Polygalae Radix has high pharmacological activity and has been widely used as a sedative and tranquilizer to increase cognitive function, prevent epilepsy, and treat respiratory diseases such as bronchitis. However, its role in delaying aging and decreasing oxidative stress and its main functional factors have not been thoroughly studied.

The purpose was to investigate the antiaging and antioxidant effects of aqueous Polygalae Radix extract (PRE) and its mechanism of action.

The effects of different concentrations (1, 5, and 10 mg/mL) of PRE on the lifespan, body length, reproductive ability, motility, lipofuscin, and reactive oxygen species (ROS) on a model of natural senescence of Caenorhabditis elegans were investigated. The effects of PRE treatment on the expression of body weight, malondialdehyde (MDA), glutathione peroxidase (GSH-PX), and mTERT content were evaluated in a D-galactose (Dgal)-induced mouse model of aging. Histopathological changes in the liver and brain of mice were analyzed by hematoxylin-eosin (HE). The enriched pathways associated with differentially expressed genes in the liver tissues of C. elegans and mice were analyzed via RNA-seq, and the results were verified via RT-qPCR, cell transfection and Western blotting. Abundance of and changes in the mouse intestinal flora were analyzed by 16S rDNA sequencing.

PRE significantly prolonged the average lifespan of C. elegans and improved the physiological indices related to senescence. In addition, PRE slowed the decrease in weight of senescent model mice; protected serum, liver and brain tissues from oxidative stress damage; increased GSH-PX expression; and reduced MDA expression. The role of PRE in the low- and middle-dose groups was similar to that of vitamin C (VC) in inhibiting oxidative stress, but the effect of PRE in the high-dose group was greater than that of VC. The RNA-seq results suggested that PRE might be related to PPARγ/MAPK, and the subsequent RT-qPCR and cell transfection results indicated that PRE decreased oxidative stress by downregulating the mRNA expression of the Fabp1, Acaa1b, Hmgcs1, Map3K5, and Rac2 genes. The Western blot results revealed that PRE decreased oxidative stress by increasing PPARγ expression and inhibiting p38 protein phosphorylation. 16S rDNA sequencing showed that PRE treatment increased the abundance of the intestinal flora in mice and inhibited the growth of pathogenic bacteria such as Helicobacter pylori and Desulfurization vibrio while promoting the growth of beneficial bacteria such as Bifidobacteria.

PRE delays aging and resists oxidative stress in organisms; it may act by regulating the PPARγ/MAPK signaling pathway and the intestinal flora. The efficacy and mechanism of PRE against oxidative stress were elucidated using RNA-seq and 16S rDNA sequencing, providing a reference for antiaging and aging-related diseases.

Osteoarthritis and rheumatoid arthritis are debilitating joint diseases marked by pain, inflammation and cartilage destruction. Current osteoarthritis treatments only relieve symptoms, while rheumatoid arthritis therapies can cause immune suppression and provide variable efficacy. Here we developed an optimized small interfering RNA targeting matrix metalloproteinase 13 for preferential delivery to arthritic joints. Chemical modifications in a stabilizing 'zipper' pattern improved RNA resistance to degradation, and two independent linkers with 18 ethylene glycol repeats connecting to tandem C18 lipids enhanced albumin binding and targeted delivery to inflamed joints following intravenous administration. In preclinical models of post-traumatic osteoarthritis and rheumatoid arthritis, a single intravenous injection of the albumin-binding small interfering RNA achieved long-term joint retention, sustained gene silencing and reduced matrix metalloproteinase 13 activity over 30 days, resulting in decreased cartilage erosion and improved clinical outcomes, including reduced joint swelling and pressure sensitivity. This approach demonstrated superior efficacy over corticosteroids and small-molecule MMP inhibitors, highlighting the therapeutic promise of albumin 'hitchhiking' for targeted, systemic delivery of gene-silencing therapeutics to treat osteoarthritis and rheumatoid arthritis.

Depression, often stress-induced, is closely related to neuroinflammation, in which microglia, the brain's immune cells, are the leading players. Microglia shift between a quiescent and an active state, promoting both pro- and anti-inflammatory responses. Cannabinoid type 2 (CB2) receptor encoded by the CNR2 gene is a key player to modulate inflammatory activity. CB2 receptor is highly controlled at the epigenetic level, especially in response to stressful stimuli, positioning it between stress, neuroinflammation, and depression. The following review addresses how epigenetic regulation of CNR2 expression affects depression and the dissection, further, of molecular pathways driving neuroinflammation-related depressive states. The present study emphasizes the therapeutic potential of CB2 receptor agonists that selectively interact with activated microglia and opens a new avenue for the treatment of depression associated with neuroinflammation. The review, therefore, provides a framework of underlying mechanisms for developing novel therapeutic strategies that focus on relieving symptoms by modulating the neuroinflammatory response. Finally, this review underlines the possibilities of therapeutic interventions taking into account CB2 receptors in combating depression.

Background/Objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic hepatic condition marked by lipid buildup, lipotoxicity, and inflammation. Prior research indicates that 3,3'-Diindolemethane (DIM), a natural indole-type phytochemical that is abundant in brassicaceae vegetables, has been reported to reduce body weight and improve lipid metabolism in mice subjected to a high-fat diet (HFD). The aryl hydrocarbon receptor (AhR), a nuclear receptor implicated in lipid metabolism and immune regulation, serves as a functional receptor for DIM. However, the underlying signaling pathways that regulate MAFLD remain elusive. Our objective is to ascertain the beneficial impact of DIM on MAFLD and the associated mechanisms. Methods: Hematoxylin and eosin staining, together with Oil Red O staining, were utilized to assess the pathological changes and lipid deposition in the liver. Biochemical analysis was employed to measure levels of triglyceride (TG), total cholesterol (TC), free fatty acid (FFA), aspartate transaminase (AST), alanine transaminase (ALT), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). The cell survival rate of HepG2 cells treated with palmitic acid (PA) and DIM was assessed using the CCK-8 assay. Flow cytometry was employed to measure the fluorescence intensity emitted by lipid droplets within cells. Western blotting analysis was performed to assess AhR pathway and fatty acid transporter expression levels in hepatic tissue. Results: Our results showed that DIM significantly attenuated body weight gain and hepatic injury brought on by HFD, decreased lipid droplet accumulation in HepG2 cells, and effectively suppressed the phosphorylation of p38 MAPK and the protein expression levels of fatty acid transporters CD36 and FATP4. Conclusions: DIM reduced lipid accumulation by activating AhR and suppressing p38 MAPK phosphorylation, thereby inhibiting fatty acid transport and inflammatory responses. These findings suggest that DIM may represent a promising therapeutic candidate for MAFLD, warranting further exploration for clinical applications.

This study aimed to assess the protective effects of Lagenaria siceraria seed oil (LSO) on fifty male Albino rats subjected to furan exposure. Furan (FU) is a small, heterocyclic compound present in the volatile fraction of various thermally processed foods and beverages. Rats were categorized into five groups, each comprising ten rats. Group 1 served as the control group, receiving corn oil. Group 2 received LSO (3 g/kg body weight orally) for 28 days. Rats in Group 3 (FU-exposed group) received an oral administration of FU at a dosage of 16 mg/kg body weight each day for 28 days. Rats in Group 4 (Therapeutic co-treated group) were administered both LSO and subsequent FU exposure according to the previously outlined dosage regimen for 28 days. Rats in Group 5 (Protective co-treated group) received LSO seed oil for 14 days as protection then received Fu at the same mentioned doses of Fu until the end of experiment. Rats administered FU and/or LSO gained noticeably more weight than the control group. LSO significantly decreased AST and LDH levels in both the protection and treatment groups as compared to the FU-only group. It also assisted in restoring testosterone and luteinizing hormone (LH) levels that were decreased by FU, especially in the protected group. LSO also reduced kidney damage markers and normalized biomarker levels when administered with FU. The LSO-only group demonstrated normal immune response markers, similar to the control group. By changing MDA levels and increasing SOD, GSH, and TAC levels, co-treatment with LSO enhanced liver health. The control and LSO groups displayed normal spleen structure, whereas the LSO/FU group had normal seminiferous tubules with mild edema and congestion. Overall, LSO demonstrated protective and therapeutic benefits against FU-induced damage in rats.

Cisplatin, a chemotherapeutic drug used to treat cancerous solid tumors, can result in ototoxicity due to serious toxic side effects resulting in irreversible hearing loss. Here, we investigated the effects of N6-methyladenosine (m6A) methylation on cisplatin-induced ototoxicity by using in vitro cochlear explants as a model system to explore the effect of the Methyltransferase-like 3 (METTL3) inhibitor STM2457 in ameliorating cisplatin-induced ototoxicity. STM2457 pretreatment was shown to significantly reduce reactive oxygen species (ROS) accumulation and the loss of hair cells (HCs) in different regions of the organ of Corti. STM2457 pretreatment led to significant reductions in TUNEL labeling, signifying a reduction in apoptosis. Additionally, expression of the apoptosis-related protein BAX was significantly decreased, while the ratio of BCL-XL was markedly increased. Transcriptomic measurements of the STM2457 + cisplatin group revealed significant enrichment of the Mitogen-Activated Protein Kinases (MAPK) signaling pathway, which when stimulated, could block the protective effect of STM2457 in cisplatin-treated HCs. Thus, we describe a mechanism by which STM2457 decreases cisplatin-related HC death in cochlear explants in vitro through activation of the MAPK pathway. This study reports for the first time that reducing RNA m6A methylation might protects against cisplatin-induced ototoxicity. Our data indicate that STM2457 can serve as an effect anti-apoptotic drug to decrease ototoxicity caused by cisplatin-induced ROS accumulation, effectively preventing cisplatin-induced hair cells loss.

Vascular dementia (VaD) is a heterogeneous group of brain disorders caused by cerebrovascular pathologies and the second most common cause of dementia, accounting for over 20% of cases and posing an important global health concern. VaD can be caused by cerebral infarction or injury in critical brain regions, including the speech area of the dominant hemisphere or arcuate fasciculus of the dominant hemisphere, leading to notable cognitive impairment. Although the exact causes of dementia remain multifactorial and complex, oxidative stress (reactive oxygen species), neuroinflammation (TNFα, IL-6, and IL-1β), and inflammasomes are considered central mechanisms in its pathology. These conditions contribute to neuronal damage, synaptic dysfunction, and cognitive decline. Thus, antioxidants and anti-inflammatory agents have emerged as potential therapeutic targets in dementia. Recent studies emphasize that cerebrovascular disease plays a dual role: first, as a primary cause of cognitive impairment and then as a contributor to the manifestation of dementia driven by other factors, such as Alzheimer's disease and other neurodegenerative conditions. This comprehensive review of VaD focuses on molecular mechanisms and their consequences. We provided up-to-date knowledge about epidemiology, pathophysiological mechanisms, and current therapeutic approaches for VaD.

Macrophages are pivotal immune cells involved in maintaining immune homeostasis and defending against pathogens. They exhibit significant plasticity and heterogeneity, enabling polarization into pro-inflammatory M1 or anti-inflammatory M2 phenotypes in response to distinct microenvironmental cues. The process of macrophage polarization is tightly regulated by complex signaling pathways and transcriptional networks. This review explores the factors influencing macrophage polarization, the associated signaling pathways, and their roles in the pathogenesis of lung diseases, including fibrosis, cancer, and chronic inflammatory conditions. By summarizing recent advances, we aim to provide insights into the immunoregulatory functions of macrophages and their therapeutic potential. Based on our review, it is believed that targeting macrophage polarization emerges as a promising approach for developing effective treatments for lung diseases, balancing inflammation and repair while mitigating disease progression.

Glioma cells exhibit high invasiveness and have the ability to evade surgical resection, radiotherapy, and chemotherapy, which are major factors contributing to the challenges in effective treatment and recurrence. The ubiquitin-proteasome system (UPS) plays a crucial role in posttranslational modification, significantly contributing to the aggressive progression of glioblastoma (GBM). This study identified the E3 ubiquitin ligase CBLB as a crucial and abnormally regulated component of the UPS in GBM, noting its significant downregulation compared to normal brain tissue and its negative correlation with malignant phenotypes and poor prognosis. Experimental studies, both in vitro and in vivo, have shown that CBLB can inhibit the migration and invasion of GBM cells. Mechanistically, CBLB directly interacts with MAP3K9 through its RING domain, leading to K48-K63-linked polyubiquitination at the Lys 193 site, thereby promoting MAP3K9 proteasomal-mediated degradation. MAP3K9 downregulation suppresses MAPK-P38 pathway activation. This study identifies CBLB as a tumor suppressor that modulates the MAPK-P38 signaling pathway by promoting the polyubiquitination and degradation of MAP3K9, offering a new therapeutic approach for GBM treatment.

Kidney clear cell carcinoma (KIRC) is a prevalent urological cancer. Despite substantial improvements in KIRC care, patients with intermediate and advanced stages of the disease lack access to appropriate medications. Doxorubicin is widely used as a chemotherapy drug for the treatment of multiple types of cancer. However, its use is associated with harmful side effects and drug resistance. ErbB3-binding protein (EBP1) is highly expressed in KIRC, and the knockdown of EBP1 reduces the phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and the expression of HIF-1α. Therefore, the present study aimed to evaluate the effectiveness of combined doxorubicin administration and EBP1 knockdown in KIRC cell lines. The KIRC cell lines 786-O and 769-P were used for the experiments, and short hairpin RNA technology was employed to specifically knock down the expression of the EBP1 gene. After treatment, cells were analyzed by western blotting to detect changes in p38MAPK phosphorylation levels and HIF-1α expression. The results showed that EBP1 knockdown significantly enhanced the antitumor effect of doxorubicin on KIRC cells through the p38MAPK/HIF-1α pathway. In conclusion, the knockdown of EBP1 in combination with doxorubicin may be a potential strategy for the treatment of KIRC.

Periodontitis, when exacerbated by diabetes, is characterized by increased M1 macrophage polarization and decreased M2 polarization. O-linked β-N-acetylglucosamine (O-GlcNAcylation), catalyzed by O-GlcNAc transferase (OGT), promotes inflammatory responses in diabetic periodontitis (DP). Additionally, p38 mitogen-activated protein kinase regulates macrophage polarization. However, the interplay between OGT, macrophage polarization, and p38 signaling in the progression of DP remains unexplored.

To investigate the effect of OGT on macrophage polarization in DP and its role in mediating O-GlcNAcylation of p38.

For in vivo experiments, mice were divided into four groups: Control, DP model, model + short hairpin (sh) RNA-negative control, and model + sh-OGT. Diabetes was induced by streptozotocin, followed by ligation and lipopolysaccharide (LPS) administration to induce periodontitis. The impact of OGT was assessed by injecting sh-OGT lentivirus. Maxillary bone destruction was evaluated using micro-computed tomography analysis and tartrate-resistant acid phosphatase staining, while macrophage polarization was determined through quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry. For in vitro experiments, RAW264.7 cells were treated with LPS and high glucose (HG) (25 mmol/L D-glucose) to establish a cell model of DP. OGT was inhibited by OGT inhibitor (OSMI4) treatment and knocked down by sh-OGT transfection. M1/M2 polarization was analyzed using qPCR, immunofluorescence, and flow cytometry. Levels of O-GlcNAcylation were measured using immunoprecipitation and western blotting.

Our results demonstrated that M1 macrophage polarization led to maxillary bone loss in DP mice, associated with elevated O-GlcNAcylation and OGT levels. Knockdown of OGT promoted the shift from M1 to M2 macrophage polarization in both mouse periodontal tissues and LPS + HG-induced RAW264.7 cells. Furthermore, LPS + HG enhanced the O-GlcNAcylation of p38 in RAW264.7 cells. OGT interacted with p38 to promote its O-GlcNAcylation at residues A28, T241, and T347, as well as its phosphorylation at residue Y221.

Inhibition of OGT-mediated p38 O-GlcNAcylation deactivates the p38 pathway by suppressing its self-phosphorylation, thereby promoting M1 to M2 macrophage polarization and mitigating DP. These findings suggested that modulating macrophage polarization through regulation of O-GlcNAcylation may represent a novel therapeutic strategy for treating DP.

The mammalian p38 MAPK pathway plays a vital role in transducing extracellular environmental stresses into numerous intracellular biological processes. The p38 MAPK have been linked to a variety of cellular processes including inflammation, cell cycle, apoptosis, development and tumorigenesis in specific cell types. The p38 MAPK pathway has been implicated in the development of many human diseases and become a target for treatment of cancer. Although MAPK p38 pathway has been extensively studied, many questions still await clarification. More comprehensive understanding of the MAPK p38 pathway will provide new possibilities for the treatment of human diseases. Hog1 in S. cerevisiae is the conserved homolog of p38 in mammalian cells and the HOG MAPK signaling pathway in S. cerevisiae has been extensively studied. The deep understanding of HOG MAPK signaling pathway will help provide clues for clarifying the p38 signaling pathway, thereby furthering our understanding of the relationship between p38 and disease. In this review, we elaborate the functions of p38 and the relationship between p38 and human disease. while also analyzing how Hog1 regulates cellular processes in response to environmental stresses. 1, p38 in response to various stresses in mammalian cells.2, The functions of mammalian p38 in human health.3, Hog1 as conserved homolog of p38 in response to environmental stresses in Saccharomyces cerevisiae. 1, p38 in response to various stresses in mammalian cells. 2, The functions of mammalian p38 in human health. 3, Hog1 as conserved homolog of p38 in response to environmental stresses in S. cerevisiae.

Pyroptosis is closely associated with chemotherapeutic drugs and immune response. Here, we investigated whether oxaliplatin, a key drug in FOLFOX-hepatic artery infusion chemotherapy (FOLFOX-HAIC), induces pyroptosis in hepatoma cells and enhances antitumor immunity after tumor cell death.

Hepatoma cells were treated with oxaliplatin. Pyroptosis and immunoreactivity were evaluated in vitro and in vivo.

Oxaliplatin activated caspase-3-mediated gasdermin E (GSDME) cleavage and induced pyroptosis in Hep G2 and SK-Hep-1 cells in vitro. Liver cancer cells with high levels of GSDME expression are prone to pyroptosis. Bioinformatic analysis revealed that pyrolysis-related genes are closely related to immunity. In vivo experiments revealed that oxaliplatin exhibited superior antitumor efficacy in mice with normal immune function and more pronounced inhibitory effect on hepatocellular carcinoma with high GSDME levels. Higher levels of cytokines and greater CD8+ T cell infiltration were observed in tumor tissues with better efficacy. Furthermore, an in vitro coculture assay confirmed that oxaliplatin-induced pyroptosis in Hep G2 cells overexpressing GSDME and activated the p38/MAPK signaling pathway to improve the cytotoxicity of CD8+ T cells. Analysis of clinical samples of HCC suggested that the efficacy of FOLFOX-HAIC in patients with high GSDME expression was better than that in patients with low GSDME expression.

Oxaliplatin induced pyroptosis in hepatoma cells by activating caspase-3-mediated cleavage of GSDME, which enhanced the cytotoxicity of CD8+ T cells by regulating the p38/MAPK signaling pathway. These results suggest that GSDME level may be used as a marker to predict the efficacy of FOLFOX-HAIC.

Gaucher disease is a lysosomal storage disease due to deficiency of glucocerebrosidase, leading to the accumulation of glucosylceramide, particularly in macrophages. In addition to storage, secondary abnormalities such as inflammation, cellular stress, and impaired autophagy may contribute to the disease pathogenesis. The onset and course of progression of these secondary abnormalities remains unclear. Owing to the increasingly widespread newborn screening programs, diagnosis can be made at a presymptomatic stage. Understanding the early natural course of the disease is important for optimal monitoring and management of such at-risk individuals.The aim of our study is to investigate secondary abnormalities in very young children with type 1 Gaucher disease identified through neonatal screening.

We enrolled five children (<4 years old) with type I Gaucher disease in a presymptomatic stage and not receiving therapy. We assessed plasma cytokine profiles (TNFα, IL1β, and IL6 by ELISA), activation of pro-inflammatory p38 mitogen-activated protein kinase (MAPK) and the abundance of LC3-II as indicator of autophagic flux, by immunoblotting.

All subjects exhibited elevated TNFα (mean 21.74 μmol/L, SD 37.48, range 2.37-88.72 μmol/L). The other cytokines analyzed were within normal range. Cellular stress (activation of p38) was present in the child with higher glucosylsphingosine (GluSph) accumulation. Additionally, all subjects showed a significant reduction in LC3-II (mean 88 %, SD 9 %, range 77-98 %), indicating reduced autophagic flux.

We have identified the presence of inflammation with inhibition of autophagic flux in presymptomatic young children with a genetically confirmed high-risk of developing Gaucher disease. These findings contribute insights into the early course of Gaucher disease and support the management of at-risk individuals identified by newborn screening. Therapeutic interventions including specific enzyme replacement or other means to address inflammation or autophagy could delay or prevent the onset of symptomatic disease and consequential disability. Further clinical studies are warranted to explore these possibilities.

Isoliquiritigenin (ISL), a phenolic compound derived from licorice, exhibits various biological activities, including anti-inflammatory, anti-viral, anti-tumor, and antioxidant effects. However, the molecular mechanisms underlying its anti-cancer effects are not well understood in SK-MEL-28 melanoma cells. Melanoma, a highly aggressive and treatment-resistant cancer, remains a significant health challenge. This study investigates the anti-cancer effects of ISL, focusing on identifying reactive oxygen species (ROS)-mediated apoptosis mechanisms on SK-MEL-28 melanoma cells. Our results show that ISL treatment induces apoptosis in SK-MEL-28 cells, as evidenced by the cleavage of caspase-9, -7, -3, and PARP. ISL increased Bax expression, decreased Bcl-2 expression, and promoted cytochrome C release into the cytosol. ISL also reduced the expression of cell cycle markers, including cyclin D1, D3, and survivin. Notably, ISL treatment markedly increased intracellular ROS levels and pretreatment with N-acetyl cysteine, a ROS scavenger, abrogated the ISL-induced inhibition of the p38/mTOR/STAT3 pathway and prevented apoptosis. Moreover, ISL significantly diminished the constitutive phosphorylation of mTOR and STAT3 in SK-MEL-28 cells by blocking the phosphorylation of p38 MAPK, an upstream kinase of mTOR. Pharmacological inhibition of mTOR attenuated the STAT3 signaling, indicating that mTOR acts as an upstream kinase of STAT3 in these cells. Collectively, these findings demonstrate that ISL inhibits SK-MEL-28 cell growth by downregulating cell survival proteins and inducing apoptosis through ROS generation.

Growth arrest and DNA damage-inducible 45 (GADD45) proteins are critical stress sensors rapidly induced in response to genotoxic/physiological stress and regulate many cellular functions. Even though the primary function of the proteins is to block the cell cycle, inhibit cell proliferation, promote cell apoptosis, and repair DNA damage to cope with the damage caused by internal and external stress on the body, evidence has shown that GADD45 also has the function to modulate innate and adaptive immunity and plays a broader role in inflammatory and autoimmune diseases. In this review, we focus on the immunomodulatory role of GADD45 in inflammatory and autoimmune diseases. First, we describe the regulatory factors that affect the expression of GADD45. Then, we introduce its immunoregulatory roles on immune cells and the critical signaling pathways mediated by GADD45. Finally, we discuss its immunomodulatory effects in various inflammatory and autoimmune diseases.

To investigate the role and mechanism of MAPK14/AIFM2 pathway in Ang II-induced atrial fibrillation in rats.

A rat model of AF was established for in vivo experiments and HL-1 cells were treated with Ang II to develop an in vitro model. In addition, HL1 cells overexpressing AIFM2 (oeAIFM2) were constructed. SB203580 was used to inhibit the expression of MAPK14. The role of MAPK14 in Ang II-AF model was investigated by in vivo electrophysiological examination and molecular biology tests. The role of MAPK14 / AIFM2 pathway on AF induced by Ang II was explored in vitro.

MAPK14 and AIFM2 were significantly up-regulated in AF induced by Ang II (all P < 0.05). In vivo experiments indicated that inhibition of MAPK14 down-regulated AIFM2, improved atrial electrical conduction, AF inducibility and durations, and alleviated the structural and functional damage of heart and mitochondria (all P < 0.05). Both in vivo and in vitro tests showed that the MAPK14/AIFM2 pathway prevented Ang II-induced AF via regulating mitophagy-dependent apoptosis.

Inhibition of the MAPK14/AIFM2 pathway improved Ang II-induced AF by inhibiting mitophagy-dependent apoptosis.

Acute kidney injury (AKI) is a common critical clinical disease that is linked to significant morbidity, recurrence, and mortality. It is characterized by a fast and prolonged loss in renal function arising from numerous etiologies and pathogenic pathways. Renal fibrosis, defined as the excessive accumulation of collagen and proliferation of fibroblasts within renal tissues, contributes to the structural damage and functional decline of the kidneys, playing a pivotal role in the advancement of Chronic Kidney Disease (CKD). Until now, while continuous renal replacement therapy (CRRT) has been utilized in the management of severe AKI, there remains a dearth of effective targeted therapies for AKI stemming from diverse etiologies. Similarly, the identification of specific biomarkers and pharmacological targets for the treatment of renal fibrosis remains a challenge. Baicalin, a naturally occurring compound classified within the flavonoid group and commonly found in the Chinese herb Scutellaria baicalensis, has shown a range of pharmacological characteristics, such as antioxidant, anti-inflammatory, antifibrotic, antitumor and antiviral effects, as evidenced by research studies. Research shows that Baicalin has potential in treating kidney diseases like AKI and renal fibrosis. This review aims to summarize Baicalin's progress in these areas, including its molecular mechanism, application in treatment, and absorption, distribution, metabolism, and excretion. Baicalin's therapeutic effects are achieved through various pathways, including antioxidant, anti-inflammatory, antifibrosis, and regulation of apoptosis and cell proliferation. Besides, we also hope this review may give some enlightenment for treating AKI and renal fibrosis in clinical practice.

Introduction: Solar dermatitis, a condition triggered by excessive exposure to ultraviolet B (UVB) radiation, results in inflammatory skin damage marked by erythema, edema, and epidermal injury. Portulaca oleracea (PO) and Patrinia scabiosaefolia (PS) have been traditionally used in dermatological treatments, though their mechanistic pathways in UVB-induced skin injury are not fully understood. Methods: In this study, a mouse model of UVB-induced solar dermatitis was employed to evaluate the therapeutic potential of combined PO and PS (POPS) extracts. After UVB irradiation, POPS extracts were administered, and their bioactive compounds were identified through ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Network pharmacology, molecular docking, and pathway analysis were performed to identify key targets, focusing on the IL-17/CCL2 pathway and oxidative stress reduction. Results: Treatment with POPS extracts significantly diminished UVB-induced inflammation, erythema, and epidermal thickening in a dose-dependent manner. Network pharmacology and docking studies identified curvularin and olmesartan medoxomil as bioactive components with high affinity for IL-17 and IL-17RA targets, modulating the IL-17/CCL2 axis. In vivo experiments demonstrated that POPS extracts suppressed the expression of IL-17 and CCL2, reduced macrophage infiltration, and alleviated oxidative stress, effectively mitigating the symptoms of solar dermatitis. Conclusion: This study provides insight into the anti-inflammatory and protective properties of POPS extracts in solar dermatitis, highlighting their potential as a treatment through IL-17/CCL2 pathway modulation and oxidative stress reduction.

Neuroinflammation and neuronal cell death are leading causes of death in the elderly and underlie various neurodegenerative diseases. These diseases involve complex pathophysiological mechanisms, including inflammatory responses, oxidative stress, and ferroptosis. Compounds derived from deep-sea fungi exhibit low toxicity and potent neuroprotective effects, offering a promising source for drug development. In this study, we isolated 44 natural products from deep-sea-derived fungi and identified isobisvertinol (17) as a compound with anti-inflammatory and ferroptosis-inhibiting effects. Using LPS-induced microglial inflammation and RSL3-induced neuronal ferroptosis models, we found that 17 targets TLR4 to provide neuroprotection. Molecular docking studies revealed that 17 inhibits TLR4 activation by occupying the hydrophobic pocket at the TLR4-MD2 binding site. Additionally, 17 suppresses TLR4, reducing p38 MAPK phosphorylation, and inhibits ferroptosis by decreasing lipid peroxidation and modulating mitochondrial membrane potential. Metabolomic analysis showed that 17 rescues alterations in multiple metabolic pathways induced by RSL3 and increases levels of antioxidant metabolites, including glutamine, glutamate, and glutathione. In summary, our results indicate that isobisvertinol (17) targets TLR4 in neural cells to reduce inflammation and inhibit p38 MAPK phosphorylation, while regulating metabolic pathways, mainly GSH synthesis, to provide antioxidant effects and prevent ferroptosis in neurons.

Obesity-related chronic kidney disease (CKD) poses a significant risk to individuals' health and wellbeing, but the pathological mechanisms and treatment strategies are currently limited. Trans-cinnamic acid (CA) is a key active monomer found in cinnamon bark and is known for its diverse pharmacological activities. However, its effect on obesity-related renal injury remains unknown. In the current study, the in vitro and in vivo experiments were combined to investigate the beneficial effect of CA on renal injury induced by HFD or PA. We found that CA significantly reduced the obesity of zebrafish body and the accumulation of fat in kidney tissues. The histopathological changes and dysfunction induced by HFD were effectively mitigated by CA administration, as evidenced by the detection of Hematoxylin-Eosin straining, NAG activity, creatinine level, and expression of functional-related genes, respectively. Additionally, the in vitro and in vivo findings demonstrated that CA dramatically reduced the oxidative stress, inflammatory, and apoptosis in HFD-induced kidney tissues or PA-treated HEK293T and HK-2 cells. Finally, the results regarding ERK, JNK, and P38 proteins phosphorylation confirmed that CA may alleviate HFD-induced renal injury by inhibiting the phosphorylation of ERK, JNK, and P38 MAPK proteins. This theory was further supported by the results of co-treatment with anisomycin (a JNK activator) or lipopolysaccharide and CA in HEK293T cells. This study proves that CA alleviates the obesity-related CKD probably through inhibition of MAPK signaling pathway.

Lipids are the key component of all membranes composed of a variety of molecules that transduce intracellular signaling and provide energy to the cells in the absence of nutrients. Alteration in lipid metabolism is a major factor for cancer heterogeneity and a newly identified cancer hallmark. Reprogramming of lipid metabolism affects the diverse cancer phenotypes, especially epithelial-mesenchymal transition (EMT). EMT activation is considered to be an essential step for tumor metastasis, which exhibits a crucial role in the biological processes including development, wound healing, and stem cell maintenance, and has been widely reported to contribute pathologically to cancer progression. Altered lipid metabolism triggers EMT and activates multiple EMT-associated oncogenic pathways. Although the role of lipid metabolism-induced EMT in tumorigenesis is an attractive field of research, there are still significant gaps in understanding the underlying mechanisms and the precise contributions of this interplay. Further study is needed to clarify the specific molecular mechanisms driving the crosstalk between lipid metabolism and EMT, as well as to determine the potential therapeutic implications. The increased dependency of tumor cells on lipid metabolism represents a novel therapeutic target, and targeting altered lipid metabolism holds promise as a strategy to suppress EMT and ultimately inhibit metastasis.

This study compared the toxicological effects of environmentally relevant microplastics (MPs) on the marine rotifer Brachionus plicatilis, focusing on MPs derived from various sources, including fossil fuel-based low-density polyethylene, bio-based polylactic acid (PLA), biodegradable poly(butylene adipate-co-terephthalate), and a novel PLA modified with β-cyclodextrin. We assessed in vivo effects such as reproductive output and mortality, alongside in vitro oxidative stress responses, including oxidative stress, antioxidant enzyme activities, and activation of the mitogen-activated protein kinase (MAPK) signaling pathway and the multixenobiotic resistance (MXR) system. Reproductive output and lifespan reduced significantly across all MP types, ranging from 0.5 to 10 mg L-1, indicating compromised reproductive fitness and life maintenance. At an environmentally relevant concentration of 0.5 mg L-1, in vitro assessments revealed differential modulation of reactive oxygen species levels and antioxidant enzyme activities, contingent upon the specific MP type. Moreover, MAPK signaling pathway and MXR assays showed changes in phosphorylation and detoxification proteins depending on the type of MPs. This study highlights the ecological risks that various MPs, including bio-based, biodegradable, and petrochemical-based MPs, could pose in marine environments.

The benefits of sleep extend beyond the nervous system. Peripheral tissues impact sleep regulation, and increased sleep is observed in response to damaging conditions, even those that selectively affect non-neuronal cells. However, the 'sleep need' signal released by stressed tissues is not known. Sleep in the nematode C. elegans is independent of circadian cues and can be triggered rapidly by damaging conditions. This stress-induced sleep is mediated by neurons that require the Epidermal Growth Factor Receptor (EGFR) for their sleep-promoting function, but the only known C. elegans EGFR ligand, LIN-3, is not required for sleep. Here we describe SISS-1 (stress-induced sleepless), an EGF family ligand that is required for stress-induced sleep. We show that SISS-1 overexpression induces sleep in an EGFR-dependent, sleep neuron-dependent manner. We find that SISS-1 undergoes stress-responsive shedding by the ADM-4/ADAM17 metalloprotease, and that the ADM-4 site of action depends on the tissue specificity of the stressor. Our findings support a model in which SISS-1 is released from damaged tissues to activate EGFR in sleep neurons, identifying a molecular link between cellular stress and organismal sleep drive. Our data also point to a mechanism insulating this sleep signal from EGFR-mediated signaling during development.

Cell death and related signaling pathways are essential during development and in various physiological and pathological conditions. Post-translational modifications such as ubiquitination and phosphorylation play an important role in these signaling pathways. The involvement of kinases - enzymes that catalyze protein phosphorylation - in cell death signaling has been extensively studied. On the other hand, not many studies have been devoted to analyzing the role in cell death of phosphatases, enzymes involved in the removal of phosphorylated residues added to proteins by kinases. Obviously, the two opposite reactions, phosphorylation and dephosphorylation, are equally important in the regulation of protein functions and subsequently in the execution of the cell death program. Here, we have summarized recent work on the involvement of serine-threonine PP2C phosphatases in cell death pathways, senescence and autophagy, focusing in particular on the most studied phosphatase PPM1D (PP2Cδ) as an example of the regulatory role of PP2Cs in cell death. The review should help to draw attention to the importance of PP2C family phosphatases in cell death checkpoints and to discover new targets for drug development.

Rhizoma Dioscoreae Bulbiferae (HYZ) is a widely utilized herb in clinical practice, known for its significant biological activities. However, the associated hepatotoxicity poses limitations to its application. Our previous research indicated that the effective mitigation of HYZ-induced hepatotoxicity through the concoction with Radix Paeoniae Alba medicinal juice involves the incorporation of paeoniflorin (Pae) and a reduction in diosbulbin B (DB), the primary toxic compound in HYZ. This finding suggests that the introduced Pae may exert a direct attenuating effect on DB. In light of this, this study represents the first investigation into Pae's detoxification effect against DB-induced hepatotoxicity after administration for 2 months in mice vivo while also exploring underlying mechanisms related to inflammation and ferroptosis based on network pharmacology results. Our findings demonstrate that Pae significantly alleviates DB-induced hepatotoxicity in a dose-dependent manner. Western blotting and ELISA analyses revealed that Pae effectively reversed elevated levels of hepatic inflammation-related markers-such as NF-κB, p38 MAPK, NLRP3, TNF-α, and IL-1β-as well as excessively high concentrations of ferroptosis-related MDA and Fe2+. Furthermore, it restored low levels of GSH, SOD, GPX4, and FTH1. In summary, introduced Pae substantially mitigated DB-induced hepatotoxicity by inhibiting both hepatocyte inflammation and ferroptosis.

The p38 mitogen-activated protein kinase (MAPK) pathway is pivotal in regulating inflammatory responses and has emerged as a key target for the development of small-molecule inhibitors aimed at treating inflammatory diseases. In arthritis, especially rheumatoid arthritis (RA), the p38 MAPK pathway contributes to chronic inflammation and joint destruction by promoting the production of pro-inflammatory cytokines. Preclinical studies have shown that small-molecule inhibitors targeting the p38 MAPK pathway hold significant promise, exhibiting the potential to reduce inflammation and preserve joint integrity. Targeting this pathway presents a novel therapeutic approach to mitigating inflammation. This review traces the evolution of p38 MAP kinase inhibitors from initial laboratory studies to clinical candidates, underscoring their potential to significantly alter the treatment approach for inflammatory diseases.

The heterogeneity of hepatocellular carcinoma (HCC) is linked to tumor malignancy and poor prognosis. Nevertheless, the precise mechanisms underlying the development of the cholangiocellular phenotype (CCA) within HCC remain unclear. Emerging studies support that the cross-talk among the host cells within tumor microenvironment (TME) sustains the cancer cell plasticity.

This study sought to identify the specific cell types involved in the formation of CCA and to elucidate their functional roles in the progression of HCC.

Single-cell RNA sequencing was employed to identify the specific cell types involved in the formation of CCA. Both in vitro and vivo analyses were used to identify the tumor-associated senescent ECs and investigate the function in TME. The diethylnitrosamine-induced model was utilized to investigate the interaction between senescent ECs and MSCs, aiming to elucidate their synergistic contributions to the progression of CCA.

Using single-cell RNA sequencing, we identified a distinct senescent-associated subset of endothelial cells (ECs), namely CD34+CLDN5+ ECs, which mainly enriched in tumor tissue. Further, the senescent ECs were observed to secrete IGF2, which recruited mesenchymal stem cells (MSCs) into the TME through IGF2R/MAPK signaling. In primary liver cancer model, MSCs exhibited a strong tumor-promoting effect, increasing the CCA and tumor malignancy after HCC formation. Interestingly, knockdown of IGF2R expression in MSCs inhibited the increase of CCA caused by MSCs in HCC. Meanwhile, it was revealed that MSCs released multiple inflammatory and trophic-related cytokines to enhance the cancer stem cell-like characteristics in HCC cells. Finally, we demonstrated that CEBPβ up-regulated IGF2 expression in tumor senescent ECs by combining with Igf2-promtor-sequence.

Together, our findings illustrated that tumor associated senescent ECs in HCC recruited the MSCs into TME, enhancing cancer stem cell (CSC)-like features of HCC cells and contributing to the CCA formation.

HBP-A is the main active component of a traditional Chinese medicine Huaizhen Yanggan Capsule, for the remarkable treatment of knee osteoarthritis (KOA). This study aimed to elucidate the ameliorative effect of HBP-A on meniscus hypertrophy and mineralisation in KOA and the molecular mechanism of its action. An Hartley guinea pig model of KOA that underwent anterior cruciate ligament transection (ACLT) and a model of rat primary meniscus fibrochondrocytes (PMFs) were used to investigate the ameliorative effect of HBP-A on meniscal hypertrophy and calcification and its signal transduction mechanism of action. The results show that Guinea pig's meniscus width, as well as the area of meniscus calcification and meniscus and articular cartilage injury score, were significantly reduced in the HBP-A intervention group compared to the ACLT group. The expression levels of mtrix metalloproteinase 13 (MMP13), runt-related transcription factor 2 (Runx2), Indian hedgehog (Ihh), alkaline phosphatase (ALP), and ankylosis homologue (ANKH) at the protein and gene level significantly decreased in the HBP-A intervention group compared to the ACLT group. In vitro study, apoptosis, hypertrophy, and calcification of rat PMFs after 10% stretch force were significantly improved with HBP-A intervention. Western blot and RT-qPCR showed that hypertrophy, calcification, and p38 MAPK signalling pathway-related markers of PMFs were incredibly depressed in the HBP-A intervention group compared to the 10% stretch force group. In conclusion, HBP-A can slow down meniscus hypertrophy and mineralisation induced by abnormal mechanical loading, and its mechanism of action may be through the p38-MAPK signalling pathway.

Activation of the p38 mitogen-activated protein kinase (MAPK) pathways is vital in regulating cell growth, differentiation, apoptosis, and stress response, significantly affecting tumorigenesis and cancer progression. We developed a bioinformatic technique to construct an interactome network-based molecular pathways for genes of interest and quantify their activation levels using high-throughput gene expression data. This study is focused on the p38α, p38β, p38γ, and p38δ kinases, examining their activation levels (PALs) based on transcriptomic data and their associations with survival and drug responsiveness across various cancer types. We analyzed 11,287 human tumor profiles from 31 cancer types and 53 datasets to assess patient survival and clinical response to 29 therapies. Activation of p38 pathways showed varying prognostic significance depending on the cancer type. In astrocytoma, glioblastoma, thymoma, renal, bladder, esophageal, colorectal, stomach cancers, and lung squamous cell carcinoma, p38 pathway activation correlated with poor survival. Conversely, it indicated better survival in the gender-associated tumors (HER2+, luminal A and B subtypes of breast cancer, prostate carcinoma), sarcomas, lung adenocarcinoma, and others. These trends are aligned with the response-to-therapy analysis. For instance, higher activation of the p38β and p38γ pathways was linked to positive responses to taxane and anthracycline therapies in breast cancer, while lower activation of the p38α and p38β pathways correlated with better responses to 5-fluorouracil-based treatments in colorectal cancer. However, associations with individual MAPK14, MAPK11, MAPK12, and MAPK13 gene expression levels were less robust. Hence, the p38 pathway activation levels could serve as potential biomarkers for predicting clinical outcomes and personalizing treatment strategies, including use of the selective p38 MAPK inhibitors.

Particulate matter (PM) is an environmental pollutant that negatively affects human health, particularly skin health. In this study, we investigated the inhibitory effects of broccoli sprout extract (BSE) on PM-induced skin aging and inflammation in human keratinocytes.

HaCaT keratinocytes were pretreated with BSE before exposure to PM. Cell viability was assessed using the MTT assay. The expression of skin aging and inflammation markers (MMP-1, COX-2, IL-6) was measured using Western blot, ELISA, and qRT-PCR. Reactive oxygen species levels were determined using the DCF-DA assay. Kinase assays and pull-down assays were conducted to investigate the interaction between BSE and p38α MAPK.

Our findings demonstrate that BSE effectively suppressed the expression of MMP-1, COX-2, and IL-6-critical skin aging and inflammation markers-by inhibiting p38 MAPK activity. BSE binds directly to p38α without competing with ATP, thereby selectively inhibiting its activity and downstream signaling pathways, including MSK1/2, AP-1, and NF-κB.

These results suggest that BSE is a potential functional ingredient in skincare products to mitigate PM-induced skin damage.

The global incidence of frozen shoulder (FS) (2% ~ 5%) and osteoporosis (OP) is high (9.1%-12.1%). Clinically, postmenopausal women are particularly at risk for both diseases. The main objective of this current research is to investigate the pathogenesis mechanism of FS and explore the connection between FS and OP.

We obtained FS and OP datasets from GEO and identified crosstalk genes. Following KEGG and GO enrich analysis, the p38 MAPK signaling pathway was focused and the specific p38α inhibitor TAK715 was screened out. We conducted flow cytometry, western blot, and PCR analyses to assess the treatment effect of TAK715 on FS synovium fibroblasts at different concentrations. Additionally, we employed SD rats to validate the treatment effects of TAK715 in vivo.

TAK715 was useful in reversing fibrosis at the concentration of 1 μM, 5 μM and 10 μM. The unbalanced apoptosis process in frozen shoulder cell and the activation of osteoclast were inhibited at the concentration of 5 μM by TAK715. Then we successfully established a FS and OP rat model, with the FS with OP rat displaying less range of motion (ROM) and thicker shoulder capsule. In FS rat that was treated with TAK715, the frozen shoulder side was corrected in ROM and bone loss.

The frozen shoulder with osteoporosis may exhibit more severe symptoms, and TAK715 is effective in protecting fibrosis and osteoporosis both in vitro and vivo. The therapy to correct FS and OP simultaneously by TAK715 provides novel approach in FS treatment and study.

This study aimed to investigate serum metabolomic biomarkers associated with incident type 2 diabetes mellitus (T2DM) and evaluate their performance in improving T2DM risk prediction.

Untargeted proton nuclear magnetic resonance (1H NMR) spectroscopy-based metabolomics analyses were conducted in the Multi-Ethnic Study of Atherosclerosis (MESA; n=3460; discovery cohort) and Rotterdam Study (RS; n=1556; replication cohort). Multivariable cause-specific hazards models were used to analyze the associations between 23,571 serum metabolomic spectral variables and incident T2DM. Replicated metabolites required an FDR-adjusted P<0.01 in MESA, P<0.05 in RS, and consistent direction of association. Pathway and network analyses were conducted to elucidate biological mechanisms underlying T2DM development. Utility of the replicated metabolites in improving T2DM risk prediction was assessed based on the Framingham Diabetes Risk Score. A 2-sample Mendelian randomization was conducted to assess causal associations.

Nineteen metabolites were significantly associated with incident T2DM. Pathway analyses revealed disturbances in aminoacyl-tRNA biosynthesis, metabolism of branched-chain amino acids (BCAAs), glycolysis/gluconeogenesis, and glycerolipid metabolism. Network analyses identified interactions with upstream regulators including p38 MAPK, c-JNK, and mTOR signaling pathways. Adding replicated metabolites to the Framingham Diabetes Risk Score showed modest to moderate improvements in prediction performance in MESA and RS, with Δ c-statistic of 0.05 (95% CI, 0.04-0.07) in MESA and 0.03 (95% CI, 0.01-0.05) in RS. Genetically increased BCAAs and mannose were associated with T2DM.

1H NMR measured metabolites involved in aminoacyl-tRNA biosynthesis, BCAA metabolism, glycolysis/gluconeogenesis, and glycerolipid metabolism were significantly associated with incident T2DM and provided modest to moderate predictive utility beyond traditional risk factors.

SMARCB1 encodes a core subunit of the SWI/SNF chromatin remodeling complex, which plays a crucial role in the regulation of gene expression. Germline mutations in the SMARCB1 gene have been linked to early childhood Coffin-Siris syndrome type 3 (CSS3), a rare congenital malformation syndrome characterized by severe developmental delay and intellectual disability. In this study, we report a family of two adult CSS3 patients with a novel missense SMARCB1 mutation (c.1091A>C, p.Lys364Thr) identified through whole-exome sequencing (WES). Both patients exhibit selective difficulties in verbal learning and experience language delays. Additionally, the development of meningioma is confirmed in one of the patients. Mechanistic studies suggest that this missense mutation may abnormally activate the MAPK signaling pathway, which is implicated in the pathogenesis of tumor progression and neurodevelopmental disorders. This is the first reported case of a germline mutation in the SMARCB1 gene associated with both CSS3 and meningioma, thereby expanding the phenotypic spectrum of SMARCB1-related disorders.

Lung cancer, a common type of malignant neoplasm, has seen significant advancements in the treatment of lung adenocarcinoma (LUAD). However, the management of lung squamous cell carcinoma (LSCC) continues to pose challenges. Traditional treatment methods for LSCC encompass surgical resection, chemotherapy, and radiotherapy. The introduction of targeted therapy and immunotherapy has greatly benefited LSCC patients, but issues such as limited immune response rates and adverse reactions persist. Therefore, gaining a deeper comprehension of the underlying mechanisms holds immense importance. This review provides an in-depth overview of classical signaling pathways and therapeutic targets, including the PI3K signaling pathway, CDK4/6 pathway, FGFR1 pathway and EGFR pathway. Additionally, we delve into alternative signaling pathways and potential targets that could offer new therapeutic avenues for LSCC. Lastly, we summarize the latest advancements in targeted therapy combined with immune checkpoint blockade (ICB) therapy for LSCC and discuss the prospects and challenges in this field.