Supramolecular Polymer-Nanomedicine Hydrogel Loaded with Tumor Associated Macrophage-Reprogramming polyTLR7/8a Nanoregulator for Enhanced Anti-Angiogenesis Therapy of Orthotopic Hepatocellular Carcinoma.

Anti-angiogenic therapies targeting inhibition of vascular endothelial growth factor (VEGF) pathway show clinical benefit in hypervascular hepatocellular carcinoma (HCC) tumors. However, HCC expresses massive pro-angiogenic factors in the tumor microenvironment (TME) in response to anti-angiogenic therapy, recruiting tumor-associated macrophages (TAMs), leading to revascularization and tumor progression. To regulate cell types in TME and promote the therapeutic efficiency of anti-angiogenic therapy, a supramolecular hydrogel drug delivery system (PLDX-PMI) co-assembled by anti-angiogenic nanomedicines (PCN-Len nanoparticles (NPs)) and oxidized dextran (DX), and loaded with TAMs-reprogramming polyTLR7/8a nanoregulators (p(Man-IMDQ) NRs) is developed for orthotopic liver cancer therapy. PCN-Len NPs target tyrosine kinases of vascular endothelial cells and blocked VEGFR signaling pathway. p(Man-IMDQ) NRs repolarize pro-angiogenic M2-type TAMs into anti-angiogenic M1-type TAMs via mannose-binding receptors, reducing the secretion of VEGF, which further compromised the migration and proliferation of vascular endothelial cells. On highly malignant orthotopic liver cancer Hepa1-6 model, it is found that a single administration of the hydrogel formulation significantly decreases tumor microvessel density, promotes tumor vascular network maturation, and reduces M2-subtype TAMs, thereby effectively inhibiting tumor progression. Collectively, findings in this work highlight the great significance of TAMs reprogramming in enhancing anti-angiogenesis treatment for orthotopic HCC, and provides an advanced hydrogel delivery system-based synergistic approach for tumor therapy.

A Review on Characteristics of Experimental Research on Acupuncture Treatment for Alzheimer's Disease: Study Design.

Background: This review aims to systematically summarize and analyze recent high-quality animal research results about the use of acupuncture in Alzheimer's disease (AD) patients. This information will be useful in providing a reference for future experimental research and an experimental basis for the clinical use of acupuncture in the treatment of AD. Methods: We utilized and referenced various electronic libraries from their inception to November 2021. Relevant information was reviewed and information such as the journal names, publication records, animal model selections and preparations, intervention measures, acupoint selections, detection methods, and detection indicators was extracted. Results. A total of 75 eligible studies were selected for additional review. Male SAMP8 mice, APP/PS1 double transgenic mice, Sprague-Dawley (SD) rats, and Wistar rats were the four commonly used animal strains in the experiments. The animals were categorized as transgenic and surgical mouse models. Experimental interventions included manual acupuncture (MA), Electro-acupuncture (EA), Moxibustion, and EA combined with Moxibustion. A retention time of 20 min was the optimal timing for experimental studies, with 14 sessions chosen as the most common treatment time. EA was the most prescribed acupuncture treatment type with continuous wave, 2 Hz frequency, and 1 mA electric current selected as frequently used parameters. A total of 78 acupoint prescriptions were analyzed involving 21 acupoints. The top 3 combinations of common acupoints were GV20 ⟶ EX-HN3, GV20 ⟶ BL23, and GV20 ⟶ GV26. A total of 39 articles had positive drug control groups, sham acupuncture, and/or nonacupoint control groups. Furthermore, 10 types of behavioral tests, 29 detection methods, 178 evaluation indicators, and 18 tissue samples were included in the analysis. Conclusions: By collating these high-quality research studies systematically and comprehensively, acupuncture was found to be a viable and effective treatment in AD animal models. In addition, when designing experiments, researchers could refer to the detailed data provided here to make better schemes and maybe conduct more investigations in unresearched areas.

[Effect of electroacupuncture on gastrointestinal motility in rats with slow transit constipation based on GDNF methylation modification].

OBJECTIVE: To observe the effect of electroacupuncture (EA) of "Tianshu"(ST25) and "Dachangshu"(BL25) on the intestinal transit function， expression level of glial cell-derived neurotrophic factor (GDNF) and methylation level of GDNF gene promoter region in colon tissue of rats with slow transit constipation (STC)， so as to explore its mechanisms underlying improvement of STC. METHODS: Male Sprague-Dawley (SD) rats were randomized into control， saline， model and EA groups (n=16 in each group). The STC model was replicated by gavage of compound diphenoxylate suspension (10 mL· kg-1· d-1) for 28 days. Rats of the saline group received the same dose of normal saline via gavage. EA (2 Hz/15 Hz， 0.1-1 mA) was applied to bila-teral ST25 and BL25 for 15 min， once daily for 14 days. The intestinal transmission function (the intestinal propulsion rate) was assessed by recording the first black grain stool discharge time and the number and weight of the discharged stool grains in 30 min after gavage of the activated carbon suspension (1 mL/100 g， 150 g/L). The score of fecal trait and the weight of stool within 24 h were recorded. The ultrastructural changes of Cajal interstitial cells in the colon tissue were observed by transmission electron microscope. The expression levels of GDNF protein and mRNA in the colon tissue were detected by using Western blot and real-time fluorescent quantitative PCR， separately， and changes of methylation level in the promoter region of GDNF gene detected by using Bisulfite sequencing method. RESULTS: Compared with the control group， the time of the 1st black stool grain discharging was obviously prolonged， and the number and weight of the discharged black stool grains were significantly decreased in the mo-del group (P<0.05)， suggesting a success of STC. The weight and trait score of stool in 24 h， intestinal propulsive rate， and the expression levels of GDNF protein and mRNA were significantly lower in the model group than in the control group (P<0.01， P<0.05). After EA， the weight and trait score of stool within 24 h， intestinal propulsive rate，and the expression levels of GDNF protein and mRNA were significantly increased in the EA group in contrast to the model group (P<0.01，P<0.05). The total CpGs methylation level of GDNF gene in colon tissue was considerably higher in the model group than in the control group (P<0.05)， and markedly lower in the EA group than in the model group (P<0.05). No significant differences were found between the control and saline groups in all the above-mentioned indexes (P>0.05). CONCLUSION: EA of back-shu and front-mu acupoints can effectively improve symptoms of constipation and intestinal transport function in STC rats， which may be related to its function in up-regulating the expression of GDNF and down-regulating the methylation level in the promoter region of GDNF gene in colon tissue.

An extremely rare case of Rosai-Dorfman disease in the spleen.

BACKGROUND: Rosai-Dorfman disease (RDD) is a rare, multisystemic histiocytic disorder, and commonly manifesting as lymphadenopathy in the young male. Abdominal manifestations of RDD are extremely rare. CASE PRESENTATION: In August 2018, a 42-year-old man underwent an abdominal ultrasonography examination due to his weight loss of 10 kg in only three months and found a giant solid tumor was found in his spleen. Then, he was admitted to our hospital and diagnosed as a splenic mass via abdominal enhanced CT and MRI. Laparoscopic splenectomy was administrated within six days of admission due to the clear surgical indications. The pathogenesis of RDD remained poorly understood and the disease should be diagnosed based on histopathology and immunohistochemistry (IHC). The mutations in ATM and NFKBIA were observed using next generation sequencing (NGS). CONCLUSION: We reported a case of splenic involvement of RDD with NGS genetic testing, indicating the difficulty of making a diagnosis before surgery. This extremely rare case offers new references for the understanding of abdominal viscera RDD.

Effects of dietary methionine on growth performance, muscle nutritive deposition, muscle fibre growth and type I collagen synthesis of on-growing grass carp (Ctenopharyngodon idella).

In the current research, a 60-d experiment was conducted with the purpose of exploring the impacts of methionine (Met) on growth performance, muscle nutritive deposition, muscle fibre growth and type I collagen synthesis as well as the related signalling pathway. Six diets (iso-nitrogenous) differing in Met concentrations (2·54, 4·85, 7·43, 10·12, 12·40 and 15·11 g/kg diets) were fed to 540 grass carp (178·47 (SD 0·36) g). Results showed (P < 0·05) that compared with Met deficiency, optimal level of dietary Met (1) increased feed intake, feed efficiency, specific growth rate and percentage weight gain (PWG); (2) increased fish muscle protein, lipid and free amino acid contents and improved fish muscle fatty acid profile as well as increased protein content in part associated with the target of rapamycin complex 1 (TORC1)/S6K1 signalling pathway; (3) increased the frequency distribution of muscle fibre with >50 µm of diameter; (4) increased type I collagen synthesis partly related to the transforming growth factor-ß1/Smads and CK2/TORC1 signalling pathways. In conclusion, dietary Met improved muscle growth, which might be due to the regulation of muscle nutritive deposition, muscle fibre growth and type I collagen synthesis-related signal molecules. Finally, according to PWG and muscle collagen content, the Met requirements for on-growing grass carp (178-626 g) were estimated to be 9·56 g/kg diet (33·26 g/kg protein of diet) and 9·28 g/kg diet (32·29 g/kg of dietary protein), respectively.

Spatial-temporal characteristics and determinants of PM2.5 in the Bohai Rim Urban Agglomeration.

Ambient particulate matter (PM) pollution of China has become a global concern and has great impact on air quality and human health. This paper adopts the PM2.5 concentration data obtained from 241 newly located observation points in the Bohai Rim Urban Agglomeration (BRUA), as well as economic, urban and industrial working population data in the study area, revealing the spatio-temporal distribution of PM2.5 and its determinants with the help of a spatial data model. The results indicate that: 1) The BRUA was the core area of PM2.5 pollution in China in 2014, the average PM2.5 concentration of which reached 74 µg/m(3), which is 13 µg/m(3) higher than the country average (61 µg/m(3)); 2) The PM2.5 concentration distribution had a characteristic of high in winter and autumn but low in spring and summer, presenting a U-shaped monthly profile and a U-impulse type daily profile; 3) The urban PM2.5 concentrations showed obvious spatial variation and agglomeration. The highest hot-spot was observed in spring, while the lowest was in summer. High concentration cities were mainly located in southern Hebei and western Shandong, and low concentration cities were in the coastal area around the Bohai Sea and the mountainous areas in northern Hebei. High hot-spot areas demonstrated an M-shaped change, with two cycles of advance and retreat from west to east. 4) The Geographically weighted regression (GWR) model shows that the GDP per capita, urbanization rate and construction of the cities were closely related to PM2.5 concentrations in the BRUA.