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Archives of Toxicology Feb 2024Fungi of the genus Alternaria are ubiquitous plant pathogens and saprophytes which are able to grow under varying temperature and moisture conditions as well as on a... (Review)
Review
Fungi of the genus Alternaria are ubiquitous plant pathogens and saprophytes which are able to grow under varying temperature and moisture conditions as well as on a large range of substrates. A spectrum of structurally diverse secondary metabolites with toxic potential has been identified, but occurrence and relative proportion of the different metabolites in complex mixtures depend on strain, substrate, and growth conditions. This review compiles the available knowledge on hazard identification and characterization of Alternaria toxins. Alternariol (AOH), its monomethylether AME and the perylene quinones altertoxin I (ATX-I), ATX-II, ATX-III, alterperylenol (ALP), and stemphyltoxin III (STTX-III) showed in vitro genotoxic and mutagenic properties. Of all identified Alternaria toxins, the epoxide-bearing analogs ATX-II, ATX-III, and STTX-III show the highest cytotoxic, genotoxic, and mutagenic potential in vitro. Under hormone-sensitive conditions, AOH and AME act as moderate xenoestrogens, but in silico modeling predicts further Alternaria toxins as potential estrogenic factors. Recent studies indicate also an immunosuppressive role of AOH and ATX-II; however, no data are available for the majority of Alternaria toxins. Overall, hazard characterization of Alternaria toxins focused, so far, primarily on the commercially available dibenzo-α-pyrones AOH and AME and tenuazonic acid (TeA). Limited data sets are available for altersetin (ALS), altenuene (ALT), and tentoxin (TEN). The occurrence and toxicological relevance of perylene quinone-based Alternaria toxins still remain to be fully elucidated. We identified data gaps on hazard identification and characterization crucial to improve risk assessment of Alternaria mycotoxins for consumers and occupationally exposed workers.
Topics: Humans; Perylene; Alternaria; Mycotoxins; Mutagens; Lactones; Risk Assessment; Food Contamination
PubMed: 38147116
DOI: 10.1007/s00204-023-03636-8 -
Molecules (Basel, Switzerland) Dec 2023Aristolochic acids (AAs) are a toxic substance present in certain natural plants. Direct human exposure to these plants containing AAs leads to a severe and irreversible... (Review)
Review
Aristolochic acids (AAs) are a toxic substance present in certain natural plants. Direct human exposure to these plants containing AAs leads to a severe and irreversible condition known as aristolochic acid nephropathy (AAN). Additionally, AAs accumulation in the food chain through environmental mediators can trigger Balkan endemic nephropathy (BEN), an environmental variant of AAN. This paper presents a concise overview of the oncogenic pathways associated with AAs and explores the various routes of environmental exposure to AAs. The detection and removal of AAs in natural plants, drugs, and environmental and biological samples were classified and summarized, and the advantages and disadvantages of the various methods were analyzed. It is hoped that this review can provide effective insights into the detection and removal of AAs in the future.
Topics: Humans; Aristolochic Acids; Balkan Nephropathy; Plants, Medicinal; Environmental Exposure
PubMed: 38202664
DOI: 10.3390/molecules29010081 -
Cells Jan 2024Peto's paradox and the epidemiologic observation of the average six degrees of tumor prevalence are studied and hypothetically solved. A simple consideration, Petho's... (Review)
Review
Peto's paradox and the epidemiologic observation of the average six degrees of tumor prevalence are studied and hypothetically solved. A simple consideration, Petho's paradox challenges our intuitive understanding of cancer risk and prevalence. Our simple consideration is that the more a cell divides, the higher the chance of acquiring cancerous mutations, and so the larger or longer-lived organisms have more cells and undergo more cell divisions over their lifetime, expecting to have a higher risk of developing cancer. Paradoxically, it is not supported by the observations. The allometric scaling of species could answer the Peto paradox. Another paradoxical human epidemiology observation in six average mutations is necessary for cancer prevalence, despite the random expectations of the tumor causes. To solve this challenge, game theory could be applied. The inherited and random DNA mutations in the replication process nonlinearly drive cancer development. The statistical variance concept does not reasonably describe tumor development. Instead, the Darwinian natural selection principle is applied. The mutations in the healthy organism's cellular population can serve the species' evolutionary adaptation by the selective pressure of the circumstances. Still, some cells collect multiple uncorrected mutations, adapt to the extreme stress in the stromal environment, and develop subclinical phases of cancer in the individual. This process needs extensive subsequent DNA replications to heritage and collect additional mutations, which are only marginal alone. Still, together, they are preparing for the first stage of the precancerous condition. In the second stage, when one of the caretaker genes is accidentally mutated, the caused genetic instability prepares the cell to fight for its survival and avoid apoptosis. This can be described as a competitive game. In the third stage, the precancerous cell develops uncontrolled proliferation with the damaged gatekeeper gene and forces the new game strategy with binary cooperation with stromal cells for alimentation. In the fourth stage, the starving conditions cause a game change again, starting a cooperative game, where the malignant cells cooperate and force the cooperation of the stromal host, too. In the fifth stage, the resetting of homeostasis finishes the subclinical stage, and in the fifth stage, the clinical phase starts. The prevention of the development of mutated cells is more complex than averting exposure to mutagens from the environment throughout the organism's lifetime. Mutagenic exposure can increase the otherwise random imperfect DNA reproduction, increasing the likelihood of cancer development, but mutations exist. Toxic exposure is more challenging; it may select the tolerant cells on this particular toxic stress, so these mutations have more facility to avoid apoptosis in otherwise collected random mutational states.
Topics: Humans; Prevalence; Biological Evolution; Cell Division; Precancerous Conditions; DNA
PubMed: 38275822
DOI: 10.3390/cells13020197 -
Biomedicine & Pharmacotherapy =... Sep 2023Chemotherapeutic agents such as doxorubicin, cyclophosphamide, fluorouracil, and cisplatin are commonly used to treat a variety of cancers and often result in...
Comparative evaluation of doxorubicin, cyclophosphamide, 5-fluorouracil, and cisplatin on cognitive dysfunction in rats: Delineating the role of inflammation of hippocampal neurons and hypothyroidism.
Chemotherapeutic agents such as doxorubicin, cyclophosphamide, fluorouracil, and cisplatin are commonly used to treat a variety of cancers and often result in chemobrain, which manifests as difficulties in learning and memory processes that can persist in the years following treatment. The current study aims to evaluate the cognitive function following treatment with these agents and the underlying mechanisms using a rat model of neuroinflammation and possible implication of thyroid toxicity in chemotherapy induced cognitive dysfunction. Wistar female rats were treated with a single dose of doxorubicin (DOX, 25 mg/kg), 5-fluorouracil (5-FU, 100 mg/kg), cisplatin (8 mg/kg), and cyclophosphamide (CYP, 200 mg/kg) by intraperitoneal injection. The cognitive performance of rats was then evaluated in spatial memory tasks using the Y-maze, novel object recognition (NOR), and elevated plus maze (EPM) tests. Serum levels of thyroid hormones (T3, T4, FT3, and FT4) and thyroid stimulating hormone (TSH) were measured, followed by estimation of TNFα, IL-6, and IL-1β in the hippocampal tissue. Results revealed that all the chemotherapeutic agents produced impairment of cognitive function, and significant increase of pro-inflammatory cytokines such as TNFα, IL-6 and IL-1β in the hippocampal tissues. There was a significant reduction in thyroid hormones (T3, FT3, and T4) and an increase in thyroid stimulating hormone (TSH) in serum, which may also have contributed to the decline in cognitive function. In conclusion, DOX, 5-FU, CYP, and cisplatin produces impairment of spatial memory possibly by inflammation of hippocampal neurons and endocrine disruption (hypothyroidism) in rats.
Topics: Rats; Female; Animals; Fluorouracil; Cisplatin; Tumor Necrosis Factor-alpha; Interleukin-6; Rats, Wistar; Cyclophosphamide; Cognitive Dysfunction; Doxorubicin; Hypothyroidism; Hippocampus; Thyroid Hormones; Thyrotropin; Inflammation; Neurons
PubMed: 37523981
DOI: 10.1016/j.biopha.2023.115245 -
Biotechnology Reports (Amsterdam,... Jun 2024Environmental contamination with dichlorodiphenyltrichloroethane (DDT) has sever effects on the ecosystem worldwide. DDT is a recalcitrant synthetic chemical with high... (Review)
Review
Environmental contamination with dichlorodiphenyltrichloroethane (DDT) has sever effects on the ecosystem worldwide. DDT is a recalcitrant synthetic chemical with high toxicity and lipophilicity. It is also bioaccumulated in the food chain and causes genotoxic, estrogenic, carcinogenic, and mutagenic effects on aquatic organisms and humans. Microbial remediation mechanism and its enzymes are very important for removing DDT from environment. DDT and its main residues dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD) can biodegrade slowly in soil and water. To enhance this process, a number of strategies are proposed, such as bio-attenuation, biostimulation, bioaugmentation and the manipulation of environmental conditions to enhance the activity of microbial enzymes. The addition of organic matter and flooding of the soil enhance DDT degradation. Microbial candidates for DDT remediation include micro-algae, fungi and bacteria. This review provide brief information and recommendation on microbial DDT remediation and its mechanisms.
PubMed: 38560709
DOI: 10.1016/j.btre.2024.e00835 -
Nature Communications Mar 2024Bacterial genotoxins damage host cells by targeting their chromosomal DNA. In the present study, we demonstrate that a genotoxin of Salmonella Typhi, typhoid toxin,...
Bacterial genotoxins damage host cells by targeting their chromosomal DNA. In the present study, we demonstrate that a genotoxin of Salmonella Typhi, typhoid toxin, triggers the senescence-associated secretory phenotype (SASP) by damaging mitochondrial DNA. The actions of typhoid toxin disrupt mitochondrial DNA integrity, leading to mitochondrial dysfunction and disturbance of redox homeostasis. Consequently, it facilitates the release of damaged mitochondrial DNA into the cytosol, activating type I interferon via the cGAS-STING pathway. We also reveal that the GCN2-mediated integrated stress response plays a role in the upregulation of inflammatory components depending on the STING signaling axis. These SASP factors can propagate the senescence effect on T cells, leading to senescence in these cells. These findings provide insights into how a bacterial genotoxin targets mitochondria to trigger a proinflammatory SASP, highlighting a potential therapeutic target for an anti-toxin intervention.
Topics: Humans; Senescence-Associated Secretory Phenotype; Typhoid Fever; Mutagens; Cellular Senescence; Mitochondria; DNA, Mitochondrial; Salmonella; Phenotype
PubMed: 38555361
DOI: 10.1038/s41467-024-47190-y -
Frontiers in Immunology 2023Despite various treatment methods, the remission rate of membranous nephropathy remains limited. Refractory membranous nephropathy especially lacks effective treatment...
Despite various treatment methods, the remission rate of membranous nephropathy remains limited. Refractory membranous nephropathy especially lacks effective treatment plans. Telitacicept achieves comprehensive inhibition of CD20-positive B cells, plasma cells, and T cells, thereby bringing new hope to the treatment of membranous nephropathy and refractory membranous nephropathy. Here, we report a case of a 46-year-old man with membranous nephropathy. Although the combined treatment with glucocorticoid, tacrolimus, mycophenolate mofetil, cyclophosphamide, and rituximab was not successful, the patient achieved complete remission of urinary protein after glucocorticoid combined with telitacicept. This is the first report on the application of telitacicept in the treatment of membranous nephropathy, especially refractory membranous nephropathy. The application of telitacicept in the treatment of membranous nephropathy deserves further attention.
Topics: Male; Humans; Middle Aged; Glomerulonephritis, Membranous; Glucocorticoids; Rituximab; Cyclophosphamide
PubMed: 37915584
DOI: 10.3389/fimmu.2023.1268929 -
CPT: Pharmacometrics & Systems... Jun 2024Polatuzumab vedotin is a CD79b-directed antibody-drug conjugate that targets B cells and delivers the cytotoxic payload monomethyl auristatin E (MMAE). The phase III... (Randomized Controlled Trial)
Randomized Controlled Trial
Polatuzumab vedotin is a CD79b-directed antibody-drug conjugate that targets B cells and delivers the cytotoxic payload monomethyl auristatin E (MMAE). The phase III POLARIX study (NCT03274492) evaluated polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) as first-line treatment of diffuse large B-cell lymphoma (DLBCL). To examine dosing decisions for this regimen, population pharmacokinetic (popPK) analysis, using a previously developed popPK model, and exposure-response (ER) analysis, were performed. The popPK analysis showed no clinically meaningful relationship between cycle 6 (C6) antibody-conjugated (acMMAE)/unconjugated MMAE area under the concentration-time curve (AUC) or maximum concentration, and weight, sex, ethnicity, region, mild or moderate renal impairment, mild hepatic impairment, or other patient and disease characteristics. In the ER analysis, C6 acMMAE AUC was significantly associated with longer progression-free and event-free survival (both p = 0.01). An increase of <50% in acMMAE/unconjugated MMAE exposure did not lead to a clinically meaningful increase in adverse events of special interest. ER data and the benefit-risk profile support the use of polatuzumab vedotin 1.8 mg/kg once every 3 weeks with R-CHP for six cycles in patients with previously untreated DLBCL.
Topics: Humans; Lymphoma, Large B-Cell, Diffuse; Male; Female; Middle Aged; Aged; Doxorubicin; Cyclophosphamide; Antineoplastic Combined Chemotherapy Protocols; Prednisone; Rituximab; Adult; Area Under Curve; Models, Biological; Immunoconjugates; Aged, 80 and over; Antibodies, Monoclonal; Dose-Response Relationship, Drug; Progression-Free Survival
PubMed: 38622879
DOI: 10.1002/psp4.13141 -
Genes and Environment : the Official... Aug 2023Understanding of metabolic processes is a key factor to evaluate biological effects of carcinogen and mutagens. Applicability of fused-grid Template* systems of CYP...
Understanding of metabolic processes is a key factor to evaluate biological effects of carcinogen and mutagens. Applicability of fused-grid Template* systems of CYP enzymes (Drug Metab Pharmacokinet 2019, 2020, 2021, and 2022) was tested for three phenomena. (1) Possible causal relationships between CYP-mediated metabolisms of β-naphthoflavone and 3-methylcholanthrene and the high inducibility of CYP enzymes were examined. Selective involvement of non-constitutive CYP1A1, but not constitutive CYP1A2, was suggested on the oxidative metabolisms of efficient inducers, β-naphthoflavone and 3-methylcholanthrene. These results supported the view of the causal link of their high inducibility with their inefficient metabolisms due to the lack of CYP1A1 in livers at early periods after the administration of both inducers. (2) Clear differences exist between human and rodent CYP1A1 enzymes on their catalyses with heterocyclic amines, dioxins and polyaromatic hydrocarbons (PAHs). Reciprocal comparison of simulation results with experimental data suggested the rodent specific site and distinct sitting-preferences of ligands on Template for human and rodent CYP1A1 enzymes. (3) Enhancement of metabolic activation and co-mutagenicity have been known as phenomena associated with Salmonella mutagenesis assay. Both the phenomena were examined on CYP-Templates in ways of simultaneous bi-molecule bindings of distinct ligands as trigger and pro-metabolized molecules. α-Naphthoflavone and norharman served consistently as trigger-molecules to support the oxidations of PAHs and arylamines sitting simultaneously as pro-metabolized molecules on Templates of CYP1A1, CYP1A2 and CYP3A4. These CYP-Template simulation systems with deciphering capabilities are promising tools to understand the mechanism basis of metabolic activations and to support confident judgements in safety assessments.
PubMed: 37544994
DOI: 10.1186/s41021-023-00275-4 -
Frontiers in Immunology 2023Although associations of IgA nephropathy (IgAN) and ANCA-associated vasculitis (AAV) have been described, this coexistence scarcely occurs and requires multidisciplinary... (Review)
Review
Although associations of IgA nephropathy (IgAN) and ANCA-associated vasculitis (AAV) have been described, this coexistence scarcely occurs and requires multidisciplinary management. Herein, we discuss a course of treatment introduced in a patient with two exacerbations. Furthermore, alterations in histopathological images between two kidney biopsies are presented. The applicability of traditional inflammatory markers, e.g., CRP, in monitoring disease severity in AAV and IgAN is limited. Based on our patient and current literature, we suggest ANCA testing in patients with rapidly progressing IgAN for therapeutic and prognostic purposes. As regards the therapy of IgAN associated with AAV, aggressive immunosuppressive regimens with methylprednisolone and cyclophosphamide are recommended. Alternatively, methylprednisolone with rituximab, plasma exchange, mycophenolate mofetil, and intravenous immunoglobulin (IVIG) could also be considered.
Topics: Humans; Glomerulonephritis, IGA; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Plasma Exchange; Cyclophosphamide; Methylprednisolone
PubMed: 37649475
DOI: 10.3389/fimmu.2023.1227878