Genetic prediction of causal association between serum bilirubin and hematologic malignancies: a two-sample Mendelian randomized and bioinformatics study

IntroductionAn increasing number of cohort studies have shown a correlation between serum bilirubin and tumors, but no definitive causal relationship has been established between serum bilirubin and hematological malignancies.Therefore, the aim of the present study was to assess the causal relationship of serum bilirubin, including total bilirubin (TBIL) and direct bilirubin (DBIL), with hematological malignancies, including leukemia, lymphoma, and myeloma.MethodsWe used a genome-wide association study (GWAS) collection of TBIL, DBIL, and hematological malignancies data. Using two-sample Mendelian randomization(MR), we assessed the impact of TBIL and DBIL on hematological malignancies. For this study, the inverse variance weighting method (IVW) was the primary method of MR analysis. In the sensitivity analysis, the weighted median method, MR Egger regression, and MR-PRESSO test were used. To understand the mechanisms behind TBIL and DBIL, we used three different approaches based on screening single nucleotide polymorphisms (SNPs) and their associated genes, followed by bioinformatics analysis.ResultsThe IVW test results showed evidence of effects of TBIL (odds ratio [OR]: 4.47, 95% confidence interval [CI]: 1.58-12.62) and DBIL (OR: 3.31, 95% CI: 1.08-10.18) on the risk of acute myeloid leukemia (AML).The findings from bioinformatics indicated that TBIL could potentially undergo xenobiotic metabolism through cytochrome P450 and contribute to chemical carcinogenesis.DiscussionIn this study, two-sample MR analysis revealed a causal relationship between TBIL, DBIL, and AML

Common Gamma Chain Cytokines Promote Rapid In Vitro Expansion of Allo-Specific Human CD8+ Suppressor T Cells

Human CD8+ regulatory T cells, particularly the CD8+CD28− T suppressor cells, have emerged as an important modulator of alloimmunity. Understanding the conditions under which these cells are induced and/or expanded would greatly facilitate their application in future clinical trials. In the current study, we develop a novel strategy that combines common gamma chain (γc) cytokines IL-2, IL-7 and IL-15 and donor antigen presenting cells (APCs) to stimulate full HLA-mismatched allogeneic human CD8+ T cells which results in significant expansions of donor-specific CD8+CD28− T suppressor cells in vitro. The expanded CD8+CD28− T cells exhibit increased expressions of CTLA-4, FoxP3, and CD25, while down-regulate expressions of CD56, CD57, CD127, and perforin. Furthermore, these cells suppress proliferation of CD4+ T cells in a contact-dependent and cytokine-independent manner. Interestingly, the specificity of suppression is restricted by the donor HLA class I antigens but promiscuous to HLA class II antigens, providing a potential mechanism for linked suppression. Taken together, our results demonstrate a novel role for common γc cytokines in combination with donor APCs in the expansion of donor-specific CD8+CD28− T suppressor cells, and represent a robust strategy for in vitro generation of such cells for adoptive cellular immunotherapy in transplantation

Borneol promotes autophagic degradation of HIF-1α and enhances chemotherapy sensitivity in malignant glioma

Background Gliomas are characterized by high mortality rates and resistance. Even with conventional chemotherapy the prognosis of glioblastoma remains poor. Many medications are not optimally effective due to limited bioavailability. The bioavailability of medicine can be enhanced by borneol, a monoterpenoid substance. In this study, we investigated the effect of borneol, a commonly used Chinese medicine, on chemosensitivity in C6 glioma and U251 human glioma cell lines and elucidated its therapeutic molecular targets. Methods The chemosensitivity-inducing effects of borneol in C6 and U251 cells were examined using CCK8 and clonal formation assays. The mechanism underlying the effect of borneol was evaluated through immunohistochemistry and western blotting assays. Further, the number of autophagosomes was determined via transmission electron microscopy. Finally, the chemical sensitization effect of borneol was evaluated in SD rats after C6 orthotopic tumor transplantation. Results Borneol increased cytotoxicity in C6 and U251 cells in response to temozolomide (TMZ). In addition, through transmission electron microscopy, western blotting, and immunohistochemical tests, we found that borneol combined with TMZ significantly increased the level of autophagy and that hypoxia inducible factor-1(HIF-1α) is a candidate target through which borneol enhances the cytotoxic effect of TMZ. Borneol’s ability to enhance HIF-1α degradation was counteracted following the administration of autophagy inhibitors. In vivo, borneol treatment was found to enhance the anticancer effect of TMZ and delay tumor progression, and this effect was closely related to its ability to promote the autophagic degradation of HIF-1α. Conclusions HIF-1α might be a valid therapeutic target of borneol, which can be potentially applied as a chemosensitizing drug used for glioma treatment

High expression of SLC27A2 predicts unfavorable prognosis and promotes inhibitory immune infiltration in acute lymphoblastic leukemia

Solute carrier family 27 member 2 (SLC27A2) is involved in fatty acid metabolism in tumors and represents a prospective target for cancer therapy. However, the role and mechanism of action of SLC27A2 in acute lymphoblastic leukemia (ALL) remain unclear. In this study, we aimed to explore the intrinsic associations between SLC27A2 and ALL and evaluate the prognostic significance, biological functions, and correlation with immune infiltration. We used the transcriptome and clinical data from the TARGET dataset. Differentially expressed genes (DEGs) in the SLC27A2 low- and high-expression groups were analyzed for prognostic implications and functional enrichment. Furthermore, we analyzed the relationship between SLC27A2 gene expression and immune cell infiltration using the ESTIMATE method, which was evaluated using the TIGER platform. Finally, we knocked down SLC27A2 in the Jurkat ALL cell line and conducted cell proliferation, western blotting, flow cytometry, and CCK-8 assays to elucidate the biological function of SLC27A2 in ALL. Patients with ALL who have higher expression levels of SLC27A2 have poorer overall survival and event-free survival. According to gene set enrichment analysis, the DEGs were primarily enriched with immune system processes and the PI3K-Akt signaling pathway. There was an inverse relationship between SLC27A2 expression and immune cell invasion, suggesting involvement of the former in tumor immune evasion. In vitro experiments showed that knockdown of SLC27A2 inhibited cell proliferation and protein expression and altered the Akt pathway, with a reduced proportion of B cells. In conclusion, SLC27A2 plays a vital role in the development of ALL

Comparing the Effects of Pond and Rice Field Culture Methods on Muscle Quality of Rice Flower Carp

Rice flower carp (Cyprinus carpio rubrofuscus) has high economic value because of its tender meat. However, a comprehensive scientific evaluation of the meat quality and nutritional value of rice flower carp is still needed. At the same time, because of its fast growth and strong disease resistance, rice flower carp is widely popularized in rice field culture but without any research comparing its quality with the pond culture method. Although rice farming has high ecological value, the fish yield is low and its specifications are abnormal, which cannot guarantee the stability and safety of the commercial fish supply and limit the potential rice flower carp industrial benefits. In addition, some studies have shown that fish muscle quality can be affected by environmental conditions. This study aimed to comprehensively evaluate the muscle quality and nutritional value of the rice flower carp and investigate the relationships between the nutritional values and its culture conditions, providing data to increase the rice flower carp yield, economic efficiency, and farmed varieties available. Therefore, 6 000 Quanzhou rice flower carp (2.35±0.08 g) were randomly divided into ponds and rice field groups for the experiment (three replicates per group, with a density of 15 000/hm2). The pond culture group was fed with 3% of the commercially established everyday food per fish weight, while the rice field group was not fed. After 12 weeks, the fish were submitted to a 24 h period without food and anesthetized using MS-222 (USA, Sigma). The length and weight of 100 fish were measured for each treatment. For the rice field group and pond group, respectively, the lengths were (13.56±0.49) cm and (14.10±0.23) cm, and the weights were (73.19±7.02) g and (101.20±4.57) g. The muscle quality of 30 fish from each treatment was measured, including basic nutritional components, texture characteristics, and amino acid and fatty acid compositions. The nutritional level was compared between the pond and rice field groups using the FAO/WHO amino acid score, whole egg protein comparison, protein amino acid score (AAS), chemical score (CS), and essential amino acid index (EAAI). Moreover, no significant differences between the two culture methods were observed in relation to the total ash (P > 0.05). The crude protein and crude fat contents in the rice field group were significantly lower than in the pond group (P 0.05). Essential amino acids (EAA) in both groups met the FAO/WHO standard. Among the 18 amino acids measured, the total amino acids (TAA), delicious amino acids (DAA), essential and nonessential amino acids (NEAA) were significantly lower in rice field conditions than in pond (P 0.05). In contrast, the contents of linoleic, linolenic, and arachidonic acids in the pond group were significantly higher than those in the rice field group (P < 0.05), while 14 other fatty acids showed significantly lower contents in the pond group (P < 0.05). The monounsaturated fatty acid (MUFA) contents in the pond group were significantly higher (P < 0.05), while the EPA+DHA and n-3PUFA/n-6PUFA were significantly lower than those in the rice field group (P < 0.05). Overall, the contents of four main flavor amino acids (glutamic acid, glycine, alanine, and aspartic acid) in the rice field group were significantly lower than those in the pond group (P < 0.05). In conclusion, rice flower carp reared in both pond and rice field is a high-quality protein source. However, different cultural environments significantly influence the rice flower carp muscle nutritional value and quality, wherein a higher nutrient composition and amino acid score were observed in the pond environment. Concerning the fatty acids content, the muscle of rice flower carp reared in rice fields had higher EPA+DHA content and N-3/N-6 polyunsaturated fatty acid ratio, which is more suitable for people with hyperlipidemia and cardiovascular diseases. In addition, in terms of texture, the muscle of rice flower carp is chewier under the rice field rearing condition. Nevertheless, N-3PUFA shortages were observed in both culture conditions. Besides, fish in the pond group had better muscle nutrition than the rice field group. Different culture conditions can change rice flower carp's fatty acid composition and content to a certain extent, but none of the two conditions tested here could completely allay the lower N-3PUFA problem. Therefore, increasing the N-3PUFA content of rice flower carp is the key to improving its nutritional value, and pond culture conditions make this process easier to be manually controlled

Recombinant Reg3&alpha; Prevents Islet &beta;-Cell Apoptosis and Promotes &beta;-Cell Regeneration

Progressive loss and dysfunction of islet &beta;-cells has not yet been solved in the treatment of diabetes. Regenerating protein (Reg) has been identified as a trophic factor which is demonstrated to be associated with pancreatic tissue regeneration. We previously produced recombinant Reg3&alpha; protein (rReg3&alpha;) and proved that it protects against acute pancreatitis in mice. Whether rReg3&alpha; protects islet &beta;-cells in diabetes has been elusive. In the present study, rReg3&alpha; stimulated MIN6 cell proliferation and resisted STZ-caused cell death. The protective effect of rReg3&alpha; was also found in mouse primary islets. In BALB/c mice, rReg3&alpha; administration largely alleviated STZ-induced diabetes by the preservation of &beta;-cell mass. The protective mechanism could be attributed to Akt/Bcl-2/-xL activation and GRP78 upregulation. Scattered insulin-expressing cells and clusters with small size, low insulin density, and exocrine distribution were observed and considered to be neogenic. In isolated acinar cells with wheat germ agglutinin (WGA) labeling, rReg3&alpha; treatment generated insulin-producing cells through Stat3/Ngn3 signaling, but these cells were not fully functional in response to glucose stimulation. Our results demonstrated that rReg3&alpha; resists STZ-induced &beta;-cell death and promotes &beta;-cell regeneration. rReg3&alpha; could serve as a potential drug for &beta;-cell maintenance in anti-diabetic treatment