Adipose-derived stem cells ameliorate radiation-induced lung injury by activating the DDAH1/ADMA/eNOS signaling pathway.

Background: Ionizing radiation-induced lung injury is caused by the initial inflammatory reaction and leads to advanced fibrosis of lung tissue. Adipose-derived stem cells (ASCs) are a type of mesenchymal stem cell that can differentiate into various functional cell types with broad application prospects in the treatment of tissue damage. The purpose of this study was to explore the protective effect of ASCs against radiation-induced lung injury and to provide a novel basis for prevention and treatment of radiation-induced lung injury. Materials and methods: Fifty mice were randomly divided into a control group (Ctrl), radiation exposure group (IR), radiation exposure plus ASC treatment group (IR + ASC), radiation exposure plus L-257 group (IR + L-257), and radiation exposure plus ASC treatment and L-257 group (IR + ASC + L-257). Mice in IR, IR + ASC, and IR + ASC + L-257 groups were exposed to a single whole-body dose of 5 Gy X-rays (160 kV/25 mA, 1.25 Gy/min). Within 2 h after irradiation, mice in IR + ASC and IR + ASC + L-257 groups were injected with 5 × 106 ASCs via the tail vein. Mice in IR + L-257 and IR + ASC + L-257 groups were intraperitoneally injected with 30 mg/kg L-257 in 0.5 mL saline. Results: The mice in the IR group exhibited lung hemorrhage, edema, pulmonary fibrosis, and inflammatory cell infiltration, increased release of proinflammatory cytokines, elevation of oxidative stress and apoptosis, and inhibition of the dimethylarginine dimethylamino hydratase 1 (DDAH1)/ADMA/eNOS signaling pathway. ASC treatment alleviated radiation-induced oxidative stress, apoptosis, and inflammation, and restored the DDAH1/ADMA/eNOS signaling pathway. However, L-257 pretreatment offset the protective effect of ASCs against lung inflammation, oxidative stress, and apoptosis. Conclusions: These data suggest that ASCs ameliorate radiation-induced lung injury, and the mechanism may be mediated through the DDAH1/ADMA/eNOS signaling pathway.

TAB182 regulates glycolytic metabolism by controlling LDHA transcription to impact tumor radiosensitivity.

Metabolic reprogramming, a hallmark of cancer, is closely associated with tumor development and progression. Changes in glycolysis play a crucial role in conferring radiation resistance to tumor cells. How radiation changes the glycolysis status of cancer cells is still unclear. Here we revealed the role of TAB182 in regulating glycolysis and lactate production in cellular response to ionizing radiation. Irradiation can significantly stimulate the production of TAB182 protein, and inhibiting TAB182 increases cellular radiosensitivity. Proteomic analysis indicated that TAB182 influences several vital biological processes, including multiple metabolic pathways. Knockdown of TAB182 results in decreased lactate production and increased pyruvate and ATP levels in cancer cells. Moreover, knocking down TAB182 reverses radiation-induced metabolic changes, such as radioresistant-related lactate production. TAB182 is necessary for activating LDHA transcription by affecting transcription factors SP1 and c-MYC; its knockdown attenuates the upregulation of LDHA by radiation, subsequently suppressing lactate production. Targeted suppression of TAB182 significantly enhances the sensitivity of murine xenograft tumors to radiotherapy. These findings advance our understanding of glycolytic metabolism regulation in response to ionizing radiation, which may offer significant implications for developing new strategies to overcome tumor radioresistance.

Competitive Risk Model Nomogram to Predict Prognosis in Patients Aged Over 65 Years with nonmetastatic Cervical Cancer: A SEER Population-Based Study.

Objective: The prognostic factors for elderly patients with cervical cancer differ from those of younger patients. Competitive risk events could cause biases in the Cox proportional hazards (PH) model. This study aimed to construct a competitive risk model (CRM) nomogram for patients aged > 65 years with nonmetastatic cervical cancer. Methods: We retrospectively analyzed data extracted from the Surveillance, Epidemiology, and End Results (SEER) database and a total of 1856 patients from 18 cancer registries across the United States diagnosed between 2010 and 2015 were included. Kaplan-Meier analysis and log-rank tests were used to compare intergroup survival. Univariate and multivariate Cox proportional regression analyses were performed to identify independent prognostic factors. The cumulative incidence function (CIF) and Fine and Gray's test were used to determine the impact of competitive risk events on prognosis. The CRM nomogram was internally and externally validated using time-dependent receiver operator characteristic (ROC) curve (time-AUC), Brier scores, Harrell's concordance index (C-index), calibration curve, and decision curve analysis (DCA). Results: Analyses revealed that histology, age, the International Federation of Gynaecologists and Obstetricians (FIGO) stage, number of in situ malignancies, chemotherapy, radiotherapy (RT), and surgery were independent prognostic factors. The CRM nomogram accurately predicted 1-year, 3-year, and 5-year disease-specific survival (DSS). The C-indexes and Brier scores of the CRM nomogram were 0.641 and 0.094, respectively, at the 1-year cut-off in the training set. The time-AUC of the CRM nomogram at the 1-year, 3-year, and 5-year intervals in the training set were 77.6%, 77.3%, and 74.5%, respectively. The calibration curve demonstrated a favorable concordance. DCA suggested that the nomogram had a good net benefit. Therefore, the Cox model underestimated the weight of risk factors compared to CRM. Conclusions: This study presents the CRM nomogram to predict DSS in patients aged > 65 years with nonmetastatic cervical cancer. It can help clinicians implement more accurate personalized diagnostic and treatment modalities for elderly patients with cervical cancer.

Irradiation-Induced Intestinal Injury is Associated With Disorders of Bile Acids Metabolism.

PURPOSE: Intestinal injury commonly occurs in radiation therapy, but its pathogenesis is not well understood. The relationship between irradiation-induced intestinal injury and bile acids (BAs) metabolism remains elusive. This study intends to clarify the role of BAs metabolism in irradiation-induced intestinal injury and the potential for supplementation with BAs to alleviate this injury. MATERIALS AND METHODS: BAs metabolomic analysis of fecal pellets from normal and 12 Gy γ-ray total abdominal irradiation (TAI) treated mice was performed. The effects of a crude bile extract (BAmix) or lithocholic acid (LCA) on mice exposed to 12 Gy γ-ray TAI were determined by analyzing weight loss, colon length, villus length, crypt number, and the expression of leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) and yes-associated protein 1 (YAP1). The effects of BAmix or LCA on intestinal organoids after 4 Gy irradiation were analyzed. ELISA assay was applied to test IL-1ß, IL-6 and TNF-α levels in mouse intestine. The expression changes of G protein-coupled receptor 1 (TGR5) and YAP1 in the colonic mucosa of patients with radiation-induced intestinal injury were determined by IHC. RESULTS: The relative abundance of secondary BAs was decreased while the relative abundance of primary BAs was increased in irradiated mice, and LCA was the most obvious change. BAmix and LCA alleviated irradiation-induced intestinal injury in a mouse model, as reflected by reduced body weight loss, longer colon, higher villus, more crypts, and increased Lgr5 expression. In intestinal organoids, BAmix and LCA enhanced newborn crypts formation after irradiation. LCA treatment improved the expression of TGR5 and YAP1 in mouse intestinal crypts. LCA has potential to reduce the inflammation levels in irradiated mice. Additionally, the expression levels of TGR5 and YAP1 in the colonic mucosa of patients with radiation enteritis were also significantly decreased. CONCLUSIONS: Radiation-induced intestinal injury is associated with disorders of BAs metabolism, and treatment with LCA had a protective effect against radiation-induced intestinal injury in mice by modulating TGR5 and YAP1.

LPAR5 confers radioresistance to cancer cells associated with EMT activation via the ERK/Snail pathway.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a critical event contributing to more aggressive phenotypes in cancer cells. EMT is frequently activated in radiation-targeted cells during the course of radiotherapy, which often endows cancers with acquired radioresistance. However, the upstream molecules driving the signaling pathways of radiation-induced EMT have not been fully delineated. METHODS: In this study, RNA-seq-based transcriptome analysis was performed to identify the early responsive genes of HeLa cells to γ-ray irradiation. EMT-associated genes were knocked down by siRNA technology or overexpressed in HeLa cells and A549 cells, and the resulting changes in phenotypes of EMT and radiosensitivity were assessed using qPCR and Western blotting analyses, migration assays, colony-forming ability and apoptosis of flow cytometer assays. RESULTS: Through RNA-seq-based transcriptome analysis, we found that LPAR5 is downregulated in the early response of HeLa cells to γ-ray irradiation. Radiation-induced alterations in LPAR5 expression were further revealed to be a bidirectional dynamic process in HeLa and A549 cells, i.e., the early downregulating phase at 2 ~ 4 h and the late upregulating phase at 24 h post-irradiation. Overexpression of LPAR5 prompts EMT programing and migration of cancer cells. Moreover, increased expression of LPAR5 is significantly associated with IR-induced EMT and confers radioresistance to cancer cells. Knockdown of LPAR5 suppressed IR-induced EMT by attenuating the activation of ERK signaling and downstream Snail, MMP1, and MMP9 expression. CONCLUSIONS: LPAR5 is an important upstream regulator of IR-induced EMT that modulates the ERK/Snail pathway. This study provides further insights into understanding the mechanism of radiation-induced EMT and identifies promising targets for improving the effectiveness of cancer radiation therapy.

Effects of astrocytes and microglia on neuroinflammation after spinal cord injury and related immunomodulatory strategies.

Spinal cord injury (SCI) is a catastrophic event which is still without adequate therapies. Neuroinflammation is the main pathogenesis of secondary damage post-SCI, leading to tissue loss and neurological dysfunction. Previous studies have shown that microglia and astrocytes are the major immune cells in the central nervous system (CNS) and play a crucial role in modulating neuroinflammatory responses. In this study, we mainly review the effects of neuroinflammation in SCI, focusing on the contributions of microglia and astrocytes and their cross-talk. Furthermore, we will also discuss therapeutic strategies on how to regulate their immunophenotype to suppress robust inflammation and facilitate injury prognosis.

Diagnosis and treatment of focal fibrocartilaginous dysplasia of the distal ulna.

Focal fibrocartilaginous dysplasia (FFCD) of the distal ulna is a rare benign lesion resulting in progressive radiocapitellar dislocation, limb deformity and limitation in function. This study reported our experience with 10 cases and it aimed to determine a reasonable strategy for diagnosis and treatment. Ten cases treated from 2010 to 2018 in our department were retrospectively reviewed. The diagnosis was based on imaging features. All patients underwent lesion excision in the early stage and five patients required ulna lengthening in the second stage. The radiographic and functional outcomes were analyzed and reported. The median age at diagnosis was 32 months (range, 6-36 months). The median age at the time of surgery was 34 months (range, 10-40 months). The median clinical and radiographic follow-up period was 37 months (range, 24-50 months). The ulna was shortened by an average of 31 mm (range, 27-35 mm). There was no new radial head dislocation after lesion excision. For five cases of radial head dislocation, the median elbow varus angle before ulnar lengthening was 20° and it decreased to 5° after ulnar lengthening. Supination and pronation of the elbow increased from 50°-10° to 70°-30°. We believe that early excision of the lesion can prevent radiocapitellar joint dislocation in patients with FFCD of the ulna. Ulna lengthening can correct limb deformity and improve the range of motion.

ZGRF1 promotes end resection of DNA homologous recombination via forming complex with BRCA1/EXO1.

To maintain genomic stability, the mammalian cells has evolved a coordinated response to DNA damage, including activation of DNA repair and cell cycle checkpoint processes. Exonuclease 1 (EXO1)-dependent excision of DNA ends is important for the initiation of homologous recombination (HR) repair of DNA breaks, which is thought to play a key role in activating the ATR-CHK1 pathway to induce G2/M cell cycle arrest. But the mechanism is still not fully understood. Here, we report that ZGRF1 forms complexes with EXO1 as well as other repair proteins and promotes DNA repair through HR. ZGRF1 is recruited to DNA damage sites in a MDC1-RNF8-BRCA1 dependent manner. Furthermore, ZGRF1 is important for the recruitment of RPA2 to DNA damage sites and the following ATR-CHK1 mediated G2/M checkpoint in response to irradiation. ZGRF1 null cells show increased sensitivity to many DNA-damaging agents, especially PARPi and irradiation. Collectively,our findings identify ZGRF1 as a novel regulator of DNA end resection and G2/M checkpoint. ZGRF1 is a potential target of radiation and PARPi cancer therapy.

Pretreatment with metformin protects mice from whole-body irradiation.

Metformin, a first-line oral drug for type II diabetes mellitus, not only reduces blood glucose levels, but also has many other biological effects. Recent studies have been conducted to determine the protective effect of metformin in irradiation injuries. However, the results are controversial and mainly focus on the time of metformin administration. In this study, we aimed to investigate the protective effect of metformin in BALB/c mice exposed to 6 Gy or 8 Gy of a 60Co source of γ-rays for total body irradiation (TBI). Survival outcomes were assessed following exposure to 8 Gy or 6 Gy TBI, and hematopoietic damage and intestinal injury were assessed after exposure to 6 Gy TBI. Metformin prolonged the survival of mice exposed to 8 Gy TBI and improved the survival rate of mice exposed to 6 Gy TBI only when administered before exposure to irradiation. Moreover, pretreatment with metformin reduced the frequency of micronuclei (MN) in the bone marrow of mice exposed to 6 Gy TBI. Pretreatment of metformin also protected the intestinal morphology of mice, reduced inflammatory response and decreased the number of apoptotic cells in intestine. In conclusion, we demonstrated that pretreatment with metformin could alleviate irradiation injury.

Nanocage-Based N-Rich Metal-Organic Framework for Luminescence Sensing toward Fe3+ and Cu2+ Ions.

Luminescent metal-organic frameworks (LMOFs) as sensors showing highly efficient detection toward toxic heavy-metal ions are in high demand for human health and environmental protection. A novel nanocage-based N-rich LMOF (LCU-103) has been constructed and characterized. It is a 2-fold interpenetrating structure built from N-rich {Zn6(dttz)4} nanocages extended by N-donor ligand Hdpa [H3dttz = 4,5-di(1H-tetrazol-5-yl)-2H-1,2,3-triazole; Hdpa = 4,4'-dipyridylamine]. Notably, LCU-103 contains abundant N functional sites anchoring on both the windows of nanocages and the inner channels of the framework that can interact with metal ions and then recognize them. As a result, it can serve as a luminescent sensing material for detecting trace amounts of Fe3+ and Cu2+ ions with low limits of detection (LODs) of 1.45 and 1.66 µM, respectively, through a luminescent quenching mechanism. Meanwhile, LCU-103 as a LMOF sensor exhibits several advantages such as high sensitivity, appropriate selectivity (for Fe3+ in H2O), recycling stability, and fast response times in N,N-dimethylformamide. Moreover, LCU-103 also displays good luminescent quenching activity toward Fe3+ in H2O and a simulated 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid biological system with low LODs of 1.51 and 1.52 µM, respectively. LCU-103 test papers were further prepared to offer easy and real-time detection of Fe3+ and Cu2+ ions. Importantly, when density functional theory calculations and multiple experimental evidence, including X-ray photoelectron spectroscopy, UV-vis absorption, luminescence decay lifetimes, and quantum efficiencies, are combined, a preferred N-donor site and possible weak interaction sensing mechanism is also proposed to elucidate the quenching effect.

Contribution of Staphylococcal Enterotoxin B to Staphylococcus aureus Systemic Infection.

Staphylococcal enterotoxin B (SEB), which is produced by the major human pathogen, Staphylococcus aureus, represents a powerful superantigenic toxin and is considered a bioweapon. However, the contribution of SEB to S. aureus pathogenesis has never been directly demonstrated with genetically defined mutants in clinically relevant strains. Many isolates of the predominant Asian community-associated methicillin-resistant S. aureus lineage sequence type (ST) 59 harbor seb, implying a significant role of SEB in the observed hypervirulence of this lineage. We created an isogenic seb mutant in a representative ST59 isolate and assessed its virulence potential in mouse infection models. We detected a significant contribution of seb to systemic ST59 infection that was associated with a cytokine storm. Our results directly demonstrate that seb contributes to S. aureus pathogenesis, suggesting the value of including SEB as a target in multipronged antistaphylococcal drug development strategies. Furthermore, they indicate that seb contributes to fatal exacerbation of community-associated methicillin-resistant S. aureus infection.

[Predictive value of comprehensive preoperative evaluation for the outcome of TURP].

Objective: To evaluate preoperative comprehensive examinations of the IPSS-voiding to storage subscore ratio (IPSS-V/S), maximum urinary flow rate (Qmax), intravesical prostatic protrusion (IPP) and postvoid residual urine volume (PVR) in predicting the outcome of transurethral resection of the prostate (TURP) for BPH. METHODS: This retrospective study included 103 cases of BPH treated by TURP in Yixing People's Hospital from December 2018 to December 2019. The patients averaged 71.92 ± 7.73 years of age, with a mean prostate volume of (58.34 ± 15.59) ml, preoperative IPSS of 23.38 ± 3.36, voiding score of 14.38 ± 2.69, storage score of 9 (8－10), V/S ratio of 1.67 (1.43－1.88), Qmax of 7 (5－8) ml/s, IPP of 4 (0－5) mm, and PVR of (117.03 ± 20.51) ml. The TURP operations were completed by the same surgeon, with mean operation time of (83.65 ± 14.31) min and intraoperative blood loss of (55.32 ± 18.92) ml. The patients were followed up for 3 months after surgery for evaluation of the outcomes based on the IPSS and quality of life (QOL) scores. RESULTS: The postoperative IPSS was significantly improved in all the patients compared with the baseline (5.36 ± 1.95 vs 23.38 ± 3.36, P < 0.05). Based on the criteria of IPSS < 7 and general satisfaction with QOL, satisfactory results were achieved in 71 (68.93%) of the patients (aged 71.04 ± 7.23 years, prostate volume: ï¼»59.68 ± 15.79ï¼½ ml, IPSS: 23.87 ± 3.42, voiding score: 14.87 ± 2.34, storage score: 9 ï¼»8－10ï¼½, V/S ratio: 1.67 ï¼»1.47－1.86ï¼½, Qmax: 6 ï¼»4－7ï¼½ ml/s, IPP: 5 ï¼»0－6ï¼½ mm, PVR: 110.53 ± 17.69 ml, operation time ï¼»85.37 ± 12.28ï¼½ min, intraoperative blood loss: ï¼»58.08 ± 14.61ï¼½ ml), and unsatisfactory results in the other 32 (31.07%) (aged 76.91 ± 8.25 years, prostate volume: ï¼»55.38 ± 14.73ï¼½ ml, IPSS: 22.53 ± 3.25, voiding score: 13.53 ± 3.21, storage score: 9 ï¼»8－12ï¼½, V/S ratio: 1.36 ï¼»1.03－1.95ï¼½, Qmax: 8 ï¼»7－9ï¼½ ml/s, IPP: 0 ï¼»0－5ï¼½ mm, PVR: ï¼»129.61 ± 20.62ï¼½ ml, operation time: ï¼»78.85 ± 10.04ï¼½ min, intraoperative blood loss: 48.76 ± 12.19 ml). CONCLUSIONS: TURP yields better results in younger BPH patients, with baseline IPSS dominantly in urinary symptoms, greater IPP, lower PVR, and lower Qmax.

TIP60 K430 SUMOylation attenuates its interaction with DNA-PKcs in S-phase cells: Facilitating homologous recombination and emerging target for cancer therapy.

Nonhomologous end joining (NHEJ) and homologous recombination (HR) are major repair pathways of DNA double-strand breaks (DSBs). The pathway choice of HR and NHEJ is tightly regulated in cellular response to DNA damage. Here, we demonstrate that the interaction of TIP60 with DNA-PKcs is attenuated specifically in S phase, which facilitates HR pathway activation. SUMO2 modification of TIP60 K430 mediated by PISA4 E3 ligase blocks its interaction with DNA-PKcs, whereas TIP60 K430R mutation recovers its interaction with DNA-PKcs, which results in abnormally increased phosphorylation of DNA-PKcs S2056 in S phase and marked inhibition of HR efficiency, but barely affects NHEJ activity. TIP60 K430R mutant cancer cells are more sensitive to radiation and PARP inhibitors in cancer cell killing and tumor growth inhibition. Collectively, coordinated regulation of TIP60 and DNA-PKcs facilitates HR pathway choice in S-phase cells. TIP60 K430R mutant is a potential target of radiation and PARPi cancer therapy.

Challenges in Quantifying Air-Water Carbon Dioxide Flux Using Estuarine Water Quality Data: Case Study for Chesapeake Bay.

Estuaries play an uncertain but potentially important role in the global carbon cycle via CO2 outgassing. The uncertainty mainly stems from the paucity of studies that document the full spatial and temporal variability of estuarine surface water partial pressure of carbon dioxide ( pCO2). Here, we explore the potential of utilizing the abundance of pH data from historical water quality monitoring programs to fill the data void via a case study of the mainstem Chesapeake Bay (eastern United States). We calculate pCO2 and the air-water CO2 flux at monthly resolution from 1998 to 2018 from tidal fresh to polyhaline waters, paying special attention to the error estimation. The biggest error is due to the pH measurement error, and errors due to the gas transfer velocity, temporal sampling, the alkalinity mixing model, and the organic alkalinity estimation are 72%, 27%, 15%, and 5%, respectively, of the error due to pH. Seasonal, interannual, and spatial variability in the air-water flux and surface pCO2 is high, and a correlation analysis with oxygen reveals that this variability is driven largely by biological processes. Averaged over 1998-2018, the mainstem bay is a weak net source of CO2 to the atmosphere of 1.2 (1.1, 1.4) mol m-2 yr-1 (best estimate and 95% confidence interval). Our findings suggest that the abundance of historical pH measurements in estuaries around the globe should be mined in order to constrain the large spatial and temporal variability of the CO2 exchange between estuaries and the atmosphere.

Salidroside induces apoptosis and triggers endoplasmic reticulum stress in human hepatocellular carcinoma.

Salidroside possesses excellent anti-tumor activity in many types of malignant tumor. In present study, we focused on the effects of salidroside on hepatocellular carcinoma (HCC). The viability of human HCC cells was assayed using MTT. Apoptosis in the cells and tissues samples were detected by Annexin V/PI or TUNEL staining assays. The levels of apoptosis and endoplasmic reticulum (ER) stress related proteins were measured by western blotting analysis. We found salidroside significantly suppressed cell viability and promoted apoptosis in HCC cells. Salidroside could activate intrinsic and extrinsic apoptotic pathways, by increasing activities of caspase-3, caspase-8 and caspase-9, up-regulating levels of Bax, Cytochrome c and decreasing level of Bcl-2 in HepG2 cells. Moreover, it was found salidroside induced ER stress and increased expression of p-PERK, eIF2a, p-eIF2a, ATF-6 and CHOP in HepG2 cells. Interestingly, knockdown of CHOP impaired salidroside induced inhibitory effects on HepG2 cells, suggesting the important role of ER stress in cytotoxic effect of salidroside. Finally, we have confirmed salidroside induced ER stress and inhibited development of HepG2 in an xenograft mouse model. In conclusion, our data suggest salidroside inhibits viability and induces apoptosis of HCC both in vitro and vivo, and this effect is partially mediated by activation of ER stress.

[Tetrandrine Induces HL-60 Cell Differentiation].

OBJECTIVE: To investigate the differentiation of acute promyelocytic leukemia (APL) cells induced by Tetrandrine targeting MUC1. METHODS: HL-60 cells at logarithmic growth phase were choosen as object of reaserch and were divided into four groups: control, ATRA, Tetrandrine and ATRA+Tetrandrine group. Cell morphologic changes in each group were observed by microscopy. The change of cell differentiation ability was analyzed by nitro-blue tetrazolium (NBT) reduction test. The expression of cell surface differentiation antigen CD11b was measured by flow cytometry. The expression of MUC1 protein was detected by Western blot. RESULTS: The differentiation of HL-60 cell could be induced by Tetrandrine. The NBT reduction-positive rate of ATRA+Tetrandrine group was significantly higher than that in ATRA group and Tetrandrine group (P<0.05). The percentage of CD11b positive cells in ATRA+Tetrandrine group(43.62％±1.38％) was significantly higher than that in Tetrandrine group(15.25％±2.11％), ATRA group (28.84％±7.53％) and control group(8.16％±1.01％) (P<0.05). The content of MUC1 protein in Tetrandrine group was significantly lower than that in control group and ATRA group (P<0.05). CONCLUSION: Tetrandrine and ATRA can synergize to promote the differentiation and maturation of HL-60 cells, and the mechanism may be related with MUC1 expression.

RBX1 prompts degradation of EXO1 to limit the homologous recombination pathway of DNA double-strand break repair in G1 phase.

End resection of DNA double-strand breaks (DSBs) to form 3' single-strand DNA (ssDNA) is critical to initiate the homologous recombination (HR) pathway of DSB repair. HR pathway is strictly limited in the G1-phase cells because of lack of homologous DNA as the templates. Exonuclease 1 (EXO1) is the key molecule responsible for 3' ssDNA formation of DSB end resection. We revealed that EXO1 is inactivated in G1-phase cells via ubiquitination-mediated degradation, resulting from an elevated expression level of RING-box protein 1 (RBX1) in G1 phase. The increased RBX1 significantly prompted the neddylation of Cullin1 and contributed to the G1 phase-specific degradation of EXO1. Knockdown of RBX1 remarkedly attenuated the degradation of EXO1 and increased the end resection and HR activity in γ-irradiated G1-phase cells, as demonstrated by the increased formation of RPA32, BrdU, and RAD51 foci. And EXO1 depletion mitigated DNA repair defects due to RBX1 reduction. Moreover, increased autophosphorylation of DNA-PKcs at S2056 was found to be responsible for the higher expression level of the RBX1 in the G1 phase. Inactivation of DNA-PKcs decreased RBX1 expression, and simultaneously increased EXO1 expression and DSB end resection in G1-phase cells. This study demonstrates a new mechanism for restraining the HR pathway of DNA DSB repair in G1 phase via RBX1-prompted inactivation of EXO1.

Effect of Modified Chaiqin Wendantang on Blood Glucose Level and Gastrointestinal Dysfunction in Patients with Diabetic Gastroparesis / 中国实验方剂学杂志

Objective:To explore the effect of modified Chaiqin Wendantang on blood glucose level and gastrointestinal dysfunction in patients with diabetic gastroparesis (DGP) of weak spleen and stomach. Method:A total of 138 patients with DGP of weak spleen and stomach in Hainan Provincial Fourth People's Hospital from February 2017 to March 2019 were enrolled, and divided into two groups according to the random number table methods. Both groups received the routine treatment. In addition to this, study group received Chaiqin Wendantang, while control group received domperidone tablets. Traditional Chinese medicine (TCM) syndrome scores, blood glucose, gastrointestinal function, hemorheology index, gastric emptying function and gastric electrical activity, Pittsburgh Sleep Quality Index (PSQI) scale and clinical efficacy were compared. Result:After treatment, TCM symptom scores and total scores decreased (P<0.05), levels of fasting blood glucose (FBG), 2 hours postprandial blood glucose (2 h PBG), and glycated hemoglobin (HbA1c) decreased (P<0.05), serum motilin (MOT) and gastrin (GAS) levels increased (P<0.05), cholecystokinin (CCK) levels decreased (P<0.05), gastric emptying time shortened, frequency, amplitude and rhythm increased (P<0.05), PSQI score decreased (P<0.05), and whole blood viscosity (WBV) and fibrinogen (FIB) levels decreased (P<0.05), all of those changes were more obvious in study group than control group (P<0.05). The total effective rate in study group was higher than that in control group (P<0.05). During the treatment period, there were no obvious adverse reactions in study group, while there were 2 cases of transient dizziness and headache in control group, which were relieved after several seconds. The recurrence rate in study group was lower than that in control group (P<0.05). Conclusion:Modified Chaiqin Wendantang can effectively ameliorate the symptoms of gastric retention, improve sleep quality, control blood glucose levels, and improve hemodynamics for DGP of weak spleen and stomach patients. Besides, it can improve the gastrointestinal function by reducing serum CCK levels, so as to stimulate the secretion of MOT and GAS, increase gastric motility, shorten gastric emptying time, and promote the recovery of gastric electrical activity. With a high safety and low recurrence rate, it has clinical application value.

Analysis of mRNA Expression Patterns in Peripheral Blood Cells of 3 Patients With Cancer After the First Fraction of 2 Gy Irradiation: An Integrated Case Report and Systematic Review.

BACKGROUND: Radiation therapy induces acute and chronic radiological toxicity, in particular hematological toxicity (HT). This study aimed to explore the mechanistic clue and potential predictors at the messenger RNA (mRNA) level. MATERIALS AND METHODS: Peripheral blood was collected from 3 patients with cervical cancer (CC), nasopharynx cancer (NC), and tongue cancer (TC) after the first 2 Gy fraction of radiotherapy (RT). High-throughput sequencing was used to assess mRNA profiles. RESULTS: Eleven genes, such as ALAS2(5-aminolevulinate synthase), SLC4A1(solute carrier family 4 member 1), HBG2(hemoglobin subunit gamma 2), TNFAIP3 (TNF α-induced protein 3), PER1 (period circadian clock 1), CCDC136 (coiled-coil domain containing 136), C9orf84 (chromosome 9 open reading frame 84), IL1B (interleukin 1ß), FOSB (FosB protooncogene), NR4A2 (nuclear receptor subfamily 4), PARP15 (polymerase family member 15), had overlapping expression changes in all 3 cancers of which 3 (ALAS2, FOSB, and HBG2) are suggested as potential predictors for the early diagnosis of HT after RT. CONCLUSIONS: ALAS2, FOSB, and HBG2 may be useful predictors of HT in patients after RT. Eleven overlapping expression mRNAs among 3 cancers might be potential predictors for early diagnosis of radiation toxicity in patients.