Hypothalamic Menin regulates systemic aging and cognitive decline.

Aging is a systemic process, which is a risk factor for impaired physiological functions, and finally death. The molecular mechanisms driving aging process and the associated cognitive decline are not fully understood. The hypothalamus acts as the arbiter that orchestrates systemic aging through neuroinflammatory signaling. Our recent findings revealed that Menin plays important roles in neuroinflammation and brain development. Here, we found that the hypothalamic Menin signaling diminished in aged mice, which correlates with systemic aging and cognitive deficits. Restoring Menin expression in ventromedial nucleus of hypothalamus (VMH) of aged mice extended lifespan, improved learning and memory, and ameliorated aging biomarkers, while inhibiting Menin in VMH of middle-aged mice induced premature aging and accelerated cognitive decline. We further found that Menin epigenetically regulates neuroinflammatory and metabolic pathways, including D-serine metabolism. Aging-associated Menin reduction led to impaired D-serine release by VMH-hippocampus neural circuit, while D-serine supplement rescued cognitive decline in aged mice. Collectively, VMH Menin serves as a key regulator of systemic aging and aging-related cognitive decline.

The role of acid-sensing ion channels in monosodium urate-induced gouty pain in mice.

Acid-sensing ion channels (ASICs) in dorsal root ganglion (DRG) neurons play an important role in inflammatory pain. The objective of this study is to observe the regulatory role of ASICs in monosodium urate (MSU) crystal-induced gout pain and explore the basis for ASICs in DRG neurons as a target for gout pain treatment. The gout arthritis model was induced by injecting MSU crystals into the ankle joint of mice. The circumference of the ankle joint was used to evaluate the degree of swelling; the von Frey filaments were used to determine the withdrawal threshold of the paw. ASIC currents and action potentials (APs) were recorded by patch clamp technique in DRG neurons. The results displayed that injecting MSU crystals caused ankle edema and mechanical hyperalgesia of the paw, which was relieved after amiloride treatment. The ASIC currents in DRG neurons were increased to a peak on the second day after injecting MSU crystals, which were decreased after amiloride treatment. MSU treatment increased the current density of ASICs in different diameter DRG cells. MSU treatment does not change the characteristics of AP. The results suggest that ASICs in DRG neurons participate in MSU crystal-induced gout pain.

Multi-omics analysis reveals GAPDH posttranscriptional regulation of IFN-γ and PHGDH as a metabolic checkpoint of microglia polarization.

A "switch" in the metabolic pattern of microglia is considered to be required to meet the metabolic demands of cell survival and functions. However, how metabolic switches regulate microglial function remains controversial. We found here that exposure to amyloid-ß triggers microglial inflammation accompanied by increasing GAPDH levels. The increase of GAPDH, a glycolysis enzyme, leads to the reduced release of interferon-γ (IFN-γ) from inflammatory microglia. Such alternation is translational and is regulated by the binding of glycolysis enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to IFN-γ mRNA. GAPDH, by engaging/disengaging glycolysis and through influencing IFN-γ expression, regulates microglia functions, including phagocytosis and cytokine production. Phosphoglycerate dehydrogenase (PHGDH), screened from different state microglia by metabolomics combined with METARECON analysis, is a metabolic enzyme adjacent downstream of GAPDH and synthesizes serine on the collateral pathway derived from glycolysis. Polarization of microglial with PHGDH as a metabolic checkpoint can be bidirectionally regulated by adding IL-4 or giving PHGDH inhibitors. Therefore, regulation of metabolic enzymes not only reprograms metabolic patterns, but also manipulates microglia functions. Further study should be performed to explore the mechanism of metabolic checkpoints in human microglia or more in vivo animal experiments, and may expand to the effects of various metabolic substrates or enzyme, such as lipids and amino acids, on the functions of microglia.

Honokiol alleviates monosodium urate-induced gouty pain by inhibiting voltage-gated proton channels in mice.

OBJECTIVE: To investigate whether honokiol (HNK) acted as an analgesic in connection with inhibiting the voltage-gated proton channel (Hv1). METHODS: The model of gouty arthritis was induced by injecting monosodium urate (MSU) crystals into the hind ankle joint of mice. HNK was given by intragastric administration. Ankle swelling degree and mechanical allodynia were evaluated using ankle joint circumference measurement and von Frey filaments, respectively. Hv1 current, tail current, and action potential in dorsal root ganglion (DRG) neurons were recorded with patch-clamp techniques. RESULTS: HNK (10, 20, 40 mg/kg) alleviated inflammatory response and mechanical allodynia in a dose-dependent manner. In normal DRG neurons, 50 µM Zn2+ or 2-GBI significantly inhibited the Hv1 current and the current density of Hv1 increased with increasing pH gradient. The amplitude of Hv1 current significantly increased on the 3rd after MSU treatment, and HNK dose-dependently reversed the upregulation of Hv1 current. Compared with MSU group, 40 mg/kg HNK shifted the activation curve to the direction of more positive voltage and increased reversal potential to the normal level. In addition, 40 mg/kg HNK reversed the down-regulation of tail current deactivation time constant (τtail) but did not alter the neuronal excitability of DRG neurons in gouty mice. CONCLUSION: HNK may be a potential analgesic by inhibiting Hv1 current.

Light-noise suppression method for the single-beam optically-pumped magnetometer arrays.

We propose a miniaturized single-beam optically pumped magnetometer (OPM) with a laser power differential structure, along with a dynamically-adjusted detection circuit. This design enables the suppression of optical fluctuation noise and the enhancement of magnetometer sensitivity. For a single-beam OPM, pump light fluctuation noise is a significant contributor to output noise. To address this, we propose an OPM with a laser differential structure that separates the pump light as a part of the reference signal before it enters the cell. The reference current and OPM output current are then subtracted to suppress the noise introduced by pump light fluctuations. To achieve optimal optical noise suppression, we implement balanced homodyne detection (BHD) with real-time current adjustment, which dynamically adjusts the reference ratio between the two currents according to their amplitude. Ultimately, we can reduce the noise introduced by pump light fluctuations by 47% of the original. The OPM with laser power differential achieves a sensitivity of 17.5 fT/Hz1/2, with the optical fluctuation equivalent noise at 13 fT/Hz1/2.

Regulation of TRPV1 channel in monosodium urate-induced gouty arthritis in mice.

OBJECTIVE: The transient receptor potential vanilloid subtype 1 (TRPV1) channel is considered to play an important regulatory role in the process of pain. The purpose of this study is to observe the change characteristics of TRPV1 channel in MSU-induced gouty arthritis and to find a new target for clinical treatment of gout pain. METHODS: Acute gouty arthritis was induced by injection of monosodium urate (MSU) crystals into the ankle joint of mice. The swelling degree was evaluated by measuring the circumference of the ankle joint. Mechanical hyperalgesia was conducted using the electronic von Frey. Calcium fluorescence and TRPV1 current were recorded by applying laser scanning confocal microscope and patch clamp in dorsal root ganglion (DRG) neurons, respectively. RESULTS: MSU treatment resulted in significant inflammatory response and mechanical hyperalgesia. The peak swelling degree appeared at 12 h, and the minimum pain threshold appeared at 8 h after MSU treatment. The fluorescence intensity of capsaicin-induced calcium response and TRPV1 current were increased in DRG cells from MSU-treated mice. The number of cells that increased calcium response after MSU treatment was mainly distributed in small-diameter DRG cells. However, the action potential was not significantly changed in small-diameter DRG cells after MSU treatment. CONCLUSIONS: These findings identified an important role of TRPV1 in mediating mechanical hyperalgesia in MSU-induced gouty arthritis and further suggest that TRPV1 can be regarded as a potential new target for the clinical treatment of gouty arthritis.

Hybrid algorithm for predicting the temperature-variation-induced wavelength drift of DBR semiconductor lasers.

In this paper, a hybrid algorithm to predict the wavelength drift induced by ambient temperature variation in distributed Bragg reflector semiconductor lasers is proposed. This algorithm combines the global search capability of a genetic algorithm (GA) and the supermapping ability of an extreme learning machine (ELM), which not only avoids the randomness of ELM but also improves its generalization performance. In addition, a tenfold cross-validation method is employed to determine the optimal activation function and the number of hidden layer nodes for ELM to construct the most suitable model. After applying multiple sets of test data, the results demonstrate that GA-ELM can quickly and accurately predict the wavelength drift, with an average rms error of 4.09×10-4nm and average mean absolute percentage error of 0.21 %. This model is expected to combine the temperature and current tuning models for a wavelength in follow-up research to achieve rapid tuning and high stability of a wavelength without additional devices.

Gradient phase and amplitude errors in atomic magnetic gradiometers for biomagnetic imaging systems.

The cross-axis projection error (CAPE) caused by residual magnetic fields has recently attracted widespread attention. In this study, we propose a more specific theoretical model and expand the CAPE in gradient measurements. We first report that differences in relaxation rate and residual magnetic field between optically pumped magnetometers (OPMs) introduce a significant error term in the output of OPM gradiometers, referred to as the gradient phase error. Furthermore, when the longitudinal field compensation is inadequate, the interaxial response interference of a single OPM is prominent, resulting in an amplitude distortion of the signal. This is further amplified in the gradiometer configuration, introducing the gradient amplitude error. Our experiments demonstrated that the efficacy of mitigating common-mode noise of OPM gradiometers was significantly impaired when existing the gradient errors. In addition, a simulation with a magnetoencephalography (MEG) system illustrated an induced source localization error of exceeding 2 cm, severely compromising the localization accuracy of OPM-MEG systems.

Expeditious Synthesis of Gwanakoside A and the Chloronaphthol Glycoside Congeners.

The synthesis of gwanakoside A, a chlorinated naphthol bis-glycoside, and its analogues was achieved through stepwise chlorination and donor-equivalent controlled regioselective phenol glycosylation with glycosyl N-phenyltrifluoroacetimidates as donors. Gwanakoside A displayed considerable inhibitory effects against various cancer cells and Staphylococcus aureus strains.

Structure-Guided Design, Synthesis, and Antivirulence Assessment of Covalent Staphylococcus aureus Sortase A Inhibitors.

Sortase A (SrtA) is a membrane-associated cysteine transpeptidase required for bacterial virulence regulation and anchors surface proteins to cell wall, thereby assisting biofilm formation. SrtA is targeted in antivirulence treatments against Gram-positive bacterial infections. However, the development of potent small-molecule SrtA inhibitors is constrained owing to the limited understanding of the mode of action of inhibitors in the SrtA binding pocket. Herein, we designed and synthesized a novel class of covalent SrtA inhibitors based on the binding mode detailed in the X-ray crystal structure of the ML346/Streptococcus pyogenes SrtA complex. ML346 analog Y40 exhibited 2-fold increased inhibitory activity on Staphylococcus aureus SrtA and showed superior inhibitory effects on biofilm formation in vitro. Y40 protected Galleria mellonella larvae fromS. aureusinfections in vivo while minimally attenuating staphylococcal growth in vitro. Our study indicates that the covalent SrtA inhibitor Y40 is an antivirulence agent that is effective againstS. aureusinfections.

Menin Reduces Parvalbumin Expression and is Required for the Anti-Depressant Function of Ketamine.

Dysfunction of parvalbumin (PV) neurons is closely involved in depression, however, the detailed mechanism remains unclear. Based on the previous finding that multiple endocrine neoplasia type 1 (Protein: Menin; Gene: Men1) mutation (G503D) is associated with a higher risk of depression, a Menin-G503D mouse model is generated that exhibits heritable depressive-like phenotypes and increases PV expression in brain. This study generates and screens a serial of neuronal specific Men1 deletion mice, and found that PV interneuron Men1 deletion mice (PcKO) exhibit increased cortical PV levels and depressive-like behaviors. Restoration of Menin, knockdown PV expression or inhibition of PV neuronal activity in PV neurons all can ameliorate the depressive-like behaviors of PcKO mice. This study next found that ketamine stabilizes Menin by inhibiting protein kinase A (PKA) activity, which mediates the anti-depressant function of ketamine. These results demonstrate a critical role for Menin in depression, and prove that Menin is key to the antidepressant function of ketamine.

Menin Deficiency Induces Autism-Like Behaviors by Regulating Foxg1 Transcription and Participates in Foxg1-Related Encephalopathy.

FOXG1 syndrome is a developmental encephalopathy caused by FOXG1 (Forkhead box G1) mutations, resulting in high phenotypic variability. However, the upstream transcriptional regulation of Foxg1 expression remains unclear. This report demonstrates that both deficiency and overexpression of Men1 (protein: menin, a pathogenic gene of MEN1 syndrome known as multiple endocrine neoplasia type 1) lead to autism-like behaviors, such as social defects, increased repetitive behaviors, and cognitive impairments. Multifaceted transcriptome analyses revealed that Foxg1 signaling is predominantly altered in Men1 deficiency mice, through its regulation of the Alpha Thalassemia/Mental Retardation Syndrome X-Linked (Atrx) factor. Atrx recruits menin to bind to the transcriptional start region of Foxg1 and mediates the regulation of Foxg1 expression by H3K4me3 (Trimethylation of histone H3 lysine 4) modification. The deficits observed in menin deficient mice are rescued by the over-expression of Foxg1, leading to normalized spine growth and restoration of hippocampal synaptic plasticity. These findings suggest that menin may have a putative role in the maintenance of Foxg1 expression, highlighting menin signaling as a potential therapeutic target for Foxg1-related encephalopathy.

Brain Energy Metabolism: Astrocytes in Neurodegenerative Diseases.

Astrocytes are the most abundant cells in the brain. They have many important functions in the central nervous system (CNS), including the maintenance of glutamate and ion homeostasis, the elimination of oxidative stress, energy storage in glycogen, tissue repair, regulating synaptic activity by releasing neurotransmitters, and participating in synaptic formation. Astrocytes have special highly ramified structure. Their branches contact with synapses of neurons inwardly, with fine structure and wrapping synapses; their feet contact with blood vessels of brain parenchyma outward, almost wrapping the whole brain. The adjacent astrocytes rarely overlap and communicate with each other through gap junction channels. The ideal location of astrocytes enables them to sense the weak changes of their surroundings and provide the structural basis for the energy supply of neurons. Neurons and astrocytes are closely coupled units of energy metabolism in the brain. Neurons consume a lot of ATPs in the process of neurotransmission. Astrocytes provide metabolic substrates for neurons, maintain high activity of neuron, and facilitate information transmission of neurons. This article reviews the characteristics of glucose metabolism, lipid metabolism, and amino acid metabolism of astrocytes. The metabolic interactions between astrocytes and neurons, astrocytes and microglia were also detailed discussed. Finally, we classified analyzed the role of metabolic disorder of astrocytes in the occurrence and development of neurodegenerative diseases.

Risk of incident type 2 diabetes in patients with psoriatic arthritis: A systematic review and meta-analysis of cohort studies.

OBJECTIVES: To determine the risk of type 2 diabetes among patients with psoriatic arthritis (PsA). METHODS: Electronic database searches of PubMed, EMBASE and Cochrane Library were performed from inception to June 2020 and updated in May 2022. Cohort studies were included if they reported hazard ratios (HR) or relative risks with 95% confidence interval (CI) of incident diabetes in patients with PsA compared with non-rheumatic populations. Pooled HR and 95% CI were calculated using a DerSimonian and Laird method random-effects model. RESULTS: A total of 5 studies comprising 37 811 PsA patients with 174 825 patient-years and 476 838 non-rheumatic controls with 2 945 358 patient-years were identified and included in our data analysis. During the follow-up, 2335 and 23 035 incident diabetes were observed in PsA and non-rheumatic control groups, corresponding to a crude incidence rate of 13.4 and 7.8 per 1000 patient-years, respectively. The pooled age- and gender-adjusted, and fully adjusted HR of incident diabetes in patients with PsA compared with non-rheumatic populations were 1.54 (95% CI: 1.43-1.67, I2  = 50.8%) and 1.38 (95% CI: 1.31-1.47, I2  = 0.0%), respectively. CONCLUSIONS: Our study indicates a 38% increase in the risk of type 2 diabetes among patients with PsA, with an incidence rate of 13.4 per 1000 patients-years. These findings suggest the awareness of managing diabetes with careful screening of PsA patients in daily practice.

Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to ß-amyloid clearance.

Microglial cells consume adenosine triphosphate (ATP) during phagocytosis to clear neurotoxic ß-amyloid in Alzheimer's disease (AD). However, the contribution of energy metabolism to microglial function in AD remains unclear. Here, we demonstrate that hexokinase 2 (HK2) is elevated in microglia from an AD mouse model (5xFAD) and AD patients. Genetic deletion or pharmacological inhibition of HK2 significantly promotes microglial phagocytosis, lowers the amyloid plaque burden and attenuates cognitive impairment in male AD mice. Notably, the ATP level is dramatically increased in HK2-deficient or inactive microglia, which can be attributed to a marked upregulation in lipoprotein lipase (LPL) expression and subsequent increase in lipid metabolism. We further show that two downstream metabolites of HK2, glucose-6-phosphate and fructose-6-phosphate, can reverse HK2-deficiency-induced upregulation of LPL, thus supporting ATP production and microglial phagocytosis. Our findings uncover a crucial role for HK2 in phagocytosis through regulation of microglial energy metabolism, suggesting a potential therapeutic strategy for AD by targeting HK2.

Acinar ATP8b1/LPC pathway promotes macrophage efferocytosis and clearance of inflammation during chronic pancreatitis development.

Noninflammatory clearance of dying cells by professional phagocytes, termed efferocytosis, is fundamental in both homeostasis and inflammatory fibrosis disease but has not been confirmed to occur in chronic pancreatitis (CP). Here, we investigated whether efferocytosis constitutes a novel regulatory target in CP and its mechanisms. PRSS1 transgenic (PRSS1Tg) mice were treated with caerulein to mimic CP development. Phospholipid metabolite profiling and epigenetic assays were performed with PRSS1Tg CP models. The potential functions of Atp8b1 in CP model were clarified using Atp8b1-overexpressing adeno-associated virus, immunofluorescence, enzyme-linked immunosorbent assay(ELISA), and lipid metabolomic approaches. ATAC-seq combined with RNA-seq was then used to identify transcription factors binding to the Atp8b1 promoter, and ChIP-qPCR and luciferase assays were used to confirm that the identified transcription factor bound to the Atp8b1 promoter, and to identify the specific binding site. Flow cytometry was performed to analyze the proportion of pancreatic macrophages. Decreased efferocytosis with aggravated inflammation was identified in CP. The lysophosphatidylcholine (LPC) pathway was the most obviously dysregulated phospholipid pathway, and LPC and Atp8b1 expression gradually decreased during CP development. H3K27me3 ChIP-seq showed that increased Atp8b1 promoter methylation led to transcriptional inhibition. Atp8b1 complementation substantially increased the LPC concentration and improved CP outcomes. Bhlha15 was identified as a transcription factor that binds to the Atp8b1 promoter and regulates phospholipid metabolism. Our study indicates that the acinar Atp8b1/LPC pathway acts as an important "find-me" signal for macrophages and plays a protective role in CP, with Atp8b1 transcription promoted by the acinar cell-specific transcription factor Bhlha15. Bhlha15, Atp8b1, and LPC could be clinically translated into valuable therapeutic targets to overcome the limitations of current CP therapies.

Application of antidepressants in depression: A systematic review and meta-analysis.

BACKGROUND: The type and quantities of antidepressants are increasing, but the efficacy and safety of first-line and emerging drugs vary between studies. In this article, we estimated the efficacy and safety of first-line and emerging antidepressants (anti-inflammatory drugs and ketamine). METHOD: ystematic search of EMBASE, ERIC, MEDLINE, psycARTICLES, and psycINFO without language restriction for studies on the depression, depressive symptoms, antidepressants, fluoxetine (Prozac), paroxetine, escitalopram, sertraline, fluvoxamine, venlafaxine, duloxetine, NSAIDs, anti-cytokine drugs or pioglitazone published before May 1st, 2019. Information on study characteristics, depression or depressive symptoms, antidepressants and the descriptive statistics (including efficacy and safety of antidepressants) was extracted independently by 2 investigators. Estimates were pooled using random-effects meta-analysis. Differences by study-level characteristics were estimated using stratified meta-analysis and meta-regression. The response and remission of antidepressants were used as clinical evaluation indicators, and the evaluation criteria were clinical depression scales. OR value of antidepressants as assessed by meta-analysis. RESULTS: The literature search retrieved 5529 potentially relevant articles of which 49 studies were finally included. We compared the efficacy of antidepressants (seven first-line antidepressants (fluoxetine, paroxetine, escitalopram, sertraline, fluvoxamine, venlafaxine, duloxetine), there kinds of anti-inflammatory drugs(NASIDs, cytokine-inhibitor, pioglitazone) and ketamine) by comparing the OR values. CONCLUSION: The three drugs with the highest OR value in response were NASID (OR = 3.62(1.58, 8.32)), venlafaxin (OR = 3.50(1.83, 6.70)) and ketamine (OR = 3.28(1.89, 5.68)), while the highest OR value in remission were NASID (OR = 3.17(1.60, 6.29)), ketamine (OR = 2.99(1.58, 5.67)) and venlafaxin (OR = 2.55(1.72, 3.78)). Through reading the literature, we found 69 SNPs associated with depression. Major depression was a debilitating disorder that could ultimately lead to enormous societal and economical challenge [1]. The number of person which affected by depression was up to 16% of the population worldwide. More than 300 million individuals were estimated to suffer depression these days [1,2]. Therefore, it is apparent that safety and effective treatments for depression are necessary. In the 1930 s, the first drug for schizophrenia was discovered. This finding was a landmark for the emerging of biological psychiatry. In the 1950 s, pharmacologists had stumbled upon the antidepressant effect of imipramine. Since then, every 30 years, the use of antidepressants had made a pulsatile leap. Selective serotonin reuptake inhibitors (SSRIs) are the most widely-prescribed psychiatric drugs for the treatment of depression. However, the efficacy was variable and incomplete: 60%-70% of the patients do not experience remission, while 30%-40% do not show a significant response [3,4]. Nevertheless, SSRIs, SNRIs (selective serotonin-norepinephrine reuptake inhibitors, which can block norepinephrine at the same time) and NaSSAs (norepinephrine and selective serotonin receptor agonist), constituted the first-line clinical drugs. Nearly 30 years after the outbreak of SSRIs, antidepressants have ushered in a new chapter. It has been found that anti-inflammatory drugs could also have the small and moderate antidepressant effect and it's widely discussed [5]. More than 40 anti-inflammatory drugs have been certificated to have antidepressant effects in preclinical and clinical studies [6]. The antidepressant that has been approved for use recently is ketamine. There is no comprehensive comparison of the efficacy of all these drugs. In this review, we tried to estimate the efficacy and safety of first-line antidepressants, anti-inflammatory drugs and ketamine. On the other hand, with the development of GWAS, SNPs related to depression have been reported, and the corresponding mechanisms have been elaborated, respectively. However, patients with these SNPs have not been treated with individualized drugs according to the mechanisms. We hope to push this process forward through the summary of this article. METHODS: Search Strategy and Study Eligibility.