Purinergic signaling systems across comparative models of spinal cord injury

Within the last several decades,the scientific community has made substantial progress in elucidating the complex pathophysiology underlying spinal cord injury.However,despite the many advances using conventional mammalian models,both cellular and axonal regeneration following spinal cord injury have remained out of reach.In this sense,turning to non-mammalian,regenerative species presents a unique opportunity to identify pro-regenerative cues and characterize a spinal cord microenvironment permissive to re-growth.Among the signaling pathways hypothesized to be dysregulated during spinal cord injury is the purinergic signaling system.In addition to its well-known role as energy currency in cells,ATP and its metabolites are small molecule neurotransmitters that mediate many diverse cellular processes within the central nervous system.While our understanding of the roles of the purinergic system following spinal cord injury is limited,this signaling pathway has been implicated in all injury-induced secondary processes,including cellular death,inflammation,reactive gliosis,and neural regeneration.Given that the purinergic system is also evolutionarily conserved between mammalian and non-mammalian species,comparisons of these roles may provide important insights into conditions responsible for recovery success.Here,we compare the secondary processes between key model species and the influence of purinergic signaling in each context.As our understanding of this signaling system and pro-regenerative conditions continues to evolve,so does the potential for the development of novel therapeutic interventions for spinal cord injury.

Purinergic signaling systems across comparative models of spinal cord injury

Within the last several decades,the scientific community has made substantial progress in elucidating the complex pathophysiology underlying spinal cord injury.However,despite the many advances using conventional mammalian models,both cellular and axonal regeneration following spinal cord injury have remained out of reach.In this sense,turning to non-mammalian,regenerative species presents a unique opportunity to identify pro-regenerative cues and chara cterize a spinal cord microenvironment permissive to re-growth.Among the signaling pathways hypothesized to be dysregulated during spinal cord injury is the purinergic signaling system.In addition to its well-known role as energy currency in cells,ATP and its metabolites are small molecule neurotransmitte rs that mediate many diverse cellular processes within the central nervous system.While our unde rstanding of the roles of the purinergic system following spinal cord injury is limited,this signaling pathway has been implicated in all injury-induced secondary processes,including cellular death,inflammation,reactive gliosis,and neural regeneration.Given that the purinergic system is also evolutionarily conserved between mammalian and non-mammalian species,comparisons of these roles may provide important insights into conditions responsible for recovery success.Here,we compare the secondary processes between key model species and the influence of purinergic signaling in each context.As our understanding of this signaling system and pro-regenerative conditions continues to evolve,so does the potential for the development of novel therapeutic interventions for spinal cord injury.

Energy Saving for Automatic Train Control in Moving Block Signaling System

With rapid development of the railway traffic, the moving block signaling system （MBS） method has become more and more important for increasing the track capacity by allowing trains to run in a shorter time-headway while maintaining the required safety margins. In this framework, the tracking target point of the following train is moving forward with its leading train. This paper focuses on the energy saving tracking control of two successive trains in MBS. Nonlinear programming method is used to optimize the energy-saving speed trajectory of the following train. The real-time location of the leading train could be integrated into the optimization process. Due to simplicity, it can be used for online implementation. The feasibility and effectiveness are verified through simulation. The results show that the new method is efficient on energy saving even when disturbances present.

Stability Analysis for the Cellular Signaling Systems Composed of Two Phosphorylation-Dephosphorylation Cyclic Reactions

The regulatory mechanisms in cellular signaling systems have been studied intensively from the viewpoint that the malfunction of the regulation is thought to be one of the substantial causes of cancer formation. On the other hand, it is rather difficult to develop the theoretical framework for investigation of the regulatory mechanisms due to their complexity and nonlinearity. In this study, more general approach is proposed for elucidation of characteristics of the stability in cellular signaling systems by construction of mathematical models for a class of cellular signaling systems and stability analysis of the models over variation of the network architectures and the parameter values. The model system is formulated as regulatory network in which every node represents a phosphorylation-dephosphorylation cyclic reaction for respective constituent enzyme. The analysis is performed for all variations of the regulatory networks comprised of two nodes with multiple feedback regulation loops. It is revealed from the analysis that the regulatory networks become mono-stable, bi-stable, tri-stable, or oscillatory and that the negative mutual feedback or positive mutual feedback is favorable for multi-stability, which is augmented by a negatively regulated node with a positive auto-regulation. Furthermore, the multi-stability or the oscillation is more likely to emerge in the case of low value of the Michaelis constant than in the case of high value, implying that the condition of higher saturation levels induces stronger nonlinearity in the networks. The analysis for the parameter regions yielding the multi-stability and the oscillation clarified that the stronger regulation shifts the systems toward multi-stability.

Gut microbiota dysbiosis contributes toα-synuclein-related pathology associated with C/EBPβ/AEP signaling activation in a mouse model of Parkinson’s disease

Parkinson’s disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction.Gastrointestinal dysfunction can precede the onset of motor symptoms by several years.Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson’s disease,whether it plays a causal role in motor dysfunction,and the mechanism underlying this potential effect,remain unknown.CCAAT/enhancer binding proteinβ/asparagine endopeptidase(C/EBPβ/AEP)signaling,activated by bacterial endotoxin,can promoteα-synuclein transcription,thereby contributing to Parkinson’s disease pathology.In this study,we aimed to investigate the role of the gut microbiota in C/EBPβ/AEP signaling,α-synuclein-related pathology,and motor symptoms using a rotenone-induced mouse model of Parkinson’s disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation.We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier,as well as activation of the C/EBP/AEP pathway,α-synuclein aggregation,and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits.However,treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics.Importantly,we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits,intestinal inflammation,and endotoxemia.Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits,intestinal inflammation,endotoxemia,and intestinal barrier impairment.These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits,C/EBPβ/AEP signaling activation,andα-synuclein-related pathology in a rotenone-induced mouse model of Parkinson’s disease.Additionally,our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson’s disease.

Melatonin improves synapse development by PI3K/Akt signaling in a mouse model of autism spectrum disorder

Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrated to exhibit decreased density of dendritic spines.The role of melatonin,as a neuro hormone capable of effectively alleviating social interaction deficits and regulating the development of dendritic spines,in Ctnnd2 deletion-induced nerve injury remains unclea r.In the present study,we discove red that the deletion of exon 2 of the Ctnnd2 gene was linked to social interaction deficits,spine loss,impaired inhibitory neurons,and suppressed phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt) signal pathway in the prefrontal cortex.Our findings demonstrated that the long-term oral administration of melatonin for 28 days effectively alleviated the aforementioned abnormalities in Ctnnd2 gene-knockout mice.Furthermore,the administration of melatonin in the prefro ntal cortex was found to improve synaptic function and activate the PI3K/Akt signal pathway in this region.The pharmacological blockade of the PI3K/Akt signal pathway with a PI3K/Akt inhibitor,wo rtmannin,and melatonin receptor antagonists,luzindole and 4-phenyl-2-propionamidotetralin,prevented the melatonin-induced enhancement of GABAergic synaptic function.These findings suggest that melatonin treatment can ameliorate GABAe rgic synaptic function by activating the PI3K/Akt signal pathway,which may contribute to the improvement of dendritic spine abnormalities in autism spectrum disorders.

Spi1 regulates the microglial/macrophage inflammatory response via the PI3K/AKT/mTOR signaling pathway after intracerebral hemorrhage

Preclinical and clinical studies have shown that microglia and macrophages participate in a multiphasic brain damage repair process following intracerebral hemorrhage.The E26 transformation-specific sequence-related transcription factor Spi1 regulates microglial/macrophage commitment and maturation.However,the effect of Spi1 on intracerebral hemorrhage remains unclear.In this study,we found that Spi1 may regulate recovery from the neuroinflammation and neurofunctional damage caused by intracerebral hemorrhage by modulating the microglial/macrophage transcriptome.We showed that high Spi1expression in microglia/macrophages after intracerebral hemorrhage is associated with the activation of many pathways that promote phagocytosis,glycolysis,and autophagy,as well as debris clearance and sustained remyelination.Notably,microglia with higher levels of Soil expression were chara cterized by activation of pathways associated with a variety of hemorrhage-related cellular processes,such as complement activation,angiogenesis,and coagulation.In conclusion,our results suggest that Spi1 plays a vital role in the microglial/macrophage inflammatory response following intracerebral hemorrhage.This new insight into the regulation of Spi1 and its target genes may advance our understanding of neuroinflammation in intracerebral hemorrhage and provide therapeutic targets for patients with intracerebral hemorrhage.

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.

Digital signal acquisition system for complex nuclear reaction experiments

A digital data-acquisition system based on XIA LLC products was used in a complex nuclear reaction experiment using radioactive ion beams.A flexible trigger system based on a field-programmable gate array(FPGA)parametrization was developed to adapt to different experimental sizes.A user-friendly interface was implemented,which allows converting script language expressions into FPGA internal control parameters.The proposed digital system can be combined with a conventional analog data acquisition system to provide more flexibility.The performance of the combined system was veri-fied using experimental data.

Hypoglycemic mechanism of Tegillarca granosa polysaccharides on type 2 diabetic mice by altering gut microbiota and regulating the PI3K-akt signaling pathwaye

Type 2 diabetes mellitus(T2DM)is a complex metabolic disease threatening human health.We investigated the effects of Tegillarca granosa polysaccharide(TGP)and determined its potential mechanisms in a mouse model of T2DM established through a high-fat diet and streptozotocin.TGP(5.1×10^(3) Da)was composed of mannose,glucosamine,rhamnose,glucuronic acid,galactosamine,glucose,galactose,xylose,and fucose.It could significantly alleviate weight loss,reduce fasting blood glucose levels,reverse dyslipidemia,reduce liver damage from oxidative stress,and improve insulin sensitivity.RT-PCR and Western blotting indicated that TGP could activate the phosphatidylinositol-3-kinase/protein kinase B signaling pathway to regulate disorders in glucolipid metabolism and improve insulin resistance.TGP increased the abundance of Allobaculum,Akkermansia,and Bifidobacterium,restored the microbiota abundance in the intestinal tracts of mice with T2DM,and promoted short-chain fatty acid production.This study provides new insights into the antidiabetic effects of TGP and highlights its potential as a natural hypoglycemic nutraceutical.

Fanlian Huazhuo Formula alleviates high-fat diet-induced nonalcoholic fatty liver disease by modulating autophagy and lipid synthesis signaling pathway

BACKGROUND Fanlian Huazhuo Formula(FLHZF)has the functions of invigorating spleen and resolving phlegm,clearing heat and purging turbidity.It has been identified to have therapeutic effects on type 2 diabetes mellitus(T2DM)in clinical application.Non-alcoholic fatty liver disease(NAFLD)is frequently diagnosed in patients with T2DM.However,the therapeutic potential of FLHZF on NAFLD and the underlying mechanisms need further investigation.AIM To elucidate the effects of FLHZF on NAFLD and explore the underlying hepatoprotective mechanisms in vivo and in vitro.METHODS HepG2 cells were treated with free fatty acid for 24 hours to induce lipid accumulation cell model.Subsequently,experiments were conducted with the different concentrations of freeze-dried powder of FLHZF for 24 hours.C57BL/6 mice were fed a high-fat diet for 8-week to establish a mouse model of NAFLD,and then treated with the different concentrations of FLHZF for 10 weeks.RESULTS FLHZF had therapeutic potential against lipid accumulation and abnormal changes in biochemical indicators in vivo and in vitro.Further experiments verified that FLHZF alleviated abnormal lipid metabolism might by reducing oxidative stress,regulating the AMPKα/SREBP-1C signaling pathway,activating autophagy,and inhibiting hepatocyte apoptosis.CONCLUSION FLHZF alleviates abnormal lipid metabolism in NAFLD models by regulating reactive oxygen species,autophagy,apoptosis,and lipid synthesis signaling pathways,indicating its potential for clinical application in NAFLD.

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.

“Baihui”(DU20)-penetrating “Qubin”(GB7) acupuncture on blood–brain barrier integrity in rat intracerebral hemorrhage models via the RhoA/ROCK Ⅱ/MLC 2 signaling pathway

Background: Blocking the Rho A/ROCK Ⅱ/MLC 2(Ras homolog gene family member A/Rho kinase Ⅱ/myosin light chain 2) signaling pathway can initiate neuroprotective mechanisms against neurological diseases such as stroke, cerebral ischemia, and subarachnoid hemorrhage. Nevertheless, it is not clear whether and how disrupting the Rho A/ROCK Ⅱ/MLC 2 signaling pathway changes the pathogenic processes of the blood–brain barrier(BBB) after intracerebral hemorrhage(ICH). The present investigation included the injection of rat caudal vein blood into the basal ganglia area to replicate the pathophysiological conditions caused by ICH. Methods: Scalp acupuncture(SA) therapy was performed on rats with ICH at the acupuncture point “Baihui”-penetrating “Qubin,” and the ROCK selective inhibitor fasudil was used as a positive control to evaluate the inhibitory effect of acupuncture on the Rho A/ROCK Ⅱ/MLC 2 signaling pathway. Post-assessments included neurological deficits, brain edema, Evans blue extravasation, Western blot, quantitative polymerase chain reaction, and transmission electron microscope imaging. Results: We found that ROCK Ⅱ acts as a promoter of the Rho A/ROCK Ⅱ/MLC 2 signaling pathway, and its expression increased at 6 h after ICH, peaked at 3 days, and then decreased at 7 days after ICH, but was still higher than the preintervention level. According to some experimental results, although 3 days is the peak, 7 days is the best time point for acupuncture treatment. Starting from 6 h after ICH, the neurovascular structure and endothelial cell morphology around the hematoma began to change. Based on the changes in the promoter ROCK Ⅱ, a 7-day time point was selected as the breakthrough point for treating ICH model rats in the main experiment. The results of this experiment showed that both SA at “Baihui”-penetrating “Qubin” and treatment with fasudil could improve the expression of endothelial-related proteins by inhibiting the Rho A/ROCK Ⅱ/MLC 2 signaling pathway and reduce neurological dysfunction, brain edema, and BBB permeability in rats. Conclusion: This study found that these experimental data indicated that SA at “Baihui”-penetrating “Qubin” could preserve BBB integrity and neurological function recovery after ICH by inhibiting Rho A/ROCK Ⅱ/MLC 2 signaling pathway activation and by regulating endothelial cell–related proteins.

Rice ONAC016 promotes leaf senescence through abscisic acid signaling pathway involving OsNAP

Senescence-induced NAC(senNAC)TFs play a crucial role in senescence during the final stage of leaf development.In this study,we identified a rice senNAC,ONAC016,which functions as a positive regulator of leaf senescence.The expression of ONAC016 increased rapidly in rice leaves during the progression of dark-induced and natural senescence.The onac016-1 knockout mutant showed a delayed leaf yellowing phenotype,whereas the overexpression of ONAC016 accelerated leaf senescence.Notably,ONAC016 expression was upregulated by abscisic acid(ABA),and thus detached leaves of the onac016-1 mutant remained green much longer under ABA treatment.Quantitative RT-PCR analysis showed that ONAC016 upregulates the genes associated with chlorophyll degradation,senescence,and ABA signaling.Yeast one-hybrid and dual-luciferase assays revealed that ONAC016 binds directly to the promoter regions of OsNAP,a key gene involved in chlorophyll degradation and ABA-induced senescence.Taken together,these results suggest that ONAC016 plays an important role in promoting leaf senescence through the ABA signaling pathway involving OsNAP.

PHD17 acts as a target of miR1320 to negatively control cold tolerance via JA-activated signaling in rice

Plant Homeo Domain(PHD)proteins are involved in diverse biological processes during plant growth.However,the regulation of PHD genes on rice cold stress response remains largely unknown.Here,we reported that PHD17 negatively regulated cold tolerance in rice seedlings as a cleavage target of miR1320.PHD17 expression was greatly induced by cold stress,and was down-regulated by miR1320 overexpression and up-regulated by miR1320 knockdown.Through 5'RACE and dual luciferase assays,we found that miR1320 targeted and cleaved the 3'UTR region of PHD17.PHD17 was a nuclearlocalized protein and acted as a transcriptional activator in yeast.PHD17 overexpression reduced cold tolerance of rice seedlings,while knockout of PHD17 increased cold tolerance,partially via the CBF cold signaling.By combining transcriptomic and physiological analyses,we demonstrated that PHD17 modulated ROS homeostasis and flavonoid accumulation under cold stress.K-means clustering analysis revealed that differentially expressed genes in PHD17 transgenic lines were significantly enriched in the jasmonic acid(JA)biosynthesis pathway,and expression of JA biosynthesis and signaling genes was verified to be affected by PHD17.Cold stress tests applied with MeJA or IBU(JA synthesis inhibitor)further suggested the involvement of PHD17 in JA-mediated cold signaling.Taken together,our results suggest that PHD17 acts downstream of miR1320 and negatively regulates cold tolerance of rice seedlings through JA-mediated signaling pathway.

Glucocorticoid receptor signaling in the brain and its involvement in cognitive function

The hypothalamic-pituitary-adrenal axis regulates the secretion of glucoco rticoids in response to environmental challenges.In the brain,a nuclear receptor transcription fa ctor,the glucocorticoid recepto r,is an important component of the hypothalamicpituitary-a d renal axis's negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity.The glucoco rticoid receptor influences cognitive processes,including glutamate neurotransmission,calcium signaling,and the activation of brain-derived neurotrophic factor-mediated pathways,through a combination of genomic and non-genomic mechanisms.Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor,there by affecting the hypothalamic-pituitary-a d renal axis and stress-related cognitive functions.An appropriate level of glucocorticoid receptor expression can improve cognitive function,while excessive glucocorticoid receptors or long-term exposure to glucoco rticoids may lead to cognitive impairment.Patients with cognitive impairment-associated diseases,such as Alzheimer's disease,aging,depression,Parkinson's disease,Huntington's disease,stroke,and addiction,often present with dysregulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor expression.This review provides a comprehensive overview of the functions of the glucoco rticoid receptor in the hypothalamic-pituitary-a d renal axis and cognitive activities.It emphasizes that appropriate glucocorticoid receptor signaling fa cilitates learning and memory,while its dysregulation can lead to cognitive impairment.This provides clues about how glucocorticoid receptor signaling can be targeted to ove rcome cognitive disability-related disorders.

Downregulation of MUC1 Inhibits Proliferation and Promotes Apoptosis by Inactivating NF-κB Signaling Pathway in Human Nasopharyngeal Carcinoma

Objective To investigate the effect of mucin 1(MUC1)on the proliferation and apoptosis of nasopharyngeal carcinoma(NPC)and its regulatory mechanism.Methods The 60 NPC and paired para-cancer normal tissues were collected from October 2020 to July 2021 in Quanzhou First Hospital.The expression of MUC1 was measured by real-time quantitative PCR(qPCR)in the patients with PNC.The 5-8F and HNE1 cells were transfected with siRNA control(si-control)or siRNA targeting MUC1(si-MUC1).Cell proliferation was analyzed by cell counting kit-8 and colony formation assay,and apoptosis was analyzed by flow cytometry analysis in the 5-8F and HNE1 cells.The qPCR and ELISA were executed to analyze the levels of TNF-αand IL-6.Western blot was performed to measure the expression of MUC1,NFкB and apoptosis-related proteins(Bax and Bcl-2).Results The expression of MUC1 was up-regulated in the NPC tissues,and NPC patients with the high MUC1 expression were inclined to EBV infection,growth and metastasis of NPC.Loss of MUC1 restrained malignant features,including the proliferation and apoptosis,downregulated the expression of p-IкB、p-P65 and Bcl-2 and upregulated the expression of Bax in the NPC cells.Conclusion Downregulation of MUC1 restrained biological characteristics of malignancy,including cell proliferation and apoptosis,by inactivating NF-κB signaling pathway in NPC.

The dopaminergic system and Alzheimer's disease

Alzheimer's disease is a common neurodegenerative disorder in older adults.Despite its prevalence,its pathogenesis remains unclea r.In addition to the most widely accepted causes,which in clude excessive amyloid-beta aggregation,tau hyperphosphorylation,and deficiency of the neurotransmitter acetylcholine,numerous studies have shown that the dopaminergic system is also closely associated with the occurrence and development of this condition.Dopamine is a crucial catecholaminergic neurotransmitter in the human body.Dopamine-associated treatments,such as drugs that target dopamine receptor D and dopamine analogs,can improve cognitive function and alleviate psychiatric symptoms as well as ameliorate other clinical manifestations.Howeve r,therapeutics targeting the dopaminergic system are associated with various adverse reactions,such as addiction and exacerbation of cognitive impairment.This review summarizes the role of the dopaminergic system in the pathology of Alzheimer's disease,focusing on currently available dopamine-based therapies for this disorder and the common side effects associated with dopamine-related drugs.The aim of this review is to provide insights into the potential connections between the dopaminergic system and Alzheimer's disease,thus helping to clarify the mechanisms underlying the condition and exploring more effective therapeutic options.

Gga-miRNA-181-5p family facilitates chicken myogenesis via targeting TGFBR1 to block TGF-βsignaling

MicroRNAs(miRNAs)have been demonstrated to control chicken skeletal muscle growth,however,the potential function of the miR-181-5p family in chicken myogenesis remains largely unknown.Here,our study identified the two chicken(Gallus gallus;Gga)miR-181-5p family members widely expressed in various tissues,specifically miR-181a-5p and miR-181b-5p.Besides,the breast muscles of fast-growing broilers expressed higher levels of miR-181a-5p and miR-181b-5p than those of slow-growing layers.Functionally,miR-181a-5p and miR-181b-5p both promote the expression level of myogenic factors including myogenin(MyoG),myogenic differentiation 1(MyoD1),and myosin heavy chain(MyHC),meanwhile accelerating the myotube formation of skeletal muscle satellite cells(SMSCs).Mechanistically,miR-181a-5p and miR-181b-5p directly bind to the 3′untranslated region(UTR)of the transforming growth factor beta receptor 1(TGFBR1)mRNA,further reducing the expression of TGFBR1.TGFBR1 is a key Transforming growth factor beta(TGF-β)signaling transduction receptor and had a negative function in muscle cell differentiation.Furthermore,knockdown of TGFBR1 facilitated the expression of chicken myogenic factors,boosted myotube formation,and decreased the SMAD family member 2/3(SMAD2/3)phosphorylation in chicken SMSCs.SMAD2/3 are downstream of TGF-βsignaling,and miR-181a-5p and miR-181b-5p could reduce the expression of TGFBR1 to further diminish the SMAD2/3 phosphorylation.Our findings revealed that the miR-181-5p family targets TGFBR1 to break the TGF-βsignaling transduction,which resulted in promoting chicken skeletal muscle development.

Diet restriction and exercise alleviate cognitive reduction of high fat diet (HFD)-induced obese mice by rescuing inflammation-mediated compromised insulin signaling pathway through activating AMPK/SIRT1 signal pathway and suppressing TLR4 signal pathway

Obesity,caused by excessive energy,leads to body weight gain and various diseases,including cognitive impairment.Current studies suggest that diet restriction such as optimal fasting and regular exercise are crucial for improving cognitive capacity.However,further exploration is needed to understand the specific mechanisms of high fat diet(HFD)-induced cognitive decline in obesity.In the present study,4-month-old mice were subjected to HFD feeding for 18 weeks,followed by aerobic exercise and high-intensity intermittent exercise,regular diet feeding,and intermittent fasting for 8 weeks,and then used to evaluate cognitive capacity,inflammation,compromised insulin signaling pathway,and apoptosis in hippocampal tissue,as well as AMPK/SIRT1 and TLR4 signal pathways.Obese mice revealed impaired cognitive capacity as compared with mice fed with regular diets.In contrast,aerobic exercise,high-intensity intermittent exercise,regular diet,and intermittent fasting could inhibit apoptosis caused by inflammation-mediated compromised insulin signaling pathway in hippocampal tissues through activating the AMPK/SIRT1 signal pathway and suppressing the TLR4 signal pathway,thereby rescuing the cognitive impairment of obese mice.Therefore,diet restriction and exercise interventions may play a positive role in reverting obesity-induced cognitive impairment.