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The ocular surface and orbit constitute unique microenvironments in the human body. Current advances in molecular research have deepened our understanding of tumor development in these regions. Tumors exhibit greater heterogeneity compared to normal tissues, as revealed by pathological and histological examinations. The tumor microenvironment (TME) plays a crucial role in the proliferation and progression of cancer cells. Factors from the external environment or the body's own inflammation and microcirculation interact within the TME, maintaining a delicate balance. Disruption of this balance, through uncontrolled signal pathway activation, can transform normal or benign tissues into malignant ones. In recent years, various systemic immunotherapies have been developed for cancer treatment. This study reviews the epidemiology of ocular surface and orbital tumors include squamous cell carcinoma, basal cell carcinoma, sebaceous carcinoma and lymphoma in conjunction with their occurrence, growth, and underlying mechanisms. We propose that by examining clinical histopathological images, we can identify specific and shared microscopic features of tumors. By collecting, classifying, and analyzing data from these clinical histopathological images, we can pinpoint independent diagnostic factors characteristic of tumors. We hope this study provides a basis for future exploration of the mechanisms underlying different ocular diseases. [ABSTRACT FROM AUTHOR]

Background: The clinical outcomes of drug treatments and surgical interventions for chronic sinusitis with nasal polyps (CRSwNPs) are suboptimal, and the high recurrence rate remains a significant challenge in clinical practice. Targeted therapies such as biologics provide new perspectives and directions for treating CRSwNP. Summary: With the continuous investigation of signaling pathways, RAS/RAF/MEK/ERK signaling pathway and other signaling pathways including Hippo, JAK-STAT, Wnt, TGF-β, PI3K, Notch, and NF-κB were confirmed to play an important role in the progression of CRSwNP. Among them, the abnormality of RAS/RAF/MEK/ERK signaling pathway is accompanied by the abnormality of this apoptotic component, which may provide new research directions for targeting the components of signaling pathways to mediate apoptosis. Key Messages: Abnormalities in signaling pathways are particularly important in studying the pathogenesis and treatment of CRSwNP. Therefore, this review summarizes the ongoing investigation and characterization of RAS/RAF/MEK/ERK signaling pathway and other signaling pathways in CRSwNP, which provides constructive ideas and directions for improving the treatment of CRSwNP. [ABSTRACT FROM AUTHOR]

Lactate has a novel function different from previously known functions despite its traditional association with hypoxia in skeletal muscle. It plays various direct and indirect physiological functions. It is a vital energy source within the central nervous system (CNS) and a signal transmitter regulating crucial processes, such as angiogenesis and inflammation. Activating lactate and its associated receptors elicits effects like synaptic plasticity and angiogenesis alterations. These effects can significantly influence the astrocyte-neuron lactate shuttle, potentially impacting cognitive performance. Decreased cognitive function relates to different neurodegenerative conditions, including Alzheimer's disease (AD), ischemic brain injury, and frontotemporal dementia. Therefore, lactic acid has significant potential for treating neurodegenerative disorders. Exercise is a method that induces the production of lactic acid, which is similar to the effect of lactate injections. It is a harmless and natural way to achieve comparable results. Animal experiments demonstrate that high-intensity intermittent exercise can increase vascular endothelial growth factor (VEGF) levels, thus promoting angiogenesis. In vivo, lactate receptor-hydroxycarboxylic acid receptor 1 (HCAR1) activation can occur by various stimuli, including variations in ion concentrations, cyclic adenosine monophosphate (cAMP) level elevations, and fluctuations in the availability of energy substrates. While several articles have been published on the benefits of physical activity on developing Alzheimer's disease in the CNS, could lactic acid act as a bridge? Understanding how HCAR1 responds to these signals and initiates associated pathways remains incomplete. This review comprehensively analyzes lactate-induced signaling pathways, investigating their influence on neuroinflammation, neurodegeneration, and cognitive decline. Consequently, this study describes the unique role of lactate in the progression of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Silique development exerts significant impacts on crop yield. CRPs (Cysteine-rich peptides) can mediate cell–cell communication during plant reproduction and development. However, the functional characterization and regulatory mechanisms of CRPs in silique development remain unclear. In this study, we identified many CRP genes downstream of the CRP gene TPD1 (TAPETUM DETERMINANT1) during silique development using a microarray assay. The novel Arabidopsis thaliana pollen-borne CRPs, the PCP-Bs (for pollen coat protein B-class) gene AtPCP-Ba, along with TPD1, are essential for silique development. The AtPCP-Ba was significantly down-regulated in tpd1 flower buds but up-regulated in OE-TPD1 flower buds and siliques. The silencing of AtPCP-Ba compromised the wider silique of OE-TPD1 plants and inhibited the morphology of OE-TPD1 siliques to the size observed in the wild type. A total of 258 CRPs were identified with the bioinformatic analysis in Arabidopsis, Brassica napus, Glycine max, Oryza sativa, Sorghum bicolor, and Zea mays. Based on the evolutionary tree classification, all CRP members can be categorized into five subgroups. Notably, 107 CRP genes were predicted to exhibit abundant expression in flowers and fruits. Most cysteine-rich peptides exhibited high expression levels in Arabidopsis and Brassica napus. These findings suggested the involvement of the CRP AtPCP-Ba in the TPD1 signaling pathway, thereby regulating silique development in Arabidopsis. [ABSTRACT FROM AUTHOR]

Objective: To investigate the molecular mechanism of extracellular long chain non coding RNA (lncRNA) TTN-AS1 mediated miR-524-5p through transforming growth factor β(TGFβ/Smads signaling pathway, then to regulate the breast cancer progression. Firstly, real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) was used to detect the expressions of lncRNA TTN-AS1 and miR-524-5p in human breast cancer cell MDA-MB-231, MCF-7, SKBR-3 and breast epithelial cell MCF-10A, Western blot was to detect TGF β1 and p-Smad2 proteins expression. Then, cell transfection technology was used to inhibit expression of lncRNA TTN-AS1, lncRNA TTN-AS1, miR-524-5p, TGFβ 1 and p-Smad2 expressions were compared between MDA-MB-231 (negative control) and transfection group. CCK8 method was to detect cell proliferation, flow cytometry was to detect cell apoptosis rate, and Transwell chamber was to detect cell migration. Compared with MCF-10A, the expression levels of lncRNA TTN-AS1 in MDA-MB-231, MCF-7, SKBR-3 were significantly higher, while miR-524-5p were significantly less, TGFβ 1 and p-Smad2 were upregulated (P<0.05). Results: Compared with the negative control group, the expressions of lncRNA TTN-AS1 in the transfection group was significantly lower, while miR-524-5p was significantly more, resulting in TGF β1 and p-Smad2 were downregulated (P<0.05). The cell proliferation rate and the number of migrating cells were significantly less, while the apoptosis rate was higher (P<0.05). Conclusion: lncRNA TTN-AS1 may play a cancer promoting role in the progression of breast cancer by inhibiting the expression of miR-524-5p and activating TGF β1/Smad2 signaling pathway, which is involved in regulating the proliferation and apoptosis of breast cancer. LncRNA TTN-AS1 is expected to become a new molecular site targeting breast cancer intervention. [ABSTRACT FROM AUTHOR]

The mechanism of bone malformation caused by osteoblast disorder is the pathological basis of common diseases related to bone metabolism in clinic. Studies have shown that Wnt/β-catenin (Wnt/β-catenin), phospholipacylol-3-kinase/protein kinase B(PI3K/AKT), nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1), adenylate activated protein kinase (AMPK), silence-message regulatory factor 6/nuclear transcription factor-κB (SIRT6/NF-κB), and other signaling pathways have the ability to regulate osteoblasts and to maintain bone homeostasis. As a first-line hypoglycemic drug, metformin not only has the ability to control blood glucose, but also plays an important role in regulating the proliferation and differentiation of osteoblasts. In this paper, by summarizing the research status of the above signaling pathways and metformin intervention, we aim to provide new ideas for osteoblast-related studies, and to provide theoretical reference and basis for improving bone formation and promoting bone homeostasis. [ABSTRACT FROM AUTHOR]

AIM: To investigate the involvement of pericyte-Müller glia interaction in retinal damage repair and assess the influence of suppressing the platelet-derived growth factor receptor β (PDGFRβ) signaling pathway in retinal pericytes on photoreceptor loss and Müller glial response. METHODS: Sprague-Dawley rats were exposed to intense light to induce retinal injury. Neutralizing antibody against PDGFRβ were deployed to block the signaling pathway in retinal pericytes through intravitreal injection. Retinal histology and Müller glial reaction were assessed following light injury. In vitro, normal and PDGFRβ-blocked retinal pericytes were cocultured with Müller cell line (rMC-1) to examine morphological and protein expression changes upon supplementation with light-injured supernatants of homogenized retinas (SHRs). RESULTS: PDGFRβ blockage 24h prior to intense light exposure resulted in a significant exacerbation of photoreceptor loss. The upregulation of GFAP and p-STAT3, observed after intense light exposure, was significantly inhibited in the PDGFRβ blockage group. Further upregulation of cytokines monocyte chemoattractant protein 1 (MCP-1) and interleukin-1β (IL-1β) was also observed following PDGFRβ inhibition. In the in vitro coculture system, the addition of light-injured SHRs induced pericyte deformation and upregulation of proliferating cell nuclear antigen (PCNA) expression, while Müller cells exhibited neuron-like morphology and expressed Nestin. However, PDGFRβ blockage in retinal pericytes abolished these cellular responses to light-induced damage, consistent with the in vivo PDGFRβ blockage findings. CONCLUSION: Pericyte-Müller glia interaction plays a potential role in the endogenous repair process of retinal injury. Impairment of this interaction exacerbates photoreceptor degeneration in light-induced retinal injury.

BACKGROUND: It has also been confirmed that ferroptosis is closely related to a variety of musculoskeletal diseases, such as rheumatoid arthritis, osteosarcoma, and osteoporosis. The pathophysiological mechanisms of ferroptosis and osteoporosis need to be further studied and elucidated to broaden our understanding of iron metabolism and osteoporosis. It will provide research ideas for the future elucidation of new mechanisms of osteoporosis and the development of new technologies and drugs for the treatment of osteoporosis. OBJECTIVE: To provide an overview of the current status of research on ferroptosis in osteoporosis, to provide a new direction for future research on the specific molecular mechanisms of osteoporosis, and to provide more effective and better options for osteoporosis treatment strategies. METHODS: The first author used the computer to search the literature published from 2000 to 2024 in CNKI, WanFang, VIP, and PubMed databases with search terms “ferroptosis, iron metabolism, osteoporosis, osteoblast, osteoclast, bone metabolism, signal pathway, musculoskeletal, review” in Chinese and English. A total of 68 articles were finally included according to the selection criteria. RESULTS AND CONCLUSION: (1) Ferroptosis is a new type of cell death discovered in recent years, which is usually accompanied by a large amount of iron accumulation and lipid peroxidation during cell death, and its occurrence is iron-dependent. This is distinctly different from several types of cell death that are currently being hotly studied (e.g., cellular pyroptosis, necrotic apoptosis, cuproptosis, and autophagy). (2) Intracellular iron homeostasis is manifested as a balance between iron uptake, export, utilization, and storage. The body’s iron regulatory system includes systemic and intracellular regulation. The main factor of systemic regulation is hepcidin produced by hepatic secretion, and cellular regulation depends on the iron regulatory protein/iron response element system. Of course, intracellular iron homeostasis can be controlled by other factors, such as hypoxia, cytokines, and hormones. (3) Lipid peroxidation causes oxidative damage to biological membranes (plasma membrane and internal organelle membranes), lipoproteins, and other lipid-containing molecules. Polyunsaturated fatty acid-containing phospholipids are important targets of lipid peroxidation. Free polyunsaturated fatty acid is an important substrate for lipid oxidation and can bind to the phospholipid bilayer, leading to over-oxidation and thus triggering lipid apoptosis. (4) Several studies have shown that osteoblasts are overloaded with iron in different ways, resulting in the accumulation of unstable ferrous iron and the generation of reactive oxygen species and lipid peroxides, causing ferroptosis of osteoblasts and ultimately a decrease in bone formation, affecting bone homeostasis and the development of osteoporosis. (5) Osteoclasts are large multinucleated cells formed by the fusion of mononuclear macrophage cell lines or bone marrow mesenchymal stem cells induced by nuclear factor-κB ligand receptor activator, and they have the function of bone resorption. Iron ions can promote osteoclast differentiation and bone resorption through the production of intracellular lipid reactive oxygen species, while iron chelators can inhibit osteoclast formation in vitro and thus affect the occurrence and development of osteoporosis. [ABSTRACT FROM AUTHOR]

forkhead box protein C1(FOXC1) is a cancer-related transcription factor that plays an important role in various signaling pathways related to cancer development.FOXC1 is involved in the regulation of cancer cells from many aspects, including proliferation, metastasis and recurrence.FOXC1 can promote cell cycle progression and cell proliferation by up-regulating the expression of oncogenes, such as cyclin D1.FOXC1 promotes epithelial-mesenchymal transition (EMT), in which cells change from polarized epithelial cells to cells with stromal characteristics, which contributes to tumor cell infiltration and migration.FOXC1 may play a role in tumor angiogenesis by regulating genes associated with angiogenesis.FOXCI can enhance cell migration and invasion by regulating reactive oxygen species and activating β-catenin expression.In summary, FOXC1 functions through a variety of mechanisms.

Anthracycline drugs mainly include doxorubicin, epirubicin, pirarubicin, and aclamycin, which are widely used to treat a variety of malignant tumors, such as breast cancer, gastrointestinal tumors, lymphoma, etc. With the accumulation of anthracycline drugs in the body, they can induce serious heart damage, limiting their clinical application. The mechanism by which anthracycline drugs cause cardiotoxicity is not yet clear. This review provides an overview of the different types of cardiac damage induced by anthracycline-class drugs and delves into the molecular mechanisms behind these injuries. Cardiac damage primarily involves alterations in myocardial cell function and pathological cell death, encompassing mitochondrial dysfunction, topoisomerase inhibition, disruptions in iron ion metabolism, myofibril degradation, and oxidative stress. Mechanisms of uptake and transport in anthracycline-induced cardiotoxicity are emphasized, as well as the role and breakthroughs of iPSC in cardiotoxicity studies. Selected novel cardioprotective therapies and mechanisms are updated. Mechanisms and protective strategies associated with anthracycline cardiotoxicity in animal experiments are examined, and the definition of drug damage in humans and animal models is discussed. Understanding these molecular mechanisms is of paramount importance in mitigating anthracycline-induced cardiac toxicity and guiding the development of safer approaches in cancer treatment. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of Peiminine on cartilage damage in knee osteoarthritis (KOA) rats by regulating the Ras homologous gene family, member A (RhoA)/Rho associated coiled coil-forming kinase (ROCK) signaling pathway. Methods A KOA rat model was prepared using the sodium iodoacetate (MIA) method and randomly grouped into a model group, a Peiminine (3.5mg/kg) group, and a Peiminine (3.5mg/kg)+LPA (RhoA activator, 1mg/kg) group, with 10 rats in each group, another 10 rats were selected as control group. Mechanical stimulation and thermal radiation methods were applied to detect knee joint pain symptoms in rats; the joint swelling degree and knee joint width of rats were measured, and their joint function was evaluated using gait scores; transmission electron microscopy was applied to detect the ultrastructure of knee joint chondrocytes in rats; TUNEL staining was applied to detect the apoptosis ratio of articular chondrocytes; enzyme-linked immunosorbent assay (ELISA) was applied to detect the levels of pro-inflammatory factors such as interleukin-18 (IL-18) and monocyte chemotactic protein-1 (MCP-1) in rat serum and joint fluid; immunoblotting was applied to detect apoptosis (Cleaved caspase-3, Bax) and the expression of RhoA/ROCK pathway related proteins in the articular cartilage tissue of rats. Results Peiminine decreased joint swelling, knee joint width, gait score, chondrocyte apoptosis ratio, serum and joint fluid IL-18, MCP-1 levels, and cartilage Cleaved caspase-3, Bax, RhoA, ROCK1, ROCK1 protein expression in KOA rats, and increased mechanical pain threshold and heat pain threshold (P<0.05); LPA could weaken the amelioration effect of Peiminine on articular cartilage injury in KOA rats..Conclusion Peiminine can inhibit joint inflammation and apoptosis of articular chondrocytes in KOA rats by inhibiting RhoA/ROCK signal activation, and alleviate cartilage injury. [ABSTRACT FROM AUTHOR]

forkhead box protein CI (FOXCI) is a cancer-related transcription factor that plays an important role in various signaling pathways related to cancer development. FOXCI is involved in the regulation of cancer cells from many aspects, including proliferation, metastasis and recurrence. FOXCI can promote cell cycle progression and cell proliferation by up-regulating the expression of oncogenes, such as cyclin D1.FOXCI promotes epithelial-mesenchymal transition (EMT), in which cells change from polarized epithelial cells to cells with stromal characteristics, which contributes to tumor cell infiltration and migration. FOXCI may play a role in tumor angiogenesis by regulating genes associated with angiogenesis. FOXCI can enhance cell migration and invasion by regulating reactive oxygen species and activating B-catenin expression. In summary, FOXC1 functions through a variety of mechanisms. [ABSTRACT FROM AUTHOR]

The study aimed to obtain the material basis and mechanism of Guiqi Yimu decoction to prevent and treat the deficiency of both qi and blood in cattle. The experiment screened out the effective active ingredients and corresponding targets of Guiqi Yimu decoction through the traditional Chinese medicine systems pharmacology (TCMSP) database. The durg-disease intersection targets were obtained through network pharmacology analysis. The targets protein interaction network was established and core targets and main active ingredients were screened out based the degree values. The GO function and KEGG signal pathway enrichment analysis of core targets were carried out and the top 10 signal pathways were obtained. The Cytoscape 3.8.2 software was used to establish the main active ingredients-core targets-top 10 signal pathway network of Guiqi Yimu decoction. The Autodock 1.5.7 software was used to conduct molecular docking between active ingredients and core targets. The results showed that 11 main ingredients of Guiqi Yimu decotion and 16 core targets were screened out. Through GO functional analysis, a total of 117 GO items were obtained, and through KEGG signaling pathway enrichment analysis, a total of 92 signaling pathways were obtained. In the network of the main active ingredient-core targe-top 10 signaling pathway, the average number of adjacent nodes was 5.78, and the network centrality was 0.18. The molecular docking energies of the main active ingredients and the core targetswere all less than -7 kcal/mol. The results indicated that the Guiqi Yimu decoction had a good material basis and mechanism of action with multiple effective active ingredients, targets, and pathways in preventing and treating the deficiency of qi and blood in cattle. [ABSTRACT FROM AUTHOR]

To explore the efftects of dexmedetomidine on autophagy in myocardial tissues of myocardial ischemia-reperfusion rats and NAD dependent deacetylase (SIRT1)/rapamycin target protein (mTOR) pathway proteins. 45 SPF grade male SD rats of 8 weeks old (mean weight 220 g) were randomly divided into sham-surgery group, model group, and dexmedetomidine group, with 15 rats in each group; the model group and dexmedetomidine group were used to replicate myocardial ischemia-reperfusion model. The dexmedetomidine group was infused with dexmedetomidine hydrochloride injection before modeling, while the other two groups were infused with equal amount of physiological saline. Serum myocardial injury markers creatine kinase isoenzyme (CK-MB) and troponin I (cTnI), inflammatory factors interleukin-6 (IL-6), and tumor necrosis factor - α (TNF-α) were detected before and 24 hours after reperfusion; after euthanizing rats, TTC staining was used to calculate the percentage of myocardial infarction area. qRT-PCR and Western blot were used to detect autophagy related proteins microtubule associated protein 1A/1B light chain 3 (LC3) II/I, beclin-1, and P62 proteins, SIRT1 and mTOR, too. CK-MB, cTnI, IL-6, and TNF-α levels in the model group and dexmedetomidine group before reperfusion were significantly higher than sham-surgery group, and the dexmedetomidine group was lower than model group (P<0.05); CK-MB, cTnI, IL-6, and TNF-α levels in the model group after reperfusion were higher than before reperfusion, while the dexmedetomidine group was lower than before reperfusion, what's more, the dexmedetomidine group was significantly lower than model group (P<0.05). The percentage of myocardial infarction area, expression levels of LC3 II/I, beclin-1 and P62 proteins, SIRT1 and mTOR in the model group and dexmedetomidine group were higher than those in the sham-surgery group, but the dexmedetomidine group was significantly lower than the model group (P<0.05). Myocardial ischemia-reperfusion may furtherly increase myocardial injury and inflammatory response. Pretreatment with dexmedetomidine can partially alleviate myocardial injury, inflammatory response, myocardial infarction, and autophagy, which may be related to the inhibition of SIRT1/mTOR signaling [ABSTRACT FROM AUTHOR]

To analyze the effect of tanshinone inhibiting oxidative stress and myocardial injury in patients with coronary heart disease through nuclear factor E2 related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway. A prospective study was conducted on 84 patients with unstable angina pectoris diagnosis in our hospital from June 2022 to June 2023. They were randomly divided into control group and observation group, with 42 patients in each group. The control group received conventional drugs and intervention, while the observation group received tanshinone IIA sulfonate sodium injection (40 mg/d) on the basis of control group for 2 weeks continuous treatment. Comparisons of peripheral blood Nrf2, ARE, and hypoxia inducible factor-1α (HIF-1α) and Caspase-1 proteins expression, oxidative stress indicators such as reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD), inflammatory mediators tumor necrosis factor (TNF)-α and interleukin (IL)-1β, myocardial injury indicators troponin I (cTnI) and creatine kinase isoenzyme (CK-MB) were made between two groups before and after treatment. There were no differences of above indicators between the two groups before treatment (P>0.05). After treatment, there were significant improvements compared to before treatment (P<0.05), and the expressions of Nrf2 and ARE proteins in observation group were significantly higher than those in control group, while HIF-1α and Caspase-1 proteins expression were significantly lower than control group, ROS level was less, MDA and SOD levels were higher, TNF-α and IL-1β levels were less, cTnI and CK-MB levels were lower, too (P<0.05). Tanshinone may inhibit oxidative stress, inflammatory response, cell apoptosis, and myocardial injury in patients with coronary heart disease by activating Nrf2/ARE signaling pathway. [ABSTRACT FROM AUTHOR]

Resveratrol (RES) has a variety of pharmacological activities. Resveratrol is a natural plant antitoxin polyphenol, which mainly mediates FoxO3a protein and NF- κB/RANKL signal through Sirt1 protein. Wnt/ β-catenin, PI3K/AKT, MAPK signal pathway, estrogen receptor, AMPK and oxidative stress affect osteoblast differentiation, inhibit osteoclast formation, improve bone joint tissue structure and bone loss, improve osteoporosis and protect bone health. Resveratrol increases bone growth and reduces bone loss in the elderly and postmenopausal people. It may be a new potential drug for the treatment of osteoporosis in the future. In this paper, CNKI, Chinese Medical Journal full-text Database, WANFANG DATE, PubMed and Web of Science databases were used to search the literature reports on the prevention and treatment of OP by RES in the last 10 years, and the mechanism of RES in preventing and treating OP was reviewed in many aspects, in order to provide new ideas and directions for the clinical application of resveratrol in the future. [ABSTRACT FROM AUTHOR]

Natural plants contain numerous chemical compounds that are beneficial to human health. The berries from the Lycium genus are widely consumed and are highly nutritious. Moreover, their chemical constituents have attracted attention for their health-promoting properties. In East Asia, there are three varieties of the Lycium genus (Lycium barbarum L., Lycium chinense Miller, and L. ruthenicum Murray) that possess medicinal value and are commonly used for treating chronic diseases and improving metabolic disorders. These varieties are locally referred to as "red Goji berries" or "black Goji berries" due to their distinct colors, and they differ in their chemical compositions, primarily in terms of carotenoid and anthocyanin content. The pharmacological functions of these berries include anti-aging, antioxidant, anti-inflammatory, and anti-exercise fatigue effects. This review aims to analyze previous and recent studies on the active ingredients and pharmacological activities of these Lycium varieties, elucidating their signaling pathways and assessing their impact on the gut microbiota. Furthermore, the potential prospects for using these active ingredients in the treatment of COVID-19 are evaluated. This review explores the potential targets of these Lycium varieties in the treatment of relevant diseases, highlighting their potential value in drug development. [ABSTRACT FROM AUTHOR]

Objective We systematically analyze the changes in the count and function of platelet at the early sepsis based on clinical study and single cell sequencing. Methods Clinical data of sepsis patients at the early stage were collected and had been compared between different prognostic groups in the prospective case⁃control study. The independent risk factors of death were analyzed by logistic regression, and the predictive efficacy of clinical indicators was evaluated by receiver operating characteristic （ROC） curve. The healthy volunteers and sepsis patients were recruited. Clinical researchers collected peripheral venous blood samples for sorting cell samples to carry out single⁃cell RNA sequencing （sc⁃RNA seq）. Through bioinformatics techniques, we analyzed the changes in platelet count， the significantly differential⁃expressed genes and its enriched functional signaling pathways in the early stages of sepsis. Results （1） A total of 224 patients were enrolled, with a 90 day survival rate of 70.5%. Compared with the survival group, the count of platelet and MAP in the death group at the early stage of sepsis were significantly lower, but the plasma lactate content and SOFA score were significantly higher.（2） Based on single cell sequencing technology, cells are annotated as six groups. The proportion of innate immune cells （neutrophils， monocytes， and dendritic cells） was significantly increased in the early stage of sepsis compared to the healthy volunteers （2.15∶1）， while platelets significantly decreased （0.31∶1）.（3） Through bioinformatics technology, CD41/ CD42a/CD61 was identified as platelet specific molecules, with significantly increased expression levels in sepsis. Three molecules can distinguish platelets together.（4）771 genes were significantly upregulated and 1101 genes were significantly downregulated in platelets of patients with sepsis, including core molecules involved in physiological functions such as cell adhesion, chemotaxis, and immune response. Functional analysis suggests that differentially expressed genes are enriched in coagulation, immune functions and cell death, participating in oxidative phosphorylation, leukocyte chemotaxis， iron death, and NOD like receptor signaling pathways. Conclusion Reduced platelet count is associated with poor prognosis in the early stage of sepsis. The specific high expression molecules CD41/ CD42a/CD61 that are significantly upregulated in platelets can serve as biomarkers for platelets. Platelets not only mediate cell adhesion and coagulation cascade， but also participate in functional changes such as immune cell chemotaxis, inflammatory response, and the pathological death of inflammatory cells. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has recently emerged as a key strategy for cancer treatment. TREM2, a key target for regulating the tumor immune microenvironment, is important in cancer treatment and progression. TREM2 is an immune signaling hub that regulates multiple pathological pathways. It not only suppresses anti-tumor immune responses by inhibiting T cell-mediated immune responses, but it also influences tumorigenesis by affecting NK cell-mediated antitumor immunity. Noticeably, TREM2 expression levels also vary significantly among different tumor cells, and it can regulate tumor progression by modulating various signaling pathways. Above all, by summarizing the role of TREM2 in cancer immunotherapy and the mechanism by which TREM2 regulates tumor progression, this paper clarifies TREM2's role in both tumor progression and cancer therapy, identifying a new therapeutic target for oncology diseases. [ABSTRACT FROM AUTHOR]

Myelination enables electrical impulses to propagate on axons at the highest speed, encoding essential life functions. The Rho family GTPases, RAC1 and CDC42, have been shown to critically regulate Schwann cell myelination. P21-activated kinase 2 (PAK2) is an effector of RAC1/CDC42, but its specific role in myelination remains undetermined. We produced a Schwann cell-specific knockout mouse of Pak2 (scPak2 −/−) to evaluate PAK2's role in myelination. Deletion of Pak2 , specifically in mouse Schwann cells, resulted in severe hypomyelination, slowed nerve conduction velocity and behaviour dysfunctions in the scPak2 −/− peripheral nerve. Many Schwann cells in scPak2 −/− sciatic nerves were arrested at the stage of axonal sorting. These abnormalities were rescued by reintroducing Pak2 , but not the kinase-dead mutation of Pak2 , via lentivirus delivery to scPak2 −/− Schwann cells in vivo. Moreover, ablation of Pak2 in Schwann cells blocked the promyelinating effect driven by neuregulin-1, prion protein and inactivated RAC1/CDC42. Conversely, the ablation of Pak2 in neurons exhibited no phenotype. Such PAK2 activity can also be either enhanced or inhibited by different myelin lipids. We have identified a novel promyelinating factor, PAK2, that acts as a critical convergence point for multiple promyelinating signalling pathways. The promyelination by PAK2 is Schwann cell-autonomous. Myelin lipids, identified as inhibitors or activators of PAK2, may be utilized to develop therapies for repairing abnormal myelin in peripheral neuropathies. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD), as a neurologically implemented disease with complex etiological factors, has a complex and variable pathogenesis. Accompanying further research, neuroinflammation has been found to be one of the possible factors in its pathogenesis. Microglia, as intrinsic immune cells in the brain, play an important role in maintaining microenvironmental homeostasis in the brain. However, over-activation of neurotoxic microglia in PD promotes neuroinflammation, which further increases dopaminergic (DA) neuronal damage and exacerbates the disease process. Therefore, targeting and regulating the functional state of microglia is expected to be a potential avenue for PD treatment. In addition, plant extracts have shown great potential in the treatment of neurodegenerative disorders due to their abundant resources, mild effects, and the presence of multiple active ingredients. However, it is worth noting that some natural products have certain toxic side effects, so it is necessary to pay attention to distinguish medicinal ingredients and usage and dosage when using to avoid aggravating the progression of diseases. In this review, the roles of microglia with different functional states in PD and the related pathways inducing microglia to transform into neuroprotective states are described. At the same time, it is discussed that abscisic acid (ABA) may regulate the polarization of microglia by targeting them, promote their transformation into neuroprotective state, reduce the neuroinflammatory response in PD, and provide a new idea for the treatment of PD and the selection of drugs. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect and mechanism of musk-containing serum on the migration of bone marrow mesenchymal stem cells (BMSCs). Methods Sixty SD rats were randomly divided into four groups: musk-high-, medium and low-dose groups and blank control group; medicated serum was prepared. Fifteen SD rats were isolated and cultured with BMSCs, and the third generation of BMSCs were identified by morphology, phenotype, osteogenic and adipogenic induction. BMSCs received medicinal healing intervention with high-, medium- and low- (16.8, 8.4, and 4.2 µL/100 g) musk, and the cell proliferation rate was detected by MTT assay. Under the intervention of the protein kinase C (PKC) signaling pathway (GF109203X), the effect of musk with pharmacition on the migration of BMSCSs was detected with the Transwell test. Results The rat BMSCs were attached to the wall, with orderly arrangement and good cell viability. Phenotypic identification revealed that the expressions of CD44 and CD90 were positive, while the expressions of CD45 and CD34 were negative, and the cells could differentiate into osteoblasts and adipocytes. The proliferation rates of BMSCSs with different concentrations at different time periods were higher than those in the blank control group (P<0.05). The number of BMSCs in the low-concentration musk group (4.2 µL/100 g) was significantly increased at 24 h, 48 h and 72 h after the addition of the blocking agent GF109203X (P<0.05). The migration quantity of the low-concentration musk group + blocker group (GF109203X) significantly decreased at different time periods, and there was no significant difference between different time groups (P>0.05). Conclusion The mechanism of musk-containing serum in promoting BMSCs migration may be related to the activation of PKC signaling pathway. [ABSTRACT FROM AUTHOR]

To explore the protective effect of exogenous adiponectin on neurological function of Alzheimer's disease mice by affecting nucleotide-binding oligomerization domain receptor/nuclear factor-kappa B/tumor necrosis factor signal pathway. 60 healthy male mice with C57BL/6J were divided into 5 groups; control (group A) (n=12), sham operation (group B) (n=12), model (group C) (n=12) and high (group D) and low dose adiponectin groups (group E) (n=12). Normal saline was given to the group A, B, C, D and E group, once a day. Adiponectin high and low dose group was given adiponectin (10 mg/kg and 2.5 mg/kg) intragastric administration. The Morris water maze test of mice in each group was analyzed, the expressions of nucleotide-binding oligomerization domain 2, nuclear factor-kappa B, toll-like receptor-4, tumor necrosis factor-alpha and interleukin-1 beta in each group were compared, and the expressions of caspase-3, c-caspase-3 and B-cell lymphoma 2 proteins in each group were studied. Compared with the group C, the latent period of the experiment was decreased and the number of diving was increased in the high and low dose groups of adiponectin. Compared with the group C, the nucleotide-binding oligomerization domain 2, nuclear factor-kappa B and toll-like receptor-4 in group D and E were lower. Compared with the group C, the levels of the above factors in the group D and E decreased. Compared with the group C, the caspase-3 and cleaved caspase-3 in the group D and E decreased, while the B-cell lymphoma 2 increased. Exogenous adiponectin can enhance the learning and memory ability of patients with Alzheimer's disease, affect the expression of nucleotide-binding oligomerization domain 2, nuclear factorkappa B, toll-like receptor-4 and other pathways, and reduce the levels of tumor necrosis factor-alpha and interleukin-1 beta, so as to inhibit the inflammatory response of nerves in the brain, reduce the damage to nerve function, and provide new therapeutic ideas for the prevention and treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Objective: To investigate the therapeutic effects of Xiaoyao pill on bone structure and morphology in mice with ovariectomy-induced osteoporosis, as well as the changes and molecular mechanism of AGES/RAGE signaling pathway based on network pharmacology and animal experiments. Methods: TCMSP and other databases were used to search for the drug ingredients of Xiaoyao pill and their related targets. "Osteoporosis" was used as the keyword in GeneCards and other databases to search for osteoporosis disease related targets; Wayne diagrams were made to obtain intersection targets; Finally, GO and KEGG enrichment analyses were performed on drug disease intersection targets through DAVID database, and the enrichment results were visualized. Additionally, mice model with ovariectomy-induced osteoporosis were established, and the influence of Xiaoyao pill on osteogenic differentiation was detected by CT scanning, HE staining and immunohistochemistry, and the prediction results of network pharmacological signaling pathways were verified. Results: Eight core active ingredients in Xiaoyao pill were found, namely chaihu, angelica, white peony, fried baiju, poria, licorice, peppermint and ginger. A total of 225 key targets of Xiaoyao Pill and OP were predicted, and these key targets were mainly involved in regulating the AGEs/RAGE signaling pathway, IL 17 signaling pathway, TNF signaling pathway, etc. In the mouse osteoporosis model, Xiaoyao pill could effectively increase the expression of ALP and COL 1 osteogenic transcription factors (P<0.05), and downregulate the expression of rage and IL 6, key proteins of the AGEs/RAGE signaling pathway (P<0.05) . Conclusion: Xiaoyao pill can effectively improve the bone morphological structure in mice with osteoporosis and has anti ovary osteoporosis effect, and its mechanism may be related to inhibition of AGES/RAGE signaling pathway and increase osteogenic marker genes ALP and COL 1. [ABSTRACT FROM AUTHOR]

IntroductionCorneal endothelial transplantation accounts for most of corneal transplantation for treating corneal diseases, however severe shortage of corneal donors is the biggest obstacle. In our previous study, we differentiated human skin-derived precursors (SKPs) into corneal endothelial cell (CEC)-like cells with a co-culture system. In this study, we aimed to investigate cell differentiation molecular mechanism and evaluate the function of CEC-like cells by developing tissue-engineered corneas in order to improve cell production efficiency and provide basic research for clinical transformation.MethodsWe performed transcriptome sequencing of SKPs and CEC-like cells. Further, we focused on the possible enriching pathways, including PI3K/Akt, MAPK/Erk, WNT/β-catenin, and important transcription factors Pitx2 and Foxc1. The PI3K and β-catenin inhibitors were also added to the culture system to observe the differentiation alteration. We developed a graft for a tissue-engineered cornea (TEC) using CEC-like cells and acellular porcine cornea matrix scaffold. The tissue-engineered corneas were transplanted into rabbits via penetrating keratoplasty.ResultsThe PI3K/Akt, MAPK/Erk, and WNT/β-catenin pathways play important roles during the differentiation of SKPs into CEC-like cells. Crosstalk existed between the PI3K/Akt and MAPK/Erk pathways. The PI3K/Akt and WNT/β-catenin pathways were connected. Pitx2 and Foxc1 were subject to temporal and spatial controls of the WNT/β-catenin pathway. The inhibition of the PI3K/Akt and WNT/β-catenin pathways both prevented cell differentiation. CEC-like cells grew well on the acellular porcine cornea matrix scaffold, and the tissue-engineered corneal graft performed well after transplantation into rabbits.ConclusionWe provide experimental basis for CEC-like cell industrial production and drive the cells to be clinically applied in cellular replacement therapy or alternative graft substitution for treating corneal diseases in the future.

Objective: To analyze the serum levels of exosome miRNA-135-5p in children with viral myocarditis, and to evaluate its clinical value to the myocardial injury degree and prognosis by inhibiting AKT/mTOR signal pathway. Methods: The 50 children with viral myocarditis in our hospital were collected and divided into the two groups according to the degree of viral myocarditis, which were severe group (15 cases) and mild group (35 cases). The 30 healthy examinees were collected to control group. The serum levels of exosome miRNA-135-5p, AKT mRNA and mTOR mRNA were detected by reverse transcription-polymerase chain reaction (RT-PCR) and compared among 3 groups. The correlations of exosome miRNA-135-5p to serum AKT mRNA and mTOR mRNA were confirmed by Pearson linear correlation analysis. The risk factors of illness degree of children with viral myocarditis to the clinical indexes were confirmed by multivariate Logistic analysis. Follow-up 12 months, the diagnostic value of exosome miRNA-135-5p to the 12 months follow-up prognosis of the children with viral myocarditis were analyzed by receiver operating characteristic curves (ROC). Results: Compared to control group, the serum levels of exosome miRNA-135-5p in severe group and mild group were higher, and severe group higher than mild group(P<0.05). The serum levels of AKT, mTOR mRNA in severe group and mild group were lower than control group, and severe group lower than mild group (P<0.05). The negative correlations of exosome miRNA-135-5p to serum AKT mRNA and mTOR mRNA were confirmed by Pearson linear correlation analysis (P<0.05). Multivariate Logistic analysis showed that the serum levels of exosome miRNA-135-5p were independent risk factors to the 12 months follow-up prognosis of children with viral myocarditis, but the levels of AKT mRNA and mTOR mRNA were the protective factors (P<0.05). When the cut-off point of exosome miRNA-135-5p was 3.32, the AUC was 0.822 and the sensitivity was 86.3 % and specificity was 80.6 %. Conclusions: The serum levels of exosome miRNA-135-5p is the risk factor to the myocardial injury degree in children with viral myocarditis by inhibiting AKT/mTOR signal pathway, and can perfect assess the 6 months follow-up prognosis. [ABSTRACT FROM AUTHOR]

Gremlin-1 is a bone morphogenetic protein (BMP) antagonist, by directly binding to the receptor and inhibiting BMP signaling and functioning, in which BMP is involved in the normal development of bone tissue and the process of maintaining homeostasis, according to studies, Gremlin-1 inhibition of BMP protein in osteoarthritis (OA) occurrence, development has great significance, nowadays, many scholars have found that Gremlin-1 and OA progression is closely related, Notably, Gremlin-1 is also involved in the process of interfering with the cell viability of mesenchymal stem cells and mediating osteoblast differentiation by related signaling pathways, leading to further deterioration of OA. Therefore, this article mainly starts from Gremlin-1 gene, discusses the relationship with OA and mediates related signaling pathways, inhibits the process of bone formation and affects the progress of OA. [ABSTRACT FROM AUTHOR]

Silicosis is a chronic illness marked by diffuse fibrosis in lung tissue resulting from continuous exposure to SiO2-rich dust in the workplace. The onset and progression of silicosis is a complicated and poorly understood pathological process involving numerous cells and molecules. However, silicosis poses a severe threat to public health in developing countries, where it is the most prevalent occupational disease. There is convincing evidence supporting that innate and adaptive immune cells, as well as their cytokines, play a significant role in the development of silicosis. In this review, we describe the roles of immune cells and cytokines in silicosis, and summarize current knowledge on several important inflammatory signaling pathways associated with the disease, aiming to provide novel targets and strategies for the treatment of silicosis-related inflammation. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) is the second most common solid cancer among men worldwide and the fifth leading cause of cancer-related deaths in men. Sulforaphane (SFN), an isothiocyanate compound, has been shown to exert inhibitory effects on a variety of cancers. However, the biological function of SFN in PCa has not been fully elucidated. The objective of this study was conducted to further investigate the possible underlying mechanism of SFN in PCa using in vitro cell culture and in vivo tumor model experiments. Methods: Cell viability, migration, invasion, and apoptosis were analyzed by Cell Counting Kit-8 (CCK-8), wound healing assay, transwell assay, or flow cytometry. Expression of microRNA (miR)-3919 was detected by quantitative real-time polymerase chain reaction (qRT-PCR) or in situ hybridization assay. Xenograft assay was conducted to validated the antitumor effect of miR-3919. The targeting relationship between miR-3919 and DJ-1 was verified by dualluciferase reporter assay. The level of DJ-1was measured by qRT-PCR or western blotting (WB). Results: In the present study, SFN downregulated mRNA and protein expression of DJ-1, an oncogenic gene. Small RNA sequencing analysis and dual-luciferase reporter assay confirmed that microRNA (miR)-3919 directly targeted DJ-1 to inhibition its expression. Furthermore, miR-3919 overexpression impeded viability, migration, and invasion and promoted apoptosis of PCa cells. Tumor growth in nude mice was also inhibited by miR-3919 overexpression, and miR-3919 expression in PCa tissues was lower than that in peritumoral tissues in an in situ hybridization assay. Transfection with miR-3919 inhibitors partially reversed the effects of SFN on cell viability, migration, invasion, and apoptosis. Conclusion: Overall, the miR-3919/DJ-1 axis may be involved in the effects of SFN on the malignant biological behavior of PCa cells, which might be a new therapeutic target in PCa. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect and mechanism of HBV 一 stimulated HTR8 一 S/Vneo mitochondrial antiviral signaling protein (MAVS) signaling pathway on the immune response of peripheral blood mononuclear cell (PBMC) to hepatitis B vaccine. Methods The HTR8 - S/Vneo were co 一 incubated with serum of HBV - DNA positive patients. MAVS siRNA transfection was hereby applied for silencing of MAVS and MAVS plasmid transfection was applied for overexpression of MAVS in HTR8 一 S/Vneo. We then cocultured them with human immune cells assembly PBMC and subsequently stimulated with hepatitis B vaccine. The mRNA and protein expression levels of MAVS, NF - kB, pNF - kB, IRF3 and pIRF3 in HTR8 一 S/Vneo were detected by reverse transcription 一 quantitative real 一 time PCR (RT 一 qPCR) and flow cytometry (FCM). The levels of IL - 2, IL - 6, IFN 一 p and IL 一 17 were detected by enzyme - linked immunosorbent assay (ELISA), and the proportion of CD4+ T cell were detected by flow cytometry. The data were analyzed for t test. Results HBV down 一 regulated the mRNA expression levels of MAVS, NF - kB, IRF3 (£ 二 6. 66, P 二 0. 003; £ 二 14. 18, P < 0. 001; £ 二 3. 70, P 二 0. 021) and the protein expression levels of MAVS, NF - kB, pNF - kB(£ 二 3. 42, P = 0. 042; £ 二 4. 23, P = 0. 013; £ 二 4. 86, P - 0. 008), and inhibited the production of IFN - p(£ 二 9. 83, P = 0. 010). Silencing MAVS down 一 regulated the mRNA and protein expression of MAVS(£ 二 31. 20, P < 0. 001; £ 二 6. 53, P = 0. 023), inhibited the expression of IFN - p(£ 二 5. 46, P =0. 032), and reduced the proportion of CD4+ T cells in PBMC(£ 二 9. 07, P = 0. 001). Overexpression of MAVS induced IFN 一 B production(£ 二一 34. 26, P < 0. 001; t - -5. 11, P = 0, 036), but the proportion of CD4 * T cells did not show significant effect (/二 一 0. 73, P 二 0. 506). Conclusion HBV can inhibit the MAVS signaling pathway in HTR8 一 S/Vneo. Overexpression of MAVS could promote the immune response to hepatitis B vaccine in PBMC. [ABSTRACT FROM AUTHOR]

Inflammation is an important immune response of the body. It is a physiological process of self-repair and defense against pathogens taken up by biological tissues when stimulated by damage factors such as trauma and infection. Inflammation is the main cause of high morbidity and mortality in most diseases and is the physiological basis of the disease. Targeted therapeutic strategies can achieve efficient toxicity clearance at the inflammatory site, reduce complications, and reduce mortality. Sphingosine-1-phosphate (S1P), a lipid signaling molecule, is involved in immune cell transport by binding to S1P receptors (S1PRs). It plays a key role in innate and adaptive immune responses and is closely related to inflammation. In homeostasis, lymphocytes follow an S1P concentration gradient from the tissues into circulation. One widely accepted mechanism is that during the inflammatory immune response, the S1P gradient is altered, and lymphocytes are blocked from entering the circulation and are, therefore, unable to reach the inflammatory site. However, the full mechanism of its involvement in inflammation is not fully understood. This review focuses on bacterial and viral infections, autoimmune diseases, and immunological aspects of the Sphks/S1P/S1PRs signaling pathway, highlighting their role in promoting intradial-adaptive immune interactions. How S1P signaling is regulated in inflammation and how S1P shapes immune responses through immune cells are explained in detail. We teased apart the immune cell composition of S1P signaling and the critical role of S1P pathway modulators in the host inflammatory immune system. By understanding the role of S1P in the pathogenesis of inflammatory diseases, we linked the genomic studies of S1P-targeted drugs in inflammatory diseases to provide a basis for targeted drug development. [ABSTRACT FROM AUTHOR]

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Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that exhibits high expression in various tumors and is associated with a poor prognosis. FAK activation promotes tumor growth, invasion, metastasis, and angiogenesis via both kinase-dependent and kinase-independent pathways. Moreover, FAK is crucial for sustaining the tumor microenvironment. The inhibition of FAK impedes tumorigenesis, metastasis, and drug resistance in cancer. Therefore, developing targeted inhibitors against FAK presents a promising therapeutic strategy. To date, numerous FAK inhibitors, including IN10018, defactinib, GSK2256098, conteltinib, and APG-2449, have been developed, which have demonstrated positive anti-tumor effects in preclinical studies and are undergoing clinical trials for several types of tumors. Moreover, many novel FAK inhibitors are currently in preclinical studies to advance targeted therapy for tumors with aberrantly activated FAK. The benefits of FAK degraders, especially in terms of their scaffold function, are increasingly evident, holding promising potential for future clinical exploration and breakthroughs. This review aims to clarify FAK's role in cancer, offering a comprehensive overview of the current status and future prospects of FAK-targeted therapy and combination approaches. The goal is to provide valuable insights for advancing anti-cancer treatment strategies. [ABSTRACT FROM AUTHOR]

Objective: The prevalence of allergic rhinitis is high, making it a relatively common chronic condition. Countless patients suffer from seasonal Allergic rhinitis (AR). The objective of this investigation is to examine the potential involvement of common pollen allergens in seasonal allergic rhinitis, and study the proposed mechanism of Toll-like receptor 4 (TLR4)/Myeloid differentiation primary response gene 88 (MyD88) signaling pathway in the induction of AR. Method: A mouse AR model (sensitized group) was constructed with pollen extracts and ovalbumin (OVA) of Artemisia annua (An), Artemisia argyi (Ar) and Artemisia Sieversiana (Si), and thereafter, AR symptom score was performed. After successful modeling, mouse serum and nasal mucosa tissues were extracted for subsequent experiments. The expression levels of immunoglobulin E (IgE), Interleukin (IL)-4, IL-5, IL-13 and Tumor Necrosis Factor-α (TNF-α) in serum were detected using Enzyme-linked immunosorbent assay (ELISA); Hematoxylin–eosin (H&E) staining methods were used to observe the pathological changes of the nasal mucosal tissue; Utilizing immunohistochemistry (IHC) staining, the expression levels of TLR4, MyD88 and Nuclear factor kappa B (NF-κB) p65 in mouse nasal mucosa were quantified; The mRNA and protein expression levels of TLR4, MyD88 and NF-κB p65 in nasal mucosa of sensitized mice were detected with Quantitative reverse transcription PCR (qRT-PCR) and Western Blot. Finally, the in vitro culture of Human nasal mucosal epithelial cells (HNEpC) cells was conducted, and cells were treated with 200 µg/ml Artemisia annua pollen extract and OVA for 24 h. Western Blot assay was used to detect the expression level of TLR4, MyD88 and NF-κB p65 proteins before and after HNEpC cells were treated with MyD88 inhibitor ST-2825. Result: On the second day after AR stimulation, the mice showed obvious AR symptoms. H&E results showed that compared to the control group, the nasal mucosal tissue in the sensitized group was significantly more inflamed. Furthermore, ELISA assay showed increased expression levels of IgE, IL-4, IL-5, IL-13 and TNF-α in serum of mice induced by OVA and Artemisia annua pollen, Artemisia argyi pollen and Artemisia Sieversiana pollen than those of the control group. However, the expression level of IL-2 was lower than that of the control group (P < 0.05). Using Immunohistochemistry staining visually observed the expression levels of TLR4, MyD88 and NF-κB p65 in mouse nasal mucosa tissues and quantitatively analyzed. The expression levels of TLR4, MyD88 and NF-κB p65 in the sensitized group were higher than those in the control group, and the differences were statistically significant (P < 0.05). The results from qRT-PCR and Western Blot showed that the mRNA and protein expression levels of TLR4, MyD88 and NF-κB p65 in nasal mucosa of the sensitized group were significantly higher than those in the control group (P < 0.05). Finally, HNEpC cells were cultured in vitro and analyzed using Western Blot. The expression levels of TLR4, MyD88 and NF-κB p65 in OVA and An groups were significantly increased (P < 0.05). After ST-2825 treatment, TLR4 protein expression was significantly increased (P < 0.05) and MyD88 and NF-κB p65 protein expression were significantly decreased (P < 0.05). Conclusion: To sum up, the occurrence and development of AR induced by OVA and pollen of Artemisia annua, Artemisia argyi and Artemisia Sieversiana were related to TLR4/MyD88 signal pathway. [ABSTRACT FROM AUTHOR]

Imbalanced bone remodeling process is one of the important mechanisms in the development of osteoporosis, which is mainly due to the resorption of bone by osteoclasts exceeding osteoblast-mediated bone formation. NFATc1 has been shown to be involved in regulating the bone resorption process. The article reviews the signaling pathways and molecular mechanisms regulated by NFATc1 in osteoclasts, which are proposed to provide new therapeutic ideas and potential therapeutic targets for osteoporosis. The following conclusion have been obtained: (1) When the intervention of osteoclasts in the process of bone resorption exceeds that of osteoblasts, the imbalance in the process of bone remodeling occurs and osteoporosis may develop. (2) The key transcriptional regulation of NFATc1 in osteoclast resorption is through the RANKL-RANK, NF-kB, MAPK, and Ca2+ signaling pathways, which regulate osteoclast generation and differentiation during bone metabolism, thereby mediating the imbalance between bone formation and bone resorption induced by osteoclast overgeneration. (3) The current anti-osteoporosis drug strategy does not have a very significant impact on the disease. (4) The research on the targeting of biomaterials to NFATc1 is in the initial stage and still needs to be explored thoroughly. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a chronic degenerative joint disease whose main characteristic is the destruction of articular cartilage, causing pain and disability in patients and seriously affecting their quality of life. OA can be induced by a variety of causes, and pathological changes in articular cartilage are considered to be one of the key driving factors for the occurrence of OA. High mobility group box-1 protein (HMGB1), as a non-histone protein in eukaryotic cells, can participate in regulating the inflammation and apoptosis process of OA chondrocytes, thus leading to the occurrence of OA. This article reviews the research on the mechanism of HMGB1 in OA chondrocytes, with a view to providing new ideas for the clinical prevention and treatment of OA.

Osteoporosis is a systemic metabolic bone disease characterized by decreased bone mass, damage to bone tissue microstructure, increased bone fragility, and susceptibility to fractures, while sarcopenia is a syndrome characterized by progressive reduction in overall muscle mass and functional decline. Based on the common pathophysiological mechanism and close correlation between the two, the concept of 'osteosarcopenia' has gradually emerged to describe the simultaneous attenuation of muscles and bones. Signaling pathways serve as important signal transmission channels between muscles and bones, and if abnormal, they can lead to osteosarcopenia. The aim of this article, therefore, is to review the signaling pathways related to osteogenesis and myogenesis, such as Hedgehog, Hippo, mTOR, MAPK, in order to provide new ideas for targeted treatment of osteosarcopenia.

Objective: To investigate the potential mechanism of Wendan decoction in obesity by screening target genes with promoter region methylation changes and constructing a multiple signaling pathways network based on promoter methylation. Methods: The methylation degree of Itgad, Col8a1, Adra2b, Jund, Rab2a, Wnt8b, Fzd9, B4galt7, Pik3cd, Creb1, Stard8, and Mmp1 in the abdominal adipose tissue of obese rats was determined using the Agena MassARRAY system. Western blot was performed to assess protein expression levels. Target genes were identified based on the methylation degree in the promoter region and protein expression. Enrichment analysis of signaling pathways was conducted to identify relevant target genes and obtain a multiple signaling pathway network associated with obesity. Core and terminal effector molecules in the pathway networks were selected as research targets for reverse transcription-polymerase chain reaction (RT-PCR) analysis. Results: Four genes (Adra2b, Creb1, Itgad, and Pik3cd) showed a degree of promoter methylation consistent with their respective protein expression levels. Among them, Adra2b, Creb1, and Pik3cd expression increased, while that of Itgad decreased. Enrichment analysis revealed that Creb1 and Pik3cd were involved in 6 signaling pathways related to obesity: tumor necrosis factor (TNF) signaling pathway, growth hormone synthesis/secretion and action, adenosine 5′-monophosphate-activated protein kinase (AMPK) signaling pathway, relaxin signaling pathway, cyclic nucleotide (cAMP) signaling pathway, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. Subsequently, a multiple signaling pathways network was constructed based on promoter methylation. Key molecules including protein kinase B (AKT), mechanistic target of rapamycin complex 1 (mTORC1), and unc-51 like autophagy activating kinase 1 (ULK1), as well as terminal effector molecules interleukin-1β (IL-1β), interleukin-6 (IL-6), and chemokine (C-X-C motif) ligand 2 (CXCL2) were selected as research targets. Wendan decoction decreased the expressions of AKT, mTORC1, IL-1β, IL-6, and CXCL2 while up-regulating ULK1 expression. Conclusion: The mechanism of Wendan decoction in preventing obesity involves the regulation of multiple signaling pathways through the control of Creb1 and Pik3cd gene promoter methylation. However, the associated multi-path gene regulation mechanism in preventing obesity is complex. Thus, further exploration is needed to elucidate the role of methylation changes in this mechanism.

Peste des petits ruminants virus (PPRV), a member of the family Paramyxoviridae, belongs to the genus Morbillivirus. It causes devastating viral diseases in small ruminants and has been rapidly spreading over various regions in Africa, the Middle East, and Asia. Although vaccination is thought to be an effective management strategy against PPR infections, the heat sensitivity of PPRV vaccines severely restricts their use in regions with hot climates. In this research, we studied the antiviral activities of ribavirin and aimed to understand the potential mechanisms of action of ribavirin in the African green monkey kidney cells (Vero cells). In brief, the adsorption, intrusion, replication, and release of PPRV, as well as the mRNA expression level of RNA-dependent RNA polymerase (RdRp), were significantly inhibited in the ribavirin-treated Vero cells compared to those in the PPRV-infected cells that were not treated with ribavirin. Additionally, ribavirin has potential as an antiviral drug against PPRV, and its antiviral activity is mediated by the Janus kinase signal transducer and activator of transcription (JAK/STAT) and PI3K/AKT pathways.

Silique development exerts significant impacts on crop yield. CRPs (Cysteine-rich peptides) can mediate cell–cell communication during plant reproduction and development. However, the functional characterization and regulatory mechanisms of CRPs in silique development remain unclear. In this study, we identified many CRP genes downstream of the CRP gene TPD1 (TAPETUM DETERMINANT1) during silique development using a microarray assay. The novel Arabidopsis thaliana pollen-borne CRPs, the PCP-Bs (for pollen coat protein B-class) gene AtPCP-Ba, along with TPD1, are essential for silique development. The AtPCP-Ba was significantly down-regulated in tpd1 flower buds but up-regulated in OE-TPD1 flower buds and siliques. The silencing of AtPCP-Ba compromised the wider silique of OE-TPD1 plants and inhibited the morphology of OE-TPD1 siliques to the size observed in the wild type. A total of 258 CRPs were identified with the bioinformatic analysis in Arabidopsis, Brassica napus, Glycine max, Oryza sativa, Sorghum bicolor, and Zea mays. Based on the evolutionary tree classification, all CRP members can be categorized into five subgroups. Notably, 107 CRP genes were predicted to exhibit abundant expression in flowers and fruits. Most cysteine-rich peptides exhibited high expression levels in Arabidopsis and Brassica napus. These findings suggested the involvement of the CRP AtPCP-Ba in the TPD1 signaling pathway, thereby regulating silique development in Arabidopsis.

Chronic kidney disease（CKD） refers to chronic kidney structure and dys-function caused by various reasons, and renal fibrosis is one of its common pathological ma-nifestations, mainly including the entire process of renal function from damage to complete loss. Long noncoding RNA（lncRNA）,as a type of non protein coding RNA,has a wide variety of types and is widely involved in various cellular biological regulatory processes in the body. It can regulate microRNAs activity, control the expression of target genes, and participate in the occurrence and evolution of various diseases, including CKD. The occurrence of chronic kidney diseases such as diabetes nephropathy, obstructive nephropathy and lupus nephritis is related to renal fibrosis, and is closely related to a variety of lncRNA and corresponding molecular signal pathways. This provides some safer and more reliable new treatment approaches for the prevention and treatment of CKD. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases represent a significant worldwide problem, jeopardizing individuals' physical and mental wellbeing as well as their quality of life as a result of their widespread incidence and fatality. With the aging society, the occurrence of Cardiovascular diseases is progressively rising each year. However, although drugs developed for treating Cardiovascular diseases have clear targets and proven efficacy, they still carry certain toxic and side effect risks. Therefore, finding safe, effective, and practical treatment options is crucial. Scutellarin is the primary constituent of Erigeron breviscapus (Vant.) Hand-Mazz. This article aims to establish a theoretical foundation for the creation and use of secure, productive, and logical medications for Scutellarin in curing heart-related illnesses. Additionally, the examination and analysis of the signal pathway and its associated mechanisms with regard to the employment of SCU in treating heart diseases will impart innovative resolving concepts for the treatment and prevention of Cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Objective Gastric cancer (GC) is prevalent worldwide but has a dismal prognosis, and its molecular and pathogenic pathways remain unknown. Kallikrein 11 (KLK11) has a reduced expression in GC and may be a promising biomarker. Method Herein, the function of KLK11 in GC and its regulatory mechanism was studied. Gene sequencing and quantitative reverse transcription-polymerase chain reaction were used to determine the expression of KLK11 in GC and precancerous lesions. Cell function tests and flow cytometry were conducted to determine the proliferative capacity and cell cycle of GC cells, respectively. A luciferase reporter test confirmed the interaction between RNA molecules. The mTOR/4E-BP1 signaling pathway was analyzed using western blotting. Result KLK11 has a suppressed expression in GC samples. KLK11 decreased the proliferative capacity of GC cells, by inhibiting the degree of mTOR/4E-BP1 phosphorylation. In contrast, miR-1304 increased GC cell proliferation by inhibiting KLK11. Moreover, KLK11 was able to limit in vivo GC cell proliferation. Conclusion These findings reveal a promising strategy to prevent and treat GC by targeting the KLK11-mediated mTOR/4E-BP1 cascade. [ABSTRACT FROM AUTHOR]

Fibrosis is a typical aging-related pathological process involving almost all organs, including the heart, kidney, liver, lung, and skin. Fibrogenesis is a highly orchestrated process defined by sequences of cellular response and molecular signals mechanisms underlying the disease. In pathophysiologic conditions associated with organ fibrosis, a variety of injurious stimuli such as metabolic disorders, epigenetic changes, and aging may induce the progression of fibrosis. Sirtuins protein is a kind of deacetylase which can regulate cell metabolism and participate in a variety of cell physiological functions. In this review, we outline our current understanding of common principles of fibrogenic mechanisms and the functional role of SIRT3/6 in aging-related fibrosis. In addition, sequences of novel protective strategies have been identified directly or indirectly according to these mechanisms. Here, we highlight the role and biological function of SIRT3/6 focus on aging fibrosis, as well as their inhibitors and activators as novel preventative or therapeutic interventions for aging-related tissue fibrosis. [ABSTRACT FROM AUTHOR]

Objective To analyze the core genes of lung ischemia-reperfusion injury and construct a competitive endogenous RNA (ceRNA) network. Methods Original data of GSE145989 were downloaded from the Gene Expression Omnibus (GEO) database as the training set, and the GSE172222 and GSE9634 datasets were used as the validation sets, and the differentially-expressed genes (DEG) were identified. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. Protein-protein interaction (PPI) network was constructed, and the core genes were screened, and the diagnostic values of these core genes and the immune infiltration levels of immune cells were evaluated. The ceRNA network was constructed and validated. The targeted drugs based on ceRNA network were assessed. Results A total of 179 DEG were identified, including 61 down-regulated and 118 up)regulated genes. GO analysis showed that DEGs were associated with multiple biological processes, such as cell migration, differentiation and regulation, etc. They were correlated with cell components, such as vesicle membrane, serosa and membrane raft, etc. They were also associated with multiple molecular functions, such as chemokine receptor, G protein)coupled receptor, immune receptor activity and antigen binding, etc. KEGG pathway enrichment analysis revealed that DEG were involved in tumor necrosis factor (TNF), Wnt, interleukin (IL)-17 and nuclear factor (NF)-κB signaling pathways, etc. PPI network suggested that CD8A, IL2RG, STAT1, CD3G and SYK were the core genes of lung ischemia)reperfusion injury. The ceRNA network prompted that miR-146a-3p, miR-28-5p and miR-593-3p were related to the expression level of CD3G. The miR-149-3p, miR-342-5p, miR-873-5p and miR-491-5p were correlated with the expression level of IL-2RG. The miR-194-3p, miR-512-3p, miR-377-3p and miR-590-3p were associated with the expression level of SYK. The miR-590-3p and miR-875-3p were related to the expression level of CD8A. The miR-143- 5p, miR-1 231, miR-590-3p and miR-875-3p were associated with the expression level of STAT1. There were 13 targeted drugs for CD3G, 4 targeted drugs for IL-2RG, 28 targeted drugs for SYK and 3 targeted drugs for lncRNA MUC2. No targeted drugs were identified for CD8A, STAT1 and other ceRNA network genes. Conclusions CD8A, IL2RG, STAT1, CD3G and SYK are the core genes of lung ischemia-reperfusion injury. The research and analysis of these core genes probably contribute to the diagnosis of lung ischemia-reperfusion injury and providing novel research ideas and therapeutic targets. [ABSTRACT FROM AUTHOR]

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Aging is a multifactorial biological process involving chronic diseases that manifest from the molecular level to the systemic level. From its inception to 31 May 2022, this study searched the PubMed, Web of Science, EBSCO, and Cochrane library databases to identify relevant research from 15,983 articles. Multiple approaches have been employed to combat aging, such as dietary restriction (DR), exercise, exchanging circulating factors, gene therapy, and anti-aging drugs. Among them, anti-aging drugs are advantageous in their ease of adherence and wide prevalence. Despite a shared functional output of aging alleviation, the current anti-aging drugs target different signal pathways that frequently cross-talk with each other. At present, six important signal pathways were identified as being critical in the aging process, including pathways for the mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), nutrient signal pathway, silent information regulator factor 2-related enzyme 1 (SIRT1), regulation of telomere length and glycogen synthase kinase-3 (GSK-3), and energy metabolism. These signal pathways could be targeted by many anti-aging drugs, with the corresponding representatives of rapamycin, metformin, acarbose, nicotinamide adenine dinucleotide (NAD+), lithium, and nonsteroidal anti-inflammatory drugs (NSAIDs), respectively. This review summarized these important aging-related signal pathways and their representative targeting drugs in attempts to obtain insights into and promote the development of mechanism-based anti-aging strategies. [ABSTRACT FROM AUTHOR]

Potassium Calcium-Activated Channel Subfamily N1 (KCNN1), an integral membrane protein, is thought to regulate neuronal excitability by contributing to the slow component of synaptic after hyperpolarization. However, the role of KCNN1 in tumorigenesis has been rarely reported, and the underlying molecular mechanism remains unclear. Here, we report that KCNN1 functions as an oncogene in promoting breast cancer cell proliferation and metastasis. KCNN1 was overexpressed in breast cancer tissues and cells. The pro-proliferative and pro-metastatic effects of KCNN1 were demonstrated by CCK8, clone formation, Edu assay, wound healing assay and transwell experiments. Transcriptomic analysis using KCNN1 overexpressing cells revealed that KCNN1 could regulate key signaling pathways affecting the survival of breast cancer cells. KCNN1 interacts with ERLIN2 and enhances the effect of ERLIN2 on Cyclin B1 stability. Overexpression of KCNN1 promoted the protein expression of Cyclin B1, enhanced its stability and promoted its K63 dependent ubiquitination, while knockdown of KCNN1 had the opposite effects on Cyclin B1. Knockdown (or overexpression) ERLNI2 partially restored Cyclin B1 stability and K63 dependent ubiquitination induced by overexpression (or knockdown) of KCNN1. Knockdown (or overexpression) ERLIN2 also partially neutralizes the effects of overexpression (or knockdown) KCNN1-induced breast cancer cell proliferation, migration and invasion. In paired breast cancer clinical samples, we found a positive expression correlations between KCNN1 and ERLIN2, KCNN1 and Cyclin B1, as well as ERLIN2 and Cyclin B1. In conclusion, this study reveals, for the first time, the role of KCNN1 in tumorigenesis and emphasizes the importance of KCNN1/ERLIN2/Cyclin B1 axis in the development and metastasis of breast cancer. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. ALS is on a pathogenetic disease spectrum with frontotemporal dementia, referred to as ALS-frontotemporal spectrum disorder (ALS-FTSD). For mutations associated with ALS-FTSD, such as the C9orf72 hexanucleotide repeat expansion, the molecular factors associated with heterogeneity along this spectrum require further characterization. Here, using a targeted NanoString molecular barcoding approach, we interrogate neuroinflammatory dysregulation and heterogeneity at the level of gene expression in post-mortem motor cortex tissue from a cohort of clinically heterogeneous C9-ALS-FTSD cases. We identified 20 dysregulated genes in C9-ALS-FTSD, with enrichment of microglial and inflammatory response gene sets. Two genes with significant correlations to available clinical metrics were selected for validation: FKBP5 , a correlate of cognitive function, and brain-derived neurotrophic factor (BDNF), a correlate of disease duration. FKBP5 and its signalling partner, NF-κB, appeared to have a cell type-specific staining distribution, with activated (i.e. nuclear) NF-κB immunoreactivity in C9-ALS-FTSD. Expression of BDNF , a correlate of disease duration, was confirmed to be higher in individuals with long compared to short disease duration using BaseScope™ in situ hybridization. Our analyses also revealed two distinct neuroinflammatory panel signatures (NPS), NPS1 and NPS2, delineated by the direction of expression of proinflammatory, axonal transport and synaptic signalling pathways. We compared NPS between C9-ALS-FTSD cases and those from sporadic ALS and SOD1-ALS cohorts and identified NPS1 and NPS2 across all cohorts. Moreover, a subset of NPS was also able to separate publicly available RNA sequencing data from independent C9-ALS and sporadic ALS cohorts into two inflammatory subgroups. Importantly, NPS subgroups did not clearly segregate with available demographic, genetic, clinical or pathological features, highlighting the value of molecular stratification in clinical trials for inflammatory subgroup identification. Our findings thus underscore the importance of tailoring therapeutic approaches based on distinct molecular signatures that exist between and within ALS-FTSD cohorts. [ABSTRACT FROM AUTHOR]