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Compound 3g also showed a distinct pharmacological effect on isolated smooth muscle tissue from rat bladder and favorable pharmacokinetics profiles, suggesting its potential as a chemical tool for probing the M3 mAChR in further research.Petrolatum ointment, which is an oleaginous ointment, is generally produced through manufacturing processes such as melting, mixing, and cooling. In this type of semisolid formulation, the manufacturing conditions of each process are empirically known to affect the quality of the resultant preparation; however, in many cases, the details of the factors are unclear. To clearly investigate the influence of the pharmaceutical properties of petrolatum ointments, we manufactured several ointments while changing the conditions of the mixing and cooling process after melting white petrolatum. As a result, the temperature at the termination was determined to influence the pharmaceutical properties of the final product. To investigate these phenomena, each petrolatum ointment sample was examined via digital microscopy and laser Raman analysis, and the distribution of the liquid-solid parts of samples was investigated. The internal structure of the ointment sample manufactured at a mixing-stop temperature of 40 °C, the needle crystals and the spherical aggregates surrounding them appropriately coexisted, while the structure exhibited a state wherein the two were linked in a semisolid phase. Meanwhile, for the ointment sample manufactured under the lowest mixing-stop temperature of 25 °C, the liquid part and the spherical aggregates were clearly separated, indicating that the liquid part was easily separated from ointments. In addition, the distribution of the hydrocarbons among the samples was measured via GC-MS; no significant difference in chemical structure was observed. In conclusion, the internal structure of the petrolatum ointment was changed by the manufacturing conditions, and this affected the pharmaceutical properties.A novel series of 7-substituted-2-[3-(2-furyl)acryloyl]-6-tetrazolyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized to clarify structure-activity relationships for peroxisome proliferator-activated receptor γ (PPARγ) partial agonist activity and identify more efficacious PPARγ partial agonists with minor adverse effects. Among the derivatives synthesized, compound 26v with a 2-(2,5-dihydropyrrol-1-yl)-5-methyloxazol-4-ylmethoxy group at the 7-position of the tetrahydroisoquinoline structure exhibited stronger PPARγ agonist and antagonist activities (EC50 = 6 nM and IC50 = 101 nM) than previously reported values for compound 1 (EC50 = 13 nM and IC50 = 512 nM). Compound 26v had very weak protein tyrosine phosphatase 1B (PTP1B) inhibitory activity and showed higher oral absorption (Cmax = 11.4 µg/mL and area under the curve (AUC) = 134.7 µg·h/mL) than compound 1 (Cmax = 7.0 µg/mL and AUC = 63.9 µg·h/mL) in male Sprague-Dawley (SD) rats. A computational docking calculation revealed that 26v bound to PPARγ in a similar manner to that of compound 1. In male Zucker fatty rats, 26v and pioglitazone at 10 and 30 mg/kg for 4 weeks similarly reduced plasma triglyceride levels, increased plasma adiponectin levels, and attenuated increases in plasma glucose levels in the oral glucose tolerance test, while only pioglitazone decreased hematocrit values. In conclusion, 6-tetrazolyl-1,2,3,4-tetrahydroisoquinoline derivatives provide a novel scaffold for selective PPARγ partial agonists and 26v attenuates insulin resistance possibly by adiponectin enhancements with minor adverse effects.Chemoresistance is one of the main factors of treatment failure of cervical cancer (CC). Perifosine Here, we intended to discover the role and mechanism of miR-509-5p in the paclitaxel chemoresistance of CC cells. RT-PCR was conducted to verify miR-509-3p expression. HCC94 and C-33A paclitaxel-resistant CC cell models were constructed. Additionally, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry were performed to verify the viability and apoptosis of HCC94 and C-33A cells after upregulating miR-509-3p. Besides, the downstream target of miR-509-3p was analyzed by bioinformatics, and the targeted relationship between miR-509-3p and RAC1 was identified by the dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Further, the expression of apoptotic proteins (Bcl2, Bax, and Caspase3) and the RAC1/PAK1/LIMK1/Cofilin pathway was monitored by Western blot. The result showed that upregulating miR-509-3p markedly inhibited the viability and promoted the apoptosis of CC cells. On the other hand, miR-509-3p was distinctly downregulated in paclitaxel-resistant HCC94 and C-33A cells (vs. normal cells). The transfection of miR-509-3p mimics notably increased their sensitivity to paclitaxel. Meanwhile, RAC1 was found as the potential target of miR-509-3p in bioinformatics analysis. Moreover, the RAC1/p21 (RAC1) activated kinase 1 (PAK1)/LIM kinase 1 (LIMK1)/Cofilin pathway was significantly activated in paclitaxel-resistant HCC94 and C-33A cells, while miR-509-3p overexpression significantly inactivated this pathway. Additionally, downregulation of RAC1 also partly reversed the paclitaxel-resistance of CC cells and inhibited PAK1/LIMK1/Cofilin. All in all, miR-509-3p enhances the apoptosis and chemosensitivity of CC cells by regulating the RAC1/PAK1/LIMK1/Cofilin pathway.We explored orally effective thyrotropin-releasing hormone (TRH) mimetics, which show high central nervous system effects in structure-activity relationship studies based on in vivo antagonistic activity on reserpine-induced hypothermia (anti-hypothermic effect) in mice starting from TRH. This led us to the TRH mimetic [(4S,5S)-(5-methyl-2-oxooxazolidine-4-yl)carbonyl]-[3-(thiazol-4-yl)-L-alanyl]-L-prolinamide 1, which shows a higher anti-hypothermic effect compared with that of TRH after oral administration. We next attempted further chemical modification of the N- and C-terminus of 1 to find more orally effective TRH mimetics. As a result, we obtained several N- and C-terminus modified TRH mimetics which showed high anti-hypothermic effects.