Astrocytes sense glymphatic-level shear stress through the interaction of sphingosine-1-phosphate with Piezo1.

Astrocyte endfeet enwrap brain vasculature, forming a boundary for perivascular glymphatic flow of fluid and solutes along and across the astrocyte endfeet into the brain parenchyma. We evaluated astrocyte sensitivity to shear stress generated by such flow, finding a set point for downstream calcium signaling that is below about 0.1 dyn/cm2. This set point is modulated by albumin levels encountered in cerebrospinal fluid (CSF) under normal conditions and following a blood-brain barrier breach or immune response. The astrocyte mechanosome responsible for the detection of shear stress includes sphingosine-1-phosphate (S1P)-mediated sensitization of the mechanosensor Piezo1. Fluid flow through perivascular channels delimited by vessel wall and astrocyte endfeet thus generates sufficient shear stress to activate astrocytes, thereby potentially controlling vasomotion and parenchymal perfusion. Moreover, S1P receptor signaling establishes a set point for Piezo1 activation that is finely tuned to coincide with CSF albumin levels and to the low shear forces resulting from glymphatic flow.

Neuronal Panx1 drives peripheral sensitization in experimental plantar inflammatory pain.

BACKGROUND: The channel-forming protein Pannexin1 (Panx1) has been implicated in both human studies and animal models of chronic pain, but the underlying mechanisms remain incompletely understood. METHODS: Wild-type (WT, n = 24), global Panx1 KO (n = 24), neuron-specific Panx1 KO (n = 20), and glia-specific Panx1 KO (n = 20) mice were used in this study at Albert Einstein College of Medicine. The von Frey test was used to quantify pain sensitivity in these mice following complete Freund's adjuvant (CFA) injection (7, 14, and 21 d). The qRT-PCR was employed to measure mRNA levels of Panx1, Panx2, Panx3, Cx43, Calhm1, and ß-catenin. Laser scanning confocal microscopy imaging, Sholl analysis, and electrophysiology were utilized to evaluate the impact of Panx1 on neuronal excitability and morphology in Neuro2a and dorsal root ganglion neurons (DRGNs) in which Panx1 expression or function was manipulated. Ethidium bromide (EtBr) dye uptake assay and calcium imaging were employed to investigate the role of Panx1 in adenosine triphosphate (ATP) sensitivity. ß-galactosidase (ß-gal) staining was applied to determine the relative cellular expression levels of Panx1 in trigeminal ganglia (TG) and DRG of transgenic mice. RESULTS: Global or neuron-specific Panx1 deletion markedly decreased pain thresholds after CFA stimuli (7, 14, and 21 d; P < 0.01 vs. WT group), indicating that Panx1 was positively correlated with pain sensitivity. In Neuro2a, global Panx1 deletion dramatically reduced neurite extension and inward currents compared to the WT group (P < 0.05), revealing that Panx1 enhanced neurogenesis and excitability. Similarly, global Panx1 deletion significantly suppressed Wnt/ß-catenin dependent DRG neurogenesis following 5 d of nerve growth factor (NGF) treatment (P < 0.01 vs. WT group). Moreover, Panx1 channels enhanced DRG neuron response to ATP after CFA injection (P < 0.01 vs. Panx1 KO group). Furthermore, ATP release increased Ca2+ responses in DRGNs and satellite glial cells surrounding them following 7 d of CFA treatment (P < 0.01 vs. Panx1 KO group), suggesting that Panx1 in glia also impacts exaggerated neuronal excitability. Interestingly, neuron-specific Panx1 deletion was found to markedly reduce differentiation in cultured DRGNs, as evidenced by stunted neurite outgrowth (P < 0.05 vs. Panx1 KO group; P < 0.01 vs. WT group or GFAP-Cre group), blunted activation of Wnt/ß-catenin signaling (P < 0.01 vs. WT, Panx1 KO and GFAP-Cre groups), and diminished cell excitability (P < 0.01 vs. GFAP-Cre group) and response to ATP stimulation (P < 0.01 vs. WT group). Analysis of ß-gal staining showed that cellular expression levels of Panx1 in neurons are significantly higher (2.5-fold increase) in the DRG than in the TG. CONCLUSIONS: The present study revealed that neuronal Panx1 is a prominent driver of peripheral sensitivity in the setting of inflammatory pain through cell-autonomous effects on neuronal excitability. This hyperexcitability dependence on neuronal Panx1 contrasts with inflammatory orofacial pain, where similar studies revealed a prominent role for glial Panx1. The apparent differences in Panx1 expression in neuronal and non-neuronal TG and DRG cells are likely responsible for the distinct impact of these cell types in the two pain models.

Astrocyte sensitivity to glymphatic shear stress is amplified by albumin and mediated by the interaction of sphingosine 1 phosphate with Piezo1.

Astrocyte endfeet enwrap brain vasculature, forming a boundary for perivascular glymphatic flow of fluid and solutes along and across the astrocyte endfeet into the brain parenchyma. To determine whether astrocytes may sense and respond to the shear forces generated by glymphatic flow, we examined intracellular calcium (Ca 2+ ) changes evoked in astrocytes to brief fluid flow applied in calibrated microfluidic chambers. Shear stresses < 20 dyn/cm 2 failed to evoke Ca 2+ responses in the absence of albumin, but cells responded to shear stress below 1 dyn/cm 2 when as little as 5 µM albumin was present in flow medium. A role for extracellular matrix in mechanotransduction was indicated by reduced sensitivity after degradation of heparan sulfate proteoglycan. Sphingosine-1-phosphate (S1P) amplified shear responses in the absence of albumin, whereas mechanosensitivity was attenuated by the S1P receptor blocker fingolimod. Piezo1 participated in the transduction as revealed by blockade by the spider toxin GsMTX and amplification by the chemical modulator Yoda1, even in absence of albumin or S1P. Our findings that astrocytes are exquisitely sensitive to shear stress and that sensitivity is greatly amplified by albumin concentrations encountered in normal and pathological CSF predict that perivascular astrocytes are responsive to glymphatic shear stress and that responsiveness is augmented by elevated CSF protein. S1P receptor signaling thus establishes a setpoint for Piezo1 activation that is finely tuned to coincide with albumin level in CSF and to the low shear forces resulting from glymphatic flow. Graphical abstract: Astrocyte endfoot responds to glymphatic shear stress when albumin is present. Mechanism involves sphingosine-1-phosphate (S1P) binding to its receptor (S1PR), activating phospholipase C (PLC) and thereby sensitizing the response of Piezo1 to flow. Ca 2+ influx triggers Ca 2+ release from intracellular stores and further downstream signaling, thereby modulating parenchymal perfusion. Illustration created using BioRender.com.

Phytochemistry, Pharmacology and Mode of Action of the Anti-Bacterial Artemisia Plants.

Over 70,000 people die of bacterial infections worldwide annually. Antibiotics have been liberally used to treat these diseases and, consequently, antibiotic resistance and drug ineffectiveness has been generated. In this environment, new anti-bacterial compounds are being urgently sought. Around 500 Artemisia species have been identified worldwide. Most species of this genus are aromatic and have multiple functions. Research into the Artemisia plants has expanded rapidly in recent years. Herein, we aim to update and summarize recent information about the phytochemistry, pharmacology and toxicology of the Artemisia plants. A literature search of articles published between 2003 to 2022 in PubMed, Google Scholar, Web of Science databases, and KNApSAcK metabolomics databases revealed that 20 Artemisia species and 75 compounds have been documented to possess anti-bacterial functions and multiple modes of action. We focus and discuss the progress in understanding the chemistry (structure and plant species source), anti-bacterial activities, and possible mechanisms of these phytochemicals. Mechanistic studies show that terpenoids, flavonoids, coumarins and others (miscellaneous group) were able to destroy cell walls and membranes in bacteria and interfere with DNA, proteins, enzymes and so on in bacteria. An overview of new anti-bacterial strategies using plant compounds and extracts is also provided.

Pharmacological and mechanistic study of PS1, a Pdia4 inhibitor, in ß-cell pathogenesis and diabetes in db/db mice.

Pdia4 has been characterized as a key protein that positively regulates ß-cell failure and diabetes via ROS regulation. Here, we investigated the function and mechanism of PS1, a Pdia4 inhibitor, in ß-cells and diabetes. We found that PS1 had an IC50 of 4 µM for Pdia4. Furthermore, PS1 alone and in combination with metformin significantly reversed diabetes in db/db mice, 6 to 7 mice per group, as evidenced by blood glucose, glycosylated hemoglobin A1c (HbA1c), glucose tolerance test, diabetic incidence, survival and longevity (P < 0.05 or less). Accordingly, PS1 reduced cell death and dysfunction in the pancreatic ß-islets of db/db mice as exemplified by serum insulin, serum c-peptide, reactive oxygen species (ROS), islet atrophy, and homeostatic model assessment (HOMA) indices (P < 0.05 or less). Moreover, PS1 decreased cell death in the ß-islets of db/db mice. Mechanistic studies showed that PS1 significantly increased cell survival and insulin secretion in Min6 cells in response to high glucose (P < 0.05 or less). This increase could be attributed to a reduction in ROS production and the activity of electron transport chain complex 1 (ETC C1) and Nox in Min6 cells by PS1. Further, we found that PS1 inhibited the enzymatic activity of Pdia4 and mitigated the interaction between Pdia4 and Ndufs3 or p22 in Min6 cells (P < 0.01 or less). Taken together, this work demonstrates that PS1 negatively regulated ß-cell pathogenesis and diabetes via reduction of ROS production involving the Pdia4/Ndufs3 and Pdia4/p22 cascades.

A Novel Phytogenic Formulation, EUBIO-BPSG, as a Promising One Health Approach to Replace Antibiotics and Promote Reproduction Performance in Laying Hens.

Gut microbiota play a key role in health maintenance and disease pathogenesis in animals. Dietary phytochemicals are crucial factors shaping gut bacteria. Here, we investigated the function and mechanism of a phytogenic formulation, EUBIO-BPSG (BP), in laying hens. We found that BP dose-dependently improved health and egg production in 54-week-old hens. Furthermore, BP was correlated with increased fecal Lactobacillus, decreased Escherichia coli and Salmonella enterica, and reduced antibiotic resistance (AR) and antibiotic resistance genes (ARG) in chicken stools. The 16S rDNA data showed that BP increased seven genera of probiotics and reduced 13 genera of pathogens in chicken feces. In vitro co-culture experiments showed that BP at 4 µg/mL and above promoted growth of L. reuteri while large 100- and 200-fold higher doses suppressed growth of E. coli and S. enterica, respectively. Mechanistic studies indicated that L. reuteri and its supernatants antagonized growth of E. coli and S. enterica but not vice-versa. Five short-chain fatty acids and derivatives (SCFA) produced from L. reuteri directly killed both pathogens via membrane destruction. Furthermore, BP inhibited conjugation and recombination of ARG via interference with conjugation machinery and integrase activity in E. coli. Collectively, this work suggests that BP promotes host health and reproductive performance in laying hens through regulation of gut microbiota through increasing probiotics and decreasing pathogens and spreading ARG.

Protein disulfide isomerase a4 promotes lung cancer development via the Stat3 pathway in stromal cells.

BACKGROUND: Protein disulfide isomerases a4 (Pdia4) is known to be involved in cancer development. Our previous publication showed that Pdia4 positively promotes cancer development via its inhibition of procaspase-dependent apoptosis in cancer cells. However, nothing is known about its role in the cancer microenvironment. RESULTS: Here, we first found that Pdia4 expression in lung cancer was negatively correlated with patient survival. Next, we investigated the impact of host Pdia4 in stromal cells during cancer development. We showed that Pdia4 was expressed at a low level in stromal cells, and this expression was up-regulated akin to its expression in cancer cells. This up-regulation was stimulated by tumour cell-derived stimuli. Genetics studies in tumour-bearing wild-type and Pdia4-/- mice showed that host Pdia4 promoted lung cancer development in the mice via cancer stroma. This promotion was abolished in Rag1-/- mice which lacked T and B cells. This promotion could be restored once T and B cells were added back to Rag1-/- mice. In addition, host Pdia4 positively regulated the number and immunosuppressive function of stromal cells. Mechanistic studies showed that host Pdia4 positively controlled the Stat3/Vegf pathway in T and B lymphocytes via its stabilization of activated Stat3 in a Thioredoxin-like domain (CGHC)-dependent manner. CONCLUSIONS: These findings identify Pdia4 as a possible target for intervention in cancer stroma, suggesting that targeting Pdia4 in cancer stroma is a promising anti-cancer approach.

Functional and Mechanistic Studies of Two Anti-coccidial Herbs, Bidens pilosa and Artemisia indica.

Currently, antibiotics are commonly used to treat coccidiosis, a severe protozoal disease in chickens. However, due to growing concerns about the antibiotic residue in meat and eggs, phytogenic formulations are becoming an attractive approach to manage this disease. In this study, we investigated the anti-coccidial function and mechanism of phytogenic formulations composed of Bidens pilosa, Artemisia indica, and both used in combination. We found that these formulations increased the survival rate and reduced body weight loss, the feed conversion ratio, oocyst excretion, bloody stools, and gut lesions of chickens. Mechanistic studies showed that A. indica, but not B. pilosa, reduced the survival of Eimeria oocysts. Accordingly, they both inhibited oocyst sporulation and sporozoite invasion into Madin-Darby bovine kidney (MDBK) cells. Overall, we demonstrate that these formulations protect chickens against coccidiosis. Moreover, a combination of B. pilosa and A. indica has an additive effect on coccidiosis control and growth performance in chickens compared to either one used alone.

Pdia4 regulates ß-cell pathogenesis in diabetes: molecular mechanism and targeted therapy.

Loss of ß-cell number and function is a hallmark of diabetes. ß-cell preservation is emerging as a promising strategy to treat and reverse diabetes. Here, we first found that Pdia4 was primarily expressed in ß-cells. This expression was up-regulated in ß-cells and blood of mice in response to excess nutrients. Ablation of Pdia4 alleviated diabetes as shown by reduced islet destruction, blood glucose and HbA1c, reactive oxygen species (ROS), and increased insulin secretion in diabetic mice. Strikingly, this ablation alone or in combination with food reduction could fully reverse diabetes. Conversely, overexpression of Pdia4 had the opposite pathophysiological outcomes in the mice. In addition, Pdia4 positively regulated ß-cell death, dysfunction, and ROS production. Mechanistic studies demonstrated that Pdia4 increased ROS content in ß-cells via its action on the pathway of Ndufs3 and p22phox . Finally, we found that 2-ß-D-glucopyranosyloxy1-hydroxytrideca 5,7,9,11-tetrayne (GHTT), a Pdia4 inhibitor, suppressed diabetic development in diabetic mice. These findings characterize Pdia4 as a crucial regulator of ß-cell pathogenesis and diabetes, suggesting Pdia4 is a novel therapeutic and diagnostic target of diabetes.

Resveratrol Preincubation Enhances the Therapeutic Efficacy of hUC-MSCs by Improving Cell Migration and Modulating Neuroinflammation Mediated by MAPK Signaling in a Mouse Model of Alzheimer's Disease.

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are promising for the treatment of Alzheimer's disease (AD). However, their low rate of migration and survival in the brain limit their clinical applicability. This study is designed to improve the therapeutic potential of hUC-MSCs by preincubating them with resveratrol, a natural polyphenol capable of regulating cell destiny. Herein, we demonstrate that resveratrol preincubation enhances the migration of hUC-MSCs in vitro, as well as their survival and homing into the hippocampus of AD mice in vivo. Moreover, resveratrol-primed MSCs were better able to inhibit amyloid-ß peptide (Aß) deposition, Tau hyperphosphorylation, and oxidative stress, all while improving learning and memory. Notably, we found that hUC-MSCs inhibited neuroinflammation by reacting with astrocytes and microglial cells and suppressing mitogen-activated protein kinases (MAPKs), extracellular signal kinases (ERK), p38 kinases (p38), and c-Jun N-terminal kinases (JNK) signaling pathways in the hippocampus of AD mice. Furthermore, resveratrol pretreatment enhanced these effects. Conclusively, the current study revealed that resveratrol preconditioning protected hUC-MSCs against the hostile microenvironment characteristic of AD and enhanced their viability and homing into the brain of AD mice. The use of resveratrol-pretreated hUC-MSCs is thereby proposed to be a promising therapy for AD.

Phytochemicals as modulators of ß-cells and immunity for the therapy of type 1 diabetes: Recent discoveries in pharmacological mechanisms and clinical potential.

Type 1 diabetes (T1D) is a lethal autoimmune disease afflicting as many as 10 million people worldwide. Considerable advances have been made in early diagnosis and understanding the cause of T1D development. However, new remedies are still in great demand as TID remains an incurable disease. Natural products, primarily phytochemicals, are an extraordinary source of discovery of drug leads for diabetes. This review covers recent findings regarding plant compounds and extracts for T1D based on a literature search of articles published between 2004-2019 in PubMed, Reaxyx, and America/European patent databases. Over this period more than 90 plant compounds and extracts were reported to have beneficial effects on T1D via multiple mechanisms involving the regulation of immunity and/or ß cells. In this review, we focus on recent progress in the understanding of the chemistry (chemical structure and plant source), anti-diabetic bioactivities, and likely mechanisms of action of plant compounds for T1D. Mechanistic studies are summarized, which indicate that flavonoids, terpenoids, and anthranoids can inhibit starch-digesting enzymes, aldose reductase, MAP kinases, NFκB, and/or IκB kinases implicated in energy metabolism, ß-cells, and immunity. Furthermore, human clinical trials centering on flavonoids, isoflavonoids, terpenoids, stilbenoids, and polyynes are discussed, and an overview of emerging anti-diabetic strategies using plant compounds and extracts for applications in T1D prophylaxis and therapy is also provided.

The TRIM protein Mitsugumin 53 enhances survival and therapeutic efficacy of stem cells in murine traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a common neurotrauma leading to brain dysfunction and death. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) hold promise in the treatment of TBI. However, their efficacy is modest due to low survival and differentiation under the harsh microenvironment of the injured brain. MG53, a member of TRIM family protein, plays a vital role in cell and tissue damage repair. The present study aims to test whether MG53 preserves hUC-MSCs against oxidative stress and enhances stem cell survival and efficacy in TBI treatment. METHODS: In this study, we performed a series of in vitro and in vivo experiments in hUC-MSCs and mice to define the function of MG53 enhancing survival, neurogenesis, and therapeutic efficacy of stem cells in murine traumatic brain injury. RESULTS: We found that recombinant human MG53 (rhMG53) protein protected hUC-MSCs against H2O2-induced oxidative damage and stimulated hUC-MSC proliferation and migration. In a mouse model of contusion-induced TBI, intravenous administration of MG53 protein preserved the survival of transplanted hUC-MSCs, mitigated brain edema, reduced neurological deficits, and relieved anxiety and depressive-like behaviors. Co-treatment of MG53 and hUC-MSCs enhanced neurogenesis by reducing apoptosis and improving PI3K/Akt-GSK3ß signaling. CONCLUSION: MG53 enhances the efficacy of hUC-MSCs in the recovery of TBI, indicating that such adjunctive therapy may provide a novel strategy to lessen damage and optimize recovery for brain injury.

Corrigendum: HDAC1 Silence Promotes Neuroprotective Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells in a Mouse Model of Traumatic Brain Injury via PI3K/AKT Pathway.

[This corrects the article DOI: 10.3389/fncel.2018.00498.].

Identification of chimeric RNAs in human infant brains and their implications in neural differentiation.

Chimeric RNAs are transcripts composed of RNA fragments from different genes and are traditionally well-known cancer-causing genetic events. Recent studies show chimeric RNAs being present in multiple non-neoplastic tissues and cells, suggesting that at least some may have roles in normal physiology. However, chimeric RNAs and their implications in brain development and neural differentiation have not been formally studied. Here, we firstly characterized the landscape of chimeric RNAs in human infant brain tissues and identified 599 chimeric RNAs. Through a series of filtering, 22 were selected and tested in a neural differentiation process starting from stem cells. Ten were validated experimentally. One of these ten chimeric RNAs, DUS4L-BCAP29, dramatically increased when human umbilical mesenchymal stem cells were induced for neural differentiation. Consistently, we found that overexpressed DUS4L-BCAP29 effectively promoted neural differentiation. Our results support the important role(s) chimeric RNAs play in neural differentiation, and are consistent with the new notion that chimeric RNAs also exist in normal physiology, and likely serve biological purposes.

Overexpression of FOXQ1 enhances anti-senescence and migration effects of human umbilical cord mesenchymal stem cells in vitro and in vivo.

Mesenchymal stem cells (MSCs) are unique precursor cells characterized by active self-renewal and differentiation potential. These cells offer the advantages of ease of isolation and limited ethical issues as a resource and represent a promising cell therapy for neurodegenerative diseases. However, replicative senescence during cell culture as well as low efficiency of cell migration and differentiation after transplantation are major obstacles. In our previous study, we found that FOXQ1 binds directly to the SIRT1 promoter to regulate cellular senescence and also promotes cell proliferation and migration in many tumor cell lines. Currently, little is known about the effects of FOXQ1 on normal somatic cells. Therefore, we examine the effects of FOXQ1 on senescence and migration of MSCs. Lentiviral vector-mediated overexpression of FOXQ1 in human umbilical cord mesenchymal stem cells (hUC-MSCs) resulted in enhanced cell proliferation and viability. Furthermore, the expression of proteins and markers positively associated with senescence (p16, p21, p53) was reduced, whereas expression of proteins negatively associated with senescence (SIRT1, PCNA) was promoted. Following transplantation of hUC-MSCs overexpressing FOXQ1 in an animal model of Alzheimer's disease (APPV717I transgenic mice) resulted in amelioration of the effects of Alzheimer's disease (AD) on cognitive function and pathological senescence accompanied the increased numbers of hUC-MSCs in the AD brain. In conclusion, FOXQ1 overexpression promotes anti-senescence and migration of hUC-MSCs in vitro and in vivo. These findings also suggest that this strategy may contribute to optimization of the efficiency of stem cell therapy.

Pharmacological activation of the Nrf2 pathway by 3H-1, 2-dithiole-3-thione is neuroprotective in a mouse model of Alzheimer disease.

Accumulating evidence suggests that oxidative stress induced by beta-amyloid (Aß) is implicated in the pathlogical progression of Alzheimer's disease (AD). 3H-1,2-dithiole-3-thione (D3T), the simplest compound of the sulfur-containing dithiolethiones, has been proved to be a strongly active antioxidant factor by regulation of the nuclear factor E2-related factor 2 (Nrf2). Previous study reported that D3T confers protection to AD cell model in vitro, however, the neuroprotective effect of D3T in the AD mammalian model is unknown. In the present study, we aimed to evaluate the therapeutic potential of D3T in the Tg2576 AD mouse model and investigate the mechanisms underlying its beneficial effects. We showed that intraperitoneal administration of D3T significantly alleviated cognitive deficits in AD mice and dramatically decreased insoluble Aß level and oxidative stress. Further mechanistic studies revealed that D3T significantly promoted hippocampal neurogenesis, and up-regulated levels of silent information regulator 1 (Sirt1), Nrf2 and heme oxygenase-1 (HO-1). Moreover, the positive effect of D3T on behavioral performance of AD mice was markedly attenuated by inhibition of the Sirt1/Nrf2 pathway by the antagonist EX527. In summary, our studies on a mouse AD model indicate that D3T could serve as a potential therapeutic agent for this devastating disease.

Resveratrol promotes hUC-MSCs engraftment and neural repair in a mouse model of Alzheimer's disease.

Mesenchymal stem cell transplantation is a promising therapeutic approach for Alzheimer's disease (AD). However, poor engraftment and limited survival rates are major obstacles for its clinical application. Resveratrol, an activator of silent information regulator 2, homolog 1 (SIRT1), regulates cell destiny and is beneficial for neurodegenerative disorders. The present study is designed to explore whether resveratrol regulates the fate of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and whether hUC-MSCs combined with resveratrol would be efficacious in the treatment of neurodegeneration in a mouse model of AD through SIRT1 signaling. Herein, we report that resveratrol facilitates hUC-MSCs engraftment in the hippocampus of AD mice and resveratrol enhances the therapeutic effects of hUC-MSCs in this model as demonstrated by improved learning and memory in the Morris water maze, enhanced neurogenesis and alleviated neural apoptosis in the hippocampus of the AD mice. Moreover, hUC-MSCs and resveratrol jointly regulate expression of hippocampal SIRT1, PCNA, p53, ac-p53, p21, and p16. These data strongly suggests that hUC-MSCs transplantation combined with resveratrol may be an effective therapy for AD.

HDAC1 Silence Promotes Neuroprotective Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells in a Mouse Model of Traumatic Brain Injury via PI3K/AKT Pathway.

Stem cell transplantation is a promising therapy for traumatic brain injury (TBI), but low efficiency of survival and differentiation of transplanted stem cells limits its clinical application. Histone deacetylase 1 (HDAC1) plays important roles in self-renewal of stem cells as well as the recovery of brain disorders. However, little is known about the effects of HDAC1 on the survival and efficacy of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in vivo. In this study, our results showed that HDAC1 silence promoted hUC-MSCs engraftment in the hippocampus and increased the neuroprotective effects of hUC-MSCs in TBI mouse model, which was accompanied by improved neurological function, enhanced neurogenesis, decreased neural apoptosis, and reduced oxidative stress in the hippocampus. Further mechanistic studies revealed that the expressions of phosphorylated PTEN (p-PTEN), phosphorylated Akt (p-Akt), and phosphorylated GSK-3ß (p-GSK-3ß) were upregulated. Intriguingly, the neuroprotective effects of hUC-MSCs with HDAC1 silence on behavioral performance of TBI mice was markedly attenuated by LY294002, an inhibitor of the PI3K/AKT pathway. Taken together, our findings suggest that hUC-MSCs transplantation with HDAC1 silence may provide a potential strategy for treating TBI in the future.