bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of human prostate smooth muscle contraction by the LIM kinase inhibitors, SR7826 and LIMKi3
Authors: Yu Qingfeng , Gratzke Christian , Wang Yiming , Herlemann Annika , Sterr Christian Maximilian , Rutz Beata , Ciotkowska Anna , Wang Xiaolong , Strittmatter Frank , Stief Christian G , Hennenberg Martin 
Published: March 2018

Background and PurposeIn men with benign prostatic hyperplasia, increased smooth muscle tone in the prostate may lead to bladder outlet obstruction and subsequent lower urinary tract symptoms. Consequently, medical treatment aims to inhibit prostate smooth muscle contraction. However, the efficacy of the treatment options available is limited, and improved understanding of mechanisms of prostate smooth muscle contraction and identification of new targets for medical intervention are mandatory. Several studies suggest that LIM kinases (LIMKs) promote smooth muscle contraction; however, this has not yet been examined. Here, we studied effects of the LIMK inhibitors on prostate smooth muscle contraction.Experimental ApproachHuman prostate tissues were obtained from radical prostatectomy. Phosphorylation of cofilin, a LIMK substrate, was examined using a phospho‐specific antibody. Smooth muscle contractions were studied in organ bath experiments.Key ResultsReal‐time PCR, Western blot and immunofluorescence suggested LIMKs are expressed in smooth muscle cells of prostate tissues. Two different LIMK inhibitors, SR7826 (1 μM) and LIMKi3 (1 μM), inhibited contractions of prostate strips, which were induced by electrical field stimulation, α1‐adrenoceptor agonists phenylephrine and methoxamine and the TXA2 analogue, U46619. LIMK inhibition in prostate tissues and cultured stromal cells (WPMY‐1) was confirmed by cofilin phosphorylation, which was reduced by SR7826 and LIMKi3. In WPMY‐1 cells, SR7826 and LIMKi3 caused breakdown of actin filaments and reduced viability.Conclusions and ImplicationsSmooth muscle tone in the hyperplastic human prostate may underlie the effects of LIMKs, which promote contraction. Contraction of prostate strips can be inhibited by small molecule LIMK inhibitors.
Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model
Authors: Khan Archie A , Shekh‐Ahmad Tawfeeq , Khalil Ayatakin , Walker Matthew C , Ali Afia B 
Published: March 2018

Background and PurposeA non‐psychoactive phytocannabinoid, cannabidiol (CBD), shows promising results as an effective potential antiepileptic drug in some forms of refractory epilepsy. To elucidate the mechanisms by which CBD exerts its anti‐seizure effects, we investigated its effects at synaptic connections and on the intrinsic membrane properties of hippocampal CA1 pyramidal cells and two major inhibitory interneurons: fast spiking, parvalbumin (PV)‐expressing and adapting, cholecystokinin (CCK)‐expressing interneurons. We also investigated whether in vivo treatment with CBD altered the fate of CCK and PV interneurons using immunohistochemistry.Experimental ApproachElectrophysiological intracellular whole‐cell recordings combined with neuroanatomy were performed in acute brain slices of rat temporal lobe epilepsy in in vivo (induced by kainic acid) and in vitro (induced by Mg2+‐free solution) epileptic seizure models. For immunohistochemistry experiments, CBD was administered in vivo (100 mg·kg−1) at zero time and 90 min post status epilepticus, induced with kainic acid.Key ResultsBath application of CBD (10 μM) dampened excitability at unitary synapses between pyramidal cells but enhanced inhibitory synaptic potentials elicited by fast spiking and adapting interneurons at postsynaptic pyramidal cells. Furthermore, CBD restored impaired membrane excitability of PV, CCK and pyramidal cells in a cell type‐specific manner. These neuroprotective effects of CBD were corroborated by immunohistochemistry experiments that revealed a significant reduction in atrophy and death of PV‐ and CCK‐expressing interneurons after CBD treatment.Conclusions and ImplicationsOur data suggest that CBD restores excitability and morphological impairments in epileptic models to pre‐epilepsy control levels through multiple mechanisms to reinstate normal network function.
Joint problems arising from lack of repair mechanisms: can cannabinoids help?
Authors: Malek Natalia , Starowicz Katarzyna 
Published: March 2018

Osteoarthritis (OA) is the most common disease of joints, which are complex organs where cartilage, bone and synovium cooperate to allow a range of movements. During progression of the disease, the function of all three main components is jeopardized. Nevertheless, the involvement of each tissue in OA development is still not established and is the topic of the present review. The OA therapies available are symptomatic, largely targeting pain management rather than disease progression. The strong need to develop a treatment for cartilage degeneration, bone deformation and synovial inflammation has led to research on the involvement of the endocannabinoid system in the development of OA. The current review discusses the research on this topic to date and notes the advantages of exploiting endocannabinoid system modulation for cartilage, bone and synovium homeostasis, which could prevent the further progression of OA.Linked ArticlesThis article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc
Targeting glial cannabinoid CB2 receptors to delay the progression of the pathological phenotype in TDP‐43 (A315T) transgenic mice, a model of amyotrophic lateral sclerosis
Authors: Espejo‐Porras Francisco , García‐Toscano Laura , Rodríguez‐Cueto Carmen , Santos‐García Irene , de Lago Eva , Fernandez‐Ruiz Javier 
Published: March 2018

Background and PurposeCannabinoid CB2 receptors are up‐regulated in reactive microglia in the spinal cord of TDP‐43 (A315T) transgenic mice, an experimental model of amyotrophic lateral sclerosis. To determine whether this up‐regulation can be exploited pharmacologically, we investigated the effects of different treatments that affect CB2 receptor function.Experimental ApproachWe treated TDP‐43 (A315T) transgenic mice with the non‐selective agonist WIN55,212‐2, alone or combined with selective CB1 or CB2 antagonists, as well as with the selective CB2 agonist HU‐308, and evaluated their effects on the pathological phenotype.Key ResultsWIN55,212‐2 had modest beneficial effects in the rotarod test, Nissl staining of motor neurons, and GFAP and Iba‐1 immunostainings in the spinal cord, which were mediated in part by CB2 receptor activation. HU‐308 significantly improved the rotarod performance of the transgenic mice, with complete preservation of Nissl‐stained motor neurons in the ventral horn. Reactive astrogliosis labelled with GFAP was also attenuated by HU‐308 in the dorsal and ventral horns, in which CB2 receptors colocalize with this astroglial marker. Furthermore, HU‐308 reduced the elevated Iba‐1 immunostaining in the ventral horn of TDP‐43 transgenic mice, but did not affect this immunoreactivity in white matter, in which CB2 receptors also colocalize with this microglial marker.Conclusions and ImplicationsOur study shows an important role for glial CB2 receptors in limiting the progression of the pathological phenotype in TDP‐43 (A315T) transgenic mice. Such benefits appear to derive from the activation of CB2 receptors concentrated in astrocytes and reactive microglia located in spinal dorsal and ventral horns.Linked ArticlesThis article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc
P2Y12 receptor modulation of ADP‐evoked intracellular Ca2+ signalling in THP‐1 human monocytic cells
Authors: Micklewright J J , Layhadi J A , Fountain S J 
Published: March 2018

Background and PurposeThe Gi‐coupled, ADP‐activated P2Y12 receptor is well characterized as playing a key role in platelet activation via crosstalk with the P2Y1 receptor in ADP‐evoked intracellular Ca2+ responses. However, there is limited knowledge on the role of P2Y12 receptors in ADP‐evoked Ca2+ responses in other blood cells. Here, we investigated the role of P2Y12 receptor activation in the modulation of ADP‐evoked Ca2+ responses in human THP‐1 monocytic cells.Experimental ApproachA combination of intracellular Ca2+ measurements, RT‐PCR, immunocytochemistry, leukocyte isolation and siRNA‐mediated gene knockdown were used to identify the role of P2Y12 receptor activation.Key ResultsADP‐evoked intracellular Ca2+ responses (EC50 2.7 μM) in THP‐1 cells were abolished by inhibition of PLC (U73122) or sarco/endoplasmic reticulum Ca2+‐ATPase (thapsigargin). Loss of ADP‐evoked Ca2+ responses following treatment with MRS2578 (IC50 200 nM) revealed a major role for P2Y6 receptors in mediating ADP‐evoked Ca2+ responses. ADP‐evoked responses were attenuated either with pertussis toxin treatment, or P2Y12 receptor inhibition with two chemically distinct antagonists (ticagrelor, IC50 5.3 μM; PSB‐0739, IC50 5.6 μM). ADP‐evoked responses were suppressed following siRNA‐mediated P2Y12 gene knockdown. The inhibitory effects of P2Y12 antagonists were fully reversed following adenylate cyclase inhibition (SQ22536). P2Y12 receptor expression was confirmed in freshly isolated human CD14+ monocytes.Conclusions and ImplicationsTaken together, these data suggest that P2Y12 receptor activation positively regulates P2Y6 receptor‐mediated intracellular Ca2+ signalling through suppression of adenylate cyclase activity in human monocytic cells.
No effects without causes: the Iron Dysregulation and Dormant Microbes hypothesis for chronic, inflammatory diseases
Authors: Kell Douglas B. , Pretorius Etheresia 
Published: March 2018

ABSTRACTSince the successful conquest of many acute, communicable (infectious) diseases through the use of vaccines and antibiotics, the currently most prevalent diseases are chronic and progressive in nature, and are all accompanied by inflammation. These diseases include neurodegenerative (e.g. Alzheimer's, Parkinson's), vascular (e.g. atherosclerosis, pre‐eclampsia, type 2 diabetes) and autoimmune (e.g. rheumatoid arthritis and multiple sclerosis) diseases that may appear to have little in common. In fact they all share significant features, in particular chronic inflammation and its attendant inflammatory cytokines. Such effects do not happen without underlying and initially ‘external’ causes, and it is of interest to seek these causes. Taking a systems approach, we argue that these causes include (i) stress‐induced iron dysregulation, and (ii) its ability to awaken dormant, non‐replicating microbes with which the host has become infected. Other external causes may be dietary. Such microbes are capable of shedding small, but functionally significant amounts of highly inflammagenic molecules such as lipopolysaccharide and lipoteichoic acid. Sequelae include significant coagulopathies, not least the recently discovered amyloidogenic clotting of blood, leading to cell death and the release of further inflammagens. The extensive evidence discussed here implies, as was found with ulcers, that almost all chronic, infectious diseases do in fact harbour a microbial component. What differs is simply the microbes and the anatomical location from and at which they exert damage. This analysis offers novel avenues for diagnosis and treatment.
The anatomical components of the cardiac outflow tract of chondrichthyans and actinopterygians
Authors: Lorenzale Miguel , López‐Unzu Miguel A. , Rodríguez Cristina , Fernández Borja , Durán Ana C. , Sans‐Coma Valentín 
Published: March 2018

ABSTRACTThe outflow tract of the fish heart is the segment interposed between the ventricle and the ventral aorta. It holds the valves that prevent blood backflow from the gill vasculature to the ventricle. The anatomical composition, histological structure and evolutionary changes in the fish cardiac outflow tract have been under discussion for nearly two centuries and are still subject to debate. This paper offers a brief historical review of the main conceptions about the cardiac outflow tract components of chondrichthyans (cartilaginous fish) and actinopterygians (ray‐finned fish) which have been put forward since the beginning of the nineteenth century up to the current day. We focus on the evolutionary origin of the outflow tract components and the changes to which they have been subject in the major extant groups of chondrichthyans and actinopterygians. In addition, an attempt is made to infer the primitive anatomical design of the heart of the gnathostomes (jawed vertebrates). Finally, several areas of further investigation are suggested. Recent work on fish heart morphology has shown that the cardiac outflow tract of chondrichthyans does not consist exclusively of the myocardial conus arteriosus as classically thought. A conus arteriosus and a bulbus arteriosus, devoid of myocardium and mainly composed of elastin and smooth muscle, are usually present in cartilaginous and ray‐finned fish. This is consistent with the suggestion that both components coexisted from the onset of the gnathostome radiation. There is evidence that the conus arteriosus appeared in the agnathans. By contrast, the evolutionary origin of the bulbus is still unclear. It is almost certain that in all fish, both the conus and bulbus develop from the embryonic second heart field. We suggest herein that the primitive anatomical heart of the jawed vertebrates consisted of a sinus venosus containing the pacemaker tissue, an atrium possessing trabeculated myocardium, an atrioventricular region with compact myocardium which supported the atrioventricular valves, a ventricle composed of mixed myocardium, and an outflow tract consisting of a conus arteriosus, with compact myocardium in its wall and valves at its luminal side, and a non‐myocardial bulbus arteriosus that connected the conus with the ventral aorta. Chondrichthyans have retained this basic anatomical design of the heart. In actinopterygians, the heart has been subject to notable changes during evolution. Among them, the following two should be highlighted: (i) a decrease in size of the conus in combination with a remarkable development of the bulbus, especially in teleosts; and (ii) loss of the myocardial compact layer of the ventricle in many teleost species.
The evolution of individuality revisited
Authors: Radzvilavicius Arunas L. , Blackstone Neil W. 
Published: March 2018

ABSTRACTEvolutionary theory is formulated in terms of individuals that carry heritable information and are subject to selective pressures. However, individuality itself is a trait that had to evolve – an individual is not an indivisible entity, but a result of evolutionary processes that necessarily begin at the lower level of hierarchical organisation. Traditional approaches to biological individuality focus on cooperation and relatedness within a group, division of labour, policing mechanisms and strong selection at the higher level. Nevertheless, despite considerable theoretical progress in these areas, a full dynamical first‐principles account of how new types of individuals arise is missing. To the extent that individuality is an emergent trait, the problem can be approached by recognising the importance of individuating mechanisms that are present from the very beginning of the transition, when only lower‐level selection is acting. Here we review some of the most influential theoretical work on the role of individuating mechanisms in these transitions, and demonstrate how a lower‐level, bottom‐up evolutionary framework can be used to understand biological complexity involved in the origin of cellular life, early eukaryotic evolution, sexual life cycles and multicellular development. Some of these mechanisms inevitably stem from environmental constraints, population structure and ancestral life cycles. Others are unique to specific transitions – features of the natural history and biochemistry that are co‐opted into conflict mediation. Identifying mechanisms of individuation that provide a coarse‐grained description of the system's evolutionary dynamics is an important step towards understanding how biological complexity and hierarchical organisation evolves. In this way, individuality can be reconceptualised as an approximate model that with varying degrees of precision applies to a wide range of biological systems.
Cluster‐randomised controlled trial of an occupational therapy intervention for children aged 11–13 years, designed to increase participation to prevent symptoms of mental illness
Authors: Tokolahi Ema , Vandal Alain C. , Kersten Paula , Pearson Janet , Hocking Clare 
Published: March 2018

BackgroundThe impact of occupational therapy on mental health outcomes for children is largely unexplored. The aim of this study was to investigate an evidence‐based occupational therapy intervention designed to increase participation in daily occupations to prevent symptoms of mental illness for children and run in schools.MethodsThe study used a pragmatic, cluster‐randomised controlled trial design with two arms. Fourteen clusters (schools), equating to 151 child participants, were stratified by school decile‐rank category and block randomised. Blinding of participants post‐randomisation was not feasible; however, outcomes assessors were blinded. Outcomes were measured at baseline, after the parallel and crossover phases, and at follow‐up; and were anxiety symptoms (primary), depression symptoms, self‐esteem, participation and wellbeing. Intention‐to‐treat analysis was applied and mixed linear modelling was used to account for clusters and repeated measures, and to adjust for covariates identified.ResultsThis trial found significant positive effects of the intervention on child‐rated satisfaction with their occupational performance and teacher‐rated child anxiety. No evidence was found to support the effect of the intervention on anxiety and depression symptoms, self‐esteem and wellbeing.ConclusionsThis was the first known cluster‐randomised controlled trial to investigate an occupational therapy intervention promoting emotional wellbeing in a non‐clinical sample of children. No compelling evidence was found to support the use of the intervention in schools in its current format, however, results were promising that the focus on occupations influenced participation. Recommendations are made to redesign the intervention as an embedded intervention in the classroom, cotaught by teachers and including parental involvement.
Retracted: Hispidulin suppresses cell growth and metastasis by targeting PIM1 through JAK2/STAT3 signaling in colorectal cancer
Authors: Liu Kaili , Gao Hui , Wang Qiaoyun , Wang Longyuan , Zhang Bin , Han Zhiwu , Chen Xuehong , Han Mei , Gao Mingquan 
Published: March 2018

Colorectal cancer (CRC) accounts for over 600 000 deaths annually worldwide. The current study aims to evaluate the value of proto‐oncogene PIM1 as a therapeutic target in CRC and investigate the anticancer activity of hispidulin, a naturally occurring phenolic flavonoid compound, against CRC. Immunohistochemistry analysis showed that PIM1 was upregulated in CRC tissue. The role of PIM1 as an oncogene was evidenced by the fact that PIM1 knockdown inhibits cell growth, induces apoptosis, and suppresses invasion. Our results showed that hispidulin exerts antitumor activity in CRC through inhibiting the expression of PIM1. Moreover, our findings revealed that hispidulin downregulated the expression of PIM1 by inhibiting JAK2/STAT3 signaling by generating reactive oxygen species. Furthermore, our in vivo studies showed that hispidulin can significantly inhibit tumor growth and metastasis in CRC. Collectively, our results provide an experimental basis for trialing hispidulin in CRC treatment. PIM1 can be considered a potential therapeutic target in CRC.
Long non‐coding RNA metastasis‐associated lung adenocarcinoma transcript 1 promotes lung adenocarcinoma by directly interacting with specificity protein 1
Authors: Li Shufeng , Ma Fang , Jiang Kunpeng , Shan Haitao , Shi Minke , Chen Baojun 
Published: March 2018

Metastasis‐associated lung adenocarcinoma transcript 1 (malat1) is an oncogenic long non‐coding RNA (lncRNA) which has been proven to be associated with various types of tumors. Transcription factor specificity protein 1 (SP1) is overexpressed in many types of cancers. Previously, we observed that malat1 expression level is regulated by SP1 in lung cancer. In the present study, we found that transfection of expression construct of malat1 5′ end fragment M5 enhances stability and transcriptional activity of SP1. Various SP1 target genes are also upregulated following overexpression of malat1 M5 in lung adenocarcinoma cells. We also showed that malat1 M5 interacts with the C‐terminal domain of SP1 by RNA immunoprecipitation (RIP) assay coupled with UV cross‐linking. Malat1‐SP1 association results in increase of SP1 stability. In turn, SP1 promotes malat1 transcription, thus forming a positive feedback loop. In conclusion, our data show that in lung adenocarcinoma cells, malat1 interacts with SP1 protein and promotes SP1‐mediated transcriptional regulation of SP1 target genes.
MicroRNA‐708‐3p mediates metastasis and chemoresistance through inhibition of epithelial‐to‐mesenchymal transition in breast cancer
Authors: Lee Jin‐Won , Guan Wei , Han Sanghak , Hong Deok‐Ki , Kim Lee‐Su , Kim Haesung 
Published: March 2018

Metastasis and chemoresistance remain major challenges in the clinical treatment of breast cancer. Recent studies show that dysregulated microRNAs (miRNAs) play an important role in metastasis and chemoresistance development in breast cancer. Herein, we identified downregulated expression of miR‐708‐3p in breast cancers. In particular, miR‐708‐3p expression was significantly decreased in specimens from breast cancer patients with metastasis compared to that in specimens from patients with no metastasis. Consistent with clinical data, our in vitro data show that miR‐708‐3p was more significantly decreased in invasive breast cancer cell lines. In addition, our data show that inhibition of miR‐708‐3p significantly stimulated breast cancer cell metastasis and induced chemoresistance both in vitro and in vivo. In contrast, overexpression of miR‐708‐3p dramatically inhibited breast cancer cell metastasis and enhanced the sensitivity of breast cancer cells to chemotherapy both in vitro and in vivo. Furthermore, we identified that miR‐708‐3p inhibits breast cancer cell epithelial‐to‐mesenchymal transition (EMT) by directly targeting EMT activators, including ZEB1, CDH2 and vimentin. Taken together, our findings suggest that miR‐708‐3p acts as a cancer suppressor miRNA and carries out its anticancer function by inhibiting EMT in breast cancer. In addition, our findings suggest that restoration of miR‐708‐3p may be a novel strategy for inhibiting breast cancer metastasis and overcoming the chemoresistance of breast cancer cells.