Gut Microbiota in Colorectal Cancer: Associations, Mechanisms, and Clinical Approaches

Colorectal cancer (CRC) is associated with the presence of particular gut microbes, as observed in many metagenomic studies to date. However, in most cases, it remains difficult to disentangle their active contribution to CRC from just a bystander role. This review focuses on the mechanisms described to date by which the CRC-associated microbiota could contribute to CRC. Bacteria like pks+ Escherichia coli, Fusobacterium nucleatum, or enterotoxigenic Bacteroides fragilis have been shown to induce mutagenesis, alter host epithelial signaling pathways, or reshape the tumor immune landscape in several experimental systems. The mechanistic roles of other bacteria, as well as newly identified fungi and viruses that are enriched in CRC, are only starting to be elucidated. Additionally, novel systems like organoids and organs-on-a-chip are emerging as powerful tools to study the direct effect of gut microbiota on healthy or tumor intestinal epithelium. Thus, the expanding knowledge of tumor-microbiota interactions holds promise for improved diagnosis and treatment of CRC. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Examination of the APOBEC3 Barrier to Cross Species Transmission of Primate Lentiviruses

The transmission of viruses from animal hosts into humans have led to the emergence of several diseases. Usually these cross-species transmissions are blocked by host restriction factors, which are proteins that can block virus replication at a specific step. In the natural virus host, the restriction factor activity is usually suppressed by a viral antagonist protein, but this is not the case for restriction factors from an unnatural host. However, due to ongoing viral evolution, sometimes the viral antagonist can evolve to suppress restriction factors in a new host, enabling cross-species transmission. Here we examine the classical case of this paradigm by reviewing research on APOBEC3 restriction factors and how they can suppress human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). APOBEC3 enzymes are single-stranded DNA cytidine deaminases that can induce mutagenesis of proviral DNA by catalyzing the conversion of cytidine to promutagenic uridine on single-stranded viral (−)DNA if they escape the HIV/SIV antagonist protein, Vif. APOBEC3 degradation is induced by Vif through the proteasome pathway. SIV has been transmitted between Old World Monkeys and to hominids. Here we examine the adaptations that enabled such events and the ongoing impact of the APOBEC3-Vif interface on HIV in humans.

Regulation of the error-prone DNA polymerase Polκ by oncogenic signaling and its contribution to drug resistance

The DNA polymerase Polκ plays a key role in translesion synthesis, an error-prone replication mechanism. Polκ is overexpressed in various tumor types. Here, we found that melanoma and lung and breast cancer cells experiencing stress from oncogene inhibition up-regulated the expression of Polκ and shifted its localization from the cytoplasm to the nucleus. This effect was phenocopied by inhibition of the kinase mTOR, by induction of ER stress, or by glucose deprivation. In unstressed cells, Polκ is continually transported out of the nucleus by exportin-1. Inhibiting exportin-1 or overexpressing Polκ increased the abundance of nuclear-localized Polκ, particularly in response to the BRAFV600E-targeted inhibitor vemurafenib, which decreased the cytotoxicity of the drug in BRAFV600E melanoma cells. These observations were analogous to how Escherichia coli encountering cell stress and nutrient deprivation can up-regulate and activate DinB/pol IV, the bacterial ortholog of Polκ, to induce mutagenesis that enables stress tolerance or escape. However, we found that the increased expression of Polκ was not excessively mutagenic, indicating that noncatalytic or other functions of Polκ could mediate its role in stress responses in mammalian cells. Repressing the expression or nuclear localization of Polκ might prevent drug resistance in some cancer cells.

Morphological mutants of Zoysia japonica Steud. induced by gamma ray irradiation

Study of Zoysia japonica morphological improvement and breeding by induced mutation using gamma ray irradiation was conducted. Mutagenesis by gamma ray irradiation was employed using 0, 20, 40, 60, 80, 100, 120 and 140 Gy to treat 30 single node stolons per treatment. It was demonstrated that single node stolon is suitable for gamma ray irradiation mutagenesis in Z. japonica. It has been identified that 76 Gy as the value LD50 is effective to induce mutagenesis on Z. japonica. Survival rate of Z. japonica stolon was greatly reduced when irradiated with higher dosages. This experiment was repeated using LD50 on 1500 single node stolons. Thirty nine morphological mutants were identified and evaluated. Most of the mutants were semi-dwarf and have horizontal growing pattern with reduced internode length and leaf blade length. The altered morphological traits were stable after third cutting back (M1V3) shown by their morphological performance. Mutation breeding is effective in improving Z. japonica when easily recognized cultivars are needed.

Optimization of UV irradiation mutation conditions for cellulase production by mutant fungal strains of Aspergillus niger through solid state fermentation

Ultraviolet (UV) irradiation was used to induce mutagenesis in

Seleksi In Vitro dan Pengujian Mutan Tanaman Pisang Ambon Kuning untuk Ketahanan terhadap Penyakit Layu Fusarium

<p>Fusarium wilt of banana (Musa spp.) caused by<br />Fusarium oxysporum f. sp. cubense (Foc) is the most serious<br />problem faced in banana cultivation in terms of plant<br />productivity and fruit quality. Mutation breeding is one of the<br />alternative method that can be applied in producing new<br />banana cultivar. Mutants can be induced by chemical<br />mutagen such as ethyl methane sulfonate (EMS) followed by<br />in vitro selection and then evaluation of the mutants to<br />fusarium wilt disease in glasshouse and Foc infected field.<br />The aim of this research was obtained EMS induced and in<br />vitro selected mutants of banana var. Ambon Kuning and<br />evaluated Foc disease resistant clones in glasshouse and<br />Foc infected field. The first step to obtain the explants for<br />this research was initiation and formation of multiple bud<br />clumps (MBC) using MS basal media supplemented with 5,<br />10, and 20 mg/l of benzyladenin. Plant regeneration of MBC<br />was also studied by using MS media containing 0, 0.2, and 1<br />mg/l of benzyladenin. To induce mutagenesis, MBC was<br />soaked in 0.1, 0.3, and 0.5% (v/v) EMS for 1, 2, and 3 hours.<br />The assesment of resistant MBC mutants to Fusarium<br />phytotoxin was conducted by using fusaric acid (FA) as<br />selection agent in concentration of 30, 45, and 60 ppm.<br />Putative mutant plants produced by in vitro selection were<br />further tested using spore solution of Foc race 4 in<br />glasshouse. Meanwhile, Foc resistance assesment in the<br />infected field was conducted in Pasirkuda Experimental<br />Station, Bogor Agricultural University. The results showed<br />that MBC can be formed in MS basal media supplemented<br />with 10 or 20 mg/l benzyladenin. The EMS played a role in<br />obtaining mutants by producing 68 MBC putative mutants<br />tolerant to Foc based on FA selection. Further evaluation in<br />the glasshouse was obtained 64 Foc resistant plants from<br />391 putative mutants produced by in vitro selection.<br />Evaluation in the Foc infected field showed six clones<br />survived until generative phase (12 month of age).</p>

Xanthine Oxidoreductase-Derived Reactive Species: Physiological and Pathological Effects

Xanthine oxidoreductase (XOR) is the enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid and is widely distributed among species. In addition to this housekeeping function, mammalian XOR is a physiological source of superoxide ion, hydrogen peroxide, and nitric oxide, which can function as second messengers in the activation of various pathways. This review intends to address the physiological and pathological roles of XOR-derived oxidant molecules. The cytocidal action of XOR products has been claimed in relation to tissue damage, in particular damage induced by hypoxia and ischemia. Attempts to exploit this activity to eliminate unwanted cells via the construction of conjugates have also been reported. Moreover, different aspects of XOR activity related to phlogosis, endothelial activation, leukocyte activation, and vascular tone regulation, have been taken into consideration. Finally, the positive and negative outcomes concerning cancer pathology have been analyzed because XOR products may induce mutagenesis, cell proliferation, and tumor progression, but they are also associated with apoptosis and cell differentiation. In conclusion, XOR activity generates free radicals and other oxidant reactive species that may result in either harmful or beneficial outcomes.

Structural Aspects of Antioxidant and Genotoxic Activities of Two Flavonoids Obtained from Ethanolic Extract ofCombretum leprosum

Combretum leprosumMart., a member of the Combretaceae family, is a traditionally used Brazilian medicinal plant, although no evidence in the literature substantiates its antioxidant action and the safety of its use. We evaluated the antioxidant properties of the ethanolic extract (EE) from flowers ofC. leprosumand its isolated products 5,3′-dihydroxy-3,7,4′-trimethoxyflavone (FCL2) and 5,3′,4′-trihydroxy-3,7-dimethoxyflavone (FCL5) inSaccharomyces cerevisiaestrains proficient and deficient in antioxidant defenses. Their mutagenic activity was also assayed inS. cerevisiae,whereas cytotoxic and genotoxic properties were evaluated by MTT and Comet Assays, respectively, in V79 cells. We show that the EE, FCL2, and FCL5 have a significant protective effect against H2O2. FCL2 showed a better antioxidant action, which can be related to the activation of the 3′-OH in the presence of a methoxyl group at 4′ position in the B-ring of the molecule, while flavonoids did not induce mutagenesis in yeast, and the EE was mutagenic at high concentrations. The toxicity of these compounds in V79 cells increases from FCL2 = FCL5 < EE; although not cytotoxic, FCL5 induced an increase in DNA damage. The antioxidant effect, along with the lower toxicity and the absence of genotoxicity, suggests that FCL2 could be suitable for pharmacological use.

Study of the correlation between blood cholinesterases activity, urinary dialkyl phosphates, and the frequency of micronucleated polychromatic erythrocytes in rats exposed to disulfoton

Organophosphates (OPs) are widely used as pesticides, and its urinary metabolites as well as the blood cholinesterases (ChEs) activity have been reported as possible biomarkers for the assessment of this pesticide exposure. Moreover, the OPs can induce mutagenesis, and the bone marrow micronucleus test is an efficient way to assess this chromosomal damage. This paper reports a study carried out to verify the correlation among the disulfoton exposure, blood ChEs activity, urinary diethyl thiophosphate (DETP), and diethyl dithiophosphate (DEDTP), as well as micronucleated polychromatic erythrocytes (MNPCEs) frequency. Four groups of rats (n=12) were exposed to disulfoton at 0, 2.8, 4.7, and 6.6 mg kg-1 body weight. The blood ChEs activity, urinary DETP and DEDTP concentrations, and MNPCEs frequency were determined. It was observed that the plasmatic and erythrocytary ChEs activity decreased from 2.9% to 0.5% and from 35.9 to 3.3%, respectively, when the disulfoton dose was increased from 0 to 6.6 mg kg-1 (correlation of 0.99). Urinary DETP and DEDTP concentrations, as well as the MNPCEs frequency, increased from 0 to 6.58 µg mL-1, from 0 to 0.04 µg mL-1, and from 0 to 1.4%, respectively, when the disulfoton dose was increased from 0 to 6.58 mg kg-1 body weight.

DNA DAMAGES AS A DEPOLYMERIZATION PROCESS

The damage of DNA chains by environmental factors like radiation or chemical pollutants is a topic that has been frequently explored from an experimental and a theoretical perspective. Such damages, like the damage of the strands of a DNA chain, are toxic for the cell and can induce mutagenesis or apoptosis. Several models make strong assumptions for the distribution of damages; for instance a frequent supposition is that these damages are Poisson distributed. [L. Ma, J. J. Wagner, W. Hu, A. J. Levine and G. A. Stolovitzki, Proc. Natl. Acad. Sci.PNAS 102, 14266 (2005).] Only few models describe in detail the damage and the mechanisms associated to the formation and evolution of this damage distribution [H. Nikjoo, P. O'neill and D. T. Goodhead, Radiat. Res. 156, 577 (2001).] Nevertheless, such models do not include the repair processes which are continuously active inside the cell. In this work we present a novel model, based on a depolymerization process, describing the distribution of damages on DNA chains coupled to the dynamics associated to its repair processes. The central aim is not to give a final and comprehensive model, but a hint to represent in more detail the complex dynamics involved in the damage and repair of DNA. We show that there are critical parameters associated to this repair process, in particular we show how critical doses can be relevant in deciding whether the cell continues its repair process or starts apoptosis. We also find out that the damage concentration is related to the dose via a power law relation.