Effects of the Anti-Tumorigenic Agent AT101 on Human Glioblastoma Cells in the Microenvironmental Glioma Stem Cell Niche

Glioblastoma (GBM) is a barely treatable disease due to its profound chemoresistance. A distinct inter- and intratumoral heterogeneity reflected by specialized microenvironmental niches and different tumor cell subpopulations allows GBMs to evade therapy regimens. Thus, there is an urgent need to develop alternative treatment strategies. A promising candidate for the treatment of GBMs is AT101, the R(-) enantiomer of gossypol. The present study evaluates the effects of AT101, alone or in combination with temozolomide (TMZ), in a microenvironmental glioma stem cell niche model of two GBM cell lines (U251MG and U87MG). AT101 was found to induce strong cytotoxic effects on U251MG and U87MG stem-like cells in comparison to the respective native cells. Moreover, a higher sensitivity against treatment with AT101 was observed upon incubation of native cells with a stem-like cell-conditioned medium. This higher sensitivity was reflected by a specific inhibitory influence on the p-p42/44 signaling pathway. Further, the expression of CXCR7 and the interleukin-6 receptor was significantly regulated upon these stimulatory conditions. Since tumor stem-like cells are known to mediate the development of tumor recurrences and were observed to strongly respond to the AT101 treatment, this might represent a promising approach to prevent the development of GBM recurrences.     

Role of the HSP70 Co-Chaperone SIL1 in Health and Disease

Cell surface and secreted proteins provide essential functions for multicellular life. They enter the endoplasmic reticulum (ER) lumen co-translationally, where they mature and fold into their complex three-dimensional structures. The ER is populated with a host of molecular chaperones, associated co-factors, and enzymes that assist and stabilize folded states. Together, they ensure that nascent proteins mature properly or, if this process fails, target them for degradation. BiP, the ER HSP70 chaperone, interacts with unfolded client proteins in a nucleotide-dependent manner, which is tightly regulated by eight DnaJ-type proteins and two nucleotide exchange factors (NEFs), SIL1 and GRP170. Loss of SIL1′s function is the leading cause of Marinesco-Sjögren syndrome (MSS), an autosomal recessive, multisystem disorder. The development of animal models has provided insights into SIL1′s functions and MSS-associated pathologies. This review provides an in-depth update on the current understanding of the molecular mechanisms underlying SIL1′s NEF activity and its role in maintaining ER homeostasis and normal physiology. A precise understanding of the underlying molecular mechanisms associated with the loss of SIL1 may allow for the development of new pharmacological approaches to treat MSS.     

Reusable Polyacrylonitrile-Sulfur Extractor of Heavy Metal Ions from Wastewater

Mercury, lead, and cadmium are among the most toxic and carcinogenic heavy metal ions (HMIs), posing serious threats to the sustainability of aquatic ecosystems and public health. There is an urgent need to remove these ions from water by a cheap but green process. Traditional methods have insufficient removal efficiency and reusability. Structurally robust, large surface-area adsorbents functionalized with high-selectivity affinity to HMIs are attractive filter materials. Here, an adsorbent prepared by vulcanization of polyacrylonitrile (PAN), a nitrogen-rich polymer, is reported, giving rise to PAN-S nanoparticles with cyclic π-conjugated backbone and electronic conductivity. PAN-S can be coated on ultra-robust melamine (ML) foam by simple dipping and drying. In agreement with hard/soft acid/base theory, N- and S-containing soft Lewis bases have strong binding to Hg²⁺, Pb²⁺, Cu²⁺, and Cd²⁺, with extraordinary capture efficiency and performance stability. Furthermore, the used filters, when collected and electrochemically biased in a recycling bath, can release the HMIs into the bath and electrodeposit on the counter-electrode as metallic Hg⁰, Pb⁰, Cu⁰, and Cd⁰, and the PAN-S@ML filter can then be reused at least 6 times as new. The electronically conductive PAN-S@ML filter can be fabricated cheaply and holds promise for scale-up applications.     

Role of Endocrine-Disrupting Chemicals in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: A Comprehensive Review

Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disorder, affecting around 25% of the population worldwide. It is a complex disease spectrum, closely linked with other conditions such as obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome, which may increase liver-related mortality. In light of this, numerous efforts have been carried out in recent years in order to clarify its pathogenesis and create new prevention strategies. Currently, the essential role of environmental pollutants in NAFLD development is recognized. Particularly, endocrine-disrupting chemicals (EDCs) have a notable influence. EDCs can be classified as natural (phytoestrogens, genistein, and coumestrol) or synthetic, and the latter ones can be further subdivided into industrial (dioxins, polychlorinated biphenyls, and alkylphenols), agricultural (pesticides, insecticides, herbicides, and fungicides), residential (phthalates, polybrominated biphenyls, and bisphenol A), and pharmaceutical (parabens). Several experimental models have proposed a mechanism involving this group of substances with the disruption of hepatic metabolism, which promotes NAFLD. These include an imbalance between lipid influx/efflux in the liver, mitochondrial dysfunction, liver inflammation, and epigenetic reprogramming. It can be concluded that exposure to EDCs might play a crucial role in NAFLD initiation and evolution. However, further investigations supporting these effects in humans are required.     

Functional Inactivation of Drosophila GCK Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2

Maturity-onset diabetes of the young (MODY) type 2 is caused by heterozygous inactivating mutations in the gene encoding glucokinase (GCK), a pivotal enzyme for glucose homeostasis. In the pancreas GCK regulates insulin secretion, while in the liver it promotes glucose utilization and storage. We showed that silencing the Drosophila GCK orthologs Hex-A and Hex-C results in a MODY-2-like hyperglycemia. Targeted knock-down revealed that Hex-A is expressed in insulin producing cells (IPCs) whereas Hex-C is specifically expressed in the fat body. We showed that Hex-A is essential for insulin secretion and it is required for Hex-C expression. Reduced levels of either Hex-A or Hex-C resulted in chromosome aberrations (CABs), together with an increased production of advanced glycation end-products (AGEs) and reactive oxygen species (ROS). This result suggests that CABs, in GCK depleted cells, are likely due to hyperglycemia, which produces oxidative stress through AGE metabolism. In agreement with this hypothesis, treating GCK-depleted larvae with the antioxidant vitamin B6 rescued CABs, whereas the treatment with a B6 inhibitor enhanced genomic instability. Although MODY-2 rarely produces complications, our data revealed the possibility that MODY-2 impacts genome integrity.     

高岭土性质对催化裂化催化剂性能的影响

采用X射线荧光分析仪、X射线衍射仪、N2物理吸附仪、场发射扫描电子显微镜等仪器表征了苏州、广西和美国佐治亚州3个产地的高岭土，并以此3种高岭土为原料制备了模型催化裂化（FCC）催化剂，在ACE评价装置上对比了模型催化剂的反应性能。结果表明:苏州及广西高岭土主要组分为高岭石，佐治亚高岭土主要组分为地开石及珍珠陶土；苏州高岭土呈片状，还含有少量棒状颗粒；广西高岭土呈多层片状，晶粒粒径较大；佐治亚高岭土呈薄片状，晶粒粒径较小；3种高岭土制备的模型催化剂反应活性、Na2O及RE2O3质量分数相近；广西高岭土制备的模型催化剂具有最大的孔体积和磨损指数，但比表面积最小，具有较强的重油转化能力，其目标产物（液化气+汽油）和副产物（干气+焦炭）收率都高于苏州、佐治亚高岭土制备的催化剂的。     

Granulation Tissue Enhanced with Aspirin and Omega-3 PUFAs as a Local Adjunct to the Surgical Treatment of Periodontitis

The topical application of aspirin and omega-3 polyunsaturated fatty acids (PUFAs) may trigger the resolution of inflammation by inducing the biosynthesis of pro-resolvers such as lipoxins and resolvins while also avoiding the side effects of systemic aspirin intake. This study assessed the effect of enhanced granulation tissue (EGT) on periodontal tissue regeneration through the local application of aspirin and omega-3 PUFAs directly to granulation tissue (GT) during periodontal surgery. This randomized controlled experiment assesses 38 pockets in 19 patients. In every patient, two similar intrabony periodontal defects are treated with an open flap debridement, one with EGT (GT extracted, enhanced with aspirin and omega-3 PUFAs, and replaced) and the other with standard GT removal. Clinical attachment level (CAL) and probing pocket depth (PPD) are assessed at baseline and 2 and 6 months after surgery. The experimental protocol (EGT) results in a greater CAL gain as compared to that in the controls at 6 months (p < 0.05), while PPD reduction is not affected. The retained GT does not compromise healing. EGT is proposed as a promising, inexpensive, and simple method that may improve the outcome of periodontal regenerative treatment. However, the described protocol requires optimization and further assessment. Practical Applications : The biosynthesis of mediators including resolvins and lipoxins triggered by aspirin and omega-3 PUFAs promote the resolution of inflammation, eventually leading to faster regeneration of inflamed tissues. While granulation tissue is a necessary component in wound healing, enhancing granulation tissue with aspirin and omega-3 PUFAs results in CAL gain in the surgical treatment of periodontal defects. Retained granulation tissue does not compromise periodontal healing. The EGT strategy is an inexpensive and simple method that may improve the clinical outcomes of regenerative periodontal procedures.     

Tempering–preservation treatment inactivated lipase in wheat bran and retained phenolic compounds

Wheat bran is rich in functional ingredients, but the high level of lipase limits its applications. Tempering–preservation treatment (at 70–90 °C with moisture of 20%–40% for 1–4 h) was exploited for stabilising wheat bran and its effect on polyphenols was investigated. The results showed that more lipase was inactivated at higher tempering moisture, temperature and longer time. The optimum condition for inactivation of wheat bran lipase was 30% moisture and 90 °C for 4 h. The inactivation rate reached 93.8% with a residual enzyme activity of 0.264 U g⁻¹. Under the optimum condition, the sum of free phenolic acids rose from 25.4 to 55.8 µg g⁻¹. As for bound phenolic acids, there was a slight increase of hydroxybenzoic acid derivatives but a slight decrease of hydroxycinnamic acid derivatives. The total contents of phenolic acids before and after stabilisation were not significantly different. This study showed the possibility of using tempering–preservation as an efficient method for inactivation of wheat bran lipase while maintaining its phenolic compounds, which could be used in the production of whole wheat flour.