Protein hydrolysis-targeted chimeras (PROTACs) are heterobifunctional molecules designed for the selective degradation of target proteins. MS4078, a novel PROTAC, shows promise for treating ALK-positive non-small cell lung cancer (NSCLC), yet its clinical efficacy is hindered by suboptimal tumor targeting and off-target toxicities. To enhance its therapeutic profile, we developed human heavy chain ferritin (HFN) as a targeted delivery system, leading to the creation of HFN@MS4078 nanocages. Prepared via passive loading, HFN@MS4078 achieved a drug loading capacity of 178 molecules per nanocage with a HFN recovery rate of 70.1 %. The nanocages exhibited a rapid release profile under lysosomal conditions (pH 5.0), with approximately 80 % drug release after 60 h, while maintaining over 80 % stability at physiological pH 7.4. In vitro, HFN@MS4078 was actively internalized into lysosomes via TfR1 receptor binding, resulting in a 2.7-2.8 times reduction in IC50 values compared to free MS4078. Furthermore, HFN@MS4078 significantly decreased the expression levels of ALK, p-ALK, p-AKT, and p-ERK in NCI-H2228 and NCI-H3122 cell lines. In vivo, HFN@MS4078 substantially reduced tumor volume and prolonged survival while exhibiting negligible systemic toxicity. These results suggest that HFN@MS4078 represents a promising strategy for targeted therapy in ALK-positive NSCLC, enhancing therapeutic efficacy while minimizing systemic toxicity.

Hippocampal sclerosis, characterized by significant hippocampal neuronal loss, oxidative stress, glial cell proliferation, and inflammatory responses, constitutes a pivotal component in the pathogenesis of temporal lobe epilepsy (TLE). Traditional treatment strategies, mainly involving anti-epileptic drugs, face challenges including ineffectiveness, drug tolerance, and adverse reactions, complicating management of the condition. Herein, we design and engineer ultrasmall potassium calcium hexacyanoferrate (III) nanoparticles, designated as KCaHNPs, which feature a broad spectrum of enzymatic activities analogous to superoxide dismutase, catalase, peroxidase, and glutathione peroxidase. KCaHNPs efficiently neutralize excessive reactive oxygen species, mitigate mitochondrial dysfunction, maintain neuronal integrity, and prevent apoptosis. Importantly, KCaHNPs significantly reduce neuronal damage, apoptosis, ferroptosis, and glial cells activation in TLE-afflicted rats, thereby improving spatial and short-term memory, and diminishing epileptic hyperexcitability. Prophylactic deployment of KCaHNPs markedly decreases the frequency and duration of seizures, extends the latency period before the onset of initial seizures, and enhances neural functions within the hippocampal CA3 area. Collectively, these findings underscore the potent therapeutic and prophylactic efficacy of KCaHNPs in mitigating TLE by bolstering cellular defense mechanisms against oxidative stress and inflammation. This innovative approach holds promise as a comprehensive and efficacious strategy for managing temporal lobe epilepsy and potentially other complex neurological disorders.

Triple-negative breast cancer (TNBC) remains a formidable clinical challenge due to its aggressive nature and limited therapeutic options. Proteolysis-targeting chimeras (PROTACs) have emerged as a promising strategy for targeted protein degradation, leveraging the ubiquitin-proteasome system to eliminate oncogenic proteins. However, their therapeutic application is hindered by off-target toxicity, poor bioavailability, and limited tumor accumulation, highlighting the need for an improved delivery system. Here, we engineered a heavy-chain ferritin (HFn)-based nanoplatform, HFn@Thal, to enhance the delivery and efficacy of the CDK9-targeting PROTAC Thal-SNS-032 in TNBC. HFn nanocages were produced via an Escherichia coli expression system and loaded with Thal-SNS-032 using a pH-triggered self-assembly strategy, achieving a high drug-loading capacity of 134.9 molecules per nanocage and releasing 80 % of the payload under lysosomal conditions (pH 5.0) within 48 h. In vitro studies revealed transferrin receptor 1 (TfR1)-mediated endocytosis, significantly enhancing drug uptake and reducing IC50 values by 1.46-to 4.16-fold compared to free Thal-SNS-032 in TNBC cells. HFn@Thal efficiently induced CDK9 degradation, inhibited the phosphorylation of its downstream target RNA polymerase II, and suppressed transcription elongation. Additionally, HFn@Thal promoted G2/M phase arrest, apoptosis, and downregulation of oncogenic pathways, particularly the CDK9-MYC-Mcl1 axis. In vivo, HFn@Thal exhibited superior tumor accumulation, inhibiting tumor growth and prolonging survival with negligible toxicity. Transcriptomic analysis further confirmed its impact on transcriptional elongation, apoptosis, and chromatin remodeling pathways. This study establishes HFn@Thal as a robust, tumor-selective PROTAC delivery platform, offering a promising strategy to overcome therapeutic limitations in TNBC.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by diverse clinical presentations, often associated with dysregulated oxidative stress mechanisms leading to heightened production of reactive oxygen species (ROS) in the brain. Due to its multifactorial etiology, effective therapeutic approaches for ASD remain challenging to ascertain. This work engineers Prussian blue nanoparticles (PB NPs) designed to mimic the enzymatic functions of key antioxidants such as superoxide dismutase, glutathione peroxidase, catalase, and peroxidase. PB NPs effectively scavenge ROS and restore cellular redox homeostasis. These nanoparticles attenuate neuronal apoptosis by reducing activation of apoptotic markers like cleaved caspase-3 and B-cell lymphoma-2 associated X protein, while enhancing the expression of anti-apoptotic protein B-cell lymphoma-2. Furthermore, PB NPs mitigate neuroinflammation by downregulating pro-inflammatory cytokines and upregulating anti-inflammatory cytokines, thereby alleviating glial cell hyperactivity. In preclinical ASD models, PB NPs significantly improve social interaction deficits, diminish anxiety-like behaviors, and enhance cognitive functions. The therapeutic application of PB NPs represents a notable advancement in ASD treatment, offering a novel approach for clinical intervention aimed at enhancing the quality of life for individuals affected by ASD.

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder with limited treatment options, largely due to its complex etiology and the inadequate delivery of therapeutics to the central nervous system. Herein, we report a novel biomimetic nanocomposite, HFn@M/R, designed for the synergistic co-delivery of metformin (Met) and rapamycin (Rapa) to restore neurodevelopmental homeostasis in ASD. Heavy-chain ferritin (HFn) nanocages, produced via an Escherichia coli expression system, were employed as a dual-drug carrier owing to their high drug loading capacity and intrinsic blood-brain barrier permeability via transferrin receptor 1 targeting. Comprehensive physicochemical characterization confirmed structural integrity, optimal drug loading, and redox/pH-responsive release under pathological conditions. In neuronal models, HFn@M/R restored mitochondrial membrane potential, enhanced AMPK-CREB-BDNF signaling, and suppressed mTOR hyperactivation and autophagic blockade. In a valproic acid-induced rat model of ASD, HFn@M/R achieved robust brain accumulation, ameliorated behavioral deficits, and normalized hippocampal electroencephalogram patterns. Transcriptomic analyses further revealed that HFn@M/R modulated key neurodevelopmental, metabolic, and immune pathways, underscoring its capacity to orchestrate a multi-target therapeutic network. Collectively, our findings establish HFn@M/R as a promising precision nanomedicine platform for ASD treatment, with potential applicability to a broad range of neurodevelopmental and neuroinflammatory disorders.

Background: Autism spectrum disorder (ASD) involves complex interactions between genetic and environmental factors. Recent studies suggest that dysregulation of β-arrestin2 (Arrb2) in the central nervous system is linked to ASD. However, its specific mechanisms remain unknown. Methods: This study employs a systems genetics approach to comprehensively investigate Arrb2 in multiple brain tissues, including the amygdala, cerebellum, hippocampus, and prefrontal cortex, using BXD recombinant inbred (RI) strains. In addition, genetic variance analysis, correlation analysis, expression quantitative trait loci (eQTL) mapping, and functional annotation were used to identify the key downstream targets of Arrb2, validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting (WB). Results: Arrb2 exhibited expression variations across the four brain regions in BXD mice. eQTL mapping revealed that Arrb2 is cis-regulated, and increased Arrb2 expression levels were significantly correlated with ASD-like symptoms, such as impaired social interactions and abnormal learning and memory. Furthermore, protein–protein interaction (PPI) network analysis, tissue correlation, functional relevance to autism, and differential expression identified eight downstream candidate genes regulated by Arrb2. The experimental results demonstrated that deletion of Arrb2 led to the downregulation of Myh9, Dnmt1, and Brd4 expression, along with protein kinase A (PKA)-induced hyperactivation of Synapsin I. These findings suggest that Arrb2 may contribute to the pathogenesis of autism by modulating the expression of these genes. Conclusions: This study highlights the role of Arrb2 in ASD pathogenesis and identifies Myh9, Dnmt1, and Brd4 as key downstream regulators. These findings provide new insights into the molecular mechanisms of ASD and pave the way for novel therapeutic targets.

The evolution of nano-drug delivery systems addresses the limitations of conventional cancer treatments with stimulus-responsive nanomaterial-based delivery systems presenting temporal and spatial advantages. Among various nanomaterials, boron nitride nanoparticles (BNNs) demonstrate significant potential in drug delivery and cancer treatment, providing a high drug loading capacity, multifunctionality, and low toxicity. However, the challenge lies in augmenting nanomaterial accumulation exclusively within tumors while preserving healthy tissues. To address this, we introduce a novel approach involving cancer cell membrane-functionalized BNNs (CM-(BIDT)-T-d) for the codelivery of doxorubicin (Dox) and indocyanine green to treat homologous tumor. The cancer cell membrane biomimetic CM-(BIDT)-T-d nanoparticles possess highly efficient homologous targeting capabilities toward tumor cells. The surface modification with acylated TAT peptides ((d)TAT) further enhances the nanoparticle intracellular accumulation. Consequently, CM-(BIDT)-T-d nanoparticles, responsive to the acidic tumor microenvironment, hydrolyze amide bonds, activate the transmembrane penetrating function, and achieve precise targeting with substantial accumulation at the tumor site. Additionally, the photothermal effect of CM-(BIDT)-T-d under laser irradiation not only kills cells through thermal ablation but also destroys the membrane on the surface of the nanoparticles, facilitating Dox release. Therefore, the fabricated CM-(BIDT)-T-d nanoparticles orchestrate chemo-photothermal combination therapy and effectively inhibit tumor growth with minimal adverse effects, holding promise as a new modality for synergistic cancer treatment.

Rationale: Autism spectrum disorder (ASD) represents a complex neurodevelopmental condition lacking specific pharmacological interventions. Given the multifaced etiology of ASD, there exist no effective treatment for ASD. Rapamycin (RAPA) can activate autophagy by inhibiting the mTOR pathway and has exhibited promising effects in treating central nervous system disorders; however, its limited ability to cross the blood-brain barrier (BBB) has hindered its clinical efficacy, leading to substantial side effects. Methods: To address this challenge, we designed a drug delivery system utilizing red blood cell membrane (CM) vesicles modified with SS31 peptides to enhance the brain penetration of RAPA for the treatment of autism. Results: The fabricated SCM@RAPA nanoparticles, with an average diameter of 110 nm, exhibit rapid release of RAPA in a pathological environment characterized by oxidative stress. In vitro results demonstrate that SCM@RAPA effectively activate cellular autophagy, reduce intracellular ROS levels, improve mitochondrial function, thereby ameliorating neuronal damage. SS31 peptide modification significantly enhances the BBB penetration and rapid brain accumulation of SCM@RAPA. Notably, SCM@RAPA nanoparticles demonstrate the potential to ameliorate social deficits, improve cognitive function, and reverse neuronal impairments in valproic acid (VPA)-induced ASD models. Conclusions: The therapeutic potential of SCM@RAPA in managing ASD signifies a paradigm shift in autism drug treatment, holding promise for clinical interventions in diverse neurological conditions.

Autism spectrum disorder (ASD) is a multifaced neurodevelopmental disorder with considerable heterogeneity, in which over-generated reactive oxygen species (ROS) induce a cascade of pathological changes, including cellular apoptosis and inflammatory responses. Given the complex etiology of ASD, no effective treatment is available for ASD. In this work, a specific catalytic nanoenzyme, calcium hexacyanoferrate (III) nanocatalysts (CaH NCs), is designed and engineered for efficient ASD treatment. CaH NCs can mimic the activities of natural enzymes including superoxide dismutase, peroxidase, catalase, and glutathione peroxidase, which mitigates intracellular excessive ROS and regulates redox equilibrium. These CaH NCs modulate mitochondrial membrane potential, elevate B-cell lymphoma-2 levels, and suppress pro-apoptotic proteins, including Caspase-3 and B-cell lymphoma-2-associated X, thus effectively reducing cellular apoptosis. Importantly, CaH NCs alleviate inflammation by upregulating anti-inflammatory cytokine interleukin-10 and downregulating pro-inflammatory factors, resulting in attenuated activation of microglial and astrocytic and subsequent reduction in neuroinflammation. Subsequently, CaH NCs enhance social abilities, decrease anxiety levels, ameliorate repetitive behaviors, and improve learning and memory in ASD animal models through inflammation regulation and apoptosis inhibition. The CaH NCs in managing and preventing ASD represents a paradigm shift in autism treatment, paving the alternative but efficient way for clinical interventions in neurological conditions.

Recent clinical studies have highlighted mutations in the voltage-gated potassium channel Kv10.2 encoded by the KCNH5 gene among individuals with autism spectrum disorder (ASD). Our preliminary study found that Kv10.2 was decreased in the hippocampus of valproic acid (VPA) - induced ASD rats. Nevertheless, it is currently unclear how KCNH5 regulates autism-like features, or becomes a new target for autism treatment. We employed KCNH5 knockout (KCNH5-/-) rats and VPA - induced ASD rats in this study. Then, we used behavioral assessments, combined with electrophysiological recordings and hippocampal brain slice, to elucidate the impact of KCNH5 deletion and environmental factors on neural development and function in rats. We found that KCNH5-/- rats showed early developmental delay, neuronal overdevelopment, and abnormal electroencephalogram (EEG) signals, but did not exhibit autism-like behavior. KCNH5-/- rats exposed to VPA (KCNH5-/--VPA) exhibit even more severe autism-like behaviors and abnormal neuronal development. The absence of KCNH5 excessively enhances the activity of the Protein Kinase B (Akt)/Mechanistic Target of Rapamycin (mTOR) signaling pathway in the hippocampus of rats after exposure to VPA. Overall, our findings underscore the deficiency of KCNH5 increases the susceptibility to autism under environmental exposures, suggesting its potential utility as a target for screening and diagnosis in ASD.

Background: Pancreatic adenocarcinoma (PAAD) is a type of malignant tumors in the digestive tract. It is extremely aggressive. However, the molecular mechanism of the occurrence and development of pancreatic cancer has not yet been elucidated. New evidence shows that the dysregulation of small nucleolar RNAs (SnoRNAs) plays an important role in tumorigenesis and has a certain connection with tumor stem cells. In this study, we screened differentially expressed SnoRNAs in pancreatic cancer, further explored whether the HGF/C-Met pathway is involved in the regulation of SNORD35A in pancreatic cancer stem cells.Materials and Methods: AffymetrixmiRNA 4.0 and QRT-PCR was used for differential screening of SnoRNA. CCK8, wound healing assay and TransWell chamber were used to detect cell proliferation, migration and invasion. QRT-PCR was used to detect the changes of epithelial - mesenchymal Transition (EMT) related genes of tumors. We detected the expression levels of HGF/C-Met pathway and its related proteins by Western blotting.Result: We found that SNORD35A is significantly overexpressed in pancreatic cancer. After disturbing the expression of SNORD35A, the epithelial markers increased and the mesenchymal markers decreased during the EMT process. At the same time, down-regulation of SNORD35A inhibited the proliferation, migration and invasion of pancreatic cancer stem cells in cellular level. In nude mouse transplanted tumor models, low expression of SNORD35A reduced tumor growth volume and attenuated its pathological features. Finally, we found that silencing SNORD35A reduced the expression levels of C-Met and its phosphorylated proteins.Conclusion: These results suggest that the regulation of SNORD35A on proliferation, migration, invasion and EMT of pancreatic cancer stem cells involves HGF/C-Met signaling pathway. SNORD35A has carcinogenic effects in pancreatic cancer and may become a prognostic biomarker and therapeutic target for pancreatic cancer patients.

Autism spectrum disorder (ASD) is a major neurodevelopmental disorder affecting 1 in 36 children in the United States. While neurons have been the focus of understanding ASD, an altered neuro-immune response in the brain may be closely associated with ASD, and a neuro-immune interaction could play a role in the disease progression. As the resident immune cells of the brain, microglia regulate brain development and homeostasis via core functions including phagocytosis of synapses. While ASD has been traditionally considered a polygenic disorder, recent large-scale human genetic studies have identified SCN2A deficiency as a leading monogenic cause of ASD and intellectual disability. We generated a Scn2a-deficient mouse model, which displays major behavioral and neuronal phenotypes. However, the role of microglia in this disease model is unknown. Here, we reported that Scn2a-deficient mice have impaired learning and memory, accompanied by reduced synaptic transmission and lower spine density in neurons of the hippocampus. Microglia in Scn2a-deficient mice are partially activated, exerting excessive phagocytic pruning of post-synapses related to the complement C3 cascades during selective developmental stages. The ablation of microglia using PLX3397 partially restores synaptic transmission and spine density. To extend our findings from rodents to human cells, we established a microglia-incorporated human cerebral organoid model carrying an SCN2A protein-truncating mutation identified in children with ASD. We found that human microglia display increased elimination of post-synapse in cerebral organoids carrying the SCN2A mutation. Our study establishes a key role of microglia in multi-species autism-associated models of SCN2A deficiency from mouse to human cells.

Boron nitride nanomaterials are being increasingly recognized as vehicles for cancer drug delivery that increase drug loading and control drug release because of their excellent physicochemical properties and biocompatibility. However, these nanoparticles are often cleared rapidly by the immune system and have poor tumor targeting effects. As a result, biomimetic nanotechnology has emerged to address these challenges in recent times. Cell-derived biomimetic carriers have the characteristics of good biocompatibility, long circulation time, and strong targeting ability. Here, we report a biomimetic nanoplatform (CM@BN/DOX) prepared by encapsulating boron nitride nanoparticles (BN) and doxorubicin (DOX) together using cancer cell membrane (CCM) for targeted drug delivery and tumor therapy. The CM@BN/DOX nanoparticles (NPs) were able to target cancer cells of the same type on its own initiative through homologous targeting of cancer cell membranes. This led to a remarkable increase in cellular uptake. In vitro simulation of an acidic tumor microenvironment could effectively promote drug release from CM@BN/DOX. Furthermore, the CM@BN/DOX complex exhibited an excellent inhibitory effect against homotypic cancer cells. These findings suggest that CM@BN/DOX are promising in targeted drug delivery and potentially personalized therapy against their homologous tumor.

The cytoplasmic multifunctional adaptor protein β-arrestin 2 (Arrb2) is involved in the occurrence of various nervous system diseases, such as Alzheimer's disease and Parkinson's disease. Previous laboratory studies have shown that the expression and function of the Arrb2 gene was increased in valproic acid-induced autistic mice models. However, few reports have examined the possible role of Arrb2 in the pathogenesis of autism spectrum disorder. Therefore, Arrb2-deficient (Arrb2-/-) mice were further studied to uncover the physiological function of Arrb2 in the nervous system. In this study, we found that Arrb2-/- mice had normal behavioral characteristics compared with wild-type mice. The autophagy marker protein LC3B was decreased in the hippocampus of Arrb2-/- mice compared to wild-type mice. Western blot analysis revealed that deletion of Arrb2 caused hyperactivation of Akt-mTOR signaling in the hippocampus. In addition, abnormal mitochondrial dysfunction was observed in Arrb2-/- hippocampal neurons, which was characterized by a reduction in mitochondrial membrane potential and adenosine triphosphate production and an increase in reactive oxygen species levels. Therefore, this study elucidates the interaction between Arrb2 and the Akt-mTOR signaling pathway and provides insights into the role of Arrb2 in hippocampal neuron autophagy.

Background: Dysfunctional neurons and microglia in the rostral ventrolateral medulla (RVLM) have been implicated in the pathogenesis of stress-induced hypertension (SIH). Functional perturbation of microglial synaptic engulfment can induce aberrant brain circuit activity. IFN-γ is a pleiotropic cytokine that plays a role in regulating neuronal activity. However, existing research on the exploration of the effects of microglia on synapses in the RVLM is lacking, particularly on the function of IFN-γ in microglial synaptic engulfment involved in SIH. Methods: A SIH rat model was established by electric foot shocks combined with noise stimulation. The underlying mechanism of IFN-γ on synaptic density and microglial synaptic engulfment was investigated through in-vivo and in-vitro experiments involving gain of function, immunofluorescence, quantitative real-time PCR, western blot, and morphometric analysis. Furthermore, the function of IFN-γ in neuronal activity, renal sympathetic nerve activity (RSNA), and blood pressure (BP) regulation was determined through in-vivo and in-vitro experiments involving Ca2+ imaging, immunofluorescence, platinum–iridium electrode recording, ELISA, the femoral artery cannulation test, and the tail-cuff method. Results: The BP, heart rate, RSNA, plasma norepinephrine, and the number of c-Fos-positive neurons in SIH rats increased compared with those in control rats. Pre and postsynaptic densities in the RVLM also increased in SIH rats. IFN-γ and CCL2 expression levels were significantly reduced in the RVLM of the SIH group, whose microglia also exhibited an impaired capacity for synapse engulfment. IFN-γ elevation increased CCL2 expression and microglial synaptic engulfment and decreased synaptic density in vivo and in vitro. However, CCL2 inhibition reversed these effects. Moreover, the reduction of neuronal excitability, RSNA, plasma norepinephrine, and BP by IFN-γ was abrogated through CCL2 expression. Conclusion: IFN-γ deficiency in the RVLM impaired the microglial engulfment of synapses by inhibiting CCL2 expression and increasing synaptic density and neuronal excitability, thereby contributing to SIH progression. Targeting IFN-γ may be considered a potential strategy to combat SIH.

Pyrola corbieri Levl has been used to strengthen bones and nourish the kidney (the kidney governs the bone and is beneficial to the brain) by the local Miao people in China. However, the functional components and neurotrophic activity have not been reported. A new acidic homogeneous heteropolysaccharide named LTC-1 was obtained and characterized by periodate oxidation, Smith degradation, partial acid hydrolysis, GC–MS spectrometry, methylation analysis, and Fourier transform infrared spectroscopy, and its molecular weight was 3239 Da. The content of mannuronic acid (Man A) in LTC-1 was 46%, and the neutral sugar was composed of L-rhamnose (L-Rha), L-arabinose (L-Ara), D-xylose (D-Xyl), D-mannose (D-Man), D-glucose (D-Glc) and D-galactose (D-Gal) with a molar ratio of 1.00:3.63:0.86:1.30:6.97:1.30. The main chain of LTC-1 was composed of Glc, Gal, Man, Man A and the branched chain Ara, Glc, Gal. The terminal residues were composed of Glc and Gal. The main chain and branched chains were linked by (1→5)-linked-Ara, (1→3)-linked-Glc, (1→4)-linked-Glc, (1→6)-linked-Glc, (1→3)-linked-Gal, (1→6)-linked-Gal, (1→3, 6)-linked-Man and ManA. Meanwhile, neurotrophic activity was evaluated through PC12 and primary hippocampal neuronal cell models. LTC-1 exhibited neurotrophic activity in a concentration-dependent manner, which significantly induced the differentiation of PC12 cells, promoted the neurite outgrowth of PC12 cells, enhanced the formation of the web architecture of dendrites, and increased the density of dendritic spines in hippocampal neurons and the expression of PSD-95. These results displayed significant neurotrophic factor-like activity of LTC-1, which suggests that LTC-1 is a potential treatment option for neurodegenerative diseases.

Growing evidence has suggested the poor correlation between brain amyloid plaque and Alzheimer's disease (AD). Presenilin1 (PS1) and presenilin2 (PS2) conditional double knockout (cDKO) mice exhibited the reduced 42-amino acid amyloid-β peptide (Aβ1-42) level and AD-like symptoms, indicating a different pathological mechanism from the amyloid cascade hypothesis for AD. Here we found that exogenous synthetic Aβ1-42 monomers could improve the impaired memory not only in cDKO mice without Aβ1-42 deposition but also in the APP/PS1/Tau triple transgenic 3 × Tg-AD mice with Aβ1-42 deposition, which were mediated by α7-nAChR. Our findings demonstrate for the first time that reduced soluble Aβ1-42 level is the main cause of cognitive dysfunction in cDKO mice, and support the opinions that low soluble Aβ1-42 level due to Aβ1-42 deposition may also cause cognitive deficits in 3 × Tg-AD mice. Therefore, "loss-of-function" of Aβ1-42 should be avoided when designing therapies aimed at reducing Aβ1-42 burden in AD.

Background: The rostral ventrolateral medulla (RVLM) plays a key role in mediating the development of stress-induced hypertension (SIH). Furthermore, enhanced glutamate transport within glutamatergic neurons in the RVLM mediates pressor responses. Data from our previous studies suggest that the voltage-gated sodium channel NaV1.6 is overexpressed in neurons in the RVLM in SIH model rats and participates in the resulting elevation of blood pressure. However, previous studies have not investigated the relationship between NaV1.6 expression and glutamatergic neurons. Methods: Here, we constructed an SIH rat model by knocking down NaV1.6 via microinjection of clustered regularly interspaced short palindromic repeats (CRISPR) guide RNA into the RVLM. Glutamate-related markers were quantified by Western blotting and immunofluorescence, and blood pressure was measured in the rats. Results: Our findings showed that vesicular glutamate transporter 1 (VGluT1) protein expression in the RVLM was higher in SIH rats than in Control rats, and GAD67 protein expression in SIH rats was lower than that in Control rats. Therefore, the number of VGluT1-positive neurons increased, while the number of GAD67-labeled neurons decreased after stress. After knocking down NaV1.6 expression in the RVLM, VGluT1 expression and the number of VGluT1-positive neurons decreased relative to those in SIH rats, while GAD67 protein expression and the number of GAD67-labeled neurons increased relative to those in SIH rats. Conclusions: These results indicate that overexpression of NaV1.6 in the RVLM may mediate the transport and transformation of glutamate in neurons, and NaV1.6 may participate in SIH.

Hepatic carcinoma (HC) is the sixth most frequently occurring malignancies and the third leading cause of cancer death worldwide. Sepantronium bromide (YM155) is a small molecule inhibitor of survivin, which has broad-spectrum anticancer therapeutic effects in various xenograft models. However, several-day continuous infusion is required to achieve greater anti-tumor efficacy because of rapid elimination from the blood circulation. Herein, a SMMC-7721 cancerous cyto-membrane-cloaked drug delivery system (DDS) (named as iM7721@GQD-YM), was developed for co-encapsulation of YM155 and graphene quantum dots (GQDs). Cytomembrane coating endowed iM7721@GQD-YM with effective targeting for homologous HC cells, excellent biocompatibility and favorable immunocompatibility for in vivo application. Surface decoration of iRGD peptide further enhanced its tumor targeting activity by iRGD-integrin recognition. In addition, under the irradiation of near-infrared ray (NIR), GQDs can directly kill tumors through photothermal effect and cause cell membrane rupture, accurately releasing YM155 at tumor sites. The physicochemical properties, in vivo andex vivo anti-tumor efficacy, and mechanisms of iM7721@GQD-YM nanoparticles (NPs) were systematically investigated in this work. The experimental results clearly indicate that the versatile biomimetic DDS holds great potential for the treatment of HC, which merits further investigation in both pre-clinical and clinical studies.

Autism is a complex neurodevelopmental disease that may be caused by genetic and environmental factors, that are incompletely understood. Overactivation of dopaminergic receptors can lead to autistic-like behavior. β-arrestin2 (Arrb2) is a scaffolding protein of the arrestin family, which function as cytosolic multifunctional adapter proteins that activate cell signal transduction and mediate the signal termination and endocytosis of G-protein-coupled receptors (GPCRs) complexes. In this study, we established an Arrb2 knockout (Arrb2-/-) mouse to explore the biological function of Arrb2 in autistic-like behavior caused by abnormality in the dopaminergic system. We found that Arrb2-/- mice did not exhibit the autistic-like behavior normally induced by SKF38393, an agonist of the dopamine receptor 1 (D1R). Compared with wild-type (WT) untreated mice, the SKF38393-treated WT mice and Arrb2-/- mice, with or without SKF38393 treatment, showed abnormalities on electroencephalography (EEG) and increased stimulation of the phosphorylated form of extracellular signal-regulated kinase (p-ERK) via the PKA/Rap1/B-Raf/MEK pathway. These results demonstrated that Arrb2 regulated the dopaminergic system through the ERK signaling pathway in the occurrence and development of autism, and that targeted deletion of Arrb2 impeded the development of autistic-like behavior.