Insulin-like growth factor 1 regulates excitatory synaptic transmission in pyramidal neurons from adult prefrontal cortex

Insulin-like growth factor 1 (IGF1) influences synaptic function in addition to its role in brain development and aging. Although the expression levels of IGF1 and IGF1 receptor (IGF1R) peak during development and decline with age, the adult brain has abundant IGF1 or IGF1R expression. Studies reveal that IGF1 regulates the synaptic transmission in neurons from young animals. However, the action of IGF1 on neurons in the adult brain is still unclear. Here, we used prefrontal cortical (PFC) slices from adult mice (∼8 weeks old) to characterize the role of IGF1 on excitatory synaptic transmission in pyramidal neurons and the underlying molecular mechanisms. We first validated IGF1R expression in pyramidal neurons using translating ribosomal affinity purification assay. Then, using whole-cell patch-clamp recording, we found that IGF1 attenuated the amplitude of evoked excitatory postsynaptic current (EPSC) without affecting the frequency and amplitude of miniature EPSC. Furthermore, this decrease in excitatory neurotransmission was blocked by pharmacological inhibition of IGF1R or conditional knockdown of IGF1R in PFC pyramidal neurons. In addition, we determined that IGF1-induced decrease of EPSC amplitude was due to postsynaptic effect (internalization of a-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid receptors [AMPAR]) rather than presynaptic glutamate release. Finally, we found that inhibition of metabotropic glutamate receptor subtype-1 (mGluR1) abolished IGF1-induced attenuation of evoked EPSC amplitude and decrease of AMPAR expression at synaptic membrane, suggesting mGluR1-mediated endocytosis of AMPAR was involved. Taken together, these data provide the first evidence that IGF1 regulates excitatory synaptic transmission in adult PFC via the interaction between IGF1R-dependent signaling pathway and mGluR1-mediated AMPAR endocytosis

Why does dissolving salt in water decrease its dielectric permittivity

The dielectric permittivity of salt water decreases on dissolving more salt. For nearly a century, this phenomenon has been explained by invoking saturation in the dielectric response of the solvent water molecules. Herein, we employ an advanced deep neural network (DNN), built using data from density functional theory, to study the dielectric permittivity of sodium chloride solutions. Notably, the decrease in the dielectric permittivity as a function of concentration, computed using the DNN approach, agrees well with experiments. Detailed analysis of the computations reveals that the dominant effect, caused by the intrusion of ionic hydration shells into the solvent hydrogen-bond network, is the disruption of dipolar correlations among water molecules. Accordingly, the observed decrease in the dielectric permittivity is mostly due to increasing suppression of the collective response of solvent waters.Comment: has accepted by Physical Review Letter

Dissolving salt is not equivalent to applying a pressure on water

Salt water is ubiquitous, playing crucial roles in geological and physiological processes. Despite centuries of investigations, whether or not water’s structure is drastically changed by dissolved ions is still debated. Based on density functional theory, we employ machine learning based molecular dynamics to model sodium chloride, potassium chloride, and sodium bromide solutions at different concentrations. The resulting reciprocal-space structure factors agree quantitatively with neutron diffraction data. Here we provide clear evidence that the ions in salt water do not distort the structure of water in the same way as neat water responds to elevated pressure. Rather, the computed structural changes are restricted to the ionic first solvation shells intruding into the hydrogen bond network, beyond which the oxygen radial-distribution function does not undergo major change relative to neat water. Our findings suggest that the widely cited pressure-like effect on the solvent in Hofmeister series ionic solutions should be carefully revisited.Temple University. College of Science and TechnologyPhysicsChemistr

Opioid induces increased DNA damage in prefrontal cortex and nucleus accumbens

Opioid use disorder (OUD) is a chronic disease characterized by compulsive opioid taking and seeking, affecting millions of people worldwide. The high relapse rate is one of the biggest challenges in treating opioid addiction. However, the cellular and molecular mechanisms underlying relapse to opioid seeking are still unclear. Recent studies have shown that DNA damage and repair processes are implicated in a broad spectrum of neurodegenerative diseases as well as in substance use disorders. In the present study, we hypothesized that DNA damage is related to relapse to heroin seeking. To test our hypothesis, we aim to examine the overall DNA damage level in prefrontal cortex (PFC) and nucleus accumbens (NAc) after heroin exposure, as well as whether manipulating DNA damage levels can alter heroin seeking. First, we observed increased DNA damage in postmortem PFC and NAc tissues from OUD individuals compared to healthy controls. Next, we found significantly increased levels of DNA damage in the dorsomedial PFC (dmPFC) and NAc from mice that underwent heroin self-administration. Moreover, increased accumulation of DNA damage persisted after prolonged abstinence in mouse dmPFC, but not in NAc. This persistent DNA damage was ameliorated by the treatment of reactive oxygen species (ROS) scavenger N-acetylcysteine, along with attenuated heroin-seeking behavior. Furthermore, intra-PFC infusions of topotecan and etoposide during abstinence, which trigger DNA single-strand breaks and double-strand breaks respectively, potentiated heroin-seeking behavior. These findings provide direct evidence that OUD is associated with the accumulation of DNA damage in the brain (especially in the PFC), which may lead to opioid relapse

Low-carbohydrate diets reduce cardiovascular risk factor levels in patients with metabolic dysfunction-associated steatotic liver disease: a systematic review and meta-analysis of randomized controlled trials

BackgroundLow-carbohydrate diets (LCDs) are increasingly advocated for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD); however, their cardiovascular safety profile remains controversial. This analysis aims to evaluate the effects of LCDs on cardiovascular risk factors in MASLD patients.MethodsPubMed, Cochrane Library, Web of Science, and Scopus were searched from inception to March 19, 2025. Two reviewers independently conducted data extraction. Meta-analyses were performed using fixed-effects or random-effects models, as determined by the heterogeneity of the included studies. Outcomes included blood pressure, glycemic markers, lipid profiles, and anthropometric indicators. Subgroup analyses explored carbohydrate thresholds (<26% vs. ≥26%) and intervention durations (<24 weeks vs. ≥24 weeks).ResultsSixteen RCTs comprising 1,056 participants were included. LCDs significantly reduced glycated hemoglobin (HbA1c: SMD, −0.27; 95% CI, −0.47 to −0.07), triglyceride (TG: SMD, −0.20; 95% CI, −0.34 to −0.06), body weight (SMD, −0.19; 95% CI, −0.36 to −0.03), and body mass index (BMI: SMD, −0.28; 95% CI, −0.42 to −0.14). Stricter carbohydrate restriction (<26% energy) further improved systolic/diastolic blood pressure, homeostatic model assessment insulin resistance index (HOMA-IR), HbA1c, TG, body weight, BMI, and waist circumference. Short-term interventions (<24 weeks) lowered HbA1c, TG, and BMI.ConclusionThis systematic review and meta-analysis found that LCDs are associated with improvements in cardiometabolic risk factors among patients with MASLD. Furthermore, short-term implementation of a strict carbohydrate-restricted dietary regimen may yield additional clinical benefits. Future research should prioritize: standardized nutrient assessment, enhanced adherence strategies, and cardiovascular endpoint trials.Systematic review registrationPROSPERO: CRD42024603432; https://www.crd.york.ac.uk/PROSPERO/view/CRD42024603432

Caffeine regulates both osteoclast and osteoblast differentiation via the AKT, NF-κB, and MAPK pathways

Background: Although caffeine generally offers benefits to human health, its impact on bone metabolism remains unclear.Aim and Methods: This study aimed to systematically evaluate the long-term effects of caffeine administration on osteoclasts, osteoblasts, and ovariectomy-induced postmenopausal osteoporosis (OP).Results: Our in vitro findings revealed that 3.125 and 12.5 μg/mL caffeine inhibited RANKL-mediated osteoclastogenesis in RAW 264.7 cells through the MAPK and NF-κB pathways, accompanied by the inactivation of nuclear translocation of nuclear factor NFATc1. Similarly, 3.125 and 12.5 μg/mL of caffeine modulated MC3T3-E1 osteogenesis via the AKT, MAPK, and NF-κB pathways. However, 50 μg/mL of caffeine promoted the phosphorylation of IκBα, P65, JNK, P38, and AKT, followed by the activation of NFATc1 and the inactivation of Runx2 and Osterix, ultimately disrupting the balance between osteoblastogenesis and osteoclastogenesis. In vivo studies showed that gavage with 55.44 mg/kg caffeine inhibited osteoclastogenesis, promoted osteogenesis, and ameliorated bone loss in ovariectomized mice.Conclusion: Conversely, long-term intake of high-dose caffeine (110.88 mg/kg) disrupted osteogenesis activity and promoted osteoclastogenesis, thereby disturbing bone homeostasis. Collectively, these findings suggest that a moderate caffeine intake (approximately 400 mg in humans) can regulate bone homeostasis by influencing both osteoclasts and osteoblasts. However, long-term high-dose caffeine consumption (approximately 800 mg in humans) could have detrimental effects on the skeletal system

Non-targeted Metabolomic Study on Anti-aging Effect of Ripe Pu-erh Tea on D-Galactose-Induced Aging Mice

Delaying aging has become a hot spot of social concern and research. Our previous studies have shown that ripe Pu-erh tea can delay aging in mice by regulating the intestinal flora, but the metabolites in response to endogenous substances in mice are not clear. In this paper, the Morris water maze test was used to detect learning and memory capacity in control, D-galactose-induced aging, and ripe Pu-erh tea-treated mice. Non-targeted metabolomics was used to detect metabolites in the brain tissue and serum of mice from each group for the purpose of exploring the anti-aging effect of ripe Pu-erh tea on D-galactose-induced aging mice, screening differential metabolites among the three groups and analyzing the related metabolic pathways. The results showed that ripe Pu-erh tea improved learning capacity, and regulated 26 differential metabolites in the brain tissue of aging mice, mainly involved in the glycerophospholipid metabolism, vitamin B6 metabolism, histidine metabolism and purine metabolism pathways, among which the glycerophospholipid metabolism and histidine metabolism pathway were the most significant. A total of 11 differential metabolites were identified in serum, mainly involved in the metabolism of vitamin B6 and arachidonic acid, among which vitamin B6 metab olism pathway was the most significant. After the intervention with ripe Pu-erh tea, the contents of glycerophospholipid metabolites including phosphatidylcholine [PC (20:5/20:4)], phosphatidyl ethanlamine [PE (22:2/14:0)], phosphatidylserine [PS (20:5/18:1)] and lysophosphatidylcholine [LysoPC (18:2)], the histidine metabolite carnosine, and the vitamin B6 metabolite pyridoxal 5’-phosphate were significantly increased in aging mice. These results suggest that ripe Pu-erh tea can delay aging by regulating lipid and amino acid metabolism

Blebbistatin as a novel antiviral agent targeting equid herpesvirus type 8

IntroductionEquid herpesvirus type 8 (EqHV-8) poses a significant threat to equine health, leading to miscarriages and respiratory diseases in horses and donkeys, and results in substantial economic losses in the donkey industry. Currently, there are no effective drugs or vaccines available for EqHV-8 infection control.MethodsIn this study, we investigated the in vitro and in vivo antiviral efficacy of Blebbistatin, a myosin II ATPase inhibitor, against EqHV-8.ResultsOur results demonstrated that Blebbistatin significantly inhibited EqHV-8 infection in Rabbit kidney (RK-13) and Madin-Darby Bovine Kidney (MDBK) cells in a concentration-dependent manner. Notably, Blebbistatin was found to disrupt EqHV-8 infection at the entry stage by modulating myosin II ATPase activity. Moreover, in vivo experiments revealed that Blebbistatin effectively reduced EqHV-8 replication and mitigated lung pathology in a mouse model.ConclusionCollectively, these findings suggest that Blebbistatin holds considerable potential as an antiviral agent for the control of EqHV-8 infection, presenting a novel approach to addressing this veterinary challenge