Discovery medicine最新文献

Immune checkpoint inhibitors (ICIs) are novel immunotherapy drugs that have significantly improved the outcomes of a variety of cancers including lung cancer. However, ICIs could induce immune-related adverse effects (irAEs) characterized by clinical manifestations that resemble autoimmune disorders. The main type of IrAEs in the kidneys is acute kidney injury (AKI). In this review, we describe the types of ICIs targeting lung cancer, especially those approved by the U.S. Food and Drug Administration for clinical trials in lung cancer patients. Next, we summarize current understandings of the mechanisms involved in ICIs-induced AKI. Finally, we highlight further directions to address ICIs-associated AKI for the benefits of lung cancer patients in the clinic.

The increase of dietary fat energy supply ratio has led to a gradual increase in obesity, and the risk of hypertension in patients with obesity is much higher than that in the normal population. Weight loss has become a popular method to control obesity and hypertension. Metabolic bariatric surgery (MBS), which is also called weight loss surgery, can have significant effects on the weight and body metabolism of the patients. Recent studies have shown that the blood pressure of obese patients with hypertension is significantly improved after MBS. Therefore, in this review we will briefly describe the relationship between obesity and hypertension, summarize the effects of MBS on hypertension, and then focus on the mechanisms by which MBS achieves satisfactory efficacy to treat hypertension.

Myeloid-derived suppressor cells (MDSCs) constitute an important component in regulating immune responses in cancer. Long non-coding RNAs (lncRNAs) are untranslated functional RNA molecules. There is growing evidence that lncRNAs are involved in modulating transcriptional factors to become complex regulatory networks that regulate the immune function and activity of MDSCs in the immunosuppressive tumor microenvironment. This review focuses on the emerging role of lncRNAs in MDSCs activity. We summarize how lncRNAs modulate the differentiation, expansion, and immunosuppressive functions of MDSCs and the underlying mechanisms. It is hoped that lncRNAs targeting may prevent the growth and development of MDSCs in the immunosuppressive tumor microenvironment.

Background and aim: Diabetic kidney disease (DKD) is the most-common cause of chronic renal failure and end-stage renal disease (ERSD) in diabetes mellitus (DM) patients. Renal inflammation and glomerular or interstitial fibrosis are mainly associated with the progression of DKD. Carbohydrate response element binding protein (ChREBP) is activated and transcribed in a glucose dependent manner. This study is aimed at exploring the role and underlying mechanisms of ChREBP in DKD.

Methods: ChREBP knockout mice, obtained by CRISPR Cas9 gene editing technology, were used to study the effects of ChREBP on inflammation and fibrosis in diabetic kidney of mice. Human renal tubular epithelial (HK-2) cells were cultured in a medium containing normal or high glucose levels. Additionally, the role of ChREBP in high glucose (HG)-induced NLRP3 inflammasome activation was assessed.

Results: We identified that renal inflammation, renal extracellular matrix deposition, and renal fibrosis were restored by ChREBP deficiency in diabetic mouse kidney. Consequently, ChREBP deficiency decreased the activation of nucleotide leukin-rich polypeptide 3 (NLRP3) inflammasome, which later restrained hyperglycemia-induced renal fibrosis. Importantly, NLRP3 inflammasome aggravated the above-mentioned renal fibrosis via TGF-β1 expression and the signaling pathways of Smad2/3 and the p38 MAPK. Additionally, ChREBP deficiency inhibited NLRP3 inflammasome activation both in HG-induced HK-2 cells and diabetic mouse kidney.

Conclusion: Our findings establish a critical role of ChREBP in engaging inflammation and renal fibrosis by regulating NLRP3 inflammasome activation in DKD.

In the past decades, the bacillus Calmette-Guerin (BCG) treatment for non-muscle invasive bladder cancer, especially for intermediate and high-risk groups, is increasingly accepted by multiple guidelines. Currently, the front-line setting for the high-risk group is still intravesical BCG instillation. However, the BCG mechanism, usage, adverse events, and the definition of BCG failure are not yet fully understood or defined. In addition, despite BCG being generally efficacious, a number of bladder cancer patients are unresponsive to the BCG immunotherapy. In this review, we summarize the history and current status of BCG immunotherapy, and highlight recent developments in designing novel strategies for the treatment of BCG-unresponsive patients.

Glycogen synthase kinase 3 beta (GSK3β) has emerged as a therapeutic target for breast cancer. As inhibitors of GSK-3β, 1,2,4-thiadiazole-3,5-dione (TDZD) family members have been reported as potential candidates for cancer treatment. In this study, the anticancer effects of ethiadin (ETD-174), one of the chemical synthesis compounds of TDZD, were investigated in MCF-7 human breast cancer cells. MCF-7 cells incubated with different doses of ETD-174 for different time periods. CCK-8 assays were carried out to test the effect of ETD-174 on the proliferation of MCF-7 cells. The occurrence of apoptosis was detected by Hoechst 33258 staining and flow cytometry. ETD-174 on cell migration and colony formation were examined by wound healing experiments and soft agar assays. Relative protein expressions were conducted with immunoblot assay. ETD-174 demonstrated a higher degree of cytotoxicity in MCF-7 cells. Topical morphological changes of apoptotic body formation after ETD-174 treatment were observed. Meanwhile, apoptosis was elicited by ETD-174. Also, ETD-174 could inhibit the migration and clonality of MCF-7 cells. After the treatment with ETD-174, the level of phosphorylation of GSK3β^Ser9 in MCF-7 cells increased significantly, and the enzymatic activity of GSK3β decreased. ETD-174 is likely to have an effective suppressor role in breast cancer, suggesting that pharmacological inhibition of GSK3β as a novel treatment modality for breast cancer should warrant further investigation.

Tyrosine kinase inhibitors (TKIs) block the activity of tyrosine kinases by competitive inhibition of ATP at the catalytic tyrosine kinase binding site and inhibit oncogenic signaling. One important target of TKIs is BCR-ABL1, which is constitutively activated in leukemia cells. In this review, we briefly describe the development of TKIs from the first generation to the third generation, and summarize their use in the treatment of chronic myeloid leukemia and acute lymphoblastic leukemia in children. We highlight several future directions in the development of TKIs for pediatric leukemia therapy. In conclusion, we focus on chronic myeloid leukemia and acute lymphoblastic leukemia as the examples of pediatric blood cancer that significantly benefit from TKIs-based target therapy. Further development of TKIs will allow us to better manage pediatric leukemia.

Prostate androgen-regulated mucin-like protein (PARM1) is known to promote cell survival via protecting the cell surface, thus being involved in cancer development. The Gene Expression Profiling Interactive Analysis (GEPIA), MEXPRESS database, LinkedOmics database, GeneMANIA database, and the Tumor Immune Estimation Resource (TIMER) database were accessed to explore the epigenetic regulation, prognostic value, biological functions and mechanisms of PARM1 in diffuse large B-cell lymphoma (DLBCL). Hypomethylation and resultant overexpression of PARM1 was found in DLBCL. The high-level expression of PARM1 was related to the poor outcome of DLBCL patients. PARM1 participated in DNA repair, cell cycle, and cellular response to stress. PARM1 was also associated with autophagy, apoptosis, Ras pathway, and MAPK cascade. Significant kinase targets of PARM1 included ATM, CDK1, and CDK2. Significant transcription factor targets of PARM1 involved ELK1, MYC and so on. Significant miRNA targets of PARM1 included miR21, miR202, miR323, and miR345. Further analysis suggested that the PARM1 regulated autophagy through the PI3K-Akt signaling. PARM1 was found to be correlated with immune cell infiltration, which indicated the important roles of PARM1 in microenvironment of DLBCL. Our study lays a foundation for further research on the impact of PARM1 in DLBCL tumorigenesis and precision therapy.

Background: Liver fibrosis is the early pathological manifestation of various chronic liver diseases (including schistosomiasis, alcoholic, viral, nonalcoholic, fatty liver, etc.), which can progress to cirrhosis and even liver cancer. Out of the 7.7 billion world population, approximately 2 billion individuals have evidence of hepatitis B virus (HBV) infection; of these, 350 to 400 million suffer from chronic HBV infection, accounting for about 5% of the global population. The global prevalence of hepatitis C is 3%. These figures indicate that liver fibrosis is quite common.

Methods: 98 patients with liver fibrosis were included in this study. The serum chitinase-3 Like Protein-1 (CHI3L1) level was measured by the double antibody Sandwich ELISA method.

Results: Serum levels of CHI3L1 were significantly different between no-fibrosis and fibrosis groups (P < 0.01). There was a strong correlation between the levels of CHI3L1, elastometry, hyaluronan, CIV (P < 0.01) and age and sex, TBIL, DBIL, ALB, AST, ALT, GGT, ALP, PLT, LN, PIINP, FIB-4, and APRI (P < 0.05). The expression of CHI3L1 was different from fibrosis grades S1, S3, and S4 (P < 0.05, P < 0.001). The expression of CHI3L1 was significantly different between F1 and F4 (P < 0.05). Serum CHI3L1 expression level can be a valuable metric for diagnosing liver fibrosis, with an AUC value of 0.812. Out of the 98 patients who had undergone liver puncture, 79 patients (30.38%) had ALT ≤ 2ULN.

Conclusions: The expression level of serum CHI3L1 was significantly higher in patients with liver fibrosis than that in patients without liver fibrosis. The expression levels of serum CHI3L1 were different in different grades of liver fibrosis and increased with the severity of liver fibrosis. Serum CHI3L1 can distinguish early stage (S1) of liver fibrosis from late stage (S3-4) of liver fibrosis. Serum CHI3L1 combined with HA is even more effective in the diagnosis of S2-4 hepatic fibrosis. The diagnostic efficacy of serum CHI3L1 in patients with ALT ≤ 2ULN was better than that of the other non-invasive diagnostic models.

Myocardial ischemia/reperfusion (I/R) injury is a common condition. This study aimed to investigate the potential mechanisms of circ_Ddx60 in the mouse model of I/R injury. Cardiac tissues were used to extract RNA for subsequent RNA sequencing analysis. Bioinformatic analysis was performed and circ_Ddx60 and Bcl2a1a (B cell leukemia/lymphoma 2 related protein A1a) were selected for further validation. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to detect the gene expression level. The effect of circ_Ddx60 on cardiac cell apoptosis was examined. The function of miR-302a-3p in cell apoptosis was further explored in circ_Ddx60-overexpressed HL-1 cells under hypoxia/reoxygenation (H/R) treatment. We have revealed a number of differentially expressed circRNAs and mRNAs between the I/R group and sham groups, with circ_Ddx60 being among them. Treatment of HL-1 cells with hypoxia/reoxygenation (H/R) led to an overexpression of circ_Ddx60, which then inhibited apoptosis and promoted the Bcl2a1a expression. Furthermore, circ_Ddx60 directly binds with miR-302a-3p, which could reverse the effect of circ_Ddx60 overexpression on cellular apoptosis and Bcl2a1a expression. Our study revealed that circ_Ddx60 inhibits apoptosis in myocardial cells by regulating the miR-302a-3p/Bcl2a1a axis, which provides novel insights into the prevention of myocardial I/R injury.