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Introduction: Renal fibrosis (RF), being the most important pathological change in the progression of CKD, is currently assessed by the evaluation of a biopsy. This present study aimed to apply a novel functional MRI (fMRI) protocol named amide proton transfer (APT) weighting to evaluate RF noninvasively. Methods: Male Sprague-Dawley (SD) rats were initially subjected to bilateral kidney ischemia/reperfusion injury (IRI), unilateral ureteral obstruction, and sham operation, respectively. All rats underwent APT mapping on the 7th and 14th days after operation. Besides, 26 patients underwent renal biopsy at the Nephrology Department of Shanghai Tongji Hospital between July 2022 and May 2023. Patients underwent APT and apparent diffusion coefficient (ADC) mappings within 1 week before biopsy. MRI results of both patients and rats were calculated by comparing with gold standard histology for fibrosis assessment. Results: In animal models, the cortical APT (cAPT) and medullary APT (mAPT) values were positively correlated with the degree of RF. Compared to the sham group, IRI group showed significantly increased cAPT and mAPT values on the 7th and 14th days after surgery, but no group differences were found in ADC values. Similar results were found in human patients. Cortical/medullary APT values were significantly increased in patients with moderate-to-severe fibrosis than in patients with mild fibrosis. ROC curve analysis indicated that APT value displayed a better diagnostic value for RF. Furthermore, combination of cADC and cAPT improved fibrosis detection by imaging variables alone (p < 0.1). Conclusion: APT values had better diagnostic capability at early stage of RF compared to ADC values, and the addition of APT imaging to conventional ADC will significantly improve the diagnostic performance for predicting kidney fibrosis. Plain Language Summary: Amide proton transfer (APT) MRI, a novel molecular MRI technique, could indirectly measure the peptide or protein concentration within tissues based on frequent exchange between amide proton and the surrounding water protons. This new technology has been used in tumor diagnosis. Given pathological conditions linked to tissue fibrogenesis are similar to carcinogenesis, we proposed the hypothesis that APT MRI can be applied to assess collagen deposition in RF. To test this, we constructed animal models for RF and enrolled CKD patients, respectively. The results suggested APT values were more sensitive to the early stage of fibrosis than ADC values, and the cortical APT was highly positively correlated with the degree of fibrosis. We further identified that the combination of two MRI protocols, cortical apparent diffusion coefficient and cortical APT, was an excellent indicator for the diagnosis of fibrosis, with much higher accuracy than a single method. To the best of our knowledge, this is the first study to explore the value of APT imaging for assessing renal interstitial fibrosis. Our findings identify APT as a novel and precise imaging diagnostic tool for future noninvasive assessment of RF. It complements with the existing imaging biomarkers and adds value to conventional MRI. [ABSTRACT FROM AUTHOR]

4'-Hydroxywogonin (4'-HW), a flavonoid, has been isolated from various plants and shown to inhibit NO production in macrophages. However, the molecular mechanisms and its in vivo activity have not been determined. Our study aimed to investigate the mechanisms underlying the anti-inflammatory effects of 4'-HW in vitro and in vivo. We showed that 4'-HW potently reduced the expression levels of COX-2 and iNOS as well as their products, prostaglandin E2 (PGE2) and nitric oxide (NO) respectively, in LPS-stimulated RAW 264.7 macrophages. 4'-HW also suppressed LPS-induced pro-inflammatory cytokines at mRNA and protein levels. Moreover, 4'-HW blocked the interaction of TAK1 and TAB1 in LPS-stimulated RAW 264.7 macrophages, resulting in an inhibition of the TAK1/IKK/NF-κB signaling pathway. Furthermore, 4'-HW also reduced the phosphorylation of MAPKs and PI3/Akt signaling pathways in LPS-stimulated RAW 264.7 macrophages. 4'-HW was also significantly decreased the intracellular reactive oxygen species (ROS) level. The effect of 4'-HW was confirmed in vivo. 4'-HW exhibited potent protective effect against LPS-induced ALI in mice. These findings indicate that 4'-HW suppresses the LPS-induced response in vitro and in vivo. It is likely that the inhibition of the TAK1/IKK/NF-κB, MAPKs and PI3/AKT signaling pathways contribute to the anti-inflammatory effects of 4'-HW. Our study suggests that 4'-HW may be an important functional constituent in the plants and has the potential value to be developed as a novel anti-inflammatory agent. [ABSTRACT FROM AUTHOR]

Bombesin receptor subtype-3(BRS-3) is an orphan receptor in the bombesin receptor family. Its signal transduction mechanism and biological function have attracted much attention. Seeking the ligand for BRS-3 is of great significance for exploring its function. Considering the fact that the activation of BRS-3 receptor can induce the change in intracellular Ca~(2+) concentration, the fluo-rometric imaging plate reader(FLIPR) was utilized for ligand screening at the cellular level. Among more than 400 monomeric compounds isolated from Chinese herbs, yuanhunine from Corydalis Rhizoma and sophoraisoflavanone A and licoriphenone from Glycyrrhizae Radix et Rhizoma antagonized BRS-3 to varying degrees. It was confirmed in HEK293 cells expressing BRS-3 that yuanhunine, sophoraisoflavanone A, and licoriphenone inhibited the calcium current response after the activation of BRS-3 by [D-Phe~6,β-Ala~(11),Phe~(13),Nle~(14)]bombesin-(6-14) in a dose-dependent manner with the IC&#95;(50) values being 8.58, 4.10, and 2.04 μmol·L~(-1), respectively. Further study indicated that yuanhunine and sophoraisoflavanone A exhibited good selectivity for BRS-3. In this study, it was found for the first time that monomers derived from Chinese herbs had antagonistic activity against orphan receptor BRS-3, which has provided a tool for further study of BRS-3 and also the potential lead compounds for new drug discovery. At the same time, it provides reference for the research and development of innovative drugs based on the active ingredients of Chinese herbs.

Background: The predominant method for Manske type IIIB and IV thumb hypoplasia is pollicization. However, for those who are not willing to sacrifice the index finger, a method that could reconstruct a functionally capable and aesthetically acceptable thumb remains desirable. This study aimed to investigate and assess the functional and radiographic outcomes of utilizing a reversed vascularized second metatarsal composite flap for thumb reconstruction as a new alternative., Methods: From May 2014 to January 2017, 15 patients with Manske type IIIB or IV thumb hypoplasia who were admitted to the Department of Hand Surgery, Beijing Jishuitan Hospital were included in this study. An osteocutaneous flap containing a section of second metatarsal and its distal head was transferred in reversed position to reconstruct carpometacarpal joint. The donor site was reconstructed by a split half of the third metatarsal. Various functional reconstructions were commenced at second stage. The reconstructed thumbs were evaluated using the Kapandji score, pinch force, and the capacities of performing daily activities through a detailed questionnaire., Results: Among these 15 patients (seven type IIIB and eight type IV), there were ten boys and five girls with median age of 4.2 years (range: 2.0-7.0 years). There were seven right, three left, and five bilateral thumbs for whom only the right thumb received surgery. There were 14 metatarsal flaps survived (14/15). With an average follow-up of 19.2 months, the reconstructed thumbs had acceptable functional and aesthetic outcomes and the donor foot presented in decent appearance without signs of impaired function. All 15 children have improved the Kapandji score (from 0 to an average of 6.7), pinch force (from 0 to an average of 1.5 kg), with ability of grip and pen holding. X-ray indicated continuous bone growth. Patients and parents had good acceptance of the new thumb., Conclusions: Reconstruction of an unstable hypoplastic thumb (Manske type IIIB and IV) with use of a vascularized metatarsal is an effective strategy. It offers an alternative solution for parents insisting on saving the thumb.