Alzheimer's disease (AD) is a major neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, neurofibrillary tangles, and progressive cognitive decline. Despite significant advances in understanding its pathophysiology, current therapeutic options provide limited symptomatic relief. The present study investigated the nootropic and anti-amnesic effects of propranolol (PRO) in a scopolamine (SCP)-induced AD-like rat model. Wistar rats received PRO (10, 30, or 50 mg/kg, p.o.) or donepezil (DPZ; 1 mg/kg) for 17 days. Cognitive deficits were induced by SCP (1 mg/kg, i.p.) administration from day 9 onward. Behavioral performance was assessed using the Novel Object Recognition (NOR) and Elevated Plus Maze (EPM) tests. Molecular and cellular analyses were conducted to evaluate synaptic plasticity markers (CaMKII, CREB, BDNF, PKMζ), mitochondrial function, oxidative stress parameters, and inflammatory markers (GFAP, TNF-α). Propranolol treatment significantly improved long-term memory performance, enhanced recognition index, and attenuated anxiety-like behavior in SCP-treated rats. These behavioral effects were associated with upregulation of CaMKII-CREB-BDNF-PKMζ signaling, improvement in mitochondrial membrane potential (Δψm), reduction in reactive oxygen species (ROS) generation and Aβ1-42 accumulation, and decreased expression of GFAP and TNF-α. The findings suggest that propranolol mitigates SCP-induced cognitive impairments, potentially through modulation of synaptic plasticity- related signaling, mitochondrial function, and neuroinflammatory responses. These results indicate the therapeutic potential of propranolol in experimental models of AD-related neurodegeneration, warranting further investigation.
Background/Objectives: Opioids paradoxically induce hypersensitivity that typically resolves after discontinuation. Despite normalization of sensitivity, the nociceptive system may remain primed. Descending pathways contribute to opioid-induced hyperalgesia (OIH), and the following latently maintained sensitization. The mechanisms underlying the latter vulnerability remain unknown. We previously showed that the dorsal reticular nucleus (DRt), a key brainstem area involved in pain facilitation, drives OIH through a maladaptation in μ-opioid receptor (MOR) signaling. Whether cellular alterations in the DRt persist after opioids are discontinued and hyperalgesia resolves is unknown. Here, we investigated the long-term effects of morphine on DRt MOR expression, signaling, and function after hyperalgesia has been resolved. Methods: Male Wistar rats received morphine for 7 days either subcutaneously or continuously. Nociceptive sensitivity was evaluated by von Frey and hot-plate tests. MOR and phosphorylated CREB (pCREB) expression in the DRt were quantified during OIH and after hyperalgesia resolution. In the post-OIH phase, we evaluated the effects of MOR activation by DAMGO at DRt, postoperative pain behavior, and systemic morphine dose-response curves. Results: Both morphine regimens induced hypersensitivity that subsided within two weeks. MOR expression in the DRt increased during OIH and normalized in the post-OIH phase, whereas pCREB levels remained elevated in both phases. In the post-OIH phase, DAMGO microinjection at the DRt reinstated robust hypersensitivity and systemic morphine showed reduced antiallodynic potency in postoperative pain. Conclusions: Chronic morphine leaves a lasting molecular imprint in the DRt, sustaining excitatory MOR signaling that can reinstate hyperalgesia and likely diminishes later opioid analgesic efficacy.
Erythropoietin (EPO), the master regulator of erythropoiesis, is emerging as a pivotal mediator of brain repair. While its capacity to mitigate neural damage is well-documented, we posit that its most profound potential lies in actively orchestrating functional restoration. In the present review we summarize the molecular biology of EPO and the evidence establishing EPO as a potent modulator of neuroplasticity. We use an experimental strategy in which a specific behavioral task marks experience-activated neural circuits, and a subsequent, temporally precise administration of EPO provides a surge of plasticity-related proteins. This creates a synergistic interaction where the proteins are selectively captured by the activated synapses, directing plastic changes with high specificity. We present experimental evidence demonstrating that this synchronized protocol enables the recovery of spatial memory, reinstates synaptic plasticity, and activates genetic programs for plasticity in rodent models of brain injury. Furthermore, we show that endogenous EPO signaling is itself activity-dependent and integral to memory formation. This redefines EPO as a precision tool for neurorestoration, a potential now being pursued with engineered, non-erythropoietic variants of EPO in clinical trials for neurological and psychiatric disorders.
The pathogenesis of pulpitis remains unclear. This study sought to investigate the molecular mechanism by which the long noncoding RNA FOXD2-AS1 participates in pulpitis through regulating the miR-338-3p/THBS1 axis. 110 irreversible pulpitis patients and 80 healthy orthodontic patients were enrolled as the pulpitis and control groups, respectively. Human dental pulp stem cells (hDPSCs) were cultured and stimulated with lipopolysaccharide (LPS) to establish a pulp inflammation model. Expression of FOXD2-AS1, miR-338-3p, and THBS1 was detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay, while levels of inflammatory cytokines and osteogenesis-related proteins were measured by enzyme-linked immunosorbent assay (ELISA). THBS1 protein expression was validated by Western blot. The target regulation was verified by RNA immunoprecipitation (RIP) and dual luciferase reporter assays. In pulpitis tissues, FOXD2-AS1 and THBS1 expression were significantly upregulated, while miR-338-3p expression was significantly downregulated. Furthermore, FOXD2-AS1 demonstrated high diagnostic value for pulpitis. Functional experiments demonstrated that FOXD2-AS1 negatively regulated osteoblast differentiation and promoted LPS-induced inflammatory responses. Specifically, it inhibited alkaline phosphatase (ALP) activity and odontogenic differentiation-related protein expression, reduced cell viability, and promoted inflammatory cytokine release. Moreover, FOXD2-AS1 targeted and adsorbed miR-338-3p, while miR-338-3p directly targeted and inhibited THBS1 expression, forming the FOXD2-AS1/miR-338-3p/THBS1 regulatory axis. Rescue experiments demonstrated that knocking down FOXD2-AS1 exerted anti-inflammatory and pro-osteogenic effects by upregulating miR-338-3p and inhibiting THBS1. Conversely, inhibiting miR-338-3p reversed these protective effects, manifesting as exacerbated inflammation and diminished odontogenic differentiation capacity. On this basis, further knocking down THBS1 reinstates the anti-inflammatory and pro-osteogenic phenotype. In conclusion, FOXD2-AS1 mediates pulpitis inflammation and odontogenic differentiation imbalance by competitively binding to miR-338-3p to upregulate THBS1 expression.
Adiponectin signaling is essential for hepatic glucose homeostasis, yet the molecular basis of adiponectin receptor responsiveness remains incompletely understood. Here, we identify the Nogo-B receptor (NgBR; NUS1) as a regulator of hepatic adiponectin sensitivity. Across human, cynomolgus monkey, and mouse datasets, hepatic NgBR expression is consistently reduced in obesity-associated diabetes, indicating a conserved metabolic signature. Hepatocyte-specific NgBR deletion abolishes the metabolic effects of the adiponectin agonist AdipoRon, resulting in impaired AMPK activation, persistent gluconeogenesis, and ceramide accumulation. Mechanistically, NgBR loss suppresses KAT7 expression and reduces histone acetylation at AdipoR1 and AdipoR2 promoters, thereby limiting receptor expression. Adeno-associated virus (AAV)-mediated restoration of hepatic NgBR reinstates KAT7-dependent chromatin activation, adiponectin receptor expression, and glucose homeostasis. These findings support a hepatocellular mechanism in which NgBR maintains adiponectin receptor competence and suggest a potential therapeutic strategy for restoring adiponectin responsiveness in metabolic disease.
Targeting post-transcriptional dysregulation of tumor suppressors represents a new frontier in cancer therapy. Here, we identify the alternative polyadenylation (APA) regulator NUDT21 as a pivotal therapeutic target in oral squamous cell carcinoma (OSCC). NUDT21 is highly upregulated, correlating strongly with poor survival and advanced clinical stage. We outline a pathogenic mechanism whereby NUDT21 drives this phenotype by forcing a network of tumor suppressor transcripts, notably PTEN, into translationally-repressed, long-3'UTR isoforms. To therapeutically "re-engineer" this APA switch, we design a "Nano-APA-editor." This platform features an HMSN core with an sgRNA-NUDT21 payload and a hierarchical targeting strategy: a cancer-educated dendritic cell (DC) membrane for biomimetic camouflage and homotypic affinity, "gated" by a TA-aptamer for final precision. This system enables potent and selective NUDT21 silencing, driving a shift toward short-3'UTR isoforms. Consequently, the Nano-APA-editor effectively reinstates PTEN and associated suppressors and inhibits multiple malignant phenotypes in vitro. In an orthotopic OSCC model, it demonstrates profound tumor regression, outperforming conventional chemotherapy (PTX) with excellent biocompatibility. In vivo analysis confirmed target engagement (NUDT21-down) and functional restoration (PTEN-, WEE1-, TGF-β-up). This work validates a "post-transcriptional re-engineering" strategy, executed by a logically designed nanoplatform, as a powerful and safe modality for precision gene therapy.
Alzheimer's disease (AD) is incurable and increasingly attributed to gene-environment interactions. Microplastics (MPs) are omnipresent in the human food chain, yet their impact on neurodegeneration is largely unknown. Here we show that chronic oral exposure to 2-µm amine-modified polystyrene microparticles accelerates cognitive decline, amplifies Aβ deposition, gliosis, and synaptic loss, and cripples autophagic flux in 5XFAD mice through the gut-brain axis. MPs accumulate in the gut, breach the epithelial barrier, and selectively expand the taurine-depleting pathobiont Bilophila, while suppressing taurine-synthesizing commensals. Untargeted metabolomics reveal a systemic taurine deficit that precedes and predicts exacerbated Aβ deposition, gliosis, synaptic loss, and autophagic blockade in 5XFAD mice. Antibiotic-mediated microbiota ablation and fecal microbiota transplantation (FMT) demonstrate that the neurotoxic phenotype is fully microbiota-dependent. Restoring taurine level rebalances microglial homeostasis, reinstates autophagic flux, and rescues memory deficits in MPs-treated 5XFAD mice. Translational validation using Alzheimer's Disease Neuroimaging Initiative (ADNI) plasma shows taurine is significantly lower in AD patients versus cognitively normal controls and inversely correlates with cognitive decline. Our findings identify MPs-induced gut-microbiota dysbiosis as a modifiable environmental driver of AD pathogenesis and establish taurine supplementation as a readily translatable intervention that simultaneously fortifies the intestinal barrier and neutralizes microbiota-mediated neurodegeneration.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rewires host metabolism to optimize virus production. Although glycolysis is necessary for virus production, the importance of mitochondrial oxidative phosphorylation (OXPHOS) is unknown. The mitochondrial DNA (mtDNA) codes for 13 critical OXPHOS polypeptides plus the 22 transfer RNAs (tRNAs) and 2 ribosomal RNAs (rRNAs) for mitochondrial protein synthesis. We found an ∼5- to 100-fold greater SARS-CoV-2 virus production in infected human ACE2-expressing A549 lung cells when OXPHOS was inhibited by mtDNA depletion (ρ0 cells), inhibition of mitochondrial translation with chloramphenicol (CAP), or chemical inhibition of OXPHOS complexes. OXPHOS inhibition led to a marked increase in the size and distribution of viral replication centers and accelerated the production and release of infectious particles, occurring ∼2 hours earlier than in parental A549-ACE2 (wild type) cells. Subsequently, we found that increased glycolytic capacity was required for enhanced viral replication whereas differences in innate immune pathway activation were not. Reintroduction of mtDNA from a well-defined maternal lineage into the ρ0 cells reinstated OXPHOS, impaired SARS-CoV-2 replication, and reversed associated viral and glycolytic correlates. Thus, metabolic balance regulates SARS-CoV-2 replication, with OXPHOS exerting an antiviral effect.
This clinical case describes the management, in an intensive care unit (ICU), of a patient with a severe form of autism spectrum disorder (ASD) Level 3, suffering from acute respiratory failure that evolved into acute respiratory distress syndrome (ARDS). Throughout the entire period of hospitalisation in the ICU, sedation of the patient played a key role in the performance of all invasive and noninvasive therapeutic procedures, in particular artificial ventilation and subsequent weaning, due to the underlying disorder that rendered the patient completely uncooperative. Dexmedetomidine was used during initial admission to the ICU for initial treatment, during the period of artificial ventilation and finally during weaning from mechanical ventilation. The α 2 agonist, due to its pharmacodynamic and pharmacokinetic characteristics, also facilitated the overlap with home antipsychotic drugs upon both discontinuation and reinstatement, allowing discharge from the ICU and safe and serene home management of the tracheostomy until its closure.
Both rare and common variants in the SRY-Box Transcription Factor 17 (SOX17) locus are associated with pulmonary arterial hypertension (PAH). SOX17 dysregulation leads to pulmonary artery endothelial cell (PAEC) dysfunction and the obstructive remodelling that characterises PAH. Impaired SOX17 expression contributes to the pathogenesis of PAH. Restoring the function of SOX17 or its downstream targets using compounds that mimic its transcriptomic signature will rescue PAEC dysfunction and prevent PAH development. We defined thousands of genes with direct SOX17 genomic binding sites and identified important potential binding partners, including ETS-transcription factors such as ERG by ChIP-seq in PAECs. Through the integration of three PAEC RNA-seq datasets involving overexpression and silencing of SOX17, we defined a robust SOX17 transcriptomic signature. In PAH patients, circulating plasma protein levels of 10 SOX17 signature genes were associated with the SOX17 common risk variants. This included EFNB2 and UNC5B; knockdown of these genes altered the viability and apoptosis of PAECs in response to TNFα treatment. The drug-transcriptome database Connectivity Map (CMap) was used to predict novel potential therapeutic compounds to correct the SOX17 transcriptomic signature. Five compounds were selected for in vitro testing and were able to partially reinstate SOX17 target gene expression in PAECs. One compound, BX-912, was selected for in vivo testing as it corrected the levels of multiple target genes, including suppressing Runt-related transcription factor-1 (RUNX1). BX-912 blocked the development of pulmonary hypertension in mice lacking the SOX17 enhancer associated with human disease. We have demonstrated the therapeutic potential of targeting SOX17 in PAH through correction of its gene targets, identifying BX-912 as a lead compound with in vivo efficacy.
Vascular endothelial dysfunction because of environmental mercuric chloride (HgCl2) exposure is well known to induce cardiovascular diseases and heightened vascular responsiveness to angiotensin II (Ang 1-8). The PI3K/AKT/eNOS signaling pathway is essential for preserving endothelial NO bioavailability. Nevertheless, the reasons underlying this dysfunction during oxidative stress are inadequately elucidated. This study explored the roles of L-arginine (LA) and tetrahydrobiopterin (BH4) both alone and in combination on Ang1-8-induced vascular responses via the endothelial PI3K/AKT/eNOS pathway against HgCl2 -induced vascular dysfunction in rat aortic rings. In comparison to control (CT) rings; HgCl2 markedly modified Ang1-8 vascular reactivity, consistent with eNOS uncoupling and oxidative dysregulation. Inhibition of PI3K or AKT further amplified these effects, thereby confirming the vasoprotective role of the PI3K/AKT/eNOS system. The co-administration of LA and BH4 significantly restored both Emax and pD2 values in the presence of HgCl2 and inhibitors, indicating improved NO bioavailability and re-coupled eNOS activity. Treatments of LA and BH4 together sustained endothelial PI3K/AKT/eNOS signaling and alleviate HgCl2-induced vascular hyperreactivity to Ang1-8 through restoration of NO/cGMP-mediated relaxation, reduces oxidative damage, and enhances antioxidant capacity. These results highlight a potential therapy strategy focused on resolving substrate-cofactor coupling and reinstating endothelial signaling to mitigate heavy metal-induced vascular dysfunction.
Endothelial dysfunction is a hallmark of diabetes, primarily driven by fluctuating blood glucose levels that contribute to vascular complications. Epigenetic regulation through histone modifications plays a crucial role in mediating such pathological gene expression changes. This study delineates the differential acetylation pattern of histone H4 lysine residues in endothelial cells exposed to intermittent high glucose (IHG) conditions. IHG treatment led to a significant deacetylation of H4K5 and H4K16 residues, whereas acetylation at H4K8 and H4K12 remained unaltered. Consistently, streptozotocin (STZ)-induced diabetic rats exhibited reduced H4K5 acetylation specifically in the glomerular endothelium after six weeks of hyperglycemia. Mechanistically, human umbilical vein endothelial cells (HUVECs), human glomerular endothelial cells (HGECs) and EA.hy926 cells demonstrated a marked upregulation of histone deacetylase 1 (HDAC1) under IHG conditions, which was corroborated by elevated expression of ICAM1, p21 and reduced eNOS and KLF2. Furthermore, we also observed an increased HDAC1 expression in diabetic rat glomeruli. Among histone acetyl transferases (HATs) specific to H4K5Ac, KAT7, KAT6A, and p300 were elevated, while PCAF showed a reduction under IHG stress. Furthermore, chromatin immunoprecipitation (ChIP)-qPCR analysis revealed a loss of H4K5 acetylation enrichment on the promoters of KLF2 and eNOS under IHG. Notably, pharmacological inhibition of HDAC1 with pyroxamide or gene silencing via siRNA restored H4K5 acetylation levels. Functionally, IHG exposure suppressed endothelial nitric oxide synthase (eNOS) and its transcriptional regulator KLF2, whereas HDAC1 inhibition reinstated their expression, suggesting epigenetic restoration of endothelial homeostasis. We also observed a reversal in the ICAM1 expression upon pyroxamide treatment, which was functionally characterized by the reduced THP1 cell binding to HUVEC exposed to IHG along with pyroxamide. Collectively, our findings uncover a previously unrecognized histone H4-driven mechanism governing endothelial dysfunction in diabetes, wherein HDAC1-mediated H4K5 deacetylation represses KLF2-eNOS signaling. Targeting HDAC1 thus presents a promising therapeutic approach for mitigating vascular complications associated with diabetes.
Renewal and reacquisition (R/R) of drug-seeking behaviors are key drivers of relapse in substance use disorders (SUDs). These processes emerge from interactions among learning, memory, and reward-related neural circuits that are engaged when individuals encounter drug-associated contexts, cues, stressors, or restored drug availability. Advances in animal models and experimental tools have improved our understanding of the neurobiological mechanisms that cause relapse, including how substance-associated memories are formed and retrieved, how context-dependent renewal happens after extinction or punishment-based interventions, and how substance seeking and taking restarts rapidly when reinforcement is restored. In this review, we synthesize evidence on behavioral, circuit-level and molecular processes that contribute to R/R across substances, highlighting translational and clinical parallels, and identifying mechanistic gaps that constrain intervention development. We conclude by outlining mechanism-informed strategies that integrate behavioral, pharmacological, and genetic interventions to strengthen the generalization (transference) and durability of extinction learning and memory updating, to reduce relapse vulnerability, particularly driven by R/R.
Landscape-scale restoration is needed to reverse declines in biodiversity, but the ecological processes that sustain biodiversity by boosting heterogeneity are often overlooked. Large herbivores are important drivers of heterogeneity and are increasingly being used to restore lost dynamic processes. With beaver populations recovering from a historic low, we test what their ecosystem engineering potential means for biodiversity and ecosystem functioning at multiple scales. We quantified 10 taxonomic groups at sample, site and landscape scale via in-situ surveys (plants and water beetles) and eDNA sampling (invertebrate and vertebrates) from nine beaver-created wetlands and nine wetlands unmodified by beavers (control wetlands) in Evo, Finland. Per taxonomic group, the mean and total number of taxa at sample and site-scale was mostly similar between wetland types, though significantly higher in beaver wetlands at sample (true flies) and site-scale (plants and true flies). 63% of all taxa were shared by beaver-created and control wetlands. However, both wetland types supported unique taxa with beaver wetlands increasing the landscape taxon pool by an average of 19% (range 0-40%), most notably for plants, beetles, true flies and may/stone/caddisflies. Plant functional diversity was 55% higher in beaver compared to control wetlands. Beaver wetlands are integral to reinstating dynamic ecological processes that provide refugia for multiple taxonomic groups, supporting taxa otherwise absent from the landscape. Our findings hint at the scale of past biodiversity loss associated with beaver-dependent wetlands, while offering a glimpse of what could be gained from their ongoing population recovery. The online version contains supplementary material available at 10.1007/s10980-026-02303-4.
A new genus, Ingrischana gen. nov. (Tetrigidae: Tetriginae) is established for winged Tetriginae from Asia with extremely setose mid femur, and toothed dorsal margin of the hind femur. Till now, many species of this genus have been erroneously assigned to the genera Bannatettix Zheng, 1993; Formosatettixoides Zheng, 1994; Ergatettix Kirby, 1914; Euparatettix Hancock, 1904; Paratettix Bolívar, 1887, and Tetrix Latreille, 1802. Altogether 2 new species, 11 new combinations, 1 new name, and 2 new synonyms are proposed, and 1 species is reinstated. Two new species are I. motbotawa gen. et sp. nov. (Brija Furry Groundhopper) and I. aspinosa gen. et sp. nov. (Toothless Furry Groundhopper), both from Nepal. New combinations are I. aptera (Zheng et Ou, 2009) comb. nov., I. barbifemura (Zheng, 1998) comb. nov., I. curvimargina (Zheng et Deng, 2004) comb. nov., I. dentifemura (Zheng, Shi et Luo, 2003) comb. nov., I. grossifemura (Zheng et Jiang, 1997) comb. nov., I. longzhouensis (Zheng et Jiang, 2000) comb. nov., I. obesa (Bolívar, 1887) comb. nov., I. serrifemora (Deng, Zheng et Wei, 2008) comb. nov., I. serrifemoralis (Zheng, 1998) comb. nov., I. serrifemoroides (Zheng et Jiang, 2002) comb. nov., and I. torulosinota (Zheng, 1998) comb. nov. The new name is I. parlungana nom. nov., proposed for Bannatettix serrifemoralis Zheng et Shi, 2009a, because of the homonymy with I. serrifemoralis (Zheng, 1998) comb. nov. Ingrischana jhapana (Ingrisch, 2001a) stat. rev. et comb. nov. is reinstated as a valid species. Two new synonyms are Formosatettixoides guangxiensis Zheng & Jiang, 2000 syn. nov. (of I. longzhouensis comb. nov.), and Ergatettix serifemoroides Zheng et Shi, 2009b syn. nov. (of I. parlungana nom. nov.). The new genus is defined not only by morphological apomorphies, but is also confirmed by mitogenome phylogeny.
Rikkunshito, a traditional Japanese herbal medicine, is used to improve gastrointestinal (GI) function. However, its mechanisms of action in irritable bowel syndrome (IBS) remain unclear. This study aimed to investigate the effects of Rikkunshito on colonic pacemaker activity, inflammation, GI hormones, pain-related behaviors, and transient receptor potential (TRP) channel activity in a zymosan-induced IBS mouse model. Rikkunshito composition was analyzed by UPLC. Pacemaker potentials were recorded in colonic interstitial cells of Cajal (ICCs) to examine ghrelin receptor-mediated Ca2+ signaling pathways. Zymosan-induced IBS was established in male C57BL/6 mice treated with Rikkunshito, sulfasalazine, or amitriptyline. Colonic pathology, inflammation, stool consistency, body weight, pain-related behaviors, gastrointestinal hormones, and epithelial barrier-related gene expression were evaluated. TRPV1, TRPV4, and TRPA1 channel activities were analyzed using whole-cell patch-clamp recordings in TRP-overexpressing HEK293T cells. Rikkunshito depolarized colonic ICCs membranes and markedly suppressed pacemaker potential amplitude. These effects were mediated through ghrelin receptor-coupled G protein signaling and required extracellular Ca2+ influx and intracellular Ca2+ release via the PLC-IP3 pathway. In addition, MAPK signaling was involved, whereas PKC and PKA signaling were not. In vivo, Rikkunshito ameliorated colonic shortening, inflammation, diarrhea, and pain-related behaviors in zymosan-induced IBS mice. TNF-α expression and VIP levels were significantly reduced, and NPY levels were restored, while 5-HT showed a downward trend. Furthermore, Rikkunshito reinstated the expression of aquaporins and tight junction-related genes, indicating reinforcement of mucosal barrier integrity. In HEK293T cells, Rikkunshito inhibited TRPV1, slightly enhanced TRPV4, and robustly activated TRPA1 currents. Rikkunshito exerts protective effects in IBS by coordinately regulating colonic pacemaker activity via ghrelin receptor-dependent Ca2+ signaling, modulating neuroendocrine balance, improving epithelial barrier function, and differentially regulating TRP channel activity. These findings support the potential of Rikkunshito as a complementary therapeutic agent for IBS through integrated modulation of gut motility, inflammation, and visceral sensory pathways.
Preclinical animal models of eating disorders show a clear relationship between stress in the adolescent period and the development of dysfunctional coping strategies, including disordered eating. Much of this work, however, has focused on male mice despite the fact that eating disorders are predominantly observed in women. To this end, we assessed the impact of social isolation and food deprivation in adolescent female mice upon feeding and other coping behaviors. We found that social isolation, together with food restriction, caused alterations in activity levels and feeding consistent with impulsive binging behaviour in adolescent female mice. Indeed, socially isolated mice that were food restricted (FR) exhibited signs of elevated feeding following exposure to a palatable food and upon reinstatement of ad libitum (AL) food chow. FR mice also showed elevated home-cage activity and together with social isolation, altered Y-maze performance. Finally, the adolescent stress regimen appeared to cause long lasting brain atrophy, as occurs in eating disorders, as reflected by reduced gross brain weight. Hence, social isolation, when combined with restricted feeding during adolescence in female mice results in a behavioral phenotype reminiscent of symptoms associated with some eating disorders, such as binge eating.
Diabetic neuropathic pain (DNP) is a common, debilitating complication of diabetes with limited disease-modifying therapies. Regulated ferroptosis in neuroimmune signaling that sustains central sensitization. We investigated whether tetrandrine (Tet), a bis-benzyl-isoquinoline alkaloid with anti-inflammatory properties, mitigates DNP by targeting ferroptotic and inflammatory pathways in the spinal cord and investigate the potential molecular mediator. We found that systemic Tet treatment markedly reduced mechanical allodynia in DNP rats and suppressed spinal glial activation and proinflammatory cytokine secretion. RNA-seq revealed Tet-reversed transcriptional changes enriched in immune pathways, with Alox15 among Tet-responsive genes, which involved in ferroptosis. In DNP rat spinal cord, Tet lowered spinal MDA and Fe2+, restored GPX4 and ferritin subunit expression, and reduced Alox15 upregulation. In rat microglial cells (RMCs), Tet rescued Erastin-induced ferroptosis, improved viability, reduced ROS, MDA, Fe2+, cytokine release, and preserved mitochondrial ultrastructure. Forced Alox15 overexpression abolished Tet's cytoprotective effects, reinstating ferroptosis and inflammatory signaling. Collectively, our findings uncover the mechanism that Tet mitigates DNP-associated mechanical allodynia by restraining spinal ferroptosis, with Alox15 acting as a key counter-regulator of Tet's protective action.
Atrophic macular degeneration comprises dry age-related macular degeneration (AMD) and autosomal recessive Stargardt disease (STGD1). These disorders lead to irreversible blindness and still lack effective therapies. The rise of all-trans-retinal (atRAL) brought on by visual cycle disruption closely links to retinal atrophy in both conditions, yet the key downstream targets remain obscure. Exendin-4 (EX-4) is a natural glucagon-like peptide-1 receptor (GLP-1R) agonist. Recent clinical retrospective studies indicate that GLP-1R agonists such as exenatide (synthetic EX-4) can markedly lower the 5-year risk of developing dry AMD. Here, we sought to clarify the protective effect of natural EX-4 against retinal degeneration in atrophic macular degeneration linked to impaired clearance of atRAL. Cell and animal paradigms of STGD1 and dry AMD were generated by atRAL-loaded 661W cells and light-exposed Abca4-/-Rdh8-/- mice, respectively. RNA-sequencing, cell viability assays, morphometric analysis, annexin V/propidium-iodide staining using flow cytometry, quantitative polymerase chain reaction (qPCR), western blotting, immunofluorescence, electroretinography (ERG), fundus photography, hematoxylin and eosin (H&E) histology, and TUNEL staining were integrated to delineate the anti-apoptotic actions of EX-4 and to uncover its underlying protective mechanism. GLP-1R/cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA)/cAMP response element-binding protein 1 (CREB1) signaling was markedly downregulated in atRAL-challenged 661W cells and in neural retina of light-exposed Abca4-/-Rdh8-/- mice. EX-4 reinstated this pathway, suppressed caspase-3 activation and DNA damage, and curtailed apoptosis in both cell and tissue contexts. Silencing of Glp1r or the PKA catalytic subunits by small interfering RNA (siRNA) abrogated EX-4-induced activation of the PKA/CREB1 axis in atRAL-loaded 661W cells. Pharmacologic blockade of CREB1 phosphorylation with the PKA inhibitor H-89 or the CREB1 inhibitor 666-15 largely nullified the DNA-protective and anti-apoptotic benefits conferred by EX-4 in 661W cells following atRAL exposure, suggesting that the GLP-1R/PKA/CREB1 signaling axis contributes to its cytoprotection action. More importantly, intraperitoneal injection of EX-4 significantly preserved retinal structure and function in Abca4-/-Rdh8-/- mice after exposure to light, and mitigated punctate lesions in the fundus. EX-4 exerted anti-apoptotic and DNA-protective effects against atRAL-induced photoreceptor loss and retinal degeneration at least partially through activating the GLP-1R/PKA/CREB1 pathway. These findings suggest that GLP-1R agonists could serve as potential preventive therapeutics for atrophic macular degeneration associated with atRAL toxicity, including dry AMD and STGD1.
Stroop effects can be influenced by context-specific cues associated with varying levels of proportion congruency, even for items that occur with equal frequency in each context. This theoretically important result points to the involvement of a cue-driven memory process in the dynamic updating of selective attention. However, attempts to replicate this result have been challenging, potentially due to limitations or confounds in the experimental design, or difficulties in inducing context-specific learning due to item-specific cues. The present study aimed to reevaluate the memory-guided hypothesis using the trial-unique Stroop paradigm, where each trial consists of a unique stimulus and response that never reappear throughout the experiment, thereby preventing trial-to-trial associative regularities. One context was associated with high conflict (20% proportion congruency), and the other with low conflict (80% proportion congruency). Experiment 1 demonstrated that trials within the low-conflict context exhibited larger congruency effects compared with those in the high-conflict context, aligning with the memory-guided selective attention hypothesis that attentional priorities become associated with contextual cues and are automatically reinstated through memory retrieval. Experiment 2 replicated this finding and examined whether both auditory and visual context cues were necessary by assigning participants to combined auditory-visual, auditory-only, or visual-only conditions. The context-specific proportion congruency effect was successfully replicated in both the combined and visual-only conditions, but not in the auditory-only condition, suggesting that visual contextual cues may be more effective than auditory cues. These findings provide compelling evidence for memory-guided selective attention while revealing important boundary conditions regarding contextual cue effectiveness.