Hepatocellular carcinoma (HCC) is an immunosuppressive tumor associated with high mortality. Photothermal and photodynamic therapies have been applied to induce immunogenic cell death (ICD) in HCC, ...successfully eliciting immune responses but facing limitations in penetration depth in clinical trials. Here, intrinsic mitochondrial hyperthermia was used to trigger thermosensitive drug release. The mitochondria were further self-heated through 2,4-dinitrophenol uncoupling, dramatically promoting free radical initiation and inducing tumor ICD. The synthesized mitochondrial-targeting TPP-HA-TDV nanoparticles specifically generated free radicals in the mitochondria without external stimulation, and obviously enhanced the release of ICD markers, subsequently evoking immune responses. The results showed that mitochondrial hyperthermia could be an endogenous target for thermosensitive drug release. Furthermore, self-heating mitochondria-induced free radical blast could be an efficient therapeutic for deep-seated tumor therapy.
TPP-HA-TDV evokes HCC ICD through mitochondrial hyperthermia-induced free radical blast, and cooperated with CTLA-4 antibody for effective immunotherapy. Display omitted
Fibrosis, which is characterized by excessive extracellular matrix (ECM) deposition, is a wound-healing response to organ injury and may promote cancer and failure in various organs, such as the ...heart, liver, lung, and kidney. Aging associated with oxidative stress and inflammation exacerbates cellular dysfunction, tissue failure, and body function disorders, all of which are closely related to fibrosis. Sirtuin-1 (SIRT1) is a class III histone deacetylase that regulates growth, transcription, aging, and metabolism in various organs. This protein is downregulated in organ injury and fibrosis associated with aging. Its expression and distribution change with age in different organs and play critical roles in tissue oxidative stress and inflammation. This review first described the background on fibrosis and regulatory functions of SIRT1. Second, we summarized the relationships of SIRT1 with other proteins and its protective action during fibrosis in the heart, liver, lung and kidney. Third, the activation of SIRT1 in therapies of tissue fibrosis, especially in liver fibrosis and aging-related tissue injury, was analyzed. In conclusion, SIRT1 targeting may be a new therapeutic strategy in fibrosis.
•Fibrosis is a dynamic response appears in various aging-related diseases.•Sirt1 as a longevity gene can regulate growth, aging and metabolism in multiple tissues and organs.•The expression and distribution of Sirt1 was changed with age in different organ.•Crosstalk between Sirt1 and other molecules can improve or prevent the process of organ fibrosis.•Activation of Sirt1 have been used in preventions and therapies of aging-related tissue fibrosis.
Mycoplasma gallisepticum (MG) is the primary causative agent of chronic respiratory disease (CRD) in chickens, characterized by respiratory inflammation. S100A9 plays a pivotal role in modulating the ...inflammatory response to microbial pathogens. Our prior investigation revealed a significant upregulation of S100A9 in the lungs of chickens following MG infection. This study delves into the immunomodulatory effects of S100A9 during MG infection, demonstrating a notable increase in S100A9 levels in the lungs, immune organs, alveolar epithelial type II cells (AECII), and macrophage HD11 cells of MG-infected chicks and embryos. In MG-infected AECII cells, S100A9 overexpression significantly enhanced MG proliferation and adhesion, suppressed AVBD1, NFκB, pro-inflammatory factors (IL1β and TNFα), and chemokines, reduced apoptosis, and promoted cell proliferation, thereby facilitating MG infection. Conversely, inhibiting S100A9 produced opposing effects. In MG-infected HD11 cells, S100A9 impeded MG proliferation and adhesion, increased AVBD1, NFκB, pro-inflammatory factors, and chemokines, and induced cell apoptosis while inhibiting proliferation. Additional results demonstrated that S100A9 facilitates MG infection by modulating the TLR7/NFκB/JAK/STAT pathway in AECII/HD11 cells. In summary, S100A9 exhibits a dual role in activating/inhibiting the natural immune response through TLR7/NFκB/JAK/STAT pathway regulation. This dual role promotes MG infection in AECII cells while enabling MG to evade immune surveillance by HD11 cells, ultimately enhancing the overall infection process. These findings advance our understanding of host-pathogen interactions during MG infection and underscore S100A9's potential as a therapeutic target for CRD in chickens.
•S100A9 Orchestrates Dual Immunomodulation in MG Infection Pathways.•S100A9's Immunomodulatory Dance in MG-Infected Cells.•S100A9's Dichotomous Influence on MG Proliferation and Apoptosis.
As crucial enzymes in the lipid metabolic network, long-chain acyl-CoA synthases (LACSs) are members of the acyl-activated enzyme superfamily and play a crucial role in epidermal wax synthesis, plant ...lipid anabolic metabolism, and stress tolerance. In this study, 11 pecan LACS genes were identified and categorized into five groups and located on nine chromosomes. The significant degree of conservation in the AtLACS and CiLACS protein sequences was demonstrated by multiple sequence alignment and conserved motif analysis. Cis-acting element analysis identified numerous stress-responsive and hormone-inducible elements in the promoter regions of CiLACS genes. The expression levels of CiLACS9 and CiLACS9-1 were considerably up-regulated under salt and drought stress, according to the qRT-RCR study. Treatment with ABA also led to increased expression levels of CiLACS1, CiLACS1-1, CiLACS2, and CiLACS9-1. Notably, CiLACS4, CiLACS4-1, CiLACS9, and CiLACS9-1 exhibited peak expression levels at 135 days after anthesis and are likely to have been crucial in the accumulation of seed kernel oil. Moreover, the CiLACS9 gene was shown to be located in the cytoplasm. These findings offer a theoretical framework for clarifying the roles of LACS genes in the processes of pecan kernel oil synthesis and response to abiotic stressors.
•Andrographolide is safely administered without side effects in the chickens and AEC II.•Andrographolide inhibits the expression of MG adhesion protein pMGA1.2.•Andrographolide attenuates MG-induced ...inflammation and apoptosis by suppressing the JAK/PI3K/AKT signal pathway.
Mycoplasma gallisepticum (MG) is the primary etiologic agent of chronic respiratory disease (CRD) in chickens. Respiratory tract inflammation and apoptosis are the main features of CRD. Andrographolide (Andro), a natural small molecule compound, is known for its excellent anti-pathogenic and anti-inflammatory properties. Hence, this study was to evaluate the anti-inflammation and anti-apoptosis effects of Andro as well as the underlying mechanism in the chicken lungs and primary alveolar type II epithelial cells (AEC II). Results showed Andro had no side effects on AEC II viability at concentrations below 200 μg/ml. Compared with the model group, terminal deoxynucleotidyl transferase-mediated dUTP nick endlabeling (TUNEL), western blot (WB), quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assays (ELISA) results showed Andro treatment significantly reduced apoptosis in the chicken lungs and AEC II, and down-regulated the expression levels of the protein of MG adhesin 1.2 (pMGA1.2), IL-1β, TNF-α, IL-6, Bax, Caspase 9 and Caspase 3, and up-regulated the expression levels of Bcl-2 and Bcl-xL in the chicken lungs, serum and AEC II (P ≤ 0.05). Moreover, Andro inhibited the MG-induced JAK/PI3K/AKT signal pathway activation in the chicken lungs and AEC II. Inhibiting of the JAK/PI3K/AKT signal pathway significantly alleviated MG-induced inflammation and apoptosis in the AEC II. Andro may exert an anti-inflammatory and anti-apoptotic effect by inhibiting the JAK/PI3K/AKT signal pathway in the chicken lungs and AEC II. In conclusion, Andro could act as a potential agent against MG infection by inhibiting the JAK/PI3K/AKT signal pathway and pMGA1.2 expression in the chickens.
Abstract An Arabidopsis (Arabidopsis thaliana) mitogen-activated protein kinase (MAPK) cascade composed of YODA (YDA)–MKK4/MKK5–MPK3/MPK6 plays an essential role downstream of the ERECTA (ER)/ER-LIKE ...(ERL) receptor complex in regulating stomatal development in the leaf epidermis. STOMAGEN (STO), a peptide ligand produced in mesophyll cells, competes with EPIDERMAL PATTERNING FACTOR2 (EPF2) for binding ER/ERL receptors to promote stomatal formation. In this study, we found that activation of MPK3/MPK6 suppresses STO expression. Using MUTE and STO promoters that confer epidermis- and mesophyll-specific expression, respectively, we generated lines with cell-specific activation and suppression of MPK3/MPK6. The activation or suppression of MPK3/MPK6 in either epidermis or mesophyll cells is sufficient to alter stomatal differentiation. Epistatic analyses demonstrated that STO overexpression can rescue the suppression of stomatal formation conferred by the mesophyll-specific expression of the constitutively active MKK4DD or MKK5DD, but not by the epidermis-specific expression of these constitutively active MKKs. These data suggest that STO is downstream of MPK3/MPK6 in mesophyll cells, but upstream of MPK3/MPK6 in epidermal cells in stomatal development signaling. This function of the MPK3/MPK6 cascade allows it to coordinate plant epidermis development based on its activity in mesophyll cells during leaf development.
Lithium (Li) deposition behavior plays an important role in dendrite formation and the subsequent performance of lithium metal batteries. This work reveals the impact of the lithiophilic sites of ...lithium-alloy on the Li plating process via the first-principles calculations. We find that the Li deposition mechanisms on the Li metal and Li22Sn5 surface are different due to the lithiophilic sites. We first propose that Li plating on the Li metal surface goes through the “adsorption–reduction–desorption–heterogeneous nucleation–cluster drop” process, while it undergoes the “adsorption–reduction–growth” process on the Li22Sn5 surface. The lower adsorption energy contributes to the easy adsorption of Li on the lithiophilic sites of the Li22Sn5 surface. The lower Li reduction energy on the Li metal surface indicates that it is easy for Li to be reduced on the Li metal surface, attributed to its higher Fermi energy level. Furthermore, the faster Li diffusion on the Li22Sn5 surface results in smooth Li deposition, which is based on a “two-Li synergy diffusion” mechanism. However, Li diffuses more slowly on the Li metal surface than on the Li22Sn5 surface due to the “single Li diffusion” mechanism. This work provides a fundamental understanding on the impact of lithiophilic sites of Li alloy on the Li plating process and points out that the future design of 3D Li-alloy substrates decorated with multilithiophilic sites can prevent dendrite formation on the lithium-alloy substrate by guiding uniform Li deposition.
Fibrosis is a common process of tissue repair response to multiple injuries in all chronic progressive diseases, which features with excessive deposition of extracellular matrix. Fibrosis can occur ...in all organs and tends to be nonreversible with the progress of the disease. Different cells types in different organs are involved in the occurrence and development of fibrosis, that is, hepatic stellate cells, pancreatic stellate cells, fibroblasts and myofibroblasts. Various types of programmed cell death, including apoptosis, autophagy, ferroptosis and necroptosis, are closely related to organ fibrosis. Among these programmed cell death types, necroptosis, an emerging regulated cell death type, is regarded as a huge potential target to ameliorate organ fibrosis. In this review, we summarize the role of necroptosis signalling in organ fibrosis and collate the small molecule compounds targeting necroptosis. In addition, we discuss the potential challenges, opportunities and open questions in using necroptosis signalling as a potential target for antifibrotic therapies.
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This article is part of a themed issue on Translational Advances in Fibrosis as a Therapeutic Target. To view the other articles in this section visit
http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.22/issuetoc
Deoxynivalenol (DON) is a common food contaminant that can impair male reproductive function. This study investigated the effects and mechanisms of DON exposure on progenitor Leydig cell (PLC) ...development in prepubertal male rats. Rats were orally administrated DON (0–4 mg/kg) from postnatal days 21–28. DON increased PLC proliferation but inhibited PLC maturation and function, including reducing testosterone levels and downregulating biomarkers like HSD11B1 and INSL3 at ≥2 mg/kg. DON also stimulated mitochondrial fission via upregulating DRP1 and FIS1 protein levels and increased oxidative stress by reducing antioxidant capacity (including NRF2, SOD1, SOD2, and CAT) in PLCs in vivo. In vitro, DON (2–4 μM) inhibited PLC androgen biosynthesis, increased reactive oxygen species production and protein levels of DRP1, FIS1, MFF, and pAMPK, decreased mitochondrial membrane potential and MFN1 protein levels, and caused mitochondrial fragmentation. The mitochondrial fission inhibitor mdivi-1 attenuated DON-induced impairments in PLCs. DON inhibited PLC steroidogenesis, increased oxidative stress, perturbed mitochondrial homeostasis, and impaired maturation. In conclusion, DON disrupts PLC development in prepubertal rats by stimulating mitochondrial fission.
Herein, by using two fluorinated and chlorinated monomers with similar structures in different molar ratios and dithieno3′,2′:3,4;2″,3″:5,6benzo1,2-c1,2,5thiadiazole (DTBT) as the third unit, a ...family of polymer donors D18, D18–20%Cl, D18–40%Cl, and D18–Cl are synthesized for OSCs. With appropriate chlorinated monomer proportion, the terpolymer D18–20%Cl exhibits proper HOMO energy level and higher packing density compared with that of other control polymers. Moreover, the D18–20%Cl:Y6 blend films have favorable morphology with better face-on crystallization and better charge transport. Consequently, the D18–20%Cl:Y6-based OSCs obtain a top-ranked PCE of 18.28% with overall improved device parameters compared to the controlled D18:Y6 or D18-Cl:Y6-based OSCs (17.50% or 17.02%), which represents the highest PCE for the reported terpolymer-based binary OSCs. Notably, the D18–20%Cl:Y6-based OSCs exhibit over 17% efficiency in a wide molecular weight range. These results demonstrate that the ternary copolymerization of DTBT and two similar moieties is an efficient approach for achieving efficient terpolymer donors with well batch-to-batch reproducibility.
