Colchicine disrupts bile acid metabolic homeostasis by affecting the enterohepatic circulation in mice.

Although the medicinal properties of colchicine (COL) have been widely known for centuries, its toxicity has been the subject of controversy. The narrow therapeutic window causes COL to induce gastrointestinal adverse effects even when taken at recommended doses, mainly manifested as nausea, vomiting, and diarrhea. However, the mechanism of COL-induced gastrointestinal toxic reactions remains obscure. In the present study, the mice were dosed with COL (2.5 mg/kg b.w./day) for a week to explore the effect of COL on bile acid metabolism and the mechanism of COL-induced diarrhea. The results showed that COL treatment affected liver biochemistry in mice, resulting in a significant down-regulation of the mRNA expression levels of bile acid biosynthesis regulators Cyp7a1, Cyp8b1, Cyp7b1, and Cyp27a1 in liver tissues. The mRNA expression levels of bile acid transporters Ntcp, Oatp1, Mrp2, Ibabp, Mrp3, Osta, and Ostb in liver and ileum tissues were also significantly down-regulated. In addition, COL treatment significantly inhibited the mRNA expression levels of Fxr and its downstream target genes Shp, Lrh1, and Fgf15 in liver and ileum tissues, affecting the feedback regulation of bile acid biosynthesis. More importantly, the inhibition of COL on bile acid transporters in ileal and hepatic tissues affected bile acid recycling in the ileum as well as their reuptake in the liver, leading to a significantly increased accumulation of bile acids in the colon, which may be an important cause of diarrhea. In conclusion, our study revealed that COL treatment affected bile acid biosynthesis and enterohepatic circulation, thereby disrupting bile acid metabolic homeostasis in mice.

Genome-wide comparison of DNA methylation patterns between yak and three cattle strains and their potential association with mRNA transcription.

Yak has evolved specific adaptative mechanisms to high-altitude environment. Up to date, only a few studies reported the DNA methylation in yak. In the present study, genome-wide DNA methylome and transcriptome profiles in lung, mammary, and biceps brachii muscle tissues were compared between yak and three cattle breeds (Tibetan cattle, Sanjiang cattle, and Holstein cattle). The association between differentially expressed genes (DEGs) and differentially methylated regions (DMRs) was analyzed, and the biological functions of DEGs potentially driven by DMRs were explored by KEGG enrichment analysis. Finally, we found that yak-specific DMRs-driven DEGs were mainly involved in neuromodulation, respiration, lung development, blood pressure regulation, cardiovascular protection, energy metabolism, DNA repair, and immune functions. The higher levels of the key genes associated with these functions were observed in yak than in cattle, suggesting that DNA methylation might regulate these genes. Overall, the present study contributes basic data at the DNA methylation level to further understand the physiological metabolism in yak.

Dynamic alterations in yak (Bos grunniens) rumen microbiome in response to seasonal variations in diet.

Rumen microorganisms play important roles in the healthy growth of yaks. This study investigated changes in yak rumen microbiome during natural grazing at the warm seasons and supplementary feeding at cold seasons. High-throughput sequencing of 16S rRNA and metagenome analysis were conducted to investigate the structures and functions of yak rumen microbial communities. The results indicated that Bacteroidetes and Firmicutes were the most abundant phyla. In addition, Bacteroidetes might play a more important role than Firmicutes during the supplementary feeding stage (spring and winter), but less during natural grazing stage (summer and autumn). KEGG analysis showed that the amino sugar and nucleotide sugar metabolism, glycolysis/gluconeogenesis, pyruvate metabolism, starch and sucrose metabolism, and fructose and mannose metabolism were the main pathways in the microbial community, which were significantly different between seasons. The carbohydrate-active enzymes (CAZyme) annotation revealed that cellulose was an important carbon source for microorganisms in yak rumen. Glycoside hydrolases (GHs) were the most abundant class of CAZymes, followed by glycosyl transferases (GTs), which were important to digestion of oil, cellulose, and hemicellulose in food. These results contribute to the understanding of microbial components and functions in yak rumen.

Genome-wide identification of SNPs associated with body weight in yak.

BACKGROUND: The yak is the most important livestock in the Qinghai-Tibet Plateau, and body weight directly affects the economic values of yak. Up to date, the genome-wide profiling of single-nucleotide polymorphisms (SNPs) associating with body weight has not been reported in yak. In the present study, the SNPs in 480 yaks from three breeds were analyzed using the commercial high-density (600 K) yak SNP chips. RESULTS: The results identified 12 and 4 SNPs potentially associated with body weight in male and female yaks, respectively. Among them, 9 and 2 SNPs showed significant difference in yak body weight between different genotypes at each locus in male and female yaks, respectively. Further exploration found 33 coding genes within the 100 kbp upstream or downstream to the SNP loci, which might be potentially affected by the variation of SNPs. Among them, G protein-coupled receptor kinase 4 (GRK4) might be potentially affected by the SNP AX-174555047, which has been reported to affect the functioning of two body-weight associated hormones (parathyroid hormone, PTH, and adrenomedullin, ADM). Determination of PTH and ADM levels in yak revealed positive relationship between PTH level and body weight, negative relationship between ADM level and body weight along with the variation of AX-174555047 mutation. CONCLUSIONS: These results suggested that the SNP AX-174555047 might potentially affect body weight through mediating GRK4 expression and then PTH and ADM functioning. Thus, the SNP AX-174555047 might be used as a biomarker for molecular breeding of yak. More investigations are required to validate this point.

Differences in proteomic profiles between yak and three cattle strains provide insights into molecular mechanisms underlying high-altitude adaptation.

Yaks display unique properties of the lung and heart, enabling their adaptation to high-altitude environments, but the underlying molecular mechanisms are still largely unknown. In the present study, the proteome differences in lung and heart tissues were compared between yak (Bos grunniens) and three cattle strains (Bos taurus, Holstein, Sanjiang and Tibetan cattle) using the sequential window acquisition of all theoretical mass spectra/data-independent acquisition (SWATH/DIA) proteomic method. In total, 51,755 peptides and 7215 proteins were identified. In the lung tissue, there were 162, 310 and 118 differential abundance proteins (DAPs) in Tibetan, Holstein and Sanjiang cattle compared to yak respectively. In the heart tissue, there were 71, 57 and 78 DAPs in Tibetan, Holstein and Sanjiang cattle compared to yak respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the DAPs were enriched for the retinol metabolism and toll-like receptor categories in lung tissue. The changes in these two pathways may regulate hypoxia-induced factor and immune function in yaks. Moreover, DAPs in heart tissues were enriched for cardiac muscle contraction, Huntington's disease, chemical carcinogenesis and drug metabolism-cytochrome P450. Further exploration indicated that yaks may alter cardiac function through regulation of type 2 ryanodine receptor (RyR2) and Ca2+ -release channels. The present results are useful to further develop an understanding of the mechanisms underlying adaptation of animals to high-altitude conditions.

Protective effect of rapamycin in models of retinal degeneration.

Age-related macular degeneration (AMD) is a complex retinal disease with no viable treatment strategy. The causative mechanistic pathway for this disease is not yet clear. Therefore, it is highly warranted to screen effective drugs to treat AMD. Rapamycin are known to inhibit inflammation and has been widely used in the clinic as an immunosuppressant. This study aimed to investigate the protective effect of rapamycin on the AMD retinal degeneration model. The AMD models were established by injection of 35 mg/kg sodium iodate (NaIO3) into the tail vein. Then the treated mice intraperitoneally received rapamycin (2 mg/kg) once a day. The histomorphological analysis showed that rapamycin could inhibit retinal structure damage and apoptosis. Experiments revealed that rapamycin significantly attenuated inflammatory response and oxidative stress. Our experimental results demonstrated that rapamycin has protected the retinal against degeneration induced by NaIO3. The therapeutic effect was more significant after 7 days of treatment. Therefore, our study potentially provides a powerful experimental support for the treatment of AMD.

Whole-genome resequencing provides insights into the evolution and divergence of the native domestic yaks of the Qinghai-Tibet Plateau.

BACKGROUND: On the Qinghai-Tibet Plateau, known as the roof ridge of the world, the yak is a precious cattle species that has been indispensable to the human beings living in this high-altitude area. However, the origin of domestication, dispersal route, and the divergence of domestic yaks from different areas are poorly understood. RESULTS: Here, we resequenced the genome of 91 domestic yak individuals from 31 populations and 1 wild yaks throughout China. Using a population genomics approach, we observed considerable genetic variation. Phylogenetic analysis suggested that the earliest domestications of yak occurred in the south-eastern QTP, followed by dispersal to the west QTP and northeast to SiChuang, Gansu, and Qinghai by two routes. Interestingly, we also found potential associations between the distribution of some breeds and historical trade routes such as the Silk Road and Tang-Tibet Ancient Road. Selective analysis identified 11 genes showing differentiation between domesticated and wild yaks and the potentially positively selected genes in each group were identified and compared among domesticated groups. We also detected an unbalanced pattern of introgression among domestic yak, wild yak, and Tibetan cattle. CONCLUSIONS: Our research revealed population genetic evidence for three groups of domestic yaks. In addition to providing genomic evidence for the domestication history of yaks, we identified potential selected genes and introgression, which provide a theoretical basis and resources for the selective breeding of superior characters and high-quality yak.

Methylome and transcriptome profiles in three yak tissues revealed that DNA methylation and the transcription factor ZGPAT co-regulate milk production.

BACKGROUND: Domestic yaks play an indispensable role in sustaining the livelihood of Tibetans and other ethnic groups on the Qinghai-Tibetan Plateau (QTP), by providing milk and meat. They have evolved numerous physiological adaptations to high-altitude environment, including strong blood oxygen transportation capabilities and high metabolism. The roles of DNA methylation and gene expression in milk production and high-altitudes adaptation need further exploration. RESULTS: We performed genome-wide DNA methylome and transcriptome analyses of breast, lung, and biceps brachii muscle tissues from yaks of different ages. We identified 432,350 differentially methylated regions (DMRs) across the age groups within each tissue. The post-mature breast tissue had considerably more differentially methylated regions (155,957) than that from the three younger age groups. Hypomethylated genes with high expression levels might regulate milk production by influencing protein processing in the endoplasmic reticulum. According to weighted gene correlation network analysis, the "hub" gene ZGPAT was highly expressed in the post-mature breast tissue, indicating that it potentially regulates the transcription of 280 genes that influence protein synthesis, processing, and secretion. The tissue network analysis indicated that high expression of HIF1A regulates energy metabolism in the lung. CONCLUSIONS: This study provides a basis for understanding the epigenetic mechanisms underlying milk production in yaks, and the results offer insight to breeding programs aimed at improving milk production.

The whole-transcriptome landscape of muscle and adipose tissues reveals the ceRNA regulation network related to intramuscular fat deposition in yak.

BACKGROUND: The Intramuscular fat (IMF) content in meat products, which is positively correlated with meat quality, is an important trait considered by consumers. The regulation of IMF deposition is species specific. However, the IMF-deposition-related mRNA and non-coding RNA and their regulatory network in yak (Bos grunniens) remain unknown. High-throughput sequencing technology provides a powerful approach for analyzing the association between transcriptome-related differences and specific traits in animals. Thus, the whole transcriptomes of yak muscle and adipose tissues were screened and analyzed to elucidate the IMF deposition-related genes. The muscle tissues were used for IMF content measurements. RESULTS: Significant differences were observed between the 0.5- and 2.5-year-old yaks. Several mRNAs, miRNAs, lncRNAs and circRNAs were generally expressed in both muscle and adipose tissues. Between the 0.5- and 2.5-year-old yaks, 149 mRNAs, 62 miRNAs, 4 lncRNAs, and 223 circRNAs were differentially expressed in muscle tissue, and 72 mRNAs, 15 miRNAs, 9 lncRNAs, and 211 circRNAs were differentially expressed in adipose tissue. KEGG annotation revelved that these differentially expressed genes were related to pathways that maintain normal biological functions of muscle and adipose tissues. Moreover, 16 mRNAs, 5 miRNAs, 3 lncRNAs, and 5 circRNAs were co-differentially expressed in both types of tissue. We suspected that these co-differentially expressed genes were involved in IMF-deposition in the yak. Additionally, LPL, ACADL, SCD, and FASN, which were previously shown to be associated with the IMF content, were identified in the competing endogenous RNA (ceRNA) regulatory network that was constructed on the basis of the IMF deposition-related genes. Three ceRNA subnetworks also revealed that TCONS-00016416 and its target SIRT1 "talk" to each other through the same miR-381-y and miR-208 response elements, whereas TCONS-00061798 and its target PRKCA, and TCONS-00084092 and its target LPL "talk" to each other through miR-122-x and miR-499-y response elements, respectively. CONCLUSION: Taken together, our results reveal the potential mRNA and noncoding RNAs involved in IMF deposition in the yak, providing a useful resource for further research on IMF deposition in this animal species.

Signature of high altitude adaptation in the gluteus proteome of the yak.

Yak is the unique Bovidae species in the Qinghai-Tibetan Plateau. A previous proteomic study has compared the yak muscle tissue to one cattle strain using the isobaric tags for relative and absolute quantification approach. In this study, to further investigate the molecular mechanisms underlying yak adaptation, the proteomic profiles of gluteus were compared between yak and one moderate-altitude cattle strain (Tibetan cattle) and two low-altitude cattle strains (Holstein and Sanjiang cattle) using a label-free quantitative method. The comparisons identified 20, 364, 143 upregulated proteins and 4, 6, 37 downregulated proteins in yak, compared with Tibetan, Holstein, and Sanjiang cattle, respectively. Protein-protein interaction analysis indicated that these differentially expressed proteins were mainly related to "oxidative phosphorylation" and "electron transport chain." Further analysis revealed that NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11, NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4, cytochrome C oxidase subunit 6A2, mitochondrial and cytochrome c oxidase subunit NDUFA4 were all increased in the yak, suggesting that yak might increase mitochondrial capacity to sustain metabolic rates under high altitude conditions, which might be a long-term adaptive mechanism underlying adaptation to high altitude environments. Yak increased the level of thioredoxin reductase 2 to protect themselves from oxidative damages. Moreover, the increased expression levels of phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform and caveolin-1 in yak suggested that yaks promoted glucose uptake for adaptation to high altitude. These results provided more information to better understand the molecular mechanisms underlying yak adaption.

Automatic Guidance Method for Laser Tracker Based on Rotary-Laser Scanning Angle Measurement.

Laser-tracking measurement systems (laser tracker) have been playing a critical role in large-scale 3D high-precision coordinate measurement. However, the existing visual guidance of laser trackers is still limited by the disadvantages of operator-dependence, small-angle view field, time-consuming laser-guided process. This paper presents an automatic guidance method for laser trackers based on the rotary-laser scanning angle measurement technology. In this method, a special target consisting of six photoelectric receivers and a retroreflector is integrated into the rotary-laser scanning transmitter' coordinate systems. Real-time constraints calculated by the proposed method would provide the coordinates of the target in a laser tracker coordinates system for guidance. Finally, the experimental results verified the automatic re-establish of sightline can be realized in horizontal 360° angle field within tens of arc-seconds, and this method is robust against the fast movement of the target.

3D bio-printing-based vascular-microtissue electrochemical biosensor for fish parvalbumin detection.

A novel 3D bio-printing vascular microtissue biosensor was developed to detect fish parvalbumin quickly. The graphite rod electrode was modified with gold and copper organic framework (Cu-MOF) to improve the sensor properties. Polydopamine-modified multi-wall carbon nanotubes (PDA-MWCNT) were mixed with gelatin methacryloyl (GelMA) to prepare a conductive hydrogel. The conductive hydrogel was mixed with mast cells and endothelial cells to produce a bio-ink for 3D bioprinting. High throughput and standardized preparation of vascular microtissue was performed by stereolithography 3D bioprinting. The vascular microtissue was immobilized on the modified electrode to construct the microtissue sensor. The biosensor's peak current was positively correlated with the fish parvalbumin concentration, and the detection linear concentration range was 0.1 ∼ 2.5 µg/mL. The standard curve equation was IDPV(µA) = 31.30 + 5.46 CPV(µg/mL), the correlation coefficient R2 was 0.990 (n = 5), and the detection limit was 0.065 µg/mL. These indicated a biomimetic microtissue sensor detecting fish parvalbumin has been successfully constructed.

Oxidation enhances the toxicity of polyethylene microplastics to mouse eye: Perspective from in vitro and in vivo.

Microplastics (MPs) are ubiquitously dispersed in the environment, and undergoing the process of oxidation that alters their physical and chemical properties. Eyes, which directly interface with the external milieu, inevitably encounter MPs. Nonetheless, the ophthalmic toxicity of MPs towards organisms remains unclear. In this study, primary mouse corneal epithelial cells (MCECs), C57BL/6 mice, and CX3CrlGFP/+ mice were utilized to evaluate the toxicity and differences between oxidized low-density polyethylene MPs (modified-MPs) and low-density polyethylene MPs (virgin-MPs) on eyes. The results manifested that virgin-MPs and modified-MPs could be endocytosed by primary MCECs, resulting in a range of cellular damage. Furthermore, they could diminish tear secretion, increase intraocular pressure, and could be internalized into cornea and retina in mice, instigating a series of detrimental reactions. Importantly, modified-MPs exhibited heightened toxicity towards mouse eyes, seemingly due to oxidation enhances the interaction between virgin-MPs/modified-MPs and tissues/cells, and leading to the release of toxic substances increased. In conclusion, our discoveries demonstrate that oxidation exacerbates the harm of virgin-MPs to eyes, and are of great significance for evaluating the risk of MPs to ocular health.

Utilizing GO/PEDOT:PSS/PtNPs-enhanced high-stability microelectrode arrays for investigating epilepsy-induced striatal electrophysiology alterations.

The striatum plays a crucial role in studying epilepsy, as it is involved in seizure generation and modulation of brain activity. To explore the complex interplay between the striatum and epilepsy, we engineered advanced microelectrode arrays (MEAs) specifically designed for precise monitoring of striatal electrophysiological activities in rats. These observations were made during and following seizure induction, particularly three and 7 days post-initial modeling. The modification of graphene oxide (GO)/poly (3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS)/platinu-m nanoparticles (PtNPs) demonstrated a marked reduction in impedance (10.5 ± 1.1 kΩ), and maintained exceptional stability, with impedance levels remaining consistently low (23 kΩ) even 14 days post-implantation. As seizure intensity escalated, we observed a corresponding increase in neuronal firing rates and local field potential power, with a notable shift towards higher frequency peaks and augmented inter-channel correlation. Significantly, during the grand mal seizures, theta and alpha bands became the dominant frequencies in the local field potential. Compared to the normal group, the spike firing rates on day 3 and 7 post-modeling were significantly higher, accompanied by a decreased firing interval. Power in both delta and theta bands exhibited an increasing trend, correlating with the duration of epilepsy. These findings offer valuable insights into the dynamic processes of striatal neural activity during the initial and latent phases of temporal lobe epilepsy and contribute to our understanding of the neural mechanisms underpinning epilepsy.

A novel 3D bio-printing "liver lobule" microtissue biosensor for the detection of AFB1.

In this paper, a novel "liver lobule" microtissue biosensor based on 3D bio-printing is developed to rapidly determine aflatoxin B1 (AFB1). Methylacylated Hyaluronic acid (HAMA) hydrogel, HepG2 cells, and carbon nanotubes are used to construct "liver lobule" models. In addition, 3D bio-printing is used to perform high-throughput and standardized preparation in order to simulate the organ morphology and induce functional formation. Afterwards, based on the electrochemical rapid detection technology, a 3D bio-printed "liver lobule" microtissue is immobilized on the screen-printed electrode, and the mycotoxin is detected by differential pulse voltammetry (DPV). The DPV response increases with the concentration of AFB1 in the range of 0.1-3.5 µg/mL. The linear detection range is 0.1-1.5 µg/mL and the calculated lowest detection limit is 0.039 µg/mL. Thus, this study develops a new mycotoxin detection method based on the 3D printing technology, which has high stability and reproducibility. It has wide application prospects in the field of detection and evaluation of food hazards.

Exposure to nitrate induced growth, intestinal histology and microbiota alterations of Bufo raddei Strauch tadpoles.

Nitrate (NO3-) is one of the ubiquitous environmental chemicals which multiplies negative impacts on aquatic life such as amphibian larvae. However, the data involving the dynamics of amphibians in response to NO3-N are scarce. This study investigated the effects of NO3-N on locomotor ability, growth performance, oxidative stress parameters, intestinal histology, and intestinal microbiota of Bufo raddei Strauch tadpoles. The tadpoles were chronically exposed to different concentrations of NO3-N (10, 50, 100, and 200 mg/L) from Gosner stage 26 to 38. Our results revealed that NO3-N exposure caused significantly reduced body weight and length, impaired locomotor activity, and severe oxidative damage to liver tissue. Moreover, the high NO3-N (50, 100, and 200 mg/L) exposure caused irregular arrangement and indistinct cell borders of mucosal epithelial cells in the tadpoles intestine. The NO3-N exposure significantly changed the structure of the intestinal microbiota. The phylum Cyanobacteria occupy the main niche of intestinal microbes and have a certain negative correlation with the growth and motility of tadpoles. In addition, the functional prediction revealed that NO3-N exposure obviously downregulated the metabolism of enzyme families in tadpoles. Our comprehensive research shows the toxicity of NO3-N exposure in B. raddei Strauch, explores the potential links between development and intestinal microbiota of tadpole, and provides a new framework for the potential health risk of nitrate in amphibians.

Air pollution, genetic factors and the risk of osteoporosis: A prospective study in the UK biobank.

Purpose: To reveal relationship between air pollution exposure and osteoporosis (OP) risk. Methods: Based on large-scale data from the UK Biobank, we evaluated the relationship between OP risk and several air pollutants. Then air pollution scores (APS) were constructed to assess the combined effects of multiple air pollutants on OP risk. Finally, we constructed a genetic risk score (GRS) based on a large genome-wide association study of femoral neck bone mineral density and assessed whether single or combined exposure to air pollutants modifies the effect of genetic risk on OP and fracture risk. Results: PM2.5, NO2, NOx, and APS were significantly associated with an increased risk of OP/fracture. OP and fracture risk raised with increasing concentrations of air pollutants: compared to the lowest APS quintile group, subjects in the highest quintile group had a hazard ratio (HR) (95% CI) estimated at 1.140 (1.072-1.213) for OP and 1.080 (1.026-1.136) for fracture. Moreover, participants with low GRS and the highest air pollutant concentration had the highest risk of OP, the HRs (95% CI) of OP were 1.706 (1.483-1.964), 1.658 (1.434-1.916), 1.696 (1.478-1.947), 1.740 (1.506-2.001) and 1.659 (1.442-1.908), respectively, for PM2.5, PM10, PM2.5-10, NO2, and NOx. Similar results were also observed for fractures. Finally, we assessed the joint effect of APS and GRS on the risk of OP. Participants with higher APS and lower GRS had a higher risk of developing OP. Similar results were observed in the joint effect of GRS and APS on fracture. Conclusions: We found that exposure to air pollution, individually or jointly, could improve the risk of developing OP and fractures, and increased the risk by interacting with genetic factors.

The intestinal microbiota and metabolic profiles of Strauchbufo raddei underwent adaptive changes during hibernation.

The intestinal microbiota help regulate hibernation in vertebrates. However, it needs to be established how hibernation modulates the gut microbiome and intestinal metabolism. In the present study, we used an artificial hibernation model to examine the responses of the gut microbiota of the Strauchbufo raddei to the environmental changes associated with this behavior. Hibernation significantly lowered the diversity of the microbiota and altered the microbial community of the gut. Proteobacteria, Firmicutes, and Bacteroidota were the major bacterial phyla in the intestines of S. raddei. However, Firmicutes and Proteobacteria predominated in the gut of active and hibernating S. raddei, respectively. Certain bacterial genera such as Pseudomonas, Vibrio, Ralstonia, and Rhodococcus could serve as biomarkers distinguishing hibernating and non-hibernating S. raddei. The gut microbiota was more resistant to environmental stress in hibernating than active S. raddei. Moreover, metabolomics revealed that metabolites implicated in fatty acid biosynthesis were highly upregulated in the intestines of hibernating S. raddei. The metabolites that were enriched during hibernation enabled S. raddei to adapt to the low temperatures and the lack of exogenous food that are characteristic of hibernation. A correlation analysis of the intestinal microbiota and their metabolites revealed that the gut microbiota might participate in the metabolic regulation of hibernating S. raddei. The present study clarified the modifications that occur in the intestinal bacteria and their symbiotic relationship with their host during hibernation. These findings are indicative of the adaptive changes in the metabolism of amphibians under different environmental conditions.

The enhancement in toxic potency of oxidized functionalized polyethylene-microplastics in mice gut and Caco-2 cells.

Microplastics (MPs) are inevitably oxidized in the environment, however, to date, no studies have discussed the biological toxicity of oxidized polyethylene (Ox-PE) MPs. In this study, oxidized low-density polyethylene (Ox-LDPE), a representative Ox-PE, was prepared using a selective oxidation method. The difference in toxicity between LDPE-MPs and Ox-LDPE-MPs were evaluated in C57BL/6 mice and Caco-2 cells. The proton nuclear magnetic resonance (1H NMR) and Fourier transform infrared (FTIR) spectroscopy analyses revealed that some hydrocarbon-containing groups were transformed into carboxyl and ketone groups during selective oxidation. In vivo experiment results showed that LDPE-MPs and Ox-LDPE-MPs exists in the intestinal (duodenum and colon) of mice, and Ox-LDPE-MPs caused more severe intestinal histological changes, oxidative stress, and inflammatory response. The gut microbiota data showed that the relative abundance of Lactobacillus decreased significantly in the LDPE-MP- and Ox-LDPE-MP-exposed groups (P < 0.05). The predicted Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathway suggested that exposure to LDPE-MPs or Ox-LDPE-MPs inhibited glycan biosynthesis and metabolism in the flora (P < 0.05). In vitro experiment results showed that selective oxidation to LDPE promoted its uptake by cells and aggravated adverse effects on cells, including reduced cell viability, damaged cell membrane, oxidative stress, and mitochondrial depolarization. The major mechanism of the increased toxicity of Ox-LDPE-MPs may be its easier accumulation and the ionic effect of oxygen-containing functional groups. Overall, these findings provide insights on the differences in toxicity between LDPE-MPs and Ox-LDPE-MPs. They also provide new perspectives for understanding the biohazards of MPs, which are necessary to accurately assess the potential environmental and health risks of these plastic pollutants.

Colchicine increases intestinal toxic load by disturbing fecal metabolome homeostasis in mice.

Colchicine (COL) has been used to treat gout for over a millennium, but its medicinal use has been controversial due to its potent toxicity in the gastrointestinal tract. Nausea, vomiting, and diarrhea are the most prominent external manifestations of COL gastrointestinal toxicity, but the cause of these adverse events remains obscure. In this study, the mice were exposed to COL (2.5 mg/kg b.w./day) for one week to study the mechanism of COL-induced diarrhea from the perspective of intestinal metabolism. The results showed that COL exposure disturbed intestinal metabolic homeostasis, resulting in a significant accumulation of 116 metabolites and, conversely, significant depletion of 64 metabolites, with the number of differential metabolites being one-eighth of the total metabolites (180/1445). Also, it was found that cAMP, Adenosine 5'-monophosphate, GDP, Inositol, and Cortisol are core metabolites that play crucial roles in COL-induced metabolic disorders. These metabolites could be used as biomarkers to differentiate control and COL-treated groups, implying that these metabolites may be closely related to COL-induced diarrhea. Furthermore, changes in the metabolic pathways (Purine metabolism, biosynthesis and metabolism of aromatic amino acids, and Bile secretion) involved in these five core metabolites increased the toxic load in the gut, which was the culprit leading to intestinal metabolic disorders. In addition, the abnormal bile secretion caused by COL exposure may play an important role in COL-induced diarrhea. In conclusion, our study opens new avenues for understanding the mechanisms of COL-induced gastrointestinal adverse reactions and broadens the scientific horizon on the interactions between COL and host metabolism.