The nanobody targeting PD-L1 and CXCR4 counteracts pancreatic stellate cell-mediated tumour progression by disrupting tumour microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy worldwide owing to its complex tumour microenvironment and dense physical barriers. Stromal-derived factor-1 (SDF-1), which is abundantly secreted by tumour stromal cells, plays a pivotal role in promoting PDAC growth and metastasis. In this study, we investigated the impact and molecular mechanisms of the anti-PD-L1&CXCR4 bispecific nanobody on the TME and their consequent interference with PDAC progression. We found that blocking the SDF-1/CXCR4 signalling pathway delayed the epithelial-mesenchymal transition in pancreatic cancer cells. Anti-PD-L1&CXCR4 bispecific nanobody effectively suppress the secretion of SDF-1 by pancreatic stellate cells and downregulate the expression of smooth muscle actin alpha(α-SMA), thereby preventing the activation of cancer-associated fibroblasts by downregulating the PI3K/AKT signaling pathway. This improves the pancreatic tumour microenvironment, favouring the infiltration of T cells into the tumour tissue. In conclusion, our results suggest that the anti-PD-L1&CXCR4 bispecific nanobody exerts an antitumor immune response by changing the pancreatic tumour microenvironment. Hence, the anti-PD-L1&CXCR4 bispecific nanobody is a potential candidate for pancreatic cancer treatment.

Theory of soliton self-frequency shift in silica optical microresonators with a modified Raman response by the Boson peak.

We theoretically study the Raman-induced self-frequency shift of dissipative Kerr soliton in silica optical resonators by taking into consideration the Boson peak. We find that the Boson peak will greatly increase the soliton self-frequency shift and contribute even more than the shift induced by the Lorentzian response for certain pulse durations. We also show that the revised Raman shock time is associated with the pulse width even for a relatively long pulse. Moreover, we demonstrate that the background continuous wave decreases the self-frequency shift of the soliton via the interference with the soliton. Our theoretical and simulated results display excellent agreement with the previous experimental values in the silica-based Kerr-soliton microcomb.

Discovery and validation of PURA as a transcription target of 20(S)-protopanaxadiol: Implications for the treatment of cognitive dysfunction.

Background: 20(S)-protopanaxadiol (PPD), a ginsenoside metabolite, has prominent benefits for the central nervous system, especially in improving learning and memory. However, its transcriptional targets in brain tissue remain unknown. Methods: In this study, we first used mass spectrometry-based drug affinity responsive target stability (DARTS) to identify the potential proteins of ginsenosides and intersected them with the transcription factor library. Second, the transcription factor PURA was confirmed as a target of PPD by biolayer interferometry (BLI) and molecular docking. Next, the effect of PPD on the transcriptional levels of target genes of PURA in brain tissues was determined by qRT-PCR. Finally, bioinformatics analysis was used to analyze the potential biological features of these target proteins. Results: The results showed three overlapping transcription factors between the proteomics of DARTS and transcription factor library. BLI analysis further showed that PPD had a higher direct interaction with PURA than parent ginsenosides. Subsequently, BLI kinetic analysis, molecular docking, and mutations in key amino acids of PURA indicated that PPD specifically bound to PURA. The results of qRT-PCR showed that PPD could increase the transcription levels of PURA target genes in brain. Finally, bioinformatics analysis showed that these target proteins were involved in learning and memory function. Conclusion: The above-mentioned findings indicate that PURA is a transcription target of PPD in brain, and PPD upregulate the transcription levels of target genes related to cognitive dysfunction by binding PURA, which could provide a chemical and biological basis for the study of treating cognitive impairment by targeting PURA.

Atractylenolide-III alleviates osteoarthritis and chondrocyte senescence by targeting NF-κB signaling.

Atractylenolide-III (AT-III) is well known as its role in antioxidant and anti-inflammatory. Present study was aimed to figure out its effects on osteoarthritis and potential mechanisms. Rat model, human osteoarthritis cartilage explants as well as rat/human chondrocyte cultures were prepared to test AT-III's effects on osteoarthritis progression and chondrocyte senescence. Potential targeted molecules of AT-III were predicted using network pharmacology and molecular docking, assessed by Western blotting and then verified with rescue experiments. AT-III treatment alleviated osteoarthritis severity (shown by OARSI grading score and micro-CT) and chondrocyte senescence (indexed by levels of SA-ß-gal, P16, P53, MMP13, ROS and ratio of healthy/collapsed mitochondrial membrane potentials). Network pharmacology and molecular docking suggested that AT-III might play role through NF-κB pathway. Further experiments revealed that AT-III reduced phosphorylation of IKKα/ß, IκBα and P65 in NF-κB pathway. As well as nuclear translocation of p65. Both in vivo and in vitro experiments indicated that AT-III's effects on osteoarthritis and anti-senescence were reversed by an NF-κB agonist. AT-III could alleviate osteoarthritis by inhibiting chondrocyte senescence through NF-κB pathway, which indicated that AT-III is a prospective drug for osteoarthritis treatment.

Yiqi Huazhuo decoction increases insulin secretion in type 2 diabetic rats by regulating the pancreatic GPR40-IP3R-1 signaling pathway.

Objective: Yiqi Huazhuo Decoction (YD) reduces blood glucose, glycated hemoglobin, body weight, and insulin resistance in patients with type 2 diabetes mellitus (T2DM), but its exact mechanisms are unknown. This study investigated the therapeutic effects and mechanisms of YD on impaired insulin secretion in T2DM rats. Methods: T2DM rats were randomized to the model, YD-lo (15 mg/kg/d YD, 10 weeks), YD-hi (30 mg/kg/d YD, 10 weeks), positive drug (TAK-875), and healthy control groups. The rats underwent an oral glucose tolerance test (OGTT), glucose-stimulated insulin secretion (GSIS) test, and serum lipid measurements. High-fat and high-glucose-injured RIN-m5f cells were treated with YD (30 or 150 mg/mL) for 48 h. GPR40 and IP3R-1 expression levels were determined by immunofluorescence, qRT-PCR, and western blot. Results: Compared with the model group, the OGTT area under the curve (AUC) in the YD-hi group was decreased by 26.7%, the insulin release test (IRT) AUC in the YD-hi group was increased by 45.9%, and the GSIS AUC was increased by 33.9% (p < 0.05). Compared with the model cells, the insulin secretion after glucose stimulation in the YD-hi group was increased by 24.5%, similar to the TAK-875 group (23.1%) (p > 0.05). GPR40 and IP3R-1 mRNA in the model cells were decreased by 49.5% and 51.2% compared with the control cells (p < 0.05). In the YD-hi group, GPR40 and IP3R-1 mRNA levels were increased by 58.1% and 39.3% (p < 0.05), similar to the TAK-875 group. The changes in protein expression were similar to mRNA. Conclusion: YD promotes insulin secretion from pancreatic islet ß-cell in T2DM rats by regulating the GPR40-IP3R-1 pathway, thereby reducing blood glucose.

Synthesis and evaluation of water-soluble imidazolium salt chitin with broad-spectrum antimicrobial activity and excellent biocompatibility for infected wound healing.

Infections caused by bacteria have long constituted a major threat to human health and the economy. Therefore, there is an urgent need to design broad-spectrum antibacterial materials possessing good biocompatibility to treat such infections. Herein, inspired by the good biocompatibility of chitin and antibacterial properties of imidazolium salts, a polysaccharide-based material, imidazolium salt chitin (IMSC), was homogeneously prepared using a facile method with epichlorohydrin as a chemical crosslinker to combine chitin with imidazole to enhance Staphylococcus aureus (S. aureus)-infected wound healing. The characteristics, antimicrobial properties, and biosafety of IMSC were evaluated. The results demonstrated successful grafting of imidazole onto chitin. Furthermore, IMSC exhibited good water solubility, broad-spectrum antimicrobial activity, hemocompatibility, and biocompatibility. Moreover, IMSC enabled complete healing of S. aureus-infected wound in Sprague-Dawley rats within 15 days of application, thus demonstrating that IMSC could reduce wound inflammation and remarkably accelerate wound healing owing to its efficient antibacterial activity and ability to promote collagen deposition in and around the wound area. Therefore, this study provides a promising and potential therapeutic strategy for infected wound healing by synthesizing a water-soluble and broad-spectrum antimicrobial material exhibiting good biocompatibility.

Protective Effect of 20(S)-Protopanaxadiol on D-Gal-Induced Cognitively Impaired Mice Based on Its Target Protein Brain-type Creatine Kinase.

Ginseng is an important medicinal herb consumed as dietary supplements. Ginsenosides and their metabolites have been reported to enhance cognitive performance, but their underlying mechanisms remain unclear. Brain-type creatine kinase (CK-BB) was previously screened out as one of the potential targets in brain tissues. In vitro, the strongest direct interaction between 20(S)-protopanaxadiol (PPD), a ginsenoside metabolite, and CK-BB was detected using biolayer interferometry (BLI). Drug affinity responsive target stability, cellular thermal shift assay, BLI, and isothermal titration calorimetry were subsequently used, and the binding of PPD to CK-BB was verified. The binding sites of the CK-BB/PPD complex were clarified by molecular docking and site-directed mutagenesis. Enzyme activity assay showed that the binding of PPD to CK-BB in vitro enhanced its activity. In vivo, PPD increased CK-BB activity in D-gal-induced mice. PPD also improved the D-gal-induced cognitive deficits and ameliorated alterations in oxidative stress and hippocampal synaptic plasticity. Therefore, the integration of PPD with its target protein CK-BB may promote CK-BB activity, thereby ameliorating hippocampal synaptic plasticity and cognitive deficits in D-gal-treated mice.

miR-301a Deficiency Attenuates the Macrophage Migration and Phagocytosis through YY1/CXCR4 Pathway.

(1) Background: the miR-301a is well known involving the proliferation and migration of tumor cells. However, the role of miR-301a in the migration and phagocytosis of macrophages is still unclear. (2) Methods: sciatic nerve injury, liver injury models, as well as primary macrophage cultures were prepared from the miR-301a knockout (KO) and wild type (WT) mice to assess the macrophage's migration and phagocytosis capabilities. Targetscan database analysis, Western blotting, siRNA transfection, and CXCR4 inhibition or activation were performed to reveal miR301a's potential mechanism. (3) Results: the macrophage's migration and phagocytosis were significantly attenuated by the miR-301a KO both in vivo and in vitro. MiR-301a can target Yin-Yang 1 (YY1), and miR-301a KO resulted in YY1 up-regulation and CXCR4 (YY1's down-stream molecule) down-regulation. siYY1 increased the expression of CXCR4 and enhanced migration and phagocytosis in KO macrophages. Meanwhile, a CXCR4 inhibitor or agonist could attenuate or accelerate, respectively, the macrophage migration and phagocytosis. (4) Conclusions: current findings indicated that miR-301a plays important roles in a macrophage's capabilities of migration and phagocytosis through the YY1/CXCR4 pathway. Hence, miR-301a might be a promising therapeutic candidate for inflammatory diseases by adjusting macrophage bio-functions.

Complete mitogenome and phylogenetic analysis of the tropical rocky shore crab Grapsus albolineatus (Lamarck, 1818) (Crustacea: Grapsoidea).

In this study, the complete mitogenome of Grapsus albolineatus (Lamarck, 1818) (Crustacea: Grapsoidea) was sequenced. The mitogenome of G. albolineatus was a circular molecule with 15,578 bp length. Its nucleotide composition was 26.81% A, 16.37% G, 34.51% T, and 22.31% C. It comprised 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA), and two ribosomal RNA (rRNA). All PCGs were initiated by ATN codons, except for the atp8 and nad1 genes. Ten PCGs used a common stop codon of TAA or TAG, and the other three ended with a truncated stop codon (a single stop nucleotide T). Phylogenetic analysis revealed that G. albolineatus was closely related to species from the genera Pachygrapsus and Metopograpsus.

Tumour inhibitory activity on pancreatic cancer by bispecific nanobody targeting PD-L1 and CXCR4.

BACKGROUND: Antibodies and derivative drugs targeting immune checkpoints have been approved for the treatment of several malignancies, but there are fewer responses in patients with pancreatic cancer. Here, we designed a nanobody molecule with bi-targeting on PD-L1 and CXCR4, as both targets are overexpressed in many cancer cells and play important roles in tumorigenesis. We characterized the biochemical and anti-tumour activities of the bispecific nanobodies in vitro and in vivo. METHODS: A nanobody molecule was designed and constructed. The nanobody sequences targeting PD-L1 and CXCR4 were linked by the (G4S)3 flexible peptide to construct the anti-PD-L1/CXCR4 bispecific nanobody. The bispecific nanobody was expressed in E. coli cells and purified by affinity chromatography. The purified nanobody was biochemically characterized by mass spectrometry, Western blotting and flow cytometry to confirm the molecule and its association with both PD-L1 and CXCR4. The biological function of the nanobody and its anti-tumour effects were examined by an in vitro tumour cell-killing assay and in vivo tumour inhibition in mouse xenograft models. RESULTS: A novel anti-PD-L1/CXCR4 bispecific nanobody was designed, constructed and characterized. The molecule specifically bound to two targets on the surface of human cancer cells and inhibited CXCL12-induced Jurkat cell migration. The bispecific nanobody increased the level of IFN-γ secreted by T-cell activation. The cytotoxicity of human peripheral blood mononuclear cells (hPBMCs) against pancreatic cancer cells was enhanced by the molecule in combination with IL-2. In a human pancreatic cancer xenograft model, the anti-PD-L1/CXCR4 nanobody markedly inhibited tumour growth and was superior to the combo-treatment by anti-PD-L1 nanobody and anti-CXCR4 nanobody or treatment with atezolizumab as a positive control. Immunofluorescence and immunohistochemical staining of xenograft tumours showed that the anti-tumour effects were associated with the inhibition of angiogenesis and the infiltration of immune cells. CONCLUSION: These results clearly revealed that the anti-PD-L1/CXCR4 bispecific nanobody exerted anti-tumour efficacy in vitro and inhibited tumour growth in vivo. This agent can be further developed as a therapeutic reagent to treat human pancreatic cancer by simultaneously blocking two critical targets.

A possible mechanism to the antidepressant-like effects of 20 (S)-protopanaxadiol based on its target protein 14-3-3 ζ.

Background: Ginsenosides and their metabolites have antidepressant-like effects, but the underlying mechanisms remain unclear. We previously identified 14-3-3 ζ as one of the target proteins of 20 (S)-protopanaxadiol (PPD), a fully deglycosylated ginsenoside metabolite. Methods: Corticosterone (CORT) was administered repeatedly to induce the depression model, and PPD was given concurrently. The tail suspension test (TST) and the forced swimming test (FST) were used for behavioral evaluation. All mice were sacrificed. Golgi-cox staining, GSK 3ß activity assay, and Western blot analysis were performed. In vitro, the kinetic binding analysis with the Biolayer Interferometry (BLI) was used to determine the molecular interactions. Results: TST and FST both revealed that PPD reversed CORT-induced behavioral deficits. PPD also ameliorated the CORT-induced expression alterations of hippocampal Ser9 phosphorylated glycogen synthase kinase 3ß (p-Ser9 GSK 3ß), Ser133 phosphorylated cAMP response element-binding protein (p-Ser133 CREB), and brain-derived neurotrophic factor (BDNF). Moreover, PPD attenuated the CORT-induced increase in GSK 3ß activity and decrease in dendritic spine density in the hippocampus. In vitro, 14-3-3 ζ protein specifically bound to p-Ser9 GSK 3ß polypeptide. PPD promoted the binding and subsequently decreased GSK 3ß activity. Conclusion: These findings demonstrated the antidepressant-like effects of PPD on the CORT-induced mouse depression model and indicated a possible target-based mechanism. The combination of PPD with the 14-3-3 ζ protein may promote the binding of 14-3-3 ζ to p-GSK 3ß (Ser9) and enhance the inhibition of Ser9 phosphorylation on GSK 3ß kinase activity, thereby activating the plasticity-related CREB-BDNF signaling pathway.

Periplaneta americana Extract Pretreatment Alleviates Oxidative Stress and Inflammation and Increases the Abundance of Gut Akkermansia muciniphila in Diquat-Induced Mice.

Studies have shown that Periplaneta americana extract (PAE) has good therapeutic effects in inflammatory disorders such as ulcerative colitis, alcoholic hepatitis, and gastric ulcers. However, whether or not PAE has good pre-protective effects has not been widely and deeply studied. In this study, we investigated the effects of PAE pretreatment for 7 days on oxidative stress and inflammation triggered by oxidative stress by using diquat-induced C57BL/6 mice as an oxidative stress model. The results showed that PAE pretreatment could significantly reduce oxidative stress in the intestine and liver by reducing the production of MDA, and improved antioxidant systems (SOD, CAT, GSH, and T-AOC). By primarily activating the anti-inflammatory cytokine (IL-10) mediated JAK1/STAT3 signaling pathway, PAE also effectively reduced oxidative stress-induced liver inflammation while also reducing liver damage, as evidenced by the reductions in serum AST and ALT. PAE pretreatment also had a significant effect on maintaining the intestinal barrier function, which was manifested by inhibiting a decrease in the expression of tight junction proteins (ZO-1 and occludin), and reducing the increased intestinal permeability (serum DAO and D-Lac) caused by diquat. The 16S rRNA sequencing analysis revealed that diquat decreased the gut microbiota diversity index and increased the abundance of pathogenic bacteria (e.g., Allobaculum, Providencia and Escherichia-Shigella), while PAE pretreatment responded to diquat-induced damage by greatly increasing the abundance of Akkermansia muciniphila. These findings elucidate potential pre-protective mechanisms of PAE in alleviating oxidative stress and inflammation, while providing a direction for the treatment of metabolic diseases by utilizing PAE to enhance the abundance of gut A. muciniphila.

A Simple Clinical Application for Locating the Anterior Ethmoidal Artery Using the Anterior Ethmoidal Foramen and the Anterior Nasal Spine.

PURPOSE: The anatomy and variations of the anterior ethmoidal artery (AEA) are clinically relevant. The anterior ethmoidal foramen (AEF) can be used to locate the initial site of the AEA, and the anterior nasal spine (ANS) is a constant bony marker in the anterior nasal atrium. However, there is no relevant research on AEF and ANS targeting the AEA. Hence, this study aimed to accurately locate the AEA through AEF and ANS using computed tomography. METHODS: A total of 120 (240 sides) sinus computed tomography scans were retrospectively selected and studied. The AEA was classified into grades I, Ⅱ, and Ⅲ group based on the relationship between the AEA and the skull base. The distance between AEF and ANS and the angle between AEF-ANS and the axial plane were measured. RESULTS: The average distance from AEF to ANS was 58.26±3.64 mm, and the corresponding angle was 60.05±5.93 degrees. The AEF-ANS distances and angles were negatively correlated with age. Moreover, the distances from AEF to ANS were significantly increased in the grade Ⅲ group compared with the grade Ⅱ group. CONCLUSION: The measurements obtained in this study add anatomic knowledge that can serve as a better intraoperative localization method of the AEA, which can help surgeons avoid relative complications during endoscopic sinus surgery.

Unilateral optic neuritis after vaccination against the coronavirus disease: two case reports.

BACKGROUND: Due to the emergence of COVID-19, many countries have started mass immunization programs. To date, no cases of optic neuritis following COVID-19 vaccination have been reported in the literature. CASE PRESENTATION: Objective: Here, we report 2 cases of unilateral optic neuritis after vaccination against COVID-19 using the Sinopharm vaccine (Sinopharm Group Co. Ltd, China). DESIGN: The clinical history, examination, and test findings of two individuals with unilateral optic neuritis associated with the timing of COVID-19 vaccination were described and further analyzed. SETTING: Two patients developed optic neuritis after receiving the COVID-19 vaccine. One patient developed optic neuritis 6 weeks after the first dose and 3 weeks after the second dose. The other patient developed optic neuritis 3 weeks after the first dose. PARTICIPANTS: Two female patients, aged 21 and 39 years. RESULT: The patients were successfully treated with intravenous methylprednisolone pulse therapy. Both patients had typical manifestations of optic neuritis and their visual acuity recovered fully after treatment. The second of these patients was positive for anti-myelin oligodendrocyte glycoprotein antibodies (MOG). CONCLUSION: Optic neuritis is a potential adverse effect after vaccination against the coronavirus disease (COVID-19).

Correlation between Serum Cystatin C Level and Retinal Blood Flow in Patients with Essential Hypertension.

INTRODUCTION: Hypertension is known to impact the structure and function of the ocular vascular system and is an established risk factor for many eye diseases. This study aimed to detect the blood flow in the optic disc and macula in patients with essential hypertension and to analyze its correlation with serum cystatin C (Cys-C) levels. METHODS: This single center, cross-sectional study included 100 patients with primary hypertension without hypertensive retinopathy, who were divided into an experimental group (50 cases, 50 eyes) with elevated serum Cys-C levels and a control group (50 cases, 50 eyes) with normal serum Cys-C. The optic disc and macular vessel density (VD) and vascular perfusion density (PD) were assessed using optical coherence tomography angiography. Data such as the area, perimeter, and circularity of the foveal avascular zone (FAZ) were analyzed. RESULTS: There were statistically significant between-group differences in the VD and PD of the optic disc (p < 0.05). Spearman correlation analysis of related indicators revealed that serum Cys-C was positively correlated with creatinine, uric acid, and FAZ circularity (p < 0.05). Furthermore, serum Cys-C was negatively correlated with optic disc VD and PD in some regions (p < 0.05). CONCLUSION: In patients with essential hypertension, serum Cys-C is negatively correlated with VD and PD in the inner layer of the optic disc (zone 10).

Overexpression of GSTP1 promotes colorectal cancer cell proliferation, invasion and metastasis by upregulating STAT3.

BACKGROUND: The abnormal expression of glutathione S-transferase P1 (GSTP1) is associated with the progression of several tumor types. However, its role and molecular mechanism in the progression of colorectal cancer (CRC) are largely unknown. OBJECTIVES: To examine the effect of GSTP1 in CRC and determine its possible mechanisms. MATERIAL AND METHODS: In the present study, immunohistochemistry (IHC) and the quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis were used to detect the expression of GSTP1 and signal transducer and activator of transcription 3 (STAT3) in CRC tissues. Western blotting was applied to detect the expression of GSTP1 and proteins of the Janus kinase (JAK)-STAT3 pathway in different CRC cell lines. The interaction and co-localization of GSTP1 and STAT3 were detected using co-immunoprecipitation (co-IP) and immunofluorescence (IF) in the SW620 cell line. RESULTS: A positive correlation was identified between the expression of GSTP1 and STAT3 in human CRC tissues. The overexpression of GSTP1 promoted the proliferation, invasion and metastasis of CRC cells by upregulating STAT3. The GSTP1 and STAT3 can directly bind to and regulate each other. The interaction between them is regulated by the upstream gene called F-box only protein 8 (FBX8). CONCLUSIONS: The present study demonstrated that GSTP1 could enhance the expression of STAT3 to promote the proliferation, invasion and metastasis of CRC cells, which provides a potential therapeutic target for the clinical treatment of CRC.

SIRT6 Negatively Regulates Schwann Cells Dedifferentiation via Targeting c-Jun During Wallerian Degeneration After Peripheral Nerve Injury.

Silent information regulator 6 (SIRT6) is a mammalian homolog of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin family. Previous studies have been reported a pro-regenerative role of SIRT6 in central nervous system injury. However, the role of SIRT6 in peripheral nerve injury is still unknown. Given the importance and necessity of Schwann cell dedifferentiation response to peripheral nerve injury, we aim to investigate the molecular mechanism of SIRT6 steering Schwann cell dedifferentiation during Wallerian degeneration in injured peripheral nerve. Herein, we first examined the expression pattern of SIRT6 after peripheral nerve injury. Using the explants of sciatic nerve, an ex vivo model of nerve degeneration, we provided evidences indicating that SIRT6 inhibitor accelerates Schwann cell dedifferentiation as well as axonal and myelin degeneration, while SIRT6 activator attenuates this process. Moreover, in an in vitro Schwann cell dedifferentiation model, we found SIRT6 inhibitor promotes Schwann cell dedifferentiation through upregulating the expression of c-Jun. In addition, downregulation of c-Jun reverse the effects of SIRT6 inhibition on the Schwann cells dedifferentiation and axonal and myelin degeneration. In summary, we first described SIRT6 acts as a negative regulator for Schwann cells dedifferentiation during Wallerian degeneration and c-Jun worked as a direct downstream partner of SIRT6 in injured peripheral nerve.

Migratory fishbones in the pharynx: A report of two cases.

The possibility of fishbone migration into the surrounding tissues, especially in cases where it cannot be identified on routine inspection. Early diagnosis of migratory fishbone and therapeutic management are essential for optimal patient survival.

Dietary Betaine Addition Promotes Hepatic Cholesterol Synthesis, Bile Acid Conversion, and Export in Rats.

It is widely reported how betaine addition regulates lipid metabolism but how betaine affects cholesterol metabolism is still unknown. This study aimed to investigate the role of betaine in hepatic cholesterol metabolism of Sprague-Dawley rats. Rats were randomly allocated to four groups and fed with a basal diet or a high-fat diet with or without 1% betaine. The experiment lasted 28 days. The results showed that dietary betaine supplementation reduced the feed intake of rats with final weight unchanged. Serum low-density-lipoprotein cholesterol was increased with the high-fat diet. The high-fat diet promoted cholesterol synthesis and excretion by enhancing the HMG-CoA reductase and ABCG5/G8, respectively, which lead to a balance of hepatic cholesterol. Rats in betaine groups showed a higher level of hepatic total cholesterol. Dietary betaine addition enhanced cholesterol synthesis as well as conversion of bile acid from cholesterol by increasing the levels of HMGCR and CYP7A1. The high-fat diet decreased the level of bile salt export pump, while dietary betaine addition inhibited this decrease and promoted bile acid efflux and increased total bile acid levels in the intestine. In summary, dietary betaine addition promoted hepatic cholesterol metabolism, including cholesterol synthesis, conversion of bile acids, and bile acid export.

The association between the supply and utilization of community-based primary care and child health in a context of hospital-oriented healthcare system in urban districts of Guangdong, China: a panel dataset, 2014-2016.

BACKGROUND: Since 2009, the Chinese government has been reforming the healthcare system and has committed to reinforcing increased use of primary care. To date, however, the Chinese healthcare system is still heavily reliant on hospital-based specialty care. Studies consistently show an association between primary care and improved health outcomes, and the same association is also found among the disadvantaged population. Due to the "hukou" system, interprovincial migrants in the urban districts are put in a weak position and become the disadvantaged. Therefore, the aim of this study is to investigate whether greater supply and utilization of primary care was associated with reduced child mortality among the entire population and the interprovincial migrants in urban districts of Guangdong province, China. METHODS: An ecological study was conducted using a 3-year panel data with repeated measurements within urban districts in Guangdong province from 2014 to 2016, with 178 observations in total. Multilevel linear mixed effects models were applied to explore the associations. RESULTS: Higher visit proportion to primary care was associated with reductions in the infant mortality rate and the under-five mortality rate in both the entire population and the interprovincial migrants (p < 0.05) in the full models. The association between visit proportion to primary care and reduced neonatal mortality rate was significant among the entire population (p < 0.05) while it was insignificant among the interprovincial migrants (p > 0.05). CONCLUSIONS: Our ecological study based in urban districts of Guangdong province found consistent associations between higher visit proportion to primary care and improvements in child health among the entire population and the interprovincial migrants, suggesting that China should continue to strengthen and develop the primary care system. The findings from China adds to the previously reported evidence on the association between primary care and improved health, especially that of the disadvantaged.