CDK4/6 inhibitor modulating active and quiescent intestinal stem cells for prevention of chemotherapy-induced diarrhea.

Chemotherapy-induced diarrhea causes dehydration, debilitation, infection, and even death, but there are currently no Food and Drug Administration (FDA)-approved drugs for treatment of chemotherapy-induced diarrhea. It is generally believed that the timely regulation of intestinal stem cell (ISC) fate may provide a meaningful solution for intestinal injuries. However, the lineage plasticity of ISCs during and after chemotherapy remains poorly understood. Here, we demonstrated that palbociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, regulated the fate of active or quiescent ISCs, provided multilineage protection from the toxicity of several different chemotherapeutics, and accelerated gastrointestinal epithelium recovery. Consistent with in vivo results, we determined that palbociclib enhanced intestinal organoid and ex vivo tissue survival after chemotherapy. Lineage tracing studies have shown that palbociclib protects active ISCs marked by Lgr5 and Olfm4 during chemotherapy and unexpectedly activates quiescent ISCs marked by Bmi1 to immediately participate in crypt regeneration after chemotherapy. Furthermore, palbociclib does not decrease the efficacy of cytotoxic chemotherapy in tumor grafts. The experimental evidence suggests that the combination of CDK4/6 inhibitors with chemotherapy could reduce damage to the gastrointestinal epithelium in patients. © 2023 The Pathological Society of Great Britain and Ireland.

Pollution load estimation and influencing factor analysis in the Tuhai River Basin in Shandong Province of China based on improved output coefficient method.

Estimating the pollution loads in the Tuhai River is essential for developing a water quality standard scheme. This study utilized the improved output coefficient method to estimate the total pollution loads in the river basin while analyzing the influencing factors based on the STIRPAT (Stochastic Impacts by Regression on Population, Affluence, and Technology) model. Findings indicated that the projected point source pollution loads for total phosphorus (TP), chemical oxygen demand (COD), and ammonia nitrogen (AN) would amount to 3937.22 ton, 335,523.25 ton, and 13,946.92 ton in 2021, respectively. Among these, COD pollution would pose the greatest concern. The primary contributors to the pollution loads were rural scattered life, large-scale livestock and poultry breeding, and surface runoff. Per capita GDP emerged as the most influential factor affecting the pollution loads, followed by cultivated land area, while the urbanization rate demonstrated the least impact.

Variation on gut microbiota diversity of endangered red pandas (Ailurus fulgens) living in captivity acrosss geographical latitudes.

The gut microbiome plays important roles in metabolic and immune system related to the health of host. This study applied non-invasive sampling and 16S rDNA high-throughput sequencing to study the gut microbiota structure of red pandas (Ailurus fulgens) for the first time under different geographical latitudes in captivity. The results showed that the two predominant phyla Firmicutes (59.30%) and Proteobacteria (38.58%) constituted 97.88% of the total microbiota in all the fecal samples from north group (red pandas from Tianjin Zoo and Jinan Zoo) and south group (red pandas from Nanjing Hongshan Forest Zoo). The relative abundance of Cyanobacteria in north group was significantly higher than that in south group. At the genus level, Escherichia-Shigella (24.82%) and Clostridium_sensu_stricto_1 (23.00%) were common dominant genera. The relative abundance of norank_f__norank_o__Chloroplast, Terrisporobacter and Anaeroplasma from south group was significantly higher than that of north group. Alpha and Beta analysis consistently showed significant differences between north group and south group, however, the main functions of intestinal microbiota were basically the same, which play an important role in metabolic pathways, biosynthesis of secondary metabolites, microbial metabolism in different environments, and amino acid biosynthesis. The variations in gut microbiota between the northern and southern populations of the same species, both kept in captivity, which are primarily driven by significant differences in climate and diet. These findings provide a deeper understanding of the gut microbiota in red pandas and have important implications for their conservation, particularly in optimizing diet and environmental conditions in captivity.

Similarities and differences: species and diet impact gut microbiota of captive pheasants.

The fecal microbiota plays an important role in maintaining animal health and is closely related to host life activities. In recent years, there have been an increasing number of studies on the fecal microbiota from birds. An exploration of the effects of species and living environments on the composition of gut microbiota will provide better protection for wildlife. In this study, non-injury sampling and 16S rDNA high-throughput sequencing were used to investigate the bacterial composition and diversity of the fecal microbiota in silver pheasants (Lophura nycthemera) and golden pheasants (Chrysolophus pictus) from Tianjin Zoo and Beijing Wildlife Park. The results showed that the abundance of Firmicutes was the highest in all fecal samples. At the genus level, Bacteroides was the common dominant bacteria, while there were some differences in other dominant bacteria genera. There were significant differences in fecal microbial composition between the golden pheasants from Tianjin Zoo and Beijing Wildlife Park. The metabolic analysis and functional prediction suggested that the gut microbiota composition and host metabolism were influenced by dietary interventions and living conditions. The results of this study provide the basis for further research of intestinal microbial of L. nycthemera and C. pictus, and valuable insights for conservation of related species.

High-efficiency electrochemical nitrate reduction to ammonia via boron-doped hydroxyl oxide cobalt induced electron delocalization.

Electrochemical nitrate reduction to ammonia is a promising alternative strategy for producing valuable ammonia. This prospective route, however, is subject to a slow electrocatalytic rate, which resulted from the weak adsorption and activation of intermediate species, and the low density electron cloud of active centers. To address this issue, we developed a novel approach by doping boron into metal hydroxyl oxides to adjust the electronic structure of active centers, and consequently, led a significant improvement in the Faraday efficiency upto approaching 100 %, as well as an impressive ammonia yield upto approximately 23 mg/h mgcat-1 at -0.6 V vs. reversible hydrogen electrode (RHE). Experimental data in mechanism demonstrate that the doped boron play a crucial role in modulating the local electronic environment surrounding the active sites Co. In situ Raman and FTIR spectra provide evidences that boron facilitates the formation of deoxidation and hydrogenation intermediates. Additionally, density functional theory (DFT) calculations support the notion that boron doping enhances the adsorption capability of intermediates, reduces the reaction barrier, and facilitates the desorption of NH3.

Spatial relationships between ecosystem services and socioecological drivers across a large-scale region: A case study in the Yellow River Basin.

Understanding the relationships between ecosystem services (ES) and their underlying socioecological drivers is essential for forming the efficient management decisions of ecosystems. We use a large watershed area as a case-study to analyze trade-offs/synergies and bundles of ESs and identify the associated socioecological variables (SEVs). This study assessed the supply of 7 ES indicators, namely, three provisioning services (crop production, livestock production, and industrial production), three regulating services (water conservation, soil conservation, and carbon sequestration), and one cultural service (recreation), across 65 municipalities in the Yellow River Basin (YRB) in China. We analyzed the paired trade-offs/synergies using Spearman's coefficient and identified the ES bundles (ESBs) by applying principal component analysis and K-means clustering. Subsequently, we detected the SEVs that affect the ES supply using the geo-detector model and characterized the associations between ESBs and socioecological clusters according to the spatial overlap. The results demonstrated that the synergies between ESs substantially exceeded the trade-offs, among which the strongest synergies were between the crop production and the livestock production, and both responded strongly to the cropland and the population density. Trade-offs were identified between provisioning services and soil conservation. Municipalities were grouped into three ESBs in the YRB. The ESB, which was dominated by provisioning ESs, was associated with areas where cropland, precipitation and socioeconomic conditions were all important, and the regulation of ESB was linked to regions with distinct ecological characteristics. We also identified an ESB that was dominated by carbon sequestration, as determined by extensive grassland and bare land. The land use/land cover strongly affected the characteristics of the ESBs. The findings can be used by land managers to identify areas in which ESs are dominant, to determine the associations of these compositions of the ESs with SEVs, and to support the formulation of optimal ES management in large-scale basins.

Smart Oral Administration of Polydopamine-Coated Nanodrugs for Efficient Attenuation of Radiation-Induced Gastrointestinal Syndrome.

High-dose ionizing radiation can lead to death from the unrecoverable damage of the gastrointestinal tract, especially the small intestine. Until now, the lack of predilection for the small intestine and rapid clearance by digestive fluids limit the effects of conventional radioprotective formulations. Herein, an innovative radioprotective strategy is developed for attenuating gastrointestinal syndrome by smart oral administration nanodrugs. The nanodrug is first engineered by encapsulating thalidomide into chitosan-based nanoparticles, and then coated with polydopamine. The behaviors of gastric acid-resistance, and pH-switchable controlled release in the small intestine enhance the oral bioavailability of the pyroptosis inhibitor thalidomide. In a mouse model, nanodrugs demonstrate prolonged small intestinal residence time and accessibility to the crypt region deep in the mucus. Furthermore, the nanodrugs ameliorate survival rates of C57BL/6J mice irradiated by 14 Gy of subtotal body irradiation and also maintain their epithelial integrity. This work may provide a promising new approach for efficiently attenuating lethal radiation-induced gastrointestinal syndrome and add insights into developing nanodrug-based therapies with improved efficacy and minimum side effects.

TIGAR/AP-1 axis accelerates the division of Lgr5- reserve intestinal stem cells to reestablish intestinal architecture after lethal radiation.

During radiologic or nuclear accidents, high-dose ionizing radiation (IR) can cause gastrointestinal syndrome (GIS), a deadly disorder that urgently needs effective therapy. Unfortunately, current treatments based on natural products and antioxidants have shown very limited effects in alleviating deadly GIS. Reserve intestinal stem cells (ISCs) and secretory progenitor cells are both reported to replenish damaged cells and contribute to crypt regeneration. However, the suppressed ß-catenin/c-MYC axis within these slow-cycling cells leads to limited regenerative response to restore intestinal integrity during fatal accidental injury. Current study demonstrates that post-IR overexpression of TIGAR, a critical downstream target of c-MYC in mouse intestine, mounts a hyperplastic response in Bmi1-creERT+ reserve ISCs, and thus rescues mice from lethal IR exposure. Critically, by eliminating damaging reactive oxygen species (ROS) yet retaining the proliferative ROS signals, TIGAR-overexpression enhances the activity of activator protein 1, which is indispensable for initiating reserve-ISC division after lethal radiation. In addition, it is identified that TIGAR-induction exclusively gears the Lgr5- subpopulation of reserve ISCs to regenerate crypts, and intestinal TIGAR-overexpression displays equivalent intestinal reconstruction to reserve-ISC-restricted TIGAR-induction. Our findings imply that precise administrations toward Lgr5- reserve ISCs are promising strategies for unpredictable lethal injury, and TIGAR can be employed as a therapeutic target for unexpected radiation-induced GIS.

A strategy for high radioprotective activity via the assembly of the PprI protein with a ROS-sensitive polymeric carrier.

With the rapid development and wide application of nuclear technology, radiation hazards present an enormous challenge for biological and medical safety. Currently, one of the major challenges in radiation protection is the discovery of more effective and less toxic radioprotectant agents. Herein, we present a strategy for high radioprotective activity via the assembly of the PprI protein with a reactive oxygen species (ROS)-sensitive polymeric carrier. The graft copolymer CS-CP5K-PEG is synthesized via the reaction of PEG-CP5K-NHS and CS, which is used for the assembly of the PprI protein. The assembly complex is less toxic to human cells and more stable to enzymatic cleavage than the PprI protein. The ROS degradability of the CS-CP5K-PEG polymer is confirmed via the SIN-1 mediated cleavage of CP5K peptide linkers through the shift in their GPC chromatogram. The radioprotection activity of the assembly complex is remarkably improved both in HUVECs and C57BL/6 mice compared to that of the PprI protein, showing more beneficial effects than the PprI protein. Thus, this work may provide a new approach for highly effective radioprotection.

A CRISPR/Cas9-Based Screening for Non-Homologous End Joining Inhibitors Reveals Ouabain and Penfluridol as Radiosensitizers.

Non-homologous end joining (NHEJ) is the major pathway responsible for the repair of ionizing radiation (IR)-induced DNA double-strand breaks (DSB), and correspondingly regulates the cellular response to IR. Identification of NHEJ inhibitors could substantially enhance the tumor radiosensitivity and improve the therapeutic efficiency of radiotherapy. In this study, we demonstrated a screening for NHEJ inhibitors using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and high-resolution melting (HRM) analysis. Because NHEJ is regarded as an error-prone mechanism, the NHEJ-mediated ligation of the site-specific DSB induced by Cas9 nuclease would eventually cause the mutation of the targeted sequence. Then, HRM analysis, a reliable and rapid assay for detecting sequence variation, was performed to evaluate the mutation efficiency of the targeted site. Validating analysis confirmed the NHEJ activities were positively correlated with the mutation frequencies. Next, an approved drug library containing 1,540 compounds was interrogated by using this screening strategy. Our results identified ouabain, a cardiotonic agent, and penfluridol, an antipsychotic agent, have the capacity to restrain NHEJ activity. Further experiments in vitro revealed the radiosensitizing effects of these compounds. Overall, we presented a cell-based screening for NHEJ inhibitors, which could promote the discovery of novel radiosensitizers. Mol Cancer Ther; 17(2); 419-31. ©2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology."

TIGAR knockdown radiosensitizes TrxR1-overexpressing glioma in vitro and in vivo via inhibiting Trx1 nuclear transport.

The up-regulation of thioredoxin reductase-1 (TrxR1) is detected in more than half of gliomas, which is significantly associated with increased malignancy grade and recurrence rate. The biological functions of NADPH-dependent TrxR1 are mainly associated with reduced thioredoxin-1 (Trx1) which plays critical roles in cellular redox signaling and tumour radio-resistance. Our previous work has proved that TP53 induced glycolysis and apoptosis regulator (TIGAR) knockdown could notably radiosensitize glioma cells. However, whether TrxR1-overexpressing glioma cells could be re-radiosensitized by TIGAR silence is still far from clear. In the present study, TrxR1 was stably over-expressed in U-87MG and T98G glioma cells. Both in vitro and in vivo data demonstrated that the radiosensitivity of glioma cells was considerably diminished by TrxR1 overexpression. TIGAR abrogation was able to radiosensitize TrxR1-overexpressing gliomas by inhibiting IR-induced Trx1 nuclear transport. Post-radiotherapy, TIGAR low-expression predicted significant longer survival time for animals suffering from TrxR1-overexpessing xenografts, which suggested that TIGAR abrogation might be a promising strategy for radiosensitizing TrxR1-overexpressing glial tumours.