Longitudinal assessment of peripheral organ metabolism and the gut microbiota in an APP/PS1 transgenic mouse model of Alzheimer’s disease

Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota.The aim of this study was to investigate systemic changes that occur in Alzheimer’s disease,in particular the association between changes in peripheral organ metabolism,changes in gut microbial composition,and Alzheimer’s disease development.To do this,we analyzed peripheral organ metabolism and the gut microbiota in amyloid precursor protein-presenilin 1(APP/PS1)transgenic and control mice at 3,6,9,and 12 months of age.Twelve-month-old APP/PS1 mice exhibited cognitive impairment,Alzheimer’s disease-related brain changes,distinctive metabolic disturbances in peripheral organs and fecal samples(as detected by untargeted metabolomics sequencing),and substantial changes in gut microbial composition compared with younger APP/PS1 mice.Notably,a strong correlation emerged between the gut microbiota and kidney metabolism in APP/PS1 mice.These findings suggest that alterations in peripheral organ metabolism and the gut microbiota are closely related to Alzheimer’s disease development,indicating potential new directions for therapeutic strategies.

Multilevel analysis of the central-peripheral-target organ pathway:contributing to recovery after peripheral nerve injury

Peripheral nerve injury is a common neurological condition that often leads to severe functional limitations and disabilities.Research on the pathogenesis of peripheral nerve injury has focused on pathological changes at individual injury sites,neglecting multilevel pathological analysis of the overall nervous system and target organs.This has led to restrictions on current therapeutic approaches.In this paper,we first summarize the potential mechanisms of peripheral nerve injury from a holistic perspective,covering the central nervous system,peripheral nervous system,and target organs.After peripheral nerve injury,the cortical plasticity of the brain is altered due to damage to and regeneration of peripheral nerves;changes such as neuronal apoptosis and axonal demyelination occur in the spinal cord.The nerve will undergo axonal regeneration,activation of Schwann cells,inflammatory response,and vascular system regeneration at the injury site.Corresponding damage to target organs can occur,including skeletal muscle atrophy and sensory receptor disruption.We then provide a brief review of the research advances in therapeutic approaches to peripheral nerve injury.The main current treatments are conducted passively and include physical factor rehabilitation,pharmacological treatments,cell-based therapies,and physical exercise.However,most treatments only partially address the problem and cannot complete the systematic recovery of the entire central nervous system-peripheral nervous system-target organ pathway.Therefore,we should further explore multilevel treatment options that produce effective,long-lasting results,perhaps requiring a combination of passive(traditional)and active(novel)treatment methods to stimulate rehabilitation at the central-peripheral-target organ levels to achieve better functional recovery.

Interactions between central nervous system and peripheral metabolic organs

According to Descartes,minds and bodies are distinct kinds of “substance”,and they cannot have causal interactions.However,in neuroscience,the two-way interaction between the brain and peripheral organs is an emerging field of research.Several lines of evidence highlight the importance of such interactions.For example,the peripheral metabolic systems are overwhelmingly regulated by the mind(brain),and anxiety and depression greatly affect the functioning of these systems.Also,psychological stress can cause a variety of physical symptoms,such as bone loss.Moreover,the gut microbiota appears to play a key role in neuropsychiatric and neurodegenerative diseases.Mechanistically,as the command center of the body,the brain can regulate our internal organs and glands through the autonomic nervous system and neuroendocrine system,although it is generally considered to be outside the realm of voluntary control.The autonomic nervous system itself can be further subdivided into the sympathetic and parasympathetic systems.The sympathetic division functions a bit like the accelerator pedal on a car,and the parasympathetic division functions as the brake.The high center of the autonomic nervous system and the neuroendocrine system is the hypothalamus,which contains several subnuclei that control several basic physiological functions,such as the digestion of food and regulation of body temperature.Also,numerous peripheral signals contribute to the regulation of brain functions.Gastrointestinal(GI) hormones,insulin,and leptin are transported into the brain,where they regulate innate behaviors such as feeding,and they are also involved in emotional and cognitive functions.The brain can recognize peripheral inflammatory cytokines and induce a transient syndrome called sick behavior(SB),characterized by fatigue,reduced physical and social activity,and cognitive impairment.In summary,knowledge of the biological basis of the interactions between the central nervous system and peripheral organs will promote the full understanding of how our body works and the rational treatment of disorders.Thus,we summarize current development in our understanding of five types of central-peripheral interactions,including neural control of adipose tissues,energy expenditure,bone metabolism,feeding involving the brain-gut axis and gut microbiota.These interactions are essential for maintaining vital bodily functions,which result in homeostasis,i.e.,a natural balance in the body’s systems.

An expanding stage for commensal microbes in host immune regulation

Gastrointestinal commensal microbiota is a concentrated mix of microbial life forms, including bacteria, fungi, archaea and viruses. These life forms are targets of host antimicrobial defense in order to establish a homeostatic symbiosis inside the host. However, they are also instrumental in shaping the functions of our immune system via a diverse set of communication mechanisms. In the gut, T helper 17, regulatory T and B cells are continuously tuned by specific microbial strains and metabolic processes. These cells in return help to establish a mutually beneficial exchange with the gut microbial contents. Imbalances in this symbiosis lead to dysregulations in the host＇s ability to control infections and the development of autoimmune diseases. In addition, the commensal microbiota has a significant and obligatory role in shaping both gut intrinsic and distal lymphoid organs, casting a large impact on the overall immune landscape in the host. This review discusses the major components of the microbial community in the gut and how its members collectively and individually exert regulatory roles in the host immune system and lymphoid structure development, as well as the functions of several major immune cell types.

Jiaotai Pill (交泰丸) Alleviates Insomnia through Regulating Monoamine and Organic Cation Transporters in Rats

Objective To reveal the effect and mechanism of Jiaotai Pill(交泰丸,JTP)on insomniac rats.Methods The insomniac model was established by intraperitoneal injection of p-chlorophenylalanine(PCPA).In behavioral experiments,rats were divided into control,insomniac model,JTP[3.3 g/(kg•d)],and diazepam[4 mg/(kg•d)]groups.The treatment effect of JTP was evaluated by weight measurement(increasement of body weight),open field test(number of crossings)and forced swimming test(immobility time).A high performance liquid chromatography-electrochemical detection(HPLC-ECD)method was built to determine the concentration of monoamine transmitters in hypothalamus and peripheral organs from normal,model,JTP,citalopram[30 mg/(kg•d)],maprotiline[40 mg/(kg•d)]and bupropion[40 mg/(kg•d)]groups.Expressions of serotonin transporter(SERT),dopamine transporter(DAT),and norepinephrine transporter(NET)were analyzed by quantitative polymerase chain reaction(qPCR)and Western blot in normal,model and JTP groups.A high performance liquid chromatography-electrospray ionization mass spectrometry(HPLC-ESI-MS/MS)method was established to determine the pharmacokinetics,urine cumulative excretion of metformin in vivo,and tissue slice uptake in vitro,which were applied to assess the activity of organic cation transporters(OCTs)in hypothalamus and peripheral organs.Results Compared with the insomniac model group,the body weight and spontaneous locomotor were increased,and the immobility time was decreased after treatment with JTP(P<0.01).Both serotonin and dopamine contents in hypothalamus and peripheral organs were increased(P<0.01).The norepinephrine content was increased in peripheral organs and decreased in hypothalamus(P<0.05 or P<0.01).At the same time,SERT,DAT,OCT1,OCT2,and OCT3 were down-regulated in hypothalamus and peripheral organs(P<0.05).NET was down-regulated in peripheral organs and up-regulated in hypothalamus(P<0.05 or P<0.01).Moreover,the activity of OCTs in hypothalamus and peripheral organs was inhibited(P<0.05).Conclusion JTP alleviates insomnia through regulation of monoaminergic system and OCTs in hypothalamus and peripheral organs.