Current Pharmaceutical Design - Volume 23, Issue 11, 2017

With the advent of novel vesicular drug delivery systems especially bilosomes, for large molecular weight proteins and peptides, their oral administration seems a viable approach. These nano-vesicles have shown promising results for the effective delivery of insulin and other therapeutics, perhaps due to their structural composition. The present review has elaborated the biopharmaceutical challenges for the oral delivery of therapeutic proteins and peptides as well as presented a novel approach to deliver the essential macromolecules through oral route as bilosomes. The extensive search has been presented related to the formulation, evaluation and in vivo performance of bilosomes. Some of the crucial findings related to bilosomes have corroborated them superior to other colloidal carriers. The successful drug delivery through bilosomes requires significant justifications related to their interaction with the biological membranes. The other aspects such as absolute absorption, safety and toxicity of bilosome drug delivery should also be equally considered.

Sulfur mustard (SM; mustard gas) is a classic chemical warfare agent that has been used in several wars and is still a potential threat especially in the Middle-East region. Victims experience acute symptoms in airexposed organs including skin, respiratory tract and the eyes. Survivors of the acute stage might develop chronic or delayed-onset complications in the exposed organs. The exact mechanism(s) of SM-induced tissue damage is still unknown, however DNA alkylation and oxidative damage are the most relevant mechanisms. Eye is the most sensitive organ to the SM vapor and ocular symptoms usually precede other manifestations. Ocular findings including blepharitis, dry eye disease, corneal vascularization, persistent epithelial defects, limbal ischemia, limbal stem cell deficiency, corneal thinning, corneal opacity and corneal innervation abnormalities have been reported several years after SM exposure. In this review, mechanisms of acute and chronic/delayed ocular manifestations of SM and their current management and potential future therapies have been discussed. We have also included recent advances in amniotic membrane transplantation, cultivated stem cell transplantation and anti-angiogenic therapies which might be considered as therapeutic options in SM-induced ocular damage in the future.

Nonsense mutations contribute to approximately 10-30% of the total human inherited diseases via disruption of protein translation. If any of the three termination codons (UGA, UAG and UAA) emerges prematurely [known as premature termination codon (PTC)] before the natural canonical stop codon, truncated nonfunctional proteins or proteins with deleterious loss or gain-of-function activities are synthesized, followed by the development of nonsense mutation-mediated diseases. In the past decade, PTC-associated diseases captured much attention in biomedical research, especially as molecular therapeutic targets via nonsense suppression (i.e. translational readthrough) regimens. In this review, we highlighted different treatment strategies of PTC targeting readthrough therapeutics including the use of aminoglycosides, ataluren (formerly known as PTC124), suppressor tRNAs, nonsense-mediated mRNA decay, pseudouridylation and CRISPR/Cas9 system to treat PTC-mediated diseases. In addition, as thrombotic disorders are a group of disease with major burdens worldwide, 19 potential genes containing a total of 705 PTCs that cause 21 thrombotic disorders have been listed based on the data reanalysis from the ‘GeneCards®-Human Gene Database’ and ‘Human Gene Mutation Database’ (HGMD®). These PTC-containing genes can be potential targets amenable for different readthrough therapeutic strategies in the future.

The therapeutic significance of bioengineering proteins has increased dramatically as a new generation of pharmacological drug with a great potential in medical treatment. Protein engineering has improved the use of new non immunoglobulin affinity proteins. The designed ankyrin repeat proteins abbreviated as DARPins is a classical example. These molecules have smaller structural size, unlike immunoglobulins, but similar target affinity is of great significance. Such molecules get more binding specificity and greater thermodynamic stability. These attributes made DARPins a favorite player in diagnostics and therapeutics of cancer. How DARPins are improved into vigorous and versatile scaffold for binding protein and selected by ribosome and phage display along with related aspects is discussed in this review.

Stevia rebaudiana Bertoni is a sweet and nutrient-rich plant belonging to the Asteraceae family. Stevia leaves contain steviol glycosides including stevioside, rebaudioside (A to F), steviolbioside, and isosteviol, which are responsible for the plant's sweet taste, and have commercial value all over the world as a sugar substitute in foods, beverages and medicines. Among the various steviol glycosides, stevioside, rebaudioside A and rebaudioside C are the major metabolites and these compounds are on average 250-300 times sweeter than sucrose. Steviol is the final product of Stevia metabolism. The metabolized components essentially leave the body and there is no accumulation. Beyond their value as sweeteners, Stevia and its glycosdies possess therapeutic effects against several diseases such as cancer, diabetes mellitus, hypertension, inflammation, cystic fibrosis, obesity and tooth decay. Studies have shown that steviol glycosides found in Stevia are not teratogenic, mutagenic or carcinogenic and cause no acute and subacute toxicity. The present review provides a summary on the biological and pharmacological properties of steviol glycosides that might be relevant for the treatment of human diseases.

Objective: To search major Traditional Persian Medicine (TPM) textbooks for medicinal plants used to treat asthma. The conformity of the TPM findings on the anti-asthmatic efficacy of plants with the findings of pharmacological studies was also explored. Methods: Major TPM textbooks were hand searched to find medicinal plants used for the treatment of asthma. Scientific names of TPM-suggested plants were determined using botanical databases and were used for a multidatabase electronic search in PubMed, Scopus, ScienceDirect and Google Scholar databases. Then, the antiasthmatic effectiveness of TPM-recommended plants was verified in view of the findings from modern pharmacological investigations. Results: According to the main TPM texts, Adianthum capillus-veneris, Boswellia oleogumresin, Crocus sativus, Glycyrrhiza glabra, Hyssopus officinalis and Ruta graveolens were the most efficacious medicinal plants for the treatment of asthma. This finding was confirmed by pharmacological studies which showed counterbalancing effects of the above-mentioned plants on inflammation, oxidative stress, allergic response, tracheal smooth muscle cell constriction and airway remodeling. Conclusion: The strong ethnobotanical background of plants used in TPM could be a valuable tool to find new anti-asthmatic medications. In this review, TPM-suggested anti-asthmatic plants were found to possess several mechanisms relevant to the treatment of respiratory diseases according to the information retrieved from modern pharmacological studies. This high degree of conformity suggested further proof-of-concept trials to ascertain the role of these plants in the routine management of asthmatic patients.

Background: The most recurrent and considered second most frequent cause of cancer-related deaths worldwide in women is the breast cancer. The key to diagnosis is early prediction and a curable stage but still treatment remains a great clinical challenge. Origin of the Problem: A number of studies have been carried out for the treatment of breast cancer which includes the targeted therapies and increased survival rates in women. Essential PI3K/mTOR signaling pathway activation has been observed in most breast cancers. The cell growth and tumor development in such cases involve phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) complex intracellular pathway. Hypothesis: Through preclinical and clinical trials, it has been observed that there are a number of other inhibitors of PI3K/Akt/mTOR pathway, which either alone or in combination with cytotoxic agents can be used for endocrine therapies. Conclusion: Structure and regulation/deregulation of mTOR provides a greater insight into the action mechanism. Also, through this review, one could easily scan first and second generation inhibitors for PI3K/Akt/mTOR pathway besides targeted therapies for breast cancer and the precise role of mTOR.

Poorly water-soluble drugs, which commonly face the issue of poor absorption and low bioavailability, have been under ongoing research of many formulation scientists for the past few decades. Solid dispersion is one of the most effective strategies in concerns for improving bioavailability of poorly water-soluble drugs. Either application of solid dispersions in dissolution enhancement of poorly water-soluble drugs or the use of swellable polymers in controlled drug release has been reported in pharmaceutical designs widely. However, a review of strategies of using swellable polymers in solid dispersion to take a full advantage of these polymers as a current perspective in facilitating drug bioavailability enhancement is still missing. In this review, we aim to provide a summary of techniques used to formulate a swellable polymer in solid dispersion especially a description of a suitable fabrication method in design of a controlled release solid dispersion.

Ginseng has gained fame as one of the most popular herbs originating from Eastern countries. Among different species which are known as ginseng, Panax ginseng C. A. Mey. (Korean or Asian ginseng) is the most frequently used one. Ginsenosides have been proposed to account for most of the biological activities of ginseng. The widely appreciated health-promoting effect of ginseng pertains to the beneficial effects of this plant against immune, cardiovascular and sexual diseases and cancer. In addition, there are some new aspects of the pharmacological activity of this plant which justify its use in dermatologic diseases. In dermatology, ginseng has been investigated mechanistically for its therapeutic effects in photoaging, wound and injury, skin cancer, dermatitis, hair loss, alopecia and cold hypersensitivity. Here, we reviewed experimental and clinical studies exploring the therapeutic efficacy of ginseng and ginsenosides in the field of dermatology.

Diabetes has increased at an unprecedented rate and is fast emerging as a global threat worldwide. The focus on pharmacological studies pertaining to diabetes has seen a remarkable shift from conventional medicines to therapeutics employing bioactive phytomolecules from natural sources. The prospective effectiveness of natural products together with their low cost and minimal side effects has revolutionized the entire concept of drug discovery and management programs. One such beneficial herb is Gymnema sylvestre, possessing remarkable hypoglycemic properties and forms the platform of diabetes therapeutics in the traditional system of medication. The present article discusses the significance of G. sylvestre in diabetes management, the herbal-formulations from the herb together with its standardization and clinical trials on animal models, and why Peroxisome Proliferator Activated Receptor gamma (PPARγ) may serve as a prospective molecular target for Gymnemic acid analogs. Such studies would define the molecular basis of bioactive molecules which would aid in the development of natural product based therapeutics in the treatment of diabetes.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in the regulation of lipid metabolism, energy production, and inflammation. It is well established that all of the three isoforms of PPARs expressed in the cardiomyocytes, and that PPARs are closely involved in the regulation of lipid metabolism and energy homeostasis as well as many other different aspects in the heart. We think that PPARs are very important therapeutic targets for drug development, however, the drugs targeting at PPARs meet some trouble in clinical practice, especially the reported side effects related to heart failure. This review summarizes different functions and mechanisms of each isoform in cardiac hypertrophy and heart failure, for the reason that if more efforts are made to investigate the interactions among different isoforms, minimize the off-target effects, and avoid PPARs-independent side effects, we can develop safer and more effective PPAR agonists for the clinical practice in the near future.

Although evidence over the last 30 years suggests that the autonomic nervous system (ANS) mediates stress-induced allostatic and immune responses, the crucial role that it plays in the tumor micro-environment has only recently been reported. Here, we review the action of ANS signaling in this micro-environment. Emerging data suggest that primary tumors are innervated by the ANS which mediates stress-related effects on tumor progression. The activation of the sympathetic nervous system (SNS) takes advantage of neurotransmitters and neuropeptides from the innervating neural circuitry and/or hypothalamic-pituitary-adrenal axis glucocorticoids via their receptors to modulate the gene expression associated with oncogenesis, the proliferation and apoptosis of tumor cells, angiogenesis, and the tumor-associated immune response. The parasympathetic nervous system has also been implicated in some tumor types, but its contribution in the tumor micro-environment remains unclear. In addition to identifying the ANS signaling pathways involved in tumor progression, recent reports suggest that the ANS could be a potential biomarker to predict tumor progression, and have identified new pharmacological strategies, such as the use of β-adrenergic blockers, to inhibit tumor progression and metastasis by targeting this system. These findings are reviewed here.

Endoplasmic reticulum (ER) has evolved an adaptive mechanism called unfolded protein response (UPR) at the initial stage to restore cellular homeostasis. The three ER transmembrane sensors, such as IRE1α, PERK, and ATF6, are the key factors to decide cell fates. They exhibit both advantageous and disadvantageous effects, depending on the micro-environmental state of cells. ER stress has been implicated in chondrocytes proliferation, differentiation, and hypertrophy through regulating transcriptional factors SOX9, Ihh, BMP-2, RUNX, and HIF1/2α. In addition, the chronic ER stress induced by the mutant proteins becomes the pathophysiology of chondrodysplasia. On the other hand, ER stress may induce chondrocytes apoptosis, leading to the degeneration of cartilage. eIF2α-CHOP and JNK activation are the remarkably apoptotic responses to ER stress, while XBP1s and Bip exhibit pro-survival effects. These factors might potentially become therapeutic targets for joint diseases management. This article reviews the pro-survival and pro-apoptotic effects of ER stress as well as their implications in cartilage and chondrocytes.

Exosome-encapsulated microRNAs are being suggested as a new class novel biomarker as diagnostic and predictive markers in colorectal cancer. These particles are released from many cell types into the extracellular space upon fusion of multivesicular bodies (MVB) with the plasma membrane. They contain a wide variety of information, including proteins, lipids, RNAs, non-transcribed RNAs, microRNAs, which can be circulated in various body fluids (e.g., blood, salvia, ascites, urine). Exosomes can be taken up by neighboring or distant cells and thereby modulate the functional of recipient cells and play a key role in disease progression or facilitate metastasis in cancers. The aim of current review is to give an overview about origin and trafficking of exosomes between cells, techniques to isolate exosomal microRNAs as well as the potential applications of exosomeencapsulated microRNAs as diagnostic markers in clinical settings in colorectal cancer. There is growing body of evidence showing the prognostic and diagnostic value of some exosomal microRNAs in colon cancer (e.g., miR- 150, miR-21, miR-192, let-7a, miR-223, and miR-23a). These findings provide a new insight on novel application of these markers as being novel non-invasive biomarkers for early detection and risk assessment of patients with colorectal cancer, although further investigations in larger population are required to explore the clinical utility of exosomal microRNAs in colorectal cancer patients.

Background: The living environment of cancer cells is complicated and information-rich. Thus, traditional 2D culture mold in vitro cannot mimic the microenvironment of cancer cells exactly. Currently, bioengineered 3D scaffolds have been developed which can better simulate the microenvironment of tumors and fill the gap between 2D culture and clinical application. Conclusion: In this review, we discuss the scaffold materials used for fabrication techniques, biological behaviors of cancer cells in 3D scaffolds and the scaffold-based drug screening. A major emphasis is placed on the description of scaffold-based epithelial to mesenchymal transition and drug screening in 3D culture. By overcoming the defects of traditional 2D culture, 3D scaffolds culture can provide a simpler, safer and more reliable approach for cancer research.