ETHNOPHARMACOLOGICAL RELEVANCE:The traditional Chinese medicine compound Babaodan (BBD), originating from Ming Dynasty in China, is known for its "clearing heat, removing toxins, circulating blood and transforming stasis" effects. Recent evidence increasingly highlights its potential in tumor treatment. However, its efficacy and underlying pharmacological mechanisms in triple-negative breast cancer (TNBC) remain underexplored. AIM OF THE STUDY:This study aimed to investigate the therapeutic potential of the traditional Chinese medicine Babaodan (BBD) on the inflammatory and vascular microenvironment in TNBC. MATERIALS AND METHODS:Using a 4T1 tumor-bearing mouse model, the effects of BBD on tumor inflammatory and vascular microenvironment were evaluated through histopathology, immunofluorescence, and immunohistochemical staining. Furthermore, serum metabolomics was employed to identify the active components and relevant pharmacological mechanisms of BBD in regulating TNBC, with validation performed by Western blot. RESULTS:Our findings demonstrated that BBD treatment significantly inhibited the activation of cGAS-STING/NF-κB signaling pathway, evidenced by reducing phosphorylation levels of STING, TBK1, IRF3, p65, and IκBα. This led to a sharp decline in downstream inflammatory cytokines, thereby ameliorating the tumor inflammatory microenvironment. Concurrently, BBD also alleviated tumor hypoxia and promoted vascular normalization, restoring intratumoral blood perfusion. CONCLUSION:These results suggested that BBD exerted its dual anti-tumor effects by suppressing the cGAS-STING/NF-κB signaling pathway, effectively improving the inflammatory and vascular microenvironment in TNBC. This study provides a novel theoretical basis and potential therapeutic strategy for the application of traditional medicine in TNBC treatment.

BackgroundHippocampal neuron damage is closely related to depression, and apoptosis is an important pathway for neuronal damage. Depression belongs to Yubing (depressive disease) in traditional Chinese medicine theory. Chaiyuwendan decoction (CYWD) has significant clinical efficacy in treating depression, however, its specific mechanism is still unclear. This study aims to explore the potential pharmacological active substances and key therapeutic targets of CYWD in treating depression from signaling pathways related with apoptosis.MethodsHPLC-MS method was used to detect the key components of CYWD. The mouse depression model was established by CORT injection. Depressive mice were administered CYWD at low, medium and high doses. Behavioral experiment, neurotransmitters in hippocampus and serum, hippocampal HE staining and Nissl staining were tested in order to evaluate the effects of CYWD in antidepressant and anti nerve damage. The potential targets and signaling pathways for CYWD against depression were predicted through network pharmacology and molecular docking. CORT intervention was used to establish a neuronal apoptosis model of HT22. The effect of CYWD on HT22 were evaluated using CCK-8 proliferation, Nissl staining and apoptotic assays by flow cytometry. According to the predicted results, Western blot and Immunofluorescence assay were used to detect AKT, pAKT, CREB, pCREB and apoptosis-related proteins in hippocampus and HT22 cells.Results134 active components in CYWD were identified, including chlorogenic acid, coumaric acid, rutinoside, naringin, and hesperidin. The in vivo studies showed that CYWD treatment improved mice’ depression-associated behaviors, decreased 5-HT, DA and NE while increased ACTH, reduced hippocampal neuronal damage. Furthermore, the AKT-CREB pathway to inhibit neuronal apoptosis was predicted as the potential key target for CYWD treatment of depression by network pharmacology methods and molecular docking. Subsequently, in vitro and in vivo experiments confirmed that CYWD can inhibit the pro-apoptotic proteins Bax and Caspase 3 by increasing AKT and CREB, and increase anti-apoptotic protein Bcl-2, thereby inhibiting CORT induced apoptosis of mouse hippocampal neurons.ConclusionCYWD can alleviate depression through protecting hippocampal neurons by activating the AKT-CREB signaling pathway, increasing the proportion of anti apoptotic proteins. These findings provided a valuable reference to CYWD as a promising alternative against depression.

Epidemiological evidence shows that diabetic patients are susceptible to high temperature weather, and brown adipose tissue (BAT) activity is closely related to type 2 diabetes (T2DM). Activation of BAT under cold stress helps improve T2DM. However, the impact of high temperature on the activity of BAT is still unclear. The study aimed to investigate the impact of heat stress on glucose and lipid metabolism in T2DM mice by influencing BAT activity. High-fat feeding and injecting streptozotocin (STZ) induced model of T2DM mice. All mice were randomly divided into three groups: a normal(N) group, a diabetes (DM) group and a heat stress diabetes (DMHS) group. The DMHS group received heat stress intervention for 3 days. Fasting blood glucose, fasting serum insulin and blood lipids were measured in all three groups. The activity of BAT was assessed by using quantitative real-time PCR (qRT-PCR), electron microscopy, and PET CT. Furthermore, the UHPLC-Q-TOF MS technique was employed to perform metabolomics analysis of BAT on both DM group and DMHS group. The results of this study indicated that heat stress aggravated the dysregulation of glucose and lipid metabolism, exacerbated mitochondrial dysfunction in BAT and reduced the activity of BAT in T2DM mice. This may be related to the abnormal accumulation of branched-chain amino acids (BCAAs) in the mitochondria of BAT.

目的 观察皂术茵陈方对非酒精性脂肪性肝炎(NASH)大鼠的作用特点及其对肝脏内质网应激肌醇需求酶1 α(IRE1 α)-X-盒结合蛋白1(XBP1)-信号转导与转录激活因子1(STAT1)信号通路的影响,探讨其治疗NASH的作用机制.方法 大鼠适应性喂养1周后,按随机数表法随机分成4组,即模型组、正常组、皂术茵陈方组、吡格列酮组,每组8只.采用高脂饮食16周建立大鼠NASH模型,在造模第9周开始给药,皂术茵陈方组每天给予皂术茵陈方10 g/kg灌胃;吡格列酮组每天给予盐酸吡格列酮10 mg/kg灌胃;正常组和模型组给予10 mL/kg双蒸水灌胃;共8周.观察大鼠一般状态;生化法检测血清谷丙转氨酶(ALT)、谷草转氨酶(AST)活性和肝组织甘油三酯(TG)、丙二醛(MDA)、还原型谷胱甘肽(GSH)含量;苏木精-伊红(HE)染色观察肝组织病理学变化;实时荧光定量聚合酶链式反应法(RT-PCR)和酶联免疫吸附测定法(ELISA)分别检测肝组织IRE1 α、XBP1、STAT1等的基因与蛋白表达.结果 与正常组比较,模型组大鼠显示出典型的NASH组织学特征,经过皂术茵陈方治疗后,肝细胞脂肪变性、炎症浸润较模型组减轻.模型组大鼠肝湿重、血清ALT、AST活性、肝脏TG、MDA、GSH含量均显著升高(P＜0.01),同时,肝组织IRE1 α、XBP1、STAT1的蛋白及基因表达亦显著升高(P＜0.01).经过皂术茵陈方治疗后,上述指标均显著降低(P＜0.05).结论 皂术茵陈方具有改善NASH大鼠肝细胞脂肪变性、气球样变性、炎症以及内质网应激损伤的药理效应,同时可显著降低肝组织IRE1α、XBP1、STAT1表达,提示皂术茵陈方治疗NASH的作用机制与调控内质网应激IRE1 α-XBP1-STAT1信号通路有关.

新型冠状病毒肺炎(以下简称新冠肺炎)归属中医"疫病"的范畴,是一类具有强烈传染性的外感时邪疫毒.古人有云"时病重舌,杂病重脉",中医舌象特征的变化体现了新冠肺炎在不同阶段的传变,对临床诊疗和判断预后均有十分重要的意义.文章通过梳理舌象在新冠肺炎诊疗中判断正气盛衰、分辨病位深浅、区别病邪性质、推断病情进退的应用价值,并举例如何应用舌象变化指导中医药治疗新冠肺炎,以期更好发挥中医药在新冠肺炎诊疗中的应用价值.

"暑邪直中"在《黄帝内经》已有相关论述,但受《伤寒论》影响,其后很长一段时期以"直中为寒"观点占据主导,而"暑邪直中"论述只见零星记载.至明清时期随着温病理论的发展,"暑邪直中"理论才随之发展.在明代,受《黄帝内经》"心应夏"思想的影响,以"暑邪直入于心"论述为主.到明末张凤逵提出"不拘表里,不以渐次,不论脏腑"的观点,"暑邪直中"理论臻于完善.到清代温病学派发展达到鼎盛,温病学家进一步阐述了暑邪直入各脏腑的理论,明确提出五脏皆可见暑邪直中证.此时,对暑邪直入于肺的论述逐渐增多,对暑邪直入心营的认识趋于完整且为多数医家认可,夏暑发自阳明常被用以说明暑邪为病即见里证的发病特点,至此对"暑邪直中"的认识趋于完善,不断充实发展.

Myeloid-derived suppressor cells (MDSCs) have attracted attention due to their important role in inflammation. Several studies have investigated the involvement of MDSCs in chronic liver disease. However, due to the difference of MDSC phenotypes, patient types, and sample sources among the studies, the results are inconsistent and controversial. We took advantage of a large well-defined cohort of 98 (24 patients with CHB, 18 with NAFLD, 13 with HCC, 16 with PBC, and 27 with AIH) patients with liver inflammation and 12 healthy controls to investigate the expression of MDSCs, and the relationships between the expression of hepatic MDSCs and the clinical characteristics were analyzed. We found that the expression of CD11b+CD33+ MDSCs is closely related to chronic liver disease and positively correlated with clinical parameters such as ALT, AST, and globulin. Ultimately, the present study suggests that hepatic CD11b+CD33+ MDSCs are increased in HCC and AIH and positively correlate with the liver stages of hepatitis activity and liver fibrosis stage.

Objective : Chlorogenic acid and geniposide (CG) are derived from traditional Chinese medicine, Yinchenhao Recipe (QCHR), and can improve the clinical efficacy of NASH patients. This study investigated the effects of CG on NASH and expounded its Potential mechanism of action through the LPS-TLR4 pathway and microbiota. Methods: Rats were randomized into Control (C), Model (M), Chlorogenic Acid and Geniposide (CG), Pioglitazone (PH) and Bifico (B) groups. After an 8-week high-fat diet (HFD), CG, PH and B oral treatment were initiated and carried out for a further 8 weeks. The stool samples were used in a16S rDNA V4 highly variable region measurement method in order to regulate the role of CG in gut microbiota. The concentrations of triglyceride (TG), cholesterol (CHO), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) in LPS were detected by the corresponding methods. Results : Observations were made that CG significantly improved the pathology of the liver and terminal ileum tissue. The accumulation of TG and the content of inflammatory cytokines in the liver were significantly decreased and the abundance of Proteobacteria was significantly down-regulated. The expression of TLR4, AP-1, MyD88, and phosphorylated NF-κB p65 were significantly decreased. All the findings above indicated that CG was highly effective in improving the composition of gut microbiota, decreasing the production of endogenous LPS, and reducing the secretion of inflammatory cytokines through the gut-liver axis. Conclusion : CG can regulate the abundance and diversity of the intestinal microbial community and improve liver inflammation and steatosis in NASH rats by reducing LPS-TLR4-mediated inflammation.

当前我国儿童亚健康状态的人群比例已超过70％.由于亚健康状态并不纳入临床疾病的范畴,只表现为个人身心感受的不适,因此常常被忽略.近年来,我国医学领域的专家学者对疾病的研究逐渐从临床疾病转向非疾病的亚健康状态.然而,多数研究只集中于成人,对儿童亚健康状态的研究尚不完善.基于中医阴阳、脏腑、气血理论,结合小儿的生理和病理特点,总结和归纳少儿临床常见的亚健康状态表现,建立少儿亚健康状态的中医辨识体系和中医防治方案,以期降低儿童亚健康状态的比例,预防疾病的发生发展.

•The p300 histone acetyltransferase enzyme was used as a ligand for virtual molecular docking to screen anti-non-alcoholic fatty liver disease phytomedicine.•Chlorogenic acid were screened as a novel histone acetyltransferase inhibitor due to its favorable molecular weight, drug similarity and low binding energy.•In vivo studies showed that CA could inhibit lipid accumulation and alleviate liver injury.•It is feasible to screen histone acetyltransferase inhibitors for the treatment of nonalcoholic fatty liver disease by targeting p300 histone acetyltransferase.

目的:基于内源性大麻素研究皂术抗纤方对肝纤维化大鼠的药理效应及其作用机制.方法:按照随机数字表法将40只Wistar雄性大鼠随机分为正常组、模型组、皂术抗纤方组和安络化纤丸组,每组10只.模型组、皂术抗纤方组和安络化纤丸组给予四氯化碳(CCl4)腹腔注射8周,复制肝纤维化模型.第5～8周,皂术抗纤方组、安络化纤丸组分别给予皂术抗纤方(16.1g/kg)、安络化纤丸(30g/kg)治疗.检测各组大鼠血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)水平,肝组织羟脯氨酸(Hyp)、N-花生四烯酸氨基乙醇(AEA)、2-花生四烯酸甘油(2-AG)及内源性大麻素水解酶脂肪酰胺水解酶(FAAH)、单酰基甘油酯酶(MGL) mRNA表达量变化.结果:与正常组比较,模型组大鼠肝组织出现明显肝纤维化,血清ALT、AST水平及肝组织Hyp、AEA、2-AG含量显著升高(P＜0.01),FAAH、MGL mRNA表达显著降低(P＜0.01).与模型组比较,皂术抗纤方组、安络化纤丸组血清ALT、AST水平及肝组织Hyp含量均显著降低(P＜0.01),皂术抗纤方组肝组织大麻素AEA、2-AG含量显著降低(P＜0.01),FAAH、MGL mRNA表达显著升高(P＜0.01).结论:皂术抗纤方治疗肝纤维化效果显著,其作用机制与调节内源性大麻素有关.

目的 比较不同模式高温对大鼠死亡率和热休克蛋白(HSP) 70表达的影响,从“热应激”角度探讨六淫相对性产生机制.方法 40只SD大鼠随机分为5组;对照组、南方1组、南方2组、北方1组、北方组2组,每组8只,湿度均为60％.对照组保持温度24 ℃.南方组初始温度28℃,第15d南方1组温度提高至35℃,南方2组则提高至41℃;北方组初始温度20℃,第15d北方1组温度提高至35 ℃,北方2组则提高至33℃.第22 d处死全部大鼠.记录各组大鼠不同时间肛温和死亡情况.RT-PCR检测五脏(心、肝、脾、肺、肾)HSP70 mRNA表达水平.结果 南方2组大鼠在温度调高至41℃后3d内全部死亡,死亡率较其他4组(均死亡0只)升高(P＜0.01).与本组初始温度和7d肛温比较,北方1组21 d肛温升高(P＜0.01).与对照组和北方2组同时间比较,北方1组21 d肛温升高(P＜0.01).与对照组比较,南方1组、北方2组大鼠五脏HSP70 mRNA表达水升高(P＜0.01,P＜0.05),南方2组大鼠五脏HSP70 mRNA表达水平降低(P＜0.01),北方1组大鼠心、肺两脏HSP70 mRNA表达水平降低(P＜0.01、P＜0.05).与南方1组比较,南方2组及北方1组五脏HSP70 mRNA表达水平降低(P＜0.01),北方2组肝脏HSP70 mR-NA表达水平升高(P＜0.05).与南方2组比较,北方1、2组五脏HSP70 mRNA表达水平升高(P＜0.01).与北方1组比较,北方2组五脏HSP70 mRNA表达水平升高(P＜0.01).结论 不同模式高温影响大鼠适应性及HSP70表达水平,心、肺二脏最为敏感,证明了中医学“六淫致病具有相对性”理论.

OBJECTIVE:To investigate the risk factors for hepatic steatosis in chronic hepatitis B (CHB), to determine its correlation with liver necroinflammation and fibrosis and response to peginterferon alpha-2a (PEG-IFNα-2a) antiviral therapy, and to explore the mechanisms underlying the poor antiviral effect of PEG-IFNα-2a in CHB patients with hepatic steatosis.METHODS:We analysed the impact of hepatic steatosis on the antiviral effect of PEG-IFNα-2a on CHB patients in a cohort of 226 patients who underwent pretherapeutic liver biopsy. To assess the complete response (CR), virological response (VR), and biochemical response (BR), the 226 patients were treated with PEG-IFNα-2a for 48 weeks and were followed-up for 24 weeks. The expressions of hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) in the liver tissue were detected in all patients to explore the possible mechanism of hepatic steatosis with regard to antiviral effects.RESULTS:The patients were divided into four groups based on the severity of hepatic steatosis: 119 with no steatosis, 76 with mild steatosis, 22 with moderate steatosis, and 9 with severe steatosis. In the hepatic steatosis groups, the proportions of male patients, patients aged >40 years, patients with hyperuricaemia, patients with a BMI > 23 kg/m2, and total cholesterol (TC), triglyceride (TG), glucose (GLU), and uric acid (UA) levels were significantly higher than those in the group without steatosis, whereas the alanine aminotransferase (ALT) and aspartate transaminase (AST) levels were significantly lower than those in the group without steatosis. The multivariate analysis results indicated that a BMI > 23 kg/m2 was independently associated with CHB patients with hepatic steatosis; the levels of baseline AST and UA were independently associated with CHB patients with significant hepatic steatosis, and the baseline AST level was independently associated with significant liver fibrosis. After 48 weeks of treatment and 24 weeks of follow-up, the rates of CR, VR, and BR had gradually decreased, whereas the severity of hepatic steatosis had increased.CONCLUSION:Hepatic steatosis can reduce the efficacy of PEG-IFNα-2a in the treatment of CHB patients, and its mechanism may be related to the different HBcAg expression patterns in liver tissue.

目的 基于内毒素血症探讨皂术茵陈方防治非酒精性脂肪性肝炎(NASH)大鼠的影响及其作用机制.方法 采用随机数字表法将40只大鼠分为5组,即正常组、模型组、皂术茵陈方组、盐酸吡格列酮组及培菲康组,每组8只.除正常组外,其余32只大鼠采用高脂饮食16周建立大鼠NASH模型,在造模第9周开始,皂术茵陈方组给予皂术茵陈方水提液60mg/(kg ·d)灌胃,盐酸吡格列酮组给予盐酸吡格列酮10mg/(kg·d)灌胃,培菲康组给予培菲康210 mg/(kg·d)灌胃,正常组及模型组均给予双蒸水10 mL/(kg·d)灌胃,共治疗8周.第16周末经腹主动脉取血,生化法检测肝组织甘油三酯(TG)水平,苏木精-伊红(HE)染色观察肝组织病理学变化.终点显色法检测血浆内毒素(LPS)含量.ELISA法检测肝组织肿瘤坏死因子-α(TNF-α)、白细胞介素(IL)-1β、IL-6等炎症因子的表达水平.结果 与正常组比较,模型组大鼠肝组织显示出典型的NASH组织学特征,出现重度脂肪变性,不同程度的炎细胞浸润和坏死灶.大鼠肝湿重、肝指数、肝脏TG含量、血浆LPS水平、肝组织TNF-α、IL-1β、IL-6等炎症因子水平均有不同程度的增高(P＜0.05,P＜0.01).经皂术茵陈方干预后,肝细胞脂肪变性、炎症浸润较模型组减轻,大鼠肝湿重、肝指数、肝脏TG含量、血浆LPS水平、肝组织TNF-α、IL-1β、IL-6等炎症因子水平较模型组有不同程度的下降(P＜0.05,P＜0.01).结论 皂术茵陈方能显著降低肝脏TG含量、血浆LPS水平,肝组织TNF-α、IL-1β、IL-6等炎症因子的表达.提示皂术茵陈方治疗NASH的作用机制与改善内毒素血症,减少内源性LPS产生、降低炎症因子的表达有关.

目的 研究皂术茵陈方对非酒精性脂肪性肝炎大鼠的药理效应及对内源性大麻素的作用机制.方法 30只Wistar雄性大鼠随机分为正常组、模型组和治疗组,每组10只.造模12周期间,正常组给予普通饲料喂养,模型组和治疗组给予高脂饲料以复制非酒精性脂肪性肝炎模型.从第7周开始,治疗组给予皂术茵陈方灌胃治疗6周.检测大鼠血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)活性,肝组织甘油三酯(TG)、总胆固醇(TC);HE染色法观察大鼠肝组织的病理变化;采用高效液相色谱-质谱联用法(LC/MS)检测肝组织2-花生四烯酸甘油(2-AG)含量;通过Real-time PCR法检测大鼠肝组织脂肪酰胺水解酶(FAAH)和单酰基甘油酯酶(MGL) mRNA表达水平.结果 与正常组比较,模型组大鼠肝组织内出现明显脂肪沉积和炎症损伤,血清ALT、AST活性明显升高(P＜0.01),肝组织TG、TC含量升高(P＜0.01);肝组织大麻素2-AG含量显著升高(P＜0.01),FAAH、MGL mRNA表达降低(P＜0.01).治疗组与模型组比较,治疗6周后血清ALT、AST活性、肝组织TG、TC、大麻素2-AG含量明显降低(P＜0.05),FAAH、MGL mRNA表达升高(P＜0.01).结论 皂术茵陈方对非酒精性脂肪性肝炎具有良好的治疗作用,其作用机制与抑制内源性大麻素密切相关.

目的 观察栀子苷对非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH)大鼠的影响,并基于肠肝轴探讨栀子苷防治NASH的作用机制.方法 将35只大鼠按随机数字表法分为5组,每组7只.即正常组、模型组、栀子苷组、盐酸吡格列酮组及培菲康组.除正常组外,其余28只大鼠采用高脂饮食16周建立大鼠NASH模型,在造模第9周开始给药,共治疗8周.第16周末经腹主动脉取血,生化法检测肝组织甘油三酯(TG)水平,苏木精-伊红(HE)染色观察肝组织、肠组织病理学变化.ELISA法检测肝组织白细胞介素(IL)-1β、IL-6、肿瘤坏死因子-α(TNF-α)等炎症因子的表达水平.终点显色法检测血浆内毒素(LPS)含量.结果 与正常组比较,模型组大鼠的肝组织显示出典型的NASH组织学特征,经栀子苷干预后,肝细胞脂肪变性、炎症浸润较模型组减轻.与正常组比较,模型组大鼠肠上皮细胞少量脱落,肠黏膜机械屏障受损.经栀子苷干预后,回肠黏膜结构完整,未见明显肠上皮细胞脱落.与正常组比较,模型组大鼠脂肪重量、肝湿重、肝指数、肝脏TG含量、血浆LPS水平、肝组织IL-1β、IL-6、TNF-α等炎症因子水平均有不同程度增高(P＜0.01).经干预后,栀子苷组大鼠脂肪重量、肝湿重、肝指数、肝脏TG含量、血浆LPS水平、肝组织IL-1β、IL-6、TNF-α等炎症因子水平均较模型组有不同程度的下降(P＜0.05,P＜0.01).结论 栀子苷能明显改善大鼠肠黏膜组织结构,保持肠黏膜屏障的完整性,显著降低血浆LPS水平,显著降低NASH大鼠肝组织IL-1 β、IL-6、TNF-α等炎症因子的表达.提示栀子苷治疗NASH的作用机制与调节肠肝轴、改善肠黏膜屏障、减少内源性LPS产生、降低炎症因子表达有关.

冻疮为冬日常见病,虽多数病情轻微,但影响美观,且反复发作,因此冻疮防治研究仍具较强临床需要.本研究通过查阅、整理历代医家对冻疮的论述发现历代医家对冻疮认识全面,治法丰富,不仅外治法用药简便、剂型丰富、分阶段用药,预防亦有明显特色.研究结果不仅给冻疮临床治疗提供借鉴,且对进一步相关药物开发提供基础.

女子在经期、妊娠、产后、哺乳、围绝经期等特殊生理时期,根据不同时期的需求,气血阴阳及脏腑功能随之变化,呈现出来的舌象也与“淡红舌,薄白苔”的正常舌象有所不同.文章根据这些特殊生理时期的体质特点,对其常见舌象做一探讨,以期对临床有所裨益.

Infertility is a common clinical disease,but it is hard to be differentiated because either there are no obvious symptoms or too many symptoms.Tongue inspection is slightly influenced by the outside environment,Tongue body signifies yin/yang,deficiency/excess of diseases and tongue coat manifests cold evil or heat evil.By tongue inspection and formula prescription,infertility is effectively treated clinically.It was summarized in this article that the common tongue manifestations and medication experience on infertility treatment.