Lei Shi

• Ph.D.
• Professor at Jinan University

Disrupted cortical neuronal migration is associated with epileptic seizures and developmental delay. However, the molecular mechanism by which disruptions of early cortical development result in neurological symptoms is poorly understood. Here we report α2-chimaerin as a key regulator of cortical neuronal migration and function. In utero suppressio...

Genetic studies of autism spectrum disorder (ASD) have revealed multigene variations that converge on synaptic dysfunction. DOCK4, a gene at 7q31.1 that encodes the Rac1 guanine nucleotide exchange factor Dock4, has been identified as a risk gene for ASD and other neuropsychiatric disorders. However, whether and how Dock4 disruption leads to ASD fe...

Regulation of mRNA translation is essential for brain development and function. Translation elongation factor eEF2 acts as a molecular hub orchestrating various synaptic signals to protein synthesis control and participates in hippocampus-dependent cognitive functions. However, whether eEF2 regulates other behaviors in different brain regions has b...

mRNA translation is critical for regulation of various aspects of the nervous system. Ionotropic glutamate and gamma‐aminobutyric acid type A (GABAA) receptors are fundamental synaptic ion channels that control excitatory and inhibitory synaptic transmission, respectively. However, little is known about the translation of these receptors during bra...

The vertebrate neuromuscular junction (NMJ), a peripheral synapse formed between motoneuron and skeletal muscle, is characterized by a protracted postnatal period of maturation and life-long maintenance. In neuromuscular disorders such as congenital myasthenic syndromes (CMSs), disruptions of NMJ maturation and/or maintenance are frequently observe...

Postoperative neurological dysfunction is a common complication caused by deep hypothermia with cerebral hypoperfusion during aortic arch surgery, but the exact pathological changes and molecular mechanisms are not yet clear. In this study, we established an adult mouse model of deep hypothermic low flow (DHLF) to simulate the ischemic-reperfusion...

Background Empathizing and systemizing abilities are respectively associated with key developmental outcomes like intelligence, executive function, and autistic traits, particularly in typically developing (TD) children. However, how specific cognitive styles—defined by the balance between empathizing and systemizing—relate to these outcomes remain...

Neuroserpin, a secreted protein that belongs to the serpin superfamily of serine protease inhibitors, is highly expressed in the central nervous system and plays multiple roles in brain development and pathology. As a natural inhibitor of recombinant tissue plasminogen activator, neuroserpin inhibits the increased activity of tissue plasminogen act...

Anxiety disorder is a major symptom of autism spectrum disorder (ASD) with a comorbidity rate of ~40%. However, the neural mechanisms of the emergence of anxiety in ASD remain unclear. In our study, we found that hyperactivity of basolateral amygdala (BLA) pyramidal neurons (PNs) in Shank3 InsG3680 knock-in (InsG3680+/+) mice is involved in the dev...

As the population ages, the worldwide prevalence of Alzheimer's disease (AD) as the most common dementia in the elderly is increasing dramatically. However, a long‐term challenge is to achieve rapid and accurate early diagnosis of AD by detecting hallmarks such as amyloid beta (Aβ42). Here, a multi‐channel microfluidic‐based plasmonic fiber‐optic b...

Objective To investigate the relationship between maternal folic acid (FA) supplementation during the pre-conceptional and prenatal periods and the subsequent risk of autism spectrum disorder (ASD) in offspring. Methods A total of 6,049 toddlers aged 16–30 months were recruited from August 2016 to March 2017 for this cross-sectional study conducte...

Optically controlled neuromodulation is a promising approach for basic research of neural circuits and the clinical treatment of neurological diseases. However, developing a non‐invasive and well‐controllable system to deliver accurate and effective neural stimulation is challenging. Micro/nanorobots have shown great potential in various biomedical...

Objective To investigate the relationship between infant feeding practices and autism spectrum disorder (ASD) among children aged 2–5 years in the United States (US). Methods Data from the 2016–2020 National Survey of Children’s Health, a nationally representative cross-sectional survey, were utilized for this study. Questionnaires were administer...

Background: Behavioral research has shown that children with autism spectrum disorder (ASD) have a higher empathizing-systemizing difference (D score) than normal children. However, there is no research about the neuroanatomical mechanisms of the empathizing-systemizing difference in children with ASD. Methods: Participants comprised 41 children...

Eight unprecedented monoterpenoid indole alkaloid (MIA) adducts and dimers, melofusinines A-H (1-8), and three undescribed melodinus-type MIA monomers, melofusinines I-K (9-11), together with six putative biogenetic precursors were isolated from the twigs and leaves of Melodinus fusiformis Champ. ex Benth. Compounds 1 and 2 are unusual hybrid indol...

Here, (-)-Tetrahydroalstonine (THA) was isolated from Alstonia scholaris and investigated for its neuroprotective effect towards oxygen–glucose deprivation/re-oxygenation (OGD/R)-induced neuronal damage. In this study, primary cortical neurons were pre-treated with THA and then subjected to OGD/R induction. The cell viability was tested by the MTT...

A few developmental genes remain persistently expressed in the adult stage, whilst their potential functions in the mature brain remain underappreciated. Here, we report the unexpected importance of Celsr2, a core Planar cell polarity (PCP) component, in maintaining the structural and functional integrity of adult neocortex. Celsr2 is highly expres...

Alzheimer’s disease (AD) is one of the most common neurodegenerative illnesses displaying the highest death rate in old persons. However, the existing AD diagnostic system remains elusive due to lack of a technology that may ensure enough sensitivity and reproducibility, detection accuracy and specificity. Here we report a straightforward approach...

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that lasts lifelong and causes noticeably higher premature mortality. Although the core symptoms and other behavioral deficits of ASD can persist or be deteriorated from early development to old age, how aging affects the behaviors and brain anatomy in ASD is largely unknown. DOCK4 is...

Purpose: Ghrelin, a gastric hormone, provides a hunger signal to the central nervous system to stimulate food intake. Ghrelin also modulates neuroinflammatory and apoptotic processes. Dedicator of cytokinesis 4 (DOCK4), a guanine nucleotide exchange factor (GEF), is involved in the regulation of neuronal polarization and axon regeneration. However...

Dynamic microtubules play a critical role in cell structure and function. In nervous system, microtubules are the major route for cargo protein trafficking and they specially extend into and out of synapses to regulate synaptic development and plasticity. However, the detailed depolymerization mechanism that regulates dynamic microtubules in synaps...

Objective To reveal the neuroprotective effect and the underlying mechanisms of a mixture of the main components of Panax notoginseng saponins (TSPN) on cerebral ischemia-reperfusion injury and oxygen-glucose deprivation/reoxygenation (OGD/R) of cultured cortical neurons.Methods The neuroprotective effect of TSPN was evaluated by 3-(4,5-dimethylthi...

Dynamic microtubules play a critical role in cell structure and function. In nervous system, microtubules specially extend into and out of synapses to regulate synaptic development and plasticity. However, the detailed polymerization especially the depolymerization mechanism that regulates dynamic microtubules in synapses is still unclear. In this...

A combined strategy of building blocks recognition and molecular network construction, termed the building blocks‐based molecular network (BBMN), was first presented to facilitate the efficient discovery of novel natural products. By mapping the BBMN of the total alkaloid fraction of Flueggea suffruticosa, three Securinega alkaloids (SEAs) with unu...

A building blocks-based molecular network (BBMN) strategy was first presented and resulted in the discovery of three novel Securinega alkaloids. Compound 1 characterized an unprecedented 8/5/6/5/6/6/6/6-fused octacyclic scaffold with a unique cage-shaped 3-azatricyclo[6.4.0.03,11]dodecane core, which also exhibited remarkable effect on neuronal dif...

Based on the typical HPLC-UV-MS profiles and characteristic ¹H NMR signals, twelve new phloroglucinol-derived lipids (1−12), featuring a long linear aliphatic side chain, together with three known ones (13–15) were isolated from the ethanol extract of the leaves of Syzygium cumini. Their structures were elucidated on the basis of extensive NMR spec...

Four novel stilbene dimers (1-4), together with their biosynthetically related stilbene monomers (5 and 6), were isolated from the leaves of Cajanus cajan. Their structures with absolute configurations were determined by comprehensive analysis of spectroscopic data and electronic circular dichroism calculations. Compounds 1 and 2 are two novel dime...

Ultrasonic vocalization (USV) characterization is useful for evaluating communication in mouse models of autism spectrum disorder (ASD). Here, by categorizing USVs into 12 types using a comprehensive classification method, we obtained the qualitative and quantitative characteristics of USV repertoire emitted by ASD-related Dock4 knockout (KO) mice...

Background: Panax notoginseng (Burkill) F.H.Chen is a traditional Chinese medicine. The present study reports the potential therapeutic effect of total saponins of Panax notoginseng (Burkill) F.H.Chen (TSPN) on ischemic stroke and investigates the underlying mechanisms. To reveal the neuroprotective effect of TSPN on cerebral ischemia-reperfusion i...

Two novel dimeric diarylheptanoids, alpinidinoids A [(±)-1] and B (2), with two unusual coupling patterns, together with a new naturally occurring diarylheptanoid dimer possessing a rare pyridine ring linkage (alpinidinoid C, 3), were isolated from the rhizomes of Alpinia officinarum. Their structures including absolute configurations were determin...

The Rho family GTPases are small G proteins that act as molecular switches shuttling between active and inactive forms. Rho GTPases are regulated by two classes of regulatory proteins, guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Rho GTPases transduce the upstream signals to downstream effectors, thus regulating...

Autism spectrum disorder (ASD) and dyslexia are both neurodevelopmental disorders with high prevalence in children. Both disorders have strong genetic basis, and share similar social communication deficits co-occurring with impairments of reading or language. However, whether these two disorders share common genetic risks remain elusive. DOCK4 (ded...

Neuroligins (NLs) are a group of postsynaptic cell adhesion molecules that function in synaptogenesis and synaptic transmission. Genetic defects in neuroligin 3 (NL3), a member of the NL protein family, are associated with autism. Studies in rodents have revealed that mutations of NL3 gene lead to increased growth and complexity in dendrites in the...

Objectives This study aims to investigate the neuroprotective effects of curcumin analogues, 7‐(4‐Hydroxy‐3‐methoxyphenyl)‐1‐phenyl‐4E‐hepten‐3‐one (AO‐2) on oxygen–glucose deprivation and re‐oxygenation (OGD/R) induced injury in cortical neurons, which is a widely accepted in‐vitro model for ischaemic reperfusion. Methods In this study, AO‐2 was...

Neuroligins (NLs) are postsynaptic cell-adhesion proteins that play important roles in synapse formation and the excitatory-inhibitory balance. They have been associated with autism in both human genetic and animal model studies, and affect synaptic connections and synaptic plasticity in several brain regions. Yet current research mainly focuses on...

Neuroserpin is a serine‐protease inhibitor mainly expressed in the CNS and involved in the inhibition of the proteolytic cascade. Animal models confirmed its neuroprotective role in perinatal hypoxia‐ischaemia and adult stroke. Although neuroserpin may be a potential therapeutic target in the treatment of the aforementioned conditions, there is sti...

Flueggeacosines A-C (1-3), three dimeric securinine-type alkaloid analogues with unprecedented skeletons, were isolated from Flueggea suffruticosa. Compounds 1 and 2 are the first examples of C-3-C-15' connected dimeric securinine-type alkaloids. Compound 3 is an unprecedented heterodimer of securinine-type and benzoquinolizidine alkaloids. Biosynt...

We have proposed and experimentally demonstrated a plasmonic titled fiber Bragg grating based biosensor for in-situ detection of the small biomolecule, S-adenosyl-L-homocysteine (AdoHcy). The sensor can also monitor the molecule's interaction with the protein Set7 in real-time. The biosensor is made by coating a 50-nm-thick gold film over an 18 $^\...

Rac1, an important Rho GTPase that regulates actin cytoskeleton, has long been suggested to participate in acetylcholine receptor (AChR) clustering at the postsynaptic neuromuscular junction. However, how Rac1 is regulated and how it influences AChR clusters have remained unexplored. This study shows that breaking the balance of Rac1 regulation, by...

Developing therapeutic approaches that target neuronal differentiation will be greatly beneficial for the regeneration of neurons and synaptic networks in neurological diseases. Protein synthesis (mRNA translation) has recently been shown to regulate neurogenesis of neural stem/progenitor cells (NSPCs). However, it has remained unknown whether engi...

Up- and down-regulated proteins.

Total proteins identified by iTRAQ.

Two pairs of new diarylheptanoid–monoterpene adduct enantiomers, (±)-alpininoids A and B [(±)-1 and (±)-2], as well as three pairs of new diarylheptanoid–sesquiterpene adduct enantiomers, (±)-alpininoids C–E [(±)-3–(±)-5], together with four known diarylheptanoids (6–9) were isolated from the rhizomes of Alpinia officinarum. Their structures with a...

Supplementary Fig. 1. Effect of Rab3a knockdown on APP surface expression and cleavage. Supplementary Table 1. Primers used for quantitative RT-PCR analysis of the expression of specific genes. Supplementary Table 1. List of proteins with a significant expression-level change of more than 20%. Supplementary material is available on the publisher’s...

Background: Several proteins have been identified as potential diagnostic biomarkers in imaging, genetic, or proteomic studies in Alzheimer disease (AD) patients and mouse models. However, biomarkers for presymptom diagnosis of AD are still under investigation, as are the presymptom molecular changes in AD pathogenesis. Objective: In this study,...

Neonatal hypoxia-ischaemia (HI) is the most common cause of death and disability in human neonates, and is often associated with persistent motor, sensory, and cognitive impairment. Improved intensive care technology has increased survival without preventing neurological disorder, increasing morbidity throughout the adult population. Early preventa...

Ervaoffine E (1), a new pseudoindoxyl alkaloid possessing a unique rearranged 1,4-diazacycloheptane skeleton, ervaoffine F (2), the first 5,6-seco-6-nor iboga-type alkaloid featuring ring C cleavage, and ervaoffine G (3), bearing an unusual contracted valerolactam ring, together with six known alkaloids were isolated from Ervatamia officinalis. The...

Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly. Increasing evidence has shown that β-amyloid protein (Aβ) production is the key pathological cause of AD. 7-(4-Hydroxy-3-methoxyphenyl)-1-phenyl-4E-hepten-3-one (AO-2), a natural diarylheptanoid, is previously found to have activities in neuronal differentiation a...

Neurite outgrowth is crucial for the maturation of neurons and the establishment of anatomical connections during development of the nervous system. We report here that Arhgef1, a RhoA guanine nucleotide exchange factor previously found expressed in the early stages of neuronal development to regulate neurite outgrowth, is also highly expressed in...

Amyloid-β (Aβ) is one of the major causative agents of Alzheimer's disease (AD), the most common neurodegenerative disorder characterized by progressive cognitive impairment. While effective drugs for AD are currently limited, identifying anti-Aβ compounds from natural products has been shown as a promising strategy which may lead to breakthroughs...

Neurite outgrowth is essential for the establishment of functional neuronal connections during brain development. The current study identifies that Arhgef1 is predominantly expressed in early neuronal developmental stages and negatively regulate neurite outgrowth. Knockdown of Arhgef1 in either Neuro-2a cells or primary cortical neurons leads to ex...

Neurite outgrowth is crucial during neuronal development and regeneration, and strategies that aim at promoting neuritogenesis are beneficial for reconstructing synaptic connections after neuronal degeneration and injury. Using a bivalent analogue strategy as a successful approach, the current study identifies a series of novel dimeric securinine a...

Seven new iboga-type alkaloids are isolated together with six known compounds.

Seven new iboga-type alkaloids (1−7) and six known ones (8−13) were obtained from Ervatamia hainanensis. Their structures with absolute configurations were determined by spectroscopic data, Mosher’s method, single crystal X-ray diffraction and electric circular dichroism (ECD) analyses. The relationship between the absolute configuration of C-7 in...

Neuronal differentiation is a critical developmental process that determines accurate synaptic connection and circuit wiring. A wide variety of naturally occurring compounds have been shown as promising drug leads for the generation and differentiation of neurons. Here we report that a diarylheptanoid from the plant Alpinia officinarum, 7-(4-hydrox...

Rho family GTPases, including RhoA, Rac1, and Cdc42 as the most studied members, are master regulators of actin cytoskeletal organization. Rho GTPases control various aspects of the nervous system and are associated with a number of neuropsychiatric and neurodegenerative diseases. The activity of Rho GTPases is controlled by two families of regulat...

Suffrutines A (1) and B (2), a pair of novel photochemical Z/E isomeric indolizidine alkaloids, with a unique and highly conjugated C20 skeleton, were isolated from the roots of Flueggea suffruticosa. The structures were elucidated by extensive analysis of NMR spectra and single-crystal X-ray diffraction. The light-induced isomerization and hypothe...

Suffrutines A (1) and B (2), a pair of novel photochemical Z/E isomeric indolizidine alkaloids, with a unique and highly conjugated C20 skeleton, were isolated from the roots of Flueggea suffruticosa. The structures were elucidated by extensive analysis of NMR spectra and single-crystal X-ray diffraction. The light-induced isomerization and hypothe...

The maintenance of a high density of neurotransmitter receptors at the postsynaptic apparatus is critical for efficient neurotransmission. Acetylcholine receptors (AChRs) are neurotransmitter receptors densely packed on the postsynaptic muscle membrane at the neuromuscular junction (NMJ) via anchoring onto the actin cytoskeletal network. However, h...

The family of dedicator of cytokinesis (Dock), a protein family that belongs to the atypical Rho guanine nucleotide exchange factors (GEFs) for Rac and/or Cdc42 GTPases, plays pivotal roles in various processes of brain development. To date, 11 members of Docks have been identified in the mammalian system. Emerging evidence has suggested that membe...

Precise regulation of neurite growth and differentiation determines accurate formation of synaptic connections, whose disruptions are frequently associated with neurological disorders. Dedicator of cytokinesis 4 (Dock4), an atypical guanine nucleotide exchange factor for Rac1, is found to be associated with neuropsychiatric diseases, including auti...

Supplementary figures. Figure S1: Comparison of HRH4 mRNA expression between matched CRC tissues and adjacent normal tissues using RT-PCR assay. GAPDH is used as the internal control. Shown is representative example of multiple experiments; Figure S2: mRNA levels of HRH4 in the colorectal cell lines were analyzed using RT-PCR assay, and normalized...

Earlier studies have reported the production of histamine in colorectal cancers (CRCs). The effect of histamine is largely determined locally by the histamine receptor expression pattern. Recent evidence suggests that the expression level of histamine receptor H4 (HRH4) is abnormal in colorectal cancer tissues. However, the role of HRH4 in CRC prog...

The adenomatous polyposis coli (APC) gene has been shown to be involved in genetic instability and to be downregluated in several human carcinomas. The chromosome locus of APC, 5q21-22, is frequently deleted in colorectal cancers (CRCs). The functional impact of such regions needs to be extensively investigated in large amount of clinical samples....

Synapse remodeling, which involves changes in the synaptic structure and their molecular composition, is required for the maturation and refinement of neural circuits. Although synapse remodeling is known to be tightly dependent on the assembly of local actin cytoskeleton, how actin directs the structural changes of synapse and targeting of synapti...

The maturation of neuromuscular junctions (NMJs) requires the topological transformation of postsynaptic acetylcholine receptor (AChR)-containing structures from a simple plaque to an elaborate structure composed of pretzel-like branches. This maturation process results in the precise apposition of the presynaptic and postsynaptic specializations....

EphA4-dependent growth cone collapse requires reorganization of actin cytoskeleton through coordinated activation of Rho family GTPases. Whereas various guanine exchange factors have recently been identified to be involved in EphA4-mediated regulation of Rho GTPases and growth cone collapse, the functional roles of GTPase-activating proteins in the...

The development of dendritic spines is thought to be crucial for synaptic plasticity. Dendritic spines are retracted upon Eph receptor A4 (EphA4) activation, but the mechanisms that control this process are not well understood. Here we report an important function of cyclin-dependent kinase 5 (Cdk5) in EphA4-dependent spine retraction in mice. We f...