Osteogenesis of renal tubular epithelial cells (RTEC) is an important trigger for calcium oxalate (CaOx) kidney stone formation, but whether macrophages are involved in RTEC osteogenesis is unclear. The purpose of this study was to investigate the role and mechanism of macrophages in CaOx kidney stones on RTEC osteogenesis. Oxalate or ethylene glycol was used to construct in vitro and in vivo CaOx kidney stone models, respectively. Macrophage-derived conditioned medium was used to induce osteogenesis in HK-2 cells, and genetic controls and pharmacological interventions were used to investigate the underlying mechanism. The results demonstrated that macrophage-conditioned medium under oxalate intervention facilitated the increase of alkaline phosphatase and calcium salts as well as the upregulation of osteogenic marker genes (BMP2 and RUNX2) expression in HK-2 cells. On the one hand, the knockdown of the JAK2 gene in HK-2 cells reverses the role of macrophage-derived conditioned medium in promoting osteogenesis in HK-2 cells. On the other hand, inhibition of prostaglandin E2 (PGE2) generation in macrophages reverses osteogenesis in HK-2 cells. Moreover, inhibition of PGE2 generation would cure ethylene glycol-induced renal injury and calcium salt deposition, as well as osteogenesis of RTEC. This study illustrates that in the presence of oxalate, macrophages secret PGE2 to activate JAK2/STAT3 signaling in RTEC, which could trigger osteogenesis. It provides new insights into the mechanism of CaOx kidney stone formation.

Cell-free regenerative strategies, such as notochordal cell (NC)-derived extracellular vesicles (EVs), are an attractive alternative in developing new therapies for intervertebral disc (IVD) degeneration. NC-EVs have been reported to elicit matrix anabolic effects on nucleus pulposus cells from degenerated IVDs cultured under basal conditions. However, the degenerative process is exacerbated by pro-inflammatory cytokines contributing to the vicious degenerative cycle. Therefore, this study explores whether NC-EVs modulate interleukin (IL)-1β-mediated pro-inflammatory responses in the degenerating disc.

This study utilized two IL-1β induced pro-catabolic culture models; a dog 3D nucleus pulposus (NP) cell pellet culture and a human patient-derived, ex vivo NP tissue culture system. Porcine NC-EVs were generated from NC-conditioned medium by differential centrifugation followed by size exclusion chromatography. Donor matched EV-depleted media were generated by overnight ultracentrifugation, whereafter the EV-depleted NCCM supernatant was subjected to size exclusion chromatography. To investigate whether observed effects were EV-associated, NC-EVs conditions were compared to EV-depleted controls in the absence and presence of IL-1β.

The size and concentration of NC-EVs were quantified by nanoparticle tracking analysis, which showed minimal donor variation and confirmed depletion of EVs in the EV-depleted media. In the IL-1β-induced catabolic cascade, the NC-EVs did not elicit anabolic effects at the matrix level nor did they rescue the pro-catabolic phenotype within dog pellets. Modification of the CCL2 secretion seemed to be context dependent in the human explants: where EVs treatment stimulated CCL2 secretion but in the presence of IL-1β this effect was counteracted. Secretion of IL-6 and C-X-C motif chemokine ligand 1 was significantly decreased in NC-EV + IL-1β vs. control+IL-1β but not compared to EV-depleted human explant controls. Altogether, this data provides evidence for a protective modulatory role of NC-EVs. Considering the homeostatic function EVs exert, inherently encompassing subtle biologic modifications, the current study may have lacked sufficient power to demonstrate statistical significance in a sample set with evident donor variation.

NC-EVs may modulate the production of specific cytokines and chemokines in human degenerate explants when the key pro-inflammatory cytokine IL-1β is present. Implementation of the technical EV-depleted controls in further studies is essential to robustly demonstrate that these effects are EV-mediated and not associated with other secreted factors co-isolated during EV-isolation.

Osteoarthritis (OA) is the most common form of degenerative joint disease that commonly affects the knees, hips and hands. OA is a mechano-inflammatory disease characterized by low-grade inflammation, which results in breakdown of the cartilage extracellular matrix within joints, leading to pain, stiffness and inflammation. TissueGene-C (TG-C) is a cell and gene therapy investigational drug for treating knee OA that comprises human allogeneic chondrocytes and an irradiated modified cell line stably expressing transforming growth factor beta 1 (TGF-β1). Previous pre-clinical animal studies have shown that TG-C provides pain relief via its anti-inflammatory effects and cartilage structural improvement in a rat OA model. The goal of this study was to investigate the mechanism of action of TG-C, explore its anti-inflammatory activity and identify the TG-C-derived active factor(s) responsible for its efficacy.

In this study, we utilized THP-1 cell line to develop an macrophage polarization model to test the anti-inflammatory activity of TG-C.

Our data showed that TG-C induces the polarization of M2 macrophages and the upregulation of interleukin 10 (IL-10) and interleukin 1 receptor antagonist (IL-1ra) while inhibiting tumor necrosis factor alpha (TNF-α) expression. Additionally, this study identified prostaglandin E2 (PGE2) as the main bioactive factor responsible for the anti-inflammatory activity of TG-C.

Our results demonstrated that PGE2 is expressed by the TG-C chondrocyte component and modulated by TGF-β1 derived from the second component of TG-C. Finally, the present study provides insight into the mechanism of action of TG-C in the treatment of OA.

Skin exposure to arsenicals such as lewisite and phenylarsine oxide leads to severe cutaneous damage. Here, we characterized the molecular pathogenesis of skin injury caused by additionally structurally distinct warfare arsenicals including diphenylchlorarsine (DPCA), diphenylcyanoarsine (DPCYA), diethylchloroarsine (DECA). Cutaneous exposure to DPCA/DPCYA showed marked increase in skin erythema and edema at 6 and 24 h followed by scar formation at 72 h, while DECA did not produce such visual injuries in mouse skin. Clinical observations showed significant increase in Draize score and skin bi-fold thickness in a time-dependent manner. DPCA or DPCYA-exposed skin histology revealed highly inflamed hypodermal areas with infiltrated immune cells at 6 and 24 h, however, epidermal cell necrosis was seen at 72 h. Significantly high number of macrophage infiltration observed at 6 h, whereas peak neutrophil infiltration occurred at 72 h. Number of micro-blisters also increased. However, these effects were nonsignificant following topical DECA exposure. RT-PCR confirmed augmented inflammatory responses in the skin challenged with both DPCA/DPCYA, which accompanied increased ROS and unfolded protein response (UPR) signaling. DECA also increased ROS with changes in UPR. Disrupted tight (Yap/ZO-1) and adherens (Yap/α-Catenin) junction proteins underlie time-dependent apoptotic cell death of epidermal keratinocytes. Thus, these studies identify arsenicals-manifested signaling pathways similar to those of lewisite.

Acetaminophen (APAP) is a commonly utilized antipyretic and analgesic drug. Overdose of APAP is a primary contributor to drug-induced liver injury and acute liver failure (ALF). SW033291 has been shown to play a role in tissue regeneration in various diseases; however, its potential to facilitate liver regeneration following APAP-induced hepatic injury remains unexamined. Thus, this study focused on exploring the therapeutic impacts and mechanisms of SW033291 on liver damage by establishing models of APAP-induced acute liver injury in mice. The results showed that treatment with SW033291 reduces serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, decreases the area of hepatic necrosis, increases glutathione (GSH) levels, and decreases tissue malondialdehyde (MDA) content, as well as the expression levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in mice with liver injury. It could also promote hepatocyte proliferation and inhibit apoptosis by increasing tissue prostaglandin E2 (PGE2) levels. In conclusion, SW033291 demonstrates the capacity to ameliorate APAP-induced hepatic injury in mice by fostering liver regeneration, attenuating oxidative stress, and modulating inflammatory responses, thereby presenting itself as a promising candidate for the development of therapeutic interventions targeting acute liver failure.

Embryonic exposures to non-steroidal anti-inflammatory drugs (NSAIDs) have been linked to preterm birth, neural tube closure defects, abnormal enteric innervation, and craniofacial malformations, potentially due to disrupted neural tube or neural crest (NC) cell development. Naproxen (NPX), a common non-steroidal anti-inflammatory drug (NSAID) used to relieve pain and inflammation, exerts its effects through non-selective cyclooxygenase (COX) inhibition. Our lab has identified that the cyclooxygenase (COX-1 and COX-2) isoenzymes are expressed during the early stages of vertebrate embryonic development, and that global inhibition of COX-1 and COX-2 function disrupts NC cell migration and differentiation in Ambystoma mexicanum (axolotl) embryos. NC cells differentiate into various adult tissues including craniofacial cartilage, bone, and neurons in the peripheral and enteric nervous systems. To investigate the specific phenotypic and molecular effects of NPX exposure on NC development and differentiation, and to identify molecular links between COX inhibition and NC derivative anomalies, we exposed late neurula and early tailbud stage axolotl embryos to various concentrations of NPX and performed immunohistochemistry (IHC) for markers of migratory and differentiating NC cells. Our results reveal that NPX exposure impairs the migration of SOX9+ NC cells, leading to abnormal development of craniofacial cartilage structures, including Meckels cartilage in the jaw. NPX exposure also alters the expression of markers associated with peripheral and central nervous system (PNS and CNS) development, suggesting concurrent neurodevelopmental changes.

Wound healing is a complex biological process involving multiple steps, including hemostasis, inflammation, proliferation, and remodeling. A novel form of regulated cell death, ferroptosis, has garnered attention because of its involvement in these processes. Ferroptosis is characterized by the accumulation of lipid peroxides and is tightly regulated by lipid metabolism, iron metabolism, and the lipid-peroxide repair network, all of which exert a significant influence on wound healing. This review highlights the current findings and emerging concepts regarding the multifaceted roles of ferroptosis throughout the stages of normal and chronic wound healing. Additionally, the potential of targeted interventions aimed at modulating ferroptosis to improve wound-healing outcomes is discussed.

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia with restrictive ventilation. Recently, the structural and functional defects of small airways have received attention in the early pathogenesis of IPF. This study aimed to elucidate the characteristics of small airway epithelial dysfunction in patients with IPF and explore novel therapeutic interventions to impede IPF progression by targeting the dysfunctional small airways.

Airway trees spanning the proximal-distal axis were harvested from control lungs and explanted lungs with end-stage IPF undergoing transplant. Qualified basal cells (BCs, p63/Krt5/ITGA6/NGFR) were expanded, and their cellular functions, feasibility, safety and efficacy for transplantation therapy in IPF were validated with experiments in vitro and mouse model. Single-cell RNA-sequencing was employed to elucidate the underlying mechanisms governing the BCs based therapy. Based upon these evidences, three patients with advanced IPF and small airway dysfunction received autologous-BCs transplantation. Post-transplantation assessments included lung function, exercise capacity and high resolution computed tomography (HRCT) scans were analyzed to quantify the clinical benefits conferred by the BCs transplantation.

An overall landscape of senescent phenotype in airway epithelial cells and airway stem/progenitor cells along the proximal-distal axis of the airway tree in IPF were outlined. In contrast to the cells situated in distal airways, BCs located in small bronchi in IPF displayed a non-senescent phenotype, with comparable proliferative, differentiative capabilities, and similar transcriptomic profiles to normal controls. In a mouse model of pulmonary fibrosis, BCs exhibited promising protective efficacy and safety for transplantation therapy. Autologous BCs transplantation in three advanced IPF patients with small airway dysfunction yielded significant clinical improvements in pulmonary function, particularly evidence in lung volume and small airway function.

Epithelia of small bronchi in IPF contain functional and expandable basal stem cells, which exert therapeutic benefits via bronchoscopic implantation. Our findings offer a potential for IPF treatment by targeting small airways.

National Natural Science Foundation of China (82430001, 81930001, and 81900059), Shanghai Shenkang Hospital Development Center (SHDC2020CR3063B), Department of Science and Technology of Shandong Province (2024HWYQ-058).

Chronic wounds are a severe complication of diabetes. Dysregulated inflammatory signalling is thought to underly the poor healing outcomes. Yet, there is little information available on the acute response following injury and its impact on healing.

Using a murine full thickness excisional wound model, the current study therefore assessed the expression of pro-inflammatory and pro-resolving lipid mediators during the early stages post injury in acute and diabetic wounds and compared the timeframe for transitioning through the phases of healing. Tissue eicosanoid (LTB4, PGE2, TxA2, MaR1, RvE1, RvD1, PD) and MMP-9 levels were assessed at 6 h post wounding using ELISAs. Wound closure, healing dynamics (histology), cellular infiltration and MPO, TNF-α expression (IHC) were assessed at 6 h, day2, day7 post wounding.

Eicosanoid expression did not differ between groups (LTB4 24-125 pg/mL, PGE2 63-177 pg/mL, TxA2 529-1184 pg/mL, MaR1 365-2052 pg/mL, RvE1 43-1157 pg/mL, RvD1 1.5-69 pg/mL, PD1 11.5-4.9 ng/mL). An inverse relationship (p < 0.05) between MMP-9 and eicosanoids were however only evident in acute and not in diabetic wounds. Diminished cellular infiltration (x5 fold) (p < 0.05) in diabetic wounds coincided with a significant delay in the expression of TNF-α (pro-inflammatory cytokine) and MPO (neutrophil marker). A significant difference in the expression of TNF-α (C 1.8 ± 0.6; DM 0.7 ± 0.1 MFI) and MPO (C 4.9 ± 1.9; DM 0.9 ± 0.4 MFI) (p < 0.05) was observed as early as 6 h post wounding, with histology parameters supporting the notion that the onset of the acute inflammatory response is delayed in diabetic wounds.

These observations imply that the immune cells are unresponsive to the initial eicosanoid expression in the diabetic wound tissue.

Atopic dermatitis (AD), also known as eczema, is an inflammatory dermatologic condition that results in inflamed, itchy skin lesions. The development of this condition is governed by a variety of genetic and environmental factors including lifestyle habits. The severity of atopic dermatitis has been attributed to be affected by various lifestyle factors, prompting the interest in utilizing lifestyle modifications as a form of treatment for atopic dermatitis symptoms. Many research studies have been conducted to investigate the effects of different factors such as sleep, stress, diet, smoking and tobacco use, exposure to various temperatures and humidity levels, and skincare and cosmetic products on atopic dermatitis symptoms, and how certain habits can be modified to manage AD conditions. Current studies have demonstrated the significant impact some lifestyle modifications can elicit with improving atopic dermatitis, while also discussing other lifestyle factors that require further research to determine their effects on AD. This review article summarizes the findings in the current literature that investigates the role of different lifestyle habits on the severity and exacerbation of atopic dermatitis, and explores the mechanisms in which these behaviors can trigger AD.

Wound healing is a highly coordinated process driven by intricate molecular signaling and dynamic interactions between diverse cell types. Nod-like receptor pyrin domain-containing protein 3 (NLRP3) has been implicated in the regulation of inflammation and tissue repair; however, its specific role in skin wound healing remains unclear. This study highlights the pivotal role of NLRP3 in effective skin wound healing, as demonstrated by delayed wound closure and altered cellular and molecular responses in NLRP3-deficient (NLRP3-/-) mice. Histological analysis revealed impaired healing processes, accompanied by reduced expression of key inflammatory mediators, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and prostaglandin E2 (PGE2). Deficiencies in apoptosis were evident through altered expression of cysteine-aspartic acid protease 3 (Caspase-3), P53, and B-cell lymphoma-2 (Bcl-2). Furthermore, critical growth factors such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and matrix metalloproteinase-9 (MMP-9) were significantly decreased at the excisional skin wound sites. Furthermore, using co-culture systems, we found that NLRP3 mediated the interaction between macrophages and myofibroblasts. Wild-type fibroblast-conditioned media (MFbCM) enhanced nitric oxide (NO), IL-6, and tumor necrosis factor-α (TNF-α) production in M1 macrophages and arginase activity, chitinase 3-like protein 1 (Ym1), and IL-10 expression in M2 macrophages, effects significantly diminished with NLRP3-/- MFbCM. Similarly, conditioned media from wild-type M1 or M2 macrophages promoted the expression of FGF-2, VEGF, and MMP-2 expression in myofibroblasts, which was attenuated when using NLRP3-/- macrophage-conditioned media. PGE2 levels were reduced in both NLRP3-/- macrophages and myofibroblasts. Supplementing NLRP3-/- conditioned media with PGE2 partially restored the impaired functions, suggesting that PGE2 acts as a downstream mediator of NLRP3-regulated macrophage-myofibroblast interactions. These findings indicate that NLRP3 is a key regulator of skin wound healing, facilitating macrophage-myofibroblast communication.

Effective communication between different cell types is essential for brain health, and dysregulation of this process leads to neuropathologies. Brain glial cells, including microglia and astrocytes, orchestrate immune defense and neuroimmune responses under pathological conditions during which interglial communication is indispensable. Our appreciation of the complexity of these processes is rapidly increasing due to recent advances in molecular biology techniques, which have identified numerous phenotypic states of both microglia and astrocytes. This review focuses on microglia-to-astrocyte communication facilitated by secreted neuroimmune modulators. The combinations of interleukin (IL)-1α, tumor necrosis factor (TNF), plus complement component C1q as well as IL-1β plus TNF are already well-established microglia-derived stimuli that induce reactive phenotypes in astrocytes. However, given the large number of inflammatory mediators secreted by microglia and the rapidly increasing number of distinct functional states recognized in astrocytes, it can be hypothesized that many more intercellular signaling molecules exist. This review identifies the following group of cytokines and gliotransmitters that, while not established as interglial mediators yet, are known to be released by microglia and elicit functional responses in astrocytes: IL-10, IL-12, IL-18, transforming growth factor (TGF)-β, interferon (IFN)-γ, C-C motif chemokine ligand (CCL)5, adenosine triphosphate (ATP), l-glutamate, and prostaglandin E2 (PGE2). The review of molecular mechanisms engaged by these mediators reveals complex, partially overlapping signaling pathways implicated in numerous neuropathologies. Additionally, lack of human-specific studies is identified as a significant knowledge gap. Further research on microglia-to-astrocyte communication is warranted, as it could discover novel interglial signaling-targeted therapies for diverse neurological disorders.

Flavonoids including quercetin, kaempferol, myricetin, rutin etc. have always been a part of traditional Chinese medicine for the treatment of several ailments. Rutin (RT), also known as rutoside, sophorin is one of the flavanol glycoside having structure resemblance with quercetin. It is found to exhibit several biological activities viz. anti-inflammatory, anticancer, antioxidant, cardioprotective, antidepressant, neuroprotective etc. but the mechanisms by which it exhibits these effects is still under research.

The protective effects of rutin against drug induced nephropathy have already been discovered. Therefore, in this study, the main focus is to explore the mechanism by which rutin provides protection against drug-induced nephropathy using modern method like network pharmacology and molecular docking.

Genes linked to drug-induced nephropathy and targets connected with rutin were obtained by searching through a number of extensive databases, including David software, Venn plot database, Swiss target prediction database, String database, Gene card & OMIM database, and Pubchem. In order to locate mapping targets, the acquired targets were examined and intersected. A protein-protein interaction (PPI) network was then built to find potential targets.

From the KEGG pathway, the target pathway responsible for drug-induced nephropathy were found to be XDH, HSD17B2, MET, PRKCB, CD38, ALDH2, CDK1, PTK2, CYP19A1, TNF, F2, PTGS2, ESR1, GSK3B, GLO1, ALOX12, MMP3, PRKCZ, CXCR1, CA4, EGFR, PDE5A, F10, AKR1B1, DRD4, TERT, CA3, PLG, TP53, PRKCH, PIK3R1, PRKACA, CYP1B1, ALOX5, PLK1, CHEK1, KCNH2, PRKCD, MAPT, MPO, NOX4, AVPR2, ACHE, MCL1, KDR, ABCG2, CCR1, PIK3CG, FLT3, ADORA1, IL2, SYK, IGF1R, CA2, SERPINE1, INSR, PRKCA, APP, MMP9. From these identified targets, the 14 selected pathways which have major role in providing protection in drug-induced nephropathy have been discussed.

As RT can inhibit various metabolic and proinflammatory pathways involved, it can help in prevention and treatment of drug-induced nephropathy.

The revelation of mode of action of bioactive constituent rutin against drug-induced nephropathy provides a theoretical basis for designing more promising compounds in future for treatment of nephropathy.

High consumption of Ultra-processed foods (UPF) have been identified as a potential risk factor for Non-alcoholic fatty liver disease (NAFLD). Nevertheless, there is limited empirical evidence regarding the impact of UPF, which are typical combination of processed foods, on liver health through alterations in gut microbiota and metabolic processes. We aim to examine the potential impact of UPF on liver health and to explore the role of gut microbiota and metabolites.

This study used Sprague-Dawley rats to mimic modern UPF diets for 90 days. Some serum biochemical indices, inflammatory factors, oxidative stress markers, hematoxylin-eosin (HE) staining of the liver, 16S ribosomal RNA (rRNA) and Liquid chromatography-mass spectrometry (LC-MS) of rat feces were detected.

The UPF diet-induced simple steatosis of the liver in rats without affecting the levels of IL-6, GSH, MDA, and SOD. Additionally, it modified the gut microbiota, increasing potentially harmful bacteria, such as norank_f__Desulfovibrionaceae and Staphylococcus, while also elevating the relative abundance of potentially beneficial bacteria, including Dubosiella and Allobaculum. Furthermore, the consumption of UPF led to a metabolomic disorder characterized by disruptions in the sphingolipid signaling pathway, sulfur relay system, and arachidonic acid metabolism.

In conclusion, the findings of this study indicate that the consumption of UPF influences the development of simple hepatic steatosis, potentially through alterations in gut microbiota and metabolomics.

Non-peptide ligands (NPLs), including lipids, amino acids, carbohydrates, and non-peptide neurotransmitters and hormones, play a critical role in ligand-receptor-mediated cell-cell communication, driving diverse physiological and pathological processes. To facilitate the study of NPL-dependent intercellular interactions, we introduce MetaLigand, an R-based and web-accessible tool designed to infer NPL production and predict NPL-receptor interactions using transcriptomic data. MetaLigand compiles data for 233 NPLs, including their biosynthetic enzymes, transporter genes, and receptor genes, through a combination of automated pipelines and manual curation from comprehensive databases. The tool integrates both de novo and salvage synthesis pathways, incorporating multiple biosynthetic steps and transport mechanisms to improve prediction accuracy. Comparisons with existing tools demonstrate MetaLigand's superior ability to account for complex biogenesis pathways and model NPL abundance across diverse tissues and cell types. Furthermore, analysis of single-nucleus RNA-seq datasets from age-related macular degeneration samples revealed that distinct retinal cell types exhibit unique NPL profiles and participate in specific NPL-mediated pathological cell-cell interactions. Finally, MetaLigand supports single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics data, enabling the visualization of predicted NPL production levels and heterogeneity at single-cell resolution.

Human amniotic epithelial cells (hAECs) have shown excellent efficacy in clinical research and have prospective applications in the treatment of many diseases. However, the properties of the hAECs and their proliferative mechanisms remain unclear. Here, single-cell RNA sequencing (scRNA-seq) is performed on hAECs obtained from amniotic tissues at different gestational ages and passages during in vitro culture. The results showed that the proliferation of hAECs is associated with epithelial-mesenchymal plasticity (EMP) during amniogenesis. Freshly isolated, full-term hAECs are identified as mature epithelial cells. Once cultured in vitro, they are observed to rapidly undergo epithelial-mesenchymal transition (EMT) and enter a partial epithelial-mesenchymal transition (pEMT) state to regain their EMP properties and proliferation capacities. With the continuous development of EMT, hAECs eventually enter a senescent state. The addition of SB431542 and microcarrier screening enabled the effective 3D expansion of hAECs by 50 fold while maintaining the EMP status in hAECs for further proliferation. This study not only elucidated the central proliferation mechanism of hAECs during development and expansion but also optimized the in vitro culture system so that it is sufficient to generate hAECs for 50 patients from a single donor amniotic membrane.

Accumulating research has shed light on the significance of skeletal interoception, in maintaining physiological and metabolic homeostasis related to bone health. This review provides a comprehensive analysis of how skeletal interoception influences bone homeostasis, delving into the complex interplay between the nervous system and skeletal system. One key focus of the review is the role of various factors such as prostaglandin E2 (PGE2) in skeletal health via skeletal interoception. It explores how nerves innervating the bone tissue communicate with the central nervous system to regulate bone remodeling, a process critical for maintaining bone strength and integrity. Additionally, the review highlights the advancements in biomaterials designed to utilize skeletal interoception for enhancing bone regeneration and treatment of bone disorders. These biomaterials, tailored to interact with the body's interoceptive pathways, are positioned at the forefront of innovative treatments for conditions like osteoporosis and fractures. They represent a convergence of bioengineering, neuroscience, and orthopedics, aiming to create more efficient and targeted therapies for bone-related disorders. In conclusion, the review underscores the importance of skeletal interoception in physiological regulation and its potential in developing more effective therapies for bone regeneration. It emphasizes the need for further research to fully understand the mechanisms of skeletal interoception and to harness its therapeutic potential fully.

Interleukin-4 (IL-4), which is traditionally associated with inflammation, has emerged as a key player in tissue regeneration. Produced primarily by T-helper 2 (Th2) and other immune cells, IL-4 activates endogenous lymphocytes and promotes M2 macrophage polarization, both of which are crucial for tissue repair. Moreover, IL-4 stimulates the proliferation and differentiation of various cell types, contributing to efficient tissue regeneration, and shows promise for promoting tissue regeneration after injury. This review explores the multifaceted roles of IL-4 in tissue repair, summarizing its mechanisms and potential for clinical application. This review delves into the multifaceted functions of IL-4, including its immunomodulatory effects, its involvement in tissue regeneration, and its potential therapeutic applications. We discuss the mechanisms underlying IL-4-induced M2 macrophage polarization, a crucial process for tissue repair. Additionally, we explore innovative strategies for delivering IL-4, including gene therapy, protein-based therapies, and cell-based therapies. By leveraging the regenerative properties of IL-4, we can potentially develop novel therapies for various diseases, including chronic inflammatory disorders, autoimmune diseases, and organ injuries. While early research has shown promise for the application of IL-4 in regenerative medicine, further studies are needed to fully elucidate its therapeutic potential and optimize its use.

Liquorice, also known as "mulaithi" in North India, has shown anti-inflammatory, antimicrobial, and anti-adherence effects that can prevent and treat various periodontal diseases.

This study aims to assess the efficacy of subgingivally delivered liquorice gel on clinical parameters and prostaglandin E2 (PGE2) levels in chronic periodontitis.

A split-mouth, single-blind, prospective, parallel, randomized controlled clinical trial was conducted. Seventeen patients diagnosed with moderate chronic periodontitis with bilateral nearly symmetrical sites having a pocket depth of ≥4 mm but ≤6 mm were included in the study. A total of 60 sites were randomly divided into two groups, with 30 sites in each group: Group A, scaling and root planing (SRP) with subgingival delivery of liquorice gel, and Group B, SRP with subgingival delivery of placebo gel. The clinical parameters, plaque index (PI), gingival index (GI), probing pocket depth (PPD), clinical attachment level (CAL), and gingival crevicular fluid (GCF), samples were collected at baseline, 15th day, and 30th day after gel placement. The collected GCF samples were subjected to biochemical analysis of PGE2 levels using an ELISA kit. The Mann-Whitney U and Wilcoxon signed-rank tests were performed for intergroup and intragroup comparisons.

Statistically significant improvements in clinical and biochemical parameters were observed in both groups over time. Intergroup comparison of PI and GI showed statistically non-significant differences at all time intervals. Similarly, intergroup comparisons of PPD, CAL, and PGE2 levels showed statistically non-significant differences at baseline and 15th day. However, on the 30th day, PPD, CAL, and PGE2 levels revealed statistically significant differences between both groups. Our result corroborated that Group A, tested with liquorice gel, showed better results than Group B.

Liquorice gel can be used as an effective local drug delivery agent as an adjunct to SRP for treating chronic periodontitis.

Traumatic injuries to spinal cord lead to severe motor, sensory, and autonomic dysfunction. The accumulation of inhibitory compounds plays a pivotal role in the secondary damage to sparing neural tissue and the failure of axonal regeneration and remyelination. Acid-sensing ion channel-1(ASIC1A) is widely activated following neurotrauma, including spinal cord injury (SCI). However, its role in SCI remains elusive.

The effects of acidic environment on the differentiation and genes changes of neural stem cells (NSCs) were assessed by immunofluorescence staining and RNA-sequencing analysis, respectively. The expression of ASIC1A and prostaglandin endoperoxide synthase 2 (PTGS2) were detected by western blot and immunofluorescence staining. The concentration of prostaglandin E2 (PGE2) within NSC-derived extracellular vesicles were evaluated by ELISA. Small-interfering RNAs (siRNAs) were used to knock down Asic1a and Ptgs2 expression in NSCs. The myelin sheath regeneration and axonal remyelination in rats and Asic1a-KO mice were assessed by immunofluorescence staining.

Following injury to the spinal cord, ASIC1A was found to be colocalized and upregulated in NSCs. ASIC1A activation prevents the differentiation of NSCs into oligodendrocytes by upregulating PTGS2, which leads to increased production and release of PGE2 within extracellular vesicles (EVs). ASIC1A or PTGS2 deficiency in NSCs counters the ASIC1A-related effects on mediating NSC differentiation by reducing PGE2 expression within NSC-derived EVs. Furthermore, intervention in ASIC1A signaling by administration of ASIC1A inhibitors or genetic deletion of ASIC1A demonstrated a pronounced advantage in enhancing myelin sheath regeneration and axonal remyelination.

The activation of ASIC1A prevents NSC differentiation into oligodendrocytes via the transcellular NSC-to-NSC delivery of PGE2, resulting in the failure of myelin sheath regeneration and axonal remyelination following SCI. The inhibition of ASIC1A presents a promising therapeutic strategy for the treatment of SCI.

Cellular senescence is a state of terminal growth arrest associated with the upregulation of different cell cycle inhibitors, mainly p16 and p21, structural and metabolic alterations, chronic DNA damage responses, and a hypersecretory state known as the senescence-associated secretory phenotype (SASP). The SASP is the major mediator of the paracrine effects of senescent cells in their tissue microenvironment and of various local and systemic biological functions. In this Review, we discuss the composition, dynamics and heterogeneity of the SASP as well as the mechanisms underlying its induction and regulation. We describe the various biological properties of the SASP, its beneficial and detrimental effects in different physiological and pathological settings, and its impact on overall health span. Finally, we discuss the use of the SASP as a biomarker and of SASP inhibitors as senomorphic interventions to treat cancer and other age-related conditions.

Opioids are the most prescribed drugs for the alleviation of pain. Both clinical and preclinical studies have reported strong evidence for sex-related divergence regarding opioid analgesia. There is an increasing amount of evidence indicating that gonadal hormones regulate the analgesic efficacy of opioids. This review presents an overview of the importance of gonadal steroids in modulating opioid analgesic responsiveness and focuses on elaborating what is currently known regarding the underlyingmechanism. We sought to identify the link between gonadal hormones and the effect of oipiod antinociception.

Skeletal muscle (SM) contains a diverse population of muscle stem (or satellite) cells, which are essential for the maintenance of muscle tissue and positively regulated by prostaglandin E2 (PGE2). However, in aged SM, PGE2 levels are reduced due to increased prostaglandin catabolism by 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a negative regulator of SM tissue repair and regeneration. Screening of a library of 80,617 natural compounds in the ZINC database against 15-PGDH was conducted from PyRx. Further, drug-likeness rules, including those of Lipinski, Ghose, Veber, Egan, and Muegge were performed. The selected complex was forwarded for MD simulations up to 100ns. Based on free energy of binding obtained from docking revealed that ZINC14557836 and ZINC14638400 more potently inhibiting to 15-PGDH than SW033291 (the control and high-affinity inhibitor of 15-PGDH). The free energies of binding obtained from PyRx for 15-PGDH-ZINC14557836, 15-PGDH-ZINC14638400, and 15-PGDH-SW033291 complexes were - 10.30, -9.80, and - 8.0 kcal/mol, respectively. Root mean square deviations (RMSDs), root mean square fluctuations (RMSFs), radii of gyration (Rg), solvent-accessible surface areas (SASAs), and H-bond parameters obtained by 100 ns MD simulations predicted ZINC14557836 and ZINC14638400 more stably complexed with 15-PGDH than SW033291. The several parameters, including physicochemical properties and drug-likenesses, were within acceptable limits, and ZINC14557836 and ZINC14638400 also satisfied other drug-likeness rules, including those of Lipinski, Ghose, Veber, Egan, and Muegge. These findings suggest that ZINC14557836 and ZINC14638400 provide starting points for the development of medications that increase SM regeneration and muscle stem (or satellite) cell numbers by inhibiting 15-PGDH.

The phenomenon of brain-bone crosstalk pertains to the intricate interaction and communication pathways between the central nervous system and the skeletal system. Disruption in brain-bone crosstalk, particularly in disorders such as osteoporosis, can result in skeletal irregularities. Consequently, investigating and comprehending this communication network holds paramount importance in the realm of bone disease prevention and management. In this study, we found that Staphylococcus aureus lipoteichoic acid promoted the conversion of arachidonic acid to PGE2 by interacting with TLR2 receptors acting on the surface of microglial cells in the pituitary gland, leading to the upregulation of COX-2 expression. Subsequently, PGE2 bound to the EP4 receptor of growth hormone-secreting cells and activated the intracellular CREB signalling pathway, promoting GH secretion and ameliorating age-related bone loss.

Intrathecal morphine pump helps alleviate pain in the advanced stages of cancer, and thus, ensuring safe intrathecal morphine pump infusion is important. In this study, we investigated the effect of healthcare failure mode and effects analysis (HFMEA) in the management of patients with intrathecal morphine pump implantation.

We included 112 cancer patients with severe pain who met the inclusion criteria for intrathecal morphine pump implantation treatment in the pain department of our hospital from November 2021 to October 2022. We analyzed the severity, likelihood, and crisis of potential failure modes, causes, and results of intrathecal morphine pumps during this period, compiled the records, and formulated the appropriate improvement measures based on the results of the analysis. From November 2022 to October 2023, the HFMEA model was applied to 125 patients in the department, and the effectiveness of the model was evaluated by assessing the patients' VAS (visual analog scale) score, SAS (self-rating anxiety scale) score, SDS score, PSQI (Pittsburgh Sleep Quality Index) score and quality of life (QOL) (self-rating depression scale) score.

The occurrence of adverse events (6 cases vs. 2 cases, p < .05), and the total incidence of adverse events (8.9% vs. 1.6%, X2= 6.600, p = .010) was significantly different before and after HFMEA was applied. For patients who received intrathecal morphine pump implantation, the VAS scores and the related pain indices were significantly lower after HFMEA than before. Additionally, the score of SAS (48.91 ± 6.03 vs. 47.02 ± 6.77), PSQI (37.30 ± 5.78 vs. 39.63 ± 5.64), and QOL (9.93 ± 3.04 vs. 8.98 ± 2.31) of patients improved significantly.

With the application of the HFMEA model, a multidisciplinary team assessed the risks associated with the use of intrathecal morphine pumps and prioritized measures to reduce them. By implementing the improvement measures, potential errors decreased significantly during the intrathecal morphine pump process. It allowed nursing managers to change the safety incidents related to drug administration using an intrathecal morphine pump from negative treatment after the event to active prevention before the event, greatly improved the level of drug use safety management, reflected the continuous improvement of nursing quality, and ensured nursing safety.

Spatial metabolomics has emerged as a powerful tool capable of revealing metabolic gradients throughout complex heterogeneous tissues. While mass spectrometry imaging (MSI) technologies designed to generate spatial metabolomic data have improved significantly over time, metabolite coverage is still a significant limitation. It is possible to achieve deeper metabolite coverage by imaging in positive and negative polarities or imaging several serial sections with different targeted biomolecular classes. However, this significantly increases the number of tissue samples required for biological studies and reduces the capacity for larger sample cohorts. Herein, we introduce lithium-doped nanospray desorption electrospray ionization (nano-DESI) as a simple and robust method to increase spatial metabolomics coverage, which is achieved through enhancements to ionization efficiencies in positive ion mode for metabolites and lipids lacking basic moieties, and improved structurally diagnostic tandem mass spectra for [M + Li]+ adducts. Specifically, signal intensities were found to be enhanced by 10-1000× for 96 compounds including small molecule metabolites, fatty acids, neutral lipids (e.g., diacylglycerols, DAG), and phospholipids when lithium was added to the ESI solvent. In addition, proof-of-principle results reveal that lithium-doped nano-DESI MSI was able to comprehensively visualize metabolites and lipids in the prostaglandin (PG) biosynthetic pathway with PG isomeric resolution in an ovarian tumor section. These data show colocalization of fatty acid (FA) 20:4 containing DAGs, FA 20:4 monoacylglycerols (MAGs), and FA 20:4 with PGE2 and disparate localizations of PGD2. Overall, this study describes a simple and powerful approach to more comprehensively probe the spatial metabolome with MSI.

Circulating tumor cells (CTCs), which have the heterogeneity and histological properties of the primary tumor and metastases, are shed from the primary tumor and/or metastatic lesions into the vasculature and initiate metastases at remote sites. In the clinic, CTCs are used extensively in liquid biopsies for early screening, diagnosis, treatment, and prognosis. Current research focuses on using CTC-derived models to study tumor heterogeneity and metastasis, with 3D organoids emerging as a promising tool in cancer research and precision oncology. However, isolating and enriching CTCs from blood remains challenging due to their scarcity, exacerbated by the lack of an optimized culture medium for CTC-derived organoids (CTCDOs). In this review, we summarize the origin, isolation, enrichment, culture, validation, and clinical application of CTCs and CTCDOs.

Uncovering mechanisms of endogenous regeneration and repair through resident stem cell activation will allow us to develop specific therapies for injuries and diseases by targeting resident stem cell lineages. Sox9+ stem cells have been reported to play an essential role in acute kidney injury (AKI). However, a complete view of the Sox9+ lineage was not well investigated to accurately elucidate the functional end state and the choice of cell fate during tissue repair after AKI. To identify the mechanisms of fate determination of Sox9+ stem cells, we set up an AKI model with prostaglandin E2 (PGE2) treatment in a Sox9 lineage tracing mouse model. Single-cell RNA sequencing (scRNA-seq) was performed to analyse the transcriptomic profile of the Sox9+ lineage. Our results revealed that PGE2 could activate renal Sox9+ cells and promote the differentiation of Sox9+ cells into renal proximal tubular epithelial cells and inhibit the development of fibrosis. Furthermore, single-cell transcriptome analysis demonstrated that PGE2 could regulate the restoration of lipid metabolism homeostasis in proximal tubular epithelial cells by participating in communication with different cell types. Our results highlight the prospects for the activation of endogenous renal Sox9+ stem cells with PGE2 for the regenerative therapy of AKI.

Prostaglandin E2 (PGE2), an eicosane, regulates the physiological activity of inflammatory cells and represents a potential therapeutic target for facilitating tissue repair in vivo. In our work, an electrochemical immunosensor employing Ketjen black-Au nanoparticles (KB-Au) and poly tannic acid nanospheres conjugated with anti-PGE2 polyclonal antibody (PTAN-Ab) was designed to ultra-sensitively analyze PGE2 levels secreted by living cells and tissues. Antibody assembly strategies were explored to achieve signal amplification. Moreover, we studied the therapy effects of docosahexaenoic acid (DHA), arachidonic acid (AA), hyaluronic acid (HA), and small molecule 15-hydroxyprostaglandin dehydrogenase inhibitor (SW033291) on inflammation and evaluated the protective functions of HA and SW033291 in a murine model subjected to colitis induced by dextran sulfate sodium (DSS) using the developed sensor. The sensor exhibited a linear range of 10-5-106 fg/mL and a detection limit (LOD) of 10-5 fg/mL. Fetal bovine serum (FBS) samples were used to achieve high recovery of target analytes. This study not only presents an effective strategy for ultra-sensitively monitoring PGE2 but also provides valuable insights into assessing the degree of inflammation and the therapeutic effect of related drugs. Research on human health monitoring and regenerative medicine could greatly benefit from the findings.

Breakthrough symptoms are thought to occur in roughly half of all gastroesophageal reflux disease (GERD) patients despite maximal acid suppression (proton pump inhibitor, PPI) therapy. Topical alginates have recently been shown to enhance mucosal defense against acid-pepsin insult during GERD. We aimed to examine potential alginate protection of transcriptomic changes in a cell culture model of PPI-recalcitrant GERD. Immortalized normal-derived human esophageal epithelial cells underwent pretreatment with commercial alginate-based anti-reflux medications (Gaviscon Advance or Gaviscon Double Action), a matched-viscosity placebo control, or pH 7.4 buffer (sham) alone for 1 min, followed by exposure to pH 6.0 + pepsin or buffer alone for 3 min. RNA sequencing was conducted, and Ingenuity Pathway Analysis was performed with a false discovery rate of ≤0.01 and absolute fold-change of ≥1.3. Pepsin-acid exposure disrupted gene expressions associated with epithelial barrier function, chromatin structure, carcinogenesis, and inflammation. Alginate formulations demonstrated protection by mitigating these changes and promoting extracellular matrix repair, downregulating proto-oncogenes, and enhancing tumor suppressor expression. These data suggest molecular mechanisms by which alginates provide topical protection against injury during weakly acidic reflux and support a potential role for alginates in the prevention of GERD-related carcinogenesis.

Peritendinous adhesion that forms after tendon injury substantially limits daily life. The pathology of adhesion involves inflammation and the associated proliferation. However, the current studies on this condition are lacking, previous studies reveal that cyclooxygenase-2 (COX2) gene inhibitors have anti-adhesion effects through reducing prostaglandin E2 (PGE2) and the proliferation of fibroblasts, are contrary to the failure in anti-adhesion through deletion of EP4 (prostaglandin E receptor 4) gene in fibroblasts in mice of another study. In this study, single-cell RNA sequencing analysis of human and mouse specimens are combined with eight types of conditional knockout mice and further reveal that deletion of COX2 in myeloid cells and deletion of EP4 gene in sensory nerves decrease adhesion and impair the biomechanical properties of repaired tendons. Furthermore, the COX2 inhibitor parecoxib reduces PGE2 but impairs the biomechanical properties of repaired tendons. Interestingly, PGE2 local treatment improves the biomechanical properties of the repaired tendons. These findings clarify the complex role of PGE2 in peritendinous adhesion formation (PAF) and tendon repair.

Lipids and their mediators have important regulatory functions in many cellular processes, including the innate antiviral response. The aim of this study was to compare the lipid membrane composition of in vitro differentiated primary bronchial epithelial cells (PBECs) with ex vivo bronchial brushings and to establish whether any changes in the lipid membrane composition affect antiviral defense of cells from donors without and with severe asthma. Using mass spectrometry, we showed that the lipid membrane of in vitro differentiated PBECs was deprived of polyunsaturated fatty acids (PUFAs) compared to ex vivo bronchial brushings. Supplementation of the culture medium with arachidonic acid (AA) increased the PUFA-content to more closely match the ex vivo membrane profile. Rhinovirus (RV16) infection of AA-supplemented cultures from healthy donors resulted in significantly reduced viral replication while release of inflammatory mediators and prostaglandin E2 (PGE2) was significantly increased. Indomethacin, an inhibitor of prostaglandin-endoperoxide synthases, suppressed RV16-induced PGE2 release and significantly reduced CXCL-8/IL-8 release from AA-supplemented cultures indicating a link between PGE2 and CXCL8/IL-8 release. In contrast, in AA-supplemented cultures from severe asthmatic donors, viral replication was enhanced whereas PTGS2 expression and PGE2 release were unchanged and CXCL8/IL-8 was significantly reduced in response to RV16 infection. While the PTGS2/COX-2 pathway is initially pro-inflammatory, its downstream products can promote symptom resolution. Thus, reduced PGE2 release during an RV-induced severe asthma exacerbation may lead to prolonged symptoms and slower recovery. Our data highlight the importance of reflecting the in vivo lipid profile in in vitro cell cultures for mechanistic studies.

This study focused on exploring the effects of SW033291, an inhibitor of 15-hydroxyprostaglandin dehydrogenase, on type 2 diabetes mellitus (T2DM) mice from a comprehensive perspective. Studies have demonstrated that SW033291 benefits tissue repair, organ function, and muscle mass in elderly mice. Our recent investigation initially reported the beneficial effect of SW033291 on T2DM progression. Herein, we used a T2DM mouse model induced by a high-fat diet and streptozotocin injection. Then, serum and liver metabolomics, as well as liver transcriptomic analyses, were performed to provide a systematic perspective of the SW033291-ameliorated T2DM. The results indicate SW033291 improved T2DM by regulating steroid hormone biosynthesis and linoleic/arachidonic acid metabolism. Furthermore, integrated transcriptomic and metabolomic analyses suggested that key genes and metabolites such as Cyp2c55, Cyp3a11, Cyp21a1, Myc, Gstm1, Gstm3, 9,10-dihydroxyoctadecenoic acid, 11-dehydrocorticosterone, and 12,13-dihydroxy-9Z-octadecenoic acid played crucial roles in these pathways. qPCR analysis validated the significant decreases in the hepatic gene expressions of Cyp2c55, Cyp3a11, Myc, Gstm1, and Gstm3 in the T2DM mice, which were reversed following SW033291 treatment. Meanwhile, the elevated mRNA level of Cyp21a1 in T2DM mice was decreased after SW033291 administration. Taken together, our findings suggest that SW033291 has promising potential in alleviating T2DM and could be a novel therapeutic candidate.

There is an increasing interest in the use of facial dermal filler injections, such as hyaluronic acid, for esthetic and rejuvenation purposes. However, their use is associated with a potential risk of complications. We report the case of a woman in her thirties, with rapidly evolving facial skin necrosis following accidental intravascular injection of hyaluronic acid and/or extravascular compression. The necrosis worsened despite early repeated local injections of hyaluronidase. However, rapid and favorable clinical evolution was observed after the patient was treated for seven consecutive days with intravenous infusion of dinoprostone (a prostaglandin E2).

Endometrosis in mares is a disease resulting from chronic inflammation characterized by peri glandular fibrosis. There is no effective treatment so far, which opens the door for exploring the use of stem cells as a candidate. Transforming growth factor beta (TGFβ) is crucial for the establishment and progression of fibrosis in mare's endometrosis. We aimed to develop regenerative approaches to treat endometrosis by using mesenchymal stem cells (MSC), for which understanding the effect of TGFβ on exogenous MSC is crucial. We isolated and characterized equine adipose MSC from six donors. Cells were pooled and exposed to 10 ng/ml of TGFβ for 0, 4, and 24 h, after which cells were analyzed for proliferation, migration, mesodermal differentiation, expression of fibrosis-related mRNAs, and prostaglandin E2 secretion. At 24 h of exposition to TGFβ, there was a progressive increase in the contraction of the monolayer, leading to nodular structures, while cell viability did not change. Exposure to TGFβ impaired adipogenic and osteogenic differentiation after 4 h of treatment, which was more marked at 24 h, represented by a decrease in Oil red and Alizarin red staining, as well as a significant drop (p < 0.05) in the expression of key gene regulators of differentiation processes (PPARG for adipose and RUNX2 for osteogenic differentiation). TGFβ increased chondrogenic differentiation as shown by the upsurge in size of the resulting 3D cell pellet and intensity of Alcian Blue staining, as well as the significant up-regulation of SOX9 expression (p < 0.05) at 4 h, which reached a maximum peak at 24 h (p < 0.01), indicative of up-regulation of glycosaminoglycan synthesis. Preconditioning MSC with TGFβ led to a significant increase (p < 0.05) in the expression of myofibroblast gene markers aSMA, COL1A1, and TGFβ at 24 h exposition time. In contrast, the expression of COL3A1 did not change with respect to the control but registered a significant downregulation compared to 4 h (p < 0.05). TGFβ also affected the expression of genes involved in PGE2 synthesis and function; COX2, PTGES, and the PGE2 receptor EP4 were all significantly upregulated early at 4 h (p < 0.05). Cells exposed to TGFβ showed a significant upregulation of PGE2 secretion at 4 h compared to untreated cells (p < 0.05); conversely, at 24 h, the PGE2 values decreased significantly compared to control cells (p < 0.05). Preconditioning MSC for 4 h led to an anti-fibrotic secretory phenotype, while a longer period (24 h) led to a pro-fibrotic one. It is tempting to propose a 4-h preconditioning of exogenous MSC with TGFβ to drive them towards an anti-fibrotic phenotype for cellular and cell-free therapies in fibrotic diseases such as endometrosis of mares.

The nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a cytosolic multi-subunit protein complex, and recent studies have demonstrated the vital role of the NLRP3 inflammasome in the pathological and physiological conditions, which cleaves gasdermin D to induce inflammatory cell death called pyroptosis and mediates the release of interleukin-1 beta and interleukin-18 in response to microbial infection or cellular injury. Over-activation of the NLRP3 inflammasome is associated with the pathogenesis of many disorders affecting bone and joints, including gouty arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, and periodontitis. Moreover, mesenchymal stem cells (MSCs) have been discovered to facilitate the inhibition of NLRP3 and maybe ideal for treating bone and joint diseases. In this review, we implicate the structure and activation of the NLRP3 inflammasome along with the detail on the involvement of NLRP3 inflammasome in bone and joint diseases pathology. In addition, we focused on MSCs and MSC-extracellular vesicles targeting NLRP3 inflammasomes in bone and joint diseases. Finally, the existing problems and future direction are also discussed.

To investigate the material basis, targets and molecular mechanism of Scutellariae Radix against periodontitis to provide theoretical basis for clinical applications.

The active compounds and targets of Scutellariae Radix were obtained from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database, and the periodontitis-related targets were collected by integrating Online Mendelian Inheritance in Man (OMIM), Therapeutic Target Database (TTD), Genecards and Gene Expression Omnibus (GEO) database together. The potential targets of Scutellariae Radix against periodontitis were obtained from the intersection of two target sets. Metascape database was used for Gene Ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Discovery Studio software was used for molecular docking between key targets and compounds to evaluate their binding affinity. Western blot was used to check the expression of PTGS2 and MMP9 to verify the regulatory effects of baicalein, the main active compound of Scutellariae Radix, on human periodontal ligament stem cells (hPDLSCs) cultured under inflammatory environment which induced by lipopolysaccharide (LPS).

15 active compounds of Scutellariae Radix and 53 common targets for periodontitis treatment were identified. Among these targets, the 10 core targets were AKT1, IL-6, TNF, VEGFA, TP53, PTGS2, CASP3, JUN, MMP9 and HIF1A. GO and KEGG analysis mainly focused on response to LPS and pathways in cancer. Molecular docking showed that the main active compounds had good binding affinity with key targets. Cell experiments confirmed that baicalein can interfere the expression of pro-inflammatory factors PTGS2 and MMP9 proteins and exert anti-inflammatory effects.

Current study preliminarily analyzed the mechanism of Scutellariae Radix against periodontitis, which provide a new idea for the utilization of Scutellariae Radix and the development of novel medicine for the clinical treatment of periodontitis.

Prostate cancer presents as an immunologically "cold" malignancy, characterized by a lack of response to immunotherapy in the majority of patients. The dysfunction of prostate tumor metabolism is recognized as a critical factor in immune evasion, resulting in reduced effectiveness of immunotherapeutic interventions. Despite this awareness, the precise molecular mechanisms underpinning metabolic dysregulation in prostate cancer and its intricate relationship with immune evasion remain incompletely elucidated. In this study, we introduce the multi-drug resistance protein ABCC4/MRP4 as a key player prominently expressed in prostate cancer, exerting a pivotal role in suppressing the activity of intratumoral CD8+ T cells. Depletion of ABCC4 in prostate cancer cells halts the release of prostaglandin E2 (PGE2), a molecule that diminishes the population of CD8+ T cells and curtails their cytotoxic capabilities. Conversely, constraining the activation of PGE2 signaling in CD8+ T cells effectively improved the efficacy of prostate cancer treatment with PD-1 blockade. During this process, downregulation of the JAK1-STAT3 pathway and depolarization of mitochondria emerge as crucial factors contributing to T cell anergy. Collectively, our research identifies the ABCC4-PGE2 axis as a promising target for reversing dysfunction within tumor-infiltrating lymphocytes (TILs) and augmenting the suboptimal responsiveness to immunotherapy in prostate cancer.

Senescence plays a key role in various physiological and pathological processes. We reported that injury-induced transient senescence correlates with heart regeneration, yet the multi-omics profile and molecular underpinnings of regenerative senescence remain obscure. Using proteomics and single-cell RNA sequencing, here we report the regenerative senescence multi-omic signature in the adult mouse heart and establish its role in neonatal heart regeneration and agrin-mediated cardiac repair in adult mice. We identified early growth response protein 1 (Egr1) as a regulator of regenerative senescence in both models. In the neonatal heart, Egr1 facilitates angiogenesis and cardiomyocyte proliferation. In adult hearts, agrin-induced senescence and repair require Egr1, activated by the integrin-FAK-ERK-Akt1 axis in cardiac fibroblasts. We also identified cathepsins as injury-induced senescence-associated secretory phenotype components that promote extracellular matrix degradation and potentially assist in reducing fibrosis. Altogether, we uncovered the molecular signature and functional benefits of regenerative senescence during heart regeneration, with Egr1 orchestrating the process.