Serotonin (5-HT) is recognized as a potential regulatory factor in neuronal development. Two subtypes of receptors for it, 5-HT2A and 5-HT2C, are distributed broadly in the rat brain, suggesting their role in a variety of brain functions. Here, we investigated the expression patterns of these 5-HT2 receptors in the rat brain during postnatal development by using Western blot and immunohistochemical analyses. By Western blot analysis, the expression of the 5-HT2A receptor was at a low level at postnatal day 3 (P3) and increased greatly during the first 3 postnatal weeks; whereas the 5-HT2C receptor was already expressed at a high level at P3, and its expression increased only slightly during postnatal development. Immunohistochemical analysis showed the different expression patterns of 5-HT2A and 5-HT2C receptor subtypes during postnatal development: the transient expression of the 5-HT2C receptor was observed in layer IV of the somatosensory, visual, and auditory cortices from P10 to P28, and in the thalamus, mainly in the ventral posterolateral and ventral posteromedial nuclei, from P7 to P21; however, the immunoreactivity of the 5-HT2A receptor was detectable slightly at P3, but thereafter the intensity of immunolabeling increased with postnatal development and at P21 reached the adult level and pattern. These results suggest that 5-HT2 receptors have potential significance in brain development, with a functional difference between 5-HT2A and 5-HT2C receptor subtypes.

OBJECTIVES To describe the longitudinal patterns and the within- and across-facility differences in hospice use and in-hospital deaths between long-term nursing home decedent residents with and without dementia. DESIGN Retrospective analyses of secondary datasets for CY2003–2007. SETTING Nursing homes in the USA. PARTICIPANTS A total of 1,261,726 decedents in 16,347 nursing homes were included in CY2003–2007 trend analysis and 236,619 decedents in 15,098 nursing homes in CY2007 were included in the within- and across-facility analyses. MEASUREMENTS Hospice use in the last 100 days of life, and in-hospital deaths were outcome measures. Dementia was defined as having a diagnosis of Alzheimer’s disease (AD) and/or dementia other than AD, based on the Minimum Data Set (MDS) health assessments. RESULTS Overall hospice use increased from 25.6% in 2003 to 35.7% in 2007. During this time, hospice use for decedents with dementia increased from 25.1% to 36.5%, compared to an increase from 26.5% to 34.4% for decedents without dementia. The rate of in-hospital deaths remained virtually unchanged. Within the same facility, decedents with dementia were significantly more likely to use hospice (OR=1.07, 95% CI: 1.04–1.11) and less likely to die in a hospital (OR=0.76, 95% CI: 0.74–0.78). Decedents in nursing homes with higher dementia prevalence, regardless of individual dementia status, were more likely to use hospice (OR=1.67, 95% CI: 1.22–2.27). CONCLUSION Nursing homes appear to provide less aggressive end of life care to decedents with dementia compared to others. Although significantly more decedent residents with dementia now receive hospice care at the end of life, the quality evaluation and monitoring of hospice programs have not been systematically conducted, and additional research in this area is warranted.

As a newly approved oral hypoglycaemic agent, the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin, which is derived from the natural product phlorizin can effectively reduce blood glucose. Recent clinical studies have found that dapagliflozin alleviates non-alcoholic fatty liver disease (NAFLD), but the specific mechanism remains to be explored. This study aimed to investigate the underlying mechanism of dapagliflozin in alleviating hepatocyte steatosis in vitro and in vivo. We fed the spontaneous type 2 diabetes mellitus rats with high-fat diets and cultured human normal liver LO2 cells and human hepatocellular carcinoma HepG2 cells with palmitic acid (PA) to induce hepatocellular steatosis. Dapagliflozin attenuated hepatic lipid accumulation both in vitro and in vivo. In Zucker diabetic fatty (ZDF) rats, dapagliflozin reduced hepatic lipid accumulation via promoting phosphorylation of acetyl-CoA carboxylase 1 (ACC1), and upregulating lipid β-oxidation enzyme acyl-CoA oxidase 1 (ACOX1). Furthermore, dapagliflozin increased the expression of the autophagy-related markers LC3B and Beclin1, in parallel with a drop in p62 level. Similar effects were observed in PA-stimulated LO2 cells and HepG2 cells. Dapagliflozin treatment could also significantly activated AMPK and reduced the phosphorylation of mTOR in ZDF rats and PA-stimulated LO2 cells and HepG2 cells. We demonstrated that dapagliflozin ameliorates hepatic steatosis by decreasing lipogenic enzyme, while inducing fatty acid oxidation enzyme and autophagy, which could be associated with AMPK activation. Moreover, our results indicate that dapagliflozin induces autophagy via the AMPK-mTOR pathway. These findings reveal a novel clinical application and functional mechanism of dapagliflozin in the treatment of NAFLD.

Previous studies on the treatment of hepatic cirrhosis have been focusing on how to inhibit liver fibrosis, while ignoring liver inflammation, a key and underlying factor that promotes cirrhosis. High mobility group box-1 (HMGB1) protein, a pro-inflammatory factor and fibroblast chemokine, can promote the proliferation of hepatic stellate cells (HSCs) and the development of hepatic inflammation and fibrosis, playing a key role in cirrhosis formation. In this study, we prepared pPB peptide (C*SRNLIDC*)-modified and HMGB1-siRNA-loaded stable nucleic acid lipid nanoparticles (HMGB1-siRNA@SNALP-pPB) to effectively treat hepatic cirrhosis by their dual antifibrotic and anti-inflammatory activities. The pPB peptide-modified and heat shock protein 47 (HSP47)-siRNA-loaded stable nucleic acid lipid nanoparticles (HSP47-siRNA@SNALP-pPB), which have only an antifibrotic effect without an anti-inflammatory effect, was used as control. The results demonstrated that HMGB1-siRNA@SNALP-pPB were actively targeted to HSCs by the mediation of pPB peptide, effectively silenced the HMGB1 gene, inhibited the activation and proliferation of HSCs, reduced the release of HMGB1 protein, inhibited collagen deposition and fibrosis formation in the liver, and significantly prolonged the survival time of cirrhotic mice models. HMGB1-siRNA@SNALP-pPB showed a stronger therapeutic effect on liver cirrhosis than HSP47-siRNA@SNALP-pPB. This study provides an actively targeted siRNA delivery system for cirrhosis treatment based on the dual antifibrotic and anti-inflammatory effects. In addition, this study clarified the role of inflammatory problems in cirrhosis treatment in addition to liver fibrosis, providing a useful idea and scientific basis for the development of cirrhosis treatment strategies in the future.

A novel catalytic asymmetric Michael addition of azomethine ylide with β-substituted alkylidene bisphosphates was realized in the presence of a chiral copper(I)/TF-BiphamPhos complex. The present system provides a unique and facile access to enantioenriched unnatural α-amino acid derivatives containing gem-bisphosphonates (gem-BPs) in high yields with excellent diastereoselectivities and enantioselectivities. Subsequent transformations lead to the expedient preparation of biologically active unnatural α-amino acid derivatives containing BPs and bisphosphonic acids without loss of diastereo- and enantiomeric excess.

Compared with patients with ICD only, CRT-ICD is associated with greater improvement in QOL among relatively asymptomatic patients, specifically among those with left bundle branch conduction disturbance.

Andrographolide (AD) is the main compound distributed in medicinal herb Andrographis paniculata and exhibits anti-inflammatory activity. AD has been used for the treatment of multiple inflammatory diseases. However, the therapeutic value of AD on human rheumatoid arthritis (RA) remains unclear. In this study, we investigated the effects of AD on collagen-induced arthritis (CIA) and human RA synovial fibroblasts (RA-SFs). CIA mice were treated with AD (dissolved in 0.5% CMC-Na, 100 mg/kg per day) or vehicle (0.5% CMC-Na) daily by oral gavage for 2 weeks. The arthritis severity and joint destruction were assessed. Serum anti-collagen II antibody (anti-CII Abs) and cytokines were determined by ELISA. TNFα-stimulated human RA-SFs were treated with varying doses of AD for in vitro investigation. Results showed that AD significantly attenuated the arthritis severity and joint damage. AD treatment significantly reduced the production of serum anti-CII, TNFα, IL-1β, and IL-6. In vitro, AD decreased the secretion of IL-1β and IL-6 from TNFα-stimulated RA-SFs in a dose-dependent manner. AD treatment reduced the TNFα-induced phosphorylation of p38 MAPK and ERK1/2 in a dose-dependent manner. Thus, our findings suggest that AD confers protective effects on autoimmune arthritis through inhibiting MAPK pathways.

Although a white spot syndrome virus (WSSV) subunit vaccine could significantly enhance the immune response and benefit the shrimp host, its practical application is currently not feasible because of drawbacks in existing expression systems. We generated a transgenic Dunaliella salina (D. salina) strain by introducing the WSSV VP28 gene to produce a novel oral WSSV subunit vaccine. Following transformation of D. salina, VP28 gene expression was assessed by reverse transcription polymerase chain reaction (RT-PCR) assays, enzyme-linked immunosorbent assays (ELISAs), and western blot analysis. The RT-PCR results indicated that the VP28 gene was successfully expressed in D. salina cells. The presence of recombinant VP28 proteins with natural bioactivity was confirmed by western blot analysis and ELISA. Animal vaccination experiments indicated that transgenic D. salina can induce protection against WSSV by oral delivery in crayfish. Our findings indicate that the VP28 gene can be successfully expressed in transgenic D. salina and can be applied as an oral vaccine to protect crayfish against WSSV. We have demonstrated that it is feasible to produce an oral vaccine using D. salina, and thereby provide a new method for controlling other viral diseases in crustaceans.