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Ulva pertusa Kjellman (U. pertusa) is a seaweed indigenous to the intertidal zone of the Korean coastline. U. pertusa exhibits immune-enhancing and antitumor activities, and its effects on intestinal health have gained attention. However, the mechanisms underlying its beneficial effects on intestinal physiology remain elusive. Here, the effect of U. pertusa intake in ameliorating loperamide-induced constipation in male mice was evaluated. Additionally, cellular levels of proinflammatory cytokines, including nuclear factor-kB and interleukin-1β, were assessed to decipher the intricate interplay between inflammation and improvements in bowel movement. U. pertusa intake increased fecal weight and water content and improved the intestinal transit rate. Moreover, it reduced the levels of proinflammatory cytokines, possibly via short-chain fatty acids implicated in modulating intestinal motility and mucosal inflammation. These findings underscore the efficacy of U. pertusa in improving bowel motility and intestinal functionality, and its potential in ameliorating constipation. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a degenerative disease of the joints, prevalent worldwide. Polydeoxyribonucleotide (PDRN) is used for treating knee OA. However, the role of PDRN in IL-1β-induced inflammatory responses in human bone marrow-derived mesenchymal stem cells (hBMSCs) remains unknown. Here, we investigated the role of PDRN in IL-1β-induced impairment of chondrogenic differentiation in hBMSCs. hBMSCs treated with PDRN showed a large micromass, enhanced safranin O and alcian blue staining intensity, and increased expression of chondrogenic genes in IL-1β-induced inflammatory responses, in addition to regulation of catabolic and anabolic genes. In addition, PDRN treatment suppressed the expression of inflammatory cytokines and mitigated IL-1β-induced apoptosis in hBMSCs. Mechanistically, PDRN treatment increased the formation of cyclic adenosine monophosphate (cAMP) and upregulated the phosphorylation of cAMP-dependent protein kinase A (PKA)/cAMP response element binding protein (CREB) through the adenosine A2A receptor in hBMSCs and thus blocked the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling pathway. Thus, IL-1β-induced expression of inflammatory cytokines in hBMSCs was directly reduced by adenosine A2A receptor activation. Based on our results, we suggest that PDRN may be a promising MSC-based therapeutic agent for OA. [ABSTRACT FROM AUTHOR]

BACKGROUND: Long intergenic non-protein coding RNA 00707 (LINC00707) and microRNA-423-5p (miR-423-5p) are both involved in the occurrence and development of osteoarthritis. Starbase predicts that LINC00707 and miR-423-5p have complementary sequences, but whether LINC00707 and miR-423-5p interact to regulate the progress of osteoarthritis still needs further research. OBJECTIVE: To investigate whether LINC00707 targets miR-423-5p to affect chondrocyte injury and inflammatory factor secretion in osteoarthritis. METHODS: Articular chondrocytes were divided into eight groups: (1) blank control group was given no treatment; (2) interleukin (IL)-1β group was cultured with 10 ng/mL IL-1β for 48 hours; (3) IL-1β+si-NC group was transfected with si-NC and then treated with 10 ng/mL IL-1β for 48 hours; (4) IL-1β+si-LINC00707 group was transfected with si-LINC00707 and then treated with 10 ng/mL IL-1β for 48 hours; (5) IL-1β+miR-NC group was transfected with miR-NC and then treated with 10 ng/mL IL-1β for 48 hours; (6) IL-1β+miR-423-5p group was transfected with miR-423-5p mimic and then treated with 10 ng/mL IL-1β for 48 hours; (7) IL-1β+si-LINC00707+anti-miR-NC group was co-transfected with si-LINC00707 and anti-miR-NC and then treated with 10 ng/mL IL-1β for 48 hours; (8) IL-1β+si-LINC00707+anti-miR-423-5p group was co-transfected with si-LINC00707 and anti-miR-423-5p and then treated with 10 ng/mL IL-1β for 48 hours. Relevant tests were performed at the end of the intervention. RESULTS AND CONCLUSION: Compared with the blank control group, the mRNA expression of LINC00707, apoptosis rate, protein expression of C-caspase3 and C-caspase9, and levels of tumor necrosis factor-α and IL-6 in articular chondrocytes were increased in the IL-1β group, while there was a decrease in miR-423-5p expression and IL-10 level (P < 0.05). Compared with the IL-1β group, the mRNA expression of LINC00707, apoptosis rate, protein expression of C-caspase3 and C-caspase9, and levels of tumor necrosis factor-α and IL-6 in articular chondrocytes were decreased in the IL-1β+si-LINC00707 group, while miR-423-5p expression and IL-10 level increased (P < 0.05). Compared with the IL-1β+miR-NC group, the protein expression of C-caspase3 and C-caspase9 and levels of tumor necrosis factor-α and IL-6 in articular chondrocytes were decreased in the IL-1β+miR-423-5p group, while miR-423-5p expression and IL-10 level increased (P < 0.05). Compared with the IL-1β+si-LINC00707+anti-miR-NC group, apoptosis rate, protein expression of C-caspase3 and C-caspase9, and levels of tumor necrosis factor-α and IL-6 in articular chondrocytes were increased in the IL-1β+si-LINC00707+anti-miR-423-5p group, while miR-423-5p expression and IL-10 level decreased (P < 0.05). To conclude, inhibiting LINC00707 by targeting miR-423-5p can reduce IL-1β-induced apoptosis and inflammation in articular chondrocytes. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion Clinicaltrial.gov registration ID Owing to its underlying inflammatory nature, atherosclerotic cardiovascular disease remains the leading global cause of mortality, particularly post‐ST‐elevation myocardial infarction (STEMI), a condition with significant risk for further cardiovascular events and mortality. This study aimed to investigate colchicine's effect on inflammation, cardiac remodelling and atherosclerotic risk in STEMI patients.We conducted a randomized controlled study on 88 STEMI patients undergoing percutaneous coronary intervention. Eligible patients were randomly assigned to 1 of 2 groups. The control group received the guideline‐directed medical therapy for STEMI, and the test group received guideline‐directed medical therapy and 0.5 mg colchicine twice daily for 3 months. The soluble suppressor of tumorigenicity (sST2), interleukin‐1β, lipid profile parameters, triglyceride (TG)/high‐density lipoprotein (HDL‐C) ratio levels and left ventricular ejection fraction were evaluated for patients at baseline and the end of the 3 months.No significant effects were reported for colchicine on sST2, interleukin‐1β levels or left ventricular ejection fraction. Colchicine significantly lowered TG levels vs. controls, 134 (46–353) vs. 176 (72–825) respectively, P = .02, as well as TG/HDL‐C ratio levels, 4.16 (2.75–5.24) vs. 5.11 (3.51–8.33),` respectively, P = .024. sST2 levels of the studied cohort were positively correlated with their TG/HDL‐C ratio levels (R = .459, P < .001) at the end of follow‐up.Our study highlights a promising impact of colchicine on atherosclerosis and cardiac remodelling factors in STEMI patients. Colchicine significantly reduced TG levels and TG/HDL‐C ratio and was safe and well tolerated. Larger long‐term studies powered to assess clinical outcomes of remodelling are necessary to confirm its beneficial effects in STEMI.NCT06054100. [ABSTRACT FROM AUTHOR]

Contagious caprine pleuropneumonia (CCPP) in goats is defined as a highly contagious and rapidly spreading mycoplasmal disease that is now among the leading causes of major economic losses on many continents (Asia, Africa and the Middle East). In this study, we aimed to evaluate immunohistochemically mast cells (MCs) profile and local interleukin (IL)-17 and IL-1β protein expressions in naturally infected CCPP according to the course of the inflammation (peracute-acute, subacute-chronic). The material of the study consisted of 40 naturally infected CCPP and 6 healthy control goat lung tissues. Appropriate samples were taken from the necropsied goats and subjected to histopathological and immunohistochemical examination. In the histopathological examination of the samples, it was determined that 29 samples had a peracute-acute course and 11 had a subacute-chronic course. In immunohistochemical examination, MC profile and local IL-17 and IL-1β protein expressions were evaluated in the peracute-acute and subacute-chronic course. Immunohistochemically, significant increases in MC number, local IL-17 and IL-1β scores were detected in the peracuteacute course compared to the control group. There were significant decreases in the relevant scores in the subacute-chronic course compared to the peracute-acute course. Current findings indicated that MC, IL-17, and IL-1β expressions played important roles in the pathogenesis of infection in naturally infected CCPP, especially in the peracute-acute course. Additionally, MC profile was evaluated for the first time in naturally infected CCPP. [ABSTRACT FROM AUTHOR]

The metabolic syndrome is characterized by obesity, insulin resistance, dyslipidemia and hypertension and predisposes to cardiorenal injury. Here, we tested our hypothesis that 8-aminoguanine, an endogenous purine, exerts beneficial effects in Zucker Diabetic-Sprague Dawley (ZDSD) rats, a preclinical model of the metabolic syndrome. ZDSD rats were instrumented for blood pressure radiotelemetry and randomized to vehicle or 8-aminoguanine (10 mg/kg/day, po). The protocol was divided into four phases: Phase 1: 17 days of tap water/normal diet; Phase 2: 30 days of 1% saline/normal diet; Phase 3: 28 days of 1% saline/diabetogenic diet; Phase 4: acute/terminal measurements. 8-Aminoguanine: (1) decreased mean arterial blood pressure (P = 0.0004; 119.5 ± 1.0 (vehicle) versus 116.3 ± 1.0 (treated) mmHg) throughout all three phases of the radiotelemetry study; (2) rebalanced the purine metabolome away from hypoxanthine (pro-inflammatory) and towards inosine (anti-inflammatory); (3) reduced by 71% circulating IL-1β, a cytokine that contributes to hypertension-induced adverse cardiovascular events and type 2 diabetes; (4) attenuated renovascular responses to angiotensin II; (5) improved cardiac and renal histopathology; (6) attenuated diet-induced polydipsia/polyuria; and (7) reduced HbA1c. In the metabolic syndrome, 8-aminoguanine lowers blood pressure, improves diabetes and reduces organ damage, likely by rebalancing the purine metabolome leading to reductions in injurious cytokines such as IL-1β. [ABSTRACT FROM AUTHOR]

Background: Retinal ischemia/reperfusion (IR) injury is a common pathological process in many ophthalmic diseases. Interleukin-1β (IL-1β) is an important inflammatory factor involved in the pathology of retinal IR injury, but the mechanism by which IL-1β is regulated in such injury remains unclear. Caspase-11 non-canonical inflammasomes can regulate the synthesis and secretion of IL-1β, but its role in retinal IR injury has not been elucidated. This study aimed to evaluate the role of caspase-11 non-canonical inflammasomes in retinal IR injury. Methods: Retinal IR injury was induced in C57BL/6J mice by increasing the intraocular pressure to 110 mmHg for 60 min. The post-injury changes in retinal morphology and function and in IL-1β expression were compared between caspase-11 gene knockout (caspase-11−/−) mice and wild-type (WT) mice. Morphological and functional changes were evaluated using hematoxylin–eosin staining and retinal whole mount staining and using electroretinography (ERG), respectively. IL-1β expression in the retina was measured using enzyme-linked immunosorbent assay (ELISA). The levels of caspase-11-related protein were measured using western blot analysis. The location of caspase-11 in the retina was determined via immunofluorescence staining. Mouse type I astrocytes C8-D1A cells were used to validate the effects of caspase-11 simulation via hypoxia in vitro. Small-interfering RNA targeting caspase-11 was constructed. Cell viability was evaluated using the MTT assay. IL-1β expression in supernatant and cell lysate was measured using ELISA. The levels of caspase-11-related protein were measured using western blot analysis. Results: Retinal ganglion cell death and retinal edema were more ameliorated, and the ERG b-wave amplitude was better after retinal IR injury in caspase-11−/− mice than in WT mice. Further, caspase-11−/− mice showed lower protein expressions of IL-1β, cleaved caspase-1, and gasdermin D (GSDMD) in the retina after retinal IR injury. Caspase-11 protein was expressed in retinal glial cells, and caspase-11 knockdown played a protective role against hypoxia in C8-D1A cells. The expression levels of IL-1β, cleaved caspase-1, and GSDMD were inhibited after hypoxia in the si-caspase-11 constructed cells. Conclusions: Retinal IR injury activates caspase-11 non-canonical inflammasomes in glial cells of the retina. This results in increased protein levels of GSDMD and IL-1β and leads to damage in the inner layer of the retina. [ABSTRACT FROM AUTHOR]

BACKGROUND: Temporomandibular joint osteoarthritis can cause severe pain, which significantly affects the patient’s quality of life and psychological health. Studies have found that medical ozone can effectively alleviate pain due to temporomandibular joint osteoarthritis, but its analgesic effect and mechanism are still unclear. OBJECTIVE: To explore the effects of medical ozone on pain relief in temporomandibular joint osteoarthritis and the potential mechanisms. METHODS: Twenty-four Sprague-Dawley rats were randomly divided into four groups (n=6 per group): control group, model group, air group, and medical ozone group. A sodium iodate-induced rat model of temporomandibular joint osteoarthritis was established in all groups except for the control group. After 1 week of modeling, rats in the air group and medical ozone group were injected with clean air and medical ozone, respectively, in the temporomandibular joint. The injection frequency for the air group and medical ozone group was once a week for three times in total. The von Frey mechanized pain measurement technique was used to assess the mechanical pain threshold of the temporomandibular joint in rats before and 28 days after modeling. ELISA was utilized to detect interleukin-1β in both serum and temporomandibular joint fluid at 28 days after modeling. Histopathologic changes of the temporomandibular joint were evaluated through hematoxylin-eosin staining. Additionally, the expression levels of hypoxia-inducible factor 1α and cyclooxygenase 2 in the temporomandibular joint were analyzed using immunohistochemistry. RESULTS AND CONCLUSION: Compared with the control group, the mechanical pain thresholds of the temporomandibular joint in the model group were decreased at 1, 3, 7, 14, 21, and 28 days after modeling (P < 0.01); and compared with the model and air groups, the mechanical pain thresholds of the temporomandibular joint in the medical ozone group were increased at 28 days after modeling (P < 0.01). Compared with the control group, the level of interleukin 1β in the serum and joint fluid of rats in the model group was elevated (P < 0.01); compared with the model and air groups, the level of interleukin 1β in the serum and joint fluid of rats in the medical ozone group was decreased (P < 0.01). Hematoxylin-eosin staining results showed derangement and degeneration of the cartilage structure in the model group and the air group, while the derangement of the cartilage structure in the medical ozone group was less than that in the model group and the air group. Immunohistochemical staining showed that the expression of hypoxia-inducible factor 1α and cyclooxygenase 2 in the temporomandibular joints of rats in the model group was elevated compared with that in the control group (P < 0.01); the expression of hypoxia-inducible factor 1α and cyclooxygenase 2 in the temporomandibular joints of rats in the medical ozone group was decreased compared with that in the model group and the air group (P < 0.01, P < 0.05). These findings suggest that medical ozone can alleviate the pain caused by osteoarthritis of the temporomandibular joints in Sprague-Dawley rats by reducing the expression of hypoxia-inducible factor 1α, interleukin 1β, and cyclooxygenase 2. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction occurs prior to atherosclerosis, which is an independent predictor of cardiovascular diseases (CVDs). Diabetes mellitus impairs endothelial function by triggering oxidative stress and inflammation in vascular tissues. Isoliquiritigenin (ISL), one of the major bioactive ingredients extracted from licorice, has been reported to inhibit inflammation and oxidative stress. However, the therapeutic effects of ISL on ameliorating type 2 diabetes (T2D)-associated endothelial dysfunction remain unknown. In our animal study, db/db male mice were utilized as a model for T2D-associated endothelial dysfunction, while their counterpart, heterozygote db/m+ male mice, served as the control. Mouse brain microvascular endothelial cells (mBMECs) were used for in vitro experiments. Interleukin-1β (IL-1β) was used to induce endothelial cell dysfunction. ISL significantly reversed the impairment of endothelium-dependent relaxations (EDRs) in db/db mouse aortas. ISL treatment decreased ROS (reactive oxygen species) levels in db/db mice aortic sections and IL-1β-treated endothelial cells. Encouragingly, ISL attenuated the overexpression of pro-inflammatory factors MCP-1, TNF-α, and IL-6 in db/db mouse aortas and IL-1β-impaired endothelial cells. The NOX2 (NADPH oxidase 2) overexpression was inhibited by ISL treatment. Notably, ISL treatment restored the expression levels of IL-10, SOD1, Nrf2, and HO-1 in db/db mouse aortas and IL-1β-impaired endothelial cells. This study illustrates, for the first time, that ISL attenuates endothelial dysfunction in T2D mice, offering new insights into the pharmacological effects of ISL. Our findings demonstrate the potential of ISL as a promising therapeutic agent for the treatment of vascular diseases, paving the way for the further exploration of novel vascular therapies. [ABSTRACT FROM AUTHOR]

Premature ovarian insufficiency (POI) is a clinical syndrome characterised by a decline in ovarian function in women before 40 years of age and is associated with oestradiol deficiency and a complex pathogenesis. However, the aetiology of POI is still unclear and effective preventative and treatment strategies are still lacking. Methyltransferase like 3 (METTL3) is an RNA methyltransferase that is involved in spermatogenesis, oocyte development and maturation, early embryonic development, and embryonic stem cell differentiation and formation, but its role in POI is unknown. In the present study, METTL3 deficiency in follicular theca cells was found to lead to reduced fertility in female mice, with a POI-like phenotype, and METTL3 knockout promoted ovarian inflammation. Further, a reduction in METTL3 in follicular theca cells led to a decrease in the m6A modification of pri-miR-21, which further reduced pri-miR-21 recognition and binding by DGCR8 proteins, leading to a decrease in the synthesis of mature miR-21-5p. Decrease of miR-21-5p promoted the secretion of interleukin-1β (IL-1β) from follicular theca cells. Acting in a paracrine manner, IL-1β inhibited the cAMP–PKA pathway and activated the NF-κB pathway in follicular granulosa cells. This activation increased the levels of reactive oxygen species in granulosa cells, causing disturbances in the intracellular Ca2+ balance and mitochondrial damage. These cellular events ultimately led to granulosa cell apoptosis and a decrease in oestradiol synthesis, resulting in POI development. Collectively, these findings reveal how METTL3 deficiency promotes the expression and secretion of IL-1β in theca cells, which regulates ovarian functions, and proposes a new theory for the development of POI disease. A model for action of premature ovarian insufficiency due to METTL3 gene deletion in ovarian theca cells. The reduction of METTL3 in theca cells (TCs) led to a decrease in the level of m6A modification of pri-miR-21, which further reduced the recognition and binding of DGCR8 proteins to pri-miR-21, leading to a decrease in the synthesis of mature miR-21-5p, which then promoted the secretion of IL-1β from TCs. IL-1β acted in a paracrine manner on granulosa cells (GCs) by inhibiting the cAMP-PKA signalling pathway and activating the NF-κB pathway, which disrupted the intracellular Ca2+ balance, causing mitochondrial damage, which in turn led to GCs apoptosis, and at the same time affected the synthesis of estradiol, ultimately leading to the occurrence of premature ovarian insufficiency. [Display omitted] • Knockout of METTL3 in mouse TCs leads to POI. • METTL3 reduction resulted in decreased pri-miR-21 m6A modifications, thus promoted IL-1β secretion from TCs. • IL-1β induces apoptosis in GCs via the cAMP-PKA –NF–κB pathway. [ABSTRACT FROM AUTHOR]

Oxidative stress contributes to the loss of skeletal muscle mass and function in cancer cachexia. However, this outcome may be mitigated by an improved endogenous antioxidant defence system. Here, using the well‐established oxidative stress‐inducing muscle atrophy model of Lewis lung carcinoma (LLC) in 13‐week‐old male C57BL/6J mice, we demonstrate that extracellular superoxide dismutase (EcSOD) levels increase in the cachexia‐prone extensor digitorum longus muscle. LLC transplantation significantly increased interleukin‐1β (IL‐1β) expression and release from extensor digitorum longus muscle fibres. Moreover, IL‐1β treatment of C2C12 myotubes increased NBR1, p62 phosphorylation at Ser351, Nrf2 nuclear translocation and EcSOD protein expression. Additional studies in vivo indicated that intramuscular IL‐1β injection is sufficient to stimulate EcSOD expression, which is prevented by muscle‐specific knockout of p62 and Nrf2 (i.e. in p62 skmKO and Nrf2 skmKO mice, respectively). Finally, since an increase in circulating IL‐1β may lead to unwanted outcomes, we demonstrate that targeting this pathway at p62 is sufficient to drive muscle EcSOD expression in an Nrf2‐dependent manner. In summary, cancer cachexia increases EcSOD expression in extensor digitorum longus muscle via muscle‐derived IL‐1β‐induced upregulation of p62 phosphorylation and Nrf2 activation. These findings provide further mechanistic evidence for the therapeutic potential of p62 and Nrf2 to mitigate cancer cachexia‐induced muscle atrophy. Key points: Oxidative stress plays an important role in muscle atrophy during cancer cachexia.EcSOD, which mitigates muscle loss during oxidative stress, is upregulated in 13‐week‐old male C57BL/6J mice of extensor digitorum longus muscles during cancer cachexia.Using mouse and cellular models, we demonstrate that cancer cachexia promotes muscle EcSOD protein expression via muscle‐derived IL‐1β‐dependent stimulation of the NBR1‐p62‐Nrf2 signalling pathway.These results provide further evidence for the potential therapeutic targeting of the NBR1‐p62‐Nrf2 signalling pathway downstream of IL‐1β to mitigate cancer cachexia‐induced muscle atrophy. [ABSTRACT FROM AUTHOR]

Adolescent carriers of the Aggregatibacter actinomycetemcomitans JP2 genotype have an increased risk of developing periodontitis, due to the bacterium's high leukotoxin (LtxA) production. LtxA contributes to marginal bone loss by killing immunity cells, thus activating the proinflammatory interleukin-1β (IL-1β), which, in turn, activates the osteoclasts. A possible strategy to prevent periodontitis might be to neutralize LtxA in JP2-infected individuals. The aim of this study was to investigate whether extracts from Matcha or Guava leaves can prolong the viability of macrophages in cell cultures by neutralizing the highly leukotoxic JP2 genotype bacteria. The A. actinomycetemcomitans JP2 genotype was pretreated with extracts from either Matcha or Guava leaves. Later, the extracts were rinsed off, before JP2 bacteria were exposed to macrophage cell cultures. The experiment was repeated, where JP2 bacteria were persistently treated with the extracts instead, i.e., the extracts were not rinsed off. The macrophage viability after bacterial exposure was analyzed and compared with that of macrophages exposed to untreated JP2 bacteria. IL-1β secretion in the cell culture medium was quantified in all group samples. Pretreatment of the A. actinomycetemcomitans JP2 genotype with Matcha or Guava leaf extracts moderately neutralized LtxA activity, which resulted in prolonged macrophage viability and decreased IL-1β secretion. These effects of prolonged macrophage viability were enhanced when extracts were persistently present during the exposure period. The results indicate that Matcha and Guava leaf extracts have effects on the virulence of the A. actinomycetemcomitans JP2 genotype that may be useful in future treatment strategies to prevent periodontitis in JP2 bacterium carriers. [ABSTRACT FROM AUTHOR]

While patients with cancer show a higher prevalence of psychiatric disorders than the general population, the mechanism underlying this interaction remains unclear. The present study examined whether tumor-bearing (TB) mice show psychological changes using the conditioned fear paradigm and the role of cytokines in these changes. TB mice were established by transplantation with mouse osteosarcoma AXT cells. These TB mice were then found to exhibit disruption in extinction of conditioned fear memory. Eighteen cytokines in serum were increased in TB mice, among which i.c.v. injection of interleukin (IL)-1β and IL-6 strengthened fear memory in normal mice. Contents of IL-17 and keratinocyte-derived cytokine (KC) in the amygdala and KC in the hippocampus were increased in TB mice. KC mRNA in both the amygdala and hippocampus was also increased in TB mice, and i.c.v. injection of KC dose-dependently strengthened fear memory in normal mice. In addition, injection of IL-1β, but not IL-6, increased KC mRNA in the amygdala and hippocampus. In TB mice KC mRNA was increased in both astrocytes and microglia of the amygdala and hippocampus. The microglia inhibitor minocycline, but not the astrocyte inhibitor fluorocitrate, alleviated disruption in extinction of conditioned fear memory in TB mice. Microinjection of KC into the hippocampus, but not into the amygdala, increased fear memory in normal mice. These findings indicate that TB mice show an increase in serum cytokines, including IL-1β, that increases KC production in microglia of the hippocampus, which then disrupts extinction of fear memory. [ABSTRACT FROM AUTHOR]

Objective: Chondrocyte apoptosis has been considered a crucial mechanism that is responsible for cartilage destruction in osteoarthritis (OA). The mechanism of interleukin-37 (IL-37) on chondrocyte apoptosis has not been clearly determined in the pathogenesis of OA. Here, we explored the role of IL-37 in the regulation of cellular apoptosis in rat chondrocytes stimulated by IL-1β. Methods: Rat chondrocytes were used in in vitro study, and were stimulated with IL-1β (10 ng/mL) and/or recombinant IL-37 (rIL-37; 100 ng/mL) after cytotoxicity assessments using these cytokines were conducted. After rIL-37 treatment of chondrocytes stimulated with IL-1β, the cell proliferation assay, apoptosis assays, including expression of mitochondrial apoptosis-related markers, flow cytometry analysis of annexin V-FITC/propidium iodide (PI), cell cycle analysis, and Hoechst 33342 staining, and reactive oxygen species (ROS) measurement were used. Results: IL-1β induced expression of inflammatory cytokines and triggered degradation of the extracellular matrix of rat chondrocytes, but this effect was significantly attenuated by rIL-37 treatment. Enhanced ROS generation following IL-1β stimulation was reduced in a dose-dependent manner after stimulation with rIL-37. IL-1β induced pro-apoptotic markers and suppressed anti-apoptotic markers in rat chondrocytes. Flow cytometry using annexin V-FITC/PI revealed that IL-1β increased the apoptosis rate of rat chondrocytes, and that this effect was markedly reversed by treatment with rIL-37. Conclusions: IL-37 potently attenuated IL-1β-mediated apoptosis of rat chondrocytes by blocking ROS production. This study suggests that IL-37 can serve as a novel anti-cytokine therapy in OA by blocking chondrocyte apoptosis. [ABSTRACT FROM AUTHOR]

Hanrui Wang,1– 4,&ast; Xiaoyu Song,1– 4,&ast; Yao Wang,1– 4 Ting Yang,1– 4 Wanchen Liu,1– 4 Yakui Mou,1– 4,&ast; Chao Ren,1– 5 Xicheng Song1– 4 1Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China; 2Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China; 3Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China; 4Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China; 5Department of Neurology, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xicheng Song; Chao Ren, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, People’s Republic of China, Tel +86535 6691999, Fax +86535 6240341, Email drxchsong@163.com; renchaotg@126.comBackground: The nasal mucosal epithelial barrier is the primary site of allergic rhinitis (AR). Interleukin-1β (IL-1β), as a crucial factor in immune inflammation, not only plays a crucial role in hypersensitivity reactions but also affects the digestive mucosa and skin epithelial barrier. However, the role of IL-1β in the nasal mucosal epithelial barrier in AR has not been reported, and this study aimed to investigate the effect and possible mechanisms involved.Methods: Dermatophagoides pteronyssinus 1 was used as an allergen to construct an AR mouse model and stimulate human nasal mucosal epithelial cells (HNEpCs) and observe the expression changes of IL-1β and epithelial barrier indicators CLDN1 and OCLN in mouse nasal mucosa and HNEpCs. Then, the possible mechanisms of action were explored via exogenous IL-1β stimulation and pharmacological inhibition of IL-1β or its receptor interleukin-1 receptor type 1 (IL-1R1).Results: The results showed that Dermatophagoides pteronyssinus 1-primed mouse nasal mucosa or human HENpCs had increased expression of IL-1β and decreased CLDN1 and OCLN, and IL-1β could directly lead to reduced expression of epithelial barrier indexes in HNEpCs. In addition, inhibition of IL-1β or IL-1R1 can effectively alleviate the damage to the epithelial barrier.Conclusion: IL-1β has a destructive effect on the nasal mucosal epithelial barrier in AR, and inhibition of IL-1β or its receptor IL-1R1 can effectively protect the nasal mucosal barrier. IL-1β is a potential target for the treatment of AR.Keywords: interleukin-1β, allergic rhinitis, nasal mucous membrane, epithelial barrier, DerP1

Abstract Osteoarthritis (OA) is a degenerative disease of the joints, prevalent worldwide. Polydeoxyribonucleotide (PDRN) is used for treating knee OA. However, the role of PDRN in IL-1β-induced inflammatory responses in human bone marrow-derived mesenchymal stem cells (hBMSCs) remains unknown. Here, we investigated the role of PDRN in IL-1β-induced impairment of chondrogenic differentiation in hBMSCs. hBMSCs treated with PDRN showed a large micromass, enhanced safranin O and alcian blue staining intensity, and increased expression of chondrogenic genes in IL-1β-induced inflammatory responses, in addition to regulation of catabolic and anabolic genes. In addition, PDRN treatment suppressed the expression of inflammatory cytokines and mitigated IL-1β-induced apoptosis in hBMSCs. Mechanistically, PDRN treatment increased the formation of cyclic adenosine monophosphate (cAMP) and upregulated the phosphorylation of cAMP-dependent protein kinase A (PKA)/cAMP response element binding protein (CREB) through the adenosine A2A receptor in hBMSCs and thus blocked the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling pathway. Thus, IL-1β-induced expression of inflammatory cytokines in hBMSCs was directly reduced by adenosine A2A receptor activation. Based on our results, we suggest that PDRN may be a promising MSC-based therapeutic agent for OA.

Background:Rheumatoid arthritis (RA) is an inflammatory condition that mostly affects synovial joints. It produces severe swelling and ongoing inflammation, and as it worsens, the cartilage and bone begin to erode, resulting in deformed joints and bone erosion. Objectives:The purpose of this study is to evaluate the levels of anti-cyclic citrullinated peptide (anti-CCP) antibodies and determine the role of interleukin-1 beta (IL-1β), interleukin-18 (IL-18), interleukin-38 (IL-38), and transforming growth factor-beta2 (TGF-β2) in studied groups (RA patients and apparently healthy control). Materials and Methods:The study included collecting blood samples from a group of patients infected with RA involving 60 patients (21 male and 39 female), and the healthy group included 50 individuals as control group (21 males and 29 females). Results:The outcomes showed of anti-CCP a highly significant difference for RA patients compared to the control group by 0.603 ± 0.02 and 0.274 ± 0.01, respectively, and some immunological parameters that involve inflammation-promoting interleukins (IL-1β and IL-18), the results showed the significant differences at the level (P < 0.01) of patients was 126.79 ± 4.18 and 194.37 ± 12.71 compared with control 91.85 ± 2.11 and 92.27 ± 2.08, respectively. The identical results to measure anti-inflammatory interleukins (IL-38, TGF-β2) represented of patients were 190.43 ± 9.82 and 403.23 ± 21.20 compared with control group was 88.39 ± 1.56 and 115.59 ± 5.63, respectively. Conclusion:The immunological parameters represented high expression of pro-inflammatory interleukins (IL-1β and IL-18), so, elevation levels of anti-inflammatory interleukins (IL-38 and TGF-β2) of RA patients.

Abstract The metabolic syndrome is characterized by obesity, insulin resistance, dyslipidemia and hypertension and predisposes to cardiorenal injury. Here, we tested our hypothesis that 8-aminoguanine, an endogenous purine, exerts beneficial effects in Zucker Diabetic-Sprague Dawley (ZDSD) rats, a preclinical model of the metabolic syndrome. ZDSD rats were instrumented for blood pressure radiotelemetry and randomized to vehicle or 8-aminoguanine (10 mg/kg/day, po). The protocol was divided into four phases: Phase 1: 17 days of tap water/normal diet; Phase 2: 30 days of 1% saline/normal diet; Phase 3: 28 days of 1% saline/diabetogenic diet; Phase 4: acute/terminal measurements. 8-Aminoguanine: (1) decreased mean arterial blood pressure (P = 0.0004; 119.5 ± 1.0 (vehicle) versus 116.3 ± 1.0 (treated) mmHg) throughout all three phases of the radiotelemetry study; (2) rebalanced the purine metabolome away from hypoxanthine (pro-inflammatory) and towards inosine (anti-inflammatory); (3) reduced by 71% circulating IL-1β, a cytokine that contributes to hypertension-induced adverse cardiovascular events and type 2 diabetes; (4) attenuated renovascular responses to angiotensin II; (5) improved cardiac and renal histopathology; (6) attenuated diet-induced polydipsia/polyuria; and (7) reduced HbA1c. In the metabolic syndrome, 8-aminoguanine lowers blood pressure, improves diabetes and reduces organ damage, likely by rebalancing the purine metabolome leading to reductions in injurious cytokines such as IL-1β.

Adolescent carriers of the Aggregatibacter actinomycetemcomitans JP2 genotype have an increased risk of developing periodontitis, due to the bacterium’s high leukotoxin (LtxA) production. LtxA contributes to marginal bone loss by killing immunity cells, thus activating the proinflammatory interleukin-1β (IL-1β), which, in turn, activates the osteoclasts. A possible strategy to prevent periodontitis might be to neutralize LtxA in JP2-infected individuals. The aim of this study was to investigate whether extracts from Matcha or Guava leaves can prolong the viability of macrophages in cell cultures by neutralizing the highly leukotoxic JP2 genotype bacteria. The A. actinomycetemcomitans JP2 genotype was pretreated with extracts from either Matcha or Guava leaves. Later, the extracts were rinsed off, before JP2 bacteria were exposed to macrophage cell cultures. The experiment was repeated, where JP2 bacteria were persistently treated with the extracts instead, i.e., the extracts were not rinsed off. The macrophage viability after bacterial exposure was analyzed and compared with that of macrophages exposed to untreated JP2 bacteria. IL-1β secretion in the cell culture medium was quantified in all group samples. Pretreatment of the A. actinomycetemcomitans JP2 genotype with Matcha or Guava leaf extracts moderately neutralized LtxA activity, which resulted in prolonged macrophage viability and decreased IL-1β secretion. These effects of prolonged macrophage viability were enhanced when extracts were persistently present during the exposure period. The results indicate that Matcha and Guava leaf extracts have effects on the virulence of the A. actinomycetemcomitans JP2 genotype that may be useful in future treatment strategies to prevent periodontitis in JP2 bacterium carriers.

Abstract Background Retinal ischemia/reperfusion (IR) injury is a common pathological process in many ophthalmic diseases. Interleukin-1β (IL-1β) is an important inflammatory factor involved in the pathology of retinal IR injury, but the mechanism by which IL-1β is regulated in such injury remains unclear. Caspase-11 non-canonical inflammasomes can regulate the synthesis and secretion of IL-1β, but its role in retinal IR injury has not been elucidated. This study aimed to evaluate the role of caspase-11 non-canonical inflammasomes in retinal IR injury. Methods Retinal IR injury was induced in C57BL/6J mice by increasing the intraocular pressure to 110 mmHg for 60 min. The post-injury changes in retinal morphology and function and in IL-1β expression were compared between caspase-11 gene knockout (caspase-11−/−) mice and wild-type (WT) mice. Morphological and functional changes were evaluated using hematoxylin–eosin staining and retinal whole mount staining and using electroretinography (ERG), respectively. IL-1β expression in the retina was measured using enzyme-linked immunosorbent assay (ELISA). The levels of caspase-11-related protein were measured using western blot analysis. The location of caspase-11 in the retina was determined via immunofluorescence staining. Mouse type I astrocytes C8-D1A cells were used to validate the effects of caspase-11 simulation via hypoxia in vitro. Small-interfering RNA targeting caspase-11 was constructed. Cell viability was evaluated using the MTT assay. IL-1β expression in supernatant and cell lysate was measured using ELISA. The levels of caspase-11-related protein were measured using western blot analysis. Results Retinal ganglion cell death and retinal edema were more ameliorated, and the ERG b-wave amplitude was better after retinal IR injury in caspase-11−/− mice than in WT mice. Further, caspase-11−/− mice showed lower protein expressions of IL-1β, cleaved caspase-1, and gasdermin D (GSDMD) in the retina after retinal IR injury. Caspase-11 protein was expressed in retinal glial cells, and caspase-11 knockdown played a protective role against hypoxia in C8-D1A cells. The expression levels of IL-1β, cleaved caspase-1, and GSDMD were inhibited after hypoxia in the si-caspase-11 constructed cells. Conclusions Retinal IR injury activates caspase-11 non-canonical inflammasomes in glial cells of the retina. This results in increased protein levels of GSDMD and IL-1β and leads to damage in the inner layer of the retina.

Objective To employ next-generation sequencing (NGS) to analyze differentially expressed mRNAs in the gingival tissue of hypertensive rats with or without periodontitis to provide a theoretical basis for the prevention and treatment of hypertension with periodontitis. Methods After obtaining approval from the Animal Experiment Ethics Committee, a hypertensive rat model was established by administering high-salt feed containing 8%（w/w） NaCl, and a periodontitis rat model was established by ligating the first molar of the mandibular region using 3-0 sterile silk thread. Rat models of the normal control (N), hypertension (H), and hypertension with periodontitis (PH) groups were established. The blood pressure, heart rate, alveolar bone resorption, and number of osteoclasts in the alveolar bone were measured, before harvesting the gingival tissues from the three groups for NGS to analyze the expression of significantly different genes. Gene ontology (GO) enrichment analysis was performed for all significantly differentially expressed genes between the H and PH groups. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed. Key genes were screened by protein-protein interaction (PPI) networks, and the key gene expression in each group was verified using immunohistochemistry (IHC). The expression of key genes in the systemic circulation of each group was analyzed using enzyme-linked immunosorbent assay (ELISA). Results At the end of the experiment (11th week), the blood pressure was higher in both the H and PH groups than that in the N group (PPPP

OBJECTIVE: To explore the role of Compound 3k in osteoarthritis caused by glycolytic overactivity based on the hypoxia-inducible factor 1 alpha (HIF-1α)/ reactive oxygen species (ROS) pathway. METHODS: ATDC5 chondroblasts at logarithmic growth phase were taken to induce osteoarthritis in an in vitro cellular model by the action of 10 ng/mL interleukin-1β for 24 hours. The cytotoxicity of Compound 3k at different concentrations (0.25, 0.5, 1, 2.5, 5, 10, 15 μmol/L) was detected by cell counting kit8 assay, and the appropriate concentrations were selected for the subsequent experiments. The chondrocytes were randomly divided into control, model and treatment groups. The model group was induced with 10 ng/mL interleukin 1β, and the treatment group was pre-stimulated with Compound 3k for 2 hours and then co-cultured with interleukin 1β. The proliferation of the cells in each group was detected by the cell counting kit-8 assay; the inflammatory level of the cells in each group was detected by the ELISA kit; the ROS, extracellular lactate and glucose contents were detected using the kit; qRT-PCR and western blot were used to detect the levels of related inflammatory factors, interleukin-6 and tumor necrosis factor-α, glycolysis-related genes glucose transporter protein-1, glyceraldehyde 3-phosphate dehydrogenase, monocarboxylate transporter protein-1 and HIF-1α. RESULTS AND CONCLUSION: Compared with the control group, the model group showed a decrease in cell proliferative activity, active glycolysis level, manifested by an increase in extracellular lactate content (P < 0.001) and a decrease in glucose content (P < 0.001), interleukin-6 (P < 0.000 1) and tumor necrosis factor-α (P < 0.001). The expression levels of glycolysis-related genes glucose transporter protein-1 (P < 0.001), glyceraldehyde 3-phosphate dehydrogenase (P < 0.001), monocarboxylic acid transporter protein-1 (P < 0.001) and HIF-1α (P < 0.001) in the model group were all up-regulated, accompanied by oxidative stress and overproduction of ROS. Compared with the model group, Compound 3k treatment effectively increased cell proliferation activity and inhibited the level of overactive glycolysis (P < 0.001), while suppressing the expression of genes related to inflammation (P < 0.001) and glycolysis in osteoarthritic chondrocytes, inhibiting oxidative stress, downregulating the expression level of HIF-1α (P < 0.000 1) and decreasing the content of ROS. To conclude, Compound 3k inhibits interleukin-1β induced chondrocyte inflammation, and its mechanism may be related to glycolysis and HIF-1α/ROS mediated oxidative stress. [ABSTRACT FROM AUTHOR]

BACKGROUND: Apoptosis is involved in the formation of degenerative joint diseases. Therefore, anti-chondrocyte apoptosis may be an effective way to treat osteoarthritis. Neferine has a wide range of pharmacological activities including anti-inflammatory, anti-tumor and anti-apoptotic activities, and its effect on OBJECTIVE: To investigate the effect of neferine on chondrocyte apoptosis induced by interleukin-1β and elucidate its possible mechanism. METHODS: (1) The rat chondrocytes at logarithmical stage were taken and intervened in five groups. The control group was cultured routinely. The model group was routinely cultured for 24 hours after treatment with interleukin-1β for 2 hours. The low-, medium-, and high-dose groups were treated with interleukin-1β for 2 hours and then cultured with 5, 10, and 20 μmol/L neferine for 24 hours, respectively. At the end of culture, cell apoptosis, chondroglycoprotein 39 and type II collagen levels in cell supernatants, mRNA and protein expression of apoptosis-related proteins, and mRNA and protein expression of proteins related to the protein kinase R-like endoplasmic reticulum kinase (PERK)/activating transcription factor 4 (ATF4) signaling pathway were detected. (2) Rat chondrocytes at logarithmic growth period were taken and divided into four groups: control group and model group were treated with the same intervention as above, drug group was treated with interleukin-1β for 2 hours and then cultured with 20 μmol/L neferine for 24 hours, and activator group was treated with interleukin1β for 2 hours and then cultured with 20 μmol/L neferine and CCT020312, an activator of PERK/ATF4 signaling pathway, for 24 hours. At the end of culture, cell proliferation was detected by cell counting kit-8 assay, apoptosis was detected by flow cytometry, and mRNA and protein expressions of apoptosis-related proteins and PERK/ATF4 signaling pathway-related proteins were detected. RESULTS AND CONCLUSION: (1) Compared with the control group, the model group showed increased apoptosis (P < 0.05), decreased proliferative activity (P < 0.05), increased level of chondroglycoprotein 39 (P < 0.05), decreased level of type II collagen (P < 0.05), decreased mRNA and protein expression of Bcl-2 protein (P < 0.05), increased mRNA and protein expression of Bax protein, increased caspase-3 mRNA expression, increased Cleaved-caspase-3 protein expression (P < 0.05), increased mRNA expression of PERK, ATF4, and C/EBP homologous protein (P < 0.05), and increased protein expression of p-PERK, ATF4, and C/EBP homologous protein (P < 0.05). Compared with the model group, neferine reversed the above effects of interleukin-1β on chondrocytes in a concentration-dependent manner. (2) Compared with the drug group, the activator group showed increased apoptosis (P < 0.05), decreased proliferative activity (P < 0.05), elevated mRNA expression of caspase-3, ATF4, and C/EBP homologous protein (P < 0.05), and elevated protein expression of Cleavedcaspase-3, ATF4, and C/EBP homologous protein (P < 0.05). (3) To conclude, neferine inhibits interleukin-1β-induced chondrocyte apoptosis and enhances cell proliferation activity, and the mechanism of action may be related to blocking the PERK/ATF4 signaling pathway in the endoplasmic reticulum. [ABSTRACT FROM AUTHOR]

• Probenecid enhances tenofovir concentration in plasma and kidneys. • Co-administration increases tenofovir entry into the brain. • Tenofovir alone elevates IL-1β concentration post-administration. • Probenecid's anti-inflammatory impact may need longer duration. • Neither drug affects dopamine concentration in the brain. The blood–brain barrier's limited permeability to tenofovir restricts its ability to clear HIV from the brain. Probenecid acting as an adjuvant increases tenofovir concentrations in plasma and the kidneys thereby enhancing its therapeutic effect. However, the probenecid effect on brain tenofovir concentration and possible adverse effects remains poorly understood. We investigated the effect of probenecid co-administered tenofovir on tenofovir brain concentration, interleukin-1β (IL-1β) and dopamine concentration in the prefrontal cortex (PFC) and the cerebellum. Ninety-six male BALB/c mice were divided into four groups viz: a control group, Tenofovir disoproxil fumarate (TDF) treated, probenecid treated, and TDF + probenecid treated. We orally administered a single dose of TDF (5 mg/kg), and probenecid (8.3 mg/kg), and sacrificed six mice per group after 1 h, 4 h, and 6 h post-treatment to collect plasma, PFC, and cerebellar tissue. Co-administered tenofovir increased tenofovir concentration, peaking at 6 h with the cerebellum having the highest concentration. This suggests that probenecid enhanced the entry of tenofovir into the brain. Tenofovir alone increased IL-1β concentration at all intervals post-administration, while probenecid alone had no impact on IL-1β concentration. Co-administered tenofovir also increased IL-1β concentration. Probenecid's limited impact on IL-1β concentration following co-administration suggests that its anti-inflammatory properties may require more than 6 h to have an effect. Furthermore, neither tenofovir nor probenecid affected dopamine concentration. In conclusion, probenecid enhances the concentration and retention of tenofovir in the brain, making it a possible pharmacokinetic enhancer. However, its anti-inflammatory effects may require a longer duration to fully manifest. [ABSTRACT FROM AUTHOR]

BACKGROUND: Diabetic ulcers are a common complication of diabetes mellitus, which is manifested as foot ulcers complicated with infection, long treatment cycle, high disability rate and mortality rate, and brings a heavy burden to patients and social care. OBJECTIVE: To review the mechanism of action and the latest treatment progress of traditional Chinese medicine (TCM) in the treatment of diabetic ulcers, and to provide a basis for further theoretical research and clinical application. METHODS: CNKI, WanFang Database and PubMed database were searched for relevant literature using the keywords of “diabetic ulcer, medicinal herb, inflammation, interleukin-1β, interleukin-6, tumor necrosis factor, hypersensitive C-reactive protein, γ-interferon, interleukin-4, interleukin-10” in Chinese and English, respectively. The relevant literature in recent years was searched, and finally 75 articles were included for review. RESULTS AND CONCLUSION: The high glucose environment of the body will increase the level of pro-inflammatory cytokines, so that diabetic ulcer wounds are in a state of chronic inflammatory response for a long time, and difficult to heal or even not heal. TCM has summed up a lot of experience in the long-term struggle with diabetic ulcer. At present, TCM divides diabetic ulcers into four syndrome types: dampness and heat poison syndrome, blood and blood stasis obstruction pattern, heat poison injury Yin pattern, and Qi and blood deficiency syndrome, as well as representative prescriptions for treatment. According to their clinical characteristics, diabetic ulcers can be also divided into three stages: primary, middle and late stages. Different treatment methods are proposed: “clear method,” “warm and clear combined use” and “maintenance method.” Under the guidance of dialectical typing and staging of TCM, TCM monomers, extracts and compounds inhibit the inflammatory response and promote the healing of diabetic ulcers by down-regulating the expression of pro-inflammatory factors and/or up-regulating the expression of anti-inflammatory factors. Compared with modern medicine, TCM has significant advantages in the treatment of diabetic ulcers. There are many TCM monomers, extracts and compounds for the treatment of diabetic ulcers, such as angelica, curcumin, improved Chonghe ointment, Sanhuang blood exhaustion prescription and sore-ulcer I. formula, etc. It has been found that TCM for the treatment of diabetic ulcers is mainly heatclearing and detoxifying, invigorating blood circulation and removing blood stasis, and amassing sores and muscle-building drugs, and the frequency of use, treatment scope and therapeutic effect of TCM compounds are obviously better than those of TCM monomers and extracts. Among them, the most commonly used are the Sanhuang blood exhaustion prescription and the sore-ulcer I as well as prescription for the treatment of damp heat toxicity syndrome and Zizhu ointment for the treatment of non-ischemic diabetic ulcers. However, there are also some shortcomings in the treatment of diabetic ulcers with TCM. First, there are few clinical syndrome studies on diabetic ulcers. Secondly, there are a wide variety of TCM monomers, extracts and compounds for the treatment of diabetic ulcers, and the relevant research is insufficiently in-depth. Finally, the research on the mechanism underlying TCM treatment of diabetic ulcers is still in the preliminary exploration stage, and the mechanism of action still needs to be further explored. In the future, it is necessary to strengthen the research on the pharmacology of TCM and the clinical syndrome of diabetic ulcers, analyze the potential targets and related signaling pathways of TCM in the treatment of diabetic ulcers, give full play to the therapeutic advantages of TCM with multiple targets, multiple pathways, multiple levels and multiple systems, and develop TCM with significant efficacy, active ingredients and clear targets. [ABSTRACT FROM AUTHOR]

Abstract Epithelial–mesenchymal transition (EMT) is a cellular process in embryonic development, wound healing, organ fibrosis, and cancer metastasis. Previously, we and others have reported that proinflammatory cytokine interleukin-1β (IL-1β) induces EMT. However, the exact mechanisms, especially the signal transduction pathways, underlying IL-1β-mediated EMT are not yet completely understood. Here, we found that IL-1β stimulation leads to the partial EMT-like phenotype in human lung epithelial A549 cells, including the gain of mesenchymal marker (vimentin) and high migratory potential, without the complete loss of epithelial marker (E-cadherin). IL-1β-mediated partial EMT induction was repressed by PI3K inhibitor LY294002, indicating that the PI3K/AKT pathway plays a significant role in the induction. In addition, ERK1/2 inhibitor FR180204 markedly inhibited the IL-1β-mediated partial EMT induction, demonstrating that the MEK/ERK pathway was also involved in the induction. Furthermore, we found that the activation of the PI3K/AKT and MEK/ERK pathways occurred downstream of the epidermal growth factor receptor (EGFR) pathway and the IL-1 receptor (IL-1R) pathway, respectively. Our findings suggest that the PI3K/AKT and MEK/ERK pathways coordinately promote the IL-1β-mediated partial EMT induction. The inhibition of not one but both pathways is expected yield clinical benefits by preventing partial EMT-related disorders such as organ fibrosis and cancer metastasis.

Abstract Background Glioma is a common tumor that occurs in the brain and spinal cord. Hypoxia is a crucial feature of the tumor microenvironment. Tumor-associated macrophages/microglia play a crucial role in the advancement of glioma. This study aims to illuminate the detailed mechanisms by which hypoxia regulates microglia and, consequently, influences the progression of glioma. Methods The glioma cell viability and proliferation were analyzed by cell counting kit-8 assay and 5-ethynyl-2’-deoxyuridine assay. Wound healing assay and transwell assay were implemented to detect glioma cell migration and invasion, respectively. Enzyme-linked immunosorbent assay was conducted to detect protein levels in cell culture medium. The protein levels in glioma cells and tumor tissues were evaluated using western blot analysis. The histological morphology of tumor tissue was determined by hematoxylin-eosin staining. The protein expression in tumor tissues was determined using immunohistochemistry. Human glioma xenograft in nude mice was employed to test the influence of hypoxic microglia-derived interleukin-1beta (IL-1β) and heparanase (HPSE) on glioma growth in vivo. Results Hypoxic HMC3 cells promoted proliferation, migration, and invasion abilities of U251 and U87 cells by secreting IL-1β, which was upregulated by hypoxia-induced activation of hypoxia inducible factor-1alpha (HIF-1α). Besides, IL-1β from HMC3 cells promoted glioma progression and caused activation of nuclear factor-κB (NF-κB) and upregulation of HPSE in vivo. We also confirmed that IL-1β facilitated HPSE expression in U251 and U87 cells by activating NF-κB. Hypoxic HMC3 cells-secreted IL-1β facilitated the proliferation, migration, and invasion of U251 and U87 cells via NF-κB-mediated upregulation of HPSE expression. Finally, we revealed that silencing HPSE curbed the proliferation and metastasis of glioma in mice. Conclusion Hypoxia-induced activation of HIF-1α/IL-1β axis in microglia promoted glioma progression via NF-κB-mediated upregulation of HPSE expression.

Objective To investigate the effect of fluid flow shear stress (FFSS) on the fluid mechanic threshold of high-mobility group box 1 (HMGB1) release by synovial cells and chondrocytes. Moreover, the mechanism of chondrocyte and synovial cell damage induced by abnormal mechanical force was investigated to provide an experimental basis for exploring the pathogenesis and pathology of temporomandibular joint osteoarthritis. Methods With the approval of the Ethics Committee for Animal Experiments of the hospital, synovial tissue and cartilage tissue blocks were obtained from the knee joints of Sprague-Dawley (SD) rats, and synovial cells and chondrocytes were cultured and digested for subsequent experiments. Synovial cells and chondrocytes of 3-4 generations were acquired, and FFSS was applied to synovial and cartilage cells using a fluid shear mechanical device. The cells were divided according to the FFSS values of different sizes. Synovial cells were stimulated for 1 h with 1, 3, 5, or 10 dyn/cm2 of FFSS, and chondrocytes were stimulated for 1 h with 4, 8, 12, or 16 dyn/cm2 of FFSS. Resting cultures (0 dyn/cm2) were used as the control group. Changes in the morphology of the cells were observed. The expression and distribution of HMGB1 and interleukin-1β (IL-1β) were observed by immunohistochemistry. The expression of HMGB1 and IL-1β in the supernatant was analyzed by ELISA. The protein expression levels of intracellular HMGB1 and IL-1β were detected by Western blot. Results With increasing FFSS, the synovial cells and chondrocytes gradually swelled and ruptured, and the number of cells decreased. With increasing FFSS, the localizationof HMGB1 and IL-1β gradually shifted from the nucleus to the cytoplasm. In synovial cells, compared with those in the control group, the expression levels of HMGB1 and IL-1β were increased both in the supernatant and cells in the 1, 3, 5 and 10 dyn/cm2 intervention groups (P2 intervention groups (PP2 intervention groups (P2 intervention groups (P2 group, the protein expression levels of IL-1β gradually increased with increasing FFSS (P2 and 8 dyn/cm2, respectively. Therefore, upon stimulation with a mechanical force, synovial damage was damaged before chondrocytes.

Abstract Background Although various anti-inflammatory medicines are widely recommended for osteoarthritis (OA) treatment, no significantly clinical effect has been observed. This study aims to examine the effects of vitamin B6, a component that has been reported to be capable of alleviating inflammation and cell death in various diseases, on cartilage degeneration in OA. Methods Collagen-induced arthritis (CIA) mice model were established and the severity of OA in cartilage was determined using the Osteoarthritis Research Society International (OARSI) scoring system. The mRNA and protein levels of indicators associated with extracellular matrix (ECM) metabolism, apoptosis and inflammation were detected. The effect of vitamin B6 (VB6) on the mice were assessed using HE staining and masson staining. The apoptosis rate of cells was assessed using TdT-mediated dUTP nick end labeling. Results Our results showed a trend of improved OARSI score in mice treated with VB6, which remarkably inhibited the hyaline cartilage thickness, chondrocyte disordering, and knees hypertrophy. Moreover, the VB6 supplementation reduced the protein expression of pro-apoptosis indicators, including Bax and cleaved caspase-3 and raised the expression level of anti-apoptosis marker Bcl-2. Importantly, VB6 improved ECM metabolism in both in vivo and in vitro experiments. Conclusions This study demonstrated that VB6 alleviates OA through regulating ECM metabolism, inflammation and apoptosis in chondrocytes and CIA mice. The findings in this study provide a theoretical basis for targeted therapy of OA, and further lay the theoretical foundation for studies of mechanisms of VB6 in treating OA.

Proinflammatory cytokines are implicated in promoting neurodegeneration in multiple sclerosis (MS) by affecting excitatory and inhibitory transmission at central synapses. Conversely, the synaptic effects of anti-inflammatory molecules remain underexplored, despite their potential neuroprotective properties and their presence in the cerebrospinal fluid (CSF) of patients. In a study involving 184 newly diagnosed relapsing-remitting (RR)-MS patients, we investigated whether CSF levels of the anti-inflammatory interleukin (IL)-10 were linked to disease severity and neurodegeneration measures. Additionally, we examined IL-10 impact on synaptic transmission in striatal medium spiny neurons and its role in counteracting inflammatory synaptopathy induced by IL-1β in female C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE). Our findings revealed a significant positive correlation between IL-10 CSF levels and changes in EDSS (Expanded Disability Status Scale) scores one year after MS diagnosis. Moreover, IL-10 levels in the CSF were positively correlated with volumes of specific subcortical brain structures, such as the nucleus caudate. In both MS patients' CSF and EAE mice striatum, IL-10 and IL-1β expressions were upregulated, suggesting possible antagonistic effects of these cytokines. Notably, IL-10 exhibited the ability to decrease glutamate transmission, increase GABA transmission in the striatum, and reverse IL-1β-induced abnormal synaptic transmission in EAE. In conclusion, our data suggest that IL-10 exerts direct neuroprotective effects in MS patients by modulating both excitatory and inhibitory transmission and attenuating IL-1β-induced inflammatory synaptopathy. These findings underscore the potential therapeutic significance of IL-10 in mitigating neurodegeneration in MS. [ABSTRACT FROM AUTHOR]

BACKGROUND: Semaphone 3A (Sema3A) is an important neurovascular growth inhibitor. It is not clear how Sema3A is involved in the pathogenesis of discogenic low back pain. Exploring the potential mechanism of Sema3A in intervertebral disc degeneration can provide a new target and theoretical basis for the prevention and treatment of discogenic low back pain. OBJECTIVE: To explore the mechanism of interleukin-1β inhibiting the expression of Sema3A by activating the nuclear factor-κB signaling pathway to induce intervertebral disc degeneration in rats. METHODS: RT-qPCR was used to detect the expression of Sema3A mRNA in normal and degenerative human nucleus pulposus tissues. Nucleus pulposus cells of Sprague-Dawley rats were isolated, cultured, and passaged to the 3rd generation. Then, passage 3 cells were divided into three groups: the blank control group was routinely cultured for 48 hours, the degeneration group was intervened with 10 ng/mL interleukin 1β for 48 hours, and the degeneration+inhibitor group was treated by 5 µmol/L nuclear factor-κB signaling pathway-specific inhibitor BAY11-7082 for 1 hour, followed by interleukin-1β for 48 hours. At the end of the intervention, cell viability was detected by cell counting kit-8, cell apoptosis was detected by Annexin V/FITC staining, mRNA expression of cellular matrix, vascular and neural markers and Sema3A was detected by RT-qPCR, and protein expression of marker proteins, p65 and p-p65 was detected by western blot. RESULTS AND CONCLUSION: RT-qPCR assay showed that the expression of Sema3A mRNA was lower in degenerative human nucleus pulposus tissue than in normal human nucleus pulposus tissue (P < 0.05). Compared with the blank control group, the nucleus pulposus cell viability decreased and the apoptotic rate increased in the degeneration group (P < 0.05); compared with the degeneration group, the nucleus pulposus cell viability increased and the apoptotic rate decreased in the degeneration + inhibitor group (P < 0.05). Compared with the blank control group, mRNA expression of type II collagen, polyproteoglycan, and Sema3A was decreased in the degeneration group (P < 0.05), while mRNA expression of CD31 and neurofilament 200 was increased (P < 0.05). Compared with the degeneration group, mRNA expression of type II collagen, polyproteoglycan, and Sema3A was elevated in the degeneration+inhibitor group (P < 0.05) and mRNA expression of CD31 and neurofilament 200 decreased (P < 0.05). Compared with the blank control group, the protein expression of type II collagen, polyproteoglycan, and Sema3A was decreased in the degeneration group (P < 0.05), and the protein expression of CD31, neurofilament protein 200, p65, and p-p65 was elevated (P < 0.05); compared with the degeneration group, the protein expression of type II collagen, polyproteoglycan, and Sema3A was elevated in the degeneration+inhibitor group (P < 0.05), and protein expression of CD31, neurofilament 200, p65, and p-p65 was decreased (P < 0.05). To conclude, interleukin-1β does inhibit the expression of Sema3A by activating the nuclear factor-κB signaling pathway, which can also increase the degradation of extracellular matrix, promote the innervation and angiogenesis in degenerative intervertebral disc, and may be one of potential factors that contribute to intervertebral disc degeneration and discogenic low back pain. [ABSTRACT FROM AUTHOR]

BACKGROUND: Studies have shown that nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, interleukin-18, and interleukin-1β levels can induce an inflammatory cascade response to release inflammatory factors, affect metabolic stress, and damage endothelial cells involved in the development and progression of diabetic foot ulcers, which can provide a reference for early infections. OBJECTIVE: To investigate the predictive effect of peripheral blood mononuclear cell NLRP3 inflammasome, interleukin-18 and interleukin-1β levels on early infection after flap repair of diabetic foot ulcers. METHODS: A total of 147 patients with diabetic foot ulcers were selected and divided into infection group and non-infection group according to whether they were infected within 1 week after operation. Logistic regression was used to analyze the relationship between NLRP3 inflammasome, interleukin-18 and interleukin-1β levels in peripheral blood mononuclear cells and early postoperative infections, and to evaluate their predictive values. RESULTS AND CONCLUSION: In 147 patients with diabetic foot ulcers, 35 cases (23.81%) were infected within 1 week after operation, and 47 strains of pathogenic bacteria were isolated, including 25 strains of Gram-positive bacteria (53.19%) and 22 strains of Gram-negative bacteria (46.81%). Univariate analysis showed that Wagner grade, presence of comorbid diabetic nephropathy, operation time, peripheral blood NLRP3 mRNA, Caspase-1 mRNA, ASC mRNA, interleukin-18 and interleukin-1β levels were risk factors for early postoperative infections (all P < 0.05). Multivariate analysis suggested that Wagner grade, NLRP3 mRNA, Caspase-1 mRNA, ASC mRNA, high interleukin-18, interleukin-1β were independent risk factors (all P < 0.05). Receiver operator characteristic curve results showed that the area under the receiver operator characteristic curve of NLRP3 mRNA, Caspase-1 mRNA, ASC mRNA, interleukin-18 and interleukin-1β for early postoperative infections in patients with diabetic foot ulcers was 0.823, 0.705, 0.676, 0.811 and 0.853, respectively, and the area under the curve of combined predictive efficacy was 0.915. To conclude, patients with diabetic foot ulcers are mainly affected by Gram-positive bacteria, and the levels of NLRP3 inflammasome, interleukin-18 and interleukin-1β in peripheral blood mononuclear cells are independent risk factors for early postoperative infections. The combined prediction efficacy of these indicators is better and deserves further in-depth study. [ABSTRACT FROM AUTHOR]

Epithelial–mesenchymal transition (EMT) is a cellular process in embryonic development, wound healing, organ fibrosis, and cancer metastasis. Previously, we and others have reported that proinflammatory cytokine interleukin-1β (IL-1β) induces EMT. However, the exact mechanisms, especially the signal transduction pathways, underlying IL-1β-mediated EMT are not yet completely understood. Here, we found that IL-1β stimulation leads to the partial EMT-like phenotype in human lung epithelial A549 cells, including the gain of mesenchymal marker (vimentin) and high migratory potential, without the complete loss of epithelial marker (E-cadherin). IL-1β-mediated partial EMT induction was repressed by PI3K inhibitor LY294002, indicating that the PI3K/AKT pathway plays a significant role in the induction. In addition, ERK1/2 inhibitor FR180204 markedly inhibited the IL-1β-mediated partial EMT induction, demonstrating that the MEK/ERK pathway was also involved in the induction. Furthermore, we found that the activation of the PI3K/AKT and MEK/ERK pathways occurred downstream of the epidermal growth factor receptor (EGFR) pathway and the IL-1 receptor (IL-1R) pathway, respectively. Our findings suggest that the PI3K/AKT and MEK/ERK pathways coordinately promote the IL-1β-mediated partial EMT induction. The inhibition of not one but both pathways is expected yield clinical benefits by preventing partial EMT-related disorders such as organ fibrosis and cancer metastasis. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of atractylenolide I (AT-I) on the inflammatory injury of articular chondrocytes induced by interleukin-1β (IL-1β). Methods Human articular chondrocytes were from Wuhan Punosai Life Technology Co., LTD. The experiment was divided into six groups: control group (untreat), model group (10 ng/mL IL-1β), AT-I-L group (25 μmol/L), AT-I-M group (50 μmol/L), AT-I-H group (100 μmol/L ), and AT-I-H+740 Y-P group (100 μmol/L AT-I and 50 μg/mL 740 Y-P phosphatidylinositol 3-kinase (PI3K) activator). CCK-8 method and flow cytometry were applied to determine the proliferation and apoptosis, respectively. ELISA method was applied to measure the level of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the supernatant. Western blotting was applied to detect the expression of PI3K/protein Kinase B (AKT)/Nuclear factor-κB (NF-κB) pathway related proteins. Results Compared to those in the control group, OD450 values (24 h, 48 h) in the model group reduced (P<0.05), the TNF-α, IL-6 expression, apoptosis rate, and PI3K/AKT/NF-κB pathway protein expression increased obviously (P<0.05). Compared with the model group, the AT-I-L group showed no obvious differences in OD450 values (24 h, 48 h), TNF-α, IL-6 expression, apoptosis rate, and PI3K/AKT/NF-κB pathway protein expression (P>0.05). OD450 values (24 h, 48 h) in the AT-I-M and AT-I-H groups increased (P<0.05), and TNF-α, IL-6 expression, apoptosis rate, and PI3K/AKT/NF-κB pathway protein expression decreased (P<0.05). Compared to those in the AT-I-H group, OD450 values (24 h, 48 h) in the AT-I-H+740 Y-P group reduced (P<0.05), TNF-α and IL-6 expression, cell apoptosis rate, and PI3K/AKT/NF-κB pathway protein expression increased (P<0.05). Conclusion AT-I improves the inflammatory injury of articular chondrocytes induced by IL-1β. The possible mechanism is to promote chondrocyte proliferation and to inhibit inflammatory response, apoptosis, and PI3K/AKT/NF-κB pathway. [ABSTRACT FROM AUTHOR]

• Function and connectivity alteration in middle frontal gyrus (MFG) and insula play important roles in BDII-D. • Lower functions of insula and MFG were related to higher level of peripheral inflammation. • Lower insular function related to greater childhood trauma; lower MFG function linked to greater physical abuse. • Enhanced MFG-insula/mACC connectivity was related to greater depressive symptom while IL-1β moderated these associations. • Words count: 4,664. The functional alterations of the brain in bipolar II depression (BDII-D) and their clinical and inflammatory associations are understudied. We aim to investigate the functional brain alterations in BDII-D and their relationships with inflammation, childhood adversity, and psychiatric symptoms, and to examine the moderating effects among these factors. Using z-normalized amplitude of low-frequency fluctuation (zALFF), we assessed the whole-brain resting-state functional activity between 147 BDII-D individuals and 150 healthy controls (HCs). Differential ALFF regions were selected as seeds for functional connectivity analysis to observe brain connectivity alterations resulting from abnormal regional activity. Four inflammatory cytokines including interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) and five clinical scales including Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), Positive and Negative Syndrome Scale (PANSS), Columbia-Suicide Severity Rating Scale (C-SSRS), and Childhood Trauma Questionnaire (CTQ) were tested and assessed in BDII-D. Partial correlations with multiple comparison corrections identified relationships between brain function and inflammation, childhood adversity, and psychiatric symptoms. Moderation analysis was conducted based on correlation results and previous findings. Compared to HCs, BDII-D individuals displayed significantly lower zALFF in the superior and middle frontal gyri (SFG and MFG) and insula, but higher zALFF in the occipital-temporal area. Only the MFG and insula-related connectivity exhibited significant differences between groups. Within BDII-D, lower right insula zALFF value correlated with higher IL-6, CRP, and emotional adversity scores, while lower right MFG zALFF was related to higher CRP and physical abuse scores. Higher right MFG-mid-anterior cingulate cortex (mACC) connectivity was associated with higher IL-1β. Moreover, IL-1β moderated associations between higher right MFG-mACC/insula connectivity and greater depressive symptoms. This study reveals that abnormal functional alterations in the right MFG and right insula were associated with elevated inflammation, childhood adversity, and depressive symptoms in BDII-D. IL-1β may moderate the relationship between MFG-related connectivity and depressive symptoms. [ABSTRACT FROM AUTHOR]

This study compared the capacity of two different models of HIIT [high‐(HC) and low‐(LC) compression], with or without the use of berberine (BBR), on NOD‐like receptor pyrin domain‐containing protein‐3 (NLRP3), H19, interleukin (IL)‐1β, high‐sensitivity C‐reactive protein (hs‐CRP), and insulin resistance markers. Fifty‐four middle‐aged men with overweight or obesity and prediabetes [fasting blood glucose (FBG) 110–180 mg/dL] were randomly and equally assigned to the HC, LC, HC + BBR, LC + BBR, BBR, and non‐exercising control (CON) groups. The HC (2:1 work‐to‐rest) and LC (1:1 work‐to‐rest) home‐based training programs included 2–4 sets of 8 exercises at 80%–95% HRmax, twice a week for 8 weeks. Participants in the berberine groups received approximately 1000 mg daily. All exercise interventions led to a significant reduction in hs‐CRP, IL‐1β, insulin, FBG, and insulin resistance index (HOMA‐IR) versus CON. Notably, there was a significant reduction in FBG and HOMA‐IR with the BBR group compared to the baseline. Both NLRP3 and H19 experienced a significant drop only with LC in comparison to the baseline. While both exercise protocols were beneficial overall, LC uniquely exhibited more anti‐inflammatory effects, as indicated by reductions in H19 and NLRP3. However, the addition of berberine to the exercise programs did not demonstrate additional benefits. [ABSTRACT FROM AUTHOR]

Urolithiasis or nephrolithiasis is a condition of kidney stone formation and is considered a painful disease of the urinary tract system. In this work, we planned to discover the therapeutic roles of myricetin on the ethylene glycol (EG)-induced nephrolithiasis in rats. The experimental rats were treated with 0.75% of EG through drinking water for 4 weeks to initiate the nephrolithiasis and subsequently treated with 25 and 50 mg/kg of myricetin. The body weight and urine volume were measured regularly. After the sacrification of rats, the samples were collected, and serum and urinary biomarkers such as creatinine, urea, Ca2 + ion, and BUN, OPN, oxalate, and citrate levels were determined using assay kits. These biomarkers, the MDA level and CAT, SOD, and GPx activities, were assessed in the kidney tissue homogenates. The IL-6, IL-1β, and TNF-α levels were also quantified using respective kits. The histopathological analysis was done on the kidney tissues. Myricetin treatment did not show major changes in the body weight and kidney weight in the EG-induced rats. The treatment with 25 and 50 mg/kg of myricetin considerably reduced the urea, creatinine, BUN, Ca2 + ion, and oxalate and increased the citrate content in serum and urine samples of EG-induced rats. Further, myricetin depleted the inflammatory cytokines and MDA levels and elevated the CAT, SOD, and GPx activities in the renal tissues. The activities of ALT, AST, ALP, GGT, and LDH were also reduced by the myricetin. Furthermore, the myricetin upheld the histoarchitecture of the kidneys. The outcomes of this investigation propose that myricetin is effective in EG-induced urolithiasis probably because of its antioxidant, anti-inflammatory, and renoprotective activities. In addition, further studies are still required to verify the precise therapeutic mechanism of myricetin. [ABSTRACT FROM AUTHOR]

Interleukin-1β (IL-1β) contributes to interstitial lung disease (ILD) and pulmonary fibrosis (PF), thus representing a potential therapeutic target for PF. In this study, we first verified the increased expression of IL-1β in human fibrotic lung specimens and mouse lung tissues after intratracheal (i.t.) instillation of bleomycin (BLM), after which the pro-inflammatory and pro-fibrotic effects of recombinant IL-1β were tested in mice. The results above suggested that vaccination against IL-1β could be an effective strategy for managing PF. An anti-IL-1β vaccine (PfTrx-IL-1β) was designed by incorporating two IL-1β-derived polypeptides, which have been verified as the key domains that mediate the binding of IL-1β to its type I receptor, into Pyrococcus furiosus thioredoxin (PfTrx). The fusion protein PfTrx-IL-1β was prepared by using E. coli expression system. The vaccine was well tolerated; it induced robust and long-lasting antibody responses in mice and neutralized the biological activity of IL-1β, as shown in cellular assays. Pre-immunization with PfTrx-IL-1β effectively protected mice from BLM-induced lung injury, inflammation, and fibrosis. In vitro experiments further showed that anti-PfTrx-IL-1β antibodies counteracted the effects of IL-1β concerning pro-inflammatory and pro-fibrotic cytokine production by primary mouse lung fibroblast, macrophages (RAW264.7), and type II alveolar epithelial cell (A549), primary mouse lung fibroblast activation and epithelial-mesenchymal transition (EMT) of alveolar epithelial cells. In addition, the vaccination did not compromise the anti-infection immunity in mice, as validated by a sepsis model. Our preliminary study suggests that the anti-IL-1β vaccine we prepared has the potential to be developed as a therapeutic measure for PF. Further experiments are warranted to evaluate whether IL-1β vaccination has the capacity of inhibiting chronic progressive PF and reversing established PF. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate the potential of Endothelin-1 (ET-1), a peptide derived from vascular endothelial cells, as a biomarker for diagnosing peri-implant diseases. Methods: A cohort of 29 patients with a total of 76 implants was included in this study and subsequently divided into three groups based on peri-implant clinical parameters and radiographic examination: healthy (peri-implant health) (n = 29), mucositis (n = 22), and peri-implantitis (n = 25) groups. The levels of ET-1 (ρg/site) and interleukin (IL)-1β (ρg/site) in peri-implant sulcus fluid (PISF) samples were determined using enzyme immunoassay. Statistical analyses were conducted using Kruskal–Wallis and Steel–Dwass tests. Logistic regression and receiver operating characteristic (ROC) curve analyses were performed to evaluate the diagnostic performance of the biomarkers. Results: ET-1 levels were significantly elevated in the peri-implantitis group compared to those in the healthy group, and were highest in the peri-implant mucositis group. Additionally, IL-1β levels were significantly higher in the peri-implantitis group than those in the healthy group. ROC curve analysis indicated that ET-1 exhibited superior area under the curve values, sensitivity, and specificity compared to those of IL-1β. Conclusions: Our findings suggest that the presence of ET-1 in PISF plays a role in peri-implant diseases. Its significantly increased expression in peri-implant mucositis indicates its potential for enabling earlier and more accurate assessments of peri-implant inflammation when combined with conventional examination methods. [ABSTRACT FROM AUTHOR]

Background: Glioma is a common tumor that occurs in the brain and spinal cord. Hypoxia is a crucial feature of the tumor microenvironment. Tumor-associated macrophages/microglia play a crucial role in the advancement of glioma. This study aims to illuminate the detailed mechanisms by which hypoxia regulates microglia and, consequently, influences the progression of glioma. Methods: The glioma cell viability and proliferation were analyzed by cell counting kit-8 assay and 5-ethynyl-2'-deoxyuridine assay. Wound healing assay and transwell assay were implemented to detect glioma cell migration and invasion, respectively. Enzyme-linked immunosorbent assay was conducted to detect protein levels in cell culture medium. The protein levels in glioma cells and tumor tissues were evaluated using western blot analysis. The histological morphology of tumor tissue was determined by hematoxylin-eosin staining. The protein expression in tumor tissues was determined using immunohistochemistry. Human glioma xenograft in nude mice was employed to test the influence of hypoxic microglia-derived interleukin-1beta (IL-1β) and heparanase (HPSE) on glioma growth in vivo. Results: Hypoxic HMC3 cells promoted proliferation, migration, and invasion abilities of U251 and U87 cells by secreting IL-1β, which was upregulated by hypoxia-induced activation of hypoxia inducible factor-1alpha (HIF-1α). Besides, IL-1β from HMC3 cells promoted glioma progression and caused activation of nuclear factor-κB (NF-κB) and upregulation of HPSE in vivo. We also confirmed that IL-1β facilitated HPSE expression in U251 and U87 cells by activating NF-κB. Hypoxic HMC3 cells-secreted IL-1β facilitated the proliferation, migration, and invasion of U251 and U87 cells via NF-κB-mediated upregulation of HPSE expression. Finally, we revealed that silencing HPSE curbed the proliferation and metastasis of glioma in mice. Conclusion: Hypoxia-induced activation of HIF-1α/IL-1β axis in microglia promoted glioma progression via NF-κB-mediated upregulation of HPSE expression. [ABSTRACT FROM AUTHOR]

Background: Although various anti-inflammatory medicines are widely recommended for osteoarthritis (OA) treatment, no significantly clinical effect has been observed. This study aims to examine the effects of vitamin B6, a component that has been reported to be capable of alleviating inflammation and cell death in various diseases, on cartilage degeneration in OA. Methods: Collagen-induced arthritis (CIA) mice model were established and the severity of OA in cartilage was determined using the Osteoarthritis Research Society International (OARSI) scoring system. The mRNA and protein levels of indicators associated with extracellular matrix (ECM) metabolism, apoptosis and inflammation were detected. The effect of vitamin B6 (VB6) on the mice were assessed using HE staining and masson staining. The apoptosis rate of cells was assessed using TdT-mediated dUTP nick end labeling. Results: Our results showed a trend of improved OARSI score in mice treated with VB6, which remarkably inhibited the hyaline cartilage thickness, chondrocyte disordering, and knees hypertrophy. Moreover, the VB6 supplementation reduced the protein expression of pro-apoptosis indicators, including Bax and cleaved caspase-3 and raised the expression level of anti-apoptosis marker Bcl-2. Importantly, VB6 improved ECM metabolism in both in vivo and in vitro experiments. Conclusions: This study demonstrated that VB6 alleviates OA through regulating ECM metabolism, inflammation and apoptosis in chondrocytes and CIA mice. The findings in this study provide a theoretical basis for targeted therapy of OA, and further lay the theoretical foundation for studies of mechanisms of VB6 in treating OA. [ABSTRACT FROM AUTHOR]

Epilepsy is one of the most prevalent and serious brain disorders and affects over 70 million people globally. Antiseizure medications (ASMs) relieve symptoms and prevent the occurrence of future seizures in epileptic patients but have a limited effect on epileptogenesis. Addressing the multifaceted nature of epileptogenesis and its association with the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation requires a comprehensive understanding of the underlying mechanisms of these medications for the development of targeted therapeutic strategies beyond conventional antiseizure treatments. Several types of NLRP3 inhibitors have been developed and their effect has been validated both in in vitro and in vivo models of epileptogenesis. In this review, we discuss the advances in understanding the regulatory mechanisms of NLRP3 activation as well as progress made, and challenges faced in the development of NLRP3 inhibitors for the treatment of epilepsy. [ABSTRACT FROM AUTHOR]

Suicide is a significant public health challenge worldwide. Statistical data confirm a strong relationship between suicidal behavior and depressive disorders (DDs), but the molecular mechanisms of these diseases are still poorly understood. A growing body of research suggests that the Klotho-mediated pathway may be a novel intracellular target for the development of suicide-related disorders (including DDs). To verify this hypothesis, the link between α-Klotho levels, Nrf2-related inflammatory status (IL-1α, IL-1β, Keap1, NFB p65), AMPA (GluA1, GluA2, p- S831-GluA1, p-S845-GluA1) receptor subunit trafficking and AMPK (AMPKα1/2; pT172-AMPKα1) signaling pathways in the brain of suicide victims as compared to controls were investigated. Commercially available enzyme-linked immunoassay (ELISA) and Western blot analysis were performed in the hippocampus (HP) and frontal cortex (FCx) of suicide victims and matched controls. Group differences were assessed using an unpaired Student's t-test. A statistically significant decrease in the level of α-Klotho (HP: p=0.001; FCx: p=0.012) with an increase in IL-1β (HP: p=0.0108) and IL-1α (FCx: p=0.009) concentrations were shown. These alterations were associated with increased Keap1 (FCx: p=0.023) and NF-B-p65 (HP: p=0.039; FCx: p=0.013 nuclear fraction) protein levels. Furthermore, a significant reduction in p-S831-GluA1 (HP: p=0.029; FCx=0.002) and p-S845-GluA1 (HP: p=0.0012) proteins was observed. Similarly, the level of GluA2 (HP: p=0.011; FCx: p=0.002) and in p-T172- AMPKα1 (HP: p=0.0288; FCx: p=0.0338) protein were statistically decreased. Our findings demonstrate that a reduction in α-Klotho levels in brain structures related to mood disorders (HP, FCx) correlates with suicidal behavior. Moreover, our study provides novel insights into the molecular mechanisms underlying suicide-related disorders, highlighting the role of α-Klotho, Nrf2-related inflammatory status, AMPA receptor trafficking, and AMPK signaling pathways in the pathophysiology of suicidal behavior. These results may have implications for the development of targeted interventions for individuals at risk of suicide. [ABSTRACT FROM AUTHOR]

Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin-family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination of intracellular replicative niches for pathogenic bacteria; and (ii) non-classical secretion of IL-1 family cytokines that amplify host-beneficial inflammatory responses to microbial infection or tissue damage. Physiological roles for gasdermin D (GSDMD) in pyroptosis and IL-1β release during inflammasome signaling have been extensively characterized in macrophages. This involves cleavage of GSDMD by caspase-1 to generate GSDMD macropores that mediate IL-1β efflux and progression to pyroptotic lysis. Neutrophils, which rapidly accumulate in large numbers at sites of tissue infection or damage, become the predominant local source of IL-1β in coordination with their potent microbiocidal capacity. Similar to macrophages, neutrophils express GSDMD and utilize the same spectrum of diverse inflammasome platforms for caspase-1-mediated cleavage of GSDMD. Distinct from macrophages, neutrophils possess a remarkable capacity to resist progression to GSDMD-dependent pyroptotic lysis to preserve their viability for efficient microbial killing while maintaining GSDMD-dependent mechanisms for export of bioactive IL-1β. Rather, neutrophils employ cell-specific mechanisms to conditionally engage GSDMD-mediated pyroptosis in response to bacterial pathogens that use neutrophils as replicative niches. GSDMD and pyroptosis have also been mechanistically linked to induction of NETosis, a signature neutrophil pathway that expels decondensed nuclear DNA into extracellular compartments for immobilization and killing of microbial pathogens. This review summarizes a rapidly growing number of recent studies that have produced new insights, unexpected mechanistic nuances, and some controversies regarding the regulation of, and roles for, neutrophil inflammasomes, pyroptosis, and GSDMs in diverse innate immune responses.

Abstract Background Influenza A viruses (IAV) are extremely common respiratory viruses for the acute exacerbation of chronic obstructive pulmonary disease (AECOPD), in which IAV infection may further evoke abnormal macrophage polarization, amplify cytokine storms. Melatonin exerts potential effects of anti-inflammation and anti-IAV infection, while its effects on IAV infection-induced AECOPD are poorly understood. Methods COPD mice models were established through cigarette smoke exposure for consecutive 24 weeks, evaluated by the detection of lung function. AECOPD mice models were established through the intratracheal atomization of influenza A/H3N2 stocks in COPD mice, and were injected intraperitoneally with melatonin (Mel). Then, The polarization of alveolar macrophages (AMs) was assayed by flow cytometry of bronchoalveolar lavage (BAL) cells. In vitro, the effects of melatonin on macrophage polarization were analyzed in IAV-infected Cigarette smoking extract (CSE)-stimulated Raw264.7 macrophages. Moreover, the roles of the melatonin receptors (MTs) in regulating macrophage polarization and apoptosis were determined using MTs antagonist luzindole. Results The present results demonstrated that IAV/H3N2 infection deteriorated lung function (reduced FEV20,50/FVC), exacerbated lung damages in COPD mice with higher dual polarization of AMs. Melatonin therapy improved airflow limitation and lung damages of AECOPD mice by decreasing IAV nucleoprotein (IAV-NP) protein levels and the M1 polarization of pulmonary macrophages. Furthermore, in CSE-stimulated Raw264.7 cells, IAV infection further promoted the dual polarization of macrophages accompanied with decreased MT1 expression. Melatonin decreased STAT1 phosphorylation, the levels of M1 markers and IAV-NP via MTs reflected by the addition of luzindole. Recombinant IL-1β attenuated the inhibitory effects of melatonin on IAV infection and STAT1-driven M1 polarization, while its converting enzyme inhibitor VX765 potentiated the inhibitory effects of melatonin on them. Moreover, melatonin inhibited IAV infection-induced apoptosis by suppressing IL-1β/STAT1 signaling via MTs. Conclusions These findings suggested that melatonin inhibited IAV infection, improved lung function and lung damages of AECOPD via suppressing IL-1β/STAT1-driven macrophage M1 polarization and apoptosis in a MTs-dependent manner. Melatonin may be considered as a potential therapeutic agent for influenza virus infection-induced AECOPD. Graphical Abstract Schematic mechanisms underlying the regulatory effects of melatonin on macrophage polarization and apoptosis in IAV infection plus cigarette stimulation-induced AECOPD model.

Purposes Osteoarthritis (OA) is a degenerative joint disease that commonly occurs in middle-aged and elderly people. Mechanical microenvironment is one of the most significant factors in the development of OA. However, when the mechanical microenvironment changes, the inflammatory response of chondrocyte is elusive. Methods By adopting polydimethylsiloxane (PDMS) substrates with varying stiffness which can mimic the physiological stiffness of chondrocyte pericellular matrix (PCM), influences of co-regulated substrate stiffness and inflammatory factors interleukin-1β (IL-1β) on chondrocyte morphology, inflammatory mediators, and PCM remodeling protein expression are quantitatively analyzed. First, prostaglandin E2 (PGE2) and nitric oxide (NO) released in different stiffness substrates and IL-1β stimulated substrates with chondrocytes are detected. Second, the changes in different stiffness substrates and IL-1β stimulated substrates through immunofluorescence technique are observed and recorded. Third, the protein expressions of type Ⅱ collagen (COLII) and matrix metalloproteinase-13 (MMP13) are measured by Western blot assay. Findings The experimental results identify that substrate stiffness regulates the response of chondrocyte to inflammatory signals. Soft substrate dramatically enhances the release of PGE2 and NO (P

BackgroundPermethrin is a commonly used pyrethroid insecticide and has been found to be potentially neurotoxic. Microglia are innate immune cells in the central nervous system and are involved in the development of a range of neurodegenerative diseases. ObjectiveTo observe possible toxic effects of permethrin on human microglia clone 3 (HMC3) in vitro and explore associated mechanism. MethodsHMC3 were treated with 0, 10, 25, and 55 μmol·L−1 permethrin for 72 h. Cell cycle and apoptosis were measured using flow cytometry. Cyclin-dependent kinase 1 (CDK1), cyclin-dependent kinase inhibitor 1A (CDKN1A), cyclin B2 (CCNB2), cellular tumor antigen p53 (p53), factor-related apoptosis (FAS), caspase 3 (CASP3), and H2A histone family member X (H2AX) were detected by quantitative real-time PCR (qPCR). The differential genes and enrichment pathways of HMC3 after 0 and 25 μmol·L−1 permethrin treatment was analyzed by RNA sequencing. HMC3 was treated by 0, 10, 25, and 55 μmol· L−1 permethrin for 72 h. The content of nitric oxide (NO) in the supernatant was detected using Griess reagent. The secretion level of interleukin-6 (IL-6) was detected by enzyme linked immunosorbent assay (ELISA). The mRNA expression levels of mitogen-activated protein kinase (MAPK) pathway (including MAPK1, MAPK8, and MAPK14), interleukin-1β (IL-1β), IL-6, and matrix metalloproteinase (MMP) families (including MMP1, MMP2, MMP3, and MMP9) were detected by qPCR. The protein expressions of phosphorylated p38 mitogen-activated protein kinase (p-p38), phosphorylated extracellular signal-regulated kinase (p-ERK), IL-1β, IL-6, and MMP1 were detected by Western blot. ResultsHMC3 was arrested in G2/M phase after 0, 10, 25, and 55 μmol·L−1 permethrin treatment for 72 h, of which there was a statistically significant difference between the 55 μmol·L−1 permethrin treatment group and the control group (P

Aims: Osteoarthritis (OA) is the most common chronic pathema of human joints. The pathogenesis is complex, involving physiological and mechanical factors. In previous studies, we found that ferroptosis is intimately related to OA, while the role of Sat1 in chondrocyte ferroptosis and OA, as well as the underlying mechanism, remains unclear. Methods: In this study, interleukin-1β (IL-1β) was used to simulate inflammation and Erastin was used to simulate ferroptosis in vitro. We used small interfering RNA (siRNA) to knock down the spermidine/spermine N1-acetyltransferase 1 (Sat1) and arachidonate 15-lipoxygenase (Alox15), and examined damage-associated events including inflammation, ferroptosis, and oxidative stress of chondrocytes. In addition, a destabilization of the medial meniscus (DMM) mouse model of OA induced by surgery was established to investigate the role of Sat1 inhibition in OA progression. Results: The results showed that inhibition of Sat1 expression can reduce inflammation, ferroptosis changes, reactive oxygen species (ROS) level, and lipid-ROS accumulation induced by IL-1β and Erastin. Knockdown of Sat1 promotes nuclear factor-E2-related factor 2 (Nrf2) signalling. Additionally, knockdown Alox15 can alleviate the inflammation-related protein expression induced by IL-1β and ferroptosis-related protein expression induced by Erastin. Furthermore, knockdown Nrf2 can reverse these protein expression alterations. Finally, intra-articular injection of diminazene aceturate (DA), an inhibitor of Sat1, enhanced type II collagen (collagen II) and increased Sat1 and Alox15 expression. Conclusion: Our results demonstrate that inhibition of Sat1 could alleviate chondrocyte ferroptosis and inflammation by downregulating Alox15 activating the Nrf2 system, and delaying the progression of OA. These findings suggest that Sat1 provides a new approach for studying and treating OA. Cite this article: Bone Joint Res 2024;13(3):110–123.

Abstract Background Osteoarthritis (OA) is a common degenerative joint disease characterized by persistent articular cartilage degeneration and synovitis. Oxymatrine (OMT) is a quinzolazine alkaloid extracted from the traditional Chinese medicine, matrine, and possesses anti-inflammatory properties that may help regulate the pathogenesis of OA; however, its mechanism has not been elucidated. This study aimed to investigate the effects of OMT on interleukin-1β (IL-1β)-induced damage and the potential mechanisms of action. Methods Chondrocytes were isolated from Sprague-Dawley rats. Toluidine blue and Collagen II immunofluorescence staining were used to determine the purity of the chondrocytes. Thereafter, the chondrocytes were subjected to IL-1β stimulation, both in the presence and absence of OMT, or the autophagy inhibitor 3-methyladenine (3-MA). Cell viability was assessed using the MTT assay and SYTOX Green staining. Additionally, flow cytometry was used to determine cell apoptosis rate and reactive oxygen species (ROS) levels. The protein levels of AKT, mTOR, LC3, P62, matrix metalloproteinase-13, and collagen II were quantitatively analyzed using western blotting. Immunofluorescence was used to assess LC3 expression. Results OMT alleviated IL-1β-induced damage in chondrocytes, by increasing the survival rate, reducing the apoptosis rates of chondrocytes, and preventing the degradation of the cartilage matrix. In addition, OMT decreased the ROS levels and inhibited the AKT/mTOR signaling pathway while promoting autophagy in IL-1β treated chondrocytes. However, the effectiveness of OMT in improving chondrocyte viability under IL-1β treatment was limited when autophagy was inhibited by 3-MA. Conclusions OMT decreases oxidative stress and inhibits the AKT/mTOR signaling pathway to enhance autophagy, thus inhibiting IL-1β-induced damage. Therefore, OMT may be a novel and effective therapeutic agent for the clinical treatment of OA.