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Most studies on anesthesia focus on the nervous system of mammals due to their interest in medicine. The fact that any life form can be anaesthetised is often overlooked although anesthesia targets ion channel activities that exist in all living beings. This study examines the impact of lidocaine on rice ( Oryza sativa ). It reveals that the cellular responses observed in rice are analogous to those documented in animals, encompassing direct effects, the inhibition of cellular responses, and the long-distance transmission of electrical signals. We show that in rice cells, lidocaine has a cytotoxic effect at a concentration of 1%, since it induces programmed reactive oxygen species (ROS) and caspase-like-dependent cell death, as already demonstrated in animal cells. Additionally, lidocaine causes changes in membrane ion conductance and induces a sharp reduction in electrical long-distance signaling following seedlings leaves burning. Finally, lidocaine was shown to inhibit osmotic stress-induced cell death and the regulation of Ca 2+ homeostasis. Thus, lidocaine treatment in rice and tobacco ( Nicotiana benthamiana ) seedlings induces not only cellular but also systemic effects similar to those induced in mammals.

Epidemiological studies consistently link environmental toxicant exposure with increased Type 2 diabetes risk. Our study investigated the diabetogenic effects of a widely used flame retardant, Dechlorane Plus (DP), on pancreatic β-cells using rodent and human model systems. We first examined pancreas tissues from male mice exposed daily to oral gavage of either vehicle (corn oil) or DP (10, 100, or 1000 μg/kg per day) and fed chow or high fat diet for 28-days in vivo . DP exposure did not affect islet size or endocrine cell composition in either diet group. Next, we assessed the effect of 48-hour exposure to vehicle (DMSO) or DP (1, 10, or 100 nM) in vitro using immortalized rat β-cells (INS-1 832/3), primary mouse and human islets, and human stem-cell derived islet-like cells (SC-islets). In INS-1 832/3 cells, DP did not impact glucose-stimulated insulin secretion (GSIS) but significantly decreased intracellular insulin content. DP had no effect on GSIS in mouse islets or SC-islets but had variable effects on GSIS in human islets depending on the donor. DP alone did not affect insulin content in mouse islets, human islets, or SC-islets, but mouse islets co-exposed to DP and glucolipotoxic (GLT) stress conditions (28.7 mM glucose + 0.5 mM palmitate) had reduced insulin content compared to control conditions. Co-exposure of mouse islets to DP + GLT amplified the upregulation of Slc30a8 compared to GLT alone. Our study highlights the importance and challenges of using different in vitro models for studying chemical toxicity.

Pulmonary arterial hypertension (PAH) is characterized by progressive vascular remodeling caused by the excessive proliferation and survival of pulmonary artery smooth muscle cells (PASMCs). Dual-specificity tyrosine regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in the regulation of multiple biological functions, including cell proliferation and survival. However, the role and underlying mechanisms of DYRK1A in PAH pathogenesis remain unclear. We found that DYRK1A was upregulated in PASMCs in response to hypoxia, both in vivo and in vitro . Inhibition of DYRK1A by harmine significantly attenuated hypoxia-induced pulmonary hypertension and pulmonary artery remodeling. Mechanistically, we found that DYRK1A promoted pulmonary arterial remodeling by enhancing the proliferation and survival of PASMCs through activating the STAT3/Pim-1/NFAT pathway, because STAT3 gain-of-function via adeno-associated virus serotype 2 (AAV2) carrying the constitutively active form of STAT3 (STAT3C) nearly abolished the protective effect of harmine on PAH. Collectively, our results reveal a significant role for DYRK1A in pulmonary arterial remodeling and suggest it as a drug target with translational potential for the treatment of PAH.

Human islets from deceased organ donors have made important contributions to our understanding of pancreatic endocrine function and continue to be an important resource for research studies aimed at understanding, treating, and preventing diabetes. Understanding the impacts of isolation and culture upon the yield of human islets for research is important for planning research studies and islet distribution to distant laboratories. Here, we examine islet isolation and cell culture outcomes at the Alberta Diabetes Institute (ADI) IsletCore ( n  = 197). Research-focused isolations typically have a lower yield of islet equivalents (IEQ), with a median of 252,876 IEQ, but a higher purity (median 85%) than clinically focused isolations before culture. The median recovery of IEQs after culture was 75%, suggesting some loss. This was associated with a shift toward smaller islet particles, indicating possible islet fragmentation, and occurred within 24 h with no further loss after longer periods of culture (up to 136 h). No overall change in stimulation index as a measure of islet function was seen with culture time. These findings were replicated in a representative cohort of clinical islet preparations from the Clinical Islet Transplant Program at the University of Alberta. Thus, loss of islets occurs within 24 h of isolation, and there is no further impact of extended culture prior to islet distribution for research.

The Phenotypic states of vascular smooth muscle cells (SMCs) are essential to understanding vascular pathophysiology. SMCs in vessels generally express a specific set of contractile proteins, but decreased contractile protein expression, indicating a phenotypic shift, is a hallmark of vascular diseases. Recent studies have suggested the relation of abnormally high wall shear stress (WSS) of approximately 20 Pa with the aortic disease pathogenesis. However, due to the lack of appropriate experimental models to assess SMC phenotypic states, the details of the phenotypic shift under high WSS conditions remain unclear. In this study, we developed a coculture model where vascular endothelial cells (ECs) were cocultured with SMCs expressing calponin 1, a contractile protein involved in the phenotypic shift of SMCs. We investigated the effects of a pathologically high WSS condition on the phenotypic states of SMCs. Increased calponin 1 expression was found upon exposure to 20 Pa WSS compared with a physiological 2 Pa condition, whereas the expression of another contractile protein, α-smooth muscle actin (αSMA) remained unchanged. Furthermore, the inhibition of EC-derived nitric oxide (NO), which is associated with endothelial dysfunction in vascular diseases, resulted in a trend of decreasing αSMA and Calponin 1 expression under 20 Pa WSS conditions compared with 2 Pa. Our findings suggest that EC-derived NO under pathologically high WSS conditions may impact the expression of contractile proteins implicated in aortic pathophysiology., 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 Elsevier Inc. All rights reserved.)

Nicotinamide adenine dinucleotide phosphate oxidase complex 2 (NOX2) is an effector molecule expressed predominantly in neutrophils. Its deficiency is present in immune disorders, including systemic lupus erythematosus, chronic granulomatous disease, and rheumatoid arthritis. Recent reports indicated that NOX2 regulates autoimmunity and programmed cell death. However, the exact mechanism is unclear. In this study, we explored the effect of NOX2 on neutrophil apoptosis. We demonstrated that NOX2 deficiency caused neutrophil pyroptosis. Mechanistically, the NOX2 inhibitor GSK2795039 application or knockdown of NOX2 components resulted in increased mitochondrial ROS, inhibition of AMP-activated protein kinase (AMPK), and activation of Gasdermin E. AMPK activators, metformin and epigallocatechin gallate, inhibited deficient NOX2-induced pyroptosis. Together, these findings illustrate the involvement of NOX2 in regulating neutrophil death and emphasize its importance in autoimmunity., 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.)

Background: Exosomes derived from primary chondrogenic stem/progenitor cells (CSPCs-EXOs) show promise in cartilage repair due to their immunomodulatory and regenerative properties. However, their specific therapeutic potential in osteoarthritis (OA), especially in modulating immune responses and enhancing chondrocyte function, requires further exploration. This study aims to clarify CSPCs-EXOs' effects on OA by investigating their role in chondrocyte proliferation, migration, inflammation inhibition, and cartilage regeneration., Methods: A rat model of osteoarthritis was established using monosodium iodoacetate (MIA). CSPCs-EXOs were isolated and characterized before being administered to the OA rats. Comprehensive transcriptomic analysis was conducted to identify differentially expressed genes (DEGs) and signaling pathways influenced by CSPCs-EXOs. Histopathological evaluation of cartilage tissue, immunohistochemistry, and in vitro assays were performed to assess chondrocyte proliferation, migration, inflammation, and intracellular environmental changes., Results: CSPCs-EXOs treatment significantly reduced OA-induced cartilage damage, shown by improved histopathological features, increased chondrocyte proliferation, migration, and enhanced cartilage matrix integrity. CSPCs-EXOs uniquely modulated immune pathways and enhanced cellular repair, setting them apart from traditional treatments. Transcriptomic analysis revealed regulation of immune response, inflammation, oxidative stress, and DNA repair pathways. CSPCs-EXOs downregulated inflammatory cytokines (TNF, IL-17) and upregulated pathways for cellular proliferation, migration, and metabolism. They also altered splicing patterns of DNA repair enzymes, indicating a role in boosting repair mechanisms., Conclusions: CSPCs-EXOs promote cartilage repair in osteoarthritis by modulating immune responses, inhibiting inflammation, and improving the intracellular environment. These findings emphasize their innovative therapeutic potential and offer key insights into their regenerative mechanisms, positioning CSPCs-EXOs as a promising strategy for OA treatment and a foundation for future clinical applications in cartilage tissue engineering and regenerative medicine., 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 Elsevier B.V. All rights reserved.)

The clinical management of neuropathic pain (NP) remains a significant challenge, as current pharmacological treatments do not fully meet clinical needs. Nicorandil, a potassium ATP channel agonist widely used in cardiovascular medicine, has recently been shown to have significant potential for analgesia. This study aimed to investigate the effects and mechanisms of nicorandil in a chronic constriction injury (CCI) mouse model. Nicorandil significantly alleviated pain hypersensitivity and reduced neuronal injury in the sciatic nerve (SN) and dorsal root ganglion (DRG) post-CCI. Nicorandil primarily affected endothelial cells and Schwann cells in the sciatic nerve, restoring the expression of the KATP channel subunit Kir6.2. Furthermore, nicorandil attenuated the hypoxia-induced apoptosis program in sciatic nerve endothelial cells, leading to reduced expression of apoptotic proteins, which provided significant endothelial protection, improved blood-nerve barrier leakage, and decreased the release of DRG inflammatory factors and pain neurotransmitter substance P. In vitro, nicorandil attenuated the apoptosis of human umbilical vein endothelial cells (HUVECs) in a hypoxic environment while maintaining cellular functions. In addition, administering the KATP channel inhibitor glibenclamide in vitro further confirmed the crucial role of Kir6.2 in reducing endothelial hypoxic stress, as confirmed by transmission electron microscopy and behavioural experiments. Overall, these findings indicate that nicorandil significantly ameliorates CCI-induced NP in mice by targeting Kir6.2 in sciatic nerve endothelial cells, thus inhibiting pain sensitization., 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 Elsevier B.V. All rights reserved.)

Infected wounds present significant challenges pertaining to healing and often demand administration of strong antibiotics to patients. Also, drug resistant microbes may alter the physiology of wounds to create biofilms, frequently leading to high morbidity and mortality. In this investigation, a biodegradable, microporous composite agarose-chitosan scaffold was fabricated. Furthermore, its surface was modified with diphenyldiselenide deposition, using low pressure pulsed plasma technology. The optimized plasma parameters, viz. 5 ON /15 OFF (ms) of plasma pulse rate and 80 min of treatment time resulted in scaffolds having enhanced anti-bacterial activity against gram positive microbes like Staphylococcus (S.) aureus and S. epidermidis. The scaffolds were non-toxic to skin cells, as confirmed by the MTT assay. Cell proliferation through plasma treated and untreated scaffolds was assessed by culturing primary human dermal fibroblasts (HdaF) and human keratinocytes (HaCaT) and visualizing via confocal microscopy. Moreover, in-vivo rat model confirmed accelerated wound healing with plasma treated scaffold (100 % on day 14), as compared to the untreated scaffold (100 % on day 16) when compared with over-the-counter (OTC) ointment Betadine (100 % on day 12)., 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 Elsevier B.V. All rights reserved.)

Background: Interleukin-1β (IL-1β) plays a crucial role in cartilage degeneration by inducing inflammatory cascades in chondrocytes, impairing their normal biological functions. Long non-coding RNA NKILA (lncRNA NKILA) has been implicated in osteoarthritis (OA), but its specific molecular mechanisms remain unclear. This study aims to elucidate the function and molecular regulatory mechanism of lncRNA NKILA in articular chondrocytes under IL-1β stimulation., Methods: Primary human articular chondrocytes were cultured to investigate the effects of IL-1β on chondrocyte proliferation, apoptosis, and extracellular matrix metabolism. We employed Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR), western blot, flow cytometry, immunofluorescence, and nuclear mass separation assays to explore the interaction between lncRNA NKILA and the NFκB signaling pathway. Additionally, animal experiments were conducted to evaluate the therapeutic potential of modulating lncRNA NKILA expression in vivo., Results: IL-1β treatment led to decreased chondrocyte proliferation and increased apoptosis. Our study demonstrated that IL-1β downregulates lncRNA NKILA, which weakens its inhibitory effect on the NFκB (Nuclear Factor Kappa B) signaling pathway. This downregulation results in increased NFκB activity and exacerbates chondrocyte degeneration. Notably, the upregulation of lncRNA NKILA significantly alleviated OA symptoms, indicating that NKILA could be a promising therapeutic target., Conclusion: IL-1β reduces lncRNA NKILA expression, weakening its inhibition of NFκB signaling and promoting articular chondrocyte degeneration. Enhancing lncRNA NKILA expression offers a promising approach to mitigating OA, suggesting that NKILA could serve as a potential therapeutic target for OA treatment., 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 B.V. All rights reserved.)

Objective: Although IL-38 is recognized for its regulatory role in a spectrum of chronic inflammatory diseases, investigations into its cardiac physiological and pathophysiological functions are nascent. Our aim was to delineate the biological impact of IL-38 in the context of myocardial ischemia-reperfusion injury (MIRI) and to uncover the mechanisms through which it exerts its effects., Methods and Results: In this study, we used an MIRI mouse model, LPS/ATP stimulation, and a hypoxia/reoxygenation cell model to determine the regulatory influence of IL-38 on MIRI. We observed that the administration of recombinant IL-38 to mice led to a reduction in infarct size, an enhancement in cardiac function, and a suppression of NLRP3 inflammasome activation. In contrast, genetic deletion of IL-38 was associated with an increase in infarct size, worsening of cardiac function, and upregulation of NLRP3 inflammasome activity. The detrimental effects associated with the absence of IL-38 were mitigated by the administration of a specific NLRP3 inhibitor, suggesting that the inhibition of NLRP3 is a critical component of the protective effect mediated by IL-38 in MIRI. In vitro assays revealed that IL-38 inhibited NLRP3 inflammasome activation in cardiac fibroblasts through the engagement of IL-1R8 and the modulation of SYK phosphorylation. Silencing of IL-1R8 negated the suppressive effect of IL-38 on the NLRP3 inflammasome., Conclusion: IL-38 acts as a potent negative regulator of inflammasome activation after MIRI. It achieves this regulatory effect within cardiac fibroblasts by inhibiting SYK phosphorylation, a process mediated by IL-1R8., 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.)

Yes-associated protein 1 (YAP1) is a crucial downstream effector of the Hippo pathway that plays a role in regulating inflammation and mitochondrial function. However, whether YAP1 regulates pyroptosis in nucleus pulposus (NP) cells caused by inflammation via mitophagy remains unclear. This study aimed to investigate the effects of YAP1 on the pyroptosis of NP cells induced by LPS. Here, we demonstrated that the protein expression of YAP1 in the NP tissue of degenerative discs was significantly reduced. Next, we found that NLRP3 inflammasome activation in YAP1-overexpressing (YAP1-ov) NP cells was further enhanced in the LPS-induced inflammatory microenvironment. YAP1-ov strongly aggravated inflammation-induced pyroptosis and senescence, but these effects were reversed by the inhibition of BNIP3-mediated mitophagy. However, comparative analysis of the overexpression of YAP1 in normal discs and discs after annulus fibrosus puncture revealed that YAP1-ov accelerated the degeneration of normal discs and attenuated the degeneration of annulus fibrosus punctured discs in vivo. Additionally, YAP1-ov upregulated the expression of TNFAIP3, an anti-inflammatory protective protein, and CLPP, a vital protein in the mitochondrial unfolded protein response, in NP cells. Collectively, the above results revealed that YAP1 exacerbates LPS-induced pyroptosis and senescence of NP cells by promoting BNIP3-mediated mitophagy, which causes disc degeneration. Notably, YAP1-ov mitigated the degeneration of the disc caused by annular needle puncture in vivo, suggesting its potential as a therapeutic candidate foracute IDD injury., 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 Elsevier B.V. All rights reserved.)

T-2 toxin is a major cause of Kashin-Beck disease (KBD), which is characterised by cartilage damage. N6-adenosine-methyltransferase-like 3 (METTL3) regulates cartilage injury; however, its role in T-2 toxin-induced cartilage injury remains elusive. Herein, we investigated the involvement of METTL3-mediated m6A modification in T-2 toxin-induced cartilage damage. METTL3-mediated m6A methylation levels were correlated with cartilage extracellular matrix (ECM) degradation, which was exacerbated following METTL3 silencing. Cathepsin K (Ctsk) was identified as a downstream target of METTL3 using m6A-methylated RNA immunoprecipitation（MeRIP）sequencing and RNA sequencing. Silencing Ctsk aggravated HT-2 toxin-induced ECM degradation. Increasing the m6A methylation levels in vivo via dietary methionine supplementation mitigated cartilage damage. In summary, HT-2 toxin induced cartilage ECM degradation by regulating the METTL3-mediated m6A modification of Ctsk. These findings highlight the METTL3/m6A/Ctsk axis as a potential therapeutic target for the treatment of KBD and other cartilage-associated diseases., (Copyright © 2024. Published by Elsevier B.V.)

Objective: Osteoarthritis (OA) is the leading joint disease without currently available disease-modified drugs. The current study aimed to identify potential drug targets that could decelerate the progression of OA., Methods: We employed Mendelian Randomization (MR) and colocalization analysis to identify therapeutic targets linked to 12 OA traits within 2645 targets. Bulk and single-cell RNA-seq analyses of cartilage samples were conducted to pinpoint GFPT1 and determine the specific cell types in which GFPT1 is expressed. Overexpression and knockdown experiments further explored the expression and potential OA-associated functions of GFPT1., Results: GFPT1 has been identified as a cross-OA therapeutic candidate gene by MR analysis. We observed a significant reduction in GFPT1 expression in OA cartilage compared to normal cartilage from public transcriptomic data of both humans and mice. In vitro experiments confirmed these findings at both mRNA and protein levels in OA chondrocytes. IL-1β stimulation leads to downregulation of GFPT1. We confirmed that supplementary glutamine can reverse the suppression of GFPT1 more effectively than glucosamine in the OA in vitro model. GFPT1 upregulation with glutamine, in turn, further increases the expression of COL2A1 and decreases the expression of MMP13., Conclusions: Our findings demonstrate that GFPT1 is downregulated in OA, and overexpressing GFPT1 can restore the anabolic metabolism of cartilage. Compared to glucosamine, enhancing GFPT1 expression with glutamine to influence the hexosamine biosynthetic pathway may offer a more effective therapeutic strategy for OA., 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 B.V. All rights reserved.)

Background: The impact and mechanisms of therapeutic hypothermia (TH) on myocardial ischemia-reperfusion (I/R) injury are still unknown., Methods: Sprague-Dawley (SD) rat model and primary cardiomyocytes were applied in our study. TTC staining evaluated myocardial infarction, while H&E staining assessed myocardial injury. ELISA quantified lactate dehydrogenase (LDH), IL-1β, IL-6, and TNF-α. Blood serum concentrations of CK, CK-MB, and cTnT were detected using a biochemical assay. TUNEL assay, flow cytometry and western blot were used to detect cell apoptosis. EdU assay was applied to examine cell proliferation. The expression of DKK3 and β-catenin protein was analyzed using Realtime PCR and Western blot., Results: TH alleviated myocardial infarction size and injury in rat models of I/R, and reduced serum levels of myocardial injury markers and inflammatory factors in animal and cell models. In addition, TH inhibited the increased apoptosis and β-catenin expression as well as decreased DKK3 expression caused by I/R in I/R cell models, while si-DKK3 reversed the changes brought by TH, and XAV939 inhibited the effects of si-DKK3., Conclusion: TH may reduce myocardial infarction size, myocardial injury, inflammatory response and apoptosis through DKK3/Wnt/β-catenin pathway, thereby alleviating myocardial I/R injury., (Copyright © 2024. Published by Elsevier B.V.)

Dendritic cells (DCs) orchestrate both immune activation and immune tolerance in multiple sclerosis (MS). Manipulating the phenotypes and functions of DCs to boost their tolerogenic potential is an appealing strategy for treating MS and its animal model experimental autoimmune encephalomyelitis (EAE). Programmed cell death 1 (PD-1) delivers the immunoinhibitory signals by interacting with PD-1 ligand 1 (PD-L1), which plays a critical role in maintaining immune tolerance. So far, the effects of PD-1/PD-L1 signalling activation on DCs in EAE are poorly understood. Here, the administration of soluble PD-L1 (sPD-L1) protein significantly alleviated the clinical symptoms of myelin oligodendrocyte glycoprotein (MOG)-induced EAE, and inhibited the expression of cluster of differentiation (CD)86, C-C motif chemokine receptor 7 (CCR7) as well as CCR7-mediated trafficking of splenic DCs, accompanied by enhancing their phagocytosis. The impact of sPD-L1 on the surface morphology and mechanical properties of DCs was investigated at the nanoscale, using scanning electron microscope and atomic force microscope. The treatment of sPD-L1 was found to mitigate morphological maturation and biomechanical alterations, specifically in terms of adhesion and elasticity, in bone marrow-derived DCs from EAE. Taken together, our findings suggest that application of exogenous sPD-L1 has a marked suppressive effect on the maturation and migration of DCs in EAE. PD-L1 administration may be a promising therapy for EAE and for MS in the future., 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: Rheumatoid arthritis (RA) can lead to joint deformity, loss of function, and even disability. Bone erosion is a common cause of disability in individuals with RA; bone resorption by osteoclasts (OCs) and bone immunity by regulatory T cells (Tregs) play key roles in this process. Human umbilical mesenchymal stem cells (HUMSCs) can be used to treat RA; however, the regulation of Tregs and OCs by HUMSCs and their therapeutic effects on RA have not been fully elucidated. This study aimed to reveal the effects of exosomes derived from HUMSCs carrying miRNA-150-5p on Tregs and OCs in individuals with RA and to provide innovative evidence for the ability of HUMSCs to alleviate RA., Methods: First, we used collagen-induced arthritis (CIA) model mice to verify the efficacy of miR-150-5p mimic -Exos and explored their effects on bone erosion in mouse joints and on Tregs in the lymph nodes. Subsequently, miR-150-5p mimic -Exos and the aryl hydrocarbon receptor (AhR) inhibitor CH223191 were used in in vitro OCs, Tregs, and OC-Treg coculture systems to determine whether miR-150-5p mimic -Exos regulate bone immune microenvironment homeostasis via AhR., Results: Treatment with miR-150-5p mimic -Exos effectively alleviated bone damage to the ankle and knee joints in CIA model mice, inhibited OC differentiation, activated the immunosuppressive function of Tregs, and regulated bone immunity by increasing the expression of AhR/CYP1A1 signalling pathway genes such as Ahr, Arnt, Ahrr, Cyp1a1/1a2 and Cyp1b1 in OCs and Tregs. By coculturing Tregs and OCs, the ability of the miR-150-5p mimic -Exos to inhibit OC differentiation was further strengthened., Conclusions: This study confirmed that miR-150-5p mimic -Exos can reduce bone destruction in mice with CIA. We first showed that miR-150-5p mimic -Exos acted on a Treg-OC coculture system to alleviate bone erosion and regulate bone immunity. This study is expected to provide new ideas for the treatment of RA., 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 Elsevier B.V. All rights reserved.)

Neutrophil extracellular traps (NETs) are implicated in the occurrence and progression of atherosclerosis (AS), which can result in adverse cardiovascular events. We investigated the potential mechanism of action of Modified Taohong Siwu Decoction (MTHSWD) against AS based on its effect on NETs. A model of unstable plaque in AS was established by tandem stenosis (TS) of the right common carotid artery in ApoE -/- mice combined with a western diet (WD). The research found that MTHSWD reduced the weight of mice with AS to varying degrees, and significantly decreased the levels of plasma total cholesterol (TC) and triglycerides (TG). Meanwhile, we found that MTHSWD not only significantly improved cardiac EF, FS, cardiac hypertrophy, and ventricular remodeling, but also ameliorated the silent and depressed hypoactivity state caused by AS in ApoE -/- mice. Additionally, the study revealed that MTHSWD improved the severity of AS, protected the vascular structure, increased plaque stability and vessel patency. It also significantly reduced vascular cell apoptosis, platelet aggregation, and the presence of inflammatory cells such as neutrophils (NEUs), as well as the expression of neutrocyte elastase (NE) and myeloperoxidase (MPO), which are components of NETs. Subsequently, NEUs studies have shown that MTHSWD not only significantly reduces the dsDNA content of NETs, but also lowers the expression of NETs components NE and citH3. NETs treating the human umbilical vein endothelial cells (HUVECs) demonstrated that NETs differentially increased the protein expression of endothelial inflammatory adhesion factors CD62P, VCAM-1 and ICAM-1, while significantly decreasing the viability of HUVECs. Pharmacological treatment discovered that MTHSWD significantly improved HUVECs viability impaired by NETs, and promoted the growth and proliferation of endothelial cells. Furthermore, it significantly reduced early and late apoptosis of HUVECs caused by NETs, decreased the expression of pro-apoptotic proteins BAX and Cleaved-Caspase-3, and increased the expression of anti-apoptotic protein Bcl-2. Thus, study suggests that MTHSWD may improve body weight, lipid levels, cardiac function, vigour, and the severity of AS in ApoE -/- AS mice. The novel effect of MTHSWD against AS may be attributed to the inhibition of endothelial injury and apoptosis through the regulation of NETs. This, in turn, reduces the levels of platelets, inflammatory cells, and components of NETs in AS plaques, achieving a benign cycle that protects endothelial cells and vascular structure and function. This result provides some clues and evidence for studying the mechanism of action and clinical application of MTHSWD and its active ingredients against AS., 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 Elsevier B.V. All rights reserved.)

Background: Osteoporosis (OP) is a common metabolic bone disease. Low-intensity pulsed ultrasound (LIPUS) can effectively promote bone formation and fracture healing. The Wnt/β-catenin signaling pathway is crucial for regulating bone homeostasis and bone diseases, and its downregulation is one of the main mechanisms of osteoporosis pathogenesis. Interleukin-11 (IL-11), which is regulated by mechanical stress, is a key factor in bone remodeling. Here, we investigated the optimal intervention parameters for LIPUS, the relationships among LIPUS, IL-11, and the Wnt/β-catenin signaling pathway, and the effects of LIPUS on bone loss and potential molecular mechanisms in ovariectomized (OVX) mice., Methods: Bone marrow mesenchymal stromal cells (BMSCs) were subjected to LIPUS intervention for 0, 10, or 20 min to determine the optimal intervention time. The mediating role of IL-11 in LIPUS intervention was explored through IL-11 knockdown and overexpression. Finally, animal experiments were conducted to investigate the in vivo therapeutic effects of LIPUS., Results: The optimal intervention time for LIPUS was 20 min. LIPUS promoted IL-11 expression and upregulated the Wnt/β-catenin signaling pathway, thereby promoting osteogenic differentiation and inhibiting adipogenic differentiation of BMSCs. IL-11 mediates the regulation of the Wnt/β-catenin signaling pathway by LIPUS. Additionally, LIPUS effectively improved the bone microstructure in ovariectomized mice, inhibited bone loss, promoted IL-11 expression in bone tissue, and activated the Wnt/β-catenin signaling pathway in the femur., Conclusion: Low-intensity pulsed ultrasound can regulate BMSCs differentiation and inhibit bone loss by promoting IL-11 expression and activating the Wnt/β-catenin signaling 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Gram-negative bacteria are the primary pathogens of endometritis in dairy cows. LPS, the primary pathogenic agent of gram-negative bacteria, triggers an ROS increase, ultimately causing epithelial-mesenchymal transformation (EMT). Its significance in endometritis pathogenesis in dairy cows cannot be overlooked., Purpose: Our previous studies showed that berberine could activate the Nrf2 signalling pathway, but whether it can inhibit the effect of LPS-induced EMT is uncharacterized., Methods: This research examined how berberine protects bovine endometrial epithelial cells (BEECs) by treating them with the compound for 2 h before exposing them to LPS to induce injury. Subsequently, the levels of reactive oxygen species (ROS) and epithelial-mesenchymal transition (EMT) markers in BEECs were quantified using the DCFH-DA probe, RT-qPCR, and Western blotting techniques., Results: Our investigation revealed that the triggering of the Nrf2 signal transduction pathway can effectively prevent LPS-induced EMT by reducing ROS levels in BEECs. Additionally, we found that berberine inhibits LPS-induced EMT by activating Nrf2 to reduce ROS levels., Conclusion: These results suggest that berberine reduces ROS levels by upregulating the Nrf2 pathway in BEECs stimulated with LPS., 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 Elsevier B.V. All rights reserved.)

Inflammation and extracellular matrix (ECM) degradation are two major factors involved in the pathogenesis of osteoarthritis (OA). Wedelolactone, a natural compound classified as a coumestan, is isolated from the medicinal plants Eclipta alba and Wedelia calendulacea. In this study, we assessed the protective effects of Wedelolactone on chondrocytes in OA. Our findings show that pretreatment with Wedelolactone effectively inhibited the IL-1β-induced upregulation of COX‑2, iNOS, TNF-α, and IL6 in chondrocytes, contributing to inflammation suppression. Moreover, pretreatment with Wedelolactone followed by IL-1β treatment significantly increased the expression of Collagen II and SOX9, while decreasing the expression of Adamts5, MMP1, MMP3, and MMP13, thereby promoting ECM protection. Through Network pharmacology Analysis, we identified 14 key targets that link Wedelolactone and OA. GO and KEGG pathway analysis suggested that Wedelolactone primarily impacted OA by targeting inflammatory responses, particularly the NF-κB signaling pathway. Further studies demonstrated Wedelolactone prevented IL-1β-induced activation of NF-κB signaling pathway by inhibiting the translocation of p65 and the preventing the degradation of IκBα in human chondrocytes. Molecular docking studies also indicated that Wedelolactone can directly bind to the NF-κB complex, thereby inhibited the nuclear localization of p65. In vivo experiments demonstrated that Wedelolactone can alleviate cartilage damage in DMM mice model. In summary, Wedelolactone appears to mitigate inflammation and cartilage degeneration by suppressing the NF-κB signaling pathway, thereby alleviating OA progression. Our results suggested Wedelolactone may offer therapeutic advantages for OA treatment., (Copyright © 2024 Elsevier B.V. All rights reserved.)

As the most predominant form of arthritis, osteoarthritis (OA) is featured with irreversible progress and involvement of the whole joint. Since OA onset, abnormal mechanical load initiates excessive osteoclastogenesis, evolving a rapid turnover of subchondral bone, cyst creation, synovitis, cartilage degradation, and ultimately resulting in joint failure. Additionally, aberrant vascularization and nociceptive pain are invoked by osteoclast-induced angiogenesis and sensory innervation in the subchondral bone. Rhizoma anemarrhenae (Zhimu) has been extensively demonstrated to show multiple pharmacological effects including anti-inflammation, anti-aging, and immunomodulation. Herein, Broussonin a (BRA), Markogein (MAN), and Isosakuranetin (ISN) derived from Rhizoma anemarrhenae, were initially discovered for their affinity with Bone marrow mononuclear cell (BMMC) membranes using the Cell membrane chromatography/Time of flight mass spectrometry (CMC/TOFMS) method, while only ISN exerted a significant inhibitory effect on RANKL-induced osteoclastogenesis in BMMC in vitro. Intriguingly, we disclosed that ISN blunted the overactivation of Tartrate-resistant acid phosphatase positive (TRAP+) osteoclasts in subchondral bone in OA mice, as indicated by enhanced bone volume/total volume (BV/TV), trabecular number (Tb.N), and trabeculae thickness (Tb.Th), as well as diminished trabecular pattern factor (Tb.pf). Treatment with ISN also impaired aberrant angiogenesis and nociceptive reaction in the subchondral bone marrow. Moreover, ISN hindered the loss of articular cartilage proteoglycan and lowered the Osteoarthritis Research Society International (OARSI) grade, boosting the expression amount of Aggrecan (ACAN) and Collagen II (COL II) positive cells while reducing Matrix metalloproteinase 13 (MMP-13) positive cells. For mechanisms, We verified that ISN hampered subchondral osteoclastogenesis by blocking nuclear factor kappa light chain enhancer of activated B cells (NF-κB) signaling and C-X-C Motif Chemokine Ligand 2 (CXCL2) stimulation. Taken together, we reveal that ISN impedes the progression of OA by preventing hyperactivated subchondral osteoclastogenesis via suppressing the NF-κB/CXCL2 axis., 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 B.V. All rights reserved.)

Periodontitis seriously affects oral health worldwide. Despite extensive efforts in prevention and treatment methods over the years, the prevalence of periodontitis in the population has not decreased. DNA damage-induced cellular senescence may be one of the mechanisms underlying periodontitis.Sirtuin7 (SIRT7) has deacetylase activity and regulates a variety of biological processes, including cell proliferation, death, and DNA damage repair.Increasing evidence confirms the crucial role of SIRT7 in age-related and inflammatory diseases. However, the mechanism of action of SIRT7 in periodontitis remains unclear. Our study demonstrates that SIRT7 is downregulated in human periodontal ligament fibroblasts induced by Porphyromonas gingivalis lipopolysaccharide (Pg-LPS). Overexpression of the SIRT7 gene significantly reduces the production of senescence-related molecules P53, P21, P16, as well as inflammatory cytokines IL-1β and TNF-α stimulated by Pg-LPS. Furthermore, overexpression of the SIRT7 gene significantly decreases the phosphorylation levels of AKT and mTOR in Pg-LPS-treated hPDLFs. Conversely, SIRT7 gene knockdown exhibits opposite effects compared to overexpression in Pg-LPS-treated hPDLFs. In conclusion, our findings indicate that SIRT7 can inhibit Pg-LPS-induced senescence and consequently suppress the secretion of inflammatory cytokines through the AKT/mTOR pathway. As a result, SIRT7 could be regarded a viable pharmaceutical target for clinical periodontitis treatment., 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 Elsevier B.V. All rights reserved.)

Background: Ischemic stroke is the leading cause of death and long-term disability worldwide. After stroke, microglia exhibit not only pro-inflammatory phenotype to aggravate the neuroinflammation, but also anti-inflammatory phenotype to play a neuroprotective role. Studies on the spatial and temporal changes in microglia and the underlying mechanisms help to elucidate the inflammatory cascade after stroke. The regulation of microglia polarization provides new insights for the intervention of post-stroke inflammation., Objective: We aimed to investigate the phenotypic change of microglia in the acute phase of ischemic stroke and the effects of Dl-3-n-butylphthalide (NBP) on microglia. TSPO-PET was used to image microglia and evaluate the efficacy of NBP., Methods: We constructed an MCAO model in rats and administered NBP daily. The infarct volumes in the NBP-treated and control groups were measured. TSPO-PET/CT was used to demonstrate the activation of microglia and the effects of NBP. Additionally, we investigated the effects of NBP on TSPO expression. In vitro, microglia were exposed to glucose oxygen deprivation, and the effects of NBP on microglia and TSPO expression were verified., Results: NBP improved neurological severity scores and reduced infarct volume in the acute phase of ischemic stroke. NBP facilitated microglia to adopt the anti-inflammatory phenotype and reduce the pro-inflammatory phenotype. NBP decreased the expressions of inflammatory cytokines. TSPO-PET/CT observed increase in uptake in the infarct lesion, and this uptake was reduced in response to NBP. NBP reduced TSPO expression in microglia after stroke. In vitro experiments further verified that NBP facilitated the transition of microglia towards the anti-inflammatory phenotype, and inhibited inflammatory cytokine secretion and TSPO expression., Conclusion: We illustrated that NBP fosters the shift of microglia towards the anti-inflammatory phenotype while diminishing their inclination towards the pro-inflammatory phenotype, thereby exerting neuroprotective effects. NBP reduces TSPO expression in microglia, which can be observed by TSPO-PET/CT imaging., 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 Elsevier B.V. All rights reserved.)

Studies have shown that androgens can alleviate the symptoms of T2 asthma and are inversely correlated with the severity of allergic asthma. METTL3, a crucial component of m6A modification, mitigates the development of T2 asthma by inhibiting Th2 cell differentiation. However, the impact of androgens, such as dihydrotestosterone (DHT), on the progression of T2 asthma through METTL3 has yet to be investigated. At the clinical level, patients with T2 asthma exhibited reduced levels of DHT and METTL3 mRNA, along with increased levels of 17β-estradiol (E2). DHT and METTL3 were found to be negatively associated with the severity of T2 asthma, while E2 was positively associated with it. Administration of DHT and E2 in induced T2 asthma mouse models showed that DHT improved lung function, reduced airway inflammation, and inhibited Th2 cell differentiation. Interestingly, DHT reversed the damage to METTL3, whereas E2 had the opposite effect. In vitro studies of mouse bronchial epithelial cells (BECs) confirmed that METTL3-dependent m6A modification inhibited the T2 inflammatory response, and DHT inhibited Th2 cell differentiation in T2 asthma by promoting METTL3 expression in BECs. In conclusion, our study suggests that DHT has therapeutic potential for T2 asthma by regulating METTL3 in BECs., 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.)

Silicosis is an occupational disease caused by long-term inhalation of free silica, resulting in a significant global health burden. Its pathogenesis remains unclear, and there is no effective treatment. Proliferative and activated myofibroblasts play a key role in the development of silicosis. Traditional studies have focused on fibroblast proliferation and collagen secretion, neglecting their functional heterogeneity. With the advancement of omics research, more pathogenic fibroblast subgroups and their functions have been identified. In this study, we applied transcriptomics to analyze gene changes in primary lung fibroblasts during silicosis development using a mouse model. Our results indicate that DEGs are enriched in collagen secretion, ECM synthesis, leukocyte migration, and chemotaxis functions. Altered core genes are associated with immune cell recruitment and cell migration. Nrf2 agonists, known for anti-inflammatory and antioxidant properties, have shown potential therapeutic effects in fibrotic diseases. However, their effects on fibroblasts in silicosis are not fully understood. We used four common Nrf2 agonists to study gene expression changes in lung fibroblasts at the transcriptome level, combined with histopathological and biochemical methods, to investigate their effects on silicosis in mice. Results show that Nrf2 agonists can exert anti-silicosis fibrosis functions by downregulating genes like Fos and Egr1, involved in cell differentiation, proliferation, and inflammation. In conclusion, this study suggests that inflammation-related co-functions of fibroblasts may be a potential mechanism in silicosis pathogenesis. Targeting Nrf2 may be a promising strategy to alleviate oxidative stress and inflammation in silicosis., 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 Elsevier B.V. All rights reserved.)

Objective: The enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) can regulate osteogenesis and osteoclastogenesis. This study aimed to further explore the effects of EZH2 modification on ferroptosis and the osteoblast-osteoclast balance in rheumatoid arthritis (RA) in vitro and in vivo., Methods: Bone marrow mesenchymal stromal cells were transfected with EZH2 overexpression (oeEZH2) and EZH2 shRNA (shEZH2) plasmids with or without ferrostatin-1 (Fer-1) treatment and subjected to an osteoblast differentiation assay. The cells were then cocultured with bone marrow-derived macrophages and subjected to an osteoclast differentiation assay. Collagen-induced arthritis (CIA) mice were generated and injected with shEZH2 adeno-associated virus (AAV)., Results: OeEZH2 repressed osteoblast differentiation, as reflected by decreased ALP and Alizarin Red S staining and increased OPN, RUNX2, OPG and RANKL; however, shEZH2 had the opposite effects. Besides, oeEZH2 promoted osteoblast ferroptosis, as suggested by increased MDA, Fe 2+ , ROS, and PTGS2 but decreased GPX4 and SLC7A11; these effects could be attenuated by Fer-1 treatment. In contrast, shEZH2 ameliorated osteoblast ferroptosis. OeEZH2 subsequently increased osteoclast differentiation, as indicated by increased TRAP + multinucleated cells, NFATC1, CTSK, and c-FOS; however, shEZH2 had the opposite effect, except that it did not regulate CTSK. In CIA mice, shEZH2 AAV decreased the clinical symptom score, histological score of cartilage, and systemic inflammation (TNF-α and IL-6) and repressed bone ferroptosis and restored the osteoblast-osteoclast balance to some extent, as reflected by immunohistochemical staining of related markers., Conclusion: Targeting EZH2 attenuates the ferroptosis-mediated osteoblast-osteoclast imbalance in RA, revealing its potential as a treatment target., 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 Elsevier B.V. All rights reserved.)

Atherosclerosis (AS) is a chronic inflammatory disease resulting from lipid metabolism disorders and immune imbalances. Dendritic cells (DCs) are key cells that regulate adaptive and adaptive immunity. When DCs engulf excessive amounts lipids, their function is altered, thereby, accelerating the inflammatory process of AS. Cellular lipophagy serves to reduce lipid accumulation and maintain cellular lipid metabolism balance. In this study, we investigated the effectiveness of 2,3,5,4'-tetrahydroxystilbene 2-O-β-D-glucoside (TSG) in intervening in the promotion of DCs lipid accumulation by ox-LDL, as well as its role in downregulating lipophagy. Our findings indicate that TSG reduces the maturity of DCs and promotes the differentiation of T cells towards Treg, thereby correcting the imbalanced Treg/Th17. These effects of TSG are closely associated with its inhibition of the PI3K-AKT-mTOR signaling pathway. After administering TSG to ApoE -/- mice that were fed a high-fat diet, there was a noticeable decrease in harmful blood lipids found in the serum. Additionally, the imbalanced Treg/Th17 levels in the spleen were restored, and the levels of pro-inflammatory factor IL-6 and IL-17A in the serum decreased, while the level of anti-inflammatory factor IL-10 increased. Furthermore, the arterial DCs showed a decrease in P62 content. Ultimately, these changes resulted in a reduction in plaque area. It is worth noting that the autophagy inhibitor chloroquine significantly altered the effects of TSG on ApoE -/- mice. In conclusion, this study reveals that TSG can alleviate AS. This is partly achieved through the activation of autophagy in DCs. By intervening in the lipophagy of DCs, it is possible to regulate the immune function of these cells, which in turn helps control the inflammation associated with AS. This presents a potential method for intervening in AS., 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.)

Objective: To investigate the effect of SO 2 on Th1/Th2/Th17 cells in allergic rhinitis (AR) and the role of JAK1, 2/STAT3 signaling pathways.To Provide potential directions for the treatment of AR., Methods: Fifteen AR patients were enrolled as the experimental group, while 15 healthy volunteers served as the normal control group. After collecting venous blood, peripheral blood mononuclear cells (PBMCs) were isolated and cultured, followed by the addition of SO 2 derivatives and the JAK inhibitor Ruxolitinib. Flow cytometry was employed to assess alterations in the Th1/Th2 and Th17/Treg cell balance upon stimulation with SO 2 and Ruxolitinib. qRT-PCR was utilized to detect the expression of Th1-related cytokines IL-2 and IFN-γ, Th2-related cytokines IL-4 and IL-5, Th17-related cytokines IL-17A and RORγt, as well as genes JAK1, JAK2, and STAT3. Flow cytometric cytokine analysis was conducted for quantitative assessment of the expression levels of inflammation-related cytokines in PBMC culture supernatants after stimulation. In addition, we stimulated the Jurkat T lymphocyte cell line with SO 2 derivatives, added Ruxolitinib as an inhibitor, and used Western blot analysis to further determine the effects of SO 2 on Th cells and the role of the JAK1,2/STAT3 signaling pathway in this process., Results: Stimulation with SO 2 derivatives upregulated the expression levels of Th2 cells and associated cytokines, as well as Th1 cells and associated cytokines. both AR patients and healthy individuals displayed increased percentages of Th17 cells and Th17/Treg ratios in PBMCs. The expression of IL-17A, RORγt, and IL-6 was also elevated. Under SO 2 stimulation, the expression of JAK1, JAK2, STAT3, and RORγt in Jurkat cells increased. Moreover, after the application of Ruxolitinib, the JAK/STAT signaling pathway was inhibited. This led to a reduction in Th17 cells and IL-17A levels in both AR patients and healthy individuals, as well as a decrease in RORγt expression in Jurkat cells. Additionally, the expression of IL-5 decreased in healthy individuals., Conclusion: SO 2 exposure exacerbated Th1/Th2/Th17 inflammation in AR patients and induced Th1 and Th17 inflammation in healthy individuals. The stimulatory effect of SO 2 on Th17 cell differentiation could be inhibited by Ruxolitinib. This suggests that the Th17 inflammation induced by SO 2 stimulation may be related to the activation of the JAK/STAT signaling pathway, and this has been confirmed in the Jurkat cell line., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Although numerous approaches have emerged to address the challenges of critical limb ischemia (CLI), their clinical trials have proven elusive. Stem cell therapy has been utilized for CLI; however, its efficacy is limited, resulting in low survival rates in patients. Here, we investigated the impact of polydeoxyribonucleotide (PDRN) on the bioactivities of stem cells derived from human exfoliated deciduous teeth (SHED) against oxidative stress. PDRN treatment increased the proliferation, migration, antioxidant properties, and mitochondrial respiration of SHED. These beneficial effects were regulated by Akt activation. Through a murine hindlimb ischemia model, PDRN treatment demonstrated augmented the survival and proliferation of transplanted SHED at ischemic injury sites, whereas the inhibition of Akt suppressed these effects. Our findings revealed that PDRN promoted the therapeutic potential of SHED via Akt phosphorylation, suggesting PDRN-primed SHED as promising candidates for the development of novel stem cell therapeutics., 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.)

Background: Conditioned medium from amnion-derived mesenchymal stem cells (AMSCs) enhances wound healing, a process that is further improved under hypoxic culture conditions. Diabetic foot ulcers are difficult to treat and are frequently complicated by a high rate of bacterial infections, mainly Staphylococcus aureus, which can lead to limb amputation and death. Here, we topically applied conditioned medium from AMSCs cultured under hypoxic conditions to S. aureus-infected wounds in diabetic mice to investigate its effect on bacterial counts and wound healing., Methods: We prepared conditioned medium by culturing AMSCs under 21 % or 1 % O 2 and investigated its effects on S. aureus. We infected skin wounds of diabetic mice with S. aureus and treated these with hydrogels containing the conditioned medium to examine its effect on bacterial inhibition and wound healing., Results: Conditioned medium from AMSCs cultured under 1 % O 2 contained higher levels of the antimicrobial peptide LL-37. It significantly inhibited S. aureus growth in vitro, reduced bacterial counts in infected wounds, and facilitated wound closure in diabetic mice., Conclusions: Hydrogels containing conditioned medium from hypoxically cultured AMSCs inhibited the growth of S. aureus and promoted wound healing in a mouse model of diabetic wounds., 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 Elsevier Inc. All rights reserved.)

N-methyl-d-aspartate receptors (NMDARs), the ligand ion glutamate receptor channels, mediate major excitatory neurotransmission in central nervous system (CNS). They highly express in CNS and involve in multiple physiological processes. Many studies implicated that NMDAR plays a crucial role in number of neurological disorders, including ischemia, dementia, and pain, indicating its potential as a therapeutic target for treatments. Chelerythrine (CHE) is a benzo-phenanthridine alkaloid extracted from Chelidonium majus with many biological activities including anti-inflammatory, anticancer effect, and antidiabetic effect. But the mechanism of CHE is not well understood. The aim of this study was to investigate the effect of CHE on the NMDAR. The results demonstrated that CHE effectively suppressed NMDA-induced currents in primary cultured cortical neurons. To elucidate the underlying mechanism, we expressed NMDARs in HEK293T cells and found that CHE and some of its structural analogues inhibited NMDAR currents and facilitated the desensitization of GluN2B NMDARs. Notably, these effects were independent of protein kinase C activity, suggesting that the effect of CHE on GluN2B-containing NMDAR may occur through a mechanism of directly interaction with NMDAR. Moreover, the inhibitory effect of CHE on GluN2B NMDARs is pH-dependent. Molecular docking prediction in conjunction with mutagenesis analysis revealed that the M3 α-helical segment of the NMDAR in close proximity to the GluN2B Thr647 amino acid plays an important role in CHE inhibition of GluN2B. This study revealed a novel function of CHE and its structural analogues in inhibiting the NMDARs and promoting GluN2B-mediated desensitization by obstructing the receptor at the channel pore region., Competing Interests: Declaration of competing interest The authors declare that there are no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Intervertebral disc degeneration (IDD) is a common cause of low back pain and disability. Recent studies have highlighted the critical role of mitochondrial dysfunction in the progression of IDD. In this study, we investigated the therapeutic potential of taurine in delaying IDD through the activation of mitophagy via the PINK1/Parkin pathway. Our in vitro and in vivo experiments demonstrate that taurine treatment significantly enhances mitophagy, reduces oxidative stress, delays cell senescence, and promotes the removal of damaged mitochondria in nucleus pulposus cells (NPC). Additionally, taurine-mediated activation of the PINK1/Parkin pathway leads to improved mitochondrial homeostasis and slows the progression of disc degeneration. These findings provide new insights into the protective effects of taurine and highlight its potential as a therapeutic agent for IDD., Competing Interests: Declaration of competing interest All authors declare no financial or personal relationships with other individuals or organizations., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neutrophil plays an important role in the early stage of wound healing. Excessive neutrophil extracellular traps (NETs) which are produced by neutrophil have been proved as a significant unfavorable factor for wound healing by impairing the function of human skin fibroblasts. However, the effect of NETs with low concentrations on fibroblasts remains unclear. The interaction between CCDC25 and ILK in fibroblast were found to be activated by NET-DNA with low concentrations. Additionally, phosphorylation of PI3K and AKT was increased in NET-stimulated fibroblasts but was inhibited by CCDC25 knockout or ILK knockdown. NETs-induces proliferation and migration ability of fibroblast were also reduced by application of CCDC25 sgRNAs or ILK shRNAs. This study demonstrates that low concentrations of NETs, upon biding with CCDC25, activates the ILK/PI3K/AKT signaling pathway in skin fibroblasts, leading to increased cell proliferation and migration activity., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The pituitary gland is the master endocrine gland, harboring stem cells with various genetic characteristics; however, data from non-rodent and non-human sources are scarce. In this study, we isolated putative stem cells from the bovine pituitary gland and investigated their potential for differentiation into hormone-producing cells. Immunohistochemical analysis revealed that in calves and heifers, stem cell marker sex-determining region Y-box 2 (SOX2)-positive cells were widely present in the pituitary gland and partially co-localized with anterior pituitary hormones. Next, a single-cell suspension of primary anterior lobe cells from bovines aged 0 and 12 months was subjected to two-dimensional culture. Consequently, some cells proliferated in the culture dishes. The expression levels of Sox2 and several other stem cell markers were higher in these cells after culture. In addition, almost all proliferating cells were positive for SOX2, whereas all were negative for hormones. In three-dimensional cultures, SOX2-positive cells presented a spheroid-like morphology and differentiated into endocrine cells. These results provide evidence that SOX2-positive cells are pituitary stem cells with the potential to differentiate into hormone-producing cells, regardless of age. Our data lay a theoretical foundation for further studies on controlling fundamental processes, such as body growth, reproduction, and lactation., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

S100 calcium-binding protein P (S100P) is a secretory protein that is expressed in various healthy tissues and tumors. Megakaryocyte-secreted S100P promotes osteoclast differentiation and function; however, its receptor and cellular signaling in osteoclasts remain unclear. Receptor for advanced glycation end products (RAGE), which is the receptor for S100P on cancer cells, was expressed in osteoclast precursors, and S100P-RAGE binding was confirmed through co-immunoprecipitation. Additionally, the phosphorylation of ERK and NF-κB was increased in S100P-stimulated osteoclast precursors but was inhibited by addition of the RAGE antagonistic peptide (RAP). S100P-induced osteoclast differentiation and excessive bone resorption activity were also reduced by the addition of RAP. This study demonstrates that S100P, upon binding with RAGE, activates the ERK and NF-κB signaling pathways in osteoclasts, leading to increased cell differentiation and bone resorption activity., 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 Elsevier Inc. All rights reserved.)

Fibrosis results in one-third of all deaths globally and is a major healthcare challenge. Fibrosis is scarring caused by the excess deposition of extracellular matrix proteins by fibroblasts. Inhibition of pathways downstream of transforming growth factor β (TGF-β) a pluripotent growth factor, has potent antifibrotic effects in different organs. Here we show that loss of bone morphogenetic protein (BMP-3) is a feature of kidney fibrosis, independent of the initiating injury, suggesting loss of this cytokine is a core fibrotic mechanism. TGF-β decreased BMP3 expression in human fibroblasts is possibly a feed-forward loop that contributes to increased and sustained TGF-β activity. Recombinant human BMP-3 reduced TGF-β induced fibroblast contraction, migration and invasion, pathways that lead to scarring and tissue stiffening. BMP-3 reduced TGF-β stimulated collagen cross-linking, and Ox-LDL receptor 1, a regulator of collagen deposition. BMP-3 inhibited TGF-β stimulated lysyl oxidase activity. Lysyl oxidase mediated collagen cross-linking is a critical process in TGF-β induced fibrosis. We propose that BMP-3 alters fibroblast responses to TGF-β, shifting the balance from fibrosis to repair. Recombinant human BMP-3 shows promise for development as a novel therapeutic for fibrosis., 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.)

Dementia-related neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), are known to be caused by accumulation of toxic proteins. However, the molecular mechanisms that cause neurodegeneration and its biophysical effects on cells remain unclear. In this study, we used juvenile neuronal ceroid lipofuscinosis (JNCL), a pediatric dementia with a clear etiology of mutations in ceroid lipofuscinosis neuronal 3 (CLN3), to explore the changes in cell adhesion, a biophysical process that regulates neuronal development and survival. We used JNCL cerebral organoid gene expression datasets to identify the biological pathways that affect neural development, and found enriched gene expression in the epithelial-mesenchymal transition (EMT) pathway and increased expression of its inducer snail family transcriptional repressor 2 (SNAI2). A cell adhesion assay using lymphoblasts from patients with JNCL revealed defective adhesion to cell culture plates, glass surfaces, collagen type I, and neuroblast-like cells. To determine whether inhibition of EMT could improve the cell adhesion of JNCL lymphoblasts, we used all-trans retinoic acid, a well-known EMT inhibitor and inducer of neural differentiation. In JNCL lymphoblasts, ATRA treatment enhanced adhesion to collagen type I and these effects were abolished by Ca 2+ chelator. These results provide new insights into the role of CLN3 and cell adhesion in the pathogenesis of NDD., 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 Elsevier Inc. All rights reserved.)

Photobiomodulation (PBM) therapy is the application of near-infrared (NIR) exposure to injuries or lesions to (among others) improve wound healing, reduce inflammation, and decreases acute and chronic pain. However, the understanding of the molecular mechanism of PBM, more specifically the effects of NIR on skin cells is still lacking behind. Lipids are essential components of cellular membranes that are integral to skin structure and function. This study aims to elucidate the impact of NIR exposure on the skin's lipidome by investigating the molecular effect of NIR exposure on single skin cells. Primary human dermal fibroblasts (NHDFa) and human epidermal keratinocytes (HEKa) were exposed to NIR (850 nm) with a dose of 6.5 J/cm 2 for 5 consecutive days between 09.00 and 12.00 am. A workflow utilizing matrix-assisted laser desorption/ionization mass spectrometry imaging combined with liquid chromatography tandem mass spectrometry for lipidomics analysis was performed. This study provides evidence that adequate exposure of NIR influences lipid metabolism in NHDFa, whereas no alterations were found in HEKa. This work lays the groundwork in explaining the beneficial properties on both skin-related effects and systemic health benefits as seen in clinical studies., Competing Interests: Declaration of Competing Interest Anne Berends was employed at Seaborough Life Science B.V. at the time of the study. The remaining authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To explore the phenotype of sclera macrophages in form-deprivation (FD) myopia mice and the effects of M2 macrophage in FD myopia development., Methods: C57BL/6 mice were under 2 weeks of unilateral FD treatment. and they were separated into two groups, including an intraperitoneally injected(IP) vehicle group and Panobinostat (LBH589) (10 mg/kg per body weight) treatment group. All biometric parameters were measured before and after treatments, and the type and density of sclera macrophages were identified by immunofluorescence and RT-qPCR. In vitro, we analyzed the M2 macrophage and primary human sclera fibroblast (HSF) co-culture system by using the transcriptome sequencing method. Gene ontology (GO) and KEGG enrichment analyses were used to pinpoint the biological functions and pathways associated with the identified Differentially Expressed Genes (DEGs). The hub genes were investigated using the STRING database and Cytoscape software and were confirmed using RT-qPCR., Results: We found that the M2-type sclera macrophage density and expression increased in FD-treated eyes. The results showed that LBH589 inhibited the M2 macrophage polarization, and reduced FDM development. GO and KEGG analyses revealed that the DEGs were predominantly involved in the synthesis and breakdown of the extracellular matrix (ECM), as well as in pathways related to ECM-receptor interaction and the PI3K-Akt signaling pathway. Five hub genes (FN-1, MMP-2, COL1A1, CD44, and IL6) were identified, and RT-qPCR validated the variation in expression levels among these genes., Conclusion: M2 macrophage polarization occurred in the sclera in FDM mice. Panobinostat-mediated inhibition of M2 macrophage polarization may decrease FDM progression, as M2 macrophages are crucial in controlling ECM remodeling by HSFs., 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 Elsevier Inc. All rights reserved.)

Microtubule-based chemotherapeutics, primarily Taxane-derived agents are still used as the major live-saving agents, yet have several side effects including serious loss of immune cells, bone density etc. which lowers the quality of life. This imposes the need to understand the effects of these agents on Mesenchymal Stem Cells (MSCs) in details. In this work we demonstrate that Taxol and Nocodazole affects the endogenous expression of TRPV1, a non-selective cation channel in MSCs. These agents also affect the status of polymerized Actin as well as Tyrosinated-tubulin, basal cytosolic Ca 2+ and mitochondrial membrane potential (ΔΨm). Notably, pharmacological modulation of TRPV1 by Capsaicin or Capsazepine can also alter the above-mentioned parameters in a context-dependent manner. We suggest that endogenous expression of TRPV1 and pharmacological modulation of TRPV1 can be utilized to rescue some of these parameters effectively. These findings may have significance in the treatments and strategies with Microtubule-based chemotherapeutics and stem-cell based therapy., Competing Interests: Declaration of competing interest All authors declare the existence of no conflict with this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

There is growing concern surrounding the human health effects following inhalation exposure to microplastic fibers (MPFs). MPFs can harbor chemical additives, such as azobenzene disperse dyes (ADDs), that may contribute to their toxicity. The goal of this study was to determine the acute biological effects of dyed polyethylene terephthalate MPFs to fully differentiated normal human bronchial epithelial (NHBE) cells cultured at an air-liquid interface. Cells were exposed to 2000 undyed MPFs (84.80 µg/cm 2 ) or 2000 dyed MPFs (129.86 µg/cm 2 ) colored with a black dye stuff containing the dye Disperse Violet 93 (DV93) using a mesh hopper delivery device. Cells were also exposed to DV93 only (1 µg/mL). Results show that the dyed MPFs caused a more pronounced decrease in cell viability and transepithelial electrical resistance compared to undyed MPFs and unexposed control cells. Additionally, the DV93 and dyed MPFs significantly upregulated the mRNA expression of CYP1A1 and CYP1B1, which was not observed in the undyed MPF group. These results support the idea that components of MPFs, specifically azobenzene disperse dyes, can leach from MPFs in biological systems and exert unique toxicity profiles. This study emphasizes the importance of considering toxicity associated with both the fibers themselves and chemical leachates in future studies., 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 B.V. All rights reserved.)

4-tert-Octylphenol (OP), an endocrine disrupting chemical is widely used in the production of industrial products. Prenatal exposure to endocrine-disrupting chemicals negatively affects the brain. However, the influence of OP exposure during neurodevelopment in adult offspring remains unclear. Thus, in the present study, we investigated the effects of maternal OP exposure on brain development in adult offspring by analyzing primary glial cell cultures and mice. Our findings revealed that OP exposure led to a specific increase in the mRNA expression of the ionized calcium-binding adapter molecule 1 (Iba-1) and the proportion of amoeboid microglia in the primary glial cell culture and adult offspring mice. Exposure to OP increased the transcriptional activation of Iba-1 and estrogen response element, which were counteracted by estrogen receptor antagonists ICI 182,780. Moreover, OP exposure increased the nuclear localization of the estrogen receptor. Remarkably, OP exposure decreased the mRNA expression levels of proinflammatory cytokines and genes associated with immune response in the brains of the offspring. OP exposure upregulated actin filament-related genes and altered cytoskeletal gene expression, as demonstrated by microarray analysis. The morphological changes in microglia did not result in an inflammatory response following lipopolysaccharide treatment. Taken together, the effects of OP exposure during neurodevelopment persist into adulthood, resulting in microglial dysfunction mediated by estrogen receptor signaling pathways in the brains of adult offspring mice., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Eui-Man Jung reports financial support was provided by the National Research Foundation of Korea (NRF) funded by the Korean Government (MSIT) (grant number: 2021R1C1C100328611) and Global - Learning & Academic research institution for Master’s·PhD students, and Postdocs (LAMP) Program of the National Research Foundation of Korea (NRF) grant funded by the Ministry of Education (No. RS-2023-00301938)., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Triclocarban (TCC) is a widely applied environmental endocrine-disrupting chemical (EDC). Similar to most of EDCs, TCC potentially damages the immunity of various species. However, whether and how TCC impacts the adaptive immunity in mammals has yet to be determined. Herein, we discovered that TCC disrupts the activation and differentiation of CD8 + T cells in primary human peripheral blood samples, purified CD8 + T cells, and in mice in vivo. Mechanistically, TCC might block the activation of the vitamin D receptor (VDR) and reduce the synthesis of cholesterol, a precursor of vitamin D, resulting in inhibition of VDR signaling due to the suppression of both its ligand and the receptor itself by TCC. Our findings elucidate the hazard and potential mechanisms of TCC in mammalian adaptive immunity and highlighted VDR as a potential therapeutic target for the immunodeficiency caused by TCC., Competing Interests: Declaration of Competing Interest The authors declare they have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: The lungs are highly susceptible to damage during sepsis, with severe lung injury potentially progressing to acute respiratory distress syndrome and even fatal sepsis. Effective efferocytosis of apoptotic cells is crucial in alleviating inflammation and tissue injury., Methods: We established a septic lung injury mouse model via intraperitoneal injection of lipopolysaccharide. Lung injury was assessed by histology, immunofluorescence, neutrophil immunohistochemistry staining, and cytokine detection. We extracted alveolar macrophages by bronchoalveolar lavage and primary macrophages from mouse bone marrow to investigate the regulatory effects of Dexmedetomidine (DEX) on efferocytosis. We further validated the molecular mechanisms underlying the regulation of macrophage efferocytosis by DEX through knockdown of AXL expression. Additionally, we examined the efferocytic ability of monocytes isolated from patients., Results: We discovered that DEX treatment effectively alleviated pulmonary injury and inflammation. Lipopolysaccharide reduced macrophage efferocytosis and AXL expression which were reversed by DEX. We also found DEX inhibited the increased activation of A Disintegrin And Metalloproteinase 10 (ADAM10) and the production of soluble AXL. Moreover, our findings demonstrated that DEX decreased the elevated ROS production linked to higher ADAM10 activation. Blocking AXL negated DEX's benefits on efferocytosis and lung protection. Efferocytosis in monocytes from septic lung injury patients was notably lower than in healthy individuals., Conclusion: Our findings demonstrated that DEX treatment effectively reduces septic lung injury by promoting macrophage efferocytosis through ROS/ADAM10/AXL signaling pathwway., 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 Elsevier B.V. All rights reserved.)

The endothelial-mesenchymal transition (EndMT) is involved in the development of atherosclerosis (AS) and is a key process in vascular endothelial injury. Oxidative stress, inflammation, and apoptosis are common causes of EndMT, and EndMT progression can further accelerate the development of AS. The metabolite trimethylamine N-oxide (TMAO) is produced by the gut microbiome and is implicated in the development of several diseases, including diabetes and chronic kidney disease. However, the impact of TMAO on transforming growth factor β1(TGF-β1)-induced EndMT remains unclear. We hypothesize that TMAO exacerbates plaque formation and cardiac function impairment by promoting EndMT. Herein, we showed that high serum TMAO levels caused plaque formation, cardiac function damage and haemodynamic changes in ApoE -/- mice. In vitro, TMAO upregulated mesenchymal markers and downregulated endothelial markers in HAECs. Furthermore, TMAO increased the migratory capacity of EndMT cells. Mechanistically, we found that PERK downregulation could alleviate TMAO-induced oxidative stress, EndMT, plaque formation and cardiac function damage. Further study showed that activated transcription factor 3 (ATF3), the downstream molecule of protein kinase RNA-like endoplasmic reticulum kinase (PERK), could bind with TGF-β1/2 and affect EndMT. Overall, TMAO promotes EndMT, possibly through the PERK-eIF2α-ATF4-CHOP or the PERk-eIF2α-ATF3-TGF-β signalling 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 Author(s). Published by Elsevier B.V. All rights reserved.)

Backgroud: Exercise training is the main strategy for stroke rehabilitation, and it has shown that shifting microglia toward M2 phenotype is beneficial for the recovery of neurological function after stroke. The mechanisms governing exercise training and inflammatory response after cerebral ischemia remain largely unexplored. Herein, the aim of this study was to investigate the role of exercise training in immune response after cerebral ischemia., Methods: The transient middle cerebral artery occlusion (MCAO) rat model and primary microglia under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions were used to mimic the ischemic stroke in vivo and in vitro respectively. Treadmill exercise with gradually increased intensity was initiated the second day after MCAO for a maximum of 14 days. The beam balance test, forelimb placement test, cornering test, modified adhesive removal test were used to assess the behavioral recovery. The right peri-infarct cortex was taken from 3 rats per group for RNA sequencing (RNA-seq) analysis. Real-time PCR, western blot, immunofluorescence, and phagocytosis assay was performed after MCAO and/or OGD/R., Results: Treadmill exercise could significantly improve behavioral outcomes and reduce the infarct volumes. In addition, treadmill exercise switched microglia polarization toward M2 phenotype (Iba + /CD206 + ) in the peri-infarct cortex, and significantly increased the levels of anti-inflammatory factors (TGF-β, IL10, Arg-1, CD206) and decreased a pool of pro-inflammatory factors (IL-1β, IL-6, TNF-α, iNOS, CD68) in the peri-infarct areas. RNA-seq analysis and further studies demonstrated that exercise training could significantly reduce the expression of MMP12. Through further immunofluorescence co-labeling analysis, we found that treadmill exercise predominantly reduced the expression of MMP-12 in microglia but not in neuron after MCAO. In primary microglia after OGD/R, MMP12 inhibition switched microglia polarization toward to M2 phenotype, increased the expression of M2 markers, and enhanced its phagocytic capacities., Conclusions: Our data demonstrate that treadmill exercise could improve the inflammatory microenvironment in the brain after ischemic stroke, which may be caused by inhibition of MMP12 expression. MMP12 suppression in primary microglia could remodel microglia immune functions. In summary, this study may provide novel insights into the immune mechanism of exercise training for stroke and suggests potential targets for therapeutic approaches., Competing Interests: Declaration of competing interests 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 B.V. All rights reserved.)

Background: Growth differentiation factor 11 (GDF11) is considered to be a potential molecular target for treating pulpitis. However, whether GDF11 regulates osteogenic/odontogenic differentiation of dental pulp stem cells (DPSCs) to mediate pulpitis process remains unclear., Methods: Lipopolysaccharide (LPS) was used to induce inflammation conditions in DPSCs. The levels of GDF11, sirtuin 3 (SIRT3), forkhead box O-3 (FOXO3), osteogenic/odontogenic differentiation-related markers were measured by quantitative real-time PCR (qRT-PCR) and western blot (WB). Immunofluorescence staining was used to measure mitophagy. Mitophagy-related proteins were analyzed by WB, and the levels of inflammation factors were examined using qRT-PCR, ELISA and immunohistochemistry. Alkaline phosphatase activity and alizarin red S intensity were evaluated to assess osteogenic differentiation. Acute pulp (AP) injury rat model was constructed to study the role of oe-GDF11 in vivo., Results: GDF11 was downregulated in LPS-induced DPSCs, and LPS suppressed osteogenic/odontogenic differentiation and mitophagy. GDF11 overexpression promoted osteogenic/odontogenic differentiation in DPSCs through the activation of mitophagy. Furthermore, GDF11 upregulated SIRT3 to enhance FOXO3 expression by inhibiting its acetylation. GDF11 ameliorated LPS-induced inflammation and promoted osteogenic/odontogenic differentiation in DPSCs via enhancing SIRT3/FOXO3-mediated mitophagy. Besides, GDF11 overexpression suppressed inflammation and promoted dentin repair in AP rat models., Conclusion: GDF11 promoted SIRT3/FOXO3-mediated mitophagy to accelerate osteogenic/odontogenic differentiation in DPSCs, providing a novel target for pulpitis treatment., 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 Elsevier B.V. All rights reserved.)

Osteoarthritis (OA) is the most common musculoskeletal disease and a leading cause of pain and disability. A key hallmark of OA is cartilage degradation, which occurs due to an imbalance between the synthesis and degradation of the extracellular matrix (ECM). Interleukin-1β(IL-1β) has been reported to regulate ECM metabolism. Nuciferine (Nuc), a natural peptide extracted from the lotus leaf, possesses several significant pharmacological properties. However, the anti-inflammation of Nuc in OA has not been reported. In this study, ELISA and Western blot analyses were used to measure the production of inflammatory mediators in IL-1β-Induced mouse chondrocytes. Additionally, mice with or without surgical destabilization of the medial meniscus (DMM) were treated with intra-articular injection of Nuc. We found that Nuc significantly reduces the level of iNOS, PEG2, and IL-6 in IL-1β-induced chondrocytes. Furthermore, Nuc can ameliorate the development of OA in mice. Mechanistically, we found that the chondrocyte-protective effects of Nuc occur via the PTEN/NF-κB pathway. These findings suggest that Nuc could be a potential therapeutic agent for improving OA development., (Copyright © 2024. Published by Elsevier B.V.)

One component of the polycomb repressor complex 2 is histone methyltransferase zeste homolog 2 (EZH2), which is also called Enhancer of zeste homolog 2. It is considered a potential therapeutic target for inhibiting endothelial dysfunction.. Hence, directing efforts towards EZH2 to weaken endothelium damage and regulate vascular lesions proves to be a highly successful therapeutic approach for enhancing endothelial dysfunction. This study aimed to investigate the mechanism by which salidroside (SAL) improves hydrogen peroxide (H 2 O 2 )-induced endothelial dysfunction. The investigation involved the use of many techniques, including western blotting, real-time polymerase chain reaction (RT-PCR), a scratch test, molecular docking, and other methods. The experimental findings demonstrated that SAL has the ability to inhibit the impaired functioning of endothelial cells caused by H 2 O 2 and decrease the levels of NF-κB p65, NLRP3, TNF-α, Beclin1, LC3, and P62 proteins. Additionally, there seems to be a targeting relationship between SAL and EZH2, and EZH2 knockdown can reproduce the protective effect of SAL on endothelial function. Overall, SAL inhibits H 2 O 2 -induced HUVEC dysfunction by regulating autophagy and inflammatory signaling pathways through EZH2., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)