Electroconvulsive therapy combined with esketamine improved depression through PI3K/AKT/GLT-1 pathway.

Neuron excitotoxic damage induced by extracellular glutamate accumulation pathologically is one of the main mechanisms of depression. Glutamate transporter-1 (GLT-1) expressed in astrocyte is responsible for glutamate clearance to maintain glutamate balance. Electroconvulsive therapy (ECT) is prevalently recommended for severe depression due to its significant anti-depressant effect. Esketamine could offer advantages of rapid anti-depressant effect and neuron protection. The aim of this study is to investigate the anti-depressant efficacy of esketamine plus ECT, and further to explore the mechanism. Firstly, total 12 patients were randomized into anesthesia with propofol (P) or propofol+esketamine (PK) before ECT. 24-Hamilton Depression Scale (HAMD) was used to evaluate the severity of depression after each ECT. Then, depressive rat model was built using chronic unpredictable mild stress method, and subsequently received infusion of esketamine (5 mg/kg) or saline before ECT treatment (0.5 mA; 100 V) for consecutive 10 days. Tests including sucrose preference test, open field test and forced swimming test were used to evaluate depression-like behaviors. In next experiments, rats were injected with RIL, DHK or LY294002 intracerebroventricularly for continuous 10 days before individual treatment. After the fifth and sixth ECT, PK group displayed lower HAMD score compared to P group. In rat model, we found that esketamine plus ECT could significantly improve depression-like behaviors and decrease glutamate level. Esketamine and ECT could both activate PI3K/Akt/GLT-1 pathway. The GLT-1 agonist RIL made equivalent effect as esketamine plus ECT. Furthermore, after using PI3K/Akt inhibitor LY294002 and GLT-1 inhibitor DHK, esketamine plus ECT could neither improve depression-like symptoms, nor upregulate GLT-1 level. Our present study suggested that esketamine plus ECT could dramatically improve depression symptom. The activation of PI3K/Akt/GLT-1 pathway may be the potential mechanism.

Influenza A virus infection activates STAT3 to enhance SREBP2 expression, cholesterol biosynthesis, and virus replication.

Cellular cholesterol plays an important role in influenza A virus (IAV) endocytosis and replication. However, how IAV infection regulates cholesterol biosynthesis remains poorly understood. Here, we report that IAV infection activates SREBP2 and induces the expression of HMGCR, a rate-limiting enzyme in cholesterol synthesis pathway. SREBP2 deficiency suppresses IAV-induced HMGCR expression and virus replication. Mechanistically, IAV infection activates JAK2 and STAT3, inhibition of JAK2 and STAT3 activity by their inhibitors or by gene knockout downregulates IAV-induced SREBP2 and HMGCR expression and IAV replication, reduces the content of cellular cholesterol and virus binding to host cells. Exogenous cholesterol reverses the inhibitory effect of S3I-201 and STAT3 deficiency on virus replication. STAT3 or JAK2 overexpression increases the expression of SREBP2 and its downstream target genes, leading to increased IAV replication. These observations collectively suggest that STAT3 activation facilitates IAV replication by inducing SREBP2 expression and increasing cholesterol biosynthesis.

Highly bioactive triple-helical nano collagens for accelerated treatment of photodamaged skin.

Skin damage caused by excessive UV exposure has gradually become one of the most common skin diseases, leading to desquamation, scab formation, inflammation and even skin cancer. Animal-derived hydrolyzed collagen peptides have been developed to treat UV-damaged skin; however, they have raised severe concerns such as potential viral transmission, random sequences and the lack of a triple helix structure. Nano collagen, a novel type of short collagen, has attracted increasing attention in the mimicking of natural collagen, while its applications in UV-damaged skin treatment remains unexplored. Herein, we have created a series of nano collagens and for the first time studied their capability of accelerating UV-damaged skin healing. Nano collagens, consisting of repetitive (GPO)n triplets and a GFOGER motif, display a stable triple-helical structure, significantly promoting fibroblast adhesion, proliferation, and migration. The repair effects of nano collagens have been investigated using an acute UV-damaged skin mouse model. Combo evaluations indicate that nano collagens contribute to recovering the dermis density and erythema index of UV-damaged skin. Histological analysis further demonstrates their capability of promoting the healing of damaged skin by accelerating re-epithelialization and collagen regeneration. These highly bioactive triple-helical nano collagens present a novel strategy for the treatment of UV-damaged skin, providing promising applications in cosmetics and dermatology.

Agarose-collagen composite microsphere implants: A biocompatible and robust approach for skin tissue regeneration.

Photoaged skin, a consequence of UV radiation-induced collagen degradation, presents a significant challenge for skin rejuvenation. Synthetic polymer microspheres, while offering collagen regeneration potential, carry risks like granulomas. To overcome this, we developed a novel agarose-collagen composite microsphere implant for skin tissue regeneration. Fabricated using an emulsification-crosslinking method, these microspheres exhibited excellent uniformity and sphericity (with a diameter of ~38.5 µm), as well as attractive injectability. In vitro studies demonstrated their superior biocompatibility, promoting cell proliferation, adhesion, and migration. Further assessments revealed favorable biosafety and blood compatibility. In vivo experiments in photoaged mice showed that implantation of these microspheres effectively reduced wrinkles, increased skin density, and improved elasticity by stimulating fibroblast encapsulation and collagen regeneration. These findings highlight the potential of agarose-collagen microspheres in dermatological and tissue engineering applications, offering a safer alternative for skin rejuvenation.

Causal relationships between immune cells, inflammatory factors, serum metabolites, and hepatic cancer: A two-sample Mendelian randomization study.

Background: Observational studies and clinical trials suggest associations between immune cells, inflammatory factors, serum metabolites, and hepatic cancer. However, the causal relationships between these factors and hepatic cancer remain to be established. Objective: To explore the causal relationships between immune cells, inflammatory factors, serum metabolites, and hepatic cancer. Methods: This study employed comprehensive two-sample Mendelian randomization (MR) utilizing publicly available genetic data (GWAS) to analyze causal relationships between 731 immune cell traits, 91 inflammatory factors, 1400 serum metabolites, and hepatic cancer. The primary analysis used inverse variance-weighted (IVW) MR, with additional sensitivity tests to assess the validity of causal relationships. Results: After correction for heterogeneity and horizontal pleiotropy, in exploring the causal relationships between immune cell groups and hepatic cancer, we found that Terminally Differentiated CD4-CD8- T cell %T cell was negatively associated with hepatic cancer, serving as a protective factor, while Effector Memory CD4-CD8- T cell %CD4-CD8- T cell was positively associated with hepatic cancer, acting as a risk factor. In investigating the causal relationships between inflammatory factors and hepatic cancer, C-C motif chemokine 19 levels were positively associated with hepatic cancer, representing a risk factor, while Interleukin-10 levels were negatively associated with hepatic cancer, acting as a protective factor. Regarding the causal relationships between serum metabolites and hepatic cancer, (N(1) + N(8))-acetylspermidine levels were negatively associated with hepatic cancer, serving as a protective factor, while 1-(1-enyl-palmitoyl)-GPC (p-16:0) levels were positively associated with hepatic cancer, acting as a risk factor. Conclusion: Our MR analysis indicates causal relationships between immune cells, inflammatory factors, serum metabolites, and hepatic cancer. However, further validation is needed to assess the potential of these immune cells, inflammatory factors, and serum metabolites as preventive or therapeutic targets for hepatic cancer.

Influenza A virus infection activates caspase-8 to enhance innate antiviral immunity by cleaving CYLD and blocking TAK1 and RIG-I deubiquitination.

Caspase-8, an aspartate-specific cysteine protease that primarily functions as an initiator caspase to induce apoptosis, can downregulate innate immunity in part by cleaving RIPK1 and IRF3. However, patients with caspase-8 mutations or deficiency develop immunodeficiency and are prone to viral infections. The molecular mechanism underlying this controversy remains unknown. Whether caspase-8 enhances or suppresses antiviral responses against influenza A virus (IAV) infection remains to be determined. Here, we report that caspase-8 is readily activated in A549 and NL20 cells infected with the H5N1, H5N6, and H1N1 subtypes of IAV. Surprisingly, caspase-8 deficiency and two caspase-8 inhibitors, Z-VAD and Z-IETD, do not enhance but rather downregulate antiviral innate immunity, as evidenced by decreased TBK1, IRF3, IκBα, and p65 phosphorylation, decreased IL-6, IFN-ß, MX1, and ISG15 gene expression; and decreased IFN-ß production but increased virus replication. Mechanistically, caspase-8 cleaves and inactivates CYLD, a tumor suppressor that functions as a deubiquitinase. Caspase-8 inhibition suppresses CYLD cleavage, RIG-I and TAK1 ubiquitination, and innate immune signaling. In contrast, CYLD deficiency enhances IAV-induced RIG-I and TAK1 ubiquitination and innate antiviral immunity. Neither caspase-3 deficiency nor treatment with its inhibitor Z-DEVD affects CYLD cleavage or antiviral innate immunity. Our study provides evidence that caspase-8 activation in two human airway epithelial cell lines does not silence but rather enhances innate immunity by inactivating CYLD.

Engineering a durable BDDE cross-linked collagen filler for skin rejuvenation.

Skin aging, characterized by reduced regeneration, chronic inflammation, and heightened skin cancer risk, poses a significant challenge. Collagen fillers have emerged as a potential solution for skin rejuvenation by stimulating collagen regeneration. However, their clinical efficacy is limited by inherent instability and vulnerability toin vivodegradation by collagenase. Chemical cross-linking presents a promising approach to enhance stability, but it carries risks such as cytotoxicity, calcification, and discoloration. Here, we introduce a highly durable 1,4-butanediol diglycidyl ether (BDDE) cross-linked collagen filler for skin rejuvenation. BDDE effectively cross-links collagen, resulting in fillers with exceptional mechanical strength and injectability. These fillers demonstrate favorable stability and durability, promoting proliferation, adhesion, and spreading of human foreskin fibroblast-1 cellsin vitro. In vivostudies confirm enhanced collagen regeneration without inducing calcification. BDDE cross-linked collagen fillers offer promising prospects for medical cosmetology and tissue regeneration.

Deformation and Annealing Behavior of Cr Coating Prepared by Pack-Cementation on the Surface of Austenitic Stainless Steel.

In this paper, a Cr coating was prepared by induction heating and pack-cementation chromizing on AISI 304 austenitic stainless steel. Then, the cold-rolling deformation and annealing treatment were introduced to refine the coarse matrix grains caused by pack-chromizing and improve the overall performance of 304 austenitic stainless steel. The phase composition, element distribution, and microstructure of the coating were carefully characterized. The microhardness, wear resistance, and corrosion resistance of the coating were tested. The results show that the Cr coating with a thickness of 100 µm is mainly composed of a (Cr,Fe)23C6, (Cr,Fe)7C3, and α-Fe-Cr solid solution. After the cold-rolling deformation and subsequent annealing treatment, the grains are significantly refined and the Cr coating is divided into two layers, consisting of carbon-chromium compounds such as Cr23C6, Cr7C3, Cr2C, and Cr3C2 in the surface layer and a Fe-Cr solid solution in the subsurface layer. The cold-rolling deformation and annealing treatment significantly improved the microhardness and wear resistance of the coated sample, and the corrosion resistance was also better than that of the uncoated sample.

Controlled Release of Ceria and Ferric Oxide Nanoparticles via Collagen Hydrogel for Enhanced Osteoarthritis Therapy.

Osteoarthritis (OA), characterized by chronic inflammation and cartilage degeneration, significantly affects over 500 million people globally. Nanoparticles have emerged as promising treatments for OA; however, current strategies often employ a single type of nanoparticle targeting specific disease stages, limiting sustained therapeutic efficacy. In this study, a novel collagen hydrogel is introduced, thiol crosslinked collagen-cerium oxide-poly(D,L-lactic-co-glycolic acid) microspheres encapsulating nanoparticles (CSH-CeO2-pFe2O3), designed for the controlled release of cerium oxide (CeO2) and ferric oxide (Fe2O3) nanoparticles for comprehensive OA management. The sulfhydryl cross-linked collagen matrix embeds CeO2 nanoparticles and poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres encapsulating Fe2O3 nanoparticles. The CSH-CeO2-pFe2O3 hydrogel exhibits enhanced mechanical strength and remarkable injectability, along with a significant promotion of cell adhesion, proliferation, and chondrogenic differentiation. Notably, the hydrogel demonstrates intelligent responsiveness to high levels of reactive oxygen species, initiating the rapid release of CeO2 nanoparticles to address the intense inflammatory responses of early-stage OA, followed by the sustained release of Fe2O3 nanoparticles to facilitate cartilage regeneration during the proliferative phase. In a rat model with cartilage defects, the hydrogel significantly alleviates inflammation and enhances cartilage regeneration, holding substantial potential for effectively managing the pathologically complex OA.

Transcription factor TaNF-YB2 interacts with partners TaNF-YA7/YC7 and transcriptionally activates distinct stress-defensive genes to modulate drought tolerance in T. Aestivum.

BACKGROUND: Drought stress limits significantly the crop productivity. However, plants have evolved various strategies to cope with the drought conditions by adopting complex molecular, biochemical, and physiological mechanisms. Members of the nuclear factor Y (NF-Y) transcription factor (TF) family constitute one of the largest TF classes and are involved in plant responses to abiotic stresses. RESULTS: TaNF-YB2, a NY-YB subfamily gene in T. aestivum, was characterized in this study focusing on its role in mediating plant adaptation to drought stress. Yeast two-hybrid (Y-2 H), biomolecular fluoresence complementation (BiFC), and Co-immunoprecipitation (Co-IP) assays indicated that TaNF-YB2 interacts with the NF-YA member TaNF-YA7 and NF-YC family member TaNF-YC7, which constitutes a heterotrimer TaNF-YB2/TaNF-YA7/TaNF-YC7. The TaNF-YB2 transcripts are induced in roots and aerial tissues upon drought signaling; GUS histochemical staining analysis demonstrated the roles of cis-regulatory elements ABRE and MYB situated in TaNF-YB2 promoter to contribute to target gene response to drought. Transgene analysis on TaNF-YB2 confirmed its functions in regulating drought adaptation via modulating stomata movement, osmolyte biosynthesis, and reactive oxygen species (ROS) homeostasis. TaNF-YB2 possessed the abilities in transcriptionally activating TaP5CS2, the P5CS family gene involving proline biosynthesis and TaSOD1, TaCAT5, and TaPOD5, the genes encoding antioxidant enzymes. Positive correlations were found between yield and the TaNF-YB2 transcripts in a core panel constituting 45 wheat cultivars under drought condition, in which two types of major haplotypes including TaNF-YB2-Hap1 and -Hap2 were included, with the former conferring more TaNF-YB2 transcripts and stronger plant drought tolerance. CONCLUSIONS: TaNF-YB2 is transcriptional response to drought stress. It is an essential regulator in mediating plant drought adaptation by modulating the physiological processes associated with stomatal movement, osmolyte biosynthesis, and reactive oxygen species (ROS) homeostasis, depending on its role in transcriptionally regulating stress response genes. Our research deepens the understanding of plant drought stress underlying NF-Y TF family and provides gene resource in efforts for molecular breeding the drought-tolerant cultivars in T. aestivum.