Background/Objectives: Metabolic dysfunction-associated steatohepatitis (MASH) has become the leading cause of hepatocellular carcinoma and liver disorders globally. Nevertheless, only one expensive drug, resmetirom (Res), has been approved by the FDA for MASH treatment to date. However, its high price has imposed a heavy financial burden on patients. Methods: In this study, half-dose Res and low-dose metformin (Met) (referred to as RM) were administered in combination to treat MASH models in vitro and in vivo. We utilized transcriptome and lipidomics sequencing to assess the efficacy of RM in improving MASH. Our goal was to systemically compare the therapeutic effects of RM, Met, and Res on MASH and elucidate the underlying mechanisms. Results: Our results demonstrated that RM was comparable to Res and superior to Met in reducing lipid production in vitro, attenuating lipid accumulation, inhibiting inflammation, and improving fibrosis in vivo. Transcriptome and lipidome analyses further revealed that RM regulated the expression of genes and lipids in a manner similar to Res, particularly in pathways related to cholesterol metabolism and inflammation. Further validation showed that RM facilitated cholesterol transformation by robustly promoting the expression of CYP7A1, thereby mitigating MASH. Conclusions: Collectively, our findings highlight that a combination of half-dose Res and Met is equivalent to Res alone in terms of MASH treatment efficacy. This study provides a novel therapeutic strategy that is not only effective for MASH treatment but also reduces the economic burden on patients.

目的：探究党参总皂苷（Total Saponins Codonopsis，TSC）对D-半乳糖诱导的衰老小鼠学习记忆功能损伤的改善作用及机制。方法：将24只雄性C57/6J小鼠随机分出正常组、模型组、党参总皂苷组(200 mg·kg-1)、多奈哌齐组(3 mg·kg-1)，每组6只。预给药1周，采用预防性给药对D-半乳糖诱导小鼠衰老模型进行干预8周，第9周采用Morris水迷宫实验检测衰老小鼠的学习和记忆能力；采用苏木素-伊红（HE）、尼氏染色法检测脑组织病理损伤及肌肉、肝、肺组织病理变化；采用免疫组化检测脑组织中核转录因子-κB（NF-κB）蛋白、肿瘤坏死因子-α（TNF-α）、脑源性神经营养因子（BDNF）的表达；采用酶联免疫吸附测定法（ELISA）测定血清谷胱甘肽过氧化物酶（GSH-Px）、过氧化氢酶（CAT）、超氧化物歧化酶（SOD）、丙二醛（MDA）、TNF-α、白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）水平，分析TSC对D-半乳糖诱导的小鼠脑部神经炎症及记忆功能损伤的改善作用。结果：与正常组比较，模型组小鼠认知功能明显下降；模型组小鼠血清中抗氧化酶CAT、SOD、GSH-Px活力显著升高（P<0.01），MDA、TNF-α、IL-1β和IL-18水平显著下调（P<0.01）；模型组海马体及皮层组织中部分神经细胞损伤退化，BDNF的表达水平明显下调（P<0.05），NF-κB、TNF-α的表达水平明显上调（P<0.05）。与模型组比较，TSC可以显著减轻D-半乳糖诱导的小鼠认知功能障碍；显著提高血清中抗氧化酶CAT、SOD、GSH-Px活力（P<0.01），显著下调血清MDA、TNF-α、IL-1β和IL-18水平（P<0.01）；明显改善海马体和大脑皮层病理结构改变；TSC组海马体和大脑皮层中BDNF的表达明显上调（P<0.05，P<0.01），NF-κB、TNF-α表达明显下调（P<0.05，P<0.01）。结论：TSC对D-半乳糖诱导的衰老小鼠的认知功能障碍具有保护作用，其保护作用可能与抑制氧化应激和炎症反应有关。

Background The inflammatory response is a key factor in the pathogenesis of cerebral ischemia/reperfusion injury (CIRI), and anti-inflammatory interventions may offer a promising therapeutic strategy. Forsythoside B (FB) is a phenylethanoid glycoside isolated from Forsythiae fructus, which has been reported to have anti-inflammatory effects. However, the mechanism of the neuroprotective effect of FB on CIRI remains unclear.Methods Adult male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion/reperfusion (MCAO/R). FB was administered intraperitoneally for 3 days prior to MCAO/R. Cerebral infarct volume and neurological deficit score were used as indices to evaluate MCAO/R injury. The serum levels of inflammatory factors and antioxidant enzymes were measured. The activation of silent information regulator 2 homolog 1 (Sirt1) and the inhibition of the nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) pathway were assessed through western blot and immunohistochemistry analysis. Furthermore, the rats were treated with Sirt1 shRNA 3 days before MCAO/R by stereotactical injection into the ipsilateral hemispheric region to assess the impact of Sirt1 knockdown on the protection of FB during MCAO/R.Results FB reduced cerebral infarct volume and neurological deficit score in MCAO/R rats. FB reduced pathological changes and cell apoptosis in the hippocampal CA1 region and cortex on the ischemic side of rats. FB inhibited the serum levels of inflammatory factors and increased the activities of antioxidant enzymes. Further study showed that FB inhibited the activation of the NLRP3 pathway and induced Sirt1 activation.Conclusion FB demonstrated neuroprotective and anti-inflammatory effects by inhibiting the NLRP3 pathway through Sirt1 activation in CIRI.

党参为桔梗科党参属植物，是中医临床应用非常广泛的一味补气类中药，其化学成分主要包括黄酮类、生物碱类、糖类、皂苷类、甾体类、氨基酸类等，主要有增强免疫功能、改善胃肠道功能、抗炎、抗肿瘤、改善学习记忆能力、调节心脑血管系统和延缓衰老等药理作用。该文基于近几年国内外大量党参的研究文献，对其药理作用进行综述，以期对党参的研究及应用提供一定的理论基础和依据。

党参为桔梗科党参属植物，是中医临床应用非常广泛的一味补气类中药，其化学成分主要包括黄酮类、生物碱类、糖类、皂苷类、甾体类、氨基酸类等，主要有增强免疫功能、改善胃肠道功能、抗炎、抗肿瘤、改善学习记忆能力、调节心脑血管系统和延缓衰老等药理作用。该文基于近几年国内外大量党参的研究文献，对其药理作用进行综述，以期对党参的研究及应用提供一定的理论基础和依据。

BACKGROUND: The phyllosphere mycobiome plays a crucial role in plant fitness and ecosystem functions. The complex microbial ecological networks (MEN) formed by these fungi remain poorly understood, particularly with regard to their organization strategy and their contributions to plant secondary metabolites such as saponin.; RESULTS: In this study, we constructed six MENs from leaf epiphytic and endophytic mycobiomes of three Panax species distributed in the northeast and southwest ends of mainland China. Hub nodes were absent in these MENs, which were significantly more complex, robust, and less efficient compared to random graphs (P<0.05), indicating a hub-independent high-robustness strategy to maintain structural homeostasis. The important roles of specific MEN modules in shaping leaf saponin profiles of each Panax species were proved by multiple machine learning algorithms. Positive regulation modules (PRMs) of total saponin content were further identified, which exhibited more deterministic ecological assembly and comprised of highly connected nodes as well as higher proportion of plant-associated fungal guilds compared to other network members, indicating their tight links with host plant. The significant and direct effects (P<0.05) of PRMs on total saponin accumulation were validated by well-fitted structural equation models (chi2<0.3, P>0.5). Taxonomic analysis revealed that Pleosporales and Chaetothyriales were significantly overrepresented by positive regulation taxa (PRT) of total saponin content (FDR<0.05). Across PRT identified in three Panax species, Epicoccum and Coniothyrium were conservatively present, while species-specific taxa such as Agaricales were also found, indicating the conservatism and specificity of plant-fungi interactions associated with leaf saponin accumulation in Panax genus.; CONCLUSIONS: These findings provide a foundation for understanding mechanisms maintaining the steady state of phyllosphere mycobiome in healthy plant, and offer clues for engineering phyllosphere mycobiome to improve the accumulation of bioactive secondary metabolites on the basis of network modules. © 2023. The Author(s).