Curcumin sensitized the antitumour effects of irradiation in promoting apoptosis of oesophageal squamous‐cell carcinoma through NF‐κB signalling pathway

Objectives

To investigate the potential synergistic effect of curcumin with irradiation (IR ) in oesophageal squamous‐cell carcinoma (ESCC ) and elucidate the underlying molecular mechanisms.

Methods

The ESCC cell lines were established from clinical samples. Cell apoptosis post‐treatment was stained by Annexin V /PI staining and analysed by flow cytometry. Cells survived IR was evaluated with clonogenic assay. Xenograft tumour model was established by subcutaneous inoculation, and tumour progression was monitored. The NF ‐κB pathway was characterized by immunoblotting.

Key findings

Curcumin enhanced the pro‐apoptotic effect of IR in ESCC cells. Pretreatment with curcumin significantly sensitized ESCC cells to IR in a dose‐dependent manner. Coadministration with curcumin remarkably extended the median survival time of ESCC xenograft mice while exposed to IR therapy. The xenograft tumour progression was significantly suppressed as well. Mechanistically, curcumin treatment was demonstrated to efficiently inhibited NF ‐κB signalling.

Conclusions

We have well‐recapitulated the pathological properties and therapeutic response of ESCC with established cell lines derived from clinical samples. We further demonstrated the significantly synergistic effect of curcumin on IR ‐elicited cell apoptosis in ESCC both in vitro and in vivo . Our data suggested the potential therapeutic values of curcumin for future clinical investigations.

     

The indane diastereoisomers,PH2 and PH5: divergence between their effects in delayed‐type hypersensitivity models and a model of colitis

Objectives

Compounds PH2 and PH5 are distereoisomers of novel indane compounds, synthesised as analogues of secondary metabolites of the fern, Onychium. In this study, we compare their effects on a variety of inflammatory models.

Methods

In an effort to extend our knowledge of their anti‐inflammatory profile, we have investigated their activity in two models of delayed‐type hypersensitivity (DTH); the methylated bovine serum albumin model (mBSA) and the oxazolone contact hypersensitivity (CHS) model, on IL2 release from Jurkat cells and in the dextran sulphate sodium (DSS) murine model of inflammatory bowel disease.

Key findings

Both diastereoisomers are equipotent in reducing paw swelling in the mBSA model and in inhibiting interleukin (IL) 2 release from Jurkat cells. They are equally ineffective in the oxazolone contact hypersensitivity model (CHS). Only the diastereoisomer, PH5, protects against DSS‐induced colitis and of its two enantiomers, only the S,S‐enantiomer, PH22, possesses this activity. PH2 is ineffective in the DSS model.

Conclusions

The results suggest that the beneficial effect of PH5, and its enantiomer PH22, in the DSS model is a consequence of an action on a target specific to the colitis model. The implications of such data suggest an unknown target in this disease model that may be exploited to therapeutic advantage.

     

Analgesic effect of S (+)‐flurbiprofen plaster in a rat model of knee arthritis: analysis of gait and synovial fluid prostaglandin E2 levels

Objectives

We developed S (+)‐flurbiprofen plaster (SFPP ), a novel NSAID patch containing S (+)‐flurbiprofen (SFP ), a potent cyclooxygenase (COX ) inhibitor. The purpose of this study was to assess efficacy of SFPP by analysing its effect on the gait disturbance and measuring the prostaglandin E₂ (PGE ₂) production in synovial fluid in a rat model of knee arthritis.

Methods

Knee inflammation was induced in rats by intra‐articular injection of a yeast suspension. Subsequently, an NSAID patch containing SFP , ketoprofen or loxoprofen was applied over the affected knee. Gait was assessed at 2, 4 and 6 h after application of the patch. The PGE ₂ concentration in the synovial fluid was measured after the gait assessment.

Key findings

Application of SFPP (0.125, 0.25, 0.5 or 1 mg/sheet) was followed by a decrease in the visual gait score at all the doses examined. In the case of the other two NSAID patches, only the ketoprofen patch (1 or 2 mg/sheet) and loxoprofen patch (5 mg/sheet) produced a decrease in the visual gait score. All of the NSAID patches decreased the PGE ₂ production in the synovial fluid.

Conclusions

These results suggest the potential usefulness of SFPP as an analgesic patch in patients with inflammatory joint pain.

     

Wound healing potential of Solanum xanthocarpum in streptozotocin‐induced diabetic rats

Objectives

The objective of the present study was to evaluate wound healing potential of Solanum xanthocarpum extract in streptozotocin‐induced diabetic rats.

Methods

Alcoholic extract of the aerial parts (ESX ) was subjected to phytochemical estimations and its standardization with chlorogenic acid using HPLC . ESX was then evaluated for wound healing potential in, streptozotocin‐induced diabetic rats using excision and incision wound models on topical and oral treatment Various biochemical evaluations, such as collagen, hexosamine, hyaluronic acid, protein, DNA along with antioxidant parameters, proinflammatory cytokines, VEGF and histopathological examination were also evaluated.

Key findings

Extract of S. xanthocarpum depicted the presence of mainly alkaloids, polyphenols, steroids, while content of chlorogenic acid was found to be 8.44% w/w. The maximum effective nature of ESX in healing was observed at 10% gel (topical) and 200 mg/kg (orally) in diabetic rats, where highest healing power was observed when treated both orally and topically. Biochemical evaluations showed significant increase in the levels of collagen, hexosamine, hyaluronic acid, protein, DNA followed by significant decline in the levels of blood glucose, lipid peroxidation, nitric oxide and expression of proinflammatory cytokines, supported by histopathology.

Conclusions

The potential healing effect in diabetic rats may be attributed to the presence of chlorogenic acid in combination with other phytoconstituents.

     

Pigment epithelium‐derived factor: a key mediator in bone homeostasis and potential for bone regenerative therapy

Objectives

Pigment epithelium‐derived factor (PEDF ), a multifunctional endogenous glycoprotein, has a very wide range of biological actions, notably in bone homeostasis. The question has been raised regarding the place of PEDF in the treatment of bone disorders and osteosarcoma, and its potential for tumour growth suppression.

Methods

The PubMed database was used to compile this review.

Key findings

Pigment epithelium‐derived factor's actions in osteoid tissues include promoting mesenchymal stem cell commitment to osteoblasts, increasing matrix mineralisation, and promoting osteoblast proliferation. It shows potential to improve therapeutic outcomes in treatment of multiple cancer types and regrowth of bone after trauma or resection in animal studies. PEDF may possibly have a reduced adverse effect profile compared with current osteo‐regenerative treatments; however, there is currently very limited evidence regarding the safety or efficacy in human models.

Summary

Pigment epithelium‐derived factor is very active within the body, particularly in osseous tissue, and its physiological actions give it potential for treatment of both bone disorders and multiple tumour types. Further research is needed to ascertain the adverse effects and safety profile of PEDF as a therapeutic agent.

     

Delivery of therapeutics for deep‐seated ocular conditions – status quo

Objectives

There is a need for research into designing effective pharmaceutical systems for delivering therapeutic drugs to the posterior of the eye for glaucoma‐related pathology, macular degeneration, diabetic retinopathy, macular oedema, retinitis and choroiditis. Conventionally, eye drops have been extensively utilised for topical drug delivery to the anterior segment of the eye, but are less effective for delivery of therapeutics to the back of the eye due to significant barriers hampering drug penetration into the target intraocular tissue. This review explores some of the current and novel delivery systems employed to deliver therapeutics to the back of the eye such as those using liposomes, ocular implants, in situ gels, and nanoparticles, and how they can overcome some of these limitations.

Key findings

Issues such as blinking, precorneal fluid drainage, tear dilution and turnover, conjunctiva and nasal drug absorption, the corneal epithelium, vitreous drug clearance, and the blood–ocular barriers are reviewed and discussed.

Summary

Further studies are needed to address their shortcomings such as drug compatibility and stability, economic viability and patient compliance.

     

The role of melatonin on chemotherapy‐induced reproductive toxicity

Objectives

Reproductive malfunctions after chemotherapy still are a reason of reducing fertility and need specialized intensive care. The aim of this review was to investigate the effect of melatonin on the reproductive system under threatening with chemotherapeutic drugs.

Methods

To find the role of melatonin in the reproductive system during chemotherapy, a full systematic literature search was carried out based on Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines in the electronic databases up to 17 April 2017 using search terms in the titles and abstracts. A total of 380 articles are screened according to our inclusion and exclusion criteria. Finally, 18 articles were included in this study.

Key findings

It has been cleared that melatonin has bilateral effects on reproductive cells. Melatonin protects normal cells via mechanisms, including decrease in oxidative stress, apoptosis, inflammation and modulating mitochondrial function, and sexual hormones. Furthermore, melatonin with antiproliferative properties and direct effects on its receptors improves reproductive injury and function during chemotherapy. On the other hand, melatonin sensitizes the effects of chemotherapeutic drugs and enhances chemotherapy‐induced toxicity in cancerous cells through increasing apoptosis, oxidative stress and mitochondrial malfunction.

Conclusions

The study provides evidence of the bilateral role of melatonin in the reproductive system during chemotherapy.

     

Endocannabinoids modulate Gq/11 protein‐coupled receptor agonist‐induced vasoconstriction via a negative feedback mechanism

Objectives

The endocannabinoid (eCB) system centrally and peripherally regulates cardiovascular parameters, including blood pressure, in health and disease. The relationship between G_q/11 protein‐coupled receptor activation, regulation of eCBs release (mainly 2‐arachidonoylglycerol) and subsequent CB₁ receptor activation was initially observed in the central nervous system. Here, we review the latest findings from systemic physiological studies which include for the first time data from pulmonary arteries. We present evidence for direct CB₁‐dependent cannabinoid ligand‐induced vasorelaxation, vascular expression of eCBs along with their degradation enzymes, and indicate the location of the described interaction.

Key findings

Endocannabinoids (mainly 2‐arachidonoylglycerol), acting via CB₁ receptors, evoke vasodilatory effects and may modulate responses of vasoconstrictors for G_q/11 protein‐coupled receptors including angiotensin II, thromboxane A₂, phenylephrine, noradrenaline in systemic or pulmonary arteries. However, the role of the endothelium in this interaction is not well‐established, and the precise vascular location of eCB system components remains unclear, which contributes to discrepancies in the interpretation of results when describing the above‐mentioned relationship.

Summary

Endocannabinoid's negative feedback is responsible for diminishing agonist‐induced vasoconstriction, which may be clinically important in the treatment of arterial and pulmonary hypertension. Further research is required to establish the importance of the eCB system and its downstream signalling pathways.

     

Transdifferentiation of adipocytes to osteoblasts: potential for orthopaedic treatment

Objectives

As both adipocytes and osteoblasts originate from the same pool of mesenchymal stem cells, increasing clinical evidence has emerged of the plasticity between the two lineages. For instance, the downregulation of osteoblast differentiation and upregulation of adipogenesis are common features of conditions such as multiple myeloma, obesity and drug‐induced bone loss in diabetes mellitus. However, despite in‐vitro and in‐vivo observations of adipocyte transdifferentiation into osteoblasts, little is known of the underlying mechanisms.

Key findings

This review summarises the current knowledge of this particular transdifferentiation process whereby the Wnt/β‐catenin signalling pathway and Runx2 overexpression have been postulated to play a critical role.

Summary

Furthermore, due to the possibility of a novel therapy in the treatment of bone conditions, a number of agents with the potential to induce adipo‐to‐osteoblast transdifferentiation have been investigated such as all‐trans retinoic acid, bone morphogenetic protein‐9 and vascular endothelial growth factor.

     

Therapeutic potency of pharmacological adenosine receptor agonist/antagonist in angiogenesis,current status and perspectives

Objectives

Adenosine concentration significantly increases in tumour microenvironment contributing to tumorigenic processes including cell proliferation, survival, invasion and of special interest in this review angiogenesis.

Key findings

This review summarizes the role of pharmacological adenosine receptor agonist and antagonist in regulating angiogenesis for a better understanding and hence a better management of angiogenesis‐associated disorders.

Summary

Depending upon the pharmacological characteristics of adenosine receptor subtypes, adenosine elicits anti‐ or pro‐angiogenic responses in stimulated cells. Inhibition of the stimulatory effect of adenosine signalling on angiogenesis using specific pharmacological adenosine receptor agonist, and antagonist is a potentially novel strategy to suppress angiogenesis in tumours.

     

Monoclonal antibody‐based therapeutics,targeting the epidermal growth factor receptor family: from herceptin to Pan HER

Objectives

Monoclonal antibody‐based of cancer therapy has been considered as one of the most successful therapeutic strategies for both haematologic malignancies and solid tumours in the last two decades. Epidermal growth factor receptor (EGFR ) family signalling pathways play a key role in the regulation of cell proliferation, survival and differentiation. Hence, anti‐EGFR family mA bs is one of the most promising approaches in cancer therapy.

Key findings

Here, recent advances in anti‐EGFR mA b including approved or successfully tested in preclinical and clinical studies have been reviewed. Although we focus on monoclonal antibodies against the EGF receptor, but the mechanisms underlying the effects of EGFR ‐specific mA b in cancer therapy, to some extend the resistance to existing anti‐EGFR therapies and some therapeutic strategies to overcome resistance such as combination of mA bs on different pathways are briefly discussed as well.

Summary

The EGFR family receptors, is considered as an attractive target for mA b development to inhibit their consecutive activities in tumour growth and resistance. However, due to resistance mechanisms, the combination therapies may become a good candidate for targeting EGFR family receptors.

     

In vitro gastrointestinal biotransformation and characterization of a Desmodium adscendens decoction: the first step in unravelling its behaviour in the human body

Objectives

The isolation and identification of the flavonoids present in a decoction of Desmodium adscendens was performed. In view of the oral use of the decoction, this work focused on the stability in gastrointestinal conditions and biotransformation by intestinal microflora in the colon of D‐pinitol, vitexin and the flavonoid fraction of the decoction, as a first step in unravelling its behaviour in the human body.

Methods

The freeze‐dried decoction was first subjected to column chromatography. Subsequently an enriched flavonoid fraction, was separated by repeated semi‐preparative high‐performance liquid chromatography (HPLC ) or by HPLC ‐SPE . The isolated compounds were elucidated by NMR . Biotransformation experiments were carried in an in vitro gastrointestinal dialysis model.

Key findings

The major flavonoids of a decoction of D. adscendens were characterized as vicenin‐2, isoschaftoside, schaftoside, 2″‐O ‐xylosylvitexin, 2″‐O ‐pentosyl‐C ‐hexosyl apigenin and a O ‐hexosyl‐C ‐hexosyl apigenin, tentatively identified as 2″‐O ‐glucosyl‐vitexin. During their passage in the gastrointestinal dialysis model, vitexin and C ‐glycosides thereof were found to be stable. Only the O ‐glycosidic bonds of O ‐glycosides of vitexin or isovitexin were hydrolysed during the colonic phase.

Conclusions

A D. adscendens decoction was found to be rich in vitexin and isovitexin glycosides from which vitexin and the C ‐glycosides thereof were found to be stable in the simulated gastrointestinal tract.

     

Multiclass mycotoxins in lotus seeds analysed by an isotope‐labelled internal standard‐based UPLC‐MS/MS

Objectives

This study aimed to explore the residue levels of multiclass mycotoxins in medicinal and edible lotus seeds.

Methods

A rapid and reliable isotope‐labelled internal standard‐based UPLC ‐MS /MS method was developed and validated for sensitive and accurate analysis of multiclass mycotoxins including aflatoxins (AFB ₁, AFB ₂, AFG ₁ and AFG ₂), ochratoxin A (OTA ), zearalenone (ZEN ), deoxynivalenol (DON ), fumonisins (FB ₁ and FB ₂), T‐2 and HT ‐2 toxins in lotus seeds. Some critical conditions such as extract solution with the addition of isotope‐labelled internal standard, type of mobile phase and the elution condition were scientifically optimized. The 11 mycotoxins obtained satisfactory resolution and sensitive detection in multiple reactions monitoring scanning mode combined with the ion switching technology in positive and negative ion switching mode.

Key findings

The developed isotope‐labelled internal standard‐based UPLC ‐MS /MS method exhibited an approving linearity (r  ≥  0.9984), high sensitivity (limit of detection in the range of 0.015–30.05 μg/kg), acceptable precision (RSD s ≤6.3%) and good recovery (76.0–116.0%) for 11 analytes, respectively. Ten batches of real lotus seed samples were tested, and three batches out of which were contaminated with AFB ₁, FB ₂, T‐2 and ZEN . AFB ₁ showed the highest occurrence rate (30%) with contents of 10.50 and 8.32 μg/kg in two samples over the official limit (5.0 μg/kg).

Conclusions

The monitoring of multiclass mycotoxins in Chinese herbal medicines is in great urgency to ensure the security of consumers. The proposed method could be further utilized for simple, sensitive and rapid detection of more mycotoxins in other complex matrices to compensate for matrix effects.

     

Salvia miltiorrhiza enhances the survival of mesenchymal stem cells under ischemic conditions

Objectives

To validate the enhanced therapeutic effect of Salvia miltiorrhiza Bunge (SM ) for brain ischemic stroke through the anti‐apoptotic and survival ability of mesenchymal stem cells (MSC s).

Methods

The viability and the expression level of cell apoptotic and survival‐related proteins in MSC s by treatment of SM were assessed in vitro . In addition, the infarcted brain region and the behavioural changes after treatment of MSC s with SM were confirmed in rat middle cerebral artery occlusion (MCA o) models.

Key findings

We demonstrated that SM attenuates apoptosis and improves the cell viability of MSC s. In the rat MCA o model, the recovery of the infarcted region and positive changes of behaviour are observed after treatment of MSC s with SM .

Conclusions

The therapy using SM enhances the therapeutic effect for brain ischemic stroke by promoting the survival of MSC s. This synergetic effect thereby proposes a new experimental approach of traditional Chinese medicine and stem cell‐based therapies for patients suffering from a variety of diseases.

     

Viscum articulatum Burm. f.: a review on its phytochemistry,pharmacology and traditional uses

Objectives

The aim of this study was to review and highlight traditional and ethnobotanical uses, phytochemical constituents, IP status, biological activity and pharmacological activity of Viscum articulatum.

Methods

Thorough literature searches were performed on Viscum articulatum, and data were analysed for reported traditional uses, pharmacological activity, phytochemicals present and patents filed. Scientific and patent databases such as PubMed, Science Direct, Google Scholar, Google patents, USPTO and Espacenet were searched using different keywords.

Key findings

Viscum articulatum has been traditionally used in different parts of the world for treatment of various ailments. Almost all the parts such as leaves, root, stem and bark are having medicinal values and are reported for their uses in Ayurvedic and Chinese system of medicine for the management of various diseases. Modern scientific studies demonstrate efficacy of this plant against hypertension, ulcer, epilepsy, inflammation, wound, nephrotoxicity, HIV, cancer, etc. Major bioactive phytochemicals include oleanolic acid, betulinic acid, eriodictyol, naringenin, β‐amyrin acetate, visartisides, etc.

Conclusions

Side effects of allopathic medicines have created a global opportunity, acceptance and demand for phytomedicines. Viscum articulatum could be an excellent source of effective and safe phytomedicine for various ailments if focused translational efforts are undertaken by integrating the existing outcomes of researches.

     

Oral insulin delivery: existing barriers and current counter‐strategies

Objectives

The chronic and progressive nature of diabetes is usually associated with micro‐ and macrovascular complications where failure of pancreatic β‐cell function and a general condition of hyperglycaemia is created. One possible factor is failure of the patient to comply with and adhere to the prescribed insulin due to the inconvenient administration route. This review summarizes the rationale for oral insulin administration, existing barriers and some counter‐strategies trialled.

Key findings

Oral insulin mimics the physiology of endogenous insulin secreted by pancreas. Following the intestinal absorption of oral insulin, it reaches the liver at high concentration via the portal vein. Oral insulin on the other hand has the potential to protect pancreatic β‐cells from autoimmune destruction. Structural modification, targeting a particular tissue/receptor, and the use of innovative pharmaceutical formulations such as nanoparticles represent strategies introduced to improve oral insulin bioavailability. They showed promising results in overcoming the hurdles facing oral insulin delivery, although delivery is far from ideal.

Summary

The use of advanced pharmaceutical technologies and further research in particulate carrier system delivery predominantly nanoparticle utilization would offer useful tools in delivering insulin via the oral route which in turn would potentially improve diabetic patient compliance to insulin and the overall management of diabetes.

     

Sterculia and Brachychiton: a comprehensive overview on their ethnopharmacology,biological activities,phytochemistry and the role of their gummy exudates in drug delivery

Objectives

Sterculia and Brachychiton are two related genera (Malvaceae) containing more than 300 species. Most of these species are ornamental trees that are native to Australia and widely cultivated in many countries. Different members of the two genera were used by various cultures for medicinal and economical purposes. This review sheds light on the medicinal values and chemical composition of various species of these two genera.

Key findings

Sterculia and Brachychiton species were used traditionally for the treatment of gastrointestinal disorders, microbial infection, skin diseases, inflammation and many other conditions. The seeds of various species were roasted and eaten by many traditional tribes. Plants from the two genera revealed their anti‐inflammatory, antioxidant, antimicrobial, antidiabetic, antiulcer, insecticidal and analgesic activity. These activities may be attributed to the presence of a wide range of secondary metabolites as flavonoids, phenolic acids, coumarins, terpenoids particularly sesquiterpenes and triterpenes in addition to sterols and fatty acids. Moreover, the gummy exudates obtained from some members of these genera played an important role in different pharmaceutical dosage forms and drug‐delivery systems.

Conclusions

More research is recommended on other species of Sterculia and Brachychiton to discover new molecular entities with potential biological and economic values.

     

Antiageing properties of Damaurone D in Caenorhabditis elegans

Objectives

This study was conducted to evaluate the longevity potential of damaurone D (DaD), a component of the damask rose, in the animal model Caenorhabditis elegans .

Methods

To investigate the effect of DaD on the longevity, lifespan assay was carried out. Fluorescence intensity of transgenic mutants was quantified to test the expression levels of stress proteins. A genetic study using single gene knockout mutants was designed to determine the target genes of DaD.

Key findings

DaD prolonged the mean lifespan of wild‐type nematodes by 16.7% under normal conditions and also improved their stress endurance under thermal, osmotic, and oxidative stress conditions. This longevity‐promoting effect could be attributed to in vivo antioxidant capacity and its up‐regulating effects on the expressions of stress‐response proteins such as SOD‐3 and HSP‐16.2. In addition, DaD treatment attenuated food intake, body length, lipofuscin accumulation and age‐dependent decline of motor ability. Gene‐specific mutant studies showed the involvement of genes such as daf‐2 , age‐1 , and daf‐16 .

Conclusions

These results suggest that DaD has beneficial effects on the longevity, and thus it can be a valuable plant origin lead compound for the development of nutraceutical preparations targeting ageing and ageing‐related diseases.

     

Antimicrobial discovery from natural and unusual sources

Objectives

Whether vertebrates/invertebrates living in polluted environments are an additional source of antimicrobials.

Key findings

Majority of antimicrobials have been discovered from prokaryotes and those which are of eukaryotic origin are derived mainly from fungal and plant sources. With this in mind, it is important to note that pests, such as cockroaches come across pathogenic bacteria routinely, yet thrive in polluted environments. Other animals, such as snakes thrive from feeding on germ‐infested rodents. Logically, such species must have developed an approach to protect themselves from these pathogens, yet they have largely been ignored as a potential source of antimicrobials despite their remarkable capability to fight disease‐causing organisms.

Summary

Animals living in polluted environments are an underutilized source for potential antimicrobials, hence it is believed that several novel bioactive molecule(s) will be identified from these sources to counter increasingly resistant bacterial infections. Further research will be necessary in the development of novel antimicrobial(s) from these unusual sources which will have huge clinical impact worldwide.