Time-restricted feeding prevents ionizing radiation-induced hematopoietic stem cell damage by inhibiting NOX-4/ROS/p38 MAPK pathway.

Ionizing radiation (IR)-induced damage to the hematopoietic system is a prominent symptom following exposure to total body irradiation (TBI). The exploration of strategies aimed at to mitigating radiation-induced hematopoietic damage assumes paramount importance. Time-restricted feeding (TRF) has garnered attention for its beneficial effects in various diseases. In this study, we evaluated the preventive effects of TRF on TBI-induced hematopoietic damage. The results suggested that TRF significantly enhanced the proportion and function of hematopoietic stem cells in mice exposed to 4 Gy TBI. These effects might be attributed to the inhibition of the NOX-4/ROS/p38 MAPK pathway in hematopoietic stem cells. TRF also influenced the expression of nuclear factor erythroid2-related factor 2 and increased glutathione peroxidase activity, thereby promoting the clearance of reactive oxygen species. Furthermore, TRF alleviated aberrations in plasma metabolism by inhibiting the mammalian target of rapamycin. These findings suggest that TRF may represent a novel approach to preventing hematopoietic radiation damage.

Empagliflozin attenuates radiation-induced hematopoietic damage via NOX-4/ROS/p38 pathway.

PURPOSE: Damage to the hematopoietic system and functional inhibition are severe consequences of radiation exposure. In this study, we have investigated the effect of empagliflozin on radiation-induced hematopoietic damage, with the aim of providing new preventive approach to such injuries. METHODS AND MATERIALS: Mice were given 4 Gy total body irradiation (TBI) 1 h after the oral administration of empagliflozin, followed by the continuous administration of the same dose of empagliflozin for 6d, and then sacrificed on the 10th day after irradiation. The reactive oxygen species (ROS) levels in hematopoietic cells and their regulatory mechanisms were also been investigated. Colony forming unit granulocyte macrophage assay and bone marrow transplantation assays were performed to detect the function of the bone marrow cells. KEY FINDINGS: Empagliflozin increased the cell viability, reduced ROS levels, and attenuated apoptosis in vitro after the bone marrow cells were exposed to 1 Gy radiation. Empagliflozin significantly attenuated ionizing radiation injuries to the hematopoietic system, increased the peripheral blood cell count, and enhanced the proportion and function of hematopoietic stem cells in mice exposed to 4 Gy TBI. These effects may be related to the NOX-4/ROS/p38 pathway-mediated suppression of MAPK in hematopoietic stem cells. Empagliflozin also influenced the expression of Nrf-2 and increased glutathione peroxidase activity, thereby promoting the clearance of reactive oxygen species. Furthermore, empagliflozin mitigated metabolic abnormalities by inhibiting the mammalian target of rapamycin. SIGNIFICANCE: Our study has demonstrated that empagliflozin can reduce radiation-induced injury in hematopoietic stem cells. This finding suggests that empagliflozin is a promising novel agent for preventing radiation-induced damage to the hematopoietic system.

Development of radiation countermeasure agents for acute radiation syndromes.

The risk of internal and external exposure to ionizing radiation (IR) has increased alongside the development and implementation of nuclear technology. Therefore, serious security issues have emerged globally, and there has been an increase in the number of studies focusing on radiological prevention and medical countermeasures. Radioprotective drugs are particularly important components of emergency medical preparedness strategies for the clinical management of IR-induced injuries. However, a few drugs have been approved to date to treat such injuries, and the related mechanisms are not entirely understood. Thus, the aim of the present review was to provide a brief overview of the World Health Organization's updated list of essential medicines for 2023 for the proper management of national stockpiles and the treatment of radiological emergencies. This review also discusses the types of radiation-induced health injuries and the related mechanisms, as well as the development of various radioprotective agents, including Chinese herbal medicines, for which significant survival benefits have been demonstrated in animal models of acute radiation syndrome.

Targeting TLK2 inhibits the progression of gastric cancer by reprogramming amino acid metabolism through the mTOR/ASNS axis.

Several recent studies have suggested that TLKs are related to tumor progression. However, the function and mechanism of action of TLK2 in gastric cancer (GC) remain elusive. In this study, TLK2 was found to be significantly upregulated in patients with GC and was identified as an independent prognostic factor for GC. Consistently, TLK2 knockdown markedly reduced the aggressiveness of GC, whereas its overexpression had the opposite effect. IP-MS revealed that the effects of TLK2 on GC were mainly associated with metabolism reprogramming. TLK2 knockdown suppressed amino acid synthesis by downregulating the mTORC1 pathway and ASNS expression in GC cells. Mechanistically, mTORC1 directly interacts with the ASNS protein and inhibits its degradation. Further experiments validated that the ASNS protein was degraded via ubiquitination instead of autophagy. Inhibiting and activating the mTORC1 pathway can upregulate and downregulate ASNS ubiquitination, respectively, and the mTORC1 pathway can reverse the regulatory effects of TLK2 on ASNS. Furthermore, TLK2 was found to regulate the mRNA expression of ASNS. TLK2 directly interacted with ATF4, a transcription factor of ASNS, and promoted its expression. The kinase inhibitor fostamatinib significantly inhibited the proliferative, invasive, and migratory capabilities of GC cells by inhibiting TLK2 activity. Altogether, this study reveals a novel functional relationship between TLK2 and the mTORC1/ASNS axis in GC. Therefore, TLK2 may serve as a potential therapeutic target for GC.

Nicotinamide riboside intervention alleviates hematopoietic system injury of ionizing radiation-induced premature aging mice.

Radiotherapy destroys cancer cells and inevitably harms normal human tissues, causing delayed effects of acute radiation exposure (DEARE) and accelerating the aging process in most survivors. However, effective methods for preventing premature aging induced by ionizing radiation are lacking. In this study, the premature aging mice of DEARE model was established after 6 Gy total body irradiation (TBI). Then the therapeutic effects and mechanism of nicotinamide riboside on the premature aging mice were evaluated. The results showed that 6 Gy TBI induced premature aging of the hematopoietic system in mice. Nicotinamide riboside treatment reversed aging spleen phenotypes by inhibiting cellular senescence and ameliorated serum metabolism profiles. Further results demonstrated that nicotinamide riboside supplementation alleviated the myeloid bias of hematopoietic stem cells and temporarily restored the regenerative capacity of hematopoietic stem cells probably by mitigating the reactive oxygen species activated GCN2/eIF2α/ATF4 signaling pathway. The results of this study firstly indicate that nicotinamide riboside shows potential as a DEARE therapeutic agent for radiation-exposed populations and patients who received radiotherapy.

Erratum: Author correction to 'Discovery of the radio-protecting effect of ecliptae herba, its constituents and targeting p53-mediated apoptosis in vitro and in vivo' [Acta Pharm Sin B 13 (2023) 1216-1230].

[This corrects the article DOI: 10.1016/j.apsb.2022.09.003.].

Senescent Stem Cell Dysfunction and Age-Related Diseases.

As the body ages, it experiences a gradual decline in the functioning of cells, tissues, and systems, which eventually leads to dysfunction and increased susceptibility to disease. At the cellular level, a reduction in the activity or number of stem cells is an important feature of cell senescence, and such changes may also directly drive the aging of the organism. Thus, finding ways to prevent or even reverse stem cell senescence holds promise for the development of aging therapies in tissues and organisms. This review discusses the relationship between changes in stem cell senescence, tissues aging, and related diseases, focusing on four categories of tissue stem cells: hematopoietic stem cells, mesenchymal stromal/stem cells (MSCs), intestinal stem cells, and muscle stem cells.

High-fat diet alters the radiation tolerance of female mice and the modulatory effect of melatonin.

High-fat diet (HFD) increases the risk of developing malignant tumors. Ionizing radiation (IR) is used as an adjuvant treatment in oncology. In this study, we investigated the effects of an 8-week 35% fat HFD on the tolerance to IR and the modulatory effect of melatonin (MLT). The results of lethal dose irradiation survival experiments revealed that the 8-week HFD altered the radiation tolerance of female mice and increased their radiosensitivity, whereas it had no comparable effects on males. Pre-treatment with MLT was, however, found to attenuate the radiation-induced hematopoietic damage in mice, promote intestinal structural repair after whole abdominal irradiation (WAI), and enhance the regeneration of Lgr5+ intestinal stem cells. 16S rRNA high-throughput sequencing and untargeted metabolome analyses revealed that HFD consumption and WAI sex-specifically altered the composition of intestinal microbiota and fecal metabolites and that MLT supplementation differentially modulated the composition of the intestinal microflora in mice. However, in both males and females, different bacteria were associated with the modulation of the metabolite 5-methoxytryptamine. Collectively, the findings indicate that MLT ameliorates the radiation-induced damage and sex-specifically shapes the composition of the gut microbiota and metabolites, protecting mice from the adverse side effects associated with HFD and IR.

PET imaging of new target CDK19 in prostate cancer.

PURPOSE: Prostate-specific membrane antigen (PSMA)-positron emission tomography (PET) is a superior method to predict patients' risk of cancer progression and response to specific therapies. However, its performance is limited for neuroendocrine prostate cancer (NEPC) and PSMA-low prostate cancer cells, resulting in diagnostic blind spots. Hence, identifying novel specific targets is our aim for diagnosing those prostate cancers with low PSMA expression. METHODS: The Cancer Genome Atlas (TCGA) database and our cohorts from men with biopsy-proven high-risk metastatic prostate cancer were used to identify CDK19 and PSMA expression. PDX lines neP-09 and P-16 primary cells were used for cellular uptake and imaging mass cytometry in vitro. To evaluate in vivo CDK19-specific uptake of gallium(Ga)-68-IRM-015-DOTA, xenograft mice models and blocking assays were used. PET/CT imaging data were obtained to estimate the absorbed dose in organs. RESULTS: Our study group had reported the overexpression of a novel tissue-specific gene CDK19 in high-risk metastatic prostate cancer and CDK19 expression correlated with metastatic status and tumor staging, independently with PSMA and PSA levels. Following up on this new candidate for use in diagnostics, small molecules targeting CDK19 labeled with Ga-68 (68Ga-IRM-015-DOTA) were used for PET in this study. We found that the 68Ga-IRM-015-DOTA was specificity for prostate cancer cells, but the other cancer cells also took up little 68Ga-IRM-015-DOTA. Importantly, mouse imaging data showed that the NEPC and CRPC xenografts exhibited similar signal strength with 68Ga-IRM-015-DOTA, but 68Ga-PSMA-11 only stained the CRPC xenografts. Furthermore, target specificity was elucidated by a blocking experiment on a CDK19-bearing tumor xenograft. These data concluded that 68Ga-CDK19 PET/CT was an effective technology to detect lesions with or without PSMA in vitro, in vivo, and in the PDX model. CONCLUSION: Thus, we have generated a novel PET small molecule with predictive value for prostate cancer. The findings indicate that 68Ga-CDK19 may merit further evaluation as a predictive biomarker for PET scans in prospective cohorts and may facilitate the identification of molecular types of prostate cancer independent of PSMA.

Lysine-specific Demethylase 6A Upregulates Cadherin-1 and Accelerates Gastric Cancer Growth.

BACKGROUND: Gastric cancer (GC) ranks fifth among all common malignancies globally. Genetic research has revealed several genes that are frequently dis-regulated in GC, such as lysine-specific demethylase 6A (KDM6A) and cadherin-1 (CDH1). OBJECTIVE: This study aimed to examine the expression profile and role of KDM6A in GC, as well as the molecular pathway involved. METHODS: The expression profile and overall survival data of KDM6A were retrieved from the TCGA database. Expression levels of KDM6A were also measured in GC patient samples and compared with those of healthy controls. Furthermore, stable silencing of KDM6A was introduced into the GC cell line NCI-N87, followed by assessments of cell proliferation, migration and invasion, in the xenograft mouse model. The metastatic status of mice injected with NCI-N87 cells was also analyzed. RESULTS: In patients diagnosed with GC, KDM6A was upregulated. Silencing KDM6A reduced the proliferation, migration and invasion of cells, as well as the growth of xenograft tumors. KDM6A knockdown also inhibited metastatic behaviors of injected NCI-N87 cells, as well as elevated CDH1 expression, leading to reversed epithelial-mesenchymal transition. CONCLUSION: KDM6A serves as an oncogene in GC and exerts its pro-tumor functions by repressing the expression of CDH1.

Ferrostatin-1 mitigates ionizing radiation-induced intestinal injuries by inhibiting apoptosis and ferroptosis: an in vitro and in vivo study.

PURPOSE: Intestinal injuries caused by ionizing radiation (IR) are a major complication of radiotherapy. Ferrostatin-1 (Fer-1) exerts antioxidant and anti-inflammatory effects. We investigated the influence of Fer-1 on IR-induced intestinal damage and explored the possible mechanisms. MATERIALS AND METHODS: IEC-6 cells were administrated with Fer-1 for 30 min and subsequently subjected to 9.0 Gy-irradiation. Flow cytometry, qPCR, and WB were used to detect changes. For in vivo experiments, Fer-1 was given intraperitoneally to mice at 1 h before and 24 h after 9.0 Gy total body irradiation (TBI) respectively. Three days after TBI, the small intestines were isolated for analysis. The diversity and composition of the gut microbiota were analyzed by 16S rRNA gene sequencing. RESULTS: In vitro, Fer-1 protected IEC-6 cells from IR injury by reducing the production of ROS and inhibiting both ferroptosis and apoptosis. In vivo, Fer-1 enhanced the survival rates of mice subjected to lethal doses of IR and restored intestinal structure and physiological function. Further investigation showed that Fer-1 protected IEC-6 cells and mice by inhibiting the p53-mediated apoptosis signaling pathway and restoring the gut-microbe balance. CONCLUSION: This study confirms that Fer-1 protects intestinal injuries through suppressing apoptosis and ferroptosis.

Discovery of the radio-protecting effect of Ecliptae Herba, its constituents and targeting p53-mediated apoptosis in vitro and in vivo.

Radiation protection drugs are often accompanied by toxicity, even amifostine, which has been the dominant radio-protecting drug for nearly 30 years. Furthermore, there is no therapeutic drug for radiation-induced intestinal injury (RIII). This paper intends to find a safe and effective radio-protecting ingredient from natural sources. The radio-protecting effect of Ecliptae Herba (EHE) was discovered preliminarily by antioxidant experiments and the mouse survival rate after 137Cs irradiation. EHE components and blood substances in vivo were identified through UPLC‒Q-TOF. The correlation network of "natural components in EHE-constituents migrating to blood-targets-pathways" was established to predict the active components and pathways. The binding force between potential active components and targets was studied by molecular docking, and the mechanism was further analyzed by Western blotting, cellular thermal shift assay (CETSA), and ChIP. Additionally, the expression levels of Lgr5, Axin2, Ki67, lysozyme, caspase-3, caspase-8,8-OHdG, and p53 in the small intestine of mice were detected. It was found for the first time that EHE is active in radiation protection and that luteolin is the material basis of this protection. Luteolin is a promising candidate for RⅢ. Luteolin can inhibit the p53 signaling pathway and regulate the BAX/BCL2 ratio in the process of apoptosis. Luteolin could also regulate the expression of multitarget proteins related to the same cell cycle.

A-Kinase Anchoring Protein 9 Promotes Gastric Cancer Progression as a Downstream Effector of Cadherin 1.

Background: Genetic studies identified a dozen of frequently mutated genes in gastric cancer, such as cadherin 1 (CDH1) and A-kinase anchoring protein 9 (AKAP9). Of note, genetic alterations including depletion and amplification frameshift mutations of AKAP9 have been observed in 10-15% of gastric cancer patients. However, it is unknown of the expression and role of AKAP9 in gastric cancer. This study is aimed to characterize the expression and function of AKAP9 in gastric cancer. Methods: Using qRT-PCR, we analyzed the mRNA levels of AKAP9 in gastric cancer patient samples. We investigated the role of AKAP9 in gastric cancer by performing cell proliferation assay, transwell assay, and mouse xenograft assay. Results: AKAP9 was upregulated in gastric cancer patients. Overexpression of AKAP9 promoted cell proliferation, migration, and gastric tumor growth. Loss of CDH1 elevated AKAP9 mRNA and protein levels. Conclusion: Our study demonstrates that AKAP9 functions as an oncoprotein to promote gastric cancer cell proliferation, migration, and tumor growth. Moreover, we reveal a possible molecular link showing that AKAP9 is a critical effector downstream of CDH1 in gastric cancer.

The protective effects of Xuebijing injection on intestinal injuries of mice exposed to irradiation.

BACKGROUND: Gastrointestinal (GI) injury is one of the most common side effects of radiotherapy. However, there is no ideal therapy method except for symptomatic treatment in the clinic. Xuebijing (XBJ) is a traditional Chinese medicine, used to treat sepsis by injection. In this study, the protective effects of XBJ on radiation-induced intestinal injury (RIII) and its mechanism were explored. METHODS: The effect of XBJ on survival of irradiated C57BL/6 mice was monitored. Histological changes including the number of crypts and the length of villi were evaluated by H&E. The expression of Lgr5+ intestinal stem cells (ISCs), Ki67+ cells, villin and lysozymes were examined by immunohistochemistry. The expression of cytokines in the intestinal crypt was detected by RT-PCR. DNA damage and apoptosis rates in the small intestine were also evaluated by immunofluorescence. RESULTS: In the present study, XBJ improved the survival rate of the mice after 8.0 and 9.0 Gy total body irradiation (TBI). XBJ attenuated structural damage of the small intestine, maintained regenerative ability and promoted proliferation and differentiation of crypt cells, decreased apoptosis rate and reduced DNA damage in the intestine. Elevation of IL-6 and TNF-α was limited, but IL-1, TNF-𝛽 and IL-10 levels were increased in XBJ-treated group after irradiation. The expression of Bax and p53 were decreased after XBJ treatment. CONCLUSIONS: Taken together, XBJ provides a protective effect on RIII by inhibiting inflammation and blocking p53-related apoptosis pathway.

FOXO4 peptide targets myofibroblast ameliorates bleomycin-induced pulmonary fibrosis in mice through ECM-receptor interaction pathway.

Pulmonary fibrosis (PF) is a progressive interstitial lung disease with limited treatment options. The incidence and prevalence of PF is increasing with age, cell senescence has been proposed as a pathogenic driver, the clearance of senescent cells could improve lung function in PF. FOXO4-D-Retro-Inverso (FOXO4-DRI), a synthesis peptide, has been reported to selectively kill senescent cells in aged mice. However, it remains unknown if FOXO4-DRI could clear senescent cells in PF and reverse this disease. In this study, we explored the effect of FOXO4-DRI on bleomycin (BLM)-induced PF mouse model. We found that similar as the approved medication Pirfenidone, FOXO4-DRI decreased senescent cells, downregulated the expression of senescence-associated secretory phenotype (SASP) and attenuated BLM-induced morphological changes and collagen deposition. Furthermore, FOXO4-DRI could increase the percentage of type 2 alveolar epithelial cells (AEC2) and fibroblasts, and decrease the myofibroblasts in bleomycin (BLM)-induced PF mouse model. Compared with mouse and human lung fibroblast cell lines, FOXO4-DRI is inclined to kill TGF-ß-induced myofibroblast in vitro. The inhibited effect of FOXO4-DRI on myofibroblast lead to a downregulation of extracellular matrix (ECM) receptor interaction pathway in BLM-induced PF. Above all, FOXO4-DRI ameliorates BLM-induced PF in mouse and may be served as a viable therapeutic option for PF.

Analysis of bowel function, urogenital function, and long-term follow-up outcomes associated with robotic and laparoscopic sphincter-preserving surgical approaches to total mesorectal excision in low rectal cancer: a retrospective cohort study.

OBJECTIVE: The present study comparatively analyzed short-term clinical effectiveness and long-term follow-up endpoints associated with robotic-assisted sphincter-preserving surgery (RAS) and laparoscopic-assisted sphincter-preserving surgery (LAS) when used to treat low rectal cancer. METHOD: Within such a single-center retrospective cohort analysis, low rectal cancer patients that underwent RAS (n=200) or LAS (n=486) between January 2015 and beginning of July 2018 were enrolled. RESULTS: The mean operative durations in the RAS and LAS cohorts were 249±64 min and 203±47 min, respectively (P<0.001). Temporary ileostomy rates in the RAS and LAS cohorts were 64.5% and 51.6% (P = 0.002). In addition, major variations across such cohorts regarding catheter removal timing, time to liquid intake, time to first leaving bed, and length of hospitalization (all P<0.001). This distal resection margin distance within the RAS cohort was diminished in comparison to LAS cohort (P=0.004). For patients within the LAS cohort, the time required to recover from reduced urinary/female sexual function was > 6 months post-surgery (P<0.0001), whereas within the RAS cohort this interval was 3 months (P<0.0001). At 6 months post-surgery, male sexual function within RAS cohort was improved in comparison to LAS cohort (P<0.001). At 6 months post-surgery, Wexner scores revealed similar results (P<0.001). No major variations within overall or disease-free survival were identified across these cohorts at 3 or 5 years post-surgery. CONCLUSION: Robotic sphincter-preserving surgery is a safe and effective surgical technique in low rectal patients in terms of postoperative oncological safety and long-term endpoints. And the RAS strategy provides certain additional benefits with respect to short-term urogenital/anorectal functional recovery in treated patients compared to LAS.

Application of Laparoscopic Gastric Jejunum Uncut Roux-en-Y Anastomosis.

Background: Uncut Roux-en-Y gastrojejunostomy, recently developed in China, is useful in the treatment of distal gastric cancer. This study is aimed at comparing laparoscopic gastric jejunum uncut Roux-en-Y anastomosis with conventional anastomosis in the surgical treatment of distal gastric malignancy. Methods: In this retrospective study, the clinical data of 178 patients and their follow-up records were analyzed. 112 cases (uncut group) were the observation group for stomach jejunum uncut Roux-en-Y anastomosis, the control group for the stomach, 66 cases (conventional group) were for jejunum Roux-en-Y anastomosis and Billroth I and Billroth II anastomosis. A comparison between the two groups was conducted based on the general situation of the patients, TNM stage, and one-year survival rate. Results: There was no significant difference reported between the two groups in terms of the general situation and TNM stage. A comparison on postoperative complications between the two groups revealed that the postoperative bleeding was 0.9% and 6.1%, the bile reflux gastritis was 1.8% and 9.1%, the anastomotic leakage was 0.0% and 3.0%, the delayed gastric emptying was 0.9% and 7.6%, and the overall complications was at 3.6% and 25.8%, which was significantly lower in the observation group than in the control group, and the difference was statistically significant. Notably, there was no significant difference in 1-year survival rate between the two groups. Conclusion: Laparoscopic gastric jejunal uncut Roux-en-Y anastomosis significantly reduces the risk of postoperative complications of the digestive tract. Its operation is easy and exhibits an effective curative effect.

MST1/2 inhibitor XMU-MP-1 alleviates the injury induced by ionizing radiation in haematopoietic and intestinal system.

The Hippo signalling pathway has been considered as potential therapeutic target in self-renewal and differentiation of stem and progenitor cells. Thus, mammalian Ste20-like kinase 1/2 (MST1/2) as the core serine-threonine kinases in the Hippo signalling pathway has been investigated for its role in immunological disease. However, little information of MST1/2 function in bone marrow suppression induced by ionizing radiation was fully investigated. Here, we reported that MST1/2 inhibitor XMU-MP-1 could rescue the impaired haematopoietic stem cells (HSCs) and progenitor cells (HPCs) function under oxidative stress condition. Also, XMU-MP-1 pretreatment markedly alleviated the small intestinal system injury caused by the total body irradiation 9 Gy and extended the average survival days of the mice exposed to the lethal dose radiation. Therefore, irradiation exposure causes the serious pathological changes of haematopoietic and intestinal system, and XMU-MP-1 could prevent the ROS production, the haematopoietic cells impairment and the intestinal injury. These detrimental effects may be associated with regulating NOX/ROS/P38MARK pathway by MST1/2.

Novel PHD2/HDACs hybrid inhibitors protect against cisplatin-induced acute kidney injury.

Acute kidney injury (AKI) is associated with high morbidity and mortality. Cisplatin is a common chemotherapeutic, but its nephrotoxicity-driven AKI limits its clinical application. Currently, there are no specific and satisfactory therapies in the clinic for AKI. Inhibitors of hypoxia-inducible factor prolyl hydroxylase 2 (HIF-PHD2) or histone deacetylase (HDACs) had shown renoprotective effects against AKI in preclinical studies. This study aimed to develop a novel therapeutic to prevent AKI progression by targeting PHD2 and HDACs simultaneously. We designed and synthesized a series of PHD2/HDACs hybrid inhibitors. The initial drug activity screening identified a candidate compound 31c, which exhibited potent inhibitory activities against PHD2 and HDAC1/2/6. Cellular analyses further showed that 31c did not affect cisplatin's antitumor activity in cancer cells but strongly protected cisplatin-induced toxicity on HK-2 cells. In vivo studies with the cisplatin-induced AKI mouse model demonstrated that 31c remarkably alleviated kidney dysfunction with suppressed plasma BUN/SCr and increased EPO levels. The potent renoprotective effects of 31c on AKI were confirmed by significant improvements in pathological kidney conditions in the mouse model. These results suggest that the novel PHD2/HDACs hybrid inhibitor, 31c, has a clinical potential as the renoprotective agent for the treatment/prevention of cisplatin-induced AKI for various cancers.

Sex Differences of Radiation Damage in High-Fat-Diet-Fed Mice and the Regulatory Effect of Melatonin.

The consumption of a high-fat diet (HFD) and exposure to ionizing radiation (IR) are closely associated with many diseases. To evaluate the interaction between HFDs and IR-induced injury, we gave mice whole abdominal irradiation (WAI) to examine the extent of intestinal injury under different dietary conditions. Melatonin (MLT) is a free radical scavenger that effectively prevents hematopoietic, immune, and gastrointestinal damage induced by IR. However, its effects on WAI-induced intestinal injury in HFD-fed mice remain unclear. We demonstrated that MLT can promote intestinal structural repair following WAI and enhance the regeneration capacity of Lgr5+ intestinal stem cells. In addition, we investigated the effects of radiation damage on sexual dimorphism in HFD-fed mice. The results showed that the degree of IR-induced intestinal injury was more severe in the HFD-fed female mice. MLT preserved the intestinal microbiota composition of HFD-fed mice and increased the abundance of Bacteroides and Proteobacteria in male and female mice, respectively. In conclusion, MLT may reduce the negative effects of HFD and IR, thereby providing assistance in preserving the structure and function of the intestine.