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Background: Airway neutrophilia has been associated with asthma severity and asthma exacerbations. This study attempted to identify biomarkers, pathogenesis, and therapeutic molecular targets for severe asthma in neutrophils using bioinformatics analysis., Methods: Fifteen healthy controls and 3 patients with neutrophilic severe asthma were screened from the Gene Expression Omnibus (GEO) database. Based on the analysis of differentially expressed genes (DEGs), functional and pathway enrichment analyses, gene set enrichment analysis, protein-protein interaction network construction, and analysis were performed. Moreover, small-molecule drug candidates have also been identified., Results: Three hundred and three upregulated and 59 downregulated genes were identified. Gene ontology function enrichment analyses were primarily related to inflammatory response, immune response, leukocyte migration, neutrophil chemotaxis, mitogen-activated protein kinase cascade, Jun N-terminal kinase cascade, I-kappaB kinase/nuclear factor-κB, and MyD88-dependent toll-like receptor signaling pathway. Pathway enrichment analyses and gene set enrichment analysis were mainly involved in cytokine-cytokine receptor interaction, the TNF signaling pathway, leukocyte transendothelial migration, and the NOD-like receptor signaling pathway. Furthermore, 1 important module and 10 hub genes (CXCL8, TLR2, CXCL1, ICAM1, CXCR4, FPR2, SELL, PTEN, TREM1, and LEP) were identified in the protein-protein interaction network. Moreover, indoprofen, mimosine, STOCK1N-35874, trapidil, iloprost, aminoglutethimide, ajmaline, levobunolol, ethionamide, cefaclor, dimenhydrinate, and bethanechol are potential drugs for the treatment of neutrophil-predominant severe asthma., Conclusion: This study identified potential biomarkers, pathogenesis, and therapeutic molecular targets for neutrophil-predominant severe asthma., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

[1,2,4]Triazolo[1,5-a]pyrimidine is an important heterocyclic scaffold known to have a wide range of pharmacological activities such as anticancer, antimicrobial, anti-tubercular, CB 2 cannabinoid agonists, feticide, and adenosine antagonists. Several clinical trials and marketed drugs such as Trapidil, Essramycin, Pyroxsulam, DSM-265, Flumetsulam, GNF-6702, and Cevipabulin indicate the potential of [1,2,4]triazolo[1,5-a]pyrimidine moiety with various functional groups in medicinal chemistry. Herein, we represent a concise report focusing on the synthetic strategies used for diversely substituted [1,2,4]triazolo[1,5-a]pyrimidine analogs and their pharmacological applications. To the best of our knowledge, since 1980, we are the first to write a review on this emerging scaffold, which reveals the synthetic strategies, and pharmacological activities of differently substituted [1,2,4]triazolo[1,5-a]pyrimidine with special emphasis on structure-activity relationship studies., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

This report outlines the long-term outcome after successful sealing of a coronary perforation with a covered stent in a patient with aspirin allergy.

Pulmonary arterial hypertension is a fatal disease, especially when it causes right heart failure (RHF). However, it is difficult to treat. It has been reported that trapidil (Tra) can improve the redox balance and cardiac conditions. In this study, we investigated the effect of Tra on RHF induced by monocrotaline (MCT) in rats. Male Wistar rats were treated with MCT or Tra. Treatment lasted 28 days, then rats were euthanized after echocardiography and catheterization. Subsequently, lungs and right ventricular myocardia were evaluated by hematoxylin and eosin, Masson, and TUNEL staining. Protein expression was detected by western blotting. We found remarkably expanded right ventricle end-diastolic volume, decreased partial pressure of oxygen (PaO 2 ), increased partial pressure of carbon dioxide (PaCO 2 ), right ventricular systolic pressure, mean pulmonary arterial pressure, lung/body weight, and liver/body weight in the RHF rat group, as well as increases in the apoptosis rate and the expression of endoplasmic reticulum stress (ERS)-related proteins. However, these changes were significantly inhibited by Tra. Our data suggested that inhibition of ERS is essential for improving RHF, and that therapeutic intervention of Tra in RHF rats works by reducing ERS.

Platelet-derived growth factor receptor (PDGFR) signaling has been shown to inhibit osteogenesis. However, therapeutic efficacy of inhibiting PDGF signaling to bone regeneration in vivo and the specific mechanisms by which PDGFR signaling inhibits osteogenic differentiation remain unclear. In the present study, we examined the osteogenic effect of inhibiting PDGFR using trapidil, a PDGFR antagonist, in vivo and in vitro, and evaluated its mechanisms. A rat calvarial defect model was analyzed by micro-computed tomography and histology to determine the pro-osteogenic effect of trapidil in vivo. In addition, primary mouse calvarial osteoblast precursors were cultured in osteogenic differentiation medium with trapidil to study the mechanisms. Trapidil greatly promoted bone regeneration in a rat calvarial defect model and osteogenic differentiation of calvarial osteoblast precursors. For the mechanisms, trapidil induced phosphorylation of Smad1/5/9 and mitogen-activated protein kinase (MAPK) leading to enhance expression of Runx2, crucial transcription factor for osteogenesis. The pro-osteogenic effects of trapidil were inhibited by LDN193189, specific inhibitor of bone morphogenetic protein (BMP) receptor, ALK2 and ALK3, and by depletion of ALK3, and treatment with noggin, an antagonist of BMPs. Moreover, trapidil showed a synergistic effect with BMP2 on osteogenic differentiation. In conclusion, trapidil induced BMPR activity through upregulation of BMP signaling, leading to promoted osteogenesis in vitro and in vivo. Attenuated BMPR activity may be involved in the inhibition of osteogenesis by PDGFR signaling., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Pulmonary arterial hypertension is a disease characterized by increased pulmonary vascular resistance and redox imbalance, leading to failure of right ventricle. Trapidil has been described to improve the redox balance and cardiac conditions., Hypothesis: Trapidil can improve the redox balance and contribute to functional improvements of the RV in PAH., Methods and Results: Male, 5week-old Wistar rats were divided into four groups: Control, Control + Trapidil, Monocrotaline and Monocrotaline + Trapidil. PAH was induced by an intraperitoneal injection of monocrotaline 60 mg/kg at day 0. Treatment started at day 7 (5 or 8 mg/kg/day) until day 14, when animals were euthanized after echocardiography and catheterism. Right ventricular systolic pressure and pressure/time derivatives were increased in monocrotaline animals. The increased right ventricular diameters in monocrotaline groups were reduced with trapidil. Monocrotaline groups showed higher lipid peroxidation and glutathione peroxidase activity. Trapidil reduced NADPH oxidases activities and increased the reduced glutathiones/total glutathiones ratio. Protein expression of phospholamban in RV was diminished in monocrotaline groups, whereas expression of RyR and SERCA was enhanced in the groups treated with trapidil., Conclusion: Our data suggest that trapidil induces an improvement in RV remodeling in PAH model, mitigating the progression of the disease., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Objectives: To evaluate the cardioprotective effects of trapidil on myocardial ischemia-reperfusion injury (MIRI) in rabbits., Materials and Methods: Rabbits were subjected to 40 min of myocardial ischemia followed by 120 min of reperfusion. Blood for superoxide dismutase (SOD) and malondialdehyde (MDA) were estimated. At the end of reperfusion, the rabbits were sacrificed and the hearts were isolated for histological examination. An apoptotic index (AI) was determined using the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end-labeling (TUNEL) method. The expression of apoptosis-related proteins Bax and Bcl-2 was analyzed using immunohistochemistry. Statistical analyses were performed by one-way analysis of variance (ANOVA), P < 0.05 considered statistically significant., Results: Trapidil caused a significant (P < 0.05) increase in SOD activity, as decreased MDA levels and significantly (P < 0.05) reduced the expression of Bax as compared with the ischemia-reperfusion (IR) control group., Conclusion: Trapidil may attenuate the myocardial damage produced by IR injury and offer potential cardioprotective action.

Background: Although bevacizumab has deleterious effects on the healing of colonic anastomoses, trapidil improves wound healing of colonic and tracheal anastomoses., Objective: We aimed to assess the effects of bevacizumab and trapidil on wound healing after tracheal transection., Materials and Methods: We evaluated 35 rats divided in 5 groups: bevacizumab (Group I, n = 7), trapidil (Group II, n = 7), trapidil + bevacizumab (Group III, n = 7), controls (Group IV, n = 7), and sham (Group V, n = 7). Anastomotic healing was assessed by measurement of bursting pressure and inflammation score at the anastomotic region on the seventh day., Results: The bursting pressures of Group II, Group III, and Group V were significantly higher than controls (P = 0.001, P = 0.033, and P = 0.035, respectively). Fibrosis was significantly high in the sham group when compared with the other four groups (P = 0.047)., Conclusions: Although bevacizumab seems to impair anastomotic healing, trapidil can be suggested to improve tracheal anastomoses.

Trapidil, a platelet-derived growth factor antagonist, was originally developed as a vasodilator and anti-platelet agent and has been used to treat patients with ischemic coronary heart, liver, and kidney disease. In this study, we investigated the effects of trapidil on osteoclastogenesis and elucidated the possible mechanism of action of trapidil. Trapidil strongly inhibited osteoclast formation in co-cultures of bone marrow cells and osteoblasts without affecting receptor activator of NF-κB ligand (RANKL) or osteoprotegerin expression in osteoblasts. In addition, trapidil suppressed RANKL-induced osteoclast formation from osteoclast precursors. Trapidil reduced RANKL-induced expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), a master transcription factor for osteoclastogenesis, without affecting the expression of c-Fos that functions as a key upstream activator of NFATc1 during osteoclastogenesis. Ectopic expression of a constitutively active form of NFATc1 reversed the anti-osteoclastogenic effect of trapidil, indicating that NFATc1 is a critical target of the anti-osteoclastogenic action of trapidil. RANKL-induced calcium oscillation and Pim-1 expression, which are required for NFATc1 induction and osteoclastogenesis, were abrogated by trapidil. Consistent with the in vitro results, trapidil had a potent inhibitory effect on osteoclast formation and bone resorption induced by interleukin-1 in an animal model. Taken together, our data demonstrate that trapidil abrogates RANKL-induced calcium oscillation and Pim-1 expression required for NFATc1 induction, thereby inhibiting osteoclastogenesis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Intestinal ischemia and reperfusion may be the primary triggers of mucosal barrier impairment, cytokine expression, and bacterial translocation (BT). Trapidil is a phosphodiesterase and platelet-derived growth factor inhibitor that reduces lipid peroxidation and inhibits the production of cytokines., Objective: The goal of this study was to assess whether trapidil might protect the intestinal epithelial barrier by inhibiting lipid peroxidation and proinflammatory cytokines by testing the effect of trapidil on intestinal barrier function in an experimental ischemia/reperfusion (I/R) rat model., Methods: Trapidil was used in a rat model of intestinal barrier dysfunction caused by intestinal ischemia for 40 minutes followed by reperfusion for 12 hours. To do this, the rats were randomized to 1 of 4 treatment groups, as follows: (1) sham surgery and saline administration (1 mL IV) (Sham group); (2) sham surgery and trapidil administration (8 mg/kg IV) (Sham+T group); (3) I/R and saline administration (1 mL IV) (I/R group); and (4) I/R and trapidil administration (8 mg/kg IV) (I/R+T group). Intestinal barrier function was assessed by histopathologic examination, blood malondialdehyde (MDA) level, and BT., Results: The I/R+T group showed significantly less incidence of BT compared with the I/R group in the liver and reduced median colony count of translocated bacteria in mesenteric lymph nodes, liver, spleen, and peritoneum compared with the I/R group. Furthermore, the mean blood MDA level demonstrated that lipid peroxidation was significantly decreased in the I/R+T group compared with the I/R group. Histopathologic findings revealed that trapidil administration before reperfusion preserved intestinal mucosal integrity and inhibited the infiltration of inflammatory cells into the intestines., Conclusions: In this experimental study, a correlation seemed to exist between intestinal barrier dysfunction and BT. Intestinal barrier dysfunction may allow a large amount of bacteria to pass from the gut to distant organs. Trapidil treatment may inhibit BT by preserving intestinal barrier by inhibiting thromboxane A2, lipid peroxidation, proinflammatory cytokines, and stimulated prostacyclin. Future dose- and time-dependent studies will be helpful in revealing the effects of trapidil on BT.

Platelet-derived growth factor (POCF) released from platelets is one ofthe mitogens in serum, which plays a major role upon the cell biology, namely enhancing cell division and controlling of the maturation, especially upon the glial cell growth and its differentiation. Trapidil, which is an anti-POCF agent, inhibits the effect of POCF, especially the proliferative effects on the glial and tumoral cells in vitro. Previous studies suggested that the astrocytic proliferation stimulated by POCF was inhibited by trapidil via the selective antagonism. Trapidil was not found to have a considerable effect on the prevention of nonpermissive astrocytes in this study. It should be theorised that trapidil, administered immediately even after the trauma, could not reach the injury site in effective measure because of secondary events such as edema and impairment of blood circulation. This suggestion should be another subject for studies concerning trapidil which is administered prior to the trauma. [Neural Res 1998; 20: 365-373].

The examination and evaluation of three experimental designs for the registration of the in-vitro availability of drugs from suppositories--evaluated by using four suppository preparations--showed the special aptitude of a modified model with a large membrane. This model which considers the spreading of the suppository under load, enables one to characterize the in-vitro drug release even for preparations with a low rate of liberation and it provides correct references to bioavailability.