Gut microbiota-brain bile acid axis orchestrates aging-related neuroinflammation and behavior impairment in mice.

Emerging evidence shows that disrupted gut microbiota-bile acid (BA) axis is critically involved in the development of neurodegenerative diseases. However, the alterations in spatial distribution of BAs among different brain regions that command important functions during aging and their exact roles in aging-related neurodegenerative diseases are poorly understood. Here, we analyzed the BA profiles in cerebral cortex, hippocampus, and hypothalamus of young and natural aging mice of both sexes. The results showed that aging altered brain BA profiles sex- and region- dependently, in which TßMCA was consistently elevated in aging mice of both sexes, particularly in the hippocampus and hypothalamus. Furthermore, we found that aging accumulated-TßMCA stimulated microglia inflammation in vitro and shortened the lifespan of C. elegans, as well as behavioral impairment and neuroinflammation in mice. In addition, metagenomic analysis suggested that the accumulation of brain TßMCA during aging was partially attributed to reduction in BSH-carrying bacteria. Finally, rejuvenation of gut microbiota by co-housing aged mice with young mice restored brain BA homeostasis and improved neurological dysfunctions in natural aging mice. In conclusion, our current study highlighted the potential of improving aging-related neuro-impairment by targeting gut microbiota-brain BA axis.

Acupuncture versus sham acupuncture and usual care for Antiandrogen-Induced hot fLashes in prostate cancer (AVAIL): study protocol for a randomized clinical trial.

BACKGROUND: Hot flashes are the common and debilitating symptom among prostate cancer (PCa) patients undergoing androgen deprivation therapy (ADT). Strong evidence from multiple rigorously designed studies indicated that pharmacological option such as venlafaxine provides partial relief, but the tolerability is poor when dose is not tapered. Hence, alternative therapy is needed. Previous studies reported that acupuncture may be helpful in the management of hot flashes. However, the insufficient randomized controlled trial limited the quality of evidence. METHODS: Five hospitals will recruit 120 acupuncture naïve patients with moderate-to-severe hot flashes after prostate cancer received ADT in China from February 2023 to December 2024. Participants will be randomly 2:1:1 allocated to the 18 sessions of verum acupuncture at true acupuncture points plus usual care, 18 sessions of non-penetrating sham acupuncture at non-acupuncture points plus usual care, or usual care alone over 6 weeks. The primary outcome measure is the change of mean weekly hot flashes symptom severity score (HFSSS) at the end of treatment compared with baseline. EXPECTED RESULTS AND CONCLUSION: We will be able to measure the effectiveness of acupuncture for patients with PCa suffering from ADT-induced hot flashes and whether acupuncture is superior to sham acupuncture and usual care. The proposed acupuncture treatment might provide an alternative option for those patients. TRIAL REGISTRATION: Clinicaltrials.gov (NCT05069467).

Impact of interstitial cells of Cajal on slow wave and gallbladder contractility in a guinea pig model of acute cholecystitis.

BACKGROUND: Impaired interstitial cells of Cajal (ICCs) are central to the pathophysiology of acute cholecystitis (AC). Common bile duct ligation is a common model of AC, producing acute inflammatory changes and decrease in gallbladder contractility. AIM: To investigate the origin of slow wave (SW) in the gallbladder and the effect of ICCs on gallbladder contractions during the process of AC. METHODS: Methylene blue (MB) with light was used to establish selective impaired ICCs gallbladder tissue. Gallbladder motility was assessed using the frequency of SW and gallbladder muscle contractility in vitro in normal control (NC), AC12h, AC24h, and AC48h groups of guinea pigs. Hematoxylin and eosin and Masson-stained gallbladder tissues were scored for inflammatory changes. ICCs pathological changes alterations were estimated using immunohistochemistry and transmission electron microscopy. The alterations of c-Kit, α-SMA, cholecystokinin A receptor (CCKAR), and connexin 43 (CX43) were assessed using Western blot. RESULTS: Impaired ICCs muscle strips resulted in the decrease in gallbladder SW frequency and contractility. The frequency of SW and gallbladder contractility were significantly lower in the AC12h group. Compared with the NC group, the density and ultrastructure of ICCs were remarkably impaired in the AC groups, especially in the AC12h group. The protein expression levels of c-Kit were significantly decreased in the AC12h group, while CCKAR and CX43 protein expression levels were significantly decreased in the AC48h group. CONCLUSION: Loss ICCs could lead to a decrease in gallbladder SW frequency and contractility. The density and ultrastructure of ICCs were clearly impaired in the early stage of AC, while CCKAR and CX43 were significantly reduced at end stage.

Pain sensitivity related to gamma oscillation of parvalbumin interneuron in primary somatosensory cortex in Dync1i1-/- mice.

Cytoplasmic dynein is an important intracellular motor protein that plays an important role in neuronal growth, axonal polarity formation, dendritic differentiation, and dendritic spine development among others. The intermediate chain of dynein, encoded by Dync1i1, plays a vital role in the dynein complex. Therefore, we assessed the behavioral and related neuronal activities in mice with dync1i1 gene knockout. Neuronal activities in primary somatosensory cortex were recorded by in vivo electrophysiology and manipulated by optogenetic and chemogenetics. Nociception of mechanical, thermal, and cold pain in Dync1i1-/- mice were impaired. The activities of parvalbumin (PV) interneurons and gamma oscillation in primary somatosensory were also impaired when exposed to mechanical nociceptive stimulation. This neuronal dysfunction was rescued by optogenetic activation of PV neurons in Dync1i1-/- mice, and mimicked by suppressing PV neurons using chemogenetics in WT mice. Impaired pain sensations in Dync1i1-/- mice were correlated with impaired gamma oscillations due to a loss of interneurons, especially the PV type. This genotype-driven approach revealed an association between impaired pain sensation and cytoplasmic dynein complex.

Smooth muscle cells, interstitial cells and neurons in the gallbladder (GB): Functional syncytium of electrical rhythmicity and GB motility (Review).

The motility of the gallbladder (GB) involves the storage, concentration and delivery of bile. GB motor functions are controlled by multiple complex factors, such as extrinsic and intrinsic innervation, humoral factors and neuropeptides. GB emptying results from coordinated contractions of the muscular layers of the GB wall. Depolarization of GB smooth muscle (GBSM) depends on the activation of the regular depolarization­repolarization potential, referred to as slow waves (SWs). These rhythmic SWs of GBSM contraction are mediated by several cell types, including smooth muscle cells (SMCs), GB neurons, telocytes (TC) and specialized pacemaker cells called interstitial cells of Cajal (ICC). The present article introduced a new GB motor unit, the SMC­TC­ICC­neuron (STIN) syncytium. In GB, STIN cells provide pacemaker activity, propagation pathways for SWs, transduction of inputs from motor and sensory neurons and mechanosensitivity. The present review provided an overview of STIN cells, mechanisms generating GBSM contractile behavior and GB motility, and discussed alterations of STIN cell function under different disease conditions.

Clinical application and research progress of extracellular slow wave recording in the gastrointestinal tract.

The physiological function of the gastrointestinal (GI) tract is based on the slow wave generated and transmitted by the interstitial cells of Cajal. Extracellular myoelectric recording techniques are often used to record the characteristics and propagation of slow wave and analyze the models of slow wave transmission under physiological and pathological conditions to further explore the mechanism of GI dysfunction. This article reviews the application and research progress of electromyography, bioelectromagnetic technology, and high-resolution mapping in animal and clinical experiments, summarizes the clinical application of GI electrical stimulation therapy, and reviews the electrophysiological research in the biliary system.

Neural excitatory rebound induced by valproic acid may predict its inadequate control of seizures.

BACKGROUND: Valproic acid (VPA) represents one of the most efficient antiseizure medications (ASMs) for both general and focal seizures, but some patients may have inadequate control by VPA monotherapy. In this study, we aimed to verify the hypothesis that excitatory dynamic rebound induced by inhibitory power may contribute to the ineffectiveness of VPA therapy and become a predictor of post-operative inadequate control of seizures. METHODS: Awake craniotomy surgeries were performed in 16 patients with intro-operative high-density electrocorticogram (ECoG) recording. The relationship between seizure control and the excitatory rebound was further determined by diagnostic test and univariate analysis. Thereafter, kanic acid (KA)-induced epileptic mouse model was used to confirm that its behavior and neural activity would be controlled by VPA. Finally, a computational simulation model was established to verify the hypothesis. FINDINGS: Inadequate control of seizures by VPA monotherapy and post-operative status epilepticus are closely related to a significant excitatory rebound after VPA injection (rebound electrodes≧5/64, p = 0.008), together with increased synchronization of the local field potential (LFP). In addition, the neural activity in the model mice showed a significant rebound on spike firing (53/77 units, 68.83%). The LFP increased the power spectral density in multiple wavebands after VPA injection in animal experiments (p < 0.001). Computational simulation experiments revealed that inhibitory power-induced excitatory rebound is an intrinsic feature in the neural network. INTERPRETATION: Despite the limitations, we provide evidence that inadequate control of seizures by VPA monotherapy could be associated with neural excitatory rebounds, which were predicted by intraoperative ECoG analysis. Combined with the evidence from computational models and animal experiments, our findings suggested that ineffective ASMs may be because of the excitatory rebound, which is mediated by increased inhibitory power. FUNDING: This work was supported by National Natural Science Foundation of China (62127810, 81970418), Shanghai Municipal Science and Technology Major Project (2018SHZDZX03) and ZJLab; Science and Technology Commission of Shanghai Municipality (18JC1410403, 19411969000, 19ZR1477700, 20Z11900100); MOE Frontiers Center for Brain Science; Shanghai Key Laboratory of Health Identification and Assessment (21DZ2271000); Shanghai Shenkang (SHDC2020CR3073B).

PACT promotes the metastasis of basal-like breast cancer through Rac1 SUMOylation and activation.

Most basal-like breast cancers (BLBCs) are triple-negative breast cancers (TNBCs), which is associated with high malignancy, high rate of recurrence and distant metastasis, and poor prognosis among all types of breast cancer. However, there are currently no effective therapies for BLBC. Furthermore, chemoresistance limits the therapeutic options for BLBC treatment. In this study, we screen out protein activator of the interferon-induced protein kinase (PACT) as an essential gene in BLBC metastasis. We find that high PACT expression level was associated with poor prognosis among BLBC patients. In vivo and in vitro investigations indicated that PACT could regulate BLBC metastasis by interacting with SUMO-conjugating enzyme Ubc9 to stimulate the SUMOylation and thus consequently the activation of Rac1. BLBC patients receiving chemotherapy presents poorer prognosis with PACT high expression, and PACT disruption sensitizes experimental mammary tumor metastases to chemotherapy, thus providing insights to consider PACT as a potential therapeutic target to overcome acquired chemoresistance in BLBC.

Altered pain sensitivity in 5×familial Alzheimer disease mice is associated with dendritic spine loss in anterior cingulate cortex pyramidal neurons.

ABSTRACT: Chronic pain is highly prevalent. Individuals with cognitive disorders such as Alzheimer disease are a susceptible population in which pain is frequently difficult to diagnosis. It is still unclear whether the pathological changes in patients with Alzheimer disease will affect pain processing. Here, we leverage animal behavior, neural activity recording, optogenetics, chemogenetics, and Alzheimer disease modeling to examine the contribution of the anterior cingulate cortex (ACC) neurons to pain response. The 5× familial Alzheimer disease mice show alleviated mechanical allodynia which can be regained by the genetic activation of ACC excitatory neurons. Furthermore, the lower peak neuronal excitation, delayed response initiation, as well as the dendritic spine reduction of ACC pyramidal neurons in 5×familial Alzheimer disease mice can be mimicked by Rac1 or actin polymerization inhibitor in wild-type (WT) mice. These findings indicate that abnormal of pain sensitivity in Alzheimer disease modeling mice is closely related to the variation of neuronal activity and dendritic spine loss in ACC pyramidal neurons, suggesting the crucial role of dendritic spine density in pain processing.

Preparation of Small-Pore Ultrafiltration Membranes with High Surface Porosity by In Situ CO2 Nanobubble-Assisted NIPS.

The fabrication of ultrafiltration (UF) membranes with a small pore size (<20 nm) and high surface porosity is still a great challenge. In this work, a nanobubble-assisted nonsolvent-induced phase separation (BNIPS) technique was developed to prepare high-performance UF membranes by adding a tiny amount of CaCO3 nanoparticles into the casting solution. The phase inversion occurred in a dilute-acid coagulation bath to simultaneously generate CO2 nanobubbles, which regulated the membrane structure. The effects of the nano-CaCO3 content in the casting solution on the structure and performance of poly(ethersulfone)/sulfonated polysulfone (PES/SPSf) UF membranes were studied. The UF membrane prepared from a casting solution with 0.3% nano-CaCO3 achieved a surface porosity of 12%, a pore diameter of 10.2 nm, and a skin-layer thickness of 80.3 nm. The superior structure of the UF membrane was mainly attributed to the in situ generation of CO2 nanobubbles because the CO2 nanobubbles were amphiphobic to water and solvents to delay the phase inversion time and acted as nanosize porogens. The produced membrane showed an unprecedented separation performance, achieving a pure water permeance of up to 1128 L·m-2·h-1·bar-1, 2.5 fold that of the control membrane. Similarly, a high bovine serum albumin rejection of above 99.0% was obtained. The overall permeability and selectivity were better than those of commercial and other previously reported UF membranes. This work provides insight toward a simple and cost-effective technique to address the trade-off between pure water permeance and solute rejection of UF membranes.

Weakened Effective Connectivity Related to Electroacupuncture in Stroke Patients with Prolonged Flaccid Paralysis: An EEG Pilot Study.

Flaccid paralysis in the upper extremity is a severe motor impairment after stroke, which exists for weeks, months, or even years. Electroacupuncture treatment is one of the most widely used TCM therapeutic interventions for poststroke flaccid paralysis. However, the response to electroacupuncture in different durations of flaccid stage poststroke as well as in the topological configuration of the cortical network remains unclear. The objectives of this study are to explore the disruption of the cortical network in patients in different durations of flaccid stage and observe dynamic network reorganization during and after electroacupuncture. Resting-state networks were constructed from 18 subjects with flaccid upper extremity by partial directed coherence (PDC) analysis of multichannel EEG. They were allocated to three groups according to time after flaccid paralysis: the short-duration group (those with flaccidity for less than two months), the medium-duration group (those with flaccidity between two months and six months), and the long-duration group (those with flaccidity over six months). Compared with short-duration flaccid subjects, weakened effective connectivity was presented in medium-duration and long-duration groups before electroacupuncture. The long-duration group has no response in the cortical network during electroacupuncture. The global network measures of EEG data (sPDC, mPDC, and N) indicated that there was no significant difference among the three groups. These results suggested that the network connectivity reduced and weakly responded to electroacupuncture in patients with flaccid paralysis for over six months. These findings may help us to modulate the formulation of electroacupuncture treatment according to different durations of the flaccid upper extremity.