Extracellular signalling molecules in the ischaemic/reperfused heart – druggable and translatable for cardioprotection?

In patients with acute myocardial infarction, timely reperfusion is essential to limit infarct size. However, reperfusion also adds to myocardial injury. Brief episodes of ischaemia/reperfusion in the myocardium or on organ remote from the heart, before or shortly after sustained myocardial ischaemia effectively reduce infarct size, provided there is eventual reperfusion. Such conditioning phenomena have been established in many experimental studies and also translated to humans. The underlying signal transduction, that is the molecular identity of triggers, mediators and effectors, is not clear yet in detail, but several extracellular signalling molecules, such as adenosine, bradykinin and opioids, have been identified to contribute to cardioprotection by conditioning manoeuvres. Several trials have attempted the translation of cardioprotection by such autacoids into a clinical scenario of myocardial ischaemia and reperfusion. Adenosine and its selective agonists reduced infarct size in a few studies, but this benefit was not translated into improved clinical outcome. All studies with bradykinin or drugs which increase bradykinin''s bioavailability reported reduced infarct size and some of them also improved clinical outcome. Synthetic opioid agonists did not result in a robust infarct size reduction, but this failure of translation may relate to the cardioprotective properties of the underlying anaesthesia per se or of the comparator drugs. The translation of findings in healthy, young animals with acute coronary occlusion/reperfusion to patients of older age, with a variety of co-morbidities and co-medications, suffering from different scenarios of myocardial ischaemia/reperfusion remains a challenge.     

International Union of Basic and Clinical Pharmacology Review: WNT/Frizzled signalling: receptor–ligand selectivity with focus on FZD-G protein signalling and its physiological relevance: IUPHAR Review 3

The wingless/int1 (WNT)/Frizzled (FZD) signalling pathway controls numerous cellular processes such as proliferation, differentiation, cell-fate decisions, migration and plays a crucial role during embryonic development. Nineteen mammalian WNTs can bind to 10 FZDs thereby activating different downstream pathways such as WNT/β-catenin, WNT/planar cell polarity and WNT/Ca²⁺. However, the mechanisms of signalling specification and the involvement of heterotrimeric G proteins are still unclear. Disturbances in the pathways can lead to various diseases ranging from cancer, inflammatory diseases to metabolic and neurological disorders. Due to the presence of seven-transmembrane segments, evidence for coupling between FZDs and G proteins and substantial structural differences in class A, B or C GPCRs, FZDs were grouped separately in the IUPHAR GPCR database as the class FZD within the superfamily of GPCRs. Recently, important progress has been made pointing to a direct activation of G proteins after WNT stimulation. WNT/FZD and G protein coupling remain to be fully explored, although the basic observation supporting the nature of FZDs as GPCRs is compelling. Because the involvement of different (i) WNTs; (ii) FZDs; and (iii) intracellular binding partners could selectively affect signalling specification, in this review we present the current understanding of receptor/ligand selectivity of FZDs and WNTs. We pinpoint what is known about signalling specification and the physiological relevance of these interactions with special emphasis on FZD–G protein interactions.LINKED ARTICLESThis article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-5     

Can intervention in inositol phosphate signalling pathways improve therapy for cystic fibrosis?

Airway epithelial cells from cystic fibrosis (CF) individuals cannot secrete adequate Cl- through cystic fibrosis transmembrane regulator, and their Na+ channel (ENaC) activity is increased so that excessive Na+ and water is absorbed from the lumen. These aberrant transport activities can, at least partly, be compensated by pharmacologically increasing the activities of Ca2+-activated Cl- channels (CaCCs). The therapeutic value of this approach is currently being examined in clinical trials of candidate CF drugs such as INS-37217 (Inspire Pharmaceuticals) and Moli1901 (Lantibio, Inc.). This review argues that these drug development programmes will be helped if one can fully understand how the CaCCs are inhibited by inositol 3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P4), so that there can be pharmacological intervention in this process. Furthermore, genes that encode enzymes controlling Ins(3,4,5,6)P4 metabolism should be viewed as impacting upon CaCC activity; this, in turn, may influence the severity of the CF condition. Expression profiling of genes that regulate inositol phosphate metabolism may also illuminate variability in patient response to treatment regimens that target CaCCs. Compounds have been developed that can activate CaCCs by antagonising their inhibition by Ins(3,4,5,6)P4. One member of this drug family (INO-4995; Inologic) was recently shown to inhibit ENaC, thereby reducing fluid absorbtion by airway epithelial cells.     

Calycosin-7-O-β-d-glucopyranoside stimulates osteoblast differentiation through regulating the BMP/WNT signaling pathways

The isoflavone calycosin-7-O-β-d-glucopyranoside (CG) is a principal constituent of Astragalus membranaceus (AR) and has been reported to inhibit osteoclast development in vitro and bone loss in vivo. The aim of this study was to investigate the osteogenic effects of CG and its underlying mechanism in ST2 cells. The results show that exposure of cells to CG in osteogenic differentiation medium increases ALP activity, osteocalcin (Ocal) mRNA expression and the osteoblastic mineralization process. Mechanistically, CG treatment increased the expression of bone morphogenetic protein 2 (BMP-2), p-Smad 1/5/8, β-catenin and Runx2, all of which are regulators of the BMP- or wingless-type MMTV integration site family (WNT)/β-catenin-signaling pathways. Moreover, the osteogenic effects of CG were inhibited by Noggin and DKK-1 which are classical inhibitors of the BMP and WNT/β-catenin-signaling pathways, respectively. Taken together, the results indicate that CG promotes the osteoblastic differentiation of ST2 cells through regulating the BMP/WNT signaling pathways. On this basis, CG may be a useful lead compound for improving the treatment of bone-decreasing diseases and enhancing bone regeneration.Abbreviations: ALP, alkaline phosphatase; AR, Astragalus membranaceus; BMP, bone morphogenetic protein; CG, calycosin-7-O-β-d-glucopyranoside; DKK-1, dickkopf-1; ECL, enhanced chemiluminescence; FGF, fibroblast growth factor; HAase, hyaluronidase; IGF1, insulin-like growth factor 1; MAPK, mitogen-activated protein kinase; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; OBM, osteogenic differentiation medium; Ocal, osteocalcin; OPN, osteopontin; OVX, ovariectomized; PVDF, polyvinylidine fluoride; TGF-β, transforming growth factor β; WNT, wingless-type MMTV integration site familyKEY WORDS: BMP signaling pathway, WNT/β-catenin signaling pathway, Osteoblastic differentiation, Calycosin-7-O-β-d-glucopyranoside, ST2 cells     

TRPV1 and SP: key elements for sepsis outcome?

Sensory neurons play important roles in many disorders, including inflammatory diseases, such as sepsis. Sepsis is a potentially lethal systemic inflammatory reaction to a local bacterial infection, affecting thousands of patients annually. Although associated with a high mortality rate, sepsis outcome depends on the severity of systemic inflammation, which can be directly influenced by several factors, including the immune response of the patient. Currently, there is a lack of effective drugs to treat sepsis, and thus there is a need to develop new drugs to improve sepsis outcome. Several mediators involved in the formation of sepsis have now been identified, but the mechanisms underlying the pathology remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) receptor and the neuropeptide substance P (SP) have recently been demonstrated as important targets for sepsis and are located on sensory neurones and non-neuronal cells. Herein, we highlight and review the importance of sensory neurones for the modulation of sepsis, with specific focus on recent findings relating to TRPV1 and SP, with their distinct abilities to alter the transition from local to systemic inflammation and also modify the overall sepsis outcome. We also emphasize the protective role of TRPV1 in this context.

LINKED ARTICLES

This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7     

JAK2/STAT5/Bcl-xL signalling is essential for erythropoietin-mediated protection against apoptosis induced in PC12 cells by the amyloid β?peptide Aβ25–35

BACKGROUND AND PURPOSE

Erythropoietin (EPO) exerts neuroprotective actions in the CNS, including protection against apoptosis induced by the amyloid β−peptide Aβ_25–35. However, it remains unclear which signalling pathway activated by EPO is involved in this neuroprotection. Here, we have investigated whether JAK2/STAT5/Bcl-xL and ERK1/2 signalling pathways are essential for EPO-mediated protection against apoptosis induced by Aβ_25–35.

EXPERIMENTAL APPROACH

EPO was added to cultures of PC12 cells, 1 h before Aβ_25–35. For kinase inhibitor studies, AG490 and PD98059 were added to PC12 cells, 0.5 h before the addition of EPO. Transfection with siRNA was used to knockdown STAT5. Activation of JAK2/STAT5/Bcl-xL and ERK1/2 signalling pathways were investigated by Western blotting. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl-tetrazolium bromide assay and apoptosis was detected by TUNEL and acridine orange–ethidium bromide double staining.

KEY RESULTS

EPO increased phosphorylation of JAK2 and STAT5 in PC12 cells treated with Aβ_25–35. Furthermore, EPO modulated the nuclear translocation of phospho-STAT5, which increased expression of Bcl-xL and decreased levels of caspase-3. These beneficial effects were blocked by the JAK2 inhibitor, AG490 or STAT5 knockdown. However, the ERK1/2 pathway did not play a crucial role in our model.

CONCLUSIONS AND IMPLICATIONS

EPO protected PC12 cells against Aβ_25–35-induced neurotoxicity. Activation of JAK2/STAT5/Bcl-xL pathway was important in EPO-mediated neuroprotection. EPO may serve as a novel protective agent against Aβ_25–35-induced cytotoxicity in, for instance, Alzheimer''s disease.     

Barriers,pathways and processes for uptake,translocation and accumulation of nanomaterials in plants – Critical review

Uptake, transport and toxicity of engineered nanomaterials (ENMs) into plant cells are complex processes that are currently still not well understood. Parts of this problem are the multifaceted plant anatomy, and analytical challenges to visualize and quantify ENMs in plants. We critically reviewed the currently known ENM uptake, translocation, and accumulation processes in plants. A vast number of studies showed uptake, clogging, or translocation in the apoplast of plants, most notably of nanoparticles with diameters much larger than the commonly assumed size exclusion limit of the cell walls of ～5–20?nm. Plants that tended to translocate less ENMs were those with low transpiration, drought-tolerance, tough cell wall architecture, and tall growth. In the absence of toxicity, accumulation was often linearly proportional to exposure concentration. Further important factors strongly affecting ENM internalization are the cell wall composition, mucilage, symbiotic microorganisms (mycorrhiza), the absence of a cuticle (submerged plants) and stomata aperture. Mostly unexplored are the roles of root hairs, leaf repellency, pit membrane porosity, xylem segmentation, wounding, lateral roots, nodes, the Casparian band, hydathodes, lenticels and trichomes. The next steps towards a realistic risk assessment of nanoparticles in plants are to measure ENM uptake rates, the size exclusion limit of the apoplast and to unravel plant physiological features favoring uptake.     

Cytokine/anti-cytokine therapy – novel treatments for asthma?

Asthma is a chronic inflammatory disease of the airways and there are no preventions or cures. Inflammatory cells through the secretion of cytokines and pro-inflammatory molecules are thought to play a critical role in pathogenesis. Type 2 CD4(+) lymphocytes (Th2 cells) and their cytokines predominate in mild to moderate allergic asthma, whereas severe steroid-resistant asthma has more of a mixed Th2/Th1 phenotype with a Th17 component. Other immune cells, particularly neutrophils, macrophages and dendritic cells, as well structural cells such as epithelial and airway smooth muscle cells also produce disease-associated cytokines in asthma. Increased levels of these immune cells and cytokines have been identified in clinical samples and their potential role in disease demonstrated in studies using mouse models of asthma. Clinical trials with inhibitors of cytokines such as interleukin (IL)-4, -5 and tumour necrosis factor-α have had success in some studies but not others. This may reflect the design of the clinical trials, including treatments regimes and the patient population included in these studies. IL-13, -9 and granulocyte-macrophage colony-stimulating factor are currently being evaluated in clinical trials or preclinically and the outcome of these studies is eagerly awaited. Roles for IL-25, -33, thymic stromal lymphopoietin, interferon-γ, IL-17 and -27 in the regulation of asthma are just emerging, identifying new ways to treat inflammation. Careful interpretation of results from mouse studies will inform the development and application of therapeutic approaches for asthma. The most effective approaches may be combination therapies that suppress multiple cytokines and a range of redundant and disconnected pathways that separately contribute to asthma pathogenesis. Astute application of these approaches may eventually lead to the development of effective asthma therapeutics. Here we review the current state of knowledge in the field.     

Inflammatory and neurodegenerative pathways in depression: a new avenue for antidepressant development?

The latest advancement in neurobiological research provided an increasing evidence that inflammatory and neurodegenerative pathways play a relevant role in depression. Preclinical and clinical studies on depression highlighted an increased production of inflammatory markers, such as interleukin (IL)-1, IL-6, tumor necrosis factor-α and interferon- α and γ. On the other hand, acute and chronic administration of cytokines or cytokine inducers were found to trigger depressive symptoms. According to the cytokine hypothesis, depression would be due to a stress-related increased production of pro-inflammatory cytokines that, in turn, would lead to increased oxidative and nitrosative brain damage and to indoleamine 2,3 dioxygenase (IDO) induction, with production of tryptophan (TRP) catabolites along the IDO pathway (TRYCATs) and consequent reduced availability of TRP and serotonin (5-HT). Cytokines would also play a role in the onset of the glucocorticoid resistance, underlying the overdrive of the hypothalamic-pituitary-adrenal axis. Therefore, the activation of the inflammatory and neurodegenerative pathways would lead to the brain damage observed in depression through both reduced neurogenesis and increased neurodegeneration. Besides the 5-HT system, other targets, possibly within the I&ND pathways, should be considered for the future treatment of depression: cytokines and their receptors, intracellular inflammatory mediators, IDO, TRYCATs, glucocorticoid receptors, neurotrophic factors may all represent possible therapeutic targets for novel antidepressants. In addition, it should be also clarified the role of the existing anti-inflammatory drugs in the treatment of depression, and those compounds with the anti-inflammatory and anti-oxidative properties should be examined either as monotherapy or adjunctive therapy. In conclusion, the molecular inflammatory and neurodegenerative pathways might provide new targets for antidepressant development and might be crucial to establish a rational treatment of depression aimed, hopefully, to its causal factors.     

Procoagulant signalling mechanisms in lung inflammation and fibrosis: novel opportunities for pharmacological intervention?

There is compelling evidence that uncontrolled activation of the coagulation cascade following lung injury contributes to the development of lung inflammation and fibrosis in acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and fibrotic lung disease. This article reviews our current understanding of the mechanisms leading to the activation of the coagulation cascade in response to lung injury and the evidence that excessive procoagulant activity is of pathophysiological significance in these disease settings. Current evidence suggests that the tissue factor-dependent extrinsic pathway is the predominant mechanism by which the coagulation cascade is locally activated in the lungs of patients with ALI/ARDS and pulmonary fibrosis. Whilst, fibrin deposition might contribute to the pathophysiology of ALI/ARDS following systemic insult; current evidence suggests that the cellular effects mediated via activation of proteinase-activated receptors (PARs) may be of particular importance in influencing inflammatory and fibroproliferative responses in experimental models involving direct injury to the lung. In this regard, studies in PAR(1) knockout mice have shown that this receptor plays a major role in orchestrating the interplay between coagulation, inflammation and lung fibrosis. This review will focus on our current understanding of excessive procoagulant signalling in acute and chronic lung injury and will highlight the novel opportunities that this may present for therapeutic intervention.     

Salidroside protects against diabetes mellitus-induced kidney injury and renal fibrosis by attenuating TGF-β1 and Wnt1/3a/β-catenin signalling

This study evaluated if the nephroprotective effect of Salidroside in type 1 diabetes mellitus (T1DM) involves modulation of Wnt/β-catenin signalling pathways. Control or Streptozotocin (STZ, 50 mg/kg, iv)-induced T1DM adult male Wister rats were treated with the vehicle and Salidroside (100 mg/kg, orally) for 8 weeks daily. As compared to T1DM-induced rats, Salidroside improved kidney structure, reduced urinary protein and albumin level, increased creatinine clearance, and suppressed renal fibrosis. It also decreased mRNA and protein levels of Wnt1, Wnt3, and TGF-β1, phosphorylation of Smad-3, total and nuclear levels of β-catenin, and levels and activities of cleaved caspase-3. Concomitantly, Salidroside significantly increased the levels of p-β-catenin (Ser^33/37/Thr⁴¹) and suppressed protein levels of Axin-2, fibronectin, and, mRNA and protein levels of collagen IIIa, the main targets of β-catenin. In both control and T1DM rats, Salidroside significantly lowered fasting glucose levels and reduced renal levels of reactive oxygen species (ROS) p-and GS3Kβ (Ser9) but significantly increased levels of SOD and GSH. In conclusion, Salidroside protected the kidney of rats against T1DM-induced injury and fibrosis by activating GS3Kβ-induced inhibition of Wnt1/Wnt3a β-catenin. This was associated with hypoglycaemic and antioxidant effects.     

Pyrroloquinoline quinone delays inflammaging induced by TNF-α through the p16/p21 and Jagged1 signalling pathways

Previous studies on the longevity effect of pyrroloquinoline quinine (PQQ) on nematode worms have revealed that PQQ can enhance the antioxidant capacity of nematode worms, thus extending the lifespan of the worms. The induction and development of cellular senescence are closely connected with inflammatory reactions. The aim of this study was to determine the effect of PQQ and ageing factors on senescent cells. To this end, we cultivated human embryonic lung fibroblasts in nutrient solution with or without tumour necrosis factor-alpha (TNF-α) to establish an inflammaging model in vitro. The cells were preincubated with or without PQQ to determine if PQQ had any anti-inflammaging effect. More senescent cells were detected with the addition of TNF-α than without (P < .01). The ratio of senescent cells to non-senescent cells in the TNF-α group was greater than that in the control group (P < .01). When cells were preincubated with PQQ prior to TNF-α treatment, there were fewer senescent cells than those in the control group, which was not pretreated with PQQ (P < .05). The same tendency was noted with regard to p21, p16, and Jagged1. In summary, we used TNF-α, a well-known pro-inflammatory cytokine associated with inflammaging, to establish an in vitro inflammaging model and provided evidence that PQQ delays TNF-α –induced cellular senescence and has anti-inflammaging properties.     

Valsartan regulates TGF-β/Smads and TGF-β/p38 pathways through lncRNA CHRF to improve doxorubicin-induced heart failure

This study investigated the interaction among valsartan (VAL), TGF-β pathways, and long non-coding RNA (lncRNA) cardiac hypertrophy-related factor (CHRF) in doxorubicin (DOX)-induced heart failure (HF), and explored their roles in DOX-induced HF progression. HF mice models in vivo were constructed by DOX induction. The expression of CHRF and TGF-β1 in hearts was detected, along with cardiac function, caspase-3 activity, and cell apoptosis. Primary myocardial cells were pretreated with VAL, followed by DOX induction in vitro for functional studies, including the detection of cell apoptosis with terminal deoxynucleotidyl transferase dUTP nick-end labeling and the expression of proteins associated with TGF-β1 pathways. HF models were established in vivo and in vitro. Expression of CHRF and TGF-β1 was up-regulated, and cell apoptosis and caspase-3 activity were increased in the hearts and cells of the HF models. VAL supplementation alleviated the cardiac dysfunction and injury in the HF process. Moreover, overexpressed CHRF up-regulated TGF-β1, promoted myocardial cell apoptosis, and reversed VAL’s cardiac protective effect, while interference of CHRF (si-CHRF) did the opposite. Down-regulation of CHRF reversed the increased expression of TGF-β1 and the downstream proteins induced by pcDNA-TGF-β1 in HL-1 cells, while overexpression of CHRF reversed the VAL’s cardiac protective effect in vivo. In conclusion, VAL regulates TGF-β pathways through lncRNA CHRF to improve DOX-induced HF.     

WNT/β-catenin signal inhibitor IC-2–derived small-molecule compounds suppress TGF-β1–induced fibrogenic response of renal epithelial cells by inhibiting SMAD2/3 signalling

Renal fibrosis compromises kidney function, and it is a risk factor for chronic kidney disease (CKD). CKD ultimately progresses to end-stage kidney disease that can be cured only by kidney transplantation. Owing to the increasing number of CKD patients, effective treatment strategies are urgently required for renal fibrosis. TGF-β is a well-established fibrogenic factor that signals through SMAD2/3 signaling pathway. It was shown that there is a cross-talk between TGF-β/SMAD and WNT/β-catenin signaling pathways in renal tubular epithelial cells, and that a WNT/β-catenin inhibitor, ICG-001, ameliorates TGF-β1induced renal fibrosis. IC-2, a derivative of ICG-001, has been shown to potently induce hepatocyte differentiation of human mesenchymal stem cells by inhibiting WNT/β-catenin signaling. In the present study, we examined the effect of ICG-001, IC-2, and IC-2 derivatives (IC-2-506-1, IC-2-506-2, IC-2-506-3, IC-2-Ar-Cl, IC-2-OH, IC-2-OTBS, and IC-2-F) on TGF-β1–induced SMAD activation and fibrogenic response in immortalized human renal tubular epithelial HK-2 cells. All these compounds inhibited LiCl-induced WNT/β-catenin reporter activation to a similar extent, whereas ICG-001, IC-2-OTBS, and IC-2-F almost completely suppressed TGF-β1–induced SMAD reporter activation without apparent cytotoxicity. Phosphorylation of SMAD2/3 by TGF-β1 was more potently inhibited by IC-2-OTBS and IC-2-F than by ICG-001 and IC-2. IC-2-F suppressed TGF-β1–induced COL1A1 protein expression, whereas IC-2-506-1 and IC-2-OTBS suppressed TGF-β1–induced epithelial-mesenchymal transition. These results demonstrated that IC-2 derivatives suppress the TGF-β1–induced fibrogenic response of tubular epithelial cells and thus could be promising therapeutic agents for the treatment of renal fibrosis.     

Ganoderic acid hinders renal fibrosis via suppressing TGF-β/Smad and MAPK signaling pathways

OBJECTIVE To investigatethe anti-renal fibrotic effect of Ganoderic acid(GA) and the related mechanisms in vivo and in vitro. METHODS We investigated whether GA could hinder renal fibrosis and the related mechanisms in a unilateral ureteral obstruction(UUO) mouse model and TGF-β1-stimulated HK-2 cells model. The C57 mice were randomly devided into sham group, sham with GA administration group, UUO group and UUO with GA treatment group. After UUO surgery,the mice were treated with GA(3.125, 12.5 and 50 mg·kg~(-1) per day, ip) for 14 d. Then the mice were sacrificed for collecting blood and kidneys. The kidney functions were revealed by blood urea nitrogen and serum creatinine.The fibrosis and tubules injury levels were detected by Masson staining and HE staining. The epithelial-mesenchymal transition(EMT) level was detected by Western blotting and immunohistochemical staining. The changes of related signaling pathways and underlying mechanisms were demonstrated by Western blotting. The cell model was adopted to identify the potent inhibitor of renal fibrosis. RESULTS After 14 d treatment, GA dosedependently attenuated UUO-induced tubular injury and renal fibrosis; GA(50 mg·kg~(-1)) significantly ameliorated renal disfunction during fibrosis progression. We further revealed that GA treatment significantly decreased the expression of mesenchymal cell markers alpha-smooth muscle actin(α-SMA) and vimentin, and up-regulated E-cadherin expression in the kidney, suggesting the suppression of tubular EMT. Further study showed that GA downregulated both TGF-β/Smad and MAPK(ERK,JNK, P38) signaling pathways both in vivo and in vitro.GA-A, a GA monomer, was identified as a potent inhibitor on renal fibrosis in TGF-β1-stimulated HK-2 cell model.CONCLUSION GA inhibits renal interstitial fibrosis induced by UUO, mostly by suppressing EMT progression and inhibiting TGF-β/Smad and MAPK signaling pathways. In conclusion, our results suggest that GA and its purified monomer GA-A might be developed as a potential therapeutic agent in the treatment of renal fibrosis.     

Schisandrin B suppresses TGFβ1 signaling by inhibiting Smad2/3 and MAPK pathways

TGFβ1 plays a crucial role in the pathogenesis of vascular fibrotic diseases. Schisandra chinensis (S. chinensis), which is used as an oriental herbal medicine, is effective in the treatment of vascular injuries that cause aberrant TGFβ1 signaling. In this study, we investigated whether S. chinensis extract and its active ingredients inhibit TGFβ1 signaling in A7r5 vascular smooth muscle cells. We found that S. chinensis extract suppressed TGFβ1 signaling via inhibition of Smad2/3 phosphorylation and nuclear translocation. Among the active ingredients of S. chinensis extract, schisandrin B (SchB) most potently inhibited TGFβ1 signaling. SchB inhibited sustained phosphorylation and nuclear translocation of Smad2/3. Moreover, SchB suppressed TGFβ1-induced phosphorylation of p38 and JNK, which contributed to Smad2/3 inactivation. The present study is the first to demonstrate that S. chinensis extract and SchB inhibit TGFβ1 signaling. Our results may help future investigations to understand vascular fibrosis pathogenesis and to develop novel therapeutic strategies for treatment of vascular fibrotic diseases.     

What knowledge and skills are essential for specialists in Clinical Pharmacology and Therapeutics? Results of a Delphi study

AIMS: To identify the knowledge and skills that should be considered essential for specialists in Clinical Pharmacology and Therapeutics (CPT) with a commitment to the National Health Service (NHS). METHODS: A Delphi study using a sample of current specialists. RESULTS: Members of the expert panel (20 in all, representative of the Clinical Section membership) identified 78 statements for consideration, in four domains (core of knowledge, therapeutic skills, educative skills, and investigative skills), of which 58 (74.4%) were accepted by more than two-thirds of respondents. Of these, 35 were knowledge items, whereas 23 were skills (11 therapeutic, 4 educative and 8 investigative). The large majority (79.3%) of these statements were endorsed by at least four out of five panel members. CONCLUSIONS: Despite the varied work patterns and responsibilities of specialists in CPT, it is possible to identify a core of knowledge and skill that most consider essential for the delivery of their commitment to the NHS. The findings will provide NHS Trusts with a clear idea of what they can expect from these specialists, and will act as a checklist for specialists themselves to direct their Continuing Professional Development within the consultant appraisal process. The results also describe a curriculum for continuing education in CPT, which the BPS Clinical Section can use to develop information resources and training opportunities.     

Lignin for pharmaceutical and biomedical applications – Could this become a reality?

Lignin is an aromatic biopolymer and a primary component of the cell walls in lignocellulosic biomass, where it constitutes between 15 and 40% of its dry mass. This percentage can vary, not only among plant species, but also among different cell types. Currently, the pulping and biorefinery industries worldwide extract large amounts of lignin, which is mostly combusted to generate the power needed to productively transform the lignocellulosic biomass. The specific composition and structure of this technical lignin depends on its botanical origin and on the extraction method applied. In general, however, lignin possesses antioxidant and antimicrobial properties, UV-absorbing capabilities, biocompatibility and low cytotoxicity. Moreover, lignin can increase the mechanical strength of numerous processed biomaterials. Accordingly, lignin is a promising aromatic raw material for the pharmaceutical and biomedical field. This work discusses the recent advances in the valorisation of lignin through the development of drug and gene delivery systems, wound dressings, tissue engineering or sunscreen actives. Finally, a brief overview on the current challenges and opportunities for making lignin-based products for pharmaceutical and medical applications a reality is also discussed.     

Therapy for Clostridium difficile infection – any news beyond Metronidazole and Vancomycin?

Introduction: Infections with Clostridium difficile (CDI) represent a major burden for the health care system. Treatment is generally by antibiotic therapy with metronidazole and vancomycin, but efficacy remains suboptimal.

Areas covered: This review discusses established and emerging treatment options for CDI, and current therapeutic guidelines, taking into account disease severity and risk of relapse.

Expert commentary: New therapeutic approaches, including antibodies and new classes of antibiotics, and new measures for preventing infection with vaccines are under development in phase II/III clinical trials. We performed a systematic literature review using the search terms ‘Clostridium difficile’ and ‘treatment’.