Inhibitors of Chemoresistance Pathways in Combination with Ara-C to Overcome Multidrug Resistance in AML. A Mini Review

Acute myeloid leukemia (AML), the most common type of leukemia in older adults, is a heterogeneous disease that originates from the clonal expansion of undifferentiated hematopoietic progenitor cells. These cells present a remarkable variety of genes and proteins with altered expression and function. Despite significant advances in understanding the molecular panorama of AML and the development of therapies that target mutations, survival has not improved significantly, and the therapy standard is still based on highly toxic chemotherapy, which includes cytarabine (Ara-C) and allogeneic hematopoietic cell transplantation. Approximately 60% of AML patients respond favorably to these treatments and go into complete remission; however, most eventually relapse, develop refractory disease or chemoresistance, and do not survive for more than five years. Therefore, drug resistance that initially occurs in leukemic cells (primary resistance) or that develops during or after treatment (acquired resistance) has become the main obstacle to AML treatment. In this work, the main molecules responsible for generating chemoresistance to Ara-C in AML are discussed, as well as some of the newer strategies to overcome it, such as the inclusion of molecules that can induce synergistic cytotoxicity with Ara-C (MNKI-8e, emodin, metformin and niclosamide), subtoxic concentrations of chemotherapy (PD0332991), and potently antineoplastic treatments that do not damage nonmalignant cells (heteronemin or hydroxyurea + azidothymidine).     

Advances in Applying Computer-Aided Drug Design for Neurodegenerative Diseases

Neurodegenerative diseases (NDs) including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease are incurable and affect millions of people worldwide. The development of treatments for this unmet clinical need is a major global research challenge. Computer-aided drug design (CADD) methods minimize the huge number of ligands that could be screened in biological assays, reducing the cost, time, and effort required to develop new drugs. In this review, we provide an introduction to CADD and examine the progress in applying CADD and other molecular docking studies to NDs. We provide an updated overview of potential therapeutic targets for various NDs and discuss some of the advantages and disadvantages of these tools.     

Virtual Screening of FDA-Approved Drugs against Triose Phosphate Isomerase from Entamoeba histolytica and Giardia lamblia Identifies Inhibitors of Their Trophozoite Growth Phase

Infectious diseases caused by intestinal protozoan, such as Entamoeba histolytica (E. histolytica) and Giardia lamblia (G. lamblia) are a worldwide public health issue. They affect more than 70 million people every year. They colonize intestines causing primarily diarrhea; nevertheless, these infections can lead to more serious complications. The treatment of choice, metronidazole, is in doubt due to adverse effects and resistance. Therefore, there is a need for new compounds against these parasites. In this work, a structure-based virtual screening of FDA-approved drugs was performed to identify compounds with antiprotozoal activity. The glycolytic enzyme triosephosphate isomerase, present in both E. histolytica and G. lamblia, was used as the drug target. The compounds with the best average docking score on both structures were selected for the in vitro evaluation. Three compounds, chlorhexidine, tolcapone, and imatinib, were capable of inhibit growth on G. lamblia trophozoites (0.05–4.935 μg/mL), while folic acid showed activity against E. histolytica (0.186 μg/mL) and G. lamblia (5.342 μg/mL).     

Human-Induced Neural and Mesenchymal Stem Cell Therapy Combined with a Curcumin Nanoconjugate as a Spinal Cord Injury Treatment

We currently lack effective treatments for the devastating loss of neural function associated with spinal cord injury (SCI). In this study, we evaluated a combination therapy comprising human neural stem cells derived from induced pluripotent stem cells (iPSC-NSC), human mesenchymal stem cells (MSC), and a pH-responsive polyacetal–curcumin nanoconjugate (PA-C) that allows the sustained release of curcumin. In vitro analysis demonstrated that PA-C treatment protected iPSC-NSC from oxidative damage in vitro, while MSC co-culture prevented lipopolysaccharide-induced activation of nuclear factor-κB (NF-κB) in iPSC-NSC. Then, we evaluated the combination of PA-C delivery into the intrathecal space in a rat model of contusive SCI with stem cell transplantation. While we failed to observe significant improvements in locomotor function (BBB scale) in treated animals, histological analysis revealed that PA-C-treated or PA-C and iPSC-NSC + MSC-treated animals displayed significantly smaller scars, while PA-C and iPSC-NSC + MSC treatment induced the preservation of β-III Tubulin-positive axons. iPSC-NSC + MSC transplantation fostered the preservation of motoneurons and myelinated tracts, while PA-C treatment polarized microglia into an anti-inflammatory phenotype. Overall, the combination of stem cell transplantation and PA-C treatment confers higher neuroprotective effects compared to individual treatments.     

pHEMA: An Overview for Biomedical Applications

Poly(2-hydroxyethyl methacrylate) (pHEMA) as a biomaterial with excellent biocompatibility and cytocompatibility elicits a minimal immunological response from host tissue making it desirable for different biomedical applications. This article seeks to provide an in-depth overview of the properties and biomedical applications of pHEMA for bone tissue regeneration, wound healing, cancer therapy (stimuli and non-stimuli responsive systems), and ophthalmic applications (contact lenses and ocular drug delivery). As this polymer has been widely applied in ophthalmic applications, a specific consideration has been devoted to this field. Pure pHEMA does not possess antimicrobial properties and the site where the biomedical device is employed may be susceptible to microbial infections. Therefore, antimicrobial strategies such as the use of silver nanoparticles, antibiotics, and antimicrobial agents can be utilized to protect against infections. Therefore, the antimicrobial strategies besides the drug delivery applications of pHEMA were covered. With continuous research and advancement in science and technology, the outlook of pHEMA is promising as it will most certainly be utilized in more biomedical applications in the near future. The aim of this review was to bring together state-of-the-art research on pHEMA and their applications.     

Red-Blood-Cell-Membrane-Coated Metal-Drug Nanoparticles for Enhanced Chemotherapy

To overcome high toxicity, low bioavailability and poor water solubility of chemotherapeutics, a variety of drug carriers have been designed. However, most carriers are severely limited by low drug loading capacity and adverse side effects. Here, a new type of metal-drug nanoparticles (MDNs) was designed and synthesized. The MDNs self-assembled with Fe(III) ions and drug molecules through coordination, resulting in nanoparticles with high drug loading. To assist systemic delivery and prolong circulation time, the obtained MDNs were camouflaged with red blood cell (RBCs) membranes (RBCs@Fe-DOX MDNs) to improve their stability and dispersity. The RBCs@Fe-DOX MDNs presented pH-responsive release functionalities, resulting in drug release accelerated in acidic tumor microenvironments. The outstanding in vitro and in vivo antitumor therapeutic outcome was realized by RBCs@Fe-DOX MDNs. This study provides an innovative design guideline for chemotherapy and demonstrates the great capacity of nanomaterials in anticancer treatments.     

Characterization of New DNA Aptamers for Anti-HIV-1 Reverse Transcriptase

HIV-1 RT is a necessary enzyme for retroviral replication, which is the main target for antiviral therapy against AIDS. Effective anti-HIV-1 RT drugs are divided into two groups; nucleoside inhibitors (NRTI) and non-nucleoside inhibitors (NNRTI), which inhibit DNA polymerase. In this study, new DNA aptamers were isolated as anti-HIV-1 RT inhibitors. The selected DNA aptamer (WT62) presented with high affinity and inhibition against wild-type (WT) HIV-1 RT and gave a KD value of 75.10±0.29 nM and an IC₅₀ value of 84.81±8.54 nM. Moreover, WT62 decreased the DNA polymerase function of K103 N/Y181 C double mutant (KY) HIV-1 RT by around 80 %. Furthermore, the ITC results showed that this aptamer has small binding enthalpies with both WT and KY HIV-1 RTs through which the complex might form a hydrophobic interaction or noncovalent bonding. The NMR result also suggested that the WT62 aptamer could bind with both WT and KY mutant HIV-1 RTs at the connection domain.     

方管两侧同时冲孔模设计

通过对零件的工艺分析，改进了工艺方案，用一副对冲孔模完成两边同时冲孔，降低了生产成本，提高了生产效率；并介绍了该对冲孔模具的结构特点、设计思路、应注意的问题和装配工艺性。     

基于CAE的虚拟注射成型系统的研究和开发

研究了虚拟制造技术在注射成型过程中的应用 ,通过建立模架装配模型和模架的运动描述 ,开发出了基于CAE的虚拟注射成型原型系统 ,并将其与注射成型CAE系统HsCAE3D集成 ,取得了良好的效果。     

压力机气垫故障分析

介绍分析了机械压力机气垫通常出现的故障现象，以及应采取的排障措施。