Cytotoxicity induced by reactive oxygen species (ROS) is critical for the effectiveness of chemotherapeutic drugs used in the treatment of acute myeloid leukemia (AML). This study aimed to investigate whether ROS contributes to cytotoxicity in AML cells when treated with homoharringtonine (HHT) and etoposide (ETP) in combination.

Previous studies have strongly recommended that KISS-1 metastasis suppressor (KISS1) plays an essential gatekeeper of the initiation of reproductive maturation in mammals. However, KISS1 has been recently reported to highly express in ovarian granulosa cells (GCs). But the biological functionalities of KISS1 on cell apoptosis, cell cycle, and synthesis of estradiol-17β (E2) have not been explored in GCs. In this study, using porcine GCs as a cellular model, the overexpression plasmid of KISS1 was built to explore the biological effects of KISS1 on the PI3K signaling pathway, estrogen signaling pathway, cell apoptosis, cell cycle, and E2 secretion. We found that mRNA of KISS1 highly expressed in the ovary and significantly increased from immature to mature follicles in gilts. Overexpression of KISS1 could significantly increase the mRNA expression of PIK3CG, PIK3C1, and PDK1, and significantly decreased the mRNA levels of FOXO3, TSC2, and BAD of PI3K signaling pathway. Furthermore, results of the flow cytometry showed that overexpression of KISS1 significantly inhibited the apoptosis of GCs and decreased the percentage of GCs at G0/G1 phase of the cell cycle. Additionally, overexpression of KISS1 could increase the mRNA levels of Star, CYP17, 3B-HSD, 17B-HSD of estrogen synthesis signaling pathway, significantly increase the concentration of E2 in the supernatant of the cultured GCs, and up-regulate the mRNA expression levels of ESR1 and ESR2. These results suggested that KISS1 might suppress cell apoptosis through activating the PI3K signaling pathway and stimulate synthesis of E2 via boosting the estrogen synthesis signaling pathway. This study would be of great interests for exploring the biological functionalities of KISS1 in the folliculogenesis and sex steroid production of the ovaries in mammals.

Depression disorder is rapidly advancing worldwide, and therapeutic strategy through gut-brain axis has been proven to be effective in the treatment. Here we studied the effect of lactic acid bacteria (LAB) treatment on depression. C57BL/6J mice were administered with LAB during a 5-week chronic unpredictable mild stress. Bifidobacterium longum subsp. infantis E41 and Bifidobacterium breve M2CF22M7, which improved the expression of Tph1 and secretion of 5-hydroxytryptophan (5-HTP) in RIN14B cells, significantly reduced depressive behaviors of mice in the forced swim test, sucrose preference test and step-down test, as well as increased the level of 5-hydroxytryptamine and brain-derived neurotrophic factor concentration in brain. Besides, M2CF22M7 reduced the serum corticosterone level. E41 increased cecal butyrate level, which significantly and positively correlated with some depression-related indexes. Using 16S rRNA-amplicon sequencing of faces, E41 and M2CF22M7 were found to improve the chronic-stress-induced microbial dysbiosis. They also normalized the host's pathways involving metabolism and gene information processing. These results indicate that Bifidobacterium E41 and M2CF22M7 have an antidepressant effect in mice partly in a 5-HTP dependent and microbiota-regulating manner. Nurturing the gut microbiota with these strains may become an emerging therapeutic way for mood disorder.

The tumor immune infiltrate, as recently evaluated with the immunoscore methodology, has been reported to be related to colorectal cancer (CRC) progression. Nevertheless, results varied from different studies. A meta-analysis was conducted to solve this problem. We collected data from included studies to evaluate the prognostic role of immunoscore in CRC patients on overall survival (OS) and disease-free survival (DFS). MEDLINE, EMBASE, and Cochrane libraries were searched through 30 June 2018. Hazard ratio (HR) with 95% confidence intervals (95% CI) was pooled using a random-effects model for OS and a fixed-effects model for DFS. Finally, eight studies (involving 4689 CRC cases) were identified as eligible publications. The results of the meta-analysis showed that low immunoscore was significantly correlated with poor OS (HR = 1.74, 95% CI: 1.43-2.13) and DFS (HR = 1.82, 95% CI: 1.64-2.03). The findings from most subgroup analyses were consistent with those from the overall analysis. The immunoscore could be a useful prognostic marker in patients with CRC. It is necessary to evaluate immunological markers in international multicenter studies.

Controlled drug release has a high priority for the development of modern medicine and biochemistry. To develop a versatile method for controlled release, a miniaturized acoustic gigahertz (GHz) resonator is designed and fabricated which can transfer electric supply to mechanical vibrations. By contacting with liquid, the GHz resonator directly excites streaming flows and induces physical shear stress to tear the multilayered polyelectrolyte (PET) thin films. Due to the ultra-high working frequency, the shear stress is greatly intensified, which results in a controlled disassembling of the PET thin films. This technique is demonstrated as an effective method to trigger and control the drug release. Both theory analysis and controlled release experiments prove the thin film destruction and the drug release.

To reduce the occurrence rate of peritoneal dialysis (PD) catheter dysfunction caused by catheter displacement or plugging, this study screened all patients with peritoneal dialysis catheterization from 2002 to 2015 from the Third Xiangya Hospital of Central South University. There were 256 patients before continuous quality improvement (CQI) (from 2002 to 2007) and 813 patients after CQI (from 2008 to 2015). The occurrence rate of catheter dysfunction was 5.9% in the preCQI group: seven cases were associated with peritonitis, six cases were involved in omentum wrapping, one case was blocked by oviduct, and one case was blocked by blood clot. Through PDCA (plan-do-check-act) four-step of CQI, the following measures were adopted: (1) Preoperative: treat complications, enema and urine catheterization (2) Intraoperative: strengthen analgesia, Lower the insert position of catheter to 7.5 ∼ 8.5 cm above the pubic symphysis, extending the straight distance of catheter in rectus abdominis and decrease the times of peritoneal dialysis catheter implantation. (3) Postoperative: strengthen the training of nurses, patients and their families. (4) strengthen anticoagulation therapy during peritonitis treatment. (5) use laparoscopic technology for refractory patients, and so on. The occurrence of catheter dysfunction was 1.5% in the postCQI group (p < 0.05): two cases were associated with peritonitis, ten cases were involved in omentum wrapping. The measures we adopted in CQI reduce the occurrence rate of catheter displacement or plugging in peritoneal dialysis.

The 5'-3' structure-specific endonuclease ERCC1/XPF (Excision Repair Cross-Complementation Group 1/Xeroderma Pigmentosum group F) plays critical roles in the repair of cisplatin-induced DNA damage. As such, it has been identified as a potential pharmacological target for enhancing clinical response to platinum-based chemotherapy. The goal of this study was to follow up on our previous identification of the compound NSC143099 as a potent inhibitor of ERCC1/XPF activity by performing an in silico screen to identify structural analogues that could inhibit ERCC1/XPF activity in vitro and in vivo. Using a fluorescence-based DNA-endonuclease incision assay, we identified the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) as a potent inhibitor of ERCC1/XPF activity with an IC50 (half maximal inhibitory concentration) in the nanomolar range in biochemical assays. Using DNA repair assays and clonogenic survival assays, we show that EGCG can inhibit DNA repair and enhance cisplatin sensitivity in human cancer cells. Finally, we show that a prodrug of EGCG, Pro-EGCG (EGCG octaacetate), can enhance response to platinum-based chemotherapy in vivo. Together these data support a novel target of EGCG in cancer cells, namely ERCC1/XPF. Our studies also corroborate previous observations that EGCG enhances sensitivity to cisplatin in multiple cancer types. Thus, EGCG or its prodrug makes an ideal candidate for further pharmacological development with the goal of enhancing cisplatin response in human tumors.

Phosphorus (P) is a key macronutrient limiting cell growth and bloom formation of marine dinoflagellates. Physiological responses to changing ambient P have been investigated in dinoflagellates; however, the molecular mechanisms behind these responses remain limited. Here, we compared the protein expression profiles of a marine dinoflagellate Alexandrium catenella grown in inorganic P-replete, P-deficient, and inorganic- and organic-P resupplied conditions using an iTRAQ-based quantitative proteomic approach. P deficiency inhibited cell growth and enhanced alkaline phosphatase activity (APA) but had no effect on photosynthetic efficiency. After P resupply, the P-deficient cells recovered growth rapidly and APA decreased. Proteins involved in sphingolipid metabolism, organic P utilization, starch and sucrose metabolism, and photosynthesis were up-regulated in the P-deficient cells, while proteins associated with protein synthesis, nutrient assimilation and energy metabolism were down-regulated. The responses of the P-deficient A. catenella to the resupply of organic and inorganic P presented significant differences: more biological processes were enhanced in the organic P-resupplied cells than those in the inorganic P-resupplied cells; A. catenella might directly utilize G-6-P for nucleic acid synthesis through the pentose phosphate pathway. Our results indicate that A. catenella has evolved diverse adaptive strategies to ambient P deficiency and specific mechanisms to utilize dissolved organic P, which might be an important reason resulting in A. catenella bloom in the low inorganic P environment. BIOLOGICAL SIGNIFICANCE: The ability of marine dinoflagellates to utilize different phosphorus (P) species and adapt to ambient P deficiency determines their success in the ocean. In this study, we investigated the response mechanisms of a dinoflagellate Alexandrium catenella to ambient P deficiency, and resupply of inorganic- and organic-P at the proteome level. Our results indicated that A. catenella initiated multiple adaptive strategies to ambient P deficiency, e.g. utilizing nonphospholipids and glycosphingolipids instead of phospholipids, enhancing expression of acid phosphatase to utilize organic P, and reallocating intracellular energy. Proteome responses of the P-deficient A. catenella to resupply of inorganic- and organic-P differed significantly, indicating different utilization pathways of inorganic and organic P, A. catenella might directly utilize low molecular weight organic P, such as G-6-P as both P and carbon sources.

Osteosarcoma (OS) is the most common malignant neoplasm in children and adolescents with a very high propensity for local invasion and poor response to current therapy. Anti-cancer effect of chamaejasmine is newly discovered from Stellera chamaejasmine L. Our study focuses on investigating the effect of chamaejasmine on the cellular apoptosis, proliferation, autophagy, and the underlying mechanisms in MG-63.

Radiofrequency ablation and microwave ablation are frequently prescribed for thoracic cancer. However, few writers have been able to draw on any systematic research into the differences between the two ablation methods.

Necroptosis is a form of programmed, caspase-independent, cell death, mediated by receptor-interacting protein kinases, RIPK1 and RIPK3, and the mixed lineage kinase domain-like (MLKL). Necroptosis contributes to the pathophysiology of various inflammatory, infectious, and degenerative diseases. Thus, identification of low MW inhibitors for necroptosis has broad therapeutic relevance. Here, we identified that the pan-Raf inhibitor TAK-632 was also an inhibitor of necroptosis. We have further generated a more selective, highly potent analogue of TAK-632 by targeting RIPK1 and RIPK3.

Esophageal anastomotic leakage (EAL) is a devastating complication for esophagectomy but the available therapies are unsatisfactory. Due to the healing effects of mesenchymal stromal cells (MSCs) and supporting capability of fibrin scaffold (FS), we evaluated the efficacy of a stem-cell therapy for EAL by engrafting adult and autologous MSCs (AAMSCs) in FS and investigated the potential mechanism. Twenty-one rabbits were assigned to AAMSC/FS group (n = 12) and control group (n = 9). After harvested, AAMSCs were identified and then labeled with lenti.GFP. To construct EAL model, a polyethylene tube was indwelled through the anastomosis for 1 week. A total of 2 × 106 AAMSCs in 0.2 ml FS were engrafted onto the EAL for the AAMSC/FS group, whereas FS was injected for control. Magnetic Resonance Imaging (MRI) examination was performed after 5 weeks. Esophageal tissues were harvested for macroscopic, histological analyses, Western blot, and immunohistochemistry at 8 weeks. The animal model of EAL was established successfully. MRI scanning revealed a decreased inflammation reaction in AAMSC/FS group. Accordingly, AAMSC/FS group presented a higher closure rate (83.3% vs. 11.1%, p = .02) and lower infection rate (33.3% vs. 88.9%, p = .02). Histological analyses showed the autografted MSCs resided in the injection site. Furthermore, milder inflammation responses and less collagen deposition were observed in AAMSC/FS group. Western blot and immunohistochemistry studies suggested that the therapeutic effect might be related to the secretions of IL-10 and MMP-9. Engrafting AAMSCs in FS could be a promising therapeutic strategy for the treatment of EAL by suppressing inflammation response and alleviating fibrosis progression. Stem Cells Translational Medicine 2019;8:548-556.

Acute kidney injury (AKI) is a common complication of sepsis characterized by a rapid degradation of renal function. The effect of vitamin D on AKI remains poorly understood. Here, we showed that vitamin D receptor (VDR) activation protects against lipopolysaccharide (LPS)-induced AKI by blocking renal tubular epithelial cell apoptosis. Mice lacking VDR developed more severe AKI than wild-type (WT) control mice after LPS treatment, which was manifested by marked increases in body weight loss and accumulation of serum blood urea nitrogen and creatinine as well as the magnitude of apoptosis of tubular epithelial cells. In the renal cortex, LPS treatment led to more dramatic downregulation of Bcl-2, more robust induction of p53-upregulated modulator of apoptosis (PUMA) and miR-155, and more severe caspase-3 activation in VDR knockout mice compared with WT control mice. Conversely, paricalcitol pretreatment markedly prevented LPS-induced AKI. Paricalcitol ameliorated body weight loss, attenuated serum blood urea nitrogen and creatinine accumulation, blocked tubular cell apoptosis, prevented the suppression of Bcl-2, and reversed PUMA and miR-155 induction and caspase-3 activation in LPS-treated WT mice. In HK2 cells, LPS induced PUMA and miR-155 by activating NF-κB, whereas 1,25(OH)2D3 blocked PUMA and miR-155 induction by repressing NF-κB activation. Both PUMA and miR-155 target Bcl-2 to promote apoptosis; namely, PUMA inhibits Bcl-2 activity, whereas miR-155 promotes Bcl-2 mRNA degradation and inhibits Bcl-2 protein translation. Collectively, these data provide strong evidence that LPS induces tubular cell apoptosis via upregulating PUMA and miR-155, whereas vitamin D/VDR signaling protects against AKI by blocking NF-κB-mediated PUMA and miR-155 upregulation.

The aim of the present study was to assess the correlations between diffusion-weighted magnetic resonance imaging (DW-MRI) features with the histologic differentiation and the expression of vascular endothelial growth factor (VEGF) in esophageal squamous cell carcinoma (ESCC). A total of 52 patients with ESCC included in the present study received radiotherapy, and all patients underwent contrast enhanced MRI and DW-MRI prior to and following radiotherapy. The diffusion sensitivity coefficient (b value) was set as 800 s/mm2. Apparent diffusion coefficient (ADC) values were automatically computed. VEGF expression was evaluated by immunohistochemical staining. The results demonstrated that the pathological grading of ESCC was positively correlated with ADC values (r=0.635, P=0.0007), and the VEGF expression was inversely correlated with ADC values (r=-0.321, P=0.008). However, no correlation was identified between the pathological grading and the VEGF expression (r=0.178, P=0.284). All patients were categorized as complete response (CR) or partial response (PR) and the ADC values were increased significantly following radiotherapy. The mean ADC values in the CR group were higher than the PR group prior to radiotherapy (t=5.156, P=0.0004). Therefore, we concluded that the DWI with ADC value measurement may represent the grade of tumor histologic differentiation and the degree of VEGF expression, and may also serve as a useful marker to predict radiotherapy and anti-VEGF response in ESCC. ADC value may be a substitution for assessing tumor angiogenesis and novel prognostic factor and contribute to the treatment of ESCC.

Tibetan pigs, which inhabit the Tibetan Plateau, exhibit distinct phenotypic and physiological characteristics from those of lowland pigs and have adapted well to the extreme conditions at high altitude. However, the genetic and epigenetic mechanisms of hypoxic adaptation in animals remain unclear.

Liver cancer was the fourth leading cause of cancer-related death in 2015. Hepatocellular carcinoma (HCC) is the most common type of liver cancer. miR-1-3p plays important roles in cancer, including prostate, bladder, lung cancer, and colorectal carcinoma. The function of miR-1-3p in HCC remains poorly understood.

Although selection of the early age at puberty in gilts will make for a favorable effect on the reproductivity of sow, a large proportion of phenotypic variation in age at puberty of gilts cannot be explained by genetics. Previous studies have implicated hypothalamic DNA methylation in the onset of puberty in mammals. However, the underlying molecular mechanism regarding the regulation of the onset of puberty has remained largely unexplored in gilts. Herein, the genome-scale DNA methylation of hypothalamus was acquired, using the reduced representation bisulfite sequencing, to compare and describe the changes of DNA methylation across Pre-, In- and Post-pubertal gilts. In this study, the average methylation levels of CpGs and CpHs (where H = C, T, or A) in CpG islands- and gene-related regions were gradually decreased in hypothalamic methylomes during the pubertal transition. Comparisons of Pre- vs. In-, In- vs. Post-, and Pre- vs. Post-pubertal stage revealed that there were 85726, 92914, and 100421 differentially methylated CpGs and 5940, 14804, and 16893 differentially methylated CpHs (where H = C, T, or A) in the hypothalamic methylomes. The methylation changes of CpHs were more dynamic than that of CpGs, and methylation changes of CpGs and CpHs were likely to be, respectively, involved in the developmental processes of reproduction and the molecular processes of cellular communications in the hypothalamus. Moreover, methylation changes of CpHs were observed to overrepresent in the quantitative trait loci of age at puberty, and the biological function of these CpH methylation changes was enriched in the pancreas development in gilts. Furthermore, the mRNA levels of several differentially CpG or CpH methylated genes related to the transcription of RNA II polymerase, GnRH signaling pathway, Estrogen signaling pathway, PI3K-AKt signaling pathway, and Insulin signaling pathway, including MAX, MMP2, FGF11, IGF1R, FGF21, and GSK3B, were significantly changed across these pubertal stages in the hypothalamus. These results will help our understanding of how DNA methylation contributes to phenotypic variation of age at puberty.

Emerging evidence showed that microRNAs (miRs) play critical roles in human cancers by functioning as either tumor suppressor or oncogene. MIR-382 was found to function as tumor suppressor in certain cancers. However, the role of MIR-382 in colorectal cancer (CRC) is largely unknown. Specificity protein 1 (SP1) is highly expressed in several cancers including CRC and is correlated with poor prognosis, but it is unclear whether or not MIR-382 can regulate the expression of SP1.

Periodontitis is the most prevalent inflammatory disease of the periodontium, and is related to oral and systemic health. Exosomes are emerging as non-invasive biomarker for liquid biopsy. We here evaluated the levels of programmed death-ligand 1 (PD-L1) mRNA in salivary exosomes from patients with periodontitis and non-periodontitis controls. The purposes of this study were to establish a procedure for isolation and detection of mRNA in exosomes from saliva of periodontitis patients, to characterize the level of salivary exosomal PD-L1, and to illustrate its clinical relevance. Bioinformatics analysis suggested that periodontitis was associated with an inflammation gene expression signature, that PD-L1 expression positively correlated with inflammation in periodontitis based on gene set enrichment analysis (GSEA) and that PD-L1 expression was remarkably elevated in periodontitis patients versus control subjects. Exosomal RNAs were successfully isolated from saliva of 61 patients and 30 controls and were subjected to qRT-PCR. Levels of PD-L1 mRNA in salivary exosomes were higher in periodontitis patients than controls (P < 0.01). Salivary exosomal PD-L1 mRNA showed significant difference between the stages of periodontitis. In summary, the protocols for isolating and detecting exosomal RNA from saliva of periodontitis patients were, for the first time, characterized. The current study suggests that assay of exosomes-based PD-L1 mRNA in saliva has potential to distinguish periodontitis from the healthy, and the levels correlate with the severity/stage of periodontitis.

The prevalence of breast cancer in elderly women (older than 80 years) is expected to rise more dramatically than its incidence. In this study, we evaluated the evidence for treatment guidelines for elderly breast cancer patients.