Genetic and clinical characteristics of acute B-cell lymphoblastic leukemia with MEF2D fusions and report of two novel MEF2D rearrangements.

The MEF2D rearrangement is a recurrent chromosomal abnormality detected in approximately 2.4-5.3% of patients with acute B-cell lymphoblastic leukemia (B-ALL). Currently, MEF2D-rearranged B-ALL is not classified as an independent subtype in the WHO classification. Consequently, the clinical significance of MEF2D rearrangement in B-ALL remains largely unexplored. In this study, we retrospectively screened 260 B-ALL patients with RNA sequencing data collected between November 2018 and December 2022. Among these, 10 patients were identified with MEF2D rearrangements (4 with MEF2D::HNRNPUL1, 3 with MEF2D::BCL9, 1 with MEF2D::ARID1B, 1 with MEF2D::DAZAP1 and 1 with MEF2D::HNRNPM). Notably, HNRNPM and ARID1B are reported as MEF2D fusion partners for the first time. The patient with the MEF2D::HNRNPM fusion was resistant to chemotherapy and chimeric antigen receptor T-cell therapy and relapsed early after allogenic stem cell transplantation. The patient with MEF2D::ARID1B experienced early extramedullary relapse after diagnosis. All 10 patients achieved complete remission after induction chemotherapy. However, 9/10 (90%) of whom experienced relapse. Three of the 9 patients relapsed with aberrant expression of myeloid antigens. The median overall survival of these patients was only 11 months. This small cohort showed a high incidence of early relapse and short survival in patients with MEF2D rearrangements.

L-Carnitine protects against tacrolimus-induced renal injury by attenuating programmed cell death via PI3K/AKT/PTEN signaling.

Reducing immunosuppressant-related complications using conventional drugs is an efficient therapeutic strategy. L-carnitine (LC) has been shown to protect against various types of renal injury. In this study, we investigated the renoprotective effects of LC in a rat model of chronic tacrolimus (TAC) nephropathy. SD rats were injected with TAC (1.5 mg · kg-1 · d-1, sc) for 4 weeks. Renoprotective effects of LC were assessed in terms of renal function, histopathology, oxidative stress, expression of inflammatory and fibrotic cytokines, programmed cell death (pyroptosis, apoptosis, and autophagy), mitochondrial function, and PI3K/AKT/PTEN signaling. Chronic TAC nephropathy was characterized by severe renal dysfunction and typical histological features of chronic nephropathy. At a molecular level, TAC markedly increased the expression of inflammatory and fibrotic cytokines in the kidney, induced oxidative stress, and led to mitochondrial dysfunction and programmed cell death through activation of PI3K/AKT and inhibition of PTEN. Coadministration of LC (200 mg · kg-1 · d-1, ip) caused a prominent improvement in renal function and ameliorated histological changes of kidneys in TAC-treated rats. Furthermore, LC exerted anti-inflammatory and antioxidant effects, prevented mitochondrial dysfunction, and modulated the expression of a series of apoptosis- and autophagy-controlling genes to promote cell survival. Human kidney proximal tubular epithelial cells (HK-2 cells) were treated with TAC (50 µg/mL) in vitro, which induced production of intracellular reactive oxygen species and expression of an array of genes controlling programmed cell death (pyroptosis, apoptosis, and autophagy) through interfering with PI3K/AKT/PTEN signaling. The harmful responses of HK-2 cells to TAC were significantly attenuated by cotreatment with LC and the PI3K inhibitor LY294002 (25 µM). In conclusion, LC treatment protects against chronic TAC nephropathy through interfering the PI3K/AKT/PTEN signaling.

Long Noncoding RNA 00472: A Novel Biomarker in Human Diseases.

Long non-coding RNAs (lncRNAs) play important roles in human diseases. They control gene expression levels and influence various biological processes through multiple mechanisms. Functional abnormalities in lncRNAs are strongly associated with occurrence and development of various diseases. LINC00472, which is located on chromosome 6q13, is involved in several human diseases, particularly cancers of the breast, lung, liver, osteosarcoma, bladder, colorectal, ovarian, pancreatic and stomach. Importantly, LINC00472 can be used as a biomarker for breast cancer cell sensitivity to chemotherapeutic regimens, including doxorubicin. LINC00472 is regulated by microRNAs and several signaling pathways. However, the significance of LINC00472 in human diseases has not been clearly established. In this review, we elucidate on the significance of LINC00472 in various human diseases, indicating that LINC00472 may be a diagnostic, prognostic as well as therapeutic target for these diseases.

[Quantitative Assessment of Human Health Risks Based on Soil Heavy Metals and PAHs Sources:Take a Polluted Industrial Site of Beijing As an Example].

In this study, 130 surface soil samples were collected at an industrial pollution site in Beijing and the contents of As, Be, Cd, Cu, Cr, Hg, Ni, Pb, Sb, Ti, Zn, and 16 PAHs were determined. The positive matrix factorization (PMF) model was used to analyze the sources of heavy metals and PAHs, and the contributions of these sources to carcinogenic risk and hazard index in the study area were calculated. The results showed that the contents of Cd, Cu, Pb, Hg, As, Zn, and Cr in the soil exceeded the background values in different degrees; Cd, Hg, Pb, Zn, and Cu exceeded the background values by>50%. Low molecular weight PAHs (two and three rings) and high molecular weight PAHs (four to six rings) accounted for 39.6% and 60.4% of the total content of 16 PAHs. The PAH content at 77% of the sampling points at the target site was more than 1000 µg ·kg-1, which suggests severe PAH pollution at the site. Heavy metals Be, Ti, As, and Ni mainly originated from natural sources. There are three major sources of 7 heavy metals and 16 PAHs at the site: coal combustion (Hg and ∑16PAHs), smelting (Cu, Cr, Pb, and Zn), and traffic (Sb and Cd). The contribution rates of these sources to the total average contents of seven heavy metals and sixteen PAHs at 130 sampling sites were 8.46% (coal combustion), 90.61% (smelting), and 0.94% (traffic). Human health risk assessment results showed that the carcinogenic risk of seven heavy metals and ∑16PAHs ranged from 4.17×10-6 to 39.38×10-4, and the hazard index ranged from 0 to 32.23. The maximum carcinogenic risk and hazard index values were calculated near the coking plant. Benzo[α]pyrene was the PAH that posed the highest carcinogenic risk and Zn was the heavy metal that had the highest hazard index value. The average carcinogenic risk of coal combustion was 2.16×10-4, accounting for 50.26% of the total average carcinogenic risk. The average hazard index of smelting was 0.834, accounting for 56.43% of the total average non-carcinogenic risk. These two pollution sources are responsible for the high levels of heavy metals and PAHs in the soil of the steel smelting sites that pose the most severe health risks. The results of this study can provide reference for soil remediation and process optimization at other heavily polluted industrial sites.

Antioxidative effect of melatonin on cryopreserved ovarian tissue in mice.

Cryopreservation of ovarian tissues (OTs) has become the most effective way to preserve the fertility of female cancer patients. However, cryopreservation of OTs is still relatively at an experimental stage. The aim of study is to examine the effect of melatonin (MTL) on cryopreserved-thawed OTs. Fragments of OTs were cryopreserved in medium containing different concentrations (0 mM, 0.001 mM, 0.01 mM, 0.1 mM and 1 mM) of MLT. The endogenous enzymes (GSH-PX, GSH, SOD, CAT and T-AOC), MDA and ROS levels were all evaluated after cryopreservation. Our results showed that the 0.1 mM of MLT significantly improved the survival and diameter of follicles (P < 0.001). Meanwhile, the antioxidant enzymes activities (including GSH-PX, GSH, SOD, CAT and T-AOC) were enhanced and MDA content were significantly decreased in 0.1 mM of MLT group compared to other groups (P < 0.001). Additionally, compared to the control group, MTL of 0.1 mM resulted in a significantly lower ROS level. In conclusion, MLT protects the quality of cryopreserved OTs by decreasing oxidative stress level and the optimal concentration is 0.1 mM.

Long non-coding RNA small nucleolar RNA host gene 6 aggravates pancreatic cancer through upregulation of far upstream element binding protein 1 by sponging microRNA-26a-5p.

BACKGROUND: Pancreatic cancer (PC) is a highly deadly malignancy with few effective therapies. We aimed to unmask the role that long non-coding RNA small nucleolar RNA host gene 6 (SNHG6) plays in PC cells by targeting far upstream element binding protein 1 (FUBP1) via microRNA-26a-5p (miR-26a-5p). METHODS: SNHG6 expression was predicted by bioinformatics, followed by verification via reverse transcription quantitative polymerase chain reaction. Then, the interactions among SNHG6, miR-26a-5p, and FUBP1 were detected through online software analysis, dual luciferase reporter assay and RNA pull-down. After that, cells were treated with different small interfering RNAs and/or mimic to determine the interactions among SNHG6, miR-26a-5p, and FUBP1 and their roles in PC cells. Finally, the role of SNHG6 in tumor growth in vivo was evaluated by measuring the growth and weight of transplanted tumors in nude mice. A t-test, one-way and two-way analysis of variance were used for data analysis. RESULTS: Compared with that in normal tissues, SNHG6 was highly expressed in PC tissues (1.00 ±â€Š0.05 vs. 1.56 ±â€Š0.06, t = 16.03, P < 0.001). Compared with that in human pancreatic duct epithelial cells (HPDE6-C7), SNHG6 showed the highest expression in PANC-1 cells (1.00 ±â€Š0.06 vs. 3.87 ±â€Š0.13, t = 34.72, P < 0.001) and the lowest expression in human pancreatic cancer cells (MIAPaCa-2) (1.00 ±â€Š0.06 vs. 1.41 ±â€Š0.07, t = 7.70, P = 0.0015). Compared with the levels in the si-negative control group, SNHG6 (0.97 ±â€Š0.05 vs. 0.21 ±â€Š0.06, t = 16.85, P < 0.001), N-cadherin (0.74 ±â€Š0.05 vs. 0.41 ±â€Š0.04, t = 8.93, P < 0.001), Vimentin (0.55 ±â€Š0.04 vs. 0.25 ±â€Š0.03, t = 10.39, P < 0.001), and ß-catenin (0.62 ±â€Š0.05 vs. 0.32 ±â€Š0.03, t = 8.91, P < 0.001) were decreased, while E-cadherin (0.65 ±â€Š0.06 vs. 1.36 ±â€Š0.07, t = 13.34, P < 0.001) was increased after SNHG6 knockdown or miR-26a-5p overexpression, accompanied by inhibited cell proliferation, migration, and invasion. SNHG6 overexpression exerted the opposite effects. SNHG6 upregulated FUBP1 expression by sponging miR-26a-5p. Silencing SNHG6 blocked the growth of PC in vivo. CONCLUSION: Silencing SNHG6 might ameliorate PC through inhibition of FUBP1 by sponging miR-26a-5p, thus providing further supporting evidence for its use in PC treatment.

Exogenous pancreatic kininogenase protects against renal fibrosis in rat model of unilateral ureteral obstruction.

Tissue kallikrein has protective function against various types of injury. In this study, we investigated whether exogenous pancreatic kininogenase (PK) conferred renoprotection in a rat model of unilateral ureteral obstruction (UUO) and H2O2-treated HK-2 cells in vitro. SD rats were subjected to UUO surgery, then PK (7.2 U/g per day, ip) was administered for 7 or 14 days. After the treatment, rats were euthanized; the obstructed kidneys were harvested for further examination. We found that PK administration significantly attenuated interstitial inflammation and fibrosis, and downregulated the expression of proinflammatory (MCP-1, TLR-2, and OPN) and profibrotic (TGF-ß1 and CTGF) cytokines in obstructed kidney. UUO-induced oxidative stress, closely associated with excessive apoptotic cell death and autophagy via PI3K/AKT/FoxO1a signaling, which were abolished by PK administration. We further showed that PK administration increased the expression of bradykinin receptors 1 and 2 (B1R and B2R) mRNA and the production of NO and cAMP in kidney tissues. Coadministration with either B1R antagonist (des-Arg9-[Leu8]-bradykinin) or B2R antagonist (icatibant) abrogated the renoprotective effects of PK, and reduced the levels of NO and cAMP in obstructed kidney. In H2O2-treated HK-2 cells, addition of PK (6 pg/mL) significantly decreased ROS production, regulated the expression of oxidant and antioxidant enzymes, suppressed the expression of TGF-ß1 and MCP-1, and inhibited cell apoptosis. Our data demonstrate that PK treatment protects against the progression of renal fibrosis in obstructed kidneys.

Investigation and comparison of the protective activities of three functional proteins-lactoferrin, α-lactalbumin, and ß-lactoglobulin-in cerebral ischemia reperfusion injury.

The objective of this study was to evaluate the protection conferred by lactoferrin, α-lactalbumin, and ß-lactoglobulin in cerebral ischemia reperfusion (I/R) injury. Rat pheochromocytoma (PC12) cells were used to construct an oxygen and glucose deprivation model in vitro, and ICR mice underwent carotid artery "ligation-relaxation" to construct a cerebral I/R injury model in vivo. The levels of toll-like receptor 4 (TLR4) and downstream factors including nuclear factor-κB, tumor necrosis factor-α, and IL-1ß were measured. Metabonomics detection and data mining were conducted to identify the specific metabolic sponsor of the 3 proteins. The results showed that lactoferrin, α-lactalbumin, and ß-lactoglobulin protected neurons from cerebral I/R injury by increasing the level of bopindolol and subsequently inhibiting the TLR4-related pathway to different degrees; ß-lactoglobulin had the strongest activity of the 3 proteins. In summary, this study is the first to investigate and compare the protective effects of lactoferrin, α-lactalbumin, and ß-lactoglobulin in a cerebral stroke model. The results implicate TLR4 as a novel target of the 3 bioactive proteins to prevent cerebral I/R injury.

Durable response to pulsatile icotinib for central nervous system metastases from EGFR-mutated non-small cell lung cancer: A case report.

BACKGROUND: Central nervous system (CNS) metastases are a catastrophic complication of non-small cell lung cancer (NSCLC), including brain and leptomeningeal carcinomatosis, and are always accompanied by a poor prognosis. Despite the continuous development of existing treatments, the therapy of CNS metastases remains challenging. CASE SUMMARY: We report a patient who was definitively diagnosed with brain and leptomeningeal metastases from NSCLC with a targeted mutation in epidermal growth factor receptor (EGFR). A standard dosage of icotinib (125 mg three times daily) was implemented but ineffective. CNS lesions developed despite stable systemic control, so pulsatile icotinib (1125 mg every 3 d) was administered. This new strategy for administration has lasted 25 mo so far, and resulted in complete remission of neurological symptoms, almost vanished lesions, and longer survival with no notable side effects. CONCLUSION: This is the first successful example of pulsatile icotinib for treating isolated CNS progression from EGFR mutation-positive NSCLC, providing a new alternative for the local treatment of CNS metastases.

Modulation activity of heat-treated and untreated lactoferrin on the TLR-4 pathway in anoxia cell model and cerebral ischemia reperfusion mouse model.

This study aimed to investigate the modulation activity of heated and nonheated lactoferrins in an inflammatory pathway in anoxia and reoxygenation cell and cerebral ischemic reperfusion mouse models. Rat pheochromocytoma 12 (PC-12) cells were subjected to oxygen and glucose deprivation in vitro to construct an anoxia and reoxygenation cell model, and Institute for Cancer Research (ICR) mice were given carotid artery "ligation-relaxation" in vivo to construct a cerebral ischemic reperfusion mouse model. The protein levels of toll-like receptor 4 (TLR-4) and downstream inflammatory proteins including nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), and IL-1ß were detected. Meanwhile, metabonomic detection of overall metabolites of PC-12 cells was performed to screen out the specific changed metabolite affected by lactoferrin at the condition of anoxia and reoxygenation. The results showed that lactoferrin could inhibit the TLR-4-related pathway triggered by anoxia and reoxygenation and ischemic reperfusion. A total of 41 significantly changed metabolites were identified by metabonomic analysis, and glutathione was seen as a metabolite of interest in suppressing TLR-4-related pathway in anoxia and reoxygenation cell models. However, heated lactoferrin lost the ability of attenuating the TLR-4-related pathway. The loss of modulation activity of heated lactoferrin might be due to its protein aggregation, which was evidenced by larger average particle diameter than the unheated lactoferrin. This study is the first to investigate the effect of heat treatment on the modulation activity of lactoferrin in the TLR-4-related pathway in anoxia and reoxygenation cell and cerebral ischemic reperfusion mouse models, and indicate that lactoferrin may serve as a dietary intervention for cerebral ischemia.

Ouabain impairs cancer metabolism and activates AMPK-Src signaling pathway in human cancer cell lines.

In addition to the well-known cardiotonic effects, cardiac glycosides (CGs) produce potent anticancer effects with various molecular mechanisms. We previously show that ouabain induces autophagic cell death in human lung cancer cells by regulating AMPK-mediated mTOR and Src-mediated ERK1/2 signaling pathways. However, whether and how AMPK and Src signaling interacts in ouabain-treated cancer cells remains unclear. Given the pivotal role of AMPK in metabolism, whether ouabain affects cancer cell metabolism remains elusive. In this study we showed that treatment with ouabain (25 nM) caused simultaneous activation of AMPK and Src signaling pathways in human lung cancer A549 cells and human breast cancer MCF7 cells. Cotreatment with AMPK inhibitor compound C or siRNA greatly abrogates ouabain-induced Src activation, whereas cotreatment with Src inhibitor PP2 has little effect on ouabain-induced AMPK activity, suggesting that AMPK served as an upstream regulator of the Src signaling pathway. On the other hand, ouabain treatment greatly depletes ATP production in A549 and MCF7 cells, and supplement of ATP (100 µM) blocked ouabain-induced AMPK activation. We further demonstrated that ouabain greatly inhibited the mitochondrial oxidative phosphorylation (OXPHOS) in the cancer cells, and exerted differential metabolic effects on glycolysis depending on cancer cell type. Taken together, this study reveals that the altered cancer cell metabolism caused by ouabain may contribute to AMPK activation, as well as its cytotoxicity towards cancer cells.

Effect of Heat Treatment on the Antitumor Activity of Lactoferrin in Human Colon Tumor (HT29) Model.

To investigate the effect of heat treatment on the antitumor activity of lactoferrin in colon cancer cells and colon tumors, the HT-29 (human intestinal epithelial tumor cell) cell line was exposed to lactoferrin and various heat treatments. The impacts on cell proliferation, invasion, and migration were observed in vitro, and nude mice bearing HT29 tumors were administered lactoferrin and underwent various heat treatments in vivo. In the HT29 cell proliferation test using transwell and scratch analyses, lactoferrin (20 mg/mL) without or with heat treatment (50 and 70 °C) significantly inhibited cell proliferation, migration, and invasion (compared with the control, p < 0.05), while lactoferrin with heat treatment (100 °C) did not affect these parameters. In vivo, HT29 tumor weight was significantly reduced in the lactoferrin (without heat treatment and with 50 and 70 °C treatment) groups (1.59 ± 0.20, 1.67 ± 0.25, and 2.41 ± 0.42 g, compared with the control, p < 0.05), and there was no significant difference between the control (3.73 ± 0.33 g) and the 100 °C treatment group (3.58 ± 0.29 g). Moreover, 100 °C heat treatment reduced inhibition of the VEGFR2/VEGFA/PI3K/Akt/Erk1/2 angiogenesis pathway by lactoferrin. In summary, HT29 tumors were effectively suppressed by lactoferrin via inhibition of VEGFR2/VEGFA/PI3K/Akt/Erk1/2 pathway, and heat treatment affected the antitumor activity of lactoferrin in a temperature-dependent manner.

Design and synthesis of novel dasatinib derivatives as inhibitors of leukemia stem cells.

We used the concept of bioisosteres to design and synthesize a novel series of dasatinib derivatives for the treatment of leukemia. Unfortunately, most of the dasatinib derivatives did not show appreciable inhibition against leukemia cell lines K562 and HL60. However, acrylamide compound 2c had comparable inhibitory activity with dasatinib against K562 cells (IC50 = 0.039 nM vs. 0.069 nM). And amide compound 2a and acrylamide compound 2c also had comparable inhibitory activity with dasatinib against the leukemia cell line HL60 (IC50 = 0.25 nM and 0.26 nM vs. 0.11 nM). Against the leukemia progenitor cell line KG1a, triazole compounds 15a and 15d-15f and oxadiazole compounds 24a-24d were more potent than dasatinib. In particular, the hydroxyl compounds 15a and 24a were about 64 and 180 fold more potent than dasatinib against KG1a cells (IC50 = 0.14 µM and 0.05 µM vs. 8.98 µM). Compounds 15a and 24a also inhibited colony formation in MCF-7 cells and inhibited cell migration in the cell wound scratch assay in B16BL6 cells. Moreover, hydroxyl compounds 15a and 24a had low toxicity in vivo.

Lactoferrin Exerts Antitumor Effects by Inhibiting Angiogenesis in a HT29 Human Colon Tumor Model.

To investigate the effect and potential mechanisms of lactoferrin on colon cancer cells and tumors, HT29 and HCT8 cells were exposed to varying concentrations of lactoferrin, and the impacts on cell proliferation, migration, and invasion were observed. Cell proliferation test showed that high dosage of lactoferrin (5-100 mg/mL) inhibited cell viability in a dose-dependent manner, with the 50% concentration of inhibition at 81.3 ± 16.7 mg/mL and 101 ± 23.8 mg/mL for HT29 and HCT8 cells, respectively. Interestingly, migration and invasion of the cells were inhibited dramatically by 20 mg/mL lactoferrin, consistent with the significant down regulation of VEGFR2, VEGFA, pPI3K, pAkt, and pErk1/2 proteins. HT29 was chosen as the sensitive cell line to construct a tumor-bearing nude mice model. Notably, HT29 tumor weight was greatly reduced in both the lactoferrin group (26.5 ± 6.7 mg) and the lactoferrin/5-Fu group (14.5 ± 5.1 mg), compared with the control one (39.3 ± 6.5 mg), indicating that lactoferrin functioned as a tumor growth inhibitor. Considering lactoferrin also reduced the growth of blood vessels and the degree of malignancy, we concluded that HT29 tumors were effectively suppressed by lactoferrin, which might be achieved by regulation of phosphorylation from various kinases and activation of the VEGFR2-PI3K/Akt-Erk1/2 pathway.

Loss of microRNA-145 expression is involved in the development and prognosis of breast cancer complicated by type 2 diabetes mellitus.

OBJECTIVE: To explore the relationships of the expression of miR-145 to the clinicopathological characteristics and prognosis of patients with breast cancer complicated by type 2 diabetes mellitus (T2DM). METHODS: A total of 257 female patients with breast cancer were enrolled for our experiment, including 140 patients with simple breast cancer (control group) and 117 patients with breast cancer complicated by T2DM (observation group). Patients were treated with modified radical mastectomy supplemented with radiotherapy, chemotherapy and endocrine therapy. qRT-PCR was used for the detection of miR-145 expression in patients of both groups. Follow-up lasted 13-60 months. RESULTS: The relative expression of miR-145 in the observation group was significantly lower than that in the control group (p<0.05). The expression of miR-145 in patients with breast cancer complicated by T2DM was related to the history of diabetes, tumor node metastasis (TNM) stage, tumor size, lymph node metastasis (LNM), estrogen receptor (ER) status, and HER2 (all p<0.05). The median disease-free survival (DFS) was significantly longer and the 5-year DFS rate significantly higher in the high-expression group than in the low-expression group. History of diabetes, TNM stage, tumor size, LNM, ER status, and HER2 were risk factors for patients with breast cancer complicated by T2DM (all p<0.05). CONCLUSIONS: Loss of miR-145 expression is related to the development of breast cancer complicated by T2DM, and low miR-145 expression might be an adverse prognostic factor in patients with this disease.

Identification of the anti-tumor activity and mechanisms of nuciferine through a network pharmacology approach.

AIM: Nuciferine is an aporphine alkaloid extracted from lotus leaves, which is a raw material in Chinese medicinal herb for weight loss. In this study we used a network pharmacology approach to identify the anti-tumor activity of nuciferine and the underlying mechanisms. METHODS: The pharmacological activities and mechanisms of nuciferine were identified through target profile prediction, clustering analysis and functional enrichment analysis using our traditional Chinese medicine (TCM) network pharmacology platform. The anti-tumor activity of nuciferine was validated by in vitro and in vivo experiments. The anti-tumor mechanisms of nuciferine were predicted through network target analysis and verified by in vitro experiments. RESULTS: The nuciferine target profile was enriched with signaling pathways and biological functions, including "regulation of lipase activity", "response to nicotine" and "regulation of cell proliferation". Target profile clustering results suggested that nuciferine to exert anti-tumor effect. In experimental validation, nuciferine (0.8 mg/mL) markedly inhibited the viability of human neuroblastoma SY5Y cells and mouse colorectal cancer CT26 cells in vitro, and nuciferine (0.05 mg/mL) significantly suppressed the invasion of 6 cancer cell lines in vitro. Intraperitoneal injection of nuciferine (9.5 mg/mL, ip, 3 times a week for 3 weeks) significantly decreased the weight of SY5Y and CT26 tumor xenografts in nude mice. Network target analysis and experimental validation in SY5Y and CT26 cells showed that the anti-tumor effect of nuciferine was mediated through inhibiting the PI3K-AKT signaling pathway and IL-1 levels in SY5Y and CT26 cells. CONCLUSION: By using a TCM network pharmacology method, nuciferine is identified as an anti-tumor agent against human neuroblastoma and mouse colorectal cancer in vitro and in vivo, through inhibiting the PI3K-AKT signaling pathways and IL-1 levels.

Sulforaphane Analogues with Heterocyclic Moieties: Syntheses and Inhibitory Activities against Cancer Cell Lines.

Recent studies have shown that sulforaphane (SFN) selectively inhibits the growth of ALDH⁺ breast cancer stem-like cells.Herein, a series of SFN analogues were synthesized and evaluated against breast cancer cell lines MCF-7 and SUM-159, and the leukemia stem cell-like cell line KG-1a. These SFN analogues were characterized by the replacement of the methyl group with heterocyclic moieties, and the replacement of the sulfoxide group with sulfide or sulfone. A growth inhibitory assay indicated that the tetrazole analogs 3d, 8d and 9d were significantly more potent than SFN against the three cancer cell lines. Compound 14c, the water soluble derivative of tetrazole sulfide 3d, demonstrated higher potency against KG-1a cell line than 3d. SFN, 3d and 14c significantly induced the activation of caspase-3, and reduced the ALDH⁺ subpopulation in the SUM159 cell line, while the marketed drug doxrubicin(DOX) increased the ALDH⁺ subpopulation.

Susceptibility of human tonsillar epithelial cells to enterovirus 71 with normal cytokine response.

A recent histopathologic study implicated human tonsillar crypt epithelium as an important site for EV71 replication in EV71-caused fatal cases. This study aimed to confirm the susceptibility of human tonsillar epithelium to EV71. Two human tonsillar epithelial cell lines (UT-SCC-60A and UT-SCC-60B) were susceptive to EV71, and PI3K/AKT, p38, ERK1/2, and JNK1/2 signal pathways were activated. Interferon-α, IL-8, IL-1ß, IL-6 and IL-12p40 were induced and regulated by PI3K/AKT, p38, ERK1/2, and JNK1/2 signal pathways. PI3K/AKT pathway activation appeared to suppress the induction of TNF-α, which induced cell survival by inhibiting GSK-3ß. The activation of NF-κB was observed but inhibited by these pathways in EV71 infection. Furthermore, ERK1/2 and JNK1/2 were essential for efficient EV71 replication. Human tonsillar epithelial cells support EV71 replication and display innate antiviral immunity in vitro, indicating that human tonsillar epithelial cells may be novel targets for EV71 infection and replication in vivo.

Gene Knockdown in Human Rhinovirus 1B Using 2'-OMe-modified siRNAs Results in the Reactivation of the Interferon Response.

The aim of this study was to investigate the knockdown efficiency of 2'-O-methylated (2'-OMe)-modified small interfering RNAs (siRNAs) on human rhinovirus 1B (HRV1B) replication and the interferon response. Thus, 24 2'-OMe-modified siRNAs were designed to target HRV1B. The RNA levels of HRV1B, Toll-like receptor 3, melanoma differentiation-associated gene 5, retinoic acid inducible gene-I, and interferons were determined in HRV1B-infected HeLa and BEAS-2B epithelial cells transfected with 2'-OMe-modified siRNAs. The results revealed that all 2'-OMe-modified siRNAs interfered with the replication of HRV1B in a cell-specific and transfection efficiency-dependent manner. Viral activation of Toll-like receptor 3, melanoma differentiation-associated gene 5, retinoic acid inducible gene-I, and the interferon response was detected. In conclusion, the 2'-OMe-modified siRNAs used in this study could interfere with HRV1B replication, possibly leading to the reactivation of the interferon response.

Syntheses and biological evaluation of 1,2,3-triazole and 1,3,4-oxadiazole derivatives of imatinib.

Three novel series of 1,2,3-triazole and 1,3,4-oxadiazole derivatives of imatinib were prepared and evaluated in vitro for their cytostatic effects against a human chronic myeloid leukemia (K562), acute myeloid leukemia (HL60), and human leukemia stem-like cell line (KG1a). The structure-activity relationship was analyzed by determining the inhibitory rate of each imatinib analog. Benzene and piperazine rings were necessary groups in these compounds for maintaining inhibitory activities against the K562 and HL60 cell lines. Introducing a trifluoromethyl group significantly enhanced the potency of the compounds against these two cell lines. Surprisingly, some compounds showed significant inhibitory activities against KG1a cells without inhibiting common leukemia cell lines (K562 and HL60). These findings suggest that these compounds are able to inhibit leukemia stem-like cells.