Lessons from nature: “Pathogen-Mimetic” systems for mucosal Nano-medicines

Mucosal surfaces establish an interface with external environments that provide a protective barrier with the capacity to selectively absorb and secrete materials important for homeostasis of the organism. In man, mucosal surfaces such as those in the gastrointestinal tract, respiratory tree and genitourinary system also represent significant barrier to the successful administration of certain pharmaceutical agents and the delivery of newly designed nano-scale therapeutic systems. This review examines morphological, physiological and biochemical aspects of these mucosal barriers and presents currently understood mechanisms used by a variety of virulence factors used by pathogenic bacteria to overcome various aspects of these mucosal barriers. Such information emphasizes the impediments that biologically active materials must overcome for absorption across these mucosal surfaces and provides a template for strategies to overcome these barriers for the successful delivery of nano-scale bioactive materials, also known as nano-medicines.     

Analysis of physicochemical properties for drugs from nature

The chemical structure of a compound has a direct influence on its physical, chemical, and biological properties. The present study describes data pertaining to calculations and statistical analysis of the physicochemical parameters of drugs obtained directly or indirectly from nature. The study projects various physiochemical parameters required for their druggability. The study reveals that most of these drugs fall close to Lipinski’s rule of five. Among the reported physicochemical parameters, the number of aromatic rings is most interesting. Illustrations regarding the same are reported, along with their statistical trends.     

Novel medicines from nature

A meeting held at the Royal Society of Medicine brought together a wide variety of people to look at a number of scientific, legal and ethical issues associated with the discovery of new drugs from nature, including plant, marine and animal sources. The meeting began with a historic overview of plant medicine, followed by presentations and discussion on particular aspects of bioprospecting and biodiversity. This was followed by an overview of the methods that can be used to identify potentially important drugs from natural products. The session on biological sources was the most important of the meeting as far as the discovery of new drugs was concerned. The final session of the meeting was pharmaco-socioeconomic in nature.     

Co-culture hydrogel micro-chamber array-based plate for anti-tumor drug development at single-element resolution

In response to the need for reliable cellular models that reflect complex tumor microenvironmental properties, and enable more precise testing of anti-cancer therapeutics effects on humans, a co-culture platform for in-vitro model that enhances the physiology of breast cancer (BC) microenvironment is presented. A six well imaging plate wherein each macro-well contains several separate compartments was designed. Three-dimensional (3D) cancer spheroids are generated and cultured in the inner compartment which is embossed with an array of nano-liter micro-chambers made of hydrogel. Stromal cells are cultured in the outer chambers. The two cell types are cultured side-by-side, sharing a common space, thus enabling extra-cellular communication via secreted molecules. As proof of concept, a model of BC tumor microenvironment was recapitulated by co-cultivating 3D MCF7 spheroids in the presence of tumor-associated macrophages (TAMs). The presence of TAMs induced an aggressive phenotype by promoting spheroid growth, enhancing survivin expression levels and enabling invasive behavior. Moreover, TAMs influenced the response of BC spheroids to cytotoxic treatment as well as hormonal drug therapy, and enhanced the effects of nitric oxide donor. The platform enables time-lapse imaging and treatment without losing spatial location of the measured spheroids, thereby allowing measurements and analysis at individual-object resolution in an easy and efficient manner.     

Aldose reductase inhibitors from the nature

Aldose reductase (AR) is an NADPH dependent enzyme that catalyses the reduction of the aldehyde to the corresponding alcohols. Diabetic complications including neuropathy, nephropathy, cataracts and retinopathy are considerately caused by accumulation of sorbitol, which is produced from glucose by AR in polyol pathway. The aim of AR inhibitor therapy is to normalize the elevated flux of blood and sorbitol through the polyol pathway in the target tissue. A large number of inhibitors have been prepared synthetically, and some of them are used therapeutically. However, none of them is satisfactory. From the plants, many AR inhibitors have been found, which are discussed in this review. By the structure based functioning of AR and its inhibitors, some will be developed promising in the treatment of diabetic complications. The main structural features of the inhibitors will be a polar head group and a hydrophobic ring system. The plants that contain the AR inhibitors may prevent from diabetic complications.     

Taxoids: cancer-fighting compounds from nature

This review covers advances in the discovery, preclinical and clinical development of potential anticancer agents based upon the diterpenoid taxane skeleton. The anticancer properties of approved clinical agents of this class are not discussed, but the review documents how, 13 years post-approval of paclitaxel (Taxol), the base taxane structure is still utilized as the starting skeleton for molecules with improved pharmacological and toxicological properties. Paclitaxel may in fact be the first example of a 'tunable' anticancer agent. In addition, paclitaxel, and perhaps other taxanes in due course, has activities beyond the known antitumor indications, with an example being the use of paclitaxel-coated stents in cardiovascular therapies.     

羟基脲对大鼠Sertoli-germ细胞共培养的影响

目的：观察羟基脲（Hydroxyurea,HU）对雄性大鼠Sertoli-germ细胞共培养的细胞毒性作用。方法：在Sertoli-germ细胞共培养模型中分别加入不同浓度HU（0、10^-3、10^-2、10^-1mol/L）后,孵育96h;以及加入10^-2mol/LHU后分别孵育24、48、72、96h。结果：在各给药组,96h时HU导致germ细胞从Sertoli细胞层的脱落增加,呈现量效关系。在10^-3mol/L以上浓度组,细胞活性逐渐下降,细胞脱落增加。同样,随着给药时间的增加,germ细胞脱落率和乳酸脱氢酶（LDH）的漏出逐渐增加,细胞活性逐渐下降。结论：HU对雄性大鼠睾丸Sertoli-germ细胞共培养模型的germ细胞具有明显毒性作用。     

Fishing for drugs from nature: zebrafish as a technology platform for natural product discovery

Emerging challenges within the current drug discovery paradigm are prompting renewed interest in natural products as a source of novel, bioactive small molecules. With the recent validation of zebrafish as a biomedically relevant model for functional genomics and in vivo drug discovery, the zebrafish bioassay-guided identification of natural products may be an attractive strategy to generate new lead compounds in a number of indication areas. Here, we review recent natural product research using zebrafish and evaluate the potential of this vertebrate model as a discovery platform for the systematic identification of bioactive natural products.     

The nature of the antiperistaltic factor from wheat gluten

The ultrafiltrate of an aqueous extract of gluten depressed the peristaltic reflex of the rat isolated jejunum. Further purification increased the activity of the extract 200-fold. Biochemical analysis showed that this purified gluten ultrafiltrate contained over 50% of adenosine. Comparative studies of the effects of adenosine and crude gluten ultrafiltrate were carried out on various biological preparations in vitro and in vivo. Both substances depressed all preparations that contained smooth or cardiac muscle, adenosine being 200- to 1,000-times more active than gluten ultrafiltrate. Large doses of gluten ultrafiltrate were spasmogenic to guinea-pig isolated intestine; this was not found with adenosine. Neither substance had any demonstrable effect on striated muscle or on neuromuscular transmission. Both substances were inactivated by incubation with mammalian small intestinal mucosa and with purified adenosine deaminase. Therefore there seems little doubt that gluten ultrafiltrate owes its antiperistaltic action to its adenosine content.     

Essramycin: a first triazolopyrimidine antibiotic isolated from nature

In the course of our screening program for new bio-active compounds, a novel triazolopyrimidine antibiotic, essramycin (1), was obtained from the culture broth of the marine Streptomyces sp., isolate Merv8102. Structure 1 was established by intensive NMR studies and by mass spectra. The compound is antibacterially active with MIC of 2 to 8 mug/ml against Gram-positive and Gram-negative bacteria, while it showed no antifungal activity. The fermentation and isolation, as well as the structure elucidation and biological activity of 1 are described.     

Demonstration of the peptidic nature of luciferin from Pyrocystis lunula

Amino acid analyses after acid hydrolysis have demonstrated that luciferin, the substrate of the bioluminescent reaction of the dinoflagellate Pyrocystis lunula and its precursor. P630, possess the same peptide moiety. The molecular weight of the resulting chromopeptides would be 5400.     

Bacterial removal from inexpensive portable water treatment systems for travelers

BACKGROUND: There are many personal portable water treatment systems for travelers on the market, including chemical agents, iodine resin purifiers and filters. However, information on the real efficacy of these systems in the field is often lacking. We have therefore estimated the capabilities of several inexpensive personal portable water treatment systems for travelers to remove bacteria in various situations of water quality, using stressed indigenous strains of bacteria. METHODS: Four chemical agents (Drinkwell chlorine, Hydroclonazone, Aquatabs, 2% iodine in ethanol), two iodine resin purifiers (the straw PentaPure Outdoor M1-E, the PentaPure Traveler purifying and filtration system) and four filters (the flexible bottle Pres2Pure, the hand-pump filters Mini Ceramic, First Need Deluxe and WalkAbout) were evaluated in triplicate using both turbid and clear water at 25 degrees C. Bacteria were counted by conventional culturing techniques, colorimetric and fluorescent assays of coliforms and Escherichia coli enzyme activities (Colilert)/Quantitray method), and viable but not culturable bacteria were assessed quantitatively by 5-cyano-2,3-dilotyl-tetrazolium staining. RESULTS: The best systems were the three hand-pump filters, Mini Ceramic, First Need Deluxe, and WalkAbout. All had a submicron filtration element that completely removed 3 log (99.9%) or more of viable bacteria, and no coliforms or E. coli were detected in the effluent. The PentaPure Traveler removed more than 99.3% of the viable bacteria. The only chemical agents that gave a bacterial inactivation of over 2 log in clear water were the Drinkwell chlorine, the Aquatabs, and the 2% iodine in ethanol. The three other devices, Hydroclonazone, Outdoor M1-E, and Pres2Pure, performed poorly, as coliforms and E. coli were detected in the treated water by the Colilert method. The chemical agents and the iodine resin straw performed poorly on raw river water; coliforms and E. coli were detected in the treated water. CONCLUSIONS: These data demonstrate the differences between the systems tested. The effectiveness of other devices on the market should also be tested, so as to help travelers and hikers select the most appropriate portable water treatment system.     

Supersensitivity of amylase secretion from rat parotid tissue--its selective nature for the beta 2-adrenergic response

In rat parotid tissue, amylase secretion and accumulation of cyclic AMP were not selective responses to the different beta-subtypes, beta 1 and beta 2. However, the supersensitivity of the amylase secretory response induced by brief pretreatment with beta-agonist was due specifically to a beta 2-adrenergic response.     

与肌源性干细胞共培养改善大鼠胰岛活性

目的研究体外共培养模型中肌源性干细胞(MDSCs)改善大鼠胰岛活性的作用。方法提取新生大鼠MDSCs原代细胞,差速贴壁培养后行结蛋白免疫细胞化学鉴定,取第4代MDSCs接种在transwell底板。提取大鼠胰岛后,双硫腙染色鉴定,胰岛在高糖环境中处理24 h后放入tran-swell板上层与MDSCs共培养。在培养的第1、3、6天分别用吖啶橙/溴化乙锭(AO/EB)双荧光染色胰岛,RT-PCR检测胰岛的Bcl-2/Bax基因表达来评价胰岛凋亡,其结果与单独胰岛培养组比较。结果与单独胰岛培养相比,共培养组第3、6天AO/EB染色见胰岛细胞明显增多,Bcl-2明显升高,而Bax明显降低(P<0.05、P<0.01)。结论大鼠胰岛与MDSCs共培养延长大鼠胰岛存活时间,改善胰岛活性。     

Drug delivery from gelatin-based systems

Introduction: Carriers for controlled drug release offer many advantages compared with conventional dosage forms. Gelatin has been investigated extensively as a drug delivery carrier, due to its properties and history of safe use in a wide range of medical applications.

Areas covered: Gelatin was shown to be versatile due to its intrinsic features that enable the design of different carrier systems, such as microparticles and nanoparticles, fibers and even hydrogels. Gelatin microparticles can serve as vehicles for cell amplification and for delivery of large bioactive molecules, whereas gelatin nanoparticles are better suited for intravenous delivery or for drug delivery to the brain. Gelatin fibers contain a high surface area-to-volume ratio, whereas gelatin hydrogels can trap molecules between the polymer’s crosslink gaps, allowing these molecules to diffuse into the blood stream. Another interesting area is the combination of tissue bioadhesive-based gelatin with controlled drug release for pain management and wound healing.

Expert opinion: The modification of gelatin and its combinations with other biomaterials have demonstrated the flexibility of these systems and can be employed for meeting the challenges of finding ideal carrier systems that enable specific, targeted and controlled release in response to demands in the body.