Removal of Uracil by Uracil DNA Glycosylase Limits Pemetrexed Cytotoxicity: Overriding the Limit with Methoxyamine to Inhibit Base Excision Repair

Uracil DNA glycosylase (UDG) specifically removes uracil bases from DNA, and its repair activity determines the sensitivity of the cell to anticancer agents that are capable of introducing uracil into DNA. In the present study, the participation of UDG in the response to pemetrexed-induced incorporation of uracil into DNA was studied using isogenic human tumor cell lines with or without UDG (UDG+/+/UDG−/−). UDG−/− cells were very sensitive to pemetrexed. Cell killing by pemetrexed was associated with genomic uracil accumulation, stalled DNA replication, and catastrophic DNA strand breaks. By contrast, UDG+/+ cells were \u3e10 times more resistant to pemetrexed due to the rapid removal of uracil from DNA by UDG and subsequent repair of the resultant AP sites (abasic sites) via the base excision repair (BER). The resistance to pemetrexed in UDG+/+ cells could be reversed by the addition of methoxyamine (MX), which binds to AP sites and interrupts BER pathway. Furthermore, MX-bound AP sites induced cell death was related to their cytotoxic effect of dual inactivation of UDG and topoisomerase IIα, two genes that are highly expressed in lung cancer cells in comparison with normal cells. Thus, targeting BER-based therapy exhibits more selective cytotoxicity on cancer cells through a synthetic lethal mechanism

Protection from ultraviolet damage and photocarcinogenesis by vitamin d compounds

© Springer Nature Switzerland AG 2020. Exposure of skin cells to UV radiation results in DNA damage, which if inadequately repaired, may cause mutations. UV-induced DNA damage and reactive oxygen and nitrogen species also cause local and systemic suppression of the adaptive immune system. Together, these changes underpin the development of skin tumours. The hormone derived from vitamin D, calcitriol (1,25-dihydroxyvitamin D3) and other related compounds, working via the vitamin D receptor and at least in part through endoplasmic reticulum protein 57 (ERp57), reduce cyclobutane pyrimidine dimers and oxidative DNA damage in keratinocytes and other skin cell types after UV. Calcitriol and related compounds enhance DNA repair in keratinocytes, in part through decreased reactive oxygen species, increased p53 expression and/or activation, increased repair proteins and increased energy availability in the cell when calcitriol is present after UV exposure. There is mitochondrial damage in keratinocytes after UV. In the presence of calcitriol, but not vehicle, glycolysis is increased after UV, along with increased energy-conserving autophagy and changes consistent with enhanced mitophagy. Reduced DNA damage and reduced ROS/RNS should help reduce UV-induced immune suppression. Reduced UV immune suppression is observed after topical treatment with calcitriol and related compounds in hairless mice. These protective effects of calcitriol and related compounds presumably contribute to the observed reduction in skin tumour formation in mice after chronic exposure to UV followed by topical post-irradiation treatment with calcitriol and some, though not all, related compounds

GROUP SELECTION EDGE EFFECTS ON THE VASCULAR PLANT COMMUNITY OF A SIERRA NEVADA OLD-GROWTH FOREST

Volume: 52Start Page: 262End Page: 26

Modeling the Complex Impacts of Timber Harvests to Find Optimal Management Regimes for Amazon Tidal Floodplain Forests

<div><p>At the Amazon estuary, the oldest logging frontier in the Amazon, no studies have comprehensively explored the potential long-term population and yield consequences of multiple timber harvests over time. Matrix population modeling is one way to simulate long-term impacts of tree harvests, but this approach has often ignored common impacts of tree harvests including incidental damage, changes in post-harvest demography, shifts in the distribution of merchantable trees, and shifts in stand composition. We designed a matrix-based forest management model that incorporates these harvest-related impacts so resulting simulations reflect forest stand dynamics under repeated timber harvests as well as the realities of local smallholder timber management systems. Using a wide range of values for management criteria (e.g., length of cutting cycle, minimum cut diameter), we projected the long-term population dynamics and yields of hundreds of timber management regimes in the Amazon estuary, where small-scale, unmechanized logging is an important economic activity. These results were then compared to find optimal stand-level and species-specific sustainable timber management (STM) regimes using a set of timber yield and population growth indicators. Prospects for STM in Amazonian tidal floodplain forests are better than for many other tropical forests. However, generally high stock recovery rates between harvests are due to the comparatively high projected mean annualized yields from fast-growing species that effectively counterbalance the projected yield declines from other species. For Amazonian tidal floodplain forests, national management guidelines provide neither the highest yields nor the highest sustained population growth for species under management. Our research shows that management guidelines specific to a region’s ecological settings can be further refined to consider differences in species demographic responses to repeated harvests. In principle, such fine-tuned management guidelines could make management more attractive, thus bridging the currently prevalent gap between tropical timber management practice and regulation.</p></div

LTRE for <i>M</i>. <i>paraensis</i> demonstrating demographic differences between harvested and unharvested plots and their contributions to population growth.

<p>LTRE for <i>M</i>. <i>paraensis</i> demonstrating demographic differences between harvested and unharvested plots and their contributions to population growth.</p

Residual stand damage from monitored timber extraction in terms of basal area (m²) of trees >5 cm DBH killed by basal area (m²) of timber extracted.

<p>Residual stand damage from monitored timber extraction in terms of basal area (m²) of trees >5 cm DBH killed by basal area (m²) of timber extracted.</p

Shifts in merchantable proportion under the 30 yr Brazilian legal management regime but without volume-based harvest limits.

<p><i>Licania heteromorpha</i> and <i>P</i>. <i>sagotiana</i> were not harvested during simulations.</p

Differences in annualized yields (m³ yr^-1 ha^-1) between species-specific and general optimal management regimes under two STM indicators.

<p>Differences in annualized yields (m³ yr^-1 ha^-1) between species-specific and general optimal management regimes under two STM indicators.</p

Simulation-based spread of mean AY and λ_H in response to varying management criteria.

<p>Simulation-based spread of mean AY and λ_H in response to varying management criteria.</p

Potential priority areas for forest bird habitat conservation.

<p>Map is based on the number of high model reliability species projected to maintain their range between now and end of century. Current protected areas are delineated in green (National parks, State parks, Natural area reserves, wildlife refuges, sea bird sanctuaries, Nature Conservancy lands and other major private conservation areas). The pink overlay shows the spatial configuration of the main Hawaiian Islands. A similar figure including all extant species is included in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140389#pone.0140389.s007" target="_blank">S7 File</a>.</p