基于AGEs-RAGE信号通路探索从脾论治糖尿病心肌病的科学内涵

糖尿病是心血管疾病的独立危险因素,糖尿病患者(39%)相比于非糖尿病患者(23%)发生心力衰竭的风险明显增加^([1])。糖尿病心肌病是糖尿病常见的慢性并发症,早期表现为心肌纤维化及相关的舒张、收缩功能障碍,最终可导致心力衰竭发生,对患者生存质量及生命安全均产生许多不利影响^([1])。

Molecular mechanism of pancreatic ductal adenocarcinoma:The heterogeneity of cancer-associated fibroblasts and key signaling pathways

Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis,leading to a notably low five-year survival rate.This study offers a detailed exploration of epidemiological trends in pancreatic cancer and key molecular drivers,such as mutations in CDKN2A,KRAS,SMAD4,and TP53,along with the influence of cancer-associated fibroblasts(CAFs)on disease progression.In particular,we focused on the pivotal roles of signaling pathways such as the transforming growth factor-βand Wnt/β-catenin pathways in the development of pancreatic cancer and investigated their application in emerging therapeutic strategies.This study provides new scientific perspectives on pancreatic cancer treatment,especially in the development of precision medicine and targeted therapeutic strategies,and demonstrates the importance of signaling pathway research in the development of effective therapeutic regimens.Future studies should explore the subtypes of CAFs and their specific roles in the tumor microenvironment to devise more effective therapeutic methods.

Effects of Bifidobacterium lactis BLa80 on fecal and mucosal flora and stem cell factor/c-kit signaling pathway in simulated microgravity rats

BACKGROUND Simulated microgravity environment can lead to gastrointestinal motility disturbance.The pathogenesis of gastrointestinal motility disorders is closely related to the stem cell factor(SCF)/c-kit signaling pathway associated with intestinal flora and Cajal stromal cells.Moreover,intestinal flora can also affect the regulation of SCF/c-kit signaling pathway,thus affecting the expression of Cajal stromal cells.Cajal cells are the pacemakers of gastrointestinal motility.AIM To investigate the effects of Bifidobacterium lactis(B.lactis)BLa80 on the intestinal flora of rats in simulated microgravity and on the gastrointestinal motility-related SCF/c-kit pathway.METHODS The internationally recognized tail suspension animal model was used to simulate the microgravity environment,and 30 rats were randomly divided into control group,tail suspension group and drug administration tail suspension group with 10 rats in each group for a total of 28 days.The tail group was given B.lactis BLa80 by intragastric administration,and the other two groups were given water intragastric administration,the concentration of intragastric administration was 0.1 g/mL,and each rat was 1 mL/day.Hematoxylin&eosin staining was used to observe the histopathological changes in each segment of the intestine of each group,and the expression levels of SCF,c-kit,extracellular signal-regulated kinase(ERK)and p-ERK in the gastric antrum of each group were detected by Western blotting and PCR.The fecal flora and mucosal flora of rats in each group were detected by 16S rRNA.RESULTS Simulated microgravity resulted in severe exfoliation of villi of duodenum,jejunum and ileum in rats,marked damage,increased space between villi,loose arrangement,shortened columnar epithelium of colon,less folds,narrower mucosal thickness,reduced goblet cell number and crypts,and significant improvement after probiotic intervention.Simulated microgravity reduced the expressions of SCF and c-kit,and increased the expressions of ERK and P-ERK in the gastric antrum of rats.However,after probiotic intervention,the expressions of SCF and ckit were increased,while the expressions of ERK and P-ERK were decreased,with statistical significance(P<0.05).In addition,simulated microgravity can reduce the operational taxonomic unit(OTU)of the overall intestinal flora of rats,B.lactis BLa80 can increase the OTU of rats,simulated microgravity can reduce the overall richness and diversity of stool flora of rats,increase the abundance of firmicutes in stool flora of rats,and reduce the abundance of Bacteroides in stool flora of rats,most of which are mainly beneficial bacteria.Simulated microgravity can increase the overall richness and diversity of mucosal flora,increase the abundance of Bacteroides and Desulphurides in the rat mucosal flora,and decrease the abundance of firmicutes,most of which are proteobacteria.After probiotics intervention,the overall Bacteroidetes trend in simulated microgravity rats was increased.CONCLUSION B.lactis BLa80 can ameliorate intestinal mucosal injury,regulate intestinal flora,inhibit ERK expression,and activate the SCF/c-kit signaling pathway,which may have a facilitating effect on gastrointestinal motility in simulated microgravity rats.

Traditional Chinese medicine in the treatment of Helicobacter pylorirelated gastritis:The mechanisms of signalling pathway regulations

Helicobacter pylori-associated gastritis(HPAG)is a common condition of the gastrointestinal tract.However,extensive and long-term antibiotic use has resulted in numerous adverse effects,including increased resistance,gastrointestinal dysfunction,and increased recurrence rates.When these concerns develop,traditional Chinese medicine(TCM)may have advantages.TCM is based on the concept of completeness and aims to eliminate pathogens and strengthen the body.It has the potential to prevent this condition while also boosting the rate of Helicobacter pylori eradication.This review elaborates on the mechanism of TCM treatment for HPAG based on cellular signalling pathways,which reflects the flexibility of TCM in treating diseases and the advantages of multi-level,multipathway,and multi-target treatments for HPAG.

Exploring the interaction between the gut microbiota and cyclic adenosine monophosphate-protein kinase A signaling pathway:a potential therapeutic approach for neurodegenerative diseases

The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut–brain axis.The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites,which activates the vagus nerve and modulates the immune and neuroendocrine systems.Conversely,alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota,creating a dynamic network of microbial-host interactions.This reciprocal regulation affects neurodevelopment,neurotransmitter control,and behavioral traits,thus playing a role in the modulation of neurological diseases.The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation,mitochondrial dysfunction,abnormal energy metabolism,microglial activation,oxidative stress,and neurotransmitter release,which collectively influence the onset and progression of neurological diseases.This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway,along with its implications for potential therapeutic interventions in neurological diseases.Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders.This can be achieved through various methods such as dietary modifications,probiotic supplements,Chinese herbal extracts,combinations of Chinese herbs,and innovative dosage forms.These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.

Crosstalk among canonical Wnt and Hippo pathway members in skeletal muscle and at the neuromuscular junction

Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways that underlie skeletal muscle function.The process of muscle contra ction,orchestrated by a complex interplay of molecular events,is at the core of skeletal muscle function.Muscle contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular junction.Within muscle fibers,calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate force.Regulation of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction coupling.The development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as myogenesis.Myogenic regulators coordinate the diffe rentiation of myoblasts into mature muscle fibers.Signaling pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient availability.Seve ral muscle-related diseases,including congenital myasthenic disorders,sarcopenia,muscular dystrophies,and metabolic myopathies,are underpinned by dys regulated molecular pathways in skeletal muscle.Therapeutic interventions aimed at preserving muscle mass and function,enhancing regeneration,and improving metabolic health hold promise by targeting specific molecular pathways.Other molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway,a critical regulator of myogenesis,muscle regeneration,and metabolic function,and the Hippo signaling pathway.In recent years,more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers,and at the neuromuscular junction.In fact,research in the last few years now suggests that these two signaling pathways are interconnected and that they jointly control physiological and pathophysiological processes in muscle fibers.In this review,we will summarize and discuss the data on these two pathways,focusing on their concerted action next to their contribution to skeletal muscle biology.However,an in-depth discussion of the noncanonical Wnt pathway,the fibro/a dipogenic precursors,or the mechanosensory aspects of these pathways is not the focus of this review.

Inhibition of the cGAS–STING pathway:contributing to the treatment of cerebral ischemia-reperfusion injury

The cGAS–STING pathway plays an important role in ischemia-reperfusion injury in the heart,liver,brain,and kidney,but its role and mechanisms in cerebral ischemia-reperfusion injury have not been systematically reviewed.Here,we outline the components of the cGAS–STING pathway and then analyze its role in autophagy,ferroptosis,cellular pyroptosis,disequilibrium of calcium homeostasis,inflammatory responses,disruption of the blood–brain barrier,microglia transformation,and complement system activation following cerebral ischemia-reperfusion injury.We further analyze the value of cGAS–STING pathway inhibitors in the treatment of cerebral ischemia-reperfusion injury and conclude that the pathway can regulate cerebral ischemia-reperfusion injury through multiple mechanisms.Inhibition of the cGAS–STING pathway may be helpful in the treatment of cerebral ischemia-reperfusion injury.

Netrin-1 signaling pathway mechanisms in neurodegenerative diseases

Netrin-1 and its receptors play crucial roles in inducing axonal growth and neuronal migration during neuronal development.Their profound impacts then extend into adulthood to encompass the maintenance of neuronal survival and synaptic function.Increasing amounts of evidence highlight several key points:(1)Diminished Netrin-1 levels exacerbate pathological progression in animal models of Alzheimer’s disease and Parkinson’s disease,and potentially,similar alterations occur in humans.(2)Genetic mutations of Netrin-1 receptors increase an individuals’susceptibility to neurodegenerative disorders.(3)Therapeutic approaches targeting Netrin-1 and its receptors offer the benefits of enhancing memory and motor function.(4)Netrin-1 and its receptors show genetic and epigenetic alterations in a variety of cancers.These findings provide compelling evidence that Netrin-1 and its receptors are crucial targets in neurodegenerative diseases.Through a comprehensive review of Netrin-1 signaling pathways,our objective is to uncover potential therapeutic avenues for neurodegenerative disorders.

C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 pathway as a therapeutic target and regulatory mechanism for spinal cord injury

Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.

益气养阴活血汤对糖尿病肾病AGEs-RAGE轴及血清TNF-α、IL-6水平的影响

目的探究益气养阴活血汤经晚期糖基化终末产物(Advanced glycation end products,AGEs)-晚期糖基化终末产物受体(Receptor of Advanced Glycation Endproducts,RAGE)轴调节机制对早期糖尿病肾病(Diabetic nephropathy,DN)的治疗价值。方法选取2019年12月—2021年8月期间达州市中西医结合医院肾病科收治的88例早期DN患者,采用随机数字表法分为对照组和治疗组,每组各44例。对照组给予常规西医治疗,治疗组在对照组基础上联合益气养阴活血汤治疗。治疗8周后,观察比较两组患者综合疗效、不良反应发生率,治疗前后中医证候积分(主症、次症、总积分)、尿液指标[尿白蛋白排泄率(Urinary albumin excretion rates,UAER)、尿微量白蛋白(Microalbunminuria,mAlb)]、AGEs-RAGE轴因子(AGEs、RAGE)、炎症因子[肿瘤坏死因子-α(Tumour necrosis factor-α,TNF-α)、白介素-6(Interleukin-6,IL-6)]水平及生活质量(A-DQOL)评分。结果治疗后治疗组总有效率93.18%(41/44)明显高于对照组79.07%(34/43),差异有统计学意义(P<0.05)。治疗后两组患者中医证候积分(主症、次症、总积分),尿液指标(UAER、mAlb),AGEs-RAGE轴因子水平(血清AGEs、RAGE)、炎症因子水平(TNF-α、IL-6),生活质量(A-DQOL各维度)评分均较治疗前降低,差异有统计学意义(P<0.05);且治疗组中医证候积分(主症、次症、总积分),尿液指标(UAER、mAlb),AGEs-RAGE轴因子水平(血清AGEs、RAGE)、炎症因子水平(TNF-α、IL-6),生活质量(A-DQOL各维度)评分均较对照组明显降低,差异有统计学意义(P<0.05)。治疗期间,治疗组不良反应发生率15.91%与对照组13.95%比较,差异无统计学意义(P>0.05)。结论益气养阴活血汤治疗早期DN安全、有效,有利于减轻蛋白尿,下调炎症反应,改善患者生活质量,可能与经AGEs-RAGE轴的调节机制有关。

妊娠期糖尿病孕鼠的子鼠发育与AGEs-RAGE轴的相关性研究

目的探讨妊娠糖尿病(GDM)孕鼠血清分泌型晚期糖基化终产物受体(sRAGE)对胎鼠发育的保护作用。方法以腹腔注射法建立SD孕鼠妊娠期糖尿病模型。随机将成功模型进行分组,分为实验及对照两组,对照组隔日尾静脉注射白蛋白溶液(5 mg/kg),实验组同时间点注射相同剂量的0.2 ml PBS稀释的重组sRAGE蛋白。第19天行剖宫产术,剥离胎盘,取出胚胎,记录胎鼠数量、体重、胎盘湿重,肉眼及病理观察胎鼠各系统器官发育畸形及缺陷情况,免疫组化显示子鼠脑、心脏组织切片中p65蛋白质入核状态,分析晚期糖基化终产物-糖基化终产物受体(AGEsRAGE)轴对妊娠期糖尿病孕鼠的胎鼠发育的保护作用。结果 (1)GDM孕鼠在子鼠的产子数量和胎盘湿重两项指标上与正常对照组差异不显著,但是GDM子鼠出现较高的子鼠发育异常和畸形,子鼠的平均体重也较对照组高(P<0.05),sRAGE处理可以降低子代发生畸形的概率,但子代畸形的概率与对照和GDM组相比仍然具有显著差异(P<0.05)。(2)GDM组孕鼠RAGE、EGFR、p65的mRNA表达呈明显上升,而经由sRAGE处理后,各项指标的mRNA表达逐渐下降接近于正常对照组的水平。(3)GDM组子鼠的脑、心脏组织切片后针对p65的免疫荧光染色显示,GDM组细胞中的p65被激活进入细胞核促进相关基因转录,而sRAGE处理显著抑制p65的入核。结论 GDM孕鼠的子代脑和心血管发育异常与孕鼠血清中AGEs水平以及组织中RAGE蛋白质表达水平显著相关,而AGEs-RAGE轴的调控平衡对子鼠发育和出生异常有显著的保护作用。

替米沙坦对自发性高血压大鼠脑组织AGEs-RAGE表达的影响

目的探讨替米沙坦对自发性高血压大鼠(SHR)脑组织晚期糖基化终产物(AGEs)和晚期糖基化终产物受体(RAGE)表达及氧化应激反应的影响。方法 SHR12只随机分为高血压对照组(HC组)和替米沙坦组(T组)各6只,同龄WKY大鼠6只作为正常对照组(NC组)。药物干预16周,测定各组脑组织AGEs、RAGE,和氧化应激指标超氧化物歧化酶(SOD)和丙二醛(MDA)。结果与NC组比较,HC组脑组织羧甲基赖氨酸(CML,AGEs主要成分)和RAGE蛋白表达明显上调(P<0.01),SOD活性显著降低,MDA含量显著升高(P<0.05);与HC组比较,T组CML和RAGE的表达显著降低(P<0.01),SOD活性升高,MDA含量减低(P<0.05)。结论脑组织中AGEs聚集,通过AGEs-RAGE导致脑组织氧化应激反应增强可能是高血压脑损害的途径之一。替米沙坦可能通过抑制AGEs的生成和聚集减轻高血压的脑损害。

AGEs-RAGE信号通路与糖尿病难愈合创面

糖尿病难愈合创面是糖尿病比较严重的并发症和致残原因,故国内外学者对它的研究越来越多。创面愈合是炎性细胞、修复细胞及细胞因子等多种因素共同调控的复杂过程,其中晚期糖基化终末产物(Advanced Glycationend Products,AGEs)及其受体协同的AGEs-RAGE信号通路是目前研究的热点,本文就其进行概述。

AGEs-RAGE/NF-κB途径对慢性间歇低氧小鼠脏器的影响及大株红景天对其脏器的保护作用

目的通过建立慢性间歇低氧小鼠模型探讨晚期糖基化终末产物(advanced glycation end prod-ucts,AGEs)-糖基化终末产物受体(advanced glycosylation end product-specific receptor,RAGE)/核因子-κB(NF-κB)途径与阻塞性睡眠呼吸暂停综合征(obstructive sleep apnea syndrome,OSAS)脏器损伤的关系以及大株红景天注射液对其脏器的保护作用.方法采用酶联免疫吸附测定法(ELISA)检测10只健康对照组小鼠(对照组)、11只单纯慢性间歇低氧小鼠(A组)、11只慢性间歇低氧后再复氧小鼠(B组)、11只慢性间歇低氧后使用大株红景天注射液腹腔注射的小鼠(C组)血清中AGEs、白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)的表达水平,用Western Blotting方法检测小鼠大脑及心脏中RAGE及NF-κB蛋白的表达情况,并观察经HE染色后组织形态学改变情况.结果ELISA结果:与对照组相比,A组小鼠血清中ACEs、IL-6、TNF-α水平显著升高(P<0.05);与A组对比,B组及C组小鼠血清AGEs水平有下降趋势(P>0.05);与A组相比,C组血清IL-6水平有所降低(P<0.05).而B组及C组之间差异无统计学意义(P>0.05);而在血清TNF-α水平方面,B组及C组均较A组下降(P<0.05);而B组及C组两组间差异无统计学意义(P>0.05).RAGE免疫组化结果:心脏组织:对照组小鼠RAGE及NF-κB的表达最弱;A组小鼠的NF-κB的表达在各组中表达最强,其RAGE蛋白表达比对照组及B组强,而与C组相仿;C组小鼠RAGE及NF-κB较对照组及B组表达增多.大脑组织:A组的RAGE及NF-κB蛋白在各组小鼠的大脑组织中表达最强;对照组小鼠RAGE表达较少,NF-κB蛋白在各组中表达最弱;与A组相比,C组的RAGE表达稍有减少,而NF-κB的表达则较其有更为明显的下降.HE染色结果:对照组小鼠心肌组织结构清晰完整、界限清楚、排列紧密;而A组小鼠心肌组织排列紊乱,结构、纹理不清,部分肌细胞核固缩深染.B组小鼠心肌结构较A组小鼠清晰,核固缩深染现象亦较其减少,而C组小鼠心肌结构较清楚,排列亦较紧密.结论OSAS可引起多器官、组织如心脏、大脑组织的损害.OSAS可激活AGEs-RAGE/NF-κB通路,调节炎症细胞释放IL-6、TNF-α等炎症因子,或是OSAS易合并多脏器损害的原因之一.大株红景天注射液有一定程度的抗炎作用,可用于防治OSAS多脏器的损害,但其作用机制与AGEs-RAGE/NF-κB信号通路的激活无明显关系.

Calculus bovis inhibits M2 tumor-associated macrophage polarization via Wnt/β-catenin pathway modulation to suppress liver cancer

BACKGROUND Calculus bovis(CB),used in traditional Chinese medicine,exhibits anti-tumor effects in various cancer models.It also constitutes an integral component of a compound formulation known as Pien Tze Huang,which is indicated for the treatment of liver cancer.However,its impact on the liver cancer tumor microenvironment,particularly on tumor-associated macrophages(TAMs),is not well understood.AIM To elucidate the anti-liver cancer effect of CB by inhibiting M2-TAM polarization via Wnt/β-catenin pathway modulation.METHODS This study identified the active components of CB using UPLC-Q-TOF-MS,evaluated its anti-neoplastic effects in a nude mouse model,and elucidated the underlying mechanisms via network pharmacology,transcriptomics,and molecular docking.In vitro assays were used to investigate the effects of CB-containing serum on HepG2 cells and M2-TAMs,and Wnt pathway modulation was validated by real-time reverse transcriptase-polymerase chain reaction and Western blot analysis.RESULTS This study identified 22 active components in CB,11 of which were detected in the bloodstream.Preclinical investigations have demonstrated the ability of CB to effectively inhibit liver tumor growth.An integrated approach employing network pharmacology,transcriptomics,and molecular docking implicated the Wnt signaling pathway as a target of the antineoplastic activity of CB by suppressing M2-TAM polarization.In vitro and in vivo experiments further confirmed that CB significantly hinders M2-TAM polarization and suppresses Wnt/β-catenin pathway activation.The inhibitory effect of CB on M2-TAMs was reversed when treated with the Wnt agonist SKL2001,confirming its pathway specificity.CONCLUSION This study demonstrated that CB mediates inhibition of M2-TAM polarization through the Wnt/β-catenin pathway,contributing to the suppression of liver cancer growth.

Cell metabolism pathways involved in the pathophysiological changes of diabetic peripheral neuropathy

Diabetic peripheral neuropathy is a common complication of diabetes mellitus.Elucidating the pathophysiological metabolic mechanism impels the generation of ideal therapies.However,existing limited treatments for diabetic peripheral neuropathy expose the urgent need for cell metabolism research.Given the lack of comprehensive understanding of energy metabolism changes and related signaling pathways in diabetic peripheral neuropathy,it is essential to explore energy changes and metabolic changes in diabetic peripheral neuropathy to develop suitable treatment methods.This review summarizes the pathophysiological mechanism of diabetic peripheral neuropathy from the perspective of cellular metabolism and the specific interventions for different metabolic pathways to develop effective treatment methods.Various metabolic mechanisms(e.g.,polyol,hexosamine,protein kinase C pathway)are associated with diabetic peripheral neuropathy,and researchers are looking for more effective treatments through these pathways.

Timosaponin AⅢ induces drug-metabolizing enzymes by activating constitutive androstane receptor (CAR) via dephosphorylation of the EGFR signaling pathway

The current study aimed to assess the effect of timosaponin AⅢ(T-AⅢ)on drug-metabolizing enzymes during anticancer therapy.The in vivo experiments were conducted on nude and ICR mice.Following a 24-day administration of T-AⅢ,the nude mice exhibited an induction of CYP2B10,MDR1,and CYP3A11 expression in the liver tissues.In the ICR mice,the expression levels of CYP2B10 and MDR1 increased after a three-day T-AⅢ administration.The in vitro assessments with HepG2 cells revealed that T-AⅢ induced the expression of CYP2B6,MDR1,and CYP3A4,along with constitutive androstane receptor(CAR)activation.Treatment with CAR siRNA reversed the T-AⅢ-induced increases in CYP2B6 and CYP3A4 expression.Furthermore,other CAR target genes also showed a significant increase in the expression.The up-regulation of murine CAR was observed in the liver tissues of both nude and ICR mice.Subsequent findings demonstrated that T-AⅢ activated CAR by inhibiting ERK1/2 phosphorylation,with this effect being partially reversed by the ERK activator t-BHQ.Inhibition of the ERK1/2 signaling pathway was also observed in vivo.Additionally,T-AⅢ inhibited the phosphorylation of EGFR at Tyr1173 and Tyr845,and suppressed EGF-induced phosphorylation of EGFR,ERK,and CAR.In the nude mice,T-AⅢ also inhibited EGFR phosphorylation.These results collectively indicate that T-AⅢ is a novel CAR activator through inhibition of the EGFR pathway.

Enterogenic Stenotrophomonas maltophilia migrates to the mammary gland to induce mastitis by activating the calcium-ROS-AMPK-mTOR-autophagy pathway

Background Mastitis is an inflammatory disease of the mammary gland that has serious economic impacts on the dairy industry and endangers food safety.Our previous study found that the body has a gut/rumen-mammary gland axis and that disturbance of the gut/rumen microbiota could result in‘gastroenterogenic mastitis'.However,the mechanism has not been fully clarified.Recently,we found that long-term feeding of a high-concentrate diet induced mastitis in dairy cows,and the abundance of Stenotrophomonas maltophilia(S.maltophilia)was significantly increased in both the rumen and milk microbiota.Accordingly,we hypothesized that‘gastroenterogenic mastitis'can be induced by the migration of endogenous gut bacteria to the mammary gland.Therefore,this study investigated the mechanism by which enterogenic S.maltophilia induces mastitis.Results First,S.maltophilia was labelled with superfolder GFP and administered to mice via gavage.The results showed that treatment with S.maltophilia promoted the occurrence of mastitis and increased the permeability of the blood-milk barrier,leading to intestinal inflammation and intestinal leakage.Furthermore,tracking of ingested S.maltophilia revealed that S.maltophilia could migrate from the gut to the mammary gland and induce mastitis.Subsequently,mammary gland transcriptome analysis showed that the calcium and AMPK signalling pathways were significantly upregulated in mice treated with S.maltophilia.Then,using mouse mammary epithelial cells(MMECs),we verified that S.maltophilia induces mastitis through activation of the calcium-ROS-AMPK-mTOR-autophagy pathway.Conclusions In conclusion,the results showed that enterogenic S.maltophilia could migrate from the gut to the mammary gland via the gut-mammary axis and activate the calcium-ROS-AMPK-mTOR-autophagy pathway to induce mastitis.Targeting the gut-mammary gland axis may also be an effective method to treat mastitis.

Argatroban promotes recovery of spinal cord injury by inhibiting the PAR1/JAK2/STAT3 signaling pathway

Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we established a rat model of T10 moderate spinal cord injury using an NYU Impactor ModerⅢand performed intraperitoneal injection of argatroban for 3 consecutive days.Our results showed that argatroban effectively promoted neurological function recovery after spinal cord injury and decreased thrombin expression and activity in the local injured spinal cord.RNA sequencing transcriptomic analysis revealed that the differentially expressed genes in the argatroban-treated group were enriched in the JAK2/STAT3 pathway,which is involved in astrogliosis and glial scar formation.Western blotting and immunofluorescence results showed that argatroban downregulated the expression of the thrombin receptor PAR1 in the injured spinal cord and the JAK2/STAT3 signal pathway.Argatroban also inhibited the activation and proliferation of astrocytes and reduced glial scar formation in the spinal cord.Taken together,these findings suggest that argatroban may inhibit astrogliosis by inhibiting the thrombin-mediated PAR1/JAK2/STAT3 signal pathway,thereby promoting the recovery of neurological function after spinal cord injury.

Myricetin induces M2 macrophage polarization to alleviate renal tubulointerstitial fibrosis in diabetic nephropathy via PI3K/Akt pathway

BACKGROUND Development of end-stage renal disease is predominantly attributed to diabetic nephropathy(DN).Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations observed in renal tissue.Never-theless,the precise molecular mechanism through which myricetin influences the progression of DN remains uncertain.AIM To investigate the effects of myricetin on DN and explore its potential therapeutic mechanism.METHODS Db/db mice were administered myricetin intragastrically on a daily basis at doses of 50 mg/kg or 100 mg/kg for a duration of 12 wk.Subsequently,blood and urine indexes were assessed,along with examination of renal tissue pathology.Kidney morphology and fibrosis were evaluated using various staining techniques including hematoxylin and eosin,periodic acid–Schiff,Masson’s trichrome,and Sirius-red.Additionally,high-glucose culturing was conducted on the RAW 264.7 cell line,treated with 25 mM myricetin or co-administered with the PI3K/Akt inhibitor LY294002 for a period of 24 h.In both in vivo and in vitro settings,quantification of inflammation factor levels was conducted using western blotting,real-time qPCR and ELISA.RESULTS In db/db mice,administration of myricetin led to a mitigating effect on DN-induced renal dysfunction and fibrosis.Notably,we observed a significant reduction in expressions of the kidney injury markers kidney injury molecule-1 and neutrophil gelatinase associated lipocalin,along with a decrease in expressions of inflammatory cytokine-related factors.Furthermore,myricetin treatment effectively inhibited the up-regulation of tumor necrosis factor-alpha,interleukin-6,and interluekin-1βinduced by high glucose in RAW 264.7 cells.Additionally,myricetin modulated the M1-type polarization of the RAW 264.7 cells.Molecular docking and bioinformatic analyses revealed Akt as the target of myricetin.The protective effect of myricetin was nullified upon blocking the polarization of RAW 264.7 via inhibition of PI3K/Akt activation using LY294002.CONCLUSION This study demonstrated that myricetin effectively mitigates kidney injury in DN mice through the regulation of macrophage polarization via the PI3K/Akt signaling pathway.