Lonicerin targets EZH2 to alleviate ulcerative colitis by autophagy-mediated NLRP3 inflammasome inactivation

Aberrant activation of NLRP3 inflammasome in colonic macrophages strongly associates with the occurrence and progression of ulcerative colitis. Although targeting NLRP3 inflammasome has been considered to be a potential therapy, the underlying mechanism through which pathway the intestinal inflammation is modulated remains controversial. By focusing on the flavonoid lonicerin, one of the most abundant constituents existed in a long historical anti-inflammatory and anti-infectious herb

Correlation between late-onset sporadic Parkinson's disease and single nucleotide polymorphism of Atg7 rs2606757 / 中华老年医学杂志

Objective To investigate the correlation between late-onset sporadic parkinson's disease(PD) and single nucleotide polymorphism (SNP) of autophagy-related genes 7 (Atg7) rs2606757 (6+1196A/T)in Han Chinese population.Methods Totally 124 patients with late-onset sporadic PD(the PD group)and 105 age-and sex-matched healthy individuals(the control group)were enrolled in this study.The SNP of Atg7 rs2606757 was detected by the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP).After gene sequencing for the detection of allele and genotype frequencies distribution and testing Hardy-Weinberg equilibrium,the differences in Atg7 rs2606757 genotype and allele frequency were compared between PD group and control group and between males and females.Results The frequency of AA genotype was statistically significantly lower in the PD group[34.7％(43/124)]than in the control group[53.3 ％ (56/105)](x2 =8.063,P=0.005,OR =0.465,95％ CI:0.273-0.791).In men's PD group versus men's control group,AA genotype of the Atg7 rs2606757 showed a lower frequency for late-onset sporadic PD[33.3 ％ (23/69)vs.53.2 ％ (33/62),x2 =5.280,P =0.022,OR =0.439,95 ％ CI:0.217-0.891].Logistic regression analysis indicated that the AA genotype frequency distribution of Atg7 rs2606757 showed a significant difference between PD and control groups (OR =2.210,95％ CI:1.289-3.789,P =0.004).Conclusions The higher frequence of AA genotype at Atg7 rs2606757 only in males might be associated with the decreased risk of late-onset sporadic PD.

A participação da autofagia na regulação da célula-tronco hemopoética em camundongos knockouts para Atg7 e transglutaminase 2 / The participation of autophagy in hemopoietic stem cell regulation in mice Knockouts for Atg7 and transglutaminase 2

A desnutrição é um dos principais problemas de saúde pública do mundo, que contribui significativamente para o aumento da morbidade e mortalidade. Estima-se um total de 815 milhões de pessoas subnutridas no mundo, e apesar da melhoria dos recursos alimentares o número de pessoas desnutridas ainda é alarmante. Estudos de nosso laboratório tem demonstrado, em modelo murino de desnutrição proteica, hipoplasia medular com evidências histológicas de alterações na matriz extracelular (MEC) e permanência da célula-tronco hemopoética (CTH) na fase G0/G1 do ciclo celular em camundongos desnutridos. Dados deste trabalho evidenciaram alterações nas proteínas Akt /mTOR, que podem contribuir para o aumento da expressão autofágica nas CTHs e CTPHs (célula-tronco progenitora). A literatura demonstra que desequilíbrios nutricionais e metabólicos podem induzir ativação autofágica. Autofagia é um processo catabólico que participa da manutenção da homeostase celular, da MEC e na regulação das CTHs, dados deste trabalho demonstram diminuição da quantidade de CTH e CTPH em camundongos desnutridos sem a presença do gene Atg7, proteína participativa no processo autofágico. Já camundongos com deleção da transglutaminase 2 (TG2) e submetidos a privação de nutrientes por 24 horas , apresentou diminuição da quantidade de CTH e aumento da diferenciação da CTPH. A TG2 tem participação na impulsão e formação do fagóforo (processo inicial autofágico). Considerando que a desnutrição proteica leva a comprometimento da hemopoese, alterações no ciclo celular das CTHs e hipoplasia medular com pancitopenia periférica e que privação e ou jejum prolongado de nutrientes pode aumentar a atividade autofágica, concluímos nesse projeto que autofagia é importante para regulação da CTH e diferenciação da CTPH, entretanto a desnutrição proteica e privação de nutrientes estimula de maneira diversa o mecanismo de diferenciação da CTH

Malnutrition is one of the world's major public health problems, which contributes significantly to increased morbidity and mortality. An estimated 815 million people are undernourished in the world, and despite the improvement in food resources the number of undernourished people is still alarming. Studies of our laboratory have demonstrated in murine model of protein malnutrition, medullary hypoplasia with histological evidence of extracellular matrix (ECM) changes and hemopoietic stem cell (HSC) stay in the G0/ G1 phase of the cell cycle in malnourished mice. Data from this work showed alterations in Akt / mTOR proteins, which may contribute to the increase of autophagic expression in HSC and HPC (progenitor stem cell). The literature demonstrates that nutritional and metabolic imbalances can induce autophagic activation. Autophagy is a catabolic process that participates in the maintenance of cellular homeostasis, ECM and in the regulation of HSC, data from this work demonstrate a decrease in the amount of HSC and HPC in malnourished mice without the presence of the Atg7 gene, a participatory protein in the autophagic process. Mice with transglutaminase 2 deletion (TG2) and submitted to nutrient deprivation for 24 hours showed a decrease in the amount of HSC and an increase in the differentiation of HPC. TG2 plays a role in the uptake and formation of phagophore (autophagic initial process). Considering that protein malnutrition leads to hemopoiesis, alterations in the cell cycle of HSC and spinal cord hypoplasia with peripheral pancytopenia, and that prolonged nutrient starvation or fasting may increase the autophagic activity, we conclude in this project that autophagy is important for regulation of HSC and differentiation of HPC, however, protein malnutrition and nutrient deprivation stimulate in a different way the mechanism of differentiation of HSC

Vitrification, in vitro fertilization, and development of Atg7 deficient mouse oocytes / 대한생식의학회지

OBJECTIVE: Autophagy contributes to the clearance and recycling of macromolecules and organelles in response to stress. We previously reported that vitrified mouse oocytes show acute increases in autophagy during warming. Herein, we investigate the potential role of Atg7 in oocyte vitrification by using an oocyte-specific deletion model of the Atg7 gene, a crucial upstream gene in the autophagic pathway. METHODS: Oocyte-specific Atg7 deficient mice were generated by crossing Atg7 floxed mice and Zp3-Cre transgenic mice. The oocytes were vitrified-warmed and then subjected to in vitro fertilization and development. The rates of survival, fertilization, and development were assessed in the Atg7 deficient oocytes in comparison with the wildtype oocytes. Light chain 3 (LC3) immunofluorescence staining was performed to determine whether this method effectively evaluates the autophagy status of oocytes. RESULTS: The survival rate of vitrified-warmed Atg7(f/f);Zp3-Cre (Atg7(d/d)) metaphase II (MII) oocytes was not significantly different from that of the wildtype (Atg7(f/f)) oocytes. Fertilization and development in the Atg7(d/d) oocytes were significantly lower than the Atg7(f/f) oocytes, comparable to the Atg5d/d oocytes previously described. Notably, the developmental rate improved slightly in vitrified-warmed Atg7(d/d) MII oocytes when compared to fresh Atg7(d/d) oocytes. LC3 immunofluorescence staining showed that this method can be reliably used to assess autophagic activation in oocytes. CONCLUSION: We confirmed that the LC3-positive signal is nearly absent in Atg7(d/d) oocytes. While autophagy is induced during the warming process after vitrification of MII oocytes, the Atg7 gene is not essential for survival of vitrified-warmed oocytes. Thus, induction of autophagy during warming of vitrified MII oocytes seems to be a natural response to manage cold or other cellular stresses.

Atg7 in development and disease: panacea or Pandora's Box?

Macroautophagy is an evolutionarily conserved intracellular degradation system used by life ranging from yeasts to mammals. The core autophagic machinery is composed of ATG (autophagy-related) protein constituents. One particular member of the ATG protein family, Atg7, has been the focus of recent research. Atg7 acts as an E1-like activating enzyme facilitating both microtubule-associated protein light chain 3 (LC3)-phosphatidylethanolamine and ATG12 conjugation. Thus, Atg7 stands at the hub of these two ubiquitin-like systems involving LC3 and Atg12 in autophagic vesicle expansion. In this review, I focus on the pleiotropic function of Atg7 in development, maintenance of health, and alternations of such control in disease.