Low-frequency repetitive transcranial magnetic stimulation alleviates abnormal behavior in valproic acid rat model of autism through rescuing synaptic plasticity and inhibiting neuroinflammation.

Autism is a complex neurodevelopmental disorder with no effective treatment available currently. Repetitive transcranial magnetic stimulation (rTMS) is emerging as a promising neuromodulation technique to treat autism. However, the mechanism how rTMS works remains unclear, which restrict the clinical application of magnetic stimulation in the autism treatment. In this study, we investigated the effect of low-frequency rTMS on the autistic-like symptoms and explored if this neuroprotective effect was associated with synaptic plasticity and neuroinflammation in the hippocampus. A rat model of autism was established by intraperitoneal injection of valproic acid (VPA) in pregnant rats and male offspring were treated with 1 Hz rTMS daily for two weeks continuously. Behavior tests were performed to identify behavioral abnormality. Synaptic plasticity was measured by in vivo electrophysiological recording and Golgi-Cox staining. Synapse and inflammation associated proteins were detected by immunofluorescence and Western blot analyses. Results showed prenatal VPA-exposed rats exhibited autistic-like and anxiety-like behaviors, and cognitive impairment. Synaptic plasticity deficits and the abnormality expression of synapse-associated proteins were found in the hippocampus of prenatal VPA-exposed rats. Prenatal VPA exposure increased the level of inflammation cytokines and promoted the excessive activation of microglia. rTMS significantly alleviated the prenatal VPA-induced abnormalities including behavioral and synaptic plasticity deficits, and excessive neuroinflammation. TMS maybe a potential strategy for autism therapy via rescuing synaptic plasticity and inhibiting neuroinflammation.

Targeted desialylation and cytolysis of tumour cells by fusing a sialidase to a bispecific T-cell engager.

Bispecific T-cell engagers (BiTEs) bring together tumour cells and cytotoxic T cells by binding to specific cell-surface tumour antigens and T-cell receptors, and have been clinically successful for the treatment of B-cell malignancies. Here we show that a BiTE-sialidase fusion protein enhances the susceptibility of solid tumours to BiTE-mediated cytolysis of tumour cells via targeted desialylation-that is, the removal of terminal sialic acid residues on glycans-at the BiTE-induced T-cell-tumour-cell interface. In xenograft and syngeneic mouse models of leukaemia and of melanoma and breast cancer, and compared with the parental BiTE molecules, targeted desialylation via the BiTE-sialidase fusion proteins enhanced the formation of immunological synapses, T-cell activation and T-cell-mediated tumour-cell cytolysis in the presence of the target antigen. The targeted desialylation of tumour cells may enhance the potency of therapies relying on T-cell engagers.

High-capacity dilithium hydroquinone cathode material for lithium-ion batteries.

Lithiated organic cathode materials show great promise for practical applications in lithium-ion batteries owing to their Li-reservoir characteristics. However, the reported lithiated organic cathode materials still suffer from strict synthesis conditions and low capacity. Here we report a thermal intermolecular rearrangement method without organic solvents to prepare dilithium hydroquinone (Li2Q), which delivers a high capacity of 323 mAh g-1 with an average discharge voltage of 2.8 V. The reversible conversion between orthorhombic Li2Q and monoclinic benzoquinone during charge/discharge processes is revealed by in situ X-ray diffraction. Theoretical calculations show that the unique Li-O channels in Li2Q are beneficial for Li+ ion diffusion. In situ ultraviolet-visible spectra demonstrate that the dissolution issue of Li2Q electrodes during charge/discharge processes can be handled by separator modification, resulting in enhanced cycling stability. This work sheds light on the synthesis and battery application of high-capacity lithiated organic cathode materials.

Improve energy use efficiency through free trade policy: evidence from the establishment of free trade zones in China.

In the context of increasing global resource and environmental problems, it is of great practical significance to accurately test the impact of various factors on energy use efficiency for maintaining national energy security and formulating relevant policies. This paper measures firms' total factor energy efficiency (TFEE) using the two-stage stochastic frontier method within the data envelopment analysis (DEA) framework, leveraging data from listed firms in China spanning 2010 to 2022. Employing the establishment of free trade zones (FTZs) as a quasi-natural experiment, we apply the staggered differences-in-differences (DID) and stacked DID methods and analyze the impact of FTZs on firms' TFEE. The results show that the establishment of FTZs significantly promotes the improvement of firms' TFEE, and it has a greater promotion effect on heavily polluting, non-manufacturing, state-owned, private, and small-scale firms. The results of the mechanistic analysis showed that the promotion effect of FTZs on firms' TFEE is mainly realized through three channels: increasing government subsidies, reducing the financing constraint effect, and encouraging the technology innovation effect. Furthermore, industry-level decomposition results indicate that the surge in industry energy efficiency primarily results from improvements within firms rather than inter-industry variations. This paper's results propose that countries can enhance energy efficiency by progressively endorsing the implementation of FTZs.

Administration of Atosiban, an oxytocin receptor antagonist, ameliorates autistic-like behaviors in a female rat model of valproic acid-induced autism.

Autism spectrum disorder (ASD) is a pervasive developmental disorder with gender differences. Oxytocin (OXT) is currently an important candidate drug for autism, but the lack of data on female autism is a big issue. It has been reported that the effect of OXT is likely to be different between male and female ASD patients. In the study, we specifically explored the role of the OXT signaling pathway in a VPA-induced female rat's model of autism. The data showed that there was an increase of either oxytocin or its receptor expressions in both the hippocampus and the prefrontal cortex of VPA-induced female offspring. To determine if the excess of OXT signaling contributed to autism symptoms in female rats, exogenous oxytocin and oxytocin receptor antagonists Atosiban were used in the experiment. It was found that exogenous oxytocin triggered autism-like behaviors in wild-type female rats by intranasal administration. More interestingly, several autism-like deficits including social interaction, anxiety, and repeat stereotypical sexual behavior in the VPA female offspring were significantly attenuated by oxytocin receptor antagonists Atosiban. Moreover, Atosiban also effectively improved the synaptic plasticity impairment induced by VPA in female offspring. Our results suggest that oxytocin receptor antagonists significantly improve autistic-like behaviors in a female rat model of valproic acid-induced autism.

Nonflammable Succinonitrile-Based Deep Eutectic Electrolyte for Intrinsically Safe High-Voltage Sodium-Ion Batteries.

Intrinsically safe sodium-ion batteries are considered as a promising candidate for large-scale energy storage systems. However, the high flammability of conventional electrolytes may pose serious safety threats and even explosions. Herein, a strategy of constructing a deep eutectic electrolyte is proposed to boost the safety and electrochemical performance of succinonitrile (SN)-based electrolyte. The strong hydrogen bond between S═O of 1,3,2-dioxathiolane-2,2-dioxide (DTD) and the α-H of SN endows the enhanced safety and compatibility of SN with Lewis bases. Meanwhile, the DTD participates in the inner Na+ sheath and weakens the coordination number of SN. The unique solvation configuration promotes the formation of robust gradient inorganic-rich electrode-electrolyte interphase, and merits stable cycling of half-cells in a wide temperature range, with a capacity retention of 82.8% after 800 cycles (25 °C) and 86.3% after 100 cycles (60 °C). Correspondingly, the full cells deliver tremendous improvement in cycling stability and rate performance.

Molecular evolution and characterization of type III polyketide synthase gene family in Aquilaria sinensis.

2-(2-Phenylethyl) chromone (PEC) and its derivatives are markers of agarwood formation and are also related to agarwood quality. However, the biosynthetic and regulatory mechanisms of PECs still remain mysterious. Several studies suggested that type III polyketide synthases (PKSs) contribute to PEC biosynthesis in Aquilaria sinensis. Furthermore, systematic studies on the evolution of PKSs in A. sinensis have rarely been reported. Herein, we comprehensively analyzed PKS genes from 12 plant genomes and characterized the AsPKSs in detail. A unique branch contained only AsPKS members was identified through evolutionary analysis, including AsPKS01 that was previously indicated to participate in PEC biosynthesis. AsPKS07 and AsPKS08, two tandem-duplicated genes of AsPKS01 and lacking orthologous genes in evolutionary models, were selected for their transient expression in the leaves of Nicotiana benthamiana. Subsequently, PECs were detected in the extracts of N. benthamiana leaves, suggesting that AsPKS07 and AsPKS08 promote PEC biosynthesis. The interaction between the promoters of AsPKS07, AsPKS08 and five basic leucine zippers (bZIPs) from the S subfamily indicated that their transcripts could be regulated by these transcription factors (TFs) and might further contribute to PECs biosynthesis in A. sinensis. Our findings provide valuable insights into the molecular evolution of the PKS gene family in A. sinensis and serve as a foundation for advancing PEC production through the bioengineering of gene clusters. Ultimately, this contribution is expected to shed light on the mechanism underlying agarwood formation.

Unveil the origin of voltage oscillation for sodium-ion batteries operating at -40 °C.

Voltage oscillation at subzero in sodium-ion batteries (SIBs) has been a common but overlooked scenario, almost yet to be understood. For example, the phenomenon seriously deteriorates the performance of Na3V2(PO4)3 (NVP) cathode in PC (propylene carbonate)/EC (ethylene carbonate)-based electrolyte at -20 °C. Here, the correlation between voltage oscillation, structural evolution, and electrolytes has been revealed based on theoretical calculations, in-/ex-situ techniques, and cross-experiments. It is found that the local phase transition of the Na3V2(PO4)3 (NVP) cathode in PC/EC-based electrolyte at -20 °C should be responsible for the oscillatory phenomenon. Furthermore, the low exchange current density originating from the high desolvation energy barrier in NVP-PC/EC system also aggravates the local phase transformation, resulting in severe voltage oscillation. By introducing the diglyme solvent with lower Na-solvent binding energy, the voltage oscillation of the NVP can be eliminated effectively at subzero. As a result, the high capacity retentions of 98.3% at -20 °C and 75.3% at -40 °C are achieved. The finding provides insight into the abnormal SIBs degradation and brings the voltage oscillation behavior of rechargeable batteries into the limelight.

Revealing the effect of conductive carbon materials on the sodium storage performance of sodium iron sulfate.

Na2Fe2(SO4)3 (NFS), as a promising cathode for sodium-ion batteries, is still plagued by its poor intrinsic conductivity. In general, hybridization with carbon materials is an effective strategy to improve the sodium storage performance of NFS. However, the role of carbon materials in the electrochemical performance of NFS cathode materials has not been thoroughly investigated. Herein, the effect of carbon materials was revealed by employing various conductive carbon materials as carbon sources. Among these, the NFS coated with Ketjen Black (NFS@KB) shows the largest specific surface area, which is beneficial for electrolyte penetration and rapid ionic/electronic migration, leading to improved electrochemical performance. Therefore, NFS@KB shows a long cycle life (74.6 mA h g-1 after 1000 cycles), superior rate performance (61.5 mA h g-1 at a 5.0 A g-1), and good temperature tolerance (-10 °C to 60 °C). Besides, the practicality of the NFS@KB cathode was further demonstrated by assembling a NFS@KB//hard carbon full cell. Therefore, this research indicates that a suitable carbon material for the NFS cathode can greatly activate the sodium storage performance.

A conductive and sodiophilic Ag coating layer regulating Na deposition behaviors for highly reversible sodium metal batteries.

Sodium metal batteries have attracted increasing interest recently, but suffer from severe dendrite growth caused by uneven Na plating/stripping behavior, which may result in the piercing of the membrane, with short circuiting and even cause explosions. Herein, a conductive and sodiophilic Ag coating layer is introduced to regulate Na deposition behaviors for highly reversible sodium metal batteries. Ag coated Zn foil with enhanced sodiophilicity, rapid Na+ transfer kinetics and superior electronic conductivity guarantee the homogenized Na+ ion and electric field distribution. This enables remarkably low overpotentials and uniform Na plating/stripping behavior with ultrahigh Coulombic efficiency of 99.9% during 500 cycles. As expected, the enhanced electrochemical performance of the anode-less battery and anode-free battery coupled with Prussian blue is achieved with the help of Ag coating. This work emphasizes the role of the conductive and sodiophilic coating layer in regulating the Na deposition behaviors for highly reversible sodium metal batteries.

Boosting Multielectron Reaction Stability of Sodium Vanadium Phosphate by High-Entropy Substitution.

Na3V2(PO4)3 (NVP) based on the multielectron reactions between V2+ and V5+ has been considered a promising cathode for sodium-ion batteries (SIBs). However, it still suffers from unsatisfactory stability, caused by the poor reversibility of the V5+/V4+ redox couple and structure evolution. Herein, we propos a strategy that combines high-entropy substitution and electrolyte optimization to boost the reversible multielectron reactions of NVP. The high reversibility of the V5+/V4+ redox couple and crystalline structure evolution are disclosed by in situ X-ray absorption near-edge structure spectra and in situ X-ray diffraction. Meanwhile, the electrochemical reaction kinetics of high-entropy substitution NVP (HE-NVP) can be further improved in the diglyme-based electrolyte. These enable HE-NVP to deliver a superior electrochemical performance (capacity retention of 93.1% after 2000 cycles; a large reversible capacity of 120 mAh g-1 even at 5.0 A g-1). Besides, the long cycle life and high power density of the HE-NVP∥natural graphite full-cell configuration demonstrated the superiority of HE-NVP cathode in SIBs. This work highlights that the synergism of high-entropy substitution and electrolyte optimization is a powerful strategy to enhance the sodium-storage performance of polyanionic cathodes for SIBs.

Therapeutic Targeting of TIM-4-L with Engineered T Cells for Acute Myeloid Leukemia.

PURPOSE: Disruption of lipid bilayer asymmetry is a common feature observed in cancer cells and offers novel routes for therapeutic targeting. We used the natural immune receptor TIM-4 to interrogate for loss of plasma membrane phospholipid polarity in primary acute myelogenous leukemia (AML) samples and evaluated the anti-leukemic activity of TIM-4-L-directed T-cell therapy in preclinical AML models. EXPERIMENTAL DESIGN: We performed FACS analysis on 33 primary AML bone marrow specimens and correlated TIM-4-L expression frequency and intensity with molecular disease characteristics. Using Kasumi-1 and MV-4-11 AML cell lines, we further tested the anti-leukemic effects of TIM-4-L-directed engineered T cells in vitro and in vivo. RESULTS: We found that 86% of untreated AML blasts displayed upregulation of cell surface TIM-4-L. These observations were agnostic to AML genetic classification, as samples with mutations in TP53, ASXL1, and RUNX1 displayed TIM-4-L upregulation similar to that seen in favorable and intermediate subtypes. TIM-4-L dysregulation was also stably present in AML cell lines. To evaluate the potential of targeting upregulated TIM-4-L with adoptive T-cell therapy, we constructed TIM-4-L-directed engineered T cells, which demonstrated potent anti-leukemic effects, effectively eliminating AML cell lines with a range of endogenous TIM-4-L expression levels both in vitro and in vivo. CONCLUSIONS: These results highlight TIM-4-L as a highly prevalent target on AML across a range of genetic classifications and novel target for T-cell-based therapy in AML. Further investigations into the role of TIM-4-L in AML pathogenesis and its potential as an anti-leukemic target for clinical development are warranted.

Trachelogenin alleviates osteoarthritis by inhibiting osteoclastogenesis and enhancing chondrocyte survival.

BACKGROUND: Osteoarthritis (OA) is a prevalent global health concern associated with the loss of articular cartilage and subchondral bone. The lack of disease-modifying drugs for OA necessitates the exploration of novel therapeutic options. Our previous study has demonstrated that traditional Chinese medical herb Trachelospermum jasminoides (Lindl.) Lem. extract suppressed osteoclastogenesis and identified trachelogenin (TCG) as a representative compound. Here, we delved into TCG's potential to alleviate OA. METHODS: We initially validated the in vivo efficacy of TCG in alleviating OA using a rat OA model. Subsequently, we isolated primary bone marrow-derived macrophages in vitro to investigate TCG's impact on osteoclastogenesis. We further employed a small molecule pull-down assay to verify TCG's binding target within osteoclasts. Finally, we isolated primary mouse chondrocytes in vitro to study TCG's regulatory effects and mechanisms on chondrocyte survival. RESULTS: TCG preserved subchondral bone integrity and protected articular cartilage in a rat OA model. Subsequently, in vitro experiments unveiled TCG's capability to inhibit osteoclastogenesis and function through binding to Ras association proximate 1 (Rap1) and inhibiting its activation. Further study demonstrated that TCG inhibited Rap1/integrin αvß3/c-Src/Pyk2 signaling cascade, and consequently led to failed F-actin ring formation. Besides, TCG promoted the proliferation of mouse primary chondrocytes while suppressing apoptosis in vitro. This is attributed to TCG's ability to upregulate HIF1α, thereby promoting glycolysis. CONCLUSION: TCG exerted inhibitory effects on osteoclastogenesis through binding to Rap1 and inhibiting Rap1 activation, consequently preventing subchondral bone loss. Moreover, TCG enhanced chondrocyte survival by upregulating HIF1α and promoting glycolysis. These dual mechanisms collectively provide a novel approach to prevented against cartilage degradation.

Equivalent radius of atmosphere aerosol in haze weather based on laser scattering.

The investigation of atmospheric aerosols holds paramount importance within the environmental realm. This significance arises from the intricate nature of aerosol distribution and size in real-life hazy weather conditions. In this work, we have employed the equivalent radius of the aerosols in haze weather obtained from the volume spectrum, and then the scattering characteristics of these aerosols are obtained using the equivalent radius. Pearson correlation coefficients have been used for revealing a strong correlation by comparing Aeronet website data and simulation results with a minimum value of 0.657.

Endogenous stimuli-responsive separating microneedles to inhibit hypertrophic scar through remodeling the pathological microenvironment.

Hypertrophic scar (HS) considerably affects the appearance and causes tissue dysfunction in patients. The low bioavailability of 5-fluorouracil poses a challenge for HS treatment. Here we show a separating microneedle (MN) consisting of photo-crosslinked GelMA and 5-FuA-Pep-MA prodrug in response to high reactive oxygen species (ROS) levels and overexpression of matrix metalloproteinases (MMPs) in the HS pathological microenvironment. In vivo experiments in female mice demonstrate that the retention of MN tips in the tissue provides a slowly sustained drug release manner. Importantly, drug-loaded MNs could remodel the pathological microenvironment of female rabbit ear HS tissues by ROS scavenging and MMPs consumption. Bulk and single cell RNA sequencing analyses confirm that drug-loaded MNs could reverse skin fibrosis through down-regulation of BCL-2-associated death promoter (BAD), insulin-like growth factor 1 receptor (IGF1R) pathways, simultaneously regulate inflammatory response and keratinocyte differentiation via up-regulation of toll-like receptors (TOLL), interleukin-1 receptor (IL1R) and keratinocyte pathways, and promote the interactions between fibroblasts and keratinocytes via ligand-receptor pair of proteoglycans 2 (HSPG2)-dystroglycan 1(DAG1). This study reveals the potential therapeutic mechanism of drug-loaded MNs in HS treatment and presents a broad prospect for clinical application.

Cayratia albifolia C.L.Li exerts anti-rheumatoid arthritis effect by inhibiting macrophage activation and neutrophil extracellular traps (NETs).

BACKGROUND: Cayratia albifolia C.L.Li (CAC), commonly known as "Jiao-Mei-Gu" in China, has been extensively utilized by the Dong minority for several millennia to effectively alleviate symptoms associated with autoimmune diseases. CAC extract is believed to possess significant anti-inflammatory properties within the context of Dong medicine. However, an in-depth understanding of the specific pharmaceutical effects and underlying mechanisms through which CAC extract acts against rheumatoid arthritis (RA) has yet to be established. METHODS: Twenty-four Sprague-Dawley rats were divided into four groups, with six rats in each group. To induce the collagen-induced arthritis (CIA) model, the rats underwent a process of double immunization with collagen and adjuvant. CAC extract (100 mg/kg) was orally administered to rats. The anti-RA effects were evaluated in CIA rats by arthritis score, hind paw volume and histopathology analysis. Pull-down assay was conducted to identify the potential targets of CAC extract from RAW264.7 macrophage lysates. Moreover, mechanism studies of CAC extract were performed by immunofluorescence assays, real-time PCR and Western blot. RESULTS: CAC extract was found to obviously down-regulate hind paw volume of CIA rats, with diminished inflammation response and damage. 177 targets were identified from CAC extract by MS-based pull-down assay. Bioinformatics analysis found that these targets were mainly enriched in macrophage activation and neutrophils extracellular traps (NETs). Additionally, we reported that CAC extract owned significant anti-inflammatory activity by regulating PI3K-Akt-mTOR signal pathway, and inhibited NETosis in response to PMA. CONCLUSIONS: We clarified that CAC extract significantly attenuated RA by inactivating macrophage and reducing NETosis via a multi-targets regulation.

Phillygenin prevents osteoclast differentiation and bone loss by targeting RhoA.

Forsythia suspensa tea is a popular traditional Chinese medicine decoction for its healthy and therapeutic benefits. However, its effects in bone metabolism were not clear. In recent study, we uncovered anti-osteoclastogenesis property of Phillygenin (Phi), a compound abundant in Forsythia suspensa leaves, and aimed to investigate the effect and mechanism of Phi on bone metabolism in vivo and in vitro. Lipopolysaccharides-induced murine calvaria osteolysis and ovariectomy-induced bone loss animal models were used to identify the bone-protective effect of Phi in vivo and micro-CT, pQCT, and TRAP staining were applied. We used CCK8, TUNEL, BrdU, and TRAP staining to evaluate the efficacy of Phi on the proliferation and formation of OCs in primary mBMMs. RNA sequence, activity-based protein profiling, molecular docking, G-LISA, and WB were used to inspect the target and underlying mechanism of Phi's actions in mBMMs. We found Phi significantly inhibited bone resorption in vivo and inhibited mBMMs osteoclastogenesis in vitro. Ras homolog gene family member A (RhoA) was identified as the direct target of Phi. It counteracted the effects of RhoA activator and acted as a RhoA inhibitor. By targeting RhoA, Phi modulated Rho-associated coiled-coil containing protein kinase 1 (ROCK1) activity and regulated its downstream NF-κB/NFATc1/c-fos pathway. Furthermore, Phi depressed the disassembling of F-actin ring through cofilin and myosin1a. Our findings provided Phi as a potential option for treating bone loss diseases by targeting RhoA and highlighted the importance of F. suspensa as a preventive approach in bone disorders.

Anti-psoriasis molecular targets and active components discovery of Optimized Yinxieling Formula via affinity-purified strategy.

Psoriasis, a prevalent inherited skin condition, involves an inflammatory response as a key pathogenic mechanism. The Optimized Yinxieling Formula (OYF), rooted in traditional Chinese medicine, is extensively utilized in clinical settings to treat psoriasis. Although previous studies have demonstrated OYF's significant anti-inflammatory effects in psoriasis, its potential molecular targets and active components remain unexplored. This study aimed to unveil the anti-psoriasis molecular targets and active components of OYF. Our findings indicated that OYF extract markedly reduced the production of several inflammatory mediators, including IL-23, nitric oxide, TNF-α, and IL-1ß, in LPS-induced RAW264.7 cells. We synthesized OYF extract-crosslinked beads to isolate pharmacological targets from RAW264.7 lysates using an affinity purification strategy, known as Target Fishing. The enriched target proteins were subsequently identified via LC-MS/MS, followed by bioinformatics analysis to map the psoriasis-associated pathway-gene network. We identified a total of 76 potential target proteins, which were highly associated with mRNA transcription mechanisms. In particular, pathway-gene network analysis revealed that the IL-23 inflammatory pathway was involved in the anti-psoriasis effect of OYF extract. We further utilized a target protein-based affinity capture strategy, combined with LC-MS and SPR analysis, to globally screen OYF's active components, focusing on the mRNA transcription regulator, fused in sarcoma (FUS). This process led to the identification of umbelliferone, vanillic acid, protocatechuic acid, gentisic acid, and echinacoside as key compounds targeting FUS to inhibit IL-23 expression. Additionally, we formulated a compound cocktail (CpdC), which significantly reduced psoriasis area and severity index (PASI) scores and the expressions of IL-23 and Ki67 in an imiquimod (IMQ)-induced psoriasis mouse model. Collectively, our study elucidates the primary molecular targets and active components of OYF, offering novel insights for psoriasis treatment.

Acidity-activated aggregation and accumulation of self-complementary zwitterionic peptide-decorated gold nanoparticles for photothermal biofilm eradication.

Drug-resistant biofilm infection is an extremely serious clinical problem, that easily leads to failure of antibiotic treatment. Although gold nanoparticles (AuNPs) as photothermal agents have been widely used in biofilm eradication, there are still challenges to be addressed, such as insignificantly redshifted absorption and slow assembly process of aggregated AuNPs. Herein, we developed an acidity-activated dispersion-to-aggregation transition to enhance the accumulation of self-complementary zwitterionic peptide-decorated AuNPs for photothermal eradication of drug-resistant biofilm infections. AuNPs were decorated with self-complementary zwitterionic peptides (ZP1 and ZP2) coupled with pH-sensitive anhydride (DMA) and pH-insensitive anhydride (SA), respectively. ZP2-decorated AuNPs with DMA modification (AuNP@ZP2(DMA)) exhibited prolonged blood circulation and enhanced accumulation in acidic biofilm microenvironment. Moreover, the electrostatic attraction between self-complementary ligands drove AuNPs to form closely packed aggregates with strong near-infrared absorption, leading to in vivo photoacoustic imaging ability and photothermal effect against drug-resistant bacteria and fungus, as well as microbial biofilms. AuNP@ZP2(DMA) with longer charge domains and a polyethylene glycol oligomer spacer showed greater photothermal antimicrobial and biofilm resistance in vitro and in vivo. This study develops an innovative acidity-activated AuNP photothermal agent, which provides an effective approach for treatment of biofilm infections.

Palmitoylation of PKCδ by ZDHHC5 in hypothalamic microglia presents as a therapeutic target for fatty liver disease.

The hypothalamus plays a fundamental role in controlling lipid metabolism through neuroendocrine signals. However, there are currently no available drug targets in the hypothalamus that can effectively improve human lipid metabolism. In this study, we found that the antimalarial drug artemether (ART) significantly improved lipid metabolism by specifically inhibiting microglial activation in the hypothalamus of high-fat diet-induced mice. Mechanically, ART protects the thyrotropin-releasing hormone (TRH) neurons surrounding microglial cells from inflammatory damage and promotes the release of TRH into the peripheral circulation. As a result, TRH stimulates the synthesis of thyroid hormone (TH), leading to a significant improvement in hepatic lipid disorders. Subsequently, we employed a biotin-labeled ART chemical probe to identify the direct cellular target in microglial cells as protein kinase Cδ (PKCδ). Importantly, ART directly targeted PKCδ to inhibit its palmitoylation modification by blocking the binding of zinc finger DHHC-type palmitoyltransferase 5 (ZDHHC5), which resulted in the inhibition of downstream neuroinflammation signaling. In vivo, hypothalamic microglia-specific PKCδ knockdown markedly impaired ART-dependent neuroendocrine regulation and lipid metabolism improvement in mice. Furthermore, single-cell transcriptomics analysis in human brain tissues revealed that the level of PKCδ in microglia positively correlated with individuals who had hyperlipemia, thereby highlighting a clinical translational value. Collectively, these data suggest that the palmitoylation of microglial PKCδ in the hypothalamus plays a role in modulating peripheral lipid metabolism through hypothalamus-liver communication, and provides a promising therapeutic target for fatty liver diseases.