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Background: Obesity is a global epidemic, and the low-grade chronic inflammation of adipose tissue in obese individuals can lead to insulin resistance and type 2 diabetes. Adipose tissue macrophages (ATMs) are the main source of pro-inflammatory cytokines in adipose tissue, making them an important target for therapy. While branched-chain amino acids (BCAA) have been strongly linked to obesity and type 2 diabetes in humans, the relationship between BCAA catabolism and adipose tissue inflammation is unclear. This study aims to investigate whether disrupted BCAA catabolism influences the function of adipose tissue macrophages and the secretion of pro-inflammatory cytokines in adipose tissue, and to determine the underlying mechanism. This research will help us better understand the role of BCAA catabolism in adipose tissue inflammation, obesity, and type 2 diabetes. Methods: In vivo, we examined whether the BCAA catabolism in ATMs was altered in high-fat diet-induced obesity mice, and if BCAA supplementation would influence obesity, glucose tolerance, insulin sensitivity, adipose tissue inflammation and ATMs polarization in mice. In vitro, we isolated ATMs from standard chow and high BCAA-fed group mice, using RNA-sequencing to investigate the potential molecular pathway regulated by BCAA accumulation. Finally, we performed targeted gene silence experiment and used immunoblotting assays to verify our findings. Results: We found that BCAA catabolic enzymes in ATMs were influenced by high-fat diet induced obesity mice, which caused the accumulation of both BCAA and its downstream BCKA. BCAA supplementation will cause obesity and insulin resistance compared to standard chow (STC) group. And high BCAA diet will induce pro-inflammatory cytokines including Interlukin-1beta (IL-1β), Tumor Necrosis Factor alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) secretion in adipose tissue as well as promoting ATMs M1 polarization (pro-inflammatory phenotype). Transcriptomic analysis revealed that a high BCAA diet would activate IFNGR1/JAK1/STAT1 pathway, and IFNGR1 specific silence can abolish the effect of BCAA supplementation-induced inflammation and ATMs M1 polarization. Conclusions: The obesity mice model reveals the catabolism of BCAA was disrupted which will cause the accumulation of BCAA, and high-level BCAA will promote ATMs M1 polarization and increase the pro-inflammatory cytokines in adipose tissue which will cause the insulin resistance in further. Therefore, reducing the circulating level of BCAA can be a therapeutic strategy in obesity and insulin resistance patients. [ABSTRACT FROM AUTHOR]

Near‐infrared (NIR) core–shell CdSeTe/CdS quantum dots (QDs) modified with l‐cysteine were synthesized in aqueous solution. The QDs had a special NIR‐emitting spectrum, high fluorescence stability and low cytotoxicity. In addition, they exhibited an obvious fluorescence quenching when Cu2+ was present. An NIR nanosensor was prepared for rapidly, sensitively, and selectively determining Cu2+ in solution quantitatively and monitoring the changes in Cu2+ in cells with fluorescence imaging in a semiquantitative way. The linear relationship between the relative fluorescence intensity (F0/F) and the concentration of Cu2+ from 5.12 × 10−8 M to 2.56 × 10−5 M in solution was observed using an NIR fluorescence spectrophotometer with R2 equal to 0.9958. Moreover, in the experiment with the fluorescence microscope, F0/F versus the concentration of Cu2+ from 5.00 × 10−8 M to 7.68 × 10−6 M also showed a good linear relationship with R2 equal to 0.9817. Practical water sample ion detecting experiments had good accuracy and recovery rates. Cell experiments showed that the NIR imaging intensity of cells was inversely proportional to the concentration of copper ions, therefore NIR QDs have great potential for detection of metal ions in solution and in cells. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) in newborns and adults is a disease that can lead to right heart failure and result in a shorter lifespan. PH was induced by maintaining pregnant rats in a hypoxic chamber for 4 h twice a day, from days 7–21 of pregnancy. Hypoxia was confirmed by a decrease in the partial pressure of oxygen (PaO2) and the oxygen saturation (SaO2) of arterial blood in the aorta. The body weight of newborns from hypoxic rats was ~20% decreased compared with the control newborns of normoxic rats. The vascular wall thickness/vascular diameter values of hypoxia treated pubs were increased compared with that of control newborns 7 days after birth; however, it decreased to similar levels than in the control group after 3 months, and then further decreased to significantly lower levels than in the control group at 6 months after birth. At birth, the lung tissues of newborns from hypoxic rats exhibited an increase in the levels of mRNA and proteins associated with PH such as HIF-1α, HIF-2α, V2R, TGF-β, TNF-α, Ang-2 and α-SMA. At 3 and 6 months after birth, the levels of both V2R mRNA and protein in offspring from hypoxic rats were at least 2-fold higher, whereas the expression of all other factors decreased compared with the control offspring. By contrast, HIF-2α and Ang-2 expression levels were significantly increased in the 6-month-old control offspring from normoxic rats. V2R overexpression in pups induced by hypoxia in maternal rats was sustained until their adulthood. V2R may be a marker for detecting PH. [ABSTRACT FROM AUTHOR]

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that was caused by the Dabie bandavirus (DBV), and it has become a global public health threat. Cytokine storm is considered to be an important pathogenesis of critical SFTS. Tripartite motif-containing 3 (TRIM3), as a member of the TRIM protein family, may contribute to the regulation of the immune and inflammatory responses after viral infection. However, whether TRIM3 plays a major role in the pathogenesis of SFTS has not yet been investigated., Methods: TRIM3 mRNA levels were detected in PBMCs between 29 SFTS patients and 29 healthy controls by qRT-PCR. We established the pathogenic IFNAR -/- SFTS mouse model successfully by inoculating subcutaneously with DBV and testing the expression levels of TRIM3 mRNA and protein by qRT-PCR and immunofluorescence in the livers, spleens, lungs, and kidneys. TRIM3 OE THP-1 cells and peritoneal macrophages extracted from TRIM3 -/- mice were infected with DBV. The effect of TRIM3 on cytokines was detected by qRT-PCR and ELISA. Then we examined Toll-like receptor 3 (TLR3) and protein phosphorylation in the MAPK pathway after DBV infection using Western blot. Flow cytometry was used to verify TLR3 expression on peripheral blood monocytes in SFTS patients. We further explored the interaction between TRIM3 and TLR3 using CO-IP and Western blot., Results: Compared to healthy controls, TRIM3 mRNA expression in PBMCs is decreased in SFTS patients, especially in severe cases. TRIM3 mRNA and protein were synchronously reduced in the livers, spleens, lungs, and kidney tissues of the IFNAR -/- SFTS mice model. In the DBV-infected cell model, TRIM3 overexpression can inhibit the DBV-induced release of IL-1β, IL-6, and TNF-α, the expression of TLR3, and protein phosphorylation in the MAPK pathway, which plays an anti-inflammatory role, while TRIM3 deficiency exacerbates the pro-inflammatory effects. We further found that TRIM3 can promote TLR3 degradation through K48-linked ubiquitination., Conclusion: TRIM3 can inhibit the production of cytokines by regulating the degradation of TLR3 through K48-linked ubiquitination, which can be a therapeutic target for improving the prognosis of SFTS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jin, Dai, Ouyang, Huang, Jiang, Yang, Zhou, Lin, Wang, Wang, Sun, Lu, Liu, Hu, Zhu, Zhu and Li.)

DNA methyltransferase (DNMT) 1, DNMT3A and DNMT3B, which affect promoter CpG methylation status, play a significant role in cancer development. Little is known regarding the clinical significance of DNMT expression in gastric cancers. Expression of DNMT1, DNMT3A and DNMT3B in paraffin sections from 54 gastric cancer patients were examined using immunohistochemistry, and their associations with the corresponding clinicopathological parameters were analyzed using the Chi-square test. Overexpression of DNMT1, DNMT3A and DNMT3B in gastric cancer tissues was observed in 35 (64.8%), 38 (70.4%) and 28 (51.9%) of 54 cases, respectively. DNMT1 was localized in the cytoplasm and nuclei of the cancer cells, whereas DNMT3A and DNMT3B were detected only in the cytoplasm. DNMT1 expression was more frequently found in tumors localizing at the cardia or body of the stomach (P=0.048). DNMT3A was associated with TNM stage (P=0.001) and lymph node metastasis (P=0.002). No significant correlation was found between DNMT3B expression and clinicopathological data (P>0.05). The co-expression of DNMT1 and DNMT3A, and of DNMT3A and DNMT3B was more frequently found in tumors localizing at the cardia or body of the stomach (P=0.005 and P=0.009 respectively). Moreover, co-expression of DNMT1 and DNMT3A was significantly associated with lymph node metastasis (P=0.035). DNMTs are overexpressed in gastric cancer, and may play a significant role in the development of aberrant promoter methylation during tumorigenesis.

HINT1, a member of the evolutionary highly conserved HIT protein superfamily, is ubiquitously expressed in diverse species including mammalian tissues. Accumulating evidence shows that HINT1 is a haploinsufficient tumor suppressor. In the present study, we explored possible correlations between the expression level of HINT1 and clinicopathological features in tissues from gastric cancer (GC) patients. Decreased expression of HINT1 detected by qPCR and Western blotting in tumor tissues was found in 58.82 and 39.2% of the patients, respectively. Significantly reduced expression of HINT1 was found in poorly differentiated tumor tissues (p = 0.027). Environmental interference (either H. pylori or EBV infection) (p = 0.005) was associated with the expression of HINT1. Moreover, compared with the GC tissues, the level of Hint1 detected by qPCR was significantly higher in the adjacent non-cancerous tissues (p = 0.03). We treated AGS cells, a GC cell line with low expression level of Hint1, with 5 and 10 µmol/l 5-Aza-dC for 72 h and found that HINT1 could be induced by 5-Aza-dC in a dose-dependent manner. These results suggested that Hint1 expression was lower in GC tissues and some etiological factors, such as H. pylori/EB infection or promoter hypermethylation may play a role in gastric tumorigenesis.

A large number of randomized controlled trials involving chemotherapy in the management of advanced colorectal cancer were conducted. 5-FU/LV in combination with irinotecan (IRI) or oxaliplatin (OXA) was used. The aim of the meta-analysis was to compare and evaluate the effectiveness and safety of the two therapeutic approaches for patients with advanced colorectal cancer. A literature search, study selection and assessment, data collection, and analysis were undertaken by two reviewers according to the Cochrane Handbook for Systematic Reviews of Interventions. Randomized controlled trials (RCTs) or quasi-RCTs comparing IRI versus OXA, in combination with 5-FU/LV in the treatment of advanced colorectal cancer were performed. Seven studies involving 2,107 patients met the inclusion criteria. The OXA + 5-FU/LV regimen showed a significant increase in survival by lower hazard ratios (HR) [HR 1.28; 95% CI (1.13-1.45)] and was associated with lower toxicities. The OXA + 5-FU/LV regimen was superior or equal to the IRI + 5-FU/LV regimen in prolonging time to progression and median survival. The IRI + 5-FU/LV regimen resulted in higher hazard ratios in nausea vomiting/emesis and diarrhea [HR 1.99, 95% CI (1.19-3.31); HR 1.83, 95% CI (1.38-2.44)] and lower hazard ratios in paresthesia, sensory neuropathy, and thrombocytopenia [HR 0.09, 95% CI (0.03-0.23); HR 0.04 95% CI (0.01-0.13); HR 0.19 95% CI (0.05-0.64)] than the OXA + 5-FU/LV regimen. Compared with IRI, OXA is more appropriate for the treatment of advanced colorectal cancer when combined with 5-FU/LV. OXA + 5-FU/LV should be considered as the first-line standard of care for advanced CRC patients.