Human cytomegalovirus in cancer: the mechanism of HCMV-induced carcinogenesis and its therapeutic potential.

Cancer is one of the leading causes of death worldwide. Human cytomegalovirus (HCMV), a well-studied herpesvirus, has been implicated in malignancies derived from breast, colorectal muscle, brain, and other cancers. Intricate host-virus interactions are responsible for the cascade of events that have the potential to result in the transformed phenotype of normal cells. The HCMV genome contains oncogenes that may initiate these types of cancers, and although the primary HCMV infection is usually asymptomatic, the virus remains in the body in a latent or persistent form. Viral reactivation causes severe health issues in immune-compromised individuals, including cancer patients, organ transplants, and AIDS patients. This review focuses on the immunologic mechanisms and molecular mechanisms of HCMV-induced carcinogenesis, methods of HCMV treatment, and other studies. Studies show that HCMV DNA and virus-specific antibodies are present in many types of cancers, implicating HCMV as an important player in cancer progression. Importantly, many clinical trials have been initiated to exploit HCMV as a therapeutic target for the treatment of cancer, particularly in immunotherapy strategies in the treatment of breast cancer and glioblastoma patients. Taken together, these findings support a link between HCMV infections and cellular growth that develops into cancer. More importantly, HCMV is the leading cause of birth defects in newborns, and infection with HCMV is responsible for abortions in pregnant women.

Preparation of 2-Methoxyestradiol Self-emulsified Drug Delivery System and the Effect on Combination Therapy with Doxorubicin Against MCF-7/ADM Cells.

Due to the poor solubility and bioavailability of 2-methoxyestradiol (2-ME), 2-ME emulsified drug delivery system (2-ME-SEDDS) was designed and characterized. After dilution with 5% glucose, 2-ME-SEDDS formed fine emulsions with mean diameter of 171 ± 14 nm and zeta potential of - 7.4 ± 0.6 mV. The cytotoxicity of 2-ME-SEDDS against MCF-7 and MCF-7/ADM cells was considerable to that of free 2-ME, and the half maximal inhibitory concentration ran up to 195 µg/mL on MCF-7/ADM cells. In order to gain a satisfactory inhibition effect on MCF-7/ADM cells, 2-ME-SEDDS combined with doxorubicin was used. It is worth noting that the combination of 2-ME-SEDDS and doxorubicin displayed a superior synergistic effect with a combined index of 0.62. And the cellular uptake of doxorubicin by MCF-7/ADM cells in the combination group was significantly higher than that of doxorubicin treatment group. The study preliminarily suggested that 2-ME-SEDDS could increase the cellular uptake of doxorubicin by MCF-7/ADM cells and the synergistic effect may be attributed to the increased cellular uptake of doxorubicin under the influence of 2-ME-SEDDS. In conclusion, SEDDS was an alternative and promising formulation for 2-ME. The combination therapy with synergistic effect by the combination of 2-ME-SEDDS and doxorubicin seems to be a promising strategy to potentiate anti-tumor efficiency against MCF-7/ADM, even other multidrug resistance tumors.

A Simple and Universal Nucleic Acid Assay Platform Based on Personal Glucose Meter Using SARS-CoV-2 N Gene as the Model.

A simple, selective, and quantitative platform for point-of-care diagnostic of COVID-19 is urgently needed as a complement in areas where resources are currently relatively scarce. To meet the needs of early diagnosis and intervention, a proof-of-concept demonstration of a universal personal glucose meter-based nucleic acid assay platform (PGM-NAAP) is presented, which converts to SARS-CoV-2 detection from glucose detection. By using magnetic bead separation together with the hand-held PGM for quantitative readout, PGM-NAAP achieves the 98 pM limit of detection for a sequence related to SARS-CoV-2. The ability to discriminate target nucleic acid from genomic DNA, the satisfactory spike recoveries of saliva and serum samples, as well as the good stability all together suggest the potential of the PGM-NAAP for the screening and diagnosis of suspected patients during the outbreaks of COVID-19 in resource-limited settings without sophisticated instruments. On the basis of these findings, PGM-NAAP can be expected to provide an accurate and convenient path for diagnosis of disease-associated nucleic acid.

[Significance of Lipopolysaccharide Lipid A Gene Mutation of Extensively Drug-resistant Acinetobacter baumanii on Polymyxin Resistance and Its Influence on Treatment].

OBJECTIVE: To explore the significance of the resistance to polymyxin resistance of the extensively drug resistant Acinetobacter baumannii (XDRAB) lipopolysaccharide (LPS) lpx A, lpx C, lpx D and to screen appropriate combination therapy. METHODS: In the past two years, 72 XDRAB in the secretions of our patients were selected as the research object. According to the minimum inhibitory concentration (MIC) of the XDRAB strain on polymyxin, they were included in the drug resistance group and the sensitive group. The gene sequences of strains lpx A, lpx C, lpx D were compared with the standard strains to analyze gene mutations and compared the mutation rates in the drug resistant group and the sensitive group. The efficacy of the combination drugs was evaluated by microcheckerboard dilution method, including polymyxin+imipenem group, polymyxin+meropenem group, polymyxin+cefoperazone/sulbactam group, polymyxin+levofloxacin group, and polymyxin+fosfomycin group. Calculated the fractional inhibitory concentration (FIC) index of the combined medication regimen and compared the percentage of strains that exhibited synergistic, additive, irrelevant, and antagonistic effects. RESULTS: Tentyone were in the drug resistant group, accounting for 21 (29.17%,) and 51 were in the sensitive group, accounting for 70.83%. Some strains had mutations in lpx A, lpx C, lpx D genes. The mutation rate in the drug resistant group was 90.48%, which was significantly higher than 11.76% in the sensitive group, the difference was statistically significant ( P<0.05). The combined drug sensitivity test showed, compared with the polymyxin+fosfomycin group, the mycotin+fosfomycin group had a higher percentage of strains with synergistic FIC index in the polymyxin+imipenem group, the difference was statistically significant ( P<0.01). CONCLUSION: XDRAB is resistant to polymyxin, which is related to mutations in LPS lipid A biosynthesis genes lpx A, lpx C, lpx D. Clinical treatment should adopt a combination of polymyxin+imipenem/meropenem and other drug combination to reduce the secondary infection of drug resistant bacteria.

Preparation, characterization, and application of soluble liquid crystalline molecularly imprinted polymer in electrochemical sensor.

A novel soluble molecularly imprinted polymer (SMIP) without chemical cross-linker was successfully synthesized. The quinine (QN), which the structure was similar to the template, was chosen as the immobile template to improve the affinity of MIP. 4-Methyl phenyl dicyclohexyl ethylene (MPDE) was used as the liquid crystal (LC) monomer to increase the rigid of the composite. The cooperative effect of QN and MPDE was demonstrated by comparing with the conventional MIP, which synthesized without QN and MPDE. The polymerization conditions of SMIP including the ratio of MAA to MPDE, template to functional monomer, and HQN to QN were also optimized. Moreover, the characterizations of the SMIP were investigated by the transmission electron microscopy (TEM), field emission scanning electron microscopy (SEM), thermogravimetric analysis (TGA), X-ray diffraction (XRD), and nitrogen adsorption. In binding behavior, the SMIP presented the maximum adsorption capacity (0.37 ± 0.06 mmol/g) and imprinting factor (3.44 ± 0.25). And above all, the obtained polymer exhibited the solubility in the organic solution. In addition, the proposed SMIP as the electrochemical sensor exhibited a significant conductivity and sensitivity with the detection limit of 0.33 µM for HQN, the recoveries for the sample analysis varied from 97.4 to 100.8%, and the intra-day precision and inter-day precision were within 5.5% and 12.5%, respectively. It turned out that the SMIP had demonstrated more excellent potential than the traditional insoluble MIP in the development of the membrane-based electrochemical sensors.Graphical abstract.

A promising nanomatrix system of simvastatin for oral delivery: Evaluation in vitro and in vivo.

Because of the low solubility, the oral bioavailability of simvastatin (SV) was poor, which restricted the application in clinic. In order to increase the dissolution and the oral absorption of simvastatin, we prepared a novel solid nanomatrix of SV with pharmaceutical acceptable nano-sized silica and Eudragit®. The nanomatrix was prepared using solvent evaporate method and the formulation was optimized. The X-ray diffraction (XRD) and differential scanning calorimetry (DSC) were used to analyze the physicochemical characterization of the SV nanomatrix. The results indicated that the SV existed in the nanomatrix was in a state of molecule or amorphous form. The optimal formulation, consisted of SV, Eudragit® L100-55 and Sylysia 350 (1:5:5, w/w/w), significantly enhanced the dissolution of SV compared with Zocor. And the relative bioavailability was 272% to Zocor. The oral absorption of simvastatin was enhanced markedly. The SV nanomatrix after storage for 1 year displayed similar performance in vitro and in vivo with the freshly prepared nanomatrix. The stability of SV nanomatrix achieved the desired objectives. In conclusion, the nanomatrix system described here had superior performance in vitro and in vivo and was expected to have a promising future as an alternative oral drug delivery system for SV.

Advances of Non-Ionic Surfactant Vesicles (Niosomes) and Their Application in Drug Delivery.

Non-Ionic surfactant based vesicles, also known as niosomes, have attracted much attention in pharmaceutical fields due to their excellent behavior in encapsulating both hydrophilic and hydrophobic agents. In recent years, it has been discovered that these vesicles can improve the bioavailability of drugs, and may function as a new strategy for delivering several typical of therapeutic agents, such as chemical drugs, protein drugs and gene materials with low toxicity and desired targeting efficiency. Compared with liposomes, niosomes are much more stable during the formulation process and storage. The required pharmacokinetic properties can be achieved by optimizing components or by surface modification. This novel delivery system is also easy to prepare and scale up with low production costs. In this paper, we summarize the structure, components, formulation methods, quality control of niosome and its applications in chemical drugs, protein drugs and gene delivery.

Preparation and evaluation of 2-methoxyestradiol-loaded pH-sensitive liposomes

The development and clinical application of 2-methoxyestradiol (2-ME) as a new type of antitumor drug are limited due to its poor solubility, rapid metabolism in vivo, and large oral dosage. 2-ME-loaded pH-sensitive liposomes (2-ME-PSLs) was prepared containing the lipids, Lipoid E-80 (E-80), cholesteryl hemisuccinate (CHEMS), and cholesterol (CHOL) via thin-film ultrasonic dispersion. First, preparation conditions of 2-ME-PSLs were optimized by orthogonal test. Then 2-ME-PSL was characterized, and the release behavior and stability of 2-ME-PSL in vitro were evaluated. The optimal preparation conditions for 2-ME-PSLs were as follows: 2-ME : E-80+CHEMS 1:15; CHOL : E-80+CHEMS 1:5; ultrasonication time 20 minutes. The mean particle size, PDI, zeta potential, and entrapment efficiency (EE) of 2-ME-PSLs were 116 ± 9 nm, 0.161 ± 0.025, −22.4 ± 1.7 mV, and 98.6 ± 0.5%, respectively. As viewed under a transmission electron microscope, 2-ME-PSLs were well dispersed and almost spherical. They exhibited significant pH-sensitive properties and were fairly stable when diluted with a physiological solution. In conclusion, 2-ME-PSLs were successfully prepared and possessed a favorable pH sensitivity and good dissolution stability with a normal solution

[Effect of paeoniflorin on oxidative stress and energy metabolism in mice with lipopolysaccharide (LPS)-induced brain injury].

Paeoniflorin is the main active ingredient of Chinese herbaceous peony. This study is to investigate the protective effect of paeoniflorin (Pae) on acute brain damage induced by lipopolysaccharide (LPS) in mice. The mice were randomly assigned to the normal control, model control (LPS), as well as groups of paeoniflorin and lipopolysaccharide (Pae + LPS). Then the mice were administered intraperitioneally with normal saline or Pae (10, 30 mg · kg(-1)) once daily for 6 d. One hour after intrapertioneally treatment on the seventh day, each group were injected LPS (5 mg · kg(-1)) to establish the endotoxin lipopolysaccharide inflammation model except the normal group. The mice were sacrificed after 6 h and the brain homogenates were prepared and measured. The malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), hydrogen peroxide (H2O2), succinatedehydrogenase (SDH), Na(+)-K(+)-ATPase and Ca(2+)-Mg(2+)-ATPase were dectected by the colorimetric method. The levels of HO-1 and Nrf2 protein in subcellular fractions of brain tissue were detected by Western blot. The results demonstrated that the administration with paeoniflorin reduced the levels of the MDA production; significantly increase the activities of antioxidant enzyme (SOD and GSH-PX). In addition, paeoniflorin could enhance the total antioxidant capacity, decrease the level of H2O2, and increase the activities of SDH, Na(+)-K(+)-ATPase and Ca(2+)-Mg(2+)-ATPase. Furthermore, paeoniflorin can increase the expression of HO-1 and activate the nuclear transfer of Nrf2. Taking together, these findings suggest that paeoniflorin alleviate the acute inflammation in mice brain damage induced by LPS, which is related with its antioxidant effect and improvement of energy metabolism.

Cremophor-free intravenous self-microemulsions for teniposide: Safety, antitumor activity in vitro and in vivo.

The study was designed to identify the safety and antitumor activity of teniposide self-microemulsified drug delivery system (TEN-SMEDDS) previously developed, and to provide evidence for the feasibility and effectiveness of TEN-SMEDDS for application in clinic. The TEN-SMEDDS could form fine emulsion with mean diameter of 279 ± 19 nm, Zeta potential of -6.9 ± 1.4 mV, drug loading of 0.04 ± 0.001% and entrapment efficiency of 98.7 ± 1.6% after dilution with 5% glucose, respectively. The safety, including hemolysis, hypersensitivity, vein irritation and toxicity in vivo, and antitumor activity were assessed, VUNON as a reference. Sulforhodamine B assays demonstrated that the IC50 of TEN-SMEDDS against C6 and U87MG cells were higher than that of VUMON. But the effect of TEN-SMEDDS on the cell cycle distribution and cell apoptotic rate was similar to that of VUMON as observed by flow cytometry. Likewise, the antitumor activity of TEN-SMEDDS was considerable to that of VUMON. Finally, the TEN-SMEDDS exhibited less body weight loss, lower hemolysis and lower myelosuppression as compared with VUMON. In conclusion, promising TEN-SMEDDS retained the antitumor activity of teniposide and was less likely to cause some side effects compared to VUMON. It may be favorable for the application in clinic.

Preparation and in vitro-in vivo evaluation of teniposide nanosuspensions.

Teniposide (TEN) is a potent, broad spectrum antitumor agent, especially for cerebroma. But the application in clinic was limited because of its poor solubility. In this paper, teniposide nanosuspensions drug delivery system (TEN-NSDDS) for intravenous administration was developed for the first time. Specifically, TEN nanosuspensions were prepared by an anti-solvent sonication-precipitation method and evaluated in comparison with teniposide injection (VUMON) in vitro and in vivo. TEN nanosuspensions prepared showed rod-like morphology and the size was 151 ± 11 nm with a narrow poly dispersion index 0.138 determined by dynamic light scattering. The obtained TEN nanosuspensions were physically stable at least 10 days at 4°C. And the freeze-drying preparations were stable during 3 months. The cytotoxicity of TEN nanosuspensions were considerable to that of VUMON against U87MG and C6 cells in vitro. When tested in rats bearing C6 tumors, the TEN concentration in the tumors treated by the nanosuspensions was more than 20 times than that by the TEN solution at 2h. The TEN nanosuspensions exhibited significant tumor growth inhibition. Overall, the results suggested that nanosuspensions was an alternative formulation for teniposide to be administered intravenously, and it would be a promising formulation in clinic.

A cremophor-free self-microemulsified delivery system for intravenous injection of teniposide: evaluation in vitro and in vivo.

In order to tackle the problems on low water solubility of teniposide, involvement of toxic surfactant in its injection, and the poor stability during infusion, a Cremophor-free teniposide self-microemulsified drug delivery system (TEN-SMEDDS) was prepared for the first time, characterized, and evaluated in comparison with teniposide injection (VUMON) in vitro and in vivo. The optimized formulation contained N, N-dimethylacetamide, medium-chain triglyceride, lecithin, and dehydrated alcohol besides teniposide. The TEN-SMEDDS could form fine droplets with mean diameter of 282 ± 21 nm and zeta potential of -7.5 ± 1.7 mV after dilution with 5% glucose, which were stable within 4 h. The release of teniposide from TEN-SMEDDS and VUMON was similar. However, the pharmacokinetic behavior of TEN-SMEDDS in rats was different from that of VUMON, evidenced by the lower area under the concentration-time curve and larger volume of distribution in emulsion group. Finally, TEN-SMEDDS was found to distribute more teniposide in most tissues, especially in reticuloendothelial system, after intravenous administration to rats. Importantly, brain drug level in TEN-SMEDDS group was higher than or similar to that in control group, although the emulsion system had a lower plasma drug concentration. In conclusion, the novel SMEDDS prepared here, without toxic surfactant and as an oil solution before use, may be potential for clinical use due to its low toxicity and high store stability. It may be favorable for the treatment of some tumors like cerebroma, since it may achieve the relatively higher drug level in brain but lower blood concentration.