Epigenetic Anti-Cancer Treatment With a Stabilized Carbocyclic Decitabine Analogue

5-Aza-2’-deoxycytidine (Decitabine, AzadC) is a nucleoside analogue, which is in clinical use to treat patients with myelodysplastic syndrome or acute myeloid leukemia. Its mode of action is unusual because the compound is one of the few drugs that act at the epigenetic level of the genetic code. AzadC is incorporated as an antimetabolite into the genome and creates covalent, inhibitory links to DNA methyltransferases (DNMTs) that methylate 2’-deoxycytidine (dC) to 5-methyl-dC (mdC). Consequently, AzadC treatment leads to a global loss of mdC, which presumably results in a reactivation of silenced genes, among them tumor suppressor and DNA damage response genes. Because AzadC suffers from severe instability, which limits its use in the clinic, a more sophisticated AzadC derivative would be highly valuable. Here, we report that a recently developed carbocyclic AzadC analogue (cAzadC) blocks DNMT1 in the AML cell line MOLM-13 as efficient as AzadC. Moreover, cAzadC has a surprisingly strong anti-proliferative effect and leads to a significantly higher number of double strand breaks compared to AzadC, while showing less off-target toxicity. These results show that cAzadC triggers more deleterious repair and apoptotic pathways in cancer cells than AzadC, which makes cAzadC a promising next generation epigenetic drug.     

An orally administered microcapsule system for treating chronic renal failure patients

Ingestible adsorbents for the removal of uremic metabolites are being investigated as adjunctive therapy in the treatment of chronic uremia. In particular, a microcapsule product containing urease and zirconium phosphate (UZP) has been investigated for removing urea. A dog model, simulating chronic uremia, was developed to investigate: (1) the concentration of various nitrogenous metabolites (urea, creatinine, and uric acid) in the GI tract, (2) flux rates of H₂O and various nitrogenous metabolites in the GI tract, and (3) the efficacy of the microcapsule product. The results of these perfusion studies suggest that urea and creatinine can be removed from the GI tract via ingestible adsorbents. In addition, the model may be useful in investigating suspect uremic toxins, e.g., guanidinosuccinic acid (GSA). The reduction of blood urea nitrogen levels in the dog model when the animal was fed the microcapsule product was limited by the capacity of the zirconium phosphate to bind ammonium ion. Preliminary clinical studies with the microcapsule product indicate that it may be of potential adjunctive therapy in patients suffering from chronic renal failure.     

Green formulation and chemical characterization of Lens culinaris seed aqueous extract conjugated gold nanoparticles for the treatment of acute myeloid leukemia in comparison to mitoxantrone in a leukemic mouse model

The high prevalence of cancer has been increased the rate of studying about the new formulation of chemotherapeutic drugs. In this regards, one of the suitable options is the use of metal nanoparticles for formulating these drugs. In the recent study, Lens culinaris seed aqueous extract conjugated gold nanoparticles (AuNPs) are reported for the first time to exert a dietary therapeutic potential compared to mitoxantrone in an animal model of acute myeloid leukemia. The synthesized AuNPs were characterized using different techniques including UV–Vis., FT-IR, XRD, FE-SEM, and TEM. DPPH free radical scavenging test was done to evaluate the antioxidant potentials of HAuCl₄, L. culinaris, AuNPs, and mitoxantrone. For the analyzing of cytotoxicity effects of HAuCl₄, L. culinaris, AuNPs, and mitoxantrone, MTT assay was used on HUVEC, 32D-FLT3-ITD, Human HL-60/vcr, and Murine C1498 cell lines. In vivo assay, induction of acute myeloid leukemia was done by 7,12-Dimethylbenz[a]anthracene (DMBA) in 75 mice. Then, the animals were randomly divided into six subgroups, including control, untreated, HAuCl₄, L. culinaris, AuNPs, and mitoxantrone. SEM and TEM images showed uniform spherical morphology and average diameters of 10–40 nm for the nanoparticles. DPPH test revealed similar antioxidant potentials for mitoxantrone and AuNPs. Similar to mitoxantrone, AuNPs had low cell viability dose-dependently against 32D-FLT3-ITD, Human HL-60/vcr, and Murine C1498 cell lines without any cytotoxicity on HUVEC cell line. AuNPs and mitoxantrone significantly (p ≤ 0.05) reduced the weight and volume of liver and spleen, the pro-inflammatory cytokines, and the total WBC, blast, neutrophil, monocyte, eosinophil, and basophil counts and increased the mRNA expression of Sphingosine-1-phosphate receptor-1 and Sphingosine-1-phosphate receptor-5, the anti-inflammatory cytokines, and the lymphocyte, platelet, and RBC parameters as compared to the untreated mice. It looks that AuNPs can be administrated as a chemotherapeutic supplement or drug for the treatment of acute myeloid leukemia in the clinical trial.     

Preparation,formulation, and chemical characterization of silver nanoparticles using Melissa officinalis leaf aqueous extract for the treatment of acute myeloid leukemia in vitro and in vivo conditions

The demand for nanoparticles is increasing day by day due to their wide range of applications in various areas including pharmaceutical industry. Nanoparticles are formally synthesized by chemical methods in which the toxic and flammable chemicals are used. Synthesis of nanoparticles from various biological systems has been reported, but among all, biosynthesis of nanoparticles from plants is considered as the most suitable method. The current study confirms the potential of aqueous extract of Melissa officinalis grown under in vitro condition for the green synthesis of silver nanoparticles (AgNPs). Also, we revealed the cytotoxicity, antioxidant, and anti-acute myeloid leukemia effects of AgNPs compared to mitoxantrone in a leukemic mouse model. The synthesized AgNPs were characterized using several techniques including UV–Vis., FT-IR, TEM, FE-SEM, and EDS. In vivo experiment, induction of acute myeloid leukemia was done by DMBA in 75 mice. The obtained results were fed into SPSS-22 software and analyzed by one-way ANOVA. By quantitative real-time PCR, S1PR1 and S1PR5 mRNA expression in lymphocytes were significantly (p ≤ 0.01) increased by treating the leukemic mice with the AgNPs and mitoxantrone. Also, AgNPs similar to mitoxantrone, significantly (p ≤ 0.01) enhanced the platelet, lymphocyte, and RBC parameters and the anti-inflammatory cytokines (IL4, IL5, IL10, IL13, and IFNα) and reduced the total WBC, blast, monocyte, neutrophil, eosinophil, and basophil counts and the pro-inflammatory cytokines (IL1, IL6, IL12, IL18, IFNY, and TNFα) as compared to the untreated mice. In vitro experiment, AgNPs similar to mitoxantrone had low cell viability dose-dependently against murine C1498, human HL-60/vcr, and 32D-FLT3-ITD cell lines without any cytotoxicity on HUVEC cell line. Furthermore, the DPPH assay showed similar antioxidant potentials for AgNPs and mitoxantrone. Above results approve the excellent anti-acute myeloid leukemia, cytotoxicity, and antioxidant properties of AgNPs compared to mitoxantrone.     

Metabolomics study of the effect of Danggui Buxue Tang on rats with chronic fatigue syndrome

Danggui Buxue Tang (DBT), a traditional Chinese medicine (TCM) formula for ‘invigorating qi and enriching blood’, has been reported to produce a good effect on chronic fatigue syndrome (CFS). However, the related mechanism remains largely undetermined. This study devised a metabolomics approach with GC–MS combined with pattern recognition to estimate the extent to which DBT alleviated CFS induced by food restriction and force swimming in rats. After 4 weeks of treatment, the endurance capability of rats was significantly better, and the motionless time was significantly shorter in the DBT group than in the CFS model group. Moreover, the activities of superoxide dismutase and glutathione peroxidase increased, whereas the levels of malondialdehyde, interleukin 6, and tumor necrosis factor alpha decreased in the DBT treatment group. Fifteen significantly changed metabolites were observed in the serum of rats with CFS, which was reversed markedly by DBT treatment. Metabolic pathway analysis showed that DBT could possibly alleviate CFS in rats by regulating the biosynthesis of phenylalanine, tyrosine, and tryptophan and the metabolism of glycine, serine, threonine, glycerolipid, glyoxylate, dicarboxylate, and tyrosine. It was observed that the metabolism of glycine, serine, and threonine was most closely related to the improvement in CFS by DBT treatment. This study showed that DBT could improve CFS effectively, and metabolomics was a powerful means to gain insights into the TCM formulas against CFS.     

降钙素原在指导慢性阻塞性肺疾病急性加重期抗感染治疗中的价值

目的观察并分析降钙素原在指导慢性阻塞性肺疾病急性加重期抗感染治疗中的价值。方法研究对象选取2015年5月期间来湖北省宜昌市第二人民医院就诊的100例慢性阻塞性肺疾病急性加重期病例,根据随机数字表法将其分为对照组与观察组各50例,对照组结合临床实际情况制订抗生素治疗方案,观察组则根据血清降钙素原(PCT)指导抗生素应用,对比两组抗生素应用时间、临床治疗效果、住院时间、病情加重与死亡率,并对研究结果相关数据作统计学处理。结果与对照组比,观察组抗生素使用时间、住院时间更短,组间差异显著而具有统计学意义(P0.05);两组临床治疗效果,病情加重率与死亡率差异并无统计学意义(P0.05)。结论在慢性阻塞性肺疾病急性加重期,监测血清降钙素原水平以指导抗感染治疗可有效降低抗生素使用量,促进患者康复,具有积极的临床意义。     

宫颈环形电切术联合纳米银凝胶应用于慢性宫颈炎的临床探讨

目的分析宫颈环形电切术联合纳米银凝胶应用于慢性宫颈炎的临床疗效。方法选择2014年10月至2015年10月在上栗县长平卫生院接受治疗的122例慢性宫颈炎患者作为研究对象。将122例患者随机分为常规组和实验组。常规组使用宫颈环形电切术进行治疗;实验组使用宫颈环形电切术联合纳米银凝胶进行治疗。对比两组患者的治疗效果以及阴道感染率及出血率。结果两组患者经过不同的治疗之后实验组患者的治疗总有效率(100.0%)显著高于常规组治疗总有效率(80.3%),数据差异显著,具备统计学意义(P0.05);实验组患者的阴道感染率(1.64%)及出血率(3.28%)分别明显低于常规组的阴道感染率(13.11%)与出血率(18.03%),两组数据差异显著,具备统计学意义(P0.05)。结论宫颈环形电切术联合纳米银凝胶应用于慢性宫颈炎的临床疗效显著,纳米银凝胶能够极大程度地帮助患者减少阴道出血、阴道感染的情况发生,能够很好地弥补宫颈环形电切术的不足,能够极大程度提升患者治疗效果,是慢性宫颈炎的理想治疗方式,值得临床推广。     

pH‐Modulating Poly(ethylene glycol)/Alginate Hydrogel Dressings for the Treatment of Chronic Wounds

The development of chronic wounds has been frequently associated with alkaline pH values. The application of pH‐modulating wound dressings can, therefore, be a promising treatment option to promote normal wound healing. This study reports on the development and characterization of acidic hydrogel dressings based on interpenetrating poly(ethylene glycol) diacrylate/acrylic acid/alginate networks. The incorporation of ionizable carboxylic acid groups results in high liquid uptake up to 500%. The combination of two separate polymer networks significantly improves the tensile and compressive stability. In a 2D cell migration assay, the application of hydrogels (0% to 1.5% acrylic acid) results in complete “wound” closure; hydrogels with 0.25% acrylic acid significantly increase the cell migration velocity to 19.8 ± 1.9 µm h⁻¹. The most promising formulation (hydrogels with 0.25% acrylic acid) is tested on 3D human skin constructs, increasing keratinocyte ingrowth into the wound by 164%.

     

Mediated Drug Release from Nanovehicles by Black Phosphorus Quantum Dots for Efficient Therapy of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is an intractable disease involving a sticky mucus layer and nanoagents with mucus-penetrating capability offer a new way to deliver drugs. However, drug release from nanovehicles requires optimization to enhance the therapeutic effects of COPD therapy. Herein, black phosphorus quantum dots (BPQDs) are combined with PEGylated chitosan nanospheres containing the antibiotic amikacin (termed PEG@CS/BPQDs-AM NPs). As a drug-delivery system, the hydrophilicity of PEG and positive charge of CS facilitate the penetration of nanovehicles through the mucus layer. The nanovehicles then adhere to the mucous membrane. Furthermore, the BPQDs degrade rapidly into nontoxic PO₄³⁻ and acidic H⁺, thereby promoting the dissociation of PEGylated CS nanospheres, accelerating the release of AM, decreasing the vitality of biofilms for ease of eradication. Our results reveal that drug delivery mediated by BPQDs is a feasible and desirable strategy for precision medicine and promising for the clinical therapy of COPD.