Tas2R activation relaxes airway smooth muscle by release of Gαt targeting on AChR signaling.

Both chronic obstructive pulmonary disease (COPD) and asthma are severe respiratory diseases. Bitter receptor-mediated bronchodilation is a potential therapy for asthma, but the mechanism underlying the agonistic relaxation of airway smooth muscle (ASM) is not well defined. By exploring the ASM relaxation mechanism of bitter substances, we observed that pretreatment with the bitter substances nearly abolished the methacholine (MCh)-induced increase in the ASM cell (ASMC) calcium concentration, thereby suppressing the calcium-induced contraction release. The ASM relaxation was significantly inhibited by simultaneous deletion of three Gαt proteins, suggesting an interaction between Tas2R and AChR signaling cascades in the relaxation process. Biochemically, the Gαt released by Tas2R activation complexes with AChR and blocks the Gαq cycling of AChR signal transduction. More importantly, a bitter substance, kudinoside A, not only attenuates airway constriction but also significantly inhibits pulmonary inflammation and tissue remodeling in COPD rats, indicating its modulation of additional Gαq-associated pathological processes. Thus, our results suggest that Tas2R activation may be an ideal strategy for halting multiple pathological processes of COPD.

Microplastic-induced NAFLD: Hepatoprotective effects of nanosized selenium.

Polystyrene microplastics (MPs) are persistent environmental pollutants commonly encountered in daily human life. Numerous studies have demonstrated their ability to induce liver damage, including oxidative stress, inflammation, and lipid accumulation. However, limited information exists regarding preventive measures against this issue. In our study, we investigated the potential preventive role of selenium nanoparticles (YC-3-SeNPs) derived from Yak-derived Bacillus cereus, a novel nanobiomaterial known for its antioxidant properties and lipid metabolism regulation. Using transcriptomic and metabolomic analyses, we identified key genes and metabolites associated with oxidative stress and lipid metabolism imbalance induced by MPs. Upregulated genes (Scd1, Fasn, Irs2, and Lpin) and elevated levels of arachidonic and palmitic acid accumulation were observed in MP-exposed mice, but not in those exposed to SeNPs. Further experiments confirmed that SeNPs significantly attenuated liver lipid accumulation and degeneration caused by MPs. Histological results and pathway screening validated our findings, revealing that MPs suppressed the Pparα pathway and Nrf2 pathway, whereas SeNPs activated both pathways. These findings suggest that MPs may contribute to the development of nonalcoholic fatty liver disease (NAFLD), while SeNPs hold promise as a future nanobio-product for its prevention.

The thymus regulates skeletal muscle regeneration by directly promoting satellite cell expansion.

The thymus is the central immune organ, but it is known to progressively degenerate with age. As thymus degeneration is paralleled by the wasting of aging skeletal muscle, we speculated that the thymus may play a role in muscle wasting. Here, using thymectomized mice, we show that the thymus is necessary for skeletal muscle regeneration, a process tightly associated with muscle aging. Compared to control mice, the thymectomized mice displayed comparable growth of muscle mass, but decreased muscle regeneration in response to injury, as evidenced by small and sparse regenerative myofibers along with inhibited expression of regeneration-associated genes myh3, myod, and myogenin. Using paired box 7 (Pax7)-immunofluorescence staining and 5-Bromo-2'-deoxyuridine-incorporation assay, we determined that the decreased regeneration capacity was caused by a limited satellite cell pool. Interestingly, the conditioned culture medium of isolated thymocytes had a potent capacity to directly stimulate satellite cell expansion in vitro. These expanded cells were enriched in subpopulations of quiescent satellite cells (Pax7highMyoDlowEdUpos) and activated satellite cells (Pax7highMyoDhighEdUpos), which were efficiently incorporated into the regenerative myofibers. We thus propose that the thymus plays an essential role in muscle regeneration by directly promoting satellite cell expansion and may function profoundly in the muscle aging process.

Gallbladder dysfunction caused by MYPT1 ablation triggers cholestasis-induced hepatic fibrosis in mice.

BACKGROUND: The incidence of gallbladder diseases is as high as 20%, but whether gallbladder diseases contribute to hepatic disorders remains unknown. METHODS: Here, we established an animal model of gallbladder dysfunction and assessed the role of a diseased gallbladder in cholestasis-induced hepatic fibrosis (CIHF). RESULTS: Mice with smooth muscle-specific deletion of Mypt1, the gene encoding the main regulatory subunit of myosin light chain phosphatase (myosin phosphatase target subunit 1 [MYPT1]), had apparent dysfunction of gallbladder motility. This dysfunction was evidenced by abnormal contractile responses, namely, inhibited cholecystokinin 8-mediated contraction and nitric oxide-resistant relaxation. As a consequence, the gallbladder displayed impaired bile filling and biliary tract dilation comparable to the alterations in CIHF. Interestingly, the mutant animals also displayed CIHF features, including necrotic loci by the age of 1 month and subsequently exhibited progressive fibrosis and hyperplastic/dilated bile ducts. This pathological progression was similar to the phenotypes of the animal model with bile duct ligation and patients with CIHF. The characteristic biomarker of CIHF, serum alkaline phosphatase activity, was also elevated in the mice. Moreover, we observed that the myosin phosphatase target subunit 1 protein level was able to be regulated by several reagents, including lipopolysaccharide, exemplifying the risk factors for gallbladder dysfunction and hence CIHF. CONCLUSIONS: We propose that gallbladder dysfunction caused by myosin phosphatase target subunit 1 ablation is sufficient to induce CIHF in mice, resulting in impairment of the bile transport system.

A Shigella species variant is causally linked to intractable functional constipation.

Intractable functional constipation (IFC) is the most severe form of constipation, but its etiology has long been unknown. We hypothesized that IFC is caused by refractory infection by a pathogenic bacterium. Here, we isolated from patients with IFC a Shigella species - peristaltic contraction-inhibiting bacterium (PIB) - that significantly inhibited peristaltic contraction of the colon by production of docosapentenoic acid (DPA). PIB colonized mice for at least 6 months. Oral administration of PIB was sufficient to induce constipation, which was reversed by PIB-specific phages. A mutated PIB with reduced DPA was incapable of inhibiting colonic function and inducing constipation, suggesting that DPA produced by PIB was the key mediator of the genesis of constipation. PIBs were detected in stools of 56% (38 of 68) of the IFC patients, but not in those of non-IFC or healthy individuals (0 of 180). DPA levels in stools were elevated in 44.12% (30 of 68) of the IFC patients but none of the healthy volunteers (0 of 97). Our results suggest that Shigella sp. PIB may be the critical causative pathogen for IFC, and detection of fecal PIB plus DPA may be a reliable method for IFC diagnosis and classification.

[Changes of soil microbial biomass carbon and their impact factors for Pinus tabuliformis plantations at different development stages on the Loess Plateau, China.] / é»„åœŸé«˜åŽŸä¸åŒç”Ÿé•¿é˜¶æ®µæ²¹æ¾äººå·¥æž—åœŸå£¤å¾®ç”Ÿç‰©ç”Ÿç‰©é‡ç¢³çš„å˜åŒ–åŠå ¶å½±å“å› ç´ .

By taking an abandoned land as control and the young (13-15 year-old), middle-age (25-27 year-old) and mature (41-43 year-old) plantations of Pinus tabuliformis as research objects, the variation characteristics and impact factors of soil microbial biomass carbon (MBC) for the P. tabuliformis plantations in 0-60 cm soil layer were studied. Results showed that the average MBC at the young, middle-age and mature plantations was 93.08, 122.64 and 191.34 mg·kg-1, respectively, which showed a significant increase with growth stage and was significantly higher than the abandoned land (42.93 mg·kg-1). The average MBC contents gradually decreased with soil depth. Compared with the abandoned land, the average MBC at the young, middle-aged and mature plantations respectively increased by 134.2%, 221.7% and 375.7% in the 0-20 cm soil layer, 101.3%, 164.3% and 337.5% in the 20-40 cm soil layer, and 103.1%, 146.2% and 303.0% in 40-60 cm soil layer. The MBC for the whole soil layer of 60 cm had a highly significant correlation with the DBH, height and root biomass of the P. tabuliformis plantation, as well as the thickness, biomass and total nitrogen of litter. Meanwhile, the MBC also showed significant correlations with soil organic carbon (SOC), total nitrogen and moisture content. Principal component analysis showed that the root biomass, litter biomass and SOC were the principal factors affecting MBC. The P. tabuliformis plantation significantly increased SOC content mainly through litter of leaf and root and improved the MBC in the growth process.

Radiological and clinical findings of osseous peripheral primitive neuroectodermal tumors.

Peripheral primitive neuroectodermal tumor (pPNET) is a rare and highly malignant undifferentiated type of tumor. The aim of the present study was to analyze the computed tomography (CT), magnetic resonance imaging (MRI) and clinical findings of osseous pPNET. The present study retrospectively analyzed the clinical data and CT findings from 15 patients with osseous pPNET; the MRI findings from 11 of these 15 patients were confirmed by histopathological examination. The 15 patients included 9 men and 6 women. The mean patient age was 29 years (range, 16-64 years) and 11 cases were aged <30 years. A CT scan was performed in 15 cases and the findings included a lytic lesion (13 cases), a lytic lesion with irregular sclerosis and dilation (2 cases), a soft tissue mass (15 cases), calcification (2 cases) and periosteal reaction (5 cases). A total of 9 cases of soft tissue mass were heterogeneous, with different sizes of lower-density necrotic areas. An enhanced MRI scan was performed in 11 cases. On T1-weighted images (WI), the soft tissue mass was isointense (8 cases) and marginally hyperintense (3 cases). On T2WI, aggressive soft tissue masses were heterogeneous iso- or hyperintense (11 cases). On contrast-enhanced T1WI, marked heterogeneous enhancement was present in 10 cases and intermediate heterogeneous enhancement in 1 case. The results indicated that osseous pPNET mainly affects male adolescents and young adults. The CT findings of osseous pPNET were destructive lesions with a soft tissue mass and, occasionally, with periosteal reaction. The tumor was often isodense, with patchy hypodense areas. Tumor calcification was uncommon. The MRI findings were those of an aggressive soft tissue mass exhibiting isointensity on T1WI and iso- or hyperintensity on T2WI, with marked heterogeneous enhancement. Although the imaging characteristics of pPNETs may be non-specific, CT and MRI may be useful in delineating the extent of the tumor, identifying distant metastases, predicting resectability and monitoring treatment.

Rare presentation of peripheral primitive neuroectodermal tumor in the maxilla and mandible: A report of two cases.

Peripheral primitive neuroectodermal tumor (pPNET) is a rare and highly malignant undifferentiated tumor, which presents in infants and young adults. pPNETs in the head and neck region are uncommon and have a varying incidence of occurrence. Peripheral PNETs of the maxilla and mandible are particularly rare. At present, only 16 cases of pPNET of the maxilla and 13 cases of pPNET of the mandible have been reported. The present study describes a case of pPNET of the maxilla in a 16-year-old male and a case of pPNET of the mandible in another 16-year-old male. The present study reports the radiological findings and the clinical courses of the two patients.