Background Studies have shown that sphingomyelin (SM) and its metabolites play signaling roles in the regulation of human health. Endogenous SM is involved in metabolic syndrome (MetS), while dietary SM supplementation may maintain lipid metabolism and prevent or alleviate MetS. Therefore, we hypothesized that dietary SM supplementation is beneficial for human health. Aims In order to examine the impacts of dietary SM on metabolic indexes in adults without MetS, we performed a meta-analysis to test our hypothesis. Methods A comprehensive search was performed to retrieve randomized controlled trials that were conducted between 2003 and 2023 to examine the effects of dietary SM supplementation on metabolic parameters in the Cochrane Library, PubMed, Web of Science, Embase, and ClinicalTrials.gov databases. RevMan 5.4 and Stata 14.0 software were used for meta-analysis, a sensitivity analysis, the risk of bias, and the overall quality of the resulted evidence. Results Eventually, 10 articles were included in this meta-analysis. Dietary SM supplementation did not affect the endline blood SM level. When compared to the control, SM supplementation reduced the blood total cholesterol level [MD: −12.97, 95% CI: (−14.57, −11.38), p < 0.00001], low-density lipoprotein cholesterol level [MD: −6.62, 95% CI: (−10.74, −2.49), p = 0.002], and diastolic blood pressure [MD: −3.31; 95% CI (−4.03, −2.58), p < 0.00001] in adults without MetS. The supplementation also increased high-density lipoprotein level [MD:1.41, 95% CI: (0.94, 1.88), p < 0.00001] and muscle fiber conduction velocity [MD: 95% 1.21 CI (0.53, 1.88), p = 0.0005]. The intake of SM had no effect on the blood phospholipids and lyso-phosphatidylcholine, but slightly decreased phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol concentrations. Dietary SM supplementation reduced insulin level [MD: −0.63; 95% CI (−0.96, −0.31), p = 0.0001] and HOMA-IR [MD: −0.23; 95% CI (−0.31, −0.16), p < 0.00001] without affecting blood levels of glucose and inflammatory cytokines. Conclusion Overall, dietary SM supplementation had a protective effect on blood lipid profiles and insulin level, but had limited impacts on other metabolic parameters in adults without MetS. More clinical trials and basic research are required. Systematic review registration PROSPERO , identifier CRD42023438460.
Objective: To investigate the effect of neuroglobin on oxygen-glucose deprivation and reoxygenation (OGD/R) induced autophagy in a human neuroblastoma cell line (SH-SY5Y). Methods: SH-SY5Y cells were transfected with plasmids (or vector) to establish a stable cell line of NGB overexpression (OE). After treated with OGD/R, cells were collected for the analyses of mRNA (Atg5, Atg7, BECN1 and FUNDC1) and protein levels of LC3. Furthermore, mitochondrial and cytosolic fractions were isolated for protein levels of PINK1 and Parkin. Results: Treatment of OGD/R significantly increased the levels of mRNA of Atg5, Atg7, BECN1 and FUNDC1 (peak levels were 4.90±0.71, 6.72±0.75, 2.71±0.39 and 3.96±0.78 fold, all P<0.05). The protein level of Parkin increased in mitochondria and decreased in cytoplasm after the treatment. Compared with the vector group, Ngb OE group showed a significant higher level of FUNDC1 mRNA (3.96±0.78 versus 6.86±0.63 fold, P<0.05), while Atg5, Atg7 and BECN1 mRNA levels showed no significant difference. Moreover, the mitochondrial or cytosolic protein levels of PINK1 or Parkin showed no significant difference between Ngb OE and vector group. Conclusions: Overexpression of Ngb can not affect autophagy or mitohpagy in OGD/R treated SH-SY5Y cells. Overexpression of Ngb can increase the mRNA level of FUNDC1 and the mechanism needs further study.目的： 探讨脑红蛋白(Ngb)对氧糖剥夺/复氧复糖(OGD/R)诱导的人神经母细胞瘤细胞系(SH-SY5Y)自噬的影响。 方法： 通过在SH-SY5Y细胞中转染Ngb质粒，建立Ngb过表达(NGB OE)及相应的空载(Vector)稳转株。细胞行OGD/R处理。聚合酶链反应(PCR)检测自噬相关基因(Atg5、Atg7、BECN1)及FUN14结构域包含蛋白-1(FUNDC1) mRNA表达水平，免疫印迹方法检测自噬相关基因(LC3 Ⅱ/Ⅰ)蛋白表达水平。差速离心法分离线粒体及细胞质，分别使用免疫印迹方法检测帕金森病相关蛋白(Parkin、Pink1)表达水平。 结果： OGD/R处理后，自噬相关基因Atg5、Atg7、BECN1、FUNDC1 mRNA水平升高(最高分别为4.90±0.71、6.72 ±0.75、2.71±0.39及3.96±0.78倍，均P<0.05)，细胞质中Parkin减少而线粒体中Parkin显著增加。过表达Ngb不能改变自噬相关基因Atg5、Atg7、BECN1 mRNA水平，细胞质或线粒体中Parkin无显著变化。但可以增加FUNDC1 mRNA含量(3.96±0.78倍比6.86±0.63倍，P<0.05)。 结论： Ngb不能影响OGD/R诱导的SH-SY5Y细胞自噬或线粒体自噬水平，而对FUNDC1基因的表达有促进作用，其作用机制需要进一步深入研究。.
The side effects of current immunosuppressive drugs have impeded the development of therapies for immune diseases. Selective regulation of STAT signaling is an attractive strategy for treating immune disorders. In this study, we used a small-molecule compound to explore possible means of targeting STAT1 for the treatment of Th1-mediated inflammation. Selective regulation of STAT1 signaling in T cells from C57BL/6 mice was accomplished using fusaruside, a small-molecule compound that triggers the tyrosine phosphorylation of Src homology 2-containing protein tyrosine phosphatase 2 (SHP-2). The interaction of tyrosine phosphorylated SHP-2 (pY-SHP-2) with cytosolic STAT1 prevented the recruitment of STAT1 to IFN-γR and specifically inhibited STAT1 signaling, resulting in a reduction in Th1 cytokine production and an improvement in 2, 4, 6-trinitrobenzene sulfonic acid-induced colitis in mice. Blocking the pY-SHP-2-STAT1 interaction, with SHP-2 inhibitor NSC-87877 or using T cells from conditional SHP-2 knockout mice, reversed the effects of fusaruside, resulting in STAT1 activation and worsened colitis. The fusaruside-induced ability of pY-SHP-2 to selectively sequestrate STAT1 from recruitment to the receptor is independent of its function as a phosphatase, demonstrating a novel role for SHP-2 in regulating both STAT1 signaling and Th1-type immune responses. These findings could lead to increased options for the treatment of Crohn's disease and other Th1-mediated inflammatory diseases.
OBJECTIVE To investigate the effect of human bone morphogenetic protein (hBMPs) 2/3/6 and 12 on osteosarcoma cell UMR106. METHODS Adenovirus-BMP2/3/6 and 12 (AdBMP2/3/6 and12) were used to treat the cell line. Their proliferation, apoptosis, and transmigration were detected by Trypan blue exclusion test, TdT-mediated biotinylated-dUTP nick end labeling (TUNEL), acridine orange-ethidium bromide (AO/EB) double fluorescent dye staining, and transwell-room test, respectively. The alkaline phosphatase (ALP) activity was detected to reflect the differentiation of tumors. RESULTS Compared with the control groups, the cell survival rate of the experimental groups treated with AdBMP2/3/6 and 12 showed a significant time-dependent decrease (P<0.01). The apoptosis indexes were increased significantly (P<0.01) and the results from TUNEL and AO/EB method were consistent. The cell numbers of transmembrane significantly decreased at 24,48, and 72 h (P<0.01). AdBMP2/3/6 and 12 treatment enhanced the activity of ALP activity from day 3 and this effect might still be observed up to day 9 of the treatment (P<0.01). CONCLUSION hBMPs2/3/6 and 12 can inhibit the proliferation and transmigration, and induce their apoptosis and differentiation in osteosarcoma cell line UMR106.
Abstract Chemoresistance posts a major hurdle for treatment of acute leukemia. There is increasing evidence that prolonged and intensive chemotherapy often fails to eradicate leukemic stem cells, which are protected by the bone marrow niche and can induce relapse. Thus, new therapeutic approaches to overcome chemoresistance are urgently needed. By conducting an ex vivo small molecule screen, here we have identified Quinacrine (QC) as a sensitizer for Cytarabine (AraC) in treating acute lymphoblastic leukemia (ALL). We show that QC enhances AraC-mediated killing of ALL cells, and subsequently abrogates AraC resistance both in vitro and in an ALL-xenograft model. However, while combo AraC+QC treatment prolongs the survival of primary transplanted recipients, the combination exhibits limited efficacy in secondary transplanted recipients, consistent with the survival of niche-protected leukemia stem cells. Introduction of C dc42 A ctivity S pecific In hibitor, CASIN, enhances the eradication of ALL leukemia stem cells by AraC+QC and prolongs the survival of both primary and secondary transplanted recipients without affecting normal long-term human hematopoiesis. Together, our findings identify a small-molecule regimen that sensitizes AraC-mediated leukemia eradication and provide a potential therapeutic approach for better ALL treatment.
The immune receptor TREM1 (Triggering receptor expressed on myeloid cells 1) is a master regulator of inflammatory response. Compelling evidence suggests important pathological roles for TREM1 in various types of solid tumors. However, the role of TREM1 in hematologic malignancies is not known. Our previous study demonstrated that TREM1 cooperates with diminished DNA damage response to induce expansion of pre-leukemic hematopoietic stem cells (HSC) in mice deficient for the Fanconi anemia gene Fanca. Here we investigated TREM1 in leukemogenesis using mouse models of the DNA repair-deficient Fanca-/- and the oncogenic MLL-AF9 or KrasG12D. We found that Trem1 was highly expressed in preleukemic HSC and leukemia stem cells (LSC). By selective deletion of the Trem1 gene in the hematopoietic compartment, we showed that ablation of Trem1 reduced leukemogenic activity of the pre-leukemic HSC and LSC in mice. Trem1 was required for the proliferation of the pre-leukemic HSC and LSC. Further analysis revealed that Trem1 expression in preleukemic HSC and LSC was associated with persistent DNA damage, prolonged oncogenic stress, and a strong inflammatory signature. Targeting several top Trem1 inflammatory signatures inhibited the proliferation of pre-leukemic HSC and LSC. Collectively, our observations uncover previously unknown expression and function of TREM1 in malignant stem cells, and identify TREM1 as a driver of leukemogenesis.
. Pyroptosis is closely related to many chronic diseases including atherosclerosis, but the potential pathomechanisms are still unclear. This research aimed to explore how lncRNAs may contribute to pyroptosis and the potential mechanisms. . We performed in vitro assays to investigate the effects of a relatively newly discovered lncRNA, NEXN-AS1, on pyroptosis. Two types of vascular wall cells, namely, human vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), were used as cell models in this study. A previously constructed lentivirus vector was used to overexpress lncRNA NEXN-AS1 and a small interfering RNA (siRNA) mimic against NEXN to knockdown NEXN. The mRNA and protein levels of molecules of pyroptosis in the canonical inflammasome pathway, including nucleotide-binding oligomerization segment-like receptor family 3 (NLRP3), caspase-1, gasdermin D (GSDMD), interleukin-1β (IL-1β), and interleukin-18 (IL-18) were detected using quantitative real-time PCR and western blot analysis, respectively. . We observed that lentivirus-mediated overexpression of lncRNA NEXN-AS1 increased the expression levels of NEXN and markedly reduced the expression of critical molecules involved in pyroptosis, including NLRP3, caspase-1, GSDMD, IL-1β, and IL-18, in both VSMCs and ECs. Furthermore, NEXN knockdown could reverse the effects of lncRNA NEXN-AS1 overexpression on pyroptosis. lncRNA NEXN-AS1 could act as an target for maintaining endothelium homeostasis, plaque stability, and delaying the progression of atherosclerosis.
Purpose This study aimed to evaluate stiffness changes of rabbit subcutaneous VX 2 tumors before and after irreversible electroporation (IRE) ablationby shearwave ultrasound elastography (SWE). Methods IRE was performed on 20 subcutaneously implanted VX 2 tumors in rabbits (R-SIVX 2 ). Tumor stiffness was measured by SWE at different time points (before IRE,120minutes after IRE,7 days after IRE and 14 days after IRE). Results Before IRE, the mean stiffness (E mean ) of tumors was (10.45 ± 1.07) KPa. 120 minutes after I RE, the E mean of tumors obviously rose to (70.53 ± 9.87) KPa. 7 days after IRE, the E mean of tumors decreased to (40.22 ± 9.01) KPa. 14 days after IRE, the E mean of tumors was (15.17 ± 1.00) KPa. A clear boundary was observed between the ablation area and the normal tissues in the pathological results. Conclusions The stiffness of the VX 2 tumors experienced a first rise process and tend to be normal in the procedure of IRE. SWE could provide tissue stiffness information of different IRE ablation period as a non-invasive method.
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