Regulation of PPAR-γ activity in lipid-laden hepatocytes affects macrophage polarization and inflammation in nonalcoholic fatty liver disease

BACKGROUNDLipid metabolism disorder and inflammatory-immune activation are vital triggers in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Various studies have shown that PPAR-γ exerts potent anti-inflammatory and immunomodulatory properties. However, little is known about the regulation of PPAR-γ activity in modulating cell crosstalk in NAFLD.AIMTo investigate whether the regulation of PPAR-γ activity in lipid-laden hepatocytes affects macrophage polarization and inflammation.METHODSPrimary hepatocytes were isolated from wild-type C57BL6/J mice or hepatocyte-specific PPAR-γ knockout mice and incubated with free fatty acids (FFAs). Macrophages were incubated with conditioned medium (CM) from lipid-laden hepatocytes with or without a PPAR-γ agonist. Wild-type C57BL/6J mice were fed a high-fat (HF) diet and administered rosiglitazone.RESULTSPrimary hepatocytes exhibited significant lipid deposition and increased ROS production after incubation with FFAs. CM from lipid-laden hepatocytes promoted macrophage polarization to the M1 type and activation of the TLR4/NF-κB pathway. A PPAR-γ agonist ameliorated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes and subsequently prevented M1 macrophage polarization. Hepatocyte-specific PPAR-γ deficiency aggravated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes, which further promoted M1 macrophage polarization. Rosiglitazone administration improved oxidative stress and NLRP3 inflammasome activation in HF diet-induced NAFLD mice in vivo.CONCLUSIONUpregulation of PPAR-γ activity in hepatocytes alleviated NAFLD by modulating the crosstalk between hepatocytes and macrophages via the reactive oxygen species-NLRP3-IL-1β pathway.     

Preparation and study of the flame retardant properties of C60/PMMA microspheres

In this paper, highly flame retardant C₆₀/PMMA composites were prepared using an in situ polymerization method by introducing fullerene (C₆₀) into polymethyl methacrylate (PMMA) to improve its combustion characteristics. The apparent morphologies of PMMA and C₆₀/PMMA microspheres were observed by scanning electron microscopy (SEM), and the structure was characterized by infrared spectroscopy (FT-IR). The thermal stability and flame retardancy were characterized using a synchronous thermal analyzer, a cone calorimeter and an oxygen index tester. The results show that the maximum initial decomposition temperature of C₆₀/PMMA-2 (prepared using C₆₀ with a concentration of 2 mg mL⁻¹) is 234.89 °C, which is about 59.89 °C higher than that of PMMA, and the thermal stability is the best. The limiting oxygen index of the C₆₀/PMMA-2 composite is 21.8, which is 28.2% higher than that of pure PMMA. In addition, the peak heat release rate (PHRR) of C₆₀/PMMA is reduced by 630.4 kW m⁻² when compared with pure PMMA, which means that the flame retardant property is improved. Meanwhile, the mechanical properties of the PMMA are also improved by adding C₆₀.

In this paper, highly flame retardant C₆₀/PMMA composites were prepared using an in situ polymerization method by introducing fullerene (C₆₀) into polymethyl methacrylate (PMMA) to improve its combustion characteristics.     

IL‐27 improves adoptive CD8+ T cells’ antitumor activity via enhancing cell survival and memory T cell differentiation

IL‐27 is an anti‐inflammatory cytokine that triggers enhanced antitumor immunity, particularly cytotoxic T lymphocyte responses. In the present study, we sought to develop IL‐27 into a therapeutic adjutant for adoptive T cell therapy using our well‐established models. We have found that IL‐27 directly improved the survival status and cytotoxicity of adoptive OT‐1 CD8⁺ T cells in vitro and in vivo. Meanwhile, IL‐27 treatment programs memory T cell differentiation in CD8⁺ T cells, characterized by upregulation of genes associated with T cell memory differentiation (T‐bet, Eomes, Blimp1, and Ly6C). Additionally, we engineered the adoptive OT‐1 CD8⁺ T cells to deliver IL‐27. In mice, the established tumors treated with OT‐1 CD8⁺ T‐IL‐27 were completely rejected, which demonstrated that IL‐27 delivered via tumor antigen–specific T cells enhances adoptive T cells’ cancer immunity. To our knowledge, this is the first application of CD8⁺ T cells as a vehicle to deliver IL‐27 to treat tumors. Thus, this study demonstrates IL‐27 is a feasible approach for enhancing CD8⁺ T cells’ antitumor immunity and can be used as a therapeutic adjutant for T cell adoptive transfer to treat cancer.     

Decreased expression of claudin-18.2 in alpha-fetoprotein-producing gastric cancer compared to conventional gastric cancer

BackgroundAlpha-fetoprotein-producing gastric cancer (AFPGC) is a subtype of gastric cancer (GC) with more aggressive biological behavior. As a highly specific tight junction component exclusively present in gastric mucosa and gastric adenocarcinomas, claudin-18.2 (CLDN18.2) has become an emerging target in GC. In this study, we aimed to provide insight into AFPGC and investigate the expression and the clinical implications of CLDN18.2 in AFPGC.MethodsWe retrospectively collected 98 cases of AFPGC and reviewed their clinical, morphological, and immunohistochemical features. Another 356 patients with stage-matched conventional GC (cGC) were enrolled as a control group. We further surveyed CLDN18.2 expression by immunohistochemistry (IHC) in 51 AFPGC tissues and explained its association with the clinicopathological parameters of AFPGC.ResultsOur results showed that AFPGC was a unique GC type with elevated serum alpha-fetoprotein (AFP), which was a predictor of a worse prognosis. AFPGC showed typical morphological features and positive staining of at least 1 hepatocytic or enteroblastic marker. The expression rate of CLDN18.2 was low, with a positivity rate of 21.6%, which was much lower than that observed in cGC tissues (38.5%). A significant correlation was found between CLDN18.2 expression and the differentiation of AFPGC. CLDN18.2 expression was negatively correlated with the serum AFP level of AFPGC. We also found that AFPGC with a hepatoid type (HPT) component showed a significantly lower CLDN18.2 expression than those without.ConclusionsThis study demonstrated that CLDN18.2 was significantly decreased in AFPGC and was negatively correlated with the patient’s preoperative serum AFP level. The negative correlation between AFP and CLDN18.2 could be explained by retro-differentiation of AFPGC. Special treatment strategies might be needed for this unique tumor type.     

UBE2C promotes the progression of pancreatic cancer and glycolytic activity via EGFR stabilization-mediated PI3K-Akt pathway activation

BackgroundPancreatic cancer (PC) is among the most prevalent and deadliest endocrine tumors, yet the mechanisms governing its pathogenesis remain to be fully clarified. While ubiquitin-conjugating enzyme E2C (UBE2C) has been identified as an important oncogene in several cancers, its importance in PC has yet to be established.MethodsUBE2C expression in PC tumor samples and cell lines was examined via quantitative real-time polymerase chain reaction (qRT-PCR), while appropriate commercial kits were used to assess lactate production, ATP generation, and the uptake of glucose.ResultsUBE2C was found to be upregulated in PC patient tumors and correlated with poorer survival outcomes. In PC cell lines, the silencing of this gene suppressed the malignant activity of cells, thus supporting its identification as an oncogene in this cancer type. Mechanistically, UBE2C was found to promote enhanced matrix metalloproteinase (MMP) protein expression via activating the PI3K-Akt pathway. Moreover, it was found to bind to the epidermal growth factor receptor (EGFR), stabilizing it and driving additional PI3K-Akt pathway activation. UBE2C knockdown in PC cells impaired their uptake of glucose and their ability to produce lactate and ATP.ConclusionsIn conclusion, the results of this study support a role for UBE2C as a driver of metastatic PC progression owing to its ability to bind to EGFR and to induce signaling via the PI3K-Akt pathway.     

Tunable Boc modification of lignin and its impact on microbial degradation rate

A new type of modified lignin, lignin-p-Boc, was obtained through reaction with di-tert-butyl dicarbonate (Boc₂O) in aqueous media catalyzed by 4-dimethylaminopyridine (DMAP). Boc modification occurred regardless of type of lignin, was tunable, and proceeded well in recovering lignin at high purity from sodium lignosulfonate (a common byproduct from pulping industry; lignin content: 60%). Lignin-p-BOC was demonstrated as a potential reactive filler in green plastic and as a potential crosslinker in design of bioresorbable composite polymeric implants. Furthermore, the effect of the modification on breakdown rate of alkali lignin by microbes was investigated, and results showed that the modification substantially decreases the breakdown rate. The tunable Boc modification process was designed via a system thinking, including availability of raw lignin, economical/green modification, potentiality of drop-in-change to current thermoplastic processing, modification impact on microbial degradability/disposed environment at the end of use life; hence the holistic consideration makes this alternative method for upgrade of technical lignins very practical for future industrial application. Via “in-situ” forming “easily breakable covalent bonds” with existing thermopolymers inside, Lignin-p-BOCs are also promising to play an important role as both excellent binders via “random match” and reductants in transforming linear plastic waste into circular plastics.     

耳蜗电图在梅尼埃病诊断中的价值

迄今尚缺乏诊断梅尼埃病的敏感且特异的客观试验，７０年代以来，若干研究探讨了耳蜗电图（Ｅｌｅｃｔｒｏｃｏｃｈｌｅｏｇｒａｍ，ＥＣｏｃｈＧ）在梅尼埃病诊断中的价值，认为典型的改变是－ＳＰ异常增大，导致－ＳＰ／ＡＰ比值增高，以及－ＳＰ－ＡＰ复合波形异常增宽。各家报告－ＳＰ／ＡＰ诊断梅尼埃病阳性率从３２％至８７％．本文报告了９７例１００耳梅尼埃病鼓室内法检测的耳蜗电图结果，４９例－ＳＰ／ＡＰ比值异常增高，阳性率４９％；波型异常增宽１７耳，总阳性率６６％．眼震电图检测的阳性率６１％．耳蜗电图和眼震电图改变一致的４３耳，二者总阳性率为８４％。对各家阳性率不一致的原因作了分析。认为耳蜗电图－ＳＰ／ＡＰ比值诊断梅尼埃病的敏感性不如文献报告的那么乐观，在目前尚无更敏感更特异的诊断手段的情况下，耳蜗电图和眼震电图在梅尼埃病的诊断中起着相互印证和相互补充的作用。     

血脂异常中医证候及与代谢综合征相关性的研究

通过对600例血脂异常患者中医证侯的研究,总结了血脂异常中医证候分布的规律,确认血脂异常患者的病机是以本虚为主,脾虚和肾虚是血脂异常发病的主要病理基础,痰浊和瘀血也是影响血脂异常中医证候的重要因素,建议在治疗时应以补脾益肾为主要治疗原则。并首次在血脂异常的辨证中提出了＂无证候可辨＂的概念。通过对血脂异常中医证候与代谢综合征（MS）相关性的研究发现血脂异常中医证候的产生与MS及其组分中的超重或肥胖及高血压密切相关,提出MS及其各组分的存在是引起血脂异常中医虚证的重要因素,阐明了应用辨证论治的方法在治疗血脂异常的同时可以改善MS,还可以提高患者的生活质量,因而优于单纯的降脂治疗。