Divergent input patterns to the central lateral amygdala play a duet in fear memory formation.

Somatostatin (SOM)-expressing neurons in the central lateral amygdala (CeL) are responsible for fear memory learning, but the circuit and molecular mechanisms underlying this biology remain elusive. Here, we found that glutamatergic neurons in the lateral parabrachial nucleus (LPB) directly dominated the activity of CeLSOM neurons, and that selectively inhibiting the LPBGlu→CeLSOM pathway suppressed fear memory acquisition. By contrast, inhibiting CeL-projecting glutamatergic neurons in the paraventricular thalamic nucleus (PVT) interfered with consolidation-related processes. Notably, CeLSOM-innervating neurons in the LPB were modulated by presynaptic cannabinoid receptor 1 (CB1R), and knock down of CB1Rs in LPB glutamatergic neurons enhanced excitatory transmission to the CeL and partially rescued the impairment in fear memory induced by CB1R activation in the CeL. Overall, our study reveals the mechanisms by which CeLSOM neurons mediate the formation of fear memories during fear conditioning in mice, which may provide a new direction for the clinical research of fear-related disorders.

Tofacitinib prevents depressive-like behaviors through decreased hippocampal microgliosis and increased BDNF levels in both LPS-induced and CSDS-induced mice.

Depressive disorders are a global mental health challenge that is closely linked to inflammation, especially in the post-COVID-19 era. The JAK-STAT pathway, which is primarily associated with inflammatory responses, is not fully characterized in the context of depressive disorders. Recently, a phase 3 retrospective cohort analysis heightened that the marketed JAK inhibitor tofacitinib is beyond immune diseases and has potential for preventing mood disorders. Inspired by these clinical facts, we investigated the role of the JAK-STAT signaling pathway in depression and comprehensively assessed the antidepressant effect of tofacitinib. We found that aberrant activation of the JAK-STAT pathway is highly conserved in the hippocampus of classical depressive mouse models: LPS-induced and chronic social defeat stress (CSDS)-induced depressive mice. Mechanistically, the JAK-STAT pathway mediates proinflammatory cytokine production and microgliosis, leading to synaptic defects in the hippocampus of both depressive models. Remarkably, the JAK inhibitor tofacitinib effectively reverses these phenomena, contributing to its antidepressant effect. These findings indicate that the JAK/STAT pathway could be implicated in depressive disorders, and suggest that the JAK inhibitor tofacitinib has a potential translational implication for preventing mood disorders far beyond its current indications.

Microbial signatures predictive of short-term prognosis in severe pneumonia.

Objective: This retrospective cohort study aimed to investigate the composition and diversity of lung microbiota in patients with severe pneumonia and explore its association with short-term prognosis. Methods: A total of 301 patients diagnosed with severe pneumonia underwent bronchoalveolar lavage fluid metagenomic next-generation sequencing (mNGS) testing from February 2022 to January 2024. After applying exclusion criteria, 236 patients were included in the study. Baseline demographic and clinical characteristics were compared between survival and non-survival groups. Microbial composition and diversity were analyzed using alpha and beta diversity metrics. Additionally, LEfSe analysis and machine learning methods were employed to identify key pathogenic microorganism associated with short-term mortality. Microbial interaction modes were assessed through network co-occurrence analysis. Results: The overall 28-day mortality rate was 37.7% in severe pneumonia. Non-survival patients had a higher prevalence of hypertension and exhibited higher APACHE II and SOFA scores, higher procalcitonin (PCT), and shorter hospitalization duration. Microbial α and ß diversity analysis showed no significant differences between the two groups. However, distinct species diversity patterns were observed, with the non-survival group showing a higher abundance of Acinetobacter baumannii, Klebsiella pneumoniae, and Enterococcus faecium, while the survival group had a higher prevalence of Corynebacterium striatum and Enterobacter. LEfSe analysis identified 29 distinct terms, with 10 potential markers in the non-survival group, including Pseudomonas sp. and Enterococcus durans. Machine learning models selected 16 key pathogenic bacteria, such as Klebsiella pneumoniae, significantly contributing to predicting short-term mortality. Network co-occurrence analysis revealed greater complexity in the non-survival group compared to the survival group, with differences in central genera. Conclusion: Our study highlights the potential significance of lung microbiota composition in predicting short-term prognosis in severe pneumonia patients. Differences in microbial diversity and composition, along with distinct microbial interaction modes, may contribute to variations in short-term outcomes. Further research is warranted to elucidate the clinical implications and underlying mechanisms of these findings.

Influence of health education based on the transtheoretical model on kinesiophobia levels and rehabilitation outcomes in elderly patients undergoing total knee arthroplasty.

Objective: In this study, we evaluated the effectiveness of health education based on the transtheoretical model in reducing symptoms of kinesiophobia and enhancing rehabilitation outcomes among elderly patients post-total knee arthroplasty. Methods: Elderly patients post-knee replacement surgery were randomly divided into a control group, which received standard health education, and an experimental group, which received transtheoretical model-based health education. The intervention commenced on the day after surgery and continued for a duration of six months. Assessments of kinesiophobia scores, rehabilitation self-efficacy, and knee function were conducted before the intervention, and then at one, three, and six months postoperatively. Results: Between January 2022 and December 2022, 130 elderly patients who met the eligibility criteria were enrolled and subsequently randomly assigned into two groups of equal size. Comparable baseline characteristics were observed between the two groups The experimental group demonstrated lower kinesiophobia scores and higher scores in rehabilitation self-efficacy and knee function at one, three, and six months following surgery, compared to the control group. Conclusion: Health education based on a transtheoretical model reduces the symptoms of kinesiophobia and enhances rehabilitation self-efficacy and knee functions in elderly patients after knee replacement surgery.

A study on the effect of using the video teach-back method in continuous nursing care of stroke patients.

Objective: To explore the effect of a video teach-back method on continuous family nursing care of stroke patients. Methods: Stroke patients hospitalized in our hospital between March 2020 and March 2023 who met the inclusion criteria were randomly divided into an intervention group (n = 45), who received routine health education plus video teach-back training of caregivers, and a control group (n = 45), who received routine health education only. The effects on nursing-related variables were compared between the two groups. Results: Total scores representing the caring ability of caregivers in the intervention group increased significantly over time relative to baseline and were higher than those of the control group. Scores representing the care burden of caregivers in the intervention group decreased significantly over time and were lower than those of the control group. Conclusion: The teach-back method combined with video education improves the nursing ability of family caregivers and can improve the self-care ability of stroke patients.

Efficacy and safety of letermovir prophylaxis for cytomegalovirus infection after hematopoietic stem cell transplantation.

Letermovir is a specific inhibitor of cytomegalovirus (CMV) terminase complex. Several studies have reported that letermovir can effectively prevent CMV activation after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aimed to identify the efficacy and safety of letermovir prophylaxis for CMV infection after allo-HSCT with a systemic review and meta-analysis. A literature search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. PubMed and Embase databases were searched. A total of 28 studies were included. The incidence of CMV activation at 14 weeks after HSCT was 0.10 (95% confidence interval [CI], 0.06-0.18), which was 0.10 (95% CI, 0.04-0.21) and 0% in adult and children (2 studies were included and both of them were 0%). In addition, the incidence of CMV activation at 14 weeks after allo-HSCT was 0.11 (95% CI, 0.06-0.21) and 0.07 (only 1 study included), respectively, in retrospective and prospective studies. The incidence of CMV activation at 100 and 200 days after HSCT was 0.23 (95% CI, 0.16-0.33) and 0.49 (95% CI, 0.32-0.67), respectively. The incidence of CMV disease at 14 weeks and at 6 months after HSCT was 0.01 (95% CI, 0.01-0.02) and 0.03 (95% CI, 0.01-0.09), respectively. Thus, our systemic review and meta-analysis suggested that letermovir prophylaxis was safe and effective for CMV activation after allo-HSCT.

MPP2 interacts with SK2 to rescue the excitability of glutamatergic neurons in the BLA and facilitate the extinction of conditioned fear in mice.

AIMS: The basolateral amygdala (BLA) plays an integral role in anxiety disorders (such as post traumatic stress disorder) stem from dysregulated fear memory. The excitability of glutamatergic neurons in the BLA correlates with fear memory, and the afterhyperpolarization current (IAHP ) mediated by small-conductance calcium-activated potassium channel subtype 2 (SK2) dominates the excitability of glutamatergicneurons. This study aimed to explore the effect of MPP2 interacts with SK2 in the excitability of glutamatergic neurons in the BLA and the extinction of conditioned fear in mice. METHODS: Fear memory was analyzed via freezing percentage. Western blotting and fluorescence quantitative PCR were used to determine the expression of protein and mRNA respectively. Electrophysiology was employed to measure the excitability of glutamatergic neurons and IAHP . RESULTS: Fear conditioning decreased the levels of synaptic SK2 channels in the BLA, which were restored following fear extinction. Notably, reduced expression of synaptic SK2 channels in the BLA during fear conditioning was caused by the increased activity of protein kinase A (PKA), while increased levels of synaptic SK2 channels in the BLA during fear extinction were mediated by interactions with membrane-palmitoylated protein 2 (MPP2). CONCLUSIONS: Our results revealed that MPP2 interacts with the SK2 channels and rescues the excitability of glutamatergic neurons by increasing the expression of synaptic SK2 channels in the BLA to promote the normalization of anxiety disorders and provide a new direction for the treatment.

AMPK role in epilepsy: a promising therapeutic target?

Epilepsy is a complex and multifaceted neurological disorder characterized by spontaneous and recurring seizures. It poses significant therapeutic challenges due to its diverse etiology and often-refractory nature. This comprehensive review highlights the pivotal role of AMP-activated protein kinase (AMPK), a key metabolic regulator involved in cellular energy homeostasis, which may be a promising therapeutic target for epilepsy. Current therapeutic strategies such as antiseizure medication (ASMs) can alleviate seizures (up to 70%). However, 30% of epileptic patients may develop refractory epilepsy. Due to the complicated nature of refractory epilepsy, other treatment options such as ketogenic dieting, adjunctive therapy, and in limited cases, surgical interventions are employed. These therapy options are only suitable for a select group of patients and have limitations of their own. Current treatment options for epilepsy need to be improved. Emerging evidence underscores a potential association between impaired AMPK functionality in the brain and the onset of epilepsy, prompting an in-depth examination of AMPK's influence on neural excitability and ion channel regulation, both critical factors implicated in epileptic seizures. AMPK activation through agents such as metformin has shown promising antiepileptic effects in various preclinical and clinical settings. These effects are primarily mediated through the inhibition of the mTOR signaling pathway, activation of the AMPK-PI3K-c-Jun pathway, and stimulation of the PGC-1α pathway. Despite the potential of AMPK-targeted therapies, several aspects warrant further exploration, including the detailed mechanisms of AMPK's role in different brain regions, the impact of AMPK under various conditional circumstances such as neural injury and zinc toxicity, the long-term safety and efficacy of chronic metformin use in epilepsy treatment, and the potential benefits of combination therapy involving AMPK activators. Moreover, the efficacy of AMPK activators in refractory epilepsy remains an open question. This review sets the stage for further research with the aim of enhancing our understanding of the role of AMPK in epilepsy, potentially leading to the development of more effective, AMPK-targeted therapeutic strategies for this challenging and debilitating disorder.

The PrLGlu→avBNSTGABA circuit rapidly modulates depression-like behaviors in male mice.

Depression is a global disease with a high prevalence. Here, we examine the role of the circuit from prelimbic mPFC (PrL) to the anterior ventral bed nucleus of the stria terminalis (avBNST) in depression-like mice through behavioral tests, immunofluorescence, chemogenetics, optogenetics, pharmacology, and fiber photometry. Mice exposed to chronic restraint stress with individual housing displayed depression-like behaviors. Optogenetic or chemogenetic activation of the avBNST-projecting glutamatergic neurons in the PrL had an antidepressant effect. Moreover, we found that α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid receptors (AMPARs) play a dominant role in this circuit. Systemic administration of ketamine profoundly alleviated depression-like behaviors in the mice and rapidly rescued the decreased activity in the PrLGlu→avBNSTGABA circuit. Furthermore, the fast-acting effect of ketamine on depressive behaviors was diminished when the circuit was inhibited. To summarize, activating the PrLGlu→avBNSTGABA circuit quickly ameliorated depression-like behaviors. Thus, we propose the PrLGlu→avBNSTGABA circuit as a target for fast regulation of depression.

Anxiolytic effect of antidiabetic metformin is mediated by AMPK activation in mPFC inhibitory neurons.

Diabetic patients receiving the antidiabetic drug metformin have been observed to exhibit a lower prevalence of anxiety disorders, yet the precise mechanism behind this phenomenon is unclear. In our study, we found that anxiety induces a region-specific reduction in AMPK activity in the medial prefrontal cortex (mPFC). Concurrently, transgenic mice with brain-specific AMPK knockout displayed abnormal anxiety-like behaviors. Treatment with metformin or the overexpression of AMPK restored normal AMPK activity in the mPFC and mitigated social stress-induced anxiety-like behaviors. Furthermore, the specific genetic deletion of AMPK in the mPFC not only instigated anxiety in mice but also nullified the anxiolytic effects of metformin. Brain slice recordings revealed that GABAergic excitation and the resulting inhibitory inputs to mPFC pyramidal neurons were selectively diminished in stressed mice. This reduction led to an excitation-inhibition imbalance, which was effectively reversed by metformin treatment or AMPK overexpression. Moreover, the genetic deletion of AMPK in the mPFC resulted in a similar defect in GABAergic inhibitory transmission and a consequent hypo-inhibition of mPFC pyramidal neurons. We also generated a mouse model with AMPK knockout specific to GABAergic neurons. The anxiety-like behaviors in this transgenic mouse demonstrated the unique role of AMPK in the GABAergic system in relation to anxiety. Therefore, our findings suggest that the activation of AMPK in mPFC inhibitory neurons underlies the anxiolytic effects of metformin, highlighting the potential of this primary antidiabetic drug as a therapeutic option for treating anxiety disorders.

Application of national early warning score in assessing postoperative illness severity in elderly patients with gastrointestinal illnesses.

BACKGROUND: Population aging is a social problem that is being faced in most countries. OBJECTIVE: To apply the National Early Warning Score (NEWS) for an early warning on the vital signs and consciousness of elderly patients who are hospitalized in the gastrointestinal surgical department and to provide a reference for early detection of changes in illness severity in elderly patients by studying the correlation between NEWS value and changes in illness severity. METHODS: We enrolled 528 elderly patients who were hospitalized in the gastrointestinal surgical department of a tertiary grade A hospital in Guizhou Province between June 2020 and May 2021, to analyze how NEWS max value correlates with illness severity and obtain the optimal NEWS cutoff value for both potentially critically ill and critically ill elderly patients using the receiver operating characteristic (ROC) curve. RESULTS: There were statistically significant differences in NEWS values between elderly patients with various illness severities (P< 0.05). NEWS values correlated positively with illness severity (r= 0.605, P< 0.001). Based on the ROC curve, early warning trigger values for NEWS to identify potentially critically ill, critically ill and terminally ill elderly patients were 6, 7 and 8, respectively. The area under the curve (AUC) for potentially critically ill, critically ill and terminally ill elderly patients was 0.907, 0.921 and 0.939, respectively. NEWS performed better in detecting patient illness severity than Modified Early Warning Score (MEWS) in AUC, sensitivity, specificity, and Youden's index, with statistically significant differences (P< 0.05). CONCLUSION: An early warning on the vital signs and consciousness of hospitalized elderly patients using NEWS can facilitate advanced detection of changes in illness severity of elderly patients by medical staff and enable timely treatment, thus significantly lowering the risks of illness deterioration.

Astrocyte metabolism and signaling pathways in the CNS.

Astrocytes comprise half of the cells in the central nervous system and play a critical role in maintaining metabolic homeostasis. Metabolic dysfunction in astrocytes has been indicated as the primary cause of neurological diseases, such as depression, Alzheimer's disease, and epilepsy. Although the metabolic functionalities of astrocytes are well known, their relationship to neurological disorders is poorly understood. The ways in which astrocytes regulate the metabolism of glucose, amino acids, and lipids have all been implicated in neurological diseases. Metabolism in astrocytes has also exhibited a significant influence on neuron functionality and the brain's neuro-network. In this review, we focused on metabolic processes present in astrocytes, most notably the glucose metabolic pathway, the fatty acid metabolic pathway, and the amino-acid metabolic pathway. For glucose metabolism, we focused on the glycolysis pathway, pentose-phosphate pathway, and oxidative phosphorylation pathway. In fatty acid metabolism, we followed fatty acid oxidation, ketone body metabolism, and sphingolipid metabolism. For amino acid metabolism, we summarized neurotransmitter metabolism and the serine and kynurenine metabolic pathways. This review will provide an overview of functional changes in astrocyte metabolism and provide an overall perspective of current treatment and therapy for neurological disorders.

Glutamatergic and GABAergic anteroventral BNST projections to PVN CRH neurons regulate maternal separation-induced visceral pain.

Early-life stress (ELS) is thought to cause the development of visceral pain disorders. While some individuals are vulnerable to visceral pain, others are resilient, but the intrinsic circuit and molecular mechanisms involved remain largely unclear. Herein, we demonstrate that inbred mice subjected to maternal separation (MS) could be separated into susceptible and resilient subpopulations by visceral hypersensitivity evaluation. Through a combination of chemogenetics, optogenetics, fiber photometry, molecular and electrophysiological approaches, we discovered that susceptible mice presented activation of glutamatergic projections or inhibition of GABAergic projections from the anteroventral bed nucleus of the stria terminalis (avBNST) to paraventricular nucleus (PVN) corticotropin-releasing hormone (CRH) neurons. However, resilience develops as a behavioral adaptation partially due to restoration of PVN SK2 channel expression and function. Our findings suggest that PVN CRH neurons are dually regulated by functionally opposing avBNST neurons and that this circuit may be the basis for neurobiological vulnerability to visceral pain.

Polyphenolic glycosides with unusual four-membered ring possessing anti-Parkinson's disease potential from black wolfberry.

This work reports the isolation of seven undescribed polyphenolic glycosides (1-7) together with fourteen known compounds (8-21) from the fruit of Lycium ruthenicum Murray. The structures of the undescribed compounds were identified based on comprehensive spectroscopic methods including IR, HRESIMS, NMR and ECD, and chemical hydrolysis. Compounds 1-3 possess an unusual four-membered ring, while 11-15 were firstly isolated from this fruit. Interestingly, compounds 1-3 inhibited monoamine oxidase B with IC50 of 25.36 ± 0.44, 35.36 ± 0.54, and 25.12 ± 1.59 µM, respectively, and showed significant neuroprotective effect on PC12 cells injured by 6-OHDA. Moreover, compound 1 improved the lifespan, dopamine level, climbing behavior, and olfactory ability of the PINK1B9 flies, a Drosophila model of Parkinson's disease. This work presents the first in vivo neuroprotective evidence of the small molecular compounds in L. ruthenicum Murray fruit, indicating its good potential as neuroprotectant.

The microglial innate immune receptors TREM-1 and TREM-2 in the anterior cingulate cortex (ACC) drive visceral hypersensitivity and depressive-like behaviors following DSS-induced colitis.

Inflammatory bowel disease (IBD) is a chronic condition with a high recurrence rate. To date, the clinical treatment of IBD mainly focuses on inflammation and gastrointestinal symptoms while ignoring the accompanying visceral pain, anxiety, depression, and other emotional symptoms. Evidence is accumulating that bi-directional communication between the gut and the brain is indispensable in the pathophysiology of IBD and its comorbidities. Increasing efforts have been focused on elucidating the central immune mechanisms in visceral hypersensitivity and depression following colitis. The triggering receptors expressed on myeloid cells-1/2 (TREM-1/2) are newly identified receptors that can be expressed on microglia. In particular, TREM-1 acts as an immune and inflammatory response amplifier, while TREM-2 may function as a molecule with a putative antagonist role to TREM-1. In the present study, using the dextran sulfate sodium (DSS)-induced colitis model, we found that peripheral inflammation induced microglial and glutamatergic neuronal activation in the anterior cingulate cortex (ACC). Microglial ablation mitigated visceral hypersensitivity in the inflammation phase rather than in the remission phase, subsequently preventing the emergence of depressive-like behaviors in the remission phase. Moreover, a further mechanistic study revealed that overexpression of TREM-1 and TREM-2 remarkably aggravated DSS-induced neuropathology. The improved outcome was achieved by modifying the balance of TREM-1 and TREM-2 via genetic and pharmacological means. Specifically, a deficiency of TREM-1 attenuated visceral hyperpathia in the inflammatory phase, and a TREM-2 deficiency improved depression-like symptoms in the remission phase. Taken together, our findings provide insights into mechanism-based therapy for inflammatory disorders and establish that microglial innate immune receptors TREM-1 and TREM-2 may represent a therapeutic target for the treatment of pain and psychological comorbidities associated with chronic inflammatory diseases by modulating neuroinflammatory responses.

Pan-genome of Citrullus genus highlights the extent of presence/absence variation during domestication and selection.

The rich genetic diversity in Citrullus lanatus and the other six species in the Citrullus genus provides important sources in watermelon breeding. Here, we present the Citrullus genus pan-genome based on the 400 Citrullus genus resequencing data, showing that 477 Mb contigs and 6249 protein-coding genes were absent in the Citrullus lanatus reference genome. In the Citrullus genus pan-genome, there are a total of 8795 (30.5%) genes that exhibit presence/absence variations (PAVs). Presence/absence variation (PAV) analysis showed that a lot of gene PAV were selected during the domestication and improvement, such as 53 favorable genes and 40 unfavorable genes were identified during the C. mucosospermus to C. lanatus landrace domestication. We also identified 661 resistance gene analogs (RGAs) in the Citrullus genus pan-genome, which contains 90 RGAs (89 variable and 1 core gene) located on the pangenome additional contigs. By gene PAV-based GWAS, 8 gene presence/absence variations were found associated with flesh color. Finally, based on the results of gene PAV selection analysis between watermelon populations with different fruit colors, we identified four non-reference candidate genes associated with carotenoid accumulation, which had a significantly higher frequency in the white flesh. These results will provide an important source for watermelon breeding.

Far-field thermal properties of ß12 borophene under an external electric field.

Borophene has been reported as the latest very promising 2D material. We theoretically investigate the thermal radiation of ß12 borophene. ß12 borophene has been composited on Ag substrate. Theoretical research frequently mentions three types of model of ß12 borophene. The energy bands of the three models are different. Homogeneous and inversion symmetric models have a gapless Dirac cone near the K(K') point, while they are gapped in the inversion non-symmetric model. The homogeneous model has gapless triplet fermions and three-band touching points at high-symmetry points. The optical conductivity exhibits peaks due to the energy transition of high-symmetry points. The radiation spectrum follows Wien's displacement law in homogeneous and inversion symmetric models, while it is broken in the inversion non-symmetric model. The total energy radiation changes as the voltage increases for the three ß12 borophene models. The radiation of energy can be controlled by applying a suitable voltage.

Chemical components and monoamine oxidase B inhibition activities from the tubers of Sauromatum giganteum (Engl.) Cusimano & Hett.

The rhizome tuber of Sauromatum giganteum is known as 'Bai Fuzi' in China and has been ethnomedicinally used to treat various neurological diseases. It is considered to possess anti-Parkinson's disease (PD) potential, but the active compounds responsible for that is still unclear. In this work, nineteen compounds were isolated and identified from rhizome tuber of this plant, among which four were firstly reported, i.e. berberine (1), nicotinamide (2), rutin (3) and 5-caffeoylquinic acid (4). Six compounds (1, 3, 4, 8, 14 and 15) exhibited moderate inhibitory activity against MAO-B with IC50 of 118.8, 45.6, 96.2, 65.8, 40.0, and 49.8 µM, and two compounds (3 and 4) displayed significant protective effect on 6-OHDA-induced PC-12 cell model. The molecular docking of the bioactive compounds and MAO-B was carried out to explore the binding mode. The findings revealed the potential of S. giganteum as anti-PD herb and its inclusion in TCM could be explored.

Neuroprotective Effects of Lycium Barbarum Fruit Extract on Pink1B9Drosophila Melanogaster Genetic Model of Parkinson's Disease.

Lycium barbarum (LB) is a famous traditional Chinese medicinal plant as well as food supplement possessing various pharmacological functions such as anti-aging and antioxidant effects. The Parkinson's disease (PD)-related kinase Pink1 plays vital role in maintaining the neuron cell homeostasis, having been recognized as a potential target for the development of anti-PD drugs. In this work, the neuroprotective effects of methanol extract of LB fruit (LBFE) were investigated using a Drosophila PD model (PINK1B9) and a human neuroblastoma SH-SY5Y cell line. We found that when LBFE was supplied to the PINK1B9 flies at 6, 12, and 18 days of age, it raised the ATP and dopamine levels at all ages, extended life span, improved motor behavior, and rescued olfactory deficits of the PINK1B9 flies. In addition, histopathological examinations indicated that muscle atrophy in thoraces of the mutant flies was significantly repaired. Finally, LBFE was able to rescue the SH-SY5Y cells against MPP+-induced neurotoxicity. This work reports for the first time the anti-PD potential of L. barbarum fruit extract in PINK1 mutant fruit flies, presenting a new viewpoint for studing the mechanism of action of LBFE.

Development of opioid-induced hyperalgesia depends on reactive astrocytes controlled by Wnt5a signaling.

Opioids are the frontline analgesics for managing various types of pain. Paradoxically, repeated use of opioid analgesics may cause an exacerbated pain state known as opioid-induced hyperalgesia (OIH), which significantly contributes to dose escalation and consequently opioid overdose. Neuronal malplasticity in pain circuits has been the predominant proposed mechanism of OIH expression. Although glial cells are known to become reactive in OIH animal models, their biological contribution to OIH remains to be defined and their activation mechanism remains to be elucidated. Here, we show that reactive astrocytes (a.k.a. astrogliosis) are critical for OIH development in both male and female mice. Genetic reduction of astrogliosis inhibited the expression of OIH and morphine-induced neural circuit polarization (NCP) in the spinal dorsal horn (SDH). We found that Wnt5a is a neuron-to-astrocyte signal that is required for morphine-induced astrogliosis. Conditional knock-out of Wnt5a in neurons or its co-receptor ROR2 in astrocytes blocked not only morphine-induced astrogliosis but also OIH and NCP. Furthermore, we showed that the Wnt5a-ROR2 signaling-dependent astrogliosis contributes to OIH via inflammasome-regulated IL-1ß. Our results reveal an important role of morphine-induced astrogliosis in OIH pathogenesis and elucidate a neuron-to-astrocyte intercellular Wnt signaling pathway that controls the astrogliosis.