HIF‐1α forms regulatory loop with YAP to coordinate hypoxia‐induced adriamycin resistance in acute myeloid leukemia cells

Despite the improvement in acute myeloid leukemia (AML) treatments, most patients had a poor prognosis and suffered from chemoresistance and disease relapse. Therefore, there is an urgent need for elucidation of mechanism(s) underlying drug resistance in AML. In the present study, we found that AML cells showed less susceptibility to adriamycin (ADR) in the presence of hypoxia, while inhibition of hypoxia‐inducible factor 1α (HIF‐1α) by CdCl₂ can make AML cells re‐susceptibile to ADR even under hypoxia. Moreover, HIF‐1α is overexpressed and plays an important role in ADR‐resistance maintenance in resistant AML cells. We further found hypoxia or induction of HIF‐1α can significantly upregulate yes‐associated protein (YAP) expression in AML cells, and resistant cells express a high level of YAP. Finally, we found that YAP may not only enhance HIF‐1α stability but also promote HIF‐1α's activity on the target gene pyruvate kinase M2. In conclusion, our data indicate that HIF‐1α or YAP may represent a therapeutic target for overcoming resistance toward adriamycin‐based chemotherapy in AML.     

Psoralen attenuates bleomycin‐induced pulmonary fibrosis in mice through inhibiting myofibroblast activation and collagen deposition

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by excessive deposition of extracellular matrix (ECM) and chronic inflammation with limited therapeutic options. Psoralen, a major active component extracted from Psoralea corylifolia L. seed, has several biological effects. However, the role of psoralen in IPF is still unclear. Here, we hypothesized that psoralen played an essential role in IPF in the inhibition of fibroblast proliferation and inflammatory response. A murine model of IPF was established by injecting bleomycin (BLM) intratracheally, and psoralen was administered for 14 days from the 7^th to 21^st day after BLM injection. Our results demonstrated that psoralen treatment reduced body weight loss and improved the survival rate of mice with IPF. Histological and immunofluorescent examination showed that psoralen alleviated BLM‐induced lung parenchymal inflammatory and fibrotic alteration. Furthermore, psoralen inhibited proliferation and collagen synthesis of mouse fibroblasts and partially reversed BLM‐induced expression of α‐smooth muscle actin at both the tissue and cell level. Moreover, psoralen decreased the expression of transforming growth factor‐β1, interleukin‐1β, and tumor necrosis factor‐α in the lungs of BLM‐stimulated mice. Our results reveale for the first time that psoralen exerts therapeutic effects against IPF in a BLM‐induced murine model.     

Melatonin Alleviates Drought-Induced Damage of Photosynthetic Apparatus in Maize Seedlings

Russian Journal of Plant Physiology - Melatonin plays an important role in the enhancement of plant tolerance to drought stress. The underlying mechanisms of this melatonin-induced protection of...     

Adoptive transfers of CD4+CD25+ Tregs partially alleviate mouse premature ovarian insufficiency

This study was designed to investigate the protective effect of CD4⁺CD25⁺ regulatory T cells (Tregs) against zona pellucida glycoprotein 3 peptide (pZP3) immunization‐induced premature ovarian insufficiency (POI) in mice. A mouse POI model was induced by two subcutaneous injections of pZP3 (50 nmol/L). Mice in the pZP3‐Treg group were intraperitoneally injected with 5 × 10⁵ CD4⁺CD25⁺ Tregs after the POI model was established. Sex hormone levels, follicle numbers, apoptotic events, and the Akt/FOXO3a signaling pathway molecules in the ovaries were assessed. Compared with control group, the weight of ovaries in both pZP3 group and pZP3‐Treg group was decreased and no difference was found between them. The number of follicles in the Treg transferred mice, like in pZP3 group, was significantly reduced compared to the control group, but showed a modest improvement when compared the pZP3 group alone. Significantly lower serum concentrations of follicle‐stimulating hormone, luteinizing hormone, and anti‐zona pellucida antibodies (AZPAbs) were found, while the concentrations of estradiol and anti‐Mullerian hormone increased. In mechanism, Treg cell transfer to ZP3 treated mice restored the levels of Caspase3 to control levels, and partially restored Bax, however, had no effect on Bcl‐2. Moreover, Treg cell transfer to ZP3 treated mice partially restored the levels of Akt and FOXO3a, and partially restored the ratios of p‐Akt/Akt and p‐FOXO3a/FOXO3a. In conclusion, Treg cells improved some aspects of ZP3‐induced POI which may be mediate by suppressing ovarian cells apoptosis and involving the Akt/FOXO3a signaling pathway. Therefore, Treg cells may be protective against autoimmune POI.     

Reduced expression of CYLD promotes cell survival and inflammation in gefitinib‐treated NSCLC PC‐9 cells: Targeting CYLD may be beneficial for acquired resistance to gefitinib therapy

The application of tyrosine kinase inhibitors (TKIs) to the epidermal growth factor receptor (EGFR) has been proven to be highly effective for non‐small‐cell lung cancer (NSCLC). However, patients often evolve into acquired resistance. The secondary mutations in EGFR account for nearly half of the acquired resistance. While the remaining 50% of patients exhibit tolerance to EGFR‐TKIs with unclear mechanism(s). Cylindromatosis (CYLD), a deubiquitinase, functions as a tumor suppressor to regulate cell apoptosis, proliferation, and immune response, and so on. The role of CYLD in NSCLC EGFR‐TKI resistance remains elusive. Here, we found CYLD was upregulated in PC‐9 cells, whereas downregulated in PC‐9 acquired gefitinib‐resistant (PC‐9/GR) cells in response to the treatment of gefitinib, which is consistent with the results in the Gene Expression Omnibus database. Overexpression of CYLD promoted a more apoptotic death ratio in PC‐9/GR cells than that in PC‐9 cells. In addition, silencing the expression of CYLD resulted in an increase of the expression level of interleukin‐6, transforming growth factor‐β and tumor necrosis factor‐α, which may contribute to acquired resistance of PC‐9 cells to gefitinib. Taken together, our data in vitro demonstrate that PC‐9/GR cells downregulated CYLD expression, enhanced subsequent CYLD‐dependent antiapoptotic capacity and inflammatory response, which may provide a possible target for acquired gefitinib‐resistant treatment in NSCLC.     

New insights into small‐cell lung cancer development and therapy

Small‐cell lung cancer (SCLC) accounts for approximately 15% of lung cancer cases; however, it is characterized by easy relapse and low survival rate, leading to one of the most intractable diseases in clinical practice. Despite decades of basic and clinical research, little progress has been made in the management of SCLC. The current standard first‐line regimens of SCLC still remain to be cisplatin or carboplatin combined with etoposide, and the adverse events of chemotherapy are by no means negligible. Besides, the immunotherapy on SCLC is still in an early stage and novel studies are urgently needed. In this review, we describe SCLC development and current therapy, aiming at providing useful advices on basic research and clinical strategy.     

LINC00667 promotes Wilms’ tumor metastasis and stemness by sponging miR‐200b/c/429 family to regulate IKK‐β

Wilms' tumor, also known as nephroblastoma, is a kind of pediatric renal cancer. Previous studies have indicated that microRNAs (miRNAs) regulate various cancers progression. However, whether miR‐200 family regulated Wilms' tumor progression remains to be elucidated. In our study, miR‐200b/c/429 expression was downregulated in Wilms' tumor tissue samples from 25 patients. And data from three independent analyses of quantitative real‐time polymerase chain reaction revealed that the expression of miR‐200b/c/429 was downregulated in Wilms' tumor cell lines. Functionally, Cell counting kit‐8 assay revealed that cell viability was reduced by overexpressing miR‐200b/c/429. Transwell assay manifested that cell migration and invasion was hindered by miR‐200b/c/429 overexpression. Sphere‐forming and western blot assays demonstrated that miR‐200b/c/429 overexpression suppressed the sphere formation ability. Mechanically, nuclear factor‐κB (NF‐κB) pathway was confirmed to be associated with Wilms' tumor progression; miR‐200b/c/429 overexpression inactivated NF‐κB pathway as miR‐200b/c/429 was identified to target IκB kinase β (IKK‐β), an NF‐κB pathway‐related gene. Moreover, miR‐200b/c/429 was sponged by LINC00667 in Wilms' tumor cells. LINC00667 competitively bound with miR‐200b/c/429 to regulate IKK‐β expression and then activated NF‐κB pathway in Wilms' tumor. Subsequently, rescue assays illustrated that silencing of IKK‐β could reverse the effect of miR‐200b/c/429 inhibition on the progression of sh‐LINC00667‐transfected Wilms' tumor cells. In summary, LINC00667 promoted Wilms' tumor progression by sponging miR‐200b/c/429 family to regulate IKK‐β.     

In Vitro Anti-HIV Effect of Voacamine from Voacanga africana Stapf Based on the SPRi Experiment

Russian Journal of Bioorganic Chemistry - AIDS/HIV is a serious life-threatening and public health problem that urges for new antiviral drugs to control. A bis-indole alkaloid voacamine has been...     

The hybrid bacterial foraging algorithm based on many-objective optimizer

A new multi-objective optimized bacterial foraging algorithm - Hybrid Multi-Objective Optimized Bacterial Foraging Algorithm (HMOBFA) is presented in this article. The proposed algorithm combines the crossover-archives strategy and the life-cycle optimization strategy, look for the best method through research area. The crossover-archive strategy with an external archive and internal archive is assigned to different selection principles to focus on diversity and convergence separately. Additionally, according to the local landscape to satisfy population diversity and variability as well as avoiding redundant local searches, individuals can switch their states periodically throughout the colony lifecycle with the life-cycle optimization strategy. all of which may perform significantly well. The performance of the algorithm was examined with several standard criterion functions and compared with other classical multi-objective majorization methods. The examiner results show that the HMOBFA algorithm can achieve a significant enhancement in performance compare with other method and handles many-objective issues with solid complexity, convergence as well as diversity. The HMOBFA algorithm has been proven to be an excellent alternative to past methods for solving the improvement of many-objective problems.     

The asymmetric relationships of the distribution of conspecific saplings and adults in forest fragments

随着土地利用方式变化的加剧,生境片段化已成为影响植物多样性的主要因子之一。通常,当成年树个体的密度越高,其周边同种幼树个体的存活率可能会下降,从而为其它物种提供了空间和资源,进而可以维持较高的局域物种多样性。因此,同种成年树和幼树个体的空间分布格局关系和作用强度可以调节植物多样性。然而,对于在片段化森林中,同种成年树和幼树个体空间分布关系的研究却很少报道,迄今尚不清楚片段化景观中同种个体的空间分布关系与物种多样性之间的联系。本研究选择千岛湖陆桥岛屿系统中的27个岛屿,基于岛屿上幼树和成年树个体的空间分布数据,利用混合效应模型分析它们之间的作用强度。同种幼树和成年树个体的空间作用强度越大,说明它们之间的负相互作用越强,即幼树和成年树个体空间分布越分散。此外,本研究分析了岛屿属性(岛屿面积、与大陆的距离和与最近岛屿的距离)与同种个体空间作用强度及物种多样性之间的关系。结果表明,同种个体的空间作用强度随着与最近岛屿距离的增加而增加。同时,物种多样性随着同种个体的空间作用强度的增加而显著增加,且岛屿面积和同种个体的空间作用强度分别解释了岛屿间物种多样性差异的26%和6%,共同解释了8%。耐阴种和非常见种比非耐阴种和常见种的同种幼树和成年树的空间分布更为分散。本研究表明,同种个体的空间分布可能会影响多度较低物种在片段化森林中的生存,反映了生物相互作用对于维持片段化森林中的植物多样性具有重要作用。 本研究也强调在检验同种密度制约时应考虑森林之间的连接度。