Accordingly, the sensitivity of CoPEC-infected cancer cells to chemotherapies was restored upon treatment with an acyl-CoA synthetase inhibitor. By contrast, such metabolic dysregulation leading to chemoresistance was not observed in human colon cancer cells that were infected with the mutant strain that did not produce colibactin (11G5). This work revealed that CoPEC locally supports an energy trade-off lipid overload within tumors for lowering tumor immunogenicity. This may pave the way for improving chemoresistance and subsequently outcome of CRC patients who are colonized by CoPEC.
Topics: Humans; Escherichia coli; Tumor Microenvironment; Drug Resistance, Neoplasm; Mutagens; Gastrointestinal Microbiome; Neoplasm Recurrence, Local; Colorectal Neoplasms; Polyketides; Lipids; Peptides
PubMed: 38417029
DOI: 10.1080/19490976.2024.2320291 -
Medicina (Kaunas, Lithuania) Nov 2023Combination therapy with glucocorticoids, cyclophosphamide, and plasmapheresis is recommended as the standard treatment for anti-glomerular basement membrane (anti-GBM)... (Review)
Review
Combination therapy with glucocorticoids, cyclophosphamide, and plasmapheresis is recommended as the standard treatment for anti-glomerular basement membrane (anti-GBM) disease, but the prognosis of this disease remains poor. Several immunobiological agents have been administered or are expected to be useful for anti-GBM disease in light of refractory disease or the standard treatments' tolerability. Many data regarding the use of biologic agents for anti-GBM disease have accumulated, verifying the effectiveness and potential of biologic agents as a new treatment option for anti-GBM disease. Tumor necrosis factor (TNF) inhibitors were shown to be useful in animal studies, but these agents have no clinical use and were even shown to induce anti-GBM disease in several cases. Although the efficacy of the TNF-receptor antagonist has been observed in animal models, there are no published case reports of its clinical use. There are also no published reports of animal or clinical studies of anti-B-cell-activating factor, which is a member of the TNF family of agents. Anti-interleukin (IL)-6 antibodies have been demonstrated to have no effect on or to exacerbate nephritis in animal models. Anti-C5 inhibitor was observed to be useful in a few anti-GBM disease cases. Among the several immunobiological agents, only rituximab has been demonstrated to be useful in refractory or poor-tolerance patients or small uncontrolled studies. Rituximab is usually used in combination with steroids and plasma exchange and is used primarily as an alternative to cyclophosphamide, but there is insufficient evidence regarding the efficacy of rituximab for anti-GBM disease, and thus, randomized controlled studies are required.
Topics: Animals; Humans; Anti-Glomerular Basement Membrane Disease; Rituximab; Autoantibodies; Cyclophosphamide; Biological Factors; Basement Membrane
PubMed: 38004064
DOI: 10.3390/medicina59112014 -
Nature May 2024International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional... (Comparative Study)
Comparative Study
International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence. Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.
Topics: Female; Humans; Male; Aristolochic Acids; Carcinoma, Renal Cell; Environmental Exposure; Genome, Human; Genomics; Geography; Hypertension; Incidence; Japan; Kidney Neoplasms; Mutagens; Mutation; Obesity; Risk Factors; Romania; Serbia; Thailand; Tobacco Smoking
PubMed: 38693263
DOI: 10.1038/s41586-024-07368-2 -
BMC Endocrine Disorders Jan 2024To evaluate the efficacy and safety of combined glucocorticoids (GCs) and cyclophosphamide (CYC) treatment in Graves' ophthalmopathy (GO). (Meta-Analysis)
Meta-Analysis
PURPOSE
To evaluate the efficacy and safety of combined glucocorticoids (GCs) and cyclophosphamide (CYC) treatment in Graves' ophthalmopathy (GO).
METHODS
We searched PubMed, Embase, Cochrane Library, and four Chinese databases (Chinese National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), WanFang, and SinoMed) for any published randomized controlled trials (RCTs) produced from inception to December 1, 2023. Articles obtained using appropriate keywords were selected independently by two reviewers according to the established inclusion and exclusion criteria.
FINDINGS
We retrieved 1120 records which were eventually reduced to 13 RCTs which were then included in this evaluation. Pooled results indicated that the experimental group (CYC/GCs) showed a higher response rate than control group (GCs or negative control) (RR 1.27; 95% confidence interval 1.19 to 1.37). The subgroup analysis showed that the difference in response rates among treatment protocols (CYC/P, CYC/MPS, CYC/DEX) was not statistically significant (p = 0.23).
IMPLICATIONS
The combination of GCs and CYC could be recommended as a therapeutic option for GO, especially in patients who experience recurrence after a withdrawal GCs, have a poor response to GCs, or cannot obtain monoclonal antibody agents for various reasons.
Topics: Humans; Glucocorticoids; Graves Ophthalmopathy; Cyclophosphamide; China
PubMed: 38273269
DOI: 10.1186/s12902-024-01545-0 -
Frontiers in Plant Science 2023Across the globe, plant breeders of different organizations are working in collaboration to bring preferred traits to crops of economic importance. Among the traits,...
Across the globe, plant breeders of different organizations are working in collaboration to bring preferred traits to crops of economic importance. Among the traits, "high yielding potential" is the most important as it is directly associated with food security and nutrition, one of the sustainable development goals. The Food and Agriculture Organization acknowledges plant breeders' role and efforts in achieving local and global food security and nutrition. Recognizing the importance of pulses and increasing pressure on food security, the United Nations General Assembly declared 2016 the "International year of Pulses" owing to their preferred traits such as climate change resilience, wide adaptability, low agriculture input, and protein- and nutrient-rich crops. Keeping all these developments in consideration, we initiated an induced mutagenesis program by treating cowpea ( L. Walp.) with different doses of gamma rays and sodium azide aiming to enhance the yielding potential of an otherwise outstanding variety viz., Gomati VU-89 and Pusa-578. We noticed a substantial increase in mean values of agronomic traits in putative mutants raised from seeds treated with lower and intermediate doses of mutagens. Statistical analysis such as correlation, path, hierarchical clustering analysis (HCA), and principal component analysis (PCA) were used to assess the difference between mutagenized and control populations. A significant and positive correlation of yield with yield-attributing traits was recorded. However, among all the yield attributing traits, seeds per pod (SPP) depicted the maximum direct impact upon yield, and therefore, working on this trait may yield better results. A widely used PCA revealed 40.46% and 33.47% of the total variation for var. Gomati VU-89 and var. Pusa-578, respectively. Cluster analysis clustered treated and control populations into separate clusters with variable cluster sizes. Cluster V in the variety Gomati VU-89 and cluster V and VI in the variety Pusa 578 comprised of putative mutants were higher yielding and hence could be recommended for selection in future breeding programs. We expect to release such mutant lines for farmer cultivation in Northern parts of India depending on the performance of such high-yielding mutant lines at multilocations.
PubMed: 37521916
DOI: 10.3389/fpls.2023.1188077 -
Haematologica Dec 2023
Topics: Humans; Multiple Myeloma; Cyclophosphamide; Antibodies, Monoclonal; Stem Cells; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone
PubMed: 37439346
DOI: 10.3324/haematol.2023.283452 -
World Journal of Oncology Aug 2023() (Lam.) Hack. plays an important role in detoxification. However, its anticancer activity has not yet been elucidated. The aim of our study was to examine the...
BACKGROUND
() (Lam.) Hack. plays an important role in detoxification. However, its anticancer activity has not yet been elucidated. The aim of our study was to examine the suppressive proliferation, anti-migration and mutagenic/antimutagenic properties of . Moreover, we set out to determine the cellular mechanism underlying its antiproliferation.
METHODS
To investigate 's anticancer ability, HCT116 and HT29 cell lines were treated with a water extract containing , and then the cell viability was examined using the trypan blue exclusion method which were compared to HEK293 (non-cancerous cells). The anticancer effects were investigated by MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) and colony formation assay. Apoptosis induction, cell cycle distribution, and migration abilities were assessed by cell death detection enzyme-linked immunoassay (ELISA), flow cytometry, and wound healing assay. Finally, the mutagenicity and antimutagenicity were evaluated using the micronucleus assay.
RESULTS
Treatment with caused a loss of cell viability in HCT116 and HT29 cells (not found in HEK293), which had an IC (half-maximal inhibitory concentration) of 1,156.2 and 1,207.0 µg/mL, respectively. We found that significantly inhibited the proliferative function of HCT116 and HT29 cells. To find the mechanism that exerts a suppressive proliferation effect on , we determined the DNA fragmentation and cell cycle distribution. We also found that treatment increased apoptosis and arrested of the cell cycle at G0/G1 remarkably when compared with the control group. Moreover, could decrease the migration of HCT116 and HT29 cancer cells. Finally, the treatment of did not induce micronucleus formation but did decrease the micronucleus frequency against mutagen-mitomycin C.
CONCLUSIONS
did not possess any toxicity (cytotoxic and mutagenic) but has the potential for anticancer activity against human colorectal cells by increasing apoptosis, which leads to the suppression of cell proliferation. also inhibits cell migration and exerts antimutagenicity, thereby suggesting that might be useful for colorectal cancer treatment.
PubMed: 37560340
DOI: 10.14740/wjon1602 -
Biomedicines Sep 2023Hyperuricemia, the metabolic alteration that leads to gout or gouty arthritis, is increasing worldwide. Glycoconjugated triazole-phthalimides show potent...
Hyperuricemia, the metabolic alteration that leads to gout or gouty arthritis, is increasing worldwide. Glycoconjugated triazole-phthalimides show potent anti-inflammatory activity. The aim of this study was to evaluate the anti-hyperuricemia effect of glycoconjugated triazole-phthalimides. To develop hyperuricemia, groups of mice received orally potassium oxonate (250 mg/kg) for 7 days, and , and glycoconjugated triazole-phthalimides (20 mg/kg), allopurinol (300 mg/kg), and 1% carboxymethylcellulose; indomethacin (2 and 4 mg/kg) was the positive control for anti-arthritic effect. Genotoxic and mutagenic effects were evaluated by the comet and micronucleus assays, respectively. The hemolytic action of the compounds was evaluated. Phthalimides , and significantly reduced the levels of serum uric acid, creatinine and urea in hyperuricemic animals. In addition, the compounds were efficient in reducing protein denaturation in a dose-dependent manner. In an interesting way, the histopathological analysis of kidneys from groups treated with , and showed a glomerular architecture, with the Bowman's capsule and renal tubules having a normal appearance and without inflammatory changes. Also, and showed a small increase in micronuclei, indicating a low mutagenic effect, whilst by comet assay only, we could infer that affected the frequency and damage index, thus indicating a very small genotoxic action. Similarly, the phthalimides showed a low degree of erythrocyte hemolysis (<3%). Our data demonstrate that the new glycoconjugate triazole-phthalimides have potential to treat hyperuricemia and its secondary complications, such as gouty arthritis, with a low to non-significant rate of erythrocytes hemolysis, genotoxicity and mutagenicity making these molecules strong candidates as pharmaceutical agents for treatment requiring uric-acid-lowering therapy.
PubMed: 37760978
DOI: 10.3390/biomedicines11092537 -
Scientific Data Feb 2024Chemotherapeutic drugs will affect the process of spermatogenesis. However, most current studies on the effects of chemotherapeutic drugs on spermatogenesis are based on...
Chemotherapeutic drugs will affect the process of spermatogenesis. However, most current studies on the effects of chemotherapeutic drugs on spermatogenesis are based on mouse models, with a shortage of human body evidence. In addition, the mechanism of chemotherapeutic drugs causing spermatogenesis disorder is not clear. Therefore, we have collected the testicular tissues of an inguinal-lipoma patient whose testes were resected after chemotherapy and a patient who had normal spermatogenesis disorder and underwent single-nucleus RNA sequencing (snRNA-Seq). After quality control, we obtained a total of 27,957 high-quality cells, including 18,612 normal cells and 9,345 drug-treated cells, which were all used in analyzing the mechanism of chemotherapeutic drugs causing spermatogenesis disorder. This study has provided data resources and references for exploring the mechanism of chemotherapeutic drugs causing spermatogenesis disorder with the insight of protecting the spermatogenic abilities of male tumor patients receiving chemotherapy.
Topics: Humans; Male; Azoospermia; Base Sequence; Cyclophosphamide; Spermatogenesis; Testis
PubMed: 38307907
DOI: 10.1038/s41597-024-02938-5 -
PeerJ 2023The objective of this study was to investigate the effects and mechanisms of adipose-derived stem cell-derived exosome (ADSCs-Exo) in treating premature ovarian failure...
OBJECTIVE
The objective of this study was to investigate the effects and mechanisms of adipose-derived stem cell-derived exosome (ADSCs-Exo) in treating premature ovarian failure (POF).
METHODS
We constructed a POF mouse model through intraperitoneal injection of cyclophosphamide, followed by the administration of the autophagy inhibitor 3-methyladenine (3-MA). Pathological injury, follicle stimulating hormone (FSH), malondialdehyde (MDA), reactive oxygen species (ROS), estradiol (E2), superoxide dismutase (SOD), granulosa cell (GC) apoptosis, and autophagy were assessed. Exosomes isolated from ADSCs were used to treat POF in mice. The AMPK-mTOR pathway and its proteins (p-AMPK and p-mTOR) were evaluated. A POF cell model was established using cyclophosphamide-treated human ovarian granulosa-like tumor (KGN) cells. We administered ADSCs-Exo and rapamycin to validate the mechanism of ADSCs-Exo against POF.
RESULTS
In POF mice, 3-MA treatment attenuated pathological injuries, decreased FSH, MDA, and ROS levels, and increased E2 and SOD levels. 3-MA treatment also inhibited GC apoptosis and autophagy. ADSCs-Exo alleviated pathological injuries, improved ovarian morphology and function, and reduced oxidative stress in POF mice. ADSCs-Exo inhibited GC apoptosis and autophagy. ADSCs-Exo downregulated the expression of AMPK/mTOR pathway proteins (p-AMPK and p-mTOR). In the POF cell model, ADSCs-Exo and rapamycin inhibited AMPK/mTOR-mediated autophagy.
CONCLUSION
ADSCs-Exo inhibits POF through the inhibition of autophagy and the AMPK/mTOR pathway. This study provides a potential target for the clinical treatment of POF.
Topics: Animals; Female; Humans; Mice; AMP-Activated Protein Kinases; Autophagy; Cyclophosphamide; Exosomes; Follicle Stimulating Hormone; Menopause, Premature; Primary Ovarian Insufficiency; Reactive Oxygen Species; Sirolimus; Stem Cells; Superoxide Dismutase; TOR Serine-Threonine Kinases
PubMed: 38107591
DOI: 10.7717/peerj.16517