Human PARP1 substrates and regulators of its catalytic activity: An updated overview.

Poly (ADP-ribose) polymerase 1 (PARP1) is a key DNA damage sensor that is recruited to damaged sites after DNA strand breaks to initiate DNA repair. This is achieved by catalyzing attachment of ADP-ribose moieties, which are donated from NAD+, on the amino acid residues of itself or other acceptor proteins. PARP inhibitors (PARPi) that inhibit PARP catalytic activity and induce PARP trapping are commonly used for treating BRCA1/2-deficient breast and ovarian cancers through synergistic lethality. Unfortunately, resistance to PARPi frequently occurs. In this review, we present the novel substrates and regulators of the PARP1-catalyzed poly (ADP-ribosyl)ation (PARylatison) that have been identified in the last 3 years. The overall aim is the presentation of protein interactions of potential therapeutic intervention for overcoming the resistance to PARPi.

Long Noncoding RNA SNHG12 Indicates the Prognosis and Accelerates Tumorigenesis of Diffuse Large B-Cell Lymphoma Through Sponging microR-195.

BACKGROUND: Small nucleolar RNA host gene 12 (SNHG12) expression is associated with multiple cancers, including renal cell carcinoma, prostate cancer, cervical cancer, nasopharyngeal carcinoma, colorectal cancer, and hepatocellular carcinoma. However, SNHG12 biological function is unclear in diffuse large B-cell lymphoma (DLBCL). METHODS: SNHG12 expression and associated clinicopathological characteristics were evaluated in DLBCL tissues. CCK-8 and transwell assay were used to analyze the in vitro role of SNHG12 in DLBCL progression. The xenograft model was used to explore the in vivo role of SNHG12 in DLBCL growth. The physical interaction between SNHG12 and miR-195 was confirmed using bioinformatics analysis and a dual luciferase assay. RESULTS: SNHG12 expression was upregulated in DLBCL tissues and correlated with patients' prognosis. SNHG12 downregulation inhibited cell growth, migration, and invasion of DLBCL cells in vitro, while its overexpression promoted these cellular processes. Moreover, SNHG12 knockdown repressed tumorigenesis of DLBCL cells in vivo. Further experiments demonstrated that miR-195 is a target of SNHG12 in DLBCL and that their expression negatively correlates in DLBCL. SNHG12 functioned as a competing endogenous RNA for miR-195 in DLBCL cells and miR-195 upregulation abolished the effects of SNHG12 on of DLBCL progression. CONCLUSION: SNHG12 predicts poor clinical outcome and serves as a novel oncogene in DLBCL via miR-195 sponging. We also suggest that SNHG12 can be used as a potential therapeutic candidate for DLBCL patients.

[Expression and Clinical Significance of Leukemia Stem Cell Antigen in Acute Myeloid Leukemia].

OBJECTIVE: To analyze the expression characteristics of leukemia stem cell (LSC) antigen in acute myeloid leukemia (AML) and to explore the correation of LSC-specific antigens with the subtypes, cytogenetics and clinical efficacy of AML. METHODS: A total of 61 newly diagnosed patients with AML (except M3) hospltalized in Department of Hematology of our hopital were selected from January 2013 to March 2016. The immun phenotypes and expression of Tim-3, CD96 and CD123 on leucamia cells were detected by direct immunofluorescenct flow cytometry. 61 patients were divided into positive expression and megative expression groups according to expression of Tim-3, CD96 and CD123; the correlation of LSC antigen expression level with high WBC count, chromosome and therapeutic efficacy was analyzed. RESULTS: Among 61 newly diagnosed patients with AML (except M3), the expression rate of Tim-3, CD96 and CD123 was 52.45%, 44.26% and 55.73% respectively. The expression rates of Tim-3, CD96 and CD123 between the AML subtypes and total patients was not stetistically different (P>0.05). The high WBC count occurred more easily in AML (except MS) patients with positive expression of Tim-3, CD96 and CD123, but compared with AML patients with negative espression, the difference was not statstically significant (P>0.05). The proportion of chromosone karyotype with poor prognosis detected in patients with positive expression of Tim-3 and CD96 was higher than that in patients with negative expreesion (P<0.05); while the preoprtion of chromosome karyotype with poor prognosis detected in patients with positive and negative expression of CD123 was not significantly different (P>0.05). After 2 courses of chemotherapy, the complete remission (CR) rate in patients with positive expression of Tim-3, CD96 and CD123 was significantly lower than that in patients with negative expression of Tim-3, CD96 and CD123 (P<0.05), the comparison of OS time in patients with positive and negative expression of Tim-3 and CD96 showed the statistical difference (P>0.05), while the difference of OS time in patients with positive and negative expression of CD123 was not significant (P>0.05). CONCLUSION: The expression levels of Tim-3, CD96 and CD123 in newly diagnosed AML (except M3) sybtype patients are not significantly different form those in total patients. The high WBC count ocours more easily in patients with positive expression of Tim-3, CD96 and CD123. After 2 course of chemotherapy, the CR rate in patients with positive expression of Tim-3, CD96 and CD123 was significantly lower than that in patients with negative expression. The proportion of chromsome karyotype with poor prognosis detected in patients with positive expression of Tim-3 and CD96 is high, moreover, OS time in patients with positive expression of Tim-3 and CD96 is shorter than that in patients with negative expression.

Case report about a successful full robotic radical gastric cancer surgery with intracorporeal robot-sewn anastomosis in a patient with situs inversus totalis and a two-and-a-half-year follow-up study.

BACKGROUND: During the last decade, total laparoscopic and laparoscopic-assisted distal gastrectomy for gastric cancer patients has been developed as alternatives to open resection. In recent years, this minimally invasive surgery has been extended using robotic-assisted surgery. CASE PRESENTATION: Here, we report a surgical intervention using a Da Vinci surgical robot in which a lower two-third stomach resection with subsequent Billroth II gastrojejunostomy was performed. The patient was a 53-year-old male with complete situs inversus gastric cancer who had received 2 cycles of neo-adjuvant oxaliplatin combined with S-1 medication. The operation took 3 h in total without complications. The amount of bleeding was about 50 mL, and on day 5 after the operation, the patient was discharged. CONCLUSIONS: This is the first report of a successful robot-assisted gastric cancer resection of advanced gastric cancer in a patient with the anatomical abnormality of situs inversus totalis.

Mild Hypothermia Combined with Hydrogen Sulfide Treatment During Resuscitation Reduces Hippocampal Neuron Apoptosis Via NR2A, NR2B, and PI3K-Akt Signaling in a Rat Model of Cerebral Ischemia-Reperfusion Injury.

We investigated whether mild hypothermia combined with sodium hydrosulfide treatment during resuscitation improves neuron survival following cerebral ischemia-reperfusion injury beyond that observed for the individual treatments. Male Sprague-Dawley rats were divided into seven groups (n = 20 for each group). All rats underwent Pulsinelli 4-vessel occlusion. Ischemia was induced for 15 min using ligatures around the common carotid arteries, except for the sham group. Immediately after initiating reperfusion, the mild hypothermia (MH), sodium hydrosulfide (NaHS), hydroxylamine (HA), MH + NaHS, MH + HA, and ischemia-reperfusion (I/R) control groups received an intraperitoneal injection of saline, sodium hydrosulfide, hydroxylamine, sodium hydrosulfide, hydroxylamine, and saline, respectively, and mild hypothermia (32 to 33 °C) was induced in the MH, MH + NaHS, and MH + HA groups for 6 h. The levels of NR2A, NR2B, p-Akt, and p-Gsk-3ß in the hippocampus of the MH, NaHS, and MH + NaHS groups were higher than those in the I/R control group, with the highest levels observed in the MH + NaHS group (P < 0.05). Treatment with hydroxylamine reduced the levels of these proteins in the HA and MH + HA groups, compared with the I/R control and MH groups, respectively. The apoptotic index of the CA1 region of the hippocampus was 45.2, 66.5, 63.5, and 84.8 % in the MH + NaHS, MH, NaHS, and I/R control groups, respectively (P < 0.05), indicating that the combination treatment shifted the NR2A/NR2B balance in favor of synaptic neuron stimulation and phosphatidylinositol 3'-kinase (PI3K)/Akt signaling. The combination of mild hypothermia and sodium hydrosulfide treatment for resuscitation following ischemia-reperfusion injury was more beneficial for reducing hippocampal apoptosis and pathology than that of mild hypothermia or hydrogen sulfide treatment alone.

Long-Term Changes in Drug Craving and Nutritional Status of Opioid Addicts with Nucleus Accumbens Ablative Stereotactic Neurosurgery at Five Years Postoperatively.

BACKGROUND: The nucleus accumbens (NAcc) has been proven to be associated with drug and food craving. NAcc ablative neurosurgery has been suggested to modulate the balance of the brain reward system and thus alleviate drug dependence in patients. It has been hypothesized that it would also alleviate food craving in patients as well as altering their nutritional status. AIMS: This study aimed to estimate the effect of NAcc neurosurgery on drug craving and nutritional status in patients with drug dependence at 5 years postoperatively. METHODS: The study included 100 patients with NAcc surgery and 92 patients without surgery. Body mass index (BMI) and body fat percentage (BF%) were examined to assess nutritional status, and questionnaires were administered to assess drug craving. RESULTS: Compared with the nonsurgery group and the relapse patients from the surgery group, the nonrelapse patients from the surgery group had higher BMI and BF% but lower drug craving. There were no significant differences between the nonsurgery group and the relapse patients in BMI, but the relapse patients had higher drug craving than the nonsurgery group. CONCLUSIONS: Long-term follow-up suggested that NAcc ablative neurosurgery would alleviate drug craving and yield a better nutritional status if individuals sustained abstinence. It would increase drug craving but would not ruin the nutritional status of patients even when individuals relapsed postoperatively.

[Prognostic significance of serial determinations of lactate dehydrogenase in follow-up for patients with myelodysplastic syndrome].

This study was aimed to dynamically observe the expression level of lactate dehydrogenase (LDH) in MDS patients and to explore the significance of LDH level for prognostic judgement of MDS patients. The expression level of LDH in 163 confirmedly diagnosed patients from 2001 to 2009 years in our hospital, the changes of LDH level in follow-up patients and relation of the LDH changes to prognosis, survival time and MDS progression, as well as the relation of LDH level to blood cell count, ratio and karyotype of blast cells in bone marrow were analyzed retrospectively. The results showed that the median LDH level in 163 MDS patients at diagnosis was 214 U/L (range 102 - 865 U/L), the median survival time of patients with increased LDH (> 240 U/L) was 25.6 months which was significantly shorter than that of patients with normal LDH level (56.8 months)(p < 0.05). When MDS patients were classified according to IPSS, the increased LDH level in MDS patients was observed in high risk and intermediate II groups (337.20 ± 298.00 U/L and 234.07 ± 216.00 U/L, respectively) which was significantly higher than that in low risk group (154.94 ± 46.08 U/L) (p < 0.05). The LDH level in patients with MDS progression was obviously enhanced while LDH level in patients without progression was not enhanced, mainly maintained in stable level as compared with LDH level at diagnosis and before progression (p < 0.005). By multivariate analysis, the increase of LDH level was found to be an independent prognostic factor. It is concluded that the LDH level may be used as indicator for judging prognosis of MDS patients, which is helpful to early recognition of MDS progression and risk stratification of disease, as well as selection of rational therapy.

Activation of the central histaminergic system is involved in hypoxia-induced stroke tolerance in adult mice.

We hypothesized that activation of the central histaminergic system is required for neuroprotection induced by hypoxic preconditioning. Wild-type (WT) and histidine decarboxylase knockout (HDC-KO) mice were preconditioned by 3 hours of hypoxia (8% O(2)) and, 48 hours later, subjected to 30 minutes of middle cerebral artery (MCA) occlusion, followed by 24 hours of reperfusion. Hypoxic preconditioning improved neurologic function and decreased infarct volume in WT or HDC-KO mice treated with histamine, but not in HDC-KO or WT mice treated with α-fluoromethylhistidine (α-FMH, an inhibitor of HDC). Laser-Doppler flowmetry analysis showed that hypoxic preconditioning ameliorated cerebral blood flow (CBF) in the periphery of the MCA territory during ischemia in WT mice but not in HDC-KO mice. Histamine decreased in the cortex of WT mice after 2, 3, and 4 hours of hypoxia, and HDC activity increased after 3 hours of hypoxia. Vascular endothelial growth factor (VEGF) mRNA and protein expressions showed a greater increase after hypoxia than those in HDC-KO or α-FMH-treated WT mice. In addition, the VEGF receptor-2 antagonist SU1498 prevented the protective effect of hypoxic preconditioning in infarct volume and reversed increased peripheral CBF in WT mice. Therefore, endogenous histamine is an essential mediator of hypoxic preconditioning. It may function by enhancing hypoxia-induced VEGF expression.

Effects of hydroxysafflor yellow A on the experimental traumatic brain injury in rats.

This paper explores the effects of hydroxysafflor yellow A (HSYA) on traumatic brain injury (TBI). Rats were divided into four groups: control, TBI, TBI combined with HSYA, and TBI combined with nimodipine. Saline, HSYA, or nimodipine was i.v. injected at 30 min before and 6 h after the onset of TBI. The contusion volume of brain, mitochondrial ATPase activity, brain malondialdehyde (MDA) content, and the concentrations of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) in the blood plasma were investigated. The results showed that the inhibitory rate of HSYA at a dose of 4 mg/kg was 59.2% compared with the TBI group. After the insult by TBI for 48 h, the activity of Na(+), K(+)-ATPase, Ca(2+)-ATPase, and Mg(2+)-ATPase decreased to 31, 35, and 38% of control group. HSYA increased these ATPase activities by 162, 96, and 131% of TBI group. HSYA also increased superoxide dismutase activity and decreased MDA content in the right parietal lobe adjacent to contusion foci in TBI rats. HSYA enhanced the t-PA activity by 64.64%, decreased the PAI-1 activity by 71.88%, and decreased the MMP-9 expression to 49.11% in the hippocampus of the TBI group at 12 h. In conclusion, HSYA may exert a potential therapeutic strategy to improve the outcome following TBI injury.

[Reversing effect of histamine on neurotoxicity induced by beta-amyloid1-42].

OBJECTIVE: To investigate the effects of histamine on the neurotoxicity induced by beta-amyloid(1-42)(Abeta42) in rat phaeochromocytoma (PC12) cells. METHODS: The in vitro model of Alzheimer's disease was constructed with A beta42-treated PC12 cells. Cell morphology and MTT assay were used to evaluate the cell toxicity and histamine effects. The different histamine antagonists were applied to investigate the involvement of receptor subtypes. RESULT: The neurotoxicity was induced by A beta42 in a concentration-dependent manner, which was reversed by histamine at concentration of 10(-7), 10(-6) mol/L. The effect was reversed by H(2) antagonist zolantidine and H(3)antagonist clobenpropit, but not by H(1) antagonist diphenhydramine. CONCLUSION: Histamine reduces neurotoxicity induced by beta-amyloid(1-42), which may be mediated by H(2) and H(3)receptors.