Objective To investigate the role of proteinase‐activated receptor 4 (PAR‐4) in mediating joint inflammation and pain in mice. Methods Knee joint blood flow, edema, and pain sensitivity (as induced by thermal and mechanical stimuli) were assessed in C57BL/6 mice following intraarticular injection of either the selective PAR‐4 agonist AYPGKF‐NH2 or the inactive control peptide YAPGKF‐NH2. The mechanism of action of AYPGKF‐NH2 was examined by pretreatment of each mouse with either the PAR‐4 antagonist pepducin P4pal‐10 or the bradykinin antagonist HOE 140. Finally, the role of PAR‐4 in mediating joint inflammation was tested by pretreating mice with acutely inflamed knees with pepducin P4pal‐10. Results PAR‐4 activation caused a long‐lasting increase in joint blood flow and edema formation, which was not seen following injection of the control peptide. The PAR‐4–activating peptide was also found to be pronociceptive in the joint, where it enhanced sensitivity to a noxious thermal stimulus and caused mechanical allodynia and hyperalgesia. The proinflammatory and pronociceptive effects of AYPGKF‐NH2 could be inhibited by pepducin P4pal‐10 and HOE 140. Finally, pepducin P4pal‐10 ameliorated the clinical and physiologic signs of acute joint inflammation. Conclusion This study demonstrates that local activation of PAR‐4 leads to proinflammatory changes in the knee joint that are dependent on the kallikrein–kinin system. We also show for the first time that PARs are involved in the modulation of joint pain, with PAR‐4 being pronociceptive in this tissue. Thus, blockade of articular PAR‐4 may be a useful means of controlling joint inflammation and pain.

No abstract

No abstract

No abstract

No abstract

Organizations face a common intertemporal choice problem, where actions suitable in the shortterm are different from those that work in the longterm. Building on the organizational ambidexterity theory, we argue that organizations can reconcile their short‐term and long‐term tensions, but this does necessitate managerial endeavours that orchestrate this reconciliation. We introduce the concept of temporal ambidexterity and define four intertemporal tensions involving an organization’s objectives, resources, markets, and uncertainty. We examine how firms can address these tensions successfully in the context of new ventures, and to do so we focus on three managerial capabilities of founder‐CEOs: expertise breadth, external connectivity, and empowering leadership. Results from 243 new ventures in China suggest that temporal ambidexterity improves with these managerial capabilities, and more so for younger ventures. Our findings shed light on solutions and mechanisms by which intertemporal balance is fulfilled, particularly for new ventures in a dynamic environment.

Abstract. The objective of the present study was to investigate the therapeutic efficacy of flavonoid components in Scutellaria baicalensis on proliferation, metastasis and lung cancer-associated inflammation during nicotine induction in the A549 and H1299 lung cancer cell lines. After experimental period, augmentation of proliferation was observed, accompanied by marked decrease in apoptotic cells in nicotine-induced lung cancer cells; additionally, nicotine-exposed cells exhibited increased invasive and migratory abilities based on invasion and wound-healing assay. Flavones in Scutellaria, baicalin, baicalein and wogonin significantly counteracted the above deleterious changes. Moreover, assessment of tumor apoptotic and metastatic factors on mRNA levels by quantitative PCR and protein levels by western blotting revealed that these phytochemical treatments effectively negated nicotine-induced upregulated expression of bcl-2, bcl-2/bax ratio, caspase-3, matrix metalloproteinase (MMP)-2 and MMP-9 as well as downregulated expression of bax. Further analysis of inflammatory markers such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 in cell culture supernatant and mRNA and protein expression of nuclear transcription factor-kappaB (NF-κB) and I kappa B-alpha (IκB-α) was carried out to substantiate the anti-inflammatory effect of flavones in Scutellaria in nicotine-exposed lung cancer cells. The therapeutic effects observed in the present study are attributed to the potent potential against proliferation, metastasis and inflammatory microenvironment by flavonoid components in Scutellaria in nicotine-induced lung cancer cells.

No abstract