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.

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.

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.

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.

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.

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.

Review on physiological and ecological characteristics and agronomic regulatory pathways of intercropping to delay root and canopy senescence of crops

Intercropping has been widely used in arid and semi-arid regions because of its high yield,stable productivity,and efficient utilization of resources.However,in recent years,the high yield of traditional intercropping is mainly attributed to the large amount of purchased resources such as water and fertilizer,plastic film,and mechanical power.These lead to a decline in cultivated land quality and exacerbate intercrops'premature root and canopy senescence.So,the application of traditional intercropping faces major challenges in crop production.This paper analyzes the manifestations,occurrence mechanisms,and agronomic regulatory pathways of crop senescence.The physiological and ecological characteristics of intercropping to delay root and canopy senescence of crops are reviewed in this paper.The main agronomic regulatory pathways of intercropping to delay root and canopy senescence of crops are based on above-and blow-ground interactions,including collocation of crop varieties,spatial arrangement,water and fertilizer management,and tillage and mulch practices.Future research fields of intercropping to delay root and canopy senescence should focus on the aspects of selecting and breeding special varieties,application of molecular biology techniques,and developing or applying models to predict and evaluate the root and canopy senescence process of intercrops.Comprehensive analysis and evaluation of different research results could provide a basis for enhancing intercropping delay root and canopy senescence through adopting innovative technologies for regulating the physio-ecological characteristics of intercrops.This would support developing and adopting high-yield,efficient,and sustainable intercropping systems in arid and semi-arid areas with high population density,limited land,and abundant light and heat resources.

Dapagliflozin exerts anti-apoptotic effects by mitigating macrophage polarization via modulation of the phosphoinositide 3-kinase/protein kinase B signaling pathway

BACKGROUND Macrophages are central to the orchestration of immune responses,inflammatory processes,and the pathogenesis of diabetic complications.The dynamic polarization of macrophages into M1 and M2 phenotypes critically modulates inflammation and contributes to the progression of diabetic nephropathy.Sodiumglucose cotransporter 2 inhibitors such as dapagliflozin,which are acclaimed for their efficacy in diabetes management,may influence macrophage polarization,thereby ameliorating diabetic nephropathy.This investigation delves into these mechanistic pathways,aiming to elucidate novel therapeutic strategies for diabetes.AIM To investigate the inhibitory effect of dapagliflozin on macrophage M1 polarization and apoptosis and to explore its mechanism of action.METHODS We established a murine model of type 2 diabetes mellitus and harvested peritoneal macrophages following treatment with dapagliflozin.Concurrently,the human monocyte cell line cells were used for in vitro studies.Macrophage viability was assessed in a cell counting kit 8 assay,whereas apoptosis was evaluated by Annexin V/propidium iodide staining.Protein expression was examined through western blotting,and the expression levels of macrophage M1 surface immunosorbent assay,and quantitative real-time polymerase chain reaction analyses.RESULTS Dapagliflozin attenuated M1 macrophage polarization and mitigated apoptosis in the abdominal macrophages of diabetic mice,evidenced by the downregulation of proapoptotic genes(Caspase 3),inflammatory cytokines[interleukin(IL)-6,tumor necrosis factor-α,and IL-1β],and M1 surface markers(inducible nitric oxide synthase,and cluster of differentiation 86),as well as the upregulation of the antiapoptotic gene BCL2.Moreover,dapagliflozin suppressed the expression of proteins associated with the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway(PI3K,AKT,phosphorylated protein kinase B).These observations were corroborated in vitro,where we found that the modulatory effects of dapagliflozin were abrogated by 740Y-P,an activator of the PI3K/AKT signaling pathway.CONCLUSION Dapagliflozin attenuates the polarization of macrophages toward the M1 phenotype,thereby mitigating inflammation and promoting macrophage apoptosis.These effects are likely mediated through the inhibition of the PI3K/AKT signaling pathway.

Reevaluating Calculus bovis:Modulating the liver cancer immune microenvironment via the Wnt/β-catenin pathway

In this article,we comment on the work published by Huang et al,which explores the mechanisms by which Calculus bovis(CB)modulates the liver cancer immune microenvironment via the Wnt/β-catenin signalling pathway.The study demon-strates that active components in CB effectively inhibit the activation of the Wnt/β-catenin pathway,significantly reducing the polarization of M2 tumor-associated macrophages.Both in vivo and in vitro experiments have validated the anti-tumour effects of CB,revealing its complex mechanisms of action through the modulation of immune cell functions within the tumour microenvironment.This article highlights CB’s therapeutic potential in liver cancer treatment and calls for further investigations into its mechanisms and clinical applications to develop safer,more effective options for patients.The study also revealed that key com-ponents of CB,such as bilirubin and bile acids,inhibit tumour cell proliferation and promote apoptosis through multiple pathways.Future research should explore the mechanisms of action of CB and its potential integration with existing treatments to improve the therapeutic outcomes of liver cancer patients.With multidisciplinary collaboration and advanced research,CB could become a key component of comprehensive liver cancer treatment,offering new hope for patients.

Unlocking the potential of Calculus bovis: A breakthrough in liver cancer treatment via Wnt/β-catenin pathway modulation

Liver cancer remains a significant global health challenge,characterized by high incidence and mortality rates.Despite advancements in medical treatments,the prognosis for liver cancer patients remains poor,highlighting the urgent need for novel therapeutic approaches.Traditional Chinese medicine(TCM),particularly Calculus bovis(CB),has shown promise in addressing this need due to its multitarget therapeutic mechanisms.CB refers to natural or synthetic gallstones,traditionally sourced from cattle,and used in TCM for their anti-inflammatory,detoxifying,and therapeutic properties.In modern practice,synthetic CB is often utilized to ensure consistent supply and safety.This article aims to discuss the findings of Huang et al,who investigated the anti-liver cancer properties of CB,focusing on its ability to inhibit M2 tumor-associated macrophage(TAM)polarization via modulation of the Wnt/β-catenin pathway.Huang et al employed a comprehensive approach integrating chemical analysis,animal model testing,and advanced bioinformatics.They identified active components of CB using UPLC-Q-TOF-MS,evaluated its anti-neoplastic effects in a nude mouse model,and elucidated the underlying mechanisms through network pharmacology,transcriptomics,and molecular docking studies.The study demonstrated that CB significantly inhibited liver tumor growth in vivo,as evidenced by reduced tumor size and weight in treated mice.Histological analyses confirmed signs of tumor regression.CB was found to modulate the tumor microenvironment by inhibiting the polarization of M2 phenotype-TAMs,as shown by reduced expression of M2 markers and downregulation of mRNA levels of C-C motif chemokine 22,arginase-1,transforming growth factor-beta 2,and interleukin-10.The study further revealed that CB’s antineoplastic activity involved the downregulation of Wnt5B andβ-catenin and upregulation of Axin2,thus inhibiting the Wnt/β-catenin signaling pathway.These findings highlight the therapeutic potential of CB in liver cancer treatment through its modulation of the Wnt/β-catenin pathway and suppression of M2 phenotype-TAM polarization.This study underscores the value of integrating TCM with modern therapeutic strategies to develop novel effective treatments for liver cancer.

Modified Pulsatilla decoction alleviates 5-fluorouracil-induced intestinal mucositis by modulating the TLR4/MyD88/NF-κB pathway and gut microbiota

BACKGROUND Modified Pulsatilla decoction(PD),a PD with licorice and ejiao,is a classic Traditional Chinese Medicine formula with significant efficacy in treating intestinal mucositis(IM)induced by tumor therapy.However,its specific molecular and biological mechanisms remain unclear.AIM To investigate the therapeutic effect and mechanism of modified PD in IM.METHODS This study used an IM mouse model established using 5-fluorouracil injections to investigate the effects of the modified PD(3,6,and 12 g/kg)in IM.The primary chemical components of the modified PD were identified using liquid chromatography-mass spectrometry.Body weight loss,diarrhea scores,intestinal length,histopathological scores,and inflammatory cytokine levels were measured to evaluate the effects of the modified PD in IM.Effects on the TLR4/MyD88/NF-κB pathway were evaluated using western blot analysis.The intestinal microbiota was characterized using Illumina NovaSeq sequencing.RESULTS The results showed that modified PD significantly improved weight loss and diarrhea and shortened the intestines in IM mice.Mechanistically,modified PD suppressed the TLR4/MyD88/NF-κB pathway and downregulated the expression of reactive oxygen species,lipopolysaccharides,and pro-inflammatory cytokines(IL-1β,TNF-α,IFN-γ,IL-6,IL-8,and IL-17),while increasing the expression of the anti-inflammatory cytokine IL-10.Furthermore,modified PD protected the intestinal mucosal barrier by increasing the expression of tight junction proteins(occludin-1,claudin-1,and ZO-1)and mucin-2.Finally,16S rDNA sequencing revealed that modified PD improved intestinal dysbiosis.CONCLUSION Our research offers new insights into the potential mechanism of modified PD in alleviating IM and provides experimental evidence supporting its pharmaceutical application in clinical IM treatment.

Bone marrow mesenchymal stem cells promote uterine healing by activating the PI3K/AKT pathway and modulating inflammation in rat models

BACKGROUND Uterine injury can cause uterine scarring,leading to a series of complications that threaten women’s health.Uterine healing is a complex process,and there are currently no effective treatments.Although our previous studies have shown that bone marrow mesenchymal stem cells(BMSCs)promote uterine damage repair,the underlying mechanisms remain unclear.However,exploring the specific regulatory roles of BMSCs in uterine injury treatment is crucial for further understanding their functions and enhancing therapeutic efficacy.AIM To investigate the underlying mechanism by which BMSCs promote the process of uterine healing.METHODS In in vivo experiments,we established a model of full-thickness uterine injury and injected BMSCs into the uterine wound.Transcriptome sequencing was per-formed to determine the enrichment of differentially expressed genes at the wound site.In in vitro experiments,we isolated rat uterine smooth muscle cells(USMCs)and cocultured them with BMSCs to observe the interaction between BMSCs and USMCs in the microenvironment.RESULTS We found that the differentially expressed genes were mainly related to cell growth,tissue repair,and angiogenesis,while the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathway was highly enriched.Quantitative reverse-transcription polymerase chain reaction was used to validate differentially expressed genes,and the results demonstrated that BMSCs can upregulate genes related to regeneration and downregulate genes related to inflammation.Coculturing BMSCs promoted the migration and proliferation of USMCs,and the USMC microenvironment promoted the myogenic differentiation of BMSCs.Finally,we validated the PI3K/AKT pathway in tissues and cells and showed that BMSCs activate the PI3K/AKT pathway to promote the regeneration of uterine smooth muscle both in vivo and in vitro.CONCLUSION BMSCs upregulated uterine wound regeneration and anti-inflammatory factors and enhanced uterine smooth muscle proliferation through the PI3K/AKT pathway both in vivo and in vitro.

Mesalazine alleviated the symptoms of spontaneous colitis in interleukin-10 knockout mice by regulating the STAT3/NF-κB signaling pathway

BACKGROUND Excessive endoplasmic reticulum(ER)stress in intestinal epithelial cells can lead to damage to the intestinal mucosal barrier,activate the signal transducer and activator of transcription 3(STAT3)/nuclear factor kappa B(NF-κB)signaling pathway,and exacerbate the inflammatory response,thus participating in the pathogenesis of ulcerative colitis(UC).Mesalazine is a commonly used drug in the clinical treatment of UC.However,further studies are needed to determine whether mesalazine regulates the ER stress of intestinal epithelial cells,downregulates the STAT3/NF-κB pathway to play a role in the treatment of UC.AIM To study the therapeutic effects of mesalazine on spontaneous colitis in interleukin-10(IL-10)-/-mice.METHODS The 24-week-old IL-10-/-mice with spontaneous colitis were divided into the model group and the 5-amino salicylic acid group.Littermates of wild-type mice of the same age group served as the control.There were eight mice in each group,four males and four females.The severity of symptoms of spontaneous colitis in IL-10-/-mice was assessed using disease activity index scores.On day 15,the mice were sacrificed.The colon length was measured,and the histopathological changes and ultrastructure of colonic epithelial cells were detected.The protein expressions of STAT3,p-STAT3,NF-κB,IκB,p-IκB,and glucoseregulated protein 78 were identified using Western blotting.The STAT3 and NF-κB mRNA expressions were identified using real-time polymerase chain reaction.The glucose-regulated protein 78 and C/EBP homologous protein expressions in colon sections were detected using immunofluorescence.RESULTS Mesalazine reduced the symptoms of spontaneous colitis in IL-10 knockout mice and the histopathological damage of colonic tissues,and alleviated the ER stress in epithelial cells of colitis mice.Western blotting and quantitative real-time polymerase chain reaction results showed that the STAT3/NF-κB pathway in the colon tissue of model mice was activated,suggesting that this pathway was involved in the pathogenesis of UC and might become a potential therapeutic target.Mesalazine could down-regulate the protein expressions of p-STAT3,NF-κB and p-IκB,and down-regulate the mRNA expression of STAT3 and NF-κB.CONCLUSION Mesalazine may play a protective role in UC by reducing ER stress by regulating the STAT3/NF-κB signaling pathway.

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.

Rational design of continuous and short-range lithium ion pathways based on polydopamine-anchored metal-organic frameworks for all-solid-state electrolytes

The immerging three dimensional(3D) metal-organic framework(MOF)-reinforced composite solid-state electrolytes have attracted great interest because of the enhanced ionic conductivity and mechanical properties. However, the defective spatial arrangement of MOFs restricted by fabrication methodology leads to insufficient lithium ion transport in electrolytes. Herein, a 3D interconnected MOF framework tailored for all-solid-state electrolytes is rationally designed by a universal polydopamine(PDA)-engineered "double-sided tape" strategy. The PDA serves as a double-sided tape, firmly adhering on the special single-layer Nylon grid as well as offering uniform nucleation sites to anchor the metal nodes to ensure continuous growth of well-ordered MOFs. Benefiting from the Lewis acid feature of MOFs and its cage effect toward TFSI^(-), a fast and homogeneous lithium ion transport can be achieved through the internal channels within neighboring MOFs and the continuous MOFs/polymer interfaces both along the short-range circumferential boundary of Nylon fiber. The resultant composite electrolytes exhibit high lithium ion conductivity and prominent mechanical properties, rendering excellent cyclic stability whether used in coin or pouch cells. This work demonstrates a widely applicable "double-sided tape"strategy for controllable spatial arrangement of MOF nanoparticles on optional substrates, which provides a scalable approach to rationally construct desired lithium ion pathways within composite electrolytes.

The potential mechanism of Isodon suzhouensis against COVID-19 via EGFR/TLR4 pathways

Corona Virus Disease 2019(COVID-19)has brought the new challenges to scientific research.Isodon suzhouensis has good anti-inflammatory and antioxidant stress effects,which is considered as a potential treatment for COVID-19.The possibility for the treatment of COVID-19 with I.suzhouensis and its potential mechanism of action were explored by employing molecular docking and network pharmacology.Network pharmacology and molecular docking were used to screen drug targets,and lipopolysaccharide(LPS)induced RAW264.7 and NR8383 cells inflammation model was used for experimental verification.Collectively a total of 209 possible linkages against 18 chemical components from I.suzhouensis and 1194 COVID-19 related targets were selected.Among these,164 common targets were obtained from the intersection of I.suzhouensis and COVID-19.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enriched 582 function targets and 87 target proteins pathways,respectively.The results from molecular docking studies revealed that rutin,vitexin,isoquercitrin and quercetin had significant binding ability with 3 chymotrypsin like protease(3CLpro)and angiotensin converting enzyme 2(ACE2).In vitro studies showed that I.suzhouensis extract(ISE)may inhibit the activation of PI3K/Akt pathway and the expression level of downstream proinflammatory factors by inhibiting the activation of epidermal growth factor receptor(EGFR)in RAW264.7 cells induced by LPS.In addition,ISE was able to inhibit the activation of TLR4/NF-κB signaling pathway in NR8383 cells exposed to LPS.Overall,the network pharmacology and in vitro studies conclude that active components from I.suzhouensis have strong therapeutic potential against COVID-19 through multi-target,multi-pathway dimensions and can be a promising candidate against COVID-19.

Masseter Vestibular evoked myogenic potentials: A new tool to assess the vestibulomasseteric reflex pathway

Purpose: This review article provides the readers with an in-depth insight in understanding and interpreting various research literatures on the masseter vestibular evoked myogenic potentials(mVEMP). The article also reviews the contemporary researches involving the clinical applications of the mVEMP. Conclusions: Masseter VEMP is an evolving yet clinically promising neuro-otology test tool that has recently gained more research interest and is considered an additional tool to diagnose various vestibular disorders. Masseter VEMP assesses the functional integrity of the acoustic-masseteric and vestibulo-masseteric reflex pathways. The mVEMP could be used as a complementary test to evaluate the same peripheral generator as the cervical VEMP but a different central pathway i.e., vestibulo-trigeminal pathway. Various research studies that have experimented on parameters such as the effect of different electrode montages(zygomatic vs mandibular configurations), stimulation rates, filter settings and stimuli used to evoke mVEMP have been discussed in this article that could assist in the optimization of a comprehensive clinical protocol. The latency and the amplitude of mVEMP waveforms serve as significant parameters in differentiating normals from those of the clinical populations. Along with the cVEMPs and oVEMPs, mVEMP might help diagnose brainstem lesions in REM Sleep behaviour disorders, Multiple Sclerosis and Parkinson's disease. However, further studies are required to probe in this area of research.

Formation of the entorhino-hippocampal pathway: a tracing study in vitro and in vivo

Objective The entorhino-hippocampal pathway is the major excitatory input from neurons of the entorhinal cortex on both ipsilateral and contralateral hippocampus/dentate gyrus. This fiber tract consists of the alvear path, the perforant path and a crossed commissural projection. In this study, the histogenesis and development of the various subsets of the entorhino-hippocampal projection have been investigated. Methods Dil, DiO and fast blue tracing as well as anti-calretinin immunocytochemistry were carried out with prenatal and postnatal rats at different ages. Results The alvear path and the commissural pathway started to develop as early as embryonic day （E） 16, while the first perforant afferents reached the stratum lacunosum-moleculare of the hippocampus at E 17 and the outer molecular layer of dentate gyrus at postnatal day （P） 2, respectively. Retrograde tracing with DiI identified entorhinal neurons in layer II to IV as the origin of entorhino-hippocampal pathway. Furthermore, anti-calretinin immunocytochemistry revealed transitory Cajal- Retzius （CR） cells in the stratum lacunosum-moleculare of the hippocampus from as early as E 16. DiI labeling of entorhinal cortex fibers and combined calretinin-immunocytochemistry showed a close association between CR cells and entorhinal afferents. Conclusion The subsets of entorhino-hippocampal pathway appear in the developmental hippocampus during El6 - P2. The temporal and spatial relationship between CR cell and perforant afferent suggests the role of this cell type as a guiding cue for entorhinal afferents at early cortical development.