HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis.

Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.

HMGA1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosis.

Chemotherapy is a primary treatment for esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapeutic drugs is an important hurdle to effective treatment. Understanding the mechanisms underlying chemotherapy resistance in ESCC is an unmet medical need to improve the survival of ESCC. Herein, we demonstrate that ferroptosis triggered by inhibiting high mobility group AT-hook 1 (HMGA1) may provide a novel opportunity to gain an effective therapeutic strategy against chemoresistance in ESCC. HMGA1 is upregulated in ESCC and works as a key driver for cisplatin (DDP) resistance in ESCC by repressing ferroptosis. Inhibition of HMGA1 enhances the sensitivity of ESCC to ferroptosis. With a transcriptome analysis and following-up assays, we demonstrated that HMGA1 upregulates the expression of solute carrier family 7 member 11 (SLC7A11), a key transporter maintaining intracellular glutathione homeostasis and inhibiting the accumulation of malondialdehyde (MDA), thereby suppressing cell ferroptosis. HMGA1 acts as a chromatin remodeling factor promoting the binding of activating transcription factor 4 (ATF4) to the promoter of SLC7A11, and hence enhancing the transcription of SLC7A11 and maintaining the redox balance. We characterized that the enhanced chemosensitivity of ESCC is primarily attributed to the increased susceptibility of ferroptosis resulting from the depletion of HMGA1. Moreover, we utilized syngeneic allograft tumor models and genetically engineered mice of HMGA1 to induce ESCC and validated that depletion of HMGA1 promotes ferroptosis and restores the sensitivity of ESCC to DDP, and hence enhances the therapeutic efficacy. Our finding uncovers a critical role of HMGA1 in the repression of ferroptosis and thus in the establishment of DDP resistance in ESCC, highlighting HMGA1-based rewiring strategies as potential approaches to overcome ESCC chemotherapy resistance. Schematic depicting that HMGA1 maintains intracellular redox homeostasis against ferroptosis by assisting ATF4 to activate SLC7A11 transcription, resulting in ESCC resistance to chemotherapy.

Metformin alleviates irradiation-induced intestinal injury by activation of FXR in intestinal epithelia.

Abdominal irradiation (IR) destroys the intestinal mucosal barrier, leading to severe intestinal infection. There is an urgent need to find safe and effective treatments to reduce IR-induced intestinal injury. In this study, we reported that metformin protected mice from abdominal IR-induced intestinal injury by improving the composition and diversity of intestinal flora. The elimination of intestinal microbiota (Abx) abrogated the protective effects of metformin on irradiated mice. We further characterized that treatment of metformin increased the murine intestinal abundance of Lactobacillus, which mediated the radioprotective effect. The administration of Lactobacillus or fecal microbiota transplantation (FMT) into Abx mice considerably lessened IR-induced intestinal damage and restored the radioprotective function of metformin in Abx mice. In addition, applying the murine intestinal organoid model, we demonstrated that IR inhibited the formation of intestinal organoids, and metformin alone bore no protective effect on organoids after IR. However, a combination of metformin and Lactobacillus or Lactobacillus alone displayed a strong radioprotection on the organoid formation. We demonstrated that metformin/Lactobacillus activated the farnesoid X receptor (FXR) signaling in intestinal epithelial cells and hence upregulated tight junction proteins and mucins in intestinal epithelia, increased the number of goblet cells, and augmented the mucus layer thickness to maintain the integrity of intestinal epithelial barrier, which eventually contributed to reduced radiation intestinal injury. In addition, we found that Lactobacillus abundance was significantly increased in the intestine of patients receiving metformin while undergoing abdominal radiotherapy and the abundance was negatively correlated with the diarrhea duration of patients. In conclusion, our results demonstrate that metformin possesses a protective effect on IR-induced intestinal injury by upregulating the abundance of Lactobacillus in the intestine.

Lactobacillus Suppresses Tumorigenesis of Oropharyngeal Cancer via Enhancing Anti-Tumor Immune Response.

Deficiency in T cell-mediated adaptive immunity, such as low CD8+ T cell infiltration, inhibits the immune surveillance, promotes malignant transformation, and facilitates tumor growth. Microbiota dysbiosis diminishes the immune system and contributes to the occurrence of cancer. However, the impact of oral dysbiosis on the occurrence and molecular mechanisms of oropharyngeal cancer (OPC) remains largely unknown. In the current study, we used 4-nitroquinoline-1-oxide (4NQO) to mimic tobacco-related carcinogenesis to generate a murine OPC model and determine the role of microbiota changes in OPC tumorigenesis. Our results showed that the oral flora composition of mice was deregulated during the tumorigenesis of OPC. The abundance of Streptococcus, Veillonella, Muribacter, Rodentibacter, and Gemella was increased, whereas the dominant genus Lactobacillus was gradually decreased with disease progression. We further demonstrated that infiltration of CD8+ T lymphocytes was markedly reduced due to the reduction of Lactobacillus. Supplementation of Lactobacillus increased the infiltration of CD8+ T cells, promoted the expression of IFN-γ and granzyme B, and lessened the OPC progression. Analyzing the metabolites of the Lactobacillus, we demonstrated that Lactobacillus enhanced the anti-tumor immune response by producing acetate in OPC development. Administration of acetate to mice could increase the expression of IFN-γ and IFN-γ-inducible chemokines in tumor tissues by activating GPR43 to promote the infiltration of CD8+ T lymphocytes and substantially delay the development of OPC. Together, our data suggest that dysbiosis of oral microbiota promotes the tumorigenesis of OPC through downregulation of cytotoxic T lymphocytes. Lactobacillus and its metabolite acetate improve the tumor microenvironment, which could be applied in the treatment of OPC.

Study on the Hg0 removal characteristics and synergistic mechanism of iron-based modified biochar doped with multiple metals.

An iron-based composite adsorbent with biochar as the support was prepared by coprecipitation and the sol-gel method. Both single-iron-based modified biochar without doping with other metals and iron-based modified biochar doped with multiple metals (Ce, Cu, Co, Mn) were synthesised. The adsorption kinetics were analysed, and temperature-programmed desorption measurements were performed to reveal the inherent difference in mechanism between the oxidation and adsorption of Hg0 by the modified biochar and to elucidate the key mechanism of Hg0 removal. The results show that the removal of Hg0 by the modified biochar mainly includes adsorption and oxidation processes. The adsorption process is divided into two stages, external and internal mass transfer, both of which occur via multilayer adsorption. HgO and Hg-OM are the main forms of Hg0 present on the modified biochar surface. Doped metal oxides can play a synergistic role in enhancing the mercury removal performance of the modified biochar.

Association Between Plasma Homocysteine Levels and Subclinical Hypothyroidism in Adult Subjects: A Meta-Analysis.

Increased plasma homocysteine (Hcy) levels have been widely documented in patients with overt hypothyroidism; however, the significance of Hcy level changes in patients with subclinical hypothyroidism (SCH) remains controversial. The aim of this meta-analysis was to determine the Hcy status in patients with SCH compared with euthyroid subjects. We searched PubMed, Embase, and Cochrane Library databases prior to December 2019 to identify eligible studies and assessed the quality of selected studies using the Newcastle-Ottawa Quality Assessment Scale. Publication bias was evaluated by Begg's test and Egger's test. Meta-regression analysis was conducted to investigate the source of heterogeneity. A likely source of heterogeneity was the year of the study. All statistical analyses were performed with RevMan 5.3 and Stata 12.0 software. Our meta-analysis of twelve observational studies with 684 patients showed that those with SCH aged between 18 and 65 years old were associated with a slightly increased plasma Hcy level compared with euthyroid controls. The pooled result of the weighted mean difference (WMD) of increased tHcy levels was 1.16 µmol/l (95% CI: 0.51, 1.82; p=0.0005). The Hcy level in patients with SCH aged between 18 and 65 years old is significantly increased compared to euthyroid controls.

[Stable hydrogen and oxygen isotope compositions in soil-plant-atmosphere continuum (SPAC) in rocky mountain area of Beijing, China]. / 北京土石山区水分在土壤-植物-大气连续体(SPAC)ä¸­çš„ç¨³å®šåŒä½ç´ ç‰¹å¾.

The stable hydrogen and oxygen isotopes are environmental isotopes, which widely exist in various kinds of water. Their relative abundance variation in water can indicate the water circulation and mechanism of water use in plant. This research selected two major kinds of greening tree species, evergreen coniferous Platycladus orientalis and deciduous broad-leaved Quercus variabilis, in Beijing mountainous area, and the water movement process in soil-plant-atmosphere continuum was investigated by the variation characteristics analysis of stable hydrogen and oxygen isotope compositions in precipitation, soil water, groundwater, plant stem water and leaf water. The results showed that the meteoric water line equation of the study area was δD=7.17δ18O+1.45 (R2=0.93), and the soil evaporation line equation was δD=3.85δ18O+1.45 (R2=0.76). A certain degree of evaporation fractionation existed in the processes of rainfall infiltration into soil water. In different seasons, the δD and δ18O values of precipitation, soil water and spring water had different variation regularity. In rainy season, the mean δD and δ18O values were in order of precipitation> spring water>soil water, with the precipitation and soil water supplied spring water together; in dry season, the order was precipitation > soil water > spring water, and the precipitation and spring water both contributed to soil water. The δD and δ18O fitting line equations of stem water of P. orienta-lis and Q. variabilis were respectively δD=5.03δ18O-30.78 and δD=3.0δ18O-48.92. The uptake water of Q. variabilis was more enriched than that of P. orientalis, and the depth of Q. variabilis water uptake in soil profile was shallower than P. orientalis. The leaf water isotopic variation of Q. varia-bilis was more sensitive to atmospheric environment, with the kinetic isotopic fractionation of Q. variabilis being more enriched than that of P. orientalis, but they had the same response to variation of environmental condition.