Prognostic and immunological potential of PPM1G in lung adenocarcinoma.

Lung cancer is one of the most common types of cancer worldwide, with the highest incidence and mortality rates. Protein phosphatase, Mg2+/Mn2+ dependent 1G (PPM1G) is a serine/threonine phosphatase, which is involved in the proliferation, invasion and metastasis of tumor cells. However, there are few reports on the role of PPM1G in lung adenocarcinoma (LUAD). The present study used publicly available data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases to evaluate the expression of PPM1G in LUAD, and to assess the relationship between PPM1G expression and the prognosis of patients with LUAD. Protein expression data of PPM1G obtained by immunohistochemical staining were collected from the Human Protein Atlas database. The correlation between PPM1G and immune cell infiltration and immune checkpoints was analyzed by single­sample gene set enrichment analysis of TCGA data. The Kaplan­Meier method was used for survival analysis, and univariate and multivariate Cox regression were used to analyze the effect of PPM1G on prognosis with data from TCGA database. The results showed that PPM1G was highly expressed in LUAD cancer tissues. The high expression of PPM1G was associated with poor clinical stage, T stage, N stage and overall survival in LUAD. The present study screened 29 genes related to PPM1G and closely related to the cell cycle in patients with LUAD. The expression of PPM1G was positively correlated with γδ­Τ cells, T helper 2 cells and natural killer CD56dim cells, and was negatively correlated with B cells, mast cells, plasmacytoid dendritic cells, T helper cells, macrophages, T cells, CD8 T cells, central memory T cells, effector memory T cells, neutrophils and T follicular helper cells. In addition, PPM1G was positively correlated with immune detection points. In conclusion, PPM1G may be involved in the control of the lung cancer cell cycle, and could be associated with prognosis and immune infiltration in patients with LUAD.

Cosmc transfection decreases malignant behavior of Tn+ cells and enhances sensitivity to apoptosis when induced by Apo2L/TRAIL via alteration of O-glycan structure.

Cosmc mutations may cause abnormal O-glycosylation and result in Tn antigen expression. In the current study, it was discovered that proliferation and migration of Tn+ cells (Jurkat T and LS174T-Tn+ cells) with mutant Cosmc decreased after transfected Cosmc, and their sensitivity to apoptosis induced by Apo2L/TRAIL increased. Core 1-, 2-, and 3-derived O-glycans were absent in Tn+ cells. After Cosmc transfection, normal extended core 1-derived O-glycans appeared and were accompanied by increased T-synthase activity. Core 2-derived O-glycans appeared in transfected LS174T-Tn+ cells, and their structural types and levels were lower than those in LS174T-Tn- cells. Core 3-derived O-glycans were present only in LS174T-Tn- cells. The activity of C3GnT in LS174T-Tn+ cells was lower than that in LS174T-Tn- cells, and it was absent in Jurkat T cells. Cosmc transfection did not alter C3GnT activity or core 3-derived O-glycans in Jurkat T and LS174T-Tn+ cells. The results demonstrated that the composition and structure of O-glycans were different among various Tn+ cells, which not only affected cell malignant behavior but also modulated sensitivity to apoptotic stimuli. Thus, Cosmc transfection may effectively decrease the malignant behavior of Tn+ tumor cells and enhance their sensitivity to apoptosis when induced by Apo2L/TRAIL through modification of O-glycans.

Tetramethylpyrazine alleviates acute kidney injury by inhibiting NLRP3/HIF­1α and apoptosis.

The aim of the present study was to investigate the protective effect and underlying mechanism of tetramethylpyrazine (TMP) on renal ischemia reperfusion injury (RIRI) in rats, which refers to the injury caused by the restoration of blood supply and reperfusion of the kidney after a period of ischemia. Sprague­Dawley rats were randomly divided into a Sham group, renal ischemia­reperfusion (I/R) group and TMP group. TMP hydrochloride (40 mg/kg, 6 h intervals) was given via intraperitoneal injection immediately after reperfusion in the TMP group, after 24 h the kidney tissues were taken for follow­up experiments. Pathological changes in the kidney tissues were observed by periodic acid­Schiff staining. Renal function was assessed by measuring levels of serum creatinine and blood urea nitrogen, and inflammatory cytokines tumor necrosis factor (TNF)­α and interleukin (IL)­6. Renal cell apoptosis was detected by TUNEL­DAPI double staining, mRNA and protein changes were analyzed by reverse transcription­quantitative PCR and western blotting. Cell viability was measured using a CCK­8 assay. It was found that the renal tissues of the sham operation group were notably abnormal, and the renal tissues of the I/R group were damaged, while the renal tissues of the TMP group were less damaged compared with those of the I/R group. Compared with the I/R group, the serum creatinine and blood urea nitrogen levels in the TMP group were low (all P<0.05), levels of inflammatory cytokines TNF­α and IL­6 decreased, the apoptotic rate was low (all P<0.05), and the relative expression levels of nucleotide­oligomerization domain­like receptor 3 (NLRP3) protein and mRNA in renal tissues were low (all P<0.05). The expression levels of hypoxia­inducible factor 1­α and NLRP3 increased after oxygen and glucose deprivation (OGD), and reduced after treatment with OGD and TMP (all P<0.05). It was concluded that TMP can reduce renal injury and improve renal function in RIRI rats, and its mechanism may be related to the reduction of NLRP3 expression in renal tissues.

NLRP3 inflammasome negatively regulates podocyte autophagy in diabetic nephropathy.

Inflammasome mechanisms are recognized as a key pathophysiology of diabetic nephropathy (DN). The nucleotide-oligomerization domain-like receptor 3 (NLRP3) inflammasome has attracted the most attention. Autophagy as a conserved intracellular catabolic pathway plays essential roles in the maintenance of podocytes. Although autophagy was involved in preventing excessive inflammatory responses in kidney diseases, a clear understanding of the regulation of NLRP3 inflammasome on autophagy in glomerular damage in DN is still lacking. In this study, we focused on the effect of the activation of NLRP3 inflammasome on the suppression of podocyte autophagy and aimed to investigate the role of autophagy in podocyte injury in DN. Podocyte autophagy has been confirmed to be inhibited in high-fat diet/streptozotocin (HFD/STZ)-induced DN mice, and NLRP3 has been found to be upregulated in both mice and human DN biopsies and in vitro. Activation of NLRP3 inflammasome exacerbated podocyte autophagy and reduced podocyte nephrin expression, while silencing of NLRP3 efficiently restored podocyte autophagy and ameliorated podocyte injury induced by high glucose. The results showed that NLRP3 was a negative regulator of autophagy and suggested that restoration of podocyte autophagy by inactivation of NLRP3 under high glucose could reduce podocyte injury. Proper modification of autophagy and inflammasome has the potential to benefit the kidney in DN.

Interleukin-18 binding protein attenuates renal injury of adriamycin-induced mouse nephropathy.

Nephrotic syndrome is one of the most common kidney diseases in children, most of which were caused by minimal change disease, which could be typically reversible with the use of corticosteroid therapy in steroid-sensitive nephrotic syndrome. At the same time, there still exist some side effects caused by drugs and steroid-resistant nephrotic syndrome. It's urgent to investigate more accurate treatment to improve the situation. In this study, we chose mice model by adriamycin to observe the effect of IL-18BP intervention. It was shown that (1) weak general conditions appeared after adriamycin administration; (2) Proteinuria showed up after adriamycin-administration and then decreased with IL-18 binding protein intervention; (3) the level of triglyceride, cholesterol, IL-18, IFN-γ, and TNF-α in the IL-18 binding protein intervening group were significantly lower than those in the adriamycin-minimal change disease MCD group (all P < 0.01), and the levels of serum total protein, albumin, and IL-4 were significantly higher than those in the adriamycin-minimal change disease MCD group (P < 0.05, P < 0.01, P < 0.05); (4) ultramicrostructural examination demonstrated wide fusion of foot processes of glomerular epithelial cells in adriamycin-minimal change disease MCD mice, while only focal fusion occurred in IL-18 binding protein intervening mice. In conclusion, IL-18BP repaired the proteinurine, histopathological injury of kidney, and the induction of serum cytokines in mice models of minimal change disease induced by adriamycin.

Euphorbia fischeriana Steud inhibits malignant melanoma via modulation of the phosphoinositide-3-kinase/Akt signaling pathway.

Euphorbia fischeriana Steud, a traditional Chinese medicine, has been shown to inhibit the growth of various cancers by the induction of apoptosis and cell cycle arrest. The purpose of the present study was to investigate the association between the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway and the inhibitory effect of Euphorbia fischeriana Steud on the growth and metastasis of melanoma B16 cells in vitro, and the underlying mechanisms. MTT assay results indicated that Euphorbia fischeriana Steud inhibited the growth of B16 cells in a time- and dose-dependent manner. Flow cytometric analysis revealed that Euphorbia fischeriana Steud markedly induced apoptosis of the B16 cells, with arrest at the G0/G1 phase of the cell cycle. In addition, in a Transwell assay Euphorbia fischeriana Steud significantly suppressed the migration of B16 cells. Western blot analysis revealed that the expression levels of phosphatase and tensin homolog (PTEN) were upregulated, and the phosphorylation of Akt was downregulated, which resulted in inhibition of the PI3K/Akt signaling pathway and the eventual suppression of its downstream targets, such as matrix metalloproteinase-2 mRNA, in B16 cells. The results demonstrated that Euphorbia fischeriana Steud inhibited the growth and migration of B16 cells, possibly via modulation of the PI3K/Akt signaling pathway and upregulation of PTEN expression levels, in addition to downregulation of p-Akt expression. The aforementioned findings suggest that Euphorbia fischeriana Steud may have broad therapeutic applications in the treatment of malignant melanoma.

Aged black garlic extract inhibits HT29 colon cancer cell growth via the PI3K/Akt signaling pathway.

Accumulating evidence indicates that aged black garlic extract (ABGE) may prove beneficial in preventing or inhibiting oncogenesis; however, the underlying mechanisms have not been fully elucidated. The present study aimed to investigate the effects of ABGE on the proliferation and apoptosis of HT29 colon cancer cells. Our results demonstrated that ABGE inhibited HT29 cell growth via the induction of apoptosis and cell cycle arrest. We further investigated the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signal transduction pathway and the molecular mechanisms underlying the ABGE-induced inhibition of HT29 cell proliferation. We observed that ABGE may regulate the function of the PI3K/Akt pathway through upregulating PTEN and downregulating Akt and p-Akt expression, as well as suppressing its downstream target, 70-kDa ribosomal protein S6 kinase 1, at the mRNA and protein levels. In conclusion, these findings suggest that the PI3K/Akt signal transduction pathway is crucial for the development of colon cancer. ABGE inhibited the growth and induced apoptosis in HT29 cells through the inhibition of the PI3K/Akt pathway, suggesting that ABGE may be effective in the prevention and treatment of colon cancer in humans.

Increased acetylcholinesterase and capase-3 expression in the brain and peripheral immune system of focal cerebral ischemic rats.

Cerebral ischemia induces rapid neuro-immunological injury as demonstrated by changes in inflammatory factors, cytokines and chemokines in the circulation and peripheral immune system. In addition, elevated acetylcholinesterase (AChE) activity was reported in ischemic brain tissue. Here, we evaluated the time dependent changes in AChE levels and cytokines and NK activity, as well as the relationship of AChE to apoptosis in the brain, spleen and thymus at different time points after focal cerebral ischemia. The data show an elevated level of immunoreactive AChE in the cortex of ischemic brains. This sustained elevated level of AChE in the brain, thymus and spleen activates capase-3 in response to cerebral ischemia. We propose that this pro-apoptotic activity may result in a T helper cell (Th1/Th2) imbalance and impaired immune function in ischemia.