Role and Mechanism of Super-enhancers in Tumor Metastasis / 肿瘤防治研究

Super-enhancers (SEs) are large clusters of enhancers located near the promoter and are necessary to determine the identity of cancer cells. The alterations of super-enhancers can cause dysregulation of the transcriptional program, which resulted in tumor cells being addicted to certain transcriptional programs. Tumor metastasis is the leading cause of death in cancer. Recently, SEs have been demonstrated to facilitate tumor metastasis by regulating lncRNA generation, tumor microenvironment, epithelial-mesenchymal transition, and cancer stem cells. In this review, the characteristics of SEs, the relationship between SEs and tumor metastasis, and inhibitors against SEs are summarized to provide a reference for the relevant mechanism of SEs regulating tumor metastasis and provide new perspectives for the diagnosis and treatment of patients with cancer metastasis.

Development of monolithic matrix type transdermal patches containing cinnarizine: Physical characterization and permeation studies

To overcome the problems associated with bioavailability and systemic side effects of the drug by oral administration, monolithic matrix type transdermal patches containing cinnarizine (CNZ) were developed. For this purpose, films based on hydroxypropyl methylcellulose and polyvinylpyrrolidone as matrix-forming polymers were designed. Physical characteristics of transdermal films and drug-excipient compatibility were investigated. Factors affecting in vitro drug release and ex vivo skin penetration and permeation of the drug were studied. It was confirmed that films displayed sufficient flexibility and mechanical strength for application onto the skin for a long time period. Ex vivo penetration experiments gave satisfactory results for transdermal drug delivery through rat skin. The parameters determining good skin penetration were also evaluated. The highest drug permeation rate was obtained with incorporation of Transcutol® (0.102 mg/cm2/h) into the base CNZ formulation, followed by propylene glycol (0.063 mg/cm2/h), menthol (0.045 mg/cm2/h), and glycerin (0.021 mg/cm2/h) as penetration enhancers (p < 0.05). As a result, the developed transdermal patches of CNZ may introduce an alternative treatment for various conditions and diseases such as idiopathic urticarial vasculitis, Ménière's disease, motion sickness, nausea, and vertigo. Thus, the risk of systemic side effects caused by the drug can be reduced or eliminated

Progress on the BRD4 of super enhancer regulatory element in hematologic oncology / 国际儿科学杂志

Abnormal transcription of oncogenes driven by super enhancers was found to be critical for maintaining tumor cell identity.The expression of oncogenes can be effectively suppressed by inhibiting the key regulator that super enhancers regulate oncogene transcription.Bromodomain protein 4(BRD4)is a key protein to recognize the super enhancer regulatory elements, which can bind to acetylated histones or non-histones to regulate gene transcription.The abnormal expression of BRD4 is closely related to the malignant development of a variety of hematologic oncology.Targeting BRD4 can effectively control the malignant development of hematologic tumors.In recent years, BRD4-targeted drugs in hematologic oncology have received extensive attention, and they showed good antitumor effects either as a single drug or in combination with other drugs.In this paper, in order to provide a new understanding of the occurrence of leukemia and treatment of hematologic oncology, the biological functions of BRD4 as well as the molecular drugs targeting BRD4 are reviewed.

Impairment of the autophagy-lysosomal pathway in Alzheimer's diseases: Pathogenic mechanisms and therapeutic potential

Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by memory loss and cognitive dysfunction. The accumulation of misfolded protein aggregates including amyloid beta (Aβ) peptides and microtubule associated protein tau (MAPT/tau) in neuronal cells are hallmarks of AD. So far, the exact underlying mechanisms for the aetiologies of AD have not been fully understood and the effective treatment for AD is limited. Autophagy is an evolutionarily conserved cellular catabolic process by which damaged cellular organelles and protein aggregates are degraded via lysosomes. Recently, there is accumulating evidence linking the impairment of the autophagy-lysosomal pathway with AD pathogenesis. Interestingly, the enhancement of autophagy to remove protein aggregates has been proposed as a promising therapeutic strategy for AD. Here, we first summarize the recent genetic, pathological and experimental studies regarding the impairment of the autophagy-lysosomal pathway in AD. We then describe the interplay between the autophagy-lysosomal pathway and two pathological proteins, Aβ and MAPT/tau, in AD. Finally, we discuss potential therapeutic strategies and small molecules that target the autophagy-lysosomal pathway for AD treatment both in animal models and in clinical trials. Overall, this article highlights the pivotal functions of the autophagy-lysosomal pathway in AD pathogenesis and potential druggable targets in the autophagy-lysosomal pathway for AD treatment.

BRD4 inhibitors kill ABC-DLBCL cells by targeting BTK / 中国病理生理杂志

AIM:To investigate the effect of bromodomain-containing protein 4(BRD4)inhibitors on the via-bility and apoptosis of activated B cell-like diffuse large B-cell lymphoma(ABC-DLBCL)cells and the molecular mecha-nism. METHODS:The ABC-DLBCL cells were treated with BRD4 inhibitors JQ1 and I-BET-762,and Bruton tyrosine kinase(BTK)inhibitor ibrutinib. The viability and death of the cells were determined by CCK-8 assay and PI staining,re-spectively. The mRNA levels of BTK,phospholipase Cγ(PLCγ),LYN,SYK,interleukin-6(IL-6),MYC,protein ki-nase Cβ(PKCβ),mucosa-associated lymphoid tissue lymphoma translocation protein 1(MALT1),MYC and RELA were detected by real-time PCR. The protein levels of BTK,PLCγ,MYC and RELA were determined by Western blot. Super-enhancer around BTK gene was revealed by bioinformatics analysis. RESULTS:The ABC-DLBCL cells were sensitive to BRD4/super-enhancer inhibitors such as JQ1 and I-BET-762. Both JQ1 and I-BET-762 inhibited the chronic active B-cell receptor(BCR)/nuclear factorκB(NFκB)signaling through reducing the transcription of BTK,but they had minimal ef-fect on other components in BCR/NFκB signaling. Interestingly,there was no super-enhancer around BTK gene,and the inhibitory effect of JQ1 was likely due to disruption of BRD4 binding within BTK gene. Inhibition of BRD4 had synergic ef-fect with BTK inhibitor ibrutinib. Moreover,inhibition of BRD4 induced significant cell death in ibrutinib-resistant ABC-DLBCL cells. CONCLUSION:Inhibitors of BRD4 induce ABC-DLBCL cell death via blocking BCR/NFκB signaling and has synergic effect with BTK inhibitor. Inhibition of BRD4 might be a promising strategy for treatment of ABC-DLBCL,es-pecially ibrutinib-resistant ABC-DLBCL.

Comparative study on penetration-enhancing effect of essential oil before and after processing fresh ginger into dried ginger / 中草药

Objective: To compare the penetration-enhancing effect and composition changes of fresh ginger and dried ginger essential oil. Methods: The essential oil was extracted before and after fresh ginger being processed into dried ginger, and the penetration- enhancing effect of them was compared by skin electrical resistance and transdermal test of ibuprofen in vitro. The main mechanism of penetration-enhancing effect of the essential oil was studied by ATR-FTIR. The skin cytotoxicity of the essential oils was compared by skin cytotoxicity test, and the composition changes were analyzed by GC-MS. Results: Thepenetration-enhancing effect of dried ginger essential oil was much better than the fresh ginger essential oil. The mechanism was mainly due to the skin stratum corneum lipids extraction. The skin cytotoxicity of fresh ginger and dried ginger essential oil was much lower than that of azone. The sesquiterpenes content of dried ginger essential oil was higher than that of fresh ginger essential oil. The intradermal sesquiterpenoids of dried ginger essential oil group after transdermal treatment were higher than those in the fresh ginger essential oil group. Conclusion: The transdermal absorption promotion effect of the processed dried ginger essential oil was much better than that of fresh ginger essential oil, which verified the existence of the rule of “hot herbs with better efficacy”.

Comparative study of penetration-enhancing effect in vitro of cinnamon oil and cinnamaldehyde on ibuprofen / 中国中药杂志

To compare the penetration-enhancing effect of cinnamon oil and its main components (cinnamaldehyde) on ibuprofen and their self-percutaneous absorption behavior in vitro. Firstly, cinnamon oil was extracted by steam distillation, then the compositions were analyzed by gas chromatography mass spectrometry (GC-MS) and the cinnamaldehyde content in cinnamon oil was determined by high performance liquid chromatography (HPLC). With azone as positive control, ibuprofen as model drug, cinnamon oil and cinnamaldehyde as penetration enhancers (PE) were prepared and administered to the SD rat's abdominal skin. The penetration-enhancing effects of cinnamon oil and cinnamaldehyde and their own transdermal absorption properties were compared. The results showed that yield of cinnamon oil was (3.55±0.36)% (=3), and the cinnamaldehyde content in cinnamon oil was (73.48±0.21)% (=3). As compared with blank group, the enhancing rate (ER) of cinnamon oil, cinnamaldehyde, and azone was 3.56, 1.13, 2.47 respectively. The cumulative penetration rate of cinnamaldehyde in cinnamon oil and cinnamaldehyde monomer in 24 h was (63.30±0.98)%, (51.03±3.34)% (=4) respectively. The penetration-enhancing effect of cinnamon oil was significantly better than that of cinnamaldehyde, indicating the existence of muti-component synergy. The penetration rate of cinnamaldehyde in cinnamon oil was higher than that of cinnamaldehyde monomer, suggesting that a "pull effect" may be present.

Development and in vitro evaluation of reservoir-type patch of coumarins in Angelicae Dahuricae Radix / 中草药

Objective To prepare the reservoir patch of coumarins in Angelicae Dahuricae Radix and investigate its release and transdermal absorption characteristics in vitro. The efficient enhancers were chosen to improve the drug’s permeation rate. Methods The reservoir patch was prepared using hydroxypropyl methylcellulose (HPMC) as medium and ethylene vinyl acetate (EVA) membrane to control the release of drug. The Franz diffusion cells were used and HPLC was used to determine imperatorin content and permeation rate. The content of imperatorin was determined by HPMC. The effect of the gel consumption, the content of coumarins and penetration enhancer on the transdermal flux were investigated by selecting porcine skin as model. The release of the selected patch in vitro was investigated. Results 1% HPMC, 1% coumarins in Angelicae Dahuricae Radix, 1% Isopropyl Myristate (IPM) and 3% Azone were the best permeation of the patch. The permeation rate reached 0.713 μg/(cm2•h). The release mechanisms of the patch in vitro coincided with zero-order kinetic. Conclusion The reservoir patch of coumarins in Angelicae Dahuricae Radix had high transdermal rate and complete in vitro release. It was indicated that the patch could be expected to be an effective transdermal drug delivery system.

Preparation technology on essential oil from Chinese materia medica as penetration enhancers / 中草药

The critical problem to be solved in the study of transdermal drug delivery system is to improve the transdermal penetration of drugs through the skin. Most essential oils from Chinese material medica, considered as a large class of penetration enhancers, possess enhanced percutaneous absorption, minor skin irritation, certain therapeutic efficacy, and a synergistic effect with transdermal drugs. However, the essential oils have poor solubility and unstable problems. Some special preparations, including patch, clathrate, gel plasters, gels, microemulsion, and so on, can increase the solubility of the essential oils, improve the effect of permeability, and can significantly boost the stability of the essential oils. In this paper, the techniques of the related preparations on essential oil from Chinese materia medica should be reviewed, and the research direction of the later stage should be discussed.

Effect of Enhancers on in vitro and in vivo Skin Permeation and Deposition of S-Methyl-(L)-Methionine

S-methyl-(L)-methionine (SMM), also known as vitamin U, is commercially available as skin care cosmetic products for its wound healing and photoprotective effects. However, the low skin permeation expected of SMM due to its hydrophilic nature with a log P value of −3.3, has not been thoroughly addressed. The purpose of this study thus was to evaluate the effect of skin permeation enhancers on the skin permeation/deposition of SMM. Among the enhancers tested for the in vitro skin permeation and deposition of SMM, oleic acid showed the most significant enhancing effect. Moreover, the combination of oleic acid and ethanol further enhanced in vitro permeation and deposition of SMM through hairless mouse skin. Furthermore, the combination of oleic acid and ethanol significantly increased the in vivo deposition of SMM in the epidermis/dermis for 12 hr, which was high enough to exert a therapeutic effect. Therefore, based on the in vitro and in vivo studies, the combination of oleic acid and ethanol was shown to be effective in improving the topical skin delivery of SMM, which may be applied in the cosmetic production process for SMM.

Screening of transdermal enhancer of naringenin in Premna fulva extract / 中草药

Objective: To screen the best transdermal enhancers of naringenin in Premna fulva extract. Methods: Using abdominal skin of rats as experimental barrier, the in vitro percutaneous absorption experiment was established by modified Franz diffusion cell method. The cumulative infiltration and permeation rate of naringenin in three different penetration enhancers were determined by HPLC. Results: The borneol, menthol, and azone could enhance transdermal absorption of naringenin in different degree. Several penetration enhancers were increased in the following order: borneol > menthol > azone. The average percutaneous rate of naringenin was 0.136 8 mg/(cm2∙h), using 5% borneol as penetration enhancer. Conclusion: The 5% borneol is an effective transdermal enhancer for naringenin in P. fulva extract.

Optimization of matrix prescription of Compound Qingfengteng Cataplasm by orthogonal test method / 中草药

Objective: To optimize the matrix prescription of Compound Qingfengteng Cataplasm (CQC). Methods: Taking the comprehensive senses as evaluation index, the types and dosage of the matrix were investigated by single factor. Further combined with the initial viscosity and holding viscosity index to optimize the matrix prescription of CQC by orthogonal test, and in vitro transdermal absorption experiments were carried out by Franz diffusion pool method to screen penetration enhancers. Results: The optimal formulation of CQC was as follows: 2.5 g of NP-700, 11 g of glycerin, 0.08 g of glycine aluminum, 0.08 g of tartaric acid, 0.8 g of PVP K90, 0.5 g of PVPP, 20 g of water, and 4.2 g of dry extract. 3% nitrile as a penetration agent could enhance penetration action. Conclusion: The preferred matrix prescription is practicable; CQC adhesion is moderate, no residue, paste traits, skin followability are good.

Promoting effect of transdermal absorption of essential oils from Chinese materia medica and problem analysis in study of topical preparations / 中草药

In recent years, essential oils have drawn more and more attention of pharmaceutical workers due to its low toxicity and strong pharmacological activity. In addition to some pharmacological effects, some volatile oil also can be used as a good transdermal absorption enhancer, which has been widely used in topical preparation. The effect and mechanism of volatile oil as transdermal enhancers are different according to different kinds and active ingredients of essential oils. This paper summarizes the related researches on the promoting effect and mechanism of essential oil absorption by skin in recent years. The author analyzes the existing problems in the application of volatile oils in the topical preparations, so as to provide a reference for the later research.

Preparation and evaluation of naloxone hydrochloride nasal spray / 国际药学研究杂志

Objective To prepare naloxone hydrochloride nasal spray and evaluate the ciliotoxicity and pharmacokinetics of the formulation. Methods The stability of naloxone hydrochloride was studied in pH3.5-5.5. Penetration promoting effects of absorp-tion enhancers on the naloxone hydrochloride were evaluated. Nasal ciliotoxicity studies were carried out using isolated toad palate. Rats were treated with naloxone hydrochloride solution by intramuscular injection of nasal drops to evaluate the pharmacokinetics. Results Naloxone hydrochloride solution was stable in pH3.5-5.5. Disodium ethylenediaminetetraacetic acid(0.2%,W/V)had the best penetration promoting effect on naloxone hydrochloride. Naloxone hydrochloride nasal spray did not exhibit obvious nasal ciliotox-icity compared to the negative control. The nasal spray had a faster therapeutic effect and its bioavailability was similar to that of the in-tramuscular injection. Conclusion Naloxone hydrochloride nasal spray prepared in this research is stable with no obvious nasal cilio-toxicity,has faster therapeutic effect,and good bioavailability,so may have a broad application prospect.

Evaluation of skin absorption of drugs from topical and transdermal formulations

ABSTRACT The skin barrier function has been attributed to the stratum corneum and represents a major challenge in clinical practice pertaining to cutaneous administration of drugs. Despite this, a large number of bioactive compounds have been successfully administered via cutaneous administration because of advances in the design of topical and transdermal formulations. In vitro and in vivo evaluations of these novel drug delivery systems are necessary to characterize their quality and efficacy. This review covers the most well-known methods for assessing the cutaneous absorption of drugs as an auxiliary tool for pharmaceutical formulation scientists in the design of drug delivery systems. In vitro methods as skin permeation assays using Franz-type diffusion cells, cutaneous retention and tape-stripping methods to study the cutaneous penetration of drugs, and in vivo evaluations as pre-clinical pharmacokinetic studies in animal models are discussed. Alternative approaches to cutaneous microdialysis are also covered. Recent advances in research on skin absorption of drugs and the effect of skin absorption enhancers, as investigated using confocal laser scanning microscopy, Raman confocal microscopy, and attenuated total reflectance Fourier-transform infrared spectroscopy, are reviewed.

MSG – demon in food

Flavor enhancers are used to bring out the flavor in a wide range of foods without adding a flavor of their own. Any food product that can be added to food to enhance its taste especially to make it taste more savoury or to add more Umami flavor. Umani taste that is found also in Glutamate. The anti MSG forces counter such information by stating that naturally occuring glutamate is different than added Glutamate is different than added glutamate. Research has demonstrated, However that the two are indeed metabolized identically.

Effects of Common Percutaneous Enhancers on Transdermal Permeability of Cetirizine Hydrochloride / 中国药房

OBJECTIVE:To study the effects of common percutaneous enhancers on transdermal permeability of cetirizine hy-drochloride(CET). METHODS:Using pH 7.4 phosphate buffer as receiving solution,accumulative permeation rate as index,mod-ified Franz diffusion cell was used to investigate the effects of common percutaneous enhancers on transdermal permeability of CET in skin of abdomen isolated from mice,such as azone (0.06%-2.5%),oleic acid (0.5%-10%),1,3-propanediol (0.5%-10%),propanetriol(0.5%-5%). RESULTS:1,3- propanediol had no improvement effect on the permeability of CET. 24 h accu-mulative permeation amount of CET in 0.06% azone,0.5% oleic acid and 1% propanetriol were the highest among same types, being 227.94,85.25 and 215.15 μg/cm2,respectively. CONCLUSIONS:Of four percutaneous enhancers,the transdermal enhanc-ing efficiencies from high to low are azone>glycerol>oleic acid>1,3-propanediol. Azone and glycerol have the conspicuous pene-tration enhancing effects.

Penetration Enhancers Screening for Compound Ketoconazole Gel / 中国药师

Objective:To study the effect of caprylic/capric acid glycerides (Lab), propylene glycol (PG) and Azone on the transdermal behavior of ketoconazole and miconazole nitrate in compound ketoconazole gel, to screen appropriate penetration enhanc-ers. Methods:Using a RYJ-6A-type transdermal drug diffusion tester, the effects of Lab, PG and Azone at different concentrations on the transdermal behavior of ketoconazole and miconazole nitrate in compound ketoconazole gel were studied. Results:3% PG showed the most obvious penetration enhancement, which could increase the permeation of ketoconazole by 2. 004 times, and increase the pen-etration of miconazole nitrate by 1. 795 times, and the differences were statistically significant (P<0. 05). Conclusion:The penetra-tion effect of 3% PG is obvious, which can be applied in compound ketoconazole gel.

Evaluation of pharmacokinetics and in vitro/in vivo correlation of ibuprofen with essential oils as penetration enhancer following transdermal administration / 中国中药杂志

The study was carried out to investigate the pharmacokinetics and in vitro/in vivo correlation of ibuprofen with essential oils as penetration enhancers (PE) following transdermal administration. With Azone as the positive control, ibuprofen hydrogels containing Chuanxiong oil, Angelica oil or Cinnamon oil as PE were prepared and administered to the rat abdominal skin. Then the pharmacokinetics of ibuprofen following transdermal administration were investigated and compared. In comparison with negative control (no PE was added), the relative bioavailability values with the addition of Chuanxiong oil, Angelica oil, Cinnamon oil and Azone as PE were determined to be 161.87%, 171.05%, 151.37% and 148.66%, respectively. In vitro/in vivo correlation analysis was performed by deconvolution method and the results demonstrated a good correlation between in vitro and in vivo percutaneous absorption studies. The correlation coefficients were measured to be 0.999 7, 0.995 2 and 0.999 4 for Chuanxiong oil, Angelica oil and Cinnamon oil respectively. In summary, Chuanxiong oil, Angelica oil and Cinnamon oil as PE could significantly enhance the bioavailability of ibuprofen following transdermal administration. A satisfactory in vitro/in vivo correlation could be obtained by using hydrogel as the dosage form.

Idea and method of regularity knowledge of Chinese materia medica on essential oils as potential penetration enhancers based on drug property characteristics / 中草药

Penetration enhancers (PE) were usually applied as the optimum strategy to improve the percutaneous absorption of active components from pharmaceutical preparations. Essential oils (EOs) were a kind of PE with satisfactory characteristics. Only 34 of among more than 300 EOs are reported to be used as PE. That is to say, about 90% EOs have not been applied until now and EOs possess great potential to act as PE. However, the research of EOs from Chinese materia medica (CMM) mainly followed the strategy of chemical PE. A large amount of studies were carried out to evaluate the transdermal penetration enhancing efficacy and pharmacological activity, resulting in the limited efficiency. EOs of CMM were also the key material basis of CMM pungent flavor. In the theory of traditional Chinese medicines (TCM), it was accepted that the pungent flavor could open the striae and interstice. The results of literature investigation revealed that the penetration enhancing efficacy of EOs directly related with drug property characteristics of CMM. Therefore, in the present paper, it was proposed that a rule existed between the penetration enhancing efficacy of EOs and drug property characteristics of CMM. A series of studies were then designed to reveal the rule with the aid of data analysis. The resultant rule will help to find the effective PE from various EOs. Moreover, to facilitate the high-throughput screening of EOs, liposomal artificial skin membrane was prepared and applied to the evaluation of in vitro penetration enhancing efficacy of EOs with optimization of the evaluation parameters. Finally, the results of the study will provide a novel strategy for the research of EOs as PE and the research of the application of TCM theory to the modern pharmaceutical study. In addition, the application of microemulsion technique will be the future trends of EOs as PE to solve the stability problems.