Irisin is a polypeptide hormone derived from the proteolytic cleavage of fibronectin-type III domain-containing 5 (FNDC5) protein. Once released to circulation upon exercise or cold exposure, irisin stimulates browning of white adipose tissue (WAT) and uncoupling protein 1 (UCP1) expression, leading to an increase in total body energy expenditure by augmented UCP1-mediated thermogenesis. It is currently unknown whether irisin is secreted by bone upon exercise or whether it regulates bone metabolism in vivo. In this study, we found that 2 weeks of voluntary wheel-running exercise induced high levels of FNDC5 messenger RNA as well as FNDC5/irisin protein expression in murine bone tissues. Increased immunoreactivity due to exercise-induced FNDC5/irisin expression was detected in different regions of exercised femoral bones, including growth plate, trabecular bone, cortical bone, articular cartilage, and bone–tendon interface. Exercise also increased expression of osteogenic markers in bone and that of UCP1 in WAT, and led to bodyweight loss. Irisin intraperitoneal (IP) administration resulted in increased trabecular and cortical bone thickness and osteoblasts numbers, and concurrently induced UCP1 expression in subcutaneous WAT. Lentiviral FNDC5 IP administration increased cortical bone thickness. In vitro studies in bone cells revealed irisin increases osteoblastogenesis and mineralization, and inhibits receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclastogenesis. Taken together, our findings show that voluntary exercise increases irisin production in bone, and that an increase in circulating irisin levels enhances osteogenesis in mice.

Temporomandibular disorders (TMDs) predominantly affect reproductive female patients, with pain the most frequent complaint. Although estrogens are believed to play important roles in TMD pain, the mechanism underlying modulation of TMD pain by estrogens remains largely unknown. Accumulating evidence implies that the hippocampus is involved in sexual dimorphism of pain sensitivity. In this study, we investigated the hippocampal TRPV1 (transient receptor potential vanilloid 1) expression in ovariectomized rats that received 17-␤-estradiol substitution and found that 17-␤-estradiol enhanced the mechanical allodynia of inflamed temporomandibular joint (TMJ) induced by complete Freund's adjuvant. Real-time PCR and immunoblotting demonstrated that TMJ inflammation significantly induced hippocampal TRPV1 expression compared with the control group but failed to induce it in the ovariectomized rats that received no estradiol replacement. In addition, estradiol potentiated TMJ inflammation-induced hippocampal TRPV1 expression in a dose-dependent manner in the ovariectomized rats. In contrast, TRPV1 transcription in amygdala, prefrontal cortex, and thalamus was not affected by TMJ inflammation and estradiol. Immunostaining showed TRPV1 localized in the processes and cytoplasm of pyramidal neurons in CA1-CA3 regions of the hippocampus. Moreover, intrahippocampal injection of TRPV1 antagonists capsazepine and 5Ј-iodoresiniferatoxin into the CA1 region of the hippocampus significantly attenuated allodynia of inflamed TMJ in both nonovariectomized and ovariectomized rats that received estradiol replacement. Our results suggested that hippocampal TRPV1 can modulate central pain processing and estradiol may contribute to the sexual dimorphism of TMD pain sensitivity through upregulation of TRPV1 expression in the hippocampus.

A self-healing hydrogel enriched with properties from a double-dynamic network (DDN) that has been prepared via two dynamic linkages (imine and borate ester) by using a single polymeric cross-linker. The four-component Ugi reaction was used for easily synthesizing multifunctional poly­(ethylene glycol) (MF-PEG) with a benzaldehyde group and phenylboronic acid group at each end of the chain. This MF-PEG simultaneously cross-linked with poly­(vinyl alcohol) through the borate ester and glycol chitosan via an imine to generate a self-healing hydrogel with a unique DDN structure in seconds under mild conditions (pH ≈ 7, 25 °C). The prepared hydrogel showed enhanced strength and mucoadhesive abilities because of the complimentary interpenetrating dynamic networks. The DDN hydrogel showed satisfying biocompatibility and was further used in an in vivo mouse model. The hydrogel was injected to successfully deliver an antitumor drug and achieved a superior performance compared to traditional delivery methods. To the best of our knowledge, this is the first report of using the Ugi reaction to prepare a DDN self-healing hydrogel. We hereby propose a general strategy for the facile preparation of self-healing materials with improved properties. The strategy also opens a new avenue for synthesizing multifunctional/reinforced materials with the combination of dynamic chemistry and multicomponent reactions.

Background and Objectives:Short-chain fatty acids (SCFAs) are gut microbial metabolites that promote the disease process in a rodent model of Parkinson’s disease (PD), but fecal levels of SCFAs in PD patients are reduced. Simultaneous assessments of fecal and plasma SCFA levels, and their inter-relationships with the PD disease process are scarce. We aimed to compare fecal and plasma levels of different SCFAs subtypes in PD patients and healthy controls to delineate their interrelations and link to gut microbiota changes and clinical severity of PD.Methods:A cohort of 96 PD patients and 85 controls were recruited from National Taiwan University Hospital. Fecal and plasma concentrations of SCFAs were measured using chromatography and mass spectrometry. Gut microbiota was analyzed using metagenomic shotgun sequencing. Body mass index and medical co-morbidities were evaluated, and dietary information was obtained using a food frequency questionnaire. To assess motor and cognitive impairment, we used the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and the Mini-Mental Status Examination (MMSE).Results:Compared with controls, PD patients had lower fecal but higher plasma concentrations of acetate, propionate, and butyrate. After adjustment for age, sex, disease duration, and anti-PD medication dosage, MDS-UPDRS part III motor scores correlated with reduced fecal levels of acetate (ρ = -0.37, p = 0.012), propionate (ρ = -0.32, p = 0.036), and butyrate (ρ = -0.40, p = 0.004) and with increased plasma propionate concentrations (ρ = 0.26, p = 0.042) in PD patients. MMSE scores negatively correlated with plasma levels of butyrate (ρ = -0.09, p = 0.027) and valerate (ρ = -0.032, p = 0.033) after adjustment for confounders. SCFAs-producing gut bacteria correlated positively with fecal levels of SCFAs in healthy controls but revealed no association in patients with PD. In the PD patient group, the abundance of pro-inflammatory microbes, such as Clostridiales bacterium NK3B98 and Ruminococcus sp. AM07-15, significantly correlated with decreased fecal levels and increased plasma levels of SCFAs, especially propionic acid.Discussion:Reductions in fecal SCFAs but increased plasma SCFAs were observed in PD patients and corelated to specific gut microbiota changes and the clinical severity of PD.Classification of evidence:This study provides Class III evidence that gut metabolite SCFAs distinguish between PD patients and controls, and are associated with disease severity in patients with PD.