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PCB126, a type of polychlorinated biphenyl (PCB), is a persistent pollutant found in both biotic and abiotic environments and poses significant public health risks due to its potential to cause cardiac damage with prolonged exposure. Hypoxia-inducible factor-2α (HIF-2α) is part of the hypoxia-inducible factor (HIF) transcription complex family. Previous studies have shown that knocking out or inhibiting HIF-2α expression can ameliorate pulmonary hypertension and right ventricular dysfunction. This study aimed to investigate whether cardiac-specific knockout of HIF-2α can alleviate the cardiotoxicity caused by PCB126. In this study, cardiac-specific knockout mice and wild-type mice were orally administered PCB126 or corn oil (50 μg/kg/week) for eight weeks. Our findings indicated that PCB126 induces cardiotoxicity and myocardial injury, as evidenced by elevated cardiac enzyme levels and increased cardiac collagen fibers. RNA sequencing revealed that PCB126-induced cardiotoxicity involves the PI3K/Akt and p53 signaling pathways, which was confirmed by western blot analysis. Notably, cardiac-specific knockout of HIF-2α mitigated the damage caused by PCB126, reducing the expression of cardiac enzymes, inflammatory cytokines, and myocardial collagen fibers. Under normal conditions, conditional knockout (CKO) of the HIF-2α gene in cardiomyocytes did not affect the morphology or function of the mouse heart. However, HIF-2α CKO in the heart reduced the cardiotoxic effects of PCB126 by decreasing apoptosis through the PI3K/Akt and p53 signaling pathways. In conclusion, inhibiting HIF-2α expression in cardiomyocytes attenuated PCB126-induced cardiotoxicity by modulating apoptosis through these signaling pathways., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Phytochrome B (phyB) and phytochrome-interacting factors (PIFs) constitute a well-established signaling module critical for plants adapting to ambient light. However, mechanisms underlying phyB photoactivation and PIF binding for signal transduction remain elusive. Here, we report the cryo-electron microscopy (cryo-EM) structures of the photoactivated phyB or the constitutively active phyB Y276H mutant in complex with PIF6, revealing a similar trimer. The light-induced configuration switch of the chromophore drives a conformational transition of the nearby tongue signature within the phytochrome-specific (PHY) domain of phyB. The resulting α-helical PHY tongue further disrupts the head-to-tail dimer of phyB in the dark-adapted state. These structural remodelings of phyB facilitate the induced-fit recognition of PIF6, consequently stabilizing the N-terminal extension domain and a head-to-head dimer of activated phyB. Interestingly, the phyB dimer exhibits slight asymmetry, resulting in the binding of only one PIF6 molecule. Overall, our findings solve a key question with respect to how light-induced remodeling of phyB enables PIF signaling in phytochrome research., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The balance between oxidation and antioxidation is crucial for the development of embryo. It is harmful to the early embryonic development if embryonic stem cells (ESCs) encounter the serious oxidative stress in vivo. Induced pluripotent stem cells (iPSCs) are very similar to ESCs and are the important cell source to replace ESCs for research and therapy. Studies show that iPSCs have better resistant ability to oxidative stress, but the involved mechanism remains unclear. In this study, we predicted that the NF-κB pathway might be involved in H 2 O 2 -induced developmental damage by network toxicology analysis. Then, the oxidative stress model was established with different concentrations of H 2 O 2 to investigate the mechanism of NF-κB pathway in oxidative stress of human induced pluripotent stem cells (hiPSCs). The results showed as follows: With the increase of H 2 O 2 concentration, the ROS level gradually went up leading to an increasing damage degree of hiPSCs; however, the MDA content was obviously high only in the 400 μM H 2 O 2 group; the activities of some antioxidant indexes such as SOD2 and T-AOC were significantly upregulated in the 100 μM group, while most of antioxidant indexes showed downregulated tendency to different degrees with the increase of H 2 O 2 concentration. The expression levels of P65, P50, IκB, SOD2, and FHC mRNA were upregulated in most H 2 O 2 -treated groups, showing a dose-dependent relationship. In subsequent experiments, the inhibitor of IκB-α phosphorylation, Bay11-7082, reversed the upregulation of P65, IκB, and FHC mRNA expression induced by 400 μM H 2 O 2 . The protein levels of P65, p-P65, P50, p-P50, IκB, p-IκB, SOD2, and FHC were upregulated in most H 2 O 2 -treated groups. However, the upregulation induced by 400 μM H 2 O 2 could be reversed by BAY 11-7082, except for IκB and SOD2. In conclusion, H 2 O 2 could promote the expressions and phosphorylations of NF-κB that could upregulate the expressions of its downstream antioxidant genes to minimize the damage of hiPSCs caused by oxidative stress. These results contribute to a fundamental understanding of the antioxidant mechanism of iPSCs and will further facilitate the application of iPSCs, as well as provide a reference for controlling the oxidative stress encountered in the early development stage of embryo., (© 2024. The Society for In Vitro Biology.)

PIM1, the proviral integration site for Moloney murine leukemia virus, is a member of the serine/threonine protein kinase family. It is involved in many biological events, such as cell survival, cell cycle progression, cell proliferation, and cell migration, and has been widely studied in malignant diseases. However, recent studies have shown that PIM1 plays a prominent role in immunoinflammatory diseases, including autoimmune uveitis, inflammatory bowel disease, asthma, and rheumatoid arthritis. PIM1 can function in inflammatory signal transduction by phosphorylating multiple inflammatory protein substrates and mediating macrophage activation and T lymphocyte cell specification, thus participating in the development of multiple immunoinflammatory diseases. Moreover, the inhibition of PIM1 has been demonstrated to ameliorate certain immunoinflammatory disorders. Based on these studies, we suggest PIM1 as a potential therapeutic target for immunoinflammatory diseases and a valid candidate for future research. Herein, for the first time, we provide a detailed review that focuses on the roles of PIM1 in the pathogenesis of immunoinflammatory diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Liu, Lei, Liu, Zhu and Zhao.)

Abstract: We report on the antileukemic activity of homoharringtonine (HHT) in T-cell acute lymphoblastic leukemia (T-ALL). We showed that HHT inhibited the NOTCH/MYC pathway and induced significantly longer survival in mouse and patient-derived T-ALL xenograft models, supporting HHT as a promising agent for T-ALL., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Tendinopathy is one of the most prevalent sports injury diseases in orthopedics. However, there is no effective treatment or medicine. Recently, the discovery of tendon stem cells (TSCs) provides a new perspective to find new therapeutic methods for Tendinopathy. Studies have shown that oxidative stress will inevitably cause TSCs injury during tendinopathy, but the mechanism has not been fully elucidated. Here, we report the oxidative damage of TSCs induced by H 2 O 2 via ferroptosis, as well, treatment with H 2 O 2 raised the proportion of mitochondria engulfed by autophagosomes in TSCs. The suppression of mitophagy by Mdivi-1 significantly attenuates the H 2 O 2 -induced ferroptosis in TSCs. Mechanically, H 2 O 2 actives the cGAS-STING pathway, which can regulate the level of mitophagy. Interfering with cGAS could impair mitophagy and the classical ferroptotic events. In the rat model of tendinopathy, interference of cGAS could relieve tendon injury by inhibiting ferroptosis. Overall, these results provided novel implications to reveal the molecular mechanism of tendinopathy, by which pointed to cGAS as a potential therapeutic target for the treatment of tendinopathy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Morroniside (MOR) has been reported to ameliorate inflammation in cardiovascular and cerebrovascular disease; however, its impact and mechanism on rheumatoid arthritis (RA) remains unclear. This study aimed to investigate the beneficial role of morroniside in treating RA and explore the anti-invasive mechanism of morroniside on joint destruction., Methods: In vitro (using primary rat articular fibroblast-like synoviocytes (FLSs)) a wound healing assay was used to detect the migration of primary rat FLSs. Quantitative RT-PCR was used to measure the transcription of matrix metalloproteinase (MMP) MMP2 and MMP9. Western blot was used to measure the expression of MMP2, MMP9, p65, phosphorylated-p65 (p-p65), inhibitor of nuclear factor (NF)-[Formula: see text]B α (I[Formula: see text]B α ), I[Formula: see text]B kinase α /β (IKK α /β), and phosphorylated-IKK α /β. Immunofluorescence assay was used to measure the nuclear translocation of p65. In vivo (using rats with collagen-induced arthritis), the joint histopathological changes were detected by routine hematoxylin and eosin. Immunohistochemistry assay was used to measure the expression MMP2 and MMP9., Results: Morroniside diminished tumor necrosis factor (TNF) α -stimulated migration of primary rat articular FLSs. Morroniside also attenuated RA-FLSs invasion into joint and joint destruction in rats with collagen-induced arthritis (CIA). Further analysis revealed that morroniside inhibited the overexpression of matrix metalloproteinase MMP2 and MMP9 in TNF α -stimulated primary rat articular FLSs and joints of CIA rats. Mechanistically, morroniside suppressed the activation of I[Formula: see text]B kinase α /β, which resulted in elevated levels of the inhibitor of nuclear factor (NF)-[Formula: see text]B., Conclusion: The present study suggested that morroniside can prevent joint destruction by suppressing the activation of the NF-[Formula: see text]B/MMPs pathway, thereby preventing FLSs invasion., (© 2024 by the Association of Clinical Scientists, Inc.)

The cGAS-STING signaling pathway plays a pivotal role in sensing cytosolic DNA and initiating innate immune responses against various threats, with disruptions in this pathway being associated with numerous immune-related disorders. Therefore, precise regulation of the cGAS-STING signaling is crucial to ensure appropriate immune responses. Recent research, including ours, underscores the importance of protein condensation in driving the activation and maintenance of innate immune signaling within the cGAS-STING pathway. Consequently, targeting condensation processes in this pathway presents a promising approach for modulating the cGAS-STING signaling and potentially managing associated disorders. In this review, we provide an overview of recent studies elucidating the role and regulatory mechanism of protein condensation in the cGAS-STING signaling pathway while emphasizing its pathological implications. Additionally, we explore the potential of understanding and manipulating condensation dynamics to develop novel strategies for mitigating cGAS-STING-related disorders in the future., (© 2024 Wiley Periodicals LLC.)

Osteosarcoma, considered as the primary cause of malignant bone tumors in children, necessitates novel therapeutic strategies to enhance overall survival rates. KAT7, a histone acetyltransferase, exerts pivotal functions in gene transcription and immune modulation. In light of this, our study identified a significant upregulation of KAT7 in the mRNA and protein levels in human osteosarcoma, boosting cell proliferation in vivo and in vitro. In addition, KAT7-mediated H3K14ac activation induced MMP14 transcription, leading to increased expression and facilitation of osteosarcoma cell metastasis. Subsequent bioinformatics analyses highlighted a correlation between KAT7 and adaptive immune responses, indicating CCL3 as a downstream target of KAT7. Mechanistically, STAT1 was found to transcriptionally upregulate CCL3 expression. Furthermore, overexpression of KAT7 suppressed CCL3 secretions, whereas knockdown of KAT7 enhanced its release. Overall, these findings underscore the oncogenic role of KAT7 in regulating immune responses for osteosarcoma treatment., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Early brain injury (EBI) is closely associated with poor prognosis in patients with subarachnoid haemorrhage (SAH), with autophagy playing a pivotal role in EBI. However, research has shown that the stimulator of interferon genes (STING) pathway impacts autophagic flux. While the regulatory impact of neuritin on EBI and autophagic flux has been established previously, the underlying mechanism remains unclear. This study aimed to determine the role of the cGAS-STING pathway in neuritin-mediated regulation of autophagic flux following SAH., Methods: A SAH model was established in male Sprague-Dawley rats via intravascular perforation. Neuritin overexpressions using adeno-associated virus, the STING antagonist "C-176," and the activator, "CMA," were determined to investigate the cGAS-STING pathway's influence on autophagic flux and brain injury post-SAH, along with the neuritin's regulatory effect on STING. In this study, SAH grade, neurological score, haematoxylin and eosin (H&E) staining, brain water content (BWC), sandwich enzyme-linked immunosorbent assay, Evans blue staining, immunofluorescence staining, western blot analysis, and transmission electron microscopy (TEM) were examined., Results: Neuritin overexpression significantly ameliorated neurobehavioural scores, blood-brain barrier injury, brain oedema, and impaired autophagic flux in SAH-induced rats. STING expression remarkably increased post-SAH. C-176 and CMA mitigated and aggravated autophagic flux injury and brain injury, respectively, while inhibiting and enhancing STING, respectively. Particularly, CMA treatment nullified the protective effects of neuritin against autophagic flux and mitigated brain injury., Conclusion: Neuritin alleviated EBI by restoring impaired autophagic flux after SAH through the regulation of the cGAS-STING pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The primary objective of this work was to delve into the potential therapeutic advantages and dissect the molecular mechanisms of salidroside in enhancing erectile function in rats afflicted with diabetic microvascular erectile dysfunction (DMED), addressing both the whole-animal and cellular dimensions.We established a DMED model in Sprague‒Dawley (SD) rats and conducted in vivo experiments. The DMED rats were administered varying doses of salidroside, the effects of which on DMED were compared. Erectile function was evaluated by applying electrical stimulation to the cavernous nerves and measuring intracavernous pressure in real time. The penile tissue underwent histological examination and Western blotting. Hydrogen peroxide (H2O2) was employed in the in vitro trial to induce an oxidative stress for the purpose of identifying alterations in cell viability. The CCK-8 assay was used to measure the viability of corpus cavernous smooth muscle cells (CCSMCs) treated with vs. without salidroside. Flow cytometry was utilized to detect alterations in intracellular reactive oxygen species (ROS). Apoptosis was assessed through Western blotting and TdT-mediated dUTP nick-end labelling (TUNEL). Animal and cellular experiments indicate that the Nrf2/HO-1 signalling pathway may be upregulated by salidroside, leading to the improvement of erectile function in diabetic male rats by alleviating oxidative stress and reducing apoptosis in corpus cavernosum tissue., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cold injury is a major environmental stress affecting the growth and yield of crops. Brassinosteroids (BRs) and salicylic acid (SA) play important roles in plant cold tolerance. However, whether or how BR signaling interacts with the SA signaling pathway in response to cold stress is still unknown. Here, we identified an SA methyltransferase, TaSAMT1 that converts SA to methyl SA (MeSA) and confers freezing tolerance in wheat (Triticum aestivum). TaSAMT1 overexpression greatly enhanced wheat freezing tolerance, with plants accumulating more MeSA and less SA, whereas Tasamt1 knockout lines were sensitive to freezing stress and accumulated less MeSA and more SA. Spraying plants with MeSA conferred freezing tolerance to Tasamt1 mutants, but SA did not. We revealed that BRASSINAZOLE-RESISTANT 1 (TaBZR1) directly binds to the TaSAMT1 promoter and induces its transcription. Moreover, TaBZR1 interacts with the histone acetyltransferase TaHAG1, which potentiates TaSAMT1 expression via increased histone acetylation and modulates the SA pathway during freezing stress. Additionally, overexpression of TaBZR1 or TaHAG1 altered TaSAMT1 expression and improved freezing tolerance. Our results demonstrate a key regulatory node that connects the BR and SA pathways in the plant cold stress response. The regulatory factors or genes identified could be effective targets for the genetic improvement of freezing tolerance in crops., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Purpose: Bone marrow mesenchymal stem cells (BMSC) have multiple biological functions and are widely involved in regulating inflammatory diseases, tissue repair and regeneration. However, the mechanism of their action in dry eye disease (DED) is currently unclear. The purpose of this study was to investigate the effect of BMSCs in the treatment of dry eye mice and to explore its specific therapeutic mechanism., Methods: Mouse corneal epithelial cells (MCECs) were treated with 500 mOsM sodium chloride hypertonic solution to induce a DED cell model. The dry eye animal model was constructed by adding 5 μL 0.2% benzalkonium chloride solution to mouse eyes. Western blotting was used to detect the expression of related proteins, and flow cytometry, enzyme-linked immunosorbent assay (ELISA), terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining, hematoxylin-eosin (HE) staining, and periodic acid schiff (PAS) staining were used to detect cell and eye tissue damage., Results: The experimental results showed that BMSCs can reduce the levels of reactive oxygen species (ROS) and inflammatory factors in MCECs, promote cell proliferation, inhibit cell apoptosis, improve the integrity of the corneal epithelial layer in vivo , promote an increase in the number of goblet cells, and alleviate DED. Further exploration of the molecular mechanism of BMSCs treatment revealed that BMSCs alleviate the progression of DED by inhibiting the ROS-NLRP3-IL-1β signaling pathway., Conclusion: BMSCs inhibit ROS-NLRP3-IL-1β signaling axis, reducing inflammation levels and alleviating dry eye symptoms. These findings provide new ideas and a basis for the treatment of DED and provide an experimental basis for further research on the application value of BMSCs in alleviating DED.

Osteoarthritis (OA) is the most common degenerative joint disorder that causes disability in aged individuals, caused by functional and structural alterations of the knee joint. To investigate whether metabolic drivers might be harnessed to promote cartilage repair, a liquid chromatography-mass spectrometry (LC-MS) untargeted metabolomics approach was carried out to screen serum biomarkers in osteoarthritic rats. Based on the correlation analyses, α-ketoglutarate (α-KG) has been demonstrated to have antioxidant and anti-inflammatory properties in various diseases. These properties make α-KG a prime candidate for further investigation of OA. Experimental results indicate that α-KG significantly inhibited H 2 O 2 -induced cartilage cell matrix degradation and apoptosis, reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), increased superoxide dismutase (SOD) and glutathione (GSH)/glutathione disulfide (GSSG) levels, and upregulated the expression of ETV4, SLC7A11 and GPX4. Further mechanistic studies observed that α-KG, like Ferrostatin-1 (Fer-1), effectively alleviated Erastin-induced apoptosis and ECM degradation. α-KG and Fer-1 upregulated ETV4, SLC7A11, and GPX4 at the mRNA and protein levels, decreased ferrous ion (Fe 2+ ) accumulation, and preserved mitochondrial membrane potential (MMP) in ATDC5 cells. In vivo, α-KG treatment inhibited ferroptosis in OA rats by activating the ETV4/SLC7A11/GPX4 pathway. Thus, these findings indicate that α-KG inhibits ferroptosis via the ETV4/SLC7A11/GPX4 signaling pathway, thereby alleviating OA. These observations suggest that α-KG exhibits potential therapeutic properties for the treatment and prevention of OA, thereby having potential clinical applications in the future., (© 2024. The Author(s).)

The gut microbiota is closely linked to atherosclerosis. However, the role of intestinal fungi, essential members of the complex microbial community, in atherosclerosis is poorly understood. Herein, we show that gut fungi dysbiosis is implicated in patients with dyslipidemia, characterized by higher levels of Candida albicans (C. albicans), which are positively correlated with plasma total cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels. Furthermore, C. albicans colonization aggravates atherosclerosis progression in a mouse model of the disease. Through gain- and loss-of-function studies, we show that an intestinal hypoxia-inducible factor 2α (HIF-2α)-ceramide pathway mediates the effect of C. albicans. Mechanistically, formyl-methionine, a metabolite of C. albicans, activates intestinal HIF-2α signaling, which drives increased ceramide synthesis to accelerate atherosclerosis. Administration of the HIF-2α selective antagonist PT2385 alleviates atherosclerosis in mice by reducing ceramide levels. Our findings identify a role for intestinal fungi in atherosclerosis progression and highlight the intestinal HIF-2α-ceramide pathway as a target for atherosclerosis treatment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Bone marrow mesenchymal stem cell (BMSC)-derived exosomes (BMSC-Exos) have a variety of biological functions and are extensively involved in the regulation of inflammatory diseases, as well as tissue repair and regeneration. However, the mechanism of action of these compounds in dry eye disease (DED) in mice is still unclear. This study demonstrated that the Treg/Th17 ratio was strongly imbalanced in DED clinical samples. BMSC-Exos can modulate the Treg/Th17 balance, improve the integrity of the corneal epithelial layer, and ameliorate DED progression in mice. Mechanistically, BMSC-Exos dramatically decreased the levels of IL-17 and IL-22; increased the levels of IL-4, IL-10, and TGF-β1; and increased tear secretion and the number of goblet cells in the conjunctiva in mice, thus alleviating the progression of DED. This effect is achieved by BMSC-Exos through the delivery of miR-21-5p to target and restrain TLR4, thereby restraining the MyD88/NF-κB pathway. Our study showed that the upregulation of miR-21-5p in BMSC-Exos may be a therapeutic target for DED. These findings support new ideas and a basis for treating DED, as well as for further study of the application value of exosomes in alleviating DED., (© 2024. The Society for In Vitro Biology.)

Copper is a toxic heavy metal that causes various damage when it accumulates in the body beyond the physiological threshold. Wilson disease (WD) is an inherited disorder characterized by impaired copper metabolism. Reproductive damage in male patients with WD is gradually attracting attention. However, the underlying mechanisms of copper toxicity are unclear. In this study, we investigated the role of inflammation and PANoptosis in testicular damage and impaired spermatogenesis caused by copper deposition using the WD model toxic milk (TX) mice. Copper chelator-penicillamine and toll-like receptor 4 (TLR4) inhibitor-eritoran were used to intervene in TX mice in our animal experiment methods. Testis samples were collected from mice for further analysis. The results showed that the morphology and ultrastructure of the testis and epididymis in TX mice were damaged, and the sperm counts decreased significantly. The TLR4/nuclear factor kappa-B (NF-κB) signaling pathway was activated by copper deposition, which led to the upregulation of serum and testicular inflammatory factors in TX mice. Meanwhile, pyroptosis, apoptosis, and necroptosis were significant in the testis of TX mice. Both chelated copper or inhibited TLR4 expression markedly suppressed the TLR4/NF-κB signaling pathway, thereby reducing the expression of inflammatory factors. PANoptosis in the testis of TX mice was also reversed. Our study indicated that pathological copper exposure induces inflammation and PANoptosis through the TLR4/NF-κB signaling pathway, leading to toxic testicular damage and impaired spermatogenesis in WD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hui Han reports financial support was provided by the National Natural Science Foundation of China. Limin Wu reports financial support was provided by the National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hypertrophic cardiomyopathy (HCM) is a monogenic cardiac disorder commonly induced by sarcomere gene mutations. However, the mechanism for HCM is not well defined. Here, we generated transgenic MYH7 R453C and MYH6 R453C piglets and found both developed typical cardiac hypertrophy. Unexpectedly, we found serious fibrosis and cardiomyocyte loss in the ventricular of MYH7 R453C, not MYH6 R453C piglets, similar to HCM patients. Then, RNA-seq analysis and western blotting identified the activation of ERK1/2 and PI3K-Akt pathways in MYH7 R453C. Moreover, we observed an increased expression of fetal genes and an excess of reactive oxygen species (ROS) in MYH7 R453C piglet models, which was produced by Nox4 and subsequently induced inflammatory response. Additionally, the phosphorylation levels of Smad2/3, ERK1/2 and NF-kB p65 proteins were elevated in cardiomyocytes with the MYH7 R453C mutation. Furthermore, epigallocatechin gallate, a natural bioactive compound, could be used as a drug to reduce cell death by adjusting significant downregulation of the protein expression of Bax and upregulated Bcl-2 levels in the H9C2 models with MYH7 R453C mutation. In conclusion, our study illustrated that TGF-β/Smad2/3, ERK1/2 and Nox4/ROS pathways have synergistic effects on cardiac remodelling and inflammation in MYH7 R453C mutation.

Inflammatory bowel disease is linked to a higher occurrence of bone loss. Oxyberberine can effectively improve experimental inflammatory bowel disease. However, no study has shown the effect of oxyberberine on inflammatory bowel disease induced bone loss. The present study was performed to investigate the role of oxyberberine in inflammatory bowel disease induced osteoporosis in chronic inflammatory bowel disease mice model. The inflammatory bowel disease mice were orally given two doses of oxyberberine daily. Blood, colon, and bone specimens were collected for biomarker assessments and histological examinations. Bone biomechanical properties and key proteins and genes involved in the receptor activator of nuclear factor kappa-B ligand/nuclear factor kappa-B signaling pathway were evaluated. Additionally, the binding characteristics of oxyberberine and receptor activator of nuclear factor kappa-B ligand were evaluated by in silico simulation. Results indicated that oxyberberine treatment significantly attenuated the macroscopic damage, colonic shortening, and histological injury from the colon. Furthermore, oxyberberine decreased serum inflammatory cytokine levels. The intervention with oxyberberine significantly mitigated the deterioration of bone mass, biomechanical properties, and microstructural parameters. Moreover, the upregulated osteoclast formation factors in model mice were significantly abolished by oxyberberine. In silico simulation results also showed that oxyberberine was firmly bound with target protein. Hence, our findings indicated that oxyberberine had the potential to mitigate inflammatory bowel disease induced inflammation in bone, inhibit osteoclast formation through regulating the receptor activator of nuclear factor kappa-B ligand/nuclear factor kappa-B signaling pathway, and might be a valuable approach in preventing bone loss associated with inflammatory bowel disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Ovarian cancer (OC) is the most lethal malignancy in women owing to its diagnosis only at the advanced stage. Elucidation of its molecular pathogenesis may help identify new tumor markers and targets for therapy. Circular RNAs (circRNAs) are stable, conserved, and functional biomolecules that can be used as effective biomarkers for various cancers., Methods: In this study, a potential circRNA related to early diagnosis of OC, circMAN1A2, was analyzed. Overexpression/knockdown of circMAN1A2 in OC cells was used to decipher its effects on cell proliferation with a Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine (EdU), cell cycle, clone formation, and wound healing assay. RNA pull-down and Dual luciferase assay were used to explain the underlying mechanism by which circMAN1A2 regulates OC cell proliferation. In vivo , the effect of circMAN1A2 in OC was evaluated using nude mouse xenograft experiments., Results: CircMAN1A2 was highly expressed in OC and promoted proliferation, clone formation, and tumorigenicity of OC cells. In addition, we found that circMAN1A2 acted as a sponge for microRNA (miR)-135a-3p; miR-135a-3p directly targeted the 3' untranslated region of interleukin 1 receptor accessory protein ( IL1RAP ) in OC cells, thereby regulating the phosphorylation of transforming growth factor-beta activated kinase 1 (TAK1), which resulted in promotion of OC cell growth., Conclusions: CircMAN1A2 promotes OC cell proliferation by inhibiting the miR-135a-3p/IL1RAP/TAK1 axis. In conclusion, circMAN1A2 may be a biomarker for early detection of OC and a target for subsequent therapy., Competing Interests: The authors declare there are no competing interests., (©2024 Li et al.)

Diabetic nephropathy (DN) is a leading cause of end-stage renal failure. The study aimed to investigate whether long noncoding RNA taurine-upregulated gene 1 (TUG1) can ameliorate the endoplasmic reticulum stress (ERS) and apoptosis of renal tubular epithelial cells in DN, and the underlying mechanism. The DN mouse model was established by streptozocin injection, and the human renal tubular epithelial cell line HK-2 was treated with high glucose (HG) to mimic DN in vitro. The molecular mechanism was explored through dual-luciferase activity assay, RNA pull-down assay, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (CHIP) assay. The expression of TUG1 was significantly decreased in the renal tubules of DN model mice. Overexpression of TUG1 reduced the levels of ERS markers and apoptosis markers by inhibiting reticulon-1 (RTN1) expression in HG-induced HK-2 cells. Furthermore, TUG1 down-regulated RTN1 expression by inhibiting the binding of transcription factor PU.1 to the RTN1 promoter, thereby reducing the levels of ERS markers and apoptosis markers. Meanwhile, TUG1-overexpression adenovirus plasmids injection significantly alleviated tubular lesions, and reduced RTN1 expression, ERS markers and apoptosis markers, whereas these results were reversed by injection of PU.1-overexpression adenovirus plasmids. TUG1 restrains the ERS and apoptosis of renal tubular epithelial cells and ameliorates DN through inhibition of transcription factor PU.1., (©2021 Society for Leukocyte Biology.)

Macrophages are highly heterogeneous immune cells that fulfill tissue-specific functions. Tissue-derived signals play a critical role in determining macrophage heterogeneity. However, these signals remain largely unknown. The BMP receptor activin receptor-like kinase 1 (ALK1) is well known for its role in blood vessel formation; however, its role within the immune system has never been revealed to our knowledge. Here, we found that BMP9/BMP10/ALK1 signaling controlled the identity and self-renewal of Kupffer cells (KCs) through a Smad4-dependent pathway. In contrast, ALK1 was dispensable for the maintenance of macrophages located in the lung, kidney, spleen, and brain. Following ALK1 deletion, KCs were lost over time and were replaced by monocyte-derived macrophages. These hepatic macrophages showed significantly reduced expression of the complement receptor VSIG4 and alterations in immune zonation and morphology, which is important for the tissue-specialized function of KCs. Furthermore, we found that this signaling pathway was important for KC-mediated Listeria monocytogenes capture, as the loss of ALK1 and Smad4 led to a failure of bacterial capture and overwhelming disseminated infections. Thus, ALK1 signaling instructs a tissue-specific phenotype that allows KCs to protect the host from systemic bacterial dissemination.

Porcine epidemic diarrhea virus (PEDV) has reemerged as the main pathogen of piglets due to its high mutation feature. Monolaurin (ML) is a natural compound with a wide range of antibacterial and antiviral activities. However, the role of ML in PEDV infection is still unknown. This study aimed to evaluate the effect of ML on the growth performance, intestinal function, virus replication and cytokine response in piglets infected with PEDV, and to reveal the mechanism through proteomics analysis. Piglets were orally administrated with ML at a dose of 100 mg/kg·BW for 7 days before PEDV infection. Results showed that although there was no significant effect on the growth performance of piglets, ML administration alleviated the diarrhea caused by PEDV infection. ML administration promoted the recovery of intestinal villi, thereby improving intestinal function. Meanwhile, PEDV replication was significantly inhibited, and PEDV-induced expression of IL-6 and IL-8 were decreased with ML administration. Proteomics analyses showed that 38 proteins were differentially expressed between PEDV and ML+PEDV groups and were significantly enriched in the interferon-related pathways. This suggests ML could promote the restoration of homeostasis by regulating the interferon pathway. Overall, the present study demonstrated ML could confer a protective effect against PEDV infection in piglets and may be developed as a drug or feed additive to prevent and control PEDV disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Yi, Ji, Wu, Wang, Guo, Wang, Zhao and Hou.)

The repair of vascular endothelial cell dysfunction is an encouraging approach for the treatment of vascular complications associated with diabetes. It has been demonstrated that members of C1q/tumor necrosis factor-related protein (CTRP) family may improve endothelial function. Nevertheless, the protective properties of CTRPs in diabetic microvascular complications continue to be mostly unknown. Here, we demonstrate that the C1q-like globular domain of CTRP3, CTRP5, and CTRP9 (gCTRP3, 5, 9) exerted a vasorelaxant effect on the microvasculature, of which gCTRP3 was the most powerful one. In a murine model of type 2 diabetes mellitus, serum gCTRP3 level and endothelial function decreased markedly compared with controls. Two weeks of gCTRP3 treatment (0.5 μg/g/d) enhanced endothelium-dependent relaxation in microvessels, increased nitric oxide (NO·) production, and reduced retinal vascular leakage. In addition, Western blotting in human retinal microvascular endothelial cells indicated that gCTRP3 triggered AMP-activated protein kinase-α (AMPKα), hence increasing the endothelial NO synthase (eNOS) level and NO· production. In addition, incubation with gCTRP3 in vitro ameliorated the endothelial dysfunction induced by high glucose in the branch of the mesenteric artery. Blockade of either eNOS or AMPKα completely abolished the effects of gCTRP3 described above. Taken together, we demonstrate for the first time that gCTRP3 improves impaired vasodilatation of microvasculature in diabetes by ameliorating endothelial cell function through the AMPK/eNOS/NO· signaling pathway. This finding may suggest an effective intervention against diabetes-associated microvascular complications., (Copyright © 2021 Elsevier Inc. All rights reserved.)

20(S)-Ginsenoside Rh2 (GRh2) has various biological activities including anticancer effects. However, no reports have investigated the connection between autophagy and apoptosis in HeLa cells treated with 20(S)-GRh2. In this study, we found that 20(S)-GRh2 suppressed proliferation and induced apoptosis in HeLa cells by activating the intrinsic apoptotic pathway and causing mitochondrial dysfunction. 20(S)-GRh2 enhanced cell autophagy through promoting the phosphorylation of AMPK, depressed the phosphorylation of AKT, and suppressed mTOR activity. Furthermore, treatment with the autophagy inhibitor 3-methyladenine (3-MA) enhanced 20(S)-GRh2-induced apoptosis, while the autophagy inducer rapamycin promoted cell survival. Moreover, the apoptosis inhibitor Z-VAD-FMK significantly restrained the apoptosis and autophagy induced by 20(S)-GRh2 in HeLa cells. We found that 20(S)-ginsenoside Rh2-induced protective autophagy promotes apoptosis of cervical cancer cells by inhibiting AMPK/mTOR pathway., (© The Author(s) 2021. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Inhibition of RTK pathways in cancer triggers an adaptive response that promotes therapeutic resistance. Because the adaptive response is multifaceted, the optimal approach to blunting it remains undetermined. TNF upregulation is a biologically significant response to EGFR inhibition in NSCLC. Here, we compared a specific TNF inhibitor (etanercept) to thalidomide and prednisone, two drugs that block TNF and also other inflammatory pathways. Prednisone is significantly more effective in suppressing EGFR inhibition-induced inflammatory signals. Remarkably, prednisone induces a shutdown of bypass RTK signaling and inhibits key resistance signals such as STAT3, YAP and TNF-NF-κB. Combined with EGFR inhibition, prednisone is significantly superior to etanercept or thalidomide in durably suppressing tumor growth in multiple mouse models, indicating that a broad suppression of adaptive signals is more effective than blocking a single component. We identify prednisone as a drug that can effectively inhibit adaptive resistance with acceptable toxicity in NSCLC and other cancers., (© 2021. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Globally, doxorubicin (DOX)-induced cardio dysfunction is a serious cause of morbidity and mortality in cancerous patients. An adverse event of cardiotoxicity is the main deem to restrict in the clinical application by oncologists. Corilagin (CN) is well known for its antioxidative, anti-fibrosis, and anticancer effects. Herein, we aimed to evaluate the action of CN on DOX-induced experimental animals and H9c2 cells. The myocardium-specific marker, CK-MB, and the influx of mitochondrial calcium levels were measured by using commercial kits. Biochemical indices reflecting oxidative stress and antioxidant attributes such as malondialdehyde, glutathione peroxidase, reduced glutathione, superoxide dismutase, and catalase were also analyzed in DOX-induced cardiotoxic animals. In addition, mitochondrial ROS were measured by DCFH-DA in H9c2 cells under fluorescence microscopy. DOX induction significantly increased oxidative stress levels and also modulated apoptosis/survival protein expressions in myocardial tissues. Western blots were used to measure the expressional levels of Bax/Bcl-2, caspase-3, PI3-K/AKT, and PPARγ signaling pathways. Histological studies were executed to observe morphological changes in myocardial tissues. All of these DOX-induced effects were attenuated by CN (100 mg/kg bw). These in vitro and in vivo results point towards the fact that CN might be a novel cardioprotective agent against DOX-induced cardiotoxicity through modulating cardio apoptosis and oxidative stress., (© 2021 Wiley Periodicals LLC.)

Vascular remodeling is a prominent trait during the development of hypertension, attributable to the phenotypic transition of vascular smooth muscle cells (VSMCs). Increasing studies demonstrate that microRNA plays an important role in this process. Here, we surprisingly found that smooth muscle cell-specific miR-214 knockout (miR-214 cKO) significantly alleviates angiotensin II (Ang II)-induced hypertension, which has the same effect as that of miR-214 global knockout mice in response to Ang II stimulation. Under the treatment of Ang II, miR-214 cKO mice exhibit substantially reduced systolic blood pressure. The vascular medial thickness and area in miR-214 cKO blood vessels were obviously reduced, the expression of collagen I and proinflammatory factors were also inhibited. VSMC-specific deletion of miR-214 blunts the response of blood vessels to the stimulation of endothelium-dependent and -independent vasorelaxation and phenylephrine and 5-HT induced vasocontraction. In vitro, Ang II-induced VSMC proliferation, migration, contraction, hypertrophy, and stiffness were all repressed with miR-214 KO in VSMC. To further explore the mechanism of miR-214 in the regulation of the VSMC function, it is very interesting to find that the TGF-β signaling pathway is mostly enriched in miR-214 KO VSMC. Smad7, the potent negative regulator of the TGF-β/Smad pathway, is identified to be the target of miR-214 in VSMC. By which, miR-214 KO sharply enhances Smad7 levels and decreases the phosphorylation of Smad3, and accordingly alleviates the downstream gene expression. Further, Ang II-induced hypertension and vascular dysfunction were reversed by antagomir-214. These results indicate that miR-214 in VSMC established a crosstalk between Ang II-induced AT1R signaling and TGF-β induced TβRI /Smad signaling, by which it exerts a pivotal role in vascular remodeling and hypertension and imply that miR-214 has the potential as a therapeutic target for the treatment of hypertension., (© 2021 Federation of American Societies for Experimental Biology.)

N 6 -methyladenosine (m 6 A) has recently emerged as an important regulatory mechanism for gene expression and aberrant m 6 A modification plays an important role in tumor progression. Emerging evidence has shown that aberrant m 6 A modification induced by cigarette smoking is involved in carcinogenesis, but whether cigarette smoking affects m 6 A modification and thus deteriorates to non-small cell lung cancer (NSCLC) is still unclear. Here, we identified a tumor suppressor gene-DAPK2 which was significantly associated with poor prognosis of NSCLC patients, especially in patients with a smoking history. Low levels of DAPK2 were detected in smokers and in NSCLC tissues. Cigarette smoking induced aberrant N 6 -methyladenosine modification of DAPK2, which resulted in decreased DAPK2 mRNA stability and expression of its mRNA and protein. This modification was mediated by the m 6 A "writer" METTL3 and the m 6 A "reader" YTHDF2. Mechanistically, we further demonstrated that DAPK2 functions as a tumor suppressor and downregulation of DAPK2 substantially enhances the proliferation and migration abilities in vitro and in vivo by activating NF-κB signaling pathway. Notably, the BAY 11-7085, a NF-κB signaling selective inhibitor, was shown to efficiently suppressed downregulation of DAPK2-induced oncogenic phenotypes of NSCLC cells. Our study reveals that cigarette smoking induces aberrant N 6 -methyladenosine of DAPK2 to promote NSCLC progression, which provides new insight into the mechanisms of NSCLC progression and a specific therapeutic target for NSCLC patients with a smoking history., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Respiratory syncytial virus (RSV) infection in early life is associated strongly with the subsequent development and exacerbation of asthma, however, the mechanism is still ambiguous. In this study, we identified that RSV nonstructural protein (NS) 1 plays a critical role. Plasmid-mediated overexpression of NS1 induced significant airway hyperresponsiveness, eosinophilia, and mucus hyperproduction in mice. In the pNS1 group, there were markedly elevated proportions of Th2 and Th17 cells, while Th1 and Foxp3+ regulatory T cells (Tregs) significantly declined compared with the control group. Serum concentrations of interleukin (IL)-4, IL-5, IL-6, IL-17, transforming growth factor-beta, and tumor necrosis factor-alpha increased but levels of interferon-gamma and interleukin-10 declined in pNS1 group. Besides, NS1 caused a significant rise of serum thymic stromal lymphopoietin (TSLP) and OX40L levels, and a neutralizing mAb anti-OX40L was capable of promoting RSV clearance and attenuating the airway allergic inflammation caused by pNS1. Otherwise, OX40L-blocking counteracts the inhibitory effect of pNS1 on Tregs in the spleen. RSV NS1 caused elevated levels of phospho-AKT, phospho-mTOR, and phospho-S6K1, which were partially attenuated by anti-OX40L. Moreover, a specific inhibitor of mTORC1 significantly relieved the inhibition of Foxp3 expression and Tregs differentiation. Together, the data indicate that RSV NS1 protein breaks immune tolerance and induces airway inflammation and hyperresponsiveness in mice. In this process, NS1-stimulated TSLP and OX40L play a major role by inhibiting the induction of Tregs, which is at least partially mediated by modulating AKT-mTOR signaling pathways., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Cerebral ischaemia is accompanied by infectious complications due to immunosuppression, known as stroke-induced immunodepression (SIID). Orexin-A (OXA), a neuropeptide produced in the hypothalamus, has been reported to have neuroprotective properties after stroke and is known to modulate inflammatory processes in peripheral tissues. The aim of this study was to determine the effects of orexin-A (OXA) on cerebral ischaemic inflammatory injury and SIID following experimental stroke. Cerebral ischaemia was induced in C57/BL6 mice by middle cerebral artery occlusion (MCAO). A mouse model of pneumonia and poststroke pneumococcal pneumonia was established by intratracheal inoculation with S. pneumoniae in a normal mouse or MCAO mouse model on the third day. We found that OXA postconditioning inhibited cerebral ischaemic inflammatory injury. The mechanism involved downregulation of the NF-κB signalling pathway. In addition, OXA may serve as a potential treatment target for attenuating stroke-induced immunodepression in mice., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Ovarian cancer (OC) is the fifth most common female malignant tumor and the leading cause of cancer-related death in women worldwide. Epithelial ovarian cancer (EOC) is the predominant type of OC. Investigating the mechanism underlying tumorigenesis and progression of EOC is urgent. Our previous research has shown that long non-coding RNAs (lncRNAs) CDKN2A-AS1 is upregulated in EOC tissues and cells. Furthermore, we have predicted that CDKN2A-AS1 is associated with the bone morphogenetic protein (BMP)-SMAD signaling pathway, which is negatively regulated by the sclerostin domain containing 1 (SOSTDC1). Therefore, we conjecture that the CDKN2A-AS1 regulate BMP-SMAD signaling pathway via interacting with SOSTDC1, which need more investigation. Moreover, the functions of the BMP-SMAD signaling pathway and the SOSTDC1 on EOC are still unclear. Herein, we unearthed that CDKN2A-AS1, BMP2/4/7, SMAD1/5/9 and phosphorylation of SMAD1/5/9 (p-SMAD1/5/9) were upregulated in EOC tissues and cells, whereas SOSTDC1 was downregulated in EOC tissues and cells. We firstly demonstrated that CDKN2A-AS1 bound directly with the SOSTDC1. CDKN2A-AS1 downregulated the expression of SOSTDC1, but upregulated the expression of BMP2/4/7, SMAD1/5/9, and p-SMAD1/5/9. CDKN2A-AS1 promoted the proliferation, migration, invasion of EOC cells and tumor growth in vivo, whereas SOSTDC1 inhibited the proliferation, migration, invasion of EOC cells. Knockdown SOSTDC1 rescued the inhibitory effect of si-lncRNA CDKN2A-AS1 on the EOC cells proliferation, migration and invasion. These results demonstrated that CDKN2A-AS1activated the BMP-SMAD signaling pathway by directly bind with SOSTDC1 to promote EOC tumor growth. CDKN2A-AS1/SOSTDC1 axis may provide a novel therapeutic strategy for EOC treatment.

Muscle atrophy, a side effect from administration of the anti‑inflammatory medication dexamethasone (DEX), is preventable by concomitant administration of the major monomeric constituent of Panax ginseng C.A. Meyer, 20(S)‑ginsenoside Rg3 (S‑Rg3). Putative S‑Rg3‑associated prevention of DEX‑induced muscle atrophy may involve S‑Rg3 mitigation of DEX‑induced mitochondrial dysfunction. In the present study, MTT assays revealed enhanced cell viability following S‑Rg3 treatment of DEX‑injured C2C12 myotubes. Subsequent PCR and western blotting results demonstrated S‑Rg3‑induced reduction of expression of muscle atrophy F‑box protein (atrogin‑1) and muscle RING‑finger protein‑1, proteins previously linked to muscle atrophy. Additionally, S‑Rg3 treatment of DEX‑injured myotubes led to aggregation of Rg3 monomers in cells and dose‑dependent increases in cellular mitochondrial basal respiratory oxygen consumption rate and intracellular ATP levels compared with their levels in untreated DEX‑injured myotubes. In addition, S‑Rg3 treatment significantly reversed DEX‑induced reductions of expression of key mitochondrial respiratory electron transport chain subunits of protein complexes II, III and V in DEX‑injured myotube cells. Furthermore, S‑Rg3 alleviation of mitochondrial dysfunction associated with DEX‑induced injury of C2C12 myotubes was linked to S‑Rg3‑associated decreases in both forkhead box O3 (FoxO3) protein expression and phosphorylation of AMP‑activated protein kinase (AMPK). Collectively, these results implicate S‑Rg3 modulation of signaling within the AMPK‑FoxO3 pathway as a putative mechanism underlying S‑Rg3 alleviation of DEX‑induced muscle atrophy.

Ethnopharmacological Relevance: Ginseng is a kind of traditional Chinese herbal medicine, known as "king of herbs" and widely used in China, South Korea, and other Asian countries. Ginsenosides are one of active components of Panax ginseng Meyer, which have many pharmacological effects, such as enhancing memory, improving immunity and cardiovascular system, delaying aging, and preventing cancer., Aims of the Review: This review aims to summarize the recent findings for ginsenosides targeting Sirtuin 1 (SIRT1) signaling pathway for the prevention and treatment of a series of diseases., Materials and Methods: An up-to-August 2020 search was carried out in databases such as PubMed, ScienceDirect, Google Scholar, China National Knowledge Infrastructure, and classic books of traditional Chinese medicine using the keywords: "SIRT1", and/or paired with "ginseng", and "ginsenosides"., Results: SIRT1 is a class-III histone deacetylase (HDAC), a nicotinamide adenine dinucleotide (NAD + )-dependent enzyme, which is deeply involved in a series of pathological processes. Based on specific intracellular localization, SIRT1 has various cytoplasmic and nuclear targets and plays a potential role in energy metabolism, oxidative stress, inflammation, tumorigenesis, and aging. Ginsenosides are generally classified into three groups and microbially transformed to final metabolites. Among of them, most ginsenosides have been reported as SIRT1 activators, especially those ginsenosides with two glucopyranosyl groups on the C-3 position. Importantly, many ginsenosides can be used to prevent and treat oxidative stress, inflammation, aging, tumorigenesis, depression, and others by targeting SIRT1 signaling pathway., Conclusions: This paper reviews recent evidences of ginsenosides targeting SIRT1 for the first time, which could provide new insights on the preclinical and clinical researches for ginsenosides against multiple disorders., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Hypoxia is a feature of the solid tumor microenvironment that is associated with poor clinical outcomes in multiple tumor types. Hypoxia-induced factor-1 alpha (HIF-1α) is a master regulator of hypoxic adaption, has been demonstrated to modulate hypoxic gene expression profiling and signaling transduction networks, and is thus a potential therapeutic target. Despite hypoxic response signaling having being extensively studied, the involvement of long non-coding RNAs (lncRNAs) in the hypoxic response has become a new focus of attention. Emerging evidence has documented complex interactions between HIF-1α and lncRNAs, which contribute to the acquisition of multiple hallmarks of cancer. In this review, we focus on recent advances in the study of hypoxia and HIF-1α-regulated lncRNAs, and summarize the molecular mechanisms and functional outcomes of the interplay between lncRNAs and HIF-1α, which may provide important insights into cancer diagnosis and prognosis, enabling better control of cancer., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

The clinical therapeutic efficacy toward esophageal squamous cell carcinoma (ESCC) is undesirable, due to the lack of targeted agents. Focal adhesion kinase (FAK), a nonreceptor tyrosine kinase involved in multiple fields of tumorigenesis, recently has been indicated as a promising therapeutic target in ESCC treatment. Here, we revealed that defactinib, a specific FAK inhibitor, effectively suppressed the malignancy of ESCC cells. Mechanistically, defactinib dose and time-dependently induced the dissociation of phosphoinositide-3-kinase (PI3K) from FAK, resultantly led to blockade of protein kinase B (AKT) signaling, and the expression of several oncogenes, such as SOX2, MYC, EGFR, MET, MDM2, or TGFBR2, identified by microarray and real-time polymerase chain reaction assay. Specifically, this FAK inhibition-mediated suppression of PI3K/AKT signaling and downstream ESCC specific biomarkers was maintained to 24 h in in vitro experiments to guarantee the treatment durability and efficacy. Importantly, defactinib suppressed tumor growth, metastatic ability, and increased overall survival of xenografted animals without producing significantly systematic toxicity. Our data suggest that FAK inhibition provides an excellent targeted therapy toward ESCC by effectively inhibiting PI3K/AKT pathway and downstream molecular network., (© 2020 Wiley Periodicals LLC.)

The disease progression of nonalcoholic fatty liver disease (NAFLD) from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is driven by multiple factors. Berberine (BBR) is an ancient Chinese medicine and has various beneficial effects on metabolic diseases, including NAFLD/NASH. However, the underlying mechanisms remain incompletely understood due to the limitation of the NASH animal models used. Methods: A high-fat and high-fructose diet-induced mouse model of NAFLD, the best available preclinical NASH mouse model, was used. RNAseq, histological, and metabolic pathway analyses were used to identify the potential signaling pathways modulated by BBR. LC-MS was used to measure bile acid levels in the serum and liver. The real-time RT-PCR and Western blot analysis were used to validate the RNAseq data. Results: BBR not only significantly reduced hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also restored the bile acid homeostasis by targeting multiple pathways. In addition, BBR markedly inhibited inflammation by reducing immune cell infiltration and inhibition of neutrophil activation and inflammatory gene expression. Furthermore, BBR was able to inhibit hepatic fibrosis by modulating the expression of multiple genes involved in hepatic stellate cell activation and cholangiocyte proliferation. Consistent with our previous findings, BBR's beneficial effects are linked with the downregulation of microRNA34a and long noncoding RNA H19, which are two important players in promoting NASH progression and liver fibrosis. Conclusion : BBR is a promising therapeutic agent for NASH by targeting multiple pathways. These results provide a strong foundation for a future clinical investigation.

Salvianolic acid B (Sal B) exhibits anti-obesity activity, yet the underlying mechanism linking this effect to metabolic endotoxemia remains unexplored. For this purpose, high-fat diet-induced obese mice were orally administered with Sal B for 10 weeks. Hematoxylin/eosin staining, transmission electron microscopy, and immunohistochemical staining were used to evaluate histopathological alterations in the white adipose tissue (WAT) and/or jejunums. The expression levels of genes related to fat and cholesterol synthesis in the WAT were determined by qPCR. The composition of fecal microbiota was profiled by 16S rRNA gene pyrosequencing. Western blotting was employed to evaluate the relative protein expressions involved in lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway in the WAT. Treatment of obese mice with Sal B improves insulin sensitivity, attenuates body weight gain and alleviates serum levels of LPS and tumor necrosis factor alpha, which is associated with an improvement in intestinal epithelial integrity and probiotic composition as well as a reduction in Gram-negative Proteobacteria and Deferribacteres. In addition, Sal B downregulates the expressions of TLR4 and myeloid differential factor-88, as well as the phosphorylation levels of Jun N-terminal kinase, nuclear factor-kappa B p65, and an insulin receptor substrate in the WAT. In summary, Sal B may attenuate body weight gain and insulin resistance through the regulation of gut microbiota abundances and LPS/TLR4 signaling pathway in obese mice, suggesting Sal B could be a promising drug candidate for protection against obesity.

Atherosclerosis (AS) is the killer of human health and longevity, which is majorly caused by oxidized lipoproteins that attack macrophages in the endarterium. The Shen-Hong-Tong-Luo (SHTL) formula has shown great clinical efficacy and vascular protective effect for over 30 years in China, to attenuate AS progression. However, its pharmacological mechanism needs more investigation. In this study, we first investigated the chemical composition of SHTL by fingerprint analysis using high-performance liquid chromatography. In primary mouse peritoneal macrophages induced by lipopolysaccharide (LPS), we found that SHTL pretreatment suppressed reactive oxygen species accumulation and reversed the increases of the inflammatory factors, TNF- α and IL-6. Moreover, lipid accumulation induced by oxidized low-density lipoprotein (Ox-LDL) in macrophages was inhibited by SHTL. Additionally, network pharmacology was used to predict the potential targets of SHTL as the PPAR- γ /LXR- α /ABCA1 signaling pathway, which was validated in macrophages and ApoE -/- mice by histopathological staining, qPCR, and Western blot analysis. Importantly, the protective effect of SHTL in the LPS- and Ox-LDL-induced macrophages against inflammation and lipid accumulation was attenuated by GW9662, a PPAR- γ antagonist, which confirmed the prediction results of network pharmacology. In summary, these results indicated that SHTL pretreatment reduced inflammation and lipid accumulation of macrophages by activating the PPAR- γ /LXR- α /ABCA1 pathway, which may provide a new insight into the mechanism of SHTL in the suppression of AS progression., Competing Interests: All authors declare no conflict of interest., (Copyright © 2020 Zepeng Zhang et al.)

Icariside II (ICAII) is a bioflavonoid compound which has demonstrated anti‑oxidative, anti‑inflammatory and anti‑apoptotic biological activities. However, to the best of our knowledge, whether ICAII can alleviate myocardial ischemia and reperfusion injury (MIRI) remains unknown. The aim of the present study was to determine whether ICAII exerted a protective effect on MIRI and to investigate the potential underlying mechanism of action. A rat MIRI model was established by ligation of the left anterior descending coronary artery for 30 min, followed by a 24 h reperfusion. Pretreatment with ICAII with or without a PI3K/AKT inhibitor was administered at the beginning of reperfusion. Morphological and histological analyses were detected using hematoxylin and eosin staining; the infarct size was measured using Evans blue and 2,3,5‑triphenyltetrazolium chloride staining; and plasma levels of lactate dehydrogenase (LDH) and creatine kinase‑myocardial band (CK‑MB) were analyzed using commercialized assay kits. In addition, the cardiac function was evaluated by echocardiography and the levels of cardiomyocyte apoptosis were determined using a TUNEL staining. The protein expression levels of Bax, Bcl‑2, cleaved caspase‑3, interleukin‑6, tumor necrosis factor‑α, PI3K, phosphorylated (p)‑PI3K, AKT and p‑AKT were analyzed using western blotting analysis. ICAII significantly reduced the infarct size, decreased the release of LDH and CK‑MB and improved the cardiac function induced by IR injury. Moreover, ICAII pretreatment significantly inhibited myocardial apoptosis and the inflammatory response. ICAII also upregulated the expression levels of p‑PI3K and p‑AKT. However, the protective effects of ICAII were abolished by an inhibitor (LY294002) of the PI3K/AKT signaling pathway. In conclusion, the findings of the present study suggested that ICAII may mitigate MIRI by activating the PI3K/AKT signaling pathway.

The past decades have witnessed hydrogen sulfide (H 2 S) serving as gaseous signaling molecule participating in diverse cellular and physiological processes in biological systems. Recently, a considerable number of studies highlight the signaling role of this redox-regulating molecule occurs via persulfidation, which is a post-translation modification of protein cysteine residues by covalent addition of thiol group form persulfide. However, our current understanding on detection of H 2 S and persulfidation in biological systems still lags behind. This review aims to summarize current approaches for measuring H 2 S and persulfidated levels in biological systems. Meanwhile, potential interference may exist in plant research has been proposed and discussed., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Ulcerative colitis is one of the IBD which cause a chronic intestinal inflammation and dysfunctional of the mucosal barrier. For now, the incident of UC was steadily increased all over the world. It has become a novel independent risk factor of several severe diseases especially colon-rectal cancer. However, the etiology of UC was still obscure. Previous studies show that high-fat diet contributed to the pathogenesis of immune system dysregulation, and farnesoid X receptor (FXR) was also implicated in the pathogenesis of various inflammatory symptoms. Yet, their inner roles in the pathogenesis of UC have not been mentioned. In this study, we aim to investigate the role of FXR in UC. High-fat diet (HFD) promotes the progression of DSS-induced UC, shows an increasing secretion of bile acid in serum, and leads to a downregulation of FXR target genes (FXR α , Shp, and lbabp). Adding FXR agonist FexD rescues the phenotype induced by high-fat diet, whereas TGFBRI inhibitor SB431542 abrogates the restoration by FexD in DSS-induced UC mice. To further verify the relationship between the FXR and TGFB signaling pathway, we made a UC-HFD model in the Caco2 cell line. Results shows the same conclusion that FXR mitigate UC inflammation through a TGFB-dependent pathway. These results expand the role of FXR in ulcerative colitis and suggest that FXR activation may be considered a therapeutic strategy for UC., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2020 Di Zhao et al.)

Modulation of alloimmune responses is critical to improving transplant outcome and promoting long-term graft survival. To determine mechanisms by which a nonhematopoietic erythropoietin (EPO) derivative, carbamylated EPO (CEPO), regulates innate and adaptive immune cells and affects renal allograft survival, we utilized a rat model of fully MHC-mismatched kidney transplantation. CEPO administration markedly extended the survival time of kidney allografts compared with the transplant alone control group. This therapeutic effect was inhibited when the recipients were given LY294002, a selective inhibitor of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway or anti-EPO receptor (EPOR) antibody, in addition to CEPO. In vitro, CEPO inhibited the differentiation and function of dendritic cells and modulated their production of pro-inflammatory and anti-inflammatory cytokines, along with activating the PI3K/AKT signaling pathway and increasing EPOR mRNA and protein expression by these innate immune cells. Moreover, after CD4 + T cells were exposed to CEPO the Th1/Th2 ratio decreased and the regulatory T cell (Treg)/Th17 ratio increased. These effects were abolished by LY294002 or anti-EPOR antibody, suggesting that CEPO regulates immune responses and promotes kidney allograft survival by activating the PI3K/AKT signaling pathway in an EPOR-dependent manner. The immunomodulatory and specific signaling pathway effects of CEPO identified in this study suggest a potential therapeutic approach to promoting kidney transplant survival.

Somatic cell reprogramming provides insight into basic principles of cell fate determination, which remain poorly understood. Here we show that the transcription factor Glis1 induces multi-level epigenetic and metabolic remodelling in stem cells that facilitates the induction of pluripotency. We find that Glis1 enables reprogramming of senescent cells into pluripotent cells and improves genome stability. During early phases of reprogramming, Glis1 directly binds to and opens chromatin at glycolytic genes, whereas it closes chromatin at somatic genes to upregulate glycolysis. Subsequently, higher glycolytic flux enhances cellular acetyl-CoA and lactate levels, thereby enhancing acetylation (H3K27Ac) and lactylation (H3K18la) at so-called 'second-wave' and pluripotency gene loci, opening them up to facilitate cellular reprogramming. Our work highlights Glis1 as a powerful reprogramming factor, and reveals an epigenome-metabolome-epigenome signalling cascade that involves the glycolysis-driven coordination of histone acetylation and lactylation in the context of cell fate determination.

Apple trees grafted on different rootstock types, including vigorous rootstock (VR), dwarfing interstock (DIR), and dwarfing self-rootstock (DSR), are widely planted in production, but the molecular determinants of tree branch architecture growth regulation induced by rootstocks are still not well known. In this study, the branch growth phenotypes of three combinations of 'Fuji' apple trees grafted on different rootstocks (VR: Malus baccata; DIR: Malus baccata/T337; DSR: T337) were investigated. The VR trees presented the biggest branch architecture. The results showed that the sugar content, sugar metabolism-related enzyme activities, and hormone content all presented obvious differences in the tender leaves and buds of apple trees grafted on these rootstocks. Transcriptomic profiles of the tender leaves adjacent to the top buds allowed us to identify genes that were potentially involved in signaling pathways that mediate the regulatory mechanisms underlying growth differences. In total, 3610 differentially expressed genes (DEGs) were identified through pairwise comparisons. The screened data suggested that sugar metabolism-related genes and complex hormone regulatory networks involved the auxin (IAA), cytokinin (CK), abscisic acid (ABA) and gibberellic acid (GA) pathways, as well as several transcription factors, participated in the complicated growth induction process. Overall, this study provides a framework for analysis of the molecular mechanisms underlying differential tree branch growth of apple trees grafted on different rootstocks., Competing Interests: The authors have declared that no competing interests exist.

Enhancer of zeste homolog 2 (EZH2), a subunit of the polycomb repressive complex 2 (PRC2), is associated with seizure development and epileptogenesis, however, the underlying mechanism of the process remains to be elucidated. This study focused on exploring whether EZH2 regulated gamma-aminobutyric acid (GABA)-mediated neurotransmission during seizure generation. Hyperthermia-induced seizures were generated in Sprague-Dawley (SD) rats using a hot (43.5 °C) bath method, and seizure severity was evaluated according to the Racine scale. The effect of treatment with the EZH2 pharmacological inhibitor GSK 126 on the GABA and pro-inflammatory cytokine levels was tested using enzyme-linked immunosorbent assay (ELISA). Miniature inhibitory postsynaptic currents (mIPSCs) were recorded using whole-cell patch clamp. In this study, our results showed that intracerebroventricular (i.c.v) injection of the EZH2 pharmacological inhibitor GSK 126 (10 nM) increased seizure severity and shortened seizure latency in a rat model of FS, and these effects were accompanied by reduced GABA content. Furthermore, GSK 126 (1 μM) treatment decreased the mean amplitude and frequency of the mIPSCs in cultured hippocampal neurons subjected to hyperthermia. Importantly, the same results were also obtained in cultured neurons infected with lentivirus carrying EZH2 shRNA. In addition, a significant increase in the pro-inflammatory cytokine (IL-1β and TNF-α) levels was observed in rats after GSK 126 treatment, and IL-1β administration increased seizure severity, suggesting that the inflammatory response was involved in the regulation of seizure development by EZH2. This study helps clarify the role of EZH2 in FS and supports EZH2 administration as an effective target for the management of seizure generation., Competing Interests: Declaration of competing interest The authors declare that there are no competing financial interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Lysosomes play important roles in cellular degradation to maintain cell homeostasis. In order to understand whether and how lysosomes alter with age and contribute to lifespan regulation, we characterized multiple properties of lysosomes during the aging process in C. elegans . We uncovered age-dependent alterations in lysosomal morphology, motility, acidity and degradation activity, all of which indicate a decline in lysosome function with age. The age-associated lysosomal changes are suppressed in the long-lived mutants daf-2 , eat-2 and isp-1 , which extend lifespan by inhibiting insulin/IGF-1 signaling, reducing food intake and impairing mitochondrial function, respectively. We found that 43 lysosome genes exhibit reduced expression with age, including genes encoding subunits of the proton pump V-ATPase and cathepsin proteases. The expression of lysosome genes is upregulated in the long-lived mutants, and this upregulation requires the functions of DAF-16/FOXO and SKN-1/NRF2 transcription factors. Impairing lysosome function affects clearance of aggregate-prone proteins and disrupts lifespan extension in daf-2 , eat-2 and isp-1 worms. Our data indicate that lysosome function is modulated by multiple longevity pathways and is important for lifespan extension., Competing Interests: YS, ML, DZ, XL, CY No competing interests declared, XW Reviewing editor, eLife, (© 2020, Sun et al.)

l-lysine is a basic amino acid that has been shown to exert neuroprotective effect. However, the underlying mechanism remains to be elucidated. In this study, we investigate how l-lysine exerts its neuroprotective effect in hemin-insulted mouse cortical neurons in vitro and the mouse model of intracerebral hemorrhage (ICH) in vivo. We demonstrate that l-lysine treatment promotes M2 microglial polarization and reduces inflammatory response both in vitro and in vivo, suggesting that l-lysine may play a neuroprotective role in ICH injury. Indeed, we show that l-lysine treatment reduces cortical neuronal death after hemin insult in vitro and decrease the number of degenerating neurons after ICH in vivo. l-lysine also improves the functional recovery of ICH animals in neurobehavioral tests. Consistent with the role of PTEN in regulating inflammatory response, we find that PTEN inhibition promotes M2 microglial polarization and suppresses pro-inflammatory response in mouse ICH injury, which contribute to the neuroprotective effect of l-lysine. Moreover, our results reveal that microRNA-575 directly suppressed PTEN to promote M2 microglial polarization and mediate the neuroprotective effect of l-lysine in ICH injury. Together, our results suggest that l-lysine confers neuroprotection after ICH injury through enhancing M2 microglial polarization and reducing inflammatory response, which is mediated by microRNA-575 upregulation and subsequent PTEN downregulation., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Oxidative stress results in cell apoptosis/death and plays a detrimental role in disease development and progression. Stressors alter the miRNA expression profile and miRNAs play a role in the cell response to stress. We previously showed that miR-711 is significantly over-expressed in extended cold ischemia reperfusion injured hearts in heart transplant. In this study, we aimed to investigate the role of miR-711 in cardiac cell damage in response to oxidative stress and how miR-711 is regulated., Methods: Rat cardiac cell line H9c2 cells were cultured and exposed to oxidative conditions (Antimycin A (AA), H 2 O 2 , CoCl 2 , or cold hypoxia/reoxygenation (H/R)) in vitro. H9c2 cells were transfected with miR-711 mimics, miR-711 inhibitors, or small interference RNA, using transfection reagents. The expression of miR-711 was measured by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Cell apoptosis/death was detected by flow cytometry and an IncuCyte system. Mitochondrial damage was detected by measuring the mitochondria membrane potential by flow cytometry. Gene expression was detected by qRT-PCR at the mRNA level and Western blotting and immunocytochemistry staining at the protein level., Results: We found that miR-711 was significantly up-regulated in cells treated with H 2 O 2 , AA, CoCl 2 , and cold H/R. Over-expression of miR-711 increased cell apoptosis/death induced by AA and H/R whereas cell death was reduced by miR-711 inhibitors. MiR-711 induced cell death through negative regulation of angiopoietin 1 (Ang-1), fibroblast growth factor 14 (FGF14) and calcium voltage-gated channel subunit alpha1C (Cacna1c) genes. Both knockdown of hypoxia inducible factor 1α (HIF-1α) and inactivation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NFКB) pathway inhibited over-expression of miR-711., Conclusion: Oxidative stress increases the expression of miR-711. Over-expression of miR-711 induces cell apoptosis/death. HIF-1α and NFКB regulate miR-711 in H9c2 cells during oxidative stress. miR-711 is a new target for preventing oxidative stress., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

EGFR inhibition is an effective treatment in the minority of non-small cell lung cancer (NSCLC) cases harboring EGFR-activating mutations, but not in EGFR wild type (EGFRwt) tumors. Here, we demonstrate that EGFR inhibition triggers an antiviral defense pathway in NSCLC. Inhibiting mutant EGFR triggers Type I IFN-I upregulation via a RIG-I-TBK1-IRF3 pathway. The ubiquitin ligase TRIM32 associates with TBK1 upon EGFR inhibition, and is required for K63-linked ubiquitination and TBK1 activation. Inhibiting EGFRwt upregulates interferons via an NF-κB-dependent pathway. Inhibition of IFN signaling enhances EGFR-TKI sensitivity in EGFR mutant NSCLC and renders EGFRwt/KRAS mutant NSCLC sensitive to EGFR inhibition in xenograft and immunocompetent mouse models. Furthermore, NSCLC tumors with decreased IFN-I expression are more responsive to EGFR TKI treatment. We propose that IFN-I signaling is a major determinant of EGFR-TKI sensitivity in NSCLC and that a combination of EGFR TKI plus IFN-neutralizing antibody could be useful in most NSCLC patients., Competing Interests: Competing Interests Statement The authors declare no competing interests.