ABSTRACT
Ischemia reperfusion injury (IRI) of organs is a major challenge for clinicians, but the mechanism is still not elucidated, and the clinical treatment effect is still unsatisfactory. PARP-1-dependent cell death (parthanatos) is a non-apototic programmed cell death pathway involved in the development of the occurrence of IRI of organs. At the same time, parthanatos is also a multi-step pathway. There are many molecules in the parthanatos cascade that can be exploited to create therapeutic interventions for IRI, including PARP1, apoptosis inducing factor (AIF), and macrophage migration inhibitory factor (MIF). These critical molecules are involved in DNA damage, energy depletion and homeostasis imbalance. Therefore, these molecular signals in the parthanatos cascade represent promising therapeutic targets for the treatment of IRI. In the following, we will elaborate on the mechanisms and molecular characteristics of the parthanatos pathway and the relation between parthanatos pathway and IRI of vital organs. It aims to explore the posibility of IRI mechanism research and clinical treatment and to provide new ideas for clinicians and researchers.
ABSTRACT
@#Parthanatos is a form of programmed cell death,which is also known as poly(ADP-ribose)polymerase 1(PARP1)-mediated apoptosis-inducing factor(AIF)and macrophage migration inhibitory factor(MIF)-dependent cell death according to its molecular mechanism. Parthanatos is the main cause of a variety of neurodegenerative diseases,such as Parkinson's disease(PD),Alzheimer's disease(AD),motor neuron disease,and is also involved in the pathogenesis of some tumors,such as lung cancer and breast cancer. Therefore,a thorough understanding of the molecular mechanism of Parthanatos is crucial for the therapeutic strategies of related diseases. In recent years,studies have found that effective regulation of the occurrence of Parthanatos by regulating the key proteins PARP1,AIF and MIF is expected to become a therapeutic target for many diseases. Based on the specific molecular mechanism of Parthanatos,this paper reviewed the research progress of therapeutic strategies for related diseases from the aspects of inhibiting and promoting Parthanatos.
ABSTRACT
【Objective】 To explore the role of RYBP in activating PARP-1 dependent Parthanatos and promoting response to YM155 in esophageal squamous cell carcinoma. 【Methods】 CCK-8 and flow cytometry were used to analyze the inhibition ratio and cell death percentage after YM155 treatment in both RYBP overexpression group and control group. Western blotting was used to detect the expression of Parthanatos-related proteins. 【Results】 Compared with control group, RYBP overexpression group showed higher inhibition ratio and cell death percentage after YM155 treatment. Overexpression of RYBP activated PARP-1 with or without YM155 treatment. Besides, after YM155 treatment, KYSE170-RYBP showed more PAR accumulation in the nucleus, AIF translocation from mitochondria to the nucleus than control cells. 【Conclusion】 RYBP can activate PARP-1/PAR/AIF-dependent induced Parthanatos in esophageal squamous cell carcinoma and enhance response to YM155.
ABSTRACT
OBJECTIVE@#To explore the effect of pretreatment of neuroblastoma cells with hot water extract of Korean ginseng on MNNG-induced parthanatos and its mechanism.@*METHODS@#Neuroblastoma SH-SY5Y cells were pretreated with 1 mg/L hot water extract of Korean ginseng before induction with 250 μmol/L MNNG for 1 h or 4 h. CCK-8 and cell flow cytometry were used to detect cell survival rate. Western blotting was used to detect the changes in poly(ADP-ribose) (PAR) expression in the treated cells. Immunofluorescence assay was used to detect nuclear distribution of apoptosis-inducing factor (AIF), and flow cytometry was used to detect the level of reactive oxygen species (ROS) in the cells.@*RESULTS@#Compared with the blank control cells, MNNG-treated SH-SY5Y cells showed significantly decreased survival rate as the concentration of MNNG and the stimulation time increased ( < 0.05). Stimulation with MNNG also resulted in significantly increased expression of PAR protein in the cells ( < 0.05). Pretreatment of the cells with hot water extract of Korean ginseng obviously inhibited MNNG-induced cell death and significantly reduced AIF expression and nucleation in the cells ( < 0.05). MNNG stimulation significantly increased ROS level in the cells, which was decreased significantly by pretreatment of the cells with the extract ( < 0.05).@*CONCLUSIONS@#Pretreatment with hot water extract of Korean ginseng reduces MNNG-induced parthanatos and ROS production in SH-SY5Y cells.
ABSTRACT
Necrosis is also tightly controlled by signaling path-ways,thus it is called as regulated necrosis,which includes ne-croptosis,ferroptosis,parthanatos and CypD-mediated necrosis. It has been shown that regulated necrosis is closely related to the occurrence,development and prognosis of injury-relevant disea-ses such as myocardial infarction,stroke,neurodegenerative dis-eases.It will be significant for prevention and therapy of injury-relevant diseases to clarify the signal transductions and regulatory mechanisms for the regulated necrosis.
ABSTRACT
Objective To investigate the protective effects and underlying molecular mechanisms of hydrogen (H2) on high glucose-induced poly (ADP-ribose) polymerase-1 (PARP-1) dependent cell death (PARthanatos) in primary rat Schwann cells. Methods Cultured primary rat Schwann cells were randomly divided into five groups: blank control group (C group), H2 control group (H2 group), high osmotic control group (M group), high glucose treatment group (HG group), and H2 treatment group (HG+H2 group). The cells in H2 group and HG+H2 group were cultured with saturated hydrogen-rich medium containing 0.6 mmol/L of H2, and those in three control groups were cultured with low sugar DMEM medium containing 5.6 mmol/L of sugar, and the cells in HG and HG+H2 groups were given 44.4 mmol/L of glucose in addition (the medium containing 50 mmol/L of glucose), the cells in C group and H2 group were given the same volume of normal saline, and the cells in M group were given the same volume of mannitol. Cytotoxicity was evaluated using lactate dehydrogenase (LDH) release rate assays after treatment for 48 hours in each group. The contents of peroxynitrite (ONOO-) and 8-hydroxy-2-deoxyguanosine (8-OHdG) reflecting oxidative stress injury and DNA damage were detected by enzyme linked immunosorbent assay (ELISA). Poly (ADP-ribose) (PAR) protein expression was analyzed by Western Blot, and immunofluorescence staining was used to determine the nuclear translocation of the apoptosis-inducing factor (AIF). Results The cytotoxicity in HG and HG+H2 groups was significantly increased as compared with that of C group [LDH release rate: (61.40±2.89)%, (42.80±2.32)% vs. (9.92±0.38)%, both P < 0.01], the levels of ONOO- and 8-OHdG were markedly elevated [ONOO- (ng/L): 853.58±51.00, 553.11±38.66 vs. 113.56±14.22; 8-OHdG (ng/L): 1 177.37±60.97, 732.06±54.29 vs. 419.67±28.77, all P < 0.01], and the PAR protein expression was up-regulated (A value: 0.603±0.028, 0.441±0.010 vs. 0.324±0.021, both P < 0.01). The cytotoxicity, the levels of ONOO- and 8-OHdG, and PAR expression in HG+H2 group were significantly lower than those of the HG group (all P < 0.01). There were no significant differences in above parameters between H2 group as well as M group and C group. It was shown by immunofluorescence that AIF was expressed in the cytoplasm in C group, H2 group and M group, AIF was expressed in the whole cell in HG group, and the expression in the nucleus was particularly increased. A small amount of AIF expression was found in the nucleus of HG+H2 group, which indicated that high glucose could promote the AIF nuclear translocation, and that hydrogen-rich medium could prevent the process of translocation. Conclusions High glucose levels could enhance DNA damage that enhance PARthanatos in primary rat Schwann cells. However, H2 can not only reduce DNA damage of injured cells, but also inhibit the special death process, reduce the cell toxicity, all of which have protective effects.